Imputing missing quality of life data as covariate in survival analysis of the International Breast Cancer Study Group Trials VI and VII

Quality of life (QoL) was an important endpoint in the adjuvant breast cancer trials International Breast Cancer Study Group (IBCSG) Trial VI and VII. Here, QoL was considered as a time-dependent effect. The hypothesis explored is that poorer QoL throughout the trial is associated with poorer disease-free survival (DFS) and vice-versa. Potential bias in the parameter estimates is an important concern associated with missing observations. Standard simple and multiple imputation methods were applied to missing QoL assessments before analysis in a time-dependent Cox model. There was no evidence that the patient's QoL is related to the patient's DFS.     

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.     

Stochastic EM algorithm of a finite mixture model from hurdle Poisson distribution with missing responses

ABSTRACT

In this article, a finite mixture model of hurdle Poisson distribution with missing outcomes is proposed, and a stochastic EM algorithm is developed for obtaining the maximum likelihood estimates of model parameters and mixing proportions. Specifically, missing data is assumed to be missing not at random (MNAR)/non ignorable missing (NINR) and the corresponding missingness mechanism is modeled through probit regression. To improve the algorithm efficiency, a stochastic step is incorporated into the E-step based on data augmentation, whereas the M-step is solved by the method of conditional maximization. A variation on Bayesian information criterion (BIC) is also proposed to compare models with different number of components with missing values. The considered model is a general model framework and it captures the important characteristics of count data analysis such as zero inflation/deflation, heterogeneity as well as missingness, providing us with more insight into the data feature and allowing for dispersion to be investigated more fully and correctly. Since the stochastic step only involves simulating samples from some standard distributions, the computational burden is alleviated. Once missing responses and latent variables are imputed to replace the conditional expectation, our approach works as part of a multiple imputation procedure. A simulation study and a real example illustrate the usefulness and effectiveness of our methodology.     

Identifying treatment effects using trimmed means when data are missing not at random

Patients often discontinue from a clinical trial because their health condition is not improving or they cannot tolerate the assigned treatment. Consequently, the observed clinical outcomes in the trial are likely better on average than if every patient had completed the trial. If these differences between trial completers and non-completers cannot be explained by the observed data, then the study outcomes are missing not at random (MNAR). One way to overcome this problem—the trimmed means approach for missing data due to study discontinuation—sets missing values as the worst observed outcome and then trims away a fraction of the distribution from each treatment arm before calculating differences in treatment efficacy (Permutt T, Li F. Trimmed means for symptom trials with dropouts. Pharm Stat. 2017;16(1):20–28). In this paper, we derive sufficient and necessary conditions for when this approach can identify the average population treatment effect. Simulation studies show the trimmed means approach's ability to effectively estimate treatment efficacy when data are MNAR and missingness due to study discontinuation is strongly associated with an unfavorable outcome, but trimmed means fail when data are missing at random. If the reasons for study discontinuation in a clinical trial are known, analysts can improve estimates with a combination of multiple imputation and the trimmed means approach when the assumptions of each hold. We compare the methodology to existing approaches using data from a clinical trial for chronic pain. An R package trim implements the method. When the assumptions are justifiable, using trimmed means can help identify treatment effects notwithstanding MNAR data.     

A structured framework for assessing sensitivity to missing data assumptions in longitudinal clinical trials

The objective of this research was to demonstrate a framework for drawing inference from sensitivity analyses of incomplete longitudinal clinical trial data via a re‐analysis of data from a confirmatory clinical trial in depression. A likelihood‐based approach that assumed missing at random (MAR) was the primary analysis. Robustness to departure from MAR was assessed by comparing the primary result to those from a series of analyses that employed varying missing not at random (MNAR) assumptions (selection models, pattern mixture models and shared parameter models) and to MAR methods that used inclusive models. The key sensitivity analysis used multiple imputation assuming that after dropout the trajectory of drug‐treated patients was that of placebo treated patients with a similar outcome history (placebo multiple imputation). This result was used as the worst reasonable case to define the lower limit of plausible values for the treatment contrast. The endpoint contrast from the primary analysis was ? 2.79 (p = .013). In placebo multiple imputation, the result was ? 2.17. Results from the other sensitivity analyses ranged from ? 2.21 to ? 3.87 and were symmetrically distributed around the primary result. Hence, no clear evidence of bias from missing not at random data was found. In the worst reasonable case scenario, the treatment effect was 80% of the magnitude of the primary result. Therefore, it was concluded that a treatment effect existed. The structured sensitivity framework of using a worst reasonable case result based on a controlled imputation approach with transparent and debatable assumptions supplemented a series of plausible alternative models under varying assumptions was useful in this specific situation and holds promise as a generally useful framework. Copyright © 2012 John Wiley & Sons, Ltd.     

