Cardiometabolic Risk

Prospective stroke risk stratification in primary care is challenging because early risk signals are distributed across routine biomarkers and unstructured clinical narratives. We propose MedGate-Fusion, a multi-modal gated architecture that integrates transformer-based embeddings of first-encounter narratives with ten routinely recorded risk markers. We used electronic medical record data from the Canadian Primary Care Sentinel Surveillance Network (CPCSSN). Starting from 808,921 encounter-level observations, we constructed a first-encounter cohort and retained 102,736 unique patient records with non-empty narratives and sufficient data to evaluate a five-year stroke outcome. To reduce explicit target leakage from diagnostic mentions in notes, we applied dictionary-based redaction of stroke-related terms prior to semantic encoding.

Cardiovascular disease (CVD) remains the leading cause of death among women, yet cardiovascular risk assessment often relies on clinical variables that may be missing, outdated, or unavailable in routine care. Screening mammography offers an opportunity for opportunistic cardiovascular risk stratification because it is routinely acquired and contains vascular features, including breast arterial calcifications (BAC), that are associated with cardiovascular risk and events. We evaluate whether mammography specific foundation models, originally pretrained for breast cancer-related tasks, can transfer to cardiovascular risk prediction without cardiovascular specific supervision or explicit BAC annotation. We constructed a 5-year major adverse cardiovascular event (MACE) cohort of 22,497 women linked to electronic health record outcomes, including 500 events (2.22% prevalence). The foundation models achieved AUROCs of 0.823 and 0.822 substantially exceeding an age-only model (AUROC 0.765), despite using only the screening mammogram as input, with no clinical variables. Both foundation models evaluated assigned substantially higher predicted risk to patients with radiologist-documented BAC, despite BAC never being used as a training label, and showed activation patterns consistent with vascular findings. Together, these findings suggest that mammography foundation models can recover clinically relevant cardiovascular risk information directly from mammographic pixels and suggest that screening mammography may provide an opportunistic source of cardiovascular risk information to complement conventional clinical assessment without additional imaging. Code is available in https://github.com/PauFeld/MammoCVD

As the population ages, the number of patients with cardiovascular diseases continues to increase, highlighting the need for early detection before progression to severe and irreversible functional decline. Consequently, estimating cardiovascular biomarkers from non-invasive biosignals, such as photoplethysmography (PPG) and arterial pressure wave (APW) signals, has attracted increasing attention. These signals can be measured using wearable and cuff-type devices. Previous studies have used PPG and APW signals to estimate cardiovascular biomarkers. However, these signals exhibit strong similarities in both the temporal and frequency domains and primarily reflect peripheral and arterial pulse waveforms. Therefore, they may provide limited information about cardiac mechanical function. In contrast, the quantitative impact of additional biosignals, such as ballistocardiography (BCG), which reflect the body's minute mechanical responses to cardiac ejection, remains unclear. In this study, we generated synthetic PPG, APW, and BCG signals from a unified whole-body cardiovascular circulation model and evaluated the complementary contribution of BCG to probabilistic cardiovascular biomarker estimation. We estimated posterior distributions of cardiovascular biomarkers using neural posterior estimation and simulation-based inference. The results showed that adding BCG signals significantly improved estimation performance. Furthermore, even in ill-posed cases where PPG and APW alone produced multimodal posterior distributions, adding BCG yielded unimodal posterior distributions. These findings provide fundamental insights into signal selection for estimating cardiovascular dynamics.

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.

Cardiovascular screening models trained on national health surveys routinely report areas under the receiver operating characteristic curve (AUROC) near 0.89. We asked whether that accuracy reflects learning or target leakage, whether tabular foundation models change the answer, and whether the properties deployment requires survive joint examination. We benchmarked ten classifiers spanning linear, tree-ensemble, neural, glass-box, and tabular foundation classes for prevalent myocardial infarction in 442,067 respondents of the 2022 Behavioral Risk Factor Surveillance System across five feature tiers of decreasing leakage risk. Each was audited for discrimination, calibration, fairness at an explicit screening threshold, conformal coverage, explanation faithfulness, and inference cost, then applied -- models and thresholds frozen -- to 430,755 respondents of 2023. Removing two post-diagnostic features cost every model 0.049-0.051 AUROC, collapsing the field into a 0.0045-wide band. The glass-box explainable boosting machine was non-inferior to every alternative within a pre-specified 0.005 margin while scoring the cohort roughly 104 times faster than the strongest foundation model. One threshold detected 75.4% of women's infarctions against 89.0% of men's; editing the model's shape functions reduced the gap to 0.010. Marginal conformal prediction gave 0.86 coverage to men and 0.82 to adults over 60; Mondrian calibration repaired every stratum. Frozen models transported within 0.002 AUROC. Reported headroom in this literature is a property of the feature set, not the learner. Transparency cost nothing measurable and made fairness repair and uncertainty conditioning directly auditable. Evaluation practice, not model capacity, is the binding constraint.

