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Development and evaluation of a secondary reference panel for BCR-ABL1 quantification on the International Scale

Identifieur interne : 000726 ( Pmc/Curation ); précédent : 000725; suivant : 000727

Development and evaluation of a secondary reference panel for BCR-ABL1 quantification on the International Scale

Auteurs : N C P. Cross [Royaume-Uni] ; H E White [Royaume-Uni] ; T. Ernst [Allemagne] ; L. Welden [Australie] ; C. Dietz [Allemagne] ; G. Saglio [Italie] ; F-X Mahon [France] ; C C Wong [États-Unis] ; D. Zheng [États-Unis] ; S. Wong [États-Unis] ; S-S Wang [États-Unis] ; S. Akiki [Royaume-Uni] ; F. Albano [Italie] ; H. Andrikovics [Hongrie] ; J. Anwar [Royaume-Uni] ; G. Balatzenko [Bulgarie] ; I. Bendit [Brésil] ; J. Beveridge [Australie] ; N. Boeckx [Belgique] ; N. Cerveira [Portugal] ; S-M Cheng [États-Unis] ; D. Colomer [Espagne] ; S. Czurda [Autriche] ; F. Daraio [Italie] ; S. Dulucq [France] ; L. Eggen [Norvège] ; H. El Housni [Belgique] ; G. Gerrard [Royaume-Uni] ; M. Gniot [Pologne] ; B. Izzo [Italie] ; D. Jacquin [États-Unis] ; J J W M. Janssen [Pays-Bas] ; S. Jeromin [Allemagne] ; T. Jurcek [République tchèque] ; D-W Kim [Corée du Sud] ; K. Machova-Polakova [République tchèque] ; J. Martinez-Lopez [Espagne] ; M. Mcbean [Australie] ; S. Mesanovic [Bosnie-Herzégovine] ; G. Mitterbauer-Hohendanner [Autriche] ; H. Mobtaker [États-Unis] ; M-J Mozziconacci [France] ; T. Paji [Slovénie] ; N. Pallisgaard [Danemark] ; P. Panagiotidis [Grèce] ; R D Press [États-Unis] ; Y-Z Qin [République populaire de Chine] ; J. Radich [États-Unis] ; T. Sacha [Pologne] ; T. Touloumenidou [Grèce] ; P. Waits [Royaume-Uni] ; E. Wilkinson [Royaume-Uni] ; R. Zadro [Croatie] ; M C Müller [Allemagne] ; A. Hochhaus [Allemagne] ; S. Branford [Australie]

Source :

RBID : PMC:5240017

Abstract

Molecular monitoring of chronic myeloid leukemia patients using robust BCR-ABL1 tests standardized to the International Scale (IS) is key to proper disease management, especially when treatment cessation is considered. Most laboratories currently use a time-consuming sample exchange process with reference laboratories for IS calibration. A World Health Organization (WHO) BCR-ABL1 reference panel was developed (MR1–MR4), but access to the material is limited. In this study, we describe the development of the first cell-based secondary reference panel that is traceable to and faithfully replicates the WHO panel, with an additional MR4.5 level. The secondary panel was calibrated to IS using digital PCR with ABL1, BCR and GUSB as reference genes and evaluated by 44 laboratories worldwide. Interestingly, we found that >40% of BCR-ABL1 assays showed signs of inadequate optimization such as poor linearity and suboptimal PCR efficiency. Nonetheless, when optimized sample inputs were used, >60% demonstrated satisfactory IS accuracy, precision and/or MR4.5 sensitivity, and 58% obtained IS conversion factors from the secondary reference concordant with their current values. Correlation analysis indicated no significant alterations in %BCR-ABL1 results caused by different assay configurations. More assays achieved good precision and/or sensitivity than IS accuracy, indicating the need for better IS calibration mechanisms.


Url:
DOI: 10.1038/leu.2016.90
PubMed: 27109508
PubMed Central: 5240017

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PMC:5240017

Le document en format XML

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<institution>Department of Hematology/Oncology, Universitätsklinikum Jena</institution>
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<institution>Department of Genetics and Molecular Pathology, Centre for Cancer Biology, SA Pathology</institution>
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<name sortKey="Dietz, C" sort="Dietz, C" uniqKey="Dietz C" first="C" last="Dietz">C. Dietz</name>
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<country xml:lang="fr">Allemagne</country>
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<name sortKey="Saglio, G" sort="Saglio, G" uniqKey="Saglio G" first="G" last="Saglio">G. Saglio</name>
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<institution>Department of Clinical and Biological Sciences, San Luigi Hospital, University of Turin</institution>
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<country xml:lang="fr">Italie</country>
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<name sortKey="Mahon, F X" sort="Mahon, F X" uniqKey="Mahon F" first="F-X" last="Mahon">F-X Mahon</name>
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<nlm:aff id="aff7">
<institution>Bergonie Institute Cancer Center Bordeaux, INSERM U1218, University of Bordeaux</institution>
, Bordeaux,
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</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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<author>
<name sortKey="Wong, C C" sort="Wong, C C" uniqKey="Wong C" first="C C" last="Wong">C C Wong</name>
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<institution>Novartis Pharmaceuticals Corporation</institution>
, East Hanover, NJ,
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<country xml:lang="fr">États-Unis</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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<name sortKey="Zheng, D" sort="Zheng, D" uniqKey="Zheng D" first="D" last="Zheng">D. Zheng</name>
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<nlm:aff id="aff8">
<institution>Novartis Pharmaceuticals Corporation</institution>
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<country xml:lang="fr">États-Unis</country>
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<name sortKey="Wong, S" sort="Wong, S" uniqKey="Wong S" first="S" last="Wong">S. Wong</name>
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<country xml:lang="fr">États-Unis</country>
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<name sortKey="Wang, S S" sort="Wang, S S" uniqKey="Wang S" first="S-S" last="Wang">S-S Wang</name>
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<nlm:aff id="aff8">
<institution>Novartis Pharmaceuticals Corporation</institution>
, East Hanover, NJ,
<country>USA</country>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
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<author>
<name sortKey="Akiki, S" sort="Akiki, S" uniqKey="Akiki S" first="S" last="Akiki">S. Akiki</name>
<affiliation wicri:level="1">
<nlm:aff id="aff9">
<institution>West Midlands Regional Genetics Laboratory</institution>
, Birmingham,
<country>UK</country>
</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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<author>
<name sortKey="Albano, F" sort="Albano, F" uniqKey="Albano F" first="F" last="Albano">F. Albano</name>
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<nlm:aff id="aff10">
<institution>Department of Hematology, University of Bari</institution>
, Bari,
<country>Italy</country>
</nlm:aff>
<country xml:lang="fr">Italie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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<name sortKey="Andrikovics, H" sort="Andrikovics, H" uniqKey="Andrikovics H" first="H" last="Andrikovics">H. Andrikovics</name>
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<nlm:aff id="aff11">
<institution>Laboratory of Molecular Diagnostics, Hungarian National Blood Transfusion Service</institution>
, Budapest,
<country>Hungary</country>
</nlm:aff>
<country xml:lang="fr">Hongrie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1">
<nlm:aff id="aff12">
<institution>Department of Pathophysiology, Semmelweis University</institution>
, Budapest,
<country>Hungary</country>
</nlm:aff>
<country xml:lang="fr">Hongrie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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<author>
<name sortKey="Anwar, J" sort="Anwar, J" uniqKey="Anwar J" first="J" last="Anwar">J. Anwar</name>
<affiliation wicri:level="1">
<nlm:aff id="aff13">
<institution>King's College Hospital London</institution>
, London,
<country>UK</country>
</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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<author>
<name sortKey="Balatzenko, G" sort="Balatzenko, G" uniqKey="Balatzenko G" first="G" last="Balatzenko">G. Balatzenko</name>
<affiliation wicri:level="1">
<nlm:aff id="aff14">
<institution>National Specialized Hospital for Active Treatment of Hematological Diseases</institution>
, Sofia,
<country>Bulgaria</country>
</nlm:aff>
<country xml:lang="fr">Bulgarie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
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<author>
<name sortKey="Bendit, I" sort="Bendit, I" uniqKey="Bendit I" first="I" last="Bendit">I. Bendit</name>
<affiliation wicri:level="1">
<nlm:aff id="aff15">
<institution>Laboratorio de Biologia Tumoral, Disciplina de Hematologia do HC-FMUSP</institution>
, São Paulo,
<country>Brazil</country>
</nlm:aff>
<country xml:lang="fr">Brésil</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Beveridge, J" sort="Beveridge, J" uniqKey="Beveridge J" first="J" last="Beveridge">J. Beveridge</name>
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<nlm:aff id="aff16">
<institution>PathWest Laboratory Medicine WA, Department of Haematology, Fiona Stanley Hospital</institution>
, Perth, WA,
<country>Australia</country>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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<name sortKey="Boeckx, N" sort="Boeckx, N" uniqKey="Boeckx N" first="N" last="Boeckx">N. Boeckx</name>
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<nlm:aff id="aff17">
<institution>Department of Laboratory Medicine, University Hospitals Leuven</institution>
, Leuven,
<country>Belgium</country>
</nlm:aff>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1">
<nlm:aff id="aff18">
<institution>Department of Oncology, KUL</institution>
, Leuven,
<country>Belgium</country>
</nlm:aff>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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<author>
<name sortKey="Cerveira, N" sort="Cerveira, N" uniqKey="Cerveira N" first="N" last="Cerveira">N. Cerveira</name>
<affiliation wicri:level="1">
<nlm:aff id="aff19">
<institution>Department of Genetics, Portuguese Oncology Institute</institution>
, Porto,
<country>Portugal</country>
</nlm:aff>
<country xml:lang="fr">Portugal</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Cheng, S M" sort="Cheng, S M" uniqKey="Cheng S" first="S-M" last="Cheng">S-M Cheng</name>
<affiliation wicri:level="1">
<nlm:aff id="aff20">
<institution>Department of Hematology and Oncology, Quest Diagnostics Nichols Institute</institution>
, San Juan Capistrano, CA,
<country>USA</country>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Colomer, D" sort="Colomer, D" uniqKey="Colomer D" first="D" last="Colomer">D. Colomer</name>
<affiliation wicri:level="1">
<nlm:aff id="aff21">
<institution>Hematopathology Unit, Hospital Clinic, IDIBAPS</institution>
, Barcelona,
<country>Spain</country>
</nlm:aff>
<country xml:lang="fr">Espagne</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Czurda, S" sort="Czurda, S" uniqKey="Czurda S" first="S" last="Czurda">S. Czurda</name>
<affiliation wicri:level="1">
<nlm:aff id="aff22">
<institution>Division of Molecular Microbiology, Children's Cancer Research Institute</institution>
, Vienna,
<country>Austria</country>
</nlm:aff>
<country xml:lang="fr">Autriche</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Daraio, F" sort="Daraio, F" uniqKey="Daraio F" first="F" last="Daraio">F. Daraio</name>
<affiliation wicri:level="1">
<nlm:aff id="aff23">
<institution>Department of Clinical and Biological Sciences, San Luigi Hospital, University of Turin</institution>
, Orbassano,
<country>Italy</country>
</nlm:aff>
<country xml:lang="fr">Italie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Dulucq, S" sort="Dulucq, S" uniqKey="Dulucq S" first="S" last="Dulucq">S. Dulucq</name>
<affiliation wicri:level="1">
<nlm:aff id="aff24">
<institution>Laboratoire Hematologie, Centre Hospitalier Universitaire de Bordeaux, Universite Bordeaux</institution>
, Bordeaux,
<country>France</country>
</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Eggen, L" sort="Eggen, L" uniqKey="Eggen L" first="L" last="Eggen">L. Eggen</name>
<affiliation wicri:level="1">
<nlm:aff id="aff25">
<institution>Laboratory of Molecular Pathology, Oslo University Hospital</institution>
, Oslo,
<country>Norway</country>
</nlm:aff>
<country xml:lang="fr">Norvège</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="El Housni, H" sort="El Housni, H" uniqKey="El Housni H" first="H" last="El Housni">H. El Housni</name>
<affiliation wicri:level="1">
<nlm:aff id="aff26">
<institution>Clinique de Genetique Oncologique-Service de genetique, Hopital Erasme</institution>
, Brussels,
<country>Belgium</country>
