IJE Advance Access originally published online on December 20, 2005
International Journal of Epidemiology 2006 35(2):345-352; doi:10.1093/ije/dyi275
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Functional status is a confounder of the association of influenza vaccine and risk of all cause mortality in seniors
1 Center for Health Studies, Group Health Cooperative, Seattle, WA, USA.
2 Department of Epidemiology, University of Washington, Seattle, WA, USA.
3 Department of Biostatistics, University of Washington, Seattle, WA, USA.
4 Department of Medicine, University of Washington, Seattle, WA, USA.
5 Department of Health Services, University of Washington, Seattle, WA, USA.
* Corresponding author. Center for Health Studies, MPE-16, 1730 Minor Avenue, Seattle, WA 98101, USA. E-mail: jackson.l{at}ghc.org
Background Functional status limitations may be associated with both an increased risk of death and a decreased likelihood of influenza vaccination, and so may confound the association of influenza vaccination and risk of all cause mortality in seniors.
Methods We conducted a nested case–control study of persons 
65 years of age that included 252 cases who died during an influenza season and 576 age-matched controls. We identified functional limitations by medical record review, and compared the effect of adjustment for those factors with that of adjustment for disease covariates defined by diagnosis codes, using methods reported by previous influenza vaccine effectiveness studies, on the association of influenza vaccination and risk of death.
Results Functional limitations, such as requiring assistance for bathing, were highly prevalent in cases, even in the subgroup defined as free of comorbidity by diagnosis code criteria, and were associated with a decreased likelihood of vaccination among controls. Adjustment for functional limitations resulted in an estimate of the relative risk of death in vaccinated persons compared with unvaccinated persons that was closer to the null [odds ratio (OR), 0.71; 95% confidence interval (95% CI), 0.47–1.06] than the unadjusted estimate (OR, 0.59; 95% CI, 0.41–0.83). In contrast, adjustment for diagnosis code covariates moved the estimate further from the null (OR, 0.45; 95% CI, 0.30–0.68).
Conclusions Functional limitations appear to be important confounders of the association of vaccination and risk of death, while adjustment for diagnosis code covariates did not control for a healthy vaccinee bias. Further research is needed on methods to reduce the influence of bias in observational studies of influenza vaccine effectiveness.
Keywords Influenza/prevention and control, influenza vaccines, case–control studies, bias (epidemiology), confounding factor, epidemiological
Accepted 3 November 2005
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