ArticleNature biotechnology2021
Evaluating the analytical validity of circulating tumor DNA sequencing assays for precision oncology.
Abstract readValidation Study
In one paragraph
Article in Nature biotechnology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 178 papers, 3 of them syntheses that pooled it.
0numbers the graph read from it
0cells of the map it votes in
178citing papers in PubMed, 3 pooled it
–field-weighted citation impact
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
178 citing papers in PubMed, 3 syntheses or guidelines pooled it.
- Circulating Tumor DNA as a Biomarker for Precision Medicine in Prostate Cancer: A Systematic Review.International journal of molecular sciences · 2025Pooled it
- A comprehensive review and case series of adjuvant and neoadjuvant therapies in acral melanoma with emerging insights from CT DNA testing.Frontiers in oncology · 2025Pooled it
- Clinical Practice Guideline for Blood-based Circulating Tumor DNA Assays.Annals of laboratory medicine · 2024Guideline
- Tucatinib plus trastuzumab for chemotherapy-refractory, HER2 + , RAS wild-type metastatic colorectal cancer (MOUNTAINEER): final analysis.Nature communications · 2026Trial
- Tumor-Informed ctDNA in Guiding First-Line Immunochemotherapy in Advanced Non-Small Cell Lung Cancers.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Trial
- A phase 1/2 study of lenalidomide and obinutuzumab with CHOP for newly diagnosed DLBCL.Blood advances · 2023Trial
- A streamlined hybrid-capture and genome-wide multi-omic platform for highly sensitive ctDNA minimal residual disease monitoring.The journal of liquid biopsy · 2026Article
- Value and research advances of ctDNA in perioperative therapy for non-small cell lung cancer.Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico · 2026Review
- Methyltransferase-assisted single duplex sequencing for detecting circulating tumor DNA.EMBO molecular medicine · 2026Article
- Towards liquid biopsy-based analysis of antitumour immunity.Nature reviews. Clinical oncology · 2026Review
- Analysis of cell-free DNA in lymphomas: from sample collection to genotyping and minimal residual disease monitoring.Blood advances · 2026Review
- Molecular sampling limits of ctDNA detection in clinical plasma samples.The journal of liquid biopsy · 2026Article
- Clinical Feasibility of Circulating Tumor DNA in Patients with Advanced Hepatocellular Carcinoma Treated with Atezolizumab plus Bevacizumab.Liver cancer · 2026Article
- Circulating tumor DNA clearance as a trial-level early efficacy signal in solid tumors: a systematic review and meta-analysis of randomized trials.Translational cancer research · 2026Article
- Association of ctDNAJournal of gastrointestinal oncology · 2026Article
- Liquid Biopsy for Minimal Residual Disease Assessment in Endometrial and Cervical Cancers: Molecular Rationale, Clinical Evidence, and Translational Barriers.International journal of molecular sciences · 2026Review
- Large-scale simulation of coverage and error rate tradeoffs for cancer detection in cell-free DNA whole-genome sequencing.Bioinformatics (Oxford, England) · 2026Article
- [Clinical Frontiers and Applications Progress of ctDNA in Precision Treatment of Non-small Cell Lung Cancer].Zhongguo fei ai za zhi = Chinese journal of lung cancer · 2026Review
- Liquid biopsy-based multi-omics approach for early detection of hepatocellular carcinoma (ASCEND-Hep): a multiphase prospective development and validation study.BMC medicine · 2026Article
- MRDsteer: quality-aware AI-driven closed-loop optimization enhances ctDNA-based minimal residual disease detection.Briefings in bioinformatics · 2026Article
118 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
87 authors.
Ira W DevesonKinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Sydney, NSW, Australia.ORCID http://orcid.org/0000-0003-3861-0472
Binsheng GongDivision of Bioinformatics and Biostatistics, National Center for Toxicological Research, US Food and Drug Administration, Jefferson, AR, USA.
Kevin LaiBioinformatics, Integrated DNA Technologies, Inc., Coralville, IA, USA.
