Resources & Training

Abstract:
The Implementation Challenge was created to select external tools and services, especially in areas of risk assessment, not completely covered by the OpenRiskNet consortium, to be prioritised for their integration into the e-infrastructure. Third parties could apply for financial and technical support offered by OpenRiskNet partners. The selection was made by the scientific advisory board. The winners were asked to become an OpenRiskNet associated partner. The selection criteria included the tools which were complementary to the tools from within the consortium, the Technology Readiness Level (TRL), availability of APIs and other technical requirements. In total, 14 applications (20 tools or services) were received, while 10 applications (12 tools or services) were awarded and entered in the associated programme and the implementation process. The services integrated cover data and knowledge sources as well as different software tools across all areas of risk assessment. The specific services were 1) the Adverse Outcome Pathway Database (AOP-DB), 2) Daphnia magna nanotoxicity database, 3) Nano-QSAR to predict cytotoxicity of metal and metal oxide nanoparticles, 4) ToxPlanet database, 5) OCHEM models, 6) FAME 3 site-of-metabolism predictor, 7) Prosilico's Human In Vivo ADME/PK-Prediction Studio, 8) Nanoinformatics Tool for the Virtual Screening of Metal Oxide Nanoparticles via Enalos Platform, 9) nanoQSAR model for the prediction of the cellular uptake and the virtual screening of nanoparticles via Enalos Platform, 10) PySquonk, 11) ToxicoDB and 12) ToxTargetLinks.

Abstract:
This report is a continuation of the first report on the management of the OpenRisknet e-infrastructure project (Deliverable 5.1) and refers to the overall management process adopted for the entire duration of the OpenRiskNet project: coordination and tracking, meetings and reporting. This process envisaged the implementation of the best project management practices to ensure the effective execution of the work plan, tracking and documentation of task progress, effective communication between partners on technical and administrative matters, as well as the communication with the EC office, associated partners, SAB and other stakeholders.

Abstract:
This report describes the final status of the service integration including numbers of active services provided by the consortium, associated partners and other third parties. The work described in this report addresses all areas and tasks of WP4 (i.e. Toxicology, Chemical Properties and Bioassay Databases, Omics Databases, Knowledge Bases and Data Mining, Ontology Services, Processing and Analysis, Predictive Toxicology, Workflows, Visualisation and Reporting). Because of their importance for service integration, we also reference to work performed in WP1 on case studies and in WP2 on e-infrastructure interoperability and deployment. The report includes examples of how the services provided by the consortium partners and associated partners are combined and integrated into workflows providing solutions to answer the specific case study questions. Further details are presented on how the services from the Implementation Challenge are strengthening the demonstration on the case studies. A detailed, up-to-date description of all services integrated in OpenRiskNet including the extensive categorization of the integration status (a process based on a predefined set of eight operations) is available on the project’s website. Here we will concentrate on statistics on the services integrated (e.g. categories, type, applicability domain and areas covered, targeted users or industries).

Abstract:
This report is based on the initial data management plan (DMP) (Deliverable 3.1) and includes the final DMP for the OpenRiskNet e-infrastructure project. The current document covers the aspects of the OpenRiskNet data management based on the FAIR (findable, accessible, interoperable and reusable) guidelines, ethics considerations for re-sharing of public datasets, and details on the data sources made available and will be sustained after the project as OpenRiskNet data sources. These are alternative access to US EPA ToxCast/Tox21 data, intensities and fold changes obtained by processing the TG-GATEs and DrugMatrix transcriptomics data, BridgeDb, semantic annotated versions of WikiPathways, AOP-Wiki and AOP-DB in RDF format, ToxicoDB including the dataset for the TGX case study, the nano Daphnia dataset, ToxPlanet, SCAIview and as a specific feature of OpenRiskNet also the library of risk assessment workflows in form of Jupyter notebooks. Sustainability of OpenRiskNet developments and achievements other than data will be covered in the separate sustainability plan being part of the second Periodic Report.

