Integrated Analysis of Toxicology
Data supported by ToxBank
OpenTox Euro 2013 Meeting
Mainz, Germany
October 1, 2013
Barry...
18M
Islands
Source: Baily Ed, U.S. Fish and Wildlife Service
Goal for next year for OpenTox - Accelerating Knowledge Flow
of Industry Application and Regulatory Acceptance of New
Pred...
Knowledge-Oriented Framework
Based on Nonaka & Takeuchi, The Knowledge Creating
Company, 1995
Socialisation Externalisatio...
Knowledge Sharing
OpenTox
We are an Open Knowledge Community!
We collaborate, solve problems and create
the best solutions we can together.
...
OpenTox standards
Feature
GET
POST
PUT
DELETE
Compound
GET
POST
PUT
DELETE
Dataset
GET
POST
PUT
DELETE
Ontology
GET
POST
P...
Plug In Components that solve Problems
Adaptor Solution in Jeddah, 2008
The Building Blocks of SEURAT-1
~ 70 research groups from European Universities, Public
Research Institutes and Companies
...
Building block 1: Scr&Tox
Stem cell differentiation for providing
human-based organ specific target cells
Coordinator:
Mar...
Building block 2: HeMiBio
Development of a hepatic
microfluidic bioreactor
Coordinator:
Catherine Verfaillie
KU LEUVEN, Be...
Building block 3: DETECTIVE
Identification of biomarkers for
prediction of toxicity in humans
Coordinator:
Jürgen Heschele...
Building block 4: COSMOS
Delivery of computational tools to predict the
effects of chemicals based on in silico
calculatio...
Building block 5: NOTOX
Coordinator:
Elmar Heinzle
Universität des
Saarlandes,
Germany
website:
www. notox-sb.eu
Developme...
ToxBank Infrastructure Project
(started Jan 2011)
Establishment of a …
… dedicated web-based
data warehouse
… database of ...
Warehouse
Gold
Compounds
Database
Biobank
Users access compounds, biological materials, data and models for
experimental p...
Compound Selection
 Compound Assessment Team: Dave Bower, Matthew
Clark, Matthew Dent, Marina Goumenou, Gabrielle
Hawkswo...
Background Assumptions:
Assay Readout Examples
 Hepatocellular necrosis: release of alanine aminotransferase and
propidiu...
Consider adverse events relevant to
cosmetics
Identify drugs demonstrated to exhibit
these adverse events in humans
Add Mo...
Adverse outcome pathway (AOP) : drug-induced cholestasis
Vinken M., Landesmann B., Goumenou M., Vinken S., Shah I., Jaesch...
Compound Selection: Reference
Toxicities to Biological Pathways
Energy
Metabolism
Lipid
Metabolism
Inflammatory
Response
S...
Compound Selection and Mechanistic Testing
ToxBank Gold Compound - Doxorubicin
ToxBank Gold Compound - Doxorubicin
ToxBank Gold Compound - Doxorubicin
ToxBank Wiki Development
wiki.toxbank.net
Information resources
• Gold compound wiki*
– Information on selection criteria
– In vivo, PB-PK data, ‘omics/IC50,
physic...
Requirements
Investigator Principal Investigator
Use templates
or define new
templates
Generate and
enter data
Generate and
write proto...
ToxBank – Initial Release & Testing
Main screen
Browse search results
Upload protocols and data
Download protocols
and dat...
Use of SEURAT-configured ISAcreator to prepare datasets
SEURAT-1 information
Investigation information
Publications
Templa...
Security
Use Open Standards on Resources but with extensive Authorisation and Authentication
facilities accompanied by con...
ToxBank System for Data and Protocol Management
Searching
Uploading
protocols
and data
Uploading a protocol
35
Research Protocol vs. Standard Operating Procedure
36
Guidelines provides suggestions on
protocol outline and content
37
Protocol review
38
Protocols are indexed using a keyword hierarchy
39
Set keywords to
support searching,
browsing and linking
Use of SEURAT-configured ISAcreator to prepare datasets
Templates are available for different experiments
SEURAT-1 informa...
Use of SEURAT-configured ISAcreator to prepare datasets
Templates for different
assays
Specify experimental
factors
Use of SEURAT-configured ISAcreator to prepare datasets
Results, with links to
files containing the raw
or processed data
...
Use of SEURAT-configured ISAcreator to prepare datasets
Mapped to terms in
ontologies
Create an ISATAB zip archive for each investigation
Test results (a… files)
with links to data
table or native file
(e.g. ...
