Joseph Tcherkezian-CARTaGENE Treena McDonald-BC Generations Project

CASE STUDY: Interoperability in the Context of a Federated Biobanking Project

Chronic diseases

The Global Burden of Disease Study

Demographic change in Canada

Source: CIHI

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.

CARTaGENE

Awadalla P., Boileau C., 2012

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Chronic diseases in CaG cohort

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

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

Canada’s Largest Population Health Research Platform, 300 000 participants !

A Pan Canadian Genotyping project within a federated cohort

CPTP: >300 000 participants

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.

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

Centralized vs Federated biobanking

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

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

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

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.

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

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

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)

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

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

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

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

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

Sample Storage

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

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.

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

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

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

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

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

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