**4. Evidence on the quality of NIPT from published literature**

The initial studies on test quality for the most common aneuploidies were performed in highrisk collectives and focused on the sensitivities and specificities of the different cell-free DNA tests [20–26]. After the rapid clinical application of NIPT including many women at low risk, there was a demand for information on the positive predictive value of each individual test. The positive predictive value then was found to vary widely depending on the investigated cohort and could be as low as 45.4% for trisomy 21 [27], meaning that when a NIPT-test was positive only 45.4% of the fetuses were affected. This underlines the fact that although cell-free DNA testing performs better than the previous screening algorithms for aneuploidy, a positive test result requires confirmation with an invasive procedure such as amniocentesis or chorionic villous sampling.

#### **4.1. Trisomy 21, 13, and 18**

The data for the three most common aneuploidies now stem from a number of large-scale studies from mainly high-risk collectives. The detection rate for trisomy 21 ranged from 97.5% to 100%, with most of the studies showing sensitivities above 99%. For trisomy 18, the outcome is similar ranging from 92.8% to 100%. The sensitivities for trisomy 13 are slightly lower ranging from 78.6% to 100% [18–32]. All of the reported screening methods have significantly lower false positive rates below 1% compared to conventional first trimester screening, which typically is set at a 5% false positive rate.
