Daily Papers

Clinical case reports encode temporal patient trajectories that are often underexploited by traditional machine learning methods relying on structured data. In this work, we introduce the forecasting problem from textual time series, where timestamped clinical findings -- extracted via an LLM-assisted annotation pipeline -- serve as the primary input for prediction. We systematically evaluate a diverse suite of models, including fine-tuned decoder-based large language models and encoder-based transformers, on tasks of event occurrence prediction, temporal ordering, and survival analysis. Our experiments reveal that encoder-based models consistently achieve higher F1 scores and superior temporal concordance for short- and long-horizon event forecasting, while fine-tuned masking approaches enhance ranking performance. In contrast, instruction-tuned decoder models demonstrate a relative advantage in survival analysis, especially in early prognosis settings. Our sensitivity analyses further demonstrate the importance of time ordering, which requires clinical time series construction, as compared to text ordering, the format of the text inputs that LLMs are classically trained on. This highlights the additional benefit that can be ascertained from time-ordered corpora, with implications for temporal tasks in the era of widespread LLM use.

Accurate prediction of biochemical recurrence (BCR) after radical prostatectomy is critical for guiding adjuvant treatment and surveillance decisions in prostate cancer. However, existing clinicopathological risk models reduce complex morphology to relatively coarse descriptors, leaving substantial prognostic information embedded in routine histopathology underexplored. We present a deep learning-based biomarker that predicts continuous, patient-specific risk of BCR directly from H&E-stained whole-slide prostatectomy specimens. Trained end-to-end on time-to-event outcomes and evaluated across four independent international cohorts, our model demonstrates robust generalization across institutions and patient populations. When integrated with the CAPRA-S clinical risk score, the deep learning risk score consistently improved discrimination for BCR, increasing concordance indices from 0.725-0.772 to 0.749-0.788 across cohorts. To support clinical interpretability, outcome-grounded analyses revealed subtle histomorphological patterns associated with recurrence risk that are not captured by conventional clinicopathological risk scores. This multicohort study demonstrates that deep learning applied to routine prostate histopathology can deliver reproducible and clinically generalizable biomarkers that augment postoperative risk stratification, with potential to support personalized management of prostate cancer in real-world clinical settings.

To overcome the limitations of manual administrative coding in geriatric Cardiovascular Risk Management, this study introduces an automated classification framework leveraging unstructured Electronic Health Records (EHRs). Using a dataset of 3,482 patients, we benchmarked three distinct modeling paradigms on longitudinal Dutch clinical narratives: classical machine learning baselines, specialized deep learning architectures optimized for large-context sequences, and general-purpose generative Large Language Models (LLMs) in a zero-shot setting. Additionally, we evaluated a late fusion strategy to integrate unstructured text with structured medication embeddings and anthropometric data. Our analysis reveals that the custom Transformer architecture outperforms both traditional methods and generative llms, achieving the highest F1-scores and Matthews Correlation Coefficients. These findings underscore the critical role of specialized hierarchical attention mechanisms in capturing long-range dependencies within medical texts, presenting a robust, automated alternative to manual workflows for clinical risk stratification.

Machine learning systems in fraud detection, credit scoring, and clinical risk assessment operate under delayed ground truth: outcome labels arrive days to months after the decision they evaluate. During this blind period, governance evidence degrades through mechanisms that neither drift detection methods nor governance frameworks adequately address. This paper formalizes an evidence sufficiency model with four dimensions (completeness, freshness, reliability, representativeness) and a decision-readiness gate that quantifies how label latency degrades evidence quality. The model maps three drift types to dimension-specific degradation trajectories. A complementary proxy indicator framework comprising seven measurement categories estimates sufficiency degradation without labels, with explicit coverage mapping and characterized blind spots per drift type. Evaluation on the IEEE-CIS Fraud Detection dataset (~590K transactions) with controlled drift injection shows that composite proxy monitoring detects covariate and mixed drift with 100% detection rate, while concept drift without feature change remains undetected -- consistent with the theoretical impossibility of unsupervised detection when P(X) is unchanged. Blind period simulation confirms monotone sufficiency degradation, with concept drift degrading fastest (S=0.242 at day 60 vs 0.418 for no-drift). The framework contributes a governance sufficiency monitoring instrument; its value lies in translating drift signals into auditable sufficiency assessments with characterized blind spots. Mapping sufficiency levels to governance actions requires deployment-specific calibration beyond this study's scope.

The long-term effects of Postacute Sequelae of SARS-CoV-2, known as PASC, pose a significant challenge to healthcare systems worldwide. Accurate identification of progression events, such as hospitalization and reinfection, is essential for effective patient management and resource allocation. However, traditional models trained on structured data struggle to capture the nuanced progression of PASC. In this study, we introduce the first publicly available cohort of 18 PASC patients, with text time series features based on Large Language Model Llama-3.1-70B-Instruct and clinical risk annotated by clinical expert. We propose an Active Attention Network to predict the clinical risk and identify progression events related to the risk. By integrating human expertise with active learning, we aim to enhance clinical risk prediction accuracy and enable progression events identification with fewer number of annotation. The ultimate goal is to improves patient care and decision-making for SARS-CoV-2 patient.

Traditional diagnosis of aortic valve disease relies on echocardiography, but its cost and required expertise limit its use in large-scale early screening. Photoplethysmography (PPG) has emerged as a promising screening modality due to its widespread availability in wearable devices and its ability to reflect underlying hemodynamic dynamics. However, the extreme scarcity of gold-standard labeled PPG data severely constrains the effectiveness of data-driven approaches. To address this challenge, we propose and validate a new paradigm, Physiology-Guided Self-Supervised Learning (PG-SSL), aimed at unlocking the value of large-scale unlabeled PPG data for efficient screening of Aortic Stenosis (AS) and Aortic Regurgitation (AR). Using over 170,000 unlabeled PPG samples from the UK Biobank, we formalize clinical knowledge into a set of PPG morphological phenotypes and construct a pulse pattern recognition proxy task for self-supervised pre-training. A dual-branch, gated-fusion architecture is then employed for efficient fine-tuning on a small labeled subset. The proposed PG-SSL framework achieves AUCs of 0.765 and 0.776 for AS and AR screening, respectively, significantly outperforming supervised baselines trained on limited labeled data. Multivariable analysis further validates the model output as an independent digital biomarker with sustained prognostic value after adjustment for standard clinical risk factors. This study demonstrates that PG-SSL provides an effective, domain knowledge-driven solution to label scarcity in medical artificial intelligence and shows strong potential for enabling low-cost, large-scale early screening of aortic valve disease.

Healthcare automation is shaped by local procedures and organizational constraints, so agent capabilities rarely transfer unchanged across settings. Agent skills, self-contained directories that package reusable procedures for AI agents, are emerging as a procedural layer for adapting healthcare agents across diverse healthcare settings. We present the first empirical analysis of healthcare agent skills, drawing on 557 healthcare-related skills filtered from 58,159 public skills on ClawHub and annotated along ten dimensions covering function, deployment context, autonomy, and safety. We find that public healthcare skills emphasize patient-facing workflow automation and monitoring rather than the diagnostic and treatment-oriented tasks foregrounded in healthcare-agent research; coverage of the healthcare lifecycle and specialized clinical inputs remains uneven; and general technical risk does not reliably capture clinical risk. These findings position healthcare skills as a procedural layer not yet addressed by current benchmarks and risk frameworks.

Safe Reinforcement Learning (RL) algorithms are typically evaluated under fixed training conditions. We investigate whether training-time safety guarantees transfer to deployment under distribution shift, using diabetes management as a safety-critical testbed. We benchmark safe RL algorithms on a unified clinical simulator and reveal a safety generalization gap: policies satisfying constraints during training frequently violate safety requirements on unseen patients. We demonstrate that test-time shielding, which filters unsafe actions using learned dynamics models, effectively restores safety across algorithms and patient populations. Across eight safe RL algorithms, three diabetes types, and three age groups, shielding achieves Time-in-Range gains of 13--14\% for strong baselines such as PPO-Lag and CPO while reducing clinical risk index and glucose variability. Our simulator and benchmark provide a platform for studying safety under distribution shift in safety-critical control domains. Code is available at https://github.com/safe-autonomy-lab/GlucoSim and https://github.com/safe-autonomy-lab/GlucoAlg.

ML models often exhibit unexpectedly poor behavior when they are deployed in real-world domains. We identify underspecification as a key reason for these failures. An ML pipeline is underspecified when it can return many predictors with equivalently strong held-out performance in the training domain. Underspecification is common in modern ML pipelines, such as those based on deep learning. Predictors returned by underspecified pipelines are often treated as equivalent based on their training domain performance, but we show here that such predictors can behave very differently in deployment domains. This ambiguity can lead to instability and poor model behavior in practice, and is a distinct failure mode from previously identified issues arising from structural mismatch between training and deployment domains. We show that this problem appears in a wide variety of practical ML pipelines, using examples from computer vision, medical imaging, natural language processing, clinical risk prediction based on electronic health records, and medical genomics. Our results show the need to explicitly account for underspecification in modeling pipelines that are intended for real-world deployment in any domain.

Hospitals struggle to predict critical outcomes. Traditional early warning systems, like NEWS and MEWS, rely on static variables and fixed thresholds, limiting their adaptability, accuracy, and personalization. We previously developed the Enhanced Transformer for Health Outcome Simulation (ETHOS), an AI model that tokenizes patient health timelines (PHTs) from EHRs and uses transformer-based architectures to predict future PHTs. ETHOS is a versatile framework for developing a wide range of applications. In this work, we develop the Adaptive Risk Estimation System (ARES) that leverages ETHOS to compute dynamic, personalized risk probabilities for clinician-defined critical events. ARES also features a personalized explainability module that highlights key clinical factors influencing risk estimates. We evaluated ARES using the MIMIC-IV v2.2 dataset together with its Emergency Department (ED) extension and benchmarked performance against both classical early warning systems and contemporary machine learning models. The entire dataset was tokenized resulting in 285,622 PHTs, comprising over 360 million tokens. ETHOS outperformed benchmark models in predicting hospital admissions, ICU admissions, and prolonged stays, achieving superior AUC scores. Its risk estimates were robust across demographic subgroups, with calibration curves confirming model reliability. The explainability module provided valuable insights into patient-specific risk factors. ARES, powered by ETHOS, advances predictive healthcare AI by delivering dynamic, real-time, personalized risk estimation with patient-specific explainability. Although our results are promising, the clinical impact remains uncertain. Demonstrating ARES's true utility in real-world settings will be the focus of our future work. We release the source code to facilitate future research.

Large language models (LLMs) are increasingly applied to clinical decision-making. However, their potential to exhibit bias poses significant risks to clinical equity. Currently, there is a lack of benchmarks that systematically evaluate such clinical bias in LLMs. While in downstream tasks, some biases of LLMs can be avoided such as by instructing the model to answer "I'm not sure...", the internal bias hidden within the model still lacks deep studies. We introduce CLIMB (shorthand for A Benchmark of Clinical Bias in Large Language Models), a pioneering comprehensive benchmark to evaluate both intrinsic (within LLMs) and extrinsic (on downstream tasks) bias in LLMs for clinical decision tasks. Notably, for intrinsic bias, we introduce a novel metric, AssocMAD, to assess the disparities of LLMs across multiple demographic groups. Additionally, we leverage counterfactual intervention to evaluate extrinsic bias in a task of clinical diagnosis prediction. Our experiments across popular and medically adapted LLMs, particularly from the Mistral and LLaMA families, unveil prevalent behaviors with both intrinsic and extrinsic bias. This work underscores the critical need to mitigate clinical bias and sets a new standard for future evaluations of LLMs' clinical bias.

The demand for emergency department (ED) services is increasing across the globe, particularly during the current COVID-19 pandemic. Clinical triage and risk assessment have become increasingly challenging due to the shortage of medical resources and the strain on hospital infrastructure caused by the pandemic. As a result of the widespread use of electronic health records (EHRs), we now have access to a vast amount of clinical data, which allows us to develop predictive models and decision support systems to address these challenges. To date, however, there are no widely accepted benchmark ED triage prediction models based on large-scale public EHR data. An open-source benchmarking platform would streamline research workflows by eliminating cumbersome data preprocessing, and facilitate comparisons among different studies and methodologies. In this paper, based on the Medical Information Mart for Intensive Care IV Emergency Department (MIMIC-IV-ED) database, we developed a publicly available benchmark suite for ED triage predictive models and created a benchmark dataset that contains over 400,000 ED visits from 2011 to 2019. We introduced three ED-based outcomes (hospitalization, critical outcomes, and 72-hour ED reattendance) and implemented a variety of popular methodologies, ranging from machine learning methods to clinical scoring systems. We evaluated and compared the performance of these methods against benchmark tasks. Our codes are open-source, allowing anyone with MIMIC-IV-ED data access to perform the same steps in data processing, benchmark model building, and experiments. This study provides future researchers with insights, suggestions, and protocols for managing raw data and developing risk triaging tools for emergency care.

Brain stroke remains one of the principal causes of death and disability worldwide, yet most tabular-data prediction models still hover below the 95% accuracy threshold, limiting real-world utility. Addressing this gap, the present work develops and validates a completely data-driven and interpretable machine-learning framework designed to predict strokes using ten routinely gathered demographic, lifestyle, and clinical variables sourced from a public cohort of 4,981 records. We employ a detailed exploratory data analysis (EDA) to understand the dataset's structure and distribution, followed by rigorous data preprocessing, including handling missing values, outlier removal, and class imbalance correction using Synthetic Minority Over-sampling Technique (SMOTE). To streamline feature selection, point-biserial correlation and random-forest Gini importance were utilized, and ten varied algorithms-encompassing tree ensembles, boosting, kernel methods, and a multilayer neural network-were optimized using stratified five-fold cross-validation. Their predictions based on probabilities helped us build the proposed model, which included Random Forest, XGBoost, LightGBM, and a support-vector classifier, with logistic regression acting as a meta-learner. The proposed model achieved an accuracy rate of 97.2% and an F1-score of 97.15%, indicating a significant enhancement compared to the leading individual model, LightGBM, which had an accuracy of 91.4%. Our study's findings indicate that rigorous preprocessing, coupled with a diverse hybrid model, can convert low-cost tabular data into a nearly clinical-grade stroke-risk assessment tool.

Biomedical Foundation Models (FMs) are rapidly transforming AI-enabled healthcare research and entering clinical validation. However, their susceptibility to learning non-biological technical features -- including variations in surgical/endoscopic techniques, laboratory procedures, and scanner hardware -- poses risks for clinical deployment. We present the first systematic investigation of pathology FM robustness to non-biological features. Our work (i) introduces measures to quantify FM robustness, (ii) demonstrates the consequences of limited robustness, and (iii) proposes a framework for FM robustification to mitigate these issues. Specifically, we developed PathoROB, a robustness benchmark with three novel metrics, including the robustness index, and four datasets covering 28 biological classes from 34 medical centers. Our experiments reveal robustness deficits across all 20 evaluated FMs, and substantial robustness differences between them. We found that non-robust FM representations can cause major diagnostic downstream errors and clinical blunders that prevent safe clinical adoption. Using more robust FMs and post-hoc robustification considerably reduced (but did not yet eliminate) the risk of such errors. This work establishes that robustness evaluation is essential for validating pathology FMs before clinical adoption and demonstrates that future FM development must integrate robustness as a core design principle. PathoROB provides a blueprint for assessing robustness across biomedical domains, guiding FM improvement efforts towards more robust, representative, and clinically deployable AI systems that prioritize biological information over technical artifacts.

Current ophthalmology clinical workflows are plagued by over-referrals, long waits, and complex and heterogeneous medical records. Large language models (LLMs) present a promising solution to automate various procedures such as triaging, preliminary tests like visual acuity assessment, and report summaries. However, LLMs have demonstrated significantly varied performance across different languages in natural language question-answering tasks, potentially exacerbating healthcare disparities in Low and Middle-Income Countries (LMICs). This study introduces the first multilingual ophthalmological question-answering benchmark with manually curated questions parallel across languages, allowing for direct cross-lingual comparisons. Our evaluation of 6 popular LLMs across 7 different languages reveals substantial bias across different languages, highlighting risks for clinical deployment of LLMs in LMICs. Existing debiasing methods such as Translation Chain-of-Thought or Retrieval-augmented generation (RAG) by themselves fall short of closing this performance gap, often failing to improve performance across all languages and lacking specificity for the medical domain. To address this issue, We propose CLARA (Cross-Lingual Reflective Agentic system), a novel inference time de-biasing method leveraging retrieval augmented generation and self-verification. Our approach not only improves performance across all languages but also significantly reduces the multilingual bias gap, facilitating equitable LLM application across the globe.

