Biomarkers in Transplantation. A Genome Canada Initiative for Human Health
Biomarkers in Transplantation
A Knowledge Base for Allograft RejectionBenjamin Good, Jon Carthy, Zsuzsanna Hollander, Axel Bergman,
Raymond Ng, Bruce McManus and Mark Wilkinson
Biomarkers in Transplantation. A Genome Canada Initiative for Human Health
http://www.newslettercartoons.com/
Biomarkers in Transplantation. A Genome Canada Initiative for Human Health
Outline
Introduction - Better Biomarkers Initiative
Definition of “Knowledge Base”
Motivation
Methods
Status
Future Plans
Biomarkers in Transplantation. A Genome Canada Initiative for Human Health
Better Biomarkers Project
Goal: identify biomarkers of acute rejection, chronic rejection, and tolerance that are accessible in the peripheral blood.
Motivation: improve prediction and diagnosis, reduce the need for biopsies, and individualize therapy.
Methods: High throughput genomics (GeneChip microarrays) and proteomics (iTRAQ).
Status: Currently collecting patient samples and commencing full-scale analytical work.
Biomarkers in Transplantation. A Genome Canada Initiative for Human Health
Analytical Stage 1
• Employ statistical techniques to identify lists of potential biomarkers based on observed relationships with disease state.
RejectionTolerance
Expression
Time
RejectionTolerance
Expression
Time
VEGF
ICAM-1
VCAM-1
…RejectionTolerance
Expression
Time
Biomarkers in Transplantation. A Genome Canada Initiative for Human Health
Analytical Stage 2
• The lists of candidate genes will then be analyzed by human experts to assess their clinical value and their biological significance
• PROBLEM, the lists may contain several hundred individual candidates and these are likely to have important interactions– Entirely manual interpretation would be
enormously time-consuming.
Biomarkers in Transplantation. A Genome Canada Initiative for Human Health
Knowledge Based Systems
• Represent qualitative human knowledge in a form that is useful for a computer.
• Using these systems, the qualitative analysis of the putative biomarkers could be conducted automatically.
Biomarkers in Transplantation. A Genome Canada Initiative for Human Health
Motivation• Given an expressed gene• Can a relationship be established with rejection
based on what is known in the world?• Define and justify this relationship• Automatically
?Gene X ?? ? ?
Acute Rejection
Biomarkers in Transplantation. A Genome Canada Initiative for Human Health
Ontology
• A specific form of knowledge based system• Represents the concepts and relationships that
describe a particular domain
AngiogenesisVEGF
Blood Vessel Morphogenesis
Part of
Blood Vessel Development
Part ofA fragment of the Gene Ontology
Biological Process
Kind of
Associated with
Biomarkers in Transplantation. A Genome Canada Initiative for Human Health
Methods Employed, So Far
• Constructed a relational database for storage of the ontology.
• Constructed a web interface for gathering and accessing knowledge linking genes to rejection.
• Begun populating the knowledge base manually via literature analysis.
Biomarkers in Transplantation. A Genome Canada Initiative for Human Health
Current Results• Work in progress!
• About 125 papers processed so far
• A working list of about 175 biomarkers, fully referenced with article links and accession numbers
• Operational database with read/write access through a web interface.
Biomarkers in Transplantation. A Genome Canada Initiative for Human Health
Web Interface
Biomarkers in Transplantation. A Genome Canada Initiative for Human Health
GO Terms Associated with Candidate Biomarkers
0 0.1 0.2 0.3 0.4 0.5 0.6
immune cell activation
regulation of cell proliferation
protein metabolism
cell surface, receptor-linked signaltransduction
response to wounding
response to external bioticstimulus
defense response
Biomarkers in Transplantation. A Genome Canada Initiative for Human Health
Summary
• To provide answers to the “why” questions about the biomarkers discovered in this initiative,– we have started creating an ontology that
defines the qualitative relationships between genes and allograft rejection based on the public record.
• The project is just beginning…
Biomarkers in Transplantation. A Genome Canada Initiative for Human Health
Future Work
• Integrate external resources like the Gene Ontology and the Kyoto Encyclopedia of Genes and Genomes
• Expand the ontology structure (by adding more kinds of relationships)
• Continuing literature curation efforts • Research in knowledge capture via natural
language processing and mass-collaboration
Biomarkers in Transplantation. A Genome Canada Initiative for Human Health
Acknowledgements
Supporting Organizations
Immunity & Infection Research Centre
USC/CHLA USC/CHLA MicroArray MicroArray
Core Core
Partnerships
Funders
GENOME CANADA
Providence Health Care, Vancouver General Hospital Foundation, St. Paul’s Hospital Foundation, UBC, Genome BC, the James Hogg iCAPTURE Centre, BC
Transplant Research Institute and Affymetrix
Supervisors, Advisors, Bosses Dr. Mark Wilkinson Dr. Raymond Ng Dr. Bruce McManus
Knowledge Capture Team Jon Carthy Zsuzsanna Hollander Axel Bergman
Top Related