title: Defining reliable disability outcomes in multiple sclerosis.
abstract: Prevention of irreversible disability is currently the most important goal of disease modifying therapy for multiple sclerosis. The disability outcomes used in most clinical trials rely on progression of Expanded Disability Status Scale score confirmed over 3 or 6 months. However, sensitivity and stability of this metric has not been extensively evaluated. Using the global MSBase cohort study, we evaluated 48 criteria of disability progression, testing three definitions of baseline disability, two definitions of progression magnitude, two definitions of long-term irreversibility and four definitions of event confirmation period. The study outcomes comprised the rates of detected progression events per 10 years and the proportions of the recorded events persistent at later time points. To evaluate the ratio of progression frequency and stability for each criterion, we calculated the proportion of events persistent over the five subsequent years once progression was achieved. Finally, we evaluated the clinical and demographic determinants characterising progression events and, for those that regressed back to baseline, determinants of their subsequent regression. The study population consisted of 16 636 patients with the minimum of three recorded disability scores, totalling 112 584 patient-years. The progression rates varied between 0.41 and 1.14 events per 10 years, with the length of required confirmation interval as the most important determinant of the observed variance. The concordance among all tested progression criteria was only 17.3%. Regression of disability occurred in 11-34% of the progression events over the five subsequent years. The most important determinant of progression stability was the length of the confirmation period. For the most accurate set of the progression criteria, the proportions of 3-, 6-, 12- or 24-month confirmed events persistent over 5 years reached 70%, 74%, 80% and 89%, respectively. Regression post progression was more common in younger patients, relapsing-remitting disease course, and after a smaller change in disability, and was inflated by higher visit frequency. These results suggest that the disability outcomes based on 3-6-month confirmed disability progression overestimate the accumulation of permanent disability by up to 30%. This could lead to spurious results in short-term clinical trials, and the issue may be magnified further in cohorts consisting predominantly of younger patients and patients with relapsing-remitting disease. Extension of the required confirmation period increases the persistence of progression events.
authors.affiliation: 1 Department of Medicine, University of Melbourne, Melbourne, Australia 2 Department of Neurology, Royal Melbourne Hospital, Melbourne, Australia tomas.kalincik@unimelb.edu.au.
authors.forename: Tomas
authors.initials: T
authors.lastname: Kalincik
authors.affiliation: 3 Department of Biostatistics, University of Alabama, Tuscaloosa, AL, USA.
authors.forename: Gary
authors.initials: G
authors.lastname: Cutter
authors.affiliation: 1 Department of Medicine, University of Melbourne, Melbourne, Australia.
authors.forename: Tim
authors.initials: T
authors.lastname: Spelman
authors.affiliation: 1 Department of Medicine, University of Melbourne, Melbourne, Australia.
authors.forename: Vilija
authors.initials: V
authors.lastname: Jokubaitis
authors.affiliation: 4 Department of Neurology and Center of Clinical Neuroscience, General University Hospital and Charles University in Prague, Czech Republic.
authors.forename: Eva
authors.initials: E
authors.lastname: Havrdova
authors.affiliation: 4 Department of Neurology and Center of Clinical Neuroscience, General University Hospital and Charles University in Prague, Czech Republic.
authors.forename: Dana
authors.initials: D
authors.lastname: Horakova
authors.affiliation: 5 Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari, Bari, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Trojano
authors.affiliation: 6 Department of Neurology, Hospital Universitario Virgen Macarena, Sevilla, Spain.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Izquierdo
authors.affiliation: 7 Department of Neurology, Hôpital Notre Dame, Montreal, Canada.
authors.forename: Marc
authors.initials: M
authors.lastname: Girard
authors.affiliation: 7 Department of Neurology, Hôpital Notre Dame, Montreal, Canada.
authors.forename: Pierre
authors.initials: P
authors.lastname: Duquette
authors.affiliation: 7 Department of Neurology, Hôpital Notre Dame, Montreal, Canada.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Prat
authors.affiliation: 8 MS Center, Department of Neuroscience, Imaging and Clinical Sciences, University 'G. d'Annunzio', Chieti, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Lugaresi
authors.affiliation: 9 Neuro Rive-Sud, Hôpital Charles LeMoyne, Quebec, Canada.
authors.forename: Francois
authors.initials: F
authors.lastname: Grand'Maison
authors.affiliation: 10 Department of Neurology, Hotel-Dieu de Levis, Quebec, Canada.
