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Reproducible integration of multiple sequencing datasets to form high-confidence SNP, indel, and reference calls for five human genome reference materials

Justin M. Zook, Jennifer McDaniel, Hemang Parikh, Haynes Heaton, Sean A. Irvine, Len Trigg, Rebecca Truty, Cory Y. McLean, Francisco M. De La Vega, Chunlin Xiao, Stephen Sherry, Marc Salit
doi: https://doi.org/10.1101/281006
Justin M. Zook
1Genome-scale Measurements Group, National Institute of Standards and Technology, 100 Bureau Dr., Gaithersburg, MD 20899
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Jennifer McDaniel
1Genome-scale Measurements Group, National Institute of Standards and Technology, 100 Bureau Dr., Gaithersburg, MD 20899
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Hemang Parikh
1Genome-scale Measurements Group, National Institute of Standards and Technology, 100 Bureau Dr., Gaithersburg, MD 20899
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Haynes Heaton
210x Genomics, 7068 Koll Center Parkway, Pleasanton CA, 94566
3Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge UK, CB10 1SA
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Sean A. Irvine
4Real Time Genomics, Level 1, South Bloc, 19 Knox St., Hamilton 3204, New Zealand
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Len Trigg
4Real Time Genomics, Level 1, South Bloc, 19 Knox St., Hamilton 3204, New Zealand
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Rebecca Truty
5Invitae Corporation, 1400 16th St., San Francisco, CA, 94103, USA
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Cory Y. McLean
6Verily Life Sciences, 269 E Grand Ave, South San Francisco, CA, 94080, USA
7Google Inc., 1600 Amphitheatre Pkwy, Mountain View, CA 94043, USA
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Francisco M. De La Vega
8Department of Biomedical Data Science, Stanford University School of Medicine, Stanford, CA, USA
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Chunlin Xiao
9National Center for Biotechnology Information, National Institutes of Health, Bethesda, MD
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Stephen Sherry
9National Center for Biotechnology Information, National Institutes of Health, Bethesda, MD
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Marc Salit
1Genome-scale Measurements Group, National Institute of Standards and Technology, 100 Bureau Dr., Gaithersburg, MD 20899
10Joint Initiative for Metrology in Biology, Stanford, CA 94305, USA
11Department of Bioengineering, Stanford University, Stanford, CA 94305
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Abstract

Benchmark small variant calls from the Genome in a Bottle Consortium (GIAB) for the CEPH/HapMap genome NA12878 (HG001) have been used extensively for developing, optimizing, and demonstrating performance of sequencing and bioinformatics methods. Here, we develop a reproducible, cloud-based pipeline to integrate multiple sequencing datasets and form benchmark calls, enabling application to arbitrary human genomes. We use these reproducible methods to form high-confidence calls with respect to GRCh37 and GRCh38 for HG001 and 4 additional broadly-consented genomes from the Personal Genome Project that are available as NIST Reference Materials. These new genomes’ broad, open consent with few restrictions on availability of samples and data is enabling a uniquely diverse array of applications. Our new methods produce 17% more high-confidence SNPs, 176% more indels, and 12% larger regions than our previously published calls. To demonstrate that these calls can be used for accurate benchmarking, we compare other high-quality callsets to ours (e.g., Illumina Platinum Genomes), and we demonstrate that the majority of discordant calls are errors in the other callsets, We also highlight challenges in interpreting performance metrics when benchmarking against imperfect high-confidence calls. We show that benchmarking tools from the Global Alliance for Genomics and Health can be used with our calls to stratify performance metrics by variant type and genome context and elucidate strengths and weaknesses of a method.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted May 25, 2018.
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Reproducible integration of multiple sequencing datasets to form high-confidence SNP, indel, and reference calls for five human genome reference materials
Justin M. Zook, Jennifer McDaniel, Hemang Parikh, Haynes Heaton, Sean A. Irvine, Len Trigg, Rebecca Truty, Cory Y. McLean, Francisco M. De La Vega, Chunlin Xiao, Stephen Sherry, Marc Salit
bioRxiv 281006; doi: https://doi.org/10.1101/281006
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Reproducible integration of multiple sequencing datasets to form high-confidence SNP, indel, and reference calls for five human genome reference materials
Justin M. Zook, Jennifer McDaniel, Hemang Parikh, Haynes Heaton, Sean A. Irvine, Len Trigg, Rebecca Truty, Cory Y. McLean, Francisco M. De La Vega, Chunlin Xiao, Stephen Sherry, Marc Salit
bioRxiv 281006; doi: https://doi.org/10.1101/281006

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