title: Subtraction MR images in a multiple sclerosis multicenter clinical trial setting.
abstract: OBJECTIVE
  To explore the applicability of subtraction magnetic resonance (MR) images to (a) detect active multiple sclerosis (MS) lesions, (b) directly quantify lesion load change, and (c) detect treatment effects (distinguish treatment arms) in a placebo-controlled multicenter clinical trial by comparing the subtraction scheme with a conventional pair-wise comparison of nonregistered MR images.
  
  
  METHODS
  Forty-six pairs of MR studies in 40 patients (31 women; mean age, 31.9 years) from a multicenter clinical trial were used. The clinical trial was approved by local ethics review boards, and all subjects gave written informed consent. Active MS lesions were scored by two independent raters, and lesion load measurements were conducted by using semiautomated software. Lesion counts were evaluated by using the Wilcoxon signed rank test, interrater agreement was evaluated by using the intraclass correlation coefficient (ICC), and treatment (interferon beta-1b) effect was evaluated by using the Mann-Whitney U test.
  
  
  RESULTS
  When subtraction images were used, there was a 1.7-fold increase in the detection of positive active lesions, as compared with native image pairs, and significantly greater interobserver agreement (ICC = 0.98 vs 0.91, P < .001). Subtraction images also allowed direct quantification of positive disease activity, a measure that provided sufficient power to distinguish treatment arms (P = .012) compared with the standard measurement of total lesion load change on native images (P = .455).
  
  
  CONCLUSIONS
  MR image subtraction enabled detection of higher numbers of active MS lesions with greater interobserver agreement and exhibited increased power to distinguish treatment arms, as compared with a conventional pair-wise comparison of nonregistered MR images.
authors.affiliation: Departments of Radiology, MS Center Amsterdam, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Bastiaan
authors.initials: B
authors.lastname: Moraal
authors.forename: Dominik S
authors.initials: DS
authors.lastname: Meier
authors.forename: Peter A
authors.initials: PA
authors.lastname: Poppe
authors.forename: Jeroen J G
authors.initials: JJ
authors.lastname: Geurts
authors.forename: Hugo
authors.initials: H
authors.lastname: Vrenken
authors.forename: William M A
authors.initials: WM
authors.lastname: Jonker
authors.forename: Dirk L
authors.initials: DL
authors.lastname: Knol
authors.forename: Ronald A
authors.initials: RA
authors.lastname: van Schijndel
authors.forename: Petra J W
authors.initials: PJ
authors.lastname: Pouwels
authors.forename: Christoph
authors.initials: C
authors.lastname: Pohl
authors.forename: Lars
authors.initials: L
authors.lastname: Bauer
authors.forename: Rupert
authors.initials: R
authors.lastname: Sandbrink
authors.forename: Charles R G
authors.initials: CR
authors.lastname: Guttmann
authors.forename: Frederik
authors.initials: F
authors.lastname: Barkhof
mesh_terms: D000328:Adult; D016477:Artifacts; D001921:Brain / Q000473:pathology*; D005260:Female; D006801:Humans; D007155:Immunologic Factors / Q000627:therapeutic use*; D016899:Interferon-beta / Q000627:therapeutic use*; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000473:pathology*; D010919:Placebos; D018709:Statistics, Nonparametric; D013382:Subtraction Technique; D016896:Treatment Outcome
chemical_list: D007155:Immunologic Factors; D010919:Placebos; D016899:Interferon-beta