authors.forename: Pierre
authors.initials: P
authors.lastname: Grammond
authors.affiliation: 11 Zuyderland Ziekenhus, Sittard-Geleen, The Netherlands.
authors.forename: Raymond
authors.initials: R
authors.lastname: Hupperts
authors.affiliation: 12 Multiple Sclerosis Unit, University Hospital San Carlos, Madrid, Spain.
authors.forename: Celia
authors.initials: C
authors.lastname: Oreja-Guevara
authors.affiliation: 13 Karadeniz Technical University, Trabzon, Turkey.
authors.forename: Cavit
authors.initials: C
authors.lastname: Boz
authors.affiliation: 14 Neurology Unit, Azienda Sanitaria Unica Regionale Marche - AV3, Macerata, Italy.
authors.forename: Eugenio
authors.initials: E
authors.lastname: Pucci
authors.affiliation: 15 C. Mondino National Neurological Institute, Pavia, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Bergamaschi
authors.affiliation: 16 Hunter Medical Research Institute, University Newcastle, Newcastle, Australia.
authors.forename: Jeannette
authors.initials: J
authors.lastname: Lechner-Scott
authors.affiliation: 17 Amiri Hospital, Kuwait City, Kuwait.
authors.forename: Raed
authors.initials: R
authors.lastname: Alroughani
authors.affiliation: 18 Cliniques Universitaires Saint-Luc, Brussels, Belgium.
authors.forename: Vincent
authors.initials: V
authors.lastname: Van Pesch
authors.affiliation: 19 Ospedali Riuniti di Salerno, Salerno, Italy.
authors.forename: Gerardo
authors.initials: G
authors.lastname: Iuliano
authors.affiliation: 20 Hospital Universitario Virgen de Valme, Seville, Spain.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Fernandez-Bolaños
authors.affiliation: 21 Hospital Germans Trias i Pujol, Badalona, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Ramo
authors.affiliation: 22 Medical Faculty, Department of Neurology, Ondokuz Mayis University, Samsun, Turkey.
authors.forename: Murat
authors.initials: M
authors.lastname: Terzi
authors.affiliation: 23 Flinders University and Medical Centre, Adelaide, Australia.
authors.forename: Mark
authors.initials: M
authors.lastname: Slee
authors.affiliation: 24 Azienda Ospedaliera di Rilievo Nazionale, San Giuseppe Moscati, Avellino, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Spitaleri
authors.affiliation: 25 Groene Hart Ziekenhuis, Gouda, The Netherlands.
authors.forename: Freek
authors.initials: F
authors.lastname: Verheul
authors.affiliation: 26 Hospital Italiano, Buenos Aires, Argentina.
authors.forename: Edgardo
authors.initials: E
authors.lastname: Cristiano
authors.affiliation: 27 Department of Neurology, Hospital de Galdakao-Usansolo, Galdakao, Spain.
authors.forename: José Luis
authors.initials: JL
authors.lastname: Sánchez-Menoyo
authors.affiliation: 28 Fundacion para la Lucha contra las Enfermedades Neurologicas de la Infancia, Buenos Aires, Argentina.
authors.forename: Marcela
authors.initials: M
authors.lastname: Fiol
authors.affiliation: 29 Craigavon Area Hospital, Portadown, UK.
authors.forename: Orla
authors.initials: O
authors.lastname: Gray
authors.affiliation: 30 Centro Internacional de Restauracion Neurologica, Havana, Cuba.
authors.forename: Jose Antonio
authors.initials: JA
authors.lastname: Cabrera-Gomez
authors.affiliation: 31 Brain and Mind Centre, Sydney, Australia.
authors.forename: Michael
authors.initials: M
authors.lastname: Barnett
authors.affiliation: 1 Department of Medicine, University of Melbourne, Melbourne, Australia 2 Department of Neurology, Royal Melbourne Hospital, Melbourne, Australia 32 Department of Neurology, Box Hill Hospital, Monash University, Melbourne, Australia.
authors.forename: Helmut
authors.initials: H
authors.lastname: Butzkueven
mesh_terms: D000328:Adult; D000367:Age Factors; D015331:Cohort Studies; D004185:Disability Evaluation; D018450:Disease Progression; D005260:Female; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D020528:Multiple Sclerosis, Chronic Progressive / Q000503:physiopathology*; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000503:physiopathology*; D017063:Outcome Assessment, Health Care; D012042:Registries
keywords: clinical trial; disability; outcome measures; prognosis; relapse