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Genomics Research & Development Initiative: Supporting Regulatory & Operational Mandates of the Canadian Government Ivy Moffat1, Julie Bourdon-Lacombe1, Carole L. Yauk2 & Andrew Atkinson3
1Regulators: Water and Air Quality Bureau, 2Research Scientist: Environmental Health Science and Research Bureau, 3Policy: Science Policy Directorate, Health Canada, Ottawa, ON, Canada
Council of Canadian Academics: Independent policy advice • Identified genomics as a global strength area for Canada (State of S&T, 2006)
Genome Canada: Funding body for non-gov’t institutions • To advance university-led large-scale genomics research & technology platforms ($840 million since 2000) • Leveraged >$900 million co-funding with partners
Genomics R&D Initiative (GRDI): Funding body for gov’t labs • Solutions to issues important to Canadians ($20 M/yr since 1999) • Build genomics capacity & research to support regulatory & operational mandates individual departments • Supports interdepartmental collaborations, sharing strategic priorities of national importance
Government of Canada’s Support for Genomics
GRDI Departments & Agencies
1. Health Canada 2. National Research Council 3. Natural Resources Canada 4. Agriculture and Agri-Food Canada 5. Environment Canada 6. Fisheries and Oceans Canada 7. Public Health Agency of Canada 8. Canadian Food and Inspection Agency (Shared Initiative)
http://grdi-irdg.collaboration.gc.ca/eng/index.html
GRDI Funding Process
Treasury department approval • Mandate, benefits, shared initiatives, risk if projects not conducted • Continuously funded for five 3-yr phases; April, 2014 reapproved for
5 years
Strategic review of research priorities & peer-reviewed competitions to allocate funds (each phase)
Evaluations: • Independent (2006, 2010): GRDI process is well-managed,
effective & efficient. Integral to genomics governmental research
• Cabinet/Strategic & Operating review (end of each phase) • Annual performance reports on GRDI funded projects: e.g.
collaborations, R&D capacity, outreach & publications
Expert and end-user opinions
• In support of GRDI funding renewal, a targetted survey of genomics researchers and end-users was conducted within Health Canada to:
• Assess the current state of genomics issues • Examine allocation of funding (e.g., departmental vs
shared; generation of new knowledge vs high through-put testing)
• Examine opportunities for knowledge translation & engaging end-users
1. Interview (2013) Health Canada genomics users: Researchers & Risk Assessors Interview guide: ensure uniform data collection 10 questions: genomics issues relationg to impact, capacity, challenges, horizontal, needs & leveraging of funds notes shared with respondants to ensure accuracy
100% response rate (underscored level of interest)
2. Analysis of responses: Common responses were grouped into categories when appropriate
Expert and end-user opinions
Groups Number of
Researchers Number of Risk
Assessors environmental contaminants & consumer products
6 4
health & food products 6 3 pesticides 0 2
12 9
Health Canada genomics users: Researchers & Risk Assessors
Findings
1. Applications & impacts of genomics to mandates 2. Capacity for genomics 3. Challenges to the application of genomics 4. Horizontal issues addressed by genomics 5. Needs & foresight for genomics application 6. Leveraging of funds
1. Applications & impacts of genomics to mandates
0 20 40 60 80
Researchers Risk assessors
Perc
enta
ge o
f st
akeh
olde
rs
n=12 n=9
Economic Impact (annually) GRDI Projects
>$30B trade chemicals - Regulatory toxicology tools - Complex mixtures
$10B health care due to foodborne-pathogens/chemicals
- Causing food allergy - Short-term cancer assay fungal toxins - Foodborne isolates: Campylobacter & Listeria
Drugs 2nd largest health care cost
- Stem cell based health products - Interferon-induced hepatic injury
Multi-million $ wireless industry - Radiation risk assessment $0.5B colorectal cancer - Dietary fibre/Prebiotics $68B Chronic disease; ensure GM foods don’t contribute to this
- Multi generation study of soybean products
Researcher & Risk Assessor Collaborations Toxicogenomic signature to classify genotoxic vs. non-genotoxic chemicals (Environ. Mol. Mutagen., submitted)
• Application of the HESI TGx-65 genomic biomarker for compounds requiring metabolic activation in human cell culture
• HTS of chemicals for hazard ID & MOA
Case study on data rich compound Tradi'onal Tradi'onal &
Toxicogenomics Toxicogenomics
MOA MOA MOA
Human relevance Human relevance Human relevance
POD POD POD
Comparison
Case Study: Toxicogenomics & traditional approaches - Both approaches ID a genotoxic MOA - Similar regulatory values (Crit. Rev. Toxicol., accepted)
BMD/BMDLs
Approach Liver Lung Fore-
stomach Traditional • Tumors 1.8 /1.2 0.8 0.8/0.5 • Mutations 7.2/4.8 2.2/1.4 0.5/0.3 Toxicogenomics • Key event before committed step 8.1/1 14.8/3.7 11.4/7.4 • Lowest MOA-associated pathway 8.1/1 14.8/3.7 11.4/7.4 • Lowest pathway (Thomas et al., 2011) 0.3/0.2 15.7/2.1 16.1/4.5
