Brown Murray G, Asbridge Mark, Hicks Vern, Kirby Sarah, Murray Thomas J, Andreou Pantelis, Lin Dong
Department of Community Health and Epidemiology, Dalhousie University and Capital District Health Authority, Centre for Clinical Research, Halifax, Nova Scotia, Canada.
Department of Community Health and Epidemiology and Department of Emergency Medicine, Dalhousie University, Halifax, Nova Scotia, Canada.
PLoS One. 2014 Oct 17;9(10):e105123. doi: 10.1371/journal.pone.0105123. eCollection 2014.
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.
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.
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.
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.
多发性硬化症（MS）是一种中枢神经系统的慢性疾病。根据临床观察对MS自然史（NH）残疾进展速度的估计在全球范围内存在差异。这可能部分反映了删失偏倚（缺失观察值）的差异以及关于不可逆残疾进展事件发生时间的假设差异。我们测试了假设不可逆残疾终点的中点生存时间的进展速度估计是否显著快于假设最大生存时间的估计，以及在不同研究组和时间段内是否更稳定。
我们的新斯科舍省NH研究人群包括2240例明确的复发型多发性硬化症（R-MS）自然史患者，在1979 - 2010年研究期间有18078次扩展残疾状态量表（EDSS）临床观察。进展速度通过EDSS 0 - 6范围内的变化率以及EDSS 1 - 9不可逆终点的生存时间来衡量。中点删失偏倚减少方法应用于临床观察。
假设中点生存时间，所有R-MS患者在EDSS 0 - 6范围内每年的典型EDSS增加估计为0.168，最终接受DMD治疗的患者为0.204，从未接受DMD治疗的患者为0.155。假设中点而非最大生存时间的估计显著更快：所有R-MS自然史患者快16%，最终接受DMD治疗的患者快6%，从未接受DMD治疗的患者快21%。当假设中点生存时间时，不同研究组和时间段内估计的变异性降低。
根据1979 - 2010年新斯科舍省临床观察对典型疾病进展速度的估计对删失偏倚和分析人员的生存时间假设敏感。与未调整的估计相比，复发型多发性硬化症患者经删失偏倚调整的典型自然史残疾进展速度估计显著更快，并且在研究组内和不同研究组之间以及时间段内变异性更小，并且可以说与各种利益相关者更相关。将删失偏倚减少方法应用于其他多发性硬化症临床数据库可能会降低全球范围内残疾进展速度估计的变异性。
