Abstract
Background: There is tremendous potential for genome sequencing to improve clinical diagnosis and care once it becomes routinely accessible, but this will require formalizing research methods into clinical best practices in the areas of sequence data generation, analysis, interpretation and reporting. The CLARITY Challenge was designed to spur convergence in methods for diagnosing genetic disease starting from clinical case history and genome sequencing data. DNA samples were obtained from three families with heritable genetic disorders and genomic sequence data were donated by sequencing platform vendors. The challenge was to analyze and interpret these data with the goals of identifying disease-causing variants and reporting the findings in a clinically useful format. Participating contestant groups were solicited broadly, and an independent panel of judges evaluated their performance. Results: A total of 30 international groups were engaged. The entries reveal a general convergence of practices on most elements of the analysis and interpretation process. However, even given this commonality of approach, only two groups identified the consensus candidate variants in all disease cases, demonstrating a need for consistent fine-tuning of the generally accepted methods. There was greater diversity of the final clinical report content and in the patient consenting process, demonstrating that these areas require additional exploration and standardization. Conclusions: The CLARITY Challenge provides a comprehensive assessment of current practices for using genome sequencing to diagnose and report genetic diseases. There is remarkable convergence in bioinformatic techniques, but medical interpretation and reporting are areas that require further development by many groups.
Original language | English |
---|---|
Article number | R53 |
Journal | Genome biology |
Volume | 15 |
Issue number | 3 |
DOIs | |
State | Published - 2014 |
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An international effort towards developing standards for best practices in analysis, interpretation and reporting of clinical genome sequencing results in the CLARITY Challenge. / Brownstein, Catherine A.; Beggs, Alan H.; Homer, Nils; Merriman, Barry; Yu, Timothy W.; Flannery, Katherine C.; DeChene, Elizabeth T.; Towne, Meghan C.; Savage, Sarah K.; Price, Emily N.; Holm, Ingrid A.; Luquette, Lovelace J.; Lyon, Elaine; Majzoub, Joseph; Neupert, Peter; McCallie, David; Szolovits, Peter; Willard, Huntington F.; Mendelsohn, Nancy J.; Temme, Renee; Finkel, Richard S.; Yum, Sabrina W.; Medne, Livija; Sunyaev, Shamil R.; Adzhubey, Ivan; Cassa, Christopher A.; De Bakker, Paul I.W.; Duzkale, Hatice; Dworzyński, Piotr; Fairbrother, William; Francioli, Laurent; Funke, Birgit H.; Giovanni, Monica A.; Handsaker, Robert E.; Lage, Kasper; Lebo, Matthew S.; Lek, Monkol; Leshchiner, Ignaty; MacArthur, Daniel G.; McLaughlin, Heather M.; Murray, Michael F.; Pers, Tune H.; Polak, Paz P.; Raychaudhuri, Soumya; Rehm, Heidi L.; Soemedi, Rachel; Stitziel, Nathan O.; Vestecka, Sara; Supper, Jochen; Gugenmus, Claudia; Klocke, Bernward; Hahn, Alexander; Schubach, Max; Menzel, Mortiz; Biskup, Saskia; Freisinger, Peter; Deng, Mario; Braun, Martin; Perner, Sven; Smith, Richard J.H.; Andorf, Janeen L.; Huang, Jian; Ryckman, Kelli; Sheffield, Val C.; Stone, Edwin M.; Bair, Thomas; Ann Black-Ziegelbein, E.; Braun, Terry A.; Darbro, Benjamin; DeLuca, Adam P.; Kolbe, Diana L.; Scheetz, Todd E.; Shearer, Aiden