Clinical Prediction

The SYNTAX score is an established tool for assessing coronary artery disease and guiding revascularization treatment decisions. However, its manual estimation from coronary angiography videos by clinical experts is time-consuming and subject to inter-reader variability. While machine learning has shown promise in automating this process, prior work has primarily focused on lesion detection, characterization, or binary disease classification, leaving direct SYNTAX score prediction relatively unexplored. We propose SynSeq, a video-based method for direct SYNTAX score prediction. It combines targeted preprocessing with a tailored training strategy using a zero-inflation-aware loss and linear target scaling. Evaluated on the public CardioSyntax dataset, SynSeq significantly outperforms previous state-of-the-art methods, improving $R^2$ by 0.55, reducing prediction bias by 93.1% and achieving more consistent performance across annotations from three independent expert graders. In addition, SynSeq achieves a weighted $F_1$-score of 0.80 for revascularization treatment recommendations, slightly below inter-expert agreement. These results demonstrate the potential of SynSeq to provide consistent, automated SYNTAX score assessment and reliable decision support for coronary revascularization planning.

Clinically useful early detection requires validated pre-recognition lead time. Yet event-based evaluations of longitudinal clinical AI can treat recognition-mediated care-process signals as shortcuts and recognition-dependent endpoints as reference standards, inflating apparent performance and lead time while undermining cross-center transport. Such results may serve prognosis without establishing detection before recognition. We define an interval-censored pre-recognition transition, an independent as-of reference standard, and a prespecified recognition proxy to make the claim testable.

A/B testing requires large sample sizes, long timelines, and significant costs. When auxiliary predictions of experimental outcomes are available from machine learning models, uncertain prediction quality precludes replacing human experiments entirely, yet these predictions may still contain useful signal. We propose a principled framework for learning-augmented hypothesis testing that leverages predictions of unknown quality to reduce sample sizes while maintaining statistical validity. Predictions naturally vary in granularity, from coarse aggregate signals to fine-grained individual-level estimates, and our framework addresses both ends of this spectrum: (1) for population-level directional predictions, where only a binary signal on the treatment effect sign is available, we use an asymmetric test and prove consistency and robustness bounds within the learning-augmented algorithms paradigm; (2) for individual-level predictions, we introduce Generalized PPI++ (GPPI), extending Prediction-Powered Inference to handle nonlinear prediction errors through higher-dimensional transformations. Both methods benefit from accurate predictions while remaining robust to inaccurate or adversarial ones. We validate our framework using persona-based LLM simulations, where AI agents equipped with user personas predict individual behavior, as a natural prediction source spanning both granularity levels. Experiments on four real-world datasets demonstrate that our methods, combined with persona-based predictions, substantially reduce experimental costs while preserving rigorous statistical validity.

Random forests (RFs) predict well but are opaque, whereas single decision trees are interpretable but unstable. Artificial representative trees (ARTs) were developed as interpretable surrogate models for RFs, but their use as standalone prediction models with uncertainty quantification has not been systematically investigated. We combine ARTs with leaf-wise Mondrian conformal predictive systems (CPS), enabling a single tree to provide continuous predictions, prediction intervals, and probabilities of exceeding arbitrary thresholds. We compared ARTs with CPS against decision trees with CPS and separate regression and probability trees across five simulation scenarios, 21 benchmark datasets, and a cross-sectional NHANES example data set. Repeated cross-validation assessed predictive performance, interpretability, and stability. ARTs with CPS yield compact, structurally stable trees with substantially more reproducible split-variable selection than decision trees across benchmark datasets and NHANES. Decision trees showed slightly better predictive performance and narrower prediction intervals, while coverage was broadly comparable. CPS-based trees generally achieved lower and less variable Brier scores than multi-model approaches. Combining ARTs with CPS therefore provides a single, interpretable, and stable model for continuous predictions and calibrated probabilities, balancing predictive performance with reproducibility and transparency in settings where stability and interpretability are essential.

Representation learning from medical code sequences in electronic health records and medical claims data has been successful in various clinical applications, such as those regarding disease prediction. However, significant challenges remain in extending this approach to the discovery of scientific hypotheses. One reason is that many existing BERT-based models fail to adequately capture the hierarchical structure of medical codes and the complex interactions between diagnoses and treatments. To address these limitations, we propose a new unified pre-training framework that explicitly integrates hierarchical sub-token aggregation, partial masking, and cross-reference mechanisms. The proposed model consistently outperformed existing methods on both pre-training objectives and downstream clinical event prediction tasks, including the onset of dementia and hospitalization. We also conducted an in silico drug repositioning case study targeting Alzheimer's disease. In the hypothesis generation step, our approach successfully rediscovered known promising drugs in a data-driven manner without relying on such external knowledge sources as the literature. Subsequently, in the hypothesis prioritization step, we introduced a Task-Adaptive Representation Approach to alleviate the over-encoding of historical prescription information within diagnostic vectors, enabling the robust prioritization of generated hypotheses. This study establishes an exploratory screening workflow for hypothesis generation and prioritization based on observational associations. Importantly, this framework is not intended to provide causal evidence, but rather to identify promising candidates for subsequent rigorous causal inference. Overall, this study demonstrates that domain-informed representation learning combined with task-adaptive representation control can enable a practical hypothesis discovery workflow.

Small clinical tabular datasets require interpretable machine learning because deep learning is often impractical and ensemble models can be difficult to inspect. A key pitfall is that statistical significance does not necessarily imply predictive utility. Using data from the Panama Aging Research Initiative--Health Disparities (PARI-HD) cohort (n=165), we implemented a leakage-safe threshold-likelihood Bernoulli/Categorical Naive Bayes (BNB/CNB) classifier. Within every training fold, each continuous predictor was reduced to a supervised chi-square-derived state, while income entered the model through a categorical likelihood. All data-dependent steps were performed within repeated stratified 10-fold cross-validation with 30 repeats. The demographic baseline achieved a ROC-AUC of 0.630 +/- 0.017. I-309 (CCL1) was the dominant incremental feature, increasing AUC by 0.110, with paired DeLong tests yielding p<0.05 in 100% of repeats. In the pre-specified primary analysis, I-309 produced a fixed-partition DeLong p=0.0018, with robustness assessed across 200 random partitions, where the median p-value was 0.0011. Within the exploratory family of 18 candidate markers, I-309 achieved a Benjamini-Hochberg-adjusted q=0.032 on the frozen partition and satisfied q<0.05 in 85% of random partitions, whereas no other marker demonstrated reliable incremental predictive value. Because the fitted model is an inspectable table of thresholds and class-conditional probabilities, these results identify I-309/CCL1 as an interpretable candidate feature for tabular prediction of cognitive impairment, pending external validation.

In various fields, such as medicine and marketing, accurately predicting individual treatment effects holds significant promise. However, achieving reliable predictions alone is often insufficient for making informed decisions; it is equally important to understand why the treatment effect is higher for some individuals than for others. To address this two-fold challenge of prediction and interpretation, we introduce an algorithm based on decision trees and random forests for estimating individual treatment effects. Our algorithm is simple: it operates exactly like a standard random forest, but with a different splitting criterion, and requires no additional workarounds such as double machine learning or orthogonalization as used in Generalized random forests. It handles observational studies with varying treatment propensities without requiring separate estimation of the full propensity function. This is achieved by combining two splitting criteria---one targeting heterogeneity in the treatment effect, the other targeting bias correction for the average treatment effect---which together improve split point selection and automatically distinguish confounders from features responsible for heterogeneity. As a result, interpretation follows directly from the fitted tree structure itself, that is, from which features the trees split on and with which split statistics, without requiring separate post-hoc analysis. For the theoretical analysis of this algorithm, we consider a change point model with step functions for potential outcomes and treatment propensity and provide insights into the theoretical underpinnings of our approach. Simulation studies show that our simple algorithm achieves comparable, and often better, prediction accuracy than existing methods, while substantially improving interpretability.

Classification and regression trees are typically constructed using a greedy splitting rule that maximizes the immediate reduction in prediction error at each node. Although this strategy is computationally efficient, it can miss splits that yield small short-term gains but create substantial downstream improvements after further partitioning. We propose a look-ahead tree-building method that evaluates each candidate split by the prediction error reduction achieved after growing a conventional CART subtree below that split. Because the full look-ahead procedure can be computationally expensive, we also describe a smart look-ahead algorithm that learns downstream split values using node-level features. The proposed framework preserves the interpretability of recursive partitioning while improving split selection in hierarchical or interaction-driven settings. We conduct a simulation study comparing conventional, full look-ahead, and smart look-ahead methods under several settings and apply the proposed methods to analyze two real data examples demonstrating the merit of the new methods.

Vision-language models are increasingly explored for clinical prediction from electronic health records and medical images, where identifying unreliable predictions is important for safe deployment. Uncertainty estimation (UE) enables detecting such predictions, but its evaluation depends on a correctness criterion that determines whether each model output is correct. If this criterion disagrees with human judgement or distorts downstream UE performance, conclusions about model reliability can be misleading. We introduce a two-axis framework that evaluates correctness criteria by their agreement with human judgements and fidelity to human-referenced UE performance. We assess eight criteria across three clinical prediction tasks and three models using 450 predictions annotated by two reviewers. Across the audited tasks, canonical exact matching (EM) achieved the highest observed human agreement and lowest UE distortion, while the BERT-based matching (BEM) and LLM-judge also showed strong human agreement. Across four UE methods and 23,254 clinical predictions, criterion choice changed error-detection AUROC by up to 0.146 and reversed the relative ranking of UE methods. The LLM-judge also selectively accepted invalid or uncertain outputs, accepting 16 of 30 such human-identified errors. These results demonstrate that correctness assessment is an integral component of clinical UE evaluation and should be validated before UE methods are compared.

