Details:

Alternative Title:
Genet Med
Publisher's site:
http://dx.doi.org/10.1038/gim.2013.37
Personal Author:
Goddard, Katrina A.B. ; Whitlock, Evelyn P. ; Berg, Jonathan S. ; Williams, Marc S. ; Webber, Elizabeth M. ; ... More +
Goddard, Katrina A.B. ; Whitlock, Evelyn P. ; Berg, Jonathan S. ; Williams, Marc S. ; Webber, Elizabeth M. ; Webster, Jennifer A. ; Lin, Jennifer S. ; Schrader, Kasmintan A. ; Campos-Outcalt, Doug ; Offit, Kenneth ; Feigelson, Heather Spencer ; Hollombe, Celine Less -
Description:
Purpose

To develop, operationalize, and pilot test a transparent, reproducible, and evidence informed method to qualify when to report incidental findings from next generation sequencing technologies.

Methods

Using evidence-based principles, we propose a three stage process. Stage I ‘rules out’ incidental findings below a minimal threshold of evidence and is evaluated using inter-rater agreement and comparison with an expert-based approach. Stage II documents criteria for clinical actionability using a standardized approach to allow experts to consistently consider and recommend whether results should be routinely reported (Stage III). We used expert opinion to determine the face validity of Stages II and III using three case studies. We evaluated the time and effort for Stages I and II.

Results

For Stage I, we assessed 99 conditions and found high inter-rater agreement (89%), and strong agreement with a separate expert-based method. Case studies for familial adenomatous polyposis, hereditary hemochromatosis, and α1-Antitrypsin Deficiency were all recommended for routine reporting as incidental findings. The method requires less than three days per topic.

Conclusion

We establish an operational definition of clinically actionable incidental findings and provide documentation and pilot testing of a feasible method that is scalable to the whole genome.


Subject:
[+]
Adenomatous Polyposis Coli
Alpha 1-Antitrypsin Deficiency
Article
Clinical Actionability
Exome
Genetic Testing
Hemochromatosis
High-Throughput Nucleotide Sequencing
Humans
Incidental Findings
Pilot Projects
Population Screening
Reproducibility Of Results
Secondary Findings
Sequence Analysis, DNA
Whole Exome Sequencing
Whole Genome Sequencing

Source:
Genet Med. 15(9):721-728.
Document Type:
Journal Article
Funding:
GD000076/GD/OGDP CDC HHS/United States ; U01 HG006487/HG/NHGRI NIH HHS/United States ; U01 HG006487-01/HG/NHGRI NIH HHS/United States
GD000076/GD/OGDP CDC HHS/United States ; U01 HG006487/HG/NHGRI NIH HHS/United States ; U01 HG006487-01/HG/NHGRI NIH HHS/United States Less -
Collection(s):
CDC Public Access
Main Document Checksum:
[+]
urn:sha256:20f04bd8727adc58bb979e2c1279850fca8cec732368f49bb389cd9ef059afa7
File Type:

Supporting Files

• 	NIHMS528571-supplement-Supplementary_tables.pdf	pdf
  	nihms528571.nxml	txt

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