{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,8,21]],"date-time":"2025-08-21T17:52:45Z","timestamp":1755798765095,"version":"3.44.0"},"reference-count":40,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2025,8,19]],"date-time":"2025-08-19T00:00:00Z","timestamp":1755561600000},"content-version":"vor","delay-in-days":49,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["U21A20513","62476157","62076154"],"award-info":[{"award-number":["U21A20513","62476157","62076154"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100013317","name":"Key Research and Development Program of Shanxi Province","doi-asserted-by":"publisher","award":["202202020101003"],"award-info":[{"award-number":["202202020101003"]}],"id":[{"id":"10.13039\/501100013317","id-type":"DOI","asserted-by":"publisher"}]},{"name":"National Innovation Fellowship Program of the MOST of China","award":["E327130001"],"award-info":[{"award-number":["E327130001"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,7,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Accurate calling of parental-child SNPs and Indels in family trios is very helpful for understanding genetic traits and diseases. Indel calling is even more important than SNP calling, as Indels may have led to substantial changes in protein structures that affect more of the traits of the organism. However, the best Indel calling methods have recall rates below 85%, precision below 92%, and F1 below 88% on $60\\times $ ONT Q20 data, much lower than their SNP calling\u2019s recall performance of 99.87%, precision of 99.86%, and F1 of 99.86%. Difficulties in Indels calling include how to distinguish sequencing errors from genuine Indels and how to optimize the Mendelian genetic model. This work proposes sparse attention learning for high-performance calling of Indels from family-trios\u2019 ONT long-read sequencing data, while still maintaining exceptional performance on SNP calling. Key steps include a sparsely connected attention network to convert fully aligned data cubes into essential features, and a deep learning on these features via ResNet and 3D convolutional blocks to enable accurate detection of family-trio variants. This attention network is in fact a dual attention network to aggregate both channel and spatial information, capable of selecting sub-cubes of critical channels and base locations that are resistant to the confounding effects of sequencing errors. Comparing with the current best-performing trio-variant detection method, our F1 is 5.6%\u201314.19% higher, recall is 7.07%\u201318.67% higher, and precision is 3.85%\u20137.87% higher on ONT Q20 datasets. Case studies of indel-dense regions in chromosome 20, including the centromere and disease-associated genes, demonstrate the significant impact of indel variations on disease pathogenesis, providing novel perspectives for future personalized and targeted therapies.<\/jats:p>","DOI":"10.1093\/bib\/bbaf430","type":"journal-article","created":{"date-parts":[[2025,8,19]],"date-time":"2025-08-19T14:18:14Z","timestamp":1755613094000},"source":"Crossref","is-referenced-by-count":0,"title":["Indel calling from ONT sequencing data of family trios via sparse attention and 3D convolution"],"prefix":"10.1093","volume":"26","author":[{"given":"Ying","family":"Shi","sequence":"first","affiliation":[{"name":"School of Computer and Information Technology , Shanxi University, Taiyuan, 030006, Shanxi Province,","place":["China"]},{"name":"Faculty of Computer Science and Control Engineering , Shenzhen University of Advanced Technology, Shenzhen, 518000, Guangdong,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chenxu","family":"Wu","sequence":"additional","affiliation":[{"name":"School of Computer and Information Technology , Shanxi University, Taiyuan, 030006, Shanxi Province,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shifu","family":"Luo","sequence":"additional","affiliation":[{"name":"Faculty of Computer Science and Control Engineering , Shenzhen University of Advanced Technology, Shenzhen, 518000, Guangdong,","place":["China"]},{"name":"Faculty of Health Sciences , University of Macau, Taipa, 999078, Macau SAR,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Songming","family":"Zhang","sequence":"additional","affiliation":[{"name":"Faculty of Computer Science and Control Engineering , Shenzhen