Objective Prediction models are commonly trained using objectives such as Bernoulli negative log-likelihood (NLL), although downstream clinical decisions may depend on specific risk thresholds. We introduce Smooth Net Benefit ($\sigma$NB), a differentiable approximation of Net Benefit designed to align model training with threshold-specific clinical utility. Materials and Methods We evaluated $\sigma$NB as a training objective for logistic regression, generalized additive models (GAMs), and XGBoost with three Hessian implementations. Experiments used the Framingham cardiovascular risk dataset and 44 TabZilla datasets comprising 72 dataset-threshold combinations. Results $\sigma$NB training did not consistently improve Net Benefit in Framingham. Across the TabZilla benchmark, mean standardized Net Benefit for logistic regression increased from 0.5669 with NLL to 0.5765 with $\sigma$NB (mean difference 0.0096, 95% CI -0.0001 to 0.0193). For GAMs, mean standardized Net Benefit decreased from 0.5921 to 0.5625 (mean difference -0.0296, 95% CI -0.0721 to 0.0129). For XGBoost, NLL achieved 0.6745 compared with 0.6723--0.6735 across $\sigma$NB implementations. In logistic regression, $\sigma$NB gains were positively associated with the performance advantage of XGBoost over NLL-trained logistic regression. Discussion The effect of $\sigma$NB was context dependent, with modest gains concentrated in logistic regression and little benefit for more flexible model classes. This suggests that decision-focused optimization may be most useful when limited model flexibility leaves greater scope for improvement. Conclusion Our results do not support $\sigma$NB as a general replacement for NLL training, but support further investigation of decision-focused objectives in settings where conventional likelihood-based training may not adequately capture decision-relevant structure.

Mobile sensing enables longitudinal monitoring of behavioral and physiological patterns in everyday settings. However, accurate prediction remains challenging in small-cohort health-sensing studies, where task-specific outcome supervision is limited relative to heterogeneous sensing data. Interpretability is also important, as model outputs should reflect meaningful behavioral and physiological patterns rather than predictive scores alone. We develop a Concept-Integrated Transformer (CIT) with LLM-guided concept supervision for explainable prediction from mobile sensing data. CIT uses a pretrained large language model to generate baseline-aware concept abnormality targets with confidence weights without manual concept annotation. Across two longitudinal datasets, CIT achieves the highest F1 score on AFFECT (0.756) and ties for the highest on a PHQ-9 dataset (0.765). The learned concept scores also reveal interpretable behavioral and physiological patterns; in AFFECT, sleep quantity and quality show the clearest difference between high and low negative affect groups. These findings support LLM-guided concept integration for accurate and interpretable prediction in small-cohort mobile sensing studies.

Pretrained diabetic retinopathy (DR) prediction models differ in their input fields, serialization formats, preprocessing requirements, and output semantics. Making these models accessible through a common clinical interface therefore requires explicit coordination between the user interface and the inference service. We designed and implemented DR-LabStack, a React-Flask web system integrating four externally developed pretrained models: RuleFit, Pruned RuleFit, Elaborative XGBoost, and Two-level Ensemble. A shared form retrieves ordered model features, renders model-specific numerical and categorical controls, and constructs a positional input vector. Backend adapters load heterogeneous artifacts and apply the ensemble's accompanying scaler, while a common JSON response supports binary classification display alongside method and source information. Functional evaluation on September 8, 2026 used copied application files and real model artifacts in a documented isolated environment. All four models loaded and exposed their 14-, 6-, 8-, and 25-field contracts. Sixty-two Flask test-client requests characterized service behavior; 12 limited-vector checks confirmed invocation-path and threshold consistency. Twenty-four browser-component scenarios with mocked transport verified input ordering and result rendering and characterized input-validation behavior. The resulting system demonstrates a reusable interaction and serving workflow for heterogeneous DR models. The contribution is web-system design, integration, and software functionality; clinical effectiveness and clinician usability require separate evaluation.

Longitudinal single cell atlases now capture matched pre treatment and post treatment states from responders and non responders, presenting an opportunity to mechanistically explain why two patients on the same drug diverge. We introduce scDEFT (single cell Drug EFfect Transducer), which treats a drug as a conditioning operator on cell representations, enabling prediction and explanation. In scDEFT, feature wise linear modulation produces drug conditioned cell latents, learned under abundant per cell supervision and then frozen. Two independent heads aggregate those latents over shared transcriptional neighborhoods to predict drug induced state change and responder status. A backward stage ranks the latent dimensions by how strongly they separate responders from non responders and maps them to genes under a cell composition control. On a harmonized inflammatory bowel disease atlas of 1.16 million cells, three cohorts and two drug classes, scDEFT predicts state change at 45% of the baseline to reproducibility ceiling headroom and stratifies responders before treatment at AUROC 0.70, where standard predictors remain at chance. These predictions and the drivers behind them support target and co target nomination, patient stratification, and counterfactual prediction of unseen drug cohort effects.

Medical claims data comprise the financial details, including the expenses and billing information, as well as the clinical information, such as the diagnoses and treatments, of patients visiting medical facilities. Recently, it has been acknowledged that large databases can be constructed from medical claims data for medical research purposes. However, the clinical information within these datasets is often medically unstructured, limiting its application in comprehensive analyses. This study enhances predictive model performance for major adverse cardiovascular events (MACE), a leading cause of death worldwide. Models that predict MACE are crucial to clinical practice guidelines. We utilize a cross-attention mechanism to develop a method that effectively weights the relationships between diagnoses and treatments. Effectively repre- senting the clinical information contained in medical claims data, this approach generates more representative features for predicting MACE. The ROC-AUC score of our proposed cross-attention-based model was 0.7720, higher than other benchmark models including the conventional atherosclerotic cardiovascular disease model, the light gradient boosting machine, and a self-attention-based model. These results indicate that integrating the clinical structure of medical claims data using a cross-attention mechanism significantly enhances the performance of predictive models.

Brain-age prediction models are commonly evaluated by predictive accuracy, yet accurate predictions alone do not establish that a model relies on reproducible or neurobiologically supported mechanisms. Post-hoc explanation methods can expose these mechanisms, but existing workflows typically stop at diagnosis or require correction targets to be specified before model analysis. We propose XAI-Refine, an automated explanation-knowledge loop for brain-age prediction from resting-state functional connectivity. At each iteration, XAI-Refine consolidates complementary post-hoc analyses across repeated training runs into reliable, structured model explanations. It converts each reliable explanation into a neutral neurobiological question, retrieves and verifies relevant literature, and compiles the verified evidence into an admissible set in the same typed explanation space. The target for refinement is defined as the minimal projection of the current model explanation onto the admissible set induced by applicable verified knowledge. This revised explanation is then translated into a differentiable constraint while preserving the originating model variable, measurement operator, and applicable scope. Candidate updates are promoted only when multi-seed validation confirms target-directed explanatory movement, predictive performance remains within a prespecified guardrail, and non-target explanatory drift remains bounded. Experiments on functional-connectivity-based brain-age prediction evaluate predictive performance, explanation reliability, literature alignment, and target-specific model revision, illustrating a structured route from post-hoc analysis to evidence-guided model refinement.

We convert black-box clinical prediction models for tabular data into standalone nomograms that can be audited term by term. PRiSM (Partial Responses in Structured Models) takes the shape of each effect and interaction from the source model, not merely which variables mattered, and lets the outcome select and weight them. We tested this in 50,356 heart transplant recipients, with validation in a later era than training. Nomograms from all 5 source models - a public clinical risk score, logistic regression, neural networks, random forests and extreme gradient boosting - met a prespecified noninferiority criterion for discrimination before any further simplification, and generally preserved calibration and clinical net benefit. Those from the 3 machine-learning models showed no detectable difference in discrimination from de novo generalized additive and explainable boosting models, exceeded neural additive models, and carried fewer terms than the explainable boosting model. PRiSM is released as an open-source Python package.

Synthetic medical time-series generation can alleviate data scarcity and support the development of reliable clinical prediction models. However, existing methods mainly focus on matching the overall distribution and temporal dynamics of real data, which does not necessarily ensure strong downstream utility on imbalanced medical datasets. Clinically informative patterns often occur at heterogeneous temporal scales, while rare minority-class characteristics can be obscured by dominant population patterns. To address these challenges, we propose MedFlow, a class-aware multi-scale flow matching framework for medical time-series synthesis. MedFlow employs a vector-quantized multi-scale tokenizer to represent medical sequences at complementary temporal resolutions, capturing both coarse clinical trends and fine-grained dynamics. We further introduce Token Marginal Guidance, which incorporates class-conditional token statistics directly into the flow matching process to steer generation toward class-specific regions of the learned tokens. This mechanism strengthens minority-class patterns, while preserving the global and tail distributions of real data. Experiments on four public datasets covering electronic health records, EEG, and ECG signals demonstrate that MedFlow consistently outperforms recent state-of-the-art diffusion-based baselines across downstream prediction tasks. On average, it improves AUPRC by 5.8%, reduces Context-FID by 88.6%, and achieves 3.8$\times$ higher sampling throughput.

