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.     

Empirical likelihood confidence intervals under imputation for missing survey data from stratified simple random sampling

Missing observations due to non‐response are commonly encountered in data collected from sample surveys. The focus of this article is on item non‐response which is often handled by filling in (or imputing) missing values using the observed responses (donors). Random imputation (single or fractional) is used within homogeneous imputation classes that are formed on the basis of categorical auxiliary variables observed on all the sampled units. A uniform response rate within classes is assumed, but that rate is allowed to vary across classes. We construct confidence intervals (CIs) for a population parameter that is defined as the solution to a smooth estimating equation with data collected using stratified simple random sampling. The imputation classes are assumed to be formed across strata. Fractional imputation with a fixed number of random draws is used to obtain an imputed estimating function. An empirical likelihood inference method under the fractional imputation is proposed and its asymptotic properties are derived. Two asymptotically correct bootstrap methods are developed for constructing the desired CIs. In a simulation study, the proposed bootstrap methods are shown to outperform traditional bootstrap methods and some non‐bootstrap competitors under various simulation settings. The Canadian Journal of Statistics 47: 281–301; 2019 © 2019 Statistical Society of Canada     

k-POD: A Method for k-Means Clustering of Missing Data

The k-means algorithm is often used in clustering applications but its usage requires a complete data matrix. Missing data, however, are common in many applications. Mainstream approaches to clustering missing data reduce the missing data problem to a complete data formulation through either deletion or imputation but these solutions may incur significant costs. Our k-POD method presents a simple extension of k-means clustering for missing data that works even when the missingness mechanism is unknown, when external information is unavailable, and when there is significant missingness in the data.

[Received November 2014. Revised August 2015.]     

Bayesian analysis of multivariate t linear mixed models with missing responses at random

The multivariate t linear mixed model (MtLMM) has been recently proposed as a robust tool for analysing multivariate longitudinal data with atypical observations. Missing outcomes frequently occur in longitudinal research even in well controlled situations. As a powerful alternative to the traditional expectation maximization based algorithm employing single imputation, we consider a Bayesian analysis of the MtLMM to account for the uncertainties of model parameters and missing outcomes through multiple imputation. An inverse Bayes formulas sampler coupled with Metropolis-within-Gibbs scheme is used to effectively draw the posterior distributions of latent data and model parameters. The techniques for multiple imputation of missing values, estimation of random effects, prediction of future responses, and diagnostics of potential outliers are investigated as well. The proposed methodology is illustrated through a simulation study and an application to AIDS/HIV data.     

Multiple imputation of censored survival data in the presence of missing covariates using restricted mean survival time

Missing covariates data with censored outcomes put a challenge in the analysis of clinical data especially in small sample settings. Multiple imputation (MI) techniques are popularly used to impute missing covariates and the data are then analyzed through methods that can handle censoring. However, techniques based on MI are available to impute censored data also but they are not much in practice. In the present study, we applied a method based on multiple imputation by chained equations to impute missing values of covariates and also to impute censored outcomes using restricted survival time in small sample settings. The complete data were then analyzed using linear regression models. Simulation studies and a real example of CHD data show that the present method produced better estimates and lower standard errors when applied on the data having missing covariate values and censored outcomes than the analysis of the data having censored outcome but excluding cases with missing covariates or the analysis when cases with missing covariate values and censored outcomes were excluded from the data (complete case analysis).     

基于随机森林模型的分类数据缺失值插补

缺失数据是影响调查问卷数据质量的重要因素,对调查问卷中的缺失值进行插补可以显著提高调查数据的质量。调查问卷的数据类型多以分类型数据为主,数据挖掘技术中的分类算法是处理属性分类问题的常用方法,随机森林模型是众多分类算法中精度较高的方法之一。将随机森林模型引入调查问卷缺失数据的插补研究中,提出了基于随机森林模型的分类数据缺失值插补方法,并根据不同的缺失模式探讨了相应的插补步骤。通过与其它方法的实证模拟比较,表明随机森林插补法得到的插补值准确度更优、可信度更高。     

Predictive performance of missing data methods for logistic regression,classification trees and neural networks

Although the effect of missing data on regression estimates has received considerable attention, their effect on predictive performance has been neglected. We studied the performance of three missing data strategies—omission of records with missing values, replacement with a mean and imputation based on regression—on the predictive performance of logistic regression (LR), classification tree (CT) and neural network (NN) models in the presence of data missing completely at random (MCAR). Models were constructed using datasets of size 500 simulated from a joint distribution of binary and continuous predictors including nonlinearities, collinearity and interactions between variables. Though omission produced models that fit better on the data from which the models were developed, imputation was superior on average to omission for all models when evaluating the receiver operating characteristic (ROC) curve area, mean squared error (MSE), pooled variance across outcome categories and calibration X ² on an independently generated test set. However, in about one-third of simulations, omission performed better. Performance was also more variable with omission including quite a few instances of extremely poor performance. Replacement and imputation generally produced similar results except with neural networks for which replacement, the strategy typically used in neural network algorithms, was inferior to imputation. Missing data affected simpler models much less than they did more complex models such as generalized additive models that focus on local structure For moderate sized datasets, logistic regressions that use simple nonlinear structures such as quadratic terms and piecewise linear splines appear to be at least as robust to randomly missing values as neural networks and classification trees.     