Abstract:
This report describes the dissemination and training activities undertaken by the OpenRiskNet partners in the second half of the project (Jun 2018 - Nov 2019) and it is a continuation of Deliverable 3.4 that reported the dissemination and training activities up to month 18 (Dec 2016-May 2018). In this report we followed a similar structure, including details on the relevant activities developed within the project: organisation of webinars, workshops, training events and hackathons, participation at conferences and workshops, peer-reviewed publications, tutorials, public communication activities, as well as the interactions initiated with other EU infrastructures or projects to support uptake of the services and their sustainability.

Abstract:
In this deliverable we present the availability of the OpenRiskNet reference system. The system is online with operational functionality and demonstrated operations in the OpenRiskNet case studies as well as within the Associated Partner Program. This deliverable is in the form of a Demonstrator, and apart from describing the reference site and examples of applications, it also summarises the recent developments in WP2 that has not been reported earlier.

Abstract:
The OpenRiskNet case studies (originally outlined in Deliverable 1.3) were developed to demonstrate the modularised application of interoperable and interlinked workflows. These workflows were designed to address specific aspects required to inform on the potential of a compound to be toxic to humans and to eventually perform a risk assessment analysis. While each case study targets a specific area including data collection, kinetics modelling, omics data and Quantitative Structure Activity Relationships (QSAR), together they address a more complete risk assessment framework. Additionally, the modules here are fine-tuned for the utilisation and application of new approach methodologies (NAMs) in order to accelerate the replacement of animals in risk assessment scenarios. These case studies guided the selection of data sources and tools for integration and acted as examples to demonstrate the OpenRiskNet achievements to improve the level of the corresponding APIs with respect to harmonisation of the API endpoints, service description and semantic annotation.

Abstract:
Metabolites may well play an important role in adverse effects of parent drug or other xenobiotic compounds. In this case study VU (CS leader), HITeC/HHU (associate partner and implementation challenge winner), JGU, and UU have worked together on making methods and tools available for metabolite and site-of-metabolism (SOM) prediction. For that purpose we integrated and used ligand-based metabolism predictors (e.g. MetPred, enviPath, FAME, SMARTCyp) and we incorporated protein-structure and -dynamics based approaches to predict SOMs by Cytochrome P450 enzymes (P450s). P450s metabolise ~75% of the currently marketed drugs and their active-site shape and plasticity often play an important role in determining the substrate’s SOM. It is expected that this work will be continued after the end of the project to make services available for the prediction of microbial biotransformation pathways by integrating the enviPath data and software developed in part by JGU. During method development, model calibration and validation we used databases such as XMetDB and other open-access databases for drugs, xenobiotics and their respective metabolites. To facilitate the combined use of the metabolite prediction approaches and their outcomes, we benefited of ongoing development in workflow management systems and we made Jupyter Notebooks available to facilitate collection and visualization of results from the different available services. We illustrated the added value of having multiple predictors and our Jupyter notebooks available, in a pilot study on retrospective consensus predictions of known SOMs for drug compounds for which possible metabolite-associated toxicity was previously reported.

Abstract:
The ModelRX case study was designed to cover the important area of generating and applying predictive models, and more specifically QSAR models in hazard assessment endorsed by different regulations, as completely in silico alternatives to animal testing and useful also in early research when no data is available for a compound. The QSAR development process schematically presented in Figure 1 begins by obtaining a training data set from an OpenRiskNet data source. A model can then be trained with OpenRiskNet modelling tools and the resulting models are packaged into a container, documented and ontologically annotated. To assure the quality of the models, they are validated using OECD guidelines (Jennings et al. 2018). Prediction for new compounds can be obtained using a specific model or a consensus of predictions of all models. This case study will present this workflow with the example of blood-brain-barrier (BBB) penetration, for which multiple models were generated using tools from OpenRiskNet consortium and associated partners used individually as well as in a consensus approach using Dempster-Shafer theory (Park et al. 2014; Rathman et al. 2018).

