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OpenTox - An Open Source Predictive Toxicology Framework

Periodic Report Summary - OPENTOX (An open source predictive toxicology framework)

Project context and objectives:

The OPENTOX project which was funded under the European Commission (EC)'s Seventh Framework Programme (FP7) (www.opentox.org) developed an open source-based predictive toxicology framework. OPENTOX supportes the creation of computer software applications and databases which provide information on the toxic properties of molecules. These applications may be used for example to design safer drug candidates, to assess the impact of a chemical on the environment, or to support industry in their risk assessment of products in the interests of the health and safety of consumers.

OPENTOX developed tools for the integration of data, for the generation of computer models for toxic effects, and scientifically sound algorithms, validation and reporting routines. The resulting OPENTOX framework of software components, interfaces and standards supports the development of applications for non-computational specialists in addition to interfaces for risk assessors, toxicological experts and model and algorithm developers. The construction of OPENTOX applications are based on Organisation for Economic Cooperation and Development (OECD) validation principles, satisfying REACH legislation guidance and user requirements, and the additional design principles of interoperability, flexibility, transparency and extensibility. OPENTOX applications are based on a set of distributed, interoperable, extensible OPENTOX web services, hence creating a semantic web for toxicology. The OPENTOX approach to ontology allows for efficient mapping of data coming from different datasets into a unifying structure having a shared terminology and meaning.

OPENTOX reached a major milestone in Spring 2010 with the development of its first two prototype applications ToxPedict (www.toxpredict.org) and ToxCreate (www.toxcreate.org). Additional application developments in the third year of the project have included the development of the Bioclipse workbench-OPENTOX integration, regulatory reporting editors, a visualisation tool, and a workflow integration. These applications have demonstrated that a variety of graphical user interfaces may build upon the OPENTOX foundation of resources to provide a diverse set of experiences to users through user-friendly interfaces and environments. In 2011 an OPENTOX virtual machine was developed which allows the user to download and install a virtual machine on their computer where OPENTOX applications can be run in a local environment. Online tutorials have also been created supporting usage of the applications on an ongoing basis.

Underlying these developments is the creation of a new standard: the OPENTOX Application programming interface (API), which is an important output of the research project (www.opentox.org/dev/apis/). It provides a specification against which development may continue by both OPENTOX partners and the broader development community. As the latest version of the API (1.2) supports authorisation and authentication, such infrastructure can support the integrated use of both open and commercial resources. Policies for controlled access to resources can also be implemented which supports user access to resources based on licences, data sharing agreements and legal contracts. As OPENTOX creates a semantic web for toxicology, it should be an ideal framework for incorporating scientific ontology developments, thus supporting both a mechanistic framework for toxicology in addition to best practices in statistical analysis, a knowledge infrastructure combination that the scientific field will surely profit from.

The evaluation of OPENTOX by numerous users provided a clear response that the project has produced valuable and concrete results. The majority of final evaluations produced answers in the excellent and very good categories, providing a sound endorsement by the user community that we have created something valuable and worthwhile from the project. OPENTOX should therefore be seen as a special success story the EC has supported through its research programme, thus enabling scientists, industry and regulators to better protect the safety of our society and its environment.

Project results:

The EC-funded OPENTOX project (www.opentox.org) developed an open source-based predictive toxicology framework. OPENTOX supports the creation of computer software applications and databases which provide information on the toxic properties of molecules. These applications may be used for example to design safer drug candidates, to assess the impact of a chemical on the environment, or to support industry in their risk assessment of products in the interests of the health and safety of consumers.

A significant testing and evaluation was carried out on OPENTOX in the final year of the project. The evaluation included assessment of OPENTOX from the following points of view a) framework, b) standards, c) ontology, d) data resources, e) services, and f) applications.

OPENTOX reached a major milestone in Spring 2010 with the development of its first two prototype applications ToxPedict (www.toxpredict.org) and ToxCreate (www.toxcreate.org) which were successfully demonstrated live at a workshop ahead of the first AXLR8 meeting in Potsdam. ToxPredict predicts and reports on toxicities for endpoints for a user-provided input chemical structure, while ToxCreate builds and validates a predictive toxicity model based on a user-provided input toxicology dataset. These applications had continued to be improved and were successfully used in the final hands-on OPENTOX workshop in Munich in August 2011 where they received overall very positive evaluations by a variety of users.

Additional application developments in the third year of the project have included the development of the Bioclipse workbench-OPENTOX integration, the Quantitative structure-activity relationship (QSAR) prediction reporting format (QPRF) reporting editor Q-Edit, the CheS-Mapper visualisation tool, and the Taverna workflow integration. These applications have demonstrated that a variety of Graphical User Interfaces may build upon the OPENTOX foundation of resources to provide a diverse set of experiences to users through user-friendly interfaces and environments, significantly increasing the user community for OPENTOX. The Bioclipse and Taverna integrations are particularly significant as they demonstrate the successful integration of OPENTOX with two other major platforms, thus accelerating the capabilities and value creation of OPENTOX. These developments all build and take advantage of the significant investment in the design of the framework and its open standards carried out during the research project.

