Development and evaluation of a secondary reference panel for BCR-ABL1 quantification on the International Scale
Identifieur interne : 000727 ( Pmc/Corpus ); précédent : 000726; suivant : 000728Development and evaluation of a secondary reference panel for BCR-ABL1 quantification on the International Scale
Auteurs : N C P. Cross ; H E White ; T. Ernst ; L. Welden ; C. Dietz ; G. Saglio ; F-X Mahon ; C C Wong ; D. Zheng ; S. Wong ; S-S Wang ; S. Akiki ; F. Albano ; H. Andrikovics ; J. Anwar ; G. Balatzenko ; I. Bendit ; J. Beveridge ; N. Boeckx ; N. Cerveira ; S-M Cheng ; D. Colomer ; S. Czurda ; F. Daraio ; S. Dulucq ; L. Eggen ; H. El Housni ; G. Gerrard ; M. Gniot ; B. Izzo ; D. Jacquin ; J J W M. Janssen ; S. Jeromin ; T. Jurcek ; D-W Kim ; K. Machova-Polakova ; J. Martinez-Lopez ; M. Mcbean ; S. Mesanovic ; G. Mitterbauer-Hohendanner ; H. Mobtaker ; M-J Mozziconacci ; T. Paji ; N. Pallisgaard ; P. Panagiotidis ; R D Press ; Y-Z Qin ; J. Radich ; T. Sacha ; T. Touloumenidou ; P. Waits ; E. Wilkinson ; R. Zadro ; M C Müller ; A. Hochhaus ; S. BranfordSource :
- Leukemia [ 0887-6924 ] ; 2016.
Abstract
Molecular monitoring of chronic myeloid leukemia patients using robust
Url:
DOI: 10.1038/leu.2016.90
PubMed: 27109508
PubMed Central: 5240017
Links to Exploration step
PMC:5240017Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">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><nlm:aff id="aff1"><institution>Wessex Regional Genetics Laboratory, Salisbury NHS Foundation Trust</institution>, Salisbury,<country>UK</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff2"><institution>Faculty of Medicine, University of Southampton</institution>, Southampton,<country>UK</country></nlm:aff></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><nlm:aff id="aff1"><institution>Wessex Regional Genetics Laboratory, Salisbury NHS Foundation Trust</institution>, Salisbury,<country>UK</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff2"><institution>Faculty of Medicine, University of Southampton</institution>, Southampton,<country>UK</country></nlm:aff></affiliation></author><author><name sortKey="Ernst, T" sort="Ernst, T" uniqKey="Ernst T" first="T" last="Ernst">T. Ernst</name><affiliation><nlm:aff id="aff3"><institution>Department of Hematology/Oncology, Universitätsklinikum Jena</institution>, Jena,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="Welden, L" sort="Welden, L" uniqKey="Welden L" first="L" last="Welden">L. Welden</name><affiliation><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></affiliation></author><author><name sortKey="Dietz, C" sort="Dietz, C" uniqKey="Dietz C" first="C" last="Dietz">C. Dietz</name><affiliation><nlm:aff id="aff5"><institution>III. Medizinische Klinik, Medizinische Fakultät Mannheim, Universität Heidelberg</institution>, Mannheim,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="Saglio, G" sort="Saglio, G" uniqKey="Saglio G" first="G" last="Saglio">G. Saglio</name><affiliation><nlm:aff id="aff6"><institution>Department of Clinical and Biological Sciences, San Luigi Hospital, University of Turin</institution>, Orbassano,<country>Italy</country></nlm:aff></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><nlm:aff id="aff7"><institution>Bergonie Institute Cancer Center Bordeaux, INSERM U1218, University of Bordeaux</institution>, Bordeaux,<country>France</country></nlm:aff></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><nlm:aff id="aff8"><institution>Novartis Pharmaceuticals Corporation</institution>, East Hanover, NJ,<country>USA</country></nlm:aff></affiliation></author><author><name sortKey="Zheng, D" sort="Zheng, D" uniqKey="Zheng D" first="D" last="Zheng">D. Zheng</name><affiliation><nlm:aff id="aff8"><institution>Novartis Pharmaceuticals Corporation</institution>, East Hanover, NJ,<country>USA</country></nlm:aff></affiliation></author><author><name sortKey="Wong, S" sort="Wong, S" uniqKey="Wong S" first="S" last="Wong">S. Wong</name><affiliation><nlm:aff id="aff8"><institution>Novartis Pharmaceuticals Corporation</institution>, East Hanover, NJ,<country>USA</country></nlm:aff></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><nlm:aff id="aff8"><institution>Novartis Pharmaceuticals Corporation</institution>, East Hanover, NJ,<country>USA</country></nlm:aff></affiliation></author><author><name sortKey="Akiki, S" sort="Akiki, S" uniqKey="Akiki S" first="S" last="Akiki">S. Akiki</name><affiliation><nlm:aff id="aff9"><institution>West Midlands Regional Genetics Laboratory</institution>, Birmingham,<country>UK</country></nlm:aff></affiliation></author><author><name sortKey="Albano, F" sort="Albano, F" uniqKey="Albano F" first="F" last="Albano">F. Albano</name><affiliation><nlm:aff id="aff10"><institution>Department of Hematology, University of Bari</institution>, Bari,<country>Italy</country></nlm:aff></affiliation></author><author><name sortKey="Andrikovics, H" sort="Andrikovics, H" uniqKey="Andrikovics H" first="H" last="Andrikovics">H. Andrikovics</name><affiliation><nlm:aff id="aff11"><institution>Laboratory of Molecular Diagnostics, Hungarian National Blood Transfusion Service</institution>, Budapest,<country>Hungary</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff12"><institution>Department of Pathophysiology, Semmelweis University</institution>, Budapest,<country>Hungary</country></nlm:aff></affiliation></author><author><name sortKey="Anwar, J" sort="Anwar, J" uniqKey="Anwar J" first="J" last="Anwar">J. Anwar</name><affiliation><nlm:aff id="aff13"><institution>King's College Hospital London</institution>, London,<country>UK</country></nlm:aff></affiliation></author><author><name sortKey="Balatzenko, G" sort="Balatzenko, G" uniqKey="Balatzenko G" first="G" last="Balatzenko">G. Balatzenko</name><affiliation><nlm:aff id="aff14"><institution>National Specialized Hospital for Active Treatment of Hematological Diseases</institution>, Sofia,<country>Bulgaria</country></nlm:aff></affiliation></author><author><name sortKey="Bendit, I" sort="Bendit, I" uniqKey="Bendit I" first="I" last="Bendit">I. Bendit</name><affiliation><nlm:aff id="aff15"><institution>Laboratorio de Biologia Tumoral, Disciplina de Hematologia do HC-FMUSP</institution>, São Paulo,<country>Brazil</country></nlm:aff></affiliation></author><author><name sortKey="Beveridge, J" sort="Beveridge, J" uniqKey="Beveridge J" first="J" last="Beveridge">J. Beveridge</name><affiliation><nlm:aff id="aff16"><institution>PathWest Laboratory Medicine WA, Department of Haematology, Fiona Stanley Hospital</institution>, Perth, WA,<country>Australia</country></nlm:aff></affiliation></author><author><name sortKey="Boeckx, N" sort="Boeckx, N" uniqKey="Boeckx N" first="N" last="Boeckx">N. Boeckx</name><affiliation><nlm:aff id="aff17"><institution>Department of Laboratory Medicine, University Hospitals Leuven</institution>, Leuven,<country>Belgium</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff18"><institution>Department of Oncology, KUL</institution>, Leuven,<country>Belgium</country></nlm:aff></affiliation></author><author><name sortKey="Cerveira, N" sort="Cerveira, N" uniqKey="Cerveira N" first="N" last="Cerveira">N. Cerveira</name><affiliation><nlm:aff id="aff19"><institution>Department of Genetics, Portuguese Oncology Institute</institution>, Porto,<country>Portugal</country></nlm:aff></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><nlm:aff id="aff20"><institution>Department of Hematology and Oncology, Quest Diagnostics Nichols Institute</institution>, San Juan Capistrano, CA,<country>USA</country></nlm:aff></affiliation></author><author><name sortKey="Colomer, D" sort="Colomer, D" uniqKey="Colomer D" first="D" last="Colomer">D. Colomer</name><affiliation><nlm:aff id="aff21"><institution>Hematopathology Unit, Hospital Clinic, IDIBAPS</institution>, Barcelona,<country>Spain</country></nlm:aff></affiliation></author><author><name sortKey="Czurda, S" sort="Czurda, S" uniqKey="Czurda S" first="S" last="Czurda">S. Czurda</name><affiliation><nlm:aff id="aff22"><institution>Division of Molecular Microbiology, Children's Cancer Research Institute</institution>, Vienna,<country>Austria</country></nlm:aff></affiliation></author><author><name sortKey="Daraio, F" sort="Daraio, F" uniqKey="Daraio F" first="F" last="Daraio">F. Daraio</name><affiliation><nlm:aff id="aff23"><institution>Department of