RT Journal Article
SR Electronic
T1 Systematic Design and Comparison of Expanded Carrier Screening Panels
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 080713
DO 10.1101/080713
A1 Kyle A. Beauchamp
A1 Dale Muzzey
A1 Kenny K. Wong
A1 Gregory J. Hogan
A1 Kambiz Karimi
A1 Sophie I. Candille
A1 Nikita Mehta
A1 Rebecca Mar-Heyming
A1 K. Eerik Kaseniit
A1 H. Peter Kang
A1 Eric A. Evans
A1 James D. Goldberg
A1 Gabriel A. Lazarin
A1 Imran S. Haque
YR 2017
UL http://biorxiv.org/content/early/2017/03/03/080713.abstract
AB Purpose The recent growth in pan-ethnic expanded carrier screening (ECS) has raised questions about how such panels might be designed and evaluated systematically. Design principles for ECS panels might improve clinical detection of at-risk couples and facilitate objective discussions of panel choice.Methods Guided by medical-society statements, we propose a method for the design of ECS panels that aims to maximize the aggregate and per-disease sensitivity and specificity across a range of Mendelian disorders considered serious by a systematic classification scheme. We evaluated this method retrospectively using results from 474,644 de-identified carrier screens. We then constructed several idealized panels to highlight strengths and limitations of different ECS methodologies.Results Based on modeled fetal risks for “severe” and “profound” diseases, a commercially available ECS panel (Counsyl) is expected to detect 183 affected conceptuses per 100,000 US births. A screen’s sensitivity is greatly impacted by two factors: (1) the methodology used (e.g., full-exon sequencing finds more affected conceptuses than targeted genotyping), and (2) the detection rate of the screen for diseases with high prevalence and complex molecular genetics (e.g., fragile X syndrome).Conclusion The described approaches allow principled, quantitative evaluation of which diseases and methodologies are appropriate for pan-ethnic expanded carrier screening.