Modelling heterogeneity in longitudinal binomial responses by generalized estimating equations

ABSTRACT

Extra-binomial variation in longitudinal/clustered binomial data is frequently observed in biomedical and observational studies. The usual generalized estimating equations method treats the extra-binomial parameter as a constant across all subjects. In this paper, a two-parameter variance function modelling the extraneous variance is proposed to account for heterogeneity among subjects. The new approach allows modelling the extra-binomial variation as a function of the mean and binomial size.     

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.     

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.     

Revealing age-specific past and future unrelated costs of pneumococcal infections by flexible generalized estimating equations

We aimed to study the excess health-care expenditures for persons with a known positive isolate of Streptococcus pneumoniae. The data set was compiled by linking the database of the largest Belgian Sickness Fund with data obtained from laboratories reporting pneumococcal isolates. We analyzed the age-specific per-patient cumulative costs over time, using generalized estimating equations (GEEs). The mean structure was described by fractional polynomials. The quasi-likelihood under the independence model criterion was used to compare different correlation structures. We show for all age groups that the health-care costs incurred by diagnosed pneumococcal patients are significantly larger than those incurred by undiagnosed matched persons. This is not only the case at the time of diagnosis but also long before and after the time of diagnosis. These findings can be informative for the current debate on unrelated costs in health economic evaluation, and GEEs could be used to estimate these costs for other diseases. Finally, these results can be used to inform policy on the expected budget impact of preventing pneumococcal infections.     

Robust weighted generalized estimating equations based on statistical depth

Most of the longitudinal data contain influential points and for analyzing them generalized and weighted generalized estimating equations (GEEs and WGEEs) are highly influenced by these points. An approach for dealing with outliers is having weight functions. In this article, we propose some new weights based on the statistical depth. These weights express centrality of points with respect to the whole sample with a smaller depth (larger depth) for the point far from the center (for the point near the center). The proposed approach leads to robust WGEE. These approaches are applied on two real datasets and some simulation studies.     

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.     

Efficiency of generalized estimating equations for binary responses

Summary.  Using standard correlation bounds, we show that in generalized estimation equations (GEEs) the so-called 'working correlation matrix' R ( α ) for analysing binary data cannot in general be the true correlation matrix of the data. Methods for estimating the correlation param-eter in current GEE software for binary responses disregard these bounds. To show that the GEE applied on binary data has high efficiency, we use a multivariate binary model so that the covariance matrix from estimating equation theory can be compared with the inverse Fisher information matrix. But R ( α ) should be viewed as the weight matrix, and it should not be confused with the correlation matrix of the binary responses. We also do a comparison with more general weighted estimating equations by using a matrix Cauchy–Schwarz inequality. Our analysis leads to simple rules for the choice of α in an exchangeable or autoregressive AR(1) weight matrix R ( α ), based on the strength of dependence between the binary variables. An example is given to illustrate the assessment of dependence and choice of α .     

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.     

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.     

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.     

Regression modelling of weighted κ by using generalized estimating equations

In many clinical studies more than one observer may be rating a characteristic measured on an ordinal scale. For example, a study may involve a group of physicians rating a feature seen on a pathology specimen or a computer tomography scan. In clinical studies of this kind, the weighted κ coefficient is a popular measure of agreement for ordinally scaled ratings. Our research stems from a study in which the severity of inflammatory skin disease was rated. The investigators wished to determine and evaluate the strength of agreement between a variable number of observers taking into account patient-specific (age and gender) as well as rater-specific (whether board certified in dermatology) characteristics. This suggested modelling κ as a function of these covariates. We propose the use of generalized estimating equations to estimate the weighted κ coefficient. This approach also accommodates unbalanced data which arise when some subjects are not judged by the same set of observers. Currently an estimate of overall κ for a simple unbalanced data set without covariates involving more than two observers is unavailable. In the inflammatory skin disease study none of the covariates were significantly associated with κ, thus enabling the calculation of an overall weighted κ for this unbalanced data set. In the second motivating example (multiple sclerosis), geographic location was significantly associated with κ. In addition we also compared the results of our method with current methods of testing for heterogeneity of weighted κ coefficients across strata (geographic location) that are available for balanced data sets.     

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.     

Joint generalized estimating equations for multivariate longitudinal binary outcomes with missing data: an application to acquired immune deficiency syndrome data

Summary.  In a large, prospective longitudinal study designed to monitor cardiac abnormalities in children born to women who are infected with the human immunodeficiency virus, instead of a single outcome variable, there are multiple binary outcomes (e.g. abnormal heart rate, abnormal blood pressure and abnormal heart wall thickness) considered as joint measures of heart function over time. In the presence of missing responses at some time points, longitudinal marginal models for these multiple outcomes can be estimated by using generalized estimating equations (GEEs), and consistent estimates can be obtained under the assumption of a missingness completely at random mechanism. When the missing data mechanism is missingness at random, i.e. the probability of missing a particular outcome at a time point depends on observed values of that outcome and the remaining outcomes at other time points, we propose joint estimation of the marginal models by using a single modified GEE based on an EM-type algorithm. The method proposed is motivated by the longitudinal study of cardiac abnormalities in children who were born to women infected with the human immunodeficiency virus, and analyses of these data are presented to illustrate the application of the method. Further, in an asymptotic study of bias, we show that, under a missingness at random mechanism in which missingness depends on all observed outcome variables, our joint estimation via the modified GEE produces almost unbiased estimates, provided that the correlation model has been correctly specified, whereas estimates from standard GEEs can lead to substantial bias.     

