Trend analysis with response incompatible formats and measurement error

The increasing popularity of longitudinal studies, along with the rapid advances in science and technology, has created a potential incompatibility between data formats, which leads to an inference problem when applying conventional statistical methods. This inference problem is further compounded by measurement error, since incompatible data format often arise in the context of measuring latent constructs. Without a systematic study of the impact of scale differences, ad-hoc approaches generally lead to inconsistent estimates and thus, invalid statistical inferences. In this paper, we examine the asymptotic properties and identify conditions that guarantee consistent estimation within the context of a trend analysis with response incompatible formats and measurement error. For model estimation, we introduce two competing methods that use a generalized estimating equation approach to provide inferences for the parameters of interest, and highlight the relative strengths of each method. The approach is illustrated by data obtained from a multi-centre AIDS cohort study (MACS), where a trend analysis of an immunologic marker of HIV infection is of interest.     

Data recycling: a response to the changing technology from the statistical perspective with application to psychiatric sleep research

Rapid technological advances have resulted in continual changes in data acquisition and reporting processes. While such advances have benefited research in these areas, the changing technologies have, at the same time, created difficulty for statistical analysis by generating outdated data which are incompatible with data based on newer technology. Relationships between these incompatible variables are complicated; not only they are stochastic, but also often depend on other variables, rendering even a simple statistical analysis, such as estimation of a population mean, difficult in the presence of mixed data formats. Thus, technological advancement has brought forth, from the statistical perspective, a methodological problem of the analysis of newer data with outdated data. In this paper, we discuss general principles for addressing the statistical issues related to the analysis of incompatible data. The approach taken to the task at hand has three desirable properties, it is readily understood, since it builds upon a linear regression setting, it is flexible to allow for data incompatibility in either the response or covariate, and it is not computationally intensive. In addition, inferences may be made for a latent variable of interest. Our considerations to this problem are motivated by the analysis of delta wave counts, as a surrogate for sleep disorder, in the sleep laboratory of the Department of Psychiatry, University of Pittsburgh Medical Center, where two major changes had occurred in the acquisition of this data, resulting in three mixed formats. By developing appropriate methods for addressing this issue, we provide statistical advancement that is compatible with technological advancement.     

A new class of measurement-error models,with applications to dietary data

Measurement-error modelling occurs when one cannot observe a covariate, but instead has possibly replicated surrogate versions of this covariate measured with error. The vast majority of the literature in measurement-error modelling assumes (typically with good reason) that given the value of the true but unobserved (latent) covariate, the replicated surrogates are unbiased for latent covariate and conditionally independent. In the area of nutritional epidemiology, there is some evidence from biomarker studies that this simple conditional independence model may break down due to two causes: (a) systematic biases depending on a person's body mass index, and (b) an additional random component of bias, so that the error structure is the same as a one-way random-effects model. We investigate this problem in the context of (1) estimating distribution of usual nutrient intake, (2) estimating the correlation between a nutrient instrument and usual nutrient intake, and (3) estimating the true relative risk from an estimated relative risk using the error-prone covariate. While systematic bias due to body mass index appears to have little effect, the additional random effect in the variance structure is shown to have a potentially important effect on overall results, both on corrections for relative risk estimates and in estimating the distribution of usual nutrient intake. However, the effect of dietary measurement error on both factors is shown via examples to depend strongly on the data set being used. Indeed, one of our data sets suggests that dietary measurement error may be masking a strong risk of fat on breast cancer, while for a second data set this masking is not so clear. Until further understanding of dietary measurement is available, measurement-error corrections must be done on a study-specific basis, sensitivity analyses should be conducted, and even then results of nutritional epidemiology studies relating diet to disease risk should be interpreted cautiously.     

