Clinical Prediction

Introduction: Objective neuroimaging biomarkers may improve Parkinson's disease motor assessment by capturing brain variation not directly observable from clinical examination. We used interpretable machine learning to predict current motor severity, measured by MDS-UPDRS Part III, from QSM and multiband multi-echo resting-state fMRI-derived ReHo features. Methods: Regional QSM and ReHo features were extracted from 28 participants, including 24 individuals with Parkinson's disease and 4 controls. Thirteen feature-set experiments evaluated imaging-only, clinical-only, imaging-plus-clinical, full, reduced, and multimodal inputs. Support vector regression, Elastic Net, Random Forest, and XGBoost models were trained using nested cross-validation. Performance was assessed using pooled held-out R^2, RMSE, MAE, Pearson correlation, permutation testing, and the proportion of participants predicted within +/-5 MDS-UPDRS Part III points. Results: Imaging-only models carried meaningful predictive signal, whereas the clinical-only model performed weakly. Full fMRI, full QSM, and clinical variables provided the strongest global fit, explaining 45.4% of variance in motor severity. Selected QSM plus clinical variables produced the most clinically close predictions, with 75.0% of participants predicted within +/-5 points and the lowest MAE among top-performing models. SHAP highlighted cerebellar, thalamic, striatal, insular, and motor cortical features. Conclusion: QSM and multiband multi-echo fMRI-derived ReHo capture distinct, interpretable dimensions of Parkinson's disease motor severity. These findings show that structural and functional imaging contribute differently depending on the clinical prediction goal.

We introduce TabPFN-CFM, a causal foundation model that can handle multiple causal problems. TabPFN-CFM predicts both causal structure and outcomes from observational data, supports queries on all three levels of Pearl's Causal Hierarchy and uses known graph structure when available to improve predictions. TabPFN-CFM is trained on synthetic datasets, and generalises to real datasets, demonstrating improved performance over both structural and outcome prediction baselines.

While WGS-based AMR prediction has reached high accuracy, existing models lack a mechanism to ground neural attributions in established biological pathways. We present KG-TRACE, a novel neuro-symbolic framework that integrates the WHO mutation knowledge graph (KG) as a structured biological constraint on a neural genomic model. Unlike existing methods that learn statistical patterns in isolation, KG-TRACE fuses genomic features and RotatE-based KG embeddings through a learned epistemic trust gate, dynamically weighting neural evidence against symbolic biological knowledge. Evaluated on the CRyPTIC M. tuberculosis cohort, KG-TRACE achieves an AUROC of 0.9760 for isoniazid, achieving competitive accuracy while its primary value lies in symbolic grounding, not predictive uplift. More importantly, we introduce the Biological Grounding Ratio (BGR), a dataset-level metric that quantifies alignment between neural attributions and established biology. Our framework achieves a 92.5% symbolic coverage of isoniazid-resistant predictions and effectively identifies MDR co-occurrence artifacts by issuing laboratory follow-up flags for 'UNCERTAIN' cases. We demonstrate that neuro-symbolic grounding provides a verifiable audit trail for clinicians, bridging the gap between predictive accuracy and clinical trust.

Background: Response to neoadjuvant imatinib in gastrointestinal stromal tumors (GISTs) is highly variable and cannot be reliably predicted using current clinical or molecular markers. This study developed and evaluated an explainable multimodal deep learning framework integrating computed tomography (CT) imaging and clinical variables to predict treatment response. Methods: Patients from four tertiary centers were retrospectively included between 2000-2023 in independent pretraining (n=935) and prediction (n=213) cohorts. A cross-attention framework integrating clinical variables and tumor-centered CT imaging was developed to predict response to neoadjuvant imatinib. Two training strategies were evaluated: (1) self-supervised pretraining with low-rank adaptation and (2) training from scratch. Hyperparameters were optimized using SMAC3. Performance was assessed through internal cross-validation and external testing. Ablation analyses and attention-based explanations were used to quantify modality contributions. Results: Among 213 patients (54.5% responders), responders had larger tumors (112 vs. 89 mm, P=0.026), higher mitotic index (3 vs. 0, P<0.001), and more frequent KIT mutations (69.0% vs. 56.7%, P=0.019). Cross-attention models achieved the highest internal performance (AUC up to 0.99) but lower external performance (AUC 0.60-0.63). Clinical-only performance was moderate (AUC 0.66), whereas imaging-only models showed limited generalizability (AUC 0.56-0.66). Explainability analyses identified significant differences in feature importance between responders and non-responders, including CD117, BRAF, PDGFRA, age, sex, disease status, and comorbidities (FDR-adjusted P<=0.036). Conclusion: The cross-attention framework shows potential for improving imatinib response prediction in GIST while providing interpretable insights into multimodal determinants of treatment response.

Mental illnesses among drug users are an increasing international issue, particularly in regions where early detection cannot be easily undertaken. The current literature tends to ignore the use of AI-based mental health analysis in drug users, and low quality of the class imbalance treatment, low interpretability, and optimal hyperparameter optimization can lower predictive quality and clinical utility. This study present a detailed, explainable machine learning (ML) model of multiclass mental health prediction, using a multidimensional data set of drug-affected persons. We combine hybrid PCA-Information Gain (PCA-IG) feature selection, Generative Adversarial Network (GAN)-based oversampling, and Dragonfly Algorithm (DA)-optimized XGBoost to address some of the limitations of existing methods. The suggested framework is effective to work with high-dimensional categorical data, address the issue of class imbalance, and improve predictive performance due to intelligent hyperparameter tuning. The experimental findings show that the XGBoost model optimized using the DA, in combination with GAN-based oversampling, has an accuracy of 94.17% and a weighted F1-score of 93.80%, which is better than the traditional and baseline models. The behavioral, lifestyle, and health factors, particularly sleep quality, physical health, and emotional regulation, are strongly predictive of mental health, with demographic factors having little impact, as seen through feature analysis. SHAP-based explainable AI provides easy-to-understand, instance-level information, enhancing interpretability and trust in models to be used in clinical settings. The results indicate that this framework has the potential to generate valid mental health forecasting tools, which would facilitate early intervention and enhance the treatment of drug-influenced people.

Risk stratification for advanced colorectal polyps typically relies on colonoscopy and/or pathology findings. However, there is growing interest in whether non-invasive features available prior to colonoscopy can help identify patients at higher risk. Such approaches may enhance clinical decision-making by prioritizing surveillance for individuals most likely to harbor high-risk polyps, when colonoscopy resources are limited while potentially reducing unnecessary procedures in lower-risk patients. Importantly, the use of non-invasive, pre-procedural information may also help promote more equitable access to risk stratification, particularly in settings where colonoscopy resources are limited or unevenly distributed. We aimed to develop and externally validate machine learning models to predict high-risk colorectal polyps using only non-invasive, pre-colonoscopy demographic, clinical, and behavioral features in a diverse, predominantly African American, urban cohort. We conducted a retrospective cohort study using demographic, lifestyle, and comorbidity data from patients who underwent colonoscopy at Howard University Hospital to develop and validate several machine learning models, including neural networks, random forest, support vector machines (SVM), Naive Bayes, logistic regression, decision trees, k-nearest neighbors (KNN), and XGBoost, for predicting high-risk colorectal polyps. High-risk polyps (HRP) were defined as villous or tubullovillous adenomas, high-grade dysplasia, polyps >= 10 mm in size, and/or the presence of >= 3 polyps per procedure; all other cases were classified as low-risk polyps (LRP). The dataset included 4,681 patients from 2015-2022 used for internal validation and 1,562 patients from 2023-2024 used for external validation.

