Concordance between Research Sequencing and Clinical Pharmacogenetic Genotyping in the eMERGE-PGx Study

Laura J. Rasmussen-Torvik, Berta Almoguera, Kimberly F. Doheny, Robert Freimuth, Adam S. Gordon, Hakon Hakonarson, Jared B. Hawkins, Ammar Husami, Lynn C. Ivacic, Iftikhar Jan Kullo, Michael D. Linderman, Teri A. Manolio, Aniwaa Owusu Obeng, Renata Pellegrino, Cynthia A. Prows, Marylyn D. Ritchie, Maureen E. Smith, Sarah C. Stallings, Wendy A. Wolf, Kejian Zhang & 1 others Stuart A. Scott

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

There has been extensive debate about both the necessity of orthogonal confirmation of next-generation sequencing (NGS) results in Clinical Laboratory Improvement Amendments–approved laboratories and return of research NGS results to participants enrolled in research studies. In eMERGE-PGx, subjects underwent research NGS using PGRNseq and orthogonal targeted genotyping in clinical laboratories, which prompted a comparison of genotyping results between platforms. Concordance (percentage agreement) was reported for 4077 samples tested across nine combinations of research and clinical laboratories. Retesting was possible on a subset of 1792 samples, and local laboratory directors determined sources of genotype discrepancy. Research NGS and orthogonal clinical genotyping had an overall per sample concordance rate of 0.972 and per variant concordance rate of 0.997. Genotype discrepancies attributed to research NGS were because of sample switching (preanalytical errors), whereas the majority of genotype discrepancies (92.3%) attributed to clinical genotyping were because of allele dropout as a result of rare variants interfering with primer hybridization (analytical errors). These results highlight the analytical quality of clinically significant pharmacogenetic variants derived from NGS and reveal important areas for research and clinical laboratories to address with quality management programs.

Original languageEnglish (US)
Pages (from-to)561-566
Number of pages6
JournalJournal of Molecular Diagnostics
Volume19
Issue number4
DOIs
StatePublished - Jul 1 2017

Fingerprint

Pharmacogenetics
Research
Genotype
Alleles

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Molecular Medicine

Cite this

Rasmussen-Torvik, L. J., Almoguera, B., Doheny, K. F., Freimuth, R., Gordon, A. S., Hakonarson, H., ... Scott, S. A. (2017). Concordance between Research Sequencing and Clinical Pharmacogenetic Genotyping in the eMERGE-PGx Study. Journal of Molecular Diagnostics, 19(4), 561-566. https://doi.org/10.1016/j.jmoldx.2017.04.002

Concordance between Research Sequencing and Clinical Pharmacogenetic Genotyping in the eMERGE-PGx Study. / Rasmussen-Torvik, Laura J.; Almoguera, Berta; Doheny, Kimberly F.; Freimuth, Robert; Gordon, Adam S.; Hakonarson, Hakon; Hawkins, Jared B.; Husami, Ammar; Ivacic, Lynn C.; Kullo, Iftikhar Jan; Linderman, Michael D.; Manolio, Teri A.; Obeng, Aniwaa Owusu; Pellegrino, Renata; Prows, Cynthia A.; Ritchie, Marylyn D.; Smith, Maureen E.; Stallings, Sarah C.; Wolf, Wendy A.; Zhang, Kejian; Scott, Stuart A.

In: Journal of Molecular Diagnostics, Vol. 19, No. 4, 01.07.2017, p. 561-566.

Research output: Contribution to journalArticle

Rasmussen-Torvik, LJ, Almoguera, B, Doheny, KF, Freimuth, R, Gordon, AS, Hakonarson, H, Hawkins, JB, Husami, A, Ivacic, LC, Kullo, IJ, Linderman, MD, Manolio, TA, Obeng, AO, Pellegrino, R, Prows, CA, Ritchie, MD, Smith, ME, Stallings, SC, Wolf, WA, Zhang, K & Scott, SA 2017, 'Concordance between Research Sequencing and Clinical Pharmacogenetic Genotyping in the eMERGE-PGx Study', Journal of Molecular Diagnostics, vol. 19, no. 4, pp. 561-566. https://doi.org/10.1016/j.jmoldx.2017.04.002
Rasmussen-Torvik, Laura J. ; Almoguera, Berta ; Doheny, Kimberly F. ; Freimuth, Robert ; Gordon, Adam S. ; Hakonarson, Hakon ; Hawkins, Jared B. ; Husami, Ammar ; Ivacic, Lynn C. ; Kullo, Iftikhar Jan ; Linderman, Michael D. ; Manolio, Teri A. ; Obeng, Aniwaa Owusu ; Pellegrino, Renata ; Prows, Cynthia A. ; Ritchie, Marylyn D. ; Smith, Maureen E. ; Stallings, Sarah C. ; Wolf, Wendy A. ; Zhang, Kejian ; Scott, Stuart A. / Concordance between Research Sequencing and Clinical Pharmacogenetic Genotyping in the eMERGE-PGx Study. In: Journal of Molecular Diagnostics. 2017 ; Vol. 19, No. 4. pp. 561-566.
@article{c3354be094e04f3fad53191e6c97a1e6,
title = "Concordance between Research Sequencing and Clinical Pharmacogenetic Genotyping in the eMERGE-PGx Study",
abstract = "There has been extensive debate about both the necessity of orthogonal confirmation of next-generation sequencing (NGS) results in Clinical Laboratory Improvement Amendments–approved laboratories and return of research NGS results to participants enrolled in research studies. In eMERGE-PGx, subjects underwent research NGS using PGRNseq and orthogonal targeted genotyping in clinical laboratories, which prompted a comparison of genotyping results between platforms. Concordance (percentage agreement) was reported for 4077 samples tested across nine combinations of research and clinical laboratories. Retesting was possible on a subset of 1792 samples, and local laboratory directors determined sources of genotype discrepancy. Research NGS and orthogonal clinical genotyping had an overall per sample concordance rate of 0.972 and per variant concordance rate of 0.997. Genotype discrepancies attributed to research NGS were because of sample switching (preanalytical errors), whereas the majority of genotype discrepancies (92.3{\%}) attributed to clinical genotyping were because of allele dropout as a result of rare variants interfering with primer hybridization (analytical errors). These results highlight the analytical quality of clinically significant pharmacogenetic variants derived from NGS and reveal important areas for research and clinical laboratories to address with quality management programs.",
author = "Rasmussen-Torvik, {Laura J.} and Berta Almoguera and Doheny, {Kimberly F.} and Robert Freimuth and Gordon, {Adam S.} and Hakon Hakonarson and Hawkins, {Jared B.} and Ammar Husami and Ivacic, {Lynn C.} and Kullo, {Iftikhar Jan} and Linderman, {Michael D.} and Manolio, {Teri A.} and Obeng, {Aniwaa Owusu} and Renata Pellegrino and Prows, {Cynthia A.} and Ritchie, {Marylyn D.} and Smith, {Maureen E.} and Stallings, {Sarah C.} and Wolf, {Wendy A.} and Kejian Zhang and Scott, {Stuart A.}",
year = "2017",
month = "7",
day = "1",
doi = "10.1016/j.jmoldx.2017.04.002",
language = "English (US)",
volume = "19",
pages = "561--566",
journal = "Journal of Molecular Diagnostics",
issn = "1525-1578",
publisher = "Association of Molecular Pathology",
number = "4",

