A risk set calibration method for failure time regression by using a covariate reliability sample

Regression parameter estimation in the Cox failure time model is considered when regression variables are subject to measurement error. Assuming that repeat regression vector measurements adhere to a classical measurement model, we can consider an ordinary regression calibration approach in which the unobserved covariates are replaced by an estimate of their conditional expectation given available covariate measurements. However, since the rate of withdrawal from the risk set across the time axis, due to failure or censoring, will typically depend on covariates, we may improve the regression parameter estimator by recalibrating within each risk set. The asymptotic and small sample properties of such a risk set regression calibration estimator are studied. A simple estimator based on a least squares calibration in each risk set appears able to eliminate much of the bias that attends the ordinary regression calibration estimator under extreme measurement error circumstances. Corresponding asymptotic distribution theory is developed, small sample properties are studied using computer simulations and an illustration is provided.     

A Profile Conditional Likelihood Approach for the Semiparametric Transformation Regression Model with Missing Covariates

We propose a profile conditional likelihood approach to handle missing covariates in the general semiparametric transformation regression model. The method estimates the marginal survival function by the Kaplan-Meier estimator, and then estimates the parameters of the survival model and the covariate distribution from a conditional likelihood, substituting the Kaplan-Meier estimator for the marginal survival function in the conditional likelihood. This method is simpler than full maximum likelihood approaches, and yields consistent and asymptotically normally distributed estimator of the regression parameter when censoring is independent of the covariates. The estimator demonstrates very high relative efficiency in simulations. When compared with complete-case analysis, the proposed estimator can be more efficient when the missing data are missing completely at random and can correct bias when the missing data are missing at random. The potential application of the proposed method to the generalized probit model with missing continuous covariates is also outlined.     

Approximate MLE for the scale parameter of the generalized exponential distribution under random censoring

In this paper, we consider the maximum likelihood estimator (MLE) of the scale parameter of the generalized exponential (GE) distribution based on a random censoring model. We assume the censoring distribution also follows a GE distribution. Since the estimator does not provide an explicit solution, we propose a simple method of deriving an explicit estimator by approximating the likelihood function. In order to compare the performance of the estimators, Monte Carlo simulation is conducted. The results show that the MLE and the approximate MLE are almost identical in terms of bias and variance.     

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.     

Tobit regression for modeling mean survival time using data subject to multiple sources of censoring

Mean survival time is often of inherent interest in medical and epidemiologic studies. In the presence of censoring and when covariate effects are of interest, Cox regression is the strong default, but mostly due to convenience and familiarity. When survival times are uncensored, covariate effects can be estimated as differences in mean survival through linear regression. Tobit regression can validly be performed through maximum likelihood when the censoring times are fixed (ie, known for each subject, even in cases where the outcome is observed). However, Tobit regression is generally inapplicable when the response is subject to random right censoring. We propose Tobit regression methods based on weighted maximum likelihood which are applicable to survival times subject to both fixed and random censoring times. Under the proposed approach, known right censoring is handled naturally through the Tobit model, with inverse probability of censoring weighting used to overcome random censoring. Essentially, the re‐weighting data are intended to represent those that would have been observed in the absence of random censoring. We develop methods for estimating the Tobit regression parameter, then the population mean survival time. A closed form large‐sample variance estimator is proposed for the regression parameter estimator, with a semiparametric bootstrap standard error estimator derived for the population mean. The proposed methods are easily implementable using standard software. Finite‐sample properties are assessed through simulation. The methods are applied to a large cohort of patients wait‐listed for kidney transplantation.     

