Analysis Of Recurrent Event Data Research Articles

Robust inference for causal mediation analysis of recurrent event data.

Recurrent events, including cardiovascular events, are commonly observed in biomedical studies. Understanding the effects of various treatments on recurrent events and investigating the underlying mediation mechanisms by which treatments may reduce the frequency of recurrent events are crucial tasks for researchers. Although causal inference methods for recurrent event data have been proposed, they cannot be used to assess mediation. This study proposed a novel methodology of causal mediation analysis that accommodates recurrent outcomes of interest in a given individual. A formal definition of causal estimands (direct and indirect effects) within a counterfactual framework is given, and empirical expressions for these effects are identified. To estimate these effects, a semiparametric estimator with triple robustness against model misspecification was developed. The proposed methodology was demonstrated in a real-world application. The method was applied to measure the effects of two diabetes drugs on the recurrence of cardiovascular disease and to examine the mediating role of kidney function in this process.

Recurrent disability progression endpoints in multiple sclerosis clinical trials

Background: The current standard endpoint to assess disability accumulation in multiple sclerosis (MS) clinical trials is the time to the first confirmed disability progression, which excludes subsequent progression events. Including recurrent progression events may permit a more comprehensive assessment of treatment effects on disability progression. Objective: To propose a definition of recurrent disability progression events and to compare time-to-first and recurrent event analysis. Methods: Recurrent disability progression events were defined by expanding the recommended first event definition. Marginal recurrent event methods (negative binomial model, Lin–Wei–Yang–Ying model) were compared with Cox regression in data from three randomized controlled trials in relapsing multiple sclerosis (RMS) and primary progressive multiple sclerosis (PPMS), and in simulated randomized controlled trial data. Results: The recurrent event analyses included a substantially larger number of progression events compared with the time-to-first-event analyses (+7.5% and +9.9% in the RMS trials and +22.7% in the PPMS trial). The increase in the number of events resulted in more precise treatment effect estimates and a corresponding gain in statistical power. Conclusion: Our results support the use of recurrent event data analysis, especially in progressive MS trials, to improve estimates of treatment effects, increase statistical power, and better capture the clinically meaningful long-term disability progression experience.

Choice of time scale for analysis of recurrent events data.

Recurrent events refer to events that over time can occur several times for each individual. Full use of such data in a clinical trial requires a method that addresses the dependence between events. For modelling this dependence, there are two time scales to consider, namely time since start of the study (running time) or time since most recent event (gap time). In the multi-state setup, it is possible to estimate parameters also in the case, where the hazard model allows for an effect of both time scales, making this an extremely flexible approach. However, for summarizing the effect of a treatment in a transparent and informative way, the choice of time scale and model requires much more care. This paper discusses these choices both from a theoretical and practical point of view. This is supported by a simulation study showing that in a frailty model with assumptions covered by both time scales, the gap time approach may give misleading results. A literature dataset is used for illustrating the issues.

C-index regression for recurrent event data

Recurrent event data analysis plays an important role in many fields, e.g., medicine, social science, and economics. While the existing approaches under the proportional rates or mean model yield poor performance when the underlying model is misspecified, we propose a novel model-free approach by introducing a lower bound on the concordance index (C-Index). We develop an estimation method through deriving a continuous lower bound on the C-Index based on the log-sigmoid function and also provide a variable selection procedure in high dimensional settings. Under both low and high dimensional settings, simulation results show that the proposed methods outperform the gamma frailty recurrent event model when the proportional mean assumption is violated. Moreover, an application to the hospital readmission dataset shows results in line with previous studies and a higher C-Index value further assures model decency.

Semiparametric Latent Class Analysis of Recurrent Event Data.

Recurrent events data frequently arise in chronic disease studies, providing rich information on disease progression. The concept of latent class offers a sensible perspective to characterize complex population heterogeneity in recurrent event trajectories that may not be adequately captured by a single regression model. However, the development of latent class methods for recurrent events data has been sparse, typically requiring strong parametric assumptions and involving algorithmic issues. In this work, we investigate latent class analysis of recurrent events data based on flexible semiparametric multiplicative modeling. We derive a robust estimation procedure through novelly adapting the conditional score technique and utilizing the special characteristics of multiplicative intensity modeling. The proposed estimation procedure can be stably and efficiently implemented based on existing computational routines. We provide solid theoretical underpinnings for the proposed method, and demonstrate its satisfactory finite sample performance via extensive simulation studies. An application to a dataset from research participants at Goizueta Alzheimer's Disease Research Center illustrates the practical utility of our proposals.

Accelerated failure time models for recurrent event data analysis and joint modeling

Accelerated failure time models for recurrent event data analysis and joint modeling

Semiparametric estimation of the proportional rates model for recurrent events data with missing event category.

