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Development of a harmonized protocol for hippocampal tracing An EADC-ADNI joint effort

AAN – New Orleans. Development of a harmonized protocol for hippocampal tracing An EADC-ADNI joint effort 5 th Meeting, New Orleans, April 24, 2012 Update as of April 2012 Principal Investigators: Giovanni B Frisoni & Clifford R Jack Project Coordinator: Marina Boccardi.

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Development of a harmonized protocol for hippocampal tracing An EADC-ADNI joint effort

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  1. AAN – New Orleans Development of a harmonized protocol for hippocampal tracing An EADC-ADNI joint effort 5th Meeting, New Orleans, April 24, 2012 Update as of April 2012 Principal Investigators: Giovanni B Frisoni & Clifford R Jack Project Coordinator: Marina Boccardi

  2. HOUSEKEEPING INFORMATION • Webinar: • Screen sharing through GotoMeeting • Audio through Première via regular telephone line. Please mute mike through *6 • Questions: • Unmute *6 and ask question

  3. PREMIERE TEL NUMBERS: Passcode: 337487 Lituania, Vilnius: +370 5205 4214 Luxembourg, Luxembourg: +352 2088 0404 Netherlands, Amsterdam: +31 (0)20 708 5030 New Zealand, Auckland: +64 (0)9 912 3296 Norway, Oslo: +47 2100 0499 Poland, Warsaw: +48 (0)22 212 0122 Portugal, Lisbon: +351 217 810 252 Romania, Bucharest: +40 (0)31 811 0025 Russia, Moscow: +7 495 646 9191 Singapore, Singapore: +65 3158 1291 Slovacchia, Bratislava: +421 (0)2 3300 6528 Slovenia, Ljubljana: +386 1 600 1435 South Africa, Johannesburg: +27 11 019 7002 South Korea, Seoul: +82 (0)2 3483 7321 Spain, Barcelona: +34 93 545 2524 Spain, Madrid: +34 91 791 7142 Sweden, Stockholm: +46 (0)8 5051 4917 Switzerland, Geneva: +41 (0)22 592 7951 Switzerland, Zurich: +41 (0)44 567 1875 UK, Belfast: +44 (0)28 9595 0006 UK, Edinburgh: +44 (0)13 1460 0034 UK, London: +44 (0)20 3059 5702 UK, Reading: +44 (0)11 8370 0027 UK: 0845 351 0340 USA, New York: +1 646 254 3345 USA, Houston: +1 832 369 1692 Australia, Melbourne: +61 (0)3 9001 1134 Australia, Sydney: +61 (0)2 9037 1678 Austria, Vienna: +43 (0)1 2530085419 Belgium, Bruxelles: +32 (0)2 792 0496 Bulgaria, Sofia: +359 (0)2 491 7281 Canada, Montreal: +1 514 315 6013 Canada, Toronto: +1 416 915 9970 Czech Republic, Prague: +420 246 019 521 Denmark, Copenhagen: +45 32 71 15 12 Estonia, Tallin: +372 616 0395 Finland, Helsinki: +358 (0)9 2310 1651 France: 0811 655 288 France, Paris: +33 (0)1 70 37 14 50 Germany: 01801 003 823 Germany, Frankfurt: +49 (0)69 667775735 Germany, Munich: +49 (0)89 710424668 Greece, Athen: +30 210 969 6406 Hong Kong, Hong Kong: +852 3071 5041 Hungary, Budapest: +36 1808 8176 Ireland: 1890 907 117 Ireland, Dublin: +353 (0)1 553 0119 Istrael, Tel Aviv: +972 3721 9261 Italy, Milan: +39 02 3626 9646 Italy, Rome: +39 06 8336 0547 Japan, Tokyo: +81 (0)3 5767 4791 Latvia, Riga: +371 6778 2513

  4. OUTLINE - Summary as of to date - Update since last meeting: Delphi panel - Landmarks defined - Segmentation modalities defined - Check for axes - Paper “Consensus” - Publication policy of project products - Project schedule - Scientific papers schedule

  5. SUMMARY AS OF TO DATE

  6. BACKGROUND • Standardized hippocampal atrophy quantification needed as: • Biomarker for early diagnosis of AD • Surrogate marker tracking disease progression in clinical trials • Validation of automated segmentation algorithms

  7. STANDARDIZATION STEPS OF MANUAL HIPPOCAMPAL VOLUMETRY Acquisition Orientation Segmentation EADC-ADNI Hippocampal Harmonization Project Funded by Alzheimer’s Association Co-funded by unrestricted grant from Wyeth and Lilly ADNI

