Description and Pilot Results from a Novel Method for Evaluating Return of Incidental Findings from Next Generation Sequencing Technologies
Published Date:Apr 04 2013
Source:Genet Med. 15(9):721-728.
Keywords:Adenomatous Polyposis Coli
Alpha 1-Antitrypsin Deficiency
High-Throughput Nucleotide Sequencing
Reproducibility Of Results
Sequence Analysis, DNA
Whole Exome Sequencing
Whole Genome Sequencing
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
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.
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.
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.
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.
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