Radiomic Profiling of Glioblastoma: Identifying an Imaging Predictor of Patient Survival with Improved Performance over Established Clinical and Radiologic Risk Models

Purpose To evaluate whether radiomic feature-based magnetic resonance (MR) imaging signatures allow prediction of survival and stratification of patients with newly diagnosed glioblastoma with improved accuracy compared with that of established clinical and radiologic risk models. Materials and Meth...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:Radiology 2016-09, Vol.280 (3), p.880-889
Hauptverfasser: Kickingereder, Philipp, Burth, Sina, Wick, Antje, Götz, Michael, Eidel, Oliver, Schlemmer, Heinz-Peter, Maier-Hein, Klaus H, Wick, Wolfgang, Bendszus, Martin, Radbruch, Alexander, Bonekamp, David
Format: Artikel
Sprache:eng
Schlagworte:
Online-Zugang:Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
container_end_page 889
container_issue 3
container_start_page 880
container_title Radiology
container_volume 280
creator Kickingereder, Philipp
Burth, Sina
Wick, Antje
Götz, Michael
Eidel, Oliver
Schlemmer, Heinz-Peter
Maier-Hein, Klaus H
Wick, Wolfgang
Bendszus, Martin
Radbruch, Alexander
Bonekamp, David
description Purpose To evaluate whether radiomic feature-based magnetic resonance (MR) imaging signatures allow prediction of survival and stratification of patients with newly diagnosed glioblastoma with improved accuracy compared with that of established clinical and radiologic risk models. Materials and Methods Retrospective evaluation of data was approved by the local ethics committee and informed consent was waived. A total of 119 patients (allocated in a 2:1 ratio to a discovery [n = 79] or validation [n = 40] set) with newly diagnosed glioblastoma were subjected to radiomic feature extraction (12 190 features extracted, including first-order, volume, shape, and texture features) from the multiparametric (contrast material-enhanced T1-weighted and fluid-attenuated inversion-recovery imaging sequences) and multiregional (contrast-enhanced and unenhanced) tumor volumes. Radiomic features of patients in the discovery set were subjected to a supervised principal component (SPC) analysis to predict progression-free survival (PFS) and overall survival (OS) and were validated in the validation set. The performance of a Cox proportional hazards model with the SPC analysis predictor was assessed with C index and integrated Brier scores (IBS, lower scores indicating higher accuracy) and compared with Cox models based on clinical (age and Karnofsky performance score) and radiologic (Gaussian normalized relative cerebral blood volume and apparent diffusion coefficient) parameters. Results SPC analysis allowed stratification based on 11 features of patients in the discovery set into a low- or high-risk group for PFS (hazard ratio [HR], 2.43; P = .002) and OS (HR, 4.33; P < .001), and the results were validated successfully in the validation set for PFS (HR, 2.28; P = .032) and OS (HR, 3.45; P = .004). The performance of the SPC analysis (OS: IBS, 0.149; C index, 0.654; PFS: IBS, 0.138; C index, 0.611) was higher compared with that of the radiologic (OS: IBS, 0.175; C index, 0.603; PFS: IBS, 0.149; C index, 0.554) and clinical risk models (OS: IBS, 0.161, C index, 0.640; PFS: IBS, 0.139; C index, 0.599). The performance of the SPC analysis model was further improved when combined with clinical data (OS: IBS, 0.142; C index, 0.696; PFS: IBS, 0.132; C index, 0.637). Conclusion An 11-feature radiomic signature that allows prediction of survival and stratification of patients with newly diagnosed glioblastoma was identified, and improved performance compared with that of establis
doi_str_mv 10.1148/radiol.2016160845
format Article
