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The Promise and Peril of Genomic Screening in the General Population

PURPOSE: Utilization of sequencing to screen the general population for preventable monogenic conditions is receiving substantial attention due to its potential to decrease morbidity and mortality. However, the selection of which variants to return is a serious implementation challenge. Procedures m...

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Autores principales: Adams, Michael C., Evans, James P., Henderson, Gail E., Berg, Jonathan S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4860183/
https://www.ncbi.nlm.nih.gov/pubmed/26540154
http://dx.doi.org/10.1038/gim.2015.136
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author Adams, Michael C.
Evans, James P.
Henderson, Gail E.
Berg, Jonathan S.
author_facet Adams, Michael C.
Evans, James P.
Henderson, Gail E.
Berg, Jonathan S.
author_sort Adams, Michael C.
collection PubMed
description PURPOSE: Utilization of sequencing to screen the general population for preventable monogenic conditions is receiving substantial attention due to its potential to decrease morbidity and mortality. However, the selection of which variants to return is a serious implementation challenge. Procedures must be investigated to ensure optimal test characteristics and avoidance of harm from false positive test results. METHODS: We scanned exome sequences from 478 well-phenotyped individuals for potentially pathogenic variants in 17 genes representing 11 conditions that are among the most medically actionable Mendelian disorders in adults. We developed 5 variant selection algorithms with increasing sensitivity and measured their specificity in these 17 genes. RESULTS: Variant selection algorithms with increasing sensitivity exhibited decreased specificity, and performance was highly dependent on the genes analyzed. The most sensitive algorithm ranged from 88.8% to 99.6% specificity among the 17 genes. CONCLUSION: For very low prevalence conditions, small reductions in specificity greatly increase false positives. This inescapable test characteristic governs the predictive value of genomic sequencing in the general population. To address this issue, test performance must be evaluated systematically for each condition so that the false negatives and false positives can be tailored for optimal outcomes, depending on the downstream clinical consequences.
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spelling pubmed-48601832016-07-08 The Promise and Peril of Genomic Screening in the General Population Adams, Michael C. Evans, James P. Henderson, Gail E. Berg, Jonathan S. Genet Med Article PURPOSE: Utilization of sequencing to screen the general population for preventable monogenic conditions is receiving substantial attention due to its potential to decrease morbidity and mortality. However, the selection of which variants to return is a serious implementation challenge. Procedures must be investigated to ensure optimal test characteristics and avoidance of harm from false positive test results. METHODS: We scanned exome sequences from 478 well-phenotyped individuals for potentially pathogenic variants in 17 genes representing 11 conditions that are among the most medically actionable Mendelian disorders in adults. We developed 5 variant selection algorithms with increasing sensitivity and measured their specificity in these 17 genes. RESULTS: Variant selection algorithms with increasing sensitivity exhibited decreased specificity, and performance was highly dependent on the genes analyzed. The most sensitive algorithm ranged from 88.8% to 99.6% specificity among the 17 genes. CONCLUSION: For very low prevalence conditions, small reductions in specificity greatly increase false positives. This inescapable test characteristic governs the predictive value of genomic sequencing in the general population. To address this issue, test performance must be evaluated systematically for each condition so that the false negatives and false positives can be tailored for optimal outcomes, depending on the downstream clinical consequences. 2015-11-05 2016-06 /pmc/articles/PMC4860183/ /pubmed/26540154 http://dx.doi.org/10.1038/gim.2015.136 Text en http://www.nature.com/authors/editorial_policies/license.html#terms Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Adams, Michael C.
Evans, James P.
Henderson, Gail E.
Berg, Jonathan S.
The Promise and Peril of Genomic Screening in the General Population
title The Promise and Peril of Genomic Screening in the General Population
title_full The Promise and Peril of Genomic Screening in the General Population
title_fullStr The Promise and Peril of Genomic Screening in the General Population
title_full_unstemmed The Promise and Peril of Genomic Screening in the General Population
title_short The Promise and Peril of Genomic Screening in the General Population
title_sort promise and peril of genomic screening in the general population
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4860183/
https://www.ncbi.nlm.nih.gov/pubmed/26540154
http://dx.doi.org/10.1038/gim.2015.136
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