An international effort towards developing standards for best practices in analysis, interpretation and reporting of clinical genome sequencing results in the CLARITY Challenge. (2024)

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 was 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 languageEnglish
JournalGenome biology
Volume15
Issue number3
DOIs
Publication statusPublished - 25 Mar 2014

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Brownstein, C. A., Beggs, A. H., Homer, N., Merriman, B., Yu, T. W., Flannery, K. C., Dechene, E. T., Towne, M. C., Savage, S. K., Price, E. N., Holm, I. A., Luquette, L. J., Lyon, E., Majzoub, J., Neupert, P., McCallie, D., Szolovits, P., Willard, H. F., Mendelsohn, N. J., ... Margulies, D. M. (2014). An international effort towards developing standards for best practices in analysis, interpretation and reporting of clinical genome sequencing results in the CLARITY Challenge. Genome biology, 15(3). https://doi.org/10.1186/gb-2014-15-3-r53

Brownstein, Catherine A ; Beggs, Alan H ; Homer, Nils et al. / An international effort towards developing standards for best practices in analysis, interpretation and reporting of clinical genome sequencing results in the CLARITY Challenge. In: Genome biology. 2014 ; Vol. 15, No. 3.

@article{18a6047071bb4491bd151b087a80c700,

title = "An international effort towards developing standards for best practices in analysis, interpretation and reporting of clinical genome sequencing results in the CLARITY Challenge.",

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 was 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.",

author = "Brownstein, {Catherine A} and Beggs, {Alan H} and Nils Homer and Barry Merriman and Yu, {Timothy W} and Flannery, {Katherine C} and Dechene, {Elizabeth T} and Towne, {Meghan C} and Savage, {Sarah K} and Price, {Emily N} and Holm, {Ingrid A} and Luquette, {Lovelace J} and Elaine Lyon and Joseph Majzoub and Peter Neupert and David McCallie and Peter Szolovits and Willard, {Huntington F} and Mendelsohn, {Nancy J} and Renee Temme and Finkel, {Richard S} and Yum, {Sabrina W} and Livija Medne and Sunyaev, {Shamil R} and Ivan Adzhubey and Cassa, {Christopher A} and {de Bakker}, {Paul Iw} and Hatice Duzkale and {Dworzy Ski}, Piotr and William Fairbrother and Laurent Francioli and Funke, {Birgit H} and Giovanni, {Monica A} and Handsaker, {Robert E} and Kasper Lage and Lebo, {Matthew S} and Monkol Lek and Ignaty Leshchiner and Macarthur, {Daniel G} and McLaughlin, {Heather M} and Murray, {Michael F} and Pers, {Tune H} and Polak, {Paz P} and Soumya Raychaudhuri and Rehm, {Heidi L} and Rachel Soemedi and Stitziel, {Nathan O} and Sara Vestecka and Jochen Supper and Claudia Gugenmus and Bernward Klocke and Alexander Hahn and Max Schubach and Mortiz Menzel and Saskia Biskup and Peter Freisinger and