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Management of safety events | EVENTS | The responsibility for collecting and assessing safety events in this study fell to the blinded investigator, who made determinations of causality based on the five principles of adverse event-drug causality assessment [ | PMC10636892 | |
Discussion | operability | SEPARATION | In the present study, there were two independent evaluations of each subject at different time points of the visit after treatment, which can be considered a sample size of 22. If we assume that Kappa=0.7 represents a better agreement, while we evaluated the blinded and non-blinded state, we found Kappa=0.248 (about 0.25). With α=0.05, proportions=0.4, 0.6, and according to the above parameters, we used PASS 22 to calculate power=0.75. The findings from our study suggest that even with a relatively small sample size, the outcomes are notably indicative of similar future investigations.The current study showed that the post-treatment IDSA/IWGDF grading results were compared in 11 subjects, and the consistency test showed inconsistent results between the non-blinded and center reading blinded evaluations (Kappa=0.248, While double-blinding is a pivotal measure to control subjective bias from investigators and subjects, it is equally crucial to establish independent blinded evaluations of investigators in scenarios where medications cannot be completely blinded. Even in double-blind trials, independent blinded evaluations are necessary to avoid investigators or patients guessing about intervention groupings by comparing study drugs or based on post-dose responses. However, a research study showed that blinded evaluations were not adequately used and reported, while open trials did not use independent evaluators more frequently than double-blind trials [One study addressed the issue of bias in determining the results of an open randomized controlled trial by administering a questionnaire to the evaluators at the end of the trial [The implementation of blinded evaluation is a significant challenge for the design and implementation of the study. In open clinical trials where wound observation is the primary indicator of efficacy, it is recommended that there be an independent blinded investigator at each trial site, and a series of standard operating procedures (SOPs) for blinded evaluation should be implemented. We have described above the basic requirements for blinded evaluations by setting up standard processes: separation of duties for investigators, subject management, collection of efficacy and safety indicators, and management of trial drugs. In some studies, when scientificity and operability permit, we propose that blinded evaluation can be conducted by taking photos and centralized evaluation by an independent evaluation committee to ensure the objectivity and consistency of the results. For some of the objective result data (e.g., essential test data, metabolomics data) for which there is a risk of blinding, we suggest that blinded management can be used, where the personnel blinded to the evaluation of efficacy and safety indicators are not exposed to these data results. Meanwhile, research team members at the back of the data chain (e.g., data management, data statistics) should also be in a blinded state to reduce bias. Research quality control personnel should follow the PDCA cycle model (e.g., planning, doing, checking, and acting) for all phases of quality management-related work. Through the above process, ensure the maintenance of blinded evaluation throughout the trial and improve the quality of open clinical trials.Although we have proposed various measures to mitigate bias in open clinical trials, further exploration and innovation are necessary to enhance the reliability of trial outcomes. For instance, introducing objective efficacy evaluation tools, like sensor-equipped insoles, can provide unbiased, quantifiable data [Despite these strengths, our study is not without limitations. The relatively small sample size may raise questions about the reliability of the results. Future research should validate our findings with larger sample sizes and further explore the best practices for maintaining blinded evaluation in clinical trials. | PMC10636892 |
Conclusions | In open clinical studies, minimizing information bias represents a significant challenge. Our findings indicate that implementing blinded evaluations can effectively reduce information bias, thereby ensuring the authenticity and reliability of trial outcomes. We strongly advocate for the appointment of an independent blinded researcher at each trial site and the implementation of a series of standard operating procedures (SOPs) for blinded evaluations. For this purpose, we propose a comprehensive set of SOPs encompassing divisions of labor among researchers, subject management, collection of efficacy and safety indices, and trial drug management. By doing so, we aim to achieve effective blinded evaluations and enhance the quality of open trials to the greatest extent possible.Importantly, our study provides a practical strategy for future clinical trials to mitigate potential biases, thereby strengthening the evidence base for clinical decision-making. | PMC10636892 | ||
Acknowledgements | We thank the investigators and participants for making this research possible. | PMC10636892 | ||
Authors’ contributions | The study was designed by the authors (RG, FL, QL ). Data was collected by the authors (HZ, YY, PQ). Data was analyzed by the authors (MX, YZ). XL provided language editing and revision. The first version of the manuscript was written by QL; all authors revised the manuscript. | PMC10636892 | ||
Funding | This work was supported by the “National Key R&D Program of China” and “Science and Technology Innovation Project of the Chinese Academy of Traditional Chinese Medicine” (No.2019YFC1709300 and No. CI2021A04704). | PMC10636892 | ||
Availability of data and materials | The datasets will be made available after a reasonable request to the investigator of the Institute of Clinical Pharmacology, Xiyuan Hospital, Chinese Academy of Traditional Chinese Medicine. | PMC10636892 | ||
Declarations | PMC10636892 | |||
Ethics approval and consent to participate | The IRB approved this study of Xiyuan Hospital of China Academy of Chinese Medical Sciences (No. 2022XLA093-1). Prior to taking part in the trial, informed consent was obtained from all participants and/or their legal guardian(s). | PMC10636892 | ||
Consent for publication | All consent forms included permission for publication of any information gained through the individual’s participation. | PMC10636892 | ||
Competing interests | The authors declare that they have no competing interests. | PMC10636892 | ||
References | PMC10636892 | |||
Objective | diabetes, Diabetes | DIABETES, DIABETES | Edited by: Martha M. Funnell, University of Michigan, United StatesReviewed by: Linda Siminerio, University of Pittsburgh, United States; Kevin Joiner, School of Nursing, University of Michigan, United StatesThis article was submitted to Clinical Diabetes, a section of the journal Frontiers in Public HealthTo evaluate the effectiveness of two technology-enhanced interventions for diabetes prevention among adults at risk for developing diabetes in a primary care setting. | PMC9998510 |
Methods | TYPE 2 DIABETES | The DiaBEAT-it study employed a hybrid 2-group preference (Choice) and 3-group randomized controlled (RCT) design. This paper presents weight related primary outcomes of the RCT arm. Patients from Southwest Virginia were identified through the Carilion Clinic electronic health records. Eligible participants (18 and older, BMI ≥ 25, no Type 2 Diabetes) were randomized to either Choice ( | PMC9998510 | |
