Title: Challenges and benefits of a federated biorepository model Abstract:Genome-based studies have provided powerful research tools for identifying genetic variants that contribute to chronic diseases. Recognition is growing, however, that chronic diseases are caused by a combination of an individual's genetic predisposition and their exposure to certain environmental risk factors. CARTaGENE was created to support the scientific community in identifying the determinants of chronic diseases of environmental and/or genetic origin. It was also created to accelerate the process of translational medicine through the identification of biomarkers for early diagnosis, disease treatment and prevention. To be competitive with the rest of the world and to increase the statistical power of its data, CARTaGENE has joined forces with four other Canadian cohorts to form the Canadian Partnership for Tomorrow Project (CPTP, http://www.partnershipfortomorrow.ca/). CPTP is the largest population based cohort study in Canada with over 300 000 participants recruited. In 2015 a CPTP Genotyping Project was launched to test drive CPTP’s biosample release procedures to help inform time and resource requirements and to identify challenges that may be present within the federated biorepository model under which the study operates. The project design included specific participant inclusion criteria, sample retrieval, DNA extraction, and genotyping of 5,000 samples. Lessons learned from this project will be shared. For more information about biosample and data access: access@cartagene.qc.ca

1. Joseph Tcherkezian-CARTaGENE
Treena McDonald-BC Generations Project
CASE STUDY: Interoperability in the Context of a Federated Biobanking Project

2. Chronic diseases
The Global Burden of Disease Study

3. Demographic change in Canada
Source: CIHI

4. Precision medicine
Source: Paving the way for
personalized medicine, FDA 2013
Giving the same
medication to all patients
is expensive, not very
efficacious and causes
severe adverse effects.

5. CARTaGENE

6. Awadalla P., Boileau C., 2012
3294
5566
11703
8000
979
404
937
1655
4950
147
2245
648
3436
1058
2546
1042
2321
166 235 307 263
883
20712007
1114
289
5051
2604
102
3232
296
4782
217 44 96
3387
0
2000
4000
6000
8000
10000
12000
14000
Diabète
Désordrethyroidien
Hypercholestérolémie
Hypertension
Angine
AVC
IM
Bronchitechronique
Asthme
Insuffisancerénale
Calculsrénaux
Infectionsrénales
Ostéoarthrite
Arthriterhumatoide
Ostéoporose
Glaucome
Cataractes
Dégénérescencemaculaire
Cirhose
Hépatitechronique
Cholecystite
Ulcère/refluxacide
Syndromecôlonirritable
Polype
Diverticulite
MaladiedeCrohn
Eczéma
Psoriasis
Lupusérythémateuxdisséminé
Dépressionmajeure
Épilepsie
Migraine
Scléroseenplaques
MaladiedeParkinson
Schizophrénie
Cancers
Nombredeparticipants
Chronic diseases in CaG cohort

7.  Quantitative data with 7 000 variables per participants
 Prospective cohort
 Representative of the population (sick and healthy)
 Linkage with administrative medial records
 Genetically homogeneous population (founder effect)
Unique features

8. A genetic main effect, in a candidate gene study.
Paul R Burton et al. Int. J. Epidemiol. 2009;38:263-273
Published by Oxford University Press on behalf of the International Epidemiological Association ©
The Author 2008; all rights reserved.
Uncommon and Common G*E
interaction
Power calculation for genetic association
study of common complexe diseases

9. Canada’s Largest Population Health
Research Platform, 300 000 participants !
A Pan Canadian Genotyping project
within a federated cohort

10. CPTP: >300 000 participants

11. CPTP: Vision and Mission
Vision: Improve population health through a better
understanding of the causes of cancer and other chronic
diseases.
Mission: To create and sustain a pan-Canadian population
health platform that promotes and supports high quality,
innovative population and health research.

12. Data and biosamples
Core questionnaire
DNA containing
samples
Physical measures Urine samples
Toenail
clippings
• >300,000
• Demographics
• Lifestyle
• Risk factors
• Several others
• Venous blood
collection
(>143,000)
• Blood spots
(>28,000)
• Saliva
(>8,000)
• Up to 90,000
• Height/weight
• Waist/hip
circumference
• BMI
• Grip strength
• 101,000 • >30,000

13. Centralized vs Federated biobanking

14. Harmonization and interoperability
OHS
CaG
Atlantic PATH
Online
Computerized
Teleform
Teleform
BCGP
TTP
Online
Computerized Online
Paper
Version 1
Version 2
2 questionnaire versions
Isabel Fortier, Maelstrom Research Group
Computerized
Computerized
Computerized

15. Requirements for Operating a Federated
Biorepository
• Standard Operating Procedures (SOP)
• Harmonize biosample data (topic for another discussion)
• Administrative procedures for receiving and processing approved CPTP
sample requests to facilitate biosample release
The above takes longer to finalize than if operating a central biorepository

16. CPTP National Biosample SOP Development,
Review & Approval Procedure
Development by
Biosample Standing
Committee (BSSC)
Working Group
Review by BSSC
- Major changes may require
further work by SOP Working
Group
Regional Review of
BSSC Approved SOP
Regional Feedback
presented to BSSC
-major changes require 2nd
regional review
OSC Review & Approval
of Submitted Draft SOP
Sign-off by OSC
designate

17. Confirming DNA Quality
• Conducted a CPTP DNA QC experiment
• Buffy coat and whole blood samples were proven to provide high
quality DNA of good yield.
• Blood spots prove to provide high quality DNA in 95% of samples
with lower and more variable yields than buffy coat and whole blood.

