Electronic Health Records

Alzheimer's Disease (AD) is a complex neurodegenerative disorder that continues to impact millions of people worldwide. Predicting AD conversion during the prodromal stage remains critical for disease understanding and patient care. As such, survival models are widely used for AD risk prediction, yet they are typically static predictors with limited interpretability and no capacity for natural language reasoning. In this work, we propose iLENS, an interpretable large language model (LLM) guided framework based on mixture-of-experts (MoE) for survival prediction in AD conversion. Our approach uses LLM to synthesize structured neuroimaging measurements and unstructured information to guide expert routing. Our framework demonstrates competitive predictive performance and capability in patient subtyping. Furthermore, our framework provides transparent, biologically grounded rationales for its routing decisions, bridging the gap between high-performance survival analysis and interpretable clinical decision support.

Computational pathology has advanced rapidly with the emergence of foundation models, yet widespread adoption remains limited by substantial technical complexity and programming requirements. Here we present PathLab, an autonomous agentic framework that translates natural-language research objectives into executable and validated computational pathology workflows through the structured composition of domain-specific skills and tools. By organizing workflow generation around reusable methodological modules, including data preprocessing, model development, evaluation and interpretation, PathLab enables studies to be specified at the level of scientific intent rather than implementation details. We evaluated PathLab across 12 public datasets spanning four representative task families: region-of-interest classification, whole-slide image classification, segmentation and survival prediction. Across all task categories, PathLab achieved non-inferior performance relative to expert implementations, while consistently enforcing semantic validity of user prompts and proactively rejecting incompatible workflow specifications prior to execution. In controlled user studies, PathLab substantially reduced the time required to generate executable analytical pipelines and enabled domain experts without programming experience to independently design, execute and evaluate computational pathology studies. Together, these results establish PathLab as a reliable interface between biomedical intent and computational execution, enabling computational pathology studies to be designed at the level of scientific questions rather than programming expertise. By lowering technical barriers to advanced AI methodologies, PathLab provides a foundation for the broader democratization of computational pathology.

Understanding how a prediction model will perform in a new environment before deployment is essential to preventing harm when algorithms inform decision-making. Two common sources of model performance degradation are (i) covariate shift, where the target covariate distribution differs from the source, and (ii) selective labels, where the observability of outcomes depends on historical decisions. We study pre-deployment model evaluation under the joint presence of covariate shift and labeling of outcomes selectively based on observed features. In particular, we present a double machine learning procedure for estimating the target risk of an arbitrary black-box prediction model under a general loss function. We show identification of this estimand under standard assumptions and derive a bias-corrected estimator based on the influence function of the target risk. Finally, we evaluate our estimator through experiments using the eICU electronic health records database, showing that it tracks the true target risk more accurately than methods that address either selective labels or covariate shift alone, as well as baselines that combine standard plug-in approaches.

Transformer-based clinical language models are increasingly integrated into high-stakes clinical decision support pipelines, yet the computational mechanisms through which demographic associations encoded in medical documentation propagate into model probability distributions remain empirically underspecified. We present a systematic computational audit of representational bias in ClinicalBERT (Alsentzer et al., 2019), a BERT-based model pretrained on MIMIC-III discharge summaries, employing two complementary probing methodologies: Log Probability Bias Analysis (LPBA), which quantifies demographic descriptor-induced shifts in masked token probability distributions across behavioral and evaluative semantic categories, and Masked Language Model-based analysis (MLM), which probes internal representational structure for demographic agency attribution encoding across 98 real clinical sentence templates and eight intersectional race-gender combinations. Corpus frequency analysis operationalizes the distinction between statistical disparity and bias amplification by benchmarking model outputs against empirical term frequencies in the MIMIC-III training corpus. Of 32 statistically significant findings, 65.6% contradict observed corpus distributions, rising to 80% for Black patients and 87.5% for agency attribution under MLM probing, providing direct empirical evidence that representational bias in ClinicalBERT operates predominantly through model-internal amplification rather than training data inheritance. Keywords: natural language processing, clinical documentation, algorithmic auditing, representational bias, health equity 1

Healthcare is essential, expert, and episodic by design - built around the roughly one hour per year a person spends with a clinician. The 8,759 hours outside clinical settings, where eating, sleeping, movement, medication, and stress actually shape long-term health, have no comparable infrastructure. The bottleneck for personalized health is not raw data or reasoning capability; it is the absence of that infrastructure layer. This paper introduces the Personal Care Utility (PCU): a layered, event-driven architecture proposed as the missing utility for everyday health, in the way that payments, networks, and power are utilities for their domains. PCU organizes continuous personal signals into semantically meaningful life events through a Personicle, estimates dynamic health state against personal baselines, reasons about cause and context, and routes guidance through an orchestrator that separates clinical decision logic, behavioral strategy selection, and natural-language expression. This separation lets large language models support reasoning and communication while keeping safety-critical clinical decisions grounded in validated evidence. We instantiate PCU for Type 2 Diabetes - turning CGM, meal, activity, medication, sleep, stress, and clinical data into glycemic events, individualized state estimates, causal explanations, and knowledge-grounded interventions. A day-in-the-life scenario shows the same infrastructure producing real-time nudges, weekly summaries, medication check-ins, silence, or deterministic safety alerts depending on context and risk. We close with how PCU generalizes to other chronic conditions and the governance questions any always-on personal health utility must address. The result is a blueprint that treats personalization not as a final messaging layer, but as an architectural property of everyday health guidance.

We present the design and implementation of a safety constrained large language model (LLM) system for public health information access, focusing on maternal and child health (MCH) resource navigation. While LLM based systems offer flexible and natural interfaces for information retrieval, their deployment in healthcare contexts introduces risks related to safety, trust, and uncontrolled generation. This work explores practical design patterns for constraining LLM behavior in safety critical environments. We introduce a multi-layered architecture that integrates domain-restricted retrieval augmented generation (RAG), strict boundary enforcement to prevent medical advice, anonymous multiuser session management, and comprehensive audit logging for monitoring and compliance. A key aspect of the design is a controlled data pipeline that grounds all responses in curated public health resources, avoiding reliance on the model pretrained medical knowledge. We implement the system in a real world public health setting and conduct scenario-based validation across in scope, out of scope, and emergency queries. Results show consistent enforcement of safety constraints, reliable resource grounding, and stable system performance, with an average response time of 5.3 seconds. Beyond the specific application, we discuss design trade offs and lessons learned in balancing safety, usability, and system flexibility. Our findings provide practical guidance for deploying LLM based systems in healthcare and other domains where strict information boundaries and accountability are required.

Accurate estimation of long-term care transition probabilities is central to disability insurance pricing, reserving, and solvency assessment. Classical actuarial multi-state models commonly rely on Markov, semi-Markov, or proportional-hazard specifications, which provide a direct connection to cohort projection but may be restrictive for irregular longitudinal health data with nonlinear aging patterns and heterogeneous covariate histories. This paper develops a well-calibrated estimator of multi-state transition probabilities for irregular longitudinal health data. The model learns from individual health history, incorporates the time elapsed between observations, and conditions transition probabilities on demographic and socioeconomic attributes. It produces a valid probability distribution over the next observed health state, with four possible states: healthy, mild disability, severe disability, and death. Individual probabilities are aggregated by age group and origin state to form transition matrices compatible with actuarial cohort projection. Using longitudinal data from the Health and Retirement Study, we compare the proposed estimator with logistic regression, gradient-boosted trees, a recurrent neural network, and a last-state persistence benchmark. The evaluation considers probabilistic accuracy, endpoint discrimination and calibration for severe disability and death, risk concentration, and transition matrix error after aggregation. The proposed estimator improves severe disability discrimination relative to logistic regression and gradient-boosted tree benchmarks, maintains strong calibration, and yields the lowest transition matrix error among the evaluated models in the held-out test analysis. Results show that a structured machine learning estimator can support long-term care transition modeling when judged by calibration and projection fidelity, beyond discrimination.

