Regression coefficient analysis for correlated binomial outcomes

At present, the generalized estimating equation (GEE) and weighted least-squares (WLS) regression methods are the most widely used methods for analyzing correlated binomial data; both are easily implemented using existing software packages. We propose an alternative technique, i.e. regression coefficient analysis (RCA), for this type of data. In RCA, a regression equation is computed for each of n individuals; regression coefficients are averaged across the n equations to produce a regression equation, which predicts marginal probabilities and which can be tested to address hypotheses of different slopes between groups, slopes different from zero, different intercepts, etc. The method is computationally simple and can be performed using standard software. Simulations and examples are used to compare the power and robustness of RCA with those of the standard GEE and WLS methods. We find that RCA is comparable with the GEE method under the conditions tested, and suggest that RCA, within specified limitations, is a viable alternative to the GEE and WLS methods in the analysis of correlated binomial data.     

To adjust or not to adjust for baseline when analyzing repeated binary responses? The case of complete data when treatment comparison at study end is of interest

The benefits of adjusting for baseline covariates are not as straightforward with repeated binary responses as with continuous response variables. Therefore, in this study, we compared different methods for analyzing repeated binary data through simulations when the outcome at the study endpoint is of interest. Methods compared included chi‐square, Fisher's exact test, covariate adjusted/unadjusted logistic regression (Adj.logit/Unadj.logit), covariate adjusted/unadjusted generalized estimating equations (Adj.GEE/Unadj.GEE), covariate adjusted/unadjusted generalized linear mixed model (Adj.GLMM/Unadj.GLMM). All these methods preserved the type I error close to the nominal level. Covariate adjusted methods improved power compared with the unadjusted methods because of the increased treatment effect estimates, especially when the correlation between the baseline and outcome was strong, even though there was an apparent increase in standard errors. Results of the Chi‐squared test were identical to those for the unadjusted logistic regression. Fisher's exact test was the most conservative test regarding the type I error rate and also with the lowest power. Without missing data, there was no gain in using a repeated measures approach over a simple logistic regression at the final time point. Analysis of results from five phase III diabetes trials of the same compound was consistent with the simulation findings. Therefore, covariate adjusted analysis is recommended for repeated binary data when the study endpoint is of interest. Copyright © 2015 John Wiley & Sons, Ltd.     

Different methods for handling incomplete longitudinal binary outcome due to missing at random dropout

This paper compares the performance of weighted generalized estimating equations (WGEEs), multiple imputation based on generalized estimating equations (MI-GEEs) and generalized linear mixed models (GLMMs) for analyzing incomplete longitudinal binary data when the underlying study is subject to dropout. The paper aims to explore the performance of the above methods in terms of handling dropouts that are missing at random (MAR). The methods are compared on simulated data. The longitudinal binary data are generated from a logistic regression model, under different sample sizes. The incomplete data are created for three different dropout rates. The methods are evaluated in terms of bias, precision and mean square error in case where data are subject to MAR dropout. In conclusion, across the simulations performed, the MI-GEE method performed better in both small and large sample sizes. Evidently, this should not be seen as formal and definitive proof, but adds to the body of knowledge about the methods’ relative performance. In addition, the methods are compared using data from a randomized clinical trial.     

A simple approach for generating correlated binary variates ∗

Correlated binary data arise frequently in medical as well as other scientific disciplines; and statistical methods, such as generalized estimating equation (GEE), have been widely used for their analysis. The need for simulating correlated binary variates arises for evaluating small sample properties of the GEE estimators when modeling such data. Also, one might generate such data to simulate and study biological phenomena such as tooth decay or periodontal disease. This article introduces a simple method for generating pairs of correlated binary data. A simple algorithm is also provided for generating an arbitrary dimensional random vector of non-negatively correlated binary variates. The method relies on the idea that correlations among the random variables arise as a result of their sharing some common components that induce such correlations. It then uses some properties of the binary variates to represent each variate in terms of these common components in addition to its own elements. Unlike most previous approaches that require solving nonlinear equations or use some distributional properties of other random variables, this method uses only some properties of the binary variate. As no intermediate random variables are required for generating the binary variates, the proposed method is shown to be faster than the other methods. To verify this claim, we compare the computational efficiency of the proposed method with those of other procedures.     

