Medical LLMs

Background: The potential of large language models (LLMs) to automate and support pharmacoepidemiologic study design is an emerging area of interest, yet their reliability remains insufficiently characterized. General-purpose LLMs often display inaccuracies, while the comparative performance of specialized biomedical LLMs in this domain remains unknown. Methods: This study evaluated general-purpose LLMs (GPT-4o and DeepSeek-R1) versus biomedically fine-tuned LLMs (QuantFactory/Bio-Medical-Llama-3-8B-GGUF and Irathernotsay/qwen2-1.5B-medical_qa-Finetune) using 46 protocols (2018-2024) from the HMA-EMA Catalogue and Sentinel System. Performance was assessed across relevance, logic of justification, and ontology-code agreement across multiple coding systems using Least-to-Most (LTM) and Active Prompting strategies. Results: GPT-4o and DeepSeek-R1 paired with LTM prompting achieved the highest relevance and logic of justification scores, with GPT-4o-LTM reaching a median relevance score of 4 in 8 of 9 questions for HMA-EMA protocols. Biomedical LLMs showed lower relevance overall and frequently generated insufficient justification. All LLMs demonstrated limited proficiency in ontology-code mapping, although LTM provided the most consistent improvements in reasoning stability. Conclusion: Off-the-shelf general-purpose LLMs currently offer superior support for pharmacoepidemiologic design compared to biomedical LLMs. Prompt strategy strongly influenced LLM performance.

Large Language Models (LLMs) have shown strong promise for mining Electronic Health Records (EHRs) by reasoning over longitudinal clinical information to capture context-rich patient trajectories. However, leveraging LLMs for structured EHRs (e.g., standardized diagnosis and medication codes) presents two key challenges. First, translating time-stamped EHR sequences into plain text can obscure both temporal structure and code identities, weakening the ability to capture code co-occurrence and longitudinal regularities. Second, unlike cohort-trained predictive models that learn a shared, task-aligned representation space across patients, LLMs are often applied in a case-isolated inference setting where each patient is processed independently without leveraging population-level patterns. To address these challenges, we introduce RePrompT, a time-aware LLM framework that integrates structured EHR encoders through prompt tuning, without modifying underlying architectures. Specifically, RePrompT recurrently incorporates latent states from prior visits to preserve longitudinal information, and injects population-level information through trainable prompt tokens derived from a cohort-trained, task-aligned EHR encoder. Experiments on MIMIC-III and MIMIC-IV demonstrate that RePrompT consistently outperforms both EHR-based and LLM-based baselines across multiple clinical prediction tasks.

Large language models are increasingly deployed to simulate patients for clinical training, research, and mental health tools, yet population-level validity remains largely untested. We introduce PsychBench, the first epidemiological audit of LLM patient simulation: 28,800 profiles from four frontier models (GPT-4o-mini, DeepSeek-V3, Gemini-3-Flash, GLM-4.7) evaluated against NHANES and NESARC-III baselines across 120 intersectional cohorts. The central finding is a coherence-fidelity dissociation: models produce clinically plausible individuals while misrepresenting the populations they are drawn from. Variance compression ranges from 14 percent (GLM-4.7) to 62 percent (DeepSeek-V3), eliminating the distributional tails of clinical reality. Despite test-retest correlations above r = 0.90, 36.66 percent of cases cross diagnostic thresholds between runs. Symptom correlation matrices diverge across demographic groups beyond split-half noise, with transgender populations diverging three to five times more than racial differences. Calibration bias is systematic and asymmetric. Models overestimate depression severity for most groups by 3.6 to 6.1 points (Cohen d = 1.13 to 1.91), consistent with training on clinical corpora with elevated base rates. For transgender women the direction inverts: models capture only 8 to 46 percent of documented minority stress elevation, yielding a -5.42 residual (d = -1.55). Models also attribute irritability to Black men and fatigue to women beyond matched controls, encoding racialized and gendered assumptions. Patterns replicate across US and Chinese architectures, indicating failures tied to current training paradigms rather than isolated implementations. For most users, LLM mental health tools risk pathologizing ordinary distress; for transgender users, algorithmic erasure of genuine need. The patients look right. They do not represent real populations.

