A functional nonlinear mixed effects modeling framework for longitudinal functional responses

Abstract

In this paper, we introduce a functional nonlinear mixed effects modeling framework designed to quantify the random, nonlinear relationship between individual spatiotemporal functional trajectories and longitudinal responses. Our proposed framework accounts for within-individual variability through a spatiotemporal process. We detail an estimation method for determining fixed and random effect functions and spatiotemporal covariance operators and establish their asymptotic properties, including uniform consistency and weak convergence. We also develop global linear hypothesis tests and bootstrap-based simultaneous confidence bands for fixed effect functions. To assess the finite-sample performance of our method, we perform a numerical analysis using both simulated and real-world datasets. Our results demonstrate that the proposed model class is significantly more flexible and effective in detecting functional fixed effects compared to existing nonlinear mixed effects models. We apply our approach to an autism research database to investigate the impact of age and spatial dynamics on fractional anisotropy along the corpus callosum white matter fiber skeleton.