Generalized linear models with covariate measurement error and unknown link function

Generalized linear models (GLMs) with error-in-covariates are useful in epidemiological research due to the ubiquity of non-normal response variables and inaccurate measurements. The link function in GLMs is chosen by the user depending on the type of response variable, frequently the canonical link function. When covariates are measured with error, incorrect inference can be made, compounded by incorrect choice of link function. In this article we propose three flexible approaches for handling error-in-covariates and estimating an unknown link simultaneously. The first approach uses a fully Bayesian (FB) hierarchical framework, treating the unobserved covariate as a latent variable to be integrated over. The second and third are approximate Bayesian approach which use a Laplace approximation to marginalize the variables measured with error out of the likelihood. Our simulation results show support that the FB approach is often a better choice than the approximate Bayesian approaches for adjusting for measurement error, particularly when the measurement error distribution is misspecified. These approaches are demonstrated on an application with binary response.     

A recommended analysis for 2 × 2 crossover trials with baseline measurements

In many two‐period, two‐treatment (2 × 2) crossover trials, for each subject, a continuous response of interest is measured before and after administration of the assigned treatment within each period. The resulting data are typically used to test a null hypothesis involving the true difference in treatment response means. We show that the power achieved by different statistical approaches is greatly influenced by (i) the ‘structure’ of the variance–covariance matrix of the vector of within‐subject responses and (ii) how the baseline (i.e., pre‐treatment) responses are accounted for in the analysis. For (ii), we compare different approaches including ignoring one or both period baselines, using a common change from baseline analysis (which we advise against), using functions of one or both baselines as period‐specific or period‐invariant covariates, and doing joint modeling of the post‐baseline and baseline responses with corresponding mean constraints for the latter. Based on theoretical arguments and simulation‐based type I error rate and power properties, we recommend an analysis of covariance approach that uses the within‐subject difference in treatment responses as the dependent variable and the corresponding difference in baseline responses as a covariate. Data from three clinical trials are used to illustrate the main points. Copyright © 2014 John Wiley & Sons, Ltd.     

Semi-parametric extended Poisson process models for count data

A general framework for the analysis of count data (with covariates) is proposed using formulations for the transition rates of a state-dependent birth process. The form for the transition rates incorporates covariates proportionally, with the residual distribution determined from a smooth non-parametric state-dependent form. Computation of the resulting probabilities is discussed, leading to model estimation using a penalized likelihood function. Two data sets are used as illustrative examples, one representing underdispersed Poisson-like data and the other overdispersed binomial-like data.     

Covariate adjustment for randomized controlled trials revisited

Covariate adjustment for the estimation of treatment effect for randomized controlled trials (RCT) is a simple approach with a long history, hence, its pros and cons have been well‐investigated and published in the literature. It is worthwhile to revisit this topic since recently there has been significant investigation and development on model assumptions, robustness to model mis‐specification, in particular, regarding the Neyman‐Rubin model and the average treatment effect estimand. This paper discusses key results of the investigation and development and their practical implication on pharmaceutical statistics. Accordingly, we recommend that appropriate covariate adjustment should be more widely used for RCTs for both hypothesis testing and estimation.     

A Logspline Estimation for a Linear Regression Model with an Interval-Censored Continuous Covariate

The study of a linear regression model with an interval-censored covariate, which was motivated by an acquired immunodeficiency syndrome (AIDS) clinical trial, was first proposed by Gómez et al. They developed a likelihood approach, together with a two-step conditional algorithm, to estimate the regression coefficients in the model. However, their method is inapplicable when the interval-censored covariate is continuous. In this article, we propose a novel and fast method to treat the continuous interval-censored covariate. By using logspline density estimation, we impute the interval-censored covariate with a conditional expectation. Then, the ordinary least-squares method is applied to the linear regression model with the imputed covariate. To assess the performance of the proposed method, we compare our imputation with the midpoint imputation and the semiparametric hierarchical method via simulations. Furthermore, an application to the AIDS clinical trial is presented.     

A Methodology to Implement Box-Cox Transformation When No Covariate is Available

Box-Cox transformation is one of the most commonly used methodologies when data do not follow normal distribution. However, its use is restricted since it usually requires the availability of covariates. In this article, the use of a non-informative auxiliary variable is proposed for the implementation of Box-Cox transformation. Simulation studies are conducted to illustrate that the proposed approach is successful in attaining normality under different sample sizes and most of the distributions and in estimating transformation parameter for different sample sizes and mean-variance combinations. Methodology is illustrated on two real-life datasets.     

Power of double-sampling tests for General Linear Hypotheses

In this paper, testing procedures based on double-sampling are proposed that yield gains in terms of power for the tests of General Linear Hypotheses. The distribution of a test statistic, involving both the measurements of the outcome on the smaller sample and of the covariates on the wider sample, is first derived. Then, approximations are provided in order to allow for a formal comparison between the powers of double-sampling and single-sampling strategies. Furthermore, it is shown how to allocate the measurements of the outcome and the covariates in order to maximize the power of the tests for a given experimental cost.     

Selecting the Optimal Transformation of a Continuous Covariate in Cox's Regression: Implications for Hypothesis Testing

ABSTRACT

Background: Many exposures in epidemiological studies have nonlinear effects and the problem is to choose an appropriate functional relationship between such exposures and the outcome. One common approach is to investigate several parametric transformations of the covariate of interest, and to select a posteriori the function that fits the data the best. However, such approach may result in an inflated Type I error. Methods: Through a simulation study, we generated data from Cox's models with different transformations of a single continuous covariate. We investigated the Type I error rate and the power of the likelihood ratio test (LRT) corresponding to three different procedures that considered the same set of parametric dose-response functions. The first unconditional approach did not involve any model selection, while the second conditional approach was based on a posteriori selection of the parametric function. The proposed third approach was similar to the second except that it used a corrected critical value for the LRT to ensure a correct Type I error. Results: The Type I error rate of the second approach was two times higher than the nominal size. For simple monotone dose-response, the corrected test had similar power as the unconditional approach, while for non monotone, dose-response, it had a higher power. A real-life application that focused on the effect of body mass index on the risk of coronary heart disease death, illustrated the advantage of the proposed approach. Conclusion: Our results confirm that a posteriori selecting the functional form of the dose-response induces a Type I error inflation. The corrected procedure, which can be applied in a wide range of situations, may provide a good trade-off between Type I error and power.     

Point and Interval Estimations of Marginal Risk Difference by Logistic Model

We use logistic model to get point and interval estimates of the marginal risk difference in observational studies and randomized trials with dichotomous outcome. We prove that the maximum likelihood estimate of the marginal risk difference is unbiased for finite sample and highly robust to the effects of dispersing covariates. We use approximate normal distribution of the maximum likelihood estimates of the logistic model parameters to get approximate distribution of the maximum likelihood estimate of the marginal risk difference and then the interval estimate of the marginal risk difference. We illustrate application of the method by a real medical example.     

The exponentiation formula of reliability and survival: Does it always hold?

In reliability and biometry, it is common practice to choose a failure model by first assessing the failure rate function subjectively, and then invoking the well known exponentiation formula. The derivation of this formula is based on the assumption that the underlying failure distribution be absolutely continuous. Thus, implicit in the above approach is the understanding that the selected failure distribution will be absolutely continuous. The purpose of this note is to point out that the absolute continuity may fail when the failure rate is assessed conditionally, and in particular when it is conditioned on certain types of covariates, called internal covariates. When such is the case, the exponentiation formula should not be used.