Publication
Evaluation of S/F94 as a proxy for COVID-19 severity
Publisher:
Cold Spring Harbor Laboratory
Date:
27-09-2022
DOI:
10.1101/2022.09.25.22280081
Abstract: Optimising statistical power in early-stage trials and observational studies accelerates discovery and improves the reliability of results. Ideally, intermediate outcomes should be continuously distributed and lie on the causal pathway between an intervention and a definitive outcome such as mortality. In order to optimise power for an intermediate outcome in the RECOVERY trial, we devised and evaluated a modification to a simple, pragmatic measure of oxygenation function - the S a O 2 / F I O 2 (S/F) ratio. We demonstrate that, because of the ceiling effect in oxyhaemoglobin saturation, S/F ceases to reflect pulmonary oxygenation function at high values of S a O 2 . Using synthetic and real data, we found that the correlation of S/F with a gold standard ( P a O 2 / F I O 2 , P/F ratio) improved substantially when measurements with S a O 2 ≥ 0.94 are excluded (Spearman r , synthetic data: S/F : 0.31 S/F 94 : 0.85). We refer to this measure as S/F 94 . In order to test the underlying assumptions and validity of S/F 94 as a predictor of a definitive outcome (mortality), we collected an observational dataset including over 39,000 hospitalised patients with COVID-19 in the ISARIC4C study. We first demonstrated that S/F 94 is predictive of mortality in COVID-19. We then compared the s le sizes required for trials using different outcome measures ( S/F 94 , the WHO ordinal scale, sustained improvement at day 28 and mortality at day 28) ensuring comparable effect sizes. The smallest s le size was needed when S/F 94 on day 5 was used as an outcome measure. To facilitate future study design, we provide an online user interface to quantify real-world power for a range of outcomes and inclusion criteria, using a synthetic dataset retaining the population-level clinical associations in real data accrued in ISARIC4C ndpoints . We demonstrated that S/F 94 is superior to S/F as a measure of pulmonary oxygenation function and is an effective intermediate outcome measure in COVID-19. It is a simple and non-invasive measurement, representative of disease severity and provides greater statistical power to detect treatment differences than other intermediate endpoints.
0000-0003-2579-4655