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) are increasingly integrated into clinical systems, making it essential to evaluate the real-world utility of these systems. However, static benchmarks tend to measure correctness rather than user acceptance, aggregate performance across queries, and require densely annotated datasets -- leading to major blind spots for evaluating clinical systems. In this work, we perform a deployment-centered evaluation of an LLM system embedded within electronic health records at an academic medical center, where user feedback is sparse but closely reflects the deployment conditions. Specifically, we train a pre-response classifier that estimates the risk that a future interaction will result in the user rejecting the LLM response, based on query content and deployment-specific context available before generation. We conduct a prospective analysis of our model over 4.5 months of user feedback, finding that our prediction model achieves an AUROC of 0.719. Further, we estimate the benefit of such predictions in two downstream use cases (guardrail triggering and abstention). Our key conceptual insight is that making use of deployment-specific context (i.e., the provider type, department name, language model used for response), as opposed to only query content, improves the ability to predict whether the user will reject the system output. Altogether, our empirical case study demonstrates the feasibility of predicting user rejection using deployment-specific context, opening the door to targeted guardrails.

Predicting how a cell's transcriptome responds to a drug it has never seen is a core, hard problem in computational cell biology: recent benchmarks show complex models often fail to beat trivial baselines once test compounds are held out by chemistry. We study one cell line and assay, THP-1 cells profiled by DRUG-seq, scored by the active-compound weighted MSE(wMSE) of the VCPI prediction contest. We propose a staged approach: dumb baselines (untreated control and mean training-compound response) that the field keeps failing to beat; non-parametric retrieval (a Tanimoto-weighted average of a held-out compound's nearest training compounds); and a fusion stage combining a frozen chemistry embedding with retrieval-support features to predict the residual over the mean, with an uncertainty head and gene programs. On the released VCPI THP-1 drug-seq data (14,026 training compounds), under a Bemis-Murcko scaffold split, the model ranking inverts depending on the metric. Under an inverse-variance per-gene proxy, a regularized linear regression on Morgan fingerprints appears to win over the deep models, retrieval, and ChemBERTa -- the textbook "simple baselines win" result. But under the contest's true active-set metric (per-(gene, compound) Mejia weights, validated against the official scorer; mean baseline 0.535 vs the organizers' 0.507 reference), that reverses: the deep models win, our fusion decoder significantly beats the linear fingerprint baseline (-0.012 wMSE, paired bootstrap p < 10^-4), and the proxy's winner becomes the worst chemistry-aware predictor. Picking the metric picks the winner -- to our knowledge the first demonstration on real held-out drug chemistry of the metric-calibration effect established largely on genetic perturbation. We release a reproducible pipeline wired to the official scorer that emits a valid submission over the real 1064 x 12,995 grid.

We present eCREAM-MedCorpus, a new and unique large-scale dataset of clinical notes produced in Emergency Departments of Italian hospitals. The corpus, in its current version, is composed of approximately 4 million clinical notes fully anonymized, covering diverse phases of patient care during the stay in the emergency department. In addition, a subset of about six thousand notes has been manually annotated by clinical experts through a structured Case Report Form (CRF) containing 132 items relevant for two patient situations in emergency departments, dyspnea and loss of consciousness. Items may assume numerical values (e.g., for blood saturation), categorical (e.g., for level of consciousness ), binary (e.g., for presence of traumas), and mixed value types. The annotation process involved multiple clinicians and underwent iterative revision to resolve ambiguities in item formulation, resulting in a richly structured (although high imbalanced) resource. The dataset aims to fill a relevant gap of data able to support both the development and the use of Large Language Models in concrete medical applications. We describe the data collection protocol, the on-site anonymisation pipeline, corpus statistics, and the annotation scheme. Finally, we propose CRF-filling as a novel structured information extraction benchmark, and provide zero-shot baseline resulting from Gemma-27B and MedGemma-27B. To the best of our knowledge, eCREAM-MedCorpus is the largest freely available dataset of clinical notes existing for the Italian language.

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.

Existing computational pathology methods predominantly operate within whole-slide image (WSI)-level multiple instance learning (MIL) paradigms, while patient-level modeling remains underexplored. In routine pathological practice, however, pathologists derive diagnostic and prognostic conclusions by integrating evidence across multiple WSIs rather than relying on any single slide. This discrepancy creates a fundamental misalignment when patient-level supervision is directly imposed on conventional MIL frameworks, often leading to unstable optimization and degraded predictive reliability. To address this issue, we propose Anchor-Guided Evidence MIL (AGE-MIL), a weakly supervised framework for patient-level prediction. AGE-MIL constructs a patient-level anchor from slide representations to capture global pathological context and guide the retrieval and integration of diagnostically relevant local patches, enabling robust patient-level modeling. Patient-level risk is further modeled as an evidence accumulation process, promoting stable optimization under weak supervision. AGE-MIL is evaluated on six clinically relevant patient-level prediction tasks from two independent cohorts. Experimental results show that the proposed framework consistently outperforms eight state-of-the-art MIL methods. Code is available at https://github.com/wodeniua/AGE-MIL.

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.

We propose a spectral-based, unsupervised representation learning framework to derive low-dimensional embeddings for clinical concepts and patients in rare disease cohorts from electronic health records, where data are high-dimensional but sample sizes are limited. To overcome this challenge, we incorporate a knowledge matrix extracted from a broader population that shares a partially overlapping subspace with the rare-disease cohort. Our method departs from existing approaches by relaxing restrictive one-to-one signal-alignment assumptions between the latent data matrix and knowledge matrix, allowing more flexible and realistic forms of structured sharing. We introduce a novel two-step spectral embedding procedure: first, we identify and remove irrelevant components from the knowledge matrix; then, we apply a projection-based method to separately recover shared and heterogeneous components. Simulations and an analysis of a real-world multiple sclerosis cohort show that the proposed method outperforms competing approaches, particularly in challenging scenarios where shared signals are weak and only partially aligned, as is common in rare-disease data.

Resistance to first-line osimertinib in EGFR-mutant non-small-cell lung cancer (NSCLC) is the canonical example of predictable clonal evolution under therapeutic pressure, yet no public benchmark exists for training or evaluating computational models on the corresponding longitudinal patient trajectories. We introduce OncoTraj, a public benchmark of 813 EGFR-mutant NSCLC patients receiving first-line osimertinib, harmonized from three real-world clinical-genomic sources: MSK-CHORD (672 patients), AACR Project GENIE BPC NSCLC (34 patients), and the FLAURA molecular-resistance supplement (107 patients). OncoTraj defines three locked tasks: (A) binary classification of progression by a fixed 12-month landmark, (B) regression of time-to-first-progression in days, and (C) six-class classification of the dominant resistance mechanism. We release the harmonized dataset, patient-level train/validation/test splits with an audited no-leakage guarantee, an open-source evaluation harness, and six reference baselines spanning a majority-class predictor, logistic regression, random forest, XGBoost, an LSTM, and a multi-task transformer. With v1's single-timepoint snapshot features, no task clears chance on clean within-source evaluation: the uniformity of this ceiling across every model class localizes the limit to the input modality (single-snapshot tissue NGS rather than serial ctDNA), not the algorithm. The benchmark does recover a reproducible literature-consistent association: TP53 co-mutation raises the 12-month progression rate from 29% to 59% cohort-wide. OncoTraj establishes a reproducible, leakage-audited baseline and converts the modality limit into concrete design requirements for a serial-ctDNA-enriched v2.