Proportional rates models are frequently used for the analysis of recurrent event data with multiple event categories. When some of the event categories are missing, a conventional approach is to either exclude the missing data for a complete-case analysis or employ a parametric model for the missing event type. It is well known that the complete-case analysis is inconsistent when the missingness depends on covariates, and the parametric approach may incur bias when the model is misspecified. In this paper, we aim to provide a more robust approach using a rate proportion method for the imputation of missing event types. We show that the log-odds of the event type can be written as a semiparametric generalized linear model, facilitating a theoretically justified estimation framework. Comprehensive simulation studies were conducted demonstrating the improved performance of the semiparametric method over parametric procedures. Multiple types of Pseudomonas aeruginosa infections of young cystic fibrosis patients were analyzed to demonstrate the feasibility of our proposed approach.

Efficient Multiple Imputation for Sensitivity Analysis of Recurrent Events Data with Informative Censoring

Missing data are commonly encountered in clinical trials due to dropout or nonadherence to study procedures. In trials in which recurrent events are of interest, the observed count can be an undercount of the events if a patient drops out before the end of the study. In many applications, the data are not necessarily missing at random and it is often not possible to test the missing at random assumption. Consequently, it is critical to conduct sensitivity analysis. We develop a control-based multiple imputation method for recurrent events data, where patients who drop out of the study are assumed to have a similar response profile to those in the control group after dropping out. Specifically, we consider the copy reference approach and the jump to reference approach. We model the recurrent event data using a semiparametric proportional intensity frailty model with the baseline hazard function completely unspecified. We develop nonparametric maximum likelihood estimation and inference procedures. We then impute the missing data based on the large sample distribution of the resulting estimators. The variance estimation is corrected by a bootstrap procedure. Simulation studies demonstrate the proposed method performs well in practical settings. We provide applications to two clinical trials.

Semiparametric estimation with spatially correlated recurrent events

AbstractThis article pertains to the analysis of recurrent event data in the presence of spatial correlation. Consider units located at n possibly spatially correlated geographical areas described by their longitude and latitude and monitored for the occurrence of an event that can recur. We propose a new class of semiparametric models for recurrent events that simultaneously account for risk factors and correlation among the spatial locations, and that subsumes the current methods. Since the parameters involved in the models are not directly estimable because of the high dimension of the likelihood, we use composite likelihood approach for estimation. The approach leads to estimates with population interpretation where their large sample properties are obtained under a reasonable set of regularity conditions. Simulation studies suggest that the resulting estimators have a very good finite sampling properties. The methods are illustrated using spatial data on recurrent esophageal cancer in the northern region of France and recurrent wildfire data in the province of Alberta, Canada.

Recurrent Event Analysis of Coronary Artery Stenosis in Patients Undergoing Angioplasty

Background: Restenosis after coronary angioplasty can have serious complications such as coronary artery bypass graft, myocardial infarction, and death. Objectives: The present study aimed at investigating the factors affecting the recurrence of coronary artery stenosis in patients undergoing angioplasty using the recurrent event data analysis. Methods: A cohort study was performed on patients undergoing coronary angioplasty from March 23, 2009, to January 21, 2011. All patients were followed up from angioplasty to January 21, 2015. First, each of the independent variables was entered into the univariate Cox model with a frailty component. Then, variables with p-values of less than 0.2 were entered into the multivariate analysis. The statistical analysis was done using R software, version 3.6, at the significance level of 0.05. Results: The present study was conducted on 1,000 patients who underwent coronary angioplasty. We found that 441 patients experienced restenosis at least once in the study period. The mean survival time to the first event of restenosis was 44.08 ± 1.06 months. Patients with a history of diabetes, unstable angina, and myocardial infarction had a significantly higher hazard of restenosis compared to other patients (P < 0.05). Conclusions: The results of the recurrent event survival analysis confirmed the significant role of risk factors such as a history of diabetes, unstable angina, and myocardial infarction. Therefore, training to enhance the patients’ awareness and attitude seems necessary to prevent them from exposing whit known risk factors. The periodic follow-up of patients with risk factors and more ongoing care are also necessary.

Group variable selection in the Andersen–Gill model for recurrent event data

In many scientific applications, such as biological studies, the predictors or covariates are naturally grouped. In this research, we consider the Andersen–Gill regression model for the analysis of recurrent event data with group covariates. In order to study the effects of the covariates on the occurrence of recurrent events, a bi-level penalized group selection method is introduced to address the group selection problem. A general group-bridge penalty function with varying weights is invoked to achieve the goal. It is shown that the performance of the bi-level selection depends on the weights. In order to select covariates more efficiently, especially for identifying the important covariates in important groups, adaptive weights are required. The asymptotic oracle properties of these methods are investigated. Three methods of tuning parameter selection are proposed. Our simulation studies show that the proposed method performs well in selecting important groups and important individual covariates in these groups simultaneously, and outperforms other popular group selection methods and the traditional unpenalized Wald testing method. We illustrate the method using a real life data set from medicine.

Nonparametric group sequential methods for recurrent and terminal events from multiple follow-up windows.

