2. Outline
• Problem: multiple ontologies of relevance to
the obesity/diabetes domain
– By species
– By category
– How can we bring these together?
• Bridging ontologies using OWL axioms
– Enables cross-domain semantic queries
• Integrated ontology-data views in Monarch
• Challenges
– Modeling strategies
– Tools
3. Ontologies for phenotype and
disease
gene 1
gene 2
disease
A
disease
B
Tools:
• OWLSim
• BOQA
• PhenoDigm / MouseFinder
• Phenomizer
• Phenomenet
4. We want to bridge species
Washington, N. L., Haendel, M. A., Mungall, C. J., Ashburner, M., Westerfield, M., &
Lewis, S. E. (2009). Linking Human Diseases to Animal Models Using Ontology-
Based Phenotype Annotation. PLoS Biol, 7(11). doi:10.1371/journal.pbio.1000247
5. Bridging across species
requires bridging across
ontologies
gene 1
gene 2
disease
A
disease
B
HP:0012093
Abnormality of endocrine pancreas physiology
MP:0009165
abnormal endocrine pancreas morphology
?
?
6. Mammalian Phenotype Ontology
Smith, C. L., Goldsmith, Carroll-A. W., &
Eppig, J. T. (2005). The Mammalian
Phenotype Ontology as a tool for
annotating, analyzing and comparing
phenotypic information. Genome
Biol, 6(1). doi:10.1186/gb-2004-6-1-r7
Used to annotate and query:
• Genotypes
• Alleles
• Genes
In mice
abnormal
pancreatic
beta cell
mass
abnormal
pancreatic
beta cell
morphology
abnormal
pancreatic islet
morphology
abnormal
endocrine
pancreas
morphology
abnormal
pancreatic
beta cell
differentiation
abnormal
pancreatic
alpha cell
morphology
abnormal
pancreatic
alpha cell
differentiation
abnormal
pancreatic
alpha cell
number
7. Human Phenotype Ontology
Robinson, P. N. P.
N., Koehler, S., Bauer, S., Seelow, D., Horn, D., Mundlos, S., K{"o}hler, S., et al. (2008). The
Human Phenotype Ontology: a tool for annotating and analyzing human hereditary
disease. American Journal of Human Genetics, 83(5), 610-615. Elsevier.
doi:10.1016/j.ajhg.2008.09.017
Used to annotate:
• Patients
• Disorders
• Genotypes
• Genes
• Sequence variants
In human
Reduced pancreatic
beta cells
Abnormality of
pancreatic islet
cells
Abnormality of endocrine
pancreas physiology
Pancreatic islet
cell adenoma
Pancreatic islet cell
adenoma
Insulinoma
Multiple pancreatic
beta-cell adenomas
Abnormality of exocrine
pancreas physiology
9. Phenotypes require more than
“phenotype ontologies”
glucose
metabolism
(GO:0006006
)
Gene/protein
function data
glucose
(CHEBI:172
34)
Metabolomics, t
oxicogenomics
Data
Disease &
phenotype
data
type II
diabetes
mellitus
(DOID:9352)
pyruvate
(CHEBI:153
61)
DISEASE GO CHEBI
pancreatic
beta cell
(CL:0000169)
transcriptomic
data
CL
10. Bridging via lexical methods
• Approach
– Create pairwise mappings between
ontologies
– Use lexical methods and/or curation
• Advantages:
– Large body of tools and willing text miners
• Disadvantages:
– Semantics-free
– Machine doesn‟t understand text
– Inexact matches
12. Enhance lexical approach with
OWL bridging axioms
• Key idea:
– Describe the phenotype in a machine-
interpretable way
• Break it down into digestible chunks!
• Logical definition
– The machine will then be able to help you
• Match phenotypes
• Automate ontology checking and addition of new terms
• Approach:
– Use Web Ontology Language (OWL), a
description logic to describe phenotypes
– Use OWL reasoning to find connections
Mungall, C. J., Gkoutos, G., Washington, N., & Lewis, S. (2007). Representing Phenotypes in OWL. In C. Golbreich, A.
