Clinical Reasoning

Large language models (LLMs) have made substantial progress on medical question-answering, yet effective medical dialogue also requires learning to ask questions that uncover relevant patient information. To train such dialogue policies, a common pipeline combines supervised fine-tuning with reinforcement learning (RL) based on final diagnostic correctness. However, this outcome-based supervision does not directly distinguish the contributions of individual questions and provides no question-level feedback for unexecuted alternatives. To address this gap, we introduce PCQC (Privileged Counterfactual Question Credit), which uses privileged patient information during training to learn from questions never asked. During training, PCQC makes alternative questions directly comparable at the same dialogue state by using privileged patient facts to construct their answers. A frozen diagnostic scorer evaluates the diagnostic utility of each resulting question-answer pair by how strongly it supports the correct diagnosis. PCQC turns these comparisons into relative question credit that teaches the policy which questions to favor, directly supervising both executed and unexecuted questions alongside outcome-based RL without requiring complete rollouts for the unexecuted alternatives. Extensive experiments across four medical benchmarks demonstrate that PCQC achieves 63.10% mean diagnostic accuracy, outperforming GRPO and ATPO by 4.38 and 4.21 percentage points, respectively. These gains are achieved with 33.1% fewer inquiry turns than GRPO.

Applying large language models to Traditional Chinese Medicine (TCM) prescription generation reveals three clinically critical gaps: models produce end-to-end mappings without auditable reasoning following the li-fa-fang-yao paradigm (SR Gap), treat each encounter in isolation without follow-up adjustment via sui zheng jia jian (LA Gap), and fail to enforce absolute contraindication rules such as Shi Ba Fan (SC Gap). We propose a progressive four-stage framework (SFT $\to$ PG-CoT $\to$ Dynamic $\to$ K-RL) that addresses each gap: PG-CoT constrains CoT distillation under the li-fa-fang-yao paradigm to produce auditable diagnostic chains, Dynamic SFT models patient trajectories with explicit transition reasoning, and K-RL encodes deterministic pharmacological rules as rule-based DPO preference signals. Across 12 fine-tuned models and 6 zero-shot baselines, our framework substantially improves prescription quality over zero-shot baselines---with a 7B model (Mistral-7B) surpassing zero-shot GPT-5 on all three TCM evaluation metrics.

Post-training quantization (PTQ) enables efficient deployment of large language models, and PTQ methods are usually optimized and evaluated with generic reconstruction, perplexity, or answer accuracy. But in explanation-critical domains, preserving only the final answer may be insufficient, since users may also inspect generated rationales to judge whether a prediction is trustworthy. We study this issue in medical multiple-choice question answering, where rationales should provide evidence that supports the selected answer. We propose an explanation-aware objective for transformation-based PTQ. Our method builds an offline faithfulness cache from full-precision teacher rationales and uses it during optimization to preserve answer-supporting evidence tokens and evidence-conditioned answer behavior. We instantiate it on OSTQuant under W4A4KV4 quantization and evaluate four 7B--8B medical and instruction-tuned LLMs on MedExQA, MedExpQA, and ChallengeClinicalQA. While a same-calibration OSTQuant baseline preserves task accuracy, it can substantially weaken answer-supporting rationales. Our objective is to preserve the full-precision model's answer-supporting behavior rather than improve gold-label accuracy, and our method better preserves the full-precision model's answer behavior and rationale-to-answer support. These results suggest that PTQ for explanation-critical settings should evaluate preservation of answer-supporting evidence, not only answer accuracy. Code and evaluation scripts are available at https://github.com/dut0817/EAQuant.

Longitudinal electronic health records (EHRs) capture years of patient history across notes, codes, labs, and procedures, and contain evidence needed to reason about likely clinical outcomes. However, comprehensive clinician review of these records is impractical, and LLM-based processing is costly and often unreliable, missing some relevant observations while hallucinating others. We therefore propose EviGen, a three-layer framework for verifiable clinical rationale generation that addresses these challenges. The first layer is a patient-conditioned retriever that uses learnable queries to find evidence predictive of, not just textually relevant to, a clinical outcome and ranks it by prediction attribution scores. The second layer is an LLM generator that consumes this ranked evidence as a scaffold to produce a clinical rationale grounded in the retrieved spans. The third layer is a process-supervised verifier that checks the generated rationale at the reasoning-step level, flagging unreliable claims. Across three medical prediction datasets, EviGen improves prediction performance and rationale faithfulness over full-context LLM and RAG baselines, and is preferred by clinical reviewers in a usability evaluation.

Large language model (LLM) driven multi-agent systems have shown promise in complex clinical reasoning, yet existing approaches rely on static strategies and lack persistent clinical memory, preventing self-evolving from prior diagnostic successes and failures. We present EMR, a self-evolving medical multi-agent system via Experience Mining and Reuse. EMR introduces a hierarchical clinical experience library that organizes accumulated knowledge into three levels: clinical principles, diagnostic patterns, and representative cases. During inference, EMR emulates multidisciplinary consultation: a planner agent coordinates domain-specific department agents for specialized reasoning, while a summary agent synthesizes their analyses into a final decision. Critically, EMR automatically extracts correct diagnostic insights and failure-related warnings from multi-agent reasoning trajectories, incrementally updating the experience library to guide future cases. Experiments on medical reasoning benchmarks demonstrate that EMR consistently outperforms state-of-the-art medical multi-agent baselines. Further analysis reveals that the hierarchical experience enables cross-specialty generalization and transfer across diverse LLM backbones, offering a scalable and in

Blinded physician evaluation has been considered by many to be the gold standard for assessing clinical reasoning in large language models (LLMs). This is difficult to scale; thus, prior studies typically rely on small physician panels, often from a single institution or specialty, which both limits the scientific questions investigated and makes it unclear whether findings would be reproduced with a different set of evaluators. To more rigorously and scalably study clinical reasoning in AI models, here we introduce PrecepTron, an LLM fine-tuned for physician-level evaluation of open-ended responses. PrecepTron was trained using low-rank adaptation (LoRA) of a 32-billion-parameter model on a small number of physician examples. We also release GRAND-ROUNDS, a new large-scale physician-annotated benchmark of 9,217 scores by 11 physicians across seven studies. We show that frontier LLMs in typical "LLM-as-a-judge" approaches often disagree with physicians and with each other, but fine-tuning PrecepTron on a small number of cases enables physician-level consistent scoring across tasks. We use PrecepTron to reproduce headline findings from five influential studies assessing LLMs for clinical care in JAMA, Science, and Nature Medicine without new human grading. Using PrecepTron, we then pose new questions about how LLMs reason in medicine that would have been infeasible with human grading alone, including measuring the diagnostic accuracy of frontier LLMs when clinical cases are provided piecemeal, even token by token. Together, PrecepTron and GRAND-ROUNDS provide a foundation for reproducible, large-scale study of how LLMs reason in medicine. All code, data, and labels are made freely available for researchers.

Electronic health record (EHR) foundation models trained on longitudinal patient trajectories have demonstrated strong performance across diverse clinical prediction tasks. However, their clinical reasoning capabilities remain constrained by next-token prediction on limited and incomplete EHR data. To address this, we propose a reinforcement learning (RL) fine-tuning framework that treats EHR foundation models as generative policies over patient trajectories. We formulate common clinical prediction problems (e.g., hospital readmission) as event-conditioned, time-windowed reasoning tasks. We then design time-aware, rollout-sensitive rewards to account for finite rollout lengths and temporally inconclusive outcomes. We find that RL fine-tuning consistently improves over pre-trained backbones and strong baselines. Notably, it enables smaller models to surpass larger pre-trained models in data-limited regimes and induces positive transfer across tasks. Further analysis shows that RL fine-tuned models generate trajectories with stronger structural and semantic alignment to ground truth and greater downstream utility.

Evidence-based medicine demands strict logical consistency, yet current evaluations of large language models (LLMs) prioritize superficial label matching over genuine reasoning. We introduce LogiMed-RoB, a benchmark grounded in Cochrane Risk of Bias (RoB) 2.0 expert logic, comprising 860 randomized controlled trials (RCTs) and 14,820 queries. It evaluates models under the Hierarchical Logical Consistency (HLC) framework across four dimensions: Atomic Consistency, Domain Consistency, Aggregation Consistency, and Evidential Faithfulness. Experiments on 10 state-of-the-art LLMs reveal a catastrophic Error Compounding Effect: despite the top model reaching 98.88% Atomic Consistency, its end-to-end consistency collapses to 45.13%, with several open-weight architectures plummeting to nearly 0%. We further uncover a systematic evidence-reasoning gap: even when models retrieve high-quality evidence, they fail to deduce correct outcomes in 18.63-40.05% of cases, while Blind Guess Rates reach 48.28%. LogiMed-RoB demonstrates that high outcome accuracy can conceal critical reasoning flaws, underscoring the necessity of white-box logical verification for clinical deployment.

