[
    {
        "pmid": "19531786",
        "meta_analysis_title": "Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis.",
        "meta_analysis_question": "Does the interaction between the serotonin transporter gene (5-HTTLPR) and stressful life events increase the risk of depression?",
        "criteria": "A search of the PubMed, EMBASE, and PsycINFO databases was conducted through March 2009 using the search terms life stress, life event, depression, depress, serotonin transporter, 5-HTTLPR, interaction, and moderation. Bibliographies of studies were also reviewed. A total of 26 articles published or set for publication were identified through this search strategy (Figure 1). Inclusion criteria for studies for the meta-analyses were published articles that included data on the association between the (1) 5-HTTLPR genotype (S, SL, or LL), (2) number of stressful life events (0, 1, 2, or \u22653) or equivalent, and (3) categorical measure of depression defined by the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) or International Statistical Classification of Diseases, 10th Revision (ICD-10) or ability to use a cut point to define depression from standardized rating scales. To maximize our ability to use a common framework for variable definition, we also requested original data from all studies that appeared to meet inclusion criteria published prior to 2008.10,15-28 We received original data in a usable format for the meta-analysis from 10 of the 14 study investigators. A total of 14 studies were included in the analysis, 15-20,23,25-27,29-32 10 of which15-20,23,25-27,29,30 were also included in a second sex-specific meta-analysis of original data. Nine other studies did not meet inclusion criteria.33-41",
        "subgroup": "Logistic Regression Analyses of Risk of Depression for 14 Studies - Risk per S allele",
        "key_reference_title": "Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene.",
        "key_reference_abstract": "In a prospective-longitudinal study of a representative birth cohort, we tested why stressful experiences lead to depression in some people but not in others. A functional polymorphism in the promoter region of the serotonin transporter (5-HT T) gene was found to moderate the influence of stressful life events on depression. Individuals with one or two copies of the short allele of the 5-HT T promoter polymorphism exhibited more depressive symptoms, diagnosable depression, and suicidality in relation to stressful life events than individuals homozygous for the long allele. This epidemiological study thus provides evidence of a gene-by-environment interaction, in which an individual's response to environmental insults is moderated by his or her genetic makeup.",
        "truth": "True"
    },
    {
        "pmid": "19531786",
        "meta_analysis_title": "Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis.",
        "meta_analysis_question": "Does the interaction between the serotonin transporter gene (5-HTTLPR) and stressful life events increase the risk of depression?",
        "criteria": "A search of the PubMed, EMBASE, and PsycINFO databases was conducted through March 2009 using the search terms life stress, life event, depression, depress, serotonin transporter, 5-HTTLPR, interaction, and moderation. Bibliographies of studies were also reviewed. A total of 26 articles published or set for publication were identified through this search strategy (Figure 1). Inclusion criteria for studies for the meta-analyses were published articles that included data on the association between the (1) 5-HTTLPR genotype (S, SL, or LL), (2) number of stressful life events (0, 1, 2, or \u22653) or equivalent, and (3) categorical measure of depression defined by the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) or International Statistical Classification of Diseases, 10th Revision (ICD-10) or ability to use a cut point to define depression from standardized rating scales. To maximize our ability to use a common framework for variable definition, we also requested original data from all studies that appeared to meet inclusion criteria published prior to 2008.10,15-28 We received original data in a usable format for the meta-analysis from 10 of the 14 study investigators. A total of 14 studies were included in the analysis, 15-20,23,25-27,29-32 10 of which15-20,23,25-27,29,30 were also included in a second sex-specific meta-analysis of original data. Nine other studies did not meet inclusion criteria.33-41",
        "subgroup": "Logistic Regression Analyses of Risk of Depression for 14 Studies - Risk per S allele",
        "key_reference_title": "Gene-environment interaction analysis of serotonin system markers with adolescent depression.",
        "key_reference_abstract": "We report analyses from a study of gene-environment interaction in adolescent depression. The sample was selected from 1990 adolescents aged 10-20 years: those with depression symptoms in the top or bottom 15% were identified and divided into high or low environmental risk groups. DNA was obtained from 377 adolescents, representing the four quadrants of high or low depression and high or low environmental risk. Markers within, or close to, each of the serotonergic genes 5HTT, HTR2A, HTR2C, MAOA (monoamine oxidase type A) and tryptophan hydroxylase (TPH) were genotyped. Environmental risk group was a nonsignificant predictor and sex was a significant predictor of the depression group. HTR2A and TPH significantly predicted the depression group, independent of the effects of sex, environmental risk group and their interaction. In addition, there was a trend for an effect of 5HTTLPR, which was significant in female subjects. Furthermore, there was a significant genotype-environmental risk interaction for 5HTTLPR in female subjects only, with the effect being in the same direction as another recent study, reaffirming that an important source of genetic heterogeneity is exposure to environmental risk.",
        "truth": "True"
    },
    {
        "pmid": "19531786",
        "meta_analysis_title": "Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis.",
        "meta_analysis_question": "Does the interaction between the serotonin transporter gene (5-HTTLPR) and stressful life events increase the risk of depression?",
        "criteria": "A search of the PubMed, EMBASE, and PsycINFO databases was conducted through March 2009 using the search terms life stress, life event, depression, depress, serotonin transporter, 5-HTTLPR, interaction, and moderation. Bibliographies of studies were also reviewed. A total of 26 articles published or set for publication were identified through this search strategy (Figure 1). Inclusion criteria for studies for the meta-analyses were published articles that included data on the association between the (1) 5-HTTLPR genotype (S, SL, or LL), (2) number of stressful life events (0, 1, 2, or \u22653) or equivalent, and (3) categorical measure of depression defined by the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) or International Statistical Classification of Diseases, 10th Revision (ICD-10) or ability to use a cut point to define depression from standardized rating scales. To maximize our ability to use a common framework for variable definition, we also requested original data from all studies that appeared to meet inclusion criteria published prior to 2008.10,15-28 We received original data in a usable format for the meta-analysis from 10 of the 14 study investigators. A total of 14 studies were included in the analysis, 15-20,23,25-27,29-32 10 of which15-20,23,25-27,29,30 were also included in a second sex-specific meta-analysis of original data. Nine other studies did not meet inclusion criteria.33-41",
        "subgroup": "Logistic Regression Analyses of Risk of Depression for 14 Studies - Risk per S allele",
        "key_reference_title": "The relationship between stressful life events, the serotonin transporter (5-HTTLPR) genotype and major depression.",
        "key_reference_abstract": "## BACKGROUND\nSerotonin is a good candidate for major depression. We attempted to replicate the study by Caspi and colleagues [Science (2003) 301, 386-389] which reported a significant interaction between serotonin transporter (5-HTTLPR) genotype and stressful life events when predicting major depression.\n## METHOD\nWe typed the serotonin promoter 5-HTTLPR gene in 1206 male and female twins aged 19-78 years (mean = 39, S.D. = 11). A DSM-IV diagnosis of major depression was available for 1199 twins. Most of these twins had participated in a 1988-1990 study which included a stressful life events inventory and self-report measure of depression based on the SCL-90 and DSSI/sAD. Complete 5-HTT genotype and life events data, self-report symptoms and major depression diagnoses were available for 1091 subjects. We regressed categorical and ordinal measures of depression onto stressful life events and genotype.\n## RESULTS\nThere were significant main effects for stressful life events but there was no evidence for any effect of 5-HTT genotype, nor a genotype x stressful life event interaction.\n## CONCLUSIONS\nRegardless of whether our results were based on binary logistic or ordinal regression analyses we found no evidence to support a main effect of 5-HTTLPR, or an interaction between the 5-HTTLPR genotype and stressful life events on major depression, Only 20 % of our subjects were aged below 30 years. It is possible that the effect reported by Caspi and colleagues is specific to young people, in which case our study has much less power in this age group.",
        "truth": "True"
    },
    {
        "pmid": "19531786",
        "meta_analysis_title": "Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis.",
        "meta_analysis_question": "Does the interaction between the serotonin transporter gene (5-HTTLPR) and stressful life events increase the risk of depression?",
        "criteria": "A search of the PubMed, EMBASE, and PsycINFO databases was conducted through March 2009 using the search terms life stress, life event, depression, depress, serotonin transporter, 5-HTTLPR, interaction, and moderation. Bibliographies of studies were also reviewed. A total of 26 articles published or set for publication were identified through this search strategy (Figure 1). Inclusion criteria for studies for the meta-analyses were published articles that included data on the association between the (1) 5-HTTLPR genotype (S, SL, or LL), (2) number of stressful life events (0, 1, 2, or \u22653) or equivalent, and (3) categorical measure of depression defined by the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) or International Statistical Classification of Diseases, 10th Revision (ICD-10) or ability to use a cut point to define depression from standardized rating scales. To maximize our ability to use a common framework for variable definition, we also requested original data from all studies that appeared to meet inclusion criteria published prior to 2008.10,15-28 We received original data in a usable format for the meta-analysis from 10 of the 14 study investigators. A total of 14 studies were included in the analysis, 15-20,23,25-27,29-32 10 of which15-20,23,25-27,29,30 were also included in a second sex-specific meta-analysis of original data. Nine other studies did not meet inclusion criteria.33-41",
        "subgroup": "Logistic Regression Analyses of Risk of Depression for 14 Studies - Risk per S allele",
        "key_reference_title": "Mental and physical distress is modulated by a polymorphism in the 5-HT transporter gene interacting with social stressors and chronic disease burden.",
        "key_reference_abstract": "Previous studies have yielded conflicting results as to the putative role of the functional polymorphism of the promoter region of the serotonin transporter gene (SLC6A4) in the etiology of anxiety-related traits and depressive disorders. Recently, a significant gene-environment interaction was found between life stressors, the short allele of the SLC6A4 polymorphism and depression. The aim of the present study was to investigate if such a gene-environment interaction could be replicated within a different population with a different risk structure. A total of 1005 subjects from a general population sample (Study of Health in Pomerania) were genotyped. Mental and physical distress were assessed on 38 items of the modified complaint scale (BL-38). The interaction between the SLC6A4 genotype, social stressors and chronic diseases with regard to the BL-38 score was evaluated by ANOVA. There was no independent association of genotype with mental and physical distress. However, significant interactions between genotype, unemployment and chronic diseases (F = 6.6; df = 3, 671; P < 0.001) were found in females but not in males. The genotype explained 2% of the total variance of the BL-38 score and 9.1% of the explained variance. The results partly confirm previous findings of a significant gene-environment interaction of the short allele, indicating a higher mental vulnerability to social stressors and chronic diseases. The relevance of this finding is sustained by the fact that the sample characteristics and the risk structure were highly different from previous studies.",
        "truth": "True"
    },
    {
        "pmid": "19531786",
        "meta_analysis_title": "Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis.",
        "meta_analysis_question": "Does the interaction between the serotonin transporter gene (5-HTTLPR) and stressful life events increase the risk of depression?",
        "criteria": "A search of the PubMed, EMBASE, and PsycINFO databases was conducted through March 2009 using the search terms life stress, life event, depression, depress, serotonin transporter, 5-HTTLPR, interaction, and moderation. Bibliographies of studies were also reviewed. A total of 26 articles published or set for publication were identified through this search strategy (Figure 1). Inclusion criteria for studies for the meta-analyses were published articles that included data on the association between the (1) 5-HTTLPR genotype (S, SL, or LL), (2) number of stressful life events (0, 1, 2, or \u22653) or equivalent, and (3) categorical measure of depression defined by the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) or International Statistical Classification of Diseases, 10th Revision (ICD-10) or ability to use a cut point to define depression from standardized rating scales. To maximize our ability to use a common framework for variable definition, we also requested original data from all studies that appeared to meet inclusion criteria published prior to 2008.10,15-28 We received original data in a usable format for the meta-analysis from 10 of the 14 study investigators. A total of 14 studies were included in the analysis, 15-20,23,25-27,29-32 10 of which15-20,23,25-27,29,30 were also included in a second sex-specific meta-analysis of original data. Nine other studies did not meet inclusion criteria.33-41",
        "subgroup": "Logistic Regression Analyses of Risk of Depression for 14 Studies - Risk per S allele",
        "key_reference_title": "Social adversity, the serotonin transporter (5-HTTLPR) polymorphism and major depressive disorder.",
        "key_reference_abstract": "## BACKGROUND\nRecent evidence has suggested that the short allele of the serotonin transporter (5-HTT) gene-linked polymorphic region (5-HTTLPR of the human serotonin gene [SLC6A4]) is associated with increased risk of depressive disorder but only among individuals exposed to social adversity. We report an investigation designed to replicate this finding.\n## METHODS\nData were available from a non-clinical sample of 4,175 adult men and women, ages 41-80 years, selected from participants in the European Prospective Investigation into Cancer and Nutrition in Norfolk (EPIC-Norfolk, United Kingdom) study. Evidence of past-year prevalent episodic major depressive disorder (MDD), defined by restricted DSM-IV diagnostic criteria, was assessed through questionnaire. Adverse experiences in childhood and in adulthood (during the five years preceding assessment) were also assessed through self-report. The 5-HTTLPR variant was genotyped according to published protocols.\n## RESULTS\nOne-year prevalent MDD criteria were met by 298 study participants. The experience of social adversity (both in childhood and adulthood) was strongly associated with increased rates of past-year prevalent MDD. No gene by environment (GxE) interactions between the 5-HTTLPR genotype, social adversity, and MDD were observed.\n## CONCLUSIONS\nThis study has not replicated a previous finding of a GxE interaction between the 5-HTTLPR genotype, social adversity, and depression.",
        "truth": "True"
    },
    {
        "pmid": "19531786",
        "meta_analysis_title": "Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis.",
        "meta_analysis_question": "Does the interaction between the serotonin transporter gene (5-HTTLPR) and stressful life events increase the risk of depression?",
        "criteria": "A search of the PubMed, EMBASE, and PsycINFO databases was conducted through March 2009 using the search terms life stress, life event, depression, depress, serotonin transporter, 5-HTTLPR, interaction, and moderation. Bibliographies of studies were also reviewed. A total of 26 articles published or set for publication were identified through this search strategy (Figure 1). Inclusion criteria for studies for the meta-analyses were published articles that included data on the association between the (1) 5-HTTLPR genotype (S, SL, or LL), (2) number of stressful life events (0, 1, 2, or \u22653) or equivalent, and (3) categorical measure of depression defined by the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) or International Statistical Classification of Diseases, 10th Revision (ICD-10) or ability to use a cut point to define depression from standardized rating scales. To maximize our ability to use a common framework for variable definition, we also requested original data from all studies that appeared to meet inclusion criteria published prior to 2008.10,15-28 We received original data in a usable format for the meta-analysis from 10 of the 14 study investigators. A total of 14 studies were included in the analysis, 15-20,23,25-27,29-32 10 of which15-20,23,25-27,29,30 were also included in a second sex-specific meta-analysis of original data. Nine other studies did not meet inclusion criteria.33-41",
        "subgroup": "Logistic Regression Analyses of Risk of Depression for 14 Studies - Risk per S allele",
        "key_reference_title": "Life events, first depression onset and the serotonin transporter gene.",
        "key_reference_abstract": "## BACKGROUND\nA relationship between the serotonin transporter gene, adverse events and onset of major depression has been reported.\n## AIMS\nTo replicate a gene x environment interaction in a cohort with longitudinal data for life events, experience of depression, parental bonding and neuroticism.\n## METHOD\nAt the 25-year follow-up, genomic DNA was obtained from 127 cohort members (mean age 48 years) to determine the genotype of the serotonin transporter gene-linked promoter region (5-HTTLPR). Associations were investigated between the 5-HTTLPR genotype, positive and adverse life events and the gene x environment interaction, and also between the 5-HTTLPR genotype and risk factors for depression.\n## RESULTS\nNo relationship was found between 5-HTTLPR genotype and either risk factors for depression or positive life events. Adverse life events had a significantly greater impact on the onset of depression for individuals with the s/s genotype.\n## CONCLUSIONS\nThe 5-HTTLPR genotype is a significant predictor of onset of major depression following multiple adverse events. This is one of the more robust findings concerning specific biological risk factors for depression.",
        "truth": "True"
    },
    {
        "pmid": "19531786",
        "meta_analysis_title": "Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis.",
        "meta_analysis_question": "Does the interaction between the serotonin transporter gene (5-HTTLPR) and stressful life events increase the risk of depression?",
        "criteria": "A search of the PubMed, EMBASE, and PsycINFO databases was conducted through March 2009 using the search terms life stress, life event, depression, depress, serotonin transporter, 5-HTTLPR, interaction, and moderation. Bibliographies of studies were also reviewed. A total of 26 articles published or set for publication were identified through this search strategy (Figure 1). Inclusion criteria for studies for the meta-analyses were published articles that included data on the association between the (1) 5-HTTLPR genotype (S, SL, or LL), (2) number of stressful life events (0, 1, 2, or \u22653) or equivalent, and (3) categorical measure of depression defined by the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) or International Statistical Classification of Diseases, 10th Revision (ICD-10) or ability to use a cut point to define depression from standardized rating scales. To maximize our ability to use a common framework for variable definition, we also requested original data from all studies that appeared to meet inclusion criteria published prior to 2008.10,15-28 We received original data in a usable format for the meta-analysis from 10 of the 14 study investigators. A total of 14 studies were included in the analysis, 15-20,23,25-27,29-32 10 of which15-20,23,25-27,29,30 were also included in a second sex-specific meta-analysis of original data. Nine other studies did not meet inclusion criteria.33-41",
        "subgroup": "Logistic Regression Analyses of Risk of Depression for 14 Studies - Risk per S allele",
        "key_reference_title": "Early family environment, current adversity, the serotonin transporter promoter polymorphism, and depressive symptomatology.",
        "key_reference_abstract": "## BACKGROUND\nMixed evidence has suggested that homozygous carriers of the short allele (s/s) of the serotonin transporter gene-linked polymorphic region (5-HTTLPR) may be at increased risk for depression, if they have also been exposed to early or current adversity/stress. We address this debate by examining the relation of a stressful early family environment, recent adversity/stress, and the 5-HTTLPR to depressive symptomatology in a normal sample.\n## METHODS\nA nonclinical sample of 118 young adult men and women completed assessments of early family environment, recent stressful events, psychosocial resources, and psychological distress, including depressive symptomatology. The 5-HTTLPR was genotyped using a standard protocol with DNA extracted from oral fluid.\n## RESULTS\nA stressful early family environment was significantly related to depressive symptomatology. In addition, gene-by-environment (GxE) interactions were observed between the 5-HTTLPR and both early family environment and current adversity/stress. Individuals homozygous for the short allele had greater depressive symptomatology if they had experienced early or recent adversity but significantly less depressive symptomatology if they reported a supportive early environment or recent positive experiences, compared with participants with the s/l or l/l genotype.\n## CONCLUSIONS\nEarly or current environment, in conjunction with the serotonin transporter polymorphism, predicts depressive symptomatology.",
        "truth": "True"
    },
    {
        "pmid": "19531786",
        "meta_analysis_title": "Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis.",
        "meta_analysis_question": "Does the interaction between the serotonin transporter gene (5-HTTLPR) and stressful life events increase the risk of depression?",
        "criteria": "A search of the PubMed, EMBASE, and PsycINFO databases was conducted through March 2009 using the search terms life stress, life event, depression, depress, serotonin transporter, 5-HTTLPR, interaction, and moderation. Bibliographies of studies were also reviewed. A total of 26 articles published or set for publication were identified through this search strategy (Figure 1). Inclusion criteria for studies for the meta-analyses were published articles that included data on the association between the (1) 5-HTTLPR genotype (S, SL, or LL), (2) number of stressful life events (0, 1, 2, or \u22653) or equivalent, and (3) categorical measure of depression defined by the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) or International Statistical Classification of Diseases, 10th Revision (ICD-10) or ability to use a cut point to define depression from standardized rating scales. To maximize our ability to use a common framework for variable definition, we also requested original data from all studies that appeared to meet inclusion criteria published prior to 2008.10,15-28 We received original data in a usable format for the meta-analysis from 10 of the 14 study investigators. A total of 14 studies were included in the analysis, 15-20,23,25-27,29-32 10 of which15-20,23,25-27,29,30 were also included in a second sex-specific meta-analysis of original data. Nine other studies did not meet inclusion criteria.33-41",
        "subgroup": "Logistic Regression Analyses of Risk of Depression for 14 Studies - Risk per S allele",
        "key_reference_title": "Relationship of 5-HTTLPR genotypes and depression risk in the presence of trauma in a female twin sample.",
        "key_reference_abstract": "Several studies have implicated an insertion/deletion polymorphism in the promoter region of the serotonin transporter gene (SLC6A4; 5-HTT) in the development of mood disorders. In the present study of a sample of 247 young adult female twins from Missouri, we examine whether this polymorphism interacts with the effect of adverse life events to increase risk for developing depression. We found a significant interaction between the number of high-activity L(A) alleles and exposure to trauma (OR = 1.70, P < 0.0001). This differs from previous reports, in that the higher activity genotypes (L(A)/L(A), L(A)/S, L(A)/L(G)), rather than the low activity genotypes (S/S, S/L(G), L(G)/L(G)), are associated with an increased incidence of major depressive disease (MDD) in the presence of environmental trauma.",
        "truth": "True"
    },
    {
        "pmid": "19531786",
        "meta_analysis_title": "Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis.",
        "meta_analysis_question": "Does the interaction between the serotonin transporter gene (5-HTTLPR) and stressful life events increase the risk of depression?",
        "criteria": "A search of the PubMed, EMBASE, and PsycINFO databases was conducted through March 2009 using the search terms life stress, life event, depression, depress, serotonin transporter, 5-HTTLPR, interaction, and moderation. Bibliographies of studies were also reviewed. A total of 26 articles published or set for publication were identified through this search strategy (Figure 1). Inclusion criteria for studies for the meta-analyses were published articles that included data on the association between the (1) 5-HTTLPR genotype (S, SL, or LL), (2) number of stressful life events (0, 1, 2, or \u22653) or equivalent, and (3) categorical measure of depression defined by the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) or International Statistical Classification of Diseases, 10th Revision (ICD-10) or ability to use a cut point to define depression from standardized rating scales. To maximize our ability to use a common framework for variable definition, we also requested original data from all studies that appeared to meet inclusion criteria published prior to 2008.10,15-28 We received original data in a usable format for the meta-analysis from 10 of the 14 study investigators. A total of 14 studies were included in the analysis, 15-20,23,25-27,29-32 10 of which15-20,23,25-27,29,30 were also included in a second sex-specific meta-analysis of original data. Nine other studies did not meet inclusion criteria.33-41",
        "subgroup": "Logistic Regression Analyses of Risk of Depression for 14 Studies - Risk per S allele",
        "key_reference_title": "Family based association analyses between the serotonin transporter gene polymorphism (5-HTTLPR) and neuroticism, anxiety and depression.",
        "key_reference_abstract": "We studied the association between the short/long promotor-based length polymorphism of the serotonin transporter gene (5-HTTLPR) and neuroticism, anxiety and depression. Subjects included twins, their siblings and parents from the Netherlands Twin Register (559 parents and 1,245 offspring). Subjects had participated between one and five times in a survey study measuring neuroticism, anxiety and depression. Offspring of these families were also approached to participate in a psychiatric interview diagnosing DSM-IV major depression. Within-family and total association between 5-HTTLPR and these traits were tested. Only three of the 36 tests showed a significant effect of 5-HTTLPR (P<0.05). These effects were in opposite directions, i.e. both negative and positive regression coefficients were found for the s allele. No additive effect of the s allele was found for DSM-IV depression. Our results strongly suggest that there is no straightforward association between 5-HTTLPR and neuroticism, anxiety and depression.",
        "truth": "True"
    },
    {
        "pmid": "19531786",
        "meta_analysis_title": "Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis.",
        "meta_analysis_question": "Does the interaction between the serotonin transporter gene (5-HTTLPR) and stressful life events increase the risk of depression?",
        "criteria": "A search of the PubMed, EMBASE, and PsycINFO databases was conducted through March 2009 using the search terms life stress, life event, depression, depress, serotonin transporter, 5-HTTLPR, interaction, and moderation. Bibliographies of studies were also reviewed. A total of 26 articles published or set for publication were identified through this search strategy (Figure 1). Inclusion criteria for studies for the meta-analyses were published articles that included data on the association between the (1) 5-HTTLPR genotype (S, SL, or LL), (2) number of stressful life events (0, 1, 2, or \u22653) or equivalent, and (3) categorical measure of depression defined by the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) or International Statistical Classification of Diseases, 10th Revision (ICD-10) or ability to use a cut point to define depression from standardized rating scales. To maximize our ability to use a common framework for variable definition, we also requested original data from all studies that appeared to meet inclusion criteria published prior to 2008.10,15-28 We received original data in a usable format for the meta-analysis from 10 of the 14 study investigators. A total of 14 studies were included in the analysis, 15-20,23,25-27,29-32 10 of which15-20,23,25-27,29,30 were also included in a second sex-specific meta-analysis of original data. Nine other studies did not meet inclusion criteria.33-41",
        "subgroup": "Logistic Regression Analyses of Risk of Depression for 14 Studies - Risk per S allele",
        "key_reference_title": "No interaction between the serotonin transporter polymorphism (5-HTTLPR) and childhood adversity or recent stressful life events on symptoms of depression: results from two community surveys.",
        "key_reference_abstract": "In this study we investigated interactions between the 5-HTTLPR genotype and environmental risk factors (G x E) on symptoms of depression in two large Australian community samples of adolescents and young adults. We postulated that a significant interaction between the 5-HTTLPR genotype and environmental risk factors of childhood adversity or stressful life events on symptoms of depression would be observed in subjects with at least one short allele (s/l or s/s) compared with subjects with no short alleles (l/l). We did not find significant G x E interactions between the 5-HTTLPR genotype and recent stressful life events or childhood adversity on symptoms of depression in our sample populations. However, we did find adolescents aged 17-18 years homozygous for the long allele (l/l) and exposed to persistently high levels of family adversity over a 6-year period were at a greater risk of depression than subjects with the same genotype exposed to no or persistently low levels of family adversity. This interaction should be interpreted cautiously due to the small number of depressed subjects in the sample with persistently high levels of family adversity.",
        "truth": "True"
    },
    {
        "pmid": "19531786",
        "meta_analysis_title": "Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis.",
        "meta_analysis_question": "Does the interaction between the serotonin transporter gene (5-HTTLPR) and stressful life events increase the risk of depression?",
        "criteria": "A search of the PubMed, EMBASE, and PsycINFO databases was conducted through March 2009 using the search terms life stress, life event, depression, depress, serotonin transporter, 5-HTTLPR, interaction, and moderation. Bibliographies of studies were also reviewed. A total of 26 articles published or set for publication were identified through this search strategy (Figure 1). Inclusion criteria for studies for the meta-analyses were published articles that included data on the association between the (1) 5-HTTLPR genotype (S, SL, or LL), (2) number of stressful life events (0, 1, 2, or \u22653) or equivalent, and (3) categorical measure of depression defined by the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) or International Statistical Classification of Diseases, 10th Revision (ICD-10) or ability to use a cut point to define depression from standardized rating scales. To maximize our ability to use a common framework for variable definition, we also requested original data from all studies that appeared to meet inclusion criteria published prior to 2008.10,15-28 We received original data in a usable format for the meta-analysis from 10 of the 14 study investigators. A total of 14 studies were included in the analysis, 15-20,23,25-27,29-32 10 of which15-20,23,25-27,29,30 were also included in a second sex-specific meta-analysis of original data. Nine other studies did not meet inclusion criteria.33-41",
        "subgroup": "Logistic Regression Analyses of Risk of Depression for 14 Studies - Risk per S allele",
        "key_reference_title": "The risk for depression conferred by stressful life events is modified by variation at the serotonin transporter 5HTTLPR genotype: evidence from the Spanish PREDICT-Gene cohort.",
        "key_reference_abstract": "We report results from the PREDICT-Gene case-control study nested in a prospective cohort designed to identify predictors of the onset of depression among adult primary-care attendees. We tested the potential gene-by-environment interaction between 5HTTLPR genotype at the serotonin transporter gene and previous exposure to threatening life events (TLEs) in depression. A total of 737 consecutively recruited participants were genotyped. Additional information was gathered on exposure to TLEs over a 6-month period, socio-demographic data and family history of psychological problems among first-degree relatives. Diagnoses of depression were ascertained using the Composite International Diagnostic Interview (CIDI) by trained interviewers. Two different depressive outcomes were used (ICD-10 depressive episode and ICD-10 severe depressive episode). Both the s/s genotype and exposure to increasing number of TLEs were significantly associated with depression. Moreover, the 5HTTLPR s/s genotype significantly modified the risk conferred by TLEs for both depressive outcomes. Thus, s/s homozygous participants required minimal exposure to TLE (1 TLE) to acquire a level of risk for depression that was only found among l/s or l/l individuals after significantly higher exposure to TLEs (two or more TLEs). The interaction was more apparent when applied to the diagnosis of ICD-10 severe depressive episode and after adjusting for gender, age and family history of psychological problems. Likelihood ratios tests for the interaction were statistically significant for both depressive outcomes (ICD-10 depressive episode: LR X(2)=4.7, P=0.09 (crude), LR-X(2)=6.4, P=0.04 (adjusted); ICD-10 severe depressive episode: LR X(2)=6.9, P=0.032 (crude), LR-X(2)=8.1, P=0.017 (adjusted)).",
        "truth": "False"
    },
    {
        "pmid": "19531786",
        "meta_analysis_title": "Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis.",
        "meta_analysis_question": "Does the interaction between the serotonin transporter gene (5-HTTLPR) and stressful life events increase the risk of depression?",
        "criteria": "A search of the PubMed, EMBASE, and PsycINFO databases was conducted through March 2009 using the search terms life stress, life event, depression, depress, serotonin transporter, 5-HTTLPR, interaction, and moderation. Bibliographies of studies were also reviewed. A total of 26 articles published or set for publication were identified through this search strategy (Figure 1). Inclusion criteria for studies for the meta-analyses were published articles that included data on the association between the (1) 5-HTTLPR genotype (S, SL, or LL), (2) number of stressful life events (0, 1, 2, or \u22653) or equivalent, and (3) categorical measure of depression defined by the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) or International Statistical Classification of Diseases, 10th Revision (ICD-10) or ability to use a cut point to define depression from standardized rating scales. To maximize our ability to use a common framework for variable definition, we also requested original data from all studies that appeared to meet inclusion criteria published prior to 2008.10,15-28 We received original data in a usable format for the meta-analysis from 10 of the 14 study investigators. A total of 14 studies were included in the analysis, 15-20,23,25-27,29-32 10 of which15-20,23,25-27,29,30 were also included in a second sex-specific meta-analysis of original data. Nine other studies did not meet inclusion criteria.33-41",
        "subgroup": "Logistic Regression Analyses of Risk of Depression for 14 Studies - Risk per S allele",
        "key_reference_title": "Interactions between life stressors and susceptibility genes (5-HTTLPR and BDNF) on depression in Korean elders.",
        "key_reference_abstract": "## BACKGROUND\nIt has been reported that the functional polymorphism in the serotonin transporter gene linked promoter region (5-HTTLPR) modifies the association between stressful life events (SLEs) and depression in child, adolescent, and adult populations. We sought to replicate this finding in elders and, additionally, to test modifying effects of the brain-derived neurotrophic factor (BDNF) val66met polymorphism.\n## METHODS\nIn 732 Korean community residents ages 65+, diagnosis of depression (Geriatric Mental State Schedule), information on SLEs, and genotypes for 5-HTTLPR and BDNF val66met were ascertained. Of those without depression at baseline, 521 (88%) were followed up 2.5 years later. Interactions between SLEs and the two genotypes were investigated for both prevalent depression at baseline and incident depression at follow-up.\n## RESULTS\nSignificant interactions of SLEs with both 5-HTTLPR and BDNF genotypes were observed on risk of depression after adjustment for age, gender, education, and disability. A significant three-way interaction between 5-HTTLPR, BDNF, and SLEs was also found. The same findings were observed for predictors of incident depression in the prospective analysis.\n## CONCLUSIONS\nThese findings suggest that environmental risk of depression is modified by at least two genes and that gene-environment interactions are found even into old age.",
        "truth": "True"
    },
    {
        "pmid": "19531786",
        "meta_analysis_title": "Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis.",
        "meta_analysis_question": "Does the interaction between the serotonin transporter gene (5-HTTLPR) and stressful life events increase the risk of depression?",
        "criteria": "A search of the PubMed, EMBASE, and PsycINFO databases was conducted through March 2009 using the search terms life stress, life event, depression, depress, serotonin transporter, 5-HTTLPR, interaction, and moderation. Bibliographies of studies were also reviewed. A total of 26 articles published or set for publication were identified through this search strategy (Figure 1). Inclusion criteria for studies for the meta-analyses were published articles that included data on the association between the (1) 5-HTTLPR genotype (S, SL, or LL), (2) number of stressful life events (0, 1, 2, or \u22653) or equivalent, and (3) categorical measure of depression defined by the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) or International Statistical Classification of Diseases, 10th Revision (ICD-10) or ability to use a cut point to define depression from standardized rating scales. To maximize our ability to use a common framework for variable definition, we also requested original data from all studies that appeared to meet inclusion criteria published prior to 2008.10,15-28 We received original data in a usable format for the meta-analysis from 10 of the 14 study investigators. A total of 14 studies were included in the analysis, 15-20,23,25-27,29-32 10 of which15-20,23,25-27,29,30 were also included in a second sex-specific meta-analysis of original data. Nine other studies did not meet inclusion criteria.33-41",
        "subgroup": "Logistic Regression Analyses of Risk of Depression for 14 Studies - Risk per S allele",
        "key_reference_title": "5-HTTLPR genotype, stressful life events and late-life depression: no evidence of interaction in a French population.",
        "key_reference_abstract": "Modification of the effect of life events on risk of depression by a polymorphism in the serotonin transporter gene promoter (5-HTTLPR) has been reported in child, adolescent, adult and elderly populations. Replication attempted on data collected from 1421 individuals aged 65 and over from a French community study provided no evidence of a similar modifying effect. In the only analysis known to the authors to be carried out in an exclusively elderly, European population, this null finding remained consistent after restriction of analysis to prevalent or incident cases.",
        "truth": "True"
    },
    {
        "pmid": "19531786",
        "meta_analysis_title": "Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis.",
        "meta_analysis_question": "Does the interaction between the serotonin transporter gene (5-HTTLPR) and stressful life events increase the risk of depression?",
        "criteria": "A search of the PubMed, EMBASE, and PsycINFO databases was conducted through March 2009 using the search terms life stress, life event, depression, depress, serotonin transporter, 5-HTTLPR, interaction, and moderation. Bibliographies of studies were also reviewed. A total of 26 articles published or set for publication were identified through this search strategy (Figure 1). Inclusion criteria for studies for the meta-analyses were published articles that included data on the association between the (1) 5-HTTLPR genotype (S, SL, or LL), (2) number of stressful life events (0, 1, 2, or \u22653) or equivalent, and (3) categorical measure of depression defined by the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) or International Statistical Classification of Diseases, 10th Revision (ICD-10) or ability to use a cut point to define depression from standardized rating scales. To maximize our ability to use a common framework for variable definition, we also requested original data from all studies that appeared to meet inclusion criteria published prior to 2008.10,15-28 We received original data in a usable format for the meta-analysis from 10 of the 14 study investigators. A total of 14 studies were included in the analysis, 15-20,23,25-27,29-32 10 of which15-20,23,25-27,29,30 were also included in a second sex-specific meta-analysis of original data. Nine other studies did not meet inclusion criteria.33-41",
        "subgroup": "Logistic Regression Analyses of Risk of Depression for 14 Studies - Risk per S allele",
        "key_reference_title": "Interaction between the 5-HTTLPR serotonin transporter polymorphism and environmental adversity for mood and anxiety psychopathology: evidence from a high-risk community sample of young adults.",
        "key_reference_abstract": "Previous research examining gene-environment interaction (GxE) with regard to vulnerability to depression and anxiety has yielded conflicting results. The present study was designed to further investigate GxE between 5-HTTLPR and exposure to environmental adversity, using different phenotypic and genotypic characterizations as well as different types of adversity within a prospective study design. Data were available from an ongoing epidemiological cohort study following the outcome of early risk factors from birth to adulthood. At age 19 yr, 309 participants (142 males, 167 females) were characterized on measures of depression and anxiety through interview and questionnaire (DSM-IV diagnosis, Beck Depression Inventory, Harm Avoidance). Environmental adversity was assessed at birth (family adversity), and at age 19 yr (stressful life events). Bi- and tri-allelic 5-HTTLPR genotypes were obtained from genomic DNA. Results indicated that depression and anxiety in 19-yr-olds were strongly associated with both family adversity and stressful life events. Individuals with the LL genotype of 5-HTTLPR who were exposed to high family adversity displayed significantly higher rates of depressive or anxiety disorders and had more depressive symptoms than those without either condition. This GxE replicates recent findings from an epidemiological cohort study of adolescents but is in contrast to many previous reports suggesting an interaction with the S allele. No evidence for GxE was obtained with regard to current stressful life events and trait anxiety. One possible source for the conflicting findings might be attributed to heterogeneity in depression phenotypes and environmental adversity.",
        "truth": "True"
    },
    {
        "pmid": "19531786",
        "meta_analysis_title": "Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis.",
        "meta_analysis_question": "Does the interaction between the serotonin transporter gene (5-HTTLPR) and stressful life events increase the risk of depression?",
        "criteria": "A search of the PubMed, EMBASE, and PsycINFO databases was conducted through March 2009 using the search terms life stress, life event, depression, depress, serotonin transporter, 5-HTTLPR, interaction, and moderation. Bibliographies of studies were also reviewed. A total of 26 articles published or set for publication were identified through this search strategy (Figure 1). Inclusion criteria for studies for the meta-analyses were published articles that included data on the association between the (1) 5-HTTLPR genotype (S, SL, or LL), (2) number of stressful life events (0, 1, 2, or \u22653) or equivalent, and (3) categorical measure of depression defined by the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) or International Statistical Classification of Diseases, 10th Revision (ICD-10) or ability to use a cut point to define depression from standardized rating scales. To maximize our ability to use a common framework for variable definition, we also requested original data from all studies that appeared to meet inclusion criteria published prior to 2008.10,15-28 We received original data in a usable format for the meta-analysis from 10 of the 14 study investigators. A total of 14 studies were included in the analysis, 15-20,23,25-27,29-32 10 of which15-20,23,25-27,29,30 were also included in a second sex-specific meta-analysis of original data. Nine other studies did not meet inclusion criteria.33-41",
        "subgroup": "Logistic Regression Analyses of Risk of Depression for 14 Studies - Risk per stressful life event",
        "key_reference_title": "Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene.",
        "key_reference_abstract": "In a prospective-longitudinal study of a representative birth cohort, we tested why stressful experiences lead to depression in some people but not in others. A functional polymorphism in the promoter region of the serotonin transporter (5-HT T) gene was found to moderate the influence of stressful life events on depression. Individuals with one or two copies of the short allele of the 5-HT T promoter polymorphism exhibited more depressive symptoms, diagnosable depression, and suicidality in relation to stressful life events than individuals homozygous for the long allele. This epidemiological study thus provides evidence of a gene-by-environment interaction, in which an individual's response to environmental insults is moderated by his or her genetic makeup.",
        "truth": "True"
    },
    {
        "pmid": "19531786",
        "meta_analysis_title": "Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis.",
        "meta_analysis_question": "Does the interaction between the serotonin transporter gene (5-HTTLPR) and stressful life events increase the risk of depression?",
        "criteria": "A search of the PubMed, EMBASE, and PsycINFO databases was conducted through March 2009 using the search terms life stress, life event, depression, depress, serotonin transporter, 5-HTTLPR, interaction, and moderation. Bibliographies of studies were also reviewed. A total of 26 articles published or set for publication were identified through this search strategy (Figure 1). Inclusion criteria for studies for the meta-analyses were published articles that included data on the association between the (1) 5-HTTLPR genotype (S, SL, or LL), (2) number of stressful life events (0, 1, 2, or \u22653) or equivalent, and (3) categorical measure of depression defined by the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) or International Statistical Classification of Diseases, 10th Revision (ICD-10) or ability to use a cut point to define depression from standardized rating scales. To maximize our ability to use a common framework for variable definition, we also requested original data from all studies that appeared to meet inclusion criteria published prior to 2008.10,15-28 We received original data in a usable format for the meta-analysis from 10 of the 14 study investigators. A total of 14 studies were included in the analysis, 15-20,23,25-27,29-32 10 of which15-20,23,25-27,29,30 were also included in a second sex-specific meta-analysis of original data. Nine other studies did not meet inclusion criteria.33-41",
        "subgroup": "Logistic Regression Analyses of Risk of Depression for 14 Studies - Risk per stressful life event",
        "key_reference_title": "Gene-environment interaction analysis of serotonin system markers with adolescent depression.",
        "key_reference_abstract": "We report analyses from a study of gene-environment interaction in adolescent depression. The sample was selected from 1990 adolescents aged 10-20 years: those with depression symptoms in the top or bottom 15% were identified and divided into high or low environmental risk groups. DNA was obtained from 377 adolescents, representing the four quadrants of high or low depression and high or low environmental risk. Markers within, or close to, each of the serotonergic genes 5HTT, HTR2A, HTR2C, MAOA (monoamine oxidase type A) and tryptophan hydroxylase (TPH) were genotyped. Environmental risk group was a nonsignificant predictor and sex was a significant predictor of the depression group. HTR2A and TPH significantly predicted the depression group, independent of the effects of sex, environmental risk group and their interaction. In addition, there was a trend for an effect of 5HTTLPR, which was significant in female subjects. Furthermore, there was a significant genotype-environmental risk interaction for 5HTTLPR in female subjects only, with the effect being in the same direction as another recent study, reaffirming that an important source of genetic heterogeneity is exposure to environmental risk.",
        "truth": "True"
    },
    {
        "pmid": "19531786",
        "meta_analysis_title": "Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis.",
        "meta_analysis_question": "Does the interaction between the serotonin transporter gene (5-HTTLPR) and stressful life events increase the risk of depression?",
        "criteria": "A search of the PubMed, EMBASE, and PsycINFO databases was conducted through March 2009 using the search terms life stress, life event, depression, depress, serotonin transporter, 5-HTTLPR, interaction, and moderation. Bibliographies of studies were also reviewed. A total of 26 articles published or set for publication were identified through this search strategy (Figure 1). Inclusion criteria for studies for the meta-analyses were published articles that included data on the association between the (1) 5-HTTLPR genotype (S, SL, or LL), (2) number of stressful life events (0, 1, 2, or \u22653) or equivalent, and (3) categorical measure of depression defined by the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) or International Statistical Classification of Diseases, 10th Revision (ICD-10) or ability to use a cut point to define depression from standardized rating scales. To maximize our ability to use a common framework for variable definition, we also requested original data from all studies that appeared to meet inclusion criteria published prior to 2008.10,15-28 We received original data in a usable format for the meta-analysis from 10 of the 14 study investigators. A total of 14 studies were included in the analysis, 15-20,23,25-27,29-32 10 of which15-20,23,25-27,29,30 were also included in a second sex-specific meta-analysis of original data. Nine other studies did not meet inclusion criteria.33-41",
        "subgroup": "Logistic Regression Analyses of Risk of Depression for 14 Studies - Risk per stressful life event",
        "key_reference_title": "The relationship between stressful life events, the serotonin transporter (5-HTTLPR) genotype and major depression.",
        "key_reference_abstract": "## BACKGROUND\nSerotonin is a good candidate for major depression. We attempted to replicate the study by Caspi and colleagues [Science (2003) 301, 386-389] which reported a significant interaction between serotonin transporter (5-HTTLPR) genotype and stressful life events when predicting major depression.\n## METHOD\nWe typed the serotonin promoter 5-HTTLPR gene in 1206 male and female twins aged 19-78 years (mean = 39, S.D. = 11). A DSM-IV diagnosis of major depression was available for 1199 twins. Most of these twins had participated in a 1988-1990 study which included a stressful life events inventory and self-report measure of depression based on the SCL-90 and DSSI/sAD. Complete 5-HTT genotype and life events data, self-report symptoms and major depression diagnoses were available for 1091 subjects. We regressed categorical and ordinal measures of depression onto stressful life events and genotype.\n## RESULTS\nThere were significant main effects for stressful life events but there was no evidence for any effect of 5-HTT genotype, nor a genotype x stressful life event interaction.\n## CONCLUSIONS\nRegardless of whether our results were based on binary logistic or ordinal regression analyses we found no evidence to support a main effect of 5-HTTLPR, or an interaction between the 5-HTTLPR genotype and stressful life events on major depression, Only 20 % of our subjects were aged below 30 years. It is possible that the effect reported by Caspi and colleagues is specific to young people, in which case our study has much less power in this age group.",
        "truth": "True"
    },
    {
        "pmid": "19531786",
        "meta_analysis_title": "Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis.",
        "meta_analysis_question": "Does the interaction between the serotonin transporter gene (5-HTTLPR) and stressful life events increase the risk of depression?",
        "criteria": "A search of the PubMed, EMBASE, and PsycINFO databases was conducted through March 2009 using the search terms life stress, life event, depression, depress, serotonin transporter, 5-HTTLPR, interaction, and moderation. Bibliographies of studies were also reviewed. A total of 26 articles published or set for publication were identified through this search strategy (Figure 1). Inclusion criteria for studies for the meta-analyses were published articles that included data on the association between the (1) 5-HTTLPR genotype (S, SL, or LL), (2) number of stressful life events (0, 1, 2, or \u22653) or equivalent, and (3) categorical measure of depression defined by the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) or International Statistical Classification of Diseases, 10th Revision (ICD-10) or ability to use a cut point to define depression from standardized rating scales. To maximize our ability to use a common framework for variable definition, we also requested original data from all studies that appeared to meet inclusion criteria published prior to 2008.10,15-28 We received original data in a usable format for the meta-analysis from 10 of the 14 study investigators. A total of 14 studies were included in the analysis, 15-20,23,25-27,29-32 10 of which15-20,23,25-27,29,30 were also included in a second sex-specific meta-analysis of original data. Nine other studies did not meet inclusion criteria.33-41",
        "subgroup": "Logistic Regression Analyses of Risk of Depression for 14 Studies - Risk per stressful life event",
        "key_reference_title": "Mental and physical distress is modulated by a polymorphism in the 5-HT transporter gene interacting with social stressors and chronic disease burden.",
        "key_reference_abstract": "Previous studies have yielded conflicting results as to the putative role of the functional polymorphism of the promoter region of the serotonin transporter gene (SLC6A4) in the etiology of anxiety-related traits and depressive disorders. Recently, a significant gene-environment interaction was found between life stressors, the short allele of the SLC6A4 polymorphism and depression. The aim of the present study was to investigate if such a gene-environment interaction could be replicated within a different population with a different risk structure. A total of 1005 subjects from a general population sample (Study of Health in Pomerania) were genotyped. Mental and physical distress were assessed on 38 items of the modified complaint scale (BL-38). The interaction between the SLC6A4 genotype, social stressors and chronic diseases with regard to the BL-38 score was evaluated by ANOVA. There was no independent association of genotype with mental and physical distress. However, significant interactions between genotype, unemployment and chronic diseases (F = 6.6; df = 3, 671; P < 0.001) were found in females but not in males. The genotype explained 2% of the total variance of the BL-38 score and 9.1% of the explained variance. The results partly confirm previous findings of a significant gene-environment interaction of the short allele, indicating a higher mental vulnerability to social stressors and chronic diseases. The relevance of this finding is sustained by the fact that the sample characteristics and the risk structure were highly different from previous studies.",
        "truth": "True"
    },
    {
        "pmid": "19531786",
        "meta_analysis_title": "Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis.",
        "meta_analysis_question": "Does the interaction between the serotonin transporter gene (5-HTTLPR) and stressful life events increase the risk of depression?",
        "criteria": "A search of the PubMed, EMBASE, and PsycINFO databases was conducted through March 2009 using the search terms life stress, life event, depression, depress, serotonin transporter, 5-HTTLPR, interaction, and moderation. Bibliographies of studies were also reviewed. A total of 26 articles published or set for publication were identified through this search strategy (Figure 1). Inclusion criteria for studies for the meta-analyses were published articles that included data on the association between the (1) 5-HTTLPR genotype (S, SL, or LL), (2) number of stressful life events (0, 1, 2, or \u22653) or equivalent, and (3) categorical measure of depression defined by the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) or International Statistical Classification of Diseases, 10th Revision (ICD-10) or ability to use a cut point to define depression from standardized rating scales. To maximize our ability to use a common framework for variable definition, we also requested original data from all studies that appeared to meet inclusion criteria published prior to 2008.10,15-28 We received original data in a usable format for the meta-analysis from 10 of the 14 study investigators. A total of 14 studies were included in the analysis, 15-20,23,25-27,29-32 10 of which15-20,23,25-27,29,30 were also included in a second sex-specific meta-analysis of original data. Nine other studies did not meet inclusion criteria.33-41",
        "subgroup": "Logistic Regression Analyses of Risk of Depression for 14 Studies - Risk per stressful life event",
        "key_reference_title": "Social adversity, the serotonin transporter (5-HTTLPR) polymorphism and major depressive disorder.",
        "key_reference_abstract": "## BACKGROUND\nRecent evidence has suggested that the short allele of the serotonin transporter (5-HTT) gene-linked polymorphic region (5-HTTLPR of the human serotonin gene [SLC6A4]) is associated with increased risk of depressive disorder but only among individuals exposed to social adversity. We report an investigation designed to replicate this finding.\n## METHODS\nData were available from a non-clinical sample of 4,175 adult men and women, ages 41-80 years, selected from participants in the European Prospective Investigation into Cancer and Nutrition in Norfolk (EPIC-Norfolk, United Kingdom) study. Evidence of past-year prevalent episodic major depressive disorder (MDD), defined by restricted DSM-IV diagnostic criteria, was assessed through questionnaire. Adverse experiences in childhood and in adulthood (during the five years preceding assessment) were also assessed through self-report. The 5-HTTLPR variant was genotyped according to published protocols.\n## RESULTS\nOne-year prevalent MDD criteria were met by 298 study participants. The experience of social adversity (both in childhood and adulthood) was strongly associated with increased rates of past-year prevalent MDD. No gene by environment (GxE) interactions between the 5-HTTLPR genotype, social adversity, and MDD were observed.\n## CONCLUSIONS\nThis study has not replicated a previous finding of a GxE interaction between the 5-HTTLPR genotype, social adversity, and depression.",
        "truth": "True"
    },
    {
        "pmid": "19531786",
        "meta_analysis_title": "Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis.",
        "meta_analysis_question": "Does the interaction between the serotonin transporter gene (5-HTTLPR) and stressful life events increase the risk of depression?",
        "criteria": "A search of the PubMed, EMBASE, and PsycINFO databases was conducted through March 2009 using the search terms life stress, life event, depression, depress, serotonin transporter, 5-HTTLPR, interaction, and moderation. Bibliographies of studies were also reviewed. A total of 26 articles published or set for publication were identified through this search strategy (Figure 1). Inclusion criteria for studies for the meta-analyses were published articles that included data on the association between the (1) 5-HTTLPR genotype (S, SL, or LL), (2) number of stressful life events (0, 1, 2, or \u22653) or equivalent, and (3) categorical measure of depression defined by the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) or International Statistical Classification of Diseases, 10th Revision (ICD-10) or ability to use a cut point to define depression from standardized rating scales. To maximize our ability to use a common framework for variable definition, we also requested original data from all studies that appeared to meet inclusion criteria published prior to 2008.10,15-28 We received original data in a usable format for the meta-analysis from 10 of the 14 study investigators. A total of 14 studies were included in the analysis, 15-20,23,25-27,29-32 10 of which15-20,23,25-27,29,30 were also included in a second sex-specific meta-analysis of original data. Nine other studies did not meet inclusion criteria.33-41",
        "subgroup": "Logistic Regression Analyses of Risk of Depression for 14 Studies - Risk per stressful life event",
        "key_reference_title": "Life events, first depression onset and the serotonin transporter gene.",
        "key_reference_abstract": "## BACKGROUND\nA relationship between the serotonin transporter gene, adverse events and onset of major depression has been reported.\n## AIMS\nTo replicate a gene x environment interaction in a cohort with longitudinal data for life events, experience of depression, parental bonding and neuroticism.\n## METHOD\nAt the 25-year follow-up, genomic DNA was obtained from 127 cohort members (mean age 48 years) to determine the genotype of the serotonin transporter gene-linked promoter region (5-HTTLPR). Associations were investigated between the 5-HTTLPR genotype, positive and adverse life events and the gene x environment interaction, and also between the 5-HTTLPR genotype and risk factors for depression.\n## RESULTS\nNo relationship was found between 5-HTTLPR genotype and either risk factors for depression or positive life events. Adverse life events had a significantly greater impact on the onset of depression for individuals with the s/s genotype.\n## CONCLUSIONS\nThe 5-HTTLPR genotype is a significant predictor of onset of major depression following multiple adverse events. This is one of the more robust findings concerning specific biological risk factors for depression.",
        "truth": "True"
    },
    {
        "pmid": "19531786",
        "meta_analysis_title": "Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis.",
        "meta_analysis_question": "Does the interaction between the serotonin transporter gene (5-HTTLPR) and stressful life events increase the risk of depression?",
        "criteria": "A search of the PubMed, EMBASE, and PsycINFO databases was conducted through March 2009 using the search terms life stress, life event, depression, depress, serotonin transporter, 5-HTTLPR, interaction, and moderation. Bibliographies of studies were also reviewed. A total of 26 articles published or set for publication were identified through this search strategy (Figure 1). Inclusion criteria for studies for the meta-analyses were published articles that included data on the association between the (1) 5-HTTLPR genotype (S, SL, or LL), (2) number of stressful life events (0, 1, 2, or \u22653) or equivalent, and (3) categorical measure of depression defined by the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) or International Statistical Classification of Diseases, 10th Revision (ICD-10) or ability to use a cut point to define depression from standardized rating scales. To maximize our ability to use a common framework for variable definition, we also requested original data from all studies that appeared to meet inclusion criteria published prior to 2008.10,15-28 We received original data in a usable format for the meta-analysis from 10 of the 14 study investigators. A total of 14 studies were included in the analysis, 15-20,23,25-27,29-32 10 of which15-20,23,25-27,29,30 were also included in a second sex-specific meta-analysis of original data. Nine other studies did not meet inclusion criteria.33-41",
        "subgroup": "Logistic Regression Analyses of Risk of Depression for 14 Studies - Risk per stressful life event",
        "key_reference_title": "Early family environment, current adversity, the serotonin transporter promoter polymorphism, and depressive symptomatology.",
        "key_reference_abstract": "## BACKGROUND\nMixed evidence has suggested that homozygous carriers of the short allele (s/s) of the serotonin transporter gene-linked polymorphic region (5-HTTLPR) may be at increased risk for depression, if they have also been exposed to early or current adversity/stress. We address this debate by examining the relation of a stressful early family environment, recent adversity/stress, and the 5-HTTLPR to depressive symptomatology in a normal sample.\n## METHODS\nA nonclinical sample of 118 young adult men and women completed assessments of early family environment, recent stressful events, psychosocial resources, and psychological distress, including depressive symptomatology. The 5-HTTLPR was genotyped using a standard protocol with DNA extracted from oral fluid.\n## RESULTS\nA stressful early family environment was significantly related to depressive symptomatology. In addition, gene-by-environment (GxE) interactions were observed between the 5-HTTLPR and both early family environment and current adversity/stress. Individuals homozygous for the short allele had greater depressive symptomatology if they had experienced early or recent adversity but significantly less depressive symptomatology if they reported a supportive early environment or recent positive experiences, compared with participants with the s/l or l/l genotype.\n## CONCLUSIONS\nEarly or current environment, in conjunction with the serotonin transporter polymorphism, predicts depressive symptomatology.",
        "truth": "True"
    },
    {
        "pmid": "19531786",
        "meta_analysis_title": "Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis.",
        "meta_analysis_question": "Does the interaction between the serotonin transporter gene (5-HTTLPR) and stressful life events increase the risk of depression?",
        "criteria": "A search of the PubMed, EMBASE, and PsycINFO databases was conducted through March 2009 using the search terms life stress, life event, depression, depress, serotonin transporter, 5-HTTLPR, interaction, and moderation. Bibliographies of studies were also reviewed. A total of 26 articles published or set for publication were identified through this search strategy (Figure 1). Inclusion criteria for studies for the meta-analyses were published articles that included data on the association between the (1) 5-HTTLPR genotype (S, SL, or LL), (2) number of stressful life events (0, 1, 2, or \u22653) or equivalent, and (3) categorical measure of depression defined by the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) or International Statistical Classification of Diseases, 10th Revision (ICD-10) or ability to use a cut point to define depression from standardized rating scales. To maximize our ability to use a common framework for variable definition, we also requested original data from all studies that appeared to meet inclusion criteria published prior to 2008.10,15-28 We received original data in a usable format for the meta-analysis from 10 of the 14 study investigators. A total of 14 studies were included in the analysis, 15-20,23,25-27,29-32 10 of which15-20,23,25-27,29,30 were also included in a second sex-specific meta-analysis of original data. Nine other studies did not meet inclusion criteria.33-41",
        "subgroup": "Logistic Regression Analyses of Risk of Depression for 14 Studies - Risk per stressful life event",
        "key_reference_title": "Relationship of 5-HTTLPR genotypes and depression risk in the presence of trauma in a female twin sample.",
        "key_reference_abstract": "Several studies have implicated an insertion/deletion polymorphism in the promoter region of the serotonin transporter gene (SLC6A4; 5-HTT) in the development of mood disorders. In the present study of a sample of 247 young adult female twins from Missouri, we examine whether this polymorphism interacts with the effect of adverse life events to increase risk for developing depression. We found a significant interaction between the number of high-activity L(A) alleles and exposure to trauma (OR = 1.70, P < 0.0001). This differs from previous reports, in that the higher activity genotypes (L(A)/L(A), L(A)/S, L(A)/L(G)), rather than the low activity genotypes (S/S, S/L(G), L(G)/L(G)), are associated with an increased incidence of major depressive disease (MDD) in the presence of environmental trauma.",
        "truth": "True"
    },
    {
        "pmid": "19531786",
        "meta_analysis_title": "Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis.",
        "meta_analysis_question": "Does the interaction between the serotonin transporter gene (5-HTTLPR) and stressful life events increase the risk of depression?",
        "criteria": "A search of the PubMed, EMBASE, and PsycINFO databases was conducted through March 2009 using the search terms life stress, life event, depression, depress, serotonin transporter, 5-HTTLPR, interaction, and moderation. Bibliographies of studies were also reviewed. A total of 26 articles published or set for publication were identified through this search strategy (Figure 1). Inclusion criteria for studies for the meta-analyses were published articles that included data on the association between the (1) 5-HTTLPR genotype (S, SL, or LL), (2) number of stressful life events (0, 1, 2, or \u22653) or equivalent, and (3) categorical measure of depression defined by the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) or International Statistical Classification of Diseases, 10th Revision (ICD-10) or ability to use a cut point to define depression from standardized rating scales. To maximize our ability to use a common framework for variable definition, we also requested original data from all studies that appeared to meet inclusion criteria published prior to 2008.10,15-28 We received original data in a usable format for the meta-analysis from 10 of the 14 study investigators. A total of 14 studies were included in the analysis, 15-20,23,25-27,29-32 10 of which15-20,23,25-27,29,30 were also included in a second sex-specific meta-analysis of original data. Nine other studies did not meet inclusion criteria.33-41",
        "subgroup": "Logistic Regression Analyses of Risk of Depression for 14 Studies - Risk per stressful life event",
        "key_reference_title": "Family based association analyses between the serotonin transporter gene polymorphism (5-HTTLPR) and neuroticism, anxiety and depression.",
        "key_reference_abstract": "We studied the association between the short/long promotor-based length polymorphism of the serotonin transporter gene (5-HTTLPR) and neuroticism, anxiety and depression. Subjects included twins, their siblings and parents from the Netherlands Twin Register (559 parents and 1,245 offspring). Subjects had participated between one and five times in a survey study measuring neuroticism, anxiety and depression. Offspring of these families were also approached to participate in a psychiatric interview diagnosing DSM-IV major depression. Within-family and total association between 5-HTTLPR and these traits were tested. Only three of the 36 tests showed a significant effect of 5-HTTLPR (P<0.05). These effects were in opposite directions, i.e. both negative and positive regression coefficients were found for the s allele. No additive effect of the s allele was found for DSM-IV depression. Our results strongly suggest that there is no straightforward association between 5-HTTLPR and neuroticism, anxiety and depression.",
        "truth": "True"
    },
    {
        "pmid": "19531786",
        "meta_analysis_title": "Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis.",
        "meta_analysis_question": "Does the interaction between the serotonin transporter gene (5-HTTLPR) and stressful life events increase the risk of depression?",
        "criteria": "A search of the PubMed, EMBASE, and PsycINFO databases was conducted through March 2009 using the search terms life stress, life event, depression, depress, serotonin transporter, 5-HTTLPR, interaction, and moderation. Bibliographies of studies were also reviewed. A total of 26 articles published or set for publication were identified through this search strategy (Figure 1). Inclusion criteria for studies for the meta-analyses were published articles that included data on the association between the (1) 5-HTTLPR genotype (S, SL, or LL), (2) number of stressful life events (0, 1, 2, or \u22653) or equivalent, and (3) categorical measure of depression defined by the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) or International Statistical Classification of Diseases, 10th Revision (ICD-10) or ability to use a cut point to define depression from standardized rating scales. To maximize our ability to use a common framework for variable definition, we also requested original data from all studies that appeared to meet inclusion criteria published prior to 2008.10,15-28 We received original data in a usable format for the meta-analysis from 10 of the 14 study investigators. A total of 14 studies were included in the analysis, 15-20,23,25-27,29-32 10 of which15-20,23,25-27,29,30 were also included in a second sex-specific meta-analysis of original data. Nine other studies did not meet inclusion criteria.33-41",
        "subgroup": "Logistic Regression Analyses of Risk of Depression for 14 Studies - Risk per stressful life event",
        "key_reference_title": "No interaction between the serotonin transporter polymorphism (5-HTTLPR) and childhood adversity or recent stressful life events on symptoms of depression: results from two community surveys.",
        "key_reference_abstract": "In this study we investigated interactions between the 5-HTTLPR genotype and environmental risk factors (G x E) on symptoms of depression in two large Australian community samples of adolescents and young adults. We postulated that a significant interaction between the 5-HTTLPR genotype and environmental risk factors of childhood adversity or stressful life events on symptoms of depression would be observed in subjects with at least one short allele (s/l or s/s) compared with subjects with no short alleles (l/l). We did not find significant G x E interactions between the 5-HTTLPR genotype and recent stressful life events or childhood adversity on symptoms of depression in our sample populations. However, we did find adolescents aged 17-18 years homozygous for the long allele (l/l) and exposed to persistently high levels of family adversity over a 6-year period were at a greater risk of depression than subjects with the same genotype exposed to no or persistently low levels of family adversity. This interaction should be interpreted cautiously due to the small number of depressed subjects in the sample with persistently high levels of family adversity.",
        "truth": "True"
    },
    {
        "pmid": "19531786",
        "meta_analysis_title": "Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis.",
        "meta_analysis_question": "Does the interaction between the serotonin transporter gene (5-HTTLPR) and stressful life events increase the risk of depression?",
        "criteria": "A search of the PubMed, EMBASE, and PsycINFO databases was conducted through March 2009 using the search terms life stress, life event, depression, depress, serotonin transporter, 5-HTTLPR, interaction, and moderation. Bibliographies of studies were also reviewed. A total of 26 articles published or set for publication were identified through this search strategy (Figure 1). Inclusion criteria for studies for the meta-analyses were published articles that included data on the association between the (1) 5-HTTLPR genotype (S, SL, or LL), (2) number of stressful life events (0, 1, 2, or \u22653) or equivalent, and (3) categorical measure of depression defined by the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) or International Statistical Classification of Diseases, 10th Revision (ICD-10) or ability to use a cut point to define depression from standardized rating scales. To maximize our ability to use a common framework for variable definition, we also requested original data from all studies that appeared to meet inclusion criteria published prior to 2008.10,15-28 We received original data in a usable format for the meta-analysis from 10 of the 14 study investigators. A total of 14 studies were included in the analysis, 15-20,23,25-27,29-32 10 of which15-20,23,25-27,29,30 were also included in a second sex-specific meta-analysis of original data. Nine other studies did not meet inclusion criteria.33-41",
        "subgroup": "Logistic Regression Analyses of Risk of Depression for 14 Studies - Risk per stressful life event",
        "key_reference_title": "The risk for depression conferred by stressful life events is modified by variation at the serotonin transporter 5HTTLPR genotype: evidence from the Spanish PREDICT-Gene cohort.",
        "key_reference_abstract": "We report results from the PREDICT-Gene case-control study nested in a prospective cohort designed to identify predictors of the onset of depression among adult primary-care attendees. We tested the potential gene-by-environment interaction between 5HTTLPR genotype at the serotonin transporter gene and previous exposure to threatening life events (TLEs) in depression. A total of 737 consecutively recruited participants were genotyped. Additional information was gathered on exposure to TLEs over a 6-month period, socio-demographic data and family history of psychological problems among first-degree relatives. Diagnoses of depression were ascertained using the Composite International Diagnostic Interview (CIDI) by trained interviewers. Two different depressive outcomes were used (ICD-10 depressive episode and ICD-10 severe depressive episode). Both the s/s genotype and exposure to increasing number of TLEs were significantly associated with depression. Moreover, the 5HTTLPR s/s genotype significantly modified the risk conferred by TLEs for both depressive outcomes. Thus, s/s homozygous participants required minimal exposure to TLE (1 TLE) to acquire a level of risk for depression that was only found among l/s or l/l individuals after significantly higher exposure to TLEs (two or more TLEs). The interaction was more apparent when applied to the diagnosis of ICD-10 severe depressive episode and after adjusting for gender, age and family history of psychological problems. Likelihood ratios tests for the interaction were statistically significant for both depressive outcomes (ICD-10 depressive episode: LR X(2)=4.7, P=0.09 (crude), LR-X(2)=6.4, P=0.04 (adjusted); ICD-10 severe depressive episode: LR X(2)=6.9, P=0.032 (crude), LR-X(2)=8.1, P=0.017 (adjusted)).",
        "truth": "False"
    },
    {
        "pmid": "19531786",
        "meta_analysis_title": "Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis.",
        "meta_analysis_question": "Does the interaction between the serotonin transporter gene (5-HTTLPR) and stressful life events increase the risk of depression?",
        "criteria": "A search of the PubMed, EMBASE, and PsycINFO databases was conducted through March 2009 using the search terms life stress, life event, depression, depress, serotonin transporter, 5-HTTLPR, interaction, and moderation. Bibliographies of studies were also reviewed. A total of 26 articles published or set for publication were identified through this search strategy (Figure 1). Inclusion criteria for studies for the meta-analyses were published articles that included data on the association between the (1) 5-HTTLPR genotype (S, SL, or LL), (2) number of stressful life events (0, 1, 2, or \u22653) or equivalent, and (3) categorical measure of depression defined by the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) or International Statistical Classification of Diseases, 10th Revision (ICD-10) or ability to use a cut point to define depression from standardized rating scales. To maximize our ability to use a common framework for variable definition, we also requested original data from all studies that appeared to meet inclusion criteria published prior to 2008.10,15-28 We received original data in a usable format for the meta-analysis from 10 of the 14 study investigators. A total of 14 studies were included in the analysis, 15-20,23,25-27,29-32 10 of which15-20,23,25-27,29,30 were also included in a second sex-specific meta-analysis of original data. Nine other studies did not meet inclusion criteria.33-41",
        "subgroup": "Logistic Regression Analyses of Risk of Depression for 14 Studies - Risk per stressful life event",
        "key_reference_title": "Interactions between life stressors and susceptibility genes (5-HTTLPR and BDNF) on depression in Korean elders.",
        "key_reference_abstract": "## BACKGROUND\nIt has been reported that the functional polymorphism in the serotonin transporter gene linked promoter region (5-HTTLPR) modifies the association between stressful life events (SLEs) and depression in child, adolescent, and adult populations. We sought to replicate this finding in elders and, additionally, to test modifying effects of the brain-derived neurotrophic factor (BDNF) val66met polymorphism.\n## METHODS\nIn 732 Korean community residents ages 65+, diagnosis of depression (Geriatric Mental State Schedule), information on SLEs, and genotypes for 5-HTTLPR and BDNF val66met were ascertained. Of those without depression at baseline, 521 (88%) were followed up 2.5 years later. Interactions between SLEs and the two genotypes were investigated for both prevalent depression at baseline and incident depression at follow-up.\n## RESULTS\nSignificant interactions of SLEs with both 5-HTTLPR and BDNF genotypes were observed on risk of depression after adjustment for age, gender, education, and disability. A significant three-way interaction between 5-HTTLPR, BDNF, and SLEs was also found. The same findings were observed for predictors of incident depression in the prospective analysis.\n## CONCLUSIONS\nThese findings suggest that environmental risk of depression is modified by at least two genes and that gene-environment interactions are found even into old age.",
        "truth": "True"
    },
    {
        "pmid": "19531786",
        "meta_analysis_title": "Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis.",
        "meta_analysis_question": "Does the interaction between the serotonin transporter gene (5-HTTLPR) and stressful life events increase the risk of depression?",
        "criteria": "A search of the PubMed, EMBASE, and PsycINFO databases was conducted through March 2009 using the search terms life stress, life event, depression, depress, serotonin transporter, 5-HTTLPR, interaction, and moderation. Bibliographies of studies were also reviewed. A total of 26 articles published or set for publication were identified through this search strategy (Figure 1). Inclusion criteria for studies for the meta-analyses were published articles that included data on the association between the (1) 5-HTTLPR genotype (S, SL, or LL), (2) number of stressful life events (0, 1, 2, or \u22653) or equivalent, and (3) categorical measure of depression defined by the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) or International Statistical Classification of Diseases, 10th Revision (ICD-10) or ability to use a cut point to define depression from standardized rating scales. To maximize our ability to use a common framework for variable definition, we also requested original data from all studies that appeared to meet inclusion criteria published prior to 2008.10,15-28 We received original data in a usable format for the meta-analysis from 10 of the 14 study investigators. A total of 14 studies were included in the analysis, 15-20,23,25-27,29-32 10 of which15-20,23,25-27,29,30 were also included in a second sex-specific meta-analysis of original data. Nine other studies did not meet inclusion criteria.33-41",
        "subgroup": "Logistic Regression Analyses of Risk of Depression for 14 Studies - Risk per stressful life event",
        "key_reference_title": "5-HTTLPR genotype, stressful life events and late-life depression: no evidence of interaction in a French population.",
        "key_reference_abstract": "Modification of the effect of life events on risk of depression by a polymorphism in the serotonin transporter gene promoter (5-HTTLPR) has been reported in child, adolescent, adult and elderly populations. Replication attempted on data collected from 1421 individuals aged 65 and over from a French community study provided no evidence of a similar modifying effect. In the only analysis known to the authors to be carried out in an exclusively elderly, European population, this null finding remained consistent after restriction of analysis to prevalent or incident cases.",
        "truth": "True"
    },
    {
        "pmid": "19531786",
        "meta_analysis_title": "Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis.",
        "meta_analysis_question": "Does the interaction between the serotonin transporter gene (5-HTTLPR) and stressful life events increase the risk of depression?",
        "criteria": "A search of the PubMed, EMBASE, and PsycINFO databases was conducted through March 2009 using the search terms life stress, life event, depression, depress, serotonin transporter, 5-HTTLPR, interaction, and moderation. Bibliographies of studies were also reviewed. A total of 26 articles published or set for publication were identified through this search strategy (Figure 1). Inclusion criteria for studies for the meta-analyses were published articles that included data on the association between the (1) 5-HTTLPR genotype (S, SL, or LL), (2) number of stressful life events (0, 1, 2, or \u22653) or equivalent, and (3) categorical measure of depression defined by the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) or International Statistical Classification of Diseases, 10th Revision (ICD-10) or ability to use a cut point to define depression from standardized rating scales. To maximize our ability to use a common framework for variable definition, we also requested original data from all studies that appeared to meet inclusion criteria published prior to 2008.10,15-28 We received original data in a usable format for the meta-analysis from 10 of the 14 study investigators. A total of 14 studies were included in the analysis, 15-20,23,25-27,29-32 10 of which15-20,23,25-27,29,30 were also included in a second sex-specific meta-analysis of original data. Nine other studies did not meet inclusion criteria.33-41",
        "subgroup": "Logistic Regression Analyses of Risk of Depression for 14 Studies - Risk per stressful life event",
        "key_reference_title": "Interaction between the 5-HTTLPR serotonin transporter polymorphism and environmental adversity for mood and anxiety psychopathology: evidence from a high-risk community sample of young adults.",
        "key_reference_abstract": "Previous research examining gene-environment interaction (GxE) with regard to vulnerability to depression and anxiety has yielded conflicting results. The present study was designed to further investigate GxE between 5-HTTLPR and exposure to environmental adversity, using different phenotypic and genotypic characterizations as well as different types of adversity within a prospective study design. Data were available from an ongoing epidemiological cohort study following the outcome of early risk factors from birth to adulthood. At age 19 yr, 309 participants (142 males, 167 females) were characterized on measures of depression and anxiety through interview and questionnaire (DSM-IV diagnosis, Beck Depression Inventory, Harm Avoidance). Environmental adversity was assessed at birth (family adversity), and at age 19 yr (stressful life events). Bi- and tri-allelic 5-HTTLPR genotypes were obtained from genomic DNA. Results indicated that depression and anxiety in 19-yr-olds were strongly associated with both family adversity and stressful life events. Individuals with the LL genotype of 5-HTTLPR who were exposed to high family adversity displayed significantly higher rates of depressive or anxiety disorders and had more depressive symptoms than those without either condition. This GxE replicates recent findings from an epidemiological cohort study of adolescents but is in contrast to many previous reports suggesting an interaction with the S allele. No evidence for GxE was obtained with regard to current stressful life events and trait anxiety. One possible source for the conflicting findings might be attributed to heterogeneity in depression phenotypes and environmental adversity.",
        "truth": "True"
    },
    {
        "pmid": "19531786",
        "meta_analysis_title": "Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis.",
        "meta_analysis_question": "Does the interaction between the serotonin transporter gene (5-HTTLPR) and stressful life events increase the risk of depression?",
        "criteria": "A search of the PubMed, EMBASE, and PsycINFO databases was conducted through March 2009 using the search terms life stress, life event, depression, depress, serotonin transporter, 5-HTTLPR, interaction, and moderation. Bibliographies of studies were also reviewed. A total of 26 articles published or set for publication were identified through this search strategy (Figure 1). Inclusion criteria for studies for the meta-analyses were published articles that included data on the association between the (1) 5-HTTLPR genotype (S, SL, or LL), (2) number of stressful life events (0, 1, 2, or \u22653) or equivalent, and (3) categorical measure of depression defined by the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) or International Statistical Classification of Diseases, 10th Revision (ICD-10) or ability to use a cut point to define depression from standardized rating scales. To maximize our ability to use a common framework for variable definition, we also requested original data from all studies that appeared to meet inclusion criteria published prior to 2008.10,15-28 We received original data in a usable format for the meta-analysis from 10 of the 14 study investigators. A total of 14 studies were included in the analysis, 15-20,23,25-27,29-32 10 of which15-20,23,25-27,29,30 were also included in a second sex-specific meta-analysis of original data. Nine other studies did not meet inclusion criteria.33-41",
        "subgroup": "Logistic Regression Analyses of Risk of Depression for 14 Studies - Interaction of genotype and stressful life events",
        "key_reference_title": "Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene.",
        "key_reference_abstract": "In a prospective-longitudinal study of a representative birth cohort, we tested why stressful experiences lead to depression in some people but not in others. A functional polymorphism in the promoter region of the serotonin transporter (5-HT T) gene was found to moderate the influence of stressful life events on depression. Individuals with one or two copies of the short allele of the 5-HT T promoter polymorphism exhibited more depressive symptoms, diagnosable depression, and suicidality in relation to stressful life events than individuals homozygous for the long allele. This epidemiological study thus provides evidence of a gene-by-environment interaction, in which an individual's response to environmental insults is moderated by his or her genetic makeup.",
        "truth": "True"
    },
    {
        "pmid": "19531786",
        "meta_analysis_title": "Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis.",
        "meta_analysis_question": "Does the interaction between the serotonin transporter gene (5-HTTLPR) and stressful life events increase the risk of depression?",
        "criteria": "A search of the PubMed, EMBASE, and PsycINFO databases was conducted through March 2009 using the search terms life stress, life event, depression, depress, serotonin transporter, 5-HTTLPR, interaction, and moderation. Bibliographies of studies were also reviewed. A total of 26 articles published or set for publication were identified through this search strategy (Figure 1). Inclusion criteria for studies for the meta-analyses were published articles that included data on the association between the (1) 5-HTTLPR genotype (S, SL, or LL), (2) number of stressful life events (0, 1, 2, or \u22653) or equivalent, and (3) categorical measure of depression defined by the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) or International Statistical Classification of Diseases, 10th Revision (ICD-10) or ability to use a cut point to define depression from standardized rating scales. To maximize our ability to use a common framework for variable definition, we also requested original data from all studies that appeared to meet inclusion criteria published prior to 2008.10,15-28 We received original data in a usable format for the meta-analysis from 10 of the 14 study investigators. A total of 14 studies were included in the analysis, 15-20,23,25-27,29-32 10 of which15-20,23,25-27,29,30 were also included in a second sex-specific meta-analysis of original data. Nine other studies did not meet inclusion criteria.33-41",
        "subgroup": "Logistic Regression Analyses of Risk of Depression for 14 Studies - Interaction of genotype and stressful life events",
        "key_reference_title": "Gene-environment interaction analysis of serotonin system markers with adolescent depression.",
        "key_reference_abstract": "We report analyses from a study of gene-environment interaction in adolescent depression. The sample was selected from 1990 adolescents aged 10-20 years: those with depression symptoms in the top or bottom 15% were identified and divided into high or low environmental risk groups. DNA was obtained from 377 adolescents, representing the four quadrants of high or low depression and high or low environmental risk. Markers within, or close to, each of the serotonergic genes 5HTT, HTR2A, HTR2C, MAOA (monoamine oxidase type A) and tryptophan hydroxylase (TPH) were genotyped. Environmental risk group was a nonsignificant predictor and sex was a significant predictor of the depression group. HTR2A and TPH significantly predicted the depression group, independent of the effects of sex, environmental risk group and their interaction. In addition, there was a trend for an effect of 5HTTLPR, which was significant in female subjects. Furthermore, there was a significant genotype-environmental risk interaction for 5HTTLPR in female subjects only, with the effect being in the same direction as another recent study, reaffirming that an important source of genetic heterogeneity is exposure to environmental risk.",
        "truth": "True"
    },
    {
        "pmid": "19531786",
        "meta_analysis_title": "Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis.",
        "meta_analysis_question": "Does the interaction between the serotonin transporter gene (5-HTTLPR) and stressful life events increase the risk of depression?",
