The effect of number of clusters and cluster size on statistical power and Type I error rates when testing random effects variance components in multilevel linear and logistic regression models

When using multilevel regression models that incorporate cluster-specific random effects, the Wald and the likelihood ratio (LR) tests are used for testing the null hypothesis that the variance of the random effects distribution is equal to zero. We conducted a series of Monte Carlo simulations to examine the effect of the number of clusters and the number of subjects per cluster on the statistical power to detect a non-null random effects variance and to compare the empirical type I error rates of the Wald and LR tests. Statistical power increased with increasing number of clusters and number of subjects per cluster. Statistical power was greater for the LR test than for the Wald test. These results applied to both the linear and logistic regressions, but were more pronounced for the latter. The use of the LR test is preferable to the use of the Wald test.     

Modeling of covariance structures of random effects and random errors in linear mixed models

Abstract

In this paper, we discuss how to model the mean and covariancestructures in linear mixed models (LMMs) simultaneously. We propose a data-driven method to modelcovariance structures of the random effects and random errors in the LMMs. Parameter estimation in the mean and covariances is considered by using EM algorithm, and standard errors of the parameter estimates are calculated through Louis’ (1982 Louis, T.A. (1982). Finding observed information using the EM algorithm. J. Royal Stat. Soc. B 44:98–130. [Google Scholar]) information principle. Kenward’s (1987 Kenward, M.G. (1987). A method for comparing profiles of repeated measurements. Appl. Stat. 36:296–308.[Crossref], [Web of Science ®] , [Google Scholar]) cattle data sets are analyzed for illustration,and comparison to the literature work is made through simulation studies. Our numerical analysis confirms the superiority of the proposed method to existing approaches in terms of Akaike information criterion.     

Computation aspects of the parameter estimates of linear mixed effects model in multivariate repeated measures set-up

The number of parameters mushrooms in a linear mixed effects (LME) model in the case of multivariate repeated measures data. Computation of these parameters is a real problem with the increase in the number of response variables or with the increase in the number of time points. The problem becomes more intricate and involved with the addition of additional random effects. A multivariate analysis is not possible in a small sample setting. We propose a method to estimate these many parameters in bits and pieces from baby models, by taking a subset of response variables at a time, and finally using these bits and pieces at the end to get the parameter estimates for the mother model, with all variables taken together. Applying this method one can calculate the fixed effects, the best linear unbiased predictions (BLUPs) for the random effects in the model, and also the BLUPs at each time of observation for each response variable, to monitor the effectiveness of the treatment for each subject. The proposed method is illustrated with an example of multiple response variables measured over multiple time points arising from a clinical trial in osteoporosis.     

Empirical evaluation of the implementation of the EMA guideline on missing data in confirmatory clinical trials: Specification of mixed models for longitudinal data in study protocols

In confirmatory clinical trials, the prespecification of the primary analysis model is a universally accepted scientific principle to allow strict control of the type I error. Consequently, both the ICH E9 guideline and the European Medicines Agency (EMA) guideline on missing data in confirmatory clinical trials require that the primary analysis model is defined unambiguously. This requirement applies to mixed models for longitudinal data handling missing data implicitly. To evaluate the compliance with the EMA guideline, we evaluated the model specifications in those clinical study protocols from development phases II and III submitted between 2015 and 2018 to the Ethics Committee at Hannover Medical School under the German Medicinal Products Act, which planned to use a mixed model for longitudinal data in the confirmatory testing strategy. Overall, 39 trials from different types of sponsors and a wide range of therapeutic areas were evaluated. While nearly all protocols specify the fixed and random effects of the analysis model (95%), only 77% give the structure of the covariance matrix used for modeling the repeated measurements. Moreover, the testing method (36%), the estimation method (28%), the computation method (3%), and the fallback strategy (18%) are given by less than half the study protocols. Subgroup analyses indicate that these findings are universal and not specific to clinical trial phases or size of company. Altogether, our results show that guideline compliance is to various degrees poor and consequently, strict type I error rate control at the intended level is not guaranteed.     

A mixed effects model for analyzing area under the curve of longitudinally measured biomarkers with missing data

A simple approach for analyzing longitudinally measured biomarkers is to calculate summary measures such as the area under the curve (AUC) for each individual and then compare the mean AUC between treatment groups using methods such as t test. This two-step approach is difficult to implement when there are missing data since the AUC cannot be directly calculated for individuals with missing measurements. Simple methods for dealing with missing data include the complete case analysis and imputation. A recent study showed that the estimated mean AUC difference between treatment groups based on the linear mixed model (LMM), rather than on individually calculated AUCs by simple imputation, has negligible bias under random missing assumptions and only small bias when missing is not at random. However, this model assumes the outcome to be normally distributed, which is often violated in biomarker data. In this paper, we propose to use a LMM on log-transformed biomarkers, based on which statistical inference for the ratio, rather than difference, of AUC between treatment groups is provided. The proposed method can not only handle the potential baseline imbalance in a randomized trail but also circumvent the estimation of the nuisance variance parameters in the log-normal model. The proposed model is applied to a recently completed large randomized trial studying the effect of nicotine reduction on biomarker exposure of smokers.     