Kalyanpur, & B. Parsia (Eds.), Proceedings of the OWLED 2007 Workshop on OWL: Experience and Directions.
Innsbruck, Austria. http://www.webont.org/owled/2007/PapersPDF/paper_40.pdf
15. abnormal
pancreatic
beta cell
mass
abnormal
pancreatic
beta cell
morphology
abnormal
pancreatic islet
morphology
type B
pancreatic
cell
islet
of
Langerhans
endocrine
pancreas
part
of
part
of
abnormal
endocrine
pancreas
morphology
part
of
mass
morphology
quality
Class: „abnormal pancreatic beta cell mass‟
EquivalentTo: „abnormal phenotype‟ and
has_entity some „type B pancreatic cell‟ and
has_quality some mass
16. Reduced pancreatic
beta cells
Abnormality of
pancreatic islet
cells
Abnormality of endocrine
pancreas physiology
Pancreatic islet
cell adenoma
Pancreatic islet cell
adenoma
Insulinoma
Multiple pancreatic
beta-cell adenomas
Abnormality of exocrine
pancreas physiology
abnormal
pancreatic
beta cell
mass
abnormal
pancreatic
beta cell
morphology
abnormal
pancreatic islet
morphology
abnormal
endocrine
pancreas
morphology
abnormal
pancreatic
beta cell
number
abnormal
pancreatic
alpha cell
morphology
abnormal
pancreatic
alpha cell
differentiation
abnormal
pancreatic
alpha cell
number
inferred
from CL
inferred
from PATO
„abnormal phenotype‟ and
has_entity some „type B pancreatic cell‟ and
has_quality some amount
„abnormal phenotype‟ and
has_entity some „type B pancreatic cell‟ and
has_quality some „reduced amount‟
17. Mungall, C.
J., Gkoutos, G., Smith, C., Haendel, M., Lewis, S., &
Ashburner, M. (2010). Integrating phenotype ontologies
across multiple species. Genome Biology, 11(1), R2.
doi:10.1186/gb-2010-11-1-r2
Köhler, S., Doelken, S. C., Ruef, B.
J., Bauer, S., Washington, N., Westerfield, M., Gkoutos, G.,
et al. (2013). Construction and accessibility of a cross-
species phenotype ontology along with gene annotations
for biomedical research. F1000Research, 1–12.
doi:10.3410/f1000research.2-30.v1
7181 / 9022 MP
Terms are described
19. Linking cell types to proteins via
GO
≡
secretion
(GO:0046903)
insulin
(PR:000009054)
⊓
∃.has_output
⊑pancreatic beta cell
(CL:0000169)
Insulin secretion
(GO:0046903)
∃.capable_of
INS_HUMAN - P01308
Meehan, T., Masci, A.
M., Abdulla, A., Cowell, L., Blake, J., Mungall, C. J., & Diehl, A.
(2011). Logical Development of the Cell Ontology. BMC
Bioinformatics, 12(1), 6. doi:10.1186/1471-2105-12-6
20. Uberon bridges single species
anatomy ontologies
Mungall, C. J., Torniai, C., Gkoutos, G. V., Lewis, S. E., & Haendel, M. A. (2012). Uberon, an integrative
multi-species anatomy ontology. Genome Biology, 13(1), R5. doi:10.1186/gb-2012-13-1-r5
21. Lexical
methods
• Obol :
grammar
approach
• Entity
matching
Curation
• Edit bridge files
• Edit source ontologies
OWL
Reasoning
• Elk
• GULO
• Jenkins
Iterative development and deployment
Kohler, S., Bauer, S., Mungall, C. J., Carletti, G., Smith, C. L., Schofield, P., Gkoutos, G. V, et al. (2011). Improving ontologies by automatic
reasoning and evaluation of logical definitions. BMC Bioinformatics, 12(1), 418. doi:10.1186/1471-2105-12-418
Mungall, C. J., Dietze, H., Carbon, S. J., Ireland, A., Bauer, S., & Lewis, S. (2012). Continuous Integration of Open Biological Ontology Libraries.
