Comparison to our human drug response database
The human response RNA-seq data for 111 compounds in the human hemodynamic co-culture model underlying this study were created as a proprietary dataset by HemoShear Therapeutics. Together, these compound responses constitute a human drug-response database (HRDB) of transcriptomic data generated in the same experimental system across 111 compounds tested in the system. Of those 111 compounds, 107 are clinical stage compounds with 33 carrying FDA boxed warnings for cardiovascular risk. The full list of compounds and any information regarding their boxed warning for cardiovascular risk can be found in We made functional comparisons to test compound treatments in the database by comparing the log fold changes of genes across Reactome pathways. For a given Reactome pathway, the Spearman correlation of log fold changes was calculated between the treatments in this study and the treatments in the HRDB. Only genes that had treatment p-value < 0.05, in either of the two contrasts being compared, were considered for analysis. Correlation values were calculated across all elements of the Cartesian product of treatments in the HRDB, the xanthine oxidase inhibitor treatments in this study, and all Reactome pathways. The resulting set of correlation values allowed us to identify pathways where the xanthine oxidase inhibitor treatments had an exceptionally high degree of similarity with HRDB drugs that are associated with cardiovascular risk. This assessment was made by identifying pathway-drug combinations where cardiovascular-risk drugs tended to have a higher correlation than drugs without known cardiovascular risk. This identification was performed with the Mann-Whitney U-test. In addition, Fisher’s exact test was used to assess the enrichment of cardiovascular-risk drugs among drugs with positive pathway-level correlation. The ultimate result of this analysis was a list of pathways for each xanthine oxidase inhibitor, where each pathway is similarly regulated by the xanthine oxidase inhibitor and the set of cardiovascular-risk drugs in the HRDB. All data and code are available at DOI: 