A tool to support risk assessment in the context of adverse outcome pathways.
Kaptis is a strategic project with the aim of developing a novel software solution, where users will develop, store, explore and share Adverse Outcome Pathway (AOP) knowledge.
Kaptis will employ a network of AOPs to organise evidence and combine it in a meaningful way to support risk assessments, through an integrated approach to testing and assessment (IATA).
The integration of assays with relevant Key Events (KEs) will help an organisation to decide which assays to run. In addition to this, associating assay data to KEs will provide the ability to perform similarity searches on compounds of interest.
Kaptis will allow users to explore toxicological hazards, using a combination of existing knowledge and assay data in the context of AOPs.
An AOP is a formalised approach to documenting a mechanism of toxicity. AOPs start with a molecular initiating event (MIE) and through additional key events (KEs), lead to an Adverse Outcome (AO). Each sequential KE (including the MIE and AO) are connected to each other through key event relationships (KERs). Formally, each KE should be measurable and therefore can be linked to a relevant assay.
Aims of the project:
The aim of the project is to provide a sustainable AOP framework to support assessment of risk of human adverse events caused by exposure to chemicals. Kaptis will achieve this aim through bringing together AOPs, assays and assay data to help improve decision-making through allowing questions such as:
- Given this chemical, what do compounds like mine do?
- Given this chemical and/or this assay result (irrespective of the chemical), what AO should I worry about?
- Given this AO, what assay should I run?
These questions will be addressed within Kaptis using a weight of evidence approach to give an overall outcome as well as statistical relationships.
History of the project:
AOPs are increasingly being developed to rationalise mechanisms of toxicity. An understanding of AOPs and relevant assays available to measure KEs is increasingly important, with the current drive towards new approach methodologies (NAMs) for toxicity assessments – such as in vitro assays.
Lhasa has developed a prototype version of Kaptis which can be used to explore toxicological hazards using a combination of existing knowledge and assay data in the context of AOPs.
The intention of the proposed Kaptis collaborative consortium over the course of the strategic project, is to develop a sustainable AOP framework to support assessment of risk of human adverse events caused by exposure to chemicals within Kaptis.
Figure 1. A graphical representation of an AOP displayed in Kaptis.
Kaptis will be an essential tool for teams working within the drug development process who are looking to use AOPs, and relevant assay data, to rationalise mechanisms of toxicity using a weight of evidence approach.
As well as visualising individual AOPs, Kaptis allows users to search for a specific key event and view any pathways leading to and from the key event alongside any associated assays.
In addition to hosting Lhasa‘s curated AOPs for carcinogenicity and developmental and reproductive toxicity (DART), Kaptis will allow for the development of custom AOPs. Custom AOPs will include the permitted addition of relevant assays and assay data. Using the software to develop AOPs allows for the reuse of KEs already within the database and development pathway networks.
By incorporating assay data, linking to various key events within an AOP, Kaptis will help users to make informed decisions on potential candidates through increased understanding of mechanistic profiles.
Work is currently being undertaken at Lhasa to determine how reasoning between assay data types associated with AOPs (e.g. in vitro, in vivo and in silico) can be used within a regulatory framework. In the future, Kaptis may assist you with meeting specific regulations such as ICH S12 as well as broader areas of regulatory toxicological assessments using AOP analysis.
Figure 2. A graphical representation of searching for a key event within Kaptis and viewing all AOPs in relation to the searched key event.
- Carcinogenicity – genotoxic and non-genotoxic mechanisms
- Developmental and reproductive toxicity (DART)
The Lhasa science team are taking a literature-based approach to AOP development. By using information within Derek Nexus, Lhasa’s expert toxicity prediction software, putative AOPs have been developed and then improved through literature research.1
Summary of Carcinogenicity AOP Progress
Investigations to date have identified 47 MIEs, resulting in 43 AOPs, with 359 unique KEs. The KEs in the putative AOPs have been grouped together at a higher biological level to aid understanding. As a result of this work, Kaptis now contains 37 MIEs, 37 AOPs with 101 unique KEs for this endpoint.
Summary of DART AOP Progress
Harvesting Derek Nexus has identified 50 MIEs, 26 resulting AOPs have been developed with 153 KEs
Where there are shared KERs between different AOPs, the KEs are linked into AOP networks.
Moving forward, development of networks of AOPs within Kaptis will continue and AOPs will be investigated and developed for additional endpoints, led by the Kaptis consortium.
Different methods of reasoning between evidence in an AOP framework will be explored by Lhasa, in order to provide the best approach for combining evidence for toxicity assessment within Kaptis.
New use cases will be identified, discussed and prioritised within the Kaptis consortium.
A consortium of experts is being built to advance future development of Kaptis.
Lhasa is open to new consortium members and is actively encouraging participation. Please contact the Global Alliances team for more information.
Lhasa Limited - an honest broker and trusted holder of data
Lhasa is a not-for-profit organisation and believes that shared knowledge can lead to shared progress. Recognised as the original "Honest Broker", Lhasa Limited has repeatedly been trusted with proprietary data and this can be seen with our involvement in other collaborative data sharing projects (such as Effiris)
- Myden, A. (2019) ‘Using an Adverse Outcome Pathway framework to ground approaches in predictive toxicology’ [PowerPoint presentation]. Available at: https://www.lhasalimited.org/library/ (Accessed: 02 Feb 2020).
- ICH Safety Guidelines [online] https://www.ich.org/page/safety-guidelines (Accessed: 17 Feb 2020).