Potential of the test-negative design for measuring influenza vaccine effectiveness: a systematic review

Expert Rev Vaccines. 2014 Dec;13(12):1571-91. doi: 10.1586/14760584.2014.966695. Epub 2014 Oct 28.


Background: The test-negative design is a variant of the case-control study being increasingly used to study influenza vaccine effectiveness (VE). In these studies, patients with influenza-like illness are tested for influenza. Vaccine coverage is compared between those testing positive versus those testing negative to estimate VE.

Objectives: We reviewed features in the design, analysis and reporting of 85 published test-negative studies.

Data sources: Studies were identified from PubMed, reference lists and email updates. Study eligibility: All studies using the test-negative design reporting end-of-season estimates were included.

Study appraisal: Design features that may affect the validity and comparability of reported estimates were reviewed, including setting, study period, source population, case definition, exposure and outcome ascertainment and statistical model.

Results: There was considerable variation in the analytic approach, with 68 unique statistical models identified among the studies.

Conclusion: Harmonization of analytic approaches may improve the potential for pooling VE estimates.

Keywords: case–control; influenza; public health; test-negative study; vaccine effectiveness.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review
  • Systematic Review

MeSH terms

  • Adolescent
  • Adult
  • Aged, 80 and over
  • Child
  • Child, Preschool
  • Epidemiologic Studies*
  • Female
  • Humans
  • Infant
  • Infant, Newborn
  • Influenza Vaccines / administration & dosage*
  • Influenza Vaccines / immunology*
  • Influenza, Human / prevention & control*
  • Male
  • Middle Aged
  • Treatment Outcome
  • Young Adult


  • Influenza Vaccines