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. 2018 Feb 1;187(2):389-397.
doi: 10.1093/aje/kwx251.

Estimating Influenza Vaccine Effectiveness With the Test-Negative Design Using Alternative Control Groups: A Systematic Review and Meta-Analysis

Free PMC article

Estimating Influenza Vaccine Effectiveness With the Test-Negative Design Using Alternative Control Groups: A Systematic Review and Meta-Analysis

Shuo Feng et al. Am J Epidemiol. .
Free PMC article


One important assumption in case-control studies is that control selection should be independent of exposure. Nevertheless, it has been hypothesized that virus interference might lead to a correlation between receipt of influenza vaccination and increased risk of infection with other respiratory viruses. We investigated whether such a phenomenon might affect a study design commonly used to estimate influenza vaccine effectiveness (VE). We searched publications in MEDLINE, PubMed, and Web of Science. We identified 12 studies using the test-negative design (2011-2017) that reported VE estimates separately derived by 3 alternative control groups: 1) all patients testing negative for influenza (FLU), VEFLU-; 2) patients who tested positive for other/another respiratory virus (ORV), VEORV+; and 3) patients who tested negative for all viruses in the panel (PAN), VEPAN-. These included VE estimates from 7 countries for all age groups from 2003/2004 to 2013/2014. We observed no difference in vaccination coverage between the ORV-positive and PAN-negative control groups. A total of 63 VEFLU- estimates, 62 VEORV+ estimates, and 33 VEPAN- estimates were extracted. Pooled estimates of the difference in VE (ΔVE) were very similar between groups. In meta-regression, no association was found between the selection of control group and VE estimates. In conclusion, we did not find any differences in VE estimates based on the choice of control group.

Keywords: epidemiologic methods; influenza; test-negative design; vaccine effectiveness; virus interference.


Figure 1.
Figure 1.
Identification of eligible studies that used the test-negative design (TND) to estimate influenza vaccine effectiveness (VE) by means of alternative control groups. FLU, influenza; ORV, other/another respiratory virus; PAN, panel.
Figure 2.
Figure 2.
Comparison of influenza vaccine effectiveness (VE) estimated using influenza (FLU)-negative controls (VEFLU−) with VE estimated using other/another respiratory virus (ORV)-positive controls (VEORV+) (A) and comparison of VE estimated using influenza-negative controls (VEFLU−) with VE estimated using panel (PAN)-negative controls (VEPAN−) (B) from all available VE estimates. Dotted lines represent the identity line. Ninety-five percent confidence intervals are shown in gray (point estimates and lower confidence limits below −110% are not shown).

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