An estimating equation for parametric shared frailty models with marginal additive hazards

Summary.  Multivariate failure time data arise when data consist of clusters in which the failure times may be dependent. A popular approach to such data is the marginal proportional hazards model with estimation under the working independence assumption. In some contexts, however, it may be more reasonable to use the marginal additive hazards model. We derive asymptotic properties of the Lin and Ying estimators for the marginal additive hazards model for multivariate failure time data. Furthermore we suggest estimating equations for the regression parameters and association parameters in parametric shared frailty models with marginal additive hazards by using the Lin and Ying estimators. We give the large sample properties of the estimators arising from these estimating equations and investigate their small sample properties by Monte Carlo simulation. A real example is provided for illustration.     

Analyzing Length-biased Data with Semiparametric Transformation and Accelerated Failure Time Models

Right-censored time-to-event data are often observed from a cohort of prevalent cases that are subject to length-biased sampling. Informative right censoring of data from the prevalent cohort within the population often makes it difficult to model risk factors on the unbiased failure times for the general population, because the observed failure times are length biased. In this paper, we consider two classes of flexible semiparametric models: the transformation models and the accelerated failure time models, to assess covariate effects on the population failure times by modeling the length-biased times. We develop unbiased estimating equation approaches to obtain the consistent estimators of the regression coefficients. Large sample properties for the estimators are derived. The methods are confirmed through simulations and illustrated by application to data from a study of a prevalent cohort of dementia patients.     

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 Transformation Models for Recurrent Events

In this article, we propose a class of additive transformation models for recurrent event data, which includes the additive rates model as a special case. The new models offer great flexibility in formulating the effects of covariates on the mean function of recurrent events. Estimating equation approaches are developed for the model parameters, and asymptotic properties of the resulting estimators are established. In addition, a model checking procedure is presented to assess the adequacy of the model. The finite sample performance of the proposed estimators is examined through simulation studies, and an application to a bladder cancer study is presented.     

Correcting for non-compliance in randomized trials using rank preserving structural failure time models

We propose correcting for non-compliance in randomized trials by estimating the parameters of a class of semi-parametric failure time models, the rank preserving structural failure time models, using a class of rank estimators. These models are the structural or strong version of the “accelerated failure time model with time-dependent covariates” of Cox and Oakes (1984). In this paper we develop a large sample theory for these estimators, derive the optimal estimator within this class, and briefly consider the construction of “partially adaptive” estimators whose efficiency may approach that of the optimal estimator. We show that in the absence of censoring the optimal estimator attains the semiparametric efficiency bound for the model.     

Additive Transformation Models for Clustered Doubly Censored Data

In this article, we propose estimating procedures for additive semiparametric transformation models with clustered doubly-censored data. A simulation study is conducted to investigate the performance of the proposed estimators. We apply the proposed methods to the dataset from the well-known Diabetic Retinopathy Study.     

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.     

Semiparametric transformation models with random effects for clustered doubly censored data

For right-censored data, Zeng et al. [Semiparametirc transformation modes with random effects for clustered data. Statist Sin. 2008;18:355–377] proposed a class of semiparametric transformation models with random effects to formulate the effects of possibly time-dependent covariates on clustered failure times. In this article, we demonstrate that the approach of Zeng et al. can be extended to analyse clustered doubly censored data. The asymptotic properties of the nonparametric maximum likelihood estimators of the model parameters are derived. A simulation study is conducted to investigate the performance of the proposed estimators.     

Gamma failure‐time mixture models: yet another way to establish efficacy

Using a Yamaguchi‐type generalized gamma failure‐time mixture model, we analyse the data from a study of autologous and allogeneic bone marrow transplantation in the treatment of high‐risk refractory acute lymphoblastic leukaemia, focusing on the time to recurrence of disease. We develop maximum likelihood techniques for the joint estimation of the surviving fractions and the survivor functions. This includes an approximation to the derivative of the survivor function with respect to the shape parameter. We obtain the maximum likelihood estimates of the model parameters. We also compute the variance‐covariance matrix of the parameter estimators. The extended family of generalized gamma failure‐time mixture models is flexible enough to include many commonly used failure‐time distributions as special cases. Yet these models are not used in practice because of computational difficulties. We claim that we have overcome this problem. The proposed approximation to the derivative of the survivor function with respect to the shape parameter can be used in any statistical package. We also address the issue of lack of identifiability. We point out that there can be a substantial advantage to using the gamma failure‐time mixture models over nonparametric methods. Copyright © 2003 John Wiley & Sons, Ltd.     

Additive–multiplicative rates model for recurrent events

Recurrent events are frequently encountered in biomedical studies. Evaluating the covariates effects on the marginal recurrent event rate is of practical interest. There are mainly two types of rate models for the recurrent event data: the multiplicative rates model and the additive rates model. We consider a more flexible additive–multiplicative rates model for analysis of recurrent event data, wherein some covariate effects are additive while others are multiplicative. We formulate estimating equations for estimating the regression parameters. The estimators for these regression parameters are shown to be consistent and asymptotically normally distributed under appropriate regularity conditions. Moreover, the estimator of the baseline mean function is proposed and its large sample properties are investigated. We also conduct simulation studies to evaluate the finite sample behavior of the proposed estimators. A medical study of patients with cystic fibrosis suffered from recurrent pulmonary exacerbations is provided for illustration of the proposed method.     

