title: Correcting for the Absence of a Gold Standard Improves Diagnostic Accuracy of Biomarkers in Alzheimer's Disease.
abstract: BACKGROUND
  Studies investigating the diagnostic accuracy of biomarkers for Alzheimer's disease (AD) are typically performed using the clinical diagnosis or amyloid-β positron emission tomography as the reference test. However, neither can be considered a gold standard or a perfect reference test for AD. Not accounting for errors in the reference test is known to cause bias in the diagnostic accuracy of biomarkers.
  
  
  OBJECTIVE
  To determine the diagnostic accuracy of AD biomarkers while taking the imperfectness of the reference test into account.
  
  
  METHODS
  To determine the diagnostic accuracy of AD biomarkers and taking the imperfectness of the reference test into account, we have developed a Bayesian method. This method establishes the biomarkers' true value in predicting the AD-pathology status by combining the reference test and the biomarker data with available information on the reliability of the reference test. The new methodology was applied to two clinical datasets to establish the joint accuracy of three cerebrospinal fluid biomarkers (amyloid-β 1 - 42, Total tau, and P-tau181p) by including the clinical diagnosis as imperfect reference test into the analysis.
  
  
  RESULTS
  The area under the receiver-operating-characteristics curve to discriminate between AD and controls, increases from 0.949 (with 95% credible interval [0.935,0.960]) to 0.990 ([0.985,0.995]) and from 0.870 ([0.817,0.912]) to 0.975 ([0.943,0.990]) for the cohorts, respectively.
  
  
  CONCLUSIONS
  Use of the Bayesian methodology enables an improved estimate of the exact diagnostic value of AD biomarkers and overcomes the lack of a gold standard for AD. Using the new method will increase the diagnostic confidence for early stages of AD.
authors: International Drug Development Institute (IDDI), Louvain-la-Neuve, Belgium.
authors: Els
authors: E
authors: Coart
authors: Interuniversity Institute for Biostatistics and statistical Bioinformatics (I-BioStat), Hasselt University, Diepenbeek, Belgium.
authors: Leandro García
authors: LG
authors: Barrado
authors: Alzheimer Center & Department of Neurology, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.
authors: Flora H
authors: FH
authors: Duits
authors: Alzheimer Center & Department of Neurology, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.
authors: Philip
authors: P
authors: Scheltens
authors: Alzheimer Center & Department of Neurology, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.|Department of Epidemiology and Biostatistics, VU University Medical Center, Amsterdam, The Netherlands.
authors: Wiesje M
authors: WM
authors: van der Flier
authors: Neurochemistry Laboratory and Biobank, Department of Clinical Chemistry, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.
authors: Charlotte E
authors: CE
authors: Teunissen
authors: Department of Pathology, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.
authors: Saskia M
authors: SM
authors: van der Vies
authors: International Drug Development Institute (IDDI), Louvain-la-Neuve, Belgium.|Interuniversity Institute for Biostatistics and statistical Bioinformatics (I-BioStat), Hasselt University, Diepenbeek, Belgium.
authors: Tomasz
authors: T
authors: Burzykowski
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid* / Q000175:diagnosis*; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid; D001499:Bayes Theorem; D015415:Biomarkers / Q000134:cerebrospinal fluid*; D015331:Cohort Studies; D016208:Databases, Factual / Q000706:statistics & numerical data; D003937:Diagnosis, Differential; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011569:Psychiatric Status Rating Scales; D012372:ROC Curve; D012016:Reference Values; D016875:tau Proteins / Q000134:cerebrospinal fluid
chemical_list: D016229:Amyloid beta-Peptides; D015415:Biomarkers; D016875:tau Proteins
keywords: Alzheimer’s disease; Bayesian method; biomarkers; diagnostic test; reference standard