</nlm:aff>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Gerrard, G" sort="Gerrard, G" uniqKey="Gerrard G" first="G" last="Gerrard">G. Gerrard</name>
<affiliation wicri:level="1">
<nlm:aff id="aff27">
<institution>Imperial Molecular Pathology, Hammersmith Hospital</institution>
, London,
<country>UK</country>
</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Gniot, M" sort="Gniot, M" uniqKey="Gniot M" first="M" last="Gniot">M. Gniot</name>
<affiliation wicri:level="1">
<nlm:aff id="aff28">
<institution>Department of Hematology and Bone Marrow Transplantation, Poznan University of Medical Sciences</institution>
, Poznan,
<country>Poland</country>
</nlm:aff>
<country xml:lang="fr">Pologne</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Izzo, B" sort="Izzo, B" uniqKey="Izzo B" first="B" last="Izzo">B. Izzo</name>
<affiliation wicri:level="1">
<nlm:aff id="aff29">
<institution>Department of Clinical Medicine and Surgery, University ‘Federico II' of Naples</institution>
, Naples,
<country>Italy</country>
</nlm:aff>
<country xml:lang="fr">Italie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1">
<nlm:aff id="aff30">
<institution>CEINGE – Biotecnologie Avanzate</institution>
, Naples,
<country>Italy</country>
</nlm:aff>
<country xml:lang="fr">Italie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Jacquin, D" sort="Jacquin, D" uniqKey="Jacquin D" first="D" last="Jacquin">D. Jacquin</name>
<affiliation wicri:level="1">
<nlm:aff id="aff31">
<institution>Genoptix, Inc.</institution>
, Carlsbad, CA,
<country>USA</country>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Janssen, J J W M" sort="Janssen, J J W M" uniqKey="Janssen J" first="J J W M" last="Janssen">J J W M. Janssen</name>
<affiliation wicri:level="1">
<nlm:aff id="aff32">
<institution>Department of Hematology and Molecular Diagnostics, VU University Medical Center</institution>
, Amsterdam,
<country>The Netherlands</country>
</nlm:aff>
<country xml:lang="fr">Pays-Bas</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Jeromin, S" sort="Jeromin, S" uniqKey="Jeromin S" first="S" last="Jeromin">S. Jeromin</name>
<affiliation wicri:level="1">
<nlm:aff id="aff33">
<institution>MLL Munich Leukemia Laboratory</institution>
, Munich,
<country>Germany</country>
</nlm:aff>
<country xml:lang="fr">Allemagne</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Jurcek, T" sort="Jurcek, T" uniqKey="Jurcek T" first="T" last="Jurcek">T. Jurcek</name>
<affiliation wicri:level="1">
<nlm:aff id="aff34">
<institution>Center of Molecular Biology and Gene Therapy, Department of Internal Medicine-Hematology and Oncology, Masaryk University and University Hospital Brno</institution>
, Brno,
<country>Czech Republic</country>
</nlm:aff>
<country xml:lang="fr">République tchèque</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Kim, D W" sort="Kim, D W" uniqKey="Kim D" first="D-W" last="Kim">D-W Kim</name>
<affiliation wicri:level="1">
<nlm:aff id="aff35">
<institution>Seoul St Mary's Hospital, Leukemia Research Institute, The Catholic University of Korea</institution>
, Seoul,
<country>Korea</country>
</nlm:aff>
<country xml:lang="fr">Corée du Sud</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Machova Polakova, K" sort="Machova Polakova, K" uniqKey="Machova Polakova K" first="K" last="Machova-Polakova">K. Machova-Polakova</name>
<affiliation wicri:level="1">
<nlm:aff id="aff36">
<institution>Department of Molecular Genetics, Institute of Hematology and Blood Transfusion</institution>
, Prague,
<country>Czech Republic</country>
</nlm:aff>
<country xml:lang="fr">République tchèque</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Martinez Lopez, J" sort="Martinez Lopez, J" uniqKey="Martinez Lopez J" first="J" last="Martinez-Lopez">J. Martinez-Lopez</name>
<affiliation wicri:level="1">
<nlm:aff id="aff37">
<institution>Department of Hematology, Hospital Universitario 12 de Octubre, Universidad Complutense, CNIO</institution>
, Madrid,
<country>Spain</country>
</nlm:aff>
<country xml:lang="fr">Espagne</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Mcbean, M" sort="Mcbean, M" uniqKey="Mcbean M" first="M" last="Mcbean">M. Mcbean</name>
<affiliation wicri:level="1">
<nlm:aff id="aff38">
<institution>Division of Cancer Medicine, Department of Pathology, Peter MacCallum Cancer Centre</institution>
, East Melbourne, VIC,
<country>Australia</country>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Mesanovic, S" sort="Mesanovic, S" uniqKey="Mesanovic S" first="S" last="Mesanovic">S. Mesanovic</name>
<affiliation wicri:level="1">
<nlm:aff id="aff39">
<institution>Pathology Department, University Clinical Center Tuzla</institution>
, Tuzla,
<country>Bosnia and Herzegovina</country>
</nlm:aff>
<country xml:lang="fr">Bosnie-Herzégovine</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Mitterbauer Hohendanner, G" sort="Mitterbauer Hohendanner, G" uniqKey="Mitterbauer Hohendanner G" first="G" last="Mitterbauer-Hohendanner">G. Mitterbauer-Hohendanner</name>
<affiliation wicri:level="1">
<nlm:aff id="aff40">
<institution>Department of Laboratory Medicine, Division of Medical and Chemical Laboratory Diagnostics, Medical University of Vienna</institution>
, Vienna,
<country>Austria</country>
</nlm:aff>
<country xml:lang="fr">Autriche</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Mobtaker, H" sort="Mobtaker, H" uniqKey="Mobtaker H" first="H" last="Mobtaker">H. Mobtaker</name>
<affiliation wicri:level="1">
<nlm:aff id="aff31">
<institution>Genoptix, Inc.</institution>
, Carlsbad, CA,
<country>USA</country>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Mozziconacci, M J" sort="Mozziconacci, M J" uniqKey="Mozziconacci M" first="M-J" last="Mozziconacci">M-J Mozziconacci</name>
<affiliation wicri:level="1">
<nlm:aff id="aff41">
<institution>Departement de Biopathologie, Institut Paoli-Calmettes</institution>
, Marseille,
<country>France</country>
</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Paji, T" sort="Paji, T" uniqKey="Paji T" first="T" last="Paji">T. Paji</name>
<affiliation wicri:level="1">
<nlm:aff id="aff42">
<institution>Specialized Haematology Laboratory, Department of Haematology, University Medical Centre Ljubljana</institution>
, Ljubljana,
<country>Slovenia</country>
</nlm:aff>
<country xml:lang="fr">Slovénie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Pallisgaard, N" sort="Pallisgaard, N" uniqKey="Pallisgaard N" first="N" last="Pallisgaard">N. Pallisgaard</name>
<affiliation wicri:level="1">
<nlm:aff id="aff43">
<institution>Department of Surgical Pathology, Zealand University Hospital</institution>
, Roskilde,
<country>Denmark</country>
</nlm:aff>
<country xml:lang="fr">Danemark</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Panagiotidis, P" sort="Panagiotidis, P" uniqKey="Panagiotidis P" first="P" last="Panagiotidis">P. Panagiotidis</name>
<affiliation wicri:level="1">
<nlm:aff id="aff44">
<institution>Hematology Unit, First Department of Internal Medicine, Laiko Hospital, University of Athens,</institution>
Athens,
<country>Greece</country>
</nlm:aff>
<country xml:lang="fr">Grèce</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Press, R D" sort="Press, R D" uniqKey="Press R" first="R D" last="Press">R D Press</name>
<affiliation wicri:level="1">
<nlm:aff id="aff45">
<institution>Department of Pathology and Knight Cancer Institute, Oregon Health and Science University</institution>
, Portland, OR,
<country>USA</country>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Qin, Y Z" sort="Qin, Y Z" uniqKey="Qin Y" first="Y-Z" last="Qin">Y-Z Qin</name>
<affiliation wicri:level="1">
<nlm:aff id="aff46">
<institution>Peking University People's Hospital, Peking University Institute of Hematology</institution>
, Beijing,
<country>China</country>
</nlm:aff>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Radich, J" sort="Radich, J" uniqKey="Radich J" first="J" last="Radich">J. Radich</name>
<affiliation wicri:level="1">
<nlm:aff id="aff47">
<institution>Fred Hutchinson Cancer Research Center</institution>
, Seattle, WA,
<country>USA</country>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Sacha, T" sort="Sacha, T" uniqKey="Sacha T" first="T" last="Sacha">T. Sacha</name>
<affiliation wicri:level="1">
<nlm:aff id="aff48">
<institution>Chair and Department of Hematology, Jagiellonian University</institution>
, Kraków,
<country>Poland</country>
</nlm:aff>
<country xml:lang="fr">Pologne</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Touloumenidou, T" sort="Touloumenidou, T" uniqKey="Touloumenidou T" first="T" last="Touloumenidou">T. Touloumenidou</name>
<affiliation wicri:level="1">
<nlm:aff id="aff49">
<institution>Laboratory of Molecular Biology, Hematology Department and HCT Unit, G. Papanicolaou Hospital</institution>
, Thessaloniki,
<country>Greece</country>
</nlm:aff>
<country xml:lang="fr">Grèce</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Waits, P" sort="Waits, P" uniqKey="Waits P" first="P" last="Waits">P. Waits</name>
<affiliation wicri:level="1">
<nlm:aff id="aff50">
<institution>Bristol Genetics Laboratory</institution>
, Bristol,
<country>UK</country>
</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Wilkinson, E" sort="Wilkinson, E" uniqKey="Wilkinson E" first="E" last="Wilkinson">E. Wilkinson</name>
<affiliation wicri:level="1">
<nlm:aff id="aff51">
<institution>HMDS, Leeds Teaching Hospitals</institution>
, Leeds,
<country>UK</country>
</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Zadro, R" sort="Zadro, R" uniqKey="Zadro R" first="R" last="Zadro">R. Zadro</name>
<affiliation wicri:level="1">
<nlm:aff id="aff52">
<institution>Faculty of Pharmacy and Biochemistry and University Hospital Center Zagreb, University of Zagreb</institution>
, Zagreb,
<country>Croatia</country>
</nlm:aff>
<country xml:lang="fr">Croatie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Muller, M C" sort="Muller, M C" uniqKey="Muller M" first="M C" last="Müller">M C Müller</name>
<affiliation wicri:level="1">
<nlm:aff id="aff5">
<institution>III. Medizinische Klinik, Medizinische Fakultät Mannheim, Universität Heidelberg</institution>
, Mannheim,
<country>Germany</country>
</nlm:aff>
<country xml:lang="fr">Allemagne</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Hochhaus, A" sort="Hochhaus, A" uniqKey="Hochhaus A" first="A" last="Hochhaus">A. Hochhaus</name>
<affiliation wicri:level="1">
<nlm:aff id="aff3">
<institution>Department of Hematology/Oncology, Universitätsklinikum Jena</institution>
, Jena,
<country>Germany</country>
</nlm:aff>
<country xml:lang="fr">Allemagne</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Branford, S" sort="Branford, S" uniqKey="Branford S" first="S" last="Branford">S. Branford</name>
<affiliation wicri:level="1">
<nlm:aff id="aff4">
<institution>Department of Genetics and Molecular Pathology, Centre for Cancer Biology, SA Pathology</institution>
, Adelaide, SA,
<country>Australia</country>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1">
<nlm:aff id="aff53">
<institution>School of Pharmacy and Medical Science, University of South Australia</institution>
, Adelaide, SA,
<country>Australia</country>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1">
<nlm:aff id="aff54">
<institution>School of Medicine, University of Adelaide</institution>
, SA, Adelaide,
<country>Australia</country>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1">
<nlm:aff id="aff55">
<institution>School of Molecular and Biomedical Science, University of Adelaide</institution>
, Adelaide, SA,
<country>Australia</country>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
</titleStmt>
<publicationStmt>
<idno type="wicri:source">PMC</idno>
<idno type="pmid">27109508</idno>
<idno type="pmc">5240017</idno>
<idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5240017</idno>
<idno type="RBID">PMC:5240017</idno>
<idno type="doi">10.1038/leu.2016.90</idno>
<date when="2016">2016</date>
<idno type="wicri:Area/Pmc/Corpus">000727</idno>
<idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000727</idno>
<idno type="wicri:Area/Pmc/Curation">000726</idno>
<idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000726</idno>
</publicationStmt>
<sourceDesc>
<biblStruct>
<analytic>
<title xml:lang="en" level="a" type="main">Development and evaluation of a secondary reference panel for
<italic>BCR-ABL1</italic>
quantification on the International Scale</title>
<author>
<name sortKey="Cross, N C P" sort="Cross, N C P" uniqKey="Cross N" first="N C P" last="Cross">N C P. Cross</name>
<affiliation wicri:level="1">
<nlm:aff id="aff1">
<institution>Wessex Regional Genetics Laboratory, Salisbury NHS Foundation Trust</institution>
, Salisbury,
<country>UK</country>
</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1">
<nlm:aff id="aff2">
<institution>Faculty of Medicine, University of Southampton</institution>
, Southampton,
<country>UK</country>
</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="White, H E" sort="White, H E" uniqKey="White H" first="H E" last="White">H E White</name>
<affiliation wicri:level="1">
<nlm:aff id="aff1">
