Nonparametric covariate adjustment for receiver operating characteristic curves

The accuracy of a diagnostic test is typically characterized using the receiver operating characteristic (ROC) curve. Summarizing indexes such as the area under the ROC curve (AUC) are used to compare different tests as well as to measure the difference between two populations. Often additional information is available on some of the covariates which are known to influence the accuracy of such measures. The authors propose nonparametric methods for covariate adjustment of the AUC. Models with normal errors and possibly non‐normal errors are discussed and analyzed separately. Nonparametric regression is used for estimating mean and variance functions in both scenarios. In the model that relaxes the assumption of normality, the authors propose a covariate‐adjusted Mann–Whitney estimator for AUC estimation which effectively uses available data to construct working samples at any covariate value of interest and is computationally efficient for implementation. This provides a generalization of the Mann–Whitney approach for comparing two populations by taking covariate effects into account. The authors derive asymptotic properties for the AUC estimators in both settings, including asymptotic normality, optimal strong uniform convergence rates and mean squared error (MSE) consistency. The MSE of the AUC estimators was also assessed in smaller samples by simulation. Data from an agricultural study were used to illustrate the methods of analysis. The Canadian Journal of Statistics 38:27–46; 2010 © 2009 Statistical Society of Canada     

Bayesian Methods for Missing Covariates in Cure Rate Models

We propose methods for Bayesian inference for missing covariate data with a novel class of semi-parametric survival models with a cure fraction. We allow the missing covariates to be either categorical or continuous and specify a parametric distribution for the covariates that is written as a sequence of one dimensional conditional distributions. We assume that the missing covariates are missing at random (MAR) throughout. We propose an informative class of joint prior distributions for the regression coefficients and the parameters arising from the covariate distributions. The proposed class of priors are shown to be useful in recovering information on the missing covariates especially in situations where the missing data fraction is large. Properties of the proposed prior and resulting posterior distributions are examined. Also, model checking techniques are proposed for sensitivity analyses and for checking the goodness of fit of a particular model. Specifically, we extend the Conditional Predictive Ordinate (CPO) statistic to assess goodness of fit in the presence of missing covariate data. Computational techniques using the Gibbs sampler are implemented. A real data set involving a melanoma cancer clinical trial is examined to demonstrate the methodology.     

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.     

ROC curve and covariates: extending induced methodology to the non-parametric framework

Continuous diagnostic tests are often used to discriminate between diseased and healthy populations. The receiver operating characteristic (ROC) curve is a widely used tool that provides a graphical visualisation of the effectiveness of such tests. The potential performance of the tests in terms of distinguishing diseased from healthy people may be strongly influenced by covariates, and a variety of regression methods for adjusting ROC curves has been developed. Until now, these methodologies have assumed that covariate effects have parametric forms, but in this paper we extend the induced methodology by allowing for arbitrary non-parametric effects of a continuous covariate. To this end, local polynomial kernel smoothers are used in the estimation procedure. Our method allows for covariate effect not only on the mean, but also on the variance of the diagnostic test. We also present a bootstrap-based method for testing for a significant covariate effect on the ROC curve. To illustrate the method, endocrine data were analysed with the aim of assessing the performance of anthropometry for predicting clusters of cardiovascular risk factors in an adult population in Galicia (NW Spain), duly adjusted for age. The proposed methodology has proved useful for providing age-specific thresholds for anthropometric measures in the Galician community.     

Conditional Akaike information under covariate shift with application to small area estimation

In this study, we consider the problem of selecting explanatory variables of fixed effects in linear mixed models under covariate shift, which is when the values of covariates in the model for prediction differ from those in the model for observed data. We construct a variable selection criterion based on the conditional Akaike information introduced by Vaida & Blanchard (2005). We focus especially on covariate shift in small area estimation and demonstrate the usefulness of the proposed criterion. In addition, numerical performance is investigated through simulations, one of which is a design‐based simulation using a real dataset of land prices. The Canadian Journal of Statistics 46: 316–335; 2018 © 2018 Statistical Society of Canada     

Model selection in finite mixture of regression models: a Bayesian approach with innovative weighted g priors and reversible jump Markov chain Monte Carlo implementation

