Weights for ordinal analyses of the modified Rankin Scale in stroke trials: A population-based cohort study

BACKGROUND: Ordinal/shift analyses of ordered measures like the modified Rankin Scale(mRS) are underused as primary trial outcomes for neurological disorders – despite statistical advantages – potentially hindered by poor clinical interpretability versus dichotomies, and by valuing state-transitions equally (linear scale). Weighted ordinal analyses incorporating step-changes at key transitions might have greater statistical validity and clinical applicability. METHODS: In a prospective population-based cohort of ischaemic stroke (Oxford Vascular Study, recruited 2002-2014), we stratified 5-year outcomes of death, dementia, and/or institutionalization, health/social-care costs, and EuroQol-derived quality-adjusted life-expectancy(QALE) by 3-month mRS. We compared root-mean-square errors(RMSEs) from linear regressions for these outcomes with the mRS coded as a linear scale versus incorporating a spline at transitions 1-2, 2-3, or 3-4. We derived 3-month mRS weights for probability of 5-year death/dementia/institutionalization using age/sex-adjusted logistic regressions, and cost and QALE weights from 1000-bootstraps. We applied these weights to analyse recent trials of thrombectomy for acute ischaemic stroke. FINDINGS: Among 1,607 patients, a non-linear (S-shaped) relationship was observed between 3-month mRS and each 5-year outcome, with RMSEs 18-73% lower using a spline at mRS 2-3 versus a linear representation. Age/sex-adjusted probability weights for 5-year death/dementia/institutionalization were: mRS 0=0.19; 1=0.27; 2=0.41; 3=0.73; 4=0.77; 5=0.94 (mRS 6=1 by definition). Similar trends were seen with costs; estimated 5-year QALEs were: mRS 0=3.88; 1=3.49; 2=3.01; 3=1.87; 4=1.30; 5=0.06; 6=0. Results were similar stratifying by age/sex, and excluding pre-morbidly disabled patients. Using a weighted ordinal approach, estimates of thrombectomy impact were more favourable than estimates with dichotomous approaches, 5-year cost reductions being 29% higher than with 0-2/3-6, and over three-fold higher than with 0-1/2-6 dichotomy. INTERPRETATION: Our findings favour weighting the mRS in ordinal analyses for stroke and other neurological disorders, as state-transitions differ in clinical prognosis, quality-of-life, and costs. These weights could also be used for prognostication and cost-effectiveness analyses. FUNDING: Wellcome Trust, Wolfson Foundation, NIHR Oxford Biomedical Research Centre, Rhodes Trust.