InterDIA: Interpretable prediction of drug-induced autoimmunity through ensemble machine learning approaches

Abstract

Drug-induced autoimmunity (DIA) is a non-IgE immune-related adverse drug reaction that poses substantial challenges in predictive toxicology due to its idiosyncratic nature, complex pathogenesis, and diverse clinical manifestations. To address these challenges, we developed InterDIA, an interpretable machine learning framework for predicting DIA toxicity based on molecular physicochemical properties. Multi-strategy feature selection and advanced ensemble resampling approaches were integrated to enhance prediction accuracy and overcome data imbalance. The optimized Easy Ensemble Classifier achieved robust performance in both 10-fold cross-validation (AUC value of 0.8836 and accuracy of 82.81 %) and external validation (AUC value of 0.8930 and accuracy of 85.00 %). Paired case studies of hydralazine/phthalazine and procainamide/N-acetylprocainamide demonstrated the model’s capacity to discriminate between structurally similar compounds with distinct immunogenic potentials. Mechanistic interpretation through SHAP (SHapley Additive exPlanations) analysis revealed critical physicochemical determinants of DIA, including molecular lipophilicity, partial charge distribution, electronic states, polarizability, and topological features. These molecular signatures were mechanistically linked to key processes in DIA pathogenesis, such as membrane permeability and tissue distribution, metabolic bioactivation susceptibility, immune protein recognition and binding specificity. SHAP dependence plots analysis identified specific threshold values for key molecular features, providing novel insights into structure-toxicity relationships in DIA. To facilitate practical application, we developed an open-access web platform enabling batch prediction with real-time visualization of molecular feature contributions through SHAP waterfall plots. This integrated framework not only advances our mechanistic understanding of DIA pathogenesis from a molecular perspective but also provides a valuable tool for early assessment of autoimmune toxicity risk during drug development.