Results | Of the 334 participants that were randomized, 232 (69%) had study measured weights at 6 months, 221 (66%) at 12 months, and 208 (62%) at 18 months. Class/IVR participants were less likely to complete weight measures than SC or DVD/IVR. Intention to treat analyses, controlling for gender, race, age and baseline BMI, showed that DVD/IVR and Class/IVR led to reductions in BMI at 6 (DVD/IVR −0.94, | PMC9998510 | ||
Conclusions | obesity, diabetes | OBESITY, DIABETES | The DiaBEAT-it interventions show promise in responding to the need for scalable, effective methods to manage obesity and prevent diabetes in primary care settings that do not over burden primary care clinics and providers. | PMC9998510 |
1. Introduction | T2D, prediabetes, Diabetes, weight loss, diabetes | DIABETES, DISEASE, PREDIABETES, DIABETES | The Centers for Disease Control and Prevention (CDC) estimates that there are 34.2 million (10.5%) Americans with diabetes, in addition to the 88 million (34.5% of the population) with prediabetes in the United States, and strongly recommends healthcare approaches to prevent diabetes (The Diabetes Prevention Program (DPP) was seminal in demonstrating that a modest weight loss achieved through diet and exercise was superior to medication in delaying the onset of T2D (To address these barriers, several interventions have used technology to successfully adapt and deliver the DPP. Several systematic reviews have shown that technology-based resources can optimize diabetes prevention intervention to achieve clinically significant weight loss (The original diaBEAT-it study ( | PMC9998510 |
2. Design and methods | diabetes | DIABETES | Patients at risk for developing diabetes were randomly assigned (2-1) by the project manager to either an RCT or Choice study arm using a blocked (groups of 4) randomization table stratified by sex created by the study statistician. Patients in the RCT arm were further randomized (1-1-1) to one of three groups: (1) a 2-h small group class designed to help patients develop a personal action plan to prevent diabetes (SC) (This paper presents weight related outcomes associated with the randomized control trial arm of the DiaBEAT-it study ( | PMC9998510 |
2.1. Participant eligibility and recruitment | BLIND | Potential participants were initially identified through a Carilion Clinic electronic health records (EHR) query of primary care patients between January 2014 and August 2015 (Individuals were eligible if they were 18 years of age or older with a BMI of at least 25 kg/mPrior to the baseline visit, the project manager created sealed opaque envelopes with group assignment information according to the blocked (groups of 4) randomization table stratified by gender created by the study statistician to blind research staff to intervention assignment. Informed consent procedures were initiated during the screening telephone call with participants receiving the informed consent | PMC9998510 | |
2.2. Interventions | PMC9998510 | |||
2.2.1. Standard care | Participants in the SC comparison group took part in a 2-h small group session class ( | PMC9998510 | ||
2.2.2. Class/IVR group | Participants in this group attended the 2-h class described above, received a workbook, completed a “Live” counseling call ( | PMC9998510 | ||
2.2.3. DVD/IVR group | diabetes | PRE-DIABETES, DIABETES | This group was identical to the Class/IVR group but was initiated with a DVD that replicated the class content. The DVD included the following segments: (1) What is pre-diabetes? (2) What are the risk factors for diabetes? (3) Developing your DiaBEAT-it action plan, (4) Goal setting for physical activity and healthy eating, (5) putting together a toolbox of resources, and (6) making a commitment to change. The DVD was about 60 min in duration with several planned pauses to allow for completion of activities. This replicated the 5 A's approach that guided the class and included the completion of an action plan page in the accompanying workbook. Finally, the DVD included an appendix with additional free-of-charge, online nutrition and physical activity informational videos. Participants received their live counseling call within 7 days of being given the DVD. Similar to the Class/IVR group, those participants that reported not watching the DVD the research assistants provided full information and guided them through developing their personal action plan during the “Live” call. The IVR structure and content was the same as described above. | PMC9998510 |
2.3. Outcome measures | weight loss, weight reduction | Trained research assistants unaware of group assignment collected data at baseline, 6, 12, and 18 months. The primary outcome was change in BMI from baseline to 18 months. Secondary outcomes included percentage of participants achieving weight loss goals of 5% or more, changes in percent weight reduction as well as maintenance of those changes at 12 and 18 months. Height was assessed in stocking feet with a calibrated stadiometer with a fixed vertical backboard and adjustable headboard. Weight was assessed with the calibrated Health-O-Meter 2101KL digital stand-on scale ( | PMC9998510 | |
2.4. Statistical analysis | Diabetes | DIABETES | Statistical analysis included descriptive statistics for age, sex, race, ethnicity, education, income, health literacy, employment, health insurance, Diabetes Risk Calculator (DRC), and weight status. Chi-square and independent Additionally, we conducted analysis based on participants completing at least 4 sessions (i.e., meeting NDPP threshold for recognition standards) ( | PMC9998510 |
3. Results | PMC9998510 | |||
3.3. Intervention participation rates: CDC recognition standards | weight loss | On average participants in the DVD/IVR group completed 15.5 (±8.6) sessions compared to 14.1 (±8.3) for Class/IVR. Approximately, 86.3% of participants in the intervention groups (DVD/IVR: 86.6%; Class/IVR: 86%) met the CDC threshold of completing at least 4 sessions with 48.4% (DVD/IVR: 52.6%; Class/IVR: 44%) staying in the program for at least 6 months, and 29.5% (DVD/IVR: 37.1%; Class/IVR: 21.5%) completing every session during the 12-month program. Average percent weight loss at 12 months for those meeting the CDC threshold were 3.24% (DVD/IVR) and 2.74% (Class/IVR) with 35.74% (DVD/IVR) and 33.44% (Class/IVR) achieving a 5% weight loss. | PMC9998510 | |
3.3.1. Adverse events | allergic reactions–21, neoplasms, infections, cardiac disorders, vascular disorders, nervous systems disorders | ADVERSE EVENTS, NEOPLASMS, RESPIRATORY DISORDERS, INFECTIONS, DISORDERS, CARDIAC DISORDERS, IMMUNE SYSTEM DISORDER, MUSCULOSKELETAL DISORDERS, VASCULAR DISORDERS, EVENTS, COMPLICATIONS | During the trial, 40 adverse events (AE) were reported; 6 were classified as serious adverse events (SAE). The majority were associated with immune system disorders (allergic reactions–21). Additional categories included cardiac disorders (1), musculoskeletal disorders (3), general disorders (1), infections (1), injury or procedure complications (3), neoplasms benign, malignant and unspecified (1), nervous systems disorders (1), respiratory disorders (1), and vascular disorders (2). Twenty-one AEs were determined to be related to the study and 3 had insufficient information to make a determination. The 21 related AEs were all associated with a skin irritation as result of the application of the accelerometer used in the study. One SAE also associated with the application of the accelerometer led to a severe reaction and hospitalization. Overall events were equally balanced between groups, with 13 in SC, 11 in Class/IVR, and 14 in DVD/IVR. | PMC9998510 |
