Polytomous logistic model for matched pairs case-control design:studies with covariates

Pair-wise matched case-control design is commonly used in epidemiological analysis for estimating odds ratios. In the most simplest situation, each subject is classified according to a binary outcome and the factor of interest being a two-level factor. Binary logistic models have beenfound to be very useful for studying such relationship. In our earlier studies we have shown that polytomous logistic model can be used for estimating odds ratios when the exposure of prime interest assumes multiple levels. In this paper, using the above model, we estimate the odds ratios for the possible levels of risk factor of interest adjusting for covariates which were notincluded in the matching process. An illustrative example is presented and discussed.     

The unreasonable effectiveness of a biased logistic regression procedure in the analysis of pair-matched case-control studies

We examine the rationale of prospective logistic regression analysis for pair-matched case-control data using explicit, parametric terms for matching variables in the model. We show that this approach can yield inconsistent estimates for the disease-exposure odds ratio, even in large samples. Some special conditions are given under which the bias for the disease-exposure odds ratio is small. It is because these conditions are not too uncommon that this flawed analytic method appears to possess an (unreasonable) effectiveness.     

Efficiently weighted estimating equations with application to proportional excess hazards

A general approach to estimation, that can lead to efficient estimation in two stages, is presented. The method will not always be available, but sufficient conditions for efficiency are provided together with four examples of its use: (1) estimation of the odds ratio in 1:M matched case-control studies with a dichotomous exposure variable; (2) estimation of the relative hazard in a two-sample survival setting; (3) estimation of the regression parameters in the proportional excess hazards model; and (4) estimation in a partly linear parametric additive hazards model. The method depends upon finding a family of weighted estimating equations, which includes a simple initial equation yielding a consistent estimate and also an equation that yields an efficient estimate, provided the optiomal weights are used.     

Cumulative logit models for matched pairs case-control design: Studies with covariates

Binary as well as polytomous logistic models have been found useful for estimating odds ratios when the exposure of prime interest assumes unordered multiple levels under matched pair case-control design. In our earlier studies, we have shown the use of a polytomous logistic model for estimating cumulative odds ratios when the exposure of prime interest assumes multiple ordered levels under matched pair case-control design. In this paper, using the above model, we estimate the covariate adjusted cumulative odds ratios, in the case of an ordinal multiple level exposure variable under a pairwise matched case-control retrospective design. An approach, based on asymptotic distributional results, is also described to investigate whether or not the response categories are distinguishable with respect to the cumulative odds ratios after adjusting the effect of covariates. An illustrative example is presented and discussed.     

Estimating Individual-Level Risk in Spatial Epidemiology Using Spatially Aggregated Information on the Population at Risk

We propose a novel alternative to case-control sampling for the estimation of individual-level risk in spatial epidemiology. Our approach uses weighted estimating equations to estimate regression parameters in the intensity function of an inhomogeneous spatial point process, when information on risk-factors is available at the individual level for cases, but only at a spatially aggregated level for the population at risk. We develop data-driven methods to select the weights used in the estimating equations and show through simulation that the choice of weights can have a major impact on efficiency of estimation. We develop a formal test to detect non-Poisson behavior in the underlying point process and assess the performance of the test using simulations of Poisson and Poisson cluster point processes. We apply our methods to data on the spatial distribution of childhood meningococcal disease cases in Merseyside, U.K. between 1981 and 2007.     

Orthogonalized Residuals for Estimation of Marginally Specified Association Parameters in Multivariate Binary Data

Abstract. This paper focuses on marginal regression models for correlated binary responses when estimation of the association structure is of primary interest. A new estimating function approach based on orthogonalized residuals is proposed. A special case of the proposed procedure allows a new representation of the alternating logistic regressions method through marginal residuals. The connections between second‐order generalized estimating equations, alternating logistic regressions, pseudo‐likelihood and other methods are explored. Efficiency comparisons are presented, with emphasis on variable cluster size and on the role of higher‐order assumptions. The new method is illustrated with an analysis of data on impaired pulmonary function.     

Properties of maximum likelihood estimates of the ratio of parameters in ordinal response regression models

The properties of a method of estimating the ratio of parameters for ordered categorical response regression models are discussed. If the link function relating the response variable to the linear combination of covariates is unknown then it is only possible to estimate the ratio of regression parameters. This ratio of parameters has a substitutability or relative importance interpretation.

