Bias from the use of generalized estimating equations to analyze incomplete longitudinal binary data

Patient dropout is a common problem in studies that collect repeated binary measurements. Generalized estimating equations (GEE) are often used to analyze such data. The dropout mechanism may be plausibly missing at random (MAR), i.e. unrelated to future measurements given covariates and past measurements. In this case, various authors have recommended weighted GEE with weights based on an assumed dropout model, or an imputation approach, or a doubly robust approach based on weighting and imputation. These approaches provide asymptotically unbiased inference, provided the dropout or imputation model (as appropriate) is correctly specified. Other authors have suggested that, provided the working correlation structure is correctly specified, GEE using an improved estimator of the correlation parameters (‘modified GEE’) show minimal bias. These modified GEE have not been thoroughly examined. In this paper, we study the asymptotic bias under MAR dropout of these modified GEE, the standard GEE, and also GEE using the true correlation. We demonstrate that all three methods are biased in general. The modified GEE may be preferred to the standard GEE and are subject to only minimal bias in many MAR scenarios but in others are substantially biased. Hence, we recommend the modified GEE be used with caution.     

Variance component models for longitudinal count data with baseline information: epilepsy data revisited

Random effect models have often been used in longitudinal data analysis since they allow for association among repeated measurements due to unobserved heterogeneity. Various approaches have been proposed to extend mixed models for repeated count data to include dependence on baseline counts. Dependence between baseline counts and individual-specific random effects result in a complex form of the (conditional) likelihood. An approximate solution can be achieved ignoring this dependence, but this approach could result in biased parameter estimates and in wrong inferences. We propose a computationally feasible approach to overcome this problem, leaving the random effect distribution unspecified. In this context, we show how the EM algorithm for nonparametric maximum likelihood (NPML) can be extended to deal with dependence of repeated measures on baseline counts.     

On generalised estimating equations for vector regression

Generalised estimating equations (GEE) for regression problems with vector‐valued responses are examined. When the response vectors are of mixed type (e.g. continuous–binary response pairs), the GEE approach is a semiparametric alternative to full‐likelihood copula methods, and is closely related to Prentice & Zhao's mean‐covariance estimation equations approach. When the response vectors are of the same type (e.g. measurements on left and right eyes), the GEE approach can be viewed as a ‘plug‐in’ to existing methods, such as the vglm function from the state‐of‐the‐art VGAM package in R. In either scenario, the GEE approach offers asymptotically correct inferences on model parameters regardless of whether the working variance–covariance model is correctly or incorrectly specified. The finite‐sample performance of the method is assessed using simulation studies based on a burn injury dataset and a sorbinil eye trial dataset. The method is applied to data analysis examples using the same two datasets, as well as to a trivariate binary dataset on three plant species in the Hunua ranges of Auckland.     

The impact of dichotomization in longitudinal data analysis: a simulation study

In this paper, a simulation study is conducted to systematically investigate the impact of dichotomizing longitudinal continuous outcome variables under various types of missing data mechanisms. Generalized linear models (GLM) with standard generalized estimating equations (GEE) are widely used for longitudinal outcome analysis, but these semi‐parametric approaches are only valid under missing data completely at random (MCAR). Alternatively, weighted GEE (WGEE) and multiple imputation GEE (MI‐GEE) were developed to ensure validity under missing at random (MAR). Using a simulation study, the performance of standard GEE, WGEE and MI‐GEE on incomplete longitudinal dichotomized outcome analysis is evaluated. For comparisons, likelihood‐based linear mixed effects models (LMM) are used for incomplete longitudinal original continuous outcome analysis. Focusing on dichotomized outcome analysis, MI‐GEE with original continuous missing data imputation procedure provides well controlled test sizes and more stable power estimates compared with any other GEE‐based approaches. It is also shown that dichotomizing longitudinal continuous outcome will result in substantial loss of power compared with LMM. Copyright © 2009 John Wiley & Sons, Ltd.     

Statistical Inference for the Multidimensional Mixed Rasch Model

Inference in generalized linear mixed models with multivariate random effects is often made cumbersome by the high-dimensional intractable integrals involved in the marginal likelihood. This article presents an inferential methodology based on the GEE approach. This method involves the approximations of the marginal likelihood and joint moments of the variables. It is also proposed an approximate Akaike and Bayesian information criterions based on the approximate marginal likelihood using the estimation of the parameters by the GEE approach. The different results are illustrated with a simulation study and with an analysis of real data from health-related quality of life.     

