Precision medicine offers a promising avenue for better therapeutic responses to pandemics such as COVID-19. This study leverages independent patient cohorts in Florence and Liege gathered under the umbrella of the DRAGON consortium for the stratification of molecular phenotypes associated with COVID-19 using topological analysis of global blood gene expression. Whole blood from 173 patients was collected and RNA was sequenced on the Novaseq platform. Molecular phenotypes were defined through topological analysis of gene expression relative to the biological network using the TopMD algorithm. The two cohorts from Florence and Liege allowed for independent validation of the findings in this study. Clustering of the topological maps of differential pathway activation revealed three distinct molecular phenotypes of COVID-19 in the Florence patient cohort, which were also observed in the Liege cohort. Cluster 1, was characterised by high activation of pathways associated with ESC pluripotency, NRF2, and TGF-B; receptor signalling. Cluster 2 displayed high activation of pathways including focal adhesion-PI3K-Akt-mTOR signalling and type I interferon induction and signalling, while Cluster 3 exhibited low IRF7-related pathway activation. TopMD was also used with the Drug-Gene Interaction Database (DGIdb), revealing pharmaceutical interventions targeting mechanisms across multiple phenotypes and individuals. The data illustrates the utility of molecular phenotyping from topological analysis of blood gene expression, and holds promise for informing personalised therapeutic strategies not only for COVID-19 but also for Disease X. Its potential transferability across multiple diseases highlights the value in pandemic response efforts, offering insights before large-scale clinical studies are initiated.

RPR is an employee at TopMD Precision Medicine Ltd. JPRS is a founding director, CEO, employee, and shareholder in TopMD Precision Medicine Ltd. FS is a founding director, CTO, employee, and shareholder in TopMD Precision Medicine Ltd. PS is a founding director, employee, and shareholder in TopMD Precision Medicine Ltd. BVE is CEO of Comunicare Solutions. TK is CTO of Comunicare Solutions.

TopMD, the University of Southampton, Imperial College London, CDISC, Comunicare Solutions, and the University of Liverpool are members of the DRAGON consortium. The DRAGON project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking (JU) under grant agreement No 101005122. The JU receives support from the European Union's Horizon 2020 research and innovation program and EFPIA. This publication reflects the author's view. Neither IMI nor the European Union, EFPIA or the DRAGON consortium, are responsible for any use that may be made of the information contained therein. JAH, TP, RPR and CH were supported by the US Food and Drug Administration Medical Countermeasures Initiative (no 75F40120C00085) awarded to JAH and work was also supported by the MRC funded MR/Y004205/1: The G2P2 virology consortium. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. DB is funded by NIHR and MRC.

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The protocol was approved by the ethics committee of the University Hospital of Liege (reference number 2021/89) and the ethics committee of the UNIFI (University of Florence) (#18085/OSS). Informed consent was obtained for every participant.

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