A structured approach to choosing estimands and estimators in longitudinal clinical trials

An important evolution in the missing data arena has been the recognition of need for clarity in objectives. The objectives of primary focus in clinical trials can often be categorized as assessing efficacy or effectiveness. The present investigation illustrated a structured framework for choosing estimands and estimators when testing investigational drugs to treat the symptoms of chronic illnesses. Key issues were discussed and illustrated using a reanalysis of the confirmatory trials from a new drug application in depression. The primary analysis used a likelihood‐based approach to assess efficacy: mean change to the planned endpoint of the trial assuming patients stayed on drug. Secondarily, effectiveness was assessed using a multiple imputation approach. The imputation model—derived solely from the placebo group—was used to impute missing values for both the drug and placebo groups. Therefore, this so‐called placebo multiple imputation (a.k.a. controlled imputation) approach assumed patients had reduced benefit from the drug after discontinuing it. Results from the example data provided clear evidence of efficacy for the experimental drug and characterized its effectiveness. Data after discontinuation of study medication were not required for these analyses. Given the idiosyncratic nature of drug development, no estimand or approach is universally appropriate. However, the general practice of pairing efficacy and effectiveness estimands may often be useful in understanding the overall risks and benefits of a drug. Controlled imputation approaches, such as placebo multiple imputation, can be a flexible and transparent framework for formulating primary analyses of effectiveness estimands and sensitivity analyses for efficacy estimands. Copyright © 2012 John Wiley & Sons, Ltd.     

Nonparametric conditional mean imputation

Imputation is a much used method for handling missing data. It is appealing as it separates the missing data part of the analysis, which is handled by imputation, and the estimation part, which is handled by complete data methods. Most imputation methods, however, either rely on strict parametric assumptions or are rather ad hoc in which case they often only work approximately under even stricter assumptions. In this paper a non-parametric imputation method is proposed. Since it is non-parametric it works under quite general assumptions. In particular, a model for the complete data is not required in the imputation step, and the complete data method used after the imputation may be a general estimating equation for estimating a finite-dimensional parameter. Large sample results for the resulting estimator are given.     

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.     

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.     

MISSING VALUES, IMPUTATION AND ERROR RATE ESTIMATORS IN DISCRIMINANT ANALYSIS

Error rate is a popular criterion for assessing the performance of an allocation rule in discriminant analysis. Training samples which involve missing values cause problems for those error rate estimators that require all variables to be observed at all data points. This paper explores imputation algorithms, their effects on, and problems of implementing them with, eight commonly used error rate estimators (three parametric and five non-parametric) in linear discriminant analysis. The results indicate that imputation should not be based on the way error rate estimators are calculated, and that imputed values may underestimate error rates.     

Imputation by power transformation

In this paper, a new power transformation estimator of population mean in the presence of non-response has been suggested. The estimator of mean obtained from proposed technique remains better than the estimators obtained from ratio or mean methods of imputation. The mean squared error of the resultant estimator is less than that of the estimator obtained on the basis of ratio method of imputation for the optinum choice of parameters. An estimator for estimating a parameter involved in the process of new method of imputation has been discussed. The MSE expressions for the proposed estimators have been derived analytically and compared empirically. Product method of imputation for negatively correlated variables has also been introduced. The work has been extended to the case of multi-auxiliary information to be used for imputation.     

Alternative imputation techniques for complex metric variables

This paper deals with imputation techniques and strategies. Usually, imputation truly commences after the first data editing, but many preceding operations are needed before that. In this editing step, the missing or deficient items are to be recognized and coded, and then it is decided which of these, if any, should be substituted by imputing. There are a number of imputation methods and their specifications. Consequently, it is not clear what method finally should be chosen, especially when an imputation method may be best in one respect, and another method in the other. In this paper, we consider these questions through the following four imputation methods: (i) random hot decking, (ii) logistic regression imputation, (iii) linear regression imputation, and (iv) regression-based nearest neighbour hot decking. The last two methods are applied with the two different specifications. The two metric variables have been used in empirical tests. The first is very complex, but the second is more ordinary, and thus easier to handle. The empirical examples are based on simulations, which clearly show the biases of the various methods and their specifications. In general, it seems that method (iv) is recommendable although the results from it are not perfect either.     