Machine learning models are predominantly evaluated through predictive performance metrics such as ranking quality, prediction error, or classification accuracy. While these metrics effectively quantify how closely predictions match the ground truth, they do not assess whether model outputs respect predefined logical or domain-specific constraints. In high-stakes applications, including healthcare, finance, and autonomous systems, logical consistency can be as critical as predictive accuracy, yet no standard metric captures this dimension. We introduce the Rule Violation Score (RVS), a complementary evaluation metric that quantifies the extent to which a predictive model respects a given set of logical rules, independently of predictive accuracy. RVS treats hard rules (strict constraints) and soft rules (statistical regularities) differently, can be evaluated on any dataset and on any predictive model expressed over a relational vocabulary, and can be computed using SQL queries that are automatically generated for Horn rules. Beyond evaluating models, RVS can also evaluate the logical consistency of training datasets and help identify poorly defined rules. We evaluate RVS on three benchmarks covering knowledge graph link prediction and relational regression, including rule-based, embedding-based, and neuro-symbolic predictive models. Our results demonstrate that two models achieving comparable predictive accuracy can exhibit substantially different levels of logical compliance, revealing differences in model behavior that standard metrics fail to capture.

On biomedical tabular data, flexible models such as deep networks, gradient-boosted trees, and kernel methods are repeatedly matched or beaten by linear and logistic regression given the same features. The usual reaction is to treat this as a model-side shortfall, to be fixed with more data, a better architecture, or tuning, on the assumption that the nonlinear structure is there and the model has failed to capture it. We argue that these fixes cannot help when the binding limit is the measurement rather than the model, as it frequently is in biomedicine. Additive noise blurs the population-optimal predictor, and because blurring removes a function's fine, rapidly varying detail before its broad shape, it erases nonlinear structure faster than linear structure. A degree-$k$ interaction is attenuated by the $k$-th power of feature reliability, while the linear part is attenuated only once. At the reliabilities typical of biomedical measurement, the nonlinear advantage can vanish even when the underlying biology is strongly nonlinear, and what the noise removes cannot be recovered by a larger cohort or a more flexible model, only by better measurement. The nonlinearity is hidden, not absent, and a tie between linear and flexible models is not by itself a verdict on the biology. These pieces are classical, drawn from measurement-error statistics, psychometrics, and Gaussian analysis, and we assemble them into an exact excess-risk identity. Measurement reliability is one of three conditions, alongside sample size and feature representation, that must align for a flexible model to help, and together they leave only a narrow window that most biomedical tasks fall outside. Across 140 UK Biobank tasks, the gap between flexible and linear models, where it exists, carries the predicted noise signature, and the three conditions can be separated by intervention but not by a benchmark alone.

Distinguishing causal adverse drug events (ADEs) from spurious correlations remains a central challenge in pharmacovigilance. The InferBERT framework integrates transformer models with Do-calculus, but its success hinges on the underlying classification model. This study evaluates the impact of model choice in InferBERT, assessing whether simpler models suffice, if domain-specific pre-training helps, whether scaling to LLMs improves causal detection, and the effect of post-hoc calibration. We performed a comparative study on two benchmarks: Analgesics-induced Acute Liver Failure (AILF) and Tramadol-related Mortalities (TRAM). Four models were evaluated-XGBoost (baseline), ALBERT (original InferBERT), BioBERT (biomedical transformer), and Med-LLaMA (medical LLM)-using 5-fold cross-validation repeated over 20 runs. We measured accuracy, Expected Calibration Error (ECE) pre- and post-isotonic regression, and Jaccard concordance of causal terms with PRR, ROR, and EBGM; significance was tested with paired t-tests. BioBERT achieved the highest accuracy on both datasets, while Med-LLaMA underperformed despite its size and parameter-efficient fine-tuning. Domain-specific pre-training was decisive. Calibration improved ECE but had mixed effects on accuracy and causal discovery. BioBERT's superiority also yielded the strongest concordance with traditional pharmacovigilance signals. These results show that domain-specific pre-training provides a clear advantage over simpler baselines and larger LLMs. Investing in manageable, domain-aware models is more effective for computational pharmacovigilance than simply scaling model size.

Dysglycemia, encompassing both prediabetes and diabetes, affects huge numbers of adults worldwide, yet many of them remain undiagnosed. We developed and validated machine-learning (ML) models for non-invasive screening of dysglycemia risk that require no laboratory tests. Pooling data from the National Health and Nutrition Examination Survey (NHANES) 2017--2023 (n=14,352), we trained six ML models with stratified 5-fold cross-validation and compared them with two established clinical risk scores. LightGBM achieved the highest area under the receiver operating characteristic curve (AUC=0.820, 95% CI: 0.806--0.835), outperforming the Finnish Diabetes Risk Score (0.745) and American Diabetes Association Risk Test (0.783). SHAP analysis identified age, race/ethnicity, and waist-to-height ratio as the most influential predictors. Subgroup analyses confirmed consistent performance across demographic strata (AUC: 0.735--0.832). These results demonstrate the feasibility of explainable, laboratory-free dysglycemia screening for deployment in community settings and self-tracking health applications.

Lung cancer is the leading cause of cancer-related mortality, with approximately 2.5 million new cases and 1.8 million deaths annually, making reliable diagnosis a clinical priority. Although deep learning models have achieved strong performance in lung cancer classification, evaluation has largely focused on predictive accuracy, leaving their decision-making processes insufficiently examined. This study compares three architecturally distinct models: a Convolutional Neural Network (CNN), a pretrained ResNet50, and a Vision Transformer (ViT), trained on the IQ-OTH/NCCD lung cancer CT dataset. Local Interpretable Model-Agnostic Explanations (LIME) were applied to investigate model reasoning. In addition to standard performance metrics, a dual-correlation framework was introduced to measure both prediction agreement and explanation agreement across model pairs. All three models achieved strong classification performance, with ResNet50 attaining 98.61% accuracy, CNN 97.91%, and ViT 93.75%, while all achieved ROC-AUC scores of 0.99. Prediction correlations exceeded 0.99 across all model pairs, indicating highly consistent outputs. However, LIME explanation correlations remained below 0.26, revealing substantial differences in the image regions used to reach those predictions. Analysis of misclassified samples further identified a consistent spatial pattern: incorrect predictions were associated with attention outside the lung parenchyma, whereas correct predictions focused primarily within lung regions. These findings demonstrate that prediction agreement is a poor proxy for reasoning consistency, and that interpretability evaluation must be treated as an independent validation criterion alongside predictive performance in clinical AI systems.