        "criteria": "A search of the PubMed, EMBASE, and PsycINFO databases was conducted through March 2009 using the search terms life stress, life event, depression, depress, serotonin transporter, 5-HTTLPR, interaction, and moderation. Bibliographies of studies were also reviewed. A total of 26 articles published or set for publication were identified through this search strategy (Figure 1). Inclusion criteria for studies for the meta-analyses were published articles that included data on the association between the (1) 5-HTTLPR genotype (S, SL, or LL), (2) number of stressful life events (0, 1, 2, or \u22653) or equivalent, and (3) categorical measure of depression defined by the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) or International Statistical Classification of Diseases, 10th Revision (ICD-10) or ability to use a cut point to define depression from standardized rating scales. To maximize our ability to use a common framework for variable definition, we also requested original data from all studies that appeared to meet inclusion criteria published prior to 2008.10,15-28 We received original data in a usable format for the meta-analysis from 10 of the 14 study investigators. A total of 14 studies were included in the analysis, 15-20,23,25-27,29-32 10 of which15-20,23,25-27,29,30 were also included in a second sex-specific meta-analysis of original data. Nine other studies did not meet inclusion criteria.33-41",
        "subgroup": "Logistic Regression Analyses of Risk of Depression for 14 Studies - Interaction of genotype and stressful life events",
        "key_reference_title": "The relationship between stressful life events, the serotonin transporter (5-HTTLPR) genotype and major depression.",
        "key_reference_abstract": "## BACKGROUND\nSerotonin is a good candidate for major depression. We attempted to replicate the study by Caspi and colleagues [Science (2003) 301, 386-389] which reported a significant interaction between serotonin transporter (5-HTTLPR) genotype and stressful life events when predicting major depression.\n## METHOD\nWe typed the serotonin promoter 5-HTTLPR gene in 1206 male and female twins aged 19-78 years (mean = 39, S.D. = 11). A DSM-IV diagnosis of major depression was available for 1199 twins. Most of these twins had participated in a 1988-1990 study which included a stressful life events inventory and self-report measure of depression based on the SCL-90 and DSSI/sAD. Complete 5-HTT genotype and life events data, self-report symptoms and major depression diagnoses were available for 1091 subjects. We regressed categorical and ordinal measures of depression onto stressful life events and genotype.\n## RESULTS\nThere were significant main effects for stressful life events but there was no evidence for any effect of 5-HTT genotype, nor a genotype x stressful life event interaction.\n## CONCLUSIONS\nRegardless of whether our results were based on binary logistic or ordinal regression analyses we found no evidence to support a main effect of 5-HTTLPR, or an interaction between the 5-HTTLPR genotype and stressful life events on major depression, Only 20 % of our subjects were aged below 30 years. It is possible that the effect reported by Caspi and colleagues is specific to young people, in which case our study has much less power in this age group.",
        "truth": "True"
    },
    {
        "pmid": "19531786",
        "meta_analysis_title": "Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis.",
        "meta_analysis_question": "Does the interaction between the serotonin transporter gene (5-HTTLPR) and stressful life events increase the risk of depression?",
        "criteria": "A search of the PubMed, EMBASE, and PsycINFO databases was conducted through March 2009 using the search terms life stress, life event, depression, depress, serotonin transporter, 5-HTTLPR, interaction, and moderation. Bibliographies of studies were also reviewed. A total of 26 articles published or set for publication were identified through this search strategy (Figure 1). Inclusion criteria for studies for the meta-analyses were published articles that included data on the association between the (1) 5-HTTLPR genotype (S, SL, or LL), (2) number of stressful life events (0, 1, 2, or \u22653) or equivalent, and (3) categorical measure of depression defined by the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) or International Statistical Classification of Diseases, 10th Revision (ICD-10) or ability to use a cut point to define depression from standardized rating scales. To maximize our ability to use a common framework for variable definition, we also requested original data from all studies that appeared to meet inclusion criteria published prior to 2008.10,15-28 We received original data in a usable format for the meta-analysis from 10 of the 14 study investigators. A total of 14 studies were included in the analysis, 15-20,23,25-27,29-32 10 of which15-20,23,25-27,29,30 were also included in a second sex-specific meta-analysis of original data. Nine other studies did not meet inclusion criteria.33-41",
        "subgroup": "Logistic Regression Analyses of Risk of Depression for 14 Studies - Interaction of genotype and stressful life events",
        "key_reference_title": "Mental and physical distress is modulated by a polymorphism in the 5-HT transporter gene interacting with social stressors and chronic disease burden.",
        "key_reference_abstract": "Previous studies have yielded conflicting results as to the putative role of the functional polymorphism of the promoter region of the serotonin transporter gene (SLC6A4) in the etiology of anxiety-related traits and depressive disorders. Recently, a significant gene-environment interaction was found between life stressors, the short allele of the SLC6A4 polymorphism and depression. The aim of the present study was to investigate if such a gene-environment interaction could be replicated within a different population with a different risk structure. A total of 1005 subjects from a general population sample (Study of Health in Pomerania) were genotyped. Mental and physical distress were assessed on 38 items of the modified complaint scale (BL-38). The interaction between the SLC6A4 genotype, social stressors and chronic diseases with regard to the BL-38 score was evaluated by ANOVA. There was no independent association of genotype with mental and physical distress. However, significant interactions between genotype, unemployment and chronic diseases (F = 6.6; df = 3, 671; P < 0.001) were found in females but not in males. The genotype explained 2% of the total variance of the BL-38 score and 9.1% of the explained variance. The results partly confirm previous findings of a significant gene-environment interaction of the short allele, indicating a higher mental vulnerability to social stressors and chronic diseases. The relevance of this finding is sustained by the fact that the sample characteristics and the risk structure were highly different from previous studies.",
        "truth": "True"
    },
    {
        "pmid": "19531786",
        "meta_analysis_title": "Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis.",
        "meta_analysis_question": "Does the interaction between the serotonin transporter gene (5-HTTLPR) and stressful life events increase the risk of depression?",
        "criteria": "A search of the PubMed, EMBASE, and PsycINFO databases was conducted through March 2009 using the search terms life stress, life event, depression, depress, serotonin transporter, 5-HTTLPR, interaction, and moderation. Bibliographies of studies were also reviewed. A total of 26 articles published or set for publication were identified through this search strategy (Figure 1). Inclusion criteria for studies for the meta-analyses were published articles that included data on the association between the (1) 5-HTTLPR genotype (S, SL, or LL), (2) number of stressful life events (0, 1, 2, or \u22653) or equivalent, and (3) categorical measure of depression defined by the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) or International Statistical Classification of Diseases, 10th Revision (ICD-10) or ability to use a cut point to define depression from standardized rating scales. To maximize our ability to use a common framework for variable definition, we also requested original data from all studies that appeared to meet inclusion criteria published prior to 2008.10,15-28 We received original data in a usable format for the meta-analysis from 10 of the 14 study investigators. A total of 14 studies were included in the analysis, 15-20,23,25-27,29-32 10 of which15-20,23,25-27,29,30 were also included in a second sex-specific meta-analysis of original data. Nine other studies did not meet inclusion criteria.33-41",
        "subgroup": "Logistic Regression Analyses of Risk of Depression for 14 Studies - Interaction of genotype and stressful life events",
        "key_reference_title": "Social adversity, the serotonin transporter (5-HTTLPR) polymorphism and major depressive disorder.",
        "key_reference_abstract": "## BACKGROUND\nRecent evidence has suggested that the short allele of the serotonin transporter (5-HTT) gene-linked polymorphic region (5-HTTLPR of the human serotonin gene [SLC6A4]) is associated with increased risk of depressive disorder but only among individuals exposed to social adversity. We report an investigation designed to replicate this finding.\n## METHODS\nData were available from a non-clinical sample of 4,175 adult men and women, ages 41-80 years, selected from participants in the European Prospective Investigation into Cancer and Nutrition in Norfolk (EPIC-Norfolk, United Kingdom) study. Evidence of past-year prevalent episodic major depressive disorder (MDD), defined by restricted DSM-IV diagnostic criteria, was assessed through questionnaire. Adverse experiences in childhood and in adulthood (during the five years preceding assessment) were also assessed through self-report. The 5-HTTLPR variant was genotyped according to published protocols.\n## RESULTS\nOne-year prevalent MDD criteria were met by 298 study participants. The experience of social adversity (both in childhood and adulthood) was strongly associated with increased rates of past-year prevalent MDD. No gene by environment (GxE) interactions between the 5-HTTLPR genotype, social adversity, and MDD were observed.\n## CONCLUSIONS\nThis study has not replicated a previous finding of a GxE interaction between the 5-HTTLPR genotype, social adversity, and depression.",
        "truth": "True"
    },
    {
        "pmid": "19531786",
        "meta_analysis_title": "Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis.",
        "meta_analysis_question": "Does the interaction between the serotonin transporter gene (5-HTTLPR) and stressful life events increase the risk of depression?",
        "criteria": "A search of the PubMed, EMBASE, and PsycINFO databases was conducted through March 2009 using the search terms life stress, life event, depression, depress, serotonin transporter, 5-HTTLPR, interaction, and moderation. Bibliographies of studies were also reviewed. A total of 26 articles published or set for publication were identified through this search strategy (Figure 1). Inclusion criteria for studies for the meta-analyses were published articles that included data on the association between the (1) 5-HTTLPR genotype (S, SL, or LL), (2) number of stressful life events (0, 1, 2, or \u22653) or equivalent, and (3) categorical measure of depression defined by the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) or International Statistical Classification of Diseases, 10th Revision (ICD-10) or ability to use a cut point to define depression from standardized rating scales. To maximize our ability to use a common framework for variable definition, we also requested original data from all studies that appeared to meet inclusion criteria published prior to 2008.10,15-28 We received original data in a usable format for the meta-analysis from 10 of the 14 study investigators. A total of 14 studies were included in the analysis, 15-20,23,25-27,29-32 10 of which15-20,23,25-27,29,30 were also included in a second sex-specific meta-analysis of original data. Nine other studies did not meet inclusion criteria.33-41",
        "subgroup": "Logistic Regression Analyses of Risk of Depression for 14 Studies - Interaction of genotype and stressful life events",
        "key_reference_title": "Life events, first depression onset and the serotonin transporter gene.",
        "key_reference_abstract": "## BACKGROUND\nA relationship between the serotonin transporter gene, adverse events and onset of major depression has been reported.\n## AIMS\nTo replicate a gene x environment interaction in a cohort with longitudinal data for life events, experience of depression, parental bonding and neuroticism.\n## METHOD\nAt the 25-year follow-up, genomic DNA was obtained from 127 cohort members (mean age 48 years) to determine the genotype of the serotonin transporter gene-linked promoter region (5-HTTLPR). Associations were investigated between the 5-HTTLPR genotype, positive and adverse life events and the gene x environment interaction, and also between the 5-HTTLPR genotype and risk factors for depression.\n## RESULTS\nNo relationship was found between 5-HTTLPR genotype and either risk factors for depression or positive life events. Adverse life events had a significantly greater impact on the onset of depression for individuals with the s/s genotype.\n## CONCLUSIONS\nThe 5-HTTLPR genotype is a significant predictor of onset of major depression following multiple adverse events. This is one of the more robust findings concerning specific biological risk factors for depression.",
        "truth": "True"
    },
    {
        "pmid": "19531786",
        "meta_analysis_title": "Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis.",
        "meta_analysis_question": "Does the interaction between the serotonin transporter gene (5-HTTLPR) and stressful life events increase the risk of depression?",
        "criteria": "A search of the PubMed, EMBASE, and PsycINFO databases was conducted through March 2009 using the search terms life stress, life event, depression, depress, serotonin transporter, 5-HTTLPR, interaction, and moderation. Bibliographies of studies were also reviewed. A total of 26 articles published or set for publication were identified through this search strategy (Figure 1). Inclusion criteria for studies for the meta-analyses were published articles that included data on the association between the (1) 5-HTTLPR genotype (S, SL, or LL), (2) number of stressful life events (0, 1, 2, or \u22653) or equivalent, and (3) categorical measure of depression defined by the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) or International Statistical Classification of Diseases, 10th Revision (ICD-10) or ability to use a cut point to define depression from standardized rating scales. To maximize our ability to use a common framework for variable definition, we also requested original data from all studies that appeared to meet inclusion criteria published prior to 2008.10,15-28 We received original data in a usable format for the meta-analysis from 10 of the 14 study investigators. A total of 14 studies were included in the analysis, 15-20,23,25-27,29-32 10 of which15-20,23,25-27,29,30 were also included in a second sex-specific meta-analysis of original data. Nine other studies did not meet inclusion criteria.33-41",
        "subgroup": "Logistic Regression Analyses of Risk of Depression for 14 Studies - Interaction of genotype and stressful life events",
        "key_reference_title": "Early family environment, current adversity, the serotonin transporter promoter polymorphism, and depressive symptomatology.",
        "key_reference_abstract": "## BACKGROUND\nMixed evidence has suggested that homozygous carriers of the short allele (s/s) of the serotonin transporter gene-linked polymorphic region (5-HTTLPR) may be at increased risk for depression, if they have also been exposed to early or current adversity/stress. We address this debate by examining the relation of a stressful early family environment, recent adversity/stress, and the 5-HTTLPR to depressive symptomatology in a normal sample.\n## METHODS\nA nonclinical sample of 118 young adult men and women completed assessments of early family environment, recent stressful events, psychosocial resources, and psychological distress, including depressive symptomatology. The 5-HTTLPR was genotyped using a standard protocol with DNA extracted from oral fluid.\n## RESULTS\nA stressful early family environment was significantly related to depressive symptomatology. In addition, gene-by-environment (GxE) interactions were observed between the 5-HTTLPR and both early family environment and current adversity/stress. Individuals homozygous for the short allele had greater depressive symptomatology if they had experienced early or recent adversity but significantly less depressive symptomatology if they reported a supportive early environment or recent positive experiences, compared with participants with the s/l or l/l genotype.\n## CONCLUSIONS\nEarly or current environment, in conjunction with the serotonin transporter polymorphism, predicts depressive symptomatology.",
        "truth": "False"
    },
    {
        "pmid": "19531786",
        "meta_analysis_title": "Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis.",
        "meta_analysis_question": "Does the interaction between the serotonin transporter gene (5-HTTLPR) and stressful life events increase the risk of depression?",
        "criteria": "A search of the PubMed, EMBASE, and PsycINFO databases was conducted through March 2009 using the search terms life stress, life event, depression, depress, serotonin transporter, 5-HTTLPR, interaction, and moderation. Bibliographies of studies were also reviewed. A total of 26 articles published or set for publication were identified through this search strategy (Figure 1). Inclusion criteria for studies for the meta-analyses were published articles that included data on the association between the (1) 5-HTTLPR genotype (S, SL, or LL), (2) number of stressful life events (0, 1, 2, or \u22653) or equivalent, and (3) categorical measure of depression defined by the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) or International Statistical Classification of Diseases, 10th Revision (ICD-10) or ability to use a cut point to define depression from standardized rating scales. To maximize our ability to use a common framework for variable definition, we also requested original data from all studies that appeared to meet inclusion criteria published prior to 2008.10,15-28 We received original data in a usable format for the meta-analysis from 10 of the 14 study investigators. A total of 14 studies were included in the analysis, 15-20,23,25-27,29-32 10 of which15-20,23,25-27,29,30 were also included in a second sex-specific meta-analysis of original data. Nine other studies did not meet inclusion criteria.33-41",
        "subgroup": "Logistic Regression Analyses of Risk of Depression for 14 Studies - Interaction of genotype and stressful life events",
        "key_reference_title": "Relationship of 5-HTTLPR genotypes and depression risk in the presence of trauma in a female twin sample.",
        "key_reference_abstract": "Several studies have implicated an insertion/deletion polymorphism in the promoter region of the serotonin transporter gene (SLC6A4; 5-HTT) in the development of mood disorders. In the present study of a sample of 247 young adult female twins from Missouri, we examine whether this polymorphism interacts with the effect of adverse life events to increase risk for developing depression. We found a significant interaction between the number of high-activity L(A) alleles and exposure to trauma (OR = 1.70, P < 0.0001). This differs from previous reports, in that the higher activity genotypes (L(A)/L(A), L(A)/S, L(A)/L(G)), rather than the low activity genotypes (S/S, S/L(G), L(G)/L(G)), are associated with an increased incidence of major depressive disease (MDD) in the presence of environmental trauma.",
        "truth": "True"
    },
    {
        "pmid": "19531786",
        "meta_analysis_title": "Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis.",
        "meta_analysis_question": "Does the interaction between the serotonin transporter gene (5-HTTLPR) and stressful life events increase the risk of depression?",
        "criteria": "A search of the PubMed, EMBASE, and PsycINFO databases was conducted through March 2009 using the search terms life stress, life event, depression, depress, serotonin transporter, 5-HTTLPR, interaction, and moderation. Bibliographies of studies were also reviewed. A total of 26 articles published or set for publication were identified through this search strategy (Figure 1). Inclusion criteria for studies for the meta-analyses were published articles that included data on the association between the (1) 5-HTTLPR genotype (S, SL, or LL), (2) number of stressful life events (0, 1, 2, or \u22653) or equivalent, and (3) categorical measure of depression defined by the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) or International Statistical Classification of Diseases, 10th Revision (ICD-10) or ability to use a cut point to define depression from standardized rating scales. To maximize our ability to use a common framework for variable definition, we also requested original data from all studies that appeared to meet inclusion criteria published prior to 2008.10,15-28 We received original data in a usable format for the meta-analysis from 10 of the 14 study investigators. A total of 14 studies were included in the analysis, 15-20,23,25-27,29-32 10 of which15-20,23,25-27,29,30 were also included in a second sex-specific meta-analysis of original data. Nine other studies did not meet inclusion criteria.33-41",
        "subgroup": "Logistic Regression Analyses of Risk of Depression for 14 Studies - Interaction of genotype and stressful life events",
        "key_reference_title": "Family based association analyses between the serotonin transporter gene polymorphism (5-HTTLPR) and neuroticism, anxiety and depression.",
        "key_reference_abstract": "We studied the association between the short/long promotor-based length polymorphism of the serotonin transporter gene (5-HTTLPR) and neuroticism, anxiety and depression. Subjects included twins, their siblings and parents from the Netherlands Twin Register (559 parents and 1,245 offspring). Subjects had participated between one and five times in a survey study measuring neuroticism, anxiety and depression. Offspring of these families were also approached to participate in a psychiatric interview diagnosing DSM-IV major depression. Within-family and total association between 5-HTTLPR and these traits were tested. Only three of the 36 tests showed a significant effect of 5-HTTLPR (P<0.05). These effects were in opposite directions, i.e. both negative and positive regression coefficients were found for the s allele. No additive effect of the s allele was found for DSM-IV depression. Our results strongly suggest that there is no straightforward association between 5-HTTLPR and neuroticism, anxiety and depression.",
        "truth": "True"
    },
    {
        "pmid": "19531786",
        "meta_analysis_title": "Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis.",
        "meta_analysis_question": "Does the interaction between the serotonin transporter gene (5-HTTLPR) and stressful life events increase the risk of depression?",
        "criteria": "A search of the PubMed, EMBASE, and PsycINFO databases was conducted through March 2009 using the search terms life stress, life event, depression, depress, serotonin transporter, 5-HTTLPR, interaction, and moderation. Bibliographies of studies were also reviewed. A total of 26 articles published or set for publication were identified through this search strategy (Figure 1). Inclusion criteria for studies for the meta-analyses were published articles that included data on the association between the (1) 5-HTTLPR genotype (S, SL, or LL), (2) number of stressful life events (0, 1, 2, or \u22653) or equivalent, and (3) categorical measure of depression defined by the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) or International Statistical Classification of Diseases, 10th Revision (ICD-10) or ability to use a cut point to define depression from standardized rating scales. To maximize our ability to use a common framework for variable definition, we also requested original data from all studies that appeared to meet inclusion criteria published prior to 2008.10,15-28 We received original data in a usable format for the meta-analysis from 10 of the 14 study investigators. A total of 14 studies were included in the analysis, 15-20,23,25-27,29-32 10 of which15-20,23,25-27,29,30 were also included in a second sex-specific meta-analysis of original data. Nine other studies did not meet inclusion criteria.33-41",
        "subgroup": "Logistic Regression Analyses of Risk of Depression for 14 Studies - Interaction of genotype and stressful life events",
        "key_reference_title": "No interaction between the serotonin transporter polymorphism (5-HTTLPR) and childhood adversity or recent stressful life events on symptoms of depression: results from two community surveys.",
        "key_reference_abstract": "In this study we investigated interactions between the 5-HTTLPR genotype and environmental risk factors (G x E) on symptoms of depression in two large Australian community samples of adolescents and young adults. We postulated that a significant interaction between the 5-HTTLPR genotype and environmental risk factors of childhood adversity or stressful life events on symptoms of depression would be observed in subjects with at least one short allele (s/l or s/s) compared with subjects with no short alleles (l/l). We did not find significant G x E interactions between the 5-HTTLPR genotype and recent stressful life events or childhood adversity on symptoms of depression in our sample populations. However, we did find adolescents aged 17-18 years homozygous for the long allele (l/l) and exposed to persistently high levels of family adversity over a 6-year period were at a greater risk of depression than subjects with the same genotype exposed to no or persistently low levels of family adversity. This interaction should be interpreted cautiously due to the small number of depressed subjects in the sample with persistently high levels of family adversity.",
        "truth": "True"
    },
    {
        "pmid": "19531786",
        "meta_analysis_title": "Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis.",
        "meta_analysis_question": "Does the interaction between the serotonin transporter gene (5-HTTLPR) and stressful life events increase the risk of depression?",
        "criteria": "A search of the PubMed, EMBASE, and PsycINFO databases was conducted through March 2009 using the search terms life stress, life event, depression, depress, serotonin transporter, 5-HTTLPR, interaction, and moderation. Bibliographies of studies were also reviewed. A total of 26 articles published or set for publication were identified through this search strategy (Figure 1). Inclusion criteria for studies for the meta-analyses were published articles that included data on the association between the (1) 5-HTTLPR genotype (S, SL, or LL), (2) number of stressful life events (0, 1, 2, or \u22653) or equivalent, and (3) categorical measure of depression defined by the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) or International Statistical Classification of Diseases, 10th Revision (ICD-10) or ability to use a cut point to define depression from standardized rating scales. To maximize our ability to use a common framework for variable definition, we also requested original data from all studies that appeared to meet inclusion criteria published prior to 2008.10,15-28 We received original data in a usable format for the meta-analysis from 10 of the 14 study investigators. A total of 14 studies were included in the analysis, 15-20,23,25-27,29-32 10 of which15-20,23,25-27,29,30 were also included in a second sex-specific meta-analysis of original data. Nine other studies did not meet inclusion criteria.33-41",
        "subgroup": "Logistic Regression Analyses of Risk of Depression for 14 Studies - Interaction of genotype and stressful life events",
        "key_reference_title": "The risk for depression conferred by stressful life events is modified by variation at the serotonin transporter 5HTTLPR genotype: evidence from the Spanish PREDICT-Gene cohort.",
        "key_reference_abstract": "We report results from the PREDICT-Gene case-control study nested in a prospective cohort designed to identify predictors of the onset of depression among adult primary-care attendees. We tested the potential gene-by-environment interaction between 5HTTLPR genotype at the serotonin transporter gene and previous exposure to threatening life events (TLEs) in depression. A total of 737 consecutively recruited participants were genotyped. Additional information was gathered on exposure to TLEs over a 6-month period, socio-demographic data and family history of psychological problems among first-degree relatives. Diagnoses of depression were ascertained using the Composite International Diagnostic Interview (CIDI) by trained interviewers. Two different depressive outcomes were used (ICD-10 depressive episode and ICD-10 severe depressive episode). Both the s/s genotype and exposure to increasing number of TLEs were significantly associated with depression. Moreover, the 5HTTLPR s/s genotype significantly modified the risk conferred by TLEs for both depressive outcomes. Thus, s/s homozygous participants required minimal exposure to TLE (1 TLE) to acquire a level of risk for depression that was only found among l/s or l/l individuals after significantly higher exposure to TLEs (two or more TLEs). The interaction was more apparent when applied to the diagnosis of ICD-10 severe depressive episode and after adjusting for gender, age and family history of psychological problems. Likelihood ratios tests for the interaction were statistically significant for both depressive outcomes (ICD-10 depressive episode: LR X(2)=4.7, P=0.09 (crude), LR-X(2)=6.4, P=0.04 (adjusted); ICD-10 severe depressive episode: LR X(2)=6.9, P=0.032 (crude), LR-X(2)=8.1, P=0.017 (adjusted)).",
        "truth": "False"
    },
    {
        "pmid": "19531786",
        "meta_analysis_title": "Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis.",
        "meta_analysis_question": "Does the interaction between the serotonin transporter gene (5-HTTLPR) and stressful life events increase the risk of depression?",
        "criteria": "A search of the PubMed, EMBASE, and PsycINFO databases was conducted through March 2009 using the search terms life stress, life event, depression, depress, serotonin transporter, 5-HTTLPR, interaction, and moderation. Bibliographies of studies were also reviewed. A total of 26 articles published or set for publication were identified through this search strategy (Figure 1). Inclusion criteria for studies for the meta-analyses were published articles that included data on the association between the (1) 5-HTTLPR genotype (S, SL, or LL), (2) number of stressful life events (0, 1, 2, or \u22653) or equivalent, and (3) categorical measure of depression defined by the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) or International Statistical Classification of Diseases, 10th Revision (ICD-10) or ability to use a cut point to define depression from standardized rating scales. To maximize our ability to use a common framework for variable definition, we also requested original data from all studies that appeared to meet inclusion criteria published prior to 2008.10,15-28 We received original data in a usable format for the meta-analysis from 10 of the 14 study investigators. A total of 14 studies were included in the analysis, 15-20,23,25-27,29-32 10 of which15-20,23,25-27,29,30 were also included in a second sex-specific meta-analysis of original data. Nine other studies did not meet inclusion criteria.33-41",
        "subgroup": "Logistic Regression Analyses of Risk of Depression for 14 Studies - Interaction of genotype and stressful life events",
        "key_reference_title": "Interactions between life stressors and susceptibility genes (5-HTTLPR and BDNF) on depression in Korean elders.",
        "key_reference_abstract": "## BACKGROUND\nIt has been reported that the functional polymorphism in the serotonin transporter gene linked promoter region (5-HTTLPR) modifies the association between stressful life events (SLEs) and depression in child, adolescent, and adult populations. We sought to replicate this finding in elders and, additionally, to test modifying effects of the brain-derived neurotrophic factor (BDNF) val66met polymorphism.\n## METHODS\nIn 732 Korean community residents ages 65+, diagnosis of depression (Geriatric Mental State Schedule), information on SLEs, and genotypes for 5-HTTLPR and BDNF val66met were ascertained. Of those without depression at baseline, 521 (88%) were followed up 2.5 years later. Interactions between SLEs and the two genotypes were investigated for both prevalent depression at baseline and incident depression at follow-up.\n## RESULTS\nSignificant interactions of SLEs with both 5-HTTLPR and BDNF genotypes were observed on risk of depression after adjustment for age, gender, education, and disability. A significant three-way interaction between 5-HTTLPR, BDNF, and SLEs was also found. The same findings were observed for predictors of incident depression in the prospective analysis.\n## CONCLUSIONS\nThese findings suggest that environmental risk of depression is modified by at least two genes and that gene-environment interactions are found even into old age.",
        "truth": "True"
    },
    {
        "pmid": "19531786",
        "meta_analysis_title": "Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis.",
        "meta_analysis_question": "Does the interaction between the serotonin transporter gene (5-HTTLPR) and stressful life events increase the risk of depression?",
        "criteria": "A search of the PubMed, EMBASE, and PsycINFO databases was conducted through March 2009 using the search terms life stress, life event, depression, depress, serotonin transporter, 5-HTTLPR, interaction, and moderation. Bibliographies of studies were also reviewed. A total of 26 articles published or set for publication were identified through this search strategy (Figure 1). Inclusion criteria for studies for the meta-analyses were published articles that included data on the association between the (1) 5-HTTLPR genotype (S, SL, or LL), (2) number of stressful life events (0, 1, 2, or \u22653) or equivalent, and (3) categorical measure of depression defined by the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) or International Statistical Classification of Diseases, 10th Revision (ICD-10) or ability to use a cut point to define depression from standardized rating scales. To maximize our ability to use a common framework for variable definition, we also requested original data from all studies that appeared to meet inclusion criteria published prior to 2008.10,15-28 We received original data in a usable format for the meta-analysis from 10 of the 14 study investigators. A total of 14 studies were included in the analysis, 15-20,23,25-27,29-32 10 of which15-20,23,25-27,29,30 were also included in a second sex-specific meta-analysis of original data. Nine other studies did not meet inclusion criteria.33-41",
        "subgroup": "Logistic Regression Analyses of Risk of Depression for 14 Studies - Interaction of genotype and stressful life events",
        "key_reference_title": "5-HTTLPR genotype, stressful life events and late-life depression: no evidence of interaction in a French population.",
        "key_reference_abstract": "Modification of the effect of life events on risk of depression by a polymorphism in the serotonin transporter gene promoter (5-HTTLPR) has been reported in child, adolescent, adult and elderly populations. Replication attempted on data collected from 1421 individuals aged 65 and over from a French community study provided no evidence of a similar modifying effect. In the only analysis known to the authors to be carried out in an exclusively elderly, European population, this null finding remained consistent after restriction of analysis to prevalent or incident cases.",
        "truth": "True"
    },
    {
        "pmid": "19531786",
        "meta_analysis_title": "Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis.",
        "meta_analysis_question": "Does the interaction between the serotonin transporter gene (5-HTTLPR) and stressful life events increase the risk of depression?",
        "criteria": "A search of the PubMed, EMBASE, and PsycINFO databases was conducted through March 2009 using the search terms life stress, life event, depression, depress, serotonin transporter, 5-HTTLPR, interaction, and moderation. Bibliographies of studies were also reviewed. A total of 26 articles published or set for publication were identified through this search strategy (Figure 1). Inclusion criteria for studies for the meta-analyses were published articles that included data on the association between the (1) 5-HTTLPR genotype (S, SL, or LL), (2) number of stressful life events (0, 1, 2, or \u22653) or equivalent, and (3) categorical measure of depression defined by the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) or International Statistical Classification of Diseases, 10th Revision (ICD-10) or ability to use a cut point to define depression from standardized rating scales. To maximize our ability to use a common framework for variable definition, we also requested original data from all studies that appeared to meet inclusion criteria published prior to 2008.10,15-28 We received original data in a usable format for the meta-analysis from 10 of the 14 study investigators. A total of 14 studies were included in the analysis, 15-20,23,25-27,29-32 10 of which15-20,23,25-27,29,30 were also included in a second sex-specific meta-analysis of original data. Nine other studies did not meet inclusion criteria.33-41",
        "subgroup": "Logistic Regression Analyses of Risk of Depression for 14 Studies - Interaction of genotype and stressful life events",
        "key_reference_title": "Interaction between the 5-HTTLPR serotonin transporter polymorphism and environmental adversity for mood and anxiety psychopathology: evidence from a high-risk community sample of young adults.",
        "key_reference_abstract": "Previous research examining gene-environment interaction (GxE) with regard to vulnerability to depression and anxiety has yielded conflicting results. The present study was designed to further investigate GxE between 5-HTTLPR and exposure to environmental adversity, using different phenotypic and genotypic characterizations as well as different types of adversity within a prospective study design. Data were available from an ongoing epidemiological cohort study following the outcome of early risk factors from birth to adulthood. At age 19 yr, 309 participants (142 males, 167 females) were characterized on measures of depression and anxiety through interview and questionnaire (DSM-IV diagnosis, Beck Depression Inventory, Harm Avoidance). Environmental adversity was assessed at birth (family adversity), and at age 19 yr (stressful life events). Bi- and tri-allelic 5-HTTLPR genotypes were obtained from genomic DNA. Results indicated that depression and anxiety in 19-yr-olds were strongly associated with both family adversity and stressful life events. Individuals with the LL genotype of 5-HTTLPR who were exposed to high family adversity displayed significantly higher rates of depressive or anxiety disorders and had more depressive symptoms than those without either condition. This GxE replicates recent findings from an epidemiological cohort study of adolescents but is in contrast to many previous reports suggesting an interaction with the S allele. No evidence for GxE was obtained with regard to current stressful life events and trait anxiety. One possible source for the conflicting findings might be attributed to heterogeneity in depression phenotypes and environmental adversity.",
        "truth": "True"
    },
    {
        "pmid": "19531786",
        "meta_analysis_title": "Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis.",
        "meta_analysis_question": "Does the interaction between the serotonin transporter gene (5-HTTLPR) and stressful life events increase the risk of depression?",
        "criteria": "A search of the PubMed, EMBASE, and PsycINFO databases was conducted through March 2009 using the search terms life stress, life event, depression, depress, serotonin transporter, 5-HTTLPR, interaction, and moderation. Bibliographies of studies were also reviewed. A total of 26 articles published or set for publication were identified through this search strategy (Figure 1). Inclusion criteria for studies for the meta-analyses were published articles that included data on the association between the (1) 5-HTTLPR genotype (S, SL, or LL), (2) number of stressful life events (0, 1, 2, or \u22653) or equivalent, and (3) categorical measure of depression defined by the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) or International Statistical Classification of Diseases, 10th Revision (ICD-10) or ability to use a cut point to define depression from standardized rating scales. To maximize our ability to use a common framework for variable definition, we also requested original data from all studies that appeared to meet inclusion criteria published prior to 2008.10,15-28 We received original data in a usable format for the meta-analysis from 10 of the 14 study investigators. A total of 14 studies were included in the analysis, 15-20,23,25-27,29-32 10 of which15-20,23,25-27,29,30 were also included in a second sex-specific meta-analysis of original data. Nine other studies did not meet inclusion criteria.33-41",
        "subgroup": "Logistic Regression Analyses of Depression for 10 Studies Stratified by Sex - Risk per S allele",
        "key_reference_title": "Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene.",
        "key_reference_abstract": "In a prospective-longitudinal study of a representative birth cohort, we tested why stressful experiences lead to depression in some people but not in others. A functional polymorphism in the promoter region of the serotonin transporter (5-HT T) gene was found to moderate the influence of stressful life events on depression. Individuals with one or two copies of the short allele of the 5-HT T promoter polymorphism exhibited more depressive symptoms, diagnosable depression, and suicidality in relation to stressful life events than individuals homozygous for the long allele. This epidemiological study thus provides evidence of a gene-by-environment interaction, in which an individual's response to environmental insults is moderated by his or her genetic makeup.",
        "truth": "False"
    },
    {
        "pmid": "19531786",
        "meta_analysis_title": "Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis.",
        "meta_analysis_question": "Does the interaction between the serotonin transporter gene (5-HTTLPR) and stressful life events increase the risk of depression?",
        "criteria": "A search of the PubMed, EMBASE, and PsycINFO databases was conducted through March 2009 using the search terms life stress, life event, depression, depress, serotonin transporter, 5-HTTLPR, interaction, and moderation. Bibliographies of studies were also reviewed. A total of 26 articles published or set for publication were identified through this search strategy (Figure 1). Inclusion criteria for studies for the meta-analyses were published articles that included data on the association between the (1) 5-HTTLPR genotype (S, SL, or LL), (2) number of stressful life events (0, 1, 2, or \u22653) or equivalent, and (3) categorical measure of depression defined by the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) or International Statistical Classification of Diseases, 10th Revision (ICD-10) or ability to use a cut point to define depression from standardized rating scales. To maximize our ability to use a common framework for variable definition, we also requested original data from all studies that appeared to meet inclusion criteria published prior to 2008.10,15-28 We received original data in a usable format for the meta-analysis from 10 of the 14 study investigators. A total of 14 studies were included in the analysis, 15-20,23,25-27,29-32 10 of which15-20,23,25-27,29,30 were also included in a second sex-specific meta-analysis of original data. Nine other studies did not meet inclusion criteria.33-41",
        "subgroup": "Logistic Regression Analyses of Depression for 10 Studies Stratified by Sex - Risk per S allele",
        "key_reference_title": "Gene-environment interaction analysis of serotonin system markers with adolescent depression.",
        "key_reference_abstract": "We report analyses from a study of gene-environment interaction in adolescent depression. The sample was selected from 1990 adolescents aged 10-20 years: those with depression symptoms in the top or bottom 15% were identified and divided into high or low environmental risk groups. DNA was obtained from 377 adolescents, representing the four quadrants of high or low depression and high or low environmental risk. Markers within, or close to, each of the serotonergic genes 5HTT, HTR2A, HTR2C, MAOA (monoamine oxidase type A) and tryptophan hydroxylase (TPH) were genotyped. Environmental risk group was a nonsignificant predictor and sex was a significant predictor of the depression group. HTR2A and TPH significantly predicted the depression group, independent of the effects of sex, environmental risk group and their interaction. In addition, there was a trend for an effect of 5HTTLPR, which was significant in female subjects. Furthermore, there was a significant genotype-environmental risk interaction for 5HTTLPR in female subjects only, with the effect being in the same direction as another recent study, reaffirming that an important source of genetic heterogeneity is exposure to environmental risk.",
        "truth": "True"
    },
    {
        "pmid": "19531786",
        "meta_analysis_title": "Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis.",
        "meta_analysis_question": "Does the interaction between the serotonin transporter gene (5-HTTLPR) and stressful life events increase the risk of depression?",
        "criteria": "A search of the PubMed, EMBASE, and PsycINFO databases was conducted through March 2009 using the search terms life stress, life event, depression, depress, serotonin transporter, 5-HTTLPR, interaction, and moderation. Bibliographies of studies were also reviewed. A total of 26 articles published or set for publication were identified through this search strategy (Figure 1). Inclusion criteria for studies for the meta-analyses were published articles that included data on the association between the (1) 5-HTTLPR genotype (S, SL, or LL), (2) number of stressful life events (0, 1, 2, or \u22653) or equivalent, and (3) categorical measure of depression defined by the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) or International Statistical Classification of Diseases, 10th Revision (ICD-10) or ability to use a cut point to define depression from standardized rating scales. To maximize our ability to use a common framework for variable definition, we also requested original data from all studies that appeared to meet inclusion criteria published prior to 2008.10,15-28 We received original data in a usable format for the meta-analysis from 10 of the 14 study investigators. A total of 14 studies were included in the analysis, 15-20,23,25-27,29-32 10 of which15-20,23,25-27,29,30 were also included in a second sex-specific meta-analysis of original data. Nine other studies did not meet inclusion criteria.33-41",
        "subgroup": "Logistic Regression Analyses of Depression for 10 Studies Stratified by Sex - Risk per S allele",
        "key_reference_title": "The relationship between stressful life events, the serotonin transporter (5-HTTLPR) genotype and major depression.",
        "key_reference_abstract": "## BACKGROUND\nSerotonin is a good candidate for major depression. We attempted to replicate the study by Caspi and colleagues [Science (2003) 301, 386-389] which reported a significant interaction between serotonin transporter (5-HTTLPR) genotype and stressful life events when predicting major depression.\n## METHOD\nWe typed the serotonin promoter 5-HTTLPR gene in 1206 male and female twins aged 19-78 years (mean = 39, S.D. = 11). A DSM-IV diagnosis of major depression was available for 1199 twins. Most of these twins had participated in a 1988-1990 study which included a stressful life events inventory and self-report measure of depression based on the SCL-90 and DSSI/sAD. Complete 5-HTT genotype and life events data, self-report symptoms and major depression diagnoses were available for 1091 subjects. We regressed categorical and ordinal measures of depression onto stressful life events and genotype.\n## RESULTS\nThere were significant main effects for stressful life events but there was no evidence for any effect of 5-HTT genotype, nor a genotype x stressful life event interaction.\n## CONCLUSIONS\nRegardless of whether our results were based on binary logistic or ordinal regression analyses we found no evidence to support a main effect of 5-HTTLPR, or an interaction between the 5-HTTLPR genotype and stressful life events on major depression, Only 20 % of our subjects were aged below 30 years. It is possible that the effect reported by Caspi and colleagues is specific to young people, in which case our study has much less power in this age group.",
        "truth": "True"
    },
    {
        "pmid": "19531786",
        "meta_analysis_title": "Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis.",
        "meta_analysis_question": "Does the interaction between the serotonin transporter gene (5-HTTLPR) and stressful life events increase the risk of depression?",
        "criteria": "A search of the PubMed, EMBASE, and PsycINFO databases was conducted through March 2009 using the search terms life stress, life event, depression, depress, serotonin transporter, 5-HTTLPR, interaction, and moderation. Bibliographies of studies were also reviewed. A total of 26 articles published or set for publication were identified through this search strategy (Figure 1). Inclusion criteria for studies for the meta-analyses were published articles that included data on the association between the (1) 5-HTTLPR genotype (S, SL, or LL), (2) number of stressful life events (0, 1, 2, or \u22653) or equivalent, and (3) categorical measure of depression defined by the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) or International Statistical Classification of Diseases, 10th Revision (ICD-10) or ability to use a cut point to define depression from standardized rating scales. To maximize our ability to use a common framework for variable definition, we also requested original data from all studies that appeared to meet inclusion criteria published prior to 2008.10,15-28 We received original data in a usable format for the meta-analysis from 10 of the 14 study investigators. A total of 14 studies were included in the analysis, 15-20,23,25-27,29-32 10 of which15-20,23,25-27,29,30 were also included in a second sex-specific meta-analysis of original data. Nine other studies did not meet inclusion criteria.33-41",
        "subgroup": "Logistic Regression Analyses of Depression for 10 Studies Stratified by Sex - Risk per S allele",
        "key_reference_title": "Mental and physical distress is modulated by a polymorphism in the 5-HT transporter gene interacting with social stressors and chronic disease burden.",
        "key_reference_abstract": "Previous studies have yielded conflicting results as to the putative role of the functional polymorphism of the promoter region of the serotonin transporter gene (SLC6A4) in the etiology of anxiety-related traits and depressive disorders. Recently, a significant gene-environment interaction was found between life stressors, the short allele of the SLC6A4 polymorphism and depression. The aim of the present study was to investigate if such a gene-environment interaction could be replicated within a different population with a different risk structure. A total of 1005 subjects from a general population sample (Study of Health in Pomerania) were genotyped. Mental and physical distress were assessed on 38 items of the modified complaint scale (BL-38). The interaction between the SLC6A4 genotype, social stressors and chronic diseases with regard to the BL-38 score was evaluated by ANOVA. There was no independent association of genotype with mental and physical distress. However, significant interactions between genotype, unemployment and chronic diseases (F = 6.6; df = 3, 671; P < 0.001) were found in females but not in males. The genotype explained 2% of the total variance of the BL-38 score and 9.1% of the explained variance. The results partly confirm previous findings of a significant gene-environment interaction of the short allele, indicating a higher mental vulnerability to social stressors and chronic diseases. The relevance of this finding is sustained by the fact that the sample characteristics and the risk structure were highly different from previous studies.",
        "truth": "True"
    },
    {
        "pmid": "19531786",
        "meta_analysis_title": "Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis.",
        "meta_analysis_question": "Does the interaction between the serotonin transporter gene (5-HTTLPR) and stressful life events increase the risk of depression?",
        "criteria": "A search of the PubMed, EMBASE, and PsycINFO databases was conducted through March 2009 using the search terms life stress, life event, depression, depress, serotonin transporter, 5-HTTLPR, interaction, and moderation. Bibliographies of studies were also reviewed. A total of 26 articles published or set for publication were identified through this search strategy (Figure 1). Inclusion criteria for studies for the meta-analyses were published articles that included data on the association between the (1) 5-HTTLPR genotype (S, SL, or LL), (2) number of stressful life events (0, 1, 2, or \u22653) or equivalent, and (3) categorical measure of depression defined by the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) or International Statistical Classification of Diseases, 10th Revision (ICD-10) or ability to use a cut point to define depression from standardized rating scales. To maximize our ability to use a common framework for variable definition, we also requested original data from all studies that appeared to meet inclusion criteria published prior to 2008.10,15-28 We received original data in a usable format for the meta-analysis from 10 of the 14 study investigators. A total of 14 studies were included in the analysis, 15-20,23,25-27,29-32 10 of which15-20,23,25-27,29,30 were also included in a second sex-specific meta-analysis of original data. Nine other studies did not meet inclusion criteria.33-41",
        "subgroup": "Logistic Regression Analyses of Depression for 10 Studies Stratified by Sex - Risk per S allele",
        "key_reference_title": "Social adversity, the serotonin transporter (5-HTTLPR) polymorphism and major depressive disorder.",
        "key_reference_abstract": "## BACKGROUND\nRecent evidence has suggested that the short allele of the serotonin transporter (5-HTT) gene-linked polymorphic region (5-HTTLPR of the human serotonin gene [SLC6A4]) is associated with increased risk of depressive disorder but only among individuals exposed to social adversity. We report an investigation designed to replicate this finding.\n## METHODS\nData were available from a non-clinical sample of 4,175 adult men and women, ages 41-80 years, selected from participants in the European Prospective Investigation into Cancer and Nutrition in Norfolk (EPIC-Norfolk, United Kingdom) study. Evidence of past-year prevalent episodic major depressive disorder (MDD), defined by restricted DSM-IV diagnostic criteria, was assessed through questionnaire. Adverse experiences in childhood and in adulthood (during the five years preceding assessment) were also assessed through self-report. The 5-HTTLPR variant was genotyped according to published protocols.\n## RESULTS\nOne-year prevalent MDD criteria were met by 298 study participants. The experience of social adversity (both in childhood and adulthood) was strongly associated with increased rates of past-year prevalent MDD. No gene by environment (GxE) interactions between the 5-HTTLPR genotype, social adversity, and MDD were observed.\n## CONCLUSIONS\nThis study has not replicated a previous finding of a GxE interaction between the 5-HTTLPR genotype, social adversity, and depression.",
        "truth": "True"
    },
    {
        "pmid": "19531786",
        "meta_analysis_title": "Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis.",
        "meta_analysis_question": "Does the interaction between the serotonin transporter gene (5-HTTLPR) and stressful life events increase the risk of depression?",
        "criteria": "A search of the PubMed, EMBASE, and PsycINFO databases was conducted through March 2009 using the search terms life stress, life event, depression, depress, serotonin transporter, 5-HTTLPR, interaction, and moderation. Bibliographies of studies were also reviewed. A total of 26 articles published or set for publication were identified through this search strategy (Figure 1). Inclusion criteria for studies for the meta-analyses were published articles that included data on the association between the (1) 5-HTTLPR genotype (S, SL, or LL), (2) number of stressful life events (0, 1, 2, or \u22653) or equivalent, and (3) categorical measure of depression defined by the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) or International Statistical Classification of Diseases, 10th Revision (ICD-10) or ability to use a cut point to define depression from standardized rating scales. To maximize our ability to use a common framework for variable definition, we also requested original data from all studies that appeared to meet inclusion criteria published prior to 2008.10,15-28 We received original data in a usable format for the meta-analysis from 10 of the 14 study investigators. A total of 14 studies were included in the analysis, 15-20,23,25-27,29-32 10 of which15-20,23,25-27,29,30 were also included in a second sex-specific meta-analysis of original data. Nine other studies did not meet inclusion criteria.33-41",
        "subgroup": "Logistic Regression Analyses of Depression for 10 Studies Stratified by Sex - Risk per S allele",
        "key_reference_title": "Life events, first depression onset and the serotonin transporter gene.",
        "key_reference_abstract": "## BACKGROUND\nA relationship between the serotonin transporter gene, adverse events and onset of major depression has been reported.\n## AIMS\nTo replicate a gene x environment interaction in a cohort with longitudinal data for life events, experience of depression, parental bonding and neuroticism.\n## METHOD\nAt the 25-year follow-up, genomic DNA was obtained from 127 cohort members (mean age 48 years) to determine the genotype of the serotonin transporter gene-linked promoter region (5-HTTLPR). Associations were investigated between the 5-HTTLPR genotype, positive and adverse life events and the gene x environment interaction, and also between the 5-HTTLPR genotype and risk factors for depression.\n## RESULTS\nNo relationship was found between 5-HTTLPR genotype and either risk factors for depression or positive life events. Adverse life events had a significantly greater impact on the onset of depression for individuals with the s/s genotype.\n## CONCLUSIONS\nThe 5-HTTLPR genotype is a significant predictor of onset of major depression following multiple adverse events. This is one of the more robust findings concerning specific biological risk factors for depression.",
        "truth": "True"
    },
    {
        "pmid": "19531786",
        "meta_analysis_title": "Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis.",
        "meta_analysis_question": "Does the interaction between the serotonin transporter gene (5-HTTLPR) and stressful life events increase the risk of depression?",
        "criteria": "A search of the PubMed, EMBASE, and PsycINFO databases was conducted through March 2009 using the search terms life stress, life event, depression, depress, serotonin transporter, 5-HTTLPR, interaction, and moderation. Bibliographies of studies were also reviewed. A total of 26 articles published or set for publication were identified through this search strategy (Figure 1). Inclusion criteria for studies for the meta-analyses were published articles that included data on the association between the (1) 5-HTTLPR genotype (S, SL, or LL), (2) number of stressful life events (0, 1, 2, or \u22653) or equivalent, and (3) categorical measure of depression defined by the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) or International Statistical Classification of Diseases, 10th Revision (ICD-10) or ability to use a cut point to define depression from standardized rating scales. To maximize our ability to use a common framework for variable definition, we also requested original data from all studies that appeared to meet inclusion criteria published prior to 2008.10,15-28 We received original data in a usable format for the meta-analysis from 10 of the 14 study investigators. A total of 14 studies were included in the analysis, 15-20,23,25-27,29-32 10 of which15-20,23,25-27,29,30 were also included in a second sex-specific meta-analysis of original data. Nine other studies did not meet inclusion criteria.33-41",
        "subgroup": "Logistic Regression Analyses of Depression for 10 Studies Stratified by Sex - Risk per S allele",
        "key_reference_title": "Early family environment, current adversity, the serotonin transporter promoter polymorphism, and depressive symptomatology.",
        "key_reference_abstract": "## BACKGROUND\nMixed evidence has suggested that homozygous carriers of the short allele (s/s) of the serotonin transporter gene-linked polymorphic region (5-HTTLPR) may be at increased risk for depression, if they have also been exposed to early or current adversity/stress. We address this debate by examining the relation of a stressful early family environment, recent adversity/stress, and the 5-HTTLPR to depressive symptomatology in a normal sample.\n## METHODS\nA nonclinical sample of 118 young adult men and women completed assessments of early family environment, recent stressful events, psychosocial resources, and psychological distress, including depressive symptomatology. The 5-HTTLPR was genotyped using a standard protocol with DNA extracted from oral fluid.\n## RESULTS\nA stressful early family environment was significantly related to depressive symptomatology. In addition, gene-by-environment (GxE) interactions were observed between the 5-HTTLPR and both early family environment and current adversity/stress. Individuals homozygous for the short allele had greater depressive symptomatology if they had experienced early or recent adversity but significantly less depressive symptomatology if they reported a supportive early environment or recent positive experiences, compared with participants with the s/l or l/l genotype.\n## CONCLUSIONS\nEarly or current environment, in conjunction with the serotonin transporter polymorphism, predicts depressive symptomatology.",
        "truth": "False"
    },
    {
        "pmid": "19531786",
        "meta_analysis_title": "Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis.",
        "meta_analysis_question": "Does the interaction between the serotonin transporter gene (5-HTTLPR) and stressful life events increase the risk of depression?",
        "criteria": "A search of the PubMed, EMBASE, and PsycINFO databases was conducted through March 2009 using the search terms life stress, life event, depression, depress, serotonin transporter, 5-HTTLPR, interaction, and moderation. Bibliographies of studies were also reviewed. A total of 26 articles published or set for publication were identified through this search strategy (Figure 1). Inclusion criteria for studies for the meta-analyses were published articles that included data on the association between the (1) 5-HTTLPR genotype (S, SL, or LL), (2) number of stressful life events (0, 1, 2, or \u22653) or equivalent, and (3) categorical measure of depression defined by the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) or International Statistical Classification of Diseases, 10th Revision (ICD-10) or ability to use a cut point to define depression from standardized rating scales. To maximize our ability to use a common framework for variable definition, we also requested original data from all studies that appeared to meet inclusion criteria published prior to 2008.10,15-28 We received original data in a usable format for the meta-analysis from 10 of the 14 study investigators. A total of 14 studies were included in the analysis, 15-20,23,25-27,29-32 10 of which15-20,23,25-27,29,30 were also included in a second sex-specific meta-analysis of original data. Nine other studies did not meet inclusion criteria.33-41",
        "subgroup": "Logistic Regression Analyses of Depression for 10 Studies Stratified by Sex - Risk per S allele",
        "key_reference_title": "Relationship of 5-HTTLPR genotypes and depression risk in the presence of trauma in a female twin sample.",
        "key_reference_abstract": "Several studies have implicated an insertion/deletion polymorphism in the promoter region of the serotonin transporter gene (SLC6A4; 5-HTT) in the development of mood disorders. In the present study of a sample of 247 young adult female twins from Missouri, we examine whether this polymorphism interacts with the effect of adverse life events to increase risk for developing depression. We found a significant interaction between the number of high-activity L(A) alleles and exposure to trauma (OR = 1.70, P < 0.0001). This differs from previous reports, in that the higher activity genotypes (L(A)/L(A), L(A)/S, L(A)/L(G)), rather than the low activity genotypes (S/S, S/L(G), L(G)/L(G)), are associated with an increased incidence of major depressive disease (MDD) in the presence of environmental trauma.",
        "truth": "True"
    },
    {
        "pmid": "19531786",
        "meta_analysis_title": "Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis.",
        "meta_analysis_question": "Does the interaction between the serotonin transporter gene (5-HTTLPR) and stressful life events increase the risk of depression?",
        "criteria": "A search of the PubMed, EMBASE, and PsycINFO databases was conducted through March 2009 using the search terms life stress, life event, depression, depress, serotonin transporter, 5-HTTLPR, interaction, and moderation. Bibliographies of studies were also reviewed. A total of 26 articles published or set for publication were identified through this search strategy (Figure 1). Inclusion criteria for studies for the meta-analyses were published articles that included data on the association between the (1) 5-HTTLPR genotype (S, SL, or LL), (2) number of stressful life events (0, 1, 2, or \u22653) or equivalent, and (3) categorical measure of depression defined by the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) or International Statistical Classification of Diseases, 10th Revision (ICD-10) or ability to use a cut point to define depression from standardized rating scales. To maximize our ability to use a common framework for variable definition, we also requested original data from all studies that appeared to meet inclusion criteria published prior to 2008.10,15-28 We received original data in a usable format for the meta-analysis from 10 of the 14 study investigators. A total of 14 studies were included in the analysis, 15-20,23,25-27,29-32 10 of which15-20,23,25-27,29,30 were also included in a second sex-specific meta-analysis of original data. Nine other studies did not meet inclusion criteria.33-41",
        "subgroup": "Logistic Regression Analyses of Depression for 10 Studies Stratified by Sex - Risk per S allele",
        "key_reference_title": "Family based association analyses between the serotonin transporter gene polymorphism (5-HTTLPR) and neuroticism, anxiety and depression.",
        "key_reference_abstract": "We studied the association between the short/long promotor-based length polymorphism of the serotonin transporter gene (5-HTTLPR) and neuroticism, anxiety and depression. Subjects included twins, their siblings and parents from the Netherlands Twin Register (559 parents and 1,245 offspring). Subjects had participated between one and five times in a survey study measuring neuroticism, anxiety and depression. Offspring of these families were also approached to participate in a psychiatric interview diagnosing DSM-IV major depression. Within-family and total association between 5-HTTLPR and these traits were tested. Only three of the 36 tests showed a significant effect of 5-HTTLPR (P<0.05). These effects were in opposite directions, i.e. both negative and positive regression coefficients were found for the s allele. No additive effect of the s allele was found for DSM-IV depression. Our results strongly suggest that there is no straightforward association between 5-HTTLPR and neuroticism, anxiety and depression.",
        "truth": "True"
    },
    {
        "pmid": "19531786",
        "meta_analysis_title": "Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis.",
        "meta_analysis_question": "Does the interaction between the serotonin transporter gene (5-HTTLPR) and stressful life events increase the risk of depression?",
        "criteria": "A search of the PubMed, EMBASE, and PsycINFO databases was conducted through March 2009 using the search terms life stress, life event, depression, depress, serotonin transporter, 5-HTTLPR, interaction, and moderation. Bibliographies of studies were also reviewed. A total of 26 articles published or set for publication were identified through this search strategy (Figure 1). Inclusion criteria for studies for the meta-analyses were published articles that included data on the association between the (1) 5-HTTLPR genotype (S, SL, or LL), (2) number of stressful life events (0, 1, 2, or \u22653) or equivalent, and (3) categorical measure of depression defined by the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) or International Statistical Classification of Diseases, 10th Revision (ICD-10) or ability to use a cut point to define depression from standardized rating scales. To maximize our ability to use a common framework for variable definition, we also requested original data from all studies that appeared to meet inclusion criteria published prior to 2008.10,15-28 We received original data in a usable format for the meta-analysis from 10 of the 14 study investigators. A total of 14 studies were included in the analysis, 15-20,23,25-27,29-32 10 of which15-20,23,25-27,29,30 were also included in a second sex-specific meta-analysis of original data. Nine other studies did not meet inclusion criteria.33-41",
        "subgroup": "Logistic Regression Analyses of Depression for 10 Studies Stratified by Sex - Risk per S allele",
        "key_reference_title": "No interaction between the serotonin transporter polymorphism (5-HTTLPR) and childhood adversity or recent stressful life events on symptoms of depression: results from two community surveys.",
        "key_reference_abstract": "In this study we investigated interactions between the 5-HTTLPR genotype and environmental risk factors (G x E) on symptoms of depression in two large Australian community samples of adolescents and young adults. We postulated that a significant interaction between the 5-HTTLPR genotype and environmental risk factors of childhood adversity or stressful life events on symptoms of depression would be observed in subjects with at least one short allele (s/l or s/s) compared with subjects with no short alleles (l/l). We did not find significant G x E interactions between the 5-HTTLPR genotype and recent stressful life events or childhood adversity on symptoms of depression in our sample populations. However, we did find adolescents aged 17-18 years homozygous for the long allele (l/l) and exposed to persistently high levels of family adversity over a 6-year period were at a greater risk of depression than subjects with the same genotype exposed to no or persistently low levels of family adversity. This interaction should be interpreted cautiously due to the small number of depressed subjects in the sample with persistently high levels of family adversity.",
        "truth": "True"
    },
    {
        "pmid": "19531786",
        "meta_analysis_title": "Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis.",
        "meta_analysis_question": "Does the interaction between the serotonin transporter gene (5-HTTLPR) and stressful life events increase the risk of depression?",
        "criteria": "A search of the PubMed, EMBASE, and PsycINFO databases was conducted through March 2009 using the search terms life stress, life event, depression, depress, serotonin transporter, 5-HTTLPR, interaction, and moderation. Bibliographies of studies were also reviewed. A total of 26 articles published or set for publication were identified through this search strategy (Figure 1). Inclusion criteria for studies for the meta-analyses were published articles that included data on the association between the (1) 5-HTTLPR genotype (S, SL, or LL), (2) number of stressful life events (0, 1, 2, or \u22653) or equivalent, and (3) categorical measure of depression defined by the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) or International Statistical Classification of Diseases, 10th Revision (ICD-10) or ability to use a cut point to define depression from standardized rating scales. To maximize our ability to use a common framework for variable definition, we also requested original data from all studies that appeared to meet inclusion criteria published prior to 2008.10,15-28 We received original data in a usable format for the meta-analysis from 10 of the 14 study investigators. A total of 14 studies were included in the analysis, 15-20,23,25-27,29-32 10 of which15-20,23,25-27,29,30 were also included in a second sex-specific meta-analysis of original data. Nine other studies did not meet inclusion criteria.33-41",
        "subgroup": "Logistic Regression Analyses of Depression for 10 Studies Stratified by Sex - Risk per S allele",
        "key_reference_title": "The risk for depression conferred by stressful life events is modified by variation at the serotonin transporter 5HTTLPR genotype: evidence from the Spanish PREDICT-Gene cohort.",
        "key_reference_abstract": "We report results from the PREDICT-Gene case-control study nested in a prospective cohort designed to identify predictors of the onset of depression among adult primary-care attendees. We tested the potential gene-by-environment interaction between 5HTTLPR genotype at the serotonin transporter gene and previous exposure to threatening life events (TLEs) in depression. A total of 737 consecutively recruited participants were genotyped. Additional information was gathered on exposure to TLEs over a 6-month period, socio-demographic data and family history of psychological problems among first-degree relatives. Diagnoses of depression were ascertained using the Composite International Diagnostic Interview (CIDI) by trained interviewers. Two different depressive outcomes were used (ICD-10 depressive episode and ICD-10 severe depressive episode). Both the s/s genotype and exposure to increasing number of TLEs were significantly associated with depression. Moreover, the 5HTTLPR s/s genotype significantly modified the risk conferred by TLEs for both depressive outcomes. Thus, s/s homozygous participants required minimal exposure to TLE (1 TLE) to acquire a level of risk for depression that was only found among l/s or l/l individuals after significantly higher exposure to TLEs (two or more TLEs). The interaction was more apparent when applied to the diagnosis of ICD-10 severe depressive episode and after adjusting for gender, age and family history of psychological problems. Likelihood ratios tests for the interaction were statistically significant for both depressive outcomes (ICD-10 depressive episode: LR X(2)=4.7, P=0.09 (crude), LR-X(2)=6.4, P=0.04 (adjusted); ICD-10 severe depressive episode: LR X(2)=6.9, P=0.032 (crude), LR-X(2)=8.1, P=0.017 (adjusted)).",
        "truth": "False"
    },
    {
        "pmid": "19531786",
        "meta_analysis_title": "Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis.",
        "meta_analysis_question": "Does the interaction between the serotonin transporter gene (5-HTTLPR) and stressful life events increase the risk of depression?",
        "criteria": "A search of the PubMed, EMBASE, and PsycINFO databases was conducted through March 2009 using the search terms life stress, life event, depression, depress, serotonin transporter, 5-HTTLPR, interaction, and moderation. Bibliographies of studies were also reviewed. A total of 26 articles published or set for publication were identified through this search strategy (Figure 1). Inclusion criteria for studies for the meta-analyses were published articles that included data on the association between the (1) 5-HTTLPR genotype (S, SL, or LL), (2) number of stressful life events (0, 1, 2, or \u22653) or equivalent, and (3) categorical measure of depression defined by the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) or International Statistical Classification of Diseases, 10th Revision (ICD-10) or ability to use a cut point to define depression from standardized rating scales. To maximize our ability to use a common framework for variable definition, we also requested original data from all studies that appeared to meet inclusion criteria published prior to 2008.10,15-28 We received original data in a usable format for the meta-analysis from 10 of the 14 study investigators. A total of 14 studies were included in the analysis, 15-20,23,25-27,29-32 10 of which15-20,23,25-27,29,30 were also included in a second sex-specific meta-analysis of original data. Nine other studies did not meet inclusion criteria.33-41",
        "subgroup": "Logistic Regression Analyses of Depression for 10 Studies Stratified by Sex - Risk per S allele",
        "key_reference_title": "Interactions between life stressors and susceptibility genes (5-HTTLPR and BDNF) on depression in Korean elders.",
        "key_reference_abstract": "## BACKGROUND\nIt has been reported that the functional polymorphism in the serotonin transporter gene linked promoter region (5-HTTLPR) modifies the association between stressful life events (SLEs) and depression in child, adolescent, and adult populations. We sought to replicate this finding in elders and, additionally, to test modifying effects of the brain-derived neurotrophic factor (BDNF) val66met polymorphism.\n## METHODS\nIn 732 Korean community residents ages 65+, diagnosis of depression (Geriatric Mental State Schedule), information on SLEs, and genotypes for 5-HTTLPR and BDNF val66met were ascertained. Of those without depression at baseline, 521 (88%) were followed up 2.5 years later. Interactions between SLEs and the two genotypes were investigated for both prevalent depression at baseline and incident depression at follow-up.\n## RESULTS\nSignificant interactions of SLEs with both 5-HTTLPR and BDNF genotypes were observed on risk of depression after adjustment for age, gender, education, and disability. A significant three-way interaction between 5-HTTLPR, BDNF, and SLEs was also found. The same findings were observed for predictors of incident depression in the prospective analysis.\n## CONCLUSIONS\nThese findings suggest that environmental risk of depression is modified by at least two genes and that gene-environment interactions are found even into old age.",
        "truth": "False"
    },
    {
        "pmid": "19531786",
        "meta_analysis_title": "Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis.",
        "meta_analysis_question": "Does the interaction between the serotonin transporter gene (5-HTTLPR) and stressful life events increase the risk of depression?",
        "criteria": "A search of the PubMed, EMBASE, and PsycINFO databases was conducted through March 2009 using the search terms life stress, life event, depression, depress, serotonin transporter, 5-HTTLPR, interaction, and moderation. Bibliographies of studies were also reviewed. A total of 26 articles published or set for publication were identified through this search strategy (Figure 1). Inclusion criteria for studies for the meta-analyses were published articles that included data on the association between the (1) 5-HTTLPR genotype (S, SL, or LL), (2) number of stressful life events (0, 1, 2, or \u22653) or equivalent, and (3) categorical measure of depression defined by the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) or International Statistical Classification of Diseases, 10th Revision (ICD-10) or ability to use a cut point to define depression from standardized rating scales. To maximize our ability to use a common framework for variable definition, we also requested original data from all studies that appeared to meet inclusion criteria published prior to 2008.10,15-28 We received original data in a usable format for the meta-analysis from 10 of the 14 study investigators. A total of 14 studies were included in the analysis, 15-20,23,25-27,29-32 10 of which15-20,23,25-27,29,30 were also included in a second sex-specific meta-analysis of original data. Nine other studies did not meet inclusion criteria.33-41",
        "subgroup": "Logistic Regression Analyses of Depression for 10 Studies Stratified by Sex - Risk per S allele",
        "key_reference_title": "5-HTTLPR genotype, stressful life events and late-life depression: no evidence of interaction in a French population.",
        "key_reference_abstract": "Modification of the effect of life events on risk of depression by a polymorphism in the serotonin transporter gene promoter (5-HTTLPR) has been reported in child, adolescent, adult and elderly populations. Replication attempted on data collected from 1421 individuals aged 65 and over from a French community study provided no evidence of a similar modifying effect. In the only analysis known to the authors to be carried out in an exclusively elderly, European population, this null finding remained consistent after restriction of analysis to prevalent or incident cases.",
        "truth": "False"
    },
    {
        "pmid": "19531786",
        "meta_analysis_title": "Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis.",
        "meta_analysis_question": "Does the interaction between the serotonin transporter gene (5-HTTLPR) and stressful life events increase the risk of depression?",
        "criteria": "A search of the PubMed, EMBASE, and PsycINFO databases was conducted through March 2009 using the search terms life stress, life event, depression, depress, serotonin transporter, 5-HTTLPR, interaction, and moderation. Bibliographies of studies were also reviewed. A total of 26 articles published or set for publication were identified through this search strategy (Figure 1). Inclusion criteria for studies for the meta-analyses were published articles that included data on the association between the (1) 5-HTTLPR genotype (S, SL, or LL), (2) number of stressful life events (0, 1, 2, or \u22653) or equivalent, and (3) categorical measure of depression defined by the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) or International Statistical Classification of Diseases, 10th Revision (ICD-10) or ability to use a cut point to define depression from standardized rating scales. To maximize our ability to use a common framework for variable definition, we also requested original data from all studies that appeared to meet inclusion criteria published prior to 2008.10,15-28 We received original data in a usable format for the meta-analysis from 10 of the 14 study investigators. A total of 14 studies were included in the analysis, 15-20,23,25-27,29-32 10 of which15-20,23,25-27,29,30 were also included in a second sex-specific meta-analysis of original data. Nine other studies did not meet inclusion criteria.33-41",
        "subgroup": "Logistic Regression Analyses of Depression for 10 Studies Stratified by Sex - Risk per S allele",
        "key_reference_title": "Interaction between the 5-HTTLPR serotonin transporter polymorphism and environmental adversity for mood and anxiety psychopathology: evidence from a high-risk community sample of young adults.",
        "key_reference_abstract": "Previous research examining gene-environment interaction (GxE) with regard to vulnerability to depression and anxiety has yielded conflicting results. The present study was designed to further investigate GxE between 5-HTTLPR and exposure to environmental adversity, using different phenotypic and genotypic characterizations as well as different types of adversity within a prospective study design. Data were available from an ongoing epidemiological cohort study following the outcome of early risk factors from birth to adulthood. At age 19 yr, 309 participants (142 males, 167 females) were characterized on measures of depression and anxiety through interview and questionnaire (DSM-IV diagnosis, Beck Depression Inventory, Harm Avoidance). Environmental adversity was assessed at birth (family adversity), and at age 19 yr (stressful life events). Bi- and tri-allelic 5-HTTLPR genotypes were obtained from genomic DNA. Results indicated that depression and anxiety in 19-yr-olds were strongly associated with both family adversity and stressful life events. Individuals with the LL genotype of 5-HTTLPR who were exposed to high family adversity displayed significantly higher rates of depressive or anxiety disorders and had more depressive symptoms than those without either condition. This GxE replicates recent findings from an epidemiological cohort study of adolescents but is in contrast to many previous reports suggesting an interaction with the S allele. No evidence for GxE was obtained with regard to current stressful life events and trait anxiety. One possible source for the conflicting findings might be attributed to heterogeneity in depression phenotypes and environmental adversity.",
        "truth": "False"
    },
    {
        "pmid": "19531786",
        "meta_analysis_title": "Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis.",
        "meta_analysis_question": "Does the interaction between the serotonin transporter gene (5-HTTLPR) and stressful life events increase the risk of depression?",
        "criteria": "A search of the PubMed, EMBASE, and PsycINFO databases was conducted through March 2009 using the search terms life stress, life event, depression, depress, serotonin transporter, 5-HTTLPR, interaction, and moderation. Bibliographies of studies were also reviewed. A total of 26 articles published or set for publication were identified through this search strategy (Figure 1). Inclusion criteria for studies for the meta-analyses were published articles that included data on the association between the (1) 5-HTTLPR genotype (S, SL, or LL), (2) number of stressful life events (0, 1, 2, or \u22653) or equivalent, and (3) categorical measure of depression defined by the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) or International Statistical Classification of Diseases, 10th Revision (ICD-10) or ability to use a cut point to define depression from standardized rating scales. To maximize our ability to use a common framework for variable definition, we also requested original data from all studies that appeared to meet inclusion criteria published prior to 2008.10,15-28 We received original data in a usable format for the meta-analysis from 10 of the 14 study investigators. A total of 14 studies were included in the analysis, 15-20,23,25-27,29-32 10 of which15-20,23,25-27,29,30 were also included in a second sex-specific meta-analysis of original data. Nine other studies did not meet inclusion criteria.33-41",
        "subgroup": "Logistic Regression Analyses of Depression for 10 Studies Stratified by Sex - Risk per stressful life event",
        "key_reference_title": "Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene.",
        "key_reference_abstract": "In a prospective-longitudinal study of a representative birth cohort, we tested why stressful experiences lead to depression in some people but not in others. A functional polymorphism in the promoter region of the serotonin transporter (5-HT T) gene was found to moderate the influence of stressful life events on depression. Individuals with one or two copies of the short allele of the 5-HT T promoter polymorphism exhibited more depressive symptoms, diagnosable depression, and suicidality in relation to stressful life events than individuals homozygous for the long allele. This epidemiological study thus provides evidence of a gene-by-environment interaction, in which an individual's response to environmental insults is moderated by his or her genetic makeup.",
        "truth": "False"
    },
    {
        "pmid": "19531786",
        "meta_analysis_title": "Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis.",
        "meta_analysis_question": "Does the interaction between the serotonin transporter gene (5-HTTLPR) and stressful life events increase the risk of depression?",
        "criteria": "A search of the PubMed, EMBASE, and PsycINFO databases was conducted through March 2009 using the search terms life stress, life event, depression, depress, serotonin transporter, 5-HTTLPR, interaction, and moderation. Bibliographies of studies were also reviewed. A total of 26 articles published or set for publication were identified through this search strategy (Figure 1). Inclusion criteria for studies for the meta-analyses were published articles that included data on the association between the (1) 5-HTTLPR genotype (S, SL, or LL), (2) number of stressful life events (0, 1, 2, or \u22653) or equivalent, and (3) categorical measure of depression defined by the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) or International Statistical Classification of Diseases, 10th Revision (ICD-10) or ability to use a cut point to define depression from standardized rating scales. To maximize our ability to use a common framework for variable definition, we also requested original data from all studies that appeared to meet inclusion criteria published prior to 2008.10,15-28 We received original data in a usable format for the meta-analysis from 10 of the 14 study investigators. A total of 14 studies were included in the analysis, 15-20,23,25-27,29-32 10 of which15-20,23,25-27,29,30 were also included in a second sex-specific meta-analysis of original data. Nine other studies did not meet inclusion criteria.33-41",
        "subgroup": "Logistic Regression Analyses of Depression for 10 Studies Stratified by Sex - Risk per stressful life event",
        "key_reference_title": "Gene-environment interaction analysis of serotonin system markers with adolescent depression.",
        "key_reference_abstract": "We report analyses from a study of gene-environment interaction in adolescent depression. The sample was selected from 1990 adolescents aged 10-20 years: those with depression symptoms in the top or bottom 15% were identified and divided into high or low environmental risk groups. DNA was obtained from 377 adolescents, representing the four quadrants of high or low depression and high or low environmental risk. Markers within, or close to, each of the serotonergic genes 5HTT, HTR2A, HTR2C, MAOA (monoamine oxidase type A) and tryptophan hydroxylase (TPH) were genotyped. Environmental risk group was a nonsignificant predictor and sex was a significant predictor of the depression group. HTR2A and TPH significantly predicted the depression group, independent of the effects of sex, environmental risk group and their interaction. In addition, there was a trend for an effect of 5HTTLPR, which was significant in female subjects. Furthermore, there was a significant genotype-environmental risk interaction for 5HTTLPR in female subjects only, with the effect being in the same direction as another recent study, reaffirming that an important source of genetic heterogeneity is exposure to environmental risk.",
        "truth": "True"
    },
    {
        "pmid": "19531786",
        "meta_analysis_title": "Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis.",
        "meta_analysis_question": "Does the interaction between the serotonin transporter gene (5-HTTLPR) and stressful life events increase the risk of depression?",
        "criteria": "A search of the PubMed, EMBASE, and PsycINFO databases was conducted through March 2009 using the search terms life stress, life event, depression, depress, serotonin transporter, 5-HTTLPR, interaction, and moderation. Bibliographies of studies were also reviewed. A total of 26 articles published or set for publication were identified through this search strategy (Figure 1). Inclusion criteria for studies for the meta-analyses were published articles that included data on the association between the (1) 5-HTTLPR genotype (S, SL, or LL), (2) number of stressful life events (0, 1, 2, or \u22653) or equivalent, and (3) categorical measure of depression defined by the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) or International Statistical Classification of Diseases, 10th Revision (ICD-10) or ability to use a cut point to define depression from standardized rating scales. To maximize our ability to use a common framework for variable definition, we also requested original data from all studies that appeared to meet inclusion criteria published prior to 2008.10,15-28 We received original data in a usable format for the meta-analysis from 10 of the 14 study investigators. A total of 14 studies were included in the analysis, 15-20,23,25-27,29-32 10 of which15-20,23,25-27,29,30 were also included in a second sex-specific meta-analysis of original data. Nine other studies did not meet inclusion criteria.33-41",
        "subgroup": "Logistic Regression Analyses of Depression for 10 Studies Stratified by Sex - Risk per stressful life event",
        "key_reference_title": "The relationship between stressful life events, the serotonin transporter (5-HTTLPR) genotype and major depression.",
        "key_reference_abstract": "## BACKGROUND\nSerotonin is a good candidate for major depression. We attempted to replicate the study by Caspi and colleagues [Science (2003) 301, 386-389] which reported a significant interaction between serotonin transporter (5-HTTLPR) genotype and stressful life events when predicting major depression.\n## METHOD\nWe typed the serotonin promoter 5-HTTLPR gene in 1206 male and female twins aged 19-78 years (mean = 39, S.D. = 11). A DSM-IV diagnosis of major depression was available for 1199 twins. Most of these twins had participated in a 1988-1990 study which included a stressful life events inventory and self-report measure of depression based on the SCL-90 and DSSI/sAD. Complete 5-HTT genotype and life events data, self-report symptoms and major depression diagnoses were available for 1091 subjects. We regressed categorical and ordinal measures of depression onto stressful life events and genotype.\n## RESULTS\nThere were significant main effects for stressful life events but there was no evidence for any effect of 5-HTT genotype, nor a genotype x stressful life event interaction.\n## CONCLUSIONS\nRegardless of whether our results were based on binary logistic or ordinal regression analyses we found no evidence to support a main effect of 5-HTTLPR, or an interaction between the 5-HTTLPR genotype and stressful life events on major depression, Only 20 % of our subjects were aged below 30 years. It is possible that the effect reported by Caspi and colleagues is specific to young people, in which case our study has much less power in this age group.",
        "truth": "True"
    },
    {
        "pmid": "19531786",
        "meta_analysis_title": "Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis.",
        "meta_analysis_question": "Does the interaction between the serotonin transporter gene (5-HTTLPR) and stressful life events increase the risk of depression?",
        "criteria": "A search of the PubMed, EMBASE, and PsycINFO databases was conducted through March 2009 using the search terms life stress, life event, depression, depress, serotonin transporter, 5-HTTLPR, interaction, and moderation. Bibliographies of studies were also reviewed. A total of 26 articles published or set for publication were identified through this search strategy (Figure 1). Inclusion criteria for studies for the meta-analyses were published articles that included data on the association between the (1) 5-HTTLPR genotype (S, SL, or LL), (2) number of stressful life events (0, 1, 2, or \u22653) or equivalent, and (3) categorical measure of depression defined by the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) or International Statistical Classification of Diseases, 10th Revision (ICD-10) or ability to use a cut point to define depression from standardized rating scales. To maximize our ability to use a common framework for variable definition, we also requested original data from all studies that appeared to meet inclusion criteria published prior to 2008.10,15-28 We received original data in a usable format for the meta-analysis from 10 of the 14 study investigators. A total of 14 studies were included in the analysis, 15-20,23,25-27,29-32 10 of which15-20,23,25-27,29,30 were also included in a second sex-specific meta-analysis of original data. Nine other studies did not meet inclusion criteria.33-41",
        "subgroup": "Logistic Regression Analyses of Depression for 10 Studies Stratified by Sex - Risk per stressful life event",
        "key_reference_title": "Mental and physical distress is modulated by a polymorphism in the 5-HT transporter gene interacting with social stressors and chronic disease burden.",
        "key_reference_abstract": "Previous studies have yielded conflicting results as to the putative role of the functional polymorphism of the promoter region of the serotonin transporter gene (SLC6A4) in the etiology of anxiety-related traits and depressive disorders. Recently, a significant gene-environment interaction was found between life stressors, the short allele of the SLC6A4 polymorphism and depression. The aim of the present study was to investigate if such a gene-environment interaction could be replicated within a different population with a different risk structure. A total of 1005 subjects from a general population sample (Study of Health in Pomerania) were genotyped. Mental and physical distress were assessed on 38 items of the modified complaint scale (BL-38). The interaction between the SLC6A4 genotype, social stressors and chronic diseases with regard to the BL-38 score was evaluated by ANOVA. There was no independent association of genotype with mental and physical distress. However, significant interactions between genotype, unemployment and chronic diseases (F = 6.6; df = 3, 671; P < 0.001) were found in females but not in males. The genotype explained 2% of the total variance of the BL-38 score and 9.1% of the explained variance. The results partly confirm previous findings of a significant gene-environment interaction of the short allele, indicating a higher mental vulnerability to social stressors and chronic diseases. The relevance of this finding is sustained by the fact that the sample characteristics and the risk structure were highly different from previous studies.",
