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The presence of such deletions can be determined in publically available <jats:italic>P. falciparum<\/jats:italic> whole genome sequencing (WGS) datasets. A computational approach was developed and validated, termed Gene Coverage Count and Classification (GC<jats:sub>3<\/jats:sub>), to analyse genome-wide sequence coverage data and provide informative outputs to assess presence and coverage profile of a target locus in WGS data. GC<jats:sub>3<\/jats:sub> was applied to detect deletions at <jats:italic>hrp2<\/jats:italic> and <jats:italic>hrp3<\/jats:italic> (<jats:italic>hrp2\/<\/jats:italic>3) and flanking genes in different geographic regions and across time points.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>GC<jats:sub>3<\/jats:sub> uses Python and R scripts to extract locus read coverage metrics from mapped WGS data according to user-defined parameters and generates relevant tables and figures. GC<jats:sub>3<\/jats:sub> was tested using WGS data for laboratory reference strains with known <jats:italic>hrp2\/3<\/jats:italic> genotypes, and its results compared to those of a <jats:italic>hrp2\/3<\/jats:italic>-specific qPCR assay. Samples with at least 25% of coding region positions with zero coverage were classified as having a deletion. Publicly available sequence data was analysed and compared with published deletion frequency estimates.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>GC<jats:sub>3<\/jats:sub> results matched the expected coverage of known laboratory reference strains. Agreement between GC<jats:sub>3<\/jats:sub> and a <jats:italic>hrp2\/3<\/jats:italic>-specific qPCR assay reported for 19\/19 (100%) <jats:italic>hrp2<\/jats:italic> deletions and 18\/19 (94.7%) <jats:italic>hrp3<\/jats:italic> deletions. Among Cambodian (n\u2009=\u2009127) and Brazilian (n\u2009=\u200920) WGS datasets, which had not been previously analysed for <jats:italic>hrp2\/3<\/jats:italic> deletions, GC<jats:sub>3<\/jats:sub> identified <jats:italic>hrp2<\/jats:italic> deletions in three and four samples, and <jats:italic>hrp3<\/jats:italic> deletions in 10 and 15 samples, respectively. Plots of <jats:italic>hrp2\/3<\/jats:italic> coding regions, grouped by year of sample collection, showed a decrease in median standardized coverage among Malawian samples (n\u2009=\u2009150) suggesting the importance of a careful, properly controlled follow up to determine if an increase in frequency of deletions has occurred between 2007\u20132008 and 2014\u20132015. Among Malian (n\u2009=\u200990) samples, median standardized coverage was lower in 2002 than 2010, indicating widespread deletions present at the gene locus in 2002.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>The GC<jats:sub>3<\/jats:sub> tool accurately classified <jats:italic>hrp2\/3<\/jats:italic> deletions and provided informative tables and figures to analyse targeted gene coverage. GC<jats:sub>3<\/jats:sub> is an appropriate tool when performing preliminary and exploratory assessment of locus coverage data.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s12936-022-04376-3","type":"journal-article","created":{"date-parts":[[2022,11,29]],"date-time":"2022-11-29T08:04:08Z","timestamp":1669709048000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Gene Coverage Count and Classification (GC3): a locus sequence coverage assessment tool using short-read whole genome sequencing data, and its application to identify and classify histidine-rich protein 2 and 3 deletions in Plasmodium falciparum"],"prefix":"10.1186","volume":"21","author":[{"given":"Thomas C.","family":"Stabler","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ankit","family":"Dwivedi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Biraj","family":"Shrestha","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sudhaunshu","family":"Joshi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tobias","family":"Schindler","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amed","family":"Ouattara","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guillermo A.","family":"Garc\u00eda","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Claudia","family":"Daubenberger","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joana C.","family":"Silva","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2022,11,29]]},"reference":[{"key":"4376_CR1","unstructured":"WHO. 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Malar J. 2014;13:374.","journal-title":"Malar J"}],"container-title":["Malaria Journal"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12936-022-04376-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s12936-022-04376-3\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12936-022-04376-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,11,30]],"date-time":"2022-11-30T05:56:26Z","timestamp":1669787786000},"score":1,"resource":{"primary":{"URL":"https:\/\/malariajournal.biomedcentral.com\/articles\/10.1186\/s12936-022-04376-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,29]]},"references-count":53,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2022,12]]}},"alternative-id":["4376"],"URL":"https:\/\/doi.org\/10.1186\/s12936-022-04376-3","relation":{},"ISSN":["1475-2875"],"issn-type":[{"type":"electronic","value":"1475-2875"}],"subject":[],"published":{"date-parts":[[2022,11,29]]},"assertion":[{"value":"15 July 2022","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 November 2022","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 November 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":"All WGS datasets used are publicly available through GenBank. <i>P. falciparum<\/i> samples for which DNA material was utilized to perform qPCR were collected during field studies in Brazil, Malawi, Mali, and Thailand. All samples were collected after recruitment\/enrollment and with written informed consent from the subject or a parent\/guardian, and assent obtained from children under 18\u00a0years old. Informed consent included authorization to generate parasite genomic data. The respective field studies were approved by the following Institutional review boards (IRBs): Institute of Biomedical Sciences, University of S\u00e3o Paulo (1368\/17\/CEPSH), for collection in Acre, Brazil; Malawi National Health Sciences Research Committee, and the IRB at the University of Maryland, Baltimore (FWA#00005976), for collection in Malawi; Comit\u00e9 D\u2019\u00c9thique de la FMPOS (Facult\u00e9 de M\u00e9decine de Pharmacie et d\u2019Odonto-stomatologie), Universit\u00e9 des Sciences, des Techniques, et des Technologies de Bamako, Mali, and the IRB at the University of Maryland, Baltimore (HP-00041382), for collection on Mali; Ethics Review Committee of the Department of Medical Research, Human Subject Protection Branch (HSPB) of the Walter Reed Army Institute of Research, Silver Spring, MD (FWA# 00000015, IRB# 00000794), and Institute for the Development of Human Research Protection (IHRP), Ministry of Public Health, Thailand (FWA# 00017503, IRB#00006539), for collections in Thailand. This study conforms to the principles established in the Helsinki Declaration.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare that they have no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"357"}}