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

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

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

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

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

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

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

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

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

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

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

Large language models (LLMs) exhibit strong natural-language reasoning abilities for clinical decision support, but struggle to effectively model structured longitudinal electronic health records (EHRs). In contrast, EHR foundation models can learn predictive patient representations, yet lack interpretable language-based reasoning. To bridge this gap, we propose ChatHealthAI, a multimodal reasoning framework that aligns structured EHR representations from a pretrained EHR foundation model with the semantic space of a frozen LLM through a task-aware resampler. By integrating longitudinal patient representations with refined clinical event descriptions, ChatHealthAI enables clinically grounded natural-language reasoning while maintaining accurate patient prediction. We evaluated ChatHealthAI on three clinical predictive tasks from the EHRSHOT benchmark. Results show that ChatHealthAI improves reasoning quality and interpretability while preserving competitive predictive performance. These findings highlight the potential of integrating EHR foundation models with pretrained LLMs for interpretable clinical prediction.

Prediction tasks over individual futures, which are inherently noisy, often admit multiple similarly accurate models. When these models produce different predictions for the same individual, they raise concerns of arbitrariness in decision-making. How severe can this arbitrariness be, in theory and in practice? How can it be resolved to support high-stakes risk assessment? We address these questions through a study of a machine learning-based decision support system for recidivism risk assessment that has been in use for over 15 years. By translating complex legal rules into an algorithm for labeling post release outcomes (recidivist or non-recidivist), we first construct a dataset of thousands of inmate releases. Using this dataset, we learn interpretable models that improve predictive performance, reduce error-rate disparities between groups, and ensure that rehabilitative progress lowers risk scores. Next, we study predictive multiplicity, by first deriving a tight lower bound on the expected predictive agreement of any finite set of models over a dataset, and then by evaluating the extent to which structural diversity (e.g., different model coefficients) within this set translates to predictive multiplicity (i.e., different predictions for the same individual). Our experiments indicate that the existence of many similarly accurate models with comparable error-rate disparities does not necessarily translate into severe predictive multiplicity. Empirically, similarly performant models can exhibit substantially higher predictive agreement than worst-case theoretical guarantees suggest. We find that a simple policy that assigns each inmate the lowest risk among these models is effective for addressing predictive arbitrariness.

Anastomotic leak remains one of the most serious complications following colorectal cancer surgery, substantially affecting patient outcomes, recovery trajectories, and healthcare costs. Despite advances in imaging technology, current preoperative assessment relies only on clinical assessment, a process that is subjective, error-prone, and highly dependent on individual expertise. To date, no validated CT-based method exists to predict anastomotic leak risk prior to surgery. This protocol paper outlines a comprehensive framework for developing and validating an AI-driven system for preoperative risk assessment using pre- and post-contrast CT imaging. The study describes the stages of data collection, ethical handling, and preprocessing of patient data in accordance with GDPR, image preprocessing, and the exploration of deep learning architectures designed to generate clinically interpretable outputs. Two integrated tools constitute the main deliverables of this workflow: 1) a risk assessment module, which quantifies the likelihood of leakage by analyzing vascular and tissue features in CT scans, and 2) a Content-Based Medical Image Retrieval (CBMIR) module, which identifies and displays similar historical cases to support evidence-based surgical decision making. The protocol paper requires close collaboration between hospitals and universities; this protocol demonstrates that such a system is technically feasible and clinically implementable within existing healthcare infrastructures. By following the proposed methodological stages and regulatory principles, other institutions can reproduce this workflow to develop analogous decision-support tools. Ultimately, this interdisciplinary framework aims to enhance surgical planning, reduce leak incidence, and contribute to a broader paradigm shift toward explainable, data-driven precision surgery.

Selection bias is a common and often unavoidable aspect of real-world data that challenges the generalizability of machine learning models. When models trained on biased data are deployed in the broader target population, poor model generalization may lead to real harm, particularly in high-risk settings such as healthcare. This risk highlights the need for practitioners to reliably assess model generalizability prior to deployment. However, existing methods for predicting model performance rely on unrealistic access to the target distribution or knowledge of the selection mechanism causing bias. To address these limitations, we propose a novel upper bound on the worst-case model performance on the target population under the realistic setting where the selection mechanism and the target population data are only partially observed. We demonstrate the validity and practical utility of our method through experiments on fully synthetic data, semi-synthetic data derived from the All of Us Research Program, and real-world selection bias in MIMIC-IV. Our work offers a principled and practical tool to estimate the impact of selection bias in an otherwise intractable setting, thereby enabling practitioners to build safer and more generalizable models in healthcare and beyond.

Under standard graphical assumptions, the Markov boundary of a target variable is the smallest set of features that renders every other feature redundant. Once the boundary is observed, the target is conditionally independent of the rest of the table. This is a tempting object for tabular prediction, since it names exactly the columns a model should need. Yet modern regressors are still trained on the full feature set. We ask whether the Markov boundary is genuinely useful for prediction on SCM3K, a 3,450-task synthetic SCM benchmark with feature counts from 40 to 1000 and six SCM families, evaluated with six regressors. The answer is more nuanced than the theory suggests. Restricting a regressor to the oracle boundary often improves prediction substantially, and the improvement grows as the feature space becomes larger and sparser. But the natural pipeline of recovering the boundary with causal discovery and training on the recovered mask does not deliver. Existing estimators exhaust the compute budget before reaching the regime where the boundary helps most, and even where they run they rarely beat the full feature set. We trace this to three causes. Discovery optimizes structural recovery rather than prediction. False negatives and false positives carry sharply asymmetric predictive cost. The exact boundary is only one of many feature sets that beat all features. We then develop what these facts imply for prediction-aligned feature selection and for tabular models that learn to use causal structure.

Disease forecasting models typically rely on a single data stream, making models brittle when histories are short or noisy. Recent top-performing models have shown that synthesizing multiple reporting systems for the same disease improves performance. Other recent work takes this idea a step further, using transfer learning to train a forecasting model for one disease using data from a different disease. We expand upon each of these approaches greatly, training machine learning models on data that span 66 infectious diseases and several data streams. We investigate the value of incorporating different data streams for forecasting 20 different disease data streams. We find that incorporating other data streams improves forecasting in the vast majority (84.9%) of time series and model structures considered. However, our work highlights that the quality of the added data matters, where adding data extremely different from the target data stream can sometimes degrade forecast performance. A major contribution of this work is in compiling a publicly-available database of data for use by the infectious disease forecasting community.