Lessons Learned: Integrating toxicogenomics into human health risk assessment (Crit. Rev. Toxicol., accepted)
• Communication: Improves experimental design, interpretation & use of data
• Appropriate values for RA: standard method of selecting PODs
Basic technical guide for evaluating toxicogenomics data • Guidance to evaluate & apply genomics data
Important Researcher & Risk Assessor Collaborations
Risk Assessors Are Beginning To Use Genomics
Risk Assessments Impact 3 drinking water guidelines Support for MOA pesticide active ingredients Support for MOA
2. Capacity for genomics: Funding ($000)
AAFC EC
DFO HC/PHAC
NRCan NRC
2. Capacity for genomics: Personnel
2. Capacity for genomics
Core genomics facility: leveraged from GRDI funds • 2 DNA microarray scanners • 1 next gen sequencer • Traditional apparatus • Collaborating labs: full proteomic analysis • Human resources: statisticians & 2 bioinformaticians – direct pipe from sample to analysis/interpretation
Outsourcing is important when no in-house capacity
3. Challenges to the application of genomics
0 10 20 30 40 50 60 70 80 90
Researchers Risk assessors
n=12 n=9
Perc
enta
ge o
f st
akeh
olde
rs
4. Horizontal issues addressed by genomics
Number of Collaborators
Genomics Working Group:
• Advisory group: both regulatory & scientific experts for genomics applications & implications
• Forum for knowledge exchange (cross-pollination) • > 70 members
5. Needs & foresight for genomics application
Needs for Genomics Application
0 20 40 60 80
100
Researcher Risk Assessor
n=12 n=9
Perc
enta
ge o
f st
akeh
olde
rs
Foresight for Genomics Application
0 20
40
60
80
100
Researcher Risk Assessor
Perc
enta
ge o
f st
akeh
olde
rs
Other: antimicrobial resistance. Counter-bioterrrism, emergency prepardness/response
6. Leveraging of GRDI funds
Core genomics facility: • Attracts collaborative national &international partnerships • Attracts 4-times level of GRDI funding outside of GRDI • No single policy approach /initiative could leverage
resources greater than current process
Encourage funding for collaborative projects • Leverage horizontal support of non-GRDI agencies &
encompass a number of common issues among Bureaus • Reduce barrier to collaboration & sharing of funds
Lessons learned from 15 years of GRDI funding:
Current State • Shared initiative projects are becoming important, but should not redirect funding from department projects • Genomics research is beginning to impact end-users
Capacity • Capacity must be developed before testing/data generation • Increased need for bioinformatic support, students & risk assessor training
Lessons learned from 15 years of GRDI funding: Cont’d
Needs
• Strong genomics research & user network to ensure effective knowledge translation (KT)
• Must demonstrate relevancy to programs through KT
• Collaboration, communication & training essential
Thank you
• http://grdi-irdg.collaboration.gc.ca/eng/index.html
• Please contact: [email protected]
For more information
Hazard iden4fica4on, dose-‐response, & human relevance were addressed in our studies
Annotate affected genes, networks & pathways
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Quan'fy & compare the BMDs of genes, pathways and apical endpoints
Iden'fy key events (lowest BMDs, plausible biology)
Build mode of ac'on (MOA)
Derive Point of Departure
Process 'ssues, generate gene expression profiles
Anchor gene
expression data to DNA damage & mutations to support
MOA
Human TK6 cells
exposed to BaP to
Confirm MoA & human relevance
Expose B6C3F1 and MutaTMMouse to BaP by oral gavage
TRADITIONAL TOXICITY TESTING Most sensi)ve toxicity endpoints
CURRENT APPROACH
TOXICOGENOMICS Most sensi)ve perturbed pathways
NEW APPROACH
Toxicogenomic POD POD
SCREENING, MOE, RISK ASSESSMENT AND RISK MANAGEMENT
Targeted tes4ng
In vitro gene'c toxicity & kine'cs/metabolism tests, In silico, HTS, QSAR
EXPOSURE CHARACTERIZATION
HAZARD IDENTIFICATION: Iden'fy appropriate endpoint(s) to determine POD
Refine if needed
Obvious toxicity/human relevance?
NO YES
Lower-‐priority
Lessons Learned from Research-Risk Assessor Collaboration for use of toxicogenomics data in risk assessments (Crit. Rev. Toxicol., final revisions)
Lessons Learned For Both Researchers & Risk Assessors
1. Communica'on Improves experimental design, interpreta'on & use of data
2. Ease SoZware applica'ons & short courses are now available
3. U'lity of high-‐content info
Wealth of info can be generated quicker/cheaper than standard assays
4 Biological significance Pathways that align with MOA can be used to determine BMDs for toxicologically relevant changes in known biology
5. Human relevance Plausibility of animal MOA can be examined with cultured human cells and toxicogenomics
6. Support MOA Toxicogenomics-‐based MOA target which test are necessary
7. Selec'on of PODs Key event preceding commibed step in MOA may be most appropriate POD value
8. Great poten'al Toxicogenomics provides data to determine MOA s & PODs for data-‐poor chemicals