<institution>Wessex Regional Genetics Laboratory, Salisbury NHS Foundation Trust</institution>
, Salisbury,
<country>UK</country>
</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1">
<nlm:aff id="aff2">
<institution>Faculty of Medicine, University of Southampton</institution>
, Southampton,
<country>UK</country>
</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Ernst, T" sort="Ernst, T" uniqKey="Ernst T" first="T" last="Ernst">T. Ernst</name>
<affiliation wicri:level="1">
<nlm:aff id="aff3">
<institution>Department of Hematology/Oncology, Universitätsklinikum Jena</institution>
, Jena,
<country>Germany</country>
</nlm:aff>
<country xml:lang="fr">Allemagne</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Welden, L" sort="Welden, L" uniqKey="Welden L" first="L" last="Welden">L. Welden</name>
<affiliation wicri:level="1">
<nlm:aff id="aff4">
<institution>Department of Genetics and Molecular Pathology, Centre for Cancer Biology, SA Pathology</institution>
, Adelaide, SA,
<country>Australia</country>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Dietz, C" sort="Dietz, C" uniqKey="Dietz C" first="C" last="Dietz">C. Dietz</name>
<affiliation wicri:level="1">
<nlm:aff id="aff5">
<institution>III. Medizinische Klinik, Medizinische Fakultät Mannheim, Universität Heidelberg</institution>
, Mannheim,
<country>Germany</country>
</nlm:aff>
<country xml:lang="fr">Allemagne</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Saglio, G" sort="Saglio, G" uniqKey="Saglio G" first="G" last="Saglio">G. Saglio</name>
<affiliation wicri:level="1">
<nlm:aff id="aff6">
<institution>Department of Clinical and Biological Sciences, San Luigi Hospital, University of Turin</institution>
, Orbassano,
<country>Italy</country>
</nlm:aff>
<country xml:lang="fr">Italie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Mahon, F X" sort="Mahon, F X" uniqKey="Mahon F" first="F-X" last="Mahon">F-X Mahon</name>
<affiliation wicri:level="1">
<nlm:aff id="aff7">
<institution>Bergonie Institute Cancer Center Bordeaux, INSERM U1218, University of Bordeaux</institution>
, Bordeaux,
<country>France</country>
</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Wong, C C" sort="Wong, C C" uniqKey="Wong C" first="C C" last="Wong">C C Wong</name>
<affiliation wicri:level="1">
<nlm:aff id="aff8">
<institution>Novartis Pharmaceuticals Corporation</institution>
, East Hanover, NJ,
<country>USA</country>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Zheng, D" sort="Zheng, D" uniqKey="Zheng D" first="D" last="Zheng">D. Zheng</name>
<affiliation wicri:level="1">
<nlm:aff id="aff8">
<institution>Novartis Pharmaceuticals Corporation</institution>
, East Hanover, NJ,
<country>USA</country>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Wong, S" sort="Wong, S" uniqKey="Wong S" first="S" last="Wong">S. Wong</name>
<affiliation wicri:level="1">
<nlm:aff id="aff8">
<institution>Novartis Pharmaceuticals Corporation</institution>
, East Hanover, NJ,
<country>USA</country>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Wang, S S" sort="Wang, S S" uniqKey="Wang S" first="S-S" last="Wang">S-S Wang</name>
<affiliation wicri:level="1">
<nlm:aff id="aff8">
<institution>Novartis Pharmaceuticals Corporation</institution>
, East Hanover, NJ,
<country>USA</country>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Akiki, S" sort="Akiki, S" uniqKey="Akiki S" first="S" last="Akiki">S. Akiki</name>
<affiliation wicri:level="1">
<nlm:aff id="aff9">
<institution>West Midlands Regional Genetics Laboratory</institution>
, Birmingham,
<country>UK</country>
</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Albano, F" sort="Albano, F" uniqKey="Albano F" first="F" last="Albano">F. Albano</name>
<affiliation wicri:level="1">
<nlm:aff id="aff10">
<institution>Department of Hematology, University of Bari</institution>
, Bari,
<country>Italy</country>
</nlm:aff>
<country xml:lang="fr">Italie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Andrikovics, H" sort="Andrikovics, H" uniqKey="Andrikovics H" first="H" last="Andrikovics">H. Andrikovics</name>
<affiliation wicri:level="1">
<nlm:aff id="aff11">
<institution>Laboratory of Molecular Diagnostics, Hungarian National Blood Transfusion Service</institution>
, Budapest,
<country>Hungary</country>
</nlm:aff>
<country xml:lang="fr">Hongrie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1">
<nlm:aff id="aff12">
<institution>Department of Pathophysiology, Semmelweis University</institution>
, Budapest,
<country>Hungary</country>
</nlm:aff>
<country xml:lang="fr">Hongrie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Anwar, J" sort="Anwar, J" uniqKey="Anwar J" first="J" last="Anwar">J. Anwar</name>
<affiliation wicri:level="1">
<nlm:aff id="aff13">
<institution>King's College Hospital London</institution>
, London,
<country>UK</country>
</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Balatzenko, G" sort="Balatzenko, G" uniqKey="Balatzenko G" first="G" last="Balatzenko">G. Balatzenko</name>
<affiliation wicri:level="1">
<nlm:aff id="aff14">
<institution>National Specialized Hospital for Active Treatment of Hematological Diseases</institution>
, Sofia,
<country>Bulgaria</country>
</nlm:aff>
<country xml:lang="fr">Bulgarie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Bendit, I" sort="Bendit, I" uniqKey="Bendit I" first="I" last="Bendit">I. Bendit</name>
<affiliation wicri:level="1">
<nlm:aff id="aff15">
<institution>Laboratorio de Biologia Tumoral, Disciplina de Hematologia do HC-FMUSP</institution>
, São Paulo,
<country>Brazil</country>
</nlm:aff>
<country xml:lang="fr">Brésil</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Beveridge, J" sort="Beveridge, J" uniqKey="Beveridge J" first="J" last="Beveridge">J. Beveridge</name>
<affiliation wicri:level="1">
<nlm:aff id="aff16">
<institution>PathWest Laboratory Medicine WA, Department of Haematology, Fiona Stanley Hospital</institution>
, Perth, WA,
<country>Australia</country>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Boeckx, N" sort="Boeckx, N" uniqKey="Boeckx N" first="N" last="Boeckx">N. Boeckx</name>
<affiliation wicri:level="1">
<nlm:aff id="aff17">
<institution>Department of Laboratory Medicine, University Hospitals Leuven</institution>
, Leuven,
<country>Belgium</country>
</nlm:aff>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1">
<nlm:aff id="aff18">
<institution>Department of Oncology, KUL</institution>
, Leuven,
<country>Belgium</country>
</nlm:aff>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Cerveira, N" sort="Cerveira, N" uniqKey="Cerveira N" first="N" last="Cerveira">N. Cerveira</name>
<affiliation wicri:level="1">
<nlm:aff id="aff19">
<institution>Department of Genetics, Portuguese Oncology Institute</institution>
, Porto,
<country>Portugal</country>
</nlm:aff>
<country xml:lang="fr">Portugal</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Cheng, S M" sort="Cheng, S M" uniqKey="Cheng S" first="S-M" last="Cheng">S-M Cheng</name>
<affiliation wicri:level="1">
<nlm:aff id="aff20">
<institution>Department of Hematology and Oncology, Quest Diagnostics Nichols Institute</institution>
, San Juan Capistrano, CA,
<country>USA</country>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Colomer, D" sort="Colomer, D" uniqKey="Colomer D" first="D" last="Colomer">D. Colomer</name>
<affiliation wicri:level="1">
<nlm:aff id="aff21">
<institution>Hematopathology Unit, Hospital Clinic, IDIBAPS</institution>
, Barcelona,
<country>Spain</country>
</nlm:aff>
<country xml:lang="fr">Espagne</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Czurda, S" sort="Czurda, S" uniqKey="Czurda S" first="S" last="Czurda">S. Czurda</name>
<affiliation wicri:level="1">
<nlm:aff id="aff22">
<institution>Division of Molecular Microbiology, Children's Cancer Research Institute</institution>
, Vienna,
<country>Austria</country>
</nlm:aff>
<country xml:lang="fr">Autriche</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Daraio, F" sort="Daraio, F" uniqKey="Daraio F" first="F" last="Daraio">F. Daraio</name>
<affiliation wicri:level="1">
<nlm:aff id="aff23">
<institution>Department of Clinical and Biological Sciences, San Luigi Hospital, University of Turin</institution>
, Orbassano,
<country>Italy</country>
</nlm:aff>
<country xml:lang="fr">Italie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Dulucq, S" sort="Dulucq, S" uniqKey="Dulucq S" first="S" last="Dulucq">S. Dulucq</name>
<affiliation wicri:level="1">
<nlm:aff id="aff24">
<institution>Laboratoire Hematologie, Centre Hospitalier Universitaire de Bordeaux, Universite Bordeaux</institution>
, Bordeaux,
<country>France</country>
</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Eggen, L" sort="Eggen, L" uniqKey="Eggen L" first="L" last="Eggen">L. Eggen</name>
<affiliation wicri:level="1">
<nlm:aff id="aff25">
<institution>Laboratory of Molecular Pathology, Oslo University Hospital</institution>
, Oslo,
<country>Norway</country>
</nlm:aff>
<country xml:lang="fr">Norvège</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="El Housni, H" sort="El Housni, H" uniqKey="El Housni H" first="H" last="El Housni">H. El Housni</name>
<affiliation wicri:level="1">
<nlm:aff id="aff26">
<institution>Clinique de Genetique Oncologique-Service de genetique, Hopital Erasme</institution>
, Brussels,
<country>Belgium</country>
</nlm:aff>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Gerrard, G" sort="Gerrard, G" uniqKey="Gerrard G" first="G" last="Gerrard">G. Gerrard</name>
<affiliation wicri:level="1">
<nlm:aff id="aff27">
<institution>Imperial Molecular Pathology, Hammersmith Hospital</institution>
, London,
<country>UK</country>
</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Gniot, M" sort="Gniot, M" uniqKey="Gniot M" first="M" last="Gniot">M. Gniot</name>
<affiliation wicri:level="1">
<nlm:aff id="aff28">
<institution>Department of Hematology and Bone Marrow Transplantation, Poznan University of Medical Sciences</institution>
, Poznan,
<country>Poland</country>
</nlm:aff>
<country xml:lang="fr">Pologne</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Izzo, B" sort="Izzo, B" uniqKey="Izzo B" first="B" last="Izzo">B. Izzo</name>
<affiliation wicri:level="1">
<nlm:aff id="aff29">
<institution>Department of Clinical Medicine and Surgery, University ‘Federico II' of Naples</institution>
, Naples,
<country>Italy</country>
</nlm:aff>
<country xml:lang="fr">Italie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1">
<nlm:aff id="aff30">
<institution>CEINGE – Biotecnologie Avanzate</institution>
, Naples,
<country>Italy</country>
</nlm:aff>
<country xml:lang="fr">Italie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Jacquin, D" sort="Jacquin, D" uniqKey="Jacquin D" first="D" last="Jacquin">D. Jacquin</name>
<affiliation wicri:level="1">
<nlm:aff id="aff31">
<institution>Genoptix, Inc.</institution>
, Carlsbad, CA,
<country>USA</country>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Janssen, J J W M" sort="Janssen, J J W M" uniqKey="Janssen J" first="J J W M" last="Janssen">J J W M. Janssen</name>
<affiliation wicri:level="1">
<nlm:aff id="aff32">
<institution>Department of Hematology and Molecular Diagnostics, VU University Medical Center</institution>
, Amsterdam,
<country>The Netherlands</country>
</nlm:aff>
<country xml:lang="fr">Pays-Bas</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Jeromin, S" sort="Jeromin, S" uniqKey="Jeromin S" first="S" last="Jeromin">S. Jeromin</name>
<affiliation wicri:level="1">
<nlm:aff id="aff33">
<institution>MLL Munich Leukemia Laboratory</institution>
, Munich,
<country>Germany</country>
</nlm:aff>
<country xml:lang="fr">Allemagne</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Jurcek, T" sort="Jurcek, T" uniqKey="Jurcek T" first="T" last="Jurcek">T. Jurcek</name>
<affiliation wicri:level="1">
<nlm:aff id="aff34">
<institution>Center of Molecular Biology and Gene Therapy, Department of Internal Medicine-Hematology and Oncology, Masaryk University and University Hospital Brno</institution>
, Brno,
<country>Czech Republic</country>
</nlm:aff>
<country xml:lang="fr">République tchèque</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Kim, D W" sort="Kim, D W" uniqKey="Kim D" first="D-W" last="Kim">D-W Kim</name>
<affiliation wicri:level="1">
<nlm:aff id="aff35">
<institution>Seoul St Mary's Hospital, Leukemia Research Institute, The Catholic University of Korea</institution>
, Seoul,
<country>Korea</country>
</nlm:aff>
<country xml:lang="fr">Corée du Sud</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Machova Polakova, K" sort="Machova Polakova, K" uniqKey="Machova Polakova K" first="K" last="Machova-Polakova">K. Machova-Polakova</name>
<affiliation wicri:level="1">
<nlm:aff id="aff36">
<institution>Department of Molecular Genetics, Institute of Hematology and Blood Transfusion</institution>
, Prague,
<country>Czech Republic</country>
</nlm:aff>
<country xml:lang="fr">République tchèque</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Martinez Lopez, J" sort="Martinez Lopez, J" uniqKey="Martinez Lopez J" first="J" last="Martinez-Lopez">J. Martinez-Lopez</name>