Clinical education must prepare medical students to conduct safe and coherent patient interviews under conditions of uncertainty. Traditional standardized patient (SP) training is resource-intensive and difficult to scale. We developed a scaffolding-oriented multi-agent Large Language Model (LLM) AI Standardized Patient (AI-SP) training platform1. The system includes a patient agent for simulated dialog, a tutor agent providing Socratic prompts without disclosing diagnostic information, and a turn-level evaluator agent that monitors clinical progress without revealing summative scores. In a randomized controlled study (N = 100 medical students), participants were assigned to either a multi-agent (MA) scaffolding condition or a control condition. All students completed two learning sessions under their assigned condition followed by an examination conducted in a patient only environment. Performance was assessed using a standardized Objective Structured Clinical Examination (OSCE) based rubric. While no significant difference was observed in final diagnostic accuracy between groups, the multi-agent AI standardized patient system improved final examination scores compared to the control group utilizing structured progressive information disclosure; the most substantial and consistent improvements were observed in communication, the expression of empathy, and specific history-taking behaviors. These findings suggest that specialized LLM agents enhance the process quality of simulated clinical interviews without artificially inflating examination outcomes. To support future research, we release a multi-expert annotated dataset comprising transcripts, checklist annotations, turn-level evaluations, and OSCE-aligned scoring outcomes. This resource aims to facilitate the development of pedagogically grounded AI-SP systems and advance research on AI-supported clinical reasoning training.

Medical question-answering datasets often contain answer labels, whereas high-quality rationales remain scarce, noisy, or costly to validate. This changes the acquisition question: rather than asking which questions should be labeled, we ask which already-labeled questions should receive rationale supervision under a fixed token budget. We study an offline version of this problem in which candidate rationales are visible to the selector but withheld from downstream training unless selected. We propose root-mean-square Robustness-based Sample Prioritization (RMS-RSP), which perturbs hidden states only at rationale tokens and measures the resulting shift in the gold-versus-best-distractor margin. Across five medical QA datasets, MedGemma-4B-IT, three training seeds, ten budgeted non-RSP selectors, and an unbudgeted full-supervision reference, RMS-RSP provides a deliberately qualified result. Its locked-budget accuracy is 60.61% on average versus 60.08% for Random, with a statistically resolved gain only on AfriMed-QA (+1.44 points). Its full-budget accuracy area is not better than Random. However, after three answer-option reorderings, RMS-RSP improves robust accuracy and semantic consistency by 1.91 and 2.85 points on average, respectively, with the same direction on all five datasets. Training on every pool rationale raises macro accuracy to 63.74%, but consumes 29--254 times more rationale tokens and does not uniformly improve robustness. These findings do not establish universal accuracy gains; they instead suggest that rationale-local boundary sensitivity can identify supervision that improves invariance to semantically equivalent formatting changes.

Oncology care operates at constant pressure of absorbing rapidly evolving evidence base in biomedicine. The American Society of Clinical Oncology (ASCO) addresses this through living guidelines, but the format introduces a new burden: any recommendation can change at any point, across multiple versioned documents. We present SENTRYLINE, a living guideline-aware clinical question answering system. SENTRYLINE retrieves guideline passages through a vectorless hierarchical RAG pipeline and returns a role-specific answer with inline citations, factual and temporal verification reports, and drift detection notes that surface when a guideline has been updated. We construct ASCOBENCH, a benchmark of 405 three-turn conversations across four question categories with gold answers from expert annotators(clinicians), and use test set to evaluate SENTRYLINE against five baselines under an LLM-as-judge framework. Experiments across three generation backbones show consistent improvements over four retrieval baselines and ASCO's guideline assistant, with particularly strong gains on Reasoning and Role-Specific questions where multi-hop synthesis and register adaptation are required

Medical imaging artificial intelligence (AI) is commonly developed as separate mappings from radiographs to diagnostic outputs or from clinical descriptions to generated images, although both arise from the same underlying radiographic state. A world-model formulation instead seeks to learn an internal representation of this state that can support both clinical readout and conditional simulation of radiographic observations. Here we introduce MedDream, a radiographic world model that learns a shared continuous latent state from paired chest radiograph-text observations for diagnostic reasoning and report-conditioned evidence generation. MedDream was pretrained on 2.65 million leakage-controlled chest radiograph-text pairs curated from 4.40 million candidates. Across eight clinical datasets and two independent reader cohorts, MedDream outperformed leading diagnostic and generative comparators. For diagnostic reasoning, MedDream showed strong generalization across disease recognition, label-scarce adaptation, severity assessment, and localization, while MedDream-supported review increased mean resident concordance with independent radiologist consensus from 56.3% to 63.0%. For evidence generation, MedDream produced radiographs that preserved clinically relevant pathology and improved downstream performance on held-out real data, with synthetic augmentation increasing external VinDr-CXR macro-AUROC from 76.4% to 81.4%. More importantly, conditioning generation on prespecified subgroup performance gaps enabled targeted evidence construction, increasing weighted F1 by 3.1 percentage points in Asian patients, whereas matched-volume unguided augmentation decreased it by 2.3 points. These findings establish radiographic world models as a path toward medical AI that learns clinically meaningful internal states for interpreting, simulating, and constructing evidence for clinical use.

Large language models (LLMs) have demonstrated strong capabilities across diverse domains, showing considerable potential in medicine. However, their application in medical settings remains limited by the scarcity of visual question answering (VQA) datasets that capture clinical reasoning and explicit image-text alignment. Here, we leverage de-identified medical images and expert commentaries shared on clinician-oriented social media. By combining an advanced LLM with clinician-in-the-loop verification, we established a rigorous pipeline to construct ThoughtMed-1M, a long-form medical VQA dataset containing over one million VQA pairs and designed to capture structured clinical logic and medical image-text alignment. To demonstrate its utility, we developed a FOundational LLM Trained on ThoughtMed-1M (FOLTMed). FOLTMed achieved state-of-the-art performance across 42 medical VQA benchmark datasets, with a macro accuracy of 85.4%, and generated more clinically coherent responses on the ThoughtMed-1M test set. It outperformed state-of-the-art models by 3--5% across factuality and similarity metrics, highlighting a scalable paradigm for advancing research on clinically grounded multimodal LLMs.

Clinical LLM assistants must reason over multi-visit patient trajectories, yet whether the compact history representations used to scale them---retrieval, structured timelines, LLM summaries, agentic memory---preserve the longitudinal signal clinical reasoning needs has not been measured. We introduce ClinTraceBench: 385 MIMIC-IV-derived verified dialogues with event-ID provenance, a nine-task taxonomy (T1--T9), and L0--L4 deterministic + L5 human-audit validation (98.92% agreement). We evaluate eight history representation strategies---a no-context floor, \textit{last-visit-only}, \textit{full-context}, BGE-M3 \textit{dense-retrieval}, two compression schemes, and two agentic-memory systems (\textit{Mem0}, \textit{A-Mem})---across four backbones (DeepSeek-V3, GPT-4o-mini, Haiku4.5, Sonnet4.6) on 6{,}271 questions: 32 cells, 200{,}672 predictions. Four findings: (SP4) a controlled T3 injection probe isolates compression-induced \textit{relation} loss---with the attribution sentence present \textit{before} construction, \textit{Mem0}, \textit{A-Mem} and \textit{llm-summary} still recover only 0--5.3% of the injected positives; (SP1) compressed strategies pay an aggregation tax on multi-visit trends and cross-patient comparisons; (SP2) the blind-to-full gap spans $+29.8$~pp (GPT-4o-mini) to $+62.7$~pp (Haiku); (SP3) abstention scales non-monotonically with context length. On the Pareto frontier Haiku dominates Sonnet under \textit{full-context} ($25.76 vs.\ $106.21), inverting the ``biggest backbone wins'' heuristic.

When medical AI systems hallucinate clinical reasoning, the consequences extend beyond incorrect answers: fabricated justifications that superficially reference retrieved evidence can mislead clinicians into unsafe treatment decisions. Medical reasoning agents must therefore produce not only correct answers but also faithful justifications that clinicians can verify against cited evidence. We identify a systematic failure mode in RL-trained retrieval agents: outcome-only rewards improve accuracy while degrading faithfulness, a phenomenon we term confident hallucination. The agent learns to answer from parametric memory and backfill plausible but unsupported justifications; citation fabrication rates rise from 16.5% to 31.8% even as accuracy improves by 5 points over the supervised baseline. We address this with a faithfulness-gated reward design: accuracy credit is conditioned on evidence grounding via a hard gate, complemented by retrieval validity and conciseness signals that close exploitation paths unique to agentic retrieval. The resulting system, MedAgent-R1, reduces citation fabrication from 31.8% to 4.7% and raises evidence completeness from 58.7 to 82.6 while maintaining 75.1% accuracy, with 13.2-point gains on HealthBench Safety. Under the same agentic retrieval setup, MedAgent-R1 outscores GPT-4o on faithfulness-specific dimensions (Factual Support 4.55 vs. 4.25; Overclaiming 4.40 vs. 4.15) while remaining below GPT-4o in overall accuracy, suggesting that explicit faithfulness training yields evidence-grounding gains not achieved by scaling alone.

