Marginal methods for clustered longitudinal binary data with incomplete covariates

Many analyses for incomplete longitudinal data are directed to examining the impact of covariates on the marginal mean responses. We consider the setting in which longitudinal responses are collected from individuals nested within clusters. We discuss methods for assessing covariate effects on the mean and association parameters when covariates are incompletely observed. Weighted first and second order estimating equations are constructed to obtain consistent estimates of mean and association parameters when covariates are missing at random. Empirical studies demonstrate that estimators from the proposed method have negligible finite sample biases in moderate samples. An application to the National Alzheimer's Coordinating Center (NACC) Uniform Data Set (UDS) demonstrates the utility of the proposed method.     

Identification of average marginal effects under misspecification when covariates are normal

A previously known result in the econometrics literature is that when covariates of an underlying data generating process are jointly normally distributed, estimates from a nonlinear model that is misspecified as linear can be interpreted as average marginal effects. This has been shown for models with exogenous covariates and separability between covariates and errors. In this paper, we extend this identification result to a variety of more general cases, in particular for combinations of separable and nonseparable models under both exogeneity and endogeneity. So long as the underlying model belongs to one of these large classes of data generating processes, our results show that nothing else must be known about the true DGP—beyond normality of observable data, a testable assumption—in order for linear estimators to be interpretable as average marginal effects. We use simulation to explore the performance of these estimators using a misspecified linear model and show they perform well when the data are normal but can perform poorly when this is not the case.     

Non-penalty shrinkage estimation of random effect models for longitudinal data with AR(1) errors

In this paper, we consider the non-penalty shrinkage estimation method of random effect models with autoregressive errors for longitudinal data when there are many covariates and some of them may not be active for the response variable. In observational studies, subjects are followed over equally or unequally spaced visits to determine the continuous response and whether the response is associated with the risk factors/covariates. Measurements from the same subject are usually more similar to each other and thus are correlated with each other but not with observations of other subjects. To analyse this data, we consider a linear model that contains both random effects across subjects and within-subject errors that follows autoregressive structure of order 1 (AR(1)). Considering the subject-specific random effect as a nuisance parameter, we use two competing models, one includes all the covariates and the other restricts the coefficients based on the auxiliary information. We consider the non-penalty shrinkage estimation strategy that shrinks the unrestricted estimator in the direction of the restricted estimator. We discuss the asymptotic properties of the shrinkage estimators using the notion of asymptotic biases and risks. A Monte Carlo simulation study is conducted to examine the relative performance of the shrinkage estimators with the unrestricted estimator when the shrinkage dimension exceeds two. We also numerically compare the performance of the shrinkage estimators to that of the LASSO estimator. A longitudinal CD4 cell count data set will be used to illustrate the usefulness of shrinkage and LASSO estimators.     

Inferences in dynamic logit models in semi-parametric setup for repeated binary data

Binary dynamic fixed and mixed logit models are extensively studied in the literature. These models are developed to examine the effects of certain fixed covariates through a parametric regression function as a part of the models. However, there are situations where one may like to consider more covariates in the model but their direct effect is not of interest. In this paper we propose a generalization of the existing binary dynamic logit (BDL) models to the semi-parametric longitudinal setup to address this issue of additional covariates. The regression function involved in such a semi-parametric BDL model contains (i) a parametric linear regression function in some primary covariates, and (ii) a non-parametric function in certain secondary covariates. We use a simple semi-parametric conditional quasi-likelihood approach for consistent estimation of the non-parametric function, and a semi-parametric likelihood approach for the joint estimation of the main regression and dynamic dependence parameters of the model. The finite sample performance of the estimation approaches is examined through a simulation study. The asymptotic properties of the estimators are also discussed. The proposed model and the estimation approaches are illustrated by reanalysing a longitudinal infectious disease data.     

Double robust estimation in longitudinal marginal structural models

In this article we consider estimation of causal parameters in a marginal structural model for the discrete intensity of the treatment specific counting process (e.g. hazard of a treatment specific survival time) based on longitudinal observational data on treatment, covariates and survival. We define three estimators: the inverse probability of treatment weighted (IPTW) estimator, the maximum likelihood estimator (MLE), and a double robust (DR) estimator. The DR estimator is obtained by following a general methodology for constructing double robust estimating functions in censored data models as described in van der Laan and Robins (Unified Methods for Censored Longitudinal Data and Causality, 2002). The double-robust estimator is consistent and asymptotically linear when either the treatment mechanism or the partial likelihood of the observed data is consistently estimated. We illustrate the superiority of the DR estimator relative to the IPTW and ML estimators in a simulation study. The proposed methodology is also applied to estimate the causal effect of exercise on physical functioning in a longitudinal study of seniors in Sonoma County.     