Bio-Ontologies 2012 http://bio-ontologies.knowledgeblog.org/405
22. Integrated views in Monarch
http://monarchinitiative.org
Linking model systems to
human diseases
23. Integrated views in Monarch
http://monarchinitiative.org
glucose
metabolism
(GO:0006006
)
Gene/protein
function data
glucose
(CHEBI:172
34)
Metabolomics,
toxicogenomics
Data
Disease &
phenotype
data
type II
diabetes
mellitus
(DOID:9352)
pyruvate
(CHEBI:153
61)
DISEASE/
PHENOTYPE
GO CHEBI
pancreatic
beta cell
(CL:0000169)
transcriptomic
data
CL
24. Roadblocks and pitfalls
• Lack of tool support for ontology
development
• Many tools for „mapping after the fact‟
– Mapping should not be retrospective
– Must be integrated into ontology
development lifecycle
• OWL Modeling pitfalls
– Over-modeling
– Under-modeling
25. Overcoming ontology
development bottlenecks with
TermGenie
• Developed for GO
– Instant compositional terms for curators
– OWL axioms are added at time of term
creation
• We are rolling out pheno-ontology
instances
– Trial run on FYPO and plant traits
http://termgenie.org
26. Modeling confusion and analysis
paralysis
• absent pancreatic beta cells
(MP:0009174)
– Tempting to use OWL cardinality
• Does this represent the biology?
• decreased pancreatic beta cell number
(MP:0003339)
– Can‟t do this with OWL cardinality!
• Lesson: don‟t over-model in OWL
27. Modeling temporal progression
• How did there come to be absence of
beta cells in the pancreas?
• What are the downstream effects?
• Changes with ages
– Hyperglycemic hypoglycemic
• Existing phenotype ontologies steer
clear of causality
– Next frontier
28. What I haven‟t talked about
• Quantitative phenotypes
• Assay vs phenotype
• Behavioral phenotypes
• Environments
• Mining disease phenotypes from the literature
• Clinical vocabularies (see Nathalie‟s talk)
• Modeling other model systems
• The data!
• Making use of the data and OWL axioms for
analysis (see Damian‟s talk)
• …a lot more
29. Questions/Summary
• Approaches to mapping
– OWL bridging axioms
• Roadblocks and pitfalls
– OWL modeling analysis paralysis
– Lack of tool support
– Need to push upstream in ontology engineering lifecycle
– Modeling complex phenomena
• From observation to temporal progression and models of
causality
• Tools
– CrossSpeciesPheno
– Available:
• GULO, TermGenie, OBO-Edit, Protégé 4, OWL Reasoners, Onto-
Jenkins
– Required: integration upstream
30. • Charite
– Sebastian Kohler
– Sandra Doelken
– Sebatian Bauer
– Peter Robinson
• U of Oregon
– Barbara Ruef
– Monte Westerfield
• OHSU
– Carlo Torniai
– Nicole Vasilesky
– Shahim Essaid
– Matt Brush
– Melissa Haendel
• Sanger
– Anika Oehlrich
– Damian Smedley
• University of Cambridge
– George Gkoutos
– Rob Hoehndorf
– Paul Schofield
• Lawrence Berkeley
– Nicole Washington
– Suzanna Lewis
• UCSD
– Amarnath Gupta
– Jeff Grethe
– Anita Bandrowski
– Maryann Martone
• U of Pitt
– Chuck Borneo
– Harry Hochheiser
• JAX
– Terry Meehan
– Cynthia Smith
Acknowledgments
Hinweis der Redaktion
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