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Anstalt \u00f6ffentlichen Rechts"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Diabetologia"],"published-print":{"date-parts":[[2025,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:sec>\n            <jats:title>Aims\/hypothesis<\/jats:title>\n            <jats:p>Despite continued interest in precision diagnostics and type 2 diabetes subtypes, the challenge of uncertainty in the classification of individuals into subtypes remains. This study introduces a novel method for quantifying and accounting for classification uncertainty in type 2 diabetes subtypes.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods<\/jats:title>\n            <jats:p>Building on recommendations from the ADA\/EASD Precision Medicine in Diabetes Initiative, we quantified classification uncertainty using the normalised relative entropy (NRE), computed from distances to cluster centroids. A lower NRE value indicates greater uncertainty in an individual\u2019s cluster assignment. We examined the NRE in a cohort of 859 individuals with recent-onset type 2 diabetes from the prospective, observational German Diabetes Study (GDS) and compared it across previously identified diabetes subtypes, defined by age, BMI, HbA<jats:sub>1c<\/jats:sub>, HOMA-IR and HOMA-B. Predicted 10 year CVD risk (SCORE2-Diabetes) of the subtypes was evaluated with and without accounting for classification uncertainty.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>Individuals with mild age-related diabetes (<jats:italic>n<\/jats:italic>=395) and mild obesity-related diabetes (<jats:italic>n<\/jats:italic>=316) had a median NRE of 0.155 (95% CI 0.142, 0.177) and 0.119 (95% CI 0.107, 0.131), respectively. By contrast, individuals with severe insulin-resistant diabetes (<jats:italic>n<\/jats:italic>=130) and severe insulin-deficient diabetes (<jats:italic>n<\/jats:italic>=18) had a lower median NRE of 0.086 (95% CI 0.075, 0.108) and 0.082 (95% CI 0.071, 0.109), respectively. After weighting individuals by classification certainty, the proportion of variation in SCORE2-Diabetes explained by the subtypes (<jats:italic>R<\/jats:italic>\n              <jats:sup>2<\/jats:sup>) increased from 17.4% (95% CI 12.8, 23.0) to 31.5% (95% CI 26.4, 37.1). The predicted 10 year CVD risk of the mild age-related diabetes subtype increased from 10.3% (95% CI 9.8, 10.7) to 11.6% (95% CI 11.2, 12.0).<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions\/interpretation<\/jats:title>\n            <jats:p>The NRE provides a means to quantify and compare individual classification uncertainty in type 2 diabetes subtypes. Classification uncertainty varied between subtypes and individuals with type 2 diabetes, and accounting for it improved the ability of the subtypes to predict 10 year CVD risk.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Graphical Abstract<\/jats:title>\n          <\/jats:sec>","DOI":"10.1007\/s00125-025-06486-4","type":"journal-article","created":{"date-parts":[[2025,7,25]],"date-time":"2025-07-25T16:00:40Z","timestamp":1753459240000},"page":"2139-2150","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Recognising, quantifying and accounting for classification uncertainty in type 2 diabetes 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However, access can be requested through a specific project agreement with the principal investigator of the German Diabetes Study (GDS) (michael.roden@ddz.de). The study protocol and detailed methodology are published in the cohort profile [] and are freely available.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Data availability"}},{"value":"The R code of this study is available upon reasonable request from the corresponding author.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Code availability statement"}},{"value":"Open Access funding enabled and organized by Projekt DEAL. The German Diabetes Study (GDS) was initiated and financed by the German Diabetes Center (which is funded by the German Federal Ministry of Health and the Ministry of Culture and Science of the state of North Rhine-Westphalia), the German Diabetes Association, the German Federal Ministry of Education and Research (to the German Center for Diabetes Research, DZD) and the Schmutzler Stiftung. JMD is supported by a Wellcome Trust Early-Career Award (227070\/Z\/23\/Z) and the NIHR Exeter Biomedical Research Centre. The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. The research of MR is further supported by grants from the European Community (HORIZON-HLTH-2022-STAYHLTH-02-01: Panel A) to the INTERCEPT-T2D consortium and the German Science Foundation (DFG; RTG\/GRK 2576 vivid, Project 3 and 493659010 Future4CSPMM). NS is supported by the German Center for Diabetes Research, DZD. The research of OPZ is supported by grants from the European Foundation for the Study of Diabetes (EFSD Rising Star Award) and the German Diabetes Association (DDG Adam Heller Prize). The project has received funding from the programme \u2018Profilbildung 2020\u2019, an initiative of the Ministry of Culture and Science of the State of North Rhine-Westphalia (PROFILNRW-2020-107-B). The current research of SK is supported by J. Rettenmaier & S\u00f6hne (Rosenberg, Germany), the Wilhelm-Doerenkamp-Foundation (Chur, Switzerland), and the Almond Board of California (Modesto, USA). SM is supported by the \u2018Advanced Clinician Scientist Program\u2019 from the University of L\u00fcbeck. TM is supported by the EASD mentorship programme. The sole responsibility for the content of this publication lies with the authors. The funding sources had no role in study design, data collection, data analysis, data interpretation, or writing of the report.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Funding"}},{"value":"KM received fees for consulting or lecturing from Eli Lilly, Novo Nordisk and Oviva, and performed investigator-initiated research with support from Sanofi-Aventis. MB received honoraria as a consultant and speaker from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Daiichi Sankyo, Lilly, MSD, Novo Nordisk and Sanofi. MR received fees for consulting or lecturing from Astra Zeneca, Boehringer Ingelheim, Echosens, Eli Lilly, Madrigal, MSD, Novo Nordisk and Pfizer, and performed investigator-initiated research with support from Boehringer Ingelheim and Novo Nordisk. NS received fees for consulting or lecturing from Allergan, AstraZeneca, Boehringer Ingelheim, Gilead, Genkyotex, GSK, Intercept Pharma, Lilly, Merck Sharpe & Dohme, Novartis, Novo Nordisk, Pfizer and Sanofi, and received research support from AstraZeneca, Sanofi, DSM Nutritional Products and Roche Diagnostics. OPZ reports receiving lecture fees from Sanofi and Chiesi. RW reports receiving lecture fees from Novo Nordisk, Sanofi-Aventis, Boehringer Ingelheim and Eli Lilly, and has served on the advisory board for Akcea Therapeutics, Daiichi Sankyo, Sanofi-Aventis, Eli Lilly and NovoNordisk. SK reports receiving lecture fees from Berlin-Chemie, Lilly, Boehringer Ingelheim and JuZo-Akademie. SM received lecture fees from Eli Lilly and Novo Nordisk, and has participated on advisory boards for Novo Nordisk. SM\u2019s husband is an employee at Novo Nordisk. The authors declare that there are no other relationships or activities that might bias, or be perceived to bias, their work.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Authors\u2019 relationships and activities"}},{"value":"TM contributed to the conceptualisation, methodology, software development, formal analysis, and writing of the original draft, as well as reviewing and editing the manuscript. OPZ, KS, JD, KM, SK, SB, JS, MB, SM, JS, AB, NS and MR contributed substantially to the interpretation of data and reviewed the article critically for important intellectual content. RW contributed to the conceptualisation, participated in reviewing and editing the manuscript and provided supervision. OK contributed to the conceptualisation and methodology, participated in reviewing and editing the manuscript, and provided supervision. All authors gave final approval of this version to be published. TM is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.","order":6,"name":"Ethics","group":{"name":"EthicsHeading","label":"Contribution statement"}}]}}