A comparison of balancing scores for estimating rate ratios of count data in observational studies

In this article, we conduct a Monte Carlo study to examine four balancing scores (BS1: propensity score, BS2: prognostic score, BS3: adjusted propensity score estimated by the estimated prognostic score, and BS4: adjusted propensity score estimated by the estimated prognostic score and other covariates) for adjusting bias in estimating the marginal and the conditional rate ratios of count data in observational studies. Simulation results show that BS1–BS4 are not much different in terms of estimating the marginal and the conditional rate ratios, however, choosing the appropriate matching algorithm is more important than selecting a balancing scores.     

Comparison of causal effect estimators under exposure misclassification

Over the past decades, various principles for causal effect estimation have been proposed, all differing in terms of how they adjust for measured confounders: either via traditional regression adjustment, by adjusting for the expected exposure given those confounders (e.g., the propensity score), or by inversely weighting each subject's data by the likelihood of the observed exposure, given those confounders. When the exposure is measured with error, this raises the question whether these different estimation strategies might be differently affected and whether one of them is to be preferred for that reason. In this article, we investigate this by comparing inverse probability of treatment weighted (IPTW) estimators and doubly robust estimators for the exposure effect in linear marginal structural mean models (MSM) with G-estimators, propensity score (PS) adjusted estimators and ordinary least squares (OLS) estimators for the exposure effect in linear regression models. We find analytically that these estimators are equally affected when exposure misclassification is independent of the confounders, but not otherwise. Simulation studies reveal similar results for time-varying exposures and when the model of interest includes a logistic link.     

A Class of Permutation Tests for the Equality of Two Marginal Survival Functions Using Paired Censored Data

We studied several test statistics for testing the equality of marginal survival functions of paired censored data. The null distribution of the test statistics was approximated by permutation. These tests do not require explicit modeling or estimation of the within-pair correlation, accommodate both paired data and singletons, and the computation is straightforward with most statistical software. Numerical studies showed that these tests have competitive size and power performance. One test statistic has higher power than previously published test statistics when the two survival functions under comparison cross. We illustrate use of these tests in a propensity score matched dataset.     

Variance estimation of the risk difference when using propensity-score matching and weighting with time-to-event outcomes

Observational studies are increasingly being used in medicine to estimate the effects of treatments or exposures on outcomes. To minimize the potential for confounding when estimating treatment effects, propensity score methods are frequently implemented. Often outcomes are the time to event. While it is common to report the treatment effect as a relative effect, such as the hazard ratio, reporting the effect using an absolute measure of effect is also important. One commonly used absolute measure of effect is the risk difference or difference in probability of the occurrence of an event within a specified duration of follow-up between a treatment and comparison group. We first describe methods for point and variance estimation of the risk difference when using weighting or matching based on the propensity score when outcomes are time-to-event. Next, we conducted Monte Carlo simulations to compare the relative performance of these methods with respect to bias of the point estimate, accuracy of variance estimates, and coverage of estimated confidence intervals. The results of the simulation generally support the use of weighting methods (untrimmed ATT weights and IPTW) or caliper matching when the prevalence of treatment is low for point estimation. For standard error estimation the simulation results support the use of weighted robust standard errors, bootstrap methods, or matching with a naïve standard error (i.e., Greenwood method). The methods considered in the article are illustrated using a real-world example in which we estimate the effect of discharge prescribing of statins on patients hospitalized for acute myocardial infarction.     

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.     

Efficient Robust Estimation for Linear Models with Missing Response at Random

Coefficient estimation in linear regression models with missing data is routinely carried out in the mean regression framework. However, the mean regression theory breaks down if the error variance is infinite. In addition, correct specification of the likelihood function for existing imputation approach is often challenging in practice, especially for skewed data. In this paper, we develop a novel composite quantile regression and a weighted quantile average estimation procedure for parameter estimation in linear regression models when some responses are missing at random. Instead of imputing the missing response by randomly drawing from its conditional distribution, we propose to impute both missing and observed responses by their estimated conditional quantiles given the observed data and to use the parametrically estimated propensity scores to weigh check functions that define a regression parameter. Both estimation procedures are resistant to heavy‐tailed errors or outliers in the response and can achieve nice robustness and efficiency. Moreover, we propose adaptive penalization methods to simultaneously select significant variables and estimate unknown parameters. Asymptotic properties of the proposed estimators are carefully investigated. An efficient algorithm is developed for fast implementation of the proposed methodologies. We also discuss a model selection criterion, which is based on an IC_Q ‐type statistic, to select the penalty parameters. The performance of the proposed methods is illustrated via simulated and real data sets.     

