Joint model for bivariate zero-inflated recurrent event data with terminal events

Bivariate recurrent event data are observed when subjects are at risk of experiencing two different type of recurrent events. In this paper, our interest is to suggest statistical model when there is a substantial portion of subjects not experiencing recurrent events but having a terminal event. In a context of recurrent event data, zero events can be related with either the risk free group or a terminal event. For simultaneously reflecting both a zero inflation and a terminal event in a context of bivariate recurrent event data, a joint model is implemented with bivariate frailty effects. Simulation studies are performed to evaluate the suggested models. Infection data from AML (acute myeloid leukemia) patients are analyzed as an application.     

Estimating Marginal Effects in Accelerated Failure Time Models for Serial Sojourn Times Among Repeated Events

Recurrent event data are commonly encountered in longitudinal studies when events occur repeatedly over time for each study subject. An accelerated failure time (AFT) model on the sojourn time between recurrent events is considered in this article. This model assumes that the covariate effect and the subject-specific frailty are additive on the logarithm of sojourn time, and the covariate effect maintains the same over distinct episodes, while the distributions of the frailty and the random error in the model are unspecified. With the ordinal nature of recurrent events, two scale transformations of the sojourn times are derived to construct semiparametric methods of log-rank type for estimating the marginal covariate effects in the model. The proposed estimation approaches/inference procedures also can be extended to the bivariate events, which alternate themselves over time. Examples and comparisons are presented to illustrate the performance of the proposed methods.     

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.     

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.     

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.     

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.     

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 regression model for recurrent event data with event-varying covariate effects and event effect

In the course of hypertension, cardiovascular disease events (e.g. stroke, heart failure) occur frequently and recurrently. The scientific interest in such study may lie in the estimation of treatment effect while accounting for the correlation among event times. The correlation among recurrent event times comes from two sources: subject-specific heterogeneity (e.g. varied lifestyles, genetic variations, and other unmeasurable effects) and event dependence (i.e. event incidences may change the risk of future recurrent events). Moreover, event incidences may change the disease progression so that there may exist event-varying covariate effects (the covariate effects may change after each event) and event effect (the effect of prior events on the future events). In this article, we propose a Bayesian regression model that not only accommodates correlation among recurrent events from both sources, but also explicitly characterizes the event-varying covariate effects and event effect. This model is especially useful in quantifying how the incidences of events change the effects of covariates and risk of future events. We compare the proposed model with several commonly used recurrent event models and apply our model to the motivating lipid-lowering trial (LLT) component of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) (ALLHAT-LLT).     

A study of grouped failure time data and the misapplication of recurrent event modeling

Clinical trials often assess whether or not subjects have a disease at predetermined follow-up times. When the response of interest is a recurrent event, a subject may respond at multiple follow-up times over the course of the study. Alternatively, when the response of interest is an irreversible event, a subject is typically only observed until the time at which the response is first detected. However, some recent studies have recorded subjects responses at follow-up times after an irreversible event is initially observed. This study compares how existing models perform when failure time data are treated as recurrent events.     

Sensitivity analyses for partially observed recurrent event data

Recurrent events involve the occurrences of the same type of event repeatedly over time and are commonly encountered in longitudinal studies. Examples include seizures in epileptic studies or occurrence of cancer tumors. In such studies, interest lies in the number of events that occur over a fixed period of time. One considerable challenge in analyzing such data arises when a large proportion of patients discontinues before the end of the study, for example, because of adverse events, leading to partially observed data. In this situation, data are often modeled using a negative binomial distribution with time‐in‐study as offset. Such an analysis assumes that data are missing at random (MAR). As we cannot test the adequacy of MAR, sensitivity analyses that assess the robustness of conclusions across a range of different assumptions need to be performed. Sophisticated sensitivity analyses for continuous data are being frequently performed. However, this is less the case for recurrent event or count data. We will present a flexible approach to perform clinically interpretable sensitivity analyses for recurrent event data. Our approach fits into the framework of reference‐based imputations, where information from reference arms can be borrowed to impute post‐discontinuation data. Different assumptions about the future behavior of dropouts dependent on reasons for dropout and received treatment can be made. The imputation model is based on a flexible model that allows for time‐varying baseline intensities. We assess the performance in a simulation study and provide an illustration with a clinical trial in patients who suffer from bladder cancer. Copyright © 2015 John Wiley & Sons, Ltd.     

Non parametric analysis of gap times for bivariate recurrent event data with cure fraction

Recurrent event data often arise in longitudinal studies. In many applications, subjects may experience two different types of events alternatively over time or a pair of subjects may experience recurrent events of the same type. Medical advances have made it possible for some patients to be cured such that the disease of interest does not recur. In this article, we consider non parametric analysis of bivariate recurrent event data with cure fraction. Using the inverse-probability weighted (IPW) approach, we propose non parametric estimators for the proportion of cured patients and for the joint distribution functions of bivariate recurrence times of the uncured ones. The asymptotic properties of the proposed estimators are established. Simulation study indicates that the proposed estimators perform well in finite samples.     

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.     

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.     

Multiple Window Discrete Scan Statistics

In this article, multiple scan statistics of variable window sizes are derived for independent and identically distributed 0-1 Bernoulli trials. Both one and two dimensional, as well as, conditional and unconditional cases are treated. The advantage in using multiple scan statistics, as opposed to single fixed window scan statistics, is that they are more sensitive in detecting a change in the underlying distribution of the observed data. We show how to derive simple approximations for the significance level of these testing procedures and present numerical results to evaluate their performance.     

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.     

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     

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.     

Simulated maximum likelihood estimation in joint models for multiple longitudinal markers and recurrent events of multiple types,in the presence of a terminal event

In medical studies we are often confronted with complex longitudinal data. During the follow-up period, which can be ended prematurely by a terminal event (e.g. death), a subject can experience recurrent events of multiple types. In addition, we collect repeated measurements from multiple markers. An adverse health status, represented by ‘bad’ marker values and an abnormal number of recurrent events, is often associated with the risk of experiencing the terminal event. In this situation, the missingness of the data is not at random and, to avoid bias, it is necessary to model all data simultaneously using a joint model. The correlations between the repeated observations of a marker or an event type within an individual are captured by normally distributed random effects. Because the joint likelihood contains an analytically intractable integral, Bayesian approaches or quadrature approximation techniques are necessary to evaluate the likelihood. However, when the number of recurrent event types and markers is large, the dimensionality of the integral is high and these methods are too computationally expensive. As an alternative, we propose a simulated maximum-likelihood approach based on quasi-Monte Carlo integration to evaluate the likelihood of joint models with multiple recurrent event types and markers.     

Nonparametric estimation of a regression function from backward recurrence times in a cross-sectional sampling

This study considers the nonparametric estimation of a regression function when the response variable is the waiting time between two consecutive events of a stationary renewal process, and where this variable is not completely observed. In these circumstances, our data are the recurrence times from the occurrence of the last event up to a pre-established time, along with the corresponding values of a certain set of covariates. Estimation of the error density function and some of its characteristics are also considered. For the proposed estimators, we first analyze their asymptotic behavior and, thereafter, carry out a simulation study to highlight their behavior in finite samples. Finally, we apply this methodology to an illustrative example with biomedical data.