@article{99922da3d60b4876894310a84b5977a7,
title = "Evaluation of cell-free DNA approaches for multi-cancer early detection",
abstract = "In the Circulating Cell-free Genome Atlas (NCT02889978) substudy 1, we evaluate several approaches for a circulating cell-free DNA (cfDNA)-based multi-cancer early detection (MCED) test by defining clinical limit of detection (LOD) based on circulating tumor allele fraction (cTAF), enabling performance comparisons. Among 10 machine-learning classifiers trained on the same samples and independently validated, when evaluated at 98% specificity, those using whole-genome (WG) methylation, single nucleotide variants with paired white blood cell background removal, and combined scores from classifiers evaluated in this study show the highest cancer signal detection sensitivities. Compared with clinical stage and tumor type, cTAF is a more significant predictor of classifier performance and may more closely reflect tumor biology. Clinical LODs mirror relative sensitivities for all approaches. The WG methylation feature best predicts cancer signal origin. WG methylation is the most promising technology for MCED and informs development of a targeted methylation MCED test.",
keywords = "cancer screening, CCGA, cfDNA, MCED, multi-cancer early detection, single nucleotide variants, somatic copy number alterations, whole-genome bisulfite sequencing, whole-genome methylation",
author = "Arash Jamshidi and Liu, {Minetta C.} and Klein, {Eric A.} and Oliver Venn and Earl Hubbell and Beausang, {John F.} and Samuel Gross and Collin Melton and Fields, {Alexander P.} and Qinwen Liu and Nan Zhang and Fung, {Eric T.} and Kurtzman, {Kathryn N.} and Hamed Amini and Craig Betts and Daniel Civello and Peter Freese and Robert Calef and Konstantin Davydov and Saniya Fayzullina and Chenlu Hou and Roger Jiang and Byoungsok Jung and Susan Tang and Vasiliki Demas and Joshua Newman and Onur Sakarya and Eric Scott and Archana Shenoy and Seyedmehdi Shojaee and Steffen, {Kristan K.} and Virgil Nicula and Chien, {Tom C.} and Siddhartha Bagaria and Nathan Hunkapiller and Mohini Desai and Zhao Dong and Richards, {Donald A.} and Yeatman, {Timothy J.} and Cohn, {Allen L.} and Thiel, {David D.} and Berry, {Donald A.} and Tummala, {Mohan K.} and Kristi McIntyre and Sekeres, {Mikkael A.} and Alan Bryce and Aravanis, {Alexander M.} and Seiden, {Michael V.} and Charles Swanton",
note = "Funding Information: This work was supported by GRAIL , LLC (Menlo Park, CA). Medical writing, logistical, and editorial support was funded by GRAIL , LLC . Medical writing support was provided by Alexis Fedorchak, PhD; Grace Wang, PharmD; Ruhi Ubale, PhD; and Megan Hall, PhD, from GRAIL, LLC. Logistical support was provided by LeAnn Berens and Rebecca Myers from Prescott Medical Communications Group (Chicago, IL). Editorial support for text and figures was provided by Erin Spohr from ENGAGE Labs, LLC (Oak Ridge, NJ), and Kristi Whitfield, PhD, from PosterDocs (Oakland, CA). Publisher Copyright: {\textcopyright} 2022 The Author(s)",
year = "2022",
month = dec,
day = "12",
doi = "10.1016/j.ccell.2022.10.022",
language = "English (US)",
volume = "40",
pages = "1537--1549.e12",
journal = "Cancer Cell",
issn = "1535-6108",
publisher = "Cell Press",
number = "12",
}