Background: Large language models (LLMs) are increasingly proposed for diagnostic support, but few evaluations use real-world multimodal inpatient data, particularly in low and middle-income country (LMIC) public hospitals. Methods: We conducted VALID, a retrospective evaluation of 539 multimodal inpatient cases from a tertiary public hospital in South Africa. Inputs included radiology imaging (CT, MRI, CXR) and reports, laboratory results, clinical notes, and vital signs. Expert panels adjudicated 300 cases (balanced and discordant subsets) to establish ground truth diagnoses, differentials, and reasoning. Ten multimodal LLMs generated zero-shot outputs. A calibrated three-model LLM Jury scored all outputs and routine ward diagnoses across diagnostic accuracy, differential quality, reasoning, and patient safety (>10,000 evaluations). Primary outcomes were composite scores ($S_3$, $S_4$) and win rates. Results: (i) LLM performance was tightly clustered (<15% variation) despite large cost differences; low-cost models performed comparably to top models. (ii) All LLMs significantly outperformed routine ward diagnoses on average diagnostic and safety scores. (iii) Top performance was achieved by GPT-5.1, followed by Gemini models. (vi) Adding radiology reports improved performance by 6%. (v) Diagnostic and reasoning scores were highly correlated ($ρ= 0.85$). (vi) Output rates varied (65-100%) due to input constraints. Results were robust across subsets and evaluation design. Conclusions: Across a real-world LMIC dataset, multimodal LLMs showed similar diagnostic performance despite large cost differences and outperformed routine care on average safety metrics. Affordability, robustness, and deployment constraints may outweigh marginal performance differences in LMIC settings.

Large Language Models (LLMs) have shown strong promise in healthcare applications. Yet deploying general-purpose models in real-world settings remains difficult due to data privacy constraints, inference costs, and limited suitability for edge or on-device use. These challenges motivate the development of smaller, more efficient models that require robust post-training strategies to ensure reliable medical reasoning. In this work, we investigate Group Relative Policy Optimization (GRPO) for post-training LLMs on heart-focused medical question answering with rubric-based supervision derived from RaR-Medicine. We propose a Variance-Aware Reward Framework that extends the Explicit Aggregation and Implicit Aggregation strategies of Rubrics as Rewards by replacing weighted binary criterion aggregation and single overall Likert-style scoring with continuous analytical reward functions derived from criterion-level rubric outcomes. This formulation provides richer optimization signals for feedback that is sparse, multi-criteria, and difficult to verify automatically, and enables more stable on-policy reinforcement learning. On a held-out heart-related subset of HealthBench, our best GRPO variant improves accuracy from 0.362 to 0.502 and F1 from 0.532 to 0.668 relative to the Qwen3-14B base model, while remaining competitive with GPT-OSS-120B (0.508 accuracy, 0.674 F1). Our findings show that carefully designed rubric-based rewards provide a practical strategy for improving heart-focused medical question answering in LLMs, with potential to extend to other rubric-based tasks.

Continuous glucose monitoring (CGM) is central to diabetes care, but explaining CGM patterns clearly and empathetically remains time-intensive. Evidence for retrieval-grounded large language model (LLM) systems in CGM-informed counseling remains limited. To evaluate whether a retrieval-grounded LLM-based conversational agent (CA) could support patient understanding of CGM data and preparation for routine diabetes consultations. We developed a retrieval-grounded LLM-based CA for CGM interpretation and diabetes counseling support. The system generated plain-language responses while avoiding individualized therapeutic advice. Twelve CGM-informed cases were constructed from publicly available datasets. Between Oct 2025 and Feb 2026, 6 senior UK diabetes clinicians each reviewed 2 assigned cases and answered 24 questions. In a blinded multi-rater evaluation, each CA-generated and clinician-authored response was independently rated by 3 clinicians on 6 quality dimensions. Safety flags and perceived source labels were also recorded. Primary analyses used linear mixed-effects models. A total of 288 unique responses (144 CA and 144 clinician) generated 864 ratings. The CA received higher quality scores than clinician responses (mean 4.37 vs 3.58), with an estimated mean difference of 0.782 points (95% CI 0.692-0.872; P<.001). The largest differences were for empathy (1.062, 95% CI 0.948-1.177) and actionability (0.992, 95% CI 0.877-1.106). Safety flag distributions were similar, with major concerns rare in both groups (3/432, 0.7% each). Retrieval-grounded LLM systems may have value as adjunct tools for CGM review, patient education, and preconsultation preparation. However, these findings do not support autonomous therapeutic decision-making or unsupervised real-world use.

