Assessing bias of multicenter trials with incomplete treatment allocation

Some multicenter randomized controlled trials (e.g. for rare diseases or with slow recruitment) involve many centers with few patients in each. Under within-center randomization, some centers might not assign each treatment to at least one patient; hence, such centers have no within-center treatment effect estimates and the center-stratified treatment effect estimate can be inefficient, perhaps to an extent with statistical and ethical implications. Recently, combining complete and incomplete centers with a priori weights has been suggested. However, a concern is whether using the incomplete centers increases bias. To study this concern, an approach with randomization models for a finite population was used to evaluate bias of the usual complete center estimator, the simple center-ignoring estimator, and the weighted estimator combining complete and incomplete centers. The situation with two treatments and many centers, each with either one or two patients, was evaluated. Various patient accrual mechanisms were considered, including one involving selection bias. The usual complete center estimator and the weighted estimator were unbiased under the overall null hypothesis, even with selection bias. An actual dermatology clinical trial motivates and illustrates these methods.     

A revised Cholesky decomposition to combat multicollinearity in multiple regression models

As known, the ordinary least-squares estimator (OLSE) is unbiased and also, has the minimum variance among all the linear unbiased estimators. However, under multicollinearity the estimator is generally unstable and poor in the sense that variance of the regression coefficients may be inflated and absolute values of the estimates may be too large. There are several classes of biased estimators in statistical literature to decrease the effect of multicollinearity in the design matrix. Here, based on the Cholesky decomposition, we propose such an estimator which makes the data to be slightly distorted. The exact risk expressions as well as the biases are derived for the proposed estimator. Also, some results demonstrating superiority of the suggested estimator over OLSE are obtained. Finally, a Monté-Carlo simulation study and a real data application related to acetylene data are presented to support our theoretical discussions.     

基于排序集样本和辅助变量中位数的均值比率估计方法

排序集抽样下利用辅助变量中位数构建了总体均值的改进比率估计模型,分析了该比率估计量的偏差和均方误差,并与简单随机抽样下的比率估计比较,证明了改进后的比率估计均方误差更小。以农作物播种面积和产量为研究对象进行实例分析,研究表明,基于排序集样本和辅助变量中位数的比率估计方法可以有效提高估计精度,验证了该构造方法的可行性。     

Bias correction of estimated proportions using inverse binomial group testing

Group testing, in which individuals are pooled together and tested as a group, can be combined with inverse sampling to estimate the prevalence of a disease. Alternatives to the MLE are desirable because of its severe bias. We propose an estimator based on the bias correction method of Firth (1993), which is almost unbiased across the range of prevalences consistent with the group testing design. For equal group sizes, this estimator is shown to be equivalent to that derived by applying the correction method of Burrows (1987), and better than existing methods. For unequal group sizes, the problem has some intractable elements, but under some circumstances our proposed estimator can be found, and we show it to be almost unbiased. Calculation of the bias requires computer‐intensive approximation because of the infinite number of possible outcomes.     

Reducing bias in parameter estimates from stepwise regression in proportional hazards regression with right-censored data

When variable selection with stepwise regression and model fitting are conducted on the same data set, competition for inclusion in the model induces a selection bias in coefficient estimators away from zero. In proportional hazards regression with right-censored data, selection bias inflates the absolute value of parameter estimate of selected parameters, while the omission of other variables may shrink coefficients toward zero. This paper explores the extent of the bias in parameter estimates from stepwise proportional hazards regression and proposes a bootstrap method, similar to those proposed by Miller (Subset Selection in Regression, 2nd edn. Chapman & Hall/CRC, 2002) for linear regression, to correct for selection bias. We also use bootstrap methods to estimate the standard error of the adjusted estimators. Simulation results show that substantial biases could be present in uncorrected stepwise estimators and, for binary covariates, could exceed 250% of the true parameter value. The simulations also show that the conditional mean of the proposed bootstrap bias-corrected parameter estimator, given that a variable is selected, is moved closer to the unconditional mean of the standard partial likelihood estimator in the chosen model, and to the population value of the parameter. We also explore the effect of the adjustment on estimates of log relative risk, given the values of the covariates in a selected model. The proposed method is illustrated with data sets in primary biliary cirrhosis and in multiple myeloma from the Eastern Cooperative Oncology Group.     

