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Whole blood transcriptome biomarkers of unruptured intracranial aneurysm

Kerry E. Poppenberg,Lu Li,Muhammad Waqas,Nikhil Paliwal,Kaiyu Jiang,James N. Jarvis,Yijun Sun,Kenneth V. Snyder,Elad I. Levy,Adnan H. Siddiqui,John Kolega,Hui Meng,Vincent M. Tutino

Abstract

Background

The rupture of an intracranial aneurysm (IA) causes devastating subarachnoid hemorrhages, yet most IAs remain undiscovered until they rupture. Recently, we found an IA RNA expression signature of circulating neutrophils, and used transcriptome data to build predictive models for unruptured IAs. In this study, we evaluate the feasibility of using whole blood transcriptomes to predict the presence of unruptured IAs.

Introduction

Intracranial aneurysms (IAs) are pathological outpouchings within cerebrovasculature whose natural history is driven by inflammation. Although the rupture of an IA occurs at a rate of approximately 1% per year, the consequences are devastating. Rupture is the main cause of non-traumatic subarachnoid hemorrhage (SAH), which carries high rates of mortality (up to 50%). Early IA detection would enable closer monitoring and preventive treatments, which can drastically reduce the rate of rupture. For instance, one study found that for a 50-year-old man with an IA, the probability of rupture during his remaining lifetime was 22.8%, but can be reduced to 1.6% after surgical clipping or 3.4% after endovascular coiling.

Methods

Study enrolment

All methods in this study were approved by the University at Buffalo Institutional Review Board (study no. 030–474433). Written informed consent was obtained from all subjects prior to sample collection and the study was carried out in accordance with the approved protocol. Patients at Gates Vascular Institute (Buffalo, NY) receiving cerebral DSA with and without IA diagnosis were enrolled in this study. Indications for DSA include confirmation of IAs detected on noninvasive imaging or follow-up noninvasive imaging of previously-detected IAs for IA group, or to identify presence or absence of vascular disease (i.e. malformations, carotid stenosis) for control group. Patients who consented to participate in this study were over 18 years old, English-speaking, and had not previously been treated for IA. Patients who were pregnant, had a fever (>100°F), recently had invasive surgery, were receiving chemotherapy treatments, had autoimmune diseases, or were on immunomodulating drugs, as noted in their medical records, were excluded. Information about patient’s history and comorbidities was collected from electronic medical records.

Discussion

There is a critical need for a minimally-invasive prescreen to identify patients who have an unruptured IA and would, therefore, maximally benefit from cerebral vascular imaging (such as MRA) for IA detection. Previously, we hypothesized that circulating blood cells have altered expression profiles after contact with IA tissue or inflammatory mediators released by IAs. We investigated this by performing a transcriptome profiling study of circulating neutrophils in patients with and without IA and found an IA signature in neutrophils, which when trained via a machine learning pipeline demonstrated predictive ability to detect unruptured IAs. In this study, we discovered that a unique IA signature exists in whole blood transcriptomes, albeit there were no common genes between neutrophil and whole blood IA biomarkers.

Acknowledgments

We thank the patients who participated in this study, Jonathan Bard MA and Brandon Marzullo MS for RNA sequencing data analysis assistance, and Jennifer L. Gay CCRP for study protocol management. This work was performed in part at the New York State Center of Excellence in Bioinformatics and Life Sciences’ Genomics and Bioinformatics Core.

Citation: Poppenberg KE, Li L, Waqas M, Paliwal N, Jiang K, Jarvis JN, et al. (2020) Whole blood transcriptome biomarkers of unruptured intracranial aneurysm. PLoS ONE 15(11): e0241838. https://doi.org/10.1371/journal.pone.0241838

Editor: Jinglu Ai, Barrow Neurological Institute, UNITED STATES

Received: August 21, 2020; Accepted: October 21, 2020; Published: November 6, 2020

Copyright: © 2020 Poppenberg et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability:

Raw next-generation RNA sequencing data files and tables of processed transcript expression levels for the 47 samples in the training cohort in this publication can be found at NCBI’s GEO (accession no. GSE159610). All expression levels for the LASSO-selected classifier transcripts measured in the 20 samples of the testing dataset are presented in their entirety in the Supporting Information file.

Funding:

This study was supported by Neurovascular Diagnostics, Inc. in the form of a National Science Foundation (https://www.nsf.gov/) grant awarded to VMT (1746694), The Brain Aneurysm Foundation (https://bafound.org/) in the form of funding awarded to VMT, The New York State Center for Advanced Technology in Big Data and Health Sciences (http://www.buffalo.edu/bioinformatics/resources/funding-incentives/ub-cat.html) in the form of funding awarded to VMT, and The Cummings Foundation (https://jameshcummings.com/) in the form of funding awarded to AHS. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests:

I have read the journal's policy and the authors of this manuscript have the following competing interests: JNJ—Principal Investigator: NIH Grant R01-AR-060604. KVS—Consulting/teaching: Canon Medical Systems Corporation, Penumbra Inc., Medtronic, Jacobs Institute. Co-Founder: Neurovascular Diagnostics, Inc. EIL—Intratech Medical Ltd. NeXtGen Biologics. Principal investigator: Medtronic US SWIFT PRIME Trials. Honoraria–Medtronic. Consultant–Pulsar Vascular. Advisory Board-Stryker, NeXtGen Biologics, MEDX, Cognition Medical. Other financial support—Abbott Vascular for carotid training sessions. AHS—Financial Interest/Investor/Stock Options/Ownership: Amnis Therapeutics, Apama Medical,BlinkTBI, Inc., Buffalo Technology Partners, Inc., Cardinal Health, Cerebrotech Medical Systems, Inc., Claret Medical, Cognition Medical, Endostream Medical, Ltd., Imperative Care, International Medical Distribution Partners, Rebound Therapeutics Corp., Silk Road Medical, StimMed, Synchron, Three Rivers Medical, Inc., Viseon Spine, Inc. Consultant/Advisory Board: Amnis Therapeutics, Boston Scientific, Canon Medical Systems USA, Inc., Cerebrotech Medical Systems, Inc., Cerenovus, Claret Medical, Corindus, Inc., Endostream Medical, Ltd., Guidepoint 15Global Consulting, Imperative Care, Integra, Medtronic, MicroVention, Northwest University—DSMB Chair for HEAT Trial, Penumbra, Rapid Medical,Rebound Therapeutics Corp., Silk Road Medical, StimMed, Stryker, Three Rivers Medical, Inc.,VasSol, W.L. Gore & Associates. National PI/Steering Committees: Cerenovus LARGE Trial and ARISE II Trial,Medtronic SWIFTPRIME and SWIFT DIRECT Trials, MicroVention FRED Trial & CONFIDENCE Study, MUSC POSITIVE Trial,Penumbra 3D Separator Trial, COMPASS Trial, INVEST Trial. Principal investigator: Cummings Foundation grant. HM—Principal investigator:NIH Grants R01-NS-091075 and R01-NS-064592. Grant support: Canon Medical Systems. Co-founder: Neurovascular Diagnostics, Inc. VMT—Principal investigator: National Science Foundation Award No. 1746694, Brain Aneurysm Foundation grant, and Center for Advanced Technology grant. Co-founder:Neurovascular Diagnostics, Inc. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

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