Large language models (LLMs) show promise in generating supportive responses for mental health and counseling applications. However, their responses often lack cultural sensitivity, contextual grounding, and clinically appropriate guidance. This work addresses the gap of how to systematically incorporate domain-specific, clinically validated knowledge into LLMs to improve counseling quality. We utilize and compare two approaches, retrieval-augmented generation (RAG) and a knowledge graph (KG)-based method, designed to support para-counselors. Our KG is constructed manually and clinically validated, capturing causal relationships between stressors, interventions, and outcomes, with contributions from multidisciplinary people. We evaluated multiple LLMs in both settings using BERTScore F1 and SBERT cosine similarity, as well as human evaluation across five metrics, which is designed to directly measure the effectiveness of counseling beyond similarity at the surface level. The results show that KG-based approaches consistently improve contextual relevance, clinical appropriateness, and practical usability compared to RAG alone, demonstrating that structured, expert-validated knowledge plays a critical role in addressing LLMs limitations in counseling tasks.

Acute poly-substance intoxication requires rapid, life-saving decisions under substantial uncertainty, as clinicians must rely on incomplete ingestion details and nonspecific symptoms. Effective diagnostic reasoning in this chaotic environment requires fusing unstructured, non-medical narratives (e.g. paramedic scene descriptions and unreliable patient self-reports or known histories), with structured medical data like vital signs. While Large Language Models (LLMs) show potential for processing such heterogeneous inputs, they struggle in this setting, often underperforming simple baselines that rely solely on patient histories. To address this, we present DeToxR (Decision-support for Toxicology with Reasoning), the first adaptation of Reinforcement Learning (RL) to emergency toxicology. We design a robust data-fusion engine for multi-label prediction across 14 substance classes based on an LLM finetuned with Group Relative Policy Optimization (GRPO). We optimize the model's reasoning directly using a clinical performance reward. By formulating a multi-label agreement metric as the reward signal, the model is explicitly penalized for missing co-ingested substances and hallucinating absent poisons. Our model significantly outperforms its unadapted base LLM counterpart and supervised baselines. Furthermore, in a preliminary clinical validation study, the model indicates a clinical advantage by achieving higher micro-F1 (0.644 vs 0.473) and recall in identifying the correct poisons. These results demonstrate the potential of RL-aligned LLMs to synthesize unstructured pre-clinical narratives and structured medical data for decision support in high-stakes environments.

Large language models (LLMs) are increasingly used for medical consultation and health information support, where safety depends not only on medical knowledge but also on robust responses to unclear, inconsistent, or misleading patient input. However, most existing medical LLM evaluations assume idealized and well-posed patient questions, limiting their realism. We study challenging patient behaviors that commonly arise in real medical consultations and complicate safe clinical reasoning. We define four clinically grounded categories of such behaviors: information contradiction, factual inaccuracy, self-diagnosis, and care resistance. For each behavior, we specify concrete failure criteria that capture unsafe responses. Building on four existing medical dialogue datasets, we introduce CPB-Bench (Challenging Patient Behaviors Benchmark), a bilingual (English and Chinese) benchmark of multi-turn dialogues annotated for these behaviors. We find that although models perform well overall, they exhibit consistent behavior-specific failures, especially when handling contradictory or medically implausible patient information. We further evaluate four intervention strategies and find inconsistent improvements, with some interventions introducing unnecessary corrections.

Assessing whether an article supports an assertion is essential for hallucination detection and claim verification. While large language models (LLMs) have the potential to automate this task, achieving strong performance requires frontier models such as GPT-5 that are prohibitively expensive to deploy at scale. To efficiently perform biomedical evidence attribution, we present Med-V1, a family of small language models with only three billion parameters. Trained on high-quality synthetic data newly developed in this study, Med-V1 substantially outperforms (+27.0% to +71.3%) its base models on five biomedical benchmarks unified into a verification format. Despite its smaller size, Med-V1 performs comparably to frontier LLMs such as GPT-5, along with high-quality explanations for its predictions. We use Med-V1 to conduct a first-of-its-kind use case study that quantifies hallucinations in LLM-generated answers under different citation instructions. Results show that the format instruction strongly affects citation validity and hallucination, with GPT-5 generating more claims but exhibiting hallucination rates similar to GPT-4o. Additionally, we present a second use case showing that Med-V1 can automatically identify high-stakes evidence misattributions in clinical practice guidelines, revealing potentially negative public health impacts that are otherwise challenging to identify at scale. Overall, Med-V1 provides an efficient and accurate lightweight alternative to frontier LLMs for practical, real-world biomedical evidence attribution. Med-V1 is available at https://github.com/NLM-DIR/Med-V1.

