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precisionFDA Truth Challenge V2: Calling variants from short- and long-reads in difficult-to-map regions

View ORCID ProfileNathan D. Olson, Justin Wagner, Jennifer McDaniel, Sarah H. Stephens, Samuel T. Westreich, Anish G. Prasanna, Elaine Johanson, View ORCID ProfileEmily Boja, Ezekiel J. Maier, Omar Serang, View ORCID ProfileDavid Jáspez, View ORCID ProfileJosé M. Lorenzo-Salazar, Adrián Muñoz-Barrera, Luis A. Rubio-Rodríguez, View ORCID ProfileCarlos Flores, Konstantinos Kyriakidis, View ORCID ProfileAndigoni Malousi, Kishwar Shafin, View ORCID ProfileTrevor Pesout, Miten Jain, Benedict Paten, Pi-Chuan Chang, Alexey Kolesnikov, Maria Nattestad, Gunjan Baid, Sidharth Goel, Howard Yang, Andrew Carroll, Robert Eveleigh, Mathieu Bourgey, View ORCID ProfileGuillaume Bourque, Gen Li, MA ChouXian, LinQi Tang, DU YuanPing, ShaoWei Zhang, View ORCID ProfileJordi Morata, View ORCID ProfileRaúl Tonda, View ORCID ProfileGenís Parra, View ORCID ProfileJean-Rémi Trotta, View ORCID ProfileChristian Brueffer, View ORCID ProfileSinem Demirkaya-Budak, Duygu Kabakci-Zorlu, Deniz Turgut, Özem Kalay, View ORCID ProfileGungor Budak, Kübra Narcı, Elif Arslan, Richard Brown, Ivan J Johnson, Alexey Dolgoborodov, Vladimir Semenyuk, Amit Jain, View ORCID ProfileH. Serhat Tetikol, Varun Jain, Mike Ruehle, Bryan Lajoie, Cooper Roddey, Severine Catreux, Rami Mehio, Mian Umair Ahsan, Qian Liu, Kai Wang, Sayed Mohammad Ebrahim Sahraeian, View ORCID ProfileLi Tai Fang, Marghoob Mohiyuddin, Calvin Hung, Chirag Jain, Hanying Feng, Zhipan Li, Luoqi Chen, View ORCID ProfileFritz J. Sedlazeck, View ORCID ProfileJustin M. Zook
doi: https://doi.org/10.1101/2020.11.13.380741
Nathan D. Olson
1Material Measurement Laboratory, National Institute of Standards and Technology, 100 Bureau Dr, MS8312, Gaithersburg, MD 20899
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  • ORCID record for Nathan D. Olson
  • For correspondence: nolson@nist.gov justin.zook@nist.gov
Justin Wagner
1Material Measurement Laboratory, National Institute of Standards and Technology, 100 Bureau Dr, MS8312, Gaithersburg, MD 20899
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Jennifer McDaniel
1Material Measurement Laboratory, National Institute of Standards and Technology, 100 Bureau Dr, MS8312, Gaithersburg, MD 20899
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Sarah H. Stephens
2Booz Allen Hamilton, 8283 Greensboro Drive Mclean, VA 22102
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Samuel T. Westreich
3DNAnexus, Inc., 1975 W El Camino Real #204, Mountain View, CA 94040
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Anish G. Prasanna
2Booz Allen Hamilton, 8283 Greensboro Drive Mclean, VA 22102
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Elaine Johanson
4Office of Health Informatics, Office of the Chief Scientist, Office of the Commissioner, US Food and Drug Administration, Silver Spring, MD, USA
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Emily Boja
4Office of Health Informatics, Office of the Chief Scientist, Office of the Commissioner, US Food and Drug Administration, Silver Spring, MD, USA
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Ezekiel J. Maier
2Booz Allen Hamilton, 8283 Greensboro Drive Mclean, VA 22102
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Omar Serang
3DNAnexus, Inc., 1975 W El Camino Real #204, Mountain View, CA 94040
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David Jáspez
5Genomics Division, Instituto Tecnológico y de Energías Renovables (ITER), Santa Cruz de Tenerife, Spain
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José M. Lorenzo-Salazar
5Genomics Division, Instituto Tecnológico y de Energías Renovables (ITER), Santa Cruz de Tenerife, Spain
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  • ORCID record for José M. Lorenzo-Salazar
Adrián Muñoz-Barrera
5Genomics Division, Instituto Tecnológico y de Energías Renovables (ITER), Santa Cruz de Tenerife, Spain
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Luis A. Rubio-Rodríguez
5Genomics Division, Instituto Tecnológico y de Energías Renovables (ITER), Santa Cruz de Tenerife, Spain
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Carlos Flores
5Genomics Division, Instituto Tecnológico y de Energías Renovables (ITER), Santa Cruz de Tenerife, Spain
6CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain
7Research Unit, Hospital Universitario N.S. de Candelaria, Santa Cruz de Tenerife, Spain
8Instituto de Tecnologías Biomédicas (ITB), Universidad de La Laguna, 38200 San Cristóbal de La Laguna, Spain
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Konstantinos Kyriakidis
9School of Pharmacy, Aristotle University of Thessaloniki (AUTH), 541 24 Thessaloniki, Greece
10Genomics and Epigenomics Translational Research (GENeTres), Center for Interdisciplinary Research and Innovation, 570 01 Thessaloniki, Greece
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Andigoni Malousi
10Genomics and Epigenomics Translational Research (GENeTres), Center for Interdisciplinary Research and Innovation, 570 01 Thessaloniki, Greece
11Laboratory of Biological Chemistry, School of Medicine, Aristotle University of Thessaloniki (AUTH), 541 24 Thessaloniki, Greece
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Kishwar Shafin
12UC Santa Cruz Genomics Institute, University of California, Santa Cruz, 1156 High Street, Santa Cruz, CA, USA
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Trevor Pesout
12UC Santa Cruz Genomics Institute, University of California, Santa Cruz, 1156 High Street, Santa Cruz, CA, USA
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Miten Jain
12UC Santa Cruz Genomics Institute, University of California, Santa Cruz, 1156 High Street, Santa Cruz, CA, USA
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Benedict Paten
12UC Santa Cruz Genomics Institute, University of California, Santa Cruz, 1156 High Street, Santa Cruz, CA, USA
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Pi-Chuan Chang
13Google Inc, 1600 Amphitheatre Pkwy, Mountain View, CA 94040
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Alexey Kolesnikov
13Google Inc, 1600 Amphitheatre Pkwy, Mountain View, CA 94040
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Maria Nattestad
13Google Inc, 1600 Amphitheatre Pkwy, Mountain View, CA 94040
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Gunjan Baid
13Google Inc, 1600 Amphitheatre Pkwy, Mountain View, CA 94040
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Sidharth Goel
