Sample sizes for brain atrophy outcomes in trials for secondary progressive multiple sclerosis

Altmann, Daniel R.; Jasperse, Bas; Barkhof, Frederik; Beckmann, Karola; Filippi, Massimo; Kappos, Ludwig; Molyneux, Pd; Polman, Chris H.; Pozzilli, Carlo; Thompson, Alan J.; Wagner, K.; Yousry, Tarek; Miller, D. H.

doi:10.1212/01.wnl.0000335765.55346.fc

Cited by 90 publications

(93 citation statements)

References 28 publications

(33 reference statements)

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“…Of the volumetric MRI measures assessed in our cohort, the SIENA measurement of WB volume change was the most reliable and most responsive to change. This is similar to a previous investigation in a secondary progressive MS cohort in which SIENA was compared with CCV and segmentedsubtracted SIENA normalized WB volumes [27]. The key methodological difference between SIENA and the other MRI techniques assessed here is that SIENA utilizes image registration to measure change rather than through a process of quantifying and then subtracting cross-sectionally measured volumes.…”

Section: Discussionsupporting

confidence: 74%

A longitudinal study of MRI-detected atrophy in secondary progressive multiple sclerosis

Furby¹,

Hayton²,

Altmann

et al. 2010

J Neurol

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MRI measures of tissue atrophy within the central nervous system may reflect the neurodegenerative process which underpins the progressive phase of multiple sclerosis (MS). There has been limited longitudinal investigation of MRI-detected atrophy in secondary progressive MS. This study includes 56 subjects with secondary progressive MS. Subjects were followed up for 2 years and MRI analysis was conducted at 12 month intervals using the following measures: (1) whole brain (WB) volume change; (2) grey and white matter (WM) volumes; (3) central brain volume; (4) upper cervical spinal cord (SC) area; (5) T2 lesion volumes. Clinical measures included the Expanded Disability Status Scale and the MS Functional Composite. All volumetric MRI measures were assessed for sensitivity, responsiveness, reliability and correlation with disability. The mean annual atrophy rate of WB was 0.59% per year and this was the most responsive atrophy measure assessed. Grey matter (GM) atrophy (-1.18% per year) was greater and more responsive than WM atrophy (0.12% per year). The SC demonstrated the highest atrophy rate at 1.63% per year. WB, GM and SC atrophy all correlated with change in the Multiple Sclerosis Functional Composite z score (r = 0.35, 0.42, 0.34), and GM atrophy was the only correlate of change in the 9 Hole Peg Test and Paced Auditory Serial Addition Test performance. None of the MRI measures correlated with Expanded Disability Status Score progression. Measures of WB, GM and SC atrophy all have attributes for use as surrogate markers in secondary progressive MS trials and improvement in the reliability of the GM and SC volume measurements may enhance these further.

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Section: Discussionsupporting

confidence: 74%

A longitudinal study of MRI-detected atrophy in secondary progressive multiple sclerosis

Furby¹,

Hayton²,

Altmann

et al. 2010

J Neurol

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“…If anything, the number of patients required using the central slab is marginally lower. The estimated sample sizes in our cohort are higher than what was previously reported [15]. However, the studies are not necessarily comparable and results from sample size calculations should not be taken as exact numbers but rough estimates to judge whether studies are feasible.…”

Section: Discussioncontrasting

confidence: 59%

“…As brain volume change was not normally distributed, sample size calculations were based on Pitman's minimal asymptotic relative efficiency of a 2-tailed Mann-Whitney U test for 2 independent groups. In order to make comparisons with previous sample size calculations [15], we assumed that the treatment effect starts immediately, is constant over time and results in zero volume loss.…”

Section: Discussionmentioning

confidence: 99%

Central Slab versus Whole Brain to Measure Brain Atrophy in Multiple Sclerosis

Ruberte¹,

Sinnecker

Amann

et al. 2018

Eur Neurol

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Background: Structural Image Evaluation using Normalization of Atrophy (SIENA) is used to measure brain atrophy in multiple sclerosis (MS). However, brain extraction is prone to artefacts in the upper and lower parts of the brain. To overcome these shortcomings, some pivotal MS trials used a central slab instead of the whole brain as input for SIENA. The aim of this study was to compare the internal consistency and statistical dispersion of atrophy measures, associations with clinical outcomes and required sample sizes in clinical trials between these two approaches. Methods: Brain volume change was assessed using SIENA in 119 MS patients with 5-years follow-up on 3D T1-weighted Magnetization Prepared Rapid Gradient Echo datasets using the whole brain or a central slab ranging from –10 to +60 mm Montreal Neurological Institute atlas coordinates. The statistical analysis included the quartile coefficient of dispersion, partial correlations with clinical outcomes and sample size calculations. Clinical outcome measures comprised the Expanded Disability Status Scale, MS Functional Composite and Symbol Digit Modalities Test. Results: Annualized brain atrophy rates were higher using central slab than whole brain as input for SIENA (–0.51 ± 0.49 vs. –0.37 ± 0.39% per year, p < 0.001). Central and whole brain volume change showed comparable statistical dispersion and similarly correlated with clinical outcomes at 5-years follow-up. Sample size calculations estimated 14% fewer patients required to detect a given treatment effect when using the central slab instead of the whole brain option in SIENA. Conclusion: Central slab and whole brain SIENA produced comparable statistical dispersion with similar associations to clinical outcomes.

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“…difference in rate of atrophy) that occurs between patients given our limited sample size and the previous literature related to the variability in the change over time in MS patients (Bermel and Bakshi, 2006;Fisher et al, 2000;Fisher et al, 2008;Hardmeier et al, 2003;Chard et al, 2002;Simon et al, 1999;Ge et al, 2000;Simon, 2006;De Stefano et al, 2007). Previous work has demonstrated that differences between patients can be very important (Anderson et al, 2007;Healy et al, 2009;Scott et al, 2003;Altmann et al, 2008;Sormani et al, 2001), and this source of variability must be considered for any sample size calculation (Anderson et al, 2007;Healy et al, 2009;Scott et al, 2003;Altmann et al, 2008;Sormani et al, 2001). These previous papers have considered all sources of variability together, rather than quantifying each source of measurement error separately as we have done here, and they have not attempted to disentangle the variability due to measurement error from fluctuations inherent in the disease course.…”

Section: Discussionmentioning

confidence: 87%

Disease modeling in multiple sclerosis: Assessment and quantification of sources of variability in brain parenchymal fraction measurements

et al. 2010

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Sample sizes for brain atrophy outcomes in trials for secondary progressive multiple sclerosis

Abstract: Background: Progressive brain atrophy in multiple sclerosis (MS) may reflect neuroaxonal and

Cited by 90 publications

References 28 publications

A longitudinal study of MRI-detected atrophy in secondary progressive multiple sclerosis

A longitudinal study of MRI-detected atrophy in secondary progressive multiple sclerosis

Central Slab versus Whole Brain to Measure Brain Atrophy in Multiple Sclerosis

Disease modeling in multiple sclerosis: Assessment and quantification of sources of variability in brain parenchymal fraction measurements

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