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.     

Adaptive robust estimation in joint mean–covariance regression model for bivariate longitudinal data

The estimation of the covariance matrix is important in the analysis of bivariate longitudinal data. A good estimator for the covariance matrix can improve the efficiency of the estimators of the mean regression coefficients. Furthermore, the covariance estimation itself is also of interest, but it is a challenging job to model the covariance matrix of bivariate longitudinal data due to the complex structure and positive definite constraint. In addition, most of existing approaches are based on the maximum likelihood, which is very sensitive to outliers or heavy-tail error distributions. In this article, an adaptive robust estimation method is proposed for bivariate longitudinal data. Unlike the existing likelihood-based methods, the proposed method can adapt to different error distributions. Specifically, at first, we utilize the modified Cholesky block decomposition to parameterize the covariance matrices. Secondly, we apply the bounded Huber's score function to develop a set of robust generalized estimating equations to estimate the parameters both in the mean and the covariance models simultaneously. A data-driven approach is presented to select the parameter c in the Huber's score function, which can ensure that the proposed method is robust and efficient. A simulation study and a real data analysis are conducted to illustrate the robustness and efficiency of the proposed approach.     

Impact of missing data on type 1 error rates in non‐inferiority trials

In this paper, a simulation study is conducted to systematically investigate the impact of different types of missing data on six different statistical analyses: four different likelihood‐based linear mixed effects models and analysis of covariance (ANCOVA) using two different data sets, in non‐inferiority trial settings for the analysis of longitudinal continuous data. ANCOVA is valid when the missing data are completely at random. Likelihood‐based linear mixed effects model approaches are valid when the missing data are at random. Pattern‐mixture model (PMM) was developed to incorporate non‐random missing mechanism. Our simulations suggest that two linear mixed effects models using unstructured covariance matrix for within‐subject correlation with no random effects or first‐order autoregressive covariance matrix for within‐subject correlation with random coefficient effects provide well control of type 1 error (T1E) rate when the missing data are completely at random or at random. ANCOVA using last observation carried forward imputed data set is the worst method in terms of bias and T1E rate. PMM does not show much improvement on controlling T1E rate compared with other linear mixed effects models when the missing data are not at random but is markedly inferior when the missing data are at random. Copyright © 2009 John Wiley & Sons, Ltd.     

Approaches to regression analysis with multiple measurements from individual sampling units

Application of ordinary least-squares regression to data sets which contain multiple measurements from individual sampling units produces an unbiased estimator of the parameters but a biased estimator of the covariance matrix of the parameter estimates. The present work considers a random coefficient, linear model to deal with such data sets: this model permits many senses in which multiple measurements are taken from a sampling unit, not just when it is measured at several times. Three procedures to estimate the covariance matrix of the error term of the model are considered. Given these, three procedures to estimate the parameters of the model and their covariance matrix are considered; these are ordinary least-squares, generalized least-squares, and an adjusted ordinary least-squares procedure which produces an unbiased estimator of the covariance matrix of the parameters with small samples. These various procedures are compared in simulation studies using three examples from the biological literature. The possibility of testing hypotheses about the vector of parameters is also considered. It is found that all three procedures for regression estimation produce estimators of the parameters with bias of no practical consequence, Both generalized least-squares and adjusted ordinary least-squares generally produce estimators of the covariance matrix of the parameter estimates with bias of no practical consequence, while ordinary least-squares produces a negatively biased estimator. Neither ordinary nor generalized least-squares provide satisfactory hypothesis tests of the vector of parameter estimates. It is concluded that adjusted ordinary least-squares, when applied with either of two of the procedures used to estimate the error coveriance matrix, shows promise for practical application with data sets of the nature considered here.     

Robust estimation of covariance parameters in partial linear model for longitudinal data

For longitudinal data, the within-subject dependence structure and covariance parameters may be of practical and theoretical interests. The estimation of covariance parameters has received much attention and been studied mainly in the framework of generalized estimating equations (GEEs). The GEEs method, however, is sensitive to outliers. In this paper, an alternative set of robust generalized estimating equations for both the mean and covariance parameters are proposed in the partial linear model for longitudinal data. The asymptotic properties of the proposed estimators of regression parameters, non-parametric function and covariance parameters are obtained. Simulation studies are conducted to evaluate the performance of the proposed estimators under different contaminations. The proposed method is illustrated with a real data analysis.     

Joint mean–covariance model in generalized partially linear varying coefficient models for longitudinal data

In longitudinal data analysis, efficient estimation of regression coefficients requires a correct specification of certain covariance structure, and efficient estimation of covariance matrix requires a correct specification of mean regression model. In this article, we propose a general semiparametric model for the mean and the covariance simultaneously using the modified Cholesky decomposition. A regression spline-based approach within the framework of generalized estimating equations is proposed to estimate the parameters in the mean and the covariance. Under regularity conditions, asymptotic properties of the resulting estimators are established. Extensive simulation is conducted to investigate the performance of the proposed estimator and in the end a real data set is analysed using the proposed approach.     

