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Data sharing in Canada through the COGR:
a unified clinical genome database as a community
resource for standardizing and ...
Overview
• Grant funded by Genome Canada
• Collaborative effort for the collection, sharing
and analysis of variants repor...
23 GeneInsight Instances Created
Organization Upload Status Sharing Status
Alberta Children's Hospital, Calgary AB Uploade...
COGR Variant Numbers
COGR Comparison 2014/2015
Variants
Copy Number
Variants
2014 3802 3339
2015 12607 4659
0
2000
4000
60...
Workflow Overview
5
The COGR Recent Initiative
• 2016 marks the COGR’s 4th year
– Focus to make data holdings both extremely
accurate and read...
7
COGR - BRCA Participating Institutions
8
A. Alberta Children’s Hospital (Calgary, AB)
B. Atlantic Cancer Research Institut...
Discrepancy Report Results Overview
1. Overall discrepancy report results
2. Total changes in classifications and reasonin...
Submission Data - Before Issuing
Discrepancy Reports
After data submission 1,148 unique variants were
identified in more t...
Tiered Discrepancy Systems
5-tiered
- Initially implemented
3-tiered
- Recommended by
participants
2-tieried
- Clinical ma...
After Review of Discrepancy
Report Results
• 42% of discordant variants changed classifications
• 28% did not change class...
After Review of Discrepancy
Report Results
• Only 18% of the discrepant variants reached a consensus for
5-tier system
– B...
Final Discrepancy Results
14
622
278
770
130
887
13
0
100
200
300
400
500
600
700
800
900
1000
Concordant Discrepant
Numbe...
Reasoning For Reclassification
15
• 9 out of 11 labs specified reasoning for some
variants
• 64% of reassessed variants pr...
Methods Used for Reassessment
43%
45%
6%
6% We used our own methodology
or tools to reassess
We used the COGR variant
asse...
Summary
• Successful exercise with positive feedback within the
COGR community
• Limited resources provide challenges for ...
opengenetics.ca
This work was funded by the Government of Canada through Genome Canada and
the Ontario Genomics Institute ...
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Data sharing in Canada through the Canadian Open Genetics Repository (COGR): a unified clinical genome database as a community resource for standardizing and sharing genetic interpretations Matthew Lebo

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We present the Canadian Open Genetics Repository (COGR) - a collaborative effort for the collection, storage, sharing and analysis of variants reported by medical diagnostics laboratories across Canada. The increasing quantity and complexity of data produced by Canadian laboratories has become difficult to analyze. There is a need for collaborative measures between institutions to better facilitate variant analysis and information transfer. The inherent collaborative structure of the COGR promotes real-time sharing between geographically distant Canadian clinical laboratories and enhances the exchange of information about DNA variants within the expert community. Each laboratory was provided a systematic Variant Assessment Tool (VAT) and a standard, structured mechanism for collecting and sharing variant level data using GeneInsight™. Participating laboratories have also been encouraged to share on both ClinVar and on VariantWire, a real-time data sharing initiative including US and Canadian laboratories.

To date, 23 Canadian institutions have become members of COGR, with 11 of these sites actively sharing data in real-time. The COGR currently contains over 17,000 single nucleotide and copy number variants being shared that encompass 90 genes and 60 genetic diseases. Members of COGR have also been provided discrepancy reports detailing differences in classification between their laboratory and other COGR sites. Additionally, consensus building meetings have begun to formalize interpretations of specific variants among the participating COGR laboratories. Recently, the COGR started an initiative to create a consensus on variants identified in the BRCA1 and BRCA2 genes, pulling in over 5,500 variants from 11 laboratories; this data is actively being reviewed. Additionally, a public-facing instance of consensus level variants has been initiated through a collaboration with the BRCA exchange. Here, we report on our methodologies for resolving variant interpretation discrepancies, a system for resolving differences, and a process for arriving at a consensus. As a continuing effort, the COGR endeavors to increase genetic knowledge and standardization through data sharing and consensus building, ultimately improving our ability to diagnose and treat genetic diseases.

