Some Properties of the Liang-Zeger Method Applied to Clustered Binary Regression

The Generalized Estimating Equation (GEE) method popularized by Liang and Zeger provides a very general method for fitting regression models to observations that occur in clusters. Features of the method are the specification of a 'working correlation' (a guess at the true correlation structure of the data) which is used to improve efficiency in estimating the regression coefficients, and the 'information sandwich' which provides a way of consistently estimating the standard errors of the estimated regression coefficients even if (as we might expect) the working correlation is wrong. This paper develops asymptotic expressions for the bias and efficiency both of the regression coefficient estimates and of the sandwich estimate, and uses them to study the behaviour of the estimates.
It looks at the effect of the choice of the working correlation on the estimate and also examines the effect of different cluster sizes and different degrees of correlation between the covariates. The performance of these methods is found to be excellent, particularly when the degree of correlation in the responses and covariates is small to moderate.     

Efficient Estimation in Marginal Partially Linear Models for Longitudinal/Clustered Data Using Splines

Abstract.  We consider marginal semiparametric partially linear models for longitudinal/clustered data and propose an estimation procedure based on a spline approximation of the non-parametric part of the model and an extension of the parametric marginal generalized estimating equations (GEE). Our estimates of both parametric part and non-parametric part of the model have properties parallel to those of parametric GEE, that is, the estimates are efficient if the covariance structure is correctly specified and they are still consistent and asymptotically normal even if the covariance structure is misspecified. By showing that our estimate achieves the semiparametric information bound, we actually establish the efficiency of estimating the parametric part of the model in a stronger sense than what is typically considered for GEE. The semiparametric efficiency of our estimate is obtained by assuming only conditional moment restrictions instead of the strict multivariate Gaussian error assumption.     

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.     

Fitting generalized linear models to retrospectively sampled clusters with categorical responses

We use simulations based on data on injury severity in car accidents to compare methods for the analysis of very large data sets containing clusters of individuals for which the measured response is polytomous. Retrospective sampling of clusters is used to expedite the analysis of the large data set while at the same time obtaining information about rare, but important, outcomes. An additional complication in the analysis of such data sets is that there can be two types of covariates: those which vary within a cluster and those which vary only among clusters. Weighted generalized estimating equations are developed to obtain consistent estimates of the regression coefficients in a proportional-odds model, along with a weighted robust covariance matrix to estimate the variabilities of these estimated coefficients.     

Variance function in regression analysis of longitudinal data using the generalized estimating equation approach

Longitudinal or clustered response data arise in many applications such as biostatistics, epidemiology and environmental studies. The repeated responses cannot in general be assumed to be independent. One method of analysing such data is by using the generalized estimating equations (GEE) approach. The current GEE method for estimating regression effects in longitudinal data focuses on the modelling of the working correlation matrix assuming a known variance function. However, correct choice of the correlation structure may not necessarily improve estimation efficiency for the regression parameters if the variance function is misspecified [Wang YG, Lin X. Effects of variance-function misspecification in analysis of longitudinal data. Biometrics. 2005;61:413–421]. In this connection two problems arise: finding a correct variance function and estimating the parameters of the chosen variance function. In this paper, we study the problem of estimating the parameters of the variance function assuming that the form of the variance function is known and then the effect of a misspecified variance function on the estimates of the regression parameters. We propose a GEE approach to estimate the parameters of the variance function. This estimation approach borrows the idea of Davidian and Carroll [Variance function estimation. J Amer Statist Assoc. 1987;82:1079–1091] by solving a nonlinear regression problem where residuals are regarded as the responses and the variance function is regarded as the regression function. A limited simulation study shows that the proposed method performs at least as well as the modified pseudo-likelihood approach developed by Wang and Zhao [A modified pseudolikelihood approach for analysis of longitudinal data. Biometrics. 2007;63:681–689]. Both these methods perform better than the GEE approach.     

Marginal semiparametric multivariate accelerated failure time model with generalized estimating equations

The semiparametric accelerated failure time (AFT) model is not as widely used as the Cox relative risk model due to computational difficulties. Recent developments in least squares estimation and induced smoothing estimating equations for censored data provide promising tools to make the AFT models more attractive in practice. For multivariate AFT models, we propose a generalized estimating equations (GEE) approach, extending the GEE to censored data. The consistency of the regression coefficient estimator is robust to misspecification of working covariance, and the efficiency is higher when the working covariance structure is closer to the truth. The marginal error distributions and regression coefficients are allowed to be unique for each margin or partially shared across margins as needed. The initial estimator is a rank-based estimator with Gehan’s weight, but obtained from an induced smoothing approach with computational ease. The resulting estimator is consistent and asymptotically normal, with variance estimated through a multiplier resampling method. In a large scale simulation study, our estimator was up to three times as efficient as the estimateor that ignores the within-cluster dependence, especially when the within-cluster dependence was strong. The methods were applied to the bivariate failure times data from a diabetic retinopathy study.     

