title: Validity of the estimates of oral cholera vaccine effectiveness derived from the test-negative design.
abstract: BACKGROUND
  The test-negative design (TND) has emerged as a simple method for evaluating vaccine effectiveness (VE). Its utility for evaluating oral cholera vaccine (OCV) effectiveness is unknown. We examined this method's validity in assessing OCV effectiveness by comparing the results of TND analyses with those of conventional cohort analyses.
  
  
  METHODS
  Randomized controlled trials of OCV were conducted in Matlab (Bangladesh) and Kolkata (India), and an observational cohort design was used in Zanzibar (Tanzania). For all three studies, VE using the TND was estimated from the odds ratio (OR) relating vaccination status to fecal test status (Vibrio cholerae O1 positive or negative) among diarrheal patients enrolled during surveillance (VE= (1-OR)×100%). In cohort analyses of these studies, we employed the Cox proportional hazard model for estimating VE (=1-hazard ratio)×100%).
  
  
  RESULTS
  OCV effectiveness estimates obtained using the TND (Matlab: 51%, 95% CI:37-62%; Kolkata: 67%, 95% CI:57-75%) were similar to the cohort analyses of these RCTs (Matlab: 52%, 95% CI:43-60% and Kolkata: 66%, 95% CI:55-74%). The TND VE estimate for the Zanzibar data was 94% (95% CI:84-98%) compared with 82% (95% CI:58-93%) in the cohort analysis. After adjusting for residual confounding in the cohort analysis of the Zanzibar study, using a bias indicator condition, we observed almost no difference in the two estimates.
  
  
  CONCLUSIONS
  Our findings suggest that the TND is a valid approach for evaluating OCV effectiveness in routine vaccination programs.
authors.affiliation: International Vaccine Institute, Seoul, Republic of Korea; Johns Hopkins Bloomberg School of Public Health, Baltimore, USA. Electronic address: mali25@jhu.edu.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Ali
authors.affiliation: International Vaccine Institute, Seoul, Republic of Korea.
authors.forename: Young Ae
authors.initials: YA
authors.lastname: You
authors.affiliation: National Institute of Cholera and Enteric Diseases, Kolkata, India.
authors.forename: Dipika
authors.initials: D
authors.lastname: Sur
authors.affiliation: National Institute of Cholera and Enteric Diseases, Kolkata, India.
authors.forename: Suman
authors.initials: S
authors.lastname: Kanungo
authors.affiliation: International Vaccine Institute, Seoul, Republic of Korea.
authors.forename: Deok Ryun
authors.initials: DR
authors.lastname: Kim
authors.affiliation: Johns Hopkins Bloomberg School of Public Health, Baltimore, USA.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Deen
authors.affiliation: University of the Philippines Manila-National Institutes of Health, Manila, Philippines.
authors.forename: Anna Lena
authors.initials: AL
authors.lastname: Lopez
authors.affiliation: International Vaccine Institute, Seoul, Republic of Korea.
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Wierzba
authors.affiliation: National Institute of Cholera and Enteric Diseases, Kolkata, India.
authors.forename: Sujit K
authors.initials: SK
authors.lastname: Bhattacharya
authors.affiliation: icddr,b, Dhaka, Bangladesh; UCLA Fielding School of Public Health, Los Angeles, USA.
authors.forename: John D
authors.initials: JD
authors.lastname: Clemens
mesh_terms: D001459:Bangladesh; D002771:Cholera / Q000517:prevention & control*; D022121:Cholera Vaccines / Q000008:administration & dosage / Q000276:immunology*; D015331:Cohort Studies; D003967:Diarrhea / Q000382:microbiology; D006801:Humans; D007194:India; D016016:Proportional Hazards Models; D012107:Research Design / Q000592:standards*; D013636:Tanzania; D041241:Vibrio cholerae O1
chemical_list: D022121:Cholera Vaccines
keywords: Case-control; Cholera; Test negative design; Vaccine efficacy; Vaccine trial