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GIAB Introduction
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Genome in a Bottle Consortium August 2014
NIST, Gaithersburg, MD
Reference Materials for Clinical Applications of Human Genome Sequencing
Marc Salit, Ph.D. and Justin Zook, Ph.DNational Institute of Standards and Technology
Advances in Biological/Medical Measurement Science (ABMS @ Stanford)
Genome in a Bottle Consortium Development
• NIST met with sequencing technology developers to assess standards needs– Stanford, June 2011
• Open, exploratory workshop– ASHG, Montreal, Canada– October 2011
• Small, invitational workshop at NIST to develop consortium for human genome reference materials– FDA, NCBI, NHGRI, NCI, CDC, Wash
U, Broad, technology developers, clinical labs, CAP, PGP, Partners, ABRF, others
– developed draft work plan– April 2012
• Open, public meeting at NIST to formally establish consortium, present draft work plan– formed working groups– identified candidate genomes– established principles of:
• reference material selection• characterization• informatics• performance metrics
– August 2012
• Open, public workshop at XGen Congress– March 2013
• Biannual workshops – August 2013 at NIST– January 2014 at Stanford– August 2014 at NIST– January 29-30 2015 at Stanford
• Website– www.genomeinabottle.org
Well-characterized, stable RMs• Obtain metrics for validation,
QC, QA, PT• Determine sources and types
of bias/error• Learn to resolve difficult
structural variants• Improve reference genome
assembly• Optimization
– integration of data from multiple platforms
– sequencing and analysis
• Enable regulated applications
Comparison of SNP Calls forNA12878 on 2 platforms, 3
analysis methods
Measurement ProcessSample
gDNA isolation
Library Prep
Sequencing
Alignment/Mapping
Variant Calling
Confidence Estimates
Downstream Analysis
• gDNA reference materials will be developed to characterize performance of a part of process– materials will be certified
for their variants against a reference sequence, with confidence estimates
gene
ric m
easu
rem
ent p
roce
ss
• NIST working with GiaB to select genomes
• Current plan– NA12878 HapMap
sample as Pilot sample• part of 17-member
pedigree
– trios from PGP as more complete set• 2 trios, focus on children• varying biogeographic
ancestry
CEPH Utah Pedigree 1463
Putting “Genomes” in Bottles
11 children, Birth Order Redacted
Genome in a Bottle Working Groups
Reference Material Selection& Design
Andrew Grupe,Celera
•Develop prioritized list of whole human genomes for Reference Materials
• Identify candidate approaches and materials for artificial RMs•Develop prioritized list
Meaurements for Reference Material Characterization
Mike Eberle, Illumina
•Develop consensus plan for experimental characterization of Reference Materials
Bioninformatics, Data Integration, and Data Representation
Steve Sherry, NCBI
•Develop plan for integrating experimental data and forming consensus variant calls and confidence estimates
•Develop consensus plan for data representation
Performance Metrics & Figures of Merit
Deanna Church, Personalis
•User interface to the Genome-in-a-Bottle Reference Material• “Dashboard”•what an end user will
see and report to understand and describe the performance of their experiment• variant call accuracy•process performance
measures to enable optimization
Update
Zook et al., Nature Biotechnology, 2014.
• methods to develop SNP/indel call set described in manuscript
• broad and quick adoption of call set for benchmarking– struck nerve
• use scenarios a highlight of this workshop
Preliminary uses of high-confidence NIST-GIAB genotypes for NA12878
• NIST have released several versions of high-confidence genotypes for its pilot RM
• These data are presently being used for benchmarking– prior to release of RMs– SNPs & indels
• ~77% of the genome
Highlights
This workshop• release plans for pilot RM• characterization plans for
HG-002 – HG-005• prioritization of next
genomes• collaborations
– ABRF– Global Alliance
Upcoming• materials and methods to
support somatic variant calling
• integrating structural variants into the GIAB call sets
• crowdsourcing analysis• data analysis/code
jamboree
Agenda
Thursday• Welcome and Status Update• Charge to Working Groups• Break• Working Group Breakout
Discussions• Lunch (in NIST cafeteria)• FDA Perspective on Future
Needs • ABRF interlaboratory NGS study • Break• Working Group Breakout
Discussions continued
Friday• Working groups meet if needed• Working Group leaders present
plans and discussion• Break• Discussion of NIST Reference
Material Development plans• Discussion of Steering
Committee agenda items• Everyone adjourn except
steering committee• Steering committee meet over
lunch
AgendaMonday• Breakfast and registration• Welcome and Context Setting• NIST RM Update and Status Report• Charge to Working Groups• Coffee Break• Working Group Breakout Discussions• Lunch (provided)• Informal Working Group Reports• Coffee Break• Breakout Topical Discussions
– Topic #1: Moving beyond the 'easy' variants and regions of the genome
– Topic #2: Selecting future genomes for Reference Materials
Tuesday• Breakfast and registration• Use cases: Experiences using the
pilot Reference Material• Discussion of plans to release pilot
Reference Material• Coffee Break• Working Group Breakout
discussions• Lunch (provided)• Working Group leaders present
plans and discussion• Steering committee Overview• First meeting of the Steering
Committee (others adjourn)
Please Note
Slides will be made available on SlideShare after the workshop (see genomeinabottle.org).
Tweets are welcome unless the speaker requests otherwise. Please use #giab as the hashtag.
Plenary sessions are being broadcast as a webinar. Questions from webinar attendees can be submitted via chat
NIST Reference Materials
Pilot RM - NA12878• 8300 10ug vials of NA12878
gDNA @ NIST 4/2013– Available for sequencing by GIAB
participants– target for release as NIST RM
12/2014• SNPs, small indels
• Sequenced at 6 labs– 4 technologies, multiple modes
• Received “Human Subjects Approval” for release of NA12878 as NIST RM
Personal Genome Project• Ashkenazim trio DNA
received Feb 2014• Asian son DNA received Feb
2014– Parents’ cell lines at Coriell
• “Human subjects review” approval for release of PGP genomes as NIST RMs
• What future RMs are needed?
Consenting Genomes for use as Reference Materials
• Risk of re-identification– this is a real risk– privacy– implications for family members
• Meaning of possibility of withdrawal• Commercial application
– indirect, research– direct, derived products
• PGP project currently state-of-art– broad and direct– test to demonstrate understanding
• “Wild West”• Coriell MTA for PGP genomes now
explicitly permits commercial redistribution/modification/…
AMP Survey Using Pilot RM
AMP Members International
AMP Survey Future RM needs
AMP Members International