Clinical and Biological Sciences, San Luigi Hospital, University of Turin</institution>, Orbassano,<country>Italy</country></nlm:aff></affiliation></author><author><name sortKey="Dulucq, S" sort="Dulucq, S" uniqKey="Dulucq S" first="S" last="Dulucq">S. Dulucq</name><affiliation><nlm:aff id="aff24"><institution>Laboratoire Hematologie, Centre Hospitalier Universitaire de Bordeaux, Universite Bordeaux</institution>, Bordeaux,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Eggen, L" sort="Eggen, L" uniqKey="Eggen L" first="L" last="Eggen">L. Eggen</name><affiliation><nlm:aff id="aff25"><institution>Laboratory of Molecular Pathology, Oslo University Hospital</institution>, Oslo,<country>Norway</country></nlm:aff></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><nlm:aff id="aff26"><institution>Clinique de Genetique Oncologique-Service de genetique, Hopital Erasme</institution>, Brussels,<country>Belgium</country></nlm:aff></affiliation></author><author><name sortKey="Gerrard, G" sort="Gerrard, G" uniqKey="Gerrard G" first="G" last="Gerrard">G. Gerrard</name><affiliation><nlm:aff id="aff27"><institution>Imperial Molecular Pathology, Hammersmith Hospital</institution>, London,<country>UK</country></nlm:aff></affiliation></author><author><name sortKey="Gniot, M" sort="Gniot, M" uniqKey="Gniot M" first="M" last="Gniot">M. Gniot</name><affiliation><nlm:aff id="aff28"><institution>Department of Hematology and Bone Marrow Transplantation, Poznan University of Medical Sciences</institution>, Poznan,<country>Poland</country></nlm:aff></affiliation></author><author><name sortKey="Izzo, B" sort="Izzo, B" uniqKey="Izzo B" first="B" last="Izzo">B. Izzo</name><affiliation><nlm:aff id="aff29"><institution>Department of Clinical Medicine and Surgery, University ‘Federico II' of Naples</institution>, Naples,<country>Italy</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff30"><institution>CEINGE – Biotecnologie Avanzate</institution>, Naples,<country>Italy</country></nlm:aff></affiliation></author><author><name sortKey="Jacquin, D" sort="Jacquin, D" uniqKey="Jacquin D" first="D" last="Jacquin">D. Jacquin</name><affiliation><nlm:aff id="aff31"><institution>Genoptix, Inc.</institution>, Carlsbad, CA,<country>USA</country></nlm:aff></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><nlm:aff id="aff32"><institution>Department of Hematology and Molecular Diagnostics, VU University Medical Center</institution>, Amsterdam,<country>The Netherlands</country></nlm:aff></affiliation></author><author><name sortKey="Jeromin, S" sort="Jeromin, S" uniqKey="Jeromin S" first="S" last="Jeromin">S. Jeromin</name><affiliation><nlm:aff id="aff33"><institution>MLL Munich Leukemia Laboratory</institution>, Munich,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="Jurcek, T" sort="Jurcek, T" uniqKey="Jurcek T" first="T" last="Jurcek">T. Jurcek</name><affiliation><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></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><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></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><nlm:aff id="aff36"><institution>Department of Molecular Genetics, Institute of Hematology and Blood Transfusion</institution>, Prague,<country>Czech Republic</country></nlm:aff></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><nlm:aff id="aff37"><institution>Department of Hematology, Hospital Universitario 12 de Octubre, Universidad Complutense, CNIO</institution>, Madrid,<country>Spain</country></nlm:aff></affiliation></author><author><name sortKey="Mcbean, M" sort="Mcbean, M" uniqKey="Mcbean M" first="M" last="Mcbean">M. Mcbean</name><affiliation><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></affiliation></author><author><name sortKey="Mesanovic, S" sort="Mesanovic, S" uniqKey="Mesanovic S" first="S" last="Mesanovic">S. Mesanovic</name><affiliation><nlm:aff id="aff39"><institution>Pathology Department, University Clinical Center Tuzla</institution>, Tuzla,<country>Bosnia and Herzegovina</country></nlm:aff></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><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></affiliation></author><author><name sortKey="Mobtaker, H" sort="Mobtaker, H" uniqKey="Mobtaker H" first="H" last="Mobtaker">H. Mobtaker</name><affiliation><nlm:aff id="aff31"><institution>Genoptix, Inc.</institution>, Carlsbad, CA,<country>USA</country></nlm:aff></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><nlm:aff id="aff41"><institution>Departement de Biopathologie, Institut Paoli-Calmettes</institution>, Marseille,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Paji, T" sort="Paji, T" uniqKey="Paji T" first="T" last="Paji">T. Paji</name><affiliation><nlm:aff id="aff42"><institution>Specialized Haematology Laboratory, Department of Haematology, University Medical Centre Ljubljana</institution>, Ljubljana,<country>Slovenia</country></nlm:aff></affiliation></author><author><name sortKey="Pallisgaard, N" sort="Pallisgaard, N" uniqKey="Pallisgaard N" first="N" last="Pallisgaard">N. Pallisgaard</name><affiliation><nlm:aff id="aff43"><institution>Department of Surgical Pathology, Zealand University Hospital</institution>, Roskilde,<country>Denmark</country></nlm:aff></affiliation></author><author><name sortKey="Panagiotidis, P" sort="Panagiotidis, P" uniqKey="Panagiotidis P" first="P" last="Panagiotidis">P. Panagiotidis</name><affiliation><nlm:aff id="aff44"><institution>Hematology Unit, First Department of Internal Medicine, Laiko Hospital, University of Athens,</institution> Athens,<country>Greece</country></nlm:aff></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><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></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><nlm:aff id="aff46"><institution>Peking University People's Hospital, Peking University Institute of Hematology</institution>, Beijing,<country>China</country></nlm:aff></affiliation></author><author><name sortKey="Radich, J" sort="Radich, J" uniqKey="Radich J" first="J" last="Radich">J. Radich</name><affiliation><nlm:aff id="aff47"><institution>Fred Hutchinson Cancer Research Center</institution>, Seattle, WA,<country>USA</country></nlm:aff></affiliation></author><author><name sortKey="Sacha, T" sort="Sacha, T" uniqKey="Sacha T" first="T" last="Sacha">T. Sacha</name><affiliation><nlm:aff id="aff48"><institution>Chair and Department of Hematology, Jagiellonian University</institution>, Kraków,<country>Poland</country></nlm:aff></affiliation></author><author><name sortKey="Touloumenidou, T" sort="Touloumenidou, T" uniqKey="Touloumenidou T" first="T" last="Touloumenidou">T. Touloumenidou</name><affiliation><nlm:aff id="aff49"><institution>Laboratory of Molecular Biology, Hematology Department and HCT Unit, G. Papanicolaou Hospital</institution>, Thessaloniki,<country>Greece</country></nlm:aff></affiliation></author><author><name sortKey="Waits, P" sort="Waits, P" uniqKey="Waits P" first="P" last="Waits">P. Waits</name><affiliation><nlm:aff id="aff50"><institution>Bristol Genetics Laboratory</institution>, Bristol,<country>UK</country></nlm:aff></affiliation></author><author><name sortKey="Wilkinson, E" sort="Wilkinson, E" uniqKey="Wilkinson E" first="E" last="Wilkinson">E. Wilkinson</name><affiliation><nlm:aff id="aff51"><institution>HMDS, Leeds Teaching Hospitals</institution>, Leeds,<country>UK</country></nlm:aff></affiliation></author><author><name sortKey="Zadro, R" sort="Zadro, R" uniqKey="Zadro R" first="R" last="Zadro">R. Zadro</name><affiliation><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></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><nlm:aff id="aff5"><institution>III. Medizinische Klinik, Medizinische Fakultät Mannheim, Universität Heidelberg</institution>, Mannheim,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="Hochhaus, A" sort="Hochhaus, A" uniqKey="Hochhaus A" first="A" last="Hochhaus">A. Hochhaus</name><affiliation><nlm:aff id="aff3"><institution>Department of Hematology/Oncology, Universitätsklinikum Jena</institution>, Jena,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="Branford, S" sort="Branford, S" uniqKey="Branford S" first="S" last="Branford">S. Branford</name><affiliation><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></affiliation><affiliation><nlm:aff id="aff53"><institution>School of Pharmacy