A Cox‐Aalen Model for Interval‐censored Data

The Cox‐Aalen model, obtained by replacing the baseline hazard function in the well‐known Cox model with a covariate‐dependent Aalen model, allows for both fixed and dynamic covariate effects. In this paper, we examine maximum likelihood estimation for a Cox‐Aalen model based on interval‐censored failure times with fixed covariates. The resulting estimator globally converges to the truth slower than the parametric rate, but its finite‐dimensional component is asymptotically efficient. Numerical studies show that estimation via a constrained Newton method performs well in terms of both finite sample properties and processing time for moderate‐to‐large samples with few covariates. We conclude with an application of the proposed methods to assess risk factors for disease progression in psoriatic arthritis.     

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     

A gradient-based algorithm for semiparametric models with missing covariates

In the parametric regression model, the covariate missing problem under missing at random is considered. It is often desirable to use flexible parametric or semiparametric models for the covariate distribution, which can reduce a potential misspecification problem. Recently, a completely nonparametric approach was developed by [H.Y. Chen, Nonparametric and semiparametric models for missing covariates in parameter regression, J. Amer. Statist. Assoc. 99 (2004), pp. 1176–1189; Z. Zhang and H.E. Rockette, On maximum likelihood estimation in parametric regression with missing covariates, J. Statist. Plann. Inference 47 (2005), pp. 206–223]. Although it does not require a model for the covariate distribution or the missing data mechanism, the proposed method assumes that the covariate distribution is supported only by observed values. Consequently, their estimator is a restricted maximum likelihood estimator (MLE) rather than the global MLE. In this article, we show the restricted semiparametric MLE could be very misleading in some cases. We discuss why this problem occurs and suggest an algorithm to obtain the global MLE. Then, we assess the performance of the proposed method via some simulation experiments.     

Estimation of the mixtures of GLMs with covariate-dependent mixing proportions

ABSTRACT

In this article, we study the estimation for a class of semiparametric mixtures of generalized linear models where mixing proportions depend on a covariate non parametrically. We investigate a backfitting estimation procedure and show the asymptotic normality of the proposed estimators under mild conditions. We conduct simulation to show the good performance of our methodology and give a real data analysis as an illustration.     

Estimation under Cox proportional hazards model with covariates missing not at random

This paper considers likelihood-based estimation under the Cox proportional hazards model in the situations where some covariate entries are missing not at random. Assuming the conditional distribution of the missing entries is known, we demonstrate the existence of the semiparametric maximum likelihood estimator of the model parameters, establish the consistency and weak convergence. By simulation, we examine the finite-sample performance of the estimation procedure, and compare the SPMLE with the one resulted from using an estimated conditional distribution of the missing entries. We analyze the data from a tuberculosis (TB) study applying the proposed approach for illustration.     

A semiparametric approach for modelling multivariate nonlinear time series

In this article, a semiparametric time‐varying nonlinear vector autoregressive (NVAR) model is proposed to model nonlinear vector time series data. We consider a combination of parametric and nonparametric estimation approaches to estimate the NVAR function for both independent and dependent errors. We use the multivariate Taylor series expansion of the link function up to the second order which has a parametric framework as a representation of the nonlinear vector regression function. After the unknown parameters are estimated by the maximum likelihood estimation procedure, the obtained NVAR function is adjusted by a nonparametric diagonal matrix, where the proposed adjusted matrix is estimated by the nonparametric kernel estimator. The asymptotic consistency properties of the proposed estimators are established. Simulation studies are conducted to evaluate the performance of the proposed semiparametric method. A real data example on short‐run interest rates and long‐run interest rates of United States Treasury securities is analyzed to demonstrate the application of the proposed approach. The Canadian Journal of Statistics 47: 668–687; 2019 © 2019 Statistical Society of Canada     

