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CAGI, the Critical Assessment of Genome Interpretation, establishes progress and prospects for computational genetic variant interpretation methods

  • Shantanu Jain
  • , Constantina Bakolitsa
  • , Steven E. Brenner
  • , Predrag Radivojac
  • , John Moult
  • , Susanna Repo
  • , Roger A. Hoskins
  • , Gaia Andreoletti
  • , Daniel Barsky
  • , Ajithavalli Chellapan
  • , Hoyin Chu
  • , Navya Dabbiru
  • , Naveen K. Kollipara
  • , Melissa Ly
  • , Andrew J. Neumann
  • , Lipika R. Pal
  • , Eric Odell
  • , Gaurav Pandey
  • , Robin C. Peters-Petrulewicz
  • , Rajgopal Srinivasan
  • Stephen F. Yee, Sri Jyothsna Yeleswarapu, Maya Zuhl, Ogun Adebali, Ayoti Patra, Michael A. Beer, Raghavendra Hosur, Jian Peng, Brady M. Bernard, Michael Berry, Shengcheng Dong, Alan P. Boyle, Aashish Adhikari, Jingqi Chen, Zhiqiang Hu, Robert Wang, Yaqiong Wang, Maximilian Miller, Yanran Wang, Yana Bromberg, Paola Turina, Emidio Capriotti, James J. Han, Kivilcim Ozturk, Hannah Carter, Giulia Babbi, Samuele Bovo, Pietro di Lena, Pier Luigi Martelli, Castrense Savojardo, Rita Casadio, Melissa S. Cline, Greet de Baets, Sandra Bonache, Orland Díez, Sara Gutiérrez-Enríquez, Alejandro Fernández, Gemma Montalban, Lars Ootes, Selen Özkan, Natàlia Padilla, Casandra Riera, Xavier de la Cruz, Mark Diekhans, Peter J. Huwe, Qiong Wei, Qifang Xu, Roland L. Dunbrack, Valer Gotea, Laura Elnitski, Gennady Margolin, Piero Fariselli, Ivan V. Kulakovskiy, Vsevolod J. Makeev, Dmitry D. Penzar, Ilya E. Vorontsov, Alexander V. Favorov, Julia R. Forman, Marcia Hasenahuer, Maria S. Fornasari, Gustavo Parisi, Ziga Avsec, Muhammed H. Çelik, Thi Yen Duong Nguyen, Julien Gagneur, Fang-Yuan Shi, Matthew D. Edwards, Yuchun Guo, Kevin Tian, Haoyang Zeng, David K. Gifford, Jonathan Göke, Jan Zaucha, Julian Gough, Graham R. S. Ritchie, Adam Frankish, Jonathan M. Mudge, Jennifer Harrow, Erin L. Young, Yao Yu, Chad D. Huff, Katsuhiko Murakami, Yoko Nagai, Tadashi Imanishi, Christopher J. Mungall, Julius O. B. Jacobsen, Dongsup Kim, Chan-Seok Jeong, David T. Jones, Mulin Jun Li, Violeta Beleva Guthrie, Rohit Bhattacharya, Yun-Ching Chen, Christopher Douville, Jean Fan, Dewey Kim, David Masica, Noushin Niknafs, Sohini Sengupta, Collin Tokheim, Tychele N. Turner, Hui Ting Grace Yeo, Rachel Karchin, Sunyoung Shin, Rene Welch, Sunduz Keles, Yue Li, Manolis Kellis, Carles Corbi-Verge, Alexey V. Strokach, Philip M. Kim, Teri E. Klein, Rahul Mohan, Nicholas A. Sinnott-Armstrong, Michael Wainberg, Anshul Kundaje, Nina Gonzaludo, Angel C. Y. Mak, Aparna Chhibber, Hugo Y. K. Lam, Dvir Dahary, Simon Fishilevich, Doron Lancet, Insuk Lee, Benjamin Bachman, Panagiotis Katsonis, Rhonald C. Lua, Stephen J. Wilson, Olivier Lichtarge, Rajendra R. Bhat, Laksshman Sundaram, Vivek Viswanath, Riccardo Bellazzi, Giovanna Nicora, Ettore Rizzo, Ivan Limongelli, Aziz M. Mezlini, Ray Chang, Serra Kim, Carmen Lai, Robert O’Connor, Scott Topper, Jeroen van den Akker, Alicia Y. Zhou, Anjali D. Zimmer, Gilad Mishne, Timothy R. Bergquist, Marcus R. Breese, Rafael F. Guerrero, Yuxiang Jiang, Nikki Kiga, Biao Li, Matthew Mort, Kymberleigh A. Pagel, Vikas Pejaver, Moses H. Stamboulian, Janita Thusberg, Sean D. Mooney, Nuttinee Teerakulkittipong, Chen Cao, Kunal Kundu, Yizhou Yin, Chen-Hsin Yu, Michael Kleyman, Chiao-Feng Lin, Mary Stackpole, Stephen M. Mount, G. kcen Eraslan, Nikola S. Mueller, Tatsuhiko Naito, Aliz R. Rao, Johnathan R. Azaria, Aharon Brodie, Yanay Ofran, Aditi Garg, Debnath Pal, Alex Hawkins-Hooker, Henry