13Google Inc, 1600 Amphitheatre Pkwy, Mountain View, CA 94040
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Howard Yang
13Google Inc, 1600 Amphitheatre Pkwy, Mountain View, CA 94040
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Andrew Carroll
13Google Inc, 1600 Amphitheatre Pkwy, Mountain View, CA 94040
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Robert Eveleigh
14The Canadian Center for Computational Genomics (C3G)
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Mathieu Bourgey
14The Canadian Center for Computational Genomics (C3G)
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Guillaume Bourque
14The Canadian Center for Computational Genomics (C3G)
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Gen Li
15HuXinDao, QingZhuHu TaiYangShan Road, KaiFu, ChangSha, HuNan, China
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MA ChouXian
15HuXinDao, QingZhuHu TaiYangShan Road, KaiFu, ChangSha, HuNan, China
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LinQi Tang
15HuXinDao, QingZhuHu TaiYangShan Road, KaiFu, ChangSha, HuNan, China
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DU YuanPing
15HuXinDao, QingZhuHu TaiYangShan Road, KaiFu, ChangSha, HuNan, China
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ShaoWei Zhang
15HuXinDao, QingZhuHu TaiYangShan Road, KaiFu, ChangSha, HuNan, China
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Jordi Morata
16CNAG-CRG, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Baldiri i Reixac 4, 08028 Barcelona, Spain; Universitat Pompeu Fabra (UPF), Barcelona, Spain
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Raúl Tonda
16CNAG-CRG, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Baldiri i Reixac 4, 08028 Barcelona, Spain; Universitat Pompeu Fabra (UPF), Barcelona, Spain
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Genís Parra
16CNAG-CRG, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Baldiri i Reixac 4, 08028 Barcelona, Spain; Universitat Pompeu Fabra (UPF), Barcelona, Spain
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Jean-Rémi Trotta
16CNAG-CRG, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Baldiri i Reixac 4, 08028 Barcelona, Spain; Universitat Pompeu Fabra (UPF), Barcelona, Spain
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Christian Brueffer
17Division of Oncology, Department of Clinical Sciences, Lund University, Lund, Sweden
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Sinem Demirkaya-Budak
18Seven Bridges Genomics, Inc, Charlestown, MA, USA
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Duygu Kabakci-Zorlu
18Seven Bridges Genomics, Inc, Charlestown, MA, USA
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Deniz Turgut
18Seven Bridges Genomics, Inc, Charlestown, MA, USA
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Özem Kalay
18Seven Bridges Genomics, Inc, Charlestown, MA, USA
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Gungor Budak
18Seven Bridges Genomics, Inc, Charlestown, MA, USA
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Kübra Narcı
18Seven Bridges Genomics, Inc, Charlestown, MA, USA
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Elif Arslan
18Seven Bridges Genomics, Inc, Charlestown, MA, USA
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Richard Brown
18Seven Bridges Genomics, Inc, Charlestown, MA, USA
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Ivan J Johnson
18Seven Bridges Genomics, Inc, Charlestown, MA, USA
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Alexey Dolgoborodov
18Seven Bridges Genomics, Inc, Charlestown, MA, USA
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Vladimir Semenyuk
18Seven Bridges Genomics, Inc, Charlestown, MA, USA
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Amit Jain
18Seven Bridges Genomics, Inc, Charlestown, MA, USA
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H. Serhat Tetikol
18Seven Bridges Genomics, Inc, Charlestown, MA, USA
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Varun Jain
19Illumina, Inc
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Mike Ruehle
19Illumina, Inc
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Bryan Lajoie
19Illumina, Inc
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Cooper Roddey
19Illumina, Inc
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Severine Catreux
19Illumina, Inc
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Rami Mehio
19Illumina, Inc
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Mian Umair Ahsan
20Raymond G. Perelman Center for Cellular and Molecular Therapeutics, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
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Qian Liu
20Raymond G. Perelman Center for Cellular and Molecular Therapeutics, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
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Kai Wang
20Raymond G. Perelman Center for Cellular and Molecular Therapeutics, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
21Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
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Sayed Mohammad Ebrahim Sahraeian
22Roche Sequencing Solutions, Santa Clara, CA, 95050, USA
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Li Tai Fang
22Roche Sequencing Solutions, Santa Clara, CA, 95050, USA
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Marghoob Mohiyuddin
22Roche Sequencing Solutions, Santa Clara, CA, 95050, USA
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Calvin Hung
23WASAI Technology, Taipei, Taiwan
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Chirag Jain
24National Human Genome Research Institute, National Institutes of Health
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Hanying Feng
25Sentieon Inc., San Jose, CA
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Zhipan Li
25Sentieon Inc., San Jose, CA
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Luoqi Chen
25Sentieon Inc., San Jose, CA
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Fritz J. Sedlazeck
26Human Genome Sequencing Center, Baylor College of Medicine, One Baylor Plaza, Houston TX 77030
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  • ORCID record for Fritz J. Sedlazeck
Justin M. Zook
1Material Measurement Laboratory, National Institute of Standards and Technology, 100 Bureau Dr, MS8312, Gaithersburg, MD 20899
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  • For correspondence: nolson@nist.gov justin.zook@nist.gov
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Summary

