{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T04:25:33Z","timestamp":1772166333581,"version":"3.50.1"},"reference-count":20,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2023,2,2]],"date-time":"2023-02-02T00:00:00Z","timestamp":1675296000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2023,2,2]],"date-time":"2023-02-02T00:00:00Z","timestamp":1675296000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100013302","name":"King Abdullah International Medical Research Center","doi-asserted-by":"publisher","award":["400016184"],"award-info":[{"award-number":["400016184"]}],"id":[{"id":"10.13039\/501100013302","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["LM010098"],"award-info":[{"award-number":["LM010098"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["LM010098"],"award-info":[{"award-number":["LM010098"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["LM010098"],"award-info":[{"award-number":["LM010098"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["LM010098"],"award-info":[{"award-number":["LM010098"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"the Netherlands CardioVascular Research Initiative","award":["CVON 2011\/B019"],"award-info":[{"award-number":["CVON 2011\/B019"]}]},{"DOI":"10.13039\/501100010767","name":"Innovative Medicines Initiative","doi-asserted-by":"publisher","award":["116074"],"award-info":[{"award-number":["116074"]}],"id":[{"id":"10.13039\/501100010767","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100010767","name":"Innovative Medicines Initiative","doi-asserted-by":"publisher","award":["116074"],"award-info":[{"award-number":["116074"]}],"id":[{"id":"10.13039\/501100010767","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002996","name":"Dutch Heart Foundation","doi-asserted-by":"crossref","award":["2017T003"],"award-info":[{"award-number":["2017T003"]}],"id":[{"id":"10.13039\/501100002996","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["BioData Mining"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Loss-of-Function (LoF) variants in human genes are important due to their impact on clinical phenotypes and frequent occurrence in the genomes of healthy individuals. The association of LoF variants with complex diseases and traits may lead to the discovery and validation of novel therapeutic targets. Current approaches predict high-confidence LoF variants without identifying the specific genes or the number of copies they affect. Moreover, there is a lack of methods for detecting knockout genes caused by compound heterozygous (CH) LoF variants.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>We have developed the Loss-of-Function ToolKit (LoFTK), which allows efficient and automated prediction of LoF variants from genotyped, imputed and sequenced genomes. LoFTK enables the identification of genes that are inactive in one or two copies and provides summary statistics for downstream analyses. LoFTK can identify CH LoF variants, which result in LoF genes with two copies lost. Using data from parents and offspring we show that 96% of CH LoF genes predicted by LoFTK in the offspring have the respective alleles donated by each parent.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      LoFTK is a command-line based tool that provides a reliable computational workflow for predicting LoF variants from genotyped and sequenced genomes, identifying genes that are inactive in 1 or 2 copies. LoFTK is an open software and is freely available to non-commercial users at\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/github.com\/CirculatoryHealth\/LoFTK\">https:\/\/github.com\/CirculatoryHealth\/LoFTK<\/jats:ext-link>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13040-023-00321-5","type":"journal-article","created":{"date-parts":[[2023,2,2]],"date-time":"2023-02-02T03:04:07Z","timestamp":1675307047000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["LoFTK: a framework for fully automated calculation of predicted Loss-of-Function variants and genes"],"prefix":"10.1186","volume":"16","author":[{"given":"Abdulrahman","family":"Alasiri","sequence":"first","affiliation":[]},{"given":"Konrad J.","family":"Karczewski","sequence":"additional","affiliation":[]},{"given":"Brian","family":"Cole","sequence":"additional","affiliation":[]},{"given":"Bao-Li","family":"Loza","sequence":"additional","affiliation":[]},{"given":"Jason H.","family":"Moore","sequence":"additional","affiliation":[]},{"given":"Sander W.","family":"van der Laan","sequence":"additional","affiliation":[]},{"given":"Folkert W.","family":"Asselbergs","sequence":"additional","affiliation":[]},{"given":"Brendan J.","family":"Keating","sequence":"additional","affiliation":[]},{"given":"Jessica","family":"van Setten","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2023,2,2]]},"reference":[{"key":"321_CR1","doi-asserted-by":"publisher","first-page":"R125","DOI":"10.1093\/hmg\/ddq365","volume":"19","author":"DG MacArthur","year":"2010","unstructured":"MacArthur DG, Tyler-Smith C. Loss-of-function variants in the genomes of healthy humans. Hum Mol Genet. 