Non‐parametric estimation for time-dependent AUC

The area under the receiver operating characteristic (ROC) curve (AUC) is one of the commonly used measure to evaluate or compare the predictive ability of markers to the disease status. Motivated by an angiographic coronary artery disease (CAD) study, our objective is mainly to evaluate and compare the performance of several baseline plasma levels in the prediction of CAD-related vital status over time. Based on censored survival data, the non-parametric estimators are proposed for the time-dependent AUC. The limiting Gaussian processes of the estimators and the estimated asymptotic variance–covariance functions enable us to further construct confidence bands and develop testing procedures. Applications and finite sample properties of the proposed estimation methods and inference procedures are demonstrated through the CAD-related death data from the British Columbia Vital Statistics Agency and Monte Carlo simulations.     

Estimation methods for time‐dependent AUC models with survival data

The performance of clinical tests for disease screening is often evaluated using the area under the receiver‐operating characteristic (ROC) curve (AUC). Recent developments have extended the traditional setting to the AUC with binary time‐varying failure status. Without considering covariates, our first theme is to propose a simple and easily computed nonparametric estimator for the time‐dependent AUC. Moreover, we use generalized linear models with time‐varying coefficients to characterize the time‐dependent AUC as a function of covariate values. The corresponding estimation procedures are proposed to estimate the parameter functions of interest. The derived limiting Gaussian processes and the estimated asymptotic variances enable us to construct the approximated confidence regions for the AUCs. The finite sample properties of our proposed estimators and inference procedures are examined through extensive simulations. An analysis of the AIDS Clinical Trials Group (ACTG) 175 data is further presented to show the applicability of the proposed methods. The Canadian Journal of Statistics 38:8–26; 2010 © 2009 Statistical Society of Canada     

Regression analysis of longitudinal data with outcome‐dependent sampling and informative censoring

We consider a regression analysis of longitudinal data in the presence of outcome‐dependent observation times and informative censoring. Existing approaches commonly require a correct specification of the joint distribution of longitudinal measurements, the observation time process, and informative censoring time under the joint modeling framework and can be computationally cumbersome due to the complex form of the likelihood function. In view of these issues, we propose a semiparametric joint regression model and construct a composite likelihood function based on a conditional order statistics argument. As a major feature of our proposed methods, the aforementioned joint distribution is not required to be specified, and the random effect in the proposed joint model is treated as a nuisance parameter. Consequently, the derived composite likelihood bypasses the need to integrate over the random effect and offers the advantage of easy computation. We show that the resulting estimators are consistent and asymptotically normal. We use simulation studies to evaluate the finite‐sample performance of the proposed method and apply it to a study of weight loss data that motivated our investigation.     

Semiparametric Quantile Regression Analysis of Right‐censored and Length‐biased Failure Time Data with Partially Linear Varying Effects

Right‐censored and length‐biased failure time data arise in many fields including cross‐sectional prevalent cohort studies, and their analysis has recently attracted a great deal of attention. It is well‐known that for regression analysis of failure time data, two commonly used approaches are hazard‐based and quantile‐based procedures, and most of the existing methods are the hazard‐based ones. In this paper, we consider quantile regression analysis of right‐censored and length‐biased data and present a semiparametric varying‐coefficient partially linear model. For estimation of regression parameters, a three‐stage procedure that makes use of the inverse probability weighted technique is developed, and the asymptotic properties of the resulting estimators are established. In addition, the approach allows the dependence of the censoring variable on covariates, while most of the existing methods assume the independence between censoring variables and covariates. A simulation study is conducted and suggests that the proposed approach works well in practical situations. Also, an illustrative example is provided.     

Analysis of generalized semiparametric mixed varying‐coefficients models for longitudinal data

The generalized semiparametric mixed varying‐coefficient effects model for longitudinal data can accommodate a variety of link functions and flexibly model different types of covariate effects, including time‐constant, time‐varying and covariate‐varying effects. The time‐varying effects are unspecified functions of time and the covariate‐varying effects are nonparametric functions of a possibly time‐dependent exposure variable. A semiparametric estimation procedure is developed that uses local linear smoothing and profile weighted least squares, which requires smoothing in the two different and yet connected domains of time and the time‐dependent exposure variable. The asymptotic properties of the estimators of both nonparametric and parametric effects are investigated. In addition, hypothesis testing procedures are developed to examine the covariate effects. The finite‐sample properties of the proposed estimators and testing procedures are examined through simulations, indicating satisfactory performances. The proposed methods are applied to analyze the AIDS Clinical Trial Group 244 clinical trial to investigate the effects of antiretroviral treatment switching in HIV‐infected patients before and after developing the T215Y antiretroviral drug resistance mutation. The Canadian Journal of Statistics 47: 352–373; 2019 © 2019 Statistical Society of Canada     

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.     