The maximum likelihood estimate of the ratio of parameters, assuming a logistic function (McCullagh, 1980), is found to have very small bias for a wide variety of true link functions. Further it is shown using Monte Carlo simulations that this maximum likelihood estimate, has good coverage properties, even if the link function is incorrectly specified. It is demonstrated that combining adjacent categories to make the response binary can result in an analysis which is appreciably less efficient. The size of the efficiency loss on, among other factors, the marginal distribution in the ordered categories     

Estimating a Marginal Causal Odds Ratio Subject to Confounding

Odds ratios are frequently used to describe the relationship between a binary treatment or exposure and a binary outcome. An odds ratio can be interpreted as a causal effect or a measure of association, depending on whether it involves potential outcomes or the actual outcome. An odds ratio can also be characterized as marginal versus conditional, depending on whether it involves conditioning on covariates. This article proposes a method for estimating a marginal causal odds ratio subject to confounding. The proposed method is based on a logistic regression model relating the outcome to the treatment indicator and potential confounders. Simulation results show that the proposed method performs reasonably well in moderate-sized samples and may even offer an efficiency gain over the direct method based on the sample odds ratio in the absence of confounding. The method is illustrated with a real example concerning coronary heart disease.     

Aalen's Linear Model for Sampled Risk Set Data: A Large Sample Study

Borgan and Langholz (1997) describe a method for estimating the parameter functions in Aalen's linear hazard regression model from sampled risk set data. Using a counting process formulation and the martingale central limit theorem, we provide a study of the asymptotic distributional properties of the estimator. The results are applied to study the efficiencies of the nested case-control and counter-matched designs relative to a full cohort analysis.     

Case-cohort analysis with semiparametric transformation models

Semiparametric transformation models provide flexible regression models for survival analysis, including the Cox proportional hazards and the proportional odds models as special cases. We consider the application of semiparametric transformation models in case-cohort studies, where the covariate data are observed only on cases and on a subcohort randomly sampled from the full cohort. We first propose an approximate profile likelihood approach with full-cohort data, which amounts to the pseudo-partial likelihood approach of Zucker [2005. A pseudo-partial likelihood method for semiparametric survival regression with covariate errors. J. Amer. Statist. Assoc. 100, 1264–1277]. Simulation results show that our proposal is almost as efficient as the nonparametric maximum likelihood estimator. We then extend this approach to the case-cohort design, applying the Horvitz–Thompson weighting method to the estimating equations from the approximated profile likelihood. Two levels of weights can be utilized to achieve unbiasedness and to gain efficiency. The resulting estimator has a closed-form asymptotic covariance matrix, and is found in simulations to be substantially more efficient than the estimator based on martingale estimating equations. The extension to left-truncated data will be discussed. We illustrate the proposed method on data from a cardiovascular risk factor study conducted in Taiwan.     

Semiparametric ROC surface estimation for continuous diagnostic tests via polytomous logistic regression procedures

In this paper, we propose a semiparametric method of estimating receiver operating characteristic (ROC) surfaces for continuous diagnostic tests under density ratio models. Implementation of our method is easy since the usual polytomous logistic regression procedures in many statistical software packages can be employed. A simulated example is provided to facilitate the implementation of our method. Simulation results show that the proposed semiparametric ROC surface estimator is more efficient than the nonparametric counterpart and the parametric counterpart whether the normality assumption of data holds or not. Moreover, some simulation results on the underlying semiparametric distribution function estimators are also reported. In addition, some discussions on the proposed method as well as analysis of a real data set are provided.     

Events per variable for risk differences and relative risks using pseudo-observations

A method based on pseudo-observations has been proposed for direct regression modeling of functionals of interest with right-censored data, including the survival function, the restricted mean and the cumulative incidence function in competing risks. The models, once the pseudo-observations have been computed, can be fitted using standard generalized estimating equation software. Regression models can however yield problematic results if the number of covariates is large in relation to the number of events observed. Guidelines of events per variable are often used in practice. These rules of thumb for the number of events per variable have primarily been established based on simulation studies for the logistic regression model and Cox regression model. In this paper we conduct a simulation study to examine the small sample behavior of the pseudo-observation method to estimate risk differences and relative risks for right-censored data. We investigate how coverage probabilities and relative bias of the pseudo-observation estimator interact with sample size, number of variables and average number of events per variable.     

Empirical Likelihood Based Synthetic Data Method for Censored Regression Analysis

In this article, we propose a new empirical likelihood method for linear regression analysis with a right censored response variable. The method is based on the synthetic data approach for censored linear regression analysis. A log-empirical likelihood ratio test statistic for the entire regression coefficients vector is developed and we show that it converges to a standard chi-squared distribution. The proposed method can also be used to make inferences about linear combinations of the regression coefficients. Moreover, the proposed empirical likelihood ratio provides a way to combine different normal equations derived from various synthetic response variables. Maximizing this empirical likelihood ratio yields a maximum empirical likelihood estimator which is asymptotically equivalent to the solution of the estimating equation that are optimal linear combination of the original normal equations. It improves the estimation efficiency. The method is illustrated by some Monte Carlo simulation studies as well as a real example.     

A Model Validation Procedure when Covariate Data are Missing at Random

Abstract. In the presence of missing covariates, standard model validation procedures may result in misleading conclusions. By building generalized score statistics on augmented inverse probability weighted complete‐case estimating equations, we develop a new model validation procedure to assess the adequacy of a prescribed analysis model when covariate data are missing at random. The asymptotic distribution and local alternative efficiency for the test are investigated. Under certain conditions, our approach provides not only valid but also asymptotically optimal results. A simulation study for both linear and logistic regression illustrates the applicability and finite sample performance of the methodology. Our method is also employed to analyse a coronary artery disease diagnostic dataset.     