4. Discussion and conclusion | obesity, Obesity, T2D, Diabetes, weight loss, diabetes | OBESITY, DIABETES, OBESITY, DIABETES | The randomized control trial arm of our study demonstrated that two technology-enhanced diabetes prevention programs both led to modest reductions in body weight over an 18-month period. Most importantly, the DVD/IVR group showed significant reductions in BMI when compared to the SC group confirming our original hypothesis. However, there were no significant differences between Class/IVR and SC groups. Participants in the DVD/IVR group lost a mean 2.79 kg over 12 months with 26.9% of participants losing 5% or more of initial body weight in ITT analyses. These numbers improve for both technology-enhanced groups as the number of sessions attended increased.Our results support the findings of several recent reviews on technology mediated DPPs (When investigating the effects of eHealth obesity interventions, Hutchesson et al. (Taken altogether, our results support existing evidence on the effectiveness of technology mediated DPPs (Additionally, while not the original purpose of this study, results from this trial seem to indicate that both the DVD/IVR and the Class/IVR groups could meet CDC recognition standards (These are important findings when considering that several barriers to large scale implementation remain for technology enhanced DPPs (The present trial is not without limitations. First, study participants in the DVD/IVR group presented significantly higher BMI with a higher proportion being at Class III Obesity status at baseline. While we used randomization procedures, we did not stratify by BMI status. Nevertheless, we accounted for these initial differences by using baseline BMI values as control variable in our models. Second, we had an overall high attrition rate. As such, our results must be seen with caution as up to 38% of our participants did not complete follow-up assessments. These numbers were particularly higher among Class/IVR participants reaching 50% at 18 months. Nonetheless, we used Intent-to-treat analysis to include all participants with a baseline value in our models. When comparing with other studies, we also see similar attrition rates for weight loss programs in primary care (In closing, our findings show that a technology-enhanced diabetes prevention program was effective in reducing BMI at 6 months and maintaining these results at 12 and 18 months in a group of primary care patients at risk for developing T2D. The DiaBEAT-it interventions respond to the need for scalable, effective methods to manage obesity and prevent diabetes in primary care settings that do not over burden primary care clinics and providers. Further, the CDC requires the inclusion of a lifestyle coach in any in-person or technology-based program as one of the standards for recognition in its National Diabetes Prevention Program ( | PMC9998510 |
Data availability statement | The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation. | PMC9998510 | ||
Ethics statement | The studies involving human participants were reviewed and approved by Carilion Clinic Institutional Review Board. The patients/participants provided their written informed consent to participate in this study. | PMC9998510 | ||
Author contributions | Camilia, RS | BROWN | FA, WY, RS, BD, MG, JH, and PE contributed to the conception of the protocol and study design. FA, WY, FB, TA, CG, and SW were involved with the data collection and analysis. All authors were involved in writing the paper and had final approval of the submitted manuscript.The authors would like to acknowledge the entire DiaBEAT-it! research team who have been vital in the support and work of this project, including Kate Jones, Nicky Young, Ashley Merritt, Kimberlee Pardo, Cynthia Karllson, Peter Moreau, Rochelle Brown, Jessica Ladage, Jessica Mays, Felipe Marta, Camilia Squarcini, Nick Bilbro, Katie Brajdic, and Visva Patel. | PMC9998510 |
Conflict of interest | The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | PMC9998510 | ||
Publisher's note | All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. | PMC9998510 | ||
Supplementary material | The Supplementary Material for this article can be found online at: Click here for additional data file. | PMC9998510 | ||
References | PMC9998510 | |||
Background | asthma-like symptoms, wheezing, asthma, exhaled breath, wheeze | ASTHMATIC, ASTHMA | The prevalence of asthma-like symptoms in preschool children is high. Despite numerous efforts, there still is no clinically available diagnostic tool to discriminate asthmatic children from children with transient wheeze at preschool age. This leads to potential overtreatment of children outgrowing their symptoms, and to potential undertreatment of children who turn out to have asthma. Our research group developed a breath test (using GC-tof–MS for VOC-analysis in exhaled breath) that is able to predict a diagnosis of asthma at preschool age. The ADEM2 study assesses the improvement in health gain and costs of care with the application of this breath test in wheezing preschool children. | PMC10068201 |
Methods | allergic sensitisation, asthma, wheeze, exhaled breath | DISEASE, ASTHMA | This study is a combination of a multi-centre, parallel group, two arm, randomised controlled trial and a multi-centre longitudinal observational cohort study. The preschool children randomised into the treatment arm of the RCT receive a probability diagnosis (and corresponding treatment recommendations) of either asthma or transient wheeze based on the exhaled breath test. Children in the usual care arm do not receive a probability diagnosis. Participants are longitudinally followed up until the age of 6 years. The primary outcome is disease control after 1 and 2 years of follow-up. Participants of the RCT, together with a group of healthy preschool children, also contribute to the parallel observational cohort study developed to assess the validity of alternative VOC-sensing techniques and to explore numerous other potential discriminating biological parameters (such as allergic sensitisation, immunological markers, epigenetics, transcriptomics, microbiomics) and the subsequent identification of underlying disease pathways and relation to the discriminative VOCs in exhaled breath. | PMC10068201 |
Discussion | asthma-like symptoms, wheezing, asthma | ASTHMA | The potential societal and clinical impact of the diagnostic tool for wheezing preschool children is substantial. By means of the breath test, it will become possible to deliver customized and high qualitative care to the large group of vulnerable preschool children with asthma-like symptoms. By applying a multi-omics approach to an extensive set of biological parameters we aim to explore (new) pathogenic mechanisms in the early development of asthma, creating potentially interesting targets for the development of new therapies. | PMC10068201 |
Trial registration | Netherlands Trial Register, NL7336, Date registered 11–10-2018. | PMC10068201 | ||
Keywords | PMC10068201 | |||
Background | cough, breathlessness, wheeze | Respiratory symptoms, such as wheeze, breathlessness, chronic cough, and sputum production, are very common in young children. Around 40% of all children under the age of 6 suffer from these asthma-like symptoms [ | PMC10068201 | |
Prediction of asthma in the guidelines | asthma-like symptoms, asthma, wheeze | ASTHMA | The prediction of asthma in preschool children with asthma-like symptoms (such as wheeze) has been an important unresolved topic. A reliable asthma diagnosis in preschool wheeze is not possible, as noted by the various (inter)national asthma guidelines [ | PMC10068201 |
