title: Do case-only designs yield consistent results across design and different databases? A case study of hip fractures and benzodiazepines.
abstract: BACKGROUND
  The case-crossover (CXO) and self-controlled case series (SCCS) designs are increasingly used in pharmacoepidemiology. In both, relative risk estimates are obtained within persons, implicitly controlling for time-fixed confounding variables.
  
  
  OBJECTIVE
  To examine the consistency of relative risk estimates of hip/femur fractures (HFF) associated with the use of benzodiazepines (BZD) across case-only designs in two databases (DBs), when a common protocol was applied.
  
  
  METHODS
  CXO and SCCS studies were conducted in BIFAP (Spain) and CPRD (UK). Exposure to BZD was divided into non-use, current, recent and past use. For CXO, odds ratios (OR; 95%CI) of current use versus non-use/past were estimated using conditional logistic regression adjusted for co-medications (AOR). For the SCCS, conditional Poisson regression was used to estimate incidence rate ratios (IRR; 95%CI) of current use versus non/past-use, adjusted for age. To investigate possible event-exposure dependence the relative risk in the 30 days prior to first BZD exposure was also evaluated.
  
  
  RESULTS
  In the CXO current use of BZD was associated with an increased risk of HFF in both DBs, AORBIFAP = 1.47 (1.29-1.67) and AORCPRD = 1.55 (1.41-1.70). In the SCCS, IRRs for current exposure was 0.79 (0.72-0.86) in BIFAP and 1.21 (1.13-1.30) in CPRD. However, when we considered separately the 30-day pre-exposure period, the IRR for current period was 1.43 (1.31-1.57) in BIFAP and 1.37 (1.27-1.47) in CPRD.
  
  
  CONCLUSIONS
  CXO designs yielded consistent results across DBs, while initial SCCS analyses did not. Accounting for event-exposure dependence, estimates derived from SCCS were more consistent across DBs and designs.
authors.affiliation: Pharmacology Unit, Department of Biomedical Sciences, School of Medicine, University of Alcalá, Madrid, Spain.
authors.forename: Gema
authors.initials: G
authors.lastname: Requena
authors.affiliation: Worldwide Epidemiology, GlaxoSmithKline, Research and Development, Uxbridge, Middlesex, UK.
authors.forename: John
authors.initials: J
authors.lastname: Logie
authors.affiliation: BIFAP Research Unit, Spanish Agency of Medicines and Medical Devices, Madrid, Spain.
authors.forename: Elisa
authors.initials: E
authors.lastname: Martin
authors.affiliation: Worldwide Epidemiology, GlaxoSmithKline, Research and Development, Uxbridge, Middlesex, UK.
authors.forename: Nada
authors.initials: N
authors.lastname: Boudiaf
authors.affiliation: BIFAP Research Unit, Spanish Agency of Medicines and Medical Devices, Madrid, Spain.
authors.forename: Rocío
authors.initials: R
authors.lastname: González González
authors.affiliation: BIFAP Research Unit, Spanish Agency of Medicines and Medical Devices, Madrid, Spain.
authors.forename: Consuelo
authors.initials: C
authors.lastname: Huerta
authors.affiliation: BIFAP Research Unit, Spanish Agency of Medicines and Medical Devices, Madrid, Spain.
authors.forename: Arturo
authors.initials: A
authors.lastname: Alvarez
authors.affiliation: Worldwide Epidemiology, GlaxoSmithKline, Research and Development, Uxbridge, Middlesex, UK.
authors.forename: David
authors.initials: D
authors.lastname: Webb
authors.affiliation: Epidemiology, Pfizer Ltd, Tadworth, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Bate
authors.affiliation: Spanish Center for Pharmacoepidemiological Research (CEIFE), Madrid, Spain.
authors.forename: Luis A
authors.initials: LA
authors.lastname: García Rodríguez
authors.affiliation: Epidemiology, Pfizer Research and Development, New York, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Reynolds
authors.affiliation: Global Clinical Epidemiology, Novartis Pharma AG, Basel, Switzerland.
authors.forename: Raymond
authors.initials: R
authors.lastname: Schlienger
authors.affiliation: Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht University, Utrecht, the Netherlands.
authors.forename: Helga
authors.initials: H
authors.lastname: Gardarsdottir
authors.affiliation: Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht University, Utrecht, the Netherlands.
authors.forename: Mark
authors.identifier: http://orcid.org/0000-0002-5764-5788
authors.initials: M
authors.lastname: de Groot
authors.affiliation: Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht University, Utrecht, the Netherlands.
authors.forename: Olaf H
authors.initials: OH
authors.lastname: Klungel
authors.affiliation: Pharmacology Unit, Department of Biomedical Sciences, School of Medicine, University of Alcalá, Madrid, Spain.|Clinical Pharmacology Unit, University Hospital Príncipe de Asturias, Madrid, Spain.
authors.forename: Fancisco
authors.initials: F
authors.lastname: de Abajo
authors.affiliation: London School of Hygiene and Tropical Medicine (LSHTM), London, UK.
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Douglas
mesh_terms: D001569:Benzodiazepines / Q000009:adverse effects*; D016022:Case-Control Studies; D016208:Databases, Factual / Q000592:standards*; D005260:Female; D006620:Hip Fractures / Q000453:epidemiology* / Q000209:etiology*; D006801:Humans; D008297:Male; D012107:Research Design
chemical_list: D001569:Benzodiazepines
keywords: benzodiazepines; case crossover (CXO); electronic healthcare records databases (DBs); hip fractures; pharmacoepidemiology; self-controlled case series (SCCS)