Inference for functions of parameters in discrete distributions based on fiducial approach: Binomial and Poisson cases

In this article, we propose a simple method of constructing confidence intervals for a function of binomial success probabilities and for a function of Poisson means. The method involves finding an approximate fiducial quantity (FQ) for the parameters of interest. A FQ for a function of several parameters can be obtained by substitution. For the binomial case, the fiducial approach is illustrated for constructing confidence intervals for the relative risk and the ratio of odds. Fiducial inferential procedures are also provided for estimating functions of several Poisson parameters. In particular, fiducial inferential approach is illustrated for interval estimating the ratio of two Poisson means and for a weighted sum of several Poisson means. Simple approximations to the distributions of the FQs are also given for some problems. The merits of the procedures are evaluated by comparing them with those of existing asymptotic methods with respect to coverage probabilities, and in some cases, expected widths. Comparison studies indicate that the fiducial confidence intervals are very satisfactory, and they are comparable or better than some available asymptotic methods. The fiducial method is easy to use and is applicable to find confidence intervals for many commonly used summary indices. Some examples are used to illustrate and compare the results of fiducial approach with those of other available asymptotic methods.     

Analysis of transformation models with right-truncated data

In many applications, statistical data are frequently observed subject to a retrospective sampling criterion resulting in right-truncated data. In this article, a general class of semiparametric transformation models that include proportional hazards model and proportional odds model as special cases is studied for the analysis of right-truncated data. We proposed two estimators for regression coefficients. The first estimator is based on martingale estimating equations. The second estimator is based on the conditional likelihood function given the truncation times. The asymptotic properties of both estimators are derived. The finite sample performance is examined through a simulation study.     

Marginal models for the association structure of hierarchical binary responses

Clustered binary responses are often found in ecological studies. Data analysis may include modeling the marginal probability response. However, when the association is the main scientific focus, modeling the correlation structure between pairs of responses is the key part of the analysis. Second-order generalized estimating equations (GEE) are established in the literature. Some of them are more efficient in computational terms, especially facing large clusters. Alternating logistic regression (ALR) and orthogonalized residual (ORTH) GEE methods are presented and compared in this paper. Simulation results show a slightly superiority of ALR over ORTH. Marginal probabilities and odds ratios are also estimated and compared in a real ecological study involving a three-level hierarchical clustering. ALR and ORTH models are useful for modeling complex association structure with large cluster sizes.     

Bayesian Survival Analysis in Proportional Hazard Models with Logistic Relative Risk

Abstract.  The traditional Cox proportional hazards regression model uses an exponential relative risk function. We argue that under various plausible scenarios, the relative risk part of the model should be bounded, suggesting also that the traditional model often might overdramatize the hazard rate assessment for individuals with unusual covariates. This motivates our working with proportional hazards models where the relative risk function takes a logistic form. We provide frequentist methods, based on the partial likelihood, and then go on to semiparametric Bayesian constructions. These involve a Beta process for the cumulative baseline hazard function and any prior with a density, for example that dictated by a Jeffreys-type argument, for the regression coefficients. The posterior is derived using machinery for Lévy processes, and a simulation recipe is devised for sampling from the posterior distribution of any quantity. Our methods are illustrated on real data. A Bernshtĕn–von Mises theorem is reached for our class of semiparametric priors, guaranteeing asymptotic normality of the posterior processes.     

The Efficiency of Simple and Counter-matched Nested Case-control Sampling

This paper presents a study of the performance of simple and counter-matched nested case-control sampling relative to a full cohort study. First we review methods for estimating the regression parameters and the integrated baseline hazard for Cox's proportional hazards model from cohort and case-control data. Then the asymptotic distributional properties of these estimators are recapitulated, and relative efficiency results are presented both for regression and baseline hazard estimation.     

Different methods for handling incomplete longitudinal binary outcome due to missing at random dropout

This paper compares the performance of weighted generalized estimating equations (WGEEs), multiple imputation based on generalized estimating equations (MI-GEEs) and generalized linear mixed models (GLMMs) for analyzing incomplete longitudinal binary data when the underlying study is subject to dropout. The paper aims to explore the performance of the above methods in terms of handling dropouts that are missing at random (MAR). The methods are compared on simulated data. The longitudinal binary data are generated from a logistic regression model, under different sample sizes. The incomplete data are created for three different dropout rates. The methods are evaluated in terms of bias, precision and mean square error in case where data are subject to MAR dropout. In conclusion, across the simulations performed, the MI-GEE method performed better in both small and large sample sizes. Evidently, this should not be seen as formal and definitive proof, but adds to the body of knowledge about the methods’ relative performance. In addition, the methods are compared using data from a randomized clinical trial.