<affiliation wicri:level="1">
<nlm:aff id="aff37">
<institution>Department of Hematology, Hospital Universitario 12 de Octubre, Universidad Complutense, CNIO</institution>
, Madrid,
<country>Spain</country>
</nlm:aff>
<country xml:lang="fr">Espagne</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Mcbean, M" sort="Mcbean, M" uniqKey="Mcbean M" first="M" last="Mcbean">M. Mcbean</name>
<affiliation wicri:level="1">
<nlm:aff id="aff38">
<institution>Division of Cancer Medicine, Department of Pathology, Peter MacCallum Cancer Centre</institution>
, East Melbourne, VIC,
<country>Australia</country>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Mesanovic, S" sort="Mesanovic, S" uniqKey="Mesanovic S" first="S" last="Mesanovic">S. Mesanovic</name>
<affiliation wicri:level="1">
<nlm:aff id="aff39">
<institution>Pathology Department, University Clinical Center Tuzla</institution>
, Tuzla,
<country>Bosnia and Herzegovina</country>
</nlm:aff>
<country xml:lang="fr">Bosnie-Herzégovine</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Mitterbauer Hohendanner, G" sort="Mitterbauer Hohendanner, G" uniqKey="Mitterbauer Hohendanner G" first="G" last="Mitterbauer-Hohendanner">G. Mitterbauer-Hohendanner</name>
<affiliation wicri:level="1">
<nlm:aff id="aff40">
<institution>Department of Laboratory Medicine, Division of Medical and Chemical Laboratory Diagnostics, Medical University of Vienna</institution>
, Vienna,
<country>Austria</country>
</nlm:aff>
<country xml:lang="fr">Autriche</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Mobtaker, H" sort="Mobtaker, H" uniqKey="Mobtaker H" first="H" last="Mobtaker">H. Mobtaker</name>
<affiliation wicri:level="1">
<nlm:aff id="aff31">
<institution>Genoptix, Inc.</institution>
, Carlsbad, CA,
<country>USA</country>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Mozziconacci, M J" sort="Mozziconacci, M J" uniqKey="Mozziconacci M" first="M-J" last="Mozziconacci">M-J Mozziconacci</name>
<affiliation wicri:level="1">
<nlm:aff id="aff41">
<institution>Departement de Biopathologie, Institut Paoli-Calmettes</institution>
, Marseille,
<country>France</country>
</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Paji, T" sort="Paji, T" uniqKey="Paji T" first="T" last="Paji">T. Paji</name>
<affiliation wicri:level="1">
<nlm:aff id="aff42">
<institution>Specialized Haematology Laboratory, Department of Haematology, University Medical Centre Ljubljana</institution>
, Ljubljana,
<country>Slovenia</country>
</nlm:aff>
<country xml:lang="fr">Slovénie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Pallisgaard, N" sort="Pallisgaard, N" uniqKey="Pallisgaard N" first="N" last="Pallisgaard">N. Pallisgaard</name>
<affiliation wicri:level="1">
<nlm:aff id="aff43">
<institution>Department of Surgical Pathology, Zealand University Hospital</institution>
, Roskilde,
<country>Denmark</country>
</nlm:aff>
<country xml:lang="fr">Danemark</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Panagiotidis, P" sort="Panagiotidis, P" uniqKey="Panagiotidis P" first="P" last="Panagiotidis">P. Panagiotidis</name>
<affiliation wicri:level="1">
<nlm:aff id="aff44">
<institution>Hematology Unit, First Department of Internal Medicine, Laiko Hospital, University of Athens,</institution>
Athens,
<country>Greece</country>
</nlm:aff>
<country xml:lang="fr">Grèce</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Press, R D" sort="Press, R D" uniqKey="Press R" first="R D" last="Press">R D Press</name>
<affiliation wicri:level="1">
<nlm:aff id="aff45">
<institution>Department of Pathology and Knight Cancer Institute, Oregon Health and Science University</institution>
, Portland, OR,
<country>USA</country>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Qin, Y Z" sort="Qin, Y Z" uniqKey="Qin Y" first="Y-Z" last="Qin">Y-Z Qin</name>
<affiliation wicri:level="1">
<nlm:aff id="aff46">
<institution>Peking University People's Hospital, Peking University Institute of Hematology</institution>
, Beijing,
<country>China</country>
</nlm:aff>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Radich, J" sort="Radich, J" uniqKey="Radich J" first="J" last="Radich">J. Radich</name>
<affiliation wicri:level="1">
<nlm:aff id="aff47">
<institution>Fred Hutchinson Cancer Research Center</institution>
, Seattle, WA,
<country>USA</country>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Sacha, T" sort="Sacha, T" uniqKey="Sacha T" first="T" last="Sacha">T. Sacha</name>
<affiliation wicri:level="1">
<nlm:aff id="aff48">
<institution>Chair and Department of Hematology, Jagiellonian University</institution>
, Kraków,
<country>Poland</country>
</nlm:aff>
<country xml:lang="fr">Pologne</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Touloumenidou, T" sort="Touloumenidou, T" uniqKey="Touloumenidou T" first="T" last="Touloumenidou">T. Touloumenidou</name>
<affiliation wicri:level="1">
<nlm:aff id="aff49">
<institution>Laboratory of Molecular Biology, Hematology Department and HCT Unit, G. Papanicolaou Hospital</institution>
, Thessaloniki,
<country>Greece</country>
</nlm:aff>
<country xml:lang="fr">Grèce</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Waits, P" sort="Waits, P" uniqKey="Waits P" first="P" last="Waits">P. Waits</name>
<affiliation wicri:level="1">
<nlm:aff id="aff50">
<institution>Bristol Genetics Laboratory</institution>
, Bristol,
<country>UK</country>
</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Wilkinson, E" sort="Wilkinson, E" uniqKey="Wilkinson E" first="E" last="Wilkinson">E. Wilkinson</name>
<affiliation wicri:level="1">
<nlm:aff id="aff51">
<institution>HMDS, Leeds Teaching Hospitals</institution>
, Leeds,
<country>UK</country>
</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Zadro, R" sort="Zadro, R" uniqKey="Zadro R" first="R" last="Zadro">R. Zadro</name>
<affiliation wicri:level="1">
<nlm:aff id="aff52">
<institution>Faculty of Pharmacy and Biochemistry and University Hospital Center Zagreb, University of Zagreb</institution>
, Zagreb,
<country>Croatia</country>
</nlm:aff>
<country xml:lang="fr">Croatie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Muller, M C" sort="Muller, M C" uniqKey="Muller M" first="M C" last="Müller">M C Müller</name>
<affiliation wicri:level="1">
<nlm:aff id="aff5">
<institution>III. Medizinische Klinik, Medizinische Fakultät Mannheim, Universität Heidelberg</institution>
, Mannheim,
<country>Germany</country>
</nlm:aff>
<country xml:lang="fr">Allemagne</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Hochhaus, A" sort="Hochhaus, A" uniqKey="Hochhaus A" first="A" last="Hochhaus">A. Hochhaus</name>
<affiliation wicri:level="1">
<nlm:aff id="aff3">
<institution>Department of Hematology/Oncology, Universitätsklinikum Jena</institution>
, Jena,
<country>Germany</country>
</nlm:aff>
<country xml:lang="fr">Allemagne</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Branford, S" sort="Branford, S" uniqKey="Branford S" first="S" last="Branford">S. Branford</name>
<affiliation wicri:level="1">
<nlm:aff id="aff4">
<institution>Department of Genetics and Molecular Pathology, Centre for Cancer Biology, SA Pathology</institution>
, Adelaide, SA,
<country>Australia</country>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1">
<nlm:aff id="aff53">
<institution>School of Pharmacy and Medical Science, University of South Australia</institution>
, Adelaide, SA,
<country>Australia</country>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1">
<nlm:aff id="aff54">
<institution>School of Medicine, University of Adelaide</institution>
, SA, Adelaide,
<country>Australia</country>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1">
<nlm:aff id="aff55">
<institution>School of Molecular and Biomedical Science, University of Adelaide</institution>
, Adelaide, SA,
<country>Australia</country>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
</analytic>
<series>
<title level="j">Leukemia</title>
<idno type="ISSN">0887-6924</idno>
<idno type="eISSN">1476-5551</idno>
<imprint>
<date when="2016">2016</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc>
<textClass></textClass>
</profileDesc>
</teiHeader>
<front>
<div type="abstract" xml:lang="en">
<p>Molecular monitoring of chronic myeloid leukemia patients using robust
<italic>BCR-ABL1</italic>
tests standardized to the International Scale (IS) is key to proper disease management, especially when treatment cessation is considered. Most laboratories currently use a time-consuming sample exchange process with reference laboratories for IS calibration. A World Health Organization (WHO)
<italic>BCR-ABL1</italic>
reference panel was developed (MR
<sup>1</sup>
–MR
<sup>4</sup>
), but access to the material is limited. In this study, we describe the development of the first cell-based secondary reference panel that is traceable to and faithfully replicates the WHO panel, with an additional MR
<sup>4.5</sup>
level. The secondary panel was calibrated to IS using digital PCR with
<italic>ABL1</italic>
,
<italic>BCR</italic>
and
<italic>GUSB</italic>
as reference genes and evaluated by 44 laboratories worldwide. Interestingly, we found that >40% of
<italic>BCR-ABL1</italic>
assays showed signs of inadequate optimization such as poor linearity and suboptimal PCR efficiency. Nonetheless, when optimized sample inputs were used, >60% demonstrated satisfactory IS accuracy, precision and/or MR
<sup>4.5</sup>
sensitivity, and 58% obtained IS conversion factors from the secondary reference concordant with their current values. Correlation analysis indicated no significant alterations in %BCR-ABL1 results caused by different assay configurations. More assays achieved good precision and/or sensitivity than IS accuracy, indicating the need for better IS calibration mechanisms.</p>
</div>
</front>
<back>
<div1 type="bibliography">
<listBibl>
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</listBibl>
</div1>
</back>
</TEI>
<pmc article-type="research-article">
<pmc-dir>properties open_access</pmc-dir>
<front>
<journal-meta>
<journal-id journal-id-type="nlm-ta">Leukemia</journal-id>
<journal-id journal-id-type="iso-abbrev">Leukemia</journal-id>
<journal-title-group>
<journal-title>Leukemia</journal-title>
</journal-title-group>
<issn pub-type="ppub">0887-6924</issn>
<issn pub-type="epub">1476-5551</issn>
<publisher>
<publisher-name>Nature Publishing Group</publisher-name>
</publisher>
</journal-meta>
<article-meta>
<article-id pub-id-type="pmid">27109508</article-id>
<article-id pub-id-type="pmc">5240017</article-id>
<article-id pub-id-type="pii">leu201690</article-id>
<article-id pub-id-type="doi">10.1038/leu.2016.90</article-id>
<article-categories>
<subj-group subj-group-type="heading">
<subject>Original Article</subject>
</subj-group>
</article-categories>
<title-group>
<article-title>Development and evaluation of a secondary reference panel for
<italic>BCR-ABL1</italic>
quantification on the International Scale</article-title>
<alt-title alt-title-type="running">
<italic>BCR-ABL</italic>
secondary reference panel</alt-title>
</title-group>
<contrib-group>
<contrib contrib-type="author">
<name>
<surname>Cross</surname>
<given-names>N C P</given-names>
</name>
<xref ref-type="aff" rid="aff1">1</xref>
<xref ref-type="aff" rid="aff2">2</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>White</surname>
<given-names>H E</given-names>
</name>
<xref ref-type="aff" rid="aff1">1</xref>
<xref ref-type="aff" rid="aff2">2</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Ernst</surname>
<given-names>T</given-names>
</name>
<xref ref-type="aff" rid="aff3">3</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Welden</surname>
<given-names>L</given-names>
</name>
<xref ref-type="aff" rid="aff4">4</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Dietz</surname>
<given-names>C</given-names>
</name>
<xref ref-type="aff" rid="aff5">5</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Saglio</surname>
<given-names>G</given-names>
</name>
<xref ref-type="aff" rid="aff6">6</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Mahon</surname>
<given-names>F-X</given-names>
</name>
<xref ref-type="aff" rid="aff7">7</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Wong</surname>
<given-names>C C</given-names>
</name>
<xref ref-type="aff" rid="aff8">8</xref>
<xref ref-type="corresp" rid="caf1">*</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Zheng</surname>
<given-names>D</given-names>
</name>
<xref ref-type="aff" rid="aff8">8</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Wong</surname>
<given-names>S</given-names>
</name>
<xref ref-type="aff" rid="aff8">8</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Wang</surname>
<given-names>S-S</given-names>
</name>
<xref ref-type="aff" rid="aff8">8</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Akiki</surname>
<given-names>S</given-names>
</name>
<xref ref-type="aff" rid="aff9">9</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Albano</surname>
<given-names>F</given-names>
</name>
<xref ref-type="aff" rid="aff10">10</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Andrikovics</surname>
