Missing Data in Clinical Research: A Tutorial on Multiple Imputation.
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ABSTRACT:
SUBMITTER: Austin PC
PROVIDER: S-EPMC8499698 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Multiple imputation is a well-established general technique for analyzing data with missing values. A convenient way to implement multiple imputation is sequential regression multiple imputation, also called chained equations multiple imputation. In this approach, we impute missing values using regression models for each variable, conditional on the other variables in the data. This approach, however, assumes that the missingness mechanism is missing at random, and it is not well-justified under not-at-random missingness without additional modification. In this paper, we describe how we can generalize the sequential regression multiple imputation imputation procedure to handle missingness not at random in the setting where missingness may depend on other variables that are also missing but not on the missing variable itself, conditioning on fully observed variables. We provide algebraic justification for several generalizations of standard sequential regression multiple imputation using Taylor series and other approximations of the target imputation distribution under missingness not at random. Resulting regression model approximations include indicators for missingness, interactions, or other functions of the missingness not at random missingness model and observed data. In a simulation study, we demonstrate that the proposed sequential regression multiple imputation modifications result in reduced bias in the final analysis compared to standard sequential regression multiple imputation, with an approximation strategy involving inclusion of an offset in the imputation model performing the best overall. The method is illustrated in a breast cancer study, where the goal is to estimate the prevalence of a specific genetic pathogenic variant.
| S-EPMC9205685 | biostudies-literature
Project description:BackgroundIncomplete categorical variables with more than two categories are common in public health data. However, most of the existing missing-data methods do not use the information from nonresponse (missingness) probabilities.MethodsWe propose a nearest-neighbour multiple imputation approach to impute a missing at random categorical outcome and to estimate the proportion of each category. The donor set for imputation is formed by measuring distances between each missing value with other non-missing values. The distance function is calculated based on a predictive score, which is derived from two working models: one fits a multinomial logistic regression for predicting the missing categorical outcome (the outcome model) and the other fits a logistic regression for predicting missingness probabilities (the missingness model). A weighting scheme is used to accommodate contributions from two working models when generating the predictive score. A missing value is imputed by randomly selecting one of the non-missing values with the smallest distances. We conduct a simulation to evaluate the performance of the proposed method and compare it with several alternative methods. A real-data application is also presented.ResultsThe simulation study suggests that the proposed method performs well when missingness probabilities are not extreme under some misspecifications of the working models. However, the calibration estimator, which is also based on two working models, can be highly unstable when missingness probabilities for some observations are extremely high. In this scenario, the proposed method produces more stable and better estimates. In addition, proper weights need to be chosen to balance the contributions from the two working models and achieve optimal results for the proposed method.ConclusionsWe conclude that the proposed multiple imputation method is a reasonable approach to dealing with missing categorical outcome data with more than two levels for assessing the distribution of the outcome. In terms of the choices for the working models, we suggest a multinomial logistic regression for predicting the missing outcome and a binary logistic regression for predicting the missingness probability.
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Project description:Missing data due to non-wear are common in accelerometer studies measuring physical activity and sedentary behavior. Accelerometer output are high-dimensional time-series data that are episodic and often highly skewed, presenting unique challenges for handling missing data. Common methods for missing accelerometry either are ad-hoc, require restrictive parametric assumptions, or do not appropriately impute bouts. This study developed a flexible hot deck multiple imputation (MI; i.e., "replacing" missing data with observed values) procedure to handle missing accelerometry. For each missing segment of accelerometry, "donor pools" contained observed segments from either the same or different participants, and 10 imputed segments were randomly drawn from the donor pool according to selection weights, where the donor pool and selection weight depended on variables associated with non-wear and/or accelerometer-based measures. A simulation study of 2,550 women compared hot deck MI to two standard methods in the field: available case (AC) analysis (i.e., analyzing all observed accelerometry with no restriction on wear time or number of days) and complete case (CC) analysis (i.e., analyzing only participants that wore the accelerometer for ≥10 hours for 4-7 days). This was repeated using accelerometry from the entire 24-hour day and daytime (10am- 8pm) only, and data were missing at random. For the entire 24-hour day, MI produced less bias and better 95% confidence interval (CI) coverage than AC and CC. For the daytime only, MI produced less bias and better 95% CI coverage than AC; CC produced similar bias and 95% CI coverage, but longer 95% CIs than MI.
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Project description:We present a framework for generating multiple imputations for continuous data when the missing data mechanism is unknown. Imputations are generated from more than one imputation model in order to incorporate uncertainty regarding the missing data mechanism. Parameter estimates based on the different imputation models are combined using rules for nested multiple imputation. Through the use of simulation, we investigate the impact of missing data mechanism uncertainty on post-imputation inferences and show that incorporating this uncertainty can increase the coverage of parameter estimates. We apply our method to a longitudinal clinical trial of low-income women with depression where nonignorably missing data were a concern. We show that different assumptions regarding the missing data mechanism can have a substantial impact on inferences. Our method provides a simple approach for formalizing subjective notions regarding nonresponse so that they can be easily stated, communicated, and compared.