Power analysis for cluster randomized trials with binary outcomes modeled by generalized linear mixed-effects models

Power analysis for cluster randomized control trials is difficult to perform when a binary response is modeled using the generalized linear mixed-effects model (GLMM). Although methods for clustered binary responses exist such as the generalized estimating equations, they do not apply to the context of GLMM. Also, because popular statistical packages such as R and SAS do not provide correct estimates of parameters for the GLMM for binary responses, Monte Carlo simulation, a popular ad-hoc method for estimating power when the power function is too complex to evaluate analytically or numerically, fails to provide correct power estimates within the current context as well. In this paper, a new approach is developed to estimate power for cluster randomized control trials when a binary response is modeled by the GLMM. The approach is easy to implement and seems to work quite well, as assessed by simulation studies. The approach is illustrated with a real intervention study to reduce suicide reattempt rates among US Veterans.     

Comparison of two methods in estimating standard error of the method of simulated moments estimators for generalized linear mixed models

ABSTRACT

The likelihood of a generalized linear mixed model (GLMM) often involves high-dimensional integrals, which in general cannot be computed explicitly. When direct computation is not available, method of simulated moments (MSM) is a fairly simple way to estimate the parameters of interest. In this research, we compared parametric bootstrap (PB) and nonparametric bootstrap methods (NPB) in estimating the standard errors of MSM estimators for GLMM. Simulation results show that when the group size is large, the PB and NPB perform similarly; when group size is medium, NPB performs better than PB in estimating standard errors of the mean.     

Exact methods of testing the homogeneity of prevalences for correlated binary data

Correlated binary data arise in many ophthalmological and otolaryngological clinical trials. To test the homogeneity of prevalences among different groups is an important issue when conducting these trials. The equal correlation coefficients model proposed by Donner in 1989 is a popular model handling correlated binary data. The asymptotic chi-square test works well when the sample size is large. However, it would fail to maintain the type I error rate when the sample size is relatively small. In this paper, we propose several exact methods to deal with small sample scenarios. Their performances are compared with respect to type I error rate and power. The ‘M approach’ and the ‘E + M approach’ seem to outperform the others. A real work example is given to further explain how these approaches work. Finally, the computational efficiency of the exact methods is discussed as a pressing issue of future work.     

Estimation of group means using Bayesian generalized linear mixed models

Generalized linear mixed models (GLMM) are commonly used to model the treatment effect over time while controlling for important clinical covariates. Standard software procedures often provide estimates of the outcome based on the mean of the covariates; however, these estimates will be biased for the true group means in the GLMM. Implementing GLMM in the frequentist framework can lead to issues of convergence. A simulation study demonstrating the use of fully Bayesian GLMM for providing unbiased estimates of group means is shown. These models are very straightforward to implement and can be used for a broad variety of outcomes (eg, binary, categorical, and count data) that arise in clinical trials. We demonstrate the proposed method on a data set from a clinical trial in diabetes.     

Zero-inflated models and estimation in zero-inflated Poisson distribution

In this paper, we briefly overview different zero-inflated probability distributions. We compare the performance of the estimates of Poisson, Generalized Poisson, ZIP, ZIGP and ZINB models through Mean square error (MSE), bias and Standard error (SE) when the samples are generated from ZIP distribution. We propose a new estimator referred to as probability estimator (PE) of inflation parameter of ZIP distribution based on moment estimator (ME) of the mean parameter and compare its performance with ME and maximum likelihood estimator (MLE) through a simulation study. We use the PE along with ME and MLE to fit ZIP distribution to various zero-inflated datasets and observe that the results do not differ significantly. We recommend using PE in place of MLE since it is easy to calculate and the simulation study in this paper demonstrates that the PE performs as good as MLE irrespective of the sample size.     

Reml estimation for repeated measures analysis

Models for repeated measures or growth curves consist of a mean response plus error and the errors are usually correlated. Both maximum likelihood and residual maximum likelihood (REML) estimators of a regression model with dependent errors are derived for cases in which the variance matrix of the error model admits a convenient Cholesky factorisation. This factorisation may be linked to methods for producing recursive estimates of the regression parameters and recursive residuals to provide a convenient computational method. The method is used to develop a general approach to repeated measures analysis.     

