An EM Algorithm for Nonlinear Random Effects Models

Abstract

The pharmaceutical industry is currently interested in the population approach and population models, also known as mixed effects models and random effects models depending on the precise form. Population models are useful in that they can account for both withinand between-individual sources of variability and serial correlation within individual observations when analyzing unbalanced repeated measures data. The modelling of population pharmacodynamic or pharmacokinetic profiles typically involves nonlinear random effects models. Each individual's observations are modelled by identical (up to unknown parameter values) nonlinear regression models, with the distribution of the observations, or a transformation of the observations, about expected responses taken to be normal, with the degree of variability described by a variance model. Between-individual variability is modelled by a population distribution for the individual regression parameter values (random effects). In a parametric analysis the population distribution is taken to be normal, the parameters of which, along with the parameters of the variance model, are known as the population parameters. Maximum likelihood estimation of the population parameters for nonlinear random effects models was pioneered by Beal and Sheiner (1979), and since then a number of algorithms have appeared for approximate maximum likelihood, including Steimer et al. (1984), Lindstrom and Bates (1990), Beal and Sheiner (1992), and Mentre and Gomeni (1995). All of these algorithms are approximate in some way. For a summary see Beal and Sheiner (1992), Wolfinger (1993), Pinheiro and Bates (1994), and Davidian and Giltinan (1995). In this paper an EM algorithm for exact maximum likelihood estimation is introduced. An EM algorithm obtaining maximum likelihood estimates for linear random effects models was introduced by Dempster, Laird, and Rubin (1977). Laird and Ware (1982), Lindstrom and Bates (1988), Jennrich and Schluchter (1986), and Liu and Rubin (1994) all describe hybrid EM algorithms for the linear random effects model. A true EM algorithm for the linear model is described by Jamshidian and Jennrich (1993). Mentre and Gomeni (1995) describe an approximate EM algorithm for nonlinear random effects models and, from the algorithm given in this paper, it can be seen clearly how their approximations arise. The present algorithm uses Monte Carlo methods to perform the E step, a strategy previously adopted in an altogether different model by Guo and Thompson (1994). Guo and Thompson require a Gibbs sampler, that is, a Markov chain Monte Carlo method for their E step, but the present algorithm uses independent samples. In Section 2 of this paper the nonlinear random effects model is described. Section 3 gives the EM algorithm without random effect covariates, while Section 4 gives the modified algorithm in the