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.     

Fast accelerated failure time modeling for case-cohort data

Semiparametric accelerated failure time (AFT) models directly relate the expected failure times to covariates and are a useful alternative to models that work on the hazard function or the survival function. For case-cohort data, much less development has been done with AFT models. In addition to the missing covariates outside of the sub-cohort in controls, challenges from AFT model inferences with full cohort are retained. The regression parameter estimator is hard to compute because the most widely used rank-based estimating equations are not smooth. Further, its variance depends on the unspecified error distribution, and most methods rely on computationally intensive bootstrap to estimate it. We propose fast rank-based inference procedures for AFT models, applying recent methodological advances to the context of case-cohort data. Parameters are estimated with an induced smoothing approach that smooths the estimating functions and facilitates the numerical solution. Variance estimators are obtained through efficient resampling methods for nonsmooth estimating functions that avoids full blown bootstrap. Simulation studies suggest that the recommended procedure provides fast and valid inferences among several competing procedures. Application to a tumor study demonstrates the utility of the proposed method in routine data analysis.     

Nonparametric quasi-likelihood for right censored data

Quasi-likelihood was extended to right censored data to handle heteroscedasticity in the frame of the accelerated failure time (AFT) model. However, the assumption of known variance function in the quasi-likelihood for right censored data is usually unrealistic. In this paper, we propose a nonparametric quasi-likelihood by replacing the specified variance function with a nonparametric variance function estimator. This nonparametric variance function estimator is obtained by smoothing a function of squared residuals via local polynomial regression. The rate of convergence of the nonparametric variance function estimator and the asymptotic limiting distributions of the regression coefficient estimators are derived. It is demonstrated in simulations that for finite samples the proposed nonparametric quasi-likelihood method performs well. The new method is illustrated with one real dataset.     

A Multiple Imputation Approach to Linear Regression with Clustered Censored Data

Weextend Wei and Tanner's (1991) multiple imputation approach insemi-parametric linear regression for univariate censored datato clustered censored data. The main idea is to iterate the followingtwo steps: 1) using the data augmentation to impute for censoredfailure times; 2) fitting a linear model with imputed completedata, which takes into consideration of clustering among failuretimes. In particular, we propose using the generalized estimatingequations (GEE) or a linear mixed-effects model to implementthe second step. Through simulation studies our proposal comparesfavorably to the independence approach (Lee et al., 1993), whichignores the within-cluster correlation in estimating the regressioncoefficient. Our proposal is easy to implement by using existingsoftwares.     

Rank Regression Analysis of Multivariate Failure Time Data Based on Marginal Linear Models

Abstract.  Multivariate failure time data arises when each study subject can potentially ex-perience several types of failures or recurrences of a certain phenomenon, or when failure times are sampled in clusters. We formulate the marginal distributions of such multivariate data with semiparametric accelerated failure time models (i.e. linear regression models for log-transformed failure times with arbitrary error distributions) while leaving the dependence structures for related failure times completely unspecified. We develop rank-based monotone estimating functions for the regression parameters of these marginal models based on right-censored observations. The estimating equations can be easily solved via linear programming. The resultant estimators are consistent and asymptotically normal. The limiting covariance matrices can be readily estimated by a novel resampling approach, which does not involve non-parametric density estimation or evaluation of numerical derivatives. The proposed estimators represent consistent roots to the potentially non-monotone estimating equations based on weighted log-rank statistics. Simulation studies show that the new inference procedures perform well in small samples. Illustrations with real medical data are provided.     

Fast Censored Linear Regression

Weighted log‐rank estimating function has become a standard estimation method for the censored linear regression model, or the accelerated failure time model. Well established statistically, the estimator defined as a consistent root has, however, rather poor computational properties because the estimating function is neither continuous nor, in general, monotone. We propose a computationally efficient estimator through an asymptotics‐guided Newton algorithm, in which censored quantile regression methods are tailored to yield an initial consistent estimate and a consistent derivative estimate of the limiting estimating function. We also develop fast interval estimation with a new proposal for sandwich variance estimation. The proposed estimator is asymptotically equivalent to the consistent root estimator and barely distinguishable in samples of practical size. However, computation time is typically reduced by two to three orders of magnitude for point estimation alone. Illustrations with clinical applications are provided.     

