Measuring and estimating the interaction between exposures on a dichotomous outcome for observational studies

In observational studies for the interaction between exposures on a dichotomous outcome of a certain population, usually one parameter of a regression model is used to describe the interaction, leading to one measure of the interaction. In this article we use the conditional risk of an outcome given exposures and covariates to describe the interaction and obtain five different measures of the interaction, that is, difference between the marginal risk differences, ratio of the marginal risk ratios, ratio of the marginal odds ratios, ratio of the conditional risk ratios, and ratio of the conditional odds ratios. These measures reflect different aspects of the interaction. By using only one regression model for the conditional risk, we obtain the maximum-likelihood (ML)-based point and interval estimates of these measures, which are most efficient due to the nature of ML. We use the ML estimates of the model parameters to obtain the ML estimates of these measures. We use the approximate normal distribution of the ML estimates of the model parameters to obtain approximate non-normal distributions of the ML estimates of these measures and then confidence intervals of these measures. The method can be easily implemented and is presented via a medical example.     

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.     

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.     

Composite conditional likelihood for sparse clustered data

Summary.  Sparse clustered data arise in finely stratified genetic and epidemiologic studies and pose at least two challenges to inference. First, it is difficult to model and interpret the full joint probability of dependent discrete data, which limits the utility of full likelihood methods. Second, standard methods for clustered data, such as pairwise likelihood and the generalized estimating function approach, are unsuitable when the data are sparse owing to the presence of many nuisance parameters. We present a composite conditional likelihood for use with sparse clustered data that provides valid inferences about covariate effects on both the marginal response probabilities and the intracluster pairwise association. Our primary focus is on sparse clustered binary data, in which case the method proposed utilizes doubly discordant quadruplets drawn from each stratum to conduct inference about the intracluster pairwise odds ratios.     

Nonparametric covariate adjustment in estimating hazard ratios

In randomized clinical trials with time‐to‐event outcomes, the hazard ratio is commonly used to quantify the treatment effect relative to a control. The Cox regression model is commonly used to adjust for relevant covariates to obtain more accurate estimates of the hazard ratio between treatment groups. However, it is well known that the treatment hazard ratio based on a covariate‐adjusted Cox regression model is conditional on the specific covariates and differs from the unconditional hazard ratio that is an average across the population. Therefore, covariate‐adjusted Cox models cannot be used when the unconditional inference is desired. In addition, the covariate‐adjusted Cox model requires the relatively strong assumption of proportional hazards for each covariate. To overcome these challenges, a nonparametric randomization‐based analysis of covariance method was proposed to estimate the covariate‐adjusted hazard ratios for multivariate time‐to‐event outcomes. However, empirical evaluations of the performance (power and type I error rate) of the method have not been studied. Although the method is derived for multivariate situations, for most registration trials, the primary endpoint is a univariate outcome. Therefore, this approach is applied to univariate outcomes, and performance is evaluated through a simulation study in this paper. Stratified analysis is also investigated. As an illustration of the method, we also apply the covariate‐adjusted and unadjusted analyses to an oncology trial. Copyright © 2015 John Wiley & Sons, Ltd.     

An estimated‐score approach for dealing with missing covariate data in matched case–control studies

Matched case–control designs are commonly used in epidemiological studies for estimating the effect of exposure variables on the risk of a disease by controlling the effect of confounding variables. Due to retrospective nature of the study, information on a covariate could be missing for some subjects. A straightforward application of the conditional logistic likelihood for analyzing matched case–control data with the partially missing covariate may yield inefficient estimators of the parameters. A robust method has been proposed to handle this problem using an estimated conditional score approach when the missingness mechanism does not depend on the disease status. Within the conditional logistic likelihood framework, an empirical procedure is used to estimate the odds of the disease for the subjects with missing covariate values. The asymptotic distribution and the asymptotic variance of the estimator when the matching variables and the completely observed covariates are categorical. The finite sample performance of the proposed estimator is assessed through a simulation study. Finally, the proposed method has been applied to analyze two matched case–control studies. The Canadian Journal of Statistics 38: 680–697; 2010 © 2010 Statistical Society of Canada     

