Sojourning With the Homogeneous Poisson Process

In this pedagogical article, distributional properties, some surprising, pertaining to the homogeneous Poisson process (HPP), when observed over a possibly random window, are presented. Properties of the gap-time that covered the termination time and the correlations among gap-times of the observed events are obtained. Inference procedures, such as estimation and model validation, based on event occurrence data over the observation window, are also presented. We envision that through the results in this article, a better appreciation of the subtleties involved in the modeling and analysis of recurrent events data will ensue, since the HPP is arguably one of the simplest among recurrent event models. In addition, the use of the theorem of total probability, Bayes’ theorem, the iterated rules of expectation, variance and covariance, and the renewal equation could be illustrative when teaching distribution theory, mathematical statistics, and stochastic processes at both the undergraduate and graduate levels. This article is targeted toward both instructors and students.     

Semiparametric transformation models for multivariate panel count data with dependent observation process

This article discusses regression analysis of multivariate panel count data in which the observation process may contain relevant information about or be related to the underlying recurrent event processes of interest. Such data occur if a recurrent event study involves several related types of recurrent events and the observation scheme or process may be subject-specific. For the problem, a class of semiparametric transformation models is presented, which provides a great flexibility for modelling the effects of covariates on the recurrent event processes. For estimation of regression parameters, an estimating equation-based inference procedure is developed and the asymptotic properties of the resulting estimates are established. Also the proposed approach is evaluated by simulation studies and applied to the data arising from a skin cancer chemoprevention trial.     

Marginal Regression of Gaps Between Recurrent Events

Recurrent event data typically exhibit the phenomenon of intra-individual correlation, owing to not only observed covariates but also random effects. In many applications, the population may be reasonably postulated as a heterogeneous mixture of individual renewal processes, and the inference of interest is the effect of individual-level covariates. In this article, we suggest and investigate a marginal proportional hazards model for gaps between recurrent events. A connection is established between observed gap times and clustered survival data with informative cluster size. We subsequently construct a novel and general inference procedure for the latter, based on a functional formulation of standard Cox regression. Large-sample theory is established for the proposed estimators. Numerical studies demonstrate that the procedure performs well with practical sample sizes. Application to the well-known bladder tumor data is given as an illustration.     

Parametric inference for quantile event times with adjustment for covariates on competing risks data

ABSTRACT

We propose parametric inferences for quantile event times with adjustment for covariates on competing risks data. We develop parametric quantile inferences using parametric regression modeling of the cumulative incidence function from the cause-specific hazard and direct approaches. Maximum likelihood inferences are developed for estimation of the cumulative incidence function and quantiles. We develop the construction of parametric confidence intervals for quantiles. Simulation studies show that the proposed methods perform well. We illustrate the methods using early stage breast cancer data.     

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 Panel Count Data with Dependent Observation Times

In this article, a semiparametric approach is proposed for the regression analysis of panel count data. Panel count data commonly arise in clinical trials and demographical studies where the response variable is the number of multiple recurrences of the event of interest and observation times are not fixed, varying from subject to subject. It is assumed that two processes exist in this data: the first is for a recurrent event and the second is for observation time. Many studies have been done to estimate mean function and regression parameters under the independency between recurrent event process and observation time process. In this article, the same statistical inference is studied, but the situation where these two processes may be related is also considered. The mixed Poisson process is applied for the recurrent event processes, and a frailty intensity function for the observation time is also used, respectively. Simulation studies are conducted to study the performance of the suggested methods. The bladder tumor data are applied to compare previous studie' results.     

Estimation of the joint survival function for three successive duration times under double truncation and right censoring

In incident cohort studies, it is common to include subjects who have experienced a certain event within a calendar time window. For all the included individuals, the time of the previous events is retrospectively confirmed and the occurrence of subsequent events is observed during the follow-up periods. During the follow-up periods, subjects may undergo three successive events. Since the second/third duration process becomes observable only if the first/second event has occurred, the data is subject to double truncation and right censoring. We consider two cases: the case when the first event time is subject to double truncation and the case when the second event time is subject to double truncation. Using the inverse-probability-weighted approach, we propose nonparametric and semiparametric estimators for the estimation of the joint survival function of three successive duration times. We establish the asymptotic properties of the proposed estimators and conduct a simulation study to investigate the finite sample properties of the proposed estimators.     