Publishing a protocol
Unique ID and
version number
Viewing the investigation record
Linking to wikis
47
wiki.toxbank.net
ToxBank Wiki Development
wiki.toxbank.net
ToxBank integrates systems biology concepts into toxicological assessment
Pekka Kohonen,[a] Emilio Benfenati,[b] David Bow...
Public Data
Analysis
Molecular function
Binding
19 genes
adjP=6.61e-01
Catalytic activity
9 genes
adjP=6.75e-01
Electron c...
onlinelibrary.wiley.com/doi/10.1002/minf.201200114/full
Web
Resources
- Open
Access
SAM ICT Architecture
CERF
Enterprise
Service Bus
Consensus Rule
Editor
CEPS
Complex Event
Pattern Service
Collaboration
Pa...
Model1
Model2
Model3
1 0 1
Model1
Model2
Model3
1 0 1
Assay1
Assay2
Assay3
- - -
Assay1
Assay2
Assay3
- - -
Recommendation...
Event-driven Weight of Evidence
Hardy and Affentranger, Drug Discovery Today.
2013 Jul;18(13-14):681-6.
ToxBank Acknowledgements
UK Stem Cell Bank,
NIBSC-HPA
Ideaconsult Ltd
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Integrated Analysis of Toxicology Data supported by ToxBank

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The SEURAT-1 (Safety Evaluation Ultimately Replacing Animal Testing-1) research cluster is comprised of seven EU FP7 Health projects and is co-financed by Cosmetics Europe. The aim is to generate a proof-of-concept to show how the latest in vitro and in silico technologies, systems toxicology and toxicogenomics can be combined to deliver a test replacement for repeated dose systemic toxicity testing on animals. The SEURAT-1 strategy is to adopt a mode-of-action framework to describe repeated dose toxicity to derive predictions of in vivo toxicity responses. ToxBank is the cross-cluster infrastructure project whose activities include the development of a data warehouse to provide a web-accessible shared repository of research data and protocols. Experiments are generating dose response data over multiple timepoints using different omics platforms including transcriptomics, proteomics, metabolomics, epigenetics over a variety of different cell lines and a common set of reference compounds. Experimental data is also being generated from functional assays and bioreactors, and supplemented with in silico approaches including kinetic information. This complex and heterogeneous data is being consolidated and harmonized through the ToxBank data warehouse. It is being organized in order to perform an integrated data analysis and ultimately predict repeated dose systemic toxicity. Core technologies used include the ISA-Tab universal data exchange format, Representational State Transfer (REST) web services, the W3C Resource Description Framework (RDF) and the OpenTox standards. We describe the design of the data warehouse based on cluster requirements and the implementation based on open standards.

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  • SEURAT-1 is a 50 Million Euro public-private partnership which started in 2011. Douglas Connect is leading the development of the infrastructure supporting all cluster activities. This includes development of data and analysis infrastructure based on OpenTox.
  • The scope of ToxBank is to establish the following resources: a data warehouse, a database of well-characterized test compounds which we call the Gold Compounds database, an actual physical repository for the selected test chemicals, and an information resource on biomaterials, namely cells and cell lines including stem cells, and tissues.We are developing the ToxBank data warehouse building on OpenTox resources and standards.The detailed scope of these different infrastructure components is mainly given by the requirements of the other projects on the program.
  • The ToxBank system vision for services delivered to the user.
  • Rules may be used to categorise and update weight of evidence supporting decision making on next steps.
  • Integrated Analysis of Toxicology Data supported by ToxBank

    1. 1. Integrated Analysis of Toxicology Data supported by ToxBank OpenTox Euro 2013 Meeting Mainz, Germany October 1, 2013 Barry.Hardy@douglasconnect.com This project is jointly funded by Cosmetics Europe and the European Commission. Any opinions expressed in these slides are those of the author. Cosmetics Europe is not liable for any use that may be made of the information contained therein.
    2. 2. 18M
    3. 3. Islands Source: Baily Ed, U.S. Fish and Wildlife Service
    4. 4. Goal for next year for OpenTox - Accelerating Knowledge Flow of Industry Application and Regulatory Acceptance of New Predictive Toxicology Methods & Testing Strategies based upon an evolving OpenTox framework based on Open Specifications
    5. 5. Knowledge-Oriented Framework Based on Nonaka & Takeuchi, The Knowledge Creating Company, 1995 Socialisation Externalisation Internalisation Combination Tacit Tacit Tacit Tacit Explicit Explicit Explicit Explicit Knowledge Sharing: Discussions Knowledge Creation from R&D: Data, Codes Learning: Apply Models Knowledege Combination: Predictive Models Acceptance
    6. 6. Knowledge Sharing
    7. 7. OpenTox We are an Open Knowledge Community! We collaborate, solve problems and create the best solutions we can together. We learn from each other. We accelerate knowledge flow and innovation.
