Atlas-CNV: a validated approach to call single-exon CNVs in the eMERGESeq gene panel

Theodore Chiang; Xiuping Liu; Tsung Jung Wu; Jianhong Hu; Fritz J. Sedlazeck; Simon White; Daniel Schaid; Mariza de Andrade; Gail P. Jarvik; David Crosslin; Ian Stanaway; David S. Carrell; John J. Connolly; Hakon Hakonarson; Emily E. Groopman; Ali G. Gharavi; Alexander Fedotov; Weimin Bi; Magalie S. Leduc; David R. Murdock; Yunyun Jiang; Linyan Meng; Christine M. Eng; Shu Wen; Yaping Yang; Donna M. Muzny; Eric Boerwinkle; William Salerno; Eric Venner; Richard A. Gibbs

doi:10.1038/s41436-019-0475-4

Atlas-CNV: a validated approach to call single-exon CNVs in the eMERGESeq gene panel

Theodore Chiang, Xiuping Liu, Tsung Jung Wu, Jianhong Hu, Fritz J. Sedlazeck, Simon White, Daniel Schaid, Mariza de Andrade, Gail P. Jarvik, David Crosslin, Ian Stanaway, David S. Carrell, John J. Connolly, Hakon Hakonarson, Emily E. Groopman, Ali G. Gharavi, Alexander Fedotov, Weimin Bi, Magalie S. Leduc, David R. MurdockYunyun Jiang, Linyan Meng, Christine M. Eng, Shu Wen, Yaping Yang, Donna M. Muzny, Eric Boerwinkle, William Salerno, Eric Venner, Richard A. Gibbs

Research output: Contribution to journal › Article › peer-review

20 Scopus citations

Abstract

Purpose: To provide a validated method to confidently identify exon-containing copy-number variants (CNVs), with a low false discovery rate (FDR), in targeted sequencing data from a clinical laboratory with particular focus on single-exon CNVs. Methods: DNA sequence coverage data are normalized within each sample and subsequently exonic CNVs are identified in a batch of samples, when the target log₂ ratio of the sample to the batch median exceeds defined thresholds. The quality of exonic CNV calls is assessed by C-scores (Z-like scores) using thresholds derived from gold standard samples and simulation studies. We integrate an ExonQC threshold to lower FDR and compare performance with alternate software (VisCap). Results: Thirteen CNVs were used as a truth set to validate Atlas-CNV and compared with VisCap. We demonstrated FDR reduction in validation, simulation, and 10,926 eMERGESeq samples without sensitivity loss. Sixty-four multiexon and 29 single-exon CNVs with high C-scores were assessed by Multiplex Ligation-dependent Probe Amplification (MLPA). Conclusion: Atlas-CNV is validated as a method to identify exonic CNVs in targeted sequencing data generated in the clinical laboratory. The ExonQC and C-score assignment can reduce FDR (identification of targets with high variance) and improve calling accuracy of single-exon CNVs respectively. We propose guidelines and criteria to identify high confidence single-exon CNVs.

Original language	English
Pages (from-to)	2135-2144
Number of pages	10
Journal	Genetics in Medicine
Volume	21
Issue number	9
DOIs	https://doi.org/10.1038/s41436-019-0475-4
State	Published - 1 Sep 2019
Externally published	Yes

Keywords

Atlas-CNV
CNV
copy-number variation
single-exon deletion duplication
targeted gene panel clinical sequencing

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10.1038/s41436-019-0475-4

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Chiang, T., Liu, X., Wu, T. J., Hu, J., Sedlazeck, F. J., White, S., Schaid, D., Andrade, M. D., Jarvik, G. P., Crosslin, D., Stanaway, I., Carrell, D. S., Connolly, J. J., Hakonarson, H., Groopman, E. E., Gharavi, A. G., Fedotov, A., Bi, W., Leduc, M. S., ... Gibbs, R. A. (2019). Atlas-CNV: a validated approach to call single-exon CNVs in the eMERGESeq gene panel. Genetics in Medicine, 21(9), 2135-2144. https://doi.org/10.1038/s41436-019-0475-4