fullrecord <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_1812891208</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>1812891208</sourcerecordid><originalsourceid>FETCH-LOGICAL-c344t-1848a75a03e0c34d36989179d356d12b0147832ef5199b838caf2aad61e88c2d3</originalsourceid><addsrcrecordid>eNpFUU1PGzEQtVARpMAP4FL52MumHns_vL1VUaCRqBoFOK9mbW8w9a6pvQniF_Vv1ttQOM1o5r03T_MIuQQ2B8jll4DaejfnDEoomcyLIzKDglcZCCg-kBljQmQyh_qUfIzxkTHIC1mdkFNeCV6WZTEjfzaTRm8VXQffWWeHLfUdvXbWtw7j6Hv8SlfaDKPtXqYlDnTV43Zq18Foq0YfJsYaR5tQ9HYX9naPjj7b8SFBn4LfG03XJnQ-9DgoQ9Mg0GUcsXU2PqTlIp21KnFw0PSfIee3ydLGxl_0h9fGxXNy3KGL5uK1npH7q-Xd4nt28_N6tfh2kymR52MGMpdYFciEYWmiRVnLGqpai6LUwNv0gUoKbroC6rqVQirsOKIuwUipuBZn5PNBN_n-vTNxbHoblXEOB-N3sQEJPClyJhMUDlAVfIzBdM1TsD2GlwZYM-XTHPJp3vNJnE-v8ru2N_qN8T8Q8Rd0Co-C</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1812891208</pqid></control><display><type>article</type><title>Radiomic Profiling of Glioblastoma: Identifying an Imaging Predictor of Patient Survival with Improved Performance over Established Clinical and Radiologic Risk Models</title><source>MEDLINE</source><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><creator>Kickingereder, Philipp ; Burth, Sina ; Wick, Antje ; Götz, Michael ; Eidel, Oliver ; Schlemmer, Heinz-Peter ; Maier-Hein, Klaus H ; Wick, Wolfgang ; Bendszus, Martin ; Radbruch, Alexander ; Bonekamp, David</creator><creatorcontrib>Kickingereder, Philipp ; Burth, Sina ; Wick, Antje ; Götz, Michael ; Eidel, Oliver ; Schlemmer, Heinz-Peter ; Maier-Hein, Klaus H ; Wick, Wolfgang ; Bendszus, Martin ; Radbruch, Alexander ; Bonekamp, David</creatorcontrib><description>Purpose To evaluate whether radiomic feature-based magnetic resonance (MR) imaging signatures allow prediction of survival and stratification of patients with newly diagnosed glioblastoma with improved accuracy compared with that of established clinical and radiologic risk models. Materials and Methods Retrospective evaluation of data was approved by the local ethics committee and informed consent was waived. A total of 119 patients (allocated in a 2:1 ratio to a discovery [n = 79] or validation [n = 40] set) with newly diagnosed glioblastoma were subjected to radiomic feature extraction (12 190 features extracted, including first-order, volume, shape, and texture features) from the multiparametric (contrast material-enhanced T1-weighted and fluid-attenuated inversion-recovery imaging sequences) and multiregional (contrast-enhanced and unenhanced) tumor volumes. Radiomic features of patients in the discovery set were subjected to a supervised principal component (SPC) analysis to predict progression-free survival (PFS) and overall survival (OS) and were validated in the validation set. The performance of a Cox proportional hazards model with the SPC analysis predictor was assessed with C index and integrated Brier scores (IBS, lower scores indicating higher accuracy) and compared with Cox models based on clinical (age and Karnofsky performance score) and radiologic (Gaussian normalized relative cerebral blood volume and apparent diffusion coefficient) parameters. Results SPC analysis allowed stratification based on 11 features of patients in the discovery set into a low- or high-risk group for PFS (hazard ratio [HR], 2.43; P = .002) and OS (HR, 4.33; P &lt; .001), and the results were validated successfully in the validation set for PFS (HR, 2.28; P = .032) and OS (HR, 3.45; P = .004). The performance of the SPC analysis (OS: IBS, 0.149; C index, 0.654; PFS: IBS, 0.138; C index, 0.611) was higher compared with that of the radiologic (OS: IBS, 0.175; C index, 0.603; PFS: IBS, 0.149; C index, 0.554) and clinical risk models (OS: IBS, 0.161, C index, 0.640; PFS: IBS, 0.139; C index, 0.599). The performance of the SPC analysis model was further improved when combined with clinical data (OS: IBS, 0.142; C index, 0.696; PFS: IBS, 0.132; C index, 0.637). Conclusion An 11-feature radiomic signature that allows prediction of survival and stratification of patients with newly diagnosed glioblastoma was identified, and improved performance compared with that of established clinical and radiologic risk models was demonstrated. (©) RSNA, 2016 Online supplemental material is available for this article.