University of Advanced Technology, Shenzhen, 518000, Guangdong,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wenjian","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Computer and Information Technology , Shanxi University, Taiyuan, 030006, Shanxi Province,","place":["China"]},{"name":"Institute of Intelligent Information Processing , Shanxi University, Taiyuan, 030006, Shanxi Province,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jinyan","family":"Li","sequence":"additional","affiliation":[{"name":"Faculty of Computer Science and Control Engineering , Shenzhen University of Advanced Technology, Shenzhen, 518000, Guangdong,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2025,8,19]]},"reference":[{"key":"2025081910143338100_ref1","doi-asserted-by":"publisher","first-page":"469","DOI":"10.1038\/nature13127","article-title":"Guidelines for investigating causality of sequence variants in human disease","volume":"508","author":"MacArthur","year":"2014","journal-title":"Nature"},{"key":"2025081910143338100_ref2","doi-asserted-by":"crossref","first-page":"bbae473","DOI":"10.1093\/bib\/bbae473","article-title":"MiniSNV: accurate and fast single nucleotide variant calling from nanopore sequencing data","volume":"25","author":"Cui","year":"2024","journal-title":"Brief Bioinform"},{"key":"2025081910143338100_ref3","doi-asserted-by":"publisher","first-page":"e1003880","DOI":"10.1371\/journal.pcbi.1003880","article-title":"FamSeq: a variant calling program for family-based sequencing data using graphics processing units","volume":"10","author":"Peng","year":"2014","journal-title":"PLoS Comput Biol"},{"key":"2025081910143338100_ref4","first-page":"593","article-title":"Indigenous australian genomes show deep structure and rich novel variation","volume":"624","author":"Silcocks","year":"2023","journal-title":"Nature"},{"key":"2025081910143338100_ref5","doi-asserted-by":"publisher","first-page":"602","DOI":"10.1038\/s41586-023-06842-7","article-title":"The landscape of genomic structural variation in indigenous australians","volume":"624","author":"Reis","year":"2023","journal-title":"Nature"},{"key":"2025081910143338100_ref6","doi-asserted-by":"crossref","first-page":"bbae613","DOI":"10.1093\/bib\/bbae613","article-title":"Repun: an accurate small variant representation unification method for multiple sequencing platforms","volume":"26","author":"Zheng","year":"2025","journal-title":"Brief Bioinform"},{"key":"2025081910143338100_ref7","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1186\/s13059-016-1110-1","article-title":"New insights into the generation and role of de novo mutations in health and disease","volume":"17","author":"Acuna-Hidalgo","year":"2016","journal-title":"Genome Biol"},{"key":"2025081910143338100_ref8","first-page":"25","article-title":"SVDF: enhancing structural variation detect from long-read sequencing via automatic filtering strategies","author":"Heng","year":"2024","journal-title":"Brief Bioinform"},{"key":"2025081910143338100_ref9","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1186\/s13073-020-00791-w","article-title":"Best practices for variant calling in clinical sequencing","volume":"12","author":"Koboldt","year":"2020","journal-title":"Genome Med"},{"key":"2025081910143338100_ref10","doi-asserted-by":"publisher","first-page":"636","DOI":"10.1126\/science.1186802","article-title":"Analysis of genetic inheritance in a family quartet by whole-genome sequencing","volume":"328","author":"Roach","year":"2010","journal-title":"Science"},{"key":"2025081910143338100_ref11","doi-asserted-by":"crossref","first-page":"5969","DOI":"10.1038\/ncomms6969","article-title":"Novel variation and de novo mutation rates in population-wide de novo assembled danish trios","volume":"6","author":"Besenbacher","year":"2015","journal-title":"Nat Commun"},{"key":"2025081910143338100_ref12","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1186\/s40246-015-0042-2","article-title":"Performance evaluation of indel calling tools using real short-read data","volume":"9","author":"Hasan","year":"2015","journal-title":"Hum Genomics"},{"key":"2025081910143338100_ref13","doi-asserted-by":"publisher","first-page":"2529","DOI":"10.1038\/nprot.2016.150","article-title":"Indel variant analysis of short-read sequencing data with scalpel","volume":"11","author":"Fang","year":"2016","journal-title":"Nat