Systematic design and comparison of expanded carrier screening panels

Area of Science:

• Genetics
• Reproductive Medicine
• Bioinformatics

Background:

• Pan-ethnic expanded carrier screening (ECS) is growing, necessitating systematic design and evaluation methods.
• Current ECS panel design lacks standardized principles, impacting clinical utility and couple counseling.
• Objective criteria are needed to guide the selection of diseases and methodologies for ECS.

Purpose of the Study:

• To propose a systematic method for designing expanded carrier screening (ECS) panels.
• To maximize aggregate and per-disease sensitivity and specificity across Mendelian disorders.
• To facilitate objective discussions regarding ECS panel selection.

Main Methods:

• Developed a design method for ECS panels guided by medical-society statements.
• Proposed a systematic classification scheme for serious Mendelian disorders.
• Retrospectively evaluated the method using 474,644 de-identified carrier screens.
• Constructed idealized panels to assess strengths and limitations of different methodologies.

Main Results:

• Modeled fetal risks indicated a commercial ECS panel could detect 183 affected conceptuses per 100,000 US births.
• Screen sensitivity is significantly influenced by methodology (e.g., full-exon sequencing vs. targeted genotyping).
• Detection rates for high-prevalence, complex genetic disorders (e.g., fragile X syndrome) critically impact overall sensitivity.

Conclusions:

• The proposed approaches enable principled, quantitative evaluation of ECS.
• This framework aids in selecting appropriate diseases and methodologies for pan-ethnic expanded carrier screening.
• Systematic evaluation improves the clinical utility and reliability of carrier screening panels.