title: Sample size considerations for trials using cerebral white matter hyperintensity progression as an intermediate outcome at 1 year after mild stroke: results of a prospective cohort study.
abstract: White matter hyperintensities (WMHs) are commonly seen on in brain imaging and are associated with stroke and cognitive decline. Therefore, they may provide a relevant intermediate outcome in clinical trials. WMH can be measured as a volume or visually on the Fazekas scale. We investigated predictors of WMH progression and design of efficient studies using WMH volume and Fazekas score as an intermediate outcome.
  
  
  
  We prospectively recruited 264 patients with mild ischaemic stroke and measured WMH volume, Fazekas score, age and cardiovascular risk factors at baseline and 1 year. We modelled predictors of WMH burden at 1 year and used the results in sample size calculations for hypothetical randomised controlled trials with different analysis plans and lengths of follow-up.
  
  
  
  Follow-up WMH volume was predicted by baseline WMH: a 0.73-ml (95% CI 0.65-0.80, p < 0.0001) increase per 1-ml baseline volume increment, and a 2.93-ml increase (95% CI 1.76-4.10, p < 0.0001) per point on the Fazekas scale. Using a mean difference of 1 ml in WMH volume between treatment groups, 80% power and 5% alpha, adjusting for all predictors and 2-year follow-up produced the smallest sample size (n = 642). Other study designs produced samples sizes from 2054 to 21,270. Sample size calculations using Fazekas score as an outcome with the same power and alpha, as well as an OR corresponding to a 1-ml difference, were sensitive to assumptions and ranged from 2504 to 18,886.
  
  
  
  Baseline WMH volume and Fazekas score predicted follow-up WMH volume. Study size was smallest using volumes and longer-term follow-up, but this must be balanced against resources required to measure volumes versus Fazekas scores, bias due to dropout and scanner drift. Samples sizes based on Fazekas scores may be best estimated with simulation studies.
authors.affiliation: Neuroimaging Sciences, Centre for Clinical Brain Sciences (CCBS) FU303e, The University of Edinburgh, Chancellor's Building, 49 Little France Crescent, Edinburgh, EH16 4SB, UK.
authors.forename: Francesca M
authors.initials: FM
authors.lastname: Chappell
authors.affiliation: Neuroimaging Sciences, Centre for Clinical Brain Sciences (CCBS) FU303e, The University of Edinburgh, Chancellor's Building, 49 Little France Crescent, Edinburgh, EH16 4SB, UK.
authors.forename: Maria
authors.initials: M
authors.lastname: Del Carmen Valdés Hernández
authors.affiliation: Neuroimaging Sciences, Centre for Clinical Brain Sciences (CCBS) FU303e, The University of Edinburgh, Chancellor's Building, 49 Little France Crescent, Edinburgh, EH16 4SB, UK.
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Makin
authors.affiliation: Neuroimaging Sciences, Centre for Clinical Brain Sciences (CCBS) FU303e, The University of Edinburgh, Chancellor's Building, 49 Little France Crescent, Edinburgh, EH16 4SB, UK.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Shuler
authors.affiliation: Neuroimaging Sciences, Centre for Clinical Brain Sciences (CCBS) FU303e, The University of Edinburgh, Chancellor's Building, 49 Little France Crescent, Edinburgh, EH16 4SB, UK.
authors.forename: Eleni
authors.initials: E
authors.lastname: Sakka
authors.affiliation: Neuroimaging Sciences, Centre for Clinical Brain Sciences (CCBS) FU303e, The University of Edinburgh, Chancellor's Building, 49 Little France Crescent, Edinburgh, EH16 4SB, UK.
authors.forename: Martin S
authors.initials: MS
authors.lastname: Dennis
authors.affiliation: Academic Unit of Radiology, University of Sheffield, C Floor, Royal Hallamshire Hospital, Sheffield, S10 2JF, UK.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Armitage
authors.affiliation: Neuroimaging Sciences, Centre for Clinical Brain Sciences (CCBS) FU303e, The University of Edinburgh, Chancellor's Building, 49 Little France Crescent, Edinburgh, EH16 4SB, UK.
authors.forename: Susana
authors.initials: S
authors.lastname: Muñoz Maniega
authors.affiliation: Neuroimaging Sciences, Centre for Clinical Brain Sciences (CCBS) FU303e, The University of Edinburgh, Chancellor's Building, 49 Little France Crescent, Edinburgh, EH16 4SB, UK. joanna.wardlaw@ed.ac.uk.
authors.forename: Joanna M
authors.initials: JM
authors.lastname: Wardlaw
mesh_terms: D000367:Age Factors; D000368:Aged; D016009:Chi-Square Distribution; D018450:Disease Progression; D005260:Female; D006801:Humans; D056784:Leukoencephalopathies / Q000000981:diagnostic imaging* / Q000503:physiopathology / Q000523:psychology; D016014:Linear Models; D016015:Logistic Models; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D011237:Predictive Value of Tests; D011379:Prognosis; D011446:Prospective Studies; D016032:Randomized Controlled Trials as Topic / Q000379:methods*; D012307:Risk Factors; D018401:Sample Size; D020521:Stroke / Q000000981:diagnostic imaging* / Q000503:physiopathology / Q000523:psychology; D013997:Time Factors; D066127:White Matter / Q000000981:diagnostic imaging* / Q000503:physiopathology
keywords: Sample size calculation; Study design; White matter hyperintensities