An international effort towards developing standards for best practices in analysis, interpretation and reporting of clinical genome sequencing results in the CLARITY Challenge
Authors: 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 Jr 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 IW , 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 JH , Andorf Janeen L , Huang Jian , Ryckman Kelli , Sheffield Val C , Stone Edwin M , Bair Thomas , Black-Ziegelbein E Ann , 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 , Lucas F Anthony San , Gonzalez-Garay Manuel L , Caskey C Thomas , 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 MK , Innes A Micheil , 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 
Published: March 2014

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.