The Immune Epitope Database - Representing Experiments Using the Ontology of Biomedical
Investigations
Bjoern Peters, La Jolla Institute for
Allergy and Immunology10/21/2011, UCSD
Presentation Overview
1. The Ontology of Biomedical Investigations (OBI)
2. The Immune Epitope Database (IEDB) 3. Representing IEDB experiments using OBI4. Flow cytometry in OBI
OBI – a user driven project
• 19 communities that recognized they were trying to solve the same / related problems
• Members typically have one or more applications that drive OBI development
• 6 year effort, 1+ phone calls per week, 1-2 meetings per year
• first stable release (Philly / 1.0) in Oct. 2009 Open project with constant addition of new
communities, please consider joining!
High level class hierarchy (partial)
OBI – Recent Development
• eagle-i project has/is integrating large vocabulary of research resources into OBI
• Evidence Ontology (ECO) codes are being mapped 1:1 to OBI classes to allow ‘round-tripping’ between simple codes (‘direct assay evidence’) and expressive OWL
• Finalization of OBI-core:– Subset of OBI with extra promises for stability and quality– Education tool for both users (where to look) and
developers (where to add stuff)
OBI inner core• planned process – investigation– study design execution– acquisition– specimen collection– human subject enrollment– material transformation– assay– data transformation– documenting
• information content entity– document– study design– hypothesis textual entity– protocol– independent variable specification– dependent variable specification– measurement datum– data item– conclusion textual entity
• dependent continuant– measure function– investigation agent role– study subject role– specimen role
• material entity– device– population– specimen
OBI outer core• biological_process from the Gene Ontology (GO)• cell from the Cell Ontology (CL)• cellular_component from the Gene Ontology (GO)• environmental material from the Environment Ontology (EnVO)• geographical location from Gazetteer• gross anatomical part from the Common Anatomy Reference Ontology (CARO)• Homo sapiens from the National Center for Biotechnology Information Taxonomy
(NCBITaxon)• measurement unit label, included to connect to the Ontology of Units of Measurement (UO)• molecular entity from Chemical Entities of Biological Interest (ChEBI)• organism, included to connect to the
National Center for Biotechnology Information Taxonomy (NCBITaxon)• quality, included to connect to the Phenotypic Quality Ontology (PATO)The following two terms are not in OBI yet:• disease course from the Ontology for General Medical Science (OGMS)• molecular_function from the Gene Ontology (GO)
Presentation Overview
1. The Ontology of Biomedical Investigations (OBI)
2. The Immune Epitope Database (IEDB) 3. Representing IEDB experiments using OBI4. Flow cytometry in OBI
Immune Epitope Definition
An immune epitope is a part of a moleculethat is directly recognized by
adaptive immune receptors, specifically by antibodies, B cell receptors, or T cell receptors
Mouse
Virus
APC
CD8+ T cell epitopes in viral infection
MHC-I
APC
MHC-I
T Cytokine Release
Cytotoxicity
TT
Proliferation
Mouse
Virus TCR CD8
ORF 1 M G Q I V T M F E A L P H I I D E V I N I V I I V L I V I T G I K A V Y N ...
ORF 2 M G L K G P D I Y K G V Y Q F K S V E F D M S H L N L T M P N A C S A N N ...
ORF 3 M H N F C N L T S A F N K K T F D H T L M S I V S S L H L S I D G N S N Y ...
ORF 4 M S A Q S Q C R T F R G R V L D M F R T A F G G K Y M R S G W G W T G S D ...
ORF 5 M H C T Y A G P F G M S R I L L S Q E K T K F F T R R L A G T F T W T L S ...
ORF 6 M K C F G N T A V A K C N V N H D A E F C D M L R L I D Y N K A A L S K F ...
ORF 7 M L M R N H L L D L M G V P Y C N Y S K F W Y L E H A K T G E T S V P K C ...
ORF 8 M N M I T E M L R K D Y I K R Q G S T P L A L M D L L M F S T S A Y L V S ...