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Project description:Whole brain fMRI analyses rarely include the entire brain because of missing data that result from data acquisition limits and susceptibility artifact, in particular. This missing data problem is typically addressed by omitting voxels from analysis, which may exclude brain regions that are of theoretical interest and increase the potential for Type II error at cortical boundaries or Type I error when spatial thresholds are used to establish significance. Imputation could significantly expand statistical map coverage, increase power, and enhance interpretations of fMRI results. We examined multiple imputation for group level analyses of missing fMRI data using methods that leverage the spatial information in fMRI datasets for both real and simulated data. Available case analysis, neighbor replacement, and regression based imputation approaches were compared in a general linear model framework to determine the extent to which these methods quantitatively (effect size) and qualitatively (spatial coverage) increased the sensitivity of group analyses. In both real and simulated data analysis, multiple imputation provided 1) variance that was most similar to estimates for voxels with no missing data, 2) fewer false positive errors in comparison to mean replacement, and 3) fewer false negative errors in comparison to available case analysis. Compared to the standard analysis approach of omitting voxels with missing data, imputation methods increased brain coverage in this study by 35% (from 33,323 to 45,071 voxels). In addition, multiple imputation increased the size of significant clusters by 58% and number of significant clusters across statistical thresholds, compared to the standard voxel omission approach. While neighbor replacement produced similar results, we recommend multiple imputation because it uses an informed sampling distribution to deal with missing data across subjects that can include neighbor values and other predictors. Multiple imputation is anticipated to be particularly useful for 1) large fMRI data sets with inconsistent missing voxels across subjects and 2) addressing the problem of increased artifact at ultra-high field, which significantly limit the extent of whole brain coverage and interpretations of results.
| S-EPMC3328786 | biostudies-literature
Project description: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.
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Project description:Based on the missing situation and actual needs of maritime search and rescue data, multiple imputation methods were used to construct complete data sets under different missing patterns. Probability density curves and overimputation diagnostics were used to explore the effects of multiple imputation. The results showed that the Data Augmentation (DA) algorithm had the characteristics of high operation efficiency and good imputation effect, but the algorithm was not suitable for data imputation when there was a high data missing rate. The EMB algorithm effectively restored the distribution of datasets with different data missing rates, and was less affected by the missing position; the EMB algorithm could obtain a good imputation effect even when there was a high data missing rate. Overimputation diagnostics could not only reflect the data imputation effect, but also show the correlation between different datasets, which was of great importance for deep data mining and imputation effect improvement. The Expectation-Maximization with Bootstrap (EMB) algorithm had a poor estimation effect on extreme data and failed to reflect the dataset's variability characteristics.
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Project description:Analysis of matched case-control studies is often complicated by missing data on covariates. Analysis can be restricted to individuals with complete data, but this is inefficient and may be biased. Multiple imputation (MI) is an efficient and flexible alternative. We describe two MI approaches. The first uses a model for the data on an individual and includes matching variables; the second uses a model for the data on a whole matched set and avoids the need to model the matching variables. Within each approach, we consider three methods: full-conditional specification (FCS), joint model MI using a normal model, and joint model MI using a latent normal model. We show that FCS MI is asymptotically equivalent to joint model MI using a restricted general location model that is compatible with the conditional logistic regression analysis model. The normal and latent normal imputation models are not compatible with this analysis model. All methods allow for multiple partially-observed covariates, non-monotone missingness, and multiple controls per case. They can be easily applied in standard statistical software and valid variance estimates obtained using Rubin's Rules. We compare the methods in a simulation study. The approach of including the matching variables is most efficient. Within each approach, the FCS MI method generally yields the least-biased odds ratio estimates, but normal or latent normal joint model MI is sometimes more efficient. All methods have good confidence interval coverage. Data on colorectal cancer and fibre intake from the EPIC-Norfolk study are used to illustrate the methods, in particular showing how efficiency is gained relative to just using individuals with complete data.
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Project description:Multiple imputation (MI) has been widely used for handling missing data in biomedical research. In the presence of high-dimensional data, regularized regression has been used as a natural strategy for building imputation models, but limited research has been conducted for handling general missing data patterns where multiple variables have missing values. Using the idea of multiple imputation by chained equations (MICE), we investigate two approaches of using regularized regression to impute missing values of high-dimensional data that can handle general missing data patterns. We compare our MICE methods with several existing imputation methods in simulation studies. Our simulation results demonstrate the superiority of the proposed MICE approach based on an indirect use of regularized regression in terms of bias. We further illustrate the proposed methods using two data examples.
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Project description:In multilevel settings such as individual participant data meta-analysis, a variable is 'systematically missing' if it is wholly missing in some clusters and 'sporadically missing' if it is partly missing in some clusters. Previously proposed methods to impute incomplete multilevel data handle either systematically or sporadically missing data, but frequently both patterns are observed. We describe a new multiple imputation by chained equations (MICE) algorithm for multilevel data with arbitrary patterns of systematically and sporadically missing variables. The algorithm is described for multilevel normal data but can easily be extended for other variable types. We first propose two methods for imputing a single incomplete variable: an extension of an existing method and a new two-stage method which conveniently allows for heteroscedastic data. We then discuss the difficulties of imputing missing values in several variables in multilevel data using MICE, and show that even the simplest joint multilevel model implies conditional models which involve cluster means and heteroscedasticity. However, a simulation study finds that the proposed methods can be successfully combined in a multilevel MICE procedure, even when cluster means are not included in the imputation models.
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