Clinical prediction can saturate for two different reasons: a fitted learner may fail to extract available information, or the recorded variables may impose a population frontier. We separate these quantities through the \emph{learner gap} and the \emph{measurement-channel ceiling}. Optimal balanced accuracy is characterized by total-variation separation, yielding architecture invariance, a sharp partial-identification result under replacement contamination, a cross-fitted ceiling estimator, and exact conditions for multimodal decision improvement. We add two finite-sample diagnostics, namely a label-permutation optimism floor and an underfit curve, and validate the audit on three real cohorts: UCI readmission ($n=99{,}343$), BRFSS diabetes ($n=253{,}680$), and NHANES HbA1c ($n=10{,}219$). Well-tuned gradient boosting nearly reaches the estimated frontier in UCI and BRFSS, whereas deliberately or practically deficient learners retain large gaps. NHANES yields a null difference between questionnaire and measured marginal frontiers but a significant joint complementarity gain, refining the simplistic claim that an objective modality must dominate. Across all cohorts, modest AUROC gains coexist with substantially larger Bayes decision-flip rates, and several architectures estimate similar frontiers while their achieved balanced accuracy differs sharply. A PRISMA-guided synthesis of 104 clinical tasks then shows that the same channel-level regularities recur across more than 18 disease categories: a broad but non-universal structured-clinical region, diminishing same-channel gains across model families, and higher performance when measurement channels change. The framework converts saturation from an empirical observation into an auditable decision: improve the learner when headroom remains; improve measurement when it does not.

Following arXiv:2607.25507, this report examines whether phase-derived features improve endpoint prediction over a combined baseline in two settings: a sealed contradiction comparison and a retrospective analysis of answer changes across matched pressure prompts. Study 1 froze a contradiction-category pipeline before sealed scoring. On 1,136 eligible primary cases, adding PC-2 produced a paired AUROC difference of +0.00087. The 99% bias-corrected accelerated interval included zero, and the prespecified +0.05 threshold was not met. A replication role with 1,063 cases showed a same-direction increment of +0.00019. The replication-direction condition passed, but both primary conditions failed, so advancement failed. Study 2 developed fifteen treatments on blocks b0-b4 using 1,415 eligible answer-change comparisons and twenty-repeat, five-fold grouped cross-validation. An execution on 9 September 2026 recomputed development statistics from saved prediction units and applied a three-condition gate; no treatment advanced. Layer 25 had the only positive mean-repeat PC-2 increment, approximately +0.00027, with a favorable sign in three of five seed blocks. These statistics measure development consistency, not whole-seed-block holdout performance. Agreement with earlier selection records does not establish an earlier notebook execution or that the rule was fixed before inspecting development results. The planned b5 selection and b6 evaluation were not completed through this gate. Neither study demonstrated the incremental benefit required by its applied advancement rule. The findings limit support for the evaluated feature constructions; they do not test the rotary score identity, its local pre-softmax bound, or the effectiveness of execution-boundary governance.

Background: Population level assessments of predictive artificial intelligence (AI) can conceal performance disparities across subgroups. Fairness evaluations commonly rely on performance analyses across subgroups. However, some performance metrics are non-collapsible, meaning that the overall population performance value does not equal the weighted average of subgroup specific values. Objective: To examine the collapsibility properties of commonly reported performance metrics in predictive AI, with a focus on the area under the receiver operating characteristic curve (AUC, also known as c-statistic). Methods: We investigate the collapsibility of 15 performance metrics, either by expressing each metric as a linear combination of its stratum specific values or, where non-collapsible, by providing a counterexample inspired by Simpson's paradox as a formal disproof. Results: Five performance metrics (AUC, calibration intercept, calibration slope, expected calibration error, and Nagelkerke R^2) are shown to be non-collapsible, and ten (O:E ratio, logloss, Brier score, accuracy, F1-score, true positive rate, true negative rate, positive predictive value, negative predictive value, and net benefit) are shown to be collapsible. The AUC is shown to be non-collapsible because it decomposes into within- and cross-group AUC terms when subpopulations coexist, such that its overall value may fall outside the range of subgroup specific AUCs. Conclusions: Non-collapsibility of performance metrics has important consequences for reporting, model appraisal, and fairness evaluation. It can generate spurious differences between subgroup and overall performance, which may mislead fairness evaluations. Explicitly acknowledging and reporting the collapsibility properties of performance metrics improves both the interpretability and transparency of fairness assessments.

Molecular toxicity prediction is increasingly used to prioritise compounds before experimental testing, but conventional benchmark performance can overstate practical utility when structurally related molecules occur across training and test folds. We introduce ToxLens, a reproducible multi-task graph-learning framework for 11 toxicity endpoints spanning Ames mutagenicity, acute oral toxicity, hERG inhibition, and Tox21 nuclear-receptor and stress-response assays. The workflow combines conservative chemical curation, sphere-exclusion filtering, a leakage-aware UMAP-HDBSCAN split, parallel graph and global-feature encoders joined by late concatenation, temperature-scaled Monte Carlo dropout with conformal-style prediction sets, applicability-domain analysis, and SHAP-guided toxicophore discovery with occlusion controls. On the leakage-controlled test fold, a five-seed soft-voting ensemble achieved a Matthews correlation coefficient score of 0.44, an area under the receiver operating characteristic curve score of 0.83, and an area under the precision-recall curve score of 0.58. It exceeded four ECFP4-based shallow baselines on all 11 endpoints under the same split and validation-based threshold-selection protocol. Controlled ablations showed that the global pathway was important, whereas late concatenation outperformed the tested gated and feature-wise linear modulation fusion variants. Conformal-style prediction sets revealed substantial endpoint-specific variation in set efficiency, and discrimination and calibration improved with similarity to the training domain. Retraining on fixed published Tox21 Challenge and TDA folds produced competitive, but not uniformly state-of-the-art, performance. SHAP-guided occlusion and consensus subgraph mining yielded model-derived structural hypotheses, 44 of which contained at least one occurrence that passed the predefined counterfactual criteria.

Electronic Health Record (EHR) prediction models in the intensive care unit must learn from sparse and irregular measurements while preserving the clinical meaning of time and supporting transparent decision-making. We present INTERVenE, a family of Transformer architectures whose input is an interval-based, knowledge-based temporal abstraction (KBTA), a token stream of named clinical concepts (states, trends, events, contexts) drawn from a curated medical ontology, rather than an unnamed bin index or a raw measurement triplet. This naming layer is what we ask KBTA to do: it makes the model's per-token attributions resolve to clinical concepts by construction. INTERVenE offers two complementary variants: an auto-regressive decoder that generates future abstraction trajectories with a per-step risk readout (localizing \emph{when} and \emph{after which events} risk rises), and a bidirectional encoder for single-pass joint risk and time-to-event prediction. Evaluated on 57,078 MIMIC-IV admissions against GRU-D, STraTS, and KarmaLego, INTERVenE-Enc reaches a support-weighted AUPRC$_w$ of 0.672, improving by 0.041 over the strongest neural baseline with non-overlapping 95% bootstrap CIs, while also taking the best AUROC$_w$ (0.901) and length-of-stay MAE (44.4,h). INTERVenE-Ar (AUROC$_w$ $0.854$, AUPRC$_w$ $0.587$ under the same evaluation contract - a strictly harder generative readout) provides a complementary token-level risk trajectory. An input-representation ablation confirms the lift transfers across structured discretizations, positioning KBTA-based intervals as the interpretable substrate that makes per-token attributions resolve to meaningful clinical concepts within the deployed model.

Clinical prediction models are often developed as if the outcome of interest were cleanly observed for every patient. This assumption fails when treatment decisions make the clinically relevant outcome permanently unobservable. As a case study of this problem, we consider post-cardiac-arrest neurological prognostication using a cohort of 2,497 patients, including 1,429 patients whose outcomes were rendered indeterminate by treatment decisions. These patients with indeterminate outcomes were reviewed by independent clinical experts, who provided their guesses of counterfactual outcomes about what would have happened to the patients. We refer to these patients as uncertain cases. We also have patients for whom we observe their clinically relevant outcomes; we refer to these patients as certain cases. We propose a framework for evaluating prediction models that explicitly splits the evaluation between certain and uncertain cases. Here, we cannot easily evaluate both types of cases in a uniform manner as the available target labels differ. We then propose a simple prediction model that uses target labels from both certain and uncertain cases in a manner that allows us to trade off between them. Across the proposed neural model and a collection of tabular baselines, models with similar certain-case AUROC can nevertheless differ substantially in both certain-case Brier score and their probability estimates for uncertain cases. Improving alignment with target labels of uncertain cases for our proposed model generally comes at the cost of worse accuracy on certain cases, highlighting an explicit tradeoff that standard evaluation conceals. These results show that when treatment decisions determine whether clinically meaningful outcomes remain observable, conventional evaluation metrics can miss important failure modes in the very patients for whom prognostic support matters most.

