Inferring fetal fractions from read heterozygosity empowers the noninvasive prenatal screening

Purpose: Fetal fraction (FF) is the percent of cell-free DNA (cfDNA) in themother’s peripheral blood that is of fetal origin, which plays a pivotal role innoninvasive prenatal screening (NIPS). We present a method that can reliablyestimate FFs by examining autosome single-nucleotide polymorphisms(SNPs). Methods: Even at a very low sequencing depth, there are plenty of SNPscovered by more than one read. At those SNPs, we define read heterozygosity anddemonstrate that the percent of read heterozygosity is a function of FF, whichallows FF to be inferred. Results: We first demonstrated the effectiveness of our method in inferringFF. Then we used the inferred FF as an informative alternative prior tocomputing Bayes factors to test for aneuploidy, and observed better power thanthe Z-test. In analysis of clinical samples,we were able to identify female–male twins thanks to the accurate FFinference. Conclusion: Knowing FF improves efficacy of NIPS. It brings a powerful Bayesianmethod, allows “no call” for samples with small FFs, renders screening for XXYsyndrome simpler, and permits an adaptive design to sequence at a higher depthfor samples with small FFs.