Information borrowing methods for covariate‐adjusted ROC curve

In medical diagnostic testing problems, the covariate adjusted receiver operating characteristic (ROC) curves have been discussed recently for achieving the best separation between disease and control. Due to various restrictions such as cost, the availability of patients, and ethical issues quite frequently only limited information is available. As a result, we are unlikely to have a large enough overall sample size to support reliable direct estimations of ROCs for all the underlying covariates of interest. For example, some genetic factors are less commonly observable compared with others. To get an accurate covariate adjusted ROC estimation, novel statistical methods are needed to effectively utilize the limited information. Therefore, it is desirable to use indirect estimates that borrow strength by employing values of the variables of interest from neighbouring covariates. In this paper we discuss two semiparametric exponential tilting models, where the density functions from different covariate levels share a common baseline density, and the parameters in the exponential tilting component reflect the difference among the covariates. With the proposed models, the estimated covariate adjusted ROC is much smoother and more efficient than the nonparametric counterpart without borrowing information from neighbouring covariates. A simulation study and a real data application are reported. The Canadian Journal of Statistics 40: 569–587; 2012 © 2012 Statistical Society of Canada     

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.     

Statistical Inference and Applications of Mixture of Varying Coefficient Models

In this paper, we consider a new mixture of varying coefficient models, in which each mixture component follows a varying coefficient model and the mixing proportions and dispersion parameters are also allowed to be unknown smooth functions. We systematically study the identifiability, estimation and inference for the new mixture model. The proposed new mixture model is rather general, encompassing many mixture models as its special cases such as mixtures of linear regression models, mixtures of generalized linear models, mixtures of partially linear models and mixtures of generalized additive models, some of which are new mixture models by themselves and have not been investigated before. The new mixture of varying coefficient model is shown to be identifiable under mild conditions. We develop a local likelihood procedure and a modified expectation–maximization algorithm for the estimation of the unknown non‐parametric functions. Asymptotic normality is established for the proposed estimator. A generalized likelihood ratio test is further developed for testing whether some of the unknown functions are constants. We derive the asymptotic distribution of the proposed generalized likelihood ratio test statistics and prove that the Wilks phenomenon holds. The proposed methodology is illustrated by Monte Carlo simulations and an analysis of a CO₂‐GDP data set.     

Joint Modeling of Event Time and Nonignorable Missing Longitudinal Data

Survival studies usually collect on each participant, both duration until some terminal event and repeated measures of a time-dependent covariate. Such a covariate is referred to as an internal time-dependent covariate. Usually, some subjects drop out of the study before occurence of the terminal event of interest. One may then wish to evaluate the relationship between time to dropout and the internal covariate. The Cox model is a standard framework for that purpose. Here, we address this problem in situations where the value of the covariate at dropout is unobserved. We suggest a joint model which combines a first-order Markov model for the longitudinaly measured covariate with a time-dependent Cox model for the dropout process. We consider maximum likelihood estimation in this model and show how estimation can be carried out via the EM-algorithm. We state that the suggested joint model may have applications in the context of longitudinal data with nonignorable dropout. Indeed, it can be viewed as generalizing Diggle and Kenward's model (1994) to situations where dropout may occur at any point in time and may be censored. Hence we apply both models and compare their results on a data set concerning longitudinal measurements among patients in a cancer clinical trial.     

Semiparametric models: a generalized self-consistency approach

Summary. In semiparametric models, the dimension d of the maximum likelihood problem is potentially unlimited. Conventional estimation methods generally behave like O ( d ³). A new O ( d ) estimation procedure is proposed for a large class of semiparametric models. Potentially unlimited dimension is handled in a numerically efficient way through a Nelson–Aalen-like estimator. Discussion of the new method is put in the context of recently developed minorization–maximization algorithms based on surrogate objective functions. The procedure for semiparametric models is used to demonstrate three methods to construct a surrogate objective function: using the difference of two concave functions, the EM way and the new quasi-EM (QEM) approach. The QEM approach is based on a generalization of the EM-like construction of the surrogate objective function so it does not depend on the missing data representation of the model. Like the EM algorithm, the QEM method has a dual interpretation, a result of merging the idea of surrogate maximization with the idea of imputation and self-consistency. The new approach is compared with other possible approaches by using simulations and analysis of real data. The proportional odds model is used as an example throughout the paper.     

