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.     

Joint covariate-adjusted score test statistics for recurrent events and a terminal event

Recurrent events data are frequently encountered and could be stopped by a terminal event in clinical trials. It is of interest to assess the treatment efficacy simultaneously with respect to both the recurrent events and the terminal event in many applications. In this paper we propose joint covariate-adjusted score test statistics based on joint models of recurrent events and a terminal event. No assumptions on the functional form of the covariates are needed. Simulation results show that the proposed tests can improve the efficiency over tests based on covariate unadjusted model. The proposed tests are applied to the SOLVD data for illustration.     

Optimal goodness-of-fit tests for recurrent event data

A class of tests for the hypothesis that the baseline intensity belongs to a parametric class of intensities is given in the recurrent event setting. Asymptotic properties of a weighted general class of processes that compare the non-parametric versus parametric estimators for the cumulative intensity are presented. These results are given for a sequence of Pitman alternatives. Test statistics are proposed and methods of obtaining critical values are examined. Optimal choices for the weight function are given for a class of chi-squared tests. Based on Khmaladze’s transformation we propose distributional free tests. These include the types of Kolmogorov–Smirnov and Cramér–von Mises. The tests are used to analyze two different data sets.     

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.     

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.     

Asymptotics for a class of dynamic recurrent event models

Asymptotic properties, both consistency and weak convergence, of estimators arising in a general class of dynamic recurrent event models are presented. The class of models take into account the impact of interventions after each event occurrence, the impact of accumulating event occurrences, the induced informative and dependent right-censoring mechanism due to the data-accrual scheme, and the effect of covariate processes on the recurrent event occurrences. The class of models subsumes as special cases many of the recurrent event models that have been considered in biostatistics, reliability, and in the social sciences. The asymptotic properties presented have the potential of being useful in developing goodness-of-fit and model validation procedures, confidence intervals and confidence bands constructions, and hypothesis testing procedures for the finite- and infinite-dimensional parameters of a general class of dynamic recurrent event models, albeit the models without frailties.     

A Marginal Additive Rates Model for Recurrent Event Data with a Terminal Event

Recurrent events data with a terminal event often arise in many longitudinal studies. Most of existing models assume multiplicative covariate effects and model the conditional recurrent event rate given survival. In this article, we propose a marginal additive rates model for recurrent events with a terminal event, and develop two procedures for estimating the model parameters. The asymptotic properties of the resulting estimators are established. In addition, some numerical procedures are presented for model checking. The finite-sample behavior of the proposed methods is examined through simulation studies, and an application to a bladder cancer study is also illustrated.     

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.     

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.     

Semiparametric inference for a general class of models for recurrent events

Procedures for estimating the parameters of the general class of semiparametric models for recurrent events proposed by Peña and Hollander [(2004). Models for recurrent events in reliability and survival analysis. In: Soyer R., Mazzuchi T., Singpurwalla N. (Eds.), Mathematical Reliability: An Expository Perspective. Kluwer Academic Publishers, Dordrecht, pp. 105–123 (Chapter 6)] are developed. This class of models incorporates an effective age function encoding the effect of changes after each event occurrence such as the impact of an intervention, it models the impact of accumulating event occurrences on the unit, it admits a link function in which the effect of possibly time-dependent covariates are incorporated, and it allows the incorporation of unobservable frailty components which induce dependencies among the inter-event times for each unit. The estimation procedures are semiparametric in that a baseline hazard function is nonparametrically specified. The sampling distribution properties of the estimators are examined through a simulation study, and the consequences of mis-specifying the model are analyzed. The results indicate that the flexibility of this general class of models provides a safeguard for analyzing recurrent event data, even data possibly arising from a frailty-less mechanism. The estimation procedures are applied to real data sets arising in the biomedical and public health settings, as well as from reliability and engineering situations. In particular, the procedures are applied to a data set pertaining to times to recurrence of bladder cancer and the results of the analysis are compared to those obtained using three methods of analyzing recurrent event data.     

A class of accelerated means regression models for recurrent event data

In this article, we propose a general class of accelerated means regression models for recurrent event data. The class includes the proportional means model, the accelerated failure time model and the accelerated rates model as special cases. The new model offers great flexibility in formulating the effects of covariates on the mean functions of counting processes while leaving the stochastic structure completely unspecified. For the inference on the model parameters, estimating equation approaches are developed and both large and final sample properties of the proposed estimators are established. In addition, some graphical and numerical procedures are presented for model checking. An illustration with multiple-infection data from a clinic study on chronic granulomatous disease is also provided.     

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     

Non-parametric Tests for Recurrent Events under Competing Risks

Abstract.  We consider a data set on nosocomial infections of patients hospitalized in a French intensive care facility. Patients may suffer from recurrent infections of different types and they also have a high risk of death. To deal with such situations, a model of recurrent events with competing risks and a terminal event is introduced. Our aim was to compare the occurrence rates of two types of events. For this purpose, we propose two tests: one to detect if the occurrence rate of a given type of event increases with time; a second to detect if the instantaneous probability of experiencing an event of a given type is always greater than the one of another type. The asymptotic properties of the test statistics are derived and Monte Carlo methods are used to study the power of the tests. Finally, the procedures developed are applied to the French nosocomial infections data set.     

Semiparametric model for recurrent event data with excess zeros and informative censoring

Recurrent event data are often encountered in longitudinal follow-up studies in many important areas such as biomedical science, econometrics, reliability, criminology and demography. Multiplicative marginal rates models have been used extensively to analyze recurrent event data, but often fail to fit the data adequately. In addition, the analysis is complicated by excess zeros in the data as well as the presence of a terminal event that precludes further recurrence. To address these problems, we propose a semiparametric model with an additive rate function and an unspecified baseline to analyze recurrent event data, which includes a parameter to accommodate excess zeros and a frailty term to account for a terminal event. Local likelihood procedure is applied to estimate the parameters, and the asymptotic properties of the estimators are established. A simulation study is conducted to evaluate the performance of the proposed methods, and an example of their application is presented on a set of tumor recurrent data for bladder cancer.     

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.     

Additive Transformation Models for Recurrent Events

In this article, we propose a class of additive transformation models for recurrent event data, which includes the additive rates model as a special case. The new models offer great flexibility in formulating the effects of covariates on the mean function of recurrent events. Estimating equation approaches are developed for the model parameters, and asymptotic properties of the resulting estimators are established. In addition, a model checking procedure is presented to assess the adequacy of the model. The finite sample performance of the proposed estimators is examined through simulation studies, and an application to a bladder cancer study is presented.     

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.     

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.     

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.     

Analysis of recurrent events with non-negligible event duration,with application to assessing hospital utilization

In an attempt to provide tools for assessing hospital utilization, this paper extends well-known models for recurrent events to address non-negligible event duration and presents a procedure for estimating the model parameters. The model extension is natural and easy to understand. Asymptotic properties of the associated inferences are derived adapting the well-developed methods based on the counting process formulation. Several specifications of the proposed modeling are illustrated with the hospitalization records of childhood cancer survivors from a health care insurance system that motivated this research. The usefulness and robustness of the proposed approach is demonstrated numerically via simulation.