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.     

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.     

AN EXTENSION OF THE EM ALGORITHM FOR OPTIMIZATION OF CONSTRAINED LIKELIHOOD: AN APPLICATION IN TOXICOLOGY

Since its introduction in the mid 1970's, the EM algorithm has found a widespread popularity for solving the likelihood equations. Several investigators have used the algorithm in a variety of problems with incomplete information to obtain maximum likelihood estimates in numerous applications. The algorithm, however, becomes inappropriate when the underlying equations are subject to some constraints. Although an extension has been proposed to derive solutions when the parameters are subject to a set of linear constraints, the evaluation of likelihood equations from incomplete data when the equations are subject to a nonlinear constraint is still an open problem. Here, we consider a mixture model, a classical example of incomplete data, and discuss the problem of maximum likelihood estimation of the model parameters when the parameters have to satisfy a nonlinear constraint. An extension of the EM algorithm based on the celebrated Lagrange multiplier will be proposed to solve the equations. An application of the methodology in animal bioassay experiments for risk assessment of toxic substances will be described and data from a toxicological experiment will be used to illustrate the results.     

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.     

Laplace-normal mixtures fitted to wind shear data

A mixture model with Laplace and normal components is fitted to wind shear data available in grouped form. A set of equations is presented for iteratively estimating the parameters of the model using an application of the EM algorithm. Twenty-four sets of data are examined with this technique, and the model is found to give a good fit to the data. Some hypotheses about the parameters in the model are discussed in light of the estimates obtained.     

On Baseline Conditions for Zero-Inflated Longitudinal Count Data

We describe a mixed-effect hurdle model for zero-inflated longitudinal count data, where a baseline variable is included in the model specification. Association between the count data process and the endogenous baseline variable is modeled through a latent structure, assumed to be dependent across equations. We show how model parameters can be estimated in a finite mixture context, allowing for overdispersion, multivariate association and endogeneity of the baseline variable. The model behavior is investigated through a large-scale simulation experiment. An empirical example on health care utilization data is provided.     

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.     

An estimating equation for parametric shared frailty models with marginal additive hazards

Summary.  Multivariate failure time data arise when data consist of clusters in which the failure times may be dependent. A popular approach to such data is the marginal proportional hazards model with estimation under the working independence assumption. In some contexts, however, it may be more reasonable to use the marginal additive hazards model. We derive asymptotic properties of the Lin and Ying estimators for the marginal additive hazards model for multivariate failure time data. Furthermore we suggest estimating equations for the regression parameters and association parameters in parametric shared frailty models with marginal additive hazards by using the Lin and Ying estimators. We give the large sample properties of the estimators arising from these estimating equations and investigate their small sample properties by Monte Carlo simulation. A real example is provided for illustration.     

Mimicking Cox-Regression

Abstract

A class of objective functions, related to the Cox partial likelihood, that generates unbiased estimating equations is proposed. These equations allow for estimation of interest parameters when nuisance parameters are proportional to expectations. Examples of the objective functions are applied to binary data with a log-link in three situations: independent observations, independent groups of observations with common random intercept and discrete survival data. It is pointed out that the Peto–Breslow approximation to the partial likelihood with discrete failure times fits a conditional model with a log-link.     

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.     

Smooth functional tempering for nonlinear differential equation models

Differential equations are used in modeling diverse system behaviors in a wide variety of sciences. Methods for estimating the differential equation parameters traditionally depend on the inclusion of initial system states and numerically solving the equations. This paper presents Smooth Functional Tempering, a new population Markov Chain Monte Carlo approach for posterior estimation of parameters. The proposed method borrows insights from parallel tempering and model based smoothing to define a sequence of approximations to the posterior. The tempered approximations depend on relaxations of the solution to the differential equation model, reducing the need for estimating the initial system states and obtaining a numerical differential equation solution. Rather than tempering via approximations to the posterior that are more heavily rooted in the prior, this new method tempers towards data features. Using our proposed approach, we observed faster convergence and robustness to both initial values and prior distributions that do not reflect the features of the data. Two variations of the method are proposed and their performance is examined through simulation studies and a real application to the chemical reaction dynamics of producing nylon.     

Bayesian penalized B-spline estimation approach for epidemic models

Ordinary differential equations (ODEs) are normally used to model dynamic processes in applied sciences such as biology, engineering, physics, and many other areas. In these models, the parameters are usually unknown, and thus they are often specified artificially or empirically. Alternatively, a feasible method is to estimate the parameters based on observed data. In this study, we propose a Bayesian penalized B-spline approach to estimate the parameters and initial values for ODEs used in epidemiology. We evaluated the efficiency of the proposed method based on simulations using the Markov chain Monte Carlo algorithm for the Kermack–McKendrick model. The proposed approach is also illustrated based on a real application to the transmission dynamics of hepatitis C virus in mainland China.     

A Robust Procedure in Nonlinear Models for Repeated Measurements

Nonlinear regression models arise when definite information is available about the form of the relationship between the response and predictor variables. Such information might involve direct knowledge of the actual form of the true model or might be represented by a set of differential equations that the model must satisfy. We develop M-procedures for estimating parameters and testing hypotheses of interest about these parameters in nonlinear regression models for repeated measurement data. Under regularity conditions, the asymptotic properties of the M-procedures are presented, including the uniform linearity, normality and consistency. The computation of the M-estimators of the model parameters is performed with iterative procedures, similar to Newton–Raphson and Fisher's scoring methods. The methodology is illustrated by using a multivariate logistic regression model with real data, along with a simulation study.     

