1. Agenda: - Axes check - Validation vs Pathology - Paper Publications - Congress presentations & Meetings VII PMT meeting – Feb 29, 2012

2. Project method 1.Delphi is required to take all decisions based on experience + evidence 2.Empirical data on SUs taken on ACPC is fed to Delphi (external & internal landmarks) 3.Delphi decides on which SUs make up harmo hippo (internal landmarks) 4.Delphi decides that best segmentation is on hippo axis (10- 5-1 in favour-neutral-against) 5.Empirical evidence collected that total hippo volume on ACPC = hippo axis

3. 1. Delphi is required to take all decisions based on experience + evidence

4. 2. Empirical data on SUs taken on ACPC is fed to Delphi (external & internal landmarks) 3. Delphi decides on which SUs make up harmo hippo (internal landmarks) Internal Landmarks (n)External Landmarks (n) SUs: Minimum Hippocampus51 Alveus/Fimbria51 Subiculum - Oblique Line51 Subiculum – Horizontal Line51 Subiculum – Morphology51 Tail - Crura42 Tail – Tail End51 Harmonized Hippo60

5. 2. Empirical data on SUs taken on ACPC is fed to Delphi (external & internal landmarks) 3. Delphi decides on which SUs make up harmo hippo (internal landmarks)

6. HippoAC-PC same Round 1: Which plane Fisher’s exact Round 2: Agree on hippo plane Disagree same Agree Rounds 3 and 4 converged on mean angle between R and L axes Fisher’s Binomial 4. Delphi decides that best segmentation is on hippo axis (10-5-1 in favour-neutral-against) DATA SHOWN IN PARIS, JULY 2011 Delphi: www.hippocampal-protocol.net/SOPs/delphipanel.html, access with user: prova, pw: provawww.hippocampal-protocol.net/SOPs/delphipanel.html

7. 5. Empirical evidence collected that total hippo volume on ACPC = hippo axis TracerHippo_LeftHippo_Right Intra-rater: same 10 subjects (20 images). different orientation (ACPC vs Hippocampal Axes) MB0.9890.993 GP0.9850.991 LA*0.9710.967 Inter-rater: all 20 images (ACPC+Hippocampal Axes) MB-GP-LA*0.9440.961 Inter-rater: only for ACPC orientation (10 images) MB-GP-LA*0.9590.961 Inter-rater: only for Hippocampal Axes orientation (10 images) MB-GP-LA0.9540.970 LA*= LA traced only 5 images oriented along ACPC line

8. Benchmark Harmonized hippos: 1.5T ADNI scans 2 x each of the 5 Scheltens’s atrophy score x 2 sides (SAME on 3T ADNI scans) (total for each rater: 40 hippos) 5 expert tracers 20 naive tracers The best 5 naive tracers Harmonized Protocol: 1.5T ADNI scans 2 sides x 5 Scheltens’s atrophy scores x 3 time points (0-12°month-24°month) x 3 scanners + retracing for timepoint 1 (SAME on 3T ADNI scans) (total for each rater: 240 hippos – including 40 hippos already traced) GOLD STANDARD Local Protocol : 1.5T 3D T1-weighted scans from (Bobinski et al., 2000) pathologically verified set (total for rater: 30 hippos) 1 tracer Qualification (20 tracers) Qualification global and local 95% confidence intervals RM-ANOVA: test of rater and rater by center terms RM-ANOVA: test of main effects side, trace- retrace, atrophy, time, scanner, rater Local Protocol : Experimental set (1.5T ADNI): 2 x each of the 5 Scheltens’s atrophy score x 2 sides (SAME on 3T ADNI scans) (total for each rater: 40 hippos) Harmonized Protocol : Experimental set (1.5T ADNI): 2 x each of the 5 Scheltens ’ s atrophy score x 2 sides (SAME on 3T ADNI scans) (total for each rater: 40 hippos) Harmonized Protocol: 1.5T 3D T1-weighted scans from (Bobinski et al., 2000) pathologically verified set (total for rater: 30 hippos) RM-ANOVA: test of protocol main effect VARIABILITY EVALUATION VALIDATION vs PATHOLOGY Training (tracing 20 hippos on 1.5T ADNI scans with each SU) (SAME on 3T ADNI scans) Delphi panel → harmonized prot VALIDATION ON 1800 HIPPOCAMPI IN TOTAL

9. Pros & Cons Methodological 1)Violate general method of the project (decisional tree) 2)Interfere with the aim of the project (define gold standard as best possible accuracy) 3)Disregard and contradict the opinion of 20 international experts of hippocampus Methodological 1)Contrast with the orientation on which evidence was gathered Note that this contrast : did not constitute a problem for 20 international hippo experts did not correspond to quantitative evidence showing any impact on the Harmo Prot Accepting the consensus on hippo axes would: Practical Reduce partial volume effects and facilitate manual tracing (tracers and panelists’ subjective reports) Changing to AC-PC would: Practical Facilitate automatic preprocessing