Doubly robust empirical likelihood inference in covariate-missing data problems

Missing covariate data occurs often in regression analysis. We study methods for estimating the regression coefficients in an assumed conditional mean function when some covariates are completely observed but other covariates are missing for some subjects. We adopt the semiparametric perspective of Robins et al. [Estimation of regression coefficients when some regressors are not always observed. J Amer Statist Assoc. 1994;89:846–866] on regression analyses with missing covariates, in which they pioneered the use of two working models, the working propensity score model and the working conditional score model. A recent approach to missing covariate data analysis is the empirical likelihood method of Qin et al. [Empirical likelihood in missing data problems. J Amer Statist Assoc. 2009;104:1492–1503], which effectively combines unbiased estimating equations. In this paper, we consider an alternative likelihood approach based on the full likelihood of the observed data. This full likelihood-based method enables us to generate estimators for the vector of the regression coefficients that are (a) asymptotically equivalent to those of Qin et al. [Empirical likelihood in missing data problems. J Amer Statist Assoc. 2009;104:1492–1503] when the working propensity score model is correctly specified, and (b) doubly robust, like the augmented inverse probability weighting (AIPW) estimators of Robins et al. [Estimation of regression coefficients when some regressors are not always observed. J Am Statist Assoc. 1994;89:846–866]. Thus, the proposed full likelihood-based estimators improve on the efficiency of the AIPW estimators when the working propensity score model is correct but the working conditional score model is possibly incorrect, and also improve on the empirical likelihood estimators of Qin, Zhang and Leung [Empirical likelihood in missing data problems. J Amer Statist Assoc. 2009;104:1492–1503] when the reverse is true, that is, the working conditional score model is correct but the working propensity score model is possibly incorrect. In addition, we consider a regression method for estimation of the regression coefficients when the working conditional score model is correctly specified; the asymptotic variance of the resulting estimator is no greater than the semiparametric variance bound characterized by the theory of Robins et al. [Estimation of regression coefficients when some regressors are not always observed. J Amer Statist Assoc. 1994;89:846–866]. Finally, we compare the finite-sample performance of various estimators in a simulation study.     

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.     

Proportional hazards estimate of the conditional survival function

We introduce a new estimator of the conditional survival function given some subset of the covariate values under a proportional hazards regression. The new estimate does not require estimating the base-line cumulative hazard function. An estimate of the variance is given and is easy to compute, involving only those quantities that are routinely calculated in a Cox model analysis. The asymptotic normality of the new estimate is shown by using a central limit theorem for Kaplan–Meier integrals. We indicate the straightforward extension of the estimation procedure under models with multiplicative relative risks, including non-proportional hazards, and to stratified and frailty models. The estimator is applied to a gastric cancer study where it is of interest to predict patients' survival based only on measurements obtained before surgery, the time at which the most important prognostic variable, stage, becomes known.     

Monte-Carlo Sensitivity Analysis for Controlled Direct Effects Using Marginal Structural Models in the Presence of Confounded Mediators

In randomized trials, investigators are frequently interested in estimating the direct effect of a treatment on an outcome that is not relayed by intermediate variables, in addition to the usual intention-to-treat (ITT) effect. Even if the ITT effect is not confounded due to randomization, the direct effect is not identified when unmeasured variables affect the intermediate and outcome variables. Although the unmeasured variables cannot be adjusted for in the models, it is still important to evaluate the potential bias of these variables quantitatively. This article proposes a sensitivity analysis method for controlled direct effects using a marginal structural model that is an extension of the sensitivity analysis method of unmeasured confounding introduced in the context of observational studies. The proposed method is illustrated using a randomized trial of depression.     

