title: The risk of acute liver injury associated with the use of antibiotics--evaluating robustness of results in the pharmacoepidemiological research on outcomes of therapeutics by a European consortium (PROTECT) project.
abstract: OBJECTIVE
  To examine the robustness of findings of case-control studies on the association between acute liver injury (ALI) and antibiotic use in the following different situations: (i) Replication of a protocol in different databases, with different data types, as well as replication in the same database, but performed by a different research team. (ii) Varying algorithms to identify cases, with and without manual case validation. (iii) Different exposure windows for time at risk.
  
  
  METHODS
  Five case-control studies in four different databases were performed with a common study protocol as starting point to harmonize study outcome definitions, exposure definitions and statistical analyses.
  
  
  RESULTS
  All five studies showed an increased risk of ALI associated with antibiotic use ranging from OR 2.6 (95% CI 1.3-5.4) to 7.7 (95% CI 2.0-29.3). Comparable trends could be observed in the five studies: (i) without manual validation the use of the narrowest definition for ALI showed higher risk estimates, (ii) narrow and broad algorithm definitions followed by manual validation of cases resulted in similar risk estimates, and (iii) the use of a larger window (30 days vs 14 days) to define time at risk led to a decrease in risk estimates.
  
  
  CONCLUSIONS
  Reproduction of a study using a predefined protocol in different database settings is feasible, although assumptions had to be made and amendments in the protocol were inevitable. Despite differences, the strength of association was comparable between the studies. In addition, the impact of varying outcome definitions and time windows showed similar trends within the data sources.
authors.affiliation: Utrecht Institute for Pharmaceutical Sciences, Utrecht University, The Netherlands.
authors.forename: Renate
authors.initials: R
authors.lastname: Udo
authors.affiliation: Global Pharmacovigilance and Epidemiology, Sanofi, Chilly-Mazarin, France.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Tcherny-Lessenot
authors.affiliation: London School of Hygiene and Tropical Medicine, Faculty of Epidemiology and Population Health, London, United Kingdom.
authors.forename: Ruth
authors.initials: R
authors.lastname: Brauer
authors.affiliation: Takeda Development Centre Europe, London, United Kingdom.
authors.forename: Paul
authors.initials: P
authors.lastname: Dolin
authors.affiliation: Takeda Development Centre Europe, London, United Kingdom.
authors.forename: David
authors.initials: D
authors.lastname: Irvine
authors.affiliation: Global Pharmacovigilance and Epidemiology, Sanofi, Chilly-Mazarin, France.
authors.forename: Yunxun
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Global Pharmacovigilance and Epidemiology, Sanofi, Chilly-Mazarin, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Auclert
authors.affiliation: Global Pharmacovigilance and Epidemiology, Sanofi, Chilly-Mazarin, France.
authors.forename: Juhaeri
authors.initials: J
authors.lastname: Juhaeri
authors.affiliation: European Medicines Agency (EMA), London, United Kingdom.
authors.forename: Xavier
authors.initials: X
authors.lastname: Kurz
authors.affiliation: LA-SER Europe Limited, London, United Kingdom.
authors.forename: Lucien
authors.initials: L
authors.lastname: Abenhaim
authors.affiliation: LA-SER Europe Limited, London, United Kingdom.
authors.forename: Lamiae
authors.initials: L
authors.lastname: Grimaldi
authors.affiliation: Utrecht Institute for Pharmaceutical Sciences, Utrecht University, The Netherlands.
authors.forename: Marie L
authors.initials: ML
authors.lastname: De Bruin
mesh_terms: D000900:Anti-Bacterial Agents / Q000009:adverse effects*; D016022:Case-Control Studies; D056486:Chemical and Drug Induced Liver Injury / Q000453:epidemiology / Q000209:etiology*; D005060:Europe / Q000453:epidemiology; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D017063:Outcome Assessment, Health Care; D017891:Pharmacoepidemiology / Q000592:standards* / Q000706:statistics & numerical data; D012306:Risk
chemical_list: D000900:Anti-Bacterial Agents
keywords: acute liver injury; antibiotics; case definition; case-control studies; pharmacoepidemiology; time window at risk