Combining count- and length-based z-scores leads to improved predictions in non-invasive prenatal testing

Budis, J.a,b,c, Gazdarica, J.b,d, Radvanszky, J.b,e, Szucs, G.f, Kucharik, M.g, Strieskova, L.b,d, Gazdaricova, I.d, Harsanyova, M.b,d, Duris, F.b,c, Minarik, G.g, Sekelska, M.g, Nagy, B.h, Turna, J.c,d,i, Szemes, T.b,d,i

aDepartment of Computer Science, Faculty of Mathematics, Physics and Informatics, Comenius University, Bratislava, Slovakia
bGeneton s.r.o., Bratislava, Slovakia
cSlovak Centre of Scientific and Technical Information, Bratislava, Slovakia
dDepartment of Molecular Biology, Faculty of Natural Sciences, Comenius University, Bratislava, Slovakia
eInstitute of Clinical and Translational Research, Biomedical Research Center, Slovak Academy of Sciences Bratislava, Slovakia
fDepartment of Applied Mathematics and Statistics, Faculty of Mathematics, Physics and Informatics, Comenius University, Bratislava, Slovakia
gMedirex a.s., Bratislava, Slovakia
hDepartment of Human Genetics, University of Debrecen, Debrecen, Hungary
iComenius University Science Park, Bratislava, Slovakia

Abstract

Motivation

Non-invasive prenatal testing or NIPT is currently among the top researched topic in obstetric care. While the performance of the current state-of-the-art NIPT solutions achieve high sensitivity and specificity, they still struggle with a considerable number of samples that cannot be concluded with certainty. Such uninformative results are often subject to repeated blood sampling and re-analysis, usually after two weeks, and this period may cause a stress to the future mothers as well as increase the overall cost of the test.

Results

We propose a supplementary method to traditional z-scores to reduce the number of such uninformative calls. The method is based on a novel analysis of the length profile of circulating cell free DNA which compares the change in such profiles when random-based and length-based elimination of some fragments is performed. The proposed method is not as accurate as the standard z-score; however, our results suggest that combination of these two independent methods correctly resolves a substantial portion of healthy samples with an uninformative result. Additionally, we discuss how the proposed method can be used to identify maternal aberrations, thus reducing the risk of false positive and false negative calls.

Availability and implementation

The open-source code of the proposed methods, together with test data, is freely available for non-commercial users at github web page https://github.com/jbudis/lambda.