The emergence of large language models (LLMs) has significantly influenced numerous fields, including healthcare, by enhancing the capabilities of automated systems to process and generate human-like text. However, despite their advancements, the reliability and accuracy of LLMs in medical contexts remain critical concerns. Current evaluation methods often lack robustness and fail to provide a comprehensive assessment of LLM performance, leading to potential risks in clinical settings. In this work, we propose Med-CoDE, a specifically designed evaluation framework for medical LLMs to address these challenges. The framework leverages a critique-based approach to quantitatively measure the degree of disagreement between model-generated responses and established medical ground truths. This framework captures both accuracy and reliability in medical settings. The proposed evaluation framework aims to fill the existing gap in LLM assessment by offering a systematic method to evaluate the quality and trustworthiness of medical LLMs. Through extensive experiments and case studies, we illustrate the practicality of our framework in providing a comprehensive and reliable evaluation of medical LLMs.

Clinical calculators play a vital role in healthcare by offering accurate evidence-based predictions for various purposes such as prognosis. Nevertheless, their widespread utilization is frequently hindered by usability challenges, poor dissemination, and restricted functionality. Augmenting large language models with extensive collections of clinical calculators presents an opportunity to overcome these obstacles and improve workflow efficiency, but the scalability of the manual curation process poses a significant challenge. In response, we introduce AgentMD, a novel language agent capable of curating and applying clinical calculators across various clinical contexts. Using the published literature, AgentMD has automatically curated a collection of 2,164 diverse clinical calculators with executable functions and structured documentation, collectively named RiskCalcs. Manual evaluations show that RiskCalcs tools achieve an accuracy of over 80% on three quality metrics. At inference time, AgentMD can automatically select and apply the relevant RiskCalcs tools given any patient description. On the newly established RiskQA benchmark, AgentMD significantly outperforms chain-of-thought prompting with GPT-4 (87.7% vs. 40.9% in accuracy). Additionally, we also applied AgentMD to real-world clinical notes for analyzing both population-level and risk-level patient characteristics. In summary, our study illustrates the utility of language agents augmented with clinical calculators for healthcare analytics and patient care.

Large Language Models (LLMs) are increasingly utilized for mental health support; however, current safety benchmarks often fail to detect the complex, longitudinal risks inherent in therapeutic dialogue. We introduce an evaluation framework that pairs AI psychotherapists with simulated patient agents equipped with dynamic cognitive-affective models and assesses therapy session simulations against a comprehensive quality of care and risk ontology. We apply this framework to a high-impact test case, Alcohol Use Disorder, evaluating six AI agents (including ChatGPT, Gemini, and Character.AI) against a clinically-validated cohort of 15 patient personas representing diverse clinical phenotypes. Our large-scale simulation (N=369 sessions) reveals critical safety gaps in the use of AI for mental health support. We identify specific iatrogenic risks, including the validation of patient delusions ("AI Psychosis") and failure to de-escalate suicide risk. Finally, we validate an interactive data visualization dashboard with diverse stakeholders, including AI engineers and red teamers, mental health professionals, and policy experts (N=9), demonstrating that this framework effectively enables stakeholders to audit the "black box" of AI psychotherapy. These findings underscore the critical safety risks of AI-provided mental health support and the necessity of simulation-based clinical red teaming before deployment.

Survival risk stratification is an important step in clinical decision making for breast cancer management. We propose a novel deep learning approach for this purpose by integrating histopathological imaging, genetic and clinical data. It employs vision transformers, specifically the MaxViT model, for image feature extraction, and self-attention to capture intricate image relationships at the patient level. A dual cross-attention mechanism fuses these features with genetic data, while clinical data is incorporated at the final layer to enhance predictive accuracy. Experiments on the public TCGA-BRCA dataset show that our model, trained using the negative log likelihood loss function, can achieve superior performance with a mean C-index of 0.64, surpassing existing methods. This advancement facilitates tailored treatment strategies, potentially leading to improved patient outcomes.

Clinical trials are pivotal for developing new medical treatments but typically carry risks such as patient mortality and enrollment failure that waste immense efforts spanning over a decade. Applying artificial intelligence (AI) to predict key events in clinical trials holds great potential for providing insights to guide trial designs. However, complex data collection and question definition requiring medical expertise have hindered the involvement of AI thus far. This paper tackles these challenges by presenting a comprehensive suite of 23 meticulously curated AI-ready datasets covering multi-modal input features and 8 crucial prediction challenges in clinical trial design, encompassing prediction of trial duration, patient dropout rate, serious adverse event, mortality rate, trial approval outcome, trial failure reason, drug dose finding, design of eligibility criteria. Furthermore, we provide basic validation methods for each task to ensure the datasets' usability and reliability. We anticipate that the availability of such open-access datasets will catalyze the development of advanced AI approaches for clinical trial design, ultimately advancing clinical trial research and accelerating medical solution development.

Large Language Models (LLMs) and Retrieval-Augmented Generation (RAG) systems are increasingly integrated into clinical workflows; however, prompt injection attacks can steer these systems toward clinically unsafe or misleading outputs. We introduce the Medical Prompt Injection Benchmark (MPIB), a dataset-and-benchmark suite for evaluating clinical safety under both direct prompt injection and indirect, RAG-mediated injection across clinically grounded tasks. MPIB emphasizes outcome-level risk via the Clinical Harm Event Rate (CHER), which measures high-severity clinical harm events under a clinically grounded taxonomy, and reports CHER alongside Attack Success Rate (ASR) to disentangle instruction compliance from downstream patient risk. The benchmark comprises 9,697 curated instances constructed through multi-stage quality gates and clinical safety linting. Evaluating MPIB across a diverse set of baseline LLMs and defense configurations, we find that ASR and CHER can diverge substantially, and that robustness depends critically on whether adversarial instructions appear in the user query or in retrieved context. We release MPIB with evaluation code, adversarial baselines, and comprehensive documentation to support reproducible and systematic research on clinical prompt injection. Code and data are available at GitHub (code) and Hugging Face (data).

Access to the right evidence does not guarantee that large language models (LLMs) will reason with it correctly. This gap between retrieval and reasoning is especially concerning in clinical settings, where outputs must align with structured protocols. We study this gap using Written Exposure Therapy (WET) guidelines as a testbed. In evaluating model responses to curated clinician-vetted questions, we find that errors persist even when authoritative passages are provided. To address this, we propose an evaluation framework that measures accuracy, consistency, and fidelity of reasoning. Our results highlight both the potential and the risks: retrieval-augmented generation (RAG) can constrain outputs, but safe deployment requires assessing reasoning as rigorously as retrieval.

Persona conditioning can be viewed as a behavioral prior for large language models (LLMs) and is often assumed to confer expertise and improve safety in a monotonic manner. However, its effects on high-stakes clinical decision-making remain poorly characterized. We systematically evaluate persona-based control in clinical LLMs, examining how professional roles (e.g., Emergency Department physician, nurse) and interaction styles (bold vs.\ cautious) influence behavior across models and medical tasks. We assess performance on clinical triage and patient-safety tasks using multidimensional evaluations that capture task accuracy, calibration, and safety-relevant risk behavior. We find systematic, context-dependent, and non-monotonic effects: Medical personas improve performance in critical care tasks, yielding gains of up to sim+20% in accuracy and calibration, but degrade performance in primary-care settings by comparable margins. Interaction style modulates risk propensity and sensitivity, but it's highly model-dependent. While aggregated LLM-judge rankings favor medical over non-medical personas in safety-critical cases, we found that human clinicians show moderate agreement on safety compliance (average Cohen's κ= 0.43) but indicate a low confidence in 95.9\% of their responses on reasoning quality. Our work shows that personas function as behavioral priors that introduce context-dependent trade-offs rather than guarantees of safety or expertise. The code is available at https://github.com/rsinghlab/Persona\_Paradox.

While machine learning shows promise for maternal health risk prediction, clinical adoption in resource-constrained settings faces a critical barrier: lack of explainability and trust. This study presents a hybrid explainable AI (XAI) framework combining ante-hoc fuzzy logic with post-hoc SHAP explanations, validated through systematic clinician feedback. We developed a fuzzy-XGBoost model on 1,014 maternal health records, achieving 88.67% accuracy (ROC-AUC: 0.9703). A validation study with 14 healthcare professionals in Bangladesh revealed strong preference for hybrid explanations (71.4% across three clinical cases) with 54.8% expressing trust for clinical use. SHAP analysis identified healthcare access as the primary predictor, with the engineered fuzzy risk score ranking third, validating clinical knowledge integration (r=0.298). Clinicians valued integrated clinical parameters but identified critical gaps: obstetric history, gestational age, and connectivity barriers. This work demonstrates that combining interpretable fuzzy rules with feature importance explanations enhances both utility and trust, providing practical insights for XAI deployment in maternal healthcare.

The identification of heterogeneous treatment effects (HTE) across subgroups is of significant interest in clinical trial analysis. Several state-of-the-art HTE estimation methods, including causal forests, apply recursive partitioning for non-parametric identification of relevant covariates and interactions. However, the partitioning criterion is typically based on differences in absolute risk. This can dilute statistical power by masking variation in the relative risk, which is often a more appropriate quantity of clinical interest. In this work, we propose and implement a methodology for modifying causal forests to target relative risk, using a novel node-splitting procedure based on exhaustive generalized linear model comparison. We present results from simulated data that suggest relative risk causal forests can capture otherwise undetected sources of heterogeneity. We implement our method on real-world trial data to explore HTEs for liraglutide in patients with type 2 diabetes.

Purpose: Accurate segmentation of clinical target volumes (CTV) and organs-at-risk is crucial for optimizing gynecologic brachytherapy (GYN-BT) treatment planning. However, anatomical variability, low soft-tissue contrast in CT imaging, and limited annotated datasets pose significant challenges. This study presents GynBTNet, a novel multi-stage learning framework designed to enhance segmentation performance through self-supervised pretraining and hierarchical fine-tuning strategies. Methods: GynBTNet employs a three-stage training strategy: (1) self-supervised pretraining on large-scale CT datasets using sparse submanifold convolution to capture robust anatomical representations, (2) supervised fine-tuning on a comprehensive multi-organ segmentation dataset to refine feature extraction, and (3) task-specific fine-tuning on a dedicated GYN-BT dataset to optimize segmentation performance for clinical applications. The model was evaluated against state-of-the-art methods using the Dice Similarity Coefficient (DSC), 95th percentile Hausdorff Distance (HD95), and Average Surface Distance (ASD). Results: Our GynBTNet achieved superior segmentation performance, significantly outperforming nnU-Net and Swin-UNETR. Notably, it yielded a DSC of 0.837 +/- 0.068 for CTV, 0.940 +/- 0.052 for the bladder, 0.842 +/- 0.070 for the rectum, and 0.871 +/- 0.047 for the uterus, with reduced HD95 and ASD compared to baseline models. Self-supervised pretraining led to consistent performance improvements, particularly for structures with complex boundaries. However, segmentation of the sigmoid colon remained challenging, likely due to anatomical ambiguities and inter-patient variability. Statistical significance analysis confirmed that GynBTNet's improvements were significant compared to baseline models.

Breast cancer is a significant health concern affecting millions of women worldwide. Accurate survival risk stratification plays a crucial role in guiding personalised treatment decisions and improving patient outcomes. Here we present BioFusionNet, a deep learning framework that fuses image-derived features with genetic and clinical data to achieve a holistic patient profile and perform survival risk stratification of ER+ breast cancer patients. We employ multiple self-supervised feature extractors, namely DINO and MoCoV3, pretrained on histopathology patches to capture detailed histopathological image features. We then utilise a variational autoencoder (VAE) to fuse these features, and harness the latent space of the VAE to feed into a self-attention network, generating patient-level features. Next, we develop a co-dual-cross-attention mechanism to combine the histopathological features with genetic data, enabling the model to capture the interplay between them. Additionally, clinical data is incorporated using a feed-forward network (FFN), further enhancing predictive performance and achieving comprehensive multimodal feature integration. Furthermore, we introduce a weighted Cox loss function, specifically designed to handle imbalanced survival data, which is a common challenge in the field. The proposed model achieves a mean concordance index (C-index) of 0.77 and a time-dependent area under the curve (AUC) of 0.84, outperforming state-of-the-art methods. It predicts risk (high versus low) with prognostic significance for overall survival (OS) in univariate analysis (HR=2.99, 95% CI: 1.88--4.78, p<0.005), and maintains independent significance in multivariate analysis incorporating standard clinicopathological variables (HR=2.91, 95% CI: 1.80--4.68, p<0.005). The proposed method not only improves model performance but also addresses a critical gap in handling imbalanced data.

Disease risk prediction has attracted increasing attention in the field of modern healthcare, especially with the latest advances in artificial intelligence (AI). Electronic health records (EHRs), which contain heterogeneous patient information, are widely used in disease risk prediction tasks. One challenge of applying AI models for risk prediction lies in generating interpretable evidence to support the prediction results while retaining the prediction ability. In order to address this problem, we propose the method of jointly embedding words and labels whereby attention modules learn the weights of words from medical notes according to their relevance to the names of risk prediction labels. This approach boosts interpretability by employing an attention mechanism and including the names of prediction tasks in the model. However, its application is only limited to the handling of textual inputs such as medical notes. In this paper, we propose a label dependent attention model LDAM to 1) improve the interpretability by exploiting Clinical-BERT (a biomedical language model pre-trained on a large clinical corpus) to encode biomedically meaningful features and labels jointly; 2) extend the idea of joint embedding to the processing of time-series data, and develop a multi-modal learning framework for integrating heterogeneous information from medical notes and time-series health status indicators. To demonstrate our method, we apply LDAM to the MIMIC-III dataset to predict different disease risks. We evaluate our method both quantitatively and qualitatively. Specifically, the predictive power of LDAM will be shown, and case studies will be carried out to illustrate its interpretability.

The absence of transparency and explainability hinders the clinical adoption of Machine learning (ML) algorithms. Although various methods of explainable artificial intelligence (XAI) have been suggested, there is a lack of literature that delves into their practicality and assesses them based on criteria that could foster trust in clinical environments. To address this gap this study evaluates two popular XAI methods used for explaining predictive models in the healthcare context in terms of whether they (i) generate domain-appropriate representation, i.e. coherent with respect to the application task, (ii) impact clinical workflow and (iii) are consistent. To that end, explanations generated at the cohort and patient levels were analysed. The paper reports the first benchmarking of the XAI methods applied to risk prediction models obtained by evaluating the concordance between generated explanations and the trigger of a future clinical deterioration episode recorded by the data collection system. We carried out an analysis using two Electronic Medical Records (EMR) datasets sourced from Australian major hospitals. The findings underscore the limitations of state-of-the-art XAI methods in the clinical context and their potential benefits. We discuss these limitations and contribute to the theoretical development of trustworthy XAI solutions where clinical decision support guides the choice of intervention by suggesting the pattern or drivers for clinical deterioration in the future.

Machine learning has successfully framed many sequential decision making problems as either supervised prediction, or optimal decision-making policy identification via reinforcement learning. In data-constrained offline settings, both approaches may fail as they assume fully optimal behavior or rely on exploring alternatives that may not exist. We introduce an inherently different approach that identifies possible "dead-ends" of a state space. We focus on the condition of patients in the intensive care unit, where a "medical dead-end" indicates that a patient will expire, regardless of all potential future treatment sequences. We postulate "treatment security" as avoiding treatments with probability proportional to their chance of leading to dead-ends, present a formal proof, and frame discovery as an RL problem. We then train three independent deep neural models for automated state construction, dead-end discovery and confirmation. Our empirical results discover that dead-ends exist in real clinical data among septic patients, and further reveal gaps between secure treatments and those that were administered.

Large language models (LLMs) show promise in clinical decision support yet risk acquiescing to patient pressure for inappropriate care. We introduce SycoEval-EM, a multi-agent simulation framework evaluating LLM robustness through adversarial patient persuasion in emergency medicine. Across 20 LLMs and 1,875 encounters spanning three Choosing Wisely scenarios, acquiescence rates ranged from 0-100\%. Models showed higher vulnerability to imaging requests (38.8\%) than opioid prescriptions (25.0\%), with model capability poorly predicting robustness. All persuasion tactics proved equally effective (30.0-36.0\%), indicating general susceptibility rather than tactic-specific weakness. Our findings demonstrate that static benchmarks inadequately predict safety under social pressure, necessitating multi-turn adversarial testing for clinical AI certification.

Following the global COVID-19 pandemic, the number of scientific papers studying the virus has grown massively, leading to increased interest in automated literate review. We present a clinical text mining system that improves on previous efforts in three ways. First, it can recognize over 100 different entity types including social determinants of health, anatomy, risk factors, and adverse events in addition to other commonly used clinical and biomedical entities. Second, the text processing pipeline includes assertion status detection, to distinguish between clinical facts that are present, absent, conditional, or about someone other than the patient. Third, the deep learning models used are more accurate than previously available, leveraging an integrated pipeline of state-of-the-art pretrained named entity recognition models, and improving on the previous best performing benchmarks for assertion status detection. We illustrate extracting trends and insights, e.g. most frequent disorders and symptoms, and most common vital signs and EKG findings, from the COVID-19 Open Research Dataset (CORD-19). The system is built using the Spark NLP library which natively supports scaling to use distributed clusters, leveraging GPUs, configurable and reusable NLP pipelines, healthcare specific embeddings, and the ability to train models to support new entity types or human languages with no code changes.