Estimation of regression parameters in generalized linear models for cluster correlated data with measurement error

Liang and Zeger (1986) introduced a class of estimating equations that gives consistent estimates of regression parameters and of their asymptotic variances in the class of generalized linear models for cluster correlated data. When the independent variables or covariates in such models are subject to measurement errors, the parameter estimates obtained from these estimating equations are no longer consistent. To correct for the effect of measurement errors, an estimator with smaller asymptotic bias is constructed along the lines of Stefanski (1985), assuming that the measurement error variance is either known or estimable. The asymptotic distribution of the bias-corrected estimator and a consistent estimator of its asymptotic variance are also given. The special case of a binary logistic regression model is studied in detail. For this case, methods based on conditional scores and quasilikelihood are also extended to cluster correlated data. Results of a small simulation study on the performance of the proposed estimators and associated tests of hypotheses are reported.     

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.     

On the simple linear regression model with correlated measurement errors

The simple linear regression model with measurement error has been subject to much research. In this work we will focus on this model when the error in the explanatory variable is correlated with the error in the regression equation. Specifically, we are interested in the comparison between the ordinary errors-in-variables estimator of the regression coefficient β$\beta$ and the estimator that takes account of the correlation between the errors. Based on large sample approximations, we compare the estimators and find that the estimator that takes account of the correlation should be preferred in most situations. We also compare the estimators in small sample situations. This is done by stochastic simulation. The results show that the estimators behave quite similarly in most of the simulated situations, but that the ordinary errors-in-variables estimator performs considerably worse than the estimator that takes account of the correlation for certain parameter combinations. In addition, we look briefly into the bias introduced by ignoring correlated errors when computing sample correlations, and in predictions.     

Recurrent events analysis in the presence of time-dependent covariates and dependent censoring

Summary.  Recurrent events models have had considerable attention recently. The majority of approaches show the consistency of parameter estimates under the assumption that censoring is independent of the recurrent events process of interest conditional on the covariates that are included in the model. We provide an overview of available recurrent events analysis methods and present an inverse probability of censoring weighted estimator for the regression parameters in the Andersen–Gill model that is commonly used for recurrent event analysis. This estimator remains consistent under informative censoring if the censoring mechanism is estimated consistently, and it generally improves on the naïve estimator for the Andersen–Gill model in the case of independent censoring. We illustrate the bias of ad hoc estimators in the presence of informative censoring with a simulation study and provide a data analysis of recurrent lung exacerbations in cystic fibrosis patients when some patients are lost to follow-up.     

Bootstrapping quantiles in a fixed design regression model with censored data

We consider the problem of estimating the quantiles of a distribution function in a fixed design regression model in which the observations are subject to random right censoring. The quantile estimator is defined via a conditional Kaplan-Meier type estimator for the distribution at a given design point. We establish an a.s. asymptotic representation for this quantile estimator, from which we obtain its asymptotic normality. Because a complicated estimation procedure is necessary for estimating the asymptotic bias and variance, we use a resampling procedure, which provides us, via an asymptotic representation for the bootstrapped estimator, with an alternative for the normal approximation.     

Estimation for Location-Scale Models with Censored Data

This article considers a class of estimators for the location and scale parameters in the location-scale model based on ‘synthetic data’ when the observations are randomly censored on the right. The asymptotic normality of the estimators is established using counting process and martingale techniques when the censoring distribution is known and unknown, respectively. In the case when the censoring distribution is known, we show that the asymptotic variances of this class of estimators depend on the data transformation and have a lower bound which is not achievable by this class of estimators. However, in the case that the censoring distribution is unknown and estimated by the Kaplan–Meier estimator, this class of estimators has the same asymptotic variance and attains the lower bound for variance for the case of known censoring distribution. This is different from censored regression analysis, where asymptotic variances depend on the data transformation. Our method has three valuable advantages over the method of maximum likelihood estimation. First, our estimators are available in a closed form and do not require an iterative algorithm. Second, simulation studies show that our estimators being moment-based are comparable to maximum likelihood estimators and outperform them when sample size is small and censoring rate is high. Third, our estimators are more robust to model misspecification than maximum likelihood estimators. Therefore, our method can serve as a competitive alternative to the method of maximum likelihood in estimation for location-scale models with censored data. A numerical example is presented to illustrate the proposed method.     

