Handling of missing data in long‐term clinical trials: a case study

Missing data in clinical trials is a well‐known problem, and the classical statistical methods used can be overly simple. This case study shows how well‐established missing data theory can be applied to efficacy data collected in a long‐term open‐label trial with a discontinuation rate of almost 50%. Satisfaction with treatment in chronically constipated patients was the efficacy measure assessed at baseline and every 3 months postbaseline. The improvement in treatment satisfaction from baseline was originally analyzed with a paired t‐test ignoring missing data and discarding the correlation structure of the longitudinal data. As the original analysis started from missing completely at random assumptions regarding the missing data process, the satisfaction data were re‐examined, and several missing at random (MAR) and missing not at random (MNAR) techniques resulted in adjusted estimate for the improvement in satisfaction over 12 months. Throughout the different sensitivity analyses, the effect sizes remained significant and clinically relevant. Thus, even for an open‐label trial design, sensitivity analysis, with different assumptions for the nature of dropouts (MAR or MNAR) and with different classes of models (selection, pattern‐mixture, or multiple imputation models), has been found useful and provides evidence towards the robustness of the original analyses; additional sensitivity analyses could be undertaken to further qualify robustness. Copyright © 2012 John Wiley & Sons, Ltd.     

追寻“真苏轼”——从《一本书读懂中国美术史》说起

研究探讨"真苏轼",应严守学术规范,作正确解读。以《一本书读懂中国美术史》为例,可见误读频仍。该文用不足两千字的篇幅介绍苏轼生平及其文人画理论,竟有十来处违背学术规范,甚至出现令人啼笑皆非的漏误。此类所谓论著歪曲了苏轼本真,因此需呼吁:"真苏轼"不要离去,"真学者"与你同在。     

从传统制度到制度缺失——箐口村的垃圾处理问题

1998年之前,箐口村是一个没有现代厕所和垃圾处理场的村寨。此后,旅游和政府介入,该村的垃圾处理便按照村民原来的方式和政府规定的方式进行,即回归自然、填埋、焚烧。2008年世博集团和当地旅游局签订旅游开发协议,聘请专门的卫生保洁员对箐口民俗村的卫生状况进行维护,但处理成效却无法达标。随着旅游的扩大,该村的垃圾开始成灾。...     

Toward Best Practices in Analyzing Datasets with Missing Data: Comparisons and Recommendations

Although several methods have been developed to allow for the analysis of data in the presence of missing values, no clear guide exists to help family researchers in choosing among the many options and procedures available. We delineate these options and examine the sensitivity of the findings in a regression model estimated in three random samples from the National Survey of Families and Households (n = 250–2,000). These results, combined with findings from simulation studies, are used to guide answers to a set of 10 common questions asked by researchers when selecting a missing data approach. Modern missing data techniques were found to perform better than traditional ones, but differences between the types of modern approaches had minor effects on the estimates and substantive conclusions. Our findings suggest that the researcher has considerable flexibility in selecting among modern options for handling missing data.     

基于数据缺失率和缺失模式的多重插补误差研究

文章通过多重插补方法对不同缺失率和缺失模式的多变量缺失样本进行插补,研究了多重插补误差与缺失率和缺失模式的依赖关系。结果表明,当缺失率为0~15%时,多重插补误差与缺失率呈线性关系;当缺失率大于15%时,两者呈偏离线性关系。多重插补误差与缺失模式的方差均值比呈正相关性,当方差均值比越大时,误差也越大。     

Effects of correlation and missing data on sample size estimation in longitudinal clinical trials

In longitudinal clinical trials, a common objective is to compare the rates of changes in an outcome variable between two treatment groups. Generalized estimating equation (GEE) has been widely used to examine if the rates of changes are significantly different between treatment groups due to its robustness to misspecification of the true correlation structure and randomly missing data. The sample size formula for repeated outcomes is based on the assumption of missing completely at random and a large sample approximation. A simulation study is conducted to investigate the performance of GEE sample size formula with small sample sizes, damped exponential family of correlation structure and non‐ignorable missing data. Copyright © 2008 John Wiley & Sons, Ltd.     

Using multiple imputation to estimate cumulative distribution functions in longitudinal data analysis with data missing at random

In longitudinal clinical studies, after randomization at baseline, subjects are followed for a period of time for development of symptoms. The interested inference could be the mean change from baseline to a particular visit in some lab values, the proportion of responders to some threshold category at a particular visit post baseline, or the time to some important event. However, in some applications, the interest may be in estimating the cumulative distribution function (CDF) at a fixed time point post baseline. When the data are fully observed, the CDF can be estimated by the empirical CDF. When patients discontinue prematurely during the course of the study, the empirical CDF cannot be directly used. In this paper, we use multiple imputation as a way to estimate the CDF in longitudinal studies when data are missing at random. The validity of the method is assessed on the basis of the bias and the Kolmogorov–Smirnov distance. The results suggest that multiple imputation yields less bias and less variability than the often used last observation carried forward method. Copyright © 2013 John Wiley & Sons, Ltd.     

Missing value imputation method for disaster decision-making using K nearest neighbor

Due to destructiveness of natural disasters, restriction of disaster scenarios and some human causes, missing data usually occur in disaster decision-making problems. In order to estimate missing values of alternatives, this paper focuses on imputing heterogeneous attribute values of disaster based on an improved K nearest neighbor imputation (KNNI) method. Firstly, some definitions of trapezoidal fuzzy numbers (TFNs) are introduced and three types of attributes (i.e. linguistic term sets, intervals and real numbers) are converted to TFNs. Then the correlated degree model is utilized to extract related attributes to form instances that will be used in K nearest neighbor algorithm, and a novel KNNI method merging with correlated degree model is presented. Finally, an illustrative example is given to verify the proposed method and to demonstrate its feasibility and effectiveness.     

An Extended Single‐index Model with Missing Response at Random

An extended single‐index model is considered when responses are missing at random. A three‐step estimation procedure is developed to define an estimator for the single‐index parameter vector by a joint estimating equation. The proposed estimator is shown to be asymptotically normal. An algorithm for computing this estimator is proposed. This algorithm only involves one‐dimensional nonparametric smoothers, thereby avoiding the data sparsity problem caused by high model dimensionality. Some simulation studies are conducted to investigate the finite sample performances of the proposed estimators.     

Mean estimation with data missing at random for functional covariables

In a missing-data setting, we want to estimate the mean of a scalar outcome, based on a sample in which an explanatory variable is observed for every subject while responses are missing by happenstance for some of them. We consider two kinds of estimates of the mean response when the explanatory variable is functional. One is based on the average of the predicted values and the second one is a functional adaptation of the Horvitz–Thompson estimator. We show that the infinite dimensionality of the problem does not affect the rates of convergence by stating that the estimates are root-n consistent, under missing at random (MAR) assumption. These asymptotic features are completed by simulated experiments illustrating the easiness of implementation and the good behaviour on finite sample sizes of the method. This is the first paper emphasizing that the insensitiveness of averaged estimates, well known in multivariate non-parametric statistics, remains true for an infinite-dimensional covariable. In this sense, this work opens the way for various other results of this kind in functional data analysis.