Imputation of missing variance data using non-linear mixed effects modelling to enable an inverse variance weighted meta-analysis of summary-level longitudinal data: a case study

Missing variances, on the basis of the summary-level data, can be a problem when an inverse variance weighted meta-analysis is undertaken. A wide range of approaches in dealing with this issue exist, such as excluding data without a variance measure, using a function of sample size as a weight and imputing the missing standard errors/deviations. A non-linear mixed effects modelling approach was taken to describe the time-course of standard deviations across 14 studies. The model was then used to make predictions of the missing standard deviations, thus, enabling a precision weighted model-based meta-analysis of a mean pain endpoint over time. Maximum likelihood and Bayesian approaches were implemented with example code to illustrate how this imputation can be carried out and to compare the output from each method. The resultant imputations were nearly identical for the two approaches. This modelling approach acknowledges the fact that standard deviations are not necessarily constant over time and can differ between treatments and across studies in a predictable way.     

General location multivariate latent variable models for mixed correlated bounded continuous,ordinal, and nominal responses with non-ignorable missing data

Using a multivariate latent variable approach, this article proposes some new general models to analyze the correlated bounded continuous and categorical (nominal or/and ordinal) responses with and without non-ignorable missing values. First, we discuss regression methods for jointly analyzing continuous, nominal, and ordinal responses that we motivated by analyzing data from studies of toxicity development. Second, using the beta and Dirichlet distributions, we extend the models so that some bounded continuous responses are replaced for continuous responses. The joint distribution of the bounded continuous, nominal and ordinal variables is decomposed into a marginal multinomial distribution for the nominal variable and a conditional multivariate joint distribution for the bounded continuous and ordinal variables given the nominal variable. We estimate the regression parameters under the new general location models using the maximum-likelihood method. Sensitivity analysis is also performed to study the influence of small perturbations of the parameters of the missing mechanisms of the model on the maximal normal curvature. The proposed models are applied to two data sets: BMI, Steatosis and Osteoporosis data and Tehran household expenditure budgets.     

Testing of homogeneity of variance and autocorrelation coefficients of nonlinear mixed models with AR(1) errors based on M-estimation

Homogeneity of between-individual variance and autocorrelation coefficients is one of assumptions in the study of longitudinal data. However, the assumption could be challenging due to the complexity of the dataset. In the paper we propose and analyze nonlinear mixed models with AR(1) errors for longitudinal data, intend to introduce Huber's function in the log-likelihood function and get robust estimation, which may help to reduce the influence of outliers, by Fisher scoring method. Testing of homogeneity of variance among individuals and autocorrelation coefficients on the basis of Huber's M-estimation is studied later in the paper. Simulation studies are carried to assess performance of score test we proposed. Results obtained from plasma concentrations data are reported as an illustrative example.     

Prediction of transplant-free survival in idiopathic pulmonary fibrosis patients using joint models for event times and mixed multivariate longitudinal data

We implement a joint model for mixed multivariate longitudinal measurements, applied to the prediction of time until lung transplant or death in idiopathic pulmonary fibrosis. Specifically, we formulate a unified Bayesian joint model for the mixed longitudinal responses and time-to-event outcomes. For the longitudinal model of continuous and binary responses, we investigate multivariate generalized linear mixed models using shared random effects. Longitudinal and time-to-event data are assumed to be independent conditional on available covariates and shared parameters. A Markov chain Monte Carlo algorithm, implemented in OpenBUGS, is used for parameter estimation. To illustrate practical considerations in choosing a final model, we fit 37 different candidate models using all possible combinations of random effects and employ a deviance information criterion to select a best-fitting model. We demonstrate the prediction of future event probabilities within a fixed time interval for patients utilizing baseline data, post-baseline longitudinal responses, and the time-to-event outcome. The performance of our joint model is also evaluated in simulation studies.     

A unified approach to estimation of nonlinear mixed effects and Berkson measurement error models

Mixed effects models and Berkson measurement error models are widely used. They share features which the author uses to develop a unified estimation framework. He deals with models in which the random effects (or measurement errors) have a general parametric distribution, whereas the random regression coefficients (or unobserved predictor variables) and error terms have nonparametric distributions. He proposes a second-order least squares estimator and a simulation-based estimator based on the first two moments of the conditional response variable given the observed covariates. He shows that both estimators are consistent and asymptotically normally distributed under fairly general conditions. The author also reports Monte Carlo simulation studies showing that the proposed estimators perform satisfactorily for relatively small sample sizes. Compared to the likelihood approach, the proposed methods are computationally feasible and do not rely on the normality assumption for random effects or other variables in the model.     

A longitudinal study of children's aggressive behaviours based on multivariate mixed models with incomplete data

The authors consider children's behavioural and emotional problems and their relationships with possible predictors. They propose a multivariate transitional mixed‐effects model for a longitudinal study and simultaneously address non‐ignorable missing data in responses and covariates, measurement errors in covariates, and multivariate modelling of the responses and covariate processes. A real dataset is analysed in details using the proposed method with some interesting results. The Canadian Journal of Statistics 37: 435–452; 2009 © 2009 Statistical Society of Canada     

Estimation of variance components in the mixed effects models: A comparison between analysis of variance and spectral decomposition

The mixed effects models with two variance components are often used to analyze longitudinal data. For these models, we compare two approaches to estimating the variance components, the analysis of variance approach and the spectral decomposition approach. We establish a necessary and sufficient condition for the two approaches to yield identical estimates, and some sufficient conditions for the superiority of one approach over the other, under the mean squared error criterion. Applications of the methods to circular models and longitudinal data are discussed. Furthermore, simulation results indicate that better estimates of variance components do not necessarily imply higher power of the tests or shorter confidence intervals.