Hyperparameter grids used for optimization.

ObjectivePrediabetes is a silent condition that often goes undetected. However, timely interventions could prevent its progression to type 2 diabetes. Traditional glycemic markers, such as hemoglobin A1c (HbA1c), have limitations, creating a need for new diagnostic biomarkers. In this study, our objective was to develop an interpretable machine learning model using biomarkers related to oxidative stress, inflammation, and lipid metabolism to classify prediabetes independently of traditional glycemic markers, such as HbA1c. We also compared multiple biomarker panels to determine which biomarkers offer the highest predictive accuracy.MethodsWe developed and validated interpretable machine learning models using clinical and biomarker data from 545 participants (405 healthy controls and 140 with prediabetes). To ensure robust and generalizable findings, we employed a nested cross-validation technique, managed feature collinearity using the variance inflation factor (VIF), and interpreted the final model with Shapley Additive exPlanations (SHAP) [Kapoor S, Narayanan A. Patterns. 4(9):100804 (2023); Vabalas A, et al. PLoS One. 14(11):e0224365 (2019); Lundberg SM, Lee SI. Adv Neural Inf Process Syst. 30:4768–77 (2017)].ResultsOur approach identified a distinct panel of inflammatory biomarkers (IL-10, IGF-1, and CRP) capable of classifying prediabetes independently of traditional glycemic markers. This non-glycemic model achieved a promising Area Under the Curve (AUC) of 0.711 on holdout validation, establishing inflammation as a key and measurable indicator of early metabolic dysfunction.ConclusionOur findings introduce a novel panel of inflammatory biomarkers that show promise in the identification of prediabetes independently of traditional glucose-based measures. By highlighting inflammation as an early indicator of metabolic dysfunction, this approach may enhance precision in the detection of prediabetes. Longitudinal studies with larger and more diverse populations are essential to clinically validate these biomarkers and confirm their value in improving the early diagnosis and management of metabolic health.