<given-names>H</given-names>
</name>
<xref ref-type="aff" rid="aff11">11</xref>
<xref ref-type="aff" rid="aff12">12</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Anwar</surname>
<given-names>J</given-names>
</name>
<xref ref-type="aff" rid="aff13">13</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Balatzenko</surname>
<given-names>G</given-names>
</name>
<xref ref-type="aff" rid="aff14">14</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Bendit</surname>
<given-names>I</given-names>
</name>
<xref ref-type="aff" rid="aff15">15</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Beveridge</surname>
<given-names>J</given-names>
</name>
<xref ref-type="aff" rid="aff16">16</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Boeckx</surname>
<given-names>N</given-names>
</name>
<xref ref-type="aff" rid="aff17">17</xref>
<xref ref-type="aff" rid="aff18">18</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Cerveira</surname>
<given-names>N</given-names>
</name>
<xref ref-type="aff" rid="aff19">19</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Cheng</surname>
<given-names>S-M</given-names>
</name>
<xref ref-type="aff" rid="aff20">20</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Colomer</surname>
<given-names>D</given-names>
</name>
<xref ref-type="aff" rid="aff21">21</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Czurda</surname>
<given-names>S</given-names>
</name>
<xref ref-type="aff" rid="aff22">22</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Daraio</surname>
<given-names>F</given-names>
</name>
<xref ref-type="aff" rid="aff23">23</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Dulucq</surname>
<given-names>S</given-names>
</name>
<xref ref-type="aff" rid="aff24">24</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Eggen</surname>
<given-names>L</given-names>
</name>
<xref ref-type="aff" rid="aff25">25</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>El Housni</surname>
<given-names>H</given-names>
</name>
<xref ref-type="aff" rid="aff26">26</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Gerrard</surname>
<given-names>G</given-names>
</name>
<xref ref-type="aff" rid="aff27">27</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Gniot</surname>
<given-names>M</given-names>
</name>
<xref ref-type="aff" rid="aff28">28</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Izzo</surname>
<given-names>B</given-names>
</name>
<xref ref-type="aff" rid="aff29">29</xref>
<xref ref-type="aff" rid="aff30">30</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Jacquin</surname>
<given-names>D</given-names>
</name>
<xref ref-type="aff" rid="aff31">31</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Janssen</surname>
<given-names>J J W M</given-names>
</name>
<xref ref-type="aff" rid="aff32">32</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Jeromin</surname>
<given-names>S</given-names>
</name>
<xref ref-type="aff" rid="aff33">33</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Jurcek</surname>
<given-names>T</given-names>
</name>
<xref ref-type="aff" rid="aff34">34</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Kim</surname>
<given-names>D-W</given-names>
</name>
<xref ref-type="aff" rid="aff35">35</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Machova-Polakova</surname>
<given-names>K</given-names>
</name>
<xref ref-type="aff" rid="aff36">36</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Martinez-Lopez</surname>
<given-names>J</given-names>
</name>
<xref ref-type="aff" rid="aff37">37</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>McBean</surname>
<given-names>M</given-names>
</name>
<xref ref-type="aff" rid="aff38">38</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Mesanovic</surname>
<given-names>S</given-names>
</name>
<xref ref-type="aff" rid="aff39">39</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Mitterbauer-Hohendanner</surname>
<given-names>G</given-names>
</name>
<xref ref-type="aff" rid="aff40">40</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Mobtaker</surname>
<given-names>H</given-names>
</name>
<xref ref-type="aff" rid="aff31">31</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Mozziconacci</surname>
<given-names>M-J</given-names>
</name>
<xref ref-type="aff" rid="aff41">41</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Pajič</surname>
<given-names>T</given-names>
</name>
<xref ref-type="aff" rid="aff42">42</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Pallisgaard</surname>
<given-names>N</given-names>
</name>
<xref ref-type="aff" rid="aff43">43</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Panagiotidis</surname>
<given-names>P</given-names>
</name>
<xref ref-type="aff" rid="aff44">44</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Press</surname>
<given-names>R D</given-names>
</name>
<xref ref-type="aff" rid="aff45">45</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Qin</surname>
<given-names>Y-Z</given-names>
</name>
<xref ref-type="aff" rid="aff46">46</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Radich</surname>
<given-names>J</given-names>
</name>
<xref ref-type="aff" rid="aff47">47</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Sacha</surname>
<given-names>T</given-names>
</name>
<xref ref-type="aff" rid="aff48">48</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Touloumenidou</surname>
<given-names>T</given-names>
</name>
<xref ref-type="aff" rid="aff49">49</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Waits</surname>
<given-names>P</given-names>
</name>
<xref ref-type="aff" rid="aff50">50</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Wilkinson</surname>
<given-names>E</given-names>
</name>
<xref ref-type="aff" rid="aff51">51</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Zadro</surname>
<given-names>R</given-names>
</name>
<xref ref-type="aff" rid="aff52">52</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Müller</surname>
<given-names>M C</given-names>
</name>
<xref ref-type="aff" rid="aff5">5</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Hochhaus</surname>
<given-names>A</given-names>
</name>
<xref ref-type="aff" rid="aff3">3</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Branford</surname>
<given-names>S</given-names>
</name>
<xref ref-type="aff" rid="aff4">4</xref>
<xref ref-type="aff" rid="aff53">53</xref>
<xref ref-type="aff" rid="aff54">54</xref>
<xref ref-type="aff" rid="aff55">55</xref>
</contrib>
<aff id="aff1">
<label>1</label>
<institution>Wessex Regional Genetics Laboratory, Salisbury NHS Foundation Trust</institution>
, Salisbury,
<country>UK</country>
</aff>
<aff id="aff2">
<label>2</label>
<institution>Faculty of Medicine, University of Southampton</institution>
, Southampton,
<country>UK</country>
</aff>
<aff id="aff3">
<label>3</label>
<institution>Department of Hematology/Oncology, Universitätsklinikum Jena</institution>
, Jena,
<country>Germany</country>
</aff>
<aff id="aff4">
<label>4</label>
<institution>Department of Genetics and Molecular Pathology, Centre for Cancer Biology, SA Pathology</institution>
, Adelaide, SA,
<country>Australia</country>
</aff>
<aff id="aff5">
<label>5</label>
<institution>III. Medizinische Klinik, Medizinische Fakultät Mannheim, Universität Heidelberg</institution>
, Mannheim,
<country>Germany</country>
</aff>
<aff id="aff6">
<label>6</label>
<institution>Department of Clinical and Biological Sciences, San Luigi Hospital, University of Turin</institution>
, Orbassano,
<country>Italy</country>
</aff>
<aff id="aff7">
<label>7</label>
<institution>Bergonie Institute Cancer Center Bordeaux, INSERM U1218, University of Bordeaux</institution>
, Bordeaux,
<country>France</country>
</aff>
<aff id="aff8">
<label>8</label>
<institution>Novartis Pharmaceuticals Corporation</institution>
, East Hanover, NJ,
<country>USA</country>
</aff>
<aff id="aff9">
<label>9</label>
<institution>West Midlands Regional Genetics Laboratory</institution>
, Birmingham,
<country>UK</country>
</aff>
<aff id="aff10">
<label>10</label>
<institution>Department of Hematology, University of Bari</institution>
, Bari,
<country>Italy</country>
</aff>
<aff id="aff11">
<label>11</label>
<institution>Laboratory of Molecular Diagnostics, Hungarian National Blood Transfusion Service</institution>
, Budapest,
<country>Hungary</country>
</aff>
<aff id="aff12">
<label>12</label>
<institution>Department of Pathophysiology, Semmelweis University</institution>
, Budapest,
<country>Hungary</country>
</aff>
<aff id="aff13">
<label>13</label>
<institution>King's College Hospital London</institution>
, London,
<country>UK</country>
</aff>
<aff id="aff14">
<label>14</label>
<institution>National Specialized Hospital for Active Treatment of Hematological Diseases</institution>
, Sofia,
<country>Bulgaria</country>
</aff>
<aff id="aff15">
<label>15</label>
<institution>Laboratorio de Biologia Tumoral, Disciplina de Hematologia do HC-FMUSP</institution>
, São Paulo,
<country>Brazil</country>
</aff>
<aff id="aff16">
<label>16</label>
<institution>PathWest Laboratory Medicine WA, Department of Haematology, Fiona Stanley Hospital</institution>
, Perth, WA,
<country>Australia</country>
</aff>
<aff id="aff17">
<label>17</label>
<institution>Department of Laboratory Medicine, University Hospitals Leuven</institution>
, Leuven,
<country>Belgium</country>
</aff>
<aff id="aff18">
<label>18</label>
<institution>Department of Oncology, KUL</institution>
, Leuven,
<country>Belgium</country>
</aff>
<aff id="aff19">
<label>19</label>
<institution>Department of Genetics, Portuguese Oncology Institute</institution>
, Porto,
<country>Portugal</country>
</aff>
<aff id="aff20">
<label>20</label>
<institution>Department of Hematology and Oncology, Quest Diagnostics Nichols Institute</institution>
, San Juan Capistrano, CA,
<country>USA</country>
</aff>
<aff id="aff21">
<label>21</label>
<institution>Hematopathology Unit, Hospital Clinic, IDIBAPS</institution>
, Barcelona,
<country>Spain</country>
</aff>
<aff id="aff22">
<label>22</label>
<institution>Division of Molecular Microbiology, Children's Cancer Research Institute</institution>
, Vienna,
<country>Austria</country>
</aff>
<aff id="aff23">
<label>23</label>
<institution>Department of Clinical and Biological Sciences, San Luigi Hospital, University of Turin</institution>
, Orbassano,
<country>Italy</country>
</aff>
<aff id="aff24">
<label>24</label>
<institution>Laboratoire Hematologie, Centre Hospitalier Universitaire de Bordeaux, Universite Bordeaux</institution>
, Bordeaux,
<country>France</country>
</aff>
<aff id="aff25">
<label>25</label>
<institution>Laboratory of Molecular Pathology, Oslo University Hospital</institution>
, Oslo,
<country>Norway</country>
</aff>
<aff id="aff26">
<label>26</label>
<institution>Clinique de Genetique Oncologique-Service de genetique, Hopital Erasme</institution>
, Brussels,
<country>Belgium</country>
</aff>
<aff id="aff27">
<label>27</label>
<institution>Imperial Molecular Pathology, Hammersmith Hospital</institution>
, London,
<country>UK</country>
</aff>
<aff id="aff28">
<label>28</label>
<institution>Department of Hematology and Bone Marrow Transplantation, Poznan University of Medical Sciences</institution>
, Poznan,
<country>Poland</country>
</aff>
<aff id="aff29">
<label>29</label>
<institution>Department of Clinical Medicine and Surgery, University ‘Federico II' of Naples</institution>
, Naples,
<country>Italy</country>
</aff>
<aff id="aff30">
<label>30</label>
<institution>CEINGE – Biotecnologie Avanzate</institution>
, Naples,
<country>Italy</country>
</aff>
<aff id="aff31">
<label>31</label>
<institution>Genoptix, Inc.</institution>
, Carlsbad, CA,
<country>USA</country>
</aff>
<aff id="aff32">
<label>32</label>
<institution>Department of Hematology and Molecular Diagnostics, VU University Medical Center</institution>
, Amsterdam,
<country>The Netherlands</country>
</aff>
<aff id="aff33">
<label>33</label>
<institution>MLL Munich Leukemia Laboratory</institution>
, Munich,
<country>Germany</country>
</aff>
<aff id="aff34">
<label>34</label>
<institution>Center of Molecular Biology and Gene Therapy, Department of Internal Medicine-Hematology and Oncology, Masaryk University and University Hospital Brno</institution>
, Brno,
<country>Czech Republic</country>
</aff>
<aff id="aff35">
<label>35</label>
<institution>Seoul St Mary's Hospital, Leukemia Research Institute, The Catholic University of Korea</institution>
, Seoul,
<country>Korea</country>
</aff>
<aff id="aff36">
<label>36</label>
<institution>Department of Molecular Genetics, Institute of Hematology and Blood Transfusion</institution>
, Prague,
<country>Czech Republic</country>
</aff>
<aff id="aff37">
<label>37</label>
<institution>Department of Hematology, Hospital Universitario 12 de Octubre, Universidad Complutense, CNIO</institution>
, Madrid,
<country>Spain</country>
</aff>
<aff id="aff38">
<label>38</label>
<institution>Division of Cancer Medicine, Department of Pathology, Peter MacCallum Cancer Centre</institution>
