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.     

Recurrent first hitting times in Wiener diffusion under several observation schemes

Recurrent events are commonly encountered in the natural sciences, engineering, and medicine. The theory of renewal and regenerative processes provides an elegant mathematical foundation for idealized recurrent event processes. In real-world applications, however, the contexts tend to be complicated by a variety of practical intricacies, including observation schemes with different phase and data structures. This paper formulates a recurrent event process as a succession of independent and identically distributed first hitting times for a Wiener sample path as it passes through successive equally-spaced levels. We develop exact mathematical results for statistical inferences based on several observation schemes that include observation initiated at a renewal point, observation of a stationary process over a finite window, and other variants. We also consider inferences drawn from different data structures, including gap times between renewal points (or fragments thereof) and counts of renewal events occurring within an observation window. We explore the precision of estimates using simulated scenarios and develop empirical regression functions for planning the sample size of a recurrent event study. We demonstrate our results using data from a clinical trial for chronic obstructive pulmonary disease in which the recurrent events are successive exacerbations of the condition. The case study demonstrates how covariates can be incorporated into the analysis using threshold regression.     

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     

A Conditional Approach for Regression Analysis of Longitudinal Data with Informative Observation Time and Non-negligible Observation Duration

Recently, there has been a great interest in the analysis of longitudinal data in which the observation process is related to the longitudinal process. In literature, the observation process was commonly regarded as a recurrent event process. Sometimes some observation duration may occur and this process is referred to as a recurrent episode process. The medical cost related to hospitalization is an example. We propose a conditional modeling approach that takes into account both informative observation process and observation duration. We conducted simulation studies to assess the performance of the method and applied it to a dataset of medical costs.     

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.     

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.     

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.     

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.     

Regression analysis of multivariate recurrent event data with a dependent terminal event

Recurrent event data occur in many clinical and observational studies (Cook and Lawless, Analysis of recurrent event data, 2007) and in these situations, there may exist a terminal event such as death that is related to the recurrent event of interest (Ghosh and Lin, Biometrics 56:554–562, 2000; Wang et al., J Am Stat Assoc 96:1057–1065, 2001; Huang and Wang, J Am Stat Assoc 99:1153–1165, 2004; Ye et al., Biometrics 63:78–87, 2007). In addition, sometimes there may exist more than one type of recurrent events, that is, one faces multivariate recurrent event data with some dependent terminal event (Chen and Cook, Biostatistics 5:129–143, 2004). It is apparent that for the analysis of such data, one has to take into account the dependence both among different types of recurrent events and between the recurrent and terminal events. In this paper, we propose a joint modeling approach for regression analysis of the data and both finite and asymptotic properties of the resulting estimates of unknown parameters are established. The methodology is applied to a set of bivariate recurrent event data arising from a study of leukemia patients.     

Bayesian Modeling of Recurrent Event Data with Dependent Censoring

The recurrent-event setting, where the subjects experience multiple occurrences of the event of interest, are encountered in many biomedical applications. In analyzing recurrent event data, non informative censoring is often assumed for the implementation of statistical methods. However, when a terminating event such as death serves as part of the censoring mechanism, validity of the censoring assumption may be violated because recurrence can be a powerful risk factor for death. We consider joint modeling of recurrent event process and terminating event under a Bayesian framework in which a shared frailty is used to model the association between the intensity of the recurrent event process and the hazard of the terminating event. Our proposed model is implemented on data from a well-known cancer study.     

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.     

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.     

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.     

Lasso penalized semiparametric regression on high-dimensional recurrent event data via coordinate descent

This paper studies a fast computational algorithm for variable selection on high-dimensional recurrent event data. Based on the lasso penalized partial likelihood function for the response process of recurrent event data, a coordinate descent algorithm is used to accelerate the estimation of regression coefficients. This algorithm is capable of selecting important predictors for underdetermined problems where the number of predictors far exceeds the number of cases. The selection strength is controlled by a tuning constant that is determined by a generalized cross-validation method. Our numerical experiments on simulated and real data demonstrate the good performance of penalized regression in model building for recurrent event data in high-dimensional settings.     

Multiple imputation methods for recurrent event data with missing event category

Frequently in clinical and epidemiologic studies, the event of interest is recurrent (i.e., can occur more than once per subject). When the events are not of the same type, an analysis which accounts for the fact that events fall into different categories will often be more informative. Often, however, although event times may always be known, information through which events are categorized may potentially be missing. Complete‐case methods (whose application may require, for example, that events be censored when their category cannot be determined) are valid only when event categories are missing completely at random. This assumption is rather restrictive. The authors propose two multiple imputation methods for analyzing multiple‐category recurrent event data under the proportional means/rates model. The use of a proper or improper imputation technique distinguishes the two approaches. Both methods lead to consistent estimation of regression parameters even when the missingness of event categories depends on covariates. The authors derive the asymptotic properties of the estimators and examine their behaviour in finite samples through simulation. They illustrate their approach using data from an international study on dialysis.     

Semiparametric Methods for Clustered Recurrent Event Data

In biomedical studies, the event of interest is often recurrent and within-subject events cannot usually be assumed independent. In addition, individuals within a cluster might not be independent; for example, in multi-center or familial studies, subjects from the same center or family might be correlated. We propose methods of estimating parameters in two semi-parametric proportional rates/means models for clustered recurrent event data. The first model contains a baseline rate function which is common across clusters, while the second model features cluster-specific baseline rates. Dependence structures for patients-within-cluster and events-within-patient are both unspecified. Estimating equations are derived for the regression parameters. For the common baseline model, an estimator of the baseline mean function is proposed. The asymptotic distributions of the model parameters are derived, while finite-sample properties are assessed through a simulation study. Using data from a national organ failure registry, the proposed methods are applied to the analysis of technique failures among Canadian dialysis patients.     

An additive–multiplicative mean model for panel count data with dependent observation and dropout processes

This paper discusses regression analysis of panel count data with dependent observation and dropout processes. For the problem, a general mean model is presented that can allow both additive and multiplicative effects of covariates on the underlying point process. In addition, the proportional rates model and the accelerated failure time model are employed to describe possible covariate effects on the observation process and the dropout or follow‐up process, respectively. For estimation of regression parameters, some estimating equation‐based procedures are developed and the asymptotic properties of the proposed estimators are established. In addition, a resampling approach is proposed for estimating a covariance matrix of the proposed estimator and a model checking procedure is also provided. Results from an extensive simulation study indicate that the proposed methodology works well for practical situations, and it is applied to a motivating set of real data.     

Dynamic path analysis—a new approach to analyzing time-dependent covariates

In this article we introduce a general approach to dynamic path analysis. This is an extension of classical path analysis to the situation where variables may be time-dependent and where the outcome of main interest is a stochastic process. In particular we will focus on the survival and event history analysis setting where the main outcome is a counting process. Our approach will be especially fruitful for analyzing event history data with internal time-dependent covariates, where an ordinary regression analysis may fail. The approach enables us to describe how the effect of a fixed covariate partly is working directly and partly indirectly through internal time-dependent covariates. For the sequence of times of event, we define a sequence of path analysis models. At each time of an event, ordinary linear regression is used to estimate the relation between the covariates, while the additive hazard model is used for the regression of the counting process on the covariates. The methodology is illustrated using data from a randomized trial on survival for patients with liver cirrhosis.     

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.     

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.