Analysis of two-phase sampling data with semiparametric additive hazards models

Under the case-cohort design introduced by Prentice (Biometrica 73:1–11, 1986), the covariate histories are ascertained only for the subjects who experience the event of interest (i.e., the cases) during the follow-up period and for a relatively small random sample from the original cohort (i.e., the subcohort). The case-cohort design has been widely used in clinical and epidemiological studies to assess the effects of covariates on failure times. Most statistical methods developed for the case-cohort design use the proportional hazards model, and few methods allow for time-varying regression coefficients. In addition, most methods disregard data from subjects outside of the subcohort, which can result in inefficient inference. Addressing these issues, this paper proposes an estimation procedure for the semiparametric additive hazards model with case-cohort/two-phase sampling data, allowing the covariates of interest to be missing for cases as well as for non-cases. A more flexible form of the additive model is considered that allows the effects of some covariates to be time varying while specifying the effects of others to be constant. An augmented inverse probability weighted estimation procedure is proposed. The proposed method allows utilizing the auxiliary information that correlates with the phase-two covariates to improve efficiency. The asymptotic properties of the proposed estimators are established. An extensive simulation study shows that the augmented inverse probability weighted estimation is more efficient than the widely adopted inverse probability weighted complete-case estimation method. The method is applied to analyze data from a preventive HIV vaccine efficacy trial.     

Estimation of conditional cumulative incidence functions under generalized semiparametric regression models with missing covariates,with application to analysis of biomarker correlates in vaccine trials

This article presents generalized semiparametric regression models for conditional cumulative incidence functions with competing risks data when covariates are missing by sampling design or happenstance. A doubly robust augmented inverse probability weighted (AIPW) complete-case approach to estimation and inference is investigated. This approach modifies IPW complete-case estimating equations by exploiting the key features in the relationship between the missing covariates and the phase-one data to improve efficiency. An iterative numerical procedure is derived to solve the nonlinear estimating equations. The asymptotic properties of the proposed estimators are established. A simulation study examining the finite-sample performances of the proposed estimators shows that the AIPW estimators are more efficient than the IPW estimators. The developed method is applied to the RV144 HIV-1 vaccine efficacy trial to investigate vaccine-induced IgG binding antibodies to HIV-1 as correlates of acquisition of HIV-1 infection while taking account of whether the HIV-1 sequences are near or far from the HIV-1 sequences represented in the vaccine construct.     

Regression Analysis of Length‐biased and Right‐censored Failure Time Data with Missing Covariates

Length‐biased and right‐censored failure time data arise from many fields, and their analysis has recently attracted a great deal of attention. Two examples of the areas that often produce such data are epidemiological studies and cancer screening trials. In this paper, we discuss regression analysis of such data in the presence of missing covariates, for which no established inference procedure seems to exist. For the problem, we consider the data arising from the proportional hazards model and propose two inverse probability weighted estimation procedures. The asymptotic properties of the resulting estimators are established, and the extensive simulation study conducted for the evaluation of the proposed methods suggests that they work well for practical situations.     

Semiparametric regression for restricted mean residual life under right censoring

A mean residual life function (MRLF) is the remaining life expectancy of a subject who has survived to a certain time point. In the presence of covariates, regression models are needed to study the association between the MRLFs and covariates. If the survival time tends to be too long or the tail is not observed, the restricted mean residual life must be considered. In this paper, we propose the proportional restricted mean residual life model for fitting survival data under right censoring. For inference on the model parameters, martingale estimating equations are developed, and the asymptotic properties of the proposed estimators are established. In addition, a class of goodness-of-fit test is presented to assess the adequacy of the model. The finite sample behavior of the proposed estimators is evaluated through simulation studies, and the approach is applied to a set of real life data collected from a randomized clinical trial.     

Variable selection for semiparametric errors-in-variables regression model with longitudinal data

In this paper, we focus on the variable selection for the semiparametric regression model with longitudinal data when some covariates are measured with errors. A new bias-corrected variable selection procedure is proposed based on the combination of the quadratic inference functions and shrinkage estimations. With appropriate selection of the tuning parameters, we establish the consistency and asymptotic normality of the resulting estimators. Extensive Monte Carlo simulation studies are conducted to examine the finite sample performance of the proposed variable selection procedure. We further illustrate the proposed procedure with an application.     

Semiparametric transformation models for multivariate panel count data with dependent observation process

This article discusses regression analysis of multivariate panel count data in which the observation process may contain relevant information about or be related to the underlying recurrent event processes of interest. Such data occur if a recurrent event study involves several related types of recurrent events and the observation scheme or process may be subject-specific. For the problem, a class of semiparametric transformation models is presented, which provides a great flexibility for modelling the effects of covariates on the recurrent event processes. For estimation of regression parameters, an estimating equation-based inference procedure is developed and the asymptotic properties of the resulting estimates are established. Also the proposed approach is evaluated by simulation studies and applied to the data arising from a skin cancer chemoprevention trial.     