Multiple imputation for ordinal longitudinal data with monotone missing data patterns

Missing data often complicate the analysis of scientific data. Multiple imputation is a general purpose technique for analysis of datasets with missing values. The approach is applicable to a variety of missing data patterns but often complicated by some restrictions like the type of variables to be imputed and the mechanism underlying the missing data. In this paper, the authors compare the performance of two multiple imputation methods, namely fully conditional specification and multivariate normal imputation in the presence of ordinal outcomes with monotone missing data patterns. Through a simulation study and an empirical example, the authors show that the two methods are indeed comparable meaning any of the two may be used when faced with scenarios, at least, as the ones presented here.     

An experiment in primary health care provision

Missing data and, more generally, imperfections in implementing a study design are an endemic problem in large scale studies involving human subjects. We present an analysis of an experiment in the interaction between general practitioners and their patients, in which the issue of missing data is addressed by a sensitivity analysis using multiple imputation. Instead of specifying a model for missingness we explore certain extreme ways of departing from the assumption of data missing at random and establish the largest extent of such departures which would still fail to supplant the evidence about the studied effect. An important advantage of the approach is that the algorithm intended for the complete data, to fit generalized linear models with random effects, is used without any alteration.     

Balanced k-nearest neighbour imputation

Random imputation is an interesting class of imputation methods to handle item nonresponse because it tends to preserve the distribution of the imputed variable. However, such methods amplify the total variance of the estimators because values are imputed at random. This increase in variance is called imputation variance. In this paper, we propose a new random hot-deck imputation method that is based on the k-nearest neighbour methodology. It replaces the missing value of a unit with the observed value of a similar unit. Calibration and balanced sampling are applied to minimize the imputation variance. Moreover, our proposed method provides triple protection against nonresponse bias. This means that if at least one out of three specified models holds, then the resulting total estimator is unbiased. Finally, our approach allows the user to perform consistency edits and to impute simultaneously.     

Comparisons of imputation methods with application to assess factors associated with self efficacy of physical activity in breast cancer survivors

ABSTRACT

Missing data are commonly encountered in self-reported measurements and questionnaires. It is crucial to treat missing values using appropriate method to avoid bias and reduction of power. Various types of imputation methods exist, but it is not always clear which method is preferred for imputation of data with non-normal variables. In this paper, we compared four imputation methods: mean imputation, quantile imputation, multiple imputation, and quantile regression multiple imputation (QRMI), using both simulated and real data investigating factors affecting self-efficacy in breast cancer survivors. The results displayed an advantage of using multiple imputation, especially QRMI when data are not normal.     

Statistical inference under imputation for proportional hazard model with missing covariates

Missing covariate data are common in biomedical studies. In this article, by using the non parametric kernel regression technique, a new imputation approach is developed for the Cox-proportional hazard regression model with missing covariates. This method achieves the same efficiency as the fully augmented weighted estimators (Qi et al. 2005. Journal of the American Statistical Association, 100:1250) and has a simpler form. The asymptotic properties of the proposed estimator are derived and analyzed. The comparisons between the proposed imputation method and several other existing methods are conducted via a number of simulation studies and a mouse leukemia data.     

Tukey's gh Distribution for Multiple Imputation

Tukey proposed a class of distributions, the g-and-h family (gh family), based on a transformation of a standard normal variable to accommodate different skewness and elongation in the distribution of variables arising in practical applications. It is easy to draw values from this distribution even though it is hard to explicitly state the probability density function. Given this flexibility, the gh family may be extremely useful in creating multiple imputations for missing data. This article demonstrates how this family, as well as its generalizations, can be used in the multiple imputation analysis of incomplete data. The focus of this article is on a scalar variable with missing values. In the absence of any additional information, data are missing completely at random, and hence the correct analysis is the complete-case analysis. Thus, the application of the gh multiple imputation to the scalar cases affords comparison with the correct analysis and with other model-based multiple imputation methods. Comparisons are made using simulated datasets and the data from a survey of adolescents ascertaining driving after drinking alcohol.     

Imputation of missing variance data using non-linear mixed effects modelling to enable an inverse variance weighted meta-analysis of summary-level longitudinal data: a case study

Missing variances, on the basis of the summary-level data, can be a problem when an inverse variance weighted meta-analysis is undertaken. A wide range of approaches in dealing with this issue exist, such as excluding data without a variance measure, using a function of sample size as a weight and imputing the missing standard errors/deviations. A non-linear mixed effects modelling approach was taken to describe the time-course of standard deviations across 14 studies. The model was then used to make predictions of the missing standard deviations, thus, enabling a precision weighted model-based meta-analysis of a mean pain endpoint over time. Maximum likelihood and Bayesian approaches were implemented with example code to illustrate how this imputation can be carried out and to compare the output from each method. The resultant imputations were nearly identical for the two approaches. This modelling approach acknowledges the fact that standard deviations are not necessarily constant over time and can differ between treatments and across studies in a predictable way.     

