A Spline‐Based Semiparametric Maximum Likelihood Estimation Method for the Cox Model with Interval‐Censored Data

Abstract. We propose a spline‐based semiparametric maximum likelihood approach to analysing the Cox model with interval‐censored data. With this approach, the baseline cumulative hazard function is approximated by a monotone B‐spline function. We extend the generalized Rosen algorithm to compute the maximum likelihood estimate. We show that the estimator of the regression parameter is asymptotically normal and semiparametrically efficient, although the estimator of the baseline cumulative hazard function converges at a rate slower than root‐n. We also develop an easy‐to‐implement method for consistently estimating the standard error of the estimated regression parameter, which facilitates the proposed inference procedure for the Cox model with interval‐censored data. The proposed method is evaluated by simulation studies regarding its finite sample performance and is illustrated using data from a breast cosmesis study.     

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.     

Estimation with Interval Censored Data and Covariates

In biostatistical applications interest often focuses on the estimation of the distribution of time T between two consecutive events. If the initial event time is observed and the subsequent event time is only known to be larger or smaller than an observed monitoring time C, then the data conforms to the well understood singly-censored current status model, also known as interval censored data, case I. Additional covariates can be used to allow for dependent censoring and to improve estimation of the marginal distribution of T. Assuming a wrong model for the conditional distribution of T, given the covariates, will lead to an inconsistent estimator of the marginal distribution. On the other hand, the nonparametric maximum likelihood estimator of FT requires splitting up the sample in several subsamples corresponding with a particular value of the covariates, computing the NPMLE for every subsample and then taking an average. With a few continuous covariates the performance of the resulting estimator is typically miserable. In van der Laan, Robins (1996) a locally efficient one-step estimator is proposed for smooth functionals of the distribution of T, assuming nothing about the conditional distribution of T, given the covariates, but assuming a model for censoring, given the covariates. The estimators are asymptotically linear if the censoring mechanism is estimated correctly. The estimator also uses an estimator of the conditional distribution of T, given the covariates. If this estimate is consistent, then the estimator is efficient and if it is inconsistent, then the estimator is still consistent and asymptotically normal. In this paper we show that the estimators can also be used to estimate the distribution function in a locally optimal way. Moreover, we show that the proposed estimator can be used to estimate the distribution based on interval censored data (T is now known to lie between two observed points) in the presence of covariates. The resulting estimator also has a known influence curve so that asymptotic confidence intervals are directly available. In particular, one can apply our proposal to the interval censored data without covariates. In Geskus (1992) the information bound for interval censored data with two uniformly distributed monitoring times at the uniform distribution (for T has been computed. We show that the relative efficiency of our proposal w.r.t. this optimal bound equals 0.994, which is also reflected in finite sample simulations. Finally, the good practical performance of the estimator is shown in a simulation study. This revised version was published online in July 2006 with corrections to the Cover Date.     

A Class of Weighted Estimating Equations for Semiparametric Transformation Models with Missing Covariates

In survival analysis, covariate measurements often contain missing observations; ignoring this feature can lead to invalid inference. We propose a class of weighted estimating equations for right‐censored data with missing covariates under semiparametric transformation models. Time‐specific and subject‐specific weights are accommodated in the formulation of the weighted estimating equations. We establish unified results for estimating missingness probabilities that cover both parametric and non‐parametric modelling schemes. To improve estimation efficiency, the weighted estimating equations are augmented by a new set of unbiased estimating equations. The resultant estimator has the so‐called ‘double robustness’ property and is optimal within a class of consistent estimators.     

