Semiparametric Mixed-effects Models Research Articles

Analysis of Relation between Virologic Responses and Immunologic Responses, Patient's Factors in AIDS Clinical Trials Using – A Semiparametric Mixed‐Effects Model

In this article we propose to use a semiparametric mixed-effects model based on an exploratory analysis of clinical trial data for a study of the relation between virologic responses and immunologic markers such as CD4+ and CD8 counts, and host-specific factors in AIDS clinical trials. The regression spline technique, used for inference for parameters in the model, reduces the unknown nonparametric components to parametric functions. It is simple and straightforward to implement the procedures using readily available software, and parameter inference can be developed from standard parametric models. We apply the model and the proposed method to an AIDS clinical study. Our findings indicate that viral load level is positively related to baseline viral load level, negatively related to CD4+ cell counts, but unrelated to CD8 cell counts and patient's age neither.

Simple fitting of subject‐specific curves for longitudinal data

We present a simple semiparametric model for fitting subject-specific curves for longitudinal data. Individual curves are modelled as penalized splines with random coefficients. This model has a mixed model representation, and it is easily implemented in standard statistical software. We conduct an analysis of the long-term effect of radiation therapy on the height of children suffering from acute lymphoblastic leukaemia using penalized splines in the framework of semiparametric mixed effects models. The analysis revealed significant differences between therapies and showed that the growth rate of girls in the study cannot be fully explained by the group-average curve and that individual curves are necessary to reflect the individual response to treatment. We also show how to implement these models in S-PLUS and R in the appendix.

Semiparametric Nonlinear Mixed-Effects Models and Their Applications

Nonlinear mixed effects models (NLMMs) and self-modeling nonlinear regression (SEMOR) models are often used to fit repeated measures data. They use a common function shared by all subjects to model variation within each subject and some fixed and/or random parameters to model variation between subjects. The parametric NLMM may be too restrictive, and the semiparametric SEMOR model ignores correlations within each subject. In this article we propose a class of semiparametric nonlinear mixed effects models (SNMMs) that extend NLMMs, SEMOR models, and many other existing models in a natural way. A SNMM assumes that the mean function depends on some parameters and nonparametric functions. The parameters provide an interpretable data summary. The nonparametric functions provide flexibility to allow the data to decide some unknown or uncertain components, such as the shape of the mean response over time. A second-stage model with fixed and random effects is used to model the parameters. Smoothing splines are used to model the nonparametric functions. Covariate effects on parameters can be built into the second-stage model, and covariate effects on nonparametric functions can be constructed using smoothing spline ANOVA decompositions. Laplace approximations to the marginal likelihood and penalized marginal likelihood are used to estimate all parameters and nonparametric functions. We propose and compare two estimation procedures, and also show how to construct approximate Bayesian confidence intervals for the nonparametric functions based on a Bayesian formulation of SNMMs. We evaluate the proposed estimation and inference procedures through a simulation study. Applications of SNMMs are illustrated with analyses of Canadian temperature data.