Rapid automated quantification of cerebral small-vessel ...
Rapid automated quantification of cerebral leukoaraiosis on CT Liang Chen1,2, Anoma Lalani Carlton Jones2, Grant Mair3, Rajiv Patel4, Anastasia Gontsarova2, Jeban Ganesalingam2, Nikhil Math2, Angela Dawson2, Aweid Basaam2, David Cohen4,, Amrish Mehta2, Joanna Wardlaw3, Daniel Rueckert1, Paul Bentley2IST-3 Collaborative Group 1 Biomedical Imaging Analysis Group, Computer Science, Imperial College London2 Division of Brain Sciences, Imperial College London, UK3 Centre for Clinical Brain Sciences, University of Edinburgh, UK4 Northwick Park Hospital, London North West Healthcare NHS Trust, UKCorresponding Author: Paul Bentley, p.bentley@ic.ac.ukAddress: 11L15, Charing Cross Hospital, Fulham Palace Road, W6 8RFFax: 0203 3117284Tel: 0203 3117284Short title: Automated quantification of SVD Abstract Word Count: 249Body Word Count: 2868Tables: 3 Figures: 3 Key words: small-vessel disease, leukoaraiosis, white-matter lesions, cerebrovascular disease, stroke, vascular dementia, imaging, machine-learningAbstractObjective: Assessment of cerebral ischemic white matter lesions (WML; or leukoaraiosis) using computerised tomography (CT) is important for the practical management of acute stroke, traumatic head injury and cognitive impairment, but limited by visual-rating systems prone to imprecision and interrater variability. We validated a fully-automated, image machine-learning method (Auto) that delineates and quantifies cerebral WML. Methods: Comparisons were made between Auto versus expert WML drawings on CT, and on co-registered FLAIR-MRIs (n=120); and between Auto versus expert ratings using two conventional scores (n=687 + 200, hospital and multicentre trial-populations respectively; all acute ischemic strokes). Results: Auto-estimated WML volumes correlated strongly with expert-drawing WML volumes on MRI and on CT (r2=0.85, 0.71 respectively; p<0.001); and showed a similar spatial-similarity measure with MRI-WML to that achieved by expert CT drawings. Expert WML drawing volumes on CT correlated strongly with each other (r2=0.85), but varied widely between experts (range: 91% of mean expert estimate). Agreements between Auto and consensus-expert ratings were superior or similar, depending upon scoring system, to agreements between pairs of experts (kappa: 0.60 vs. 0.51; 0.64 vs. 0.67 for the two score types; p<0.01 for first comparison only). Image preprocessing failure rate was 4%; Auto ratings errors (scores >1 point from expert consensus) occurred in a further 4%. Processing time averaged 109s per scan using Auto (including image preprocessing). Conclusions: We validate a rapid, fully-automated method for quantifying leukoaraiosis on CT in a large real-world case mix of samples. IntroductionCerebral small-vessel disease (SVD) - a major cause of age-related physical and cognitive morbidity - is most sensitively detected by FLAIR-MRIPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XYXJkbGF3PC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XYXJkbGF3PC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48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ADDIN EN.CITE.DATA 1, typically as leukoaraiosis, i.e. white matter lesions, WML, and lacunar infarcts. In practice, WML are most commonly observed on CT ADDIN EN.CITE <EndNote><Cite><Author>Rossi</Author><Year>2005</Year><IDText>Pathological validation of a CT-based scale for subcortical vascular disease. The OPTIMA Study</IDText><DisplayText><style face="superscript">2</style></DisplayText><record><keywords><keyword>Aged</keyword><keyword>Aged, 80 and over</keyword><keyword>Brain</keyword><keyword>Cerebral Angiography</keyword><keyword>Cerebral Arteries</keyword><keyword>Dementia, Multi-Infarct</keyword><keyword>Dementia, Vascular</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Leukoaraiosis</keyword><keyword>Longitudinal Studies</keyword><keyword>Male</keyword><keyword>Microcirculation</keyword><keyword>Middle Aged</keyword><keyword>Prospective Studies</keyword><keyword>Reproducibility of Results</keyword><keyword>Sensitivity and Specificity</keyword><keyword>Statistics as Topic</keyword><keyword>Tomography, X-Ray Computed</keyword></keywords><urls><related-urls><url> validation of a CT-based scale for subcortical vascular disease. The OPTIMA Study</title><secondary-title>Dement Geriatr Cogn Disord</secondary-title></titles><pages>61-6</pages><number>2-3</number><contributors><authors><author>Rossi, R.</author><author>Joachim, C.</author><author>Geroldi, C.</author><author>Esiri, M. M.</author><author>Smith, A. D.</author><author>Frisoni, G. B.</author></authors></contributors><language>ENG</language><added-date format="utc">1478697809</added-date><ref-type name="Journal Article">17</ref-type><dates><year>2005</year></dates><rec-number>543</rec-number><last-updated-date format="utc">1478697809</last-updated-date><accession-num>15572873</accession-num><electronic-resource-num>10.1159/000082350</electronic-resource-num><volume>19</volume></record></Cite></EndNote>2, rather than MRI, because of scanner-type availability and accessibility considerations in target populations. In acute stroke and traumatic head injury, CT is the first-line imaging modality of choice ADDIN EN.CITE <EndNote><Cite><Author>Sanossian</Author><Year>2016</Year><IDText>Utilization of Emergent Neuroimaging for Thrombolysis-Eligible Stroke Patients</IDText><DisplayText><style face="superscript">3</style></DisplayText><record><dates><pub-dates><date>Jun</date></pub-dates><year>2016</year></dates><urls><related-urls><url> of Emergent Neuroimaging for Thrombolysis-Eligible Stroke Patients</title><secondary-title>J Neuroimaging</secondary-title></titles><contributors><authors><author>Sanossian, N.</author><author>Fu, K. A.</author><author>Liebeskind, D. S.</author><author>Starkman, S.</author><author>Hamilton, S.</author><author>Villablanca, J. P.</author><author>Burgos, A. M.</author><author>Conwit, R.</author><author>Saver, J. L.</author></authors></contributors><language>ENG</language><added-date format="utc">1478706286</added-date><ref-type name="Journal Article">17</ref-type><rec-number>552</rec-number><last-updated-date format="utc">1478706286</last-updated-date><accession-num>27300498</accession-num><electronic-resource-num>10.1111/jon.12369</electronic-resource-num></record></Cite></EndNote>3; yet WML burden is an important variable, being a prognostic marker of functional outcomePEVuZE5vdGU+PENpdGU+PEF1dGhvcj5JU1QtMzwvQXV0aG9yPjxZZWFyPjIwMTU8L1llYXI+PElE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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5JU1QtMzwvQXV0aG9yPjxZZWFyPjIwMTU8L1llYXI+PElE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ADDIN EN.CITE.DATA 4-6 and hemorrhagic transformation of ischemiaPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DaGFyaWRpbW91PC9BdXRob3I+PFllYXI+MjAxNjwvWWVh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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DaGFyaWRpbW91PC9BdXRob3I+PFllYXI+MjAxNjwvWWVh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ADDIN EN.CITE.DATA 4, 7, 8. For dementia, even though MRI is well-recognised to be superior in contributing towards diagnosis, hospital audits suggest that CT is used exclusively in the majority of casesPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BbGFjaGthcjwvQXV0aG9yPjxZZWFyPjIwMTQ8L1llYXI+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=
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BbGFjaGthcjwvQXV0aG9yPjxZZWFyPjIwMTQ8L1llYXI+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=
ADDIN EN.CITE.DATA 9-11.Assessment of cerebral WML on CT, is more challenging than using MRI, because signal characteristics of WML (hypoattenuation) are less distinctive relative to background white matter on CTPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XYWhsdW5kPC9BdXRob3I+PFllYXI+MjAwMTwvWWVhcj48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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XYWhsdW5kPC9BdXRob3I+PFllYXI+MjAwMTwvWWVhcj48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ADDIN EN.CITE.DATA 12. Moreover, sensitivity of CT decreases with smaller WML volumesPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TaW1vbmk8L0F1dGhvcj48WWVhcj4yMDEyPC9ZZWFyPjxJ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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TaW1vbmk8L0F1dGhvcj48WWVhcj4yMDEyPC9ZZWFyPjxJ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ADDIN EN.CITE.DATA 12, 13, and varies between brain regionsPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XYWhsdW5kPC9BdXRob3I+PFllYXI+MjAwMTwvWWVhcj48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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XYWhsdW5kPC9BdXRob3I+PFllYXI+MjAwMTwvWWVhcj48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ADDIN EN.CITE.DATA 12. Studies measuring inter-rater reliability of expert-based WML ratings show poorer agreement using CT than MRIPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TY2hlbHRlbnM8L0F1dGhvcj48WWVhcj4xOTk4PC9ZZWFy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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TY2hlbHRlbnM8L0F1dGhvcj48WWVhcj4xOTk4PC9ZZWFy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ADDIN EN.CITE.DATA 13, 14 (kappa values ~0.5–0.6 for CT, versus 0.7-0.8 for MRIPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XYWhsdW5kPC9BdXRob3I+PFllYXI+MjAwMTwvWWVhcj48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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XYWhsdW5kPC9BdXRob3I+PFllYXI+MjAwMTwvWWVhcj48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ADDIN EN.CITE.DATA 12, 15). Furthermore, WML scoring systems typically allow for only a small number of ordinal ratings (4-6 ADDIN EN.CITE <EndNote><Cite><Author>Pantoni</Author><Year>2002</Year><IDText>Visual rating scales for age-related white matter changes (leukoaraiosis): can the heterogeneity be reduced?