Use of cell-free DNA for secondary screening in women at high risk of Down syndrome

The flowchart assumes the prevalence of Down syndrome (trisomy 21) is 1:100 in the high-risk population. In addition, the cfDNA detection rate for Down syndrome is 99.5%, the associated false-positive rate is 0.05%, and the overall test failure rate is 1%. Among the 12,000 high-risk singleton pregnancies, 120 will have Down syndrome, and for simplicity, the remaining population will be euploid (unaffected). Among the 120 Down syndrome pregnancies, 1 will be a test failure, 1 will be screen negative, and the remaining 118 will be screen positive. Among the 11,880 euploid pregnancies, 6 will be false positive, 11,755 will be screen negative, and 119 will have a test failure.
The associated table shows a summary of those pregnancies that screen positive (118 TP and 6 FP or approximately 1% of the 12,000), screen negative (1 FN and 11,755 TN or approximately 98%), as well as those in which the test failed to provide a result (1 TP and 119 TN or approximately 1%). Women who were screen positive would be offered diagnostic testing and would, as a group, have a PPV of 95% (odds 20:1). Among those women who screen negative, no further testing for Down syndrome would be warranted (routine care) as their risk has been reduced to approximately 1:12,000. Among those women with a failed test, there would be several options as their residual risk of 1:119 is quite similar to their group risk of 1:100 prior to testing. The test could be repeated and the subsequent result used, or, since the woman was a high risk to begin with and her risk has not changed, the offer of diagnostic testing is reasonable.