Additive–multiplicative rates model for recurrent events

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.

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.

Modeling recurrent event data with multiple event types has drawn interest in recent biomedical studies due to its flexibility for understanding different risk factors for multiple recurrent event processes. However, in such data type, missing event type appears frequently because of various reasons such as recording ignorance or resource limitation. In this study, we aim to propose an inverse probability weighted estimation that is commonly used in the missing data literature to correct possibly biased estimation by a complete-case analysis. This approach is not limited to a specific form of the recurrent event model. We derive the large sample theory in a general form. We demonstrate that our approach can be applied to either multiplicative or additive rates model with practical sample size via comprehensive simulations. Nonmucoid and mucoid Pseudomonas aeruginosa infections of 14888 patients in 2016 Cystic Fibrosis Foundation Patient Registry data are analyzed to show that, without including 12% events with missing event type in the analysis, several factors may be misidentified as risk factors for the nonmucoid type of infections.

Recurrent event data, which represent the occurrence of repeated incidences, are common in observational studies. Furthermore, collecting possible spatial correlations in health and environmental data is likely to provide more information for risk prediction. This article proposes a comprehensive proportional intensity model considering spatial random effects for recurrent event data using a Bayesian approach. The spatial information for areal data (where the spatial location is known up to a geographic unit such as a county) and georeferenced data (where the location is exactly observed) is examined. A traditional constant baseline intensity function, as well as a flexible piecewise constant baseline intensity function, are both under consideration. To estimate the parameters, a Markov chain Monte Carlo method with the Metropolis-Hastings algorithm and the adaptive Metropolis algorithm are applied. To assess the performance of model fitting, the deviance information criterion and log pseudo marginal likelihood are proposed. Overall, simulation studies demonstrate that the proposed model is significantly better than models that do not consider spatial effects if spatial correlations exist. Finally, our approach is implemented using a dataset related to the recurrence of cardiovascular diseases, which incorporates spatial information.

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.

In this paper, we consider the analysis of recurrent event data that examines the differences between two treatments. The outcomes that are considered in the analysis are the pre-randomisation event count and post-randomisation times to first and second events with associated cure fractions. We develop methods that allow pre-randomisation counts and two post-randomisation survival times to be jointly modelled under a Poisson process framework, assuming that outcomes are predicted by (unobserved) event rates. We apply these methods to data that examine the difference between immediate and deferred treatment policies in patients presenting with single seizures or early epilepsy. We find evidence to suggest that post-randomisation seizure rates change at randomisation and following a first seizure after randomisation. We also find that there are cure rates associated with the post-randomisation times to first and second seizures. The increase in power over standard survival techniques, offered by the joint models that we propose, resulted in more precise estimates of the treatment effect and the ability to detect interactions with covariate effects.

Recurrent event data analyses are usually conducted under the assumption that the censoring time is independent of the recurrent event process. In many applications the censoring time can be informative about the underlying recurrent event process, especially in situations where a correlated failure event could potentially terminate the observation of recurrent events. In this article, we consider a semiparametric model of recurrent event data that allows correlations between censoring times and recurrent event process via frailty. This flexible framework incorporates both time-dependent and time-independent covariates in the formulation, while leaving the distributions of frailty and censoring times unspecified. We propose a novel semiparametric inference procedure that depends on neither the frailty nor the censoring time distribution. Large sample properties of the regression parameter estimates and the estimated baseline cumulative intensity functions are studied. Numerical studies demonstrate that the proposed methodology performs well for realistic sample sizes. An analysis of hospitalization data for patients in an AIDS cohort study is presented to illustrate the proposed method.

A general class of additive semiparametric models for recurrent event data

Introduction: Recurrent event data are common in many longitudinal studies. Often, a terminating event such as death can be correlated with the recurrent event process. A shared frailty model applied to account for the association between recurrent and terminal events. In some situations, a fraction of subjects experience neither recurrent events nor death; these subjects are cured.
 Methods: In this paper, we discussed the Bayesian approach of a joint frailty model for recurrent and terminal events in the presence of cure fraction. We compared estimates of parameters in the Frequentist and Bayesian approaches via simulation studies in various sample sizes; we applied the joint frailty model in the presence of cure fraction with Frequentist and Bayesian approaches for breast cancer.
 Results: In small sample size Bayesian approach compared to Frequentist approach had a smaller standard error and mean square error, and the coverage probabilities close to nominal level of 95%. Also, in Bayesian approach, the sampling means of the estimated standard errors were close to the empirical standard error.
 Conclusion: The simulation results suggested that when sample size was small, the use of Bayesian joint frailty model in the presence of cure fraction led to more efficiency in parameter estimation and statistical inference.

Recurrent event data often arises in biomedical studies, and individuals within a cluster might not be independent. We propose a semiparametric additive rates model for clustered recurrent event data, wherein the covariates are assumed to add to the unspecified baseline rate. For the inference on the model parameters, estimating equation approaches are developed, and both large and finite sample properties of the proposed estimators are established.

