Model Selection Criterion Based on the Multivariate Quasi‐Likelihood for Generalized Estimating Equations

The generalized estimating equations (GEE) approach has attracted considerable interest for the analysis of correlated response data. This paper considers the model selection criterion based on the multivariate quasi‐likelihood (MQL) in the GEE framework. The GEE approach is closely related to the MQL. We derive a necessary and sufficient condition for the uniqueness of the risk function based on the MQL by using properties of differential geometry. Furthermore, we establish a formal derivation of model selection criterion as an asymptotically unbiased estimator of the prediction risk under this condition, and we explicitly take into account the effect of estimating the correlation matrix used in the GEE procedure.     

ASYMPTOTIC DISTRIBUTIONS OF SEMIPARAMETRIC MAXIMUM LIKELIHOOD ESTIMATORS WITH ESTIMATING EQUATIONS FOR GROUP-CENSORED DATA

Semiparametric maximum likelihood estimation with estimating equations (SMLE) is more flexible than traditional methods; it has fewer restrictions on distributions and regression models. The required information about distribution and regression structures is incorporated in estimating equations of the SMLE to improve the estimation quality of non‐parametric methods. The likelihood of SMLE for censored data involves complicated implicit functions without closed‐form expressions, and the first derivatives of the log‐profile‐likelihood cannot be expressed as summations of independent and identically distributed random variables; it is challenging to derive asymptotic properties of the SMLE for censored data. For group‐censored data, the paper shows that all the implicit functions are well defined and obtains the asymptotic distributions of the SMLE for model parameters and lifetime distributions. With several examples the paper compares the SMLE, the regular non‐parametric likelihood estimation method and the parametric MLEs in terms of their asymptotic efficiencies, and illustrates application of SMLE. Various asymptotic distributions of the likelihood ratio statistics are derived for testing the adequacy of estimating equations and a partial set of parameters equal to some known values.     

Multiple imputation compared with restricted pseudo‐likelihood and generalized estimating equations for analysis of binary repeated measures in clinical studies

Non‐likelihood‐based methods for repeated measures analysis of binary data in clinical trials can result in biased estimates of treatment effects and associated standard errors when the dropout process is not completely at random. We tested the utility of a multiple imputation approach in reducing these biases. Simulations were used to compare performance of multiple imputation with generalized estimating equations and restricted pseudo‐likelihood in five representative clinical trial profiles for estimating (a) overall treatment effects and (b) treatment differences at the last scheduled visit. In clinical trials with moderate to high (40–60%) dropout rates with dropouts missing at random, multiple imputation led to less biased and more precise estimates of treatment differences for binary outcomes based on underlying continuous scores. Copyright © 2005 John Wiley & Sons, Ltd.     

Semi-parametric modelling and likelihood estimation with estimating equations

This paper proposes a semi-parametric modelling and estimating method for analysing censored survival data. The proposed method uses the empirical likelihood function to describe the information in data, and formulates estimating equations to incorporate knowledge of the underlying distribution and regression structure. The method is more flexible than the traditional methods such as the parametric maximum likelihood estimation (MLE), Cox's (1972) proportional hazards model, accelerated life test model, quasi-likelihood (Wedderburn, 1974) and generalized estimating equations (Liang & Zeger, 1986). This paper shows the existence and uniqueness of the proposed semi-parametric maximum likelihood estimates (SMLE) with estimating equations. The method is validated with known cases studied in the literature. Several finite sample simulation and large sample efficiency studies indicate that when the sample size is larger than 100 the SMLE is compatible with the parametric MLE; and in all case studies, the SMLE is about 15% better than the parametric MLE with a mis-specified underlying distribution.     

Nonparametric estimating equations based on a penalized information criterion

It has recently been observed that, given the mean‐variance relation, one can improve on the accuracy of the quasi‐likelihood estimator by the adaptive estimator based on the estimation of the higher moments. The estimation of such moments is usually unstable, however, and consequently only for large samples does the improvement become evident. The author proposes a nonparametric estimating equation that does not depend on the estimation of such moments, but instead on the penalized minimization of asymptotic variance. His method provides a strong improvement over the quasi‐likelihood estimator and the adaptive estimators, for a wide range of sample sizes.     

Robust inference in generalized linear models for longitudinal data

The author develops a robust quasi‐likelihood method, which appears to be useful for down‐weighting any influential data points when estimating the model parameters. He illustrates the computational issues of the method in an example. He uses simulations to study the behaviour of the robust estimates when data are contaminated with outliers, and he compares these estimates to those obtained by the ordinary quasi‐likelihood method.     

