Unifying ontology services for functional genomic annotations
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The document provides information about the Experimental Factor Ontology (EFO). EFO models experimental factors from genomic studies stored in the ArrayExpress archive, including species, diseases, and cell lines. It captures about 30% of terms not already in the UMLS. EFO uses reference ontologies and automatic mapping to import synonyms and definitions. Regression testing verifies ontology changes. EFO has a web interface and content negotiation support, and defines experimental factor hierarchies used in the Gene Expression Atlas to aggregate experiments.
![Step 2: definitions and synonyms are pulled in
from reference ontologies via NCBO BioPortal
S acute lymphoblastic leukemia
http://www.ebi.ac.uk/efo/EFO_0000220
T
E xref:
xref:
SNOMEDCT:91857003 translate IDs
P DOID:9952
xref:
xref:
NCIt:C3167
1 NCIt:C3167
synonym:
Acute lymphoid leukaemia, disease
definition:
S Leukemia with an acute onset [...] fetch
T bioportal_provenance:
E Acute Lymphocytic Leukaemia
[accessedResource: NCIt:C3167]
P [accessDate: 05-04-2011]
bioportal_provenance:
2 Leukemia with an acute onset [...]
+ provenance
[accessedResource: NCIt:C3167]
[accessDate: 05-04-2011]
10](https://image.slidesharecdn.com/2011brownbagtomaszfgattheebiv6ssh-111212130423-phpapp02/85/Unifying-ontology-services-for-functional-genomic-annotations-10-320.jpg)
![Step 3: regression testing package produces a
report for manual verification of the import
• 13 different tests
• Shared xrefs, e.g. NCIt:C17459 (Hispanic or Latino)
• Hispanic (EFO_0003169)
• Latino (EFO_0003166)
• Shared synonyms, e.g. head kidney (ZFA:0000669)
• pronephros (EFO_0000927)
• bone marrow (EFO_0000868)
• Changes in external sources (11/2010 vs. 5/2010):
• synonym Spinocerebellar Ataxias (EFO_0002624) no longer in
DOID:1441
• definition Organ with organ cavity which connects the cavity of the
urinary bladder to the exterior. […] (EFO_0000931) no longer in
FMAID:1966
11](https://image.slidesharecdn.com/2011brownbagtomaszfgattheebiv6ssh-111212130423-phpapp02/85/Unifying-ontology-services-for-functional-genomic-annotations-11-320.jpg)
![The Semantic Web provides a common framework that allows data to
be shared and reused across application, enterprise, and community
boundaries (W3C)
If you want to put something on the web there are three rules:
1. All kinds of conceptual things, they have names now that start with
HTTP.
2. If I take one of these HTTP names and I look it up [...] I fetch the
data using the HTTP protocol from the web, I will get back some
data in a standard format
3. It's got relationships [..] the other thing that it's related to is given
one of those names that starts HTTP. So, I can go ahead and look
that thing up.
Sir Tim Berners-Lee on the next Web (TED2009)
15](https://image.slidesharecdn.com/2011brownbagtomaszfgattheebiv6ssh-111212130423-phpapp02/85/Unifying-ontology-services-for-functional-genomic-annotations-15-320.jpg)
![Acknowledgments
• Morris A. Swertz’s group at the Genomics Coordination Center (GCC),
University of Groningen
This work was supported by the European
• K Joeri van der Velde
Community's Seventh Framework
• Despoina Antonakaki Programmes GEN2PHEN [grant number
• Dasha Zhernakova 200754], SLING [grant number 226073], and
SYBARIS [grant number 242220], the
• James Malone European Molecular Biology Laboratory, the
• Helen Parkinson Netherlands Organisation for Scientific
Research [NWO/Rubicon grant number
• FuzzyRecogniser: Emma Hastings 825.09.008], and the Netherlands
• Niran Abeygunawardena Bioinformatics Centre [BioAssist/Biobanking
platform and BioRange grant SP1.2.3]
• Ele Holloway
• Tim Rayner OntoCAT logo courtesy of Eamonn Maguire
• Zooma: Tony Burdett
• Bioconductor/R package: Natalja Kurbatova, Pavel Kurnosov, Misha
Kapushesky
Special thanks go to NCBO BioPortal and
EBI OLS support teams for all the
comprehensive help they provide
44](https://image.slidesharecdn.com/2011brownbagtomaszfgattheebiv6ssh-111212130423-phpapp02/85/Unifying-ontology-services-for-functional-genomic-annotations-44-320.jpg)
Unifying ontology services for functional genomic annotations
- 1. Unifying ontology services for functional genomic annotations Tomasz Adamusiak MD PhD 7omasz Postdoc at LHC CgSB since 10/2011 1 EBI is an Outstation of the European Molecular Biology Laboratory.
