chemical biology
standards
caspase activity
PubChem
domain
cheminformatics
nomenclature
semantic
activity
enzyme reporter viability
fluorescence
binding based
programming
data sets
search
knowledge
screening
technology
end point
thesauri
article
object
XML
enzyme substrate based
high-thoughput screeningversioning
(HTS)
natural language
software
classification
polysemes
biological pathways
Beta-Lactamase Induction dehydrogenase activity
specificity
subject indexing schemes
properties
GFP induction annotation
Fluorogenic substrate
chemical probes information exchange
Stephan
Schürer,
PhD
servers
ATP Luciferin Coupled
classes
synonyms search tool
controlled vocabulary
biological assay
biomedical knowledge
ICBO, Buffalo, July 30 2011 disease networks
concepts
meta-data
small molecule structure
taxonomies
subject headings
cyclic
AMP
redistribution
RDF
calcium redistribution OWL sschurer@med.miami.edu
novel chemical tools
indexing
pharmaceutical
semantic web
library
authorized terms
structural biology
individuals
homographs energy transfer
tags
PDSP
BioAssay Ontology (BAO)
ChemBank
Background for BioAssay Ontology
High-throughput screening
 One of the most important approaches to find novel
entry points for drug discovery programs
 Historically in pharmaceutical companies
 Since ~2005, massive NIH effort (MLI) to make HTS
accessible to public sector research
 PubChem is the major repository of HTS data
 More recently: EU-OpenScreen project
2
Motivation for BioAssay Ontology
Large public screening data sets
PubChem, ChEMBL, PDSP, ChemBank, Binding DB
 Lack of standardized assay annotations
 No standardized endpoint names or formats
Data is rarely re-used(!)
Common queries cannot be asked
Analysis across different data sets is difficult
Integration with other databases is difficult
No knowledge model for assays and screening results
3
Queries the Ontology should be able
to answer
• Identify inhibitors of kinases in biochemical assays.
• Identify compounds active in multiple luciferase reporter
gene assays.
• Identify compounds active in cell viability assays and
organize by cell lines and assay types.
• Identify active compounds in assays related to pathway X.
• …
4
Leverage the aggregated corpus of publically
available HTS data to infer molecular
mechanism of actions (MMOA) of small
molecule perturbagens in biological model
systems.
Schürer et al. “BioAssay Ontology Annotations Facilitate Cross-Analysis of Diverse
High-throughput Screening Data Sets” J Biomol Screen 2011 (16), 415-426.
5
BAO Products and Resources
 BAOSearch Software (beta):
http://baosearch.ccs.miami.edu
 Query, explore, download BAO-annotated PubChem content
 Some semantic search capabilities
 Project Website and Wiki with relevant materials and
documentation:
http://www.bioassayontology.org/
http://www.bioassayontology.org/wiki
6
Questions / Discussion points
 Application / user focus vs. “universal” ontologies
 Efficiency vs. “realism” of representations
 Rapid application development
 Orthogonal ontologies vs. Ontology mapping
 Universal “realism” vs. domain or application-specific
 Chemical bond: 2D structure graph, 3D rule based,
molecular mechanics, semi-empirical, up-initio QM
 Disease
 Virtual world
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Questions / Discussion points
 Collaborative ontology development




Collaborative vs. individual effort
Control over development and focus / application focus
Rapid application development
Quality
 Aligning BAO to upper level ontology (BFO)
 Benefits vs. required resources
 Do upper level ontologies matter for specialized
applications?
8
Questions / Discussion points
 Aligning BAO with OBI
 Some level of overlap
 OBI: process-oriented (model the investigation)
 BAO: purpose of categorization and analysis of HTS data
 BAO model becomes more complex if based on OBI
 How do we do it practically
 Define missing assays to OBI and MIREOT back?
 Quick term templates (QTT)?
 Define our relations as short-cut relationships (using RO)?
9
Additional slides
10
BAO-facilitated Example for Analysis
(Luciferase Assays)
Details in: Schürer et al. “BioAssay Ontology Annotations Facilitate Cross-Analysis of
Diverse High-throughput Screening Data Sets” J Biomol Screen 2011 (16), 415-426.
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Assay Count
Most promiscuous reporter gene compounds
Panel Assay
Single Conc
Other
Conc-response
Most promiscuous reporter gene compounds
Compounds
Assay_PCIdxCorrelation
Promiscuity Index
1
0 0.2
Luciferase
Enzyme
Inhibitors
Generally
cytotoxic
PCIdx =
N ( Active)
N (Tested)
Examples: Cytotoxic Series
Daunorubicin
Cluster Reporter PCIdx: 0.56
Cluster Reporter Active: 58
Cluster Viability PCIdx: 0.64
Cluster Viability Active 27
Emetine
Cluster Reporter PCIdx: 0.48
Cluster Reporter Active: 23
Cluster Viability PCIdx: 0.45
Cluster Viability Active 10
Cluster Reporter PCIdx: 0.41
Cluster Reporter Active: 29
Cluster Viability PCIdx: 0.57
Cluster Viability Active 13
Examples: Luciferase Inhibitor Series
Cluster Size: 6
Cluster Reporter PCIdx: 0.61
Cluster Reporter Active: 101
Cluster EnzActivity PCIdx: 0.58
Cluster EnzActivity: 15
Cluster Size: 4
Cluster Reporter PCIdx: 0.38
Cluster Reporter Active: 52
Cluster EnzActivity PCIdx: 0.61
Cluster EnzActivity: 11
Cluster Size: 5
Cluster Reporter PCIdx: 0.46
Cluster Reporter Active: 77
Cluster EnzActivity PCIdx: 0.58
Cluster EnzActivity: 14
Schürer et al. “BioAssay Ontology Annotations Facilitate Cross-Analysis of Diverse
High-throughput Screening Data Sets” J Biomol Screen 2011 (16), 415-426.
BAO Project: Three major components
1) Development of the Bioassay Ontology
2) Annotation of assays and assay results
(content curation)
3) Development of software tools
16
BAO design to describe assays
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meta target
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assay design
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endpoint
Ontology class
Asserted relation, (I) is inverse
More subclasses
Inferred relation
Primitive class
Application of BAO: BAO Search Software
18
http://baosearch.ccs.miami.edu/baosearch/
19
BAO: Concept Search
20
Biochemical Assays with IC50 < 1 mM
21
22
Chemical structure search
23
BAO Products and Resources
 BioAssay Ontology (NCBO bioportal and project site):
http://bioportal.bioontology.org/ontologies/45410
http://www.bioassayontology.org/visualize/
 Terminology / annotations for biochemical assays:
http://www.bioassayontology.org/
>Assay Annotation Template
 Over 1000 BAO-annotated assays from PubChem
(available in BAOSearch)
24
Acknowledgements
• Ubbo Visser
• Vance Lemmon
• Mitsunori Ogihara
• Nick Tsinoremas
•
•
•
•
•
•
•
Saminda Abeyruwan
Uma Vempati
Magdalena Przydzial
Kunie Sakurai
Robin Smith
Yuanyuan Jia
Caty Chung
•
•
•
•
Chris Mader
Amar Koleti
Nakul Datar
Sreeharsha
Venkatapuram
• Felimon Gayanilo
• Mark Southern
http://bioassayontology.org
sschurer@med.miami.edu
25