The measurement of brain atrophy from magnetic resonance imaging (MRI) has become an established method of estimating disease severity and progression in multiple sclerosis (MS). Most commonly reported in the form of brain parenchymal fraction (BPF), it is more sensitive to the degenerative component of the disease and shows progression more reliably than lesion burden. Typically, the reliability of BPF and other morphometric measurements is assessed by evaluating scan-rescan experiments. While these experiments provide good estimates of real-life error related to imperfect patient repositioning in the MRI scanner, measurement variance due to physiological and reversible pathological fluctuations in brain volume are not taken into account. In this work, we propose a new model for estimating variability in serial morphometry, particularly the BPF measurement. Specifically, we attempt to detect and explicitly model the remaining sources of error to more accurately describe the overall variability in BPF measurements. Our results show that sources of variability beyond subject repositioning error are important and cannot be ignored. We demonstrate that scan-rescan experiments only provide a lower bound on the true error in repeated measurements of patients' BPF. We have estimated the variance due to patient repositioning during scan-rescan (sigma(sr)(2) = 3.0e-06), variance assigned to physiological fluctuations (sigma(p)(2) = 5.74e-06) and the variance associated with lesion activity (sigma(les)(2) = 1.09e-05). These variance components can be used to determine the relative impact of their sources on sample size estimates for studies investigating change over time in MS patients. Our results demonstrate that sample size calculations based exclusively on scan-rescan variability (sigma(sr)) are likely to underestimate the number of patients required. If the physiological variability (sigma(p)) is incorporated in sample size calculations, the required sample size would increase by a factor of 5.69 based on standard t-test sample size calculation.
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