With an estimated 160,000 deaths in 2018, lung cancer is the most common cause of cancer death in the United States. Lung cancer CT screening has been shown to reduce mortality by up to 40% and is now included in US screening guidelines. Reducing the high error rates in lung cancer screening is imperative because of the high clinical and financial costs caused by diagnosis mistakes. Despite the use of standards for radiological diagnosis, persistent inter-grader variability and incomplete characterization of comprehensive imaging findings remain as limitations of current methods. These limitations suggest opportunities for more sophisticated systems to improve performance and inter-reader consistency. In this report, we reproduce a state-of-the-art deep learning algorithm for lung cancer risk prediction. Our model predicts malignancy probability and risk bucket classification from lung CT studies. This allows for risk categorization of patients being screened and suggests the most appropriate surveillance and management. Combining our solution high accuracy, consistency and fully automated nature, our approach may enable highly efficient screening procedures and accelerate the adoption of lung cancer screening.

As Large Language Models (LLMs) are increasingly integrated into healthcare to address complex inquiries, ensuring their reliability remains a critical challenge. Recent studies have highlighted that generic LLMs often struggle in clinical contexts, occasionally producing misleading guidance. To mitigate these risks, this research focuses on the domain-specific adaptation of Llama-2-7B using the Low-Rank Adaptation (LoRA) technique. By injecting trainable low-rank matrices into the Transformer layers, we efficiently adapted the model using authentic patient-physician transcripts while preserving the foundational knowledge of the base model. Our objective was to enhance precision and contextual relevance in responding to medical queries by capturing the specialized nuances of clinical discourse. Due to the resource-intensive nature of large-scale human validation, the model's performance was evaluated through a dual-track framework: Track A utilized traditional lexical similarity metrics (e.g., BLEU, ROUGE), while Track B employed an "LLM-as-a-Judge" paradigm using GPT-4 for semantic assessment. Our results demonstrate that while the LoRA-enhanced model achieved significant improvements across all quantitative lexical dimensions, a profound disagreement surfaced in the GPT-4 evaluation, which marginally favored the baseline model's conversational flow. This metric divergence underscores a pivotal finding: traditional automated scores may not fully reflect clinical utility. Consequently, we propose that while automated metrics and LLM judges serve as valuable developmental proxies, rigorous validation by human medical experts remains an indispensable requirement for the safe deployment of LLMs in healthcare settings.

Data augmentation is a widely used strategy to improve model robustness and generalization by enriching training datasets with synthetic examples. While large language models (LLMs) have demonstrated strong generative capabilities for this purpose, their applications in high-stakes domains like healthcare present unique challenges due to the risk of generating clinically incorrect or misleading information. In this work, we propose a novel query-based model collaboration framework that integrates expert-level domain knowledge to guide the augmentation process to preserve critical medical information. Experiments on clinical prediction tasks demonstrate that our lightweight collaboration-based approach consistently outperforms existing LLM augmentation methods while improving safety through reduced factual errors. This framework addresses the gap between LLM augmentation potential and the safety requirements of specialized domains.

Accurate and contrast-free Major Adverse Cardiac Events (MACE) prediction from Cine MRI sequences remains a critical challenge. Existing methods typically necessitate supervised learning based on human-refined masks in the ventricular myocardium, which become impractical without contrast agents. We introduce a self-supervised framework, namely Codebook-based Temporal-Spatial Learning (CTSL), that learns dynamic, spatiotemporal representations from raw Cine data without requiring segmentation masks. CTSL decouples temporal and spatial features through a multi-view distillation strategy, where the teacher model processes multiple Cine views, and the student model learns from reduced-dimensional Cine-SA sequences. By leveraging codebook-based feature representations and dynamic lesion self-detection through motion cues, CTSL captures intricate temporal dependencies and motion patterns. High-confidence MACE risk predictions are achieved through our model, providing a rapid, non-invasive solution for cardiac risk assessment that outperforms traditional contrast-dependent methods, thereby enabling timely and accessible heart disease diagnosis in clinical settings.

Predictive artificial intelligence (AI) offers an opportunity to improve clinical practice and patient outcomes, but risks perpetuating biases if fairness is inadequately addressed. However, the definition of "fairness" remains unclear. We conducted a scoping review to identify and critically appraise fairness metrics for clinical predictive AI. We defined a "fairness metric" as a measure quantifying whether a model discriminates (societally) against individuals or groups defined by sensitive attributes. We searched five databases (2014-2024), screening 820 records, to include 41 studies, and extracted 62 fairness metrics. Metrics were classified by performance-dependency, model output level, and base performance metric, revealing a fragmented landscape with limited clinical validation and overreliance on threshold-dependent measures. Eighteen metrics were explicitly developed for healthcare, including only one clinical utility metric. Our findings highlight conceptual challenges in defining and quantifying fairness and identify gaps in uncertainty quantification, intersectionality, and real-world applicability. Future work should prioritise clinically meaningful metrics.

Predicting clinical outcomes from preclinical data is essential for identifying safe and effective drug combinations. Current models rely on structural or target-based features to identify high-efficacy, low-toxicity drug combinations. However, these approaches fail to incorporate the multimodal data necessary for accurate, clinically-relevant predictions. Here, we introduce MADRIGAL, a multimodal AI model that learns from structural, pathway, cell viability, and transcriptomic data to predict drug combination effects across 953 clinical outcomes and 21842 compounds, including combinations of approved drugs and novel compounds in development. MADRIGAL uses a transformer bottleneck module to unify preclinical drug data modalities while handling missing data during training and inference--a major challenge in multimodal learning. It outperforms single-modality methods and state-of-the-art models in predicting adverse drug interactions. MADRIGAL performs virtual screening of anticancer drug combinations and supports polypharmacy management for type II diabetes and metabolic dysfunction-associated steatohepatitis (MASH). It identifies transporter-mediated drug interactions. MADRIGAL predicts resmetirom, the first and only FDA-approved drug for MASH, among therapies with the most favorable safety profile. It supports personalized cancer therapy by integrating genomic profiles from cancer patients. Using primary acute myeloid leukemia samples and patient-derived xenograft models, it predicts the efficacy of personalized drug combinations. Integrating MADRIGAL with a large language model allows users to describe clinical outcomes in natural language, improving safety assessment by identifying potential adverse interactions and toxicity risks. MADRIGAL provides a multimodal approach for designing combination therapies with improved predictive accuracy and clinical relevance.

Large language models (LLMs) and agentic systems have shown promise for clinical decision support, but existing works largely assume that evidence has already been curated and handed to the model. Real-world clinical workflows instead require agents to actively seek, iteratively plan, and synthesize multimodal evidence from heterogeneous sources. In this paper, we introduce ClinSeekAgent, an automated agentic framework for dynamic multimodal evidence seeking that shifts the paradigm from passive evidence consumption to active evidence acquisition. Given only a clinical query and access to raw data sources, ClinSeekAgent gathers evidence by querying medical knowledge bases, navigating raw EHRs, and invoking medical imaging tools; refines its hypotheses as new information emerges; and integrates the collected evidence into grounded clinical decisions. ClinSeekAgent serves both as an inference-time agent for frontier LLMs and as a training-time pipeline for distilling high-quality agent trajectories into compact open-source models. To validate its inference-time effectiveness, we construct ClinSeek-Bench, which pairs Curated Input reasoning from fixed pre-selected evidence with Automated Evidence-Seeking over raw clinical data. On text-only EHR tasks, ClinSeekAgent improves Claude Opus 4.6 from 60.0 to 63.2 overall F1 and MiniMax M2.5 from 43.1 to 47.3, with positive risk-prediction gains in 7 out of 9 evaluated host models. On multimodal tasks, ClinSeekAgent improves Claude Opus 4.6 from 47.5 to 62.6 (+15.1); all evaluated models improve across the three CXR-related task groups. We further validate ClinSeekAgent as a training pipeline by distilling agentic evidence-seeking trajectories into ClinSeek-35B-A3B, which achieves 34.0 average F1 on existing AgentEHR-Bench, improving over its Qwen3.5-35B-A3B baseline by +11.9 points and approaching Claude Opus 4.6.

Diagnosing and treating skin diseases require advanced visual skills across domains and the ability to synthesize information from multiple imaging modalities. While current deep learning models excel at specific tasks like skin cancer diagnosis from dermoscopic images, they struggle to meet the complex, multimodal requirements of clinical practice. Here, we introduce PanDerm, a multimodal dermatology foundation model pretrained through self-supervised learning on over 2 million real-world skin disease images from 11 clinical institutions across 4 imaging modalities. We evaluated PanDerm on 28 diverse benchmarks, including skin cancer screening, risk stratification, differential diagnosis of common and rare skin conditions, lesion segmentation, longitudinal monitoring, and metastasis prediction and prognosis. PanDerm achieved state-of-the-art performance across all evaluated tasks, often outperforming existing models when using only 10% of labeled data. We conducted three reader studies to assess PanDerm's potential clinical utility. PanDerm outperformed clinicians by 10.2% in early-stage melanoma detection through longitudinal analysis, improved clinicians' skin cancer diagnostic accuracy by 11% on dermoscopy images, and enhanced non-dermatologist healthcare providers' differential diagnosis by 16.5% across 128 skin conditions on clinical photographs. These results demonstrate PanDerm's potential to improve patient care across diverse clinical scenarios and serve as a model for developing multimodal foundation models in other medical specialties, potentially accelerating the integration of AI support in healthcare. The code can be found at https://github.com/SiyuanYan1/PanDerm.

Reliable uncertainty estimation is critical for medical image segmentation, where automated contours feed downstream quantification and clinical decision support. Many strong uncertainty methods require repeated inference, while efficient single-forward-pass alternatives often provide weaker failure ranking or rely on restrictive feature-space assumptions. We present SegWithU, a post-hoc framework that augments a frozen pretrained segmentation backbone with a lightweight uncertainty head. SegWithU taps intermediate backbone features and models uncertainty as perturbation energy in a compact probe space using rank-1 posterior probes. It produces two voxel-wise uncertainty maps: a calibration-oriented map for probability tempering and a ranking-oriented map for error detection and selective prediction. Across ACDC, BraTS2024, and LiTS, SegWithU is the strongest and most consistent single-forward-pass baseline, achieving AUROC/AURC of 0.9838/2.4885, 0.9946/0.2660, and 0.9925/0.8193, respectively, while preserving segmentation quality. These results suggest that perturbation-based uncertainty modeling is an effective and practical route to reliability-aware medical segmentation. Source code is available at https://github.com/ProjectNeura/SegWithU.

Despite its significant promise and continuous technical advances, real-world applications of artificial intelligence (AI) remain limited. We attribute this to the "domain expert-AI-conundrum": while domain experts, such as clinician scientists, should be able to build predictive models such as risk scores, they face substantial barriers in accessing state-of-the-art (SOTA) tools. While automated machine learning (AutoML) has been proposed as a partner in clinical predictive modeling, many additional requirements need to be fulfilled to make machine learning accessible for clinician scientists. To address this gap, we introduce CliMB, a no-code AI-enabled partner designed to empower clinician scientists to create predictive models using natural language. CliMB guides clinician scientists through the entire medical data science pipeline, thus empowering them to create predictive models from real-world data in just one conversation. CliMB also creates structured reports and interpretable visuals. In evaluations involving clinician scientists and systematic comparisons against a baseline GPT-4, CliMB consistently demonstrated superior performance in key areas such as planning, error prevention, code execution, and model performance. Moreover, in blinded assessments involving 45 clinicians from diverse specialties and career stages, more than 80% preferred CliMB over GPT-4. Overall, by providing a no-code interface with clear guidance and access to SOTA methods in the fields of data-centric AI, AutoML, and interpretable ML, CliMB empowers clinician scientists to build robust predictive models. The proof-of-concept version of CliMB is available as open-source software on GitHub: https://github.com/vanderschaarlab/climb.

We consider the problem of predicting how the likelihood of an outcome of interest for a patient changes over time as we observe more of the patient data. To solve this problem, we propose a supervised contrastive learning framework that learns an embedding representation for each time step of a patient time series. Our framework learns the embedding space to have the following properties: (1) nearby points in the embedding space have similar predicted class probabilities, (2) adjacent time steps of the same time series map to nearby points in the embedding space, and (3) time steps with very different raw feature vectors map to far apart regions of the embedding space. To achieve property (3), we employ a nearest neighbor pairing mechanism in the raw feature space. This mechanism also serves as an alternative to data augmentation, a key ingredient of contrastive learning, which lacks a standard procedure that is adequately realistic for clinical tabular data, to our knowledge. We demonstrate that our approach outperforms state-of-the-art baselines in predicting mortality of septic patients (MIMIC-III dataset) and tracking progression of cognitive impairment (ADNI dataset). Our method also consistently recovers the correct synthetic dataset embedding structure across experiments, a feat not achieved by baselines. Our ablation experiments show the pivotal role of our nearest neighbor pairing.

Multimodal large language models (MLLMs) have recently achieved remarkable progress in radiology by integrating visual perception with natural language understanding. However, they often generate clinically unsupported descriptions, known as medical hallucinations, which pose serious risks in medical applications that demand accuracy and image-grounded outputs. Through empirical analysis, we find that prompt-induced hallucinations remain prevalent in radiology MLLMs, largely due to over-sensitivity to clinical sections. To address this, we introduce Clinical Contrastive Cecoding (CCD), a training-free and retrieval-free inference framework that integrates structured clinical signals from task-specific radiology expert models. CCD introduces a dual-stage contrastive mechanism to refine token-level logits during generation, thereby enhancing clinical fidelity without modifying the base MLLM. Experiments on three datasets and multiple models demonstrate that CCD consistently improves overall performance on radiology report generation (RRG). On the MIMIC-CXR dataset, it yields up to a 17% improvement in RadGraph-F1 when applied to state-of-the-art RRG models. Our approach provides a lightweight and generalisable solution for mitigating medical hallucinations, effectively bridging expert models and MLLMs in radiology.

Clinical LLMs are often scaled by increasing model size, context length, retrieval complexity, or inference-time compute, with the implicit expectation that higher accuracy implies safer behavior. This assumption is incomplete in medicine, where a few confident, high-risk, or evidence-contradicting errors can matter more than average benchmark performance. We introduce SaFE-Scale, a framework for measuring how clinical LLM safety changes across model scale, evidence quality, retrieval strategy, context exposure, and inference-time compute. To instantiate this framework, we introduce RadSaFE-200, a Radiology Safety-Focused Evaluation benchmark of 200 multiple-choice questions with clinician-defined clean evidence, conflict evidence, and option-level labels for high-risk error, unsafe answer, and evidence contradiction. We evaluated 34 locally deployed LLMs across six deployment conditions: closed-book prompting (zero-shot), clean evidence, conflict evidence, standard RAG, agentic RAG, and max-context prompting. Clean evidence produced the strongest improvement, increasing mean accuracy from 73.5% to 94.1%, while reducing high-risk error from 12.0% to 2.6%, contradiction from 12.7% to 2.3%, and dangerous overconfidence from 8.0% to 1.6%. Standard RAG and agentic RAG did not reproduce this safety profile: agentic RAG improved accuracy over standard RAG and reduced contradiction, but high-risk error and dangerous overconfidence remained elevated. Max-context prompting increased latency without closing the safety gap, and additional inference-time compute produced only limited gains. Worst-case analysis showed that clinically consequential errors concentrated in a small subset of questions. Clinical LLM safety is therefore not a passive consequence of scaling, but a deployment property shaped by evidence quality, retrieval design, context construction, and collective failure behavior.

Heart failure (HF) affects 11.8% of adults aged 65 and older, reducing quality of life and longevity. Preventing HF can reduce morbidity and mortality. We hypothesized that artificial intelligence (AI) applied to 24-hour single-lead electrocardiogram (ECG) data could predict the risk of HF within five years. To research this, the Technion-Leumit Holter ECG (TLHE) dataset, including 69,663 recordings from 47,729 patients, collected over 20 years was used. Our deep learning model, DeepHHF, trained on 24-hour ECG recordings, achieved an area under the receiver operating characteristic curve of 0.80 that outperformed a model using 30-second segments and a clinical score. High-risk individuals identified by DeepHHF had a two-fold chance of hospitalization or death incidents. Explainability analysis showed DeepHHF focused on arrhythmias and heart abnormalities, with key attention between 8 AM and 3 PM. This study highlights the feasibility of deep learning to model 24-hour continuous ECG data, capturing paroxysmal events and circadian variations essential for reliable risk prediction. Artificial intelligence applied to single-lead Holter ECG is non-invasive, inexpensive, and widely accessible, making it a promising tool for HF risk prediction.