        "truth": "True"
    },
    {
        "pmid": "19531786",
        "meta_analysis_title": "Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis.",
        "meta_analysis_question": "Does the interaction between the serotonin transporter gene (5-HTTLPR) and stressful life events increase the risk of depression?",
        "criteria": "A search of the PubMed, EMBASE, and PsycINFO databases was conducted through March 2009 using the search terms life stress, life event, depression, depress, serotonin transporter, 5-HTTLPR, interaction, and moderation. Bibliographies of studies were also reviewed. A total of 26 articles published or set for publication were identified through this search strategy (Figure 1). Inclusion criteria for studies for the meta-analyses were published articles that included data on the association between the (1) 5-HTTLPR genotype (S, SL, or LL), (2) number of stressful life events (0, 1, 2, or \u22653) or equivalent, and (3) categorical measure of depression defined by the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) or International Statistical Classification of Diseases, 10th Revision (ICD-10) or ability to use a cut point to define depression from standardized rating scales. To maximize our ability to use a common framework for variable definition, we also requested original data from all studies that appeared to meet inclusion criteria published prior to 2008.10,15-28 We received original data in a usable format for the meta-analysis from 10 of the 14 study investigators. A total of 14 studies were included in the analysis, 15-20,23,25-27,29-32 10 of which15-20,23,25-27,29,30 were also included in a second sex-specific meta-analysis of original data. Nine other studies did not meet inclusion criteria.33-41",
        "subgroup": "Logistic Regression Analyses of Depression for 10 Studies Stratified by Sex - Risk per stressful life event",
        "key_reference_title": "Social adversity, the serotonin transporter (5-HTTLPR) polymorphism and major depressive disorder.",
        "key_reference_abstract": "## BACKGROUND\nRecent evidence has suggested that the short allele of the serotonin transporter (5-HTT) gene-linked polymorphic region (5-HTTLPR of the human serotonin gene [SLC6A4]) is associated with increased risk of depressive disorder but only among individuals exposed to social adversity. We report an investigation designed to replicate this finding.\n## METHODS\nData were available from a non-clinical sample of 4,175 adult men and women, ages 41-80 years, selected from participants in the European Prospective Investigation into Cancer and Nutrition in Norfolk (EPIC-Norfolk, United Kingdom) study. Evidence of past-year prevalent episodic major depressive disorder (MDD), defined by restricted DSM-IV diagnostic criteria, was assessed through questionnaire. Adverse experiences in childhood and in adulthood (during the five years preceding assessment) were also assessed through self-report. The 5-HTTLPR variant was genotyped according to published protocols.\n## RESULTS\nOne-year prevalent MDD criteria were met by 298 study participants. The experience of social adversity (both in childhood and adulthood) was strongly associated with increased rates of past-year prevalent MDD. No gene by environment (GxE) interactions between the 5-HTTLPR genotype, social adversity, and MDD were observed.\n## CONCLUSIONS\nThis study has not replicated a previous finding of a GxE interaction between the 5-HTTLPR genotype, social adversity, and depression.",
        "truth": "True"
    },
    {
        "pmid": "19531786",
        "meta_analysis_title": "Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis.",
        "meta_analysis_question": "Does the interaction between the serotonin transporter gene (5-HTTLPR) and stressful life events increase the risk of depression?",
        "criteria": "A search of the PubMed, EMBASE, and PsycINFO databases was conducted through March 2009 using the search terms life stress, life event, depression, depress, serotonin transporter, 5-HTTLPR, interaction, and moderation. Bibliographies of studies were also reviewed. A total of 26 articles published or set for publication were identified through this search strategy (Figure 1). Inclusion criteria for studies for the meta-analyses were published articles that included data on the association between the (1) 5-HTTLPR genotype (S, SL, or LL), (2) number of stressful life events (0, 1, 2, or \u22653) or equivalent, and (3) categorical measure of depression defined by the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) or International Statistical Classification of Diseases, 10th Revision (ICD-10) or ability to use a cut point to define depression from standardized rating scales. To maximize our ability to use a common framework for variable definition, we also requested original data from all studies that appeared to meet inclusion criteria published prior to 2008.10,15-28 We received original data in a usable format for the meta-analysis from 10 of the 14 study investigators. A total of 14 studies were included in the analysis, 15-20,23,25-27,29-32 10 of which15-20,23,25-27,29,30 were also included in a second sex-specific meta-analysis of original data. Nine other studies did not meet inclusion criteria.33-41",
        "subgroup": "Logistic Regression Analyses of Depression for 10 Studies Stratified by Sex - Risk per stressful life event",
        "key_reference_title": "Life events, first depression onset and the serotonin transporter gene.",
        "key_reference_abstract": "## BACKGROUND\nA relationship between the serotonin transporter gene, adverse events and onset of major depression has been reported.\n## AIMS\nTo replicate a gene x environment interaction in a cohort with longitudinal data for life events, experience of depression, parental bonding and neuroticism.\n## METHOD\nAt the 25-year follow-up, genomic DNA was obtained from 127 cohort members (mean age 48 years) to determine the genotype of the serotonin transporter gene-linked promoter region (5-HTTLPR). Associations were investigated between the 5-HTTLPR genotype, positive and adverse life events and the gene x environment interaction, and also between the 5-HTTLPR genotype and risk factors for depression.\n## RESULTS\nNo relationship was found between 5-HTTLPR genotype and either risk factors for depression or positive life events. Adverse life events had a significantly greater impact on the onset of depression for individuals with the s/s genotype.\n## CONCLUSIONS\nThe 5-HTTLPR genotype is a significant predictor of onset of major depression following multiple adverse events. This is one of the more robust findings concerning specific biological risk factors for depression.",
        "truth": "True"
    },
    {
        "pmid": "19531786",
        "meta_analysis_title": "Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis.",
        "meta_analysis_question": "Does the interaction between the serotonin transporter gene (5-HTTLPR) and stressful life events increase the risk of depression?",
        "criteria": "A search of the PubMed, EMBASE, and PsycINFO databases was conducted through March 2009 using the search terms life stress, life event, depression, depress, serotonin transporter, 5-HTTLPR, interaction, and moderation. Bibliographies of studies were also reviewed. A total of 26 articles published or set for publication were identified through this search strategy (Figure 1). Inclusion criteria for studies for the meta-analyses were published articles that included data on the association between the (1) 5-HTTLPR genotype (S, SL, or LL), (2) number of stressful life events (0, 1, 2, or \u22653) or equivalent, and (3) categorical measure of depression defined by the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) or International Statistical Classification of Diseases, 10th Revision (ICD-10) or ability to use a cut point to define depression from standardized rating scales. To maximize our ability to use a common framework for variable definition, we also requested original data from all studies that appeared to meet inclusion criteria published prior to 2008.10,15-28 We received original data in a usable format for the meta-analysis from 10 of the 14 study investigators. A total of 14 studies were included in the analysis, 15-20,23,25-27,29-32 10 of which15-20,23,25-27,29,30 were also included in a second sex-specific meta-analysis of original data. Nine other studies did not meet inclusion criteria.33-41",
        "subgroup": "Logistic Regression Analyses of Depression for 10 Studies Stratified by Sex - Risk per stressful life event",
        "key_reference_title": "Early family environment, current adversity, the serotonin transporter promoter polymorphism, and depressive symptomatology.",
        "key_reference_abstract": "## BACKGROUND\nMixed evidence has suggested that homozygous carriers of the short allele (s/s) of the serotonin transporter gene-linked polymorphic region (5-HTTLPR) may be at increased risk for depression, if they have also been exposed to early or current adversity/stress. We address this debate by examining the relation of a stressful early family environment, recent adversity/stress, and the 5-HTTLPR to depressive symptomatology in a normal sample.\n## METHODS\nA nonclinical sample of 118 young adult men and women completed assessments of early family environment, recent stressful events, psychosocial resources, and psychological distress, including depressive symptomatology. The 5-HTTLPR was genotyped using a standard protocol with DNA extracted from oral fluid.\n## RESULTS\nA stressful early family environment was significantly related to depressive symptomatology. In addition, gene-by-environment (GxE) interactions were observed between the 5-HTTLPR and both early family environment and current adversity/stress. Individuals homozygous for the short allele had greater depressive symptomatology if they had experienced early or recent adversity but significantly less depressive symptomatology if they reported a supportive early environment or recent positive experiences, compared with participants with the s/l or l/l genotype.\n## CONCLUSIONS\nEarly or current environment, in conjunction with the serotonin transporter polymorphism, predicts depressive symptomatology.",
        "truth": "False"
    },
    {
        "pmid": "19531786",
        "meta_analysis_title": "Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis.",
        "meta_analysis_question": "Does the interaction between the serotonin transporter gene (5-HTTLPR) and stressful life events increase the risk of depression?",
        "criteria": "A search of the PubMed, EMBASE, and PsycINFO databases was conducted through March 2009 using the search terms life stress, life event, depression, depress, serotonin transporter, 5-HTTLPR, interaction, and moderation. Bibliographies of studies were also reviewed. A total of 26 articles published or set for publication were identified through this search strategy (Figure 1). Inclusion criteria for studies for the meta-analyses were published articles that included data on the association between the (1) 5-HTTLPR genotype (S, SL, or LL), (2) number of stressful life events (0, 1, 2, or \u22653) or equivalent, and (3) categorical measure of depression defined by the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) or International Statistical Classification of Diseases, 10th Revision (ICD-10) or ability to use a cut point to define depression from standardized rating scales. To maximize our ability to use a common framework for variable definition, we also requested original data from all studies that appeared to meet inclusion criteria published prior to 2008.10,15-28 We received original data in a usable format for the meta-analysis from 10 of the 14 study investigators. A total of 14 studies were included in the analysis, 15-20,23,25-27,29-32 10 of which15-20,23,25-27,29,30 were also included in a second sex-specific meta-analysis of original data. Nine other studies did not meet inclusion criteria.33-41",
        "subgroup": "Logistic Regression Analyses of Depression for 10 Studies Stratified by Sex - Risk per stressful life event",
        "key_reference_title": "Relationship of 5-HTTLPR genotypes and depression risk in the presence of trauma in a female twin sample.",
        "key_reference_abstract": "Several studies have implicated an insertion/deletion polymorphism in the promoter region of the serotonin transporter gene (SLC6A4; 5-HTT) in the development of mood disorders. In the present study of a sample of 247 young adult female twins from Missouri, we examine whether this polymorphism interacts with the effect of adverse life events to increase risk for developing depression. We found a significant interaction between the number of high-activity L(A) alleles and exposure to trauma (OR = 1.70, P < 0.0001). This differs from previous reports, in that the higher activity genotypes (L(A)/L(A), L(A)/S, L(A)/L(G)), rather than the low activity genotypes (S/S, S/L(G), L(G)/L(G)), are associated with an increased incidence of major depressive disease (MDD) in the presence of environmental trauma.",
        "truth": "True"
    },
    {
        "pmid": "19531786",
        "meta_analysis_title": "Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis.",
        "meta_analysis_question": "Does the interaction between the serotonin transporter gene (5-HTTLPR) and stressful life events increase the risk of depression?",
        "criteria": "A search of the PubMed, EMBASE, and PsycINFO databases was conducted through March 2009 using the search terms life stress, life event, depression, depress, serotonin transporter, 5-HTTLPR, interaction, and moderation. Bibliographies of studies were also reviewed. A total of 26 articles published or set for publication were identified through this search strategy (Figure 1). Inclusion criteria for studies for the meta-analyses were published articles that included data on the association between the (1) 5-HTTLPR genotype (S, SL, or LL), (2) number of stressful life events (0, 1, 2, or \u22653) or equivalent, and (3) categorical measure of depression defined by the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) or International Statistical Classification of Diseases, 10th Revision (ICD-10) or ability to use a cut point to define depression from standardized rating scales. To maximize our ability to use a common framework for variable definition, we also requested original data from all studies that appeared to meet inclusion criteria published prior to 2008.10,15-28 We received original data in a usable format for the meta-analysis from 10 of the 14 study investigators. A total of 14 studies were included in the analysis, 15-20,23,25-27,29-32 10 of which15-20,23,25-27,29,30 were also included in a second sex-specific meta-analysis of original data. Nine other studies did not meet inclusion criteria.33-41",
        "subgroup": "Logistic Regression Analyses of Depression for 10 Studies Stratified by Sex - Risk per stressful life event",
        "key_reference_title": "Family based association analyses between the serotonin transporter gene polymorphism (5-HTTLPR) and neuroticism, anxiety and depression.",
        "key_reference_abstract": "We studied the association between the short/long promotor-based length polymorphism of the serotonin transporter gene (5-HTTLPR) and neuroticism, anxiety and depression. Subjects included twins, their siblings and parents from the Netherlands Twin Register (559 parents and 1,245 offspring). Subjects had participated between one and five times in a survey study measuring neuroticism, anxiety and depression. Offspring of these families were also approached to participate in a psychiatric interview diagnosing DSM-IV major depression. Within-family and total association between 5-HTTLPR and these traits were tested. Only three of the 36 tests showed a significant effect of 5-HTTLPR (P<0.05). These effects were in opposite directions, i.e. both negative and positive regression coefficients were found for the s allele. No additive effect of the s allele was found for DSM-IV depression. Our results strongly suggest that there is no straightforward association between 5-HTTLPR and neuroticism, anxiety and depression.",
        "truth": "True"
    },
    {
        "pmid": "19531786",
        "meta_analysis_title": "Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis.",
        "meta_analysis_question": "Does the interaction between the serotonin transporter gene (5-HTTLPR) and stressful life events increase the risk of depression?",
        "criteria": "A search of the PubMed, EMBASE, and PsycINFO databases was conducted through March 2009 using the search terms life stress, life event, depression, depress, serotonin transporter, 5-HTTLPR, interaction, and moderation. Bibliographies of studies were also reviewed. A total of 26 articles published or set for publication were identified through this search strategy (Figure 1). Inclusion criteria for studies for the meta-analyses were published articles that included data on the association between the (1) 5-HTTLPR genotype (S, SL, or LL), (2) number of stressful life events (0, 1, 2, or \u22653) or equivalent, and (3) categorical measure of depression defined by the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) or International Statistical Classification of Diseases, 10th Revision (ICD-10) or ability to use a cut point to define depression from standardized rating scales. To maximize our ability to use a common framework for variable definition, we also requested original data from all studies that appeared to meet inclusion criteria published prior to 2008.10,15-28 We received original data in a usable format for the meta-analysis from 10 of the 14 study investigators. A total of 14 studies were included in the analysis, 15-20,23,25-27,29-32 10 of which15-20,23,25-27,29,30 were also included in a second sex-specific meta-analysis of original data. Nine other studies did not meet inclusion criteria.33-41",
        "subgroup": "Logistic Regression Analyses of Depression for 10 Studies Stratified by Sex - Risk per stressful life event",
        "key_reference_title": "No interaction between the serotonin transporter polymorphism (5-HTTLPR) and childhood adversity or recent stressful life events on symptoms of depression: results from two community surveys.",
        "key_reference_abstract": "In this study we investigated interactions between the 5-HTTLPR genotype and environmental risk factors (G x E) on symptoms of depression in two large Australian community samples of adolescents and young adults. We postulated that a significant interaction between the 5-HTTLPR genotype and environmental risk factors of childhood adversity or stressful life events on symptoms of depression would be observed in subjects with at least one short allele (s/l or s/s) compared with subjects with no short alleles (l/l). We did not find significant G x E interactions between the 5-HTTLPR genotype and recent stressful life events or childhood adversity on symptoms of depression in our sample populations. However, we did find adolescents aged 17-18 years homozygous for the long allele (l/l) and exposed to persistently high levels of family adversity over a 6-year period were at a greater risk of depression than subjects with the same genotype exposed to no or persistently low levels of family adversity. This interaction should be interpreted cautiously due to the small number of depressed subjects in the sample with persistently high levels of family adversity.",
        "truth": "True"
    },
    {
        "pmid": "19531786",
        "meta_analysis_title": "Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis.",
        "meta_analysis_question": "Does the interaction between the serotonin transporter gene (5-HTTLPR) and stressful life events increase the risk of depression?",
        "criteria": "A search of the PubMed, EMBASE, and PsycINFO databases was conducted through March 2009 using the search terms life stress, life event, depression, depress, serotonin transporter, 5-HTTLPR, interaction, and moderation. Bibliographies of studies were also reviewed. A total of 26 articles published or set for publication were identified through this search strategy (Figure 1). Inclusion criteria for studies for the meta-analyses were published articles that included data on the association between the (1) 5-HTTLPR genotype (S, SL, or LL), (2) number of stressful life events (0, 1, 2, or \u22653) or equivalent, and (3) categorical measure of depression defined by the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) or International Statistical Classification of Diseases, 10th Revision (ICD-10) or ability to use a cut point to define depression from standardized rating scales. To maximize our ability to use a common framework for variable definition, we also requested original data from all studies that appeared to meet inclusion criteria published prior to 2008.10,15-28 We received original data in a usable format for the meta-analysis from 10 of the 14 study investigators. A total of 14 studies were included in the analysis, 15-20,23,25-27,29-32 10 of which15-20,23,25-27,29,30 were also included in a second sex-specific meta-analysis of original data. Nine other studies did not meet inclusion criteria.33-41",
        "subgroup": "Logistic Regression Analyses of Depression for 10 Studies Stratified by Sex - Risk per stressful life event",
        "key_reference_title": "The risk for depression conferred by stressful life events is modified by variation at the serotonin transporter 5HTTLPR genotype: evidence from the Spanish PREDICT-Gene cohort.",
        "key_reference_abstract": "We report results from the PREDICT-Gene case-control study nested in a prospective cohort designed to identify predictors of the onset of depression among adult primary-care attendees. We tested the potential gene-by-environment interaction between 5HTTLPR genotype at the serotonin transporter gene and previous exposure to threatening life events (TLEs) in depression. A total of 737 consecutively recruited participants were genotyped. Additional information was gathered on exposure to TLEs over a 6-month period, socio-demographic data and family history of psychological problems among first-degree relatives. Diagnoses of depression were ascertained using the Composite International Diagnostic Interview (CIDI) by trained interviewers. Two different depressive outcomes were used (ICD-10 depressive episode and ICD-10 severe depressive episode). Both the s/s genotype and exposure to increasing number of TLEs were significantly associated with depression. Moreover, the 5HTTLPR s/s genotype significantly modified the risk conferred by TLEs for both depressive outcomes. Thus, s/s homozygous participants required minimal exposure to TLE (1 TLE) to acquire a level of risk for depression that was only found among l/s or l/l individuals after significantly higher exposure to TLEs (two or more TLEs). The interaction was more apparent when applied to the diagnosis of ICD-10 severe depressive episode and after adjusting for gender, age and family history of psychological problems. Likelihood ratios tests for the interaction were statistically significant for both depressive outcomes (ICD-10 depressive episode: LR X(2)=4.7, P=0.09 (crude), LR-X(2)=6.4, P=0.04 (adjusted); ICD-10 severe depressive episode: LR X(2)=6.9, P=0.032 (crude), LR-X(2)=8.1, P=0.017 (adjusted)).",
        "truth": "False"
    },
    {
        "pmid": "19531786",
        "meta_analysis_title": "Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis.",
        "meta_analysis_question": "Does the interaction between the serotonin transporter gene (5-HTTLPR) and stressful life events increase the risk of depression?",
        "criteria": "A search of the PubMed, EMBASE, and PsycINFO databases was conducted through March 2009 using the search terms life stress, life event, depression, depress, serotonin transporter, 5-HTTLPR, interaction, and moderation. Bibliographies of studies were also reviewed. A total of 26 articles published or set for publication were identified through this search strategy (Figure 1). Inclusion criteria for studies for the meta-analyses were published articles that included data on the association between the (1) 5-HTTLPR genotype (S, SL, or LL), (2) number of stressful life events (0, 1, 2, or \u22653) or equivalent, and (3) categorical measure of depression defined by the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) or International Statistical Classification of Diseases, 10th Revision (ICD-10) or ability to use a cut point to define depression from standardized rating scales. To maximize our ability to use a common framework for variable definition, we also requested original data from all studies that appeared to meet inclusion criteria published prior to 2008.10,15-28 We received original data in a usable format for the meta-analysis from 10 of the 14 study investigators. A total of 14 studies were included in the analysis, 15-20,23,25-27,29-32 10 of which15-20,23,25-27,29,30 were also included in a second sex-specific meta-analysis of original data. Nine other studies did not meet inclusion criteria.33-41",
        "subgroup": "Logistic Regression Analyses of Depression for 10 Studies Stratified by Sex - Risk per stressful life event",
        "key_reference_title": "Interactions between life stressors and susceptibility genes (5-HTTLPR and BDNF) on depression in Korean elders.",
        "key_reference_abstract": "## BACKGROUND\nIt has been reported that the functional polymorphism in the serotonin transporter gene linked promoter region (5-HTTLPR) modifies the association between stressful life events (SLEs) and depression in child, adolescent, and adult populations. We sought to replicate this finding in elders and, additionally, to test modifying effects of the brain-derived neurotrophic factor (BDNF) val66met polymorphism.\n## METHODS\nIn 732 Korean community residents ages 65+, diagnosis of depression (Geriatric Mental State Schedule), information on SLEs, and genotypes for 5-HTTLPR and BDNF val66met were ascertained. Of those without depression at baseline, 521 (88%) were followed up 2.5 years later. Interactions between SLEs and the two genotypes were investigated for both prevalent depression at baseline and incident depression at follow-up.\n## RESULTS\nSignificant interactions of SLEs with both 5-HTTLPR and BDNF genotypes were observed on risk of depression after adjustment for age, gender, education, and disability. A significant three-way interaction between 5-HTTLPR, BDNF, and SLEs was also found. The same findings were observed for predictors of incident depression in the prospective analysis.\n## CONCLUSIONS\nThese findings suggest that environmental risk of depression is modified by at least two genes and that gene-environment interactions are found even into old age.",
        "truth": "False"
    },
    {
        "pmid": "19531786",
        "meta_analysis_title": "Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis.",
        "meta_analysis_question": "Does the interaction between the serotonin transporter gene (5-HTTLPR) and stressful life events increase the risk of depression?",
        "criteria": "A search of the PubMed, EMBASE, and PsycINFO databases was conducted through March 2009 using the search terms life stress, life event, depression, depress, serotonin transporter, 5-HTTLPR, interaction, and moderation. Bibliographies of studies were also reviewed. A total of 26 articles published or set for publication were identified through this search strategy (Figure 1). Inclusion criteria for studies for the meta-analyses were published articles that included data on the association between the (1) 5-HTTLPR genotype (S, SL, or LL), (2) number of stressful life events (0, 1, 2, or \u22653) or equivalent, and (3) categorical measure of depression defined by the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) or International Statistical Classification of Diseases, 10th Revision (ICD-10) or ability to use a cut point to define depression from standardized rating scales. To maximize our ability to use a common framework for variable definition, we also requested original data from all studies that appeared to meet inclusion criteria published prior to 2008.10,15-28 We received original data in a usable format for the meta-analysis from 10 of the 14 study investigators. A total of 14 studies were included in the analysis, 15-20,23,25-27,29-32 10 of which15-20,23,25-27,29,30 were also included in a second sex-specific meta-analysis of original data. Nine other studies did not meet inclusion criteria.33-41",
        "subgroup": "Logistic Regression Analyses of Depression for 10 Studies Stratified by Sex - Risk per stressful life event",
        "key_reference_title": "5-HTTLPR genotype, stressful life events and late-life depression: no evidence of interaction in a French population.",
        "key_reference_abstract": "Modification of the effect of life events on risk of depression by a polymorphism in the serotonin transporter gene promoter (5-HTTLPR) has been reported in child, adolescent, adult and elderly populations. Replication attempted on data collected from 1421 individuals aged 65 and over from a French community study provided no evidence of a similar modifying effect. In the only analysis known to the authors to be carried out in an exclusively elderly, European population, this null finding remained consistent after restriction of analysis to prevalent or incident cases.",
        "truth": "False"
    },
    {
        "pmid": "19531786",
        "meta_analysis_title": "Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis.",
        "meta_analysis_question": "Does the interaction between the serotonin transporter gene (5-HTTLPR) and stressful life events increase the risk of depression?",
        "criteria": "A search of the PubMed, EMBASE, and PsycINFO databases was conducted through March 2009 using the search terms life stress, life event, depression, depress, serotonin transporter, 5-HTTLPR, interaction, and moderation. Bibliographies of studies were also reviewed. A total of 26 articles published or set for publication were identified through this search strategy (Figure 1). Inclusion criteria for studies for the meta-analyses were published articles that included data on the association between the (1) 5-HTTLPR genotype (S, SL, or LL), (2) number of stressful life events (0, 1, 2, or \u22653) or equivalent, and (3) categorical measure of depression defined by the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) or International Statistical Classification of Diseases, 10th Revision (ICD-10) or ability to use a cut point to define depression from standardized rating scales. To maximize our ability to use a common framework for variable definition, we also requested original data from all studies that appeared to meet inclusion criteria published prior to 2008.10,15-28 We received original data in a usable format for the meta-analysis from 10 of the 14 study investigators. A total of 14 studies were included in the analysis, 15-20,23,25-27,29-32 10 of which15-20,23,25-27,29,30 were also included in a second sex-specific meta-analysis of original data. Nine other studies did not meet inclusion criteria.33-41",
        "subgroup": "Logistic Regression Analyses of Depression for 10 Studies Stratified by Sex - Risk per stressful life event",
        "key_reference_title": "Interaction between the 5-HTTLPR serotonin transporter polymorphism and environmental adversity for mood and anxiety psychopathology: evidence from a high-risk community sample of young adults.",
        "key_reference_abstract": "Previous research examining gene-environment interaction (GxE) with regard to vulnerability to depression and anxiety has yielded conflicting results. The present study was designed to further investigate GxE between 5-HTTLPR and exposure to environmental adversity, using different phenotypic and genotypic characterizations as well as different types of adversity within a prospective study design. Data were available from an ongoing epidemiological cohort study following the outcome of early risk factors from birth to adulthood. At age 19 yr, 309 participants (142 males, 167 females) were characterized on measures of depression and anxiety through interview and questionnaire (DSM-IV diagnosis, Beck Depression Inventory, Harm Avoidance). Environmental adversity was assessed at birth (family adversity), and at age 19 yr (stressful life events). Bi- and tri-allelic 5-HTTLPR genotypes were obtained from genomic DNA. Results indicated that depression and anxiety in 19-yr-olds were strongly associated with both family adversity and stressful life events. Individuals with the LL genotype of 5-HTTLPR who were exposed to high family adversity displayed significantly higher rates of depressive or anxiety disorders and had more depressive symptoms than those without either condition. This GxE replicates recent findings from an epidemiological cohort study of adolescents but is in contrast to many previous reports suggesting an interaction with the S allele. No evidence for GxE was obtained with regard to current stressful life events and trait anxiety. One possible source for the conflicting findings might be attributed to heterogeneity in depression phenotypes and environmental adversity.",
        "truth": "False"
    },
    {
        "pmid": "19531786",
        "meta_analysis_title": "Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis.",
        "meta_analysis_question": "Does the interaction between the serotonin transporter gene (5-HTTLPR) and stressful life events increase the risk of depression?",
        "criteria": "A search of the PubMed, EMBASE, and PsycINFO databases was conducted through March 2009 using the search terms life stress, life event, depression, depress, serotonin transporter, 5-HTTLPR, interaction, and moderation. Bibliographies of studies were also reviewed. A total of 26 articles published or set for publication were identified through this search strategy (Figure 1). Inclusion criteria for studies for the meta-analyses were published articles that included data on the association between the (1) 5-HTTLPR genotype (S, SL, or LL), (2) number of stressful life events (0, 1, 2, or \u22653) or equivalent, and (3) categorical measure of depression defined by the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) or International Statistical Classification of Diseases, 10th Revision (ICD-10) or ability to use a cut point to define depression from standardized rating scales. To maximize our ability to use a common framework for variable definition, we also requested original data from all studies that appeared to meet inclusion criteria published prior to 2008.10,15-28 We received original data in a usable format for the meta-analysis from 10 of the 14 study investigators. A total of 14 studies were included in the analysis, 15-20,23,25-27,29-32 10 of which15-20,23,25-27,29,30 were also included in a second sex-specific meta-analysis of original data. Nine other studies did not meet inclusion criteria.33-41",
        "subgroup": "Logistic Regression Analyses of Depression for 10 Studies Stratified by Sex - Interaction of genotype and stressful life events",
        "key_reference_title": "Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene.",
        "key_reference_abstract": "In a prospective-longitudinal study of a representative birth cohort, we tested why stressful experiences lead to depression in some people but not in others. A functional polymorphism in the promoter region of the serotonin transporter (5-HT T) gene was found to moderate the influence of stressful life events on depression. Individuals with one or two copies of the short allele of the 5-HT T promoter polymorphism exhibited more depressive symptoms, diagnosable depression, and suicidality in relation to stressful life events than individuals homozygous for the long allele. This epidemiological study thus provides evidence of a gene-by-environment interaction, in which an individual's response to environmental insults is moderated by his or her genetic makeup.",
        "truth": "False"
    },
    {
        "pmid": "19531786",
        "meta_analysis_title": "Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis.",
        "meta_analysis_question": "Does the interaction between the serotonin transporter gene (5-HTTLPR) and stressful life events increase the risk of depression?",
        "criteria": "A search of the PubMed, EMBASE, and PsycINFO databases was conducted through March 2009 using the search terms life stress, life event, depression, depress, serotonin transporter, 5-HTTLPR, interaction, and moderation. Bibliographies of studies were also reviewed. A total of 26 articles published or set for publication were identified through this search strategy (Figure 1). Inclusion criteria for studies for the meta-analyses were published articles that included data on the association between the (1) 5-HTTLPR genotype (S, SL, or LL), (2) number of stressful life events (0, 1, 2, or \u22653) or equivalent, and (3) categorical measure of depression defined by the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) or International Statistical Classification of Diseases, 10th Revision (ICD-10) or ability to use a cut point to define depression from standardized rating scales. To maximize our ability to use a common framework for variable definition, we also requested original data from all studies that appeared to meet inclusion criteria published prior to 2008.10,15-28 We received original data in a usable format for the meta-analysis from 10 of the 14 study investigators. A total of 14 studies were included in the analysis, 15-20,23,25-27,29-32 10 of which15-20,23,25-27,29,30 were also included in a second sex-specific meta-analysis of original data. Nine other studies did not meet inclusion criteria.33-41",
        "subgroup": "Logistic Regression Analyses of Depression for 10 Studies Stratified by Sex - Interaction of genotype and stressful life events",
        "key_reference_title": "Gene-environment interaction analysis of serotonin system markers with adolescent depression.",
        "key_reference_abstract": "We report analyses from a study of gene-environment interaction in adolescent depression. The sample was selected from 1990 adolescents aged 10-20 years: those with depression symptoms in the top or bottom 15% were identified and divided into high or low environmental risk groups. DNA was obtained from 377 adolescents, representing the four quadrants of high or low depression and high or low environmental risk. Markers within, or close to, each of the serotonergic genes 5HTT, HTR2A, HTR2C, MAOA (monoamine oxidase type A) and tryptophan hydroxylase (TPH) were genotyped. Environmental risk group was a nonsignificant predictor and sex was a significant predictor of the depression group. HTR2A and TPH significantly predicted the depression group, independent of the effects of sex, environmental risk group and their interaction. In addition, there was a trend for an effect of 5HTTLPR, which was significant in female subjects. Furthermore, there was a significant genotype-environmental risk interaction for 5HTTLPR in female subjects only, with the effect being in the same direction as another recent study, reaffirming that an important source of genetic heterogeneity is exposure to environmental risk.",
        "truth": "True"
    },
    {
        "pmid": "19531786",
        "meta_analysis_title": "Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis.",
        "meta_analysis_question": "Does the interaction between the serotonin transporter gene (5-HTTLPR) and stressful life events increase the risk of depression?",
        "criteria": "A search of the PubMed, EMBASE, and PsycINFO databases was conducted through March 2009 using the search terms life stress, life event, depression, depress, serotonin transporter, 5-HTTLPR, interaction, and moderation. Bibliographies of studies were also reviewed. A total of 26 articles published or set for publication were identified through this search strategy (Figure 1). Inclusion criteria for studies for the meta-analyses were published articles that included data on the association between the (1) 5-HTTLPR genotype (S, SL, or LL), (2) number of stressful life events (0, 1, 2, or \u22653) or equivalent, and (3) categorical measure of depression defined by the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) or International Statistical Classification of Diseases, 10th Revision (ICD-10) or ability to use a cut point to define depression from standardized rating scales. To maximize our ability to use a common framework for variable definition, we also requested original data from all studies that appeared to meet inclusion criteria published prior to 2008.10,15-28 We received original data in a usable format for the meta-analysis from 10 of the 14 study investigators. A total of 14 studies were included in the analysis, 15-20,23,25-27,29-32 10 of which15-20,23,25-27,29,30 were also included in a second sex-specific meta-analysis of original data. Nine other studies did not meet inclusion criteria.33-41",
        "subgroup": "Logistic Regression Analyses of Depression for 10 Studies Stratified by Sex - Interaction of genotype and stressful life events",
        "key_reference_title": "The relationship between stressful life events, the serotonin transporter (5-HTTLPR) genotype and major depression.",
        "key_reference_abstract": "## BACKGROUND\nSerotonin is a good candidate for major depression. We attempted to replicate the study by Caspi and colleagues [Science (2003) 301, 386-389] which reported a significant interaction between serotonin transporter (5-HTTLPR) genotype and stressful life events when predicting major depression.\n## METHOD\nWe typed the serotonin promoter 5-HTTLPR gene in 1206 male and female twins aged 19-78 years (mean = 39, S.D. = 11). A DSM-IV diagnosis of major depression was available for 1199 twins. Most of these twins had participated in a 1988-1990 study which included a stressful life events inventory and self-report measure of depression based on the SCL-90 and DSSI/sAD. Complete 5-HTT genotype and life events data, self-report symptoms and major depression diagnoses were available for 1091 subjects. We regressed categorical and ordinal measures of depression onto stressful life events and genotype.\n## RESULTS\nThere were significant main effects for stressful life events but there was no evidence for any effect of 5-HTT genotype, nor a genotype x stressful life event interaction.\n## CONCLUSIONS\nRegardless of whether our results were based on binary logistic or ordinal regression analyses we found no evidence to support a main effect of 5-HTTLPR, or an interaction between the 5-HTTLPR genotype and stressful life events on major depression, Only 20 % of our subjects were aged below 30 years. It is possible that the effect reported by Caspi and colleagues is specific to young people, in which case our study has much less power in this age group.",
        "truth": "True"
    },
    {
        "pmid": "19531786",
        "meta_analysis_title": "Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis.",
        "meta_analysis_question": "Does the interaction between the serotonin transporter gene (5-HTTLPR) and stressful life events increase the risk of depression?",
        "criteria": "A search of the PubMed, EMBASE, and PsycINFO databases was conducted through March 2009 using the search terms life stress, life event, depression, depress, serotonin transporter, 5-HTTLPR, interaction, and moderation. Bibliographies of studies were also reviewed. A total of 26 articles published or set for publication were identified through this search strategy (Figure 1). Inclusion criteria for studies for the meta-analyses were published articles that included data on the association between the (1) 5-HTTLPR genotype (S, SL, or LL), (2) number of stressful life events (0, 1, 2, or \u22653) or equivalent, and (3) categorical measure of depression defined by the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) or International Statistical Classification of Diseases, 10th Revision (ICD-10) or ability to use a cut point to define depression from standardized rating scales. To maximize our ability to use a common framework for variable definition, we also requested original data from all studies that appeared to meet inclusion criteria published prior to 2008.10,15-28 We received original data in a usable format for the meta-analysis from 10 of the 14 study investigators. A total of 14 studies were included in the analysis, 15-20,23,25-27,29-32 10 of which15-20,23,25-27,29,30 were also included in a second sex-specific meta-analysis of original data. Nine other studies did not meet inclusion criteria.33-41",
        "subgroup": "Logistic Regression Analyses of Depression for 10 Studies Stratified by Sex - Interaction of genotype and stressful life events",
        "key_reference_title": "Mental and physical distress is modulated by a polymorphism in the 5-HT transporter gene interacting with social stressors and chronic disease burden.",
        "key_reference_abstract": "Previous studies have yielded conflicting results as to the putative role of the functional polymorphism of the promoter region of the serotonin transporter gene (SLC6A4) in the etiology of anxiety-related traits and depressive disorders. Recently, a significant gene-environment interaction was found between life stressors, the short allele of the SLC6A4 polymorphism and depression. The aim of the present study was to investigate if such a gene-environment interaction could be replicated within a different population with a different risk structure. A total of 1005 subjects from a general population sample (Study of Health in Pomerania) were genotyped. Mental and physical distress were assessed on 38 items of the modified complaint scale (BL-38). The interaction between the SLC6A4 genotype, social stressors and chronic diseases with regard to the BL-38 score was evaluated by ANOVA. There was no independent association of genotype with mental and physical distress. However, significant interactions between genotype, unemployment and chronic diseases (F = 6.6; df = 3, 671; P < 0.001) were found in females but not in males. The genotype explained 2% of the total variance of the BL-38 score and 9.1% of the explained variance. The results partly confirm previous findings of a significant gene-environment interaction of the short allele, indicating a higher mental vulnerability to social stressors and chronic diseases. The relevance of this finding is sustained by the fact that the sample characteristics and the risk structure were highly different from previous studies.",
        "truth": "True"
    },
    {
        "pmid": "19531786",
        "meta_analysis_title": "Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis.",
        "meta_analysis_question": "Does the interaction between the serotonin transporter gene (5-HTTLPR) and stressful life events increase the risk of depression?",
        "criteria": "A search of the PubMed, EMBASE, and PsycINFO databases was conducted through March 2009 using the search terms life stress, life event, depression, depress, serotonin transporter, 5-HTTLPR, interaction, and moderation. Bibliographies of studies were also reviewed. A total of 26 articles published or set for publication were identified through this search strategy (Figure 1). Inclusion criteria for studies for the meta-analyses were published articles that included data on the association between the (1) 5-HTTLPR genotype (S, SL, or LL), (2) number of stressful life events (0, 1, 2, or \u22653) or equivalent, and (3) categorical measure of depression defined by the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) or International Statistical Classification of Diseases, 10th Revision (ICD-10) or ability to use a cut point to define depression from standardized rating scales. To maximize our ability to use a common framework for variable definition, we also requested original data from all studies that appeared to meet inclusion criteria published prior to 2008.10,15-28 We received original data in a usable format for the meta-analysis from 10 of the 14 study investigators. A total of 14 studies were included in the analysis, 15-20,23,25-27,29-32 10 of which15-20,23,25-27,29,30 were also included in a second sex-specific meta-analysis of original data. Nine other studies did not meet inclusion criteria.33-41",
        "subgroup": "Logistic Regression Analyses of Depression for 10 Studies Stratified by Sex - Interaction of genotype and stressful life events",
        "key_reference_title": "Social adversity, the serotonin transporter (5-HTTLPR) polymorphism and major depressive disorder.",
        "key_reference_abstract": "## BACKGROUND\nRecent evidence has suggested that the short allele of the serotonin transporter (5-HTT) gene-linked polymorphic region (5-HTTLPR of the human serotonin gene [SLC6A4]) is associated with increased risk of depressive disorder but only among individuals exposed to social adversity. We report an investigation designed to replicate this finding.\n## METHODS\nData were available from a non-clinical sample of 4,175 adult men and women, ages 41-80 years, selected from participants in the European Prospective Investigation into Cancer and Nutrition in Norfolk (EPIC-Norfolk, United Kingdom) study. Evidence of past-year prevalent episodic major depressive disorder (MDD), defined by restricted DSM-IV diagnostic criteria, was assessed through questionnaire. Adverse experiences in childhood and in adulthood (during the five years preceding assessment) were also assessed through self-report. The 5-HTTLPR variant was genotyped according to published protocols.\n## RESULTS\nOne-year prevalent MDD criteria were met by 298 study participants. The experience of social adversity (both in childhood and adulthood) was strongly associated with increased rates of past-year prevalent MDD. No gene by environment (GxE) interactions between the 5-HTTLPR genotype, social adversity, and MDD were observed.\n## CONCLUSIONS\nThis study has not replicated a previous finding of a GxE interaction between the 5-HTTLPR genotype, social adversity, and depression.",
        "truth": "True"
    },
    {
        "pmid": "19531786",
        "meta_analysis_title": "Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis.",
        "meta_analysis_question": "Does the interaction between the serotonin transporter gene (5-HTTLPR) and stressful life events increase the risk of depression?",
        "criteria": "A search of the PubMed, EMBASE, and PsycINFO databases was conducted through March 2009 using the search terms life stress, life event, depression, depress, serotonin transporter, 5-HTTLPR, interaction, and moderation. Bibliographies of studies were also reviewed. A total of 26 articles published or set for publication were identified through this search strategy (Figure 1). Inclusion criteria for studies for the meta-analyses were published articles that included data on the association between the (1) 5-HTTLPR genotype (S, SL, or LL), (2) number of stressful life events (0, 1, 2, or \u22653) or equivalent, and (3) categorical measure of depression defined by the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) or International Statistical Classification of Diseases, 10th Revision (ICD-10) or ability to use a cut point to define depression from standardized rating scales. To maximize our ability to use a common framework for variable definition, we also requested original data from all studies that appeared to meet inclusion criteria published prior to 2008.10,15-28 We received original data in a usable format for the meta-analysis from 10 of the 14 study investigators. A total of 14 studies were included in the analysis, 15-20,23,25-27,29-32 10 of which15-20,23,25-27,29,30 were also included in a second sex-specific meta-analysis of original data. Nine other studies did not meet inclusion criteria.33-41",
        "subgroup": "Logistic Regression Analyses of Depression for 10 Studies Stratified by Sex - Interaction of genotype and stressful life events",
        "key_reference_title": "Life events, first depression onset and the serotonin transporter gene.",
        "key_reference_abstract": "## BACKGROUND\nA relationship between the serotonin transporter gene, adverse events and onset of major depression has been reported.\n## AIMS\nTo replicate a gene x environment interaction in a cohort with longitudinal data for life events, experience of depression, parental bonding and neuroticism.\n## METHOD\nAt the 25-year follow-up, genomic DNA was obtained from 127 cohort members (mean age 48 years) to determine the genotype of the serotonin transporter gene-linked promoter region (5-HTTLPR). Associations were investigated between the 5-HTTLPR genotype, positive and adverse life events and the gene x environment interaction, and also between the 5-HTTLPR genotype and risk factors for depression.\n## RESULTS\nNo relationship was found between 5-HTTLPR genotype and either risk factors for depression or positive life events. Adverse life events had a significantly greater impact on the onset of depression for individuals with the s/s genotype.\n## CONCLUSIONS\nThe 5-HTTLPR genotype is a significant predictor of onset of major depression following multiple adverse events. This is one of the more robust findings concerning specific biological risk factors for depression.",
        "truth": "True"
    },
    {
        "pmid": "19531786",
        "meta_analysis_title": "Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis.",
        "meta_analysis_question": "Does the interaction between the serotonin transporter gene (5-HTTLPR) and stressful life events increase the risk of depression?",
        "criteria": "A search of the PubMed, EMBASE, and PsycINFO databases was conducted through March 2009 using the search terms life stress, life event, depression, depress, serotonin transporter, 5-HTTLPR, interaction, and moderation. Bibliographies of studies were also reviewed. A total of 26 articles published or set for publication were identified through this search strategy (Figure 1). Inclusion criteria for studies for the meta-analyses were published articles that included data on the association between the (1) 5-HTTLPR genotype (S, SL, or LL), (2) number of stressful life events (0, 1, 2, or \u22653) or equivalent, and (3) categorical measure of depression defined by the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) or International Statistical Classification of Diseases, 10th Revision (ICD-10) or ability to use a cut point to define depression from standardized rating scales. To maximize our ability to use a common framework for variable definition, we also requested original data from all studies that appeared to meet inclusion criteria published prior to 2008.10,15-28 We received original data in a usable format for the meta-analysis from 10 of the 14 study investigators. A total of 14 studies were included in the analysis, 15-20,23,25-27,29-32 10 of which15-20,23,25-27,29,30 were also included in a second sex-specific meta-analysis of original data. Nine other studies did not meet inclusion criteria.33-41",
        "subgroup": "Logistic Regression Analyses of Depression for 10 Studies Stratified by Sex - Interaction of genotype and stressful life events",
        "key_reference_title": "Early family environment, current adversity, the serotonin transporter promoter polymorphism, and depressive symptomatology.",
        "key_reference_abstract": "## BACKGROUND\nMixed evidence has suggested that homozygous carriers of the short allele (s/s) of the serotonin transporter gene-linked polymorphic region (5-HTTLPR) may be at increased risk for depression, if they have also been exposed to early or current adversity/stress. We address this debate by examining the relation of a stressful early family environment, recent adversity/stress, and the 5-HTTLPR to depressive symptomatology in a normal sample.\n## METHODS\nA nonclinical sample of 118 young adult men and women completed assessments of early family environment, recent stressful events, psychosocial resources, and psychological distress, including depressive symptomatology. The 5-HTTLPR was genotyped using a standard protocol with DNA extracted from oral fluid.\n## RESULTS\nA stressful early family environment was significantly related to depressive symptomatology. In addition, gene-by-environment (GxE) interactions were observed between the 5-HTTLPR and both early family environment and current adversity/stress. Individuals homozygous for the short allele had greater depressive symptomatology if they had experienced early or recent adversity but significantly less depressive symptomatology if they reported a supportive early environment or recent positive experiences, compared with participants with the s/l or l/l genotype.\n## CONCLUSIONS\nEarly or current environment, in conjunction with the serotonin transporter polymorphism, predicts depressive symptomatology.",
        "truth": "False"
    },
    {
        "pmid": "19531786",
        "meta_analysis_title": "Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis.",
        "meta_analysis_question": "Does the interaction between the serotonin transporter gene (5-HTTLPR) and stressful life events increase the risk of depression?",
        "criteria": "A search of the PubMed, EMBASE, and PsycINFO databases was conducted through March 2009 using the search terms life stress, life event, depression, depress, serotonin transporter, 5-HTTLPR, interaction, and moderation. Bibliographies of studies were also reviewed. A total of 26 articles published or set for publication were identified through this search strategy (Figure 1). Inclusion criteria for studies for the meta-analyses were published articles that included data on the association between the (1) 5-HTTLPR genotype (S, SL, or LL), (2) number of stressful life events (0, 1, 2, or \u22653) or equivalent, and (3) categorical measure of depression defined by the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) or International Statistical Classification of Diseases, 10th Revision (ICD-10) or ability to use a cut point to define depression from standardized rating scales. To maximize our ability to use a common framework for variable definition, we also requested original data from all studies that appeared to meet inclusion criteria published prior to 2008.10,15-28 We received original data in a usable format for the meta-analysis from 10 of the 14 study investigators. A total of 14 studies were included in the analysis, 15-20,23,25-27,29-32 10 of which15-20,23,25-27,29,30 were also included in a second sex-specific meta-analysis of original data. Nine other studies did not meet inclusion criteria.33-41",
        "subgroup": "Logistic Regression Analyses of Depression for 10 Studies Stratified by Sex - Interaction of genotype and stressful life events",
        "key_reference_title": "Relationship of 5-HTTLPR genotypes and depression risk in the presence of trauma in a female twin sample.",
        "key_reference_abstract": "Several studies have implicated an insertion/deletion polymorphism in the promoter region of the serotonin transporter gene (SLC6A4; 5-HTT) in the development of mood disorders. In the present study of a sample of 247 young adult female twins from Missouri, we examine whether this polymorphism interacts with the effect of adverse life events to increase risk for developing depression. We found a significant interaction between the number of high-activity L(A) alleles and exposure to trauma (OR = 1.70, P < 0.0001). This differs from previous reports, in that the higher activity genotypes (L(A)/L(A), L(A)/S, L(A)/L(G)), rather than the low activity genotypes (S/S, S/L(G), L(G)/L(G)), are associated with an increased incidence of major depressive disease (MDD) in the presence of environmental trauma.",
        "truth": "True"
    },
    {
        "pmid": "19531786",
        "meta_analysis_title": "Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis.",
        "meta_analysis_question": "Does the interaction between the serotonin transporter gene (5-HTTLPR) and stressful life events increase the risk of depression?",
        "criteria": "A search of the PubMed, EMBASE, and PsycINFO databases was conducted through March 2009 using the search terms life stress, life event, depression, depress, serotonin transporter, 5-HTTLPR, interaction, and moderation. Bibliographies of studies were also reviewed. A total of 26 articles published or set for publication were identified through this search strategy (Figure 1). Inclusion criteria for studies for the meta-analyses were published articles that included data on the association between the (1) 5-HTTLPR genotype (S, SL, or LL), (2) number of stressful life events (0, 1, 2, or \u22653) or equivalent, and (3) categorical measure of depression defined by the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) or International Statistical Classification of Diseases, 10th Revision (ICD-10) or ability to use a cut point to define depression from standardized rating scales. To maximize our ability to use a common framework for variable definition, we also requested original data from all studies that appeared to meet inclusion criteria published prior to 2008.10,15-28 We received original data in a usable format for the meta-analysis from 10 of the 14 study investigators. A total of 14 studies were included in the analysis, 15-20,23,25-27,29-32 10 of which15-20,23,25-27,29,30 were also included in a second sex-specific meta-analysis of original data. Nine other studies did not meet inclusion criteria.33-41",
        "subgroup": "Logistic Regression Analyses of Depression for 10 Studies Stratified by Sex - Interaction of genotype and stressful life events",
        "key_reference_title": "Family based association analyses between the serotonin transporter gene polymorphism (5-HTTLPR) and neuroticism, anxiety and depression.",
        "key_reference_abstract": "We studied the association between the short/long promotor-based length polymorphism of the serotonin transporter gene (5-HTTLPR) and neuroticism, anxiety and depression. Subjects included twins, their siblings and parents from the Netherlands Twin Register (559 parents and 1,245 offspring). Subjects had participated between one and five times in a survey study measuring neuroticism, anxiety and depression. Offspring of these families were also approached to participate in a psychiatric interview diagnosing DSM-IV major depression. Within-family and total association between 5-HTTLPR and these traits were tested. Only three of the 36 tests showed a significant effect of 5-HTTLPR (P<0.05). These effects were in opposite directions, i.e. both negative and positive regression coefficients were found for the s allele. No additive effect of the s allele was found for DSM-IV depression. Our results strongly suggest that there is no straightforward association between 5-HTTLPR and neuroticism, anxiety and depression.",
        "truth": "True"
    },
    {
        "pmid": "19531786",
        "meta_analysis_title": "Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis.",
        "meta_analysis_question": "Does the interaction between the serotonin transporter gene (5-HTTLPR) and stressful life events increase the risk of depression?",
        "criteria": "A search of the PubMed, EMBASE, and PsycINFO databases was conducted through March 2009 using the search terms life stress, life event, depression, depress, serotonin transporter, 5-HTTLPR, interaction, and moderation. Bibliographies of studies were also reviewed. A total of 26 articles published or set for publication were identified through this search strategy (Figure 1). Inclusion criteria for studies for the meta-analyses were published articles that included data on the association between the (1) 5-HTTLPR genotype (S, SL, or LL), (2) number of stressful life events (0, 1, 2, or \u22653) or equivalent, and (3) categorical measure of depression defined by the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) or International Statistical Classification of Diseases, 10th Revision (ICD-10) or ability to use a cut point to define depression from standardized rating scales. To maximize our ability to use a common framework for variable definition, we also requested original data from all studies that appeared to meet inclusion criteria published prior to 2008.10,15-28 We received original data in a usable format for the meta-analysis from 10 of the 14 study investigators. A total of 14 studies were included in the analysis, 15-20,23,25-27,29-32 10 of which15-20,23,25-27,29,30 were also included in a second sex-specific meta-analysis of original data. Nine other studies did not meet inclusion criteria.33-41",
        "subgroup": "Logistic Regression Analyses of Depression for 10 Studies Stratified by Sex - Interaction of genotype and stressful life events",
        "key_reference_title": "No interaction between the serotonin transporter polymorphism (5-HTTLPR) and childhood adversity or recent stressful life events on symptoms of depression: results from two community surveys.",
        "key_reference_abstract": "In this study we investigated interactions between the 5-HTTLPR genotype and environmental risk factors (G x E) on symptoms of depression in two large Australian community samples of adolescents and young adults. We postulated that a significant interaction between the 5-HTTLPR genotype and environmental risk factors of childhood adversity or stressful life events on symptoms of depression would be observed in subjects with at least one short allele (s/l or s/s) compared with subjects with no short alleles (l/l). We did not find significant G x E interactions between the 5-HTTLPR genotype and recent stressful life events or childhood adversity on symptoms of depression in our sample populations. However, we did find adolescents aged 17-18 years homozygous for the long allele (l/l) and exposed to persistently high levels of family adversity over a 6-year period were at a greater risk of depression than subjects with the same genotype exposed to no or persistently low levels of family adversity. This interaction should be interpreted cautiously due to the small number of depressed subjects in the sample with persistently high levels of family adversity.",
        "truth": "True"
    },
    {
        "pmid": "19531786",
        "meta_analysis_title": "Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis.",
        "meta_analysis_question": "Does the interaction between the serotonin transporter gene (5-HTTLPR) and stressful life events increase the risk of depression?",
        "criteria": "A search of the PubMed, EMBASE, and PsycINFO databases was conducted through March 2009 using the search terms life stress, life event, depression, depress, serotonin transporter, 5-HTTLPR, interaction, and moderation. Bibliographies of studies were also reviewed. A total of 26 articles published or set for publication were identified through this search strategy (Figure 1). Inclusion criteria for studies for the meta-analyses were published articles that included data on the association between the (1) 5-HTTLPR genotype (S, SL, or LL), (2) number of stressful life events (0, 1, 2, or \u22653) or equivalent, and (3) categorical measure of depression defined by the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) or International Statistical Classification of Diseases, 10th Revision (ICD-10) or ability to use a cut point to define depression from standardized rating scales. To maximize our ability to use a common framework for variable definition, we also requested original data from all studies that appeared to meet inclusion criteria published prior to 2008.10,15-28 We received original data in a usable format for the meta-analysis from 10 of the 14 study investigators. A total of 14 studies were included in the analysis, 15-20,23,25-27,29-32 10 of which15-20,23,25-27,29,30 were also included in a second sex-specific meta-analysis of original data. Nine other studies did not meet inclusion criteria.33-41",
        "subgroup": "Logistic Regression Analyses of Depression for 10 Studies Stratified by Sex - Interaction of genotype and stressful life events",
        "key_reference_title": "The risk for depression conferred by stressful life events is modified by variation at the serotonin transporter 5HTTLPR genotype: evidence from the Spanish PREDICT-Gene cohort.",
        "key_reference_abstract": "We report results from the PREDICT-Gene case-control study nested in a prospective cohort designed to identify predictors of the onset of depression among adult primary-care attendees. We tested the potential gene-by-environment interaction between 5HTTLPR genotype at the serotonin transporter gene and previous exposure to threatening life events (TLEs) in depression. A total of 737 consecutively recruited participants were genotyped. Additional information was gathered on exposure to TLEs over a 6-month period, socio-demographic data and family history of psychological problems among first-degree relatives. Diagnoses of depression were ascertained using the Composite International Diagnostic Interview (CIDI) by trained interviewers. Two different depressive outcomes were used (ICD-10 depressive episode and ICD-10 severe depressive episode). Both the s/s genotype and exposure to increasing number of TLEs were significantly associated with depression. Moreover, the 5HTTLPR s/s genotype significantly modified the risk conferred by TLEs for both depressive outcomes. Thus, s/s homozygous participants required minimal exposure to TLE (1 TLE) to acquire a level of risk for depression that was only found among l/s or l/l individuals after significantly higher exposure to TLEs (two or more TLEs). The interaction was more apparent when applied to the diagnosis of ICD-10 severe depressive episode and after adjusting for gender, age and family history of psychological problems. Likelihood ratios tests for the interaction were statistically significant for both depressive outcomes (ICD-10 depressive episode: LR X(2)=4.7, P=0.09 (crude), LR-X(2)=6.4, P=0.04 (adjusted); ICD-10 severe depressive episode: LR X(2)=6.9, P=0.032 (crude), LR-X(2)=8.1, P=0.017 (adjusted)).",
        "truth": "False"
    },
    {
        "pmid": "19531786",
        "meta_analysis_title": "Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis.",
        "meta_analysis_question": "Does the interaction between the serotonin transporter gene (5-HTTLPR) and stressful life events increase the risk of depression?",
        "criteria": "A search of the PubMed, EMBASE, and PsycINFO databases was conducted through March 2009 using the search terms life stress, life event, depression, depress, serotonin transporter, 5-HTTLPR, interaction, and moderation. Bibliographies of studies were also reviewed. A total of 26 articles published or set for publication were identified through this search strategy (Figure 1). Inclusion criteria for studies for the meta-analyses were published articles that included data on the association between the (1) 5-HTTLPR genotype (S, SL, or LL), (2) number of stressful life events (0, 1, 2, or \u22653) or equivalent, and (3) categorical measure of depression defined by the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) or International Statistical Classification of Diseases, 10th Revision (ICD-10) or ability to use a cut point to define depression from standardized rating scales. To maximize our ability to use a common framework for variable definition, we also requested original data from all studies that appeared to meet inclusion criteria published prior to 2008.10,15-28 We received original data in a usable format for the meta-analysis from 10 of the 14 study investigators. A total of 14 studies were included in the analysis, 15-20,23,25-27,29-32 10 of which15-20,23,25-27,29,30 were also included in a second sex-specific meta-analysis of original data. Nine other studies did not meet inclusion criteria.33-41",
        "subgroup": "Logistic Regression Analyses of Depression for 10 Studies Stratified by Sex - Interaction of genotype and stressful life events",
        "key_reference_title": "Interactions between life stressors and susceptibility genes (5-HTTLPR and BDNF) on depression in Korean elders.",
        "key_reference_abstract": "## BACKGROUND\nIt has been reported that the functional polymorphism in the serotonin transporter gene linked promoter region (5-HTTLPR) modifies the association between stressful life events (SLEs) and depression in child, adolescent, and adult populations. We sought to replicate this finding in elders and, additionally, to test modifying effects of the brain-derived neurotrophic factor (BDNF) val66met polymorphism.\n## METHODS\nIn 732 Korean community residents ages 65+, diagnosis of depression (Geriatric Mental State Schedule), information on SLEs, and genotypes for 5-HTTLPR and BDNF val66met were ascertained. Of those without depression at baseline, 521 (88%) were followed up 2.5 years later. Interactions between SLEs and the two genotypes were investigated for both prevalent depression at baseline and incident depression at follow-up.\n## RESULTS\nSignificant interactions of SLEs with both 5-HTTLPR and BDNF genotypes were observed on risk of depression after adjustment for age, gender, education, and disability. A significant three-way interaction between 5-HTTLPR, BDNF, and SLEs was also found. The same findings were observed for predictors of incident depression in the prospective analysis.\n## CONCLUSIONS\nThese findings suggest that environmental risk of depression is modified by at least two genes and that gene-environment interactions are found even into old age.",
        "truth": "False"
    },
    {
        "pmid": "19531786",
        "meta_analysis_title": "Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis.",
        "meta_analysis_question": "Does the interaction between the serotonin transporter gene (5-HTTLPR) and stressful life events increase the risk of depression?",
        "criteria": "A search of the PubMed, EMBASE, and PsycINFO databases was conducted through March 2009 using the search terms life stress, life event, depression, depress, serotonin transporter, 5-HTTLPR, interaction, and moderation. Bibliographies of studies were also reviewed. A total of 26 articles published or set for publication were identified through this search strategy (Figure 1). Inclusion criteria for studies for the meta-analyses were published articles that included data on the association between the (1) 5-HTTLPR genotype (S, SL, or LL), (2) number of stressful life events (0, 1, 2, or \u22653) or equivalent, and (3) categorical measure of depression defined by the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) or International Statistical Classification of Diseases, 10th Revision (ICD-10) or ability to use a cut point to define depression from standardized rating scales. To maximize our ability to use a common framework for variable definition, we also requested original data from all studies that appeared to meet inclusion criteria published prior to 2008.10,15-28 We received original data in a usable format for the meta-analysis from 10 of the 14 study investigators. A total of 14 studies were included in the analysis, 15-20,23,25-27,29-32 10 of which15-20,23,25-27,29,30 were also included in a second sex-specific meta-analysis of original data. Nine other studies did not meet inclusion criteria.33-41",
        "subgroup": "Logistic Regression Analyses of Depression for 10 Studies Stratified by Sex - Interaction of genotype and stressful life events",
        "key_reference_title": "5-HTTLPR genotype, stressful life events and late-life depression: no evidence of interaction in a French population.",
        "key_reference_abstract": "Modification of the effect of life events on risk of depression by a polymorphism in the serotonin transporter gene promoter (5-HTTLPR) has been reported in child, adolescent, adult and elderly populations. Replication attempted on data collected from 1421 individuals aged 65 and over from a French community study provided no evidence of a similar modifying effect. In the only analysis known to the authors to be carried out in an exclusively elderly, European population, this null finding remained consistent after restriction of analysis to prevalent or incident cases.",
        "truth": "False"
    },
    {
        "pmid": "19531786",
        "meta_analysis_title": "Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis.",
        "meta_analysis_question": "Does the interaction between the serotonin transporter gene (5-HTTLPR) and stressful life events increase the risk of depression?",
        "criteria": "A search of the PubMed, EMBASE, and PsycINFO databases was conducted through March 2009 using the search terms life stress, life event, depression, depress, serotonin transporter, 5-HTTLPR, interaction, and moderation. Bibliographies of studies were also reviewed. A total of 26 articles published or set for publication were identified through this search strategy (Figure 1). Inclusion criteria for studies for the meta-analyses were published articles that included data on the association between the (1) 5-HTTLPR genotype (S, SL, or LL), (2) number of stressful life events (0, 1, 2, or \u22653) or equivalent, and (3) categorical measure of depression defined by the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) or International Statistical Classification of Diseases, 10th Revision (ICD-10) or ability to use a cut point to define depression from standardized rating scales. To maximize our ability to use a common framework for variable definition, we also requested original data from all studies that appeared to meet inclusion criteria published prior to 2008.10,15-28 We received original data in a usable format for the meta-analysis from 10 of the 14 study investigators. A total of 14 studies were included in the analysis, 15-20,23,25-27,29-32 10 of which15-20,23,25-27,29,30 were also included in a second sex-specific meta-analysis of original data. Nine other studies did not meet inclusion criteria.33-41",
        "subgroup": "Logistic Regression Analyses of Depression for 10 Studies Stratified by Sex - Interaction of genotype and stressful life events",
        "key_reference_title": "Interaction between the 5-HTTLPR serotonin transporter polymorphism and environmental adversity for mood and anxiety psychopathology: evidence from a high-risk community sample of young adults.",
        "key_reference_abstract": "Previous research examining gene-environment interaction (GxE) with regard to vulnerability to depression and anxiety has yielded conflicting results. The present study was designed to further investigate GxE between 5-HTTLPR and exposure to environmental adversity, using different phenotypic and genotypic characterizations as well as different types of adversity within a prospective study design. Data were available from an ongoing epidemiological cohort study following the outcome of early risk factors from birth to adulthood. At age 19 yr, 309 participants (142 males, 167 females) were characterized on measures of depression and anxiety through interview and questionnaire (DSM-IV diagnosis, Beck Depression Inventory, Harm Avoidance). Environmental adversity was assessed at birth (family adversity), and at age 19 yr (stressful life events). Bi- and tri-allelic 5-HTTLPR genotypes were obtained from genomic DNA. Results indicated that depression and anxiety in 19-yr-olds were strongly associated with both family adversity and stressful life events. Individuals with the LL genotype of 5-HTTLPR who were exposed to high family adversity displayed significantly higher rates of depressive or anxiety disorders and had more depressive symptoms than those without either condition. This GxE replicates recent findings from an epidemiological cohort study of adolescents but is in contrast to many previous reports suggesting an interaction with the S allele. No evidence for GxE was obtained with regard to current stressful life events and trait anxiety. One possible source for the conflicting findings might be attributed to heterogeneity in depression phenotypes and environmental adversity.",
        "truth": "False"
    },
    {
        "pmid": "28697252",
        "meta_analysis_title": "Association of Positive Airway Pressure With Cardiovascular Events and Death in Adults With Sleep Apnea: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Does the use of positive airway pressure (PAP) to treat sleep apnea reduce risk of cardiovascular events and death?",
        "criteria": "A systematic search of the scientific literature was done according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statement for the conduct of meta-analyses of intervention studies. The searches included MEDLINE via Ovid (from January 1, 1946, to March 2017), EMBASE (from January 1, 1974, to March 2017), and the Cochrane Library database (Cochrane Central Register of Controlled Trials, no date restriction) using relevant text words and Medical Subject Headings that consisted of terms relating to randomized trial and sleep apnea (see the eAppendix in the Supplement for detailed search strategy). The search was limited to randomized clinical trials (RCTs) but without language restriction. Additionally, reference lists from trials, review articles, and reports were manually scanned to identify any other relevant data (including conference abstracts). The clinicaltrials.gov website was searched for RCTs that were registered as completed but not yet published.",
        "subgroup": "Meta-analysis of the Association of Positive Airway Pressure With Cardiovascular Events and Death - Major adverse cardiovascular events",
        "key_reference_title": "Continuous positive airway pressure for central sleep apnea and heart failure.",
        "key_reference_abstract": "## BACKGROUND\nThe Canadian Continuous Positive Airway Pressure for Patients with Central Sleep Apnea and Heart Failure trial tested the hypothesis that continuous positive airway pressure (CPAP) would improve the survival rate without heart transplantation of patients who have central sleep apnea and heart failure.\n## METHODS\nAfter medical therapy was optimized, 258 patients who had heart failure (mean age [+/-SD], 63+/-10 years; ejection fraction, 24.5+/-7.7 percent) and central sleep apnea (number of episodes of apnea and hypopnea per hour of sleep, 40+/-16) were randomly assigned to receive CPAP (128 patients) or no CPAP (130 patients) and were followed for a mean of two years. During follow-up, sleep studies were conducted and measurements of the ejection fraction, exercise capacity, quality of life, and neurohormones were obtained.\n## RESULTS\nThree months after undergoing randomization, the CPAP group, as compared with the control group, had greater reductions in the frequency of episodes of apnea and hypopnea (-21+/-16 vs. -2+/-18 per hour, P<0.001) and in norepinephrine levels (-1.03+/-1.84 vs. 0.02+/-0.99 nmol per liter, P=0.009), and greater increases in the mean nocturnal oxygen saturation (1.6+/-2.8 percent vs. 0.4+/-2.5 percent, P<0.001), ejection fraction (2.2+/-5.4 percent vs. 0.4+/-5.3 percent, P=0.02), and the distance walked in six minutes (20.0+/-55 vs. -0.8+/-64.8 m, P=0.016). There were no differences between the control group and the CPAP group in the number of hospitalizations, quality of life, or atrial natriuretic peptide levels. An early divergence in survival rates without heart transplantation favored the control group, but after 18 months the divergence favored the CPAP group, yet the overall event rates (death and heart transplantation) did not differ (32 vs. 32 events, respectively; P=0.54).\n## CONCLUSIONS\nAlthough CPAP attenuated central sleep apnea, improved nocturnal oxygenation, increased the ejection fraction, lowered norepinephrine levels, and increased the distance walked in six minutes, it did not affect survival. Our data do not support the use of CPAP to extend life in patients who have central sleep apnea and heart failure.",
        "truth": "False"
    },
    {
        "pmid": "28697252",
        "meta_analysis_title": "Association of Positive Airway Pressure With Cardiovascular Events and Death in Adults With Sleep Apnea: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Does the use of positive airway pressure (PAP) to treat sleep apnea reduce risk of cardiovascular events and death?",
        "criteria": "A systematic search of the scientific literature was done according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statement for the conduct of meta-analyses of intervention studies. The searches included MEDLINE via Ovid (from January 1, 1946, to March 2017), EMBASE (from January 1, 1974, to March 2017), and the Cochrane Library database (Cochrane Central Register of Controlled Trials, no date restriction) using relevant text words and Medical Subject Headings that consisted of terms relating to randomized trial and sleep apnea (see the eAppendix in the Supplement for detailed search strategy). The search was limited to randomized clinical trials (RCTs) but without language restriction. Additionally, reference lists from trials, review articles, and reports were manually scanned to identify any other relevant data (including conference abstracts). The clinicaltrials.gov website was searched for RCTs that were registered as completed but not yet published.",
        "subgroup": "Meta-analysis of the Association of Positive Airway Pressure With Cardiovascular Events and Death - Major adverse cardiovascular events",
        "key_reference_title": "Effect of continuous positive airway pressure on the incidence of hypertension and cardiovascular events in nonsleepy patients with obstructive sleep apnea: a randomized controlled trial.",
        "key_reference_abstract": "## CONTEXT\nContinuous positive airway pressure (CPAP) is the first-line treatment for patients with symptomatic obstructive sleep apnea (OSA). However, its indication for all patients with sleep-disordered breathing, regardless of daytime symptoms, is unclear.\n## OBJECTIVE\nTo evaluate the effect of CPAP treatment on the incidence of hypertension or cardiovascular events in a cohort of nonsleepy patients with OSA.\n## DESIGN, SETTING, AND PATIENTS\nMulticenter, parallel-group, randomized controlled trial in 14 teaching hospitals in Spain. Between May 2004 and May 2006, 725 consecutive patients were enrolled who had an apnea-hypopnea index of 20 h(-1) or greater and an Epworth Sleepiness Scale score of 10 or less (scores range from 0-24, with values <10 suggesting no daytime sleepiness). Exclusion criteria were previous cardiovascular event, physical or psychological incapacity, chronic disease, or drug or alcohol addiction. Follow-up ended in May 2009.\n## INTERVENTION\nPatients were allocated to receive CPAP treatment or no active intervention. All participants received dietary counseling and sleep hygiene advice.\n## MAIN OUTCOME MEASURES\nIncidence of either systemic hypertension (taking antihypertensive medication or blood pressure greater than 140/90 mm Hg) or cardiovascular event (nonfatal myocardial infarction, nonfatal stroke, transient ischemic attack, hospitalization for unstable angina or arrhythmia, heart failure, or cardiovascular death).\n## RESULTS\nSeven hundred twenty-three patients underwent follow-up for a median of 4 (interquartile range, 2.7-4.4) years (1 patient from each group did not receive allocated treatment); 357 in the CPAP group and 366 in the control group were included in the analysis. In the CPAP group there were 68 patients with new hypertension and 28 cardiovascular events (17 unstable angina or arrhythmia, 3 nonfatal stroke, 3 heart failure, 2 nonfatal myocardial infarction, 2 transient ischemic attack, 1 cardiovascular death). In the control group there were 79 patients with new hypertension and 31 cardiovascular events (11 unstable angina or arrhythmia, 8 nonfatal myocardial infarction, 5 transient ischemic attack, 5 heart failure, 2 nonfatal stroke). The hypertension or cardiovascular event incidence density rate was 9.20 per 100 person-years (95% CI, 7.36-11.04) in the CPAP group and 11.02 per 100 person-years (95% CI, 8.96-13.08) in the control group. The incidence density ratio was 0.83 (95% CI, 0.63-1.1; P = .20).\n## CONCLUSIONS\nIn patients with OSA without daytime sleepiness, the prescription of CPAP compared with usual care did not result in a statistically significant reduction in the incidence of hypertension or cardiovascular events. However, the study may have had limited power to detect a significant difference.\n## TRIAL REGISTRATION\nclinicaltrials.gov Identifier: NCT00127348.",
        "truth": "True"
    },
    {
        "pmid": "28697252",
        "meta_analysis_title": "Association of Positive Airway Pressure With Cardiovascular Events and Death in Adults With Sleep Apnea: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Does the use of positive airway pressure (PAP) to treat sleep apnea reduce risk of cardiovascular events and death?",
        "criteria": "A systematic search of the scientific literature was done according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statement for the conduct of meta-analyses of intervention studies. The searches included MEDLINE via Ovid (from January 1, 1946, to March 2017), EMBASE (from January 1, 1974, to March 2017), and the Cochrane Library database (Cochrane Central Register of Controlled Trials, no date restriction) using relevant text words and Medical Subject Headings that consisted of terms relating to randomized trial and sleep apnea (see the eAppendix in the Supplement for detailed search strategy). The search was limited to randomized clinical trials (RCTs) but without language restriction. Additionally, reference lists from trials, review articles, and reports were manually scanned to identify any other relevant data (including conference abstracts). The clinicaltrials.gov website was searched for RCTs that were registered as completed but not yet published.",
        "subgroup": "Meta-analysis of the Association of Positive Airway Pressure With Cardiovascular Events and Death - Major adverse cardiovascular events",
        "key_reference_title": "Continuous positive airway pressure improves sleepiness but not calculated vascular risk in patients with minimally symptomatic obstructive sleep apnoea: the MOSAIC randomised controlled trial.",
        "key_reference_abstract": "## BACKGROUND\nContinuous positive airway pressure (CPAP) for symptomatic obstructive sleep apnoea (OSA) improves sleepiness and reduces vascular risk, but such treatment for the more prevalent, minimally symptomatic disease is contentious.\n## METHODS\nThis multicentre, randomised controlled, parallel, hospital-based trial across the UK and Canada, recruited 391 patients with confirmed OSA (oxygen desaturation index >7.5/h) but insufficient symptoms to warrant CPAP therapy. Patients were randomised to 6 months of auto-adjusting CPAP therapy, or standard care. Coprimary endpoints were change in Epworth Sleepiness Score (ESS) and predicted 5-year mortality using a cardiovascular risk score (components: age, sex, height, systolic blood pressure, smoking, diabetes, cholesterol, creatinine, left ventricular hypertrophy, previous myocardial infarction or stroke). Secondary endpoints included some of the individual components of the vascular risk score, objectively measured sleepiness and self-assessed health status.\n## RESULTS\nOf 391 patients randomised, 14 withdrew, 347 attended for their follow-up visit at 6 months within the predefined time window, of which 341 had complete ESS data (baseline mean 8.0, SD 4.3) and 310 had complete risk score data. 22% of patients in the CPAP group reported stopping treatment and overall median CPAP use was 2\u2009:\u200939 h per night. CPAP significantly improved subjective daytime sleepiness (adjusted treatment effect on ESS -2.0 (95% CI -2.6 to -1.4), p<0.0001), objectively measured sleepiness and self-assessed health status. CPAP did not improve the 5-year calculated vascular risk or any of its components.\n## CONCLUSIONS\nIn patients with minimally symptomatic OSA, CPAP can reduce subjective and objective daytime sleepiness, and improve self-assessed health status, but does not appear to improve calculated vascular risk.",
        "truth": "True"
    },
    {
        "pmid": "28697252",
        "meta_analysis_title": "Association of Positive Airway Pressure With Cardiovascular Events and Death in Adults With Sleep Apnea: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Does the use of positive airway pressure (PAP) to treat sleep apnea reduce risk of cardiovascular events and death?",
        "criteria": "A systematic search of the scientific literature was done according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statement for the conduct of meta-analyses of intervention studies. The searches included MEDLINE via Ovid (from January 1, 1946, to March 2017), EMBASE (from January 1, 1974, to March 2017), and the Cochrane Library database (Cochrane Central Register of Controlled Trials, no date restriction) using relevant text words and Medical Subject Headings that consisted of terms relating to randomized trial and sleep apnea (see the eAppendix in the Supplement for detailed search strategy). The search was limited to randomized clinical trials (RCTs) but without language restriction. Additionally, reference lists from trials, review articles, and reports were manually scanned to identify any other relevant data (including conference abstracts). The clinicaltrials.gov website was searched for RCTs that were registered as completed but not yet published.",
        "subgroup": "Meta-analysis of the Association of Positive Airway Pressure With Cardiovascular Events and Death - Major adverse cardiovascular events",
        "key_reference_title": "Effects of continuous positive airway pressure on neurocognitive function in obstructive sleep apnea patients: The Apnea Positive Pressure Long-term Efficacy Study (APPLES).",
        "key_reference_abstract": "## STUDY OBJECTIVE\nTo determine the neurocognitive effects of continuous positive airway pressure (CPAP) therapy on patients with obstructive sleep apnea (OSA).\n## DESIGN, SETTING, AND PARTICIPANTS\nThe Apnea Positive Pressure Long-term Efficacy Study (APPLES) was a 6-month, randomized, double-blind, 2-arm, sham-controlled, multicenter trial conducted at 5 U.S. university, hospital, or private practices. Of 1,516 participants enrolled, 1,105 were randomized, and 1,098 participants diagnosed with OSA contributed to the analysis of the primary outcome measures.\n## INTERVENTION\nActive or sham CPAP MEASUREMENTS: THREE NEUROCOGNITIVE VARIABLES, EACH REPRESENTING A NEUROCOGNITIVE DOMAIN: Pathfinder Number Test-Total Time (attention and psychomotor function [A/P]), Buschke Selective Reminding Test-Sum Recall (learning and memory [L/M]), and Sustained Working Memory Test-Overall Mid-Day Score (executive and frontal-lobe function [E/F])\n## RESULTS\nThe primary neurocognitive analyses showed a difference between groups for only the E/F variable at the 2 month CPAP visit, but no difference at the 6 month CPAP visit or for the A/P or L/M variables at either the 2 or 6 month visits. When stratified by measures of OSA severity (AHI or oxygen saturation parameters), the primary E/F variable and one secondary E/F neurocognitive variable revealed transient differences between study arms for those with the most severe OSA. Participants in the active CPAP group had a significantly greater ability to remain awake whether measured subjectively by the Epworth Sleepiness Scale or objectively by the maintenance of wakefulness test.\n## CONCLUSIONS\nCPAP treatment improved both subjectively and objectively measured sleepiness, especially in individuals with severe OSA (AHI > 30). CPAP use resulted in mild, transient improvement in the most sensitive measures of executive and frontal-lobe function for those with severe disease, which suggests the existence of a complex OSA-neurocognitive relationship.\n## CLINICAL TRIAL INFORMATION\nRegistered at clinicaltrials.gov. Identifier: NCT00051363.\n## CITATION\nKushida CA; Nichols DA; Holmes TH; Quan SF; Walsh JK; Gottlieb DJ; Simon RD; Guilleminault C; White DP; Goodwin JL; Schweitzer PK; Leary EB; Hyde PR; Hirshkowitz M; Green S; McEvoy LK; Chan C; Gevins A; Kay GG; Bloch DA; Crabtree T; Demen WC. Effects of continuous positive airway pressure on neurocognitive function in obstructive sleep apnea patients: the Apnea Positive Pressure Long-term Efficacy Study (APPLES). SLEEP 2012;35(12):1593-1602.",
        "truth": "False"
    },
    {
        "pmid": "28697252",
        "meta_analysis_title": "Association of Positive Airway Pressure With Cardiovascular Events and Death in Adults With Sleep Apnea: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Does the use of positive airway pressure (PAP) to treat sleep apnea reduce risk of cardiovascular events and death?",
        "criteria": "A systematic search of the scientific literature was done according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statement for the conduct of meta-analyses of intervention studies. The searches included MEDLINE via Ovid (from January 1, 1946, to March 2017), EMBASE (from January 1, 1974, to March 2017), and the Cochrane Library database (Cochrane Central Register of Controlled Trials, no date restriction) using relevant text words and Medical Subject Headings that consisted of terms relating to randomized trial and sleep apnea (see the eAppendix in the Supplement for detailed search strategy). The search was limited to randomized clinical trials (RCTs) but without language restriction. Additionally, reference lists from trials, review articles, and reports were manually scanned to identify any other relevant data (including conference abstracts). The clinicaltrials.gov website was searched for RCTs that were registered as completed but not yet published.",
        "subgroup": "Meta-analysis of the Association of Positive Airway Pressure With Cardiovascular Events and Death - Major adverse cardiovascular events",
        "key_reference_title": "Continuous positive airway pressure in older people with obstructive sleep apnoea syndrome (PREDICT): a 12-month, multicentre, randomised trial.",