E.; Sompallae, Rama; Wang, Kai; Bassuk, Alexander G.; Edens, Erik; Mathews, Katherine; Moore, Steven A.; Shchelochkov, Oleg A.; Trapane, Pamela; Bossler, Aaron; Campbell, Colleen A.; Heusel, Jonathan W.; Kwitek, Anne; Maga, Tara; Panzer, Karin; Wassink, Thomas; Van Daele, Douglas; Azaiez, Hela; Booth, Kevin; Meyer, Nic; Segal, Michael M.; Williams, Marc S.; Tromp, Gerard; White, Peter; Corsmeier, Donald; Fitzgerald-Butt, Sara; Herman, Gail; Lamb-Thrush, Devon; McBride, Kim L.; Newsom, David; Pierson, Christopher R.; Rakowsky, Alexander T.; Maver, Aleš; Lovrečić, Luca; Palandačić, Anja; Peterlin, Borut; Torkamani, Ali; Wedell, Anna; Huss, Mikael; Alexeyenko, Andrey; Lindvall, Jessica M.; Magnusson, Måns; Nilsson, Daniel; Stranneheim, Henrik; Taylan, Fulya; Gilissen, Christian; Hoischen, Alexander; Van Bon, Bregje; Yntema, Helger; Nelen, Marcel; Zhang, Weidong; Sager, Jason; Zhang, Lu; Blair, Kathryn; Kural, Deniz; Cariaso, Michael; Lennon, Greg G.; Javed, Asif; Agrawal, Saloni; Ng, Pauline C.; Sandhu, Komal S.; Krishna, Shuba; Veeramachaneni, Vamsi; Isakov, Ofer; Halperin, Eran; Friedman, Eitan; Shomron, Noam; Glusman, Gustavo; Roach, Jared C.; Caballero, Juan; Cox, Hannah C.; Mauldin, Denise; Ament, Seth A.; Rowen, Lee; Richards, Daniel R.; Anthony San Lucas, F.; Gonzalez-Garay, Manuel L.; Thomas Caskey, C.; Bai, Yu; Huang, Ying; Fang, Fang; Zhang, Yan; Wang, Zhengyuan; Barrera, Jorge; Garcia-Lobo, Juan M.; González-Lamuño, Domingo; Llorca, Javier; Rodriguez, Maria C.; Varela, Ignacio; Reese, Martin G.; De La Vega, Francisco M.; Kiruluta, Edward; Cargill, Michele; Hart, Reece K.; Sorenson, Jon M.; Lyon, Gholson J.; Stevenson, David A.; Bray, Bruce E.; Moore, Barry M.; Eilbeck, Karen; Yandell, Mark; Zhao, Hongyu; Hou, Lin; Chen, Xiaowei; Yan, Xiting; Chen, Mengjie; Li, Cong; Yang, Can; Gunel, Murat; Li, Peining; Kong, Yong; Alexander, Austin C.; Albertyn, Zayed I.; Boycott, Kym M.; Bulman, Dennis E.; Gordon, Paul M.K.; Micheil Innes, A.; Knoppers, Bartha M.; Majewski, Jacek; Marshall, Christian R.; Parboosingh, Jillian S.; Sawyer, Sarah L.; Samuels, Mark E.; Schwartzentruber, Jeremy; Kohane, Isaac S.; Margulies, David M.
In: Genome biology, Vol. 15, No. 3, R53, 2014.Research output: Contribution to journal › Article › peer-review
TY - JOUR
T1 - An international effort towards developing standards for best practices in analysis, interpretation and reporting of clinical genome sequencing results in the CLARITY Challenge
AU - Brownstein, Catherine A.
AU - Beggs, Alan H.
AU - Homer, Nils
AU - Merriman, Barry
AU - Yu, Timothy W.
AU - Flannery, Katherine C.
AU - DeChene, Elizabeth T.
AU - Towne, Meghan C.
AU - Savage, Sarah K.
AU - Price, Emily N.
AU - Holm, Ingrid A.
AU - Luquette, Lovelace J.
AU - Lyon, Elaine
AU - Majzoub, Joseph
AU - Neupert, Peter
AU - McCallie, David
AU - Szolovits, Peter
AU - Willard, Huntington F.
AU - Mendelsohn, Nancy J.
AU - Temme, Renee
AU - Finkel, Richard S.
AU - Yum, Sabrina W.
AU - Medne, Livija
AU - Sunyaev, Shamil R.
AU - Adzhubey, Ivan
AU - Cassa, Christopher A.
AU - De Bakker, Paul I.W.
AU - Duzkale, Hatice
AU - Dworzyński, Piotr
AU - Fairbrother, William
AU - Francioli, Laurent
AU - Funke, Birgit H.
AU - Giovanni, Monica A.
AU - Handsaker, Robert E.
AU - Lage, Kasper
AU - Lebo, Matthew S.
AU - Lek, Monkol
AU - Leshchiner, Ignaty
AU - MacArthur, Daniel G.
AU - McLaughlin, Heather M.
AU - Murray, Michael F.
AU - Pers, Tune H.
AU - Polak, Paz P.
AU - Raychaudhuri, Soumya
AU - Rehm, Heidi L.
AU - Soemedi, Rachel
AU - Stitziel, Nathan O.