Jennifer S LoCocoIllumina, Inc., San Diego, CA, USA.ORCID http://orcid.org/0000-0002-7437-5177
Todd A RichmondMarket & Application Development Bioinformatics, Roche Sequencing Solutions Inc., Pleasanton, CA, USA.ORCID http://orcid.org/0000-0003-1508-6540
Jeoffrey SchagemanClinical Sequencing Division, Thermo Fisher Scientific, Austin, TX, USA.
Zhihong ZhangResearch and Development, Burning Rock Biotech, Shanghai, China.
Natalia NovoradovskayaAgilent Technologies, La Jolla, CA, USA.
James C WilleyDepartments of Medicine, Pathology, and Cancer Biology, College of Medicine and Life Sciences, University of Toledo Health Sciences Campus, Toledo, OH, USA.
Wendell JonesQ2 Solutions - EA Genomics, Morrisville, NC, USA.ORCID http://orcid.org/0000-0002-9676-5387
Rebecca KuskoImmuneering Corporation, Cambridge, MA, USA.ORCID http://orcid.org/0000-0001-6730-5990
Guangchun ChenDepartment of Immunology, Genomics and Microarray Core Facility, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Bindu Swapna MadalaGenomics and Epigenetics Theme, Garvan Institute of Medical Research, Sydney, NSW, Australia.
James BlackburnCancer Theme, Garvan Institute of Medical Research, Sydney, NSW, Australia.ORCID http://orcid.org/0000-0001-5216-8815
Igor StevanovskiKinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Sydney, NSW, Australia.
Ambica BhandariResearchDx, Inc., Irvine, CA, USA.
Devin CloseR&D Genomics MPS, Institute for Clinical and Experimental Pathology ARUP Laboratories, Salt Lake City, UT, USA.
Jeffrey ConroyOmniSeq, Inc., Buffalo, NY, USA.
Michael HubankNIHR Biomedical Research Centre, Royal Marsden Hospital, Sutton, Surrey, UK.
Narasimha MarellaCancer Genetics, Inc., Rutherford, NJ, USA.
Piotr A MieczkowskiDepartment of Genetics, University of North Carolina, Chapel Hill, NC, USA.ORCID http://orcid.org/0000-0003-2418-0096
Fujun QiuResearch and Development, Burning Rock Biotech, Shanghai, China.
Robert SebraIcahn Institute and Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Daniel StetsonAstrazeneca Pharmaceuticals, Waltham, MA, USA.
Lihyun SunElim Biopharmaceuticals, Inc., Hayward, CA, USA.
Philippe SzankasiR&D Genomics MPS, Institute for Clinical and Experimental Pathology ARUP Laboratories, Salt Lake City, UT, USA.
Haowen TanPrimbio Genes Biotechnology, East Lake High-tech Development Zone, Wuhan, Hubei, China.
Lin-Ya TangInstitute for Personalized Cancer Therapy, MD Anderson Cancer Center, Houston, TX, USA.
Hanane AribIcahn Institute and Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Hunter BestR&D Genomics MPS, Institute for Clinical and Experimental Pathology ARUP Laboratories, Salt Lake City, UT, USA.
Blake BurgherOmniSeq, Inc., Buffalo, NY, USA.
Pierre R BushelNational Institute of Environmental Health Sciences, Research Triangle Park, Morrisville, NC, USA.
Fergal CaseyMarket & Application Development Bioinformatics, Roche Sequencing Solutions Inc., Pleasanton, CA, USA.
Simon CawleyClinical Sequencing Division, Thermo Fisher Scientific, South San Francisco, CA, USA.
Chia-Jung ChangStanford Genome Technology Center, Stanford University, Palo Alto, CA, USA.
Jonathan ChoiRoche Sequencing Solutions, Inc., Pleasanton, CA, USA.
Jorge DinisRoche Sequencing Solutions, Inc., Pleasanton, CA, USA.
Daniel DuncanCancer Genetics, Inc., Rutherford, NJ, USA.
Agda Karina EterovicInstitute for Personalized Cancer Therapy, MD Anderson Cancer Center, Houston, TX, USA.