        "key_reference_abstract": "## BACKGROUND\nThe therapeutic and economic benefits of continuous positive airway pressure (CPAP) for moderate to severe obstructive sleep apnoea (OSA) syndrome have been established in middle-aged people; however, the benefits in older people are unknown. This trial was designed to address this evidence gap.\n## METHODS\nThis 12-month, multicentre, randomised trial enrolled patients across 14 National Health Service sleep centres in the UK. Consecutive patients aged 65 years or older with newly diagnosed OSA syndrome were eligible to join the trial. Patients were randomly assigned (1:1) into parallel groups to receive either CPAP with best supportive care (BSC) or BSC alone for 12 months. Randomisation was done by the Medical Research Council Clinical Trials Unit with computer-generated randomisation. The main investigator at each centre was masked to the trial randomisation. Coprimary endpoints were Epworth sleepiness score (ESS) at 3 months and cost-effectiveness over the 12-month trial period. Secondary outcomes were subjective sleepiness at 12 months, plus objective sleepiness, quality of life, mood, functionality, nocturia, mobility, accidents, cognitive function, and cardiovascular risk factors and events at 3 months and 12 months. The analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN90464927.\n## FINDINGS\nBetween Feb 24, 2010, and May 30, 2012, 278 patients were randomly assigned to the trial, of whom 231 (83%) completed the trial. 140 patients were allocated to and received CPAP plus BSC and 138 were allocated to and received BSC only. CPAP reduced ESS by 2\u00b71 points (95% CI -3\u00b70 to -1\u00b73; p<0\u00b70001) at 3 months for 124 (89%) of 140 patients compared with 124 (90%) of 138 patients given BSC, and by 2\u00b70 points (-2\u00b78 to -1\u00b72; p<0\u00b70001) at 12 months for 116 patients compared with 122 patients given BSC. The effect was greater in patients with higher CPAP usage or higher baseline ESS. Quality-adjusted life-years were similar between the groups (treatment effect 0\u00b701 (95% CI -0\u00b703 to 0\u00b704; p=0\u00b7787) and health-care costs were marginally reduced with CPAP (-\u00a335, -390 to 321; p=0\u00b7847). CPAP improved objective sleepiness (p=0\u00b7024), mobility (p=0\u00b7029), total cholesterol (p=0\u00b7048), and LDL cholesterol (p=0\u00b7042) at 3 months, but these were not sustained at 12 months. Measures of mood, functionality, nocturia, accidents, cognitive function, and cardiovascular events remained unchanged. Systolic blood pressure fell in the BSC group. 37 serious adverse events occurred in the CPAP group, and 22 in BSC group; all were independently classified as being unrelated to the trial and no significant harm was attributed to CPAP use.\n## INTERPRETATION\nIn older people with OSA syndrome, CPAP reduces sleepiness and is marginally more cost effective over 12 months than is BSC alone. On the basis of these results, we recommend that CPAP treatment should be offered routinely to older patients with OSA syndrome.\n## FUNDING\nNational Institute of Health Research (NIHR) Health Technology Assessment, NIHR Respiratory Biomedical Research Unit at the Royal Brompton and Harefield NHS Foundation Trust and Imperial College London.",
        "truth": "False"
    },
    {
        "pmid": "28697252",
        "meta_analysis_title": "Association of Positive Airway Pressure With Cardiovascular Events and Death in Adults With Sleep Apnea: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Does the use of positive airway pressure (PAP) to treat sleep apnea reduce risk of cardiovascular events and death?",
        "criteria": "A systematic search of the scientific literature was done according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statement for the conduct of meta-analyses of intervention studies. The searches included MEDLINE via Ovid (from January 1, 1946, to March 2017), EMBASE (from January 1, 1974, to March 2017), and the Cochrane Library database (Cochrane Central Register of Controlled Trials, no date restriction) using relevant text words and Medical Subject Headings that consisted of terms relating to randomized trial and sleep apnea (see the eAppendix in the Supplement for detailed search strategy). The search was limited to randomized clinical trials (RCTs) but without language restriction. Additionally, reference lists from trials, review articles, and reports were manually scanned to identify any other relevant data (including conference abstracts). The clinicaltrials.gov website was searched for RCTs that were registered as completed but not yet published.",
        "subgroup": "Meta-analysis of the Association of Positive Airway Pressure With Cardiovascular Events and Death - Major adverse cardiovascular events",
        "key_reference_title": "Adaptive Servo-Ventilation for Central Sleep Apnea in Systolic Heart Failure.",
        "key_reference_abstract": "## BACKGROUND\nCentral sleep apnea is associated with poor prognosis and death in patients with heart failure. Adaptive servo-ventilation is a therapy that uses a noninvasive ventilator to treat central sleep apnea by delivering servo-controlled inspiratory pressure support on top of expiratory positive airway pressure. We investigated the effects of adaptive servo-ventilation in patients who had heart failure with reduced ejection fraction and predominantly central sleep apnea.\n## METHODS\nWe randomly assigned 1325 patients with a left ventricular ejection fraction of 45% or less, an apnea-hypopnea index (AHI) of 15 or more events (occurrences of apnea or hypopnea) per hour, and a predominance of central events to receive guideline-based medical treatment with adaptive servo-ventilation or guideline-based medical treatment alone (control). The primary end point in the time-to-event analysis was the first event of death from any cause, lifesaving cardiovascular intervention (cardiac transplantation, implantation of a ventricular assist device, resuscitation after sudden cardiac arrest, or appropriate lifesaving shock), or unplanned hospitalization for worsening heart failure.\n## RESULTS\nIn the adaptive servo-ventilation group, the mean AHI at 12 months was 6.6 events per hour. The incidence of the primary end point did not differ significantly between the adaptive servo-ventilation group and the control group (54.1% and 50.8%, respectively; hazard ratio, 1.13; 95% confidence interval [CI], 0.97 to 1.31; P=0.10). All-cause mortality and cardiovascular mortality were significantly higher in the adaptive servo-ventilation group than in the control group (hazard ratio for death from any cause, 1.28; 95% CI, 1.06 to 1.55; P=0.01; and hazard ratio for cardiovascular death, 1.34; 95% CI, 1.09 to 1.65; P=0.006).\n## CONCLUSIONS\nAdaptive servo-ventilation had no significant effect on the primary end point in patients who had heart failure with reduced ejection fraction and predominantly central sleep apnea, but all-cause and cardiovascular mortality were both increased with this therapy. (Funded by ResMed and others; SERVE-HF ClinicalTrials.gov number, NCT00733343.).",
        "truth": "False"
    },
    {
        "pmid": "28697252",
        "meta_analysis_title": "Association of Positive Airway Pressure With Cardiovascular Events and Death in Adults With Sleep Apnea: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Does the use of positive airway pressure (PAP) to treat sleep apnea reduce risk of cardiovascular events and death?",
        "criteria": "A systematic search of the scientific literature was done according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statement for the conduct of meta-analyses of intervention studies. The searches included MEDLINE via Ovid (from January 1, 1946, to March 2017), EMBASE (from January 1, 1974, to March 2017), and the Cochrane Library database (Cochrane Central Register of Controlled Trials, no date restriction) using relevant text words and Medical Subject Headings that consisted of terms relating to randomized trial and sleep apnea (see the eAppendix in the Supplement for detailed search strategy). The search was limited to randomized clinical trials (RCTs) but without language restriction. Additionally, reference lists from trials, review articles, and reports were manually scanned to identify any other relevant data (including conference abstracts). The clinicaltrials.gov website was searched for RCTs that were registered as completed but not yet published.",
        "subgroup": "Meta-analysis of the Association of Positive Airway Pressure With Cardiovascular Events and Death - Major adverse cardiovascular events",
        "key_reference_title": "Long-term effects of continuous positive airway pressure on blood pressure and prognosis in hypertensive patients with coronary heart disease and obstructive sleep apnea: a randomized controlled trial.",
        "key_reference_abstract": "## BACKGROUND\nObstructive sleep apnea (OSA) can result in hypertension and significantly increase cardiovascular morbidity and mortality. There are few reports on the long-term effects of continuous positive airway pressure (CPAP) on blood pressure in patients with uncontrolled hypertension with coronary heart disease (CHD) and OSA.\n## METHODS\nWe conducted a prospective, long-term follow-up study in 83 patients with uncontrolled hypertension, CHD, and OSA randomized to control or CPAP groups. Daytime systolic blood pressure (SBP), diastolic blood pressure (DBP), and severe cardiovascular and cerebrovascular events (SCCEs) were recorded at baseline and follow-up.\n## RESULTS\nSeventy-three patients completed the study with a median follow-up of 36 (interquartile range = 24-54) months. The 2 groups had similar characteristics at baseline. CPAP was used for 4.5\u00b11.1 hour/night. SBP in the CPAP group was significantly reduced at follow-up (143\u00b17 mm Hg vs. 139\u00b17 mm Hg, P = 0.04), and SBP decreased by 8mm Hg (95% confidence interval = 1.4-9.9; P = 0.01). Hypertension control was improved (CPAP, 69.4% for CPAP users vs. 43.2% for control subjects; P = 0.02); however, DBP did not reach statistical difference between the groups (81\u00b110 mm Hg vs. 79\u00b18 mm Hg; P = 0.49). In the CPAP group, the Epworth Sleepiness Scale was markedly reduced (7.0\u00b13.4 vs. 3.7\u00b12.3; P < 0.001). There was 1 SCCE in the CPAP group (heart failure), and 5 SCCEs in the control group (acute myocardial infarction: 2 (with 1 death); stroke: 3), but there was no significant difference identified.\n## CONCLUSIONS\nLong-term CPAP application in uncontrolled hypertension with CHD and OSA significantly reduced daytime SBP, improved hypertension control and daytime sleepiness, and decreased the trend in SCCEs compared with control subjects.\n## CLINICAL TRIAL REGISTRATION NUMBER\nClinicalTrials.gov NCT02059993.",
        "truth": "True"
    },
    {
        "pmid": "28697252",
        "meta_analysis_title": "Association of Positive Airway Pressure With Cardiovascular Events and Death in Adults With Sleep Apnea: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Does the use of positive airway pressure (PAP) to treat sleep apnea reduce risk of cardiovascular events and death?",
        "criteria": "A systematic search of the scientific literature was done according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statement for the conduct of meta-analyses of intervention studies. The searches included MEDLINE via Ovid (from January 1, 1946, to March 2017), EMBASE (from January 1, 1974, to March 2017), and the Cochrane Library database (Cochrane Central Register of Controlled Trials, no date restriction) using relevant text words and Medical Subject Headings that consisted of terms relating to randomized trial and sleep apnea (see the eAppendix in the Supplement for detailed search strategy). The search was limited to randomized clinical trials (RCTs) but without language restriction. Additionally, reference lists from trials, review articles, and reports were manually scanned to identify any other relevant data (including conference abstracts). The clinicaltrials.gov website was searched for RCTs that were registered as completed but not yet published.",
        "subgroup": "Meta-analysis of the Association of Positive Airway Pressure With Cardiovascular Events and Death - Major adverse cardiovascular events",
        "key_reference_title": "Efficacy of continuous positive airway pressure treatment on 5-year survival in patients with ischaemic stroke and obstructive sleep apnea: a randomized controlled trial.",
        "key_reference_abstract": "The main purpose of the present analysis is to assess the influence of introducing early nasal continuous positive airway pressure (nCPAP) treatment on cardiovascular recurrences and mortality in patients with a first-ever ischaemic stroke and moderate-severe obstructive sleep apnea (OSA) with an apnea-hypopnea index (AHI) \u226520 events h(-1) during a 5-year follow-up. Patients received conventional treatment for stroke and were assigned randomly to the nCPAP group (n = 71) or the control group (n = 69). Cardiovascular events and mortality were registered for all patients. Survival and cardiovascular event-free survival analysis were performed after 5-year follow-up using the Kaplan-Meier test. Patients in the nCPAP group had significantly higher cardiovascular survival than the control group (100 versus 89.9%, log-rank test 5.887; P = 0.015) However, and also despite a positive tendency, there were no significant differences in the cardiovascular event-free survival at 68 months between the nCPAP and control groups (89.5 versus 75.4%, log-rank test 3.565; P = 0.059). Early nCPAP therapy has a positive effect on long-term survival in ischaemic stroke patients and moderate-severe OSA.",
        "truth": "False"
    },
    {
        "pmid": "28697252",
        "meta_analysis_title": "Association of Positive Airway Pressure With Cardiovascular Events and Death in Adults With Sleep Apnea: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Does the use of positive airway pressure (PAP) to treat sleep apnea reduce risk of cardiovascular events and death?",
        "criteria": "A systematic search of the scientific literature was done according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statement for the conduct of meta-analyses of intervention studies. The searches included MEDLINE via Ovid (from January 1, 1946, to March 2017), EMBASE (from January 1, 1974, to March 2017), and the Cochrane Library database (Cochrane Central Register of Controlled Trials, no date restriction) using relevant text words and Medical Subject Headings that consisted of terms relating to randomized trial and sleep apnea (see the eAppendix in the Supplement for detailed search strategy). The search was limited to randomized clinical trials (RCTs) but without language restriction. Additionally, reference lists from trials, review articles, and reports were manually scanned to identify any other relevant data (including conference abstracts). The clinicaltrials.gov website was searched for RCTs that were registered as completed but not yet published.",
        "subgroup": "Meta-analysis of the Association of Positive Airway Pressure With Cardiovascular Events and Death - Major adverse cardiovascular events",
        "key_reference_title": "CPAP for Prevention of Cardiovascular Events in Obstructive Sleep Apnea.",
        "key_reference_abstract": "## BACKGROUND\nObstructive sleep apnea is associated with an increased risk of cardiovascular events; whether treatment with continuous positive airway pressure (CPAP) prevents major cardiovascular events is uncertain.\n## METHODS\nAfter a 1-week run-in period during which the participants used sham CPAP, we randomly assigned 2717 eligible adults between 45 and 75 years of age who had moderate-to-severe obstructive sleep apnea and coronary or cerebrovascular disease to receive CPAP treatment plus usual care (CPAP group) or usual care alone (usual-care group). The primary composite end point was death from cardiovascular causes, myocardial infarction, stroke, or hospitalization for unstable angina, heart failure, or transient ischemic attack. Secondary end points included other cardiovascular outcomes, health-related quality of life, snoring symptoms, daytime sleepiness, and mood.\n## RESULTS\nMost of the participants were men who had moderate-to-severe obstructive sleep apnea and minimal sleepiness. In the CPAP group, the mean duration of adherence to CPAP therapy was 3.3 hours per night, and the mean apnea-hypopnea index (the number of apnea or hypopnea events per hour of recording) decreased from 29.0 events per hour at baseline to 3.7 events per hour during follow-up. After a mean follow-up of 3.7 years, a primary end-point event had occurred in 229 participants in the CPAP group (17.0%) and in 207 participants in the usual-care group (15.4%) (hazard ratio with CPAP, 1.10; 95% confidence interval, 0.91 to 1.32; P=0.34). No significant effect on any individual or other composite cardiovascular end point was observed. CPAP significantly reduced snoring and daytime sleepiness and improved health-related quality of life and mood.\n## CONCLUSIONS\nTherapy with CPAP plus usual care, as compared with usual care alone, did not prevent cardiovascular events in patients with moderate-to-severe obstructive sleep apnea and established cardiovascular disease. (Funded by the National Health and Medical Research Council of Australia and others; SAVE ClinicalTrials.gov number, NCT00738179 ; Australian New Zealand Clinical Trials Registry number, ACTRN12608000409370 .).",
        "truth": "True"
    },
    {
        "pmid": "28697252",
        "meta_analysis_title": "Association of Positive Airway Pressure With Cardiovascular Events and Death in Adults With Sleep Apnea: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Does the use of positive airway pressure (PAP) to treat sleep apnea reduce risk of cardiovascular events and death?",
        "criteria": "A systematic search of the scientific literature was done according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statement for the conduct of meta-analyses of intervention studies. The searches included MEDLINE via Ovid (from January 1, 1946, to March 2017), EMBASE (from January 1, 1974, to March 2017), and the Cochrane Library database (Cochrane Central Register of Controlled Trials, no date restriction) using relevant text words and Medical Subject Headings that consisted of terms relating to randomized trial and sleep apnea (see the eAppendix in the Supplement for detailed search strategy). The search was limited to randomized clinical trials (RCTs) but without language restriction. Additionally, reference lists from trials, review articles, and reports were manually scanned to identify any other relevant data (including conference abstracts). The clinicaltrials.gov website was searched for RCTs that were registered as completed but not yet published.",
        "subgroup": "Meta-analysis of the Association of Positive Airway Pressure With Cardiovascular Events and Death - Major adverse cardiovascular events",
        "key_reference_title": "Effect of Positive Airway Pressure on Cardiovascular Outcomes in Coronary Artery Disease Patients with Nonsleepy Obstructive Sleep Apnea. The RICCADSA Randomized Controlled Trial.",
        "key_reference_abstract": "## RATIONALE\nObstructive sleep apnea (OSA) is common in patients with coronary artery disease (CAD), many of whom do not report daytime sleepiness. First-line treatment for symptomatic OSA is continuous positive airway pressure (CPAP), but its value in patients without daytime sleepiness is uncertain.\n## OBJECTIVES\nTo determine the effects of CPAP on long-term adverse cardiovascular outcome risk in patients with CAD with nonsleepy OSA.\n## METHODS\nThis single-center, prospective, randomized, controlled, open-label, blinded evaluation trial was conducted between December 2005 and November 2010. Consecutive patients with newly revascularized CAD and OSA (apnea-hypopnea index \u226515/h) without daytime sleepiness (Epworth Sleepiness Scale score <10) were randomized to auto-titrating CPAP (n\u2009=\u2009122) or no positive airway pressure (n\u2009=\u2009122).\n## MEASUREMENTS AND MAIN RESULTS\nThe primary endpoint was the first event of repeat revascularization, myocardial infarction, stroke, or cardiovascular mortality. Median follow-up was 57 months. The incidence of the primary endpoint did not differ significantly in patients who did versus did not receive CPAP (18.1% vs. 22.1%; hazard ratio, 0.80; 95% confidence interval, 0.46-1.41; P\u2009=\u20090.449). Adjusted on-treatment analysis showed a significant cardiovascular risk reduction in those who used CPAP for \u22654 versus <4 hours per night or did not receive treatment (hazard ratio, 0.29; 95% confidence interval, 0.10-0.86; P\u2009=\u20090.026).\n## CONCLUSIONS\nRoutine prescription of CPAP to patients with CAD with nonsleepy OSA did not significantly reduce long-term adverse cardiovascular outcomes in the intention-to-treat population. There was a significant reduction after adjustment for baseline comorbidities and compliance with the treatment. Clinical trial registered with www.clinicaltrials.gov (NCT 00519597).",
        "truth": "True"
    },
    {
        "pmid": "28697252",
        "meta_analysis_title": "Association of Positive Airway Pressure With Cardiovascular Events and Death in Adults With Sleep Apnea: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Does the use of positive airway pressure (PAP) to treat sleep apnea reduce risk of cardiovascular events and death?",
        "criteria": "A systematic search of the scientific literature was done according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statement for the conduct of meta-analyses of intervention studies. The searches included MEDLINE via Ovid (from January 1, 1946, to March 2017), EMBASE (from January 1, 1974, to March 2017), and the Cochrane Library database (Cochrane Central Register of Controlled Trials, no date restriction) using relevant text words and Medical Subject Headings that consisted of terms relating to randomized trial and sleep apnea (see the eAppendix in the Supplement for detailed search strategy). The search was limited to randomized clinical trials (RCTs) but without language restriction. Additionally, reference lists from trials, review articles, and reports were manually scanned to identify any other relevant data (including conference abstracts). The clinicaltrials.gov website was searched for RCTs that were registered as completed but not yet published.",
        "subgroup": "Meta-analysis of the Association of Positive Airway Pressure With Cardiovascular Events and Death - Major adverse cardiovascular events plus",
        "key_reference_title": "Continuous positive airway pressure for central sleep apnea and heart failure.",
        "key_reference_abstract": "## BACKGROUND\nThe Canadian Continuous Positive Airway Pressure for Patients with Central Sleep Apnea and Heart Failure trial tested the hypothesis that continuous positive airway pressure (CPAP) would improve the survival rate without heart transplantation of patients who have central sleep apnea and heart failure.\n## METHODS\nAfter medical therapy was optimized, 258 patients who had heart failure (mean age [+/-SD], 63+/-10 years; ejection fraction, 24.5+/-7.7 percent) and central sleep apnea (number of episodes of apnea and hypopnea per hour of sleep, 40+/-16) were randomly assigned to receive CPAP (128 patients) or no CPAP (130 patients) and were followed for a mean of two years. During follow-up, sleep studies were conducted and measurements of the ejection fraction, exercise capacity, quality of life, and neurohormones were obtained.\n## RESULTS\nThree months after undergoing randomization, the CPAP group, as compared with the control group, had greater reductions in the frequency of episodes of apnea and hypopnea (-21+/-16 vs. -2+/-18 per hour, P<0.001) and in norepinephrine levels (-1.03+/-1.84 vs. 0.02+/-0.99 nmol per liter, P=0.009), and greater increases in the mean nocturnal oxygen saturation (1.6+/-2.8 percent vs. 0.4+/-2.5 percent, P<0.001), ejection fraction (2.2+/-5.4 percent vs. 0.4+/-5.3 percent, P=0.02), and the distance walked in six minutes (20.0+/-55 vs. -0.8+/-64.8 m, P=0.016). There were no differences between the control group and the CPAP group in the number of hospitalizations, quality of life, or atrial natriuretic peptide levels. An early divergence in survival rates without heart transplantation favored the control group, but after 18 months the divergence favored the CPAP group, yet the overall event rates (death and heart transplantation) did not differ (32 vs. 32 events, respectively; P=0.54).\n## CONCLUSIONS\nAlthough CPAP attenuated central sleep apnea, improved nocturnal oxygenation, increased the ejection fraction, lowered norepinephrine levels, and increased the distance walked in six minutes, it did not affect survival. Our data do not support the use of CPAP to extend life in patients who have central sleep apnea and heart failure.",
        "truth": "False"
    },
    {
        "pmid": "28697252",
        "meta_analysis_title": "Association of Positive Airway Pressure With Cardiovascular Events and Death in Adults With Sleep Apnea: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Does the use of positive airway pressure (PAP) to treat sleep apnea reduce risk of cardiovascular events and death?",
        "criteria": "A systematic search of the scientific literature was done according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statement for the conduct of meta-analyses of intervention studies. The searches included MEDLINE via Ovid (from January 1, 1946, to March 2017), EMBASE (from January 1, 1974, to March 2017), and the Cochrane Library database (Cochrane Central Register of Controlled Trials, no date restriction) using relevant text words and Medical Subject Headings that consisted of terms relating to randomized trial and sleep apnea (see the eAppendix in the Supplement for detailed search strategy). The search was limited to randomized clinical trials (RCTs) but without language restriction. Additionally, reference lists from trials, review articles, and reports were manually scanned to identify any other relevant data (including conference abstracts). The clinicaltrials.gov website was searched for RCTs that were registered as completed but not yet published.",
        "subgroup": "Meta-analysis of the Association of Positive Airway Pressure With Cardiovascular Events and Death - Major adverse cardiovascular events plus",
        "key_reference_title": "Effect of continuous positive airway pressure on the incidence of hypertension and cardiovascular events in nonsleepy patients with obstructive sleep apnea: a randomized controlled trial.",
        "key_reference_abstract": "## CONTEXT\nContinuous positive airway pressure (CPAP) is the first-line treatment for patients with symptomatic obstructive sleep apnea (OSA). However, its indication for all patients with sleep-disordered breathing, regardless of daytime symptoms, is unclear.\n## OBJECTIVE\nTo evaluate the effect of CPAP treatment on the incidence of hypertension or cardiovascular events in a cohort of nonsleepy patients with OSA.\n## DESIGN, SETTING, AND PATIENTS\nMulticenter, parallel-group, randomized controlled trial in 14 teaching hospitals in Spain. Between May 2004 and May 2006, 725 consecutive patients were enrolled who had an apnea-hypopnea index of 20 h(-1) or greater and an Epworth Sleepiness Scale score of 10 or less (scores range from 0-24, with values <10 suggesting no daytime sleepiness). Exclusion criteria were previous cardiovascular event, physical or psychological incapacity, chronic disease, or drug or alcohol addiction. Follow-up ended in May 2009.\n## INTERVENTION\nPatients were allocated to receive CPAP treatment or no active intervention. All participants received dietary counseling and sleep hygiene advice.\n## MAIN OUTCOME MEASURES\nIncidence of either systemic hypertension (taking antihypertensive medication or blood pressure greater than 140/90 mm Hg) or cardiovascular event (nonfatal myocardial infarction, nonfatal stroke, transient ischemic attack, hospitalization for unstable angina or arrhythmia, heart failure, or cardiovascular death).\n## RESULTS\nSeven hundred twenty-three patients underwent follow-up for a median of 4 (interquartile range, 2.7-4.4) years (1 patient from each group did not receive allocated treatment); 357 in the CPAP group and 366 in the control group were included in the analysis. In the CPAP group there were 68 patients with new hypertension and 28 cardiovascular events (17 unstable angina or arrhythmia, 3 nonfatal stroke, 3 heart failure, 2 nonfatal myocardial infarction, 2 transient ischemic attack, 1 cardiovascular death). In the control group there were 79 patients with new hypertension and 31 cardiovascular events (11 unstable angina or arrhythmia, 8 nonfatal myocardial infarction, 5 transient ischemic attack, 5 heart failure, 2 nonfatal stroke). The hypertension or cardiovascular event incidence density rate was 9.20 per 100 person-years (95% CI, 7.36-11.04) in the CPAP group and 11.02 per 100 person-years (95% CI, 8.96-13.08) in the control group. The incidence density ratio was 0.83 (95% CI, 0.63-1.1; P = .20).\n## CONCLUSIONS\nIn patients with OSA without daytime sleepiness, the prescription of CPAP compared with usual care did not result in a statistically significant reduction in the incidence of hypertension or cardiovascular events. However, the study may have had limited power to detect a significant difference.\n## TRIAL REGISTRATION\nclinicaltrials.gov Identifier: NCT00127348.",
        "truth": "True"
    },
    {
        "pmid": "28697252",
        "meta_analysis_title": "Association of Positive Airway Pressure With Cardiovascular Events and Death in Adults With Sleep Apnea: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Does the use of positive airway pressure (PAP) to treat sleep apnea reduce risk of cardiovascular events and death?",
        "criteria": "A systematic search of the scientific literature was done according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statement for the conduct of meta-analyses of intervention studies. The searches included MEDLINE via Ovid (from January 1, 1946, to March 2017), EMBASE (from January 1, 1974, to March 2017), and the Cochrane Library database (Cochrane Central Register of Controlled Trials, no date restriction) using relevant text words and Medical Subject Headings that consisted of terms relating to randomized trial and sleep apnea (see the eAppendix in the Supplement for detailed search strategy). The search was limited to randomized clinical trials (RCTs) but without language restriction. Additionally, reference lists from trials, review articles, and reports were manually scanned to identify any other relevant data (including conference abstracts). The clinicaltrials.gov website was searched for RCTs that were registered as completed but not yet published.",
        "subgroup": "Meta-analysis of the Association of Positive Airway Pressure With Cardiovascular Events and Death - Major adverse cardiovascular events plus",
        "key_reference_title": "Continuous positive airway pressure improves sleepiness but not calculated vascular risk in patients with minimally symptomatic obstructive sleep apnoea: the MOSAIC randomised controlled trial.",
        "key_reference_abstract": "## BACKGROUND\nContinuous positive airway pressure (CPAP) for symptomatic obstructive sleep apnoea (OSA) improves sleepiness and reduces vascular risk, but such treatment for the more prevalent, minimally symptomatic disease is contentious.\n## METHODS\nThis multicentre, randomised controlled, parallel, hospital-based trial across the UK and Canada, recruited 391 patients with confirmed OSA (oxygen desaturation index >7.5/h) but insufficient symptoms to warrant CPAP therapy. Patients were randomised to 6 months of auto-adjusting CPAP therapy, or standard care. Coprimary endpoints were change in Epworth Sleepiness Score (ESS) and predicted 5-year mortality using a cardiovascular risk score (components: age, sex, height, systolic blood pressure, smoking, diabetes, cholesterol, creatinine, left ventricular hypertrophy, previous myocardial infarction or stroke). Secondary endpoints included some of the individual components of the vascular risk score, objectively measured sleepiness and self-assessed health status.\n## RESULTS\nOf 391 patients randomised, 14 withdrew, 347 attended for their follow-up visit at 6 months within the predefined time window, of which 341 had complete ESS data (baseline mean 8.0, SD 4.3) and 310 had complete risk score data. 22% of patients in the CPAP group reported stopping treatment and overall median CPAP use was 2\u2009:\u200939 h per night. CPAP significantly improved subjective daytime sleepiness (adjusted treatment effect on ESS -2.0 (95% CI -2.6 to -1.4), p<0.0001), objectively measured sleepiness and self-assessed health status. CPAP did not improve the 5-year calculated vascular risk or any of its components.\n## CONCLUSIONS\nIn patients with minimally symptomatic OSA, CPAP can reduce subjective and objective daytime sleepiness, and improve self-assessed health status, but does not appear to improve calculated vascular risk.",
        "truth": "True"
    },
    {
        "pmid": "28697252",
        "meta_analysis_title": "Association of Positive Airway Pressure With Cardiovascular Events and Death in Adults With Sleep Apnea: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Does the use of positive airway pressure (PAP) to treat sleep apnea reduce risk of cardiovascular events and death?",
        "criteria": "A systematic search of the scientific literature was done according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statement for the conduct of meta-analyses of intervention studies. The searches included MEDLINE via Ovid (from January 1, 1946, to March 2017), EMBASE (from January 1, 1974, to March 2017), and the Cochrane Library database (Cochrane Central Register of Controlled Trials, no date restriction) using relevant text words and Medical Subject Headings that consisted of terms relating to randomized trial and sleep apnea (see the eAppendix in the Supplement for detailed search strategy). The search was limited to randomized clinical trials (RCTs) but without language restriction. Additionally, reference lists from trials, review articles, and reports were manually scanned to identify any other relevant data (including conference abstracts). The clinicaltrials.gov website was searched for RCTs that were registered as completed but not yet published.",
        "subgroup": "Meta-analysis of the Association of Positive Airway Pressure With Cardiovascular Events and Death - Major adverse cardiovascular events plus",
        "key_reference_title": "Effects of continuous positive airway pressure on neurocognitive function in obstructive sleep apnea patients: The Apnea Positive Pressure Long-term Efficacy Study (APPLES).",
        "key_reference_abstract": "## STUDY OBJECTIVE\nTo determine the neurocognitive effects of continuous positive airway pressure (CPAP) therapy on patients with obstructive sleep apnea (OSA).\n## DESIGN, SETTING, AND PARTICIPANTS\nThe Apnea Positive Pressure Long-term Efficacy Study (APPLES) was a 6-month, randomized, double-blind, 2-arm, sham-controlled, multicenter trial conducted at 5 U.S. university, hospital, or private practices. Of 1,516 participants enrolled, 1,105 were randomized, and 1,098 participants diagnosed with OSA contributed to the analysis of the primary outcome measures.\n## INTERVENTION\nActive or sham CPAP MEASUREMENTS: THREE NEUROCOGNITIVE VARIABLES, EACH REPRESENTING A NEUROCOGNITIVE DOMAIN: Pathfinder Number Test-Total Time (attention and psychomotor function [A/P]), Buschke Selective Reminding Test-Sum Recall (learning and memory [L/M]), and Sustained Working Memory Test-Overall Mid-Day Score (executive and frontal-lobe function [E/F])\n## RESULTS\nThe primary neurocognitive analyses showed a difference between groups for only the E/F variable at the 2 month CPAP visit, but no difference at the 6 month CPAP visit or for the A/P or L/M variables at either the 2 or 6 month visits. When stratified by measures of OSA severity (AHI or oxygen saturation parameters), the primary E/F variable and one secondary E/F neurocognitive variable revealed transient differences between study arms for those with the most severe OSA. Participants in the active CPAP group had a significantly greater ability to remain awake whether measured subjectively by the Epworth Sleepiness Scale or objectively by the maintenance of wakefulness test.\n## CONCLUSIONS\nCPAP treatment improved both subjectively and objectively measured sleepiness, especially in individuals with severe OSA (AHI > 30). CPAP use resulted in mild, transient improvement in the most sensitive measures of executive and frontal-lobe function for those with severe disease, which suggests the existence of a complex OSA-neurocognitive relationship.\n## CLINICAL TRIAL INFORMATION\nRegistered at clinicaltrials.gov. Identifier: NCT00051363.\n## CITATION\nKushida CA; Nichols DA; Holmes TH; Quan SF; Walsh JK; Gottlieb DJ; Simon RD; Guilleminault C; White DP; Goodwin JL; Schweitzer PK; Leary EB; Hyde PR; Hirshkowitz M; Green S; McEvoy LK; Chan C; Gevins A; Kay GG; Bloch DA; Crabtree T; Demen WC. Effects of continuous positive airway pressure on neurocognitive function in obstructive sleep apnea patients: the Apnea Positive Pressure Long-term Efficacy Study (APPLES). SLEEP 2012;35(12):1593-1602.",
        "truth": "False"
    },
    {
        "pmid": "28697252",
        "meta_analysis_title": "Association of Positive Airway Pressure With Cardiovascular Events and Death in Adults With Sleep Apnea: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Does the use of positive airway pressure (PAP) to treat sleep apnea reduce risk of cardiovascular events and death?",
        "criteria": "A systematic search of the scientific literature was done according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statement for the conduct of meta-analyses of intervention studies. The searches included MEDLINE via Ovid (from January 1, 1946, to March 2017), EMBASE (from January 1, 1974, to March 2017), and the Cochrane Library database (Cochrane Central Register of Controlled Trials, no date restriction) using relevant text words and Medical Subject Headings that consisted of terms relating to randomized trial and sleep apnea (see the eAppendix in the Supplement for detailed search strategy). The search was limited to randomized clinical trials (RCTs) but without language restriction. Additionally, reference lists from trials, review articles, and reports were manually scanned to identify any other relevant data (including conference abstracts). The clinicaltrials.gov website was searched for RCTs that were registered as completed but not yet published.",
        "subgroup": "Meta-analysis of the Association of Positive Airway Pressure With Cardiovascular Events and Death - Major adverse cardiovascular events plus",
        "key_reference_title": "Continuous positive airway pressure in older people with obstructive sleep apnoea syndrome (PREDICT): a 12-month, multicentre, randomised trial.",
        "key_reference_abstract": "## BACKGROUND\nThe therapeutic and economic benefits of continuous positive airway pressure (CPAP) for moderate to severe obstructive sleep apnoea (OSA) syndrome have been established in middle-aged people; however, the benefits in older people are unknown. This trial was designed to address this evidence gap.\n## METHODS\nThis 12-month, multicentre, randomised trial enrolled patients across 14 National Health Service sleep centres in the UK. Consecutive patients aged 65 years or older with newly diagnosed OSA syndrome were eligible to join the trial. Patients were randomly assigned (1:1) into parallel groups to receive either CPAP with best supportive care (BSC) or BSC alone for 12 months. Randomisation was done by the Medical Research Council Clinical Trials Unit with computer-generated randomisation. The main investigator at each centre was masked to the trial randomisation. Coprimary endpoints were Epworth sleepiness score (ESS) at 3 months and cost-effectiveness over the 12-month trial period. Secondary outcomes were subjective sleepiness at 12 months, plus objective sleepiness, quality of life, mood, functionality, nocturia, mobility, accidents, cognitive function, and cardiovascular risk factors and events at 3 months and 12 months. The analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN90464927.\n## FINDINGS\nBetween Feb 24, 2010, and May 30, 2012, 278 patients were randomly assigned to the trial, of whom 231 (83%) completed the trial. 140 patients were allocated to and received CPAP plus BSC and 138 were allocated to and received BSC only. CPAP reduced ESS by 2\u00b71 points (95% CI -3\u00b70 to -1\u00b73; p<0\u00b70001) at 3 months for 124 (89%) of 140 patients compared with 124 (90%) of 138 patients given BSC, and by 2\u00b70 points (-2\u00b78 to -1\u00b72; p<0\u00b70001) at 12 months for 116 patients compared with 122 patients given BSC. The effect was greater in patients with higher CPAP usage or higher baseline ESS. Quality-adjusted life-years were similar between the groups (treatment effect 0\u00b701 (95% CI -0\u00b703 to 0\u00b704; p=0\u00b7787) and health-care costs were marginally reduced with CPAP (-\u00a335, -390 to 321; p=0\u00b7847). CPAP improved objective sleepiness (p=0\u00b7024), mobility (p=0\u00b7029), total cholesterol (p=0\u00b7048), and LDL cholesterol (p=0\u00b7042) at 3 months, but these were not sustained at 12 months. Measures of mood, functionality, nocturia, accidents, cognitive function, and cardiovascular events remained unchanged. Systolic blood pressure fell in the BSC group. 37 serious adverse events occurred in the CPAP group, and 22 in BSC group; all were independently classified as being unrelated to the trial and no significant harm was attributed to CPAP use.\n## INTERPRETATION\nIn older people with OSA syndrome, CPAP reduces sleepiness and is marginally more cost effective over 12 months than is BSC alone. On the basis of these results, we recommend that CPAP treatment should be offered routinely to older patients with OSA syndrome.\n## FUNDING\nNational Institute of Health Research (NIHR) Health Technology Assessment, NIHR Respiratory Biomedical Research Unit at the Royal Brompton and Harefield NHS Foundation Trust and Imperial College London.",
        "truth": "False"
    },
    {
        "pmid": "28697252",
        "meta_analysis_title": "Association of Positive Airway Pressure With Cardiovascular Events and Death in Adults With Sleep Apnea: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Does the use of positive airway pressure (PAP) to treat sleep apnea reduce risk of cardiovascular events and death?",
        "criteria": "A systematic search of the scientific literature was done according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statement for the conduct of meta-analyses of intervention studies. The searches included MEDLINE via Ovid (from January 1, 1946, to March 2017), EMBASE (from January 1, 1974, to March 2017), and the Cochrane Library database (Cochrane Central Register of Controlled Trials, no date restriction) using relevant text words and Medical Subject Headings that consisted of terms relating to randomized trial and sleep apnea (see the eAppendix in the Supplement for detailed search strategy). The search was limited to randomized clinical trials (RCTs) but without language restriction. Additionally, reference lists from trials, review articles, and reports were manually scanned to identify any other relevant data (including conference abstracts). The clinicaltrials.gov website was searched for RCTs that were registered as completed but not yet published.",
        "subgroup": "Meta-analysis of the Association of Positive Airway Pressure With Cardiovascular Events and Death - Major adverse cardiovascular events plus",
        "key_reference_title": "Adaptive Servo-Ventilation for Central Sleep Apnea in Systolic Heart Failure.",
        "key_reference_abstract": "## BACKGROUND\nCentral sleep apnea is associated with poor prognosis and death in patients with heart failure. Adaptive servo-ventilation is a therapy that uses a noninvasive ventilator to treat central sleep apnea by delivering servo-controlled inspiratory pressure support on top of expiratory positive airway pressure. We investigated the effects of adaptive servo-ventilation in patients who had heart failure with reduced ejection fraction and predominantly central sleep apnea.\n## METHODS\nWe randomly assigned 1325 patients with a left ventricular ejection fraction of 45% or less, an apnea-hypopnea index (AHI) of 15 or more events (occurrences of apnea or hypopnea) per hour, and a predominance of central events to receive guideline-based medical treatment with adaptive servo-ventilation or guideline-based medical treatment alone (control). The primary end point in the time-to-event analysis was the first event of death from any cause, lifesaving cardiovascular intervention (cardiac transplantation, implantation of a ventricular assist device, resuscitation after sudden cardiac arrest, or appropriate lifesaving shock), or unplanned hospitalization for worsening heart failure.\n## RESULTS\nIn the adaptive servo-ventilation group, the mean AHI at 12 months was 6.6 events per hour. The incidence of the primary end point did not differ significantly between the adaptive servo-ventilation group and the control group (54.1% and 50.8%, respectively; hazard ratio, 1.13; 95% confidence interval [CI], 0.97 to 1.31; P=0.10). All-cause mortality and cardiovascular mortality were significantly higher in the adaptive servo-ventilation group than in the control group (hazard ratio for death from any cause, 1.28; 95% CI, 1.06 to 1.55; P=0.01; and hazard ratio for cardiovascular death, 1.34; 95% CI, 1.09 to 1.65; P=0.006).\n## CONCLUSIONS\nAdaptive servo-ventilation had no significant effect on the primary end point in patients who had heart failure with reduced ejection fraction and predominantly central sleep apnea, but all-cause and cardiovascular mortality were both increased with this therapy. (Funded by ResMed and others; SERVE-HF ClinicalTrials.gov number, NCT00733343.).",
        "truth": "False"
    },
    {
        "pmid": "28697252",
        "meta_analysis_title": "Association of Positive Airway Pressure With Cardiovascular Events and Death in Adults With Sleep Apnea: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Does the use of positive airway pressure (PAP) to treat sleep apnea reduce risk of cardiovascular events and death?",
        "criteria": "A systematic search of the scientific literature was done according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statement for the conduct of meta-analyses of intervention studies. The searches included MEDLINE via Ovid (from January 1, 1946, to March 2017), EMBASE (from January 1, 1974, to March 2017), and the Cochrane Library database (Cochrane Central Register of Controlled Trials, no date restriction) using relevant text words and Medical Subject Headings that consisted of terms relating to randomized trial and sleep apnea (see the eAppendix in the Supplement for detailed search strategy). The search was limited to randomized clinical trials (RCTs) but without language restriction. Additionally, reference lists from trials, review articles, and reports were manually scanned to identify any other relevant data (including conference abstracts). The clinicaltrials.gov website was searched for RCTs that were registered as completed but not yet published.",
        "subgroup": "Meta-analysis of the Association of Positive Airway Pressure With Cardiovascular Events and Death - Major adverse cardiovascular events plus",
        "key_reference_title": "Long-term effects of continuous positive airway pressure on blood pressure and prognosis in hypertensive patients with coronary heart disease and obstructive sleep apnea: a randomized controlled trial.",
        "key_reference_abstract": "## BACKGROUND\nObstructive sleep apnea (OSA) can result in hypertension and significantly increase cardiovascular morbidity and mortality. There are few reports on the long-term effects of continuous positive airway pressure (CPAP) on blood pressure in patients with uncontrolled hypertension with coronary heart disease (CHD) and OSA.\n## METHODS\nWe conducted a prospective, long-term follow-up study in 83 patients with uncontrolled hypertension, CHD, and OSA randomized to control or CPAP groups. Daytime systolic blood pressure (SBP), diastolic blood pressure (DBP), and severe cardiovascular and cerebrovascular events (SCCEs) were recorded at baseline and follow-up.\n## RESULTS\nSeventy-three patients completed the study with a median follow-up of 36 (interquartile range = 24-54) months. The 2 groups had similar characteristics at baseline. CPAP was used for 4.5\u00b11.1 hour/night. SBP in the CPAP group was significantly reduced at follow-up (143\u00b17 mm Hg vs. 139\u00b17 mm Hg, P = 0.04), and SBP decreased by 8mm Hg (95% confidence interval = 1.4-9.9; P = 0.01). Hypertension control was improved (CPAP, 69.4% for CPAP users vs. 43.2% for control subjects; P = 0.02); however, DBP did not reach statistical difference between the groups (81\u00b110 mm Hg vs. 79\u00b18 mm Hg; P = 0.49). In the CPAP group, the Epworth Sleepiness Scale was markedly reduced (7.0\u00b13.4 vs. 3.7\u00b12.3; P < 0.001). There was 1 SCCE in the CPAP group (heart failure), and 5 SCCEs in the control group (acute myocardial infarction: 2 (with 1 death); stroke: 3), but there was no significant difference identified.\n## CONCLUSIONS\nLong-term CPAP application in uncontrolled hypertension with CHD and OSA significantly reduced daytime SBP, improved hypertension control and daytime sleepiness, and decreased the trend in SCCEs compared with control subjects.\n## CLINICAL TRIAL REGISTRATION NUMBER\nClinicalTrials.gov NCT02059993.",
        "truth": "True"
    },
    {
        "pmid": "28697252",
        "meta_analysis_title": "Association of Positive Airway Pressure With Cardiovascular Events and Death in Adults With Sleep Apnea: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Does the use of positive airway pressure (PAP) to treat sleep apnea reduce risk of cardiovascular events and death?",
        "criteria": "A systematic search of the scientific literature was done according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statement for the conduct of meta-analyses of intervention studies. The searches included MEDLINE via Ovid (from January 1, 1946, to March 2017), EMBASE (from January 1, 1974, to March 2017), and the Cochrane Library database (Cochrane Central Register of Controlled Trials, no date restriction) using relevant text words and Medical Subject Headings that consisted of terms relating to randomized trial and sleep apnea (see the eAppendix in the Supplement for detailed search strategy). The search was limited to randomized clinical trials (RCTs) but without language restriction. Additionally, reference lists from trials, review articles, and reports were manually scanned to identify any other relevant data (including conference abstracts). The clinicaltrials.gov website was searched for RCTs that were registered as completed but not yet published.",
        "subgroup": "Meta-analysis of the Association of Positive Airway Pressure With Cardiovascular Events and Death - Major adverse cardiovascular events plus",
        "key_reference_title": "Efficacy of continuous positive airway pressure treatment on 5-year survival in patients with ischaemic stroke and obstructive sleep apnea: a randomized controlled trial.",
        "key_reference_abstract": "The main purpose of the present analysis is to assess the influence of introducing early nasal continuous positive airway pressure (nCPAP) treatment on cardiovascular recurrences and mortality in patients with a first-ever ischaemic stroke and moderate-severe obstructive sleep apnea (OSA) with an apnea-hypopnea index (AHI) \u226520 events h(-1) during a 5-year follow-up. Patients received conventional treatment for stroke and were assigned randomly to the nCPAP group (n = 71) or the control group (n = 69). Cardiovascular events and mortality were registered for all patients. Survival and cardiovascular event-free survival analysis were performed after 5-year follow-up using the Kaplan-Meier test. Patients in the nCPAP group had significantly higher cardiovascular survival than the control group (100 versus 89.9%, log-rank test 5.887; P = 0.015) However, and also despite a positive tendency, there were no significant differences in the cardiovascular event-free survival at 68 months between the nCPAP and control groups (89.5 versus 75.4%, log-rank test 3.565; P = 0.059). Early nCPAP therapy has a positive effect on long-term survival in ischaemic stroke patients and moderate-severe OSA.",
        "truth": "False"
    },
    {
        "pmid": "28697252",
        "meta_analysis_title": "Association of Positive Airway Pressure With Cardiovascular Events and Death in Adults With Sleep Apnea: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Does the use of positive airway pressure (PAP) to treat sleep apnea reduce risk of cardiovascular events and death?",
        "criteria": "A systematic search of the scientific literature was done according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statement for the conduct of meta-analyses of intervention studies. The searches included MEDLINE via Ovid (from January 1, 1946, to March 2017), EMBASE (from January 1, 1974, to March 2017), and the Cochrane Library database (Cochrane Central Register of Controlled Trials, no date restriction) using relevant text words and Medical Subject Headings that consisted of terms relating to randomized trial and sleep apnea (see the eAppendix in the Supplement for detailed search strategy). The search was limited to randomized clinical trials (RCTs) but without language restriction. Additionally, reference lists from trials, review articles, and reports were manually scanned to identify any other relevant data (including conference abstracts). The clinicaltrials.gov website was searched for RCTs that were registered as completed but not yet published.",
        "subgroup": "Meta-analysis of the Association of Positive Airway Pressure With Cardiovascular Events and Death - Major adverse cardiovascular events plus",
        "key_reference_title": "CPAP for Prevention of Cardiovascular Events in Obstructive Sleep Apnea.",
        "key_reference_abstract": "## BACKGROUND\nObstructive sleep apnea is associated with an increased risk of cardiovascular events; whether treatment with continuous positive airway pressure (CPAP) prevents major cardiovascular events is uncertain.\n## METHODS\nAfter a 1-week run-in period during which the participants used sham CPAP, we randomly assigned 2717 eligible adults between 45 and 75 years of age who had moderate-to-severe obstructive sleep apnea and coronary or cerebrovascular disease to receive CPAP treatment plus usual care (CPAP group) or usual care alone (usual-care group). The primary composite end point was death from cardiovascular causes, myocardial infarction, stroke, or hospitalization for unstable angina, heart failure, or transient ischemic attack. Secondary end points included other cardiovascular outcomes, health-related quality of life, snoring symptoms, daytime sleepiness, and mood.\n## RESULTS\nMost of the participants were men who had moderate-to-severe obstructive sleep apnea and minimal sleepiness. In the CPAP group, the mean duration of adherence to CPAP therapy was 3.3 hours per night, and the mean apnea-hypopnea index (the number of apnea or hypopnea events per hour of recording) decreased from 29.0 events per hour at baseline to 3.7 events per hour during follow-up. After a mean follow-up of 3.7 years, a primary end-point event had occurred in 229 participants in the CPAP group (17.0%) and in 207 participants in the usual-care group (15.4%) (hazard ratio with CPAP, 1.10; 95% confidence interval, 0.91 to 1.32; P=0.34). No significant effect on any individual or other composite cardiovascular end point was observed. CPAP significantly reduced snoring and daytime sleepiness and improved health-related quality of life and mood.\n## CONCLUSIONS\nTherapy with CPAP plus usual care, as compared with usual care alone, did not prevent cardiovascular events in patients with moderate-to-severe obstructive sleep apnea and established cardiovascular disease. (Funded by the National Health and Medical Research Council of Australia and others; SAVE ClinicalTrials.gov number, NCT00738179 ; Australian New Zealand Clinical Trials Registry number, ACTRN12608000409370 .).",
        "truth": "True"
    },
    {
        "pmid": "28697252",
        "meta_analysis_title": "Association of Positive Airway Pressure With Cardiovascular Events and Death in Adults With Sleep Apnea: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Does the use of positive airway pressure (PAP) to treat sleep apnea reduce risk of cardiovascular events and death?",
        "criteria": "A systematic search of the scientific literature was done according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statement for the conduct of meta-analyses of intervention studies. The searches included MEDLINE via Ovid (from January 1, 1946, to March 2017), EMBASE (from January 1, 1974, to March 2017), and the Cochrane Library database (Cochrane Central Register of Controlled Trials, no date restriction) using relevant text words and Medical Subject Headings that consisted of terms relating to randomized trial and sleep apnea (see the eAppendix in the Supplement for detailed search strategy). The search was limited to randomized clinical trials (RCTs) but without language restriction. Additionally, reference lists from trials, review articles, and reports were manually scanned to identify any other relevant data (including conference abstracts). The clinicaltrials.gov website was searched for RCTs that were registered as completed but not yet published.",
        "subgroup": "Meta-analysis of the Association of Positive Airway Pressure With Cardiovascular Events and Death - Major adverse cardiovascular events plus",
        "key_reference_title": "Effect of Positive Airway Pressure on Cardiovascular Outcomes in Coronary Artery Disease Patients with Nonsleepy Obstructive Sleep Apnea. The RICCADSA Randomized Controlled Trial.",
        "key_reference_abstract": "## RATIONALE\nObstructive sleep apnea (OSA) is common in patients with coronary artery disease (CAD), many of whom do not report daytime sleepiness. First-line treatment for symptomatic OSA is continuous positive airway pressure (CPAP), but its value in patients without daytime sleepiness is uncertain.\n## OBJECTIVES\nTo determine the effects of CPAP on long-term adverse cardiovascular outcome risk in patients with CAD with nonsleepy OSA.\n## METHODS\nThis single-center, prospective, randomized, controlled, open-label, blinded evaluation trial was conducted between December 2005 and November 2010. Consecutive patients with newly revascularized CAD and OSA (apnea-hypopnea index \u226515/h) without daytime sleepiness (Epworth Sleepiness Scale score <10) were randomized to auto-titrating CPAP (n\u2009=\u2009122) or no positive airway pressure (n\u2009=\u2009122).\n## MEASUREMENTS AND MAIN RESULTS\nThe primary endpoint was the first event of repeat revascularization, myocardial infarction, stroke, or cardiovascular mortality. Median follow-up was 57 months. The incidence of the primary endpoint did not differ significantly in patients who did versus did not receive CPAP (18.1% vs. 22.1%; hazard ratio, 0.80; 95% confidence interval, 0.46-1.41; P\u2009=\u20090.449). Adjusted on-treatment analysis showed a significant cardiovascular risk reduction in those who used CPAP for \u22654 versus <4 hours per night or did not receive treatment (hazard ratio, 0.29; 95% confidence interval, 0.10-0.86; P\u2009=\u20090.026).\n## CONCLUSIONS\nRoutine prescription of CPAP to patients with CAD with nonsleepy OSA did not significantly reduce long-term adverse cardiovascular outcomes in the intention-to-treat population. There was a significant reduction after adjustment for baseline comorbidities and compliance with the treatment. Clinical trial registered with www.clinicaltrials.gov (NCT 00519597).",
        "truth": "True"
    },
    {
        "pmid": "28697252",
        "meta_analysis_title": "Association of Positive Airway Pressure With Cardiovascular Events and Death in Adults With Sleep Apnea: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Does the use of positive airway pressure (PAP) to treat sleep apnea reduce risk of cardiovascular events and death?",
        "criteria": "A systematic search of the scientific literature was done according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statement for the conduct of meta-analyses of intervention studies. The searches included MEDLINE via Ovid (from January 1, 1946, to March 2017), EMBASE (from January 1, 1974, to March 2017), and the Cochrane Library database (Cochrane Central Register of Controlled Trials, no date restriction) using relevant text words and Medical Subject Headings that consisted of terms relating to randomized trial and sleep apnea (see the eAppendix in the Supplement for detailed search strategy). The search was limited to randomized clinical trials (RCTs) but without language restriction. Additionally, reference lists from trials, review articles, and reports were manually scanned to identify any other relevant data (including conference abstracts). The clinicaltrials.gov website was searched for RCTs that were registered as completed but not yet published.",
        "subgroup": "Meta-analysis of the Association of Positive Airway Pressure With Cardiovascular Outcomes - Acute coronary syndromes",
        "key_reference_title": "Continuous positive airway pressure for central sleep apnea and heart failure.",
        "key_reference_abstract": "## BACKGROUND\nThe Canadian Continuous Positive Airway Pressure for Patients with Central Sleep Apnea and Heart Failure trial tested the hypothesis that continuous positive airway pressure (CPAP) would improve the survival rate without heart transplantation of patients who have central sleep apnea and heart failure.\n## METHODS\nAfter medical therapy was optimized, 258 patients who had heart failure (mean age [+/-SD], 63+/-10 years; ejection fraction, 24.5+/-7.7 percent) and central sleep apnea (number of episodes of apnea and hypopnea per hour of sleep, 40+/-16) were randomly assigned to receive CPAP (128 patients) or no CPAP (130 patients) and were followed for a mean of two years. During follow-up, sleep studies were conducted and measurements of the ejection fraction, exercise capacity, quality of life, and neurohormones were obtained.\n## RESULTS\nThree months after undergoing randomization, the CPAP group, as compared with the control group, had greater reductions in the frequency of episodes of apnea and hypopnea (-21+/-16 vs. -2+/-18 per hour, P<0.001) and in norepinephrine levels (-1.03+/-1.84 vs. 0.02+/-0.99 nmol per liter, P=0.009), and greater increases in the mean nocturnal oxygen saturation (1.6+/-2.8 percent vs. 0.4+/-2.5 percent, P<0.001), ejection fraction (2.2+/-5.4 percent vs. 0.4+/-5.3 percent, P=0.02), and the distance walked in six minutes (20.0+/-55 vs. -0.8+/-64.8 m, P=0.016). There were no differences between the control group and the CPAP group in the number of hospitalizations, quality of life, or atrial natriuretic peptide levels. An early divergence in survival rates without heart transplantation favored the control group, but after 18 months the divergence favored the CPAP group, yet the overall event rates (death and heart transplantation) did not differ (32 vs. 32 events, respectively; P=0.54).\n## CONCLUSIONS\nAlthough CPAP attenuated central sleep apnea, improved nocturnal oxygenation, increased the ejection fraction, lowered norepinephrine levels, and increased the distance walked in six minutes, it did not affect survival. Our data do not support the use of CPAP to extend life in patients who have central sleep apnea and heart failure.",
        "truth": "False"
    },
    {
        "pmid": "28697252",
        "meta_analysis_title": "Association of Positive Airway Pressure With Cardiovascular Events and Death in Adults With Sleep Apnea: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Does the use of positive airway pressure (PAP) to treat sleep apnea reduce risk of cardiovascular events and death?",
        "criteria": "A systematic search of the scientific literature was done according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statement for the conduct of meta-analyses of intervention studies. The searches included MEDLINE via Ovid (from January 1, 1946, to March 2017), EMBASE (from January 1, 1974, to March 2017), and the Cochrane Library database (Cochrane Central Register of Controlled Trials, no date restriction) using relevant text words and Medical Subject Headings that consisted of terms relating to randomized trial and sleep apnea (see the eAppendix in the Supplement for detailed search strategy). The search was limited to randomized clinical trials (RCTs) but without language restriction. Additionally, reference lists from trials, review articles, and reports were manually scanned to identify any other relevant data (including conference abstracts). The clinicaltrials.gov website was searched for RCTs that were registered as completed but not yet published.",
        "subgroup": "Meta-analysis of the Association of Positive Airway Pressure With Cardiovascular Outcomes - Acute coronary syndromes",
        "key_reference_title": "Effect of continuous positive airway pressure on the incidence of hypertension and cardiovascular events in nonsleepy patients with obstructive sleep apnea: a randomized controlled trial.",
        "key_reference_abstract": "## CONTEXT\nContinuous positive airway pressure (CPAP) is the first-line treatment for patients with symptomatic obstructive sleep apnea (OSA). However, its indication for all patients with sleep-disordered breathing, regardless of daytime symptoms, is unclear.\n## OBJECTIVE\nTo evaluate the effect of CPAP treatment on the incidence of hypertension or cardiovascular events in a cohort of nonsleepy patients with OSA.\n## DESIGN, SETTING, AND PATIENTS\nMulticenter, parallel-group, randomized controlled trial in 14 teaching hospitals in Spain. Between May 2004 and May 2006, 725 consecutive patients were enrolled who had an apnea-hypopnea index of 20 h(-1) or greater and an Epworth Sleepiness Scale score of 10 or less (scores range from 0-24, with values <10 suggesting no daytime sleepiness). Exclusion criteria were previous cardiovascular event, physical or psychological incapacity, chronic disease, or drug or alcohol addiction. Follow-up ended in May 2009.\n## INTERVENTION\nPatients were allocated to receive CPAP treatment or no active intervention. All participants received dietary counseling and sleep hygiene advice.\n## MAIN OUTCOME MEASURES\nIncidence of either systemic hypertension (taking antihypertensive medication or blood pressure greater than 140/90 mm Hg) or cardiovascular event (nonfatal myocardial infarction, nonfatal stroke, transient ischemic attack, hospitalization for unstable angina or arrhythmia, heart failure, or cardiovascular death).\n## RESULTS\nSeven hundred twenty-three patients underwent follow-up for a median of 4 (interquartile range, 2.7-4.4) years (1 patient from each group did not receive allocated treatment); 357 in the CPAP group and 366 in the control group were included in the analysis. In the CPAP group there were 68 patients with new hypertension and 28 cardiovascular events (17 unstable angina or arrhythmia, 3 nonfatal stroke, 3 heart failure, 2 nonfatal myocardial infarction, 2 transient ischemic attack, 1 cardiovascular death). In the control group there were 79 patients with new hypertension and 31 cardiovascular events (11 unstable angina or arrhythmia, 8 nonfatal myocardial infarction, 5 transient ischemic attack, 5 heart failure, 2 nonfatal stroke). The hypertension or cardiovascular event incidence density rate was 9.20 per 100 person-years (95% CI, 7.36-11.04) in the CPAP group and 11.02 per 100 person-years (95% CI, 8.96-13.08) in the control group. The incidence density ratio was 0.83 (95% CI, 0.63-1.1; P = .20).\n## CONCLUSIONS\nIn patients with OSA without daytime sleepiness, the prescription of CPAP compared with usual care did not result in a statistically significant reduction in the incidence of hypertension or cardiovascular events. However, the study may have had limited power to detect a significant difference.\n## TRIAL REGISTRATION\nclinicaltrials.gov Identifier: NCT00127348.",
        "truth": "True"
    },
    {
        "pmid": "28697252",
        "meta_analysis_title": "Association of Positive Airway Pressure With Cardiovascular Events and Death in Adults With Sleep Apnea: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Does the use of positive airway pressure (PAP) to treat sleep apnea reduce risk of cardiovascular events and death?",
        "criteria": "A systematic search of the scientific literature was done according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statement for the conduct of meta-analyses of intervention studies. The searches included MEDLINE via Ovid (from January 1, 1946, to March 2017), EMBASE (from January 1, 1974, to March 2017), and the Cochrane Library database (Cochrane Central Register of Controlled Trials, no date restriction) using relevant text words and Medical Subject Headings that consisted of terms relating to randomized trial and sleep apnea (see the eAppendix in the Supplement for detailed search strategy). The search was limited to randomized clinical trials (RCTs) but without language restriction. Additionally, reference lists from trials, review articles, and reports were manually scanned to identify any other relevant data (including conference abstracts). The clinicaltrials.gov website was searched for RCTs that were registered as completed but not yet published.",
        "subgroup": "Meta-analysis of the Association of Positive Airway Pressure With Cardiovascular Outcomes - Acute coronary syndromes",
        "key_reference_title": "Continuous positive airway pressure improves sleepiness but not calculated vascular risk in patients with minimally symptomatic obstructive sleep apnoea: the MOSAIC randomised controlled trial.",
        "key_reference_abstract": "## BACKGROUND\nContinuous positive airway pressure (CPAP) for symptomatic obstructive sleep apnoea (OSA) improves sleepiness and reduces vascular risk, but such treatment for the more prevalent, minimally symptomatic disease is contentious.\n## METHODS\nThis multicentre, randomised controlled, parallel, hospital-based trial across the UK and Canada, recruited 391 patients with confirmed OSA (oxygen desaturation index >7.5/h) but insufficient symptoms to warrant CPAP therapy. Patients were randomised to 6 months of auto-adjusting CPAP therapy, or standard care. Coprimary endpoints were change in Epworth Sleepiness Score (ESS) and predicted 5-year mortality using a cardiovascular risk score (components: age, sex, height, systolic blood pressure, smoking, diabetes, cholesterol, creatinine, left ventricular hypertrophy, previous myocardial infarction or stroke). Secondary endpoints included some of the individual components of the vascular risk score, objectively measured sleepiness and self-assessed health status.\n## RESULTS\nOf 391 patients randomised, 14 withdrew, 347 attended for their follow-up visit at 6 months within the predefined time window, of which 341 had complete ESS data (baseline mean 8.0, SD 4.3) and 310 had complete risk score data. 22% of patients in the CPAP group reported stopping treatment and overall median CPAP use was 2\u2009:\u200939 h per night. CPAP significantly improved subjective daytime sleepiness (adjusted treatment effect on ESS -2.0 (95% CI -2.6 to -1.4), p<0.0001), objectively measured sleepiness and self-assessed health status. CPAP did not improve the 5-year calculated vascular risk or any of its components.\n## CONCLUSIONS\nIn patients with minimally symptomatic OSA, CPAP can reduce subjective and objective daytime sleepiness, and improve self-assessed health status, but does not appear to improve calculated vascular risk.",
        "truth": "True"
    },
    {
        "pmid": "28697252",
        "meta_analysis_title": "Association of Positive Airway Pressure With Cardiovascular Events and Death in Adults With Sleep Apnea: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Does the use of positive airway pressure (PAP) to treat sleep apnea reduce risk of cardiovascular events and death?",
        "criteria": "A systematic search of the scientific literature was done according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statement for the conduct of meta-analyses of intervention studies. The searches included MEDLINE via Ovid (from January 1, 1946, to March 2017), EMBASE (from January 1, 1974, to March 2017), and the Cochrane Library database (Cochrane Central Register of Controlled Trials, no date restriction) using relevant text words and Medical Subject Headings that consisted of terms relating to randomized trial and sleep apnea (see the eAppendix in the Supplement for detailed search strategy). The search was limited to randomized clinical trials (RCTs) but without language restriction. Additionally, reference lists from trials, review articles, and reports were manually scanned to identify any other relevant data (including conference abstracts). The clinicaltrials.gov website was searched for RCTs that were registered as completed but not yet published.",
        "subgroup": "Meta-analysis of the Association of Positive Airway Pressure With Cardiovascular Outcomes - Acute coronary syndromes",
        "key_reference_title": "Effects of continuous positive airway pressure on neurocognitive function in obstructive sleep apnea patients: The Apnea Positive Pressure Long-term Efficacy Study (APPLES).",
        "key_reference_abstract": "## STUDY OBJECTIVE\nTo determine the neurocognitive effects of continuous positive airway pressure (CPAP) therapy on patients with obstructive sleep apnea (OSA).\n## DESIGN, SETTING, AND PARTICIPANTS\nThe Apnea Positive Pressure Long-term Efficacy Study (APPLES) was a 6-month, randomized, double-blind, 2-arm, sham-controlled, multicenter trial conducted at 5 U.S. university, hospital, or private practices. Of 1,516 participants enrolled, 1,105 were randomized, and 1,098 participants diagnosed with OSA contributed to the analysis of the primary outcome measures.\n## INTERVENTION\nActive or sham CPAP MEASUREMENTS: THREE NEUROCOGNITIVE VARIABLES, EACH REPRESENTING A NEUROCOGNITIVE DOMAIN: Pathfinder Number Test-Total Time (attention and psychomotor function [A/P]), Buschke Selective Reminding Test-Sum Recall (learning and memory [L/M]), and Sustained Working Memory Test-Overall Mid-Day Score (executive and frontal-lobe function [E/F])\n## RESULTS\nThe primary neurocognitive analyses showed a difference between groups for only the E/F variable at the 2 month CPAP visit, but no difference at the 6 month CPAP visit or for the A/P or L/M variables at either the 2 or 6 month visits. When stratified by measures of OSA severity (AHI or oxygen saturation parameters), the primary E/F variable and one secondary E/F neurocognitive variable revealed transient differences between study arms for those with the most severe OSA. Participants in the active CPAP group had a significantly greater ability to remain awake whether measured subjectively by the Epworth Sleepiness Scale or objectively by the maintenance of wakefulness test.\n## CONCLUSIONS\nCPAP treatment improved both subjectively and objectively measured sleepiness, especially in individuals with severe OSA (AHI > 30). CPAP use resulted in mild, transient improvement in the most sensitive measures of executive and frontal-lobe function for those with severe disease, which suggests the existence of a complex OSA-neurocognitive relationship.\n## CLINICAL TRIAL INFORMATION\nRegistered at clinicaltrials.gov. Identifier: NCT00051363.\n## CITATION\nKushida CA; Nichols DA; Holmes TH; Quan SF; Walsh JK; Gottlieb DJ; Simon RD; Guilleminault C; White DP; Goodwin JL; Schweitzer PK; Leary EB; Hyde PR; Hirshkowitz M; Green S; McEvoy LK; Chan C; Gevins A; Kay GG; Bloch DA; Crabtree T; Demen WC. Effects of continuous positive airway pressure on neurocognitive function in obstructive sleep apnea patients: the Apnea Positive Pressure Long-term Efficacy Study (APPLES). SLEEP 2012;35(12):1593-1602.",
        "truth": "False"
    },
    {
        "pmid": "28697252",
        "meta_analysis_title": "Association of Positive Airway Pressure With Cardiovascular Events and Death in Adults With Sleep Apnea: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Does the use of positive airway pressure (PAP) to treat sleep apnea reduce risk of cardiovascular events and death?",
        "criteria": "A systematic search of the scientific literature was done according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statement for the conduct of meta-analyses of intervention studies. The searches included MEDLINE via Ovid (from January 1, 1946, to March 2017), EMBASE (from January 1, 1974, to March 2017), and the Cochrane Library database (Cochrane Central Register of Controlled Trials, no date restriction) using relevant text words and Medical Subject Headings that consisted of terms relating to randomized trial and sleep apnea (see the eAppendix in the Supplement for detailed search strategy). The search was limited to randomized clinical trials (RCTs) but without language restriction. Additionally, reference lists from trials, review articles, and reports were manually scanned to identify any other relevant data (including conference abstracts). The clinicaltrials.gov website was searched for RCTs that were registered as completed but not yet published.",
        "subgroup": "Meta-analysis of the Association of Positive Airway Pressure With Cardiovascular Outcomes - Acute coronary syndromes",
        "key_reference_title": "Continuous positive airway pressure in older people with obstructive sleep apnoea syndrome (PREDICT): a 12-month, multicentre, randomised trial.",
        "key_reference_abstract": "## BACKGROUND\nThe therapeutic and economic benefits of continuous positive airway pressure (CPAP) for moderate to severe obstructive sleep apnoea (OSA) syndrome have been established in middle-aged people; however, the benefits in older people are unknown. This trial was designed to address this evidence gap.\n## METHODS\nThis 12-month, multicentre, randomised trial enrolled patients across 14 National Health Service sleep centres in the UK. Consecutive patients aged 65 years or older with newly diagnosed OSA syndrome were eligible to join the trial. Patients were randomly assigned (1:1) into parallel groups to receive either CPAP with best supportive care (BSC) or BSC alone for 12 months. Randomisation was done by the Medical Research Council Clinical Trials Unit with computer-generated randomisation. The main investigator at each centre was masked to the trial randomisation. Coprimary endpoints were Epworth sleepiness score (ESS) at 3 months and cost-effectiveness over the 12-month trial period. Secondary outcomes were subjective sleepiness at 12 months, plus objective sleepiness, quality of life, mood, functionality, nocturia, mobility, accidents, cognitive function, and cardiovascular risk factors and events at 3 months and 12 months. The analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN90464927.\n## FINDINGS\nBetween Feb 24, 2010, and May 30, 2012, 278 patients were randomly assigned to the trial, of whom 231 (83%) completed the trial. 140 patients were allocated to and received CPAP plus BSC and 138 were allocated to and received BSC only. CPAP reduced ESS by 2\u00b71 points (95% CI -3\u00b70 to -1\u00b73; p<0\u00b70001) at 3 months for 124 (89%) of 140 patients compared with 124 (90%) of 138 patients given BSC, and by 2\u00b70 points (-2\u00b78 to -1\u00b72; p<0\u00b70001) at 12 months for 116 patients compared with 122 patients given BSC. The effect was greater in patients with higher CPAP usage or higher baseline ESS. Quality-adjusted life-years were similar between the groups (treatment effect 0\u00b701 (95% CI -0\u00b703 to 0\u00b704; p=0\u00b7787) and health-care costs were marginally reduced with CPAP (-\u00a335, -390 to 321; p=0\u00b7847). CPAP improved objective sleepiness (p=0\u00b7024), mobility (p=0\u00b7029), total cholesterol (p=0\u00b7048), and LDL cholesterol (p=0\u00b7042) at 3 months, but these were not sustained at 12 months. Measures of mood, functionality, nocturia, accidents, cognitive function, and cardiovascular events remained unchanged. Systolic blood pressure fell in the BSC group. 37 serious adverse events occurred in the CPAP group, and 22 in BSC group; all were independently classified as being unrelated to the trial and no significant harm was attributed to CPAP use.\n## INTERPRETATION\nIn older people with OSA syndrome, CPAP reduces sleepiness and is marginally more cost effective over 12 months than is BSC alone. On the basis of these results, we recommend that CPAP treatment should be offered routinely to older patients with OSA syndrome.\n## FUNDING\nNational Institute of Health Research (NIHR) Health Technology Assessment, NIHR Respiratory Biomedical Research Unit at the Royal Brompton and Harefield NHS Foundation Trust and Imperial College London.",
        "truth": "False"
    },
    {
        "pmid": "28697252",
        "meta_analysis_title": "Association of Positive Airway Pressure With Cardiovascular Events and Death in Adults With Sleep Apnea: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Does the use of positive airway pressure (PAP) to treat sleep apnea reduce risk of cardiovascular events and death?",
        "criteria": "A systematic search of the scientific literature was done according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statement for the conduct of meta-analyses of intervention studies. The searches included MEDLINE via Ovid (from January 1, 1946, to March 2017), EMBASE (from January 1, 1974, to March 2017), and the Cochrane Library database (Cochrane Central Register of Controlled Trials, no date restriction) using relevant text words and Medical Subject Headings that consisted of terms relating to randomized trial and sleep apnea (see the eAppendix in the Supplement for detailed search strategy). The search was limited to randomized clinical trials (RCTs) but without language restriction. Additionally, reference lists from trials, review articles, and reports were manually scanned to identify any other relevant data (including conference abstracts). The clinicaltrials.gov website was searched for RCTs that were registered as completed but not yet published.",
        "subgroup": "Meta-analysis of the Association of Positive Airway Pressure With Cardiovascular Outcomes - Acute coronary syndromes",
        "key_reference_title": "Adaptive Servo-Ventilation for Central Sleep Apnea in Systolic Heart Failure.",
        "key_reference_abstract": "## BACKGROUND\nCentral sleep apnea is associated with poor prognosis and death in patients with heart failure. Adaptive servo-ventilation is a therapy that uses a noninvasive ventilator to treat central sleep apnea by delivering servo-controlled inspiratory pressure support on top of expiratory positive airway pressure. We investigated the effects of adaptive servo-ventilation in patients who had heart failure with reduced ejection fraction and predominantly central sleep apnea.\n## METHODS\nWe randomly assigned 1325 patients with a left ventricular ejection fraction of 45% or less, an apnea-hypopnea index (AHI) of 15 or more events (occurrences of apnea or hypopnea) per hour, and a predominance of central events to receive guideline-based medical treatment with adaptive servo-ventilation or guideline-based medical treatment alone (control). The primary end point in the time-to-event analysis was the first event of death from any cause, lifesaving cardiovascular intervention (cardiac transplantation, implantation of a ventricular assist device, resuscitation after sudden cardiac arrest, or appropriate lifesaving shock), or unplanned hospitalization for worsening heart failure.\n## RESULTS\nIn the adaptive servo-ventilation group, the mean AHI at 12 months was 6.6 events per hour. The incidence of the primary end point did not differ significantly between the adaptive servo-ventilation group and the control group (54.1% and 50.8%, respectively; hazard ratio, 1.13; 95% confidence interval [CI], 0.97 to 1.31; P=0.10). All-cause mortality and cardiovascular mortality were significantly higher in the adaptive servo-ventilation group than in the control group (hazard ratio for death from any cause, 1.28; 95% CI, 1.06 to 1.55; P=0.01; and hazard ratio for cardiovascular death, 1.34; 95% CI, 1.09 to 1.65; P=0.006).\n## CONCLUSIONS\nAdaptive servo-ventilation had no significant effect on the primary end point in patients who had heart failure with reduced ejection fraction and predominantly central sleep apnea, but all-cause and cardiovascular mortality were both increased with this therapy. (Funded by ResMed and others; SERVE-HF ClinicalTrials.gov number, NCT00733343.).",
        "truth": "False"
    },
    {
        "pmid": "28697252",
        "meta_analysis_title": "Association of Positive Airway Pressure With Cardiovascular Events and Death in Adults With Sleep Apnea: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Does the use of positive airway pressure (PAP) to treat sleep apnea reduce risk of cardiovascular events and death?",
        "criteria": "A systematic search of the scientific literature was done according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statement for the conduct of meta-analyses of intervention studies. The searches included MEDLINE via Ovid (from January 1, 1946, to March 2017), EMBASE (from January 1, 1974, to March 2017), and the Cochrane Library database (Cochrane Central Register of Controlled Trials, no date restriction) using relevant text words and Medical Subject Headings that consisted of terms relating to randomized trial and sleep apnea (see the eAppendix in the Supplement for detailed search strategy). The search was limited to randomized clinical trials (RCTs) but without language restriction. Additionally, reference lists from trials, review articles, and reports were manually scanned to identify any other relevant data (including conference abstracts). The clinicaltrials.gov website was searched for RCTs that were registered as completed but not yet published.",
        "subgroup": "Meta-analysis of the Association of Positive Airway Pressure With Cardiovascular Outcomes - Acute coronary syndromes",
        "key_reference_title": "Long-term effects of continuous positive airway pressure on blood pressure and prognosis in hypertensive patients with coronary heart disease and obstructive sleep apnea: a randomized controlled trial.",
        "key_reference_abstract": "## BACKGROUND\nObstructive sleep apnea (OSA) can result in hypertension and significantly increase cardiovascular morbidity and mortality. There are few reports on the long-term effects of continuous positive airway pressure (CPAP) on blood pressure in patients with uncontrolled hypertension with coronary heart disease (CHD) and OSA.\n## METHODS\nWe conducted a prospective, long-term follow-up study in 83 patients with uncontrolled hypertension, CHD, and OSA randomized to control or CPAP groups. Daytime systolic blood pressure (SBP), diastolic blood pressure (DBP), and severe cardiovascular and cerebrovascular events (SCCEs) were recorded at baseline and follow-up.\n## RESULTS\nSeventy-three patients completed the study with a median follow-up of 36 (interquartile range = 24-54) months. The 2 groups had similar characteristics at baseline. CPAP was used for 4.5\u00b11.1 hour/night. SBP in the CPAP group was significantly reduced at follow-up (143\u00b17 mm Hg vs. 139\u00b17 mm Hg, P = 0.04), and SBP decreased by 8mm Hg (95% confidence interval = 1.4-9.9; P = 0.01). Hypertension control was improved (CPAP, 69.4% for CPAP users vs. 43.2% for control subjects; P = 0.02); however, DBP did not reach statistical difference between the groups (81\u00b110 mm Hg vs. 79\u00b18 mm Hg; P = 0.49). In the CPAP group, the Epworth Sleepiness Scale was markedly reduced (7.0\u00b13.4 vs. 3.7\u00b12.3; P < 0.001). There was 1 SCCE in the CPAP group (heart failure), and 5 SCCEs in the control group (acute myocardial infarction: 2 (with 1 death); stroke: 3), but there was no significant difference identified.\n## CONCLUSIONS\nLong-term CPAP application in uncontrolled hypertension with CHD and OSA significantly reduced daytime SBP, improved hypertension control and daytime sleepiness, and decreased the trend in SCCEs compared with control subjects.\n## CLINICAL TRIAL REGISTRATION NUMBER\nClinicalTrials.gov NCT02059993.",
        "truth": "True"
    },
    {
        "pmid": "28697252",
        "meta_analysis_title": "Association of Positive Airway Pressure With Cardiovascular Events and Death in Adults With Sleep Apnea: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Does the use of positive airway pressure (PAP) to treat sleep apnea reduce risk of cardiovascular events and death?",
        "criteria": "A systematic search of the scientific literature was done according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statement for the conduct of meta-analyses of intervention studies. The searches included MEDLINE via Ovid (from January 1, 1946, to March 2017), EMBASE (from January 1, 1974, to March 2017), and the Cochrane Library database (Cochrane Central Register of Controlled Trials, no date restriction) using relevant text words and Medical Subject Headings that consisted of terms relating to randomized trial and sleep apnea (see the eAppendix in the Supplement for detailed search strategy). The search was limited to randomized clinical trials (RCTs) but without language restriction. Additionally, reference lists from trials, review articles, and reports were manually scanned to identify any other relevant data (including conference abstracts). The clinicaltrials.gov website was searched for RCTs that were registered as completed but not yet published.",
        "subgroup": "Meta-analysis of the Association of Positive Airway Pressure With Cardiovascular Outcomes - Acute coronary syndromes",
        "key_reference_title": "Efficacy of continuous positive airway pressure treatment on 5-year survival in patients with ischaemic stroke and obstructive sleep apnea: a randomized controlled trial.",
        "key_reference_abstract": "The main purpose of the present analysis is to assess the influence of introducing early nasal continuous positive airway pressure (nCPAP) treatment on cardiovascular recurrences and mortality in patients with a first-ever ischaemic stroke and moderate-severe obstructive sleep apnea (OSA) with an apnea-hypopnea index (AHI) \u226520 events h(-1) during a 5-year follow-up. Patients received conventional treatment for stroke and were assigned randomly to the nCPAP group (n = 71) or the control group (n = 69). Cardiovascular events and mortality were registered for all patients. Survival and cardiovascular event-free survival analysis were performed after 5-year follow-up using the Kaplan-Meier test. Patients in the nCPAP group had significantly higher cardiovascular survival than the control group (100 versus 89.9%, log-rank test 5.887; P = 0.015) However, and also despite a positive tendency, there were no significant differences in the cardiovascular event-free survival at 68 months between the nCPAP and control groups (89.5 versus 75.4%, log-rank test 3.565; P = 0.059). Early nCPAP therapy has a positive effect on long-term survival in ischaemic stroke patients and moderate-severe OSA.",
        "truth": "False"
    },
    {
        "pmid": "28697252",
        "meta_analysis_title": "Association of Positive Airway Pressure With Cardiovascular Events and Death in Adults With Sleep Apnea: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Does the use of positive airway pressure (PAP) to treat sleep apnea reduce risk of cardiovascular events and death?",
        "criteria": "A systematic search of the scientific literature was done according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statement for the conduct of meta-analyses of intervention studies. The searches included MEDLINE via Ovid (from January 1, 1946, to March 2017), EMBASE (from January 1, 1974, to March 2017), and the Cochrane Library database (Cochrane Central Register of Controlled Trials, no date restriction) using relevant text words and Medical Subject Headings that consisted of terms relating to randomized trial and sleep apnea (see the eAppendix in the Supplement for detailed search strategy). The search was limited to randomized clinical trials (RCTs) but without language restriction. Additionally, reference lists from trials, review articles, and reports were manually scanned to identify any other relevant data (including conference abstracts). The clinicaltrials.gov website was searched for RCTs that were registered as completed but not yet published.",
        "subgroup": "Meta-analysis of the Association of Positive Airway Pressure With Cardiovascular Outcomes - Acute coronary syndromes",
        "key_reference_title": "CPAP for Prevention of Cardiovascular Events in Obstructive Sleep Apnea.",
        "key_reference_abstract": "## BACKGROUND\nObstructive sleep apnea is associated with an increased risk of cardiovascular events; whether treatment with continuous positive airway pressure (CPAP) prevents major cardiovascular events is uncertain.\n## METHODS\nAfter a 1-week run-in period during which the participants used sham CPAP, we randomly assigned 2717 eligible adults between 45 and 75 years of age who had moderate-to-severe obstructive sleep apnea and coronary or cerebrovascular disease to receive CPAP treatment plus usual care (CPAP group) or usual care alone (usual-care group). The primary composite end point was death from cardiovascular causes, myocardial infarction, stroke, or hospitalization for unstable angina, heart failure, or transient ischemic attack. Secondary end points included other cardiovascular outcomes, health-related quality of life, snoring symptoms, daytime sleepiness, and mood.\n## RESULTS\nMost of the participants were men who had moderate-to-severe obstructive sleep apnea and minimal sleepiness. In the CPAP group, the mean duration of adherence to CPAP therapy was 3.3 hours per night, and the mean apnea-hypopnea index (the number of apnea or hypopnea events per hour of recording) decreased from 29.0 events per hour at baseline to 3.7 events per hour during follow-up. After a mean follow-up of 3.7 years, a primary end-point event had occurred in 229 participants in the CPAP group (17.0%) and in 207 participants in the usual-care group (15.4%) (hazard ratio with CPAP, 1.10; 95% confidence interval, 0.91 to 1.32; P=0.34). No significant effect on any individual or other composite cardiovascular end point was observed. CPAP significantly reduced snoring and daytime sleepiness and improved health-related quality of life and mood.\n## CONCLUSIONS\nTherapy with CPAP plus usual care, as compared with usual care alone, did not prevent cardiovascular events in patients with moderate-to-severe obstructive sleep apnea and established cardiovascular disease. (Funded by the National Health and Medical Research Council of Australia and others; SAVE ClinicalTrials.gov number, NCT00738179 ; Australian New Zealand Clinical Trials Registry number, ACTRN12608000409370 .).",
        "truth": "True"
    },
    {
        "pmid": "28697252",
        "meta_analysis_title": "Association of Positive Airway Pressure With Cardiovascular Events and Death in Adults With Sleep Apnea: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Does the use of positive airway pressure (PAP) to treat sleep apnea reduce risk of cardiovascular events and death?",
        "criteria": "A systematic search of the scientific literature was done according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statement for the conduct of meta-analyses of intervention studies. The searches included MEDLINE via Ovid (from January 1, 1946, to March 2017), EMBASE (from January 1, 1974, to March 2017), and the Cochrane Library database (Cochrane Central Register of Controlled Trials, no date restriction) using relevant text words and Medical Subject Headings that consisted of terms relating to randomized trial and sleep apnea (see the eAppendix in the Supplement for detailed search strategy). The search was limited to randomized clinical trials (RCTs) but without language restriction. Additionally, reference lists from trials, review articles, and reports were manually scanned to identify any other relevant data (including conference abstracts). The clinicaltrials.gov website was searched for RCTs that were registered as completed but not yet published.",
        "subgroup": "Meta-analysis of the Association of Positive Airway Pressure With Cardiovascular Outcomes - Acute coronary syndromes",
        "key_reference_title": "Effect of Positive Airway Pressure on Cardiovascular Outcomes in Coronary Artery Disease Patients with Nonsleepy Obstructive Sleep Apnea. The RICCADSA Randomized Controlled Trial.",
        "key_reference_abstract": "## RATIONALE\nObstructive sleep apnea (OSA) is common in patients with coronary artery disease (CAD), many of whom do not report daytime sleepiness. First-line treatment for symptomatic OSA is continuous positive airway pressure (CPAP), but its value in patients without daytime sleepiness is uncertain.\n## OBJECTIVES\nTo determine the effects of CPAP on long-term adverse cardiovascular outcome risk in patients with CAD with nonsleepy OSA.\n## METHODS\nThis single-center, prospective, randomized, controlled, open-label, blinded evaluation trial was conducted between December 2005 and November 2010. Consecutive patients with newly revascularized CAD and OSA (apnea-hypopnea index \u226515/h) without daytime sleepiness (Epworth Sleepiness Scale score <10) were randomized to auto-titrating CPAP (n\u2009=\u2009122) or no positive airway pressure (n\u2009=\u2009122).\n## MEASUREMENTS AND MAIN RESULTS\nThe primary endpoint was the first event of repeat revascularization, myocardial infarction, stroke, or cardiovascular mortality. Median follow-up was 57 months. The incidence of the primary endpoint did not differ significantly in patients who did versus did not receive CPAP (18.1% vs. 22.1%; hazard ratio, 0.80; 95% confidence interval, 0.46-1.41; P\u2009=\u20090.449). Adjusted on-treatment analysis showed a significant cardiovascular risk reduction in those who used CPAP for \u22654 versus <4 hours per night or did not receive treatment (hazard ratio, 0.29; 95% confidence interval, 0.10-0.86; P\u2009=\u20090.026).\n## CONCLUSIONS\nRoutine prescription of CPAP to patients with CAD with nonsleepy OSA did not significantly reduce long-term adverse cardiovascular outcomes in the intention-to-treat population. There was a significant reduction after adjustment for baseline comorbidities and compliance with the treatment. Clinical trial registered with www.clinicaltrials.gov (NCT 00519597).",
        "truth": "True"
    },
    {
        "pmid": "28697252",
        "meta_analysis_title": "Association of Positive Airway Pressure With Cardiovascular Events and Death in Adults With Sleep Apnea: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Does the use of positive airway pressure (PAP) to treat sleep apnea reduce risk of cardiovascular events and death?",
        "criteria": "A systematic search of the scientific literature was done according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statement for the conduct of meta-analyses of intervention studies. The searches included MEDLINE via Ovid (from January 1, 1946, to March 2017), EMBASE (from January 1, 1974, to March 2017), and the Cochrane Library database (Cochrane Central Register of Controlled Trials, no date restriction) using relevant text words and Medical Subject Headings that consisted of terms relating to randomized trial and sleep apnea (see the eAppendix in the Supplement for detailed search strategy). The search was limited to randomized clinical trials (RCTs) but without language restriction. Additionally, reference lists from trials, review articles, and reports were manually scanned to identify any other relevant data (including conference abstracts). The clinicaltrials.gov website was searched for RCTs that were registered as completed but not yet published.",
        "subgroup": "Meta-analysis of the Association of Positive Airway Pressure With Cardiovascular Outcomes - Stroke",
        "key_reference_title": "Continuous positive airway pressure for central sleep apnea and heart failure.",
