ToxicogenOMICS Omics standards, resources and data at EBI

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ToxicogenOMICSOmics standards, resources and
data at EBI
Susanna-Assunta Sansone Nutr/Toxicogenomics
Projects Coordinator

• EMBL EBI
• The European Bioinformatics Institute
• Cambridge,UK
• 5th Virtual Conference on Genomics and
  Bioinformatics (2005)

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Talk Structure

• Setting the scene
• EMBL-EBI
• - Activities and tox-relevant collaborations
• Data communication standards
• Standardization initiatives
• - A review
• Standards-compliant implementation _at_ EBI
• ArrayExpress infrastructure
• - Array-based toxicogenomics resources and data

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European Molecular Biology Laboratory

• Status
• Non-profit, academic
• International network
• Research institutes
• Services (EBI)
• Funds
• EU member statesIsrael
• EU, UK, NIH Grants
• Collaborations

Heidelberg
Grenoble
Hamburg
Monterotondo
Cambridge UK
EBI
Service
Research
Training
Industry
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Services _at_ EBI
Cambridge UK
EBI
Service
Research
Training
Industry
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Industry Programme _at_ EBI

• Support large companies and SMEs
• Including pharma, biotech and software vendors
• Provide training and education
• Contribute to open data communication standards
• Defining submission and publication requirements
• Optimizing database/software interoperability
• Ensuring data quality and integrity

Cambridge UK
EBI
Service
Research
Training
Industry
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Toxicogenomics - Collaborations

• Standard-compatible infrastructure, data
  exchange
• NCTR-FDA Center for Toxicoinformatics
• NIEHS National Center for Toxicogenomics (NCT)
• Netherlands Toxicogenomics Center (NTC)
• UK Natural Environmental Research Council (NERC)
  Data Center
• Data reposition, software development
• ILSI-HESI Toxicogenomics Committee
• European Nutrigenomics Organization (NuGO)
• Quality metrics, confidence measures
• UK Measurement for Biotechnology (MfB)
  tox-project

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The European Scenario

• The 7th Amendment to the Cosmetics Directive
• REACH Chemical Policy
• 3 Rs (refine, reduce and replace animals)

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The European Scenario

• The 7th Amendment to the Cosmetics Directive
• REACH Chemical Policy
• 3 Rs (refine, reduce and replace animals)

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Toxicogenomics - Potentials

• Improving methods to assess toxicity
• Gain insight into the molecular mechanisms
• Reduce the length of long-term toxicology study
• Limit the numbers of animals used
• Holding promises for
• Drug/biologics discovery and development
• - Target selection, risk assessment and quality
  control
• Chemical/drug-induced disease processes
• - Evaluation and prediction
• Medical practice
• - Diagnostic, therapeutic decisions and
  monitoring
• Regulatory science
• - Support and facilitate the decision-making
  process

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Toxicogenomics - Challenges

• Technical validation
• Reproducibility, specificity, sensitivity and
  accuracy
• QA, QC and SOPs
• International gold standards
• -gt Data comparability
• Scientific validation
• Biological/toxicological relevance of the
  findings
• -gt Signatures, biomarkers and mechanism of
  actions
• Data communication
• Data management
• Data review
• -gt Expertise acquisition

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Communicating Omics Data

• Unlock the value in the data
• Large in volume, data and metadata
• Heterogeneous in data types
• Incompatible in formats
• Standards are required
• Content -gt Minimal descriptors
• - Report the same core essentials
• Semantic -gt Controlled vocabularies or ontology
• - Use the same word and mean the same thing
• Storage -gt Database models
• - Optimize data queries and mining
• Exchange -gt Common formats
• - Enable interoperability and data integration

12
Talk Structure

• Setting the scene
• EMBL-EBI
• - Activities and tox-relevant collaborations
• Data communication standards
• Standardization initiatives
• - A review
• Standards-compliant implementation _at_ EBI
• ArrayExpress infrastructure
• - Array-based toxicogenomics resources and data

13
Standardization Initiatives

• Open efforts
• Community vetted
• Vendor neutral
• Multidisciplinary
• Data management
• Different driving forces
• Data submission to regulatory bodies
• Data exchange/deposition to databases
• Categories
• Regulatory driven discussion (broader
  understanding)
• World-wide organizations (agreed
  recommendations)
• Measurements and methods validation focus
• Omics technology communities