</IDText><DisplayText><style face="superscript">16</style></DisplayText><record><dates><pub-dates><date>Dec</date></pub-dates><year>2002</year></dates><keywords><keyword>Aging</keyword><keyword>Brain</keyword><keyword>Brain Diseases</keyword><keyword>Cognition Disorders</keyword><keyword>Feasibility Studies</keyword><keyword>Gait Disorders, Neurologic</keyword><keyword>Humans</keyword><keyword>Hypertension</keyword><keyword>Linear Models</keyword><keyword>Magnetic Resonance Imaging</keyword><keyword>Middle Aged</keyword><keyword>Predictive Value of Tests</keyword><keyword>Risk Factors</keyword><keyword>Sensitivity and Specificity</keyword><keyword>Statistics, Nonparametric</keyword><keyword>Tomography, X-Ray Computed</keyword></keywords><urls><related-urls><url> rating scales for age-related white matter changes (leukoaraiosis): can the heterogeneity be reduced?</title><secondary-title>Stroke</secondary-title></titles><pages>2827-33</pages><number>12</number><contributors><authors><author>Pantoni, L.</author><author>Simoni, M.</author><author>Pracucci, G.</author><author>Schmidt, R.</author><author>Barkhof, F.</author><author>Inzitari, D.</author></authors></contributors><language>ENG</language><added-date format="utc">1478699064</added-date><ref-type name="Journal Article">17</ref-type><rec-number>546</rec-number><last-updated-date format="utc">1478699064</last-updated-date><accession-num>12468777</accession-num><volume>33</volume></record></Cite></EndNote>16), and use visual criteria (e.g. restricted to periventricular regions versus extending to cortex) that are imprecise, and do not convert directly to an estimate of total WML load ADDIN EN.CITE <EndNote><Cite><Author>Scheltens</Author><Year>1998</Year><IDText>White matter changes on CT and MRI: an overview of visual rating scales. European Task Force on Age-Related White Matter Changes</IDText><DisplayText><style face="superscript">14</style></DisplayText><record><keywords><keyword>Brain Ischemia</keyword><keyword>Dementia</keyword><keyword>Disability Evaluation</keyword><keyword>Humans</keyword><keyword>Magnetic Resonance Imaging</keyword><keyword>Observer Variation</keyword><keyword>Tomography, X-Ray Computed</keyword></keywords><urls><related-urls><url> matter changes on CT and MRI: an overview of visual rating scales. European Task Force on Age-Related White Matter Changes</title><secondary-title>Eur Neurol</secondary-title></titles><pages>80-9</pages><number>2</number><contributors><authors><author>Scheltens, P.</author><author>Erkinjunti, T.</author><author>Leys, D.</author><author>Wahlund, L. O.</author><author>Inzitari, D.</author><author>del Ser, T.</author><author>Pasquier, F.</author><author>Barkhof, F.</author><author>M?ntyl?, R.</author><author>Bowler, J.</author><author>Wallin, A.</author><author>Ghika, J.</author><author>Fazekas, F.</author><author>Pantoni, L.</author></authors></contributors><language>ENG</language><added-date format="utc">1478699064</added-date><ref-type name="Journal Article">17</ref-type><dates><year>1998</year></dates><rec-number>548</rec-number><last-updated-date format="utc">1478699064</last-updated-date><accession-num>9520068</accession-num><volume>39</volume></record></Cite></EndNote>14. As such, visual estimates of WML severity, although providing valuable prognostic information ADDIN EN.CITE <EndNote><Cite><Author>IST-3</Author><Year>2015</Year><IDText>Association between brain imaging signs, early and late outcomes, and response to intravenous alteplase after acute ischaemic stroke in the third International Stroke Trial (IST-3): secondary analysis of a randomised controlled trial</IDText><DisplayText><style face="superscript">4</style></DisplayText><record><dates><pub-dates><date>May</date></pub-dates><year>2015</year></dates><keywords><keyword>Adult</keyword><keyword>Aged</keyword><keyword>Aged, 80 and over</keyword><keyword>Brain Ischemia</keyword><keyword>Data Interpretation, Statistical</keyword><keyword>Female</keyword><keyword>Fibrinolytic Agents</keyword><keyword>Humans</keyword><keyword>Magnetic Resonance Imaging, Cine</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Outcome Assessment (Health Care)</keyword><keyword>Radiography</keyword><keyword>Single-Blind Method</keyword><keyword>Stroke</keyword><keyword>Thrombolytic Therapy</keyword><keyword>Tissue Plasminogen Activator</keyword></keywords><urls><related-urls><url> between brain imaging signs, early and late outcomes, and response to intravenous alteplase after acute ischaemic stroke in the third International Stroke Trial (IST-3): secondary analysis of a randomised controlled trial</title><secondary-title>Lancet Neurol</secondary-title></titles><pages>485-96</pages><number>5</number><contributors><authors><author>IST-3 collaborative group</author></authors></contributors><edition>2015/03/27</edition><language>eng</language><added-date format="utc">1488458505</added-date><ref-type name="Journal Article">17</ref-type><rec-number>573</rec-number><last-updated-date format="utc">1488458505</last-updated-date><accession-num>25819484</accession-num><electronic-resource-num>10.1016/S1474-4422(15)00012-5</electronic-resource-num><volume>14</volume></record></Cite></EndNote>4, have limited sensitivity as diagnostic markers, for monitoring disease progression, or in research. Our group have previously described a machine-learning method for automatically delineating WML on standard unenhanced CT, that performed favourably on a limited test against expert WML ratingsPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DaGVuPC9BdXRob3I+PFllYXI+MjAxNTwvWWVhcj48SURU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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DaGVuPC9BdXRob3I+PFllYXI+MjAxNTwvWWVhcj48SURU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ADDIN EN.CITE.DATA 17, 18. In the current study, we validate the method more comprehensively, comparing the automated output with expert delineations on CT and MRI (i.e. gold-standard), and ratings in ~1000 stroke patients, using images originating from a wide range of scanner types, thus reflecting typical populations that the technique is likely to be used in. MethodsStudy populationsSince one of the primary potential applications for automated WML estimation is prognostication of acute ischemic stroke, the study focused on this patient population. The test cohorts comprised (Fig. 1A): 1) all acute ischemic stroke patients presenting to Imperial College (IC) Hyperacute Stroke Unit between 2010-14 who subsequently received thrombolysis treatment (IC-thrombolysed, cohort; n=627); 2) all acute ischemic stroke patients from IC from the same time-period who underwent both CT and MRI within 1 week of each other (IC CT-MRI cohort; n=255; mean scan interval: 2 days; excludes IC-thrombolysed subjects); 3) a random sample of patients recruited to the Third International Stroke TrialPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TYW5kZXJjb2NrPC9BdXRob3I+PFllYXI+MjAxMjwvWWVh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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TYW5kZXJjb2NrPC9BdXRob3I+PFllYXI+MjAxMjwvWWVh
cj48SURUZXh0PlRoZSBiZW5lZml0cyBhbmQgaGFybXMgb2YgaW50cmF2ZW5vdXMgdGhyb21ib2x5
c2lzIHdpdGggcmVjb21iaW5hbnQgdGlzc3VlIHBsYXNtaW5vZ2VuIGFjdGl2YXRvciB3aXRoaW4g
NiBoIG9mIGFjdXRlIGlzY2hhZW1pYyBzdHJva2UgKHRoZSB0aGlyZCBpbnRlcm5hdGlvbmFsIHN0
cm9rZSB0cmlhbCBbSVNULTNdKTogYSByYW5kb21pc2VkIGNvbnRyb2xsZWQgdHJpYWw8L0lEVGV4
dD48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0Ij4xOTwvc3R5bGU+PC9EaXNw
bGF5VGV4dD48cmVjb3JkPjxkYXRlcz48cHViLWRhdGVzPjxkYXRlPkp1bjwvZGF0ZT48L3B1Yi1k
YXRlcz48eWVhcj4yMDEyPC95ZWFyPjwvZGF0ZXM+PGtleXdvcmRzPjxrZXl3b3JkPkFkb2xlc2Nl
bnQ8L2tleXdvcmQ+PGtleXdvcmQ+QWR1bHQ8L2tleXdvcmQ+PGtleXdvcmQ+QWdlIERpc3RyaWJ1
dGlvbjwva2V5d29yZD48a2V5d29yZD5BZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPkFnZWQsIDgwIGFu
ZCBvdmVyPC9rZXl3b3JkPjxrZXl3b3JkPkJyYWluIElzY2hlbWlhPC9rZXl3b3JkPjxrZXl3b3Jk
PkRvdWJsZS1CbGluZCBNZXRob2Q8L2tleXdvcmQ+PGtleXdvcmQ+RHJ1ZyBBZG1pbmlzdHJhdGlv
biBTY2hlZHVsZTwva2V5d29yZD48a2V5d29yZD5GZW1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+Rmli
cmlub2x5dGljIEFnZW50czwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdv
cmQ+SW5mdXNpb25zLCBJbnRyYXZlbm91czwva2V5d29yZD48a2V5d29yZD5NYWxlPC9rZXl3b3Jk
PjxrZXl3b3JkPk1pZGRsZSBBZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPlJlY29tYmluYW50IFByb3Rl
aW5zPC9rZXl3b3JkPjxrZXl3b3JkPlJlY3VycmVuY2U8L2tleXdvcmQ+PGtleXdvcmQ+U2V2ZXJp
dHkgb2YgSWxsbmVzcyBJbmRleDwva2V5d29yZD48a2V5d29yZD5TdHJva2U8L2tleXdvcmQ+PGtl
eXdvcmQ+VGhyb21ib2x5dGljIFRoZXJhcHk8L2tleXdvcmQ+PGtleXdvcmQ+VGlzc3VlIFBsYXNt
aW5vZ2VuIEFjdGl2YXRvcjwva2V5d29yZD48a2V5d29yZD5UcmVhdG1lbnQgT3V0Y29tZTwva2V5
d29yZD48a2V5d29yZD5Zb3VuZyBBZHVsdDwva2V5d29yZD48L2tleXdvcmRzPjx1cmxzPjxyZWxh
dGVkLXVybHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzIyNjMyOTA4
PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxpc2JuPjE0NzQtNTQ3WDwvaXNibj48Y3VzdG9t
Mj5QTUMzMzg2NDk1PC9jdXN0b20yPjx0aXRsZXM+PHRpdGxlPlRoZSBiZW5lZml0cyBhbmQgaGFy
bXMgb2YgaW50cmF2ZW5vdXMgdGhyb21ib2x5c2lzIHdpdGggcmVjb21iaW5hbnQgdGlzc3VlIHBs
YXNtaW5vZ2VuIGFjdGl2YXRvciB3aXRoaW4gNiBoIG9mIGFjdXRlIGlzY2hhZW1pYyBzdHJva2Ug
KHRoZSB0aGlyZCBpbnRlcm5hdGlvbmFsIHN0cm9rZSB0cmlhbCBbSVNULTNdKTogYSByYW5kb21p
c2VkIGNvbnRyb2xsZWQgdHJpYWw8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+TGFuY2V0PC9zZWNv
bmRhcnktdGl0bGU+PC90aXRsZXM+PHBhZ2VzPjIzNTItNjM8L3BhZ2VzPjxudW1iZXI+OTgzNDwv
bnVtYmVyPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5TYW5kZXJjb2NrLCBQLjwvYXV0
aG9yPjxhdXRob3I+V2FyZGxhdywgSi4gTS48L2F1dGhvcj48YXV0aG9yPkxpbmRsZXksIFIuIEku
PC9hdXRob3I+PGF1dGhvcj5EZW5uaXMsIE0uPC9hdXRob3I+PGF1dGhvcj5Db2hlbiwgRy48L2F1
dGhvcj48YXV0aG9yPk11cnJheSwgRy48L2F1dGhvcj48YXV0aG9yPklubmVzLCBLLjwvYXV0aG9y
PjxhdXRob3I+VmVuYWJsZXMsIEcuPC9hdXRob3I+PGF1dGhvcj5Demxvbmtvd3NrYSwgQS48L2F1
dGhvcj48YXV0aG9yPktvYmF5YXNoaSwgQS48L2F1dGhvcj48YXV0aG9yPlJpY2NpLCBTLjwvYXV0
aG9yPjxhdXRob3I+TXVycmF5LCBWLjwvYXV0aG9yPjxhdXRob3I+QmVyZ2UsIEUuPC9hdXRob3I+
PGF1dGhvcj5TbG90LCBLLiBCLjwvYXV0aG9yPjxhdXRob3I+SGFua2V5LCBHLiBKLjwvYXV0aG9y
