A safety-oriented hypothetico-deductive framework for AI-assisted differential diagnosis

Diagnostic error is a major threat to patient safety, yet current large language model (LLM) systems often treat diagnosis as a one-shot prediction task, lacking safeguards against missed high-risk alternatives or rigorous verification of their reasoning. Here, we present AegisDx, a safety-oriented framework for hypothetico-deductive clinical reasoning. AegisDx coordinates specialized LLM components through role-specific contracts, structured intermediate outputs, evidence-retrieval interfaces, and verification gates to generate broad differential diagnoses, enforce explicit screening for dangerous "must-not-miss" conditions, verify reasoning against grounded medical evidence, and structure actionable next steps. We evaluated AegisDx across three layers. On literature-derived case reports from NEJM and JAMA, with GPT-oss-120B as the shared backbone, Top-3 diagnostic accuracy was 59.9% versus 52.1% for the standalone LLM on JAMA cases and 62.7% versus 51.4% on NEJM cases. On cases from Annals of Emergency Medicine, Top-3 accuracy was 85.7% versus 68.6%; against physician-consensus must-not-miss diagnosis sets, AegisDx captured at least one such condition among its top three diagnoses in 78.0% of cases versus 52.0%. In a blinded physician evaluation of 43 real-world emergency department notes from the Yale New Haven Health System compared against GPT-5, AegisDx improved the physician-rated composite safety score from 4.31 to 4.55 on a 5-point scale (adjusted p = 2.1x10^-4), with qualitative gains in must-not-miss identification and reasoning safety. Our findings suggest that engineering diagnostic AI as a safety-oriented reasoning framework, rather than optimizing raw predictive accuracy alone, can provide a safer, more transparent, and clinically meaningful layer of bedside decision support for acute care workflows.

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 Many rely on static or outdated datasets that fail to capture the dynamic, context-rich, and high-stakes nature of biomedical knowledge.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.

AgentMD: Empowering Language Agents for Risk Prediction with Large-Scale Clinical Tool Learning

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.