Information attainable in some randomly incomplete data models

The Fisher information is intricately linked to the asymptotic (first-order) optimality of maximum likelihood estimators for parametric complete-data models. When data are missing completely at random in a multivariate setup, it is shown that information in a single observation is well-defined and it plays the same role as in the complete-data model in characterizing the first-order asymptotic optimality properties of associated maximum likelihood estimators; computational aspects are also thoroughly appraised. As an illustration, the logistic regression model with incomplete binary responses and an incomplete categorical covariate is worked out.     

Partially linear transformation model for length-biased and right-censored data

In this paper, we consider a partially linear transformation model for data subject to length-biasedness and right-censoring which frequently arise simultaneously in biometrics and other fields. The partially linear transformation model can account for nonlinear covariate effects in addition to linear effects on survival time, and thus reconciles a major disadvantage of the popular semiparamnetric linear transformation model. We adopt local linear fitting technique and develop an unbiased global and local estimating equations approach for the estimation of unknown covariate effects. We provide an asymptotic justification for the proposed procedure, and develop an iterative computational algorithm for its practical implementation, and a bootstrap resampling procedure for estimating the standard errors of the estimator. A simulation study shows that the proposed method performs well in finite samples, and the proposed estimator is applied to analyse the Oscar data.     

Testing the linearity of negative binomial regression models

The negative binomial (NB) is frequently used to model overdispersed Poisson count data. To study the effect of a continuous covariate of interest in an NB model, a flexible procedure is used to model the covariate effect by fixed-knot cubic basis-splines or B-splines with a second-order difference penalty on the adjacent B-spline coefficients to avoid undersmoothing. A penalized likelihood is used to estimate parameters of the model. A penalized likelihood ratio test statistic is constructed for the null hypothesis of the linearity of the continuous covariate effect. When the number of knots is fixed, its limiting null distribution is the distribution of a linear combination of independent chi-squared random variables, each with one degree of freedom. The smoothing parameter value is determined by setting a specified value equal to the asymptotic expectation of the test statistic under the null hypothesis. The power performance of the proposed test is studied with simulation experiments.     

Sampling Adjusted Analysis of Dynamic Additive Regression Models for Longitudinal Data

We consider a modelling approach to longitudinal data that aims at estimating flexible covariate effects in a model where the sampling probabilities are modelled explicitly. The joint modelling yields simple estimators that are easy to compute and analyse, even if the sampling of the longitudinal responses interacts with the response level. An incorrect model for the sampling probabilities results in biased estimates. Non-representative sampling occurs, for example, if patients with an extreme development (based on extreme values of the response) are called in for additional examinations and measurements. We allow covariate effects to be time-varying or time-constant. Estimates of covariate effects are obtained by solving martingale equations locally for the cumulative regression functions. Using Aalen's additive model for the sampling probabilities, we obtain simple expressions for the estimators and their asymptotic variances. The asymptotic distributions for the estimators of the non-parametric components as well as the parametric components of the model are derived drawing on general martingale results. Two applications are presented. We consider the growth of cystic fibrosis patients and the prothrombin index for liver cirrhosis patients. The conclusion about the growth of the cystic fibrosis patients is not altered when adjusting for a possible non-representativeness in the sampling, whereas we reach substantively different conclusions about the treatment effect for the liver cirrhosis patients.     

Marginal hazard regression for correlated failure time data with auxiliary covariates

In many biomedical studies, it is common that due to budget constraints, the primary covariate is only collected in a randomly selected subset from the full study cohort. Often, there is an inexpensive auxiliary covariate for the primary exposure variable that is readily available for all the cohort subjects. Valid statistical methods that make use of the auxiliary information to improve study efficiency need to be developed. To this end, we develop an estimated partial likelihood approach for correlated failure time data with auxiliary information. We assume a marginal hazard model with common baseline hazard function. The asymptotic properties for the proposed estimators are developed. The proof of the asymptotic results for the proposed estimators is nontrivial since the moments used in estimating equation are not martingale-based and the classical martingale theory is not sufficient. Instead, our proofs rely on modern empirical process theory. The proposed estimator is evaluated through simulation studies and is shown to have increased efficiency compared to existing methods. The proposed method is illustrated with a data set from the Framingham study.     