PjxhdXRob3I+Q29ycmVpYSwgTS48L2F1dGhvcj48YXV0aG9yPlBlZXRlcnMsIEEuPC9hdXRob3I+
PGF1dGhvcj5NYXR6LCBLLjwvYXV0aG9yPjxhdXRob3I+THlyZXIsIFAuPC9hdXRob3I+PGF1dGhv
cj5HdWJpdHosIEcuPC9hdXRob3I+PGF1dGhvcj5QaGlsbGlwcywgUy4gSi48L2F1dGhvcj48YXV0
aG9yPkFyYXV6LCBBLjwvYXV0aG9yPjxhdXRob3I+SVNULTMgY29sbGFib3JhdGl2ZSBncm91cDwv
YXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48bGFuZ3VhZ2U+ZW5nPC9sYW5ndWFnZT48
YWRkZWQtZGF0ZSBmb3JtYXQ9InV0YyI+MTM4NzU0NzU0MjwvYWRkZWQtZGF0ZT48cmVmLXR5cGUg
bmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PHJlYy1udW1iZXI+MzQ5PC9yZWMt
bnVtYmVyPjxsYXN0LXVwZGF0ZWQtZGF0ZSBmb3JtYXQ9InV0YyI+MTM4NzU0NzU0MjwvbGFzdC11
cGRhdGVkLWRhdGU+PGFjY2Vzc2lvbi1udW0+MjI2MzI5MDg8L2FjY2Vzc2lvbi1udW0+PGVsZWN0
cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMTYvUzAxNDAtNjczNigxMik2MDc2OC01PC9lbGVjdHJv
bmljLXJlc291cmNlLW51bT48dm9sdW1lPjM3OTwvdm9sdW1lPjwvcmVjb3JkPjwvQ2l0ZT48L0Vu
ZE5vdGU+AAA=
ADDIN EN.CITE.DATA 19 (IST-3 cohort n=200; median age: 82), from which patients with obvious extensive acute ischemic changes were first excluded (this subset therefore being more typical of patients who might also present to a cognitive impairment clinic). Validation of the automated WML quantification method was assessed by comparison with experts’: 1) drawings of WML outlines on CTs and co-registered FLAIR-MRIs (the latter considered to be a ground-truth), and 2) ratings using two conventional ordinal qualitative WML scoring systemsPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XYWhsdW5kPC9BdXRob3I+PFllYXI+MjAwMTwvWWVhcj48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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XYWhsdW5kPC9BdXRob3I+PFllYXI+MjAwMTwvWWVhcj48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ADDIN EN.CITE.DATA 12, 15. For the drawing study, 60 CTs were selected randomly from the IC-thrombolysed cohort, and 60 from the IC CT-MRI cohort, whilst ensuring that there were equal proportions of absent/mild, moderate and severe SVD (based upon expert ratings). For the ratings study, ratings were obtained on all subjects from IC-thrombolysed cohort, and CT-MRI and IST-3 subsets (Fig. 1A; Table 1 describes subject characteristics, including imaging features, for each study.) CT images used for validation from IC were derived from two types of CT scanner (GE, Siemens); comprised a range of slice thicknesses (voxel resolutions: ~ 0.4 x 0.4 x [1 – 7] mm), that in 70% of cases differed between the top- and bottom-halves of the brain (i.e. two image files per patient); and in the remainder, were uniform volumetric images. IST-3 cohort CT images comprised an even more heterogeneous set (details provided in original reportPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TYW5kZXJjb2NrPC9BdXRob3I+PFllYXI+MjAxMjwvWWVh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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TYW5kZXJjb2NrPC9BdXRob3I+PFllYXI+MjAxMjwvWWVh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ADDIN EN.CITE.DATA 19). Automated SVD quantification methodCerebral WML were segmented from CT images using a supervised machine learning method, based upon random forests, developed and described previouslyPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DaGVuPC9BdXRob3I+PFllYXI+MjAxNTwvWWVhcj48SURU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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DaGVuPC9BdXRob3I+PFllYXI+MjAxNTwvWWVhcj48SURU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ADDIN EN.CITE.DATA 17, 18. Briefly, a training model was derived from expert manual delineations of CT WML (leukoaraiosis including areas with lacunar infarcts ADDIN EN.CITE <EndNote><Cite><Author>Rossi</Author><Year>2005</Year><IDText>Pathological validation of a CT-based scale for subcortical vascular disease. The OPTIMA Study</IDText><DisplayText><style face="superscript">2</style></DisplayText><record><keywords><keyword>Aged</keyword><keyword>Aged, 80 and over</keyword><keyword>Brain</keyword><keyword>Cerebral Angiography</keyword><keyword>Cerebral Arteries</keyword><keyword>Dementia, Multi-Infarct</keyword><keyword>Dementia, Vascular</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Leukoaraiosis</keyword><keyword>Longitudinal Studies</keyword><keyword>Male</keyword><keyword>Microcirculation</keyword><keyword>Middle Aged</keyword><keyword>Prospective Studies</keyword><keyword>Reproducibility of Results</keyword><keyword>Sensitivity and Specificity</keyword><keyword>Statistics as Topic</keyword><keyword>Tomography, X-Ray Computed</keyword></keywords><urls><related-urls><url> validation of a CT-based scale for subcortical vascular disease. The OPTIMA Study</title><secondary-title>Dement Geriatr Cogn Disord</secondary-title></titles><pages>61-6</pages><number>2-3</number><contributors><authors><author>Rossi, R.</author><author>Joachim, C.</author><author>Geroldi, C.</author><author>Esiri, M. M.</author><author>Smith, A. D.</author><author>Frisoni, G. B.</author></authors></contributors><language>ENG</language><added-date format="utc">1478697809</added-date><ref-type name="Journal Article">17</ref-type><dates><year>2005</year></dates><rec-number>543</rec-number><last-updated-date format="utc">1478697809</last-updated-date><accession-num>15572873</accession-num><electronic-resource-num>10.1159/000082350</electronic-resource-num><volume>19</volume></record></Cite></EndNote>2). These were taken from 90 representative slices, of 50 subjects, showing moderate or severe WML, selected from a pool of 1000 acute ischemic stroke CT images (< 4.5 hours from symptom onset) from a single stroke centre (Northwick Park Hospital). Increasing the number of training slices, or using alternative experts, did not influence model accuracy significantly ADDIN EN.CITE <EndNote><Cite><Author>Chen</Author><Year>2015</Year><IDText>Identification of Cerebral Small Vessel Disease Using Multiple Instance Learning</IDText><DisplayText><style face="superscript">17</style></DisplayText><record><isbn>0302-9743</isbn><titles><title>Identification of Cerebral Small Vessel Disease Using Multiple Instance Learning</title><secondary-title>Medical Image Computing and Computer-Assisted Intervention (MICCAI 2015)</secondary-title></titles><pages>523-530</pages><contributors><authors><author>Chen, Liang</author><author>Tong, Tong</author><author>Pang Ho, Chin</author><author>Patel, Rajiv</author><author>Cohen, David</author><author>Dawson, Angela C</author><author>Halse, Omid</author><author>Geraghty, Olivia</author><author>Rinne, Paul</author><author>White, Christopher</author><author>Nakornchai, Tagore</author><author>Bentley, Paul</author><author>Rueckert, Daniel</author></authors></contributors><edition>18 Nov 2015</edition><added-date format="utc">1478181792</added-date><ref-type name="Journal Article">17</ref-type><dates><year>2015</year></dates><rec-number>534</rec-number><last-updated-date format="utc">1478182231</last-updated-date><electronic-resource-num>10.1007/978-3-319-24553-9_64</electronic-resource-num><volume>9349</volume></record></Cite></EndNote>17. From these images, 106 multiscale patches were generated randomly, classified according to whether the central pixel is labelled SVD or not, thus enabling a random-forest classifier to be constructed ADDIN EN.CITE <EndNote><Cite><Author>Liaw</Author><Year>2002</Year><IDText>Classification and regression by randomForest</IDText><DisplayText><style face="superscript">20</style></DisplayText><record><isbn>1609-3631</isbn><titles><title>Classification and regression by randomForest</title><secondary-title>R News</secondary-title></titles><pages>18-22</pages><contributors><authors><author>Liaw, Andy</author><author>Wiener, Matthew</author></authors></contributors><added-date format="utc">1478263044</added-date><ref-type name="Journal Article">17</ref-type><dates><year>2002</year></dates><rec-number>536</rec-number><last-updated-date format="utc">1478263185</last-updated-date><volume>2/3</volume></record></Cite></EndNote>20. For test images, the classifier generates a voxelwise WML probability map, modified by a prior probability map of cerebral WML location. The latter was generated from a separate cohort of 277 expert WML drawings on FLAIR-MRI, normalized into a common space. Optimization of probability thresholds for WML classification is performed with reference to the original 90 image delineations. WML lesion volume is calculated from the sum of suprathreshold WML voxels. For comparison with ordinal rating scores, Auto-estimated WML volume was thresholded into ranks equivalent in number to the score systemPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XYWhsdW5kPC9BdXRob3I+PFllYXI+MjAwMTwvWWVhcj48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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XYWhsdW5kPC9BdXRob3I+PFllYXI+MjAwMTwvWWVhcj48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ADDIN EN.CITE.DATA 12, 15 used by experts (4 or 3; see also next section). Thresholds were derived from both an unsupervised histogram method (for Wahlund ratingPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XYWhsdW5kPC9BdXRob3I+PFllYXI+MjAwMTwvWWVhcj48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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XYWhsdW5kPC9BdXRob3I+PFllYXI+MjAwMTwvWWVhcj48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ADDIN EN.CITE.DATA 12 validation); and a supervised method using ratings from half the dataset to optimize thresholds for the other half (for van Swieten ADDIN EN.CITE <EndNote><Cite><Author>van Swieten</Author><Year>1990</Year><IDText>Grading white matter lesions on CT and MRI: a simple scale</IDText><DisplayText><style face="superscript">15</style></DisplayText><record><dates><pub-dates><date>Dec</date></pub-dates><year>1990</year></dates><keywords><keyword>Brain</keyword><keyword>Brain Diseases</keyword><keyword>Cross-Sectional Studies</keyword><keyword>Data Interpretation, Statistical</keyword><keyword>Humans</keyword><keyword>Ischemic Attack, Transient</keyword><keyword>Longitudinal Studies</keyword><keyword>Magnetic Resonance Imaging</keyword><keyword>Tomography, X-Ray Computed</keyword></keywords><urls><related-urls><url> white matter lesions on CT and MRI: a simple scale</title><secondary-title>J Neurol Neurosurg Psychiatry</secondary-title></titles><pages>1080-3</pages><number>12</number><contributors><authors><author>van Swieten, J. C.