Truncated Midzuno–Sen Sampling Schemes for Estimating Distribution Functions

We consider a truncated Midzuno–Sen sampling scheme. The proposed method can be used to estimate the distribution function of a study variable assuming that the distribution function of an auxiliary variable is known. The ratio estimator for estimating the distribution function is shown to remain unbiased. We introduce the first- and second-order inclusion probabilities under the truncated Midzuno–Sen sampling scheme. Numerical examples are provided to support our theoretical results.     

Inference for domains under imputation for missing survey data

The authors study the estimation of domain totals and means under survey‐weighted regression imputation for missing items. They use two different approaches to inference: (i) design‐based with uniform response within classes; (ii) model‐assisted with ignorable response and an imputation model. They show that the imputed domain estimators are biased under (i) but approximately unbiased under (ii). They obtain a bias‐adjusted estimator that is approximately unbiased under (i) or (ii). They also derive linearization variance estimators. They report the results of a simulation study on the bias ratio and efficiency of alternative estimators, including a complete case estimator that requires the knowledge of response indicators.     

Nonparametric Additive Instrumental Variable Estimator: A Group Shrinkage Estimation Perspective

In this article, we study a nonparametric approach regarding a general nonlinear reduced form equation to achieve a better approximation of the optimal instrument. Accordingly, we propose the nonparametric additive instrumental variable estimator (NAIVE) with the adaptive group Lasso. We theoretically demonstrate that the proposed estimator is root-n consistent and asymptotically normal. The adaptive group Lasso helps us select the valid instruments while the dimensionality of potential instrumental variables is allowed to be greater than the sample size. In practice, the degree and knots of B-spline series are selected by minimizing the BIC or EBIC criteria for each nonparametric additive component in the reduced form equation. In Monte Carlo simulations, we show that the NAIVE has the same performance as the linear instrumental variable (IV) estimator for the truly linear reduced form equation. On the other hand, the NAIVE performs much better in terms of bias and mean squared errors compared to other alternative estimators under the high-dimensional nonlinear reduced form equation. We further illustrate our method in an empirical study of international trade and growth. Our findings provide a stronger evidence that international trade has a significant positive effect on economic growth.     

Conditional estimation using prior information in 2‐stage group sequential designs assuming asymptotic normality when the trial terminated early

Two‐stage designs are widely used to determine whether a clinical trial should be terminated early. In such trials, a maximum likelihood estimate is often adopted to describe the difference in efficacy between the experimental and reference treatments; however, this method is known to display conditional bias. To reduce such bias, a conditional mean‐adjusted estimator (CMAE) has been proposed, although the remaining bias may be nonnegligible when a trial is stopped for efficacy at the interim analysis. We propose a new estimator for adjusting the conditional bias of the treatment effect by extending the idea of the CMAE. This estimator is calculated by weighting the maximum likelihood estimate obtained at the interim analysis and the effect size prespecified when calculating the sample size. We evaluate the performance of the proposed estimator through analytical and simulation studies in various settings in which a trial is stopped for efficacy or futility at the interim analysis. We find that the conditional bias of the proposed estimator is smaller than that of the CMAE when the information time at the interim analysis is small. In addition, the mean‐squared error of the proposed estimator is also smaller than that of the CMAE. In conclusion, we recommend the use of the proposed estimator for trials that are terminated early for efficacy or futility.     

SUR Approach for IV Estimation of Canonical Contagion Models

Seemingly unrelated regression (SUR) method is applied to the instrumental variable (IV) estimation of the canonical contagion models. A finite sample Monte Carlo experiment shows that the resulting estimator, IV-SUR estimator, is substantially better than the existing IV estimator in terms of both bias and mean squares error under diverse circumstance of instrument, conditional heteroscedasticity, and cross-section correlation.     

Unbiased and almost unbiased ratio estimators of the population mean in ranked set sampling

In this paper we study the problem of reducing the bias of the ratio estimator of the population mean in a ranked set sampling (RSS) design. We first propose a jackknifed RSS-ratio estimator and then introduce a class of almost unbiased RSS-ratio estimators of the population mean. We also present an unbiased RSS-ratio estimator of the mean using the idea of Hartley and Ross (Nature 174:270?C271, 1954) which performs better than its counterpart with simple random sample data. We show that under certain conditions the proposed unbiased and almost unbiased RSS-ratio estimators perform better than the commonly used (biased) RSS-ratio estimator in estimating the population mean in terms of the mean square error. The theoretical results are augmented by a simulation study using a wheat yield data set from the Iranian Ministry of Agriculture to demonstrate the practical benefits of our proposed ratio-type estimators relative to the RSS-ratio estimator in reducing the bias in estimating the average wheat production.     

