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Abstract Choosing optimal outcome measures maximizes statistical power, accelerates discovery and improves reliability in early-phase trials. We devised and evaluated a modification to a pragmatic measure of oxygenation function, the $$S/F$$ S / F ratio. Because of the ceiling effect in oxyhaemoglobin saturation, $$S/F$$ S / F ratio ceases to reflect pulmonary oxygenation function at high $${S}_{p}{O}_{2}$$ S p O 2 values. We found that the correlation of $$S/F$$ S / F with the reference standard ( $${P}_{a}{O}_{2}$$ P a O 2 / $${F}_{I}{O}_{2}$$ F I O 2 ratio) improves substantially when excluding $${S}_{p}{O}_{2} > 0.94$$ S p O 2 > 0.94 and refer to this measure as $$S/{F}_{94}$$ S / F 94 . Using observational data from 39,765 hospitalised COVID-19 patients, we demonstrate that $$S/{F}_{94}$$ S / F 94 is predictive of mortality, and compare the sample sizes required for trials using four different outcome measures. We show that a significant difference in outcome could be detected with the smallest sample size using $$S/{F}_{94}$$ S / F 94 . We demonstrate that $$S/{F}_{94}$$ S / F 94 is an effective intermediate outcome measure in COVID-19. It is a non-invasive measurement, representative of disease severity and provides greater statistical power.

Objectives: Interleukin (IL)-6 inhibitors are administered to treat patients hospitalized with COVID-19. In 2021, due to shortages, different dosing regimens of tocilizumab, and a switch to sarilumab, were consecutively implemented. Using real-world data, we compare the effectiveness of these IL-6 inhibitors. Methods: Hospitalized patients with COVID-19, treated with IL-6 inhibitors, were included in this natural experiment study. Sixty-day survival, hospital- and intensive care unit (ICU) length of stay, and progression to ICU or death were compared between 8 mg/kg tocilizumab, fixed-dose tocilizumab, low-dose tocilizumab, and fixed-dose sarilumab treatment groups. Results: A total of 5485 patients from 49 hospitals were included. After correction for confounding, increased hazard ratios (HRs) for 60-day mortality were observed for fixed-dose tocilizumab (HR 1.20, 95% confidence interval [CI] 1.04-1.39), low-dose tocilizumab (HR 1.12, 95% CI 0.97-1.31), and sarilumab (HR 1.24, 95% CI 1.08-1.42), all relative to 8 mg/kg. The 8 mg/kg dosing regimen had lower odds of progression to ICU or death. Both hospital- and ICU length of stay were shorter for low-dose tocilizumab than for the 8 mg/kg group. Conclusion: We found differences in the probability of 60-day survival and the incidence of the combined outcome of mortality or ICU admission, mostly favoring 8 mg/kg tocilizumab. Because of potential time-associated residual confounding, further clinical studies are warranted.

Abstract The increasing body of literature describing the role of host factors in COVID-19 pathogenesis demonstrates the need to combine diverse, multi-omic data to evaluate and substantiate the most robust evidence and inform development of therapies. Here we present a dynamic ranking of host genes implicated in human betacoronavirus infection (SARS-CoV-2, SARS-CoV, MERS-CoV, seasonal coronaviruses). We conducted an extensive systematic review of experiments identifying potential host factors. Gene lists from diverse sources were integrated using Meta-Analysis by Information Content (MAIC). This previously described algorithm uses data-driven gene list weightings to produce a comprehensive ranked list of implicated host genes. From 32 datasets, the top ranked gene was PPIA, encoding cyclophilin A, a druggable target using cyclosporine. Other highly-ranked genes included proposed prognostic factors (CXCL10, CD4, CD3E) and investigational therapeutic targets (IL1A) for COVID-19. Gene rankings also inform the interpretation of COVID-19 GWAS results, implicating FYCO1 over other nearby genes in a disease-associated locus on chromosome 3. Researchers can search and review the gene rankings and the contribution of different experimental methods to gene rank at https://baillielab.net/maic/covid19 . As new data are published we will regularly update the list of genes as a resource to inform and prioritise future studies.

Abstract BackgroundIn March 2022, a concerning rise in cases of unexplained pediatric hepatitis was reported in multiple countries. Cases were defined as acute hepatitis with serum transaminases >500 U/L (aspartate transaminase [AST] or alanine transaminase [ALT]) in children aged 16 years or younger. We explored a simple federated data analytics method to search for evidence of unreported cases using routinely held data. We conducted a pragmatic survey to analyze changes in the proportion of hospitalized children with elevated AST or ALT over time. In addition, we studied the feasibility of using routinely collected clinical laboratory results to detect or follow-up the outbreak of an infectious disease. ObjectiveWe explored a simple federated data analytics method to search for evidence of unreported cases using routinely held data. MethodsWe provided hospitals with a simple computational tool to enable laboratories to share nondisclosive summary-level data. Summary statistics for AST and ALT measurements were collected from the last 10 years across all age groups. Measurements were considered elevated if ALT or AST was >200 U/L. The rate of elevated AST or ALT test for 3-week- to 5-year-olds was compared between a period of interest in which cases of hepatitis were reported (December 1, 2021, to August 31, 2022) and a prepandemic baseline period (January 1, 2012, to December 31, 2019). We calculated a z ResultsOur approach of sharing a simple software tool for local use enabled rapid, federated data analysis. A total of 34 hospitals in the United Kingdom, the Netherlands, Ireland, and Curaçao were asked to contribute summary data, and 30 (88%) submitted their data. For all locations combined, the rate of elevated AST or ALT measurements in the period of interest was not elevated (zP=zP ConclusionsHospital laboratories collect large amounts of data on a daily basis that can potentially be of use for disease surveillance, but these are currently not optimally used. Federated analytics using nondisclosive, summary-level laboratory data sharing was successful, safe, and efficient. The approach holds potential as a tool for pandemic surveillance in future outbreaks. Our findings do not indicate the presence of a broader outbreak of mild hepatitis cases among young children, although there was an increase in elevated AST or ALT values locally in the Netherlands.