Background: Type 2 diabetes mellitus (T2DM) is increasingly recognised as a systemic disease characterised by coordinated dysfunction across metabolic, renal, lipid, and inflammatory pathways. Existing clinical assessments often fail to capture this multi-dimensional burden. Methods: We conducted a retrospective study of 1,195 patients using routinely collected laboratory biomarkers. System-level abnormality indices were constructed to quantify organ-specific dysfunction, and multi-system involvement was defined as abnormalities in two or more systems. Supervised machine learning models, including logistic regression, random forest, and gradient boosting, were trained to predict multi-system dysregulation. Model interpretability was achieved using SHapley Additive exPlanations (SHAP). Results: The gradient boosting model demonstrated near-perfect discrimination (AUC = 1.000), significantly outperforming logistic regression (AUC = 0.925). Feature attribution analysis revealed that hyperglycaemia, renal impairment, dyslipidaemia, and inflammation were the dominant drivers of multi-system risk. Dose-response relationships observed in partial dependence analyses further supported the biological plausibility of model predictions. Conclusion: This study presents an interpretable, data-driven framework for quantifying systemic disease burden in T2DM. By linking routine biomarkers to multi-organ dysfunction, our approach provides both predictive accuracy and mechanistic insight, offering potential for improved risk stratification and precision medicine in diabetes care. The data and code used in this study are openly available on GitHub at: https://github.com/MiniHanWang/Type-2-Diabetes-1.git

Deploying clinical prediction models across healthcare systems often fails when key training covariates are unavailable at deployment and labeled outcomes are limited in the target domain. For example, high-performing models for out-of-hospital cardiac arrest (OHCA) rely on detailed prehospital measurements routinely collected in high-resource settings but unavailable in many international registries. Existing methods either discard missing covariates, sacrificing predictive information, or rely on untestable assumptions about their target distribution. We propose DRUM (\underline{D}istributionally \underline{R}obust \underline{U}nsupervised transfer learning with structurally \underline{M}issing covariates), a framework that transfers prediction models to target populations where certain covariates are structurally absent and outcome labels are unavailable. DRUM partitions covariates into shared components ($X$), observed across all settings, and missing components ($A$), observed only in the source. Rather than imputing missing covariates, DRUM optimizes worst-case predictive performance over the unknown target distribution of $A \mid X$ using a neural network generator, with a robustness parameter controlling allowable deviation from the source conditional. We further develop a bias correction procedure that reduces sensitivity to nuisance estimation error. Simulations show substantial improvements in both mean and worst-case prediction error under distribution shift. Applied to cross-national OHCA prediction, transferring models from a US registry to multiple Asian registries where prehospital variables are unrecorded, DRUM yields better-calibrated predictions and improved clinical classification performance across sites.

Biological systems are governed by structured molecular interactions, where pathways, regulatory circuits, and functional gene relationships shape cellular behavior and disease progression. Much of this knowledge is naturally represented as graphs. However, most biomedical AI models cannot directly use graph-encoded biological knowledge and instead require compressed low-dimensional representations, which can lose important structure and reduce performance, especially in limited-sample clinical studies. Here, we introduce Graph-in-Graph (GiG), a knowledge graph-modulated deep learning framework for data-efficient clinical prediction. GiG represents each patient as a standalone modular graph, in which curated biological knowledge graphs define edges and patient-specific measurements, such as gene expression, define node features. This design allows multiple biological knowledge graphs to be integrated while preserving gene-gene interactions and pathway topology during patient-level representation learning. Across cohorts comprising nearly 9,700 patients and five clinical tasks, including liquid biopsy cancer detection, prostate cancer diagnosis, and 32-class pan-cancer classification, GiG consistently outperforms traditional and state-of-the-art methods, with the largest gains in limited-sample settings. On the challenging prostate cancer diagnosis task, GiG improves macro-F1 by up to 49 percentage points relative to competing methods. Control experiments replacing real pathway graphs with random topologies confirm that these gains arise from biologically grounded knowledge graph structure rather than graph modeling alone. These findings show that knowledge graph-modulated deep learning can improve robustness, interpretability, and sample efficiency in clinical data analysis, and provide a principled framework for integrating biological knowledge graphs into predictive modeling.

Predictive modelling is important for health data analysis and data-driven clinical decision-making. However, predictive studies are challenging to design optimally by hand when tens or even hundreds of features require selection, transformation, or interaction modelling. While complex machine learning models offer high performance, their "black-box" nature limits the clinical trust, transparency, and interpretability required for decision-making. We developed and evaluated an Exploratory AI Recommender that provides data-driven recommendations to improve predictive performance of existing interpretable statistical models. The developed framework uses flexible AI modelling to capture complex data patterns and explainable AI techniques to translate the patterns into three recommendation types: feature exclusion, non-linear terms, and feature interactions. We evaluated the framework by comparing predictive performance of a baseline (i.e., no interactions or non-linear terms) Cox Proportional Hazards (CPH) model against an augmented CPH incorporating recommendations suggested by our method. The primary analysis predicts the time to the first occurrence of a fall or related injury in 245,614 patients. Our method recommended excluding 23 features, including non-linear terms for two features, and including 221 suggested feature interactions. The C-index improved from 0.805 (95% CI 0.798-0.812) to 0.815 (95% CI 0.809-0.822), and so did calibration (intercept: -0.006 to 0.003; slope: 1.063 to 0.950). All recommendations were supported by existing literature. The method also proved effective on two additional public datasets, demonstrating wider applicability. The proposed Exploratory AI Recommender demonstrates the potential of explainable AI and data-driven study design to improve the process of developing, and the performance of high-dimensional transparent predictive models.

Machine learning models for chronic kidney disease (CKD) risk prediction often post strong discrimination scores on internal test sets. Calibration and uncertainty quantification get far less attention, leaving clinicians without reliable information about whether the probability outputs are accurate. We trained five classifiers on the UCI CKD dataset (400 patients, 62.5% CKD prevalence): logistic regression, random forest, XGBoost, SVM with Platt scaling, and Gaussian naive Bayes. We evaluated each across calibration quality, conformal prediction coverage, and an eight-criterion deployment readiness framework. A distributional stress-test applied the best-calibrated variant of each model to the open-access MIMIC-IV demo cohort (97 patients, 23.7% CKD) to assess behaviour under prevalence shift and feature missingness. We measured calibration before and after Platt scaling and isotonic regression using Expected Calibration Error and Brier Score, and quantified uncertainty through split conformal prediction targeting 90% marginal coverage. All five models reached AUROC 1.00 on the UCI test set. Isotonic recalibration reduced internal ECE to 0.000-0.022. On MIMIC-IV, AUROC fell to 0.48-0.58, ECE rose to 0.68-0.76, and conformal coverage dropped from 0.80-0.98 to 0.21-0.25 against a 90% target. No model scored above 4 out of 16 on the deployment readiness checklist. Near-perfect internal performance did not transfer. Calibration stability and conformal coverage should be evaluated on external data before any clinical prediction model moves toward deployment.

Precision oncology requires predicting which drugs will suppress a specific tumor from its molecular profile, but drug-blind sensitivity prediction has plateaued despite increasingly complex drug representations. Here we show that this stagnation reflects a metric artifact rather than a representational bottleneck. The standard benchmark, global Pearson r, is dominated by between-drug potency differences that a trivial drug-mean predictor captures without any cell-specific learning. Per-drug Pearson r, which isolates within-drug cell ranking, reveals that no drug encoding improves over cell-only features across four independent datasets. A controlled experiment channeling mechanism-of-action identity as either a drug feature or a training-distribution constraint identifies the cause. Supplying MoA as a feature yields negligible benefit, whereas using it to stratify training raises per-drug r substantially for targeted kinase inhibitors, because pan-cancer co-training suppresses pathway-specific sensitivity signals. Mechanism-stratified training and response matching from pilot observations provide two deployable strategies that together recover the principal sources of predictive gain in drug-blind sensitivity prediction.