In 2011 an OPENTOX virtual machine was developed. This allows the user to download and install a virtual machine on their computer where OPENTOX applications can be run in a local environment. Hence although OPENTOX supports a distributed set of resources, it may also be collapsed to run as a local stand-alone application. We brought the virtual machine software to SETAC Africa and successfully installed it on approximately 40 laptops of workshop participants.

OPENTOX developments were disseminated and evaluated through a number of means, ranging from internal testing and evaluation by non-developers within the OPENTOX project, to provision of online tutorials and exercises on the OPENTOX website, to a hands-on workshop involving nine exercises carried out in the final month of the project, which was subsequently made available online for further evaluation, and to dissemination at a variety of international conferences.

Internal testing and evaluation supported the development of a number of OPENTOX resources, services and applications so that they reached the stage of prototypes that could be provided to users to carry out exercises in a workshop setting or on their own. Underlying these is the OPENTOX API, which is an important output of the FP7 research project (www.opentox.org/dev/apis/) It provides a specification against which development may continue by both OPENTOX partners and the broader development community. In addition to further development of existing resources and applications, new ones may be created compliant with the specifications, thus supporting a growing set of interoperable linked resources for the field of toxicology. As the specification is an open standard it may also continue to develop and improve. As the latest version of the API (1.2) supports authorisation and authentication, such infrastructure can support the integrated use of both open and commercial resources. Policies for controlled access to resources can also be implemented which support user access to resources based on licences, data sharing agreements and legal contracts. The use of OPENTOX API-compliant web services to communicate instructions between linked resources supports the use of a wide variety of commands to carry out operations such as data integration, algorithm use, model building and validation. OPENTOX thus provides a powerful interoperable programming language to database and application developers.

The OPENTOX ontology development made good progress in the project and included development of an ontology to support endpoints and organ effects, and the capability to convert from the existing ToxML data standard into a semantic web format. From the OpenTox-EBI toxicology ontology workshop held in November 2010 resulted a perspective review and a toxicology ontology roadmap that provides guidance to the field. As OPENTOX creates a semantic web for toxicology, it should be an ideal framework for incorporating such future ontology developments, thus supporting both a mechanistic framework for toxicology in addition to best practices in statistical analysis, a combination that the field will surely profit from.

A number of (Q)SAR models were built with OPENTOX for a number of REACH endpoints (carcinogenicity, mutagenicity, aquatic / fish toxicity, LogP). Several of these models were made available with validation reports through the ToxPredict application. We propose a 'challenge' should be organised in which the community could develop different models using OPENTOX services applied to different REACH endpoints.

The OPENTOX 2011 conference in Munich, held at the end of the FP7 project in August 2011, attracted a diverse and knowledgeable audience including many principle investigators in the field, working in different areas. Hence, the group of approximately 80 scientists was strongly cross-disciplinary, cross-sector and international. With this backdrop we also ran a final workshop in which nine different OPENTOX exercises and applications were run by participants in groups in a hands-on format. The evaluation of OPENTOX by these users provided a clear response that the project has produced very valuable and concrete results. Moreover, although still at the prototyping stage, many users were able to carry out activities with applications of significant scientific interest, including activities that had not been previously possible for them. The majority of evaluation answers to our questions produced answers in the excellent and very good categories, providing a sound endorsement by the user community that we have created something really valuable and worthwhile from the project. OPENTOX should therefore be seen as a special success story the European Commission has supported through its research programme.

The OPENTOX framework currently includes, with its APIs, services for compounds, datasets, features, algorithms, models, ontologies, tasks, validation, and reporting, and authentication and authorisation, which may be combined into multiple applications satisfying a variety of different user needs. The guiding principles in the construction of OPENTOX applications are based on the OECD principles of (Q)SAR validation, satisfying REACH legislation guidance and user requirements, and the additional design principles of interoperability, flexibility, transparency and extensibility. OPENTOX applications are based on a set of distributed, interoperable, extensible OPENTOX API-compliant web services. The OPENTOX approach to ontology allows for efficient mapping of similar and / or complementary data coming from different datasets into a unifying structure having a shared terminology and meaning.

Potential impact:

OPENTOX is relevant for the implementation of the REACH legislation as it potentially allows risk assessors to access experimental data, (Q)SAR models and toxicological information from a unified interface. The software adheres to European and international regulatory requirements including OECD guidelines for validation and reporting, and emerging guidelines from the European Chemicals Agency (EChA) and European Joint Research Centre (JRC). OPENTOX was initiated as a collaborative project involving a combination of different enterprise, university and government research groups to design and build the initial framework. Additionally, numerous organisations with industry, regulatory or expert interests were included from the start in providing guidance and direction.