{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T10:32:40Z","timestamp":1785407560800,"version":"3.56.0"},"reference-count":38,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T00:00:00Z","timestamp":1782777600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004242","name":"Princess Nourah bint Abdulrahman University","doi-asserted-by":"publisher","award":["PNURSP2026R716"],"award-info":[{"award-number":["PNURSP2026R716"]}],"id":[{"id":"10.13039\/501100004242","id-type":"DOI","asserted-by":"publisher"}]},{"award":["PNURSP2026R716"],"award-info":[{"award-number":["PNURSP2026R716"]}],"id":[{"id":"https:\/\/ror.org\/05b0cyh02","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>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\u2014Explainable Boosting Machine (EBM), XGBoost, and LightGBM\u2014for 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\u20130.949) and area under the receiver operating characteristic curve (AUC: 0.940; 95% CI: 0.909\u20130.983), with XGBoost and LightGBM performing comparably. Interpretability analyses revealed that pairwise metabolite interaction terms\u2014particularly proline &amp; indole-3-lactate, tyrosine &amp; N-acetylornithine, and maleic acid &amp; arachidic acid\u2014contributed 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\u2013kynurenine 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.<\/jats:p>","DOI":"10.3390\/ijms27135920","type":"journal-article","created":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T00:50:37Z","timestamp":1782867037000},"page":"5920","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Metabolomic Classification of Myalgic Encephalomyelitis\/Chronic Fatigue Syndrome via Explainable Ensemble Learning and Pareto-Guided Feature Selection"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9848-7958","authenticated-orcid":false,"given":"Fatma Hilal","family":"Yagin","sequence":"first","affiliation":[{"name":"Department of Biostatistics, Faculty of Medicine, Malatya Turgut Ozal University, Malatya 44210, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1570-9402","authenticated-orcid":false,"given":"Yavuz","family":"Korkmaz","sequence":"additional","affiliation":[{"name":"Department of Family Medicine, Faculty of Medicine, Malatya Turgut Ozal University, Malatya 44210, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5406-098X","authenticated-orcid":false,"given":"Cemil","family":"Colak","sequence":"additional","affiliation":[{"name":"Department of Biostatistics and Medical Informatics, Faculty of Medicine, Inonu University, Malatya 44280, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8265-2421","authenticated-orcid":false,"given":"Sarah A.","family":"Alzakari","sequence":"additional","affiliation":[{"name":"Department of Computer Sciences, College of Computer and Information Sciences, Princess Nourah bint Abdulrahman University, P.O. Box 84428, Riyadh 11671, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7273-4041","authenticated-orcid":false,"given":"Amal K.","family":"Alkhalifa","sequence":"additional","affiliation":[{"name":"Department of Computer Sciences, College of Computer and Information Sciences, Princess Nourah bint Abdulrahman University, P.O. Box 84428, Riyadh 11671, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5795-9966","authenticated-orcid":false,"given":"Fahaid","family":"Al-Hashem","sequence":"additional","affiliation":[{"name":"Department of Physiology, College of Medicine, King Khalid University, Abha 61421, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5735-3825","authenticated-orcid":false,"given":"Mohammadreza","family":"Aghaei","sequence":"additional","affiliation":[{"name":"Department of Ocean Operations and Civil Engineering, Norwegian University of Science and Technology (NTNU), 6009 \u00c5lesund, Norway"},{"name":"Department of Sustainable Systems Engineering (INATECH), Albert Ludwigs University of Freiburg, 79110 Freiburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1023\/A:1026459027453","article-title":"Comparison of Euroqol EQ-5D and SF-36 in patients with chronic fatigue syndrome","volume":"8","author":"Myers","year":"1999","journal-title":"Qual. 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