  8. THE EADC-ADNI WORKING GROUP ON THE Harmonized Protocol for Hippocampal Volumetry J O’Brien, M Firbank, E Burton Newcastle L-O Wahlund, B WinbaldStockholm G Waldemar Copenhagen A Simmons London L CollinsMontreal S Duchesne, N Robitaille Quebec City N Fox, J Barnes, M Blair London S Taipel, M Grothe Rostock H Soininen, MPihlajamäki, Y Liu Kuopio J Pruessner, S PietrantonioMontreal R Camicioli, N MalykhinEdmonton F Barkhof, P Scheltens, W Henneman, M Pronk, F van Dommelen Amsterdam L Froelich Mannheim H Hampel Frankfurt CR Jack, G Preboske, C Ward Rochester M Geerlings, L Gerritsen, M Portegies (SMART-Medea Study) L deToledo-Morrell, D Bennet, T Stoub Chicago J Pantel Frankfurt C Watson Detroit PJ Visser Maastricht J Kaye, L Silbert, T Swihart Portland C Hock, H Wolf, Zurich T denHeijer (Rotterdam Scan Study) JG Csernansky, L Wang, A Christensen Evanston RJ Killiany, C Bauer Boston C deCarli, S Hollander Davis M Albert Baltimore GB Frisoni, M Boccardi, M Bocchetta, R Ganzola, A Redolfi, D Tolomeo, G Corbetta, E Cavedo, M Lanfredi Brescia M deLeon New York B Dubois, S Lehericy, C Boutet Paris M Weiner, S Mueller San Francisco P Pasqualetti, Rome L Launer Bethesda W Jagust Berkeley B Bartzokis, PM Thompson, L Apostolova, M Tinley Los Angeles P Sachdev, JJ Maller (PATH through life Study)

  9. METHODS Break down into segmentation units Assessment of measurement properties of SUs Survey and operationalization Jack, 1994; deToledo-Morrell, 2004 Bartzokis, 1998 Haller, 1997 Convit, 1997 Pruessner, 2000 Malykhin, 2007 Killiany, 1993 Pantel, 2000 Soininen, 1994 Lehericy, 1994 Watson, 1992

  10. METHODS Assessment of measurement properties of SUs Delphi panel 5 ROUNDS HARMONIZED HIPPOCAMPUS

  11. DELPHI PANEL

  12. Hippo experts participated to evidence-based Delphi panel P.I. City Delphi Panelist Barkhof/Scheltens Amsterdam Wouter Henneman George Bartzokis Los AngelesGeorge Bartzokis Richard Camicioli Edmonton Nikolai Malykhin John Csernansky Chicago Lei Wang Charles DeCarli Sacramento Charles DeCarli Leyla DeToledo-Morrell Chicago Leyla DeToledo-Morrell Nick Fox London Josephine Barnes Mirjam Geerlings Stockholm Lotte Gerritsen Clifford Jack Rochester Clifford Jack/Greg Preboske Ronald Killiany Boston Ronald Killiany John O’Brien Newcastle Michael Firbank Jens Pruessner Montreal Jens Pruessner Hilkka Soininen Kuopio H. Soininen/M. Pihlajamäki Paul Thompson Los Angeles Liana Apostolova Craig Watson Detroit Craig Watson Christoph Hock Zurich Henrike Wolf

  13. Delphi panel results

  14. LANDMARKS

  15. Delphi consensus - LANDMARKS “Alveus/Fimbria”: The hyperintense tissue located on the dorso-lateral aspect of the hippocampal head and body. Significant agreement on Round II p=0.021

  16. Delphi consensus - LANDMARKS “Subiculum-Morphology”: A line following the visible contour of the medial border of the hippocampus, and relying on the morphological details. Significant agreement on “Morphology” as first choice criterion on Round III P=0.006

  17. Delphi consensus - LANDMARKS “Subiculum- Horizontal”: A horizontal line connecting the highest point of the parahippocampal WM medially, to the ambient cistern. Significant agreement on “Horizontal” as second choice criterion on Round III p=0.021 Oblique Horizontal Line as second choice

  18. Delphi consensus - LANDMARKS “Tail”: all hippocampal tissue visible from the joint visualization of the superior and inferior colliculi, to the most caudal slice where GM mass is visible inferomedially to the trigone of the lateral ventricle. Significant agreement on Round III p=0.013

  19. Delphi consensus - LANDMARKS “Harmonized Hippocampus”: Global definition of hippocampus, including all SUs Significant agreement on Round IIp=0.001

  20. Delphi consensus - LANDMARKS Covers 100% of hippocampus proper Captures 100% of AD-related atrophy Intra-rater (BS-Mayo-LONI-Mainz):0.98 Inter-rater (BS-Mayo-LONI-Mainz): 0.94

  21. Delphi Landmark Consensus movie "Movie 1“

  22. SEGMENTATION MODALITIES

  23. Delphi consensus – Discrimination Amy/Hippo Significant agreement for discrimination based on 3D navigation Round II p<0.0005 Not possible Possible

  24. Delphi consensus – Vestigial Disagreement for discrimination based on 3D navigation in round III Include exclude vestigial

  25. Delphi consensus – CSF pools

  26. Delphi consensus – CSF pools Round III p=0.004 The CSF located internal to the hippocampus, also in unexpected regions, must be excluded from the segmentation when the tracer is sufficiently sure that the hypointense voxels correspond to CSF, and not to partial volume effect. disagree agree with definition

  27. Delphi consensus – hardly visible structures

  28. Delphi consensus – hardly visible structures Round III p<0.0005 “…a priori knowledge of hippocampal morphology must be used to carry out additional checks to ascertain whether hippocampal tissue can be detected in atrophic patients.”