The impact of missing data and how it is handled on the rate of false-positive results in drug development

In drug development, a common choice for the primary analysis is to assess mean changes via analysis of (co)variance with missing data imputed by carrying the last or baseline observations forward (LOCF, BOCF). These approaches assume that data are missing completely at random (MCAR). Multiple imputation (MI) and likelihood-based repeated measures (MMRM) are less restrictive as they assume data are missing at random (MAR). Nevertheless, LOCF and BOCF remain popular, perhaps because it is thought that the bias in these methods lead to protection against falsely concluding that a drug is more effective than the control. We conducted a simulation study that compared the rate of false positive results or regulatory risk error (RRE) from BOCF, LOCF, MI, and MMRM in 32 scenarios that were generated from a 2(5) full factorial arrangement with data missing due to a missing not at random (MNAR) mechanism. Both BOCF and LOCF inflated RRE were compared to MI and MMRM. In 12 of the 32 scenarios, BOCF yielded inflated RRE compared with eight scenarios for LOCF, three scenarios for MI and four scenarios for MMRM. In no situation did BOCF or LOCF provide adequate control of RRE when MI and MMRM did not. Both MI and MMRM are better choices than either BOCF or LOCF for the primary analysis.     

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.     

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.     

Data-driven sensitivity analysis to detect missing data mechanism with applications to structural equation modelling

Missing data are a common problem in almost all areas of empirical research. Ignoring the missing data mechanism, especially when data are missing not at random (MNAR), can result in biased and/or inefficient inference. Because MNAR mechanism is not verifiable based on the observed data, sensitivity analysis is often used to assess it. Current sensitivity analysis methods primarily assume a model for the response mechanism in conjunction with a measurement model and examine sensitivity to missing data mechanism via the parameters of the response model. Recently, Jamshidian and Mata (Post-modelling sensitivity analysis to detect the effect of missing data mechanism, Multivariate Behav. Res. 43 (2008), pp. 432–452) introduced a new method of sensitivity analysis that does not require the difficult task of modelling the missing data mechanism. In this method, a single measurement model is fitted to all of the data and to a sub-sample of the data. Discrepancy in the parameter estimates obtained from the the two data sets is used as a measure of sensitivity to missing data mechanism. Jamshidian and Mata describe their method mainly in the context of detecting data that are missing completely at random (MCAR). They used a bootstrap type method, that relies on heuristic input from the researcher, to test for the discrepancy of the parameter estimates. Instead of using bootstrap, the current article obtains confidence interval for parameter differences on two samples based on an asymptotic approximation. Because it does not use bootstrap, the developed procedure avoids likely convergence problems with the bootstrap methods. It does not require heuristic input from the researcher and can be readily implemented in statistical software. The article also discusses methods of obtaining sub-samples that may be used to test missing at random in addition to MCAR. An application of the developed procedure to a real data set, from the first wave of an ongoing longitudinal study on aging, is presented. Simulation studies are performed as well, using two methods of missing data generation, which show promise for the proposed sensitivity method. One method of missing data generation is also new and interesting in its own right.     

Missing data mechanisms and their implications on the analysis of categorical data

We review some issues related to the implications of different missing data mechanisms on statistical inference for contingency tables and consider simulation studies to compare the results obtained under such models to those where the units with missing data are disregarded. We confirm that although, in general, analyses under the correct missing at random and missing completely at random models are more efficient even for small sample sizes, there are exceptions where they may not improve the results obtained by ignoring the partially classified data. We show that under the missing not at random (MNAR) model, estimates on the boundary of the parameter space as well as lack of identifiability of the parameters of saturated models may be associated with undesirable asymptotic properties of maximum likelihood estimators and likelihood ratio tests; even in standard cases the bias of the estimators may be low only for very large samples. We also show that the probability of a boundary solution obtained under the correct MNAR model may be large even for large samples and that, consequently, we may not always conclude that a MNAR model is misspecified because the estimate is on the boundary of the parameter space.     

Comparison of alternative imputation methods for ordinal data

In this article, we compare alternative missing imputation methods in the presence of ordinal data, in the framework of CUB (Combination of Uniform and (shifted) Binomial random variable) models. Various imputation methods are considered, as are univariate and multivariate approaches. The first step consists of running a simulation study designed by varying the parameters of the CUB model, to consider and compare CUB models as well as other methods of missing imputation. We use real datasets on which to base the comparison between our approach and some general methods of missing imputation for various missing data mechanisms.     

The Effects of Imputing the Missing Standard Deviations on the Standard Error of Meta Analysis Estimates

A common problem in the meta analysis of continuous data is that some studies do not report sufficient information to calculate the standard deviation (SDs) of the treatment effect. One of the approaches in handling this problem is through imputation. This article examines the empirical implications of imputing the missing SDs on the standard error (SE) of the overall meta analysis estimate. The simulation results show that if the SDs are missing under Missing Completely at Random and Missing at Random mechanism, imputation is recommended. With non random missing, imputation can lead to overestimation of the SE of the estimate.     