- 2. The European Molecular Biology Laboratory, a “European NIH” for molecular biology Heidelberg Hamburg Hinxton Basic research in Structural biology Bioinformatics molecular biology Administration Grenoble Monterotondo EMBO • 1500 staff • >60 nationalities Structural biology Mouse biology 2 2
- 3. EMBL-EBI external funding • Sources of external funding as of December 2010 And no taxes! 3 3
- 4. Focus on providing database services to bioinformatics community Literature and ontologies CiteXplore, GO Genomes Ensembl Ensembl Genomes Protein families, EGA motifs and domains Functional InterPro Nucleotide sequence genomics ENA ArrayExpress Expression Atlas Macromolecular EFO PDBe Protein activity IntAct , PRIDE Pathways Reactome Protein Sequences UniProt Chemical entities Systems ChEBI BioModels BioSamples Chemogenomics ChEMBL 4
- 5. ArrayExpress is the 2nd largest resource for public transcriptomics data (CIBEX < AE < GEO) ‘blood cancer’ ‘hematological neoplasm’ ‘haematological neoplasm’ Archive ‘lymphoma/leukemia’ EFO: lymphoid neoplasm Atlas ‘leukaemia’ ‘haematological cancer’ 25k exps 2.6k exps EFO 5
- 6. Experimental Factor Ontology (EFO) • Modelling experimental factors currently in Archive: species, diseases, cell lines, etc. • Capture ~30% not in UMLS • Determined by Atlas, Ensembl, external requests (Upenn) and EBI site-wide search 6
- 7. Developed a process to automatically import metadata from reference ontologies and validate changes 20000 SYNONYMS 18000 16000 Number of classes or synonyms 14000 12000 10000 8000 6000 CLASSES 4000 2000 0 Aug-08 Jan-09 Jan-10 Jan-11 Aug-11 Time 7
- 8. Step 1: xrefs are acquired by fuzzy lexical matching to domain ontologies Disease Ontology acute lymphoblastic leukemia acute lymphocytic leukemia http://www.ebi.ac.uk/efo/EFO_0000220 DOID:9952 xref: NCI Thesaurus DOID:9952 xref: Acute Lymphoblastic Leukemia NCIt:C3167 C3167 map to EFO xref: DOID:9952 potential synonymy Perl mapping scripts xref: EBI::FGPT::FuzzyRecogniser NCIt:C3167 OWL::Simple::Parser 8
- 9. Did not evaluate Norm in this context • Production requirements (Perl, OWL) • Improvement (ngrams) over legacy code • Primary use case mapping EFO against AE annotations: • 2'-deoxy-5-azacytidine to 5-aza-2'-deoxycytidine CHEBI:50131 • Barrett's Esophagus to Barrett's esophagus • Difficult to use MetaMap on non-UMLS ontologies 9
- 10. Step 2: definitions and synonyms are pulled in from reference ontologies via NCBO BioPortal S acute lymphoblastic leukemia http://www.ebi.ac.uk/efo/EFO_0000220 T E xref: xref: SNOMEDCT:91857003 translate IDs P DOID:9952 xref: xref: NCIt:C3167 1 NCIt:C3167 synonym: Acute lymphoid leukaemia, disease definition: S Leukemia with an acute onset [...] fetch T bioportal_provenance: E Acute Lymphocytic Leukaemia [accessedResource: NCIt:C3167] P [accessDate: 05-04-2011] bioportal_provenance: 2 Leukemia with an acute onset [...] + provenance [accessedResource: NCIt:C3167] [accessDate: 05-04-2011] 10
- 11. Step 3: regression testing package produces a report for manual verification of the import • 13 different tests • Shared xrefs, e.g. NCIt:C17459 (Hispanic or Latino) • Hispanic (EFO_0003169) • Latino (EFO_0003166) • Shared synonyms, e.g. head kidney (ZFA:0000669) • pronephros (EFO_0000927) • bone marrow (EFO_0000868) • Changes in external sources (11/2010 vs. 5/2010): • synonym Spinocerebellar Ataxias (EFO_0002624) no longer in DOID:1441 • definition Organ with organ cavity which connects the cavity of the urinary bladder to the exterior. […] (EFO_0000931) no longer in FMAID:1966 11
