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The positivity assumption and marginal structural models: the example of warfarin use and risk of bleeding

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Abstract

Estimates of the average causal effect (ACE) of warfarin on the risk of bleeding may be confounded by indication as patients at high risk of bleeding are unlikely to be prescribed warfarin. One approach to estimating the ACE is inverse probability of treatment weighting (IPTW). This study was designed to examine the use of IPTW in this setting, and to demonstrate problems with the violation of the positivity assumption. We analyzed a case–control study on 4,028 cases of gastro-intestinal bleeding and 79,239 controls set in the United Kingdom’s General Practice Research Database. Warfarin exposure was defined as a prescription issued in the 90 days before the index date. Secondary analyses were conducted restricted to patients more likely to receive warfarin and with a truncated weight distribution, to exclude subjects highly unlikely to be treated. The estimated association between warfarin use and bleeding was stronger with IPTW [odds ratio (OR): 17.2; 95% confidence interval (CI): 6.5–37.7] than with a standard logistic regression model (OR: 2.1; 95% CI: 1.7–2.5). The presence of large weights (five subjects with stabilized weight >500) indicated a potential violation of the positivity assumption. In the restricted analysis, both IPTW (OR: 2.0; 95% CI: 0.4–9.6) and standard regression (OR: 1.6; 95% CI: 1.3–2.0) were compatible with a meta-analysis of randomized trials inverse probability of treatment weighting is sensitive to the positivity assumption; however, such sensitivity may assist in diagnosing off-support inference.

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Acknowledgments

The authors thank Stephen Cole for comments on an earlier version of this work. This study was funded by the Canadian Institutes of Health Research (CIHR) and the Canadian Foundation for Innovation. Robert Platt holds a Chercheur-boursier award from the Fonds de Recherche en Sante du Quebec (FRSQ) and is a member of the Research Institute of the McGill University Health Centre, which receives operating funds from the FRSQ.

Conflict of interest

The authors declare no conflict of interest.

Ethical review

Ethical review for this study was done by the Independent Scientific Advisory Committee for MHRA database research.

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Authors and Affiliations

  1. Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, QC, Canada

    Robert William Platt & Samy Suissa

  2. Department of Pediatrics, McGill University, Montreal, QC, Canada

    Robert William Platt

  3. Department of Pharmaceutical Outcomes and Policy, College of Pharmacy, University of Florida, Gainesville, FL, USA

    Joseph Austin Christopher Delaney

  4. McGill Pharmacoepidemiology Research Unit, Jewish General Hospital, Montreal, QC, Canada

    Samy Suissa

  5. Department of Medicine, McGill University, Montreal, QC, Canada

    Samy Suissa

  6. Montréal Children’s Hospital Research Institute, 4060 Ste Catherine W #205, Montreal, QC, H3Z 2Z3, Canada

    Robert William Platt

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  1. Robert William Platt
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  2. Joseph Austin Christopher Delaney
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  3. Samy Suissa
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Correspondence to Robert William Platt.

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Platt, R.W., Delaney, J.A.C. & Suissa, S. The positivity assumption and marginal structural models: the example of warfarin use and risk of bleeding. Eur J Epidemiol 27, 77–83 (2012). https://doi.org/10.1007/s10654-011-9637-7

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  • DOI: https://doi.org/10.1007/s10654-011-9637-7

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