Normative age models are trained to predict chronological age in a nominally healthy cohort. Applied to patients, they deviate, and the gap between predicted and chronological age is read as disease risk. Here, we attribute the disease-related effect size of the age gap directly to individual training samples, rather than using a prediction-level loss as the attribution target. For Cohen's $d$, the resulting closed-form influence functional, validated against leave-one-out retraining, ranks training samples by their effect on held-out case-control separation. Across four diseases and two biomarker modalities in UK Biobank, removing the 10% most influential training samples raises held-out disease-related effect size in every seed. It more than doubles the metabolomic-age effect for type-2 diabetes and raises the brain-age effect for multiple sclerosis by roughly a third. Random removal leaves effect size flat even at 50% removal, confirming the gain comes from which samples are removed, not how many. Flagged subjects carry subclinical cardiometabolic burden that diagnosis-based exclusion misses, on markers the model never sees. For type-2 diabetes, where the method gains most, the marker recovered is HbA1c, the standard measure of blood sugar control. We release pyinfluence, our influence-function package, for reproducibility and reuse.

Continuous hemodynamic monitoring guides treatment decisions in surgery and intensive care. However, gold-standard signals are only measured in severe cases due to risks associated with invasive measurement. In this work, we introduce HIPNO (Hemodynamic Inference via Physics-informed Neural Operators) to recover hemodynamic state from ubiquitous, non-invasive signals and expand access to advanced monitoring. HIPNO addresses a problem of scale symmetry in physics-informed hemodynamic inference, where different combinations of flow, resistance, and compliance can generate the same observed pressure. We identify the symmetry group of the observation model and parameterize the network in its quotient space. For the 3-element Windkessel model, the quotient coordinates are the compliance-normalized flow $U=Q/C$, the decay time constant $τ_{WK}=R_2 C$, and the characteristic-impedance coordinate $κ=R_1 C$. Across 945499 intraoperative windows from 2562 patients, HIPNO predicts $τ_{wave}$, a proxy for vascular decay derived from pressure, with 32% lower error on the log scale than a population baseline while preserving mean arterial pressure accuracy. Because vascular decay and flow drive occupy separate coordinates, counterfactual perturbations produce the expected directional responses in at least 90% of windows in almost all prespecified scenarios, a separation unavailable to pressure-only baselines. The coordinates are also used as inputs to a calibration model for monitored cardiac output. Finally, the formulation identifies the external compliance or flow reference required to recover absolute physical scale.

Fractional flow reserve derived from CT angiography (FFR-CT) simulates flow through a patient-specific vessel model, so its accuracy depends on the connectedness of the segmented tree, not only on volumetric overlap: a segmentation can reach high Dice yet sever a bifurcation, dropping the downstream subtree and reversing the treatment decision. Topology-aware losses such as clDice and Skeleton Recall act on the global centreline and can miss localised breaks. We study the Bifurcation Connectedness Score (BCS), which scores connectedness at each ground-truth bifurcation, and soft-BCS, its differentiable training surrogate. BCS captures a property of segmentation quality the standard metrics miss: it responds strongly to breaks in connectedness while staying largely unchanged under connectedness-preserving narrowing. Higher BCS accompanies closer agreement between the FFR-CT decisions a solver makes on predicted versus ground-truth geometry, most clearly in severe disease (OR 2.16, CI [1.23, 4.18]). Both decisions come from the same solver, so this reflects geometric, not clinical, fidelity. In training, soft-BCS and Skeleton Recall recover the same branches but build different trees. Recovering branches and keeping them connected are separable properties, so we recommend reporting a measure of each.

Traditional randomized trials often obscure clinically meaningful heterogeneity in treatment response by focusing on average effects. Leveraging real-world data to emulate clinical trials and estimate heterogeneous treatment effects (HTEs) offers a promising path toward more precise and efficient trial design. In this study, we emulate the DAPA-HF trial using electronic health records from the Mayo Clinic Cloud (MCC) to investigate whether HTE-guided stratification can identify patient subgroups with distinct treatment responses to dapagliflozin versus placebo in patients with heart failure with reduced ejection fraction. All-cause mortality was evaluated using Cox proportional hazards models, with HTEs estimated using a Meta-S learner and subgroups defined using a decision tree-based thresholding approach. In the overall cohort of the emulation, no significant treatment difference was observed (HR, 1.681; 95% CI, 0.828-3.413; p = 0.1507). However, compared with the overall emulated cohort, in which dapagliflozin showed no statistically significant survival benefit, HTE-driven stratification identified subgroups with significant and directionally distinct treatment effects. The beneficial (low-HTE) subgroup showed a significant survival benefit from dapagliflozin (HR = 0.203, 95% CI, 0.087-0.476, p = 0.0002), whereas the harmful (high-HTE) subgroup showed a significant harmful association with markedly increased mortality risk (HR = 6.680, 95% CI, 2.759-16.171, p < 0.0001). These findings indicate that HTE-guided stratification can uncover clinically meaningful beneficial and harmful treatment-effect patterns that are masked in the full-cohort emulation.