}

TY - JOUR

T1 - Concordance between Research Sequencing and Clinical Pharmacogenetic Genotyping in the eMERGE-PGx Study

AU - Rasmussen-Torvik, Laura J.

AU - Almoguera, Berta

AU - Doheny, Kimberly F.

AU - Freimuth, Robert

AU - Gordon, Adam S.

AU - Hakonarson, Hakon

AU - Hawkins, Jared B.

AU - Husami, Ammar

AU - Ivacic, Lynn C.

AU - Kullo, Iftikhar Jan

AU - Linderman, Michael D.

AU - Manolio, Teri A.

AU - Obeng, Aniwaa Owusu

AU - Pellegrino, Renata

AU - Prows, Cynthia A.

AU - Ritchie, Marylyn D.

AU - Smith, Maureen E.

AU - Stallings, Sarah C.

AU - Wolf, Wendy A.

AU - Zhang, Kejian

AU - Scott, Stuart A.

PY - 2017/7/1

Y1 - 2017/7/1

N2 - There has been extensive debate about both the necessity of orthogonal confirmation of next-generation sequencing (NGS) results in Clinical Laboratory Improvement Amendments–approved laboratories and return of research NGS results to participants enrolled in research studies. In eMERGE-PGx, subjects underwent research NGS using PGRNseq and orthogonal targeted genotyping in clinical laboratories, which prompted a comparison of genotyping results between platforms. Concordance (percentage agreement) was reported for 4077 samples tested across nine combinations of research and clinical laboratories. Retesting was possible on a subset of 1792 samples, and local laboratory directors determined sources of genotype discrepancy. Research NGS and orthogonal clinical genotyping had an overall per sample concordance rate of 0.972 and per variant concordance rate of 0.997. Genotype discrepancies attributed to research NGS were because of sample switching (preanalytical errors), whereas the majority of genotype discrepancies (92.3%) attributed to clinical genotyping were because of allele dropout as a result of rare variants interfering with primer hybridization (analytical errors). These results highlight the analytical quality of clinically significant pharmacogenetic variants derived from NGS and reveal important areas for research and clinical laboratories to address with quality management programs.

AB - There has been extensive debate about both the necessity of orthogonal confirmation of next-generation sequencing (NGS) results in Clinical Laboratory Improvement Amendments–approved laboratories and return of research NGS results to participants enrolled in research studies. In eMERGE-PGx, subjects underwent research NGS using PGRNseq and orthogonal targeted genotyping in clinical laboratories, which prompted a comparison of genotyping results between platforms. Concordance (percentage agreement) was reported for 4077 samples tested across nine combinations of research and clinical laboratories. Retesting was possible on a subset of 1792 samples, and local laboratory directors determined sources of genotype discrepancy. Research NGS and orthogonal clinical genotyping had an overall per sample concordance rate of 0.972 and per variant concordance rate of 0.997. Genotype discrepancies attributed to research NGS were because of sample switching (preanalytical errors), whereas the majority of genotype discrepancies (92.3%) attributed to clinical genotyping were because of allele dropout as a result of rare variants interfering with primer hybridization (analytical errors). These results highlight the analytical quality of clinically significant pharmacogenetic variants derived from NGS and reveal important areas for research and clinical laboratories to address with quality management programs.

UR - http://www.scopus.com/inward/record.url?scp=85021273137&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85021273137&partnerID=8YFLogxK

U2 - 10.1016/j.jmoldx.2017.04.002

DO - 10.1016/j.jmoldx.2017.04.002

M3 - Article

VL - 19

SP - 561

EP - 566

JO - Journal of Molecular Diagnostics

JF - Journal of Molecular Diagnostics

SN - 1525-1578

IS - 4

ER -