Toward the simultaneous detection of multiple diseases with a highly cost-effective cell-free DNA methylome test
Abstract
Plasma cell-free DNA (cfDNA), originating from multiple organs, holds significant potential for noninvasive diagnostics and prognostics. Current cfDNA methylation assays primarily focus on single clinical indications by targeting specific genomic loci. In contrast, comprehensive profiling of cfDNA methylome can enable simultaneous detection of multiple diseases by capturing organ-specific methylation signatures, thereby offering a holistic view of health, when disease etiology is unclear or when conventional biochemical diagnostics are unavailable. However, deep sequencing required for sensitive detection of methylation abnormalities remains prohibitively expensive, limiting widespread clinical use. To overcome this barrier, we developed MethylScan , a highly cost-effective approach for cfDNA methylome sequencing. We demonstrated its broad clinical utility in a cohort of 1,061 individuals across diverse applications, including multicancer detection in general population, liver cancer surveillance in high-risk individuals, liver disease classification, identification of organ abnormalities, and race prediction from cfDNA. In multicancer detection (liver, lung, ovarian, and stomach cancers), MethylScan achieved an area under the receiver operating characteristic curve (AUROC) of 0.938 (95% CI: 0.920 to 0.954), with a sensitivity of 63.3% (95% CI: 58.9 to 67.9%) at 98.0% specificity for all cancer stages. For early-stage cancers, the AUROC was 0.916 (95% CI: 0.890 to 0.940), with 55.3% sensitivity (95% CI: 49.1 to 62.1%) at the same specificity. In liver cancer surveillance, MethylScan achieved an AUROC of 0.927 (95% CI: 0.889 to 0.959), with 79.6% sensitivity (95% CI: 70.6 to 87.8%) at 90.4% specificity. The assay also demonstrated strong performance in additional diagnostic tasks, supporting its potential as a versatile platform for comprehensive cfDNA-based health monitoring.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (54)
Weihua Zeng
Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California at Los Angeles
Chun-Chi Liu
EarlyDiagnostics Inc.
Shuo Li
Yonggang Zhou
Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California at Los Angeles
Mary L. Stackpole
EarlyDiagnostics Inc.
Ying Xiao
CIBM Center for Biomedical Imaging
Ran Hu
State Key Laboratory of Water Resources Engineering and Management, Wuhan University
Caitlin Tang
Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California at Los Angeles
Qiao Liu
Wanwen Zeng
Department of Statistics, Stanford University
Angela Yeh
Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles
Andrew Melehy
Department of Surgery, David Geffen School of Medicine, University of California at Los Angeles
Benjamin Tran
Department of Surgery, David Geffen School of Medicine, University of California at Los Angeles
Zorawar Noor
Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles
Megumi Yokomizo
Department of Radiological Sciences, David Geffen School of Medicine, University of California at Los Angeles
Dominic Amara
Department of Surgery, David Geffen School of Medicine, University of California at Los Angeles
Shreya Gumate
Department of Surgery, David Geffen School of Medicine, University of California at Los Angeles
Preeti Ahuja
Department of Radiological Sciences, David Geffen School of Medicine, University of California at Los Angeles
David Yuanze Li
Thousand Oaks High School
Junting Zhao
Sage Hill School
Inga Rose
Reference Medicine
Cattlena Walker
Crown Bioscience
Sadaf Malik
Crown Bioscience
Yazhen Zhu
Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California at Los Angeles
Hsian-Rong Tseng
Jonsson Comprehensive Cancer Center, University of California at Los Angeles
Edward B. Garon
Samuel W. French
Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California at Los Angeles
Clara E. Magyar
Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California at Los Angeles
Sarah M. Dry
Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California at Los Angeles
Clara M. Lajonchere
Jonsson Comprehensive Cancer Center, University of California at Los Angeles
Daniel Geschwind
Gina Choi
Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles
Sammy Saab
Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles
Akshay Shetty
Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles
Carrie R. Wong
Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, University of California
Kevin G. King
Department of Radiological Sciences, David Geffen School of Medicine, University of California at Los Angeles
David S. Lu
Department of Radiological Sciences, David Geffen School of Medicine, University of California at Los Angeles
Steven S. Raman
Department of Radiological Sciences, David Geffen School of Medicine, University of California at Los Angeles
Xiyan Xiang
Kirti Shetty
Division of Gastroenterology and Hepatology, School of Medicine, University of Maryland
Lopa Mishra
Sanaz Memarzadeh
Jonsson Comprehensive Cancer Center, University of California at Los Angeles
Yan Liu
Frank Alber
William Hsu
Department of Radiological Sciences, David Geffen School of Medicine, University of California at Los Angeles
Kostyantyn Krysan
Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles
Steven M. Dubinett
Denise R. Aberle
Department of Radiological Sciences, David Geffen School of Medicine, University of California at Los Angeles
Vatche Agopian
Department of Surgery, David Geffen School of Medicine, University of California at Los Angeles
Steven-Huy B. Han
Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles
Wing Hung Wong
Department of Statistics, Stanford University
Xiaohui Ni
EarlyDiagnostics Inc.
Wenyuan Li
Department of Biochemistry, The University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, Texas 75390, United States
Xianghong Jasmine Zhou
Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California at Los Angeles