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.     

Additive transformation models for clustered failure time data

We propose a class of additive transformation risk models for clustered failure time data. Our models are motivated by the usual additive risk model for independent failure times incorporating a frailty with mean one and constant variability which is a natural generalization of the additive risk model from univariate failure time to multivariate failure time. An estimating equation approach based on the marginal hazards function is proposed. Under the assumption that cluster sizes are completely random, we show the resulting estimators of the regression coefficients are consistent and asymptotically normal. We also provide goodness-of-fit test statistics for choosing the transformation. Simulation studies and real data analysis are conducted to examine the finite-sample performance of our estimators.     

Marginal Analysis For Clustered Failure Time Data

Clustered failure time data are commonly encountered in biomedical research where the study subjects from the same cluster (e.g., family) share the common genetic and/or environmental factors such that the failure times within the same cluster are correlated. Two approaches that are commonly used to account for the intra-cluster association are frailty models and marginal models. In this paper, we study the marginal proportional hazards model, where the structure of dependence between individuals within a cluster is unspecified. An estimation procedure is developed based on a pseudo-likelihood approach, and a risk set sampling method is proposed for the formulation of the pseudo-likelihood. The asymptotic properties of the proposed estimators are studied, and the related issues regarding the statistical efficiencies are discussed. The performances of the proposed estimator are demonstrated by the simulation studies. A data example from a child vitamin A supplementation trial in Nepal (Nepal Nutrition Intervention Project-Sarlahi, or NNIPS) is used to illustrate this methodology.     

Estimation of average causal effect using the restricted mean residual lifetime as effect measure

Although mean residual lifetime is often of interest in biomedical studies, restricted mean residual lifetime must be considered in order to accommodate censoring. Differences in the restricted mean residual lifetime can be used as an appropriate quantity for comparing different treatment groups with respect to their survival times. In observational studies where the factor of interest is not randomized, covariate adjustment is needed to take into account imbalances in confounding factors. In this article, we develop an estimator for the average causal treatment difference using the restricted mean residual lifetime as target parameter. We account for confounding factors using the Aalen additive hazards model. Large sample property of the proposed estimator is established and simulation studies are conducted in order to assess small sample performance of the resulting estimator. The method is also applied to an observational data set of patients after an acute myocardial infarction event.     

Mark-specific additive hazards regression with continuous marks

For survival data, mark variables are only observed at uncensored failure times, and it is of interest to investigate whether there is any relationship between the failure time and the mark variable. The additive hazards model, focusing on hazard differences rather than hazard ratios, has been widely used in practice. In this article, we propose a mark-specific additive hazards model in which both the regression coefficient functions and the baseline hazard function depend nonparametrically on a continuous mark. An estimating equation approach is developed to estimate the regression functions, and the asymptotic properties of the resulting estimators are established. In addition, some formal hypothesis tests are constructed for various hypotheses concerning the mark-specific treatment effects. The finite sample behavior of the proposed estimators is evaluated through simulation studies, and an application to a data set from the first HIV vaccine efficacy trial is provided.     

On a deconvolution problem under competing risks

Bagai and Prakasa Rao [Analysis of survival data with two dependent competing risks. Biometr J. 1992;7:801–814] considered a competing risks model with two dependent risks. The two risks are initially independent but dependence arises because of the additive effect of an independent risk on the two initially independent risks. They showed that the ratio of failure rates are identifiable in the nonparametric set-up. In this paper, we consider it as a measurement error/deconvolution problem and suggest a nonparametric kernel-type estimator for the ratio of two failure rates. The local error properties of the proposed estimator are studied. Simulation studies show the efficacy of the proposed estimator.     

A class of goodness-of-fit test for the additive hazards model with case-cohort data

The case-cohort design is commonly used in epidemiological studies due to its cost-effectiveness. The additive hazards model is widely used in survival analysis when the hazards difference is constant. In this article, we propose a class of goodness-of-fit test statistics for the assumption of the additive hazards model with case-cohort data through a class of asymptotically mean-zero multiparameter stochastic processes. We also establish the asymptotic theory of the proposed test statistics and a resampling scheme is adopted to approximate its asymptotic distribution. The performance of the proposed test statistics is evaluated through simulation studies and a real dataset is analyzed to illustrate the proposed method.     

A regularized variable selection procedure in additive hazards model with stratified case-cohort design

Case-cohort designs are commonly used in large epidemiological studies to reduce the cost associated with covariate measurement. In many such studies the number of covariates is very large. An efficient variable selection method is needed for case-cohort studies where the covariates are only observed in a subset of the sample. Current literature on this topic has been focused on the proportional hazards model. However, in many studies the additive hazards model is preferred over the proportional hazards model either because the proportional hazards assumption is violated or the additive hazards model provides more relevent information to the research question. Motivated by one such study, the Atherosclerosis Risk in Communities (ARIC) study, we investigate the properties of a regularized variable selection procedure in stratified case-cohort design under an additive hazards model with a diverging number of parameters. We establish the consistency and asymptotic normality of the penalized estimator and prove its oracle property. Simulation studies are conducted to assess the finite sample performance of the proposed method with a modified cross-validation tuning parameter selection methods. We apply the variable selection procedure to the ARIC study to demonstrate its practical use.     