Finite mixture of regression (FMR) models are aimed at characterizing subpopulation heterogeneity stemming from different sets of covariates that impact different groups in a population. We address the contemporary problem of simultaneously conducting covariate selection and determining the number of mixture components from a Bayesian perspective that can incorporate prior information. We propose a Gibbs sampling algorithm with reversible jump Markov chain Monte Carlo implementation to accomplish concurrent covariate selection and mixture component determination in FMR models. Our Bayesian approach contains innovative features compared to previously developed reversible jump algorithms. In addition, we introduce component-adaptive weighted g priors for regression coefficients, and illustrate their improved performance in covariate selection. Numerical studies show that the Gibbs sampler with reversible jump implementation performs well, and that the proposed weighted priors can be superior to non-adaptive unweighted priors.     

Nonparametric covariate adjustment in estimating hazard ratios

In randomized clinical trials with time‐to‐event outcomes, the hazard ratio is commonly used to quantify the treatment effect relative to a control. The Cox regression model is commonly used to adjust for relevant covariates to obtain more accurate estimates of the hazard ratio between treatment groups. However, it is well known that the treatment hazard ratio based on a covariate‐adjusted Cox regression model is conditional on the specific covariates and differs from the unconditional hazard ratio that is an average across the population. Therefore, covariate‐adjusted Cox models cannot be used when the unconditional inference is desired. In addition, the covariate‐adjusted Cox model requires the relatively strong assumption of proportional hazards for each covariate. To overcome these challenges, a nonparametric randomization‐based analysis of covariance method was proposed to estimate the covariate‐adjusted hazard ratios for multivariate time‐to‐event outcomes. However, empirical evaluations of the performance (power and type I error rate) of the method have not been studied. Although the method is derived for multivariate situations, for most registration trials, the primary endpoint is a univariate outcome. Therefore, this approach is applied to univariate outcomes, and performance is evaluated through a simulation study in this paper. Stratified analysis is also investigated. As an illustration of the method, we also apply the covariate‐adjusted and unadjusted analyses to an oncology trial. Copyright © 2015 John Wiley & Sons, Ltd.     

Calculating the power or sample size for the logistic and proportional hazards models

An algorithm is presented for calculating the power for the logistic and proportional hazards models in which some of the covariates are discrete and the remainders are multivariate normal. The mean and covariance matrix of the multivariate normal covariates may depend on the discrete covariates.

The algorithm, which finds the power of the Wald test, uses the result that the information matrix can be calculated using univariate numerical integration even when there are several continuous covariates. The algorithm is checked using simulation and in certain situations gives more accurate results than current methods which are based on simple formulae. The algorithm is used to explore properties of these models, in particular, the power gain from a prognostic covariate in the analysis of a clinical trial or observational study. The methods can be extended to determine power for other generalized linear models.     

Robustness of Approaches to ROC Curve Modeling under Misspecification of the Underlying Probability Model

A variety of statistical regression models have been proposed for the comparison of ROC curves for different markers across covariate groups. Pepe developed parametric models for the ROC curve that induce a semiparametric model for the market distributions to relax the strong assumptions in fully parametric models. We investigate the analysis of the power ROC curve using these ROC-GLM models compared to the parametric exponential model and the estimating equations derived from the usual partial likelihood methods in time-to-event analyses. In exploring the robustness to violations of distributional assumptions, we find that the ROC-GLM provides an extra measure of robustness.     

Joint modeling of degradation and failure time data

This paper surveys some approaches to model the relationship between failure time data and covariate data like internal degradation and external environmental processes. These models which reflect the dependency between system state and system reliability include threshold models and hazard-based models. In particular, we consider the class of degradation–threshold–shock models (DTS models) in which failure is due to the competing causes of degradation and trauma. For this class of reliability models we express the failure time in terms of degradation and covariates. We compute the survival function of the resulting failure time and derive the likelihood function for the joint observation of failure times and degradation data at discrete times. We consider a special class of DTS models where degradation is modeled by a process with stationary independent increments and related to external covariates through a random time scale and extend this model class to repairable items by a marked point process approach. The proposed model class provides a rich conceptual framework for the study of degradation–failure issues.     