Statistical inference on partial linear additive models with distortion measurement errors

We consider statistical inference for partial linear additive models (PLAMs) when the linear covariates are measured with errors and distorted by unknown functions of commonly observable confounding variables. A semiparametric profile least squares estimation procedure is proposed to estimate unknown parameter under unrestricted and restricted conditions. Asymptotic properties for the estimators are established. To test a hypothesis on the parametric components, a test statistic based on the difference between the residual sums of squares under the null and alternative hypotheses is proposed, and we further show that its limiting distribution is a weighted sum of independent standard chi-squared distributions. A bootstrap procedure is further proposed to calculate critical values. Simulation studies are conducted to demonstrate the performance of the proposed procedure and a real example is analyzed for an illustration.     

Bayesian inference for generalized additive mixed models based on Markov random field priors

Most regression problems in practice require flexible semiparametric forms of the predictor for modelling the dependence of responses on covariates. Moreover, it is often necessary to add random effects accounting for overdispersion caused by unobserved heterogeneity or for correlation in longitudinal or spatial data. We present a unified approach for Bayesian inference via Markov chain Monte Carlo simulation in generalized additive and semiparametric mixed models. Different types of covariates, such as the usual covariates with fixed effects, metrical covariates with non-linear effects, unstructured random effects, trend and seasonal components in longitudinal data and spatial covariates, are all treated within the same general framework by assigning appropriate Markov random field priors with different forms and degrees of smoothness. We applied the approach in several case-studies and consulting cases, showing that the methods are also computationally feasible in problems with many covariates and large data sets. In this paper, we choose two typical applications.     

Structural identification and variable selection in high-dimensional varying-coefficient models

Varying-coefficient models have been widely used to investigate the possible time-dependent effects of covariates when the response variable comes from normal distribution. Much progress has been made for inference and variable selection in the framework of such models. However, the identification of model structure, that is how to identify which covariates have time-varying effects and which have fixed effects, remains a challenging and unsolved problem especially when the dimension of covariates is much larger than the sample size. In this article, we consider the structural identification and variable selection problems in varying-coefficient models for high-dimensional data. Using a modified basis expansion approach and group variable selection methods, we propose a unified procedure to simultaneously identify the model structure, select important variables and estimate the coefficient curves. The unique feature of the proposed approach is that we do not have to specify the model structure in advance, therefore, it is more realistic and appropriate for real data analysis. Asymptotic properties of the proposed estimators have been derived under regular conditions. Furthermore, we evaluate the finite sample performance of the proposed methods with Monte Carlo simulation studies and a real data analysis.     

Regression Analysis of Longitudinal Data with Time‐Dependent Covariates and Informative Observation Times

Abstract. Longitudinal data frequently occur in many studies, and longitudinal responses may be correlated with observation times. In this paper, we propose a new joint modelling for the analysis of longitudinal data with time‐dependent covariates and possibly informative observation times via two latent variables. For inference about regression parameters, estimating equation approaches are developed and asymptotic properties of the proposed estimators are established. In addition, a lack‐of‐fit test is presented for assessing the adequacy of the model. The proposed method performs well in finite‐sample simulation studies, and an application to a bladder tumour study is provided.     

Ultrahigh-dimensional sufficient dimension reduction for censored data with measurement error in covariates

In this paper, we consider the ultrahigh-dimensional sufficient dimension reduction (SDR) for censored data and measurement error in covariates. We first propose the feature screening procedure based on censored data and the covariates subject to measurement error. With the suitable correction of mismeasurement, the error-contaminated variables detected by the proposed feature screening procedure are the same as the truly important variables. Based on the selected active variables, we develop the SDR method to estimate the central subspace and the structural dimension with both censored data and measurement error incorporated. The theoretical results of the proposed method are established. Simulation studies are reported to assess the performance of the proposed method. The proposed method is implemented to NKI breast cancer data.     

A class of accelerated means regression models for recurrent event data

In this article, we propose a general class of accelerated means regression models for recurrent event data. The class includes the proportional means model, the accelerated failure time model and the accelerated rates model as special cases. The new model offers great flexibility in formulating the effects of covariates on the mean functions of counting processes while leaving the stochastic structure completely unspecified. For the inference on the model parameters, estimating equation approaches are developed and both large and final sample properties of the proposed estimators are established. In addition, some graphical and numerical procedures are presented for model checking. An illustration with multiple-infection data from a clinic study on chronic granulomatous disease is also provided.     

