Finite-Sample Properties of the Maximum Likelihood Estimator for the Poisson Regression Model With Random Covariates

We examine the small-sample behaviour of the maximum likelihood estimator for the Poisson regression model with random covariates. Analytic expressions for the second-order bias and mean squared error are derived, and we undertake some numerical evaluations to illustrate these results for the single covariate case. The properties of the bias-adjusted maximum likelihood estimator are investigated in a Monte Carlo experiment. Correcting the estimator for its second-order bias is found to be effective in the cases considered, and we recommend its use when the Poisson regression model is estimated by maximum likelihood with small samples.     

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.     

A Mixed Model Approach for Geoadditive Hazard Regression

Abstract.  Mixed model based approaches for semiparametric regression have gained much interest in recent years, both in theory and application. They provide a unified and modular framework for penalized likelihood and closely related empirical Bayes inference. In this article, we develop mixed model methodology for a broad class of Cox-type hazard regression models where the usual linear predictor is generalized to a geoadditive predictor incorporating non-parametric terms for the (log-)baseline hazard rate, time-varying coefficients and non-linear effects of continuous covariates, a spatial component, and additional cluster-specific frailties. Non-linear and time-varying effects are modelled through penalized splines, while spatial components are treated as correlated random effects following either a Markov random field or a stationary Gaussian random field prior. Generalizing existing mixed model methodology, inference is derived using penalized likelihood for regression coefficients and (approximate) marginal likelihood for smoothing parameters. In a simulation we study the performance of the proposed method, in particular comparing it with its fully Bayesian counterpart using Markov chain Monte Carlo methodology, and complement the results by some asymptotic considerations. As an application, we analyse leukaemia survival data from northwest England.     

Estimation with Interval Censored Data and Covariates

In biostatistical applications interest often focuses on the estimation of the distribution of time T between two consecutive events. If the initial event time is observed and the subsequent event time is only known to be larger or smaller than an observed monitoring time C, then the data conforms to the well understood singly-censored current status model, also known as interval censored data, case I. Additional covariates can be used to allow for dependent censoring and to improve estimation of the marginal distribution of T. Assuming a wrong model for the conditional distribution of T, given the covariates, will lead to an inconsistent estimator of the marginal distribution. On the other hand, the nonparametric maximum likelihood estimator of FT requires splitting up the sample in several subsamples corresponding with a particular value of the covariates, computing the NPMLE for every subsample and then taking an average. With a few continuous covariates the performance of the resulting estimator is typically miserable. In van der Laan, Robins (1996) a locally efficient one-step estimator is proposed for smooth functionals of the distribution of T, assuming nothing about the conditional distribution of T, given the covariates, but assuming a model for censoring, given the covariates. The estimators are asymptotically linear if the censoring mechanism is estimated correctly. The estimator also uses an estimator of the conditional distribution of T, given the covariates. If this estimate is consistent, then the estimator is efficient and if it is inconsistent, then the estimator is still consistent and asymptotically normal. In this paper we show that the estimators can also be used to estimate the distribution function in a locally optimal way. Moreover, we show that the proposed estimator can be used to estimate the distribution based on interval censored data (T is now known to lie between two observed points) in the presence of covariates. The resulting estimator also has a known influence curve so that asymptotic confidence intervals are directly available. In particular, one can apply our proposal to the interval censored data without covariates. In Geskus (1992) the information bound for interval censored data with two uniformly distributed monitoring times at the uniform distribution (for T has been computed. We show that the relative efficiency of our proposal w.r.t. this optimal bound equals 0.994, which is also reflected in finite sample simulations. Finally, the good practical performance of the estimator is shown in a simulation study. This revised version was published online in July 2006 with corrections to the Cover Date.     

Robust Correlation Structure for Multivariate Failure Time Data

When incomplete repeated failure times are collected from a large number of independent individuals, interest is focused primarily on the consistent and efficient estimation of the effects of the associated covariates on the failure times. Since repeated failure times are likely to be correlated, it is important to exploit the correlation structure of the failure data in order to obtain such consistent and efficient estimates. However, it may be difficult to specify an appropriate correlation structure for a real life data set. We propose a robust correlation structure that can be used irrespective of the true correlation structure. This structure is used in constructing an estimating equation for the hazard ratio parameter, under the assumption that the number of repeated failure times for an individual is random. The consistency and efficiency of the estimates is examined through a simulation study, where we consider failure times that marginally follow an exponential distribution and a Poisson distribution is assumed for the random number of repeated failure times. We conclude by using the proposed method to analyze a bladder cancer dataset.     

