Clinical Decision Support

Clinical decision-making in emergency medicine demands rapid, accurate diagnoses under uncertainty. Despite benchmark progress, evidence for LLMs as interactive aids in live physician workflows remains sparse. MedSyn lets physicians iteratively query an LLM provided with the full clinical record while initially viewing only the chief complaint. Seven physicians (three seniors, four residents) completed baseline and AI-assisted sessions across 52 MIMIC-IV cases stratified by difficulty. Blinded evaluation showed residents' Hard-case correctness rose from 0.589 to 0.734; difficulty-standardised completely-correct rates confirmed a medium effect (Δ = 0.092; p = 0.071; d = 0.47). Automated metrics corroborated these gains: standardised any-match accuracy improved by 0.156 (p < 0.0001), and residents showed the largest F1 gain (Δ = 0.138; p < 0.0001). Dialogue analysis revealed expertise-dependent strategies (seniors asked targeted, hypothesis-driven questions; residents relied on broader queries) and cross-expertise concordance increased (Δ = 0.145; p < 0.0001). Interactive LLM support meaningfully enhances diagnostic reasoning.

Motivated by the challenge to improve the adversarial robustness, security, and trust of medical decision making intelligent agents, this study develops a full-link security enhancement framework, which describes "input risk perception - medical evidence constraint - knowledge consistency verification - decision confidence reweighting - security output control - adversarial feedback update." We propose ARSM-Agent and define a weighted joint objective consisting of decision accuracy loss, adversarial robustness loss, safety refusal loss, and knowledge consistency loss, with weights of 0.3, 0.3, 0.2, and 0.2, respectively. The whole medical decision formulation is implemented by multi-module collaborative linkage. We verify that the algorithm is more efficient than four baselines, including LLM-Agent, Retrieval-Agent, Filter-Agent, and Adv-Train-Agent. Under semantic perturbation, prompt injection, drug-name confusion, and false-evidence attacks, ARSM-Agent reduces the overall attack success rate to 8.7% and achieves a knowledge consistency score of 0.91. Ablation experiments quantify each module's contribution: removing risk perception, evidence retrieval, consistency verification, and confidence reweighting reduces accuracy by 6.7%, 9.1%, 7.6%, and 4.4%, respectively, and increases attack success rate by 13.8%, 11.1%, 8.6%, and 6.9%. The proposed approach addresses key security issues of medical decision making intelligent agents, obtains secure decision making in challenging scenarios, and provides reliable intelligent support for medical decision-making intelligent agents.

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

Clinical dietary assessment can generate detailed but high-dimensional nutrient and food-group information that is difficult to translate quickly into counselling priorities. This paper proposes an explainable unsupervised-to-supervised machine learning framework for discovering, reproducing and interpreting dietary patterns using public UK National Diet and Nutrition Survey data. Adult participants aged 19 years and above from NDNS Years 12-15 were represented using 25 energy-adjusted nutrient and food-group features. K-means, Gaussian Mixture Models and Agglomerative Clustering were compared across k = 2-8, with stability and dietetic interpretability used alongside internal validation metrics. The selected K-means k = 4 solution identified four interpretable dietary patterns: high fat/meat and sodium, higher fibre fruit-vegetable micronutrient, high free-sugar snacks and sugary drinks, and dairy/cereal calcium-rich saturated-fat. A supervised surrogate classifier reproduced held-out cluster membership with high test performance (macro-F1 = 0.963), but was interpreted only as an explanatory surrogate rather than as an independent clinical prediction model. SHAP analysis linked predictions to dietetically meaningful drivers, suggesting potential value for dietitian-in-the-loop assessment, counselling prioritisation and follow-up monitoring.