- 12. EFO has a unique XSLT-based web presence http://www.ebi.ac.uk/efo/overview 12
- 13. EFO URIs are readable by humans and computers 13
- 14. Content negotiation is an alternative approach Tuckey’s server side urlrewritefilter <rule> <condition name="Accept" type="header"> application/rdf+xml</condition> <from>^/$</from> <to type="redirect">/efo/efo.owl</to> </rule> 14
- 15. The Semantic Web provides a common framework that allows data to be shared and reused across application, enterprise, and community boundaries (W3C) If you want to put something on the web there are three rules: 1. All kinds of conceptual things, they have names now that start with HTTP. 2. If I take one of these HTTP names and I look it up [...] I fetch the data using the HTTP protocol from the web, I will get back some data in a standard format 3. It's got relationships [..] the other thing that it's related to is given one of those names that starts HTTP. So, I can go ahead and look that thing up. Sir Tim Berners-Lee on the next Web (TED2009) 15
- 16. RDF triple is the core concept underpinning the semantic web subject predicate object <http://www.example.com/index.html> <http://purl.org/dc/elements/1.1/creator> „John Smith” dc:creator example:index.html John Smith Entity Attribute Value (EAV) model with well defined semantics 16
- 17. Open linked data lacks central URI reconciliation • Responsibility for URIs: http://bio2rdf.org/mesh:68009154 http://bio2rdf.org/pubmed:11992264 http://bio2rdf.org/go:0016458 http://purl.org/obo/owl/GO#GO_0016458 • Versioning: http://sig.uw.edu/fma#Anatomical_entity (FMA 3.1) http://sig.biostr.washington.edu/fma3.0#Anatomical_entity (FMA 3.0) http://purl.obolibrary.org/obo/GO_0016458 (Foundry-compliant URI) • Requires institutional support • Would be great to have public UMLS in RDF 17
- 18. Common Ontology Application Tasks (OntoCAT) ‘blood cancer’ ‘hematological neoplasm’ ‘haematological neoplasm’ Archive ‘lymphoma/leukemia’ EFO: lymphoid neoplasm Atlas ‘leukaemia’ ‘haematological cancer’ 25k exps 2.6k exps EFO 18
- 19. There is no single ontology resource that covers all the use cases Local ontologies in OWL/OBO NCBO BioPortal EBI Ontology Lookup Service ...and no huffing and puffing will blow all of them down... Leonard Leslie Brooke (1904) 19
- 20. EBI Ontology Lookup Service • 82 ontologies • OBO ontologies • SOAP web services/Java client • First out there Cote RG, Jones P, Apweiler R, Hermjakob H.The ontology lookup service, a lightweight cross-platform tool for controlled vocabulary queries. BMC Bioinformatics. 2006 Feb 28;7(1):97 20
- 21. NCBO BioPortal • 267 ontologies and growing • Both OWL and OBO • REST web services • Rich in functionality Noy, N.F., Shah, N.H., Whetzel, P.L., Dai, B., Dorf, M., Griffith, N., Jonquet, C., Rubin, D.L., Storey, M.A., Chute, C.G., Musen, M.A.BioPortal: ontologies and integrated data resources at the click of a mouse. Nucleic Acids Res. 2009 Jul 1;37(Web Server issue):W170-3. 21
- 22. OLS vs. BioPortal (July, 2010) 22