Estimation with unbalanced panel data having covariate measurement error

Panel data with covariate measurement error appear frequently in various studies. Due to the sampling design and/or missing data, panel data are often unbalanced in the sense that panels have different sizes. For balanced panel data (i.e., panels having the same size), there exists a generalized method of moments (GMM) approach for adjusting covariate measurement error, which does not require additional validation data. This paper extends the GMM approach of adjusting covariate measurement error to unbalanced panel data. Two health related longitudinal surveys are used to illustrate the implementation of the proposed method.     

Correcting data for measurement error in generalized linear models

This paper discusses a general strategy for reducing measurement-error-induced bias in statistical models. It is assumed that the measurement error is unbiased with a known variance although no other distributional assumptions on the measurement-error are employed,

Using a preliminary fit of the model to the observed data, a transformation of the variable measured with error is estimated. The transformation is constructed so that the estimates obtained by refitting the model to the ‘corrected’ data have smaller bias,

Whereas the general strategy can be applied in a number of settings, this paper focuses on the problem of covariate measurement error in generalized linear models, Two estimators are derived and their effectiveness at reducing bias is demonstrated in a Monte Carlo study.     

Estimation and Prediction in the Presence of Spatial Confounding for Spatial Linear Models

In studies that produce data with spatial structure, it is common that covariates of interest vary spatially in addition to the error. Because of this, the error and covariate are often correlated. When this occurs, it is difficult to distinguish the covariate effect from residual spatial variation. In an i.i.d. normal error setting, it is well known that this type of correlation produces biased coefficient estimates, but predictions remain unbiased. In a spatial setting, recent studies have shown that coefficient estimates remain biased, but spatial prediction has not been addressed. The purpose of this paper is to provide a more detailed study of coefficient estimation from spatial models when covariate and error are correlated and then begin a formal study regarding spatial prediction. This is carried out by investigating properties of the generalized least squares estimator and the best linear unbiased predictor when a spatial random effect and a covariate are jointly modelled. Under this setup, we demonstrate that the mean squared prediction error is possibly reduced when covariate and error are correlated.     

Latent Variable Models for Mixed Discrete and Continuous Outcomes

We propose a latent variable model for mixed discrete and continuous outcomes. The model accommodates any mixture of outcomes from an exponential family and allows for arbitrary covariate effects, as well as direct modelling of covariates on the latent variable. An EM algorithm is proposed for parameter estimation and estimates of the latent variables are produced as a by-product of the analysis. A generalized likelihood ratio test can be used to test the significance of covariates affecting the latent outcomes. This method is applied to birth defects data, where the outcomes of interest are continuous measures of size and binary indicators of minor physical anomalies. Infants who were exposed in utero to anticonvulsant medications are compared with controls.     

Cox regression for mixed case interval-censored data with covariate errors

Covariate measurement error problems have been extensively studied in the context of right-censored data but less so for interval-censored data. Motivated by the AIDS Clinical Trial Group 175 study, where the occurrence time of AIDS was examined only at intermittent clinic visits and the baseline covariate CD4 count was measured with error, we describe a semiparametric maximum likelihood method for analyzing mixed case interval-censored data with mismeasured covariates under the proportional hazards model. We show that the estimator of the regression coefficient is asymptotically normal and efficient and provide a very stable and efficient algorithm for computing the estimators. We evaluate the method through simulation studies and illustrate it with AIDS data.     

Errors-in-Variables Regression Using Stein Estimates

A method is proposed for estimating regression parameters from data containing covariate measurement errors by using Stein estimates of the unobserved true covariates. The method produces consistent estimates for the slope parameter in the classical linear errors-in-variables model and applies to a broad range of nonlinear regression problems, provided the measurement error is Gaussian with known variance. Simulations are used to examine the performance of the estimates in a nonlinear regression problem and to compare them with the usual naive ones obtained by ignoring error and with other estimates proposed recently in the literature.     