Effective medication management in Parkinson's Disease (PD) is challenging due to heterogeneous disease progression, variable patient response, and medication side effects. While AI models can forecast levodopa equivalent daily dose (LEDD) as a measure of medication needs, standard uncertainty quantification often fails to communicate the reliability of these predictions, treating high and low confidence clinical decisions identically. We introduce CASCADE (Calibrated Adaptive Scaling via Conformal And Distributional Estimation), a novel conformal prediction framework that propagates epistemic uncertainty from a screening classifier to adapt downstream predictions. Unlike standard conformal methods that rely on auxiliary residual regression, we leverage epistemic uncertainty from a primary classification task (identifying whether a medication change is needed) to dynamically scale the prediction intervals of a secondary regression task (predicting how much change). By mapping Venn-Abers multi-probabilistic uncertainty directly to non-conformity scores, our framework achieves continuous risk adaptation. We demonstrate that this ``cascade effect'' produces highly efficient intervals for confident patients (38.9% narrower than standard conformal baselines) while automatically expanding intervals to ensure robust coverage for uncertain cases, bridging the gap between discrete clinical decision-making and continuous dose forecasting in PD.

Self-supervised learning (SSL) is now a standard way to pretrain medical image models, but performance is still mostly judged by downstream accuracy. For safety-critical screening tasks such as diabetic retinopathy grading, this is not enough: a model must also know when its predictions are unreliable and defer uncertain cases for clinical review. In this work, we examine how the length of SSL pretraining influences calibrated confidence and confidence-based abstention. We evaluate multiple SSL checkpoints under a fixed fine-tuning protocol and assess calibrated confidence, coverage, selective accuracy, and selective macro-F1. Across datasets and data regimes, SSL pretraining improves selective prediction compared to training from scratch. Unlike prior SSL studies that primarily evaluate downstream accuracy or AUROC, we analyze how SSL pretraining duration influences confidence behavior under calibrated confidence-based abstention. However, once accuracy saturates, selective performance can still change markedly across checkpoints, and longer pretraining does not consistently improve reliability. These results underscore the importance of abstention-aware evaluation and suggest that pretraining length should be treated as an important reliability-related design choice rather than only a computational detail. Code is available at GitHub.

Clinical decision-making is a feedback system where risk estimates influence treatment, which in turn changes disease trajectories, and both shape clinicians' measurement practices. Static prediction often fails clinically: models trained on observational care logs conflate disease biology with clinician behavior, particularly under treatment confounder feedback and irregular or informative observation. This Review focuses on intervention-aware disease trajectory modeling in clinical AI--methods estimating patient-specific longitudinal disease evolution and assessing trajectory changes under alternative treatments. We organize the field around six linked components: three decision tasks (factual forecasting, counterfactual estimation, policy evaluation) and three data-generating mechanisms (disease evolution, treatment assignment, observation process) that determine identifiability. We present the first unified framework bridging forecasting, counterfactual trajectories, and policy evaluation across discrete/continuous time, explicitly addressing treatment assignment, time-varying confounding, and observation bias. We synthesize key method families (multistate/joint models, temporal point-process, deep sequence architectures, longitudinal causal inference), map them to relevant components, and align evaluation with claim strength via overlap diagnostics, uncertainty quantification, off-policy robustness, and target-trial validation. This synthesis advances benchmark prediction to decision-grade clinical evidence, enabling treatment-sensitive individualized futures, pre-deployment policy stress-testing, and safer closed-loop learning health systems that adapt/abstain when evidence is insufficient.

Multimodal clinical prediction faces three challenges: multiple foundation models (FMs) with complementary strengths per modality, pervasive missing modalities at training and test time, and sample-specific variation in modality contributions. We introduce MedMIX, a multimodal framework that combines intra-modality expert fusion, learned inter-modality fusion, and training-only large--small model collaboration for robust medical prediction under incomplete modalities. Within each modality, MedMIX aggregates complementary embeddings from multiple small expert models; across modalities, it performs learned fusion over available modalities; and during training, it leverages large teacher models to improve deployed representations without additional inference cost. Across three heterogeneous benchmarks (OpenI, MIMIC-IV-MM, and MMIST-ccRCC), MedMIX achieves consistently strong performance while remaining robust under controlled missing-modality perturbations, and further demonstrates sustained robustness under cross-cohort shift on MIMIC-III. These results highlight MedMIX as a practical framework that unifies within-modality expert collaboration, sample-specific cross-modality fusion, and efficient large--small model collaboration while remaining robust to incomplete modalities.

Probabilistic forecasting of infectious diseases is crucial for public health but relies on labor-intensive manual model curation by expert modeling teams. This bespoke development bottlenecks scalability to granular geographic resolutions or emerging pathogens. Here, we present an autonomous system using Large Language Model (LLM)-guided tree search to iteratively generate, evaluate, and optimize executable forecasting software. In a fully prospective, real-time evaluation during the 2025-2026 US respiratory season, the system autonomously discovered methodologically diverse models for influenza, COVID-19, and respiratory syncytial virus (RSV). Aggregating these machine-generated models yielded an ensemble that consistently matched or outperformed the gold-standard, human-curated Centers for Disease Control and Prevention (CDC) hub ensembles out-of-sample. The system successfully navigated data-scarce "cold start" scenarios for RSV. Moreover, controlled retrospective ablations revealed that optimizing log-scale distance metrics prevents reward hacking, while an automated judge-in-the-loop ensures structural fidelity to complex scientific theories. By autonomously translating epidemiological theory into accurate, transparent code, this framework overcomes the modeling labor bottleneck, enabling rapid deployment of expert-level disease forecasting at unprecedented scales.

Accurate disease trajectory prediction is critical for early intervention, resource allocation, and improving long-term outcomes. While electronic health records (EHRs) provide a rich longitudinal view of patient health in clinical environments, models trained on curated research cohorts may not reflect routine deployment settings, and those trained on single-hospital datasets capture only fragments of each patient's trajectory. This highlights the importance of leveraging large, multi-hospital health systems for training and validation to better reflect real-world clinical complexity. In this work, we develop DT-Transformer, a foundation model trained on 57.1M structured EHR entries over 1.7M patients from Mass General Brigham (MGB), spanning 11 hospitals and a broad network of outpatient clinics. DT-Transformer achieves strong discrimination in both held-out and prospective validation settings. Next-event prediction achieves a median age- and sex-stratified AUC of 0.871 across 896 disease categories, with all categories exceeding AUC 0.5. These results support health system-scale training as a path toward foundation models suited to real-world clinical forecasting.