Introduction: NICE guidelines provide evidence-based recommendations for clinical care but remain largely in unstructured natural language. Existing approaches to converting them into computable representations often focus on individual diseases, require substantial manual encoding, and do not scale. Large language models (LLMs) may enable much of this translation to be automated. Methods: We present an end-to-end approach that converts textual clinical guidelines into executable models capable of generating explainable, patient-specific recommendations. A stepwise LLM-based transformation with in-context examples produces human-inspectable intermediate artifacts. We apply the approach to NICE pancreatic and lung cancer guidelines, use expert review to assess rule alignment, and evaluate the executable pancreatic cancer model on 20 patient vignettes. Results: Expert review showed strong alignment between the source guidelines and generated executable models. Most discrepancies were partial omissions rather than incorrect logic, while hallucinated or fundamentally incorrect rules were rare. On the patient vignettes, the executable model achieved an F1 score of 82.5%. Conclusion: LLMs can transform natural-language NICE guidelines into interpretable, executable models that preserve guideline structure, support transparent inspection and modification, and generate patient-specific recommendations. These findings demonstrate the feasibility of scalable automated generation of computable clinical guidelines.

Understanding the temporal progression of symptoms in clinical narratives is critical for disease monitoring, safety surveillance, and causality assessment. Clinical narratives, however, rarely provide explicit temporal anchors. Current approaches to temporal information reasoning focus predominantly on pairwise relation classification across multi-visit and timestamp-rich records, leaving the reconstruction of structured symptom trajectories from individual anchor-sparse reports largely unaddressed. We propose CRAFT, an LLM framework that pairs a generator with a constraint-based verifier to iteratively produce and refine stage-wise symptom timelines through targeted feedback. We conduct evaluation on MedTempo, a new benchmark of 5,347 vaccine adverse-event narratives spanning three COVID-19 vaccine types, with expert-validated temporal stage annotations for 3,166 reports. Experiments across four LLM backbones demonstrate that CRAFT consistently improves temporal ordering accuracy, with ablation analysis isolating the contribution of generator and verifier components across model capability levels.

In medical imaging, the clinical value of Computed Tomography (CT) lies not only in depicting current disease status, but crucially in enabling longitudinal comparison of serial scans to determine disease evolution, a process that underpins response assessment, recurrence detection, and ongoing patient management. Yet, despite this central role of temporal comparison in clinical decision-making, existing medical foundation models remain largely confined to single-study understanding, leaving temporally grounded cross-examination insufficiently addressed. To address this gap, we study longitudinal imaging difference reporting, a task in which a model takes two temporally separated scans from the same patient and generates a clinically meaningful report describing interval changes between them. We introduce CT-$Δ$Bench, a dedicated benchmark for this task with patient-level splitting to prevent information leakage. To better evaluate this task beyond surface-level text similarity, we further develop change-aware metrics specifically designed to capture clinically meaningful longitudinal changes, and conduct an independent physician validation to assess the reliability of the synthesized references and event extraction pipeline. We also compare direct paired-CT reasoning with an indirect two-stage pipeline that first generates single-timepoint reports and then performs textual differencing. Finally, we propose DeltaMed, a baseline model for direct paired-CT difference reporting, and train it on the benchmark training set. Together, these contributions lay the groundwork for temporally aware medical foundation models that better reflect real-world longitudinal clinical reasoning.

Reinforcement Fine-Tuning (RFT) has enabled medical Multimodal Large Language Models (MLLMs) to produce Chain-of-Thought (CoT) reasoning for visual question answering, yet these models suffer from $\textit{confidence miscalibration}$---a systematic gap between expressed certainty and actual diagnostic accuracy that undermines clinical trust. We propose $\textbf{CARE}$, a $\textbf{C}$onfidence-$\textbf{A}$ware medical $\textbf{RE}$asoning framework that jointly optimizes accuracy and calibration through a dual-stage pipeline. First, a scalable Medical-CoT synthesis provides structured cold-start data for Supervised Fine-Tuning. Second, Group Relative Policy Optimization (GRPO) with a novel $\textbf{Confidence-Aware Reward (CAR)}$ mechanism ties the model's confidence to diagnostic correctness within the reward signal. Across three Medical VQA benchmarks, $\textbf{CARE}$ achieves the highest diagnostic accuracy while obtaining the lowest Expected Calibration Error and Hallucination Rate, establishing a foundation for trustworthy clinical decision support. Our code is available at https://github.com/anotherbricki/CARE.

Cardiologists interpret electrocardiograms by localizing waveform components, measuring rhythm and interval patterns, and translating these structured observations into diagnostic evidence. Whether this expert reading process can serve as an effective prior for ECG agents remains unclear. To address this question, we introduce LuminaECG, a clinically structured ECG reasoning framework that reformulates ECG interpretation as measurement-grounded visual reading. ECG signals are rendered on standard electrocardiographic grid paper to preserve the spatial and scale cues used in clinical reading. P-wave, QRS-complex, and T-wave boundaries are explicitly delineated, and color-coded segmentation decomposes the waveform into discrete visual measurement primitives. A general 2B vision-language backbone is then trained with low-rank supervised fine-tuning to associate these primitives with diagnostic reasoning, without architectural modification. Across open, proprietary, and ECG-specialist zero-shot baselines, LuminaECG improves both waveform measurement and diagnostic recovery. It reaches a clinically meaningful reader tier on the CODE-test benchmark, transfers across geographically diverse ECG datasets without retraining, and generates reports whose structure contains an emergent prognostic signal. These findings suggest that effective ECG agents require not only larger models, but supervision that preserves the alignment between measurable waveform evidence and clinical knowledge.

In medical education, physicians convert academic knowledge into clinical expertise through residency: years of training across thousands of encounters, with diverse sources of feedback and progressively greater autonomy. Much of clinical reasoning relies on the patient encounter, a dialogue in which a clinician elicits history, refines diagnostic hypotheses, and decides management under uncertainty. While large language models (LLMs) excel on static medical benchmarks, methods to optimize the full sequence of clinical decisions remain underdeveloped. We present ResidencyRL, a reinforcement learning (RL) method for training clinical artificial intelligence (AI) agents through simulated multi-turn clinical encounters (up to 60 dialogue turns and 8 tool calls per trajectory). ResidencyRL pairs the policy agent with LLM simulators capable of complex, adversarial behaviors, training against a structured reward aligned to diagnostic accuracy, management quality, communication, documentation, and safety. On held-out evaluations, the ResidencyRL agent improves diagnostic accuracy by 7.0% under adversarial conditions (88.0% vs. 81.0%) and reduces missed red flag rates by 31%, demonstrating rigorous mitigation of premature closure. Blinded expert clinicians validated these gains, preferring the trained agent in 87.6% of side-by-side comparisons. The procedural competencies transfer to unseen benchmarks: the agent outperforms the base model across all six clinical axes of the AMIE multi-visit benchmark, and shows consistent directional improvements on AgentClinic and CRAFT-MD. Our findings demonstrate that sequential clinical decision-making can be effectively learned through multi-turn RL in simulation, yielding robust, generalizable capabilities, paving the way towards clinical mastery. Prospective validation with real-world workflows remains necessary to establish clinical utility.

Electronic health record (EHR) feature engineering is a major bottleneck in clinical research and AI, accounting for 39-45% of data scientists' workload. This is especially pronounced in heart failure, which affects an estimated 6.7 million U.S. adults and requires integrating fragmented EHR data with disease-specific, guideline-based clinical reasoning. Existing rule-based and large language model (LLM)-based approaches offer only partial automation with limited maintainability and evidence traceability. We developed the Nimblemind Multi-Agent System (nMAS), an evidence-linked, rubric-grounded pipeline for automated heart-failure feature engineering, and evaluated it on 500 dummy patient records from nine EHR source tables. nMAS generated 132 structured and 70 rubric-scored aggregated features, verified for structural integrity, rubric compliance, and provenance, and audited by a restricted LLM. Adding the aggregated features improved held-out AUROC from 0.895 to 0.963 for HFrEF and 0.870 to 0.910 for HFpEF phenotyping, and an independent LLM-based rubric assessment of evidence support and methodological soundness scored the features at 81.5% of maximum points. These results demonstrate the feasibility of automated, auditable feature engineering for complex cardiovascular EHR data, though evaluation was limited to a single-institution cohort and external validation is needed.

