Incorporating DNA sequencing into current prenatal screening practice for Down's syndrome

Area of Science:

• Maternal-fetal medicine
• Genetics
• Biochemistry

Background:

• Prenatal screening for Down syndrome commonly uses the Integrated test with biochemical and ultrasound markers.
• Emerging non-invasive prenatal testing (NIPT) using cell-free DNA in maternal plasma shows high performance but is costly and has failure rates.
• A novel protocol merging the Integrated test with NIPT was evaluated to optimize performance and cost-effectiveness.

Purpose of the Study:

• To assess the screening performance of a hybrid protocol combining the Integrated test with NIPT for Down syndrome.
• To determine if this protocol can achieve high detection rates and low false-positive rates while reducing costs compared to universal NIPT.
• To evaluate the impact of test failures in the NIPT component within the proposed protocol.

Main Methods:

• A modeling approach using published data to simulate screening performance.
• The protocol involves initial Integrated test screening at 11 weeks, with reflex NIPT for higher-risk individuals.
• Lower-risk and NIPT-failed cases proceed to the second stage of the Integrated test at 15 weeks.

Main Results:

• A detection rate of 95% with a 0.1% false-positive rate was achieved when 20% of women underwent NIPT.
• Universal NIPT offered marginal detection rate increases but significantly higher false-positive rates.
• The proposed protocol reduced screening costs to approximately one-fifth of universal NIPT, assuming NIPT is 20 times more expensive than the Integrated test.

Conclusions:

• The integrated screening protocol effectively achieves high Down syndrome detection rates with minimal false positives.
• This hybrid approach significantly lowers costs compared to universal NIPT.
• The protocol successfully mitigates NIPT-related test failures, ensuring program integrity.