Department of Biomedical Informatics and Data Science, Yale School of Medicine, New Haven, CT
Abstract:Objective: Large language models (LLMs) are increasingly applied in biomedical settings, and existing benchmark datasets have played an important role in supporting model development and evaluation. However, these benchmarks often have limitations. Many rely on static or outdated datasets that fail to capture the dynamic, context-rich, and high-stakes nature of biomedical knowledge. They also carry increasing risk of data leakage due to overlap with model pretraining corpora and often overlook critical dimensions such as robustness to linguistic variation and potential demographic biases. Materials and Methods: To address these gaps, we introduce BioPulse-QA, a benchmark that evaluates LLMs on answering questions from newly published biomedical documents including drug labels, trial protocols, and clinical guidelines. BioPulse-QA includes 2,280 expert-verified question answering (QA) pairs and perturbed variants, covering both extractive and abstractive formats. We evaluate four LLMs - GPT-4o, GPT-o1, Gemini-2.0-Flash, and LLaMA-3.1 8B Instruct - released prior to the publication dates of the benchmark documents. Results: GPT-o1 achieves the highest relaxed F1 score (0.92), followed by Gemini-2.0-Flash (0.90) on drug labels. Clinical trials are the most challenging source, with extractive F1 scores as low as 0.36. Discussion and Conclusion: Performance differences are larger for paraphrasing than for typographical errors, while bias testing shows negligible differences. BioPulse-QA provides a scalable and clinically relevant framework for evaluating biomedical LLMs.
Abstract:Clinical decision-making increasingly relies on timely and context-aware access to patient information within Electronic Health Records (EHRs), yet most existing natural language question-answering (QA) systems are evaluated solely on benchmark datasets, limiting their practical relevance. To overcome this limitation, we introduce EHRNavigator, a multi-agent framework that harnesses AI agents to perform patient-level question answering across heterogeneous and multimodal EHR data. We assessed its performance using both public benchmark and institutional datasets under realistic hospital conditions characterized by diverse schemas, temporal reasoning demands, and multimodal evidence integration. Through quantitative evaluation and clinician-validated chart review, EHRNavigator demonstrated strong generalization, achieving 86% accuracy on real-world cases while maintaining clinically acceptable response times. Overall, these findings confirm that EHRNavigator effectively bridges the gap between benchmark evaluation and clinical deployment, offering a robust, adaptive, and efficient solution for real-world EHR question answering.
Abstract:Understanding how individuals with Parkinson's disease (PD) describe cognitive experiences in their daily lives can offer valuable insights into disease-related cognitive and emotional changes. However, extracting such information from unstructured patient narratives is challenging due to the subtle, overlapping nature of cognitive constructs. This study developed and evaluated natural language processing (NLP) models to automatically identify categories that reflect various cognitive processes from de-identified first-person narratives. Three model families, a Bio_ClinicalBERT-based span categorization model for nested entity recognition, a fine-tuned Meta-Llama-3-8B-Instruct model using QLoRA for instruction following, and GPT-4o mini evaluated under zero- and few-shot settings, were compared on their performance on extracting seven categories. Our findings indicated that model performance varied substantially across categories and model families. The fine-tuned Meta-Llama-3-8B-Instruct achieved the highest overall F1-scores (0.74 micro-average and 0.59 macro-average), particularly excelling in context-dependent categories such as thought and social interaction. Bio_ClinicalBERT exhibited high precision but low recall and performed comparable to Llama for some category types such as location and time but failed on other categories such as thought, emotion and social interaction. Compared to conventional information extraction tasks, this task presents a greater challenge due to the abstract and overlapping nature of narrative accounts of complex cognitive processes. Nonetheless, with continued refinement, these NLP systems hold promise for enabling low-burden, longitudinal monitoring of cognitive function and serving as a valuable complement to formal neuropsychological assessments in PD.
