New perspective on the benefits of the gene–environment independence in case–control studies

We study the benefit of exploiting the gene–environment independence (GEI) assumption for inferring the joint effect of genotype and environmental exposure on disease risk in a case–control study. By transforming the problem into a constrained maximum likelihood estimation problem we derive the asymptotic distribution of the maximum likelihood estimator (MLE) under the GEI assumption (MLE‐GEI) in a closed form. Our approach uncovers a transparent explanation of the efficiency gained by exploiting the GEI assumption in more general settings, thus bridging an important gap in the existing literature. Moreover, we propose an easy‐to‐implement numerical algorithm for estimating the model parameters in practice. Finally, we conduct simulation studies to compare the proposed method with the traditional prospective logistic regression method and the case‐only estimator. The Canadian Journal of Statistics 47: 473–486; 2019 © 2019 Statistical Society of Canada     

ROBUST ESTIMATION OF SMALL‐AREA MEANS AND QUANTILES

Small‐area estimation techniques have typically relied on plug‐in estimation based on models containing random area effects. More recently, regression M‐quantiles have been suggested for this purpose, thus avoiding conventional Gaussian assumptions, as well as problems associated with the specification of random effects. However, the plug‐in M‐quantile estimator for the small‐area mean can be shown to be the expected value of this mean with respect to a generally biased estimator of the small‐area cumulative distribution function of the characteristic of interest. To correct this problem, we propose a general framework for robust small‐area estimation, based on representing a small‐area estimator as a functional of a predictor of this small‐area cumulative distribution function. Key advantages of this framework are that it naturally leads to integrated estimation of small‐area means and quantiles and is not restricted to M‐quantile models. We also discuss mean squared error estimation for the resulting estimators, and demonstrate the advantages of our approach through model‐based and design‐based simulations, with the latter using economic data collected in an Australian farm survey.     

Empirical Uncertain Bayes Methods in Area‐level Models

Random effects model can account for the lack of fitting a regression model and increase precision of estimating area‐level means. However, in case that the synthetic mean provides accurate estimates, the prior distribution may inflate an estimation error. Thus, it is desirable to consider the uncertain prior distribution, which is expressed as the mixture of a one‐point distribution and a proper prior distribution. In this paper, we develop an empirical Bayes approach for estimating area‐level means, using the uncertain prior distribution in the context of a natural exponential family, which we call the empirical uncertain Bayes (EUB) method. The regression model considered in this paper includes the Poisson‐gamma and the binomial‐beta, and the normal‐normal (Fay–Herriot) model, which are typically used in small area estimation. We obtain the estimators of hyperparameters based on the marginal likelihood by using a well‐known expectation‐maximization algorithm and propose the EUB estimators of area means. For risk evaluation of the EUB estimator, we derive a second‐order unbiased estimator of a conditional mean squared error by using some techniques of numerical calculation. Through simulation studies and real data applications, we evaluate a performance of the EUB estimator and compare it with the usual empirical Bayes estimator.     

One‐sample and two‐sample analysis of heterogeneous person–time data in clinical trials

In this paper, we investigate the performance of different parametric and nonparametric approaches for analyzing overdispersed person–time–event rates in the clinical trial setting. We show that the likelihood‐based parametric approach may not maintain the right size for the tested overdispersed person–time–event data. The nonparametric approaches may use an estimator as either the mean of the ratio of number of events over follow‐up time within each subjects or the ratio of the mean of the number of events over the mean follow‐up time in all the subjects. Among these, the ratio of the means is a consistent estimator and can be studied analytically. Asymptotic properties of all estimators were studied through numerical simulations. This research shows that the nonparametric ratio of the mean estimator is to be recommended in analyzing overdispersed person–time data. When sample size is small, some resampling‐based approaches can yield satisfactory results. Copyright © 2012 John Wiley & Sons, Ltd.     