Data leakage -- contamination of a model with information unavailable at baseline -- is the dominant reproducibility failure in machine-learning-based science, yet detection tools require training code, external data, or domain expertise. None operates on the artifact an auditor most often holds: the model's output. We ask what can be decided about leakage from predictions and outcomes alone. We give a decision-theoretic framework in which leakage diagnostics are functionals of the predicted-risk/outcome law, parameterized by a threshold-weighting linked to proper scoring rules and decision-curve analysis. We prove a sharp impossibility: a recalibrated leak matching an honest model's calibration and discrimination is indistinguishable from honest performance by \emph{any} function of the predictions, so the broad class is detectable only against an externally supplied ceiling on achievable discrimination. We then prove what leakage cannot hide: a near-deterministic subgroup -- the signature of a near-label leak -- produces a sustained unit-purity head that no legitimate predictor of a non-deterministic outcome can manufacture, yielding a prior-free test. These results organize leakage into a trichotomy -- miscalibrated, broad-calibrated, and deterministic -- each with a matched detector and failure mode. We validate on UK Biobank using time-windowed comorbidity leakage with known, graded severity, measuring a detection floor of $Δ\cstar \approx 0.007$ on this endpoint, below which residual leakage is undetectable from output and too small to alter conclusions. The numerical floor is cohort- and endpoint-specific; the structural lesson is general: output-only detection fails where residual leakage is indistinguishable from an honestly stronger predictor. The test returns a verdict on a prediction vector in under a second on commodity hardware.

Supervised fine-tuning with synthetic rationale data is widely assumed to improve language model performance on clinical prediction tasks by teaching models not just what to predict but why. We test this assumption on five-year Alzheimer's disease and related dementias (ADRD) prediction from longitudinal health histories. Across a large-scale controlled experiment of 504 configurations, we find that rationale-based SFT consistently and substantially hurts prediction performance relative to label-only fine-tuning. The degradation persists across model families and data scales, and is not resolved by using a reasoning-oriented base model. Crucially, the failure is not explained by poor rationale quality: human expert annotation confirms that the generated rationales are medically accurate and faithfully grounded in patient-specific evidence, and few-shot experiments show that the same rationales improve performance when used as inference-time demonstrations rather than training targets. We identify the root cause as a structural conflict between narrative plausibility and discriminative optimization. We hope our work paves the path toward a more precise understanding of when and how rationale-based supervision helps and when it does not, guiding the responsible development of language models for high-stakes clinical prediction.

Demand for older-adult and patient care is growing rapidly as populations age worldwide. Foundation models are increasingly being integrated into robots and interactive agents, with the promise of more flexible communication and personalized assistance. However, care settings require reliable and workflow-compatible systems with accountable human oversight, and it remains unclear whether current embodied systems can translate technical advances into clinical impact. This Perspective synthesizes foundation model-based care robots across three areas: design features, user experience, and evidence for care-related outcomes. Current systems most commonly use foundation models as conversational and reasoning layers within voice-centered socially assistive embodiments, while multimodal grounding and physical autonomy remain limited. Empirical evaluations report positive usability and engagement benefits, but reliability failures persist across the interaction pipeline such as hallucinations and conversational breakdowns. Evidence for care impact remains concentrated in proximal outcomes such as cognitive engagement and participation, with limited evidence for validated clinical or care-related changes. We argue that future research should transition toward care-specific evaluation standards, accountable autonomy, and integration into care workflows to support more responsive and responsible care technologies.

Respiratory diseases remain a leading cause of global mortality, where timely and accurate diagnosis is critical to improving patient outcomes and reducing healthcare burdens. While prior work has explored audio-based models for respiratory disease detection, such unimodal approaches often suffer from limited generalizability and diagnostic precision. In this paper, we propose RespiraMFM, a Multimodal Foundation Model that integrates respiratory sounds with patient medical history and symptoms to enhance diagnostic accuracy and disease detection capabilities. We introduce an effective contrastive alignment strategy for audio-text multimodal integration, allowing the model to learn better cross-modal representations between respiratory sounds and corresponding textual clinical information. We evaluate RespiraMFM across five major respiratory diseases using seven real-world datasets in both supervised fine-tuning and zero-shot settings, achieving a 9.15% improvement in AUROC on supervised tasks and a 20.98% gain on zero-shot tasks over existing baselines. These findings underscore the potential of our framework to advance early diagnosis and improve clinical decision-making in respiratory disease management.

Alzheimer's disease (AD) progression is highly heterogeneous and is typically observed through sparse and irregular longitudinal data, posing challenges for prediction and personalised monitoring. Existing machine learning approaches have improved AD prediction using multimodal data, yet often focus on static classification or cohort-level risk estimation, providing limited support for subject-specific modelling and uncertainty-aware reasoning. To address these limitations, we present a personalised digital twin framework for AD prediction and scenario-based analysis using multimodal longitudinal data. The proposed approach integrates complementary modelling strategies to capture clinical transitions and temporal dependencies across visits. Using data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), including cognitive assessments, clinical variables, and MRI-derived phenotypes, the framework predicts cognitive status and diagnostic categories while quantifying predictive uncertainty and enabling patient-specific what-if trajectory analysis. Evaluation on leak-free subject-level splits demonstrates strong performance in score forecasting and diagnosis classification. In this sparse and irregular ADNI setting, transition-based modelling of adjacent visits achieved higher predictive accuracy than the sequence-based branch, suggesting that local transition modelling may be more data-efficient. While sequence models remain valuable for uncertainty-aware trajectory forecasting, local transition modelling offers a more data-efficient and robust predictive strategy. These findings highlight the importance of aligning temporal modelling strategies with clinical data structure and suggest that transition-based digital twin formulations may provide a practical and interpretable approach for personalised disease forecasting in neurodegenerative disorders.

Foundation models offer a promising route to compress multi-modal physiological signals into compact representations of human health, with broad applications across sleep medicine, cardiology, neurology and other healthcare domains. Existing models have typically been trained with masked-reconstruction or contrastive objectives. However, masked reconstruction may be poorly suited to the stochastic nature of these signals, while contrastive approaches rely on positive-pair definitions despite the semantic invariances of physiological signals being poorly understood. In this work, we show that next-token prediction is a simple and scalable alternative. We develop Hypnos, a multi-modal sleep foundation model trained using eight different sensing modalities (e.g. EEG, ECG, respiratory signals) drawn from over 20,000 overnight polysomnography recordings. We tokenize each modality into streams of discrete tokens using residual vector quantization, then train a large auto-regressive RQ-Transformer to jointly predict the next token across all modalities in parallel. After training, Hypnos can be applied to continuous streams of sensor data from any subset of supported modalities, generating embeddings for downstream tasks. Across a range of benchmarks, Hypnos significantly outperforms existing foundation models. In sleep stage classification, we match the performance of strong supervised baselines on held-out test sets whilst using $100\times$ less labelled data. Hypnos even generalises to daytime physiology, surpassing a dedicated ECG foundation model at detecting atrial fibrillation. Our results demonstrate that next-token prediction is a strong self-supervised objective for representation learning from multi-modal physiological signals.

