Multimorbidity

Patient preference, defined as a patient's demonstrated willingness and capacity to adhere to clinical recommendations, is a primary determinant of therapeutic effect yet remains structurally absent from existing computational treatment planning models. We address this gap by presenting patient-centered factored-action hierarchical option-critic (FAHOC), a hierarchical reinforcement learning (HRL) framework that jointly learns high-level options corresponding to therapeutic strategies and factored intra-option policies that decompose the joint action space into disease- and intervention-specific subcomponents, while imposing a cooperation-aware action masking mechanism. This enables structured exploration, improved credit assignment across hierarchy levels, and more interpretable decision pathways, while enforcing patients' preferences. Formal guarantees establish that cooperative patients achieve higher optimal expected health outcomes than non-cooperative patients, and that the factored Q-function approximation error is provably bounded. The framework is evaluated using longitudinal data collected from approximately 50,000 comorbid hypertension and type 2 diabetes mellitus patients from five hospitals in the Southeast U.S. FAHOC achieves a quality-adjusted life year expectancy equivalent improvement of 0.669 (vs -0.133 observed clinician practice), correctly identifies cooperative patients in 95.9% of cases and never violates a patient's preference in held-out test, demonstrating that HRL with explicit preference constraints can support preference-consistent, clinically safe decision-making in multimorbidity management.

Patients often have several co-occurring clinical conditions, and the findings needed to identify and disambiguate them emerge over the course of a consultation. Evaluating clinical reasoning in this setting requires both multi-turn interaction and multi-label diagnosis. We introduce CLIMB, a benchmark in which a doctor model interviews a simulated patient to recover a ground truth set of co-occurring clinical conditions. Cases are synthesized from clinical decision algorithms and diagnostic datasets, grounding multimorbid presentations in structured clinical knowledge. Across six frontier and open models, none recovers the exact set of conditions in more than 10% of interactive cases. Diagnostic performance declines when conditions co-occur, even when models receive the full clinical record and the true number of conditions. Interaction reduces performance further. In controlled experiments, models behave like single-hypothesis trackers: they anchor on the diagnosis suggested by the opening findings, keep questioning around it, and recover a second condition mainly when a finding in view points to it. Questioning them further does not complete the set but adds mostly wrong diagnoses. We formalise this pattern with a theoretical reference model of single-hypothesis tracking. The benchmark, generator, and evaluation code are available at https://anonymous.4open.science/r/CLIMB-8340.

Pneumonia is difficult to diagnose in older long-term care residents; multimorbidity and atypical presentations obscure signs, motivating operationally efficient objective testing. We analyzed multi-channel digital stethoscope recordings from 185 Japanese residents (73 pneumonia, 112 symptomatic without), using radiologist-confirmed chest X-rays and clinician diagnoses as supervisory signals that train convolutional neural networks, multimodal fusion, and channel-based variants with time-domain Grad-CAM interpretability. Models were evaluated with repeated patient-level cross-validation showing models with X-ray supervision outperformed clinician supervision (F1 0.729, accuracy 0.783 vs. F1 0.637, accuracy 0.711). Additionally, a three-channel selection protocol maintained performance (F1 0.736; accuracy 0.803), with two mid-thoracic sites ranking highest and Grad-CAM attention overlapping adventitious sounds. These findings indicate automated multi-channel lung-sound analysis can aid long-term care pneumonia diagnosis, with X-ray supervision being more reliable than clinical, and fewer channels preserving performance while lowering acquisition times.

Large language model (LLM) agents can support medication review between clinical visits, but safe choices for older adults with multimorbidity depend on conditions, medications, and geriatric risks that users may omit. We introduce ATLAS, a coupled graph--policy distillation framework for patient-adaptive medication safety. ATLAS structures guideline evidence as a medication-safety graph. Targeted questions update the patient state and distill relevant relations into a patient-specific medication conflict graph (PMCG). A risk-first multi-agent policy uses the PMCG to screen contraindications, assess cautions and monitoring needs, identify safer alternatives, and verify the final medication plan. We also introduce GeriMedBench, an interactive benchmark that tests safety-critical information acquisition and evidence-based decision revision. Across a European non-interactive multimorbidity benchmark, an Asian interactive multimorbidity benchmark, and an Asian non-interactive cross-guideline benchmark, ATLAS achieves the strongest complete-decision performance among the compared systems. On the European non-interactive multimorbidity benchmark, it exceeds the strongest proprietary LLM baseline by 53.73 points in Strict Success Rate and 14.63 points in overall safety reasoning score (OSRS), with no unsafe recommendations under the automated evaluator. A blinded clinician evaluation gives ATLAS higher mean ratings across all five criteria and flags potentially unsafe recommendations in one ATLAS case and two Gemini cases.