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Standardization Initiatives

• SEND Consortium (Standard for Exchange of
  NonClinical Data)
• v1.6 model, flat file format to report animal
  toxicity study
• SEND CDISC Study Data Tabulation Model
  (SDTM)
• -gt Electronic, toxicity data submission to FDA
• Pharmacogenomics Standards Group (CDISC, HL7 and
  I3C)
• Clinical pharmacology, Clinical genomics and
  Pre-clinical/non-clinical genomics
• Minimal descriptors, data content and format
• -gt Requirements for pharmacogenomics data
  submission to FDA
• DSSTox (US EPA) (Distributed Structure-
  Searchable Toxicity)
• Database network project
• Standard Chemical Fields and Structure Data
  Format
• -gt Standard, structure-annotated chemical
  toxicity data

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Standardization Initiatives

• NAS (National Academy of Science)
• Committee on Emerging Issues and Data on
  Environmental Contaminants
• Expert workshops and recommendations
• -gt Application of genomics in risk assessment
• ECVAM (ICCVAM / NICEATM)
• (European Center for the Validation of
  Alternative Methods )
• Expert workshops and recommendations
• Toxicogenomics Task Force
• -gt Validation of array-based toxicogenomics test
  methods
• OECD / IPCS (Organization for Economical
  Cooperation and Development / International
  Program for Chemical Safety)
• Internationally agreed instruments, decisions
  and recommendations 
• Expert workshops and recommendations
• -gt Toxicogenomics methods in chemical assessment

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Transcriptomics DomainMicroarray Gene
Expression Data(MGED) Since 1999
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MGED Society
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MIAME - Reporting Structure
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MAGE-ML - Exchange Format
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MGED Ontology - Semantics
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RSBI - Outreach
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Proteomics DomainHuman Proteome
Organization(HUPO) Proteomics Standard
Initiative (PSI)Since 2001
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PSI Group
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PSI MI - Exchange Format
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PSI MS - Exchange Format
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PSI GPS - General Proteomics

• Standards for integrated representation of
  methods and data from proteomics experiments
• Minimum Information About a Proteomics
  Experiment (MIAPE)
• Technology-specific modules associated with a
  parent document
• Extensive review process (ongoing)
• XML formats for data exchange and submission
• Ontology for unambiguously worded metadata/data
  files
• Include terms for mzData format

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Metabolomics DomainMetabolomics SocietySince
.few months ago!
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The SMRS Group - Reporting
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The Metabolomics Society - Journal
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Removing political barriers
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A MGED/PSI-like stamp of authority
                                       
 
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Synergy - Obstacles?

• ILSI HESI Toxicogenomics Genomics Committee
• Multi-stakeholders consortium (Industry,
  Regulators, Academia, Government)
• Data Exchange and Evaluation sub-Committee
• -gt Promote synergy Coordination and mediation
  (??!!)

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Functional Genomics Context

• Standardization activities in omics technologies
• Reporting structures, object models and
  CVs/ontology
• Pieces of the functional genomics puzzle
• Standards should stand alone
• Standards should also function together
• - Build it in a modular way
• - Maximize interactions
• Benefits
• Facilitate integration of omics data
• - Experimentalists, data miners, reviewers
• Optimize development of tools (time and costs)
• - Manufactures and vendors covering in multiple
  technologies

                                       
 
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Functional Genomics Context
Community-specific efforts (e.g. toxicology,
nutrition, environment)
Biology
Generic features
-gt Design of investigations -gt Sample descriptors
Technology
Significantly affect structure and content of
each standards
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Functional Genomics Standards

• Functional Genomics Experiment (FuGE) OM, XML
  and API
• Generic classes to fit any type of experiment
• - Does NOT replace, but underpins different
  formats
• Open effort, driven by MGED and PSI developers
• - Use cases supplied by the MGED RSBI WGs (Tox,
  Nutr, Env)
• Functional Genomics Ontology (FuGO) in OWL
• Core descriptors to support computational
  analysis of datasets
• - Common to any type of functional genomics
  experiment
• Open effort, driven by MGED and PSI developers
• Engaging with metabolomics groups
• - Use cases supplied by the MGED RSBI WGs (Tox,
  Nutr, Env)

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Talk Structure

• Setting the scene
• EMBL-EBI
• - Activities and tox-relevant collaborations
• Data communication standards
• Standardization initiatives
• - A review
• Standards-compliant implementation _at_ EBI
• ArrayExpress infrastructure
• - Array-based toxicogenomics resources and data

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ArrayExpress Tox-Infrastructure
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ArrayExpress - Content
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ArrayExpress - Main Tox Datasets