Treating patients with combinations of drugs reduces the risk of resistance to any individual drug. Finding effective combinations is difficult because the large search space makes combinatorial screens prohibitively expensive, time consuming, and often technically infeasible. Predictive models can fill this gap, yet existing methods typically require molecular profiling of each sample and per-cohort training, limiting their applicability when time and tissue are scarce. To address this challenge, we introduce ScreenShot, a hierarchical transformer pretrained on 40 drug screening datasets covering 3,700 drugs and 6,000 biological samples, whose architecture mirrors the nested structure of screening data. Given a few-shot context of observations from a new patient, ScreenShot predicts the response of the sample to combination therapies through in-context learning, operating directly on functional measurements with no fine-tuning and no molecular profiling. On four held-out datasets, ScreenShot outperforms all baselines in both prediction accuracy and identification of selectively effective treatments. ScreenShot's internal representations are directly useful for experimental design: we use them to drive a weighted k-means++ active learning strategy that selects which experiments to run, achieving the same hit detection as uniform screening with a third of the budget. Source code and interactive dashboard: https://github.com/tansey-lab/screenshot.

Estimating counterfactual outcomes over time from longitudinal observational data is central to clinical decision support. Existing methods rely on domain confusion -- adversarial training that renders representations invariant to treatment assignment -- yet this invariance creates a mutual information conflict: it suppresses treatment-correlated covariate signals necessary for accurate outcome prediction. We formalise this tension via a Jensen-Shannon divergence bound on counterfactual prediction error and develop two complementary models. CSSD (Causal State-Space model with Direct decoder) adapts selective State Space Models with a parallel multi-step decoder that eliminates accumulated rollout error by producing all prediction horizons simultaneously in a single forward pass. CSSPD (Causal State-Space model with Predictive regularisation and Direct decoder) augments CSSD with Contrastive Predictive Coding and Local Information Maximisation to reinforce temporal predictability in the balancing representation and recover local covariate information destroyed by domain confusion. On MIMIC-III, CSSPD achieves lower counterfactual RMSE than the Causal Transformer at every horizon tau >= 2 at O(T) encoder cost, with gains from 0.02 (2-step) to 0.07 (6-step). On Cancer Simulation across confounding strengths gamma in {0,1,2,3,4}, CSSPD outperforms CT at gamma <= 3 (margins 25.9%--37.0%), and CSSD achieves the lowest overall average RMSE (12.7% reduction over CT), confirming the MI conflict analysis. To our knowledge, this is the first work to formalise the balancing-prediction MI conflict and propose a structured resolution through complementary predictive and information-theoretic training objectives.

Interval prediction aims to achieve a target coverage level while producing intervals that are as short as possible. Many conformal regression pipelines first predict an uncertainty surrogate and then convert it into an interval through calibration or selection. This separation supports coverage calibration, but post hoc rules largely determine the final interval and do not fully use the learned output distribution. We observe that the resulting intervals have inherently hierarchical geometry: an interval can be recursively refined into nested subintervals, and binary trees naturally represent this structure. We formulate this hierarchy as next-interval prediction and propose PATH, which learns how probability mass flows from each interval to its next nested subintervals. PATH predicts a base leaf distribution and uses an autoregressive decoder to refine branch probabilities. Matching the distribution to the interval hierarchy aligns learning with extraction: PATH accumulates probability over adjacent output intervals and returns the shortest contiguous range reaching a selected mass. We compare PATH with 24 baselines for interval prediction on PATHBench, comprising 56 OpenML regression datasets. PATH substantially shortens the resulting intervals, achieving the lowest mean normalized length, 0.1473, while maintaining mean coverage of 0.9144. These results establish hierarchical output modeling as an effective approach for compact interval prediction on tabular data. Code is publicly available at https://github.com/pxcai/PATH.

Metabolomics knowledge is distributed across heterogeneous resources and remains difficult to translate into predictive representations. We developed MetaboLLM, a metabolomics-specialized large language model adapted through continual pretraining, supervised fine-tuning, and structured retrieval, together with MetaboLLM-GIN, which converts generated biochemical descriptions into metabolite graphs for patient-level prediction using a graph isomorphism network. Across four backbone families, MetaboLLM outperformed corresponding base and medically adapted models on metabolomics knowledge, relational, and description tasks, and transferred to an external public benchmark. MetaboLLM-GIN achieved the highest AUC for stress hyperglycemia prediction after coronary artery bypass grafting (0.8616) and postmenopausal hormone-regimen classification (0.8123), outperforming conventional models, alternative graph constructions, and graphs generated from unadapted or non-retrieval LLM configurations. Model interpretation further produced biologically meaningful findings in both applications. These results show that domain-specialized language models can organize heterogeneous biochemical knowledge into predictive and interpretable metabolite graph representations.

Inadequate target--disease linkage accounts for 40--50% of PhaseII efficacy failures, so anticipating which programmes will advance would let sponsors back the hypotheses most likely to reach patients. What a programme can be judged on is the evidence that supported its linkage \emph{when it entered the clinic}. No existing biomedical knowledge graph allows that evidence profile to be assembled as of a past date. We present the Temporal Heterogeneous Biomedical Knowledge Graph (THBKG), which describes and predicts therapeutic target--disease links through time: 110,396 entities and 11.1M edges across nineteen relation types, each edge carrying the year its evidence changed, so a pair's profile can be recovered as it stood when its own decision fell due. On this graph we define a decision-aligned benchmark that predicts, for a target--disease pair entering PhaseII, whether it advances to Phase~III on evidence datable before that decision. Graph propagation over the THBKG outranks every direct-evidence reference scored under the same decision-aligned protocol, reaching a relative success of 4.3--4.5 at the top ten pairs per therapeutic area. The gain concentrates on the 72.8% of pairs with no direct target--disease evidence at their decision point, where a direct-edge model has nothing to read: the encoders still rank five- to sixfold above chance, recovering the signal by propagating over the intervening biology. Adapting a path-based explainer to the decision-time subgraph decomposes each prediction into the evidence landscape behind the hypothesis for explainable prediction. We release the THBKG as a continually updated substrate for studying therapeutic target hypotheses by retrospective validation.

CASCADE is an agentic framework that predicts downstream transcriptional effects of gene perturbation from precomputed ARACNe regulatory networks, exposed via MCP. Prior work validates such tools by checking whether predicted genes are known cancer genes (membership); we instead test whether the predicted direction of change matches reality, using focal-gene copy-number amplification as a dosage-based proxy for the inverse of knockdown against real TCGA patient tumor data. For MYC, CASCADE's predicted knockdown targets show strong concordance with real amplified-vs-non-amplified tumor expression across three cancer types (BRCA: 90.0%, COAD: 72.0%, STAD: 85.7%; all p<0.0013), well above permutation baselines, surviving a PAM50 subtype control and replicating in an independent cohort (METABRIC, 87.2%). Compared against curated MSigDB gene-set baselines via Fisher's exact test, CASCADE's accuracy is not shown to exceed existing public knowledge of MYC- or E2F-driven biology, though its gene-specific direction-calling clearly outperforms a naive uniform guess. Extending to fifteen additional genes, validation proves gene-specific rather than universal: proliferation-machinery regulators mostly replicate, while lineage-identity transcription factors and one cyclin-D paralog (CCND2) consistently fail, a pattern we discuss as a hedged, post-hoc hypothesis. We separately benchmark whether an LLM-based agent correctly grounds natural-language requests into CASCADE's real MCP tool calls. Across 35 queries, a documented local model reaches 71.4% exact match (85.7% for a larger model); schema and gene-alias failures are resolved by scale or server-side correction, but both models confidently default to the wrong perturbation type on ambiguous queries, a failure a targeted fix could not resolve because its trigger condition never occurs.

Language models (LMs) offer strong textual representations for electronic health records (EHRs), but they encode patient sequences in isolation and provide limited explainability. Graph neural networks (GNNs) complement LMs by incorporating inter-patient relationships and enabling reference-patient attribution, yet they rely on high-quality patient representations. We propose Patients-like-me (PLM), a unified LM--GNN framework that integrates local patient semantics with global cohort structure. To train PLM efficiently, we introduce a Variational Expectation-Maximization algorithm that alternates LM and GNN updates under a supervised variational objective. Extensive experiments on MIMIC-III and MIMIC-IV show that PLM consistently outperforms state-of-the-art methods, with improvements generalizing across encoder-only and decoder-only LM backbones. These gains are achieved with only modest additional computational overhead. PLM also provides reference-patient explanations by retrieving influential similar patients, while edge-masking experiments confirm that the highest-ranked references have the greatest impact on model predictions.

Feature selection is a critical step in electronic health record (EHR)-based predictive modeling, where input variables are often high-dimensional, sparse, noisy, and redundant. Large feature sets not only increase computational burden and overfitting risk, but also make model interpretation difficult, leading to limited usefulness in clinical settings. In this study, we focus on diagnosis-related features and compare five feature selection paradigms for opioid use disorder (OUD) prediction: recurrence enrichment, NTK-motivated early gradient sensitivity, LightGBM-SHAP, Elastic Net, and large language model (LLM)-guided semantic selection. We use a unified preprocessing and evaluation framework and assess each method by downstream predictive performance, resampling stability, and representation of infrequent diagnosis codes. Our results demonstrate that performance improves with larger feature budgets with diminishing returns beyond a moderate size. NTK sensitivity provides the best overall balance of accuracy and stability, and LLM-guided selection contributes complementary clinically meaningful signals despite lower standalone performance.