Medical vision-language models (VLMs) generate chain-of-thought (CoT) reasoning before answering clinical questions, but whether this reasoning causally influences predictions remains unclear. We present CoT-Mediate, a behavioral framework that perturbs a single clinically meaningful attribute within a model's own generated reasoning and measures whether the resulting prediction follows the edited reasoning. Our framework combines a dual-arm protocol comparing re-prompted evidence with prefix-forced continuation, together with a provenance-controlled intervention that varies only the attributed source of identical reasoning to disentangle reasoning mediation from sycophancy. We evaluate LLaVA-Med and MedGemma on 1,000 VQA-RAD samples each. Prefix-forced continuation consistently yields higher mediation faithfulness than re-prompting, while the provenance analysis reveals distinct model-specific deference behaviors. Across both models, removing visual evidence increases reliance on injected reasoning, whereas laterality is the least faithfully tracked clinical attribute. These results show that the mechanism used to inject reasoning substantially affects measured faithfulness and that contextual position, rather than stated provenance, is the primary determinant of whether medical VLMs use their generated reasoning.

Vision-language pre-training (VLP) serves as a cornerstone for medical multimodal representation learning. However, existing medical VLP frameworks are often constrained by the limited context windows and shallow representational capacities of lightweight text encoders when processing lengthy, terminology-dense clinical reports. While integrating medical large language models (LLMs) offers unprecedented clinical reasoning capabilities, it introduces three major bottlenecks: (i) the anisotropic representational collapse of generative LLMs under standard contrastive objectives, (ii) the prohibitive memory overhead of joint end-to-end training with large batch sizes, and (iii) the medical hallucinations induced by vanilla contrastive losses that ignore fine-grained anatomical laterality and negation modifiers. To address these challenges, we propose \textbf{SCALPEL}, a \textbf{S}emantic \textbf{C}ross-modal \textbf{A}lignment framework via \textbf{L}LM-\textbf{P}owered \textbf{E}ncoder \textbf{L}earning. First, Clinical Report Contrastive fine-tuning converts a generative LLM into an isotropic encoder via domain-specific clinical text adaptation. Second, an asymmetric alignment strategy leverages offline feature caching to enable efficient training. Critically, we formulate an Anatomy-Negation Aware Objective that explicitly penalizes mismatched image-text pairs involving laterality confusion or false negations. Extensive experiments across MIMIC-CXR, CheXpert, and IU X-Ray benchmarks demonstrate that SCALPEL achieves state-of-the-art performance in cross-modal retrieval, zero-shot disease classification and medical visual question answering.

Clinical practice guidelines (CPGs) encode diagnostic criteria, but LLM systems typically retrieve guideline text or absorb it through training rather than execute its rules. We introduce GuideSkill, an external reasoning layer that compiles disease-specific criteria into executable functions returning ordinal diagnostic-support scores. GuideSkill-Zero is initialized from guidelines, while GuideSkill-Evo uses case--diagnosis pairs to refine covered skills and add missing diagnoses. At inference, an LLM proposes a differential diagnosis, grounds the features required by each matched skill, and fuses its ranking with the executed skill scores. Across four benchmarks and four backbones, GuideSkill-Zero improves macro-average accuracy over guideline RAG by 13.45% on average. GuideSkill-Evo achieves the highest macro-average for every backbone, improves over direct inference by 18.49% relatively, and increases gold-label skill coverage from 56.5% to 99.5%. On Qwen3.5-9B, it also exceeds the strongest parameter-update baseline by 11.16% without updating the backbone. Expert evaluation further indicates that GuideSkill produces clinically sound and broadly acceptable skills, suggesting that its initialized and evolved rules are reliable and practically meaningful. These results support executable skills as a model-agnostic mechanism for combining guideline-derived procedures with case-derived diagnostic patterns.

Clinical diagnostic evaluation should not only assess whether models can provide correct diagnoses, but also reflect the realities of clinical practice, including progressive disclosure of multimodal information, dynamic updating of diagnostic hypotheses, and continuous refinement of clinical reasoning. However, existing evaluations of multimodal large language models (MLLMs) typically rely on single-turn or isolated tasks, making it difficult to fully capture the complexity of real-world clinical diagnosis. To bridge this gap, we developed ClinMM-Bench, the largest multi-turn multimodal clinical diagnostic evaluation benchmark to date. ClinMM-Bench contains 1,089 challenging real-world clinical cases and 3,760 medical images across eight specialties. We systematically evaluated 15 representative MLLMs using a two-level evaluation framework that assessed both diagnostic accuracy and diagnostic reasoning quality. Results showed that proprietary models achieved the highest overall diagnostic accuracy, but the proportion of completely correct diagnoses remained limited across all models. In terms of diagnostic reasoning quality, current models can identify plausible diagnostic directions but still have considerable limitations in generating reliable diagnostic reasoning. Error analysis further identified five representative failure modes: information synthesis failure, knowledge mapping error, perception error, premature closure, and visual hallucination.

Rare diseases represent one of the most challenging settings for clinical decision-making, where heterogeneous presentations, sparse evidence and limited expertise create persistent uncertainty throughout the care pathway. Although artificial intelligence could help, existing systems largely address isolated tasks, particularly diagnosis, and usually rely on downstream investigations rather than information available at initial presentation. Here we show that clinical AI performance under uncertainty can be improved not by scaling a single model, but by exploiting the diversity of multiple imperfect reasoning systems. Across heterogeneous large language models, we identify divergent reasoning trajectories with complementary error patterns and develop RareLens, which learns to reconcile these perspectives into actionable decisions across four stages of rare disease care: risk screening, diagnosis, treatment planning and prognosis prediction. Built on RarelensBench, a real-world dataset of 157,525 cases spanning all 33 Orphanet categories and more than 7,000 conditions, RareLens outperformed every frontier model tested, including GPT-5, DeepSeek-R1, Claude-3.7-Sonnet and Gemini-2.5-Pro, across all stages. It achieved an area under the curve of 0.917 for screening and top-1 accuracies of 65.5% and 89.8% for diagnosis and treatment. In an external evaluation involving 1,287 cases and 23 physicians, autonomous RareLens and physicians assisted by RareLens both outperformed unaided physicians, while demonstrating that effective human-AI collaboration requires more than simply providing model outputs. These findings establish divergent model reasoning as an exploitable source of information and suggest a general strategy for building AI systems that operate reliably under high clinical uncertainty.

In medical multiple-choice question answering (MCQA), Retrieval-Augmented Generation (RAG) can supplement the domain knowledge of language models (LMs). However, since vanilla RAG indiscriminately utilizes retrieved documents, it can degrade LM performance. To address this, we propose MedJudgeRAG. Our framework represents retrieved documents as a dynamic knowledge graph (KG) composed of entities and relations. For each option, the model judges an evidence verdict from the retrieved documents and the KG. Based on the verdict combination, the model determines a knowledge utilization strategy to reason toward the final answer. These capabilities are trained via supervised fine-tuning using structured reasoning traces generated by a teacher LM. The training employs a weighted cross-entropy loss that differentially weights the KG and reasoning segments. Experiments on two medical MCQA benchmarks demonstrate that MedJudgeRAG consistently outperforms both vanilla RAG and parametric baselines. Furthermore, ablation analysis reveals that the dynamic KG is more effective as graph-conditioned supervision at training time than as an explicit output at inference time. Our code is available at https://github.com/hyu-amllab/medjudgerag, and the generated reasoning traces are released at https://huggingface.co/datasets/youarethewon/medjudgerag.

Clinical NLP evaluation remains dominated by multiple-choice question answering (MCQA), which scores only final-answer accuracy and cannot detect when a model reaches the correct diagnosis while grounding it in irrelevant, absent, or contradictory evidence. We introduce MIRA-Ev, a clinical argument mining benchmark built on Spanish Médico Interno Residente (MIR) licensing-exam cases, re-annotated by expert clinicians with span-level premises, claims, and directed support/attack relations, and released in parallel Spanish (native), English, and Basque versions, the first clinical argumentation resource in Basque. MIRA-Ev organizes evaluation into a three-tier task hierarchy: evidence sentence retrieval, argumentative component extraction, and relation classification.

Large language models achieve high scores on medical knowledge assessments, yet clinical reasoning requires actively deciding what to investigate under uncertainty. We developed an agentic evaluation framework in hematologic oncology in which models must proactively request clinical data across three sequential rounds before committing to a diagnosis and treatment plan. Across 32 frontier models, the best achieved only 68% overall accuracy. Information utilization, the fraction of available data actually requested, was the strongest predictor of diagnostic accuracy (R = 0.69, P < 0.001), yet utilization collapsed from 57% to 26% in the final round, leaving molecular and cytogenetic data critical for treatment selection unexamined. Reasoning traces scored high on a clinical reasoning rubric (91% above threshold) but decorrelated from accuracy, revealing a gap between locally coherent rationales and globally correct conclusions. Error analysis identified search satisficing, anchoring and premature closure as the dominant failure modes, the same cognitive biases that characterize novice clinicians under dual-process models of diagnostic reasoning. These findings demonstrate that the primary limitation of current models in clinical oncology is not insufficient medical knowledge but a systematic failure of information-seeking under uncertainty.