The precisionFDA Truth Challenge V2 aimed to assess the state-of-the-art of variant calling in difficult-to-map regions and the Major Histocompatibility Complex (MHC). Starting with FASTQ files, 20 challenge participants applied their variant calling pipelines and submitted 64 variant callsets for one or more sequencing technologies (~35X Illumina, ~35X PacBio HiFi, and ~50X Oxford Nanopore Technologies). Submissions were evaluated following best practices for benchmarking small variants with the new GIAB benchmark sets and genome stratifications. Challenge submissions included a number of innovative methods for all three technologies, with graph-based and machine-learning methods scoring best for short-read and long-read datasets, respectively. New methods out-performed the 2016 Truth Challenge winners, and new machine-learning approaches combining multiple sequencing technologies performed particularly well. Recent developments in sequencing and variant calling have enabled benchmarking variants in challenging genomic regions, paving the way for the identification of previously unknown clinically relevant variants.

Competing Interest Statement

C.B. is an employee and shareholder of SAGA Diagnostics AB.

A.C., P.C., A.K., M.N., G.B., S.G., and H.Y. are employees of Google and A.C. is a shareholder.

S.D., D.K., D.T., O.K., G.B., K.N., E.A., R.B., I.J.J., A.D., V.S., A.J., and H.S.T. are employees of Seven Bridges Genomics.

O.S. and S.T.W. are employees of DNAnexus.

G.L, C.M, L.T., Y.D., and S.Z. are employees of Genetalks.