Abstract:
DataCure establishes a process for data curation and annotation that makes use of APIs (eliminating the need for manual file sharing) and semantic annotations for a more systematic and reproducible data curation workflow. In this case study, users are provided with capabilities to allow access to different OpenRiskNet data sources and target specific entries in an automated fashion for the purpose of identifying data and metadata associated with a chemical in general to identify possible areas of concern or for a specific endpoint of interest (Figure 1B). The datasets can be curated using OpenRiskNet workflows developed for this case study and, in this way, cleansed e.g. for their use in model development (Figure 1A). Text mining facilities and workflows are also included for the purposes of data searching, extraction and annotation (Figure 1C). A first step in this process was to define APIs and provide the semantic annotation for selected databases (e.g. FDA datasets, ToxCast/Tox21 and ChEMBL). During the preparation for these use cases, it became clear that the existing ontologies do not cover all requirements of the semantic interoperability layer. Nevertheless, the design of the annotation process as an online or an offline/preprocessing step forms an ancillary part of this case study even though the ontology development and improvement cannot be fully covered by OpenRiskNet and is instead organized as a collaborative activity of the complete chemical and nano risk assessment community.

Abstract:
This case-study demonstrates and documents the use of a web interface to physiologically-based pharmacokinetic models for forward and reverse dosimetry calculations. Forward calculations compute internal concentrations from given exposure doses. Reverse calculations compute exposure doses from internal concentrations or measured biomarker levels (e.g., urine concentration data). The result of those calculations can be used in risk assessments to help with in vitro to in vivo extrapolations or interspecies extrapolations. Three tools have been developed for this case-study at NTUA and have been integrated into the OpenRiskNet infrastructure through the Jaqpot web-based computational platform. More specifically, the popular high-throughput toxicokinetic (httk) R package and the PKSim software tool for whole-body physiologically based pharmacokinetic modeling were integrated, but we also developed infrastructure for developing and deploying user-defined model. For each of these three web tools, simulations are performed and results are presented for reference chemicals or drugs, namely Imazalil for the httk model, Diazepam and Chlorpyrifos for showcasing the In-house R PBPK workflow and Theophylline for the PKSim model. The exposure scenarios chosen are in the range of corresponding environmental or therapeutic levels.

Abstract:
The Adverse Outcome Pathway (AOP) concept has been introduced to support risk assessment (Ankley et al., 2010). An AOP is initiated upon exposure to a stressor that causes a Molecular Initiating Event (MIE), followed by a series of Key Events (KEs) on increasing levels of biological organization. Eventually, the chain of KEs ends with the Adverse Outcome (AO), which describes the phenotypic outcome, disease, or the effect on the population. In general, an AOP captures mechanistic knowledge of a sequence of toxicological responses after exposure to a stressor. While starting with molecular information, for example, the initial interaction of a chemical with a cell, the AOPs contain information of downstream responses of the tissue, organ, individual and population. Currently, AOPs are stored in the AOP-Wiki, a collaborative platform to exchange mechanistic toxicological knowledge as a part of the AOP-KB, an initiative by the OECD. Normally, AOP development starts with a thorough literature search for existing knowledge, describing the sequence of KEs that form the AOP. However, the use of AOPs for regulatory purposes also requires detailed validation and linking to existing knowledge (Knapen et al., 2015; Burgdorf et al., 2017). Part of the development of AOPs is the search for data that supports the occurrence and biological plausibility of KEs and their relationships (KERs). This type of data can be found in literature, and increasingly in public databases. The main goal of this case study is to establish the links between AOPs of the AOP-Wiki and experimental data to support a particular AOP. This will allow finding AOPs related to experimental data, and finding data related to a particular AOP.

Abstract:
This case study will use the approach of the diXa / DECO2 (Cefic-LRI AIMT4) projects to reproduce and extend the results obtained on the identification of hepatotoxicant groups based on similarity in mechanisms of action (omics-based) and chemical structure using services from OpenRiskNet.

Abstract:
In this case study a transcriptomics-based hazard prediction model for identification of specific molecular initiating events (MIE) was foreseen based on (A) top-down and (B) bottom-up approaches. The MIEs can include, but are not limited to: (1) Genotoxicity (p53 activation), (2) Oxidative stress (Nrf2 activation), (3) Endoplasmic Reticulum Stress (unfolded protein response), (4) Dioxin-like activity (AhR receptor activation), (5) HIF1 alpha activation and (6) Nuclear receptor activation (e.g. for endocrine disruption). This case study focussed on two top-down approaches for genotoxicity prediction. The first approach resulted in the creation of a Nextflow-based workflow from the publication “A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo” by Magkoufopoulou et al. (2012), thereby reproducing their work as proof of principle. The Nextflow-based workflow has been translated into a more generic approach, especially for step 1, forming the basis of the second top-down approach. In this approach transcriptomics data together with toxicological compound information were collected from multiple toxicogenomics studies and used for building a metadata genotoxicity prediction model.

