Gap Time Data Research Articles

Semiparametric Trend Analysis for Stratified Recurrent Gap Times Under Weak Comparability Constraint

Recurrent event data are frequently encountered in many longitudinal studies where each individual may experience more than one event. Wang and Chen (Biometrics 56(3):789–794, 2000) proposed a comparability constraint to estimate the time trend for the gap times, where the gap time pairs that satisfy the constraint have the same conditional distribution. However, the comparable paired gap times are also independent. Therefore, the comparable gap time pairs will be subject to a stronger constraint than needed for the estimation. Thus their procedure is subject to information loss. Under the accelerated failure time model, we propose a new comparability constraint that can overcome the drawback mentioned above. The gap time pairs being selected by the proposed comparability constraint will still have the same distribution, but they do not need to be independent of each other. We showed that the proposed comparability constraint will utilize more gap time data pairs than the strong comparability. And we showed via various simulation studies that the variance will be smaller than Wang and Chen’s (2000) estimator. We apply the proposed method to the HIV Prevention Trial Network 052 study.

Modeling and maximum likelihood based inference ofinterval-censored data with unknown upper limits andtime-dependent covariates.

Due to the nature of study design or other reasons, the upper limits of the interval-censored data with multiple visits are unknown. A naïve approach is to treat the last observed time as the exact event time, which may induce biased estimators of the model parameters. In this paper, we first develop a Cox model with time-dependent covariates for the event time and a proportional hazards model with frailty for the gap time. We then construct the upper limits using the latent gap times to resolve the issue of interval-censored event time data with unknown upper limits. A data-augmentation technique and a Monte Carlo EM (MCEM) algorithm are developed to facilitate computation. Theoretical properties of the computational algorithm are also investigated. Additionally, new model comparison criteria are developed to assess the fit of the gap time data as well as the fit of the event time data conditional on the gap time data. Our proposed method compares favorably with competing methods in both simulation study and real data analysis.

Induced smoothing for rank-based regression with recurrent gap time data.

Various semiparametric regression models have recently been proposed for the analysis of gap times between consecutive recurrent events. Among them, the semiparametric accelerated failure time (AFT) model is especially appealing owing to its direct interpretation of covariate effects on the gap times. In general, estimation of the semiparametric AFT model is challenging because the rank-based estimating function is a nonsmooth step function. As a result, solutions to the estimating equations do not necessarily exist. Moreover, the popular resampling-based variance estimation for the AFT model requires solving rank-based estimating equations repeatedly and hence can be computationally cumbersome and unstable. In this paper, we extend the induced smoothing approach to the AFT model for recurrent gap time data. Our proposed smooth estimating function permits the application of standard numerical methods for both the regression coefficients estimation and the standard error estimation. Large-sample properties and an asymptotic variance estimator are provided for the proposed method. Simulation studies show that the proposed method outperforms the existing nonsmooth rank-based estimating function methods in both point estimation and variance estimation. The proposed method is applied to the data analysis of repeated hospitalizations for patients in the Danish Psychiatric Center Register.

Semiparametric regression analysis for alternating recurrent event data.

Alternating recurrent event data arise frequently in clinical and epidemiologic studies, where 2 types of events such as hospital admission and discharge occur alternately over time. The 2 alternating states defined by these recurrent events could each carry important and distinct information about a patient's underlying health condition and/or the quality of care. In this paper, we propose a semiparametric method for evaluating covariate effects on the 2 alternating states jointly. The proposed methodology accounts for the dependence among the alternating states as well as the heterogeneity across patients via a frailty with unspecified distribution. Moreover, the estimation procedure, which is based on smooth estimating equations, not only properly addresses challenges such as induced dependent censoring and intercept sampling bias commonly confronted in serial event gap time data but also is more computationally tractable than the existing rank-based methods. The proposed methods are evaluated by simulation studies and illustrated by analyzing psychiatric contacts from the South Verona Psychiatric Case Register.

A class of partially linear transformation models for recurrent gap times

ABSTRACTIn this article, we propose a general class of partially linear transformation models for recurrent gap time data, which extends the linear transformation models by incorporating non linear covariate effects and includes the partially linear proportional hazards and the partially linear proportional odds models as special cases. Both global and local estimating equations are developed to estimate the parametric and non parametric covariate effects, 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 clinic study on chronic granulomatous disease is provided.

Regression analysis for bivariate gap time with missing first gap time data.

We consider ordered bivariate gap time while data on the first gap time are unobservable. This study is motivated by the HIV infection and AIDS study, where the initial HIV contracting time is unavailable, but the diagnosis times for HIV and AIDS are available. We are interested in studying the risk factors for the gap time between initial HIV contraction and HIV diagnosis, and gap time between HIV and AIDS diagnoses. Besides, the association between the two gap times is also of interest. Accordingly, in the data analysis we are faced with two-fold complexity, namely data on the first gap time is completely missing, and the second gap time is subject to induced informative censoring due to dependence between the two gap times. We propose a modeling framework for regression analysis of bivariate gap time under the complexity of the data. The estimating equations for the covariate effects on, as well as the association between, the two gap times are derived through maximum likelihood and suitable counting processes. Large sample properties of the resulting estimators are developed by martingale theory. Simulations are performed to examine the performance of the proposed analysis procedure. An application of data from the HIV and AIDS study mentioned above is reported for illustration.

