March 2013 Introduction

Genome-in-a-Bottle Consortium

Reference Materials for Clinical Applications of Human Genome Sequencing

Marc Salit, Ph.D. and Justin Zook, Ph.DNational Institute of Standards and Technology

VisionReference Samples

Variant List, Performance

Metrics

SamplePreparation

Sequencing

Bioinformatics

NIST in partnership with FDA

• FDA calls for NIST RMs for WGS– “An RM from NIST has great

potential to facilitate FDA's regulatory approach to WGS, and would help provide assurance that different sequencers at different locations had a particular level of ongoing performance.”• Elizabeth Mansfield, Director,

Personalized Medicine Staff, OIVD/CDRH/FDA

• FDA funding work at NIST to develop reference materials suitable to support regulatory oversight– materials to be used as

part of evaluation of technical performance of sequencing instruments as devices

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

Why a consortium?

NHGRI

ACLA

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

• Expect to be sequencing candidate genomes Q4 2012– developing large RM batches to

characterize in 2013

• Website– www.genomeinabottle.org

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

Elliott Margulies & 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

Justin Johnson, EdgeBio

•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