Testing the Unconfoundedness Assumption via Inverse Probability Weighted Estimators of (L)ATT

We propose inverse probability weighted estimators for the local average treatment effect (LATE) and the local average treatment effect for the treated (LATT) under instrumental variable assumptions with covariates. We show that these estimators are asymptotically normal and efficient. When the (binary) instrument satisfies one-sided noncompliance, we propose a Durbin–Wu–Hausman-type test of whether treatment assignment is unconfounded conditional on some observables. The test is based on the fact that under one-sided noncompliance LATT coincides with the average treatment effect for the treated (ATT). We conduct Monte Carlo simulations to demonstrate, among other things, that part of the theoretical efficiency gain afforded by unconfoundedness in estimating ATT survives pretesting. We illustrate the implementation of the test on data from training programs administered under the Job Training Partnership Act in the United States. This article has online supplementary material.     

Some conditions for optimality of the almost unbiased estimators of regression coefficients

The purpose of this paper is to examine the asymptotic properties of the operational almost unbiased estimator of regression coefficients which includes almost unbiased ordinary ridge estimator a s a special case. The small distrubance approximations for the bias and mean square error matrix of the estimator are derived. As a consequence, it is proved that, under certain conditions, the estimator is more efficient than a general class of estimators given by Vinod and Ullah (1981). Also it is shown that, if the ordinary ridge estimator (ORE) dominates the ordinary least squares estimator then the almost unbiased ordinary ridge estimator does not dominate ORE under the mean square error criterion.     

Trimmed least squares estimator as best trimmed linear conditional estimator for linear regression model

A class of trimmed linear conditional estimators based on regression quantiles for the linear regression model is introduced. This class serves as a robust analogue of non-robust linear unbiased estimators. Asymptotic analysis then shows that the trimmed least squares estimator based on regression quantiles ( Koenker and Bassett ( 1978 ) ) is the best in this estimator class in terms of asymptotic covariance matrices. The class of trimmed linear conditional estimators contains the Mallows-type bounded influence trimmed means ( see De Jongh et al ( 1988 ) ) and trimmed instrumental variables estimators. A large sample methodology based on trimmed instrumental variables estimator for confidence ellipsoids and hypothesis testing is also provided.     

Likelihood methods in randomized trials with noncompliance and subsequent nonresponse

This article considers likelihood methods for estimating the causal effect of treatment assignment for a two-armed randomized trial assuming all-or-none treatment noncompliance and allowing for subsequent nonresponse. We first derive the observed data likelihood function as a closed form expression of the parameter given the observed data where both response and compliance state are treated as variables with missing values. Then we describe an iterative procedure which maximizes the observed data likelihood function directly to compute a maximum likelihood estimator (MLE) of the causal effect of treatment assignment. Closed form expressions at each iterative step are provided. Finally we compare the MLE with an alternative estimator where the probability distribution of the compliance state is estimated independent of the response and its missingness mechanism. Our work indicates that direct maximum likelihood inference is straightforward for this problem. Extensive simulation studies are provided to examine the finite sample performance of the proposed methods.     