Kenlay, John Reid, Eliseos J. Mucaki, Peter K. Rogan, Jana M. Schwarz, David B. Searls, Gyu Rie Lee, Chaok Seok, Andreas Krämer, Sohela Shah, ChengLai V. Huang, Jack F. Kirsch, Maxim Shatsky, Yue Cao, Haoran Chen, Mostafa Karimi, Oluwaseyi Moronfoye, Yuanfei Sun, Yang Shen, Ron Shigeta, Colby T. Ford, Conor Nodzak, Aneeta Uppal, Xinghua Shi, Thomas Joseph, Sujatha Kotte, Sadhna Rana, Aditya Rao, V. G. Saipradeep, Naveen Sivadasan, Uma Sunderam, Mario Stanke, Andrew Su, Ivan Adzhubey, Daniel M. Jordan, Shamil Sunyaev, Frederic Rousseau, Joost Schymkowitz, Joost van Durme, Sean V. Tavtigian, Marco Carraro, Manuel Giollo, Silvio C. E. Tosatto, Orit Adato, Liran Carmel, Noa E. Cohen, Tzila Fenesh, Tamar Holtzer, Tamar Juven-Gershon, Ron Unger, Abhishek Niroula, Ayodeji Olatubosun, Jouni Väliaho, Yang Yang, Mauno Vihinen, Mary E. Wahl, Billy Chang, Ka Chun Chong, Inchi Hu, Rui Sun, William Ka Kei Wu, Xiaoxuan Xia, Benny C. Zee, Maggie H. Wang, Meng Wang, Chunlei Wu, Yutong Lu, Ken Chen, Yuedong Yang, Christopher M. Yates, Anat Kreimer, Zhongxia Yan, Nir Yosef, Huying Zhao, Zhipeng Wei, Zhaomin Yao, Fengfeng Zhou, Lukas Folkman, Yaoqi Zhou, Roxana Daneshjou, Russ B. Altman, Fumitaka Inoue, Nadav Ahituv, Adam P. Arkin, Federica Lovisa, Paolo Bonvini, Sarah Bowdin, Stefano Gianni, Elide Mantuano, Velia Minicozzi, Leonore Novak, Alessandra Pasquo, Annalisa Pastore, Maria Petrosino, Rita Puglisi, Angelo Toto, Liana Veneziano, Roberta Chiaraluce, Mad P. Ball, Jason R. Bobe, George M. Church, Valerio Consalvi, David N. Cooper, Bethany A. Buckley, Molly B. Sheridan, Garry R. Cutting, Maria Chiara Scaini, Kamil J. Cygan, Alger M. Fredericks, David T. Glidden, Christopher Neil, Christy L. Rhine, William G. Fairbrother, Aileen Y. Alontaga, Aron W. Fenton, Kenneth A. Matreyek, Lea M. Starita, Douglas M. Fowler, Britt-Sabina Löscher, Andre Franke, Scott I. Adamson, Brenton R. Graveley, Joe W. Gray, Mary J. Malloy, John P. Kane, Maria Kousi, Nicholas Katsanis, Max Schubach, Martin Kircher, Angel C. Y. Mak, Paul L. F. Tang, Pui-Yan Kwok, Richard H. Lathrop, Wyatt T. Clark, Guoying K. Yu, Jonathan H. LeBowitz, Francesco Benedicenti, Elisa Bettella, Stefania Bigoni, Federica Cesca, Isabella Mammi, Cristina Marino-Buslje, Donatella Milani, Angela Peron, Roberta Polli, Stefano Sartori, Franco Stanzial, Irene Toldo, Licia Turolla, Maria C. Aspromonte, Mariagrazia Bellini, Emanuela Leonardi, Xiaoming Liu, Christian Marshall, W. Richard McCombie, Lisa Elefanti, Chiara Menin, M. Stephen Meyn, Alessandra Murgia, Kari C. Y. Nadeau, Susan L. Neuhausen, Robert L. Nussbaum, Mehdi Pirooznia, James B. Potash, Dago F. Dimster-Denk, Jasper D. Rine, Jeremy R. Sanford, Michael Snyder, Atina G. Cote, Song Sun, Marta W. Verby, Jochen Weile, Frederick P. Roth, Ryan Tewhey, Pardis C. Sabeti, Joan Campagna, Marwan M. Refaat, Julianne Wojciak, Soren Grubb, Nicole Schmitt, Jay Shendure, Amanda B. Spurdle, Dimitri J. Stavropoulos, Nephi A. Walton, Peter P. Zandi, Elad Ziv, Wylie Burke, Flavia Chen, Lawrence R. Carr, Selena Martinez, Jodi Paik, Julie Harris-Wai, Mark Yarborough, Stephanie M. Fullerton, Barbara A. Koenig, Gregory McInnes, Dustin Shigaki, John-Marc Chandonia, Mabel Furutsuki, Laura Kasak, Changhua Yu, Rui Chen, Iddo Friedberg, Gad A. Getz, Qian Cong, Lisa N. Kinch, Jing Zhang, Nick V. Grishin, Alin Voskanian, Maricel G. Kann, Elizabeth Tran, Nilah M. Ioannidis, Jesse M. Hunter, Rupa Udani, Binghuang Cai, Alexander A. Morgan, Artem Sokolov, Joshua M. Stuart, Giovanni Minervini, Alexander M. Monzon, Serafim Batzoglou, Atul J. Butte, Marc S. Greenblatt, Reece K. Hart, Ryan Hernandez, Tim J. P. Hubbard, Scott Kahn, Anne O’Donnell-Luria, Pauline C. Ng, John Shon, Joris Veltman, The Critical Assessment of Genome Interpretation Consortium
