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NGS Leaders :: Okay, You've Sequenced My Genome: Are You Sure You Got it Right?

Okay, You've Sequenced My Genome: Are You Sure You Got it Right?

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Editor’s Note: We are pleased to share a guest post submitted by Justin Zook and Marc Salit from the National Institute of Standards and Technology. 


January 3, 2013 : Clinical application of “Next-Generation Sequencing” for hereditary genetic diseases, oncology, and other purposes is rapidly growing.  At present, there are no widely accepted genomic standards or quantitative performance metrics for confidence in variant calling. These are needed to achieve the confidence in measurement results expected for sound, reproducible research and regulated applications in the clinic.  On April 13, 2012, the National Institute of Standards and Technology (NIST) convened the workshop Genome in a Bottle to initiate a consortium to develop the reference materials, reference methods, and reference data needed to assess confidence in human whole genome variant calls. A principal motivation for this consortium is to develop widely accepted reference materials and accompanying performance metrics to provide a strong scientific foundation for the development of regulations and professional standards for clinical sequencing.

The consortium has four working groups with the listed responsibilities:

  • Reference Material (RM) Selection and Design
  • Select appropriate cell lines for whole genome RMs and design synthetic DNA constructs that could be spiked-in to samples
  • Measurements for Reference Material Characterization,
  • Design and carry out experiments to characterize the RMs using multiple sequencing methods, other methods, and validation of selected variants using orthogonal technologies
  • Bioinformatics, Data Integration, and Data Representation
  • Develop methods to analyze and integrate the data for each RM, as well as select appropriate formats to represent the data
  • Performance Metrics and Figures of Merit
  • Develop useful performance metrics and figures of merit that can be obtained through measurement of the RMs

The products of these working groups will be a set of well-characterized whole genome and synthetic DNA RMs along with the methods (documentary standards) and reference data necessary for use of the RMs. These products will be designed to help enable translation of whole genome sequencing to clinical applications by providing widely accepted materials, methods, and data for performance assessment.

An open meeting was held August 16-17, 2012 at NIST in Gaithersburg, MD to receive public comment on this proposed work plan for the “Genome in a Bottle” Consortium.  Each working group developed a more detailed work plan, which is available in the slides and summary of the workshop. 

Since the workshop, there has been considerable discussion about what is an appropriate informed consent for whole genome Reference Materials from NIST. The consortium has decided to use the extensive existing data fromHapMap/CEPH/Utah Genetic Repository sample NA12878 and her pedigree for bioinformatics methods development, and NIST is seeking guidance from its IRB regarding the propriety of the current consent for a NIST Reference Material.  In parallel, the consortium has selected three father-mother-child trios with a more recent open consent from the Personal Genome Project for an initial set of NIST Reference Materials. When cell lines for these trios are available (hopefully in the next few months), the consortium will begin sequencing them with multiple sequencing technologies and library preparation methods. Over the next year, the consortium plans to select five additional trios from the Personal Genome Project as additional ethnic groups may choose to enroll.

On March 21, 2013 at 8:30am, the Genome in a Bottle Consortium is planning a morning session co-located with the XGen Congress in San Diego, CA. Each working group will present their progress and work plans and NIST will present its work forming consensus variant calls from multiple datasets on a single genome, followed by an open panel discussion with questions from the audience. All are welcome to attend this event free of charge, and we hope to see many of you there.  More information about the consortium can be found on the website www.genomeinabottle.org, and the consortium is always open to new members from public, private, and academic sectors. To receive updates, you can register and choose to receive newsletters by email on the website.


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