Interpretable Machine Learning for Serum-Based Metabolomics in Breast Cancer Diagnostics: Insights from Multi-Objective Feature Selection-Driven LightGBM-SHAP Models

<i>Background and Objectives:</i> Breast cancer accounts for 12.5% of all new cancer cases in women worldwide. Early detection significantly improves survival rates, but traditional biomarkers like CA 15-3 and HER2 lack sensitivity and specificity, particularly for early-stage disease. Advances in metabolomics and machine learning, particularly explainable artificial intelligence (XAI), offer new opportunities for identifying robust biomarkers and improving diagnostic accuracy. This study aimed to identify and validate serum-based metabolic biomarkers for breast cancer using advanced metabolomic profiling techniques and a Light Gradient Boosting Machine (LightGBM) model. Additionally, SHapley Additive exPlanations (SHAP) were applied to enhance model interpretability and biological insight. <i>Materials and Methods:</i> The study included 103 breast cancer patients and 31 healthy controls. Serum samples underwent liquid and gas chromatography-time-of-flight mass spectrometry (LC-TOFMS and GC-TOFMS). Mutual Information (MI), Sparse Partial Least Squares (sPLS), Boruta, and Multi-Objective Feature Selection (MOFS) approaches were applied to the data for biomarker discovery. LightGBM, AdaBoost, and Random Forest were employed for classification and to identify class imbalance with the Synthetic Minority Oversampling Technique (SMOTE). SHAP analysis ranked metabolites based on their contribution to model predictions. <i>Results:</i> Compared to other feature selection approaches, the MOFS approach was more robust in terms of predictive performance, and metabolites identified by this method were used in subsequent analyses for biomarker discovery. LightGBM outperformed the AdaBoost and Random Forest models, achieving 86.6% accuracy, 89.1% sensitivity, 84.2% specificity, and an F1-score of 87.0%. SHAP analysis identified 2-Aminobutyric acid, choline, and coproporphyrin as the most influential metabolites, with dysregulation of these markers associated with breast cancer risk. <i>Conclusions:</i> This study is among the first to integrate SHAP explainability with metabolomic profiling, bridging computational predictions and biological insights for improved clinical adoption. This study demonstrates the effectiveness of combining metabolomics with XAI-driven machine learning for breast cancer diagnostics. The identified biomarkers not only improve diagnostic accuracy but also reveal critical metabolic dysregulations associated with disease progression.