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.

Cardiovascular disease risk prediction models often rely on data from a single institution or centrally pooled datasets. Extending these models across institutions could be limited by privacy regulations and constraints on sharing patient-level data. Federated learning enables collaborative model development without transferring sensitive patient data, but its application in healthcare remains challenging because datasets often differ in size, population characteristics, and outcome definitions. In this study, we present a federated deep learning approach for privacy-preserving cardiovascular disease risk prediction that integrates two population-based cohorts with different characteristics: Lifelines, including 148,230 participants meeting the study inclusion criteria with self-reported outcomes, and the Rotterdam Study, including a smaller cohort of 10,155 participants with digitally linked clinical outcomes. Model performance was primarily evaluated on the Rotterdam Study because of its complete follow-up. Deep survival models trained using federated learning achieved higher predictive performance than models trained locally without federation. For the Rotterdam Study, the C-statistic increased from 0.728 (95% CI: 0.717-0.739) to 0.739 (95% CI: 0.728-0.749). For Lifelines, the C-statistic increased from 0.783 (95% CI: 0.775-0.791) to 0.787 (95% CI: 0.780-0.792). These findings suggest that federated deep learning across heterogeneous cohorts can improve cardiovascular disease risk prediction while preserving the privacy of individual-level patient data.

Structured tabular data dominates clinical medicine, yet existing benchmarks fail to reflect real-world properties like complex survey sampling, demographic oversampling, and subgroup fairness. We introduce the NHANES Accelerometry Cardiometabolic Benchmark, derived from NHANES 2003-2006, comprising 1,381 adults with hip-worn accelerometry, fasting laboratory biomarkers, dietary intake, and anthropometrics. We evaluate three tabular learning methods -- ridge regression, XGBoost, and the foundation model TabPFN v2 -- to predict glycated haemoglobin (HbA1c), fasting triglycerides, and C-reactive protein (CRP) from activity phenotypes and lifestyle covariates. TabPFN v2 achieves the best overall performance (HbA1c R^2=0.156, CRP R^2=0.383), while triglycerides remain largely unpredictable (R^2 < 0.05), consistent with known genetic dominance. We apply split conformal prediction to generate distribution-free 90% prediction intervals and evaluate demographic coverage equity across sex and race/ethnicity subgroups. Marginal coverage aligns with the 90% target for CRP and HbA1c but falls below for triglycerides. At the subgroup level, we observe localized undercoverage (e.g., HbA1c for Mexican American participants), illustrating the gap between marginal guarantees and the conditional coverage required for clinical fairness. Code and data are at https://github.com/felizzi/nhanes-accel-cardiometabolic-benchmark.

Identifying robust associations between cardiac imaging phenotypes and clinical diseases is fundamental to population-scale cardiovascular research and reliable risk stratification. However, current phenome-wide association studies rely on pre-defined, single-variable phenotypes or expert-crafted features, which limits their ability to capture clinically meaningful non-linear effects and cross-phenotype interactions. To address this, we propose CPAgents, an iterative phenotype-Composition framework for cardiovascular Phenome-wide association study (PheWAS) that automatically constructs and validates interpretable composite phenotypes (e.g., polynomial, ratio, and interaction forms) from base imaging features. Specifically, our system coordinates three agents: (i) an Analyst that identifies statistical pathologies and nominates candidate transformations; (ii) a Proposer that generates constrained, medically and statistically motivated expressions under numerical safety rules; and (iii) a Verifier that evaluates candidates using multi-stage criteria and produces transparent evidence trails for accepted phenotypes. Evaluated on a population-scale cardiac imaging cohort, the discovered composite phenotypes markedly improve disease discrimination: across 72 classifier-disease-metric combinations, our variants achieve the top rank in 56 cases versus 18 for baselines, with gains observed across all nine clinical disease categories. Our framework yields compact, clinically interpretable phenotype formulas with transparent evidence trails, enabling scalable discovery of stronger phenotype-disease associations beyond expert-driven feature selection.

Risk stratification for pulmonary embolism (PE) is critical for clinical decision-making. Stratification guidelines are based on patient medical records, parameters measured from computed tomography pulmonary angiography (CTPA), and blood tests. However, blood tests are often missing in routine practice. This work studies whether state-of-the-art models can accurately classify risk stratification from only medical records and biomarkers extracted from CTPA images. We benchmark different approaches to combine medical records and cardiac biomarkers with rich pulmonary vascular information; we add vascular biomarkers to tabular models and apply graph neural networks (GNNs) on the vascular tree's intrinsic graph representation. We use a private dataset (n=353) with uniquely complete data for PE risk stratification. Our results show that, among global features, medical records and cardiac biomarkers are the most significant predictors, while vascular biomarkers do not further improve stratification. Even more surprising, even GNNs on vascular graphs fail to outperform strong tabular baseline on global features. We consider hypotheses, on both models and data, that could explain this suboptimal performance. Our investigation suggests that, counter-intuitively, vascular graphs might hold no discriminative information for PE risk stratification. Code is available from https://github.com/creatis-myriad/GENESIS.