Published in: Science
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Data sharing in Canada through the Canadian Open Genetics Repository (COGR): a unified clinical genome database as a community resource for standardizing and sharing genetic interpretations Matthew Lebo

  1. 1. Data sharing in Canada through the COGR: a unified clinical genome database as a community resource for standardizing and sharing genetic interpretations Dr. Matthew Lebo, Kathleen-Rose Zakoor, Dr. Jordan Lerner-Ellis and the Canadian Open Genetics Repository Working Group
  2. 2. Overview • Grant funded by Genome Canada • Collaborative effort for the collection, sharing and analysis of variants reported by medical diagnostic laboratories across Canada • Collaborate with other global initiatives including ClinVar, BRCA Challenge, Human Variome Project 2
  3. 3. 23 GeneInsight Instances Created Organization Upload Status Sharing Status Alberta Children's Hospital, Calgary AB Uploaded Sharing Atlantic Cancer Research Institute, Moncton NB Pending - British Columbia Cancer Agency, Vancouver BC Uploaded Sharing Children’s & Women’s Health Centre of BC, Vancouver BC Uploading - Children's Hospital of Eastern Ontario, Ottawa ON Uploaded Sharing* Credit Valley Hospital, Trillium Health Centre, Mississauga ON Uploaded Sharing Dept of Medical Genetics, University of Alberta, Edmonton AB Uploading - Hamilton Health Sciences, McMaster University, Hamilton ON Uploaded - Impact Genetics Inc., Bowmanville ON Pending - Izaak Walton Killam Health Centre, Dalhousie University, Halifax NS Uploading - Jewish General Hospital, Montréal QC Uploading Kingston General Hospital, Queen’s University, Kingston ON Uploaded Sharing McGill University Health Complex, Montréal QC Uploaded - Memorial Health University Medical Center, St. John’s NL Pending - Mount Sinai Hospital, University of Toronto, Toronto ON Uploaded Sharing* North York General Hospital, Toronto ON Uploaded Sharing Ontario Institute of Cancer Research (OICR), Toronto ON Uploaded Sharing Regional Health Authority, University of Manitoba, Winnipeg MB Uploading Sharing Sainte-Justine Hospital, University of Montreal, Montréal QC Uploading - SickKids Hospital and McLaughlin Centre, Toronto ON Uploaded Sharing University Hospital, Western University, London ON Pending - Women's College Hospital, University of Toronto, Toronto ON Uploaded Sharing* *Also sharing with VariantWire 3
  4. 4. COGR Variant Numbers COGR Comparison 2014/2015 Variants Copy Number Variants 2014 3802 3339 2015 12607 4659 0 2000 4000 6000 8000 10000 12000 14000 4 • >17,000 variants • 1,266 genes • 66 diseases
  5. 5. Workflow Overview 5
  6. 6. The COGR Recent Initiative • 2016 marks the COGR’s 4th year – Focus to make data holdings both extremely accurate and readily accessible • Focus on creating and dispersing lab specific discrepancy reports – Build consensus clinical interpretations on variants identified in Canadian diagnostic laboratories and academic medical centers – Initial project looked at BRCA1/2 6
  7. 7. 7
  8. 8. COGR - BRCA Participating Institutions 8 A. Alberta Children’s Hospital (Calgary, AB) B. Atlantic Cancer Research Institute (Moncton, NB) C. British Columbia Cancer Agency (Vancouver BC) D. Children’s & Women’s Health Centre of BC (Vancouver BC) E. Children’s Hospital of Eastern Ontario (Ottawa ON) F. Credit Valley Hospital, Trillium Health Centre (Mississauga ON) G. Dept of Medical Genetics, University of Alberta (Edmonton, AB) H. Hamilton Health Sciences, McMaster University (Hamilton, ON) I. Impact Genetics Inc. (Bowmanville, ON) J. Izaak Walton Killam Health Centre (Halifax, NS) K. Kingston General Hospital, Queen’s University (Kingston, ON) L. McGill University Health Complex (Montréal, QC) M. Memorial Health University Medical Center (St. John’s, NL) N. Mount Sinai Hospital, University of Toronto (Toronto, ON) O. North York General Hospital (Toronto ON) P. Ontario Institute of Cancer Research (OICR) (Toronto, ON) Q. Regional Health Authority, University of Manitoba (Winnipeg, MB) R. Sainte-Justine Hospital, University of Montreal (Montréal, QC) S. SickKids Hospital and McLaughlin Centre (Toronto, ON) T. University Hospital, Western University (London, ON) U. Women’s College Hospital, University of Toronto (Toronto, ON) V. Jewish General Hospital, Montreal (Montréal, QC) COGR-BRCA Participant COGR Participant