</author><author>Hijdra, A.</author><author>Koudstaal, P. J.</author><author>van Gijn, J.</author></authors></contributors><language>ENG</language><added-date format="utc">1478177600</added-date><ref-type name="Journal Article">17</ref-type><rec-number>531</rec-number><last-updated-date format="utc">1478177600</last-updated-date><accession-num>2292703</accession-num><volume>53</volume></record></Cite></EndNote>15 rating method: these were excluded for validation testing of Auto ratings; but all cases were used for correlations of ratings with Auto volumes). All images used for training and testing were first resampled into a common dimensional space (allowing for differences in slice thickness within and between images), skull-stripped, and co-registered into a common template space ADDIN EN.CITE <EndNote><Cite><Author>Rueckert</Author><Year>1999</Year><IDText>Nonrigid registration using free-form deformations: application to breast MR images</IDText><DisplayText><style face="superscript">21</style></DisplayText><record><dates><pub-dates><date>Aug</date></pub-dates><year>1999</year></dates><keywords><keyword>Breast</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Image Processing, Computer-Assisted</keyword><keyword>Magnetic Resonance Imaging</keyword></keywords><urls><related-urls><url> registration using free-form deformations: application to breast MR images</title><secondary-title>IEEE Trans Med Imaging</secondary-title></titles><pages>712-21</pages><number>8</number><contributors><authors><author>Rueckert, D.</author><author>Sonoda, L. I.</author><author>Hayes, C.</author><author>Hill, D. L.</author><author>Leach, M. O.</author><author>Hawkes, D. J.</author></authors></contributors><language>ENG</language><added-date format="utc">1478259678</added-date><ref-type name="Journal Article">17</ref-type><rec-number>535</rec-number><last-updated-date format="utc">1478259678</last-updated-date><accession-num>10534053</accession-num><electronic-resource-num>10.1109/42.796284</electronic-resource-num><volume>18</volume></record></Cite></EndNote>21 (Fig. 1B). Expert WML drawings and ratingsExperts were neuroradiologists or stroke physicians with >5 years of regular stroke experience. Those who performed validation drawings or ratings of WML were different to those who contributed to model training. Experts were trained in WML rating scores and/or digital lesion drawings prior to their assessments. Digital drawings were performed using MRICroN software (mccauslandcenter.sc.edu/crnl/mricron/), wherein CT window settings could be adjusted by the expert to their own preference. FLAIR-MRIs were also annotated for WML, after first being aligned with each patient’s contemporaneous CT ADDIN EN.CITE <EndNote><Cite><Author>Rueckert</Author><Year>1999</Year><IDText>Nonrigid registration using free-form deformations: application to breast MR images</IDText><DisplayText><style face="superscript">21</style></DisplayText><record><dates><pub-dates><date>Aug</date></pub-dates><year>1999</year></dates><keywords><keyword>Breast</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Image Processing, Computer-Assisted</keyword><keyword>Magnetic Resonance Imaging</keyword></keywords><urls><related-urls><url> registration using free-form deformations: application to breast MR images</title><secondary-title>IEEE Trans Med Imaging</secondary-title></titles><pages>712-21</pages><number>8</number><contributors><authors><author>Rueckert, D.</author><author>Sonoda, L. I.</author><author>Hayes, C.</author><author>Hill, D. L.</author><author>Leach, M. O.</author><author>Hawkes, D. J.</author></authors></contributors><language>ENG</language><added-date format="utc">1478259678</added-date><ref-type name="Journal Article">17</ref-type><rec-number>535</rec-number><last-updated-date format="utc">1478259678</last-updated-date><accession-num>10534053</accession-num><electronic-resource-num>10.1109/42.796284</electronic-resource-num><volume>18</volume></record></Cite></EndNote>21, so as to minimise CT/MRI differences in WML appearances caused by variations in slice orientation. CT WML ratings used either the WahlundPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XYWhsdW5kPC9BdXRob3I+PFllYXI+MjAwMTwvWWVhcj48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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XYWhsdW5kPC9BdXRob3I+PFllYXI+MjAwMTwvWWVhcj48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ADDIN EN.CITE.DATA 12 or van Swieten ADDIN EN.CITE <EndNote><Cite><Author>van Swieten</Author><Year>1990</Year><IDText>Grading white matter lesions on CT and MRI: a simple scale</IDText><DisplayText><style face="superscript">15</style></DisplayText><record><dates><pub-dates><date>Dec</date></pub-dates><year>1990</year></dates><keywords><keyword>Brain</keyword><keyword>Brain Diseases</keyword><keyword>Cross-Sectional Studies</keyword><keyword>Data Interpretation, Statistical</keyword><keyword>Humans</keyword><keyword>Ischemic Attack, Transient</keyword><keyword>Longitudinal Studies</keyword><keyword>Magnetic Resonance Imaging</keyword><keyword>Tomography, X-Ray Computed</keyword></keywords><urls><related-urls><url> white matter lesions on CT and MRI: a simple scale</title><secondary-title>J Neurol Neurosurg Psychiatry</secondary-title></titles><pages>1080-3</pages><number>12</number><contributors><authors><author>van Swieten, J. C.</author><author>Hijdra, A.</author><author>Koudstaal, P. J.</author><author>van Gijn, J.</author></authors></contributors><language>ENG</language><added-date format="utc">1478177600</added-date><ref-type name="Journal Article">17</ref-type><rec-number>531</rec-number><last-updated-date format="utc">1478177600</last-updated-date><accession-num>2292703</accession-num><volume>53</volume></record></Cite></EndNote>15 scoring systems, reflecting 4 or 3 grades of WML severity respectively. For the Wahlund system, experts were asked to record the median WML score across frontal, parieto-occipital and temporal regionsPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XYWhsdW5kPC9BdXRob3I+PFllYXI+MjAwMTwvWWVhcj48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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XYWhsdW5kPC9BdXRob3I+PFllYXI+MjAwMTwvWWVhcj48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ADDIN EN.CITE.DATA 12. For the van Swieten system, anterior and posterior scores ADDIN EN.CITE <EndNote><Cite><Author>van Swieten</Author><Year>1990</Year><IDText>Grading white matter lesions on CT and MRI: a simple scale</IDText><DisplayText><style face="superscript">15</style></DisplayText><record><dates><pub-dates><date>Dec</date></pub-dates><year>1990</year></dates><keywords><keyword>Brain</keyword><keyword>Brain Diseases</keyword><keyword>Cross-Sectional Studies</keyword><keyword>Data Interpretation, Statistical</keyword><keyword>Humans</keyword><keyword>Ischemic Attack, Transient</keyword><keyword>Longitudinal Studies</keyword><keyword>Magnetic Resonance Imaging</keyword><keyword>Tomography, X-Ray Computed</keyword></keywords><urls><related-urls><url> white matter lesions on CT and MRI: a simple scale</title><secondary-title>J Neurol Neurosurg Psychiatry</secondary-title></titles><pages>1080-3</pages><number>12</number><contributors><authors><author>van Swieten, J. C.</author><author>Hijdra, A.</author><author>Koudstaal, P. J.</author><author>van Gijn, J.</author></authors></contributors><language>ENG</language><added-date format="utc">1478177600</added-date><ref-type name="Journal Article">17</ref-type><rec-number>531</rec-number><last-updated-date format="utc">1478177600</last-updated-date><accession-num>2292703</accession-num><volume>53</volume></record></Cite></EndNote>15 (3 grades each) were averaged and rounded. CT drawings and ratings were performed by 3 experts for each case, drawn from a pool of 3-13 for each experiment, allowing a consensus to be deduced for WML volume and rating score (mean and median respectively). Comparisons between each combination of rater pairs was performed to identify any experts who differed significantly (p<0.05) in their performance.D. Validation testsFrom expert drawings of cerebral WML on CT or MRI, total lesion volume was calculated, and correlated with Auto-estimated WML volume, using Spearman’s correlation. Comparisons of Spearman correlation coefficients were performed using an appropriate Fisher Z transformation ADDIN EN.CITE <EndNote><Cite><Author>Myers</Author><Year>2006</Year><IDText>Spearman Correlation Coefficients, Difference between</IDText><DisplayText><style face="superscript">22</style></DisplayText><record><titles><title>Spearman Correlation Coefficients, Difference between</title><secondary-title>Encyclopedia of Statistical Sciences</secondary-title></titles><contributors><authors><author>Myers, Leann</author><author>Sirois, Maria J</author></authors></contributors><added-date format="utc">1478276922</added-date><ref-type name="Journal Article">17</ref-type><dates><year>2006</year></dates><rec-number>537</rec-number><last-updated-date format="utc">1478277029</last-updated-date><electronic-resource-num>10.1002/0471667196.ess5050.pub2</electronic-resource-num><volume>12</volume></record></Cite></EndNote>22. Drawings (of WML on CT and MRI) were also compared for spatial similarity with Auto segmentations using patch-based evaluation of imaging similarity (PEIS), that is an unbiased version of the Dice scorePEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MZWRpZzwvQXV0aG9yPjxZZWFyPjIwMTQ8L1llYXI+PElE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=