Robust estimation in generalized linear mixed models

Generalized linear mixed models (GLMMs) are widely used to analyse non-normal response data with extra-variation, but non-robust estimators are still routinely used. We propose robust methods for maximum quasi-likelihood and residual maximum quasi-likelihood estimation to limit the influence of outlying observations in GLMMs. The estimation procedure parallels the development of robust estimation methods in linear mixed models, but with adjustments in the dependent variable and the variance component. The methods proposed are applied to three data sets and a comparison is made with the nonparametric maximum likelihood approach. When applied to a set of epileptic seizure data, the methods proposed have the desired effect of limiting the influence of outlying observations on the parameter estimates. Simulation shows that one of the residual maximum quasi-likelihood proposals has a smaller bias than those of the other estimation methods. We further discuss the equivalence of two GLMM formulations when the response variable follows an exponential family. Their extensions to robust GLMMs and their comparative advantages in modelling are described. Some possible modifications of the robust GLMM estimation methods are given to provide further flexibility for applying the method.     

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.     

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.     

Marginal methods for clustered longitudinal binary data with incomplete covariates

Many analyses for incomplete longitudinal data are directed to examining the impact of covariates on the marginal mean responses. We consider the setting in which longitudinal responses are collected from individuals nested within clusters. We discuss methods for assessing covariate effects on the mean and association parameters when covariates are incompletely observed. Weighted first and second order estimating equations are constructed to obtain consistent estimates of mean and association parameters when covariates are missing at random. Empirical studies demonstrate that estimators from the proposed method have negligible finite sample biases in moderate samples. An application to the National Alzheimer's Coordinating Center (NACC) Uniform Data Set (UDS) demonstrates the utility of the proposed method.     

Robust Small Sample Inference for Generalised Estimating Equations: An Application of the Anova‐type Test

Asymptotically, the Wald‐type test for generalised estimating equations (GEE) models can control the type I error rate at the nominal level. However in small sample studies, it may lead to inflated type I error rates. Even with currently available small sample corrections for the GEE Wald‐type test, the type I error rate inflation is still serious when the tested contrast is multidimensional. This paper extends the ANOVA‐type test for heteroscedastic factorial designs to GEE and shows that the proposed ANOVA‐type test can also control the type I error rate at the nominal level in small sample studies while still maintaining robustness with respect to mis‐specification of the working correlation matrix. Differences of inference between the Wald‐type test and the proposed test are observed in a two‐way repeated measures ANOVA model for a diet‐induced obesity study and a two‐way repeated measures logistic regression for a collagen‐induced arthritis study. Simulation studies confirm that the proposed test has better control of the type I error rate than the Wald‐type test in small sample repeated measures models. Additional simulation studies further show that the proposed test can even achieve larger power than the Wald‐type test in some cases of the large sample repeated measures ANOVA models that were investigated.     

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.     

Fitting the generalized Pareto distribution to data based on transformations of order statistics

Generalized Pareto distribution (GPD) has been widely used to model exceedances over thresholds. In this article we propose a new method called weighted nonlinear least squares (WNLS) to estimate the parameters of the GPD. The WNLS estimators always exist and are simple to compute. Some asymptotic results of the proposed method are provided. The simulation results indicate that the proposed method performs well compared to existing methods in terms of mean squared error and bias. Its advantages are further illustrated through the analysis of two real data sets.     

Two-step and likelihood methods for joint models of longitudinal and survival data

We compare the commonly used two-step methods and joint likelihood method for joint models of longitudinal and survival data via extensive simulations. The longitudinal models include LME, GLMM, and NLME models, and the survival models include Cox models and AFT models. We find that the full likelihood method outperforms the two-step methods for various joint models, but it can be computationally challenging when the dimension of the random effects in the longitudinal model is not small. We thus propose an approximate joint likelihood method which is computationally efficient. We find that the proposed approximation method performs well in the joint model context, and it performs better for more “continuous” longitudinal data. Finally, a real AIDS data example shows that patients with higher initial viral load or lower initial CD4 are more likely to drop out earlier during an anti-HIV treatment.     

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.     

Estimation for the Parameters of Generalized Half-normal Distribution Based on Progressive Type-I Interval Censoring

Based on progressively Type-I interval censored sample, the problem of estimating unknown parameters of a two parameter generalized half-normal(GHN) distribution is considered. Different methods of estimation are discussed. They include the maximum likelihood estimation, midpoint approximation method, approximate maximum likelihood estimation, method of moments, and estimation based on probability plot. Several Bayesian estimates with respect to different symmetric and asymmetric loss functions such as squared error, LINEX, and general entropy is calculated. The Lindley’s approximation method is applied to determine Bayesian estimates. Monte Carlo simulations are performed to compare the performances of the different methods. Finally, analysis is also carried out for a real dataset.