Systematic design and comparison of expanded carrier screening panels

Abstract

PurposeThe 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.MethodsGuided 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.ResultsBased 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: (i) the methodology used (e.g., full-exon sequencing finds more affected conceptuses than targeted genotyping) and (ii) the detection rate of the screen for diseases with high prevalence and complex molecular genetics (e.g., fragile X syndrome).ConclusionThe described approaches enable principled, quantitative evaluation of which diseases and methodologies are appropriate for pan-ethnic expanded carrier screening.

Figure 1

The disease risk contribution of each severe or profound condition on Counsyl Family Prep Screen is shown for a US census–weighted population. 78 conditions contributing fewer than 2 affected fetuses per 100,000 are lumped into one category (“78 Other”) for visual clarity; individual component diseases are outlined but not labeled. For each condition, the number of affected fetuses (per 100,000) is shown, along with the percentage of the total disease risk. The area of each box is proportional to the disease risk. Reported numbers include panel-wide deletion predictions when applicable (see Supplementary Methods).

Figure 2

The sensitivity of several hypothetical ECS panels is compared using the disease risk as a proxy. The absolute disease risk, in affected fetuses per 100,000, is plotted on the bottom axis. The top axis shows the contribution as a percent of the total assessed disease risk of the most comprehensive panel considered (full-exon sequencing + special cases + CNV). CNV, copy-number variant; ECS, expanded carrier screening.