The Use of Active Comparators in Self-Controlled Designs

Jesper Hallas, Heather Whitaker, Joseph A. Delaney, Suzanne M. Cadarette, Nicole Pratt, Malcolm Maclure

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)


For self-controlled studies of medication-related effects, time-varying confounding by indication can occur if the indication varies over time. We describe how active comparators might mitigate such bias, using an empirical example. Approaches to using active comparators are described for case-crossover design, case-time-control design, self-controlled case-series, and sequence symmetry analyses. In the empirical example, we used Danish data from 1996-2018 to study the association between penicillin and venous thromboembolism (VTE), using roxithromycin, a macrolide antibiotic, as comparator. Upper respiratory infection is a transient risk factor for VTE, thus representing time-dependent confounding by indication. Odds ratios for case-crossover analysis were 3.35 (95% confidence interval: 3.23, 3.49) for penicillin and 3.56 (95% confidence interval: 3.30, 3.83) for roxithromycin. We used a Wald-based method or an interaction term to estimate the odds ratio for penicillin with roxithromycin as comparator. These 2 estimates were 0.94 (95% confidence interval: 0.87, 1.03) and 1.03 (95% confidence interval: 0.95, 1.13). Results were similar for the case-time-control analysis, but both the self-controlled case-series and sequence symmetry analysis suggested a weak protective effect of penicillin, seemingly explained by VTE affecting future exposure exclusively for penicillin. The strong association of antibiotics with VTE suggests presence of confounding by indication. Such confounding can be mitigated by using an active comparator.

Original languageEnglish
Pages (from-to)2181-2187
Number of pages7
JournalAmerican Journal of Epidemiology
Issue number10
Early online date16 Apr 2021
Publication statusPublished - 1 Oct 2021

Bibliographical note

Funding Information: No funding information.

Open Access: No Open Access licence

Publisher Copyright: © The Author(s) 2021. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail:

Citation: Jesper Hallas, Heather Whitaker, Joseph A Delaney, Suzanne M Cadarette, Nicole Pratt, Malcolm Maclure, The Use of Active Comparators in Self-Controlled Designs, American Journal of Epidemiology, Volume 190, Issue 10, October 2021, Pages 2181–2187.



  • active comparators
  • case-only designs
  • confounding-by-indication


Dive into the research topics of 'The Use of Active Comparators in Self-Controlled Designs'. Together they form a unique fingerprint.

Cite this