</description><identifier>ISSN: 0033-8419</identifier><identifier>EISSN: 1527-1315</identifier><identifier>DOI: 10.1148/radiol.2016160845</identifier><identifier>PMID: 27326665</identifier><language>eng</language><publisher>United States</publisher><subject>Brain Neoplasms - diagnostic imaging ; Brain Neoplasms - pathology ; Contrast Media ; Female ; Germany ; Glioblastoma - diagnostic imaging ; Glioblastoma - pathology ; Humans ; Image Interpretation, Computer-Assisted ; Magnetic Resonance Imaging - methods ; Male ; Meglumine ; Organometallic Compounds ; Predictive Value of Tests ; Retrospective Studies ; Risk Assessment ; Survival Rate ; Tumor Burden</subject><ispartof>Radiology, 2016-09, Vol.280 (3), p.880-889</ispartof><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c344t-1848a75a03e0c34d36989179d356d12b0147832ef5199b838caf2aad61e88c2d3</citedby><cites>FETCH-LOGICAL-c344t-1848a75a03e0c34d36989179d356d12b0147832ef5199b838caf2aad61e88c2d3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,778,782,27907,27908</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27326665$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kickingereder, Philipp</creatorcontrib><creatorcontrib>Burth, Sina</creatorcontrib><creatorcontrib>Wick, Antje</creatorcontrib><creatorcontrib>Götz, Michael</creatorcontrib><creatorcontrib>Eidel, Oliver</creatorcontrib><creatorcontrib>Schlemmer, Heinz-Peter</creatorcontrib><creatorcontrib>Maier-Hein, Klaus H</creatorcontrib><creatorcontrib>Wick, Wolfgang</creatorcontrib><creatorcontrib>Bendszus, Martin</creatorcontrib><creatorcontrib>Radbruch, Alexander</creatorcontrib><creatorcontrib>Bonekamp, David</creatorcontrib><title>Radiomic Profiling of Glioblastoma: Identifying an Imaging Predictor of Patient Survival with Improved Performance over Established Clinical and Radiologic Risk Models</title><title>Radiology</title><addtitle>Radiology</addtitle><description>Purpose To evaluate whether radiomic feature-based magnetic resonance (MR) imaging signatures allow prediction of survival and stratification of patients with newly diagnosed glioblastoma with improved accuracy compared with that of established clinical and radiologic risk models. Materials and Methods Retrospective evaluation of data was approved by the local ethics committee and informed consent was waived. A total of 119 patients (allocated in a 2:1 ratio to a discovery [n = 79] or validation [n = 40] set) with newly diagnosed glioblastoma were subjected to radiomic feature extraction (12 190 features extracted, including first-order, volume, shape, and texture features) from the multiparametric (contrast material-enhanced T1-weighted and fluid-attenuated inversion-recovery imaging sequences) and multiregional (contrast-enhanced and unenhanced) tumor volumes. Radiomic features of patients in the discovery set were subjected to a supervised principal component (SPC) analysis to predict progression-free survival (PFS) and overall survival (OS) and were validated in the validation set. The performance of a Cox proportional hazards model with the SPC analysis predictor was assessed with C index and integrated Brier scores (IBS, lower scores indicating higher accuracy) and compared with Cox models based on clinical (age and Karnofsky performance score) and radiologic (Gaussian normalized relative cerebral blood volume and apparent diffusion coefficient) parameters. Results SPC analysis allowed stratification based on 11 features of patients in the discovery set into a low- or high-risk group for PFS (hazard ratio [HR], 2.43; P = .002) and OS (HR, 4.33; P &lt; .001), and the results were validated successfully in the validation set for PFS (HR, 2.28; P = .032) and OS (HR, 3.45; P = .004). The performance of the SPC analysis (OS: IBS, 0.149; C index, 0.654; PFS: IBS, 0.138; C index, 0.611) was higher compared with that of the radiologic (OS: IBS, 0.175; C index, 0.603; PFS: IBS, 0.149; C index, 0.554) and clinical risk models (OS: IBS, 0.161, C index, 0.640; PFS: IBS, 0.139; C index, 0.599). The performance of the SPC analysis model was further improved when combined with clinical data (OS: IBS, 0.142; C index, 0.696; PFS: IBS, 0.132; C index, 0.637). Conclusion An 11-feature radiomic signature that allows prediction of survival and stratification of patients with newly diagnosed glioblastoma was identified, and improved performance compared with that of established clinical and radiologic risk models was demonstrated. (©) RSNA, 2016 Online supplemental material is available for this article.