Non‐parametric Copula Estimation Under Bivariate Censoring

In this paper, we consider non‐parametric copula inference under bivariate censoring. Based on an estimator of the joint cumulative distribution function, we define a discrete and two smooth estimators of the copula. The construction that we propose is valid for a large range of estimators of the distribution function and therefore for a large range of bivariate censoring frameworks. Under some conditions on the tails of the distributions, the weak convergence of the corresponding copula processes is obtained in l^∞([0,1]²). We derive the uniform convergence rates of the copula density estimators deduced from our smooth copula estimators. Investigation of the practical behaviour of these estimators is performed through a simulation study and two real data applications, corresponding to different censoring settings. We use our non‐parametric estimators to define a goodness‐of‐fit procedure for parametric copula models. A new bootstrap scheme is proposed to compute the critical values.     

Using categorical markers as auxiliary variables in log‐rank tests and hazard ratio estimation

Markers, which are prognostic longitudinal variables, can be used to replace some of the information lost due to right censoring. They may also be used to remove or reduce bias due to informative censoring. In this paper, the authors propose novel methods for using markers to increase the efficiency of log‐rank tests and hazard ratio estimation, as well as parametric estimation. They propose a «plug‐in» methodology that consists of writing the test statistic or estimate of interest as a functional of Kaplan–Meier estimators. The latter are then replaced by an efficient estimator of the survival curve that incorporates information from markers. Using simulations, the authors show that the resulting estimators and tests can be up to 30% more efficient than the usual procedures, provided that the marker is highly prognostic and that the frequency of censoring is high.     

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.     

A class of partially linear single‐index survival models

The authors define a class of “partially linear single‐index” survival models that are more flexible than the classical proportional hazards regression models in their treatment of covariates. The latter enter the proposed model either via a parametric linear form or a nonparametric single‐index form. It is then possible to model both linear and functional effects of covariates on the logarithm of the hazard function and if necessary, to reduce the dimensionality of multiple covariates via the single‐index component. The partially linear hazards model and the single‐index hazards model are special cases of the proposed model. The authors develop a likelihood‐based inference to estimate the model components via an iterative algorithm. They establish an asymptotic distribution theory for the proposed estimators, examine their finite‐sample behaviour through simulation, and use a set of real data to illustrate their approach.     

基于时间序列分析方法的连续性抽样调查研究

针对连续性抽样调查中如何利用过去各期的调查信息来提高现期抽样估计精度的问题，引入时间序列分析方法，分别考虑连续性抽样调查中重复样本和重叠样本等不同情况，建立了不同情况下的时间序列模型，利用成熟的时间序列分析方法给出了总体特征的线性组合估计量。由于时间序列分析方法能够充分利用以往各期的调查信息，从而能够给出精度更高的估计量。     

Optimal sample size allocation for multi-level stress testing with Weibull regression under Type-II censoring

We discuss the optimal allocation problem in a multi-level stress test with Type-II censoring and Weibull (extreme value) regression model. We derive the maximum-likelihood estimators and their asymptotic variance–covariance matrix through the Fisher information. Four optimality criteria are used to discuss the optimal allocation problem. Optimal allocation of units, both exactly for small sample sizes and asymptotically for large sample sizes, for two- and four-stress-level situations are determined numerically. Conclusions and discussions are provided based on the numerical studies.     

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.     

Local composite partial likelihood estimation for length-biased and right-censored data

Length-biased data, which are often encountered in engineering, economics and epidemiology studies, are generally subject to right censoring caused by the research ending or the follow-up loss. The structure of length-biased data is distinct from conventional survival data, since the independent censoring assumption is often violated due to the biased sampling. In this paper, a proportional hazard model with varying coefficients is considered for the length-biased and right-censored data. A local composite likelihood procedure is put forward for the estimation of unknown coefficient functions in the model, and large sample properties of the proposed estimators are also obtained. Additionally, an extensive simulation studies are conducted to assess the finite sample performance of the proposed method and a data set from the Academy Awards is analyzed.     

Detecting diagnostic accuracy of two biomarkers through a bivariate log-normal ROC curve

In biomedical research, two or more biomarkers may be available for diagnosis of a particular disease. Selecting one single biomarker which ideally discriminate a diseased group from a healthy group is confront in a diagnostic process. Frequently, most of the people use the accuracy measure, area under the receiver operating characteristic (ROC) curve to choose the best diagnostic marker among the available markers for diagnosis. Some authors have tried to combine the multiple markers by an optimal linear combination to increase the discriminatory power. In this paper, we propose an alternative method that combines two continuous biomarkers by direct bivariate modeling of the ROC curve under log-normality assumption. The proposed method is applied to simulated data set and prostate cancer diagnostic biomarker data set.     