Liang FengMarket & Application Development Bioinformatics, Roche Sequencing Solutions Inc., Pleasanton, CA, USA.
Abhisek GhosalResearchDx, Inc., Irvine, CA, USA.
Kristina GiordaMarketing, Integrated DNA Technologies, Inc., Coralville, IA, USA.
Sean GlennOmniSeq, Inc., Buffalo, NY, USA.
Scott HappeAgilent Technologies, Cedar Creek, TX, USA.
Nathan HaseleyIllumina, Inc., San Diego, CA, USA.
Kyle HorvathResearchDx, Inc., Irvine, CA, USA.
Li-Yuan HungMassachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
Mirna JaroszNGS Products and Services, Integrated DNA Technologies, Inc., Coralville, IA, USA.
Garima KushwahaMarket & Application Development Bioinformatics, Roche Sequencing Solutions Inc., Pleasanton, CA, USA.
Dan LiDivision of Bioinformatics and Biostatistics, National Center for Toxicological Research, US Food and Drug Administration, Jefferson, AR, USA.ORCID http://orcid.org/0000-0001-6394-7953
Quan-Zhen LiDepartment of Immunology, Genomics and Microarray Core Facility, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Zhiguang LiIntramural Research Program, Laboratory of Epidemiology and Population Sciences, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA.
Liang-Chun LiuClinical Diagnostic Division, Thermo Fisher Scientific, Fremont, CA, USA.
Zhichao LiuDivision of Bioinformatics and Biostatistics, National Center for Toxicological Research, US Food and Drug Administration, Jefferson, AR, USA.
Charles MaCancer Genetics, Inc., Rutherford, NJ, USA.
Christopher E MasonDepartment of Physiology and Biophysics, Weill Cornell Medicine, Cornell University, New York, NY, USA.ORCID http://orcid.org/0000-0002-1850-1642
Dalila B MegherbiCMINDS Research Center, Department of Electrical and Computer Engineering, College of Engineering, University of Massachusetts Lowell, Lowell, MA, USA.
Tom MorrisonAccugenomics, Inc., Wilmington, NC, USA.
Carlos Pabón-PeñaAgilent Technologies, Santa Clara, CA, USA.
Mehdi PiroozniaBioinformatics and Computational Biology Laboratory, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA.ORCID http://orcid.org/0000-0002-4210-6458
Paula Z ProszekNIHR Biomedical Research Centre, Royal Marsden Hospital, Sutton, Surrey, UK.
Amelia RaymondAstrazeneca Pharmaceuticals, Waltham, MA, USA.
Paul RindlerR&D Genomics MPS, Institute for Clinical and Experimental Pathology ARUP Laboratories, Salt Lake City, UT, USA.
Rebecca RinglerResearchDx, Inc., Irvine, CA, USA.
Andreas SchererInstitute for Molecular Medicine Finland (FIMM), Nordic EMBL Partnership for Molecular Medicine, HiLIFE Unit, Biomedicum Helsinki 2U (D302b), University of Helsinki, Helsinki, Finland.ORCID http://orcid.org/0000-0002-4254-7122
Rita ShaknovichCancer Genetics, Inc., Rutherford, NJ, USA.
Tieliu ShiCenter for Bioinformatics and Computational Biology and the Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai, China.
Melissa SmithIcahn Institute and Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Ping SongInstitute for Personalized Cancer Therapy, MD Anderson Cancer Center, Houston, TX, USA.
Maya StrahlIcahn Institute and Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Venkat J ThodimaCancer Genetics, Inc., Rutherford, NJ, USA.
Nikola TomEATRIS ERIC- European Infrastructure for Translational Medicine, Amsterdam, The Netherlands.
Suman VermaResearchDx, Inc., Irvine, CA, USA.
Jiashi WangResearch and Development, Integrated DNA Technologies, Inc., Coralville, IA, USA.
Leihong WuDivision of Bioinformatics and Biostatistics, National Center for Toxicological Research, US Food and Drug Administration, Jefferson, AR, USA.