and Medical Science, University of South Australia</institution>, Adelaide, SA,<country>Australia</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff54"><institution>School of Medicine, University of Adelaide</institution>, SA, Adelaide,<country>Australia</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff55"><institution>School of Molecular and Biomedical Science, University of Adelaide</institution>, Adelaide, SA,<country>Australia</country></nlm:aff></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></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><nlm:aff id="aff1"><institution>Wessex Regional Genetics Laboratory, Salisbury NHS Foundation Trust</institution>, Salisbury,<country>UK</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff2"><institution>Faculty of Medicine, University of Southampton</institution>, Southampton,<country>UK</country></nlm:aff></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><nlm:aff id="aff1"><institution>Wessex Regional Genetics Laboratory, Salisbury NHS Foundation Trust</institution>, Salisbury,<country>UK</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff2"><institution>Faculty of Medicine, University of Southampton</institution>, Southampton,<country>UK</country></nlm:aff></affiliation></author><author><name sortKey="Ernst, T" sort="Ernst, T" uniqKey="Ernst T" first="T" last="Ernst">T. Ernst</name><affiliation><nlm:aff id="aff3"><institution>Department of Hematology/Oncology, Universitätsklinikum Jena</institution>, Jena,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="Welden, L" sort="Welden, L" uniqKey="Welden L" first="L" last="Welden">L. Welden</name><affiliation><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></affiliation></author><author><name sortKey="Dietz, C" sort="Dietz, C" uniqKey="Dietz C" first="C" last="Dietz">C. Dietz</name><affiliation><nlm:aff id="aff5"><institution>III. Medizinische Klinik, Medizinische Fakultät Mannheim, Universität Heidelberg</institution>, Mannheim,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="Saglio, G" sort="Saglio, G" uniqKey="Saglio G" first="G" last="Saglio">G. Saglio</name><affiliation><nlm:aff id="aff6"><institution>Department of Clinical and Biological Sciences, San Luigi Hospital, University of Turin</institution>, Orbassano,<country>Italy</country></nlm:aff></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><nlm:aff id="aff7"><institution>Bergonie Institute Cancer Center Bordeaux, INSERM U1218, University of Bordeaux</institution>, Bordeaux,<country>France</country></nlm:aff></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><nlm:aff id="aff8"><institution>Novartis Pharmaceuticals Corporation</institution>, East Hanover, NJ,<country>USA</country></nlm:aff></affiliation></author><author><name sortKey="Zheng, D" sort="Zheng, D" uniqKey="Zheng D" first="D" last="Zheng">D. Zheng</name><affiliation><nlm:aff id="aff8"><institution>Novartis Pharmaceuticals Corporation</institution>, East Hanover, NJ,<country>USA</country></nlm:aff></affiliation></author><author><name sortKey="Wong, S" sort="Wong, S" uniqKey="Wong S" first="S" last="Wong">S. Wong</name><affiliation><nlm:aff id="aff8"><institution>Novartis Pharmaceuticals Corporation</institution>, East Hanover, NJ,<country>USA</country></nlm:aff></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><nlm:aff id="aff8"><institution>Novartis Pharmaceuticals Corporation</institution>, East Hanover, NJ,<country>USA</country></nlm:aff></affiliation></author><author><name sortKey="Akiki, S" sort="Akiki, S" uniqKey="Akiki S" first="S" last="Akiki">S. Akiki</name><affiliation><nlm:aff id="aff9"><institution>West Midlands Regional Genetics Laboratory</institution>, Birmingham,<country>UK</country></nlm:aff></affiliation></author><author><name sortKey="Albano, F" sort="Albano, F" uniqKey="Albano F" first="F" last="Albano">F. Albano</name><affiliation><nlm:aff id="aff10"><institution>Department of Hematology, University of Bari</institution>, Bari,<country>Italy</country></nlm:aff></affiliation></author><author><name sortKey="Andrikovics, H" sort="Andrikovics, H" uniqKey="Andrikovics H" first="H" last="Andrikovics">H. Andrikovics</name><affiliation><nlm:aff id="aff11"><institution>Laboratory of Molecular Diagnostics, Hungarian National Blood Transfusion Service</institution>, Budapest,<country>Hungary</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff12"><institution>Department of Pathophysiology, Semmelweis University</institution>, Budapest,<country>Hungary</country></nlm:aff></affiliation></author><author><name sortKey="Anwar, J" sort="Anwar, J" uniqKey="Anwar J" first="J" last="Anwar">J. Anwar</name><affiliation><nlm:aff id="aff13"><institution>King's College Hospital London</institution>, London,<country>UK</country></nlm:aff></affiliation></author><author><name sortKey="Balatzenko, G" sort="Balatzenko, G" uniqKey="Balatzenko G" first="G" last="Balatzenko">G. Balatzenko</name><affiliation><nlm:aff id="aff14"><institution>National Specialized Hospital for Active Treatment of Hematological Diseases</institution>, Sofia,<country>Bulgaria</country></nlm:aff></affiliation></author><author><name sortKey="Bendit, I" sort="Bendit, I" uniqKey="Bendit I" first="I" last="Bendit">I. Bendit</name><affiliation><nlm:aff id="aff15"><institution>Laboratorio de Biologia Tumoral, Disciplina de Hematologia do HC-FMUSP</institution>, São Paulo,<country>Brazil</country></nlm:aff></affiliation></author><author><name sortKey="Beveridge, J" sort="Beveridge, J" uniqKey="Beveridge J" first="J" last="Beveridge">J. Beveridge</name><affiliation><nlm:aff id="aff16"><institution>PathWest Laboratory Medicine WA, Department of Haematology, Fiona Stanley Hospital</institution>, Perth, WA,<country>Australia</country></nlm:aff></affiliation></author><author><name sortKey="Boeckx, N" sort="Boeckx, N" uniqKey="Boeckx N" first="N" last="Boeckx">N. Boeckx</name><affiliation><nlm:aff id="aff17"><institution>Department of Laboratory Medicine, University Hospitals Leuven</institution>, Leuven,<country>Belgium</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff18"><institution>Department of Oncology, KUL</institution>, Leuven,<country>Belgium</country></nlm:aff></affiliation></author><author><name sortKey="Cerveira, N" sort="Cerveira, N" uniqKey="Cerveira N" first="N" last="Cerveira">N. Cerveira</name><affiliation><nlm:aff id="aff19"><institution>Department of Genetics, Portuguese Oncology Institute</institution>, Porto,<country>Portugal</country></nlm:aff></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><nlm:aff id="aff20"><institution>Department of Hematology and Oncology, Quest Diagnostics Nichols Institute</institution>, San Juan Capistrano, CA,<country>USA</country></nlm:aff></affiliation></author><author><name sortKey="Colomer, D" sort="Colomer, D" uniqKey="Colomer D" first="D" last="Colomer">D. Colomer</name><affiliation><nlm:aff id="aff21"><institution>Hematopathology Unit, Hospital Clinic, IDIBAPS</institution>, Barcelona,<country>Spain</country></nlm:aff></affiliation></author><author><name sortKey="Czurda, S" sort="Czurda, S" uniqKey="Czurda S" first="S" last="Czurda">S. Czurda</name><affiliation><nlm:aff id="aff22"><institution>Division of Molecular Microbiology, Children's Cancer Research Institute</institution>, Vienna,<country>Austria</country></nlm:aff></affiliation></author><author><name sortKey="Daraio, F" sort="Daraio, F" uniqKey="Daraio F" first="F" last="Daraio">F. Daraio</name><affiliation><nlm:aff id="aff23"><institution>Department of Clinical and Biological Sciences, San Luigi Hospital, University of Turin</institution>, Orbassano,<country>Italy</country></nlm:aff></affiliation></author><author><name sortKey="Dulucq, S" sort="Dulucq, S" uniqKey="Dulucq S" first="S" last="Dulucq">S. Dulucq</name><affiliation><nlm:aff id="aff24"><institution>Laboratoire Hematologie, Centre Hospitalier Universitaire de Bordeaux, Universite Bordeaux</institution>, Bordeaux,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Eggen, L" sort="Eggen, L" uniqKey="Eggen L" first="L" last="Eggen">L. Eggen</name><affiliation><nlm:aff id="aff25"><institution>Laboratory of Molecular Pathology, Oslo University Hospital</institution>, Oslo,<country>Norway</country></nlm:aff></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><nlm:aff id="aff26"><institution>Clinique de Genetique