Doubly robust empirical likelihood inference in covariate-missing data problems

Missing covariate data occurs often in regression analysis. We study methods for estimating the regression coefficients in an assumed conditional mean function when some covariates are completely observed but other covariates are missing for some subjects. We adopt the semiparametric perspective of Robins et al. [Estimation of regression coefficients when some regressors are not always observed. J Amer Statist Assoc. 1994;89:846–866] on regression analyses with missing covariates, in which they pioneered the use of two working models, the working propensity score model and the working conditional score model. A recent approach to missing covariate data analysis is the empirical likelihood method of Qin et al. [Empirical likelihood in missing data problems. J Amer Statist Assoc. 2009;104:1492–1503], which effectively combines unbiased estimating equations. In this paper, we consider an alternative likelihood approach based on the full likelihood of the observed data. This full likelihood-based method enables us to generate estimators for the vector of the regression coefficients that are (a) asymptotically equivalent to those of Qin et al. [Empirical likelihood in missing data problems. J Amer Statist Assoc. 2009;104:1492–1503] when the working propensity score model is correctly specified, and (b) doubly robust, like the augmented inverse probability weighting (AIPW) estimators of Robins et al. [Estimation of regression coefficients when some regressors are not always observed. J Am Statist Assoc. 1994;89:846–866]. Thus, the proposed full likelihood-based estimators improve on the efficiency of the AIPW estimators when the working propensity score model is correct but the working conditional score model is possibly incorrect, and also improve on the empirical likelihood estimators of Qin, Zhang and Leung [Empirical likelihood in missing data problems. J Amer Statist Assoc. 2009;104:1492–1503] when the reverse is true, that is, the working conditional score model is correct but the working propensity score model is possibly incorrect. In addition, we consider a regression method for estimation of the regression coefficients when the working conditional score model is correctly specified; the asymptotic variance of the resulting estimator is no greater than the semiparametric variance bound characterized by the theory of Robins et al. [Estimation of regression coefficients when some regressors are not always observed. J Amer Statist Assoc. 1994;89:846–866]. Finally, we compare the finite-sample performance of various estimators in a simulation study.     

The em algorithm for the quasi-likelihood regression model

The objective of this paper is to present a method which can accommodate certain types of missing data by using the quasi-likelihood function for the complete data. This method can be useful when we can make first and second moment assumptions only; in addition, it can be helpful when the EM algorithm applied to the actual likelihood becomes overly complicated. First we derive a loss function for the observed data using an exponential family density which has the same mean and variance structure of the complete data. This loss function is the counterpart of the quasi-deviance for the observed data. Then the loss function is minimized using the EM algorithm. The use of the EM algorithm guarantees a decrease in the loss function at every iteration. When the observed data can be expressed as a deterministic linear transformation of the complete data, or when data are missing completely at random, the proposed method yields consistent estimators. Examples are given for overdispersed polytomous data, linear random effects models, and linear regression with missing covariates. Simulation results for the linear regression model with missing covariates show that the proposed estimates are more efficient than estimates based on completely observed units, even when outcomes are bimodal or skewed.     

Bayesian Analysis of Nonlinear Reproductive Dispersion Mixed Models for Longitudinal Data with Nonignorable Missing Covariates

This article proposes a Bayesian approach, which can simultaneously obtain the Bayesian estimates of unknown parameters and random effects, to analyze nonlinear reproductive dispersion mixed models (NRDMMs) for longitudinal data with nonignorable missing covariates and responses. The logistic regression model is employed to model the missing data mechanisms for missing covariates and responses. A hybrid sampling procedure combining the Gibber sampler and the Metropolis-Hastings algorithm is presented to draw observations from the conditional distributions. Because missing data mechanism is not testable, we develop the logarithm of the pseudo-marginal likelihood, deviance information criterion, the Bayes factor, and the pseudo-Bayes factor to compare several competing missing data mechanism models in the current considered NRDMMs with nonignorable missing covaraites and responses. Three simulation studies and a real example taken from the paediatric AIDS clinical trial group ACTG are used to illustrate the proposed methodologies. Empirical results show that our proposed methods are effective in selecting missing data mechanism models.     

Weighted quantile regression with missing covariates using empirical likelihood

This paper proposes an empirical likelihood-based weighted (ELW) quantile regression approach for estimating the conditional quantiles when some covariates are missing at random. The proposed ELW estimator is computationally simple and achieves semiparametric efficiency if the probability of missingness is correctly specified. The limiting covariance matrix of the ELW estimator can be estimated by a resampling technique, which does not involve nonparametric density estimation or numerical derivatives. Simulation results show that the ELW method works remarkably well in finite samples. A real data example is used to illustrate the proposed ELW method.     

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.     

Semiparametric Analysis of Isotonic Errors-in-Variables Regression Models with Missing Response

This article is concerned with the estimation problem in the semiparametric isotonic regression model when the covariates are measured with additive errors and the response is missing at random. An inverse marginal probability weighted imputation approach is developed to estimate the regression parameters and a least-square approach under monotone constraint is employed to estimate the functional component. We show that the proposed estimator of the regression parameter is root-n consistent and asymptotically normal and the isotonic estimator of the functional component, at a fixed point, is cubic root-n consistent. A simulation study is conducted to examine the finite-sample properties of the proposed estimators. A data set is used to demonstrate the proposed approach.     

