Some estimators and tests for accelerated hazards model using weighted cumulative hazard difference

For a censored two-sample problem, Chen and Wang [Y.Q. Chen and M.-C. Wang, Analysis of accelerated hazards models, J. Am. Statist. Assoc. 95 (2000), pp. 608–618] introduced the accelerated hazards model. The scale-change parameter in this model characterizes the association of two groups. However, its estimator involves the unknown density in the asymptotic variance. Thus, to make an inference on the parameter, numerically intensive methods are needed. The goal of this article is to propose a simple estimation method in which estimators are asymptotically normal with a density-free asymptotic variance. Some lack-of-fit tests are also obtained from this. These tests are related to Gill–Schumacher type tests [R.D. Gill and M. Schumacher, A simple test of the proportional hazards assumption, Biometrika 74 (1987), pp. 289–300] in which the estimating functions are evaluated at two different weight functions yielding two estimators that are close to each other. Numerical studies show that for some weight functions, the estimators and tests perform well. The proposed procedures are illustrated in two applications.     

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.     

Proportional cause-specific reversed hazards model

The proportional reversed hazards model explains the multiplicative effect of covariates on the baseline reversed hazard rate function of lifetimes. In the present study, we introduce a proportional cause-specific reversed hazards model. The proposed regression model facilitates the analysis of failure time data with multiple causes of failure under left censoring. We estimate the regression parameters using a partial likelihood approach. We provide Breslow's type estimators for the cumulative cause-specific reversed hazard rate functions. Asymptotic properties of the estimators are discussed. Simulation studies are conducted to assess their performance. We illustrate the applicability of the proposed model using a real data set.     

Statistical Inferences Based on Extended Weighted Log-Rank Estimating Function for Censored Regression Model

In the regression model with censored data, it is not straightforward to estimate the covariances of the regression estimators, since their asymptotic covariances may involve the unknown error density function and its derivative. In this article, a resampling method for making inferences on the parameter, based on some estimating functions, is discussed for the censored regression model. The inference procedures are associated with a weight function. To find the best weight functions for the proposed procedures, extensive simulations are performed. The validity of the approximation to the distribution of the estimator by a resampling technique is also examined visually. Implementation of the procedures is discussed and illustrated in a real data example.     

Rank Regression Analysis of Multivariate Failure Time Data Based on Marginal Linear Models

Abstract.  Multivariate failure time data arises when each study subject can potentially ex-perience several types of failures or recurrences of a certain phenomenon, or when failure times are sampled in clusters. We formulate the marginal distributions of such multivariate data with semiparametric accelerated failure time models (i.e. linear regression models for log-transformed failure times with arbitrary error distributions) while leaving the dependence structures for related failure times completely unspecified. We develop rank-based monotone estimating functions for the regression parameters of these marginal models based on right-censored observations. The estimating equations can be easily solved via linear programming. The resultant estimators are consistent and asymptotically normal. The limiting covariance matrices can be readily estimated by a novel resampling approach, which does not involve non-parametric density estimation or evaluation of numerical derivatives. The proposed estimators represent consistent roots to the potentially non-monotone estimating equations based on weighted log-rank statistics. Simulation studies show that the new inference procedures perform well in small samples. Illustrations with real medical data are provided.     

New aspects of Bregman divergence in regression and classification with parametric and nonparametric estimation

In statistical learning, regression and classification concern different types of the output variables, and the predictive accuracy is quantified by different loss functions. This article explores new aspects of Bregman divergence (BD), a notion which unifies nearly all of the commonly used loss functions in regression and classification. The authors investigate the duality between BD and its generating function. They further establish, under the framework of BD, asymptotic consistency and normality of parametric and nonparametric regression estimators, derive the lower bound of their asymptotic covariance matrices, and demonstrate the role that parametric and nonparametric regression estimation play in the performance of classification procedures and related machine learning techniques. These theoretical results and new numerical evidence show that the choice of loss function affects estimation procedures, whereas has an asymptotically relatively negligible impact on classification performance. Applications of BD to statistical model building and selection with non‐Gaussian responses are also illustrated. The Canadian Journal of Statistics 37: 119‐139; 2009 © 2009 Statistical Society of Canada     

Checking the Short‐Term and Long‐Term Hazard Ratio Model for Survival Data

Abstract. The short‐term and long‐term hazard ratio model includes the proportional hazards model and the proportional odds model as submodels, and allows a wider range of hazard ratio patterns compared with some of the more traditional models. We propose two omnibus tests for checking this model, based, respectively, on the martingale residuals and the contrast between the non‐parametric and model‐based estimators of the survival function. These tests are shown to be consistent against any departure from the model. The empirical behaviours of the tests are studied in simulations, and the tests are illustrated with some real data examples.     

