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Mori, T.* ; Zaharia, O.P.* ; Straßburger, K.* ; Dennis, J.M.* ; Mai, K.* ; Kabisch, S.* ; Bornstein, S.* ; Szendroedi, J.* ; Blüher, M. ; Meyhöfer, S.* ; Seissler, J.* ; Birkenfeld, A.L.* ; Stefan, N.* ; Roden, M.* ; Wagner, R.* ; Kuß, O.*

Recognising, quantifying and accounting for classification uncertainty in type 2 diabetes subtypes.

Diabetologia 68, 2139-2150 (2025)
Publ. Version/Full Text Research data DOI PMC
Open Access Hybrid
Creative Commons Lizenzvertrag
AIMS/HYPOTHESIS: 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. METHODS: 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's 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, HbA1c, HOMA-IR and HOMA-B. Predicted 10 year CVD risk (SCORE2-Diabetes) of the subtypes was evaluated with and without accounting for classification uncertainty. RESULTS: Individuals with mild age-related diabetes (n=395) and mild obesity-related diabetes (n=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 (n=130) and severe insulin-deficient diabetes (n=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 (R2) 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). CONCLUSIONS/INTERPRETATION: 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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Classification Uncertainty ; Clusters ; German Diabetes Study ; Precision Medicine ; Relative Entropy ; Subtypes ; Type 2 Diabetes Mellitus; Precision Medicine; Risk
ISSN (print) / ISBN 0012-186X
e-ISSN 1432-0428
Journal Diabetologia
Quellenangaben Volume: 68, Issue: 10, Pages: 2139-2150 Article Number: , Supplement: ,
Publisher Springer
Publishing Place Berlin ; Heidelberg [u.a.]
Reviewing status Peer reviewed
Institute(s) Helmholtz Institute for Metabolism, Obesity and Vascular Research (HI-MAG)
Grants EASD mentorship programme
European Community
NIHR Exeter Bio-medical Research Centre
Wellcome Trust
Schmutzler Stiftung
German Federal Ministry of Education and Research
German Diabetes Association
Ministry of Culture and Science of the state of North Rhine-Westphalia
German Federal Ministry of Health
German Science Foundation (DFG)
University of Luebeck
Almond Board of California (Modesto, USA)
Wilhelm-Doerenkamp-Foundation (Chur, Switzerland)
J. Rettenmaier & Soehne (Rosenberg, Germany)
German Diabetes Association (DDG Adam Heller Prize)
European Foundation for the Study of Diabetes (EFSD Rising Star Award)
German Center for Diabetes Research, DZD
Projekt DEAL