Estimation of group means when adjusting for covariates in generalized linear models

Generalized linear models are commonly used to analyze categorical data such as binary, count, and ordinal outcomes. Adjusting for important prognostic factors or baseline covariates in generalized linear models may improve the estimation efficiency. The model‐based mean for a treatment group produced by most software packages estimates the response at the mean covariate, not the mean response for this treatment group for the studied population. Although this is not an issue for linear models, the model‐based group mean estimates in generalized linear models could be seriously biased for the true group means. We propose a new method to estimate the group mean consistently with the corresponding variance estimation. Simulation showed the proposed method produces an unbiased estimator for the group means and provided the correct coverage probability. The proposed method was applied to analyze hypoglycemia data from clinical trials in diabetes. Copyright © 2014 John Wiley & Sons, Ltd.     

Spatial measurement error in infectious disease models

Individual-level models (ILMs) for infectious disease can be used to model disease spread between individuals while taking into account important covariates. One important covariate in determining the risk of infection transfer can be spatial location. At the same time, measurement error is a concern in many areas of statistical analysis, and infectious disease modelling is no exception. In this paper, we are concerned with the issue of measurement error in the recorded location of individuals when using a simple spatial ILM to model the spread of disease within a population. An ILM that incorporates spatial location random effects is introduced within a hierarchical Bayesian framework. This model is tested upon both simulated data and data from the UK 2001 foot-and-mouth disease epidemic. The ability of the model to successfully identify both the spatial infection kernel and the basic reproduction number (R ₀) of the disease is tested.     

Survival trees with time-dependent covariates: Application to estimating changes in the incubation period of AIDS

Tree-structured methods for exploratory data analysis have previously been extended to right-censored survival data. We further extend these methods to allow for truncation and time-dependent covariates. We apply the new methods to a data set on incubation times of acquired immunodeficiency syndrome (AIDS), using calendar time as a time-dependent covariate. Contrary to expectation, we find that rates of progression to AIDS appear to be faster after August 1989 than before.     

A Better Alternative to Non-parametric Approaches for Adjusting for Covariate Measurement Errors in Logistic Regression

In this article, we propose a flexible parametric (FP) approach for adjusting for covariate measurement errors in regression that can accommodate replicated measurements on the surrogate (mismeasured) version of the unobserved true covariate on all the study subjects or on a sub-sample of the study subjects as error assessment data. We utilize the general framework of the FP approach proposed by Hossain and Gustafson in 2009 for adjusting for covariate measurement errors in regression. The FP approach is then compared with the existing non-parametric approaches when error assessment data are available on the entire sample of the study subjects (complete error assessment data) considering covariate measurement error in a multiple logistic regression model. We also developed the FP approach when error assessment data are available on a sub-sample of the study subjects (partial error assessment data) and investigated its performance using both simulated and real life data. Simulation results reveal that, in comparable situations, the FP approach performs as good as or better than the competing non-parametric approaches in eliminating the bias that arises in the estimated regression parameters due to covariate measurement errors. Also, it results in better efficiency of the estimated parameters. Finally, the FP approach is found to perform adequately well in terms of bias correction, confidence coverage, and in achieving appropriate statistical power under partial error assessment data.     

To adjust or not to adjust for baseline when analyzing repeated binary responses? The case of complete data when treatment comparison at study end is of interest

The benefits of adjusting for baseline covariates are not as straightforward with repeated binary responses as with continuous response variables. Therefore, in this study, we compared different methods for analyzing repeated binary data through simulations when the outcome at the study endpoint is of interest. Methods compared included chi‐square, Fisher's exact test, covariate adjusted/unadjusted logistic regression (Adj.logit/Unadj.logit), covariate adjusted/unadjusted generalized estimating equations (Adj.GEE/Unadj.GEE), covariate adjusted/unadjusted generalized linear mixed model (Adj.GLMM/Unadj.GLMM). All these methods preserved the type I error close to the nominal level. Covariate adjusted methods improved power compared with the unadjusted methods because of the increased treatment effect estimates, especially when the correlation between the baseline and outcome was strong, even though there was an apparent increase in standard errors. Results of the Chi‐squared test were identical to those for the unadjusted logistic regression. Fisher's exact test was the most conservative test regarding the type I error rate and also with the lowest power. Without missing data, there was no gain in using a repeated measures approach over a simple logistic regression at the final time point. Analysis of results from five phase III diabetes trials of the same compound was consistent with the simulation findings. Therefore, covariate adjusted analysis is recommended for repeated binary data when the study endpoint is of interest. Copyright © 2015 John Wiley & Sons, Ltd.     