Abstract:
This report details the work involved in the federation of compute and data resources between the OpenRiskNet e-infrastructure and external resources. The reference environment has been designed to be capable of handling the majority of requirements for users’ wishes to deploy and run services. However specific situations demand solutions where either the computation, the data or both reside outside the OpenRiskNet e-infrastructure. This deliverable is related to Tasks 2.7 (Interconnecting virtual environment with external infrastructures) and Tasks 2.8 (Federation between virtual environments). Resource intensive analyses, such as those performed in toxicogenomics, can have CPU, memory or disk requirements that cannot be assumed to be available across all deployment scenarios. Human sequencing data may have restrictions on where it can be processed and the vast quantity of this data often predicates that it is more efficient to “bring the computation to the data”. In achieving Tasks 2.7 and 2.8, we can demonstrate how the virtual environment can utilise external infrastructure including commercial cloud providers and data stores.

Abstract:
This document reports the work on the final API specification for semantic interoperability that was developed as part of the OpenRiskNet e-infrastructure. It briefly outlines the challenges encountered and the solution that has been implemented and is now in use in OpenRiskNet. This deliverable is related to Task 2.2 (API specification and semantic interoperability) and in a continuation of the work performed within Deliverable 2.2 (Initial API version provided to providers of services), that are now in the process of being incorporated into OpenRiskNet as part of the service catalogue. Deliverable 2.2 gives in-depth information on the evaluation of the various technologies for describing APIs we considered, whereas this report focuses on the solution that was finally chosen and put in place, and the justification of this choice to support other databases / e-infrastructures in their deliberations on API solutions.

Abstract:
This report describes the status of the service integration including numbers of active services provided by the consortium, associated partners and other third parties. The work described in this report addresses all areas and tasks of WP4 (i.e. Toxicology, Chemical Properties and Bioassay Databases, Omics Databases, Knowledge Bases and Data Mining, Ontology Services, Processing and Analysis, Predictive Toxicology, Workflows, Visualisation and Reporting). Due to their importance for service integration, we also reference to work performed in WP1 on case studies and in WP2 on e-infrastructure interoperability and deployment.

Abstract:
This report describes the first updated version of the data management plan (DMP) for the OpenRiskNet e-infrastructure projects. The current DMP covers the general aspects of the OpenRiskNet data management based on the FAIR (findable, accessible, interoperable and reusable) guidelines, ethics considerations for re-sharing of public datasets and the first examples of shared data sources including diXa, BridgeDb, WikiPathways, AOP-Wiki and ToxCast/Tox21. More specific data source and clearly-defined measures will be added in parallel to their integration into the infrastructure, which will follow the time plan enforced by the case study requirements on data availability.

Abstract:
OpenRiskNet is developing an e-infrastructure for predictive toxicology and safety assessment (of chemicals, pharmaceuticals, nanomaterials etc.) in the form of virtual research environments (VREs) and data, analysis and modelling services coming from the consortium but also from third parties, which can be deployed to these. This deliverable describes the support functions set up and how they were customised for specific user groups. Due to its specific purpose of being an infrastructure where public and commercial services are offered to the community, OpenRiskNet services different types of users and roles, which can be grouped into: End users (e.g. members of academia, industry, and regulatory agencies) who are defined as users who log into an OpenRiskNet VRE and consume one or more services or applications; Developers who are involved in developing or setting up parts of the OpenRiskNet VRE, such as middleware, frameworks, data, or tools packaged as services or applications; in the latter case also referred to as tool provider; System administrators, who are in charge of creating and managing the OpenShift environment for the VRE and deploying the basic services.

Abstract:
This report describes the results obtained from the survey, interviews and interactions with associated partners and project stakeholders as part of the requirements analysis. The requirements analysis included surveys sent out to a large number of experts and designed to address issues relevant to: End users (e.g. members of academia, industry and regulatory agencies), and Developers (tools developers, infrastructure provider and data managers.

