Classification of longitudinal profiles using semi-parametric nonlinear mixed models with P-Splines and the SAEM algorithm.

In this work, we propose an extension of a semiparametric nonlinear mixed-effects model for longitudinal data that incorporates more flexibility with penalized splines (P-splines) as smooth terms. The novelty of the proposed approach consists of the formulation of the model within the stochastic approximation version of the EM algorithm for maximum likelihood, the so-called SAEM algorithm. The proposed approach takes advantage of the formulation of a P-spline as a mixed-effects model and the use of the computational advantages of the existing software for the SAEM algorithm for the estimation of the random effects and the variance components. Additionally, we developed a supervised classification method for these non-linear mixed models using an adaptive importance sampling scheme. To illustrate our proposal, we consider two studies on pregnant women where two biomarkers are used as indicators of changes during pregnancy. In both studies, information about the women's pregnancy outcomes is known. Our proposal provides a unified framework for the classification of longitudinal profiles that may have important implications for the early detection and monitoring of pregnancy-related changes and contribute to improved maternal and fetal health outcomes. We show that the proposed models improve the analysis of this type of data compared to previous studies. These improvements are reflected both in the fit of the models and in the classification of the groups.