        "key_reference_abstract": "## BACKGROUND\nThe Canadian Continuous Positive Airway Pressure for Patients with Central Sleep Apnea and Heart Failure trial tested the hypothesis that continuous positive airway pressure (CPAP) would improve the survival rate without heart transplantation of patients who have central sleep apnea and heart failure.\n## METHODS\nAfter medical therapy was optimized, 258 patients who had heart failure (mean age [+/-SD], 63+/-10 years; ejection fraction, 24.5+/-7.7 percent) and central sleep apnea (number of episodes of apnea and hypopnea per hour of sleep, 40+/-16) were randomly assigned to receive CPAP (128 patients) or no CPAP (130 patients) and were followed for a mean of two years. During follow-up, sleep studies were conducted and measurements of the ejection fraction, exercise capacity, quality of life, and neurohormones were obtained.\n## RESULTS\nThree months after undergoing randomization, the CPAP group, as compared with the control group, had greater reductions in the frequency of episodes of apnea and hypopnea (-21+/-16 vs. -2+/-18 per hour, P<0.001) and in norepinephrine levels (-1.03+/-1.84 vs. 0.02+/-0.99 nmol per liter, P=0.009), and greater increases in the mean nocturnal oxygen saturation (1.6+/-2.8 percent vs. 0.4+/-2.5 percent, P<0.001), ejection fraction (2.2+/-5.4 percent vs. 0.4+/-5.3 percent, P=0.02), and the distance walked in six minutes (20.0+/-55 vs. -0.8+/-64.8 m, P=0.016). There were no differences between the control group and the CPAP group in the number of hospitalizations, quality of life, or atrial natriuretic peptide levels. An early divergence in survival rates without heart transplantation favored the control group, but after 18 months the divergence favored the CPAP group, yet the overall event rates (death and heart transplantation) did not differ (32 vs. 32 events, respectively; P=0.54).\n## CONCLUSIONS\nAlthough CPAP attenuated central sleep apnea, improved nocturnal oxygenation, increased the ejection fraction, lowered norepinephrine levels, and increased the distance walked in six minutes, it did not affect survival. Our data do not support the use of CPAP to extend life in patients who have central sleep apnea and heart failure.",
        "truth": "False"
    },
    {
        "pmid": "28697252",
        "meta_analysis_title": "Association of Positive Airway Pressure With Cardiovascular Events and Death in Adults With Sleep Apnea: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Does the use of positive airway pressure (PAP) to treat sleep apnea reduce risk of cardiovascular events and death?",
        "criteria": "A systematic search of the scientific literature was done according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statement for the conduct of meta-analyses of intervention studies. The searches included MEDLINE via Ovid (from January 1, 1946, to March 2017), EMBASE (from January 1, 1974, to March 2017), and the Cochrane Library database (Cochrane Central Register of Controlled Trials, no date restriction) using relevant text words and Medical Subject Headings that consisted of terms relating to randomized trial and sleep apnea (see the eAppendix in the Supplement for detailed search strategy). The search was limited to randomized clinical trials (RCTs) but without language restriction. Additionally, reference lists from trials, review articles, and reports were manually scanned to identify any other relevant data (including conference abstracts). The clinicaltrials.gov website was searched for RCTs that were registered as completed but not yet published.",
        "subgroup": "Meta-analysis of the Association of Positive Airway Pressure With Cardiovascular Outcomes - Stroke",
        "key_reference_title": "Effect of continuous positive airway pressure on the incidence of hypertension and cardiovascular events in nonsleepy patients with obstructive sleep apnea: a randomized controlled trial.",
        "key_reference_abstract": "## CONTEXT\nContinuous positive airway pressure (CPAP) is the first-line treatment for patients with symptomatic obstructive sleep apnea (OSA). However, its indication for all patients with sleep-disordered breathing, regardless of daytime symptoms, is unclear.\n## OBJECTIVE\nTo evaluate the effect of CPAP treatment on the incidence of hypertension or cardiovascular events in a cohort of nonsleepy patients with OSA.\n## DESIGN, SETTING, AND PATIENTS\nMulticenter, parallel-group, randomized controlled trial in 14 teaching hospitals in Spain. Between May 2004 and May 2006, 725 consecutive patients were enrolled who had an apnea-hypopnea index of 20 h(-1) or greater and an Epworth Sleepiness Scale score of 10 or less (scores range from 0-24, with values <10 suggesting no daytime sleepiness). Exclusion criteria were previous cardiovascular event, physical or psychological incapacity, chronic disease, or drug or alcohol addiction. Follow-up ended in May 2009.\n## INTERVENTION\nPatients were allocated to receive CPAP treatment or no active intervention. All participants received dietary counseling and sleep hygiene advice.\n## MAIN OUTCOME MEASURES\nIncidence of either systemic hypertension (taking antihypertensive medication or blood pressure greater than 140/90 mm Hg) or cardiovascular event (nonfatal myocardial infarction, nonfatal stroke, transient ischemic attack, hospitalization for unstable angina or arrhythmia, heart failure, or cardiovascular death).\n## RESULTS\nSeven hundred twenty-three patients underwent follow-up for a median of 4 (interquartile range, 2.7-4.4) years (1 patient from each group did not receive allocated treatment); 357 in the CPAP group and 366 in the control group were included in the analysis. In the CPAP group there were 68 patients with new hypertension and 28 cardiovascular events (17 unstable angina or arrhythmia, 3 nonfatal stroke, 3 heart failure, 2 nonfatal myocardial infarction, 2 transient ischemic attack, 1 cardiovascular death). In the control group there were 79 patients with new hypertension and 31 cardiovascular events (11 unstable angina or arrhythmia, 8 nonfatal myocardial infarction, 5 transient ischemic attack, 5 heart failure, 2 nonfatal stroke). The hypertension or cardiovascular event incidence density rate was 9.20 per 100 person-years (95% CI, 7.36-11.04) in the CPAP group and 11.02 per 100 person-years (95% CI, 8.96-13.08) in the control group. The incidence density ratio was 0.83 (95% CI, 0.63-1.1; P = .20).\n## CONCLUSIONS\nIn patients with OSA without daytime sleepiness, the prescription of CPAP compared with usual care did not result in a statistically significant reduction in the incidence of hypertension or cardiovascular events. However, the study may have had limited power to detect a significant difference.\n## TRIAL REGISTRATION\nclinicaltrials.gov Identifier: NCT00127348.",
        "truth": "True"
    },
    {
        "pmid": "28697252",
        "meta_analysis_title": "Association of Positive Airway Pressure With Cardiovascular Events and Death in Adults With Sleep Apnea: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Does the use of positive airway pressure (PAP) to treat sleep apnea reduce risk of cardiovascular events and death?",
        "criteria": "A systematic search of the scientific literature was done according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statement for the conduct of meta-analyses of intervention studies. The searches included MEDLINE via Ovid (from January 1, 1946, to March 2017), EMBASE (from January 1, 1974, to March 2017), and the Cochrane Library database (Cochrane Central Register of Controlled Trials, no date restriction) using relevant text words and Medical Subject Headings that consisted of terms relating to randomized trial and sleep apnea (see the eAppendix in the Supplement for detailed search strategy). The search was limited to randomized clinical trials (RCTs) but without language restriction. Additionally, reference lists from trials, review articles, and reports were manually scanned to identify any other relevant data (including conference abstracts). The clinicaltrials.gov website was searched for RCTs that were registered as completed but not yet published.",
        "subgroup": "Meta-analysis of the Association of Positive Airway Pressure With Cardiovascular Outcomes - Stroke",
        "key_reference_title": "Continuous positive airway pressure improves sleepiness but not calculated vascular risk in patients with minimally symptomatic obstructive sleep apnoea: the MOSAIC randomised controlled trial.",
        "key_reference_abstract": "## BACKGROUND\nContinuous positive airway pressure (CPAP) for symptomatic obstructive sleep apnoea (OSA) improves sleepiness and reduces vascular risk, but such treatment for the more prevalent, minimally symptomatic disease is contentious.\n## METHODS\nThis multicentre, randomised controlled, parallel, hospital-based trial across the UK and Canada, recruited 391 patients with confirmed OSA (oxygen desaturation index >7.5/h) but insufficient symptoms to warrant CPAP therapy. Patients were randomised to 6 months of auto-adjusting CPAP therapy, or standard care. Coprimary endpoints were change in Epworth Sleepiness Score (ESS) and predicted 5-year mortality using a cardiovascular risk score (components: age, sex, height, systolic blood pressure, smoking, diabetes, cholesterol, creatinine, left ventricular hypertrophy, previous myocardial infarction or stroke). Secondary endpoints included some of the individual components of the vascular risk score, objectively measured sleepiness and self-assessed health status.\n## RESULTS\nOf 391 patients randomised, 14 withdrew, 347 attended for their follow-up visit at 6 months within the predefined time window, of which 341 had complete ESS data (baseline mean 8.0, SD 4.3) and 310 had complete risk score data. 22% of patients in the CPAP group reported stopping treatment and overall median CPAP use was 2\u2009:\u200939 h per night. CPAP significantly improved subjective daytime sleepiness (adjusted treatment effect on ESS -2.0 (95% CI -2.6 to -1.4), p<0.0001), objectively measured sleepiness and self-assessed health status. CPAP did not improve the 5-year calculated vascular risk or any of its components.\n## CONCLUSIONS\nIn patients with minimally symptomatic OSA, CPAP can reduce subjective and objective daytime sleepiness, and improve self-assessed health status, but does not appear to improve calculated vascular risk.",
        "truth": "True"
    },
    {
        "pmid": "28697252",
        "meta_analysis_title": "Association of Positive Airway Pressure With Cardiovascular Events and Death in Adults With Sleep Apnea: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Does the use of positive airway pressure (PAP) to treat sleep apnea reduce risk of cardiovascular events and death?",
        "criteria": "A systematic search of the scientific literature was done according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statement for the conduct of meta-analyses of intervention studies. The searches included MEDLINE via Ovid (from January 1, 1946, to March 2017), EMBASE (from January 1, 1974, to March 2017), and the Cochrane Library database (Cochrane Central Register of Controlled Trials, no date restriction) using relevant text words and Medical Subject Headings that consisted of terms relating to randomized trial and sleep apnea (see the eAppendix in the Supplement for detailed search strategy). The search was limited to randomized clinical trials (RCTs) but without language restriction. Additionally, reference lists from trials, review articles, and reports were manually scanned to identify any other relevant data (including conference abstracts). The clinicaltrials.gov website was searched for RCTs that were registered as completed but not yet published.",
        "subgroup": "Meta-analysis of the Association of Positive Airway Pressure With Cardiovascular Outcomes - Stroke",
        "key_reference_title": "Effects of continuous positive airway pressure on neurocognitive function in obstructive sleep apnea patients: The Apnea Positive Pressure Long-term Efficacy Study (APPLES).",
        "key_reference_abstract": "## STUDY OBJECTIVE\nTo determine the neurocognitive effects of continuous positive airway pressure (CPAP) therapy on patients with obstructive sleep apnea (OSA).\n## DESIGN, SETTING, AND PARTICIPANTS\nThe Apnea Positive Pressure Long-term Efficacy Study (APPLES) was a 6-month, randomized, double-blind, 2-arm, sham-controlled, multicenter trial conducted at 5 U.S. university, hospital, or private practices. Of 1,516 participants enrolled, 1,105 were randomized, and 1,098 participants diagnosed with OSA contributed to the analysis of the primary outcome measures.\n## INTERVENTION\nActive or sham CPAP MEASUREMENTS: THREE NEUROCOGNITIVE VARIABLES, EACH REPRESENTING A NEUROCOGNITIVE DOMAIN: Pathfinder Number Test-Total Time (attention and psychomotor function [A/P]), Buschke Selective Reminding Test-Sum Recall (learning and memory [L/M]), and Sustained Working Memory Test-Overall Mid-Day Score (executive and frontal-lobe function [E/F])\n## RESULTS\nThe primary neurocognitive analyses showed a difference between groups for only the E/F variable at the 2 month CPAP visit, but no difference at the 6 month CPAP visit or for the A/P or L/M variables at either the 2 or 6 month visits. When stratified by measures of OSA severity (AHI or oxygen saturation parameters), the primary E/F variable and one secondary E/F neurocognitive variable revealed transient differences between study arms for those with the most severe OSA. Participants in the active CPAP group had a significantly greater ability to remain awake whether measured subjectively by the Epworth Sleepiness Scale or objectively by the maintenance of wakefulness test.\n## CONCLUSIONS\nCPAP treatment improved both subjectively and objectively measured sleepiness, especially in individuals with severe OSA (AHI > 30). CPAP use resulted in mild, transient improvement in the most sensitive measures of executive and frontal-lobe function for those with severe disease, which suggests the existence of a complex OSA-neurocognitive relationship.\n## CLINICAL TRIAL INFORMATION\nRegistered at clinicaltrials.gov. Identifier: NCT00051363.\n## CITATION\nKushida CA; Nichols DA; Holmes TH; Quan SF; Walsh JK; Gottlieb DJ; Simon RD; Guilleminault C; White DP; Goodwin JL; Schweitzer PK; Leary EB; Hyde PR; Hirshkowitz M; Green S; McEvoy LK; Chan C; Gevins A; Kay GG; Bloch DA; Crabtree T; Demen WC. Effects of continuous positive airway pressure on neurocognitive function in obstructive sleep apnea patients: the Apnea Positive Pressure Long-term Efficacy Study (APPLES). SLEEP 2012;35(12):1593-1602.",
        "truth": "False"
    },
    {
        "pmid": "28697252",
        "meta_analysis_title": "Association of Positive Airway Pressure With Cardiovascular Events and Death in Adults With Sleep Apnea: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Does the use of positive airway pressure (PAP) to treat sleep apnea reduce risk of cardiovascular events and death?",
        "criteria": "A systematic search of the scientific literature was done according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statement for the conduct of meta-analyses of intervention studies. The searches included MEDLINE via Ovid (from January 1, 1946, to March 2017), EMBASE (from January 1, 1974, to March 2017), and the Cochrane Library database (Cochrane Central Register of Controlled Trials, no date restriction) using relevant text words and Medical Subject Headings that consisted of terms relating to randomized trial and sleep apnea (see the eAppendix in the Supplement for detailed search strategy). The search was limited to randomized clinical trials (RCTs) but without language restriction. Additionally, reference lists from trials, review articles, and reports were manually scanned to identify any other relevant data (including conference abstracts). The clinicaltrials.gov website was searched for RCTs that were registered as completed but not yet published.",
        "subgroup": "Meta-analysis of the Association of Positive Airway Pressure With Cardiovascular Outcomes - Stroke",
        "key_reference_title": "Continuous positive airway pressure in older people with obstructive sleep apnoea syndrome (PREDICT): a 12-month, multicentre, randomised trial.",
        "key_reference_abstract": "## BACKGROUND\nThe therapeutic and economic benefits of continuous positive airway pressure (CPAP) for moderate to severe obstructive sleep apnoea (OSA) syndrome have been established in middle-aged people; however, the benefits in older people are unknown. This trial was designed to address this evidence gap.\n## METHODS\nThis 12-month, multicentre, randomised trial enrolled patients across 14 National Health Service sleep centres in the UK. Consecutive patients aged 65 years or older with newly diagnosed OSA syndrome were eligible to join the trial. Patients were randomly assigned (1:1) into parallel groups to receive either CPAP with best supportive care (BSC) or BSC alone for 12 months. Randomisation was done by the Medical Research Council Clinical Trials Unit with computer-generated randomisation. The main investigator at each centre was masked to the trial randomisation. Coprimary endpoints were Epworth sleepiness score (ESS) at 3 months and cost-effectiveness over the 12-month trial period. Secondary outcomes were subjective sleepiness at 12 months, plus objective sleepiness, quality of life, mood, functionality, nocturia, mobility, accidents, cognitive function, and cardiovascular risk factors and events at 3 months and 12 months. The analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN90464927.\n## FINDINGS\nBetween Feb 24, 2010, and May 30, 2012, 278 patients were randomly assigned to the trial, of whom 231 (83%) completed the trial. 140 patients were allocated to and received CPAP plus BSC and 138 were allocated to and received BSC only. CPAP reduced ESS by 2\u00b71 points (95% CI -3\u00b70 to -1\u00b73; p<0\u00b70001) at 3 months for 124 (89%) of 140 patients compared with 124 (90%) of 138 patients given BSC, and by 2\u00b70 points (-2\u00b78 to -1\u00b72; p<0\u00b70001) at 12 months for 116 patients compared with 122 patients given BSC. The effect was greater in patients with higher CPAP usage or higher baseline ESS. Quality-adjusted life-years were similar between the groups (treatment effect 0\u00b701 (95% CI -0\u00b703 to 0\u00b704; p=0\u00b7787) and health-care costs were marginally reduced with CPAP (-\u00a335, -390 to 321; p=0\u00b7847). CPAP improved objective sleepiness (p=0\u00b7024), mobility (p=0\u00b7029), total cholesterol (p=0\u00b7048), and LDL cholesterol (p=0\u00b7042) at 3 months, but these were not sustained at 12 months. Measures of mood, functionality, nocturia, accidents, cognitive function, and cardiovascular events remained unchanged. Systolic blood pressure fell in the BSC group. 37 serious adverse events occurred in the CPAP group, and 22 in BSC group; all were independently classified as being unrelated to the trial and no significant harm was attributed to CPAP use.\n## INTERPRETATION\nIn older people with OSA syndrome, CPAP reduces sleepiness and is marginally more cost effective over 12 months than is BSC alone. On the basis of these results, we recommend that CPAP treatment should be offered routinely to older patients with OSA syndrome.\n## FUNDING\nNational Institute of Health Research (NIHR) Health Technology Assessment, NIHR Respiratory Biomedical Research Unit at the Royal Brompton and Harefield NHS Foundation Trust and Imperial College London.",
        "truth": "False"
    },
    {
        "pmid": "28697252",
        "meta_analysis_title": "Association of Positive Airway Pressure With Cardiovascular Events and Death in Adults With Sleep Apnea: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Does the use of positive airway pressure (PAP) to treat sleep apnea reduce risk of cardiovascular events and death?",
        "criteria": "A systematic search of the scientific literature was done according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statement for the conduct of meta-analyses of intervention studies. The searches included MEDLINE via Ovid (from January 1, 1946, to March 2017), EMBASE (from January 1, 1974, to March 2017), and the Cochrane Library database (Cochrane Central Register of Controlled Trials, no date restriction) using relevant text words and Medical Subject Headings that consisted of terms relating to randomized trial and sleep apnea (see the eAppendix in the Supplement for detailed search strategy). The search was limited to randomized clinical trials (RCTs) but without language restriction. Additionally, reference lists from trials, review articles, and reports were manually scanned to identify any other relevant data (including conference abstracts). The clinicaltrials.gov website was searched for RCTs that were registered as completed but not yet published.",
        "subgroup": "Meta-analysis of the Association of Positive Airway Pressure With Cardiovascular Outcomes - Stroke",
        "key_reference_title": "Adaptive Servo-Ventilation for Central Sleep Apnea in Systolic Heart Failure.",
        "key_reference_abstract": "## BACKGROUND\nCentral sleep apnea is associated with poor prognosis and death in patients with heart failure. Adaptive servo-ventilation is a therapy that uses a noninvasive ventilator to treat central sleep apnea by delivering servo-controlled inspiratory pressure support on top of expiratory positive airway pressure. We investigated the effects of adaptive servo-ventilation in patients who had heart failure with reduced ejection fraction and predominantly central sleep apnea.\n## METHODS\nWe randomly assigned 1325 patients with a left ventricular ejection fraction of 45% or less, an apnea-hypopnea index (AHI) of 15 or more events (occurrences of apnea or hypopnea) per hour, and a predominance of central events to receive guideline-based medical treatment with adaptive servo-ventilation or guideline-based medical treatment alone (control). The primary end point in the time-to-event analysis was the first event of death from any cause, lifesaving cardiovascular intervention (cardiac transplantation, implantation of a ventricular assist device, resuscitation after sudden cardiac arrest, or appropriate lifesaving shock), or unplanned hospitalization for worsening heart failure.\n## RESULTS\nIn the adaptive servo-ventilation group, the mean AHI at 12 months was 6.6 events per hour. The incidence of the primary end point did not differ significantly between the adaptive servo-ventilation group and the control group (54.1% and 50.8%, respectively; hazard ratio, 1.13; 95% confidence interval [CI], 0.97 to 1.31; P=0.10). All-cause mortality and cardiovascular mortality were significantly higher in the adaptive servo-ventilation group than in the control group (hazard ratio for death from any cause, 1.28; 95% CI, 1.06 to 1.55; P=0.01; and hazard ratio for cardiovascular death, 1.34; 95% CI, 1.09 to 1.65; P=0.006).\n## CONCLUSIONS\nAdaptive servo-ventilation had no significant effect on the primary end point in patients who had heart failure with reduced ejection fraction and predominantly central sleep apnea, but all-cause and cardiovascular mortality were both increased with this therapy. (Funded by ResMed and others; SERVE-HF ClinicalTrials.gov number, NCT00733343.).",
        "truth": "False"
    },
    {
        "pmid": "28697252",
        "meta_analysis_title": "Association of Positive Airway Pressure With Cardiovascular Events and Death in Adults With Sleep Apnea: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Does the use of positive airway pressure (PAP) to treat sleep apnea reduce risk of cardiovascular events and death?",
        "criteria": "A systematic search of the scientific literature was done according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statement for the conduct of meta-analyses of intervention studies. The searches included MEDLINE via Ovid (from January 1, 1946, to March 2017), EMBASE (from January 1, 1974, to March 2017), and the Cochrane Library database (Cochrane Central Register of Controlled Trials, no date restriction) using relevant text words and Medical Subject Headings that consisted of terms relating to randomized trial and sleep apnea (see the eAppendix in the Supplement for detailed search strategy). The search was limited to randomized clinical trials (RCTs) but without language restriction. Additionally, reference lists from trials, review articles, and reports were manually scanned to identify any other relevant data (including conference abstracts). The clinicaltrials.gov website was searched for RCTs that were registered as completed but not yet published.",
        "subgroup": "Meta-analysis of the Association of Positive Airway Pressure With Cardiovascular Outcomes - Stroke",
        "key_reference_title": "Long-term effects of continuous positive airway pressure on blood pressure and prognosis in hypertensive patients with coronary heart disease and obstructive sleep apnea: a randomized controlled trial.",
        "key_reference_abstract": "## BACKGROUND\nObstructive sleep apnea (OSA) can result in hypertension and significantly increase cardiovascular morbidity and mortality. There are few reports on the long-term effects of continuous positive airway pressure (CPAP) on blood pressure in patients with uncontrolled hypertension with coronary heart disease (CHD) and OSA.\n## METHODS\nWe conducted a prospective, long-term follow-up study in 83 patients with uncontrolled hypertension, CHD, and OSA randomized to control or CPAP groups. Daytime systolic blood pressure (SBP), diastolic blood pressure (DBP), and severe cardiovascular and cerebrovascular events (SCCEs) were recorded at baseline and follow-up.\n## RESULTS\nSeventy-three patients completed the study with a median follow-up of 36 (interquartile range = 24-54) months. The 2 groups had similar characteristics at baseline. CPAP was used for 4.5\u00b11.1 hour/night. SBP in the CPAP group was significantly reduced at follow-up (143\u00b17 mm Hg vs. 139\u00b17 mm Hg, P = 0.04), and SBP decreased by 8mm Hg (95% confidence interval = 1.4-9.9; P = 0.01). Hypertension control was improved (CPAP, 69.4% for CPAP users vs. 43.2% for control subjects; P = 0.02); however, DBP did not reach statistical difference between the groups (81\u00b110 mm Hg vs. 79\u00b18 mm Hg; P = 0.49). In the CPAP group, the Epworth Sleepiness Scale was markedly reduced (7.0\u00b13.4 vs. 3.7\u00b12.3; P < 0.001). There was 1 SCCE in the CPAP group (heart failure), and 5 SCCEs in the control group (acute myocardial infarction: 2 (with 1 death); stroke: 3), but there was no significant difference identified.\n## CONCLUSIONS\nLong-term CPAP application in uncontrolled hypertension with CHD and OSA significantly reduced daytime SBP, improved hypertension control and daytime sleepiness, and decreased the trend in SCCEs compared with control subjects.\n## CLINICAL TRIAL REGISTRATION NUMBER\nClinicalTrials.gov NCT02059993.",
        "truth": "True"
    },
    {
        "pmid": "28697252",
        "meta_analysis_title": "Association of Positive Airway Pressure With Cardiovascular Events and Death in Adults With Sleep Apnea: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Does the use of positive airway pressure (PAP) to treat sleep apnea reduce risk of cardiovascular events and death?",
        "criteria": "A systematic search of the scientific literature was done according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statement for the conduct of meta-analyses of intervention studies. The searches included MEDLINE via Ovid (from January 1, 1946, to March 2017), EMBASE (from January 1, 1974, to March 2017), and the Cochrane Library database (Cochrane Central Register of Controlled Trials, no date restriction) using relevant text words and Medical Subject Headings that consisted of terms relating to randomized trial and sleep apnea (see the eAppendix in the Supplement for detailed search strategy). The search was limited to randomized clinical trials (RCTs) but without language restriction. Additionally, reference lists from trials, review articles, and reports were manually scanned to identify any other relevant data (including conference abstracts). The clinicaltrials.gov website was searched for RCTs that were registered as completed but not yet published.",
        "subgroup": "Meta-analysis of the Association of Positive Airway Pressure With Cardiovascular Outcomes - Stroke",
        "key_reference_title": "Efficacy of continuous positive airway pressure treatment on 5-year survival in patients with ischaemic stroke and obstructive sleep apnea: a randomized controlled trial.",
        "key_reference_abstract": "The main purpose of the present analysis is to assess the influence of introducing early nasal continuous positive airway pressure (nCPAP) treatment on cardiovascular recurrences and mortality in patients with a first-ever ischaemic stroke and moderate-severe obstructive sleep apnea (OSA) with an apnea-hypopnea index (AHI) \u226520 events h(-1) during a 5-year follow-up. Patients received conventional treatment for stroke and were assigned randomly to the nCPAP group (n = 71) or the control group (n = 69). Cardiovascular events and mortality were registered for all patients. Survival and cardiovascular event-free survival analysis were performed after 5-year follow-up using the Kaplan-Meier test. Patients in the nCPAP group had significantly higher cardiovascular survival than the control group (100 versus 89.9%, log-rank test 5.887; P = 0.015) However, and also despite a positive tendency, there were no significant differences in the cardiovascular event-free survival at 68 months between the nCPAP and control groups (89.5 versus 75.4%, log-rank test 3.565; P = 0.059). Early nCPAP therapy has a positive effect on long-term survival in ischaemic stroke patients and moderate-severe OSA.",
        "truth": "False"
    },
    {
        "pmid": "28697252",
        "meta_analysis_title": "Association of Positive Airway Pressure With Cardiovascular Events and Death in Adults With Sleep Apnea: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Does the use of positive airway pressure (PAP) to treat sleep apnea reduce risk of cardiovascular events and death?",
        "criteria": "A systematic search of the scientific literature was done according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statement for the conduct of meta-analyses of intervention studies. The searches included MEDLINE via Ovid (from January 1, 1946, to March 2017), EMBASE (from January 1, 1974, to March 2017), and the Cochrane Library database (Cochrane Central Register of Controlled Trials, no date restriction) using relevant text words and Medical Subject Headings that consisted of terms relating to randomized trial and sleep apnea (see the eAppendix in the Supplement for detailed search strategy). The search was limited to randomized clinical trials (RCTs) but without language restriction. Additionally, reference lists from trials, review articles, and reports were manually scanned to identify any other relevant data (including conference abstracts). The clinicaltrials.gov website was searched for RCTs that were registered as completed but not yet published.",
        "subgroup": "Meta-analysis of the Association of Positive Airway Pressure With Cardiovascular Outcomes - Stroke",
        "key_reference_title": "CPAP for Prevention of Cardiovascular Events in Obstructive Sleep Apnea.",
        "key_reference_abstract": "## BACKGROUND\nObstructive sleep apnea is associated with an increased risk of cardiovascular events; whether treatment with continuous positive airway pressure (CPAP) prevents major cardiovascular events is uncertain.\n## METHODS\nAfter a 1-week run-in period during which the participants used sham CPAP, we randomly assigned 2717 eligible adults between 45 and 75 years of age who had moderate-to-severe obstructive sleep apnea and coronary or cerebrovascular disease to receive CPAP treatment plus usual care (CPAP group) or usual care alone (usual-care group). The primary composite end point was death from cardiovascular causes, myocardial infarction, stroke, or hospitalization for unstable angina, heart failure, or transient ischemic attack. Secondary end points included other cardiovascular outcomes, health-related quality of life, snoring symptoms, daytime sleepiness, and mood.\n## RESULTS\nMost of the participants were men who had moderate-to-severe obstructive sleep apnea and minimal sleepiness. In the CPAP group, the mean duration of adherence to CPAP therapy was 3.3 hours per night, and the mean apnea-hypopnea index (the number of apnea or hypopnea events per hour of recording) decreased from 29.0 events per hour at baseline to 3.7 events per hour during follow-up. After a mean follow-up of 3.7 years, a primary end-point event had occurred in 229 participants in the CPAP group (17.0%) and in 207 participants in the usual-care group (15.4%) (hazard ratio with CPAP, 1.10; 95% confidence interval, 0.91 to 1.32; P=0.34). No significant effect on any individual or other composite cardiovascular end point was observed. CPAP significantly reduced snoring and daytime sleepiness and improved health-related quality of life and mood.\n## CONCLUSIONS\nTherapy with CPAP plus usual care, as compared with usual care alone, did not prevent cardiovascular events in patients with moderate-to-severe obstructive sleep apnea and established cardiovascular disease. (Funded by the National Health and Medical Research Council of Australia and others; SAVE ClinicalTrials.gov number, NCT00738179 ; Australian New Zealand Clinical Trials Registry number, ACTRN12608000409370 .).",
        "truth": "True"
    },
    {
        "pmid": "28697252",
        "meta_analysis_title": "Association of Positive Airway Pressure With Cardiovascular Events and Death in Adults With Sleep Apnea: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Does the use of positive airway pressure (PAP) to treat sleep apnea reduce risk of cardiovascular events and death?",
        "criteria": "A systematic search of the scientific literature was done according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statement for the conduct of meta-analyses of intervention studies. The searches included MEDLINE via Ovid (from January 1, 1946, to March 2017), EMBASE (from January 1, 1974, to March 2017), and the Cochrane Library database (Cochrane Central Register of Controlled Trials, no date restriction) using relevant text words and Medical Subject Headings that consisted of terms relating to randomized trial and sleep apnea (see the eAppendix in the Supplement for detailed search strategy). The search was limited to randomized clinical trials (RCTs) but without language restriction. Additionally, reference lists from trials, review articles, and reports were manually scanned to identify any other relevant data (including conference abstracts). The clinicaltrials.gov website was searched for RCTs that were registered as completed but not yet published.",
        "subgroup": "Meta-analysis of the Association of Positive Airway Pressure With Cardiovascular Outcomes - Stroke",
        "key_reference_title": "Effect of Positive Airway Pressure on Cardiovascular Outcomes in Coronary Artery Disease Patients with Nonsleepy Obstructive Sleep Apnea. The RICCADSA Randomized Controlled Trial.",
        "key_reference_abstract": "## RATIONALE\nObstructive sleep apnea (OSA) is common in patients with coronary artery disease (CAD), many of whom do not report daytime sleepiness. First-line treatment for symptomatic OSA is continuous positive airway pressure (CPAP), but its value in patients without daytime sleepiness is uncertain.\n## OBJECTIVES\nTo determine the effects of CPAP on long-term adverse cardiovascular outcome risk in patients with CAD with nonsleepy OSA.\n## METHODS\nThis single-center, prospective, randomized, controlled, open-label, blinded evaluation trial was conducted between December 2005 and November 2010. Consecutive patients with newly revascularized CAD and OSA (apnea-hypopnea index \u226515/h) without daytime sleepiness (Epworth Sleepiness Scale score <10) were randomized to auto-titrating CPAP (n\u2009=\u2009122) or no positive airway pressure (n\u2009=\u2009122).\n## MEASUREMENTS AND MAIN RESULTS\nThe primary endpoint was the first event of repeat revascularization, myocardial infarction, stroke, or cardiovascular mortality. Median follow-up was 57 months. The incidence of the primary endpoint did not differ significantly in patients who did versus did not receive CPAP (18.1% vs. 22.1%; hazard ratio, 0.80; 95% confidence interval, 0.46-1.41; P\u2009=\u20090.449). Adjusted on-treatment analysis showed a significant cardiovascular risk reduction in those who used CPAP for \u22654 versus <4 hours per night or did not receive treatment (hazard ratio, 0.29; 95% confidence interval, 0.10-0.86; P\u2009=\u20090.026).\n## CONCLUSIONS\nRoutine prescription of CPAP to patients with CAD with nonsleepy OSA did not significantly reduce long-term adverse cardiovascular outcomes in the intention-to-treat population. There was a significant reduction after adjustment for baseline comorbidities and compliance with the treatment. Clinical trial registered with www.clinicaltrials.gov (NCT 00519597).",
        "truth": "True"
    },
    {
        "pmid": "28697252",
        "meta_analysis_title": "Association of Positive Airway Pressure With Cardiovascular Events and Death in Adults With Sleep Apnea: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Does the use of positive airway pressure (PAP) to treat sleep apnea reduce risk of cardiovascular events and death?",
        "criteria": "A systematic search of the scientific literature was done according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statement for the conduct of meta-analyses of intervention studies. The searches included MEDLINE via Ovid (from January 1, 1946, to March 2017), EMBASE (from January 1, 1974, to March 2017), and the Cochrane Library database (Cochrane Central Register of Controlled Trials, no date restriction) using relevant text words and Medical Subject Headings that consisted of terms relating to randomized trial and sleep apnea (see the eAppendix in the Supplement for detailed search strategy). The search was limited to randomized clinical trials (RCTs) but without language restriction. Additionally, reference lists from trials, review articles, and reports were manually scanned to identify any other relevant data (including conference abstracts). The clinicaltrials.gov website was searched for RCTs that were registered as completed but not yet published.",
        "subgroup": "Meta-analysis of the Association of Positive Airway Pressure With Cardiovascular Outcomes - Hospitalization for unstable angina",
        "key_reference_title": "Continuous positive airway pressure for central sleep apnea and heart failure.",
        "key_reference_abstract": "## BACKGROUND\nThe Canadian Continuous Positive Airway Pressure for Patients with Central Sleep Apnea and Heart Failure trial tested the hypothesis that continuous positive airway pressure (CPAP) would improve the survival rate without heart transplantation of patients who have central sleep apnea and heart failure.\n## METHODS\nAfter medical therapy was optimized, 258 patients who had heart failure (mean age [+/-SD], 63+/-10 years; ejection fraction, 24.5+/-7.7 percent) and central sleep apnea (number of episodes of apnea and hypopnea per hour of sleep, 40+/-16) were randomly assigned to receive CPAP (128 patients) or no CPAP (130 patients) and were followed for a mean of two years. During follow-up, sleep studies were conducted and measurements of the ejection fraction, exercise capacity, quality of life, and neurohormones were obtained.\n## RESULTS\nThree months after undergoing randomization, the CPAP group, as compared with the control group, had greater reductions in the frequency of episodes of apnea and hypopnea (-21+/-16 vs. -2+/-18 per hour, P<0.001) and in norepinephrine levels (-1.03+/-1.84 vs. 0.02+/-0.99 nmol per liter, P=0.009), and greater increases in the mean nocturnal oxygen saturation (1.6+/-2.8 percent vs. 0.4+/-2.5 percent, P<0.001), ejection fraction (2.2+/-5.4 percent vs. 0.4+/-5.3 percent, P=0.02), and the distance walked in six minutes (20.0+/-55 vs. -0.8+/-64.8 m, P=0.016). There were no differences between the control group and the CPAP group in the number of hospitalizations, quality of life, or atrial natriuretic peptide levels. An early divergence in survival rates without heart transplantation favored the control group, but after 18 months the divergence favored the CPAP group, yet the overall event rates (death and heart transplantation) did not differ (32 vs. 32 events, respectively; P=0.54).\n## CONCLUSIONS\nAlthough CPAP attenuated central sleep apnea, improved nocturnal oxygenation, increased the ejection fraction, lowered norepinephrine levels, and increased the distance walked in six minutes, it did not affect survival. Our data do not support the use of CPAP to extend life in patients who have central sleep apnea and heart failure.",
        "truth": "False"
    },
    {
        "pmid": "28697252",
        "meta_analysis_title": "Association of Positive Airway Pressure With Cardiovascular Events and Death in Adults With Sleep Apnea: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Does the use of positive airway pressure (PAP) to treat sleep apnea reduce risk of cardiovascular events and death?",
        "criteria": "A systematic search of the scientific literature was done according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statement for the conduct of meta-analyses of intervention studies. The searches included MEDLINE via Ovid (from January 1, 1946, to March 2017), EMBASE (from January 1, 1974, to March 2017), and the Cochrane Library database (Cochrane Central Register of Controlled Trials, no date restriction) using relevant text words and Medical Subject Headings that consisted of terms relating to randomized trial and sleep apnea (see the eAppendix in the Supplement for detailed search strategy). The search was limited to randomized clinical trials (RCTs) but without language restriction. Additionally, reference lists from trials, review articles, and reports were manually scanned to identify any other relevant data (including conference abstracts). The clinicaltrials.gov website was searched for RCTs that were registered as completed but not yet published.",
        "subgroup": "Meta-analysis of the Association of Positive Airway Pressure With Cardiovascular Outcomes - Hospitalization for unstable angina",
        "key_reference_title": "Effect of continuous positive airway pressure on the incidence of hypertension and cardiovascular events in nonsleepy patients with obstructive sleep apnea: a randomized controlled trial.",
        "key_reference_abstract": "## CONTEXT\nContinuous positive airway pressure (CPAP) is the first-line treatment for patients with symptomatic obstructive sleep apnea (OSA). However, its indication for all patients with sleep-disordered breathing, regardless of daytime symptoms, is unclear.\n## OBJECTIVE\nTo evaluate the effect of CPAP treatment on the incidence of hypertension or cardiovascular events in a cohort of nonsleepy patients with OSA.\n## DESIGN, SETTING, AND PATIENTS\nMulticenter, parallel-group, randomized controlled trial in 14 teaching hospitals in Spain. Between May 2004 and May 2006, 725 consecutive patients were enrolled who had an apnea-hypopnea index of 20 h(-1) or greater and an Epworth Sleepiness Scale score of 10 or less (scores range from 0-24, with values <10 suggesting no daytime sleepiness). Exclusion criteria were previous cardiovascular event, physical or psychological incapacity, chronic disease, or drug or alcohol addiction. Follow-up ended in May 2009.\n## INTERVENTION\nPatients were allocated to receive CPAP treatment or no active intervention. All participants received dietary counseling and sleep hygiene advice.\n## MAIN OUTCOME MEASURES\nIncidence of either systemic hypertension (taking antihypertensive medication or blood pressure greater than 140/90 mm Hg) or cardiovascular event (nonfatal myocardial infarction, nonfatal stroke, transient ischemic attack, hospitalization for unstable angina or arrhythmia, heart failure, or cardiovascular death).\n## RESULTS\nSeven hundred twenty-three patients underwent follow-up for a median of 4 (interquartile range, 2.7-4.4) years (1 patient from each group did not receive allocated treatment); 357 in the CPAP group and 366 in the control group were included in the analysis. In the CPAP group there were 68 patients with new hypertension and 28 cardiovascular events (17 unstable angina or arrhythmia, 3 nonfatal stroke, 3 heart failure, 2 nonfatal myocardial infarction, 2 transient ischemic attack, 1 cardiovascular death). In the control group there were 79 patients with new hypertension and 31 cardiovascular events (11 unstable angina or arrhythmia, 8 nonfatal myocardial infarction, 5 transient ischemic attack, 5 heart failure, 2 nonfatal stroke). The hypertension or cardiovascular event incidence density rate was 9.20 per 100 person-years (95% CI, 7.36-11.04) in the CPAP group and 11.02 per 100 person-years (95% CI, 8.96-13.08) in the control group. The incidence density ratio was 0.83 (95% CI, 0.63-1.1; P = .20).\n## CONCLUSIONS\nIn patients with OSA without daytime sleepiness, the prescription of CPAP compared with usual care did not result in a statistically significant reduction in the incidence of hypertension or cardiovascular events. However, the study may have had limited power to detect a significant difference.\n## TRIAL REGISTRATION\nclinicaltrials.gov Identifier: NCT00127348.",
        "truth": "True"
    },
    {
        "pmid": "28697252",
        "meta_analysis_title": "Association of Positive Airway Pressure With Cardiovascular Events and Death in Adults With Sleep Apnea: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Does the use of positive airway pressure (PAP) to treat sleep apnea reduce risk of cardiovascular events and death?",
        "criteria": "A systematic search of the scientific literature was done according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statement for the conduct of meta-analyses of intervention studies. The searches included MEDLINE via Ovid (from January 1, 1946, to March 2017), EMBASE (from January 1, 1974, to March 2017), and the Cochrane Library database (Cochrane Central Register of Controlled Trials, no date restriction) using relevant text words and Medical Subject Headings that consisted of terms relating to randomized trial and sleep apnea (see the eAppendix in the Supplement for detailed search strategy). The search was limited to randomized clinical trials (RCTs) but without language restriction. Additionally, reference lists from trials, review articles, and reports were manually scanned to identify any other relevant data (including conference abstracts). The clinicaltrials.gov website was searched for RCTs that were registered as completed but not yet published.",
        "subgroup": "Meta-analysis of the Association of Positive Airway Pressure With Cardiovascular Outcomes - Hospitalization for unstable angina",
        "key_reference_title": "Continuous positive airway pressure improves sleepiness but not calculated vascular risk in patients with minimally symptomatic obstructive sleep apnoea: the MOSAIC randomised controlled trial.",
        "key_reference_abstract": "## BACKGROUND\nContinuous positive airway pressure (CPAP) for symptomatic obstructive sleep apnoea (OSA) improves sleepiness and reduces vascular risk, but such treatment for the more prevalent, minimally symptomatic disease is contentious.\n## METHODS\nThis multicentre, randomised controlled, parallel, hospital-based trial across the UK and Canada, recruited 391 patients with confirmed OSA (oxygen desaturation index >7.5/h) but insufficient symptoms to warrant CPAP therapy. Patients were randomised to 6 months of auto-adjusting CPAP therapy, or standard care. Coprimary endpoints were change in Epworth Sleepiness Score (ESS) and predicted 5-year mortality using a cardiovascular risk score (components: age, sex, height, systolic blood pressure, smoking, diabetes, cholesterol, creatinine, left ventricular hypertrophy, previous myocardial infarction or stroke). Secondary endpoints included some of the individual components of the vascular risk score, objectively measured sleepiness and self-assessed health status.\n## RESULTS\nOf 391 patients randomised, 14 withdrew, 347 attended for their follow-up visit at 6 months within the predefined time window, of which 341 had complete ESS data (baseline mean 8.0, SD 4.3) and 310 had complete risk score data. 22% of patients in the CPAP group reported stopping treatment and overall median CPAP use was 2\u2009:\u200939 h per night. CPAP significantly improved subjective daytime sleepiness (adjusted treatment effect on ESS -2.0 (95% CI -2.6 to -1.4), p<0.0001), objectively measured sleepiness and self-assessed health status. CPAP did not improve the 5-year calculated vascular risk or any of its components.\n## CONCLUSIONS\nIn patients with minimally symptomatic OSA, CPAP can reduce subjective and objective daytime sleepiness, and improve self-assessed health status, but does not appear to improve calculated vascular risk.",
        "truth": "True"
    },
    {
        "pmid": "28697252",
        "meta_analysis_title": "Association of Positive Airway Pressure With Cardiovascular Events and Death in Adults With Sleep Apnea: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Does the use of positive airway pressure (PAP) to treat sleep apnea reduce risk of cardiovascular events and death?",
        "criteria": "A systematic search of the scientific literature was done according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statement for the conduct of meta-analyses of intervention studies. The searches included MEDLINE via Ovid (from January 1, 1946, to March 2017), EMBASE (from January 1, 1974, to March 2017), and the Cochrane Library database (Cochrane Central Register of Controlled Trials, no date restriction) using relevant text words and Medical Subject Headings that consisted of terms relating to randomized trial and sleep apnea (see the eAppendix in the Supplement for detailed search strategy). The search was limited to randomized clinical trials (RCTs) but without language restriction. Additionally, reference lists from trials, review articles, and reports were manually scanned to identify any other relevant data (including conference abstracts). The clinicaltrials.gov website was searched for RCTs that were registered as completed but not yet published.",
        "subgroup": "Meta-analysis of the Association of Positive Airway Pressure With Cardiovascular Outcomes - Hospitalization for unstable angina",
        "key_reference_title": "Effects of continuous positive airway pressure on neurocognitive function in obstructive sleep apnea patients: The Apnea Positive Pressure Long-term Efficacy Study (APPLES).",
        "key_reference_abstract": "## STUDY OBJECTIVE\nTo determine the neurocognitive effects of continuous positive airway pressure (CPAP) therapy on patients with obstructive sleep apnea (OSA).\n## DESIGN, SETTING, AND PARTICIPANTS\nThe Apnea Positive Pressure Long-term Efficacy Study (APPLES) was a 6-month, randomized, double-blind, 2-arm, sham-controlled, multicenter trial conducted at 5 U.S. university, hospital, or private practices. Of 1,516 participants enrolled, 1,105 were randomized, and 1,098 participants diagnosed with OSA contributed to the analysis of the primary outcome measures.\n## INTERVENTION\nActive or sham CPAP MEASUREMENTS: THREE NEUROCOGNITIVE VARIABLES, EACH REPRESENTING A NEUROCOGNITIVE DOMAIN: Pathfinder Number Test-Total Time (attention and psychomotor function [A/P]), Buschke Selective Reminding Test-Sum Recall (learning and memory [L/M]), and Sustained Working Memory Test-Overall Mid-Day Score (executive and frontal-lobe function [E/F])\n## RESULTS\nThe primary neurocognitive analyses showed a difference between groups for only the E/F variable at the 2 month CPAP visit, but no difference at the 6 month CPAP visit or for the A/P or L/M variables at either the 2 or 6 month visits. When stratified by measures of OSA severity (AHI or oxygen saturation parameters), the primary E/F variable and one secondary E/F neurocognitive variable revealed transient differences between study arms for those with the most severe OSA. Participants in the active CPAP group had a significantly greater ability to remain awake whether measured subjectively by the Epworth Sleepiness Scale or objectively by the maintenance of wakefulness test.\n## CONCLUSIONS\nCPAP treatment improved both subjectively and objectively measured sleepiness, especially in individuals with severe OSA (AHI > 30). CPAP use resulted in mild, transient improvement in the most sensitive measures of executive and frontal-lobe function for those with severe disease, which suggests the existence of a complex OSA-neurocognitive relationship.\n## CLINICAL TRIAL INFORMATION\nRegistered at clinicaltrials.gov. Identifier: NCT00051363.\n## CITATION\nKushida CA; Nichols DA; Holmes TH; Quan SF; Walsh JK; Gottlieb DJ; Simon RD; Guilleminault C; White DP; Goodwin JL; Schweitzer PK; Leary EB; Hyde PR; Hirshkowitz M; Green S; McEvoy LK; Chan C; Gevins A; Kay GG; Bloch DA; Crabtree T; Demen WC. Effects of continuous positive airway pressure on neurocognitive function in obstructive sleep apnea patients: the Apnea Positive Pressure Long-term Efficacy Study (APPLES). SLEEP 2012;35(12):1593-1602.",
        "truth": "False"
    },
    {
        "pmid": "28697252",
        "meta_analysis_title": "Association of Positive Airway Pressure With Cardiovascular Events and Death in Adults With Sleep Apnea: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Does the use of positive airway pressure (PAP) to treat sleep apnea reduce risk of cardiovascular events and death?",
        "criteria": "A systematic search of the scientific literature was done according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statement for the conduct of meta-analyses of intervention studies. The searches included MEDLINE via Ovid (from January 1, 1946, to March 2017), EMBASE (from January 1, 1974, to March 2017), and the Cochrane Library database (Cochrane Central Register of Controlled Trials, no date restriction) using relevant text words and Medical Subject Headings that consisted of terms relating to randomized trial and sleep apnea (see the eAppendix in the Supplement for detailed search strategy). The search was limited to randomized clinical trials (RCTs) but without language restriction. Additionally, reference lists from trials, review articles, and reports were manually scanned to identify any other relevant data (including conference abstracts). The clinicaltrials.gov website was searched for RCTs that were registered as completed but not yet published.",
        "subgroup": "Meta-analysis of the Association of Positive Airway Pressure With Cardiovascular Outcomes - Hospitalization for unstable angina",
        "key_reference_title": "Continuous positive airway pressure in older people with obstructive sleep apnoea syndrome (PREDICT): a 12-month, multicentre, randomised trial.",
        "key_reference_abstract": "## BACKGROUND\nThe therapeutic and economic benefits of continuous positive airway pressure (CPAP) for moderate to severe obstructive sleep apnoea (OSA) syndrome have been established in middle-aged people; however, the benefits in older people are unknown. This trial was designed to address this evidence gap.\n## METHODS\nThis 12-month, multicentre, randomised trial enrolled patients across 14 National Health Service sleep centres in the UK. Consecutive patients aged 65 years or older with newly diagnosed OSA syndrome were eligible to join the trial. Patients were randomly assigned (1:1) into parallel groups to receive either CPAP with best supportive care (BSC) or BSC alone for 12 months. Randomisation was done by the Medical Research Council Clinical Trials Unit with computer-generated randomisation. The main investigator at each centre was masked to the trial randomisation. Coprimary endpoints were Epworth sleepiness score (ESS) at 3 months and cost-effectiveness over the 12-month trial period. Secondary outcomes were subjective sleepiness at 12 months, plus objective sleepiness, quality of life, mood, functionality, nocturia, mobility, accidents, cognitive function, and cardiovascular risk factors and events at 3 months and 12 months. The analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN90464927.\n## FINDINGS\nBetween Feb 24, 2010, and May 30, 2012, 278 patients were randomly assigned to the trial, of whom 231 (83%) completed the trial. 140 patients were allocated to and received CPAP plus BSC and 138 were allocated to and received BSC only. CPAP reduced ESS by 2\u00b71 points (95% CI -3\u00b70 to -1\u00b73; p<0\u00b70001) at 3 months for 124 (89%) of 140 patients compared with 124 (90%) of 138 patients given BSC, and by 2\u00b70 points (-2\u00b78 to -1\u00b72; p<0\u00b70001) at 12 months for 116 patients compared with 122 patients given BSC. The effect was greater in patients with higher CPAP usage or higher baseline ESS. Quality-adjusted life-years were similar between the groups (treatment effect 0\u00b701 (95% CI -0\u00b703 to 0\u00b704; p=0\u00b7787) and health-care costs were marginally reduced with CPAP (-\u00a335, -390 to 321; p=0\u00b7847). CPAP improved objective sleepiness (p=0\u00b7024), mobility (p=0\u00b7029), total cholesterol (p=0\u00b7048), and LDL cholesterol (p=0\u00b7042) at 3 months, but these were not sustained at 12 months. Measures of mood, functionality, nocturia, accidents, cognitive function, and cardiovascular events remained unchanged. Systolic blood pressure fell in the BSC group. 37 serious adverse events occurred in the CPAP group, and 22 in BSC group; all were independently classified as being unrelated to the trial and no significant harm was attributed to CPAP use.\n## INTERPRETATION\nIn older people with OSA syndrome, CPAP reduces sleepiness and is marginally more cost effective over 12 months than is BSC alone. On the basis of these results, we recommend that CPAP treatment should be offered routinely to older patients with OSA syndrome.\n## FUNDING\nNational Institute of Health Research (NIHR) Health Technology Assessment, NIHR Respiratory Biomedical Research Unit at the Royal Brompton and Harefield NHS Foundation Trust and Imperial College London.",
        "truth": "False"
    },
    {
        "pmid": "28697252",
        "meta_analysis_title": "Association of Positive Airway Pressure With Cardiovascular Events and Death in Adults With Sleep Apnea: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Does the use of positive airway pressure (PAP) to treat sleep apnea reduce risk of cardiovascular events and death?",
        "criteria": "A systematic search of the scientific literature was done according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statement for the conduct of meta-analyses of intervention studies. The searches included MEDLINE via Ovid (from January 1, 1946, to March 2017), EMBASE (from January 1, 1974, to March 2017), and the Cochrane Library database (Cochrane Central Register of Controlled Trials, no date restriction) using relevant text words and Medical Subject Headings that consisted of terms relating to randomized trial and sleep apnea (see the eAppendix in the Supplement for detailed search strategy). The search was limited to randomized clinical trials (RCTs) but without language restriction. Additionally, reference lists from trials, review articles, and reports were manually scanned to identify any other relevant data (including conference abstracts). The clinicaltrials.gov website was searched for RCTs that were registered as completed but not yet published.",
        "subgroup": "Meta-analysis of the Association of Positive Airway Pressure With Cardiovascular Outcomes - Hospitalization for unstable angina",
        "key_reference_title": "Adaptive Servo-Ventilation for Central Sleep Apnea in Systolic Heart Failure.",
        "key_reference_abstract": "## BACKGROUND\nCentral sleep apnea is associated with poor prognosis and death in patients with heart failure. Adaptive servo-ventilation is a therapy that uses a noninvasive ventilator to treat central sleep apnea by delivering servo-controlled inspiratory pressure support on top of expiratory positive airway pressure. We investigated the effects of adaptive servo-ventilation in patients who had heart failure with reduced ejection fraction and predominantly central sleep apnea.\n## METHODS\nWe randomly assigned 1325 patients with a left ventricular ejection fraction of 45% or less, an apnea-hypopnea index (AHI) of 15 or more events (occurrences of apnea or hypopnea) per hour, and a predominance of central events to receive guideline-based medical treatment with adaptive servo-ventilation or guideline-based medical treatment alone (control). The primary end point in the time-to-event analysis was the first event of death from any cause, lifesaving cardiovascular intervention (cardiac transplantation, implantation of a ventricular assist device, resuscitation after sudden cardiac arrest, or appropriate lifesaving shock), or unplanned hospitalization for worsening heart failure.\n## RESULTS\nIn the adaptive servo-ventilation group, the mean AHI at 12 months was 6.6 events per hour. The incidence of the primary end point did not differ significantly between the adaptive servo-ventilation group and the control group (54.1% and 50.8%, respectively; hazard ratio, 1.13; 95% confidence interval [CI], 0.97 to 1.31; P=0.10). All-cause mortality and cardiovascular mortality were significantly higher in the adaptive servo-ventilation group than in the control group (hazard ratio for death from any cause, 1.28; 95% CI, 1.06 to 1.55; P=0.01; and hazard ratio for cardiovascular death, 1.34; 95% CI, 1.09 to 1.65; P=0.006).\n## CONCLUSIONS\nAdaptive servo-ventilation had no significant effect on the primary end point in patients who had heart failure with reduced ejection fraction and predominantly central sleep apnea, but all-cause and cardiovascular mortality were both increased with this therapy. (Funded by ResMed and others; SERVE-HF ClinicalTrials.gov number, NCT00733343.).",
        "truth": "False"
    },
    {
        "pmid": "28697252",
        "meta_analysis_title": "Association of Positive Airway Pressure With Cardiovascular Events and Death in Adults With Sleep Apnea: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Does the use of positive airway pressure (PAP) to treat sleep apnea reduce risk of cardiovascular events and death?",
        "criteria": "A systematic search of the scientific literature was done according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statement for the conduct of meta-analyses of intervention studies. The searches included MEDLINE via Ovid (from January 1, 1946, to March 2017), EMBASE (from January 1, 1974, to March 2017), and the Cochrane Library database (Cochrane Central Register of Controlled Trials, no date restriction) using relevant text words and Medical Subject Headings that consisted of terms relating to randomized trial and sleep apnea (see the eAppendix in the Supplement for detailed search strategy). The search was limited to randomized clinical trials (RCTs) but without language restriction. Additionally, reference lists from trials, review articles, and reports were manually scanned to identify any other relevant data (including conference abstracts). The clinicaltrials.gov website was searched for RCTs that were registered as completed but not yet published.",
        "subgroup": "Meta-analysis of the Association of Positive Airway Pressure With Cardiovascular Outcomes - Hospitalization for unstable angina",
        "key_reference_title": "Long-term effects of continuous positive airway pressure on blood pressure and prognosis in hypertensive patients with coronary heart disease and obstructive sleep apnea: a randomized controlled trial.",
        "key_reference_abstract": "## BACKGROUND\nObstructive sleep apnea (OSA) can result in hypertension and significantly increase cardiovascular morbidity and mortality. There are few reports on the long-term effects of continuous positive airway pressure (CPAP) on blood pressure in patients with uncontrolled hypertension with coronary heart disease (CHD) and OSA.\n## METHODS\nWe conducted a prospective, long-term follow-up study in 83 patients with uncontrolled hypertension, CHD, and OSA randomized to control or CPAP groups. Daytime systolic blood pressure (SBP), diastolic blood pressure (DBP), and severe cardiovascular and cerebrovascular events (SCCEs) were recorded at baseline and follow-up.\n## RESULTS\nSeventy-three patients completed the study with a median follow-up of 36 (interquartile range = 24-54) months. The 2 groups had similar characteristics at baseline. CPAP was used for 4.5\u00b11.1 hour/night. SBP in the CPAP group was significantly reduced at follow-up (143\u00b17 mm Hg vs. 139\u00b17 mm Hg, P = 0.04), and SBP decreased by 8mm Hg (95% confidence interval = 1.4-9.9; P = 0.01). Hypertension control was improved (CPAP, 69.4% for CPAP users vs. 43.2% for control subjects; P = 0.02); however, DBP did not reach statistical difference between the groups (81\u00b110 mm Hg vs. 79\u00b18 mm Hg; P = 0.49). In the CPAP group, the Epworth Sleepiness Scale was markedly reduced (7.0\u00b13.4 vs. 3.7\u00b12.3; P < 0.001). There was 1 SCCE in the CPAP group (heart failure), and 5 SCCEs in the control group (acute myocardial infarction: 2 (with 1 death); stroke: 3), but there was no significant difference identified.\n## CONCLUSIONS\nLong-term CPAP application in uncontrolled hypertension with CHD and OSA significantly reduced daytime SBP, improved hypertension control and daytime sleepiness, and decreased the trend in SCCEs compared with control subjects.\n## CLINICAL TRIAL REGISTRATION NUMBER\nClinicalTrials.gov NCT02059993.",
        "truth": "True"
    },
    {
        "pmid": "28697252",
        "meta_analysis_title": "Association of Positive Airway Pressure With Cardiovascular Events and Death in Adults With Sleep Apnea: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Does the use of positive airway pressure (PAP) to treat sleep apnea reduce risk of cardiovascular events and death?",
        "criteria": "A systematic search of the scientific literature was done according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statement for the conduct of meta-analyses of intervention studies. The searches included MEDLINE via Ovid (from January 1, 1946, to March 2017), EMBASE (from January 1, 1974, to March 2017), and the Cochrane Library database (Cochrane Central Register of Controlled Trials, no date restriction) using relevant text words and Medical Subject Headings that consisted of terms relating to randomized trial and sleep apnea (see the eAppendix in the Supplement for detailed search strategy). The search was limited to randomized clinical trials (RCTs) but without language restriction. Additionally, reference lists from trials, review articles, and reports were manually scanned to identify any other relevant data (including conference abstracts). The clinicaltrials.gov website was searched for RCTs that were registered as completed but not yet published.",
        "subgroup": "Meta-analysis of the Association of Positive Airway Pressure With Cardiovascular Outcomes - Hospitalization for unstable angina",
        "key_reference_title": "Efficacy of continuous positive airway pressure treatment on 5-year survival in patients with ischaemic stroke and obstructive sleep apnea: a randomized controlled trial.",
        "key_reference_abstract": "The main purpose of the present analysis is to assess the influence of introducing early nasal continuous positive airway pressure (nCPAP) treatment on cardiovascular recurrences and mortality in patients with a first-ever ischaemic stroke and moderate-severe obstructive sleep apnea (OSA) with an apnea-hypopnea index (AHI) \u226520 events h(-1) during a 5-year follow-up. Patients received conventional treatment for stroke and were assigned randomly to the nCPAP group (n = 71) or the control group (n = 69). Cardiovascular events and mortality were registered for all patients. Survival and cardiovascular event-free survival analysis were performed after 5-year follow-up using the Kaplan-Meier test. Patients in the nCPAP group had significantly higher cardiovascular survival than the control group (100 versus 89.9%, log-rank test 5.887; P = 0.015) However, and also despite a positive tendency, there were no significant differences in the cardiovascular event-free survival at 68 months between the nCPAP and control groups (89.5 versus 75.4%, log-rank test 3.565; P = 0.059). Early nCPAP therapy has a positive effect on long-term survival in ischaemic stroke patients and moderate-severe OSA.",
        "truth": "False"
    },
    {
        "pmid": "28697252",
        "meta_analysis_title": "Association of Positive Airway Pressure With Cardiovascular Events and Death in Adults With Sleep Apnea: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Does the use of positive airway pressure (PAP) to treat sleep apnea reduce risk of cardiovascular events and death?",
        "criteria": "A systematic search of the scientific literature was done according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statement for the conduct of meta-analyses of intervention studies. The searches included MEDLINE via Ovid (from January 1, 1946, to March 2017), EMBASE (from January 1, 1974, to March 2017), and the Cochrane Library database (Cochrane Central Register of Controlled Trials, no date restriction) using relevant text words and Medical Subject Headings that consisted of terms relating to randomized trial and sleep apnea (see the eAppendix in the Supplement for detailed search strategy). The search was limited to randomized clinical trials (RCTs) but without language restriction. Additionally, reference lists from trials, review articles, and reports were manually scanned to identify any other relevant data (including conference abstracts). The clinicaltrials.gov website was searched for RCTs that were registered as completed but not yet published.",
        "subgroup": "Meta-analysis of the Association of Positive Airway Pressure With Cardiovascular Outcomes - Hospitalization for unstable angina",
        "key_reference_title": "CPAP for Prevention of Cardiovascular Events in Obstructive Sleep Apnea.",
        "key_reference_abstract": "## BACKGROUND\nObstructive sleep apnea is associated with an increased risk of cardiovascular events; whether treatment with continuous positive airway pressure (CPAP) prevents major cardiovascular events is uncertain.\n## METHODS\nAfter a 1-week run-in period during which the participants used sham CPAP, we randomly assigned 2717 eligible adults between 45 and 75 years of age who had moderate-to-severe obstructive sleep apnea and coronary or cerebrovascular disease to receive CPAP treatment plus usual care (CPAP group) or usual care alone (usual-care group). The primary composite end point was death from cardiovascular causes, myocardial infarction, stroke, or hospitalization for unstable angina, heart failure, or transient ischemic attack. Secondary end points included other cardiovascular outcomes, health-related quality of life, snoring symptoms, daytime sleepiness, and mood.\n## RESULTS\nMost of the participants were men who had moderate-to-severe obstructive sleep apnea and minimal sleepiness. In the CPAP group, the mean duration of adherence to CPAP therapy was 3.3 hours per night, and the mean apnea-hypopnea index (the number of apnea or hypopnea events per hour of recording) decreased from 29.0 events per hour at baseline to 3.7 events per hour during follow-up. After a mean follow-up of 3.7 years, a primary end-point event had occurred in 229 participants in the CPAP group (17.0%) and in 207 participants in the usual-care group (15.4%) (hazard ratio with CPAP, 1.10; 95% confidence interval, 0.91 to 1.32; P=0.34). No significant effect on any individual or other composite cardiovascular end point was observed. CPAP significantly reduced snoring and daytime sleepiness and improved health-related quality of life and mood.\n## CONCLUSIONS\nTherapy with CPAP plus usual care, as compared with usual care alone, did not prevent cardiovascular events in patients with moderate-to-severe obstructive sleep apnea and established cardiovascular disease. (Funded by the National Health and Medical Research Council of Australia and others; SAVE ClinicalTrials.gov number, NCT00738179 ; Australian New Zealand Clinical Trials Registry number, ACTRN12608000409370 .).",
        "truth": "True"
    },
    {
        "pmid": "28697252",
        "meta_analysis_title": "Association of Positive Airway Pressure With Cardiovascular Events and Death in Adults With Sleep Apnea: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Does the use of positive airway pressure (PAP) to treat sleep apnea reduce risk of cardiovascular events and death?",
        "criteria": "A systematic search of the scientific literature was done according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statement for the conduct of meta-analyses of intervention studies. The searches included MEDLINE via Ovid (from January 1, 1946, to March 2017), EMBASE (from January 1, 1974, to March 2017), and the Cochrane Library database (Cochrane Central Register of Controlled Trials, no date restriction) using relevant text words and Medical Subject Headings that consisted of terms relating to randomized trial and sleep apnea (see the eAppendix in the Supplement for detailed search strategy). The search was limited to randomized clinical trials (RCTs) but without language restriction. Additionally, reference lists from trials, review articles, and reports were manually scanned to identify any other relevant data (including conference abstracts). The clinicaltrials.gov website was searched for RCTs that were registered as completed but not yet published.",
        "subgroup": "Meta-analysis of the Association of Positive Airway Pressure With Cardiovascular Outcomes - Hospitalization for unstable angina",
        "key_reference_title": "Effect of Positive Airway Pressure on Cardiovascular Outcomes in Coronary Artery Disease Patients with Nonsleepy Obstructive Sleep Apnea. The RICCADSA Randomized Controlled Trial.",
        "key_reference_abstract": "## RATIONALE\nObstructive sleep apnea (OSA) is common in patients with coronary artery disease (CAD), many of whom do not report daytime sleepiness. First-line treatment for symptomatic OSA is continuous positive airway pressure (CPAP), but its value in patients without daytime sleepiness is uncertain.\n## OBJECTIVES\nTo determine the effects of CPAP on long-term adverse cardiovascular outcome risk in patients with CAD with nonsleepy OSA.\n## METHODS\nThis single-center, prospective, randomized, controlled, open-label, blinded evaluation trial was conducted between December 2005 and November 2010. Consecutive patients with newly revascularized CAD and OSA (apnea-hypopnea index \u226515/h) without daytime sleepiness (Epworth Sleepiness Scale score <10) were randomized to auto-titrating CPAP (n\u2009=\u2009122) or no positive airway pressure (n\u2009=\u2009122).\n## MEASUREMENTS AND MAIN RESULTS\nThe primary endpoint was the first event of repeat revascularization, myocardial infarction, stroke, or cardiovascular mortality. Median follow-up was 57 months. The incidence of the primary endpoint did not differ significantly in patients who did versus did not receive CPAP (18.1% vs. 22.1%; hazard ratio, 0.80; 95% confidence interval, 0.46-1.41; P\u2009=\u20090.449). Adjusted on-treatment analysis showed a significant cardiovascular risk reduction in those who used CPAP for \u22654 versus <4 hours per night or did not receive treatment (hazard ratio, 0.29; 95% confidence interval, 0.10-0.86; P\u2009=\u20090.026).\n## CONCLUSIONS\nRoutine prescription of CPAP to patients with CAD with nonsleepy OSA did not significantly reduce long-term adverse cardiovascular outcomes in the intention-to-treat population. There was a significant reduction after adjustment for baseline comorbidities and compliance with the treatment. Clinical trial registered with www.clinicaltrials.gov (NCT 00519597).",
        "truth": "True"
    },
    {
        "pmid": "36306133",
        "meta_analysis_title": "COVID-19 Pandemic and Infant Neurodevelopmental Impairment: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Are neurodevelopmental outcomes during infancy changed by the COVID-19 pandemic?",
        "criteria": "A total of 1880 articles were retrieved. Of these, 670 articles were excluded as duplicates, and the remaining 1210 studies were screened for eligibility. Screening of the title and abstract resulted in 21 potentially eligible studies. Following full-text assessment, 8 studies met the inclusion criteria defined earlier (Figure 1).",
        "subgroup": "Prevalence of Risk for Neurodevelopmental Impairment (NDI) Among Infants Screened During the Pandemic, In Utero SARS-CoV-2\u2013Exposed Cohort, and In Utero SARS-CoV-2\u2013Unexposed Cohort - Infants screened during pandemic",
        "key_reference_title": "Association of Birth During the COVID-19 Pandemic With Neurodevelopmental Status at 6 Months in Infants With and Without In Utero Exposure to Maternal SARS-CoV-2 Infection.",
        "key_reference_abstract": "## IMPORTANCE\nAssociations between in utero exposure to maternal SARS-CoV-2 infection and neurodevelopment are speculated, but currently unknown.\n## OBJECTIVE\nTo examine the associations between maternal SARS-CoV-2 infection during pregnancy, being born during the COVID-19 pandemic regardless of maternal SARS-CoV-2 status, and neurodevelopment at age 6 months.\n## DESIGN, SETTING, AND PARTICIPANTS\nA cohort of infants exposed to maternal SARS-CoV-2 infection during pregnancy and unexposed controls was enrolled in the COVID-19 Mother Baby Outcomes Initiative at Columbia University Irving Medical Center in New York City. All women who delivered at Columbia University Irving Medical Center with a SARS-CoV-2 infection during pregnancy were approached. Women with unexposed infants were approached based on similar gestational age at birth, date of birth, sex, and mode of delivery. Neurodevelopment was assessed using the Ages & Stages Questionnaire, 3rd Edition (ASQ-3) at age 6 months. A historical cohort of infants born before the pandemic who had completed the 6-month ASQ-3 were included in secondary analyses.\n## EXPOSURES\nMaternal SARS-CoV-2 infection during pregnancy and birth during the COVID-19 pandemic.\n## MAIN OUTCOMES AND MEASURES\nOutcomes were scores on the 5 ASQ-3 subdomains, with the hypothesis that maternal SARS-CoV-2 infection during pregnancy would be associated with decrements in social and motor development at age 6 months.\n## RESULTS\nOf 1706 women approached, 596 enrolled; 385 women were invited to a 6-month assessment, of whom 272 (70.6%) completed the ASQ-3. Data were available for 255 infants enrolled in the COVID-19 Mother Baby Outcomes Initiative (114 in utero exposed, 141 unexposed to SARS-CoV-2; median maternal age at delivery, 32.0 [IQR, 19.0-45.0] years). Data were also available from a historical cohort of 62 infants born before the pandemic. In utero exposure to maternal SARS-CoV-2 infection was not associated with significant differences on any ASQ-3 subdomain, regardless of infection timing or severity. However, compared with the historical cohort, infants born during the pandemic had significantly lower scores on gross motor (mean difference, -5.63; 95% CI, -8.75 to -2.51; F1,267\u2009=\u200912.63; P<.005), fine motor (mean difference, -6.61; 95% CI, -10.00 to -3.21; F1,267\u2009=\u200914.71; P\u2009<\u2009.005), and personal-social (mean difference, -3.71; 95% CI, -6.61 to -0.82; F1,267\u2009=\u20096.37; P<.05) subdomains in fully adjusted models.\n## CONCLUSIONS AND RELEVANCE\nIn this study, birth during the pandemic, but not in utero exposure to maternal SARS-CoV-2 infection, was associated with differences in neurodevelopment at age 6 months. These early findings support the need for long-term monitoring of children born during the COVID-19 pandemic.",
        "truth": "True"
    },
    {
        "pmid": "36306133",
        "meta_analysis_title": "COVID-19 Pandemic and Infant Neurodevelopmental Impairment: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Are neurodevelopmental outcomes during infancy changed by the COVID-19 pandemic?",
        "criteria": "A total of 1880 articles were retrieved. Of these, 670 articles were excluded as duplicates, and the remaining 1210 studies were screened for eligibility. Screening of the title and abstract resulted in 21 potentially eligible studies. Following full-text assessment, 8 studies met the inclusion criteria defined earlier (Figure 1).",
        "subgroup": "Prevalence of Risk for Neurodevelopmental Impairment (NDI) Among Infants Screened During the Pandemic, In Utero SARS-CoV-2\u2013Exposed Cohort, and In Utero SARS-CoV-2\u2013Unexposed Cohort - Infants screened during pandemic",
        "key_reference_title": "Effects of SARS-CoV-2 Infection During Late Pregnancy on Early Childhood Development: A Prospective Cohort Study.",
        "key_reference_abstract": "Background: There is little direct or indirect evidence of the effects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection during pregnancy on early childhood development. Methods: We conducted a prospective, observational cohort study in China from May 1 to October 31, 2020, that enrolled 135 mother-infant dyads: 57 dyads in the infection cohort and 78 in the non-infection cohort. Among all infants, 14.0% were preterm birth in the infection cohort and 6.4% in the non-infection cohort. Participants were followed by telephone interviews to collect demographic characteristics, medical records of coronavirus disease 2019, breastfeeding data, and early childhood development was assessed by the Age and Stage Questionnaire (ASQ-3) and Age and Stage Questionnaire Social-Emotional (ASQ:SE-2) Chinese versions at 3 months after childbirth. We used multivariable Poisson regression models to estimate the relative risk (RR) of SARS-CoV-2 infection. Multivariable linear regression models and a mediation model were used to test the direct and indirect associations between SARS-CoV-2 infection and the ASQ-3 score. This study was approved by the Peking University Third Hospital Medical Science Research Ethics Committee (No. IRB00006761-M2020127). Results: In the infection cohort, 13.6% of the children showed social-emotional developmental delay, and 13.5% showed overall developmental delay. The corresponding rates in the non-infection cohort were 23.4 and 8.1%. Compared with the non-infection cohort, SARS-CoV-2 infection during pregnancy did not increase the risk of social-emotional (RR = 0.87, 95% CI: 0.51-1.49) or overall (RR = 1.02, 95% CI: 0.60-1.73) developmental delay. The mediation model showed that SARS-CoV-2 infection indirectly affected the ASQ-3 score by increasing the length of mother-infant separation. Conclusions: SARS-CoV-2 during late pregnancy did not increase the risk of developmental delay of the offspring 3 months after delivery. However, SARS-CoV-2 may have indirect effects on early childhood development by increasing mother-infant separation.",
        "truth": "True"
    },
    {
        "pmid": "36306133",
        "meta_analysis_title": "COVID-19 Pandemic and Infant Neurodevelopmental Impairment: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Are neurodevelopmental outcomes during infancy changed by the COVID-19 pandemic?",
        "criteria": "A total of 1880 articles were retrieved. Of these, 670 articles were excluded as duplicates, and the remaining 1210 studies were screened for eligibility. Screening of the title and abstract resulted in 21 potentially eligible studies. Following full-text assessment, 8 studies met the inclusion criteria defined earlier (Figure 1).",
        "subgroup": "Prevalence of Risk for Neurodevelopmental Impairment (NDI) Among Infants Screened During the Pandemic, In Utero SARS-CoV-2\u2013Exposed Cohort, and In Utero SARS-CoV-2\u2013Unexposed Cohort - Infants screened during pandemic",
        "key_reference_title": "The impact of the COVID-19 pandemic on infant and toddler development.",
        "key_reference_abstract": "## BACKGROUND\nThe COVID-19 pandemic has created new cultural norms with pervasive societal implications. Families have experienced a heightened amount of physical, psychological, emotional, and financial stress. Infants and children living with stress have the potential for delayed developmental milestones, difficulty with emotional regulation, and social or behavioral issues.\n## PURPOSE\nThis study aims to determine if the pandemic has affected developmental outcomes in infants and toddlers.\n## METHODOLOGY\nPrepandemic and postpandemic developmental (ASQ-3) scores were obtained from charts of 1,024 patients (6, 12, 18, 24, and 36 months) from two pediatric practices.\n## RESULTS\nThere were no significant differences in prepandemic and postpandemic ASQ-3 scores for the overall sample. Age-group analysis showed statistically significant differences in domain scores. Postpandemic problem-solving scores decreased among 6-month-olds while increasing among 24-month-olds. Categorization by score interpretation categories showed a slight decrease in postpandemic scores in the communication domain among 6- and 12-month-olds.\n## CONCLUSIONS\nThe pandemic has the potential to affect childhood development. However, the results of this study are reassuring, showing only slight differences in developmental scores prepandemic versus postpandemic. More studies are needed to establish causation and possible trends in future developmental trajectories.\n## IMPLICATIONS\nAn increased focus on communication screening and promotion of language and communication skills in young children postpandemic is needed. Education about the importance of parent-child engagement, nurturing relationships, opportunities for free-play and exploration, and caregiver support and stress reduction will continue to be of paramount importance.",
        "truth": "False"
    },
    {
        "pmid": "36306133",
        "meta_analysis_title": "COVID-19 Pandemic and Infant Neurodevelopmental Impairment: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Are neurodevelopmental outcomes during infancy changed by the COVID-19 pandemic?",
        "criteria": "A total of 1880 articles were retrieved. Of these, 670 articles were excluded as duplicates, and the remaining 1210 studies were screened for eligibility. Screening of the title and abstract resulted in 21 potentially eligible studies. Following full-text assessment, 8 studies met the inclusion criteria defined earlier (Figure 1).",
        "subgroup": "Prevalence of Risk for Neurodevelopmental Impairment (NDI) Among Infants Screened During the Pandemic, In Utero SARS-CoV-2\u2013Exposed Cohort, and In Utero SARS-CoV-2\u2013Unexposed Cohort - Infants screened during pandemic",
        "key_reference_title": "Association Between the COVID-19 Pandemic and Infant Neurodevelopment: A Comparison Before and During COVID-19.",
        "key_reference_abstract": "None",
        "truth": "True"
    },
    {
        "pmid": "36306133",
        "meta_analysis_title": "COVID-19 Pandemic and Infant Neurodevelopmental Impairment: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Are neurodevelopmental outcomes during infancy changed by the COVID-19 pandemic?",
        "criteria": "A total of 1880 articles were retrieved. Of these, 670 articles were excluded as duplicates, and the remaining 1210 studies were screened for eligibility. Screening of the title and abstract resulted in 21 potentially eligible studies. Following full-text assessment, 8 studies met the inclusion criteria defined earlier (Figure 1).",
        "subgroup": "Prevalence of Risk for Neurodevelopmental Impairment (NDI) Among Infants Screened During the Pandemic, In Utero SARS-CoV-2\u2013Exposed Cohort, and In Utero SARS-CoV-2\u2013Unexposed Cohort - Infants screened during pandemic",
        "key_reference_title": "Impact of SARS-CoV-2 Infection During Pregnancy on Infant Neurobehavioral Development: A Case-Control Study.",
        "key_reference_abstract": "Background: Previous studies on the pneumonia outbreak caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have focused on the general population and pregnant women, while little is known about the effects of SARS-CoV-2 on retardation during and after pregnancy. The purpose of this study was to evaluate the potential influence of SARS-CoV-2 on infant neurobehavioral development. Methods: A case-control study was conducted in Wuhan Maternal and Child Health Hospital, China. Nine pregnant women with SARS-CoV-2 infection and 9 controls matched by maternal age, parity, and status of chronic disease were included. Infantile neurobehavioral development was assessed through the Ages and Stages Questionnaires Edition 3 (ASQ-3). Results: The majority of pregnant women with SARS-CoV-2 experienced cesarean section (7 of 9), which was higher than the control group (5 of 9). The throat swabs of all newborn were negative. We found that compared with the control group, neonates of mothers with SARS-CoV-2 infection during pregnancy had lower scores in communication, gross movement, fine movement, problem solving, and personal-social domains; but only fine movement domain yielded statistical significance (P = 0.031). Conclusion: Infection with SARS-CoV-2 during pregnancy may have a certain impact on infant neurobehavioral development. Further studies with larger sample size are warranted for validation.",
        "truth": "False"
    },
    {
        "pmid": "36306133",
        "meta_analysis_title": "COVID-19 Pandemic and Infant Neurodevelopmental Impairment: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Are neurodevelopmental outcomes during infancy changed by the COVID-19 pandemic?",
        "criteria": "A total of 1880 articles were retrieved. Of these, 670 articles were excluded as duplicates, and the remaining 1210 studies were screened for eligibility. Screening of the title and abstract resulted in 21 potentially eligible studies. Following full-text assessment, 8 studies met the inclusion criteria defined earlier (Figure 1).",
        "subgroup": "Prevalence of Risk for Neurodevelopmental Impairment (NDI) Among Infants Screened During the Pandemic, In Utero SARS-CoV-2\u2013Exposed Cohort, and In Utero SARS-CoV-2\u2013Unexposed Cohort - Infants screened during pandemic",
        "key_reference_title": "Increased risk for developmental delay among babies born during the pandemic.",
        "key_reference_abstract": "The COVID-19 pandemic has resulted in substantial and widespread changes to many prenatal (e.g., maternal stress) and postnatal (e.g., socialization) factors contributing to early child development. We compared developmental screening of 1-year old infants born between April 17, 2020-November 11, 2020 to data from infants born pre-pandemic. We aimed to determine whether risk for developmental delay was elevated among infants born during the pandemic compared to infants born prior to the pandemic. Data were available from 1623 PdP participants. PdP infants had lower mean scores relative to pooled pre-pandemic data on all domains except Problem Solving. PdP infants also had significantly higher risk for developmental delay in the Communication and Personal-Social domains, where the odds ratios for scoring 2 SD below the mean were 2.5 and 1.5, respectively, relative to pre-pandemic data. When stratified by sex, the odds ratios for risk of developmental delay were generally higher among female infants. In conclusions, risks for developmental delay in the Communication and Personal-Social domains were elevated in infants born during the COVID-19 pandemic compared to pre-pandemic infants, especially among girls.",
        "truth": "False"
    },
    {
        "pmid": "36306133",
        "meta_analysis_title": "COVID-19 Pandemic and Infant Neurodevelopmental Impairment: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Are neurodevelopmental outcomes during infancy changed by the COVID-19 pandemic?",
        "criteria": "A total of 1880 articles were retrieved. Of these, 670 articles were excluded as duplicates, and the remaining 1210 studies were screened for eligibility. Screening of the title and abstract resulted in 21 potentially eligible studies. Following full-text assessment, 8 studies met the inclusion criteria defined earlier (Figure 1).",
        "subgroup": "Prevalence of Risk for Neurodevelopmental Impairment (NDI) Among Infants Screened During the Pandemic, In Utero SARS-CoV-2\u2013Exposed Cohort, and In Utero SARS-CoV-2\u2013Unexposed Cohort - Infants screened during pandemic",
        "key_reference_title": "Neurodevelopmental outcomes of infants secondary to in utero exposure to maternal 2 SARS-CoV-2 infection: A national prospective study in Kuwait.",
        "key_reference_abstract": "## Background\nAn increasing proportion of women are being infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) during pregnancy. Intrauterine viral infections induce an increase in the levels of proinflammatory cytokines, which inhibit the proliferation of neuronal precursor cells and stimulate oligodendrocyte cell death, leading to abnormal neurodevelopment. Whether a maternal cytokine storm can affect neonatal brain development is unclear. The objective of the present study is to assess neurodevelopmental outcomes in neonates born to mothers with SARS-CoV-2 infections during pregnancy. ## Methods\nIn this prospective cohort study, the neurodevelopment status of infants (N=298) born to women with SARS-CoV-2 infections during pregnancy was assessed at 10-12 months post discharge using the Ages and Stages Questionnaire, 3rd edition (ASQ-3). The ASQ-3 scores were classified into developmental delays (cutoff score: \u22642 standard deviations (SDs) below the population mean) and no delay (score >2 SDs above the population mean). ## Results\nApproximately 10% of infants born to mothers with SARS-CoV-2 infections during pregnancy showed developmental delays. Two of 298 infants tested positive for SARS-CoV-2, and both had normal ASQ-3 scores. The majority of the pregnant women had SARS-CoV-2 infection during their third trimester. The risk of developmental delays among infants was higher in those whose mothers had SARS-CoV-2 infections during the first (P=0.039) and second trimesters (P=0.001) than in those whose mothers had SARS-CoV-2 infections during the third trimester. Infants born at <31 weeks gestation were more prone to developmental delays than those born at >31 weeks gestation (10% versus 0.8%; P=0.002). ## Conclusion\nThe findings of the study highlight the need for long term neurodevelopmental assessment of infants born to mothers with SARS-CoV-2 infection.",
        "truth": "False"
    },
    {
        "pmid": "36306133",
        "meta_analysis_title": "COVID-19 Pandemic and Infant Neurodevelopmental Impairment: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Are neurodevelopmental outcomes during infancy changed by the COVID-19 pandemic?",
        "criteria": "A total of 1880 articles were retrieved. Of these, 670 articles were excluded as duplicates, and the remaining 1210 studies were screened for eligibility. Screening of the title and abstract resulted in 21 potentially eligible studies. Following full-text assessment, 8 studies met the inclusion criteria defined earlier (Figure 1).",
        "subgroup": "Prevalence of Risk for Neurodevelopmental Impairment (NDI) Among Infants Screened During the Pandemic, In Utero SARS-CoV-2\u2013Exposed Cohort, and In Utero SARS-CoV-2\u2013Unexposed Cohort - Infants screened during pandemic",
        "key_reference_title": "Neurodevelopmental outcomes at one year in offspring of mothers who test positive for SARS-CoV-2 during pregnancy.",
        "key_reference_abstract": "## Importance\nEpidemiologic studies suggest maternal immune activation during pregnancy may be associated with neurodevelopmental effects in offspring. \n## Objective\nTo determine whether in utero exposure to the novel coronavirus SARS-CoV-2 is associated with risk for neurodevelopmental disorders in the first 12 months after birth. \n## Design\nRetrospective cohort\n## Participants\nLive offspring of all mothers who delivered between March and September 2020 at one of six Massachusetts hospitals across two health systems. \n## Exposure\nSARS-CoV-2 infection confirmed by PCR during pregnancy \n## Main Outcome and Measures\nNeurodevelopmental disorders determined from ICD-10 diagnostic codes over 12 months; sociodemographic and clinical features of mothers and offspring; all drawn from the electronic health record. \n## Results\nThe cohort included 7,772 live births (7,466 pregnancies, 96% singleton, 222 births to SARS-CoV-2 positive mothers), with mean maternal age of 32.9 years; offspring were 9.9% Asian, 8.4% Black, and 69.0% white; 15.1% were of Hispanic ethnicity. Preterm delivery was more likely among exposed mothers (14% versus 8.7%; p=.003). Maternal SARS-CoV-2 positivity during pregnancy was associated with greater rate of neurodevelopmental diagnoses (crude OR 2.17 [95% CI 1.24-3.79, p=0.006]) as well as models adjusted for race, ethnicity, insurance status, offspring sex, maternal age, and preterm status (adjusted OR 1.86 [95% CI 1.03-3.36, p=0.04]). Third-trimester infection was associated with effects of larger magnitude (adjusted OR 2.34, 95% CI 1.23-4.44, p=0.01) \n## Conclusion and Relevance\nOur results provide preliminary evidence that maternal SARS-CoV-2 may be associated with neurodevelopmental sequelae in some offspring. Prospective studies with longer follow-up duration will be required to exclude confounding and confirm these effects.\n## Trial Registration\nNA## Key Points\n## Question\nDoes COVID-19 exposure in utero increase the risk for neurodevelopmental disorders in the first year of life? ## Findings\nIn a cohort of babies delivered during COVID-19, those born to mothers with a positive SARS-CoV-2 PCR test during pregnancy were more likely to receive a neurodevelopmental diagnosis in the first 12 months after delivery, even after accounting for preterm delivery. ## Meaning\nThese preliminary findings suggest that COVID-19 exposure may impact neurodevelopment, and highlight the need for prospective investigation of outcomes in children exposed to COVID-19 in utero.",
        "truth": "True"
    },
    {
        "pmid": "36306133",
        "meta_analysis_title": "COVID-19 Pandemic and Infant Neurodevelopmental Impairment: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Are neurodevelopmental outcomes during infancy changed by the COVID-19 pandemic?",
        "criteria": "A total of 1880 articles were retrieved. Of these, 670 articles were excluded as duplicates, and the remaining 1210 studies were screened for eligibility. Screening of the title and abstract resulted in 21 potentially eligible studies. Following full-text assessment, 8 studies met the inclusion criteria defined earlier (Figure 1).",
        "subgroup": "Prevalence of Risk for Neurodevelopmental Impairment (NDI) Among Infants Screened During the Pandemic, In Utero SARS-CoV-2\u2013Exposed Cohort, and In Utero SARS-CoV-2\u2013Unexposed Cohort - In utero SARS-CoV-2 exposed cohort",
        "key_reference_title": "Association of Birth During the COVID-19 Pandemic With Neurodevelopmental Status at 6 Months in Infants With and Without In Utero Exposure to Maternal SARS-CoV-2 Infection.",
