A unified approach to risk assessment for fetal aneuploidies

To examine the potential impact of combining measures from cell-free DNA (cfDNA) testing with maternal age and first-trimester biomarkers in screening for fetal trisomies.

This was a theoretical study using Bayes' theorem to combine the a priori risk for fetal trisomy 21 derived from maternal age with likelihoods from nuchal translucency thickness, serum pregnancy-associated plasma protein-A, serum free β-human chorionic gonadotropin and plasma cfDNA. We adopted a binomial counting model for the cfDNA likelihoods and developed a model to account for errors in estimating fetal fraction.

When Bayes' theorem was used to combine the a priori risk for trisomy 21 derived from the first-trimester combined test with likelihoods from the cfDNA test, and when the true fetal fraction was known, the detection rate increased from 62% at a fetal fraction of 4% to 100% at a fetal fraction of ≥ 9%; the positive likelihood ratio (trisomic/euploid) increased from 620 to 1000 and the negative likelihood ratio (euploid/trisomic) increased from 3 to > 10 000. When the fetal fraction is < 4%, the cfDNA test has traditionally been considered to be a failure, but the cfDNA results can be used to improve the performance of screening by the combined test.

In contingent policies that use the first-trimester combined test for first-line screening to select the subgroup for cfDNA testing, the data from the latter should be used to update the risk from the former. Individual patient results from cfDNA testing depend crucially on the fetal fraction and the precision of its measurement.