Medication recommendation from electronic health records must balance predictive accuracy against the risk of adverse drug-drug interactions (DDIs) under polypharmacy. Existing safety-aware recommenders operate at one of two granularities: the drug code, which treats each medication as an indivisible token, or the molecular substructure, which is finer than pharmacological interaction knowledge is actually organized. We argue that the active ingredient is the missing granularity, and introduce GRAIN, a medication recommendation framework built around it. GRAIN encodes longitudinal patient trajectories (diagnoses, procedures, past medications) with a selective state space backbone that handles long, irregular visit sequences in linear time. On top of it we introduce a joint objective unifying three knowledge sources aligned to a common medication vocabulary: a drug-level DDI graph, an ingredient-level DDI graph obtained by normalizing medication codes to active ingredients via RxNorm, and an EHR-derived co-prescription graph. A proportional controller adapts the accuracy-safety trade-off to the observed validation DDI rate rather than fixing it a priori. Under strictly matched settings -- identical preprocessing, cohort, vocabulary, split, and evaluation code -- GRAIN improves over a re-implemented MambaHealth baseline on MIMIC-IV across all standard multi-label metrics (Jaccard 0.4488 to 0.4983, PRAUC 0.6911 to 0.7485, F1 0.5989 to 0.6453) while reducing the drug-level DDI rate from 0.1875 to 0.0948. We further define an ingredient-level DDI rate, a safety measure invisible to drug-code-level evaluation. The results indicate that ingredient-level normalization recovers predictive signal erased by code-level aggregation, and that it is complementary to, rather than in competition with, accurate sequence modeling.

Objective: Concept bottleneck models route prediction through interpretable intermediate variables, and their validity is normally judged by how accurately those variables are predicted. We ask whether that judgement is sufficient, using left ventricular volumes as the concepts underlying ejection fraction estimation from echocardiographic video. Methods: A video transformer encoder was trained on a publicly available echocardiography dataset. End-systolic and end-diastolic volumes formed a concept layer from which ejection fraction was computed analytically, with no residual path to the output. We compared training under an ejection fraction objective alone against training with additional supervision of the volumes in millilitres, and evaluated both on 1276 held-out studies. Results: The concept bottleneck did not increase ejection fraction error relative to direct regression, at 6.89 against 7.13 mean absolute error. Without volume supervision, however, the spread of predicted volumes collapsed to 0.1 millilitres against reference spreads of 35.7 and 45.7 millilitres, while correlation was partly preserved. We show that this follows from an invariance property of the objective: ejection fraction is a ratio and is unchanged when both volumes are rescaled, so the loss determines the concept layer only up to scale. Supervision in absolute units reduced volume error from 89.8 to 25.8 millilitres at a cost of 0.4 in ejection fraction error. Conclusion: Concept accuracy alone can conceal a concept layer that carries no physical scale. Significance: Interpretable intermediate variables in clinical models should be validated against the invariance structure of the training objective, not only against prediction accuracy.

Modern predictive systems are expected to adapt their behavior to the specific situation they are facing. A clinical model should not treat every patient the same; a retrieval-augmented model should change its answer when given different evidence; a mixture-of-experts model should route different inputs to different experts. We call this capability context-adaptive inference: before predicting, the system uses information about the current context to specialize its parameters or computation for that instance. This article provides a unified view of context-adaptive inference across three traditions that are usually treated separately: (i) explicit adaptation in statistics (e.g. varying-coefficient models, local regression, hierarchical sharing), (ii) rapid task-specific adaptation in meta-learning and transfer, and (iii) implicit adaptation in large foundation models via prompting, retrieval, and expert routing. We formalize these approaches under a common objective: to map context $c$ to adapted parameters $θ(c)$, then to predict via $f(x; θ(c))$. Under squared loss, linear prediction heads, and fixed features, we prove that explicit parameter adaptation and implicit routing are mathematically equivalent to kernel ridge regression on joint features of inputs and context. Building on this bridge, we propose practical design principles and evaluation metrics including adaptation-efficiency, routing stability, and context-specific robustness to guide when to specialize, how to constrain that specialization, and how to audit context-adaptive models in deployment. Finally, we identify open problems in identifiability, robustness under distribution shift, and efficient large-scale adaptation, outlining design principles for methods that are scalable, reliable, and transparent in real-world settings.

