CSF biomarker variability in the Alzheimer's Association quality control program

Alzheimer's Association QC Program Work Group

Research output: Contribution to journalArticle

Abstract

Background: The cerebrospinal fluid (CSF) biomarkers amyloid beta 1-42, total tau, and phosphorylated tau are used increasingly for Alzheimer's disease (AD) research and patient management. However, there are large variations in biomarker measurements among and within laboratories. Methods: Data from the first nine rounds of the Alzheimer's Association quality control program was used to define the extent and sources of analytical variability. In each round, three CSF samples prepared at the Clinical Neurochemistry Laboratory (Mölndal, Sweden) were analyzed by single-analyte enzyme-linked immunosorbent assay (ELISA), a multiplexing xMAP assay, or an immunoassay with electrochemoluminescence detection. Results: A total of 84 laboratories participated. Coefficients of variation (CVs) between laboratories were around 20% to 30%; within-run CVs, less than 5% to 10%; and longitudinal within-laboratory CVs, 5% to 19%. Interestingly, longitudinal within-laboratory CV differed between biomarkers at individual laboratories, suggesting that a component of it was assay dependent. Variability between kit lots and between laboratories both had a major influence on amyloid beta 1-42 measurements, but for total tau and phosphorylated tau, between-kit lot effects were much less than between-laboratory effects. Despite the measurement variability, the between-laboratory consistency in classification of samples (using prehoc-derived cutoffs for AD) was high (>90% in 15 of 18 samples for ELISA and in 12 of 18 samples for xMAP). Conclusions: The overall variability remains too high to allow assignment of universal biomarker cutoff values for a specific intended use. Each laboratory must ensure longitudinal stability in its measurements and use internally qualified cutoff levels. Further standardization of laboratory procedures and improvement of kit performance will likely increase the usefulness of CSF AD biomarkers for researchers and clinicians.

Original languageEnglish (US)
Pages (from-to)251-261
Number of pages11
JournalAlzheimer's and Dementia
Volume9
Issue number3
DOIs
StatePublished - May 1 2013
Externally publishedYes

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Quality Control
Cerebrospinal Fluid
Biomarkers
Alzheimer Disease
Enzyme-Linked Immunosorbent Assay
Neurochemistry
Immunoassay
Sweden
Research Personnel

Keywords

  • Alzheimer's disease
  • Biomarkers
  • Cerebrospinal fluid
  • External assurance
  • Proficiency testing
  • Quality control

ASJC Scopus subject areas

  • Epidemiology
  • Health Policy
  • Developmental Neuroscience
  • Clinical Neurology
  • Geriatrics and Gerontology
  • Cellular and Molecular Neuroscience
  • Psychiatry and Mental health

Cite this

CSF biomarker variability in the Alzheimer's Association quality control program. / Alzheimer's Association QC Program Work Group.

In: Alzheimer's and Dementia, Vol. 9, No. 3, 01.05.2013, p. 251-261.