Privacy and computational constraints limit the use of large language models in psychiatry, while adapting small language models (SLMs) often requires substantial data and expert annotation. We developed ClinMPO, an evidence-guided reinforcement-learning framework guided by the psychiatrist-defined Clinical Psychiatry Thinking Strategy (CPTS). ClinMPO uses ClinRM, a reward model trained on 18,569 question--answer pairs from 4,474 psychiatry articles. We evaluated four Qwen3 sizes on 1,737 model-screened questions. ClinMPO outperformed Base, supervised fine-tuning and standard group relative policy optimization across scales. From responses by 300 senior pre-licensure medical students, we established the human baseline, a medical-student reference. The 4B model approached this baseline, whereas the 8B model surpassed it and ranked first among 31 models and post-training variants. ClinMPO improved performance across two complementary schemes covering ICD-11 diagnostic categories and psychiatric practice competencies. Blinded assessment by three clinicians showed improved rationale quality across CPTS criteria. These findings highlight how existing clinical evidence and specialist knowledge can be incorporated into the development of medical AI systems through evidence-guided learning.

Large language models (LLMs) deployed in clinical decision support may acquiesce to patient requests for care that conflicts with evidence-based guidelines. We developed SycoEval-EM, a multi-agent simulation framework to evaluate LLM robustness to adversarial patient persuasion in emergency medicine. Across 19 contemporary LLMs and 1,425 simulated clinical encounters spanning three Choosing Wisely scenarios, acquiescence rates ranged from 0% to 100%, revealing a bimodal distribution. Seven models maintained near-perfect guideline adherence, while six acquiesced in the majority of encounters. Vulnerability varied substantially across clinical scenarios. Acquiescence was highest for CT imaging requests, intermediate for antibiotic prescriptions for sinusitis, and lowest for opioid prescriptions for acute back pain. Model scale, recency, and performance on static medical benchmarks did not consistently predict robustness. All five persuasion tactics produced similar acquiescence rates, with no statistically significant differences after correction for multiple comparisons, suggesting a generalized susceptibility rather than tactic-specific weaknesses. LLM-as-judge evaluation was validated against two independent physician raters across 95 matched conversations and demonstrated near-perfect agreement for the primary outcome of acquiescence (Cohens kappa = 0.957). These findings indicate that static medical benchmarks are insufficient to predict safety performance under sustained social pressure and support incorporating multi-turn adversarial testing into clinical AI evaluation. Notably, two models achieved perfect guideline adherence across all encounters, demonstrating that robustness to patient pressure is attainable without sacrificing effective clinical communication.

Counterfactual explanations (CFEs) provide human-centric interpretability by identifying the minimal, actionable changes required to alter a machine learning model's prediction. Therefore, CFs can be used as (i) interventions for abnormality prevention and (ii) augmented data for training robust models. We conduct a comprehensive evaluation of CF generation using large language models (LLMs), including GPT-4 (zero-shot and few-shot) and two open-source models-BioMistral-7B and LLaMA-3.1-8B, in both pretrained and fine-tuned configurations. Using the multimodal AI-READI clinical dataset, we assess CFs across three dimensions: intervention quality, feature diversity, and augmentation effectiveness. Fine-tuned LLMs, particularly LLaMA-3.1-8B, produce CFs with high plausibility (up to 99%), strong validity (up to 0.99), and realistic, behaviorally modifiable feature adjustments. When used for data augmentation under controlled label-scarcity settings, LLM-generated CFs substantially restore classifier performance, yielding an average 20% F1 recovery across three scarcity scenarios. Compared with optimization-based baselines such as DiCE, CFNOW, and NICE, LLMs offer a flexible, model-agnostic approach that generates more clinically actionable and semantically coherent counterfactuals. Overall, this work demonstrates the promise of LLM-driven counterfactuals for both interpretable intervention design and data-efficient model training in sensor-based digital health. Impact: SenseCF fine-tunes an LLM to generate valid, representative counterfactual explanations and supplement minority class in an imbalanced dataset for improving model training and boosting model robustness and predictive performance

