International Initiative for Traumatic Brain Injury meeting

Molecular and Physiologic Biomarkers Jamie Hutchison, MD, FRCPC

Director of Research, Department of Critical Care and Senior Scientist, Neuroscience and Mental Health Research Program, SickKids

Professor of Paediatrics, University of Toronto

June 28, 2014San Francisco

Oligodendrocyte: MBP

Astrocyte: S100B GFAP

Microglia: IL-6, IL-8

Adherent leukocyte: IL-6, IL-8

Neuron: NSE pNF-H

Blood-brain barrier

Endothelial cell:sE-selectinsICAM-1, sVCAM-1, NCAM

Neurovascular unitPrognostic serum proteins analyzed

Biobank - Serum and CSF from N > 200 infants, children and adolescents with mild, moderate and severe TBI recruited from International PICUs and Emergency Departments.

Proof of principal studies1) Association between GCS + serum S100B on day 1 post-injury and worsened cerebral function at 12 months post-injuryArea under the multi-variable ROC curve (AUC) = 0.99

S100B aloneAUC = 0.92

GCS aloneAUC = 0.75

2) N-methyl histidine has an AUC = 1 for prediction of unfavorable outcome

‘Omics - Examples

• Genomics• Transcriptomics• Proteomics

• Metabolomics• Lipidomics• Secretomics

• Visualization– Integrate data streams– Clinician interaction– Low Information Technology footprint

• Accessibility– Transform data sets– Scalable, remote access, web-based– Stable and reliable

T3 - Physiologic Data RepresentationDr. Peter Laussen

Unit View

Stability index (hemodynamic)We are developing a neurological index with continuous ICP, NIRS and EEG

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Ramona Hicks Questions - 1What are some examples of progress in developing standard protocols for fluid biomarker research?

– CCCTBG website–Protocol for prioritizing studies using our biobank and database

What are critical gaps in standardization that need to be addressed?– Other SOPs for fluids (e.g. saliva, urine), cells and brain

Are the common data elements for fluid biomarker research sufficient?  What are their limitations, if any?

–Excellent start – change title to molecular and physiologic biomarker research –Increase the number of ‘omics’

Where are you planning to store your biosamples for your InTBIR project?– Peter Gilgan Research and Learning Centre – SickKids– Freezers have alarms, back up freezers and call system and software for tracking of specimens– Bar codes are best!

       

Ramona Hicks Questions - 2What are your plans for sharing biospecimens?

–We have an SOP – projects are approved by a steering committee – based on scientific merit, funding, collaboration

What TBI repositories are available for fluid biomarker research and would it be advantageous to use them for InTBIR projects?  Why or why not?

– Pediatric biobanks have limited blood and CSF specimens - smaller size for infants and young children so volume of blood taken is limited. – Should still use them with a strict collaboration protocol to accelerate and improve the efficiency of the research.

Do the protocols for biomarker studies meet industry and regulatory standards.–These vary across countries and institutions. Be careful – different protocols may result in changes to the molecules being measured.

Are your InTBIR biomarker studies likely to lead to the development of clinically useful TBI biomarkers by 2020?  If not, what would be required to meet this goal?

–A cost effective bedside test(s) of one or more biomarkers–Validation in large cohorts–Knowledge translation

Acknowledgements• Research coordinator Judy Van Huyse• Co-principal Investigators – Russell Schachar and Vicki Anderson• Co-investigators – Maureen Dennis, Anne-Marie Guerguerian, Vera

Nenadovic, Helena Frndova, Miriam Beauchamp, Dean Ferguson, and site investigators

• Biomarkers –Hayley Craig-Barnes, Milly Lo, Kentaro Ide, Dana Stanimirovic, Martin Post

• CCCTG and CCCTBG - John Marshall, Deborah Cook, Paul Hebert and Brent Winston

• Funding – ONF, VNI, Eli Lily, SickKids and CIHR