A Versatile AI Agent for Rare Disease Diagnosis and Risk Gene Prioritization

Accurate and timely diagnosis is essential for effective treatment, particularly in the context of rare diseases. However, current diagnostic workflows often lead to prolonged assessment times and low accuracy. To address these limitations, we introduce Hygieia, a multi-modal AI agent system designed to support precision disease diagnosis by integrating diverse data sources, including phenotypic features, genetic profiles, and clinical records. Hygieia features a router-based and knowledge-enhanced framework that mitigates hallucination and tailors diagnostic strategies to different disease categories. Notably, it prioritizes risk-related genomic factors for rare diseases and provides confidence scores to assist clinical decision-making. We conducted a comprehensive evaluation demonstrating that Hygieia achieves state-of-the-art performance across multiple diagnostic benchmarks. In collaboration with clinical experts from Yale School of Medicine and Duke-NUS Medical School, we further validated its practical utility by showing (1) Hygieia's superior diagnostic performance compared to physicians with an improvement from 12%-60% and (2) its effectiveness in assisting clinicians with medical records for handling real-world cases. Our findings indicate that Hygieia not only enhances diagnostic accuracy and interpretability but also significantly reduces clinician workload, highlighting its potential as a valuable tool in clinical decision support systems.

Foundation Models to Unlock Real-World Evidence from Nationwide Medical Claims

Evidence derived from large-scale real-world data (RWD) is increasingly informing regulatory evaluation and healthcare decision-making. Administrative claims provide population-scale, longitudinal records of healthcare utilization, expenditure, and detailed coding of diagnoses, procedures, and medications, yet their potential as a substrate for healthcare foundation models remains largely unexplored. Here we present ReClaim, a generative transformer trained from scratch on 43.8 billion medical events from more than 200 million enrollees in the MarketScan claims data spanning 2008-2022. ReClaim models longitudinal trajectories across diagnoses, procedures, medications, and expenditure, and was scaled to 140 million, 700 million, and 1.7 billion parameters. Across over 1,000 disease-onset prediction tasks, ReClaim achieved a mean AUC of 75.6%, substantially outperforming disease-specific LightGBM (66.3%) and the transformer-based Delphi model (69.4%), with the largest gains for rare diseases. These advantages held across retrospective and prospective evaluations and in external validation on two independent datasets. Performance improved monotonically with scale, and post-training added 13.8 percentage points over pre-training alone. Beyond disease prediction, ReClaim captured financial outcomes and improved real-world evidence (RWE) analyses: for healthcare expenditure forecasting it increased explained variance from 0.28 to 0.37 relative to LightGBM, and in a target trial emulation it reduced systematic bias by 72% on average relative to Delphi. Together, these results establish administrative claims as a scalable substrate for healthcare foundation models and show that learned representations generalize across time periods and data sources, supporting disease surveillance, expenditure forecasting, and RWE generation.

A Very Big Video Reasoning Suite

Rapid progress in video models has largely focused on visual quality, leaving their reasoning capabilities underexplored. Video reasoning grounds intelligence in spatiotemporally consistent visual environments that go beyond what text can naturally capture, enabling intuitive reasoning over spatiotemporal structure such as continuity, interaction, and causality. However, systematically studying video reasoning and its scaling behavior is hindered by the lack of large-scale training data. To address this gap, we introduce the Very Big Video Reasoning (VBVR) Dataset, an unprecedentedly large-scale resource spanning 200 curated reasoning tasks following a principled taxonomy and over one million video clips, approximately three orders of magnitude larger than existing datasets. We further present VBVR-Bench, a verifiable evaluation framework that moves beyond model-based judging by incorporating rule-based, human-aligned scorers, enabling reproducible and interpretable diagnosis of video reasoning capabilities. Leveraging the VBVR suite, we conduct one of the first large-scale scaling studies of video reasoning and observe early signs of emergent generalization to unseen reasoning tasks. Together, VBVR lays a foundation for the next stage of research in generalizable video reasoning. The data, benchmark toolkit, and models are publicly available at https://video-reason.com/ .

An artificial intelligence framework for end-to-end rare disease phenotyping from clinical notes using large language models

Phenotyping is fundamental to rare disease diagnosis, but manual curation of structured phenotypes from clinical notes is labor-intensive and difficult to scale. Existing artificial intelligence approaches typically optimize individual components of phenotyping but do not operationalize the full clinical workflow of extracting features from clinical text, standardizing them to Human Phenotype Ontology (HPO) terms, and prioritizing diagnostically informative HPO terms. We developed RARE-PHENIX, an end-to-end AI framework for rare disease phenotyping that integrates large language model-based phenotype extraction, ontology-grounded standardization to HPO terms, and supervised ranking of diagnostically informative phenotypes. We trained RARE-PHENIX using data from 2,671 patients across 11 Undiagnosed Diseases Network clinical sites, and externally validated it on 16,357 real-world clinical notes from Vanderbilt University Medical Center. Using clinician-curated HPO terms as the gold standard, RARE-PHENIX consistently outperformed a state-of-the-art deep learning baseline (PhenoBERT) across ontology-based similarity and precision-recall-F1 metrics in end-to-end evaluation (i.e., ontology-based similarity of 0.70 vs. 0.58). Ablation analyses demonstrated performance improvements with the addition of each module in RARE-PHENIX (extraction, standardization, and prioritization), supporting the value of modeling the full clinical phenotyping workflow. By modeling phenotyping as a clinically aligned workflow rather than a single extraction task, RARE-PHENIX provides structured, ranked phenotypes that are more concordant with clinician curation and has the potential to support human-in-the-loop rare disease diagnosis in real-world settings.

