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.     

Semiparametric regression for restricted mean residual life under right censoring

A mean residual life function (MRLF) is the remaining life expectancy of a subject who has survived to a certain time point. In the presence of covariates, regression models are needed to study the association between the MRLFs and covariates. If the survival time tends to be too long or the tail is not observed, the restricted mean residual life must be considered. In this paper, we propose the proportional restricted mean residual life model for fitting survival data under right censoring. For inference on the model parameters, martingale estimating equations are developed, and the asymptotic properties of the proposed estimators are established. In addition, a class of goodness-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 the approach is applied to a set of real life data collected from a randomized clinical trial.     

Goodness-of-fit tests for additive mean residual life model under right censoring

The mean residual life (MRL) measures the remaining life expectancy and is useful in actuarial studies, biological experiments and clinical trials. To assess the covariate effect, an additive MRL regression model has been proposed in the literature. In this paper, we focus on the topic of model checking. Specifically, we develop two goodness-of-fit tests to test the additive MRL model assumption. We explore the large sample properties of the test statistics and show that both of them are based on asymptotic Gaussian processes so that resampling approaches can be applied to find the rejection regions. Simulation studies indicate that our methods work reasonably well for sample sizes ranging from 50 to 200. Two empirical data sets are analyzed to illustrate the approaches.     

Some stochastic orders of dynamic additive mean residual life model

Sometimes additive hazard rate model becomes more important to study than the celebrated (Cox, 1972) proportional hazard rate model. But the concept of the hazard function is sometimes abstract, in comparison to the concept of mean residual life function. In this paper, we have defined a new model called ‘dynamic additive mean residual life model’ where the covariates are time dependent, and study the closure of this model under different stochastic orders.     

An additive subdistribution hazard model for competing risks data

The cumulative incidence function plays an important role in assessing its treatment and covariate effects with competing risks data. In this article, we consider an additive hazard model allowing the time-varying covariate effects for the subdistribution and propose the weighted estimating equation under the covariate-dependent censoring by fitting the Cox-type hazard model for the censoring distribution. When there exists some association between the censoring time and the covariates, the proposed coefficients’ estimations are unbiased and the large-sample properties are established. The finite-sample properties of the proposed estimators are examined in the simulation study. The proposed Cox-weighted method is applied to a competing risks dataset from a Hodgkin's disease study.     

An Additive–Multiplicative Cox–Aalen Regression Model

We propose an additive–multiplicative intensity model that extends the Cox regression model as well as the additive Aalen model. Instead of having a simple baseline intensity the extended model uses an additive Aalen model as its covariate dependent baseline. Approximate maximum likelihood estimators of the baseline intensity functions and the relative risk parameters of the Cox model are suggested by solving the score equations. The derived estimator is efficient. We establish the large sample properties of the estimator. The model provides a simple pragmatic way of including time-varying covariate effects.     

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.     

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.     

Semiparametric lack-of-fit tests in an additive hazard regression model

In the semiparametric additive hazard regression model of McKeague and Sasieni (Biometrika 81: 501–514), the hazard contributions of some covariates are allowed to change over time, without parametric restrictions (Aalen model), while the contributions of other covariates are assumed to be constant. In this paper, we develop tests that help to decide which of the covariate contributions indeed change over time. The remaining covariates may be modelled with constant hazard coefficients, thus reducing the number of curves that have to be estimated nonparametrically. Several bootstrap tests are proposed. The behavior of the tests is investigated in a simulation study. In a practical example, the tests consistently identify covariates with constant and with changing hazard contributions.     

Goodness-of-fit Tests for GEE with Correlated Binary Data

The marginal logistic regression, in combination with GEE, is an increasingly important method in dealing with correlated binary data. As for independent binary data, when the number of possible combinations of the covariate values in a logistic regression model is much larger than the sample size, such as when the logistic model contains at least one continuous covariate, many existing chi-square goodness-of-fit tests either are not applicable or have some serious drawbacks. In this paper two residual based normal goodness-of-fit test statistics are proposed: the Pearson chi-square and an unweighted sum of residual squares. Easy-to-calculate approximations to the mean and variance of either statistic are also given. Their performance, in terms of both size and power, was satisfactory in our simulation studies. For illustration we apply them to a real data set.     

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.     

Modeling restricted mean survival time under general censoring mechanisms

Restricted mean survival time (RMST) is often of great clinical interest in practice. Several existing methods involve explicitly projecting out patient-specific survival curves using parameters estimated through Cox regression. However, it would often be preferable to directly model the restricted mean for convenience and to yield more directly interpretable covariate effects. We propose generalized estimating equation methods to model RMST as a function of baseline covariates. The proposed methods avoid potentially problematic distributional assumptions pertaining to restricted survival time. Unlike existing methods, we allow censoring to depend on both baseline and time-dependent factors. Large sample properties of the proposed estimators are derived and simulation studies are conducted to assess their finite sample performance. We apply the proposed methods to model RMST in the absence of liver transplantation among end-stage liver disease patients. This analysis requires accommodation for dependent censoring since pre-transplant mortality is dependently censored by the receipt of a liver transplant.     