Estimating individualized treatment effects from longitudinal observational data is central to data-driven medicine, yet existing methods face a fundamental limitation: reducing confounding bias often suppresses clinically informative heterogeneity, degrading patient-specific predictions. Here, we identify this tension as a bias-precision paradox in causal representation learning and introduce sampling-based maximum mean discrepancy (sMMD), a stochastic alignment strategy that replaces global adversarial balancing with subset-level matching. We instantiate this approach in a framework for counterfactual outcome prediction with attribution-grounded interpretability. Across two large-scale ICU cohorts (n = 27,783), our framework improves accuracy under distribution shift, reducing error by up to 11.5% and substantially increasing recall in high-risk tasks. Mechanistic analyses show that sMMD selectively preserves clinically decisive variables. In human-AI evaluation, our method outperforms clinicians-in-training and large language models, and improves clinician accuracy by 14.7% while reducing decision time, enabling interpretable, real-time clinical decision support.

We develop and evaluate a data-driven approach for detecting unusual (anomalous) patient-management actions using past patient cases stored in an electronic health record (EHR) system. Our hypothesis is that patient-management actions that are unusual with respect to past patients may be due to a potential error and that it is worthwhile to raise an alert if such a condition is encountered. We evaluate this hypothesis using data obtained from the electronic health records of 4,486 post-cardiac surgical patients. We base the evaluation on the opinions of a panel of experts. The results support that anomaly-based alerting can have reasonably low false alert rates and that stronger anomalies are correlated with higher alert rates.

Anomaly detection methods can be very useful in identifying interesting or concerning events. In this work, we develop and examine new probabilistic anomaly detection methods that let us evaluate management decisions for a specific patient and identify those decisions that are highly unusual with respect to patients with the same or similar condition. The statistics used in this detection are derived from probabilistic models such as Bayesian networks that are learned from a database of past patient cases. We apply our methods to the problem of identifying unusual patient-management decisions in post-surgical cardiac patients.

Pathology foundation models have shown strong retrospective performance, but whether such systems can support clinically relevant use remains unclear. This challenge is particularly important in breast cancer, where pathological assessment serves as the gold standard for diagnosis and guides treatment planning, surgical decision-making and risk stratification across pre-, intra- and post-operative stages. Here we present \textbf{BRAVE}, a breast-adaptive pathology foundation model developed and evaluated using a total resource of 101,638 breast whole-slide images from 32 sources across Asia, Europe and North America. We assessed BRAVE across 34 tasks in 82 cohorts spanning pre-operative biopsy, intra-operative frozen section and post-operative resection, using an evidence chain comprising retrospective benchmarking, clinically challenging scenarios, workflow-oriented clinical impact simulations, prospective observational validation with the thresholds locked in the retrospective cohorts and crossover pathologist-AI interaction studies. Across these settings, BRAVE supported practical roles in the clinical workflow, including safe exclusion of low-risk cases from routine review, AI-assisted second-review rescue of initially missed positives and prioritization of cases for further assessment. In prospective validation across three centres, BRAVE excluded 76.9% of negative biopsy cases (NPV 0.953) and 70.1% of negative frozen-section cases (NPV 0.973), and triaged 78.8% of post-operative subtyping cases as high-confidence clear-cut cases (NPV 1.000). In reader studies, AI assistance improved balanced accuracy from 88.5% to 95.1% (OR 3.14, P<0.001), with better efficiency, confidence and inter-rater agreement. BRAVE-derived scores also independently predicted disease-free survival (adjusted HR 4.79, P<0.001) and overall survival (adjusted HR 8.14, P<0.001).

Question: Does atomic fact-checking, which decomposes AI treatment recommendations into individually verifiable claims linked to source guideline documents, increase clinician trust compared to traditional explainability approaches? Findings: In this randomized trial of 356 clinicians generating 7,476 trust ratings, atomic fact-checking produced a large effect on trust (Cohen's d = 0.94), increasing the proportion of clinicians expressing trust from 26.9% to 66.5%. Traditional transparency mechanisms showed a dose-response gradient of improvement over baseline (d = 0.25 to 0.50). Meaning: Decomposing AI recommendations into individually verifiable claims linked to source guidelines produces substantially higher clinician trust than traditional explainability approaches in high-stakes clinical decisions.