Estimators Based on Data‐Driven Generalized Weighted Cramér‐von Mises Distances under Censoring – with Applications to Mixture Models

Abstract. Estimators based on data‐driven generalized weighted Cramér‐von Mises distances are defined for data that are subject to a possible right censorship. The function used to measure the distance between the data, summarized by the Kaplan–Meier estimator, and the target model is allowed to depend on the sample size and, for example, on the number of censored items. It is shown that the estimators are consistent and asymptotically multivariate normal for every p dimensional parametric family fulfiling some mild regularity conditions. The results are applied to finite mixtures. Simulation results for finite mixtures indicate that the estimators are useful for moderate sample sizes. Furthermore, the simulation results reveal the usefulness of sample size dependent and censoring sensitive distance functions for moderate sample sizes. Moreover, the estimators for the mixing proportion seem to be fairly robust against a ‘symmetric’ contamination model even when censoring is present.     

The weighted general linear model for longitudinal medical cost data – an application in colorectal cancer

Identifying cost-effective decisions that can take into account of medical cost and health outcome is an important issue under very limited resources. Analyzing medical costs has been challenged owing to skewness of cost distributions, heterogeneity across samples and censoring. When censoring is due to administrative reasons, the total cost might be related to the survival time since longer survivals are likely to be censored and the corresponding total cost will be censored as well. This paper uses the general linear model for the longitudinal data to model the repeated medical cost data and the weighted estimating equation is used to find more accurate estimates for the parameter. Furthermore, the asymptotic properties for the proposed model are discussed. Simulations are used to evaluate the performance of estimators under various scenarios. Finally, the proposed model is implemented on the data extracted from National Health Insurance database for patients with the colorectal cancer.     

Large sample properties and confidence bands for component-wise varying-coefficient regression with longitudinal dependent variable

Longitudinal studies with repeatedly measured dependent variable (out-come) and time-invariant covariates are common in biomedical and epidemi-ological studies. A useful statistical tool to evaluate the effects of covariates on the outcome variable over time is the varying-coefficient regression, which considers a linear relationship between the covariates and the outcome at a specific time point but assumes the linear coefficients to be smooth curves over time. In order to provide adequate smoothing for each coefficient curve, Wu and Chiang ( 1999 ) proposed a class of component-wise kernel estimators and determined the large sample convergence rates and some of the constant terms of the mean squared errors of their estimators. In this paper we calcu¬late the explicit large sample mean squared errors, including the convergence rates and ail the constant terms, and the asymptotic distributions of the kernel estimators of Wu and Chiang ( 1999 ). These asymptotic distributions are used to construct point-wise confidence intervals and Bonferroni-type confidence bands for the coefficient curves. Through a Monte Carlo simulation, wre show that our confidence regions have adequate coverage probabilities. Applying our procedures to a NIH fetal growth study, we show that our procedures are useful to determine the effects of maternal height, cigarette smoking and al¬cohol consumption on the growth of fetal abdominal circumference over time during pregnancy.     

Estimating the association parameter for copula models under dependent censoring

Summary. Many biomedical studies involve the analysis of multiple events. The dependence between the times to these end points is often of scientific interest. We investigate a situation when one end point is subject to censoring by the other. The model assumptions of Day and co-workers and Fine and co-workers are extended to more general structures where the level of association may vary with time. Two types of estimating function are proposed. Asymptotic properties of the proposed estimators are derived. Their finite sample performance is studied via simulations. The inference procedures are applied to two real data sets for illustration.     

Random Weighted Bootstrap Method for Recurrent Events with Informative Censoring

Using the data from the AIDS Link to Intravenous Experiences cohort study as an example, an informative censoring model was used to characterize the repeated hospitalization process of a group of patients. Under the informative censoring assumption, the estimators of the baseline rate function and the regression parameters were shown to be related to a latent variable. Hence, it becomes impractical to directly estimate the unknown quantities in the moments of the estimators for the bandwidth selection of a smoothing estimator and the construction of confidence intervals, which are respectively based on the asymptotic mean squared errors and the asymptotic distributions of the estimators. To overcome these difficulties, we develop a random weighted bootstrap procedure to select appropriate bandwidths and to construct approximated confidence intervals. One can see that our method is simple and faster to implement from a practical point of view, and is at least as accurate as other bootstrap methods. In this article, it is shown that the proposed method is useful through the performance of a Monte Carlo simulation. An application of our procedure is also illustrated by a recurrent event sample of intravenous drug users for inpatient cares over time.