Breast arterial calcification (BAC) on screening mammograms is an emerging cardiovascular risk biomarker, but quantitative use requires reproducible segmentation and expert pixel-level labels are costly. We present BAC-JEPA, a label-efficient segmentation framework trained on procedurally generated arterial calcification inserted into real mammographic backgrounds with exact masks. Candidate backgrounds were selected from model-screened mammograms with low predicted BAC response; the generator samples arterial structure, disease burden, radiographic appearance, and hard-negative distractors including nonarterial calcifications and metallic objects. Synthetic masks are paired with mammography self-supervised Vision Transformer encoders and a high-resolution convolutional decoder to produce full-resolution segmentation maps. The study used 75,472 mammography studies from 34,956 patients for background selection and representation learning, trained on synthetic images from 10,000 backgrounds, selected checkpoints with 1,000 development backgrounds, and evaluated transfer on all 1,000 human-labeled BacSeg synthetic 2D mammograms. On held-out synthetic validation data, the larger backbone achieved IoU 0.5325 and Dice 0.6357. On BacSeg, image-level classification from segmentation probability maps reached AUROC 0.8719, with 0.8547 for the smaller backbone. Four-view inference required 110.68--213.63 ms on an RTX 5090 GPU, and severe-preset synthetic image generation averaged 2.7071 s per image on a multicore workstation. These results indicate that BAC-specific synthetic supervision can produce useful image-level transfer without human pixel-level training masks, while expert-reviewed real-mammogram segmentation remains necessary for clinical validation and calibration.

The cardiovascular system evolves along a bounded trajectory in physiological state space that converges to a compact geometric object: the cardiac attractor. A wearable photoplethysmograph (PPG) or electrocardiograph (ECG) observes a one-dimensional projection of this attractor; by Takens' embedding theorem, delay coordinates reconstruct its full geometry. Three decades of nonlinear cardiac dynamics have extracted Lyapunov exponents, recurrence statistics, and sample entropy from reconstructed attractors, yet no principled account exists of which attractor properties capture which cardiovascular quantities, or why, leaving feature selection as a search problem and negative results uninterpretable. We introduce Attractor Domain Theory (ADT), which proves that the reconstructed attractor's information partitions into three mutually non-redundant domains: the Geometry Domain G (delay embedding; native capability: artifact rejection), the Ergodic Domain S (asymptotic statistical invariants; native capability: stability estimation), and the Variational Domain V (finite-time Lyapunov exponent field; native capability: hemodynamic inference). We prove a Domain Sufficiency Theorem (the Parseval analog for attractor information) and establish that three domains are necessary and sufficient. Geometry Domain validation via the SCSI framework across 176,742 PPG segments from four datasets yields AUC = 0.757 [0.686-0.828] and NPV = 0.966 after correcting three systematic evaluation artifacts (+0.179 net inflation). Ablation confirms C_NL as the dominant Geometry Domain component (Delta AUC = -0.413) and intra-domain redundancy across five components.

Background. Atrial fibrillation (AF) is the most prevalent cardiac arrhythmia and a major determinant of prognosis. Established AF risk scores rely on factors (older age, hypertension) nearly ubiquitous among patients with cardiovascular disease (CVD), offering limited stratification in this high-risk group. Most target long-term (5-10 year) rather than medium-term prediction. We developed interpretable ML models predicting AF risk over a 24-month and entire follow-up horizon in CVD patients using routinely collected hospital data. Methods. Single-center retrospective study of electronic health records from the National Research Cardiology Center (Russia) for patients aged >=18 with CVD but without pre-existing AF, hospitalized more than once between January 2012 and May 2019. A custom NLP pipeline transformed unstructured discharge reports into 73 structured features, combining a rule-based parser with transformer-based NER. Using LightAutoML we built a full model (73 features), a simple model (reduced subset), and a linear model for a bedside risk score. Performance was assessed by ROC AUC, compared with CHARGE-AF, C2HEST, MHS, and HAVOC, and interpreted via SHAP. Results. Of 80,576 records from 45,000 patients, 17,562 met inclusion criteria; 1,438 (8.19%) developed AF. The full model reached ROC AUC 0.735 (24-month) and 0.696 (entire follow-up); the simple model was nearly identical (0.725, 0.696). All non-linear models outperformed the four clinical risk scores (ROC AUC 0.53-0.64). The simple model uses 13 features and is named Pre-AF 13. SHAP identified age and left atrial volume as dominant predictors. A linear risk score (Pre-AF 9) stratified observed 24-month AF incidence from ~7% to 36%. Conclusion. Interpretable ML models built from routinely collected EHR data identify high-AF-risk CVD patients, outperforming established clinical risk scores.

