Biomarkers in Transplantation. A Genome Canada Initiative for Human Health Biomarkers in Transplantation A Knowledge Base for Allograft Rejection Benjamin Good, Jon Carthy, Zsuzsanna Hollander, Axel Bergman, Raymond Ng, Bruce McManus and Mark Wilkinson

Biomarkers in Transplantation. A Genome Canada Initiative for Human Health

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. VEGF ICAM-1 VCAM-1 …

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 Angiogenesis VEGF Blood Vessel Morphogenesis Part of Blood Vessel Development Part of A 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

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 MicroArray Core USC/CHLA MicroArray 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