Nonparametric Methods for Analyzing Recurrent Gap Time Data with Application to Infections After Hematopoietic Cell Transplant

Infection is one of the most common complications after hematopoietic cell transplantation. Many patients experience infectious complications repeatedly after transplant. Existing statistical methods for recurrent gap time data typically assume that patients are enrolled due to the occurrence of an event of interest, and subsequently experience recurrent events of the same type; moreover, for one-sample estimation, the gap times between consecutive events are usually assumed to be identically distributed. Applying these methods to analyze the post-transplant infection data will inevitably lead to incorrect inferential results because the time from transplant to the first infection has a different biological meaning than the gap times between consecutive recurrent infections. Some unbiased yet inefficient methods include univariate survival analysis methods based on data from the first infection or bivariate serial event data methods based on the first and second infections. In this article, we propose a nonparametric estimator of the joint distribution of time from transplant to the first infection and the gap times between consecutive infections. The proposed estimator takes into account the potentially different distributions of the two types of gap times and better uses the recurrent infection data. Asymptotic properties of the proposed estimators are established.

Serial association analyses of recurrent gap time data via Kendall's tau.

Recurrent event data are frequently encountered in long-term follow-up studies. In many applications, the gap times between two successive recurrent events are natural outcomes of interest. Investigation on patterns of associations among recurrent gap times within subjects is an important inferential issue. In this paper, we introduce flexible functions of previous gap times to create a class of summary measures of serial associations for a sequence of recurrent gap times through Kendall's tau. Such a general class of serial association measures provides a useful tool to quantify the predictive abilities of event history with different aspects. Non-parametric estimators of the proposed measures of serial associations are developed by generalizing the existing estimator of Kendall's tau for two serial gap times, in which inverse probability of censoring weights is used to overcome the induced dependent censoring. Various tests are further constructed for testing the constancy of serial associations over different events. Our method is applied to Denmark schizophrenia data and the results show that association structures are different for distinct ages of onset of schizophrenia.

Additive mixed effect model for recurrent gap time data.

Gap times between recurrent events are often of primary interest in medical and observational studies. The additive hazards model, focusing on risk differences rather than risk ratios, has been widely used in practice. However, the marginal additive hazards model does not take the dependence among gap times into account. In this paper, we propose an additive mixed effect model to analyze gap time data, and the proposed model includes a subject-specific random effect to account for the dependence among the gap times. Estimating equation approaches are developed for parameter estimation, and the asymptotic properties of the resulting estimators are established. In addition, some graphical and numerical procedures are presented for model checking. The finite sample behavior of the proposed methods is evaluated through simulation studies, and an application to a data set from a clinic study on chronic granulomatous disease is provided.

Buckley–James-type estimation of quantile regression with recurrent gap time data

In longitudinal studies, an individual may potentially undergo a series of repeated recurrence events. The gap times, which are referred to as the times between successive recurrent events, are typically the outcome variables of interest. Various regression models have been developed in order to evaluate covariate effects on gap times based on recurrence event data. The proportional hazards model, additive hazards model, and the accelerated failure time model are all notable examples. Quantile regression is a useful alternative to the aforementioned models for survival analysis since it can provide great flexibility to assess covariate effects on the entire distribution of the gap time. In order to analyze recurrence gap time data, we must overcome the problem of the last gap time subjected to induced dependent censoring, when numbers of recurrent events exceed one time. In this paper, we adopt the Buckley–James-type estimation method in order to construct a weighted estimation equation for regression coefficients under the quantile model, and develop an iterative procedure to obtain the estimates. We use extensive simulation studies to evaluate the finite-sample performance of the proposed estimator. Finally, analysis of bladder cancer data is presented as an illustration of our proposed methodology.

A class of transformed hazards models for recurrent gap times

In this article, a class of transformed hazards models is proposed for recurrent gap time data, including both the proportional and additive hazards models as special cases. An estimating equation-based inference procedure is developed for the model parameters, and the asymptotic properties of the resulting estimators are established. In addition, a lack-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 clinic study on chronic granulomatous disease (CGD) is illustrated.

Quantile Regression for Recurrent Gap Time Data

Evaluating covariate effects on gap times between successive recurrent events is of interest in many medical and public health studies. While most existing methods for recurrent gap time analysis focus on modeling the hazard function of gap times, a direct interpretation of the covariate effects on the gap times is not available through these methods. In this article, we consider quantile regression that can provide direct assessment of covariate effects on the quantiles of the gap time distribution. Following the spirit of the weighted risk-set method by Luo and Huang (2011, Statistics in Medicine 30, 301-311), we extend the martingale-based estimating equation method considered by Peng and Huang (2008, Journal of the American Statistical Association 103, 637-649) for univariate survival data to analyze recurrent gap time data. The proposed estimation procedure can be easily implemented in existing software for univariate censored quantile regression. Uniform consistency and weak convergence of the proposed estimators are established. Monte Carlo studies demonstrate the effectiveness of the proposed method. An application to data from the Danish Psychiatric Central Register is presented to illustrate the methods developed in this article.

