title: Impact of Training Method on the Robustness of the Visual Assessment of 18F-Florbetaben PET Scans: Results from a Phase-3 Study.
abstract: Training for accurate image interpretation is essential for the clinical use of β-amyloid PET imaging, but the role of interpreter training and the accuracy of the algorithm for routine visual assessment of florbetaben PET scans are unclear. The aim of this study was to test the robustness of the visual assessment method for florbetaben scans, comparing efficacy readouts across different interpreters and training methods and against a histopathology standard of truth (SoT).
  
  
  METHODS
  Analysis was based on data from an international open-label, nonrandomized, multicenter phase-3 study in patients with or without dementia (ClinicalTrials.gov: NCT01020838). Florbetaben scans were assessed visually and quantitatively, and results were compared with amyloid plaque scores. For visual assessment, either in-person training (n = 3 expert interpreters) or an electronic training method (n = 5 naïve interpreters) was used. Brain samples from participants who died during the study were used to determine the histopathologic SoT using Bielschowsky silver staining (BSS) and immunohistochemistry for β-amyloid plaques.
  
  
  RESULTS
  Data were available from 82 patients who died and underwent postmortem histopathology. When visual assessment results were compared with BSS + immunohistochemistry as SoT, median sensitivity was 98.2% for the in-person-trained interpreters and 96.4% for the e-trained interpreters, and median specificity was 92.3% and 88.5%, respectively. Median accuracy was 95.1% and 91.5%, respectively. On the basis of BSS only as the SoT, median sensitivity was 98.1% and 96.2%, respectively; median specificity was 80.0% and 76.7%, respectively; and median accuracy was 91.5% and 86.6%, respectively. Interinterpreter agreement (Fleiss κ) was excellent (0.89) for in-person-trained interpreters and very good (0.71) for e-trained interpreters. Median intrainterpreter agreement was 0.9 for both in-person-trained and e-trained interpreters. Visual and quantitative assessments were concordant in 88.9% of scans for in-person-trained interpreters and in 87.7% of scans for e-trained interpreters.
  
  
  CONCLUSIONS
  Visual assessment of florbetaben images was robust in challenging scans from elderly end-of-life individuals. Sensitivity, specificity, and interinterpreter agreement were high, independent of expertise and training method. Visual assessment was accurate and reliable for detection of plaques using BSS and immunohistochemistry and well correlated with quantitative assessments.
authors.affiliation: Molecular Neuroimaging LLC, New Haven, Connecticut jseibyl@indd.org.
authors.forename: John
authors.initials: J
authors.lastname: Seibyl
authors.affiliation: Piramal Imaging GmbH, Berlin, Germany.
authors.forename: Ana M
authors.initials: AM
authors.lastname: Catafau
authors.affiliation: Leipzig University, Leipzig, Germany.
authors.forename: Henryk
authors.initials: H
authors.lastname: Barthel
authors.affiliation: Department of Positron Medical Center, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Ishii
authors.affiliation: Austin Health, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Rowe
authors.affiliation: Virginia-Puget Sound Health Care System and University of Washington, Seattle, Washington.
authors.forename: James B
authors.initials: JB
authors.lastname: Leverenz
authors.affiliation: Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Bernardino
authors.initials: B
authors.lastname: Ghetti
authors.affiliation: University of Edinburgh, Edinburgh, Scotland.
authors.forename: James W
authors.initials: JW
authors.lastname: Ironside
authors.affiliation: Mihara Memorial Hospital, Isesaki, Japan Department of Neurology, Saitama International Medical Center, Saitama Medical University, Saitama, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Takao
authors.affiliation: Fukushimura Hospital, Toyohashi, Japan Departments of Community-Based Medicine and Neurology, Nagoya City University Graduate School of Medical Sciences, Nagoya City, Aichi, Japan.
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Akatsu
authors.affiliation: Department of Neurology and Neuropathology (the Brain Bank for Aging Research), Tokyo Metropolitan Geriatric Hospital, Tokyo, Japan Institute of Gerontology, Tokyo, Japan.
authors.forename: Shigeo
authors.initials: S
authors.lastname: Murayama
authors.affiliation: Piramal Imaging GmbH, Berlin, Germany.
authors.forename: Santiago
authors.initials: S
authors.lastname: Bullich
authors.affiliation: Piramal Imaging GmbH, Berlin, Germany.
authors.forename: Andre
authors.initials: A
authors.lastname: Mueller
authors.affiliation: Piramal Imaging GmbH, Berlin, Germany.
authors.forename: Norman
authors.initials: N
authors.lastname: Koglin
authors.affiliation: Georg-August University Göttingen, Göttingen, Germany.
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Schulz-Schaeffer
authors.affiliation: Bayer Pharma AG, Berlin, Germany; and.
authors.forename: Anja
authors.initials: A
authors.lastname: Hoffmann
authors.affiliation: Alzheimer's and Memory Disorders Division, Department of Neurology, Barrow Neurological Institute, Phoenix, Arizona.
authors.forename: Marwan N
authors.initials: MN
authors.lastname: Sabbagh
authors.affiliation: Piramal Imaging GmbH, Berlin, Germany.
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Stephens
authors.affiliation: Leipzig University, Leipzig, Germany.
authors.forename: Osama
authors.initials: O
authors.lastname: Sabri
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000814:Aniline Compounds; D005260:Female; D006801:Humans; D007091:Image Processing, Computer-Assisted / Q000379:methods*; D008297:Male; D008875:Middle Aged; D015588:Observer Variation; D049268:Positron-Emission Tomography; D012680:Sensitivity and Specificity; D013267:Stilbenes
chemical_list: D016229:Amyloid beta-Peptides; D000814:Aniline Compounds; D013267:Stilbenes; C527756:4-(N-methylamino)-4'-(2-(2-(2-fluoroethoxy)ethoxy)ethoxy)stilbene
keywords: Alzheimer’s disease; florbetaben; positron-emission tomography