In modern biomedical datasets, it is common for recurrent outcomes data to be collected in an incomplete manner. More specifically, information on recurrent events is routinely recorded as a mixture of recurrent event data, panel count data, and panel binary data; we refer to this structure as general mixed recurrent event data. Although the aforementioned data types are individually well-studied, there does not appear to exist an established approach for regression analysis of the three component combination. Often, ad-hoc measures such as imputation or discarding of data are used to homogenize records prior to the analysis, but such measures lead to obvious concerns regarding robustness, loss of efficiency, and other issues. This work proposes a maximum likelihood regression estimation procedure for the combination of general mixed recurrent event data and establishes the asymptotic properties of the proposed estimators. In addition, we generalize the approach to allow for the existence of terminal events, a common complicating feature in recurrent event analysis. Numerical studies and application to the Childhood Cancer Survivor Study suggest that the proposed procedures work well in practical situations.

This research develops multivariable restricted time models appropriate for analysis of recurrent events data, where data is repurposed into censored longitudinal time-to-first-event outcomes in τ-length follow-up windows. We develop two approaches for addressing the censored nature of the outcomes: a pseudo-observation (PO) approach and a multiple-imputation (MI) approach. Each of these approaches allows for complete data methods, such as generalized estimating equations, to be used for the analysis of the newly constructed correlated outcomes. Through simulation, this manuscript assesses the performance of the proposed PO and MI methods. Both PO and MI approaches show attractive results with either correlated or independent gap times in an individual. We also demonstrate how to apply the proposed methods in the data from azithromycin in Chronic Obstructive Pulmonary Disease Trial.

BackgroundGlobally, the estimated recurrent childbirth of one forth of women happens every two years or fewer. Next to Nigeria, Ethiopia is the second populist country in Africa and the first populist country in sub-Saharan Africa which consists of over 114 million population. There are prevalent short successive birth intervals problems in underdeveloped nations such as Ethiopia that contributes to adverse effects on mother and child health. However, studies that explore recurrent birth events and associated factors are very limited. Thus, this study aimed to explore and model the recurrent birth event by considering its subsequent within a mother and identifying its important determinants. As a result, the research findings of this study will be one of the preliminary research papers on the recurrent birth events that take into account the subsequent event and enable to be input for the policymakers, health institutions, and future researchers.MethodsA total of 4676 mothers with their 16833 corresponding children were involved in this study. The data was obtained from the 2019 Ethiopian Mini Demographic and Health Survey (EMDHS). In this study, extended cox regression models such as Andersen-Gill (AG), Prentice, Williams, and Peterson total time (PWP-TT) model, PWP-gap time (PWP-GT) model, and Frailty model were employed. These all models are used to consider recurrent events within mothers and determine the potential determinants. AG, PWP-TT, and PWP-GT estimate the effect of covariates by considering the correlation between event times for a person can be explained by past events given the covariates, kth event since the entry time, kth event since the time from the previous event, respectively.ResultsAmong mothers who have first and ninth recurrent birth events, 75.5% and 80.1% of them respectively were rural residents while 57.6% and 70.6% of them respectively were a place of delivery in the health sector. The highest prevalence of first recurrent births (44.3%) was obtained from Muslim mothers. Mothers' education level (HR: 1.210; 95%CI: 1.010, 1.460), mothers' age at first birth (HR: 0.713; 95% CI: 0.614, 0.828), household wealth index (HR: 0.776; 95% CI: 0.625, 0.965), child mortality (HR: 0.673; 95%CI: 0.514, 0.881), household size (HR: 1.914; 95%CI:1.539,2.381) and sex of child (HR:0.836; 95%CI = 0.755,0.926) were important determinants of recurrent birth event. This indicates mothers’ education level and household size were positively associated with recurrent birth events. Whereas mothers’ age at first birth, household wealth index, child mortality, and sex of the child was negatively associated with recurrent birth events.ConclusionThe WHO recommends a minimum of 33 months between two consecutive births, which is longer than the Ethiopian recurrent birth intervals observed in this study. The highest recurrent birth occurred during the age of fewer than twenty years old of mothers at first birth as compared to mothers whose age was older at first birth. Mothers, children, and household characteristics had significant effects on recurrent birth events. We authors would like to recommend communities, governmental and non-governmental stakeholders consider the associated factors of frequent recurrence of birth noticed in this study. Besides, we would also like to recommend women start birth while they got mature in age to reduce frequent recurrent birth and its corresponding adverse effects.

In this paper, we consider an inference method for recurrent event data in which the primary exposure covariate is assessed only in a validation set, while as an auxiliary covariate for the main exposure is available for the full cohort. Additive rate model is considered. The existing estimating equations in the absence of primary exposure are corrected by taking use of the validation data and auxiliary information, which yield consistent and asymptotically normal estimators of the regression parameters. The estimated baseline mean process is shown to converge weakly to a zero-mean Gaussian process. Extensive simulations are conducted to evaluate finite sample performance.

To investigate pairwise interactions arising from recurrent event processes in a longitudinal network, the framework of the stochastic block model is followed, where every node belongs to a latent group and interactions between node pairs from two specified groups follow a conditional nonhomogeneous Poisson process. Our focus lies on discrete observation times, which are commonly encountered in reality for cost-saving purposes. The variational EM algorithm and variational maximum likelihood estimation are applied for statistical inference. A specific method based on the defined distribution function F and self-consistency algorithm for recurrent events is used when estimating the intensity functions of edges. Numerical simulations illustrate the performance of our proposed estimation procedure in uncovering the underlying structure in the longitudinal networks with recurrent event processes. The dataset of interactions between French schoolchildren for influenza monitoring is analyzed.