Healthcare systems around the world are grappling with issues such as inefficient diagnostics, rising costs, and limited access to specialists. These challenges often contribute to delays in treatment and poorer health outcomes. Most existing AI and deep learning based health assessment systems offer limited interactivity and transparency, reducing their usefulness for user-centered health support. This research introduces a conversational chatbot powered by a Large Language Model (LLM), using GPT-4o, Retrieval-Augmented Generation, and explainable AI techniques. The chatbot engages users in a dynamic conversation to extract and normalize symptoms while identifying and ranking potential health conditions through similarity matching and adaptive questioning. Using Chain-of-Thought prompting, the system also provides more transparent explanations of its reasoning process. When evaluated against traditional machine learning models, including Naive Bayes, Logistic Regression, SVM, Random Forest, and KNN using both TF-IDF and CountVectorizer feature extraction, the proposed LLM-based system achieved a Top-1 accuracy of 90% and a Top-3 accuracy of 100%. The system was additionally evaluated through a cross-sectional expert evaluation involving 17 physicians across all 14 conditions, with the results indicating generally favorable assessments of conversational quality, early diagnostic plausibility, and safety-related criteria. These findings demonstrate the potential of explainable conversational AI as a health and well-being support tool for early symptom assessment. However, the proposed system is not intended for clinical diagnosis or clinical decision-making, and further validation would be required before any use in healthcare practice.

People use LLMs for reproductive-health questions, including abortion-related support. A response can sound supportive while answers reinforce harmful assumptions: judgment is likely, secrecy is safer, and support is limited. We introduce behavioral coherence evaluation, a design-time method that uses validation evidence from an established instrument to test relations among outputs. Using the Individual Level Abortion Stigma Scale, we prompted five LLMs to complete questionnaires for 627 personas and reviewed flagged patterns with five reproductive-health experts. Models scored personas lower on self-judgment but higher on worries about judgment; most made worries the highest-scoring dimension, although it was lowest in the ILAS reference sample. Four of five models reversed the reference direction by generating significantly higher worries about judgment scores for Black personas. Models defaulted to extreme secrecy after abortion despite varying stigma patterns across personas. Expert review showed that disclosure guidance requires context about relationship safety, legal risk, and trusted support.

Large Language Models (LLMs) with reasoning capabilities have recently demonstrated strong potential in medical Question Answering (QA). Existing approaches are largely English-focused and primarily rely on distillation from general-purpose LLMs, raising concerns about the reliability of their medical knowledge. In this work, we present a method to generate multilingual reasoning traces based on medical knowledge extracted from Wikipedia. We produce 500k traces in English, Italian, and Spanish, using a retrieval-augmented generation approach over medical information from Wikipedia. The traces are generated to solve medical questions drawn from MedQA and MedMCQA, which we extend to Italian and Spanish. We test our pipeline in both in-domain and out-of-domain settings across Medical QA benchmarks, and demonstrate that our reasoning traces improve performance both when utilized via in-context learning (few-shot) and supervised fine-tuning, yielding state-of-the-art results among 8B-parameter LLMs. We believe that these resources can support the development of more transparent clinical decision-support tools in multilingual settings. We release the full suite of resources: reasoning traces, translated QA datasets, Medical-Wikipedia, and fine-tuned models.

Engineering LLMs to accelerate life sciences research requires a robust alignment with biomedical knowledge. We observe that biomedical text exhibits a fundamentally different uncertainty structure from general text: dense low-confidence runs encode epistemic knowledge gaps (dense causal chains, rare entities) rather than the sparse aleatoric stylistic variation typical of general text. Based on this discovery, we propose Balanced Fine-Tuning (BFT), a dual-scale post-training method that combines group-normalized token reweighting with sequence-level reallocation toward knowledge-dense samples exhibiting dense epistemic uncertainty. Across medical evaluation, biological reasoning, sparse-reward RL, and biological representation tasks, BFT provides more consistent gains than SFT and DFT under a shared training setup. When replacing the default closed-source backbones in GeneAgent (GPT-4o) and VCWorld (Gemini-2.5-Flash), the BFT-aligned 70B model delivers stronger performance across biological process reasoning and chemical perturbation prediction. Critically, all BFT variants further improve after subsequent GRPO with sparse rewards, while SFT and DFT degrade, suggesting that epistemic-aware post-training provides a more robust policy initialization. Beyond text generation, BFT-aligned LLMs produce more accurate and professional biomedical profile texts; after encoding these profiles with a text embedding model, the resulting representations support gene-level, cell-level, and perturbation-response tasks, suggesting that BFT-enhanced generation can facilitate biological representation and, in turn, broader biomedical downstream tasks.

