title: Pandemic influenza vaccine & narcolepsy: simulations on the potential impact of bias.
abstract: Several studies have identified an association between Pandemrix(TM), an AS03 adjuvanted pandemic influenza A(H1N1) vaccine, and narcolepsy, a rare and under-diagnosed sleep disorder with a median onset-to-diagnosis interval of ten years. This paper reviews potential sources of bias in published studies and aims to provide, through simulation, methodological recommendations for assessment of vaccine safety signals. Our simulation study showed that in the absence of an association between the vaccine and the outcome, presence of detection bias and differential exposure misclassification could account for elevated risk estimates. These may play a major role, particularly in alert situations when observation times are limited and the disease has a long latency period. Estimates from the case-control design were less inflated than those from the cohort design when these biases were present. Overall, these simulations provide useful insights for the design and interpretation of future studies.
authors.affiliation: a Department of Medical Informatics Erasmus MC Rotterdam , The Netherlands.|b Pharmacotherapeutic group IV, Medicines Evaluation Board , Utrecht , The Netherlands.
authors.forename: Leonoor
authors.initials: L
authors.lastname: Wijnans
authors.affiliation: a Department of Medical Informatics Erasmus MC Rotterdam , The Netherlands.
authors.forename: Caitlin
authors.initials: C
authors.lastname: Dodd
authors.affiliation: a Department of Medical Informatics Erasmus MC Rotterdam , The Netherlands.
authors.forename: Maria
authors.initials: M
authors.lastname: de Ridder
authors.affiliation: a Department of Medical Informatics Erasmus MC Rotterdam , The Netherlands.|c Department of Statistics and Quantitative Methods, Division of Biostatistics, Epidemiology and Public Health, Laboratory of Healthcare Research and Pharmacoepidemiology , University of Milano-Bicocca , Milan , Italy.
authors.forename: Silvana
authors.initials: S
authors.lastname: Romio
authors.affiliation: a Department of Medical Informatics Erasmus MC Rotterdam , The Netherlands.
authors.forename: Daniel
authors.initials: D
authors.lastname: Weibel
authors.affiliation: d Sleep Medicine Center Kempenhaeghe , Heeze , The Netherlands.
authors.forename: Sebastiaan
authors.initials: S
authors.lastname: Overeem
authors.affiliation: e Department of Neurology , Leiden University Medical Center , Leiden , The Netherlands.|f Sleep Wake Center SEIN Heemstede , Heemstede , The Netherlands.
authors.forename: Gert Jan
authors.initials: GJ
authors.lastname: Lammers
authors.affiliation: g Brighton Collaboration Foundation , Basel , Switzerland.|h University Children's Hospital , Basel , Switzerland.
authors.forename: Jan
authors.initials: J
authors.lastname: Bonhoeffer
authors.affiliation: i Center for Global Health, Cincinnati Children's Hospital , Cincinnati , OH , USA.
authors.forename: Steve
authors.initials: S
authors.lastname: Black
authors.affiliation: a Department of Medical Informatics Erasmus MC Rotterdam , The Netherlands.
authors.forename: Miriam
authors.initials: M
authors.lastname: Sturkenboom
mesh_terms: D000293:Adolescent; D000328:Adult; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D064420:Drug-Related Side Effects and Adverse Reactions / Q000453:epidemiology*; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007252:Influenza Vaccines / Q000008:administration & dosage* / Q000009:adverse effects*; D007837:Latency Period, Psychological; D008297:Male; D008962:Models, Theoretical; D009290:Narcolepsy / Q000139:chemically induced* / Q000453:epidemiology*; D055815:Young Adult
chemical_list: D007252:Influenza Vaccines; C556153:pandemrix
keywords: Bias; Narcolepsy; Pandemic Influenza; Pandemrix; Simulation; Vaccine Safety