Child malnutrition remains a major public health challenge in low- and middle-income countries, particularly in South Asia, where early identification of vulnerable children is critical for timely intervention and resource allocation. This study aims to evaluate the feasibility, fairness, and temporal robustness of using a pretrained large language model (LLM) in a zero-shot setting for child stunting prediction using population health survey data. Using Bangladesh Demographic and Health Survey (BDHS) data collected between 2007 and 2022, we transformed maternal, child, healthcare, and household characteristics into semantically interpretable prompt-based representations and evaluated GPT-4o-mini for zero-shot stunting prediction, comparing its performance against a random forest baseline and assessing fairness across demographic and socioeconomic groups as well as temporal robustness across survey waves. The results demonstrate that zero-shot inference using GPT-4o-mini achieved comparable balanced accuracy to the supervised baseline while exhibiting substantially higher sensitivity for identifying stunting cases, relatively consistent performance across child sex groups, and stable predictive behaviour across BDHS waves; however, important fairness disparities were observed across residence and household wealth categories, highlighting the need for further investigation before deployment of foundation models in public health prediction settings.

In many domains such as Palliative Care, Credit Assignment and Recommender Systems, predictions may causally influence the outcomes they predict. This phenomena is known as Outcome Performativity. This paper formalises an approach for detecting Outcome Performativity using prediction intervention called Outcome Performativity A/B Detection (OPAB). OPAB enables the detection of Outcome Performativity by assessing the dissimilarity in outcome distributions produced by different predictions groups (interventions). If that dissimilarity is significant, Outcome Performativity is detected. We derive sample complexity bounds for OPAB under various Outcome Performative assumption classes which we empirically validate. Results show that detecting Outcome Performativity using OPAB is achievable in numerous cases. Results also show the presence of regions of indistinguishability which describe settings where the allotted number of interventions are insufficient for detecting Outcome Performativity. The results of which have broader practical implications for the detectability of Outcome Performativity in settings where samples are scarce, cost-prohibitive or potentially unethical to obtain. The paper concludes with a case study on the efficacy of OPAB on the Open Bandits dataset, and provides directions for future work.

Large language models and multimodal foundation models are enabling medical artificial intelligence (AI) systems to move beyond isolated prediction and undertake multistep clinical tasks that require planning, tool use, memory, iterative correction, and coordination among specialized agents. However, the scope of agentic AI in medicine remains unsettled, and current evaluation practices are not yet aligned with the requirements of clinical use. We conducted a scoping review with systematic evidence mapping across five electronic sources, screened 1,649 exportable records, and provisionally included 557 unique studies that met predefined criteria for goal-directed task execution, tool use, interaction with external resources, feedback-based refinement, or multi-agent collaboration. The included studies describe single agents that use external tools, workflows supported by retrieval and external knowledge, multimodal agents, and multi-agent systems applied to medical question answering, image interpretation, electronic health record analysis, drug safety, and clinical trial prediction. The evidence base remains dominated by public benchmarks, simulated settings, retrospective datasets, and small-scale expert evaluation. Process reliability, evidence traceability, uncertainty, safety, workflow impact, and external validity are evaluated less consistently. Clinical translation will depend on clearer definitions, reproducible evaluation, auditable oversight, interoperable system design, and prospective validation in real-world clinical workflows.

Chronic Kidney Disease (CKD), characterized by the gradual loss of kidney function, remains a significant public health challenge. Early detection is crucial for preventing severe complications and enhancing patient outcomes. In this study, Federated Learning (FL) with a VotingClassifier was used to predict CKD using a clinical dataset, where Random Forest, AdaBoost, and XGBoost were utilized to compare and identify the best-fitting model for the global server. Additionally, GridSearchCV was applied to optimize the models' performance on the client's side. To enhance model transparency and trustworthiness, explainable AI (XAI) techniques were incorporated to interpret the prediction mechanisms. The global model's average accuracy was 99%, highlighting the potential of interpretable FL models in supporting early CKD diagnosis and advancing data-driven healthcare solutions.

Electrocardiograms (ECGs) are widely used for cardiovascular risk prediction, yet models often fail to transfer across hospitals because of protocol, population, and measurement differences. We benchmark cross-dataset generalization on three tasks - heart failure classification, 30-day all-cause mortality, and 30-day mortality among sinus-rhythm ECGs - using two large cohorts (MIMIC-IV and the Alberta Cohort). To reduce vendor-specific measurement mismatch, we build a harmonized, interpretable feature representation computed directly from raw waveforms: FeatureDB morphology/heart-rate-variability summaries plus compact time-frequency descriptors (autoregressive and wavelet features). We train XGBoost models on this unified feature space and evaluate with patient-disjoint internal and bidirectional external testing. We pre-specify two hypotheses: (H1) external AUROC retains at least 90% of source-site internal AUROC under transfer, and (H2) internal AUROC of the harmonized feature set stays within 10% of dataset-native machine-measurement models. Across tasks, internal AUROC is 0.79-0.82 and cross-dataset AUROC is 0.74-0.78, with larger and direction-dependent AUPRC shifts under transfer. As an exploratory benchmark, an end-to-end ConvNeXt model trained directly on raw ECG waveforms with age and sex achieves higher internal AUROC, while the harmonized representation remains competitive in relative cross-dataset transfer stability. These findings show that a consistent waveform-derived feature interface preserves performance, supports realistic external validation, and provides a transparent alternative for cross-site clinical prediction.

Dysphagia is a debilitating late effect of head and neck cancer (HNC) treatment, yet timely identification of at-risk patients remains challenging in survivorship care. Definitive assessment relies on videofluoroscopic imaging, as captured by the Dynamic Imaging Grade of Swallowing Toxicity (CTCAE-DIGEST), which, while validated, requires specialized equipment, trained personnel, and significant patient burden, limiting its routine use in surveillance. Patient-reported outcomes (PROs), by contrast, are low-cost, scalable, and easily collected at any clinical encounter, making them an attractive alternative signal for identifying patients who may warrant further evaluation. However, a clear clinical framework for translating PRO responses into actionable interventions is still evolving. In particular, uncertainty remains regarding when a patient's self-reported symptom burden should prompt escalation of care. This study addresses this gap by formulating a single-visit PRO-clinical prediction framework and introducing a clinically interpretable two-stage stacking model to predict swallowing impairment risk using PRO responses and structured clinical variables, without requiring videofluoroscopic imaging. The proposed framework quantifies the independent contributions of patient-reported symptoms and clinical factors within a unified and interpretable risk assessment model. Our findings demonstrate that individual MDADI responses contain predictive information beyond that captured by composite or global summary scores, while interpretability analyses reveal symptom patterns and clinical risk factors associated with swallowing impairment. Together, these results support the use of structured PRO-clinical integration as a practical, imaging-free approach for dysphagia risk stratification in HNC survivorship.

Predictive machine learning (ML) models are increasingly used to aid human decision-makers across various high-risk domains such as healthcare and criminal justice. There is a growing recognition of the need to evaluate the causal impact of deploying these systems on downstream outcomes, such as patient survival or crime recidivism. Randomized control trials (RCTs) can provide high-quality evidence on the impact of a deployed model, but they run into a challenge: it is often infeasible to run repeated trials when models are updated or retrained to improve predictive performance. In this work, we present a partial-identification approach to using prior RCT data to construct bounds on the causal effect of a new model. The core innovation in our approach is to leverage assumptions relating fine-grained predictive accuracy to downstream outcomes. We do so via two monotonicity assumptions: first, on individual-level `counterfactual correctness' (all else being equal, a correct prediction leads to non-inferior outcomes); and second, on the relation between subgroup predictive performance and outcomes, interpretable as an assumption regarding trust in model outputs. We demonstrate our method with a simulation study, illustrating how incorporating this information can lead to more informative bounds compared to prior work.

Federated learning (FL) offers a promising approach to privacy-preserving clinical risk prediction, but its deployment remains limited by restricted data sharing, client heterogeneity, class imbalance, and the lack of realistic tabular electronic health record (EHR) benchmarks. Synthetic data generation may alleviate data scarcity, yet its integration with federated optimisation has received limited systematic study. We propose SynPre-FL, a unified framework combining high-fidelity synthetic EHR generation with synthetic-pretrained FL for robust prediction under non-IID conditions. A latent autoencoder-diffusion model generates privacy-preserving synthetic cohorts, which are used to warm-start federated training. This pretraining is followed by heterogeneity-aware optimisation using class-balanced local objectives, proximal regularisation, and adaptive server aggregation. Post-hoc calibration and federated-safe explainability support reliable and interpretable risk estimates. Experiments show that the synthetic generator preserves univariate, bivariate, and multivariate structure while protecting against membership-inference and reconstruction attacks. The generated data achieve strong downstream utility under TSTR, TRTS, and model-based evaluations. Across federated settings with 5, 10, and 15 heterogeneous clients, SynPre-FL consistently improves robustness and scalability over baseline methods, especially under severe non-IID fragmentation. Calibration improves probability reliability, while SHAP analysis produces stable and clinically coherent feature attributions across federation sizes. SynPre-FL therefore provides a practical and reproducible framework for combining synthetic data with FL to enable privacy-aware, interpretable, and robust clinical prediction from distributed tabular EHR data.