Partial Linear Models for Longitudinal Data Based on Quadratic Inference Functions

In this paper, we consider improved estimating equations for semiparametric partial linear models (PLM) for longitudinal data, or clustered data in general. We approximate the non‐parametric function in the PLM by a regression spline, and utilize quadratic inference functions (QIF) in the estimating equations to achieve a more efficient estimation of the parametric part in the model, even when the correlation structure is misspecified. Moreover, we construct a test which is an analogue to the likelihood ratio inference function for inferring the parametric component in the model. The proposed methods perform well in simulation studies and real data analysis conducted in this paper.     

Orthogonalized Residuals for Estimation of Marginally Specified Association Parameters in Multivariate Binary Data

Abstract. This paper focuses on marginal regression models for correlated binary responses when estimation of the association structure is of primary interest. A new estimating function approach based on orthogonalized residuals is proposed. A special case of the proposed procedure allows a new representation of the alternating logistic regressions method through marginal residuals. The connections between second‐order generalized estimating equations, alternating logistic regressions, pseudo‐likelihood and other methods are explored. Efficiency comparisons are presented, with emphasis on variable cluster size and on the role of higher‐order assumptions. The new method is illustrated with an analysis of data on impaired pulmonary function.     

Comparison of GEE1 and GEE2 estimation applied to clustered logistic regression

Generalized estimating equations (GEE) have become a popular method for marginal regression modelling of data that occur in clusters. Features of the GEE methodology are the use of a ‘working covariance’, an approximation to the underlying covariance, which is used to improve the efficiency in estimating the regression coefficients, and the ‘sandwich’ estimate of variance, which provides a way of consistently estimating their standard errors. These techniques have been extended to include estimating equations for the underlying correlation structure, both to improve the efficiency of the regression coefficient estimates and to provide estimates of correlations between units in a cluster, when these are of interest. If the mean structure is of primary interest, then a simpler set of equations (GEE1) can be used, whereas if the underlying covariance structure is of interest in its own right, the use of the more complex GEE2 estimating equations is often recommended. In this paper, we compare the effect of increasing the complexity of the ‘working covariances’ on the variance of the parameter estimates, as well as the mean-squared error of the ‘sandwich’ estimate of variance. We give asymptotic expressions for these variances and mean-squared error terms. We use these to study the behaviour of different variants of GEE1 and GEE2 when we change the number of clusters, the cluster size, and the within-cluster correlation. We conclude that the extra complexity of the full GEE2 approach is not usually justified if the mean structure is of primary interest.     

Use of generalized estimating equations in a trial in influenza to explore treatment effects over time

For trials with repeated measurements of outcome, analyses often focus on univariate outcomes, such as analysis of summary measures or of the last on‐treatment observation. Methods which model the whole data set provide a rich source of approaches to analysis. For continuous data, mixed‐effect modelling is increasingly used. For binary and categorical data, models based on use of generalized estimating equations account for intra‐subject correlation and allow exploration of the time course of response, as well as providing a useful way to account for missing data, when such data can be maintained as missing in the analysis. The utility of this approach is illustrated by an example from a trial in influenza. Copyright © 2004 John Wiley & Sons Ltd.     

Parameter Orthogonality and Bias Adjustment for Estimating Functions

Abstract.  We consider an extended notion of parameter orthogonality for estimating functions, called nuisance parameter insensitivity, which allows a unified treatment of nuisance parameters for a wide range of methods, including Liang and Zeger's generalized estimating equations. Nuisance parameter insensitivity has several important properties in common with conventional parameter orthogonality, such as the nuisance parameter causing no loss of efficiency for estimating the interest parameter, and a simplified estimation algorithm. We also consider bias adjustment for profile estimating functions, and apply the results to restricted maximum likelihood estimation of dispersion parameters in generalized estimating equations.     

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.     

Expected estimating equations to accommodate covariate measurement error

Estimating equations which are not necessarily likelihood-based score equations are becoming increasingly popular for estimating regression model parameters. This paper is concerned with estimation based on general estimating equations when true covariate data are missing for all the study subjects, but surrogate or mismeasured covariates are available instead. The method is motivated by the covariate measurement error problem in marginal or partly conditional regression of longitudinal data. We propose to base estimation on the expectation of the complete data estimating equation conditioned on available data. The regression parameters and other nuisance parameters are estimated simultaneously by solving the resulting estimating equations. The expected estimating equation (EEE) estimator is equal to the maximum likelihood estimator if the complete data scores are likelihood scores and conditioning is with respect to all the available data. A pseudo-EEE estimator, which requires less computation, is also investigated. Asymptotic distribution theory is derived. Small sample simulations are conducted when the error process is an order 1 autoregressive model. Regression calibration is extended to this setting and compared with the EEE approach. We demonstrate the methods on data from a longitudinal study of the relationship between childhood growth and adult obesity.     