Wheezing phenotypes and clinical predictive indices | asthma, wheeze | THORACIC, ASTHMA | Whilst no tests diagnose asthma with certainty, various attempts were done to improve an asthma diagnosis in young children. For example, different phenotypes have been described based on triggers of wheeze obtained by clinical history, including episodic (viral) wheeze and multi-trigger wheeze. This was adopted by the European Respiratory Society (ERS) and American Thoracic Society (ATS) taskforce in 2008 [ | PMC10068201 |
Consequences of an absent diagnostic instrument for an early diagnosis in wheezing children | palpitations, tremor, wheezing, underdiagnosis, asthma, wheeze | ASTHMA | In current clinical practice, the absence of a proper diagnostic test for an early asthma diagnosis in young children leads to at least 2 major health problems: 1) children with asthma are frequently underdiagnosed and undertreated; 2) children with transient wheeze are often overtreated with asthma medication.Considerable underdiagnosis and undertreatment occurs in young children with asthma [Overtreatment of children with transient wheeze occurs with an increased risk of side effects of ICS and bronchodilators such as reduced linear growth, tremor, and palpitations [Therefore, a predictive instrument for an early asthma diagnosis will be of great importance to improve treatment of and care for the large group of young children with wheezing symptoms, and will probably lead to a substantial reduction in the cost of care. | PMC10068201 |
Volatile organic compounds | exhaled breath | Over the past decades, exhaled breath has evolved as a new bodily matrix that has great potential for diagnostic and monitoring purposes [ | PMC10068201 | |
A predictive breath test for asthma in preschool children | wheezing, asthma, exhaled breath | ASTHMA, ASTHMA | In 2015 we published the results of a longitudinal study in 202 wheezing children, in which we assessed the potential of exhaled breath biomarkers for a paediatric asthma diagnosis, called the ADEM study (Asthma DEtection and Monitoring study) [the chemical identity of the 9 most predictive VOCs of the ADEM algorithm. BCa 95%CI: Bias Corrected accelerated 95% Confidence Interval [ | PMC10068201 |
VOCs-sensing techniques in daily clinical practice | In the ADEM study, we used gas chromatography– | PMC10068201 | ||
Pathophysiological mechanisms | asthma, airway inflammation, asthma [ | DISEASE, OXIDATIVE STRESS, ASTHMA | Although the assessment of VOCs is attractive by the non-invasive nature, there is limited understanding of their origin in asthma. VOCs can be formed during various pathophysiological processes, such as airway inflammation and oxidative stress, induced by host and coexisting micro-organisms. Analysing the underlying mechanisms resulting in the formation of predictive exhaled biomarkers such as VOCs, may give insight in the underlying disease pathways leading to the early development of asthma [ | PMC10068201 |
Objectives of the new study: the ADEM2 study | wheezing, asthma, exhaled breath | PATHOGENESIS, ASTHMA | The previous ADEM study generated a lot of insight in the diagnostic potential of VOC patterns in exhaled breath with respect to an early diagnosis of asthma, and in multiple potential underlying pathophysiological mechanisms leading to the development of asthma. However, since then, many new questions arose. For example with regards to the feasibility of bringing the assessment of VOCs in exhaled breath into daily clinical practice, and with respect to the impact an early diagnosis of asthma will have on wheezing preschool children and their parents. Also, recent developments in the evolving field of multi-omics generated new approaches to investigate the early pathogenesis of asthma. Therefore, a new randomised controlled trial and prospective study in wheezing preschool children was designed, the ADEM2 study.The primary objective of the ADEM2 study is to prove health gain and reduction in costs by application of a point-of-care (POC) breath test for an early asthma diagnosis in preschool children. A multicentre randomised controlled trial (RCT) in 220 wheezing preschool children will be performed. Children will be randomised into an intervention group ( | PMC10068201 |
Hypotheses of the ADEM2 study | exacerbations, airway remodelling, asthma-like symptoms, wheezing, allergy, asthma, wheeze | ALLERGY, ASTHMA, SEQUELA | The hypothesis of the clinical trial of the ADEM2 study is that application of the breath test in preschool children with asthma-like symptoms will result in important health gain and reduction of costs of care. In children with asthma, we expect that an early diagnosis by the breath test will result in more targeted and better treatment. This will facilitate better asthma control, improved lung function, less exacerbations, less hospital admissions, improved quality of life, and probably less airway remodelling. In children with transient wheeze, we hypothesise that an early diagnosis will diminish uncertainty of parents and treating doctors, with less referrals, less additional examinations (X-rays, allergy tests, microbial cultures or viral PCR tests), and less ineffective treatment (antibiotics, corticosteroids, or antihistamines). Parents will be reassured by the early diagnosis of transient wheeze, which will probably increase quality of life and decrease medical consumption. In both cases, cost savings are expected because of a proper diagnosis by the breath test due to significantly reduced hospital based care and medication use in children with transient wheeze, and prevention of undertreatment related sequela in children with asthma.Our hypothesis of the observational cohort study with respect to the feasibility, reproducibility and accuracy of the alternative VOC-sensing techniques is that innovative techniques such as SIFT-MS are not inferior to the current golden standard GC–MS. We also hypothesise that new (combinations of) biomarkers will be found that improve the diagnostic accuracy to identify the wheezing preschool child developing asthma, such as epigenetic signatures of blood eosinophils, microbiome data of both nasopharyngeal swabs and faecal samples, whole RNA sequencing on blood, gene-expression of relevant asthma genes, and immunological markers. | PMC10068201 |
Methods | PMC10068201 | |||
Study design | The proposed study is a combination of a multi-centre, parallel group, two arm, randomised controlled trial and a multi-centre longitudinal observational cohort study. All children that participate in the RCT will also contribute to the observational cohort study.I | PMC10068201 | ||
Study setting | Preschool | DISEASE | In order to achieve a good mixture of disease variability and severity in the study population (to maximise the external validity of the study results), the trial will be conducted in primary care practices and in the paediatric wards and outpatient departments of several general hospitals and university hospitals in the Netherlands. Preschool children aged 2 or 3 years will be recruited. The participating recruiting primary care practices are located in the southern and northern region of the Netherlands. The participating general hospitals are located throughout the country, as well as the participating university hospitals (Maastricht University Medical Centre, University Medical Centre Groningen, and Radboud University Medical Centre).The healthy children that contribute to the observational cohort study will be recruited at day-care centres, via centres for youth health care, and by means of primary care practices, and (social) media. | PMC10068201 |
Eligibility criteria | wheezing | The proposed study protocol includes both wheezing preschool children and healthy preschool children. In the RCT only wheezing preschool children will participate, whereas in the longitudinal cohort study both wheezing and healthy preschool children participate. | PMC10068201 | |