Neurological diseases are the leading global cause of disability, yet most lack disease-modifying treatments. We present PROTON, a heterogeneous graph transformer that generates testable hypotheses across molecular, organoid, and clinical systems. To evaluate PROTON, we apply it to Parkinson's disease (PD), bipolar disorder (BD), and Alzheimer's disease (AD). In PD, PROTON linked genetic risk loci to genes essential for dopaminergic neuron survival and predicted pesticides toxic to patient-derived neurons, including the insecticide endosulfan, which ranked within the top 1.29% of predictions. In silico screens performed by PROTON reproduced six genome-wide α-synuclein experiments, including a split-ubiquitin yeast two-hybrid system (normalized enrichment score [NES] = 2.30, FDR-adjusted p < 1 times 10^{-4}), an ascorbate peroxidase proximity labeling assay (NES = 2.16, FDR < 1 times 10^{-4}), and a high-depth targeted exome sequencing study in 496 synucleinopathy patients (NES = 2.13, FDR < 1 times 10^{-4}). In BD, PROTON predicted calcitriol as a candidate drug that reversed proteomic alterations observed in cortical organoids derived from BD patients. In AD, we evaluated PROTON predictions in health records from n = 610,524 patients at Mass General Brigham, confirming that five PROTON-predicted drugs were associated with reduced seven-year dementia risk (minimum hazard ratio = 0.63, 95% CI: 0.53-0.75, p < 1 times 10^{-7}). PROTON generated neurological hypotheses that were evaluated across molecular, organoid, and clinical systems, defining a path for AI-driven discovery in neurological disease.

The Quantum-Inspired Stacked Integrated Concept Graph Model (QISICGM) is an innovative machine learning framework that harnesses quantum-inspired techniques to predict diabetes risk with exceptional accuracy and efficiency. Utilizing the PIMA Indians Diabetes dataset augmented with 2,000 synthetic samples to mitigate class imbalance (total: 2,768 samples, 1,949 positives), QISICGM integrates a self-improving concept graph with a stacked ensemble comprising Random Forests (RF), Extra Trees (ET), transformers, convolutional neural networks (CNNs), and feed-forward neural networks (FFNNs). This approach achieves an out-of-fold (OOF) F1 score of 0.8933 and an AUC of 0.8699, outperforming traditional methods. Quantum inspired elements, such as phase feature mapping and neighborhood sequence modeling, enrich feature representations, enabling CPU-efficient inference at 8.5 rows per second. This paper presents a detailed architecture, theoretical foundations, code insights, and performance evaluations, including visualizations from the outputs subfolder. The open-source implementation (v1.0.0) is available at https://github.com/keninayoung/QISICGM, positioning QISICGM as a potential benchmark for AI-assisted clinical triage in diabetes and beyond. Ultimately, this work emphasizes trustworthy AI through calibration, interpretability, and open-source reproducibility.

Despite the growing use of large language models (LLMs) in clinical dialogue systems, existing evaluations focus on task completion or fluency, offering little insight into the behavioral and risk management requirements essential for safety-critical systems. This paper presents MATRIX (Multi-Agent simulaTion fRamework for safe Interactions and conteXtual clinical conversational evaluation), a structured, extensible framework for safety-oriented evaluation of clinical dialogue agents. MATRIX integrates three components: (1) a safety-aligned taxonomy of clinical scenarios, expected system behaviors and failure modes derived through structured safety engineering methods; (2) BehvJudge, an LLM-based evaluator for detecting safety-relevant dialogue failures, validated against expert clinician annotations; and (3) PatBot, a simulated patient agent capable of producing diverse, scenario-conditioned responses, evaluated for realism and behavioral fidelity with human factors expertise, and a patient-preference study. Across three experiments, we show that MATRIX enables systematic, scalable safety evaluation. BehvJudge with Gemini 2.5-Pro achieves expert-level hazard detection (F1 0.96, sensitivity 0.999), outperforming clinicians in a blinded assessment of 240 dialogues. We also conducted one of the first realism analyses of LLM-based patient simulation, showing that PatBot reliably simulates realistic patient behavior in quantitative and qualitative evaluations. Using MATRIX, we demonstrate its effectiveness in benchmarking five LLM agents across 2,100 simulated dialogues spanning 14 hazard scenarios and 10 clinical domains. MATRIX is the first framework to unify structured safety engineering with scalable, validated conversational AI evaluation, enabling regulator-aligned safety auditing. We release all evaluation tools, prompts, structured scenarios, and datasets.

Although large language models (LLMs) have been assessed for general medical knowledge using medical licensing exams, their ability to effectively support clinical decision-making tasks, such as selecting and using medical calculators, remains uncertain. Here, we evaluate the capability of both medical trainees and LLMs to recommend medical calculators in response to various multiple-choice clinical scenarios such as risk stratification, prognosis, and disease diagnosis. We assessed eight LLMs, including open-source, proprietary, and domain-specific models, with 1,009 question-answer pairs across 35 clinical calculators and measured human performance on a subset of 100 questions. While the highest-performing LLM, GPT-4o, provided an answer accuracy of 74.3% (CI: 71.5-76.9%), human annotators, on average, outperformed LLMs with an accuracy of 79.5% (CI: 73.5-85.0%). With error analysis showing that the highest-performing LLMs continue to make mistakes in comprehension (56.6%) and calculator knowledge (8.1%), our findings emphasize that humans continue to surpass LLMs on complex clinical tasks such as calculator recommendation.

Large language model (LLM) agents extend generative models with reasoning, tool use, and persistent memory, thereby enabling the automation of complex tasks. In healthcare, such systems could support documentation, care coordination, and clinical decision making. Their reliable deployment in hospitals, however, remains constrained by safety risks, limited transparency, and inadequate mechanisms for handling longitudinal clinical context. Here we propose an architecture that adapts LLM agents to hospital environments. The design comprises four components: a restricted execution environment inspired by multi-user operating systems, a document-centric interaction model linking patient and clinician agents, a page-indexed memory architecture for longitudinal context management, and a curated library of composable medical skills. Implemented on top of OpenClaw, an open-source agent orchestration framework, this design provides the basis for an Agentic Operating System for Hospitals: a computing layer for coordinating clinical workflows while preserving safety, transparency, and auditability. To evaluate the memory component, we introduce manifest-guided retrieval for hierarchical navigation of longitudinal patient records. In a benchmark derived from the MIMIC-IV dataset (v2.2) comprising 100 de-identified patient records and 300 clinical queries stratified across three difficulty tiers (100 per tier), manifest-guided retrieval matched a metadata-filtered RAG baseline on overall recall (0.877 versus 0.876) while achieving 2.2x higher precision (0.779 versus 0.352) and retrieving fewer documents; on tier-3 longitudinal queries, manifest recall was 21% higher (0.846 versus 0.701), confirming that LLM-guided hierarchical navigation is most valuable when queries span multiple care episodes. These results outline a practical path toward hospital-scale agentic infrastructure.

As large language models transition from text-based interfaces to audio interactions in clinical settings, they might introduce new vulnerabilities through paralinguistic cues in audio. We evaluated these models on 170 clinical cases, each synthesized into speech from 36 distinct voice profiles spanning variations in age, gender, and emotion. Our findings reveal a severe modality bias: surgical recommendations for audio inputs varied by as much as 35% compared to identical text-based inputs, with one model providing 80% fewer recommendations. Further analysis uncovered age disparities of up to 12% between young and elderly voices, which persisted in most models despite chain-of-thought prompting. While explicit reasoning successfully eliminated gender bias, the impact of emotion was not detected due to poor recognition performance. These results demonstrate that audio LLMs are susceptible to making clinical decisions based on a patient's voice characteristics rather than medical evidence, a flaw that risks perpetuating healthcare disparities. We conclude that bias-aware architectures are essential and urgently needed before the clinical deployment of these models.

Large language models (LLMs) have significantly advanced natural language processing tasks, yet they are susceptible to generating inaccurate or unreliable responses, a phenomenon known as hallucination. In critical domains such as health and medicine, these hallucinations can pose serious risks. This paper introduces HALO, a novel framework designed to enhance the accuracy and reliability of medical question-answering (QA) systems by focusing on the detection and mitigation of hallucinations. Our approach generates multiple variations of a given query using LLMs and retrieves relevant information from external open knowledge bases to enrich the context. We utilize maximum marginal relevance scoring to prioritize the retrieved context, which is then provided to LLMs for answer generation, thereby reducing the risk of hallucinations. The integration of LangChain further streamlines this process, resulting in a notable and robust increase in the accuracy of both open-source and commercial LLMs, such as Llama-3.1 (from 44% to 65%) and ChatGPT (from 56% to 70%). This framework underscores the critical importance of addressing hallucinations in medical QA systems, ultimately improving clinical decision-making and patient care. The open-source HALO is available at: https://github.com/ResponsibleAILab/HALO.

Personalized nutrition intervention for patients with multimorbidity is critical for improving health outcomes, yet remains challenging because it requires the simultaneous integration of heterogeneous clinical conditions, medications, and dietary guidelines. Single-agent large language models (LLMs) often suffer from context overload and attention dilution when processing such high-dimensional patient profiles. We introduce NutriOrion, a hierarchical multi-agent framework with a parallel-then-sequential reasoning topology. NutriOrion decomposes nutrition planning into specialized domain agents with isolated contexts to mitigate anchoring bias, followed by a conditional refinement stage. The framework includes a multi-objective prioritization algorithm to resolve conflicting dietary requirements and a safety constraint mechanism that injects pharmacological contraindications as hard negative constraints during synthesis, ensuring clinical validity by construction rather than post-hoc filtering. For clinical interoperability, NutriOrion maps synthesized insights into the ADIME standard and FHIR R4 resources. Evaluated on 330 stroke patients with multimorbidity, NutriOrion outperforms multiple baselines, including GPT-4.1 and alternative multi-agent architectures. It achieves a 12.1 percent drug-food interaction violation rate, demonstrates strong personalization with negative correlations (-0.26 to -0.35) between patient biomarkers and recommended risk nutrients, and yields clinically meaningful dietary improvements, including a 167 percent increase in fiber and a 27 percent increase in potassium, alongside reductions in sodium (9 percent) and sugars (12 percent).

Gait analysis is crucial for the diagnosis and monitoring of movement disorders like Parkinson's Disease. While computer vision models have shown potential for objectively evaluating parkinsonian gait, their effectiveness is limited by scarce clinical datasets and the challenge of collecting large and well-labelled data, impacting model accuracy and risk of bias. To address these gaps, we propose GAITGen, a novel framework that generates realistic gait sequences conditioned on specified pathology severity levels. GAITGen employs a Conditional Residual Vector Quantized Variational Autoencoder to learn disentangled representations of motion dynamics and pathology-specific factors, coupled with Mask and Residual Transformers for conditioned sequence generation. GAITGen generates realistic, diverse gait sequences across severity levels, enriching datasets and enabling large-scale model training in parkinsonian gait analysis. Experiments on our new PD-GaM (real) dataset demonstrate that GAITGen outperforms adapted state-of-the-art models in both reconstruction fidelity and generation quality, accurately capturing critical pathology-specific gait features. A clinical user study confirms the realism and clinical relevance of our generated sequences. Moreover, incorporating GAITGen-generated data into downstream tasks improves parkinsonian gait severity estimation, highlighting its potential for advancing clinical gait analysis.

Large Language Models (LLMs) are increasingly used for clinical decision support, where hallucinations and unsafe suggestions may pose direct risks to patient safety. These risks are particularly challenging as they often manifest as subtle clinical errors that evade detection by generic metrics, while expert-authored fine-grained rubrics remain costly to construct and difficult to scale. In this paper, we propose a retrieval-augmented multi-agent framework designed to automate the generation of instance-specific evaluation rubrics. Our approach grounds evaluation in authoritative medical evidence by decomposing retrieved content into atomic facts and synthesizing them with user interaction constraints to form verifiable, fine-grained evaluation criteria. Evaluated on HealthBench, our framework achieves a Clinical Intent Alignment (CIA) score of 60.12%, a statistically significant improvement over the GPT-4o baseline (55.16%). In discriminative tests, our rubrics yield a mean score delta (μ_Δ = 8.658) and an AUROC of 0.977, nearly doubling the quality separation achieved by GPT-4o baseline (4.972). Beyond evaluation, our rubrics effectively guide response refinement, improving quality by 9.2% (from 59.0% to 68.2%). This provides a scalable and transparent foundation for both evaluating and improving medical LLMs. The code is available at https://anonymous.4open.science/r/Automated-Rubric-Generation-AF3C/.

With the growing use of language models (LMs) in clinical environments, there is an immediate need to evaluate the accuracy and safety of LM-generated medical text. Currently, such evaluation relies solely on manual physician review. However, detecting errors in LM-generated text is challenging because 1) manual review is costly and 2) expert-composed reference outputs are often unavailable in real-world settings. While the "LM-as-judge" paradigm (a LM evaluating another LM) offers scalable evaluation, even frontier LMs can miss subtle but clinically significant errors. To address these challenges, we propose MedVAL, a self-supervised framework that leverages synthetic data to train evaluator LMs to assess whether LM-generated medical outputs are factually consistent with inputs, without requiring physician labels or reference outputs. To evaluate LM performance, we introduce MedVAL-Bench, a dataset containing 840 outputs annotated by physicians, following a physician-defined taxonomy of risk levels and error categories. Across 6 diverse medical tasks and 10 state-of-the-art LMs spanning open-source, proprietary, and medically adapted models, MedVAL fine-tuning significantly improves (p < 0.001) alignment with physicians on both seen and unseen tasks, increasing average F1 scores from 66% to 83%, with per-sample safety classification scores up to 86%. MedVAL improves the performance of even the best-performing proprietary LM (GPT-4o) by 8%. To support a scalable, risk-aware pathway towards clinical integration, we open-source the 1) codebase ( https://github.com/StanfordMIMI/MedVAL ), 2) MedVAL-Bench ( https://huggingface.co/datasets/stanfordmimi/MedVAL-Bench ), and 3) MedVAL-4B ( https://huggingface.co/stanfordmimi/MedVAL-4B ), the best-performing open-source LM. Our research provides the first evidence of LMs approaching expert-level validation ability for medical text.

Ensuring the safety and reliability of large language models (LLMs) in clinical practice is critical to prevent patient harm and promote trustworthy healthcare applications of AI. However, LLMs are advancing so rapidly that static safety benchmarks often become obsolete upon publication, yielding only an incomplete and sometimes misleading picture of model trustworthiness. We demonstrate that a Dynamic, Automatic, and Systematic (DAS) red-teaming framework that continuously stress-tests LLMs can reveal significant weaknesses of current LLMs across four safety-critical domains: robustness, privacy, bias/fairness, and hallucination. A suite of adversarial agents is applied to autonomously mutate test cases, identify/evolve unsafe-triggering strategies, and evaluate responses, uncovering vulnerabilities in real time without human intervention. Applying DAS to 15 proprietary and open-source LLMs revealed a stark contrast between static benchmark performance and vulnerability under adversarial pressure. Despite a median MedQA accuracy exceeding 80\%, 94\% of previously correct answers failed our dynamic robustness tests. We observed similarly high failure rates across other domains: privacy leaks were elicited in 86\% of scenarios, cognitive-bias priming altered clinical recommendations in 81\% of fairness tests, and we identified hallucination rates exceeding 66\% in widely used models. Such profound residual risks are incompatible with routine clinical practice. By converting red-teaming from a static checklist into a dynamic stress-test audit, DAS red-teaming offers the surveillance that hospitals/regulators/technology vendors require as LLMs become embedded in patient chatbots, decision-support dashboards, and broader healthcare workflows. Our framework delivers an evolvable, scalable, and reliable safeguard for the next generation of medical AI.

Accurate prediction of major adverse cardiac events (MACE) remains a central challenge in cardiovascular prognosis. We present PRISM (Prompt-guided Representation Integration for Survival Modeling), a self-supervised framework that integrates visual representations from non-contrast cardiac cine magnetic resonance imaging with structured electronic health records (EHRs) for survival analysis. PRISM extracts temporally synchronized imaging features through motion-aware multi-view distillation and modulates them using medically informed textual prompts to enable fine-grained risk prediction. Across four independent clinical cohorts, PRISM consistently surpasses classical survival prediction models and state-of-the-art (SOTA) deep learning baselines under internal and external validation. Further clinical findings demonstrate that the combined imaging and EHR representations derived from PRISM provide valuable insights into cardiac risk across diverse cohorts. Three distinct imaging signatures associated with elevated MACE risk are uncovered, including lateral wall dyssynchrony, inferior wall hypersensitivity, and anterior elevated focus during diastole. Prompt-guided attribution further identifies hypertension, diabetes, and smoking as dominant contributors among clinical and physiological EHR factors.