@article{e0ccdc8101b2473eb5dc0e0bf02b5346,

title = "Atlas-CNV: a validated approach to call single-exon CNVs in the eMERGESeq gene panel",

abstract = "Purpose: To provide a validated method to confidently identify exon-containing copy-number variants (CNVs), with a low false discovery rate (FDR), in targeted sequencing data from a clinical laboratory with particular focus on single-exon CNVs. Methods: DNA sequence coverage data are normalized within each sample and subsequently exonic CNVs are identified in a batch of samples, when the target log2 ratio of the sample to the batch median exceeds defined thresholds. The quality of exonic CNV calls is assessed by C-scores (Z-like scores) using thresholds derived from gold standard samples and simulation studies. We integrate an ExonQC threshold to lower FDR and compare performance with alternate software (VisCap). Results: Thirteen CNVs were used as a truth set to validate Atlas-CNV and compared with VisCap. We demonstrated FDR reduction in validation, simulation, and 10,926 eMERGESeq samples without sensitivity loss. Sixty-four multiexon and 29 single-exon CNVs with high C-scores were assessed by Multiplex Ligation-dependent Probe Amplification (MLPA). Conclusion: Atlas-CNV is validated as a method to identify exonic CNVs in targeted sequencing data generated in the clinical laboratory. The ExonQC and C-score assignment can reduce FDR (identification of targets with high variance) and improve calling accuracy of single-exon CNVs respectively. We propose guidelines and criteria to identify high confidence single-exon CNVs.",

keywords = "Atlas-CNV, CNV, copy-number variation, single-exon deletion duplication, targeted gene panel clinical sequencing",

author = "Theodore Chiang and Xiuping Liu and Wu, {Tsung Jung} and Jianhong Hu and Sedlazeck, {Fritz J.} and Simon White and Daniel Schaid and Andrade, {Mariza de} and Jarvik, {Gail P.} and David Crosslin and Ian Stanaway and Carrell, {David S.} and Connolly, {John J.} and Hakon Hakonarson and Groopman, {Emily E.} and Gharavi, {Ali G.} and Alexander Fedotov and Weimin Bi and Leduc, {Magalie S.} and Murdock, {David R.} and Yunyun Jiang and Linyan Meng and Eng, {Christine M.} and Shu Wen and Yaping Yang and Muzny, {Donna M.} and Eric Boerwinkle and William Salerno and Eric Venner and Gibbs, {Richard A.}",

note = "Publisher Copyright: {\textcopyright} 2019, The Author(s).",

year = "2019",

month = sep,

day = "1",

doi = "10.1038/s41436-019-0475-4",

language = "English",

volume = "21",

pages = "2135--2144",

journal = "Genetics in Medicine",

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Chiang, T, Liu, X, Wu, TJ, Hu, J, Sedlazeck, FJ, White, S, Schaid, D, Andrade, MD, Jarvik, GP, Crosslin, D, Stanaway, I, Carrell, DS, Connolly, JJ, Hakonarson, H, Groopman, EE, Gharavi, AG, Fedotov, A, Bi, W, Leduc, MS, Murdock, DR, Jiang, Y, Meng, L, Eng, CM, Wen, S, Yang, Y, Muzny, DM, Boerwinkle, E, Salerno, W, Venner, E & Gibbs, RA 2019, 'Atlas-CNV: a validated approach to call single-exon CNVs in the eMERGESeq gene panel', Genetics in Medicine, vol. 21, no. 9, pp. 2135-2144. https://doi.org/10.1038/s41436-019-0475-4

TY - JOUR

T1 - Atlas-CNV

T2 - a validated approach to call single-exon CNVs in the eMERGESeq gene panel

AU - Chiang, Theodore

AU - Liu, Xiuping

AU - Wu, Tsung Jung

AU - Hu, Jianhong

AU - Sedlazeck, Fritz J.

AU - White, Simon

AU - Schaid, Daniel

AU - Andrade, Mariza de

AU - Jarvik, Gail P.

