title: Minimizing errors in acute traumatic spinal cord injury trials by acknowledging the heterogeneity of spinal cord anatomy and injury severity: an observational Canadian cohort analysis.
abstract: Clinical trials of therapies for acute traumatic spinal cord injury (tSCI) have failed to convincingly demonstrate efficacy in improving neurologic function. Failing to acknowledge the heterogeneity of these injuries and under-appreciating the impact of the most important baseline prognostic variables likely contributes to this translational failure. Our hypothesis was that neurological level and severity of initial injury (measured by the American Spinal Injury Association Impairment Scale [AIS]) act jointly and are the major determinants of motor recovery. Our objective was to quantify the influence of these variables when considered together on early motor score recovery following acute tSCI. Eight hundred thirty-six participants from the Rick Hansen Spinal Cord Injury Registry were analyzed for motor score improvement from baseline to follow-up. In AIS A, B, and C patients, cervical and thoracic injuries displayed significantly different motor score recovery. AIS A patients with thoracic (T2-T10) and thoracolumbar (T11-L2) injuries had significantly different motor improvement. High (C1-C4) and low (C5-T1) cervical injuries demonstrated differences in upper extremity motor recovery in AIS B, C, and D. A hypothetical clinical trial example demonstrated the benefits of stratifying on neurological level and severity of injury. Clinically meaningful motor score recovery is predictably related to the neurological level of injury and the severity of the baseline neurological impairment. Stratifying clinical trial cohorts using a joint distribution of these two variables will enhance a study's chance of identifying a true treatment effect and minimize the risk of misattributed treatment effects. Clinical studies should stratify participants based on these factors and record the number of participants and their mean baseline motor scores for each category of this joint distribution as part of the reporting of participant characteristics. Improved clinical trial design is a high priority as new therapies and interventions for tSCI emerge.
authors.affiliation: 1 Department of Orthopedics, University of British Columbia , Vancouver, British Columbia, Canada .
authors.forename: Marcel F
authors.initials: MF
authors.lastname: Dvorak
authors.forename: Vanessa K
authors.initials: VK
authors.lastname: Noonan
authors.forename: Nader
authors.initials: N
authors.lastname: Fallah
authors.forename: Charles G
authors.initials: CG
authors.lastname: Fisher
authors.forename: Carly S
authors.initials: CS
authors.lastname: Rivers
authors.forename: Henry
authors.initials: H
authors.lastname: Ahn
authors.forename: Eve C
authors.initials: EC
authors.lastname: Tsai
authors.forename: A G
authors.initials: AG
authors.lastname: Linassi
authors.forename: Sean D
authors.initials: SD
authors.lastname: Christie
authors.forename: Najmedden
authors.initials: N
authors.lastname: Attabib
authors.forename: R John
authors.initials: RJ
authors.lastname: Hurlbert
authors.forename: Daryl R
authors.initials: DR
authors.lastname: Fourney
authors.forename: Michael G
authors.initials: MG
authors.lastname: Johnson
authors.forename: Michael G
authors.initials: MG
authors.lastname: Fehlings
authors.forename: Brian
authors.initials: B
authors.lastname: Drew
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Bailey
authors.forename: Jérôme
authors.initials: J
authors.lastname: Paquet
authors.forename: Stefan
authors.initials: S
authors.lastname: Parent
authors.forename: Andrea
authors.initials: A
authors.lastname: Townson
authors.forename: Chester
authors.initials: C
authors.lastname: Ho
authors.forename: B C
authors.initials: BC
authors.lastname: Craven
authors.forename: Dany
authors.initials: D
authors.lastname: Gagnon
authors.forename: Deborah
authors.initials: D
authors.lastname: Tsui
authors.forename: Richard
authors.initials: R
authors.lastname: Fox
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Mac-Thiong
authors.forename: Brian K
authors.initials: BK
authors.lastname: Kwon
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002170:Canada; D015331:Cohort Studies; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D016032:Randomized Controlled Trials as Topic / Q000592:standards*; D020127:Recovery of Function / Q000502:physiology*; D013119:Spinal Cord Injuries / Q000175:diagnosis / Q000473:pathology / Q000628:therapy; D015599:Trauma Severity Indices; D055815:Young Adult
keywords: bias; motor score; neurological recovery; spinal cord injury; statistical error