10. Validation versus pathology Local Protocol : 1.5T 3D T1-weighted scans from (Bobinski et al., 2000) pathologically verified set (total for rater: 30 hippos) 1 tracer Qualification on benchmark images (total for each rater: 40 hippos) Harmonized Protocol: 1.5T 3D T1-weighted scans from (Bobinski et al., 2000) pathologically verified set (total for rater: 30 hippos) RM-ANOVA: test of protocol main effect WHICH SAMPLE?

11. Paper Operationalization Alzheimer’s and Dementia

12. Papers describing the project Survey of protocols (preliminary phase; published, JAD 2011) Operationalization (preliminary phase; to be completed) Delphi consensus (Brescia Team) Master tracers’ practice and reliability (Brescia Team) Development of certification platform (Duchesne and coll?) Validation data and Protocol definition (Brescia Team) Validation vs pathology (TBD)

13. Benchmark Harmonized hippos: 1.5T ADNI scans 2 x each of the 5 Scheltens’s atrophy score x 2 sides (SAME on 3T ADNI scans) (total for each rater: 40 hippos) 5 expert tracers 20 naive tracers The best 5 naive tracers Harmonized Protocol: 1.5T ADNI scans 2 sides x 5 Scheltens’s atrophy scores x 3 time points (0-12°month-24°month) x 3 scanners + retracing for timepoint 1 (SAME on 3T ADNI scans) (total for each rater: 240 hippos – including 40 hippos already traced) GOLD STANDARD Local Protocol : 1.5T 3D T1-weighted scans from (Bobinski et al., 2000) pathologically verified set (total for rater: 30 hippos) 1 tracer Qualification (20 tracers) Qualification global and local 95% confidence intervals RM-ANOVA: test of rater and rater by center terms RM-ANOVA: test of main effects side, trace- retrace, atrophy, time, scanner, rater Local Protocol : Experimental set (1.5T ADNI): 2 x each of the 5 Scheltens’s atrophy score x 2 sides (SAME on 3T ADNI scans) (total for each rater: 40 hippos) Harmonized Protocol : Experimental set (1.5T ADNI): 2 x each of the 5 Scheltens’s atrophy score x 2 sides (SAME on 3T ADNI scans) (total for each rater: 40 hippos) Harmonized Protocol: 1.5T 3D T1-weighted scans from (Bobinski et al., 2000) pathologically verified set (total for rater: 30 hippos) RM-ANOVA: test of protocol main effect VARIABILITY EVALUATION VALIDATION vs PATHOLOGY Training (tracing 20 hippos on 1.5T ADNI scans with each SU) (SAME on 3T ADNI scans) Delphi panel → harmonized prot

14. Congress presentations - AAN 2012, New Orleans Oral Presentation S04.003, April 24, Aging and Dementia: Therapeutic Interventions, 1.30 pm M Boccardi, M Bocchetta, L Apostolova, J Barnes, G Bartzokis, G Corbetta, C DeCarli, L DeToledo-Morrell, M Firbank, R Ganzola, L Gerritsen, W Henneman, R Killiany, N Malykhin, P Pasqualetti, J Pruessner, A Redolfi, N Robitaille, H Soininen, D Tolomeo, L Wang, C Watson, H Wolf, S Duchesne, CR Jack, GB Frisoni. Delphi consensus on landmarks for the manual segmentation of the hippocampus on MRI: preliminary results from the EADC- ADNI Harmonized Protocol working group. - AAIC 2012, Vancouver Abstract n. 26291, submitted to AAIC 2012 M Boccardi, M Bocchetta, A Redolfi, P Pasqualetti, R Ganzola, N Robitaille, S Duchesne, CR Jack, GB Frisoni and the EADC-ADNI Hippocampal Harmonization Group. Definition of Harmonized Protocol for Hippocampal Segmentation Abstract n. 26292, submitted to AIC 2012 M Boccardi, M Bocchetta, A Redolfi, P Pasqualetti, R Ganzola, N Robitaille, S Duchesne, CR Jack, GB Frisoni and the EADC-ADNI Hippocampal Harmonization Group. Definition of Harmonized Protocol for Hippocampal Segmentation

15. AAN – April 24, 2012 AGENDA: 1. Delphi Paper; 2. Publication policy AAIC – July 2012 AGENDA: 1. Presentation of Harmonized Protocol; 2. Reliability figures SOPs periodical meetings

16. GANTT