Estimation of Causal Odds of Concordance using the Aalen Additive Model

A simple summary of a treatment effect is attractive, which is part of the explanation of the success of the Cox model when analysing time‐to‐event data since the relative risk measure is such a convenient summary measure. In practice, however, the Cox model may fail to give a reasonable fit, very often because of time‐changing treatment effect. The Aalen additive hazards model may be a good alternative as time‐changing effects are easily modelled within this model, but results are then evidently more complicated to communicate. In such situations, the odds of concordance measure (OC) is a convenient way of communicating results, and recently Martinussen & Pipper (2012) showed how a variant of the OC measure may be estimated based on the Aalen additive hazards model. In this study, we propose an estimator that should be preferred in observational studies as it always estimates the causal effect on the chosen scale, only assuming that there are no un‐measured confounders. The resulting estimator is shown to be consistent and asymptotically normal, and an estimator of its limiting variance is provided. Two real applications are provided.     

On Local Polynomial Modelling of the Additive Risk Model

The additive risk model provides an alternative modelling technique for failure time data to the proportional hazards model. In this article, we consider the additive risk model with a nonparametric risk effect. We study estimation of the risk function and its derivatives with a parametric and an unspecified baseline hazard function respectively. The resulting estimators are the local likelihood and the local score estimators. We establish the asymptotic normality of the estimators and show that both methods have the same formula for asymptotic bias but different formula for variance. It is found that, in some special cases, the local score estimator is of the same efficiency as the local likelihood estimator though it does not use the information about the baseline hazard function. Another advantage of the local score estimator is that it has a closed form and is easy to implement. Some simulation studies are conducted to evaluate and compare the performance of the two estimators. A numerical example is used for illustration.     

Additive hazards model with auxiliary subgroup survival information

Lifetime Data Analysis - The semiparametric additive hazards model is an important way for studying the effect of potential risk factors for right-censored time-to-event data. In this paper, we...     

Marginal Regression of Gaps Between Recurrent Events

Recurrent event data typically exhibit the phenomenon of intra-individual correlation, owing to not only observed covariates but also random effects. In many applications, the population may be reasonably postulated as a heterogeneous mixture of individual renewal processes, and the inference of interest is the effect of individual-level covariates. In this article, we suggest and investigate a marginal proportional hazards model for gaps between recurrent events. A connection is established between observed gap times and clustered survival data with informative cluster size. We subsequently construct a novel and general inference procedure for the latter, based on a functional formulation of standard Cox regression. Large-sample theory is established for the proposed estimators. Numerical studies demonstrate that the procedure performs well with practical sample sizes. Application to the well-known bladder tumor data is given as an illustration.     

Estimation of dependence between paired correlated failure times in the presence of covariate measurement error

Summary. In many biomedical studies, covariates are subject to measurement error. Although it is well known that the regression coefficients estimators can be substantially biased if the measurement error is not accommodated, there has been little study of the effect of covariate measurement error on the estimation of the dependence between bivariate failure times. We show that the dependence parameter estimator in the Clayton–Oakes model can be considerably biased if the measurement error in the covariate is not accommodated. In contrast with the typical bias towards the null for marginal regression coefficients, the dependence parameter can be biased in either direction. We introduce a bias reduction technique for the bivariate survival function in copula models while assuming an additive measurement error model and replicated measurement for the covariates, and we study the large and small sample properties of the dependence parameter estimator proposed.     

Comparing waiting times in a multi-stage model: A log-rank approach

A proper log-rank test for comparing two waiting (i.e. sojourn, gap) times under right censored data has been absent in the survival literature. The classical log-rank test provides a biased comparison even under independent right censoring since the censoring induced on the time since state entry depends on the entry time unless the hazards are semi-Markov. We develop test statistics for comparing K waiting time distributions from a multi-stage model in which censoring and waiting times may be dependent upon the transition history in the multi-stage model. To account for such dependent censoring, the proposed test statistics utilize an inverse probability of censoring weighted (IPCW) approach previously employed to define estimators for the cumulative hazard and survival function for waiting times in multi-stage models. We develop the test statistics as analogues to K-sample log-rank statistics for failure time data, and weak convergence to a Gaussian limit is demonstrated. A simulation study demonstrates the appropriateness of the test statistics in designs that violate typical independence assumptions for multi-stage models, under which naive test statistics for failure time data perform poorly, and illustrates the superiority of the test under proportional hazards alternatives to a Mann–Whitney type test. We apply the test statistics to an existing data set of burn patients.     