Oncologique-Service de genetique, Hopital Erasme</institution>, Brussels,<country>Belgium</country></nlm:aff></affiliation></author><author><name sortKey="Gerrard, G" sort="Gerrard, G" uniqKey="Gerrard G" first="G" last="Gerrard">G. Gerrard</name><affiliation><nlm:aff id="aff27"><institution>Imperial Molecular Pathology, Hammersmith Hospital</institution>, London,<country>UK</country></nlm:aff></affiliation></author><author><name sortKey="Gniot, M" sort="Gniot, M" uniqKey="Gniot M" first="M" last="Gniot">M. Gniot</name><affiliation><nlm:aff id="aff28"><institution>Department of Hematology and Bone Marrow Transplantation, Poznan University of Medical Sciences</institution>, Poznan,<country>Poland</country></nlm:aff></affiliation></author><author><name sortKey="Izzo, B" sort="Izzo, B" uniqKey="Izzo B" first="B" last="Izzo">B. Izzo</name><affiliation><nlm:aff id="aff29"><institution>Department of Clinical Medicine and Surgery, University ‘Federico II' of Naples</institution>, Naples,<country>Italy</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff30"><institution>CEINGE – Biotecnologie Avanzate</institution>, Naples,<country>Italy</country></nlm:aff></affiliation></author><author><name sortKey="Jacquin, D" sort="Jacquin, D" uniqKey="Jacquin D" first="D" last="Jacquin">D. Jacquin</name><affiliation><nlm:aff id="aff31"><institution>Genoptix, Inc.</institution>, Carlsbad, CA,<country>USA</country></nlm:aff></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><nlm:aff id="aff32"><institution>Department of Hematology and Molecular Diagnostics, VU University Medical Center</institution>, Amsterdam,<country>The Netherlands</country></nlm:aff></affiliation></author><author><name sortKey="Jeromin, S" sort="Jeromin, S" uniqKey="Jeromin S" first="S" last="Jeromin">S. Jeromin</name><affiliation><nlm:aff id="aff33"><institution>MLL Munich Leukemia Laboratory</institution>, Munich,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="Jurcek, T" sort="Jurcek, T" uniqKey="Jurcek T" first="T" last="Jurcek">T. Jurcek</name><affiliation><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></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><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></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><nlm:aff id="aff36"><institution>Department of Molecular Genetics, Institute of Hematology and Blood Transfusion</institution>, Prague,<country>Czech Republic</country></nlm:aff></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><nlm:aff id="aff37"><institution>Department of Hematology, Hospital Universitario 12 de Octubre, Universidad Complutense, CNIO</institution>, Madrid,<country>Spain</country></nlm:aff></affiliation></author><author><name sortKey="Mcbean, M" sort="Mcbean, M" uniqKey="Mcbean M" first="M" last="Mcbean">M. Mcbean</name><affiliation><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></affiliation></author><author><name sortKey="Mesanovic, S" sort="Mesanovic, S" uniqKey="Mesanovic S" first="S" last="Mesanovic">S. Mesanovic</name><affiliation><nlm:aff id="aff39"><institution>Pathology Department, University Clinical Center Tuzla</institution>, Tuzla,<country>Bosnia and Herzegovina</country></nlm:aff></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><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></affiliation></author><author><name sortKey="Mobtaker, H" sort="Mobtaker, H" uniqKey="Mobtaker H" first="H" last="Mobtaker">H. Mobtaker</name><affiliation><nlm:aff id="aff31"><institution>Genoptix, Inc.</institution>, Carlsbad, CA,<country>USA</country></nlm:aff></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><nlm:aff id="aff41"><institution>Departement de Biopathologie, Institut Paoli-Calmettes</institution>, Marseille,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Paji, T" sort="Paji, T" uniqKey="Paji T" first="T" last="Paji">T. Paji</name><affiliation><nlm:aff id="aff42"><institution>Specialized Haematology Laboratory, Department of Haematology, University Medical Centre Ljubljana</institution>, Ljubljana,<country>Slovenia</country></nlm:aff></affiliation></author><author><name sortKey="Pallisgaard, N" sort="Pallisgaard, N" uniqKey="Pallisgaard N" first="N" last="Pallisgaard">N. Pallisgaard</name><affiliation><nlm:aff id="aff43"><institution>Department of Surgical Pathology, Zealand University Hospital</institution>, Roskilde,<country>Denmark</country></nlm:aff></affiliation></author><author><name sortKey="Panagiotidis, P" sort="Panagiotidis, P" uniqKey="Panagiotidis P" first="P" last="Panagiotidis">P. Panagiotidis</name><affiliation><nlm:aff id="aff44"><institution>Hematology Unit, First Department of Internal Medicine, Laiko Hospital, University of Athens,</institution> Athens,<country>Greece</country></nlm:aff></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><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></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><nlm:aff id="aff46"><institution>Peking University People's Hospital, Peking University Institute of Hematology</institution>, Beijing,<country>China</country></nlm:aff></affiliation></author><author><name sortKey="Radich, J" sort="Radich, J" uniqKey="Radich J" first="J" last="Radich">J. Radich</name><affiliation><nlm:aff id="aff47"><institution>Fred Hutchinson Cancer Research Center</institution>, Seattle, WA,<country>USA</country></nlm:aff></affiliation></author><author><name sortKey="Sacha, T" sort="Sacha, T" uniqKey="Sacha T" first="T" last="Sacha">T. Sacha</name><affiliation><nlm:aff id="aff48"><institution>Chair and Department of Hematology, Jagiellonian University</institution>, Kraków,<country>Poland</country></nlm:aff></affiliation></author><author><name sortKey="Touloumenidou, T" sort="Touloumenidou, T" uniqKey="Touloumenidou T" first="T" last="Touloumenidou">T. Touloumenidou</name><affiliation><nlm:aff id="aff49"><institution>Laboratory of Molecular Biology, Hematology Department and HCT Unit, G. Papanicolaou Hospital</institution>, Thessaloniki,<country>Greece</country></nlm:aff></affiliation></author><author><name sortKey="Waits, P" sort="Waits, P" uniqKey="Waits P" first="P" last="Waits">P. Waits</name><affiliation><nlm:aff id="aff50"><institution>Bristol Genetics Laboratory</institution>, Bristol,<country>UK</country></nlm:aff></affiliation></author><author><name sortKey="Wilkinson, E" sort="Wilkinson, E" uniqKey="Wilkinson E" first="E" last="Wilkinson">E. Wilkinson</name><affiliation><nlm:aff id="aff51"><institution>HMDS, Leeds Teaching Hospitals</institution>, Leeds,<country>UK</country></nlm:aff></affiliation></author><author><name sortKey="Zadro, R" sort="Zadro, R" uniqKey="Zadro R" first="R" last="Zadro">R. Zadro</name><affiliation><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></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><nlm:aff id="aff5"><institution>III. Medizinische Klinik, Medizinische Fakultät Mannheim, Universität Heidelberg</institution>, Mannheim,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="Hochhaus, A" sort="Hochhaus, A" uniqKey="Hochhaus A" first="A" last="Hochhaus">A. Hochhaus</name><affiliation><nlm:aff id="aff3"><institution>Department of Hematology/Oncology, Universitätsklinikum Jena</institution>, Jena,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="Branford, S" sort="Branford, S" uniqKey="Branford S" first="S" last="Branford">S. Branford</name><affiliation><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></affiliation><affiliation><nlm:aff id="aff53"><institution>School of Pharmacy and Medical Science, University of South Australia</institution>, Adelaide, SA,<country>Australia</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff54"><institution>School of Medicine, University of Adelaide</institution>, SA, Adelaide,<country>Australia</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff55"><institution>School of Molecular and Biomedical Science, University of Adelaide</institution>, Adelaide, SA,<country>Australia</country></nlm:aff></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><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct></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 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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><body><sec><title>Introduction</title><p>The development of <italic>BCR-ABL1</italic> tyrosine kinase inhibitors, from the first-generation imatinib to newer agents such as nilotinib and dasatinib, has enabled progressively deeper molecular responses in chronic myeloid leukemia (CML) patients undergoing tyrosine kinase inhibitor therapy.