Research output: Contribution to journalArticle

Alzheimer's Association QC Program Work Group. / CSF biomarker variability in the Alzheimer's Association quality control program. In: Alzheimer's and Dementia. 2013 ; Vol. 9, No. 3. pp. 251-261.
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abstract = "Background: The cerebrospinal fluid (CSF) biomarkers amyloid beta 1-42, total tau, and phosphorylated tau are used increasingly for Alzheimer's disease (AD) research and patient management. However, there are large variations in biomarker measurements among and within laboratories. Methods: Data from the first nine rounds of the Alzheimer's Association quality control program was used to define the extent and sources of analytical variability. In each round, three CSF samples prepared at the Clinical Neurochemistry Laboratory (M{\"o}lndal, Sweden) were analyzed by single-analyte enzyme-linked immunosorbent assay (ELISA), a multiplexing xMAP assay, or an immunoassay with electrochemoluminescence detection. Results: A total of 84 laboratories participated. Coefficients of variation (CVs) between laboratories were around 20{\%} to 30{\%}; within-run CVs, less than 5{\%} to 10{\%}; and longitudinal within-laboratory CVs, 5{\%} to 19{\%}. Interestingly, longitudinal within-laboratory CV differed between biomarkers at individual laboratories, suggesting that a component of it was assay dependent. Variability between kit lots and between laboratories both had a major influence on amyloid beta 1-42 measurements, but for total tau and phosphorylated tau, between-kit lot effects were much less than between-laboratory effects. Despite the measurement variability, the between-laboratory consistency in classification of samples (using prehoc-derived cutoffs for AD) was high (>90{\%} in 15 of 18 samples for ELISA and in 12 of 18 samples for xMAP). Conclusions: The overall variability remains too high to allow assignment of universal biomarker cutoff values for a specific intended use. Each laboratory must ensure longitudinal stability in its measurements and use internally qualified cutoff levels. Further standardization of laboratory procedures and improvement of kit performance will likely increase the usefulness of CSF AD biomarkers for researchers and clinicians.",
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author = "{Alzheimer's Association QC Program Work Group} and Niklas Mattsson and Ulf Andreasson and Staffan Persson and Carrillo, {Maria C.} and Steven Collins and Sonia Chalbot and Neal Cutler and Diane Dufour-Rainfray and Fagan, {Anne M.} and Heegaard, {Niels H.H.} and {Robin Hsiung}, {Ging Yuek} and Bradley Hyman and Khalid Iqbal and Lachno, {D. Richard} and Alberto Lle{\'o} and Piotr Lewczuk and Molinuevo, {Jos{\'e} L.} and Piero Parchi and Axel Regeniter and Robert Rissman and Hanna Rosenmann and Giuseppe Sancesario and Johannes Schr{\"o}der and Shaw, {Leslie M.} and Teunissen, {Charlotte E.} and Trojanowski, {John Q.} and Hugo Vanderstichele and Manu Vandijck and Verbeek, {Marcel M.} and Henrik Zetterberg and Kaj Blennow and Rojo, {Aladro Jos{\'e} A.} and Marilyn Albert and Daniel Alcolea and Anna Antonell and Hiroyuki Arai and Silvana Archetti and Eva Arkblad and In{\^e}s Baldeiras and Ales Bartos and Dev Batish and Aur{\'e}lie Bedel and Daniele Bentue-Ferrer and Flora Berisha and Sergio Bernardini and Marinus Blankenstein and Olivier Bousiges and Camuso, {Michael C.} and Tiziana Casoli and Sebastiano Cavallaro",
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TY - JOUR

T1 - CSF biomarker variability in the Alzheimer's Association quality control program

AU - Alzheimer's Association QC Program Work Group

AU - Mattsson, Niklas

AU - Andreasson, Ulf

AU - Persson, Staffan

AU - Carrillo, Maria C.

AU - Collins, Steven

AU - Chalbot, Sonia

AU - Cutler, Neal

AU - Dufour-Rainfray, Diane

AU - Fagan, Anne M.

AU - Heegaard, Niels H.H.

AU - Robin Hsiung, Ging Yuek

AU - Hyman, Bradley

AU - Iqbal, Khalid

AU - Lachno, D. Richard

AU - Lleó, Alberto

AU - Lewczuk, Piotr

AU - Molinuevo, José L.

AU - Parchi, Piero

AU - Regeniter, Axel

AU - Rissman, Robert

AU - Rosenmann, Hanna

AU - Sancesario, Giuseppe

AU - Schröder, Johannes

AU - Shaw, Leslie M.

AU - Teunissen, Charlotte E.

AU - Trojanowski, John Q.

AU - Vanderstichele, Hugo

AU - Vandijck, Manu

AU - Verbeek, Marcel M.

AU - Zetterberg, Henrik

AU - Blennow, Kaj

AU - Rojo, Aladro José A.

AU - Albert, Marilyn

AU - Alcolea, Daniel

AU - Antonell, Anna

AU - Arai, Hiroyuki

AU - Archetti, Silvana

AU - Arkblad, Eva

AU - Baldeiras, Inês

AU - Bartos, Ales

AU - Batish, Dev

AU - Bedel, Aurélie

AU - Bentue-Ferrer, Daniele

AU - Berisha, Flora

AU - Bernardini, Sergio

AU - Blankenstein, Marinus

AU - Bousiges, Olivier

AU - Camuso, Michael C.