Inclusion criteria | shortness of breathHealthy, wheezing, Wheezing |
Wheezing children: age between 2 and 4 years old and presence of two or more objectified (by a physician or nurse) episodes of wheezing and shortness of breathHealthy children: age between 2 and 4 years old | PMC10068201 | |
Exclusion criteria | kidney or liver disease, Wheezing, prematurity, congenital lung disease, auto-immune disorders, asthma, wheeze, mental disability | CARDIAC DISEASE, ASTHMA, INFLAMMATORY DISEASE, INFLAMMATORY BOWEL DISEASE |
Wheezing children: presence of chronic and/or inflammatory disease other than asthma (e.g. inflammatory bowel disease, auto-immune disorders, cardiac disease, congenital lung disease, kidney or liver disease), prematurity < 35 weeks gestational age, postnatal need for oxygen, CPAP, non-invasive or invasive ventilation, or mental disability.Healthy children: a history of asthma or wheeze, other chronic and/or inflammatory disease other than asthma (e.g. inflammatory bowel disease, auto-immune disorders, cardiac disease, congenital lung disease, kidney or liver disease), prematurity < 35 weeks gestational age, postnatal need for oxygen, CPAP, non-invasive or invasive ventilation or mental disability.Children with a recent course of systemic corticosteroids or antibiotics are not excluded from participation, but the baseline visit will be postponed until at least one month after the treatment. | PMC10068201 |
Intervention | asthma, wheeze | ASTHMA | The intervention in the RCT consists of providing a probability diagnosis of either asthma or transient wheeze based on the earlier developed breath test of the ADEM study [ | PMC10068201 |
Outcomes | PMC10068201 | |||
Randomised controlled trial | asthma-like symptoms |
Primary outcome: difference between the intervention group and the usual care group in the percentage of well controlled asthma-like symptoms after 1- and 2-year follow-up. The percentage well controlled asthma-like symptoms will be based on the validated TRACK questionnaire.Secondary outcomes: differences after one year and at the end of the study between the intervention group and usual care group will be assessed with respect to:Number of exacerbationsLung function (spirometry) at 6 years of ageAirway resistance with forced oscillation techniqueQuality of life of children and their parentsPharmacotherapy (frequency and dosage of used medication)Growth velocity over 12, 24 and 36 months (cm/y), change in height SD scores over 12, 24 and 36 monthsPatient reported side-effects of medicationHealthcare resource use and –costs (standard and extra clinical visits, hospital admissions, referrals, laboratory tests, imaging tests)Costs outside healthcare (over-the-counter drugs)Absence of school and work (parents); | PMC10068201 | |
Prospective cohort study | allergic sensitisation, asthma, wheeze | DISEASE, ASTHMA |
Secondary outcomesThe sensitivity and specificity of new VOC sensing techniques (e.g. SIFT-MS and VOC sensors) for a diagnosis of asthma or transient wheeze in preschool children. Assessment at the start of the study in relation to the current gold standard in breath research (GC–MS) and at the age of 6 years in relation to the final diagnosis.Identification of other potential discriminating biological parameters (such as allergic sensitisation, immunological markers, epigenetics, transcriptomics, microbiome) between asthma, transient wheeze, and healthy controls, and the subsequent identification of underlying disease pathways and relation to the discriminative VOCs in exhaled breath. Assessment of data collected at the start of the study and at the end in relation to the final diagnosis at the age of 6 years.Identification of discriminative exhaled VOCs (based on GC- | PMC10068201 |
Participant timeline | wheezing | Both wheezing participants and healthy participants follow the same timeline (Fig. Flow of participantsSchedule of enrolment, interventions, and assessments. * Children can enrol the study at 2 or 3 years of age. ** Only applicable for patients enrolling the study at 2 years of ageSchedule of questionnaires. | PMC10068201 | |
Recruitment | Wheezing | RECRUITMENT | Wheezing participants will be recruited at the participating primary care centres and participating hospitals. Potential candidates will be identified by their treating physicians and (specialised) nurses at the primary care practices, outpatient departments, paediatric wards or emergency departments during the recruitment and enrolment phase of the study. Subject information sheets on the study will be handed out to these patients and the parents will be asked to contact the research team for more information about participating in the study.Healthy participants will be recruited through advertisement and distribution of subject information sheets to all parents of 1- to 4-year old toddlers at day-care centres, via centres for youth health care, via general practitioners practices and during pre-operative screening at the outpatient department of the paediatric anaesthesia department of Maastricht University Medical Centre. Also a variety of (social) media will be used for open advertisement.All recruiting materials and subject information sheets have prior approval of the institutional Medical Research Ethics Committee (MREC). | PMC10068201 |
Allocation and blinding | wheezing, CTCM | SECONDARY, RECRUITMENT | The wheezing preschool children that participate in the RCT will be randomly assigned (1:1), with a secure computer-generated block randomisation procedure (block size of 6), into a usual care group and an intervention group. The randomisation will be organised by the Clinical Trial Centre Maastricht (CTCM) and MEMIC (centre for data and information management at the Faculty of Health, Medicine and Life Sciences of Maastricht University and MUMC +). Randomisation is stratified per measurement centre. The participants, treating physicians and the researchers or research assistants involved in conducting the baseline visit are not blinded to the results of the randomization procedure. The assessment of the primary outcomes and secondary outcomes after one year and at the end of the study will be done by researches who were not involved in the recruitment and randomization procedures. These researchers will be blinded towards the allocation in randomisation group and (final) diagnosis of the participants. | PMC10068201 |
Data collection | During the annual visits, various study procedures will be conducted. Each centre in which the study visits take place (the “measurement centres”) has a dedicated team consisting of one or two research nurses, and one or two p that execute all study-related procedures. All study personnel will be trained in the study requirements and study procedures. Standard Operating Procedures (SOPs) will be provided to all study sites to enhance data quality and reduce variability in measurements as much as possible.Parents will be instructed that their children should refrain from eating, brushing teeth, using inhalation medication, and moderate to severe exercise as much as possible within 60 min prior to the visit. Drinking of water is allowed prior to the tests. Prior to the annual visits, electronic questionnaires will be sent to the parents. In the RCT study group, a subset of these questionnaires will also be sent at three monthly intervals. The parameters that are measured are listed in Fig. A web-based study management system Ldot ( | PMC10068201 | ||
