{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T22:20:17Z","timestamp":1791498017604,"version":"4.3.4"},"update-to":[{"DOI":"10.1371\/journal.pcbi.1014505","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T00:00:00Z","timestamp":1786060800000}}],"reference-count":45,"publisher":"Public Library of Science (PLoS)","issue":"7","license":[{"start":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T00:00:00Z","timestamp":1785110400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"L\u2019association Jules Bordet","award":["2021-08"],"award-info":[{"award-number":["2021-08"]}]}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"<jats:p>\n                    The analysis of cell\u2011free DNA (cfDNA) is transforming cancer diagnostics, yet quantifying the fraction of circulating tumour DNA (ctDNA) from shallow whole\u2011genome sequencing (sWGS) remains challenging in tumours with low copy\u2011number aberration burden. We introduce\n                    <jats:bold>ALFAssay<\/jats:bold>\n                    , a feed\u2011forward neural network that estimates ctDNA fraction from fragmentation profiles of cfDNA in breast cancer. Using cfDNA from 896 plasma samples spanning early and metastatic HR\u2009+\u2009\/HER2\u2013 and triple\u2011negative breast cancer, and healthy controls, (id: NCT03616886, NCT02028364, NCT03065621) we extract 204 bin\u2011level fragmentation features by computing the ratio of short fragments (90\u2013150 bp) to all reads within 5 Mb genomic windows, while accounting for coverage effects by incorporating the total number of reads for each bin as an additional input feature. The resulting 408\u2011dimensional vectors are input to a fully connected network trained against ichorCNA\u2011derived ctDNA fractions using five\u2011fold cross\u2011validation. ALFAssay demonstrates high sensitivity (0.87) and specificity (0.94) for ctDNA detection and correlates with ichorCNA (r\u2009=\u20090.89) and the fragmentation\u2011based tool Fragle (r\u2009=\u20090.81). Its ctDNA predictions stratify patients by progression\u2011free survival and add complementary prognostic value to available tools. ALFAssay thus expands the bioinformatics toolkit for ctDNA quantification and highlights the potential of fragmentation signatures to augment multi\u2011modal liquid\u2011biopsy workflows.\n                  <\/jats:p>","DOI":"10.1371\/journal.pcbi.1014505","type":"journal-article","created":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T17:41:31Z","timestamp":1785174091000},"page":"e1014505","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["ALFAssay: A feed\u2011forward neural network for quantitative fragmentomics\u2011based ctDNA profiling in breast cancer"],"prefix":"10.1371","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-8599-9369","authenticated-orcid":true,"given":"Alexandra","family":"Stanciu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Gombos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisa","family":"Agostinetto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Delphine","family":"Vincent","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurence","family":"Buisseret","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Papagiannis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francoise","family":"Rothe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicola","family":"Occelli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christos","family":"Sotiriou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Venet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michail","family":"Ignatiadis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,7,27]]},"reference":[{"issue":"4","key":"pcbi.1014505.ref001","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1038\/nrc.2017.7","article-title":"Liquid biopsies come of age: towards implementation of circulating tumour DNA","volume":"17","author":"JCM Wan","year":"2017","journal-title":"Nat Rev Cancer"},{"issue":"3","key":"pcbi.1014505.ref002","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1038\/s43018-020-0043-5","article-title":"Circulating tumor DNA and liquid biopsy in oncology","volume":"1","author":"DW Cescon","year":"2020","journal-title":"Nat Cancer"},{"issue":"5","key":"pcbi.1014505.ref003","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1038\/s41571-020-00457-x","article-title":"Liquid biopsy enters the clinic - implementation issues and future challenges","volume":"18","author":"M Ignatiadis","year":"2021","journal-title":"Nat Rev Clin Oncol"},{"issue":"224","key":"pcbi.1014505.ref004","doi-asserted-by":"crossref","DOI":"10.1126\/scitranslmed.3007094","article-title":"Detection of circulating tumor DNA in early- and late-stage human malignancies","volume":"6","author":"C Bettegowda","year":"2014","journal-title":"Sci Transl Med"},{"issue":"5","key":"pcbi.1014505.ref005","doi-asserted-by":"crossref","first-page":"548","DOI":"10.1038\/nm.3519","article-title":"An ultrasensitive method for quantitating circulating tumor DNA with broad patient coverage","volume":"20","author":"AM Newman","year":"2014","journal-title":"Nat Med"},{"issue":"1","key":"pcbi.1014505.ref006","doi-asserted-by":"crossref","first-page":"1324","DOI":"10.1038\/s41467-017-00965-y","article-title":"Scalable whole-exome sequencing of cell-free DNA reveals high concordance with metastatic tumors","volume":"8","author":"VA Adalsteinsson","year":"2017","journal-title":"Nat Commun"},{"key":"pcbi.1014505.ref007","doi-asserted-by":"crossref","unstructured":"Heitzer E, et al. 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