Small sample characteristics of generalized estimating equations

The aim of this study was to investigate the Type I error rate of hypothesis testing based on generalized estimating equations (GEE) for data characteristic of periodontal clinical trials. The data in these studies consist of a large number of binary responses from each subject and a small number of subjects (Haffajee et al. (1983), Goodson (1986), Jenkins et al. (1988)) Computer simulations were employed to investigate GEE based both on an empirical estimate of the variance-covariance matrix and a model-based estimate. Results from this investigation indicate that hypothesis testing based on GEE resulted in inappropriate Type I error rates when small samples are employed. Only an increase in the number of subjects to the point where it matched the number of observations per subject resulted in appropriate Type I error rates     

A generalized Q–Q plot for longitudinal data

Most biomedical research is carried out using longitudinal studies. The method of generalized estimating equations (GEEs) introduced by Liang and Zeger [Longitudinal data analysis using generalized linear models, Biometrika 73 (1986), pp. 13–22] and Zeger and Liang [Longitudinal data analysis for discrete and continuous outcomes, Biometrics 42 (1986), pp. 121–130] has become a standard method for analyzing non-normal longitudinal data. Since then, a large variety of GEEs have been proposed. However, the model diagnostic problem has not been explored intensively. Oh et al. [Modeldiagnostic plots for repeated measures data using the generalized estimating equations approach, Comput. Statist. Data Anal. 53 (2008), pp. 222–232] proposed residual plots based on the quantile–quantile (Q–Q) plots of the χ²-distribution for repeated-measures data using the GEE methodology. They considered the Pearson, Anscombe and deviance residuals. In this work, we propose to extend this graphical diagnostic using a generalized residual. A simulation study is presented as well as two examples illustrating the proposed generalized Q–Q plots.     

Variable selection in generalized estimating equations via empirical likelihood and Gaussian pseudo-likelihood

AIC and BIC based on either empirical likelihood (EAIC and EBIC) or Gaussian pseudo-likelihood (GAIC and GBIC) are proposed to select variables in longitudinal data analysis. Their performances are evaluated in the framework of the generalized estimating equations via intensive simulation studies. Our findings are: (i) GAIC and GBIC outperform other existing methods in selecting variables; (ii) EAIC and EBIC are effective in selecting covariates only when the working correlation structure is correctly specified; (iii) GAIC and GBIC perform well regardless the working correlation structure is correctly specified or not. A real dataset is also provided to illustrate the findings.     

Robust statistical inference: weighted likelihoods or usual m-estimation?

We review the weighted likelihood estimating equations methodology introduced by Markatou, Basu and Lindsay (1995). and Basu, Markatou and Lindsay (1995) and compare it, in the case of symmetric and asymmetric contamination, with Huber's M-estimators of location. The simulation study shows that the weighted likelihood estimating equations estimator is at least as competitive as Huber's M-estimators in the case of symmetric contamination. In the case of asymmetric contamination it may be superior than Huber's M-estimators     

Modelling Correlated Zero-inflated Count Data

This paper extends the two-component approach to modelling count data with extra zeros, considered by Mullahy (1986), Heilbron (1994) and Welsh et al. (1996), to take account of possible serial dependence between repeated observations. Generalized estimating equations (Liang & Zeger, 1986) are constructed for each component of the model by incorporating correlation matrices into each of the maximum likelihood estimating equations. The proposed method is demonstrated on weekly counts of Noisy Friarbirds ( Philemon cornic-ulatus ), which were recorded by observers for the Canberra Garden Bird Survey (Hermes, 1981).     

A robust approach to longitudinal data analysis

The author introduces robust techniques for estimation, inference and variable selection in the analysis of longitudinal data. She first addresses the problem of the robust estimation of the regression and nuisance parameters, for which she derives the asymptotic distribution. She uses weighted estimating equations to build robust quasi‐likelihood functions. These functions are then used to construct a class of test statistics for variable selection. She derives the limiting distribution of these tests and shows its robustness properties in terms of stability of the asymptotic level and power under contamination. An application to a real data set allows her to illustrate the benefits of a robust analysis.     

A Class of Weighted Estimating Equations for Semiparametric Transformation Models with Missing Covariates

In survival analysis, covariate measurements often contain missing observations; ignoring this feature can lead to invalid inference. We propose a class of weighted estimating equations for right‐censored data with missing covariates under semiparametric transformation models. Time‐specific and subject‐specific weights are accommodated in the formulation of the weighted estimating equations. We establish unified results for estimating missingness probabilities that cover both parametric and non‐parametric modelling schemes. To improve estimation efficiency, the weighted estimating equations are augmented by a new set of unbiased estimating equations. The resultant estimator has the so‐called ‘double robustness’ property and is optimal within a class of consistent estimators.