Approximate testing in two-stage nonlinear mixed models

We investigate here small sample properties of approximate F-tests about fixed effects parameters in nonlinear mixed models. For estimation of population fixed effects parameters as well as variance components, we apply the two-stage approach. This method is useful and popular when the number of observations per sampling unit is large enough. The approximate F-test is constructed based on large-sample approximation to the distribution of nonlinear least-squares estimates of subject-specific parameters. We recommend a modified test statistic that takes into consideration approximation to the large-sample Fisher information matrix (See [Volaufova J, Burton JH. Note on hypothesis testing in mixed models. Oral presentation at: LINSTAT 2012/21st IWMS; 2012; Bedlewo, Poland]). Our main focus is on comparing finite sample properties of broadly used approximate tests (Wald test and likelihood ratio test) and the modified F-test under the null hypothesis, especially accuracy of p-values (See [Volaufova J, LaMotte L. Comparison of approximate tests of fixed effects in linear repeated measures design models with covariates. Tatra Mountains. 2008;39:17-25]). For that purpose two extensive simulation studies are conducted based on pharmacokinetic models (See [Hartford A, Davidian M. Consequences of misspecifying assumptions in nonlinear mixed effects models. Comput Stat and Data Anal. 2000;34:139-164; Pinheiro J, Bates D. Approximations to the log-likelihood function in the non-linear mixed-effects model. J Comput Graph Stat. 1995;4(1):12-35]).