Clinical time-series forecasting is increasingly studied for decision support, yet standard aggregate metrics can obscure whether a model is actually useful for the task it is meant to serve. In safety-critical settings, low average error can coexist with dangerous failures in exactly the high-risk regimes that matter most. We present a task-aware evaluation framework for blood glucose forecasting built around two downstream uses: hypoglycemia early warning and insulin dosing decision support. For early warning, we evaluate on real data from three clinical cohorts using event-level recall and false alarms per patient-day, metrics that reflect operational alarm burden rather than aggregate accuracy. We show that models appearing acceptable overall, with recall above 0.9 on the full test set, can fail badly in the post-bolus slice, where insulin-on-board is elevated and missed warnings carry the greatest clinical consequences. Standard forecasting evaluation, however, does not test whether a model can reason about the effects of actions, a requirement for supporting insulin dosing decisions. We therefore add a second, interventional arm using the FDA-accepted UVA/Padova simulator, where we evaluate whether forecasters can predict glucose responses to altered insulin plans in paired factual/counterfactual scenarios. We show that models that look strong on real-data forecasting often fail to predict the direction, magnitude, or ranking of intervention effects, and choose poor insulin doses when evaluated under a clinically motivated cost. Taken together, the two arms reveal a consistent gap between forecasting accuracy and task-relevant usefulness. We release the benchmark, the standardized preprocessing pipeline for public cohorts, and the simulator-based interventional dataset as a reproducible toolkit.

Multimodal large language models (MLLMs) have demonstrated promise on publicly available dermatology benchmarks. However, benchmark performance may not generalize to real-world dermatologic decision-making. To quantify this benchmark-to-bedside gap, we evaluated four open-weight MLLMs (InternVL-Chat v1.5, LLaVA-Med v1.5, SkinGPT4 and MedGemma-4B-Instruct) and one commercial MLLM (GPT-4.1) across three publicly available dermatology datasets and a retrospective multi-site hospital-based dermatology consultation cohort comprising 5,811 cases and 46,405 clinical images. Models were evaluated on two clinically relevant tasks: differential diagnosis generation and severity-based triage. Diagnostic performance was modest on public datasets and declined substantially in the real-world cohort. On public benchmarks, top-3 diagnostic accuracy reached 26.55% for the best open-weight model and 42.25% for GPT-4.1. On real-world consultation cases using images alone, top-3 diagnostic accuracy fell to 1.50%-13.35% among open-weight models and 24.65% for GPT-4.1. Incorporating clinical context improved performance across all models, increasing top-3 diagnostic accuracy up to 28.75% among open-weight models and 38.93% for GPT-4.1. However, model outputs were highly sensitive to incomplete or erroneous consultation context. For severity-based triage, models achieved moderate sensitivity (above 60%), suggesting potential utility for screening but insufficient reliability for clinical deployment. These findings demonstrate that benchmark performance substantially overestimates the real-world clinical capability of current dermatology MLLMs.

We reframe clinician overrides of clinical AI recommendations as implicit preference data - the same signal structure exploited by reinforcement learning from human feedback (RLHF), but richer: the annotator is a domain expert, the alternatives carry real consequences, and downstream outcomes are observable. We present a formal framework extending standard preference learning with three contributions: a five-category override taxonomy mapping override types to distinct model update targets; a preference formulation conditioned on patient state s, organizational context c, and clinician capability kappa, where kappa decomposes into execution capability kappa-exec and alignment capability kappa-align; and a dual learning architecture that jointly trains a reward model and a capability model via alternating optimization, preventing a failure mode we term suppression bias-the systematic suppression of correct-but-difficult recommendations when clinician capability falls below the execution threshold. We argue that chronic disease management under outcome-based payment contracts produces override data with uniquely favorable properties-longitudinal density, concentrated decision space, outcome labels, and natural capability variation-and that training environments combining longitudinal outcome measurement with aligned financial incentives are a necessary condition for learning a reward model aligned with patient trajectory rather than with encounter economics. This framework emerged from operational work to improve clinician capability in a live value-based care deployment.

