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Title:
FAIR-compliant Physiological Mapping as a basis for Building Disease Ontology Maps: Case Studies in Toxicology

Authors:
Bernard Staumont, Luiz Ladeira, Alessio Gamba, Harm J. Heusinkveld, Aldert Piersma, Ellen Fritsche, Rosalinde Masereeuw, Tamara Vanhaecke, Marc Teunis, Thomas H. Luechtefeld, Thomas Hartung, Ramiro Jover, Mathieu Vinken and Liesbet Geris

Abstract:
Physiological Maps (PMs) can be defined as comprehensive graphical representations of cellular and molecular processes related to specific organ functions (Vinken et al., 2021). Like Disease Maps, PMs encapsulate comprehensive knowledge (in this case, physiological mechanisms) in a standardized graphical notation that is designed for human comprehension and is also machine readable. Organ-specific PMs are currently being developed as part of the H2020 ONTOX project: bile secretion and lipid metabolism (liver), nephron physiology (kidney), neural tube closure and cognitive function development (developing brain).

The workflow used to build and exploit PMs in ONTOX is strongly inspired by that of the Disease Maps Project (Mazein et al., 2023). The first step is for domain experts and curators to define the objective and scope of the PM, identify the biological mechanisms to be mapped, determine granularity and list the key components in terms of cell types, molecules and pathways. A curation phase recovers knowledge and data available in the literature and databases, which are then integrated into a PM using CellDesigner (Funahashi et al., 2008). The PM is then uploaded to the Molecular Interaction NEtwoRks VisuAlization (MINERVA) Platform, (Hoksza et al., 2020), enabling better visualization, feedback from domain experts and updating of the PM.

To ensure a FAIR development and update of the maps, we designed curation guidelines for PMs providing recommendations in terms of design, annotation, documentation, quality control, and storage. PMs are designed with a modularized architecture, facilitating the integration of new data and updates, as well as the identification of data gaps, and enhancing the PMs’ usability and scalability. The use of annotations and controlled vocabularies allows for connections between different communities and initiatives. Altogether, the structure and annotation scheme are expected to improve data management, accessibility, interoperability and reuse of PMs.

PMs can be exploited in many possible ways. In the context of ONTOX, PMs allow for: (omics) data visualization, benchmarking and filling gaps in adverse outcomes pathways (AOPs), identifying new in vitro assays, exploring drug targets and developing in silico models. Importantly, in ONTOX, PMs represent a foundation for the development of (disease) ontology maps that will integrate pathological, toxicological, chemical and kinetic information in addition to physiology. The development of PMs and ontology maps is expected to support and accelerate the generation of new approach methodologies (NAMs) for next-generation toxicological risk assessment, only possible through collaborative efforts between the toxicology and systems biology communities.