A Pan-Cancer Multi-Omic SuperLearner for Regulated Cell Death Survival Topologies

Abstract

IntroductionRegulated cell death (RCD) pathways profoundly influence tumor progression and immune modulation. In prior work, we constructed a comprehensive database mapping 25 forms of RCD across seven multi-omic layers encompassing 33 tumor types (CancerRCDShiny). Despite their robust ability to identify risk populations, translating these prognostic signatures into personalized clinical workflows requires a shift from generalized cohort stratification to individualized risk mapping. This necessitates mapping the complex geometric landscape of patient risk--Survival Topologies--to accurately capture the non-linear dynamics of RCD signatures. MethodsWe engineered a Pan-Cancer Multi-Omic SuperLearner pipeline evaluating 33 cancer types. Phase I performed zero-leakage data harmonization and groupwise imputation to prevent cross-cohort amalgamation. Phase II utilized Elastic Net-regularized Cox (CoxNet) regression as an audit-compliant CANARY diagnostic to map mathematical proportional-hazards failures. Admissible strata enforcing a rigid 35% topological missingness barrier entered Phase III, deploying an advanced non-linear Quadripartite Base-Learner Ensemble (Random Survival Forests (RSF), Extreme Gradient Boosting (XGBoost), insulated Survival-Boruta, and Multi-Task Logistic Regression (MTLR))--fused within an Elastic Net Multi-View Meta-Learner (MVL)--with local interpretability guaranteed via post-hoc SHAPley Additive exPlanations (TreeSHAP) and Local Interpretable Model-agnostic Explanations (LIME). ResultsThe CANARY diagnostic empirically proved the structural invalidity of pan-cancer geometric proportional-hazards. Advancing 96 verified matrices into the Quadripartite Machine Learning Ensemble, Phase III executed a structural algorithmic displacement: dense continuous multi-omic topologies computationally suppressed static genomic mutations and Copy Number Variations (CNVs) during multidimensional competition (85.7% vs 0.0% apex retention). Furthermore, the MVL stabilized global predictions against extreme biological variance, while surrogate LIME validations (R{superscript 2} < 0.10) confirmed the absolute failure of linear interpretative proxies. Extracting N-dimensional TreeSHAP interactions natively bypassed generalized risk parameters, mapping exact Survival Topologies. This dynamically exposed multi-omic synergistic (lethal peaks) and antagonistic (protective valleys) rescue trajectories invisible to additive models. We integrated this architecture into CancerRCDPredictor, a Shiny application operating as a digital tumor board. ConclusionDeploying a Pan-Cancer Multi-Omic SuperLearner to bypass linear topological failures, this study advances beyond generalized cohort stratifications, establishing a deterministically mapped architecture for predicting RCD-related Survival Topologies. Through the CancerRCDPredictor interface, we directly translate multi-omic insights into individualized precision oncology interception.