Millions of clinicians use ChatGPT to support clinical care, but evaluations of the most common use cases in model-clinician conversations are limited. We introduce HealthBench Professional, an open benchmark for evaluating large language models on real tasks that clinicians bring to ChatGPT in the course of their work. The benchmark is organized around three common use cases central to clinical practice: care consult, writing and documentation, and medical research. Each example includes a physician-authored conversation with ChatGPT for Clinicians and is scored via rubrics written and iteratively adjudicated by three or more physicians across three phases. HealthBench Professional examples were carefully selected for quality, representativeness, and difficulty for OpenAI's current frontier models, to enable continued measurement of progress. Difficult examples for recent OpenAI models were enriched by roughly 3.5 times relative to the candidate pool of 15,079 examples. Additionally, about one-third of examples involve physicians conducting deliberate adversarial testing of models. As a strong baseline, we also collected human physician responses for all tasks (unbounded time, specialist-matched, web access). The best scoring system, GPT-5.4 in ChatGPT for Clinicians, outperforms base GPT-5.4, all other models, and human physicians. We hope HealthBench Professional provides the healthcare AI community a measure to track frontier model progress in real-world clinical tasks and build systems that clinicians can trust to improve care.

Trust in clinical artificial intelligence (AI) cannot be reduced to model accuracy, fluency of generation, or overall positive user impression. In medicine, trust must be engineered as a measurable system property grounded in evidence, supervision, and operational boundaries of AI autonomy. This article proposes a practical framework for trustworthy clinical AI built around three principles: evidence, supervision, and staged autonomy. Rather than replacing deterministic clinical logic wholesale with end-to-end black-box models, the proposed approach combines a deterministic core, a patient-specific AI assistant for contextual validation, a multi-tier model escalation mechanism, and a human supervision layer for verification, escalation, and risk control. We demonstrate that trust also depends on selective verification of clinically critical findings, bounded clinical context, disciplined prompt architecture, and careful evaluation on realistic cases. Classifier-driven modular prompting is examined as an incremental path to scaling clinical depth without sacrificing prompt performance and without waiting for complete rule-based coverage. To operationalize trust, a set of trust metrics is proposed, built on metrological principles -- measurement uncertainty, calibration, traceability -- enabling quantitative rather than subjective assessment of each architectural layer. In this perspective, trustworthy clinical AI emerges not as a property of an individual model, but as an architectural outcome of a system into which evidence trails, human oversight, tiered escalation, and graduated action rights are embedded from the outset.

Multimodal artificial intelligence models for endometrial cancer (EC) risk stratification typically optimize aggregate predictive performance but provide limited mechanisms for enforcing mandatory guideline overrides, such as assigning POLE-mutated tumors to the low-risk group despite high-grade morphology. We present EndoGov, a two-tier multi-agent expert system that factorizes the decision process as D(x) = G(P(x), R), where specialist agents P extract structured evidence and a governance agent G applies an executable rule set R. Tier 1 comprises pathology, molecular, and clinical agents that independently generate schema-constrained reports from frozen foundation-model features or structured records. Tier 2 queries an evidence-level-weighted Guideline Knowledge Graph, using deterministic hard-path rules for high-priority overrides and constrained soft-path reasoning for ambiguous cases. In TCGA-UCEC (n=541), EndoGov achieved 0.943 accuracy, 0.973 macro AUC, and a conditional logic-violation rate (C-LVR) of 0.93% among trigger-exposed cases. In CPTAC-UCEC (n=95), where reference labels are guideline-derived, EndoGov reached 0.842 accuracy compared with < 0.31 for locked-transfer neural baselines, supporting governance-pathway transfer under distribution shift rather than validation against independent clinical truth. End-to-end safety decomposition localized residual failures primarily to upstream molecular detection rather than downstream governance. Backend-swap experiments further showed that hard-path compliance is invariant to the LLM backend. These findings indicate that explicit clinical-rule governance can provide guideline-compliant, auditable EC risk assignment while preserving competitive discrimination.

