Estimating treatment effects on the marginal recurrent event mean in the presence of a terminating event

In biomedical studies where the event of interest is recurrent (e.g., hospitalization), it is often the case that the recurrent event sequence is subject to being stopped by a terminating event (e.g., death). In comparing treatment options, the marginal recurrent event mean is frequently of interest. One major complication in the recurrent/terminal event setting is that censoring times are not known for subjects observed to die, which renders standard risk set based methods of estimation inapplicable. We propose two semiparametric methods for estimating the difference or ratio of treatment-specific marginal mean numbers of events. The first method involves imputing unobserved censoring times, while the second methods uses inverse probability of censoring weighting. In each case, imbalances in the treatment-specific covariate distributions are adjusted out through inverse probability of treatment weighting. After the imputation and/or weighting, the treatment-specific means (then their difference or ratio) are estimated nonparametrically. Large-sample properties are derived for each of the proposed estimators, with finite sample properties assessed through simulation. The proposed methods are applied to kidney transplant data.     

Semiparametric regression methods for temporal processes subject to multiple sources of censoring

Process regression methodology is underdeveloped relative to the frequency with which pertinent data arise. In this article, the response-190 is a binary indicator process representing the joint event of being alive and remaining in a specific state. The process is indexed by time (e.g., time since diagnosis) and observed continuously. Data of this sort occur frequently in the study of chronic disease. A general area of application involves a recurrent event with non-negligible duration (e.g., hospitalization and associated length of hospital stay) and subject to a terminating event (e.g., death). We propose a semiparametric multiplicative model for the process version of the probability of being alive and in the (transient) state of interest. Under the proposed methods, the regression parameter is estimated through a procedure that does not require estimating the baseline probability. Unlike the majority of process regression methods, the proposed methods accommodate multiple sources of censoring. In particular, we derive a computationally convenient variant of inverse probability of censoring weighting based on the additive hazards model. We show that the regression parameter estimator is asymptotically normal, and that the baseline probability function estimator converges to a Gaussian process. Simulations demonstrate that our estimators have good finite sample performance. We apply our method to national end-stage liver disease data. The Canadian Journal of Statistics 48: 222–237; 2020 © 2019 Statistical Society of Canada     

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.     

Multiple event times in the presence of informative censoring: modeling and analysis by copulas

Motivated by a breast cancer research program, this paper is concerned with the joint survivor function of multiple event times when their observations are subject to informative censoring caused by a terminating event. We formulate the correlation of the multiple event times together with the time to the terminating event by an Archimedean copula to account for the informative censoring. Adapting the widely used two-stage procedure under a copula model, we propose an easy-to-implement pseudo-likelihood based procedure for estimating the model parameters. The approach yields a new estimator for the marginal distribution of a single event time with semicompeting-risks data. We conduct both asymptotics and simulation studies to examine the proposed approach in consistency, efficiency, and robustness. Data from the breast cancer program are employed to illustrate this research.

     

A semiparametric additive rates model for recurrent event data

Recurrent event data often arise in biomedical studies, with examples including hospitalizations, infections, and treatment failures. In observational studies, it is often of interest to estimate the effects of covariates on the marginal recurrent event rate. The majority of existing rate regression methods assume multiplicative covariate effects. We propose a semiparametric model for the marginal recurrent event rate, wherein the covariates are assumed to add to the unspecified baseline rate. Covariate effects are summarized by rate differences, meaning that the absolute effect on the rate function can be determined from the regression coefficient alone. We describe modifications of the proposed method to accommodate a terminating event (e.g., death). Proposed estimators of the regression parameters and baseline rate are shown to be consistent and asymptotically Gaussian. Simulation studies demonstrate that the asymptotic approximations are accurate in finite samples. The proposed methods are applied to a state-wide kidney transplant data set.     

Recurrent Events Analysis in the Presence of Terminal Event and Zero-recurrence Subjects

Recurrent event data are often encountered in longitudinal follow-up studies related to biomedical science, econometrics, reliability, and demography. In many situations, a terminal event such as death can happen during the follow-up period that precludes further recurrences. In this article, we will review some existing models for recurrent event with information censoring, and then extend them to allow zero-recurrence subjects as well as a terminal event. Estimating equations and partial likelihood are employed to estimate the coefficients of covariates, accumulative rate functions and the proportions of zero-recurrence subjects. The large-sample properties ofthe estimators are established as well. Simulations are performed to evaluate the estimationprocedure and an example of application on a set of migration data is provided to illustrateour proposed models and methods.     

Kernel Estimation of Rate Function for Recurrent Event Data

Abstract.  Recurrent event data are largely characterized by the rate function but smoothing techniques for estimating the rate function have never been rigorously developed or studied in statistical literature. This paper considers the moment and least squares methods for estimating the rate function from recurrent event data. With an independent censoring assumption on the recurrent event process, we study statistical properties of the proposed estimators and propose bootstrap procedures for the bandwidth selection and for the approximation of confidence intervals in the estimation of the occurrence rate function. It is identified that the moment method without resmoothing via a smaller bandwidth will produce a curve with nicks occurring at the censoring times, whereas there is no such problem with the least squares method. Furthermore, the asymptotic variance of the least squares estimator is shown to be smaller under regularity conditions. However, in the implementation of the bootstrap procedures, the moment method is computationally more efficient than the least squares method because the former approach uses condensed bootstrap data. The performance of the proposed procedures is studied through Monte Carlo simulations and an epidemiological example on intravenous drug users.     

