Predictive Toxicology Applications CMTPI 2009 Conference, Istanbul - PowerPoint PPT Presentation

Collaborative Development of Predictive Toxicology Applications CMTPI 2009 Conference, Istanbul Barry Hardy Douglas Connect OpenTox Project Coordinator

Introduction – Collaboration and Community So now I have explained ed our game, e, how does your urs work? From Conservation Project Trip in Caprivi Delta

Acknowledgements – Co-workers and Co-Authors Fabian Buchwald Tatyana Gloriozova Barry Hardy Jörg Wicker Sergey Novikov Nicki Douglas Andreas Karwath Natalia Skvortsova Christoph Helma Martin Gütlein Sunil Chawla Michael Rautenberg Andreas Maunz Steve Bowlus Nina Jeliazkova Haralambos Sarimveis Indira Ghosh Vedrin Jeliazkov Georgia Melagraki Surajit Ray Luben Boyanov Antreas Afantitis Gaurav Singhai Chelsea Jiang Pantelis Sopasakis Om Prakash Martin Martinov David Gallagher Sylvia Escher Romualdo Benigni Vladimir Poroikov Sara Weiss Olga Tcheremenskaia Dmitry Filimonov Stefan Kramer Alexey Zakharov Tobias Girschick Alexey Lagunin

Acknowledgements – OpenTox Partners Douglas Connect, Albert Ludwigs University Switzerland In Silico Toxicology, Freiburg, Germany Switzerland Ideaconsult, National Technical Bulgaria University of Athens, Greece Istituto Superiore di Sanità,Italy Fraunhofer Institute for Toxicology & Experimental Medicine, Technical University Germany of Munich, Germany David Gallagher, UK Institute of Biomedical Seascape Learning, Chemistry of the Russian India Academy of Medical Sciences, Russia

OpenTox Advisory Board  European Centre for the  LHASA Validation of Alternative Methods  Leadscope  European Chemicals Bureau  University of North Carolina  U.S Environmental Protection  EC Environment Directorate Agency General  U.S. Food & Drug Administration  Organisation for Economic  Nestlé Cooperation & Development  Roche  CADASTER  AstraZeneca  Bayer Healthcare

Presentation Outline  Introduction  User Requirements  The OpenTox Framework  Ontologies  Algorithms  Validation and Reporting  Community and Collaboration  Building Collaborations  Discussion and Conclusions

Introduction - REACH

Introduction – REACH registration Import/manufacturing of not less than 1 ton ECHA / Member countries European chemical substance • Document-based evaluation Registration Evaluation Chemical • Properties • Material evaluation • Confirmed use Agency • Safe management Registration Registration Materials that need to be regulated Non-Action Demand of additional Materials with very Unacceptable materials information high hazard potential with very high hazards Authorisation Limitations Use prohibited • Review of need for control of hazards • Consideration of alternative materials Authorisation Approval

Introduction – REACH, QSAR and 3Rs ECB study showed new regulations will require an estimated 3.9 million additional test animals if no alternative methods are accepted Same study pointed to possible reduction by using existing experimental data in conjunction with QSAR Largest number of test animals will be required for chronic and reproductive toxicity, mutagenicity, carcinogenicity endpoints because no alternative in vitro assays currently available

Introduction – Goal of reduced animal testing Visit with Lions at Mukuni Project, Livingstone, Zambia

Introduction – Taking a look at the Challenges It was 3 days ago he had his last meal!? Visit with Lions at Mukuni Project, Livingstone, Zambia

Introduction – Challenges to in silico Applications • Toxicity data collected in many • There is no straightforward different databases using different integration of predictions from formats, frequently incompatible with various programs QSAR programs • No commonly accepted framework for • Many databases lack important validation of QSAR predictions, many information for QSAR modeling (e.g. QSAR tools provide limited support for chemical structures) reliable validation procedures • Hard to integrate confidential in- • Application, interpretation, and house data with public data for model development of QSAR models is still building and validation difficult for most toxicological experts • QSAR models have been published in a variety of different formats (ranging • It requires a considerable amount of from simple regression based statistical, cheminformatics and equations to full-fledged computer computer science expertise - programs) procedures are labor intensive and prone to human errors

