Drug Safety

, Volume 36, Supplement 1, pp 73–82 | Cite as

Empirical Performance of the Case–Control Method: Lessons for Developing a Risk Identification and Analysis System

  • David Madigan
  • Martijn J. Schuemie
  • Patrick B. Ryan
Original Research Article



Considerable attention now focuses on the use of large-scale observational healthcare data for understanding drug safety. In this context, analysts utilize a variety of statistical and epidemiological approaches such as case–control, cohort, and self-controlled methods. The operating characteristics of these methods are poorly understood.


Establish the operating characteristics of the case–control method for large scale observational analysis in drug safety.

Research Design

We empirically evaluated the case–control approach in 5 real observational healthcare databases and 6 simulated datasets. We retrospectively studied the predictive accuracy of the method when applied to a collection of 165 positive controls and 234 negative controls across 4 outcomes: acute liver injury, acute myocardial infarction, acute kidney injury, and upper gastrointestinal bleeding.


In our experiment, the case–control method provided weak discrimination between positive and negative controls. Furthermore, the method yielded positively biased estimates and confidence intervals that had poor coverage properties.


For the four outcomes we examined, the case–control method may not be the method of choice for estimating potentially harmful effects of drugs.


Acute Kidney Injury Index Date Salmeterol Coverage Probability Darbepoetin Alfa 
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The Observational Medical Outcomes Partnership is funded by the Foundation for the National Institutes of Health (FNIH) through generous contributions from the following: Abbott, Amgen Inc., AstraZeneca, Bayer Healthcare Pharmaceuticals, Inc., Biogen Idec, Bristol-Myers Squibb, Eli Lilly & Company, GlaxoSmithKline, Janssen Research and Development, Lundbeck, Inc., Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Pfizer Inc, Pharmaceutical Research Manufacturers of America (PhRMA), Roche, Sanofi-aventis, Schering-Plough Corporation, and Takeda. Drs. Ryan and Schuemie are employees of Janssen Research and Development. Dr. Schuemie received a fellowship from the Office of Medical Policy, Center for Drug Evaluation and Research, Food and Drug Administration. Drs. Schuemie and Madigan have both received a grant previously from FNIH.

This article was published in a supplement sponsored by the Foundation for the National Institutes of Health (FNIH). The supplement was guest edited by Stephen J.W. Evans. It was peer reviewed by Olaf H. Klungel who received a small honorarium to cover out-of-pocket expenses. S.J.W.E has received travel funding from the FNIH to travel to the OMOP symposium and received a fee from FNIH for the review of a protocol for OMOP. O.H.K has received funding for the IMI-PROTECT project from the Innovative Medicines Initiative Joint Undertaking ( under Grant Agreement no 115004, resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP7/2007-2013) and EFPIA companies’ in kind contribution.


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Copyright information

© Springer International Publishing Switzerland 2013

Authors and Affiliations

  • David Madigan
    • 1
    • 4
  • Martijn J. Schuemie
    • 2
    • 4
  • Patrick B. Ryan
    • 3
    • 4
  1. 1.Department of StatisticsColumbia UniversityNew YorkUSA
  2. 2.Department of Medical InformaticsErasmus University Medical Center RotterdamRotterdamThe Netherlands
  3. 3.Janssen Research and Development LLCTitusvilleUSA
  4. 4.Observational Medical Outcomes Partnership, Foundation for the National Institutes of HealthBethesdaUSA

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