Bayesian variable selection for the Cox regression model with missing covariates

In this paper, we develop Bayesian methodology and computational algorithms for variable subset selection in Cox proportional hazards models with missing covariate data. A new joint semi-conjugate prior for the piecewise exponential model is proposed in the presence of missing covariates and its properties are examined. The covariates are assumed to be missing at random (MAR). Under this new prior, a version of the Deviance Information Criterion (DIC) is proposed for Bayesian variable subset selection in the presence of missing covariates. Monte Carlo methods are developed for computing the DICs for all possible subset models in the model space. A Bone Marrow Transplant (BMT) dataset is used to illustrate the proposed methodology.     

Using the EM-algorithm for survival data with incomplete categorical covariates

Incomplete covariate data is a common occurrence in many studies in which the outcome is survival time. With generalized linear models, when the missing covariates are categorical, a useful technique for obtaining parameter estimates is the EM by the method of weights proposed in Ibrahim (1990). In this article, we extend the EM by the method of weights to survival outcomes whose distributions may not fall in the class of generalized linear models. This method requires the estimation of the parameters of the distribution of the covariates. We present a clinical trials example with five covariates, four of which have some missing values.     

Feature screening for case‐cohort studies with failure time outcome

Case‐cohort design has been demonstrated to be an economical and efficient approach in large cohort studies when the measurement of some covariates on all individuals is expensive. Various methods have been proposed for case‐cohort data when the dimension of covariates is smaller than sample size. However, limited work has been done for high‐dimensional case‐cohort data which are frequently collected in large epidemiological studies. In this paper, we propose a variable screening method for ultrahigh‐dimensional case‐cohort data under the framework of proportional model, which allows the covariate dimension increases with sample size at exponential rate. Our procedure enjoys the sure screening property and the ranking consistency under some mild regularity conditions. We further extend this method to an iterative version to handle the scenarios where some covariates are jointly important but are marginally unrelated or weakly correlated to the response. The finite sample performance of the proposed procedure is evaluated via both simulation studies and an application to a real data from the breast cancer study.     

Semiparametric inference for estimating equations with nonignorably missing covariates

We consider statistical inference of unknown parameters in estimating equations (EEs) when some covariates have nonignorably missing values, which is quite common in practice but has rarely been discussed in the literature. When an instrument, a fully observed covariate vector that helps identifying parameters under nonignorable missingness, is available, the conditional distribution of the missing covariates given other covariates can be estimated by the pseudolikelihood method of Zhao and Shao [(2015), ‘Semiparametric pseudo likelihoods in generalised linear models with nonignorable missing data’, Journal of the American Statistical Association, 110, 1577–1590)] and be used to construct unbiased EEs. These modified EEs then constitute a basis for valid inference by empirical likelihood. Our method is applicable to a wide range of EEs used in practice. It is semiparametric since no parametric model for the propensity of missing covariate data is assumed. Asymptotic properties of the proposed estimator and the empirical likelihood ratio test statistic are derived. Some simulation results and a real data analysis are presented for illustration.     

A Graphical Tool for Interpreting Regression Coefficients of Trinomial Logit Models

Multinomial logit (also termed multi-logit) models permit the analysis of the statistical relation between a categorical response variable and a set of explicative variables (called covariates or regressors). Although multinomial logit is widely used in both the social and economic sciences, the interpretation of regression coefficients may be tricky, as the effect of covariates on the probability distribution of the response variable is nonconstant and difficult to quantify. The ternary plots illustrated in this article aim at facilitating the interpretation of regression coefficients and permit the effect of covariates (either singularly or jointly considered) on the probability distribution of the dependent variable to be quantified. Ternary plots can be drawn both for ordered and for unordered categorical dependent variables, when the number of possible outcomes equals three (trinomial response variable); these plots allow not only to represent the covariate effects over the whole parameter space of the dependent variable but also to compare the covariate effects of any given individual profile. The method is illustrated and discussed through analysis of a dataset concerning the transition of master’s graduates of the University of Trento (Italy) from university to employment.     