Clinical language models often assign high confidence to incorrect predictions, particularly in high-severity and out-of-distribution cases. We present MedBayes-Lite, a retraining-free uncertainty governance layer for transformer-based clinical predictors. It combines Monte Carlo dropout, predictive calibration, and confidence-guided abstention to defer low-confidence predictions for human review, adding no trainable parameters. Evaluated on MedMCQA and MedQA-USMLE, MedBayes-Lite reduces expected calibration error by 0.23 to 0.33 and drives harmful overconfident errors (confident, incorrect, high-severity predictions) toward zero. Under domain shift from MedMCQA to MedQA-USMLE, it reduces confident high-severity errors from about 21% to near zero while roughly halving calibration drift. We also introduce the Clinical Uncertainty Score (CUS), which strongly correlates with harmful overconfidence (r approximately 0.88). Although the framework does not improve risk-coverage ranking, and temperature scaling or deep ensembles may provide advantages in calibration cost or risk ranking, MedBayes-Lite offers a practical calibration-and-abstention layer that reduces confident high-severity errors in clinical question-answering benchmarks.

Large language models (LLMs) show promise in medical applications, but their ability to detect and correct errors in clinical texts remains under-evaluated, particularly beyond English. We introduce MedRECT, a bilingual benchmark for Japanese and English that formulates medical error handling as three subtasks: error detection, error sentence extraction, and error correction. MedRECT-ja contains 663 samples derived from the Japanese Medical Licensing Examinations, while the separately sourced MedRECT-en contains 458 samples curated from MEDEC. We evaluate 11 LLMs across 17 configurations that cover proprietary and open-weight models, medical-domain specialization, and multiple reasoning settings. Qwen3-32B scores higher in its thinking mode than in its non-thinking mode on error detection F1 and sentence extraction accuracy in both subsets, with sentence extraction accuracy higher by 24.5 percentage points on MedRECT-ja and 10.3 on MedRECT-en. Several leading general-purpose reasoning models outperform all three evaluated medical-domain models on these two subtasks. Most models have lower point estimates on the Japanese subset, although absolute scores are not directly comparable because the subsets differ in source material and error distributions. LoRA fine-tuning yields higher sentence extraction accuracy and higher point estimates on all three reference-based correction similarity metrics in both languages. MedRECT provides an open, reusable evaluation resource for studying medical error correction and reasoning across Japanese and English. Our dataset and code are available at https://github.com/pfnet-research/medrect.

Data augmentation is a widely used strategy to improve model robustness and generalization by enriching training datasets with synthetic examples. While large language models (LLMs) have demonstrated strong generative capabilities for this purpose, their applications in high-stakes domains like healthcare present unique challenges due to the risk of generating clinically incorrect or misleading information. In this work, we propose a novel query-based model collaboration framework that integrates expert-level domain knowledge to guide the augmentation process to preserve critical medical information. Compared to existing LLM-based and traditional augmentation methods, our generated data significantly improves preservation of critical medical information and reduces hallucinations at both the token and concept levels. Experiments on downstream clinical prediction tasks demonstrate consistent performance gains over existing augmentation methods. This lightweight collaborative framework addresses the gap between LLM augmentation potential and the safety requirements of specialized domains.

Interactive medical questioning is essential in clinical consultations, where physicians must actively gather necessary patient information. Yet existing medical Large Language Models (LLMs) predominantly follow a reactive paradigm, risking diagnostic errors by answering before seeking sufficient details. To bridge this gap, we propose ProMed, a reinforcement learning framework that transitions LLMs toward a proactive paradigm, enabling them to ask clinically valuable questions before decision-making. Central to ProMed is the Shapley Information Gain (SIG) reward, which quantifies a question's clinical utility as the amount of newly acquired information, while considering its contextual importance via Shapley values. We integrate SIG into a two-stage training pipeline: (1) SIG-Guided Model Initialization uses Monte Carlo Tree Search to construct high-reward interaction trajectories for supervision, and (2) SIG-Augmented Policy Optimization, with a novel SIG-guided Reward Distribution Mechanism that prioritizes informative questions for fine-grained optimization. Experiments on partial-information medical benchmarks show that ProMed significantly outperforms state-of-the-art methods by 6.29% on average and delivers a 54.45% gain over the reactive paradigm, and generalizes robustly to out-of-domain cases. Our codes are available at https://github.com/hxxding/ProMed.