Mario Deng and Martin Braun and Sven Perner and Smith, {Richard Jh} and Andorf, {Janeen L} and Jian Huang and Kelli Ryckman and Sheffield, {Val C} and Stone, {Edwin M} and Thomas Bair and Black-Ziegelbein, {E Ann} and Braun, {Terry A} and Benjamin Darbro and Deluca, {Adam P} and Kolbe, {Diana L} and Scheetz, {Todd E} and Shearer, {Aiden E} and Rama Sompallae and Kai Wang and Bassuk, {Alexander G} and Erik Edens and Katherine Mathews and Moore, {Steven A} and Shchelochkov, {Oleg A} and Pamela Trapane and Aaron Bossler and Campbell, {Colleen A} and Heusel, {Jonathan W} and Anne Kwitek and Tara Maga and Karin Panzer and Thomas Wassink and {Van Daele}, Douglas and Hela Azaiez and Kevin Booth and Nic Meyer and Segal, {Michael M} and Williams, {Marc S} and Gerard Tromp and Peter White and Donald Corsmeier and Sara Fitzgerald-Butt and Gail Herman and Devon Lamb-Thrush and McBride, {Kim L} and David Newsom and Pierson, {Christopher R} and Rakowsky, {Alexander T} and Ale Maver and {Lovre I}, Luca and {Palanda I}, Anja and Borut Peterlin and Ali Torkamani and Anna Wedell and Mikael Huss and Andrey Alexeyenko and Lindvall, {Jessica M} and M{\aa}ns Magnusson and Daniel Nilsson and Henrik Stranneheim and Fulya Taylan and Christian Gilissen and Alexander Hoischen and {van Bon}, Bregje and Helger Yntema and Marcel Nelen and Weidong Zhang and Jason Sager and Lu Zhang and Kathryn Blair and Deniz Kural and Michael Cariaso and Lennon, {Greg G} and Asif Javed and Saloni Agrawal and Ng, {Pauline C} and Sandhu, {Komal S} and Shuba Krishna and Vamsi Veeramachaneni and Ofer Isakov and Eran Halperin and Eitan Friedman and Noam Shomron and Gustavo Glusman and Roach, {Jared C} and Juan Caballero and Cox, {Hannah C} and Denise Mauldin and Ament, {Seth A} and Lee Rowen and Richards, {Daniel R} and Lucas, {F Anthony} and Gonzalez-Garay, {Manuel L} and Caskey, {C Thomas} and Yu Bai and Ying Huang and Fang Fang and Yan Zhang and Zhengyuan Wang and Jorge Barrera and Garcia-Lobo, {Juan M} and Domingo Gonz{\'a}lez-Lamu{\~n}o and Javier Llorca and Rodriguez, {Maria C} and Ignacio Varela and Reese, {Martin G} and {De La Vega}, {Francisco M} and Edward Kiruluta and Michele Cargill and Hart, {Reece K} and Sorenson, {Jon M} and Lyon, {Gholson J} and Stevenson, {David A} and Bray, {Bruce E} and Moore, {Barry M} and Karen Eilbeck and Mark Yandell and Hongyu Zhao and Lin Hou and Xiaowei Chen and Xiting Yan and Mengjie Chen and Cong Li and Can Yang and Murat Gunel and Peining Li and Yong Kong and Alexander, {Austin C} and Albertyn, {Zayed I} and Boycott, {Kym M} and Bulman, {Dennis E} and Gordon, {Paul Mk} and Innes, {A Micheil} and Knoppers, {Bartha M} and Jacek Majewski and Marshall, {Christian R} and Parboosingh, {Jillian S} and Sawyer, {Sarah L} and Samuels, {Mark E} and Jeremy Schwartzentruber and Kohane, {Isaac S} and Margulies, {David M}",