Buccal swab | asthma | ASTHMATIC, MINOR, ASTHMA | Isohelix Buccal swabs with RapiDri™ pouch will be used to sample buccal cells for isolating DNA at the baseline visit. The extracted DNA is used to study gene polymorphisms in selected candidate genes. The inclusion of genes for SNP analysis is based on the following criteria: association with asthma based on biomedical literature, a functional difference between the variant allele and the wild-type allele, and a minor allele frequency of at least 5% in the (asthmatic) population. | PMC10068201 |
Nasal epithelial brush | STERILE | Nasal epithelial cells will be collected at the baseline visit by brushing nylon flocked swabs (FLOQSwabs®, COPAN, CA, USA) against the lateral side of the inferior turbinate of both nostrils. Two swabs will be transferred into sterile National Lab Cryovials, and two swabs will be transferred into sterile National Lab Cryovials filled with RNAlater™ stabilisation solution. All cryovials will be stored at -80°C until DNA and RNA extraction and subsequent determination of DNA methylation and RNA-sequencing. | PMC10068201 | |
Venous blood sample | inflammation, wheeze | BLOOD, OXIDATIVE STRESS, STERILE, INFLAMMATION | Six millilitres of venous blood will be sampled at baseline visit and at the end visit. One to two hours prior to the blood puncture, lidocaine 1% gel with 4 × 4 cm plaster will be applied. This blood will be used for.allergy testing: total immunoglobulin E (IgE) and determination of specific IgE antibodies to inhalant allergens (ImmunoCAP allergens gx3 (grass pollen), tx9 (tree pollen), wx3 (weed pollen), mx1 (moulds), d1 (house dust mite), e1 (cat dander), e5 (dog dander) (Phadiatop test; Phadia, Uppsala, Sweden)white blood cell count and absolute number of eosinophils will be determinedleukocyte subset analysis by flow cytometry: Extended phenotyping will be performed to evaluate B-cell maturation and differentiation (CD19, CD27, CD38, and IgD), and T-cell maturation and differentiation (CD3, CD4, CD8, CD28, CD45RA and CD127). These panels enable the distinction of pro- and anti-inflammatory lymphocyte subsets, the degree of memory formation as a marker for pathogen exposure, and early senescence. In addition, monocyte subsets (classical and non-classical) and dendritic cell subsets (myeloid and plasmacytoid dendritic cells) will be evaluated (CD11c, CD14, CD16, CD123, HLA-Dr, BDCA-2, and BDCA-3)isolation of peripheral blood mononuclear cells (PBMC’s): PBMC’s will be stored in liquid nitrogen for in vitro activation with distinct stimuli followed by analyses of the produced cytokine repertoire.isolation of eosinophils: In a subset of children (80 children with wheeze, 40 healthy controls) peripheral blood eosinophils will be isolated by FACS sorting. Blood eosinophils will be isolated from 2 ml of EDTA blood using an adapted FACS sorting strategy based on Mori et al. within 24 h of blood sampling, sorting Siglec8 + and CD193 + cells [whole transcriptome RNA sequencing for gene expression of markers of inflammation and oxidative stress. One millilitre of venous blood will be transferred into sterile National Lab Cryovials. Invitrogen™ RNA | PMC10068201 |
API and modified API (mAPI) | atopy, wheezing, asthma, eczema | ATOPY, ALLERGIC RHINITIS, ASTHMA, COLDS, ECZEMA | The API and mAPI (based on parental asthma, eczema, allergic rhinitis, wheezing apart from colds, and atopy) will be assessed at baseline [ | PMC10068201 |
Cost-effectiveness | DISEASE | Cost-effectiveness will be calculated as the incremental costs per child with well-controlled disease (based on the TRACK questionnaire) and incremental costs per quality-adjusted life year (QALY) (based onEQ-5-DY). | PMC10068201 | |
Pharmacotherapy | asthma | DISEASE, ASTHMA | Use of asthma medication and antibiotics will be continually registered: drugs, dosage, and period of use. Parents will be asked to register this using the app “Qdot studies” developed by Maastricht University. This app is specifically designed to collect data for scientific studies through questionnaires. We will assess whether children with asthma get bronchodilators (for symptom relief) and maintenance use of ICS (in case of more severe symptoms and less controlled disease) according to (inter) national guidelines [ | PMC10068201 |
Exacerbation of wheezing | exacerbations of asthma-like symptoms | Parents will be asked to register all exacerbations of asthma-like symptoms. This is facilitated by the same mobile application as is used for registration of pharmacotherapy. | PMC10068201 | |
Growth | Weight and height will be assessed in height standard deviation (SD) z-scores according to national growth data. Height velocity will be calculated. | PMC10068201 | ||
Asthma or transient wheeze diagnosis at 6 years | wheeze, asthma | ASTHMA | The final diagnosis of transient wheeze or asthma will be made by two paediatric pulmonologists after the clinical visit at the age of 6 years. These paediatric pulmonologists will be blinded for the probability diagnosis (if applicable) of the participants. The asthma diagnostic algorithm for children as published by the ERS taskforce in 2021 [Statistical methodsGeneral descriptive statistics will be applied to describe the baseline characteristics. Table outcome parameters and corresponding outcome measures and methods of analysis (see Fig. * based on algorithmCorresponding analysis groups | PMC10068201 |
Assessment of differences in asthma control between the intervention group and the usual care group in the percentage of well controlled asthma-like symptoms after 1- and 2-year follow-up. | asthma | ASTHMA, ASTHMA | The effect of the intervention on asthma control will be assessed by comparing the outcome measures between the intervention and the usual care group in the RCT. Asthma control will be scored using the validated TRACK questionnaire. Differences of the continuous outcome measure between the intervention group and the usual care group will be tested for significance with the unpaired t-test for normally distributed parameters and the Mann Whitney-U test in case of a not-normal distribution. | PMC10068201 |
Assessment of improvement in health gain and costs of care with the application of the breath test in wheezing preschool children | asthma-like symptoms | The effect of the intervention will be assessed by comparing the outcome measures between the intervention and the usual care group in the RCT. Dichotomous parameters will be tested with the chi-square test. Continuous variables will be tested for significance with the unpaired t-test for normally distributed parameters and the Mann Whitney-U test in case of a not-normal distribution.Total treatment costs will be calculated by multiplying resource use with the costs per unit. Resource use (visits to the general practitioner or specialist, emergency visits, hospital admission, lung function tests and other diagnostic procedures, the breath test, (over-the-counter) medication, and lost work days by parents due to sickness of the child) will be obtained from a specially designed questionnaire with a recall period of three months. The parents will fill out this questionnaire at baseline and at 3 months interval during the follow-up. Sources for valuation of the costs will be cost-prices of the Dutch manual for costing and cost-prices from the Dutch pharmacotherapeutic compass [The cost-effectiveness analysis from the healthcare perspective will be based on symptom control according to the TRACK questionnaire at 1 year follow-up (primary outcome measure). The cost-effectiveness analysis from the societal perspective will be based on the EQ-5D-Y. The EQ-5D-Y will be completed at baseline and at 3 months intervals during the follow-up, and will be filled out by one of the parents.A cost-effectiveness analysis will be performed from a societal and healthcare perspective with a time horizon of 2 years. Incremental cost-effectiveness ratios will be calculated as societal cost per QALY (societal perspective) and health care cost per additional child with control of asthma-like symptoms (healthcare perspective). Standard sensitivity- and bootstrap analysis will be performed to address uncertainty regarding costs and cost-effectiveness outcomes. Cost-effectiveness acceptability curves will be constructed reflecting the probability that the diagnostic breath test is cost-effective for a range of threshold values. Costs and effects after one year will be discounted at 4.0% and 1.5% respectively, according to the Dutch guidelines for health economic evaluation [All outcome parameters and corresponding outcome measures and methods of analysis are listed in Table | PMC10068201 | |