, East Melbourne, VIC,
<country>Australia</country>
</aff>
<aff id="aff39">
<label>39</label>
<institution>Pathology Department, University Clinical Center Tuzla</institution>
, Tuzla,
<country>Bosnia and Herzegovina</country>
</aff>
<aff id="aff40">
<label>40</label>
<institution>Department of Laboratory Medicine, Division of Medical and Chemical Laboratory Diagnostics, Medical University of Vienna</institution>
, Vienna,
<country>Austria</country>
</aff>
<aff id="aff41">
<label>41</label>
<institution>Departement de Biopathologie, Institut Paoli-Calmettes</institution>
, Marseille,
<country>France</country>
</aff>
<aff id="aff42">
<label>42</label>
<institution>Specialized Haematology Laboratory, Department of Haematology, University Medical Centre Ljubljana</institution>
, Ljubljana,
<country>Slovenia</country>
</aff>
<aff id="aff43">
<label>43</label>
<institution>Department of Surgical Pathology, Zealand University Hospital</institution>
, Roskilde,
<country>Denmark</country>
</aff>
<aff id="aff44">
<label>44</label>
<institution>Hematology Unit, First Department of Internal Medicine, Laiko Hospital, University of Athens,</institution>
Athens,
<country>Greece</country>
</aff>
<aff id="aff45">
<label>45</label>
<institution>Department of Pathology and Knight Cancer Institute, Oregon Health and Science University</institution>
, Portland, OR,
<country>USA</country>
</aff>
<aff id="aff46">
<label>46</label>
<institution>Peking University People's Hospital, Peking University Institute of Hematology</institution>
, Beijing,
<country>China</country>
</aff>
<aff id="aff47">
<label>47</label>
<institution>Fred Hutchinson Cancer Research Center</institution>
, Seattle, WA,
<country>USA</country>
</aff>
<aff id="aff48">
<label>48</label>
<institution>Chair and Department of Hematology, Jagiellonian University</institution>
, Kraków,
<country>Poland</country>
</aff>
<aff id="aff49">
<label>49</label>
<institution>Laboratory of Molecular Biology, Hematology Department and HCT Unit, G. Papanicolaou Hospital</institution>
, Thessaloniki,
<country>Greece</country>
</aff>
<aff id="aff50">
<label>50</label>
<institution>Bristol Genetics Laboratory</institution>
, Bristol,
<country>UK</country>
</aff>
<aff id="aff51">
<label>51</label>
<institution>HMDS, Leeds Teaching Hospitals</institution>
, Leeds,
<country>UK</country>
</aff>
<aff id="aff52">
<label>52</label>
<institution>Faculty of Pharmacy and Biochemistry and University Hospital Center Zagreb, University of Zagreb</institution>
, Zagreb,
<country>Croatia</country>
</aff>
<aff id="aff53">
<label>53</label>
<institution>School of Pharmacy and Medical Science, University of South Australia</institution>
, Adelaide, SA,
<country>Australia</country>
</aff>
<aff id="aff54">
<label>54</label>
<institution>School of Medicine, University of Adelaide</institution>
, SA, Adelaide,
<country>Australia</country>
</aff>
<aff id="aff55">
<label>55</label>
<institution>School of Molecular and Biomedical Science, University of Adelaide</institution>
, Adelaide, SA,
<country>Australia</country>
</aff>
</contrib-group>
<author-notes>
<corresp id="caf1">
<label>*</label>
<institution>Companion Diagnostics, Novartis Pharmaceuticals Corporation</institution>
, 45 Sidney Street, Cambridge, MA 02139,
<country>USA</country>
. E-mail:
<email>connie.wong@novartis.com</email>
</corresp>
</author-notes>
<pub-date pub-type="ppub">
<month>09</month>
<year>2016</year>
</pub-date>
<pub-date pub-type="epreprint">
<day>25</day>
<month>04</month>
<year>2016</year>
</pub-date>
<pub-date pub-type="epub">
<day>03</day>
<month>06</month>
<year>2016</year>
</pub-date>
<volume>30</volume>
<issue>9</issue>
<fpage>1844</fpage>
<lpage>1852</lpage>
<history>
<date date-type="received">
<day>22</day>
<month>03</month>
<year>2016</year>
</date>
<date date-type="accepted">
<day>11</day>
<month>04</month>
<year>2016</year>
</date>
</history>
<permissions>
<copyright-statement>Copyright © 2016 Macmillan Publishers Limited</copyright-statement>
<copyright-year>2016</copyright-year>
<copyright-holder>Macmillan Publishers Limited</copyright-holder>
<license license-type="open-access" xlink:href="http://creativecommons.org/licenses/by/4.0/">
<pmc-comment>author-paid</pmc-comment>
<license-p>This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit
<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link>
</license-p>
</license>
</permissions>
<abstract>
<p>Molecular monitoring of chronic myeloid leukemia patients using robust
<italic>BCR-ABL1</italic>
tests standardized to the International Scale (IS) is key to proper disease management, especially when treatment cessation is considered. Most laboratories currently use a time-consuming sample exchange process with reference laboratories for IS calibration. A World Health Organization (WHO)
<italic>BCR-ABL1</italic>
reference panel was developed (MR
<sup>1</sup>
–MR
<sup>4</sup>
), but access to the material is limited. In this study, we describe the development of the first cell-based secondary reference panel that is traceable to and faithfully replicates the WHO panel, with an additional MR
<sup>4.5</sup>
level. The secondary panel was calibrated to IS using digital PCR with
<italic>ABL1</italic>
,
<italic>BCR</italic>
and
<italic>GUSB</italic>
as reference genes and evaluated by 44 laboratories worldwide. Interestingly, we found that >40% of
<italic>BCR-ABL1</italic>
assays showed signs of inadequate optimization such as poor linearity and suboptimal PCR efficiency. Nonetheless, when optimized sample inputs were used, >60% demonstrated satisfactory IS accuracy, precision and/or MR
<sup>4.5</sup>
sensitivity, and 58% obtained IS conversion factors from the secondary reference concordant with their current values. Correlation analysis indicated no significant alterations in %BCR-ABL1 results caused by different assay configurations. More assays achieved good precision and/or sensitivity than IS accuracy, indicating the need for better IS calibration mechanisms.</p>
</abstract>
</article-meta>
</front>
<floats-group>
<fig id="fig1">
<label>Figure 1</label>
<caption>
<p>The
<italic>BCR-ABL1</italic>
secondary reference panel was calibrated to the WHO standards using RT-ddPCR against (
<bold>a</bold>
)
<italic>ABL1</italic>
, (
<bold>b</bold>
)
<italic>BCR</italic>
and (
<bold>c</bold>
)
<italic>GUSB</italic>
for IS conversion (
<italic>n</italic>
=40 from MR
<sup>1</sup>
to MR
<sup>4</sup>
,
<italic>n</italic>
=80 for MR
<sup>4.5</sup>
). The IS CFs for the RT-ddPCR assays were determined to be 0.93 for the
<italic>BCR-ABL1/ABL1</italic>
assay, 1.85 for the
<italic>BCR-ABL1/BCR</italic>
assay and 1.28 for the
<italic>BCR-ABL1/GUSB</italic>
assay. Blue dotted lines represent the nominal %BCR-ABL1 value of the WHO panel at different levels.</p>
</caption>
<graphic xlink:href="leu201690f1"></graphic>
</fig>
<fig id="fig2">
<label>Figure 2</label>
<caption>
<p>Study design for the international multi-center evaluation of the secondary panel, including (
<bold>a</bold>
) Study 1 for one-step RT-qPCR tests, (
<bold>b</bold>
) Study 1 for two-step RT-qPCR tests and (
<bold>c</bold>
) Study 2.</p>
</caption>
<graphic xlink:href="leu201690f2"></graphic>
</fig>
<fig id="fig3">
<label>Figure 3</label>
<caption>
<p>Examples of different assay results from Study 1 of the multi-center evaluation study. A properly optimized assay should yield similar %BCR-ABL1 results at different sample inputs and both the
<italic>BCR-ABL1</italic>
and reference gene assays should have a PCR efficiency close to 1 (
<bold>a</bold>
<bold>c</bold>
). Some assays showed decreasing %BCR-ABL1 measurements with increasing sample input (
<bold>d</bold>
<bold>f</bold>
), whereas others showed increasing %BCR-ABL1 measurements instead (
<bold>g</bold>
<bold>i</bold>
). The PCR efficiency of these assays tended to be suboptimal (<0.9 or >1.1), resulting in disproportional increase of
<italic>BCR-ABL1</italic>
or reference gene copy number with increasing sample input (
<bold>e</bold>
,
<bold>f</bold>
,
<bold>h</bold>
and
<bold>i</bold>
), which subsequently led to the unstable %BCR-ABL1 measurements (
<bold>d</bold>
and
<bold>g</bold>
). Occasionally,
<italic>BCR-ABL1</italic>
and reference gene assays that were suboptimal in a similar manner could cancel each other's defects, to achieve artificially stable %BCR-ABL1 measurements (
<bold>j</bold>
<bold>l</bold>
). Red lines represent the linear regression fit based on actual data and blue lines represent what ideal data should resemble.</p>
</caption>
<graphic xlink:href="leu201690f3"></graphic>
</fig>
<table-wrap id="tbl1">
<label>Table 1</label>
<caption>
<title>Primer and probe sequences for the RT-ddPCR assays</title>
</caption>
<table frame="hsides" rules="groups" border="1">
<colgroup>
<col align="left"></col>
<col align="left"></col>
<col align="left"></col>
</colgroup>
<thead valign="bottom">
<tr>
<th align="left" valign="top" charoff="50">
<italic>Gene</italic>
</th>
<th align="left" valign="top" charoff="50">
<italic>Primer</italic>
<italic>/probe</italic>
</th>
<th align="left" valign="top" charoff="50">
<italic>Sequence (5′–3′)</italic>
</th>
</tr>
</thead>
<tbody valign="top">
<tr>
<td align="left" valign="top" charoff="50">
<italic>BCR-ABL1</italic>
</td>
<td align="left" valign="top" charoff="50">Forward primer</td>
<td align="left" valign="top" charoff="50">CCGCTGACCATCAATAAGGAA</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50"> </td>
<td align="left" valign="top" charoff="50">FAM MGB probe</td>
<td align="left" valign="top" charoff="50">AAGCCCTTCAGCGGC</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50"> </td>
<td align="left" valign="top" charoff="50">Reverse primer</td>
<td align="left" valign="top" charoff="50">CTGAGGCTCAAAGTCAGATGCTACT</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50">
<italic>ABL1</italic>
</td>
<td align="left" valign="top" charoff="50">Forward primer</td>
<td align="left" valign="top" charoff="50">ACCACTGACGTGCCTGAGATG</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50"> </td>
<td align="left" valign="top" charoff="50">FAM MGB probe</td>
<td align="left" valign="top" charoff="50">AGAGAGCGATCCTCTGG</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50"> </td>
<td align="left" valign="top" charoff="50">Reverse primer</td>
<td align="left" valign="top" charoff="50">GAGACACGGCAGGCTCATG</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50">
<italic>BCR</italic>
</td>
<td align="left" valign="top" charoff="50">Forward primer</td>
<td align="left" valign="top" charoff="50">CACTCAGCCACTGGATTTAAGC</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50"> </td>
<td align="left" valign="top" charoff="50">FAM MGB probe</td>
<td align="left" valign="top" charoff="50">CCTGGAGGTGGATTC</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50"> </td>
<td align="left" valign="top" charoff="50">Reverse primer</td>
<td align="left" valign="top" charoff="50">CGCGTCTTTGCTTTATTCACAA</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50">
<italic>GUSB</italic>
</td>
<td align="left" valign="top" charoff="50">Forward primer</td>
<td align="left" valign="top" charoff="50">ACGCAGAAAATACGTGGTTGG</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50"> </td>
<td align="left" valign="top" charoff="50">FAM MGB probe</td>
<td align="left" valign="top" charoff="50">CTCATTTGGAATTTTGCCGAT</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50"> </td>
<td align="left" valign="top" charoff="50">Reverse primer</td>
<td align="left" valign="top" charoff="50">GCCGAGTGAAGATCCCCTTT</td>
</tr>
</tbody>
</table>
<table-wrap-foot>
<fn id="t1-fn1">
<p>Abbreviation: RT-ddPCR, reverse-transcription droplet digital PCR.</p>
</fn>
</table-wrap-foot>
</table-wrap>
<table-wrap id="tbl2">
<label>Table 2</label>
<caption>
<title>The
<italic>BCR-ABL1</italic>
secondary reference panel was highly concordant with the WHO panel</title>
</caption>
<table frame="hsides" rules="groups" border="1">
<colgroup>
<col align="left"></col>
<col align="char" char="."></col>
<col align="center"></col>
<col align="char" char="."></col>
<col align="char" char="."></col>
<col align="center"></col>
<col align="char" char="."></col>
<col align="char" char="."></col>
</colgroup>
<thead valign="bottom">
<tr>
<th align="left" valign="top" charoff="50">
<italic>Reference gene</italic>
</th>
<th align="center" valign="top" char="." charoff="50">
<italic>RT-ddPCR IS CF</italic>
</th>
<th colspan="3" align="center" valign="top" charoff="50">
<italic>WHO panel</italic>
<hr></hr>
</th>
<th colspan="3" align="center" valign="top" charoff="50">
<italic>Secondary panel</italic>
<hr></hr>
</th>
</tr>
<tr>
<th align="left" valign="top" charoff="50"> </th>
<th align="char" valign="top" char="." charoff="50"> </th>
<th align="center" valign="top" charoff="50">
<italic>Panel member</italic>
</th>
<th align="center" valign="top" char="." charoff="50">
<italic>Mean empirical %BCR-ABL1</italic>
</th>
<th align="center" valign="top" char="." charoff="50">
<italic>Nominal %BCR-ABL1</italic>
<sup>
<italic>IS</italic>
