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In this study, the performance of a support vector machine (SVM)-based classifier will be tested against pathological ground truths and its performance determined in cognitively healthy older adults.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>We applied SVM with a linear kernel to an <jats:sup>18<\/jats:sup>F-Flutemetamol end-of-life dataset to determine the regions with the highest feature weights in a data-driven manner and to compare between two different pathological ground truths: based on neuritic amyloid plaque density or on amyloid phases, respectively. We also trained and tested classifiers based on the 10% voxels with the highest amplitudes of feature weights for each of the two neuropathological ground truths. Next, we tested the classifiers\u2019 diagnostic performance in the asymptomatic Alzheimer\u2019s disease (AD) phase, a phase of interest for future drug development, in an independent dataset of cognitively intact older adults, the Flemish Prevent AD Cohort-KU Leuven (F-PACK). A regression analysis was conducted between the Centiloid (CL) value in a composite volume of interest (VOI), as index for amyloid load, and the distance to the hyperplane for each of the two classifiers, based on the two pathological ground truths. A receiver operating characteristic analysis was also performed to determine the CL threshold that optimally discriminates between neuritic amyloid plaque positivity versus negativity, or amyloid phase positivity versus negativity, within F-PACK.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>The classifiers yielded adequate specificity and sensitivity within the end-of-life dataset (neuritic amyloid plaque density classifier: specificity of 90.2% and sensitivity of 83.7%; amyloid phase classifier: specificity of 98.4% and sensitivity of 84.0%). The regions with the highest feature weights corresponded to precuneus, caudate, anteromedial prefrontal, and also posterior inferior temporal and inferior parietal cortex. In the cognitively normal cohort, the correlation coefficient between CL and distance to the hyperplane was\u2009\u22120.66 for the classifier trained with neuritic amyloid plaque density, and\u2009\u22120.88 for the classifier trained with amyloid phases. This difference was significant. The optimal CL cut-off for discriminating positive versus negative scans was <jats:italic>CL<\/jats:italic>\u2009=\u200948\u201351 for the different classifiers (area under the curve (<jats:italic>AUC<\/jats:italic>)\u2009=\u200999.9%), except for the classifier trained with amyloid phases and based on the 10% voxels with highest feature weights. There the cut-off was <jats:italic>CL<\/jats:italic>\u2009=\u200926 (<jats:italic>AUC<\/jats:italic>\u2009=\u200999.5%), which closely matched the CL threshold for discriminating phases 0\u20132 from 3\u20135 based on the end-of-life dataset and the neuropathological ground truth.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Discussion<\/jats:title>\n                <jats:p>Among a set of neuropathologically validated classifiers trained with end-of-life cases, transfer to a cognitively normal population works best for a classifier trained with amyloid phases and using only voxels with the highest amplitudes of feature weights.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1007\/s00259-022-05808-7","type":"journal-article","created":{"date-parts":[[2022,5,6]],"date-time":"2022-05-06T04:20:48Z","timestamp":1651810848000},"page":"3772-3786","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Classification of 18F-Flutemetamol scans in cognitively normal older adults using machine learning trained with neuropathology as ground truth"],"prefix":"10.1007","volume":"49","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7964-7963","authenticated-orcid":false,"given":"Mariska","family":"Reinartz","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1777-4742","authenticated-orcid":false,"given":"Emma Susanne","family":"Luckett","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jolien","family":"Schaeverbeke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steffi","family":"De Meyer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katarzyna","family":"Adamczuk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dietmar Rudolf","family":"Thal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koen","family":"Van Laere","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1980-2540","authenticated-orcid":false,"given":"Patrick","family":"Dupont","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6237-2502","authenticated-orcid":false,"given":"Rik","family":"Vandenberghe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,5,6]]},"reference":[{"key":"5808_CR1","doi-asserted-by":"publisher","first-page":"669","DOI":"10.1016\/S1474-4422(12)70142-4","volume":"11","author":"CM Clark","year":"2012","unstructured":"Clark CM, Pontecorvo MJ, Beach TG, Bedell BJ, Coleman RE, Doraiswamy PM, et al. 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J Neuropathol Exp Neurol England. 2000;59:733\u201348.","journal-title":"J Neuropathol Exp Neurol England"}],"container-title":["European Journal of Nuclear Medicine and Molecular Imaging"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00259-022-05808-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00259-022-05808-7\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00259-022-05808-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,8,23]],"date-time":"2022-08-23T07:11:31Z","timestamp":1661238691000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00259-022-05808-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,5,6]]},"references-count":32,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2022,9]]}},"alternative-id":["5808"],"URL":"https:\/\/doi.org\/10.1007\/s00259-022-05808-7","relation":{},"ISSN":["1619-7070","1619-7089"],"issn-type":[{"value":"1619-7070","type":"print"},{"value":"1619-7089","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,5,6]]},"assertion":[{"value":"20 December 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 April 2022","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"6 May 2022","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The F-PACK cohort study has been approved by the UZ\/KU Leuven Ethics Committee for Clinical studies (study number S51125). The <sup>18<\/sup>F-flutemetamol end-of-life study was approved by the Institutional Review Boards or Ethics Committees at the following institutions which approved the study protocol before initiation: Compass Research, Galiz Research, LasVegas Radiology, Premier Research Institute, Banner Sun Health Research Institute, Mt Sinai Medical Center,Wien Center for Alzheimer\u2019s Disease,Warren Alpert Medical School of Brown University, Banner Alzheimer\u2019s Institute, University of Michigan, Moorgreen Hospital, VERITAS Research, St Margaret\u2019s Hospital, Miami Jewish Health Systems, Memory Enhancement Center, Oxford Radcliffe Hospitals, Michigan State University, Exodon LLC, and Barrows Neurological Institute.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval"}},{"value":"Written informed consent was obtained from all individual participants included in the F-PACK study. Written informed consent was obtained from all individual participants or their legal representatives for the <sup>18<\/sup>F-flutemetamol end-of-life study.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to participate"}},{"value":"DRT received honoraria as consultant for assessing amyloid pathology for the GE-067\u2013026 trial from GE-HC and Convance. He also received speaker honoraria from Novartis Pharma Basel (Switzerland) and Biogen (USA); travel reimbursement from GE-Healthcare (UK), and UCB (Belgium); and collaborated with GE-Healthcare (UK), Novartis Pharma Basel (Switzerland), Probiodrug (Germany), and Janssen Pharmaceutical Companies (Belgium). JS is a junior postdoctoral fellow of the FWO (12Y1620N). KA is a full time employee of Bioclinica, Newark, CA, USA. KVL has received speaker fees by GE-HC. RV has received research grants from Research Foundation\u2014Flanders (FWO) and KU Leuven, has had a clinical trial agreement for phase 1 and 2 study between University Hospitals Leuven and GE-HC, has received a non-financial support from GE-HC (provision of <sup>18<\/sup>F-Flutemetamol for conduct of investigator-driven trial free of cost), and has a clinical trial agreement (local principal investigator) between University Hospitals Leuven and Biogen, J&J, NovoNordisk, Roche, and UCB. All other authors declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}