Conformal Prediction and Ensemble Learning for Uncertainty-Aware ICU Mortality Stratification

Background. Conventional ICU severity scores - SOFA, qSOFA, and APACHE-II - use additive integer weightings that cannot capture non-linear organ failure interactions; prospective validations consistently report AUC near 0.73. None quantifies prediction uncertainty, evaluates demographic equity, or acknowledges that their key biomarkers (albumin, creatinine, BUN, lactate, GCS) are also primary confounders of emerging Alzheimer's disease (AD) blood biomarkers p-tau217 and neurofilament light chain (NfL). Methods. Fourteen classifiers were trained on a SOFA-calibrated synthetic ICU cohort (N = 90,000; mortality 29.2%), including an FT-Transformer, XGBoost, and LightGBM tuned by Bayesian optimisation. Seven composite features were engineered from clinical first principles; the novel lactate/albumin ratio (rLA) mirrors the albumin-adjusted p-tau217 correction formula. Post-hoc analyses included nine-method aggregated permutation importance, Monte Carlo Dropout uncertainty decomposition (T = 50), distribution-free conformal prediction, a three-zone triage system, formal ablation, survival analysis, temporal deployment validation, and demographic fairness evaluation. Results. On a natural-distribution held-out cohort (n = 18,000; mortality 29.3%), XGBoost achieved AUC = 0.967 (95% CI 0.965-0.970), surpassing SOFA (AUC = 0.731) by +0.236 (DeLong z = 55.8, p < 0.001; NRI = +0.740). Selective prediction raised FT-Transformer AUC from 0.917 to 0.980 at 50% abstention. Removing neurodegeneration-proxy features reduced AUC by 9.51 percentage points. ML probability was the sole significant covariate in adjusted Cox regression (HR = 6.19, p < 0.001); SOFA, age, lactate, and albumin were non-significant. Temporal AUC range was 0.003 across four deployment windows; sex and age AUC gaps were 0.005 each. Conclusions. This framework delivers well-calibrated, uncertainty-aware ICU mortality prediction with formal coverage guarantees and demographic equity. Ablation-confirmed contributions of neurodegeneration-proxy features, with PDP inflection points aligning with established clinical thresholds, provide a hypothesis-generating quantitative link between routine ICU biomarkers and the AD neurodegeneration pathway warranting prospective validation.