Systematic evaluation of NIPT aneuploidy detection software tools with clinically validated NIPT samples

PLoS Comput Biol. 2021 Dec 20;17(12):e1009684. doi: 10.1371/journal.pcbi.1009684. eCollection 2021 Dec.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aneuploidy*
  • Computational Biology
  • Diagnosis, Computer-Assisted / methods*
  • Female
  • Humans
  • Noninvasive Prenatal Testing / methods*
  • Pregnancy
  • Software*
  • Whole Genome Sequencing

Grants and funding

This work was supported by the Ettevõtluse Arendamise Sihtasutus [EU48695 to AS, EU53935 to AS and PPalta] (PP, HT, AS, KK, PPalta); and by the Eesti Teadusagentuur [PRG1076 to AS] (PP, HT, AS, KK, PPalta); and Horizon 2020 Framework Programme [EU952516 to AS] (PP, HT, AS, KK, PPalta). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.