title: Sample size requirements for one-year treatment effects using deep gray matter volume from 3T MRI in progressive forms of multiple sclerosis.
abstract: OBJECTIVE
  The subcortical deep gray matter (DGM) develops selective, progressive, and clinically relevant atrophy in progressive forms of multiple sclerosis (PMS). This patient population is the target of active neurotherapeutic development, requiring the availability of outcome measures. We tested a fully automated MRI analysis pipeline to assess DGM atrophy in PMS.
  
  
  METHODS
  Consistent 3D T1-weighted high-resolution 3T brain MRI was obtained over one year in 19 consecutive patients with PMS [15 secondary progressive, 4 primary progressive, 53% women, age (mean±SD) 50.8±8.0 years, Expanded Disability Status Scale (median, range) 5.0, 2.0-6.5)]. DGM segmentation applied the fully automated FSL-FIRST pipeline ( http://fsl.fmrib.ox.ac.uk ). Total DGM volume was the sum of the caudate, putamen, globus pallidus, and thalamus. On-study change was calculated using a random-effects linear regression model.
  
  
  RESULTS
  We detected one-year decreases in raw [mean (95% confidence interval): -0.749 ml (-1.455, -0.043), p = 0.039] and annualized [-0.754 ml/year (-1.492, -0.016), p = 0.046] total DGM volumes. A treatment trial for an intervention that would show a 50% reduction in DGM brain atrophy would require a sample size of 123 patients for a single-arm study (one-year run-in followed by one-year on-treatment). For a two-arm placebo-controlled one-year study, 242 patients would be required per arm. The use of DGM fraction required more patients. The thalamus, putamen, and globus pallidus, showed smaller effect sizes in their on-study changes than the total DGM; however, for the caudate, the effect sizes were somewhat larger.
  
  
  CONCLUSIONS
  DGM atrophy may prove efficient as a short-term outcome for proof-of-concept neurotherapeutic trials in PMS.
authors.affiliation: a Departments of Neurology Brigham and Women's Hospital, Laboratory for Neuroimaging Research , Partners MS Center, Harvard Medical School , Boston , MA , USA.
authors.forename: Gloria
authors.initials: G
authors.lastname: Kim
authors.affiliation: a Departments of Neurology Brigham and Women's Hospital, Laboratory for Neuroimaging Research , Partners MS Center, Harvard Medical School , Boston , MA , USA.
authors.forename: Renxin
authors.initials: R
authors.lastname: Chu
authors.affiliation: a Departments of Neurology Brigham and Women's Hospital, Laboratory for Neuroimaging Research , Partners MS Center, Harvard Medical School , Boston , MA , USA.
authors.forename: Fawad
authors.initials: F
authors.lastname: Yousuf
authors.affiliation: a Departments of Neurology Brigham and Women's Hospital, Laboratory for Neuroimaging Research , Partners MS Center, Harvard Medical School , Boston , MA , USA.
authors.forename: Shahamat
authors.initials: S
authors.lastname: Tauhid
authors.affiliation: a Departments of Neurology Brigham and Women's Hospital, Laboratory for Neuroimaging Research , Partners MS Center, Harvard Medical School , Boston , MA , USA.
authors.forename: Lynn
authors.initials: L
authors.lastname: Stazzone
authors.affiliation: a Departments of Neurology Brigham and Women's Hospital, Laboratory for Neuroimaging Research , Partners MS Center, Harvard Medical School , Boston , MA , USA.
authors.forename: Maria K
authors.initials: MK
authors.lastname: Houtchens
authors.affiliation: a Departments of Neurology Brigham and Women's Hospital, Laboratory for Neuroimaging Research , Partners MS Center, Harvard Medical School , Boston , MA , USA.
authors.forename: James M
authors.initials: JM
authors.lastname: Stankiewicz
authors.affiliation: a Departments of Neurology Brigham and Women's Hospital, Laboratory for Neuroimaging Research , Partners MS Center, Harvard Medical School , Boston , MA , USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Severson
authors.affiliation: a Departments of Neurology Brigham and Women's Hospital, Laboratory for Neuroimaging Research , Partners MS Center, Harvard Medical School , Boston , MA , USA.
authors.forename: Dorlan
authors.initials: D
authors.lastname: Kimbrough
authors.affiliation: a Departments of Neurology Brigham and Women's Hospital, Laboratory for Neuroimaging Research , Partners MS Center, Harvard Medical School , Boston , MA , USA.
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Quintana
authors.affiliation: a Departments of Neurology Brigham and Women's Hospital, Laboratory for Neuroimaging Research , Partners MS Center, Harvard Medical School , Boston , MA , USA.
authors.forename: Tanuja
authors.initials: T
authors.lastname: Chitnis
authors.affiliation: a Departments of Neurology Brigham and Women's Hospital, Laboratory for Neuroimaging Research , Partners MS Center, Harvard Medical School , Boston , MA , USA.
authors.forename: Howard L
authors.initials: HL
authors.lastname: Weiner
authors.affiliation: a Departments of Neurology Brigham and Women's Hospital, Laboratory for Neuroimaging Research , Partners MS Center, Harvard Medical School , Boston , MA , USA.
authors.forename: Brian C
authors.initials: BC
authors.lastname: Healy
authors.affiliation: a Departments of Neurology Brigham and Women's Hospital, Laboratory for Neuroimaging Research , Partners MS Center, Harvard Medical School , Boston , MA , USA.|b Radiology Brigham and Women's Hospital, Laboratory for Neuroimaging Research , Partners MS Center, Harvard Medical School , Boston , MA , USA.
authors.forename: Rohit
authors.identifier: http://orcid.org/0000-0001-8601-5534
authors.initials: R
authors.lastname: Bakshi
mesh_terms: D000328:Adult; D001284:Atrophy / Q000473:pathology; D000068456:Clinical Studies as Topic; D018450:Disease Progression; D005260:Female; D005500:Follow-Up Studies; D066128:Gray Matter / Q000000981:diagnostic imaging / Q000473:pathology*; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008297:Male; D008875:Middle Aged; D020528:Multiple Sclerosis, Chronic Progressive / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000473:pathology*; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000000981:diagnostic imaging / Q000178:diet therapy / Q000473:pathology*; D017063:Outcome Assessment, Health Care / Q000379:methods; D018401:Sample Size; D055815:Young Adult
keywords: 3T; MRI; Multiple sclerosis; brain atrophy; deep gray matter; progressive MS