Automatic depression detection with deep learning has shown promise but often suffers from limited generalization due to domain shift arising from inter-speaker variability. To address this critical issue, we present the first patient-independent multimodal depression detection framework that incorporates domain generalization (DG), jointly leveraging both acoustic and textual modalities. The proposed model integrates bidirectional Long Short-Term Memory (BiLSTM) with intra- and cross-modal attention mechanisms, accompanied by segment-level fusion for decision-making. Generalization is further enhanced by applying a gradient reversal layer inspired by Domain-Adversarial Training of Neural Networks (DANN), which promotes domain-invariant representations by adversarially limiting the model's ability to identify individual speakers, effectively reducing patient-specific bias. Conducting experiments on the Androids-Corpus dataset with a 5-fold cross-validation (CV) protocol, various pairings of audio and text feature extractors were evaluated over different segment durations, determining MelSpec and ItalianBERT as the optimal baseline at a 30-second segment duration. The addition of DG to this baseline yields a 2.5% increase in accuracy and 3.3% in F1-score, achieving 93.2% accuracy, 93.2% precision, 96.2% recall, and 94.2% F1-score, surpassing all existing benchmarks. Extensive ablation studies assess the impact of multimodal fusion, deep architectural choices, and DG, highlighting their combined contribution to robust and generalizable depression detection.

Chronic disease management relies on regular patient-provider interactions to follow-up on disease progression and control. For Type 2 Diabetes (T2D), current guidelines prescribe fixed time intervals between subsequent primary care visits for all patients, overlooking heterogeneity in clinical trajectories and patient characteristics. This study introduces a Contextual Markov Decision Process (CMDP) model to optimize subpopulation-specific follow-up interval decisions using Electronic Health Record (EHR) data from 22,154 T2D patients across 10 primary care clinics. Contexts are identified by: i) dimensionality reduction of variables representing the individual health trajectories utilizing Principal Component Analysis, and ii) assigning patients to contexts via principal components and additional patient-level features using clustering. Two distinct contexts emerged, representing a lower- and a higher-risk subpopulation. CMDP-derived policies recommend: (i) follow-up within 1 month if lab value at current visit is unmeasured; (ii) up to 3 months for elevated lab values or recent hospitalizations; and (iii) 6 to 12 months for sustained glycemic control, with shorter follow-up intervals for patients in high-risk context. The optimal policies achieved lower expected cumulative cost than benchmarks (e.g., in the higher-comorbidity context, the CMDP policy reduced cost by about 34.8%, and in the lower-comorbidity context by about 6.4%, relative to an American Diabetes Association-like fixed interval follow-up policy. These findings demonstrate how context-aware approaches can inform adaptive follow-up strategies, and have the potential to advance chronic care management in primary care by synthesizing machine learning and probabilistic decision models.

Traditional comorbidity scores (e.g., Charlson and Elixhauser) are widely used for risk adjustment and patient stratification, but they have two key limitations: (i) they are largely mortality-centric and do not align well with other clinical outcomes, and (ii) their linear, rule-based structure cannot capture nonlinear, outcome-specific risk relationships. We propose a Machine-Learned Comorbidity Index (MLCI) that maps diagnosis codes to a single scalar by maximizing the normalized Hilbert-Schmidt Independence Criterion (nHSIC) between the learned score and multiple clinical outcomes. MLCI captures nonlinear risk-outcome dependence and is supported by a theory that characterizes when a unified, informative admission-level ordering can be achieved across outcomes. Empirical results on multiple benchmark electronic health record (EHR) datasets show that MLCI outperforms strong baselines across multiple evaluation metrics.

Knowledge graphs (KGs) have emerged as a promising solution for integrating and reasoning over complex biomedical and clinical data in healthcare. By representing structured relationships among entities such as diseases, drugs, symptoms, and patient records, KGs provide a semantic backbone for decision-making, prediction, recommendation, and personalized care. Recent advances have demonstrated their utility across diverse medical applications--including clinical decision support systems, disease and treatment outcome prediction, health recommender systems, precision medicine, and medical question answering--where KGs often enhance interpretability, semantic coherence, and patient-specific reasoning. In parallel, a growing body of work focuses on medical KG generation itself, proposing frameworks that construct graphs from EHRs, clinical narratives, biomedical literature, and web resources using ontologies, semantic web technologies, deep-learning-based information extraction, and hybrid neuro-symbolic pipelines. Despite this progress, significant challenges remain, including limited and fragmented knowledge coverage, difficulties in aligning heterogeneous data sources, the fragility of current reasoning and representation-learning methods on dense multi-relational graphs, and unresolved issues related to privacy, bias, and accountability. This survey reviews and categorizes current research on KGs in medicine along both application-oriented and methodology-oriented dimensions, discusses their benefits and technical foundations, and outlines key limitations and open research directions. By analyzing trends, architectures, and evaluation practices, this work aims to guide future developments in KG-driven medical AI systems and support their safe and effective integration into healthcare environments.