Dynamic Random Effects Models for Times Between Repeated Events

We consider recurrent event data when the duration or gap times between successive event occurrences are of intrinsic interest. Subject heterogeneity not attributed to observed covariates is usually handled by random effects which result in an exchangeable correlation structure for the gap times of a subject. Recently, efforts have been put into relaxing this restriction to allow non-exchangeable correlation. Here we consider dynamic models where random effects can vary stochastically over the gap times. We extend the traditional Gaussian variance components models and evaluate a previously proposed proportional hazards model through a simulation study and some examples. Besides, semiparametric estimation of the proportional hazards models is considered. Both models are easily used. The Gaussian models are easily interpreted in terms of the variance structure. On the other hand, the proportional hazards models would be more appropriate in the context of survival analysis, particularly in the interpretation of the regression parameters. They can be sensitive to the choice of model for random effects but not to the choice of the baseline hazard function.     

Maximum likelihood estimation for the proportional odds model with mixed interval-censored failure time data

This article discusses regression analysis of mixed interval-censored failure time data. Such data frequently occur across a variety of settings, including clinical trials, epidemiologic investigations, and many other biomedical studies with a follow-up component. For example, mixed failure times are commonly found in the two largest studies of long-term survivorship after childhood cancer, the datasets that motivated this work. However, most existing methods for failure time data consider only right-censored or only interval-censored failure times, not the more general case where times may be mixed. Additionally, among regression models developed for mixed interval-censored failure times, the proportional hazards formulation is generally assumed. It is well-known that the proportional hazards model may be inappropriate in certain situations, and alternatives are needed to analyze mixed failure time data in such cases. To fill this need, we develop a maximum likelihood estimation procedure for the proportional odds regression model with mixed interval-censored data. We show that the resulting estimators are consistent and asymptotically Gaussian. An extensive simulation study is performed to assess the finite-sample properties of the method, and this investigation indicates that the proposed method works well for many practical situations. We then apply our approach to examine the impact of age at cranial radiation therapy on risk of growth hormone deficiency in long-term survivors of childhood cancer.     

Analysis of two-phase sampling data with semiparametric additive hazards models

Under the case-cohort design introduced by Prentice (Biometrica 73:1–11, 1986), the covariate histories are ascertained only for the subjects who experience the event of interest (i.e., the cases) during the follow-up period and for a relatively small random sample from the original cohort (i.e., the subcohort). The case-cohort design has been widely used in clinical and epidemiological studies to assess the effects of covariates on failure times. Most statistical methods developed for the case-cohort design use the proportional hazards model, and few methods allow for time-varying regression coefficients. In addition, most methods disregard data from subjects outside of the subcohort, which can result in inefficient inference. Addressing these issues, this paper proposes an estimation procedure for the semiparametric additive hazards model with case-cohort/two-phase sampling data, allowing the covariates of interest to be missing for cases as well as for non-cases. A more flexible form of the additive model is considered that allows the effects of some covariates to be time varying while specifying the effects of others to be constant. An augmented inverse probability weighted estimation procedure is proposed. The proposed method allows utilizing the auxiliary information that correlates with the phase-two covariates to improve efficiency. The asymptotic properties of the proposed estimators are established. An extensive simulation study shows that the augmented inverse probability weighted estimation is more efficient than the widely adopted inverse probability weighted complete-case estimation method. The method is applied to analyze data from a preventive HIV vaccine efficacy trial.     

Checking a Semiparametric Additive Risk Model

McKeague and Sasieni [A partly parametric additive risk model. Biometrika 81 (1994) 501] propose a restriction of Aalen’s additive risk model by the additional hypothesis that some of the covariates have time-independent influence on the intensity of the observed counting process. We introduce goodness-of-fit tests for this semiparametric Aalen model. The asymptotic distribution properties of the test statistics are derived by means of martingale techniques. The tests can be adjusted to detect particular alternatives. As one of the most important alternatives we consider Cox’s proportional hazards model. We present simulation studies and an application to a real data set.     

Nonparametric tests for stratified additive hazards model based on current status data

Stratified regression models are commonly employed when study subjects may come from possibly different strata such as different medical centers, and for the situation, one common question of interest is to test the existence of the stratum effect. To address this, there exists some literature on the testing of the stratum effects under the framework of the proportional hazards model when one observes right-censored data or interval-censored data. In this paper, we consider the situation under the additive hazards model when one faces current status data, for which there does not seem to exist an established test procedure. The asymptotic distributions of the proposed test procedure are provided. Also a simulation study is performed to evaluate the performance of the proposed method and indicates that it works well for practical situations. The approach is applied to a set of real current status data from a tumorigenicity study.