Multicentre comparison of a diagnostic assay: aquaporin-4 antibodies in neuromyelitis optica

Patrick Waters, Markus Reindl, Albert Saiz, Kathrin Schanda, Friederike Tuller, Vlastimil Kral, Petra Nytrova, Ondrej Sobek, Helle Hvilsted Nielsen, Torben Barington, Søren T Lillevang, Zsolt Illes, Kristin Rentzsch, Achim Berthele, Tímea Berki, Letizia Granieri, Antonio Bertolotto, Bruno Giometto, Luigi Zuliani, Dörte HamannE Daniëlle van Pelt, Rogier Hintzen, Romana Höftberger, Carme Costa, Manuel Comabella, Xavier Montalban, Mar Tintoré, Aksel Siva, Ayse Altintas, Günnur Deniz, Mark Woodhall, Jacqueline Palace, Friedemann Paul, Hans-Peter Hartung, Orhan Aktas, Sven Jarius, Brigitte Wildemann, Christian Vedeler, Anne Ruiz, M Isabel Leite, Peter Trillenberg, Monika Probst, Sandra Saschenbrecker, Angela Vincent, Romain Marignier

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

OBJECTIVE: Antibodies to cell surface central nervous system proteins help to diagnose conditions which often respond to immunotherapies. The assessment of antibody assays needs to reflect their clinical utility. We report the results of a multicentre study of aquaporin (AQP) 4 antibody (AQP4-Ab) assays in neuromyelitis optica spectrum disorders (NMOSD).

METHODS: Coded samples from patients with neuromyelitis optica (NMO) or NMOSD (101) and controls (92) were tested at 15 European diagnostic centres using 21 assays including live (n=3) or fixed cell-based assays (n=10), flow cytometry (n=4), immunohistochemistry (n=3) and ELISA (n=1).

RESULTS: Results of tests on 92 controls identified 12assays as highly specific (0-1 false-positive results). 32 samples from 50 (64%) NMO sera and 34 from 51 (67%) NMOSD sera were positive on at least two of the 12 highly specific assays, leaving 35 patients with seronegative NMO/spectrum disorder (SD). On the basis of a combination of clinical phenotype and the highly specific assays, 66 AQP4-Ab seropositive samples were used to establish the sensitivities (51.5-100%) of all 21 assays. The specificities (85.8-100%) were based on 92 control samples and 35 seronegative NMO/SD patient samples.

CONCLUSIONS: The cell-based assays were most sensitive and specific overall, but immunohistochemistry or flow cytometry could be equally accurate in specialist centres. Since patients with AQP4-Ab negative NMO/SD require different management, the use of both appropriate control samples and defined seronegative NMOSD samples is essential to evaluate these assays in a clinically meaningful way. The process described here can be applied to the evaluation of other antibody assays in the newly evolving field of autoimmune neurology.

Original languageEnglish
JournalJournal of Neurology, Neurosurgery and Psychiatry
Volume87
Issue number9
Pages (from-to)1005-1015
ISSN0022-3050
DOIs
Publication statusPublished - 2016

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Neuromyelitis Optica
Flow Cytometry
Neurology
Serum
Multicenter Studies
Central Nervous System