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.

The Charlson Comorbidities Index (CCI) is a weighted additive index widely used to estimate ten-year mortality risk, but its original weights may not reflect contemporary prognoses. This limitation is critical in Prostate Cancer (PCa), where radical treatment is recommended only for patients with a life expectancy of at least ten years. For candidates eligible for Radical Prostatectomy (RP), accurate estimation of ten-year other-cause mortality is essential to balance oncological benefit against competing risks and avoid overtreatment. We propose a data-driven framework to derive a comorbidity index tailored to PCa patients considered for RP. Using a retrospective single-institution cohort, we apply Population-Based Bio-Inspired Algorithms (PBBIAs) to recalibrate comorbidity weights and evolve alternative symbolic formulations optimized for ten-year survival discrimination. We compared six optimization strategies, including symbolic regression approaches based on Genetic Programming (GP), population-based metaheuristics, clinically validated baselines, and survival prediction models. Results show that GA, FST-PSO, and SLIM outperform both the original CCI and the PCCI, particularly when PCa-specific variables are included, improving the Concordance Index by up to 0.1. GPLearn yields compact and interpretable models with competitive performance. Overall, the proposed approach provides an updated and interpretable tool to improve patient selection for RP.

Many clinical risk scores are deployed as additive rules with nonnegative integer points assigned to relevant binary predictive features. These integer weights not only make the score easier to use in practice but also promote sparsity in the resulting prediction model. Such risk scores are often derived by first fitting a regression model and then rounding the estimated coefficients to the nearest integer after appropriate scaling. This approach is computationally fast but does not guarantee optimality of the resulting score. Alternatively, one may search over all possible integer weights to directly optimize a value function by posing the problem as an integer programming task. However, the associated computational burden can be substantial, especially when the value function is nonconcave or even discontinuous. In this paper, we develop new machine learning algorithms that employ a flexible greedy optimization strategy to learn such additive scoring directly under explicit and sensible optimality objectives. We apply the proposed method to a large electronic health record (EHR) cohort in Epic Cosmos to construct an integer-weighted comorbidity score for measuring the risk of post-discharge mortality. We also conduct a simulation study to examine the finite-sample operating characteristics.

Brain MRI foundation models learn rich representations of anatomy, but interpreting what clinical information they encode remains an open problem. Standard sparse autoencoders (SAEs) suffer from severe feature collapse in deep transformer layers, and in Alzheimer's disease (AD) research, aging confounds nearly every clinical variable, making naive annotation unreliable. We propose GeoSAE, a geometry-guided SAE framework that uses the foundation model's learned manifold structure to prevent feature collapse and annotates each surviving feature via age-deconfounded partial correlations. Applied to ~14k T1-weighted MRI scans from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and the Australian Imaging biomarkers and Lifestyle (AIBL) datasets, GeoSAE identifies a compact, fully interpretable feature set that predicts mild cognitive impairment (MCI)-to-AD conversion (AUC 0.746) using only 2% of the embedding dimensions, while comorbidity-annotated features achieve only chance-level performance. The identified features replicate across cohorts without retraining (r=0.97) and localize to neuroanatomically distinct regions consistent with Braak staging. This shows that geometry-guided SAEs can extract interpretable, biomarkers from frozen brain MRI foundation models.

Conditional medical image generation plays an important role in many clinically relevant imaging tasks. However, existing methods still face a fundamental challenge in balancing inference efficiency, patient-specific fidelity, and distribution-level plausibility, particularly in high-dimensional 3D medical imaging. In this work, we propose GDM, a generative drifting framework that reformulates deterministic medical image prediction as a multi-objective learning problem to jointly promote distribution-level plausibility and patient-specific fidelity while retaining one-step inference. GDM extends drifting to 3D medical imaging through an attractive-repulsive drift that minimizes the discrepancy between the generator pushforward and the target distribution. To enable stable drifting-based learning in 3D volumetric data, GDM constructs a multi-level feature bank from a medical foundation encoder to support reliable affinity estimation and drifting field computation across complementary global, local, and spatial representations. In addition, a gradient coordination strategy in the shared output space improves optimization balance under competing distribution-level and fidelity-oriented objectives. We evaluate the proposed framework on two representative tasks, MRI-to-CT synthesis and sparse-view CT reconstruction. Experimental results show that GDM consistently outperforms a wide range of baselines, including GAN-based, flow-matching-based, and SDE-based generative models, as well as supervised regression methods, while improving the balance among anatomical fidelity, quantitative reliability, perceptual realism, and inference efficiency. These findings suggest that GDM provides a practical and effective framework for conditional 3D medical image generation.

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.