Retrieval-augmented generation evaluation checks whether model claims are factually grounded in retrieved documents. It does not check whether retrieved evidence is attributed to the correct entity. A clinical RAG response can pass every automated check (zero hallucinations, near-perfect faithfulness, real citations) while presenting drug Y's clinical evidence as evidence about queried drug X. We term this deceptive grounding (DG): a failure invisible to faithfulness, hallucination, and citation checks because every claim is sourced from a real document, about the wrong entity. Using a controlled factorial benchmark across 13 models, we find DG rates spanning 8-87% at peak adversarial conditions. Medical and biomedical fine-tuned models reach up to 86.7%; domain specialization amplifies the failure rather than mitigating it. A controlled ablation identifies the mechanism: removing entity-specific clinical evidence from retrieved documents eliminates entity-attribution failure entirely, shifting all failures to confabulation. The two failure modes respond to the same trigger, taking different paths. Production measurement across 740 drug-disease pairs finds 7.8% overall DG in a deployed RAG system, rising to 13.6% for recently approved drugs. Entity-attribution verification (checking that cited evidence applies to the queried entity) detects DG at 97.0% precision and 98.7% DG recall (IPW-adjusted human gold standard); no existing framework implements it.

Hepatocellular carcinoma (HCC) is a common malignancy and a leading cause of cancer-related mortality. Current guidelines and staging systems provide coarse categories, but often miss within-stage heterogeneity and the clinical context in electronic medical records (EMRs). We present HCC-STAR (Hepatocellular Carcinoma Staging, Treatment And pRognosis), a clinically aligned large language model that reads routine EMR narratives and jointly outputs risk score-based staging, ranked guideline-consistent treatments with evidence-based rationales, and individualized survival estimates. We curated about 30,000 HCC cases from SEER and expanded them into EMR-style narrative training data using a clinician-validated, prompt-based augmentation workflow. On this corpus, we developed a knowledge-aligned reasoning framework optimized with a step-verifiable composite reward, moving beyond text-level memorization of clinical guidelines. In a multi-center cohort of 6,668 patients from 12 hospitals in China, HCC-STAR achieved state-of-the-art performance in treatment recommendation and risk stratification compared with clinical guidelines and competitive models, including GPT-5 and Gemini-2.5 Pro. Hypothetical overall-survival analysis showed a median survival of 51 months under adherence to HCC-STAR recommendations, compared with 29 and 32 months under BCLC and CNLC. In clinician-centric evaluations, blinded hepatobiliary specialists rated HCC-STAR's reasoning and evidence-based justifications as trustworthy. The model surpassed resident and attending physicians in treatment accuracy and helped physicians make more accurate decisions faster when used as an assistant. These findings support HCC-STAR as a reliable and verifiable decision-support system for risk stratification and precision therapy in HCC.

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.

While Large Vision-Language Models (VLMs) demonstrate remarkable generic capabilities, their clinical reasoning in specialized domains like ocular surface diseases (OSDs) is severely hindered by a paucity of high-fidelity, multimodal instruction-tuning data. To dismantle this data bottleneck, we introduce IRIS, an Intelligent Recognition and Interaction System tailored for fine-grained OSD understanding via external eye photography. First, we curate IRIS-120K, the largest and most comprehensive OSD visual question-answering (VQA) dataset to date. Crucially, to overcome the semantic shallowness of conventional image-caption pairs, we propose a synergistic data generation paradigm to explicitly inject clinical priors. Our data engine operates via a dual-branch framework: 1) a Topic Finding Tree (TFT) that hierarchically anchors visual features to precise anatomical and pathological concepts, enforcing rigorous medical deduction logic; and 2) a Scene-driven strategy that synthesizes role-adaptive clinical dialogues to ensure pragmatic generalization. By explicitly aligning a compact 4B-parameter VLM on this structurally enriched corpus, IRIS achieves state-of-the-art performance, comprehensively outperforming both generalist and specialized medical VLMs with up to 34B parameters. Our findings underscore that structured knowledge injection profoundly prevails over sheer parameter scaling, unlocking the potential for resource-efficient, expert-level AI deployment on mobile edge devices for scalable OSD screening. Code, datasets, and model weights will be publicly released by this repo.

Faithful reasoning is essential in medicine, where clinical decisions require transparent justification grounded in reliable evidence. Current medical LLMs either lack active access to evidence or use retrieved evidence without supervising how it should be appraised and applied during reasoning. To address this, we formalize evidence-based medicine principles as process-level criteria and introduce FaithMed, a framework that combines clinician-designed, automatically refined rubrics with reinforcement learning using step-level process reward assignment and advantage grouping. Across seven medical benchmarks, FaithMed improves over agentic-search baselines (+9% on average) and outcome-only RL (+5.8%), while raising average evidence-based medicine rubric scores over agentic-search Qwen3 baselines (+15.5%). This work demonstrates that explicit step-level supervision can improve both task success and the faithfulness of the reasoning process. Code is available at https://github.com/cxcscmu/FaithMed.

Rare disease differential diagnosis is a critical yet arduous clinical task, requiring physicians to identify precise phenotypes from complex, unstructured patient symptoms and execute intricate reasoning within a vast search space. However, existing AI approaches typically rely on pipeline-based phenotype extraction or retrieval-augmented generation, which suffer from critical information loss due to predefined ontologies, retrieval bottlenecks, and a lack of diagnostic logic. To address these challenges, we introduce RareDxR1, an end-to-end reasoning-centric large language model designed for open-domain rare disease diagnosis directly from unstructured clinical notes. We design a progressive end-to-end training framework by synergizing knowledge internalization with autonomous evolutionary learning, thereby bypassing reliance on structured phenotypes and closed-set decision-making. To overcome the limitations of RAG and phenotype restriction, we enabled the deep internalization of fragmented rare-disease knowledge directly into the model's parameters. Moreover, to bridge the gap between model generation and expert reasoning, we propose Reflection-Enhanced Reasoning Sampling (RERS), a strategy that synthesizes expert-level diagnostic trajectories by learning from failures without human annotation. Additionally, we propose a dual-level curriculum reinforcement learning approach for gradually mastering rare disease diagnosis. Experimental results demonstrate that RareDxR1 achieves state-of-the-art accuracy across different benchmarks, marking a significant breakthrough in open-domain rare disease diagnosis. Our code and dataset will be publicly available.

Large Language Models (LLMs) achieve strong results on many medical benchmarks, but their clinical reasoning remains difficult to evaluate reliably. A central risk is an evaluation illusion: fluent and well-structured explanations can appear clinically convincing even when the final diagnosis is incorrect. We introduce CLExEval, a human-in-the-loop framework for evaluating LLM clinical reasoning under progressive information masking. CLExEval combines 5,600 expert-physician annotations with 200 clinical reasoning traces derived from 40 rare diagnostic cases. Our analysis identifies three recurring failure patterns: (i) verbosity bias, where GPT-4o-mini's diagnostic accuracy drops from 95.0% to 32.5% under information scarcity; (ii) a hidden knowledge paradox, where a specialist model reaches 92.5% maximum diagnostic potential but fails to retrieve that knowledge reliably in verbose contexts; and (iii) a 68.6% reasoning-to-output mismatch, where correct diagnoses appear in reasoning traces but are not reflected in final answers. We further evaluate the LLM-as-a-Judge paradigm on a human-verified failure set (n = 142). GPT-4o-mini approved 47.9% of clinically incorrect outputs, while HuatuoGPT-o1 approved all validly scored failures and showed a positive self-preference bias. These results suggest that standalone automated clinical evaluations can substantially overestimate clinical reliability without expert-grounded validation.

Medical multiple-choice question answering requires parameter-efficient adaptation across heterogeneous knowledge domains and reasoning operations. A medication question, a diagnostic decision, a public-health item, and a nursing-action item may require different low-rank updates, while some recall items should preserve the base model's representation with only mild adapter intervention. We propose BiRG-LoRA, a single-adapter rank-gated LoRA method for medical question answering. BiRG-LoRA keeps one LoRA module per target layer but makes its rank dimension input-conditioned: for each question, a biaxial gate combines hidden semantic evidence with specialty/profession priors, clinical-operation priors, and their interaction to select a sparse top-$k$ subset of rank atoms. A scalar injection coefficient further controls the strength of the selected adapter update. Under a matched Qwen3-8B CMB-source protocol, BiRG-LoRA achieves the highest four-benchmark macro-average accuracy among trainable PEFT baselines and matched routing controls: 69.31% averaged over CMB, CMExam, MedQA, and MedMCQA. It improves over MoELoRA by 0.89 percentage points while using 28.1% fewer trainable parameters; a paired, benchmark-stratified bootstrap over final predictions gives a 95% confidence interval of [0.42, 1.37] for this macro-average gain. Basic controls show that BiRG-LoRA also improves over vanilla LoRA r16 and active-rank-matched LoRA r4 by 0.83 macro points, and an evaluation-time weak-axis perturbation check suggests that performance is not brittle to moderate tag noise. The results support a bounded claim: clinically structured rank allocation improves cross-benchmark medical QA under a matched single-seed protocol, while training-seed variance remains future work.