<sup><xref ref-type="bibr" rid="bib1">1</xref>, <xref ref-type="bibr" rid="bib2">2</xref></sup> Deeper molecular responses are defined as <italic>BCR-ABL1</italic> levels of ⩽0.01% (MR<sup>4</sup>) and ⩽0.0032% (MR<sup>4.5</sup>) on the international reporting scale (International Scale (IS)) and are important milestones for patients considering treatment cessation.<sup><xref ref-type="bibr" rid="bib3">3</xref></sup> Other landmarks on the IS also represent different treatment decision thresholds and prognostic outcomes.<sup><xref ref-type="bibr" rid="bib4">4</xref></sup> For example, patients who reach 10% IS or below at 3 months after treatment have significantly higher rates of MR<sup>4.5</sup> by 5 years,<sup><xref ref-type="bibr" rid="bib5">5</xref></sup> and reaching 0.1% IS (major molecular response) by 12 months of treatment is predictive of subsequently achieving undetectable <italic>BCR-ABL1</italic> levels.<sup><xref ref-type="bibr" rid="bib6">6</xref></sup> Thus, regular molecular monitoring using real-time reverse-transcription quantitative PCR (RT-qPCR) is recommended for optimal disease management, and treatment decisions rely on achieving milestone molecular responses in the first year of therapy and beyond.<sup><xref ref-type="bibr" rid="bib2">2</xref>, <xref ref-type="bibr" rid="bib7">7</xref></sup></p><p>As treatment decisions are directly impacted by test results, accuracy and precision of <italic>BCR-ABL1</italic> assays across the entire measurement range is crucial for patient management, especially in patients with deep molecular responses when considering possible treatment cessation. It is well known that high variability exists between RT-qPCR methods used in different laboratories.<sup><xref ref-type="bibr" rid="bib8">8</xref>, <xref ref-type="bibr" rid="bib9">9</xref></sup> The first international standardization attempt occurred in 2003, when different <italic>BCR-ABL1</italic> assays used in the International Randomised Study of Interferon versus STI571 (IRIS) trial established IS based on 30 CML patient samples.<sup><xref ref-type="bibr" rid="bib10">10</xref></sup> Subsequently, a process for establishing a test-specific IS conversion factor (CF) by exchanging 20–30 CML patient samples with a reference laboratory was developed.<sup><xref ref-type="bibr" rid="bib11">11</xref></sup> Although this process works well for laboratories with tests that show good stability over time, it is time consuming, expensive and difficult to access for smaller laboratories.<sup><xref ref-type="bibr" rid="bib12">12</xref>, <xref ref-type="bibr" rid="bib13">13</xref></sup></p><p>In 2010, the ‘first International Genetic Reference Panel for quantitation of <italic>BCR-ABL</italic> mRNA' was developed as a primary standard for <italic>BCR-ABL1</italic> assay IS calibration and accredited by the World Health Organization (WHO).<sup><xref ref-type="bibr" rid="bib14">14</xref></sup> The WHO panel is made of lyophilized K562 and HL-60 cell line mixtures, which allows the inclusion of cellular RNA extraction in the IS calibration against the two major <italic>BCR-ABL1</italic> breakpoints (e13a2 and e14a2) and carries three sets of nominal %BCR-ABL1 values using <italic>ABL1</italic>, <italic>BCR</italic> and <italic>GUSB</italic> as reference genes. Owing to restricted access, the WHO panel is currently only available to manufacturers of <italic>BCR-ABL1</italic> test kits and secondary standards.<sup><xref ref-type="bibr" rid="bib13">13</xref></sup> The commercial secondary standards available to date are made of RNA;<sup><xref ref-type="bibr" rid="bib15">15</xref>, <xref ref-type="bibr" rid="bib16">16</xref></sup> thus, RNA extraction is not included in the IS calibration process, except when the standards are artificially spiked into the cell samples. Furthermore, none of these are calibrated to the WHO panel against all three reference genes.</p><p>In this study, we describe the successful development of the first cell-based <italic>BCR-ABL1</italic> secondary reference panel that is traceable to and faithfully replicates the WHO panel in both raw materials (lyophilized K562 and HL-60 cell mixes) and manufacturing process, with the addition of a MR<sup>4.5</sup> level. Nominal %BCR-ABL1 IS values were assigned to the secondary panel using reverse-transcription droplet digital PCR (RT-ddPCR) against <italic>ABL1</italic>, <italic>BCR</italic> and <italic>GUSB</italic>. The secondary panel was successfully evaluated by 45 different <italic>BCR-ABL1</italic> assays in a subsequent international multi-center evaluation study.</p></sec><sec><title>Materials and methods</title><sec><title>Manufacturing and IS calibration of secondary reference panel</title><p>K562 (ATCC CCL-243) and HL-60 cells (ATCC CCL-240) (American Type Culture Collection, Manassas, VA, USA) were cultured, mixed and lyophilized following methods described by White <italic>et al.</italic><sup><xref ref-type="bibr" rid="bib14">14</xref></sup> with minor modifications (<xref ref-type="supplementary-material" rid="sup1">Supplementary Information</xref>). Calibration to the WHO standards was performed as described.<sup><xref ref-type="bibr" rid="bib14">14</xref></sup> IS calibration using <italic>ABL1</italic> as a reference gene was conducted using 10 sets of WHO ‘first International Genetic Reference Panel for quantitation of BCR-ABL mRNA' panels (National Institute for Biological Standards and Control, South Mimms, UK). Calibration using <italic>BCR</italic> and <italic>GUSB</italic> was conducted in a second study using another 10 sets of WHO panels. On each day of 10 non-consecutive days, 1 WHO panel and 2–3 secondary panels were tested using RT-ddPCR in 4 replicates for the MR<sup>1</sup> (10% BCR-ABL<sup>IS</sup>) to MR<sup>4</sup> (0.01% BCR-ABL<sup>IS</sup>) samples and in 8 replicates for the MR<sup>4.5</sup> (0.0032% BCR-ABL<sup>IS</sup>) sample, to enhance assay precision. Data analysis was performed using the statistical methods described by White <italic>et al.</italic><sup><xref ref-type="bibr" rid="bib14">14</xref></sup></p></sec><sec><title>Reverse-transcription droplet digital PCR</title><p>RNA extraction from the secondary panel was performed using RNeasy mini kits (Qiagen, Hilden, Germany). Reverse transcription was performed using ABI High Capacity cDNA reverse-transcription kit (Thermo Fisher Scientific, Waltham, MA, USA) and ddPCR was performed using 2X ddPCR Supermix (Bio-Rad, Hercules, CA, USA) on the QX-100 or QX-200 ddPCR system (Bio-Rad). All primer and probe sequences are listed in <xref rid="tbl1" ref-type="table">Table 1</xref>. <italic>BCR-ABL1</italic> and reference genes were run as singleplex reactions in separate wells. To achieve optimal assay precision and avoid signal saturation, cDNA input for <italic>BCR-ABL1</italic> per 20 μl reaction was 80 ng for the MR<sup>1</sup> sample, 400 ng for the MR<sup>2</sup> sample and 675 ng for samples ⩽MR<sup>3</sup>. cDNA input for reference genes was 10 ng per 20 μl reaction for all three reference genes. For each RT-ddPCR run, wells with >9025 accepted droplets were considered valid as per the manufacturer's recommendations.</p></sec></sec><sec><title>Results</title><sec><title>Manufacturing and IS calibration of the WHO <italic>BCR-ABL1</italic> secondary reference panel</title><p>We successfully manufactured >12 000 vials of secondary <italic>BCR-ABL1</italic> lyophilized cell reference panel, using the same K562 and HL-60 cell lines and following similar manufacturing procedures as the primary WHO panel (<xref ref-type="supplementary-material" rid="sup1">Supplementary Information</xref>).<sup><xref ref-type="bibr" rid="bib14">14</xref></sup> An MR<sup>4.5</sup> level was added to the secondary panel, to enable more accurate IS calibration at this critical level, as CML patients reaching this deep molecular response are increasingly being considered for treatment cessation. Quality-control assessments indicated that the secondary panel had minimal residual moisture, excellent vial-to-vial homogeneity and >2.5 years of real-time stability (<xref ref-type="supplementary-material" rid="sup1">Supplementary Information</xref>).