An additive–multiplicative mean model for panel count data with dependent observation and dropout processes

This paper discusses regression analysis of panel count data with dependent observation and dropout processes. For the problem, a general mean model is presented that can allow both additive and multiplicative effects of covariates on the underlying point process. In addition, the proportional rates model and the accelerated failure time model are employed to describe possible covariate effects on the observation process and the dropout or follow‐up process, respectively. For estimation of regression parameters, some estimating equation‐based procedures are developed and the asymptotic properties of the proposed estimators are established. In addition, a resampling approach is proposed for estimating a covariance matrix of the proposed estimator and a model checking procedure is also provided. Results from an extensive simulation study indicate that the proposed methodology works well for practical situations, and it is applied to a motivating set of real data.     

Regression analysis of competing risks data via semi-parametric additive hazard model

When the subjects in a study possess different demographic and disease characteristics and are exposed to more than one types of failure, a practical problem is to assess the covariate effects on each type of failure as well as on all-cause failure. The most widely used method is to employ the Cox models on each cause-specific hazard and the all-cause hazard. It has been pointed out that this method causes the problem of internal inconsistency. To solve such a problem, the additive hazard models have been advocated. In this paper, we model each cause-specific hazard with the additive hazard model that includes both constant and time-varying covariate effects. We illustrate that the covariate effect on all-cause failure can be estimated by the sum of the effects on all competing risks. Using data from a longitudinal study on breast cancer patients, we show that the proposed method gives simple interpretation of the final results, when the primary covariate effect is constant in the additive manner on each cause-specific hazard. Based on the given additive models on the cause-specific hazards, we derive the inferences for the adjusted survival and cumulative incidence functions.     

A linear model-based test for the heterogeneity of conditional correlations

Current methods of testing the equality of conditional correlations of bivariate data on a third variable of interest (covariate) are limited due to discretizing of the covariate when it is continuous. In this study, we propose a linear model approach for estimation and hypothesis testing of the Pearson correlation coefficient, where the correlation itself can be modeled as a function of continuous covariates. The restricted maximum likelihood method is applied for parameter estimation, and the corrected likelihood ratio test is performed for hypothesis testing. This approach allows for flexible and robust inference and prediction of the conditional correlations based on the linear model. Simulation studies show that the proposed method is statistically more powerful and more flexible in accommodating complex covariate patterns than the existing methods. In addition, we illustrate the approach by analyzing the correlation between the physical component summary and the mental component summary of the MOS SF-36 form across a fair number of covariates in the national survey data.     

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.     

Joint Modeling of Event Time and Nonignorable Missing Longitudinal Data

Survival studies usually collect on each participant, both duration until some terminal event and repeated measures of a time-dependent covariate. Such a covariate is referred to as an internal time-dependent covariate. Usually, some subjects drop out of the study before occurence of the terminal event of interest. One may then wish to evaluate the relationship between time to dropout and the internal covariate. The Cox model is a standard framework for that purpose. Here, we address this problem in situations where the value of the covariate at dropout is unobserved. We suggest a joint model which combines a first-order Markov model for the longitudinaly measured covariate with a time-dependent Cox model for the dropout process. We consider maximum likelihood estimation in this model and show how estimation can be carried out via the EM-algorithm. We state that the suggested joint model may have applications in the context of longitudinal data with nonignorable dropout. Indeed, it can be viewed as generalizing Diggle and Kenward's model (1994) to situations where dropout may occur at any point in time and may be censored. Hence we apply both models and compare their results on a data set concerning longitudinal measurements among patients in a cancer clinical trial.     

A note on the asymptotic relative efficiency of estimators from the additive hazards model

In this note, the asymptotic variance formulas are explicitly derived and compared between the parametric and semiparametric estimators of a regression parameter and survival probability under the additive hazards model. To obtain explicit formulas, it is assumed that the covariate term including a regression coefficient follows a gamma distribution and the baseline hazard function is constant. The results show that the semiparametric estimator of the regression coefficient parameter is fully efficient relative to the parametric counterpart when the survival time and a covariate are independent, as in the proportional hazards model. Relative to a more realistic case of the parametric additive hazards model with a Weibull baseline, the loss of efficiency of the semiparametric estimator of survival probability is moderate.     

Additive hazards model with truncated and doubly censored data

In longitudinal studies, the additive hazard model is often used to analyze covariate effects on the duration time, defined as the elapsed time between the first and the second event. In this article, we consider the situation when the first event suffers partly interval censoring and the second event suffers left truncation and right-censoring. We proposed a two-step estimation procedure for estimating the regression coefficients of the additive hazards model. A simulation study is conducted to investigate the performance of the proposed estimator. The proposed method is applied to the Centers for Disease Control acquired immune deficiency syndrome blood transfusion data.