InTBIR meeting: San Francisco June 2014 Development of joint projects

1. InTBIR meeting: San Francisco June 2014 Development of joint projects

2. Areas of Collaboration Protocol harmonisation: TRACK-TBI/CENTER-TBI; ADAPT/CENTER-TBI; Canadian pediatric CDE project aligned with TRACK-TBI; & collaborative work between Canadian teams Coordinated data collection : TRACK-TBI/CENTER-TBI; CENTER-TBI/CREACTIVE Processing and analysis alignment: Sample processing, outcomes, imaging, genetics Novel collaborations: CANTAB-NIH Toolbox cross-comparison, GAIN, EpiBios, ICON

3. 5 additional CANTAB platforms for use in US sites for cross-validation

4. Diaz-Arrastia (USUHS), Hammond (Indiana), McAllister (Indiana), Manley (UCSF), Menon (Cambridge), Richardson (Cambridge) Neale (Broad), Palotie (FIMM/Broad), Rosand (Broad/MGH), Tenovuo (Turku), van Gils (VTT) Wagner (UPMC) • Clinical implications of genetic variability uncertain • However, only ~30% of outcome variation explained • Need larger sample sizes which determine incremental benefit of knowing genetic variability • No single large dataset; many moderately sized datasets • Methods experts (Palotie, Richardson, Rosand, Neale) • Collaborative study may be more than sum of its parts • Federated data collection overcomes many barriers

5. GAIN solutions • Initial plans aimed at: • Existing datasets and sample banks (~4000 patients) • Included TRACK-TBI pilot and TBIcare • Candidate gene approach • Subsequent discussions • Federated analysis (FIMM/Broad Institute) – no sample transfer • Move to GWAS + exome enrichment (Ben Neale; Broad Institute) • Use available population controls • Sample transfer in process, but funds are limiting • A basis for shared analysis plans in TRACK-TBI/CENTER-TBI • Consent for wider comparisons - other diseases (e.g. PGC) • Potential application to Wellcome Trust (initial discussions+)

6. Epilepsy Bioinformatics study (EpiBios) • PIs: Vespa, Engel, Jensen, Pitkanen, Litt, Toga • Epilepsy Bioinformatics Study (EpiBioS): • Center without walls Working Group • 100 contributors: leading figures in animal and human epilepsy • Bioinformatics approach to identify reliable epilepsy biomarkers • Goals of the project are to: • Determine biomarkers of epileptogenesis • Identify patients at highest risk for epilepsy after a brain insult, • Study mechanisms of epileptogenesis • Stage the epileptogenic process. • Funding: • P20 grant support at present (1P20NS080181-01) • UO1 application Fall 2014

7. Rationale for Collaboration • TBI major acute brain insult leading to epilepsy • Attributable risk from TBI ~15% of all epilepsy • TBI - excellent clinical model for epileptogenesis • Temporally defined insult, tracking of patients feasible • Informatics approach feasible • Existing resources in place • Database structure (LONI-USC) • Preliminary feasibility and risk factor data (UCLA; NNTS Poster A1-15) • Current EEG collaborations several centres, Moberg, iEEGcentre (UPenn) • Economic benefits of collaborative research and increased scale • Enhanced data collection in InTBIR study sites (n) • TRACK-TBI (5), CENTER-TBI (3), ADAPT(3) leads positive • Additional funding allows enhanced use of data already being collected to address an important question

8. Proposed strategy for EpiBioS • Incidence and determinants of PTE in large clinical cohort: TRACK-TBI, CENTER-TBI, ADAPT (n=5000/2 years) • High temporal resolution cEEG data from severe TBI (n=900/2 yrs) • Animal study to develop valid biomarkers for PTE • Translational study: PTE > other acquired epilepsy • New UO1 & supplementary funding to parent studies for: • Primary epilepsy-related data collection • Biomarker analysis, EEG analysis, imaging analysis • The informatics process • Network functions and workshops • The NINDS special program in Epileptogensis as UO1 mechanism

9. Specifics of the collaboration • Data sharing of all primary data for informatics analysis to determine risk factors/ consequences of PTE • Harmonization of MRI protocols to meet PTE hypotheses • Add cEEG and blood biomarkers for PTE in the subgroup of severe TBI (ICU cohort) high temporal resolution study • Add telephone follow up for epilepsy at 1 and 2 years after TBI • Add blood biomarker assays at serial times points to detect PTE biomarkers (2 wks, 3 mo, 6 mo, 12 mo) • Add confirmatory assessment on subset of patients screening positive by telephone for PTE (EEG, clinic visit) at 1 or 2 years

10. CD3/43 MBP Merge

11. Investigation of neuroinflammation in TBI Temporal pattern and outcome impact Experimental-human comparisons; biology – innate/adaptive; M1/M2 Four groups + industrial partner (GSK) Cambridge (Menon, Hutchinson, Coles) Calgary (Barlow, Gallagher, Milan (Zanier) Glasgow (Stewart, McMillan) Four clinical cohorts Paediatric mTBI (Calgary) Adult Mod/severe TBI (Cambridge) Repeated mTBI (Rugby- Glasgow) Neuropathology archive (Glasgow) Two experimental models Mild TBI (Calgary) Mod/Severe TBI & microglial biology (Milan) International Collaboration On Neuroinflammation in TBI • ICON-TBI • ERANET-NEURON grant • Outline application • Science rated well • Not shortlisted • “limited evidence of collaboration between partners” • Combined pilot data collection - resubmit

12. Lessons learned • InTBIR is more than the sum of its parts • Major collaborative opportunities • Many potential strategies – depends on goal • Advantage in clinical studies self-evident, but success in funding remains unproven • Translational approaches may hold substantial potential, but need nurturing/maturing