title: Application of Probabilistic Multiple-Bias Analyses to a Cohort- and a Case-Control Study on the Association between Pandemrix™ and Narcolepsy.
abstract: BACKGROUND
  An increase in narcolepsy cases was observed in Finland and Sweden towards the end of the 2009 H1N1 influenza pandemic. Preliminary observational studies suggested a temporal link with the pandemic influenza vaccine Pandemrix™, leading to a number of additional studies across Europe. Given the public health urgency, these studies used readily available retrospective data from various sources. The potential for bias in such settings was generally acknowledged. Although generally advocated by key opinion leaders and international health authorities, no systematic quantitative assessment of the potential joint impact of biases was undertaken in any of these studies.
  
  
  METHODS
  We applied bias-level multiple-bias analyses to two of the published narcolepsy studies: a pediatric cohort study from Finland and a case-control study from France. In particular, we developed Monte Carlo simulation models to evaluate a potential cascade of biases, including confounding by age, by indication and by natural H1N1 infection, selection bias, disease- and exposure misclassification. All bias parameters were evidence-based to the extent possible.
  
  
  RESULTS
  Given the assumptions used for confounding, selection bias and misclassification, the Finnish rate ratio of 13.78 (95% CI: 5.72-28.11) reduced to a median value of 6.06 (2.5th- 97.5th percentile: 2.49-15.1) and the French odds ratio of 5.43 (95% CI: 2.6-10.08) to 1.85 (2.5th-97.5th percentile: 0.85-4.08).
  
  
  CONCLUSIONS
  We illustrate multiple-bias analyses using two studies on the Pandemrix™-narcolepsy association and advocate their use to better understand the robustness of study findings. Based on our multiple-bias models, the observed Pandemrix™-narcolepsy association consistently persists in the Finnish study. For the French study, the results of our multiple-bias models were inconclusive.
authors.affiliation: P95 Pharmacovigilance and Epidemiology Services, Koning Leopold III Laan 1, 3001 Leuven, Belgium.
authors.forename: Kaatje
authors.initials: K
authors.lastname: Bollaerts
authors.affiliation: GSK Vaccines, 2301 Renaissance Boulevard, King of Prussia, PA 19406, United States of America.
authors.forename: Vivek
authors.initials: V
authors.lastname: Shinde
authors.affiliation: Business & Decision Life Sciences (contractor for GSK Vaccines), Rue Saint Lambert 141, 1200 Brussels, Belgium.
authors.forename: Gaël
authors.initials: G
authors.lastname: Dos Santos
authors.affiliation: GSK Vaccines, Avenue Fleming 20, B-1300 Wavre, Belgium.
authors.forename: Germano
authors.initials: G
authors.lastname: Ferreira
authors.affiliation: GSK Vaccines, Avenue Fleming 20, B-1300 Wavre, Belgium.
authors.forename: Vincent
authors.initials: V
authors.lastname: Bauchau
authors.affiliation: GSK Vaccines, Avenue Fleming 20, B-1300 Wavre, Belgium.
authors.forename: Catherine
authors.initials: C
authors.lastname: Cohet
authors.affiliation: P95 Pharmacovigilance and Epidemiology Services, Koning Leopold III Laan 1, 3001 Leuven, Belgium.
authors.forename: Thomas
authors.initials: T
authors.lastname: Verstraeten
mesh_terms: D000293:Adolescent; D000328:Adult; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D005260:Female; D005387:Finland / Q000453:epidemiology; D005602:France / Q000453:epidemiology; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype; D007252:Influenza Vaccines / Q000008:administration & dosage / Q000009:adverse effects*; D007251:Influenza, Human / Q000453:epidemiology / Q000517:prevention & control*; D008297:Male; D009290:Narcolepsy / Q000139:chemically induced / Q000453:epidemiology*; D058873:Pandemics; D013548:Sweden / Q000453:epidemiology
chemical_list: D007252:Influenza Vaccines; C556153:pandemrix