Bayesian analysis of outlier problems using divergence measures

A Bayesian approach is presented for detecting influential observations using general divergence measures on the posterior distributions. A sampling-based approach using a Gibbs or Metropolis-within-Gibbs method is used to compute the posterior divergence measures. Four specific measures are proposed, which convey the effects of a single observation or covariate on the posterior. The technique is applied to a generalized linear model with binary response data, an overdispersed model and a nonlinear model. An asymptotic approximation using Laplace method to obtain the posterior divergence is also briefly discussed.     

Partial covariate adjusted regression

Covariate adjusted regression (CAR) is a recently proposed adjustment method for regression analysis where both the response and predictors are not directly observed [?entürk, D., Müller, H.G., 2005. Covariate adjusted regression. Biometrika 92, 75–89]. The available data have been distorted by unknown functions of an observable confounding covariate. CAR provides consistent estimators for the coefficients of the regression between the variables of interest, adjusted for the confounder. We develop a broader class of partial covariate adjusted regression (PCAR) models to accommodate both distorted and undistorted (adjusted/unadjusted) predictors. The PCAR model allows for unadjusted predictors, such as age, gender and demographic variables, which are common in the analysis of biomedical and epidemiological data. The available estimation and inference procedures for CAR are shown to be invalid for the proposed PCAR model. We propose new estimators and develop new inference tools for the more general PCAR setting. In particular, we establish the asymptotic normality of the proposed estimators and propose consistent estimators of their asymptotic variances. Finite sample properties of the proposed estimators are investigated using simulation studies and the method is also illustrated with a Pima Indians diabetes data set.     

ROC Curves in Non‐Parametric Location‐Scale Regression Models

Abstract. The receiver operating characteristic (ROC) curve is a tool of extensive use to analyse the discrimination capability of a diagnostic variable in medical studies. In certain situations, the presence of a covariate related to the diagnostic variable can increase the discriminating power of the ROC curve. In this article, we model the effect of the covariate over the diagnostic variable by means of non‐parametric location‐scale regression models. We propose a new non‐parametric estimator of the conditional ROC curve and study its asymptotic properties. We also present some simulations and an illustration to a data set concerning diagnosis of diabetes.     

A Marginal Additive Rates Model for Recurrent Event Data with a Terminal Event

Recurrent events data with a terminal event often arise in many longitudinal studies. Most of existing models assume multiplicative covariate effects and model the conditional recurrent event rate given survival. In this article, we propose a marginal additive rates model for recurrent events with a terminal event, and develop two procedures for estimating the model parameters. The asymptotic properties of the resulting estimators are established. In addition, some numerical procedures are presented for model checking. The finite-sample behavior of the proposed methods is examined through simulation studies, and an application to a bladder cancer study is also illustrated.     

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     

Continuous covariate frailty models for censored and truncated clustered data

Using some logarithmic and integral transformation we transform a continuous covariate frailty model into a polynomial regression model with a random effect. The responses of this mixed model can be ‘estimated’ via conditional hazard function estimation. The random error in this model does not have zero mean and its variance is not constant along the covariate and, consequently, these two quantities have to be estimated. Since the asymptotic expression for the bias is complicated, the two-large-bandwidth trick is proposed to estimate the bias. The proposed transformation is very useful for clustered incomplete data subject to left truncation and right censoring (and for complex clustered data in general). Indeed, in this case no standard software is available to fit the frailty model, whereas for the transformed model standard software for mixed models can be used for estimating the unknown parameters in the original frailty model. A small simulation study illustrates the good behavior of the proposed method. This method is applied to a bladder cancer data set.     

The proportional hazards model with covariate measurement error

The proportional hazards regression model is commonly used to evaluate the relationship between survival and covariates. Covariates are frequently measured with error. Substituting mismeasured values for the true covariates leads to biased estimation. Hu et al. (Biometrics 88 (1998) 447) have proposed to base estimation in the proportional hazards model with covariate measurement error on a joint likelihood for survival and the covariate variable. Nonparametric maximum likelihood estimation (NPMLE) was used and simulations were conducted to assess the asymptotic validity of this approach. In this paper, we derive a rigorous proof of asymptotic normality of the NPML estimators.     

Cox regression in cohort studies with validation sampling

An estimation procedure is proposed for the Cox model in cohort studies with validation sampling, where crude covariate information is observed for the full cohort and true covariate information is collected on a validation set sampled randomly from the full cohort. The method proposed makes use of the partial information from data that are available on the entire cohort by fitting a working Cox model relating crude covariates to the failure time. The resulting estimator is consistent regardless of the specification of the working model and is asymptotically more efficient than the validation-set-only estimator. Approximate asymptotic relative efficiencies with respect to some alternative methods are derived under a simple scenario and further studied numerically. The finite sample performance is investigated and compared with alternative methods via simulation studies. A similar procedure also works for the case where the validation set is a stratified random sample from the cohort.     

