Title | Evaluation of Cerebrospinal Fluid Assay Variability in Alzheimer's Disease. |
Publication Type | Journal Article |
Year of Publication | 2016 |
Authors | White, MT, Shaw, LM, Xie, SX |
Corporate Authors | Alzheimer’s Disease Neuroimaging Initiative, National Alzheimer’s Coordinating Center |
Journal | J Alzheimers Dis |
Volume | 51 |
Issue | 2 |
Pagination | 463-70 |
Date Published | 2016 |
ISSN | 1875-8908 |
Keywords | Alzheimer Disease, Amyloid beta-Peptides, Area Under Curve, Biomarkers, Databases, Factual, Female, Humans, Likelihood Functions, Male, Peptide Fragments, Phosphorylation, ROC Curve, tau Proteins |
Abstract | Studies of cerebrospinal fluid (CSF) biomarkers in Alzheimer's disease (AD) have indicated that much of the variability observed in the biomarkers may be due to measurement error. Biomarkers are often obtained with measurement error, which may make the diagnostic biomarker appear less effective than it truly is. In the Alzheimer's Disease Neuroimaging Initiative (ADNI) database, technical replicates of CSF biomarkers are available; the National Alzheimer's Coordinating Center database contains longitudinal replicates of CSF biomarkers. We focus on the area under the receiver operating characteristic curve (AUC) as the measure of diagnostic effectiveness for differentiating AD from normal cognition using CSF biomarkers and compare AUC estimates obtained by a more standard, naïve method (which uses a single observation per subject and ignores measurement error) to a maximum likelihood (ML) based method (which uses all replicates per subject and adjusts for measurement error). The choice of analysis method depends upon the noise to signal ratio (i.e., the magnitude of the measurement error variability relative to the true biomarker variability); moderate to high ratios may significantly bias the naïve AUC estimate, and the ML-based method would be preferred. The noise to signal ratios were low for the ADNI biomarkers but high for the tTau and pTau biomarkers in NACC. Correspondingly, the naïve and ML-based AUC estimates were nearly identical in the ADNI data but dissimilar for the tTau and pTau biomarkers in the NACC data. Therefore, using the naïve method is adequate for analysis of CSF biomarkers in the ADNI study, but the ML method is recommended for the NACC data. |
DOI | 10.3233/JAD-151045 |
Alternate Journal | J. Alzheimers Dis. |
PubMed ID | 26890778 |
PubMed Central ID | PMC4930357 |
Grant List | P30 AG013854 / AG / NIA NIH HHS / United States P01 AG032953 / AG / NIA NIH HHS / United States P30AG028383 / AG / NIA NIH HHS / United States P30 AG010124 / AG / NIA NIH HHS / United States P50 AG023501 / AG / NIA NIH HHS / United States AG-17586 / AG / NIA NIH HHS / United States P50 AG005142 / AG / NIA NIH HHS / United States P50 AG005131 / AG / NIA NIH HHS / United States P30 AG010133 / AG / NIA NIH HHS / United States P50 AG016574 / AG / NIA NIH HHS / United States P50 AG005146 / AG / NIA NIH HHS / United States P01 AG017586 / AG / NIA NIH HHS / United States P50AG023501 / AG / NIA NIH HHS / United States U01 AG024904 / AG / NIA NIH HHS / United States P30 AG035982 / AG / NIA NIH HHS / United States P50 AG008702 / AG / NIA NIH HHS / United States U01 AG016976 / AG / NIA NIH HHS / United States P30 AG008051 / AG / NIA NIH HHS / United States P50 AG005681 / AG / NIA NIH HHS / United States P30 AG013846 / AG / NIA NIH HHS / United States P50 NS053488 / NS / NINDS NIH HHS / United States P50 AG005136 / AG / NIA NIH HHS / United States P30 AG012300 / AG / NIA NIH HHS / United States P50AG016574 / AG / NIA NIH HHS / United States P50 AG016573 / AG / NIA NIH HHS / United States P50 AG016570 / AG / NIA NIH HHS / United States P50 AG005134 / AG / NIA NIH HHS / United States AG-10124 / AG / NIA NIH HHS / United States P30 AG008017 / AG / NIA NIH HHS / United States / / Canadian Institutes of Health Research / Canada P30 AG010161 / AG / NIA NIH HHS / United States P50 AG025688 / AG / NIA NIH HHS / United States P50 AG005133 / AG / NIA NIH HHS / United States P50 AG005138 / AG / NIA NIH HHS / United States NS-053488 / NS / NINDS NIH HHS / United States P30 AG010129 / AG / NIA NIH HHS / United States P30 AG019610 / AG / NIA NIH HHS / United States P30AG019610 / AG / NIA NIH HHS / United States P30 AG028383 / AG / NIA NIH HHS / United States P50 AG033514 / AG / NIA NIH HHS / United States AG-32953 / AG / NIA NIH HHS / United States |