Building an Adverse Outcome Pathway network for COVID-19 Provisionally Accepted

Penny Nymark¹ Laure-Alix Clerbaux^2* Maria Joao Amorim^{3, 4} Christos Andronis⁵ Francesca de Bernardi⁶ Gillina Bezemer^{7, 8} Sandra COECKE⁹ Felicity N. Gavins¹⁰ Daniel Jacobson¹¹ Eftychia Lekka⁵ Luigi Margiotta-Casaluci¹² Marvin Martens¹³ Sally Mayaisch¹⁴ Holly M. Mortensen¹⁵ Youngjun Kim¹⁶ Magdalini Sachana¹⁷ Shihori Tanabe¹⁸ Vassilis Virvilis⁵ Steve Edwards¹⁹ Sabina Halappanavar^20*

• ¹Karolinska Institutet (KI), Sweden
• ²Université Catholique de Louvain, Belgium
• ³Instituto Gulbenkian de Ciência, Fundação Calouste Gulbenkian, Oeiras, Portugal, Portugal
• ⁴Católica Biomedical Research Centre, Faculty of Medicine, Catholic University of Portugal, Portugal
• ⁵Biovista, Greece
• ⁶Division of Otorhinolaryngology, Department of Biotechnologies and Life Sciences, University of Insubria, Ospedale di Circolo e Fondazione Macchi, Italy
• ⁷Utrecht University, Netherlands
• ⁸Impact Station,, Netherlands
• ⁹Joint Research Centre (Italy), Italy
• ¹⁰Centre for Inflammation Research and Translational Medicine, College of Health, Medicine and Life Sciences, Brunel University London, United Kingdom
• ¹¹Biosciences Division, Oak Ridge National Laboratory (DOE), United States
• ¹²Institute of Pharmaceutical Science, School of Cancer & Pharmaceutical Sciences, Faculty of Life Sciences & Medicine, King's College London, United Kingdom
• ¹³Department of Bioinformatics (BiGCaT), NUTRIM, Maastricht University, Netherlands
• ¹⁴Aquatic Sciences Center, University of Wisconsin‐Madison, Madison, Wisconsin, USA at US Environmental Protection Agency, Duluth,, United States
• ¹⁵U.S. Environmental Protection Agency (US EPA), Research Triangle Park,, United States
• ¹⁶Environmental Safety Group, KIST Europe,, Germany
• ¹⁷Environment Health and Safety Division, Environment Directorate, Organisation for Economic Cooperation and Development (OECD), France
• ¹⁸National Institute of Health Sciences, Japan
• ¹⁹RTI International, Research Triangle Park, United States
• ²⁰Environmental Health Science and Research Bureau, Canada

The COVID-19 pandemic generated large amount 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 defined 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 multifaced 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. Besides 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.