Description and Pilot Results from a Novel Method for Evaluating Return of Incidental Findings from Next Generation Sequencing Technologies

Details

• Alternative Title:
  Genet Med
• Personal Author:
  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
  More +
• 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.
• Subjects:
  • Adenomatous Polyposis Coli
  • Exome
  • Genetic Testing
  • Hemochromatosis
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Incidental Findings
  • Pilot Projects
  • Reproducibility of Results
  • Sequence Analysis, DNA
  More +
• Keywords:
  • whole genome sequencing
  • clinical actionability
  • population screening
  • secondary findings
  • whole exome sequencing
• Source:
  Genet Med. 15(9):721-728
• Pubmed ID:
  23558254
• Pubmed Central ID:
  PMC3927794
• Document Type:
  Journal Article
• Funding:
  U01 HG006487/HG/NHGRI NIH HHSUnited States/ ; U18 GD000076/GD/OGDP CDC HHSUnited States/ ; U01 HG006487-01/HG/NHGRI NIH HHSUnited States/ ; GD000076/GD/OGDP CDC HHSUnited States/
• Volume:
  15
• Issue:
  9
• Download URL:
  https://stacks.cdc.gov/view/cdc/29851/cdc_29851_DS1.pdf
• File Type:
  [PDF - 197.05 KB]
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha256:20f04bd8727adc58bb979e2c1279850fca8cec732368f49bb389cd9ef059afa7