Liver cirrhosis is a major global health problem causing millions of deaths annually, and timely detection with aggressive treatment can significantly improve patients' quality of life. Modelling complex diseases from biomedical data is computationally challenging due to high dimensionality, strong feature correlations, noise, and limited labelled samples. Conventional Machine Learning (ML) pipelines often struggle with robustness, interpretability, and generalisation under such conditions. In this study, we propose an ML-driven multi-stage decision framework for complex disease modelling and therapeutic exploration. The framework integrates single-cell transcriptomic profiling, high-dimensional network-based feature stabilisation, multi-model learning, deep representation construction, and post-hoc decision support. Specifically, single-cell sequencing data were analysed to identify key cellular subpopulations, followed by high-dimensional weighted gene co-expression network analysis (hdWGCNA) to stabilise gene modules under sparsity and noise. To enhance non-linear feature interaction modelling, tabular molecular features were restructured into two-dimensional disease maps and analysed using a CNN. Finally, molecular docking was incorporated as a decision-support module to evaluate candidate therapeutic compounds. Using liver cirrhosis as a representative case, the framework identified a disease-associated endothelial subpopulation and extracted seven robust signature genes (HSPB1, GADD45A, CLDN5, ATP1B3, C1QBP, ENPP2, and PARL). The CNN-based representation learning module outperformed conventional pipelines in classification. The framework is disease-agnostic and readily extends to other omics-driven biomedical applications involving uncertainty, heterogeneity, and limited samples.

The application of large language models (LLMs) in clinical decision support faces significant challenges of "tunnel vision" and diagnostic hallucinations present in their processing unstructured electronic health records (EHRs). To address these challenges, we propose a novel chain-based clinical reasoning framework, called DxChain, which transforms the diagnostic workflow into an iterative process by mirroring a clinician's cognitive trajectory that consists of "Memory Anchoring", "Navigation" and "Verification" phases. DxChain introduces three key methodological innovations to elicit the potential of LLM: (i) a Profile-Then-Plan paradigm to mitigate cold-start hallucinations by establishing a panoramic patient baseline, (ii) a Medical Tree-of-Thoughts (Med-ToT) algorithm for strategic look ahead planning and resource aware navigation, and (iii) a Dialectical Diagnostic Verification procedure utilizing "Angel-Devil" adversarial debates to resolve complex evidence conflicts. Evaluated on two real world benchmarks, MIMIC-IV-Ext Cardiac Disease and MIMIC-IV-Ext CDM, DxChain achieves state-of-the-art performances in both diagnostic accuracy and logical consistency, offering a modular and reliable architecture for next-generation clinical AI. The code is at https://anonymous.4open.science/r/Dx-Chain.

Timely detection of concerning events is an important problem in clinical practice. In this paper, we consider the problem of conditional anomaly detection that aims to identify data instances with an unusual response, such as the omission of an important lab test. We develop a new non-parametric approach for conditional anomaly detection based on the soft harmonic solution, with which we estimate the confidence of the label to detect anomalous mislabeling. We further regularize the solution to avoid the detection of isolated examples and examples on the boundary of the distribution support. We demonstrate the efficacy of the proposed method in detecting unusual labels on a real-world electronic health record dataset and compare it to several baseline approaches.

\textbf{Background:} Regulatory frameworks for AI in healthcare, including the EU AI Act and FDA guidance on AI/ML-based medical devices, require clinical decision support to demonstrate not only accuracy but auditability. Existing formal languages for clinical logic validate syntactic and structural correctness but not whether decision rules use epistemologically appropriate evidence. \textbf{Methods:} Drawing on design-by-contract principles, we introduce meta-predicates -- predicates about predicates -- for asserting epistemological constraints on clinical decision rules expressed in a DSL. An epistemological type system classifies annotations along four dimensions: purpose, knowledge domain, scale, and method of acquisition. Meta-predicates assert which evidence types are permissible in any given rule. The framework is instantiated in AnFiSA, an open-source platform for genetic variant curation, and demonstrated using the Brigham Genomics Medicine protocol on 5.6 million variants from the Genome in a Bottle benchmark. \textbf{Results:} Decision trees used in variant interpretation can be reformulated as unate cascades, enabling per-variant audit trails that identify which rule classified each variant and why. Meta-predicate validation catches epistemological errors before deployment, whether rules are human-written or AI-generated. The approach complements post-hoc methods such as LIME and SHAP: where explanation reveals what evidence was used after the fact, meta-predicates constrain what evidence may be used before deployment, while preserving human readability. \textbf{Conclusions:} Meta-predicate validation is a step toward demonstrating not only that decisions are accurate but that they rest on appropriate evidence in ways that can be independently audited. While demonstrated in genomics, the approach generalises to any domain requiring auditable decision logic.