Estimation in a model for a semi-Markov process with covariates under right-censoring

A semi-Markov model with covariates is proposed for a multi-state process with a finite number of states such that the transition probabilities between the states and the distribution functions of the duration times between the occurrence of two states depend on a discrete covariate. The hazard rates for the time elapsed between two successive states depend on the covariate through a proportional hazards model involving a set of regression parameters, while the transition probabilities depend on the covariate in an unspecified way. We propose estimators for these parameters and for the cumulative hazard functions of the sojourn times. A difficulty comes from the fact that when a sojourn time in a state is right-censored, the next state is unknown. We prove that our estimators are consistent and asymptotically Gaussian under the model constraints.     

Mean square error matrix comparisons of estimators in linear regression

The aim of this paper is to provide criteria which allow to compare two estimators of the parameter vector in the linear regression model with respect to their mean square error matrices, where the main interest is focussed on the case when the difference of the covariance matrices is singular. The results obtained are applied to equality restricted and pretest estimators.     

Accent on Teaching Materials

Estimation of covariance components in the multivariate random-effect model with nested covariance structure is discussed. There are two covariance matrices to be estimated, namely, the between-group and the within-group covariance matrices. These two covariance matrices are most often estimated by forming a multivariate analysis of variance and equating mean square matrices to their expectations. Such a procedure involves taking the difference between the between-group mean square and the within-group mean square matrices, and often produces an estimated between-group covariance matrix that is not nonnegative definite. We present estimators of the two covariance matrices that are always proper covariance matrices. The estimators are the restricted maximum likelihood estimators if the random effects are normally distributed. The estimation procedure is extended to more complicated models, including the twofold nested and the mixed-effect models. A numerical example is presented to illustrate the use of the estimation procedure.     

A nonparametric test to compare survival distributions with covariate adjustment

Summary.  The analysis of covariance is a technique that is used to improve the power of a k -sample test by adjusting for concomitant variables. If the end point is the time of survival, and some observations are right censored, the score statistic from the Cox proportional hazards model is the method that is most commonly used to test the equality of conditional hazard functions. In many situations, however, the proportional hazards model assumptions are not satisfied. Specifically, the relative risk function is not time invariant or represented as a log-linear function of the covariates. We propose an asymptotically valid k -sample test statistic to compare conditional hazard functions which does not require the assumption of proportional hazards, a parametric specification of the relative risk function or randomization of group assignment. Simulation results indicate that the performance of this statistic is satisfactory. The methodology is demonstrated on a data set in prostate cancer.     

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.     

Approaches to regression analysis with multiple measurements from individual sampling units

Application of ordinary least-squares regression to data sets which contain multiple measurements from individual sampling units produces an unbiased estimator of the parameters but a biased estimator of the covariance matrix of the parameter estimates. The present work considers a random coefficient, linear model to deal with such data sets: this model permits many senses in which multiple measurements are taken from a sampling unit, not just when it is measured at several times. Three procedures to estimate the covariance matrix of the error term of the model are considered. Given these, three procedures to estimate the parameters of the model and their covariance matrix are considered; these are ordinary least-squares, generalized least-squares, and an adjusted ordinary least-squares procedure which produces an unbiased estimator of the covariance matrix of the parameters with small samples. These various procedures are compared in simulation studies using three examples from the biological literature. The possibility of testing hypotheses about the vector of parameters is also considered. It is found that all three procedures for regression estimation produce estimators of the parameters with bias of no practical consequence, Both generalized least-squares and adjusted ordinary least-squares generally produce estimators of the covariance matrix of the parameter estimates with bias of no practical consequence, while ordinary least-squares produces a negatively biased estimator. Neither ordinary nor generalized least-squares provide satisfactory hypothesis tests of the vector of parameter estimates. It is concluded that adjusted ordinary least-squares, when applied with either of two of the procedures used to estimate the error coveriance matrix, shows promise for practical application with data sets of the nature considered here.     

Efficient Estimation of the Partly Linear Additive Hazards Model with Current Status Data

This paper focuses on efficient estimation, optimal rates of convergence and effective algorithms in the partly linear additive hazards regression model with current status data. We use polynomial splines to estimate both cumulative baseline hazard function with monotonicity constraint and nonparametric regression functions with no such constraint. We propose a simultaneous sieve maximum likelihood estimation for regression parameters and nuisance parameters and show that the resultant estimator of regression parameter vector is asymptotically normal and achieves the semiparametric information bound. In addition, we show that rates of convergence for the estimators of nonparametric functions are optimal. We implement the proposed estimation through a backfitting algorithm on generalized linear models. We conduct simulation studies to examine the finite‐sample performance of the proposed estimation method and present an analysis of renal function recovery data for illustration.     