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MZWRpZzwvQXV0aG9yPjxZZWFyPjIwMTQ8L1llYXI+PElE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=
ADDIN EN.CITE.DATA 23, 24; and tested for group differences with the ranksum test. Agreements between Auto versus expert ratings were assessed with linear weighted-kappa scores (kw), while comparisons between agreements were tested with validated bootstrap methods ADDIN EN.CITE <EndNote><Cite><Author>Vanbelle</Author><Year>2008</Year><IDText>A bootstrap method for comparing correlated</IDText><DisplayText><style face="superscript">25</style></DisplayText><record><titles><title>A bootstrap method for comparing correlated kappa coefficients</title><secondary-title>Journal of Statistical Computation and Simulation</secondary-title></titles><pages>1009-1015</pages><number>11</number><contributors><authors><author>Vanbelle, S</author><author>Albert, A</author></authors></contributors><added-date format="utc">1478277330</added-date><ref-type name="Journal Article">17</ref-type><dates><year>2008</year></dates><rec-number>539</rec-number><last-updated-date format="utc">1478277822</last-updated-date><electronic-resource-num>10.1080/00949650701410249</electronic-resource-num><volume>78</volume></record></Cite></EndNote>25. Statistical analyses were conducted in Matlab vR2012b.ResultsImage pre-processing Image pre-processing failures occurred in 39/882 hospital-derived CTs, and 4/200 trial-derived CTs (3.98% total failure rate; Fig. 1). Inspection of these cases identified poor image quality, due to inappropriate intensity windowing, incomplete brain coverage, extensive movement, beam-hardening artefact, or extreme head tilt - in 18/43 (42%). Pre-processing time took 77.3s (± 25s; mean ±95% confidence intervals). Median age in the four study samples was 76, 76, 75 and 82 years. Sample size, and proportions with acute/old ischemic lesions (proceeding to analysis) were 120 (19%/38%), 60 (22%/38%), 650 (36%/42%) and 196 (0%/59%) (i.e. numbers with acute ischemia or old infarcts were 257 and 319 respectively). Drawing validationWML volumes estimated using Auto correlated closely with those derived from expert CT-drawings (n=120, r2: 0.71; Table 2, Fig. 2A). Correlation between expert CT-volumes themselves was higher (r2: 0.85; ?r: Z=3.1, p<0.01), but the range of expert CT-volumes per scan was wide (median range: 91% of mean expert estimate; IQR: 55-148%; shown as vertical lines in Fig. 2A). Correlation of Auto WML volumes with expert drawings of WML volumes improved when the latter were based upon coregistered FLAIR-MRI (r2: 0.85), than CT (?r: Z=3.8; p<0.001); and was comparable to the correlation between expert-CT versus expert-MRI WML volumes (r2 0.82; ?r: Z=0.54, p>0.1; Fig. 2B; examples shown in Fig. 3). Auto-volumes of WML were more conservative than experts’, being lower than the lowest of three expert estimates in 43% (p<0.001), and taking 61% the value of mean expert CT-volumes (IQR: 40-112%). However, spatial similarityPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MZWRpZzwvQXV0aG9yPjxZZWFyPjIwMTQ8L1llYXI+PElE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=
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MZWRpZzwvQXV0aG9yPjxZZWFyPjIwMTQ8L1llYXI+PElE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=
ADDIN EN.CITE.DATA 23, 24 between Auto WML and expert MRI-WML drawings (median PEIS: 0.53, IQR: 0.48-0.57) was not significantly different to that between expert CT-WML and MRI-WML drawings (median PEIS: 0.54; IQR: 0.49-0.58; ranksum test, Z=1.0; p>0.1). Strength of correlation between Auto CT and expert drawings (CT or MRI) were not significantly influenced by age, sex, or co-existence of the following commonly-associated CT features: acute ischemic change, old infarct, central or peripheral atrophy, or other lesion (Z≤2.3, p>0.05 corrected; Table 1 lists frequencies of these features; see last example in Fig. 3 of WML segmentation adjacent to a co-existing old territorial infarct). Expert drawings took a median of 7.9 minutes per scan (range: 6.9 – 9.4), whereas Auto method (after pre-processing) took a median of 32s (95% CIs: 31-33s) per scan. Correlation coefficients between rater pairs (CT-CT or CT-MRI) were not significantly different from one another (?r: Z<1.8; p>0.1 corrected). Ordinal rating validationAgreement between Auto-derived ratings (i.e. thresholded WML-volume estimates) and individual experts’ ratings, using the Wahlund systemPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XYWhsdW5kPC9BdXRob3I+PFllYXI+MjAwMTwvWWVhcj48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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XYWhsdW5kPC9BdXRob3I+PFllYXI+MjAwMTwvWWVhcj48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ADDIN EN.CITE.DATA 12, was moderate (kw=0.529), but not significantly different to agreements between expert pairs (kw=0.506; ?kw p>0.10; n=650; Table 3). However, agreement between Auto and expert consensus (kw=0.599) was superior to agreements between expert pairs (?kw p<0.001; Fig. 4A). Correlations of Auto WML volume with expert ratings was also greater using consensus (r2=0.582), than individual expert ratings (r2=0.506; ?r: Z=2.05, p<0.05).Using the alternative van Swieten grading system ADDIN EN.CITE <EndNote><Cite><Author>van Swieten</Author><Year>1990</Year><IDText>Grading white matter lesions on CT and MRI: a simple scale</IDText><DisplayText><style face="superscript">15</style></DisplayText><record><dates><pub-dates><date>Dec</date></pub-dates><year>1990</year></dates><keywords><keyword>Brain</keyword><keyword>Brain Diseases</keyword><keyword>Cross-Sectional Studies</keyword><keyword>Data Interpretation, Statistical</keyword><keyword>Humans</keyword><keyword>Ischemic Attack, Transient</keyword><keyword>Longitudinal Studies</keyword><keyword>Magnetic Resonance Imaging</keyword><keyword>Tomography, X-Ray Computed</keyword></keywords><urls><related-urls><url> white matter lesions on CT and MRI: a simple scale</title><secondary-title>J Neurol Neurosurg Psychiatry</secondary-title></titles><pages>1080-3</pages><number>12</number><contributors><authors><author>van Swieten, J. C.</author><author>Hijdra, A.</author><author>Koudstaal, P. J.</author><author>van Gijn, J.</author></authors></contributors><language>ENG</language><added-date format="utc">1478177600</added-date><ref-type name="Journal Article">17</ref-type><rec-number>531</rec-number><last-updated-date format="utc">1478177600</last-updated-date><accession-num>2292703</accession-num><volume>53</volume></record></Cite></EndNote>15, inter-expert agreements were higher (kw=0.665) than using the Wahlund system (?kw p<0.01), and also higher than the agreement between Auto method and individual experts (kw=0.571; ?kw p<0.05). However, inter-expert agreement was not significantly different to the agreement between Auto and expert consensus (kw=0.636; ?kw p>0.10). Correlations between Auto WML volume and expert consensus van Swieten ratings (r2=0.629) did not differ to that between Auto and expert-consensus Wahlund ratings, and individual-expert van Swieten ratings (p>0.10, for both). The proportion of cases in which Auto rating was >1 point different from expert consensus, i.e. strong disagreement, was 0.046, and 0.020, for Wahlund and van Swieten ratings, respectively (representing 72% false positives, and 28% false-negatives; outliers in Fig. 4B, D). Inter-rater agreements between any particular expert pairs, using either rating system, did not differ significantly from one another (p>0.05). Time-charts of raters (for Wahlund ratings) suggested that 30 scans took ~45-60 minutes to rate, ie about 1.5 to 2 mins each in total (including image-file selection, contrast adjustment, and judgements of three cerebral locations).DiscussionWe validate a novel machine-learning software that enables accurate, fully-automated, and rapid quantification of cerebral leukoaraiosis (WML) on CT. The automated method performed similarly to detailed, expert CT WML delineations – both in terms of lesion volume and spatial similarity - relative to a gold-standard of expert delineation of white-matter hyperintensities on coregistered T2-FLAIRPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XYXJkbGF3PC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XYXJkbGF3PC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48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ADDIN EN.CITE.DATA 1. Additionally, by thresholding automated WML volumes into ‘ratings’, agreements with experts’ CT-WML visual ratings were similar to those comparing agreements between expert pairs themselves. In the largest of our cohorts, agreement was greater for comparisons of automated method versus expert consensus ratings, than versus expert individual ratings (or agreements between expert individuals themselves) - which supports the automated method, given that consensus opinions generally lie closer to the truth ADDIN EN.CITE <EndNote><Cite><Author>Galton</Author><Year>1907</Year><IDText>Vox populi</IDText><DisplayText><style face="superscript">26</style></DisplayText><record><titles><title>Vox populi</title><secondary-title>Nature</secondary-title></titles><pages>450-451</pages><contributors><authors><author>Galton, Francis</author></authors></contributors><added-date format="utc">1478519585</added-date><ref-type name="Journal Article">17</ref-type><dates><year>1907</year></dates><rec-number>540</rec-number><last-updated-date format="utc">1478519954</last-updated-date><volume>75</volume></record></Cite></EndNote>26. Images comprised a range of image resolutions, scanner qualities, and hospital origins, and were derived from centres separate to that which contributed training images – indicating the technique’s robustness. Furthermore, accuracy of automated WML estimation was not hindered by common, co-existing hypoattenuating lesions e.g. acute or chronic ischemia (seen in 27% and 45% of our entire sample; equivalent to n=257 and 434 respectively). At the same time, our study confirmed previous findings that standard