The Performance of Two Data-Generation Processes for Data with Specified Marginal Treatment Odds Ratios

Monte Carlo simulation methods are increasingly being used to evaluate the property of statistical estimators in a variety of settings. The utility of these methods depends upon the existence of an appropriate data-generating process. Observational studies are increasingly being used to estimate the effects of exposures and interventions on outcomes. Conventional regression models allow for the estimation of conditional or adjusted estimates of treatment effects. There is an increasing interest in statistical methods for estimating marginal or average treatment effects. However, in many settings, conditional treatment effects can differ from marginal treatment effects. Therefore, existing data-generating processes for conditional treatment effects are of little use in assessing the performance of methods for estimating marginal treatment effects. In the current study, we describe and evaluate the performance of two different data-generation processes for generating data with a specified marginal odds ratio. The first process is based upon computing Taylor Series expansions of the probabilities of success for treated and untreated subjects. The expansions are then integrated over the distribution of the random variables to determine the marginal probabilities of success for treated and untreated subjects. The second process is based upon an iterative process of evaluating marginal odds ratios using Monte Carlo integration. The second method was found to be computationally simpler and to have superior performance compared to the first method.     

Simple Formulae for Evaluating the Potential Impact of Confounding Bias

Unmeasured confounding is a common problem in observational studies. This article presents simple formulae that can set the bounds of the confounding risk ratio under three standard populations of the exposed, unexposed, and total groups. The bounds are derived by considering the confounding risk ratio as a function of the prevalence of a covariate, and can be constructed using only information about either the exposure–confounder or the disease–confounder relationship. The formulae can be extended to the confounding odds ratio in case–control studies, and the confounding risk difference is discussed. The application of these formulae is demonstrated using an example in which estimation may suffer from bias due to population stratification. The formulae can help to provide a realistic picture of the potential impact of bias due to confounding.     

A Bayesian Adjustment for Covariate Misclassification with Correlated Binary Outcome Data

Estimated associations between an outcome variable and misclassified covariates tend to be biased when the methods of estimation that ignore the classification error are applied. Available methods to account for misclassification often require the use of a validation sample (i.e. a gold standard). In practice, however, such a gold standard may be unavailable or impractical. We propose a Bayesian approach to adjust for misclassification in a binary covariate in the random effect logistic model when a gold standard is not available. This Markov Chain Monte Carlo (MCMC) approach uses two imperfect measures of a dichotomous exposure under the assumptions of conditional independence and non-differential misclassification. A simulated numerical example and a real clinical example are given to illustrate the proposed approach. Our results suggest that the estimated log odds of inpatient care and the corresponding standard deviation are much larger in our proposed method compared with the models ignoring misclassification. Ignoring misclassification produces downwardly biased estimates and underestimate uncertainty.     

Marginal Likelihood Estimation for Proportional Odds Models with Right Censored Data

One majoraspect in medical research is to relate the survival times ofpatients with the relevant covariates or explanatory variables.The proportional hazards model has been used extensively in thepast decades with the assumption that the covariate effects actmultiplicatively on the hazard function, independent of time.If the patients become more homogeneous over time, say the treatmenteffects decrease with time or fade out eventually, then a proportionalodds model may be more appropriate. In the proportional oddsmodel, the odds ratio between patients can be expressed as afunction of their corresponding covariate vectors, in which,the hazard ratio between individuals converges to unity in thelong run. In this paper, we consider the estimation of the regressionparameter for a semiparametric proportional odds model at whichthe baseline odds function is an arbitrary, non-decreasing functionbut is left unspecified. Instead of using the exact survivaltimes, only the rank order information among patients is used.A Monte Carlo method is used to approximate the marginal likelihoodfunction of the rank invariant transformation of the survivaltimes which preserves the information about the regression parameter.The method can be applied to other transformation models withcensored data such as the proportional hazards model, the generalizedprobit model or others. The proposed method is applied to theVeteran's Administration lung cancer trial data.     