Protoc"},{"key":"2025081910143338100_ref14","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1186\/s13073-014-0089-z","article-title":"Reducing indel calling errors in whole genome and exome sequencing data","volume":"6","author":"Fang","year":"2014","journal-title":"Genome Med"},{"key":"2025081910143338100_ref15","doi-asserted-by":"publisher","first-page":"383","DOI":"10.1016\/j.scib.2023.02.006","article-title":"Identification of a novel frameshift mutation in the SCNN1B causing liddle syndrome","volume":"68","author":"Yi","year":"2023","journal-title":"Science bulletin"},{"key":"2025081910143338100_ref16","doi-asserted-by":"publisher","first-page":"1009","DOI":"10.1016\/S1470-2045(17)30516-8","article-title":"Insertion-and-deletion-derived tumour-specific neoantigens and the immunogenic phenotype: A pan-cancer analysis","volume":"18","author":"Turajlic","year":"2017","journal-title":"Lancet Oncol"},{"key":"2025081910143338100_ref17","doi-asserted-by":"publisher","first-page":"983","DOI":"10.1038\/nbt.4235","article-title":"A universal SNP and small-indel variant caller using deep neural networks","volume":"36","author":"Poplin","year":"2018","journal-title":"Nat Biotechnol"},{"key":"2025081910143338100_ref18","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-09025-z","article-title":"A multi-task convolutional deep neural network for variant calling in single molecule sequencing","volume":"10","author":"Luo","year":"2019","journal-title":"Nat Commun"},{"key":"2025081910143338100_ref19","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-09027-x","article-title":"Deep convolutional neural networks for accurate somatic mutation detection","volume":"10","author":"Sahraeian","year":"2019","journal-title":"Nat Commun"},{"key":"2025081910143338100_ref20","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1186\/s13059-021-02472-2","article-title":"Nanocaller for accurate detection of snps and indels in difficult-to-map regions from long-read sequencing by haplotype-aware deep neural networks","volume":"22","author":"Ahsan","year":"2021","journal-title":"Genome Biol"},{"journal-title":"Medaka,","key":"2025081910143338100_ref21","article-title":"Oxford nanopore technologies"},{"key":"2025081910143338100_ref22","doi-asserted-by":"publisher","first-page":"4660","DOI":"10.1038\/s41467-019-12493-y","article-title":"Longshot enables accurate variant calling in diploid genomes from single-molecule long read sequencing","volume":"10","author":"Edge","year":"2019","journal-title":"Nat Commun"},{"key":"2025081910143338100_ref23","doi-asserted-by":"publisher","first-page":"220","DOI":"10.1038\/s42256-020-0167-4","article-title":"Exploring the limit of using a deep neural network on pileup data for germline variant calling","volume":"2","author":"Luo","year":"2020","journal-title":"Nature Machine Intelligence"},{"key":"2025081910143338100_ref24","doi-asserted-by":"publisher","first-page":"1322","DOI":"10.1038\/s41592-021-01299-w","article-title":"Haplotype-aware variant calling with pepper-margin-deepvariant enables high accuracy in nanopore long-reads","volume":"18","author":"Shafin","year":"2021","journal-title":"Nat Methods"},{"key":"2025081910143338100_ref25","doi-asserted-by":"crossref","first-page":"797","DOI":"10.1038\/s43588-022-00387-x","article-title":"Symphonizing pileup and full-alignment for deep learning-based long-read variant calling","volume":"2","author":"Zheng","year":"2022","journal-title":"Nature computational Science"},{"key":"2025081910143338100_ref26","doi-asserted-by":"publisher","first-page":"3549","DOI":"10.1093\/bioinformatics\/btaa116","article-title":"dv-trio: a family-based variant calling pipeline using deepvariant","volume":"36","author":"Ip","year":"2020","journal-title":"Bioinformatics"},{"key":"2025081910143338100_ref27","doi-asserted-by":"crossref","first-page":"694","DOI":"10.1093\/bioinformatics\/btab737","article-title":"Deeptrio: a ternary prediction system for protein\u2013protein interaction using mask multiple parallel convolutional neural networks","volume":"38","author":"Xiaotian","year":"2022","journal-title":"Bioinformatics"},{"key":"2025081910143338100_ref28","doi-asserted-by":"crossref","first-page":"bbac301","DOI":"10.1093\/bib\/bbac301","article-title":"Clair3-trio: High-performance nanopore long-read variant calling in family trios with trio-to-trio