Methods for addressing “innocent bystanders” when evaluating safety of concomitant vaccines

Shirley V. Wang, Abdurrahman Abdurrob, Julia Spoendlin, Edwin Lewis, Sophia R. Newcomer, Bruce Fireman, Matthew F. Daley, Jason M. Glanz, Jonathan Duffy, Eric S. Weintraub, Martin Kulldorff

Research output: Contribution to journalArticlepeer-review

3 Scopus citations


Purpose: The need to develop methods for studying the safety of childhood immunization schedules has been recognized by the Institute of Medicine and Department of Health and Human Services. The recommended childhood immunization schedule includes multiple vaccines in a visit. A key concern is safety of concomitant (same day) versus separate day vaccination. This paper addresses a methodological challenge for observational studies using a self-controlled design to investigate the safety of concomitant vaccination. Methods: We propose a process for distinguishing which of several concomitantly administered vaccines is responsible for increased risk of an adverse event while adjusting for confounding due to relationships between effect modifying risk factors and concomitant vaccine combinations. We illustrate the approach by re-examining the known increase in risk of seizure 7 to 10 days after measles-mumps-rubella (MMR) vaccination and evaluating potential independent or modifying effects of other vaccines. Results: Initial analyses suggested that DTaP had both an independent and potentiating effect on seizure. After accounting for the relationship between age at vaccination and vaccine combination, there was little evidence for increased risk of seizure with same day administration of DTaP and MMR; incidence rate ratio, 95% confidence interval 1.2 (0.9–1.6), P value = θ.226. Conclusion: We have shown that when using a self-controlled design to investigate safety of concomitant vaccination, it can be critically important to adjust for time-invariant effect modifying risk factors, such as age at time of vaccination, which are structurally related to vaccination patterns due to recommended immunization schedules.

Original languageEnglish
Pages (from-to)405-412
Number of pages8
JournalPharmacoepidemiology and Drug Safety
Issue number4
StatePublished - Apr 2018


  • immunization schedule
  • methods
  • seizure
  • self-controlled
  • vaccine safety


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