On kernel machine learning for propensity score estimation under complex confounding structures

Post marketing data offer rich information and cost-effective resources for physicians and policy-makers to address some critical scientific questions in clinical practice. However, the complex confounding structures (e.g., nonlinear and nonadditive interactions) embedded in these observational data often pose major analytical challenges for proper analysis to draw valid conclusions. Furthermore, often made available as electronic health records (EHRs), these data are usually massive with hundreds of thousands observational records, which introduce additional computational challenges. In this paper, for comparative effectiveness analysis, we propose a statistically robust yet computationally efficient propensity score (PS) approach to adjust for the complex confounding structures. Specifically, we propose a kernel-based machine learning method for flexibly and robustly PS modeling to obtain valid PS estimation from observational data with complex confounding structures. The estimated propensity score is then used in the second stage analysis to obtain the consistent average treatment effect estimate. An empirical variance estimator based on the bootstrap is adopted. A split-and-merge algorithm is further developed to reduce the computational workload of the proposed method for big data, and to obtain a valid variance estimator of the average treatment effect estimate as a by-product. As shown by extensive numerical studies and an application to postoperative pain EHR data comparative effectiveness analysis, the proposed approach consistently outperforms other competing methods, demonstrating its practical utility.     

Inclusion of binary proxy variables in logistic regression improves treatment effect estimation in observational studies in the presence of binary unmeasured confounding variables

We present a simulation study and application that shows inclusion of binary proxy variables related to binary unmeasured confounders improves the estimate of a related treatment effect in binary logistic regression. The simulation study included 60,000 randomly generated parameter scenarios of sample size 10,000 across six different simulation structures. We assessed bias by comparing the probability of finding the expected treatment effect relative to the modeled treatment effect with and without the proxy variable. Inclusion of a proxy variable in the logistic regression model significantly reduced the bias of the treatment or exposure effect when compared to logistic regression without the proxy variable. Including proxy variables in the logistic regression model improves the estimation of the treatment effect at weak, moderate, and strong association with unmeasured confounders and the outcome, treatment, or proxy variables. Comparative advantages held for weakly and strongly collapsible situations, as the number of unmeasured confounders increased, and as the number of proxy variables adjusted for increased.     

Implications of Model Misspecification in Robust Tests for Recurrent Events

Chronic disease processes often feature transient recurrent adverse clinical events. Treatment comparisons in clinical trials of such disorders must be based on valid and efficient methods of analysis. We discuss robust strategies for testing treatment effects with recurrent events using methods based on marginal rate functions, partially conditional rate functions, and methods based on marginal failure time models. While all three approaches lead to valid tests of the null hypothesis when robust variance estimates are used, they differ in power. Moreover, some approaches lead to estimators of treatment effect which are more easily interpreted than others. To investigate this, we derive the limiting value of estimators of treatment effect from marginal failure time models and illustrate their dependence on features of the underlying point process, as well as the censoring mechanism. Through simulation, we show that methods based on marginal failure time distributions are shown to be sensitive to treatment effects delaying the occurrence of the very first recurrences. Methods based on marginal or partially conditional rate functions perform well in situations where treatment effects persist or in settings where the aim is to summarizee long-term data on efficacy.     

Comparison of adjusted and unadjusted marginal probabilities for estimating binomial parameters in observational studies

In this study, we demonstrate how generalized propensity score estimators (Imbens’ weighted estimator, the propensity score weighted estimator and the generalized doubly robust estimator) can be used to calculate the adjusted marginal probabilities for estimating the three common binomial parameters: the risk difference (RD), the relative risk (RR), and the odds ratio (OR). We further conduct a simulation study to compare the estimated RD, RR, and OR using the adjusted and the unadjusted marginal probabilities in terms of the bias and mean-squared error (MSE). Although there is no clear winner in terms of the MSE for estimating RD, RR, and OR, simulation results surprisingly show thatthe unadjusted marginal probabilities produce the smallest bias compared with the adjusted marginal probabilities in most of the estimates. Hence, in conclusion, we recommend using the unadjusted marginal probabilities to estimate RD, RR, and OR, in practice.     