note = "R01 HL109758, NHLBI NIH HHS, United States",

year = "2014",

month = mar,

day = "25",

doi = "10.1186/gb-2014-15-3-r53",

language = "English",

volume = "15",

journal = "Genome biology",

issn = "1465-6914",

publisher = "Springer Nature",

number = "3",

}

Brownstein, CA, Beggs, AH, Homer, N, Merriman, B, Yu, TW, Flannery, KC, Dechene, ET, Towne, MC, Savage, SK, Price, EN, Holm, IA, Luquette, LJ, Lyon, E, Majzoub, J, Neupert, P, McCallie, D, Szolovits, P, Willard, HF, Mendelsohn, NJ, Temme, R, Finkel, RS, Yum, SW, Medne, L, Sunyaev, SR, Adzhubey, I, Cassa, CA, de Bakker, PI, Duzkale, H, Dworzy Ski, P, Fairbrother, W, Francioli, L, Funke, BH, Giovanni, MA, Handsaker, RE, Lage, K, Lebo, MS, Lek, M, Leshchiner, I, Macarthur, DG, McLaughlin, HM, Murray, MF, Pers, TH, Polak, PP, Raychaudhuri, S, Rehm, HL, Soemedi, R, Stitziel, NO, Vestecka, S, Supper, J, Gugenmus, C, Klocke, B, Hahn, A, Schubach, M, Menzel, M, Biskup, S, Freisinger, P, Deng, M, Braun, M, Perner, S, Smith, RJ, Andorf, JL, Huang, J, Ryckman, K, Sheffield, VC, Stone, EM, Bair, T, Black-Ziegelbein, EA, Braun, TA, Darbro, B, Deluca, AP, Kolbe, DL, Scheetz, TE, Shearer, AE, Sompallae, R, Wang, K, Bassuk, AG, Edens, E, Mathews, K, Moore, SA, Shchelochkov, OA, Trapane, P, Bossler, A, Campbell, CA, Heusel, JW, Kwitek, A, Maga, T, Panzer, K, Wassink, T, Van Daele, D, Azaiez, H, Booth, K, Meyer, N, Segal, MM, Williams, MS, Tromp, G, White, P, Corsmeier, D, Fitzgerald-Butt, S, Herman, G, Lamb-Thrush, D, McBride, KL, Newsom, D, Pierson, CR, Rakowsky, AT, Maver, A, Lovre I, L, Palanda I, A, Peterlin, B, Torkamani, A, Wedell, A, Huss, M, Alexeyenko, A, Lindvall, JM, Magnusson, M, Nilsson, D, Stranneheim, H, Taylan, F, Gilissen, C, Hoischen, A, van Bon, B, Yntema, H, Nelen, M, Zhang, W, Sager, J, Zhang, L, Blair, K, Kural, D, Cariaso, M, Lennon, GG, Javed, A, Agrawal, S, Ng, PC, Sandhu, KS, Krishna, S, Veeramachaneni, V, Isakov, O, Halperin, E, Friedman, E, Shomron, N, Glusman, G, Roach, JC, Caballero, J, Cox, HC, Mauldin, D, Ament, SA, Rowen, L, Richards, DR, Lucas, FA, Gonzalez-Garay, ML, Caskey, CT, Bai, Y, Huang, Y, Fang, F, Zhang, Y, Wang, Z, Barrera, J, Garcia-Lobo, JM, González-Lamuño, D, Llorca, J, Rodriguez, MC, Varela, I, Reese, MG, De La Vega, FM, Kiruluta, E, Cargill, M, Hart, RK, Sorenson, JM, Lyon, GJ, Stevenson, DA, Bray, BE, Moore, BM, Eilbeck, K, Yandell, M, Zhao, H, Hou, L, Chen, X, Yan, X, Chen, M, Li, C, Yang, C, Gunel, M, Li, P, Kong, Y, Alexander, AC, Albertyn, ZI, Boycott, KM, Bulman, DE, Gordon, PM, Innes, AM, Knoppers, BM, Majewski, J, Marshall, CR, Parboosingh, JS, Sawyer, SL, Samuels, ME, Schwartzentruber, J, Kohane, IS & Margulies, DM 2014, 'An international effort towards developing standards for best practices in analysis, interpretation and reporting of clinical genome sequencing results in the CLARITY Challenge.', Genome biology, vol. 15, no. 3. https://doi.org/10.1186/gb-2014-15-3-r53

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 et al.
In: Genome biology, Vol. 15, No. 3, 25.03.2014.

Research output: Contribution to journalArticlepeer-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 Iw

AU - Duzkale, Hatice

AU - Dworzy Ski, 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 Jh

AU - Andorf, Janeen L

AU - Huang, Jian

AU - Ryckman, Kelli

AU - Sheffield, Val C

AU - Stone, Edwin M

AU - Bair, Thomas

AU - Black-Ziegelbein, E Ann

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, Ale

AU - Lovre I, Luca

AU - Palanda I, 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 - Lucas, F Anthony

AU - Gonzalez-Garay, Manuel L

AU - Caskey, C Thomas

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 Mk

AU - Innes, A Micheil

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 - R01 HL109758, NHLBI NIH HHS, United States

PY - 2014/3/25

Y1 - 2014/3/25

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 was 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 was 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.

U2 - 10.1186/gb-2014-15-3-r53

DO - 10.1186/gb-2014-15-3-r53

M3 - Article

C2 - 24667040

SN - 1465-6914

VL - 15

JO - Genome biology

JF - Genome biology

IS - 3

ER -

Brownstein CA, Beggs AH, Homer N, Merriman B, Yu TW, Flannery KC et al. An international effort towards developing standards for best practices in analysis, interpretation and reporting of clinical genome sequencing results in the CLARITY Challenge. Genome biology. 2014 Mar 25;15(3). doi: 10.1186/gb-2014-15-3-r53

An international effort towards developing standards for best practices in analysis, interpretation and reporting of clinical genome sequencing results in the CLARITY Challenge. (2024)
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