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JAX-CNV: A Whole-genome Sequencing-based Algorithm for Copy Number Detection at Clinical Grade Level

We aimed to develop a whole-genome sequencing (WGS)-based copy number variant (CNV) calling algorithm with the potential of replacing chromosomal microarray assay (CMA) for clinical diagnosis. JAX-CNV is thus developed for CNV detection from WGS data. The performance of this CNV calling algorithm wa...

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Autores principales: Lee, Wan-Ping, Zhu, Qihui, Yang, Xiaofei, Liu, Silvia, Cerveira, Eliza, Ryan, Mallory, Mil-Homens, Adam, Bellfy, Lauren, Ye, Kai, Lee, Charles, Zhang, Chengsheng
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10225484/
https://www.ncbi.nlm.nih.gov/pubmed/35085778
http://dx.doi.org/10.1016/j.gpb.2021.06.003
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author Lee, Wan-Ping
Zhu, Qihui
Yang, Xiaofei
Liu, Silvia
Cerveira, Eliza
Ryan, Mallory
Mil-Homens, Adam
Bellfy, Lauren
Ye, Kai
Lee, Charles
Zhang, Chengsheng
author_facet Lee, Wan-Ping
Zhu, Qihui
Yang, Xiaofei
Liu, Silvia
Cerveira, Eliza
Ryan, Mallory
Mil-Homens, Adam
Bellfy, Lauren
Ye, Kai
Lee, Charles
Zhang, Chengsheng
author_sort Lee, Wan-Ping
collection PubMed
description We aimed to develop a whole-genome sequencing (WGS)-based copy number variant (CNV) calling algorithm with the potential of replacing chromosomal microarray assay (CMA) for clinical diagnosis. JAX-CNV is thus developed for CNV detection from WGS data. The performance of this CNV calling algorithm was evaluated in a blinded manner on 31 samples and compared to the 112 CNVs reported by clinically validated CMAs for these 31 samples. The result showed that JAX-CNV recalled 100% of these CNVs. Besides, JAX-CNV identified an average of 30 CNVs per individual, respresenting an approximately seven-fold increase compared to calls of clinically validated CMAs. Experimental validation of 24 randomly selected CNVs showed one false positive, i.e., a false discovery rate (FDR) of 4.17%. A robustness test on lower-coverage data revealed a 100% sensitivity for CNVs larger than 300 kb (the current threshold for College of American Pathologists) down to 10× coverage. For CNVs larger than 50 kb, sensitivities were 100% for coverages deeper than 20×, 97% for 15×, and 95% for 10×. We developed a WGS-based CNV pipeline, including this newly developed CNV caller JAX-CNV, and found it capable of detecting CMA-reported CNVs at a sensitivity of 100% with about a FDR of 4%. We propose that JAX-CNV could be further examined in a multi-institutional study to justify the transition of first-tier genetic testing from CMAs to WGS. JAX-CNV is available at https://github.com/TheJacksonLaboratory/JAX-CNV.
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spelling pubmed-102254842023-05-30 JAX-CNV: A Whole-genome Sequencing-based Algorithm for Copy Number Detection at Clinical Grade Level Lee, Wan-Ping Zhu, Qihui Yang, Xiaofei Liu, Silvia Cerveira, Eliza Ryan, Mallory Mil-Homens, Adam Bellfy, Lauren Ye, Kai Lee, Charles Zhang, Chengsheng Genomics Proteomics Bioinformatics Method We aimed to develop a whole-genome sequencing (WGS)-based copy number variant (CNV) calling algorithm with the potential of replacing chromosomal microarray assay (CMA) for clinical diagnosis. JAX-CNV is thus developed for CNV detection from WGS data. The performance of this CNV calling algorithm was evaluated in a blinded manner on 31 samples and compared to the 112 CNVs reported by clinically validated CMAs for these 31 samples. The result showed that JAX-CNV recalled 100% of these CNVs. Besides, JAX-CNV identified an average of 30 CNVs per individual, respresenting an approximately seven-fold increase compared to calls of clinically validated CMAs. Experimental validation of 24 randomly selected CNVs showed one false positive, i.e., a false discovery rate (FDR) of 4.17%. A robustness test on lower-coverage data revealed a 100% sensitivity for CNVs larger than 300 kb (the current threshold for College of American Pathologists) down to 10× coverage. For CNVs larger than 50 kb, sensitivities were 100% for coverages deeper than 20×, 97% for 15×, and 95% for 10×. We developed a WGS-based CNV pipeline, including this newly developed CNV caller JAX-CNV, and found it capable of detecting CMA-reported CNVs at a sensitivity of 100% with about a FDR of 4%. We propose that JAX-CNV could be further examined in a multi-institutional study to justify the transition of first-tier genetic testing from CMAs to WGS. JAX-CNV is available at https://github.com/TheJacksonLaboratory/JAX-CNV. Elsevier 2022-12 2022-01-25 /pmc/articles/PMC10225484/ /pubmed/35085778 http://dx.doi.org/10.1016/j.gpb.2021.06.003 Text en © 2022 The Authors. Published by Elsevier B.V. and Science Press on behalf of Beijing Institute of Genomics, Chinese Academy of Sciences / China National Center for Bioinformation and Genetics Society of China. https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Method
Lee, Wan-Ping
Zhu, Qihui
Yang, Xiaofei
Liu, Silvia
Cerveira, Eliza
Ryan, Mallory
Mil-Homens, Adam
Bellfy, Lauren
Ye, Kai
Lee, Charles
Zhang, Chengsheng
JAX-CNV: A Whole-genome Sequencing-based Algorithm for Copy Number Detection at Clinical Grade Level
title JAX-CNV: A Whole-genome Sequencing-based Algorithm for Copy Number Detection at Clinical Grade Level
title_full JAX-CNV: A Whole-genome Sequencing-based Algorithm for Copy Number Detection at Clinical Grade Level
title_fullStr JAX-CNV: A Whole-genome Sequencing-based Algorithm for Copy Number Detection at Clinical Grade Level
title_full_unstemmed JAX-CNV: A Whole-genome Sequencing-based Algorithm for Copy Number Detection at Clinical Grade Level
title_short JAX-CNV: A Whole-genome Sequencing-based Algorithm for Copy Number Detection at Clinical Grade Level
title_sort jax-cnv: a whole-genome sequencing-based algorithm for copy number detection at clinical grade level
topic Method
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10225484/
https://www.ncbi.nlm.nih.gov/pubmed/35085778
http://dx.doi.org/10.1016/j.gpb.2021.06.003
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