        "key_reference_abstract": "## IMPORTANCE\nAssociations between in utero exposure to maternal SARS-CoV-2 infection and neurodevelopment are speculated, but currently unknown.\n## OBJECTIVE\nTo examine the associations between maternal SARS-CoV-2 infection during pregnancy, being born during the COVID-19 pandemic regardless of maternal SARS-CoV-2 status, and neurodevelopment at age 6 months.\n## DESIGN, SETTING, AND PARTICIPANTS\nA cohort of infants exposed to maternal SARS-CoV-2 infection during pregnancy and unexposed controls was enrolled in the COVID-19 Mother Baby Outcomes Initiative at Columbia University Irving Medical Center in New York City. All women who delivered at Columbia University Irving Medical Center with a SARS-CoV-2 infection during pregnancy were approached. Women with unexposed infants were approached based on similar gestational age at birth, date of birth, sex, and mode of delivery. Neurodevelopment was assessed using the Ages & Stages Questionnaire, 3rd Edition (ASQ-3) at age 6 months. A historical cohort of infants born before the pandemic who had completed the 6-month ASQ-3 were included in secondary analyses.\n## EXPOSURES\nMaternal SARS-CoV-2 infection during pregnancy and birth during the COVID-19 pandemic.\n## MAIN OUTCOMES AND MEASURES\nOutcomes were scores on the 5 ASQ-3 subdomains, with the hypothesis that maternal SARS-CoV-2 infection during pregnancy would be associated with decrements in social and motor development at age 6 months.\n## RESULTS\nOf 1706 women approached, 596 enrolled; 385 women were invited to a 6-month assessment, of whom 272 (70.6%) completed the ASQ-3. Data were available for 255 infants enrolled in the COVID-19 Mother Baby Outcomes Initiative (114 in utero exposed, 141 unexposed to SARS-CoV-2; median maternal age at delivery, 32.0 [IQR, 19.0-45.0] years). Data were also available from a historical cohort of 62 infants born before the pandemic. In utero exposure to maternal SARS-CoV-2 infection was not associated with significant differences on any ASQ-3 subdomain, regardless of infection timing or severity. However, compared with the historical cohort, infants born during the pandemic had significantly lower scores on gross motor (mean difference, -5.63; 95% CI, -8.75 to -2.51; F1,267\u2009=\u200912.63; P<.005), fine motor (mean difference, -6.61; 95% CI, -10.00 to -3.21; F1,267\u2009=\u200914.71; P\u2009<\u2009.005), and personal-social (mean difference, -3.71; 95% CI, -6.61 to -0.82; F1,267\u2009=\u20096.37; P<.05) subdomains in fully adjusted models.\n## CONCLUSIONS AND RELEVANCE\nIn this study, birth during the pandemic, but not in utero exposure to maternal SARS-CoV-2 infection, was associated with differences in neurodevelopment at age 6 months. These early findings support the need for long-term monitoring of children born during the COVID-19 pandemic.",
        "truth": "True"
    },
    {
        "pmid": "36306133",
        "meta_analysis_title": "COVID-19 Pandemic and Infant Neurodevelopmental Impairment: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Are neurodevelopmental outcomes during infancy changed by the COVID-19 pandemic?",
        "criteria": "A total of 1880 articles were retrieved. Of these, 670 articles were excluded as duplicates, and the remaining 1210 studies were screened for eligibility. Screening of the title and abstract resulted in 21 potentially eligible studies. Following full-text assessment, 8 studies met the inclusion criteria defined earlier (Figure 1).",
        "subgroup": "Prevalence of Risk for Neurodevelopmental Impairment (NDI) Among Infants Screened During the Pandemic, In Utero SARS-CoV-2\u2013Exposed Cohort, and In Utero SARS-CoV-2\u2013Unexposed Cohort - In utero SARS-CoV-2 exposed cohort",
        "key_reference_title": "Effects of SARS-CoV-2 Infection During Late Pregnancy on Early Childhood Development: A Prospective Cohort Study.",
        "key_reference_abstract": "Background: There is little direct or indirect evidence of the effects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection during pregnancy on early childhood development. Methods: We conducted a prospective, observational cohort study in China from May 1 to October 31, 2020, that enrolled 135 mother-infant dyads: 57 dyads in the infection cohort and 78 in the non-infection cohort. Among all infants, 14.0% were preterm birth in the infection cohort and 6.4% in the non-infection cohort. Participants were followed by telephone interviews to collect demographic characteristics, medical records of coronavirus disease 2019, breastfeeding data, and early childhood development was assessed by the Age and Stage Questionnaire (ASQ-3) and Age and Stage Questionnaire Social-Emotional (ASQ:SE-2) Chinese versions at 3 months after childbirth. We used multivariable Poisson regression models to estimate the relative risk (RR) of SARS-CoV-2 infection. Multivariable linear regression models and a mediation model were used to test the direct and indirect associations between SARS-CoV-2 infection and the ASQ-3 score. This study was approved by the Peking University Third Hospital Medical Science Research Ethics Committee (No. IRB00006761-M2020127). Results: In the infection cohort, 13.6% of the children showed social-emotional developmental delay, and 13.5% showed overall developmental delay. The corresponding rates in the non-infection cohort were 23.4 and 8.1%. Compared with the non-infection cohort, SARS-CoV-2 infection during pregnancy did not increase the risk of social-emotional (RR = 0.87, 95% CI: 0.51-1.49) or overall (RR = 1.02, 95% CI: 0.60-1.73) developmental delay. The mediation model showed that SARS-CoV-2 infection indirectly affected the ASQ-3 score by increasing the length of mother-infant separation. Conclusions: SARS-CoV-2 during late pregnancy did not increase the risk of developmental delay of the offspring 3 months after delivery. However, SARS-CoV-2 may have indirect effects on early childhood development by increasing mother-infant separation.",
        "truth": "True"
    },
    {
        "pmid": "36306133",
        "meta_analysis_title": "COVID-19 Pandemic and Infant Neurodevelopmental Impairment: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Are neurodevelopmental outcomes during infancy changed by the COVID-19 pandemic?",
        "criteria": "A total of 1880 articles were retrieved. Of these, 670 articles were excluded as duplicates, and the remaining 1210 studies were screened for eligibility. Screening of the title and abstract resulted in 21 potentially eligible studies. Following full-text assessment, 8 studies met the inclusion criteria defined earlier (Figure 1).",
        "subgroup": "Prevalence of Risk for Neurodevelopmental Impairment (NDI) Among Infants Screened During the Pandemic, In Utero SARS-CoV-2\u2013Exposed Cohort, and In Utero SARS-CoV-2\u2013Unexposed Cohort - In utero SARS-CoV-2 exposed cohort",
        "key_reference_title": "The impact of the COVID-19 pandemic on infant and toddler development.",
        "key_reference_abstract": "## BACKGROUND\nThe COVID-19 pandemic has created new cultural norms with pervasive societal implications. Families have experienced a heightened amount of physical, psychological, emotional, and financial stress. Infants and children living with stress have the potential for delayed developmental milestones, difficulty with emotional regulation, and social or behavioral issues.\n## PURPOSE\nThis study aims to determine if the pandemic has affected developmental outcomes in infants and toddlers.\n## METHODOLOGY\nPrepandemic and postpandemic developmental (ASQ-3) scores were obtained from charts of 1,024 patients (6, 12, 18, 24, and 36 months) from two pediatric practices.\n## RESULTS\nThere were no significant differences in prepandemic and postpandemic ASQ-3 scores for the overall sample. Age-group analysis showed statistically significant differences in domain scores. Postpandemic problem-solving scores decreased among 6-month-olds while increasing among 24-month-olds. Categorization by score interpretation categories showed a slight decrease in postpandemic scores in the communication domain among 6- and 12-month-olds.\n## CONCLUSIONS\nThe pandemic has the potential to affect childhood development. However, the results of this study are reassuring, showing only slight differences in developmental scores prepandemic versus postpandemic. More studies are needed to establish causation and possible trends in future developmental trajectories.\n## IMPLICATIONS\nAn increased focus on communication screening and promotion of language and communication skills in young children postpandemic is needed. Education about the importance of parent-child engagement, nurturing relationships, opportunities for free-play and exploration, and caregiver support and stress reduction will continue to be of paramount importance.",
        "truth": "False"
    },
    {
        "pmid": "36306133",
        "meta_analysis_title": "COVID-19 Pandemic and Infant Neurodevelopmental Impairment: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Are neurodevelopmental outcomes during infancy changed by the COVID-19 pandemic?",
        "criteria": "A total of 1880 articles were retrieved. Of these, 670 articles were excluded as duplicates, and the remaining 1210 studies were screened for eligibility. Screening of the title and abstract resulted in 21 potentially eligible studies. Following full-text assessment, 8 studies met the inclusion criteria defined earlier (Figure 1).",
        "subgroup": "Prevalence of Risk for Neurodevelopmental Impairment (NDI) Among Infants Screened During the Pandemic, In Utero SARS-CoV-2\u2013Exposed Cohort, and In Utero SARS-CoV-2\u2013Unexposed Cohort - In utero SARS-CoV-2 exposed cohort",
        "key_reference_title": "Association Between the COVID-19 Pandemic and Infant Neurodevelopment: A Comparison Before and During COVID-19.",
        "key_reference_abstract": "None",
        "truth": "False"
    },
    {
        "pmid": "36306133",
        "meta_analysis_title": "COVID-19 Pandemic and Infant Neurodevelopmental Impairment: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Are neurodevelopmental outcomes during infancy changed by the COVID-19 pandemic?",
        "criteria": "A total of 1880 articles were retrieved. Of these, 670 articles were excluded as duplicates, and the remaining 1210 studies were screened for eligibility. Screening of the title and abstract resulted in 21 potentially eligible studies. Following full-text assessment, 8 studies met the inclusion criteria defined earlier (Figure 1).",
        "subgroup": "Prevalence of Risk for Neurodevelopmental Impairment (NDI) Among Infants Screened During the Pandemic, In Utero SARS-CoV-2\u2013Exposed Cohort, and In Utero SARS-CoV-2\u2013Unexposed Cohort - In utero SARS-CoV-2 exposed cohort",
        "key_reference_title": "Impact of SARS-CoV-2 Infection During Pregnancy on Infant Neurobehavioral Development: A Case-Control Study.",
        "key_reference_abstract": "Background: Previous studies on the pneumonia outbreak caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have focused on the general population and pregnant women, while little is known about the effects of SARS-CoV-2 on retardation during and after pregnancy. The purpose of this study was to evaluate the potential influence of SARS-CoV-2 on infant neurobehavioral development. Methods: A case-control study was conducted in Wuhan Maternal and Child Health Hospital, China. Nine pregnant women with SARS-CoV-2 infection and 9 controls matched by maternal age, parity, and status of chronic disease were included. Infantile neurobehavioral development was assessed through the Ages and Stages Questionnaires Edition 3 (ASQ-3). Results: The majority of pregnant women with SARS-CoV-2 experienced cesarean section (7 of 9), which was higher than the control group (5 of 9). The throat swabs of all newborn were negative. We found that compared with the control group, neonates of mothers with SARS-CoV-2 infection during pregnancy had lower scores in communication, gross movement, fine movement, problem solving, and personal-social domains; but only fine movement domain yielded statistical significance (P = 0.031). Conclusion: Infection with SARS-CoV-2 during pregnancy may have a certain impact on infant neurobehavioral development. Further studies with larger sample size are warranted for validation.",
        "truth": "False"
    },
    {
        "pmid": "36306133",
        "meta_analysis_title": "COVID-19 Pandemic and Infant Neurodevelopmental Impairment: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Are neurodevelopmental outcomes during infancy changed by the COVID-19 pandemic?",
        "criteria": "A total of 1880 articles were retrieved. Of these, 670 articles were excluded as duplicates, and the remaining 1210 studies were screened for eligibility. Screening of the title and abstract resulted in 21 potentially eligible studies. Following full-text assessment, 8 studies met the inclusion criteria defined earlier (Figure 1).",
        "subgroup": "Prevalence of Risk for Neurodevelopmental Impairment (NDI) Among Infants Screened During the Pandemic, In Utero SARS-CoV-2\u2013Exposed Cohort, and In Utero SARS-CoV-2\u2013Unexposed Cohort - In utero SARS-CoV-2 exposed cohort",
        "key_reference_title": "Increased risk for developmental delay among babies born during the pandemic.",
        "key_reference_abstract": "The COVID-19 pandemic has resulted in substantial and widespread changes to many prenatal (e.g., maternal stress) and postnatal (e.g., socialization) factors contributing to early child development. We compared developmental screening of 1-year old infants born between April 17, 2020-November 11, 2020 to data from infants born pre-pandemic. We aimed to determine whether risk for developmental delay was elevated among infants born during the pandemic compared to infants born prior to the pandemic. Data were available from 1623 PdP participants. PdP infants had lower mean scores relative to pooled pre-pandemic data on all domains except Problem Solving. PdP infants also had significantly higher risk for developmental delay in the Communication and Personal-Social domains, where the odds ratios for scoring 2 SD below the mean were 2.5 and 1.5, respectively, relative to pre-pandemic data. When stratified by sex, the odds ratios for risk of developmental delay were generally higher among female infants. In conclusions, risks for developmental delay in the Communication and Personal-Social domains were elevated in infants born during the COVID-19 pandemic compared to pre-pandemic infants, especially among girls.",
        "truth": "False"
    },
    {
        "pmid": "36306133",
        "meta_analysis_title": "COVID-19 Pandemic and Infant Neurodevelopmental Impairment: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Are neurodevelopmental outcomes during infancy changed by the COVID-19 pandemic?",
        "criteria": "A total of 1880 articles were retrieved. Of these, 670 articles were excluded as duplicates, and the remaining 1210 studies were screened for eligibility. Screening of the title and abstract resulted in 21 potentially eligible studies. Following full-text assessment, 8 studies met the inclusion criteria defined earlier (Figure 1).",
        "subgroup": "Prevalence of Risk for Neurodevelopmental Impairment (NDI) Among Infants Screened During the Pandemic, In Utero SARS-CoV-2\u2013Exposed Cohort, and In Utero SARS-CoV-2\u2013Unexposed Cohort - In utero SARS-CoV-2 exposed cohort",
        "key_reference_title": "Neurodevelopmental outcomes of infants secondary to in utero exposure to maternal 2 SARS-CoV-2 infection: A national prospective study in Kuwait.",
        "key_reference_abstract": "## Background\nAn increasing proportion of women are being infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) during pregnancy. Intrauterine viral infections induce an increase in the levels of proinflammatory cytokines, which inhibit the proliferation of neuronal precursor cells and stimulate oligodendrocyte cell death, leading to abnormal neurodevelopment. Whether a maternal cytokine storm can affect neonatal brain development is unclear. The objective of the present study is to assess neurodevelopmental outcomes in neonates born to mothers with SARS-CoV-2 infections during pregnancy. ## Methods\nIn this prospective cohort study, the neurodevelopment status of infants (N=298) born to women with SARS-CoV-2 infections during pregnancy was assessed at 10-12 months post discharge using the Ages and Stages Questionnaire, 3rd edition (ASQ-3). The ASQ-3 scores were classified into developmental delays (cutoff score: \u22642 standard deviations (SDs) below the population mean) and no delay (score >2 SDs above the population mean). ## Results\nApproximately 10% of infants born to mothers with SARS-CoV-2 infections during pregnancy showed developmental delays. Two of 298 infants tested positive for SARS-CoV-2, and both had normal ASQ-3 scores. The majority of the pregnant women had SARS-CoV-2 infection during their third trimester. The risk of developmental delays among infants was higher in those whose mothers had SARS-CoV-2 infections during the first (P=0.039) and second trimesters (P=0.001) than in those whose mothers had SARS-CoV-2 infections during the third trimester. Infants born at <31 weeks gestation were more prone to developmental delays than those born at >31 weeks gestation (10% versus 0.8%; P=0.002). ## Conclusion\nThe findings of the study highlight the need for long term neurodevelopmental assessment of infants born to mothers with SARS-CoV-2 infection.",
        "truth": "True"
    },
    {
        "pmid": "36306133",
        "meta_analysis_title": "COVID-19 Pandemic and Infant Neurodevelopmental Impairment: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Are neurodevelopmental outcomes during infancy changed by the COVID-19 pandemic?",
        "criteria": "A total of 1880 articles were retrieved. Of these, 670 articles were excluded as duplicates, and the remaining 1210 studies were screened for eligibility. Screening of the title and abstract resulted in 21 potentially eligible studies. Following full-text assessment, 8 studies met the inclusion criteria defined earlier (Figure 1).",
        "subgroup": "Prevalence of Risk for Neurodevelopmental Impairment (NDI) Among Infants Screened During the Pandemic, In Utero SARS-CoV-2\u2013Exposed Cohort, and In Utero SARS-CoV-2\u2013Unexposed Cohort - In utero SARS-CoV-2 exposed cohort",
        "key_reference_title": "Neurodevelopmental outcomes at one year in offspring of mothers who test positive for SARS-CoV-2 during pregnancy.",
        "key_reference_abstract": "## Importance\nEpidemiologic studies suggest maternal immune activation during pregnancy may be associated with neurodevelopmental effects in offspring. \n## Objective\nTo determine whether in utero exposure to the novel coronavirus SARS-CoV-2 is associated with risk for neurodevelopmental disorders in the first 12 months after birth. \n## Design\nRetrospective cohort\n## Participants\nLive offspring of all mothers who delivered between March and September 2020 at one of six Massachusetts hospitals across two health systems. \n## Exposure\nSARS-CoV-2 infection confirmed by PCR during pregnancy \n## Main Outcome and Measures\nNeurodevelopmental disorders determined from ICD-10 diagnostic codes over 12 months; sociodemographic and clinical features of mothers and offspring; all drawn from the electronic health record. \n## Results\nThe cohort included 7,772 live births (7,466 pregnancies, 96% singleton, 222 births to SARS-CoV-2 positive mothers), with mean maternal age of 32.9 years; offspring were 9.9% Asian, 8.4% Black, and 69.0% white; 15.1% were of Hispanic ethnicity. Preterm delivery was more likely among exposed mothers (14% versus 8.7%; p=.003). Maternal SARS-CoV-2 positivity during pregnancy was associated with greater rate of neurodevelopmental diagnoses (crude OR 2.17 [95% CI 1.24-3.79, p=0.006]) as well as models adjusted for race, ethnicity, insurance status, offspring sex, maternal age, and preterm status (adjusted OR 1.86 [95% CI 1.03-3.36, p=0.04]). Third-trimester infection was associated with effects of larger magnitude (adjusted OR 2.34, 95% CI 1.23-4.44, p=0.01) \n## Conclusion and Relevance\nOur results provide preliminary evidence that maternal SARS-CoV-2 may be associated with neurodevelopmental sequelae in some offspring. Prospective studies with longer follow-up duration will be required to exclude confounding and confirm these effects.\n## Trial Registration\nNA## Key Points\n## Question\nDoes COVID-19 exposure in utero increase the risk for neurodevelopmental disorders in the first year of life? ## Findings\nIn a cohort of babies delivered during COVID-19, those born to mothers with a positive SARS-CoV-2 PCR test during pregnancy were more likely to receive a neurodevelopmental diagnosis in the first 12 months after delivery, even after accounting for preterm delivery. ## Meaning\nThese preliminary findings suggest that COVID-19 exposure may impact neurodevelopment, and highlight the need for prospective investigation of outcomes in children exposed to COVID-19 in utero.",
        "truth": "True"
    },
    {
        "pmid": "36306133",
        "meta_analysis_title": "COVID-19 Pandemic and Infant Neurodevelopmental Impairment: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Are neurodevelopmental outcomes during infancy changed by the COVID-19 pandemic?",
        "criteria": "A total of 1880 articles were retrieved. Of these, 670 articles were excluded as duplicates, and the remaining 1210 studies were screened for eligibility. Screening of the title and abstract resulted in 21 potentially eligible studies. Following full-text assessment, 8 studies met the inclusion criteria defined earlier (Figure 1).",
        "subgroup": "Prevalence of Risk for Neurodevelopmental Impairment (NDI) Among Infants Screened During the Pandemic, In Utero SARS-CoV-2\u2013Exposed Cohort, and In Utero SARS-CoV-2\u2013Unexposed Cohort - In utero SARS-CoV-2 unexposed cohort",
        "key_reference_title": "Association of Birth During the COVID-19 Pandemic With Neurodevelopmental Status at 6 Months in Infants With and Without In Utero Exposure to Maternal SARS-CoV-2 Infection.",
        "key_reference_abstract": "## IMPORTANCE\nAssociations between in utero exposure to maternal SARS-CoV-2 infection and neurodevelopment are speculated, but currently unknown.\n## OBJECTIVE\nTo examine the associations between maternal SARS-CoV-2 infection during pregnancy, being born during the COVID-19 pandemic regardless of maternal SARS-CoV-2 status, and neurodevelopment at age 6 months.\n## DESIGN, SETTING, AND PARTICIPANTS\nA cohort of infants exposed to maternal SARS-CoV-2 infection during pregnancy and unexposed controls was enrolled in the COVID-19 Mother Baby Outcomes Initiative at Columbia University Irving Medical Center in New York City. All women who delivered at Columbia University Irving Medical Center with a SARS-CoV-2 infection during pregnancy were approached. Women with unexposed infants were approached based on similar gestational age at birth, date of birth, sex, and mode of delivery. Neurodevelopment was assessed using the Ages & Stages Questionnaire, 3rd Edition (ASQ-3) at age 6 months. A historical cohort of infants born before the pandemic who had completed the 6-month ASQ-3 were included in secondary analyses.\n## EXPOSURES\nMaternal SARS-CoV-2 infection during pregnancy and birth during the COVID-19 pandemic.\n## MAIN OUTCOMES AND MEASURES\nOutcomes were scores on the 5 ASQ-3 subdomains, with the hypothesis that maternal SARS-CoV-2 infection during pregnancy would be associated with decrements in social and motor development at age 6 months.\n## RESULTS\nOf 1706 women approached, 596 enrolled; 385 women were invited to a 6-month assessment, of whom 272 (70.6%) completed the ASQ-3. Data were available for 255 infants enrolled in the COVID-19 Mother Baby Outcomes Initiative (114 in utero exposed, 141 unexposed to SARS-CoV-2; median maternal age at delivery, 32.0 [IQR, 19.0-45.0] years). Data were also available from a historical cohort of 62 infants born before the pandemic. In utero exposure to maternal SARS-CoV-2 infection was not associated with significant differences on any ASQ-3 subdomain, regardless of infection timing or severity. However, compared with the historical cohort, infants born during the pandemic had significantly lower scores on gross motor (mean difference, -5.63; 95% CI, -8.75 to -2.51; F1,267\u2009=\u200912.63; P<.005), fine motor (mean difference, -6.61; 95% CI, -10.00 to -3.21; F1,267\u2009=\u200914.71; P\u2009<\u2009.005), and personal-social (mean difference, -3.71; 95% CI, -6.61 to -0.82; F1,267\u2009=\u20096.37; P<.05) subdomains in fully adjusted models.\n## CONCLUSIONS AND RELEVANCE\nIn this study, birth during the pandemic, but not in utero exposure to maternal SARS-CoV-2 infection, was associated with differences in neurodevelopment at age 6 months. These early findings support the need for long-term monitoring of children born during the COVID-19 pandemic.",
        "truth": "True"
    },
    {
        "pmid": "36306133",
        "meta_analysis_title": "COVID-19 Pandemic and Infant Neurodevelopmental Impairment: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Are neurodevelopmental outcomes during infancy changed by the COVID-19 pandemic?",
        "criteria": "A total of 1880 articles were retrieved. Of these, 670 articles were excluded as duplicates, and the remaining 1210 studies were screened for eligibility. Screening of the title and abstract resulted in 21 potentially eligible studies. Following full-text assessment, 8 studies met the inclusion criteria defined earlier (Figure 1).",
        "subgroup": "Prevalence of Risk for Neurodevelopmental Impairment (NDI) Among Infants Screened During the Pandemic, In Utero SARS-CoV-2\u2013Exposed Cohort, and In Utero SARS-CoV-2\u2013Unexposed Cohort - In utero SARS-CoV-2 unexposed cohort",
        "key_reference_title": "Effects of SARS-CoV-2 Infection During Late Pregnancy on Early Childhood Development: A Prospective Cohort Study.",
        "key_reference_abstract": "Background: There is little direct or indirect evidence of the effects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection during pregnancy on early childhood development. Methods: We conducted a prospective, observational cohort study in China from May 1 to October 31, 2020, that enrolled 135 mother-infant dyads: 57 dyads in the infection cohort and 78 in the non-infection cohort. Among all infants, 14.0% were preterm birth in the infection cohort and 6.4% in the non-infection cohort. Participants were followed by telephone interviews to collect demographic characteristics, medical records of coronavirus disease 2019, breastfeeding data, and early childhood development was assessed by the Age and Stage Questionnaire (ASQ-3) and Age and Stage Questionnaire Social-Emotional (ASQ:SE-2) Chinese versions at 3 months after childbirth. We used multivariable Poisson regression models to estimate the relative risk (RR) of SARS-CoV-2 infection. Multivariable linear regression models and a mediation model were used to test the direct and indirect associations between SARS-CoV-2 infection and the ASQ-3 score. This study was approved by the Peking University Third Hospital Medical Science Research Ethics Committee (No. IRB00006761-M2020127). Results: In the infection cohort, 13.6% of the children showed social-emotional developmental delay, and 13.5% showed overall developmental delay. The corresponding rates in the non-infection cohort were 23.4 and 8.1%. Compared with the non-infection cohort, SARS-CoV-2 infection during pregnancy did not increase the risk of social-emotional (RR = 0.87, 95% CI: 0.51-1.49) or overall (RR = 1.02, 95% CI: 0.60-1.73) developmental delay. The mediation model showed that SARS-CoV-2 infection indirectly affected the ASQ-3 score by increasing the length of mother-infant separation. Conclusions: SARS-CoV-2 during late pregnancy did not increase the risk of developmental delay of the offspring 3 months after delivery. However, SARS-CoV-2 may have indirect effects on early childhood development by increasing mother-infant separation.",
        "truth": "True"
    },
    {
        "pmid": "36306133",
        "meta_analysis_title": "COVID-19 Pandemic and Infant Neurodevelopmental Impairment: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Are neurodevelopmental outcomes during infancy changed by the COVID-19 pandemic?",
        "criteria": "A total of 1880 articles were retrieved. Of these, 670 articles were excluded as duplicates, and the remaining 1210 studies were screened for eligibility. Screening of the title and abstract resulted in 21 potentially eligible studies. Following full-text assessment, 8 studies met the inclusion criteria defined earlier (Figure 1).",
        "subgroup": "Prevalence of Risk for Neurodevelopmental Impairment (NDI) Among Infants Screened During the Pandemic, In Utero SARS-CoV-2\u2013Exposed Cohort, and In Utero SARS-CoV-2\u2013Unexposed Cohort - In utero SARS-CoV-2 unexposed cohort",
        "key_reference_title": "The impact of the COVID-19 pandemic on infant and toddler development.",
        "key_reference_abstract": "## BACKGROUND\nThe COVID-19 pandemic has created new cultural norms with pervasive societal implications. Families have experienced a heightened amount of physical, psychological, emotional, and financial stress. Infants and children living with stress have the potential for delayed developmental milestones, difficulty with emotional regulation, and social or behavioral issues.\n## PURPOSE\nThis study aims to determine if the pandemic has affected developmental outcomes in infants and toddlers.\n## METHODOLOGY\nPrepandemic and postpandemic developmental (ASQ-3) scores were obtained from charts of 1,024 patients (6, 12, 18, 24, and 36 months) from two pediatric practices.\n## RESULTS\nThere were no significant differences in prepandemic and postpandemic ASQ-3 scores for the overall sample. Age-group analysis showed statistically significant differences in domain scores. Postpandemic problem-solving scores decreased among 6-month-olds while increasing among 24-month-olds. Categorization by score interpretation categories showed a slight decrease in postpandemic scores in the communication domain among 6- and 12-month-olds.\n## CONCLUSIONS\nThe pandemic has the potential to affect childhood development. However, the results of this study are reassuring, showing only slight differences in developmental scores prepandemic versus postpandemic. More studies are needed to establish causation and possible trends in future developmental trajectories.\n## IMPLICATIONS\nAn increased focus on communication screening and promotion of language and communication skills in young children postpandemic is needed. Education about the importance of parent-child engagement, nurturing relationships, opportunities for free-play and exploration, and caregiver support and stress reduction will continue to be of paramount importance.",
        "truth": "False"
    },
    {
        "pmid": "36306133",
        "meta_analysis_title": "COVID-19 Pandemic and Infant Neurodevelopmental Impairment: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Are neurodevelopmental outcomes during infancy changed by the COVID-19 pandemic?",
        "criteria": "A total of 1880 articles were retrieved. Of these, 670 articles were excluded as duplicates, and the remaining 1210 studies were screened for eligibility. Screening of the title and abstract resulted in 21 potentially eligible studies. Following full-text assessment, 8 studies met the inclusion criteria defined earlier (Figure 1).",
        "subgroup": "Prevalence of Risk for Neurodevelopmental Impairment (NDI) Among Infants Screened During the Pandemic, In Utero SARS-CoV-2\u2013Exposed Cohort, and In Utero SARS-CoV-2\u2013Unexposed Cohort - In utero SARS-CoV-2 unexposed cohort",
        "key_reference_title": "Association Between the COVID-19 Pandemic and Infant Neurodevelopment: A Comparison Before and During COVID-19.",
        "key_reference_abstract": "None",
        "truth": "False"
    },
    {
        "pmid": "36306133",
        "meta_analysis_title": "COVID-19 Pandemic and Infant Neurodevelopmental Impairment: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Are neurodevelopmental outcomes during infancy changed by the COVID-19 pandemic?",
        "criteria": "A total of 1880 articles were retrieved. Of these, 670 articles were excluded as duplicates, and the remaining 1210 studies were screened for eligibility. Screening of the title and abstract resulted in 21 potentially eligible studies. Following full-text assessment, 8 studies met the inclusion criteria defined earlier (Figure 1).",
        "subgroup": "Prevalence of Risk for Neurodevelopmental Impairment (NDI) Among Infants Screened During the Pandemic, In Utero SARS-CoV-2\u2013Exposed Cohort, and In Utero SARS-CoV-2\u2013Unexposed Cohort - In utero SARS-CoV-2 unexposed cohort",
        "key_reference_title": "Impact of SARS-CoV-2 Infection During Pregnancy on Infant Neurobehavioral Development: A Case-Control Study.",
        "key_reference_abstract": "Background: Previous studies on the pneumonia outbreak caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have focused on the general population and pregnant women, while little is known about the effects of SARS-CoV-2 on retardation during and after pregnancy. The purpose of this study was to evaluate the potential influence of SARS-CoV-2 on infant neurobehavioral development. Methods: A case-control study was conducted in Wuhan Maternal and Child Health Hospital, China. Nine pregnant women with SARS-CoV-2 infection and 9 controls matched by maternal age, parity, and status of chronic disease were included. Infantile neurobehavioral development was assessed through the Ages and Stages Questionnaires Edition 3 (ASQ-3). Results: The majority of pregnant women with SARS-CoV-2 experienced cesarean section (7 of 9), which was higher than the control group (5 of 9). The throat swabs of all newborn were negative. We found that compared with the control group, neonates of mothers with SARS-CoV-2 infection during pregnancy had lower scores in communication, gross movement, fine movement, problem solving, and personal-social domains; but only fine movement domain yielded statistical significance (P = 0.031). Conclusion: Infection with SARS-CoV-2 during pregnancy may have a certain impact on infant neurobehavioral development. Further studies with larger sample size are warranted for validation.",
        "truth": "False"
    },
    {
        "pmid": "36306133",
        "meta_analysis_title": "COVID-19 Pandemic and Infant Neurodevelopmental Impairment: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Are neurodevelopmental outcomes during infancy changed by the COVID-19 pandemic?",
        "criteria": "A total of 1880 articles were retrieved. Of these, 670 articles were excluded as duplicates, and the remaining 1210 studies were screened for eligibility. Screening of the title and abstract resulted in 21 potentially eligible studies. Following full-text assessment, 8 studies met the inclusion criteria defined earlier (Figure 1).",
        "subgroup": "Prevalence of Risk for Neurodevelopmental Impairment (NDI) Among Infants Screened During the Pandemic, In Utero SARS-CoV-2\u2013Exposed Cohort, and In Utero SARS-CoV-2\u2013Unexposed Cohort - In utero SARS-CoV-2 unexposed cohort",
        "key_reference_title": "Increased risk for developmental delay among babies born during the pandemic.",
        "key_reference_abstract": "The COVID-19 pandemic has resulted in substantial and widespread changes to many prenatal (e.g., maternal stress) and postnatal (e.g., socialization) factors contributing to early child development. We compared developmental screening of 1-year old infants born between April 17, 2020-November 11, 2020 to data from infants born pre-pandemic. We aimed to determine whether risk for developmental delay was elevated among infants born during the pandemic compared to infants born prior to the pandemic. Data were available from 1623 PdP participants. PdP infants had lower mean scores relative to pooled pre-pandemic data on all domains except Problem Solving. PdP infants also had significantly higher risk for developmental delay in the Communication and Personal-Social domains, where the odds ratios for scoring 2 SD below the mean were 2.5 and 1.5, respectively, relative to pre-pandemic data. When stratified by sex, the odds ratios for risk of developmental delay were generally higher among female infants. In conclusions, risks for developmental delay in the Communication and Personal-Social domains were elevated in infants born during the COVID-19 pandemic compared to pre-pandemic infants, especially among girls.",
        "truth": "False"
    },
    {
        "pmid": "36306133",
        "meta_analysis_title": "COVID-19 Pandemic and Infant Neurodevelopmental Impairment: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Are neurodevelopmental outcomes during infancy changed by the COVID-19 pandemic?",
        "criteria": "A total of 1880 articles were retrieved. Of these, 670 articles were excluded as duplicates, and the remaining 1210 studies were screened for eligibility. Screening of the title and abstract resulted in 21 potentially eligible studies. Following full-text assessment, 8 studies met the inclusion criteria defined earlier (Figure 1).",
        "subgroup": "Prevalence of Risk for Neurodevelopmental Impairment (NDI) Among Infants Screened During the Pandemic, In Utero SARS-CoV-2\u2013Exposed Cohort, and In Utero SARS-CoV-2\u2013Unexposed Cohort - In utero SARS-CoV-2 unexposed cohort",
        "key_reference_title": "Neurodevelopmental outcomes of infants secondary to in utero exposure to maternal 2 SARS-CoV-2 infection: A national prospective study in Kuwait.",
        "key_reference_abstract": "## Background\nAn increasing proportion of women are being infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) during pregnancy. Intrauterine viral infections induce an increase in the levels of proinflammatory cytokines, which inhibit the proliferation of neuronal precursor cells and stimulate oligodendrocyte cell death, leading to abnormal neurodevelopment. Whether a maternal cytokine storm can affect neonatal brain development is unclear. The objective of the present study is to assess neurodevelopmental outcomes in neonates born to mothers with SARS-CoV-2 infections during pregnancy. ## Methods\nIn this prospective cohort study, the neurodevelopment status of infants (N=298) born to women with SARS-CoV-2 infections during pregnancy was assessed at 10-12 months post discharge using the Ages and Stages Questionnaire, 3rd edition (ASQ-3). The ASQ-3 scores were classified into developmental delays (cutoff score: \u22642 standard deviations (SDs) below the population mean) and no delay (score >2 SDs above the population mean). ## Results\nApproximately 10% of infants born to mothers with SARS-CoV-2 infections during pregnancy showed developmental delays. Two of 298 infants tested positive for SARS-CoV-2, and both had normal ASQ-3 scores. The majority of the pregnant women had SARS-CoV-2 infection during their third trimester. The risk of developmental delays among infants was higher in those whose mothers had SARS-CoV-2 infections during the first (P=0.039) and second trimesters (P=0.001) than in those whose mothers had SARS-CoV-2 infections during the third trimester. Infants born at <31 weeks gestation were more prone to developmental delays than those born at >31 weeks gestation (10% versus 0.8%; P=0.002). ## Conclusion\nThe findings of the study highlight the need for long term neurodevelopmental assessment of infants born to mothers with SARS-CoV-2 infection.",
        "truth": "False"
    },
    {
        "pmid": "36306133",
        "meta_analysis_title": "COVID-19 Pandemic and Infant Neurodevelopmental Impairment: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Are neurodevelopmental outcomes during infancy changed by the COVID-19 pandemic?",
        "criteria": "A total of 1880 articles were retrieved. Of these, 670 articles were excluded as duplicates, and the remaining 1210 studies were screened for eligibility. Screening of the title and abstract resulted in 21 potentially eligible studies. Following full-text assessment, 8 studies met the inclusion criteria defined earlier (Figure 1).",
        "subgroup": "Prevalence of Risk for Neurodevelopmental Impairment (NDI) Among Infants Screened During the Pandemic, In Utero SARS-CoV-2\u2013Exposed Cohort, and In Utero SARS-CoV-2\u2013Unexposed Cohort - In utero SARS-CoV-2 unexposed cohort",
        "key_reference_title": "Neurodevelopmental outcomes at one year in offspring of mothers who test positive for SARS-CoV-2 during pregnancy.",
        "key_reference_abstract": "## Importance\nEpidemiologic studies suggest maternal immune activation during pregnancy may be associated with neurodevelopmental effects in offspring. \n## Objective\nTo determine whether in utero exposure to the novel coronavirus SARS-CoV-2 is associated with risk for neurodevelopmental disorders in the first 12 months after birth. \n## Design\nRetrospective cohort\n## Participants\nLive offspring of all mothers who delivered between March and September 2020 at one of six Massachusetts hospitals across two health systems. \n## Exposure\nSARS-CoV-2 infection confirmed by PCR during pregnancy \n## Main Outcome and Measures\nNeurodevelopmental disorders determined from ICD-10 diagnostic codes over 12 months; sociodemographic and clinical features of mothers and offspring; all drawn from the electronic health record. \n## Results\nThe cohort included 7,772 live births (7,466 pregnancies, 96% singleton, 222 births to SARS-CoV-2 positive mothers), with mean maternal age of 32.9 years; offspring were 9.9% Asian, 8.4% Black, and 69.0% white; 15.1% were of Hispanic ethnicity. Preterm delivery was more likely among exposed mothers (14% versus 8.7%; p=.003). Maternal SARS-CoV-2 positivity during pregnancy was associated with greater rate of neurodevelopmental diagnoses (crude OR 2.17 [95% CI 1.24-3.79, p=0.006]) as well as models adjusted for race, ethnicity, insurance status, offspring sex, maternal age, and preterm status (adjusted OR 1.86 [95% CI 1.03-3.36, p=0.04]). Third-trimester infection was associated with effects of larger magnitude (adjusted OR 2.34, 95% CI 1.23-4.44, p=0.01) \n## Conclusion and Relevance\nOur results provide preliminary evidence that maternal SARS-CoV-2 may be associated with neurodevelopmental sequelae in some offspring. Prospective studies with longer follow-up duration will be required to exclude confounding and confirm these effects.\n## Trial Registration\nNA## Key Points\n## Question\nDoes COVID-19 exposure in utero increase the risk for neurodevelopmental disorders in the first year of life? ## Findings\nIn a cohort of babies delivered during COVID-19, those born to mothers with a positive SARS-CoV-2 PCR test during pregnancy were more likely to receive a neurodevelopmental diagnosis in the first 12 months after delivery, even after accounting for preterm delivery. ## Meaning\nThese preliminary findings suggest that COVID-19 exposure may impact neurodevelopment, and highlight the need for prospective investigation of outcomes in children exposed to COVID-19 in utero.",
        "truth": "True"
    },
    {
        "pmid": "36306133",
        "meta_analysis_title": "COVID-19 Pandemic and Infant Neurodevelopmental Impairment: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Are neurodevelopmental outcomes during infancy changed by the COVID-19 pandemic?",
        "criteria": "A total of 1880 articles were retrieved. Of these, 670 articles were excluded as duplicates, and the remaining 1210 studies were screened for eligibility. Screening of the title and abstract resulted in 21 potentially eligible studies. Following full-text assessment, 8 studies met the inclusion criteria defined earlier (Figure 1).",
        "subgroup": "Meta-analysis of Overall Risk of Neurodevelopmental Impairment and Gross Motor, Fine Motor, and Personal-Social Domains Among Infants Screened During Pandemic vs Before Pandemic - Overall risk of NDI",
        "key_reference_title": "Association of Birth During the COVID-19 Pandemic With Neurodevelopmental Status at 6 Months in Infants With and Without In Utero Exposure to Maternal SARS-CoV-2 Infection.",
        "key_reference_abstract": "## IMPORTANCE\nAssociations between in utero exposure to maternal SARS-CoV-2 infection and neurodevelopment are speculated, but currently unknown.\n## OBJECTIVE\nTo examine the associations between maternal SARS-CoV-2 infection during pregnancy, being born during the COVID-19 pandemic regardless of maternal SARS-CoV-2 status, and neurodevelopment at age 6 months.\n## DESIGN, SETTING, AND PARTICIPANTS\nA cohort of infants exposed to maternal SARS-CoV-2 infection during pregnancy and unexposed controls was enrolled in the COVID-19 Mother Baby Outcomes Initiative at Columbia University Irving Medical Center in New York City. All women who delivered at Columbia University Irving Medical Center with a SARS-CoV-2 infection during pregnancy were approached. Women with unexposed infants were approached based on similar gestational age at birth, date of birth, sex, and mode of delivery. Neurodevelopment was assessed using the Ages & Stages Questionnaire, 3rd Edition (ASQ-3) at age 6 months. A historical cohort of infants born before the pandemic who had completed the 6-month ASQ-3 were included in secondary analyses.\n## EXPOSURES\nMaternal SARS-CoV-2 infection during pregnancy and birth during the COVID-19 pandemic.\n## MAIN OUTCOMES AND MEASURES\nOutcomes were scores on the 5 ASQ-3 subdomains, with the hypothesis that maternal SARS-CoV-2 infection during pregnancy would be associated with decrements in social and motor development at age 6 months.\n## RESULTS\nOf 1706 women approached, 596 enrolled; 385 women were invited to a 6-month assessment, of whom 272 (70.6%) completed the ASQ-3. Data were available for 255 infants enrolled in the COVID-19 Mother Baby Outcomes Initiative (114 in utero exposed, 141 unexposed to SARS-CoV-2; median maternal age at delivery, 32.0 [IQR, 19.0-45.0] years). Data were also available from a historical cohort of 62 infants born before the pandemic. In utero exposure to maternal SARS-CoV-2 infection was not associated with significant differences on any ASQ-3 subdomain, regardless of infection timing or severity. However, compared with the historical cohort, infants born during the pandemic had significantly lower scores on gross motor (mean difference, -5.63; 95% CI, -8.75 to -2.51; F1,267\u2009=\u200912.63; P<.005), fine motor (mean difference, -6.61; 95% CI, -10.00 to -3.21; F1,267\u2009=\u200914.71; P\u2009<\u2009.005), and personal-social (mean difference, -3.71; 95% CI, -6.61 to -0.82; F1,267\u2009=\u20096.37; P<.05) subdomains in fully adjusted models.\n## CONCLUSIONS AND RELEVANCE\nIn this study, birth during the pandemic, but not in utero exposure to maternal SARS-CoV-2 infection, was associated with differences in neurodevelopment at age 6 months. These early findings support the need for long-term monitoring of children born during the COVID-19 pandemic.",
        "truth": "True"
    },
    {
        "pmid": "36306133",
        "meta_analysis_title": "COVID-19 Pandemic and Infant Neurodevelopmental Impairment: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Are neurodevelopmental outcomes during infancy changed by the COVID-19 pandemic?",
        "criteria": "A total of 1880 articles were retrieved. Of these, 670 articles were excluded as duplicates, and the remaining 1210 studies were screened for eligibility. Screening of the title and abstract resulted in 21 potentially eligible studies. Following full-text assessment, 8 studies met the inclusion criteria defined earlier (Figure 1).",
        "subgroup": "Meta-analysis of Overall Risk of Neurodevelopmental Impairment and Gross Motor, Fine Motor, and Personal-Social Domains Among Infants Screened During Pandemic vs Before Pandemic - Overall risk of NDI",
        "key_reference_title": "Effects of SARS-CoV-2 Infection During Late Pregnancy on Early Childhood Development: A Prospective Cohort Study.",
        "key_reference_abstract": "Background: There is little direct or indirect evidence of the effects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection during pregnancy on early childhood development. Methods: We conducted a prospective, observational cohort study in China from May 1 to October 31, 2020, that enrolled 135 mother-infant dyads: 57 dyads in the infection cohort and 78 in the non-infection cohort. Among all infants, 14.0% were preterm birth in the infection cohort and 6.4% in the non-infection cohort. Participants were followed by telephone interviews to collect demographic characteristics, medical records of coronavirus disease 2019, breastfeeding data, and early childhood development was assessed by the Age and Stage Questionnaire (ASQ-3) and Age and Stage Questionnaire Social-Emotional (ASQ:SE-2) Chinese versions at 3 months after childbirth. We used multivariable Poisson regression models to estimate the relative risk (RR) of SARS-CoV-2 infection. Multivariable linear regression models and a mediation model were used to test the direct and indirect associations between SARS-CoV-2 infection and the ASQ-3 score. This study was approved by the Peking University Third Hospital Medical Science Research Ethics Committee (No. IRB00006761-M2020127). Results: In the infection cohort, 13.6% of the children showed social-emotional developmental delay, and 13.5% showed overall developmental delay. The corresponding rates in the non-infection cohort were 23.4 and 8.1%. Compared with the non-infection cohort, SARS-CoV-2 infection during pregnancy did not increase the risk of social-emotional (RR = 0.87, 95% CI: 0.51-1.49) or overall (RR = 1.02, 95% CI: 0.60-1.73) developmental delay. The mediation model showed that SARS-CoV-2 infection indirectly affected the ASQ-3 score by increasing the length of mother-infant separation. Conclusions: SARS-CoV-2 during late pregnancy did not increase the risk of developmental delay of the offspring 3 months after delivery. However, SARS-CoV-2 may have indirect effects on early childhood development by increasing mother-infant separation.",
        "truth": "False"
    },
    {
        "pmid": "36306133",
        "meta_analysis_title": "COVID-19 Pandemic and Infant Neurodevelopmental Impairment: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Are neurodevelopmental outcomes during infancy changed by the COVID-19 pandemic?",
        "criteria": "A total of 1880 articles were retrieved. Of these, 670 articles were excluded as duplicates, and the remaining 1210 studies were screened for eligibility. Screening of the title and abstract resulted in 21 potentially eligible studies. Following full-text assessment, 8 studies met the inclusion criteria defined earlier (Figure 1).",
        "subgroup": "Meta-analysis of Overall Risk of Neurodevelopmental Impairment and Gross Motor, Fine Motor, and Personal-Social Domains Among Infants Screened During Pandemic vs Before Pandemic - Overall risk of NDI",
        "key_reference_title": "The impact of the COVID-19 pandemic on infant and toddler development.",
        "key_reference_abstract": "## BACKGROUND\nThe COVID-19 pandemic has created new cultural norms with pervasive societal implications. Families have experienced a heightened amount of physical, psychological, emotional, and financial stress. Infants and children living with stress have the potential for delayed developmental milestones, difficulty with emotional regulation, and social or behavioral issues.\n## PURPOSE\nThis study aims to determine if the pandemic has affected developmental outcomes in infants and toddlers.\n## METHODOLOGY\nPrepandemic and postpandemic developmental (ASQ-3) scores were obtained from charts of 1,024 patients (6, 12, 18, 24, and 36 months) from two pediatric practices.\n## RESULTS\nThere were no significant differences in prepandemic and postpandemic ASQ-3 scores for the overall sample. Age-group analysis showed statistically significant differences in domain scores. Postpandemic problem-solving scores decreased among 6-month-olds while increasing among 24-month-olds. Categorization by score interpretation categories showed a slight decrease in postpandemic scores in the communication domain among 6- and 12-month-olds.\n## CONCLUSIONS\nThe pandemic has the potential to affect childhood development. However, the results of this study are reassuring, showing only slight differences in developmental scores prepandemic versus postpandemic. More studies are needed to establish causation and possible trends in future developmental trajectories.\n## IMPLICATIONS\nAn increased focus on communication screening and promotion of language and communication skills in young children postpandemic is needed. Education about the importance of parent-child engagement, nurturing relationships, opportunities for free-play and exploration, and caregiver support and stress reduction will continue to be of paramount importance.",
        "truth": "False"
    },
    {
        "pmid": "36306133",
        "meta_analysis_title": "COVID-19 Pandemic and Infant Neurodevelopmental Impairment: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Are neurodevelopmental outcomes during infancy changed by the COVID-19 pandemic?",
        "criteria": "A total of 1880 articles were retrieved. Of these, 670 articles were excluded as duplicates, and the remaining 1210 studies were screened for eligibility. Screening of the title and abstract resulted in 21 potentially eligible studies. Following full-text assessment, 8 studies met the inclusion criteria defined earlier (Figure 1).",
        "subgroup": "Meta-analysis of Overall Risk of Neurodevelopmental Impairment and Gross Motor, Fine Motor, and Personal-Social Domains Among Infants Screened During Pandemic vs Before Pandemic - Overall risk of NDI",
        "key_reference_title": "Association Between the COVID-19 Pandemic and Infant Neurodevelopment: A Comparison Before and During COVID-19.",
        "key_reference_abstract": "None",
        "truth": "True"
    },
    {
        "pmid": "36306133",
        "meta_analysis_title": "COVID-19 Pandemic and Infant Neurodevelopmental Impairment: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Are neurodevelopmental outcomes during infancy changed by the COVID-19 pandemic?",
        "criteria": "A total of 1880 articles were retrieved. Of these, 670 articles were excluded as duplicates, and the remaining 1210 studies were screened for eligibility. Screening of the title and abstract resulted in 21 potentially eligible studies. Following full-text assessment, 8 studies met the inclusion criteria defined earlier (Figure 1).",
        "subgroup": "Meta-analysis of Overall Risk of Neurodevelopmental Impairment and Gross Motor, Fine Motor, and Personal-Social Domains Among Infants Screened During Pandemic vs Before Pandemic - Overall risk of NDI",
        "key_reference_title": "Impact of SARS-CoV-2 Infection During Pregnancy on Infant Neurobehavioral Development: A Case-Control Study.",
        "key_reference_abstract": "Background: Previous studies on the pneumonia outbreak caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have focused on the general population and pregnant women, while little is known about the effects of SARS-CoV-2 on retardation during and after pregnancy. The purpose of this study was to evaluate the potential influence of SARS-CoV-2 on infant neurobehavioral development. Methods: A case-control study was conducted in Wuhan Maternal and Child Health Hospital, China. Nine pregnant women with SARS-CoV-2 infection and 9 controls matched by maternal age, parity, and status of chronic disease were included. Infantile neurobehavioral development was assessed through the Ages and Stages Questionnaires Edition 3 (ASQ-3). Results: The majority of pregnant women with SARS-CoV-2 experienced cesarean section (7 of 9), which was higher than the control group (5 of 9). The throat swabs of all newborn were negative. We found that compared with the control group, neonates of mothers with SARS-CoV-2 infection during pregnancy had lower scores in communication, gross movement, fine movement, problem solving, and personal-social domains; but only fine movement domain yielded statistical significance (P = 0.031). Conclusion: Infection with SARS-CoV-2 during pregnancy may have a certain impact on infant neurobehavioral development. Further studies with larger sample size are warranted for validation.",
        "truth": "False"
    },
    {
        "pmid": "36306133",
        "meta_analysis_title": "COVID-19 Pandemic and Infant Neurodevelopmental Impairment: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Are neurodevelopmental outcomes during infancy changed by the COVID-19 pandemic?",
        "criteria": "A total of 1880 articles were retrieved. Of these, 670 articles were excluded as duplicates, and the remaining 1210 studies were screened for eligibility. Screening of the title and abstract resulted in 21 potentially eligible studies. Following full-text assessment, 8 studies met the inclusion criteria defined earlier (Figure 1).",
        "subgroup": "Meta-analysis of Overall Risk of Neurodevelopmental Impairment and Gross Motor, Fine Motor, and Personal-Social Domains Among Infants Screened During Pandemic vs Before Pandemic - Overall risk of NDI",
        "key_reference_title": "Increased risk for developmental delay among babies born during the pandemic.",
        "key_reference_abstract": "The COVID-19 pandemic has resulted in substantial and widespread changes to many prenatal (e.g., maternal stress) and postnatal (e.g., socialization) factors contributing to early child development. We compared developmental screening of 1-year old infants born between April 17, 2020-November 11, 2020 to data from infants born pre-pandemic. We aimed to determine whether risk for developmental delay was elevated among infants born during the pandemic compared to infants born prior to the pandemic. Data were available from 1623 PdP participants. PdP infants had lower mean scores relative to pooled pre-pandemic data on all domains except Problem Solving. PdP infants also had significantly higher risk for developmental delay in the Communication and Personal-Social domains, where the odds ratios for scoring 2 SD below the mean were 2.5 and 1.5, respectively, relative to pre-pandemic data. When stratified by sex, the odds ratios for risk of developmental delay were generally higher among female infants. In conclusions, risks for developmental delay in the Communication and Personal-Social domains were elevated in infants born during the COVID-19 pandemic compared to pre-pandemic infants, especially among girls.",
        "truth": "False"
    },
    {
        "pmid": "36306133",
        "meta_analysis_title": "COVID-19 Pandemic and Infant Neurodevelopmental Impairment: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Are neurodevelopmental outcomes during infancy changed by the COVID-19 pandemic?",
        "criteria": "A total of 1880 articles were retrieved. Of these, 670 articles were excluded as duplicates, and the remaining 1210 studies were screened for eligibility. Screening of the title and abstract resulted in 21 potentially eligible studies. Following full-text assessment, 8 studies met the inclusion criteria defined earlier (Figure 1).",
        "subgroup": "Meta-analysis of Overall Risk of Neurodevelopmental Impairment and Gross Motor, Fine Motor, and Personal-Social Domains Among Infants Screened During Pandemic vs Before Pandemic - Overall risk of NDI",
        "key_reference_title": "Neurodevelopmental outcomes of infants secondary to in utero exposure to maternal 2 SARS-CoV-2 infection: A national prospective study in Kuwait.",
        "key_reference_abstract": "## Background\nAn increasing proportion of women are being infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) during pregnancy. Intrauterine viral infections induce an increase in the levels of proinflammatory cytokines, which inhibit the proliferation of neuronal precursor cells and stimulate oligodendrocyte cell death, leading to abnormal neurodevelopment. Whether a maternal cytokine storm can affect neonatal brain development is unclear. The objective of the present study is to assess neurodevelopmental outcomes in neonates born to mothers with SARS-CoV-2 infections during pregnancy. ## Methods\nIn this prospective cohort study, the neurodevelopment status of infants (N=298) born to women with SARS-CoV-2 infections during pregnancy was assessed at 10-12 months post discharge using the Ages and Stages Questionnaire, 3rd edition (ASQ-3). The ASQ-3 scores were classified into developmental delays (cutoff score: \u22642 standard deviations (SDs) below the population mean) and no delay (score >2 SDs above the population mean). ## Results\nApproximately 10% of infants born to mothers with SARS-CoV-2 infections during pregnancy showed developmental delays. Two of 298 infants tested positive for SARS-CoV-2, and both had normal ASQ-3 scores. The majority of the pregnant women had SARS-CoV-2 infection during their third trimester. The risk of developmental delays among infants was higher in those whose mothers had SARS-CoV-2 infections during the first (P=0.039) and second trimesters (P=0.001) than in those whose mothers had SARS-CoV-2 infections during the third trimester. Infants born at <31 weeks gestation were more prone to developmental delays than those born at >31 weeks gestation (10% versus 0.8%; P=0.002). ## Conclusion\nThe findings of the study highlight the need for long term neurodevelopmental assessment of infants born to mothers with SARS-CoV-2 infection.",
        "truth": "False"
    },
    {
        "pmid": "36306133",
        "meta_analysis_title": "COVID-19 Pandemic and Infant Neurodevelopmental Impairment: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Are neurodevelopmental outcomes during infancy changed by the COVID-19 pandemic?",
        "criteria": "A total of 1880 articles were retrieved. Of these, 670 articles were excluded as duplicates, and the remaining 1210 studies were screened for eligibility. Screening of the title and abstract resulted in 21 potentially eligible studies. Following full-text assessment, 8 studies met the inclusion criteria defined earlier (Figure 1).",
        "subgroup": "Meta-analysis of Overall Risk of Neurodevelopmental Impairment and Gross Motor, Fine Motor, and Personal-Social Domains Among Infants Screened During Pandemic vs Before Pandemic - Overall risk of NDI",
        "key_reference_title": "Neurodevelopmental outcomes at one year in offspring of mothers who test positive for SARS-CoV-2 during pregnancy.",
        "key_reference_abstract": "## Importance\nEpidemiologic studies suggest maternal immune activation during pregnancy may be associated with neurodevelopmental effects in offspring. \n## Objective\nTo determine whether in utero exposure to the novel coronavirus SARS-CoV-2 is associated with risk for neurodevelopmental disorders in the first 12 months after birth. \n## Design\nRetrospective cohort\n## Participants\nLive offspring of all mothers who delivered between March and September 2020 at one of six Massachusetts hospitals across two health systems. \n## Exposure\nSARS-CoV-2 infection confirmed by PCR during pregnancy \n## Main Outcome and Measures\nNeurodevelopmental disorders determined from ICD-10 diagnostic codes over 12 months; sociodemographic and clinical features of mothers and offspring; all drawn from the electronic health record. \n## Results\nThe cohort included 7,772 live births (7,466 pregnancies, 96% singleton, 222 births to SARS-CoV-2 positive mothers), with mean maternal age of 32.9 years; offspring were 9.9% Asian, 8.4% Black, and 69.0% white; 15.1% were of Hispanic ethnicity. Preterm delivery was more likely among exposed mothers (14% versus 8.7%; p=.003). Maternal SARS-CoV-2 positivity during pregnancy was associated with greater rate of neurodevelopmental diagnoses (crude OR 2.17 [95% CI 1.24-3.79, p=0.006]) as well as models adjusted for race, ethnicity, insurance status, offspring sex, maternal age, and preterm status (adjusted OR 1.86 [95% CI 1.03-3.36, p=0.04]). Third-trimester infection was associated with effects of larger magnitude (adjusted OR 2.34, 95% CI 1.23-4.44, p=0.01) \n## Conclusion and Relevance\nOur results provide preliminary evidence that maternal SARS-CoV-2 may be associated with neurodevelopmental sequelae in some offspring. Prospective studies with longer follow-up duration will be required to exclude confounding and confirm these effects.\n## Trial Registration\nNA## Key Points\n## Question\nDoes COVID-19 exposure in utero increase the risk for neurodevelopmental disorders in the first year of life? ## Findings\nIn a cohort of babies delivered during COVID-19, those born to mothers with a positive SARS-CoV-2 PCR test during pregnancy were more likely to receive a neurodevelopmental diagnosis in the first 12 months after delivery, even after accounting for preterm delivery. ## Meaning\nThese preliminary findings suggest that COVID-19 exposure may impact neurodevelopment, and highlight the need for prospective investigation of outcomes in children exposed to COVID-19 in utero.",
        "truth": "False"
    },
    {
        "pmid": "36306133",
        "meta_analysis_title": "COVID-19 Pandemic and Infant Neurodevelopmental Impairment: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Are neurodevelopmental outcomes during infancy changed by the COVID-19 pandemic?",
        "criteria": "A total of 1880 articles were retrieved. Of these, 670 articles were excluded as duplicates, and the remaining 1210 studies were screened for eligibility. Screening of the title and abstract resulted in 21 potentially eligible studies. Following full-text assessment, 8 studies met the inclusion criteria defined earlier (Figure 1).",
        "subgroup": "Meta-analysis of Overall Risk of Neurodevelopmental Impairment and Gross Motor, Fine Motor, and Personal-Social Domains Among Infants Screened During Pandemic vs Before Pandemic - At risk of gross motor impairment",
        "key_reference_title": "Association of Birth During the COVID-19 Pandemic With Neurodevelopmental Status at 6 Months in Infants With and Without In Utero Exposure to Maternal SARS-CoV-2 Infection.",
        "key_reference_abstract": "## IMPORTANCE\nAssociations between in utero exposure to maternal SARS-CoV-2 infection and neurodevelopment are speculated, but currently unknown.\n## OBJECTIVE\nTo examine the associations between maternal SARS-CoV-2 infection during pregnancy, being born during the COVID-19 pandemic regardless of maternal SARS-CoV-2 status, and neurodevelopment at age 6 months.\n## DESIGN, SETTING, AND PARTICIPANTS\nA cohort of infants exposed to maternal SARS-CoV-2 infection during pregnancy and unexposed controls was enrolled in the COVID-19 Mother Baby Outcomes Initiative at Columbia University Irving Medical Center in New York City. All women who delivered at Columbia University Irving Medical Center with a SARS-CoV-2 infection during pregnancy were approached. Women with unexposed infants were approached based on similar gestational age at birth, date of birth, sex, and mode of delivery. Neurodevelopment was assessed using the Ages & Stages Questionnaire, 3rd Edition (ASQ-3) at age 6 months. A historical cohort of infants born before the pandemic who had completed the 6-month ASQ-3 were included in secondary analyses.\n## EXPOSURES\nMaternal SARS-CoV-2 infection during pregnancy and birth during the COVID-19 pandemic.\n## MAIN OUTCOMES AND MEASURES\nOutcomes were scores on the 5 ASQ-3 subdomains, with the hypothesis that maternal SARS-CoV-2 infection during pregnancy would be associated with decrements in social and motor development at age 6 months.\n## RESULTS\nOf 1706 women approached, 596 enrolled; 385 women were invited to a 6-month assessment, of whom 272 (70.6%) completed the ASQ-3. Data were available for 255 infants enrolled in the COVID-19 Mother Baby Outcomes Initiative (114 in utero exposed, 141 unexposed to SARS-CoV-2; median maternal age at delivery, 32.0 [IQR, 19.0-45.0] years). Data were also available from a historical cohort of 62 infants born before the pandemic. In utero exposure to maternal SARS-CoV-2 infection was not associated with significant differences on any ASQ-3 subdomain, regardless of infection timing or severity. However, compared with the historical cohort, infants born during the pandemic had significantly lower scores on gross motor (mean difference, -5.63; 95% CI, -8.75 to -2.51; F1,267\u2009=\u200912.63; P<.005), fine motor (mean difference, -6.61; 95% CI, -10.00 to -3.21; F1,267\u2009=\u200914.71; P\u2009<\u2009.005), and personal-social (mean difference, -3.71; 95% CI, -6.61 to -0.82; F1,267\u2009=\u20096.37; P<.05) subdomains in fully adjusted models.\n## CONCLUSIONS AND RELEVANCE\nIn this study, birth during the pandemic, but not in utero exposure to maternal SARS-CoV-2 infection, was associated with differences in neurodevelopment at age 6 months. These early findings support the need for long-term monitoring of children born during the COVID-19 pandemic.",
        "truth": "True"
    },
    {
        "pmid": "36306133",
        "meta_analysis_title": "COVID-19 Pandemic and Infant Neurodevelopmental Impairment: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Are neurodevelopmental outcomes during infancy changed by the COVID-19 pandemic?",
        "criteria": "A total of 1880 articles were retrieved. Of these, 670 articles were excluded as duplicates, and the remaining 1210 studies were screened for eligibility. Screening of the title and abstract resulted in 21 potentially eligible studies. Following full-text assessment, 8 studies met the inclusion criteria defined earlier (Figure 1).",
        "subgroup": "Meta-analysis of Overall Risk of Neurodevelopmental Impairment and Gross Motor, Fine Motor, and Personal-Social Domains Among Infants Screened During Pandemic vs Before Pandemic - At risk of gross motor impairment",
        "key_reference_title": "Effects of SARS-CoV-2 Infection During Late Pregnancy on Early Childhood Development: A Prospective Cohort Study.",
        "key_reference_abstract": "Background: There is little direct or indirect evidence of the effects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection during pregnancy on early childhood development. Methods: We conducted a prospective, observational cohort study in China from May 1 to October 31, 2020, that enrolled 135 mother-infant dyads: 57 dyads in the infection cohort and 78 in the non-infection cohort. Among all infants, 14.0% were preterm birth in the infection cohort and 6.4% in the non-infection cohort. Participants were followed by telephone interviews to collect demographic characteristics, medical records of coronavirus disease 2019, breastfeeding data, and early childhood development was assessed by the Age and Stage Questionnaire (ASQ-3) and Age and Stage Questionnaire Social-Emotional (ASQ:SE-2) Chinese versions at 3 months after childbirth. We used multivariable Poisson regression models to estimate the relative risk (RR) of SARS-CoV-2 infection. Multivariable linear regression models and a mediation model were used to test the direct and indirect associations between SARS-CoV-2 infection and the ASQ-3 score. This study was approved by the Peking University Third Hospital Medical Science Research Ethics Committee (No. IRB00006761-M2020127). Results: In the infection cohort, 13.6% of the children showed social-emotional developmental delay, and 13.5% showed overall developmental delay. The corresponding rates in the non-infection cohort were 23.4 and 8.1%. Compared with the non-infection cohort, SARS-CoV-2 infection during pregnancy did not increase the risk of social-emotional (RR = 0.87, 95% CI: 0.51-1.49) or overall (RR = 1.02, 95% CI: 0.60-1.73) developmental delay. The mediation model showed that SARS-CoV-2 infection indirectly affected the ASQ-3 score by increasing the length of mother-infant separation. Conclusions: SARS-CoV-2 during late pregnancy did not increase the risk of developmental delay of the offspring 3 months after delivery. However, SARS-CoV-2 may have indirect effects on early childhood development by increasing mother-infant separation.",
        "truth": "False"
    },
    {
        "pmid": "36306133",
        "meta_analysis_title": "COVID-19 Pandemic and Infant Neurodevelopmental Impairment: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Are neurodevelopmental outcomes during infancy changed by the COVID-19 pandemic?",
        "criteria": "A total of 1880 articles were retrieved. Of these, 670 articles were excluded as duplicates, and the remaining 1210 studies were screened for eligibility. Screening of the title and abstract resulted in 21 potentially eligible studies. Following full-text assessment, 8 studies met the inclusion criteria defined earlier (Figure 1).",
        "subgroup": "Meta-analysis of Overall Risk of Neurodevelopmental Impairment and Gross Motor, Fine Motor, and Personal-Social Domains Among Infants Screened During Pandemic vs Before Pandemic - At risk of gross motor impairment",
        "key_reference_title": "The impact of the COVID-19 pandemic on infant and toddler development.",
        "key_reference_abstract": "## BACKGROUND\nThe COVID-19 pandemic has created new cultural norms with pervasive societal implications. Families have experienced a heightened amount of physical, psychological, emotional, and financial stress. Infants and children living with stress have the potential for delayed developmental milestones, difficulty with emotional regulation, and social or behavioral issues.\n## PURPOSE\nThis study aims to determine if the pandemic has affected developmental outcomes in infants and toddlers.\n## METHODOLOGY\nPrepandemic and postpandemic developmental (ASQ-3) scores were obtained from charts of 1,024 patients (6, 12, 18, 24, and 36 months) from two pediatric practices.\n## RESULTS\nThere were no significant differences in prepandemic and postpandemic ASQ-3 scores for the overall sample. Age-group analysis showed statistically significant differences in domain scores. Postpandemic problem-solving scores decreased among 6-month-olds while increasing among 24-month-olds. Categorization by score interpretation categories showed a slight decrease in postpandemic scores in the communication domain among 6- and 12-month-olds.\n## CONCLUSIONS\nThe pandemic has the potential to affect childhood development. However, the results of this study are reassuring, showing only slight differences in developmental scores prepandemic versus postpandemic. More studies are needed to establish causation and possible trends in future developmental trajectories.\n## IMPLICATIONS\nAn increased focus on communication screening and promotion of language and communication skills in young children postpandemic is needed. Education about the importance of parent-child engagement, nurturing relationships, opportunities for free-play and exploration, and caregiver support and stress reduction will continue to be of paramount importance.",
        "truth": "True"
    },
    {
        "pmid": "36306133",
        "meta_analysis_title": "COVID-19 Pandemic and Infant Neurodevelopmental Impairment: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Are neurodevelopmental outcomes during infancy changed by the COVID-19 pandemic?",
        "criteria": "A total of 1880 articles were retrieved. Of these, 670 articles were excluded as duplicates, and the remaining 1210 studies were screened for eligibility. Screening of the title and abstract resulted in 21 potentially eligible studies. Following full-text assessment, 8 studies met the inclusion criteria defined earlier (Figure 1).",
        "subgroup": "Meta-analysis of Overall Risk of Neurodevelopmental Impairment and Gross Motor, Fine Motor, and Personal-Social Domains Among Infants Screened During Pandemic vs Before Pandemic - At risk of gross motor impairment",
        "key_reference_title": "Association Between the COVID-19 Pandemic and Infant Neurodevelopment: A Comparison Before and During COVID-19.",
        "key_reference_abstract": "None",
        "truth": "True"
    },
    {
        "pmid": "36306133",
        "meta_analysis_title": "COVID-19 Pandemic and Infant Neurodevelopmental Impairment: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Are neurodevelopmental outcomes during infancy changed by the COVID-19 pandemic?",
        "criteria": "A total of 1880 articles were retrieved. Of these, 670 articles were excluded as duplicates, and the remaining 1210 studies were screened for eligibility. Screening of the title and abstract resulted in 21 potentially eligible studies. Following full-text assessment, 8 studies met the inclusion criteria defined earlier (Figure 1).",
        "subgroup": "Meta-analysis of Overall Risk of Neurodevelopmental Impairment and Gross Motor, Fine Motor, and Personal-Social Domains Among Infants Screened During Pandemic vs Before Pandemic - At risk of gross motor impairment",
        "key_reference_title": "Impact of SARS-CoV-2 Infection During Pregnancy on Infant Neurobehavioral Development: A Case-Control Study.",
        "key_reference_abstract": "Background: Previous studies on the pneumonia outbreak caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have focused on the general population and pregnant women, while little is known about the effects of SARS-CoV-2 on retardation during and after pregnancy. The purpose of this study was to evaluate the potential influence of SARS-CoV-2 on infant neurobehavioral development. Methods: A case-control study was conducted in Wuhan Maternal and Child Health Hospital, China. Nine pregnant women with SARS-CoV-2 infection and 9 controls matched by maternal age, parity, and status of chronic disease were included. Infantile neurobehavioral development was assessed through the Ages and Stages Questionnaires Edition 3 (ASQ-3). Results: The majority of pregnant women with SARS-CoV-2 experienced cesarean section (7 of 9), which was higher than the control group (5 of 9). The throat swabs of all newborn were negative. We found that compared with the control group, neonates of mothers with SARS-CoV-2 infection during pregnancy had lower scores in communication, gross movement, fine movement, problem solving, and personal-social domains; but only fine movement domain yielded statistical significance (P = 0.031). Conclusion: Infection with SARS-CoV-2 during pregnancy may have a certain impact on infant neurobehavioral development. Further studies with larger sample size are warranted for validation.",
        "truth": "False"
    },
    {
        "pmid": "36306133",
        "meta_analysis_title": "COVID-19 Pandemic and Infant Neurodevelopmental Impairment: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Are neurodevelopmental outcomes during infancy changed by the COVID-19 pandemic?",
        "criteria": "A total of 1880 articles were retrieved. Of these, 670 articles were excluded as duplicates, and the remaining 1210 studies were screened for eligibility. Screening of the title and abstract resulted in 21 potentially eligible studies. Following full-text assessment, 8 studies met the inclusion criteria defined earlier (Figure 1).",
        "subgroup": "Meta-analysis of Overall Risk of Neurodevelopmental Impairment and Gross Motor, Fine Motor, and Personal-Social Domains Among Infants Screened During Pandemic vs Before Pandemic - At risk of gross motor impairment",
        "key_reference_title": "Increased risk for developmental delay among babies born during the pandemic.",
        "key_reference_abstract": "The COVID-19 pandemic has resulted in substantial and widespread changes to many prenatal (e.g., maternal stress) and postnatal (e.g., socialization) factors contributing to early child development. We compared developmental screening of 1-year old infants born between April 17, 2020-November 11, 2020 to data from infants born pre-pandemic. We aimed to determine whether risk for developmental delay was elevated among infants born during the pandemic compared to infants born prior to the pandemic. Data were available from 1623 PdP participants. PdP infants had lower mean scores relative to pooled pre-pandemic data on all domains except Problem Solving. PdP infants also had significantly higher risk for developmental delay in the Communication and Personal-Social domains, where the odds ratios for scoring 2 SD below the mean were 2.5 and 1.5, respectively, relative to pre-pandemic data. When stratified by sex, the odds ratios for risk of developmental delay were generally higher among female infants. In conclusions, risks for developmental delay in the Communication and Personal-Social domains were elevated in infants born during the COVID-19 pandemic compared to pre-pandemic infants, especially among girls.",
        "truth": "True"
    },
    {
        "pmid": "36306133",
        "meta_analysis_title": "COVID-19 Pandemic and Infant Neurodevelopmental Impairment: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Are neurodevelopmental outcomes during infancy changed by the COVID-19 pandemic?",
        "criteria": "A total of 1880 articles were retrieved. Of these, 670 articles were excluded as duplicates, and the remaining 1210 studies were screened for eligibility. Screening of the title and abstract resulted in 21 potentially eligible studies. Following full-text assessment, 8 studies met the inclusion criteria defined earlier (Figure 1).",
        "subgroup": "Meta-analysis of Overall Risk of Neurodevelopmental Impairment and Gross Motor, Fine Motor, and Personal-Social Domains Among Infants Screened During Pandemic vs Before Pandemic - At risk of gross motor impairment",
        "key_reference_title": "Neurodevelopmental outcomes of infants secondary to in utero exposure to maternal 2 SARS-CoV-2 infection: A national prospective study in Kuwait.",
        "key_reference_abstract": "## Background\nAn increasing proportion of women are being infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) during pregnancy. Intrauterine viral infections induce an increase in the levels of proinflammatory cytokines, which inhibit the proliferation of neuronal precursor cells and stimulate oligodendrocyte cell death, leading to abnormal neurodevelopment. Whether a maternal cytokine storm can affect neonatal brain development is unclear. The objective of the present study is to assess neurodevelopmental outcomes in neonates born to mothers with SARS-CoV-2 infections during pregnancy. ## Methods\nIn this prospective cohort study, the neurodevelopment status of infants (N=298) born to women with SARS-CoV-2 infections during pregnancy was assessed at 10-12 months post discharge using the Ages and Stages Questionnaire, 3rd edition (ASQ-3). The ASQ-3 scores were classified into developmental delays (cutoff score: \u22642 standard deviations (SDs) below the population mean) and no delay (score >2 SDs above the population mean). ## Results\nApproximately 10% of infants born to mothers with SARS-CoV-2 infections during pregnancy showed developmental delays. Two of 298 infants tested positive for SARS-CoV-2, and both had normal ASQ-3 scores. The majority of the pregnant women had SARS-CoV-2 infection during their third trimester. The risk of developmental delays among infants was higher in those whose mothers had SARS-CoV-2 infections during the first (P=0.039) and second trimesters (P=0.001) than in those whose mothers had SARS-CoV-2 infections during the third trimester. Infants born at <31 weeks gestation were more prone to developmental delays than those born at >31 weeks gestation (10% versus 0.8%; P=0.002). ## Conclusion\nThe findings of the study highlight the need for long term neurodevelopmental assessment of infants born to mothers with SARS-CoV-2 infection.",
        "truth": "False"
    },
    {
        "pmid": "36306133",
        "meta_analysis_title": "COVID-19 Pandemic and Infant Neurodevelopmental Impairment: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Are neurodevelopmental outcomes during infancy changed by the COVID-19 pandemic?",
        "criteria": "A total of 1880 articles were retrieved. Of these, 670 articles were excluded as duplicates, and the remaining 1210 studies were screened for eligibility. Screening of the title and abstract resulted in 21 potentially eligible studies. Following full-text assessment, 8 studies met the inclusion criteria defined earlier (Figure 1).",
        "subgroup": "Meta-analysis of Overall Risk of Neurodevelopmental Impairment and Gross Motor, Fine Motor, and Personal-Social Domains Among Infants Screened During Pandemic vs Before Pandemic - At risk of gross motor impairment",
        "key_reference_title": "Neurodevelopmental outcomes at one year in offspring of mothers who test positive for SARS-CoV-2 during pregnancy.",
        "key_reference_abstract": "## Importance\nEpidemiologic studies suggest maternal immune activation during pregnancy may be associated with neurodevelopmental effects in offspring. \n## Objective\nTo determine whether in utero exposure to the novel coronavirus SARS-CoV-2 is associated with risk for neurodevelopmental disorders in the first 12 months after birth. \n## Design\nRetrospective cohort\n## Participants\nLive offspring of all mothers who delivered between March and September 2020 at one of six Massachusetts hospitals across two health systems. \n## Exposure\nSARS-CoV-2 infection confirmed by PCR during pregnancy \n## Main Outcome and Measures\nNeurodevelopmental disorders determined from ICD-10 diagnostic codes over 12 months; sociodemographic and clinical features of mothers and offspring; all drawn from the electronic health record. \n## Results\nThe cohort included 7,772 live births (7,466 pregnancies, 96% singleton, 222 births to SARS-CoV-2 positive mothers), with mean maternal age of 32.9 years; offspring were 9.9% Asian, 8.4% Black, and 69.0% white; 15.1% were of Hispanic ethnicity. Preterm delivery was more likely among exposed mothers (14% versus 8.7%; p=.003). Maternal SARS-CoV-2 positivity during pregnancy was associated with greater rate of neurodevelopmental diagnoses (crude OR 2.17 [95% CI 1.24-3.79, p=0.006]) as well as models adjusted for race, ethnicity, insurance status, offspring sex, maternal age, and preterm status (adjusted OR 1.86 [95% CI 1.03-3.36, p=0.04]). Third-trimester infection was associated with effects of larger magnitude (adjusted OR 2.34, 95% CI 1.23-4.44, p=0.01) \n## Conclusion and Relevance\nOur results provide preliminary evidence that maternal SARS-CoV-2 may be associated with neurodevelopmental sequelae in some offspring. Prospective studies with longer follow-up duration will be required to exclude confounding and confirm these effects.\n## Trial Registration\nNA## Key Points\n## Question\nDoes COVID-19 exposure in utero increase the risk for neurodevelopmental disorders in the first year of life? ## Findings\nIn a cohort of babies delivered during COVID-19, those born to mothers with a positive SARS-CoV-2 PCR test during pregnancy were more likely to receive a neurodevelopmental diagnosis in the first 12 months after delivery, even after accounting for preterm delivery. ## Meaning\nThese preliminary findings suggest that COVID-19 exposure may impact neurodevelopment, and highlight the need for prospective investigation of outcomes in children exposed to COVID-19 in utero.",
        "truth": "False"
    },
    {
        "pmid": "36306133",
        "meta_analysis_title": "COVID-19 Pandemic and Infant Neurodevelopmental Impairment: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Are neurodevelopmental outcomes during infancy changed by the COVID-19 pandemic?",
        "criteria": "A total of 1880 articles were retrieved. Of these, 670 articles were excluded as duplicates, and the remaining 1210 studies were screened for eligibility. Screening of the title and abstract resulted in 21 potentially eligible studies. Following full-text assessment, 8 studies met the inclusion criteria defined earlier (Figure 1).",
        "subgroup": "Meta-analysis of Overall Risk of Neurodevelopmental Impairment and Gross Motor, Fine Motor, and Personal-Social Domains Among Infants Screened During Pandemic vs Before Pandemic - At risk of fine motor impairment",
        "key_reference_title": "Association of Birth During the COVID-19 Pandemic With Neurodevelopmental Status at 6 Months in Infants With and Without In Utero Exposure to Maternal SARS-CoV-2 Infection.",
        "key_reference_abstract": "## IMPORTANCE\nAssociations between in utero exposure to maternal SARS-CoV-2 infection and neurodevelopment are speculated, but currently unknown.\n## OBJECTIVE\nTo examine the associations between maternal SARS-CoV-2 infection during pregnancy, being born during the COVID-19 pandemic regardless of maternal SARS-CoV-2 status, and neurodevelopment at age 6 months.\n## DESIGN, SETTING, AND PARTICIPANTS\nA cohort of infants exposed to maternal SARS-CoV-2 infection during pregnancy and unexposed controls was enrolled in the COVID-19 Mother Baby Outcomes Initiative at Columbia University Irving Medical Center in New York City. All women who delivered at Columbia University Irving Medical Center with a SARS-CoV-2 infection during pregnancy were approached. Women with unexposed infants were approached based on similar gestational age at birth, date of birth, sex, and mode of delivery. Neurodevelopment was assessed using the Ages & Stages Questionnaire, 3rd Edition (ASQ-3) at age 6 months. A historical cohort of infants born before the pandemic who had completed the 6-month ASQ-3 were included in secondary analyses.\n## EXPOSURES\nMaternal SARS-CoV-2 infection during pregnancy and birth during the COVID-19 pandemic.\n## MAIN OUTCOMES AND MEASURES\nOutcomes were scores on the 5 ASQ-3 subdomains, with the hypothesis that maternal SARS-CoV-2 infection during pregnancy would be associated with decrements in social and motor development at age 6 months.\n## RESULTS\nOf 1706 women approached, 596 enrolled; 385 women were invited to a 6-month assessment, of whom 272 (70.6%) completed the ASQ-3. Data were available for 255 infants enrolled in the COVID-19 Mother Baby Outcomes Initiative (114 in utero exposed, 141 unexposed to SARS-CoV-2; median maternal age at delivery, 32.0 [IQR, 19.0-45.0] years). Data were also available from a historical cohort of 62 infants born before the pandemic. In utero exposure to maternal SARS-CoV-2 infection was not associated with significant differences on any ASQ-3 subdomain, regardless of infection timing or severity. However, compared with the historical cohort, infants born during the pandemic had significantly lower scores on gross motor (mean difference, -5.63; 95% CI, -8.75 to -2.51; F1,267\u2009=\u200912.63; P<.005), fine motor (mean difference, -6.61; 95% CI, -10.00 to -3.21; F1,267\u2009=\u200914.71; P\u2009<\u2009.005), and personal-social (mean difference, -3.71; 95% CI, -6.61 to -0.82; F1,267\u2009=\u20096.37; P<.05) subdomains in fully adjusted models.\n## CONCLUSIONS AND RELEVANCE\nIn this study, birth during the pandemic, but not in utero exposure to maternal SARS-CoV-2 infection, was associated with differences in neurodevelopment at age 6 months. These early findings support the need for long-term monitoring of children born during the COVID-19 pandemic.",
        "truth": "True"
    },
    {
        "pmid": "36306133",
        "meta_analysis_title": "COVID-19 Pandemic and Infant Neurodevelopmental Impairment: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Are neurodevelopmental outcomes during infancy changed by the COVID-19 pandemic?",
        "criteria": "A total of 1880 articles were retrieved. Of these, 670 articles were excluded as duplicates, and the remaining 1210 studies were screened for eligibility. Screening of the title and abstract resulted in 21 potentially eligible studies. Following full-text assessment, 8 studies met the inclusion criteria defined earlier (Figure 1).",
        "subgroup": "Meta-analysis of Overall Risk of Neurodevelopmental Impairment and Gross Motor, Fine Motor, and Personal-Social Domains Among Infants Screened During Pandemic vs Before Pandemic - At risk of fine motor impairment",
        "key_reference_title": "Effects of SARS-CoV-2 Infection During Late Pregnancy on Early Childhood Development: A Prospective Cohort Study.",
        "key_reference_abstract": "Background: There is little direct or indirect evidence of the effects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection during pregnancy on early childhood development. Methods: We conducted a prospective, observational cohort study in China from May 1 to October 31, 2020, that enrolled 135 mother-infant dyads: 57 dyads in the infection cohort and 78 in the non-infection cohort. Among all infants, 14.0% were preterm birth in the infection cohort and 6.4% in the non-infection cohort. Participants were followed by telephone interviews to collect demographic characteristics, medical records of coronavirus disease 2019, breastfeeding data, and early childhood development was assessed by the Age and Stage Questionnaire (ASQ-3) and Age and Stage Questionnaire Social-Emotional (ASQ:SE-2) Chinese versions at 3 months after childbirth. We used multivariable Poisson regression models to estimate the relative risk (RR) of SARS-CoV-2 infection. Multivariable linear regression models and a mediation model were used to test the direct and indirect associations between SARS-CoV-2 infection and the ASQ-3 score. This study was approved by the Peking University Third Hospital Medical Science Research Ethics Committee (No. IRB00006761-M2020127). Results: In the infection cohort, 13.6% of the children showed social-emotional developmental delay, and 13.5% showed overall developmental delay. The corresponding rates in the non-infection cohort were 23.4 and 8.1%. Compared with the non-infection cohort, SARS-CoV-2 infection during pregnancy did not increase the risk of social-emotional (RR = 0.87, 95% CI: 0.51-1.49) or overall (RR = 1.02, 95% CI: 0.60-1.73) developmental delay. The mediation model showed that SARS-CoV-2 infection indirectly affected the ASQ-3 score by increasing the length of mother-infant separation. Conclusions: SARS-CoV-2 during late pregnancy did not increase the risk of developmental delay of the offspring 3 months after delivery. However, SARS-CoV-2 may have indirect effects on early childhood development by increasing mother-infant separation.",
        "truth": "False"
    },
    {
        "pmid": "36306133",
        "meta_analysis_title": "COVID-19 Pandemic and Infant Neurodevelopmental Impairment: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Are neurodevelopmental outcomes during infancy changed by the COVID-19 pandemic?",
        "criteria": "A total of 1880 articles were retrieved. Of these, 670 articles were excluded as duplicates, and the remaining 1210 studies were screened for eligibility. Screening of the title and abstract resulted in 21 potentially eligible studies. Following full-text assessment, 8 studies met the inclusion criteria defined earlier (Figure 1).",
        "subgroup": "Meta-analysis of Overall Risk of Neurodevelopmental Impairment and Gross Motor, Fine Motor, and Personal-Social Domains Among Infants Screened During Pandemic vs Before Pandemic - At risk of fine motor impairment",
        "key_reference_title": "The impact of the COVID-19 pandemic on infant and toddler development.",
        "key_reference_abstract": "## BACKGROUND\nThe COVID-19 pandemic has created new cultural norms with pervasive societal implications. Families have experienced a heightened amount of physical, psychological, emotional, and financial stress. Infants and children living with stress have the potential for delayed developmental milestones, difficulty with emotional regulation, and social or behavioral issues.\n## PURPOSE\nThis study aims to determine if the pandemic has affected developmental outcomes in infants and toddlers.\n## METHODOLOGY\nPrepandemic and postpandemic developmental (ASQ-3) scores were obtained from charts of 1,024 patients (6, 12, 18, 24, and 36 months) from two pediatric practices.\n## RESULTS\nThere were no significant differences in prepandemic and postpandemic ASQ-3 scores for the overall sample. Age-group analysis showed statistically significant differences in domain scores. Postpandemic problem-solving scores decreased among 6-month-olds while increasing among 24-month-olds. Categorization by score interpretation categories showed a slight decrease in postpandemic scores in the communication domain among 6- and 12-month-olds.\n## CONCLUSIONS\nThe pandemic has the potential to affect childhood development. However, the results of this study are reassuring, showing only slight differences in developmental scores prepandemic versus postpandemic. More studies are needed to establish causation and possible trends in future developmental trajectories.\n## IMPLICATIONS\nAn increased focus on communication screening and promotion of language and communication skills in young children postpandemic is needed. Education about the importance of parent-child engagement, nurturing relationships, opportunities for free-play and exploration, and caregiver support and stress reduction will continue to be of paramount importance.",
        "truth": "True"
    },
    {
        "pmid": "36306133",
        "meta_analysis_title": "COVID-19 Pandemic and Infant Neurodevelopmental Impairment: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Are neurodevelopmental outcomes during infancy changed by the COVID-19 pandemic?",
        "criteria": "A total of 1880 articles were retrieved. Of these, 670 articles were excluded as duplicates, and the remaining 1210 studies were screened for eligibility. Screening of the title and abstract resulted in 21 potentially eligible studies. Following full-text assessment, 8 studies met the inclusion criteria defined earlier (Figure 1).",
        "subgroup": "Meta-analysis of Overall Risk of Neurodevelopmental Impairment and Gross Motor, Fine Motor, and Personal-Social Domains Among Infants Screened During Pandemic vs Before Pandemic - At risk of fine motor impairment",
        "key_reference_title": "Association Between the COVID-19 Pandemic and Infant Neurodevelopment: A Comparison Before and During COVID-19.",
        "key_reference_abstract": "None",
        "truth": "True"
    },
    {
        "pmid": "36306133",
        "meta_analysis_title": "COVID-19 Pandemic and Infant Neurodevelopmental Impairment: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Are neurodevelopmental outcomes during infancy changed by the COVID-19 pandemic?",
        "criteria": "A total of 1880 articles were retrieved. Of these, 670 articles were excluded as duplicates, and the remaining 1210 studies were screened for eligibility. Screening of the title and abstract resulted in 21 potentially eligible studies. Following full-text assessment, 8 studies met the inclusion criteria defined earlier (Figure 1).",
        "subgroup": "Meta-analysis of Overall Risk of Neurodevelopmental Impairment and Gross Motor, Fine Motor, and Personal-Social Domains Among Infants Screened During Pandemic vs Before Pandemic - At risk of fine motor impairment",
        "key_reference_title": "Impact of SARS-CoV-2 Infection During Pregnancy on Infant Neurobehavioral Development: A Case-Control Study.",