Likelihood‐based and marginal inference methods for recurrent event data with covariate measurement error

Recurrent event data arise commonly in medical and public health studies. The analysis of such data has received extensive research attention and various methods have been developed in the literature. Depending on the focus of scientific interest, the methods may be broadly classified as intensity‐based counting process methods, mean function‐based estimating equation methods, and the analysis of times to events or times between events. These methods and models cover a wide variety of practical applications. However, there is a critical assumption underlying those methods–variables need to be correctly measured. Unfortunately, this assumption is frequently violated in practice. It is quite common that some covariates are subject to measurement error. It is well known that covariate measurement error can substantially distort inference results if it is not properly taken into account. In the literature, there has been extensive research concerning measurement error problems in various settings. However, with recurrent events, there is little discussion on this topic. It is the objective of this paper to address this important issue. In this paper, we develop inferential methods which account for measurement error in covariates for models with multiplicative intensity functions or rate functions. Both likelihood‐based inference and robust inference based on estimating equations are discussed. The Canadian Journal of Statistics 40: 530–549; 2012 © 2012 Statistical Society of Canada     

A Semi-parametric Bayesian Analysis of Survival Data Based on Lévy-driven Processes

In the presence of covariate information, the proportional hazards model is one of the most popular models. In this paper, in a Bayesian nonparametric framework, we use a Markov (Lévy-driven) process to model the baseline hazard rate. Previous Bayesian nonparametric models have been based on neutral to the right processes, which have a number of drawbacks, such as discreteness of the cumulative hazard function. We allow the covariates to be time dependent functions and develop a full posterior analysis via substitution sampling. A detailed illustration is presented.     

Cumulative logit models for matched pairs case-control design: Studies with covariates

Binary as well as polytomous logistic models have been found useful for estimating odds ratios when the exposure of prime interest assumes unordered multiple levels under matched pair case-control design. In our earlier studies, we have shown the use of a polytomous logistic model for estimating cumulative odds ratios when the exposure of prime interest assumes multiple ordered levels under matched pair case-control design. In this paper, using the above model, we estimate the covariate adjusted cumulative odds ratios, in the case of an ordinal multiple level exposure variable under a pairwise matched case-control retrospective design. An approach, based on asymptotic distributional results, is also described to investigate whether or not the response categories are distinguishable with respect to the cumulative odds ratios after adjusting the effect of covariates. An illustrative example is presented and discussed.     

Statistical estimation for partially linear error-in-variable models with error-prone covariates

Motivated by a heart disease data, we propose a new partially linear error-in-variable models with error-prone covariates, in which mismeasured covariate appears in the noparametric part and the covariates in the parametric part are not observed, but ancillary variables are available. In this case, we first calibrate the linear covariates, and then use the least-square method and the local linear method to estimate parametric and nonparametric components. Also, under certain conditions the asymptotic distributions of proposed estimates are obtained. Simulated and real examples are conducted to illustrate our proposed methodology.     

IMPORTANCE BOOTSTRAP RESAMPLING FOR PROPORTIONAL HAZARDS REGRESSION

Importance resampling is an approach that uses exponential tilting to reduce the resampling necessary for the construction of nonparametric bootstrap confidence intervals. The properties of bootstrap importance confidence intervals are well established when the data is a smooth function of means and when there is no censoring. However, in the framework of survival or time-to-event data, the asymptotic properties of importance resampling have not been rigorously studied, mainly because of the unduly complicated theory incurred when data is censored. This paper uses extensive simulation to show that, for parameter estimates arising from fitting Cox proportional hazards models, importance bootstrap confidence intervals can be constructed if the importance resampling probabilities of the records for the n individuals in the study are determined by the empirical influence function for the parameter of interest. Our results show that, compared to uniform resampling, importance resampling improves the relative mean-squared-error (MSE) efficiency by a factor of nine (for n = 200). The efficiency increases significantly with sample size, is mildly associated with the amount of censoring, but decreases slightly as the number of bootstrap resamples increases. The extra CPU time requirement for calculating importance resamples is negligible when compared to the large improvement in MSE efficiency. The method is illustrated through an application to data on chronic lymphocytic leukemia, which highlights that the bootstrap confidence interval is the preferred alternative to large sample inferences when the distribution of a specific covariate deviates from normality. Our results imply that, because of its computational efficiency, importance resampling is recommended whenever bootstrap methodology is implemented in a survival framework. Its use is particularly important when complex covariates are involved or the survival problem to be solved is part of a larger problem; for instance, when determining confidence bounds for models linking survival time with clusters identified in gene expression microarray data.