A data-driven approach for evaluating multi-modal therapy in traumatic brain injury

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.