Non parametric hazard estimation with dependent censoring using penalized likelihood and an assumed copula

This article introduces a novel non parametric penalized likelihood hazard estimation when the censoring time is dependent on the failure time for each subject under observation. More specifically, we model this dependence using a copula, and the method of maximum penalized likelihood (MPL) is adopted to estimate the hazard function. We do not consider covariates in this article. The non negatively constrained MPL hazard estimation is obtained using a multiplicative iterative algorithm. The consistency results and the asymptotic properties of the proposed hazard estimator are derived. The simulation studies show that our MPL estimator under dependent censoring with an assumed copula model provides a better accuracy than the MPL estimator under independent censoring if the sign of dependence is correctly specified in the copula function. The proposed method is applied to a real dataset, with a sensitivity analysis performed over various values of correlation between failure and censoring times.     

Wavelet estimation in time-varying coefficient time series models with measurement errors

The article studies a time-varying coefficient time series model in which some of the covariates are measured with additive errors. In order to overcome the bias of estimator of the coefficient functions when measurement errors are ignored, we propose a modified least squares estimator based on wavelet procedures. The advantage of the wavelet method is to avoid the restrictive smoothness requirement for varying-coefficient functions of the traditional smoothing approaches, such as kernel and local polynomial methods. The asymptotic properties of the proposed wavelet estimators are established under the α-mixing conditions and without specifying the error distribution. These results can be used to make asymptotically valid statistical inference.     

Improved precision in the analysis of randomized trials with survival outcomes,without assuming proportional hazards

We present a new estimator of the restricted mean survival time in randomized trials where there is right censoring that may depend on treatment and baseline variables. The proposed estimator leverages prognostic baseline variables to obtain equal or better asymptotic precision compared to traditional estimators. Under regularity conditions and random censoring within strata of treatment and baseline variables, the proposed estimator has the following features: (i) it is interpretable under violations of the proportional hazards assumption; (ii) it is consistent and at least as precise as the Kaplan–Meier and inverse probability weighted estimators, under identifiability conditions; (iii) it remains consistent under violations of independent censoring (unlike the Kaplan–Meier estimator) when either the censoring or survival distributions, conditional on covariates, are estimated consistently; and (iv) it achieves the nonparametric efficiency bound when both of these distributions are consistently estimated. We illustrate the performance of our method using simulations based on resampling data from a completed, phase 3 randomized clinical trial of a new surgical treatment for stroke; the proposed estimator achieves a 12% gain in relative efficiency compared to the Kaplan–Meier estimator. The proposed estimator has potential advantages over existing approaches for randomized trials with time-to-event outcomes, since existing methods either rely on model assumptions that are untenable in many applications, or lack some of the efficiency and consistency properties (i)–(iv). We focus on estimation of the restricted mean survival time, but our methods may be adapted to estimate any treatment effect measure defined as a smooth contrast between the survival curves for each study arm. We provide R code to implement the estimator.

     

Asymptotic efficiency of a competing risks model: A two-sample case

A generalized Cox regression model is studied for the covariance analysis of competing risks data subject to independent random censoring. The information of the maximum partial likelihood estimates is compared with that of maximum likelihood estimates assuming a log linear hazard function.The method of generalized variance is used to define the efficiency of estimation between the two models. This is then applied to two-sample problems with two exponentially censoring rates. Numerical results are summarized ane presented graphically.The detailed results indicate that the semi-parametric model wrks well for a higher rate of censoring. A method of generalizing the result to type 1 censoring and the efficiency of estimating the coefficient of the covariate are discussecd. A brief account of using the results to help design experiments is also given.     