ORF 9 M S L S K E V K S F Q W T Q A L R R E L Q S F T S D V K A A V I K D A T N ...
T cell epitope mapping
ORF 1 M G Q I V T M F E A L P H I I D E V I N I V I I V L I V I T G I K A V Y N ...
ORF 2 M G L K G P D I Y K G V Y Q F K S V E F D M S H L N L T M P N A C S A N N ...
ORF 3 M H N F C N L T S A F N K K T F D H T L M S I V S S L H L S I D G N S N Y ...
ORF 4 M S A Q S Q C R T F R G R V L D M F R T A F G G K Y M R S G W G W T G S D ...
ORF 5 M H C T Y A G P F G M S R I L L S Q E K T K F F T R R L A G T F T W T L S ...
ORF 6 M K C F G N T A V A K C N V N H D A E F C D M L R L I D Y N K A A L S K F ...
ORF 7 M L M R N H L L D L M G V P Y C N Y S K F W Y L E H A K T G E T S V P K C ...
ORF 8 M N M I T E M L R K D Y I K R Q G S T P L A L M D L L M F S T S A Y L V S ...
ORF 9 M S L S K E V K S F Q W T Q A L R R E L Q S F T S D V K A A V I K D A T N ...
T cell epitope mapping
CD8+ T cell epitopes in viral infection
Goals of the Immune Epitope Database and Analysis Resource (IEDB)
• To catalog, organize and make accessible immune epitope related information– B and T cell epitopes, MHC binding, MHC ligand elution– Scope: infectious diseases, allergy, autoimmunity ,
transplantation. (HIV LANL database; no cancer)• Develop new methods to predict and model immune
responses ( IEDB Analysis Resource)
www.iedb.org
Name 74AChemical Type Peptide/ProteinSequence CLTEYILWVDomain / Region Defined EpitopeSpecies Vaccinia virus AnkaraStrain Ankara (MVA)Antigen putative 21.7k proteinAntigen Accession 2772819Antigen Positions 79-87Immunized Species Homo sapiensImmunogen Type Source SpeciesAdministration ScarificationAntigen Type EpitopeAssay Type ELISPOTResponse Measured Cytokine Release-IFN-gMHC Allele HLA-A*0201
Epitope
Structure
Source
Context
Immunization
Assay
IEDBwww.iedb.org
Literature curationEpitope discovery contract submission
Populating the IEDBPart III: Data representationPart II: Document
categorization
Literature Curation Status
Category#Relevant
articlesPercent
completedInfectious disease 10,260 99.5%Allergy 1,639 99.1%Autoimmunity 5,160 99.1%Transplant 977 99.3%Total 18,036 99.3%
>99% in all categories since 2011
IEDB applications
Meta-Analyses
Prediction tool development
Presentation Overview
1. The Ontology of Biomedical Investigations (OBI)
2. The Immune Epitope Database (IEDB) 3. Representing IEDB experiments using OBI4. Flow cytometry in OBI
Using OBI to represent experiments in the IEDB
epitope mapping experiments
T
APC
T Cell Response
T B
B Cell Response
journal article
reference (document)
B cell response
has part
High level database structure
is about
T cell response
author submission
epitope structure(material
entity)
peptide
discontinuous protein residues
carbohydrate
epitope source
(material entity)
organism
protein
protein complex
immune recognition
assay (process) MHC binding
has participant
Natural Infection
Administered Immunization
immunization (process)
preceded by
Replacing IEDB controlled vocabularies with OBI classes
• Benefits:– Increase consistency in data curation– Avoid duplicates– Improve documentation to external users– Enhance search capabilities
Original approach: controlled vocabularies• Used existing external ontologies as source where possible
(none available for epitope specific T cell assays) • Maintain list of assays; if a publication uses an assay that is
different, add to this list 140 T cell assays• Challenges :
– Ensure curators pick the right assays– Communicate to external users what each assay is– Avoid introducing duplicates (“MCP-1 IFA” = “CCL-2 histostain”)
• In addition we want to – Search for groups of related assays– Interoperability (lots of it)
Create an OBI class for each entry in our list of assay types
OBI hierarchy
Assay definition: A planned process with the objective to produce information about an evaluant
OWL (partial):has_specified_input some (material_entity and (has_role some 'evaluant role'))