While powerful in image-conditioned generation, multimodal large language models (MLLMs) can display uneven performance across demographic groups, highlighting fairness risks. In safety-critical clinical settings, such disparities risk producing unequal diagnostic narratives and eroding trust in AI-assisted decision-making. While fairness has been studied extensively in vision-only and language-only models, its impact on MLLMs remains largely underexplored. To address these biases, we introduce FairLLaVA, a parameter-efficient fine-tuning method that mitigates group disparities in visual instruction tuning without compromising overall performance. By minimizing the mutual information between target attributes, FairLLaVA regularizes the model's representations to be demographic-invariant. The method can be incorporated as a lightweight plug-in, maintaining efficiency with low-rank adapter fine-tuning, and provides an architecture-agnostic approach to fair visual instruction following. Extensive experiments on large-scale chest radiology report generation and dermoscopy visual question answering benchmarks show that FairLLaVA consistently reduces inter-group disparities while improving both equity-scaled clinical performance and natural language generation quality across diverse medical imaging modalities. Code can be accessed at https://github.com/bhosalems/FairLLaVA.

Large language models are increasingly used for mental health support, yet their conversational coherence alone does not ensure clinical appropriateness. Existing general-purpose safeguards often fail to distinguish between therapeutic disclosures and genuine clinical crises, leading to safety failures. To address this gap, we introduce a clinically grounded risk taxonomy, developed in collaboration with PhD-level psychologists, that identifies actionable harm (e.g., self-harm and harm to others) while preserving space for safe, non-crisis therapeutic content. We release MindGuard-testset, a dataset of real-world multi-turn conversations annotated at the turn level by clinical experts. Using synthetic dialogues generated via a controlled two-agent setup, we train MindGuard, a family of lightweight safety classifiers (with 4B and 8B parameters). Our classifiers reduce false positives at high-recall operating points and, when paired with clinician language models, help achieve lower attack success and harmful engagement rates in adversarial multi-turn interactions compared to general-purpose safeguards. We release all models and human evaluation data.

Accurate prediction of major adverse cardiovascular events recurrence risk in acute myocardial infarction patients based on postoperative cardiac MRI and associated clinical notes is crucial for precision treatment and personalized intervention. Existing methods primarily focus on risk stratification capability while overlooking the need for intermediate robust reasoning and model interpretability in clinical practice. Moreover, end-to-end risk prediction using LLM/VLM faces significant challenges due to data limitations and modeling complexity. To bridge this gap, we propose CardioCoT, a novel two-stage hierarchical reasoning-enhanced survival analysis framework designed to enhance both model interpretability and predictive performance. In the first stage, we employ an evidence-augmented self-refinement mechanism to guide LLM/VLMs in generating robust hierarchical reasoning trajectories based on associated radiological findings. In the second stage, we integrate the reasoning trajectories with imaging data for risk model training and prediction. CardioCoT demonstrates superior performance in MACE recurrence risk prediction while providing interpretable reasoning processes, offering valuable insights for clinical decision-making.

Hepatocellular carcinoma (HCC), ranking as the third leading cause of cancer-related mortality worldwide, demands urgent improvements in early detection to enhance patient survival. While ultrasound remains the preferred screening modality due to its cost-effectiveness and real-time capabilities, its sensitivity (59%-78%) heavily relies on radiologists' expertise, leading to inconsistent diagnostic outcomes and operational inefficiencies. Recent advancements in AI technology offer promising solutions to bridge this gap. This study introduces the Hierarchical Sparse Query Transformer (HSQformer), a novel hybrid architecture that synergizes CNNs' local feature extraction with Vision Transformers' global contextual awareness through latent space representation and sparse learning. By dynamically activating task-specific experts via a Mixture-of-Experts (MoE) framework, HSQformer achieves hierarchical feature integration without structural redundancy. Evaluated across three clinical scenarios: single-center, multi-center, and high-risk patient cohorts, HSQformer outperforms state-of-the-art models (e.g., 95.38% AUC in multi-center testing) and matches senior radiologists' diagnostic accuracy while significantly surpassing junior counterparts. These results highlight the potential of AI-assisted tools to standardize HCC screening, reduce dependency on human expertise, and improve early diagnosis rates. The full code is available at https://github.com/Asunatan/HSQformer.

Radiotherapy (RT) planning is complex, subjective, and time-intensive. Advances in artificial intelligence (AI) promise to improve its precision, efficiency, and consistency, but progress is often limited by the scarcity of large, standardized datasets. To address this, we introduce the Automated Iterative RT Planning (AIRTP) system, a scalable solution for generating high-quality treatment plans. This scalable solution is designed to generate substantial volumes of consistently high-quality treatment plans, overcoming a key obstacle in the advancement of AI-driven RT planning. Our AIRTP pipeline adheres to clinical guidelines and automates essential steps, including organ-at-risk (OAR) contouring, helper structure creation, beam setup, optimization, and plan quality improvement, using AI integrated with RT planning software like Eclipse of Varian. Furthermore, a novel approach for determining optimization parameters to reproduce 3D dose distributions, i.e. a method to convert dose predictions to deliverable treatment plans constrained by machine limitations. A comparative analysis of plan quality reveals that our automated pipeline produces treatment plans of quality comparable to those generated manually, which traditionally require several hours of labor per plan. Committed to public research, the first data release of our AIRTP pipeline includes nine cohorts covering head-and-neck and lung cancer sites to support an AAPM 2025 challenge. This data set features more than 10 times the number of plans compared to the largest existing well-curated public data set to our best knowledge. Repo:{https://github.com/RiqiangGao/GDP-HMM_AAPMChallenge}

Understanding how deep learning models predict oncology patient risk can provide critical insights into disease progression, support clinical decision-making, and pave the way for trustworthy and data-driven precision medicine. Building on recent advances in the spatial modeling of the tumor microenvironment using graph neural networks, we present an explainable cell graph (xCG) approach for survival prediction. We validate our model on a public cohort of imaging mass cytometry (IMC) data for 416 cases of lung adenocarcinoma. We explain survival predictions in terms of known phenotypes on the cell level by computing risk attributions over cell graphs, for which we propose an efficient grid-based layer-wise relevance propagation (LRP) method. Our ablation studies highlight the importance of incorporating the cancer stage and model ensembling to improve the quality of risk estimates. Our xCG method, together with the IMC data, is made publicly available to support further research.

The Circle of Willis (CoW) is an important network of arteries connecting major circulations of the brain. Its vascular architecture is believed to affect the risk, severity, and clinical outcome of serious neurovascular diseases. However, characterizing the highly variable CoW anatomy is still a manual and time-consuming expert task. The CoW is usually imaged by two non-invasive angiographic imaging modalities, magnetic resonance angiography (MRA) and computed tomography angiography (CTA), but there exist limited datasets with annotations on CoW anatomy, especially for CTA. Therefore, we organized the TopCoW challenge with the release of an annotated CoW dataset. The TopCoW dataset is the first public dataset with voxel-level annotations for 13 CoW vessel components, enabled by virtual reality technology. It is also the first large dataset using 200 pairs of MRA and CTA from the same patients. As part of the benchmark, we invited submissions worldwide and attracted over 250 registered participants from six continents. The submissions were evaluated on both internal and external test datasets of 226 scans from over five centers. The top performing teams achieved over 90% Dice scores at segmenting the CoW components, over 80% F1 scores at detecting key CoW components, and over 70% balanced accuracy at classifying CoW variants for nearly all test sets. The best algorithms also showed clinical potential in classifying fetal-type posterior cerebral artery and locating aneurysms with CoW anatomy. TopCoW demonstrated the utility and versatility of CoW segmentation algorithms for a wide range of downstream clinical applications with explainability. The annotated datasets and best performing algorithms have been released as public Zenodo records to foster further methodological development and clinical tool building.

Coronary microvascular dysfunction (CMD), characterized by impaired regulation of blood flow in the coronary microcirculation, plays a key role in the pathogenesis of ischemic heart disease and is increasingly recognized as a contributor to adverse cardiovascular outcomes. Despite its clinical importance, CMD remains underdiagnosed due to the reliance on invasive procedures such as pressure wire-based measurements of the index of microcirculatory resistance (IMR) and coronary flow reserve (CFR), which are costly, time-consuming, and carry procedural risks. To date, no study has sought to quantify CMD indices using data-driven approaches while leveraging the rich information contained in coronary angiograms. To address these limitations, this study proposes a novel data-driven framework for inference of CMD indices based on coronary angiography. A physiologically validated multi-physics model was used to generate synthetic datasets for data-driven model training, consisting of CMD indices and computational angiograms with corresponding contrast intensity profiles (CIPs). Two neural network architectures were developed: a single-input-channel encoder-MLP model for IMR prediction and a dual-input-channel encoder-MLP model for CFR prediction, both incorporating epistemic uncertainty estimation to quantify prediction confidence. Results demonstrate that the data-driven models achieve high predictive accuracy when evaluated against physics-based synthetic datasets, and that the uncertainty estimates are positively correlated with prediction errors. Furthermore, the utility of CIPs as informative surrogates for coronary physiology is demonstrated, underscoring the potential of the proposed framework to enable accurate, real-time, image-based CMD assessment using routine angiography without the need for more invasive approaches.

Large language models (LLMs) have received much attention and shown their potential in digital health, while their application in mental health is subject to ongoing debate. This systematic review aims to summarize and characterize the use of LLMs in mental health by investigating the strengths and limitations of the latest work in LLMs and discusses the challenges and opportunities for early screening, digital interventions, and other clinical applications in mental health. Following PRISMA guidelines, we examined English articles from PubMed, DBLP Computer Science Bibliography, and IEEE Xplore, published between 1 January 2017, and 1 September 2023, focusing on mental health and LLMs. The review analyzed 32 articles, including mental health analysis using social media datasets (n=13), mental health chatbots (n=10), and other mental health applications (n=9). Findings reveal LLMs' effectiveness in mental health issue detection and the enhancement of telepsychological services through personalised healthcare. Nonetheless, risks like text inconsistencies, hallucinatory content, and the lack of an ethical framework raise concerns about their clinical use. Despite these challenges, the advancement of LLMs underscores their potential as innovative clinical tools, necessitating further research and development. The review emphasizes that LLMs should complement, not replace, professional mental health services.

Breast cancer is one of the leading causes of death among women worldwide. We introduce Mammo-FM, the first foundation model specifically for mammography, pretrained on the largest and most diverse dataset to date - 140,677 patients (821,326 mammograms) across four U.S. institutions. Mammo-FM provides a unified foundation for core clinical tasks in breast imaging, including cancer diagnosis, pathology localization, structured report generation, and cancer risk prognosis within a single framework. Its alignment between images and text enables both visual and textual interpretability, improving transparency and clinical auditability, which are essential for real-world adoption. We rigorously evaluate Mammo-FM across diagnosis, prognosis, and report-generation tasks in in- and out-of-distribution datasets. Despite operating on native-resolution mammograms and using only one-third of the parameters of state-of-the-art generalist FMs, Mammo-FM consistently outperforms them across multiple public and private benchmarks. These results highlight the efficiency and value of domain-specific foundation models designed around the full spectrum of tasks within a clinical domain and emphasize the importance of rigorous, domain-aligned evaluation.

Advancements in Large Language Models (LLMs) and their increasing use in medical question-answering necessitate rigorous evaluation of their reliability. A critical challenge lies in hallucination, where models generate plausible yet factually incorrect outputs. In the medical domain, this poses serious risks to patient safety and clinical decision-making. To address this, we introduce MedHallu, the first benchmark specifically designed for medical hallucination detection. MedHallu comprises 10,000 high-quality question-answer pairs derived from PubMedQA, with hallucinated answers systematically generated through a controlled pipeline. Our experiments show that state-of-the-art LLMs, including GPT-4o, Llama-3.1, and the medically fine-tuned UltraMedical, struggle with this binary hallucination detection task, with the best model achieving an F1 score as low as 0.625 for detecting "hard" category hallucinations. Using bidirectional entailment clustering, we show that harder-to-detect hallucinations are semantically closer to ground truth. Through experiments, we also show incorporating domain-specific knowledge and introducing a "not sure" category as one of the answer categories improves the precision and F1 scores by up to 38% relative to baselines.

Vision-Language Models (VLMs) are increasingly used in clinical diagnostics, yet their robustness to adversarial attacks remains largely unexplored, posing serious risks. Existing medical attacks focus on secondary objectives such as model stealing or adversarial fine-tuning, while transferable attacks from natural images introduce visible distortions that clinicians can easily detect. To address this, we propose MedFocusLeak, a highly transferable black-box multimodal attack that induces incorrect yet clinically plausible diagnoses while keeping perturbations imperceptible. The method injects coordinated perturbations into non-diagnostic background regions and employs an attention distraction mechanism to shift the model's focus away from pathological areas. Extensive evaluations across six medical imaging modalities show that MedFocusLeak achieves state-of-the-art performance, generating misleading yet realistic diagnostic outputs across diverse VLMs. We further introduce a unified evaluation framework with novel metrics that jointly capture attack success and image fidelity, revealing a critical weakness in the reasoning capabilities of modern clinical VLMs.

Hallucinations in large language models (LLMs) during summarization of patient-clinician dialogues pose significant risks to patient care and clinical decision-making. However, the phenomenon remains understudied in the clinical domain, with uncertainty surrounding the applicability of general-domain hallucination detectors. The rarity and randomness of hallucinations further complicate their investigation. In this paper, we conduct an evaluation of hallucination detection methods in the medical domain, and construct two datasets for the purpose: A fact-controlled Leave-N-out dataset -- generated by systematically removing facts from source dialogues to induce hallucinated content in summaries; and a natural hallucination dataset -- arising organically during LLM-based medical summarization. We show that general-domain detectors struggle to detect clinical hallucinations, and that performance on fact-controlled hallucinations does not reliably predict effectiveness on natural hallucinations. We then develop fact-based approaches that count hallucinations, offering explainability not available with existing methods. Notably, our LLM-based detectors, which we developed using fact-controlled hallucinations, generalize well to detecting real-world clinical hallucinations. This research contributes a suite of specialized metrics supported by expert-annotated datasets to advance faithful clinical summarization systems.

Automatic medical report generation supports clinical diagnosis, reduces the workload of radiologists, and holds the promise of improving diagnosis consistency. However, existing evaluation metrics primarily assess the accuracy of key medical information coverage in generated reports compared to human-written reports, while overlooking crucial details such as the location and certainty of reported abnormalities. These limitations hinder the comprehensive assessment of the reliability of generated reports and pose risks in their selection for clinical use. Therefore, we propose a Granular Explainable Multi-Agent Score (GEMA-Score) in this paper, which conducts both objective quantification and subjective evaluation through a large language model-based multi-agent workflow. Our GEMA-Score parses structured reports and employs NER-F1 calculations through interactive exchanges of information among agents to assess disease diagnosis, location, severity, and uncertainty. Additionally, an LLM-based scoring agent evaluates completeness, readability, and clinical terminology while providing explanatory feedback. Extensive experiments validate that GEMA-Score achieves the highest correlation with human expert evaluations on a public dataset, demonstrating its effectiveness in clinical scoring (Kendall coefficient = 0.70 for Rexval dataset and Kendall coefficient = 0.54 for RadEvalX dataset). The anonymous project demo is available at: https://github.com/Zhenxuan-Zhang/GEMA_score.

Machine learning techniques are effective for building predictive models because they identify patterns in large datasets. Development of a model for complex real-life problems often stop at the point of publication, proof of concept or when made accessible through some mode of deployment. However, a model in the medical domain risks becoming obsolete as patient demographics, systems and clinical practices change. The maintenance and monitoring of predictive model performance post-publication is crucial to enable their safe and effective long-term use. We will assess the infrastructure required to monitor the outputs of a machine learning algorithm, and present two scenarios with examples of monitoring and updates of models, firstly on a breast cancer prognosis model trained on public longitudinal data, and secondly on a neurodegenerative stratification algorithm that is currently being developed and tested in clinic.

Pain is a complex and pervasive condition that affects a significant portion of the population. Accurate and consistent assessment is essential for individuals suffering from pain, as well as for developing effective management strategies in a healthcare system. Automatic pain assessment systems enable continuous monitoring, support clinical decision-making, and help minimize patient distress while mitigating the risk of functional deterioration. Leveraging physiological signals offers objective and precise insights into a person's state, and their integration in a multimodal framework can further enhance system performance. This study has been submitted to the Second Multimodal Sensing Grand Challenge for Next-Gen Pain Assessment (AI4PAIN). The proposed approach introduces Tiny-BioMoE, a lightweight pretrained embedding model for biosignal analysis. Trained on 4.4 million biosignal image representations and consisting of only 7.3 million parameters, it serves as an effective tool for extracting high-quality embeddings for downstream tasks. Extensive experiments involving electrodermal activity, blood volume pulse, respiratory signals, peripheral oxygen saturation, and their combinations highlight the model's effectiveness across diverse modalities in automatic pain recognition tasks. The model's architecture (code) and weights are available at https://github.com/GkikasStefanos/Tiny-BioMoE.

