Abstract
Non-invasive prenatal testing (NIPT) is a powerful screening method for fetal aneuploidy detection, relying on laboratory and computational analysis of cell-free DNA. Although several published computational NIPT analysis tools are available, no prior comprehensive, head-to-head accuracy comparison of the various tools has been published. Here, we compared the outcome accuracies obtained for clinically validated samples with five commonly used computational NIPT aneuploidy analysis tools (WisecondorX, NIPTeR, NIPTmer, RAPIDR, and GIPseq) across various sequencing depths (coverage) and fetal DNA fractions. The sample set included cases of fetal trisomy 21 (Down syndrome), trisomy 18 (Edwards syndrome), and trisomy 13 (Patau syndrome). We determined that all of the compared tools were considerably affected by lower sequencing depths, such that increasing proportions of undetected trisomy cases (false negatives) were observed as the sequencing depth decreased. We summarised our benchmarking results and highlighted the advantages and disadvantages of each computational NIPT software. To conclude, trisomy detection for lower coverage NIPT samples (e.g. 2.5M reads per sample) is technically possible but can, with some NIPT tools, produce troubling rates of inaccurate trisomy detection, especially in low-FF samples.
Highlights
Non-invasive prenatal testing (NIPT) is widely used and enable highly accurate fetal chromosomal aneuploidy screening [1]
We describe and quantify a previously undocumented aneuploidy risk uncertainty that is mainly relevant in cases of very low sequencing coverage and could, in the worst-case scenario, lead to a false negative rate of 245 undetected trisomies per 1,000 trisomy cases
As NIPT relies on whole-genome sequencing (WGS) or targeted sequencing of cell-free DNA extracted from the peripheral blood samples from the pregnant woman, it reduces the number of invasive fetal testing procedures [2,3]
Summary
Non-invasive prenatal testing (NIPT) is widely used and enable highly accurate fetal chromosomal aneuploidy screening [1]. Several computational NIPT analysis tools for WGS-based NIPT have been examined in the literature These include GIPseq [3], NIPTmer [5], NIPTeR [6], RAPIDR [7], DASAF R [8], Wisecondor [9], and WisecondorX [9,10]. While these computational tools are commonly used, no head-to-head evaluation studies of these NIPT tools on the same clinically validated samples is available
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