Large language models (LLMs) are increasingly used for conversational clinical decision support, yet they conflate next token prediction with probabilistic decision making. We argue that this conflation reflects an architectural limitation: such systems lack explicit posterior tracking, controllable abstention thresholds, and auditable reasoning chains. We introduce MoBayes, a Modular Bayesian dialogue framework that separates reasoning from language. The LLM acts only as a language interface, parsing patient conversation into structured observations, while a Bayesian module performs probabilistic inference over these observations to update posteriors, select follow-up questions via expected-information-gain and determine when to stop or defer through calibrated decision thresholds. This design enables explicit posterior tracking, controllable selective decision-making, and replaceable population-specific statistical backends without retraining the language model. Across empirical and LLM-generated knowledge bases, MoBayes outperforms standalone frontier LLM doctors, including matched model-family comparisons where inexpensive sensor models paired with MoBayes exceed larger autonomous models at lower cost. The advantage persists under adversarial patient communication styles and across varying diagnostic scenarios. These results suggest that reliable conversational clinical decision support systems should separate probabilistic reasoning from language generation rather than scaling model size alone. Code is available at https://anonymous.4open.science/r/MoBayes/

Privacy represents one of the most critical yet underaddressed barriers to AI adoption in mental healthcare -- particularly in high-sensitivity operational environments such as military, correctional, and remote healthcare settings, where the risk of patient data exposure can deter help-seeking behavior entirely. Existing AI-enabled psychiatric decision support systems predominantly rely on cloud-based inference pipelines, requiring sensitive patient data to leave the device and traverse external servers, creating unacceptable privacy and security risks in these contexts. In this paper, we propose a zero-egress, on-device AI platform for privacy-preserving psychiatric decision support, deployed as a cross-platform mobile application. The proposed system extends our prior work on fine-tuned LLM consortiums for psychiatric diagnosis standardization by fundamentally re-architecting the inference pipeline for fully local execution -- ensuring that no patient data is transmitted to, processed by, or stored on any external server at any stage. The platform integrates a consortium of three lightweight, fine-tuned, and quantized open-source LLMs -- Gemma, Phi-3.5-mini, and Qwen2 -- selected for their compact architectures and proven efficiency on resource-constrained mobile hardware. An on-device orchestration layer coordinates ensemble inference and consensus-based diagnostic reasoning, producing DSM-5-aligned assessments for conditions. The platform is designed to assist clinicians with differential diagnosis and evidence-linked symptom mapping, as well as to support patient-facing self-screening with appropriate clinical safeguards. Initial evaluation demonstrates that the proposed zero-egress deployment achieves diagnostic accuracy comparable to its server-side predecessor while sustaining real-time inference latency on commodity mobile hardware.

Clinical guidelines, typically developed by independent specialty societies, inherently exhibit substantial fragmentation, redundancy, and logical contradiction. These inconsistencies, particularly when applied to patients with multimorbidity, not only cause cognitive dissonance for clinicians but also introduce catastrophic noise into AI systems, rendering the standard Retrieval-Augmented Generation (RAG) system fragile and prone to hallucination. To address this fundamental reliability crisis, we introduce a Neuro-Symbolic framework that automates the detection of recommendation redundancies and conflicts. Our pipeline employs a multi-agent system to translate unstructured clinical natural language into rigorous symbolic logic language, which is then verified by a Satisfiability (SAT) solver. By formulating a hierarchical taxonomy of logical rule interactions, we identify a critical category termed Local Conflict - a decision conflict arising from the intersection of comorbidities. Evaluating our system on a curated benchmark of 12 authoritative SGLT2 inhibitor guidelines, we reveal that 90.6% of conflicts are Local, a structural complexity that single-disease guidelines fail to address. While state-of-the-art LLMs fail in detecting these conflicts, our neuro-symbolic approach achieves an F1 score of 0.861. This work demonstrates that logical verification must precede retrieval, establishing a new technical standard for automated knowledge coordination in medical AI.

