Use of cell-free DNA for secondary screening in women at high risk of Down syndrome
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)
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.
Courtesy of Glenn E Palomaki, PhD, Geralyn M Messerlian, PhD, and Jacquelyn V Halliday, MS.
Graphic 103823 Version 5.0