- 23. OWL API • Reference implementation for manipulating and serialising OWL2 • Multiple parsers (incl. OBO) • Reasoner interfaces • Low level access Sean Bechhofer, Phillip Lord, Raphael Volz. Cooking the Semantic Web with the OWL API. 2nd International Semantic Web Conference, ISWC, Sanibel Island, Florida, October 2003 23
- 24. We wanted to annotate data with ontology terms within the MOLGENIS framework – ontology browser OWL API EFO Bioportal Import Ontology Browser 24
- 25. Integration is hard 25
- 26. A simple facade to ontology resources providing a set of functions most common to ontology APIs (e.g. HL7 CTS2, UMLS API) under a single interface http://www.ontocat.org BioPortal searchAll() searchOntology() getChildren() EBI OLS getParents() getSynonyms() getDefinitions() OWL getAllParents() getAllChildren() getRelations() OBO ... ? 26
- 27. There are many ways how you could use OntoCAT • Store data and annotate with ontology terms • OntoCAT database and browser • Work with ontologies in R • Bioconductor ontocat R package • Integrate a number of ontologies in a local repository • OntoCAT REST server • Add ontology support to your GWT web application • OntoCAT GoogleApp http://www.ontocat.org/wiki/OntocatDownload 27
- 28. The curious case of OntoFox, OntoBee, and OntoCAT 28
- 29. Developed for internal and external use cases Example 11@ontocat.org • Automatically obtain CUIs from UMLS sources for extracted terms via BioPortal • Shamim Mollah, Bleeding History Phenotype Ontology, Rockefeller University Center for Clinical and Translational Science, New York, NY 1. Get all terms from BHP 2. Search for corresponding UMLS terms (also MetaMap) 3. Obtain CUIs for mapped terms through BioPortal 29
- 30. ontocat R is first on Google 30
- 31. Use case – explore beyond subsumption Example 16@ontocat.org • Requested by reviewer for partonomy in GO • Easy in OBO, hard in OWL • Computationally intensive: • (starting from the root node) • 1. classify all children of inverse_relation some class • 2. repeat 1. on all new nodes • 3. finish if all nodes were seen • OWL API is not thread safe 31
- 32. Reasoning is fundamental to exploring the hierarchies of more expressive ontologies Heart Heart Component Left Heart partOf is_a Mitral Valve 32
- 33. When ontologies classify as inconsistent it is not often obvious why (Open World Assumption) • Mary is_a CitizenOfFrance Is Paul a citizen of France? Closed World, e.g. SQL databases: NO Ontologies: ? • OWL is more expressive: classes, individuals, closure axioms, value partitions, cardinality restrictions, property chains; disjoint, reflexive, irreflexive, symmetric and anti- symmetric, inverse or transitive properties • Explanation in OWL (http://owl.cs.manchester.ac.uk/explanation/) 33
- 34. The extra information is used in QC of EFO, but not in query expansion ventricular subClassOf cardiomyopathy myocardium part_of has_disease_location myocardium atrial myocardium cardiac ventricle atrium heart atrial fibrillation Heart disease? 34
- 35. Google analytics for ontocat.org 35
- 36. OntoCAT is enterprise-grade, low-maintenance, headache-free, zero-configuration software • Java6, maven and ant support • Open source (LGPL v3) • 137 unit tests • Hudson daily builds Tests passed • Flexibility through design patterns: • Decorators • Proxies • Composites Daily builds 36
