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Impact of Methodological Choices in Comparative Effectiveness Studies: Application in Natalizumab Versus Fingolimod Comparison Among Patients With Multiple Sclerosis Publisher Pubmed



Lefort M1, 2 ; Sharmin S3, 4 ; Andersen JB5 ; Vukusic S6, 7, 8 ; Casey R6, 7, 8, 9 ; Debouverie M10 ; Edan G11 ; Ciron J12 ; Ruet A13 ; De Seze J14 ; Maillart E15 ; Zephir H16 ; Labauge P17 ; Defer G18 Show All Authors
Authors
  1. Lefort M1, 2
  2. Sharmin S3, 4
  3. Andersen JB5
  4. Vukusic S6, 7, 8
  5. Casey R6, 7, 8, 9
  6. Debouverie M10
  7. Edan G11
  8. Ciron J12
  9. Ruet A13
  10. De Seze J14
  11. Maillart E15
  12. Zephir H16
  13. Labauge P17
  14. Defer G18
  15. Lebrunfrenay C19
  16. Moreau T20
  17. Berger E21
  18. Clavelou P22
  19. Pelletier J23
  20. Stankoff B24
  21. Gout O25
  22. Thouvenot E26
  23. Heinzlef O27
  24. Alkhedr A28
  25. Bourre B29
  26. Casez O30
  27. Cabre P31
  28. Montcuquet A32
  29. Wahab A33
  30. Camdessanche JP34
  31. Maurousset A35
  32. Ben Nasr H36
  33. Hankiewicz K37
  34. Pottier C38
  35. Maubeuge N39
  36. Dimitriboulos D40
  37. Nifle C41
  38. Laplaud DA42, 43
  39. Horakova D44
  40. Havrdova EK44
  41. Alroughani R45
  42. Izquierdo G46
  43. Eichau S46
  44. Ozakbas S47
  45. Patti F48, 49
  46. Onofrj M50
  47. Lugaresi A51, 52
  48. Terzi M53
  49. Grammond P54
  50. Grandmaison F55
  51. Yamout B56
  52. Prat A57, 58
  53. Girard M57, 58
  54. Duquette P57, 58
  55. Boz C59
  56. Trojano M60
  57. Mccombe P61, 62
  58. Slee M63
  59. Lechnerscott J64, 65
  60. Turkoglu R66
  61. Sola P67
  62. Ferraro D67
  63. Granella F68, 69
  64. Shaygannejad V70
  65. Prevost J71
  66. Maimone D72
  67. Skibina O73
  68. Buzzard K73
  69. Van Der Walt A73
  70. Karabudak R74
  71. Van Wijmeersch B75
  72. Csepany T76
  73. Spitaleri D77
  74. Vucic S78
  75. Kochhenriksen N79
  76. Sellebjerg F80
  77. Soerensen PS80
  78. Hilt Christensen CC81
  79. Rasmussen PV82
  80. Jensen MB83
  81. Frederiksen JL84
  82. Bramow S80
  83. Mathiesen HK85
  84. Schreiber KI80
  85. Butzkueven H86, 87, 88
  86. Magyari M4, 80
  87. Kalincik T3
  88. Leray E1, 2
Show Affiliations
Authors Affiliations
  1. 1. Arenes - UMR 6051, RSMS (Recherche sur les Services et Management en Sante) - U 1309, Univ Rennes, EHESP, CNRS, Inserm, Rennes, France
  2. 2. Univ Rennes, CHU Rennes, Investigation Clinique de Rennes)], CIC 1414 [(Centre d, InsermRennes, 35000, France
  3. 3. Department of Medicine, University of Melbourne, Melbourne, Australia
  4. 4. Melbourne MS Centre, Department of Neurology, Royal Melbourne Hospital, Melbourne, Australia
  5. 5. Department of Neurology, The Danish Multiple Sclerosis Registry, Copenhagen University Hospital, Rigshospitalet Glostrup, Denmark
  6. 6. Service de Neurologie, Sclerose en Plaques, Pathologies de La Myeline Et Neuro-Inflammation, Hopital Neurologique Pierre Wertheimer, Hospices Civils de Lyon, Lyon/Bron, 69677, France
  7. 7. Centre Des Neurosciences de Lyon, UMR5292, Observatoire Francais de La Sclerose en Plaques, INSERM, 1028 et CNRS, Lyon, 69003, France
  8. 8. Universite, Claude Bernard Lyon 1, Faculte de medecine Lyon Est, Lyon, 69000, France
  9. 9. Eugene Devic EDMUS Foundation, Lyon/Bron, 69677, France
  10. 10. Centre Hospitalier Regional Universitaire de Nancy, Hopital Central, Service de neurologie, Nancy, France
  11. 11. Centre Hospitalier Universitaire de Rennes, Hopital Pontchaillou, Service de neurologie, Rennes, France
  12. 12. Centre Hospitalier Universitaire de Toulouse, Hopital Purpan, CRC-SEP, Departement de neurologie, Toulouse, France
  13. 13. Centre Hospitalier Universitaire de Bordeaux, Hopital Pellegrin, Service de neurologie, Bordeaux, France
  14. 14. Service des maladies inflammatoires du systeme nerveux – neurologie, centre d’investigation clinique de Strasbourg, Hopitaux Universitaire de Strasbourg, Hopital de Hautepierre, INSERM 1434, Strasbourg, France
  15. 15. Assistance Publique Des Hopitaux de Paris, Hopital de La Pitie-Salpetriere, Service de neurologie, Paris, France
  16. 16. Centre Hospitalier Universitaire de Lille, Hopital Salengro, Service de neurologie D, Lille, France
  17. 17. Centre Hospitalier Universitaire de Montpellier, Hopital Gui de Chauliac, Service de neurologie, Montpellier, France
