TY - JOUR T1 - Systematic Design and Comparison of Expanded Carrier Screening Panels JF - bioRxiv DO - 10.1101/080713 SP - 080713 AU - Kyle A. Beauchamp AU - Dale Muzzey AU - Kenny K. Wong AU - Gregory J. Hogan AU - Kambiz Karimi AU - Sophie I. Candille AU - Nikita Mehta AU - Rebecca Mar-Heyming AU - K. Eerik Kaseniit AU - H. Peter Kang AU - Eric A. Evans AU - James D. Goldberg AU - Gabriel A. Lazarin AU - Imran S. Haque Y1 - 2017/01/01 UR - http://biorxiv.org/content/early/2017/03/03/080713.abstract N2 - 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. ER -