  • Northeastern University
  • University of California at Berkeley
  • Indiana University Bloomington
  • University of Maryland, College Park
  • Tata Consultancy Services
  • Dana-Farber Cancer Institute
  • Broad Institute
  • Icahn School of Medicine at Mount Sinai
  • ICF International
  • University of Tennessee, Knoxville
  • Sabanci University
  • Johns Hopkins University
  • Intel
  • Massachusetts Institute of Technology
  • Encoded Genomics
  • Institute for Systems Biology
  • Earle A. Chiles Research Institute
  • University of Michigan, Ann Arbor
  • Illumina, Inc.
  • Fudan University
  • University of Pennsylvania
  • Rutgers - The State University of New Jersey, New Brunswick
  • Genentech Incorporated
  • Oncologia ed Ematologia Pediatrica “Lalla Seràgnoli” Ospedale Sant'Orsola Malpighi Università di Bologna
  • University of California at San Diego
  • University of California at Santa Cruz
  • University of Leuven
  • Vall d'Hebron Institute of Oncology
  • Hospital Universitari Germans Trias i Pujol
  • Hospital Vall d’Hebron
  • Université Laval
  • Fox Chase Cancer Center
  • Belmont University
  • Microsoft Research Asia
  • National Human Genome Research Institute
  • University of Padua
  • University of Turin
  • Russian Academy of Sciences
  • RAS - Institute of Protein Research
  • Lomonosov Moscow State University
  • University of Cambridge
  • King's College London
  • Universidad Nacional de Quilmes
  • European Molecular Biology Laboratory
  • Technical University of Munich
  • University of California at Irvine
  • Peking University
  • Alphabet Inc.
  • camp4 Therapeutics
  • Stanford University
  • Insitro
  • Agency for Science, Technology and Research, Singapore
  • University of Bristol
  • AstraZeneca
  • Medical Research Council
  • Amazon.com, Inc.
  • Wellcome Sanger Institute
  • ELIXIR
  • University of Utah
  • University of Texas MD Anderson Cancer Center
  • National Institute of Advanced Industrial Science and Technology
  • Fujitsu
  • Varinos Inc.
  • Tokai University
  • Lawrence Berkeley National Laboratory
  • Queen Mary University of London
  • Korea Advanced Institute of Science and Technology
  • Korea Institute of Science and Technology Information
  • University College London
  • The University of Hong Kong
  • Tianjin Medical University
  • Williams College
  • Johnson & Johnson
  • PierianDx, Inc.
  • Harvard T.H. Chan School of Public Health
  • Washington University St. Louis
  • Pohang University of Science and Technology
  • University of Wisconsin-Madison
  • McGill University
  • University of Toronto
  • Cyclica Inc.
  • Stanford University Medical Center
  • Dashworks
  • Centre for Addiction and Mental Health
  • University of California, San Francisco
  • Pacific Biosciences
  • CytomX Therapeutics
  • F. Hoffmann-La Roche AG
  • Bristol-Myers Squibb
  • HypaHub
  • LifeMap Sciences Inc.
  • Weizmann Institute of Science
  • Yonsei University
  • Baylor College of Medicine
  • Calm
  • University of Florida
  • University of Pavia
  • enGenome srl
  • Color Genomics
  • Syapse
  • Swedish Medical Center and University of Washington
  • Sage Bionetworks
  • Buck Institute for Age Research
  • North Carolina State University
  • Gilead
  • Cardiff University
  • Burapha University
  • Regeneron Pharmaceuticals, Inc.