Abstract:Large language models (LLMs) are transforming the landscape of medicine, yet two fundamental challenges persist: keeping up with rapidly evolving medical knowledge and providing verifiable, evidence-grounded reasoning. Retrieval-augmented generation (RAG) has been widely adopted to address these limitations by supplementing model outputs with retrieved evidence. However, whether RAG reliably achieves these goals remains unclear. Here, we present the most comprehensive expert evaluation of RAG in medicine to date. Eighteen medical experts contributed a total of 80,502 annotations, assessing 800 model outputs generated by GPT-4o and Llama-3.1-8B across 200 real-world patient and USMLE-style queries. We systematically decomposed the RAG pipeline into three components: (i) evidence retrieval (relevance of retrieved passages), (ii) evidence selection (accuracy of evidence usage), and (iii) response generation (factuality and completeness of outputs). Contrary to expectation, standard RAG often degraded performance: only 22% of top-16 passages were relevant, evidence selection remained weak (precision 41-43%, recall 27-49%), and factuality and completeness dropped by up to 6% and 5%, respectively, compared with non-RAG variants. Retrieval and evidence selection remain key failure points for the model, contributing to the overall performance drop. We further show that simple yet effective strategies, including evidence filtering and query reformulation, substantially mitigate these issues, improving performance on MedMCQA and MedXpertQA by up to 12% and 8.2%, respectively. These findings call for re-examining RAG's role in medicine and highlight the importance of stage-aware evaluation and deliberate system design for reliable medical LLM applications.




Abstract:Directly solving large-scale Integer Linear Programs (ILPs) using traditional solvers is slow due to their NP-hard nature. While recent frameworks based on Large Neighborhood Search (LNS) can accelerate the solving process, their performance is often constrained by the difficulty in generating sufficiently effective neighborhoods. To address this challenge, we propose HyP-ASO, a hybrid policy-based adaptive search optimization framework that combines a customized formula with deep Reinforcement Learning (RL). The formula leverages feasible solutions to calculate the selection probabilities for each variable in the neighborhood generation process, and the RL policy network predicts the neighborhood size. Extensive experiments demonstrate that HyP-ASO significantly outperforms existing LNS-based approaches for large-scale ILPs. Additional experiments show it is lightweight and highly scalable, making it well-suited for solving large-scale ILPs.




Abstract:Sample size calculations for power analysis are critical for clinical research and trial design, yet their complexity and reliance on statistical expertise create barriers for many researchers. We introduce PowerGPT, an AI-powered system integrating large language models (LLMs) with statistical engines to automate test selection and sample size estimation in trial design. In a randomized trial to evaluate its effectiveness, PowerGPT significantly improved task completion rates (99.3% vs. 88.9% for test selection, 99.3% vs. 77.8% for sample size calculation) and accuracy (94.1% vs. 55.4% in sample size estimation, p < 0.001), while reducing average completion time (4.0 vs. 9.3 minutes, p < 0.001). These gains were consistent across various statistical tests and benefited both statisticians and non-statisticians as well as bridging expertise gaps. Already under deployment across multiple institutions, PowerGPT represents a scalable AI-driven approach that enhances accessibility, efficiency, and accuracy in statistical power analysis for clinical research.
Abstract:Large Language Models (LLMs) have demonstrated significant potential in medicine. To date, LLMs have been widely applied to tasks such as diagnostic assistance, medical question answering, and clinical information synthesis. However, a key open question remains: to what extent do LLMs memorize medical training data. In this study, we present the first comprehensive evaluation of memorization of LLMs in medicine, assessing its prevalence (how frequently it occurs), characteristics (what is memorized), volume (how much content is memorized), and potential downstream impacts (how memorization may affect medical applications). We systematically analyze common adaptation scenarios: (1) continued pretraining on medical corpora, (2) fine-tuning on standard medical benchmarks, and (3) fine-tuning on real-world clinical data, including over 13,000 unique inpatient records from Yale New Haven Health System. The results demonstrate that memorization is prevalent across all adaptation scenarios and significantly higher than reported in the general domain. Memorization affects both the development and adoption of LLMs in medicine and can be categorized into three types: beneficial (e.g., accurate recall of clinical guidelines and biomedical references), uninformative (e.g., repeated disclaimers or templated medical document language), and harmful (e.g., regeneration of dataset-specific or sensitive clinical content). Based on these findings, we offer practical recommendations to facilitate beneficial memorization that enhances domain-specific reasoning and factual accuracy, minimize uninformative memorization to promote deeper learning beyond surface-level patterns, and mitigate harmful memorization to prevent the leakage of sensitive or identifiable patient information.




