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J Mol Diagn. 2017 Jul;19(4):561-566. doi: 10.1016/j.jmoldx.2017.04.002. Epub 2017 May 11.

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

Author information

1
Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois. Electronic address: ljrtorvik@northwestern.edu.
2
Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
3
Center for Inherited Disease Research, Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
4
Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota.
5
Division of Medical Genetics, University of Washington, Seattle, Washington.
6
Computational Health Informatics Program, Boston Children's Hospital, Boston, Massachusetts.
7
Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
8
Integrated Research and Development Laboratory, Marshfield Clinic Research Foundation, Marshfield, Wisconsin.
9
Department of Cardiovascular Disease, Mayo Clinic, Rochester, Minnesota.
10
Department of Computer Science, Middlebury College, Middlebury, Vermont.
11
Division of Genomic Medicine, National Human Genome Research Institute, Bethesda, Maryland.
12
The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, New York; Pharmacy Department, The Mount Sinai Hospital, New York, New York.
13
Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Division Patient Services, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
14
Department of Biomedical and Translational Informatics, Geisinger Health System, Danville, Pennsylvania.
15
Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
16
Vanderbilt Institute for Clinical and Translational Research, Nashville, Tennessee.
17
Division of Genetics and Genomics, Boston Children's Hospital, Boston, Massachusetts.
18
Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio.
19
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.

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.

PMID:
28502727
PMCID:
PMC5500823
DOI:
10.1016/j.jmoldx.2017.04.002
[Indexed for MEDLINE]
Free PMC Article

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