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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.

Summary: Background: Cancer, coronary heart disease, dementia, and stroke are major contributors to morbidity and mortality in England. We aimed to assess the economic burden (including health-care, social care, and informal care costs, as well as productivity losses) of these four conditions in England in 2018, and forecast this cost to 2050 using population projections. Methods: We used individual patient-level data from the Clinical Practice Research Datalink (CPRD) Aurum, which contains primary care electronic health records of patients from 738 general practices in England, to calculate health-care and residential and nursing home resource use, and data from the English Longitudinal Study on Ageing (ELSA) to calculate informal and formal care costs. From CPRD Aurum, we included patients registered on Jan 1, 2018, in a CPRD general practice with Hospital Episode Statistics (HES)-linked records, omitting all children younger than 1 year. From ELSA, we included data collected from wave 9 (2018–19). Aggregate English resource use data on morbidity, mortality, and health-care, social care, and informal care were obtained and apportioned, using multivariable regression analyses, to cancer, coronary heart disease, dementia, and stroke. Findings: We included 4 161 558 patients from CPRD Aurum with HES-linked data (mean age 41 years [SD 23], with 2 079 679 [50·0%] men and 2 081 879 [50·0%] women) and 8736 patients in ELSA (68 years [11], with 4882 [55·9 %] men and 3854 [44·1%] women). In 2018, the total cost was £18·9 billion (95% CI 18·4–19·4) for cancer, £12·7 billion (12·3–13·0) for coronary heart disease, £11·7 billion (9·6–12·7) for dementia, and £8·6 billion (8·2–9·0) for stroke. Using 2050 English population projections, we estimated that costs would rise by 40% (39–41) for cancer, 54% (53–55) for coronary heart disease, 100% (97–102) for dementia, and 85% (84–86) for stroke, for a total of £26·5 billion (25·7–27·3), £19·6 billion (18·9–20·2), £23·5 billion (19·3–25·3), and £16·0 billion (15·3–16·6), respectively. Interpretation: This study provides contemporary estimates of the wide-ranging impact of the most important chronic conditions on all aspects of the economy in England. The data will help to inform evidence-based polices to reduce the impact of chronic disease, promoting care access, better health outcomes, and economic sustainability. Funding: Alzheimer's Research UK.