Using structural equation modelling to detect measurement bias and response shift in longitudinal data

We propose a three step procedure to investigate measurement bias and response shift, a special case of measurement bias in longitudinal data. Structural equation modelling is used in each of the three steps, which can be described as (1) establishing a measurement model using confirmatory factor analysis, (2) detecting measurement bias by testing the equivalence of model parameters across measurement occasions, (3) detecting measurement bias with respect to additional exogenous variables by testing their direct effects on the indicator variables. The resulting model can be used to investigate true change in the attributes of interest, by testing changes in common factor means. Solutions for the issue of constraint interaction and for chance capitalisation in model specification searches are discussed as part of the procedure. The procedure is illustrated by applying it to longitudinal health-related quality-of-life data of HIV/AIDS patients, collected at four semi-annual measurement occasions.     

A joint-modeling approach to assess the impact of biomarker variability on the risk of developing clinical outcome

In some clinical trials and epidemiologic studies, investigators are interested in knowing whether the variability of a biomarker is independently predictive of clinical outcomes. This question is often addressed via a naïve approach where a sample-based estimate (e.g., standard deviation) is calculated as a surrogate for the “true” variability and then used in regression models as a covariate assumed to be free of measurement error. However, it is well known that the measurement error in covariates causes underestimation of the true association. The issue of underestimation can be substantial when the precision is low because of limited number of measures per subject. The joint analysis of survival data and longitudinal data enables one to account for the measurement error in longitudinal data and has received substantial attention in recent years. In this paper we propose a joint model to assess the predictive effect of biomarker variability. The joint model consists of two linked sub-models, a linear mixed model with patient-specific variance for longitudinal data and a full parametric Weibull distribution for survival data, and the association between two models is induced by a latent Gaussian process. Parameters in the joint model are estimated under Bayesian framework and implemented using Markov chain Monte Carlo (MCMC) methods with WinBUGS software. The method is illustrated in the Ocular Hypertension Treatment Study to assess whether the variability of intraocular pressure is an independent risk of primary open-angle glaucoma. The performance of the method is also assessed by simulation studies.     

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.     

A comparison of regression calibration approaches for designs with internal validation data

We compare the asymptotic relative efficiency of several regression calibration methods of correcting for measurement error in studies with internal validation data, when a single covariate is measured with error. The estimators we consider are appropriate in main study/hybrid validation study designs, where the latter study includes internal validation and may include external validation data. Although all of the methods we consider produce consistent estimates, the method proposed by Spiegelman et al. (Statistics in Medicine, 20 (2001) 139) has an asymptotically smaller variance than the other methods. The methods for measurement error correction are illustrated using a study of the effect of in utero lead exposure on infant birth weight.     

Analysis of ordinal outcomes with longitudinal covariates subject to missingness

We propose a mixture model for data with an ordinal outcome and a longitudinal covariate that is subject to missingness. Data from a tailored telephone delivered, smoking cessation intervention for construction laborers are used to illustrate the method, which considers as an outcome a categorical measure of smoking cessation, and evaluates the effectiveness of the motivational telephone interviews on this outcome. We propose two model structures for the longitudinal covariate, for the case when the missing data are missing at random, and when the missing data mechanism is non-ignorable. A generalized EM algorithm is used to obtain maximum likelihood estimates.