title: A data-driven approach for evaluating multi-modal therapy in traumatic brain injury.
abstract: Combination therapies targeting multiple recovery mechanisms have the potential for additive or synergistic effects, but experimental design and analyses of multimodal therapeutic trials are challenging. To address this problem, we developed a data-driven approach to integrate and analyze raw source data from separate pre-clinical studies and evaluated interactions between four treatments following traumatic brain injury. Histologic and behavioral outcomes were measured in 202 rats treated with combinations of an anti-inflammatory agent (minocycline), a neurotrophic agent (LM11A-31), and physical therapy consisting of assisted exercise with or without botulinum toxin-induced limb constraint. Data was curated and analyzed in a linked workflow involving non-linear principal component analysis followed by hypothesis testing with a linear mixed model. Results revealed significant benefits of the neurotrophic agent LM11A-31 on learning and memory outcomes after traumatic brain injury. In addition, modulations of LM11A-31 effects by co-administration of minocycline and by the type of physical therapy applied reached statistical significance. These results suggest a combinatorial effect of drug and physical therapy interventions that was not evident by univariate analysis. The study designs and analytic techniques applied here form a structured, unbiased, internally validated workflow that may be applied to other combinatorial studies, both in animals and humans.
authors.affiliation: Brain and Spinal Injury Center (BASIC), Department of Neurological Surgery, University of California, San Francisco, CA, United States.
authors.forename: Jenny
authors.initials: J
authors.lastname: Haefeli
authors.affiliation: Brain and Spinal Injury Center (BASIC), Department of Neurological Surgery, University of California, San Francisco, CA, United States.|San Francisco Veterans Affairs Medical Center, San Francisco, CA, United States.
authors.forename: Adam R
authors.initials: AR
authors.lastname: Ferguson
authors.affiliation: San Francisco Veterans Affairs Medical Center, San Francisco, CA, United States.
authors.forename: Deborah
authors.initials: D
authors.lastname: Bingham
authors.affiliation: San Francisco Veterans Affairs Medical Center, San Francisco, CA, United States.
authors.forename: Adrienne
authors.initials: A
authors.lastname: Orr
authors.affiliation: San Francisco Veterans Affairs Medical Center, San Francisco, CA, United States.|Department of Neurology, University of California, San Francisco, CA, United States.
authors.forename: Seok Joon
authors.initials: SJ
authors.lastname: Won
authors.affiliation: San Francisco Veterans Affairs Medical Center, San Francisco, CA, United States.|Department of Neurology, University of California, San Francisco, CA, United States.
authors.forename: Tina I
authors.initials: TI
authors.lastname: Lam
authors.affiliation: San Francisco Veterans Affairs Medical Center, San Francisco, CA, United States.|Department of Neurology, University of California, San Francisco, CA, United States.
authors.forename: Jian
authors.initials: J
authors.lastname: Shi
authors.affiliation: San Francisco Veterans Affairs Medical Center, San Francisco, CA, United States.
authors.forename: Sarah
authors.initials: S
authors.lastname: Hawley
authors.affiliation: Brain and Spinal Injury Center (BASIC), Department of Neurological Surgery, University of California, San Francisco, CA, United States.|San Francisco Veterans Affairs Medical Center, San Francisco, CA, United States.
authors.forename: Jialing
authors.initials: J
authors.lastname: Liu
authors.affiliation: San Francisco Veterans Affairs Medical Center, San Francisco, CA, United States.|Department of Neurology, University of California, San Francisco, CA, United States.
authors.forename: Raymond A
authors.initials: RA
authors.lastname: Swanson
authors.affiliation: San Francisco Veterans Affairs Medical Center, San Francisco, CA, United States.|Department of Neurology, University of California, San Francisco, CA, United States.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Massa
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D000070642:Brain Injuries, Traumatic / Q000175:diagnosis / Q000628:therapy*; D003131:Combined Modality Therapy / Q000379:methods; D004195:Disease Models, Animal; D006801:Humans; D016896:Treatment Outcome