has_specified_output some ('information content entity' and ('is about' some (continuant and (has_role some 'evaluant role'))))
T cell epitope assay design pattern• Majority of assays could be defined with N&S conditions after
specifying two variables: <parent assay type> and has_specified_output some 'measurement datum‘ and 'is about' some (<GO process Y> and 'process is result of' some 'MHC:epitope complex binding to TCR')
• For example: “IL-17 ELISPOT” in the IEDB is logically defined as= 'ELISPOT assay‘ and has_specified_output some
'measurement datum‘ and 'is about' some (‘IL-17 production’ and process is result of' some 'MHC:epitope complex binding to TCR')
• Required expanding parent assay types (OBI) and GO process
Adding parent assay types to OBI• label: cytometric bead array assay• definition: An assay in which a series of beads coated with
antibodies specific for different analytes and marked with discrete fluorescent labels are used to simultaneously capture and quantitate soluble analytes using flow cytometric analysis.
• alternative term: multiplexed bead assay, CBA assay• example of usage: Using a Luminex machine to detect IFN-
gamma and IL-10 in the supernatant of a cell culture “Parent” assay definitions are discussed in OBI as a group and
derived by consensus, to ensure exactness and ability to re-use. Child terms that follow design patterns are added without
group discussion
Modifying external ontologies• Requests for new / modified terms are made through their
respective trackers (sometimes additional prodding is needed)
• Often results in email discussions that clarify issues and result in improved definitions (but take time)
• Succeeded with GO, ChEBI, PRO, OGMS, IDO, PATO, UO, …• Resulting terms are imported into OBI to reference them in
logical definitions (Using MIREOT mechanism)
• Some terms have no ‘natural home ontology’, and are kept in OBI until they can be moved
Mapping IEDB assay types to OBI classesIEDB Assay ID
OBI ID rdfs:label is about biological process (epitope specific T cell response)
assay type (technique)
198 OBI_0000891 assay of epitope specific T cell proliferation epitope specific T cell proliferation assay52 OBI_0001194 ELISPOT assay of epitope specific transforming
growth factor-beta production by T cellsepitope specific transforming growth factor-beta production by T cells
ELISPOT assay
61 OBI_0001196 cytometric bead array assay of epitope specific IP-10 production by T cells
epitope specific IP-10 production by T cells cytometric bead array assay
62 OBI_0001198 assay of epitope specific interleukin-27 production by T cells
epitope specific interleukin-27 production by T cells
assay
64 OBI_0001203 detection of specific nucleic acids with complementary probes of epitope specific transforming growth factor-beta production by T cells
epitope specific transforming growth factor-beta production by T cells
detection of specific nucleic acids with complementary probes
65 OBI_0001206 ELISPOT assay of epitope specific granulocyte macrophage colony-stimulating factor production by T cells
epitope specific granulocyte macrophage colony-stimulating factor production by T cells
ELISPOT assay
66 OBI_0001209 assay of epitope specific interleukin-10 production by T cells
epitope specific interleukin-10 production by T cells
assay
84 OBI_0001210 cytometric bead array assay of epitope specific transforming growth factor-beta production by T cells
epitope specific transforming growth factor-beta production by T cells
cytometric bead array assay
143 OBI_0001215 intracellular cytokine staining assay of epitope specific cytotoxic T cell degranulation
epitope specific cytotoxic T cell degranulation intracellular cytokine staining assay
153 OBI_0001216 cell culture analyte detection bioassay of epitope specific interleukin-2 production by T cells
epitope specific interleukin-2 production by T cells
cell culture analyte detection bioassay
154 OBI_0001217 assay of epitope specific interleukin-22 production by T cells