Time-varying coefficients in a multivariate frailty model: Application to breast cancer recurrences of several types and death

During their follow-up, patients with cancer can experience several types of recurrent events and can also die. Over the last decades, several joint models have been proposed to deal with recurrent events with dependent terminal event. Most of them require the proportional hazard assumption. In the case of long follow-up, this assumption could be violated. We propose a joint frailty model for two types of recurrent events and a dependent terminal event to account for potential dependencies between events with potentially time-varying coefficients. For that, regression splines are used to model the time-varying coefficients. Baseline hazard functions (BHF) are estimated with piecewise constant functions or with cubic M-Splines functions. The maximum likelihood estimation method provides parameter estimates. Likelihood ratio tests are performed to test the time dependency and the statistical association of the covariates. This model was driven by breast cancer data where the maximum follow-up was close to 20 years.     

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.     

Semiparametric models of longitudinal and time-to-event data with applications to HIV viral dynamics and CD4 counts

We propose a semiparametric approach based on proportional hazards and copula method to jointly model longitudinal outcomes and the time-to-event. The dependence between the longitudinal outcomes on the covariates is modeled by a copula-based times series, which allows non-Gaussian random effects and overcomes the limitation of the parametric assumptions in existing linear and nonlinear random effects models. A modified partial likelihood method using estimated covariates at failure times is employed to draw statistical inference. The proposed model and method are applied to analyze a set of progression to AIDS data in a study of the association between the human immunodeficiency virus viral dynamics and the time trend in the CD4/CD8 ratio with measurement errors. Simulations are also reported to evaluate the proposed model and method.     

Robust Poisson likelihood estimation for frailty Cox models: A simulation study

Frailty models can be fit as mixed-effects Poisson models after transforming time-to-event data to the Poisson model framework. We assess, through simulations, the robustness of Poisson likelihood estimation for Cox proportional hazards models with log-normal frailties under misspecified frailty distribution. The log-gamma and Laplace distributions were used as true distributions for frailties on a natural log scale. Factors such as the magnitude of heterogeneity, censoring rate, number and sizes of groups were explored. In the simulations, the Poisson modeling approach that assumes log-normally distributed frailties provided accurate estimates of within- and between-group fixed effects even under a misspecified frailty distribution. Non-robust estimation of variance components was observed in the situations of substantial heterogeneity, large event rates, or high data dimensions.     

Bayesian variable selection in Poisson change-point regression analysis

In this article, we develop a Bayesian variable selection method that concerns selection of covariates in the Poisson change-point regression model with both discrete and continuous candidate covariates. Ranging from a null model with no selected covariates to a full model including all covariates, the Bayesian variable selection method searches the entire model space, estimates posterior inclusion probabilities of covariates, and obtains model averaged estimates on coefficients to covariates, while simultaneously estimating a time-varying baseline rate due to change-points. For posterior computation, the Metropolis-Hastings within partially collapsed Gibbs sampler is developed to efficiently fit the Poisson change-point regression model with variable selection. We illustrate the proposed method using simulated and real datasets.     

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.     

Regression analysis based on conditional likelihood approach under semi-competing risks data

Medical studies often involve semi-competing risks data, which consist of two types of events, namely terminal event and non-terminal event. Because the non-terminal event may be dependently censored by the terminal event, it is not possible to make inference on the non-terminal event without extra assumptions. Therefore, this study assumes that the dependence structure on the non-terminal event and the terminal event follows a copula model, and lets the marginal regression models of the non-terminal event and the terminal event both follow time-varying effect models. This study uses a conditional likelihood approach to estimate the time-varying coefficient of the non-terminal event, and proves the large sample properties of the proposed estimator. Simulation studies show that the proposed estimator performs well. This study also uses the proposed method to analyze AIDS Clinical Trial Group (ACTG 320).     

Recurrent events analysis in the presence of time-dependent covariates and dependent censoring

Summary.  Recurrent events models have had considerable attention recently. The majority of approaches show the consistency of parameter estimates under the assumption that censoring is independent of the recurrent events process of interest conditional on the covariates that are included in the model. We provide an overview of available recurrent events analysis methods and present an inverse probability of censoring weighted estimator for the regression parameters in the Andersen–Gill model that is commonly used for recurrent event analysis. This estimator remains consistent under informative censoring if the censoring mechanism is estimated consistently, and it generally improves on the naïve estimator for the Andersen–Gill model in the case of independent censoring. We illustrate the bias of ad hoc estimators in the presence of informative censoring with a simulation study and provide a data analysis of recurrent lung exacerbations in cystic fibrosis patients when some patients are lost to follow-up.     

An Additive–Multiplicative Cox–Aalen Regression Model

We propose an additive–multiplicative intensity model that extends the Cox regression model as well as the additive Aalen model. Instead of having a simple baseline intensity the extended model uses an additive Aalen model as its covariate dependent baseline. Approximate maximum likelihood estimators of the baseline intensity functions and the relative risk parameters of the Cox model are suggested by solving the score equations. The derived estimator is efficient. We establish the large sample properties of the estimator. The model provides a simple pragmatic way of including time-varying covariate effects.     

