The Alzheimer's Association external quality control program for cerebrospinal fluid biomarkers

Abstract

Background The cerebrospinal fluid (CSF) biomarkers amyloid β (Aβ)-42, total-tau (T-tau), and phosphorylated-tau (P-tau) demonstrate good diagnostic accuracy for Alzheimer’s disease (AD). However, there are large variations in biomarker measurements between studies, and between and within laboratories. The Alzheimer’s Association has initiated a global quality control program to estimate and monitor variability of measurements, quantify batch-to-batch assay variations, and identify sources of variability. In this article, we present the results from the first two rounds of the program. Methods The program is open for laboratories using commercially available kits for Aβ, T-tau, or P-tau. CSF samples (aliquots of pooled CSF) are sent for analysis several times a year from the Clinical Neurochemistry Laboratory at the Molndal campus of the University of Gothenburg, Sweden. Each round consists of three quality control samples. Results Forty laboratories participated. Twenty-six used INNOTESTenzyme-linked immunosorbent assay kits, 14 used Luminex xMAP with the INNO-BIA AlzBio3 kit (both measure Aβ-(1-42), P-tau(181P), and T-tau), and 5 used Meso Scale Discovery with the Aβ triplex (AβN-42, AβN-40, and AβN-38) or T-tau kits. The total coefficients of variation between the laboratories were 13% to 36%. Five laboratories analyzed the samples six times on different occasions. Within-laboratory precisions differed considerably between biomarkers within individual laboratories. Conclusions Measurements of CSF AD biomarkers show large between-laboratory variability, likely caused by factors related to analytical procedures and the analytical kits. Standardization of laboratory procedures and efforts by kit vendors to increase kit performance might lower variability, and will likely increase the usefulness of CSF AD biomarkers.

P1–178: CSF biomarker variability in the Alzheimer's Association quality control program

“…Ab, amyloid beta; T-tau, total tau; P-tau, phosphorylated tau. result is comparable with what has been observed in a previous QC program report (including only the first two rounds [15]), and with other QC monitoring initiatives [18][19][20]. A small part of the overall variability was caused by within-run variability (CV, ,5%-10%, which is in agreement with previous reports and information from kit vendors regarding assay performance [21][22][23]).…”

“…As expected [15], there was a large bias in analyte concentrations when evaluated against the different assay formats (see Fig. 1, but for measurements correlated between assay formats, see Supplemental Fig.…”

“…As reported previously [15], human CSF pools were prepared in M€ olndal, Sweden, from a large number of fresh, deidentified samples obtained during routine clinical workflow (all samples underwent one freeze/thaw cycle before pooling). No extra amount (spiking) of analyte was added to the samples.…”

“…The Alzheimer's Association launched an international quality control (QC) program for CSF biomarkers in 2009 [15]. The program was established to monitor total analytical variability for Ab and tau proteins in CSF, to provide a network where sources of variation could be identified, and to implement actions originating from standardization efforts.…”

“…Moreover, five experienced laboratories that process large numbers of samples routinely serve as reference laboratories and analyze the samples multiple times. The results from the first two rounds, involving 40 laboratories, have been described previously [15].…”