1. MGED Ontology: An Ontology of Biomaterial Descriptions for Microarrays Microarray Data Analysis and Management: Bio-ontologies for Microarrays EMBL-EBI, Hinxton, Cambridge, UK Dec. 5, 2001 Chris Stoeckert, U. Penn

2. Ontology Usage for Genes in EpoDB EpoDB is a prototype system of genes expressed during erythropoiesis Built before microarrays were readily available Illustrate usage of an ontology of gene parts and controlled vocabularies of gene (and gene family) names

3. EpoDB “Gene Ontology”

4. http://www.cbil.upenn.edu/EpoDB Stoeckert, Salas, Brunk, Overton (1999) Nucl. Acids Res. 26:288

5. EpoDB Gene Landmark Query

6. What is an ontology? (In the computer science not philosophy sense) An ontology is a specification of concepts that includes the relationships between those concepts. Removes ambiguity. Provides semantics and constraints. Allows for computational inferences and reliable comparisons

7. Types of Ontologies Taxonomy –Tree structure. IS-A hierachy –Variants - Gene Ontology (DAG) Frame-based (object-oriented) –Classes and attributes –EcoCyc Description logic (DL) –Reasoning about concept (class) relationships –Combine terms with constraints (sanctioning) –GRAIL (GALEN, TAMBIS) Ontology Inference Layer (OIL) –Combines Frames and DLs –Uses Web standards XML and RDF

8. Taxonomy Terms for common usage –Homo sapiens, not human, not homo sapeins –NCBI ID = 9606 Hierarchy provides unambiguous levels of equivalence –Homo sapiens and Mus musculus are of the class Mammalia but Drosophila melanogaster is not. Can use taxonomic hierarchies for other types of information –e.g., Human Developmental Anatomy (U. of Edinburgh)

9. Microarray Information to be Captured Figure from: David J. Duggan et al. (1999) Expression Profiling using cDNA microarrays. Nature Genetics 21: 10-14

10. Tables Describing Samples in RAD (RNA Abundance Database) Experiment ExpGroupsGroups RelExperiments Exp.ControlGenes ControlGenes Hybridization Conditions Label Sample TreatmentDisease Devel. Stage ExperimentSample Taxon Anatomy

11. CBIL Anatomy Hierarchy

12. Anatomy Table Used by RAD

13. Usage of Anatomy Hierarchy to Query RAD

14. Standardisation of Microarray Data and Annotations -MGED Group The MGED group is a grass roots movement initially established at the Microarray Gene Expression Database meeting MGED 1 (14-15 November, 1999, Cambridge, UK). The goal of the group is to facilitate the adoption of standards for DNA-array experiment annotation and data representation, as well as the introduction of standard experimental controls and data normalisation methods. Members are from around the world in academia, government, and industry. http://www.mged.org

15. MGED Working Groups Annotation: Experiment description and data representation standards (Alvis Brazma, EMBL- EBI) Format: Microarray data XML exchange format (Paul Spellman, UC Berkeley) Ontology: Ontologies for sample description (Chris Stoeckert, U Penn) Normalization: Normalization, quality control and cross-platform comparison (Gavin Sherlock, Stanford U)

16. MGED Documents Annotation -> Minimal Information About a Microarray Experiment (MIAME) –What should go into a microarray database –Brazma et al. Nature Genetics 29:365-371, 2001 Format -> Microarray Gene Expression (MAGE) Object Model and XML DTD –How microarray databases will talk to each other

17. Relationship of MGED Efforts MAGE MIAME DB MIAME DB External Ontologies/CVs MGED Ontology  Annotation  Format  Ontologies  External  Internal Ontologies provide common terms and their definitions for describing microarray experiments.