Assessment accuracy of the VOC sensing techniques (GC-tof–MS, SIFT-MS) | The primary outcome of the prospective cohort study is assessed in two ways, namely by comparing the VOCs data of the two VOCs-sensing techniques (GC- | PMC10068201 | ||
Assessment of pathogenic pathways in the early development of asthma | SECONDARY | The secondary outcomes of the prospective cohort study will be assessed by an integrative omics approach. The high dimensional multi-omics data require advanced statistical analyses. We will use machine learning and multi-variate statistical approaches (such as elastic net and weighted gene co-expression network analysis) that have been proven successful in analysing complex, multilevel datasets. Also, mechanistic models that provide a detailed understanding of biological networks will be used. Such models (e.g. Recon2) provide a comprehensive ‘reconstruction’ of the human biology and can be used to infer causality by integrating several layers of information (e.g. gene expression, metabolomics, and microbiomics) [ | PMC10068201 | |
Data monitoring and management | CTCM, CRF | CRF | Despite the fact that this study will be conducted in a paediatric population, the implementation of a Data Management Committee is not indicated. This decision was mainly based on the fact that the intervention of the study (probability diagnosis based on the breath test) provides caregivers and treating physicians with disease-specific treatment recommendations, but does not obligate them to adhere to a specific treatment protocol.The ADEM2 database is developed by the Clinical Trial Centre Maastricht (CTCM) in collaboration with MEMIC (centre for data and information management at the Faculty of Health, Medicine and Life Sciences of Maastricht University and MUMC +). CTCM is one of the leading Academic Research Organizations (ARO’s) in the Netherlands, and provides services to facilitate research, including the set-up of databases that meet the highest quality standards and newest guidelines. The data are collected by using the CASTOR application, an electronic tool that is adapted to the ADEM2 requirements. Data are collected by using the CTCM coding, which can easily be supplemented with an International coding (for example SNOMED). Metadata is included in the application of the electronic Case Report File (CRF) (CASTOR). This includes, for example, the units that are used, but also the coding of the variables. Data is securely stored for 15 years at CTCM. CASTOR provides export to various data formats, including SPSS, SAS, XML, CSV and Excel. By using CASTOR, the data collected in ADEM2 are according to the FAIR (Findable, Accessible, Interoperable and Reusable) criteria. By using clear coding with metadata and having the possibility to export the data to different formats, the data are interchangeable and reusable. | PMC10068201 |
Auditing | Independent review of core trial processes and documents will be executed through periodic, scheduled, on-site, monitoring visits. Processes such as participant enrolment, consent, eligibility, allocation to study groups, adherence to trial interventions, policies to protect participants, and completeness and accuracy of data collection will be reviewed during these visits. Audits will be conducted at all measurement sites that participate in this multi-centre trial. | PMC10068201 | ||
Ethics | wheezing | RECRUITMENT | NL64912.068.18 (11Both wheezing children and healthy children will be invited through an invitation letter combined with the Subject Information (see section on recruitment for more details). Parents are encouraged to contact the study team in case of any questions. We will ask the parents, if they decide to participate in the study to fill in the informed consent form (by both parents) and send it back to us.This study is registered by the Netherlands Trial Register (NTR) ( | PMC10068201 |
Confidentiality and access to data | wheezing | DISEASE | Data will get a code and will be handled confidentially in accordance with the General Data Protection Regulation (GDPR). The code is based on an unique participant number, the disease status (healthy versus wheezing participants), and the centre and region where the participant comes from. Our secured, web-based study management system “Ldot” will be used to link the data to the subject in case it is necessary to trace data to an individual subject. The key to the code will be safeguarded by the investigator (in accordance with | PMC10068201 |
Public disclosure and publication policy | POSITIVE | We will comply with the ‘CCMO statement publication policy’. Positive as well as negative findings will be published. After completion, the study results will be made known to the CCMO and the public. | PMC10068201 | |
Biological specimens | All biological specimens (faeces, blood, nasopharyngeal swabs, buccal swabs for DNA extraction, nasal swabs) will be coded and stored in the BioBank Maastricht UMC + and the UMCG for 10 years. These specimens will be used for the current trial and may be used for future research questions or analyses of new biomarkers. The data of the BioBank (such as the project number, respondent number, numbers, amount of samples available, and information about the quality) will be stored in a fully automatic web-based BioBank Information System (BIS). | PMC10068201 | ||
Discussion | wheezing, asthma, wheeze | ASTHMA | In this study protocol we described the assessment of the three main objectives of the ADEM2 study: with respect to the first objective, a multicentre RCT will be performed to assess the potential gain in health and reduction of health care related costs by means of a proper early diagnosis through the breath test in wheezing preschool children. Parallel to the RCT, a longitudinal observational cohort study will be executed to unravel early and important pathogenic mechanisms of asthma and transient wheeze (second objective), and to assess the diagnostic potential of alternative VOCs sensing techniques besides GC-tof–MS as well as other multi-omics measurements (third objective). | PMC10068201 |
Relevance and societal and clinical impact | asthma-like symptoms | The potential societal and clinical impact of the diagnostic tool for the children and the relevance of the project is substantial. By means of the breath test, it will become possible to deliver high qualitative care to the large group of vulnerable children with asthma-like symptoms, which will be more effective, safe, early and on time, and customised based on the individual results of the children. That will be a great step forward. The development of the current non-invasive breath test (GC- | PMC10068201 | |