Abstract:
To ensure the usability of the infrastructure, alignment with the community needs as well as pursuing complete coverage of important tools incorporated into the e-infrastructure and available to Users, OpenRiskNet will work with a continuously expanding network of partners. To make the interaction with the OpenRiskNet consortium, to give feedback and to contribute to the developments and case study work as simple as possible but also give the opportunity to share confidential information, foster collaborative developments between consortium and associated partners and even allow integration of tools as in-kind work, three different ways to associate with the project as a third party are available: 1) testing the infrastructure as a early adopter and give feedback and state requirements via the online surveys (see also updated deliverable report D1.1), 2) become an official associated partner allowing the exchange of confidential information like source code with examples of service integration and 3) applying to the implementation challenge, which will provide additionally to the technical support also financial support for service integration. This updated deliverable report describes these options organised in the Associated Partner Programme.

Abstract:
This report cover the possible risks with respect to security, privacy and re-identification of personal data as well as present the private by design risk management concept.

Abstract:
This report summarises the management process adopted within the OpenRiskNet project. This process envisaged the implementation of best project management practices to ensure the effective execution of the work plan, tracking and documentation of task progress, an effective communication between partners on technical and administrative matters, as well as the communication with the EC office and external stakeholders.

Abstract:
This report describes the first documentation of the core OpenRisknet e-infrastructure with examples of an initial development status implementation. This report forms part of this documentation, along with other parts located in the OpenRiskNet GitHub repository. This documentation describes the creation of the e-infrastructure and the deployment of the first partner application to the e-infrastructure.

Abstract:
Tis report describes the status of selection of services of high priority for the OpenRiskNet infrastructure and their integration including active services provided by the consortium, associated partners and other third parties.

Abstract:
OpenRiskNet case studies are used to test and evaluate solutions provided by the project to the predictive toxicology and risk assessment community, especially regarding the usability of the developed Application Programming Interfaces (APIs) and the interoperability layer. These case studies will demonstrate the capabilities to satisfy the requirements of the different stakeholder groups, including researchers, risk assessors and regulators and present real-world applications such as systems biology approaches for grouping compounds, read-across applications using chemical and biological similarity, and identifying areas of concern based on in vitro and in silico approaches for compounds lacking any previous knowledge from animal experiments (ab initio case).

Abstract:
This document reports the work towards the first version of the OpenRiskNet application programming interfaces (APIs) to be released to all partners of the consortium and associated partners for feedback and usage. Based on the diversity of the requirement foreseeable when developing the case studies to validate the infrastructure with real-world applications across all areas of predictive toxicology and risk assessment, a bottom-up approach to start with existing APIs and then harmonize them and bring them collectively to higher levels by integrating richer scientific annotation (semantic interoperability layer) was adopted in contrast to a top-down approach, where the API specification is defined by the consortium first and then all services have to be changed to comply to this specification.

Abstract:
This report documents the Demonstrator for the Deliverable 2.3, describing the deployment of virtual infrastructure and applications making up the OpenRiskNet Virtual Research Environment (VRE). It outlines the system analysis, deployment fundamentals, service discovery, and a list of the currently available services. The production reference instance is deployed on the Swedish Science Cloud (SSC), and end user access is available at https://home.prod.openrisknet.org.

Abstract:
This report describes the dissemination and training activities undertaken by the OpenRiskNet partners in the first half of the project. These activities were gathered formally within WP3 (Training, Support and Dissemination) but they cover aspects related to all WPs. Details and links to the various activities developed in the first half of the project were included, e.g. organisation of workshops, training events and hackathons, participation at conferences and workshops, peer-review publications, tutorials, public communication activities, the project website and visual identity development as well as the interactions initiated with other EU initiatives. The main dissemination activities related to OpenRiskNet are summarised on the project website at: https://openrisknet.org/library/. The report, follows the agreed Plan for the Exploitation and Dissemination of Results (PEDR).

Abstract:
This Deliverable describes the computational infrastructure, frameworks and systems for the development and testing of the Virtual Research Environments, APIs and data and software integration of the OpenRiskNet project. Development tools selected for source code control, issue tracking, continuous integration and deployment, and containerization and container orchestration are discussed and guideline for service development are outlined. Finally the current development environment is described and its operation is demonstrated with a simple example.