</description><subject>Brain Neoplasms - diagnostic imaging</subject><subject>Brain Neoplasms - pathology</subject><subject>Contrast Media</subject><subject>Female</subject><subject>Germany</subject><subject>Glioblastoma - diagnostic imaging</subject><subject>Glioblastoma - pathology</subject><subject>Humans</subject><subject>Image Interpretation, Computer-Assisted</subject><subject>Magnetic Resonance Imaging - methods</subject><subject>Male</subject><subject>Meglumine</subject><subject>Organometallic Compounds</subject><subject>Predictive Value of Tests</subject><subject>Retrospective Studies</subject><subject>Risk Assessment</subject><subject>Survival Rate</subject><subject>Tumor Burden</subject><issn>0033-8419</issn><issn>1527-1315</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpFUU1PGzEQtVARpMAP4FL52MumHns_vL1VUaCRqBoFOK9mbW8w9a6pvQniF_Vv1ttQOM1o5r03T_MIuQQ2B8jll4DaejfnDEoomcyLIzKDglcZCCg-kBljQmQyh_qUfIzxkTHIC1mdkFNeCV6WZTEjfzaTRm8VXQffWWeHLfUdvXbWtw7j6Hv8SlfaDKPtXqYlDnTV43Zq18Foq0YfJsYaR5tQ9HYX9naPjj7b8SFBn4LfG03XJnQ-9DgoQ9Mg0GUcsXU2PqTlIp21KnFw0PSfIee3ydLGxl_0h9fGxXNy3KGL5uK1npH7q-Xd4nt28_N6tfh2kymR52MGMpdYFciEYWmiRVnLGqpai6LUwNv0gUoKbroC6rqVQirsOKIuwUipuBZn5PNBN_n-vTNxbHoblXEOB-N3sQEJPClyJhMUDlAVfIzBdM1TsD2GlwZYM-XTHPJp3vNJnE-v8ru2N_qN8T8Q8Rd0Co-C</recordid><startdate>201609</startdate><enddate>201609</enddate><creator>Kickingereder, Philipp</creator><creator>Burth, Sina</creator><creator>Wick, Antje</creator><creator>Götz, Michael</creator><creator>Eidel, Oliver</creator><creator>Schlemmer, Heinz-Peter</creator><creator>Maier-Hein, Klaus H</creator><creator>Wick, Wolfgang</creator><creator>Bendszus, Martin</creator><creator>Radbruch, Alexander</creator><creator>Bonekamp, David</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>201609</creationdate><title>Radiomic Profiling of Glioblastoma: Identifying an Imaging Predictor of Patient Survival with Improved Performance over Established Clinical and Radiologic Risk Models</title><author>Kickingereder, Philipp ; Burth, Sina ; Wick, Antje ; Götz, Michael ; Eidel, Oliver ; Schlemmer, Heinz-Peter ; Maier-Hein, Klaus H ; Wick, Wolfgang ; Bendszus, Martin ; Radbruch, Alexander ; Bonekamp, David</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c344t-1848a75a03e0c34d36989179d356d12b0147832ef5199b838caf2aad61e88c2d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Brain Neoplasms - diagnostic imaging</topic><topic>Brain Neoplasms - pathology</topic><topic>Contrast Media</topic><topic>Female</topic><topic>Germany</topic><topic>Glioblastoma - diagnostic imaging</topic><topic>Glioblastoma - pathology</topic><topic>Humans</topic><topic>Image Interpretation, Computer-Assisted</topic><topic>Magnetic Resonance Imaging - methods</topic><topic>Male</topic><topic>Meglumine</topic><topic>Organometallic Compounds</topic><topic>Predictive Value of Tests</topic><topic>Retrospective Studies</topic><topic>Risk Assessment</topic><topic>Survival Rate</topic><topic>Tumor Burden</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kickingereder, Philipp</creatorcontrib><creatorcontrib>Burth, Sina</creatorcontrib><creatorcontrib>Wick, Antje</creatorcontrib><creatorcontrib>Götz, Michael</creatorcontrib><creatorcontrib>Eidel, Oliver</creatorcontrib><creatorcontrib>Schlemmer, Heinz-Peter</creatorcontrib><creatorcontrib>Maier-Hein, Klaus H</creatorcontrib><creatorcontrib>Wick, Wolfgang</creatorcontrib><creatorcontrib>Bendszus, Martin</creatorcontrib><creatorcontrib>Radbruch, Alexander</creatorcontrib><creatorcontrib>Bonekamp, David</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Radiology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kickingereder, Philipp</au><au>Burth, Sina</au><au>Wick, Antje</au><au>Götz, Michael</au><au>Eidel, Oliver</au><au>Schlemmer, Heinz-Peter</au><au>Maier-Hein, Klaus H</au><au>Wick, Wolfgang</au><au>Bendszus, Martin</au><au>Radbruch, Alexander</au><au>Bonekamp, David</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Radiomic Profiling of Glioblastoma: Identifying an Imaging Predictor of Patient Survival with Improved Performance over Established Clinical and Radiologic Risk Models</atitle><jtitle>Radiology</jtitle><addtitle>Radiology</addtitle><date>2016-09</date><risdate>2016</risdate><volume>280</volume><issue>3</issue><spage>880</spage><epage>889</epage><pages>880-889</pages><issn>0033-8419</issn><eissn>1527-1315</eissn><abstract>Purpose To evaluate whether radiomic