Non-alcoholic fatty liver disease (NAFLD) affects roughly 25% of global adults, posing substantial hepatic and cardiovascular risks. Yet, population-level screening tools remain inadequate. We present Method, a machine-learning framework for NAFLD risk prediction coupling gradient-boosted decision trees with conformal prediction to yield calibrated, distribution-free coverage guarantees on individual risk estimates. It integrates a mutual-information-based stability selection procedure to identify a compact, clinically interpretable feature subset via bootstrap resampling, constructing prediction sets whose marginal coverage provably exceeds a user-specified confidence level. We evaluated Method on a multicenter cohort from Guangzhou, China (primary n=2,187; external validation n=412) using 78 candidate features across demographics, metabolic biomarkers, and lifestyle factors. Method achieves an AUROC of 0.912 internally and 0.891 externally, outperforming deep neural networks, TabNet, support vector machines, and logistic regression. Conformal prediction sets achieve 91.3% empirical coverage at the 90% nominal level. A three-tier risk stratification derived from these scores separates the population into distinct groups, with the high-risk subgroup showing a 12-month progression rate 4.7 times that of the low-risk tier. The selected features -- notably waist circumference, ALT, GGT, triglycerides, fasting glucose, and BMI -- align with established metabolic risk factors, providing biological plausibility.

Non-contrast computed tomography calcium scoring (CTCS) is a cost-effective imaging modality widely used to detect coronary artery calcifications. This study aimed to develop an advanced machine learning framework that utilizes quantitative analyses of coronary calcium and epicardial fat from CTCS images to predict obstructive coronary artery disease (CAD). The study population consisted of 1,324 patients from the SCOT-HEART clinical trial who underwent both CTCS and coronary CT angiography. We extracted and analyzed a broad range of features, including 24 clinical variables, 189 calcium-omics, and 211 epicardial fat-omics features from the CTCS images. Feature selection was conducted using the CatBoost algorithm combined with SHapley Additive exPlanation (SHAP) values. Predictive modeling utilized the CatBoost gradient boosting method, focusing on the most informative features. From an initial set of 424 candidate features, 14 were identified as most predictive through the CatBoost-SHAP method. The top two predictive features originated from fat-omics, with the remaining 12 features derived from calcium-omics. The optimized model achieved robust predictive capabilities, demonstrating a sensitivity of 83.1+/-4.6%, specificity of 93.8+/-1.7%, accuracy of 85.3+/-2.0%, and an F1 score of 73.9+/-3.3%. Inclusion of calcium-omics and fat-omics data significantly improved predictive performance. Notably, the model also showed reliable predictive accuracy in patients with diverse coronary calcium scores, including cases with obstructive CAD despite a zero-calcium score. This innovative approach holds promise for improving clinical decision-making and potentially reducing dependence on contrast-enhanced or invasive diagnostic procedures, particularly within low-to intermediate-risk patient groups.

Non-contrast computed tomography calcium scoring (CTCS) is widely recognized as an effective tool for cardiovascular risk stratification. This study aimed to develop a novel machine learning framework for predicting myocardial ischemia from routine non-contrast CTCS scans using quantitative coronary calcium assessment. This study analyzed 1,375 patients who underwent both non-contrast CTCS and regadenoson stress cardiac positron emission tomography myocardial perfusion imaging within one year at University Hospitals Cleveland Medical Center. A total of 74 variables, including clinical variables, Agatston score, and calcium-omics features, were evaluated. Relevant features were identified using XGBoost with Shapley Additive exPlanations (SHAP). Predictive models were trained and evaluated using 5-fold cross-validation. Among 987 patients, 89 (9%) were positive for myocardial ischemia. The final model incorporated the Agatston score, eight calcium-omics features, and age. The proposed model achieved a precision of 98.9+/-3.0%, sensitivity of 79.2+/-8.4, and F1 score of 87.7+/-5.3%. The addition of calcium-omics features significantly improved predictive performance compared with models using clinical variables alone or clinical variables with the Agatston score (p<0.05). Interestingly, the number of calcified arteries, despite being the lowest-ranked feature based on SHAP analysis, showed the strongest association with myocardial ischemia in logistic regression analysis (odds ratio: 3.63, 95% confidence interval: 2.80-4.77, p<0.00001). We developed a machine learning approach for predicting myocardial ischemia using routinely acquired non-contrast CTCS scans. Calcium-omics features provided incremental predictive value beyond conventional risk factors and Agatston scoring and may support more accessible cardiovascular risk stratification.

