Topological network analysis of patient similarity for precision management of acute blood pressure in spinal cord injury
- University of California, San Francisco, United States
- University of New Mexico School of Medicine, United States
- Lawrence Berkeley National Laboratory, United States
- Santa Clara Valley Medical Center, United States
- University of Minnesota, United States
Abstract
Background: Predicting neurological recovery after spinal cord injury (SCI) is challenging. Using topological data analysis, we have previously shown that mean arterial pressure (MAP) during SCI surgery predicts long-term functional recovery in rodent models, motivating the present multicenter study in patients.
Methods: Intra-operative monitoring records and neurological outcome data were extracted (n=118 patients). We built a similarity network of patients from a low-dimensional space embedded using a non-linear algorithm, Isomap, and ensured topological extraction using persistent homology metrics. Confirmatory analysis was conducted through regression methods.
Results: Network analysis suggested that time outside of an optimum MAP range (hypotension or hypertension) during surgery was associated with lower likelihood of neurological recovery at hospital discharge. Logistic and LASSO regression confirmed these findings, revealing an optimal MAP range of 76-[104-117] mmHg associated with neurological recovery.
Conclusion: We show that deviation from this optimal MAP range during SCI surgery predicts lower probability of neurological recovery and suggest new targets for therapeutic intervention.
Funding: NIH/NINDS: R01NS088475 (ARF); R01NS122888 (ARF); UH3NS106899 (ARF); Department of Veterans Affairs: 1I01RX002245 (ARF), I01RX002787 (ARF); Wings for Life Foundation (ARF)(ATE); Craig H. Neilsen Foundation (ARF); and DOD: SC150198 (MSB); SC190233 (MSB).
Data availability
Source data has been deposited to the Open Data Commons for Spinal Cord Injury (odc-sci.org; RRID:SCR_016673) under the accession number ODC-SCI:245 (doi: 10.34945/F5R59) and ODC-SCI:246 (doi: 10.34945/F5MG68)
-
Intraoperative time series mean arterial pressure and heart rate after spinal cord injury in patients in a multi-site retrospective TRACK-SCI cohort: site 2 of 2Open Data Commons for Spinal Cord Injury, ODC-SCI:246.
Article and author information
Author details
Funding
National Institute of Neurological Disorders and Stroke (R01NS088475)
- Adam R Ferguson
National Institute of Neurological Disorders and Stroke (UG3NS106899)
- Adam R Ferguson
U.S. Department of Veterans Affairs (1I01RX002245)
- Adam R Ferguson
U.S. Department of Veterans Affairs (I01RX002787)
- Adam R Ferguson
Wings for Life Foundation
- Abel Torres Espín
Wings for Life Foundation
- Adam R Ferguson
Craig H. Neilsen Foundation
- Adam R Ferguson
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Human subjects: This study constitutes a retrospective data analysis. All data was de-identified before pre-processing and analysis. Protocols for retrospective data extraction were approved by Institutional Research Board (IRB) under protocol numbers 11-07639 and 11-06997.
Copyright
© 2021, Torres Espín et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 1,926
- views
-
- 278
- downloads
-
- 22
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Topological network analysis of patient similarity for precision management of acute blood pressure in spinal cord injury
eLife 10:e68015.
https://doi.org/10.7554/eLife.68015
Further reading
-
- Computational and Systems Biology
- Genetics and Genomics
Untranslated regions (UTRs) contain crucial regulatory elements for RNA stability, translation and localization, so their integrity is indispensable for gene expression. Approximately 3.7% of genetic variants associated with diseases occur in UTRs, yet a comprehensive understanding of UTR variant functions remains limited due to inefficient experimental and computational assessment methods. To systematically evaluate the effects of UTR variants on RNA stability, we established a massively parallel reporter assay on 6555 UTR variants reported in human disease databases. We examined the RNA degradation patterns mediated by the UTR library in two cell lines, and then applied LASSO regression to model the influential regulators of RNA stability. We found that UA dinucleotides and UA-rich motifs are the most prominent destabilizing element. Gain of UA dinucleotide outlined mutant UTRs with reduced stability. Studies on endogenous transcripts indicate that high UA-dinucleotide ratios in UTRs promote RNA degradation. Conversely, elevated GC content and protein binding on UA dinucleotides protect high-UA RNA from degradation. Further analysis reveals polarized roles of UA-dinucleotide-binding proteins in RNA protection and degradation. Furthermore, the UA-dinucleotide ratio of both UTRs is a common characteristic of genes in innate immune response pathways, implying a coordinated stability regulation through UTRs at the transcriptomic level. We also demonstrate that stability-altering UTRs are associated with changes in biobank-based health indices, underscoring the importance of precise UTR regulation for wellness. Our study highlights the importance of RNA stability regulation through UTR primary sequences, paving the way for further exploration of their implications in gene networks and precision medicine.
-
- Computational and Systems Biology
- Medicine
Excessive consumption of sucrose, in the form of sugar-sweetened beverages, has been implicated in the pathogenesis of metabolic dysfunction‐associated fatty liver disease (MAFLD) and other related metabolic syndromes. The c-Jun N-terminal kinase (JNK) pathway plays a crucial role in response to dietary stressors, and it was demonstrated that the inhibition of the JNK pathway could potentially be used in the treatment of MAFLD. However, the intricate mechanisms underlying these interventions remain incompletely understood given their multifaceted effects across multiple tissues. In this study, we challenged rats with sucrose-sweetened water and investigated the potential effects of JNK inhibition by employing network analysis based on the transcriptome profiling obtained from hepatic and extrahepatic tissues, including visceral white adipose tissue, skeletal muscle, and brain. Our data demonstrate that JNK inhibition by JNK-IN-5A effectively reduces the circulating triglyceride accumulation and inflammation in rats subjected to sucrose consumption. Coexpression analysis and genome-scale metabolic modeling reveal that sucrose overconsumption primarily induces transcriptional dysfunction related to fatty acid and oxidative metabolism in the liver and adipose tissues, which are largely rectified after JNK inhibition at a clinically relevant dose. Skeletal muscle exhibited minimal transcriptional changes to sucrose overconsumption but underwent substantial metabolic adaptation following the JNK inhibition. Overall, our data provides novel insights into the molecular basis by which JNK inhibition exerts its metabolic effect in the metabolically active tissues. Furthermore, our findings underpin the critical role of extrahepatic metabolism in the development of diet-induced steatosis, offering valuable guidance for future studies focused on JNK-targeting for effective treatment of MAFLD.
