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Download Hi-Res ImageDownload to MS-PowerPointCite This:Anal. Chem. 2017, 89, 3, 1724-1733
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    International Interlaboratory Digital PCR Study Demonstrating High Reproducibility for the Measurement of a Rare Sequence Variant
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    † Molecular and Cell Biology Team, LGC, Queens Road, Teddington, Middlesex TW11 0LY, United Kingdom
    ‡ Digital Biology Center, Bio-Rad Laboratories, 5731 West Las Positas, Pleasanton, California 94588, United States
    § Statistics Team, LGC, Queens Road, Teddington, Middlesex TW11 0LY, United Kingdom
    ∥ Chronix Biomedical, Goetheallee 8, 37073 Goettingen, Germany
    ⊥ Department of Internal Medicine I, Ulm University, Albert-Einstein-Allee 23, 89081, Ulm, Germany
    # Laboratoire de Recherche Translationnelle, Centre Léon-Bérard, Lyon, F-69008, France
    ∇ Sjællands Universitetshospital, Klinisk Biokemisk Afdeling, Molekylærenhed, Sygehusvej 10, 4000 Roskilde, Denmark
    ○ Genoptix Inc., 1811 Aston Avenue, Carlsbad, California 92008, United States
    ◆ Service de Transfert d’Oncologie Biologique, Laboratoire de Biologie Médicale, Faculte de médecine Nord, Boulevard Pierre Dramard, Marseille 13916 cedex 20, France
    UCL Cancer Institute, Paul O’Gorman Building, 72 Huntley Street, London WC1E 6DD, United Kingdom
    ◊ Department of Clinical Immunology and Biochemistry, Vejle Hospital, Kabbeltoft 25, 7100 Vejle, Denmark
    ⧫ Division of Genetics and Cell Biology, IRCCS San Raffaele Scientific Institute, via Olgettina 60, 20132 Milano, Italy
    ● Department of Pediatrics and CIMA LAB Diagnostics, Clínica Universidad de Navarra, Avenida Pío XII 36, 31008 Pamplona, Spain
    ■ Michael Smith Laboratories, University of British Columbia, 301 Michael Smith Building, 2185 East Mall, Vancouver, BC V6T 1Z4, Canada
    □ The University of Texas MD Anderson Cancer Center, Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), 1515 Holcombe Boulevard 0455, Houston, Texas 77030, United States
    ◇ Solid Tumours Genomics Unit, Tenon Hospital, APHP and Université Pierre et Marie Curie, 4 rue de la Chine, 75970 Paris, France
    ◑ Johns Hopkins, 1650 Orleans St., Baltimore, Maryland 21287, United States
    ▱ Department of Cancer Studies, University of Leicester, Robert Kilpatrick Clinical Sciences Building, Leicester Royal Infirmary, Leicester LE2 7LX, United Kingdom
    △ Lung Cancer Group, Division of Molecular Pathology, The Institute of Cancer Research, 123 Old Brompton Road, London SW7 3RP, United Kingdom
    ▲ Institut Claudius Regaud − IUCTO, Laboratoire de Biologie Medicale Oncologique, 1 avenue Irène Joliot-Curie, Toulouse 31059 cedex 9, France
    ▼ Institut Curie, PSL Research University, SiRIC, Laboratory of Circulating Tumor Biomarkers, 26 rue d’Ulm, 75005 Paris, France
    ⬡ Department of Oncology and Pathology, Lund University, Scheelevägen 2, MV 404-B2, SE-22381, Lund, Sweden
    ⬢ Department of Pediatrics, Benioff Children’s Hospital, UCSF Helen Diller Family Comprehensive Cancer Center, 1450 Third Street, San Francisco, California 94158, United States
    ⌽ Dana Farber Cancer Institute, Belfer Center for Applied Cancer Science and Department of Medical Oncology, Boston, Massachusetts 02115, United States
    ◒ School of Biosciences & Medicine, Faculty of Health & Medical Science, University of Surrey, Guildford, Surrey GU2 7XH, United Kingdom
    *Phone: +44 (0)20 8943 7655. Fax: +44 (0)20 8943 2767. E-mail: [email protected]
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    Analytical Chemistry

    Cite this: Anal. Chem. 2017, 89, 3, 1724–1733
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    https://doi.org/10.1021/acs.analchem.6b03980
    Published December 9, 2016
    Copyright © 2016 American Chemical Society
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    Abstract

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    This study tested the claim that digital PCR (dPCR) can offer highly reproducible quantitative measurements in disparate laboratories. Twenty-one laboratories measured four blinded samples containing different quantities of a KRAS fragment encoding G12D, an important genetic marker for guiding therapy of certain cancers. This marker is challenging to quantify reproducibly using quantitative PCR (qPCR) or next generation sequencing (NGS) due to the presence of competing wild type sequences and the need for calibration. Using dPCR, 18 laboratories were able to quantify the G12D marker within 12% of each other in all samples. Three laboratories appeared to measure consistently outlying results; however, proper application of a follow-up analysis recommendation rectified their data. Our findings show that dPCR has demonstrable reproducibility across a large number of laboratories without calibration. This could enable the reproducible application of molecular stratification to guide therapy and, potentially, for molecular diagnostics.

    Copyright © 2016 American Chemical Society

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    Supporting Information

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    The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.analchem.6b03980.

    • dMIQE checklist for authors, reviewers and editors; submitted values for each sample from the 21 participant laboratories; analysis parameters for each sample from the 21 participant laboratories; resubmitted values for the 4 participant laboratories; number of positive partitions per well of the nine negative control reactions; number of positive partitions per well of the eight no template control reactions (PDF)

    • Overview of the workflow applied to the study; KRAS G12D and wt study materials; homogeneity study; short and long term stability; interlaboratory comparison of control samples; effect of threshold positioning on the quantification of the KRAS G12D and wt molecules in the same data set; quantification of KRAS wt following threshold setting guidelines and effect on the G12D fractional abundance; effect of different protocol procedures (PDF)

    • Invitation to participate in a droplet digital PCR interlaboratory study: Measurement of rare sequence variants (PDF)

    • Packing slip and delivery form (PDF)

    • Protocol for KRAS interlab study (PDF)

    • Guidelines for classifying droplets in rare mutation quantification experiments in the KRAS interlab study (PDF)

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    Analytical Chemistry

    Cite this: Anal. Chem. 2017, 89, 3, 1724–1733
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acs.analchem.6b03980
    Published December 9, 2016
    Copyright © 2016 American Chemical Society
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