Bootstrapping the conditional copula

This paper is concerned with inference about the dependence or association between two random variables conditionally upon the given value of a covariate. A way to describe such a conditional dependence is via a conditional copula function. Nonparametric estimators for a conditional copula then lead to nonparametric estimates of conditional association measures such as a conditional Kendall's tau. The limiting distributions of nonparametric conditional copula estimators are rather involved. In this paper we propose a bootstrap procedure for approximating these distributions and their characteristics, and establish its consistency. We apply the proposed bootstrap procedure for constructing confidence intervals for conditional association measures, such as a conditional Blomqvist beta and a conditional Kendall's tau. The performances of the proposed methods are investigated via a simulation study involving a variety of models, ranging from models in which the dependence (weak or strong) on the covariate is only through the copula and not through the marginals, to models in which this dependence appears in both the copula and the marginal distributions. As a conclusion we provide practical recommendations for constructing bootstrap-based confidence intervals for the discussed conditional association measures.     

Controlling for confounding via propensity score methods can result in biased estimation of the conditional AUC: A simulation study

In the medical literature, there has been an increased interest in evaluating association between exposure and outcomes using nonrandomized observational studies. However, because assignments to exposure are not random in observational studies, comparisons of outcomes between exposed and nonexposed subjects must account for the effect of confounders. Propensity score methods have been widely used to control for confounding, when estimating exposure effect. Previous studies have shown that conditioning on the propensity score results in biased estimation of conditional odds ratio and hazard ratio. However, research is lacking on the performance of propensity score methods for covariate adjustment when estimating the area under the ROC curve (AUC). In this paper, AUC is proposed as measure of effect when outcomes are continuous. The AUC is interpreted as the probability that a randomly selected nonexposed subject has a better response than a randomly selected exposed subject. A series of simulations has been conducted to examine the performance of propensity score methods when association between exposure and outcomes is quantified by AUC; this includes determining the optimal choice of variables for the propensity score models. Additionally, the propensity score approach is compared with that of the conventional regression approach to adjust for covariates with the AUC. The choice of the best estimator depends on bias, relative bias, and root mean squared error. Finally, an example looking at the relationship of depression/anxiety and pain intensity in people with sickle cell disease is used to illustrate the estimation of the adjusted AUC using the proposed approaches.     

Marginal inhomogeneity models for square contingency tables with nominal categories

For the analysis of square contingency tables with nominal categories, this paper proposes two kinds of models that indicate the structure of marginal inhomogeneity. One model states that the absolute values of log odds of the row marginal probability to the corresponding column marginal probability for each category i are constant for every i. The other model states that, on the condition that an observation falls in one of the off-diagonal cells in the square table, the absolute values of log odds of the conditional row marginal probability to the corresponding conditional column marginal probability for each category i are constant for every i. These models are used when the marginal homogeneity model does not hold, and the values of parameters in the models are useful for seeing the degree of departure from marginal homogeneity for the data on a nominal scale. Examples are given.     

Balanced covariates with response adaptive randomization

Response adaptive randomization (RAR) methods for clinical trials are susceptible to imbalance in the distribution of influential covariates across treatment arms. This can make the interpretation of trial results difficult, because observed differences between treatment groups may be a function of the covariates and not necessarily because of the treatments themselves. We propose a method for balancing the distribution of covariate strata across treatment arms within RAR. The method uses odds ratios to modify global RAR probabilities to obtain stratum‐specific modified RAR probabilities. We provide illustrative examples and a simple simulation study to demonstrate the effectiveness of the strategy for maintaining covariate balance. The proposed method is straightforward to implement and applicable to any type of RAR method or outcome.     

Adjusted homogeneity tests of odds ratios when data are clustered

Three modified tests for homogeneity of the odds ratio for a series of 2 × 2 tables are studied when the data are clustered. In the case of clustered data, the standard tests for homogeneity of odds ratios ignore the variance inflation caused by positive correlation among responses of subjects within the same cluster, and therefore have inflated Type I error. The modified tests adjust for the variance inflation in the three existing standard tests: Breslow–Day, Tarone and the conditional score test. The degree of clustering effect is measured by the intracluster correlation coefficient, ρ. A variance correction factor derived from ρ is then applied to the variance estimator in the standard tests of homogeneity of the odds ratio. The proposed tests are an application of the variance adjustment method commonly used in correlated data analysis and are shown to maintain the nominal significance level in a simulation study. Copyright © 2004 John Wiley & Sons, Ltd.     