WML estimation methods, using CT images, result in relatively modest interrater agreement: with kappa values of 0.5 – 0.6 being typical for common rating systemsPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XYWhsdW5kPC9BdXRob3I+PFllYXI+MjAwMTwvWWVhcj48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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XYWhsdW5kPC9BdXRob3I+PFllYXI+MjAwMTwvWWVhcj48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ADDIN EN.CITE.DATA 12-15. This was also shown by the finding that expert CT delineations resulted in a wide range of estimated WML-volumes (mean range of 3 experts: 91% of expert mean), even though they correlated strongly with each other (r2: 0.85). By contrast, the automated method always results in the same estimate of WML volume, once model parameters have been set. Importantly, the parameters of the model tested here did not alter, and were based upon an independent prior dataset. Thus the automated method allows for a reduction in variable noise compared to existing WML scoring techniques, potentially enabling more reliable diagnostic and prognostic models to be developed. A further asset of the automated method is that processing time averaged 109 s (including image pre-processing), with the range being < 3 minutes (similar to experts performing visual ratings). Considering that images originated from a number of centres, and CT-scanners, this performance metric suggests that the automated method could be used widely in emergency-rooms for rapid estimation of background WML from CT. The technique’s option of superimposing machine-identified WML (Fig. 3) can provide extra physician reassurance regarding the algorithm’s output, and assist imaging interpretation by clinicians who are not so experienced in this. Notwithstanding the automated method’s advantages, we also draw attention to its limitations. CT images could not be processed in ~ 4% of cases, that were only partially accountable by poor image-quality issues. Additionally, among images that were processed, significant errors were made (>1 point from consensus rating) in~4%. Although smaller discrepancies with consensus (±1 point from consensus rating) were made in ~30% of cases, it is important to note that expert ratings were based upon judging categorical features (e.g. focal versus confluent lesions; extension to cortex or not) that are not directly proportional to lesion volume. Hence a better judge of Auto method’s accuracy is measuring discrepancy of automated estimates from volumes of expert drawings. In this regard, while Auto-versus-expert drawing correlations were strong, there is also a consistent underestimation of Auto WML volume relative to expert volumes (seen increasingly as WML volume increases: Fig. 2). The fact that this underestimate was of a predictable size relative to the ground-truth of MRI-estimated WML, suggests a suitable scaling factor could be applied. Furthermore, the fact that Auto WML segmentations spatial similarity to MRI-WML was not significantly different to experts’ CT annotations, despite the former being smaller, indicates that the additional areas annotated by experts are not as accurate as the core areas identified by both Auto and expert. The main reason for wishing to quantify WML on CT, rather than MRI, is practicality. CT is the principle neuroimaging modality for emergencies such as acute stroke ADDIN EN.CITE <EndNote><Cite><Author>Sanossian</Author><Year>2016</Year><IDText>Utilization of Emergent Neuroimaging for Thrombolysis-Eligible Stroke Patients</IDText><DisplayText><style face="superscript">3</style></DisplayText><record><dates><pub-dates><date>Jun</date></pub-dates><year>2016</year></dates><urls><related-urls><url> of Emergent Neuroimaging for Thrombolysis-Eligible Stroke Patients</title><secondary-title>J Neuroimaging</secondary-title></titles><contributors><authors><author>Sanossian, N.</author><author>Fu, K. A.</author><author>Liebeskind, D. S.</author><author>Starkman, S.</author><author>Hamilton, S.</author><author>Villablanca, J. P.</author><author>Burgos, A. M.</author><author>Conwit, R.</author><author>Saver, J. L.</author></authors></contributors><language>ENG</language><added-date format="utc">1478706286</added-date><ref-type name="Journal Article">17</ref-type><rec-number>552</rec-number><last-updated-date format="utc">1478706286</last-updated-date><accession-num>27300498</accession-num><electronic-resource-num>10.1111/jon.12369</electronic-resource-num></record></Cite></EndNote>3, and head trauma; and is often the sole imaging technique for investigation of dementiaPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LdXJ1dmlsbGE8L0F1dGhvcj48WWVhcj4yMDE0PC9ZZWFy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=
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LdXJ1dmlsbGE8L0F1dGhvcj48WWVhcj4yMDE0PC9ZZWFy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=
ADDIN EN.CITE.DATA 9-11. CT-analytic software have been developed recently to try to delineate chronic ADDIN EN.CITE <EndNote><Cite><Author>Gillebert</Author><Year>2014</Year><IDText>Automated delineation of stroke lesions using brain CT images</IDText><DisplayText><style face="superscript">27</style></DisplayText><record><keywords><keyword>Aged</keyword><keyword>Aged, 80 and over</keyword><keyword>Algorithms</keyword><keyword>Brain</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Information Storage and Retrieval</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Pattern Recognition, Automated</keyword><keyword>Radiographic Image Enhancement</keyword><keyword>Radiographic Image Interpretation, Computer-Assisted</keyword><keyword>Reproducibility of Results</keyword><keyword>Sensitivity and Specificity</keyword><keyword>Software</keyword><keyword>Stroke</keyword><keyword>Tomography, X-Ray Computed</keyword></keywords><urls><related-urls><url> delineation of stroke lesions using brain CT images</title><secondary-title>Neuroimage Clin</secondary-title></titles><pages>540-8</pages><contributors><authors><author>Gillebert, C. R.</author><author>Humphreys, G. W.</author><author>Mantini, D.</author></authors></contributors><language>ENG</language><added-date format="utc">1478697855</added-date><ref-type name="Journal Article">17</ref-type><dates><year>2014</year></dates><rec-number>544</rec-number><last-updated-date format="utc">1478697855</last-updated-date><accession-num>24818079</accession-num><electronic-resource-num>10.1016/j.nicl.2014.03.009</electronic-resource-num><volume>4</volume></record></Cite></EndNote>27, and acute ischemia ADDIN EN.CITE <EndNote><Cite><Author>Herweh</Author><Year>2016</Year><IDText>Performance of e-ASPECTS software in comparison to that of stroke physicians on assessing CT scans of acute ischemic stroke patients</IDText><DisplayText><style face="superscript">28</style></DisplayText><record><dates><pub-dates><date>Jun</date></pub-dates><year>2016</year></dates><urls><related-urls><url> of e-ASPECTS software in comparison to that of stroke physicians on assessing CT scans of acute ischemic stroke patients</title><secondary-title>Int J Stroke</secondary-title></titles><pages>438-45</pages><number>4</number><contributors><authors><author>Herweh, C.</author><author>Ringleb, P. A.</author><author>Rauch, G.</author><author>Gerry, S.</author><author>Behrens, L.</author><author>M?hlenbruch, M.</author><author>Gottorf, R.</author><author>Richter, D.</author><author>Schieber, S.</author><author>Nagel, S.</author></authors></contributors><language>ENG</language><added-date format="utc">1478701794</added-date><ref-type name="Journal Article">17</ref-type><rec-number>549</rec-number><last-updated-date format="utc">1478701794</last-updated-date><accession-num>26880058</accession-num><electronic-resource-num>10.1177/1747493016632244</electronic-resource-num><volume>11</volume></record></Cite></EndNote>28, as well as to predict hemorrhagic transformation after ischemic stroke ADDIN EN.CITE <EndNote><Cite><Author>Bentley</Author><Year>2014</Year><IDText>Prediction of stroke thrombolysis outcome using CT brain machine learning</IDText><DisplayText><style face="superscript">29</style></DisplayText><record><keywords><keyword>Area Under Curve</keyword><keyword>Artificial Intelligence</keyword><keyword>Brain</keyword><keyword>Female</keyword><keyword>Fibrinolytic Agents</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Outcome Assessment (Health Care)</keyword><keyword>Predictive Value of Tests</keyword><keyword>Retrospective Studies</keyword><keyword>Severity of Illness Index</keyword><keyword>Stroke</keyword><keyword>Tissue Plasminogen Activator</keyword><keyword>Tomography, X-Ray Computed</keyword></keywords><urls><related-urls><url> of stroke thrombolysis outcome using CT brain machine learning</title><secondary-title>Neuroimage Clin</secondary-title></titles><pages>635-40</pages><contributors><authors><author>Bentley, P.</author><author>Ganesalingam, J.</author><author>Carlton Jones, A. L.</author><author>Mahady, K.</author><author>Epton, S.</author><author>Rinne, P.</author><author>Sharma, P.</author><author>Halse, O.</author><author>Mehta, A.</author><author>Rueckert, D.</author></authors></contributors><language>ENG</language><added-date format="utc">1478701914</added-date><ref-type name="Journal Article">17</ref-type><dates><year>2014</year></dates><rec-number>550</rec-number><last-updated-date format="utc">1478701914</last-updated-date><accession-num>24936414</accession-num><electronic-resource-num>10.1016/j.nicl.2014.02.003</electronic-resource-num><volume>4</volume></record></Cite></EndNote>29. One promising application for WML quantification is treatment-selection for acute ischemic stroke, given that cerebral WML load predicts poor functional outcomePEVuZE5vdGU+PENpdGU+PEF1dGhvcj5JU1QtMzwvQXV0aG9yPjxZZWFyPjIwMTU8L1llYXI+PElE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==
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5JU1QtMzwvQXV0aG9yPjxZZWFyPjIwMTU8L1llYXI+PElE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==