Marginal semiparametric multivariate accelerated failure time model with generalized estimating equations

The semiparametric accelerated failure time (AFT) model is not as widely used as the Cox relative risk model due to computational difficulties. Recent developments in least squares estimation and induced smoothing estimating equations for censored data provide promising tools to make the AFT models more attractive in practice. For multivariate AFT models, we propose a generalized estimating equations (GEE) approach, extending the GEE to censored data. The consistency of the regression coefficient estimator is robust to misspecification of working covariance, and the efficiency is higher when the working covariance structure is closer to the truth. The marginal error distributions and regression coefficients are allowed to be unique for each margin or partially shared across margins as needed. The initial estimator is a rank-based estimator with Gehan’s weight, but obtained from an induced smoothing approach with computational ease. The resulting estimator is consistent and asymptotically normal, with variance estimated through a multiplier resampling method. In a large scale simulation study, our estimator was up to three times as efficient as the estimateor that ignores the within-cluster dependence, especially when the within-cluster dependence was strong. The methods were applied to the bivariate failure times data from a diabetic retinopathy study.     

Inference in Semi‐Parametric Dynamic Models for Repeated Count Data

This paper deals with a longitudinal semi‐parametric regression model in a generalised linear model setup for repeated count data collected from a large number of independent individuals. To accommodate the longitudinal correlations, we consider a dynamic model for repeated counts which has decaying auto‐correlations as the time lag increases between the repeated responses. The semi‐parametric regression function involved in the model contains a specified regression function in some suitable time‐dependent covariates and a non‐parametric function in some other time‐dependent covariates. As far as the inference is concerned, because the non‐parametric function is of secondary interest, we estimate this function consistently using the independence assumption‐based well‐known quasi‐likelihood approach. Next, the proposed longitudinal correlation structure and the estimate of the non‐parametric function are used to develop a semi‐parametric generalised quasi‐likelihood approach for consistent and efficient estimation of the regression effects in the parametric regression function. The finite sample performance of the proposed estimation approach is examined through an intensive simulation study based on both large and small samples. Both balanced and unbalanced cluster sizes are incorporated in the simulation study. The asymptotic performances of the estimators are given. The estimation methodology is illustrated by reanalysing the well‐known health care utilisation data consisting of counts of yearly visits to a physician by 180 individuals for four years and several important primary and secondary covariates.     

Empirical Likelihood for Censored Linear Regression and Variable Selection

The linear regression model for right censored data, also known as the accelerated failure time model using the logarithm of survival time as the response variable, is a useful alternative to the Cox proportional hazards model. Empirical likelihood as a non‐parametric approach has been demonstrated to have many desirable merits thanks to its robustness against model misspecification. However, the linear regression model with right censored data cannot directly benefit from the empirical likelihood for inferences mainly because of dependent elements in estimating equations of the conventional approach. In this paper, we propose an empirical likelihood approach with a new estimating equation for linear regression with right censored data. A nested coordinate algorithm with majorization is used for solving the optimization problems with non‐differentiable objective function. We show that the Wilks' theorem holds for the new empirical likelihood. We also consider the variable selection problem with empirical likelihood when the number of predictors can be large. Because the new estimating equation is non‐differentiable, a quadratic approximation is applied to study the asymptotic properties of penalized empirical likelihood. We prove the oracle properties and evaluate the properties with simulated data. We apply our method to a Surveillance, Epidemiology, and End Results small intestine cancer dataset.     

A general quantile residual life model for length‐biased right‐censored data

The quantile residual lifetime function provides comprehensive quantitative measures for residual life, especially when the distribution of the latter is skewed or heavy‐tailed and/or when the data contain outliers. In this paper, we propose a general class of semiparametric quantile residual life models for length‐biased right‐censored data. We use the inverse probability weighted method to correct the bias due to length‐biased sampling and informative censoring. Two estimating equations corresponding to the quantile regressions are constructed in two separate steps to obtain an efficient estimator. Consistency and asymptotic normality of the estimator are established. The main difficulty in implementing our proposed method is that the estimating equations associated with the quantiles are nondifferentiable, and we apply the majorize–minimize algorithm and estimate the asymptotic covariance using an efficient resampling method. We use simulation studies to evaluate the proposed method and illustrate its application by a real‐data example.     