</p><p>To calibrate the secondary panel to the WHO ‘first International Genetic Reference Panel for quantitation of <italic>BCR-ABL1</italic> mRNA', we followed the study design described by White <italic>et al.</italic>,<sup><xref ref-type="bibr" rid="bib14">14</xref></sup> except that the sample size was doubled to strengthen the statistical power (<xref ref-type="supplementary-material" rid="sup1">Supplementary Information</xref>). RT-ddPCR was chosen as the calibration method, owing to its superior sensitivity, precision and absolute quantification capability compared with RT-qPCR.<sup><xref ref-type="bibr" rid="bib17">17</xref>, <xref ref-type="bibr" rid="bib18">18</xref></sup> At the time of this study, no commercially available <italic>BCR-ABL1</italic> test used <italic>BCR</italic> or <italic>GUSB</italic> as reference genes. We developed three sets of RT-ddPCR assays, including <italic>BCR-ABL1/ABL1</italic>, <italic>BCR-ABL1/BCR</italic> and <italic>BCR-ABL1/GUSB</italic>, to enable IS calibration of the secondary panel against all three reference genes. All RT-ddPCR assays were validated following a combination of industry best practices, Minimum Information for Publication of Quantitative Real-Time PCR Experiments guideline, and Clinical and Laboratory Standards Institute guideline, to ensure proper accuracy, precision, sensitivity and linearity were achieved (<xref ref-type="supplementary-material" rid="sup1">Supplementary Information</xref>).<sup><xref ref-type="bibr" rid="bib19">19</xref>, <xref ref-type="bibr" rid="bib20">20</xref>, <xref ref-type="bibr" rid="bib21">21</xref>, <xref ref-type="bibr" rid="bib22">22</xref></sup> Using methods described by White <italic>et al.</italic>,<sup><xref ref-type="bibr" rid="bib14">14</xref></sup> we determined the IS CF for the RT-ddPCR assays to be 0.93 for <italic>BCR-ABL1/ABL1</italic>, 1.85 for <italic>BCR-ABL1/BCR</italic> and 1.28 for <italic>BCR-ABL1/GUSB</italic>.</p><p>Each CF was subsequently applied to the empirical %BCR-ABL1 of the secondary panel measured by RT-ddPCR, to obtain the assigned %BCR-ABL1<sup>IS</sup> values (<xref ref-type="fig" rid="fig1">Figure 1</xref> and <xref rid="tbl2" ref-type="table">Table 2a</xref>). We found that the mean %BCR-ABL1 for each level of the secondary panel met all targeted <italic>BCR-ABL1</italic> levels and were within 1.3-fold of the WHO standards values. The assigned %BCR-ABL1<sup>IS</sup> of level E was 0.0038%, 0.0050% and 0.0029% for <italic>ABL1</italic>, <italic>BCR</italic> and <italic>GUSB</italic>, respectively, indicating that an MR<sup>4.5</sup> level was successfully created. Moreover, the mean copy number of <italic>BCR-ABL1</italic>, <italic>ABL1</italic>, <italic>BCR</italic> and <italic>GUSB</italic> per ng of RNA measured using RT-ddPCR was highly similar between the WHO and secondary panels (<xref rid="tbl2" ref-type="table">Table 2b</xref>). This demonstrated that the secondary panel replicated the primary WHO panel faithfully, with the successful addition of an MR<sup>4.5</sup> level.</p></sec><sec><title>Laboratory evaluation of the WHO <italic>BCR-ABL1</italic> secondary reference panel</title><sec><title>Study design</title><p>The secondary panel was sent to 44 clinical laboratories from 24 countries worldwide for evaluation, including 34 laboratories from Europe (<xref ref-type="supplementary-material" rid="sup1">Supplementary Table 2</xref>). One laboratory tested the panel with two different <italic>BCR-ABL1</italic> assays, resulting in a total of 45 <italic>BCR-ABL1</italic> tests included in this report. The laboratories were asked to conduct two studies with the secondary panel. In Study 1, to determine the optimal sample input of the secondary panel specific for each <italic>BCR-ABL1</italic> test, a standard curve experiment was run with Vial A (MR<sup>1</sup>) and Vial C (MR<sup>3</sup>) of the panel using 50, 100, 200 and 400 ng of RNA (for one-step assays) or cDNA (for two-step assays) input per PCR reaction; three replicates were run per sample at each input level (<xref ref-type="fig" rid="fig2">Figures 2a and b</xref>). In Study 2, to assess the usability of the secondary panel and performance of the <italic>BCR-ABL1</italic> tests, laboratories used the optimal sample input determined in Study 1 to test three sets of the panel on six different days (<xref ref-type="fig" rid="fig2">Figure 2c</xref>).</p></sec><sec><title>Study 1: sample input optimization</title><p>The WHO panel did not offer recommendations on sample input for IS calibration. Nonetheless, sample input outside of the linear dynamic range of a RT-qPCR assay might potentially lead to inaccurate results. Thus, we designed a standard curve experiment to help laboratories determine the optimal sample input of the secondary panel for their <italic>BCR-ABL1</italic> tests (<xref ref-type="fig" rid="fig2">Figures 2a and b</xref>). Surprisingly, approximately half of the tests showed different %BCR-ABL1 results against different sample inputs of the same sample (<italic>P</italic><0.05), even when data from either the highest or lowest sample input were allowed to be removed based on auxiliary-pick-regression analysis (<xref ref-type="fig" rid="fig3">Figure 3</xref> and <xref ref-type="supplementary-material" rid="sup1">Supplementary Information</xref>). Among the 42 assays that tested Vial A (MR<sup>1</sup>), 29% (12 of 42) showed decreasing %BCR-ABL1 with increasing sample input (<xref ref-type="fig" rid="fig3">Figure 3d</xref>) and 24% (10 of 42) showed increasing %BCR-ABL1 (<xref ref-type="fig" rid="fig3">Figure 3g</xref> and <xref ref-type="supplementary-material" rid="sup1">Supplementary Figure 2</xref>). Among the 45 assays that tested Vial C (MR<sup>3</sup>), 22% (10 of 45) showed decreasing %BCR-ABL1 with increasing sample input (<xref ref-type="fig" rid="fig3">Figure 3d</xref>) and 18% (8 of 45) showed increasing %BCR-ABL1 (<xref ref-type="fig" rid="fig3">Figure 3g</xref> and <xref ref-type="supplementary-material" rid="sup1">Supplementary Figure 3</xref>).</p><p>In this study, we observed that the mean standard deviation (s.d.) in %BCR-ABL1 measurements from all 45 assays was 0.2log, which was mathematically equivalent to a 1.6-fold difference in the linear scale. Based on recommendations by Thiers <italic>et al.</italic>,<sup><xref ref-type="bibr" rid="bib23">23</xref></sup> 1 s.d. (0.2log) was considered the optimal cutoff value for determining differences in measurements in this study. Selecting 1 s.d. as the cutoff value took into consideration the fact that a <1-s.d. cutoff value would require a substantially larger sample size to be considered statistically robust, whereas >1 s.d. would increase the number of misclassifications.<sup><xref ref-type="bibr" rid="bib23">23</xref></sup> Thus, in this study, a mean difference of ⩾0.2log in %BCR-ABL1 value at different sample inputs by the same test was considered as beyond the inherent variability of an assay. We found that among the assays that showed changing %BCR-ABL1 against different sample inputs, 55% (12 of 22) at MR<sup>1</sup> and 78% (14 of 18) at MR<sup>3</sup> obtained results with ⩾0.2log difference. Overall, these results showed that some <italic>BCR-ABL1</italic> tests were nonlinear and might therefore yield statistically different %BCR-ABL1 results against different sample inputs. To mitigate the risk of inaccurate %BCR-ABL1 measurements from using an inappropriate sample input, it is highly recommended that laboratories standardize CML patient sample inputs by quantifying the extracted RNA before performing RT-qPCR.</p><p>To further investigate the cause of the unstable %BCR-ABL1 measurements across different sample inputs, we calculated the PCR efficiency and efficiency ratio for each individual <italic>BCR-ABL1</italic> and reference gene assay using the formula ‘Efficiency=−1+10<sup>(−1/slope)</sup>' (<xref ref-type="supplementary-material" rid="sup1">Supplementary Information</xref>).