Accurate protein-ligand binding affinity prediction is central to computational drug discovery, yet modern docking engines frequently disagree without indicating which prediction to trust. Consensus scoring and ensemble methods improve mean accuracy but treat all predictions identically without interpretable confidence measures or uncertainty decomposition, ignoring the chemical context of each protein-ligand pair. To address this limitation, we introduce RELIABLE-BA (RELIABiLity-aware Evidential fusion for Binding Affinity), an evidential framework for multi-engine binding affinity prediction. Our model comprises three steps: (1) modeling each engine as an evidential expert via Normal-Inverse-Gamma distributions, (2) scaling epistemic uncertainty through learned reliability from molecular context while preserving each expert's predictive mean, and (3) fusing experts through closed-form aggregation that captures both individual uncertainty and inter-engine disagreement. Experiments on the PDBBind and BDB2020+ benchmarks demonstrate competitive point prediction with substantially improved uncertainty calibration, and additional validation on the SARS-CoV-2 Mpro dataset and 5HT2A receptor demonstrates applicability to clinically relevant drug targets. Crucially, these uncertainty estimates enable reliable filtering of protein-ligand pairs, reducing prediction error by up to 25% when retaining only high-confidence pairs. To our knowledge, RELIABLE-BA is the first multi-engine binding affinity prediction framework to combine evidential fusion with context-dependent reliability, offering a principled path toward trustworthy AI-guided drug discovery. Our code is publicly available at https://github.com/yongchand/RELIABLE-BA.

We introduce Retrieval-Augmented Interpretable Learning (RAIL), a probabilistic meta-learning framework for zero-shot generation of task-specific interpretable models that synthesizes coefficient-space structure from natural-language task descriptions and a memory of previously learned task-specific predictors. RAIL retrieves related source tasks, transfers structure through coefficient space, and generates a new predictor in the original diagnostic-feature space, enabling zero-shot and few-shot clinical procedure prediction with feature-level explanations. Its probabilistic formulation provides uncertainty over retrieval, model coefficients, and predictions, supporting reliability-aware deployment: uncertain predictions or unstable explanations can be flagged for additional clinical review rather than treated as automatic decisions. This makes RAIL particularly suited for healthcare settings, where prediction tasks are highly long-tailed, new clinical targets arise frequently, and models must remain inspectable, uncertainty-aware, and compatible with human oversight. Across long-tailed clinical procedure prediction tasks, RAIL maintains reliable performance across data-availability regimes: it achieves 73.4% accuracy in the held-out zero-shot settings, where no supervised task-specific model can be trained, and remains near 73.2% accuracy in the extreme few-shot regime with only 2-4 examples, where supervised task-specific models perform close to chance. RAIL further benefits from clinically informed task representations and yields retrieval, uncertainty, and coefficient-level diagnostics that make model behavior more transparent. These results suggest a path toward scalable clinical prediction systems that can adapt to new tasks while preserving interpretability and reliability.

Air pollution and climate-related stressors are increasingly important concerns for respiratory health, especially in settings with unequal environmental exposure and healthcare capacity. This study evaluates an interpretable machine learning framework for predicting respiratory disease rates and air-quality status using structured country-level weekly data. Two supervised learning tasks were considered: regression of respiratory disease rate per 100,000 population and binary classification of air-quality status. Nine regression models and nine classification models were compared using nested cross-validation. Model interpretation was conducted using SHAP values, and subgroup analysis was performed across income levels and geographic regions. The results showed that PM2.5 concentration was the dominant predictor of respiratory disease rate, with linear and regularized linear models achieving the strongest regression performance. For air-quality classification, models achieved high balanced accuracy when PM2.5 was included, but performance decreased substantially when PM2.5 was removed, indicating strong dependence on pollutant-related information. SHAP analysis showed that, without PM2.5, socioeconomic and meteorological variables such as GDP per capita, precipitation, and healthcare access became more influential. Subgroup analysis showed similar aggregate regression error across income groups, but PM2.5 contributed more strongly to predictions in lower-middle-income countries. These results show that model accuracy alone is not sufficient for climate-health prediction. Interpretable models can help identify dominant pollution-related signals, test whether results depend on key pollutant variables, and show whether prediction patterns differ across socioeconomic groups.

Cardiometabolic diseases remain among the most persistent drivers of preventable morbidity because diabetes, hypertension, and cardiovascular disease frequently co-occur and share metabolic, vascular, demographic, and behavioral determinants. Existing machine learning studies for chronic disease prediction often emphasize discrimination on a single dataset, while underreporting label leakage, calibration, temporal robustness, external transportability, and subgroup reliability. This paper presents CardioMeta, a calibrated multi-task framework for joint prediction of diabetes, hypertension, and cardiovascular disease across population survey and electronic health record (EHR) data. The study uses NHANES for population-level model development and temporal validation, and MIMIC-IV for EHR-domain evaluation under substantial distribution shift. To reduce circular label reconstruction, the primary analysis excludes disease-defining variables from the corresponding prediction heads, while a full-clinical feature setting is retained only as sensitivity analysis. CardioMeta combines a shared cardiometabolic encoder with disease-specific gated heads and post-hoc probability calibration. In the leakage-reduced temporal validation setting, the model achieved a macro-AUROC of 0.839, macro-AUPRC of 0.536, macro-F1 of 0.614, and expected calibration error of 0.024, with modest but consistent improvements over strong gradient-boosting and neural tabular baselines. External evaluation on MIMIC-IV showed clear degradation under domain shift, while limited fine-tuning partially recovered performance. The findings indicate that the principal value of multi-task cardiometabolic modeling lies not in inflated accuracy, but in reproducible leakage control, calibrated probabilities, and transparent reliability reporting across heterogeneous healthcare data sources.

Pediatric electronic health records capture developmentally structured clinical trajectories, yet their potential for generative healthcare foundation models remains largely unexplored. Here we present TEDDY (Temporal Event Decoder for Disease in Youth), a 1.84-million-parameter decoder transformer trained on approximately 73 million ICD-10 diagnoses from 1.6 million children at a single pediatric institution. TEDDY models longitudinal diagnosis trajectories and visit timing. Predictions were made before visit codes were revealed, limited to first occurrences, and evaluated against sex- and age-matched controls. Across 797 disease-onset prediction tasks spanning 16 ICD-10 chapters, TEDDY achieved a median AUC of 72.0%, outperforming same-data DenseNet (50.0%), CNN (57.2%), RNN (60.1%), and LSTM (62.7%) baselines on 96-99% of tasks. Performance held across sex and age and was strongest among lower-prevalence diagnoses; 202 of the 225 rarest conditions (90%) had 95% confidence intervals above chance. Predictive signal remained detectable more than two years before first recorded diagnosis, with median AUCs of 59.7% in the unrestricted analysis and 64.4% in a fixed-cohort sensitivity analysis. In asthma and attention-deficit/hyperactivity disorder benchmarks, AUCs were 79.3% and 84.7%, compared with 62.7% and 71.7% for the strongest comparators, including a general-purpose language model three orders of magnitude larger. Visit-timing predictions had a 3.0-day mean absolute restricted mean survival-time error over 365 days, although median and long-tail return intervals remained miscalibrated. Together, these results establish pediatric diagnostic histories as a substrate for compact generative models supporting broad, rare-disease, and long-horizon risk forecasting without population-scale data or billion-parameter models.

Early screening of chronic kidney disease (CKD) is essential for preventing irreversible progression; however, many machine learning (ML)-based screening methods remain difficult to deploy in community and resource-limited screening settings due to their reliance on large labeled datasets, resource-intensive pathology tests, or high-dimensional clinical features, and limited robustness to population and distributional shifts. This study examines the feasibility of using large language models (LLMs) for early-stage CKD screening in a zero-shot setting, without dataset-specific training. We propose a feature-guided zero-shot framework that evaluates LLM performance using a selected set of clinically meaningful, readily available community-based features, rather than exhaustive clinical inputs. Feature selection was guided by ML-based analysis to identify a compact, clinically relevant subset of variables. Tabular patient records were subsequently serialized into text using standardized prompt templates to enable zero-shot inference. The zero-shot performance of four LLMs (LLaMA-3, Qwen-3, Mistral, and GPT-4o-mini) was evaluated using both the full feature set and the selected subset. Generalizability was assessed across three heterogeneous CKD datasets spanning three countries. Across models and datasets, the selected feature set yielded consistent and statistically significant improvements in balanced accuracy and probability estimates, achieving performance levels suitable for screening purposes. These findings suggest that LLMs can support clinically meaningful, training-free CKD screening using minimal community-accessible patient features, offering a practical complement to conventional ML methods in real-world screening contexts.