Estimation and testing for semiparametric mixtures of partially linear models

In this paper, we study the estimation and inference for a class of semiparametric mixtures of partially linear models. We prove that the proposed models are identifiable under mild conditions, and then give a PL–EM algorithm estimation procedure based on profile likelihood. The asymptotic properties for the resulting estimators and the ascent property of the PL–EM algorithm are investigated. Furthermore, we develop a test statistic for testing whether the non parametric component has a linear structure. Monte Carlo simulations and a real data application highlight the interest of the proposed procedures.     

Spatial generalized linear mixed models in small area estimation

In survey sampling, policy decisions regarding the allocation of resources to sub‐groups of a population depend on reliable predictors of their underlying parameters. However, in some sub‐groups, called small areas due to small sample sizes relative to the population, the information needed for reliable estimation is typically not available. Consequently, data on a coarser scale are used to predict the characteristics of small areas. Mixed models are the primary tools in small area estimation (SAE) and also borrow information from alternative sources (e.g., previous surveys and administrative and census data sets). In many circumstances, small area predictors are associated with location. For instance, in the case of chronic disease or cancer, it is important for policy makers to understand spatial patterns of disease in order to determine small areas with high risk of disease and establish prevention strategies. The literature considering SAE with spatial random effects is sparse and mostly in the context of spatial linear mixed models. In this article, small area models are proposed for the class of spatial generalized linear mixed models to obtain small area predictors and corresponding second‐order unbiased mean squared prediction errors via Taylor expansion and a parametric bootstrap approach. The performance of the proposed approach is evaluated through simulation studies and application of the models to a real esophageal cancer data set from Minnesota, U.S.A. The Canadian Journal of Statistics 47: 426–437; 2019 © 2019 Statistical Society of Canada     

How Many Iterations are Sufficient for Efficient Semiparametric Estimation?

Abstract. A common practice in obtaining an efficient semiparametric estimate is through iteratively maximizing the (penalized) full log‐likelihood w.r.t. its Euclidean parameter and functional nuisance parameter. A rigorous theoretical study of this semiparametric iterative estimation approach is the main purpose of this study. We first show that the grid search algorithm produces an initial estimate with the proper convergence rate. Our second contribution is to provide a formula in calculating the minimal number of iterations k ^* needed to produce an efficient estimate . We discover that (i) k ^* depends on the convergence rates of the initial estimate and the nuisance functional estimate, and (ii) k ^* iterations are also sufficient for recovering the estimation sparsity in high dimensional data. The last contribution is the novel construction of which does not require knowing the explicit expression of the efficient score function. The above general conclusions apply to semiparametric models estimated under various regularizations, for example, kernel or penalized estimation. As far as we are aware, this study provides a first general theoretical justification for the ‘one‐/two‐step iteration’ phenomena observed in the semiparametric literature.     

Case-cohort analysis with semiparametric transformation models

Semiparametric transformation models provide flexible regression models for survival analysis, including the Cox proportional hazards and the proportional odds models as special cases. We consider the application of semiparametric transformation models in case-cohort studies, where the covariate data are observed only on cases and on a subcohort randomly sampled from the full cohort. We first propose an approximate profile likelihood approach with full-cohort data, which amounts to the pseudo-partial likelihood approach of Zucker [2005. A pseudo-partial likelihood method for semiparametric survival regression with covariate errors. J. Amer. Statist. Assoc. 100, 1264–1277]. Simulation results show that our proposal is almost as efficient as the nonparametric maximum likelihood estimator. We then extend this approach to the case-cohort design, applying the Horvitz–Thompson weighting method to the estimating equations from the approximated profile likelihood. Two levels of weights can be utilized to achieve unbiasedness and to gain efficiency. The resulting estimator has a closed-form asymptotic covariance matrix, and is found in simulations to be substantially more efficient than the estimator based on martingale estimating equations. The extension to left-truncated data will be discussed. We illustrate the proposed method on data from a cardiovascular risk factor study conducted in Taiwan.     

