title: Instrumental variables analysis using multiple databases: an example of antidepressant use and risk of hip fracture.
abstract: OBJECTIVE
  Instrumental variable (IV) analysis can control for unmeasured confounding, yet it has not been widely used in pharmacoepidemiology. We aimed to assess the performance of IV analysis using different IVs in multiple databases in a study of antidepressant use and hip fracture.
  
  
  METHODS
  Information on adults with at least one prescription of a selective serotonin reuptake inhibitor (SSRI) or tricyclic antidepressant (TCA) during 2001-2009 was extracted from the THIN (UK), BIFAP (Spain), and Mondriaan (Netherlands) databases. IVs were created using the proportion of SSRI prescriptions per practice or using the one, five, or ten previous prescriptions by a physician. Data were analysed using conventional Cox regression and two-stage IV models.
  
  
  RESULTS
  In the conventional analysis, SSRI (vs. TCA) was associated with an increased risk of hip fracture, which was consistently found across databases: the adjusted hazard ratio (HR) was approximately 1.35 for time-fixed and 1.50 to 2.49 for time-varying SSRI use, while the IV analysis based on the IVs that appeared to satisfy the IV assumptions showed conflicting results, e.g. the adjusted HRs ranged from 0.55 to 2.75 for time-fixed exposure. IVs for time-varying exposure violated at least one IV assumption and were therefore invalid.
  
  
  CONCLUSIONS
  This multiple database study shows that the performance of IV analysis varied across the databases for time-fixed and time-varying exposures and strongly depends on the definition of IVs. It remains challenging to obtain valid IVs in pharmacoepidemiological studies, particularly for time-varying exposure, and IV analysis should therefore be interpreted cautiously.
authors.affiliation: Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, the Netherlands.|Department of Statistics, Shahjalal University of Science and Technology, Sylhet, Bangladesh.
authors.forename: Md Jamal
authors.initials: MJ
authors.lastname: Uddin
authors.affiliation: Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, the Netherlands.|Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Rolf H H
authors.initials: RH
authors.lastname: Groenwold
authors.affiliation: Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, the Netherlands.
authors.forename: Anthonius
authors.initials: A
authors.lastname: de Boer
authors.affiliation: Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, the Netherlands.|Department of Clinical Pharmacy, Division of Laboratory and Pharmacy, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Helga
authors.initials: H
authors.lastname: Gardarsdottir
authors.affiliation: BIFAP Research Unit. Division of Pharmacoepidemiology and Pharmacovigilance, Medicines for Human Use Department, Spanish Agency for Medicines and Medical Devices (AEMPS), Madrid, Spain.
authors.forename: Elisa
authors.initials: E
authors.lastname: Martin
authors.affiliation: European Medicines Agency (EMA), London, UK.
authors.forename: Gianmario
authors.initials: G
authors.lastname: Candore
authors.affiliation: Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, the Netherlands.
authors.forename: Svetlana V
authors.initials: SV
authors.lastname: Belitser
authors.affiliation: Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Arno W
authors.initials: AW
authors.lastname: Hoes
authors.affiliation: Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Kit C B
authors.initials: KC
authors.lastname: Roes
authors.affiliation: Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, the Netherlands.|Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Olaf H
authors.initials: OH
authors.lastname: Klungel
mesh_terms: D000928:Antidepressive Agents / Q000009:adverse effects*; D019992:Databases as Topic; D005260:Female; D006620:Hip Fractures / Q000209:etiology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D017891:Pharmacoepidemiology; D012306:Risk
chemical_list: D000928:Antidepressive Agents
keywords: antidepressant; hip/femur fracture; instrumental variables; multiple general practice databases; pharmacoepidemiology; physician's prescribing preference; unmeasured confounding