@article {Beauchamp080713, author = {Kyle A. Beauchamp and Dale Muzzey and Kenny K. Wong and Gregory J. Hogan and Kambiz Karimi and Sophie I. Candille and Nikita Mehta and Rebecca Mar-Heyming and K. Eerik Kaseniit and H. Peter Kang and Eric A. Evans and James D. Goldberg and Gabriel A. Lazarin and Imran S. Haque}, title = {Systematic Design and Comparison of Expanded Carrier Screening Panels}, elocation-id = {080713}, year = {2017}, doi = {10.1101/080713}, publisher = {Cold Spring Harbor Laboratory}, abstract = {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 {\textquotedblleft}severe{\textquotedblright} and {\textquotedblleft}profound{\textquotedblright} diseases, a commercially available ECS panel (Counsyl) is expected to detect 183 affected conceptuses per 100,000 US births. A screen{\textquoteright}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.}, URL = {https://www.biorxiv.org/content/early/2017/03/03/080713}, eprint = {https://www.biorxiv.org/content/early/2017/03/03/080713.full.pdf}, journal = {bioRxiv} }