CENTER-TBI has received funding from the European Union Seventh Framework Programme (FP7/2007-2013) under grant agreement n°602150

InTBIR meeting: San Francisco June 2014Development of joint projects

AREAS OF COLLABORATION

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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

• 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

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)

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+)

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

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, iEEG centre (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

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

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

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-TBIERANET-NEURON grant

• Outline application• Science rated well• Not shortlisted

o “limited evidence of collaboration between partners”

o Combined pilot data collection - resubmit

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