Bibliographical note

Online first, published on May 10, 2016

Cite this

Waters, Patrick ; Reindl, Markus ; Saiz, Albert ; Schanda, Kathrin ; Tuller, Friederike ; Kral, Vlastimil ; Nytrova, Petra ; Sobek, Ondrej ; Nielsen, Helle Hvilsted ; Barington, Torben ; Lillevang, Søren T ; Illes, Zsolt ; Rentzsch, Kristin ; Berthele, Achim ; Berki, Tímea ; Granieri, Letizia ; Bertolotto, Antonio ; Giometto, Bruno ; Zuliani, Luigi ; Hamann, Dörte ; van Pelt, E Daniëlle ; Hintzen, Rogier ; Höftberger, Romana ; Costa, Carme ; Comabella, Manuel ; Montalban, Xavier ; Tintoré, Mar ; Siva, Aksel ; Altintas, Ayse ; Deniz, Günnur ; Woodhall, Mark ; Palace, Jacqueline ; Paul, Friedemann ; Hartung, Hans-Peter ; Aktas, Orhan ; Jarius, Sven ; Wildemann, Brigitte ; Vedeler, Christian ; Ruiz, Anne ; Leite, M Isabel ; Trillenberg, Peter ; Probst, Monika ; Saschenbrecker, Sandra ; Vincent, Angela ; Marignier, Romain. / Multicentre comparison of a diagnostic assay : aquaporin-4 antibodies in neuromyelitis optica. In: Journal of Neurology, Neurosurgery and Psychiatry. 2016 ; Vol. 87, No. 9. pp. 1005-1015.
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title = "Multicentre comparison of a diagnostic assay: aquaporin-4 antibodies in neuromyelitis optica",
abstract = "OBJECTIVE: Antibodies to cell surface central nervous system proteins help to diagnose conditions which often respond to immunotherapies. The assessment of antibody assays needs to reflect their clinical utility. We report the results of a multicentre study of aquaporin (AQP) 4 antibody (AQP4-Ab) assays in neuromyelitis optica spectrum disorders (NMOSD).METHODS: Coded samples from patients with neuromyelitis optica (NMO) or NMOSD (101) and controls (92) were tested at 15 European diagnostic centres using 21 assays including live (n=3) or fixed cell-based assays (n=10), flow cytometry (n=4), immunohistochemistry (n=3) and ELISA (n=1).RESULTS: Results of tests on 92 controls identified 12assays as highly specific (0-1 false-positive results). 32 samples from 50 (64{\%}) NMO sera and 34 from 51 (67{\%}) NMOSD sera were positive on at least two of the 12 highly specific assays, leaving 35 patients with seronegative NMO/spectrum disorder (SD). On the basis of a combination of clinical phenotype and the highly specific assays, 66 AQP4-Ab seropositive samples were used to establish the sensitivities (51.5-100{\%}) of all 21 assays. The specificities (85.8-100{\%}) were based on 92 control samples and 35 seronegative NMO/SD patient samples.CONCLUSIONS: The cell-based assays were most sensitive and specific overall, but immunohistochemistry or flow cytometry could be equally accurate in specialist centres. Since patients with AQP4-Ab negative NMO/SD require different management, the use of both appropriate control samples and defined seronegative NMOSD samples is essential to evaluate these assays in a clinically meaningful way. The process described here can be applied to the evaluation of other antibody assays in the newly evolving field of autoimmune neurology.",
author = "Patrick Waters and Markus Reindl and Albert Saiz and Kathrin Schanda and Friederike Tuller and Vlastimil Kral and Petra Nytrova and Ondrej Sobek and Nielsen, {Helle Hvilsted} and Torben Barington and Lillevang, {S{\o}ren T} and Zsolt Illes and Kristin Rentzsch and Achim Berthele and T{\'i}mea Berki and Letizia Granieri and Antonio Bertolotto and Bruno Giometto and Luigi Zuliani and D{\"o}rte Hamann and {van Pelt}, {E Dani{\"e}lle} and Rogier Hintzen and Romana H{\"o}ftberger and Carme Costa and Manuel Comabella and Xavier Montalban and Mar Tintor{\'e} and Aksel Siva and Ayse Altintas and G{\"u}nnur Deniz and Mark Woodhall and Jacqueline Palace and Friedemann Paul and Hans-Peter Hartung and Orhan Aktas and Sven Jarius and Brigitte Wildemann and Christian Vedeler and Anne Ruiz and Leite, {M Isabel} and Peter Trillenberg and Monika Probst and Sandra Saschenbrecker and Angela Vincent and Romain Marignier",
note = "Online first, published on May 10, 2016",
year = "2016",
doi = "10.1136/jnnp-2015-312601",
language = "English",
volume = "87",
pages = "1005--1015",
journal = "Journal of Neurology, Neurosurgery and Psychiatry",
issn = "0022-3050",
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Waters, P, Reindl, M, Saiz, A, Schanda, K, Tuller, F, Kral, V, Nytrova, P, Sobek, O, Nielsen, HH, Barington, T, Lillevang, ST, Illes, Z, Rentzsch, K, Berthele, A, Berki, T, Granieri, L, Bertolotto, A, Giometto, B, Zuliani, L, Hamann, D, van Pelt, ED, Hintzen, R, Höftberger, R, Costa, C, Comabella, M, Montalban, X, Tintoré, M, Siva, A, Altintas, A, Deniz, G, Woodhall, M, Palace, J, Paul, F, Hartung, H-P, Aktas, O, Jarius, S, Wildemann, B, Vedeler, C, Ruiz, A, Leite, MI, Trillenberg, P, Probst, M, Saschenbrecker, S, Vincent, A & Marignier, R 2016, 'Multicentre comparison of a diagnostic assay: aquaporin-4 antibodies in neuromyelitis optica', Journal of Neurology, Neurosurgery and Psychiatry, vol. 87, no. 9, pp. 1005-1015. https://doi.org/10.1136/jnnp-2015-312601