AU - Vestecka, Sara
AU - Supper, Jochen
AU - Gugenmus, Claudia
AU - Klocke, Bernward
AU - Hahn, Alexander
AU - Schubach, Max
AU - Menzel, Mortiz
AU - Biskup, Saskia
AU - Freisinger, Peter
AU - Deng, Mario
AU - Braun, Martin
AU - Perner, Sven
AU - Smith, Richard J.H.
AU - Andorf, Janeen L.
AU - Huang, Jian
AU - Ryckman, Kelli
AU - Sheffield, Val C.
AU - Stone, Edwin M.
AU - Bair, Thomas
AU - Ann Black-Ziegelbein, E.
AU - Braun, Terry A.
AU - Darbro, Benjamin
AU - DeLuca, Adam P.
AU - Kolbe, Diana L.
AU - Scheetz, Todd E.
AU - Shearer, Aiden E.
AU - Sompallae, Rama
AU - Wang, Kai
AU - Bassuk, Alexander G.
AU - Edens, Erik
AU - Mathews, Katherine
AU - Moore, Steven A.
AU - Shchelochkov, Oleg A.
AU - Trapane, Pamela
AU - Bossler, Aaron
AU - Campbell, Colleen A.
AU - Heusel, Jonathan W.
AU - Kwitek, Anne
AU - Maga, Tara
AU - Panzer, Karin
AU - Wassink, Thomas
AU - Van Daele, Douglas
AU - Azaiez, Hela
AU - Booth, Kevin
AU - Meyer, Nic
AU - Segal, Michael M.
AU - Williams, Marc S.
AU - Tromp, Gerard
AU - White, Peter
AU - Corsmeier, Donald
AU - Fitzgerald-Butt, Sara
AU - Herman, Gail
AU - Lamb-Thrush, Devon
AU - McBride, Kim L.
AU - Newsom, David
AU - Pierson, Christopher R.
AU - Rakowsky, Alexander T.
AU - Maver, Aleš
AU - Lovrečić, Luca
AU - Palandačić, Anja
AU - Peterlin, Borut
AU - Torkamani, Ali
AU - Wedell, Anna
AU - Huss, Mikael
AU - Alexeyenko, Andrey
AU - Lindvall, Jessica M.
AU - Magnusson, Måns
AU - Nilsson, Daniel
AU - Stranneheim, Henrik
AU - Taylan, Fulya
AU - Gilissen, Christian
AU - Hoischen, Alexander
AU - Van Bon, Bregje
AU - Yntema, Helger
AU - Nelen, Marcel
AU - Zhang, Weidong
AU - Sager, Jason
AU - Zhang, Lu
AU - Blair, Kathryn
AU - Kural, Deniz
AU - Cariaso, Michael
AU - Lennon, Greg G.
AU - Javed, Asif
AU - Agrawal, Saloni
AU - Ng, Pauline C.
AU - Sandhu, Komal S.
AU - Krishna, Shuba
AU - Veeramachaneni, Vamsi
AU - Isakov, Ofer
AU - Halperin, Eran
AU - Friedman, Eitan
AU - Shomron, Noam
AU - Glusman, Gustavo
AU - Roach, Jared C.
AU - Caballero, Juan
AU - Cox, Hannah C.
AU - Mauldin, Denise
AU - Ament, Seth A.
AU - Rowen, Lee
AU - Richards, Daniel R.
AU - Anthony San Lucas, F.
AU - Gonzalez-Garay, Manuel L.
AU - Thomas Caskey, C.
AU - Bai, Yu
AU - Huang, Ying
AU - Fang, Fang
AU - Zhang, Yan
AU - Wang, Zhengyuan
AU - Barrera, Jorge
AU - Garcia-Lobo, Juan M.
AU - González-Lamuño, Domingo
AU - Llorca, Javier
AU - Rodriguez, Maria C.
AU - Varela, Ignacio
AU - Reese, Martin G.
AU - De La Vega, Francisco M.
AU - Kiruluta, Edward
AU - Cargill, Michele
AU - Hart, Reece K.
AU - Sorenson, Jon M.
AU - Lyon, Gholson J.
AU - Stevenson, David A.
AU - Bray, Bruce E.
AU - Moore, Barry M.
AU - Eilbeck, Karen
AU - Yandell, Mark
AU - Zhao, Hongyu
AU - Hou, Lin
AU - Chen, Xiaowei
AU - Yan, Xiting
AU - Chen, Mengjie
AU - Li, Cong
AU - Yang, Can
AU - Gunel, Murat
AU - Li, Peining
AU - Kong, Yong
AU - Alexander, Austin C.