Estimation in the Cox cure model with covariates missing not at random,with application to disease screening/prediction

In an attempt to provide a statistical tool for disease screening and prediction, we propose a semiparametric approach to analysis of the Cox proportional hazards cure model in situations where the observations on the event time are subject to right censoring and some covariates are missing not at random. To facilitate the methodological development, we begin with semiparametric maximum likelihood estimation (SPMLE) assuming that the (conditional) distribution of the missing covariates is known. A variant of the EM algorithm is used to compute the estimator. We then adapt the SPMLE to a more practical situation where the distribution is unknown and there is a consistent estimator based on available information. We establish the consistency and weak convergence of the resulting pseudo-SPMLE, and identify a suitable variance estimator. The application of our inference procedure to disease screening and prediction is illustrated via empirical studies. The proposed approach is used to analyze the tuberculosis screening study data that motivated this research. Its finite-sample performance is examined by simulation.     

Efficient inverse probability weighting method for quantile regression with nonignorable missing data

Quantitle regression (QR) is a popular approach to estimate functional relations between variables for all portions of a probability distribution. Parameter estimation in QR with missing data is one of the most challenging issues in statistics. Regression quantiles can be substantially biased when observations are subject to missingness. We study several inverse probability weighting (IPW) estimators for parameters in QR when covariates or responses are subject to missing not at random. Maximum likelihood and semiparametric likelihood methods are employed to estimate the respondent probability function. To achieve nice efficiency properties, we develop an empirical likelihood (EL) approach to QR with the auxiliary information from the calibration constraints. The proposed methods are less sensitive to misspecified missing mechanisms. Asymptotic properties of the proposed IPW estimators are shown under general settings. The efficiency gain of EL-based IPW estimator is quantified theoretically. Simulation studies and a data set on the work limitation of injured workers from Canada are used to illustrated our proposed methodologies.     

Cure rate survival models with missing covariates: a simulation study

In this paper we study the cure rate survival model involving a competitive risk structure with missing categorical covariates. A parametric distribution that can be written as a sequence of one-dimensional conditional distributions is specified for the missing covariates. We consider the missing data at random situation so that the missing covariates may depend only on the observed ones. Parameter estimates are obtained by using the EM algorithm via the method of weights. Extensive simulation studies are conducted and reported to compare estimates efficiency with and without missing data. As expected, the estimation approach taking into consideration the missing covariates presents much better efficiency in terms of mean square errors than the complete case situation. Effects of increasing cured fraction and censored observations are also reported. We demonstrate the proposed methodology with two real data sets. One involved the length of time to obtain a BS degree in Statistics, and another about the time to breast cancer recurrence.     

Semiparametric inference for estimating equations with nonignorably missing covariates

We consider statistical inference of unknown parameters in estimating equations (EEs) when some covariates have nonignorably missing values, which is quite common in practice but has rarely been discussed in the literature. When an instrument, a fully observed covariate vector that helps identifying parameters under nonignorable missingness, is available, the conditional distribution of the missing covariates given other covariates can be estimated by the pseudolikelihood method of Zhao and Shao [(2015), ‘Semiparametric pseudo likelihoods in generalised linear models with nonignorable missing data’, Journal of the American Statistical Association, 110, 1577–1590)] and be used to construct unbiased EEs. These modified EEs then constitute a basis for valid inference by empirical likelihood. Our method is applicable to a wide range of EEs used in practice. It is semiparametric since no parametric model for the propensity of missing covariate data is assumed. Asymptotic properties of the proposed estimator and the empirical likelihood ratio test statistic are derived. Some simulation results and a real data analysis are presented for illustration.     

Product-limit Estimators and Cox Regression with Missing Censoring Information

The Kaplan–Meier estimator of a survival function requires that the censoring indicator is always observed. A method of survival function estimation is developed when the censoring indicators are missing completely at random (MCAR). The resulting estimator is a smooth functional of the Nelson–Aalen estimators of certain cumulative transition intensities. The asymptotic properties of this estimator are derived. A simulation study shows that the proposed estimator has greater efficiency than competing MCAR-based estimators. The approach is extended to the Cox model setting for the estimation of a conditional survival function given a covariate.     

Generation of pseudo random numbers and estimation under Cox models with time-dependent covariates

ABSTRACT

We study the method for generating pseudo random numbers under various special cases of the Cox model with time-dependent covariates when the baseline hazard function may not be constant and the random variable may equal infinity with a positive probability. During our simulation studies in computing the partial likelihood estimates, in between 3% and 20% of the time with a moderate sample size, it happens that the partial likelihood estimate of the regression coefficient is ∞ for the data from the Cox model. We propose a semi-parametric estimator as a modification for such a case. We present simulation results on the asymptotic properties of the semi-parametric estimator.     