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.     

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.     

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.     

Dependence Estimation for Marginal Models of Multivariate Survival Data

We have previously(Segal and Neuhaus, 1993) devised methods for obtaining marginal regression coefficients and associated variance estimates for multivariate survival data, using a synthesis of the Poisson regression formulation for univariate censored survival analysis and generalized estimating equations (GEE's). The method is parametric in that a baseline survival distribution is specified. Analogous semiparametric models, with unspecified baseline survival, have also been developed (Wei, Lin and Weissfeld, 1989; Lin, 1994).Common to both these approaches is the provision of robust variances for the regression parameters. However, none of this work has addressed the more difficult area of dependence estimation. While GEE approaches ostensibly provide such estimates, we show that there are problems adopting these with multivariate survival data. Further, we demonstrate that these problems can affect estimation of the regression coefficients themselves. An alternate, ad hoc approach to dependence estimation, based on design effects, is proposed and evaluated via simulation and illustrative examples. This revised version was published online in July 2006 with corrections to the Cover Date.     

A semiparametric extended hazard regression model with time-dependent covariates

We introduce a general class of semiparametric hazard regression models, called extended hazard (EH) models, that are designed to accommodate various survival schemes with time-dependent covariates. The EH model contains both the Cox model and the accelerated failure time (AFT) model as its subclasses so that we can use this nested structure to perform model selection between the Cox model and the AFT model. A class of estimating equations using counting process and martingale techniques is developed to estimate the regression parameters of the proposed model. The performance of the estimating procedure and the impact of model misspecification are assessed through simulation studies. Two data examples, Stanford heart transplant data and Mediterranean fruit flies, egg-laying data, are used to demonstrate the usefulness of the EH model.     

Statistical inference on transformation models: a self-induced smoothing approach

This paper deals with a general class of transformation models that contains many important semiparametric regression models as special cases. It develops a self-induced smoothing for the maximum rank correlation estimator, resulting in simultaneous point and variance estimation. The self-induced smoothing does not require bandwidth selection, yet provides the right amount of smoothness so that the estimator is asymptotically normal with mean zero (unbiased) and variance–covariance matrix consistently estimated by the usual sandwich-type estimator. An iterative algorithm is given for the variance estimation and shown to numerically converge to a consistent limiting variance estimator. The approach is applied to a data set involving survival times of primary biliary cirrhosis patients. Simulation results are reported, showing that the new method performs well under a variety of scenarios.     

A general quantile residual life model for length‐biased right‐censored data

The quantile residual lifetime function provides comprehensive quantitative measures for residual life, especially when the distribution of the latter is skewed or heavy‐tailed and/or when the data contain outliers. In this paper, we propose a general class of semiparametric quantile residual life models for length‐biased right‐censored data. We use the inverse probability weighted method to correct the bias due to length‐biased sampling and informative censoring. Two estimating equations corresponding to the quantile regressions are constructed in two separate steps to obtain an efficient estimator. Consistency and asymptotic normality of the estimator are established. The main difficulty in implementing our proposed method is that the estimating equations associated with the quantiles are nondifferentiable, and we apply the majorize–minimize algorithm and estimate the asymptotic covariance using an efficient resampling method. We use simulation studies to evaluate the proposed method and illustrate its application by a real‐data example.     

