title: The EADC-ADNI Harmonized Protocol for manual hippocampal segmentation on magnetic resonance: evidence of validity.
abstract: BACKGROUND
  An international Delphi panel has defined a harmonized protocol (HarP) for the manual segmentation of the hippocampus on MR. The aim of this study is to study the concurrent validity of the HarP toward local protocols, and its major sources of variance.
  
  
  METHODS
  Fourteen tracers segmented 10 Alzheimer's Disease Neuroimaging Initiative (ADNI) cases scanned at 1.5 T and 3T following local protocols, qualified for segmentation based on the HarP through a standard web-platform and resegmented following the HarP. The five most accurate tracers followed the HarP to segment 15 ADNI cases acquired at three time points on both 1.5 T and 3T.
  
  
  RESULTS
  The agreement among tracers was relatively low with the local protocols (absolute left/right ICC 0.44/0.43) and much higher with the HarP (absolute left/right ICC 0.88/0.89). On the larger set of 15 cases, the HarP agreement within (left/right ICC range: 0.94/0.95 to 0.99/0.99) and among tracers (left/right ICC range: 0.89/0.90) was very high. The volume variance due to different tracers was 0.9% of the total, comparing favorably to variance due to scanner manufacturer (1.2), atrophy rates (3.5), hemispheric asymmetry (3.7), field strength (4.4), and significantly smaller than the variance due to atrophy (33.5%, P < .001), and physiological variability (49.2%, P < .001).
  
  
  CONCLUSIONS
  The HarP has high measurement stability compared with local segmentation protocols, and good reproducibility within and among human tracers. Hippocampi segmented with the HarP can be used as a reference for the qualification of human tracers and automated segmentation algorithms.
authors.affiliation: LENITEM (Laboratory of Epidemiology, Neuroimaging and Telemedicine) IRCCS - Istituto Centro S. Giovanni di Dio - Fatebenefratelli, Brescia, Italy; Memory Clinic and LANVIE - Laboratory of Neuroimaging of Aging, University Hospitals and University of Geneva, Geneva, Switzerland.
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authors.affiliation: Department of Diagnostic Radiology, Mayo Clinic and Foundation, Rochester, MN, USA.
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authors.affiliation: LENITEM (Laboratory of Epidemiology, Neuroimaging and Telemedicine) IRCCS - Istituto Centro S. Giovanni di Dio - Fatebenefratelli, Brescia, Italy; Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
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authors.affiliation: Department of Anatomy and Neurobiology, Boston University School of Medicine, Boston, MA, USA.
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authors.affiliation: Memory Disorders Research Group, Department of Neurology, Rigshospitalet, Copenhagen, Denmark.
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authors.affiliation: Department of Neurology, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland.
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authors.affiliation: Department of Diagnostic Radiology, Mayo Clinic and Foundation, Rochester, MN, USA.
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authors.affiliation: LENITEM (Laboratory of Epidemiology, Neuroimaging and Telemedicine) IRCCS - Istituto Centro S. Giovanni di Dio - Fatebenefratelli, Brescia, Italy.
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authors.affiliation: Memory Disorders Research Group, Department of Neurology, Rigshospitalet, Copenhagen, Denmark.
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authors.affiliation: LENITEM (Laboratory of Epidemiology, Neuroimaging and Telemedicine) IRCCS - Istituto Centro S. Giovanni di Dio - Fatebenefratelli, Brescia, Italy.
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authors.affiliation: LENITEM (Laboratory of Epidemiology, Neuroimaging and Telemedicine) IRCCS - Istituto Centro S. Giovanni di Dio - Fatebenefratelli, Brescia, Italy. Electronic address: mboccardifbf@gmail.com.
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mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000235:genetics / Q000473:pathology; D001284:Atrophy; D005260:Female; D007839:Functional Laterality; D006624:Hippocampus / Q000473:pathology*; D006801:Humans; D007091:Image Processing, Computer-Assisted / Q000379:methods*; D021621:Imaging, Three-Dimensional / Q000379:methods; D020407:Internet; D008279:Magnetic Resonance Imaging / Q000295:instrumentation / Q000379:methods*; D008297:Male; D008875:Middle Aged; D059906:Neuroimaging / Q000379:methods*; D009929:Organ Size; D015203:Reproducibility of Results
keywords: Alzheimer's disease; Biomarkers; Clinical trials; Diagnostic criteria; Enrichment; Harmonized protocol; Hippocampal volumetry; Magnetic resonance; Manual segmentation; Standard operating procedures; Validation