Some Notes on Refereeing

Analysis of longitudinal data using a general linear mixed model requires the specification of a form for the covariance matrix of within-subject observations. Graphical diagnostics, such as the scatterplot matrix, can be of substantial help in making this specification. I introduce another graphical diagnostic, the Partial-Regression-on-Intervenors Scatterplot Matrix (PRISM), which complements the ordinary scatterplot matrix and which is more useful for identifying certain kinds of correlation structures. PRISMs corresponding to several commonly used correlation structures are displayed. The PRISM's usefulness in model specification is illustrated with an example of longitudinal data from a 100-kilometer road race.     

Effects of the estimation of covariance matrix parameters in the generalized multivariate linear model

We Consider the generalized multivariate linear model and assume the covariance matrix of the p x 1 vector of responses on a given individual can be represented in the general linear structure form described by Anderson (1973). The effects of the use of estimates of the parameters of the covariance matrix on the generalized least squares estimator of the regression coefficients and on the prediction of a portion of a future vector, when only the first portion of the vector has been observed, are investigated. Approximations are derived for the covariance matrix of the generalized least squares estimator and for the mean square error matrix of the usual predictor, for the practical case where estimated parameters are used.     

A general joint model for longitudinal measurements and competing risks survival data with heterogeneous random effects

This article studies a general joint model for longitudinal measurements and competing risks survival data. The model consists of a linear mixed effects sub-model for the longitudinal outcome, a proportional cause-specific hazards frailty sub-model for the competing risks survival data, and a regression sub-model for the variance–covariance matrix of the multivariate latent random effects based on a modified Cholesky decomposition. The model provides a useful approach to adjust for non-ignorable missing data due to dropout for the longitudinal outcome, enables analysis of the survival outcome with informative censoring and intermittently measured time-dependent covariates, as well as joint analysis of the longitudinal and survival outcomes. Unlike previously studied joint models, our model allows for heterogeneous random covariance matrices. It also offers a framework to assess the homogeneous covariance assumption of existing joint models. A Bayesian MCMC procedure is developed for parameter estimation and inference. Its performances and frequentist properties are investigated using simulations. A real data example is used to illustrate the usefulness of the approach.     

Criterion for the Selection of a Working Correlation Structure in the Generalized Estimating Equation Approach for Longitudinal Balanced Data

The generalized estimating equation is a popular method for analyzing correlated response data. It is important to determine a proper working correlation matrix at the time of applying the generalized estimating equation since an improper selection sometimes results in inefficient parameter estimates. We propose a criterion for the selection of an appropriate working correlation structure. The proposed criterion is based on a statistic to test the hypothesis that the covariance matrix equals a given matrix, and also measures the discrepancy between the covariance matrix estimator and the specified working covariance matrix. We evaluated the performance of the proposed criterion through simulation studies assuming that for each subject, the number of observations remains the same. The results revealed that when the proposed criterion was adopted, the proportion of selecting a true correlation structure was generally higher than that when other competing approaches were adopted. The proposed criterion was applied to longitudinal wheeze data, and it was suggested that the resultant correlation structure was the most accurate.     

Robust estimation of mean and covariance for longitudinal data with dropouts

In this paper, we study estimation of linear models in the framework of longitudinal data with dropouts. Under the assumptions that random errors follow an elliptical distribution and all the subjects share the same within-subject covariance matrix which does not depend on covariates, we develop a robust method for simultaneous estimation of mean and covariance. The proposed method is robust against outliers, and does not require to model the covariance and missing data process. Theoretical properties of the proposed estimator are established and simulation studies show its good performance. In the end, the proposed method is applied to a real data analysis for illustration.     

Bayesian analysis of joint mean and covariance models for longitudinal data

Efficient estimation of the regression coefficients in longitudinal data analysis requires a correct specification of the covariance structure. If misspecification occurs, it may lead to inefficient or biased estimators of parameters in the mean. One of the most commonly used methods for handling the covariance matrix is based on simultaneous modeling of the Cholesky decomposition. Therefore, in this paper, we reparameterize covariance structures in longitudinal data analysis through the modified Cholesky decomposition of itself. Based on this modified Cholesky decomposition, the within-subject covariance matrix is decomposed into a unit lower triangular matrix involving moving average coefficients and a diagonal matrix involving innovation variances, which are modeled as linear functions of covariates. Then, we propose a fully Bayesian inference for joint mean and covariance models based on this decomposition. A computational efficient Markov chain Monte Carlo method which combines the Gibbs sampler and Metropolis–Hastings algorithm is implemented to simultaneously obtain the Bayesian estimates of unknown parameters, as well as their standard deviation estimates. Finally, several simulation studies and a real example are presented to illustrate the proposed methodology.     