Regularization in dynamic random-intercepts models for analysis of longitudinal data

This paper addresses the problem of simultaneous variable selection and estimation in the random-intercepts model with the first-order lag response. This type of model is commonly used for analyzing longitudinal data obtained through repeated measurements on individuals over time. This model uses random effects to cover the intra-class correlation, and the first lagged response to address the serial correlation, which are two common sources of dependency in longitudinal data. We demonstrate that the conditional likelihood approach by ignoring correlation among random effects and initial responses can lead to biased regularized estimates. Furthermore, we demonstrate that joint modeling of initial responses and subsequent observations in the structure of dynamic random-intercepts models leads to both consistency and Oracle properties of regularized estimators. We present theoretical results in both low- and high-dimensional settings and evaluate regularized estimators' performances by conducting simulation studies and analyzing a real dataset. Supporting information is available online.     

Mixture of linear mixed models using multivariate t distribution

Linear mixed models are widely used when multiple correlated measurements are made on each unit of interest. In many applications, the units may form several distinct clusters, and such heterogeneity can be more appropriately modelled by a finite mixture linear mixed model. The classical estimation approach, in which both the random effects and the error parts are assumed to follow normal distribution, is sensitive to outliers, and failure to accommodate outliers may greatly jeopardize the model estimation and inference. We propose a new mixture linear mixed model using multivariate t distribution. For each mixture component, we assume the response and the random effects jointly follow a multivariate t distribution, to conveniently robustify the estimation procedure. An efficient expectation conditional maximization algorithm is developed for conducting maximum likelihood estimation. The degrees of freedom parameters of the t distributions are chosen data adaptively, for achieving flexible trade-off between estimation robustness and efficiency. Simulation studies and an application on analysing lung growth longitudinal data showcase the efficacy of the proposed approach.     

Comparing alternating logistic regressions to other approaches to modelling correlated binary data

Alternating logistic regressions (ALRs) seem to offer some of the advantages of marginal models estimated via generalized estimating equations (GEE) and generalized linear mixed models (GLMMs). Via simulation study we compared ALRs to marginal models estimated via GEE and subject-specific models estimated via GLMMs, with a focus on estimation of the correlation structure in three-level data sets (e.g. students in classes in schools). Data set size and structure, and amount of correlation in the data sets were varied. For simple correlation structures, ALRs performed well. For three-level correlation structures, all approaches, but especially ALRs, had difficulty assigning the correlation to the correct level, though sample sizes used were small. In addition, ALRs and GEEs had trouble attaching correct inference to the mean effects, though this improved as overall sample size improved. ALRs are a valuable addition to the data analyst's toolkit, though care should be taken when modelling data with three-level structures.     

Assessing inter- and intra-agreement for dependent binary data: a Bayesian hierarchical correlation approach

Agreement measures are designed to assess consistency between different instruments rating measurements of interest. When the individual responses are correlated with multilevel structure of nestings and clusters, traditional approaches are not readily available to estimate the inter- and intra-agreement for such complex multilevel settings. Our research stems from conformity evaluation between optometric devices with measurements on both eyes, equality tests of agreement in high myopic status between monozygous twins and dizygous twins, and assessment of reliability for different pathologists in dysplasia. In this paper, we focus on applying a Bayesian hierarchical correlation model incorporating adjustment for explanatory variables and nesting correlation structures to assess the inter- and intra-agreement through correlations of random effects for various sources. This Bayesian generalized linear mixed-effects model (GLMM) is further compared with the approximate intra-class correlation coefficients and kappa measures by the traditional Cohen’s kappa statistic and the generalized estimating equations (GEE) approach. The results of comparison studies reveal that the Bayesian GLMM provides a reliable and stable procedure in estimating inter- and intra-agreement simultaneously after adjusting for covariates and correlation structures, in marked contrast to Cohen’s kappa and the GEE approach.     