  18. 18. Centre Hospitalier Universitaire de Caen Normandie, Hopital Cote de Nacre, Service de neurologie, Caen, France
  19. 19. Centre Hospitalier Universitaire de Nice, UR2CA-URRIS, Universite Nice Cote d’Azur, Hopital, Pasteur 2, Service de neurologie, Nice, France
  20. 20. Centre Hospitalier Universitaire Dijon Bourgogne, Hopital Francois Mitterrand, Maladies Inflammatoires du Systeme Nerveux Et Neurologie Generale, Service de neurologie, Dijon, France
  21. 21. Centre Hospitalier Regional Universitaire de Besancon, Hopital Jean Minjoz, Service de neurologie, Besancon, France
  22. 22. Centre Hospitalier Universitaire de Clermont-Ferrand, Hopital Gabriel-Montpied, Service de neurologie, Clermont-Ferrand, France
  23. 23. Service de Neurologie, Aix Marseille Univ, APHM, Hopital de La Timone, Pole de Neurosciences Cliniques, Marseille, 13005, France
  24. 24. Assistance Publique Des Hopitaux de Paris, Hopital Saint-Antoine, Service de neurologie, Paris, France
  25. 25. Fondation Adolphe de Rothschild de L’oeil Et du Cerveau, Service de neurologie, Paris, France
  26. 26. Centre Hospitalier Universitaire de Nimes, Hopital Caremeau, Service de neurologie, Nimes, France
  27. 27. Centre Hospitalier Intercommunal de Poissy Saint-Germain-en-Laye, Service de neurologie, Poissy, France
  28. 28. Centre Hospitalier Universitaire d’Amiens Picardie, Site sud, Service de neurologie, Amiens, France
  29. 29. Rouen University Hospital, Rouen, 76000, France
  30. 30. Centre Hospitalier Universitaire Grenoble-Alpes, Site nord, Service de neurologie, Grenoble/La Tronche, France
  31. 31. Centre Hospitalier Universitaire de Martinique, Hopital Pierre Zobda-Quitman, Service de neurologie, Fort-de-France, France
  32. 32. Centre Hospitalier Universitaire Limoges, Hopital Dupuytren, Service de neurologie, Limoges, France
  33. 33. Assistance Publique Des Hopitaux de Paris, Hopital Henri Mondor, Service de neurologie, Creteil, France
  34. 34. Centre Hospitalier Universitaire de Saint-Etienne, Hopital Nord, Service de neurologie, Saint-Etienne, France
  35. 35. Centre Hospitalier Regional Universitaire de Tours, Hopital Bretonneau, Service de neurologie, Tours, France
  36. 36. Centre Hospitalier Sud Francilien, Service de neurologie, Corbeil-Essonnes, France
  37. 37. Centre Hospitalier de Saint-Denis, Hopital Casanova, Service de neurologie, Saint-Denis, France
  38. 38. Centre Hospitalier de Pontoise, Service de neurologie, Pontoise, France
  39. 39. Centre Hospitalier Universitaire de Poitiers, Site de La Miletrie, Service de neurologie, Poitiers, France
  40. 40. Assistance Publique Des Hopitaux de Paris, Hopital Bicetre, Service de neurologie, Le Kremlin-Bicetre, France
  41. 41. Centre Hospitalier de Versailles, Hopital Andre-Mignot, Service de neurologie, Le Chesnay, France
  42. 42. CHU de Nantes, Service de Neurologie & CIC015 INSERM, Nantes, 44093, France
  43. 43. INSERM CR1064, Nantes, 44000, France
  44. 44. Department of Neurology and Center of Clinical Neuroscience, First Faculty of Medicine, Charles University in Prague and General University Hospital, Prague, Czech Republic
  45. 45. Division of Neurology, Department of Medicine, Amiri Hospital, Sharq, Kuwait
  46. 46. Hospital Universitario Virgen Macarena, Seville, Spain
  47. 47. Dokuz Eylul University, Konak/Izmir, Turkiye
  48. 48. GF Ingrassia Department, University of Catania, Catania, Italy
  49. 49. Policlinico G Rodolico, Catania, Italy
  50. 50. Department of Neuroscience, Imaging, and Clinical Sciences, University G. d’Annunzio, Chieti, Italy
  51. 51. Dipartimento Di Scienze Biomediche E Neuromotorie, Universita Di Bologna, Bologna, Italy
  52. 52. IRCCS Istituto Delle Scienze Neurologiche Di Bologna, Bologna, Italy
  53. 53. Medical Faculty, 19 Mayis University, Samsun, Turkiye
  54. 54. CISSS Chaudiere-Appalache, Levis, Canada
  55. 55. Neuro Rive-Sud, Longueuil, QC, Canada
  56. 56. Nehme and Therese Tohme Multiple Sclerosis Center, American University of Beirut Medical Center, Beirut, Lebanon
  57. 57. Hopital Notre Dame, Montreal, Canada
  58. 58. CHUM and Universite de Montreal, Montreal, Canada
  59. 59. KTU Medical Faculty Farabi Hospital, Trabzon, Turkiye
  60. 60. Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari, Bari, Italy
  61. 61. University of Queensland, Brisbane, Australia
