biomarkers in transplantation. a genome canada initiative for human health biomarkers in...

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


http://www.newslettercartoons.com/


Outline

Introduction - Better Biomarkers Initiative

Definition of “Knowledge Base”

Motivation

Methods

Status

Future Plans


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.


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


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.


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.


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


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


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.


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.


Web Interface


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


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…


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


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

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