Multicentre comparison of a diagnostic assay : aquaporin-4 antibodies in neuromyelitis optica. / Waters, Patrick; Reindl, Markus; Saiz, Albert; Schanda, Kathrin; Tuller, Friederike; Kral, Vlastimil; Nytrova, Petra; Sobek, Ondrej; Nielsen, Helle Hvilsted; Barington, Torben; Lillevang, Søren T; Illes, Zsolt; Rentzsch, Kristin; Berthele, Achim; Berki, Tímea; Granieri, Letizia; Bertolotto, Antonio; Giometto, Bruno; Zuliani, Luigi; Hamann, Dörte; van Pelt, E Daniëlle; Hintzen, Rogier; Höftberger, Romana; Costa, Carme; Comabella, Manuel; Montalban, Xavier; Tintoré, Mar; Siva, Aksel; Altintas, Ayse; Deniz, Günnur; Woodhall, Mark; Palace, Jacqueline; Paul, Friedemann; Hartung, Hans-Peter; Aktas, Orhan; Jarius, Sven; Wildemann, Brigitte; Vedeler, Christian; Ruiz, Anne; Leite, M Isabel; Trillenberg, Peter; Probst, Monika; Saschenbrecker, Sandra; Vincent, Angela; Marignier, Romain.

In: Journal of Neurology, Neurosurgery and Psychiatry, Vol. 87, No. 9, 2016, p. 1005-1015.