Language Models (LMs) are being proposed for mental health applications where the heightened risk of adverse outcomes means predictive performance may not be a sufficient litmus test of a model's utility in clinical practice. A model that can be trusted for practice should have a correspondence between explanation and clinical determination, yet no prior research has examined the attention fidelity of these models and their effect on ground truth explanations. We introduce an evaluation design that focuses on the robustness and explainability of LMs in identifying Wellness Dimensions (WDs). We focus on two existing mental health and well-being datasets: (a) Multi-label Classification-based MultiWD, and (b) WellXplain for evaluating attention mechanism veracity against expert-labeled explanations. The labels are based on Halbert Dunn's theory of wellness, which gives grounding to our evaluation. We reveal four surprising results about LMs/LLMs: (1) Despite their human-like capabilities, GPT-3.5/4 lag behind RoBERTa, and MedAlpaca, a fine-tuned LLM on WellXplain fails to deliver any remarkable improvements in performance or explanations. (2) Re-examining LMs' predictions based on a confidence-oriented loss function reveals a significant performance drop. (3) Across all LMs/LLMs, the alignment between attention and explanations remains low, with LLMs scoring a dismal 0.0. (4) Most mental health-specific LMs/LLMs overlook domain-specific knowledge and undervalue explanations, causing these discrepancies. This study highlights the need for further research into their consistency and explanations in mental health and well-being.

Large Language Models (LLMs) are increasingly adopted across domains such as education, healthcare, and finance. In healthcare, LLMs support tasks including disease diagnosis, abnormality classification, and clinical decision-making. Among these, multi-abnormality classification of radiology reports is critical for clinical workflow automation and biomedical research. Leveraging strong natural language processing capabilities, LLMs enable efficient processing of unstructured medical text and reduce the administrative burden of manual report analysis. To improve performance, LLMs are often fine-tuned on private, institution-specific datasets such as radiology reports. However, this raises significant privacy concerns: LLMs may memorize training data and become vulnerable to data extraction attacks, while sharing fine-tuned models risks exposing sensitive patient information. Despite growing interest in LLMs for medical text classification, privacy-preserving fine-tuning for multi-abnormality classification remains underexplored. To address this gap, we propose a differentially private (DP) fine-tuning framework for multi-abnormality classification from free-text radiology reports. Our approach integrates differential privacy with Low-Rank Adaptation (LoRA) to efficiently fine-tune LLMs on sensitive clinical data while mitigating leakage risks. We further employ labels generated by a larger LLM to train smaller models, enabling efficient inference under strong privacy guarantees. Experiments on MIMIC-CXR and CT-RATE demonstrate the effectiveness of our DP-LoRA framework across varying privacy regimes. On MIMIC-CXR, our method achieves weighted F1-scores up to 0.89 under moderate privacy budgets, approaching non-private LoRA (0.90) and full fine-tuning (0.96), confirming that strong privacy can be achieved with only modest performance trade-offs.

Background: Electronic Health Records hold detailed longitudinal information about each patient's health status and general clinical history, a large portion of which is stored within the unstructured text. Existing approaches focus mostly on structured data and a subset of single-domain outcomes. We explore how temporal modelling of patients from free text and structured data, using deep generative transformers can be used to forecast a wide range of future disorders, substances, procedures or findings. Methods: We present Foresight, a novel transformer-based pipeline that uses named entity recognition and linking tools to convert document text into structured, coded concepts, followed by providing probabilistic forecasts for future medical events such as disorders, substances, procedures and findings. We processed the entire free-text portion from three different hospital datasets totalling 811336 patients covering both physical and mental health. Findings: On tests in two UK hospitals (King's College Hospital, South London and Maudsley) and the US MIMIC-III dataset precision@10 0.68, 0.76 and 0.88 was achieved for forecasting the next disorder in a patient timeline, while precision@10 of 0.80, 0.81 and 0.91 was achieved for forecasting the next biomedical concept. Foresight was also validated on 34 synthetic patient timelines by five clinicians and achieved relevancy of 97% for the top forecasted candidate disorder. As a generative model, it can forecast follow-on biomedical concepts for as many steps as required. Interpretation: Foresight is a general-purpose model for biomedical concept modelling that can be used for real-world risk forecasting, virtual trials and clinical research to study the progression of disorders, simulate interventions and counterfactuals, and educational purposes.

Objective: We develop a deep learning framework based on the pre-trained Bidirectional Encoder Representations from Transformers (BERT) model using unstructured clinical notes from electronic health records (EHRs) to predict the risk of disease progression from Mild Cognitive Impairment (MCI) to Alzheimer's Disease (AD). Materials and Methods: We identified 3657 patients diagnosed with MCI together with their progress notes from Northwestern Medicine Enterprise Data Warehouse (NMEDW) between 2000-2020. The progress notes no later than the first MCI diagnosis were used for the prediction. We first preprocessed the notes by deidentification, cleaning and splitting, and then pretrained a BERT model for AD (AD-BERT) based on the publicly available Bio+Clinical BERT on the preprocessed notes. The embeddings of all the sections of a patient's notes processed by AD-BERT were combined by MaxPooling to compute the probability of MCI-to-AD progression. For replication, we conducted a similar set of experiments on 2563 MCI patients identified at Weill Cornell Medicine (WCM) during the same timeframe. Results: Compared with the 7 baseline models, the AD-BERT model achieved the best performance on both datasets, with Area Under receiver operating characteristic Curve (AUC) of 0.8170 and F1 score of 0.4178 on NMEDW dataset and AUC of 0.8830 and F1 score of 0.6836 on WCM dataset. Conclusion: We developed a deep learning framework using BERT models which provide an effective solution for prediction of MCI-to-AD progression using clinical note analysis.

For patients suffering from central nervous system tumors, prognosis estimation, treatment decisions, and postoperative assessments are made from the analysis of a set of magnetic resonance (MR) scans. Currently, the lack of open tools for standardized and automatic tumor segmentation and generation of clinical reports, incorporating relevant tumor characteristics, leads to potential risks from inherent decisions' subjectivity. To tackle this problem, the proposed Raidionics open-source software has been developed, offering both a user-friendly graphical user interface and stable processing backend. The software includes preoperative segmentation models for each of the most common tumor types (i.e., glioblastomas, lower grade gliomas, meningiomas, and metastases), together with one early postoperative glioblastoma segmentation model. Preoperative segmentation performances were quite homogeneous across the four different brain tumor types, with an average Dice around 85% and patient-wise recall and precision around 95%. Postoperatively, performances were lower with an average Dice of 41%. Overall, the generation of a standardized clinical report, including the tumor segmentation and features computation, requires about ten minutes on a regular laptop. The proposed Raidionics software is the first open solution enabling an easy use of state-of-the-art segmentation models for all major tumor types, including preoperative and postsurgical standardized reports.

Large language models (LLMs) are increasingly applied in educational, clinical, and professional settings, but their tendency for sycophancy -- prioritizing user agreement over independent reasoning -- poses risks to reliability. This study introduces a framework to evaluate sycophantic behavior in ChatGPT-4o, Claude-Sonnet, and Gemini-1.5-Pro across AMPS (mathematics) and MedQuad (medical advice) datasets. Sycophantic behavior was observed in 58.19% of cases, with Gemini exhibiting the highest rate (62.47%) and ChatGPT the lowest (56.71%). Progressive sycophancy, leading to correct answers, occurred in 43.52% of cases, while regressive sycophancy, leading to incorrect answers, was observed in 14.66%. Preemptive rebuttals demonstrated significantly higher sycophancy rates than in-context rebuttals (61.75% vs. 56.52%, Z=5.87, p<0.001), particularly in computational tasks, where regressive sycophancy increased significantly (preemptive: 8.13%, in-context: 3.54%, p<0.001). Simple rebuttals maximized progressive sycophancy (Z=6.59, p<0.001), while citation-based rebuttals exhibited the highest regressive rates (Z=6.59, p<0.001). Sycophantic behavior showed high persistence (78.5%, 95% CI: [77.2%, 79.8%]) regardless of context or model. These findings emphasize the risks and opportunities of deploying LLMs in structured and dynamic domains, offering insights into prompt programming and model optimization for safer AI applications.

When applying offline reinforcement learning (RL) in healthcare scenarios, the out-of-distribution (OOD) issues pose significant risks, as inappropriate generalization beyond clinical expertise can result in potentially harmful recommendations. While existing methods like conservative Q-learning (CQL) attempt to address the OOD issue, their effectiveness is limited by only constraining action selection by suppressing uncertain actions. This action-only regularization imitates clinician actions that prioritize short-term rewards, but it fails to regulate downstream state trajectories, thereby limiting the discovery of improved long-term treatment strategies. To safely improve policy beyond clinician recommendations while ensuring that state-action trajectories remain in-distribution, we propose Offline Guarded Safe Reinforcement Learning (OGSRL), a theoretically grounded model-based offline RL framework. OGSRL introduces a novel dual constraint mechanism for improving policy with reliability and safety. First, the OOD guardian is established to specify clinically validated regions for safe policy exploration. By constraining optimization within these regions, it enables the reliable exploration of treatment strategies that outperform clinician behavior by leveraging the full patient state history, without drifting into unsupported state-action trajectories. Second, we introduce a safety cost constraint that encodes medical knowledge about physiological safety boundaries, providing domain-specific safeguards even in areas where training data might contain potentially unsafe interventions. Notably, we provide theoretical guarantees on safety and near-optimality: policies that satisfy these constraints remain in safe and reliable regions and achieve performance close to the best possible policy supported by the data.

Precision therapeutics require multimodal adaptive models that generate personalized treatment recommendations. We introduce TxAgent, an AI agent that leverages multi-step reasoning and real-time biomedical knowledge retrieval across a toolbox of 211 tools to analyze drug interactions, contraindications, and patient-specific treatment strategies. TxAgent evaluates how drugs interact at molecular, pharmacokinetic, and clinical levels, identifies contraindications based on patient comorbidities and concurrent medications, and tailors treatment strategies to individual patient characteristics. It retrieves and synthesizes evidence from multiple biomedical sources, assesses interactions between drugs and patient conditions, and refines treatment recommendations through iterative reasoning. It selects tools based on task objectives and executes structured function calls to solve therapeutic tasks that require clinical reasoning and cross-source validation. The ToolUniverse consolidates 211 tools from trusted sources, including all US FDA-approved drugs since 1939 and validated clinical insights from Open Targets. TxAgent outperforms leading LLMs, tool-use models, and reasoning agents across five new benchmarks: DrugPC, BrandPC, GenericPC, TreatmentPC, and DescriptionPC, covering 3,168 drug reasoning tasks and 456 personalized treatment scenarios. It achieves 92.1% accuracy in open-ended drug reasoning tasks, surpassing GPT-4o and outperforming DeepSeek-R1 (671B) in structured multi-step reasoning. TxAgent generalizes across drug name variants and descriptions. By integrating multi-step inference, real-time knowledge grounding, and tool-assisted decision-making, TxAgent ensures that treatment recommendations align with established clinical guidelines and real-world evidence, reducing the risk of adverse events and improving therapeutic decision-making.

Conventional medical cancer screening methods are costly, labor-intensive, and extremely difficult to scale. Although AI can improve cancer detection, most systems rely on complex or specialized medical data, making them impractical for large-scale screening. We introduce Can-SAVE, a lightweight AI system that ranks population-wide cancer risks solely based on medical history events. By integrating survival model outputs into a gradient-boosting framework, our approach detects subtle, long-term patient risk patterns - often well before clinical symptoms manifest. Can-SAVE was rigorously evaluated on a real-world dataset of 2.5 million adults spanning five Russian regions, marking the study as one of the largest and most comprehensive deployments of AI-driven cancer risk assessment. In a retrospective oncologist-supervised study over 1.9M patients, Can-SAVE achieves a 4-10x higher detection rate at identical screening volumes and an Average Precision (AP) of 0.228 vs. 0.193 for the best baseline (LoRA-tuned Qwen3-Embeddings via DeepSeek-R1 summarization). In a year-long prospective pilot (426K patients), our method almost doubled the cancer detection rate (+91%) and increased population coverage by 36% over the national screening protocol. The system demonstrates practical scalability: a city-wide population of 1 million patients can be processed in under three hours using standard hardware, enabling seamless clinical integration. This work proves that Can-SAVE achieves nationally significant cancer detection improvements while adhering to real-world public healthcare constraints, offering immediate clinical utility and a replicable framework for population-wide screening. Code for training and feature engineering is available at https://github.com/sb-ai-lab/Can-SAVE.

Realistic practice and tailored feedback are key processes for training peer counselors with clinical skills. However, existing mechanisms of providing feedback largely rely on human supervision. Peer counselors often lack mechanisms to receive detailed feedback from experienced mentors, making it difficult for them to support the large number of people with mental health issues who use peer counseling. Our work aims to leverage large language models to provide contextualized and multi-level feedback to empower peer counselors, especially novices, at scale. To achieve this, we co-design with a group of senior psychotherapy supervisors to develop a multi-level feedback taxonomy, and then construct a publicly available dataset with comprehensive feedback annotations of 400 emotional support conversations. We further design a self-improvement method on top of large language models to enhance the automatic generation of feedback. Via qualitative and quantitative evaluation with domain experts, we demonstrate that our method minimizes the risk of potentially harmful and low-quality feedback generation which is desirable in such high-stakes scenarios.

Estimating the impact of continuous treatment variables (e.g., dosage amount) on binary outcomes presents significant challenges in modeling and estimation because many existing approaches make strong assumptions that do not hold for certain continuous treatment variables. For instance, traditional logistic regression makes strong linearity assumptions that do not hold for continuous treatment variables like time of initiation. In this work, we propose a semiparametric regression framework that decomposes effects into two interpretable components: a prognostic score that captures baseline outcome risk based on a combination of clinical, genetic, and sociodemographic features, and a treatment-interaction score that flexibly models the optimal treatment level via a nonparametric link function. By connecting these two parametric scores with Nadaraya-Watson regression, our approach is both interpretable and flexible. The potential of our approach is demonstrated through numerical simulations that show empirical estimation convergence. We conclude by applying our approach to a real-world case study using the International Warfarin Pharmacogenomics Consortium (IWPC) dataset to show our approach's clinical utility by deriving personalized warfarin dosing recommendations that integrate both genetic and clinical data, providing insights towards enhancing patient safety and therapeutic efficacy in anticoagulation therapy.

Heart disease, also known as cardiovascular disease, is a prevalent and critical medical condition characterized by the impairment of the heart and blood vessels, leading to various complications such as coronary artery disease, heart failure, and myocardial infarction. The timely and accurate detection of heart disease is of paramount importance in clinical practice. Early identification of individuals at risk enables proactive interventions, preventive measures, and personalized treatment strategies to mitigate the progression of the disease and reduce adverse outcomes. In recent years, the field of heart disease detection has witnessed notable advancements due to the integration of sophisticated technologies and computational approaches. These include machine learning algorithms, data mining techniques, and predictive modeling frameworks that leverage vast amounts of clinical and physiological data to improve diagnostic accuracy and risk stratification. In this work, we propose to detect heart disease from ECG images using cutting-edge technologies, namely vision transformer models. These models are Google-Vit, Microsoft-Beit, and Swin-Tiny. To the best of our knowledge, this is the initial endeavor concentrating on the detection of heart diseases through image-based ECG data by employing cuttingedge technologies namely, transformer models. To demonstrate the contribution of the proposed framework, the performance of vision transformer models are compared with state-of-the-art studies. Experiment results show that the proposed framework exhibits remarkable classification results.

Multi-modal large language models (MM-LLMs) have shown strong performance in medical image understanding and clinical reasoning. Recent medical agent systems extend them with tool use and multi-agent collaboration, enabling complex decision-making. However, these systems rely almost entirely on frontier models (e.g., GPT), whose API-based deployment incurs high cost, high latency, and privacy risks that conflict with on-premise clinical requirements. We present Meissa, a lightweight 4B-parameter medical MM-LLM that brings agentic capability offline. Instead of imitating static answers, Meissa learns both when to engage external interaction (strategy selection) and how to execute multi-step interaction (strategy execution) by distilling structured trajectories from frontier models. Specifically, we propose: (1) Unified trajectory modeling: trajectories (reasoning and action traces) are represented within a single state-action-observation formalism, allowing one model to generalize across heterogeneous medical environments. (2) Three-tier stratified supervision: the model's own errors trigger progressive escalation from direct reasoning to tool-augmented and multi-agent interaction, explicitly learning difficulty-aware strategy selection. (3) Prospective-retrospective supervision: pairing exploratory forward traces with hindsight-rationalized execution traces enables stable learning of effective interaction policies. Trained on 40K curated trajectories, Meissa matches or exceeds proprietary frontier agents in 10 of 16 evaluation settings across 13 medical benchmarks spanning radiology, pathology, and clinical reasoning. Using over 25x fewer parameters than typical frontier models like Gemini-3, Meissa operates fully offline with 22x lower end-to-end latency compared to API-based deployment. Data, models, and environments are released at https://github.com/Schuture/Meissa.

