1. 2004 All Hands Meeting Function BIRN 2004

2. The Development of Schizophrenia Sheitman BB, Lieberman JA. J Psychiatr Res. 1998(May-Aug);32(3-4):143-150 Age (Years) Good Function Poor 15203040506070 Premorbid Progression Stable Relapsing Prodrome ? Improving First Episode

3. What to do?  Insufficient by themselves in understanding development, course and treatment response Clinical profiles Cognitive assessments Neuroimaging measures Genetic measures  In combination: Can we improve diagnosis, treatment, and pathophysiology?

4. Endophenotypes  Definition  Hypothesis driven: Does DLPFC dysfunction correlate with severity of negative symptoms?  Exploratory: What combinations of brain activation patterns and genetic patterns best predict clinical symptoms in chronic schizophrenics?

5. Endophenotypes  “measurable components unseen by the unaided eye along the pathway between disease and distal genotype, and thus closer to the biological expression or pathophysiology of the illness than clinical symptoms” Gottesman and Gould, 2003  we are defining endophenotypes as unique clusters of clinical, imaging, genetic, and behavioral data that are “unseen by the unaided eye” and have predictive power in terms of course of illness, response to treatment, or greater understanding of pathophysiology. By our working definition, endophenotypes also have to have predictive power. We have expanded Gottesman and Gould’s definition to include emergent combinations of clinical measures, imaging data, and other neuro­physiological measures with genetic information to enhance understanding of the disease process and improve treatment.

6. Endophenotypes  “measurable components unseen by the unaided eye along the pathway between disease and distal genotype, and thus closer to the biological expression or pathophysiology of the illness than clinical symptoms” Gottesman and Gould, 2003  The emergent combinations of clinical measures, imaging data, and other neuro­physiological measures with genetic information to enhance understanding of the disease process and improve treatment.

7. Function BIRN  Began in October 2002 as 11 sites Initial challenge: Assess intersite variability in fMRI and develop correction methods  Now it involves 14 sites New involvement: Yale (Judy Ford & Dan Mathalon), MIT (Polina Golland), UCSF (Michael Weiner & Norbert Schuff)  Evaluation efforts already begun: Human Computer Interactions through Cal-(IT)2 at UCI and UCSD

8. Structure of the FBIRN

9. Past progress  AHM 2003: We reported on Phase I, the traveling human phantom study  The Calibration, Cognitive, Statistics and IT presentations will highlight those results  Preparing for Phase II: Collect clinical, imaging, and genetic data On schizophrenics and controls By site

10. Last Year Successes 2003  Developed the QA and calibration imaging protocol  Extended Morph BIRN database schema to include functional scans  Developed XML translation methods  Implemented calibration protocol and QA at all sites  Achieved IRB approval at all sites  Beta-tested the cognitive paradigms  Completed the traveling phantom data collection  Developed initial automated methods and uploaded preliminary datasets to the SRB

11. FBIRN All Hands, March 2004 TimeWedThursFri 9 am 10:45 Opening: Agenda and goals for the meeting Review progress since October and identify obstacles 9-9:10 welcome 9:10-10 DB and tools 10-10:45 Summarizing Calib Methods results 9-9:30 Feedback on the demos 9:45-10:15 Interactions with BIRN-CC 10:30 -11 Cognitive Update 11 to noon Specific Aims update 9-9:30 MIND plans and interactions 9:45-10:45 Cognitive/Calibration joint mtg on Image analysis path 10:45Break 1111-11:30 Calibration tasks for phase II overview 11:30-Noon Cognitive task overview Statistics for Renewal Clinical Aims Discussion 12 -2 pmLunch and discussions Preview of NIH demos for general feedback (Board Room, 1-2 pm) Lunch and discussions DB and fMRI discussion of data methods, storage, and needs (Patio) Lunch and discussions Site PI lunch 2-3:30DB working group meeting 2- 6 pm Calib/Stats Presentations Clinical WG and Database group discussion (Board Room) Calibration Methods Discussion “Show your new analysis” demos (Huntington Room) 2-2:45 NIH Panel presentations and feedback 3-4 Renewal Discussion 3:30Break 4Cognitive Task Presentations Cognitive Action Plan Discussions: Immediate plans Timeline and milestones development 5Calibration Action Plan Discussions: Immediate plans 6END 5:30 Reception

12. Refinement of Phase I for Phase II  Phase I data analysis  Expansion of IT and analysis tools  Refinements Calibration tasks modifications  What can the patient population do? Cognitive task changes  What gives the most robust results? Statistical methods applied and explored  What are the variabilities in the datasets? IT methods improved and new interfaces developed

13. Protocols tested by MIND  MIND consortium study in April/May 2004  Applied the new Phase II FBIRN sensorimotor and breathold protocol  Tested the new working memory task  10 healthy subjects sent to MGH, UNM, UMN, IA  Included diffusion tensor imaging

14. Phase II (until June 2005)  Subjects: Fifteen chronic schizophrenics by site Fifteen age-matched controls by site  Clinical assessment protocol Medical history Symptom assessments  Genetic sample SNP analysis  Imaging protocol New sensorimotor task New SIRP task New Auditory Oddball Task New sensorimotor (repeat) New Breathhold task Site-specific protocol  Scanned again at least 24 hours later for repeatability

15.  All data will be uploaded to the SRB and the HID for BIRN access according to current policy Including the site-specific protocols  This 300-subject dataset will again be unique Intersite variability across subjects Intersession variability within subjects and across sites Reliability of patient/control differences across site Initial data regarding cognitive paradigm comparisons  The combination of genetic, imaging, behavioral and clinical data ENDOPHENOTYPES Phase II

16.  Reports from: Statistics Working Group - Hal Stern Calibration Working Group - Bryon Mueller Cognitive Working Group – Gregory McCarthy IT Working Group – Dave Keator

18. Future plans  Phase II dataset: homogenous and distributed population  Beginning June 2005: Wave I protocol Using the Phase II protocol Distributed and heterogenous population Site-specific patient populations and age-matched controls Covering the full range of the disease from prodromal to chronic  This ambitious dataset in combination with Phase II is the foundation for Multi-site cross-sectional and longitudinal studies Datamining method development Endophenotype identification

19. FBIRN Subject Groups Phase I. 5 healthy volunteers who traveled to all sites, summer 2003. Phase II. 150 chronic schizophrenics and 150 matched controls collected at all sites, fall 2004-spring 2005. Wave I. A group of site-specific special subpopulations, 15 at each site with matched controls, recruited in fall 2005 (Y01). Wave II. A group of site-specific special subpopulations, 15 at each site with matched controls, recruited in Y02. Wave I-R. Wave I, returning in Y03. Wave II-R. Wave II, returning in Y04.

20. FBIRN Subject Groups Phase I. 5 healthy volunteers who traveled to all sites, summer 2003. Phase II. 150 chronic schizophrenics and 150 matched controls collected at all sites, fall 2004-spring 2005. Wave I. A group of site-specific special subpopulations, 15 at each site with matched controls, recruited in fall 2005 (Y01). Wave II. A group of site-specific special subpopulations, 15 at each site with matched controls, recruited in Y02. Wave I-R. Wave I, returning in Y03. Wave II-R. Wave II, returning in Y04.