Enhancing LLM reasoning in federated settings is nontrivial due to stringent computational, communication, and privacy constraints, especially in healthcare, where clinically consequential decisions require not only accuracy but also interpretable, auditable rationales to meet safety, accountability, and regulatory requirements. Conventional federated fine-tuning largely imitates final answers rather than cultivating step-by-step reasoning, often relying on privacy-sensitive centralized distillation and still incurring substantial communication overhead. We address this gap with \textbf{\ours{}}, a federated reasoning framework that combines lightweight chain-of-thought resampling with a compact discriminator for selection, and client-aware LoRA stacking with weighted classifier aggregation to accommodate heterogeneity while reducing aggregation noise and communication; clients generate candidate chains and supervision locally, and only lightweight modules are aggregated on the server. Experiments on medical reasoning benchmarks show consistent gains under tight resource budgets while keeping data local and respecting privacy, offering an interpretable and resource-efficient solution. Our code is made publicly available at https://github.com/DIaacKr/FedCoT

The proliferation of Large Language Models (LLMs) in medicine has enabled impressive capabilities, yet a critical gap remains in their ability to perform systematic, transparent, and verifiable reasoning, a cornerstone of clinical practice. This has catalyzed a shift from single-step answer generation to the development of LLMs explicitly designed for medical reasoning. This paper provides the first systematic review of this emerging field. We propose a taxonomy of reasoning enhancement techniques, categorized into training-time strategies (e.g., supervised fine-tuning, reinforcement learning) and test-time mechanisms (e.g., prompt engineering, multi-agent systems). We analyze how these techniques are applied across different data modalities (text, image, code) and in key clinical applications such as diagnosis, education, and treatment planning. Furthermore, we survey the evolution of evaluation benchmarks from simple accuracy metrics to sophisticated assessments of reasoning quality and visual interpretability. Based on an analysis of 60 seminal studies from 2022-2025, we conclude by identifying critical challenges, including the faithfulness-plausibility gap and the need for native multimodal reasoning, and outlining future directions toward building efficient, robust, and sociotechnically responsible medical AI.

Large language models (LLMs) are increasingly used to answer health-related questions and support healthcare workflows, yet evidence for their safety still relies heavily on static benchmarks that can rapidly become obsolete or be optimized against. Here we introduce a Dynamic, Automatic, and Systematic (DAS) red-teaming audit framework that continuously stress-tests LLMs for health across four safety-critical axes: robustness, privacy, bias/fairness, and hallucination/factual inaccuracies. Validated against board-certified clinicians with high concordance, a suite of adversarial agents autonomously mutates health-related test cases to uncover vulnerabilities in real time. Applying DAS to 15 proprietary and open-source LLMs revealed a profound gap between high static benchmark performance and low dynamic reliability--the "Benchmarking Gap". Despite median MedQA accuracy exceeding 80%, 94% of previously correct answers failed under dynamic robustness testing. This brittleness generalized to the realistic, open-ended HealthBench dataset, where top-tier models exhibited failure rates exceeding 70% and sharp shifts in model rankings across evaluations, suggesting that high scores on established static benchmarks may reflect superficial memorization. We observed similarly high failure rates across other domains: privacy leaks were elicited in 86% of scenarios, cognitive-bias priming altered recommendations in 81% of fairness tests, and hallucination rates exceeded 74% in widely used models. By converting LLM safety evaluation for health from a static checklist into a living adversarial audit, DAS provides a scalable framework for surfacing latent risks before such systems are deployed in consumer-facing health assistants, clinician-facing tools, and broader healthcare workflows. Code is available at https://github.com/JZPeterPan/DAS-Medical-Red-Teaming-Agents.