Effect of assay measurement error on parameter estimation in concentration–QTc interval modeling

Linear mixed‐effects models (LMEMs) of concentration–double‐delta QTc intervals (QTc intervals corrected for placebo and baseline effects) assume that the concentration measurement error is negligible, which is an incorrect assumption. Previous studies have shown in linear models that independent variable error can attenuate the slope estimate with a corresponding increase in the intercept. Monte Carlo simulation was used to examine the impact of assay measurement error (AME) on the parameter estimates of an LMEM and nonlinear MEM (NMEM) concentration–ddQTc interval model from a ‘typical’ thorough QT study. For the LMEM, the type I error rate was unaffected by assay measurement error. Significant slope attenuation ( > 10%) occurred when the AME exceeded > 40% independent of the sample size. Increasing AME also decreased the between‐subject variance of the slope, increased the residual variance, and had no effect on the between‐subject variance of the intercept. For a typical analytical assay having an assay measurement error of less than 15%, the relative bias in the estimates of the model parameters and variance components was less than 15% in all cases. The NMEM appeared to be more robust to AME error as most parameters were unaffected by measurement error. Monte Carlo simulation was then used to determine whether the simulation–extrapolation method of parameter bias correction could be applied to cases of large AME in LMEMs. For analytical assays with large AME ( > 30%), the simulation–extrapolation method could correct biased model parameter estimates to near‐unbiased levels. Copyright © 2013 John Wiley & Sons, Ltd.     

Empirical Likelihood Intervals for Conditional Value‐at‐Risk in Heteroscedastic Regression Models

Abstract. Non‐parametric regression models have been studied well including estimating the conditional mean function, the conditional variance function and the distribution function of errors. In addition, empirical likelihood methods have been proposed to construct confidence intervals for the conditional mean and variance. Motivated by applications in risk management, we propose an empirical likelihood method for constructing a confidence interval for the pth conditional value‐at‐risk based on the non‐parametric regression model. A simulation study shows the advantages of the proposed method.     

Regression analysis for a summed missing data problem under an outcome‐dependent sampling scheme

In this paper, we consider a regression analysis for a missing data problem in which the variables of primary interest are unobserved under a general biased sampling scheme, an outcome‐dependent sampling (ODS) design. We propose a semiparametric empirical likelihood method for accessing the association between a continuous outcome response and unobservable interesting factors. Simulation study results show that ODS design can produce more efficient estimators than the simple random design of the same sample size. We demonstrate the proposed approach with a data set from an environmental study for the genetic effects on human lung function in COPD smokers. The Canadian Journal of Statistics 40: 282–303; 2012 © 2012 Statistical Society of Canada     

Focused Information Criterion for Capture–Recapture Models for Closed Populations

Abstract. We propose a criterion for selecting a capture–recapture model for closed populations, which follows the basic idea of the focused information criterion (FIC) of Claeskens and Hjort. The proposed criterion aims at selecting the model which, among the available models, leads to the smallest mean‐squared error (MSE) of the resulting estimator of the population size and is based on an index which, up to a constant term, is equal to the asymptotic MSE of the estimator. Two alternative approaches to estimate this FIC index are proposed. We also deal with multimodel inference; in this case, the population size is estimated by using a weighted average of the estimates coming from different models, with weights chosen so as to minimize the MSE of the resulting estimator. The proposed model selection approach is compared with more common approaches through a series of simulations. It is also illustrated by an application based on a dataset coming from a live‐trapping experiment.     

Bias‐reduced marginal Akaike information criteria based on a Monte Carlo method for linear mixed‐effects models

In linear mixed‐effects (LME) models, if a fitted model has more random‐effect terms than the true model, a regularity condition required in the asymptotic theory may not hold. In such cases, the marginal Akaike information criterion (AIC) is positively biased for (?2) times the expected log‐likelihood. The asymptotic bias of the maximum log‐likelihood as an estimator of the expected log‐likelihood is evaluated for LME models with balanced design in the context of parameter‐constrained models. Moreover, bias‐reduced marginal AICs for LME models based on a Monte Carlo method are proposed. The performance of the proposed criteria is compared with existing criteria by using example data and by a simulation study. It was found that the bias of the proposed criteria was smaller than that of the existing marginal AIC when a larger model was fitted and that the probability of choosing a smaller model incorrectly was decreased.     

