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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 - PowerPoint PPT Presentation
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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
• 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
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• 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