{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T23:18:32Z","timestamp":1788218312777,"version":"build-2803163510"},"reference-count":55,"publisher":"American Chemical Society (ACS)","issue":"33","license":[{"start":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T00:00:00Z","timestamp":1786579200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100018493","name":"Taipei Medical University-Shuang Ho Hospital, Ministry of Health and Welfare","doi-asserted-by":"publisher","award":["113TMU-SHH-11"],"award-info":[{"award-number":["113TMU-SHH-11"]}],"id":[{"id":"10.13039\/100018493","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100020950","name":"National Science and Technology Council","doi-asserted-by":"publisher","award":["NSTC112-2314-B-038-106"],"award-info":[{"award-number":["NSTC112-2314-B-038-106"]}],"id":[{"id":"10.13039\/501100020950","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,8,25]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Coronary artery disease (CAD) is the leading cause of mortality in type 2 diabetes mellitus (T2DM). This study explores the two-hit oxidative\u2013immune hypothesis by evaluating malondialdehyde (MDA)-modified protein (MDA-protein) adducts and their corresponding autoantibodies for precise and fair CAD severity stratification and classification. Novel MDA-peptide epitopes (apolipoprotein B-100 (ApoB-100), fibronectin (FINC), and complement C4A\/C4B (C4A\/C4B)) were identified via proteomics, and plasma levels of MDA, adducts, and autoantibodies were measured in 165 Taiwanese T2DM patients. Multivariate logistic regression estimated odds ratios (ORs) per 1-SD increase. Machine learning with Shapley additive explanations (SHAP)-interpretable analysis and nested cross validation distinguished obstructive from nonobstructive CAD. Fairness was assessed across age and sex subgroups. MDA (OR 3.148) and MDA-protein adducts (OR 2.090) were independent markers associated with advanced CAD severity, while IgG anti-ApoB-1001662\u20131683 MDA (OR 0.481) was independently associated with a lower risk. In differentiating obstructive CAD in T2DM patients, random forest achieved a pooled AUC of 0.958, a Brier score of 0.089, and a net benefit of 0.433 at the 20% threshold, outperforming conventional markers. SHAP analysis highlighted IgG anti-C4A\/B167\u2013187 as the dominant positive contributor within the machine learning framework, suggesting a possible proinflammatory signature, underscoring nonlinear push\u2013pull dynamics between oxidative\u2013immune signatures. As an exploratory finding, fairness analysis demonstrated consistent performance across sexes and a notable benefit in older patients, while revealing age-related imbalance in calibration and decision utility. Integrating MDA-related immune signatures into interpretable, fairness-aware categorical boosting and logistic regression models provides a robust, noninvasive framework for CAD severity stratification in T2DM, clarifying immunometabolic interactions and supporting equitable clinical decision-making.<\/jats:p>","DOI":"10.1021\/acsomega.6c05628","type":"journal-article","created":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T15:06:46Z","timestamp":1786633606000},"page":"50168-50184","source":"Crossref","is-referenced-by-count":0,"title":["Development of\na Shapley Additive Explanations (SHAP)-Interpretable\nModel for Cardiovascular Risk Stratification in Type 2 Diabetes Mellitus:\nImplications of MDA-Modified Protein Adducts and Autoantibodies"],"prefix":"10.1021","volume":"11","author":[{"given":"Chien-Yi","family":"Hsu","sequence":"first","affiliation":[{"name":"Taipei Heart Institute, Taipei Medical University , , ,","place":["Taipei, Taiwan, 11031"]},{"name":"Taipei Medical University Hospital , , ,","place":["Taipei, Taiwan, 11031"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shou-Cheng","family":"Lu","sequence":"additional","affiliation":[{"name":"Shuang Ho Hospital, Taipei Medical University , , ,","place":["New Taipei City, Taiwan, 23561"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liang-Wei","family":"Lin","sequence":"additional","affiliation":[{"name":"Taiwan Adventist Hospital , , ,","place":["Taipei, Taiwan, 10556"]},{"name":"Taipei Medical University , , ,","place":["Taipei, Taiwan, 11031"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chu-Heng","family":"Yen","sequence":"additional","affiliation":[{"name":"Shuang Ho Hospital, Taipei Medical University , , ,","place":["New Taipei City, Taiwan, 23561"]},{"name":"Taipei Medical University , , ,","place":["Taipei, Taiwan, 11031"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hung-Tse","family":"Lin","sequence":"additional","affiliation":[{"name":"LinKou Chang Gung Memorial Hospital , , ,","place":["Taoyuan, Taiwan, 33305"]},{"name":"Chang Gung University , , ,","place":["Taoyuan, Taiwan, 