Variance Estimation in Spatial Regression Using a Non-parametric Semivariogram Based on Residuals

Abstract.  The empirical semivariogram of residuals from a regression model with stationary errors may be used to estimate the covariance structure of the underlying process. For prediction (kriging) the bias of the semivariogram estimate induced by using residuals instead of errors has only a minor effect because the bias is small for small lags. However, for estimating the variance of estimated regression coefficients and of predictions, the bias due to using residuals can be quite substantial. Thus we propose a method for reducing this bias. The adjusted empirical semivariogram is then isotonized and made conditionally negative-definite and used to estimate the variance of estimated regression coefficients in a general estimating equations setup. Simulation results for least squares and robust regression show that the proposed method works well in linear models with stationary correlated errors.     

The pseudo‐GEE approach to the analysis of longitudinal surveys

Longitudinal surveys have emerged in recent years as an important data collection tool for population studies where the primary interest is to examine population changes over time at the individual level. Longitudinal data are often analyzed through the generalized estimating equations (GEE) approach. The vast majority of existing literature on the GEE method; however, is developed under non‐survey settings and are inappropriate for data collected through complex sampling designs. In this paper the authors develop a pseudo‐GEE approach for the analysis of survey data. They show that survey weights must and can be appropriately accounted in the GEE method under a joint randomization framework. The consistency of the resulting pseudo‐GEE estimators is established under the proposed framework. Linearization variance estimators are developed for the pseudo‐GEE estimators when the finite population sampling fractions are small or negligible, a scenario often held for large‐scale surveys. Finite sample performances of the proposed estimators are investigated through an extensive simulation study using data from the National Longitudinal Survey of Children and Youth. The results show that the pseudo‐GEE estimators and the linearization variance estimators perform well under several sampling designs and for both continuous and binary responses. The Canadian Journal of Statistics 38: 540–554; 2010 © 2010 Statistical Society of Canada     

GEE estimation of the covariance structure of a bivariate panel data model with an application to wage dynamics and the incidence of profit-sharing in West Germany

We propose a generalized estimating equations (GEE) approach to the estimation of the mean and covariance structure of bivariate time series processes of panel data. The one-step approach allows for mixed continuous and discrete dependent variables. A Monte Carlo Study is presented to compare our particular GEE estimator with more standard GEE-estimators. In the empirical illustration, we apply our estimator to the analysis of individual wage dynamics and the incidence of profit-sharing in West Germany. Our findings show that time-invariant unobserved individual ability jointly influences individual wages and participation in profit sharing schemes.     

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.     

A Pairwise Likelihood Procedure for Analyzing Exchangeable Binary Data with Random Cluster Sizes

For the exchangeable binary data with random cluster sizes, we use a pairwise likelihood procedure to give a set of approximately optimal unbiased estimating equations for estimating the mean and variance parameters. Theoretical results are obtained establishing the large sample properties of the solutions to the estimating equations. An application to a developmental toxicity study is given. Simulation results show that the pairwise likelihood procedure is valid and performs better than the GEE procedure for the exchangeable binary data.     

Marginal models for the association structure of hierarchical binary responses

Clustered binary responses are often found in ecological studies. Data analysis may include modeling the marginal probability response. However, when the association is the main scientific focus, modeling the correlation structure between pairs of responses is the key part of the analysis. Second-order generalized estimating equations (GEE) are established in the literature. Some of them are more efficient in computational terms, especially facing large clusters. Alternating logistic regression (ALR) and orthogonalized residual (ORTH) GEE methods are presented and compared in this paper. Simulation results show a slightly superiority of ALR over ORTH. Marginal probabilities and odds ratios are also estimated and compared in a real ecological study involving a three-level hierarchical clustering. ALR and ORTH models are useful for modeling complex association structure with large cluster sizes.     

Modification of GEE1 and linear mixed-effects models for heteroscedastic longitudinal Gaussian data

A characterization of GLMs is given. Modification of the Gaussian GEE1, modified GEE1, was applied to heteroscedastic longitudinal data, to which linear mixed-effects models are usually applied. The modified GEE1 models scale multivariate data to homoscedastic data maintaining the correlation structure and apply usual GEE1 to homoscedastic data, which needs no-diagnostics for diagonal variances. Relationships among multivariate linear regression methods, ordinary/generalized LS, naïve/modified GEE1, and linear mixed-effects models were discussed. An application showed modified GEE1 gave most efficient parameter estimation. Correct specification of the main diagonals of heteroscedastic data variance appears to be more important for efficient mean parameter estimation.     