Local Linear Regression in Proportional Hazards Model with Censored Data

In this article we study the method of nonparametric regression based on a transformation model, under which an unknown transformation of the survival time is nonlinearly, even more, nonparametrically, related to the covariates with various error distributions, which are parametrically specified with unknown parameters. Local linear approximations and locally weighted least squares are applied to obtain estimators for the effects of covariates with censored observations. We show that the estimators are consistent and asymptotically normal. This transformation model, coupled with local linear approximation techniques, provides many alternatives to the more general proportional hazards models with nonparametric covariates.     

Omitted variables in longitudinal data models

The omission of important variables is a well‐known model specification issue in regression analysis and mixed linear models. The author considers longitudinal data models that are special cases of the mixed linear models; in particular, they are linear models of repeated observations on a subject. Models of omitted variables have origins in both the econometrics and biostatistics literatures. The author describes regression coefficient estimators that are robust to and that provide the basis for detecting the influence of certain types of omitted variables. New robust estimators and omitted variable tests are introduced and illustrated with a case study that investigates the determinants of tax liability.     

Modelling Survival Events with Longitudinal Covariates Measured with Error

In survival analysis, time-dependent covariates are usually present as longitudinal data collected periodically and measured with error. The longitudinal data can be assumed to follow a linear mixed effect model and Cox regression models may be used for modelling of survival events. The hazard rate of survival times depends on the underlying time-dependent covariate measured with error, which may be described by random effects. Most existing methods proposed for such models assume a parametric distribution assumption on the random effects and specify a normally distributed error term for the linear mixed effect model. These assumptions may not be always valid in practice. In this article, we propose a new likelihood method for Cox regression models with error-contaminated time-dependent covariates. The proposed method does not require any parametric distribution assumption on random effects and random errors. Asymptotic properties for parameter estimators are provided. Simulation results show that under certain situations the proposed methods are more efficient than the existing methods.     

ASYMPTOTIC PROPERTIES OF RESTRICTED MAXIMUM LIKELIHOOD (REML) ESTIMATES FOR HIERARCHICAL MIXED LINEAR MODELS

This paper explores the asymptotic distribution of the restricted maximum likelihood estimator of the variance components in a general mixed model. Restricting attention to hierarchical models, central limit theorems are obtained using elementary arguments with only mild conditions on the covariates in the fixed part of the model and without having to assume that the data are either normally or spherically symmetrically distributed. Further, the REML and maximum likelihood estimators are shown to be asymptotically equivalent in this general framework, and the asymptotic distribution of the weighted least squares estimator (based on the REML estimator) of the fixed effect parameters is derived.     

COVARIATE-ADJUSTED REGRESSION FOR LONGITUDINAL DATA INCORPORATING CORRELATION BETWEEN REPEATED MEASUREMENTS

We propose an estimation method that incorporates the correlation/covariance structure between repeated measurements in covariate-adjusted regression models for distorted longitudinal data. In this distorted data setting, neither the longitudinal response nor (possibly time-varying) predictors are directly observable. The unobserved response and predictors are assumed to be distorted/contaminated by unknown functions of a common observable confounder. The proposed estimation methodology adjusts for the distortion effects both in estimation of the covariance structure and in the regression parameters using generalized least squares. The finite-sample performance of the proposed estimators is studied numerically by means of simulations. The consistency and convergence rates of the proposed estimators are also established. The proposed method is illustrated with an application to data from a longitudinal study of cognitive and social development in children.     

SHRINKAGE, PRETEST AND ABSOLUTE PENALTY ESTIMATORS IN PARTIALLY LINEAR MODELS

We consider a partially linear model in which the vector of coefficients β in the linear part can be partitioned as ( β ₁, β ₂) , where β ₁ is the coefficient vector for main effects (e.g. treatment effect, genetic effects) and β ₂ is a vector for ‘nuisance’ effects (e.g. age, laboratory). In this situation, inference about β ₁ may benefit from moving the least squares estimate for the full model in the direction of the least squares estimate without the nuisance variables (Steinian shrinkage), or from dropping the nuisance variables if there is evidence that they do not provide useful information (pretesting). We investigate the asymptotic properties of Stein‐type and pretest semiparametric estimators under quadratic loss and show that, under general conditions, a Stein‐type semiparametric estimator improves on the full model conventional semiparametric least squares estimator. The relative performance of the estimators is examined using asymptotic analysis of quadratic risk functions and it is found that the Stein‐type estimator outperforms the full model estimator uniformly. By contrast, the pretest estimator dominates the least squares estimator only in a small part of the parameter space, which is consistent with the theory. We also consider an absolute penalty‐type estimator for partially linear models and give a Monte Carlo simulation comparison of shrinkage, pretest and the absolute penalty‐type estimators. The comparison shows that the shrinkage method performs better than the absolute penalty‐type estimation method when the dimension of the β ₂ parameter space is large.     