V.J., M.R., B.L., C.R, S.C., and R.M are employees of Illumina.

S.M.E.S., and M.M. are employees of Roche.

C.H. is an employee of Wasai Technology.

H.F., Z.L, and L.C. are employees of Sentieon Inc.

Footnotes

  • Updated data availability section to include DOI for the archived dataset.

  • https://doi.org/10.18434/mds2-2336

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. This article is a US Government work. It is not subject to copyright under 17 USC 105 and is also made available for use under a CC0 license.
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precisionFDA Truth Challenge V2: Calling variants from short- and long-reads in difficult-to-map regions
Nathan D. Olson, Justin Wagner, Jennifer McDaniel, Sarah H. Stephens, Samuel T. Westreich, Anish G. Prasanna, Elaine Johanson, Emily Boja, Ezekiel J. Maier, Omar Serang, David Jáspez, José M. Lorenzo-Salazar, Adrián Muñoz-Barrera, Luis A. Rubio-Rodríguez, Carlos Flores, Konstantinos Kyriakidis, Andigoni Malousi, Kishwar Shafin, Trevor Pesout, Miten Jain, Benedict Paten, Pi-Chuan Chang, Alexey Kolesnikov, Maria Nattestad, Gunjan Baid, Sidharth Goel, Howard Yang, Andrew Carroll, Robert Eveleigh, Mathieu Bourgey, Guillaume Bourque, Gen Li, MA ChouXian, LinQi Tang, DU YuanPing, ShaoWei Zhang, Jordi Morata, Raúl Tonda, Genís Parra, Jean-Rémi Trotta, Christian Brueffer, Sinem Demirkaya-Budak, Duygu Kabakci-Zorlu, Deniz Turgut, Özem Kalay, Gungor Budak, Kübra Narcı, Elif Arslan, Richard Brown, Ivan J Johnson, Alexey Dolgoborodov, Vladimir Semenyuk, Amit Jain, H. Serhat Tetikol, Varun Jain, Mike Ruehle, Bryan Lajoie, Cooper Roddey, Severine Catreux, Rami Mehio, Mian Umair Ahsan, Qian Liu, Kai Wang, Sayed Mohammad Ebrahim Sahraeian, Li Tai Fang, Marghoob Mohiyuddin, Calvin Hung, Chirag Jain, Hanying Feng, Zhipan Li, Luoqi Chen, Fritz J. Sedlazeck, Justin M. Zook
bioRxiv 2020.11.13.380741; doi: https://doi.org/10.1101/2020.11.13.380741
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precisionFDA Truth Challenge V2: Calling variants from short- and long-reads in difficult-to-map regions
Nathan D. Olson, Justin Wagner, Jennifer McDaniel, Sarah H. Stephens, Samuel T. Westreich, Anish G. Prasanna, Elaine Johanson, Emily Boja, Ezekiel J. Maier, Omar Serang, David Jáspez, José M. Lorenzo-Salazar, Adrián Muñoz-Barrera, Luis A. Rubio-Rodríguez, Carlos Flores, Konstantinos Kyriakidis, Andigoni Malousi, Kishwar Shafin, Trevor Pesout, Miten Jain, Benedict Paten, Pi-Chuan Chang, Alexey Kolesnikov, Maria Nattestad, Gunjan Baid, Sidharth Goel, Howard Yang, Andrew Carroll, Robert Eveleigh, Mathieu Bourgey, Guillaume Bourque, Gen Li, MA ChouXian, LinQi Tang, DU YuanPing, ShaoWei Zhang, Jordi Morata, Raúl Tonda, Genís Parra, Jean-Rémi Trotta, Christian Brueffer, Sinem Demirkaya-Budak, Duygu Kabakci-Zorlu, Deniz Turgut, Özem Kalay, Gungor Budak, Kübra Narcı, Elif Arslan, Richard Brown, Ivan J Johnson, Alexey Dolgoborodov, Vladimir Semenyuk, Amit Jain, H. Serhat Tetikol, Varun Jain, Mike Ruehle, Bryan Lajoie, Cooper Roddey, Severine Catreux, Rami Mehio, Mian Umair Ahsan, Qian Liu, Kai Wang, Sayed Mohammad Ebrahim Sahraeian, Li Tai Fang, Marghoob Mohiyuddin, Calvin Hung, Chirag Jain, Hanying Feng, Zhipan Li, Luoqi Chen, Fritz J. Sedlazeck, Justin M. Zook
bioRxiv 2020.11.13.380741; doi: https://doi.org/10.1101/2020.11.13.380741

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