Explainable machine learning (XML) pipelines applied to composite mental health outcomes can produce apparently-robust, cross-population-stable risk hierarchies that are largely artefacts of how the outcome was constructed. We demonstrate this using an ElasticNet pipeline applied to 886 medical students at the University of Lausanne (primary cohort, 2022), validated across 2,580 longitudinal observations at three time points and 701 non-medical students from eight faculties; all three datasets share identical instruments. The pipeline produces a hierarchy in which trait anxiety and health satisfaction dominate wherever the outcome is measured, with Kendall $τ= 1.0$ for the top-two positions across all five evaluation sets and consistent transfer performance ($R^2$: 0.41-0.49). Two residualization experiments, which isolate shared variance between correlated variables via regression, reveal the mechanism: when trait anxiety (STAI-T) is residualized against the co-included depression subscale (CES-D, $r = 0.72$), model $R^2$ drops from 0.41 to 0.16 and STAI-T falls from rank 1 to rank 6; when burnout subscales are residualized against CES-D, $R^2$ collapses to 0.016. Prediction intervals average 35.4 units on a 0-100 scale (2.4 outcome standard deviations), independently ruling out individual-level deployment. The residualization protocol is the paper's transferable contribution: any XAI study combining correlated predictor and outcome constructs should apply this check before interpreting apparent stability as a finding.

Clinical code prediction maps unstructured discharge summaries to ICD-10-CM leaf codes in a large, sparse, and deeply hierarchical label space. Most systems treat the task as flat multi-label classification, scoring codes independently and providing limited training signal for rare labels. We propose a graph-constrained traversal policy that formulates ICD prediction as a finite-horizon decision process over a pruned code hierarchy. A single language model descends the graph level by level, selecting valid child nodes until billable leaf codes are reached. This converts extreme multi-label prediction into sparse, hierarchy-aware subset decisions while guaranteeing structurally valid outputs. On MIMIC-IV discharge summaries, our best supervised policy, SFT-1+, achieves 0.709 micro-F1 on a curated 50-code subset and 0.527 micro-F1 on the full 15,761-code space, outperforming flat baselines including CAML, LAAT, and PLM-ICD. In the full setting, SFT-1+ improves over the strongest flat baseline by 0.044 micro-F1 and 0.157 macro-F1, suggesting that graph-constrained decomposition mitigates the rare-code bottleneck. A controlled factorial study evaluates architecture, training algorithm, and data budget. Across both scales, one shared policy matches a three-specialist cascade while avoiding its context-window overflow on 28-32% of full-space test notes. Increasing supervised trajectory data is the only intervention that consistently improves performance, while GRPO reinforcement learning provides no benefit over supervised continuation with matched data. These results show that simple graph-constrained policy learning can outperform more complex flat, cascaded, and reinforcement-learning alternatives for extreme clinical code prediction.

Electronic health record (EHR) data are inherently multimodal, and leveraging multiple modalities can improve predictive performance. However, most existing approaches rely on deep fusion, which obscures how individual modalities contribute to predictions and limits the interpretability of multimodal reasoning. We propose an explicit multimodal routing framework for clinical prediction that enables interpretable, robust, and auditable reasoning across three EHR modalities: structured longitudinal variables (L), clinical notes (N), and chest X-rays (I). Our model constructs discrete unimodal, directional bimodal, and trimodal routes to capture both individual modality signals and asymmetric cross-modal interactions. To audit multimodal reasoning and assess robustness, we introduce inference-time route masking, which simulates missing modalities and reweights the remaining routes without retraining. We analyze changes in performance and routing weights under these scenarios to understand model decision-making. We evaluate our framework on multi-label phenotype prediction (K = 25) and binary ICU mortality prediction using trimodal patient stays from MIMIC-IV, revealing systematic differences in modality reliance across clinical condition groups. Overall, our framework offers a transparent, auditable, and practical approach to multimodal clinical prediction, providing interpretability, robustness, and insights into how different data sources drive model decisions.

Achieving early and timely diagnosis and treatment for disease is a major challenge. Recent applications of machine learning (ML) algorithms trained on patient data have shown promise in many different settings for predicting the patient health state. A challenge often faced when applying these ML algorithms is that at any given time, not all clinical variables (features) needed as input to perform prediction tasks are available. We define the concept of full-feature-capacity (FFC) to refer to prediction performance when such algorithms make use of all features on which they were trained. We then introduce Feature Sufficiency Analysis (FSA) - an analysis for determining whether a subset of all clinical features needed by an AI model is sufficient to achieve FFC. FSA estimates the underlying distributions of missing variables conditioned on features that are available. FSA provides a patient-specific assessment of whether the existing set of measured features achieves FFC. If yes, then there is no need to acquire further inputs and a ML-based prediction. We provide two case studies: prediction of need for postoperative prolonged ventilation in patients recovering from heart surgery; 10-year mortality prediction in an outpatient cohort. We also demonstrate that FSA also provides a clinically interpretable feature-ranking methodology based on prediction sufficiency, identifies intrinsically hard-to-predict patient populations, and has the potential to perform cost-aware optimization for clinical data acquisition. FSA provides a generic computational approach for determining whether incomplete clinical information is sufficient to support trustworthy AI-assisted clinical decision-making, thereby facilitating the prospective deployment of healthcare AI systems across diverse clinical settings.

Algorithmic fairness methods are increasingly used to identify and mitigate bias in machine learning models, yet most approaches are evaluated in isolation and along single demographic axes. This limits practical guidance for selecting fairness strategies, where disparities may arise across intersectional subgroups and across multiple stages of the modeling lifecycle. This work presents FairSelect, a toolkit for systematically evaluating fairness mitigation strategies applied individually and in combination across preprocessing, inprocessing, and postprocessing stages. FairSelect supports multiple model architectures, intersectional subgroup evaluation, and comparison of fairness utility tradeoffs across baseline, single method, and multi level configurations. The framework was validated using synthetic clinical datasets designed to represent specific bias mechanisms and a real-world replication of two-year stroke risk prediction among patients with atrial fibrillation. Synthetic experiments showed that targeted fairness methods generally reduced intended subgroup disparities, while combined strategies produced larger average fairness improvements with modest utility tradeoffs. In the clinical prediction task, mitigation effects were highly variable, with some combinations improving both fairness and predictive performance while others were ineffective or counterproductive. These findings demonstrate that fairness interventions interact in nonadditive and context dependent ways. FairSelect provides a practical framework for systematically identifying fairness strategies that improve subgroup equity while preserving model performance in clinical machine learning.

Background: Graph neural networks improve computational prediction of polypharmacy side effects, but standard binary cross-entropy training allocates equal capacity to well-classified and difficult examples, potentially missing clinically significant interactions. We evaluated whether an asymmetric focal objective could improve multi-relational drug-drug interaction (DDI) prediction by emphasizing difficult positive interactions. Methods: ClinicalFocal loss was integrated into a relation-aware graph convolutional network using molecular fingerprints, physicochemical descriptors, and learned embeddings. The model was evaluated on TWOSIDES using five-fold cross-validation with identical experimental conditions (architecture, features, data partitions, hyperparameters, and random seeds) for ClinicalFocal loss and binary cross-entropy baseline. Results: ClinicalFocal loss increased accuracy from 0.699 to 0.892 (+19.3 percentage points) and F1 score from 0.700 to 0.894 (+19.4 percentage points). AUROC increased from 0.766 to 0.914, and AUCPR increased from 0.714 to 0.860. The false-negative rate decreased from 29.8% to 9.1%, while specificity increased from 69.6% to 87.5%. Overall classification error decreased from 30.1% to 10.8%, corresponding to a 64.1% relative reduction. Improvements were consistent across all five folds. Conclusions: Asymmetric focal optimization improved classification and ranking performance while achieving 90.9% recall for observed interaction triples, without modifying the underlying architecture. Loss-function design is a direct, tunable lever for improving graph-based DDI prediction.

Conformal prediction is being adopted in drug discovery to put an honest number on model reliability: pick an error rate alpha, and the method returns prediction sets containing the true label with probability at least 1 - alpha. We show this guarantee can be dangerous on imbalanced datasets. Across four datasets, standard (marginal) conformal prediction hits its global 90% coverage target while leaving the minority class badly exposed: realized minority coverage falls to 64.8% on blood-brain-barrier penetration and to 4.2% on clinical-trial toxicity, where the rare class is nearly abandoned. The failure is not tied to one model: a random forest, a graph network, and a frozen chemical language model all reproduce it (p < 0.001 in every case), with severity tracking baseline calibration on rare labels rather than architecture. A conservation identity explains the effect: the minority's shortfall equals the majority's surplus amplified by the imbalance ratio, predicting the measured gap to within one point and ordering severity across datasets. The failure survives realistic scaffold splits and a second conformal score, while aggregate accuracy and overall coverage stay reassuringly high, which is exactly why it is easy to miss. Class-conditional (Mondrian) conformal prediction closes the gap on every dataset, restoring minority coverage to target for a modest increase in prediction-set size. We localize the failures to generic molecular scaffolds - plain benzene and pyridine cores occurring in both classes - propose a one-number diagnostic, and show with a cost model that abstaining on affected compounds flips a screening campaign from net-negative to net-positive utility. Our contribution is demonstrating on real chemistry how severe and invisible this known conformal-theory gap becomes under imbalance, and laying out a practical protocol restoring per-class reliability.