Research output: Contribution to journalJournal articleResearchpeer-review

TY - JOUR

T1 - Multicentre comparison of a diagnostic assay

T2 - aquaporin-4 antibodies in neuromyelitis optica

AU - Waters, Patrick

AU - Reindl, Markus

AU - Saiz, Albert

AU - Schanda, Kathrin

AU - Tuller, Friederike

AU - Kral, Vlastimil

AU - Nytrova, Petra

AU - Sobek, Ondrej

AU - Nielsen, Helle Hvilsted

AU - Barington, Torben

AU - Lillevang, Søren T

AU - Illes, Zsolt

AU - Rentzsch, Kristin

AU - Berthele, Achim

AU - Berki, Tímea

AU - Granieri, Letizia

AU - Bertolotto, Antonio

AU - Giometto, Bruno

AU - Zuliani, Luigi

AU - Hamann, Dörte

AU - van Pelt, E Daniëlle

AU - Hintzen, Rogier

AU - Höftberger, Romana

AU - Costa, Carme

AU - Comabella, Manuel

AU - Montalban, Xavier

AU - Tintoré, Mar

AU - Siva, Aksel

AU - Altintas, Ayse

AU - Deniz, Günnur

AU - Woodhall, Mark

AU - Palace, Jacqueline

AU - Paul, Friedemann

AU - Hartung, Hans-Peter

AU - Aktas, Orhan

AU - Jarius, Sven

AU - Wildemann, Brigitte

AU - Vedeler, Christian

AU - Ruiz, Anne

AU - Leite, M Isabel

AU - Trillenberg, Peter

AU - Probst, Monika

AU - Saschenbrecker, Sandra

AU - Vincent, Angela

AU - Marignier, Romain

N1 - Online first, published on May 10, 2016

PY - 2016

Y1 - 2016

N2 - OBJECTIVE: Antibodies to cell surface central nervous system proteins help to diagnose conditions which often respond to immunotherapies. The assessment of antibody assays needs to reflect their clinical utility. We report the results of a multicentre study of aquaporin (AQP) 4 antibody (AQP4-Ab) assays in neuromyelitis optica spectrum disorders (NMOSD).METHODS: Coded samples from patients with neuromyelitis optica (NMO) or NMOSD (101) and controls (92) were tested at 15 European diagnostic centres using 21 assays including live (n=3) or fixed cell-based assays (n=10), flow cytometry (n=4), immunohistochemistry (n=3) and ELISA (n=1).RESULTS: Results of tests on 92 controls identified 12assays as highly specific (0-1 false-positive results). 32 samples from 50 (64%) NMO sera and 34 from 51 (67%) NMOSD sera were positive on at least two of the 12 highly specific assays, leaving 35 patients with seronegative NMO/spectrum disorder (SD). On the basis of a combination of clinical phenotype and the highly specific assays, 66 AQP4-Ab seropositive samples were used to establish the sensitivities (51.5-100%) of all 21 assays. The specificities (85.8-100%) were based on 92 control samples and 35 seronegative NMO/SD patient samples.CONCLUSIONS: The cell-based assays were most sensitive and specific overall, but immunohistochemistry or flow cytometry could be equally accurate in specialist centres. Since patients with AQP4-Ab negative NMO/SD require different management, the use of both appropriate control samples and defined seronegative NMOSD samples is essential to evaluate these assays in a clinically meaningful way. The process described here can be applied to the evaluation of other antibody assays in the newly evolving field of autoimmune neurology.

AB - OBJECTIVE: Antibodies to cell surface central nervous system proteins help to diagnose conditions which often respond to immunotherapies. The assessment of antibody assays needs to reflect their clinical utility. We report the results of a multicentre study of aquaporin (AQP) 4 antibody (AQP4-Ab) assays in neuromyelitis optica spectrum disorders (NMOSD).METHODS: Coded samples from patients with neuromyelitis optica (NMO) or NMOSD (101) and controls (92) were tested at 15 European diagnostic centres using 21 assays including live (n=3) or fixed cell-based assays (n=10), flow cytometry (n=4), immunohistochemistry (n=3) and ELISA (n=1).RESULTS: Results of tests on 92 controls identified 12assays as highly specific (0-1 false-positive results). 32 samples from 50 (64%) NMO sera and 34 from 51 (67%) NMOSD sera were positive on at least two of the 12 highly specific assays, leaving 35 patients with seronegative NMO/spectrum disorder (SD). On the basis of a combination of clinical phenotype and the highly specific assays, 66 AQP4-Ab seropositive samples were used to establish the sensitivities (51.5-100%) of all 21 assays. The specificities (85.8-100%) were based on 92 control samples and 35 seronegative NMO/SD patient samples.CONCLUSIONS: The cell-based assays were most sensitive and specific overall, but immunohistochemistry or flow cytometry could be equally accurate in specialist centres. Since patients with AQP4-Ab negative NMO/SD require different management, the use of both appropriate control samples and defined seronegative NMOSD samples is essential to evaluate these assays in a clinically meaningful way. The process described here can be applied to the evaluation of other antibody assays in the newly evolving field of autoimmune neurology.

U2 - 10.1136/jnnp-2015-312601

DO - 10.1136/jnnp-2015-312601

M3 - Journal article

C2 - 27113605

VL - 87

SP - 1005

EP - 1015

JO - Journal of Neurology, Neurosurgery and Psychiatry

JF - Journal of Neurology, Neurosurgery and Psychiatry

SN - 0022-3050

IS - 9

ER -