Testing hypotheses for the growth curve model when the data are incomplete

Kleinbaum (1973) developed a generalized growth curve model for analyzing incomplete longitudinal data. In this paper the small sample properties of several related test statistics are investigated via Monte Carlo techniques. The covariance matrix is estimated by each of three non-iterative methods. The null and non-null distributions of these test statistics are examined.     

Adaptive fitting of linear mixed-effects models with correlated random effects

Linear mixed-effects model has been widely used in longitudinal data analyses. In practice, the fitting algorithm can fail to converge due to boundary issues of the estimated random-effects covariance matrix G, that is, being near-singular, non-positive definite, or both. Current available algorithms are not computationally optimal because the condition number of matrix G is unnecessarily increased when the random-effects correlation estimate is not zero. We propose an adaptive fitting (AF) algorithm using an optimal linear transformation of the random-effects design matrix. It is a data-driven adaptive procedure, aiming at reducing subsequent random-effects correlation estimates down to zero in the optimal transformed estimation space. Simulations show that AF significantly improves the convergent properties, especially under small sample size, relative large noise and high correlation settings. One real data for insulin-like growth factor protein is used to illustrate the application of this algorithm implemented with software package R (nlme).     

Maximum likelihood estimates in the multivariate normal with patterned mean and covariance via the em algorithm

The maximum likelihood equations for a multivariate normal model with structured mean and structured covariance matrix may not have an explicit solution. In some cases the model's error term may be decomposed as the sum of two independent error terms, each having a patterned covariance matrix, such that if one of the unobservable error terms is artificially treated as "missing data", the EM algorithm can be used to compute the maximum likelihood estimates for the original problem. Some decompositions produce likelihood equations which do not have an explicit solution at each iteration of the EM algorithm, but within-iteration explicit solutions are shown for two general classes of models including covariance component models used for analysis of longitudinal data.     

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.     

Two-Part Models for Analysis of Agatston Scores with Possible Proportionality Constraints

ABSTRACT

Logit-linear and probit-linear two-part models can be used to analyze data that are a mixture of zeros and positive continuous responses. The slopes in the linear part of a model can be constrained to be proportional to the slopes in the logit or probit part. In this article, it is shown that implementing such a constraint will decrease (in Loewner ordering) the asymptotic covariance matrix of the maximum likelihood estimates. A case study is provided using coronary artery calcification data from the Multi-Ethnic Study of Atherosclerosis.     

The Asymptotic Covariance Matrix of the Least Squares Estimator in the Stochastic Linear Regression Model: The Case of Elliptically Symmetric Distribution

This article considers the unconditional asymptotic covariance matrix of the least squares estimator in the linear regression model with stochastic explanatory variables. The asymptotic covariance matrix of the least squares estimator of regression parameters is evaluated relative to the standard asymptotic covariance matrix when the joint distribution of the dependent and explanatory variables is in the class of elliptically symmetric distributions. An empirical example using financial data is presented. Numerical examples and simulation experiments are given to illustrate the difference of the two asymptotic covariance matrices.     

Efficient estimation in partially linear single‐index models for longitudinal data

In this paper, we consider the estimation of both the parameters and the nonparametric link function in partially linear single‐index models for longitudinal data that may be unbalanced. In particular, a new three‐stage approach is proposed to estimate the nonparametric link function using marginal kernel regression and the parametric components with generalized estimating equations. The resulting estimators properly account for the within‐subject correlation. We show that the parameter estimators are asymptotically semiparametrically efficient. We also show that the asymptotic variance of the link function estimator is minimized when the working error covariance matrices are correctly specified. The new estimators are more efficient than estimators in the existing literature. These asymptotic results are obtained without assuming normality. The finite‐sample performance of the proposed method is demonstrated by simulation studies. In addition, two real‐data examples are analyzed to illustrate the methodology.     

On repeated measures analysis with misspecified covariance structure

In recent years various sophisticated methods have been developed for the analysis of repeated measures, or longitudinal data. The more traditional approach, based on a normal likelihood function, has been shown to be unsatisfactory, in the sense of yielding asymptotically biased estimates when the covariance structure is misspecified. More recent methodology, based on generalized linear models and quasi-likelihood estimation, has gained widespread acceptance as 'generalized estimating equations'. However, this also has theoretical problems. In this paper a suggestion is made for improving the asymptotic behaviour of estimators by using the older approach, implemented via Gaussian estimation. The resulting estimating equations include the quasi-score function as one component, so the methodology proposed can be viewed as a combination of Gaussian estimation and generalized estimating equations which has a firmer asymptotic basis than either alone has.