Scientific machine learning reports predictive performance. It does not report whether the same prediction would survive a different draw of training data. Across $9$ chemistry benchmarks, two classifiers trained on independent bootstraps of the same training set agree on aggregate accuracy to within $1.3\text{--}4.2$ percentage points but disagree on the class label of $8.0\text{--}21.8\%$ of test molecules. We call this gap \emph{cross-sample prediction churn}. The standard parameter-side techniques (deep ensembles, MC dropout, stochastic weight averaging) do not reduce this gap; two data-side methods do. The first is $K$-bootstrap bagging, which cuts the rate $40\text{--}54\%$ on every dataset at no accuracy cost ($K{\times}$-ERM compute). The second is \emph{twin-bootstrap}, our proposal: two networks trained jointly on independent bootstraps with a sym-KL consistency loss between their predictions, which at matched $2{\times}$-ERM compute reduces churn a further median $45\%$ beyond bagging-$K{=}2$. Cross-sample prediction churn deserves a column alongside predictive performance in scientific-ML benchmark reports, because without it the parameter-side and data-side methods are indistinguishable on the metric they actually differ on.

Longitudinal clinical notes contain rich evidence of how patients evolve over time, but converting this signal into training supervision for clinical prediction remains challenging. We extend Foresight Learning to clinical prediction by converting time-ordered MIMIC-III notes into examples consisting of past patient context, a natural-language question about a possible future event, and a label resolved from later documentation. This process yields 6,900 prediction examples from 702 admissions across medications, procedures, organ support, microbiology, and mortality. A small LoRA adapter trained on these examples improves over the prompted base model, reducing expected calibration error from 0.1269 to 0.0398 and Brier score from 0.199 to 0.145, while slightly outperforming GPT-5 point estimates on held-out questions. The approach enables reusable clinical prediction supervision from longitudinal notes without hand-engineered structured features or endpoint-specific classifiers.

By processing electronic health records (EHRs) as natural language sequences, large language models (LLMs) have shown potential in clinical prediction tasks such as mortality prediction and phenotyping. However, longitudinal or highly frequent EHRs often yield excessively long token sequences that result in high computational costs and even reduced performance. Existing solutions either add modules for compression or remove less important tokens, which introduce additional inference latency or risk losing clinical information. To achieve lossless compression of token sequences without additional cost or loss of performance, we propose Medical Token-Pair Encoding (MedTPE), a layered method that extends standard tokenisation for EHR sequences. MedTPE merges frequently co-occurring medical token pairs into composite tokens, providing lossless compression while preserving the computational complexity through a dependency-aware replacement strategy. Only the embeddings of the newly introduced tokens of merely 0.5-1.0% of the LLM's parameters are fine-tuned via self-supervised learning. Experiments on real-world datasets for two clinical scenarios demonstrate that MedTPE reduces input token length by up to 31% and inference latency by 34-63%, while maintaining or even improving both predictive performance and output format compliance across multiple LLMs and four clinical prediction tasks. Furthermore, MedTPE demonstrates robustness across different input context lengths and generalisability to scientific and financial domains and different languages.

Deep neural networks for medical image diagnosis often achieve high predictive accuracy while relying on spurious or clinically irrelevant visual cues, limiting their trustworthiness in practice. Post-hoc explanation methods are widely used to visualize model decisions in the form of saliency maps; however, these explanations do not influence how models learn during training, allowing non-causal or confounding features to persist. This motivates the incorporation of explanation supervision directly into the training objective to guide model attention toward clinically meaningful regions and promote clinically grounded decision-making. This paper presents a systematic approach to integrate explanation loss into model training and analyzes how different explanation loss designs and supervision strengths influence both predictive performance and spatial faithfulness of explanations. To quantitatively assess interpretability, two complementary explanation performance metrics-annotation coverage and saliency precision-are introduced, enabling rigorous evaluation beyond qualitative visualization. Our experimental results reveal a clear trade-off between explanation quality and explanation loss coefficients. Furthermore, quantitative statistical analysis yields consistently improved explanation alignment while maintaining comparable accuracy. Experiments were conducted on annotated chest X-ray datasets; however, the proposed framework is applicable to a broad range of annotated biomedical imaging modalities. Overall, these findings demonstrate that explanation supervision is not a monolithic design choice and provide practical guidance for incorporating explanation loss into training objectives under noisy clinical annotations.

Medicine is rife with high-stakes uncertainty. Doctors routinely make clinical judgments and decisions that juggle many fundamental unknowns, like predictions about what might be causing a patients' symptoms or decisions about what treatment to try next. Despite increasing interest in developing AI systems that aid or even replace doctors in clinical settings, current systems struggle with calibrated reasoning under uncertainty, and are often deeply opaque about their reasoning. We propose a framework for AI systems that can make practically useful but formally transparent clinical predictions under uncertainty. Given a clinical situation, our framework (MedMSA) uses language models to retrieve relevant prior knowledge, but constructs a formal probabilistic model to support calibrated and verifiable inferences under uncertainty. We show how an initial proof-of-concept of this framework can be used for differential diagnosis, producing an uncertainty-weighted list of potential diagnoses that could explain a patients' symptoms, and discuss future applications and directions for applying this framework more generally for safe clinical collaborations.

Post-deployment monitoring of healthcare AI requires statistically valid, label-efficient methods, but gold-standard labels from clinician chart review are expensive. Prediction-powered inference (PPI) and active statistical inference (ASI) reduce label cost by combining a small labeled sample with abundant model predictions, but both are restricted to a single predictor, a poor fit for modern clinical pipelines that have multiple predictors of differing cost and accuracy available at inference time. We propose Active Multiple-Prediction-Powered Inference (AM-PPI), which routes each instance to a cost-appropriate predictor subset, samples gold-standard labels in proportion to the chosen subset's residual uncertainty, and reweights predictions to minimize estimator variance, all under a single deployment-time budget. AM-PPI generalizes ASI to leverage multiple predictors and extends Multiple-PPI from global per-predictor allocation to per-instance adaptive routing. We derive closed-form Karush-Kuhn-Tucker (KKT) conditions for all three decisions and prove, via biconvexity and strong duality, that the resulting fixed point is a global optimum despite the joint problem being non-jointly-convex. We establish asymptotic normality with valid coverage, minimum-variance unbiasedness within the linear-prediction augmented inverse propensity weighted (AIPW) class, and a closed-form criterion identifying when multiple predictors help. On synthetic data and three healthcare monitoring tasks, AM-PPI produces 10 to 40 percent narrower confidence intervals (CIs) than single-predictor ASI in the budget regime where routing matters, and matches the better baseline elsewhere.