  62. 62. Royal Brisbane and Women’s Hospital, Herston, Australia
  63. 63. Flinders University, Adelaide, Australia
  64. 64. School of Medicine and Public Health, University Newcastle, Newcastle, Australia
  65. 65. Department of Neurology, John Hunter Hospital, Hunter New England Health, Newcastle, Australia
  66. 66. Haydarpasa Numune Training and Research Hospital, Istanbul, Turkiye
  67. 67. Department of Neuroscience, Azienda Ospedaliera Universitaria, Modena, Italy
  68. 68. Department of Medicine and Surgery, University of Parma, Parma, Italy
  69. 69. Department of Emergency and General Medicine, Parma University Hospital, Parma, Italy
  70. 70. Isfahan University of Medical Sciences, Isfahan, Iran
  71. 71. CSSS Saint-Jerome, Saint-Jerome, Canada
  72. 72. Garibaldi Hospital, Catania, Italy
  73. 73. Monash University, Melbourne, Australia
  74. 74. Hacettepe University, Ankara, Turkiye
  75. 75. Rehabilitation and MS-Centre Overpelt and Hasselt University, Hasselt, Belgium
  76. 76. Department of Neurology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
  77. 77. Azienda Ospedaliera Di Rilievo Nazionale San Giuseppe Moscati Avellino, Avellino, Italy
  78. 78. Westmead Hospital, Sydney, Australia
  79. 79. Department of Clinical Epidemiology, Aarhus University Hospital Aarhus, Aarhus, Denmark
  80. 80. Danish Multiple Sclerosis Centre, Department of Neurology, Copenhagen University Hospital, Rigshospitalet Glostrup, Glostrup, 2600, Denmark
  81. 81. Department of Neurology, Aalborg University Hospital, Multiple Sclerosis Unit, Aalborg, Denmark
  82. 82. Aarhus University Hospital, Neurology, PJJ Boulevard, Aarhus N, DK-8200, Denmark
  83. 83. Department of Neurology, University Hospital of Northern Sealand, Copenhagen, Denmark
  84. 84. Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
  85. 85. Department of Neurology, Copenhagen University Hospital Herlev, Copenhagen, Denmark
  86. 86. Central Clinical School, Monash University, Melbourne, Australia
  87. 87. Department of Neurology, The Alfred Hospital, Melbourne, Australia
  88. 88. Department of Neurology, Box Hill Hospital, Monash University, Melbourne, Australia

Source: BMC Medical Research Methodology Published:2022


Abstract

Background: Natalizumab and fingolimod are used as high-efficacy treatments in relapsing–remitting multiple sclerosis. Several observational studies comparing these two drugs have shown variable results, using different methods to control treatment indication bias and manage censoring. The objective of this empirical study was to elucidate the impact of methods of causal inference on the results of comparative effectiveness studies. Methods: Data from three observational multiple sclerosis registries (MSBase, the Danish MS Registry and French OFSEP registry) were combined. Four clinical outcomes were studied. Propensity scores were used to match or weigh the compared groups, allowing for estimating average treatment effect for treated or average treatment effect for the entire population. Analyses were conducted both in intention-to-treat and per-protocol frameworks. The impact of the positivity assumption was also assessed. Results: Overall, 5,148 relapsing–remitting multiple sclerosis patients were included. In this well-powered sample, the 95% confidence intervals of the estimates overlapped widely. Propensity scores weighting and propensity scores matching procedures led to consistent results. Some differences were observed between average treatment effect for the entire population and average treatment effect for treated estimates. Intention-to-treat analyses were more conservative than per-protocol analyses. The most pronounced irregularities in outcomes and propensity scores were introduced by violation of the positivity assumption. Conclusions: This applied study elucidates the influence of methodological decisions on the results of comparative effectiveness studies of treatments for multiple sclerosis. According to our results, there are no material differences between conclusions obtained with propensity scores matching or propensity scores weighting given that a study is sufficiently powered, models are correctly specified and positivity assumption is fulfilled. © 2022, The Author(s).
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