AI Scientist agents are often evaluated as if capability were mainly a function of model quality, prompting, or reasoning scaffolds. We test a different hypothesis in drug-asset valuation: for knowledge-intensive scientific decisions, the limiting factor is often the evidence substrate the agent can access. We run a controlled three-arm ablation on a production valuation agent: A is a plain web-only LLM analyst, B adds public structured tools plus a 14-dimension valuation playbook, verifier, objectivity policy and red-team, and C adds the proprietary Noah AI corpus of curated pipeline, trial and deal intelligence. Across a 13-asset stratified benchmark, B improves calibration and audit discipline: tier-in-range accuracy rises from 0.80 to 0.89 and objectivity from 3.16 to 3.30. But B does not remove the factual ceiling. Under capability-superset accounting, A and B recover only 0.25 and 0.38 of the curated gold competitive record, while C recovers 0.96; on the curated long-tail subset, C reaches 0.93 vs. 0.26/0.30. Raw blind-panel decision quality is similar for A and B (7.01 vs. 6.96), so we introduce completeness-aware decision utility: informed decision-quality = decision-quality x gold-coverage. On this metric, C reaches 7.43 vs. 1.76/2.57 for A/B. Even a perfect non-proprietary-data report would be capped at 3.83 by B's coverage. The result is not that reasoning scaffolds are unimportant; they improve calibration and discipline. Rather, proprietary evidence sets the upper bound of what the AI Scientist can know and therefore decide.

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 .

Large language models (LLMs) are increasingly used for medical summarization, but their outputs can omit medically important information and introduce unsupported claims. Existing error-detection methods produce heuristic or uncalibrated scores, providing no formal control over missed errors and no principled way to trade off safety against clinician review burden. We introduce Conformal Assessment for Risk Evaluation (CARE), a post-hoc, model-agnostic safety layer that uses conformal risk control to overlay calibrated omission and hallucination flags onto summaries from any LLM without retraining. CARE provides finite-sample, distribution-free guarantees through two controllers: a hallucination controller that bounds the probability of a document containing any unflagged hallucinated sentence, and an omission controller that bounds the expected fraction of important omissions not surfaced for review. Unlike hallucination detection, omissions depend jointly on whether a source sentence is important and whether it is covered by the summary. We show that calibrating only one dimension can violate the target risk bound, while marginal decompositions remain valid but overly conservative. By jointly calibrating over the full $(τ,γ)$ threshold space, CARE preserves formal guarantees while surfacing up to 5$\times$ fewer sentences than alternative calibrated baselines. Across five medical summarization tasks, CARE satisfies the target risk bound at $α= 0.15$ with 95% confidence across 100 calibration/test resplits, using only ~100 labeled documents per domain. In a preliminary clinician study (75 document reviews), calibrated flags improved omission detection by 28.6 percentage points on average. These results show that sentence-level safety guarantees are feasible for LLM-assisted medical summarization and offer a tunable mechanism for balancing residual risk and review effort.

Synthetic healthcare data are widely proposed as privacy-preserving substitutes for real patient data, yet their evaluation remains dominated by statistical similarity and predictive performance that do not reflect clinical validity. We introduce a multi-dimensional evaluation framework grounded in epidemiology, assessing descriptive fidelity, clinical utility, and structural validity, corresponding to descriptive, predictive, and causal questions. We evaluate four representative generative paradigms - GAN-based, VAE-boosted, diffusion-based, and masked modelling - using PRIME-CVD, a 50,000-person cohort with known ground-truth structure. While all models reproduce marginal distributions, none simultaneously preserve subgroup structure, effect estimates, and dependency structure. Notably, models with strong distributional fidelity can exhibit poor calibration and distorted relationships, leading to unreliable inference. These results show that current evaluation practices can overestimate synthetic data quality and motivate domain-informed assessment based on the ability to support valid clinical and scientific conclusions.

Telehealth, the delivery of medical care remotely, is hoped to increase access to specialty services or decrease health care utilization. Physicians can provide telehealth to each other or to patients. Specialists often treat complex patients who can be adequately cared for only in academic hospitals, suggesting that providing specialty services via telehealth will reallocate rather than reduce system utilization. Here I use agent-based modeling to investigate telehealth's effects on clinical outcomes and system utilization in medical toxicology. I found that physician-physician telehealth increased patient health but system utilization did not change. The effects were more pronounced as clinical complexity increased. Physician-patient telehealth increased cost and system utilization but not clinical outcomes. Within the limitations of our approach, these results suggest that telehealth is more cost-effective for improving generalist access to specialist knowledge than in providing care to the public.

Electronic health record (EHR) notes are dense medical documents containing large amounts of information, often filled with complex medical jargon. Highlighting all details in EHRs helps reduce the likelihood of missing crucial information by drawing attention to key content. This study proposes the design of a Cardiology Interface Terminology (CIT) to accurately highlight all details in EHR notes of cardiology patients. We introduce an innovative Machine Learning (ML) technique for the design of CIT. The ML technique requires training data. Manual preparation of such training data is time-consuming and expensive. The process of the CIT design includes three phases. In the first two phases, we innovatively derive a training data CIT to be used by the third phase, ML technique. We start by designing an initial CIT, composed of several components: the cardiology-related sub-hierarchies of SNOMED, other SNOMED concepts mined from EHRs of build set, and necessary components of terms e.g., medical abbreviations and medications. Utilizing an iterative process, fine-grained phrases containing initial CIT concepts are extracted from build set as CIT concept candidates. The candidate concepts are semi-automatically reviewed before being added to CIT, yielding the training data CIT, TCIT. In the third phase, a ML model is trained with TCIT to identify candidates fitting to be concepts in the CIT. This model is used to extract further concepts from build set, yielding the final CIT. The final CIT is then used to highlight the test set and evaluate the extent to which it captures details in an unseen EHR dataset. For this purpose, four evaluation metrics, coverage, breadth, completeness, and conciseness are used. The highlighted test set has a coverage of 74.21%, with a breadth of 1.68. For 20 random notes in test set, the average completeness is 98.2% and average conciseness is 84.2%.

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.

Linking FDA-approved medical devices to their underlying United States Patent and Trademark Office (USPTO) patents enables critical applications such as recall root-cause analysis, M&A-driven IP discovery, and technology trajectory mapping. However, this cross-domain entity linking task remains unexplored due to severe semantic gaps: FDA documents focus on clinical outcomes, while patents describe technical mechanisms, yielding minimal lexical overlap. We formalize medical device-patent linking as a challenging cross-domain entity linking problem characterized by label scarcity and domain shifts. Using cardiovascular devices as a high-impact, representative domain featuring diverse technologies, high recall rates, and abundant disclosures, we construct a benchmark with 434 devices, 698K patents, and 585 high-fidelity expert-verified pairs. To address these challenges, we propose Bridge-MedDevKG, a coarse-to-fine framework that integrates (1) MedDevOnto, a domain-specific ontology that anchors device concepts via three-tier UMLS normalization; (2) Multi-signal candidate generation fusing company affiliation, semantic similarity, and ontology-weighted entity overlap; and (3) Heterogeneous reranking with multi-signal scoring and XGBoost classification on hard negatives. Our approach achieves a conservative lower-bound recall of 91.6% on the gold standard with 50.9% noise reduction, substantially outperforming LLM baselines under comparable evaluation. The resulting MedDevKG provides 6.8M high-confidence links, laying a scalable foundation for regulatory-IP integration across medical specialties.