Landmark estimation of survival and treatment effects in observational studies

Clinical studies aimed at identifying effective treatments to reduce the risk of disease or death often require long term follow-up of participants in order to observe a sufficient number of events to precisely estimate the treatment effect. In such studies, observing the outcome of interest during follow-up may be difficult and high rates of censoring may be observed which often leads to reduced power when applying straightforward statistical methods developed for time-to-event data. Alternative methods have been proposed to take advantage of auxiliary information that may potentially improve efficiency when estimating marginal survival and improve power when testing for a treatment effect. Recently, Parast et al. (J Am Stat Assoc 109(505):384–394, 2014) proposed a landmark estimation procedure for the estimation of survival and treatment effects in a randomized clinical trial setting and demonstrated that significant gains in efficiency and power could be obtained by incorporating intermediate event information as well as baseline covariates. However, the procedure requires the assumption that the potential outcomes for each individual under treatment and control are independent of treatment group assignment which is unlikely to hold in an observational study setting. In this paper we develop the landmark estimation procedure for use in an observational setting. In particular, we incorporate inverse probability of treatment weights (IPTW) in the landmark estimation procedure to account for selection bias on observed baseline (pretreatment) covariates. We demonstrate that consistent estimates of survival and treatment effects can be obtained by using IPTW and that there is improved efficiency by using auxiliary intermediate event and baseline information. We compare our proposed estimates to those obtained using the Kaplan–Meier estimator, the original landmark estimation procedure, and the IPTW Kaplan–Meier estimator. We illustrate our resulting reduction in bias and gains in efficiency through a simulation study and apply our procedure to an AIDS dataset to examine the effect of previous antiretroviral therapy on survival.     

Asymptotic and finite sample behavior of the time on test estimator under random censorship when lifetimes are not Exponetial

The robustness of the time on test estimator of mean life is studied in both asymptotic and finite sample situations under random censorship. The estimator is shown t o be asymptotically normal and generally in consistent , unless the life time sare exponential . The limiting value of the estimator depends on both the life time and censorship distributions . A simulations tudy of finite sample behavior shows that biases a reslight under exponentiality and serious if exponentia lity is viol at ed . The finite sample behavior is not well described by the limiting normal distribution . Jackknifing produces a useful variance estimate, but is of little value in bias correction.     

Approaches to regression analysis with multiple measurements from individual sampling units

Application of ordinary least-squares regression to data sets which contain multiple measurements from individual sampling units produces an unbiased estimator of the parameters but a biased estimator of the covariance matrix of the parameter estimates. The present work considers a random coefficient, linear model to deal with such data sets: this model permits many senses in which multiple measurements are taken from a sampling unit, not just when it is measured at several times. Three procedures to estimate the covariance matrix of the error term of the model are considered. Given these, three procedures to estimate the parameters of the model and their covariance matrix are considered; these are ordinary least-squares, generalized least-squares, and an adjusted ordinary least-squares procedure which produces an unbiased estimator of the covariance matrix of the parameters with small samples. These various procedures are compared in simulation studies using three examples from the biological literature. The possibility of testing hypotheses about the vector of parameters is also considered. It is found that all three procedures for regression estimation produce estimators of the parameters with bias of no practical consequence, Both generalized least-squares and adjusted ordinary least-squares generally produce estimators of the covariance matrix of the parameter estimates with bias of no practical consequence, while ordinary least-squares produces a negatively biased estimator. Neither ordinary nor generalized least-squares provide satisfactory hypothesis tests of the vector of parameter estimates. It is concluded that adjusted ordinary least-squares, when applied with either of two of the procedures used to estimate the error coveriance matrix, shows promise for practical application with data sets of the nature considered here.     

抽样调查中基于平衡样本的稳健预测

抽样调查中基于模型推断方法获得的估计量性质是依赖于模型的。在恰当的模型下比率估计和扩张估计是最优线性无偏估计。当模型设定错误时,比率估计和扩张估计是有偏估计,但如果样本是平衡的,可以消除偏倚,从而实现了复杂问题简单处理的思想。     

Efficient mean estimation in log-normal linear models

Log-normal linear models are widely used in applications, and many times it is of interest to predict the response variable or to estimate the mean of the response variable at the original scale for a new set of covariate values. In this paper we consider the problem of efficient estimation of the conditional mean of the response variable at the original scale for log-normal linear models. Several existing estimators are reviewed first, including the maximum likelihood (ML) estimator, the restricted ML (REML) estimator, the uniformly minimum variance unbiased (UMVU) estimator, and a bias-corrected REML estimator. We then propose two estimators that minimize the asymptotic mean squared error and the asymptotic bias, respectively. A parametric bootstrap procedure is also described to obtain confidence intervals for the proposed estimators. Both the new estimators and the bootstrap procedure are very easy to implement. Comparisons of the estimators using simulation studies suggest that our estimators perform better than the existing ones, and the bootstrap procedure yields confidence intervals with good coverage properties. A real application of estimating the mean sediment discharge is used to illustrate the methodology.