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.     

Variance estimation when donor imputation is used to fill in missing values

Donor imputation is frequently used in surveys. However, very few variance estimation methods that take into account donor imputation have been developed in the literature. This is particularly true for surveys with high sampling fractions using nearest donor imputation, often called nearest‐neighbour imputation. In this paper, the authors develop a variance estimator for donor imputation based on the assumption that the imputed estimator of a domain total is approximately unbiased under an imputation model; that is, a model for the variable requiring imputation. Their variance estimator is valid, irrespective of the magnitude of the sampling fractions and the complexity of the donor imputation method, provided that the imputation model mean and variance are accurately estimated. They evaluate its performance in a simulation study and show that nonparametric estimation of the model mean and variance via smoothing splines brings robustness with respect to imputation model misspecifications. They also apply their variance estimator to real survey data when nearest‐neighbour imputation has been used to fill in the missing values. The Canadian Journal of Statistics 37: 400–416; 2009 © 2009 Statistical Society of Canada     

A new method of imputation in survey sampling

In this paper, an alternative estimator of population mean in the presence of non-response has been suggested which comes in the form of Walsh's estimator. The estimator of mean obtained from the proposed technique remains better than the estimators obtained from ratio or mean methods of imputation. The mean-squared error (MSE) of the resultant estimator is less than that of the estimator obtained on the basis of ratio method of imputation for the optimum choice of parameters. An estimator for estimating a parameter involved in the process of new method of imputation has been discussed. A suggestion to form ‘warm deck’ method of imputation has been suggested. The MSE expressions for the proposed estimators have been derived analytically and compared empirically. The work has been extended to the case of multi-auxiliary information to be used for imputation. Numerical illustrations are also provided.     

Imputation of Household Survey Data Using Linear Mixed Models

Mixed models are regularly used in the analysis of clustered data, but are only recently being used for imputation of missing data. In household surveys where multiple people are selected from each household, imputation of missing values should preserve the structure pertaining to people within households and should not artificially change the apparent intracluster correlation (ICC). This paper focuses on the use of multilevel models for imputation of missing data in household surveys. In particular, the performance of a best linear unbiased predictor for both stochastic and deterministic imputation using a linear mixed model is compared to imputation based on a single level linear model, both with and without information about household respondents. In this paper an evaluation is carried out in the context of imputing hourly wage rate in the Household, Income and Labour Dynamics of Australia Survey. Nonresponse is generated under various assumptions about the missingness mechanism for persons and households, and with low, moderate and high intra‐household correlation to assess the benefits of the multilevel imputation model under different conditions. The mixed model and single level model with information about the household respondent lead to clear improvements when the ICC is moderate or high, and when there is informative missingness.     

A fresh imputing survey methodology using sensible constraints on study and auxiliary variables: dubious random non-response

In this paper, we introduce a fresh methodology for imputing missing values by making use of sensible constraints on both a study variable and auxiliary variables that are correlated with the variable of interest. The resultant estimator based on these imputed values is shown to lead to the regression type method of imputation in survey sampling. Furthermore, when the data are hybrid of both that missing at random and missing complexly at random, the resultant estimator is shown to be a consistent estimator that has asymptotic mean squared error equal to that of the linear regression method of imputation. A generalization to any type of method of imputation is possible and has been included at the end.     

Fully efficient estimation of coefficients of correlation in the presence of imputed survey data

Marginal imputation, that consists of imputing items separately, generally leads to biased estimators of bivariate parameters such as finite population coefficients of correlation. To overcome this problem, two main approaches have been considered in the literature: the first consists of using customary imputation methods such as random hot‐deck imputation and adjusting for the bias at the estimation stage. This approach was studied in Skinner & Rao 2002 . In this paper, we extend the results of Skinner & Rao 2002 to the case of arbitrary sampling designs and three variants of random hot‐deck imputation. The second approach consists of using an imputation method, which preserves the relationship between variables. Shao & Wang 2002 proposed a joint random regression imputation procedure that succeeds in preserving the relationships between two study variables. One drawback of the Shao–Wang procedure is that it suffers from an additional variability (called the imputation variance) due to the random selection of residuals, resulting in potentially inefficient estimators. Following Chauvet, Deville, & Haziza 2011 , we propose a fully efficient version of the Shao–Wang procedure that preserves the relationship between two study variables, while virtually eliminating the imputation variance. Results of a simulation study support our findings. An application using data from the Workplace and Employees Survey is also presented. The Canadian Journal of Statistics 40: 124–149; 2012 © 2011 Statistical Society of Canada     