Alzheimer's disease is a progressive neurodegenerative disorder, and its progression varies substantially across patients. Existing work aims to forecast patients' future cognitive state, with minimal focus on reconstructing the state from past visits. Furthermore, in current research, quantifying predictive uncertainty remains underexplored and relies on costly modalities such as MRI, PET, and CSF, limiting their deployment in resource-limited settings. In this research, our primary objectives are: First, bidirectional prediction of cognitive scores from irregular visits to present the complete disease trajectory. Second, to enable interpolation and extrapolation capabilities to assist clinicians in informed prognostic decision making, and third, to provide a well-calibrated uncertainty estimate for all predictions, and finally, to achieve the objectives using the modalities available during routine visits. We propose a unified framework, GNOVA: A GRU-Neural ODE Variational Autoencoder. The architecture combines a Gated Recurrent Unit encoder and a Neural ODE decoder within a variational autoencoder framework. In our work, we forecast the CDR-SB and MMSE Scores. The GRU encoder allows for any number of inputs at any time point. The Neural-ODE decoder performs continuous estimation, allowing interpolation and extrapolation at any desired time point. The Variational autoencoder allows for uncertainty estimation in predictions. We worked with 1,727 patients from the ADNI dataset over 10 years; the model achieved mean absolute errors of 1.35 and 2.28 for CDR-SB and MMSE scores, respectively, without requiring any neuroimaging or biomarker data. Feature-ablation studies revealed that age, BMI, and APOE4 status were strong predictors. The proposed framework enables the reconstruction of incomplete patient histories and the anticipation of future cognitive states.

Photoplethysmography (PPG), a non-invasive measure of changes in blood volume, is widely used in both wearable devices and clinical settings. Recent PPG foundation models either use open-source ICU datasets with pretraining paradigms that require curated data and thus complicate generalization to field-like data, or use closed-source field-like PPG data. In contrast, we propose a PPG foundation model that does not require high-quality or field-like pretraining data, and instead leverages accompanying electrocardiogram and respiratory signals in ICU datasets to select contrastive samples during pretraining. Our approach allows the model to retain and learn from noisy PPG segments, improving robustness at inference. Our model, pretrained on 3x fewer subjects than existing state-of-the-art approaches, achieves performance improvements on 14 out of 15 diverse downstream tasks, including field-like daily activity and heart rate prediction. Our results demonstrate that multimodal supervision can integrate complementary physiological information to improve the robustness of PPG foundation models and enhance their generalization to consumer-grade data.

Large Language Models (LLMs) are increasingly used in healthcare for tasks such as clinical question answering, diagnosis support, and report summarization. Despite their promise, these models remain highly sensitive to subtle prompt perturbations, both lexical and syntactic, posing serious risks in safety-critical clinical applications. In this study, we conduct a systematic sensitivity analysis to evaluate the robustness of both general-purpose (e.g., GPT-3.5, Llama3) and medical-specific LLMs (e.g., ClinicalBERT, BioLlama3, BioBERT) using the MedMCQA benchmark. We categorize perturbations into natural and adversarial types and examine their effect on model consistency, accuracy, and reliability in clinical reasoning tasks. Our findings reveal that medical LLMs are not intrinsically safe. Even minor variations in phrasing can alter clinical advice, and targeted adversarial prompts can provoke harmful outputs. In high-stakes settings like healthcare, such unpredictability is unacceptable-models that change diagnoses due to reworded inputs or hallucinate medications when slightly rephrased cannot be reliably trusted by clinicians. While models tend to show resilience to simple lexical substitutions or paraphrasing, they often break down under syntactic reordering or misleading contextual cues. This fragility is evident across both general-purpose and domain-specific LLMs. Notably, adversarial manipulations can lead to clinically dangerous outputs, such as recommending incorrect dosages or omitting critical findings.

Language models trained for clinical disease inference are trained on patient data, which may include sensitive and private information, and data owners may request the removal of their data from a trained model due to privacy or copyright concerns. However, exactly unlearning patient-specific data is intractable, and retraining with minor data removal is resource-intensive. While there exists several machine unlearning methods that can be used, their utility is generally restricted to non-medical domains. Moreover, the existing benchmarks for evaluating such unlearning methods primarily utilize synthetically curated datasets, which are not truly representative of real-world systems. Hence, the effectiveness of these unlearning methods in the medical domain is largely unclear. To this end, we introduce REMEDI, an extensive benchmark for machine unlearning tailored to multi-label and multiclass clinical disease inference, where label correlations, longitudinal structure, and safety constraints make unlearning particularly challenging. Unlike the existing benchmarks, REMEDI considers: (1) a relevant application domain (medical), (2) comprehensive unlearning setups involving diverse sets of forget instances, (3) challenging unlearning scenarios including multi-label and multi-class classification tasks, and (4) evaluation metrics involving performance both in terms of utility and extent of unlearning achieved. REMEDI is developed using the MIMIC-III clinical database that contains comprehensive clinical data of patients. Experiments with existing unlearning methods indicate that there exists a trade-off between utility and unlearning performance. They are also largely unsuited to multi-label classification tasks. To facilitate reproducibility, we make our benchmark publicly available.

The generation of high-fidelity synthetic Electronic Health Records (EHR) is crucial for advancing medical research while preserving patient privacy. However, head-to-head comparison of existing generative models is hindered by disjointed codebases, incompatible data loaders, conflicting library dependencies, and inconsistent evaluation protocols. To address these gaps, we introduce a lightweight, end-to-end benchmarking framework for reproducible synthetic EHR evaluation, organized as a unified pipeline spanning data ingestion, standardized model training, and architecture-agnostic evaluation. Our current implementation targets the generation of longitudinal ICD diagnosis codes -- the most commonly studied modality in this literature -- and is built on the community-maintained PyHealth library. We reimplement and unify strong baselines (MedGAN, CorGAN, PromptEHR, HALO) under full ICD-9 vocabulary granularity, and add a lightweight GPT-2 baseline from the general-purpose sequence-modeling literature. We contribute a rigorous, architecture-agnostic privacy-utility evaluation suite that applies identically to GAN- and transformer-based generators, and report bootstrapped confidence intervals across all metrics. We further analyze the poor long-tailed performance of existing models and discuss the extensibility of our framework beyond diagnosis codes. By lowering the engineering barrier to running, extending, and evaluating under a single pipeline, we introduce a starting point for community-driven reproducibility and benchmarking synthetic EHR models.

Foundation models for wearable biosignals have matched or exceeded supervised specialists across a range of clinical tasks, yet all rely on modalities that require deliberate user action--wearing a device or visiting a sleep lab. We introduce BCG-FM, the first foundation model for ambient mechanical biosignals. A piezoelectric sensor embedded in the bed surface records ballistocardiography (BCG) each night without user effort; we pretrain BCG-FM with participant-level contrastive learning and using a total of 2.75 million hours of nightly recordings from 145,985 individuals, the largest raw-waveform biosignal pretraining corpus to date. Frozen BCG-FM embeddings achieve 3.26-year MAE on biological-age estimation (the lowest reported for any ambient, contactless modality) and yield clinically relevant discrimination across 15 self-reported health conditions and three independent external cohorts. Pretrained representations from only 500 labeled participants outperform a fully supervised baseline trained on 3,372, and representation quality scales log-linearly with contrastive batch size. These results establish ambient, longitudinal mechanical biosignals as a viable modality for health foundation models.

Electronic health records (EHR) pose large-scale multi-disease modeling problems in which many outcomes are rare and strongly influenced by shared risk factors. While modern approaches achieve strong predictive performance, they often treat diseases independently or rely on black-box architectures, offering limited insight into how risk factors organize disease risk and little principled uncertainty quantification. We introduce a Bayesian hypergraph inference framework that reframes multi-disease modeling around latent, risk-factor-modulated disease pathways. Risk factors act on hyperedges, latent disease subsets with shared risk patterns, allowing diseases to participate in multiple distinct pathways and enabling interpretable, higher-order structure beyond pairwise associations. A repulsion prior encourages parsimonious and identifiable structure, while posterior inference provides calibrated uncertainty over both disease groupings and risk-factor influence. To enable scalable inference on large EHR datasets, we develop a structured variational inference algorithm that preserves logical dependencies among hyperedge existence, disease membership, and pathway-level effects. Experiments on simulated data and UK Biobank demonstrate stable and interpretable disease pathway structure, well-calibrated uncertainty, improved estimation for rare diseases, and competitive predictive performance.