Testing for violations of the homogeneity needed for conditional logistic regression

In epidemiologic studies where the outcome is binary, the data often arise as clusters, as when siblings, friends or neighbors are used as matched controls in a case-control study. Conditional logistic regression (CLR) is typically used for such studies to estimate the odds ratio for an exposure of interest. However, CLR assumes the exposure coefficient is the same in every cluster, and CLR-based inference can be badly biased when homogeneity is violated. Existing methods for testing goodness-of-fit for CLR are not designed to detect such violations. Good alternative methods of analysis exist if one suspects there is heterogeneity across clusters. However, routine use of alternative robust approaches when there is no appreciable heterogeneity could cause loss of precision and be computationally difficult, particularly if the clusters are small. We propose a simple non-parametric test, the test of heterogeneous susceptibility (THS), to assess the assumption of homogeneity of a coefficient across clusters. The test is easy to apply and provides guidance as to the appropriate method of analysis. Simulations demonstrate that the THS has reasonable power to reveal violations of homogeneity. We illustrate by applying the THS to a study of periodontal disease.     

Some solutions to the multivariate Behrens–Fisher problem for dissimilarity‐based analyses

The essence of the generalised multivariate Behrens–Fisher problem (BFP) is how to test the null hypothesis of equality of mean vectors for two or more populations when their dispersion matrices differ. Solutions to the BFP usually assume variables are multivariate normal and do not handle high‐dimensional data. In ecology, species' count data are often high‐dimensional, non‐normal and heterogeneous. Also, interest lies in analysing compositional dissimilarities among whole communities in non‐Euclidean (semi‐metric or non‐metric) multivariate space. Hence, dissimilarity‐based tests by permutation (e.g., PERMANOVA, ANOSIM) are used to detect differences among groups of multivariate samples. Such tests are not robust, however, to heterogeneity of dispersions in the space of the chosen dissimilarity measure, most conspicuously for unbalanced designs. Here, we propose a modification to the PERMANOVA test statistic, coupled with either permutation or bootstrap resampling methods, as a solution to the BFP for dissimilarity‐based tests. Empirical simulations demonstrate that the type I error remains close to nominal significance levels under classical scenarios known to cause problems for the un‐modified test. Furthermore, the permutation approach is found to be more powerful than the (more conservative) bootstrap for detecting changes in community structure for real ecological datasets. The utility of the approach is shown through analysis of 809 species of benthic soft‐sediment invertebrates from 101 sites in five areas spanning 1960 km along the Norwegian continental shelf, based on the Jaccard dissimilarity measure.     

SIMEX method for censored quantile regression with measurement error

Censored quantile regression serves as an important supplement to the Cox proportional hazards model in survival analysis. In addition to being exposed to censoring, some covariates may subject to measurement error. This leads to substantially biased estimate without taking this error into account. The SIMulation-EXtrapolation (SIMEX) method is an effective tool to handle the measurement error issue. We extend the SIMEX approach to the censored quantile regression with covariate measurement error. The algorithm is assessed via extensive simulations. A lung cancer study is analyzed to verify the validation of the proposed method.     

Generalised quasi‐likelihood inference in a semi‐parametric binary dynamic mixed logit model

There exists a recent study where dynamic mixed‐effects regression models for count data have been extended to a semi‐parametric context. However, when one deals with other discrete data such as binary responses, the results based on count data models are not directly applicable. In this paper, we therefore begin with existing binary dynamic mixed models and generalise them to the semi‐parametric context. For inference, we use a new semi‐parametric conditional quasi‐likelihood (SCQL) approach for the estimation of the non‐parametric function involved in the semi‐parametric model, and a semi‐parametric generalised quasi‐likelihood (SGQL) approach for the estimation of the main regression, dynamic dependence and random effects variance parameters. A semi‐parametric maximum likelihood (SML) approach is also used as a comparison to the SGQL approach. The properties of the estimators are examined both asymptotically and empirically. More specifically, the consistency of the estimators is established and finite sample performances of the estimators are examined through an intensive simulation study.     

On a Unified Generalized Quasi–likelihood Approach for Familial–Longitudinal Non‐Stationary Count Data

Abstract. In this paper, conditional on random family effects, we consider an auto‐regression model for repeated count data and their corresponding time‐dependent covariates, collected from the members of a large number of independent families. The count responses, in such a set up, unconditionally exhibit a non‐stationary familial–longitudinal correlation structure. We then take this two‐way correlation structure into account, and develop a generalized quasilikelihood (GQL) approach for the estimation of the regression effects and the familial correlation index parameter, whereas the longitudinal correlation parameter is estimated by using the well‐known method of moments. The performance of the proposed estimation approach is examined through a simulation study. Some model mis‐specification effects are also studied. The estimation methodology is illustrated by analysing real life healthcare utilization count data collected from 36 families of size four over a period of 4 years.     

