Joint Modeling of Conditional Mean and Variability in Multilevel Functional Data: Application to Postprandial Glucose Trajectories in the AEGIS Study

Abstract

Functional data analysis provides a framework for studying time-varying associations between covariates and high-frequency biological signals. In digital health, participants often contribute repeated functional trajectories, yet existing multilevel regression methods largely focus on the conditional mean, overlooking variability and its role in biological heterogeneity. We propose a heteroskedastic functional mixed-effects regression framework that jointly models the conditional mean and variance of repeated trajectories, with participant-specific random effects in both components. We also develop a participant-level bootstrap to quantify uncertainty in estimated functional parameters. We apply the method to postprandial glucose trajectories from the AEGIS study. Premeal glucose, carbohydrate intake, and meal type show distinct time-dependent associations with glucose variability, whereas HbA1c is more strongly associated with the conditional mean than with variability. Substantial between-participant differences in residual variability remain even after accounting for observed covariates. These findings show that modeling conditional variability alongside the mean provides insights into glucose regulation and individual heterogeneity that mean-focused analyses may miss. More broadly, the proposed framework enables joint characterization of average responses, variability, and participant-specific heterogeneity in repeated biological signals.