Estimating Typical Multiple Sclerosis Disability Progression Speed from Clinical Observations

<div><p>Introduction</p><p>Multiple 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.</p><p>Methods</p><p>Our 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.</p><p>Findings</p><p>Typical 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.</p><p>Conclusions</p><p>Estimates 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.</p></div

Kaplan-Meier estimates of natural history survival time at EDSS disability endpoints for 408 eventually-DMD-treated patients, assuming midpoint (top) or maximum (bottom) survival time, Nova Scotia, 1979–2010.

<p>Footnote: The study group is a synthetic onset cohort of 408 definite relapsing-onset multiple sclerosis patients who were eventually treated with disease-modifying-drugs in period 1 August 1998–31 December 2010 and who had an assessed year-of-onset and at least two natural history EDSS clinical observations in period 1979–2010. The top graph shows Kaplan-Meier survival distribution function estimates at irreversible endpoints EDSS 1–9, assuming midpoint survival time (obs+Exp = 3702). The bottom graph shows Kaplan-Meier survival distribution function estimates at irreversible endpoints EDSS 1–9, assuming maximum survival time (obs = 2170). obs = an EDSS clinical observation, including assessed year-of-onset. Exp = an expected EDSS midpoint measure.</p

Assessment rates for EDSS clinical observations (obs) and expected midpoint observations (Exp), by relapsing-onset MS study groups and study periods, Nova Scotia, 1979–2010.

<p>Footnote: obs = an EDSS clinical observation. obs+Exp = obs and expected EDSS measures, assuming midpoint survival time at irreversible disability endpoints.</p

Irreversible progression paths – assuming maximum, minimum or midpoint survival time.

<p>Footnote: Part (a) shows a hypothetical multiple sclerosis patient’s clinical observations by years since onset. EDSS = Expanded Disability Status Scale. EDSS = 0 at onset is assumed. Of = first clinical observation at an irreversible EDSS endpoint. Or = last repeat clinical observation at an irreversible EDSS endpoint (repeat clinical observations between Of and Or are not shown). Ot = a transitorily high EDSS clinical observation (Ot are not shown in parts (b), (c) and (d)). Max = maximum survival time. Min = minimum survival time. Exp = expected midpoint survival time. <b>bold lines</b> = irreversible disability progression paths.</p