Bioinformatics Approaches for Fetal DNA Fraction Estimation in Noninvasive Prenatal Testing

Abstract

The discovery of cell-free fetal DNA molecules in plasma of pregnant women has created a paradigm shift in noninvasive prenatal testing (NIPT). Circulating cell-free DNA in maternal plasma has been increasingly recognized as an important proxy to detect fetal abnormalities in a noninvasive manner. A variety of approaches for NIPT using next-generation sequencing have been developed, which have been rapidly transforming clinical practices nowadays. In such approaches, the fetal DNA fraction is a pivotal parameter governing the overall performance and guaranteeing the proper clinical interpretation of testing results. In this review, we describe the current bioinformatics approaches developed for estimating the fetal DNA fraction and discuss their pros and cons.

Fetal fraction evaluation in non-invasive prenatal screening (NIPS)

“…Indeed, some laboratories may not be checking FF or using optimal methods for detection that could potentially provide false-negative results to patients [1]. Technical factors that can influence FF and its estimation are sample handling [2] and the choice of bioinformatics tools (reviewed in [3]) [4]. Multiple biological factors have been identified that affect FF, including gestational age [4][5][6][7][8][9], weight and/or body mass index (BMI) [6][7][8][9][10][11][12], trisomies [7,[10][11][12][13], fetal crown-rump length [6,10,12], serum pregnancy-associated plasma protein-A [6,10,12], serum free β-human chorionic gonadotropin [6,10,12], hypertension [7], twins [7], smoking [10], and assisted conception [8,12].…”

Noninvasive reconstruction of placental methylome from maternal plasma DNA: Potential for prenatal testing and monitoring

“…In addition, the apparent fetal DNA fractions serve as key parameter in the FEMER algorithm. Even though there are many alternative methods for estimating fetal DNA fraction, SNP‐based methods are still widely considered as the gold‐standard and universal approach for this task . In our algorithm, we used DNA‐seq data but not the BS‐seq data for mining the fetal‐specific informative SNPs.…”

“…Even though there are many alternative methods for estimating fetal DNA fraction, SNP-based methods are still widely considered as the gold-standard and universal approach for this task. 23 In our algorithm, we used DNA-seq data but not the BS-seq data for mining the fetal-specific informative SNPs. We had made this choice because of the following considerations: (i) compared to the DNA-seq data, the BS-seq data showed higher base-calling errors and bias in genome coverage because of the extreme GC content caused by the bisulfite conversion 32 and (ii) more importantly, the informative SNPs deduced from the DNA-seq data would not bias the estimation of the fetal DNA fraction in the BS-seq data as these 2 datasets were generated by independent libraries.…”

Is cell-free DNA in spent embryo culture medium an alternative to embryo biopsy for preimplantation genetic testing? A systematic review

“…Therefore, SCM-PGT requires strategies to discriminate between exogenous and maternal DNA and embryonic DNA in SCM to improve the general and full concordance rates, but this was only carried out in 30% (three out of 10) of studies Vera-Rodriguez et al, 2018;Capalbo et al, 2018). Embryonic cf-DNA differs in size and contains different preferred ends than maternal fragments (Chan et al, 2016;Peng and Jiang, 2017). These features could be used to develop new approaches that will allow discriminating embryonic cf-DNA from exogenous DNA in SCM to improve SCM-PGT sensitivity and specificity.…”