Penalized inverse probability weighted estimators for weighted rank regression with missing covariates

Abstract

In this article, we study the variable selection and estimation for linear regression models with missing covariates. The proposed estimation method is almost as efficient as the popular least-squares-based estimation method for normal random errors and empirically shown to be much more efficient and robust with respect to heavy tailed errors or outliers in the responses and covariates. To achieve sparsity, a variable selection procedure based on SCAD is proposed to conduct estimation and variable selection simultaneously. The procedure is shown to possess the oracle property. To deal with the covariates missing, we consider the inverse probability weighted estimators for the linear model when the selection probability is known or unknown. It is shown that the estimator by using estimated selection probability has a smaller asymptotic variance than that with true selection probability, thus is more efficient. Therefore, the important Horvitz-Thompson property is verified for penalized rank estimator with the covariates missing in the linear model. Some numerical examples are provided to demonstrate the performance of the estimators.     

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.     

Buckley–James-type estimation of quantile regression with recurrent gap time data

In longitudinal studies, an individual may potentially undergo a series of repeated recurrence events. The gap times, which are referred to as the times between successive recurrent events, are typically the outcome variables of interest. Various regression models have been developed in order to evaluate covariate effects on gap times based on recurrence event data. The proportional hazards model, additive hazards model, and the accelerated failure time model are all notable examples. Quantile regression is a useful alternative to the aforementioned models for survival analysis since it can provide great flexibility to assess covariate effects on the entire distribution of the gap time. In order to analyze recurrence gap time data, we must overcome the problem of the last gap time subjected to induced dependent censoring, when numbers of recurrent events exceed one time. In this paper, we adopt the Buckley–James-type estimation method in order to construct a weighted estimation equation for regression coefficients under the quantile model, and develop an iterative procedure to obtain the estimates. We use extensive simulation studies to evaluate the finite-sample performance of the proposed estimator. Finally, analysis of bladder cancer data is presented as an illustration of our proposed methodology.     

Estimation of Median in Two-Phase Sampling Using Two Auxiliary Variables

In recent years, zero-inflated count data models, such as zero-inflated Poisson (ZIP) models, are widely used as the count data with extra zeros are very common in many practical problems. In order to model the correlated count data which are either clustered or repeated and to assess the effects of continuous covariates or of time scales in a flexible way, a class of semiparametric mixed-effects models for zero-inflated count data is considered. In this article, we propose a fully Bayesian inference for such models based on a data augmentation scheme that reflects both random effects of covariates and mixture of zero-inflated distribution. A computational efficient MCMC method which combines the Gibbs sampler and M-H algorithm is implemented to obtain the estimate of the model parameters. Finally, a simulation study and a real example are used to illustrate the proposed methodologies.     

A Profile Conditional Likelihood Approach for the Semiparametric Transformation Regression Model with Missing Covariates

We propose a profile conditional likelihood approach to handle missing covariates in the general semiparametric transformation regression model. The method estimates the marginal survival function by the Kaplan-Meier estimator, and then estimates the parameters of the survival model and the covariate distribution from a conditional likelihood, substituting the Kaplan-Meier estimator for the marginal survival function in the conditional likelihood. This method is simpler than full maximum likelihood approaches, and yields consistent and asymptotically normally distributed estimator of the regression parameter when censoring is independent of the covariates. The estimator demonstrates very high relative efficiency in simulations. When compared with complete-case analysis, the proposed estimator can be more efficient when the missing data are missing completely at random and can correct bias when the missing data are missing at random. The potential application of the proposed method to the generalized probit model with missing continuous covariates is also outlined.     

Analysis of two-phase sampling data with semiparametric additive hazards models

Under the case-cohort design introduced by Prentice (Biometrica 73:1–11, 1986), the covariate histories are ascertained only for the subjects who experience the event of interest (i.e., the cases) during the follow-up period and for a relatively small random sample from the original cohort (i.e., the subcohort). The case-cohort design has been widely used in clinical and epidemiological studies to assess the effects of covariates on failure times. Most statistical methods developed for the case-cohort design use the proportional hazards model, and few methods allow for time-varying regression coefficients. In addition, most methods disregard data from subjects outside of the subcohort, which can result in inefficient inference. Addressing these issues, this paper proposes an estimation procedure for the semiparametric additive hazards model with case-cohort/two-phase sampling data, allowing the covariates of interest to be missing for cases as well as for non-cases. A more flexible form of the additive model is considered that allows the effects of some covariates to be time varying while specifying the effects of others to be constant. An augmented inverse probability weighted estimation procedure is proposed. The proposed method allows utilizing the auxiliary information that correlates with the phase-two covariates to improve efficiency. The asymptotic properties of the proposed estimators are established. An extensive simulation study shows that the augmented inverse probability weighted estimation is more efficient than the widely adopted inverse probability weighted complete-case estimation method. The method is applied to analyze data from a preventive HIV vaccine efficacy trial.