We introduce CheXGenBench, a rigorous and multifaceted evaluation framework for synthetic chest radiograph generation that simultaneously assesses fidelity, privacy risks, and clinical utility across state-of-the-art text-to-image generative models. Despite rapid advancements in generative AI for real-world imagery, medical domain evaluations have been hindered by methodological inconsistencies, outdated architectural comparisons, and disconnected assessment criteria that rarely address the practical clinical value of synthetic samples. CheXGenBench overcomes these limitations through standardised data partitioning and a unified evaluation protocol comprising over 20 quantitative metrics that systematically analyse generation quality, potential privacy vulnerabilities, and downstream clinical applicability across 11 leading text-to-image architectures. Our results reveal critical inefficiencies in the existing evaluation protocols, particularly in assessing generative fidelity, leading to inconsistent and uninformative comparisons. Our framework establishes a standardised benchmark for the medical AI community, enabling objective and reproducible comparisons while facilitating seamless integration of both existing and future generative models. Additionally, we release a high-quality, synthetic dataset, SynthCheX-75K, comprising 75K radiographs generated by the top-performing model (Sana 0.6B) in our benchmark to support further research in this critical domain. Through CheXGenBench, we establish a new state-of-the-art and release our framework, models, and SynthCheX-75K dataset at https://raman1121.github.io/CheXGenBench/

Deep neural networks excel in radiological image classification but frequently suffer from poor interpretability, limiting clinical acceptance. We present MedicalPatchNet, an inherently self-explainable architecture for chest X-ray classification that transparently attributes decisions to distinct image regions. MedicalPatchNet splits images into non-overlapping patches, independently classifies each patch, and aggregates predictions, enabling intuitive visualization of each patch's diagnostic contribution without post-hoc techniques. Trained on the CheXpert dataset (223,414 images), MedicalPatchNet matches the classification performance (AUROC 0.907 vs. 0.908) of EfficientNet-B0, while substantially improving interpretability: MedicalPatchNet demonstrates substantially improved interpretability with higher pathology localization accuracy (mean hit-rate 0.485 vs. 0.376 with Grad-CAM) on the CheXlocalize dataset. By providing explicit, reliable explanations accessible even to non-AI experts, MedicalPatchNet mitigates risks associated with shortcut learning, thus improving clinical trust. Our model is publicly available with reproducible training and inference scripts and contributes to safer, explainable AI-assisted diagnostics across medical imaging domains. We make the code publicly available: https://github.com/TruhnLab/MedicalPatchNet

This paper presents a differentially private approach to Kaplan-Meier estimation that achieves accurate survival probability estimates while safeguarding individual privacy. The Kaplan-Meier estimator is widely used in survival analysis to estimate survival functions over time, yet applying it to sensitive datasets, such as clinical records, risks revealing private information. To address this, we introduce a novel algorithm that applies time-indexed Laplace noise, dynamic clipping, and smoothing to produce a privacy-preserving survival curve while maintaining the cumulative structure of the Kaplan-Meier estimator. By scaling noise over time, the algorithm accounts for decreasing sensitivity as fewer individuals remain at risk, while dynamic clipping and smoothing prevent extreme values and reduce fluctuations, preserving the natural shape of the survival curve. Our results, evaluated on the NCCTG lung cancer dataset, show that the proposed method effectively lowers root mean squared error (RMSE) and enhances accuracy across privacy budgets (epsilon). At epsilon = 10, the algorithm achieves an RMSE as low as 0.04, closely approximating non-private estimates. Additionally, membership inference attacks reveal that higher epsilon values (e.g., epsilon geq 6) significantly reduce influential points, particularly at higher thresholds, lowering susceptibility to inference attacks. These findings confirm that our approach balances privacy and utility, advancing privacy-preserving survival analysis.

Linguistic expressions of emotions such as depression, anxiety, and trauma-related states are pervasive in clinical notes, counseling dialogues, and online mental health communities, and accurate recognition of these emotions is essential for clinical triage, risk assessment, and timely intervention. Although large language models (LLMs) have demonstrated strong generalization ability in emotion analysis tasks, their diagnostic reliability in high-stakes, context-intensive medical settings remains highly sensitive to prompt design. Moreover, existing methods face two key challenges: emotional comorbidity, in which multiple intertwined emotional states complicate prediction, and inefficient exploration of clinically relevant cues. To address these challenges, we propose APOLO (Automated Prompt Optimization for Linguistic Emotion Diagnosis), a framework that systematically explores a broader and finer-grained prompt space to improve diagnostic efficiency and robustness. APOLO formulates instruction refinement as a Partially Observable Markov Decision Process and adopts a multi-agent collaboration mechanism involving Planner, Teacher, Critic, Student, and Target roles. Within this closed-loop framework, the Planner defines an optimization trajectory, while the Teacher-Critic-Student agents iteratively refine prompts to enhance reasoning stability and effectiveness, and the Target agent determines whether to continue optimization based on performance evaluation. Experimental results show that APOLO consistently improves diagnostic accuracy and robustness across domain-specific and stratified benchmarks, demonstrating a scalable and generalizable paradigm for trustworthy LLM applications in mental healthcare.

Pathology text mining is a challenging task given the reporting variability and constant new findings in cancer sub-type definitions. However, successful text mining of a large pathology database can play a critical role to advance 'big data' cancer research like similarity-based treatment selection, case identification, prognostication, surveillance, clinical trial screening, risk stratification, and many others. While there is a growing interest in developing language models for more specific clinical domains, no pathology-specific language space exist to support the rapid data-mining development in pathology space. In literature, a few approaches fine-tuned general transformer models on specialized corpora while maintaining the original tokenizer, but in fields requiring specialized terminology, these models often fail to perform adequately. We propose PathologyBERT - a pre-trained masked language model which was trained on 347,173 histopathology specimen reports and publicly released in the Huggingface repository. Our comprehensive experiments demonstrate that pre-training of transformer model on pathology corpora yields performance improvements on Natural Language Understanding (NLU) and Breast Cancer Diagnose Classification when compared to nonspecific language models.

Sepsis remains one of the leading causes of mortality in intensive care units, where timely and accurate treatment decisions can significantly impact patient outcomes. In this work, we propose an interpretable decision support framework. Our system integrates four core components: (1) a clustering-based stratification module that categorizes patients into low, intermediate, and high-risk groups upon ICU admission, using clustering with statistical validation; (2) a synthetic data augmentation pipeline leveraging variational autoencoders (VAE) and diffusion models to enrich underrepresented trajectories such as fluid or vasopressor administration; (3) an offline reinforcement learning (RL) agent trained using Advantage Weighted Regression (AWR) with a lightweight attention encoder and supported by an ensemble models for conservative, safety-aware treatment recommendations; and (4) a rationale generation module powered by a multi-modal large language model (LLM), which produces natural-language justifications grounded in clinical context and retrieved expert knowledge. Evaluated on the MIMIC-III and eICU datasets, our approach achieves high treatment accuracy while providing clinicians with interpretable and robust policy recommendations.

Large language models (LLMs) are routinely used by physicians and patients for medical advice, yet their clinical safety profiles remain poorly characterized. We present NOHARM (Numerous Options Harm Assessment for Risk in Medicine), a benchmark using 100 real primary care-to-specialist consultation cases to measure frequency and severity of harm from LLM-generated medical recommendations. NOHARM covers 10 specialties, with 12,747 expert annotations for 4,249 clinical management options. Across 31 LLMs, potential for severe harm from LLM recommendations occurs in up to 22.2% (95% CI 21.6-22.8%) of cases, with harm of omission accounting for 76.6% (95% CI 76.4-76.8%) of errors. Safety performance is only moderately correlated (r = 0.61-0.64) with existing AI and medical knowledge benchmarks. The best models outperform generalist physicians on safety (mean difference 9.7%, 95% CI 7.0-12.5%), and a diverse multi-agent approach improves safety compared to solo models (mean difference 8.0%, 95% CI 4.0-12.1%). Therefore, despite strong performance on existing evaluations, widely used AI models can produce severely harmful medical advice at nontrivial rates, underscoring clinical safety as a distinct performance dimension necessitating explicit measurement.

Large-language models have recently demonstrated impressive zero-shot capabilities in a variety of natural language tasks such as summarization, dialogue generation, and question-answering. Despite many promising applications in clinical medicine, adoption of these models in real-world settings has been largely limited by their tendency to generate incorrect and sometimes even toxic statements. In this study, we develop Almanac, a large language model framework augmented with retrieval capabilities for medical guideline and treatment recommendations. Performance on a novel dataset of clinical scenarios (n = 130) evaluated by a panel of 5 board-certified and resident physicians demonstrates significant increases in factuality (mean of 18% at p-value < 0.05) across all specialties, with improvements in completeness and safety. Our results demonstrate the potential for large language models to be effective tools in the clinical decision-making process, while also emphasizing the importance of careful testing and deployment to mitigate their shortcomings.

Adverse drug events (ADEs) significantly impact clinical research, causing many clinical trial failures. ADE prediction is key for developing safer medications and enhancing patient outcomes. To support this effort, we introduce CT-ADE, a dataset for multilabel predictive modeling of ADEs in monopharmacy treatments. CT-ADE integrates data from 2,497 unique drugs, encompassing 168,984 drug-ADE pairs extracted from clinical trials, annotated with patient and contextual information, and comprehensive ADE concepts standardized across multiple levels of the MedDRA ontology. Preliminary analyses with large language models (LLMs) achieved F1-scores up to 55.90%. Models using patient and contextual information showed F1-score improvements of 21%-38% over models using only chemical structure data. Our results highlight the importance of target population and treatment regimens in the predictive modeling of ADEs, offering greater performance gains than LLM domain specialization and scaling. CT-ADE provides an essential tool for researchers aiming to leverage artificial intelligence and machine learning to enhance patient safety and minimize the impact of ADEs on pharmaceutical research and development. The dataset is publicly accessible at https://github.com/ds4dh/CT-ADE.

Cardiotoxicity induced by the breast cancer treatments (i.e., chemotherapy, targeted therapy and radiation therapy) is a significant problem for breast cancer patients. The cardiotoxicity risk for breast cancer patients receiving different treatments remains unclear. We developed and evaluated risk predictive models for cardiotoxicity in breast cancer patients using EHR data. The AUC scores to predict the CHF, CAD, CM and MI are 0.846, 0.857, 0.858 and 0.804 respectively. After adjusting for baseline differences in cardiovascular health, patients who received chemotherapy or targeted therapy appeared to have higher risk of cardiotoxicity than patients who received radiation therapy. Due to differences in baseline cardiac health across the different breast cancer treatment groups, caution is recommended in interpreting the cardiotoxic effect of these treatments.

Large Language Models (LLMs) hold great promise to revolutionize current clinical systems for their superior capacities on medical text processing tasks and medical licensing exams. Meanwhile, traditional ML models such as SVM and XGBoost have still been mainly adopted in clinical prediction tasks. An emerging question is Can LLMs beat traditional ML models in clinical prediction? Thus, we build a new benchmark ClinicalBench to comprehensively study the clinical predictive modeling capacities of both general-purpose and medical LLMs, and compare them with traditional ML models. ClinicalBench embraces three common clinical prediction tasks, two databases, 14 general-purpose LLMs, 8 medical LLMs, and 11 traditional ML models. Through extensive empirical investigation, we discover that both general-purpose and medical LLMs, even with different model scales, diverse prompting or fine-tuning strategies, still cannot beat traditional ML models in clinical prediction yet, shedding light on their potential deficiency in clinical reasoning and decision-making. We call for caution when practitioners adopt LLMs in clinical applications. ClinicalBench can be utilized to bridge the gap between LLMs' development for healthcare and real-world clinical practice.

Risk scores are simple classification models that let users make quick risk predictions by adding and subtracting a few small numbers. These models are widely used in medicine and criminal justice, but are difficult to learn from data because they need to be calibrated, sparse, use small integer coefficients, and obey application-specific operational constraints. In this paper, we present a new machine learning approach to learn risk scores. We formulate the risk score problem as a mixed integer nonlinear program, and present a cutting plane algorithm for non-convex settings to efficiently recover its optimal solution. We improve our algorithm with specialized techniques to generate feasible solutions, narrow the optimality gap, and reduce data-related computation. Our approach can fit risk scores in a way that scales linearly in the number of samples, provides a certificate of optimality, and obeys real-world constraints without parameter tuning or post-processing. We benchmark the performance benefits of this approach through an extensive set of numerical experiments, comparing to risk scores built using heuristic approaches. We also discuss its practical benefits through a real-world application where we build a customized risk score for ICU seizure prediction in collaboration with the Massachusetts General Hospital.

Bronchopulmonary dysplasia (BPD) is a chronic lung disease affecting 35% of extremely low birth weight infants. Defined by oxygen dependence at 36 weeks postmenstrual age, it causes lifelong respiratory complications. However, preventive interventions carry severe risks, including neurodevelopmental impairment, ventilator-induced lung injury, and systemic complications. Therefore, early BPD prognosis and prediction of BPD outcome is crucial to avoid unnecessary toxicity in low risk infants. Admission radiographs of extremely preterm infants are routinely acquired within 24h of life and could serve as a non-invasive prognostic tool. In this work, we developed and investigated a deep learning approach using chest X-rays from 163 extremely low-birth-weight infants (leq32 weeks gestation, 401-999g) obtained within 24 hours of birth. We fine-tuned a ResNet-50 pretrained specifically on adult chest radiographs, employing progressive layer freezing with discriminative learning rates to prevent overfitting and evaluated a CutMix augmentation and linear probing. For moderate/severe BPD outcome prediction, our best performing model with progressive freezing, linear probing and CutMix achieved an AUROC of 0.78 pm 0.10, balanced accuracy of 0.69 pm 0.10, and an F1-score of 0.67 pm 0.11. In-domain pre-training significantly outperformed ImageNet initialization (p = 0.031) which confirms domain-specific pretraining to be important for BPD outcome prediction. Routine IRDS grades showed limited prognostic value (AUROC 0.57 pm 0.11), confirming the need of learned markers. Our approach demonstrates that domain-specific pretraining enables accurate BPD prediction from routine day-1 radiographs. Through progressive freezing and linear probing, the method remains computationally feasible for site-level implementation and future federated learning deployments.

Large Language Models (LLMs) and multi-agent systems have shown impressive capabilities in natural language tasks but face challenges in clinical trial applications, primarily due to limited access to external knowledge. Recognizing the potential of advanced clinical trial tools that aggregate and predict based on the latest medical data, we propose an integrated solution to enhance their accessibility and utility. We introduce Clinical Agent System (ClinicalAgent), a clinical multi-agent system designed for clinical trial tasks, leveraging GPT-4, multi-agent architectures, LEAST-TO-MOST, and ReAct reasoning technology. This integration not only boosts LLM performance in clinical contexts but also introduces novel functionalities. The proposed method achieves competitive predictive performance in clinical trial outcome prediction (0.7908 PR-AUC), obtaining a 0.3326 improvement over the standard prompt Method. Publicly available code can be found at https://anonymous.4open.science/r/ClinicalAgent-6671.

Accurate breast lesion risk estimation can significantly reduce unnecessary biopsies and help doctors decide optimal treatment plans. Most existing computer-aided systems rely solely on mammogram features to classify breast lesions. While this approach is convenient, it does not fully exploit useful information in clinical reports to achieve the optimal performance. Would clinical features significantly improve breast lesion classification compared to using mammograms alone? How to handle missing clinical information caused by variation in medical practice? What is the best way to combine mammograms and clinical features? There is a compelling need for a systematic study to address these fundamental questions. This paper investigates several multimodal deep networks based on feature concatenation, cross-attention, and co-attention to combine mammograms and categorical clinical variables. We show that the proposed architectures significantly increase the lesion classification performance (average area under ROC curves from 0.89 to 0.94). We also evaluate the model when clinical variables are missing.

The increasing use of tools and solutions based on Large Language Models (LLMs) for various tasks in the medical domain has become a prominent trend. Their use in this highly critical and sensitive domain has thus raised important questions about their robustness, especially in response to variations in input, and the reliability of the generated outputs. This study addresses these questions by constructing a textual dataset based on the ICD-10-CM code descriptions, widely used in US hospitals and containing many clinical terms, and their easily reproducible rephrasing. We then benchmarked existing embedding models, either generalist or specialized in the clinical domain, in a semantic search task where the goal was to correctly match the rephrased text to the original description. Our results showed that generalist models performed better than clinical models, suggesting that existing clinical specialized models are more sensitive to small changes in input that confuse them. The highlighted problem of specialized models may be due to the fact that they have not been trained on sufficient data, and in particular on datasets that are not diverse enough to have a reliable global language understanding, which is still necessary for accurate handling of medical documents.