Simultaneous confidexce intervals in an extended crow iii curve model

This paper deals with estimation problems under an extended growth curve model with two hierarchical within-individuals design matrices. The model in cludes the one whose mean structure consists of polynomial growth curves with two different degrees. First we propose certain simple estimators of the mean and covariance parameters which are closely related to the MEE's. Some basic properties of the estimators are given. Simultaneous confidence intervals are constructed, based on the estimators, for each and both of two growth curves. We give asymptotic approximations for the corresponding critical points. A numerical example is also given.     

Improved inference for MCP-Mod approach using time-to-event endpoints with small sample sizes

The Multiple Comparison Procedures with Modeling Techniques (MCP-Mod) framework has been recently approved by the U.S. Food, Administration, and European Medicines Agency as fit-for-purpose for phase II studies. Nonetheless, this approach relies on the asymptotic properties of Maximum Likelihood (ML) estimators, which might not be reasonable for small sample sizes. In this paper, we derived improved ML estimators and correction for their covariance matrices in the censored Weibull regression model based on the corrective and preventive approaches. We performed two simulation studies to evaluate ML and improved ML estimators with their covariance matrices in (i) a regression framework (ii) the Multiple Comparison Procedures with Modeling Techniques framework. We have shown that improved ML estimators are less biased than ML estimators yielding Wald-type statistics that controls type I error without loss of power in both frameworks. Therefore, we recommend the use of improved ML estimators in the MCP-Mod approach to control type I error at nominal value for sample sizes ranging from 5 to 25 subjects per dose.     

Small sample confidence intervals for survival functions under the proportional hazards model

We develop a saddlepoint-based method for generating small sample confidence bands for the population surviival function from the Kaplan-Meier (KM), the product limit (PL), and Abdushukurov-Cheng-Lin (ACL) survival function estimators, under the proportional hazards model. In the process we derive the exact distribution of these estimators and developed mid-ppopulation tolerance bands for said estimators. Our saddlepoint method depends upon the Mellin transform of the zero-truncated survival estimator which we derive for the KM, PL, and ACL estimators. These transforms are inverted via saddlepoint approximations to yield highly accurate approximations to the cumulative distribution functions of the respective cumulative hazard function estimators and these distribution functions are then inverted to produce our saddlepoint confidence bands. For the KM, PL and ACL estimators we compare our saddlepoint confidence bands with those obtained from competing large sample methods as well as those obtained from the exact distribution. In our simulation studies we found that the saddlepoint confidence bands are very close to the confidence bands derived from the exact distribution, while being much easier to compute, and outperform the competing large sample methods in terms of coverage probability.     

Matrix mean square error comparisons based on a certain covariance structure

For two given estimators of a parameter vector the covariance structure of their difference is used to compare them in terms of their mean square error matrices. The results obtained are applied to the covariance adjustment technique and regression     

Maximum likelihood estimation for the proportional hazards model with partly interval-censored data

Summary. The maximum likelihood estimator (MLE) for the proportional hazards model with partly interval-censored data is studied. Under appropriate regularity conditions, the MLEs of the regression parameter and the cumulative hazard function are shown to be consistent and asymptotically normal. Two methods to estimate the variance–covariance matrix of the MLE of the regression parameter are considered, based on a generalized missing information principle and on a generalized profile information procedure. Simulation studies show that both methods work well in terms of the bias and variance for samples of moderate size. An example illustrates the methods.     

Locally Efficient Semiparametric Estimators for Proportional Hazards Models with Measurement Error

We propose a new class of semiparametric estimators for proportional hazards models in the presence of measurement error in the covariates, where the baseline hazard function, the hazard function for the censoring time, and the distribution of the true covariates are considered as unknown infinite dimensional parameters. We estimate the model components by solving estimating equations based on the semiparametric efficient scores under a sequence of restricted models where the logarithm of the hazard functions are approximated by reduced rank regression splines. The proposed estimators are locally efficient in the sense that the estimators are semiparametrically efficient if the distribution of the error‐prone covariates is specified correctly and are still consistent and asymptotically normal if the distribution is misspecified. Our simulation studies show that the proposed estimators have smaller biases and variances than competing methods. We further illustrate the new method with a real application in an HIV clinical trial.