Optimal Estimator for Logistic Model with Distribution‐free Random Intercept

Logistic models with a random intercept are prevalent in medical and social research where clustered and longitudinal data are often collected. Traditionally, the random intercept in these models is assumed to follow some parametric distribution such as the normal distribution. However, such an assumption inevitably raises concerns about model misspecification and misleading inference conclusions, especially when there is dependence between the random intercept and model covariates. To protect against such issues, we use a semiparametric approach to develop a computationally simple and consistent estimator where the random intercept is distribution‐free. The estimator is revealed to be optimal and achieve the efficiency bound without the need to postulate or estimate any latent variable distributions. We further characterize other general mixed models where such an optimal estimator exists.     

Pseudo-Likelihood Methodology for Hierarchical Count Data

Generalized Estimating Equations (GEE) are a widespread tool for modeling correlated data, based on properly formulating a marginal regression function, combined with working assumptions about the correlation function. Should interest be placed in addition on the correlation function, then, apart from second-order GEE, pseudo-likelihood (PL) also provides an attractive alternative, especially in its pairwise form, where the covariance between each pair of the response vector is modeled as well. An elegant PL approach is formulated in this paper, based on a flexible bivariate Poisson model. The performance of the PL-method is studied, relative to GEE, using simulations. Data on repeated counts of epileptic seizures in a two-arm clinical trial are analyzed. A macro has been developed by the authors and made available on their web pages.     

Modified regression coefficient analysis for repeated binary measurements

Myers & Broyles (2000a, 2000b) illustrate that regression coefficient analysis (RCA) is a viable alternative to a generalized estimating equation (GEE) in the analysis of correlated binomial data. Since the regression coefficients (b i ' s ) may have different precisions, we modify RCA by weighting b i ' s by the inverses of their variances for statistical optimality. We perform the simulation study to evaluate the performance of RCA, modified RCA and GEE in terms of empirical type I errors and empirical powers of the regression coefficients in repeated binary measurement designs with and without dropouts. Two thousand data sets are generated using autoregressive (AR(1)) and compound symmetry (CS) correlation structures. We compare the type I errors and powers of RCA, modified RCA and GEE for the analysis of repeated binary measurement data as affected by different dropout mechanisms such as random dropouts and treatment dependent dropouts.     

Some Comments on Hassairi et al.'s “Implicit Distributions and Estimation”

In social interaction studies, one commonly encounters repeated displays of behaviors along with their duration data. Statistical methods for the analysis of such data use either parametric (e.g., Weibull) or semi-nonparametric (e.g., Cox) proportional hazard models, modified to include random effects (frailty) which account for the correlation of repeated occurrences of behaviors within a unit (dyad). However, dyad-specific random effects by themselves are not able to account for the ordering of event occurrences within dyads. The occurrence of an event (behavior) can make further occurrences of the same behavior to be more or less likely during an interaction. This article develops event-dependent random effects models for analyzing repeated behaviors data using a Bayesian approach. The models are illustrated by a dataset relating to emotion regulation in families with children who have behavioral or emotional problems.     

Simultaneous Confidence Intervals for Ratios of Fixed Effect Parameters in Linear Mixed Models

In multiple comparisons of fixed effect parameters in linear mixed models, treatment effects can be reported as relative changes or ratios. Simultaneous confidence intervals for such ratios had been previously proposed based on Bonferroni adjustments or multivariate normal quantiles accounting for the correlation among the multiple contrasts. We propose Fieller-type intervals using multivariate t quantiles and the application of Markov chain Monte Carlo techniques to sample from the joint posterior distribution and construct percentile-based simultaneous intervals. The methods are compared in a simulation study including bioassay problems with random intercepts and slopes, repeated measurements designs, and multicenter clinical trials.     

Rank correlation plots for use with correlated input variables

A method for inducing a desired rank correlation matrix on multivariate input vectors for simulation studies has recently been developed by Iman and Conover (1982). The primary intention of this procedure is to produce correlated input variables for use with computer models. Since this procedure is distribution free and allows the exact marginal distributions to remain intact it can be used with any marginal distributions for which it is reasonable to think in terms of correlation. In this paper we present a series of rank correlation plots based on this procedure when the marginal distributions are normal, lognormal, uniform and loguniform. These plots provide a convenient tool both for aiding the modeler in determining the degree of dependence among input variables (rather than guessing) and for communicating with the modeler the effect of different correlation assumptions. In addition this procedure can be used with sample multivariate data by sampling directly from the respective marginal empirical distribution functions.     