The rapid development of large language models (LLMs) has transformed many industries, including healthcare. In practice, hospitals and patients increasingly seek LLM-based systems capable of interpreting personal health records and providing healthcare guidance. However, existing approaches mainly rely on general medical knowledge and often fail to account for individual variability, limiting their ability to provide personalized guidance. To address this, we propose personalized prompt learning (PPL), a framework that learns individualized prompts to guide LLMs in generating personalized healthcare recommendations. PPL constructs initial personalized prompts by leveraging both self-informed patient information and peer-informed signals derived from clinically similar cases. These prompts are then refined using reinforcement learning (RL) to better align the generated responses with physician recommendations written for each patient. PPL operates with hard prompts, enabling seamless integration with proprietary LLMs without modifying the underlying models. We evaluate PPL on real-world obstetrics and gynecology data. The results show that our approach produces more personalized healthcare guidance and wins 97 out of 100 comparisons in expert evaluation, demonstrating its potential for broader healthcare applications. Our code is publicly available at https://github.com/CGCL-codes/PPL.

Cancer treatments are known to introduce cardiotoxicity, negatively impacting outcomes and survivorship. Identifying cancer patients at risk of heart failure (HF) is critical to improving cancer treatment outcomes and safety. This study examined machine learning (ML) models to identify cancer patients at risk of HF using electronic health records (EHRs), including traditional ML, Time-Aware long short-term memory (T-LSTM), and large language models (LLMs) using novel narrative features derived from the structured medical codes. We identified a cancer cohort of 12,806 patients from the University of Florida Health, diagnosed with lung, breast, and colorectal cancers, among which 1,602 individuals developed HF after cancer. The LLM, GatorTron-3.9B, achieved the best F1 scores, outperforming the traditional support vector machines by 39%, the T-LSTM deep learning model by 7%, and a widely used transformer model, BERT, by 5.6%. The analysis shows that the proposed narrative features remarkably increased feature density and improved performance.

Large-scale language models (LLMs) often offer clinical judgments based on incomplete information, increasing the risk of misdiagnosis. Existing studies have primarily evaluated confidence in single-turn, static settings, overlooking the coupling between confidence and correctness as clinical evidence accumulates during real consultations, which limits their support for reliable decision-making. We propose the first benchmark for assessing confidence in multi-turn interaction during realistic medical consultations. Our benchmark unifies three types of medical data for open-ended diagnostic generation and introduces an information sufficiency gradient to characterize the confidence-correctness dynamics as evidence increases. We implement and compare 27 representative methods on this benchmark; two key insights emerge: (1) medical data amplifies the inherent limitations of token-level and consistency-level confidence methods, and (2) medical reasoning must be evaluated for both diagnostic accuracy and information completeness. Based on these insights, we present MedConf, an evidence-grounded linguistic self-assessment framework that constructs symptom profiles via retrieval-augmented generation, aligns patient information with supporting, missing, and contradictory relations, and aggregates them into an interpretable confidence estimate through weighted integration. Across two LLMs and three medical datasets, MedConf consistently outperforms state-of-the-art methods on both AUROC and Pearson correlation coefficient metrics, maintaining stable performance under conditions of information insufficiency and multimorbidity. These results demonstrate that information adequacy is a key determinant of credible medical confidence modeling, providing a new pathway toward building more reliable and interpretable large medical models.

Medical large language models are typically evaluated on idealized patient cases that do not reflect how real patients communicate. We introduce VeriSim, a patient simulation framework that injects controllable noise along six clinically grounded communication dimensions while substantially preserving each patient's medical record. Truth adherence is supported by a verifier that extracts atomic claims from each candidate utterance and judges them against a UMLS-grounded vector index built with BioLORD embeddings, using the retrieved atoms' structured clinical metadata (e.g., drug class, anatomical site, treats-condition relations) rather than surface-text similarity alone. Across seven open-weight LLMs, realistic noise reduces diagnostic accuracy by 15-25 percentage points and increases conversation length by 34-55%; the 7-8B models degrade 1.4x more than 70B+ models. A board-certified physician and a licensed nurse rate VeriSim's conversations highly on truth, realism, clinical utility, and noise fidelity (inter-annotator agreement >= 0.80 across all dimensions), and an LLM-as-judge closely tracks their ratings, enabling scalable evaluation. We release VeriSim as an open-source framework for rigorous stress-testing of clinical AI: https://github.com/mohitmarvania/VeriSim