Explanations of multiple instance learning (MIL) models are widely used for validation and discovery in digital histopathology. Existing methods primarily rely on heatmaps that highlight influential regions but do not explain how evidence from different tissue regions is combined to produce a prediction. This limits interpretability, especially when decisions depend on interactions between tissue features. We introduce Symbolic explainable MIL (Symb-xMIL), a post-hoc explanation framework that quantifies how a MIL model's behavior aligns with human-readable decision rules, expressed as logical relationships (e.g., AND, OR, NOT) between input features. These alignment scores reveal semantic patterns underlying the model's predictions. We evaluate Symb-xMIL on synthetic and real-world histopathology datasets. On synthetic MIL data, Symb-xMIL reliably recovers ground-truth logical rules. In a clinical tumor detection task, the best-aligned rules uncover heterogeneous decision patterns and expose hidden model errors. On an HPV-prediction task on TCGA-HNSCC, a cohort of head and neck cancer, our framework refines patient survival stratification beyond HPV status with potential clinical relevance. Overall, Symb-xMIL extends MIL explainability beyond visual attribution toward structured, rule-based reasoning, enabling more transparent and semantically grounded interpretation of model predictions.

Huntington's disease (HD) is a progressive brain disorder that gradually affects movement, cognitive function, and behavior. Identifying the stage of the disease accurately and consistently is important for understanding its course, grouping patients, personalized care, and discovering treatment. Existing clinical staging frameworks rely primarily on predefined clinical measurement thresholds and clinical expert decisions, yet these discrete cut-offs may obscure meaningful intra-stage variability and remain vulnerable to inter-rater differences, especially in motor and functional assessments. To address these limitations, we developed an unsupervised machine learning framework based on dynamic graph representation learning to capture temporal relationships within and across patients from longitudinal clinical measurements. Using the learned representations, we applied K-means++ clustering to identify well-separated groups. We then iteratively increased the number of clusters (k), using stability analysis to assess robustness and reveal additional meaningful clusters beyond the initial optimal solution. We applied the framework to 302 individuals from the Enroll-HD cohort (1,477 visits, 44 clinical variables per visit; 80% manifest participants), enabling data-driven discovery of HD stages reflecting natural clinical progression. Despite the limited cohort size, the proposed framework achieved robust clustering performance using a four-dimensional latent space, identifying four meaningful and statistically distinct disease stages through clustering stability analysis. Each stage corresponded to well-defined clinical measurement boundaries, with minimal overlap compared to previously established clinical staging methods.

Medical knowledge graphs (MKGs) infused with clinical knowledge have been increasingly used to model electronic health records (EHRs) to support interpretable predictions in healthcare domain. However, existing MKG-based approaches are limited in capturing pairwise relations between clinical concepts (e.g., conditions, procedures, and medications), and restricts their ability to model higher-order interactions among co-occurring or semantically related concepts. In addition, most representation learning methods that leverage MKGs either collapse temporal information across visits or lack an explicit mechanism for modeling long-range temporal dependencies, which is critical for clinical tasks such as mortality prediction. To mitigate these limitations, we propose HoT-SSM, a parameter efficient and higher-order temporal graph reasoning with state space models. For each visit, HoT-SSM constructs hypergraphs by grouping semantically related clinical concepts into hyperedges using domain knowledge, thereby preserving visit-level clinical context. Further, to model the temporal dynamics while learning the representations, we introduce a novel dynamic hypergraph-based state space model that explicitly captures patients latent state evolution over time while preserving long-range information. The learned representations are used for downstream clinical prediction and reasoning. Experiments on MIMIC-III and MIMIC-IV datasets shows significant performance improvement over the current state-of-the-art models, demonstrating the effectiveness of jointly modeling higher-order clinical interactions and long-range temporal dependencies.

Data-driven Prognostics and Health Management (PHM) uses time-varying condition-monitoring data to diagnose system states and estimate remaining useful life in engineered assets. These tasks are central to maintenance planning, but industrial PHM data are often fragmented, partially observed, and poorly labeled, which hinders supervised learning. Foundation models offer a route toward reusable predictive systems, yet most time-series foundation models are designed for forecasting and assume long, coherent, regularly sampled sequences. To address this gap, we propose a framework for applying Tabular Foundation Models to industrial time series using in-context learning, and we evaluate them on a variety of PHM tasks. By converting raw unit-level signals into tabular rows, we show that these models perform well across multiple tasks - including prognostics, and diagnostics - and are highly data efficient. We compare them directly with sequence models, transformer baselines, and gradient-boosted trees under a common evaluation protocol. The results indicate that tabular foundation models achieve the best average ranks across prognostic and diagnostic tasks. Our findings further show that PFN-based models are competitive in low-data regimes, that temporal context can be preserved in the tabular representation, and that performance depends on representative context construction under subsampling. These results demonstrate that tabular foundation models provide a practical and general interface for heterogeneous PHM problems.

Purpose: To develop an interpretable and trustworthy AI framework that combines deep learning based MRI Osteoarthritis Knee Score (MOAKS) prediction with interpretable statistical modeling to study structure-pain relationships at scale using data from the Osteoarthritis Initiative (OAI). Materials and Methods: We first developed a deep learning framework to predict MOAKS features directly from knee MRIs and incorporated conformal prediction to provide prediction uncertainty quantification. This uncertainty-aware strategy enables explicit filtering of model outputs, retaining only high-confidence MOAKS predictions at the knee level. Second, we applied a longitudinal latent class mixed model (LCMM) to examine associations between key structural abnormalities and four complementary knee pain measurements. Results: Among the three MRI-defined abnormalities (i.e., bone marrow lesions (BML), cartilage loss (CART), and meniscal extrusion (ME)), our framework substantially improved the Matthews correlation coefficient (MCC) and some other metrics. For example, MCC increased from 0.69 to 0.91 for BML, from 0.45 to 0.80 for CART, and from 0.59 to 0.89 for ME. Using these high-confidence predictions, we expanded the sample size to 2,175 knees for the LCMM analysis. Two distinct pain trajectories were identified (rapid and stable pain progression). The estimated odds ratios (95% CI) for the rapid progression group were 1.62 (1.12-2.35) for BML, 1.83 (1.24-2.70) for CART loss, and 2.50 (1.75-3.57) for ME. Conclusion: These results highlight the importance of these structural abnormalities as risk factors for pain and functional progression in osteoarthritis.

Accurate computational prediction of T cell receptor (TCR) antigen specificity would transform the study of T cell biology and enable scalable immune engineering, yet existing models lack sufficient sensitivity and specificity for broad applications. A major limitation is the absence of rigorously defined, unseen benchmark datasets that allow unbiased evaluation of model performance and generalizability. Here, we describe two complementary classes of datasets that meet this criterion and argue that they provide both a robust framework for model assessment and a foundation for next-generation TCR-antigen prediction algorithm development.

CARE-link is an open-source, web-based clinical support platform designed to improve the management of gestational diabetes by linking clinicians and patients through an LLM-mediated workflow. The system aggregates patient-generated data outside the hospital, summarizes relevant clinical information, and delivers context-aware decision support to clinicians. For patients, CARE-link provides clear explanations of management plans and delivers timely lifestyle guidance through a WhatsApp interface. The integrated dual-facing design aims to promote continuous monitoring, support individualized care, and reduce the burden of in-clinic follow-ups. Built with a modular architecture, the platform can be adapted to other chronic conditions requiring longitudinal tracking and behavioral support. CARE-link has the potential to enhance clinical oversight, promote patient compliance, and strengthen continuity of care particularly in resource-constrained settings.