Semiparametric analysis of recurrent events: artificial censoring,truncation, pairwise estimation and inference

The analysis of recurrent failure time data from longitudinal studies can be complicated by the presence of dependent censoring. There has been a substantive literature that has developed based on an artificial censoring device. We explore in this article the connection between this class of methods with truncated data structures. In addition, a new procedure is developed for estimation and inference in a joint model for recurrent events and dependent censoring. Estimation proceeds using a mixed U-statistic based estimating function approach. New resampling-based methods for variance estimation and model checking are also described. The methods are illustrated by application to data from an HIV clinical trial as with a limited simulation study.     

THE ASYMPTOTIC EQUIVALENCE OF THE FISHER INFORMATION MATRICES FOR TYPE I AND TYPE II CENSORED DATA FROM LOCATION-SCALE FAMILIES

Type I and Type II censored data arise frequently in controlled laboratory studies concerning time to a particular event (e.g., death of an animal or failure of a physical device). Log-location-scale distributions (e.g., Weibull, lognormal, and loglogistic) are commonly used to model the resulting data. Maximum likelihood (ML) is generally used to obtain parameter estimates when the data are censored. The Fisher information matrix can be used to obtain large-sample approximate variances and covariances of the ML estimates or to estimate these variances and covariances from data. The derivations of the Fisher information matrix proceed differently for Type I (time censoring) and Type II (failure censoring) because the number of failures is random in Type I censoring, but length of the data collection period is random in Type II censoring. Under regularity conditions (met with the above-mentioned log-location-scale distributions), we outline the different derivations and show that the Fisher information matrices for Type I and Type II censoring are asymptotically equivalent.     

Semiparametric inference for the recurrent events process by means of a single-index model

In this paper, we introduce new parametric and semiparametric regression techniques for a recurrent event process subject to random right censoring. We develop models for the cumulative mean function and provide asymptotically normal estimators. Our semiparametric model which relies on a single-index assumption can be seen as a dimension reduction technique that, contrary to a fully nonparametric approach, is not stroke by the curse of dimensionality when the number of covariates is high. We discuss data-driven techniques to choose the parameters involved in the estimation procedures and provide a simulation study to support our theoretical results.     

Random Weighted Bootstrap Method for Recurrent Events with Informative Censoring

Using the data from the AIDS Link to Intravenous Experiences cohort study as an example, an informative censoring model was used to characterize the repeated hospitalization process of a group of patients. Under the informative censoring assumption, the estimators of the baseline rate function and the regression parameters were shown to be related to a latent variable. Hence, it becomes impractical to directly estimate the unknown quantities in the moments of the estimators for the bandwidth selection of a smoothing estimator and the construction of confidence intervals, which are respectively based on the asymptotic mean squared errors and the asymptotic distributions of the estimators. To overcome these difficulties, we develop a random weighted bootstrap procedure to select appropriate bandwidths and to construct approximated confidence intervals. One can see that our method is simple and faster to implement from a practical point of view, and is at least as accurate as other bootstrap methods. In this article, it is shown that the proposed method is useful through the performance of a Monte Carlo simulation. An application of our procedure is also illustrated by a recurrent event sample of intravenous drug users for inpatient cares over time.     

Rate/Mean Regression for Multiple-Sequence Recurrent Event Data with Missing Event Category

Abstract.  Censored recurrent event data frequently arise in biomedical studies. Often, the events are not homogenous, and may be categorized. We propose semiparametric regression methods for analysing multiple-category recurrent event data and consider the setting where event times are always known, but the information used to categorize events may be missing. Application of existing methods after censoring events of unknown category (i.e. 'complete-case' methods) produces consistent estimators only when event types are missing completely at random, an assumption which will frequently fail in practice. We propose methods, based on weighted estimating equations, which are applicable when event category missingness is missing at random. Parameter estimators are shown to be consistent and asymptotically normal. Finite sample properties are examined through simulations and the proposed methods are applied to an end-stage renal disease data set obtained from a national organ failure registry.     

Semiparametric estimation method for accelerated failure time model with dependent censoring

Independent censoring is commonly assumed in survival analysis. However, it may be questionable when censoring is related to event time. We model the event and censoring time marginally through accelerated failure time models, and model their association by a known copula. An iteration algorithm is proposed to estimate the regression parameters. Simulation results show the improvement of the proposed method compared to the naive method under independent censoring. Sensitivity analysis gives the evidences that the proposed method can obtain reasonable estimates even when the forms of copula are misspecified. We illustrate its application by analyzing prostate cancer data.     