Accurate prediction of patient-specific therapeutic response from pre-treatment transcriptomes is hindered by the scarcity of matched clinical response labels and post-treatment molecular profiles. Preclinical transfer-learning models can simulate drug-induced expression changes but are often hard to interpret and unstable, whereas knowledge-graph methods provide mechanistic context yet remain static and fail to capture drug-induced transcriptomic perturbation dynamics. We propose PREDIKTOR, a patient-centered multi-view framework that aligns a personalized network view with a transferable transcriptomic perturbation view to predict clinical drug response. For each patient, we construct an individualized gene regulatory network from tumor expression using DysRegNet and augment it with drug-target links from DrugBank; a graph neural encoder yields a drug-centric, mechanistically grounded embedding. In parallel, a frozen condition-specific gene-gene attention model pretrained on LINCS L1000 generates a simulated post-perturbation transcriptomic profile for the same patient-drug pair. We align the two views in a shared latent space via a CLIP-style contrastive objective with drug-context hard negatives, then concatenate the representations for end-to-end response classification. On TCGA, PREDIKTOR consistently outperforms state-of-the-art baselines under patient-, drug-, and tissue-split evaluations, and transfers zero-shot to the I-SPY2 trial, improving AUROC by 5.6% over competing methods. The aligned embeddings yield stable gene and pathway attributions that recover known mechanisms, supporting actionable and interpretable precision oncology.

Current Legal Judgment Prediction (LJP) is constrained by its reliance on post-hoc judicial materials, increasing the likelihood that models perform retrospective classification rather than true forecasting. This paper empirically investigates shortcut learning in this context by studying claim-level outcome prediction in UK Employment Tribunal (UKET) decisions. Using a corpus of 33,158 individual claims, we predict outcomes from claim texts and LLM-extracted case summaries, evaluating models ranging from interpretable TF-IDF-based classifiers to black-box LLMs. While headline predictive performance figures appear strong, we demonstrate that such performance in LJP systems trained on post-hoc judicial text can be driven by the retrospective nature of the source material. Stratifying the test data by human judgments of leakage reveals that performance increases where outcome-revealing cues are embedded in the narrative. Moreover, a model trained on just the 4% of features identified as leakage achieves high performance, outperforming human experts. These findings substantiate concerns that LJP performance may be exaggerated by linguistic artefacts. Yet this vulnerability is not fatal to the research agenda. Instead, post-hoc judgments might be treated as potentially contaminated texts, requiring active auditing. Retraining models after masking leakage features results in only a negligible reduction in Macro-F1. Hence, while models will opportunistically exploit shortcuts when available, they remain capable of extracting useful predictive signals when these artefacts are removed.

Microbial keratitis requires rapid pathogen identification to guide treatment, but culture- and PCR-based diagnostics are slow and resource-intensive. We developed a triple-phase multimodal framework for bacterial-versus-fungal keratitis classification using slit-lamp photographs acquired under blue-light, sclerotic-scatter, and white-light illumination, together with clinical metadata. The model combines cross-modality contrastive learning, modality-specific fine-tuning, and feature-level multimodal ensemble learning for patient-level prediction. We evaluated the framework on a multicenter dataset of 1,645 patients and 17,158 images from India and the United States. The model achieved 85.84% accuracy, 84.46% average F1-score, and 0.885 AUC. Site-specific evaluation showed that pooled results were overly optimistic, whereas resampling- and balance-based re-evaluation provided a more realistic assessment of cross-site generalization. Under all settings, our framework remained the top-performing approach. The code is available at https://github.com/yqwang01/TPMKA and dataset access will be provided subject to University of Michigan data-sharing clearance.

Cold-start drug-drug interaction (DDI) prediction for new drugs is critical for minimizing unexpected adverse drug reactions. The key challenge is to capture similarity between new and known drugs. However, such similarity is closely associated with complex relationships and mechanisms among drugs, enzymes, transporters, molecular structures, and other biomedical entities. Existing methods have three limitations in capturing such similarity: (1) only partial relationships and mechanisms are considered, which overlooks cross-modal information and yields incomplete or biased similarity modeling; (2) similarity computation between new and known drugs is conducted separately across modalities and performed offline for cold-start DDI prediction, leading to misalignment between similarity computation and DDI prediction; and (3) existing interpretability analyses are typically single-modality and focus primarily on key determinants of the perpetrator drug, while the underlying causes of susceptibility for the victim drug are seldom investigated. To address these issues, this paper proposes a novel Cross-Modal-Fused End-to-End Learning Network (CMF-ELN) with three components. First, diverse multimodal information is leveraged to construct four types of drug-centered knowledge graphs, enabling comprehensive similarity modeling under reconstruction-based supervision. Second, a four-channel graph autoencoder is designed to fuse cross-modal similarity within an end-to-end learning framework. Finally, a two-stage interpretability scheme is devised to precisely localize key factors for both perpetrator and victim drugs. Extensive experiments on two real datasets demonstrate that CMF-ELN achieves significantly higher prediction accuracy and more comprehensive interpretability of mechanisms than its peers.

Predicting cancer drug response from transcriptomic profiles is a cornerstone of precision oncology, yet the scientific value of machine learning models hinges not solely on predictive accuracy, but also on their capacity to generate reliable biological insights. Current explainability approaches in this setting are computationally costly, lack robustness, and reduce complex drug response to univariate gene importance scores, overlooking the coordinated gene activity that drives sensitivity and resistance. In this work, we present ILLUME+, a scalable post-hoc explainability framework that moves beyond single-gene assessments to capture multiple, complementary forms of explanation. Integrated into our end-to-end pipeline, ILLUME+ produces more stable gene importance scores than existing baselines, recovers established drug-gene associations and mechanisms of action, and enables AI-assisted hypothesis generation to uncover novel interaction-driven molecular signals in cancer biology.

Neoadjuvant chemotherapy (NAC) response prediction is clinically important for treatment stratification in breast cancer. However, robust pre-treatment pathological complete response (pCR) prediction remains challenging due to insufficient cross-modal modeling, multicenter imaging heterogeneity, and weak evidence-grounded interpretability. We propose ClinRAG-GRAPH, a Clinically informed Retrieval-Augmented Generation Graph framework, for pre-treatment pCR prediction from DCE-MRI, structured clinical variables, and biopsy-derived pathological biomarkers. ClinRAG-GRAPH constructs an intra-patient clinical-prior graph and applies a prior-guided relation-aware graph convolutional network for structured multimodal representation learning. To improve cross-center robustness, we introduce a dual-branch domain-adversarial learning strategy to suppress protocol-related MRI bias while preserving pCR-relevant features. To enhance interpretability, we further incorporate large language model (LLM)-driven subgraph RAG module that retrieves clinically analogous historical cases and integrates retrieved evidence for pCR inference. We assemble a large-scale multicenter NAC breast cancer cohort for extensive validation, drawing from two public sources and three in-house centers.Results show that ClinRAG-GRAPH achieves AUCs of 0.815 on the internal test set and 0.774/0.712 on two external test sets, demonstrating robust pre-treatment pCR prediction across centers. The code is available at the anonymized https://github.com/miccai26-1181/ClinRAG-GRAPH.

T cell receptor (TCR)-epitope binding prediction is essential for understanding adaptive immunity and developing immunotherapies. Existing sequence- and structure-based models often generalize poorly to unseen epitopes and provide limited interpretability. Furthermore, the impact of generated structures on model learning remains unclear. We present TCR-SRIM, a structure-regularized interpretable-by-design model that combines protein language model embeddings with interpretable contact prototypes to capture residue-level TCR-epitope interactions. TCR-SRIM achieves state-of-the-art predictive performance and improved interpretation quality on the TCR-XAI benchmark. Using its inherent interpretability, we further evaluate the effect of generated structures on model learning. While structures predicted by AlphaFold3, TCRModel2, and tFold-TCR yield competitive performance, they lead to less accurate interaction patterns and reduced binding-site diversity than experimentally-resolved structures. Our results highlight limitations of current structure prediction models for TCR-epitope learning and demonstrate the value of interpretable-by-design models for studying generated biological structures.

Predicting student performance and characterizing metacognitive calibration are essential for personalization in intelligent tutoring systems. Prior research treats performance prediction, calibration error calculation, and variance decomposition as separate pipelines, preventing unified interpretation. I propose the Unified Behavioral Prediction and Calibration Analysis Pipeline (UBP-CAP), an integrated framework processing student pre-execution behavioral telemetry through three linked modules: (1) a LightGBM classifier with SHAP for binary correctness prediction, (2) formal calibration metrics (ECE, MCE, and Brier score decomposition) to evaluate metacognitive alignment, and (3) a crossed Generalized Linear Mixed-Effects Model (GLMM) for decomposing calibration deviations. I introduce the Predictive-Explanatory Divergence Index (PEDI), which quantifies structural divergence between predictive and explanatory feature profiles. Evaluated on 1,195 interaction records (27 students, 45 tasks), Logistic Regression achieves AUC-ROC = 0.903, outperforming LightGBM (0.878). Student naive ECE (0.109) significantly exceeds model ECE (0.068), confirming systematic miscalibration. The crossed GLMM yields ICCStudent = 0.123, showing calibration is situational rather than dispositional. PEDIcos = 0.081 (p = 0.327) indicates structural alignment between prediction and explanation on shared behavioral features.