Thank you for your interest in our study that compared predicted aneuploidy detection rates of sequential vs cell-free DNA (cfDNA) screening in a large cohort. We agree that modeling of the performance of alternate tests, as was done in our study, may result in estimates that differ from what would be found in clinical practice or in a clinical trial; thus ideally, a prospective comparative effectiveness trial should be completed. However, our goal was to model differences in performance by taking into account aspects of screening that are not considered in reports of cfDNA screening, namely other aneuploidies and failed tests, and thereby to account for significant biases in those reports.

As you note, the California Chromosome Registry may not have ascertained all cases of Down syndrome, despite the resources given by the program for the collection of outcomes. This concerted effort contrasts with many studies of cfDNA screening in clinical practice that have limited ascertainment of outcomes when testing is negative. This is often justified by assuming that “…it is likely that FNs [false negatives] would be voluntarily reported.”

Estimates of the number of “missing” cases of Down syndrome are highly dependent on the loss rates between first or second trimester and term; the data surrounding this have large confidence intervals. Recent reports indicate that spontaneous loss rates of Down syndrome fetuses are lower than earlier estimates. However, if the hypothesized 246 additional cases of Down syndrome did undergo screening, we calculate that, with sequential screening, 229 cases would be detected and 17 cases would have false-negative results; with cfDNA, 237 cases would be detected; 7 cases would have a failed screen, and 2 cases would have a false-negative result; this difference in detection is not significant ( P = .15). If patients with failed screens all had diagnostic testing, obviously the detection rate would be higher as would the false-positive rate.

With regard to screening for conditions such as neural tube defects, this emphasizes the point that sequential screening has the benefit of being a broad screen for many congenital disorders. If cfDNA screening is used as a primary tool for aneuploidy screening, additional tests (such as maternal serum alpha-fetoprotein and nuchal translucency screening) must be added, thereby increasing costs and complexity of the overall screening program. Modeling of screening programs can never provide as accurate a comparison of outcomes as a prospective study, which ideally would be performed to determine the effectiveness of different approaches.