基于分层模型的缺失数据插补方法研究

大规模抽样调查多采用复杂抽样设计,得到具有分层嵌套结构的调查数据集,其中不可避免会遇到数据缺失问题,针对分层结构含缺失数据集的插补策略目前鲜有研究。本文将Gibbs算法应用到分层含缺失数据集的多重插补过程中,分别研究了固定效应模型插补法和随机效应模型插补法,进而通过理论推导和数值模拟,在不同组内相关系数、群组规模、数据缺失比例等情形下,从参数估计结果的无偏性和有效性两方面,比较不同方法的插补效果,给出插补模型的选择建议。研究结果表明,采用随机效应模型作为插补模型时,得到的参数估计结果更准确,而固定效应模型作为插补模型操作相对简便,在数据缺失比例较小、组内相关系数较大、群组规模较大等情形下,可以采用固定效应插补模型,否则建议采用随机效应插补模型。     

Latent class based multiple imputation approach for missing categorical data

In this paper we propose a latent class based multiple imputation approach for analyzing missing categorical covariate data in a highly stratified data model. In this approach, we impute the missing data assuming a latent class imputation model and we use likelihood methods to analyze the imputed data. Via extensive simulations, we study its statistical properties and make comparisons with complete case analysis, multiple imputation, saturated log-linear multiple imputation and the Expectation–Maximization approach under seven missing data mechanisms (including missing completely at random, missing at random and not missing at random). These methods are compared with respect to bias, asymptotic standard error, type I error, and 95% coverage probabilities of parameter estimates. Simulations show that, under many missingness scenarios, latent class multiple imputation performs favorably when jointly considering these criteria. A data example from a matched case–control study of the association between multiple myeloma and polymorphisms of the Inter-Leukin 6 genes is considered.     

Split Questionnaire Designs: collecting only the data that you need through MCAR and MAR designs

We call a sample design that allows for different patterns, or sets, of data items to be collected from different sample units a Split Questionnaire Design (SQD). SQDs can be thought of as incorporating missing data into survey design. This paper examines the situation where data that are not collected by an SQD can be treated as Missing Completely At Random or Missing At Random, targets are regression coefficients in a generalised linear model fitted to binary variables, and targets are estimated using Maximum Likelihood. A key finding is that it can be easy to measure the relative contribution of a respondent to the accuracy of estimated model parameters before collecting all the respondent's model covariates. We show empirically and theoretically that we could achieve a significant reduction in respondent burden with a negligible impact on the accuracy of estimates by not collecting model covariates from respondents who we identify as contributing little to the accuracy of estimates. We discuss the general implications for SQDs.     

Estimation of total electricity consumption curves by sampling in a finite population when some trajectories are partially unobserved

Millions of smart meters that are able to collect individual load curves, that is, electricity consumption time series, of residential and business customers at fine scale time grids are now deployed by electricity companies all around the world. It may be complex and costly to transmit and exploit such a large quantity of information, therefore it can be relevant to use survey sampling techniques to estimate mean load curves of specific groups of customers. Data collection, like every mass process, may undergo technical problems at every point of the metering and collection chain resulting in missing values. We consider imputation approaches (linear interpolation, kernel smoothing, nearest neighbours, principal analysis by conditional estimation) that take advantage of the specificities of the data, that is to say the strong relation between the consumption at different instants of time. The performances of these techniques are compared on a real example of Irish electricity load curves under various scenarios of missing data. A general variance approximation of total estimators is also given which encompasses nearest neighbours, kernel smoothers imputation and linear imputation methods. The Canadian Journal of Statistics 47: 65–89; 2019 © 2018 Statistical Society of Canada     

A note on dealing with missing standard errors in meta-analyses of continuous outcome measures in WinBUGS

A meta-analysis of a continuous outcome measure may involve missing standard errors. This is not a problem depending on assumptions made about the population standard deviation. Multiple imputation can be used to impute missing values while allowing for uncertainty in the imputation. Markov chain Monte Carlo simulation is a multiple imputation technique for generating posterior predictive distributions for missing data. We present an example of imputing missing variances using WinBUGS. The example highlights the importance of checking model assumptions, whether for missing or observed data.     

Illuminate the unknown: evaluation of imputation procedures based on the SAVE survey

Questions about monetary variables (such as income, wealth or savings) are key components of questionnaires on household finances. However, missing information on such sensitive topics is a well-known phenomenon which can seriously bias any inference based only on complete-case analysis. Many imputation techniques have been developed and implemented in several surveys. Using the German SAVE data, a new estimation technique is necessary to overcome the upward bias of monetary variables caused by the initially implemented imputation procedure. The upward bias is the result of adding random draws to the implausible negative values predicted by OLS regressions until all values are positive. To overcome this problem the logarithm of the dependent variable is taken and the predicted values are retransformed to the original scale by Duan’s smearing estimate. This paper evaluates the two different techniques for the imputation of monetary variables implementing a simulation study, where a random pattern of missingness is imposed on the observed values of the variables of interest. A Monte-Carlo simulation based on the observed data shows the superiority of the newly implemented smearing estimate to construct the missing data structure. All waves are consistently imputed using the new method.