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A critical look at methods for handling missing covariates in epidemiologic regression analyses.
Abstract
Epidemiologic studies often encounter missing covariate values. While simple methods such as stratification on missing-data status, conditional-mean imputation, and complete-subject analysis are commonly employed for handling this problem, several studies have shown that these methods can be biased under reasonable circumstances. The authors review these results in the context of logistic regression and present simulation experiments showing the limitations of the methods. The method based on missing-data indicators can exhibit severe bias even when the data are missing completely at random, and regression (conditional-mean) imputation can be inordinately sensitive to model misspecification. Even complete-subject analysis can outperform these methods. More sophisticated methods, such as maximum likelihood, multiple imputation, and weighted estimating equations, have been given extensive attention in the statistics literature. While these methods are superior to simple methods, they are not commonly used in epidemiology, no doubt due to their complexity and the lack of packaged software to apply these methods. The authors contrast the results of multiple imputation to simple methods in the analysis of a case-control study of endometrial cancer, and they find a meaningful difference in results for age at menarche. In general, the authors recommend that epidemiologists avoid using the missing-indicator method and use more sophisticated methods whenever a large proportion of data are missing.
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In the citing paper
“Commonly missing values are related to observed participant or disease characteristics.”
From Reporting and Methods in Clinical Prediction Research: A Systematic Review (2012) · cites this paper as [24]
In the citing paper
“Missing values in clinical study data rarely occur completely at random.”
From Reporting and Methods in Clinical Prediction Research: A Systematic Review (2012) · cites this paper as [24]
In the citing paper
“Exclusion of participants with missing values will therefore not only lead to loss of statistical power, but often also to biased results 10,12,13,23,24,57,58.”
From Reporting and Methods in Clinical Prediction Research: A Systematic Review (2012) · cites this paper as [24]
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Sorted by citations
Applied Longitudinal Data Analysis: Modeling Change and Event Occurrence
Singer, J. D., & Willett, J. B. (2003) · doi:10.1093/acprof:oso/9780195152968.001.0001 · Cited by 10,647
Matching Methods for Causal Inference: A Review and a Look Forward
Stuart, E. A. (2010) · Statistical Science · doi:10.1214/09-sts313 · Cited by 5,478
Multiple imputation by chained equations: what is it and how does it work?
Azur, M. J., Stuart, E. A., Frangakis, C., & Leaf, P. J. (2011) · International Journal of Methods in Psychiatric Research · doi:10.1002/mpr.329 · Cited by 3,542
“In contrast, if the observed data are highly predictive of the missing values the imputations will be more consistent across imputations, resulting in smaller, but still accurate, standard errors (Greenland and Finkle, 1995).”
ResultMultiple imputation after 18+ years
Rubin, D. B. (1996) · Journal of the American Statistical Association · doi:10.1080/01621459.1996.10476908 · Cited by 4,072
Multiple imputation of discrete and continuous data by fully conditional specification
van Buuren, S. (2007) · Statistical Methods in Medical Research · doi:10.1177/0962280206074463 · Cited by 2,827
Metadata
- Authors
- Greenland, S., & Finkle, W. D.
- Affiliations
- University of California, Los Angeles (US)
- Corresponding author
- Greenland, Sander
- ORCID
- Greenland, Sander
- Venue
- American Journal of Epidemiology
- Publisher
- Oxford University Press (OUP)
- Published
- 1995-12-15
- Volume
- 142
- Issue
- 12
- Pages
- 1255-1264
- ISSN
- 0002-9262 (ISSN-L)
- 1476-6256
- OpenAlex
- W2166561686
- Cited by
- 891
- References
- 0
- Citations by year
- 2026: 13 · 2025: 18 · 2024: 13 · 2023: 24 · 2022: 26 · 2021: 21 · 2020: 33 · 2019: 29 · 2018: 34 · 2017: 32 · 2016: 27 · 2015: 40 · 2014: 57 · 2013: 53 · 2012: 67
- FWCI
- 6.57
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- American Journal of Epidemiology (publishedVersion)
- PubMed (publishedVersion)
- American Journal of Epidemiology
- Funders
- National Institutes of Health (n01cp095680-001)
- National Cancer Institute (N01 CP 95680)
- Topics
- Physical Sciences › Mathematics › Statistics and Probability › Statistical Methods and Bayesian Inference
- Physical Sciences › Mathematics › Statistics and Probability › Statistical Methods in Epidemiology
- Physical Sciences › Mathematics › Statistics and Probability › Advanced Causal Inference Techniques
- Keywords
- missing covariates, missing data, logistic regression, bias, model misspecification, multiple imputation, maximum likelihood estimation, weighted estimating equations, endometrial cancer, age at menarche, case-control study
- MeSH terms
- Epidemiologic Methods, Female, Humans, Menarche, Research Design, Logistic Models, Odds Ratio, Case-Control Studies, Endometrial Neoplasms
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