On double hysteretic heteroskedastic model

ABSTRACT

This paper proposes a hysteretic autoregressive model with GARCH specification and a skew Student's t-error distribution for financial time series. With an integrated hysteresis zone, this model allows both the conditional mean and conditional volatility switching in a regime to be delayed when the hysteresis variable lies in a hysteresis zone. We perform Bayesian estimation via an adaptive Markov Chain Monte Carlo sampling scheme. The proposed Bayesian method allows simultaneous inferences for all unknown parameters, including threshold values and a delay parameter. To implement model selection, we propose a numerical approximation of the marginal likelihoods to posterior odds. The proposed methodology is illustrated using simulation studies and two major Asia stock basis series. We conduct a model comparison for variant hysteresis and threshold GARCH models based on the posterior odds ratios, finding strong evidence of the hysteretic effect and some asymmetric heavy-tailness. Versus multi-regime threshold GARCH models, this new collection of models is more suitable to describe real data sets. Finally, we employ Bayesian forecasting methods in a Value-at-Risk study of the return series.     

A Profile Conditional Likelihood Approach for the Semiparametric Transformation Regression Model with Missing Covariates

We propose a profile conditional likelihood approach to handle missing covariates in the general semiparametric transformation regression model. The method estimates the marginal survival function by the Kaplan-Meier estimator, and then estimates the parameters of the survival model and the covariate distribution from a conditional likelihood, substituting the Kaplan-Meier estimator for the marginal survival function in the conditional likelihood. This method is simpler than full maximum likelihood approaches, and yields consistent and asymptotically normally distributed estimator of the regression parameter when censoring is independent of the covariates. The estimator demonstrates very high relative efficiency in simulations. When compared with complete-case analysis, the proposed estimator can be more efficient when the missing data are missing completely at random and can correct bias when the missing data are missing at random. The potential application of the proposed method to the generalized probit model with missing continuous covariates is also outlined.     

Estimation and Inference of Distributional Partial Effects: Theory and Application

This article considers nonparametric and semiparametric estimation and inference of the effects of a covariate, either discrete or continuous, on the conditional distribution of a response outcome. It also proposes various uniform tests following estimation. This type of analysis is useful in situations where the econometrician or policy-maker is interested in knowing the effect of a variable or policy on the whole distribution of the response outcome conditional on covariates and is not willing to make parametric functional form assumptions. Monte Carlo experiments show that the proposed estimators and tests are well-behaved in small samples. The empirical section studies the effect of minimum wage hikes on household labor earnings. It is found that the minimum wage has a heterogenous impact on household earnings in the U.S. and that small hikes in the minimum wage are more effective in improving the household earnings distribution.     

Estimation of odds ratios under order restrictions

A new method for estimating a set of odds ratios under an order restriction based on estimating equations is proposed. The method is applied to those of the conditional maximum likelihood estimators and the Mantel-Haenszel estimators. The estimators derived from the conditional likelihood estimating equations are shown to maximize the conditional likelihoods. It is also seen that the restricted estimators converge almost surely to the respective odds ratios when the respective sample sizes become large regularly. The restricted estimators are compared with the unrestricted maximum likelihood estimators by a Monte Carlo simulation. The simulation studies show that the restricted estimates improve the mean squared errors remarkably, while the Mantel-Haenszel type estimates are competitive with the conditional maximum likelihood estimates, being slightly worse.     

Marginal and hazard ratio specific random data generation: Applications to semi-parametric bootstrapping

Cox's partial likelihood for censored time-to-event data can be interpreted as a permutation probability, whereby covariate values are permuted to the observed times-to-event and censoring times. This interpretation facilitates a simple method for jointly generating times-to-event and covariate tuples with considerable flexibility, including time dependence of the hazard ratio and specification of both the marginal time-to-event and covariate distributions. This interpretation also facilitates a method for semi-parametric bootstrapping of hazard ratio estimators.