ADDIN EN.CITE.DATA 4, 5 and intracranial hemorrhagic (ICH) transformationPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DaGFyaWRpbW91PC9BdXRob3I+PFllYXI+MjAxNjwvWWVh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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DaGFyaWRpbW91PC9BdXRob3I+PFllYXI+MjAxNjwvWWVh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ADDIN EN.CITE.DATA 7, 8. Currently though this CT-imaging predictor, and others e.g. acute ischemia extent, have not been found to interact with thrombolysis (or thrombectomy) treatment in their association with ICH – and so are not recommended for hyperacute treatment stratificationPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XaGl0ZWxleTwvQXV0aG9yPjxZZWFyPjIwMTI8L1llYXI+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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XaGl0ZWxleTwvQXV0aG9yPjxZZWFyPjIwMTI8L1llYXI+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ADDIN EN.CITE.DATA 4, 30. Since automated CT feature extraction, as presented here for WML, offers a reduction in variable noise relative to expert ratings, it would be interesting to explore whether such machine-learning methods can identify treatment-specific ICH or functional outcomes. A related application would be to see if CT WML quantification could be used to predict anticoagulant-associated intracranial haemorrhage ADDIN EN.CITE <EndNote><Cite><Author>Smith</Author><Year>2002</Year><IDText>Leukoaraiosis is associated with warfarin-related hemorrhage following ischemic stroke</IDText><DisplayText><style face="superscript">31</style></DisplayText><record><dates><pub-dates><date>Jul</date></pub-dates><year>2002</year></dates><keywords><keyword>Aged</keyword><keyword>Aged, 80 and over</keyword><keyword>Anticoagulants</keyword><keyword>Brain</keyword><keyword>Brain Ischemia</keyword><keyword>Case-Control Studies</keyword><keyword>Cerebral Hemorrhage</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>International Normalized Ratio</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Risk Factors</keyword><keyword>Severity of Illness Index</keyword><keyword>Warfarin</keyword></keywords><urls><related-urls><url> is associated with warfarin-related hemorrhage following ischemic stroke</title><secondary-title>Neurology</secondary-title></titles><pages>193-7</pages><number>2</number><contributors><authors><author>Smith, E. E.</author><author>Rosand, J.</author><author>Knudsen, K. A.</author><author>Hylek, E. M.</author><author>Greenberg, S. M.</author></authors></contributors><language>ENG</language><added-date format="utc">1478712503</added-date><ref-type name="Journal Article">17</ref-type><rec-number>554</rec-number><last-updated-date format="utc">1478712503</last-updated-date><accession-num>12136056</accession-num><volume>59</volume></record></Cite></EndNote>31 or hematoma growth and early deterioration after primary intracranial haemorrhage ADDIN EN.CITE <EndNote><Cite><Author>Lou</Author><Year>2010</Year><IDText>Relationship between white-matter hyperintensities and hematoma volume and growth in patients with intracerebral hemorrhage</IDText><DisplayText><style face="superscript">32</style></DisplayText><record><dates><pub-dates><date>Jan</date></pub-dates><year>2010</year></dates><keywords><keyword>Aged</keyword><keyword>Aged, 80 and over</keyword><keyword>Cerebral Hemorrhage</keyword><keyword>Female</keyword><keyword>Hematoma, Epidural, Cranial</keyword><keyword>Humans</keyword><keyword>Leukoaraiosis</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Nerve Fibers, Myelinated</keyword><keyword>Prospective Studies</keyword><keyword>Retrospective Studies</keyword><keyword>Risk Factors</keyword></keywords><urls><related-urls><url> between white-matter hyperintensities and hematoma volume and growth in patients with intracerebral hemorrhage</title><secondary-title>Stroke</secondary-title></titles><pages>34-40</pages><number>1</number><contributors><authors><author>Lou, M.</author><author>Al-Hazzani, A.</author><author>Goddeau, R. P.</author><author>Novak, V.</author><author>Selim, M.</author></authors></contributors><edition>2009/11/19</edition><language>eng</language><added-date format="utc">1486061768</added-date><ref-type name="Journal Article">17</ref-type><rec-number>570</rec-number><last-updated-date format="utc">1486061768</last-updated-date><accession-num>19926840</accession-num><electronic-resource-num>10.1161/STROKEAHA.109.564955</electronic-resource-num><volume>41</volume></record></Cite></EndNote>32. More generally, WML quantification may be important in diagnosing, grading and monitoring vascular dementia (and possibly other types of dementia); and for prognosis after head injury ADDIN EN.CITE <EndNote><Cite><Author>Henninger</Author><Year>2014</Year><IDText>Severe leukoaraiosis portends a poor outcome after traumatic brain injury</IDText><DisplayText><style face="superscript">6</style></DisplayText><record><dates><pub-dates><date>Dec</date></pub-dates><year>2014</year></dates><keywords><keyword>Age Factors</keyword><keyword>Aged</keyword><keyword>Aged, 80 and over</keyword><keyword>Brain Injuries</keyword><keyword>Cohort Studies</keyword><keyword>Female</keyword><keyword>Glasgow Coma Scale</keyword><keyword>Glasgow Outcome Scale</keyword><keyword>Humans</keyword><keyword>Leukoaraiosis</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Prognosis</keyword><keyword>Retrospective Studies</keyword><keyword>Severity of Illness Index</keyword><keyword>Tomography, X-Ray Computed</keyword><keyword>White Matter</keyword></keywords><urls><related-urls><url> leukoaraiosis portends a poor outcome after traumatic brain injury</title><secondary-title>Neurocrit Care</secondary-title></titles><pages>483-95</pages><number>3</number><contributors><authors><author>Henninger, N.</author><author>Izzy, S.</author><author>Carandang, R.</author><author>Hall, W.</author><author>Muehlschlegel, S.</author></authors></contributors><language>eng</language><added-date format="utc">1486060288</added-date><ref-type name="Journal Article">17</ref-type><rec-number>569</rec-number><last-updated-date format="utc">1486060288</last-updated-date><accession-num>24752459</accession-num><electronic-resource-num>10.1007/s12028-014-9980-0</electronic-resource-num><volume>21</volume></record></Cite></EndNote>6. In summary, automated WML quantification enables reliable parameterization of a common and clinically-relevant neuroimaging biomarker. Clinical research into cerebral white-matter lesions, in contexts where CT is the predominant imaging modality, may benefit from the method more than existing observer-dependent visual ratings. AcknowledgementsThis work was supported by NIHR Grant i4i: Decision-assist software for management of acute ischaemic stroke using brain-imaging machine-learning (Ref: II-LA-0814-20007).Funding sources for IST-3 trial are listed elsewherePEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TYW5kZXJjb2NrPC9BdXRob3I+PFllYXI+MjAxMjwvWWVh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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TYW5kZXJjb2NrPC9BdXRob3I+PFllYXI+MjAxMjwvWWVh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ADDIN EN.CITE.DATA 19 : primarily the UK Medical Research Council (MRC G0400069 and EME 09-800-15). We thank the IST-3 Investigators. Conflicts of interestNone declared.TablesTable 1: Sample characteristics of four validation studiesDrawing volume studiesOrdinal rating studiesCT only CT-MRI pairs Wahlund Scorevan Swieten ScoreN112060650196Population descriptionRandom selection of patients presenting to acute stroke ward; equal proportions of SVD severity: absent-mild/moderate/severeAll, unselected thrombolysed patients (+ CT-MRI pairs cohort)Random selection of participants from, thrombolysis trial IST-34Age (median, IQR)76 (66-85)76 (67-84)75 (63-82)82 (77-86)Male (%)52585445CT features:-- acute parenchymal Ischemia (%)1922360- old infarcts (%)38384259- central atrophy2 (%)72756787- peripheral atrophy2 (%)82877585- other lesions3 (%)6850Expert Raters (n) – pool number33613 – per scan33331 Numbers able to be processed by Auto WML quantification method (i.e. excluding image processing failures) 2 using atrophy grading system described in ADDIN EN.CITE <EndNote><Cite><Author>Farrell</Author><Year>2009</Year><IDText>Development and initial testing of normal reference MR images for the brain at ages 65-70 and 75-80 years</IDText><DisplayText><style face="superscript">33</style></DisplayText><record><dates><pub-dates><date>Jan</date></pub-dates><year>2009</year></dates><keywords><keyword>Aged</keyword><keyword>Aged, 80 and over</keyword><keyword>Aging</keyword><keyword>Atrophy</keyword><keyword>Brain</keyword><keyword>Female</keyword><keyword>Great Britain</keyword><keyword>Humans</keyword><keyword>Image Interpretation, Computer-Assisted</keyword><keyword>Magnetic Resonance Imaging</keyword><keyword>Male</keyword><keyword>Reference Values</keyword><keyword>Reproducibility of Results</keyword><keyword>Sensitivity and Specificity</keyword></keywords><urls><related-urls><url> and initial testing of normal reference MR images for the brain at ages 65-70 and 75-80 years</title><secondary-title>Eur Radiol</secondary-title></titles><pages>177-83</pages><number>1</number><contributors><authors><author>Farrell, C.</author><author>Chappell, F.</author><author>Armitage, P. A.</author><author>Keston, P.</author><author>Maclullich, A.</author><author>Shenkin, S.</author><author>Wardlaw, J. M.</author></authors></contributors><language>ENG</language><added-date format="utc">1478621838</added-date><ref-type name="Journal Article">17</ref-type><rec-number>541</rec-number><last-updated-date format="utc">1478621838</last-updated-date><accession-num>18690455</accession-num><electronic-resource-num>10.1007/s00330-008-1119-2</electronic-resource-num><volume>19</volume></record></Cite></EndNote>33. 3 e.g. hydrocephalus, arachnoid cyst, meningioma, aneurysm, haemorrhage. 