Physical activity (PA) plays an important role in maintaining and improving health. Daily steps have been a key PA measure that is easily accessible with common wearable devices. However, methods are lacking to recommend a personalized optimal distribution of daily steps over a period of time for the best of certain health biomarkers. In this paper, we fill this void based on the data from the All of Us Research Program which includes months of step counts as well as repeated measurements of key health biomarkers. We develop a new offline reinforcement learning (RL) algorithm to learn personalized and optimal PA distributions associated with cardiometabolic risk, where the action is a function representing the daily step distribution over a period of time. Simulation studies demonstrate the advantage of the proposed approach over existing continuous-action RL methods. The learned optimal policy from the All of Us data generally suggests people take more daily steps and also follow a more consistent pattern of PA over time while offering tailored recommendations for subgroups in blood glucose level, body mass index, blood pressure, age, and sex.

Defining vascular age in terms of physiological function has become one focal point of the extensive studies to categorize and track chronological age. Transcranial Doppler (TCD) is a method by which cerebral blood flow velocity is measured along the major arteries feeding the human brain. This study aims to use features extracted from TCD to estimate chronological age and assess accelerated aging in subjects with various brain diseases. We predict subjects with various brain diseases to present with accelerated cerebrovascular aging when tested on various regression models trained by healthy subjects. 168 healthy subjects and 277 diseased subjects with bilateral TCD recordings of the middle cerebral artery were analyzed using the Morphological Analysis and Clustering of Intracranial Pressure (MOCAIP) algorithm. MOCAIP-generated features and heart rate variability features were used as input features for regression models to predict the brain vascular age. 66 subjects with acute stroke, 27 subjects with post stroke, 26 subjects with Alzheimer's disease, 23 subjects with mild cognitive impairment, and 135 established subjects were tested against the machine learning model to assess for accelerated cerebrovascular age. The trained model, on average, predicted healthy subjects' cerebrovascular age to be 3.69 years above their chronological age. Subjects with different disease conditions exhibited varying levels of age acceleration. The differences in healthy and diseased subjects' performances suggest that features generated using TCD may be relevant when evaluating accelerated cerebrovascular aging. Moreover, imbalanced datasets have been observed to affect the performance of machine-learning-based brain age prediction models.

Hospital readmission within 30 days of discharge is a leading driver of morbidity, mortality, and avoidable healthcare expenditure in congestive heart failure (CHF). Current clinical risk stratification tools rely primarily on non-imaging data and exhibit limited predictive performance. Point-of-care lung ultrasound (LUS) offers a sensitive, noninvasive window into the pulmonary congestion that characterizes CHF decompensation, yet its prognostic utility for readmission prediction remains largely unexplored. We present a pilot feasibility study, the first systematic machine learning study using B-mode LUS acquired during hospitalization to predict 30-day CHF readmission. Quantitative spatiotemporal embeddings are extracted from a pretrained Temporal Shift Module (TSM) ResNet-18 encoder, and interpretable biomarker features are separately evaluated. Through structured ablations over lung view, temporal representation, multi-view fusion, and cross-lung augmentation, we identify the key imaging factors driving readmission risk. Our findings reveal that (1) dependent lower-lung regions (Left-3, Right-3) carry the strongest prognostic signal, consistent with their greater susceptibility to hydrostatic congestion; (2) temporal difference features between sequential examinations substantially outperform single-timepoint representations, highlighting the importance of capturing disease trajectory; and (3) multi-view feature concatenation yields the best overall performance, with our top MLP model achieving an F1 score of 0.80 (95% CI: 0.62-0.96). Biomarker analysis further reveals that pleural-line abnormalities, including breaks and indentations, are as informative as the canonical A-line and B-line markers. These results support POCUS-derived biomarkers as practical, interpretable tools for noninvasive CHF risk stratification.

Carotid atherosclerosis is a major contributor to ischemic stroke and transient ischemic attack. Conventional ultrasound assessment is commonly based on intima-media thickness, plaque appearance, stenosis degree, and peak systolic velocity, but these morphology- and velocity-based indicators may not fully capture patient-specific vascular risk. This study presents AtheroFlow-XNet, a CUBS-compatible ultrasound morphology and uncertainty-aware learning baseline for carotid intima-media segmentation and preliminary risk prediction. Using the Carotid Ultrasound Boundary Study dataset, manual lumen-intima and media-adventitia boundary annotations were converted into dense intima-media masks for supervised segmentation. Clinical variables were incorporated into an auxiliary risk-prediction branch, and Monte Carlo dropout was used for uncertainty-aware inference. The model was evaluated using a patient-level train-validation-test split with 1,522 training images, 326 validation images, and 328 testing images. The proposed model achieved a Dice coefficient of 0.7930 for LI-MA mask segmentation, a segmentation loss of 0.2359, and an area under the receiver operating characteristic curve of 0.6910 for preliminary risk prediction. Qualitative results showed that predicted masks were generally aligned with manual annotations, while uncertainty maps highlighted ambiguous wall-boundary regions. These results suggest that ultrasound-derived carotid morphology can support automated wall analysis and uncertainty-aware interpretation. Since CUBS does not provide Doppler waveforms or CFD-derived hemodynamic biomarkers, this work should be interpreted as a reproducible morphology-driven baseline. Future work will incorporate Doppler-derived flow profiles, patient-specific vascular reconstruction, and CFD-based wall shear biomarkers.