A copula model for marked point processes

Many chronic diseases feature recurring clinically important events. In addition, however, there often exists a random variable which is realized upon the occurrence of each event reflecting the severity of the event, a cost associated with it, or possibly a short term response indicating the effect of a therapeutic intervention. We describe a novel model for a marked point process which incorporates a dependence between continuous marks and the event process through the use of a copula function. The copula formulation ensures that event times can be modeled by any intensity function for point processes, and any multivariate model can be specified for the continuous marks. The relative efficiency of joint versus separate analyses of the event times and the marks is examined through simulation under random censoring. An application to data from a recent trial in transfusion medicine is given for illustration.     

The effect of omitted covariates in marginal and partially conditional recurrent event analyses

There have been many advances in statistical methodology for the analysis of recurrent event data in recent years. Multiplicative semiparametric rate-based models are widely used in clinical trials, as are more general partially conditional rate-based models involving event-based stratification. The partially conditional model provides protection against extra-Poisson variation as well as event-dependent censoring, but conditioning on outcomes post-randomization can induce confounding and compromise causal inference. The purpose of this article is to examine the consequences of model misspecification in semiparametric marginal and partially conditional rate-based analysis through omission of prognostic variables. We do so using estimating function theory and empirical studies.

     

An additive-multiplicative rates model for recurrent event data with informative terminal event

In this article, we propose an additive-multiplicative rates model for recurrent event data in the presence of a terminal event such as death. The association between recurrent and terminal events is nonparametric. For inference on the model parameters, estimating equation approaches are developed, and the asymptotic properties of the resulting estimators are established. The finite sample behavior of the proposed estimators is evaluated through simulation studies, and an application to a bladder cancer study is provided.     

Weak convergence for the conditional distribution function in a Koziol–Green model under dependent censoring

In this paper we consider the conditional Koziol–Green model of Braekers and Veraverbeke [2008. A conditional Koziol–Green model under dependent censoring. Statist. Probab. Lett., accepted for publication] in which they generalized the Koziol–Green model of Veraverbeke and Cadarso Suárez [2000. Estimation of the conditional distribution in a conditional Koziol–Green model. Test 9, 97–122] by assuming that the association between a censoring time and a time until an event is described by a known Archimedean copula function. They got in this way, an informative censoring model with two different types of informative censoring. Braekers and Veraverbeke [2008. A conditional Koziol–Green model under dependent censoring. Statist. Probab. Lett., accepted for publication] derived in this model a non-parametric Koziol–Green estimator for the conditional distribution function of the time until an event, for which they showed the uniform consistency and the asymptotic normality. In this paper we extend their results and prove the weak convergence of the process associated to this estimator. Furthermore we show that the conditional Koziol–Green estimator is asymptotically more efficient in this model than the general copula-graphic estimator of Braekers and Veraverbeke [2005. A copula-graphic estimator for the conditional survival function under dependent censoring. Canad. J. Statist. 33, 429–447]. As last result, we construct an asymptotic confidence band for the conditional Koziol–Green estimator. Through a simulation study, we investigate the small sample properties of this asymptotic confidence band. Afterwards we apply this estimator and its confidence band on a practical data set.     

An additive marginal regression model for clustered recurrent event in the presence of a terminal event

In this article, an additive rate model is proposed for clustered recurrent event with a terminal event. The subjects are clustered by some property. For the clustered subjects, the recurrent event is precluded by the death. An estimating equation is developed for the model parameter and the baseline rate function. The asymptotic properties of the resulting estimators are established. In addition, a goodness-of-fit test is presented to assess the adequacy of the model. The finite-sample behavior of the proposed estimators is evaluated through simulation studies, and an application to a bladder cancer data is illustrated.     

Alternating event processes during lifetimes: population dynamics and statistical inference

In the literature studying recurrent event data, a large amount of work has been focused on univariate recurrent event processes where the occurrence of each event is treated as a single point in time. There are many applications, however, in which univariate recurrent events are insufficient to characterize the feature of the process because patients experience nontrivial durations associated with each event. This results in an alternating event process where the disease status of a patient alternates between exacerbations and remissions. In this paper, we consider the dynamics of a chronic disease and its associated exacerbation-remission process over two time scales: calendar time and time-since-onset. In particular, over calendar time, we explore population dynamics and the relationship between incidence, prevalence and duration for such alternating event processes. We provide nonparametric estimation techniques for characteristic quantities of the process. In some settings, exacerbation processes are observed from an onset time until death; to account for the relationship between the survival and alternating event processes, nonparametric approaches are developed for estimating exacerbation process over lifetime. By understanding the population dynamics and within-process structure, the paper provide a new and general way to study alternating event processes.     

A copula model for bivariate hybrid censored survival data with application to the MACS study

A copula model for bivariate survival data with hybrid censoring is proposed to study the association between survival time of individuals infected with HIV and persistence time of infection with an additional virus. Survival with HIV is right censored and the persistence time of the additional virus is subject to interval censoring case 1. A pseudo-likelihood method is developed to study the association between the two event times under such hybrid censoring. Asymptotic consistency and normality of the pseudo-likelihood estimator are established based on empirical process theory. Simulation studies indicate good performance of the estimator with moderate sample size. The method is applied to a motivating HIV study which investigates the effect of GB virus type C (GBV-C) co-infection on survival time of HIV infected individuals.