A Note on the Role of the Propensity Score for Estimating Average Treatment Effects

Hahn [Hahn, J. (1998). On the role of the propensity score in efficient semiparametric estimation of average treatment effects. Econometrica 66:315-331] derived the semiparametric efficiency bounds for estimating the average treatment effect (ATE) and the average treatment effect on the treated (ATET). The variance of ATET depends on whether the propensity score is known or unknown. Hahn attributes this to “dimension reduction.” In this paper, an alternative explanation is given: Knowledge of the propensity score improves upon the estimation of the distribution of the confounding variables.     

Prognostic score matching methods for estimating the average effect of a non-reversible binary time-dependent treatment on the survival function

In evaluating the benefit of a treatment on survival, it is often of interest to compare post-treatment survival with the survival function that would have been observed in the absence of treatment. In many practical settings, treatment is time-dependent in the sense that subjects typically begin follow-up untreated, with some going on to receive treatment at some later time point. In observational studies, treatment is not assigned at random and, therefore, may depend on various patient characteristics. We have developed semi-parametric matching methods to estimate the average treatment effect on the treated (ATT) with respect to survival probability and restricted mean survival time. Matching is based on a prognostic score which reflects each patient’s death hazard in the absence of treatment. Specifically, each treated patient is matched with multiple as-yet-untreated patients with similar prognostic scores. The matched sets do not need to be of equal size, since each matched control is weighted in order to preserve risk score balancing across treated and untreated groups. After matching, we estimate the ATT non-parametrically by contrasting pre- and post-treatment weighted Nelson–Aalen survival curves. A closed-form variance is proposed and shown to work well in simulation studies. The proposed methods are applied to national organ transplant registry data.

     

Expressing Estimators of Expected Quality Adjusted Survival as Functions of Nelson-Aalen Estimators

Quality adjusted survival has been increasingly advocated in clinical trials to be assessed as a synthesis of survival and quality of life. We investigate nonparametric estimation of its expectation for a general multistate process with incomplete follow-up data. Upon establishing a representation of expected quality adjusted survival through marginal distributions of a set of defined events, we propose two estimators for expected quality adjusted survival. Expressed as functions of Nelson-Aalen estimators, the two estimators are strongly consistent and asymptotically normal. We derive their asymptotic variances and propose sample-based variance estimates, along with evaluation of asymptotic relative efficiency. Monte Carlo studies show that these estimation procedures perform well for practical sample sizes. We illustrate the methods using data from a national, multicenter AIDS clinical trial.     

存在测量误差时分层抽样层均值方差的估计

利用模型的方法研究出现测量误差时多变量间的关系是目前国际上的流行方法,但这不利于对单指标的估计。因此,通过在估计量的设计中纳入测量误差信息,推导测量误差方差的定量测度方法,实现了存在测量误差时分层抽样各层均值方差的估计。采用2007年广东省三个市（县）城镇住户调查中的人均消费性支出数据进行实证分析,定量测度了测量误差在层均值方差估计中的大小及其影响,并对不考虑测量误差的估计结果进行了修正。     

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     

基于协变量平衡加权的平均处理效应的稳健有效估计

倾向性得分是估计平均处理效应的重要工具。但在观察性研究中,通常会由于协变量在处理组与对照组分布的不平衡性而导致极端倾向性得分的出现,即存在十分接近于0或1的倾向性得分,这使得因果推断的强可忽略假设接近于违背,进而导致平均处理效应的估计出现较大的偏差与方差。Li等(2018a)提出了协变量平衡加权法,在无混杂性假设下通过实现协变量分布的加权平衡,解决了极端倾向性得分带来的影响。本文在此基础上,提出了基于协变量平衡加权法的稳健且有效的估计方法,并通过引入超级学习算法提升了模型在实证应用中的稳健性;更进一步,将前一方法推广至理论上不依赖于结果回归模型和倾向性得分模型假设的基于协变量平衡加权的稳健有效估计。蒙特卡洛模拟表明,本文提出的两种方法在结果回归模型和倾向性得分模型均存在误设时仍具有极小的偏差和方差。实证部分将两种方法应用于右心导管插入术数据,发现右心导管插入术大约会增加患者6. 3%死亡率。