Assessing Treatment Effects in Observational Data With Missing Confounders: A Comparative Study of Practical Doubly‐Robust and Traditional Missing Data Methods
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| Format: | Artículo Open Access |
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Wiley
2026
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| author | Brian D. Williamson Chloe Krakauer Eric Johnson Susan Gruber Bryan E. Shepherd Mark J. van der Laan Thomas Lumley Hana Lee José J. Hernández‐Muñoz Fengyu Zhao Sarah K. Dutcher Rishi Desai Gregory E. Simon Susan M. Shortreed Jennifer C. Nelson Pamela A. Shaw |
| author_facet | Brian D. Williamson Chloe Krakauer Eric Johnson Susan Gruber Bryan E. Shepherd Mark J. van der Laan Thomas Lumley Hana Lee José J. Hernández‐Muñoz Fengyu Zhao Sarah K. Dutcher Rishi Desai Gregory E. Simon Susan M. Shortreed Jennifer C. Nelson Pamela A. Shaw Brian D. Williamson Chloe Krakauer Eric Johnson Susan Gruber Bryan E. Shepherd Mark J. van der Laan Thomas Lumley Hana Lee José J. Hernández‐Muñoz Fengyu Zhao Sarah K. Dutcher Rishi Desai Gregory E. Simon Susan M. Shortreed Jennifer C. Nelson Pamela A. Shaw |
| collection | Wiley Open Access |
| contents | Assessing Treatment Effects in Observational Data With Missing Confounders: A Comparative Study of Practical Doubly‐Robust and Traditional Missing Data Methods Brian D. Williamson Chloe Krakauer Eric Johnson Susan Gruber Bryan E. Shepherd Mark J. van der Laan Thomas Lumley Hana Lee José J. Hernández‐Muñoz Fengyu Zhao Sarah K. Dutcher Rishi Desai Gregory E. Simon Susan M. Shortreed Jennifer C. Nelson Pamela A. Shaw Statistics in Medicine ABSTRACT In pharmacoepidemiology, safety and effectiveness are frequently evaluated using readily available administrative and electronic health records data. In these settings, detailed confounder data are often not available in all data sources and therefore missing on a subset of individuals. Multiple imputation (MI) and inverse‐probability weighting (IPW) are go‐to analytical methods to handle missing data and are dominant in the biomedical literature. Doubly‐robust methods, which are consistent under fewer assumptions, can be more efficient with respect to mean‐squared error. We discuss two practical‐to‐implement doubly‐robust estimators, generalized raking and inverse probability‐weighted targeted maximum likelihood estimation (TMLE), which are both currently under‐utilized in biomedical studies. We compare their performance to IPW and MI in a detailed numerical study for a variety of synthetic data‐generating and missingness scenarios, including scenarios with rare outcomes and a high missingness proportion. Further, we consider plasmode simulation studies that emulate the complex data structure of a large electronic health records cohort in order to compare anti‐depressant therapies in a rare‐outcome setting where a key confounder is prone to more than 50% missingness. We provide guidance on selecting a missing data analysis approach, based on which methods excelled with respect to the bias‐variance trade‐off across the different scenarios studied. 10.1002/sim.70366 http://onlinelibrary.wiley.com/termsAndConditions#vor |
| doi_str_mv | 10.1002/sim.70366 |
| format | Artículo Open Access |
| id | wiley_oa_10_1002_sim_70366 |
| institution | Wiley Open Access |
| license_str_mv | http://onlinelibrary.wiley.com/termsAndConditions#vor |
| publishDate | 2026 |
| publisher | Wiley |
| record_format | wiley_oa |
| spellingShingle | Assessing Treatment Effects in Observational Data With Missing Confounders: A Comparative Study of Practical Doubly‐Robust and Traditional Missing Data Methods Brian D. Williamson Chloe Krakauer Eric Johnson Susan Gruber Bryan E. Shepherd Mark J. van der Laan Thomas Lumley Hana Lee José J. Hernández‐Muñoz Fengyu Zhao Sarah K. Dutcher Rishi Desai Gregory E. Simon Susan M. Shortreed Jennifer C. Nelson Pamela A. Shaw Statistics in Medicine Assessing Treatment Effects in Observational Data With Missing Confounders: A Comparative Study of Practical Doubly‐Robust and Traditional Missing Data Methods Brian D. Williamson Chloe Krakauer Eric Johnson Susan Gruber Bryan E. Shepherd Mark J. van der Laan Thomas Lumley Hana Lee José J. Hernández‐Muñoz Fengyu Zhao Sarah K. Dutcher Rishi Desai Gregory E. Simon Susan M. Shortreed Jennifer C. Nelson Pamela A. Shaw Statistics in Medicine ABSTRACT In pharmacoepidemiology, safety and effectiveness are frequently evaluated using readily available administrative and electronic health records data. In these settings, detailed confounder data are often not available in all data sources and therefore missing on a subset of individuals. Multiple imputation (MI) and inverse‐probability weighting (IPW) are go‐to analytical methods to handle missing data and are dominant in the biomedical literature. Doubly‐robust methods, which are consistent under fewer assumptions, can be more efficient with respect to mean‐squared error. We discuss two practical‐to‐implement doubly‐robust estimators, generalized raking and inverse probability‐weighted targeted maximum likelihood estimation (TMLE), which are both currently under‐utilized in biomedical studies. We compare their performance to IPW and MI in a detailed numerical study for a variety of synthetic data‐generating and missingness scenarios, including scenarios with rare outcomes and a high missingness proportion. Further, we consider plasmode simulation studies that emulate the complex data structure of a large electronic health records cohort in order to compare anti‐depressant therapies in a rare‐outcome setting where a key confounder is prone to more than 50% missingness. We provide guidance on selecting a missing data analysis approach, based on which methods excelled with respect to the bias‐variance trade‐off across the different scenarios studied. 10.1002/sim.70366 http://onlinelibrary.wiley.com/termsAndConditions#vor |
| title | Assessing Treatment Effects in Observational Data With Missing Confounders: A Comparative Study of Practical Doubly‐Robust and Traditional Missing Data Methods |
| topic | Statistics in Medicine |
| url | https://onlinelibrary.wiley.com/doi/10.1002/sim.70366 |