deep neural networks","volume":"23","author":"Junhao","year":"2022","journal-title":"Brief Bioinform"},{"key":"2025081910143338100_ref29","doi-asserted-by":"publisher","first-page":"100128","DOI":"10.1016\/j.xgen.2022.100128","article-title":"Benchmarking challenging small variants with linked and long reads","volume":"2","author":"Wagner","year":"2022","journal-title":"Cell genomics"},{"key":"2025081910143338100_ref30","first-page":"085050","article-title":"Whatshap: Fast and accurate read-based phasing","author":"Martin","year":"2016"},{"key":"2025081910143338100_ref31","first-page":"3","article-title":"In so Kweon. CBAM: Convolutional block attention module","volume-title":"Proceedings of the European Conference on Computer Vision (ECCV)","author":"Woo","year":"2018"},{"key":"2025081910143338100_ref32","first-page":"11534","article-title":"ECA-net: Efficient channel attention for deep convolutional neural networks","volume-title":"Proceedings of the IEEE\/CVF Cconference on Computer Vision and Pattern Recognition","author":"Wang","year":"2020"},{"key":"2025081910143338100_ref33","doi-asserted-by":"publisher","first-page":"555","DOI":"10.1038\/s41587-019-0054-x","article-title":"Best practices for benchmarking germline small-variant calls in human genomes","volume":"37","author":"Krusche","year":"2019","journal-title":"Nat Biotechnol"},{"key":"2025081910143338100_ref34","doi-asserted-by":"publisher","first-page":"100023","DOI":"10.1016\/j.xhgg.2021.100023","article-title":"Long-read genome sequencing for the molecular diagnosis of neurodevelopmental disorders","volume":"2","author":"Hiatt","year":"2021","journal-title":"Hum Genet Genomics Adv"},{"key":"2025081910143338100_ref35","doi-asserted-by":"publisher","DOI":"10.1186\/s13293-024-00622-2","article-title":"Relationship between sex biases in gene expression and sex biases in autism and Alzheimer\u2019s disease","volume":"15","author":"Fass","year":"2024","journal-title":"Biol Sex Differ"},{"key":"2025081910143338100_ref36","doi-asserted-by":"publisher","first-page":"241","DOI":"10.1097\/YPG.0000000000000052","article-title":"MACROD2 gene associated with autistic-like traits in a general population sample","volume":"24","author":"Jones","year":"2014","journal-title":"Psychiatr Genet"},{"key":"2025081910143338100_ref37","first-page":"272","article-title":"MACROD2 gene expression profile in autism spectrum disorder: a case-control study","volume":"29","author":"Alnak","year":"2019","journal-title":"Psychiatry and clinical Psychopharmacology"},{"key":"2025081910143338100_ref38","doi-asserted-by":"crossref","first-page":"eadi2687","DOI":"10.1126\/sciadv.adi2687","article-title":"PARP14 is a PARP with both ADP-ribosyl transferase and hydrolase activities","volume":"9","author":"Duki\u0107","year":"2023","journal-title":"Science Advances"},{"key":"2025081910143338100_ref39","doi-asserted-by":"publisher","first-page":"e164","DOI":"10.1093\/nar\/gkq603","article-title":"Annovar: Functional annotation of genetic variants from high-throughput sequencing data","volume":"38","author":"Wang","year":"2010","journal-title":"Nucleic Acids Res"},{"key":"2025081910143338100_ref40","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1186\/s12859-021-04556-z","article-title":"Chromomap: An R package for interactive visualization of multi-omics data and annotation of chromosomes","volume":"23","author":"Anand","year":"2022","journal-title":"BMC Bioinf"}],"container-title":["Briefings in Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/bib\/article-pdf\/26\/4\/bbaf430\/64083649\/bbaf430.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bib\/article-pdf\/26\/4\/bbaf430\/64083649\/bbaf430.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,8,19]],"date-time":"2025-08-19T14:18:17Z","timestamp":1755613097000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/bib\/article\/doi\/10.1093\/bib\/bbaf430\/8238019"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7]]},"references-count":40,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2025,7,2]]}},"URL":"https:\/\/doi.org\/10.1093\/bib\/bbaf430","relation":{},"ISSN":["1467-5463","1477-4054"],"issn-type":[{"type":"print","value":"1467-5463"},{"type":"electronic","value":"1477-4054"}],"subject":[],"published-other":{"date-parts":[[2025,7]]},"published":{"date-parts":[[2025,7]]},"article-number":"bbaf430"}}