Neural surrogates enable orders-of-magnitude acceleration of computational fluid dynamics (CFD) simulations, with the potential to transform engineering and healthcare workflows. Neural surrogate use in real-world applications requires addressing scalability to large, high-resolution surface and volume meshes, as well as to bespoke architectures, and accounting for limited training data through the use of inductive biases. Group-equivariant architectures are a principled way to introduce such bias, yet they can be detrimental when the learning problem itself breaks symmetry, for example, due to strong distributional alignment in the dataset. In this work, we investigate under which conditions equivariance improves generalization in neural CFD surrogates across tasks with increasing levels of distributional alignment and realism, covering automotive aerodynamics and blood flow (hemodynamics). To systematically assess the added value of equivariance at the limit of problem scaling, we introduce the Anchored-Branched Geometric Algebra Transformer (AB-GATr), a neural surrogate that integrates scalability and symmetry preservation to efficiently model coupled surface and volume quantities in an $E(3)$-equivariant manner. We find that on strongly aligned aerodynamics datasets, i.e., those that break symmetry, enforcing equivariance can degrade in-distribution performance. In contrast, across hemodynamic benchmarks with diverse geometries and varying alignment, equivariance is consistently beneficial. Moreover, across all benchmarks, the explicit equivariance of AB-GATr reliably outperforms implicit symmetry learning through data augmentation. Our findings showcase that equivariance is not universally beneficial across domains, yet it brings tangible advantages in problems lacking strong data regularities.

We propose a new class of waveform foundation models that departs from conventional sequence based representations by modeling physiological time series as realizations of latent event processes. Rather than treating signals as collections of local tokens or patches, our approach assumes that clinically meaningful structure arises from temporally extended, interacting events whose boundaries and dynamics are not directly observed. To capture this structure, we introduce a self supervised learning framework that enforces consistency across stochastic segmentations and time frequency projections of the same waveform, encouraging representations that are invariant to signal level perturbations while preserving event level organization. The resulting model combines a segmentation aware encoder with a latent interaction operator that captures dependencies among inferred events, and naturally extends to multimodal settings by aligning modalities through shared event representations. Across a range of physiological benchmarks, including arrhythmia classification, hemodynamic prediction, and waveform retrieval, the proposed method improves performance, robustness, and label efficiency relative to strong sequence based baselines. These results suggest that shifting from signal centric to event centric representations provides a more appropriate inductive bias for modeling physiological dynamics and offers a complementary path to scaling foundation models in healthcare.

Protecting sensitive health data while enabling collaborative analysis is a central challenge in healthcare. Traditional machine learning (ML) requires institutions to pool anonymized patient records, centralizing analytical development and privacy risks at a single site. Privacy-enhancing technologies (PETs), including Differential Privacy (DP) and Homomorphic Encryption (HE), can mitigate these risks. However, they are mainly studied in conventional data-sharing settings and often introduce trade-offs, including reduced model utility, higher computational cost, and increased implementation complexity. Federated Learning (FL) reduces data centralization by enabling institutions to train models locally and share only model updates. Nevertheless, FL does not eliminate privacy risks, as shared parameters or gradients may still reveal sensitive information. Integrating DP or HE into FL can strengthen privacy guarantees, yet their comparative performance and deployment implications in real-world healthcare settings remain unclear. We systematically evaluated DP and HE integration in FL under real-world conditions, comparing them with standard FL and centralized ML (cML) to quantify privacy-utility trade-offs in multi-institutional settings. Using nationwide Swedish healthcare data, we evaluated cardiovascular disease risk prediction using logistic regression (LR) and neural network (NN) learners. FL with HE achieved performance comparable to cML but introduced measurable cryptographic overhead, particularly in the NN implementation. FL with DP incurred lower computational cost; however, LR was more sensitive to calibrated noise than the NN, resulting in greater performance degradation. Our findings provide practical guidance for deploying privacy-preserving FL in fragmented healthcare systems.

Nonlinear Mixed Effects (NLME) models are widely used in pharmacometrics and related fields to analyze hierarchical and longitudinal data. However, as the number of parameters and random effects increases, traditional methods for maximizing the marginal likelihood become computationally expensive. This paper explores the Variational Expectation Maximization (VEM) algorithm, a scalable alternative for fitting NLME models. Originally introduced in the context of probabilistic graphical models and later popularized through variational autoencoders, VEM has not been extensively applied to NLME modeling. By leveraging flexible variational families and reverse-mode automatic differentiation, VEM can efficiently maximize the marginal likelihood, scaling to NLME models with over 15,000 population parameters. This work provides a detailed description of VEM, compares it to other NLME fitting algorithms, and highlights its scalability through computational experiments. Using the Pumas statistical software, we fit two test models: 1) a standard warfarin model, and 2) an unnecessarily over-parameterized DeepNLME Friberg model with 15,410 population parameters and 16 random effects. The warfarin model was fitted to completion to demonstrate the correctness of VEM, while the DeepNLME Friberg model instead demonstrates VEM's scalability on a toy but large model. VEM improves the log likelihood steadily over hundreds of iterations at a practical per-iteration cost, while FOCE fails to complete even one iteration within a day. The model is deliberately over-parameterized for its small dataset and over-fits it, so what this experiment establishes is that VEM optimizes the objective of a model of this size at a practical cost. Applying VEM to large models that are genuinely useful is left to future work.

