A leakage-controlled machine learning framework for postprandial triglyceride phenotyping using synthetic clinical data

BACKGROUND: Whole blood viscosity (WBV) has been linked to cardiometabolic risk, yet its relationship with short-term postprandial triglyceride (TG) response remains unclear. We evaluated this question within a fully de-identified, statistically reconstructed synthetic cohort ([Formula: see text]), with a primary methodological objective: to demonstrate a rigorously leakage-controlled machine-learning framework for assessing candidate physiological associations. METHODS: A strictly leakage-controlled pipeline was implemented, with fold-specific preprocessing and probability calibration confined to training data. WBV was estimated using the de Simone formulation. Model development employed stratified [Formula: see text] nested cross-validation, repeated [Formula: see text] resampling, 1,000-bootstrap uncertainty estimation, calibration assessment (sigmoid and isotonic), threshold-sensitivity analysis across [Formula: see text] percentiles, and SHAP-based interpretability. RESULTS: Within the synthetic reconstruction, WBV showed negligible association with postprandial response across correlation testing ([Formula: see text]), multivariable modeling, robustness analyses, and explainability assessments. In contrast, fasting triglycerides (TG[Formula: see text]) exhibited stable monotonic effects and clear phenotype discrimination. Under the primary 75th-percentile [Formula: see text] definition, the L2-penalized logistic regression model achieved stable discrimination (nested AUROC [Formula: see text]; Brier [Formula: see text]) with bootstrap AUROC [Formula: see text] (95% CI [0.8957, 0.9314]) and consistent calibration-aware performance. CONCLUSIONS: Within this synthetic framework, WBV did not provide reproducible predictive or attributional value for short-term postprandial TG response. These findings represent methodological evidence under modeled assumptions rather than definitive physiological conclusions. The study illustrates how leakage-controlled, calibration-aware ML workflows can evaluate candidate metabolic associations in privacy-preserving settings; external validation in real-world cohorts remains necessary.