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.

Background: Dermatology AI has mainly focused on image-based diagnosis, while chronic disease workflows have received less attention. We surveyed Indian dermatologists to map routine clinical challenges, with a focus on atopic dermatitis (AD), and assess current AI use. Methods: A nationwide cross-sectional survey commissioned by the Society for Eczema Studies included 377 practicing Indian dermatologists. The survey assessed clinical challenges, AD workflow barriers, AI use, adoption barriers, and ethical concerns. Analyses used descriptive statistics, chi-square tests, false discovery rate correction, and multivariable logistic regression. Results: Patient adherence (61.3%) and treatment planning in difficult or refractory cases (57.0%) were reported more often than diagnostic uncertainty (48.0%). In AD care, severity scoring was reported as a challenge by 47.7% and had the lowest satisfaction among measured workflow areas. Current AI use was reported by 49.9%, most often involving general large language models for literature synthesis, documentation, and academic tasks rather than specialized image analysis. Barriers differed by experience: dermatologists with more than 20 years of practice more often cited lack of training, while those with 5 years or less more often cited lack of clinical utility after trying AI tools. AI users were more likely than non-users to report concern about patient self-misdiagnosis and anxiety, which remained significant after adjustment for experience and academic affiliation. Conclusion: Respondents reported using general-purpose AI mainly for cognitive and administrative tasks, while their clinical needs centered on chronic disease management and AD workflow support. Clinician-supervised workflow tools may be more useful than standalone diagnostic applications.

Hereditary stomatocytosis (HS) comprises red blood cell (RBC) disorders characterized by cup-shaped erythrocytes that respond oppositely to splenectomy: curative in overhydrated HS (OHS) but potentially thrombogenic in dehydrated HS (DHS/xerocytosis). This paradox persists because RBC biomechanics is governed by partly independent parameters--shear modulus, bending rigidity, surface-to-volume ratio (S/V), and cytoplasmic viscosity--that existing assays capture only piecemeal. Here we combine dissipative particle dynamics (DPD) simulations with microfluidic imaging to construct a control discocyte and three stomatocyte models (ST-RBC1-3) at fixed membrane area and decreasing volume (109.7, 101.5, 89.8 fL), spanning the OHS-to-DHS range. Tracing this parameter set through five mechanically orthogonal assays, we find that interendothelial-slit (IES) traversal is geometry-dominated: overhydrated ST-RBC1 requires an order of magnitude higher critical pressure than healthy RBCs, whereas dehydrated ST-RBC3 passes freely. ST-RBC3 nonetheless suppresses membrane tank-treading and raises low-shear whole-blood viscosity by ~29% at physiological haematocrit, comparable to Gaucher-disease hyperviscosity. A funnel-obstacle chip amplifies these differences into a label-free centerline-offset signal predicted to separate all four RBC types (~4.5 standard deviations between extreme phenotypes). These results unite single-cell mechanics, splenic filtration, and hemorheology in one framework, resolve the splenectomy paradox, and point toward microfluidic pre-operative risk stratification in HS.

Electronic health records (EHRs) are central to clinical prediction, but existing methods either rely on correlation-driven deep models or use single large language models (LLMs), making it difficult to support multidisciplinary clinical reasoning. Recent multi-agent systems (MAS) provide a promising alternative, yet current EHR-grounded MAS methods still suffer from weak evidence differentiation across agents and redundant multi-round interaction. We propose D2MDT, a Department-aware MultiDisciplinary Team Consultation with Deliberation for Efficient clinical prediction. D2MDT first constructs structured EHR evidence and consultation-ready semantic evidence for multi-agent consultation. It then assigns patient-specific department perspectives to doctor agents and retrieves complementary evidence for collaborative consultation. To improve efficiency, D2MDT further introduces residual deliberation, which updates only unresolved consensus rather than replaying the full discussion history. Finally, D2MDT fuses the refined consensus report with structured EHR representations for prediction. Experiments on mortality prediction show that D2MDT improves both predictive performance and consultation efficiency. We release the code online to ease the reproducibility of this paper.

Untargeted liquid chromatography-high-resolution mass spectrometry (LC-HRMS) detects thousands of molecular features per sample, yet only 2-20% receive confident structural annotations. A root cause of this "dark metabolome" is that tandem MS/MS acquisition is reactive: instruments select precursors only after ions appear, blind to what elutes next. We reframe chromatographic elution as an autoregressive sequence prediction task. Because reversed-phase elution order is governed by hydrophobicity, successive features form a physically constrained sequence, like tokens in language. We discretize the mass-to-charge (m/z) axis into 110 bins and train long short-term memory (LSTM) and Transformer models to predict the next eluting m/z bin from five annotation-free per-token features: m/z bin, mass defect, retention-time gap, polarity, and intensity rank. Trained on 15,242 features from four clinical lipidomics cohorts (342 plasma samples; SCIEX TripleTOF 6600+, Waters CSH C18), the LSTM reaches 98.4% top-1 accuracy (99.99% top-5; mean absolute error 3.6 Da) and the Transformer 98.0%. Ablation shows autoregressive context accounts for 55.5 percentage points while no single feature contributes more than 0.2 pp: the sequential pattern, not molecular properties, drives prediction. Models transfer across instruments sharing the method (r=0.999 on an independent Agilent 6530 dataset) but fail under a different column chemistry (5.1% top-1) or polarity mode (2.6%), confirming method- and mode-specificity. Fine-tuning on as few as two to five quality-control injections recovers held-out accuracy from 2.6% to nearly 50%, so cross-condition deployment needs minimal calibration. These results establish that elution sequences are highly predictable and lay the groundwork for predictive MS/MS acquisition to improve annotation coverage in untargeted metabolomics.

While large language models (LLMs) are increasingly used for clinical applications, many existing pipelines require sending raw sensitive health information to remote servers for processing, which heightens the risk of privacy leakage. A natural approach to mitigate this risk is to encrypt the data before transmission. However, straightforward solutions such as encrypting the entire dataset introduce prohibitive computational, alignment, and communication overheads, rendering large-scale practical deployment infeasible. To preserve privacy while maintaining usability, we present Healthcare Encryption & Redaction via Adaptive Linguistic Decomposition (HERALD), a token-level cryptographic redaction framework designed to achieve this balance by encrypting only sensitive tokens while preserving the surrounding context for downstream model utility. HERALD combines medical named-entity recognizer (NER) with part-of-speech (POS) driven policies to select candidate tokens, performs targeted lemmatization to stabilize surface forms, and substitutes each protected token with a deterministic ciphertext wrapped in explicit delimiters. Notably, HERALD is model-agnostic and operates entirely on the client side, ensuring that sensitive content remains encrypted throughout storage, transmission, and processing without requiring changes to downstream models. We evaluated HERALD on both classification and medical question answering (MQA) tasks on public datasets. Across different tasks, experiments illustrate that fully secured baselines suffer significant utility loss, whereas HERALD consistently recovers performance close to plaintext. Overall, HERALD provides a novel utilization pipeline.

