title: Evaluating different physician's prescribing preference based instrumental variables in two primary care databases: a study of inhaled long-acting beta2-agonist use and the risk of myocardial infarction.
abstract: OBJECTIVE
  Instrumental variable (IV) analysis with physician's prescribing preference (PPP) as IV is increasingly used in pharmacoepidemiology. However, it is unclear whether this IV performs consistently across databases. We aimed to evaluate the validity of different PPPs in a study of inhaled long-acting beta2-agonist (LABA) use and myocardial infarction (MI).
  
  
  METHODS
  Information on adults with asthma and/or COPD and at least one prescription of beta2-agonist, or muscarinic antagonist was extracted from the CPRD (UK) and the Mondriaan (Netherlands) databases. LABA exposure was considered time-fixed or time-varying. We measured PPPs using previous LABA prescriptions of physicians or proportion of LABA prescriptions per practice. Correlation (r) and standardized difference (SDif) were used to assess assumption of IV analysis.
  
  
  RESULTS
  For time-fixed LABA, the IV based on 10 previous prescriptions outperformed the other IVs regarding strength of the IV (r ≥ 0.15) and balance of confounders between IV categories (SDif < 0.10). None of the IVs we considered appeared to be valid for time-varying LABA. In CPRD (n = 490,499), which included approximately 18 times more subjects than Mondriaan (n = 27,459), IVs appeared more valid. LABA was not associated with MI; hazard ratios ranged from 0.86 to 1.18 for conventional analysis, and from 0.61 to 1.24 for the IV analyses with apparent valid IVs.
  
  
  CONCLUSIONS
  The validity of physician's prescribing preference as IV strongly depends on how this IV is defined and in which database it is applied. Hence, general recommendations cannot be made, other than to generate several plausible IVs, assess their validity, and report the estimate(s) from apparently valid IVs.
authors.affiliation: Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, University of Utrecht, Utrecht, The Netherlands.|Department of Statistics, Shahjalal University of Science and Technology, Sylhet, 3114, Bangladesh.
authors.forename: Md Jamal
authors.initials: MJ
authors.lastname: Uddin
authors.affiliation: Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, University of Utrecht, 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, University of Utrecht, 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, University of Utrecht, Utrecht, The Netherlands.
authors.forename: Ana S M
authors.initials: AS
authors.lastname: Afonso
authors.affiliation: Global Epidemiology, Novartis Pharma AG, Basel, Switzerland.
authors.forename: Paola
authors.initials: P
authors.lastname: Primatesta
authors.affiliation: Basel Pharmacoepidemiology Unit, Division of Clinical Pharmacy and Epidemiology, Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland.
authors.forename: Claudia
authors.initials: C
authors.lastname: Becker
authors.affiliation: Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, University of Utrecht, 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, University of Utrecht, 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: D058666:Adrenergic beta-2 Receptor Agonists / Q000009:adverse effects* / Q000627:therapeutic use; D000328:Adult; D000368:Aged; D001249:Asthma / Q000188:drug therapy; D019992:Databases as Topic; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000209:etiology*; D063868:Patient Outcome Assessment; D010818:Practice Patterns, Physicians' / Q000706:statistics & numerical data*; D011320:Primary Health Care / Q000706:statistics & numerical data*; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy; D012307:Risk Factors
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists
keywords: beta2-agonist; general practice databases; instrumental variables; myocardial infarction; pharmacoepidemiology; physician's prescribing preference; unmeasured confounding