WP2 Framework for pharmacoepidemiological studies WG1 Databases Study Protocol Use of Antidepressants and risk of hip/femur fracture. A methodological comparison across data sources and epidemiological design. Version: Final Nov 14, 2011 with Amendment 5 22 Jan , 2014 PROTECT WP2_ Final protocol_ Antidep_Hip 14Nov2011_Amend5_22Jan2014 Page 1 of 80 WG1 Drug AE group Name Role Gardarsdottir, Helga 1,2 Protocol lead Marieke De Bruin 1 Protocol backup Liset van Dijk 1,3 Protocol reviewer Montserrat Miret 4 Protocol reviewer Frank de Vries 1 Protocol reviewer Marietta Rottenkolber 5 Database 1 (Bavaria) lead Joerg Hasford 5 Database 1 (Bavaria) backup Consuelo Huerta 6 Database 2 (Bifap) lead Miguel Gil 6 Database 2 (Bifap) backup Ulrik Hesse7 Database 3 (DKMA) lead Frank de Vries1 Database 3 (DKMA) backup Edmond Ng /Jenny Campbell78 Database 4 (CPRD) lead/backup Olaf Klungel 1 Database 5 (Mondriaan) lead Liset van Dijk 1, 2 Database 5 (Mondriaan) backup Yolanda Alvarez 9 Database 6 (THIN) lead Ana Ruigomez 10 Database 6 (THIN) backup 1 Universiteit Utrecht, Utrecht, The Netherlands (UU) 2 University Medical Center Utrecht, Utrecht, The Netherlands (UU) 3 Netherlands Institute for Healthcare Research, Utrecht, The Netherlands (NIVEL) 4 Merck KGaA, Geneva, Switzerland (ME) 5 Ludwig-Maximilians-Universität-München, Munich, Germany (LMU- Muenchen) 6 Agencia Espanola de Medicamentos y Productos Sanitarios, Madrid, Spain (AEMPS) 7 Lægemiddelstyrelsen (Danish Medicines Agency), Copenhagen, Denmark (DKMA) 8 Clinical Practice Research Datalink, London, United Kingdom (CPRD) 9 European Medicines Agency, London, United Kingdom (EMA) 10 Fundación Centro Español de Investigación Farmacoepidemiológica, Madrid, Spain (CEIFE) PROTECT WP2_ Final protocol_ Antidep_Hip 14Nov2011_Amend5_22Jan2014 Page 2 of 80 Content 1 Context of the studies and objective ............................................................................................................ 66 2 Background.................................................................................................................................................. 66 3 Objectives .................................................................................................................................................... 66 4 Methods ....................................................................................................................................................... 66 4.1 Data sources ....................................................................................................................................... 66 4.2 The Health Improvement Network (THIN) ....................................................................................... 66 4.3 Mondriaan .......................................................................................................................................... 77 4.4 BIFAP ................................................................................................................................................ 77 4.5 Bavaria database ................................................................................................................................ 77 4.6 National Databases (Denmark) .......................................................................................................... 77 4.7 Clinical Practice Research Datalink (UK).......................................................................................... 88 4.8 Period of valid data collection ............................................................................................................ 88 4.8.1 THIN/Mondriaan/BIFAP ................................................................................................................... 88 4.8.2 Bavarian claims .................................................................................................................................. 99 5 Study Designs .............................................................................................................................................. 99 5.1 Descriptive studies ............................................................................................................................. 99 5.1.1 Study population and period .............................................................................................................. 99 5.1.2 Exposure description .......................................................................................................................... 99 5.1.3 Outcome description ...................................................................................................................... 1111 5.2 Analytical studies ........................................................................................................................... 1212 5.2.1 Study population and study period ................................................................................................. 1212 5.2.2 Outcome definition ........................................................................................................................ 1414 5.2.3 Exposure definition ........................................................................................................................ 1414 5.2.4 Potential confounders ..................................................................................................................... 1515 5.2.5 Analysis ......................................................................................................................................... 1616 5.3 Cohort ............................................................................................................................................ 1616 5.3.1 Follow-up ....................................................................................................................................... 1616 5.3.2 Analysis ......................................................................................................................................... 1717 5.4 Nested case-control ........................................................................................................................ 1717 5.4.1 Case definition ............................................................................................................................... 1717 5.4.2 Selection of controls....................................................................................................................... 1818 5.4.3 Confounders ................................................................................................................................... 1919 5.4.4 Analysis ......................................................................................................................................... 1919 5.5 Case-crossover ............................................................................................................................... 1919 5.5.1 Study population ............................................................................................................................ 1919 5.5.2 Case and control dates .................................................................................................................... 2020 5.5.1 Exposure definition ........................................................................................................................ 2020 5.5.2 Confounders ................................................................................................................................... 2020 5.5.3 Analysis ......................................................................................................................................... 2121 5.6 Self-controlled-case-series (SCCS) ................................................................................................ 2121 5.6.1 Study population ............................................................................................................................ 2121 5.6.2 Exposure definition ........................................................................................................................ 2222 5.6.1 Outcome definition ........................................................................................................................ 2323 5.6.2 Confounders ................................................................................................................................... 2323 5.6.3 Analysis ......................................................................................................................................... 2323 5.6.3.1 Sensitivity Analysis ......................................................................................................... 2424 6 Limitations ............................................................................................................................................... 2525 7 References ............................................................................................................................................... 2525 8 Annexes ................................................................................................................................................... 2727 8.1 Annex I codes for exposure and outcome ...................................................................................... 2727 8.1.1 List of Antidepressants, ATC codes and DDD ............................................................................. 2727 8.1.2