</sup>
</th>
<th align="center" valign="top" charoff="50">
<italic>Panel member</italic>
</th>
<th align="center" valign="top" char="." charoff="50">
<italic>Mean empirical %BCR-ABL1</italic>
</th>
<th align="center" valign="top" char="." charoff="50">
<italic>Assigned %BCR-ABL1</italic>
<sup>
<italic>IS</italic>
</sup>
</th>
</tr>
</thead>
<tbody valign="top">
<tr>
<td colspan="8" align="left" valign="top" charoff="50">
<italic>(a) Empirical and %BCR-ABL</italic>
<sup>
<italic>IS</italic>
</sup>
<italic>values</italic>
</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50">
<italic> ABL1</italic>
</td>
<td align="char" valign="top" char="." charoff="50">0.93</td>
<td align="center" valign="top" charoff="50">4 (08/198)</td>
<td align="char" valign="top" char="." charoff="50">11.2250</td>
<td align="char" valign="top" char="." charoff="50">10.7469</td>
<td align="center" valign="top" charoff="50">A</td>
<td align="char" valign="top" char="." charoff="50">13.7178</td>
<td align="char" valign="top" char="." charoff="50">12.7575</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50"> </td>
<td align="char" valign="top" char="." charoff="50"> </td>
<td align="center" valign="top" charoff="50">3 (08/196)</td>
<td align="char" valign="top" char="." charoff="50">1.2540</td>
<td align="char" valign="top" char="." charoff="50">1.1672</td>
<td align="center" valign="top" charoff="50">B</td>
<td align="char" valign="top" char="." charoff="50">1.2841</td>
<td align="char" valign="top" char="." charoff="50">1.1942</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50"> </td>
<td align="char" valign="top" char="." charoff="50"> </td>
<td align="center" valign="top" charoff="50">2 (08/194)</td>
<td align="char" valign="top" char="." charoff="50">0.1260</td>
<td align="char" valign="top" char="." charoff="50">0.1112</td>
<td align="center" valign="top" charoff="50">C</td>
<td align="char" valign="top" char="." charoff="50">0.1095</td>
<td align="char" valign="top" char="." charoff="50">0.1019</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50"> </td>
<td align="char" valign="top" char="." charoff="50"> </td>
<td align="center" valign="top" charoff="50">1 (08/192)</td>
<td align="char" valign="top" char="." charoff="50">0.0130</td>
<td align="char" valign="top" char="." charoff="50">0.0118</td>
<td align="center" valign="top" charoff="50">D</td>
<td align="char" valign="top" char="." charoff="50">0.0116</td>
<td align="char" valign="top" char="." charoff="50">0.0108</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50"> </td>
<td align="char" valign="top" char="." charoff="50"> </td>
<td align="center" valign="top" charoff="50"> </td>
<td align="char" valign="top" char="." charoff="50"> </td>
<td align="char" valign="top" char="." charoff="50"> </td>
<td align="center" valign="top" charoff="50">E</td>
<td align="char" valign="top" char="." charoff="50">0.0041</td>
<td align="char" valign="top" char="." charoff="50">0.0038</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50">
<italic> BCR</italic>
</td>
<td align="char" valign="top" char="." charoff="50">1.85</td>
<td align="center" valign="top" charoff="50">4 (08/198)</td>
<td align="char" valign="top" char="." charoff="50">9.8135</td>
<td align="char" valign="top" char="." charoff="50">16.3129</td>
<td align="center" valign="top" charoff="50">A</td>
<td align="char" valign="top" char="." charoff="50">11.5502</td>
<td align="char" valign="top" char="." charoff="50">21.3678</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50"> </td>
<td align="char" valign="top" char="." charoff="50"> </td>
<td align="center" valign="top" charoff="50">3 (08/196)</td>
<td align="char" valign="top" char="." charoff="50">0.8441</td>
<td align="char" valign="top" char="." charoff="50">1.6627</td>
<td align="center" valign="top" charoff="50">B</td>
<td align="char" valign="top" char="." charoff="50">0.7300</td>
<td align="char" valign="top" char="." charoff="50">1.3505</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50"> </td>
<td align="char" valign="top" char="." charoff="50"> </td>
<td align="center" valign="top" charoff="50">2 (08/194)</td>
<td align="char" valign="top" char="." charoff="50">0.0988</td>
<td align="char" valign="top" char="." charoff="50">0.1753</td>
<td align="center" valign="top" charoff="50">C</td>
<td align="char" valign="top" char="." charoff="50">0.0759</td>
<td align="char" valign="top" char="." charoff="50">0.1404</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50"> </td>
<td align="char" valign="top" char="." charoff="50"> </td>
<td align="center" valign="top" charoff="50">1 (08/192)</td>
<td align="char" valign="top" char="." charoff="50">0.0098</td>
<td align="char" valign="top" char="." charoff="50">0.0195</td>
<td align="center" valign="top" charoff="50">D</td>
<td align="char" valign="top" char="." charoff="50">0.0081</td>
<td align="char" valign="top" char="." charoff="50">0.0150</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50"> </td>
<td align="char" valign="top" char="." charoff="50"> </td>
<td align="center" valign="top" charoff="50"> </td>
<td align="char" valign="top" char="." charoff="50"> </td>
<td align="char" valign="top" char="." charoff="50"> </td>
<td align="center" valign="top" charoff="50">E</td>
<td align="char" valign="top" char="." charoff="50">0.0027</td>
<td align="char" valign="top" char="." charoff="50">0.0050</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50">
<italic> GUSB</italic>
</td>
<td align="char" valign="top" char="." charoff="50">1.28</td>
<td align="center" valign="top" charoff="50">4 (08/198)</td>
<td align="char" valign="top" char="." charoff="50">6.5834</td>
<td align="char" valign="top" char="." charoff="50">10.1235</td>
<td align="center" valign="top" charoff="50">A</td>
<td align="char" valign="top" char="." charoff="50">9.1800</td>
<td align="char" valign="top" char="." charoff="50">11.7504</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50"> </td>
<td align="char" valign="top" char="." charoff="50"> </td>
<td align="center" valign="top" charoff="50">3 (08/196)</td>
<td align="char" valign="top" char="." charoff="50">0.5924</td>
<td align="char" valign="top" char="." charoff="50">0.8295</td>
<td align="center" valign="top" charoff="50">B</td>
<td align="char" valign="top" char="." charoff="50">0.6219</td>
<td align="char" valign="top" char="." charoff="50">0.7960</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50"> </td>
<td align="char" valign="top" char="." charoff="50"> </td>
<td align="center" valign="top" charoff="50">2 (08/194)</td>
<td align="char" valign="top" char="." charoff="50">0.0677</td>
<td align="char" valign="top" char="." charoff="50">0.0749</td>
<td align="center" valign="top" charoff="50">C</td>
<td align="char" valign="top" char="." charoff="50">0.0628</td>
<td align="char" valign="top" char="." charoff="50">0.0804</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50"> </td>
<td align="char" valign="top" char="." charoff="50"> </td>
<td align="center" valign="top" charoff="50">1 (08/192)</td>
<td align="char" valign="top" char="." charoff="50">0.0065</td>
<td align="char" valign="top" char="." charoff="50">0.0071</td>
<td align="center" valign="top" charoff="50">D</td>
<td align="char" valign="top" char="." charoff="50">0.0068</td>
<td align="char" valign="top" char="." charoff="50">0.0087</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50"> </td>
<td align="char" valign="top" char="." charoff="50"> </td>
<td align="center" valign="top" charoff="50"> </td>
<td align="char" valign="top" char="." charoff="50"> </td>
<td align="char" valign="top" char="." charoff="50"> </td>
<td align="center" valign="top" charoff="50">E</td>
<td align="char" valign="top" char="." charoff="50">0.0023</td>
<td align="char" valign="top" char="." charoff="50">0.0029</td>
</tr>
</tbody>
</table>
<table frame="hsides" rules="groups" border="1">
<colgroup>
<col align="left"></col>
<col align="center"></col>
<col align="char" char="."></col>
<col align="center"></col>
<col align="char" char="."></col>
</colgroup>
<thead valign="bottom">
<tr>
<th align="left" valign="top" charoff="50">
<italic>Reference gene</italic>
</th>
<th colspan="2" align="center" valign="top" charoff="50">
<italic>WHO panel</italic>
<hr></hr>
</th>
<th colspan="2" align="center" valign="top" charoff="50">
<italic>Secondary panel</italic>
<hr></hr>
</th>
</tr>
<tr>
<th align="left" valign="top" charoff="50"> </th>
<th align="center" valign="top" charoff="50">
<italic>Panel member</italic>
</th>
<th align="center" valign="top" char="." charoff="50">
<italic>Mean copy number per ng RNA</italic>
</th>
<th align="center" valign="top" charoff="50">
<italic>Panel member</italic>
</th>
<th align="center" valign="top" char="." charoff="50">
<italic>Mean copy number per ng RNA</italic>
</th>
</tr>
</thead>
<tbody valign="top">
<tr>
<td colspan="5" align="left" valign="top" charoff="50">
<italic>(b) Copy numbers of BCR-ABL1, ABL1, BCR and GUSB per ng of RNA</italic>
</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50">
<italic> BCR-ABL1</italic>
</td>
<td align="center" valign="top" charoff="50">4 (08/198)</td>
<td align="char" valign="top" char="." charoff="50">92.98</td>
<td align="center" valign="top" charoff="50">A</td>
<td align="char" valign="top" char="." charoff="50">103.27</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50"> </td>
<td align="center" valign="top" charoff="50">3 (08/196)</td>
<td align="char" valign="top" char="." charoff="50">9.75</td>
<td align="center" valign="top" charoff="50">B</td>
<td align="char" valign="top" char="." charoff="50">8.56</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50"> </td>
<td align="center" valign="top" charoff="50">2 (08/194)</td>
<td align="char" valign="top" char="." charoff="50">0.99</td>
<td align="center" valign="top" charoff="50">C</td>
<td align="char" valign="top" char="." charoff="50">0.72</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50"> </td>
<td align="center" valign="top" charoff="50">1 (08/192)</td>
<td align="char" valign="top" char="." charoff="50">0.10</td>
<td align="center" valign="top" charoff="50">D</td>
<td align="char" valign="top" char="." charoff="50">0.08</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50"> </td>
<td align="center" valign="top" charoff="50"> </td>
<td align="char" valign="top" char="." charoff="50"> </td>
<td align="center" valign="top" charoff="50">E</td>
<td align="char" valign="top" char="." charoff="50">0.03</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50">
<italic> ABL1</italic>
</td>
<td align="center" valign="top" charoff="50">4 (08/198)</td>
<td align="char" valign="top" char="." charoff="50">831.74</td>
<td align="center" valign="top" charoff="50">A</td>
<td align="char" valign="top" char="." charoff="50">754.55</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50"> </td>
<td align="center" valign="top" charoff="50">3 (08/196)</td>
<td align="char" valign="top" char="." charoff="50">778.56</td>
<td align="center" valign="top" charoff="50">B</td>
<td align="char" valign="top" char="." charoff="50">665.80</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50"> </td>
<td align="center" valign="top" charoff="50">2 (08/194)</td>
<td align="char" valign="top" char="." charoff="50">784.95</td>
<td align="center" valign="top" charoff="50">C</td>
<td align="char" valign="top" char="." charoff="50">651.95</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50"> </td>
<td align="center" valign="top" charoff="50">1 (08/192)</td>
<td align="char" valign="top" char="." charoff="50">785.90</td>
<td align="center" valign="top" charoff="50">D</td>
<td align="char" valign="top" char="." charoff="50">653.85</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50"> </td>
<td align="center" valign="top" charoff="50"> </td>
<td align="char" valign="top" char="." charoff="50"> </td>
<td align="center" valign="top" charoff="50">E</td>
<td align="char" valign="top" char="." charoff="50">642.71</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50">
<italic> BCR</italic>
</td>
<td align="center" valign="top" charoff="50">4 (08/198)</td>
<td align="char" valign="top" char="." charoff="50">948.59</td>
<td align="center" valign="top" charoff="50">A</td>
<td align="char" valign="top" char="." charoff="50">973.44</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50"> </td>
<td align="center" valign="top" charoff="50">3 (08/196)</td>
<td align="char" valign="top" char="." charoff="50">1036.91</td>
<td align="center" valign="top" charoff="50">B</td>
<td align="char" valign="top" char="." charoff="50">1058.25</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50"> </td>
<td align="center" valign="top" charoff="50">2 (08/194)</td>
<td align="char" valign="top" char="." charoff="50">1004.05</td>
<td align="center" valign="top" charoff="50">C</td>
<td align="char" valign="top" char="." charoff="50">1012.51</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50"> </td>