Drug-drug interaction (DDI) prediction is essential for medication safety, yet it requires reasoning over heterogeneous biomedical evidence whose relevance changes across interaction mechanisms. We propose DDIAgents, a mechanism-conditioned multi-agent framework that performs DDI prediction through dynamic knowledge orchestration. Given a drug pair, a planner agent instantiates specialized expert agents, routes mechanism-relevant knowledge sources to each agent, and aggregates their analyses through a conclusion agent. By adapting context flow to the inferred interaction mechanism, DDIAgents reduces irrelevant information, supports complementary expert reasoning, and produces interpretable agent-level rationales. Extensive experiments on realistic DDI prediction benchmarks show that DDIAgents consistently outperforms existing feature-based, graph-based, LLM-based, and agent-based baselines. Beyond prediction performance, DDIAgents demonstrates how multi-agent systems can organize heterogeneous scientific knowledge for adaptive and interpretable AI4Science reasoning.

Modern large language models (LLMs) reach 60-70% diagnostic accuracy on complex clinical case benchmarks, but accuracy alone cannot distinguish stable clinically-grounded reasoning from pattern matching. We introduce clinical reasoning graphs, structured graph representations extracted from free-text LLM diagnostic traces using a domain-grounded ontology with 5 node types and 7 edge types. We apply this pipeline to 750 traces from five LLMs across 50 New England Journal of Medicine Clinicopathological Conference cases and three prompt conditions, and test whether diagnostic traces show stable structured reasoning patterns, or diagnostic schemas, for clinically similar cases. We operationalize this as higher graph similarity among clinically similar cases than among clinically dissimilar ones. Across 15 model-condition comparisons, within-cluster and between-cluster composite similarity are nearly equal, and no comparison survives multiple-testing correction; a component-level analysis finds any residual content signal far below schema scale. Graph similarity is also nearly identical for pairs of models that are both correct (0.488) and both incorrect (0.484), suggesting that graph structure captures a dimension not reflected in diagnostic accuracy. Structured reflection prompting increases explicit discriminating-feature analysis within traces (+33%) but does not increase cross-case consistency. These results show diagnostic competence without schema-scale reasoning consistency, and indicate that final-answer accuracy should be complemented by process-level evaluation. We release the ontology, extraction pipeline, validation protocol, and the extracted reasoning graphs and similarity artifacts as resources for structured evaluation of LLM clinical reasoning.

Reasoning in multimodal large language models (MLLMs) has shown strong promise in medical imaging. However, this reasoning is usually free-form text judged only by its final answer, making it hard to interpret and verify, especially in 3D radiology, where a diagnosis should be traceable to evidence in the scan. Existing chest CT question-answering datasets compound this by reducing expert radiology reports to answer-only pairs, dropping the reasoning that links findings to conclusions and omitting the patient history clinicians rely on. As a result, reasoning-capable 3D chest CT MLLMs remain out of reach, as neither the structured supervision needed to train them nor the protocol needed to verify their reasoning yet exists. We introduce CORTEX (Clinically Organized Reasoning and sTructured EXplanation), a structured reasoning benchmark for 3D chest CT. For each question, CORTEX restores the missing reasoning as a four-stage diagnostic trace mirroring a radiologist's workflow: task understanding, visual observation, diagnostic reasoning, and answer synthesis. We generate these traces using frontier large language models with broad medical and general-domain knowledge, then filter and verify them with a stage-level evaluation protocol combining automated rubric scoring with expert radiologist review. Crucially, both the reasoning structure and evaluation rubrics are designed in close collaboration with clinicians. Built on CT-RATE, a large, publicly available chest CT dataset without reasoning annotations, CORTEX comprises 76,177 validated reasoning traces across open-ended VQA, closed-ended VQA, and report generation, providing both the structured supervision and the stage-level evaluation protocol needed to build and evaluate trustworthy reasoning models for 3D chest CT. Our dataset and evaluation code is available at https://huggingface.co/datasets/aneesurhashmi/cortex

Large language models (LLMs) have shown promising performance across a wide range of biomedical applications, including medical question answering (QA), yet they remain prone to hallucinations and outdated knowledge. Although retrieval-augmented generation (RAG) can alleviate this issue by incorporating external documents, there still exist two fundamental limitations. First, medical knowledge is often fragmented across documents, while most RAG methods rely on a single retrieval path, which makes it challenging to jointly preserve fine-grained semantic information and structured global associations. Second, static retrieval strategies are typically insufficient to support deep reasoning that is important in complex medical QA. In this paper, we present a dual-path retrieval framework with an iterative retrieval-reasoning mechanism termed "Hybrid-IR" for complex medical QA. The proposed Hybrid-IR integrates graph-based retrieval for exploration of structured knowledge and dense retrieval for fine-grained semantic matching. Moreover, the reasoning trajectory can be progressively refined through an iterative retrieve-reason loop. Experiments on three widely used medical QA benchmarks demonstrate the effectiveness of our Hybrid-IR.

Rare diseases affect millions of individuals worldwide, yet timely diagnosis remains a major public health challenge due to scarcity of specialized clinical expertise. While large language models (LLMs) show promise to support rare disease diagnosis, current models are constrained by insufficient clinical deployability, limited clinically grounded evidence, and scarcity of training data. Here we present RaDaR (Rare Disease navigatoR), an open-source, compact reasoning LLM (32B parameters) for rare disease diagnosis. RaDaR was trained with 49,170 publicly available free-text cases and 104,666 synthetic cases with reasoning-enhanced training. RaDaR showed the strongest performance among evaluated open-source models, including the 671B DeepSeek-R1, across public benchmarks and four external validation centers. In a retrospective cohort, RaDaR prioritized the final diagnosis before documented clinical suspicion in 61.06 percent of cases, corresponding to a potential lead time of 1.87 months and 50.18 percent of the within-center interval. In a randomized physician-assistance trial, RaDaR assistance improved physicians' rare-disease diagnostic accuracy by 21.44 percentage points compared with internet search alone. Synthetic-data ablations suggested that phenotype-anchored narratives provide useful training signal for long-tail rare diseases, with a monotonic scaling trend within the tested data range. Together, RaDaR and its development and validation framework provide a deployable rare-disease reasoning model and a reproducible development framework for diagnostic AI under data scarcity.

Clinical agents promise to democratize access to electronic health records (EHRs), yet existing benchmarks fail to reflect the complexity of practical EHR analysis, e.g., often operating on idealized, clean EHRs via static SQL generation rather than interactive execution. In this work, we introduce EHR-Complex, a large-scale benchmark designed for interactive clinical database reasoning. Built on the large MIMIC-IV substrate (365K patients, 31 tables, 500M+ records), EHR-Complex comprises about 52K tasks spanning six clinical intents, supporting both patient-level and population-level queries, where each task requires an agent to interact with a sandboxed environment by executing SQL queries or Python code. Notably, EHR-Complex considers the real-world SQL task complexity for longitudinal multi-table aggregation and compositional reasoning, resulting in 31.93 SQL structural components per query on average. Evaluation results on EHR-Complex reveal the clinical difficulty of these EHR reasoning scenarios, with the top-performing model achieving only 62.3% exact-match accuracy. Pass^k consistency drops below 50% for nearly all evaluated models at k=4, exposing broad stochastic fragility. A fine-grained analysis of more than 3,800 failed trajectories for representative LLMs reveals three dominant failure modes: SQL logic errors, medical-code lookup failures, and semantic misunderstandings. EHR-Complex provides a rigorous testbed for clinical agents and highlights remaining gaps in robust reasoning for large-scale EHR analysis.

High-stakes reasoning tasks necessitate transparent and verifiable workflows, yet conventional single-model large language models (LLMs) often struggle with hallucination and low interpretability under zero-shot paradigms. To address this general AI challenge, we propose a Multi-Agent Audit Framework that simulates a collaborative, multi-step verification process. We empirically validate this architecture in the sensitive domain of clinical mental health screening using a modular LangChain workflow. Our framework decomposes the reasoning process into a Perception Agent, Knowledge Retrieval-Augmented Generation (RAG), Chain-of-Thought (CoT) clinical inference, and a critical Audit verification stage. We evaluated this framework on the DAIC-WOZ dataset using locally deployed open-source models. Experimental results demonstrate that our multi-agent pipeline significantly outperforms single-agent baselines, reducing the Mean Absolute Error (MAE) for PHQ-8 depression severity prediction from 5.35 to 5.02. By exposing cross-agent validation traces, the framework mitigates reasoning drift and provides highly interpretable diagnostic rationales, offering a generalizable paradigm for reliable AI-assisted decision support beyond isolated model scaling. We make data and code open access on GitHub for replicability.

