Estimation of cell-free fetal DNA fraction from maternal plasma based on linkage disequilibrium information

Abstract

Cell-free fetal DNA fraction (FF) in maternal plasma is a key parameter affecting the performance of noninvasive prenatal testing (NIPT). Accurate quantitation of FF plays a pivotal role in these tests. However, there are few methods that could determine FF with high accuracy using shallow‐depth whole‐genome sequencing data. In this study, we hypothesized that the actual FF in maternal plasma should be proportional to the discrepancy rate between the observed genotypes and inferred genotypes based on the linkage disequilibrium rule in certain polymorphism sites. Based on this hypothesis, we developed a method named Linkage Disequilibrium information-based cell-free Fetal DNA Fraction (LDFF) to accurately quantify FF in maternal plasma. This method achieves a high performance and outperforms existing methods in the fetal DNA fraction estimation. As LDFF is a gender-independent method and developed on shallow-depth samples, it can be easily incorporated into routine NIPT test and may enhance the current NIPT performance.

Detection of early-onset severe preeclampsia by cell-free DNA fragmentome

“…placenta) or the mother (i.e. predominantly the hematopoietic cells), we reanalyzed the plasma DNA of one healthy and one PE pregnant woman with matched sequencing data of maternal and paternal buffy coat from our previously published paper( 31 ) (Figure 5A). Fetal- and maternal-derived cfDNA were determined by the parental specific alleles (See Methods).…”

“…The sequencing data of plasma DNA and paired parental genomic DNA of a healthy and a preeclampsia pregnancy were obtained from our previous study( 31 ). The parental informative single-nucleotide polymorphisms (SNPs) where the mother was homozygous (AA) and the fetus was heterozygous (i.e.…”