Imputation using higher order moments of an auxiliary variable

In this article, we propose a new method of imputation that makes use of higher order moments of an auxiliary variable while imputing missing values. The mean, ratio, and regression methods of imputation are shown to be special cases and less efficient than the newly developed method of imputation, which makes use of higher order moments. Analytical comparisons show that the first-order mean squared error approximation for the proposed new method of imputation is always smaller than that for the regression method of imputation. At the end, the proposed higher order moments-based imputation method has been applied to a real dataset.     

Comparison of methods for incomplete repeated measures data analysis in small samples

This paper presents missing data methods for repeated measures data in small samples. Most methods currently available are for large samples. In particular, no studies have compared the performance of multiple imputation methods to that of non-imputation incomplete analysis methods. We first develop a strategy for multiple imputations for repeated measures data under a cell-means model that is applicable for any multivariate data with small samples. Multiple imputation inference procedures are applied to the resulting multiply imputed complete data sets. Comparisons to other available non-imputation incomplete data methods is made via simulation studies to conclude that there is not much gain in using the computer intensive multiple imputation methods for small sample repeated measures data analysis in terms of the power of testing hypotheses of parameters of interest.     

Mass imputation for two-phase sampling

Two-phase sampling is a cost-effective method of data collection using outcome-dependent sampling for the second-phase sample. In order to make efficient use of auxiliary information and to improve domain estimation, mass imputation can be used in two-phase sampling. Rao and Sitter (1995) introduce mass imputation for two-phase sampling and its variance estimation under simple random sampling in both phases. In this paper, we extend the Rao–Sitter method to general sampling design. The proposed method is further extended to mass imputation for categorical data. A limited simulation study is performed to examine the performance of the proposed methods.     

Nonparametric methods for the estimation of imputation uncertainty

It is cleared in recent researches that the raising of missing values in datasets is inevitable. Imputation of missing data is one of the several methods which have been introduced to overcome this issue. Imputation techniques are trying to answer the case of missing data by covering missing values with reasonable estimates permanently. There are a lot of benefits for these procedures rather than their drawbacks. The operation of these methods has not been clarified, which means that they provide mistrust among analytical results. One approach to evaluate the outcomes of the imputation process is estimating uncertainty in the imputed data. Nonparametric methods are appropriate to estimating the uncertainty when data are not followed by any particular distribution. This paper deals with a nonparametric method for estimation and testing the significance of the imputation uncertainty, which is based on Wilcoxon test statistic, and which could be employed for estimating the precision of the imputed values created by imputation methods. This proposed procedure could be employed to judge the possibility of the imputation process for datasets, and to evaluate the influence of proper imputation methods when they are utilized to the same dataset. This proposed approach has been compared with other nonparametric resampling methods, including bootstrap and jackknife to estimate uncertainty in the imputed data under the Bayesian bootstrap imputation method. The ideas supporting the proposed method are clarified in detail, and a simulation study, which indicates how the approach has been employed in practical situations, is illustrated.     

Comparison of several imputation methods for missing baseline data in propensity scores analysis of binary outcome

We performed a simulation study comparing the statistical properties of the estimated log odds ratio from propensity scores analyses of a binary response variable, in which missing baseline data had been imputed using a simple imputation scheme (Treatment Mean Imputation), compared with three ways of performing multiple imputation (MI) and with a Complete Case analysis. MI that included treatment (treated/untreated) and outcome (for our analyses, outcome was adverse event [yes/no]) in the imputer's model had the best statistical properties of the imputation schemes we studied. MI is feasible to use in situations where one has just a few outcomes to analyze. We also found that Treatment Mean Imputation performed quite well and is a reasonable alternative to MI in situations where it is not feasible to use MI. Treatment Mean Imputation performed better than MI methods that did not include both the treatment and outcome in the imputer's model. Copyright © 2009 John Wiley & Sons, Ltd.     

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.     

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.