Computer-use agents could automate repetitive screen-based clinical work, but their reliability in medical graphical user interfaces remains largely unvalidated. Existing benchmarks focus on general web or desktop tasks and underrepresent medical software, which requires domain knowledge, exhibits markedly different UI design from mainstream applications, lacks public testing environments, and demands safety validation beyond task completion. We introduce MedCUA-Bench, an interactive benchmark for clinical computer-use agents. It covers 18 clinical scenarios across 10 medical domains, reconstructed from real product manuals and open-source medical systems to capture authentic clinical interfaces while avoiding licensing and privacy constraints. Each task ships with paired intent- and step-level goals to disentangle clinical reasoning from UI execution, and is evaluated by a deterministic checker over task completion and five clinical safety dimensions. Across 23 agents, the best closed-source model reaches 54.2% strict success, while all models remain below 9% on the real OpenEMR. Open-source agents average only 2.5%, with the best reaching 16.2%. MedCUA-Bench exposes the gap between current agents and reliable clinical software use, providing a reproducible testbed for future research.

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) have been widely adopted in healthcare, yet they still encounter significant challenges in complex clinical decision-making scenarios. Existing benchmarks primarily assess LLM performance in single-course settings and lack systematic evaluation in multi-course scenarios, where a patient's condition evolves over time. To address this gap, we propose ClinicalMC, a benchmark for multi-course clinical decision-making. It includes 1,275 Chinese and 5,804 English samples across four stages from admission to discharge. These stages cover triage, first-course examination/diagnosis/treatment, subsequent multi-course examination/assessment/treatment, and final diagnosis. In ClinicalMC, patients in the English dataset undergo an average of 5.11 clinical courses, whereas those in the Chinese dataset undergo 3.42. To assess LLM performance, we construct a multi-agent evaluation framework that includes patient, examiner, and doctor agents. Based on the benchmark and framework, we design two experimental settings -- a single-turn static setting and a multi-turn dynamic setting -- and assess three categories of LLMs: 1) closed-source LLMs like GPT5-mini; 2) open-source LLMs like DeepSeek-V3.2; and 3) medical LLMs like HuatuoGPT-o1. Through extensive evaluation, we aim to better understand LLM performance in the medical domain and support its effective deployment in healthcare.

Deep reinforcement learning (DRL) is increasingly applied to de novo molecular design, but choices in data, rewards, and evaluation can yield uneven performance across disease areas and chemotypes. Despite this, there is no concise synthesis of how fairness is defined, measured, and tested in DRL-based drug discovery. In this rapid evidence review, we synthesize fairness definitions and metrics for DRL-driven molecule generation in healthcare. We focus on three questions: (i) how dataset composition and split strategies, especially scaffold versus random splits, affect evaluation and distribution shift; (ii) how reward design (e.g., QED, docking, toxicity, synthetic accessibility) can create or mitigate bias, with emphasis on cancer targets; and (iii) which measurable metrics best capture fairness. This includes parity across cancer versus non-cancer indications and across cancer subtypes. It also includes distributional balance in key physicochemical descriptors, scaffold/chemotype diversity, groupwise validity, toxicity, and synthetic accessibility. From 2017 onward, we searched major biomedical, computer science, and engineering literature databases and used arXiv for horizon scanning. Records were screened using PRISMA-style procedures and analyzed via content coding to link reported parity outcomes to dataset and reward choices. Our review provides a concise set of fairness definitions and metrics for DRL molecule generation. It offers practical guidance for reporting distribution parity and outcome parity. It also summarizes how dataset and reward choices relate to observed parity effects and identifies open gaps relevant to trustworthy, cancer-relevant DRL generation.

Modeling patient trajectories from longitudinal electronic health records (EHRs) requires reasoning over sparse, noisy, and long-context multimodal sequences. Existing LLM-based multi-agent systems address context length but process patients in isolation, failing to mirror how clinicians leverage accumulated experience from similar prior cases. We present Traj-Evolve, a self-evolving multi-agent system with two complementary evolving mechanisms. First, an Experience Pool (ExPool) acts as a non-parametric memory, indexing rejection-sampled reasoning traces to retrieve similar patients as few-shot contexts. Second, multi-agent reinforcement learning (MARL) via reward-ranked fine-tuning parametrically optimizes inter-agent and agent-memory collaboration. A leave-one-out cross-retrieval strategy unifies the two, aligning training- and inference-time behavior under retrieval augmentation. On a lung cancer prediction task utilizing up to five years of multimodal EHRs, Traj-Evolve outperforms 9 strong baselines on the overall population and a challenging never-smoker population. Analysis of the evolving dynamics highlights three key findings: (1) expanding the ExPool shifts optimal retrieval from diverse to specific samples; (2) under MARL, the manager agent's prediction loss converges quickly while the worker agents' temporal reasoning continues to benefit from more verified patients; and (3) the two mechanisms are complementary on the predicted risk, where ExPool improves specificity while MARL improves sensitivity.

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.

Clinical practice is not the selection of an answer from enumerated options: a physician gathers heterogeneous information incrementally and commits to sequential, irreversible decisions under uncertainty. Static benchmarks cannot probe and existing interactive medical benchmarks each compromise on at least one of them. We present ClinEnv, an interactive benchmark that evaluates LLMs as attending physicians over real inpatient admissions under a paradigm we term Longitudinal Inpatient Simulation. Each case is automatically constructed into an ordered sequence of decision stages; at every stage the model must actively query four specialized agents before committing to medications, procedures, and diagnoses. ClinEnv scores both what the model decides, through deterministic ontology-grounded matching, and how it gathers information. Across seven models, the strongest reaches only 0.31 decision F1, and outcome quality is sharply decoupled from process quality. Difficulty concentrates in management decisions and later stages, where models recover discharge diagnoses far more reliably than management actions (0.51 vs. 0.17 F1) and continue to issue redundant queries as cases progress. ClinEnv makes this information-acquisition gap, invisible to outcome-only evaluation, directly measurable.

Systematic reviews rely on forest plots to synthesise quantitative evidence across biomedical studies, but generating them remains a fragmented and labour-intensive process. Researchers must interpret complex clinical texts, manually extract outcome data from trials, define appropriate interventions and comparators, harmonise inconsistent study designs, and carry out meta-analytic computations-typically using specialised software that demands structured inputs and domain expertise. While recent work has demonstrated that large language models can extract study-level data from unstructured text, no existing system automates the complete pipeline from raw documents to synthesised forest plots. To address this gap, we introduce AutoForest, the first end-to-end system that generates publication-ready forest plots directly from biomedical papers. Given one or more study papers, AutoForest automatically suggests ICO (Intervention, Comparator, Outcome) elements, extracts outcome data, performs statistical synthesis, and renders the final forest plot. We describe the system architecture, user interface and demonstrate its effectiveness on real-world examples through a user study involving clinicians, showing how AutoForest can accelerate evidence synthesis and substantially lower the barrier to conducting meta-analyses.

Medical imaging is central to modern diagnostics, and artificial intelligence (AI) systems are increasingly used to support image-based analysis by improving efficiency, accuracy, and access to care. However, inequities in healthcare access and differential disease prevalence create severe demographic imbalances in clinical image data. Such imbalances are compounded by the fact that diseases can manifest with distinct features across demographic groups, rendering certain phenotypic presentations naturally rare. AI models trained on such imbalanced data risk perpetuating diagnostic bias and widening healthcare disparities. Here we introduce FairGen, a fairness-aware diffusion framework that synthesizes demographically balanced medical images while preserving pathology-relevant visual features. By embedding physician-aligned preferences into the generation process, FairGen improves subgroup coverage during synthesis and downstream classification. Applied to dermatology, radiology, and neuroimaging benchmark tasks, FairGen achieves fairness improvements of 95.9% for skin images, 80.0% for chest radiography, and 35.2% for brain MRI, while maintaining competitive diagnostic accuracy relative to models trained on original clinical data. Clinician-facing expert review and external validation on independent cohorts further support that these gains extend beyond standard fidelity metrics and are not confined to the original in-distribution datasets.