We present Cardiac Stability Theory (CST), an axiomatically grounded framework formally defining cardiovascular health as a stability margin around a cardiac dynamical attractor. From four axioms we derive the Cardiac Stability Index (CSI), a composite scalar in [0,1] integrating the largest Lyapunov exponent, recurrence determinism, and signal entropy via time-delay embedding. The ECG-based model (CSISurrogateV2, CNN-Transformer) achieves $R^2=0.8788$, MAE$=0.0234$ on PTB-XL (21,799 recordings). We extend CSI to smartphone PPG via Complementary Domain Transfer (CDT): CSISurrogateV2 generates pseudo-labels for the BUT PPG dataset (48 recordings, 12 subjects), training TinyCSINet (122,849 parameters), achieving MAE$=0.0557$, $ρ=0.660$ on the held-out test set ($n=1065$ windows) at ${<}30$ ms mobile latency. CDT is validated on BIDMC, Welltory, and RWS-PPG. Paired validation on 5,035 BIDMC windows yields $r=0.454$ ($ρ=0.485$, $p<10^{-295}$), confirming correlated cardiac stability across modalities. CSI is negatively correlated with age (slope $= -0.000225$ CSI/year, PTB-XL), discriminates atrial fibrillation from normal sinus rhythm (AUROC$=0.89$), and is robust under Perturbation Invariance Training (max AUC drop 1.65%). We derive HeartSpan, a longitudinal stability metric relative to population age norms, enabling continuous non-invasive cardiac monitoring from commodity smartphones for longevity tracking and cardiac risk stratification.

Coronary artery disease (CAD) remains one of the leading causes of death globally, highlighting the need for reliable predictive systems to support early diagnosis and risk assessment. While traditional machine learning models perform well on structured clinical data, large language models (LLMs) present new possibilities to interpret medical information expressed in natural language. In this work, we develop a hybrid framework that bridges structured clinical data and natural-language representations for CAD prediction. Using a publicly available dataset of 1,190 patient records with 11 clinical attributes, structured variables are converted into interpretable feature representations and synthetic clinical narratives using LLMs. A validation pipeline performs reverse extraction of clinical variables and computes a consistency score with the original records, achieving an average fidelity of 94.61%. We then evaluate four conventional machine learning models and compare their performance with LLM-based classification under zero-shot and few-shot prompting settings. We use two LLMs here, GPT and Gemini. Experimental results show that Random Forest achieves the highest accuracy. Despite this advantage, LLM-based classification remains beneficial in real-world clinical settings. This is because LLMs operate directly on natural language patient descriptions, meaning that sensitive numerical patient data such as exact lab values, blood pressure readings, and diagnostic codes are kept private. Findings suggest that combining structured clinical data with LLM-generated narratives can enable new directions for hybrid clinical prediction systems.

The scarcity of temporally aligned pre-event physiological data limits the study of stroke risk states before documented clinical recognition. We focus on patients who experienced stroke during hospitalization while undergoing continuous monitoring, enabling retrospective analysis of pre-anchor photoplethysmography (PPG). Using MIMIC-III and MC-MED, an LLM-assisted pipeline generated candidate stroke anchors from unstructured notes. All retained anchors underwent physician adjudication, and a stratified 100-case double-review audit showed 95.0% candidate-to-adjudicated agreement within +/-15 min. We identified 176 MIMIC-III patients and 154 MC-MED patients with eligible synchronized pre-anchor PPG. A fixed 17-channel hemodynamic representation and ResNet-1D classifier were evaluated using patient-level five-fold internal validation and frozen external testing. At validation-selected operating points, F1-scores were 0.7956, 0.8759, and 0.9406 for 4-, 5-, and 6-hour horizons in MIMIC-III and 0.9256, 0.9595, and 0.9888 in MC-MED; the corresponding threshold-free AUCs ranged from 0.6124 to 0.7079. The PPG model achieved higher F1 than four non-waveform clinical and structured-EHR comparators in all six cohort-horizon settings. On high-risk non-stroke controls, window-level false-positive rates ranged from 0.1371 to 0.2938 and decreased to 0.0183-0.1739 after persistence aggregation. These retrospective findings support measurable pre-anchor PPG structure, but do not establish biological stroke onset, a calibrated bedside alarm, or a clinically validated prediction lead time.