Wenzhong XiaoStanford Genome Technology Center, Stanford University, Palo Alto, CA, USA.
Chang XuResearch and Development, QIAGEN Sciences, Inc., Frederick, MD, USA.
Mary YangDepartment of Information Science, University of Arkansas at Little Rock, Little Rock, AR, USA.
Guangliang ZhangClinical Laboratory, Burning Rock Biotech, Guangzhou, China.
Sa ZhangClinical Laboratory, Burning Rock Biotech, Guangzhou, China.
Yilin ZhangElim Biopharmaceuticals, Inc., Hayward, CA, USA.
Leming ShiState Key Laboratory of Genetic Engineering, School of Life Sciences and Shanghai Cancer Hospital/Cancer Institute, Fudan University, Shanghai, China.
Weida TongDivision of Bioinformatics and Biostatistics, National Center for Toxicological Research, US Food and Drug Administration, Jefferson, AR, USA.
Donald J JohannWinthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA. djjohann@uams.edu.
Timothy R MercerSt. Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia. t.mercer@garvan.org.au.ORCID http://orcid.org/0000-0001-8780-894X
Joshua XuDivision of Bioinformatics and Biostatistics, National Center for Toxicological Research, US Food and Drug Administration, Jefferson, AR, USA. joshua.xu@fda.hhs.gov.ORCID http://orcid.org/0000-0001-5313-5847
SEQC2 Oncopanel Sequencing Working Group
Funding
WOUND HEALINGP50GM021700 · NIGMS · MASSACHUSETTS GENERAL HOSPITAL · PI MARTYN, JEEVENDRA · 1985 to 2017
$27.2MMicroarray and Genome InformaticsZIAES102345 · NIEHS · NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES · PI BUSHEL, ROBERT · 2009 to 2021
$10.8MBioinformatics CoreZICHL006228 · NHLBI · NATIONAL HEART, LUNG, AND BLOOD INSTITUTE · PI PIROOZNIA, MEHDI · 2017 to 2021
$6.6MDEVELOP NOVEL DEEP LEARNING AND COMBINATORIAL OPTIMIZATION METHODS TO IDENTIFY KEY DISEASE REGULATORY ELEMENTS FOR SINGLE-CELL DATAR15GM137288 · NIGMS · UNIVERSITY OF ARKANSAS AT LITTLE ROCK · PI YANG, MARY · 2020 to 2020
$444kDeveloping integrative approaches for identifying disease-causing genes and dysfunctional networksR15GM114739 · NIGMS · UNIVERSITY OF ARKANSAS AT LITTLE ROCK · PI YANG, MARY · 2015 to 2015
$374kFDA HHS HHSF223201510172CIntramural FDA HHS FD999999NIGMS NIH HHS R15 GM114739NIGMS NIH HHS R15 GM137288
Abstract
Circulating tumor DNA (ctDNA) sequencing is being rapidly adopted in precision oncology, but the accuracy, sensitivity and reproducibility of ctDNA assays is poorly understood. Here we report the findings of a multi-site, cross-platform evaluation of the analytical performance of five industry-leading ctDNA assays. We evaluated each stage of the ctDNA sequencing workflow with simulations, synthetic DNA spike-in experiments and proficiency testing on standardized, cell-line-derived reference samples. Above 0.5% variant allele frequency, ctDNA mutations were detected with high sensitivity, precision and reproducibility by all five assays, whereas, below this limit, detection became unreliable and varied widely between assays, especially when input material was limited. Missed mutations (false negatives) were more common than erroneous candidates (false positives), indicating that the reliable sampling of rare ctDNA fragments is the key challenge for ctDNA assays. This comprehensive evaluation of the analytical performance of ctDNA assays serves to inform best practice guidelines and provides a resource for precision oncology.
Indexed as
Medical OncologyPrecision MedicineCirculating Tumor DNAHigh-Throughput Nucleotide SequencingHumansLimit of DetectionNeoplasmsPractice Guidelines as TopicReproducibility of ResultsSequence Analysis, DNACirculating Tumor DNA
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