Decisions about managing patients on the heart transplant waitlist are currently made by committees of doctors who consider multiple factors, but the process remains largely ad-hoc. With the growing volume of longitudinal patient, donor, and organ data collected by the United Network for Organ Sharing (UNOS) since 2018, there is increasing interest in analytical approaches to support clinical decision-making at the time of organ availability. In this study, we benchmark machine learning models that leverage longitudinal waitlist history data for time-dependent, time-to-event modeling of waitlist mortality. We train on 23,807 patient records with 77 variables and evaluate both survival prediction and discrimination at a 1-year horizon. Our best model achieves a C-Index of 0.94 and AUROC of 0.89, significantly outperforming previous models. Key predictors align with known risk factors while also revealing novel associations. Our findings can support urgency assessment and policy refinement in heart transplant decision making.

This paper introduces RiskCards, a framework for structured assessment and documentation of risks associated with an application of language models. As with all language, text generated by language models can be harmful, or used to bring about harm. Automating language generation adds both an element of scale and also more subtle or emergent undesirable tendencies to the generated text. Prior work establishes a wide variety of language model harms to many different actors: existing taxonomies identify categories of harms posed by language models; benchmarks establish automated tests of these harms; and documentation standards for models, tasks and datasets encourage transparent reporting. However, there is no risk-centric framework for documenting the complexity of a landscape in which some risks are shared across models and contexts, while others are specific, and where certain conditions may be required for risks to manifest as harms. RiskCards address this methodological gap by providing a generic framework for assessing the use of a given language model in a given scenario. Each RiskCard makes clear the routes for the risk to manifest harm, their placement in harm taxonomies, and example prompt-output pairs. While RiskCards are designed to be open-source, dynamic and participatory, we present a "starter set" of RiskCards taken from a broad literature survey, each of which details a concrete risk presentation. Language model RiskCards initiate a community knowledge base which permits the mapping of risks and harms to a specific model or its application scenario, ultimately contributing to a better, safer and shared understanding of the risk landscape.

The global cost of drug discovery and development exceeds $200 billion annually. The main results of drug discovery and development are the outcomes of clinical trials, which directly influence the regulatory approval of new drug candidates and ultimately affect patient outcomes. Despite their significance, large-scale, high-quality clinical trial outcome data are not readily available to the public. Suppose a large clinical trial outcome dataset is provided; machine learning researchers can potentially develop accurate prediction models using past trials and outcome labels, which could help prioritize and optimize therapeutic programs, ultimately benefiting patients. This paper introduces Clinical Trial Outcome (CTO) dataset, the largest trial outcome dataset with around 479K clinical trials, aggregating outcomes from multiple sources of weakly supervised labels, minimizing the noise from individual sources, and eliminating the need for human annotation. These sources include large language model (LLM) decisions on trial-related documents, news headline sentiments, stock prices of trial sponsors, trial linkages across phases, and other signals such as patient dropout rates and adverse events. CTO's labels show unprecedented agreement with supervised clinical trial outcome labels from test split of the supervised TOP dataset, with a 91 F1.

Clinical natural language processing requires methods that can address domain-specific challenges, such as complex medical terminology and clinical contexts. Recently, large language models (LLMs) have shown promise in this domain. Yet, their direct deployment can lead to privacy issues and are constrained by resources. To address this challenge, we delve into synthetic clinical text generation using LLMs for clinical NLP tasks. We propose an innovative, resource-efficient approach, ClinGen, which infuses knowledge into the process. Our model involves clinical knowledge extraction and context-informed LLM prompting. Both clinical topics and writing styles are drawn from external domain-specific knowledge graphs and LLMs to guide data generation. Our extensive empirical study across 7 clinical NLP tasks and 16 datasets reveals that ClinGen consistently enhances performance across various tasks, effectively aligning the distribution of real datasets and significantly enriching the diversity of generated training instances. We will publish our code and all the generated data in https://github.com/ritaranx/ClinGen.

As the performance of large language models (LLMs) continues to advance, their adoption is expanding across a wide range of domains, including the medical field. The integration of LLMs into medical applications raises critical safety concerns, particularly due to their use by users with diverse roles, e.g. patients and clinicians, and the potential for model's outputs to directly affect human health. Despite the domain-specific capabilities of medical LLMs, prior safety evaluations have largely focused only on general safety benchmarks. In this paper, we introduce a safety evaluation protocol tailored to the medical domain in both patient user and clinician user perspectives, alongside general safety assessments and quantitatively analyze the safety of medical LLMs. We bridge a gap in the literature by building the PatientSafetyBench containing 466 samples over 5 critical categories to measure safety from the perspective of the patient. We apply our red-teaming protocols on the MediPhi model collection as a case study. To our knowledge, this is the first work to define safety evaluation criteria for medical LLMs through targeted red-teaming taking three different points of view - patient, clinician, and general user - establishing a foundation for safer deployment in medical domains.

The objective of this paper is to understand what characteristics and features of clinical data influence physician's decision about ordering laboratory tests or prescribing medications the most. We conduct our analysis on data and decisions extracted from electronic health records of 4486 post-surgical cardiac patients. The summary statistics for 335 different lab order decisions and 407 medication decisions are reported. We show that in many cases, physician's lab-order and medication decisions can be well predicted from a small subset of all features.

Clinical trials disruption has always represented a non negligible part of the ending of interventional studies. While the SARS-CoV-2 (COVID-19) pandemic has led to an impressive and unprecedented initiation of clinical research, it has also led to considerable disruption of clinical trials in other disease areas, with around 80% of non-COVID-19 trials stopped or interrupted during the pandemic. In many cases the disrupted trials will not have the planned statistical power necessary to yield interpretable results. This paper describes methods to compensate for the information loss arising from trial disruptions by incorporating additional information available from auxiliary data sources. The methods described include the use of auxiliary data on baseline and early outcome data available from the trial itself and frequentist and Bayesian approaches for the incorporation of information from external data sources. The methods are illustrated by application to the analysis of artificial data based on the Primary care pediatrics Learning Activity Nutrition (PLAN) study, a clinical trial assessing a diet and exercise intervention for overweight children, that was affected by the COVID-19 pandemic. We show how all of the methods proposed lead to an increase in precision relative to use of complete case data only.

Generative models trained using self-supervision of tokenized electronic health record (EHR) timelines show promise for clinical outcome prediction. This is typically done using Monte Carlo simulation for future patient trajectories. However, existing approaches suffer from three key limitations: sparse estimate distributions that poorly differentiate patient risk levels, extreme computational costs, and high sampling variance. We propose two new estimators: the Sum of Conditional Outcome Probability Estimator (SCOPE) and Risk Estimation from Anticipated Conditional Hazards (REACH), that leverage next-token probability distributions discarded by standard Monte Carlo. We prove both estimators are unbiased and that REACH guarantees variance reduction over Monte Carlo sampling for any model and outcome. Empirically, on hospital mortality prediction in MIMIC-IV using the ETHOS-ARES framework, SCOPE and REACH match 100-sample Monte Carlo performance using only 10-11 samples (95% CI: [9,11]), representing a ~10x reduction in inference cost without degrading calibration. For ICU admission prediction, efficiency gains are more modest (~1.2x), which we attribute to the outcome's lower "spontaneity," a property we characterize theoretically and empirically. These methods substantially improve the feasibility of deploying generative EHR models in resource-constrained clinical settings.

Clinical evidence, derived from rigorous research and data analysis, provides healthcare professionals with reliable scientific foundations for informed decision-making. Integrating clinical evidence into real-time practice is challenging due to the enormous workload, complex professional processes, and time constraints. This highlights the need for tools that automate evidence synthesis to support more efficient and accurate decision making in clinical settings. This study introduces Quicker, an evidence-based clinical decision support system powered by large language models (LLMs), designed to automate evidence synthesis and generate clinical recommendations modeled after standard clinical guideline development processes. Quicker implements a fully automated chain that covers all phases, from questions to clinical recommendations, and further enables customized decision-making through integrated tools and interactive user interfaces. To evaluate Quicker's capabilities, we developed the Q2CRBench-3 benchmark dataset, based on clinical guideline development records for three different diseases. Experimental results highlighted Quicker's strong performance, with fine-grained question decomposition tailored to user preferences, retrieval sensitivities comparable to human experts, and literature screening performance approaching comprehensive inclusion of relevant studies. In addition, Quicker-assisted evidence assessment effectively supported human reviewers, while Quicker's recommendations were more comprehensive and logically coherent than those of clinicians. In system-level testing, collaboration between a single reviewer and Quicker reduced the time required for recommendation development to 20-40 minutes. In general, our findings affirm the potential of Quicker to help physicians make quicker and more reliable evidence-based clinical decisions.

Numerous medical systems powered by Large Language Models (LLMs) have achieved remarkable progress in diverse healthcare tasks. However, research on their medication safety remains limited due to the lack of real world datasets, constrained by privacy and accessibility issues. Moreover, evaluation of LLMs in realistic clinical consultation settings, particularly regarding medication safety, is still underexplored. To address these gaps, we propose a framework that simulates and evaluates clinical consultations to systematically assess the medication safety capabilities of LLMs. Within this framework, we generate inquiry diagnosis dialogues with embedded medication risks and construct a dedicated medication safety database, RxRisk DB, containing 6,725 contraindications, 28,781 drug interactions, and 14,906 indication-drug pairs. A two-stage filtering strategy ensures clinical realism and professional quality, resulting in the benchmark RxSafeBench with 2,443 high-quality consultation scenarios. We evaluate leading open-source and proprietary LLMs using structured multiple choice questions that test their ability to recommend safe medications under simulated patient contexts. Results show that current LLMs struggle to integrate contraindication and interaction knowledge, especially when risks are implied rather than explicit. Our findings highlight key challenges in ensuring medication safety in LLM-based systems and provide insights into improving reliability through better prompting and task-specific tuning. RxSafeBench offers the first comprehensive benchmark for evaluating medication safety in LLMs, advancing safer and more trustworthy AI-driven clinical decision support.

With the increasing availability of wearable devices, photoplethysmography (PPG) has emerged as a promising non-invasive tool for monitoring human hemodynamics. We propose a deep learning framework to estimate vascular age (AI-vascular age) from PPG signals, incorporating a distribution-aware loss to address biases caused by imbalanced data. The model was developed using data from the UK Biobank (UKB), with 98,672 participants in the development cohort and 113,559 participants (144,683 data pairs) for clinical evaluation. After adjusting for key confounders, individuals with a vascular age gap (AI-vascular age minus calendar age) exceeding 9 years had a significantly higher risk of major adverse cardiovascular and cerebrovascular events (MACCE) (HR = 2.37, p < 0.005) and secondary outcomes, including diabetes (HR = 2.69, p < 0.005), hypertension (HR = 2.88, p < 0.005), coronary heart disease (HR = 2.20, p < 0.005), heart failure (HR = 2.15, p < 0.005), myocardial infarction (HR = 2.51, p < 0.005), stroke (HR = 2.55, p < 0.005), and all-cause mortality (HR = 2.51, p < 0.005). Conversely, participants with a vascular age gap below -9 years exhibited a significantly lower incidence of these outcomes. We further evaluated the longitudinal applicability of AI-vascular age using serial PPG data from the UKB, demonstrating its value in risk stratification by leveraging AI-vascular age at two distinct time points to predict future MACCE incidence. External validation was performed on a MIMIC-III-derived cohort (n = 2,343), where each one-year increase in vascular age gap was significantly associated with elevated in-hospital mortality risk (OR = 1.02, p < 0.005). In conclusion, our study establishes AI-vascular age as a novel, non-invasive digital biomarker for cardiovascular health assessment.

Large language models have the potential to be valuable in the healthcare industry, but it's crucial to verify their safety and effectiveness through rigorous evaluation. For this purpose, we comprehensively evaluated both open-source LLMs and Google's new multimodal LLM called Gemini across Medical reasoning, hallucination detection, and Medical Visual Question Answering tasks. While Gemini showed competence, it lagged behind state-of-the-art models like MedPaLM 2 and GPT-4 in diagnostic accuracy. Additionally, Gemini achieved an accuracy of 61.45\% on the medical VQA dataset, significantly lower than GPT-4V's score of 88\%. Our analysis revealed that Gemini is highly susceptible to hallucinations, overconfidence, and knowledge gaps, which indicate risks if deployed uncritically. We also performed a detailed analysis by medical subject and test type, providing actionable feedback for developers and clinicians. To mitigate risks, we applied prompting strategies that improved performance. Additionally, we facilitated future research and development by releasing a Python module for medical LLM evaluation and establishing a dedicated leaderboard on Hugging Face for medical domain LLMs. Python module can be found at https://github.com/promptslab/RosettaEval

Machine learning models are often trained to predict the outcome resulting from a human decision. For example, if a doctor decides to test a patient for disease, will the patient test positive? A challenge is that historical decision-making determines whether the outcome is observed: we only observe test outcomes for patients doctors historically tested. Untested patients, for whom outcomes are unobserved, may differ from tested patients along observed and unobserved dimensions. We propose a Bayesian model class which captures this setting. The purpose of the model is to accurately estimate risk for both tested and untested patients. Estimating this model is challenging due to the wide range of possibilities for untested patients. To address this, we propose two domain constraints which are plausible in health settings: a prevalence constraint, where the overall disease prevalence is known, and an expertise constraint, where the human decision-maker deviates from purely risk-based decision-making only along a constrained feature set. We show theoretically and on synthetic data that domain constraints improve parameter inference. We apply our model to a case study of cancer risk prediction, showing that the model's inferred risk predicts cancer diagnoses, its inferred testing policy captures known public health policies, and it can identify suboptimalities in test allocation. Though our case study is in healthcare, our analysis reveals a general class of domain constraints which can improve model estimation in many settings.

Quantitative tools are increasingly appealing for decision support in healthcare, driven by the growing capabilities of advanced AI systems. However, understanding the predictive uncertainties surrounding a tool's output is crucial for decision-makers to ensure reliable and transparent decisions. In this paper, we present a case study on pulmonary nodule detection for lung cancer screening, enhancing an advanced detection model with an uncertainty quantification technique called conformal risk control (CRC). We demonstrate that prediction sets with conformal guarantees are attractive measures of predictive uncertainty in the safety-critical healthcare domain, allowing end-users to achieve arbitrary validity by trading off false positives and providing formal statistical guarantees on model performance. Among ground-truth nodules annotated by at least three radiologists, our model achieves a sensitivity that is competitive with that generally achieved by individual radiologists, with a slight increase in false positives. Furthermore, we illustrate the risks of using off-the-shelve prediction models when faced with ontological uncertainty, such as when radiologists disagree on what constitutes the ground truth on pulmonary nodules.

Learning to represent free text is a core task in many clinical machine learning (ML) applications, as clinical text contains observations and plans not otherwise available for inference. State-of-the-art methods use large language models developed with immense computational resources and training data; however, applying these models is challenging because of the highly varying syntax and vocabulary in clinical free text. Structured information such as International Classification of Disease (ICD) codes often succinctly abstracts the most important facts of a clinical encounter and yields good performance, but is often not as available as clinical text in real-world scenarios. We propose a multi-view learning framework that jointly learns from codes and text to combine the availability and forward-looking nature of text and better performance of ICD codes. The learned text embeddings can be used as inputs to predictive algorithms independent of the ICD codes during inference. Our approach uses a Graph Neural Network (GNN) to process ICD codes, and Bi-LSTM to process text. We apply Deep Canonical Correlation Analysis (DCCA) to enforce the two views to learn a similar representation of each patient. In experiments using planned surgical procedure text, our model outperforms BERT models fine-tuned to clinical data, and in experiments using diverse text in MIMIC-III, our model is competitive to a fine-tuned BERT at a tiny fraction of its computational effort.

Many clinical tasks require an understanding of specialized data, such as medical images and genomics, which is not typically found in general-purpose large multimodal models. Building upon Gemini's multimodal models, we develop several models within the new Med-Gemini family that inherit core capabilities of Gemini and are optimized for medical use via fine-tuning with 2D and 3D radiology, histopathology, ophthalmology, dermatology and genomic data. Med-Gemini-2D sets a new standard for AI-based chest X-ray (CXR) report generation based on expert evaluation, exceeding previous best results across two separate datasets by an absolute margin of 1% and 12%, where 57% and 96% of AI reports on normal cases, and 43% and 65% on abnormal cases, are evaluated as "equivalent or better" than the original radiologists' reports. We demonstrate the first ever large multimodal model-based report generation for 3D computed tomography (CT) volumes using Med-Gemini-3D, with 53% of AI reports considered clinically acceptable, although additional research is needed to meet expert radiologist reporting quality. Beyond report generation, Med-Gemini-2D surpasses the previous best performance in CXR visual question answering (VQA) and performs well in CXR classification and radiology VQA, exceeding SoTA or baselines on 17 of 20 tasks. In histopathology, ophthalmology, and dermatology image classification, Med-Gemini-2D surpasses baselines across 18 out of 20 tasks and approaches task-specific model performance. Beyond imaging, Med-Gemini-Polygenic outperforms the standard linear polygenic risk score-based approach for disease risk prediction and generalizes to genetically correlated diseases for which it has never been trained. Although further development and evaluation are necessary in the safety-critical medical domain, our results highlight the potential of Med-Gemini across a wide range of medical tasks.