Properties of the Estimators for Additive-Accelerated Hazard Ratio Model

Recurrent events gap time is the time difference between two adjacent failures of recurrent events. In this paper, an additive-accelerated hazard ratio model is presented for multiple type recurrent events gap time data, and the estimation methods of unknown parameter and non-parameter function is given. Moreover, the asymptotic properties of estimators are proved.

Event‐weighted proportional hazards modelling for recurrent gap time data

The analysis of gap times in recurrent events requires an adjustment to standard marginal models. One can perform this adjustment with a modified within-cluster resampling technique; however, this method is computationally intensive. In this paper, we describe a simple adjustment to the standard Cox proportional hazards model analysis that mimics the intent of within-cluster resampling and results in similar parameter estimates. This method essentially weights the partial likelihood contributions by the inverse of the number of gap times observed within the individual while assuming a working independence correlation matrix. We provide an example involving recurrent mammary tumours in female rats to illustrate the methods considered in this paper.

Additive hazards models for gap time data with multiple causes

Recurrent event data with multiple causes are often observed in biomedical studies. The additive hazards model describes a different aspect of the association between covariates and the failure time than does the proportional hazards model. In this paper, we introduce additive hazards models for the analysis of gap time data of recurrent events with multiple causes. We estimate the regression parameter vector and cumulative baseline cause specific hazard rate function using counting process approach. Asymptotic properties of the estimators are studied. The proposed model is applied to the kidney dialysis data given in Lawless (2003). A simulation study is carried out to assess the performance of the estimates.

Additive-Multiplicative Hazards Model with Recurrent Event Data

In this paper, the additive-multiplicative hazards model with gap time data of recurrent events is studied. Based on this model, two cases are discussed, i.e., the observed data are gap time of recurrent event, and the observed data are a group recurrent events recurrence one time, and the parametric and nonparametric estimations are given. Then the efficiency of estimators for these two cases is compared.

Asymptotic Properties for Estimators of Hazards Model

In this paper, the additive-multiplicative hazards model for gap time data of recurrent events is investigated, and the estimating equation approach is presented for inference about regression parameters. Both asymptotic and finite sample properties of the proposed parameter estimates are established

A model checking method for the proportional hazards model with recurrent gap time data

Recurrent events are the natural outcome in many medical and epidemiology studies. To assess covariate effects on the gaps between consecutive recurrent events, the Cox proportional hazards model is frequently employed in data analysis. The validity of statistical inference, however, depends on the appropriateness of the Cox model. In this paper, we propose a class of graphical techniques and formal tests for checking the Cox model with recurrent gap time data. The building block of our model checking method is an averaged martingale-like process, based on which a class of multiparameter stochastic processes is proposed. This maneuver is very general and can be used to assess different aspects of model fit. Numerical simulations are conducted to examine finite-sample performance, and the proposed model checking techniques are illustrated with data from the Danish Psychiatric Central Register.

Analysis of recurrent gap time data using the weighted risk‐set method and the modified within‐cluster resampling method

The gap times between recurrent events are often of primary interest in medical and epidemiology studies. The observed gap times cannot be naively treated as clustered survival data in analysis because of the sequential structure of recurrent events. This paper introduces two important building blocks, the averaged counting process and the averaged at-risk process, for the development of the weighted risk-set (WRS) estimation methods. We demonstrate that with the use of these two empirical processes, existing risk-set based methods for univariate survival time data can be easily extended to analyze recurrent gap times. Additionally, we propose a modified within-cluster resampling (MWCR) method that can be easily implemented in standard software. We show that the MWCR estimators are asymptotically equivalent to the WRS estimators. An analysis of hospitalization data from the Danish Psychiatric Central Register is presented to illustrate the proposed methods.

A Regression Model for Dependent Gap Times

A natural choice of time scale for analyzing recurrent event data is the ``gap" (or soujourn) time between successive events. In many situations it is reasonable to assume correlation exists between the successive events experienced by a given subject. This paper looks at the problem of extending the accelerated failure time (AFT) model to the case of dependent recurrent event data via intensity modeling. Specifically, the accelerated gap times model of Strawderman (2005), a semiparametric intensity model for independent gap time data, is extended to the case of multiplicative gamma frailty. As argued in Aalen & Husebye (1991), incorporating frailty captures the heterogeneity between subjects and the ``hazard" portion of the intensity model captures gap time variation within a subject. Estimators are motivated using semiparametric efficiency theory and lead to useful generalizations of the rank statistics considered in Strawderman (2005). Several interesting distinctions arise in comparison to the Cox-Andersen-Gill frailty model (e.g., Nielsen et al, 1992; Klein, 1992). The proposed methodology is illustrated by simulation and data analysis.