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.
Highlights
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
In recent studies of traumatic brain injury (TBI) and spinal cord injury, pooled multicenter and multispecies data coupled to data-driven multidimensional analysis has revealed information with significant potential for therapeutic translation, which would not have been identified through univariate analysis of a single end-point[10,11,12]
A representative example of lesion extent and location resulting from controlled cortical impact (CCI) is shown in Supplementary Fig. 1
Summary
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. 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. Injured central nervous system the complexity of the relevant outcome measures and their analysis provide a difficult challenge for developing this approach[14]
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