In routine care, individuals identified a priori as high-risk are usually tested for conditions more frequently. Protected attributes, such as sex or ethnicity may also determine testing frequency. Such heterogeneous detection rates across a population induce label error. This causes systematic model error for specific groups and biases performance metrics during validation. This paper proposes a method to correct for such bias in prediction models due to differential diagnostic delay. We use a causal inference framework to define our target estimand: an individual's diagnosis probability in a counterfactual scenario where their diagnosis rate matches that of a reference group. We model the longitudinal process as a hidden Markov model, in which confirmatory test results are emissions from a latent progressive disease stage. We validate our approach in simulated data and apply it to a case study of chronic kidney disease prediction using electronic health records. In simulations, our method reduces prediction bias and improves calibration-in-the-large, correcting the Observed:Expected ratio in the underdiagnosed group from 1.34 (standard deviation: 0.09) in a model developed without any correction for underdiagnosis bias to 1.02 (0.09). Violations of assumptions in the simulation affected the estimation of model parameters, but the proposed approach nonetheless remained better calibrated than the standard model. In the clinical case study, we identify diabetes as the main driver of observability, with an odds ratio of 10.36 (95% confidence interval, 9.80 - 11.02) in 6-month urine albumin-creatinine ratio testing rate. Using our approach to predict the counterfactual diagnostic rate in patients without diabetes, we improved the Observed:Expected ratio of a developed clinical prediction model from 1.55 (1.51 - 1.59) to 1.01 (0.98 - 1.04).

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

Automated mental health prediction using textual data has shown promising results with deep learning and large language models. However, deploying these models in high-stakes real-world settings remains challenging, as existing approaches largely rely on semantic representations and often produce overconfident predictions under ambiguous, noisy, or shifted data. Moreover, most methods lack reliable uncertainty estimation, undermining trust in risk-sensitive mental health applications. To address these limitations, we formulate the task as a multi-view learning problem that integrates semantic information from encoder-only models with higher-level reasoning information from decoder-only models, where reasoning-aware representations and uncertainty modeling are obtained in a trustworthy manner. To ensure reliable fusion, we adopt an evidential learning framework based on Subjective Logic to explicitly model uncertainty and introduce an evidential fusion strategy that balances complementary views while discounting unreliable evidence. Benchmarking on three real-world datasets, Dreaddit, SDCNL, and DepSeverity, reports accuracies of 0.835, 0.731, and 0.751, respectively, demonstrating its potential for reliable mental health prediction. Additional experiments on robustness to noise and case studies for interpretability confirm that our proposed framework not only improves predictive performance but also provides trustworthy uncertainty estimates and human-understandable reasoning signals, making it suitable for risk-sensitive applications in mental health assessment.

Real-world clinical data is inherently multimodal, providing complementary evidence that mirrors the practical necessity of jointly assessing multiple related outcomes. Although multi-task learning can improve efficiency by sharing information across outcomes, existing approaches often fail to balance shared representation learning with outcome-specific modeling. Hard parameter sharing can trigger negative transfer when task gradients conflict, while flexible sharing may still entangle shared and task-specific signals. To address this, we propose a multi-task framework built on a unified Transformer for multimodal fusion, augmented with Orthogonal Task Decomposition (OrthTD) to split patient representations into shared and task-specific subspaces and impose a geometric orthogonality constraint to reduce redundancy and isolate task-specific signals. We evaluated OrthTD on a real-world cohort of 12,430 surgical patients for predicting four outcomes. OrthTD achieved average AUC (area under the receiver operating characteristic curve) of 87.5% and average AUPRC (area under the precision-recall curve) of 37.2%, consistently outperformed advanced tabular and multi-task methods. Notably, OrthTD achieves substantial gains in AUPRC, indicating superior performance in identifying rare events within imbalanced clinical data. These results suggest that enforcing non-redundant shared and task-specific representations can improve multi-outcome prediction from multimodal clinical data.

Drug-induced liver injury (DILI) remains a leading cause of late-stage clinical trial attrition. However, existing computational predictors primarily rely on binary classification, a framing that limits generalization and yields no mechanistic insight to guide translational decisions. We argue that DILI prediction is better posed as an explainable hypothesis-generation problem. To support this shift, we introduce the DILER Benchmark, a dataset that extends beyond binary labels by augmenting a curated set of molecules with mechanistic hepatotoxicity hypotheses derived from biomedical literature. We further present HADES, an agentic system designed to generate transparent and auditable reasoning traces. By combining molecular-level predictions, metabolite decomposition, structural understanding, and toxicity pathway evidence, HADES mechanistically assesses DILI risk. Evaluated on the DILER Benchmark, HADES outperforms existing models in binary classification, achieving a ROC-AUC of 0.68 on the Test Set and 0.59 on the challenging Post-2021 Set, compared with 0.63 and 0.50 for DILI-Predictor, respectively. More importantly, we establish a baseline for mechanistic hypothesis generation, where HADES achieves a Hypothesis Alignment Fuzzy Jaccard Index of 0.16. This result underscores the inherent complexity of the task while highlighting the need for advanced explainable approaches in predictive toxicology.

Risk scores are an interpretable and actionable class of machine learning models with applications in medicine, insurance, and risk management. Unlike most computational methods, risk scores are designed to be computed by a human by attributing points to a data sample based on a limited set of criteria. The most common approaches for generating risk scores use linear regressions to estimate the effect of selected variables. We propose a simple and effective approach towards building compact and predictive risk scores. We provide an algorithm based on gradient boosting that is capable of modeling nonlinear effects, along with a C++ implementation with Python and R bindings. Through extensive empirical evaluation on twelve tabular datasets spanning regression, classification, and time-to-event tasks, we show that our method achieves competitive predictive performance while producing substantially more compact scores than regression-based alternatives, with 60% fewer rules for classification tasks and 16% fewer rules for time-to-event tasks on average, compared to AutoScore.

Accurate prediction of physician referral links is essential for optimizing care coordination and reducing fragmentation in healthcare delivery. However, existing computational methods, ranging from triadic closure heuristics to graph neural networks, fail to capture the intrinsic properties of physician referral networks, including sparsity, disassortative degree mixing, and hub-dominated topology. Here, we propose H3, a healthcare three-hop index that addresses these limitations by modeling indirect referral pathways through intermediate physicians, with degree-based normalization and a redundancy penalty to mitigate hub-mediated noise. Using Medicare Physician Shared Patient Patterns data, we evaluate H3 under two complementary prediction regimes: within-period prediction, which assesses recovery of contemporaneous referral links under sparse conditions, and cross-period prediction, which tests robustness to temporal shift as referral windows expand. Across both regimes, H3 consistently outperforms classical heuristics and deep learning-based baselines. Unlike black-box neural network approaches, H3 produces fully decomposable predictions traceable to specific intermediary physicians, offering a transparent and deployable solution for referral network completion.

Deep learning models for drug--target interaction (DTI) prediction often achieve strong benchmark performance without necessarily relying on mechanistically meaningful molecular features, a limitation that standard accuracy-based evaluation cannot detect. We introduce ISAAC (Intervention-based Structural Auditing Approach for Causal Reasoning), a post-hoc framework that evaluates prior-relative structural sensitivity by probing frozen models through matched mechanistic and spurious input-level interventions, independently of predictive accuracy. Applied to three sequence-based DTI architectures on the Davis benchmark, ISAAC reveals approximately 25% relative differences in reasoning scores across models with comparable AUROC (within around 3%), stable across training and intervention seeds and two distinct perturbation operators. These discrepancies, undetectable under conventional accuracy metrics, motivate the use of post-hoc structural auditing as a complement to standard performance evaluation in scientific machine learning for molecular modeling.

