Abstract

BACKGROUND: Low cerebrospinal fluid (CSF) amyloid-β 1-42 (Aβ 1-42) concentrations indicate amyloid plaque accumulation in the brain, a pathological hallmark of Alzheimer disease (AD). Innotest assay values of Aβ 1-42 have gradually increased over the past 2 decades, which might lead to misclassification of AD when a single cutpoint for abnormality is used. We propose an unbiased approach to statistically correct for drift.

METHODS: We determined year-specific cutpoints with Gaussian mixture modeling, based on the cross-section of bimodal distributions of Aβ 1-42 concentrations in 4397 memory clinic patients. This allowed us to realign year-specific cutpoints as an unbiased method to remove drift from the data. Sensitivity and specificity to detect AD dementia were compared between corrected and uncorrected values.

RESULTS: Aβ 1-42 values increased 22 pg/mL annually, and this could not be explained by changes in cohort composition. Our approach removed time dependencies [β (SE) = 0.07 (0.59);P= 0.91]. Statistically correcting for drift improved the sensitivity to detect AD dementia to 0.90 (95% CI, 0.89-0.92) from at least 0.66 (95% CI, 0.64-0.69) based on uncorrected data. Specificity became lower (0.69; 95% CI, 0.67-0.70) vs at most 0.80 (95% CI, 0.79-0.82) for uncorrected data.

CONCLUSIONS: This approach may also be useful to standardize Aβ 1-42 CSF concentrations across different centers and/or platforms, and to optimize use of CSF biomarker data collected over a long period.

Original languageEnglish
Pages (from-to)576-585
Number of pages10
Journalthe Journal of Applied Laboratory Medicine
Volume64
Issue number3
DOIs
Publication statusPublished - Mar 2018

Cite this

@article{c9c868dfdfbc4520b2ad2ccedd1ec9a1,
title = "Unbiased Approach to Counteract Upward Drift in Cerebrospinal Fluid Amyloid-β 1-42 Analysis Results",
abstract = "BACKGROUND: Low cerebrospinal fluid (CSF) amyloid-β 1-42 (Aβ 1-42) concentrations indicate amyloid plaque accumulation in the brain, a pathological hallmark of Alzheimer disease (AD). Innotest assay values of Aβ 1-42 have gradually increased over the past 2 decades, which might lead to misclassification of AD when a single cutpoint for abnormality is used. We propose an unbiased approach to statistically correct for drift.METHODS: We determined year-specific cutpoints with Gaussian mixture modeling, based on the cross-section of bimodal distributions of Aβ 1-42 concentrations in 4397 memory clinic patients. This allowed us to realign year-specific cutpoints as an unbiased method to remove drift from the data. Sensitivity and specificity to detect AD dementia were compared between corrected and uncorrected values.RESULTS: Aβ 1-42 values increased 22 pg/mL annually, and this could not be explained by changes in cohort composition. Our approach removed time dependencies [β (SE) = 0.07 (0.59);P= 0.91]. Statistically correcting for drift improved the sensitivity to detect AD dementia to 0.90 (95{\%} CI, 0.89-0.92) from at least 0.66 (95{\%} CI, 0.64-0.69) based on uncorrected data. Specificity became lower (0.69; 95{\%} CI, 0.67-0.70) vs at most 0.80 (95{\%} CI, 0.79-0.82) for uncorrected data.CONCLUSIONS: This approach may also be useful to standardize Aβ 1-42 CSF concentrations across different centers and/or platforms, and to optimize use of CSF biomarker data collected over a long period.",
keywords = "Journal Article",
author = "Tijms, {Betty M} and Willemse, {Eline A J} and Zwan, {Marissa D} and Mulder, {Sandra D} and Visser, {Pieter Jelle} and {van Berckel}, {Bart N M} and {van der Flier}, {Wiesje M} and Philip Scheltens and Teunissen, {Charlotte E}",
note = "{\circledC} 2017 American Association for Clinical Chemistry.",
year = "2018",
month = "3",
doi = "10.1373/clinchem.2017.281055",
language = "English",
volume = "64",
pages = "576--585",
journal = "the Journal of Applied Laboratory Medicine",
issn = "0009-9147",
number = "3",