<sup><xref ref-type="bibr" rid="bib24">24</xref></sup> A well-optimized PCR assay should have PCR efficiency between 0.9 and 1.1,<sup><xref ref-type="bibr" rid="bib25">25</xref></sup> which would result in a PCR efficiency ratio of ~1 between the <italic>BCR-ABL1</italic> and reference gene assays. Indeed, we found that most assays that successfully achieved stable %BCR-ABL1 across different sample inputs had a PCR efficiency close to 1 for both the <italic>BCR-ABL1</italic> and reference gene assays, resulting in a mean efficiency ratio of 1.03 (<italic>n</italic>=43; abnormal efficiency ratios of <0 and >10 were excluded from the analysis) (<xref ref-type="fig" rid="fig3">Figures 3a–c</xref>). Assays that showed decreasing %BCR-ABL1 against increasing sample input had a mean PCR efficiency ratio of 1.51 (<italic>n</italic>=20) (<xref ref-type="fig" rid="fig3">Figures 3d–f</xref>), whereas assays that showed increasing %BCR-ABL1 had a mean PCR efficiency ratio of 0.63 (<italic>n</italic>=16) (<xref ref-type="fig" rid="fig3">Figures 3g–i</xref>). This indicated that the lack of stability in %BCR-ABL1 against sample input was directly correlated with suboptimal PCR efficiency. Surprisingly, <italic>BCR-ABL1</italic> and reference gene assays that were suboptimal in a similar manner could artificially cancel each other's defects to achieve artificially stable %BCR-ABL1 results (<xref ref-type="fig" rid="fig3">Figures 3j–l</xref>). Overall, these results illustrated that both the <italic>BCR-ABL1</italic> and reference gene assays needed to be properly optimized and validated, in order to achieve good quality %BCR-ABL1 testing.<sup><xref ref-type="bibr" rid="bib26">26</xref>, <xref ref-type="bibr" rid="bib27">27</xref>, <xref ref-type="bibr" rid="bib28">28</xref></sup></p><p>As different assays had different linear dynamic ranges, we observed a >30-fold range of optimal sample input for the secondary panel calculated for the different <italic>BCR-ABL1</italic> tests. Interestingly, among the 31 laboratories that routinely quantified their CML patient sample inputs, the reported patient sample input was on average 2.4-fold higher than the calculated optimal input of the secondary panel, after two extreme outlier values of 11.6- and 48.3-fold were identified using robust regression analysis and excluded from the calculation (<xref ref-type="supplementary-material" rid="sup1">Supplementary Information</xref>). This was concordant with the fact that although the mean copy number of <italic>ABL1</italic>, <italic>BCR</italic> and <italic>GUSB</italic> per ng of RNA in the secondary panel was 674, 1028 and 1245 (<xref rid="tbl2" ref-type="table">Table 2b</xref>), the mean copy per ng of human EDTA anticoagulated blood RNA was only 289 for <italic>ABL1</italic> (<italic>n</italic>=40), 750 for <italic>BCR</italic> (<italic>n</italic>=6) and 420 for <italic>GUSB</italic> (<italic>n</italic>=5) (data not shown). These results indicated that the optimal sample input of the secondary panel was approximately half of the patient sample input typically used by the laboratory in terms of ng RNA or cDNA. Thus, when using the secondary panel, laboratories might consider using twofold less cDNA input per PCR reaction compared with CML patient samples, to achieve similar copy numbers and avoid exceeding the linear dynamic range of their assay. Nonetheless, it is recommended that laboratories perform a similar standard curve experiment to identify the optimal sample input specific for their assay before using the secondary panel for the first time. The optimized sample input should maximize copy number detection but minimize potential PCR inhibition caused by carryover from the reverse-transcription reactions.</p></sec><sec><title>Study 2: performance of clinical BCR-ABL1 tests on the secondary panel</title><p>A robust <italic>BCR-ABL1</italic> test should demonstrate good IS accuracy, precision and sensitivity within statistical limits, especially at the lower disease levels. In Study 2, laboratories were asked to use the optimal sample input determined in Study 1 to test three sets of the secondary panel on six different days, following the design previously used by White <italic>et al.</italic> (<xref ref-type="fig" rid="fig2">Figure 2c</xref>).<sup><xref ref-type="bibr" rid="bib14">14</xref></sup> Results from each assay were subsequently analyzed to assess accuracy, precision and sensitivity. For IS accuracy, the overall mean %BCR-ABL1 from all 45 assays, calculated using robust regression analysis to minimize effects of outliers, were highly concordant with the assigned values of the secondary panel (<xref rid="tbl3" ref-type="table">Table 3</xref> and <xref ref-type="supplementary-material" rid="sup1">Supplementary Figure 5</xref>). The mean ratios for all reference genes at all levels were within 1.5-fold or 0.16log of the panel's assigned values, with the exception of Vial D (MR<sup>4</sup>) for <italic>GUSB</italic>, which differed by 1.7-fold/0.24log. For results from individual assays, 60% (27 of 45) obtained mean %BCR-ABL1 within twofold of the panel's assigned values at all levels (<xref ref-type="supplementary-material" rid="sup1">Supplementary Figure 5</xref>). The observed concordance was most likely due to three factors. First, optimal sample input calculated in Study 1 was used for each assay, thus restricting the PCR reactions within the assay's linear dynamic range. Second, even though many different assay configurations were used by the laboratories (<xref ref-type="supplementary-material" rid="sup1">Supplementary Table 2</xref>), 60% (27 of 45) followed the EAC recommendations for the PCR primer design<sup><xref ref-type="bibr" rid="bib26">26</xref></sup> and 18% (8 of 45) used commercial <italic>BCR-ABL1</italic> kits (<xref ref-type="supplementary-material" rid="sup1">Supplementary Table 2</xref> and <xref ref-type="supplementary-material" rid="sup1">Supplementary Figure 5</xref>), which are generally well optimized and validated. Lastly, 51% (23 of 45) of assays were IS calibrated via sample exchange with the reference laboratory in Mannheim, Germany, and 20% (9 of 45) with Adelaide, Australia. This demonstrated that <italic>BCR-ABL1</italic> tests can be effectively harmonized by using the same PCR primer designs and by standardizing the IS calibration process. Thus, commercial availability of a common IS reference material could contribute to worldwide IS standardization.</p><p>Most clinical samples are typically run in only one or two replicates, which requires a high degree of assay precision to ensure accuracy of each of the final <italic>BCR-ABL1</italic> test results. To enable ⩾95% confidence for the true value of a CML patient sample to be within 0.5log on each side of the measured value, an s.d. of ⩽0.25log for the <italic>BCR-ABL1</italic> test is required. Accordingly, if a sample is measured at MR<sup>4.5</sup>, there will be ⩾95% confidence that the true value of the sample is not above MR<sup>4</sup> or below MR<sup>5</sup>.<sup><xref ref-type="bibr" rid="bib29">29</xref></sup> We calculated the intra-lab s.d. for each <italic>BCR-ABL1</italic> test and noted that 84% (38 of 45) successfully achieved an s.d. of ⩽0.25 log from MR<sup>1</sup> to MR<sup>4</sup>. For <italic>BCR-ABL1</italic> tests that obtained >0.25log s.d., precision may be improved by performing further assay optimization and increasing the number of replicates per patient sample.<sup><xref ref-type="bibr" rid="bib28">28</xref>, <xref ref-type="bibr" rid="bib30">30</xref></sup></p><p>For monitoring deep molecular response, good <italic>BCR-ABL1</italic> assay sensitivity and precision are key performance characteristics. In Study 2, we found that 93% (42 of 45) assays successfully detected all replicates at MR<sup>4</sup> and 76% (34 of 45) detected all replicates at MR<sup>4.5</sup>. To further understand how sample input affected assay sensitivity and precision, we analyzed results from the 32 <italic>ABL1</italic> assays, as this provided the largest sample size. Among the <italic>ABL1</italic> assays, 56% (18 of 32) detected all replicates at MR<sup>4.5</sup> and achieved ⩽0.25log s.d., 19% (6 of 32) detected all replicates but had >0.25log s.d. and 25% (8 of 32) assays had at least 1 undetected replicate. Logistic regression analysis showed a strong positive correlation between increased sample input and increased detection rate (<italic>P</italic>=0.001). In addition, the median <italic>ABL1</italic> copy number per PCR reaction was 98 202 for laboratories that achieved good detection rate and precision, 74 923 for those that achieved good detection rate but suboptimal precision and 29 717 for those that had undetected replicates at MR<sup>4.5</sup>, further illustrating that an increased sample input could improve the sensitivity and precision of MR<sup>4.5</sup> detection.