Predicting future clinical outcomes from electronic health records (EHR) remains challenging due to the complexity and heterogeneity of patient data. LLMs have shown strong potential for such predictive tasks, yet existing approaches mainly focus on enhancing medical knowledge through distillation or RAG while relying on the model's internal ability to interpret contextual information. In this work, we present ReMedi (Reasoner for Medical Clinical Prediction), a framework for improving clinical outcome prediction from EHR. ReMedi generates rationale-answer pairs using a challenging sample regeneration mechanism for complex clinical questions, which leverages ground-truth answers as hints to enhance reasoning for further fine-tuning and preference tuning. ReMedi integrates ground-truth outcome guidance into the preference data construction loop, regenerating rationale-answer variants. By tuning on these rationale-answer pairs, the model improves its predictive performance. Experiments on multiple EHR prediction tasks demonstrate substantial gains of up to 19.9 percent over state-of-the-art baselines in terms of F1 score, underscoring ReMedi's effectiveness in real-world clinical prediction.

Predicting complex human traits from genetic data is challenging because different genetic, clinical, and molecular data sources often contain different parts of the signal. Here, we present EFGPP, a reproducible framework for generating, ranking, and combining multiple types of data for genotype-to-phenotype prediction. We applied EFGPP to migraine prediction using UK Biobank data from 733 individuals. The framework combined genotype-derived features, principal components, clinical and metabolomic covariates, and polygenic risk scores generated from migraine and depression GWAS using PLINK, PRSice-2, AnnoPred, and LDAK-GWAS. The best single data type achieved a test AUC of 0.644, while combining multiple data types improved performance to 0.688 using migraine-focused inputs and 0.663 using cross-trait depression-derived inputs. Genetic features alone did not outperform the covariates-only baseline, but genotype-derived features performed better than PRS alone, and depression-derived PRS showed useful predictive signal. Overall, EFGPP provides a practical proof-of-concept framework for prioritising and integrating heterogeneous genetic data sources for complex phenotype prediction.

The rapid growth of molecular foundation models and large language models (LLMs) has encouraged a scale centred view of AI in drug discovery, in which larger pretrained models are expected to supersede compact cheminformatics models. We test this assumption across 26 ADME, toxicity and bioactivity endpoints, covering 165,541 endpoint level compound label records. The benchmark contains 78 endpoint and split entries evaluated under random, Murcko scaffold and structure separated 5-fold cross validation protocols, representing increasing chemical generalization difficulty. Across 156 task and metric comparisons, classical machine learning (ML) provides the largest share of best performing entries (47.4%), followed by pretrained molecular sequence models (28.8%), graph neural networks (21.8%) and LLM based SAR baselines (1.9%). Classical ML dominates random split interpolation and remains the largest winner family overall. GNN and sequence models are competitive in selected harder splits, but their strict winner shares decrease under a fixed final-window readout, indicating sensitivity to training settings and model selection. Paired bootstrap analyses show that small numerical differences between individual models should not be read as decisive victories. SAR knowledge from training folds improves GPT5.5-SAR and Opus4.7-SAR metrics but does not make rule based reasoning a universal substitute for supervised predictors. Compact specialized models remain highly effective, and predictive performance depends on the fit among model, task and validation scenario, not on scale alone.

Skull-base meningiomas are often characterized by favorable long-term prognosis, yet their anatomical complexity and proximity to critical neurovascular structures make treatment selection challenging. Stereotactic radiosurgery with CyberKnife represents an effective therapeutic option when surgical resection is not feasible; however, not all patients benefit equally from this treatment. Early identification of patients likely to respond to radiosurgery remains an open clinical problem. In this study, we propose a radiomics- and clinical feature-driven framework for predicting volumetric response in skull-base meningiomas treated with CyberKnife. Unlike most existing approaches that focus on progression-free survival or recurrence, our method targets volumetric response as an indicator of treatment efficacy. Pre-treatment MRI images from 104 patients were processed to extract radiomic features, which were combined with clinical variables and analyzed using six models. To ensure methodological rigor, the entire modeling process was implemented within a nested cross-validation scheme. Among the evaluated models, TabPFN achieved the best overall performance, with an AUC of 0.81 and consistently favorable classification metrics. These results suggest that advanced machine learning architectures, when combined with robust validation strategies, can effectively capture patterns associated with treatment response even in small-sample, high-dimensional settings.

We instruct an AI agent to construct two separate agentic AI platforms: one for autonomous training of predictive ML models for human-human and virus-human PPI, and the other for inducing explicit general rules governing human-human and virus-human PPI. The first agentic AI platform for autonomous training of predictive ML models for PPI is designed to consist of five AI agents that handle autonomous data collection, data verification, feature embedding, model design, and training and validation on three-way protein-disjoint cross-fold datasets. For human-human and human-virus PPIs, the final three-way protein-disjoint ensemble achieves an accuracy of 87.3% and 86.5%, respectively. For cross-checking and interpretability purposes, the second agentic AI platform is designed to replace ML predictions with human-readable rules derived from protein embeddings, physicochemical autocovariance descriptors, compartment annotations, pathway-domain overlap, and graph contexts. For human-human PPI, it is defined by a two-rule induction, whereas human-virus is induced by a more complex set of weighted rules. The rules induced by the second agentic platform align with the SHAP-identified features from the predictive ML models built by the first agentic platform. Taken together, our work demonstrates the agentic AI's ability to orchestrate from data planning to execution, and from rule induction to explanation in ML, opening the door to various applications.

Purpose: Gaze-following, the task of inferring where individuals are looking, has been widely studied in computer vision, advancing research in visual attention modeling, social scene understanding, and human-robot interaction. However, gaze-following has never been explored in the operating room (OR), a complex, high-stakes environment where visual attention plays an important role in surgical workflow analysis. In this work, we introduce the concept of gaze-following to the surgical domain, and demonstrate its great potential for understanding clinical roles, surgical phases, and team communications in the OR. Methods: We extend the 4D-OR dataset with gaze-following annotations, and extend the Team-OR dataset with gaze-following and a new team communication activity annotations. Then, we propose novel approaches to address clinical role prediction, surgical phase recognition, and team communication detection using a gaze-following model. For role and phase recognition, we propose a gaze heatmap-based approach that uses gaze predictions solely; for team communication detection, we train a spatial-temporal model in a self-supervised way that encodes gaze-based clip features, and then feed the features into a temporal activity detection model. Results: Experimental results on the 4D-OR and Team-OR datasets demonstrate that our approach achieves state-of-the-art performance on all downstream tasks. Quantitatively, our approach obtains F1 scores of 0.92 for clinical role prediction and 0.95 for surgical phase recognition. Furthermore, it significantly outperforms existing baselines in team communication detection, improving previous best performances by over 30%. Conclusion: We introduce gaze-following in the OR as a novel research direction in surgical data science, highlighting its great potential to advance surgical workflow analysis in computer-assisted interventions.