Abstract:Suicide remains a pressing global health crisis, with over 720,000 deaths annually and millions more affected by suicide ideation (SI) and suicide attempts (SA). Early identification of suicidality-related factors (SrFs), including SI, SA, exposure to suicide (ES), and non-suicidal self-injury (NSSI), is critical for timely intervention. While prior studies have applied AI to detect SrFs in clinical notes, most treat suicidality as a binary classification task, overlooking the complexity of cooccurring risk factors. This study explores the use of generative large language models (LLMs), specifically GPT-3.5 and GPT-4.5, for multi-label classification (MLC) of SrFs from psychiatric electronic health records (EHRs). We present a novel end to end generative MLC pipeline and introduce advanced evaluation methods, including label set level metrics and a multilabel confusion matrix for error analysis. Finetuned GPT-3.5 achieved top performance with 0.94 partial match accuracy and 0.91 F1 score, while GPT-4.5 with guided prompting showed superior performance across label sets, including rare or minority label sets, indicating a more balanced and robust performance. Our findings reveal systematic error patterns, such as the conflation of SI and SA, and highlight the models tendency toward cautious over labeling. This work not only demonstrates the feasibility of using generative AI for complex clinical classification tasks but also provides a blueprint for structuring unstructured EHR data to support large scale clinical research and evidence based medicine.
Abstract:Irregular Multivariate Time Series (IMTS) forecasting is challenging due to the unaligned nature of multi-channel signals and the prevalence of extensive missing data. Existing methods struggle to capture reliable temporal patterns from such data due to significant missing values. While pre-trained foundation models show potential for addressing these challenges, they are typically designed for Regularly Sampled Time Series (RTS). Motivated by the visual Mask AutoEncoder's (MAE) powerful capability for modeling sparse multi-channel information and its success in RTS forecasting, we propose VIMTS, a framework adapting Visual MAE for IMTS forecasting. To mitigate the effect of missing values, VIMTS first processes IMTS along the timeline into feature patches at equal intervals. These patches are then complemented using learned cross-channel dependencies. Then it leverages visual MAE's capability in handling sparse multichannel data for patch reconstruction, followed by a coarse-to-fine technique to generate precise predictions from focused contexts. In addition, we integrate self-supervised learning for improved IMTS modeling by adapting the visual MAE to IMTS data. Extensive experiments demonstrate VIMTS's superior performance and few-shot capability, advancing the application of visual foundation models in more general time series tasks. Our code is available at https://github.com/WHU-HZY/VIMTS.
Abstract:Mixed-Integer Linear Programming (MILP) is widely used in fields such as scheduling, logistics, and planning. Enhancing the performance of MILP solvers, particularly learning-based solvers, requires substantial amounts of high-quality data. However, existing methods for MILP instance generation typically necessitate training a separate model for each problem class and are computationally intensive when generating new instances. To address these limitations, we reformulate the MILP Instance Generation task as MILP Code Generation task, enabling efficient, flexible, and interpretable instance generation through code. Since MILP instances generated from code can vary significantly in scale, we introduce MILP-EmbedSim, a new similarity metric that accurately measures the similarity between instances of varying sizes within the same problem class. Leveraging this metric, we propose MILP-Retrieval, a pipeline that retrieves generation code from library to produce MILP instances highly similar to target instance. MILP-Retrieval outperforms baselines in both MILP Code Generation and Instance Generation tasks, provides a novel perspective on MILP instance generation and opens new possibilities for learning-based solvers.