A new look at the difference between the GEE and the GLMM when modeling longitudinal count responses

Poisson log-linear regression is a popular model for count responses. We examine two popular extensions of this model – the generalized estimating equations (GEE) and the generalized linear mixed-effects model (GLMM) – to longitudinal data analysis and complement the existing literature on characterizing the relationship between the two dueling paradigms in this setting. Unlike linear regression, the GEE and the GLMM carry significant conceptual and practical implications when applied to modeling count data. Our findings shed additional light on the differences between the two classes of models when used for count data. Our considerations are demonstrated by both real study and simulated data.     

An alternative approach to the analysis of longitudinal data via generalized estimating equations

The generalized estimating equations (GEE) introduced by Liang and Zeger (Biometrika 73 (1986) 13–22) have been widely used over the past decade to analyze longitudinal data. The method uses a generalized quasi-score function estimate for the regression coefficients, and moment estimates for the correlation parameters. Recently, Crowder (Biometrika 82 (1995) 407–410) has pointed out some pitfalls with the estimation of the correlation parameters in the GEE method. In this paper we present a new method for estimating the correlation parameters which overcomes those pitfalls. For some commonly assumed correlation structures, we obtain unique feasible estimates for the correlation parameters. Large sample properties of our estimates are also established.     

Estimated estimating equations: semiparametric inference for clustered and longitudinal data

Summary.  We introduce a flexible marginal modelling approach for statistical inference for clustered and longitudinal data under minimal assumptions. This estimated estimating equations approach is semiparametric and the proposed models are fitted by quasi-likelihood regression, where the unknown marginal means are a function of the fixed effects linear predictor with unknown smooth link, and variance–covariance is an unknown smooth function of the marginal means. We propose to estimate the nonparametric link and variance–covariance functions via smoothing methods, whereas the regression parameters are obtained via the estimated estimating equations. These are score equations that contain nonparametric function estimates. The proposed estimated estimating equations approach is motivated by its flexibility and easy implementation. Moreover, if data follow a generalized linear mixed model, with either a specified or an unspecified distribution of random effects and link function, the model proposed emerges as the corresponding marginal (population-average) version and can be used to obtain inference for the fixed effects in the underlying generalized linear mixed model, without the need to specify any other components of this generalized linear mixed model. Among marginal models, the estimated estimating equations approach provides a flexible alternative to modelling with generalized estimating equations. Applications of estimated estimating equations include diagnostics and link selection. The asymptotic distribution of the proposed estimators for the model parameters is derived, enabling statistical inference. Practical illustrations include Poisson modelling of repeated epileptic seizure counts and simulations for clustered binomial responses.     

Robust inference for bivariate point processes

In the analysis of recurrent events where the primary interest lies in studying covariate effects on the expected number of events occurring over a period of time, it is appealing to base models on the cumulative mean function (CMF) of the processes (Lawless & Nadeau 1995). In many chronic diseases, however, more than one type of event is manifested. Here we develop a robust inference procedure for joint regression models for the CMFs arising from a bivariate point process. Consistent parameter estimates with robust variance estimates are obtained via unbiased estimating functions for the CMFs. In most situations, the covariance structure of the bivariate point processes is difficult to specify correctly, but when it is known, an optimal estimating function for the CMFs can be obtained. As a convenient model for more general settings, we suggest the use of the estimating functions arising from bivariate mixed Poisson processes. Simulation studies demonstrate that the estimators based on this working model are practically unbiased with robust variance estimates. Furthermore, hypothesis tests may be based on the generalized Wald or generalized score tests. Data from a trial of patients with bronchial asthma are analyzed to illustrate the estimation and inference procedures.     

Joint Mean-Covariance Models with Applications to Longitudinal Data in Partially Linear Model

Semiparametric regression models and estimating covariance functions are very useful in longitudinal study. Unfortunately, challenges arise in estimating the covariance function of longitudinal data collected at irregular time points. In this article, for mean term, a partially linear model is introduced and for covariance structure, a modified Cholesky decomposition approach is proposed to heed the positive-definiteness constraint. We estimate the regression function by using the local linear technique and propose quasi-likelihood estimating equations for both the mean and covariance structures. Moreover, asymptotic normality of the resulting estimators is established. Finally, simulation study and real data analysis are used to illustrate the proposed approach.