Nonparametric modeling of the gap time in recurrent event data

Recurrent event data arise in many biomedical and engineering studies when failure events can occur repeatedly over time for each study subject. In this article, we are interested in nonparametric estimation of the hazard function for gap time. A penalized likelihood model is proposed to estimate the hazard as a function of both gap time and covariate. Method for smoothing parameter selection is developed from subject-wise cross-validation. Confidence intervals for the hazard function are derived using the Bayes model of the penalized likelihood. An eigenvalue analysis establishes the asymptotic convergence rates of the relevant estimates. Empirical studies are performed to evaluate various aspects of the method. The proposed technique is demonstrated through an application to the well-known bladder tumor cancer data.     

Structured Modeling for Post-Mortem Brain Tissue Data

Structured means have been used in studying possible covariate effects on responses, whereas patterned covariances deal with random effects, missing data, and differing study designs. In this article, we develop new multivariate models with patterned means and covariance matrices to deal with special structures of the post-mortem brain tissue data collected in the Conte Center for the Neuroscience of Mental Disorders at the University of Pittsburgh. We obtain maximum likelihood estimates via the method of scoring for these new structured models. One-iteration estimators from a consistent starting point are used to derive the asymptotic distributions. The model fitting algorithms, as well as the asymptotic distributions, are examined using simulated data, and are applied to data from post-mortem tissue studies in schizophrenia.     

Variable selection for partially linear proportional hazards model with covariate measurement error

In survival analysis, we may encounter the following three problems: nonlinear covariate effect, variable selection and measurement error. Existing studies only address one or two of these problems. The goal of this study is to fill the knowledge gap and develop a novel approach to simultaneously address all three problems. Specifically, a partially time-varying coefficient proportional hazards model is proposed to more flexibly describe covariate effects. Corrected score and conditional score approaches are employed to accommodate potential measurement error. For the selection of relevant variables and regularised estimation, a penalisation approach is adopted. It is shown that the proposed approach has satisfactory asymptotic properties. It can be effectively realised using an iterative algorithm. The performance of the proposed approach is assessed via simulation studies and further illustrated by application to data from an AIDS clinical trial.     

Covariate classification by post–stratification

The plug–in Anderson's covariate classification statistic is constructed on the basis of an initially unclassified training sample by means of posty–stratification. The asymptotic efficiency relative to the discriminant based on an initially classified training sample is evaluated for the case where a covariate is present. Effect of post–stratification is examined.     

An estimated‐score approach for dealing with missing covariate data in matched case–control studies

Matched case–control designs are commonly used in epidemiological studies for estimating the effect of exposure variables on the risk of a disease by controlling the effect of confounding variables. Due to retrospective nature of the study, information on a covariate could be missing for some subjects. A straightforward application of the conditional logistic likelihood for analyzing matched case–control data with the partially missing covariate may yield inefficient estimators of the parameters. A robust method has been proposed to handle this problem using an estimated conditional score approach when the missingness mechanism does not depend on the disease status. Within the conditional logistic likelihood framework, an empirical procedure is used to estimate the odds of the disease for the subjects with missing covariate values. The asymptotic distribution and the asymptotic variance of the estimator when the matching variables and the completely observed covariates are categorical. The finite sample performance of the proposed estimator is assessed through a simulation study. Finally, the proposed method has been applied to analyze two matched case–control studies. The Canadian Journal of Statistics 38: 680–697; 2010 © 2010 Statistical Society of Canada     

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     

Dimension-reduced empirical likelihood inference for response mean with data missing at random

To make efficient inference for mean of a response variable when the data are missing at random and the dimension of covariate is not low, we construct three bias-corrected empirical likelihood (EL) methods in conjunction with dimension-reduced kernel estimation of propensity or/and conditional mean response function. Consistency and asymptotic normality of the maximum dimension-reduced EL estimators are established. We further study the asymptotic properties of the resulting dimension-reduced EL ratio functions and the corresponding EL confidence intervals for the response mean are constructed. The finite-sample performance of the proposed estimators is studied through simulation, and an application to HIV-CD4 data set is also presented.