1321-P: Quantifying and Adjusting for Classification Uncertainty in Type 2 Diabetes Subtypes

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Introduction and Objective: Despite continued interest in 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 adjusting for classification uncertainty in type 2 diabetes subtypes. Methods: Building on recommendations from the ADA/EASD Precision Medicine in Diabetes Initiative, we quantified individual classification uncertainty using the normalized relative entropy (NRE), computed from distances to cluster centroids. A lower NRE value indicates greater uncertainty. We examined the NRE of 859 individuals with recent-onset type 2 diabetes from the 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 cardiovascular disease (CVD) risk (SCORE2-Diabetes) of the subtypes was evaluated with and without adjustment for classification uncertainty. Results: The median NRE of individuals with type 2 diabetes (age 54±10 years, BMI 31.6±6.2 kg/m2, HbA1c 6.4±0.9%) was 0.127 (95% CI: 0.119-0.135). 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). 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). After adjustment, 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). Conclusion: Classification uncertainty varied between subtypes and individuals with type 2 diabetes, and adjusting for it improved the ability of the subtypes to predict 10-year CVD risk. Disclosure T. Mori: None. O.P. Zaharia: None. K. Strassburger: None. J.M. Dennis: None. M. Roden: Research Support; Boehringer-Ingelheim. Advisory Panel; Echosens. Speaker's Bureau; Madrigal Pharmaceuticals, Inc. Advisory Panel; MSD Life Science Foundation. Board Member; Novo Nordisk. Advisory Panel; TARGET PharmaSolutions, Inc. R. Wagner: Speaker's Bureau; Boehringer-Ingelheim, Novo Nordisk. Advisory Panel; Sanofi. Speaker's Bureau; Sanofi. Advisory Panel; Lilly Diabetes. O. Kuss: None.

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