• ILSI-HESI, EHP Mar 2004
• Genotoxicity E-TOXM-1-9 408 hybs
• Nephrotoxicity E-TOXM-10-12 218 hybs
• Hepatotoxicity E-TOXM-13-14 247 hybs
• Syngenta CTL, EHP Nov 2004
• Estrogens E-AFMX-12-13 61 hybs (Affy
  MG_U74Av2)
• Procter Gamble , Tox Science, 2004
• Estrogen receptor (ER) agonists E-TABM-12 118
  hybs (Affy RG_U34A / RAE230A)
• Dutch National Institute for Public Health, EHP
  May 2004
• Hexachlorobenzene E-TOXM-15 96 hybs (Affy
  RG_U34A)
• Bayer, Tox Science, 2004
• Hepatotoxicants E-TOXM-16 137 hybs (Affy
  RG_U34A)
• Foreseen from our direct collaborators
• Netherland Toxicogenomics Center, NuGO (nutr),
  NERC (ecotox)

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Querying Data - 3 Interfaces
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Querying Data -1- Repository
QUERY THE WAREHOUSE Simple
Tox-MIAMExpress (MySQL)
www
2
QUERY THE REPOSITORY
www
1
QUERY THE WAREHOUSE Complex

• Retrieve elements
• of the submission(s)
• Experiment descriptions
• Data
• Array descriptions
• Protocols

HTML
www
3
Expression Profiler
Other Databases _at_ EBI Genomics -gt EnsEMBL,
GO Proteins -gt UniProt Chemicals -gt ChEBI
www.ebi.ac.uk/arrayexpress
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Querying Data -1- Repository
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Querying Data -1- Repository

• Current functionalities
• - Data Selection
• - Data Transformation
• - Missing Value Imputation
• - Hierarchical Clustering K-groups Clustering
• - Clustering Comparison
• - Signature Algorithm
• - Sequence Homology
• - SPEXS Promoter Discovery
• - Visual Pattern Matching
• - Ordination (COA, PCA)
• - Between Group Analysis
• - Three-way Similarity Analysis
• - GO Annotation
• - Statistical methods (in R)
• -gt T-Test, Bonferroni and Hochberg
  corrections
• Analytical Methods (under development)
• - Text-based data mining

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Querying Data -2- Warehouse
QUERY THE WAREHOUSE Simple
Tox-MIAMExpress (MySQL)
www
2
QUERY THE REPOSITORY

• Perform gene-centric queries
• Gene descriptors
• Protein IDs

www
1
QUERY THE WAREHOUSE Complex

• Retrieve elements
• of the submission(s)
• Experiment descriptions
• Data
• Array descriptions
• Protocols

HTML
www
3
Expression Profiler
Other Databases _at_ EBI Genomics -gt EnsEMBL,
GO Proteins -gt UniProt Chemicals -gt ChEBI
www.ebi.ac.uk/arrayexpress
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Querying Data -2- Warehouse
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Querying Data -3- Warehouse
QUERY THE WAREHOUSE Simple
Tox-MIAMExpress (MySQL)
www
2
QUERY THE REPOSITORY

• Perform gene-centric queries
• Gene descriptors
• Protein IDs

www
1
QUERY THE WAREHOUSE Complex

• Retrieve elements
• of the submission(s)
• Experiment descriptions
• Data
• Array descriptions
• Protocols

HTML
www
3
Expression Profiler

• Combined queries
• Submissions elements vs
• Expression values vs
• Tox endpoints data

Other Databases _at_ EBI Genomics -gt EnsEMBL,
GO Proteins -gt UniProt Chemicals -gt ChEBI
www.ebi.ac.uk/arrayexpress
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Querying Data -3- Warehouse
Prototype interface not final!
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Querying Data -3- Warehouse
Prototype interface not final!
Show me gene expression values
for Bayer samples with
plasma glucose gt 10 mM/L and
bilirubins(s) total gt 4 uM/L
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Acknowledgements and Resources

• Toxicogenomics/Nutrigenomics Project, in
  particular
• Philippe Rocca-Serra
• Sergio Contrino
• ArrayExpress Group -lead by Alvis Brazma- in
  particular
• Ugis Sarkans
• Misha Kapushesky
• Funding
• EU projects
• BBSRC
• ILSI-HESI
• NIEHS-NCT

                                       
 
www.ebi.ac.uk/microarray/Projects/tox-nutri