Semiparametric Regression Analysis of Longitudinal Skewed Data

In this paper, we develop a semiparametric regression model for longitudinal skewed data. In the new model, we allow the transformation function and the baseline function to be unknown. The proposed model can provide a much broader class of models than the existing additive and multiplicative models. Our estimators for regression parameters, transformation function and baseline function are asymptotically normal. Particularly, the estimator for the transformation function converges to its true value at the rate n ^{? 1 ∕ 2}, the convergence rate that one could expect for a parametric model. In simulation studies, we demonstrate that the proposed semiparametric method is robust with little loss of efficiency. Finally, we apply the new method to a study on longitudinal health care costs.     

Regression analysis of informative current status data with the semiparametric linear transformation model

Many methods have been developed in the literature for regression analysis of current status data with noninformative censoring and also some approaches have been proposed for semiparametric regression analysis of current status data with informative censoring. However, the existing approaches for the latter situation are mainly on specific models such as the proportional hazards model and the additive hazard model. Corresponding to this, in this paper, we consider a general class of semiparametric linear transformation models and develop a sieve maximum likelihood estimation approach for the inference. In the method, the copula model is employed to describe the informative censoring or relationship between the failure time of interest and the censoring time, and Bernstein polynomials are used to approximate the nonparametric functions involved. The asymptotic consistency and normality of the proposed estimators are established, and an extensive simulation study is conducted and indicates that the proposed approach works well for practical situations. In addition, an illustrative example is provided.     

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.     

A continuous-time Markov model for estimating readmission risk for hospital inpatients

Research concerning hospital readmissions has mostly focused on statistical and machine learning models that attempt to predict this unfortunate outcome for individual patients. These models are useful in certain settings, but their performance in many cases is insufficient for implementation in practice, and the dynamics of how readmission risk changes over time is often ignored. Our objective is to develop a model for aggregated readmission risk over time – using a continuous-time Markov chain – beginning at the point of discharge. We derive point and interval estimators for readmission risk, and find the asymptotic distributions for these probabilities. Finally, we validate our derived estimators using simulation, and apply our methods to estimate readmission risk over time using discharge and readmission data for surgical patients.     

Two-step variable selection in partially linear additive models with time series data

Lots of semi-parametric and nonparametric models are used to fit nonlinear time series data. They include partially linear time series models, nonparametric additive models, and semi-parametric single index models. In this article, we focus on fitting time series data by partially linear additive model. Combining the orthogonal series approximation and the adaptive sparse group LASSO regularization, we select the important variables between and within the groups simultaneously. Specially, we propose a two-step algorithm to obtain the grouped sparse estimators. Numerical studies show that the proposed method outperforms LASSO method in both fitting and forecasting. An empirical analysis is used to illustrate the methodology.     

Local Linear Regression in Proportional Hazards Model with Censored Data

In this article we study the method of nonparametric regression based on a transformation model, under which an unknown transformation of the survival time is nonlinearly, even more, nonparametrically, related to the covariates with various error distributions, which are parametrically specified with unknown parameters. Local linear approximations and locally weighted least squares are applied to obtain estimators for the effects of covariates with censored observations. We show that the estimators are consistent and asymptotically normal. This transformation model, coupled with local linear approximation techniques, provides many alternatives to the more general proportional hazards models with nonparametric covariates.     

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.     

Additive hazards regression of current status data with auxiliary covariates

This paper discusses the regression analysis of current status failure time data arising from the additive hazards model with auxiliary covariates. As often occurs in practice, it is impossible or impractical to measure the exact magnitude of covariates for all subjects in a study. To compensate the missing information, some auxiliary covariates are utilized instead. We propose two easy-to-implement procedures for estimation of regression parameters by making use of auxiliary information. The asymptotic properties of the resulting estimators are established and extensive numerical studies indicate that both procedures work well in practice.     

Weighted Estimator for the Linear Transformation Models with Multivariate Failure Time Data

In this article, a simple and efficient weighted method is proposed to improve the estimation efficiency for the linear transformation models with multivariate failure time data. Asymptotic properties of the estimators with a closed-form variance-covariance matrix are established. In addition, a goodness-of-fit test is developed to evaluate the adequacy of the model. The performance of proposed method and the comparison on the efficiency between the proposed method and the working independence method (Lu, 2005) are conducted in finite-sample situation by simulation studies. Finally a real data set from the Busselton Population Health Surveys is illustrated to validate the proposed methodology. The related proofs of the theorems are given in the Appendix.     

Non-parametric Maximum-Likelihood Estimation in a Semiparametric Mixture Model for Competing-Risks Data

Abstract.  This paper describes our studies on non-parametric maximum-likelihood estimators in a semiparametric mixture model for competing-risks data, in which proportional hazards models are specified for failure time models conditional on cause and a multinomial model is specified for the marginal distribution of cause conditional on covariates. We provide a verifiable identifiability condition and, based on it, establish an asymptotic profile likelihood theory for this model. We also provide efficient algorithms for the computation of the non-parametric maximum-likelihood estimate and its asymptotic variance. The success of this method is demonstrated in simulation studies and in the analysis of Taiwan severe acute respiratory syndrome data.