Biomarker Signal Architecture in Cardiovascular Machine Learning: Stability, Redundancy, and Minimal High-Yield Panels After Myocardial Infarction
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Background
Machine-learning models based on circulating biomarkers are increasingly used in cardiovascular research; however, model performance alone provides limited insight into how the predictive signal is distributed across features. We aimed to characterize the biomarker signal architecture of a machine-learning model distinguishing ST-elevation myocardial infarction (STEMI) from non-ST-elevation myocardial infarction (NSTEMI), with a focus on signal concentration, redundancy, and conditional complementarity.
Methods
We conducted a structured secondary analysis of a previously established, leakage-controlled machine-learning framework (n = 152 patients). The BIOMARKERS feature-set variant (10 biomarkers) was evaluated using outer-fold cross-validation. Model structure was interrogated using (i) leave-one-biomarker-out analysis, (ii) pairwise leave-two-out analysis with pair-excess estimation, (iii) cumulative ablation of top-ranked biomarkers, and (iv) forward reconstruction of minimal biomarker panels. Uncertainty was assessed using bootstrap resampling across folds.
Results
The full biomarker model achieved a mean ROC-AUC approaching 0.94. The predictive signal was highly non-uniform, with MMP-2 showing the largest single-feature contribution (mean ΔAUC ≈ 0.16). Pairwise analysis identified conditional complementarity between selected non-lipid biomarkers, particularly MMP-2 and EMMPRIN (pair ΔAUC ≈ 0.26; positive excess over single-feature effects), whereas lipid-related markers formed a highly correlated and largely redundant sub-cluster. Cumulative ablation demonstrated rapid performance collapse following removal of top-ranked biomarkers, consistent with structural signal concentration. Forward panel analysis showed that a compact subset of biomarkers (three features) achieved performance within ∼0.01 ROC-AUC of the full model, indicating the presence of a minimal high-yield panel. Bootstrap confidence intervals suggested that small performance differences should be interpreted with caution.
Conclusions
Predictive performance in this biomarker-based model arises from a structured and unevenly distributed signal architecture, characterized by a dominant core biomarker, conditionally complementary contributors, and a redundant lipid cluster. These findings highlight the importance of evaluating model structure, not only aggregate performance, and suggest that biomarker-based machine-learning systems may benefit from architecture-aware interpretation and simplification strategies.
