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

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InTBIR meeting: San Francisco June 2014

Development of joint projects

Areas of collaboration
Areas of Collaboration

Protocol harmonisation:


Canadian pediatric CDE project aligned with TRACK-TBI; & collaborative work between Canadian teams

Coordinated data collection :


Processing and analysis alignment:

Sample processing, outcomes, imaging, genetics

Novel collaborations:

CANTAB-NIH Toolbox cross-comparison, GAIN, EpiBios, ICON

Diaz- cross-validationArrastia (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

Gain solutions
GAIN solutions cross-validation

  • 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
Epilepsy Bioinformatics study ( cross-validationEpiBios)

  • 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
Rationale for Collaboration cross-validation

  • 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

Proposed strategy for epibios
Proposed strategy for EpiBioS cross-validation

  • 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
Specifics of the collaboration cross-validation

  • 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 cross-validation



International collaboration on neuroinflammation in tbi

Investigation of cross-validationneuroinflammation 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



  • Outline application

  • Science rated well

  • Not shortlisted

  • “limited evidence of collaboration between partners”

  • Combined pilot data collection - resubmit

Lessons learned
Lessons learned cross-validation

  • 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