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.     

Nonparametric analysis of recurrent gap time data

Abstract

Recurrent event data are frequently encountered in longitudinal studies. In many applications, the times between successive recurrent events (gap times) are often of interest and lead to problems that have received much attention recently. In this article, using the approach of inverse probability-of-censoring weights (IPCW), we propose nonparametric estimators for the estimation of the bivariate distribution and survival functions for gap times of recurrent event data. We also consider the estimation of Kendall’s tau for two gap times by expressing it as an integral functional of the bivariate survival function. The asymptotic properties of the proposed estimators are established. Simulation studies are conducted to investigate their finite sample performance.     

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.     

Variable selection for recurrent event data via nonconcave penalized estimating function

Variable selection is an important issue in all regression analysis and in this paper, we discuss this in the context of regression analysis of recurrent event data. Recurrent event data often occur in long-term studies in which individuals may experience the events of interest more than once and their analysis has recently attracted a great deal of attention (Andersen et al., Statistical models based on counting processes, 1993; Cook and Lawless, Biometrics 52:1311–1323, 1996, The analysis of recurrent event data, 2007; Cook et al., Biometrics 52:557–571, 1996; Lawless and Nadeau, Technometrics 37:158-168, 1995; Lin et al., J R Stat Soc B 69:711–730, 2000). However, it seems that there are no established approaches to the variable selection with respect to recurrent event data. For the problem, we adopt the idea behind the nonconcave penalized likelihood approach proposed in Fan and Li (J Am Stat Assoc 96:1348–1360, 2001) and develop a nonconcave penalized estimating function approach. The proposed approach selects variables and estimates regression coefficients simultaneously and an algorithm is presented for this process. We show that the proposed approach performs as well as the oracle procedure in that it yields the estimates as if the correct submodel was known. Simulation studies are conducted for assessing the performance of the proposed approach and suggest that it works well for practical situations. The proposed methodology is illustrated by using the data from a chronic granulomatous disease study.     

Multilevel models for longitudinal data

Summary.  Repeated measures and repeated events data have a hierarchical structure which can be analysed by using multilevel models. A growth curve model is an example of a multilevel random-coefficients model, whereas a discrete time event history model for recurrent events can be fitted as a multilevel logistic regression model. The paper describes extensions to the basic growth curve model to handle auto-correlated residuals, multiple-indicator latent variables and correlated growth processes, and event history models for correlated event processes. The multilevel approach to the analysis of repeated measures data is contrasted with structural equation modelling. The methods are illustrated in analyses of children's growth, changes in social and political attitudes, and the interrelationship between partnership transitions and childbearing.     

Semiparametric additive marginal regression models for multiple type recurrent events

Recurrent event data are often encountered in biomedical research, for example, recurrent infections or recurrent hospitalizations for patients after renal transplant. In many studies, there are more than one type of events of interest. Cai and Schaube (Lifetime Data Anal 10:121-138, 2004) advocated a proportional marginal rate model for multiple type recurrent event data. In this paper, we propose a general additive marginal rate regression model. Estimating equations approach is used to obtain the estimators of regression coefficients and baseline rate function. We prove the consistency and asymptotic normality of the proposed estimators. The finite sample properties of our estimators are demonstrated by simulations. The proposed methods are applied to the India renal transplant study to examine risk factors for bacterial, fungal and viral infections.     

Control‐based imputation for sensitivity analyses in informative censoring for recurrent event data

In clinical trials, missing data commonly arise through nonadherence to the randomized treatment or to study procedure. For trials in which recurrent event endpoints are of interests, conventional analyses using the proportional intensity model or the count model assume that the data are missing at random, which cannot be tested using the observed data alone. Thus, sensitivity analyses are recommended. We implement the control‐based multiple imputation as sensitivity analyses for the recurrent event data. We model the recurrent event using a piecewise exponential proportional intensity model with frailty and sample the parameters from the posterior distribution. We impute the number of events after dropped out and correct the variance estimation using a bootstrap procedure. We apply the method to an application of sitagliptin study.     

