Metabolomic Classification of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome via Explainable Ensemble Learning and Pareto-Guided Feature Selection.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating multisystem illness characterised by post-exertional malaise, non-restorative sleep, and cognitive impairment, yet no objective diagnostic biomarkers have been established. Untargeted plasma metabolomics provides a broad view of the biochemical disturbances underlying ME/CFS; however, the high dimensionality of omics datasets and the limited interpretability of conventional classifiers nevertheless hinder translation into clinical practice. This study evaluates three ensemble classifiers-Explainable Boosting Machine (EBM), XGBoost, and LightGBM-for binary ME/CFS classification using plasma metabolomic and lipidomic profiles from 197 participants (106 ME/CFS; 91 healthy controls; 888 features). Feature dimensionality was reduced using a Pareto-Guided Recursive Neural Network (PRNN) pipeline. Model performance was assessed via 50-repeat stratified hold-out validation. EBM achieved the highest accuracy (0.909; 95% CI: 0.868-0.949) and area under the receiver operating characteristic curve (AUC: 0.940; 95% CI: 0.909-0.983), with XGBoost and LightGBM performing comparably. Interpretability analyses revealed that pairwise metabolite interaction terms-particularly proline & indole-3-lactate, tyrosine & N-acetylornithine, and maleic acid & arachidic acid-contributed the greatest discriminative signal. An ablation analysis comparing the full interaction-augmented EBM (AUC = 0.940) with a main-effects-only EBM (AUC = 0.882) confirmed that pairwise metabolite co-variation contributes additional discriminative value beyond individual metabolite levels, implicating amino acid catabolism, tryptophan-kynurenine pathway dysregulation, mitochondrial energy impairment, and lipid remodelling as central pathophysiological features. Global and instance-level explanations jointly demonstrated population-level metabolic signatures alongside individual heterogeneity, highlighting the added clinical value of explainable artificial intelligence (XAI) in metabolomics. These findings support EBM-based metabolomic profiling as an internally validated approach for ME/CFS classification, subject to external validation, calibration assessment, and prospective testing.