Empirical Uncertain Bayes Methods in Area‐level Models

Random effects model can account for the lack of fitting a regression model and increase precision of estimating area‐level means. However, in case that the synthetic mean provides accurate estimates, the prior distribution may inflate an estimation error. Thus, it is desirable to consider the uncertain prior distribution, which is expressed as the mixture of a one‐point distribution and a proper prior distribution. In this paper, we develop an empirical Bayes approach for estimating area‐level means, using the uncertain prior distribution in the context of a natural exponential family, which we call the empirical uncertain Bayes (EUB) method. The regression model considered in this paper includes the Poisson‐gamma and the binomial‐beta, and the normal‐normal (Fay–Herriot) model, which are typically used in small area estimation. We obtain the estimators of hyperparameters based on the marginal likelihood by using a well‐known expectation‐maximization algorithm and propose the EUB estimators of area means. For risk evaluation of the EUB estimator, we derive a second‐order unbiased estimator of a conditional mean squared error by using some techniques of numerical calculation. Through simulation studies and real data applications, we evaluate a performance of the EUB estimator and compare it with the usual empirical Bayes estimator.     

Proportional hazards estimate of the conditional survival function

We introduce a new estimator of the conditional survival function given some subset of the covariate values under a proportional hazards regression. The new estimate does not require estimating the base-line cumulative hazard function. An estimate of the variance is given and is easy to compute, involving only those quantities that are routinely calculated in a Cox model analysis. The asymptotic normality of the new estimate is shown by using a central limit theorem for Kaplan–Meier integrals. We indicate the straightforward extension of the estimation procedure under models with multiplicative relative risks, including non-proportional hazards, and to stratified and frailty models. The estimator is applied to a gastric cancer study where it is of interest to predict patients' survival based only on measurements obtained before surgery, the time at which the most important prognostic variable, stage, becomes known.     

Buckley–James Type Estimator for Censored Data with Covariates Missing by Design

Abstract. The Buckley–James estimator (BJE) is a well‐known estimator for linear regression models with censored data. Ritov has generalized the BJE to a semiparametric setting and demonstrated that his class of Buckley–James type estimators is asymptotically equivalent to the class of rank‐based estimators proposed by Tsiatis. In this article, we revisit such relationship in censored data with covariates missing by design. By exploring a similar relationship between our proposed class of Buckley–James type estimating functions to the class of rank‐based estimating functions recently generalized by Nan, Kalbfleisch and Yu, we establish asymptotic properties of our proposed estimators. We also conduct numerical studies to compare asymptotic efficiencies from various estimators.     

MODEL‐BASED DIRECT ESTIMATION OF SMALL‐AREA DISTRIBUTIONS

Much of the small‐area estimation literature focuses on population totals and means. However, users of survey data are often interested in the finite‐population distribution of a survey variable and in the measures (e.g. medians, quartiles, percentiles) that characterize the shape of this distribution at the small‐area level. In this paper we propose a model‐based direct estimator (MBDE, Chandra and Chambers) of the small‐area distribution function. The MBDE is defined as a weighted sum of sample data from the area of interest, with weights derived from the calibrated spline‐based estimate of the finite‐population distribution function introduced by Harms and Duchesne, under an appropriately specified regression model with random area effects. We also discuss the mean squared error estimation of the MBDE. Monte Carlo simulations based on both simulated and real data sets show that the proposed MBDE and its associated mean squared error estimator perform well when compared with alternative estimators of the area‐specific finite‐population distribution function.     

A Note on the Large Sample Properties of Estimators Based on Generalized Linear Models for Correlated Pseudo‐observations

Pseudo‐values have proven very useful in censored data analysis in complex settings such as multi‐state models. It was originally suggested by Andersen et al., Biometrika, 90, 2003, 335 who also suggested to estimate standard errors using classical generalized estimating equation results. These results were studied more formally in Graw et al., Lifetime Data Anal., 15, 2009, 241 that derived some key results based on a second‐order von Mises expansion. However, results concerning large sample properties of estimates based on regression models for pseudo‐values still seem unclear. In this paper, we study these large sample properties in the simple setting of survival probabilities and show that the estimating function can be written as a U‐statistic of second order giving rise to an additional term that does not vanish asymptotically. We further show that previously advocated standard error estimates will typically be too large, although in many practical applications the difference will be of minor importance. We show how to estimate correctly the variability of the estimator. This is further studied in some simulation studies.     