Trustworthiness and transparency are essential for the clinical adoption of artificial intelligence (AI) in healthcare and biomedical research. Recent deep research systems aim to accelerate evidence-grounded scientific discovery by integrating AI agents with multi-hop information retrieval, reasoning, and synthesis. However, most existing systems lack explicit and inspectable criteria for evidence appraisal, creating a risk of compounding errors and making it difficult for researchers and clinicians to assess the reliability of their outputs. In parallel, current benchmarking approaches rarely evaluate performance on complex, real-world medical questions. Here, we introduce DeepER-Med, a Deep Evidence-based Research framework for Medicine with an agentic AI system. DeepER-Med frames deep medical research as an explicit and inspectable workflow of evidence-based generation, consisting of three modules: research planning, agentic collaboration, and evidence synthesis. To support realistic evaluation, we also present DeepER-MedQA, an evidence-grounded dataset comprising 100 expert-level research questions derived from authentic medical research scenarios and curated by a multidisciplinary panel of 11 biomedical experts. Expert manual evaluation demonstrates that DeepER-Med consistently outperforms widely used production-grade platforms across multiple criteria, including the generation of novel scientific insights. We further demonstrate the practical utility of DeepER-Med through eight real-world clinical cases. Human clinician assessment indicates that DeepER-Med's conclusions align with clinical recommendations in seven cases, highlighting its potential for medical research and decision support.

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.

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.

In this work, we propose Oph-Guid-RAG, a multimodal visual RAG system for ophthalmology clinical question answering and decision support. We treat each guideline page as an independent evidence unit and directly retrieve page images, preserving tables, flowcharts, and layout information. We further design a controllable retrieval framework with routing and filtering, which selectively introduces external evidence and reduces noise. The system integrates query decomposition, query rewriting, retrieval, reranking, and multimodal reasoning, and provides traceable outputs with guideline page references. We evaluate our method on HealthBench using a doctor-based scoring protocol. On the hard subset, our approach improves the overall score from 0.2969 to 0.3861 (+0.0892, +30.0%) compared to GPT-5.2, and achieves higher accuracy, improving from 0.5956 to 0.6576 (+0.0620, +10.4%). Compared to GPT-5.4, our method achieves a larger accuracy gain of +0.1289 (+24.4%). These results show that our method is more effective on challenging cases that require precise, evidence-based reasoning. Ablation studies further show that reranking, routing, and retrieval design are critical for stable performance, especially under difficult settings. Overall, we show how combining visionbased retrieval with controllable reasoning can improve evidence grounding and robustness in clinical AI applications,while pointing out that further work is needed to be more complete.

Drug recommendation requires a deep understanding of individual patient context, especially for complex conditions like Parkinson's disease. While LLMs possess broad medical knowledge, they fail to capture the subtle nuances of actual prescribing patterns. Existing RAG methods also struggle with these complexities because guideline-based retrieval remains too generic and similar-patient retrieval often replicates majority patterns without accounting for the unique clinical nuances of individual patients. To bridge this gap, we propose PACE-RAG (Patient-Aware Contextual and Evidence-Constrained RAG). Rather than directly copying frequent medications from retrieved patients, PACE-RAG personalizes recommendations by first extracting patient-specific clinical features, retrieving cases around these features, and then refining the final prescription using the patient's current symptoms, active medication history, and focus-specific prescribing tendencies. By analyzing treatment patterns tailored to specific clinical features, PACE-RAG generates patient-specific medication recommendations along with an explainable clinical summary. PACE-RAG achieved the strongest performance among the evaluated inference-only LLM-based methods, reaching F1 scores of 80.84% and 47.22% on the Parkinson's disease and MIMIC-IV cohorts, respectively. Our code is available at: https://github.com/ChaeYoungHuh/PACE-RAG.