  9. 9. Discrepancy Report Results Overview 1. Overall discrepancy report results 2. Total changes in classifications and reasoning 3. Changes in discrepant variant classifications 4. Methods for reassessment • 11 participating labs across 4 provinces – ON, BC, AB, MB • Received total of 5,554 BRCA1/2 variants – 3014 unique variants • 1,148 seen in >2 labs – 110 to 1072 variants per lab (505 on average) 9
  10. 10. Submission Data - Before Issuing Discrepancy Reports After data submission 1,148 unique variants were identified in more than one lab • 550 (48%) of variants had concordant classifications • 350 (30%) were discordant • 248 (22%) were unclassified by all labs *According to 5-tier classification system 10
  11. 11. Tiered Discrepancy Systems 5-tiered - Initially implemented 3-tiered - Recommended by participants 2-tieried - Clinical management 11
  12. 12. After Review of Discrepancy Report Results • 42% of discordant variants changed classifications • 28% did not change classifications • 30% were not reassessed 12 Initial Interpretations Final Interpretations # Variants % # Variants % Overall Change Benign 526 37% 637 45% 111 (8%) Likely Benign 271 19% 321 23% 50 (4%) VUS 342 24% 211 15% 127 (9%) Likely Pathogenic 60 4% 64 5% 4 (>1%) Pathogenic 136 10% 170 12% 34 (2%) Unclassified 75 5% 9 1% 72 (5%) Total 1410 1410 398 (28%)
  13. 13. After Review of Discrepancy Report Results • Only 18% of the discrepant variants reached a consensus for 5-tier system – But most labs did not review minor discrepancies • Benign vs Likely Benign • Pathogenic vs Likely Pathogenic • In total, for 5-tier system: – 69% (622/900) of all unique & classified variants were concordant • In total, for 3-tier system (LB/B, VUS, LP/P) – 86% (770/900) of all unique & classified variants were concordant 13
  14. 14. Final Discrepancy Results 14 622 278 770 130 887 13 0 100 200 300 400 500 600 700 800 900 1000 Concordant Discrepant NumberofUniqueVariants 5-Tier 3-Tier 2-Tier
  15. 15. Reasoning For Reclassification 15 • 9 out of 11 labs specified reasoning for some variants • 64% of reassessed variants provided reclassification reasoning: 13% 37%42% 8% Typographical error Based on new evidence provided Revised classification criteria Other (Please specify)
  16. 16. Methods Used for Reassessment 43% 45% 6% 6% We used our own methodology or tools to reassess We used the COGR variant assessment tool (VAT) We used the ACMG reclassification tool provided Other 16 • Most labs did not review variants through the COGR network • 8 out of 11 labs specified their reassessment methods • 34% of variants had specified reassessment methods:
  17. 17. Summary • Successful exercise with positive feedback within the COGR community • Limited resources provide challenges for labs to do this without guidance and help • Continuing initiatives: – Release quarterly discrepancy reports – Provide consensus variant interpretations through public database – Further collaboration with other international data-sharing efforts including ClinVar, the HVP and the GA4GH 17
  18. 18. opengenetics.ca This work was funded by the Government of Canada through Genome Canada and the Ontario Genomics Institute (OGI-070) 18

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