AU - Crosslin, David

AU - Stanaway, Ian

AU - Carrell, David S.

AU - Connolly, John J.

AU - Hakonarson, Hakon

AU - Groopman, Emily E.

AU - Gharavi, Ali G.

AU - Fedotov, Alexander

AU - Bi, Weimin

AU - Leduc, Magalie S.

AU - Murdock, David R.

AU - Jiang, Yunyun

AU - Meng, Linyan

AU - Eng, Christine M.

AU - Wen, Shu

AU - Yang, Yaping

AU - Muzny, Donna M.

AU - Boerwinkle, Eric

AU - Salerno, William

AU - Venner, Eric

AU - Gibbs, Richard A.

PY - 2019/9/1

Y1 - 2019/9/1

N2 - Purpose: To provide a validated method to confidently identify exon-containing copy-number variants (CNVs), with a low false discovery rate (FDR), in targeted sequencing data from a clinical laboratory with particular focus on single-exon CNVs. Methods: DNA sequence coverage data are normalized within each sample and subsequently exonic CNVs are identified in a batch of samples, when the target log2 ratio of the sample to the batch median exceeds defined thresholds. The quality of exonic CNV calls is assessed by C-scores (Z-like scores) using thresholds derived from gold standard samples and simulation studies. We integrate an ExonQC threshold to lower FDR and compare performance with alternate software (VisCap). Results: Thirteen CNVs were used as a truth set to validate Atlas-CNV and compared with VisCap. We demonstrated FDR reduction in validation, simulation, and 10,926 eMERGESeq samples without sensitivity loss. Sixty-four multiexon and 29 single-exon CNVs with high C-scores were assessed by Multiplex Ligation-dependent Probe Amplification (MLPA). Conclusion: Atlas-CNV is validated as a method to identify exonic CNVs in targeted sequencing data generated in the clinical laboratory. The ExonQC and C-score assignment can reduce FDR (identification of targets with high variance) and improve calling accuracy of single-exon CNVs respectively. We propose guidelines and criteria to identify high confidence single-exon CNVs.

AB - Purpose: To provide a validated method to confidently identify exon-containing copy-number variants (CNVs), with a low false discovery rate (FDR), in targeted sequencing data from a clinical laboratory with particular focus on single-exon CNVs. Methods: DNA sequence coverage data are normalized within each sample and subsequently exonic CNVs are identified in a batch of samples, when the target log2 ratio of the sample to the batch median exceeds defined thresholds. The quality of exonic CNV calls is assessed by C-scores (Z-like scores) using thresholds derived from gold standard samples and simulation studies. We integrate an ExonQC threshold to lower FDR and compare performance with alternate software (VisCap). Results: Thirteen CNVs were used as a truth set to validate Atlas-CNV and compared with VisCap. We demonstrated FDR reduction in validation, simulation, and 10,926 eMERGESeq samples without sensitivity loss. Sixty-four multiexon and 29 single-exon CNVs with high C-scores were assessed by Multiplex Ligation-dependent Probe Amplification (MLPA). Conclusion: Atlas-CNV is validated as a method to identify exonic CNVs in targeted sequencing data generated in the clinical laboratory. The ExonQC and C-score assignment can reduce FDR (identification of targets with high variance) and improve calling accuracy of single-exon CNVs respectively. We propose guidelines and criteria to identify high confidence single-exon CNVs.

KW - Atlas-CNV

KW - CNV

KW - copy-number variation

KW - single-exon deletion duplication

KW - targeted gene panel clinical sequencing

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U2 - 10.1038/s41436-019-0475-4

DO - 10.1038/s41436-019-0475-4

M3 - Article

C2 - 30890783

AN - SCOPUS:85063301236

SN - 1098-3600

VL - 21

SP - 2135

EP - 2144

JO - Genetics in Medicine

JF - Genetics in Medicine

IS - 9

ER -

Atlas-CNV: a validated approach to call single-exon CNVs in the eMERGESeq gene panel

Abstract

Keywords

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