Few methods are currently available for group sequential analysis of recurrent events data subject to a terminal event in the clinical trial setting. This research helps fill this gap by developing a completely nonparametric group sequential monitoring procedure for use with the two-sample Tayob and Murray statistic. Advantages of the Tayob and Murray statistic include high power to detect treatment differences when there is correlation between recurrent event times or between recurrent and terminal events in an individual. This statistic does not suffer bias from dependent censoring, regardless of the correlation between event times in an individual. This manuscript briefly reviews the Tayob and Murray statistic, develops and describes how to use methods for its group sequential analysis, and through simulation, compares its operating characteristics with those of Cook and Lawless, which is currently in use as the only available nonparametric method for group sequential analysis of recurrent event data. The merits of our proposed approach are most clearly demonstrated when gap times between recurrent events are correlated; when gap times between events are independent, the Cook and Lawless method is difficult to beat. Simulations demonstrate that as correlation between recurrent event times grows, the reduction in power using the Cook and Lawless approach is substantial when compared to our method. Finally, we use our method to analyze recurrent acute exacerbation outcomes from the azithromycin in chronic obstructive pulmonary disease trial.

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.

Joint analysis of recurrent event data with additive–multiplicative hazards model for the terminal event time

Recurrent event data are often collected in longitudinal follow-up studies. In this article, we propose a semiparametric method to model the recurrent and terminal events jointly. We present an additive–multiplicative hazards model for the terminal event and a proportional intensity model for the recurrent events, and a shared frailty is used to model the dependence between the recurrent and terminal events. We adopt estimating equation approaches for inference, and the asymptotic properties of the resulting estimators are established. The finite sample behavior of the proposed estimators is evaluated through simulation studies. An application to a medical cost study of chronic heart failure patients from the University of Virginia Health System is illustrated.

Joint analysis of recurrent event data with a dependent terminal event

Recurrent event data frequently occur in many longitudinal studies, and the observation on recurrent events could be stopped by a terminal event such as death. This paper considers joint modeling and analysis of recurrent event and terminal event data through a common subject-specific frailty, in which the proportional intensity model is used for modeling the recurrent event process and the additive hazards model is used for modeling the terminal event time. Estimating equation approaches are developed for parameter estimation and asymptotic properties of the resulting estimators are established. In addition, some procedures are presented for model checking. The finite sample behavior of the proposed estimators is evaluated through simulation studies, and an application to a heart failure study is provided.

Enhanced Global Score Test for Multivariate Survival Analysis of Recurrent Events Data

Enhanced Global Score Test for Multivariate Survival Analysis of Recurrent Events Data

Median Analysis of Repeated Measures Associated with Recurrent Events in Presence of Terminal Event

Recurrent events are often encountered in medical follow up studies. In addition, such recurrences have other quantities associated with them that are of considerable interest, for instance medical costs of the repeated hospitalizations and tumor size in cancer recurrences. These processes can be viewed as point processes, i.e. processes with arbitrary positive jump at each recurrence. An analysis of the mean function for such point processes have been proposed in the literature. However, such point processes are often skewed, leading to median as a more appropriate measure than the mean. Furthermore, the analysis of recurrent event data is often complicated by the presence of death. We propose a semiparametric model for assessing the effect of covariates on the quantiles of the point processes. We investigate both the finite sample as well as the large sample properties of the proposed estimators. We conclude with a real data analysis of the medical cost associated with the treatment of ovarian cancer.

Sojourning With the Homogeneous Poisson Process

ABSTRACTIn 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.

Accelerated lifetime modelling with frailty in a non-homogeneous Poisson Process for analysis of recurrent events data

In survival analysis, the hazard function for each individual may be influenced by risk variables, but commonly we have some variables that cannot be observed nor measured. Besides, when lifetime data present more than one observed event for each individual, frailty is a common factor among such recurrence times. In this paper, we present a natural extension of the conventional accelerated failure time (AFT) model for recurrent events with frailty, in order to take into account possible correlations and heterogeneity between event times. We include the effects of covariates on the intensity function of the non-homogeneous Poisson process for recurrent events. The proposed model retains the direct physical interpretation of the original AFT model in that the role of the covariates is to accelerate or decelerate the time to each recurrence. These include parametric approaches to model fitting, we consider to estimate the vector of regression parameters under this model and the parameter in the baseline hazard functions. This methodology is illustrated with a simulation study and also with a known real dataset.

Recurrent event data analysis with intermittently observed time-varying covariates.

Although recurrent event data analysis is a rapidly evolving area of research, rigorous studies on estimation of the effects of intermittently observed time-varying covariates on the risk of recurrent events have been lacking. Existing methods for analyzing recurrent event data usually require that the covariate processes are observed throughout the entire follow-up period. However, covariates are often observed periodically rather than continuously. We propose a novel semiparametric estimator for the regression parameters in the popular proportional rate model. The proposed estimator is based on an estimated score function where we kernel smooth the mean covariate process. We show that the proposed semiparametric estimator is asymptotically unbiased, normally distributed, and derives the asymptotic variance. Simulation studies are conducted to compare the performance of the proposed estimator and the simple methods carrying forward the last covariates. The different methods are applied to an observational study designed to assess the effect of group A streptococcus on pharyngitis among school children in India. Copyright © 2016 John Wiley & Sons, Ltd.