AU - Casoli, Tiziana

AU - Cavallaro, Sebastiano

PY - 2013/5/1

Y1 - 2013/5/1

N2 - Background: The cerebrospinal fluid (CSF) biomarkers amyloid beta 1-42, total tau, and phosphorylated tau are used increasingly for Alzheimer's disease (AD) research and patient management. However, there are large variations in biomarker measurements among and within laboratories. Methods: Data from the first nine rounds of the Alzheimer's Association quality control program was used to define the extent and sources of analytical variability. In each round, three CSF samples prepared at the Clinical Neurochemistry Laboratory (Mölndal, Sweden) were analyzed by single-analyte enzyme-linked immunosorbent assay (ELISA), a multiplexing xMAP assay, or an immunoassay with electrochemoluminescence detection. Results: A total of 84 laboratories participated. Coefficients of variation (CVs) between laboratories were around 20% to 30%; within-run CVs, less than 5% to 10%; and longitudinal within-laboratory CVs, 5% to 19%. Interestingly, longitudinal within-laboratory CV differed between biomarkers at individual laboratories, suggesting that a component of it was assay dependent. Variability between kit lots and between laboratories both had a major influence on amyloid beta 1-42 measurements, but for total tau and phosphorylated tau, between-kit lot effects were much less than between-laboratory effects. Despite the measurement variability, the between-laboratory consistency in classification of samples (using prehoc-derived cutoffs for AD) was high (>90% in 15 of 18 samples for ELISA and in 12 of 18 samples for xMAP). Conclusions: The overall variability remains too high to allow assignment of universal biomarker cutoff values for a specific intended use. Each laboratory must ensure longitudinal stability in its measurements and use internally qualified cutoff levels. Further standardization of laboratory procedures and improvement of kit performance will likely increase the usefulness of CSF AD biomarkers for researchers and clinicians.

AB - Background: The cerebrospinal fluid (CSF) biomarkers amyloid beta 1-42, total tau, and phosphorylated tau are used increasingly for Alzheimer's disease (AD) research and patient management. However, there are large variations in biomarker measurements among and within laboratories. Methods: Data from the first nine rounds of the Alzheimer's Association quality control program was used to define the extent and sources of analytical variability. In each round, three CSF samples prepared at the Clinical Neurochemistry Laboratory (Mölndal, Sweden) were analyzed by single-analyte enzyme-linked immunosorbent assay (ELISA), a multiplexing xMAP assay, or an immunoassay with electrochemoluminescence detection. Results: A total of 84 laboratories participated. Coefficients of variation (CVs) between laboratories were around 20% to 30%; within-run CVs, less than 5% to 10%; and longitudinal within-laboratory CVs, 5% to 19%. Interestingly, longitudinal within-laboratory CV differed between biomarkers at individual laboratories, suggesting that a component of it was assay dependent. Variability between kit lots and between laboratories both had a major influence on amyloid beta 1-42 measurements, but for total tau and phosphorylated tau, between-kit lot effects were much less than between-laboratory effects. Despite the measurement variability, the between-laboratory consistency in classification of samples (using prehoc-derived cutoffs for AD) was high (>90% in 15 of 18 samples for ELISA and in 12 of 18 samples for xMAP). Conclusions: The overall variability remains too high to allow assignment of universal biomarker cutoff values for a specific intended use. Each laboratory must ensure longitudinal stability in its measurements and use internally qualified cutoff levels. Further standardization of laboratory procedures and improvement of kit performance will likely increase the usefulness of CSF AD biomarkers for researchers and clinicians.

KW - Alzheimer's disease

KW - Biomarkers

KW - Cerebrospinal fluid

KW - External assurance

KW - Proficiency testing

KW - Quality control

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U2 - 10.1016/j.jalz.2013.01.010

DO - 10.1016/j.jalz.2013.01.010

M3 - Article

VL - 9

SP - 251

EP - 261

JO - Alzheimer's and Dementia

JF - Alzheimer's and Dementia

SN - 1552-5260

IS - 3

ER -