18. MGED Ontology Working Group Goals 1.Identify concepts 2.Collect available controlled vocabularies and ontologies for concepts 3.Define concepts 4.Formalize concept relationships

19. http://www.cbil.upenn.edu/Ontology/

20. Species Resources

22. Concept Definitions

24. MGED Ontology Working Group Goals 1.Identify concepts 2.Collect available controlled vocabularies and ontologies for concepts 3.Define concepts 4.Formalize concept relationships

25. Usage of Concepts and Resources for Microarrays MIAME glossary –Provide definitions for types of information (concepts) listed in MIAME MIAME qualifier, value, source –Provide pointers to relevant sources that can be used to

26. sample source and treatment ID as used in section 1 organism (NCBI taxonomy) additional "qualifier, value, source" list; the list includes: cell source and type (if derived from primary sources (s)) sex age growth conditions development stage organism part (tissue) animal/plant strain or line genetic variation (e.g., gene knockout, transgenic variation) individual individual genetic characteristics (e.g., disease alleles, polymorphisms) disease state or normal target cell type cell line and source (if applicable) in vivo treatments (organism or individual treatments) in vitro treatments (cell culture conditions) treatment type (e.g., small molecule, heat shock, cold shock, food deprivation) compound is additional clinical information available (link) separation technique (e.g., none, trimming, microdissection, FACS) laboratory protocol for sample treatment MIAME Section on Sample Source and Treatment

27. Excerpts from a Sample Description courtesy of M. Hoffman, S. Schmidtke, Lion BioSciences Organism: mus musculus [ NCBI taxonomy browser ] Cell source: in-house bred mice (contact: norma.howells@itg.fzk.de) Sex: female [ MGED ] Age: 3 - 4 weeks after birth [ MGED ] Growth conditions: normal controlled environment 20 - 22 o C average temperature housed in cages according to German and EU legislation specified pathogen free conditions (SPF) 14 hours light cycle 10 hours dark cycle Developmental stage: stage 28 (juvenile (young) mice) [ GXD "Mouse Anatomical Dictionary" ] Organism part: thymus [ GXD "Mouse Anatomical Dictionary" ] Strain or line: C57BL/6 [International Committee on Standardized Genetic Nomenclature for Mice] Genetic Variation: Inbr (J) 150. Origin: substrains 6 and 10 were separated prior to 1937. This substrain is now probably the most widely used of all inbred strains. Substrain 6 and 10 differ at the H9, Igh2 and Lv loci. Maint. by J,N, Ola. [International Committee on Standardized Genetic Nomenclature for Mice ] Treatment: in vivo [MGED] intraperitoneal injection of Dexamethasone into mice, 10 microgram per 25 g bodyweight of the mouse Compound: drug [MGED] synthetic glucocorticoid Dexamethasone, dissolved in PBS

28. MGED Ontology Working Group Goals 1.Identify concepts 2.Collect available controlled vocabularies and ontologies for concepts 3.Define concepts 4.Formalize concept relationships

29. MGED Biomaterial Ontology Under construction –Using OILed (Not wedded to any one tool) –Generate multiple formats: RDFS, DAML+OIL Define classes, provide relations and constraints, identify instances Motivated by MIAME and coordinated with MAGE

30. MAGE BioMaterial Model

31. Building a Microarray Ontology http://www.cbil.upenn.edu/Ontology/Build_Ontology2.html

32. Ontology Available as RDFS

33. Ontology in Browseable Form

34. Example of Internal Terms

35. Example of External Terms

36. Example of Combined Internal and External: Treatment

37. OWG Use Cases Return a summary of all experiments that use a specified type of biosource. –Use “age” to select and order experiments –Use Mouse Anatomical Dictionary Stage 28 to pick experiments according to “organism part” Return a summary of all experiments done examining effects of a specified treatment –E.g., Look for “CompoundBasedTreatment”, “in vivo” –Select “Compound” based on CAS registry number –Order based on “CompoundMeasurement” Build gene networks based on biomaterial description –Generate a distance metric based on biosource and use in calculation of correlation with gene expression level –Generate an error estimation based on biosample (i.e., even when biosources are identical, there will be variation resulting from different treatments)

38. Ontology Working Group Highlights First pass ontology of biomaterial descriptions Participated in Bio-ontologies Consortium Meeting at ISMB 2001. Mail list of about 200 subscribers

39. Ontology Working Group Plans Finish building biomaterial description ontology Expand efforts to include remaining parts of a microarray experiment Demonstrate usage to the microarray community

40. Acknowledgements Past and present members of CBIL for their work on EpoDB and RAD The members of the MGED Ontology Working Group for their contributions The Bio-Ontologies Consortium for encouragement and guidance This presentation is available at http://www.cbil.upenn.edu/Ontology/MGEDOntology1201.ppt