    8. 8. OpenTox standards Feature GET POST PUT DELETE Compound GET POST PUT DELETE Dataset GET POST PUT DELETE Ontology GET POST PUT DELETE Algorithm GET POST PUT DELETE Model GET POST PUT DELETE AppDomain GET POST PUT DELETE Validation GET POST PUT DELETE Report GET POST PUT DELETE www.opentox.org/dev/apis/api-1.2 Working Group formed to update for end of March 2014. You are invited to join and participate.
    9. 9. Plug In Components that solve Problems Adaptor Solution in Jeddah, 2008
    10. 10. The Building Blocks of SEURAT-1 ~ 70 research groups from European Universities, Public Research Institutes and Companies (more than 30% SMEs) www.seurat-1.eu This project is jointly funded by Cosmetics Europe and the EC. Any opinions expressed in this slide are those of the author. Cosmetics Europe is not liable for any use that may be made of the information contained therein.
    11. 11. Building block 1: Scr&Tox Stem cell differentiation for providing human-based organ specific target cells Coordinator: Marc Peschanski INSERM/i-STEM France website: www.scrtox.eu The cell factory
    12. 12. Building block 2: HeMiBio Development of a hepatic microfluidic bioreactor Coordinator: Catherine Verfaillie KU LEUVEN, Belgium website: www.hemibio.eu The in vitro liver
    13. 13. Building block 3: DETECTIVE Identification of biomarkers for prediction of toxicity in humans Coordinator: Jürgen Hescheler Klinikum der Universität Köln, Germany website: Biomarkers and functional assays PC 1 #15.3 % PC2# 12.4% Day 0 Day 7- EBs Day 7- Thalidomide Td Day 7- Cytarabine Td Day 14 - EBs Day 14- Thalidomide Td Day 14- Cytarabine Td
    14. 14. Building block 4: COSMOS Delivery of computational tools to predict the effects of chemicals based on in silico calculations and estimation techniques Coordinator: Mark Cronin Liverpool John Moores University, UK website: www.cosmos-tox.eu In silico toxicology
    15. 15. Building block 5: NOTOX Coordinator: Elmar Heinzle Universität des Saarlandes, Germany website: www. notox-sb.eu Development of systems biological tools for organotypic human cell cultures Bioreactor Thinking in systems
    16. 16. ToxBank Infrastructure Project (started Jan 2011) Establishment of a … … dedicated web-based data warehouse … database of reference test compounds … repository for the selected test compounds … cell and tissue banking information resource This project is jointly funded by Cosmetics Europe and the EC. Any opinions expressed in this slide are those of the author. Cosmetics Europe is not liable for any use that may be made of the information contained therein. www.toxbank.net
    17. 17. Warehouse Gold Compounds Database Biobank Users access compounds, biological materials, data and models for experimental planning and integrated analysis of experimental results Data Models SOPs Compounds SOPs Biological Materials Our Infrastructure Vision for ToxBank supporting all steps of Predictive Toxicology Research based on Alternative Testing methods This project is jointly funded by Cosmetics Europe and the EC. Any opinions expressed in this slide are those of the author. Cosmetics Europe is not liable for any use that may be made of the information contained therein. Data Models RES www.toxbank.net
    18. 18. Compound Selection  Compound Assessment Team: Dave Bower, Matthew Clark, Matthew Dent, Marina Goumenou, Gabrielle Hawksworth, Nina Jeliazkova, Brigitte Landesmann, Silvia Maggioni, Andrew White, Egon Willighagen, Jeffrey Wiseman  Gold Compound Working Group: Roman Affentranger, Gordana Apic, Emilio Benfenati, Ian Cotgreave, Barry Hardy, Jan Hengstler, Susanne Bremer-Hoffmann, Paul Jennings, Giovanna Lazzari, Inge Mangelsdorf, Filomain Nguemo, Foozia Noor, Agapios Sachinidis, Michael Schwarz, Leo van Grunsven, Mathieu Vinken, Manfred Watzele, Jose-Manuel Zaldivar
    19. 19. Background Assumptions: Assay Readout Examples  Hepatocellular necrosis: release of alanine aminotransferase and propidium iodide uptake without apoptosis  Apoptosis: NF-κB/p53, caspase-3 activation , and Hoechst/annexin staining  Inhibition of transporters, e.g. members of the ABC cassette transporter class  Intra-hepatic cholestatis  Steatosis and phospholipidosis: staining  Hepatocyte function: urea synthesis, glycogen storage, albumin secretion, fibrinogen secretion, P450 transformation capacity  Mitochondrial function: adenosine triphosphate (ATP) and membrane potential  Oxidative stress: glutathione (GSH) levels & lipid peroxidation
    20. 20. Consider adverse events relevant to cosmetics Identify drugs demonstrated to exhibit these adverse events in humans Add Mode of Action (MoA) standards with simpler profiles mapped against key events within Adverse Outcome Pathways (AOPs) Add non-reactive analogues where needed Mapping Mechanism to Pathway
    21. 21. Adverse outcome pathway (AOP) : drug-induced cholestasis Vinken M., Landesmann B., Goumenou M., Vinken S., Shah I., Jaeschke H., Willett C., Whelan M., Rogiers V. (2013) Development of an adverse outcome pathway from drug-mediated bile salt export pump inhibition to cholestatic liver injury. Archives of Toxicology: submitted .
