Precision medicine for pandemics: stratification of COVID-19 molecular phenotypes defined by topological analysis of global blood gene expression.

Precision medicine offers a promising pathway for improving therapeutic responses to pandemics like COVID-19. This study utilises independent patient cohorts from Florence and Liege, collected under the DRAGON consortium, to classify molecular phenotypes associated with COVID-19 through topological analysis of whole blood gene expression. Samples from 173 patients were collected, and RNA was sequenced using the Novaseq platform. Molecular phenotypes were identified through topological analysis of gene expression in relation to the biological network using the TopMD algorithm. Clustering of patients topological maps of differential pathway activation uncovered three distinct molecular phenotypes of COVID-19 in the Florence cohort, which were also found in the Liege cohort. Cluster 1 was characterised by high activation of pathways linked to ESC pluripotency, NRF2, and TGF-{beta} receptor signalling. Cluster 2 showed high activation of pathways, including focal adhesion-PI3K-Akt-mTOR signalling and type I interferon induction and signalling, while Cluster 3 displayed low IRF7-related pathway activation. TopMD was also used alongside the Drug-Gene Interaction Database (DGIdb), revealing pharmaceutical interventions that target mechanisms across multiple phenotypes and individuals. The data demonstrate the usefulness of molecular phenotyping through topological analysis of blood gene expression and hold promise for guiding personalised therapeutic strategies, not only for COVID-19 but also for Disease X. Its potential for transferability across various diseases emphasises its value in pandemic response efforts, providing insights before large-scale clinical studies are undertaken.