Evaluating the case-positive, control test-negative study design for influenza vaccine effectiveness for the frailty bias

Introduction: Previous influenza vaccine effectiveness studies were criticized for their failure to control for frailty. This study was designed to see if the test-negative study design overcomes this bias. Methods: Adults >= 50 years of age with respiratory symptoms were enrolled from November 2006 through May 2012 during the influenza season (excluding the 2009-2010 H1N1 pandemic season) to perform yearly test-negative control influenza vaccine effectiveness studies in Nashville, TN. At enrollment, both a nasal and throat swab sample were obtained and tested for influenza by RT-PCR. Frailty was calculated using a modified Rockwood Index that included 60 variables ascertained in a retrospective chart review giving a score of 0 to 1. Subjects were divided into three strata: non frail (<= 0.08), pre-frail (>0.08 to <0.25), and frail (>= 0.25). Vaccine effectiveness was calculated using the formula [1-adjusted odds ratio (OR)] x 100%. Adjusted ORs for individual years and all years combined were estimated by penalized multivariable logistic regression. Results: Of 1023 hospitalized adults enrolled, 866 (84.7%) participants had complete immunization status, molecular influenza testing and covariates to calculate frailty. There were 83 influenza-positive cases and 783 test-negative controls overall, who were 74% white, 25% black, and 59% female. The median frailty index was 0.167 (Interquartile: 0.117, 0.267). The frailty index was 0.167 (0.100, 0.233) for the influenza positive cases compared to 0.183 (0.133, 0.267) for influenza negative controls (p = 0.07). Vaccine effectiveness estimates were 55.2% (95%CI: 30.5, 74.2), 60.4% (95%CI: 29.5, 74.4), and 54.3% (95%CI: 28.8, 74.0) without the frailty variable, including frailty as a continuous variable, and including frailty as a categorical variable, respectively. Conclusions: Using the case positive test negative study design to assess vaccine effectiveness, our measure of frailty was not a significant confounder as inclusion of this measure did not significantly change vaccine effectiveness estimates. (C) 2016 Elsevier Ltd. All rights reserved.