Analysis of longitudinal data with irregular, outcome-dependent follow-up

Summary.  A frequent problem in longitudinal studies is that subjects may miss scheduled visits or be assessed at self-selected points in time. As a result, observed outcome data may be highly unbalanced and the availability of the data may be directly related to the outcome measure and/or some auxiliary factors that are associated with the outcome. If the follow-up visit and outcome processes are correlated, then marginal regression analyses will produce biased estimates. Building on the work of Robins, Rotnitzky and Zhao, we propose a class of inverse intensity-of-visit process-weighted estimators in marginal regression models for longitudinal responses that may be observed in continuous time. This allows us to handle arbitrary patterns of missing data as embedded in a subject's visit process. We derive the large sample distribution for our inverse visit-intensity-weighted estimators and investigate their finite sample behaviour by simulation. Our approach is illustrated with a data set from a health services research study in which homeless people with mental illness were randomized to three different treatments and measures of homelessness (as percentage days homeless in the past 3 months) and other auxiliary factors were recorded at follow-up times that are not fixed by design.     

Application of an imputation method for variance estimation under pseudo-likelihood when missing data are NMAR

When data are outcome-dependent non response, pseudo-likelihood yields consistent regression coefficients without specifying the missing data mechanism. However, it is onerous to derive parameter estimators including their standard errors from the regression coefficients under pseudo-likelihood (PL). The present study applies an imputation method to compute the asymptotic standard errors of parameter estimators. The proposed method is simpler than Delta method and it showed similar effect size of the standard errors to bootstrapping in simulation and application studies.     

Variance Reduction in Smoothing Splines

Abstract.  We develop a variance reduction method for smoothing splines. For a given point of estimation, we define a variance-reduced spline estimate as a linear combination of classical spline estimates at three nearby points. We first develop a variance reduction method for spline estimators in univariate regression models. We then develop an analogous variance reduction method for spline estimators in clustered/longitudinal models. Simulation studies are performed which demonstrate the efficacy of our variance reduction methods in finite sample settings. Finally, a real data analysis with the motorcycle data set is performed. Here we consider variance estimation and generate 95% pointwise confidence intervals for the unknown regression function.     

Semiparametric analysis of longitudinal data with informative observation times and censoring times

We focus on regression analysis of irregularly observed longitudinal data which often occur in medical follow-up studies and observational investigations. The model for such data involves two processes: a longitudinal response process of interest and an observation process controlling observation times. Restrictive models and questionable assumptions, such as Poisson assumption and independent censoring time assumption, were posed in previous works for analysing longitudinal data. In this paper, we propose a more general model together with a robust estimation approach for longitudinal data with informative observation times and censoring times, and the asymptotic normalities of the proposed estimators are established. Both simulation studies and real data application indicate that the proposed method is promising.     

Estimation of exponential regression parameters using binary data

Exponential regression model is important in analyzing data from heterogeneous populations. In this paper we propose a simple method to estimate the regression parameters using binary data. Under certain design distributions, including ellipticaily symmetric distributions, for the explanatory variables, the estimators are shown to be consistent and asymptotically normal when sample size is large. For finite samples, the new estimates were shown to behave reasonably well. They are competitive with the maximum likelihood estimates and more importantly, according to our simulation results, the cost of CPU time for computing new estimates is only 1/7 of that required for computing the usual maximum likelihood estimates. We expect the savings in CPU time would be more dramatic with larger dimension of the regression parameter space.     

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.     

Estimation of regression parameters in generalized linear models for cluster correlated data with measurement error

Liang and Zeger (1986) introduced a class of estimating equations that gives consistent estimates of regression parameters and of their asymptotic variances in the class of generalized linear models for cluster correlated data. When the independent variables or covariates in such models are subject to measurement errors, the parameter estimates obtained from these estimating equations are no longer consistent. To correct for the effect of measurement errors, an estimator with smaller asymptotic bias is constructed along the lines of Stefanski (1985), assuming that the measurement error variance is either known or estimable. The asymptotic distribution of the bias-corrected estimator and a consistent estimator of its asymptotic variance are also given. The special case of a binary logistic regression model is studied in detail. For this case, methods based on conditional scores and quasilikelihood are also extended to cluster correlated data. Results of a small simulation study on the performance of the proposed estimators and associated tests of hypotheses are reported.     

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.     