    22. 22. Compound Selection: Reference Toxicities to Biological Pathways Energy Metabolism Lipid Metabolism Inflammatory Response Steatosis Cholestasis Necrosis / Apoptosis Fibrosis Regeneration (Phospho- lipidosis)
    23. 23. Compound Selection and Mechanistic Testing
    24. 24. ToxBank Gold Compound - Doxorubicin
    25. 25. ToxBank Gold Compound - Doxorubicin
    26. 26. ToxBank Gold Compound - Doxorubicin
    27. 27. ToxBank Wiki Development wiki.toxbank.net
    28. 28. Information resources • Gold compound wiki* – Information on selection criteria – In vivo, PB-PK data, ‘omics/IC50, physical data and sources – Discussion forum • Biomaterials wiki – Information on cells (stem cells, hES/iPS-derived cells, primary cells), reagents (e.g. antibodies, growth factors) and suppliers – Discussion forum * See published Open Access materials at wiki.toxbank.net
    29. 29. Requirements
    30. 30. Investigator Principal Investigator Use templates or define new templates Generate and enter data Generate and write protocol Review protocol Upload/update and assign: - summary info - access level - keywords Send email alert Investigator Register interest Investigator Investigator Search for information Access protocols and data Request access to confidential information Bilateral agreement Phase 2: Integrated data analysis Other sources Phase 1: Unified data access Review data Comment Outline of the ToxBank Data Warehouse
    31. 31. ToxBank – Initial Release & Testing Main screen Browse search results Upload protocols and data Download protocols and data Preparing data
    32. 32. Use of SEURAT-configured ISAcreator to prepare datasets SEURAT-1 information Investigation information Publications Templates for different assays Specify experimental factors Materials and results, with links to files containing the raw or processed data Each step linked to a SEURAT-1 protocol Terms mapped to ontologies
    33. 33. Security Use Open Standards on Resources but with extensive Authorisation and Authentication facilities accompanied by confidential data policies. e.g. Validation against Confidential Data Case implemented Spring 2011
    34. 34. ToxBank System for Data and Protocol Management Searching Uploading protocols and data
    35. 35. Uploading a protocol 35
    36. 36. Research Protocol vs. Standard Operating Procedure 36
    37. 37. Guidelines provides suggestions on protocol outline and content 37
    38. 38. Protocol review 38
    39. 39. Protocols are indexed using a keyword hierarchy 39 Set keywords to support searching, browsing and linking
    40. 40. Use of SEURAT-configured ISAcreator to prepare datasets Templates are available for different experiments SEURAT-1 information Investigation information Publications
    41. 41. Use of SEURAT-configured ISAcreator to prepare datasets Templates for different assays Specify experimental factors
    42. 42. Use of SEURAT-configured ISAcreator to prepare datasets Results, with links to files containing the raw or processed data Results, with each step linked to a SEURAT-1 protocol
    43. 43. Use of SEURAT-configured ISAcreator to prepare datasets Mapped to terms in ontologies
    44. 44. Create an ISATAB zip archive for each investigation Test results (a… files) with links to data table or native file (e.g. CEL files) Overall investigation design and information (i… files) Study description (s… files)
    45. 45. Publishing a protocol Unique ID and version number
    46. 46. Viewing the investigation record
    47. 47. Linking to wikis 47 wiki.toxbank.net
    48. 48. ToxBank Wiki Development wiki.toxbank.net