<td align="center" valign="top" charoff="50">1 (08/192)</td>
<td align="char" valign="top" char="." charoff="50">1033.21</td>
<td align="center" valign="top" charoff="50">D</td>
<td align="char" valign="top" char="." charoff="50">1079.15</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50"> </td>
<td align="center" valign="top" charoff="50"> </td>
<td align="char" valign="top" char="." charoff="50"> </td>
<td align="center" valign="top" charoff="50">E</td>
<td align="char" valign="top" char="." charoff="50">1017.74</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50">
<italic> GUSB</italic>
</td>
<td align="center" valign="top" charoff="50">4 (08/198)</td>
<td align="char" valign="top" char="." charoff="50">1380.43</td>
<td align="center" valign="top" charoff="50">A</td>
<td align="char" valign="top" char="." charoff="50">1198.94</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50"> </td>
<td align="center" valign="top" charoff="50">3 (08/196)</td>
<td align="char" valign="top" char="." charoff="50">1454.12</td>
<td align="center" valign="top" charoff="50">B</td>
<td align="char" valign="top" char="." charoff="50">1238.22</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50"> </td>
<td align="center" valign="top" charoff="50">2 (08/194)</td>
<td align="char" valign="top" char="." charoff="50">1390.83</td>
<td align="center" valign="top" charoff="50">C</td>
<td align="char" valign="top" char="." charoff="50">1261.53</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50"> </td>
<td align="center" valign="top" charoff="50">1 (08/192)</td>
<td align="char" valign="top" char="." charoff="50">1388.23</td>
<td align="center" valign="top" charoff="50">D</td>
<td align="char" valign="top" char="." charoff="50">1283.79</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50"> </td>
<td align="center" valign="top" charoff="50"> </td>
<td align="char" valign="top" char="." charoff="50"> </td>
<td align="center" valign="top" charoff="50">E</td>
<td align="char" valign="top" char="." charoff="50">1244.11</td>
</tr>
</tbody>
</table>
<table-wrap-foot>
<fn id="t2-fn1">
<p>Abbreviations: CF, conversion factor; IS, International Scale; RT-ddPCR, reverse-transcription droplet digital PCR; WHO, World Health Organization.</p>
</fn>
</table-wrap-foot>
</table-wrap>
<table-wrap id="tbl3">
<label>Table 3</label>
<caption>
<title>Summary results of the secondary panel international multi-center evaluation study</title>
</caption>
<table frame="hsides" rules="groups" border="1">
<colgroup>
<col align="left"></col>
<col align="center"></col>
<col align="center"></col>
<col align="char" char="."></col>
<col align="char" char="."></col>
<col align="char" char="."></col>
<col align="char" char="."></col>
<col align="char" char="."></col>
<col align="char" char="."></col>
</colgroup>
<thead valign="bottom">
<tr>
<th align="left" valign="top" charoff="50">
<italic>Reference gene</italic>
</th>
<th align="center" valign="top" charoff="50">
<italic>Number of assays</italic>
</th>
<th align="center" valign="top" charoff="50">
<italic>Vial (WHO/secondary panel)</italic>
</th>
<th colspan="6" align="center" valign="top" char="." charoff="50">
<italic>%BCR-ABL1</italic>
<sup>
<italic>IS</italic>
</sup>
<hr></hr>
</th>
</tr>
<tr>
<th align="left" valign="top" charoff="50"> </th>
<th align="center" valign="top" charoff="50"> </th>
<th align="center" valign="top" charoff="50"> </th>
<th align="center" valign="top" char="." charoff="50">
<italic>WHO panel</italic>
<italic>Nominal</italic>
</th>
<th align="center" valign="top" char="." charoff="50">
<italic>Secondary panel</italic>
<italic>Assigned</italic>
</th>
<th colspan="4" align="center" valign="top" char="." charoff="50">
<italic>Results from 45 BCR-ABL1 assays</italic>
<hr></hr>
</th>
</tr>
<tr>
<th align="left" valign="top" charoff="50"> </th>
<th align="center" valign="top" charoff="50"> </th>
<th align="center" valign="top" charoff="50"> </th>
<th align="center" valign="top" char="." charoff="50"> </th>
<th align="center" valign="top" char="." charoff="50"> </th>
<th align="center" valign="top" char="." charoff="50">
<italic>Mean</italic>
</th>
<th align="center" valign="top" char="." charoff="50">
<italic>s.d.</italic>
</th>
<th align="center" valign="top" char="." charoff="50">
<italic>Minimum</italic>
</th>
<th align="center" valign="top" char="." charoff="50">
<italic>Maximum</italic>
</th>
</tr>
</thead>
<tbody valign="top">
<tr>
<td align="left" valign="top" charoff="50">
<italic>ABL1</italic>
</td>
<td align="center" valign="top" charoff="50">32</td>
<td align="center" valign="top" charoff="50">4 (08/198)/A</td>
<td align="char" valign="top" char="." charoff="50">10.7469</td>
<td align="char" valign="top" char="." charoff="50">12.7575</td>
<td align="char" valign="top" char="." charoff="50">11.4450</td>
<td align="char" valign="top" char="." charoff="50">8.2225</td>
<td align="char" valign="top" char="." charoff="50">3.6127</td>
<td align="char" valign="top" char="." charoff="50">37.4603</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50"> </td>
<td align="center" valign="top" charoff="50"> </td>
<td align="center" valign="top" charoff="50">3 (08/196)/B</td>
<td align="char" valign="top" char="." charoff="50">1.1672</td>
<td align="char" valign="top" char="." charoff="50">1.1942</td>
<td align="char" valign="top" char="." charoff="50">1.1771</td>
<td align="char" valign="top" char="." charoff="50">0.9994</td>
<td align="char" valign="top" char="." charoff="50">0.4014</td>
<td align="char" valign="top" char="." charoff="50">4.4109</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50"> </td>
<td align="center" valign="top" charoff="50"> </td>
<td align="center" valign="top" charoff="50">2 (08/194)/C</td>
<td align="char" valign="top" char="." charoff="50">0.1112</td>
<td align="char" valign="top" char="." charoff="50">0.1019</td>
<td align="char" valign="top" char="." charoff="50">0.1013</td>
<td align="char" valign="top" char="." charoff="50">0.0931</td>
<td align="char" valign="top" char="." charoff="50">0.0362</td>
<td align="char" valign="top" char="." charoff="50">0.4553</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50"> </td>
<td align="center" valign="top" charoff="50"> </td>
<td align="center" valign="top" charoff="50">1 (08/192)/D</td>
<td align="char" valign="top" char="." charoff="50">0.0118</td>
<td align="char" valign="top" char="." charoff="50">0.0108</td>
<td align="char" valign="top" char="." charoff="50">0.0110</td>
<td align="char" valign="top" char="." charoff="50">0.0232</td>
<td align="char" valign="top" char="." charoff="50">0.0033</td>
<td align="char" valign="top" char="." charoff="50">0.1323</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50"> </td>
<td align="center" valign="top" charoff="50"> </td>
<td align="center" valign="top" charoff="50">NA/E</td>
<td align="char" valign="top" char="." charoff="50"> </td>
<td align="char" valign="top" char="." charoff="50">0.0038</td>
<td align="char" valign="top" char="." charoff="50">0.0038</td>
<td align="char" valign="top" char="." charoff="50">0.0038</td>
<td align="char" valign="top" char="." charoff="50">0.0013</td>
<td align="char" valign="top" char="." charoff="50">0.0159</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50">
<italic>BCR</italic>
</td>
<td align="center" valign="top" charoff="50">5</td>
<td align="center" valign="top" charoff="50">4 (08/198)/A</td>
<td align="char" valign="top" char="." charoff="50">16.3129</td>
<td align="char" valign="top" char="." charoff="50">21.3678</td>
<td align="char" valign="top" char="." charoff="50">21.3999</td>
<td align="char" valign="top" char="." charoff="50">12.3547</td>
<td align="char" valign="top" char="." charoff="50">13.6781</td>
<td align="char" valign="top" char="." charoff="50">42.5295</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50"> </td>
<td align="center" valign="top" charoff="50"> </td>
<td align="center" valign="top" charoff="50">3 (08/196)/B</td>
<td align="char" valign="top" char="." charoff="50">1.6627</td>
<td align="char" valign="top" char="." charoff="50">1.3505</td>
<td align="char" valign="top" char="." charoff="50">1.7243</td>
<td align="char" valign="top" char="." charoff="50">1.2662</td>
<td align="char" valign="top" char="." charoff="50">1.0215</td>
<td align="char" valign="top" char="." charoff="50">4.2655</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50"> </td>
<td align="center" valign="top" charoff="50"> </td>
<td align="center" valign="top" charoff="50">2 (08/194)/C</td>
<td align="char" valign="top" char="." charoff="50">0.1753</td>
<td align="char" valign="top" char="." charoff="50">0.1404</td>
<td align="char" valign="top" char="." charoff="50">0.1615</td>
<td align="char" valign="top" char="." charoff="50">0.0863</td>
<td align="char" valign="top" char="." charoff="50">0.0881</td>
<td align="char" valign="top" char="." charoff="50">0.3025</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50"> </td>
<td align="center" valign="top" charoff="50"> </td>
<td align="center" valign="top" charoff="50">1 (08/192)/D</td>
<td align="char" valign="top" char="." charoff="50">0.0195</td>
<td align="char" valign="top" char="." charoff="50">0.0150</td>
<td align="char" valign="top" char="." charoff="50">0.0153</td>
<td align="char" valign="top" char="." charoff="50">0.0105</td>
<td align="char" valign="top" char="." charoff="50">0.0071</td>
<td align="char" valign="top" char="." charoff="50">0.0302</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50"> </td>
<td align="center" valign="top" charoff="50"> </td>
<td align="center" valign="top" charoff="50">NA/E</td>
<td align="char" valign="top" char="." charoff="50"> </td>
<td align="char" valign="top" char="." charoff="50">0.0050</td>
<td align="char" valign="top" char="." charoff="50">0.0056</td>
<td align="char" valign="top" char="." charoff="50">0.0047</td>
<td align="char" valign="top" char="." charoff="50">0.0028</td>
<td align="char" valign="top" char="." charoff="50">0.0134</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50">
<italic>GUSB</italic>
</td>
<td align="center" valign="top" charoff="50">8</td>
<td align="center" valign="top" charoff="50">4 (08/198)/A</td>
<td align="char" valign="top" char="." charoff="50">10.1235</td>
<td align="char" valign="top" char="." charoff="50">11.7504</td>
<td align="char" valign="top" char="." charoff="50">8.9008</td>
<td align="char" valign="top" char="." charoff="50">3.7900</td>
<td align="char" valign="top" char="." charoff="50">4.5344</td>
<td align="char" valign="top" char="." charoff="50">14.9359</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50"> </td>
<td align="center" valign="top" charoff="50"> </td>
<td align="center" valign="top" charoff="50">3 (08/196)/B</td>
<td align="char" valign="top" char="." charoff="50">0.8295</td>
<td align="char" valign="top" char="." charoff="50">0.7960</td>
<td align="char" valign="top" char="." charoff="50">0.7346</td>
<td align="char" valign="top" char="." charoff="50">0.4133</td>
<td align="char" valign="top" char="." charoff="50">0.3514</td>
<td align="char" valign="top" char="." charoff="50">1.5494</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50"> </td>
<td align="center" valign="top" charoff="50"> </td>
<td align="center" valign="top" charoff="50">2 (08/194)/C</td>
<td align="char" valign="top" char="." charoff="50">0.0749</td>
<td align="char" valign="top" char="." charoff="50">0.0804</td>
<td align="char" valign="top" char="." charoff="50">0.0587</td>
<td align="char" valign="top" char="." charoff="50">0.0351</td>
<td align="char" valign="top" char="." charoff="50">0.0218</td>
<td align="char" valign="top" char="." charoff="50">0.1149</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50"> </td>
<td align="center" valign="top" charoff="50"> </td>
<td align="center" valign="top" charoff="50">1 (08/192)/D</td>
<td align="char" valign="top" char="." charoff="50">0.0071</td>
<td align="char" valign="top" char="." charoff="50">0.0087</td>
<td align="char" valign="top" char="." charoff="50">0.0050</td>
<td align="char" valign="top" char="." charoff="50">0.0033</td>
<td align="char" valign="top" char="." charoff="50">0.0010</td>
<td align="char" valign="top" char="." charoff="50">0.0106</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50"> </td>
<td align="center" valign="top" charoff="50"> </td>
<td align="center" valign="top" charoff="50">NA/E</td>
<td align="char" valign="top" char="." charoff="50"> </td>
<td align="char" valign="top" char="." charoff="50">0.0029</td>
<td align="char" valign="top" char="." charoff="50">0.0020</td>
<td align="char" valign="top" char="." charoff="50">0.0018</td>
<td align="char" valign="top" char="." charoff="50">0.0005</td>
<td align="char" valign="top" char="." charoff="50">0.0054</td>
</tr>
</tbody>
</table>
<table-wrap-foot>
<fn id="t3-fn1">
<p>Abbreviations: NA, not applicable; WHO, World Health Organization.</p>
</fn>
</table-wrap-foot>
</table-wrap>
</floats-group>
</pmc>
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