Semiparametric Time-Varying Coefficients Regression Model for Longitudinal Data

Abstract.  In this paper, we consider a semiparametric time-varying coefficients regression model where the influences of some covariates vary non-parametrically with time while the effects of the remaining covariates follow certain parametric functions of time. The weighted least squares type estimators for the unknown parameters of the parametric coefficient functions as well as the estimators for the non-parametric coefficient functions are developed. We show that the kernel smoothing that avoids modelling of the sampling times is asymptotically more efficient than a single nearest neighbour smoothing that depends on the estimation of the sampling model. The asymptotic optimal bandwidth is also derived. A hypothesis testing procedure is proposed to test whether some covariate effects follow certain parametric forms. Simulation studies are conducted to compare the finite sample performances of the kernel neighbourhood smoothing and the single nearest neighbour smoothing and to check the empirical sizes and powers of the proposed testing procedures. An application to a data set from an AIDS clinical trial study is provided for illustration.     

The Kalman Filter from the Perspective of Goldberger—Theil Estimators

This article is designed to point out the close connection between recursive estimation procedures, such as Kalman filter theory, familiar to control engineers, and linear least squares estimators and estimators that include prior information in the form of linear restrictions, such as mixed estimators and ridge estimators, familiar to statisticians. The only difference between the two points of view seems to be a difference in terminology. To demonstrate this point, it is shown how the Kalman filter equations can be derived from an existing textbook account of linear least squares theory and the notion of combining prior information in linear models, that is, the Goldberger—Theil mixed estimators' point of view. The author advocates the inclusion of these ideas early when least squares estimation concepts are being taught.     

Covariate adjustment and estimation of mean response in randomised trials

Analyses of randomised trials are often based on regression models which adjust for baseline covariates, in addition to randomised group. Based on such models, one can obtain estimates of the marginal mean outcome for the population under assignment to each treatment, by averaging the model‐based predictions across the empirical distribution of the baseline covariates in the trial. We identify under what conditions such estimates are consistent, and in particular show that for canonical generalised linear models, the resulting estimates are always consistent. We show that a recently proposed variance estimator underestimates the variance of the estimator around the true marginal population mean when the baseline covariates are not fixed in repeated sampling and provide a simple adjustment to remedy this. We also describe an alternative semiparametric estimator, which is consistent even when the outcome regression model used is misspecified. The different estimators are compared through simulations and application to a recently conducted trial in asthma.     

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.     

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.     

Semiparametric log-linear regression for longitudinal measurements subject to outcome-dependent follow-up

A common problem for longitudinal data analyses is that subjects follow-up is irregular, often related to the past outcome or other factors associated with the outcome measure that are not included in the regression model. Analyses unadjusted for outcome-dependent follow-up yield biased estimates. We propose a longitudinal data analysis that can provide consistent estimates in regression models that are subject to outcome-dependent follow-up. We focus on semiparametric marginal log-link regression with arbitrary unspecified baseline function. Based on estimating equations, the proposed class of estimators are root n consistent and asymptotically normal. We present simulation studies that assess the performance of the estimators under finite samples. We illustrate our approach using data from a health services research study.     

A Likelihood Based Estimating Equation for the Clayton–Oakes Model with Marginal Proportional Hazards

Multivariate failure time data arise when data consist of clusters in which the failure times may be dependent. A popular approach to such data is the marginal proportional hazards model with estimation under the working independence assumption. In this paper, we consider the Clayton–Oakes model with marginal proportional hazards and use the full model structure to improve on efficiency compared with the independence analysis. We derive a likelihood based estimating equation for the regression parameters as well as for the correlation parameter of the model. We give the large sample properties of the estimators arising from this estimating equation. Finally, we investigate the small sample properties of the estimators through Monte Carlo simulations.     

Additive–multiplicative rates model for recurrent events

Recurrent events are frequently encountered in biomedical studies. Evaluating the covariates effects on the marginal recurrent event rate is of practical interest. There are mainly two types of rate models for the recurrent event data: the multiplicative rates model and the additive rates model. We consider a more flexible additive–multiplicative rates model for analysis of recurrent event data, wherein some covariate effects are additive while others are multiplicative. We formulate estimating equations for estimating the regression parameters. The estimators for these regression parameters are shown to be consistent and asymptotically normally distributed under appropriate regularity conditions. Moreover, the estimator of the baseline mean function is proposed and its large sample properties are investigated. We also conduct simulation studies to evaluate the finite sample behavior of the proposed estimators. A medical study of patients with cystic fibrosis suffered from recurrent pulmonary exacerbations is provided for illustration of the proposed method.     

A Comparison of REML and Covariance Adjustment Method in the Estimation of Growth Curve Models

The classical growth curve model is considered when one continuous characteristic is measured at q time points. The covariance adjusted estimator of growth curve parameters is the OLS estimator adjusted using analysis of covariance. The covariates are obtained from functions of within individuals error contrasts. On the other hand, REML estimators emerge from maximization of the likelihood of OLS residuals. We compare the efficiency of estimators of growth curve parameters obtained by REML with that of covariance-adjusted least squares estimators with covariates selected via CAIC.