  29. Delphi consensus – separate Fimbria/Fornix

  30. Delphi consensus – separate Fimbria/Fornix Round IV p=0.003 “Include the WM as alveus/fimbria whenever it appears attached to the hippocampal GM. Exclude the above WM as fornix. this part diverges from the plane parallel to the parahippocampal WM, taking a different angle, and is clearly detached from hippocampal GM”

  31. Delphi consensus – image orientation Methodological problem: data fed to Delphi were collected on the AC-PC axis. Shift to hippo axis may represent an inconsistency. We compared the topographic and volumetric stability (TRTR and IRR of master tracers) of segmentation on hippo and AC-PC axes.

  32. Design of axis check Liana Apostolova Gregory Preboske Martina Bocchetta segmented (based on Harmonized Prot) 10 ADNI subjects (R+L) on hippo axis on AC-PC axis Volume agreement within and between tracers and Dice’s coefficients for spatial overlapping were computed.

  33. Image orientation better overlapping of segmentation in AC-PC Dice’s coefficients for spatial overlapping agreement between MB and GP.

  34. Image orientation: visualization of tracings shows better overlapping in AC-PC "Movie 2"Maximum Dice for AC-PC (0.8908) computed between Tracer 2 and Tracer 3, and corresponding to Subject 3, Right hippo.

  35. Delphi panel V: agreement for AC-PC Round V p=0.006 The Delphi panel agreed to keep AC-PC, in consideration of the methodological problem and the new evidence: Median 8.5 Binomial p=0.006 disagreement agreement

  36. PUBLICATION POLICY

  37. Publication policy Latest release: March 28 Steering Committee Applicability Availability of deliverables Authorships Acknowledgements Revisions http://www.hippocampal-protocol.net/SOPs/LINK_PAGE/Publication_Policy_V3-2.pdf

  38. Availability of deliverables The Harmonized Protocol (i.e. the text description and illustrative material), the digital master tracer masks, and digital training sets (masks developed by the 5 best naïve tracers) will be available only to beta-test users in the period (about 1 year) between the end of the Delphi Panel and the publication of the full validation results (i.e. the analysis of the whole set of hippocampal tracings by all naïve tracers). To qualify as beta-testers, users will submit proposals to the SC; if accepted, beta-testers will be granted access to deliverables under conditions dictated by a written cooperation agreement that will be signed by the user and the Chair of the SC. Assuming mutual benefit, the cooperation agreement will include provisions related to scientific publications, donations, and feedback that beta users will provide on their exploitation of the Harmonized Protocol.

  39. PROJECT SCHEDULE

  40. FUTURE STEPS 1. Develop a qualification environment and qualification thresholds for naïve tracers and automated algorithms (by June 2012) "Movie 3“ Prototype of qualification environment and thresholds

  41. FUTURE STEPS • 2. Validate on: • 1800 ADNI hippocampi segmented by 20 human tracers • 20x2 (R&L) hippocampi with volume on pathology, neuronal density, and ex vivo MR • (by January 2013) Variability Sources Examination: Effects of: rater, trace-retrace, side, atrophy, time/progression, scanner, strength field

  42. GANTT

  43. PAPERS SCHEDULE

  44. Papers describing the project 1. Survey of protocols (preliminary phase; published, JAD 2011) 2. Operationalization (preliminary phase; submitted to Alzheimer’s & Dementia, MS n. ADJ-D-12-00094) 3. Orientation check (Brescia Team, in progress) 4. Delphi consensus (Brescia Team, in progress) 5. Master tracers’ practice and reliability (Brescia Team, in progress) 6. Development of certification platform (Duchesne & coll) 7. Validation data and Protocol definition (Brescia Team) 8. Validation vs pathology (TBD)

  45. Results will be presented at AAN - Session S04: Aging and Dementia: Therapeutic Interventions “Delphi Consensus on Landmarks for the Manual Segmentation of the Hippocampus on MRI: Preliminary Results from the EADC−ADNI Harmonized Protocol Working Group” platform presentation number S04.003 Tuesday, April 24, 2012 at 1:30 pm

  46. Results will be highlighted at Geriatric Neurology Section Highlights in the Field Wednesday, April 25th from 5:30-6:30 p.m. Room 356/357 (Drs. Ringman and Apostolova) More info about the project at www.hippocampal-protocol.net

  47. Acknowledgements Maria Carrillo, Meredith McNeil Alzheimer’s Association, Chicago IL All partners!

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