title: Evaluating the case-positive, control test-negative study design for influenza vaccine effectiveness for the frailty bias.
abstract: BACKGROUND
  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)] × 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.
authors.affiliation: Departments of Medicine, Vanderbilt University Medical Center, Nashville, TN, United States. Electronic address: Keipp.talbot@vanderbilt.edu.
authors.forename: H Keipp
authors.initials: HK
authors.lastname: Talbot
authors.affiliation: Departments of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, United States.
authors.forename: Hui
authors.initials: H
authors.lastname: Nian
authors.affiliation: Departments of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, United States.
authors.forename: Qingxia
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Departments of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, United States.
authors.forename: Yuwei
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Departments of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, United States.
authors.forename: Kathryn M
authors.initials: KM
authors.lastname: Edwards
authors.affiliation: Departments of Medicine, Vanderbilt University Medical Center, Nashville, TN, United States; Departments of Health Policy, Vanderbilt University Medical Center, Nashville, TN, United States; Mid-South Geriatric Research Education and Clinical Center and Clinical Research Center of Excellence, VA TN Valley Health Care System, Nashville, TN, United States.
authors.forename: Marie R
authors.initials: MR
authors.lastname: Griffin
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D015982:Bias; D005260:Female; D016330:Frail Elderly; D006760:Hospitalization / Q000706:statistics & numerical data; D006801:Humans; D007252:Influenza Vaccines / Q000276:immunology*; D007251:Influenza, Human / Q000517:prevention & control*; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D012107:Research Design; D012189:Retrospective Studies; D013714:Tennessee; D064166:Vaccine Potency
chemical_list: D007252:Influenza Vaccines
keywords: Frailty; Influenza vaccine; Test-negative study design