Introduction – OpenTox Goals • Toxicity data • QSAR models Framework • Validation support • Interpretation aids • Toxicologists • QSAR Modelers Unified Access • API for new QSAR algorithm development & integration • To optimise impact • To allow inspection / review Open Source • To attract external contributors

Introduction - About OpenTox • EC FP7 Funded - started September 2008 • Initial research has defined: – essential components for framework architecture – approach to data access, schema and management – use of controlled vocabularies and ontologies – web service and communications protocols – selection & integration of predictive modeling algorithms – interface specifications • Analyses of use cases ongoing

Introduction - OpenTox Work Packages WP1: Framework Design WP2: Framework Implementation WP3: Toxicity Databases WP4: QSAR Algorithms WP5: QSAR Validation WP6: Dissemination WP7: Management

User Requirements – Use Cases  OpenTox needs to be very flexible to meet individual needs  A use case driven development & testing approach  Cases may be submitted through opentox.org website for evaluation for inclusion in development planning  3 hierarchical classes of Use Cases: 1. Collaboration / Project Level eg 3-month development project 2. Application Level eg carry out a REACH-compliant risk assessment for group of chemicals 3. Task Level eg. Given an endpoint – and a dataset for a chemical structure category for that endpoint – develop and store a predictive model resource for a chemical space

OpenTox Use Case – given a structure, predict endpoints Input Structure Out – Toxic or Not? LD50   Liver Toxicity Secondary Metabolites  Interaction with the hERG Channel?   Renal Clearance Bioavailability  Mutagenicity   Carcogenicity ReproductiveToxicology   Skin Irritation Aqua Toxicity  Combined predictions for arrays of  mutiple end points Virtual Patient Populations 

OpenTox Use Case – given a structure, predict endpoints OpenTox Clean up, conversion to The structure is data resources are 3D, valences saturated checked for chemical searched for with hydrogen atoms, correctness and chemical id number partially optimized with number of molecules or structure molecular mechanics An image of the molecule is displayed, with the results of structure check and clean-up. If A check on the chemical serious problems with the structure are found, correctness is made the user is asked if they want to continue, or if (bond distances, appropriate, the process is terminated charges, valences, etc.) automatically with an error message.

OpenTox Use Case – given a structure, predict endpoints If experimental results for the molecule are found in the database, then the following is printed "Experimental data for this structure is available in the OpenTox database and is summarized here:" All necessary descriptors are calculated, results of regression obtained, and chemical similarity to calibration molecules The prediction report is provided evaluated. including the details of the basis for model prediction and including statistical reporting on the reliability of the prediction

OpenTox Use Case – given a structure, predict endpoints

OpenTox Framework - definition  OpenTox is a platform-independent collection of components that interact via well defined language-independent interfaces  The preferred form of communication between components is through web services (REST)  OpenTox is an Open Source project  OpenTox is committed to the support and further development of Open Standards and ontologies

OpenTox Framework - Standards Minimum Information Standards Toxicity Data for Biological Experiments en.wikipedia.org/wiki/Minimum_Informat • DSSTox www.epa.gov/ncct/dsstox/ ion_Standards) • ToxML www.leadscope.com/toxml.php • Minimum Information for Biological and • PubChem pubchem.ncbi.nlm.nih.gov/ Biomedical Investigations (MIBBI) www.mibbi.org • OECD Harmonised Templates www.oecd.org/document/13/0,3343,en_ • Functional Genomics Experiment (FuGE) 2649_34365_36206733_1_1_1_1,00.html fuge.sourceforge.net/ • IUCLID5 templates • MAGE www.mged.org/index.html, iuclid.eu/ • MIAPE www.psidev.info/index.php?q=node/91 • Predictive Model Markup Language (PMML) www.dmg.org/pmml-v3-0.html