Fitting Cox Models with Doubly Censored Data Using Spline‐Based Sieve Marginal Likelihood

In some applications, the failure time of interest is the time from an originating event to a failure event while both event times are interval censored. We propose fitting Cox proportional hazards models to this type of data using a spline‐based sieve maximum marginal likelihood, where the time to the originating event is integrated out in the empirical likelihood function of the failure time of interest. This greatly reduces the complexity of the objective function compared with the fully semiparametric likelihood. The dependence of the time of interest on time to the originating event is induced by including the latter as a covariate in the proportional hazards model for the failure time of interest. The use of splines results in a higher rate of convergence of the estimator of the baseline hazard function compared with the usual non‐parametric estimator. The computation of the estimator is facilitated by a multiple imputation approach. Asymptotic theory is established and a simulation study is conducted to assess its finite sample performance. It is also applied to analyzing a real data set on AIDS incubation time.     

Covariate Decomposition Methods for Longitudinal Missing‐at‐Random Data and Predictors Associated with Subject‐Specific Effects

Investigators often gather longitudinal data to assess changes in responses over time within subjects and to relate these changes to within‐subject changes in predictors. Missing data are common in such studies and predictors can be correlated with subject‐specific effects. Maximum likelihood methods for generalized linear mixed models provide consistent estimates when the data are ‘missing at random’ (MAR) but can produce inconsistent estimates in settings where the random effects are correlated with one of the predictors. On the other hand, conditional maximum likelihood methods (and closely related maximum likelihood methods that partition covariates into between‐ and within‐cluster components) provide consistent estimation when random effects are correlated with predictors but can produce inconsistent covariate effect estimates when data are MAR. Using theory, simulation studies, and fits to example data this paper shows that decomposition methods using complete covariate information produce consistent estimates. In some practical cases these methods, that ostensibly require complete covariate information, actually only involve the observed covariates. These results offer an easy‐to‐use approach to simultaneously protect against bias from both cluster‐level confounding and MAR missingness in assessments of change.     

Inference in Targeted Group‐Sequential Covariate‐Adjusted Randomized Clinical Trials

This article is devoted to the construction and asymptotic study of adaptive, group‐sequential, covariate‐adjusted randomized clinical trials analysed through the prism of the semiparametric methodology of targeted maximum likelihood estimation. We show how to build, as the data accrue group‐sequentially, a sampling design that targets a user‐supplied optimal covariate‐adjusted design. We also show how to carry out sound statistical inference based on such an adaptive sampling scheme (therefore extending some results known in the independent and identically distributed setting only so far), and how group‐sequential testing applies on top of it. The procedure is robust (i.e. consistent even if the working model is mis‐specified). A simulation study confirms the theoretical results and validates the conjecture that the procedure may also be efficient.     

Accelerated hazards mixture cure model

We propose a new cure model for survival data with a surviving or cure fraction. The new model is a mixture cure model where the covariate effects on the proportion of cure and the distribution of the failure time of uncured patients are separately modeled. Unlike the existing mixture cure models, the new model allows covariate effects on the failure time distribution of uncured patients to be negligible at time zero and to increase as time goes by. Such a model is particularly useful in some cancer treatments when the treat effect increases gradually from zero, and the existing models usually cannot handle this situation properly. We develop a rank based semiparametric estimation method to obtain the maximum likelihood estimates of the parameters in the model. We compare it with existing models and methods via a simulation study, and apply the model to a breast cancer data set. The numerical studies show that the new model provides a useful addition to the cure model literature.     

A parametric model fitting time to first event for overdispersed data: application to time to relapse in multiple sclerosis

In this article, we propose a parametric model for the distribution of time to first event when events are overdispersed and can be properly fitted by a Negative Binomial distribution. This is a very common situation in medical statistics, when the occurrence of events is summarized as a count for each patient and the simple Poisson model is not adequate to account for overdispersion of data. In this situation, studying the time of occurrence of the first event can be of interest. From the Negative Binomial distribution of counts, we derive a new parametric model for time to first event and apply it to fit the distribution of time to first relapse in multiple sclerosis (MS). We develop the regression model with methods for covariate estimation. We show that, as the Negative Binomial model properly fits relapse counts data, this new model matches quite perfectly the distribution of time to first relapse, as tested in two large datasets of MS patients. Finally we compare its performance, when fitting time to first relapse in MS, with other models widely used in survival analysis (the semiparametric Cox model and the parametric exponential, Weibull, log-logistic and log-normal models).