}

TY - JOUR

T1 - Unbiased Approach to Counteract Upward Drift in Cerebrospinal Fluid Amyloid-β 1-42 Analysis Results

AU - Tijms, Betty M

AU - Willemse, Eline A J

AU - Zwan, Marissa D

AU - Mulder, Sandra D

AU - Visser, Pieter Jelle

AU - van Berckel, Bart N M

AU - van der Flier, Wiesje M

AU - Scheltens, Philip

AU - Teunissen, Charlotte E

N1 - © 2017 American Association for Clinical Chemistry.

PY - 2018/3

Y1 - 2018/3

N2 - BACKGROUND: Low cerebrospinal fluid (CSF) amyloid-β 1-42 (Aβ 1-42) concentrations indicate amyloid plaque accumulation in the brain, a pathological hallmark of Alzheimer disease (AD). Innotest assay values of Aβ 1-42 have gradually increased over the past 2 decades, which might lead to misclassification of AD when a single cutpoint for abnormality is used. We propose an unbiased approach to statistically correct for drift.METHODS: We determined year-specific cutpoints with Gaussian mixture modeling, based on the cross-section of bimodal distributions of Aβ 1-42 concentrations in 4397 memory clinic patients. This allowed us to realign year-specific cutpoints as an unbiased method to remove drift from the data. Sensitivity and specificity to detect AD dementia were compared between corrected and uncorrected values.RESULTS: Aβ 1-42 values increased 22 pg/mL annually, and this could not be explained by changes in cohort composition. Our approach removed time dependencies [β (SE) = 0.07 (0.59);P= 0.91]. Statistically correcting for drift improved the sensitivity to detect AD dementia to 0.90 (95% CI, 0.89-0.92) from at least 0.66 (95% CI, 0.64-0.69) based on uncorrected data. Specificity became lower (0.69; 95% CI, 0.67-0.70) vs at most 0.80 (95% CI, 0.79-0.82) for uncorrected data.CONCLUSIONS: This approach may also be useful to standardize Aβ 1-42 CSF concentrations across different centers and/or platforms, and to optimize use of CSF biomarker data collected over a long period.

AB - BACKGROUND: Low cerebrospinal fluid (CSF) amyloid-β 1-42 (Aβ 1-42) concentrations indicate amyloid plaque accumulation in the brain, a pathological hallmark of Alzheimer disease (AD). Innotest assay values of Aβ 1-42 have gradually increased over the past 2 decades, which might lead to misclassification of AD when a single cutpoint for abnormality is used. We propose an unbiased approach to statistically correct for drift.METHODS: We determined year-specific cutpoints with Gaussian mixture modeling, based on the cross-section of bimodal distributions of Aβ 1-42 concentrations in 4397 memory clinic patients. This allowed us to realign year-specific cutpoints as an unbiased method to remove drift from the data. Sensitivity and specificity to detect AD dementia were compared between corrected and uncorrected values.RESULTS: Aβ 1-42 values increased 22 pg/mL annually, and this could not be explained by changes in cohort composition. Our approach removed time dependencies [β (SE) = 0.07 (0.59);P= 0.91]. Statistically correcting for drift improved the sensitivity to detect AD dementia to 0.90 (95% CI, 0.89-0.92) from at least 0.66 (95% CI, 0.64-0.69) based on uncorrected data. Specificity became lower (0.69; 95% CI, 0.67-0.70) vs at most 0.80 (95% CI, 0.79-0.82) for uncorrected data.CONCLUSIONS: This approach may also be useful to standardize Aβ 1-42 CSF concentrations across different centers and/or platforms, and to optimize use of CSF biomarker data collected over a long period.

KW - Journal Article

U2 - 10.1373/clinchem.2017.281055

DO - 10.1373/clinchem.2017.281055

M3 - Article

VL - 64

SP - 576

EP - 585

JO - the Journal of Applied Laboratory Medicine

JF - the Journal of Applied Laboratory Medicine

SN - 0009-9147

IS - 3

ER -