AU - Albertyn, Zayed I.
AU - Boycott, Kym M.
AU - Bulman, Dennis E.
AU - Gordon, Paul M.K.
AU - Micheil Innes, A.
AU - Knoppers, Bartha M.
AU - Majewski, Jacek
AU - Marshall, Christian R.
AU - Parboosingh, Jillian S.
AU - Sawyer, Sarah L.
AU - Samuels, Mark E.
AU - Schwartzentruber, Jeremy
AU - Kohane, Isaac S.
AU - Margulies, David M.
N1 - Funding Information: This work was supported by funds provided through the Gene Partnership and the Manton Center for Orphan Disease Research at Boston Children’s Hospital and the Center for Biomedical Informatics at Harvard Medical School and by generous donations in-kind of genomic sequencing services by Life Technologies (Carlsbad, CA, USA) and Complete Genomics (Mountain View, CA, USA). All the authors would especially like to thank the families for their participation and resulting critical contributions to this study. The study organizers would also like to thank Elizabeth Andrews and Keri Steadman for seminal contributions to the contest planning, Peter Kang for assistance tabulating patient phenotypes, Lindsay Swanson for assistance with return of results, and Elizabeth Torosian for help with manuscript preparation. This manuscript is dedicated to the memory of David Newsom. Publisher Copyright: © 2014 Brownstein et al.
PY - 2014
Y1 - 2014
N2 - Background: There is tremendous potential for genome sequencing to improve clinical diagnosis and care once it becomes routinely accessible, but this will require formalizing research methods into clinical best practices in the areas of sequence data generation, analysis, interpretation and reporting. The CLARITY Challenge was designed to spur convergence in methods for diagnosing genetic disease starting from clinical case history and genome sequencing data. DNA samples were obtained from three families with heritable genetic disorders and genomic sequence data were donated by sequencing platform vendors. The challenge was to analyze and interpret these data with the goals of identifying disease-causing variants and reporting the findings in a clinically useful format. Participating contestant groups were solicited broadly, and an independent panel of judges evaluated their performance. Results: A total of 30 international groups were engaged. The entries reveal a general convergence of practices on most elements of the analysis and interpretation process. However, even given this commonality of approach, only two groups identified the consensus candidate variants in all disease cases, demonstrating a need for consistent fine-tuning of the generally accepted methods. There was greater diversity of the final clinical report content and in the patient consenting process, demonstrating that these areas require additional exploration and standardization. Conclusions: The CLARITY Challenge provides a comprehensive assessment of current practices for using genome sequencing to diagnose and report genetic diseases. There is remarkable convergence in bioinformatic techniques, but medical interpretation and reporting are areas that require further development by many groups.
AB - Background: There is tremendous potential for genome sequencing to improve clinical diagnosis and care once it becomes routinely accessible, but this will require formalizing research methods into clinical best practices in the areas of sequence data generation, analysis, interpretation and reporting. The CLARITY Challenge was designed to spur convergence in methods for diagnosing genetic disease starting from clinical case history and genome sequencing data. DNA samples were obtained from three families with heritable genetic disorders and genomic sequence data were donated by sequencing platform vendors. The challenge was to analyze and interpret these data with the goals of identifying disease-causing variants and reporting the findings in a clinically useful format. Participating contestant groups were solicited broadly, and an independent panel of judges evaluated their performance. Results: A total of 30 international groups were engaged. The entries reveal a general convergence of practices on most elements of the analysis and interpretation process. However, even given this commonality of approach, only two groups identified the consensus candidate variants in all disease cases, demonstrating a need for consistent fine-tuning of the generally accepted methods. There was greater diversity of the final clinical report content and in the patient consenting process, demonstrating that these areas require additional exploration and standardization. Conclusions: The CLARITY Challenge provides a comprehensive assessment of current practices for using genome sequencing to diagnose and report genetic diseases. There is remarkable convergence in bioinformatic techniques, but medical interpretation and reporting are areas that require further development by many groups.
UR - http://www.scopus.com/inward/record.url?scp=84965181241&partnerID=8YFLogxK
U2 - 10.1186/gb-2014-15-3-r53
DO - 10.1186/gb-2014-15-3-r53
M3 - Article
C2 - 24667040
AN - SCOPUS:84965181241
VL - 15
JO - Genome Biology
JF - Genome Biology
SN - 1474-7596
IS - 3
M1 - R53
ER -