title: Case-only designs for studying the association of antidepressants and hip or femur fracture.
abstract: OBJECTIVE
  The purpose of this study is to evaluate the performance and validity of the case-crossover (CCO) and self-controlled case-series (SCCS) designs when studying the association between hip/femur fracture (HF) and antidepressant (AD) use in general practitioner databases. In addition, comparability with cohort and case-control designs is discussed.
  
  
  METHODS
  Adult patients with HF and who received an AD prescription during 2001-2009 were identified from UK's The Health Improvement Network (THIN) and the Dutch Mondriaan databases. AD exposure was classified into current, recent and past/non-use (reference). In the CCO, for each patient, a case moment (date of HF) and four prior control moments at -91, -182, -273 and -365 days were defined. In SCCS, incidence of HF was compared between exposure states. Conditional logistic regression was used in the CCO and Poisson regression in the SCCS to compute odds ratios and incidence rate ratios, respectively. In CCO, we adjusted for time-varying co-medication and in SCCS for age.
  
  
  RESULTS
  Adjusted estimates for the effect of current AD exposure on HF were higher in the CCO (co-medication-adjusted odds ratio, THIN: 2.24, 95% confidence interval [CI]: 2.04-2.47; Mondriaan: 2.57, 95%CI [1.50, 4.43]) than in the SCCS (age-adjusted incidence rate ratio, THIN: 1.41, 95%CI [1.32, 1.49]; Mondriaan: 2.14, 95%CI [1.51, 3.03]). The latter were comparable with the traditional designs.
  
  
  CONCLUSIONS
  Case-only designs confirmed the association between AD and HF. The CCO design violated assumptions in this study with regard to exchangeability and length of exposure, and transient effects on outcome. The SCCS seems to be an appropriate design for assessing AD-HF association.
authors.affiliation: Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.|Department of Clinical Chemistry and Haematology, Division of Laboratory and Pharmacy, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Mark C H
authors.identifier: http://orcid.org/0000-0002-5764-5788
authors.initials: MC
authors.lastname: de Groot
authors.affiliation: European Medicines Agency, 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.|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.
authors.forename: Patrick C
authors.initials: PC
authors.lastname: Souverein
authors.affiliation: Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.
authors.forename: M Sanni
authors.initials: MS
authors.lastname: Ali
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: BIFAP Research Unit, Division of Pharmacoepidemiology and Pharmacovigilance, Agencia Española de Medicamentos y Productos Sanitarios (AEMPS), Madrid, Spain.
authors.forename: Consuelo
authors.initials: C
authors.lastname: Huerta
authors.affiliation: 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: European Medicines Agency, London, UK.
authors.forename: Yolanda
authors.initials: Y
authors.lastname: Alvarez
authors.affiliation: European Medicines Agency, London, UK.
authors.forename: Jim
authors.initials: J
authors.lastname: Slattery
authors.affiliation: NIVEL, Netherlands Institute for Health Services Research, Utrecht, The Netherlands.
authors.forename: Joke
authors.initials: J
authors.lastname: Korevaar
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.
authors.forename: Anthonius
authors.initials: A
authors.lastname: de Boer
authors.affiliation: London School of Hygiene and Tropical Medicine (LSHTM), London, UK.
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Douglas
authors.affiliation: Global Clinical Epidemiology, Novartis Pharma AG, Basel, Switzerland.
authors.forename: Raymond G
authors.initials: RG
authors.lastname: Schlienger
authors.affiliation: Department of Epidemiology, Pfizer Inc., New York, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Reynolds
authors.affiliation: Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.
authors.forename: Olaf H
authors.initials: OH
authors.lastname: Klungel
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
mesh_terms: D000368:Aged; D000928:Antidepressive Agents / Q000009:adverse effects*; D016022:Case-Control Studies; D018592:Cross-Over Studies; D005260:Female; D005269:Femur / Q000293:injuries*; D006620:Hip Fractures / Q000209:etiology*; D006801:Humans; D008297:Male
chemical_list: D000928:Antidepressive Agents
keywords: antidepressant; case-crossover; case-only design; hip/femur fracture; methodology; pharmacoepidemiology; self-controlled case series