4 patients with acute ischemic parenchymal changes were excluded in advanceTable 2: Correlations between expert drawing and Auto volumesStudyCorrelation of lesion volume between:-r2RangeCT onlyAuto versus consensus-Expert CT lesion volumes (mean of 3)0.7100.645-0.713*Expert CT drawings between themselves (x3)0.8450.813-0.867CT-MRI pairsAuto versus consensus-Expert MR lesion volumes (mean of 2) 0.8500.823-0.833*Expert CT drawings with Expert MRI drawings0.8190.767-0.856Expert MR drawings between each other (x2)0.937-*range here refers to Auto vs individual expert drawing volumes All correlations are significant at p<0.001Table 3: Agreements and correlations between expert scores and Auto scores or volumesStudyAgreement (weighted Kappa) of SVD score ratings between:-KwRangeWahlundScore (0-3) Experts amongst themselves (x6) [see Fig. 4A.]0.5060.473-0.552 Auto versus Experts (individuals)0.5290.465-0.579 Auto versus Expert (consensus) [see Fig. 4B.]0.5990.586-0.611Correlation of Expert SVD score rating and Auto volumer2 Expert individuals0.5060.462-0.549 Expert consensus0.582-Van Swieten Score (0-4)Agreement (weighted Kappa) of SVD score ratings between:-KwRange Experts amongst themselves (x3) [see Fig. 4C.]0.6650.648-0.674 Auto versus Experts (individuals)0.5710.534-0.597 Auto versus Expert (consensus) [see Fig. 4D.]0.6360.517-0.747Correlation of Expert SVD score rating and Auto volumer2 Expert individuals0.5710.522-0.614 Expert consensus0.629-FiguresFigure 1. Flow-chart of validation cohorts (A.), and image-processing (B.) stepsFigure 2. A : Correlations of Auto WML volumes with Expert drawings on CT. Each of three experts is indicated by a ‘X’, with a connected line showing range of expert values. B : Correlations of gold-standard WML volumes (expert drawings on FLAIR-MRI) with Auto-estimated volumes (blue squares), and expert drawings on CT (each of 3 experts marked by ‘X’; range shown by vertical line). Line of equality shown in each case, indicating that estimated WML volumes for any one patient tend be in order: Auto WML < expert CT WML < expert MRI WML.Figure 3: Examples of WML delineations by Auto method and Expert drawings (three colors represent specific experts’ annotations). The final column shows WML on co-registered FLAIRs, that were also delineated by experts (not shown here) and provided the ground-truth. Figure 4. Agreement plots of expert-expert and Auto-expert consensus for two WML scoring systems. Auto score based upon thresholding of Auto-delineated WML volumes26098560960Expert?Expert consensus?Expert?Expert?Auto?Auto?Van Swieten score?Expert?Expert consensus?Wahlund scoreA.B.C.D.00Expert?Expert consensus?Expert?Expert?Auto?Auto?Van Swieten score?Expert?Expert consensus?Wahlund scoreA.B.C.D.References ADDIN EN.REFLIST 1.Wardlaw JM, Smith EE, Biessels GJ, Cordonnier C, Fazekas F, Frayne R, et al. Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration. Lancet Neurol. 2013;12:822-8382.Rossi R, Joachim C, Geroldi C, Esiri MM, Smith AD, Frisoni GB. Pathological validation of a ct-based scale for subcortical vascular disease. The optima study. Dement Geriatr Cogn Disord. 2005;19:61-663.Sanossian N, Fu KA, Liebeskind DS, Starkman S, Hamilton S, Villablanca JP, et al. Utilization of emergent neuroimaging for thrombolysis-eligible stroke patients. J Neuroimaging. 20164.group I-c. Association between brain imaging signs, early and late outcomes, and response to intravenous alteplase after acute ischaemic stroke in the third international stroke trial (ist-3): Secondary analysis of a randomised controlled trial. Lancet Neurol. 2015;14:485-4965.Ryu WS, Woo SH, Schellingerhout D, Jang MU, Park KJ, Hong KS, et al. Stroke outcomes are worse with larger leukoaraiosis volumes. Brain. 2017;140:158-1706.Henninger N, Izzy S, Carandang R, Hall W, Muehlschlegel S. Severe leukoaraiosis portends a poor outcome after traumatic brain injury. Neurocrit Care. 2014;21:483-4957.Charidimou A, Pasi M, Fiorelli M, Shams S, von Kummer R, Pantoni L, et al. Leukoaraiosis, cerebral hemorrhage, and outcome after intravenous thrombolysis for acute ischemic stroke: A meta-analysis (v1). Stroke. 2016;47:2364-23728.Willer L, Havsteen I, Ovesen C, Christensen AF, Christensen H. Computed tomography--verified leukoaraiosis is a risk factor for post-thrombolytic hemorrhage. J Stroke Cerebrovasc Dis. 2015;24:1126-11309.Alachkar M. Neuroimaging in dementia: How best to use the guidelines? Psychiatr Bull (2014). 2014;38:137-13810.Kuruvilla T, Zheng R, Soden B, Greef S, Lyburn I. Neuroimaging in a memory assessment service: A completed audit cycle. Psychiatr Bull (2014). 2014;38:24-2811.Riello R, Albini C, Galluzzi S, Pasqualetti P, Frisoni GB. Prescription practices of diagnostic imaging in dementia: A survey of 47 alzheimer's centres in northern italy. Int J Geriatr Psychiatry. 2003;18:577-58512.Wahlund LO, Barkhof F, Fazekas F, Bronge L, Augustin M, Sj?gren M, et al. A new rating scale for age-related white matter changes applicable to mri and ct. Stroke. 2001;32:1318-132213.Simoni M, Li L, Paul NL, Gruter BE, Schulz UG, Küker W, et al. Age- and sex-specific rates of leukoaraiosis in tia and stroke patients: Population-based study. Neurology. 2012;79:1215-122214.Scheltens P, Erkinjunti T, Leys D, Wahlund LO, Inzitari D, del Ser T, et al. White matter changes on ct and mri: An overview of visual rating scales. European task force on age-related white matter changes. Eur Neurol. 1998;39:80-8915.van Swieten JC, Hijdra A, Koudstaal PJ, van Gijn J. Grading white matter lesions on ct and mri: A simple scale. J Neurol Neurosurg Psychiatry. 1990;53:1080-108316.Pantoni L, Simoni M, Pracucci G, Schmidt R, Barkhof F, Inzitari D. Visual rating scales for age-related white matter changes (leukoaraiosis): Can the heterogeneity be reduced? Stroke. 2002;33:2827-283317.Chen L, Tong T, Pang Ho C, Patel R, Cohen D, Dawson AC, et al. Identification of cerebral small vessel disease using multiple instance learning. Medical Image Computing and Computer-Assisted Intervention (MICCAI 2015). 2015;9349:523-53018.Maier O, Menze BH, von der Gablentz J, H?ni L, Heinrich MP, Liebrand M, et al. Isles 2015 - a public evaluation benchmark for ischemic stroke lesion segmentation from multispectral mri. Med Image Anal. 2017;35:250-26919.Sandercock P, Wardlaw JM, Lindley RI, Dennis M, Cohen G, Murray G, et al. The benefits and harms of intravenous thrombolysis with recombinant tissue plasminogen activator within 6 h of acute ischaemic stroke (the third international stroke trial [ist-3]): A randomised controlled trial. Lancet. 2012;379:2352-236320.Liaw A, Wiener M. Classification and regression by randomforest. R News. 2002;2/3:18-2221.Rueckert D, Sonoda LI, Hayes C, Hill DL, Leach MO, Hawkes DJ. Nonrigid registration using free-form deformations: Application to breast mr images. IEEE Trans Med Imaging. 1999;18:712-72122.Myers L, Sirois MJ. Spearman correlation coefficients, difference between. Encyclopedia of Statistical Sciences. 2006;1223.Ledig C, Shi W, Bai W, Rueckert D. Patch-based evaluation of image segmentation. Proceedings of CVPR. 2014:3065-307224.Ledig C, Heckemann RA, Hammers A, Lopez JC, Newcombe VF, Makropoulos A, et al. Robust whole-brain segmentation: Application to traumatic brain injury. Med Image Anal. 2015;21:40-5825.Vanbelle S, Albert A. A bootstrap method for comparing correlated kappa coefficients. Journal of Statistical Computation and Simulation. 2008;78:1009-101526.Galton F. Vox populi. Nature. 1907;75:450-45127.Gillebert CR, Humphreys GW, Mantini D. Automated delineation of stroke lesions using brain ct images. Neuroimage Clin. 2014;4:540-54828.Herweh C, Ringleb PA, Rauch G, Gerry S, Behrens L, M?hlenbruch M, et al. Performance of e-aspects software in comparison to that of stroke physicians on assessing ct scans of acute ischemic stroke patients. Int J Stroke. 2016;11:438-44529.Bentley P, Ganesalingam J, Carlton Jones AL, Mahady K, Epton S, Rinne P, et al. Prediction of stroke thrombolysis outcome using ct brain machine learning. Neuroimage Clin. 2014;4:635-64030.Whiteley WN, Slot KB, Fernandes P, Sandercock P, Wardlaw J. Risk factors for intracranial hemorrhage in acute ischemic stroke patients treated with recombinant tissue plasminogen activator: A systematic review and meta-analysis of 55 studies. Stroke. 2012;43:2904-290931.Smith EE, Rosand J, Knudsen KA, Hylek EM, Greenberg SM. Leukoaraiosis is associated with warfarin-related hemorrhage following ischemic stroke. Neurology. 2002;59:193-19732.Lou M, Al-Hazzani A, Goddeau RP, Novak V, Selim M. Relationship between white-matter hyperintensities and hematoma volume and growth in patients with intracerebral hemorrhage. Stroke. 2010;41:34-4033.Farrell C, Chappell F, Armitage PA, Keston P, Maclullich A, Shenkin S, et al. Development and initial testing of normal reference mr images for the brain at ages 65-70 and 75-80 years. Eur Radiol. 2009;19:177-183 ................
................
In order to avoid copyright disputes, this page is only a partial summary.
To fulfill the demand for quickly locating and searching documents.
It is intelligent file search solution for home and business.
Related download
- table 4 reporting mr imaging changes of presumed vascular
- viktor s notes ischemic stroke
- stroke what happens next
- my thoughts re rehab programme pilot
- cerebrovascular prevention strategies for dementia
- chapter 26 the nervous system
- rapid automated quantification of cerebral small vessel
- update on small vessel diseases university of edinburgh
Related searches
- icd 10 code for small vessel disease
- periventricular small vessel ischemic disease
- chronic small vessel ischemic changes brain
- small vessel brain disease prognosis
- chronic small vessel ischemic disease
- what is chronic small vessel disease
- chronic small vessel ischemic disease on mri
- chronic small vessel ischemia symptoms
- small vessel disease in brain
- small vessel heart disease lifespan
- small vessel disease brain prognosis
- small vessel disease brain treatment