Purpose: The recent growth in pan-ethnic expanded carrier screening (ECS) has raised questions about how such panels might be designed and evaluated in a principled manner. Systematic 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 both the aggregate and per-disease sensitivity and specificity across a range of Mendelian disorders considered "severe" or "profound" by a systematic classification scheme. We evaluated this method retrospectively using results from 405,195 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 Family Prep Screen) is expected to detect 183 affected conceptuses per 100,000 in the US population. A screen's sensitivity is greatly impacted by two factors: (1) the methodology used (e.g., full-exon sequencing finds up to 48 more affected fetuses per 100,000 than targeted genotyping with an optimal 50 variant panel), and (2) the detection rate of the screen for diseases with high prevalence and complex molecular genetics (e.g., fragile X syndrome, spinal muscular atrophy, 21-hydroxylase deficiency, and alpha-thalassemia account for 54 affected fetuses per 100,000). Conclusion: The described approaches allow principled, quantitative evaluation of which diseases and methodologies are appropriate for pan-ethnic expanded carrier screening.