ESTIMATION FOR THE GENERAL SAMPLE SELECTION MODELS

Consider a general regression model with an arbitrary and unknown link function and a stochastic selection variable that determines whether the outcome variable is observable or missing. The paper proposes U-statistics that are based on kernel functions as estimators for the directions of the parameter vectors in the link function and the selection equation, and shows that these estimators are consistent and asymptotically normal.     

Semiparametric statistical inferences for longitudinal data with nonparametric covariance modelling

In this paper, semiparametric modelling for longitudinal data with an unstructured error process is considered. We propose a partially linear additive regression model for longitudinal data in which within-subject variances and covariances of the error process are described by unknown univariate and bivariate functions, respectively. We provide an estimating approach in which polynomial splines are used to approximate the additive nonparametric components and the within-subject variance and covariance functions are estimated nonparametrically. Both the asymptotic normality of the resulting parametric component estimators and optimal convergence rate of the resulting nonparametric component estimators are established. In addition, we develop a variable selection procedure to identify significant parametric and nonparametric components simultaneously. We show that the proposed SCAD penalty-based estimators of non-zero components have an oracle property. Some simulation studies are conducted to examine the finite-sample performance of the proposed estimation and variable selection procedures. A real data set is also analysed to demonstrate the usefulness of the proposed method.     

Reducing bias in parameter estimates from stepwise regression in proportional hazards regression with right-censored data

When variable selection with stepwise regression and model fitting are conducted on the same data set, competition for inclusion in the model induces a selection bias in coefficient estimators away from zero. In proportional hazards regression with right-censored data, selection bias inflates the absolute value of parameter estimate of selected parameters, while the omission of other variables may shrink coefficients toward zero. This paper explores the extent of the bias in parameter estimates from stepwise proportional hazards regression and proposes a bootstrap method, similar to those proposed by Miller (Subset Selection in Regression, 2nd edn. Chapman & Hall/CRC, 2002) for linear regression, to correct for selection bias. We also use bootstrap methods to estimate the standard error of the adjusted estimators. Simulation results show that substantial biases could be present in uncorrected stepwise estimators and, for binary covariates, could exceed 250% of the true parameter value. The simulations also show that the conditional mean of the proposed bootstrap bias-corrected parameter estimator, given that a variable is selected, is moved closer to the unconditional mean of the standard partial likelihood estimator in the chosen model, and to the population value of the parameter. We also explore the effect of the adjustment on estimates of log relative risk, given the values of the covariates in a selected model. The proposed method is illustrated with data sets in primary biliary cirrhosis and in multiple myeloma from the Eastern Cooperative Oncology Group.     

Combining information from multiple surveys by using regression for efficient small domain estimation

Summary.  In sample surveys of finite populations, subpopulations for which the sample size is too small for estimation of adequate precision are referred to as small domains. Demand for small domain estimates has been growing in recent years among users of survey data. We explore the possibility of enhancing the precision of domain estimators by combining comparable information collected in multiple surveys of the same population. For this, we propose a regression method of estimation that is essentially an extended calibration procedure whereby comparable domain estimates from the various surveys are calibrated to each other. We show through analytic results and an empirical study that this method may greatly improve the precision of domain estimators for the variables that are common to these surveys, as these estimators make effective use of increased sample size for the common survey items. The design-based direct estimators proposed involve only domain-specific data on the variables of interest. This is in contrast with small domain (mostly small area) indirect estimators, based on a single survey, which incorporate through modelling data that are external to the targeted small domains. The approach proposed is also highly effective in handling the closely related problem of estimation for rare population characteristics.     

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.     

Logistic regression analysis of randomized response data with missing covariates

Randomized response is an interview technique designed to eliminate response bias when sensitive questions are asked. In this paper, we present a logistic regression model on randomized response data when the covariates on some subjects are missing at random. In particular, we propose Horvitz and Thompson (1952)-type weighted estimators by using different estimates of the selection probabilities. We present large sample theory for the proposed estimators and show that they are more efficient than the estimator using the true selection probabilities. Simulation results support theoretical analysis. We also illustrate the approach using data from a survey of cable TV.     

A two-stage procedure to pool information across quantile levels in linear quantile regression

In linear quantile regression, the regression coefficients for different quantiles are typically estimated separately. Efforts to improve the efficiency of estimators are often based on assumptions of commonality among the slope coefficients. We propose instead a two-stage procedure whereby the regression coefficients are first estimated separately and then smoothed over quantile level. Due to the strong correlation between coefficient estimates at nearby quantile levels, existing bandwidth selectors will pick bandwidths that are too small. To remedy this, we use 10-fold cross-validation to determine a common bandwidth inflation factor for smoothing the intercept as well as slope estimates. Simulation results suggest that the proposed method is effective in pooling information across quantile levels, resulting in estimates that are typically more efficient than the separately obtained estimates and the interquantile shrinkage estimates derived using a fused penalty function. The usefulness of the proposed method is demonstrated in a real data example.     