Regression analysis of recurrent events data with incomplete observation gaps

For analyzing recurrent event data, either total time scale or gap time scale is adopted according to research interest. In particular, gap time scale is known to be more appropriate for modeling a renewal process. In this paper, we adopt gap time scale to analyze recurrent event data with repeated observation gaps which cannot be observed completely because of unknown termination times of observation gaps. In order to estimate termination times, interval-censored mechanism is applied. Simulation studies are done to compare the suggested methods with the unadjusted method ignoring incomplete observation gaps. As a real example, conviction data set with suspensions is analyzed with suggested methods.     

Marginal Regression of Multivariate Event Times Based on Linear Transformation Models

Multivariate event time data are common in medical studies and have received much attention recently. In such data, each study subject may potentially experience several types of events or recurrences of the same type of event, or event times may be clustered. Marginal distributions are specified for the multivariate event times in multiple events and clustered events data, and for the gap times in recurrent events data, using the semiparametric linear transformation models while leaving the dependence structures for related events unspecified. We propose several estimating equations for simultaneous estimation of the regression parameters and the transformation function. It is shown that the resulting regression estimators are asymptotically normal, with variance–covariance matrix that has a closed form and can be consistently estimated by the usual plug-in method. Simulation studies show that the proposed approach is appropriate for practical use. An application to the well-known bladder cancer tumor recurrences data is also given to illustrate the methodology.     

Inferences from logistic regression models in the presence of small samples,rare events,nonlinearity, and multicollinearity with observational data

The logistic regression model has been widely used in the social and natural sciences and results from studies using this model can have significant policy impacts. Thus, confidence in the reliability of inferences drawn from these models is essential. The robustness of such inferences is dependent on sample size. The purpose of this article is to examine the impact of alternative data sets on the mean estimated bias and efficiency of parameter estimation and inference for the logistic regression model with observational data. A number of simulations are conducted examining the impact of sample size, nonlinear predictors, and multicollinearity on substantive inferences (e.g. odds ratios, marginal effects) when using logistic regression models. Findings suggest that small sample size can negatively affect the quality of parameter estimates and inferences in the presence of rare events, multicollinearity, and nonlinear predictor functions, but marginal effects estimates are relatively more robust to sample size.     

Semiparametric analysis of panel count data with correlated observation and follow-up times

This paper discusses regression analysis of panel count data that often arise in longitudinal studies concerning occurrence rates of certain recurrent events. Panel count data mean that each study subject is observed only at discrete time points rather than under continuous observation. Furthermore, both observation and follow-up times can vary from subject to subject and may be correlated with the recurrent events. For inference, we propose some shared frailty models and estimating equations are developed for estimation of regression parameters. The proposed estimates are consistent and have asymptotically a normal distribution. The finite sample properties of the proposed estimates are investigated through simulation and an illustrative example from a cancer study is provided.     

Nonparametric inference for panel count data with competing risks

In survival and reliability studies, panel count data arise when we investigate a recurrent event process and each study subject is observed only at discrete time points. If recurrent events of several types are possible, we obtain panel count data with competing risks. Such data arise frequently from transversal studies on recurrent events in demography, epidemiology and reliability experiments where the individuals cannot be observed continuously. In the present paper, we propose an isotonic regression estimator for the cause specific mean function of the underlying recurrent event process of a competing risks panel count data. Further, a nonparametric test is proposed to compare the cause specific mean functions of the panel count competing risks data. Asymptotic properties of the proposed estimator and test statistic are studied. A simulation study is conducted to assess the finite sample behaviour of the proposed estimator and test statistic. Finally, the procedures developed are applied to a real data arising from skin cancer chemo prevention trial.     

Analyzing panel count data with a dependent observation process and a terminal event

Panel count data occur in many fields and a number of approaches have been developed. However, most of these approaches are for situations where there is no terminal event and the observation process is independent of the underlying recurrent event process unconditionally or conditional on the covariates. In this paper, we discuss a more general situation where the observation process is informative and there exists a terminal event which precludes further occurrence of the recurrent events of interest. For the analysis, a semiparametric transformation model is presented for the mean function of the underlying recurrent event process among survivors. To estimate the regression parameters, an estimating equation approach is proposed in which an inverse survival probability weighting technique is used. The asymptotic distribution of the proposed estimates is provided. Simulation studies are conducted and suggest that the proposed approach works well for practical situations. An illustrative example is provided. The Canadian Journal of Statistics 41: 174–191; 2013 © 2012 Statistical Society of Canada