epitope specific interleukin-22 production by T cells
assay
171 OBI_0001218 assay of epitope specific interleukin-8 production by T cells
epitope specific interleukin-8 production by T cells
assay
174 OBI_0001220 cell culture analyte detection bioassay of epitope specific interleukin-10 production by T cells
epitope specific interleukin-10 production by T cells
cell culture analyte detection bioassay
194 OBI_0001222 ELISA of epitope specific RANTES production by T cells
epitope specific RANTES production by T cells
ELISA
196 OBI_0001223 cytometric bead array assay of epitope specific interleukin-1 beta production by T cells
epitope specific interleukin-1 beta production by T cells
cytometric bead array assay
224 OBI_0001227 ELISPOT assay of epitope specific interleukin-6 production by T cells
epitope specific interleukin-6 production by T cells
ELISPOT assay
254 OBI_0001228 assay of epitope specific T cell enhancement of B cell mediated immune response
epitope specific T cell enhancement of B cell mediated immune response
assay
Spreadsheet based template
Benefits of using OBI classes for IEDB assay types internally
• Formal definitions of assay types serve as curation rules• Issues arising in curation are reflected 1:1 by issues in
writing definitions• Linking to GO identified duplicate assay types
(introduced in the IEDB controlled vocabulary as a result of changes in nomenclature over time)
The same could have been achieved by carefully writing definitions for our controlled vocabulary terms, but ontologies can do more…
Reasoning introduces hierarchy
Display with community specific“IEDB alternative label”
Assay type ID [Primary Key]
Assay type name
Ontology ID[could be more than just OBI]
1 IFN-g ELISPOT http://purl.obolibrary.org/obo/OBI_00014142 Survival http://purl.obolibrary.org/obo/OBI_00013343 IL-10 FACS http://purl.obolibrary.org/obo/OBI_00004144 DTH http://purl.obolibrary.org/obo/OBI_0002114 … … …
Benefits of using OBI for external users
Required (minimal) modification of the assay type table
This allowed us to use OBI
Ontology driven search interface
• Search for groups of related assays• Search using synonyms•Use IEDB specific labels
Future work
• Export IEDB data into triple store, enabling Sparql queries seamless interoperability
• Integration into rule based validation system
Overall Conclusions
• The IEDB catalogs and organizes experimental data characterizing immune epitopes
• We implemented a machine learning pipeline to identify and triage journal articles relevant for subject areas of interest
• OBI provides a framework to represent experimental information in an interoperable and semantically rich format that has immediate benefits for database resources such as the IEDB
Flow cytometry for IEDB• IL-10 production (GO)• Epitope specific IL-10 production by T cells (OBI helper
term).– Textual Definition: “A biological process where T cells produce
IL-10 resulting from the recognition of a T cell epitope”– Logical definition:
“'interleukin-10 production‘ and ('process is result of' some 'MHC:epitope complex binding to TCR')”
• Intracellular cytokine staining assay (OBI)• T cell epitope intracellular cytokine staining IL-10 assay
(OBI, term that really just the IEDB wants) Tie to cells, cell populations
Immunology terms in OBI• There is no ‘immune epitope ontology’ merged into OBI
• These terms are looking for a new home: – disposition to be bound by immune receptor– binding– Epitope, antigen, immunogen, allergen, host– ‘epitope specific cytokine production by T cells’– Environmental exposure / proximity to infectious agent (IDO)
Thanks!SAIC• Stephen Greenlee• Jason Cantrell• Jason Buell• Robert Hinman• Kelly Wheeler• Eric Gutt
San Diego Supercomputer Center
• Phil Bourne• Julia Ponomarenko
Technical University of Denmark• Ole Lund• Morten Nielsen
University of Copenhagen• Søren Buus
La Jolla Institute for Allergy & Immunology