        "key_reference_abstract": "Background: Previous studies on the pneumonia outbreak caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have focused on the general population and pregnant women, while little is known about the effects of SARS-CoV-2 on retardation during and after pregnancy. The purpose of this study was to evaluate the potential influence of SARS-CoV-2 on infant neurobehavioral development. Methods: A case-control study was conducted in Wuhan Maternal and Child Health Hospital, China. Nine pregnant women with SARS-CoV-2 infection and 9 controls matched by maternal age, parity, and status of chronic disease were included. Infantile neurobehavioral development was assessed through the Ages and Stages Questionnaires Edition 3 (ASQ-3). Results: The majority of pregnant women with SARS-CoV-2 experienced cesarean section (7 of 9), which was higher than the control group (5 of 9). The throat swabs of all newborn were negative. We found that compared with the control group, neonates of mothers with SARS-CoV-2 infection during pregnancy had lower scores in communication, gross movement, fine movement, problem solving, and personal-social domains; but only fine movement domain yielded statistical significance (P = 0.031). Conclusion: Infection with SARS-CoV-2 during pregnancy may have a certain impact on infant neurobehavioral development. Further studies with larger sample size are warranted for validation.",
        "truth": "False"
    },
    {
        "pmid": "36306133",
        "meta_analysis_title": "COVID-19 Pandemic and Infant Neurodevelopmental Impairment: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Are neurodevelopmental outcomes during infancy changed by the COVID-19 pandemic?",
        "criteria": "A total of 1880 articles were retrieved. Of these, 670 articles were excluded as duplicates, and the remaining 1210 studies were screened for eligibility. Screening of the title and abstract resulted in 21 potentially eligible studies. Following full-text assessment, 8 studies met the inclusion criteria defined earlier (Figure 1).",
        "subgroup": "Meta-analysis of Overall Risk of Neurodevelopmental Impairment and Gross Motor, Fine Motor, and Personal-Social Domains Among Infants Screened During Pandemic vs Before Pandemic - At risk of fine motor impairment",
        "key_reference_title": "Increased risk for developmental delay among babies born during the pandemic.",
        "key_reference_abstract": "The COVID-19 pandemic has resulted in substantial and widespread changes to many prenatal (e.g., maternal stress) and postnatal (e.g., socialization) factors contributing to early child development. We compared developmental screening of 1-year old infants born between April 17, 2020-November 11, 2020 to data from infants born pre-pandemic. We aimed to determine whether risk for developmental delay was elevated among infants born during the pandemic compared to infants born prior to the pandemic. Data were available from 1623 PdP participants. PdP infants had lower mean scores relative to pooled pre-pandemic data on all domains except Problem Solving. PdP infants also had significantly higher risk for developmental delay in the Communication and Personal-Social domains, where the odds ratios for scoring 2 SD below the mean were 2.5 and 1.5, respectively, relative to pre-pandemic data. When stratified by sex, the odds ratios for risk of developmental delay were generally higher among female infants. In conclusions, risks for developmental delay in the Communication and Personal-Social domains were elevated in infants born during the COVID-19 pandemic compared to pre-pandemic infants, especially among girls.",
        "truth": "True"
    },
    {
        "pmid": "36306133",
        "meta_analysis_title": "COVID-19 Pandemic and Infant Neurodevelopmental Impairment: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Are neurodevelopmental outcomes during infancy changed by the COVID-19 pandemic?",
        "criteria": "A total of 1880 articles were retrieved. Of these, 670 articles were excluded as duplicates, and the remaining 1210 studies were screened for eligibility. Screening of the title and abstract resulted in 21 potentially eligible studies. Following full-text assessment, 8 studies met the inclusion criteria defined earlier (Figure 1).",
        "subgroup": "Meta-analysis of Overall Risk of Neurodevelopmental Impairment and Gross Motor, Fine Motor, and Personal-Social Domains Among Infants Screened During Pandemic vs Before Pandemic - At risk of fine motor impairment",
        "key_reference_title": "Neurodevelopmental outcomes of infants secondary to in utero exposure to maternal 2 SARS-CoV-2 infection: A national prospective study in Kuwait.",
        "key_reference_abstract": "## Background\nAn increasing proportion of women are being infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) during pregnancy. Intrauterine viral infections induce an increase in the levels of proinflammatory cytokines, which inhibit the proliferation of neuronal precursor cells and stimulate oligodendrocyte cell death, leading to abnormal neurodevelopment. Whether a maternal cytokine storm can affect neonatal brain development is unclear. The objective of the present study is to assess neurodevelopmental outcomes in neonates born to mothers with SARS-CoV-2 infections during pregnancy. ## Methods\nIn this prospective cohort study, the neurodevelopment status of infants (N=298) born to women with SARS-CoV-2 infections during pregnancy was assessed at 10-12 months post discharge using the Ages and Stages Questionnaire, 3rd edition (ASQ-3). The ASQ-3 scores were classified into developmental delays (cutoff score: \u22642 standard deviations (SDs) below the population mean) and no delay (score >2 SDs above the population mean). ## Results\nApproximately 10% of infants born to mothers with SARS-CoV-2 infections during pregnancy showed developmental delays. Two of 298 infants tested positive for SARS-CoV-2, and both had normal ASQ-3 scores. The majority of the pregnant women had SARS-CoV-2 infection during their third trimester. The risk of developmental delays among infants was higher in those whose mothers had SARS-CoV-2 infections during the first (P=0.039) and second trimesters (P=0.001) than in those whose mothers had SARS-CoV-2 infections during the third trimester. Infants born at <31 weeks gestation were more prone to developmental delays than those born at >31 weeks gestation (10% versus 0.8%; P=0.002). ## Conclusion\nThe findings of the study highlight the need for long term neurodevelopmental assessment of infants born to mothers with SARS-CoV-2 infection.",
        "truth": "False"
    },
    {
        "pmid": "36306133",
        "meta_analysis_title": "COVID-19 Pandemic and Infant Neurodevelopmental Impairment: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Are neurodevelopmental outcomes during infancy changed by the COVID-19 pandemic?",
        "criteria": "A total of 1880 articles were retrieved. Of these, 670 articles were excluded as duplicates, and the remaining 1210 studies were screened for eligibility. Screening of the title and abstract resulted in 21 potentially eligible studies. Following full-text assessment, 8 studies met the inclusion criteria defined earlier (Figure 1).",
        "subgroup": "Meta-analysis of Overall Risk of Neurodevelopmental Impairment and Gross Motor, Fine Motor, and Personal-Social Domains Among Infants Screened During Pandemic vs Before Pandemic - At risk of fine motor impairment",
        "key_reference_title": "Neurodevelopmental outcomes at one year in offspring of mothers who test positive for SARS-CoV-2 during pregnancy.",
        "key_reference_abstract": "## Importance\nEpidemiologic studies suggest maternal immune activation during pregnancy may be associated with neurodevelopmental effects in offspring. \n## Objective\nTo determine whether in utero exposure to the novel coronavirus SARS-CoV-2 is associated with risk for neurodevelopmental disorders in the first 12 months after birth. \n## Design\nRetrospective cohort\n## Participants\nLive offspring of all mothers who delivered between March and September 2020 at one of six Massachusetts hospitals across two health systems. \n## Exposure\nSARS-CoV-2 infection confirmed by PCR during pregnancy \n## Main Outcome and Measures\nNeurodevelopmental disorders determined from ICD-10 diagnostic codes over 12 months; sociodemographic and clinical features of mothers and offspring; all drawn from the electronic health record. \n## Results\nThe cohort included 7,772 live births (7,466 pregnancies, 96% singleton, 222 births to SARS-CoV-2 positive mothers), with mean maternal age of 32.9 years; offspring were 9.9% Asian, 8.4% Black, and 69.0% white; 15.1% were of Hispanic ethnicity. Preterm delivery was more likely among exposed mothers (14% versus 8.7%; p=.003). Maternal SARS-CoV-2 positivity during pregnancy was associated with greater rate of neurodevelopmental diagnoses (crude OR 2.17 [95% CI 1.24-3.79, p=0.006]) as well as models adjusted for race, ethnicity, insurance status, offspring sex, maternal age, and preterm status (adjusted OR 1.86 [95% CI 1.03-3.36, p=0.04]). Third-trimester infection was associated with effects of larger magnitude (adjusted OR 2.34, 95% CI 1.23-4.44, p=0.01) \n## Conclusion and Relevance\nOur results provide preliminary evidence that maternal SARS-CoV-2 may be associated with neurodevelopmental sequelae in some offspring. Prospective studies with longer follow-up duration will be required to exclude confounding and confirm these effects.\n## Trial Registration\nNA## Key Points\n## Question\nDoes COVID-19 exposure in utero increase the risk for neurodevelopmental disorders in the first year of life? ## Findings\nIn a cohort of babies delivered during COVID-19, those born to mothers with a positive SARS-CoV-2 PCR test during pregnancy were more likely to receive a neurodevelopmental diagnosis in the first 12 months after delivery, even after accounting for preterm delivery. ## Meaning\nThese preliminary findings suggest that COVID-19 exposure may impact neurodevelopment, and highlight the need for prospective investigation of outcomes in children exposed to COVID-19 in utero.",
        "truth": "False"
    },
    {
        "pmid": "36306133",
        "meta_analysis_title": "COVID-19 Pandemic and Infant Neurodevelopmental Impairment: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Are neurodevelopmental outcomes during infancy changed by the COVID-19 pandemic?",
        "criteria": "A total of 1880 articles were retrieved. Of these, 670 articles were excluded as duplicates, and the remaining 1210 studies were screened for eligibility. Screening of the title and abstract resulted in 21 potentially eligible studies. Following full-text assessment, 8 studies met the inclusion criteria defined earlier (Figure 1).",
        "subgroup": "Meta-analysis of Overall Risk of Neurodevelopmental Impairment and Gross Motor, Fine Motor, and Personal-Social Domains Among Infants Screened During Pandemic vs Before Pandemic - At risk of personal-social impairment",
        "key_reference_title": "Association of Birth During the COVID-19 Pandemic With Neurodevelopmental Status at 6 Months in Infants With and Without In Utero Exposure to Maternal SARS-CoV-2 Infection.",
        "key_reference_abstract": "## IMPORTANCE\nAssociations between in utero exposure to maternal SARS-CoV-2 infection and neurodevelopment are speculated, but currently unknown.\n## OBJECTIVE\nTo examine the associations between maternal SARS-CoV-2 infection during pregnancy, being born during the COVID-19 pandemic regardless of maternal SARS-CoV-2 status, and neurodevelopment at age 6 months.\n## DESIGN, SETTING, AND PARTICIPANTS\nA cohort of infants exposed to maternal SARS-CoV-2 infection during pregnancy and unexposed controls was enrolled in the COVID-19 Mother Baby Outcomes Initiative at Columbia University Irving Medical Center in New York City. All women who delivered at Columbia University Irving Medical Center with a SARS-CoV-2 infection during pregnancy were approached. Women with unexposed infants were approached based on similar gestational age at birth, date of birth, sex, and mode of delivery. Neurodevelopment was assessed using the Ages & Stages Questionnaire, 3rd Edition (ASQ-3) at age 6 months. A historical cohort of infants born before the pandemic who had completed the 6-month ASQ-3 were included in secondary analyses.\n## EXPOSURES\nMaternal SARS-CoV-2 infection during pregnancy and birth during the COVID-19 pandemic.\n## MAIN OUTCOMES AND MEASURES\nOutcomes were scores on the 5 ASQ-3 subdomains, with the hypothesis that maternal SARS-CoV-2 infection during pregnancy would be associated with decrements in social and motor development at age 6 months.\n## RESULTS\nOf 1706 women approached, 596 enrolled; 385 women were invited to a 6-month assessment, of whom 272 (70.6%) completed the ASQ-3. Data were available for 255 infants enrolled in the COVID-19 Mother Baby Outcomes Initiative (114 in utero exposed, 141 unexposed to SARS-CoV-2; median maternal age at delivery, 32.0 [IQR, 19.0-45.0] years). Data were also available from a historical cohort of 62 infants born before the pandemic. In utero exposure to maternal SARS-CoV-2 infection was not associated with significant differences on any ASQ-3 subdomain, regardless of infection timing or severity. However, compared with the historical cohort, infants born during the pandemic had significantly lower scores on gross motor (mean difference, -5.63; 95% CI, -8.75 to -2.51; F1,267\u2009=\u200912.63; P<.005), fine motor (mean difference, -6.61; 95% CI, -10.00 to -3.21; F1,267\u2009=\u200914.71; P\u2009<\u2009.005), and personal-social (mean difference, -3.71; 95% CI, -6.61 to -0.82; F1,267\u2009=\u20096.37; P<.05) subdomains in fully adjusted models.\n## CONCLUSIONS AND RELEVANCE\nIn this study, birth during the pandemic, but not in utero exposure to maternal SARS-CoV-2 infection, was associated with differences in neurodevelopment at age 6 months. These early findings support the need for long-term monitoring of children born during the COVID-19 pandemic.",
        "truth": "True"
    },
    {
        "pmid": "36306133",
        "meta_analysis_title": "COVID-19 Pandemic and Infant Neurodevelopmental Impairment: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Are neurodevelopmental outcomes during infancy changed by the COVID-19 pandemic?",
        "criteria": "A total of 1880 articles were retrieved. Of these, 670 articles were excluded as duplicates, and the remaining 1210 studies were screened for eligibility. Screening of the title and abstract resulted in 21 potentially eligible studies. Following full-text assessment, 8 studies met the inclusion criteria defined earlier (Figure 1).",
        "subgroup": "Meta-analysis of Overall Risk of Neurodevelopmental Impairment and Gross Motor, Fine Motor, and Personal-Social Domains Among Infants Screened During Pandemic vs Before Pandemic - At risk of personal-social impairment",
        "key_reference_title": "Effects of SARS-CoV-2 Infection During Late Pregnancy on Early Childhood Development: A Prospective Cohort Study.",
        "key_reference_abstract": "Background: There is little direct or indirect evidence of the effects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection during pregnancy on early childhood development. Methods: We conducted a prospective, observational cohort study in China from May 1 to October 31, 2020, that enrolled 135 mother-infant dyads: 57 dyads in the infection cohort and 78 in the non-infection cohort. Among all infants, 14.0% were preterm birth in the infection cohort and 6.4% in the non-infection cohort. Participants were followed by telephone interviews to collect demographic characteristics, medical records of coronavirus disease 2019, breastfeeding data, and early childhood development was assessed by the Age and Stage Questionnaire (ASQ-3) and Age and Stage Questionnaire Social-Emotional (ASQ:SE-2) Chinese versions at 3 months after childbirth. We used multivariable Poisson regression models to estimate the relative risk (RR) of SARS-CoV-2 infection. Multivariable linear regression models and a mediation model were used to test the direct and indirect associations between SARS-CoV-2 infection and the ASQ-3 score. This study was approved by the Peking University Third Hospital Medical Science Research Ethics Committee (No. IRB00006761-M2020127). Results: In the infection cohort, 13.6% of the children showed social-emotional developmental delay, and 13.5% showed overall developmental delay. The corresponding rates in the non-infection cohort were 23.4 and 8.1%. Compared with the non-infection cohort, SARS-CoV-2 infection during pregnancy did not increase the risk of social-emotional (RR = 0.87, 95% CI: 0.51-1.49) or overall (RR = 1.02, 95% CI: 0.60-1.73) developmental delay. The mediation model showed that SARS-CoV-2 infection indirectly affected the ASQ-3 score by increasing the length of mother-infant separation. Conclusions: SARS-CoV-2 during late pregnancy did not increase the risk of developmental delay of the offspring 3 months after delivery. However, SARS-CoV-2 may have indirect effects on early childhood development by increasing mother-infant separation.",
        "truth": "False"
    },
    {
        "pmid": "36306133",
        "meta_analysis_title": "COVID-19 Pandemic and Infant Neurodevelopmental Impairment: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Are neurodevelopmental outcomes during infancy changed by the COVID-19 pandemic?",
        "criteria": "A total of 1880 articles were retrieved. Of these, 670 articles were excluded as duplicates, and the remaining 1210 studies were screened for eligibility. Screening of the title and abstract resulted in 21 potentially eligible studies. Following full-text assessment, 8 studies met the inclusion criteria defined earlier (Figure 1).",
        "subgroup": "Meta-analysis of Overall Risk of Neurodevelopmental Impairment and Gross Motor, Fine Motor, and Personal-Social Domains Among Infants Screened During Pandemic vs Before Pandemic - At risk of personal-social impairment",
        "key_reference_title": "The impact of the COVID-19 pandemic on infant and toddler development.",
        "key_reference_abstract": "## BACKGROUND\nThe COVID-19 pandemic has created new cultural norms with pervasive societal implications. Families have experienced a heightened amount of physical, psychological, emotional, and financial stress. Infants and children living with stress have the potential for delayed developmental milestones, difficulty with emotional regulation, and social or behavioral issues.\n## PURPOSE\nThis study aims to determine if the pandemic has affected developmental outcomes in infants and toddlers.\n## METHODOLOGY\nPrepandemic and postpandemic developmental (ASQ-3) scores were obtained from charts of 1,024 patients (6, 12, 18, 24, and 36 months) from two pediatric practices.\n## RESULTS\nThere were no significant differences in prepandemic and postpandemic ASQ-3 scores for the overall sample. Age-group analysis showed statistically significant differences in domain scores. Postpandemic problem-solving scores decreased among 6-month-olds while increasing among 24-month-olds. Categorization by score interpretation categories showed a slight decrease in postpandemic scores in the communication domain among 6- and 12-month-olds.\n## CONCLUSIONS\nThe pandemic has the potential to affect childhood development. However, the results of this study are reassuring, showing only slight differences in developmental scores prepandemic versus postpandemic. More studies are needed to establish causation and possible trends in future developmental trajectories.\n## IMPLICATIONS\nAn increased focus on communication screening and promotion of language and communication skills in young children postpandemic is needed. Education about the importance of parent-child engagement, nurturing relationships, opportunities for free-play and exploration, and caregiver support and stress reduction will continue to be of paramount importance.",
        "truth": "True"
    },
    {
        "pmid": "36306133",
        "meta_analysis_title": "COVID-19 Pandemic and Infant Neurodevelopmental Impairment: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Are neurodevelopmental outcomes during infancy changed by the COVID-19 pandemic?",
        "criteria": "A total of 1880 articles were retrieved. Of these, 670 articles were excluded as duplicates, and the remaining 1210 studies were screened for eligibility. Screening of the title and abstract resulted in 21 potentially eligible studies. Following full-text assessment, 8 studies met the inclusion criteria defined earlier (Figure 1).",
        "subgroup": "Meta-analysis of Overall Risk of Neurodevelopmental Impairment and Gross Motor, Fine Motor, and Personal-Social Domains Among Infants Screened During Pandemic vs Before Pandemic - At risk of personal-social impairment",
        "key_reference_title": "Association Between the COVID-19 Pandemic and Infant Neurodevelopment: A Comparison Before and During COVID-19.",
        "key_reference_abstract": "None",
        "truth": "True"
    },
    {
        "pmid": "36306133",
        "meta_analysis_title": "COVID-19 Pandemic and Infant Neurodevelopmental Impairment: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Are neurodevelopmental outcomes during infancy changed by the COVID-19 pandemic?",
        "criteria": "A total of 1880 articles were retrieved. Of these, 670 articles were excluded as duplicates, and the remaining 1210 studies were screened for eligibility. Screening of the title and abstract resulted in 21 potentially eligible studies. Following full-text assessment, 8 studies met the inclusion criteria defined earlier (Figure 1).",
        "subgroup": "Meta-analysis of Overall Risk of Neurodevelopmental Impairment and Gross Motor, Fine Motor, and Personal-Social Domains Among Infants Screened During Pandemic vs Before Pandemic - At risk of personal-social impairment",
        "key_reference_title": "Impact of SARS-CoV-2 Infection During Pregnancy on Infant Neurobehavioral Development: A Case-Control Study.",
        "key_reference_abstract": "Background: Previous studies on the pneumonia outbreak caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have focused on the general population and pregnant women, while little is known about the effects of SARS-CoV-2 on retardation during and after pregnancy. The purpose of this study was to evaluate the potential influence of SARS-CoV-2 on infant neurobehavioral development. Methods: A case-control study was conducted in Wuhan Maternal and Child Health Hospital, China. Nine pregnant women with SARS-CoV-2 infection and 9 controls matched by maternal age, parity, and status of chronic disease were included. Infantile neurobehavioral development was assessed through the Ages and Stages Questionnaires Edition 3 (ASQ-3). Results: The majority of pregnant women with SARS-CoV-2 experienced cesarean section (7 of 9), which was higher than the control group (5 of 9). The throat swabs of all newborn were negative. We found that compared with the control group, neonates of mothers with SARS-CoV-2 infection during pregnancy had lower scores in communication, gross movement, fine movement, problem solving, and personal-social domains; but only fine movement domain yielded statistical significance (P = 0.031). Conclusion: Infection with SARS-CoV-2 during pregnancy may have a certain impact on infant neurobehavioral development. Further studies with larger sample size are warranted for validation.",
        "truth": "False"
    },
    {
        "pmid": "36306133",
        "meta_analysis_title": "COVID-19 Pandemic and Infant Neurodevelopmental Impairment: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Are neurodevelopmental outcomes during infancy changed by the COVID-19 pandemic?",
        "criteria": "A total of 1880 articles were retrieved. Of these, 670 articles were excluded as duplicates, and the remaining 1210 studies were screened for eligibility. Screening of the title and abstract resulted in 21 potentially eligible studies. Following full-text assessment, 8 studies met the inclusion criteria defined earlier (Figure 1).",
        "subgroup": "Meta-analysis of Overall Risk of Neurodevelopmental Impairment and Gross Motor, Fine Motor, and Personal-Social Domains Among Infants Screened During Pandemic vs Before Pandemic - At risk of personal-social impairment",
        "key_reference_title": "Increased risk for developmental delay among babies born during the pandemic.",
        "key_reference_abstract": "The COVID-19 pandemic has resulted in substantial and widespread changes to many prenatal (e.g., maternal stress) and postnatal (e.g., socialization) factors contributing to early child development. We compared developmental screening of 1-year old infants born between April 17, 2020-November 11, 2020 to data from infants born pre-pandemic. We aimed to determine whether risk for developmental delay was elevated among infants born during the pandemic compared to infants born prior to the pandemic. Data were available from 1623 PdP participants. PdP infants had lower mean scores relative to pooled pre-pandemic data on all domains except Problem Solving. PdP infants also had significantly higher risk for developmental delay in the Communication and Personal-Social domains, where the odds ratios for scoring 2 SD below the mean were 2.5 and 1.5, respectively, relative to pre-pandemic data. When stratified by sex, the odds ratios for risk of developmental delay were generally higher among female infants. In conclusions, risks for developmental delay in the Communication and Personal-Social domains were elevated in infants born during the COVID-19 pandemic compared to pre-pandemic infants, especially among girls.",
        "truth": "True"
    },
    {
        "pmid": "36306133",
        "meta_analysis_title": "COVID-19 Pandemic and Infant Neurodevelopmental Impairment: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Are neurodevelopmental outcomes during infancy changed by the COVID-19 pandemic?",
        "criteria": "A total of 1880 articles were retrieved. Of these, 670 articles were excluded as duplicates, and the remaining 1210 studies were screened for eligibility. Screening of the title and abstract resulted in 21 potentially eligible studies. Following full-text assessment, 8 studies met the inclusion criteria defined earlier (Figure 1).",
        "subgroup": "Meta-analysis of Overall Risk of Neurodevelopmental Impairment and Gross Motor, Fine Motor, and Personal-Social Domains Among Infants Screened During Pandemic vs Before Pandemic - At risk of personal-social impairment",
        "key_reference_title": "Neurodevelopmental outcomes of infants secondary to in utero exposure to maternal 2 SARS-CoV-2 infection: A national prospective study in Kuwait.",
        "key_reference_abstract": "## Background\nAn increasing proportion of women are being infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) during pregnancy. Intrauterine viral infections induce an increase in the levels of proinflammatory cytokines, which inhibit the proliferation of neuronal precursor cells and stimulate oligodendrocyte cell death, leading to abnormal neurodevelopment. Whether a maternal cytokine storm can affect neonatal brain development is unclear. The objective of the present study is to assess neurodevelopmental outcomes in neonates born to mothers with SARS-CoV-2 infections during pregnancy. ## Methods\nIn this prospective cohort study, the neurodevelopment status of infants (N=298) born to women with SARS-CoV-2 infections during pregnancy was assessed at 10-12 months post discharge using the Ages and Stages Questionnaire, 3rd edition (ASQ-3). The ASQ-3 scores were classified into developmental delays (cutoff score: \u22642 standard deviations (SDs) below the population mean) and no delay (score >2 SDs above the population mean). ## Results\nApproximately 10% of infants born to mothers with SARS-CoV-2 infections during pregnancy showed developmental delays. Two of 298 infants tested positive for SARS-CoV-2, and both had normal ASQ-3 scores. The majority of the pregnant women had SARS-CoV-2 infection during their third trimester. The risk of developmental delays among infants was higher in those whose mothers had SARS-CoV-2 infections during the first (P=0.039) and second trimesters (P=0.001) than in those whose mothers had SARS-CoV-2 infections during the third trimester. Infants born at <31 weeks gestation were more prone to developmental delays than those born at >31 weeks gestation (10% versus 0.8%; P=0.002). ## Conclusion\nThe findings of the study highlight the need for long term neurodevelopmental assessment of infants born to mothers with SARS-CoV-2 infection.",
        "truth": "False"
    },
    {
        "pmid": "36306133",
        "meta_analysis_title": "COVID-19 Pandemic and Infant Neurodevelopmental Impairment: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Are neurodevelopmental outcomes during infancy changed by the COVID-19 pandemic?",
        "criteria": "A total of 1880 articles were retrieved. Of these, 670 articles were excluded as duplicates, and the remaining 1210 studies were screened for eligibility. Screening of the title and abstract resulted in 21 potentially eligible studies. Following full-text assessment, 8 studies met the inclusion criteria defined earlier (Figure 1).",
        "subgroup": "Meta-analysis of Overall Risk of Neurodevelopmental Impairment and Gross Motor, Fine Motor, and Personal-Social Domains Among Infants Screened During Pandemic vs Before Pandemic - At risk of personal-social impairment",
        "key_reference_title": "Neurodevelopmental outcomes at one year in offspring of mothers who test positive for SARS-CoV-2 during pregnancy.",
        "key_reference_abstract": "## Importance\nEpidemiologic studies suggest maternal immune activation during pregnancy may be associated with neurodevelopmental effects in offspring. \n## Objective\nTo determine whether in utero exposure to the novel coronavirus SARS-CoV-2 is associated with risk for neurodevelopmental disorders in the first 12 months after birth. \n## Design\nRetrospective cohort\n## Participants\nLive offspring of all mothers who delivered between March and September 2020 at one of six Massachusetts hospitals across two health systems. \n## Exposure\nSARS-CoV-2 infection confirmed by PCR during pregnancy \n## Main Outcome and Measures\nNeurodevelopmental disorders determined from ICD-10 diagnostic codes over 12 months; sociodemographic and clinical features of mothers and offspring; all drawn from the electronic health record. \n## Results\nThe cohort included 7,772 live births (7,466 pregnancies, 96% singleton, 222 births to SARS-CoV-2 positive mothers), with mean maternal age of 32.9 years; offspring were 9.9% Asian, 8.4% Black, and 69.0% white; 15.1% were of Hispanic ethnicity. Preterm delivery was more likely among exposed mothers (14% versus 8.7%; p=.003). Maternal SARS-CoV-2 positivity during pregnancy was associated with greater rate of neurodevelopmental diagnoses (crude OR 2.17 [95% CI 1.24-3.79, p=0.006]) as well as models adjusted for race, ethnicity, insurance status, offspring sex, maternal age, and preterm status (adjusted OR 1.86 [95% CI 1.03-3.36, p=0.04]). Third-trimester infection was associated with effects of larger magnitude (adjusted OR 2.34, 95% CI 1.23-4.44, p=0.01) \n## Conclusion and Relevance\nOur results provide preliminary evidence that maternal SARS-CoV-2 may be associated with neurodevelopmental sequelae in some offspring. Prospective studies with longer follow-up duration will be required to exclude confounding and confirm these effects.\n## Trial Registration\nNA## Key Points\n## Question\nDoes COVID-19 exposure in utero increase the risk for neurodevelopmental disorders in the first year of life? ## Findings\nIn a cohort of babies delivered during COVID-19, those born to mothers with a positive SARS-CoV-2 PCR test during pregnancy were more likely to receive a neurodevelopmental diagnosis in the first 12 months after delivery, even after accounting for preterm delivery. ## Meaning\nThese preliminary findings suggest that COVID-19 exposure may impact neurodevelopment, and highlight the need for prospective investigation of outcomes in children exposed to COVID-19 in utero.",
        "truth": "False"
    },
    {
        "pmid": "36306133",
        "meta_analysis_title": "COVID-19 Pandemic and Infant Neurodevelopmental Impairment: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Are neurodevelopmental outcomes during infancy changed by the COVID-19 pandemic?",
        "criteria": "A total of 1880 articles were retrieved. Of these, 670 articles were excluded as duplicates, and the remaining 1210 studies were screened for eligibility. Screening of the title and abstract resulted in 21 potentially eligible studies. Following full-text assessment, 8 studies met the inclusion criteria defined earlier (Figure 1).",
        "subgroup": "Meta-analysis of Overall Risk of Neurodevelopmental Impairment (NDI) and Gross Motor, Fine Motor, and Personal-Social Domains Among In Utero Exposed vs Unexposed Pandemic-Born Cohorts - At risk of NDI",
        "key_reference_title": "Association of Birth During the COVID-19 Pandemic With Neurodevelopmental Status at 6 Months in Infants With and Without In Utero Exposure to Maternal SARS-CoV-2 Infection.",
        "key_reference_abstract": "## IMPORTANCE\nAssociations between in utero exposure to maternal SARS-CoV-2 infection and neurodevelopment are speculated, but currently unknown.\n## OBJECTIVE\nTo examine the associations between maternal SARS-CoV-2 infection during pregnancy, being born during the COVID-19 pandemic regardless of maternal SARS-CoV-2 status, and neurodevelopment at age 6 months.\n## DESIGN, SETTING, AND PARTICIPANTS\nA cohort of infants exposed to maternal SARS-CoV-2 infection during pregnancy and unexposed controls was enrolled in the COVID-19 Mother Baby Outcomes Initiative at Columbia University Irving Medical Center in New York City. All women who delivered at Columbia University Irving Medical Center with a SARS-CoV-2 infection during pregnancy were approached. Women with unexposed infants were approached based on similar gestational age at birth, date of birth, sex, and mode of delivery. Neurodevelopment was assessed using the Ages & Stages Questionnaire, 3rd Edition (ASQ-3) at age 6 months. A historical cohort of infants born before the pandemic who had completed the 6-month ASQ-3 were included in secondary analyses.\n## EXPOSURES\nMaternal SARS-CoV-2 infection during pregnancy and birth during the COVID-19 pandemic.\n## MAIN OUTCOMES AND MEASURES\nOutcomes were scores on the 5 ASQ-3 subdomains, with the hypothesis that maternal SARS-CoV-2 infection during pregnancy would be associated with decrements in social and motor development at age 6 months.\n## RESULTS\nOf 1706 women approached, 596 enrolled; 385 women were invited to a 6-month assessment, of whom 272 (70.6%) completed the ASQ-3. Data were available for 255 infants enrolled in the COVID-19 Mother Baby Outcomes Initiative (114 in utero exposed, 141 unexposed to SARS-CoV-2; median maternal age at delivery, 32.0 [IQR, 19.0-45.0] years). Data were also available from a historical cohort of 62 infants born before the pandemic. In utero exposure to maternal SARS-CoV-2 infection was not associated with significant differences on any ASQ-3 subdomain, regardless of infection timing or severity. However, compared with the historical cohort, infants born during the pandemic had significantly lower scores on gross motor (mean difference, -5.63; 95% CI, -8.75 to -2.51; F1,267\u2009=\u200912.63; P<.005), fine motor (mean difference, -6.61; 95% CI, -10.00 to -3.21; F1,267\u2009=\u200914.71; P\u2009<\u2009.005), and personal-social (mean difference, -3.71; 95% CI, -6.61 to -0.82; F1,267\u2009=\u20096.37; P<.05) subdomains in fully adjusted models.\n## CONCLUSIONS AND RELEVANCE\nIn this study, birth during the pandemic, but not in utero exposure to maternal SARS-CoV-2 infection, was associated with differences in neurodevelopment at age 6 months. These early findings support the need for long-term monitoring of children born during the COVID-19 pandemic.",
        "truth": "True"
    },
    {
        "pmid": "36306133",
        "meta_analysis_title": "COVID-19 Pandemic and Infant Neurodevelopmental Impairment: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Are neurodevelopmental outcomes during infancy changed by the COVID-19 pandemic?",
        "criteria": "A total of 1880 articles were retrieved. Of these, 670 articles were excluded as duplicates, and the remaining 1210 studies were screened for eligibility. Screening of the title and abstract resulted in 21 potentially eligible studies. Following full-text assessment, 8 studies met the inclusion criteria defined earlier (Figure 1).",
        "subgroup": "Meta-analysis of Overall Risk of Neurodevelopmental Impairment (NDI) and Gross Motor, Fine Motor, and Personal-Social Domains Among In Utero Exposed vs Unexposed Pandemic-Born Cohorts - At risk of NDI",
        "key_reference_title": "Effects of SARS-CoV-2 Infection During Late Pregnancy on Early Childhood Development: A Prospective Cohort Study.",
        "key_reference_abstract": "Background: There is little direct or indirect evidence of the effects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection during pregnancy on early childhood development. Methods: We conducted a prospective, observational cohort study in China from May 1 to October 31, 2020, that enrolled 135 mother-infant dyads: 57 dyads in the infection cohort and 78 in the non-infection cohort. Among all infants, 14.0% were preterm birth in the infection cohort and 6.4% in the non-infection cohort. Participants were followed by telephone interviews to collect demographic characteristics, medical records of coronavirus disease 2019, breastfeeding data, and early childhood development was assessed by the Age and Stage Questionnaire (ASQ-3) and Age and Stage Questionnaire Social-Emotional (ASQ:SE-2) Chinese versions at 3 months after childbirth. We used multivariable Poisson regression models to estimate the relative risk (RR) of SARS-CoV-2 infection. Multivariable linear regression models and a mediation model were used to test the direct and indirect associations between SARS-CoV-2 infection and the ASQ-3 score. This study was approved by the Peking University Third Hospital Medical Science Research Ethics Committee (No. IRB00006761-M2020127). Results: In the infection cohort, 13.6% of the children showed social-emotional developmental delay, and 13.5% showed overall developmental delay. The corresponding rates in the non-infection cohort were 23.4 and 8.1%. Compared with the non-infection cohort, SARS-CoV-2 infection during pregnancy did not increase the risk of social-emotional (RR = 0.87, 95% CI: 0.51-1.49) or overall (RR = 1.02, 95% CI: 0.60-1.73) developmental delay. The mediation model showed that SARS-CoV-2 infection indirectly affected the ASQ-3 score by increasing the length of mother-infant separation. Conclusions: SARS-CoV-2 during late pregnancy did not increase the risk of developmental delay of the offspring 3 months after delivery. However, SARS-CoV-2 may have indirect effects on early childhood development by increasing mother-infant separation.",
        "truth": "True"
    },
    {
        "pmid": "36306133",
        "meta_analysis_title": "COVID-19 Pandemic and Infant Neurodevelopmental Impairment: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Are neurodevelopmental outcomes during infancy changed by the COVID-19 pandemic?",
        "criteria": "A total of 1880 articles were retrieved. Of these, 670 articles were excluded as duplicates, and the remaining 1210 studies were screened for eligibility. Screening of the title and abstract resulted in 21 potentially eligible studies. Following full-text assessment, 8 studies met the inclusion criteria defined earlier (Figure 1).",
        "subgroup": "Meta-analysis of Overall Risk of Neurodevelopmental Impairment (NDI) and Gross Motor, Fine Motor, and Personal-Social Domains Among In Utero Exposed vs Unexposed Pandemic-Born Cohorts - At risk of NDI",
        "key_reference_title": "The impact of the COVID-19 pandemic on infant and toddler development.",
        "key_reference_abstract": "## BACKGROUND\nThe COVID-19 pandemic has created new cultural norms with pervasive societal implications. Families have experienced a heightened amount of physical, psychological, emotional, and financial stress. Infants and children living with stress have the potential for delayed developmental milestones, difficulty with emotional regulation, and social or behavioral issues.\n## PURPOSE\nThis study aims to determine if the pandemic has affected developmental outcomes in infants and toddlers.\n## METHODOLOGY\nPrepandemic and postpandemic developmental (ASQ-3) scores were obtained from charts of 1,024 patients (6, 12, 18, 24, and 36 months) from two pediatric practices.\n## RESULTS\nThere were no significant differences in prepandemic and postpandemic ASQ-3 scores for the overall sample. Age-group analysis showed statistically significant differences in domain scores. Postpandemic problem-solving scores decreased among 6-month-olds while increasing among 24-month-olds. Categorization by score interpretation categories showed a slight decrease in postpandemic scores in the communication domain among 6- and 12-month-olds.\n## CONCLUSIONS\nThe pandemic has the potential to affect childhood development. However, the results of this study are reassuring, showing only slight differences in developmental scores prepandemic versus postpandemic. More studies are needed to establish causation and possible trends in future developmental trajectories.\n## IMPLICATIONS\nAn increased focus on communication screening and promotion of language and communication skills in young children postpandemic is needed. Education about the importance of parent-child engagement, nurturing relationships, opportunities for free-play and exploration, and caregiver support and stress reduction will continue to be of paramount importance.",
        "truth": "False"
    },
    {
        "pmid": "36306133",
        "meta_analysis_title": "COVID-19 Pandemic and Infant Neurodevelopmental Impairment: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Are neurodevelopmental outcomes during infancy changed by the COVID-19 pandemic?",
        "criteria": "A total of 1880 articles were retrieved. Of these, 670 articles were excluded as duplicates, and the remaining 1210 studies were screened for eligibility. Screening of the title and abstract resulted in 21 potentially eligible studies. Following full-text assessment, 8 studies met the inclusion criteria defined earlier (Figure 1).",
        "subgroup": "Meta-analysis of Overall Risk of Neurodevelopmental Impairment (NDI) and Gross Motor, Fine Motor, and Personal-Social Domains Among In Utero Exposed vs Unexposed Pandemic-Born Cohorts - At risk of NDI",
        "key_reference_title": "Association Between the COVID-19 Pandemic and Infant Neurodevelopment: A Comparison Before and During COVID-19.",
        "key_reference_abstract": "None",
        "truth": "False"
    },
    {
        "pmid": "36306133",
        "meta_analysis_title": "COVID-19 Pandemic and Infant Neurodevelopmental Impairment: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Are neurodevelopmental outcomes during infancy changed by the COVID-19 pandemic?",
        "criteria": "A total of 1880 articles were retrieved. Of these, 670 articles were excluded as duplicates, and the remaining 1210 studies were screened for eligibility. Screening of the title and abstract resulted in 21 potentially eligible studies. Following full-text assessment, 8 studies met the inclusion criteria defined earlier (Figure 1).",
        "subgroup": "Meta-analysis of Overall Risk of Neurodevelopmental Impairment (NDI) and Gross Motor, Fine Motor, and Personal-Social Domains Among In Utero Exposed vs Unexposed Pandemic-Born Cohorts - At risk of NDI",
        "key_reference_title": "Impact of SARS-CoV-2 Infection During Pregnancy on Infant Neurobehavioral Development: A Case-Control Study.",
        "key_reference_abstract": "Background: Previous studies on the pneumonia outbreak caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have focused on the general population and pregnant women, while little is known about the effects of SARS-CoV-2 on retardation during and after pregnancy. The purpose of this study was to evaluate the potential influence of SARS-CoV-2 on infant neurobehavioral development. Methods: A case-control study was conducted in Wuhan Maternal and Child Health Hospital, China. Nine pregnant women with SARS-CoV-2 infection and 9 controls matched by maternal age, parity, and status of chronic disease were included. Infantile neurobehavioral development was assessed through the Ages and Stages Questionnaires Edition 3 (ASQ-3). Results: The majority of pregnant women with SARS-CoV-2 experienced cesarean section (7 of 9), which was higher than the control group (5 of 9). The throat swabs of all newborn were negative. We found that compared with the control group, neonates of mothers with SARS-CoV-2 infection during pregnancy had lower scores in communication, gross movement, fine movement, problem solving, and personal-social domains; but only fine movement domain yielded statistical significance (P = 0.031). Conclusion: Infection with SARS-CoV-2 during pregnancy may have a certain impact on infant neurobehavioral development. Further studies with larger sample size are warranted for validation.",
        "truth": "False"
    },
    {
        "pmid": "36306133",
        "meta_analysis_title": "COVID-19 Pandemic and Infant Neurodevelopmental Impairment: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Are neurodevelopmental outcomes during infancy changed by the COVID-19 pandemic?",
        "criteria": "A total of 1880 articles were retrieved. Of these, 670 articles were excluded as duplicates, and the remaining 1210 studies were screened for eligibility. Screening of the title and abstract resulted in 21 potentially eligible studies. Following full-text assessment, 8 studies met the inclusion criteria defined earlier (Figure 1).",
        "subgroup": "Meta-analysis of Overall Risk of Neurodevelopmental Impairment (NDI) and Gross Motor, Fine Motor, and Personal-Social Domains Among In Utero Exposed vs Unexposed Pandemic-Born Cohorts - At risk of NDI",
        "key_reference_title": "Increased risk for developmental delay among babies born during the pandemic.",
        "key_reference_abstract": "The COVID-19 pandemic has resulted in substantial and widespread changes to many prenatal (e.g., maternal stress) and postnatal (e.g., socialization) factors contributing to early child development. We compared developmental screening of 1-year old infants born between April 17, 2020-November 11, 2020 to data from infants born pre-pandemic. We aimed to determine whether risk for developmental delay was elevated among infants born during the pandemic compared to infants born prior to the pandemic. Data were available from 1623 PdP participants. PdP infants had lower mean scores relative to pooled pre-pandemic data on all domains except Problem Solving. PdP infants also had significantly higher risk for developmental delay in the Communication and Personal-Social domains, where the odds ratios for scoring 2 SD below the mean were 2.5 and 1.5, respectively, relative to pre-pandemic data. When stratified by sex, the odds ratios for risk of developmental delay were generally higher among female infants. In conclusions, risks for developmental delay in the Communication and Personal-Social domains were elevated in infants born during the COVID-19 pandemic compared to pre-pandemic infants, especially among girls.",
        "truth": "False"
    },
    {
        "pmid": "36306133",
        "meta_analysis_title": "COVID-19 Pandemic and Infant Neurodevelopmental Impairment: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Are neurodevelopmental outcomes during infancy changed by the COVID-19 pandemic?",
        "criteria": "A total of 1880 articles were retrieved. Of these, 670 articles were excluded as duplicates, and the remaining 1210 studies were screened for eligibility. Screening of the title and abstract resulted in 21 potentially eligible studies. Following full-text assessment, 8 studies met the inclusion criteria defined earlier (Figure 1).",
        "subgroup": "Meta-analysis of Overall Risk of Neurodevelopmental Impairment (NDI) and Gross Motor, Fine Motor, and Personal-Social Domains Among In Utero Exposed vs Unexposed Pandemic-Born Cohorts - At risk of NDI",
        "key_reference_title": "Neurodevelopmental outcomes of infants secondary to in utero exposure to maternal 2 SARS-CoV-2 infection: A national prospective study in Kuwait.",
        "key_reference_abstract": "## Background\nAn increasing proportion of women are being infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) during pregnancy. Intrauterine viral infections induce an increase in the levels of proinflammatory cytokines, which inhibit the proliferation of neuronal precursor cells and stimulate oligodendrocyte cell death, leading to abnormal neurodevelopment. Whether a maternal cytokine storm can affect neonatal brain development is unclear. The objective of the present study is to assess neurodevelopmental outcomes in neonates born to mothers with SARS-CoV-2 infections during pregnancy. ## Methods\nIn this prospective cohort study, the neurodevelopment status of infants (N=298) born to women with SARS-CoV-2 infections during pregnancy was assessed at 10-12 months post discharge using the Ages and Stages Questionnaire, 3rd edition (ASQ-3). The ASQ-3 scores were classified into developmental delays (cutoff score: \u22642 standard deviations (SDs) below the population mean) and no delay (score >2 SDs above the population mean). ## Results\nApproximately 10% of infants born to mothers with SARS-CoV-2 infections during pregnancy showed developmental delays. Two of 298 infants tested positive for SARS-CoV-2, and both had normal ASQ-3 scores. The majority of the pregnant women had SARS-CoV-2 infection during their third trimester. The risk of developmental delays among infants was higher in those whose mothers had SARS-CoV-2 infections during the first (P=0.039) and second trimesters (P=0.001) than in those whose mothers had SARS-CoV-2 infections during the third trimester. Infants born at <31 weeks gestation were more prone to developmental delays than those born at >31 weeks gestation (10% versus 0.8%; P=0.002). ## Conclusion\nThe findings of the study highlight the need for long term neurodevelopmental assessment of infants born to mothers with SARS-CoV-2 infection.",
        "truth": "False"
    },
    {
        "pmid": "36306133",
        "meta_analysis_title": "COVID-19 Pandemic and Infant Neurodevelopmental Impairment: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Are neurodevelopmental outcomes during infancy changed by the COVID-19 pandemic?",
        "criteria": "A total of 1880 articles were retrieved. Of these, 670 articles were excluded as duplicates, and the remaining 1210 studies were screened for eligibility. Screening of the title and abstract resulted in 21 potentially eligible studies. Following full-text assessment, 8 studies met the inclusion criteria defined earlier (Figure 1).",
        "subgroup": "Meta-analysis of Overall Risk of Neurodevelopmental Impairment (NDI) and Gross Motor, Fine Motor, and Personal-Social Domains Among In Utero Exposed vs Unexposed Pandemic-Born Cohorts - At risk of NDI",
        "key_reference_title": "Neurodevelopmental outcomes at one year in offspring of mothers who test positive for SARS-CoV-2 during pregnancy.",
        "key_reference_abstract": "## Importance\nEpidemiologic studies suggest maternal immune activation during pregnancy may be associated with neurodevelopmental effects in offspring. \n## Objective\nTo determine whether in utero exposure to the novel coronavirus SARS-CoV-2 is associated with risk for neurodevelopmental disorders in the first 12 months after birth. \n## Design\nRetrospective cohort\n## Participants\nLive offspring of all mothers who delivered between March and September 2020 at one of six Massachusetts hospitals across two health systems. \n## Exposure\nSARS-CoV-2 infection confirmed by PCR during pregnancy \n## Main Outcome and Measures\nNeurodevelopmental disorders determined from ICD-10 diagnostic codes over 12 months; sociodemographic and clinical features of mothers and offspring; all drawn from the electronic health record. \n## Results\nThe cohort included 7,772 live births (7,466 pregnancies, 96% singleton, 222 births to SARS-CoV-2 positive mothers), with mean maternal age of 32.9 years; offspring were 9.9% Asian, 8.4% Black, and 69.0% white; 15.1% were of Hispanic ethnicity. Preterm delivery was more likely among exposed mothers (14% versus 8.7%; p=.003). Maternal SARS-CoV-2 positivity during pregnancy was associated with greater rate of neurodevelopmental diagnoses (crude OR 2.17 [95% CI 1.24-3.79, p=0.006]) as well as models adjusted for race, ethnicity, insurance status, offspring sex, maternal age, and preterm status (adjusted OR 1.86 [95% CI 1.03-3.36, p=0.04]). Third-trimester infection was associated with effects of larger magnitude (adjusted OR 2.34, 95% CI 1.23-4.44, p=0.01) \n## Conclusion and Relevance\nOur results provide preliminary evidence that maternal SARS-CoV-2 may be associated with neurodevelopmental sequelae in some offspring. Prospective studies with longer follow-up duration will be required to exclude confounding and confirm these effects.\n## Trial Registration\nNA## Key Points\n## Question\nDoes COVID-19 exposure in utero increase the risk for neurodevelopmental disorders in the first year of life? ## Findings\nIn a cohort of babies delivered during COVID-19, those born to mothers with a positive SARS-CoV-2 PCR test during pregnancy were more likely to receive a neurodevelopmental diagnosis in the first 12 months after delivery, even after accounting for preterm delivery. ## Meaning\nThese preliminary findings suggest that COVID-19 exposure may impact neurodevelopment, and highlight the need for prospective investigation of outcomes in children exposed to COVID-19 in utero.",
        "truth": "False"
    },
    {
        "pmid": "36306133",
        "meta_analysis_title": "COVID-19 Pandemic and Infant Neurodevelopmental Impairment: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Are neurodevelopmental outcomes during infancy changed by the COVID-19 pandemic?",
        "criteria": "A total of 1880 articles were retrieved. Of these, 670 articles were excluded as duplicates, and the remaining 1210 studies were screened for eligibility. Screening of the title and abstract resulted in 21 potentially eligible studies. Following full-text assessment, 8 studies met the inclusion criteria defined earlier (Figure 1).",
        "subgroup": "Meta-analysis of Overall Risk of Neurodevelopmental Impairment (NDI) and Gross Motor, Fine Motor, and Personal-Social Domains Among In Utero Exposed vs Unexposed Pandemic-Born Cohorts - At risk of gross motor impairment",
        "key_reference_title": "Association of Birth During the COVID-19 Pandemic With Neurodevelopmental Status at 6 Months in Infants With and Without In Utero Exposure to Maternal SARS-CoV-2 Infection.",
        "key_reference_abstract": "## IMPORTANCE\nAssociations between in utero exposure to maternal SARS-CoV-2 infection and neurodevelopment are speculated, but currently unknown.\n## OBJECTIVE\nTo examine the associations between maternal SARS-CoV-2 infection during pregnancy, being born during the COVID-19 pandemic regardless of maternal SARS-CoV-2 status, and neurodevelopment at age 6 months.\n## DESIGN, SETTING, AND PARTICIPANTS\nA cohort of infants exposed to maternal SARS-CoV-2 infection during pregnancy and unexposed controls was enrolled in the COVID-19 Mother Baby Outcomes Initiative at Columbia University Irving Medical Center in New York City. All women who delivered at Columbia University Irving Medical Center with a SARS-CoV-2 infection during pregnancy were approached. Women with unexposed infants were approached based on similar gestational age at birth, date of birth, sex, and mode of delivery. Neurodevelopment was assessed using the Ages & Stages Questionnaire, 3rd Edition (ASQ-3) at age 6 months. A historical cohort of infants born before the pandemic who had completed the 6-month ASQ-3 were included in secondary analyses.\n## EXPOSURES\nMaternal SARS-CoV-2 infection during pregnancy and birth during the COVID-19 pandemic.\n## MAIN OUTCOMES AND MEASURES\nOutcomes were scores on the 5 ASQ-3 subdomains, with the hypothesis that maternal SARS-CoV-2 infection during pregnancy would be associated with decrements in social and motor development at age 6 months.\n## RESULTS\nOf 1706 women approached, 596 enrolled; 385 women were invited to a 6-month assessment, of whom 272 (70.6%) completed the ASQ-3. Data were available for 255 infants enrolled in the COVID-19 Mother Baby Outcomes Initiative (114 in utero exposed, 141 unexposed to SARS-CoV-2; median maternal age at delivery, 32.0 [IQR, 19.0-45.0] years). Data were also available from a historical cohort of 62 infants born before the pandemic. In utero exposure to maternal SARS-CoV-2 infection was not associated with significant differences on any ASQ-3 subdomain, regardless of infection timing or severity. However, compared with the historical cohort, infants born during the pandemic had significantly lower scores on gross motor (mean difference, -5.63; 95% CI, -8.75 to -2.51; F1,267\u2009=\u200912.63; P<.005), fine motor (mean difference, -6.61; 95% CI, -10.00 to -3.21; F1,267\u2009=\u200914.71; P\u2009<\u2009.005), and personal-social (mean difference, -3.71; 95% CI, -6.61 to -0.82; F1,267\u2009=\u20096.37; P<.05) subdomains in fully adjusted models.\n## CONCLUSIONS AND RELEVANCE\nIn this study, birth during the pandemic, but not in utero exposure to maternal SARS-CoV-2 infection, was associated with differences in neurodevelopment at age 6 months. These early findings support the need for long-term monitoring of children born during the COVID-19 pandemic.",
        "truth": "True"
    },
    {
        "pmid": "36306133",
        "meta_analysis_title": "COVID-19 Pandemic and Infant Neurodevelopmental Impairment: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Are neurodevelopmental outcomes during infancy changed by the COVID-19 pandemic?",
        "criteria": "A total of 1880 articles were retrieved. Of these, 670 articles were excluded as duplicates, and the remaining 1210 studies were screened for eligibility. Screening of the title and abstract resulted in 21 potentially eligible studies. Following full-text assessment, 8 studies met the inclusion criteria defined earlier (Figure 1).",
        "subgroup": "Meta-analysis of Overall Risk of Neurodevelopmental Impairment (NDI) and Gross Motor, Fine Motor, and Personal-Social Domains Among In Utero Exposed vs Unexposed Pandemic-Born Cohorts - At risk of gross motor impairment",
        "key_reference_title": "Effects of SARS-CoV-2 Infection During Late Pregnancy on Early Childhood Development: A Prospective Cohort Study.",
        "key_reference_abstract": "Background: There is little direct or indirect evidence of the effects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection during pregnancy on early childhood development. Methods: We conducted a prospective, observational cohort study in China from May 1 to October 31, 2020, that enrolled 135 mother-infant dyads: 57 dyads in the infection cohort and 78 in the non-infection cohort. Among all infants, 14.0% were preterm birth in the infection cohort and 6.4% in the non-infection cohort. Participants were followed by telephone interviews to collect demographic characteristics, medical records of coronavirus disease 2019, breastfeeding data, and early childhood development was assessed by the Age and Stage Questionnaire (ASQ-3) and Age and Stage Questionnaire Social-Emotional (ASQ:SE-2) Chinese versions at 3 months after childbirth. We used multivariable Poisson regression models to estimate the relative risk (RR) of SARS-CoV-2 infection. Multivariable linear regression models and a mediation model were used to test the direct and indirect associations between SARS-CoV-2 infection and the ASQ-3 score. This study was approved by the Peking University Third Hospital Medical Science Research Ethics Committee (No. IRB00006761-M2020127). Results: In the infection cohort, 13.6% of the children showed social-emotional developmental delay, and 13.5% showed overall developmental delay. The corresponding rates in the non-infection cohort were 23.4 and 8.1%. Compared with the non-infection cohort, SARS-CoV-2 infection during pregnancy did not increase the risk of social-emotional (RR = 0.87, 95% CI: 0.51-1.49) or overall (RR = 1.02, 95% CI: 0.60-1.73) developmental delay. The mediation model showed that SARS-CoV-2 infection indirectly affected the ASQ-3 score by increasing the length of mother-infant separation. Conclusions: SARS-CoV-2 during late pregnancy did not increase the risk of developmental delay of the offspring 3 months after delivery. However, SARS-CoV-2 may have indirect effects on early childhood development by increasing mother-infant separation.",
        "truth": "True"
    },
    {
        "pmid": "36306133",
        "meta_analysis_title": "COVID-19 Pandemic and Infant Neurodevelopmental Impairment: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Are neurodevelopmental outcomes during infancy changed by the COVID-19 pandemic?",
        "criteria": "A total of 1880 articles were retrieved. Of these, 670 articles were excluded as duplicates, and the remaining 1210 studies were screened for eligibility. Screening of the title and abstract resulted in 21 potentially eligible studies. Following full-text assessment, 8 studies met the inclusion criteria defined earlier (Figure 1).",
        "subgroup": "Meta-analysis of Overall Risk of Neurodevelopmental Impairment (NDI) and Gross Motor, Fine Motor, and Personal-Social Domains Among In Utero Exposed vs Unexposed Pandemic-Born Cohorts - At risk of gross motor impairment",
        "key_reference_title": "The impact of the COVID-19 pandemic on infant and toddler development.",
        "key_reference_abstract": "## BACKGROUND\nThe COVID-19 pandemic has created new cultural norms with pervasive societal implications. Families have experienced a heightened amount of physical, psychological, emotional, and financial stress. Infants and children living with stress have the potential for delayed developmental milestones, difficulty with emotional regulation, and social or behavioral issues.\n## PURPOSE\nThis study aims to determine if the pandemic has affected developmental outcomes in infants and toddlers.\n## METHODOLOGY\nPrepandemic and postpandemic developmental (ASQ-3) scores were obtained from charts of 1,024 patients (6, 12, 18, 24, and 36 months) from two pediatric practices.\n## RESULTS\nThere were no significant differences in prepandemic and postpandemic ASQ-3 scores for the overall sample. Age-group analysis showed statistically significant differences in domain scores. Postpandemic problem-solving scores decreased among 6-month-olds while increasing among 24-month-olds. Categorization by score interpretation categories showed a slight decrease in postpandemic scores in the communication domain among 6- and 12-month-olds.\n## CONCLUSIONS\nThe pandemic has the potential to affect childhood development. However, the results of this study are reassuring, showing only slight differences in developmental scores prepandemic versus postpandemic. More studies are needed to establish causation and possible trends in future developmental trajectories.\n## IMPLICATIONS\nAn increased focus on communication screening and promotion of language and communication skills in young children postpandemic is needed. Education about the importance of parent-child engagement, nurturing relationships, opportunities for free-play and exploration, and caregiver support and stress reduction will continue to be of paramount importance.",
        "truth": "False"
    },
    {
        "pmid": "36306133",
        "meta_analysis_title": "COVID-19 Pandemic and Infant Neurodevelopmental Impairment: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Are neurodevelopmental outcomes during infancy changed by the COVID-19 pandemic?",
        "criteria": "A total of 1880 articles were retrieved. Of these, 670 articles were excluded as duplicates, and the remaining 1210 studies were screened for eligibility. Screening of the title and abstract resulted in 21 potentially eligible studies. Following full-text assessment, 8 studies met the inclusion criteria defined earlier (Figure 1).",
        "subgroup": "Meta-analysis of Overall Risk of Neurodevelopmental Impairment (NDI) and Gross Motor, Fine Motor, and Personal-Social Domains Among In Utero Exposed vs Unexposed Pandemic-Born Cohorts - At risk of gross motor impairment",
        "key_reference_title": "Association Between the COVID-19 Pandemic and Infant Neurodevelopment: A Comparison Before and During COVID-19.",
        "key_reference_abstract": "None",
        "truth": "False"
    },
    {
        "pmid": "36306133",
        "meta_analysis_title": "COVID-19 Pandemic and Infant Neurodevelopmental Impairment: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Are neurodevelopmental outcomes during infancy changed by the COVID-19 pandemic?",
        "criteria": "A total of 1880 articles were retrieved. Of these, 670 articles were excluded as duplicates, and the remaining 1210 studies were screened for eligibility. Screening of the title and abstract resulted in 21 potentially eligible studies. Following full-text assessment, 8 studies met the inclusion criteria defined earlier (Figure 1).",
        "subgroup": "Meta-analysis of Overall Risk of Neurodevelopmental Impairment (NDI) and Gross Motor, Fine Motor, and Personal-Social Domains Among In Utero Exposed vs Unexposed Pandemic-Born Cohorts - At risk of gross motor impairment",
        "key_reference_title": "Impact of SARS-CoV-2 Infection During Pregnancy on Infant Neurobehavioral Development: A Case-Control Study.",
        "key_reference_abstract": "Background: Previous studies on the pneumonia outbreak caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have focused on the general population and pregnant women, while little is known about the effects of SARS-CoV-2 on retardation during and after pregnancy. The purpose of this study was to evaluate the potential influence of SARS-CoV-2 on infant neurobehavioral development. Methods: A case-control study was conducted in Wuhan Maternal and Child Health Hospital, China. Nine pregnant women with SARS-CoV-2 infection and 9 controls matched by maternal age, parity, and status of chronic disease were included. Infantile neurobehavioral development was assessed through the Ages and Stages Questionnaires Edition 3 (ASQ-3). Results: The majority of pregnant women with SARS-CoV-2 experienced cesarean section (7 of 9), which was higher than the control group (5 of 9). The throat swabs of all newborn were negative. We found that compared with the control group, neonates of mothers with SARS-CoV-2 infection during pregnancy had lower scores in communication, gross movement, fine movement, problem solving, and personal-social domains; but only fine movement domain yielded statistical significance (P = 0.031). Conclusion: Infection with SARS-CoV-2 during pregnancy may have a certain impact on infant neurobehavioral development. Further studies with larger sample size are warranted for validation.",
        "truth": "False"
    },
    {
        "pmid": "36306133",
        "meta_analysis_title": "COVID-19 Pandemic and Infant Neurodevelopmental Impairment: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Are neurodevelopmental outcomes during infancy changed by the COVID-19 pandemic?",
        "criteria": "A total of 1880 articles were retrieved. Of these, 670 articles were excluded as duplicates, and the remaining 1210 studies were screened for eligibility. Screening of the title and abstract resulted in 21 potentially eligible studies. Following full-text assessment, 8 studies met the inclusion criteria defined earlier (Figure 1).",
        "subgroup": "Meta-analysis of Overall Risk of Neurodevelopmental Impairment (NDI) and Gross Motor, Fine Motor, and Personal-Social Domains Among In Utero Exposed vs Unexposed Pandemic-Born Cohorts - At risk of gross motor impairment",
        "key_reference_title": "Increased risk for developmental delay among babies born during the pandemic.",
        "key_reference_abstract": "The COVID-19 pandemic has resulted in substantial and widespread changes to many prenatal (e.g., maternal stress) and postnatal (e.g., socialization) factors contributing to early child development. We compared developmental screening of 1-year old infants born between April 17, 2020-November 11, 2020 to data from infants born pre-pandemic. We aimed to determine whether risk for developmental delay was elevated among infants born during the pandemic compared to infants born prior to the pandemic. Data were available from 1623 PdP participants. PdP infants had lower mean scores relative to pooled pre-pandemic data on all domains except Problem Solving. PdP infants also had significantly higher risk for developmental delay in the Communication and Personal-Social domains, where the odds ratios for scoring 2 SD below the mean were 2.5 and 1.5, respectively, relative to pre-pandemic data. When stratified by sex, the odds ratios for risk of developmental delay were generally higher among female infants. In conclusions, risks for developmental delay in the Communication and Personal-Social domains were elevated in infants born during the COVID-19 pandemic compared to pre-pandemic infants, especially among girls.",
        "truth": "False"
    },
    {
        "pmid": "36306133",
        "meta_analysis_title": "COVID-19 Pandemic and Infant Neurodevelopmental Impairment: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Are neurodevelopmental outcomes during infancy changed by the COVID-19 pandemic?",
        "criteria": "A total of 1880 articles were retrieved. Of these, 670 articles were excluded as duplicates, and the remaining 1210 studies were screened for eligibility. Screening of the title and abstract resulted in 21 potentially eligible studies. Following full-text assessment, 8 studies met the inclusion criteria defined earlier (Figure 1).",
        "subgroup": "Meta-analysis of Overall Risk of Neurodevelopmental Impairment (NDI) and Gross Motor, Fine Motor, and Personal-Social Domains Among In Utero Exposed vs Unexposed Pandemic-Born Cohorts - At risk of gross motor impairment",
        "key_reference_title": "Neurodevelopmental outcomes of infants secondary to in utero exposure to maternal 2 SARS-CoV-2 infection: A national prospective study in Kuwait.",
        "key_reference_abstract": "## Background\nAn increasing proportion of women are being infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) during pregnancy. Intrauterine viral infections induce an increase in the levels of proinflammatory cytokines, which inhibit the proliferation of neuronal precursor cells and stimulate oligodendrocyte cell death, leading to abnormal neurodevelopment. Whether a maternal cytokine storm can affect neonatal brain development is unclear. The objective of the present study is to assess neurodevelopmental outcomes in neonates born to mothers with SARS-CoV-2 infections during pregnancy. ## Methods\nIn this prospective cohort study, the neurodevelopment status of infants (N=298) born to women with SARS-CoV-2 infections during pregnancy was assessed at 10-12 months post discharge using the Ages and Stages Questionnaire, 3rd edition (ASQ-3). The ASQ-3 scores were classified into developmental delays (cutoff score: \u22642 standard deviations (SDs) below the population mean) and no delay (score >2 SDs above the population mean). ## Results\nApproximately 10% of infants born to mothers with SARS-CoV-2 infections during pregnancy showed developmental delays. Two of 298 infants tested positive for SARS-CoV-2, and both had normal ASQ-3 scores. The majority of the pregnant women had SARS-CoV-2 infection during their third trimester. The risk of developmental delays among infants was higher in those whose mothers had SARS-CoV-2 infections during the first (P=0.039) and second trimesters (P=0.001) than in those whose mothers had SARS-CoV-2 infections during the third trimester. Infants born at <31 weeks gestation were more prone to developmental delays than those born at >31 weeks gestation (10% versus 0.8%; P=0.002). ## Conclusion\nThe findings of the study highlight the need for long term neurodevelopmental assessment of infants born to mothers with SARS-CoV-2 infection.",
        "truth": "False"
    },
    {
        "pmid": "36306133",
        "meta_analysis_title": "COVID-19 Pandemic and Infant Neurodevelopmental Impairment: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Are neurodevelopmental outcomes during infancy changed by the COVID-19 pandemic?",
        "criteria": "A total of 1880 articles were retrieved. Of these, 670 articles were excluded as duplicates, and the remaining 1210 studies were screened for eligibility. Screening of the title and abstract resulted in 21 potentially eligible studies. Following full-text assessment, 8 studies met the inclusion criteria defined earlier (Figure 1).",
        "subgroup": "Meta-analysis of Overall Risk of Neurodevelopmental Impairment (NDI) and Gross Motor, Fine Motor, and Personal-Social Domains Among In Utero Exposed vs Unexposed Pandemic-Born Cohorts - At risk of gross motor impairment",
        "key_reference_title": "Neurodevelopmental outcomes at one year in offspring of mothers who test positive for SARS-CoV-2 during pregnancy.",
        "key_reference_abstract": "## Importance\nEpidemiologic studies suggest maternal immune activation during pregnancy may be associated with neurodevelopmental effects in offspring. \n## Objective\nTo determine whether in utero exposure to the novel coronavirus SARS-CoV-2 is associated with risk for neurodevelopmental disorders in the first 12 months after birth. \n## Design\nRetrospective cohort\n## Participants\nLive offspring of all mothers who delivered between March and September 2020 at one of six Massachusetts hospitals across two health systems. \n## Exposure\nSARS-CoV-2 infection confirmed by PCR during pregnancy \n## Main Outcome and Measures\nNeurodevelopmental disorders determined from ICD-10 diagnostic codes over 12 months; sociodemographic and clinical features of mothers and offspring; all drawn from the electronic health record. \n## Results\nThe cohort included 7,772 live births (7,466 pregnancies, 96% singleton, 222 births to SARS-CoV-2 positive mothers), with mean maternal age of 32.9 years; offspring were 9.9% Asian, 8.4% Black, and 69.0% white; 15.1% were of Hispanic ethnicity. Preterm delivery was more likely among exposed mothers (14% versus 8.7%; p=.003). Maternal SARS-CoV-2 positivity during pregnancy was associated with greater rate of neurodevelopmental diagnoses (crude OR 2.17 [95% CI 1.24-3.79, p=0.006]) as well as models adjusted for race, ethnicity, insurance status, offspring sex, maternal age, and preterm status (adjusted OR 1.86 [95% CI 1.03-3.36, p=0.04]). Third-trimester infection was associated with effects of larger magnitude (adjusted OR 2.34, 95% CI 1.23-4.44, p=0.01) \n## Conclusion and Relevance\nOur results provide preliminary evidence that maternal SARS-CoV-2 may be associated with neurodevelopmental sequelae in some offspring. Prospective studies with longer follow-up duration will be required to exclude confounding and confirm these effects.\n## Trial Registration\nNA## Key Points\n## Question\nDoes COVID-19 exposure in utero increase the risk for neurodevelopmental disorders in the first year of life? ## Findings\nIn a cohort of babies delivered during COVID-19, those born to mothers with a positive SARS-CoV-2 PCR test during pregnancy were more likely to receive a neurodevelopmental diagnosis in the first 12 months after delivery, even after accounting for preterm delivery. ## Meaning\nThese preliminary findings suggest that COVID-19 exposure may impact neurodevelopment, and highlight the need for prospective investigation of outcomes in children exposed to COVID-19 in utero.",
        "truth": "False"
    },
    {
        "pmid": "36306133",
        "meta_analysis_title": "COVID-19 Pandemic and Infant Neurodevelopmental Impairment: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Are neurodevelopmental outcomes during infancy changed by the COVID-19 pandemic?",
        "criteria": "A total of 1880 articles were retrieved. Of these, 670 articles were excluded as duplicates, and the remaining 1210 studies were screened for eligibility. Screening of the title and abstract resulted in 21 potentially eligible studies. Following full-text assessment, 8 studies met the inclusion criteria defined earlier (Figure 1).",
        "subgroup": "Meta-analysis of Overall Risk of Neurodevelopmental Impairment (NDI) and Gross Motor, Fine Motor, and Personal-Social Domains Among In Utero Exposed vs Unexposed Pandemic-Born Cohorts - At risk of fine motor impairment",
        "key_reference_title": "Association of Birth During the COVID-19 Pandemic With Neurodevelopmental Status at 6 Months in Infants With and Without In Utero Exposure to Maternal SARS-CoV-2 Infection.",
        "key_reference_abstract": "## IMPORTANCE\nAssociations between in utero exposure to maternal SARS-CoV-2 infection and neurodevelopment are speculated, but currently unknown.\n## OBJECTIVE\nTo examine the associations between maternal SARS-CoV-2 infection during pregnancy, being born during the COVID-19 pandemic regardless of maternal SARS-CoV-2 status, and neurodevelopment at age 6 months.\n## DESIGN, SETTING, AND PARTICIPANTS\nA cohort of infants exposed to maternal SARS-CoV-2 infection during pregnancy and unexposed controls was enrolled in the COVID-19 Mother Baby Outcomes Initiative at Columbia University Irving Medical Center in New York City. All women who delivered at Columbia University Irving Medical Center with a SARS-CoV-2 infection during pregnancy were approached. Women with unexposed infants were approached based on similar gestational age at birth, date of birth, sex, and mode of delivery. Neurodevelopment was assessed using the Ages & Stages Questionnaire, 3rd Edition (ASQ-3) at age 6 months. A historical cohort of infants born before the pandemic who had completed the 6-month ASQ-3 were included in secondary analyses.\n## EXPOSURES\nMaternal SARS-CoV-2 infection during pregnancy and birth during the COVID-19 pandemic.\n## MAIN OUTCOMES AND MEASURES\nOutcomes were scores on the 5 ASQ-3 subdomains, with the hypothesis that maternal SARS-CoV-2 infection during pregnancy would be associated with decrements in social and motor development at age 6 months.\n## RESULTS\nOf 1706 women approached, 596 enrolled; 385 women were invited to a 6-month assessment, of whom 272 (70.6%) completed the ASQ-3. Data were available for 255 infants enrolled in the COVID-19 Mother Baby Outcomes Initiative (114 in utero exposed, 141 unexposed to SARS-CoV-2; median maternal age at delivery, 32.0 [IQR, 19.0-45.0] years). Data were also available from a historical cohort of 62 infants born before the pandemic. In utero exposure to maternal SARS-CoV-2 infection was not associated with significant differences on any ASQ-3 subdomain, regardless of infection timing or severity. However, compared with the historical cohort, infants born during the pandemic had significantly lower scores on gross motor (mean difference, -5.63; 95% CI, -8.75 to -2.51; F1,267\u2009=\u200912.63; P<.005), fine motor (mean difference, -6.61; 95% CI, -10.00 to -3.21; F1,267\u2009=\u200914.71; P\u2009<\u2009.005), and personal-social (mean difference, -3.71; 95% CI, -6.61 to -0.82; F1,267\u2009=\u20096.37; P<.05) subdomains in fully adjusted models.\n## CONCLUSIONS AND RELEVANCE\nIn this study, birth during the pandemic, but not in utero exposure to maternal SARS-CoV-2 infection, was associated with differences in neurodevelopment at age 6 months. These early findings support the need for long-term monitoring of children born during the COVID-19 pandemic.",
        "truth": "True"
    },
    {
        "pmid": "36306133",
        "meta_analysis_title": "COVID-19 Pandemic and Infant Neurodevelopmental Impairment: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Are neurodevelopmental outcomes during infancy changed by the COVID-19 pandemic?",
        "criteria": "A total of 1880 articles were retrieved. Of these, 670 articles were excluded as duplicates, and the remaining 1210 studies were screened for eligibility. Screening of the title and abstract resulted in 21 potentially eligible studies. Following full-text assessment, 8 studies met the inclusion criteria defined earlier (Figure 1).",
        "subgroup": "Meta-analysis of Overall Risk of Neurodevelopmental Impairment (NDI) and Gross Motor, Fine Motor, and Personal-Social Domains Among In Utero Exposed vs Unexposed Pandemic-Born Cohorts - At risk of fine motor impairment",
        "key_reference_title": "Effects of SARS-CoV-2 Infection During Late Pregnancy on Early Childhood Development: A Prospective Cohort Study.",
        "key_reference_abstract": "Background: There is little direct or indirect evidence of the effects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection during pregnancy on early childhood development. Methods: We conducted a prospective, observational cohort study in China from May 1 to October 31, 2020, that enrolled 135 mother-infant dyads: 57 dyads in the infection cohort and 78 in the non-infection cohort. Among all infants, 14.0% were preterm birth in the infection cohort and 6.4% in the non-infection cohort. Participants were followed by telephone interviews to collect demographic characteristics, medical records of coronavirus disease 2019, breastfeeding data, and early childhood development was assessed by the Age and Stage Questionnaire (ASQ-3) and Age and Stage Questionnaire Social-Emotional (ASQ:SE-2) Chinese versions at 3 months after childbirth. We used multivariable Poisson regression models to estimate the relative risk (RR) of SARS-CoV-2 infection. Multivariable linear regression models and a mediation model were used to test the direct and indirect associations between SARS-CoV-2 infection and the ASQ-3 score. This study was approved by the Peking University Third Hospital Medical Science Research Ethics Committee (No. IRB00006761-M2020127). Results: In the infection cohort, 13.6% of the children showed social-emotional developmental delay, and 13.5% showed overall developmental delay. The corresponding rates in the non-infection cohort were 23.4 and 8.1%. Compared with the non-infection cohort, SARS-CoV-2 infection during pregnancy did not increase the risk of social-emotional (RR = 0.87, 95% CI: 0.51-1.49) or overall (RR = 1.02, 95% CI: 0.60-1.73) developmental delay. The mediation model showed that SARS-CoV-2 infection indirectly affected the ASQ-3 score by increasing the length of mother-infant separation. Conclusions: SARS-CoV-2 during late pregnancy did not increase the risk of developmental delay of the offspring 3 months after delivery. However, SARS-CoV-2 may have indirect effects on early childhood development by increasing mother-infant separation.",
        "truth": "True"
    },
    {
        "pmid": "36306133",
        "meta_analysis_title": "COVID-19 Pandemic and Infant Neurodevelopmental Impairment: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Are neurodevelopmental outcomes during infancy changed by the COVID-19 pandemic?",
        "criteria": "A total of 1880 articles were retrieved. Of these, 670 articles were excluded as duplicates, and the remaining 1210 studies were screened for eligibility. Screening of the title and abstract resulted in 21 potentially eligible studies. Following full-text assessment, 8 studies met the inclusion criteria defined earlier (Figure 1).",
        "subgroup": "Meta-analysis of Overall Risk of Neurodevelopmental Impairment (NDI) and Gross Motor, Fine Motor, and Personal-Social Domains Among In Utero Exposed vs Unexposed Pandemic-Born Cohorts - At risk of fine motor impairment",
        "key_reference_title": "The impact of the COVID-19 pandemic on infant and toddler development.",
        "key_reference_abstract": "## BACKGROUND\nThe COVID-19 pandemic has created new cultural norms with pervasive societal implications. Families have experienced a heightened amount of physical, psychological, emotional, and financial stress. Infants and children living with stress have the potential for delayed developmental milestones, difficulty with emotional regulation, and social or behavioral issues.\n## PURPOSE\nThis study aims to determine if the pandemic has affected developmental outcomes in infants and toddlers.\n## METHODOLOGY\nPrepandemic and postpandemic developmental (ASQ-3) scores were obtained from charts of 1,024 patients (6, 12, 18, 24, and 36 months) from two pediatric practices.\n## RESULTS\nThere were no significant differences in prepandemic and postpandemic ASQ-3 scores for the overall sample. Age-group analysis showed statistically significant differences in domain scores. Postpandemic problem-solving scores decreased among 6-month-olds while increasing among 24-month-olds. Categorization by score interpretation categories showed a slight decrease in postpandemic scores in the communication domain among 6- and 12-month-olds.\n## CONCLUSIONS\nThe pandemic has the potential to affect childhood development. However, the results of this study are reassuring, showing only slight differences in developmental scores prepandemic versus postpandemic. More studies are needed to establish causation and possible trends in future developmental trajectories.\n## IMPLICATIONS\nAn increased focus on communication screening and promotion of language and communication skills in young children postpandemic is needed. Education about the importance of parent-child engagement, nurturing relationships, opportunities for free-play and exploration, and caregiver support and stress reduction will continue to be of paramount importance.",
        "truth": "False"
    },
    {
        "pmid": "36306133",
        "meta_analysis_title": "COVID-19 Pandemic and Infant Neurodevelopmental Impairment: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Are neurodevelopmental outcomes during infancy changed by the COVID-19 pandemic?",
        "criteria": "A total of 1880 articles were retrieved. Of these, 670 articles were excluded as duplicates, and the remaining 1210 studies were screened for eligibility. Screening of the title and abstract resulted in 21 potentially eligible studies. Following full-text assessment, 8 studies met the inclusion criteria defined earlier (Figure 1).",
        "subgroup": "Meta-analysis of Overall Risk of Neurodevelopmental Impairment (NDI) and Gross Motor, Fine Motor, and Personal-Social Domains Among In Utero Exposed vs Unexposed Pandemic-Born Cohorts - At risk of fine motor impairment",
        "key_reference_title": "Association Between the COVID-19 Pandemic and Infant Neurodevelopment: A Comparison Before and During COVID-19.",
        "key_reference_abstract": "None",
        "truth": "False"
    },
    {
        "pmid": "36306133",
        "meta_analysis_title": "COVID-19 Pandemic and Infant Neurodevelopmental Impairment: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Are neurodevelopmental outcomes during infancy changed by the COVID-19 pandemic?",
        "criteria": "A total of 1880 articles were retrieved. Of these, 670 articles were excluded as duplicates, and the remaining 1210 studies were screened for eligibility. Screening of the title and abstract resulted in 21 potentially eligible studies. Following full-text assessment, 8 studies met the inclusion criteria defined earlier (Figure 1).",
        "subgroup": "Meta-analysis of Overall Risk of Neurodevelopmental Impairment (NDI) and Gross Motor, Fine Motor, and Personal-Social Domains Among In Utero Exposed vs Unexposed Pandemic-Born Cohorts - At risk of fine motor impairment",
        "key_reference_title": "Impact of SARS-CoV-2 Infection During Pregnancy on Infant Neurobehavioral Development: A Case-Control Study.",
        "key_reference_abstract": "Background: Previous studies on the pneumonia outbreak caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have focused on the general population and pregnant women, while little is known about the effects of SARS-CoV-2 on retardation during and after pregnancy. The purpose of this study was to evaluate the potential influence of SARS-CoV-2 on infant neurobehavioral development. Methods: A case-control study was conducted in Wuhan Maternal and Child Health Hospital, China. Nine pregnant women with SARS-CoV-2 infection and 9 controls matched by maternal age, parity, and status of chronic disease were included. Infantile neurobehavioral development was assessed through the Ages and Stages Questionnaires Edition 3 (ASQ-3). Results: The majority of pregnant women with SARS-CoV-2 experienced cesarean section (7 of 9), which was higher than the control group (5 of 9). The throat swabs of all newborn were negative. We found that compared with the control group, neonates of mothers with SARS-CoV-2 infection during pregnancy had lower scores in communication, gross movement, fine movement, problem solving, and personal-social domains; but only fine movement domain yielded statistical significance (P = 0.031). Conclusion: Infection with SARS-CoV-2 during pregnancy may have a certain impact on infant neurobehavioral development. Further studies with larger sample size are warranted for validation.",
        "truth": "False"
    },
    {
        "pmid": "36306133",
        "meta_analysis_title": "COVID-19 Pandemic and Infant Neurodevelopmental Impairment: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Are neurodevelopmental outcomes during infancy changed by the COVID-19 pandemic?",
        "criteria": "A total of 1880 articles were retrieved. Of these, 670 articles were excluded as duplicates, and the remaining 1210 studies were screened for eligibility. Screening of the title and abstract resulted in 21 potentially eligible studies. Following full-text assessment, 8 studies met the inclusion criteria defined earlier (Figure 1).",
        "subgroup": "Meta-analysis of Overall Risk of Neurodevelopmental Impairment (NDI) and Gross Motor, Fine Motor, and Personal-Social Domains Among In Utero Exposed vs Unexposed Pandemic-Born Cohorts - At risk of fine motor impairment",
        "key_reference_title": "Increased risk for developmental delay among babies born during the pandemic.",
        "key_reference_abstract": "The COVID-19 pandemic has resulted in substantial and widespread changes to many prenatal (e.g., maternal stress) and postnatal (e.g., socialization) factors contributing to early child development. We compared developmental screening of 1-year old infants born between April 17, 2020-November 11, 2020 to data from infants born pre-pandemic. We aimed to determine whether risk for developmental delay was elevated among infants born during the pandemic compared to infants born prior to the pandemic. Data were available from 1623 PdP participants. PdP infants had lower mean scores relative to pooled pre-pandemic data on all domains except Problem Solving. PdP infants also had significantly higher risk for developmental delay in the Communication and Personal-Social domains, where the odds ratios for scoring 2 SD below the mean were 2.5 and 1.5, respectively, relative to pre-pandemic data. When stratified by sex, the odds ratios for risk of developmental delay were generally higher among female infants. In conclusions, risks for developmental delay in the Communication and Personal-Social domains were elevated in infants born during the COVID-19 pandemic compared to pre-pandemic infants, especially among girls.",
        "truth": "False"
    },
    {
        "pmid": "36306133",
        "meta_analysis_title": "COVID-19 Pandemic and Infant Neurodevelopmental Impairment: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Are neurodevelopmental outcomes during infancy changed by the COVID-19 pandemic?",
        "criteria": "A total of 1880 articles were retrieved. Of these, 670 articles were excluded as duplicates, and the remaining 1210 studies were screened for eligibility. Screening of the title and abstract resulted in 21 potentially eligible studies. Following full-text assessment, 8 studies met the inclusion criteria defined earlier (Figure 1).",
        "subgroup": "Meta-analysis of Overall Risk of Neurodevelopmental Impairment (NDI) and Gross Motor, Fine Motor, and Personal-Social Domains Among In Utero Exposed vs Unexposed Pandemic-Born Cohorts - At risk of fine motor impairment",
        "key_reference_title": "Neurodevelopmental outcomes of infants secondary to in utero exposure to maternal 2 SARS-CoV-2 infection: A national prospective study in Kuwait.",
        "key_reference_abstract": "## Background\nAn increasing proportion of women are being infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) during pregnancy. Intrauterine viral infections induce an increase in the levels of proinflammatory cytokines, which inhibit the proliferation of neuronal precursor cells and stimulate oligodendrocyte cell death, leading to abnormal neurodevelopment. Whether a maternal cytokine storm can affect neonatal brain development is unclear. The objective of the present study is to assess neurodevelopmental outcomes in neonates born to mothers with SARS-CoV-2 infections during pregnancy. ## Methods\nIn this prospective cohort study, the neurodevelopment status of infants (N=298) born to women with SARS-CoV-2 infections during pregnancy was assessed at 10-12 months post discharge using the Ages and Stages Questionnaire, 3rd edition (ASQ-3). The ASQ-3 scores were classified into developmental delays (cutoff score: \u22642 standard deviations (SDs) below the population mean) and no delay (score >2 SDs above the population mean). ## Results\nApproximately 10% of infants born to mothers with SARS-CoV-2 infections during pregnancy showed developmental delays. Two of 298 infants tested positive for SARS-CoV-2, and both had normal ASQ-3 scores. The majority of the pregnant women had SARS-CoV-2 infection during their third trimester. The risk of developmental delays among infants was higher in those whose mothers had SARS-CoV-2 infections during the first (P=0.039) and second trimesters (P=0.001) than in those whose mothers had SARS-CoV-2 infections during the third trimester. Infants born at <31 weeks gestation were more prone to developmental delays than those born at >31 weeks gestation (10% versus 0.8%; P=0.002). ## Conclusion\nThe findings of the study highlight the need for long term neurodevelopmental assessment of infants born to mothers with SARS-CoV-2 infection.",
        "truth": "False"
    },
    {
        "pmid": "36306133",
        "meta_analysis_title": "COVID-19 Pandemic and Infant Neurodevelopmental Impairment: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Are neurodevelopmental outcomes during infancy changed by the COVID-19 pandemic?",
        "criteria": "A total of 1880 articles were retrieved. Of these, 670 articles were excluded as duplicates, and the remaining 1210 studies were screened for eligibility. Screening of the title and abstract resulted in 21 potentially eligible studies. Following full-text assessment, 8 studies met the inclusion criteria defined earlier (Figure 1).",
        "subgroup": "Meta-analysis of Overall Risk of Neurodevelopmental Impairment (NDI) and Gross Motor, Fine Motor, and Personal-Social Domains Among In Utero Exposed vs Unexposed Pandemic-Born Cohorts - At risk of fine motor impairment",
        "key_reference_title": "Neurodevelopmental outcomes at one year in offspring of mothers who test positive for SARS-CoV-2 during pregnancy.",
        "key_reference_abstract": "## Importance\nEpidemiologic studies suggest maternal immune activation during pregnancy may be associated with neurodevelopmental effects in offspring. \n## Objective\nTo determine whether in utero exposure to the novel coronavirus SARS-CoV-2 is associated with risk for neurodevelopmental disorders in the first 12 months after birth. \n## Design\nRetrospective cohort\n## Participants\nLive offspring of all mothers who delivered between March and September 2020 at one of six Massachusetts hospitals across two health systems. \n## Exposure\nSARS-CoV-2 infection confirmed by PCR during pregnancy \n## Main Outcome and Measures\nNeurodevelopmental disorders determined from ICD-10 diagnostic codes over 12 months; sociodemographic and clinical features of mothers and offspring; all drawn from the electronic health record. \n## Results\nThe cohort included 7,772 live births (7,466 pregnancies, 96% singleton, 222 births to SARS-CoV-2 positive mothers), with mean maternal age of 32.9 years; offspring were 9.9% Asian, 8.4% Black, and 69.0% white; 15.1% were of Hispanic ethnicity. Preterm delivery was more likely among exposed mothers (14% versus 8.7%; p=.003). Maternal SARS-CoV-2 positivity during pregnancy was associated with greater rate of neurodevelopmental diagnoses (crude OR 2.17 [95% CI 1.24-3.79, p=0.006]) as well as models adjusted for race, ethnicity, insurance status, offspring sex, maternal age, and preterm status (adjusted OR 1.86 [95% CI 1.03-3.36, p=0.04]). Third-trimester infection was associated with effects of larger magnitude (adjusted OR 2.34, 95% CI 1.23-4.44, p=0.01) \n## Conclusion and Relevance\nOur results provide preliminary evidence that maternal SARS-CoV-2 may be associated with neurodevelopmental sequelae in some offspring. Prospective studies with longer follow-up duration will be required to exclude confounding and confirm these effects.\n## Trial Registration\nNA## Key Points\n## Question\nDoes COVID-19 exposure in utero increase the risk for neurodevelopmental disorders in the first year of life? ## Findings\nIn a cohort of babies delivered during COVID-19, those born to mothers with a positive SARS-CoV-2 PCR test during pregnancy were more likely to receive a neurodevelopmental diagnosis in the first 12 months after delivery, even after accounting for preterm delivery. ## Meaning\nThese preliminary findings suggest that COVID-19 exposure may impact neurodevelopment, and highlight the need for prospective investigation of outcomes in children exposed to COVID-19 in utero.",
        "truth": "False"
    },
    {
        "pmid": "36306133",
        "meta_analysis_title": "COVID-19 Pandemic and Infant Neurodevelopmental Impairment: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Are neurodevelopmental outcomes during infancy changed by the COVID-19 pandemic?",
        "criteria": "A total of 1880 articles were retrieved. Of these, 670 articles were excluded as duplicates, and the remaining 1210 studies were screened for eligibility. Screening of the title and abstract resulted in 21 potentially eligible studies. Following full-text assessment, 8 studies met the inclusion criteria defined earlier (Figure 1).",
        "subgroup": "Meta-analysis of Overall Risk of Neurodevelopmental Impairment (NDI) and Gross Motor, Fine Motor, and Personal-Social Domains Among In Utero Exposed vs Unexposed Pandemic-Born Cohorts - At risk of personal-social impairment",
        "key_reference_title": "Association of Birth During the COVID-19 Pandemic With Neurodevelopmental Status at 6 Months in Infants With and Without In Utero Exposure to Maternal SARS-CoV-2 Infection.",