Optimal model averaging estimation for correlation structure in generalized estimating equations

Longitudinal data analysis requires a proper estimation of the within-cluster correlation structure in order to achieve efficient estimates of the regression parameters. When applying likelihood-based methods one may select an optimal correlation structure by the AIC or BIC. However, such information criteria are not applicable for estimating equation based approaches. In this paper we develop a model averaging approach to estimate the correlation matrix by a weighted sum of a group of patterned correlation matrices under the GEE framework. The optimal weight is determined by minimizing the difference between the weighted sum and a consistent yet inefficient estimator of the correlation structure. The computation of our proposed approach only involves a standard quadratic programming on top of the standard GEE procedure and can be easily implemented in practice. We provide theoretical justifications and extensive numerical simulations to support the application of the proposed estimator. A couple of well-known longitudinal data sets are revisited where we implement and illustrate our methodology.     

A practical extension of the generalized estimating equation approach for longitudinal data

Liang and Zeger (1986) proposed an extension of generalized linear models to the analysis of longitudinal data. In their formulation, a common dispersion parameter assumption across observation times is required. However, this assumption is not expected to hold in most situations. Park (1993) proposed a simple extension of Liang and Zeger's formulation to allow for different dispersion parameters for each time point. The proposed model is easy to apply without heavy computations and useful to handle the cases when variations in over-dispersion over time exist. In this paper, we focus on evaluating the effect of additional dispersion parameters on the estimators of model parameters. Through a Monte Carlo simulation study, efficiency of Park's method is compared with the Liang and Zeger's method.     

Efficiently weighted estimating equations with application to proportional excess hazards

A general approach to estimation, that can lead to efficient estimation in two stages, is presented. The method will not always be available, but sufficient conditions for efficiency are provided together with four examples of its use: (1) estimation of the odds ratio in 1:M matched case-control studies with a dichotomous exposure variable; (2) estimation of the relative hazard in a two-sample survival setting; (3) estimation of the regression parameters in the proportional excess hazards model; and (4) estimation in a partly linear parametric additive hazards model. The method depends upon finding a family of weighted estimating equations, which includes a simple initial equation yielding a consistent estimate and also an equation that yields an efficient estimate, provided the optiomal weights are used.     

Deletion diagnostics for marginal mean and correlation model parameters in estimating equations

Regression diagnostics are introduced for parameters in marginal association models for clustered binary outcomes in an implementation of generalized estimating equations. Estimating equations for intracluster correlations facilitate computational formulae for one-step deletion diagnostics in an extension of earlier work on diagnostics for parameters in the marginal mean model. The proposed diagnostics measure the influence of an observation or a cluster of observations on the estimated regression parameters and on the overall fit of the model. The diagnostics are applied to data from four research studies from public health and medicine.     

A GEE approach to estimating accuracy and its confidence intervals for correlated data

In this paper, we provide a method for constructing confidence interval for accuracy in correlated observations, where one sample of patients is being rated by two or more diagnostic tests. Confidence intervals for other measures of diagnostic tests, such as sensitivity, specificity, positive predictive value, and negative predictive value, have already been developed for clustered or correlated observations using the generalized estimating equations (GEE) method. Here, we use the GEE and delta‐method to construct confidence intervals for accuracy, the proportion of patients who are correctly classified. Simulation results verify that the estimated confidence intervals exhibit consistent/appropriate coverage rates.     

Robust modified profile estimating function with application to the generalized estimating equation

We consider methods for reducing the effect of fitting nuisance parameters on a general estimating function, when the estimating function depends on not only a vector of parameters of interest, θ$\theta$, but also on a vector of nuisance parameters, λ$\lambda$. We propose a class of modified profile estimating functions with plug-in bias reduced by two orders. A robust version of the adjustment term does not require any information about the probability mechanism beyond that required by the original estimating function. An important application of this method is bias correction for the generalized estimating equation in analyzing stratified longitudinal data, where the stratum-specific intercepts are considered as fixed nuisance parameters, the dependence of the expected outcome on the covariates is of interest, and the intracluster correlation structure is unknown. Furthermore, when the quasi-scores for θ$\theta$ and λ$\lambda$ are available, we propose an additional multiplicative adjustment term such that the modified profile estimating function is approximately information unbiased. This multiplicative adjustment term can serve as an optimal weight in the analysis of stratified studies. A brief simulation study shows that the proposed method considerably reduces the impact of the nuisance parameters.