18. Work Flow for Releasing Biosamples:
receiving and processing approved CPTP
sample requests
• Developed pictorials and text to describe how work flow would
occur
• Identified 5 areas: request initiation, sample retrieval, sample
processing, sample storage, sample documentation & release
• Regions identify limitations/challenges for each of the 5 areas
• Information presented to the CPTP Operational Steering Committee
for input
Resulted in the CPTP Genotyping Project

19. CPTP Genotyping Project Goals
• Inform workflows and SOPs by identifying strengths and limitations
• Develop a cost model using project obtain data on time, resource
and cost requirements
• Strengthen the resource by supplying a densely genotyped sub
cohort that can serve as a control group for future genomic
research projects

20. Genotyping project
• Genotype 5000 CPTP participants on the Affymetrix UK Biobank
Axiom array gene chip (836 727 SNPs)
• Participant eligibility criteria included:
– Stored buffy coat or whole blood
– Age 40-69 years at baseline
– Completed all aspects of the study (questionnaires, physical
measures)
– Cancer free at baseline
– Excluded participants who already had extracted DNA or were
of non-European ancestry
– 50% female, 50% male
– Regional specific criteria (e.g. if other data were available on the
participants)

21. Request Initiation
• Confirm study requirements
– Participant selection criteria
– Regional requirements resulted in additional considerations
when insufficient numbers of participants per sub-group were
identified.
– >5,000 participants were selected in case insufficient DNA was
available.
• Decide where the work will be performed
• Arrange service contracts

22. Federated Biorepository and Contracts
• You may need more than you think!
– Service agreement(s)
– Material Transfer Agreement(s)
– Data Transfer Agreement(s)
• Consider the time requirement
• Designate a study administrative/laboratory lead to help move the
process along
One Federated
agreement

23. Federated Biorepository and Contracts
• Service contract
– Re-engaging previously used service contractor
• Can be quicker to initiate service contract
• Don’t assume same service contract terms are applicable if the
dollar amount of work increases
– Engaging a new service contractor
• New territory so expect some time to complete contract
– If a federated agreement not available then MTA may also be required
• Material Transfer Agreements and Data Transfer Agreements
– Harmonize on work description
– Harmonize, whenever possible or required, the legal text

24. Sample Retrieval
• Opportunity for each cohort to create a sample retrieval list
involving a large number of samples
– List are regional specific and therefore allowed each cohort to
test their processes and format
– Identified the need to not only include sample ID but also
sample type
• Opportunity to performed sample location QA checks – i.e. was the
sample in the place you intended it to be
• Cost modeling data was obtained for personnel and supplies

25. Sample Processing: Federated Biorepository
using a central laboratory
• Advantages of a central laboratory
– Fewer technicians involved so less personnel inter-variability
– Access to robotics
– Frees up time in the regions to perform other duties
– Standardized data format
• Disadvantages of a central laboratory
– May require administrative time to finalize legal agreements
– Less control
– Need to consider all possible processing factors upfront (could also be
an advantage!)
– The processing rate may be slower as fewer technicians involved
– Requires uploading of external data into regional LIMS

26. Sample Storage
• Processing samples almost always will result in progeny that
stay in the biorepository. Need to plan for storage

27. Biosample Documentation & Release
• Shipping SOP
• Genotyping was performed by a 2nd service provider. Initial
step was to perform sample QA on 8% of samples – benefit as
it confirms input sample quality.

28. Genotype Data Analysis
• Genotyping Files are large (2.7Gb/plate) - prearrange a sFTP site with
sufficient data capacity to allow for file transfer
• Define your QC approach prior to obtaining the results
• Confirm sex, ethnicity & identify relatedness between samples
• In 960 BC samples analyzed on the UK Biobank Array:
– >98% of samples had a call rate >99%
– 6% of sites were monomorphic, 2.5% of sites were out of HWE, and 11% of sites
had a MAF <1%.
– One pair of siblings was identified
– All samples were of western European ethnicity

29. Cost Modeling
• Developed a detailed time and resource spreadsheet, along with
instructions for how to complete
• Although much time and effort had been put into the spreadsheet it
wasn’t always clear for personnel where and if something was to be
recorded
• Feedback overwhelmingly indicated that the time data is an estimate
• Regional time differences were identified, although this was less
pronounce when multiple steps were grouped

30. Summary
• Inform workflows and SOPs
• Able to test the administrative component of providing samples for approved
requests
• Better insight into the required legal agreements
• Provides guidance for how best to provide samples for approved requests
• Develop a cost model
• Better understanding of the time and cost requirements
• Strengthen the resource
– DNA available on a subset of CPTP participants
– Extracted DNA is of high quality as demonstrated by the ability to meet the
Axiom gene chip requirements
– Will soon have genotype data on 5000 CPTP “healthy” Caucasian individuals

31. Acknowledgement
Philip Awadalla Jason Hicks
John Spinelli Melissa Moore
Mark Purdue Kelly McDonald
Trevor Dummer Catherine Boileau
Paula Robson Wendy Powell
Sebastien Jacquemont Heather Whelan
Anne Monique Nuyt Linda Greenhorn
Louise Parker Will Rosner
Alexandra Obadia Genevieve David
Anne-Marie Mes-Masson Jason Xu
Isabel Fortier Brenda Hahn
Bartha Knoppers Vanessa Bruat
Funding provided by Canadian Partnership Against Cancer

32. CPTP Portal: Single Point of Access
https://portal.partnershipfortomorrow.ca/
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