Inference on Survival Data with Covariate Measurement Error – An Imputation-based Approach

Abstract.  We propose a new method for fitting proportional hazards models with error-prone covariates. Regression coefficients are estimated by solving an estimating equation that is the average of the partial likelihood scores based on imputed true covariates. For the purpose of imputation, a linear spline model is assumed on the baseline hazard. We discuss consistency and asymptotic normality of the resulting estimators, and propose a stochastic approximation scheme to obtain the estimates. The algorithm is easy to implement, and reduces to the ordinary Cox partial likelihood approach when the measurement error has a degenerate distribution. Simulations indicate high efficiency and robustness. We consider the special case where error-prone replicates are available on the unobserved true covariates. As expected, increasing the number of replicates for the unobserved covariates increases efficiency and reduces bias. We illustrate the practical utility of the proposed method with an Eastern Cooperative Oncology Group clinical trial where a genetic marker, c- myc expression level, is subject to measurement error.     

Non‐parametric Bayesian Hazard Regression for Chronic Disease Risk Assessment

Assessing the absolute risk for a future disease event in presently healthy individuals has an important role in the primary prevention of cardiovascular diseases (CVD) and other chronic conditions. In this paper, we study the use of non‐parametric Bayesian hazard regression techniques and posterior predictive inferences in the risk assessment task. We generalize our previously published Bayesian multivariate monotonic regression procedure to a survival analysis setting, combined with a computationally efficient estimation procedure utilizing case–base sampling. To achieve parsimony in the model fit, we allow for multidimensional relationships within specified subsets of risk factors, determined either on a priori basis or as a part of the estimation procedure. We apply the proposed methods for 10‐year CVD risk assessment in a Finnish population. © 2014 Board of the Foundation of the Scandinavian Journal of Statistics     

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     

Testing Monotonicity of Regression Functions – An Empirical Process Approach

We propose several new tests for monotonicity of regression functions based on different empirical processes of residuals and pseudo‐residuals. The residuals are obtained from an unconstrained kernel regression estimator whereas the pseudo‐residuals are obtained from an increasing regression estimator. Here, in particular, we consider a recently developed simple kernel‐based estimator for increasing regression functions based on increasing rearrangements of unconstrained non‐parametric estimators. The test statistics are estimated distance measures between the regression function and its increasing rearrangement. We discuss the asymptotic distributions, consistency and small sample performances of the tests.     

When exposure is subject to nondifferential misclassification,are validation data helpful in testing for an exposure–disease association?

Consider assessing the evidence for an exposure variable and a disease variable being associated, when the true exposure variable is more costly to obtain than an error‐prone but nondifferential surrogate exposure variable. From a study design perspective, there are choices regarding the best use of limited resources. Should one acquire the true exposure status for fewer subjects or the surrogate exposure status for more subjects? The issue of validation is also central, i.e., should we simultaneously measure the true and surrogate exposure variables on a subset of study subjects? Using large‐sample theory, we provide a framework for quantifying the power of testing for an exposure–disease association as a function of study cost. This enables us to present comparisons of different study designs under different suppositions about both the relative cost and the performance (sensitivity and specificity) of the surrogate variable. We present simulations to show the applicability of our theoretical framework, and we provide a case‐study comparing results from an actual study to what could have been seen had true exposure status been ascertained for a different proportion of study subjects. We also describe an extension of our ideas to a more complex situation involving covariates. The Canadian Journal of Statistics 47: 222–237; 2019 © 2019 Statistical Society of Canada     

Adjusting regression attenuation in the Cox proportional hazards model

In the measurement error Cox proportional hazards model, the naive maximum partial likelihood estimator (MPLE) is asymptotically biased. In this paper, we give the formula of the asymptotic bias for the additive measurement error Cox model. By adjusting for this error, we derive an adjusted MPLE that is less biased. The bias can be further reduced by adjusting for the estimator second and even third time. This estimator has the advantage of being easy to apply. The performance of the proposed estimator is evaluated through a simulation study.