- 37. Semantic Web Atlas of Gene Expression ‘blood cancer’ ‘hematological neoplasm’ ‘haematological neoplasm’ Archive ‘lymphoma/leukemia’ EFO: lymphoid neoplasm Atlas ‘leukaemia’ ‘haematological cancer’ 25k exps 2.6k exps EFO 37
- 38. EFO inferred is_a hierarchy defines how experiments are aggregated in Atlas for re-analysis http://www.ebi.ac.uk/gxa 38
- 39. It is possible to infer diseases of heart computationally rather than asserting this information directly ventricular subClassOf cardiomyopathy myocardium part_of has_disease_location myocardium atrial myocardium cardiac ventricle atrium heart atrial fibrillation has_disease_location ∃ (heart ∪ part_of ∃ heart) heart disease ≡ 39
- 40. One RDF graph per experiment accession Context-specific gene expression is grouped with blank nodes experiment accession Predicates Homo sapiens efo:EFO_0004033 rdf:type rdf:type liver organism OBI_0100026 E-AFMX-1 gxa:E-AFMX-1 is_about IAO_0000136 NONDE gene EFO_0002606 experimental factor EFO_0000001 1.0E30 discretized differential EFO_0004034 expression p value OBI_0000175 PRDX2 ensembl:ENSG00000167815 gene efo:EFO_0002606 W3C Note on RDF Approach to Gene Expression Data (in progress) 40 Semantic Web for Health Care and Life Sciences Interest Group, BioRDF task force
- 41. One RDF graph per experiment accession Context-specific gene expression is grouped with blank nodes experiment accession Predicates Homo sapiens efo:EFO_0004033 rdf:type rdf:type liver organism OBI_0100026 E-AFMX-1 gxa:E-AFMX-1 is_about IAO_0000136 NONDE gene EFO_0002606 experimental factor EFO_0000001 1.0E30 discretized differential EFO_0004034 expression p value OBI_0000175 approximately 14 PRDX2 weeks ensembl:ENSG00000167815 NONDE gene efo:EFO_0002606 1.0E30 W3C Note on RDF Approach to Gene Expression Data (in progress) 41 Semantic Web for Health Care and Life Sciences Interest Group, BioRDF task force
- 42. Sesame triplestore provided the shortest Time-to-Market REST + XSLT = RDF WAR RDF Jun Zhao @ Oxford tc-test-3 tomcat-7 tomcat-8 Load Balancer Jena TDB Milarq wwwdev www.ebi.ac.uk www.open- 42 biomed.org.uk
- 43. Semantic Web is unlikely to take over the web, but has the potential to unify all of bioinformatics OntoCAT EFO Semantic Atlas http://gigaom.com/broadband/the-storage-vs-bandwidth-debate/ 43
- 44. Acknowledgments • Morris A. Swertz’s group at the Genomics Coordination Center (GCC), University of Groningen This work was supported by the European • K Joeri van der Velde Community's Seventh Framework • Despoina Antonakaki Programmes GEN2PHEN [grant number • Dasha Zhernakova 200754], SLING [grant number 226073], and SYBARIS [grant number 242220], the • James Malone European Molecular Biology Laboratory, the • Helen Parkinson Netherlands Organisation for Scientific Research [NWO/Rubicon grant number • FuzzyRecogniser: Emma Hastings 825.09.008], and the Netherlands • Niran Abeygunawardena Bioinformatics Centre [BioAssist/Biobanking platform and BioRange grant SP1.2.3] • Ele Holloway • Tim Rayner OntoCAT logo courtesy of Eamonn Maguire • Zooma: Tony Burdett • Bioconductor/R package: Natalja Kurbatova, Pavel Kurnosov, Misha Kapushesky Special thanks go to NCBO BioPortal and EBI OLS support teams for all the comprehensive help they provide 44
- 45. slides @ www.slideshare.net/adamusiak Thank you! 45 4 5