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Confounding by indication in non-experimental evaluation of vaccine effectiveness: the example of prevention of influenza complications
  1. E Hak1,
  2. Th J M Verheij1,
  3. D E Grobbee1,
  4. K L Nichol2,
  5. A W Hoes1
  1. 1Julius Centre for General Practice and Patient Oriented Research, University Medical Centre Utrecht, Netherlands
  2. 2Medicine Service, Veterans Affairs Medical Center and University of Minnesota, Minneapolis, USA
  1. Correspondence to:
 Dr E Hak, University Medical Center Utrecht, Julius Center for General Practice and Patient Oriented Research, Location Stratenum, PO Box 85060, 3508 AB Utrecht, Netherlands;


Randomised allocation of vaccine or placebo is the preferred method to assess the effects of the vaccine on clinical outcomes relevant to the individual patient. In the absence of phase 3 trials using clinical end points, notably post-influenza complications, alternative non-experimental designs to evaluate vaccine effects or safety are often used. The application of these designs may, however, lead to invalid estimates of vaccine effectiveness or safety. As patients with poor prognosis are more likely to be immunised, selection for vaccination is confounded by patient factors that are also related to clinical end points. This paper describes several design and analytical methods aimed at limiting or preventing this confounding by indication in non-experimental studies. In short, comparison of study groups with similar prognosis, restriction of the study population, and statistical adjustment for dissimilarities in prognosis are important tools and should be considered. Only if the investigator is able to show that confounding by indication is sufficiently controlled for, results of a non-experimental study may be of use to direct an evidence based vaccine policy.

  • influenza
  • vaccine
  • confounding
  • observational studies

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  • Funding: UMC Utrecht and The Netherlands Asthma Foundation (no 97.51).

  • Conflicts of interest: none

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