Case-cohort analysis with semiparametric transformation models

Semiparametric transformation models provide flexible regression models for survival analysis, including the Cox proportional hazards and the proportional odds models as special cases. We consider the application of semiparametric transformation models in case-cohort studies, where the covariate data are observed only on cases and on a subcohort randomly sampled from the full cohort. We first propose an approximate profile likelihood approach with full-cohort data, which amounts to the pseudo-partial likelihood approach of Zucker [2005. A pseudo-partial likelihood method for semiparametric survival regression with covariate errors. J. Amer. Statist. Assoc. 100, 1264–1277]. Simulation results show that our proposal is almost as efficient as the nonparametric maximum likelihood estimator. We then extend this approach to the case-cohort design, applying the Horvitz–Thompson weighting method to the estimating equations from the approximated profile likelihood. Two levels of weights can be utilized to achieve unbiasedness and to gain efficiency. The resulting estimator has a closed-form asymptotic covariance matrix, and is found in simulations to be substantially more efficient than the estimator based on martingale estimating equations. The extension to left-truncated data will be discussed. We illustrate the proposed method on data from a cardiovascular risk factor study conducted in Taiwan.     

Generalized M-estimation for the accelerated failure time model

The accelerated failure time (AFT) model is an important regression tool to study the association between failure time and covariates. In this paper, we propose a robust weighted generalized M (GM) estimation for the AFT model with right-censored data by appropriately using the Kaplan–Meier weights in the GM–type objective function to estimate the regression coefficients and scale parameter simultaneously. This estimation method is computationally simple and can be implemented with existing software. Asymptotic properties including the root-n consistency and asymptotic normality are established for the resulting estimator under suitable conditions. We further show that the method can be readily extended to handle a class of nonlinear AFT models. Simulation results demonstrate satisfactory finite sample performance of the proposed estimator. The practical utility of the method is illustrated by a real data example.     

A PRESS statistic for working correlation structure selection in generalized estimating equations

Generalized estimating equations (GEE) is one of the most commonly used methods for regression analysis of longitudinal data, especially with discrete outcomes. The GEE method accounts for the association among the responses of a subject through a working correlation matrix and its correct specification ensures efficient estimation of the regression parameters in the marginal mean regression model. This study proposes a predicted residual sum of squares (PRESS) statistic as a working correlation selection criterion in GEE. A simulation study is designed to assess the performance of the proposed GEE PRESS criterion and to compare its performance with its counterpart criteria in the literature. The results show that the GEE PRESS criterion has better performance than the weighted error sum of squares SC criterion in all cases but is surpassed in performance by the Gaussian pseudo-likelihood criterion. Lastly, the working correlation selection criteria are illustrated with data from the Coronary Artery Risk Development in Young Adults study.     

Methods of Statistical Inference for Median Regression Models with Doubly Censored Data

Recently, least absolute deviations (LAD) estimator for median regression models with doubly censored data was proposed and the asymptotic normality of the estimator was established. However, it is invalid to make inference on the regression parameter vectors, because the asymptotic covariance matrices are difficult to estimate reliably since they involve conditional densities of error terms. In this article, three methods, which are based on bootstrap, random weighting, and empirical likelihood, respectively, and do not require density estimation, are proposed for making inference for the doubly censored median regression models. Simulations are also done to assess the performance of the proposed methods.     

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.     

Building adaptive estimating equations when inverse of covariance estimation is difficult

Summary. To construct an optimal estimating function by weighting a set of score functions, we must either know or estimate consistently the covariance matrix for the individual scores. In problems with high dimensional correlated data the estimated covariance matrix could be unreliable. The smallest eigenvalues of the covariance matrix will be the most important for weighting the estimating equations, but in high dimensions these will be poorly determined. Generalized estimating equations introduced the idea of a working correlation to minimize such problems. However, it can be difficult to specify the working correlation model correctly. We develop an adaptive estimating equation method which requires no working correlation assumptions. This methodology relies on finding a reliable approximation to the inverse of the variance matrix in the quasi-likelihood equations. We apply a multivariate generalization of the conjugate gradient method to find estimating equations that preserve the information well at fixed low dimensions. This approach is particularly useful when the estimator of the covariance matrix is singular or close to singular, or impossible to invert owing to its large size.