33302"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shao-Chun","family":"Lin","sequence":"additional","affiliation":[{"name":"Chia Nan University of Pharmacy & Science , , ,","place":["Tainan City, Taiwan, 717301"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ching-Yu","family":"Lin","sequence":"additional","affiliation":[{"name":"Taipei Medical University , , ,","place":["Taipei, Taiwan, 11031"]},{"name":"Taipei Medical University , , ,","place":["Taipei, Taiwan, 11031"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao-Lien","family":"Liu","sequence":"additional","affiliation":[{"name":"Taipei Medical University , , ,","place":["Taipei, Taiwan, 11031"]},{"name":"Taipei Medical University , , ,","place":["Taipei, Taiwan, 11031"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,13]]},"reference":[{"issue":"1","key":"2026083119122931200_cit1","doi-asserted-by":"publisher","DOI":"10.1186\/s12933-023-01748-0","article-title":"Diagnosis of coronary artery disease in patients with type 2 diabetes\nmellitus based on computed tomography and pericoronary adipose tissue\nradiomics: a retrospective cross-sectional study","volume":"22","author":"Dong","year":"2023","journal-title":"Cardiovasc. Diabetol."},{"issue":"1","key":"2026083119122931200_cit2","doi-asserted-by":"publisher","DOI":"10.1186\/s12933-018-0728-6","article-title":"Prevalence\nof cardiovascular disease\nin type 2 diabetes: a systematic literature review of scientific evidence\nfrom across the world in 2007\u20132017","volume":"17","author":"Einarson","year":"2018","journal-title":"Cardiovasc.\nDiabetol."},{"issue":"2","key":"2026083119122931200_cit3","doi-asserted-by":"publisher","first-page":"149","DOI":"10.1016\/S2213-8587(25)00299-2","article-title":"11th edition\nof the IDF Diabetes Atlas: Global, Regional,\nand National Diabetes Prevalence Estimates for 2024 and Projections\nfor 2050","volume":"14","author":"Genitsaridi","year":"2026","journal-title":"Lancet Diabetes Endocrinol."},{"issue":"1","key":"2026083119122931200_cit4","doi-asserted-by":"publisher","DOI":"10.1186\/s12967-021-03217-2","article-title":"Diabetes,\nhypertension, and cardiovascular disease development","volume":"20","author":"Yen","year":"2022","journal-title":"J. Transl. Med."},{"issue":"9","key":"2026083119122931200_cit5","doi-asserted-by":"publisher","DOI":"10.7759\/cureus.69756","article-title":"Estimation\nof Serum Malondialdehyde (a Marker of Oxidative Stress) as a Predictive\nBiomarker for the Severity of Coronary Artery Disease (CAD) and Cardiovascular\nOutcomes","volume":"16","author":"Asfandiyar","year":"2024","journal-title":"Cureus"},{"issue":"4","key":"2026083119122931200_cit6","doi-asserted-by":"publisher","DOI":"10.1097\/IN9.0000000000000032","article-title":"Macrophage immunometabolism in diabetes-associated\natherosclerosis","volume":"5","author":"Dos Santos","year":"2023","journal-title":"Immunometabolism"},{"key":"2026083119122931200_cit7","first-page":"1","article-title":"Malondialdehyde\nEpitopes as Targets of Immunity and the Implications for Atherosclerosis","volume-title":"Adv. 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Cardiol."},{"issue":"1","key":"2026083119122931200_cit41","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1007\/s11883-025-01279-x","article-title":"Inflammation-Driven Plaque Erosion\nin Atherosclerosis:\nA Focus on Complement System Pathways","volume":"27","author":"Ramoni","year":"2025","journal-title":"Curr.\nAtheroscler. Rep."},{"issue":"6","key":"2026083119122931200_cit42","doi-asserted-by":"publisher","first-page":"1851","DOI":"10.1016\/S0002-9440(10)62494-7","article-title":"Autoantibodies\nto vascular smooth muscle are pathogenic for vasculitis","volume":"166","author":"Baiu","year":"2005","journal-title":"Am. J. Pathol."},{"issue":"3","key":"2026083119122931200_cit43","doi-asserted-by":"publisher","first-page":"528","DOI":"10.1093\/cvr\/cvr101","article-title":"Immunization\nof apoE\u2013\/\u2013\nmice with aldehyde-modified fibronectin inhibits the development of\natherosclerosis","volume":"91","author":"Dune\u0301r","year":"2011","journal-title":"Cardiovasc. 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Cardiovasc.\nMed."},{"key":"2026083119122931200_cit49","volume-title":"Applied linear statistical models","author":"Kutner","year":"2005","edition":"5"},{"issue":"85","key":"2026083119122931200_cit50","first-page":"2825","article-title":"Scikit-learn:\nMachine learning in Python","volume":"12","author":"Pedregosa","year":"2011","journal-title":"J. Mach. Learn.\nRes."},{"issue":"7","key":"2026083119122931200_cit51","doi-asserted-by":"publisher","first-page":"1276","DOI":"10.1002\/sim.7992","article-title":"Minimum sample size\nfor developing a multivariable prediction model: PART II - binary\nand time-to-event outcomes","volume":"38","author":"Riley","year":"2019","journal-title":"Stat. 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