</p><p>The laboratories that participated in this study used diverse assay configurations for <italic>BCR-ABL1</italic> testing (<xref ref-type="supplementary-material" rid="sup1">Supplementary Table 2</xref>). To determine whether assay configurations affected assay performance in terms of IS accuracy, precision and sensitivity, we performed Bayesian average analysis and found no statistically significant relationship between assay performance versus choice of reference gene, RNA extraction method and the usage of commercial versus laboratory-developed tests. Interestingly, among the assays that successfully achieved good accuracy (within twofold of assigned values), good precision (⩽0.25log s.d.) and good MR<sup>4.5</sup> sensitivity (no undetected replicate), 82% (14 of 17) showed stable %BCR-ABL1 measurements against sample inputs at MR<sup>3</sup> in Study 1, compared with 46% (13 of 28) among assays with less optimal assay performance. This illustrated that although <italic>BCR-ABL1</italic> assays of different designs can perform equally well, proper PCR optimization is required to ensure good clinical performance. Interestingly, the number of assays that achieved good precision (84%) and MR<sup>4.5</sup> sensitivity (76%) exceeded the number that achieved good IS accuracy (60%), indicating that there remains an unmet need for a simple and broadly available IS calibration mechanism.</p></sec><sec><title>Calculating WHO IS CF from the secondary panel</title><p>Using the assigned <italic>BCR-ABL1</italic> IS values of the secondary panel, it was possible to calculate an IS CF traceable to the WHO panel for each test. Before CF calculation, Bland–Altman analysis was performed for each assay as described by White <italic>et al.</italic>,<sup><xref ref-type="bibr" rid="bib14">14</xref></sup> to assess whether bias was linear across the %BCR-ABL1 range. Of all the assays, 69% (31 of 45) showed no statistically significant trend in the Bland–Altman analysis, indicating that a valid CF could be calculated for these assays and compared with the laboratory's current CF, most of which were obtained from sample exchange. Mathematically, when the ratio between the assay's current CF and the CF calculated from the secondary panel is <0.63 or >1.58, the resulting %BCR-ABL1 values will have a >0.2log difference (<xref ref-type="supplementary-material" rid="sup1">Supplementary Information</xref>). Among the 31 assays, 58% (18 of 31) achieved a CF ratio between 0.63 and 1.58, indicating that their current CF was equivalent to the CF from the secondary panel. This was concordant with the fact that 60% of assays obtained mean %BCR-ABL1 within twofold of the panel's assigned values. This also indicated that the secondary panel can be effectively used to obtain IS CFs equivalent to sample exchange.</p></sec></sec></sec><sec><title>Discussions</title><p>In this study, we successfully created the first cell-based <italic>BCR-ABL1</italic> secondary reference panel that faithfully replicated the WHO <italic>BCR-ABL1</italic> International Genetic Reference Panel in both raw material and manufacturing methods,<sup><xref ref-type="bibr" rid="bib14">14</xref></sup> with an additional MR<sup>4.5</sup> level. The secondary panel was manufactured under Good Manufacturing Practice and confirmed to have low residual moisture content, vial-to-vial homogeneity and >2.5-year stability. <italic>BCR-ABL1</italic> IS values traceable to the WHO panel were assigned to the secondary panel using RT-ddPCR against <italic>ABL1</italic>, <italic>BCR</italic> and <italic>GUSB</italic>. Both the assigned IS values and absolute copy numbers of the secondary panel were found to be highly concordant with the primary WHO standards.</p><p>Many of the 44 laboratories that participated in the secondary panel evaluation currently act as a national reference laboratory for their country. The panel was successfully processed by all laboratories, indicating that it is compatible with many different <italic>BCR-ABL1</italic> test configurations. Through a standard curve experiment, we found that close to half of the tests showed signs of inadequate PCR optimization such as poor linearity against different sample inputs and suboptimal PCR efficiency. Interestingly, when a customized optimal sample input was used, 60% (27 of 45) of assays achieved mean %BCR-ABL1 values within twofold of the panel's assigned values, 84% (38 of 45) achieved good precision (⩽ 0.25log s.d.) from MR<sup>1</sup> to MR<sup>4</sup> and 76% (34 of 45) achieved 100% detection rate down to MR<sup>4.5</sup>. Three factors probably contributed to these excellent results: usage of a validated optimized sample input specific to the assay, the fact that 78% (35 of 45) assays used either the EAC primer design or a commercial kit and that 71% (32 of 45) assays were IS calibrated via sample exchange with one of the two major international reference centers. This indicated that using published assay designs and a harmonized IS calibration approach may lead to <italic>BCR-ABL1</italic> test standardization. Nonetheless, we noted that the number of assays that achieved good precision and sensitivity exceeded the number that achieved good IS accuracy, indicating that there remains an unmet need for a simple and broadly available calibration mechanism, such as this secondary panel, to ensure IS accuracy is maintained in laboratories over time.</p><p>We also showed that different assay designs including different reference genes, RNA extraction methods and usage of commercial kits versus laboratory-developed tests did not affect assay performance. Nonetheless, better PCR optimization correlated with better assay performance and increased sample input improved detection rate and precision at MR<sup>4.5</sup>. In addition to being a reference sample for IS calibration,<sup><xref ref-type="bibr" rid="bib14">14</xref></sup> the secondary reference material and its derivatives could also be used in assay analytical validation and optimization. For example, it can be used as standardized samples in External Quality Assessment programs for proficiency testing,<sup><xref ref-type="bibr" rid="bib31">31</xref></sup> especially as nominal values (that is, correct answers) are available for each member of the panel. Second, it can become a source of positive control samples to be run alongside patient samples for quality assurance. This can become especially powerful when multiple laboratories participate in a peer group quality-control monitoring program, in which results from such positive control samples are compared and monitored regularly. Lastly, the MR<sup>4.5</sup> sample in the reference panel can be used to validate the sensitivity and MR<sup>4.5</sup> detection capability of an assay.</p><p>In conclusion, a secondary reference panel traceable to the WHO panel with an additional MR<sup>4.5</sup> level can provide easier access to IS calibration, as well as act as a tool for assay optimization, validation and quality assurance.</p></sec></body><back><ack><p>We thank Dr James Garrett (Novartis Pharmaceuticals Corporation) for assisting with the biostatistical analysis in this report and Dr Nancy Krunic (Novartis Pharmaceuticals Corporation) for reviewing and providing editorial assistance with this manuscript.</p></ack><fn-group><fn><p><xref ref-type="supplementary-material" rid="sup1">Supplementary Information</xref> accompanies this paper on the Leukemia website (http://www.nature.com/leu)</p></fn><fn fn-type="COI-statement"><p>This study was designed and funded by Novartis Pharmaceuticals Corporation. CW, DZ, SW and SSW are employed by Novartis Pharmaceuticals Corporation. None of the co-authors, participating laboratories or institutions received any payments for participating in this study. All authors have read and agreed with the contents of the manuscript. 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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></record>Pour manipuler ce document sous Unix (Dilib)
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