1. Development of a harmonized protocol for hippocampal tracing An EADC-ADNI joint effort 1 th Project Management Team Meeting August 31, 2011

2. Project Management Team Principal Investigators: Giovanni B. Frisoni \ Clifford R. Jack Project Coordination: Marina Boccardi \ Martina Bocchetta Statistical Coordination: Simon Duchesne Industry Advisors: Lennart Thurfjell \ Gunnar Krueger

3. Preliminary Phase - Survey of literature - Certified extraction of landmarks (Boccardi et al., J Alzheimers Dis, 2011) - Operationalization of differences (Segmentation Units, SUs) - Quantification of relevant features of SUs (reliability, impact on hippo volume, informative value for AD-related atrophy) - Quantitative data used for Delphi Questionnaires

4. Benchmark Harmonized hippocampi: total for each rater: 40 hippos 5 expert tracers 20 naive tracers The best 5 naive tracers Harmonized Protocol: total for each rater: 240 hippos GOLD STANDARD Local Protocol : total for rater: 30 hippos 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 : total for each rater: 40 hippos Harmonized Protocol : total for each rater: 40 hippos Harmonized Protocol: total for rater: 30 hippos RM-ANOVA: test of protocol main effect VARIABILITY EVALUATION VALIDATION vs PATHOLOGY Training Delphi panel → harmonized prot 1 tracer Qualification

5. Benchmark Harmonized hippocampi: 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 global and local 95% confidence intervals Training Learning SUs tracing criteria (teleconferences, feedback) (tracing 20 hippos on 1.5 ADNI scans with each SU) Gold Standard Variability Evaluation

6. Tracer certification - System

7. Tracer certification – System (II)

8. Tracer certification – System (III)

9. Tracer certification – System (IV)

10. Tracer certification - Metric

11. Tracer certification – Metric (II)

12. Tracer certification – Metric (III)

13. Qualification on Benchmark hippocampi: (total for each rater: 40 hippos) 20 naive tracers RM-ANOVA: test of rater and rater by center terms 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) SELECTION of the BEST 5 naive tracers: 1- High Qualification inter-rater ICC 2- High Harmonized Tracing “1.5Tvs3T intra-rater” ICC 3- Cluster Homogeneity global inter- rater ICC 1 2 3 Variability Evaluation 1/2 Gold Standard

14. The best 5 naive tracers RM-ANOVA: test of main effects side, trace- retrace, atrophy, time, scanner, rater 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) Variability Evaluation 2/2

15. Project Steps Completed so far - 2 Delphi rounds - Tracing with local protocol (9/20) - Master tracers practice (4/5) - Pilot platform for tracers qualification

16. GANTT chart

17. Delphi Panel – Preliminary Results P=0.021 P=0.057 P=0.035 Covers 100% of hippocampus proper Captures 100% of AD-related atrophy P for agreement among panelists) Intra-rater (BS-BS): 0.993 Inter-rater (BS-BS): 0.985 Preliminary ICC (BS-Mayo-LONI): 0.95

18. Delphi – Preliminary Results This model includes some tissue which is not hippocampus proper: - A/F is white matter - Tail end may include some vestigial tissue - The medial boundary of the body may include some entorhinal cortex