Building an Adverse Outcome Pathway network for COVID-19

Abstract

The COVID-19 pandemic generated large amounts of data on the disease pathogenesis leading to a need for organizing the vast knowledge in a succinct manner. Between April 2020 and February 2023, the CIAO consortium exploited the Adverse Outcome Pathway (AOP) framework to comprehensively gather and systematically organize published scientific literature on COVID-19 pathology. The project considered 24 pathways relevant for COVID-19 by identifying essential key events (KEs) leading to 19 adverse outcomes observed in patients. While an individual AOP defines causally linked perturbed KEs towards an outcome, building an AOP network visually reflect the interrelatedness of the various pathways and outcomes. In this study, 17 of those COVID-19 AOPs were selected based on quality criteria to computationally derive an AOP network. This primary network highlighted the need to consider tissue specificity and helped to identify missing or redundant elements which were then manually implemented in the final network. Such a network enabled visualization of the complex interactions of the KEs leading to the various outcomes of the multifaceted COVID-19 and confirmed the central role of the inflammatory response in the disease. In addition, this study disclosed the importance of terminology harmonization and of tissue/organ specificity for network building. Furthermore the unequal completeness and quality of information contained in the AOPs highlighted the need for tighter implementation of the FAIR principles to improve AOP findability, accessibility, interoperability and re-usability. Finally, the study underlined that describing KEs specific to SARS-CoV-2 replication and discriminating physiological from pathological inflammation is necessary but requires adaptations to the framework. Hence, based on the challenges encountered, we proposed recommendations relevant for ongoing and future AOP-aligned consortia aiming to build computationally biologically meaningful AOP networks in the context of, but not limited to, viral diseases.

Keywords: COVID-19; adverse outcome pathway (AOP); event; inflammation; network.

FIGURE 1

Computational derivation of a primary network using Cytoscape.

FIGURE 2

Network of COVID-19 AOPs as generated by Biovista Vizit tool.

FIGURE 3

COVID-19 AOP network involving 14 individual adverse outcome pathways. Green nodes indicate molecular initiating events (MIEs), Orange nodes are key events (KEs) and Red nodes are adverse outcomes (AOs). Transparent boxes depict KEs including MIEs clustered by the disease phase and tissue specificity. The color code for KER belonging indicates which AOP a specific KER (edge in the network) belongs to.

FIGURE 4

Bird’s-eye view of the COVID-19 AOP network providing insight into the interconnection between the various stages and tissue-specificities of the disease.