Abstract
IntroductionMultiple sclerosis (MS) is a chronic disease of the central nervous system. Estimates of MS natural history (NH) disability progression speed from clinical observations vary worldwide. This may reflect, in part, variance in censoring-bias) (missing observations) and assumptions about when irreversible disability progression events occurred. We test whether estimates of progression speed which assume midpoint survival time at irreversible disability endpoints are significantly faster than estimates which assume maximum survival time, and are more stable across study groups and time periods.MethodsOur Nova Scotia NH study population includes 2,240 definite relapsing-onset multiple sclerosis (R-MS) natural history patients with 18,078 Expanded Disability Status Scale (EDSS) clinical observations in study period 1979–2010. Progression speed is measured by rate-of-change in range EDSS 0–6 and by survival time at irreversible endpoints EDSS 1–9. Midpoint censoring-bias-reduction methods are applied to clinical observations.FindingsTypical EDSS increase per year in range EDSS 0–6, assuming midpoint survival time, is estimated to be 0.168 for all R-MS, 0.204 for eventually-DMD-treated patients and 0.155 for never-DMD-treated patients. Estimates assuming midpoint rather than maximum survival time are significantly faster: 16% faster for all R-MS natural history patients, 6% faster for eventually-DMD-treated patients, and 21% faster for never-DMD-treated patients. The variability of estimates across study groups and time periods decreased when midpoint survival time was assumed.ConclusionsEstimates of typical disease progression speed from 1979–2010 Nova Scotia clinical observations are sensitive to censoring-bias and to analysts’ survival time assumptions. Censoring-bias-adjusted estimates of typical natural history disability progression speed in relapsing-onset multiple sclerosis patients are significantly faster, and less variable within and across study groups and time periods, than unadjusted estimates, and are, arguably, more relevant for various stakeholders. The application of censoring-bias-reduction methods to other multiple sclerosis clinical databases may reduce variability in estimates of disability progression speed worldwide.
Highlights
Multiple sclerosis (MS) is a chronic disease of the central nervous system
The estimated midpointsurvival- curve lies to the left of the maximumsurvivalcurve, Figure 2
These results suggest that, at least for observations collected at Dalhousie Multiple Sclerosis Research Unit (DMSRU) clinics from 1979– 2010, the missing information between clinical observations is too large and variable to ignore
Summary
Estimates of MS natural history (NH) disability progression speed from clinical observations vary worldwide. This may reflect, in part, variance in censoring-bias) (missing observations) and assumptions about when irreversible disability progression events occurred. When modeling progression speed from clinical observations, analysts are forced to make assumptions about when irreversible progression events occurred during an interval. They can assume maximum survival time, minimum survival time, or somewhere in between [1]. Only rarely do patients experience maximum survival times In reality, their disease may progress at any point during the interval
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