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Nonlinear mixed‐effects models with misspecified random‐effects distribution
Author(s) -
Drikvandi Reza
Publication year - 2019
Publication title -
pharmaceutical statistics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.421
H-Index - 38
eISSN - 1539-1612
pISSN - 1539-1604
DOI - 10.1002/pst.1981
Subject(s) - random effects model , mixed model , mathematics , econometrics , nonlinear system , generalized linear mixed model , statistics , marginal distribution , unobservable , random variable , physics , quantum mechanics , medicine , meta analysis
Nonlinear mixed‐effects models are being widely used for the analysis of longitudinal data, especially from pharmaceutical research. They use random effects which are latent and unobservable variables so the random‐effects distribution is subject to misspecification in practice. In this paper, we first study the consequences of misspecifying the random‐effects distribution in nonlinear mixed‐effects models. Our study is focused on Gauss‐Hermite quadrature, which is now the routine method for calculation of the marginal likelihood in mixed models. We then present a formal diagnostic test to check the appropriateness of the assumed random‐effects distribution in nonlinear mixed‐effects models, which is very useful for real data analysis. Our findings show that the estimates of fixed‐effects parameters in nonlinear mixed‐effects models are generally robust to deviations from normality of the random‐effects distribution, but the estimates of variance components are very sensitive to the distributional assumption of random effects. Furthermore, a misspecified random‐effects distribution will either overestimate or underestimate the predictions of random effects. We illustrate the results using a real data application from an intensive pharmacokinetic study.