Real-world clinical decision support requires reasoning over heterogeneous and longitudinal patient information rather than answering isolated medical questions. However, current medical large language models and retrieval-augmented generation systems often rely on single-step prompting or retrieval, which can be fragile when clinical evidence is distributed across long electronic health records, medical images, sensor streams, guidelines, and referral constraints. This paper proposes MedRLM, a Recursive Multimodal Health Intelligence framework for long-context clinical reasoning, sensor-guided screening, and community-to-tertiary referral support. Instead of compressing all patient information into one prompt, MedRLM treats the patient case as an external clinical environment that can be recursively inspected, decomposed, retrieved, verified, and synthesized. The framework coordinates specialized agents for clinical text, longitudinal EHR, medical imaging, physiological sensor signals, guideline retrieval, uncertainty auditing, and referral planning. It further introduces a Clinical Evidence Graph Memory to connect patient-specific observations with retrieved evidence, standardized definitions, sensor-derived biomarkers, and referral criteria. A sensor-guided recursive triggering mechanism activates deeper reasoning when abnormal physiological or behavioral patterns are detected, while uncertainty-gated refinement supports clinician review for high-risk or low-confidence cases. We also outline a real-data evaluation design using public and credentialed clinical datasets spanning EHR, radiology, ECG, ICU time series, and referral-proxy outcomes. MedRLM aims to move medical AI from static question answering toward auditable, multimodal, and workflow-aware clinical decision support.

Chronic wound assessment remains a clinically challenging task that requires accurate interpretation of wound morphology, tissue composition, vascular characteristics, and infection risk. Recent advances in Vision-Language Models (VLMs) have introduced the possibility of automated multimodal wound analysis through image understanding combined with clinical reasoning. This study evaluates the performance of several general-purpose and medically specialized open-source and proprietary VLMs for clinical wound assessment using an expanded, curated dataset of 20 clinically diverse wounds spanning vascular, surgical, ischemic, venous, lymphedema, and amputation-related etiologies. Six VLMs were evaluated using a structured twelve-question clinical framework covering wound classification, infection risk, vascular intervention recommendations, debridement urgency, wound therapy selection, and advanced management planning. Across 20 wound cases and 240 clinician-graded wound-analysis decisions, ChatGPT achieved the highest overall performance with 174/240 correct responses (72.50%), followed by Claude with 149/240 (62.08%). Among the open-source and medically specialized models, HuluMed achieved the strongest performance with 96/240 correct responses (40.00%), followed by Gemma 3 (81/240, 33.75%), MedGemma 4B (62/240, 25.83%), and MedGemma 27B (42/240, 17.50%). The findings suggest that frontier general-purpose multimodal systems currently demonstrate substantially stronger wound-analysis performance than medically specialized alternatives, highlighting the continued importance of broad multimodal reasoning capabilities alongside domain-specific medical knowledge. Although current VLMs demonstrate promising potential for clinical decision support, substantial limitations remain in advanced wound-management reasoning, procedural planning, and autonomous clinical reliability.

Aggregate accuracy benchmarks conceal a systematic structure in how large language models fail at electronic health record (EHR) question answering: questions requiring more inferential steps produce disproportionately more errors. Motivated by theoretical results on transformer compositionality limits, we introduce a pre-specified hop-count taxonomy -- the number of distinct reasoning steps required to answer a clinical question from an EHR -- as a principled predictor of model failure. We annotate 313 clinician-generated MedAlign EHR question-answer pairs across four hop levels and evaluate 301 questions in a within-model ablation (claude-sonnet-4-6, zero-shot vs. extended thinking) and cross-architecture replications (gpt-4o and gpt-5.4-2026-03-05, zero-shot). All three models, spanning two providers and two OpenAI generations (GPT-4 and GPT-5), show monotone accuracy decline with hop count: Claude Sonnet zero-shot falls from 30.6% (hop=1) to 17.6% (hop=4) (Cochran-Armitage z=-2.30, p=0.011; OR per hop 0.72, 95% CI [0.56,0.92], p=0.008); GPT-4o replicates this (37.8% to 14.7%; OR 0.58 [0.45,0.75], p<0.001); and gpt-5.4-2026-03-05 confirms it (37.8% to 23.5%; OR 0.80 [0.66,0.98], p=0.027). A pre-specified context-sufficiency audit shows higher-hop questions are not differentially disadvantaged by EHR truncation (answerability 93-95% at hops 2-4 vs. 79% at hop=1), so the decline reflects compositional reasoning difficulty. Extended thinking did not significantly flatten the accuracy-depth curve across three reasoning conditions, and thinking-token usage scaled with hop count (r=0.31, p<0.0001), consistent with the predicted O(k) computational requirement. Hop count is thus a theory-motivated, cross-architecture predictor of large-language-model error on EHR question answering, with direct implications for deployment risk stratification of clinical AI.

Rare disease diagnosis depends on expert reasoning that is scarce and difficult to transfer. Large language models rank the correct disease first in only 35.4% of benchmark cases and often rely on learned phenotype-disease associations rather than reusable diagnostic reasoning strategies. We developed liteOdyssey through Policy Iteration with Human Feedback, a process in which model failures and expert corrections are iteratively consolidated into a clinician-gated, natural-language policy executed by a language model. Across 1,243 public benchmark cases spanning 722 rare diseases, liteOdyssey ranked the correct disease first in 59.3% of cases versus 26.5% without the policy, with comparable gains in cases involving diseases excluded from policy development. The same policy transferred across model families and sizes without retraining. Adaptation of the policy to the Undiagnosed Diseases Network (UDN) improved diagnostic accuracy among 515 UDN patients, with gains confirmed by blinded physician adjudication. These results show that expert reasoning can be externalized into an inspectable and revisable natural-language policy that generalizes across rare diseases, transfers across model backbones, and adapts to a real-world patient cohort.

Historical medical archives and traditional medicines hold immense potential for drug discovery and remain a primary source for current drug development. However, pre-ontological prose and idiosyncratic taxonomies prevent the standardization and medical modernization of the data for use in current biomedical pipelines. Furthermore, no existing LLM agent system, whether tool-calling, retrieval-augmented, or agentic deep-research, can convert such text into verifiable drug-discovery leads at scale. We close this gap with DeepRoot, a multi-agent LLM system that jointly builds and utilizes a verified knowledge graph, showing that grounding and reasoning -- often conflated -- are separable axes the system can compose for therapeutic reasoning. Applied to the Shen Nong Ben Cao Jing, DeepRoot recovers $10$ of $21$ held-out compound-disease treatment pairs at R@$20$ ($47.6\%$ vs $4.8\%$ for a raw corpus LLM and $\sim\!2.4\%$ random) and dominates an LLM-as-judge audit for reasoning quality over baseline LLMs and LLMs with direct tool-call access to the same APIs DeepRoot itself queries. Tool-using LLMs hallucinate evidence on $87\%$ of claims, versus 7-10% for DeepRoot. Graph-only inference hallucinates $0\%$ but ranks lowest on reasoning coherence; DeepRoot KG+LLM is the only condition to win on both axes, pointing toward a route for systematic mining and repurposing of historical medical knowledge.

Building trustworthy medical multimodal large language models (MLLMs) is critical for reliable clinical decision support. Existing medical hallucination benchmarks mainly focus on data collection, but often ignore where hallucinations originate within the reasoning process. We find that hallucination sources vary across samples: errors may arise from visual misrecognition, incorrect medical knowledge recall, or flawed reasoning integration. To enable source-level hallucination diagnosis, we introduce ClinHallu, a benchmark for stage-wise hallucination diagnosis in medical MLLM reasoning. ClinHallu contains 7,031 validated instances, where each instance is augmented with a structured reasoning trace decomposed into Visual Recognition, Knowledge Recall, and Reasoning Integration. We also use stage-replacement interventions to measure how correcting specific stages affects the final answer. Beyond evaluation, we show that trace-supervised fine-tuning reduces stage-wise hallucinations. ClinHallu provides a fine-grained hallucination testbed for diagnosing and mitigating reasoning failures in medical MLLMs. The benchmark is publicly available at https://github.com/alibaba-damo-academy/ClinHallu.

Mental health problems such as anxiety, depression, and suicide remain urgent global challenges, where timely and accurate assessment is critical for effective intervention. Recently, large language models have been explored for mental health assessment. However, existing general-purpose post-training methods do not align with the cognitive processes of human assessment, which may lead to unreliable reasoning outcomes. To bridge this gap, we propose Cognitive Relative Policy Optimization (CRPO), a reinforcement learning framework tailored for the mental health domain. CRPO extends group relative policy optimization by integrating stage-dependent uncertainty modeling into the policy optimization process. Specifically, we introduce a stage-wise entropy regularization mechanism that encourages broad exploration in early reasoning phases and progressively enforces confident decision-making in later stages, mimicking the human cognitive shift from uncertainty to certainty. In addition, inspired by cognitive appraisal theory, we formalize cognitive reasoning stages, thereby guiding theory-grounded interpretable inference. Experiments on 8 mental health datasets show that CRPO achieves an average improvement of 10.4 percentage points in weighted F1-score over the best reinforcement learning baseline. Furthermore, the CRPO-trained model Mental-R1 demonstrates clear advantages compared with existing large language models on reasoning-intensive cases, suggesting that CRPO enhances reasoning capabilities for mental health assessment.