2010;19:R125\u201330.","journal-title":"Hum Mol Genet"},{"key":"321_CR2","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1101\/gad.1968411","volume":"25","author":"S Balasubramanian","year":"2011","unstructured":"Balasubramanian S, Habegger L, Frankish A, MacArthur DG, Harte R, Tyler-Smith C, Harrow J, Gerstein M. Gene inactivation and its implications for annotation in the era of personal genomics. Genes Dev. 2011;25:1\u201310.","journal-title":"Genes Dev"},{"key":"321_CR3","doi-asserted-by":"publisher","first-page":"823","DOI":"10.1126\/science.1215040","volume":"335","author":"DG MacArthur","year":"2012","unstructured":"MacArthur DG, Balasubramanian S, Frankish A, et al. A systematic survey of loss-of-function variants in human protein-coding genes. Science. 2012;335:823\u20138.","journal-title":"Science"},{"key":"321_CR4","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1038\/nature11632","volume":"491","author":"GR Abecasis","year":"2012","unstructured":"Genomes Project Consortium, Abecasis GR, Auton A, Brooks LD, DePristo MA, Durbin RM, Handsaker RE, Kang HM, Marth GT, McVean GA. An integrated map of genetic variation from 1,092 human genomes. Nature. 2012;491:56\u201365.","journal-title":"Nature"},{"key":"321_CR5","doi-asserted-by":"publisher","first-page":"285","DOI":"10.1038\/nature19057","volume":"536","author":"M Lek","year":"2016","unstructured":"Lek M, Karczewski KJ, Minikel EV, et al. Analysis of protein-coding genetic variation in 60,706 humans. 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Filtering for compound heterozygous sequence variants in non-consanguineous pedigrees. PLoS ONE. 2013;8: e70151.","journal-title":"PLoS ONE"},{"key":"321_CR9","doi-asserted-by":"publisher","first-page":"259","DOI":"10.1016\/j.neuron.2012.11.002","volume":"77","author":"TW Yu","year":"2013","unstructured":"Yu TW, Chahrour MH, Coulter ME, et al. Using whole-exome sequencing to identify inherited causes of autism. Neuron. 2013;77:259\u201373.","journal-title":"Neuron"},{"key":"321_CR10","doi-asserted-by":"publisher","first-page":"235","DOI":"10.1016\/j.neuron.2012.12.029","volume":"77","author":"ET Lim","year":"2013","unstructured":"Lim ET, Raychaudhuri S, Sanders SJ, et al. Rare complete knockouts in humans: population distribution and significant role in autism spectrum disorders. 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Nature. 2021;599:628\u201334.","journal-title":"Nature"}],"container-title":["BioData Mining"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13040-023-00321-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s13040-023-00321-5\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13040-023-00321-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,2,2]],"date-time":"2023-02-02T03:05:30Z","timestamp":1675307130000},"score":1,"resource":{"primary":{"URL":"https:\/\/biodatamining.biomedcentral.com\/articles\/10.1186\/s13040-023-00321-5"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,2,2]]},"references-count":20,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2023,12]]}},"alternative-id":["321"],"URL":"https:\/\/doi.org\/10.1186\/s13040-023-00321-5","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2021.08.09.455694","asserted-by":"object"}]},"ISSN":["1756-0381"],"issn-type":[{"value":"1756-0381","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,2,2]]},"assertion":[{"value":"4 March 2022","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 January 2023","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"2 February 2023","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"UK Biobank (UKBB) had acquired ethics approval from the North West Multi-centre Research Ethics Committee, which covers the UK (approval number: 11\/NW\/0382) and had obtained informed consent from all participants. UKBB data used in this study were obtained under application ID 24711. Collection of the Genome of the Netherlands (GoNL) data was approved by the committee of GoNL and all necessary participant consent has been obtained. GoNL data used in this study were obtained under application ID 2021217.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"All participants provided written informed consent for their anonymized information to be used for health-related research purposes and the results thereof to be published.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare that they have no competing interests. Dr. Sander W. van der Laan has received Roche funding for unrelated work.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"3"}}