Jackknife Empirical Likelihood for the Accelerated Failure Time Model with Censored Data

Kendall and Gehan estimating functions are commonly used to estimate the regression parameter in accelerated failure time model with censored observations in survival analysis. In this paper, we apply the jackknife empirical likelihood method to overcome the computation difficulty about interval estimation. A Wilks’ theorem of jackknife empirical likelihood for U-statistic type estimating equations is established, which is used to construct the confidence intervals for the regression parameter. We carry out an extensive simulation study to compare the Wald-type procedure, the empirical likelihood method, and the jackknife empirical likelihood method. The proposed jackknife empirical likelihood method has a better performance than the existing methods. We also use a real data set to compare the proposed methods.     

Estimation of the association for bivariate doubly censored data

We study the problem of estimating the association between two related survival variables when they follow a copula model and the bivariate doubly censored data is available. A two-stage estimation procedure is proposed and the asymptotic properties of the proposed estimator are established. Simulation studies are conducted to investigate the finite sample properties of the proposed estimate.     

Double robust estimation in longitudinal marginal structural models

In this article we consider estimation of causal parameters in a marginal structural model for the discrete intensity of the treatment specific counting process (e.g. hazard of a treatment specific survival time) based on longitudinal observational data on treatment, covariates and survival. We define three estimators: the inverse probability of treatment weighted (IPTW) estimator, the maximum likelihood estimator (MLE), and a double robust (DR) estimator. The DR estimator is obtained by following a general methodology for constructing double robust estimating functions in censored data models as described in van der Laan and Robins (Unified Methods for Censored Longitudinal Data and Causality, 2002). The double-robust estimator is consistent and asymptotically linear when either the treatment mechanism or the partial likelihood of the observed data is consistently estimated. We illustrate the superiority of the DR estimator relative to the IPTW and ML estimators in a simulation study. The proposed methodology is also applied to estimate the causal effect of exercise on physical functioning in a longitudinal study of seniors in Sonoma County.     

A Convolution Estimator for the Density of Nonlinear Regression Observations

Abstract. The problem of estimating an unknown density function has been widely studied. In this article, we present a convolution estimator for the density of the responses in a nonlinear heterogenous regression model. The rate of convergence for the mean square error of the convolution estimator is of order n ^?1 under certain regularity conditions. This is faster than the rate for the kernel density method. We derive explicit expressions for the asymptotic variance and the bias of the new estimator, and further a data‐driven bandwidth selector is proposed. We conduct simulation experiments to check the finite sample properties, and the convolution estimator performs substantially better than the kernel density estimator for well‐behaved noise densities.     

Efficient Rank Regression with Wavelet Estimated Scores

We provide an estimate of the score function for rank regression using compactly supported wavelets. This estimate is then used to find a rank-based asymptotically efficient estimator for the slope parameter of a linear model. We also provide a consistent estimator of the asymptotic variance of the rank estimator. For related mixed models, the asymptotic relative efficiency is also discussed     

Inverse censoring weighted median regression

We implement semiparametric random censorship model aided inference for censored median regression models. This is based on the idea that, when the censoring is specified by a common distribution, a semiparametric survival function estimator acts as an improved weight in the so-called inverse censoring weighted estimating function. We show that the proposed method will always produce estimates of the model parameters that are as good as or better than an existing estimator based on the traditional Kaplan–Meier weights. We also provide an illustration of the method through an analysis of a lung cancer data set.     

Estimation for the censored partially linear quantile regression models

In this article, we develop estimation procedures for partially linear quantile regression models, where some of the responses are censored by another random variable. The nonparametric function is estimated by basis function approximations. The estimation procedure is easy to implement through existing weighted quantile regression, and it requires no specification of the error distributions. We show the large-sample properties of the resulting estimates, the proposed estimator of the regression parameter is root-n consistent and asymptotically normal and the estimator of the functional component achieves the optimal convergence rate of the nonparametric function. The proposed method is studied via simulations and illustrated with the analysis of a primary biliary cirrhosis (BPC) data.