Estimating stage occupation probabilities in non-Markov models

We study non-Markov multistage models under dependent censoring regarding estimation of stage occupation probabilities. The individual transition and censoring mechanisms are linked together through covariate processes that affect both the transition intensities and the censoring hazard for the corresponding subjects. In order to adjust for the dependent censoring, an additive hazard regression model is applied to the censoring times, and all observed counting and “at risk” processes are subsequently given an inverse probability of censoring weighted form. We examine the bias of the Datta–Satten and Aalen–Johansen estimators of stage occupation probability, and also consider the variability of these estimators by studying their estimated standard errors and mean squared errors. Results from different simulation studies of frailty models indicate that the Datta–Satten estimator is approximately unbiased, whereas the Aalen–Johansen estimator either under- or overestimates the stage occupation probability due to the dependent nature of the censoring process. However, in our simulations, the mean squared error of the latter estimator tends to be slightly smaller than that of the former estimator. Studies on development of nephropathy among diabetics and on blood platelet recovery among bone marrow transplant patients are used as demonstrations on how the two estimation methods work in practice. Our analyses show that the Datta–Satten estimator performs well in estimating stage occupation probability, but that the censoring mechanism has to be quite selective before a deviation from the Aalen-Johansen estimator is of practical importance. N. Gunnes—Supported by a grant from the Norwegian Cancer Society.     

Semiparametric regression methods for temporal processes subject to multiple sources of censoring

Process regression methodology is underdeveloped relative to the frequency with which pertinent data arise. In this article, the response-190 is a binary indicator process representing the joint event of being alive and remaining in a specific state. The process is indexed by time (e.g., time since diagnosis) and observed continuously. Data of this sort occur frequently in the study of chronic disease. A general area of application involves a recurrent event with non-negligible duration (e.g., hospitalization and associated length of hospital stay) and subject to a terminating event (e.g., death). We propose a semiparametric multiplicative model for the process version of the probability of being alive and in the (transient) state of interest. Under the proposed methods, the regression parameter is estimated through a procedure that does not require estimating the baseline probability. Unlike the majority of process regression methods, the proposed methods accommodate multiple sources of censoring. In particular, we derive a computationally convenient variant of inverse probability of censoring weighting based on the additive hazards model. We show that the regression parameter estimator is asymptotically normal, and that the baseline probability function estimator converges to a Gaussian process. Simulations demonstrate that our estimators have good finite sample performance. We apply our method to national end-stage liver disease data. The Canadian Journal of Statistics 48: 222–237; 2020 © 2019 Statistical Society of Canada     

A theorem on the covariance matrix of a generalized least squares estimator under an elliptically symmetric error

In a general linear regression model, a generalized least squares estimator (GLSE) is widely employed as an estimator of regression coefficient. The efficiency of the GLSE is usually measured by its covariance (or risk) matrix. In this paper, it is shown that the covariance matrix remains the same as long as the distribution of the error term is elliptically symmetric. This implies that every efficiency result obtained under normal distribution assumption is still valid under elliptical symmetry. An application to a heteroscedastic linear model is also illustrated.     

A Proportional Hazards Regression Model for the Subdistribution with Covariates‐adjusted Censoring Weight for Competing Risks Data

With competing risks data, one often needs to assess the treatment and covariate effects on the cumulative incidence function. Fine and Gray proposed a proportional hazards regression model for the subdistribution of a competing risk with the assumption that the censoring distribution and the covariates are independent. Covariate‐dependent censoring sometimes occurs in medical studies. In this paper, we study the proportional hazards regression model for the subdistribution of a competing risk with proper adjustments for covariate‐dependent censoring. We consider a covariate‐adjusted weight function by fitting the Cox model for the censoring distribution and using the predictive probability for each individual. Our simulation study shows that the covariate‐adjusted weight estimator is basically unbiased when the censoring time depends on the covariates, and the covariate‐adjusted weight approach works well for the variance estimator as well. We illustrate our methods with bone marrow transplant data from the Center for International Blood and Marrow Transplant Research. Here, cancer relapse and death in complete remission are two competing risks.