        "key_reference_abstract": "## IMPORTANCE\nAssociations between in utero exposure to maternal SARS-CoV-2 infection and neurodevelopment are speculated, but currently unknown.\n## OBJECTIVE\nTo examine the associations between maternal SARS-CoV-2 infection during pregnancy, being born during the COVID-19 pandemic regardless of maternal SARS-CoV-2 status, and neurodevelopment at age 6 months.\n## DESIGN, SETTING, AND PARTICIPANTS\nA cohort of infants exposed to maternal SARS-CoV-2 infection during pregnancy and unexposed controls was enrolled in the COVID-19 Mother Baby Outcomes Initiative at Columbia University Irving Medical Center in New York City. All women who delivered at Columbia University Irving Medical Center with a SARS-CoV-2 infection during pregnancy were approached. Women with unexposed infants were approached based on similar gestational age at birth, date of birth, sex, and mode of delivery. Neurodevelopment was assessed using the Ages & Stages Questionnaire, 3rd Edition (ASQ-3) at age 6 months. A historical cohort of infants born before the pandemic who had completed the 6-month ASQ-3 were included in secondary analyses.\n## EXPOSURES\nMaternal SARS-CoV-2 infection during pregnancy and birth during the COVID-19 pandemic.\n## MAIN OUTCOMES AND MEASURES\nOutcomes were scores on the 5 ASQ-3 subdomains, with the hypothesis that maternal SARS-CoV-2 infection during pregnancy would be associated with decrements in social and motor development at age 6 months.\n## RESULTS\nOf 1706 women approached, 596 enrolled; 385 women were invited to a 6-month assessment, of whom 272 (70.6%) completed the ASQ-3. Data were available for 255 infants enrolled in the COVID-19 Mother Baby Outcomes Initiative (114 in utero exposed, 141 unexposed to SARS-CoV-2; median maternal age at delivery, 32.0 [IQR, 19.0-45.0] years). Data were also available from a historical cohort of 62 infants born before the pandemic. In utero exposure to maternal SARS-CoV-2 infection was not associated with significant differences on any ASQ-3 subdomain, regardless of infection timing or severity. However, compared with the historical cohort, infants born during the pandemic had significantly lower scores on gross motor (mean difference, -5.63; 95% CI, -8.75 to -2.51; F1,267\u2009=\u200912.63; P<.005), fine motor (mean difference, -6.61; 95% CI, -10.00 to -3.21; F1,267\u2009=\u200914.71; P\u2009<\u2009.005), and personal-social (mean difference, -3.71; 95% CI, -6.61 to -0.82; F1,267\u2009=\u20096.37; P<.05) subdomains in fully adjusted models.\n## CONCLUSIONS AND RELEVANCE\nIn this study, birth during the pandemic, but not in utero exposure to maternal SARS-CoV-2 infection, was associated with differences in neurodevelopment at age 6 months. These early findings support the need for long-term monitoring of children born during the COVID-19 pandemic.",
        "truth": "True"
    },
    {
        "pmid": "36306133",
        "meta_analysis_title": "COVID-19 Pandemic and Infant Neurodevelopmental Impairment: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Are neurodevelopmental outcomes during infancy changed by the COVID-19 pandemic?",
        "criteria": "A total of 1880 articles were retrieved. Of these, 670 articles were excluded as duplicates, and the remaining 1210 studies were screened for eligibility. Screening of the title and abstract resulted in 21 potentially eligible studies. Following full-text assessment, 8 studies met the inclusion criteria defined earlier (Figure 1).",
        "subgroup": "Meta-analysis of Overall Risk of Neurodevelopmental Impairment (NDI) and Gross Motor, Fine Motor, and Personal-Social Domains Among In Utero Exposed vs Unexposed Pandemic-Born Cohorts - At risk of personal-social impairment",
        "key_reference_title": "Effects of SARS-CoV-2 Infection During Late Pregnancy on Early Childhood Development: A Prospective Cohort Study.",
        "key_reference_abstract": "Background: There is little direct or indirect evidence of the effects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection during pregnancy on early childhood development. Methods: We conducted a prospective, observational cohort study in China from May 1 to October 31, 2020, that enrolled 135 mother-infant dyads: 57 dyads in the infection cohort and 78 in the non-infection cohort. Among all infants, 14.0% were preterm birth in the infection cohort and 6.4% in the non-infection cohort. Participants were followed by telephone interviews to collect demographic characteristics, medical records of coronavirus disease 2019, breastfeeding data, and early childhood development was assessed by the Age and Stage Questionnaire (ASQ-3) and Age and Stage Questionnaire Social-Emotional (ASQ:SE-2) Chinese versions at 3 months after childbirth. We used multivariable Poisson regression models to estimate the relative risk (RR) of SARS-CoV-2 infection. Multivariable linear regression models and a mediation model were used to test the direct and indirect associations between SARS-CoV-2 infection and the ASQ-3 score. This study was approved by the Peking University Third Hospital Medical Science Research Ethics Committee (No. IRB00006761-M2020127). Results: In the infection cohort, 13.6% of the children showed social-emotional developmental delay, and 13.5% showed overall developmental delay. The corresponding rates in the non-infection cohort were 23.4 and 8.1%. Compared with the non-infection cohort, SARS-CoV-2 infection during pregnancy did not increase the risk of social-emotional (RR = 0.87, 95% CI: 0.51-1.49) or overall (RR = 1.02, 95% CI: 0.60-1.73) developmental delay. The mediation model showed that SARS-CoV-2 infection indirectly affected the ASQ-3 score by increasing the length of mother-infant separation. Conclusions: SARS-CoV-2 during late pregnancy did not increase the risk of developmental delay of the offspring 3 months after delivery. However, SARS-CoV-2 may have indirect effects on early childhood development by increasing mother-infant separation.",
        "truth": "True"
    },
    {
        "pmid": "36306133",
        "meta_analysis_title": "COVID-19 Pandemic and Infant Neurodevelopmental Impairment: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Are neurodevelopmental outcomes during infancy changed by the COVID-19 pandemic?",
        "criteria": "A total of 1880 articles were retrieved. Of these, 670 articles were excluded as duplicates, and the remaining 1210 studies were screened for eligibility. Screening of the title and abstract resulted in 21 potentially eligible studies. Following full-text assessment, 8 studies met the inclusion criteria defined earlier (Figure 1).",
        "subgroup": "Meta-analysis of Overall Risk of Neurodevelopmental Impairment (NDI) and Gross Motor, Fine Motor, and Personal-Social Domains Among In Utero Exposed vs Unexposed Pandemic-Born Cohorts - At risk of personal-social impairment",
        "key_reference_title": "The impact of the COVID-19 pandemic on infant and toddler development.",
        "key_reference_abstract": "## BACKGROUND\nThe COVID-19 pandemic has created new cultural norms with pervasive societal implications. Families have experienced a heightened amount of physical, psychological, emotional, and financial stress. Infants and children living with stress have the potential for delayed developmental milestones, difficulty with emotional regulation, and social or behavioral issues.\n## PURPOSE\nThis study aims to determine if the pandemic has affected developmental outcomes in infants and toddlers.\n## METHODOLOGY\nPrepandemic and postpandemic developmental (ASQ-3) scores were obtained from charts of 1,024 patients (6, 12, 18, 24, and 36 months) from two pediatric practices.\n## RESULTS\nThere were no significant differences in prepandemic and postpandemic ASQ-3 scores for the overall sample. Age-group analysis showed statistically significant differences in domain scores. Postpandemic problem-solving scores decreased among 6-month-olds while increasing among 24-month-olds. Categorization by score interpretation categories showed a slight decrease in postpandemic scores in the communication domain among 6- and 12-month-olds.\n## CONCLUSIONS\nThe pandemic has the potential to affect childhood development. However, the results of this study are reassuring, showing only slight differences in developmental scores prepandemic versus postpandemic. More studies are needed to establish causation and possible trends in future developmental trajectories.\n## IMPLICATIONS\nAn increased focus on communication screening and promotion of language and communication skills in young children postpandemic is needed. Education about the importance of parent-child engagement, nurturing relationships, opportunities for free-play and exploration, and caregiver support and stress reduction will continue to be of paramount importance.",
        "truth": "False"
    },
    {
        "pmid": "36306133",
        "meta_analysis_title": "COVID-19 Pandemic and Infant Neurodevelopmental Impairment: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Are neurodevelopmental outcomes during infancy changed by the COVID-19 pandemic?",
        "criteria": "A total of 1880 articles were retrieved. Of these, 670 articles were excluded as duplicates, and the remaining 1210 studies were screened for eligibility. Screening of the title and abstract resulted in 21 potentially eligible studies. Following full-text assessment, 8 studies met the inclusion criteria defined earlier (Figure 1).",
        "subgroup": "Meta-analysis of Overall Risk of Neurodevelopmental Impairment (NDI) and Gross Motor, Fine Motor, and Personal-Social Domains Among In Utero Exposed vs Unexposed Pandemic-Born Cohorts - At risk of personal-social impairment",
        "key_reference_title": "Association Between the COVID-19 Pandemic and Infant Neurodevelopment: A Comparison Before and During COVID-19.",
        "key_reference_abstract": "None",
        "truth": "False"
    },
    {
        "pmid": "36306133",
        "meta_analysis_title": "COVID-19 Pandemic and Infant Neurodevelopmental Impairment: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Are neurodevelopmental outcomes during infancy changed by the COVID-19 pandemic?",
        "criteria": "A total of 1880 articles were retrieved. Of these, 670 articles were excluded as duplicates, and the remaining 1210 studies were screened for eligibility. Screening of the title and abstract resulted in 21 potentially eligible studies. Following full-text assessment, 8 studies met the inclusion criteria defined earlier (Figure 1).",
        "subgroup": "Meta-analysis of Overall Risk of Neurodevelopmental Impairment (NDI) and Gross Motor, Fine Motor, and Personal-Social Domains Among In Utero Exposed vs Unexposed Pandemic-Born Cohorts - At risk of personal-social impairment",
        "key_reference_title": "Impact of SARS-CoV-2 Infection During Pregnancy on Infant Neurobehavioral Development: A Case-Control Study.",
        "key_reference_abstract": "Background: Previous studies on the pneumonia outbreak caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have focused on the general population and pregnant women, while little is known about the effects of SARS-CoV-2 on retardation during and after pregnancy. The purpose of this study was to evaluate the potential influence of SARS-CoV-2 on infant neurobehavioral development. Methods: A case-control study was conducted in Wuhan Maternal and Child Health Hospital, China. Nine pregnant women with SARS-CoV-2 infection and 9 controls matched by maternal age, parity, and status of chronic disease were included. Infantile neurobehavioral development was assessed through the Ages and Stages Questionnaires Edition 3 (ASQ-3). Results: The majority of pregnant women with SARS-CoV-2 experienced cesarean section (7 of 9), which was higher than the control group (5 of 9). The throat swabs of all newborn were negative. We found that compared with the control group, neonates of mothers with SARS-CoV-2 infection during pregnancy had lower scores in communication, gross movement, fine movement, problem solving, and personal-social domains; but only fine movement domain yielded statistical significance (P = 0.031). Conclusion: Infection with SARS-CoV-2 during pregnancy may have a certain impact on infant neurobehavioral development. Further studies with larger sample size are warranted for validation.",
        "truth": "False"
    },
    {
        "pmid": "36306133",
        "meta_analysis_title": "COVID-19 Pandemic and Infant Neurodevelopmental Impairment: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Are neurodevelopmental outcomes during infancy changed by the COVID-19 pandemic?",
        "criteria": "A total of 1880 articles were retrieved. Of these, 670 articles were excluded as duplicates, and the remaining 1210 studies were screened for eligibility. Screening of the title and abstract resulted in 21 potentially eligible studies. Following full-text assessment, 8 studies met the inclusion criteria defined earlier (Figure 1).",
        "subgroup": "Meta-analysis of Overall Risk of Neurodevelopmental Impairment (NDI) and Gross Motor, Fine Motor, and Personal-Social Domains Among In Utero Exposed vs Unexposed Pandemic-Born Cohorts - At risk of personal-social impairment",
        "key_reference_title": "Increased risk for developmental delay among babies born during the pandemic.",
        "key_reference_abstract": "The COVID-19 pandemic has resulted in substantial and widespread changes to many prenatal (e.g., maternal stress) and postnatal (e.g., socialization) factors contributing to early child development. We compared developmental screening of 1-year old infants born between April 17, 2020-November 11, 2020 to data from infants born pre-pandemic. We aimed to determine whether risk for developmental delay was elevated among infants born during the pandemic compared to infants born prior to the pandemic. Data were available from 1623 PdP participants. PdP infants had lower mean scores relative to pooled pre-pandemic data on all domains except Problem Solving. PdP infants also had significantly higher risk for developmental delay in the Communication and Personal-Social domains, where the odds ratios for scoring 2 SD below the mean were 2.5 and 1.5, respectively, relative to pre-pandemic data. When stratified by sex, the odds ratios for risk of developmental delay were generally higher among female infants. In conclusions, risks for developmental delay in the Communication and Personal-Social domains were elevated in infants born during the COVID-19 pandemic compared to pre-pandemic infants, especially among girls.",
        "truth": "False"
    },
    {
        "pmid": "36306133",
        "meta_analysis_title": "COVID-19 Pandemic and Infant Neurodevelopmental Impairment: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Are neurodevelopmental outcomes during infancy changed by the COVID-19 pandemic?",
        "criteria": "A total of 1880 articles were retrieved. Of these, 670 articles were excluded as duplicates, and the remaining 1210 studies were screened for eligibility. Screening of the title and abstract resulted in 21 potentially eligible studies. Following full-text assessment, 8 studies met the inclusion criteria defined earlier (Figure 1).",
        "subgroup": "Meta-analysis of Overall Risk of Neurodevelopmental Impairment (NDI) and Gross Motor, Fine Motor, and Personal-Social Domains Among In Utero Exposed vs Unexposed Pandemic-Born Cohorts - At risk of personal-social impairment",
        "key_reference_title": "Neurodevelopmental outcomes of infants secondary to in utero exposure to maternal 2 SARS-CoV-2 infection: A national prospective study in Kuwait.",
        "key_reference_abstract": "## Background\nAn increasing proportion of women are being infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) during pregnancy. Intrauterine viral infections induce an increase in the levels of proinflammatory cytokines, which inhibit the proliferation of neuronal precursor cells and stimulate oligodendrocyte cell death, leading to abnormal neurodevelopment. Whether a maternal cytokine storm can affect neonatal brain development is unclear. The objective of the present study is to assess neurodevelopmental outcomes in neonates born to mothers with SARS-CoV-2 infections during pregnancy. ## Methods\nIn this prospective cohort study, the neurodevelopment status of infants (N=298) born to women with SARS-CoV-2 infections during pregnancy was assessed at 10-12 months post discharge using the Ages and Stages Questionnaire, 3rd edition (ASQ-3). The ASQ-3 scores were classified into developmental delays (cutoff score: \u22642 standard deviations (SDs) below the population mean) and no delay (score >2 SDs above the population mean). ## Results\nApproximately 10% of infants born to mothers with SARS-CoV-2 infections during pregnancy showed developmental delays. Two of 298 infants tested positive for SARS-CoV-2, and both had normal ASQ-3 scores. The majority of the pregnant women had SARS-CoV-2 infection during their third trimester. The risk of developmental delays among infants was higher in those whose mothers had SARS-CoV-2 infections during the first (P=0.039) and second trimesters (P=0.001) than in those whose mothers had SARS-CoV-2 infections during the third trimester. Infants born at <31 weeks gestation were more prone to developmental delays than those born at >31 weeks gestation (10% versus 0.8%; P=0.002). ## Conclusion\nThe findings of the study highlight the need for long term neurodevelopmental assessment of infants born to mothers with SARS-CoV-2 infection.",
        "truth": "False"
    },
    {
        "pmid": "36306133",
        "meta_analysis_title": "COVID-19 Pandemic and Infant Neurodevelopmental Impairment: A Systematic Review and Meta-analysis.",
        "meta_analysis_question": "Are neurodevelopmental outcomes during infancy changed by the COVID-19 pandemic?",
        "criteria": "A total of 1880 articles were retrieved. Of these, 670 articles were excluded as duplicates, and the remaining 1210 studies were screened for eligibility. Screening of the title and abstract resulted in 21 potentially eligible studies. Following full-text assessment, 8 studies met the inclusion criteria defined earlier (Figure 1).",
        "subgroup": "Meta-analysis of Overall Risk of Neurodevelopmental Impairment (NDI) and Gross Motor, Fine Motor, and Personal-Social Domains Among In Utero Exposed vs Unexposed Pandemic-Born Cohorts - At risk of personal-social impairment",
        "key_reference_title": "Neurodevelopmental outcomes at one year in offspring of mothers who test positive for SARS-CoV-2 during pregnancy.",
        "key_reference_abstract": "## Importance\nEpidemiologic studies suggest maternal immune activation during pregnancy may be associated with neurodevelopmental effects in offspring. \n## Objective\nTo determine whether in utero exposure to the novel coronavirus SARS-CoV-2 is associated with risk for neurodevelopmental disorders in the first 12 months after birth. \n## Design\nRetrospective cohort\n## Participants\nLive offspring of all mothers who delivered between March and September 2020 at one of six Massachusetts hospitals across two health systems. \n## Exposure\nSARS-CoV-2 infection confirmed by PCR during pregnancy \n## Main Outcome and Measures\nNeurodevelopmental disorders determined from ICD-10 diagnostic codes over 12 months; sociodemographic and clinical features of mothers and offspring; all drawn from the electronic health record. \n## Results\nThe cohort included 7,772 live births (7,466 pregnancies, 96% singleton, 222 births to SARS-CoV-2 positive mothers), with mean maternal age of 32.9 years; offspring were 9.9% Asian, 8.4% Black, and 69.0% white; 15.1% were of Hispanic ethnicity. Preterm delivery was more likely among exposed mothers (14% versus 8.7%; p=.003). Maternal SARS-CoV-2 positivity during pregnancy was associated with greater rate of neurodevelopmental diagnoses (crude OR 2.17 [95% CI 1.24-3.79, p=0.006]) as well as models adjusted for race, ethnicity, insurance status, offspring sex, maternal age, and preterm status (adjusted OR 1.86 [95% CI 1.03-3.36, p=0.04]). Third-trimester infection was associated with effects of larger magnitude (adjusted OR 2.34, 95% CI 1.23-4.44, p=0.01) \n## Conclusion and Relevance\nOur results provide preliminary evidence that maternal SARS-CoV-2 may be associated with neurodevelopmental sequelae in some offspring. Prospective studies with longer follow-up duration will be required to exclude confounding and confirm these effects.\n## Trial Registration\nNA## Key Points\n## Question\nDoes COVID-19 exposure in utero increase the risk for neurodevelopmental disorders in the first year of life? ## Findings\nIn a cohort of babies delivered during COVID-19, those born to mothers with a positive SARS-CoV-2 PCR test during pregnancy were more likely to receive a neurodevelopmental diagnosis in the first 12 months after delivery, even after accounting for preterm delivery. ## Meaning\nThese preliminary findings suggest that COVID-19 exposure may impact neurodevelopment, and highlight the need for prospective investigation of outcomes in children exposed to COVID-19 in utero.",
        "truth": "False"
    },
    {
        "pmid": "38594408",
        "meta_analysis_title": "Human-AI interaction in skin cancer diagnosis: a systematic review and meta-analysis.",
        "meta_analysis_question": "Does AI assistance improve the accuracy of skin cancer diagnosis by clinicians compared to diagnosis without AI assistance?",
        "criteria": "We searched four electronic databases, including PubMed, Embase, Institute of Electrical and Electronics Engineers Xplore (IEE Xplore) and Scopus for peer-reviewed articles of AI-assisted skin cancer diagnosis without language restriction from January 1, 2017, until November 8, 2022. Search terms were combined for four key concepts: (1) AI, (2) skin cancer, (3) diagnosis, (4) doctors. The full search strategy is available in the Supplementary material (Supplementary Table 3). We chose 2017 as the cutoff for this review since this was the year when deep learning was first reported as performing at a level comparable to dermatologists, notably in the seminal study by Esteva et al9, which suggested that AI technology had reached a clinically useful level in assisting skin cancer diagnosis.",
        "subgroup": "Meta-analysis results of the diagnostic performance of clinicians - Without AI-assisted clinicians",
        "key_reference_title": "Convolutional neural network assistance significantly improves dermatologists' diagnosis of cutaneous tumours using clinical images.",
        "key_reference_abstract": "## BACKGROUND\nConvolutional neural networks (CNNs) have demonstrated expert-level performance in cutaneous tumour classification using clinical images, but most previous studies have focused on dermatologist-versus-CNN comparisons rather than their combination. The objective of our study was to evaluate the potential impact of CNN assistance on dermatologists for clinical image interpretation.\n## METHODS\nA multi-class CNN was trained and validated using a dataset of 25,773 clinical images comprising 10 categories of cutaneous tumours. The CNN's performance was tested on an independent dataset of 2107 images. A total of 400 images (40 per category) were randomly selected from the test dataset. A fully crossed, self-control, multi-reader multi-case (MRMC) study was conducted to compare the performance of 18 board-certified dermatologists (experience: 13/18\u00a0\u2264\u00a010 years; 5/18\uff1e10 years) in interpreting the 400 clinical images with or without CNN assistance.\n## RESULTS\nThe CNN achieved an overall accuracy of 78.45% and kappa of 0.73 in the classification of 10 types of cutaneous tumours on 2107 images. CNN-assisted dermatologists achieved a higher accuracy (76.60% vs. 62.78%, P\u00a0<\u00a00.001) and kappa (0.74 vs. 0.59, P\u00a0<\u00a00.001) than unassisted dermatologists in interpreting the 400 clinical images. Dermatologists with less experience benefited more from CNN assistance. At the binary classification level (malignant or benign), the sensitivity (89.56% vs. 83.21%, P\u00a0<\u00a00.001) and specificity (87.90% vs. 80.92%, P\u00a0<\u00a00.001) of dermatologists with CNN assistance were also significantly improved than those without.\n## CONCLUSIONS\nCNN assistance improved dermatologist accuracy in interpreting cutaneous tumours and could further boost the acceptance of this new technique.",
        "truth": "False"
    },
    {
        "pmid": "38594408",
        "meta_analysis_title": "Human-AI interaction in skin cancer diagnosis: a systematic review and meta-analysis.",
        "meta_analysis_question": "Does AI assistance improve the accuracy of skin cancer diagnosis by clinicians compared to diagnosis without AI assistance?",
        "criteria": "We searched four electronic databases, including PubMed, Embase, Institute of Electrical and Electronics Engineers Xplore (IEE Xplore) and Scopus for peer-reviewed articles of AI-assisted skin cancer diagnosis without language restriction from January 1, 2017, until November 8, 2022. Search terms were combined for four key concepts: (1) AI, (2) skin cancer, (3) diagnosis, (4) doctors. The full search strategy is available in the Supplementary material (Supplementary Table 3). We chose 2017 as the cutoff for this review since this was the year when deep learning was first reported as performing at a level comparable to dermatologists, notably in the seminal study by Esteva et al9, which suggested that AI technology had reached a clinically useful level in assisting skin cancer diagnosis.",
        "subgroup": "Meta-analysis results of the diagnostic performance of clinicians - Without AI-assisted clinicians",
        "key_reference_title": "Augmented Intelligence Dermatology: Deep Neural Networks Empower Medical Professionals in Diagnosing Skin Cancer and\u00a0Predicting Treatment Options for 134 Skin\u00a0Disorders.",
        "key_reference_abstract": "Although deep learning algorithms have demonstrated expert-level performance, previous efforts were mostly binary classifications of limited disorders. We trained an algorithm with 220,680 images of 174 disorders and validated it using Edinburgh (1,300 images; 10 disorders) and SNU datasets (2,201 images; 134 disorders). The algorithm could accurately predict malignancy, suggest primary treatment options, render multi-class classification among 134 disorders, and improve the performance of medical professionals. The area under the curves for malignancy detection were 0.928 \u00b1 0.002 (Edinburgh) and 0.937 \u00b1 0.004 (SNU). The area under the curves of primary treatment suggestion (SNU) were 0.828 \u00b1 0.012, 0.885 \u00b1 0.006, 0.885 \u00b1 0.006, and 0.918 \u00b1 0.006 for steroids, antibiotics, antivirals, and antifungals, respectively. For multi-class classification, the mean top-1 and top-5 accuracies were 56.7 \u00b1 1.6% and 92.0 \u00b1 1.1% (Edinburgh) and 44.8 \u00b1 1.2% and 78.1 \u00b1 0.3% (SNU), respectively. With the assistance of our algorithm, the sensitivity and specificity of 47 clinicians (21 dermatologists and 26 dermatology residents) for malignancy prediction (SNU; 240 images) were improved by 12.1% (P < 0.0001) and 1.1% (P < 0.0001), respectively. The malignancy prediction sensitivity of 23 non-medical professionals was significantly increased by 83.8% (P < 0.0001). The top-1 and top-3 accuracies of four doctors in the multi-class classification of 134 diseases (SNU; 2,201 images) were increased by 7.0% (P\u00a0= 0.045) and 10.1% (P\u00a0= 0.0020), respectively. The results suggest that our algorithm may serve as augmented intelligence that can empower medical professionals in diagnostic dermatology.",
        "truth": "False"
    },
    {
        "pmid": "38594408",
        "meta_analysis_title": "Human-AI interaction in skin cancer diagnosis: a systematic review and meta-analysis.",
        "meta_analysis_question": "Does AI assistance improve the accuracy of skin cancer diagnosis by clinicians compared to diagnosis without AI assistance?",
        "criteria": "We searched four electronic databases, including PubMed, Embase, Institute of Electrical and Electronics Engineers Xplore (IEE Xplore) and Scopus for peer-reviewed articles of AI-assisted skin cancer diagnosis without language restriction from January 1, 2017, until November 8, 2022. Search terms were combined for four key concepts: (1) AI, (2) skin cancer, (3) diagnosis, (4) doctors. The full search strategy is available in the Supplementary material (Supplementary Table 3). We chose 2017 as the cutoff for this review since this was the year when deep learning was first reported as performing at a level comparable to dermatologists, notably in the seminal study by Esteva et al9, which suggested that AI technology had reached a clinically useful level in assisting skin cancer diagnosis.",
        "subgroup": "Meta-analysis results of the diagnostic performance of clinicians - Without AI-assisted clinicians",
        "key_reference_title": "Evaluation of Artificial Intelligence-Assisted Diagnosis of Skin Neoplasms: A Single-Center, Paralleled, Unmasked, Randomized Controlled Trial.",
        "key_reference_abstract": "## TRIAL DESIGN\nThis was a single-center, unmasked, paralleled, randomized controlled trial.\n## METHODS\nA randomized trial was conducted in a tertiary care institute in South Korea to validate whether artificial intelligence (AI) could augment the accuracy of nonexpert physicians in the real-world settings, which included diverse out-of-distribution conditions. Consecutive patients aged >19 years, having one or more skin lesions suspicious for skin cancer detected by either the patient or physician, were randomly allocated to four nondermatology trainees and four dermatology residents. The attending dermatologists examined the randomly allocated patients with (AI-assisted group) or without (unaided group) the real-time assistance of AI algorithm (https://b2020.modelderm.com#world; convolutional neural networks; unmasked design) after simple randomization of the patients.\n## RESULTS\nUsing 576 consecutive cases (Fitzpatrick skin phototypes III or IV) with suspicious lesions out of the initial 603 recruitments, the accuracy of the AI-assisted group (n\u00a0= 295, 53.9%) was found to be significantly higher than those of the unaided group (n\u00a0= 281, 43.8%; P\u00a0= 0.019). Whereas the augmentation was more significant from 54.7% (n\u00a0= 150) to 30.7% (n\u00a0= 138; P < 0.0001) in the nondermatology trainees who had the least experience in dermatology, it was not significant in the dermatology residents. The algorithm could help trainees in the AI-assisted group include more differential diagnoses than the unaided group (2.09 vs. 1.95 diagnoses; P\u00a0= 0.0005). However, a 12.2% drop in Top-1 accuracy of the trainees was observed in cases in which all Top-3 predictions given by the algorithm were incorrect.\n## CONCLUSIONS\nThe multiclass AI algorithm augmented the diagnostic accuracy of nonexpert physicians in dermatology.",
        "truth": "False"
    },
    {
        "pmid": "38594408",
        "meta_analysis_title": "Human-AI interaction in skin cancer diagnosis: a systematic review and meta-analysis.",
        "meta_analysis_question": "Does AI assistance improve the accuracy of skin cancer diagnosis by clinicians compared to diagnosis without AI assistance?",
        "criteria": "We searched four electronic databases, including PubMed, Embase, Institute of Electrical and Electronics Engineers Xplore (IEE Xplore) and Scopus for peer-reviewed articles of AI-assisted skin cancer diagnosis without language restriction from January 1, 2017, until November 8, 2022. Search terms were combined for four key concepts: (1) AI, (2) skin cancer, (3) diagnosis, (4) doctors. The full search strategy is available in the Supplementary material (Supplementary Table 3). We chose 2017 as the cutoff for this review since this was the year when deep learning was first reported as performing at a level comparable to dermatologists, notably in the seminal study by Esteva et al9, which suggested that AI technology had reached a clinically useful level in assisting skin cancer diagnosis.",
        "subgroup": "Meta-analysis results of the diagnostic performance of clinicians - Without AI-assisted clinicians",
        "key_reference_title": "Over-Detection of Melanoma-Suspect Lesions by a CE-Certified Smartphone App: Performance in Comparison to Dermatologists, 2D and 3D Convolutional Neural Networks in a Prospective Data Set of 1204 Pigmented Skin Lesions Involving Patients' Perception.",
        "key_reference_abstract": "The exponential increase in algorithm-based mobile health (mHealth) applications (apps) for melanoma screening is a reaction to a growing market. However, the performance of available apps remains to be investigated. In this prospective study, we investigated the diagnostic accuracy of a class 1 CE-certified smartphone app in melanoma risk stratification and its patient and dermatologist satisfaction. Pigmented skin lesions \u2265 3 mm and any suspicious smaller lesions were assessed by the smartphone app SkinVision",
        "truth": "False"
    },
    {
        "pmid": "38594408",
        "meta_analysis_title": "Human-AI interaction in skin cancer diagnosis: a systematic review and meta-analysis.",
        "meta_analysis_question": "Does AI assistance improve the accuracy of skin cancer diagnosis by clinicians compared to diagnosis without AI assistance?",
        "criteria": "We searched four electronic databases, including PubMed, Embase, Institute of Electrical and Electronics Engineers Xplore (IEE Xplore) and Scopus for peer-reviewed articles of AI-assisted skin cancer diagnosis without language restriction from January 1, 2017, until November 8, 2022. Search terms were combined for four key concepts: (1) AI, (2) skin cancer, (3) diagnosis, (4) doctors. The full search strategy is available in the Supplementary material (Supplementary Table 3). We chose 2017 as the cutoff for this review since this was the year when deep learning was first reported as performing at a level comparable to dermatologists, notably in the seminal study by Esteva et al9, which suggested that AI technology had reached a clinically useful level in assisting skin cancer diagnosis.",
        "subgroup": "Meta-analysis results of the diagnostic performance of clinicians - Without AI-assisted clinicians",
        "key_reference_title": "Development and Assessment of an Artificial Intelligence-Based Tool for Skin Condition Diagnosis by Primary Care Physicians and Nurse Practitioners in Teledermatology Practices.",
        "key_reference_abstract": "## IMPORTANCE\nMost dermatologic cases are initially evaluated by nondermatologists such as primary care physicians (PCPs) or nurse practitioners (NPs).\n## OBJECTIVE\nTo evaluate an artificial intelligence (AI)-based tool that assists with diagnoses of dermatologic conditions.\n## DESIGN, SETTING, AND PARTICIPANTS\nThis multiple-reader, multiple-case diagnostic study developed an AI-based tool and evaluated its utility. Primary care physicians and NPs retrospectively reviewed an enriched set of cases representing 120 different skin conditions. Randomization was used to ensure each clinician reviewed each case either with or without AI assistance; each clinician alternated between batches of 50 cases in each modality. The reviews occurred from February 21 to April 28, 2020. Data were analyzed from May 26, 2020, to January 27, 2021.\n## EXPOSURES\nAn AI-based assistive tool for interpreting clinical images and associated medical history.\n## MAIN OUTCOMES AND MEASURES\nThe primary analysis evaluated agreement with reference diagnoses provided by a panel of 3 dermatologists for PCPs and NPs. Secondary analyses included diagnostic accuracy for biopsy-confirmed cases, biopsy and referral rates, review time, and diagnostic confidence.\n## RESULTS\nForty board-certified clinicians, including 20 PCPs (14 women [70.0%]; mean experience, 11.3 [range, 2-32] years) and 20 NPs (18 women [90.0%]; mean experience, 13.1 [range, 2-34] years) reviewed 1048 retrospective cases (672 female [64.2%]; median age, 43 [interquartile range, 30-56] years; 41\u202f920 total reviews) from a teledermatology practice serving 11 sites and provided 0 to 5 differential diagnoses per case (mean [SD], 1.6 [0.7]). The PCPs were located across 12 states, and the NPs practiced in primary care without physician supervision across 9 states. The NPs had a mean of 13.1 (range, 2-34) years of experience and practiced in primary care without physician supervision across 9 states. Artificial intelligence assistance was significantly associated with higher agreement with reference diagnoses. For PCPs, the increase in diagnostic agreement was 10% (95% CI, 8%-11%; P\u2009<\u2009.001), from 48% to 58%; for NPs, the increase was 12% (95% CI, 10%-14%; P\u2009<\u2009.001), from 46% to 58%. In secondary analyses, agreement with biopsy-obtained diagnosis categories of maglignant, precancerous, or benign increased by 3% (95% CI, -1% to 7%) for PCPs and by 8% (95% CI, 3%-13%) for NPs. Rates of desire for biopsies decreased by 1% (95% CI, 0-3%) for PCPs and 2% (95% CI, 1%-3%) for NPs; the rate of desire for referrals decreased by 3% (95% CI, 1%-4%) for PCPs and NPs. Diagnostic agreement on cases not indicated for a dermatologist referral increased by 10% (95% CI, 8%-12%) for PCPs and 12% (95% CI, 10%-14%) for NPs, and median review time increased slightly by 5 (95% CI, 0-8) seconds for PCPs and 7 (95% CI, 5-10) seconds for NPs per case.\n## CONCLUSIONS AND RELEVANCE\nArtificial intelligence assistance was associated with improved diagnoses by PCPs and NPs for 1 in every 8 to 10 cases, indicating potential for improving the quality of dermatologic care.",
        "truth": "True"
    },
    {
        "pmid": "38594408",
        "meta_analysis_title": "Human-AI interaction in skin cancer diagnosis: a systematic review and meta-analysis.",
        "meta_analysis_question": "Does AI assistance improve the accuracy of skin cancer diagnosis by clinicians compared to diagnosis without AI assistance?",
        "criteria": "We searched four electronic databases, including PubMed, Embase, Institute of Electrical and Electronics Engineers Xplore (IEE Xplore) and Scopus for peer-reviewed articles of AI-assisted skin cancer diagnosis without language restriction from January 1, 2017, until November 8, 2022. Search terms were combined for four key concepts: (1) AI, (2) skin cancer, (3) diagnosis, (4) doctors. The full search strategy is available in the Supplementary material (Supplementary Table 3). We chose 2017 as the cutoff for this review since this was the year when deep learning was first reported as performing at a level comparable to dermatologists, notably in the seminal study by Esteva et al9, which suggested that AI technology had reached a clinically useful level in assisting skin cancer diagnosis.",
        "subgroup": "Meta-analysis results of the diagnostic performance of clinicians - Without AI-assisted clinicians",
        "key_reference_title": "Augmenting the accuracy of trainee doctors in diagnosing skin lesions suspected of skin neoplasms in a real-world setting: A prospective controlled before-and-after study.",
        "key_reference_abstract": "## BACKGROUND\nAlthough deep neural networks have shown promising results in the diagnosis of skin cancer, a prospective evaluation in a real-world setting could confirm these results. This study aimed to evaluate whether an algorithm (http://b2019.modelderm.com) improves the accuracy of nondermatologists in diagnosing skin neoplasms.\n## METHODS\nA total of 285 cases (random series) with skin neoplasms suspected of malignancy by either physicians or patients were recruited in two tertiary care centers located in South Korea. An artificial intelligence (AI) group (144 cases, mean [SD] age, 57.0 [17.7] years; 62 [43.1%] men) was diagnosed via routine examination with photographic review and assistance by the algorithm, whereas the control group (141 cases, mean [SD] age, 61.0 [15.3] years; 52 [36.9%] men) was diagnosed only via routine examination with a photographic review. The accuracy of the nondermatologists before and after the interventions was compared.\n## RESULTS\nAmong the AI group, the accuracy of the first impression (Top-1 accuracy; 58.3%) after the assistance of AI was higher than that before the assistance (46.5%, P = .008). The number of differential diagnoses of the participants increased from 1.9 \u00b1 0.5 to 2.2 \u00b1 0.6 after the assistance (P < .001). In the control group, the difference in the Top-1 accuracy between before and after reviewing photographs was not significant (before, 46.1%; after, 51.8%; P = .19), and the number of differential diagnoses did not significantly increase (before, 2.0 \u00b1 0.4; after, 2.1 \u00b1 0.5; P = .57).\n## CONCLUSIONS\nIn real-world settings, AI augmented the diagnostic accuracy of trainee doctors. The limitation of this study is that the algorithm was tested only for Asians recruited from a single region. Additional international randomized controlled trials involving various ethnicities are required.",
        "truth": "True"
    },
    {
        "pmid": "38594408",
        "meta_analysis_title": "Human-AI interaction in skin cancer diagnosis: a systematic review and meta-analysis.",
        "meta_analysis_question": "Does AI assistance improve the accuracy of skin cancer diagnosis by clinicians compared to diagnosis without AI assistance?",
        "criteria": "We searched four electronic databases, including PubMed, Embase, Institute of Electrical and Electronics Engineers Xplore (IEE Xplore) and Scopus for peer-reviewed articles of AI-assisted skin cancer diagnosis without language restriction from January 1, 2017, until November 8, 2022. Search terms were combined for four key concepts: (1) AI, (2) skin cancer, (3) diagnosis, (4) doctors. The full search strategy is available in the Supplementary material (Supplementary Table 3). We chose 2017 as the cutoff for this review since this was the year when deep learning was first reported as performing at a level comparable to dermatologists, notably in the seminal study by Esteva et al9, which suggested that AI technology had reached a clinically useful level in assisting skin cancer diagnosis.",
        "subgroup": "Meta-analysis results of the diagnostic performance of clinicians - Without AI-assisted clinicians",
        "key_reference_title": "Augmented decision-making for acral lentiginous melanoma detection using deep convolutional neural networks.",
        "key_reference_abstract": "## BACKGROUND\nSeveral studies have achieved high-level performance of melanoma detection using convolutional neural networks (CNNs). However, few have described the extent to which the implementation of CNNs improves the diagnostic performance of the physicians.\n## OBJECTIVE\nThis study is aimed at developing a CNN for detecting acral lentiginous melanoma (ALM) and investigating whether its implementation can improve the initial decision for ALM detection made by the physicians.\n## METHODS\nA CNN was trained using 1072 dermoscopic images of acral benign nevi, ALM and intermediate tumours. To investigate whether the implementation of CNN can improve the initial decision for ALM detection, 60 physicians completed a three-stage survey. In Stage I, they were asked for their decisions solely on the basis of dermoscopic images provided to them. In Stage II, they were also provided with clinical information. In Stage III, they were provided with the additional diagnosis and probability predicted by the CNN.\n## RESULTS\nThe accuracy of ALM detection in the participants was 74.7% (95% confidence interval [CI], 72.6-76.8%) in Stage I and 79.0% (95% CI, 76.7-81.2%) in Stage II. In Stage III, it was 86.9% (95% CI, 85.3-88.4%), which exceeds the accuracy delivered in Stage I by 12.2%p (95% CI, 10.1-14.3%p) and Stage II by 7.9%p (95% CI, 6.0-9.9%p). Moreover, the concordance between the participants considerably increased (Fleiss-\u03ba of 0.436 [95% CI, 0.437-0.573] in Stage I, 0.506 [95% CI, 0.621-0.749] in Stage II and 0.684 [95% CI, 0.621-0.749] in Stage III).\n## CONCLUSIONS\nAugmented decision-making improved the performance of and concordance between the clinical decisions of a diverse group of experts. This study demonstrates the potential use of CNNs as an adjoining, decision-supporting system for physicians' decisions.",
        "truth": "True"
    },
    {
        "pmid": "38594408",
        "meta_analysis_title": "Human-AI interaction in skin cancer diagnosis: a systematic review and meta-analysis.",
        "meta_analysis_question": "Does AI assistance improve the accuracy of skin cancer diagnosis by clinicians compared to diagnosis without AI assistance?",
        "criteria": "We searched four electronic databases, including PubMed, Embase, Institute of Electrical and Electronics Engineers Xplore (IEE Xplore) and Scopus for peer-reviewed articles of AI-assisted skin cancer diagnosis without language restriction from January 1, 2017, until November 8, 2022. Search terms were combined for four key concepts: (1) AI, (2) skin cancer, (3) diagnosis, (4) doctors. The full search strategy is available in the Supplementary material (Supplementary Table 3). We chose 2017 as the cutoff for this review since this was the year when deep learning was first reported as performing at a level comparable to dermatologists, notably in the seminal study by Esteva et al9, which suggested that AI technology had reached a clinically useful level in assisting skin cancer diagnosis.",
        "subgroup": "Meta-analysis results of the diagnostic performance of clinicians - Without AI-assisted clinicians",
        "key_reference_title": "Deep Neural Frameworks Improve the Accuracy of General Practitioners in the Classification of Pigmented Skin Lesions.",
        "key_reference_abstract": "This study evaluated whether deep learning frameworks trained in large datasets can help non-dermatologist physicians improve their accuracy in categorizing the seven most common pigmented skin lesions. Open-source skin images were downloaded from the International Skin Imaging Collaboration (ISIC) archive. Different deep neural networks (DNNs) (",
        "truth": "False"
    },
    {
        "pmid": "38594408",
        "meta_analysis_title": "Human-AI interaction in skin cancer diagnosis: a systematic review and meta-analysis.",
        "meta_analysis_question": "Does AI assistance improve the accuracy of skin cancer diagnosis by clinicians compared to diagnosis without AI assistance?",
        "criteria": "We searched four electronic databases, including PubMed, Embase, Institute of Electrical and Electronics Engineers Xplore (IEE Xplore) and Scopus for peer-reviewed articles of AI-assisted skin cancer diagnosis without language restriction from January 1, 2017, until November 8, 2022. Search terms were combined for four key concepts: (1) AI, (2) skin cancer, (3) diagnosis, (4) doctors. The full search strategy is available in the Supplementary material (Supplementary Table 3). We chose 2017 as the cutoff for this review since this was the year when deep learning was first reported as performing at a level comparable to dermatologists, notably in the seminal study by Esteva et al9, which suggested that AI technology had reached a clinically useful level in assisting skin cancer diagnosis.",
        "subgroup": "Meta-analysis results of the diagnostic performance of clinicians - Without AI-assisted clinicians",
        "key_reference_title": "Artificial Intelligence and Its Effect on Dermatologists' Accuracy in Dermoscopic Melanoma Image Classification: Web-Based Survey Study.",
        "key_reference_abstract": "## BACKGROUND\nEarly detection of melanoma can be lifesaving but this remains a challenge. Recent diagnostic studies have revealed the superiority of artificial intelligence (AI) in classifying dermoscopic images of melanoma and nevi, concluding that these algorithms should assist a dermatologist's diagnoses.\n## OBJECTIVE\nThe aim of this study was to investigate whether AI support improves the accuracy and overall diagnostic performance of dermatologists in the dichotomous image-based discrimination between melanoma and nevus.\n## METHODS\nTwelve board-certified dermatologists were presented disjoint sets of 100 unique dermoscopic images of melanomas and nevi (total of 1200 unique images), and they had to classify the images based on personal experience alone (part I) and with the support of a trained convolutional neural network (CNN, part II). Additionally, dermatologists were asked to rate their confidence in their final decision for each image.\n## RESULTS\nWhile the mean specificity of the dermatologists based on personal experience alone remained almost unchanged (70.6% vs 72.4%; P=.54) with AI support, the mean sensitivity and mean accuracy increased significantly (59.4% vs 74.6%; P=.003 and 65.0% vs 73.6%; P=.002, respectively) with AI support. Out of the 10% (10/94; 95% CI 8.4%-11.8%) of cases where dermatologists were correct and AI was incorrect, dermatologists on average changed to the incorrect answer for 39% (4/10; 95% CI 23.2%-55.6%) of cases. When dermatologists were incorrect and AI was correct (25/94, 27%; 95% CI 24.0%-30.1%), dermatologists changed their answers to the correct answer for 46% (11/25; 95% CI 33.1%-58.4%) of cases. Additionally, the dermatologists' average confidence in their decisions increased when the CNN confirmed their decision and decreased when the CNN disagreed, even when the dermatologists were correct. Reported values are based on the mean of all participants. Whenever absolute values are shown, the denominator and numerator are approximations as every dermatologist ended up rating a varying number of images due to a quality control step.\n## CONCLUSIONS\nThe findings of our study show that AI support can improve the overall accuracy of the dermatologists in the dichotomous image-based discrimination between melanoma and nevus. This supports the argument for AI-based tools to aid clinicians in skin lesion classification and provides a rationale for studies of such classifiers in real-life settings, wherein clinicians can integrate additional information such as patient age and medical history into their decisions.",
        "truth": "True"
    },
    {
        "pmid": "38594408",
        "meta_analysis_title": "Human-AI interaction in skin cancer diagnosis: a systematic review and meta-analysis.",
        "meta_analysis_question": "Does AI assistance improve the accuracy of skin cancer diagnosis by clinicians compared to diagnosis without AI assistance?",
        "criteria": "We searched four electronic databases, including PubMed, Embase, Institute of Electrical and Electronics Engineers Xplore (IEE Xplore) and Scopus for peer-reviewed articles of AI-assisted skin cancer diagnosis without language restriction from January 1, 2017, until November 8, 2022. Search terms were combined for four key concepts: (1) AI, (2) skin cancer, (3) diagnosis, (4) doctors. The full search strategy is available in the Supplementary material (Supplementary Table 3). We chose 2017 as the cutoff for this review since this was the year when deep learning was first reported as performing at a level comparable to dermatologists, notably in the seminal study by Esteva et al9, which suggested that AI technology had reached a clinically useful level in assisting skin cancer diagnosis.",
        "subgroup": "Meta-analysis results of the diagnostic performance of clinicians - Without AI-assisted clinicians",
        "key_reference_title": "Performance of a deep neural network in teledermatology: a single-centre prospective diagnostic study.",
        "key_reference_abstract": "## BACKGROUND\nThe use of artificial intelligence (AI) algorithms for the diagnosis of skin diseases has shown promise in experimental settings but has not been yet tested in real-life conditions.\n## OBJECTIVE\nTo assess the diagnostic performance and potential clinical utility of a 174-multiclass AI algorithm in a real-life telemedicine setting.\n## METHODS\nProspective, diagnostic accuracy study including consecutive patients who submitted images for teledermatology evaluation. The treating dermatologist chose a single image to upload to a web application during teleconsultation. A follow-up reader study including nine healthcare providers (3 dermatologists, 3 dermatology residents and 3 general practitioners) was performed.\n## RESULTS\nA total of 340 cases from 281 patients met study inclusion criteria. The mean (SD) age of patients was 33.7 (17.5) years; 63% (n\u00a0=\u00a0177) were female. Exposure to the AI algorithm results was considered useful in 11.8% of visits (n\u00a0=\u00a040) and the teledermatologist correctly modified the real-time diagnosis in 0.6% (n\u00a0=\u00a02) of cases. The overall top-1 accuracy of the algorithm (41.2%) was lower than that of the dermatologists (60.1%), residents (57.8%) and general practitioners (49.3%) (all comparisons P\u00a0<\u00a00.05, in the reader study). When the analysis was limited to the diagnoses on which the algorithm had been explicitly trained, the balanced top-1 accuracy of the algorithm (47.6%) was comparable to the dermatologists (49.7%) and residents (47.7%) but superior to the general practitioners (39.7%; P\u00a0=\u00a00.049). Algorithm performance was associated with patient skin type and image quality.\n## CONCLUSIONS\nA 174-disease class AI algorithm appears to be a promising tool in the triage and evaluation of lesions with patient-taken photographs via telemedicine.",
        "truth": "False"
    },
    {
        "pmid": "38594408",
        "meta_analysis_title": "Human-AI interaction in skin cancer diagnosis: a systematic review and meta-analysis.",
        "meta_analysis_question": "Does AI assistance improve the accuracy of skin cancer diagnosis by clinicians compared to diagnosis without AI assistance?",
        "criteria": "We searched four electronic databases, including PubMed, Embase, Institute of Electrical and Electronics Engineers Xplore (IEE Xplore) and Scopus for peer-reviewed articles of AI-assisted skin cancer diagnosis without language restriction from January 1, 2017, until November 8, 2022. Search terms were combined for four key concepts: (1) AI, (2) skin cancer, (3) diagnosis, (4) doctors. The full search strategy is available in the Supplementary material (Supplementary Table 3). We chose 2017 as the cutoff for this review since this was the year when deep learning was first reported as performing at a level comparable to dermatologists, notably in the seminal study by Esteva et al9, which suggested that AI technology had reached a clinically useful level in assisting skin cancer diagnosis.",
        "subgroup": "Meta-analysis results of the diagnostic performance of clinicians - Without AI-assisted clinicians",
        "key_reference_title": "Human-computer collaboration for skin cancer recognition.",
        "key_reference_abstract": "The rapid increase in telemedicine coupled with recent advances in diagnostic artificial intelligence (AI) create the imperative to consider the opportunities and risks of inserting AI-based support into new paradigms of care. Here we build on recent achievements in the accuracy of image-based AI for skin cancer diagnosis to address the effects of varied representations of AI-based support across different levels of clinical expertise and multiple clinical workflows. We find that good quality AI-based support of clinical decision-making improves diagnostic accuracy over that of either AI or physicians alone, and that the least experienced clinicians gain the most from AI-based support. We further find that AI-based multiclass probabilities outperformed content-based image retrieval (CBIR) representations of AI in the mobile technology environment, and AI-based support had utility in simulations of second opinions and of telemedicine triage. In addition to demonstrating the potential benefits associated with good quality AI in the hands of non-expert clinicians, we find that faulty AI can mislead the entire spectrum of clinicians, including experts. Lastly, we show that insights derived from AI class-activation maps can inform improvements in human diagnosis. Together, our approach and findings offer a framework for future studies across the spectrum of image-based diagnostics to improve human-computer collaboration in clinical practice.",
        "truth": "True"
    },
    {
        "pmid": "38594408",
        "meta_analysis_title": "Human-AI interaction in skin cancer diagnosis: a systematic review and meta-analysis.",
        "meta_analysis_question": "Does AI assistance improve the accuracy of skin cancer diagnosis by clinicians compared to diagnosis without AI assistance?",
        "criteria": "We searched four electronic databases, including PubMed, Embase, Institute of Electrical and Electronics Engineers Xplore (IEE Xplore) and Scopus for peer-reviewed articles of AI-assisted skin cancer diagnosis without language restriction from January 1, 2017, until November 8, 2022. Search terms were combined for four key concepts: (1) AI, (2) skin cancer, (3) diagnosis, (4) doctors. The full search strategy is available in the Supplementary material (Supplementary Table 3). We chose 2017 as the cutoff for this review since this was the year when deep learning was first reported as performing at a level comparable to dermatologists, notably in the seminal study by Esteva et al9, which suggested that AI technology had reached a clinically useful level in assisting skin cancer diagnosis.",
        "subgroup": "Meta-analysis results of the diagnostic performance of clinicians - Without AI-assisted clinicians",
        "key_reference_title": "Dermatologist-level classification of malignant lip diseases using a deep convolutional neural network.",
        "key_reference_abstract": "## BACKGROUND\nDeep convolutional neural networks (DCNNs) can classify skin diseases at a level equivalent to a dermatologist, but their performance in specific areas requires further research.\n## OBJECTIVE\nTo evaluate the performance of a trained DCNN-based algorithm in classifying benign and malignant lip diseases.\n## METHODS\nA training set of 1629 images (743 malignant, 886 benign) was used with Inception-Resnet-V2. Performance was evaluated using another set of 344 images and 281 images from other hospitals. Classifications by 44 participants (six board-certified dermatologists, 12 dermatology residents, nine medical doctors not specialized in dermatology and 17 medical students) were used for comparison.\n## RESULTS\nThe outcomes based on the area under curve, sensitivity and specificity were 0\u00b7827 [95% confidence interval (CI) 0\u00b7782-0\u00b7873], 0\u00b7755 (95% CI 0\u00b7673-0\u00b7827) and 0\u00b7803 (95% CI 0\u00b7752-0\u00b7855), respectively, for the set of 344 images; and 0\u00b7774 (95% CI 0\u00b7699-0\u00b7849), 0\u00b7702 (95% CI 0\u00b7579-0\u00b7808) and 0\u00b7759 (95% CI 0\u00b7701-0\u00b7813), respectively, for the set of 281 images. The DCNN was equivalent to the dermatologists and superior to the nondermatologists in classifying malignancy. After referencing the DCNN result, the mean \u00b1 SD Youden index increased significantly for nondermatologists, from 0\u00b7201 \u00b1 0\u00b7156 to 0\u00b7322 \u00b1 0\u00b7141 (P < 0\u00b7001).\n## CONCLUSIONS\nDCNNs can classify lip diseases at a level similar to dermatologists. This will help unskilled physicians discriminate between benign and malignant lip diseases. What's already known about this topic? Deep convolutional neural networks (DCNNs) can classify malignant and benign skin diseases at a level equivalent to dermatologists. The lips are a unique feature in terms of histology and morphology. Previous studies of DCNNs have not investigated tumours on specific locations. What does this study add? This study shows that DCNNs can distinguish rare malignant and benign lip disorders at the same rate as dermatologists. DCNNs can help nondermatologists to distinguish malignant lip diseases. What are the clinical implications of this work? DCNNs can distinguish malignant and benign skin diseases even at specific locations such as the lips, as well as board-certified dermatologists. Malignant lip diseases are rare and difficult for less trained doctors to differentiate them from benign lesions. This study shows that in dermatology, DCNN can help improve decision-making processes for rare skin diseases in specific areas of the body.",
        "truth": "True"
    },
    {
        "pmid": "38594408",
        "meta_analysis_title": "Human-AI interaction in skin cancer diagnosis: a systematic review and meta-analysis.",
        "meta_analysis_question": "Does AI assistance improve the accuracy of skin cancer diagnosis by clinicians compared to diagnosis without AI assistance?",
        "criteria": "We searched four electronic databases, including PubMed, Embase, Institute of Electrical and Electronics Engineers Xplore (IEE Xplore) and Scopus for peer-reviewed articles of AI-assisted skin cancer diagnosis without language restriction from January 1, 2017, until November 8, 2022. Search terms were combined for four key concepts: (1) AI, (2) skin cancer, (3) diagnosis, (4) doctors. The full search strategy is available in the Supplementary material (Supplementary Table 3). We chose 2017 as the cutoff for this review since this was the year when deep learning was first reported as performing at a level comparable to dermatologists, notably in the seminal study by Esteva et al9, which suggested that AI technology had reached a clinically useful level in assisting skin cancer diagnosis.",
        "subgroup": "Meta-analysis results of the diagnostic performance of clinicians - With AI-assisted clinicians",
        "key_reference_title": "Convolutional neural network assistance significantly improves dermatologists' diagnosis of cutaneous tumours using clinical images.",
        "key_reference_abstract": "## BACKGROUND\nConvolutional neural networks (CNNs) have demonstrated expert-level performance in cutaneous tumour classification using clinical images, but most previous studies have focused on dermatologist-versus-CNN comparisons rather than their combination. The objective of our study was to evaluate the potential impact of CNN assistance on dermatologists for clinical image interpretation.\n## METHODS\nA multi-class CNN was trained and validated using a dataset of 25,773 clinical images comprising 10 categories of cutaneous tumours. The CNN's performance was tested on an independent dataset of 2107 images. A total of 400 images (40 per category) were randomly selected from the test dataset. A fully crossed, self-control, multi-reader multi-case (MRMC) study was conducted to compare the performance of 18 board-certified dermatologists (experience: 13/18\u00a0\u2264\u00a010 years; 5/18\uff1e10 years) in interpreting the 400 clinical images with or without CNN assistance.\n## RESULTS\nThe CNN achieved an overall accuracy of 78.45% and kappa of 0.73 in the classification of 10 types of cutaneous tumours on 2107 images. CNN-assisted dermatologists achieved a higher accuracy (76.60% vs. 62.78%, P\u00a0<\u00a00.001) and kappa (0.74 vs. 0.59, P\u00a0<\u00a00.001) than unassisted dermatologists in interpreting the 400 clinical images. Dermatologists with less experience benefited more from CNN assistance. At the binary classification level (malignant or benign), the sensitivity (89.56% vs. 83.21%, P\u00a0<\u00a00.001) and specificity (87.90% vs. 80.92%, P\u00a0<\u00a00.001) of dermatologists with CNN assistance were also significantly improved than those without.\n## CONCLUSIONS\nCNN assistance improved dermatologist accuracy in interpreting cutaneous tumours and could further boost the acceptance of this new technique.",
        "truth": "True"
    },
    {
        "pmid": "38594408",
        "meta_analysis_title": "Human-AI interaction in skin cancer diagnosis: a systematic review and meta-analysis.",
        "meta_analysis_question": "Does AI assistance improve the accuracy of skin cancer diagnosis by clinicians compared to diagnosis without AI assistance?",
        "criteria": "We searched four electronic databases, including PubMed, Embase, Institute of Electrical and Electronics Engineers Xplore (IEE Xplore) and Scopus for peer-reviewed articles of AI-assisted skin cancer diagnosis without language restriction from January 1, 2017, until November 8, 2022. Search terms were combined for four key concepts: (1) AI, (2) skin cancer, (3) diagnosis, (4) doctors. The full search strategy is available in the Supplementary material (Supplementary Table 3). We chose 2017 as the cutoff for this review since this was the year when deep learning was first reported as performing at a level comparable to dermatologists, notably in the seminal study by Esteva et al9, which suggested that AI technology had reached a clinically useful level in assisting skin cancer diagnosis.",
        "subgroup": "Meta-analysis results of the diagnostic performance of clinicians - With AI-assisted clinicians",
        "key_reference_title": "Augmented Intelligence Dermatology: Deep Neural Networks Empower Medical Professionals in Diagnosing Skin Cancer and\u00a0Predicting Treatment Options for 134 Skin\u00a0Disorders.",
        "key_reference_abstract": "Although deep learning algorithms have demonstrated expert-level performance, previous efforts were mostly binary classifications of limited disorders. We trained an algorithm with 220,680 images of 174 disorders and validated it using Edinburgh (1,300 images; 10 disorders) and SNU datasets (2,201 images; 134 disorders). The algorithm could accurately predict malignancy, suggest primary treatment options, render multi-class classification among 134 disorders, and improve the performance of medical professionals. The area under the curves for malignancy detection were 0.928 \u00b1 0.002 (Edinburgh) and 0.937 \u00b1 0.004 (SNU). The area under the curves of primary treatment suggestion (SNU) were 0.828 \u00b1 0.012, 0.885 \u00b1 0.006, 0.885 \u00b1 0.006, and 0.918 \u00b1 0.006 for steroids, antibiotics, antivirals, and antifungals, respectively. For multi-class classification, the mean top-1 and top-5 accuracies were 56.7 \u00b1 1.6% and 92.0 \u00b1 1.1% (Edinburgh) and 44.8 \u00b1 1.2% and 78.1 \u00b1 0.3% (SNU), respectively. With the assistance of our algorithm, the sensitivity and specificity of 47 clinicians (21 dermatologists and 26 dermatology residents) for malignancy prediction (SNU; 240 images) were improved by 12.1% (P < 0.0001) and 1.1% (P < 0.0001), respectively. The malignancy prediction sensitivity of 23 non-medical professionals was significantly increased by 83.8% (P < 0.0001). The top-1 and top-3 accuracies of four doctors in the multi-class classification of 134 diseases (SNU; 2,201 images) were increased by 7.0% (P\u00a0= 0.045) and 10.1% (P\u00a0= 0.0020), respectively. The results suggest that our algorithm may serve as augmented intelligence that can empower medical professionals in diagnostic dermatology.",
        "truth": "False"
    },
    {
        "pmid": "38594408",
        "meta_analysis_title": "Human-AI interaction in skin cancer diagnosis: a systematic review and meta-analysis.",
        "meta_analysis_question": "Does AI assistance improve the accuracy of skin cancer diagnosis by clinicians compared to diagnosis without AI assistance?",
        "criteria": "We searched four electronic databases, including PubMed, Embase, Institute of Electrical and Electronics Engineers Xplore (IEE Xplore) and Scopus for peer-reviewed articles of AI-assisted skin cancer diagnosis without language restriction from January 1, 2017, until November 8, 2022. Search terms were combined for four key concepts: (1) AI, (2) skin cancer, (3) diagnosis, (4) doctors. The full search strategy is available in the Supplementary material (Supplementary Table 3). We chose 2017 as the cutoff for this review since this was the year when deep learning was first reported as performing at a level comparable to dermatologists, notably in the seminal study by Esteva et al9, which suggested that AI technology had reached a clinically useful level in assisting skin cancer diagnosis.",
        "subgroup": "Meta-analysis results of the diagnostic performance of clinicians - With AI-assisted clinicians",
        "key_reference_title": "Evaluation of Artificial Intelligence-Assisted Diagnosis of Skin Neoplasms: A Single-Center, Paralleled, Unmasked, Randomized Controlled Trial.",
        "key_reference_abstract": "## TRIAL DESIGN\nThis was a single-center, unmasked, paralleled, randomized controlled trial.\n## METHODS\nA randomized trial was conducted in a tertiary care institute in South Korea to validate whether artificial intelligence (AI) could augment the accuracy of nonexpert physicians in the real-world settings, which included diverse out-of-distribution conditions. Consecutive patients aged >19 years, having one or more skin lesions suspicious for skin cancer detected by either the patient or physician, were randomly allocated to four nondermatology trainees and four dermatology residents. The attending dermatologists examined the randomly allocated patients with (AI-assisted group) or without (unaided group) the real-time assistance of AI algorithm (https://b2020.modelderm.com#world; convolutional neural networks; unmasked design) after simple randomization of the patients.\n## RESULTS\nUsing 576 consecutive cases (Fitzpatrick skin phototypes III or IV) with suspicious lesions out of the initial 603 recruitments, the accuracy of the AI-assisted group (n\u00a0= 295, 53.9%) was found to be significantly higher than those of the unaided group (n\u00a0= 281, 43.8%; P\u00a0= 0.019). Whereas the augmentation was more significant from 54.7% (n\u00a0= 150) to 30.7% (n\u00a0= 138; P < 0.0001) in the nondermatology trainees who had the least experience in dermatology, it was not significant in the dermatology residents. The algorithm could help trainees in the AI-assisted group include more differential diagnoses than the unaided group (2.09 vs. 1.95 diagnoses; P\u00a0= 0.0005). However, a 12.2% drop in Top-1 accuracy of the trainees was observed in cases in which all Top-3 predictions given by the algorithm were incorrect.\n## CONCLUSIONS\nThe multiclass AI algorithm augmented the diagnostic accuracy of nonexpert physicians in dermatology.",
        "truth": "False"
    },
    {
        "pmid": "38594408",
        "meta_analysis_title": "Human-AI interaction in skin cancer diagnosis: a systematic review and meta-analysis.",
        "meta_analysis_question": "Does AI assistance improve the accuracy of skin cancer diagnosis by clinicians compared to diagnosis without AI assistance?",
        "criteria": "We searched four electronic databases, including PubMed, Embase, Institute of Electrical and Electronics Engineers Xplore (IEE Xplore) and Scopus for peer-reviewed articles of AI-assisted skin cancer diagnosis without language restriction from January 1, 2017, until November 8, 2022. Search terms were combined for four key concepts: (1) AI, (2) skin cancer, (3) diagnosis, (4) doctors. The full search strategy is available in the Supplementary material (Supplementary Table 3). We chose 2017 as the cutoff for this review since this was the year when deep learning was first reported as performing at a level comparable to dermatologists, notably in the seminal study by Esteva et al9, which suggested that AI technology had reached a clinically useful level in assisting skin cancer diagnosis.",
        "subgroup": "Meta-analysis results of the diagnostic performance of clinicians - With AI-assisted clinicians",
        "key_reference_title": "Over-Detection of Melanoma-Suspect Lesions by a CE-Certified Smartphone App: Performance in Comparison to Dermatologists, 2D and 3D Convolutional Neural Networks in a Prospective Data Set of 1204 Pigmented Skin Lesions Involving Patients' Perception.",
        "key_reference_abstract": "The exponential increase in algorithm-based mobile health (mHealth) applications (apps) for melanoma screening is a reaction to a growing market. However, the performance of available apps remains to be investigated. In this prospective study, we investigated the diagnostic accuracy of a class 1 CE-certified smartphone app in melanoma risk stratification and its patient and dermatologist satisfaction. Pigmented skin lesions \u2265 3 mm and any suspicious smaller lesions were assessed by the smartphone app SkinVision",
        "truth": "False"
    },
    {
        "pmid": "38594408",
        "meta_analysis_title": "Human-AI interaction in skin cancer diagnosis: a systematic review and meta-analysis.",
        "meta_analysis_question": "Does AI assistance improve the accuracy of skin cancer diagnosis by clinicians compared to diagnosis without AI assistance?",
        "criteria": "We searched four electronic databases, including PubMed, Embase, Institute of Electrical and Electronics Engineers Xplore (IEE Xplore) and Scopus for peer-reviewed articles of AI-assisted skin cancer diagnosis without language restriction from January 1, 2017, until November 8, 2022. Search terms were combined for four key concepts: (1) AI, (2) skin cancer, (3) diagnosis, (4) doctors. The full search strategy is available in the Supplementary material (Supplementary Table 3). We chose 2017 as the cutoff for this review since this was the year when deep learning was first reported as performing at a level comparable to dermatologists, notably in the seminal study by Esteva et al9, which suggested that AI technology had reached a clinically useful level in assisting skin cancer diagnosis.",
        "subgroup": "Meta-analysis results of the diagnostic performance of clinicians - With AI-assisted clinicians",
        "key_reference_title": "Development and Assessment of an Artificial Intelligence-Based Tool for Skin Condition Diagnosis by Primary Care Physicians and Nurse Practitioners in Teledermatology Practices.",
        "key_reference_abstract": "## IMPORTANCE\nMost dermatologic cases are initially evaluated by nondermatologists such as primary care physicians (PCPs) or nurse practitioners (NPs).\n## OBJECTIVE\nTo evaluate an artificial intelligence (AI)-based tool that assists with diagnoses of dermatologic conditions.\n## DESIGN, SETTING, AND PARTICIPANTS\nThis multiple-reader, multiple-case diagnostic study developed an AI-based tool and evaluated its utility. Primary care physicians and NPs retrospectively reviewed an enriched set of cases representing 120 different skin conditions. Randomization was used to ensure each clinician reviewed each case either with or without AI assistance; each clinician alternated between batches of 50 cases in each modality. The reviews occurred from February 21 to April 28, 2020. Data were analyzed from May 26, 2020, to January 27, 2021.\n## EXPOSURES\nAn AI-based assistive tool for interpreting clinical images and associated medical history.\n## MAIN OUTCOMES AND MEASURES\nThe primary analysis evaluated agreement with reference diagnoses provided by a panel of 3 dermatologists for PCPs and NPs. Secondary analyses included diagnostic accuracy for biopsy-confirmed cases, biopsy and referral rates, review time, and diagnostic confidence.\n## RESULTS\nForty board-certified clinicians, including 20 PCPs (14 women [70.0%]; mean experience, 11.3 [range, 2-32] years) and 20 NPs (18 women [90.0%]; mean experience, 13.1 [range, 2-34] years) reviewed 1048 retrospective cases (672 female [64.2%]; median age, 43 [interquartile range, 30-56] years; 41\u202f920 total reviews) from a teledermatology practice serving 11 sites and provided 0 to 5 differential diagnoses per case (mean [SD], 1.6 [0.7]). The PCPs were located across 12 states, and the NPs practiced in primary care without physician supervision across 9 states. The NPs had a mean of 13.1 (range, 2-34) years of experience and practiced in primary care without physician supervision across 9 states. Artificial intelligence assistance was significantly associated with higher agreement with reference diagnoses. For PCPs, the increase in diagnostic agreement was 10% (95% CI, 8%-11%; P\u2009<\u2009.001), from 48% to 58%; for NPs, the increase was 12% (95% CI, 10%-14%; P\u2009<\u2009.001), from 46% to 58%. In secondary analyses, agreement with biopsy-obtained diagnosis categories of maglignant, precancerous, or benign increased by 3% (95% CI, -1% to 7%) for PCPs and by 8% (95% CI, 3%-13%) for NPs. Rates of desire for biopsies decreased by 1% (95% CI, 0-3%) for PCPs and 2% (95% CI, 1%-3%) for NPs; the rate of desire for referrals decreased by 3% (95% CI, 1%-4%) for PCPs and NPs. Diagnostic agreement on cases not indicated for a dermatologist referral increased by 10% (95% CI, 8%-12%) for PCPs and 12% (95% CI, 10%-14%) for NPs, and median review time increased slightly by 5 (95% CI, 0-8) seconds for PCPs and 7 (95% CI, 5-10) seconds for NPs per case.\n## CONCLUSIONS AND RELEVANCE\nArtificial intelligence assistance was associated with improved diagnoses by PCPs and NPs for 1 in every 8 to 10 cases, indicating potential for improving the quality of dermatologic care.",
        "truth": "True"
    },
    {
        "pmid": "38594408",
        "meta_analysis_title": "Human-AI interaction in skin cancer diagnosis: a systematic review and meta-analysis.",
        "meta_analysis_question": "Does AI assistance improve the accuracy of skin cancer diagnosis by clinicians compared to diagnosis without AI assistance?",
        "criteria": "We searched four electronic databases, including PubMed, Embase, Institute of Electrical and Electronics Engineers Xplore (IEE Xplore) and Scopus for peer-reviewed articles of AI-assisted skin cancer diagnosis without language restriction from January 1, 2017, until November 8, 2022. Search terms were combined for four key concepts: (1) AI, (2) skin cancer, (3) diagnosis, (4) doctors. The full search strategy is available in the Supplementary material (Supplementary Table 3). We chose 2017 as the cutoff for this review since this was the year when deep learning was first reported as performing at a level comparable to dermatologists, notably in the seminal study by Esteva et al9, which suggested that AI technology had reached a clinically useful level in assisting skin cancer diagnosis.",
        "subgroup": "Meta-analysis results of the diagnostic performance of clinicians - With AI-assisted clinicians",
        "key_reference_title": "Augmenting the accuracy of trainee doctors in diagnosing skin lesions suspected of skin neoplasms in a real-world setting: A prospective controlled before-and-after study.",
        "key_reference_abstract": "## BACKGROUND\nAlthough deep neural networks have shown promising results in the diagnosis of skin cancer, a prospective evaluation in a real-world setting could confirm these results. This study aimed to evaluate whether an algorithm (http://b2019.modelderm.com) improves the accuracy of nondermatologists in diagnosing skin neoplasms.\n## METHODS\nA total of 285 cases (random series) with skin neoplasms suspected of malignancy by either physicians or patients were recruited in two tertiary care centers located in South Korea. An artificial intelligence (AI) group (144 cases, mean [SD] age, 57.0 [17.7] years; 62 [43.1%] men) was diagnosed via routine examination with photographic review and assistance by the algorithm, whereas the control group (141 cases, mean [SD] age, 61.0 [15.3] years; 52 [36.9%] men) was diagnosed only via routine examination with a photographic review. The accuracy of the nondermatologists before and after the interventions was compared.\n## RESULTS\nAmong the AI group, the accuracy of the first impression (Top-1 accuracy; 58.3%) after the assistance of AI was higher than that before the assistance (46.5%, P = .008). The number of differential diagnoses of the participants increased from 1.9 \u00b1 0.5 to 2.2 \u00b1 0.6 after the assistance (P < .001). In the control group, the difference in the Top-1 accuracy between before and after reviewing photographs was not significant (before, 46.1%; after, 51.8%; P = .19), and the number of differential diagnoses did not significantly increase (before, 2.0 \u00b1 0.4; after, 2.1 \u00b1 0.5; P = .57).\n## CONCLUSIONS\nIn real-world settings, AI augmented the diagnostic accuracy of trainee doctors. The limitation of this study is that the algorithm was tested only for Asians recruited from a single region. Additional international randomized controlled trials involving various ethnicities are required.",
        "truth": "True"
    },
    {
        "pmid": "38594408",
        "meta_analysis_title": "Human-AI interaction in skin cancer diagnosis: a systematic review and meta-analysis.",
        "meta_analysis_question": "Does AI assistance improve the accuracy of skin cancer diagnosis by clinicians compared to diagnosis without AI assistance?",
        "criteria": "We searched four electronic databases, including PubMed, Embase, Institute of Electrical and Electronics Engineers Xplore (IEE Xplore) and Scopus for peer-reviewed articles of AI-assisted skin cancer diagnosis without language restriction from January 1, 2017, until November 8, 2022. Search terms were combined for four key concepts: (1) AI, (2) skin cancer, (3) diagnosis, (4) doctors. The full search strategy is available in the Supplementary material (Supplementary Table 3). We chose 2017 as the cutoff for this review since this was the year when deep learning was first reported as performing at a level comparable to dermatologists, notably in the seminal study by Esteva et al9, which suggested that AI technology had reached a clinically useful level in assisting skin cancer diagnosis.",
        "subgroup": "Meta-analysis results of the diagnostic performance of clinicians - With AI-assisted clinicians",
        "key_reference_title": "Augmented decision-making for acral lentiginous melanoma detection using deep convolutional neural networks.",
        "key_reference_abstract": "## BACKGROUND\nSeveral studies have achieved high-level performance of melanoma detection using convolutional neural networks (CNNs). However, few have described the extent to which the implementation of CNNs improves the diagnostic performance of the physicians.\n## OBJECTIVE\nThis study is aimed at developing a CNN for detecting acral lentiginous melanoma (ALM) and investigating whether its implementation can improve the initial decision for ALM detection made by the physicians.\n## METHODS\nA CNN was trained using 1072 dermoscopic images of acral benign nevi, ALM and intermediate tumours. To investigate whether the implementation of CNN can improve the initial decision for ALM detection, 60 physicians completed a three-stage survey. In Stage I, they were asked for their decisions solely on the basis of dermoscopic images provided to them. In Stage II, they were also provided with clinical information. In Stage III, they were provided with the additional diagnosis and probability predicted by the CNN.\n## RESULTS\nThe accuracy of ALM detection in the participants was 74.7% (95% confidence interval [CI], 72.6-76.8%) in Stage I and 79.0% (95% CI, 76.7-81.2%) in Stage II. In Stage III, it was 86.9% (95% CI, 85.3-88.4%), which exceeds the accuracy delivered in Stage I by 12.2%p (95% CI, 10.1-14.3%p) and Stage II by 7.9%p (95% CI, 6.0-9.9%p). Moreover, the concordance between the participants considerably increased (Fleiss-\u03ba of 0.436 [95% CI, 0.437-0.573] in Stage I, 0.506 [95% CI, 0.621-0.749] in Stage II and 0.684 [95% CI, 0.621-0.749] in Stage III).\n## CONCLUSIONS\nAugmented decision-making improved the performance of and concordance between the clinical decisions of a diverse group of experts. This study demonstrates the potential use of CNNs as an adjoining, decision-supporting system for physicians' decisions.",
        "truth": "True"
    },
    {
        "pmid": "38594408",
        "meta_analysis_title": "Human-AI interaction in skin cancer diagnosis: a systematic review and meta-analysis.",
        "meta_analysis_question": "Does AI assistance improve the accuracy of skin cancer diagnosis by clinicians compared to diagnosis without AI assistance?",
        "criteria": "We searched four electronic databases, including PubMed, Embase, Institute of Electrical and Electronics Engineers Xplore (IEE Xplore) and Scopus for peer-reviewed articles of AI-assisted skin cancer diagnosis without language restriction from January 1, 2017, until November 8, 2022. Search terms were combined for four key concepts: (1) AI, (2) skin cancer, (3) diagnosis, (4) doctors. The full search strategy is available in the Supplementary material (Supplementary Table 3). We chose 2017 as the cutoff for this review since this was the year when deep learning was first reported as performing at a level comparable to dermatologists, notably in the seminal study by Esteva et al9, which suggested that AI technology had reached a clinically useful level in assisting skin cancer diagnosis.",
        "subgroup": "Meta-analysis results of the diagnostic performance of clinicians - With AI-assisted clinicians",
        "key_reference_title": "Deep Neural Frameworks Improve the Accuracy of General Practitioners in the Classification of Pigmented Skin Lesions.",
        "key_reference_abstract": "This study evaluated whether deep learning frameworks trained in large datasets can help non-dermatologist physicians improve their accuracy in categorizing the seven most common pigmented skin lesions. Open-source skin images were downloaded from the International Skin Imaging Collaboration (ISIC) archive. Different deep neural networks (DNNs) (",
        "truth": "False"
    },
    {
        "pmid": "38594408",
        "meta_analysis_title": "Human-AI interaction in skin cancer diagnosis: a systematic review and meta-analysis.",
        "meta_analysis_question": "Does AI assistance improve the accuracy of skin cancer diagnosis by clinicians compared to diagnosis without AI assistance?",
        "criteria": "We searched four electronic databases, including PubMed, Embase, Institute of Electrical and Electronics Engineers Xplore (IEE Xplore) and Scopus for peer-reviewed articles of AI-assisted skin cancer diagnosis without language restriction from January 1, 2017, until November 8, 2022. Search terms were combined for four key concepts: (1) AI, (2) skin cancer, (3) diagnosis, (4) doctors. The full search strategy is available in the Supplementary material (Supplementary Table 3). We chose 2017 as the cutoff for this review since this was the year when deep learning was first reported as performing at a level comparable to dermatologists, notably in the seminal study by Esteva et al9, which suggested that AI technology had reached a clinically useful level in assisting skin cancer diagnosis.",
        "subgroup": "Meta-analysis results of the diagnostic performance of clinicians - With AI-assisted clinicians",
        "key_reference_title": "Artificial Intelligence and Its Effect on Dermatologists' Accuracy in Dermoscopic Melanoma Image Classification: Web-Based Survey Study.",
        "key_reference_abstract": "## BACKGROUND\nEarly detection of melanoma can be lifesaving but this remains a challenge. Recent diagnostic studies have revealed the superiority of artificial intelligence (AI) in classifying dermoscopic images of melanoma and nevi, concluding that these algorithms should assist a dermatologist's diagnoses.\n## OBJECTIVE\nThe aim of this study was to investigate whether AI support improves the accuracy and overall diagnostic performance of dermatologists in the dichotomous image-based discrimination between melanoma and nevus.\n## METHODS\nTwelve board-certified dermatologists were presented disjoint sets of 100 unique dermoscopic images of melanomas and nevi (total of 1200 unique images), and they had to classify the images based on personal experience alone (part I) and with the support of a trained convolutional neural network (CNN, part II). Additionally, dermatologists were asked to rate their confidence in their final decision for each image.\n## RESULTS\nWhile the mean specificity of the dermatologists based on personal experience alone remained almost unchanged (70.6% vs 72.4%; P=.54) with AI support, the mean sensitivity and mean accuracy increased significantly (59.4% vs 74.6%; P=.003 and 65.0% vs 73.6%; P=.002, respectively) with AI support. Out of the 10% (10/94; 95% CI 8.4%-11.8%) of cases where dermatologists were correct and AI was incorrect, dermatologists on average changed to the incorrect answer for 39% (4/10; 95% CI 23.2%-55.6%) of cases. When dermatologists were incorrect and AI was correct (25/94, 27%; 95% CI 24.0%-30.1%), dermatologists changed their answers to the correct answer for 46% (11/25; 95% CI 33.1%-58.4%) of cases. Additionally, the dermatologists' average confidence in their decisions increased when the CNN confirmed their decision and decreased when the CNN disagreed, even when the dermatologists were correct. Reported values are based on the mean of all participants. Whenever absolute values are shown, the denominator and numerator are approximations as every dermatologist ended up rating a varying number of images due to a quality control step.\n## CONCLUSIONS\nThe findings of our study show that AI support can improve the overall accuracy of the dermatologists in the dichotomous image-based discrimination between melanoma and nevus. This supports the argument for AI-based tools to aid clinicians in skin lesion classification and provides a rationale for studies of such classifiers in real-life settings, wherein clinicians can integrate additional information such as patient age and medical history into their decisions.",
        "truth": "True"
    },
    {
        "pmid": "38594408",
        "meta_analysis_title": "Human-AI interaction in skin cancer diagnosis: a systematic review and meta-analysis.",
        "meta_analysis_question": "Does AI assistance improve the accuracy of skin cancer diagnosis by clinicians compared to diagnosis without AI assistance?",
        "criteria": "We searched four electronic databases, including PubMed, Embase, Institute of Electrical and Electronics Engineers Xplore (IEE Xplore) and Scopus for peer-reviewed articles of AI-assisted skin cancer diagnosis without language restriction from January 1, 2017, until November 8, 2022. Search terms were combined for four key concepts: (1) AI, (2) skin cancer, (3) diagnosis, (4) doctors. The full search strategy is available in the Supplementary material (Supplementary Table 3). We chose 2017 as the cutoff for this review since this was the year when deep learning was first reported as performing at a level comparable to dermatologists, notably in the seminal study by Esteva et al9, which suggested that AI technology had reached a clinically useful level in assisting skin cancer diagnosis.",
        "subgroup": "Meta-analysis results of the diagnostic performance of clinicians - With AI-assisted clinicians",
        "key_reference_title": "Performance of a deep neural network in teledermatology: a single-centre prospective diagnostic study.",
        "key_reference_abstract": "## BACKGROUND\nThe use of artificial intelligence (AI) algorithms for the diagnosis of skin diseases has shown promise in experimental settings but has not been yet tested in real-life conditions.\n## OBJECTIVE\nTo assess the diagnostic performance and potential clinical utility of a 174-multiclass AI algorithm in a real-life telemedicine setting.\n## METHODS\nProspective, diagnostic accuracy study including consecutive patients who submitted images for teledermatology evaluation. The treating dermatologist chose a single image to upload to a web application during teleconsultation. A follow-up reader study including nine healthcare providers (3 dermatologists, 3 dermatology residents and 3 general practitioners) was performed.\n## RESULTS\nA total of 340 cases from 281 patients met study inclusion criteria. The mean (SD) age of patients was 33.7 (17.5) years; 63% (n\u00a0=\u00a0177) were female. Exposure to the AI algorithm results was considered useful in 11.8% of visits (n\u00a0=\u00a040) and the teledermatologist correctly modified the real-time diagnosis in 0.6% (n\u00a0=\u00a02) of cases. The overall top-1 accuracy of the algorithm (41.2%) was lower than that of the dermatologists (60.1%), residents (57.8%) and general practitioners (49.3%) (all comparisons P\u00a0<\u00a00.05, in the reader study). When the analysis was limited to the diagnoses on which the algorithm had been explicitly trained, the balanced top-1 accuracy of the algorithm (47.6%) was comparable to the dermatologists (49.7%) and residents (47.7%) but superior to the general practitioners (39.7%; P\u00a0=\u00a00.049). Algorithm performance was associated with patient skin type and image quality.\n## CONCLUSIONS\nA 174-disease class AI algorithm appears to be a promising tool in the triage and evaluation of lesions with patient-taken photographs via telemedicine.",
        "truth": "False"
    },
    {
        "pmid": "38594408",
        "meta_analysis_title": "Human-AI interaction in skin cancer diagnosis: a systematic review and meta-analysis.",
        "meta_analysis_question": "Does AI assistance improve the accuracy of skin cancer diagnosis by clinicians compared to diagnosis without AI assistance?",
        "criteria": "We searched four electronic databases, including PubMed, Embase, Institute of Electrical and Electronics Engineers Xplore (IEE Xplore) and Scopus for peer-reviewed articles of AI-assisted skin cancer diagnosis without language restriction from January 1, 2017, until November 8, 2022. Search terms were combined for four key concepts: (1) AI, (2) skin cancer, (3) diagnosis, (4) doctors. The full search strategy is available in the Supplementary material (Supplementary Table 3). We chose 2017 as the cutoff for this review since this was the year when deep learning was first reported as performing at a level comparable to dermatologists, notably in the seminal study by Esteva et al9, which suggested that AI technology had reached a clinically useful level in assisting skin cancer diagnosis.",
        "subgroup": "Meta-analysis results of the diagnostic performance of clinicians - With AI-assisted clinicians",
        "key_reference_title": "Human-computer collaboration for skin cancer recognition.",
        "key_reference_abstract": "The rapid increase in telemedicine coupled with recent advances in diagnostic artificial intelligence (AI) create the imperative to consider the opportunities and risks of inserting AI-based support into new paradigms of care. Here we build on recent achievements in the accuracy of image-based AI for skin cancer diagnosis to address the effects of varied representations of AI-based support across different levels of clinical expertise and multiple clinical workflows. We find that good quality AI-based support of clinical decision-making improves diagnostic accuracy over that of either AI or physicians alone, and that the least experienced clinicians gain the most from AI-based support. We further find that AI-based multiclass probabilities outperformed content-based image retrieval (CBIR) representations of AI in the mobile technology environment, and AI-based support had utility in simulations of second opinions and of telemedicine triage. In addition to demonstrating the potential benefits associated with good quality AI in the hands of non-expert clinicians, we find that faulty AI can mislead the entire spectrum of clinicians, including experts. Lastly, we show that insights derived from AI class-activation maps can inform improvements in human diagnosis. Together, our approach and findings offer a framework for future studies across the spectrum of image-based diagnostics to improve human-computer collaboration in clinical practice.",
        "truth": "True"
    },
    {
        "pmid": "38594408",
        "meta_analysis_title": "Human-AI interaction in skin cancer diagnosis: a systematic review and meta-analysis.",
        "meta_analysis_question": "Does AI assistance improve the accuracy of skin cancer diagnosis by clinicians compared to diagnosis without AI assistance?",
        "criteria": "We searched four electronic databases, including PubMed, Embase, Institute of Electrical and Electronics Engineers Xplore (IEE Xplore) and Scopus for peer-reviewed articles of AI-assisted skin cancer diagnosis without language restriction from January 1, 2017, until November 8, 2022. Search terms were combined for four key concepts: (1) AI, (2) skin cancer, (3) diagnosis, (4) doctors. The full search strategy is available in the Supplementary material (Supplementary Table 3). We chose 2017 as the cutoff for this review since this was the year when deep learning was first reported as performing at a level comparable to dermatologists, notably in the seminal study by Esteva et al9, which suggested that AI technology had reached a clinically useful level in assisting skin cancer diagnosis.",
        "subgroup": "Meta-analysis results of the diagnostic performance of clinicians - With AI-assisted clinicians",
        "key_reference_title": "Dermatologist-level classification of malignant lip diseases using a deep convolutional neural network.",
        "key_reference_abstract": "## BACKGROUND\nDeep convolutional neural networks (DCNNs) can classify skin diseases at a level equivalent to a dermatologist, but their performance in specific areas requires further research.\n## OBJECTIVE\nTo evaluate the performance of a trained DCNN-based algorithm in classifying benign and malignant lip diseases.\n## METHODS\nA training set of 1629 images (743 malignant, 886 benign) was used with Inception-Resnet-V2. Performance was evaluated using another set of 344 images and 281 images from other hospitals. Classifications by 44 participants (six board-certified dermatologists, 12 dermatology residents, nine medical doctors not specialized in dermatology and 17 medical students) were used for comparison.\n## RESULTS\nThe outcomes based on the area under curve, sensitivity and specificity were 0\u00b7827 [95% confidence interval (CI) 0\u00b7782-0\u00b7873], 0\u00b7755 (95% CI 0\u00b7673-0\u00b7827) and 0\u00b7803 (95% CI 0\u00b7752-0\u00b7855), respectively, for the set of 344 images; and 0\u00b7774 (95% CI 0\u00b7699-0\u00b7849), 0\u00b7702 (95% CI 0\u00b7579-0\u00b7808) and 0\u00b7759 (95% CI 0\u00b7701-0\u00b7813), respectively, for the set of 281 images. The DCNN was equivalent to the dermatologists and superior to the nondermatologists in classifying malignancy. After referencing the DCNN result, the mean \u00b1 SD Youden index increased significantly for nondermatologists, from 0\u00b7201 \u00b1 0\u00b7156 to 0\u00b7322 \u00b1 0\u00b7141 (P < 0\u00b7001).\n## CONCLUSIONS\nDCNNs can classify lip diseases at a level similar to dermatologists. This will help unskilled physicians discriminate between benign and malignant lip diseases. What's already known about this topic? Deep convolutional neural networks (DCNNs) can classify malignant and benign skin diseases at a level equivalent to dermatologists. The lips are a unique feature in terms of histology and morphology. Previous studies of DCNNs have not investigated tumours on specific locations. What does this study add? This study shows that DCNNs can distinguish rare malignant and benign lip disorders at the same rate as dermatologists. DCNNs can help nondermatologists to distinguish malignant lip diseases. What are the clinical implications of this work? DCNNs can distinguish malignant and benign skin diseases even at specific locations such as the lips, as well as board-certified dermatologists. Malignant lip diseases are rare and difficult for less trained doctors to differentiate them from benign lesions. This study shows that in dermatology, DCNN can help improve decision-making processes for rare skin diseases in specific areas of the body.",
        "truth": "True"
    }
]