feature-based magnetic resonance (MR) imaging signatures allow prediction of survival and stratification of patients with newly diagnosed glioblastoma with improved accuracy compared with that of established clinical and radiologic risk models. Materials and Methods Retrospective evaluation of data was approved by the local ethics committee and informed consent was waived. A total of 119 patients (allocated in a 2:1 ratio to a discovery [n = 79] or validation [n = 40] set) with newly diagnosed glioblastoma were subjected to radiomic feature extraction (12 190 features extracted, including first-order, volume, shape, and texture features) from the multiparametric (contrast material-enhanced T1-weighted and fluid-attenuated inversion-recovery imaging sequences) and multiregional (contrast-enhanced and unenhanced) tumor volumes. Radiomic features of patients in the discovery set were subjected to a supervised principal component (SPC) analysis to predict progression-free survival (PFS) and overall survival (OS) and were validated in the validation set. The performance of a Cox proportional hazards model with the SPC analysis predictor was assessed with C index and integrated Brier scores (IBS, lower scores indicating higher accuracy) and compared with Cox models based on clinical (age and Karnofsky performance score) and radiologic (Gaussian normalized relative cerebral blood volume and apparent diffusion coefficient) parameters. Results SPC analysis allowed stratification based on 11 features of patients in the discovery set into a low- or high-risk group for PFS (hazard ratio [HR], 2.43; P = .002) and OS (HR, 4.33; P &lt; .001), and the results were validated successfully in the validation set for PFS (HR, 2.28; P = .032) and OS (HR, 3.45; P = .004). The performance of the SPC analysis (OS: IBS, 0.149; C index, 0.654; PFS: IBS, 0.138; C index, 0.611) was higher compared with that of the radiologic (OS: IBS, 0.175; C index, 0.603; PFS: IBS, 0.149; C index, 0.554) and clinical risk models (OS: IBS, 0.161, C index, 0.640; PFS: IBS, 0.139; C index, 0.599). The performance of the SPC analysis model was further improved when combined with clinical data (OS: IBS, 0.142; C index, 0.696; PFS: IBS, 0.132; C index, 0.637). Conclusion An 11-feature radiomic signature that allows prediction of survival and stratification of patients with newly diagnosed glioblastoma was identified, and improved performance compared with that of established clinical and radiologic risk models was demonstrated. (©) RSNA, 2016 Online supplemental material is available for this article.</abstract><cop>United States</cop><pmid>27326665</pmid><doi>10.1148/radiol.2016160845</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record>
fulltext fulltext
identifier ISSN: 0033-8419
ispartof Radiology, 2016-09, Vol.280 (3), p.880-889
issn 0033-8419
1527-1315
language eng
recordid cdi_proquest_miscellaneous_1812891208
source MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals
subjects Brain Neoplasms - diagnostic imaging
Brain Neoplasms - pathology
Contrast Media
Female
Germany
Glioblastoma - diagnostic imaging
Glioblastoma - pathology
Humans
Image Interpretation, Computer-Assisted
Magnetic Resonance Imaging - methods
Male
Meglumine
Organometallic Compounds
Predictive Value of Tests
Retrospective Studies
Risk Assessment
Survival Rate
Tumor Burden
title Radiomic Profiling of Glioblastoma: Identifying an Imaging Predictor of Patient Survival with Improved Performance over Established Clinical and Radiologic Risk Models
url https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-16T21%3A41%3A38IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Radiomic%20Profiling%20of%20Glioblastoma:%20Identifying%20an%20Imaging%20Predictor%20of%20Patient%20Survival%20with%20Improved%20Performance%20over%20Established%20Clinical%20and%20Radiologic%20Risk%20Models&rft.jtitle=Radiology&rft.au=Kickingereder,%20Philipp&rft.date=2016-09&rft.volume=280&rft.issue=3&rft.spage=880&rft.epage=889&rft.pages=880-889&rft.issn=0033-8419&rft.eissn=1527-1315&rft_id=info:doi/10.1148/radiol.2016160845&rft_dat=%3Cproquest_cross%3E1812891208%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1812891208&rft_id=info:pmid/27326665&rfr_iscdi=true