Cox Regression with Incomplete Covariate Measurements using the EM-algorithm

Ibrahim (1990) used the EM-algorithm to obtain maximum likelihood estimates of the regression parameters in generalized linear models with partially missing covariates. The technique was termed EM by the method of weights. In this paper, we generalize this technique to Cox regression analysis with missing values in the covariates. We specify a full model letting the unobserved covariate values be random and then maximize the observed likelihood. The asymptotic covariance matrix is estimated by the inverse information matrix. The missing data are allowed to be missing at random but also the non-ignorable non-response situation may in principle be considered. Simulation studies indicate that the proposed method is more efficient than the method suggested by Paik & Tsai (1997). We apply the procedure to a clinical trials example with six covariates with three of them having missing values.     

Inference for proportional hazard model with propensity score

Since the publication of the seminal paper by Cox (1972), proportional hazard model has become very popular in regression analysis for right censored data. In observational studies, treatment assignment may depend on observed covariates. If these confounding variables are not accounted for properly, the inference based on the Cox proportional hazard model may perform poorly. As shown in Rosenbaum and Rubin (1983), under the strongly ignorable treatment assignment assumption, conditioning on the propensity score yields valid causal effect estimates. Therefore we incorporate the propensity score into the Cox model for causal inference with survival data. We derive the asymptotic property of the maximum partial likelihood estimator when the model is correctly specified. Simulation results show that our method performs quite well for observational data. The approach is applied to a real dataset on the time of readmission of trauma patients. We also derive the asymptotic property of the maximum partial likelihood estimator with a robust variance estimator, when the model is incorrectly specified.     

A SEMIPARAMETRIC MIXTURE MODEL FOR THE ANALYSIS OF COMPETING RISKS DATA

This paper deals with the regression analysis of failure time data when there are censoring and multiple types of failures. We propose a semiparametric generalization of a parametric mixture model of Larson & Dinse (1985), for which the marginal probabilities of the various failure types are logistic functions of the covariates. Given the type of failure, the conditional distribution of the time to failure follows a proportional hazards model. A marginal like lihood approach to estimating regression parameters is suggested, whereby the baseline hazard functions are eliminated as nuisance parameters. The Monte Carlo method is used to approximate the marginal likelihood; the resulting function is maximized easily using existing software. Some guidelines for choosing the number of Monte Carlo replications are given. Fixing the regression parameters at their estimated values, the full likelihood is maximized via an EM algorithm to estimate the baseline survivor functions. The methods suggested are illustrated using the Stanford heart transplant data.     

Cox regression of clustered event times with covariates missing not at random

Motivated by a recent tuberculosis (TB) study, this paper is concerned with covariates missing not at random (MNAR) and models the potential intracluster correlation by a frailty. We consider the regression analysis of right‐censored event times from clustered subjects under a Cox proportional hazards frailty model and present the semiparametric maximum likelihood estimator (SPMLE) of the model parameters. An easy‐to‐implement pseudo‐SPMLE is then proposed to accommodate more realistic situations using readily available supplementary information on the missing covariates. Algorithms are provided to compute the estimators and their consistent variance estimators. We demonstrate that both the SPMLE and the pseudo‐SPMLE are consistent and asymptotically normal by the arguments based on the theory of modern empirical processes. The proposed approach is examined numerically via simulation and illustrated with an analysis of the motivating TB study data.     

A gradient-based algorithm for semiparametric models with missing covariates

In the parametric regression model, the covariate missing problem under missing at random is considered. It is often desirable to use flexible parametric or semiparametric models for the covariate distribution, which can reduce a potential misspecification problem. Recently, a completely nonparametric approach was developed by [H.Y. Chen, Nonparametric and semiparametric models for missing covariates in parameter regression, J. Amer. Statist. Assoc. 99 (2004), pp. 1176–1189; Z. Zhang and H.E. Rockette, On maximum likelihood estimation in parametric regression with missing covariates, J. Statist. Plann. Inference 47 (2005), pp. 206–223]. Although it does not require a model for the covariate distribution or the missing data mechanism, the proposed method assumes that the covariate distribution is supported only by observed values. Consequently, their estimator is a restricted maximum likelihood estimator (MLE) rather than the global MLE. In this article, we show the restricted semiparametric MLE could be very misleading in some cases. We discuss why this problem occurs and suggest an algorithm to obtain the global MLE. Then, we assess the performance of the proposed method via some simulation experiments.     

A study of regression calibration in a partially observed stratified Cox model

Regression calibration is a simple method for estimating regression models when covariate data are missing for some study subjects. It consists in replacing an unobserved covariate by an estimator of its conditional expectation given available covariates. Regression calibration has recently been investigated in various regression models such as the linear, generalized linear, and proportional hazards models. The aim of this paper is to investigate the appropriateness of this method for estimating the stratified Cox regression model with missing values of the covariate defining the strata. Despite its practical relevance, this problem has not yet been discussed in the literature. Asymptotic distribution theory is developed for the regression calibration estimator in this setting. A simulation study is also conducted to investigate the properties of this estimator.