Methodological issues | asthma-like symptoms, wheezing, exacerbations | RECRUITMENT | We decided to choose a RCT design for the following reasons: 1) to assess the full potential of the breath test in health gain and costs of care, a comparative study design is needed; 2) the breath test is not standard care yet; 3) in the usual care group, it is not unethical to provide the test result in a later phase, eventually all children/parents will benefit from the breath test result; 4) a safety rule will be applied in the usual care group so that parents/treating doctors can get the result of the breath test in an urgent situation (e.g. severe exacerbations, hospital admissions).At first, we did not expect any problems with the feasibility of patient recruitment based on the high prevalence of children with asthma-like symptoms and our experiences during the first ADEM study. However, the outbreak of the SARS-CoV-2 pandemic in 2020 significantly affected the recruitment of participants. In the beginning of the pandemic, we were not allowed to perform research anymore by the Board of Directors of our hospitals. In a later phase, less preschool children with wheezing symptoms presented themselves at the outpatient clinic, emergency departments, and primary care facilities than before the crisis, which probably was the consequence of preventive measures taken (e.g. the lock-downs and temporary closure of schools and day-care facilities). As most of our patients were selected during and after the pandemic, this influenced intervention and control group equally.We do not expect problems with drop-outs during the study because the breath test and the questionnaires are non-invasive, and the parents, children and treating doctors are highly motivated. Moreover, the ADEM study had a comparable design and burden with only 2% loss to follow-up [ | PMC10068201 |
Feasibility of implementation | asthma-like symptoms | LUNG | The current breath test is based on GC-It is our goal to implement a breath test at all levels of care: from primary care (general practitioner offices) to regional hospitals (with general paediatric care) and academic hospitals (with paediatric pulmonologists). The breath test will certainly help to overcome the problem of the absence of a diagnostic test in the large group of children with asthma-like symptoms.We expect that the feasibility of the implementation of results is high because patients and health care professionals recognise the clinical problem, ask for a diagnostic test, and are involved in this proposal. The topic has been selected by the Lung Foundation Netherlands as one of the important research themes. | PMC10068201 |
Health gain and cost saving | asthma, wheeze, exacerbations | ASTHMA | The health gain will directly arise as a consequence of a higher proportion of children with asthma control. Furthermore, a considerable annual cost-saving might occur because of reduced referrals and hospital visits after a diagnosis of transient wheeze is established. Not included in the calculations are positive quality of life (QoL) effects due to reductions in side-effects of asthma medication in children with transient wheeze, and broader QoL effects due to better asthma control and less exacerbations, which will impact quality-adjusted-life-years but is hard to estimate. Therefore, both the overall health effect and cost savings are expected to be larger than calculated above. As a consequence, the cost-efficiency of health care to this large group of children will substantially improve. Moreover, by means of the breath test, the cost-effectiveness of pharmacotherapy in this group of children will increase. The breath test will result in concrete and significant improvements for daily clinical care: by using the test, a substantial gain in health outcome parameters as well as in costs of care will occur. | PMC10068201 |
Insights in pathogenic mechanisms in the early development of asthma | wheezing, asthma, wheeze | ASTHMA | With our multi-omics approach we expect to unravel important pathogenic pathways in the early development of asthma and transient wheeze. We will apply genomics, transcriptomics of blood and nasal epithelium, microbiomics, epigenetics, and metabolomics to establish an integral pathogenic mechanisms for the early development of asthma.In the ADEM-study we found an interaction between bacterial colonisation of the upper airways, genetic variants in the Since the ADEM-study, multi-omics techniques extended and improved substantially, which increase the possibility to identify basic pathogenic mechanisms in ADEM2. Once fundamental pathways have been revealed, potential new therapies can be developed and tested, which hopefully can prevent the early development of asthma in wheezing preschool children. | PMC10068201 |
Conclusion | wheezing, asthma, wheeze | ASTHMA | In summary, the ADEM2 project covers 3 main areas. First, a multicentre RCT will be performed to assess the hypothesised gain in health and reduction of health care related costs by means of a proper early diagnosis using the breath test in wheezing preschool children. Second, the longitudinal observational cohort study is set up to unravel early and important pathogenic mechanisms of asthma and transient wheeze. And third, this project facilitates the development and assessment of the diagnostic potential of alternative VOCs sensing techniques besides GC-tof–MS as well as other multi-omics measurements. | PMC10068201 |
Acknowledgements | We would like to thank Karen Groot for her extensive help in organising the ADEM2 project. | PMC10068201 | ||
Authors’ contributions | ED, OvS, and RJ initiated the research project. ED, OvS, RJ, MB, SK, FvS and AS designed the randomized controlled trial and observational cohort study protocol. AS and FvS developed and reviewed the VOC-based breath test analysis. GK and EK developed the genomic analysis. JD initiated and facilitated the collaboration between the different laboratories and uniformed laboratory analyses. SK drafted the manuscript. All authors read and revised the manuscript. All authors approved the final manuscript. | PMC10068201 | ||
Funding | LUNG | The ADEM2 study is supported by The Netherlands Organisation for Health Research (ZonMW) (project number 848101008), a Netherlands Lung Foundation Grant (project number 6.1.18.221), and two grants of Top Sector Life Sciences and Health Health (TKI Topconsortia voor Kennis en Innovatie) (project number 10.1.17.183 and LSHM17071). These funding bodies assessed the design of the study in their grant application processes, but have no role in collection, analysis or interpretation of data. Genomic analysis in the ADEM2 is supported by a ZON-MW VICI grant to Gerard Koppelman (project number 09150182110046). Eosinophil analysis is funded by a grant from the Beatrix Children’s Hospital Foundation. | PMC10068201 | |
Availability of data and materials | Not applicable. | PMC10068201 | ||
Declarations | PMC10068201 | |||
Ethics approval and consent to participate | LUNG | Ethical approval is obtained from the accredited Medical Research Ethics Committee (MREC) Academic Hospital Maastricht / University Maastricht. Also, the study protocol is extensively studied by the funding organizations: Netherlands Lung Foundation, The Netherlands Organisation for Health Research and Development (ZonMW), Top Sector Life Sciences and Health (TKI Topconsortia voor Kennis en Innovatie).Informed consent for study participation will be obtained from all parents and/or legal guardians of the participants. In case of publication of identifying information and/or images in an online open-access publication, a separate informed consent will be obtained from the respective parent and/or legal guardian for this specific purpose. | PMC10068201 | |
Consent for publication | Consent for publication of Fig. | PMC10068201 | ||
Competing interests | The authors declare that they have no competing interests. | PMC10068201 | ||
References | PMC10068201 |
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