Psychiatric consultation requires agents to elicit discriminative evidence, map uncertain narratives to diagnostic criteria, and decide when evidence suffices. Existing dialogue and retrieval-augmented systems condition policies on raw histories or appended passages, leaving observed evidence, missing checks, differentials, and support reliability entangled. We introduce MIND, a criteria-grounded evidence-state decision interface. At each turn, MIND constructs a typed state containing observed evidence, unresolved criterion checks, active differentials, criterion-linked supports, and reliability metadata. A training-split Psychiatric Reasoning Bank supplies gated supports, turning retrieval into state construction rather than prompt injection. The same state conditions action selection, process rewards, information-gain scoring, and trajectory rectification. Under EMR-grounded simulator protocols, MIND improves accuracy by 8.8 and 7.3 points over strong inference-only, RAG, and RL baselines, with gains transferring to public MDD-5k dialogues. Matched interventions attribute these gains to the shared state rather than prompt length, retrieval text, or formatting. MIND targets screening-level decision support, not autonomous diagnosis. Code is available at https://github.com/Lingxi-mental-health/MIND.Å

Objective: This study develops and validates a patient simulation framework that aligns with the National Institute of Standards and Technology AI Risk Management Framework MAP and MEASURE functions, providing an empirical basis for identifying and characterizing performance risks in conversational clinical AI across medical, linguistic, and behavioral patient variation. We applied the framework to a conversational decision aid for antidepressant selection in major depressive disorder. Methods: The simulator integrates three profile dimensions: (1) medical profiles constructed from All of Us electronic health records using risk-ratio gating; (2) linguistic profiles modeling a health literacy gradient and condition-specific communication; and (3) behavioral profiles representing cooperative, distracted, and adversarial engagement. We generated 500 simulated conversations and evaluated profile fidelity through human annotation and a large language model (LLM) judge, then assessed downstream effects on the AI Decision Aid's concept retrieval and antidepressant recommendations. Results: The patient simulator expressed medical concepts with high fidelity (96.6% accurate across 8,210 concepts), with human inter-annotator agreement of 0.73$κ$ and LLM-judge agreement against human annotators of 0.78$κ$, both indicating substantial agreement. Behavioral profiles were reliably distinguished (0.93$κ$, near perfect agreement), and linguistic profiles showed substantial agreement at the lower bound of the substantial range (0.61$κ$), adequate to support profile-level analysis. The framework revealed monotonic degradation in AI Decision Aid performance across the health literacy gradient. Rank-1 concept retrieval increased from 47.6% for limited health literacy to 81.9% for proficient health literacy, with corresponding declines in antidepressant recommendation accuracy.

Transcatheter Aortic Valve Replacement (TAVR) has emerged as a prominent, minimally invasive treatment for patients with severe aortic stenosis, a life-threatening cardiovascular condition. Multiple transcatheter heart valves (THV) have been approved for use in TAVR, but current guidelines regarding valve type prescription remain a topic of ongoing debate within the medical community. We propose a data-driven clinical support tool to identify the optimal valve type with the objective of minimizing the risk of permanent pacemaker implantation (PPI), a predominant postoperative complication. We synthesize a novel dataset, combining U.S. and Greek patient populations, that integrates data from three distinct sources (patient demographics, computed tomography scans, echocardiograms) while harmonizing the different encoding processes specific to each country's record system. We propose leaf-level analysis to leverage the heterogeneity of the patient populations and avoid benchmarking against uncertain counterfactual risk estimates. The final prescriptive model shows a reduction in PPI rates of 26% and 16% compared to the current standard of care in our internal U.S. population and external, Greek validation set, respectively. To the best of our knowledge, this work represents the first unified, personalized prescription strategy for THV selection in TAVR.