Bayesian testing for independence of two categorical variables under two-stage cluster sampling with covariates

We consider Bayesian testing for independence of two categorical variables with covariates for a two-stage cluster sample. This is a difficult problem because we have a complex sample (i.e. cluster sample), not a simple random sample. Our approach is to convert the cluster sample with covariates into an equivalent simple random sample without covariates, which provides a surrogate of the original sample. Then, this surrogate sample is used to compute the Bayes factor to make an inference about independence. We apply our methodology to the data from the Trend in International Mathematics and Science Study [30] for fourth grade US students to assess the association between the mathematics and science scores represented as categorical variables. We show that if there is strong association between two categorical variables, there is no significant difference between the tests with and without the covariates. We also performed a simulation study to further understand the effect of covariates in various situations. We found that for borderline cases (moderate association between the two categorical variables), there are noticeable differences in the test with and without covariates.     

Asymptotics and bootstrap for random-effects panel data transformation models

This article investigates the asymptotic properties of quasi-maximum likelihood (QML) estimators for random-effects panel data transformation models where both the response and (some of) the covariates are subject to transformations for inducing normality, flexible functional form, homoskedasticity, and simple model structure. We develop a QML-type procedure for model estimation and inference. We prove the consistency and asymptotic normality of the QML estimators, and propose a simple bootstrap procedure that leads to a robust estimate of the variance-covariance (VC) matrix. Monte Carlo results reveal that the QML estimators perform well in finite samples, and that the gains by using the robust VC matrix estimate for inference can be enormous.     

Weighted composite quantile regression analysis for nonignorable missing data using nonresponse instrument

Efficient statistical inference on nonignorable missing data is a challenging problem. This paper proposes a new estimation procedure based on composite quantile regression (CQR) for linear regression models with nonignorable missing data, that is applicable even with high-dimensional covariates. A parametric model is assumed for modelling response probability, which is estimated by the empirical likelihood approach. Local identifiability of the proposed strategy is guaranteed on the basis of an instrumental variable approach. A set of data-based adaptive weights constructed via an empirical likelihood method is used to weight CQR functions. The proposed method is resistant to heavy-tailed errors or outliers in the response. An adaptive penalisation method for variable selection is proposed to achieve sparsity with high-dimensional covariates. Limiting distributions of the proposed estimators are derived. Simulation studies are conducted to investigate the finite sample performance of the proposed methodologies. An application to the ACTG 175 data is analysed.     

Instrumental variable-based empirical likelihood inferences for varying-coefficient models with error-prone covariates

This paper presents the empirical likelihood inferences for a class of varying-coefficient models with error-prone covariates. We focus on the case that the covariance matrix of the measurement errors is unknown and neither repeated measurements nor validation data are available. We propose an instrumental variable-based empirical likelihood inference method and show that the proposed empirical log-likelihood ratio is asymptotically chi-squared. Then, the confidence intervals for the varying-coefficient functions are constructed. Some simulation studies and a real data application are used to assess the finite sample performance of the proposed empirical likelihood procedure.     

Inference in generalized additive mixed modelsby using smoothing splines

Generalized additive mixed models are proposed for overdispersed and correlated data, which arise frequently in studies involving clustered, hierarchical and spatial designs. This class of models allows flexible functional dependence of an outcome variable on covariates by using nonparametric regression, while accounting for correlation between observations by using random effects. We estimate nonparametric functions by using smoothing splines and jointly estimate smoothing parameters and variance components by using marginal quasi-likelihood. Because numerical integration is often required by maximizing the objective functions, double penalized quasi-likelihood is proposed to make approximate inference. Frequentist and Bayesian inferences are compared. A key feature of the method proposed is that it allows us to make systematic inference on all model components within a unified parametric mixed model framework and can be easily implemented by fitting a working generalized linear mixed model by using existing statistical software. A bias correction procedure is also proposed to improve the performance of double penalized quasi-likelihood for sparse data. We illustrate the method with an application to infectious disease data and we evaluate its performance through simulation.     

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     

Failure time regression with continuous covariates measured with error

We consider failure time regression analysis with an auxiliary variable in the presence of a validation sample. We extend the nonparametric inference procedure of Zhou and Pepe to handle a continuous auxiliary or proxy covariate. We estimate the induced relative risk function with a kernel smoother and allow the selection probability of the validation set to depend on the observed covariates. We present some asymptotic properties for the kernel estimator and provide some simulation results. The method proposed is illustrated with a data set from an on-going epidemiologic study.     

Multi-type insurance claim processes with high-dimensional covariates

Multi-type insurance claim processes have attracted considerable research interest in the literature. The existing statistical inference for such processes, however, may encounter “curse of dimensionality” due to high-dimensional covariates. In this article, a technique of sufficient dimension reduction is applied to multiple-type insurance claim data, which uses a copula to model the dependence between different types of claim processes, and incorporates a one-dimensional frailty to fit the dependence of claims “within” the same claim process. A two-step procedure is proposed to estimate model parameters. The first step develops nonparametric estimators of the baseline, the basis of the central subspace and its dimension, and the regression function. Then the second step estimates the copula parameter. Simulations are performed to evaluate and confirm the theoretical results.