Large language models (LLMs) in medicine are mainly evaluated using multiple-choice question answering (MCQA), which can overestimate real clinical ability due to guessing strategies and answer biases. To address these limitations, we introduce an expanded and more challenging benchmark based on Polish medical exams, adding over 15,000 questions, two new domains, and four structural modifications that reduce MCQA-specific artifacts and better test reasoning. We evaluate 21 LLMs and show that evaluation design strongly affects results. Under our harder setup, the best model (Qwen3.5-122B) drops by 28.4 and 31 pp on English and Polish exams, respectively. Despite low evidence of data contamination, standard MCQA scores do not reliably reflect true medical competence. To facilitate further research, we make our benchmark publicly available.

Diagnosing pulmonary diseases requires integrating heterogeneous evidence amid phenotypic variability and cross-disease overlap. Although large language models (LLMs) have shown progress on pulmonary knowledge question answering (QA) and information-processing tasks, reliable pulmonary diagnosis requires patient-specific, relation-aware reasoning over electronic medical record (EMR) evidence rather than isolated knowledge recall. We define this gap between pulmonary knowledge and case-level diagnostic reasoning as the Pulmonary Knowledge-to-Diagnosis Gap. To address it, we introduce LungKG, the first structured pulmonary knowledge graph for diagnostic knowledge organization and record-grounded reasoning. LungKG contains 59,038 nodes and 164,308 edges across 15 entity types and 112 relation types, serving as both a reusable pulmonary knowledge resource and the foundation for LungKG-guided model adaptation. Built on LungKG, we propose Lung-R1, a LungKG-guided pulmonary LLM trained through KG-constrained reasoning-chain construction and KG-guided reinforcement learning. In a 20-system evaluation, Lung-R1-14B achieves state-of-the-art performance across Choice, Pulmonary-QA, and EMR Diagnosis, reaching an EMR Diagnosis score of 4.3583 and surpassing the strongest non-Lung-R1 baseline by 0.1476 points. These results demonstrate the value of LungKG-guided training for EMR-based pulmonary diagnosis.

Objective: Conformance checking in healthcare seeks to assess whether patient care pathways adhere to clinical guidelines. However, its practical application often depends on the availability of formal, machine-interpretable representations of guidelines, such as Computer-Interpretable Guidelines (CIGs), which are seldom available in real-world clinical settings. Methods: This work introduces a modular framework based on the orchestration of Large Language Models (LLMs) to support medical conformance checking directly from unstructured clinical and guideline texts, without requiring predefined CIGs. The proposed architecture integrates multiple LLMs and supporting components to extract patient traces from clinical discharge letters, identify normative rules from textual clinical guidelines, translate these rules into executable scripts, and compute a Trace Conformance Indicator to quantify compliance within the event log. Results: The framework was implemented and evaluated in the stroke care domain at the neurological ward of Alessandria Hospital. Hundreds of patient traces were automatically extracted from hospital data and assessed against 50 rules derived from the reference guideline. The analysis showed that more than 86% of the available traces were conformant. Conclusion: The results demonstrate the feasibility of using orchestrated LLMs for practical healthcare conformance analysis. At the same time, the study provides evidence of a high level of adherence to stroke care guidelines at Alessandria Hospital.

Clinical early warning systems built on electronic health records, in which clinical observations are recorded as irregularly sampled medical time series (ISMTS), must deliver both calibrated risk scores for patient triage and interpretable rationales that clinicians can verify. Large Language Models (LLMs) have been explored for this task, yet they collapse graded clinical risk into overconfident binary predictions. This risk polarization undermines both calibration and cross-patient comparability. To address this, we propose TRIAGE, a framework that trains an LLM to generate dialectical reasoning over competing clinical outcomes by eliciting outcome-specific rationales. This dialectical formulation mitigates risk polarization, enabling a single LLM to yield continuous risk scores grounded in explicit clinical reasoning. Evaluated on three ISMTS benchmarks, TRIAGE achieves an average AUPRC improvement of 3.3% and reduces calibration error by 81% compared to the competitive baselines. An LLM-as-a-judge assessment further shows that our rationales surpass post-hoc explanations from the baseline by 20% in clinical reasoning quality. The source code is available at https://github.com/HyeongWon-Jang/TRIAGE .

Reliable evaluation of large language models in surgery remains underdeveloped. Broad medical benchmarks test clinical knowledge, while surgery requires procedural reasoning, management trade-offs, negation handling, and selection among plausible operative decisions. We present SurgiQ, a text-only, source-grounded benchmark of 13,055 four-option multiple-choice questions spanning six surgical domains and four question formats: case-based, reasoning, best-option, and negative. SurgiQ is constructed from surgical textbooks, open-access papers, and examination material using a multi-stage generation, verification, and expert-audit pipeline. We evaluate 35 open-weight LLMs under a unified log-likelihood protocol. Our results show substantial remaining headroom: smaller models often remain near the 25% random baseline, while the best model reaches 68.1% accuracy. General-purpose models, especially Qwen2.5, outperform most biomedical models, suggesting that current medical specialization does not yet provide sufficiently broad surgical coverage. Calibration and error analysis further show that even strong models make confident mistakes on clinically plausible distractors, motivating more reliable and broader surgical LLM evaluation.

Breast cancer remains a leading cause of cancer-related mortality among women. Its clinical management requires multimodal reasoning across a clinical workflow that spans \textit{screening}, \textit{diagnosis} and \textit{treatment planning}, where each stage involves distinct imaging modalities, task objectives, and reasoning patterns. However, constrained by data scarcity and model versatility, existing medical MLLMs are typically evaluated on isolated modalities or narrow task families, limiting their ability to support workflow-level clinical reasoning. In this work, we first introduce \textbf{BreastStage}, a workflow-aligned breast imaging instruction corpus comprising 1.86M instruction-following pairs curated from 17 sub-datasets across 5 imaging modalities and 136 task templates. Its held-out split, \textbf{BreastStage-Bench}, provides a comprehensive benchmark for evaluating multimodal reasoning across the breast cancer care continuum. Building on this corpus, we propose \textbf{BreastGPT}, a unified MLLM equipped with a dual-branch visual encoder and concept-preserving token compression to bridge the scale gap between standard radiology and gigapixel pathology. On BreastStage-Bench, BreastGPT achieves 75.66% closed-ended accuracy and 89.92% open-ended score, outperforming both general-purpose and medical-specific MLLMs across clinical stages and task formats. These results suggest that workflow-aligned data and cross-scale visual modeling are critical for clinically grounded medical MLLMs. All data, code, and model checkpoints are released at https://yangyy-liu.github.io/BreastGPT.io.

Clinical AI evaluation increasingly delegates scoring to large language models (LLMs) acting as AI raters, yet their scoring behavior across evaluation conditions has not been quantitatively characterized. We address this gap through a factorial study of AI rater behavior in adult type 2 diabetes (T2D) pharmacotherapy at 12-month outpatient follow-up, a clinical task involving complex decision-making operationalized across seven evaluation questions. Four open-source LLMs served simultaneously as clinical decision support system (CDSS) models and AI raters. Each CDSS output was scored under two scoring protocols: a rubric-anchored Gold Rubric (GR) protocol incorporating a patient-specific rubric, and a rubric-free Non Gold Rubric (Non-GR) protocol. Linear mixed effects models crossed the scoring protocol factor with five design factors -- CDSS model, CDSS prompt configuration (document-referenced generation [DRG] vs.\ Baseline), rater model, prompt character, and prompt type -- and estimated main effects together with their protocol interactions. Across all questions, AI raters yielded consistently higher scores within a very narrow range (74--78 points on average) under Non-GR compared to those under GR (7.69 to 49.64 points lower mean scores; 1.68 to 3.67 times wider interquartile ranges). Within each question, GR amplified the AI rater's discrimination between DRG and Baseline CDSS outputs by factors of 1.76 to 5.10, while also revealing substantial behavioral variation across rater models that Non-GR suppressed. These findings support rubric anchoring as the scoring protocol that preserves discriminative power in clinical AI evaluation; rubric-free scoring cannot substitute when questions require patient-specific or jurisdiction-specific criteria that rater models cannot infer from parametric knowledge alone.

Large language models (LLMs) exhibit strong natural-language reasoning abilities for clinical decision support, but struggle to effectively model structured longitudinal electronic health records (EHRs). In contrast, EHR foundation models can learn predictive patient representations, yet lack interpretable language-based reasoning. To bridge this gap, we propose ChatHealthAI, a multimodal reasoning framework that aligns structured EHR representations from a pretrained EHR foundation model with the semantic space of a frozen LLM through a task-aware resampler. By integrating longitudinal patient representations with refined clinical event descriptions, ChatHealthAI enables clinically grounded natural-language reasoning while maintaining accurate patient prediction. We evaluated ChatHealthAI on three clinical predictive tasks from the EHRSHOT benchmark. Results show that ChatHealthAI improves reasoning quality and interpretability while preserving competitive predictive performance. These findings highlight the potential of integrating EHR foundation models with pretrained LLMs for interpretable clinical prediction.