Additive–multiplicative rates model for recurrent events

Recurrent events are frequently encountered in biomedical studies. Evaluating the covariates effects on the marginal recurrent event rate is of practical interest. There are mainly two types of rate models for the recurrent event data: the multiplicative rates model and the additive rates model. We consider a more flexible additive–multiplicative rates model for analysis of recurrent event data, wherein some covariate effects are additive while others are multiplicative. We formulate estimating equations for estimating the regression parameters. The estimators for these regression parameters are shown to be consistent and asymptotically normally distributed under appropriate regularity conditions. Moreover, the estimator of the baseline mean function is proposed and its large sample properties are investigated. We also conduct simulation studies to evaluate the finite sample behavior of the proposed estimators. A medical study of patients with cystic fibrosis suffered from recurrent pulmonary exacerbations is provided for illustration of the proposed method.     

Analysis of Circular Longitudinal Data Based on Generalized Estimating Equations

This paper derives estimating equations for modelling circular data with longitudinal structure for a family of circular distributions with two parameters. Estimating equations for modelling the circular mean and the resultant length are given separately. Estimating equations are then derived for a mixed model. This paper shows that the estimators that follow from these equations are consistent and asymptotically normal. The results are illustrated by an example about the direction taken by homing pigeons.     

Robust testing with generalized partial linear models for longitudinal data

By approximating the nonparametric component using a regression spline in generalized partial linear models (GPLM), robust generalized estimating equations (GEE), involving bounded score function and leverage-based weighting function, can be used to estimate the regression parameters in GPLM robustly for longitudinal data or clustered data. In this paper, score test statistics are proposed for testing the regression parameters with robustness, and their asymptotic distributions under the null hypothesis and a class of local alternative hypotheses are studied. The proposed score tests reply on the estimation of a smaller model without the testing parameters involved, and perform well in the simulation studies and real data analysis conducted in this paper.     

Estimable functions in the nonlinear model

When the method of least squares is used to estimate the parameters in a general model and the generated system of normal equations is linearly dependent, the estimate of the vector of parameters which satisfies the criterion is not unique. However, there exist certain functions of the estimated vector of parameters which are invariant to the least squares solution obtained from the normal equations. We define those invariant functions to be estimable, and present a technique to determine the functions of the parameters which are estimable for the general model. The method results in solving either a linear first order partial differential equation or a system of linear first order partial differential equations corresponding, respectively, to a single or multiple dependency between columns of the Jacobian matrix of the mean of the model. The usual results concerning estimability for linear models are a special case of the general results developed.     

Quantile Regression Methods for Longitudinal Data with Drop-outs: Application to CD4 Cell Counts of Patients Infected with the Human Immunodeficiency Virus

Patients infected with the human immunodeficiency virus (HIV) generally experience a decline in their CD4 cell count (a count of certain white blood cells). We describe the use of quantile regression methods to analyse longitudinal data on CD4 cell counts from 1300 patients who participated in clinical trials that compared two therapeutic treatments: zidovudine and didanosine. It is of scientific interest to determine any treatment differences in the CD4 cell counts over a short treatment period. However, the analysis of the CD4 data is complicated by drop-outs: patients with lower CD4 cell counts at the base-line appear more likely to drop out at later measurement occasions. Motivated by this example, we describe the use of `weighted' estimating equations in quantile regression models for longitudinal data with drop-outs. In particular, the conventional estimating equations for the quantile regression parameters are weighted inversely proportionally to the probability of drop-out. This approach requires the process generating the missing data to be estimable but makes no assumptions about the distribution of the responses other than those imposed by the quantile regression model. This method yields consistent estimates of the quantile regression parameters provided that the model for drop-out has been correctly specified. The methodology proposed is applied to the CD4 cell count data and the results are compared with those obtained from an `unweighted' analysis. These results demonstrate how an analysis that fails to account for drop-outs can mislead.     

Semiparametric proportional means model for marker data contingent on recurrent event

In many biomedical studies with recurrent events, some markers can only be measured when events happen. For example, medical cost attributed to hospitalization can only incur when patients are hospitalized. Such marker data are contingent on recurrent events. In this paper, we present a proportional means model for modelling the markers using the observed covariates contingent on the recurrent event. We also model the recurrent event via a marginal rate model. Estimating equations are constructed to derive the point estimators for the parameters in the proposed models. The estimators are shown to be asymptotically normal. Simulation studies are conducted to examine the finite-sample properties of the proposed estimators and the proposed method is applied to a data set from the Vitamin A Community Trial.     

Conditional versus unconditional analysis in some regression models

This paper discusses extensions of the variability of the parameters (or functions of parameters) in a recursive system of regression models, and shows that conditioning on the carriers may lead to drastically different conclusions than when the carriers are viewed as stochastic. The relationships among the variables in these models are derived by a sequence of regressions, in which the dependent variable of one equation may reappear as a carrier in a later equation. The model to be fitted need not be identical with the generating equations. In these recursive systems of equations, when the models are miss-specified, or when functions of parameters from different equations are to be estimated, the variability of the estimators is shown to depend critically on the level of conditioning assumed. Various jackknife and bootstrap methods of estimating the variability of the estimators are suggested. In particular the bootstrap estimators of variability can be adopted to captured the correct level of conditioning, by mimicking the conditioning in their design. Two problems in which the level of conditioning matters are described and analysed under the general chained regression models. A real data problem. Omission of variables is sometimes advocated for reducting the variance of the remaining estimators. In both cases the effectiveness of the nonparametric variance estimators is demonstrated using simulation studies.