Bayesian outlier analysis in binary regression

We propose alternative approaches to analyze residuals in binary regression models based on random effect components. Our preferred model does not depend upon any tuning parameter, being completely automatic. Although the focus is mainly on accommodation of outliers, the proposed methodology is also able to detect them. Our approach consists of evaluating the posterior distribution of random effects included in the linear predictor. The evaluation of the posterior distributions of interest involves cumbersome integration, which is easily dealt with through stochastic simulation methods. We also discuss different specifications of prior distributions for the random effects. The potential of these strategies is compared in a real data set. The main finding is that the inclusion of extra variability accommodates the outliers, improving the adjustment of the model substantially, besides correctly indicating the possible outliers.     

A test of the missing data mechanism for repeated measures data

The occurrence of missing data is an often unavoidable consequence of repeated measures studies. Fortunately, multivariate general linear models such as growth curve models and linear mixed models with random effects have been well developed to analyze incomplete normally-distributed repeated measures data. Most statistical methods have assumed that the missing data occur at random. This assumption may include two types of missing data mechanism: missing completely at random (MCAR) and missing at random (MAR) in the sense of Rubin (1976). In this paper, we develop a test procedure for distinguishing these two types of missing data mechanism for incomplete normally-distributed repeated measures data. The proposed test is similar in spiril to the test of Park and Davis (1992). We derive the test for incomplete normally-distribrlted repeated measures data using linear mixed models. while Park and Davis (1992) cleirved thr test for incomplete repeatctl categorical data in the framework of Grizzle Starmer. and Koch (1969). Thr proposed procedure can be applied easily to any other multivariate general linear model which allow for missing data. The test is illustrated using the hip-replacernent patient.data from Crowder and Hand (1990).     

Bayesian Inference for Skew-normal Linear Mixed Models

Linear mixed models (LMM) are frequently used to analyze repeated measures data, because they are more flexible to modelling the correlation within-subject, often present in this type of data. The most popular LMM for continuous responses assumes that both the random effects and the within-subjects errors are normally distributed, which can be an unrealistic assumption, obscuring important features of the variations present within and among the units (or groups). This work presents skew-normal liner mixed models (SNLMM) that relax the normality assumption by using a multivariate skew-normal distribution, which includes the normal ones as a special case and provides robust estimation in mixed models. The MCMC scheme is derived and the results of a simulation study are provided demonstrating that standard information criteria may be used to detect departures from normality. The procedures are illustrated using a real data set from a cholesterol study.     

Multivariate generalized linear mixed models with random intercepts to analyze cardiovascular risk markers in type-1 diabetic patients

Statistical approaches tailored to analyzing longitudinal data that have multiple outcomes with different distributions are scarce. This paucity is due to the non-availability of multivariate distributions that jointly model outcomes with different distributions other than the multivariate normal. A plethora of research has been done on the specific combination of binary-Gaussian bivariate outcomes but a more general approach that allows other mixtures of distributions for multiple longitudinal outcomes has not been thoroughly demonstrated and examined. Here, we study a multivariate generalized linear mixed models approach that jointly models multiple longitudinal outcomes with different combinations of distributions and incorporates the correlations between the various outcomes through separate yet correlated random intercepts. Every outcome is linked to the set of covariates through a proper link function that allows the incorporation and joint modeling of different distributions. A novel application was demonstrated on a cohort study of Type-1 diabetic patients to jointly model a mix of longitudinal cardiovascular outcomes and to explore for the first time the effect of glycemic control treatment, plasma prekallikrein biomarker, gender and age on cardiovascular risk factors collectively.     

Modeling the correlation structure of data that have multiple levels of association

Some modem approaches for the analysis of non-normally distributed and correlated data, including Liang and Zeger's ( 1986 ) method of generalized estimating equations (GEE), model the pattern of association among outcomes by assuming a structure for their correlation matrix. A number of relatively simple patterned correlation matrices are available for measurements with one level of correlation. However, modeling the correlation structure of data with multiple levels, or causes, of association is not as straightforward; this note discusses some of the difficulties and discusses a simple class of correlation models that may prove useful in this endeavor.