Monotone Nonparametric Regression and Confidence Intervals

Several variations of monotone nonparametric regression have been developed over the past 30 years. One approach is to first apply nonparametric regression to data and then monotone smooth the initial estimates to “iron out” violations to the assumed order. Here, such estimators are considered, where local polynomial regression is first used, followed by either least squares isotonic regression or a monotone method using simple averages. The primary focus of this work is to evaluate different types of confidence intervals for these monotone nonparametric regression estimators through Monte Carlo simulation. Most of the confidence intervals use bootstrap or jackknife procedures. Estimation of a response variable as a function of two continuous predictor variables is considered, where the estimation is performed at the observed values of the predictors (instead of on a grid). The methods are then applied to data involving subjects that worked at plants that use beryllium metal who have developed chronic beryllium disease.     

A semi-parametric cox’s regression model for zero-inflated left-censored time to event data

Abstract

In some clinical, environmental, or economical studies, researchers are interested in a semi-continuous outcome variable which takes the value zero with a discrete probability and has a continuous distribution for the non-zero values. Due to the measuring mechanism, it is not always possible to fully observe some outcomes, and only an upper bound is recorded. We call this left-censored data and observe only the maximum of the outcome and an independent censoring variable, together with an indicator. In this article, we introduce a mixture semi-parametric regression model. We consider a parametric model to investigate the influence of covariates on the discrete probability of the value zero. For the non-zero part of the outcome, a semi-parametric Cox’s regression model is used to study the conditional hazard function. The different parameters in this mixture model are estimated using a likelihood method. Hereby the infinite dimensional baseline hazard function is estimated by a step function. As results, we show the identifiability and the consistency of the estimators for the different parameters in the model. We study the finite sample behaviour of the estimators through a simulation study and illustrate this model on a practical data example.     

Empirical likelihood-based inference in nonlinear regression models with missing responses at random

This paper investigates the estimations of regression parameters and response mean in nonlinear regression models in the presence of missing response variables that are missing with missingness probabilities depending on covariates. We propose four empirical likelihood (EL)-based estimators for the regression parameters and the response mean. The resulting estimators are shown to be consistent and asymptotically normal under some general assumptions. To construct the confidence regions for the regression parameters as well as the response mean, we develop four EL ratio statistics, which are proven to have the χ² distribution asymptotically. Simulation studies and an artificial data set are used to illustrate the proposed methodologies. Empirical results show that the EL method behaves better than the normal approximation method and that the coverage probabilities and average lengths depend on the selection probability function.     

The Cox–Aalen model for left-truncated and right-censored data

We analyze left-truncated and right-censored (LTRC) data using an additive-multiplicative Cox–Aalen model proposed by Scheike and Zhang (2002), which extends the Cox regression model as well as the additive Aalen model. Based on the conditional likelihood function, we derive the weighted least-squared (WLS) estimators for the regression parameters and cumulative intensity functions of the model. The estimators are shown to be consistent and asymptotically normal. A simulation study is conducted to investigate the performance of the proposed estimators.     

Analysis of longitudinal health-related quality of life data with terminal events

Longitudinal health-related quality of life data arise naturally from studies of progressive and neurodegenerative diseases. In such studies, patients’ mental and physical conditions are measured over their follow-up periods and the resulting data are often complicated by subject-specific measurement times and possible terminal events associated with outcome variables. Motivated by the “Predictor’s Cohort” study on patients with advanced Alzheimer disease, we propose in this paper a semiparametric modeling approach to longitudinal health-related quality of life data. It builds upon and extends some recent developments for longitudinal data with irregular observation times. The new approach handles possibly dependent terminal events. It allows one to examine time-dependent covariate effects on the evolution of outcome variable and to assess nonparametrically change of outcome measurement that is due to factors not incorporated in the covariates. The usual large-sample properties for parameter estimation are established. In particular, it is shown that relevant parameter estimators are asymptotically normal and the asymptotic variances can be estimated consistently by the simple plug-in method. A general procedure for testing a specific parametric form in the nonparametric component is also developed. Simulation studies show that the proposed approach performs well for practical settings. The method is applied to the motivating example.