Data-driven discovery in complex neurological disorders has potential to extract meaningful syndromic knowledge from large, heterogeneous data sets to enhance potential for precision medicine. Here we describe the application of topological data analysis (TDA) for data-driven discovery in preclinical traumatic brain injury (TBI) and spinal cord injury (SCI) data sets mined from the Visualized Syndromic Information and Outcomes for Neurotrauma-SCI (VISION-SCI) repository. Through direct visualization of inter-related histopathological, functional and health outcomes, TDA detected novel patterns across the syndromic network, uncovering interactions between SCI and co-occurring TBI, as well as detrimental drug effects in unpublished multicentre preclinical drug trial data in SCI. TDA also revealed that perioperative hypertension predicted long-term recovery better than any tested drug after thoracic SCI in rats. TDA-based data-driven discovery has great potential application for decision-support for basic research and clinical problems such as outcome assessment, neurocritical care, treatment planning and rapid, precision-diagnosis.

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Published in Nature Communications, v. 6, article 8581, p. 1-12.

© 2015 Macmillan Publishers Limited. All rights reserved.

This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

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This work was funded by the Craig H. Neilsen Foundation Grant 224308, the National Institutes of Health (NIH) NS067092 (A.R.F.), NS069537 (A.R.F), NS038079 (J.C.B. and M.S.B.), NS031193 and AG032518 (M.S.B. and J.C.B.), NS079030 (J.L.N.), NS032000 (W.Y.; M.S.B. site PI, multicentre study); NYSCoRE CO19772 (M.S.B. and J.C.B.), the Department of Defense (DoD) grants W81XWH-10-1-0910 (M.S.B.) and W81XWH-13- 1-0297 (M.S.B.), and Wings for Life Foundation grants WFLUS008/12 and WFLUS006/ 14 (A.R.F.).

ncomms9581-s1.zip (262 kB)
Supplementary Software 1: TBI-SCI syndromic network topology. An HTML viewer exported from the TDA to visualize functional recovery and histopathology of a combined unilateral mild TBI and unilateral 75kdyn force-driven SCI contusion preclinical model in rats. Results for the deficits caused by this model have been reported previously (Inoue et al 2013). Here we show the novel application of syndromic TDA to visually characterize the network topology of this emerging preclinical model to confirm the published findings. The drop-down menu (upper-right) allows for rapid exploration through all outcomes and injury models within the network. Combined SCI+TBI ipsilateral to each other restores balance of function between the forelimbs on measures of skilled forelimb function, including paw preference, grooming and object manipulation.

ncomms9581-s2.zip (333 kB)
Supplementary Software 2: Cervical SCI syndromic network topology. The HTML viewer was exported from the TDA, which contains a drop-down menu (upper right) that allows for rapid exploration through all outcomes and injury models within the network. This visual mapping allows for the reader to orient themselves to the location of each injury models within the topology, and scroll through each outcome over time to view the relationship to recovery. Data-driven discovery of functional deficits in forelimb openfield and grooming tasks in subjects that received 12.5mm weight-drop contusions revealed decreased MN sparing and tissue area at the lesion epicenter in subjects that received either Minocycline or Methylprednisolone, compared to no drug controls.

ncomms9581-s3.zip (257 kB)
Supplementary Software 3: MP treatment trials in thoracic SCI SVD network. The drop-down menu (upper right) allows for rapid exploration through all outcomes and injury models within the network. In a cross-validation test the detrimental effects of methylprednisolone (MP1 and MCP) we saw no significant impact of drug on either functional recovery on the BBB (p=0.24) or tissue sparing (p=0.20) relative to vehicle control.

ncomms9581-s4.zip (395 kB)
Supplementary Software 4: The entire thoracic SCI syndromic network topology. The drop-down menu (upper right) allows for rapid exploration through all outcomes within the network. Data-driven identification of elevated perioperative blood pressure predicting functional deficits following thoracic contusions was uncovered in 2 separate datasets (Figure 5). The relationship between blood pressure and functional deficits was confirmed when all datasets were combined, and assessed over time (Figure 6). All outcomes for tissue sparing, locomotor recovery, bladder function and perioperative vitals and blood gases were mapped onto the network topology for rapid exploration of the relationship between autonomic complications and recovery of locomotion (N=334).

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