1. Genome-in-a-Bottle Consortium
Reference Materials for Clinical Applications of
Human Genome Sequencing
Marc Salit, Ph.D. and Justin Zook, Ph.D
National Institute of Standards and Technology

2. Vision
Reference Samples
12889 12890 12891 12892
12877 12878
Sample
Preparation
12879 12880 12881 12882 12883 12884 12885 12886 12887 12888 12893
Sequencing
Variant
Bioinformatics List, Performanc
e Metrics

3. NIST in partnership with FDA
• FDA calls for NIST RMs for • FDA funding work at NIST
WGS to develop reference
– “An RM from NIST has materials suitable to
great potential to facilitate support regulatory
FDA's regulatory approach oversight
to WGS, and would help
provide assurance that – materials to be used as
different sequencers at part of evaluation of
different locations had a technical performance of
particular level of ongoing sequencing instruments as
performance.” devices
• Elizabeth Mansfield,
Director, Personalized
Medicine Staff,
OIVD/CDRH/FDA

4. Value of a NIST RM
• NIST commitment to:
– Maintain availability of RM
– Maintain data on RM – ongoing
aggregation of sequence data to
increase accuracy and minimize
biases
– Be a neutral arbiter in aggregation
of data from different platforms
• NIST infrastructure to distribute
RM
• NIST investment in genomic
measurement science
• NIST imprimatur as an
internationally recognized source
of “higher order” RMs for
regulatory and commercial
purposes

5. Why a consortium?

6. NHGRI
ACLA

7. Genome in a Bottle
Consortium Development
• NIST met with sequencing • Open, public meeting at NIST to
technology developers to assess formally establish consortium,
standards needs present draft work plan
– Stanford, June 2011 – formed working groups
• Open, exploratory workshop – identified candidate genomes
– ASHG, Montreal, Canada – established principles of:
– October 2011 • reference material selection
• characterization
• Small, invitational workshop at • informatics
NIST to develop consortium for • performance metrics
human genome reference – August 2012
materials • Expect to be sequencing
– FDA, NCBI, NHGRI, NCI, CDC, Wash candidate genomes Q4 2012
U, Broad, technology developers,
clinical labs, CAP, PGP, Partners, – developing large RM batches to
ABRF, others characterize in 2013
– developed draft work plan • Website
– April 2012 – www.genomeinabottle.org

8. Genome in a Bottle Working Groups
Reference Material Meaurements for Bioninformatics, Dat Performance Metrics
Selection Reference Material a Integration, and & Figures of Merit
& Design Characterization Data Representation
Andrew Grupe, Elliott Margulies & Steve Sherry, NCBI Justin Johnson,
Celera Mike Eberle, Illumina EdgeBio
•Develop prioritized list •Develop consensus •Develop plan for •User interface to the
of whole human plan for experimental integrating Genome-in-a-Bottle
genomes for Reference characterization of experimental data and Reference Material
Materials Reference Materials forming consensus •“Dashboard”
•Identify candidate variant calls and •what an end user will
approaches and confidence estimates see and report to
materials for artificial •Develop consensus understand and
RMs plan for data describe the
•Develop prioritized representation performance of their
list experiment
•variant call accuracy
•process performance
measures to enable
optimization