title: Steps to standardization and validation of hippocampal volumetry as a biomarker in clinical trials and diagnostic criterion for Alzheimer's disease.
abstract: BACKGROUND
  The promise of Alzheimer's disease biomarkers has led to their incorporation in new diagnostic criteria and in therapeutic trials; however, significant barriers exist to widespread use. Chief among these is the lack of internationally accepted standards for quantitative metrics. Hippocampal volumetry is the most widely studied quantitative magnetic resonance imaging measure in Alzheimer's disease and thus represents the most rational target for an initial effort at standardization.
  
  
  RESULTS
  The authors of this position paper propose a path toward this goal. The steps include the following: (1) Establish and empower an oversight board to manage and assess the effort, (2) adopt the standardized definition of anatomic hippocampal boundaries on magnetic resonance imaging arising from the European Alzheimer's Disease Centers-Alzheimer's Disease Neuroimaging Initiative hippocampal harmonization effort as a reference standard, (3) establish a scientifically appropriate, publicly available reference standard data set based on manual delineation of the hippocampus in an appropriate sample of subjects (Alzheimer's Disease Neuroimaging Initiative), and (4) define minimum technical and prognostic performance metrics for validation of new measurement techniques using the reference standard data set as a benchmark.
  
  
  CONCLUSIONS
  Although manual delineation of the hippocampus is the best available reference standard, practical application of hippocampal volumetry will require automated methods. Our intent was to establish a mechanism for credentialing automated software applications to achieve internationally recognized accuracy and prognostic performance standards that lead to the systematic evaluation and then widespread acceptance and use of hippocampal volumetry. The standardization and assay validation process outlined for hippocampal volumetry was envisioned as a template that could be applied to other imaging biomarkers.
authors.affiliation: Department of Radiology, Mayo Clinic, Rochester, MN, USA. Jack.Clifford@mayo.edu
authors.forename: Clifford R
authors.initials: CR
authors.lastname: Jack
authors.forename: Frederik
authors.initials: F
authors.lastname: Barkhof
authors.forename: Matt A
authors.initials: MA
authors.lastname: Bernstein
authors.forename: Marc
authors.initials: M
authors.lastname: Cantillon
authors.forename: Patricia E
authors.initials: PE
authors.lastname: Cole
authors.forename: Charles
authors.initials: C
authors.lastname: Decarli
authors.forename: Bruno
authors.initials: B
authors.lastname: Dubois
authors.forename: Simon
authors.initials: S
authors.lastname: Duchesne
authors.forename: Nick C
authors.initials: NC
authors.lastname: Fox
authors.forename: Giovanni B
authors.initials: GB
authors.lastname: Frisoni
authors.forename: Harald
authors.initials: H
authors.lastname: Hampel
authors.forename: Derek L G
authors.initials: DL
authors.lastname: Hill
authors.forename: Keith
authors.initials: K
authors.lastname: Johnson
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Mangin
authors.forename: Philip
authors.initials: P
authors.lastname: Scheltens
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Schwarz
authors.forename: Reisa
authors.initials: R
authors.lastname: Sperling
authors.forename: Joyce
authors.initials: J
authors.lastname: Suhy
authors.forename: Paul M
authors.initials: PM
authors.lastname: Thompson
authors.forename: Michael
authors.initials: M
authors.lastname: Weiner
authors.forename: Norman L
authors.initials: NL
authors.lastname: Foster
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000175:diagnosis*; D015415:Biomarkers / Q000032:analysis; D005060:Europe; D005260:Female; D006624:Hippocampus / Q000473:pathology*; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008279:Magnetic Resonance Imaging / Q000379:methods* / Q000592:standards*; D008297:Male; D012372:ROC Curve; D012016:Reference Values; D015203:Reproducibility of Results
chemical_list: D015415:Biomarkers