A comparison study of nonparametric imputation methods

Consider estimation of a population mean of a response variable when the observations are missing at random with respect to the covariate. Two common approaches to imputing the missing values are the nonparametric regression weighting method and the Horvitz-Thompson (HT) inverse weighting approach. The regression approach includes the kernel regression imputation and the nearest neighbor imputation. The HT approach, employing inverse kernel-estimated weights, includes the basic estimator, the ratio estimator and the estimator using inverse kernel-weighted residuals. Asymptotic normality of the nearest neighbor imputation estimators is derived and compared to kernel regression imputation estimator under standard regularity conditions of the regression function and the missing pattern function. A comprehensive simulation study shows that the basic HT estimator is most sensitive to discontinuity in the missing data patterns, and the nearest neighbors estimators can be insensitive to missing data patterns unbalanced with respect to the distribution of the covariate. Empirical studies show that the nearest neighbor imputation method is most effective among these imputation methods for estimating a finite population mean and for classifying the species of the iris flower data.     

Validity and efficiency in analyzing ordinal responses with missing observations

This article addresses issues in creating public-use data files in the presence of missing ordinal responses and subsequent statistical analyses of the dataset by users. The authors propose a fully efficient fractional imputation (FI) procedure for ordinal responses with missing observations. The proposed imputation strategy retrieves the missing values through the full conditional distribution of the response given the covariates and results in a single imputed data file that can be analyzed by different data users with different scientific objectives. Two most critical aspects of statistical analyses based on the imputed data set,  validity  and  efficiency, are examined through regression analysis involving the ordinal response and a selected set of covariates. It is shown through both theoretical development and simulation studies that, when the ordinal responses are missing at random, the proposed FI procedure leads to valid and highly efficient inferences as compared to existing methods. Variance estimation using the fractionally imputed data set is also discussed. The Canadian Journal of Statistics 48: 138–151; 2020 © 2019 Statistical Society of Canada     

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.     

Model selection of generalized partially linear models with missing covariates

In this paper, a generalized partially linear model (GPLM) with missing covariates is studied and a Monte Carlo EM (MCEM) algorithm with penalized-spline (P-spline) technique is developed to estimate the regression coefficients and nonparametric function, respectively. As classical model selection procedures such as Akaike's information criterion become invalid for our considered models with incomplete data, some new model selection criterions for GPLMs with missing covariates are proposed under two different missingness mechanism, say, missing at random (MAR) and missing not at random (MNAR). The most attractive point of our method is that it is rather general and can be extended to various situations with missing observations based on EM algorithm, especially when no missing data involved, our new model selection criterions are reduced to classical AIC. Therefore, we can not only compare models with missing observations under MAR/MNAR settings, but also can compare missing data models with complete-data models simultaneously. Theoretical properties of the proposed estimator, including consistency of the model selection criterions are investigated. A simulation study and a real example are used to illustrate the proposed methodology.     

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。     

Missing at random (MAR) in nonparametric regression - A simulation experiment

The additive model is considered when some observations on x are missing at random but corresponding observations on y are available. Especially for this model, missing at random is an interesting case because the complete case analysis is expected to be no more suitable. A simulation experiment is reported and the different methods are compared based on their superiority with respect to the sample mean squared error. Some focus is also given on the sample variance and the estimated bias. In detail, the complete case analysis, a kind of stochastic mean imputation, a single imputation and the nearest neighbor imputation are discussed.     

A mixed effects model for analyzing area under the curve of longitudinally measured biomarkers with missing data

A simple approach for analyzing longitudinally measured biomarkers is to calculate summary measures such as the area under the curve (AUC) for each individual and then compare the mean AUC between treatment groups using methods such as t test. This two-step approach is difficult to implement when there are missing data since the AUC cannot be directly calculated for individuals with missing measurements. Simple methods for dealing with missing data include the complete case analysis and imputation. A recent study showed that the estimated mean AUC difference between treatment groups based on the linear mixed model (LMM), rather than on individually calculated AUCs by simple imputation, has negligible bias under random missing assumptions and only small bias when missing is not at random. However, this model assumes the outcome to be normally distributed, which is often violated in biomarker data. In this paper, we propose to use a LMM on log-transformed biomarkers, based on which statistical inference for the ratio, rather than difference, of AUC between treatment groups is provided. The proposed method can not only handle the potential baseline imbalance in a randomized trail but also circumvent the estimation of the nuisance variance parameters in the log-normal model. The proposed model is applied to a recently completed large randomized trial studying the effect of nicotine reduction on biomarker exposure of smokers.     

Missing data sensitivity analysis for recurrent event data using controlled imputation

Statistical analyses of recurrent event data have typically been based on the missing at random assumption. One implication of this is that, if data are collected only when patients are on their randomized treatment, the resulting de jure estimator of treatment effect corresponds to the situation in which the patients adhere to this regime throughout the study. For confirmatory analysis of clinical trials, sensitivity analyses are required to investigate alternative de facto estimands that depart from this assumption. Recent publications have described the use of multiple imputation methods based on pattern mixture models for continuous outcomes, where imputation for the missing data for one treatment arm (e.g. the active arm) is based on the statistical behaviour of outcomes in another arm (e.g. the placebo arm). This has been referred to as controlled imputation or reference‐based imputation. In this paper, we use the negative multinomial distribution to apply this approach to analyses of recurrent events and other similar outcomes. The methods are illustrated by a trial in severe asthma where the primary endpoint was rate of exacerbations and the primary analysis was based on the negative binomial model. Copyright © 2014 John Wiley & Sons, Ltd.