  • Moderna Therapeutics
  • DNAnexus
  • EarlyDiagnostics Inc.
  • Helmholtz Zentrum München - German Research Center for Environmental Health
  • The University of Tokyo
  • Bar-Ilan University
  • Imperva
  • Indian Institute of Science Bangalore
  • Oxford University Children's Hospital
  • Blue Prism
  • Western University
  • Charité – Universitätsmedizin Berlin
  • Seoul National University
  • Qiagen
  • Invitae Corporation
  • Texas A&M University
  • Carnegie Mellon University
  • IndieBio
  • iAccelerate
  • University of North Carolina at Charlotte
  • Vindara
  • Temple University
  • University of Greifswald
  • Scripps Research Institute
  • Harvard Medical School
  • Harvard University
  • Hebrew University of Jerusalem
  • Azrieli College of Engineering
  • Lund University
  • Tampere University
  • First Affiliated Hospital of Soochow University
  • Chinese University of Hong Kong
  • Hong Kong University of Science and Technology
  • George Mason University
  • Sun Yat-Sen University
  • Indiana University-Purdue University Indianapolis
  • Imperial College London
  • Vertex Pharmaceuticals, Inc.
  • Jilin University
  • Northeastern University China
  • Griffith University Queensland
  • Austrian Academy of Sciences
  • Shenzhen Bay Laboratory
  • Kyoto University
  • Institute of Pediatric Research Città della Speranza
  • University of Rome La Sapienza
  • National Research Council of Italy
  • University of Rome Tor Vergata
  • Agenzia nazionale per le nuove tecnologie, l'energia e lo sviluppo economico sostenibile
  • Francis Crick Institute
  • University of Rome
  • University of Fribourg
  • Open Humans Foundation
  • PersonalGenomes.org
  • Johns Hopkins University School of Medicine
  • IRCCS Istituto Oncologico Veneto - Padova
  • Brown University
  • Remix Therapeutics
  • University of Kansas
  • Case Western Reserve University
  • Kiel University
  • University of Connecticut Health Center
  • Oregon Health and Science University
  • Third Rock Ventures
  • Northwestern University
  • Rescindo Therapeutics Inc.
  • AccuraGen Inc.
  • BioMarin Pharmaceutical Inc.
  • Global Blood Therapeutics, Inc.
  • Regional Hospital of Bolzano
  • Sant’Anna University-Hospital
  • Mirano Hospital
  • Fundación Instituto Leloir-IIBBA-CONICET
  • Polyclinic Hospital of Milan
  • Università degli Studi di Milano
  • University of Utah School of Medicine
  • Aulss 2 Marca Trevigiana
  • University of Texas Health Science Center at Houston
  • University of South Florida
  • Cold Spring Harbor Laboratory
  • City of Hope National Med Center
  • National Institutes of Health
  • Mount Sinai Hospital Medical Center
  • Jackson Laboratory
  • American University of Beirut
  • University of Copenhagen
  • QIMR Berghofer Medical Research Institute
  • Geisinger Genomic Medicine Institute
  • Primary Children's Medical Center
  • University of California at Davis
  • University of Washington
  • Empirico Inc.
  • University of Tartu
  • California Institute of Technology
  • Iowa State University
  • Massachusetts General Hospital
  • University of Texas Southwestern Medical Center
  • University of Maryland, Baltimore County
  • Nationwide Children’s Hospital
  • Sema4
  • Khosla Ventures
  • Seer, Inc.
  • University of Vermont
  • MyOme Inc
  • LunaPBC
  • SerImmune
  • Newcastle University
  • National Institute of Standards and Technology

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

Background: The Critical Assessment of Genome Interpretation (CAGI) aims to advance the state-of-the-art for computational prediction of genetic variant impact, particularly where relevant to disease. The five complete editions of the CAGI community experiment comprised 50 challenges, in which participants made blind predictions of phenotypes from genetic data, and these were evaluated by independent assessors. Results: Performance was particularly strong for clinical pathogenic variants, including some difficult-to-diagnose cases, and extends to interpretation of cancer-related variants. Missense variant interpretation methods were able to estimate biochemical effects with increasing accuracy. Assessment of methods for regulatory variants and complex trait disease risk was less definitive and indicates performance potentially suitable for auxiliary use in the clinic. Conclusions: Results show that while current methods are imperfect, they have major utility for research and clinical applications. Emerging methods and increasingly large, robust datasets for training and assessment promise further progress ahead.
Original languageEnglish
Article number53
JournalGenome biology
Volume25
Issue number1
DOIs
Publication statusPublished - 1 Dec 2024

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

  1. SDG 3 - Good Health and Well-being
    SDG 3 Good Health and Well-being

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