Calibrated Bayesian Deep Learning for Explainable Decision Support Systems Based on Medical Imaging

In critical decision support systems based on medical imaging, the reliability of AI-assisted decision-making is as relevant as predictive accuracy. Although deep learning models have demonstrated significant accuracy, they frequently suffer from miscalibration, manifested as overconfidence in erroneous predictions. To facilitate clinical acceptance, it is imperative that models quantify uncertainty in a manner that correlates with prediction correctness, allowing clinicians to identify unreliable outputs for further review. In order to address this necessity, the present paper proposes a generalizable probabilistic optimization framework grounded in Bayesian deep learning. Specifically, a novel Confidence-Uncertainty Boundary Loss (CUB-Loss) is introduced that imposes penalties on high-certainty errors and low-certainty correct predictions, explicitly enforcing alignment between prediction correctness and uncertainty estimates. Complementing this training-time optimization, a Dual Temperature Scaling (DTS) strategy is devised for post-hoc calibration, further refining the posterior distribution to improve intuitive explainability. The proposed framework is validated on three distinct medical imaging tasks: automatic screening of pneumonia, diabetic retinopathy detection, and identification of skin lesions. Empirical results demonstrate that the proposed approach achieves consistent calibration improvements across diverse modalities, maintains robust performance in data-scarce scenarios, and remains effective on severely imbalanced datasets, underscoring its potential for real clinical deployment.

A Federated and Parameter-Efficient Framework for Large Language Model Training in Medicine

Large language models (LLMs) have demonstrated strong performance on medical benchmarks, including question answering and diagnosis. To enable their use in clinical settings, LLMs are typically further adapted through continued pretraining or post-training using clinical data. However, most medical LLMs are trained on data from a single institution, which faces limitations in generalizability and safety in heterogeneous systems. Federated learning (FL) is a promising solution for enabling collaborative model development across healthcare institutions. Yet applying FL to LLMs in medicine remains fundamentally limited. First, conventional FL requires transmitting the full model during each communication round, which becomes impractical for multi-billion-parameter LLMs given the limited computational resources. Second, many FL algorithms implicitly assume data homogeneity, whereas real-world clinical data are highly heterogeneous across patients, diseases, and institutional practices. We introduce the model-agnostic and parameter-efficient federated learning framework for adapting LLMs to medical applications. Fed-MedLoRA transmits only low-rank adapter parameters, reducing communication and computation overhead, while Fed-MedLoRA+ further incorporates adaptive, data-aware aggregation to improve convergence under cross-site heterogeneity. We apply the framework to clinical information extraction (IE), which transforms patient narratives into structured medical entities and relations. Accuracy was assessed across five patient cohorts through comparisons with BERT models, and LLaMA-3 and DeepSeek-R1, GPT-4o models. Evaluation settings included (1) in-domain training and testing, (2) external validation on independent cohorts, and (3) a low-resource new-site adaptation scenario using real-world clinical notes from the Yale New Haven Health System.

MedViz: An Agent-based, Visual-guided Research Assistant for Navigating Biomedical Literature

Biomedical researchers face increasing challenges in navigating millions of publications in diverse domains. Traditional search engines typically return articles as ranked text lists, offering little support for global exploration or in-depth analysis. Although recent advances in generative AI and large language models have shown promise in tasks such as summarization, extraction, and question answering, their dialog-based implementations are poorly integrated with literature search workflows. To address this gap, we introduce MedViz, a visual analytics system that integrates multiple AI agents with interactive visualization to support the exploration of the large-scale biomedical literature. MedViz combines a semantic map of millions of articles with agent-driven functions for querying, summarizing, and hypothesis generation, allowing researchers to iteratively refine questions, identify trends, and uncover hidden connections. By bridging intelligent agents with interactive visualization, MedViz transforms biomedical literature search into a dynamic, exploratory process that accelerates knowledge discovery.

ctELM: Decoding and Manipulating Embeddings of Clinical Trials with Embedding Language Models

Text embeddings have become an essential part of a variety of language applications. However, methods for interpreting, exploring and reversing embedding spaces are limited, reducing transparency and precluding potentially valuable generative use cases. In this work, we align Large Language Models to embeddings of clinical trials using the recently reported Embedding Language Model (ELM) method. We develop an open-source, domain-agnostic ELM architecture and training framework, design training tasks for clinical trials, and introduce an expert-validated synthetic dataset. We then train a series of ELMs exploring the impact of tasks and training regimes. Our final model, ctELM, can accurately describe and compare unseen clinical trials from embeddings alone and produce plausible clinical trials from novel vectors. We further show that generated trial abstracts are responsive to moving embeddings along concept vectors for age and sex of study subjects. Our public ELM implementation and experimental results will aid the alignment of Large Language Models to embedding spaces in the biomedical domain and beyond.

BioPulse-QA: A Dynamic Biomedical Question-Answering Benchmark for Evaluating Factuality, Robustness, and Bias in Large Language Models

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.

EHRNavigator: A Multi-Agent System for Patient-Level Clinical Question Answering over Heterogeneous Electronic Health Records

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.