    49. 49. ToxBank integrates systems biology concepts into toxicological assessment Pekka Kohonen,[a] Emilio Benfenati,[b] David Bower,[c] Rebecca Ceder,[a] Michael Crump,[c] Kevin Cross,[c] Roland C. Grafstrçm,[a] Lyn Healy,[d] Christoph Helma,[e] Nina Jeliazkova,[f] Vedrin Jeliazkov,[f] Silvia Maggioni,[b] Scott Miller,[c] Glenn Myatt,[c] Michael Rautenberg,[e] Glyn Stacey,[d] Egon Willighagen,[a] Jeff Wiseman,[g] and Barry Hardy*[h]; [a]Karolinska Institutet, Institute for Environmental Medicine, Molecular Toxicology,Stockholm, Sweden; [b], Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy; [c] Leadscope, Columbus, USA; [d] National Institute for Biological Standards and Control, Potters Bar, UK; [e]In silico toxicology, Basel, Switzerland; [f]Ideaconsult, Sofia, Bulgaria; [g]Pharmatrope,Wayne, USA; [h]Douglas Connect, Zeiningen, Switzerland. Figure 1. Multiple tools will be, step by step, implemented into an innovative toxicity testing strategy based on mode-of-action. Figure 2. Clustering of ToxBank Gold Compounds by biological similarity using chemical-genome links from Comparative Toxicogenomics Database (CTD). Compounds with similar Mode-of-Action cluster together. Systems toxicology - principles Understanding the toxicological interactions in biological systems under compound challenges Based on developments in high-throughput biology  ‘Omics profiling: gene expression, proteins, metabolites and others  cell-based screening: High-Throughput and High-Content analyses Risk assessment carried out primarily using  in vitro  In silico methods Conclusions - great potential to contribute to toxicity evaluation based on Mode-of-Action decreased need for animal experiments ToxBank builds databases and data management solutions to aid in systems toxicology-based risk assessment Clustering by Gene Clustering by Gene Ontology BA Figure 3. A) Enriched gene ontology (GO) categories of genes associated with the oxidizing agent mode-of-action (MOA) B) Protein-protein association network around the Asah1 protein Associated with phospholipid binding MOA. Kohonen P. et al. The ToxBank Data Warehouse: Supporting the Replacement of In Vivo Repeated Dose Systemic Toxicity Testing. Molecular Informatics. 17 JAN 2013, DOI: 10.1002/minf.201200114.
    50. 50. Public Data Analysis Molecular function Binding 19 genes adjP=6.61e-01 Catalytic activity 9 genes adjP=6.75e-01 Electron carrier activity 3 genes adjP=1.75e-02 Transporter activity Nucleoside binding 3 genes adjP=6.75e-01 Nucleotide binding Protein binding 12 genes adjP=6.75e-01 Oxidoreductase activity 5 genes adjP=1.75e-02 Transmembrane transporter activity 3 genes adjP=6.61e-01 Phospholipid Binding Oxidative Agent Clustering by Gene Ontology associations from CTD* *CTD = Comparative Toxicogenomics Database (www.ctd.org) Kohonen P. et al. The ToxBank Data Warehouse: Supporting the Replacement of In Vivo Repeated Dose Systemic Toxicity Testing. Mol. Inf.17 JAN 2013.
    51. 51. onlinelibrary.wiley.com/doi/10.1002/minf.201200114/full Web Resources - Open Access
    52. 52. SAM ICT Architecture CERF Enterprise Service Bus Consensus Rule Editor CEPS Complex Event Pattern Service Collaboration Pattern Assistant Data, Protocols, Results Data Data Events Consensus Rule Outcome Collaboration Pattern Suggestions • There is a data conflict. • Method A is not providing accurate predictions. • New information is available. • etc. • Hold a meeting! • Discuss a new strategy! • Contact partner Y! Data is exchanged as ontology-based messages SAM partners generate data/protocols using external tools and platforms (e.g. OpenTox) Data Hardy and Affentranger, Drug Discovery Today. 2013 Jul;18(13-14):681-6.
    53. 53. Model1 Model2 Model3 1 0 1 Model1 Model2 Model3 1 0 1 Assay1 Assay2 Assay3 - - - Assay1 Assay2 Assay3 - - - Recommendation Rules: 0 0 1 0 1 1 1 0 0 1 0 1 1 1 0 0 1 0 Hit, high confidence Not a hit, high confidence Inconclusive results, further study needed Synergy OpenTox 1 1 1 0 0 0 Event Driven Weight of Evidence Consensus Rule Editor
    54. 54. Event-driven Weight of Evidence Hardy and Affentranger, Drug Discovery Today. 2013 Jul;18(13-14):681-6.
    55. 55. ToxBank Acknowledgements UK Stem Cell Bank, NIBSC-HPA Ideaconsult Ltd

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