Department of Biostatistics and Bioinformatics, Duke University School of Medicine, Durham, NC, USA.
Beijing USCI Medical Laboratory, Beijing, China.
Genet Med. 2020 Feb;22(2):301-308. doi: 10.1038/s41436-019-0636-5. Epub 2019 Aug 30.
Fetal fraction (FF) is the percent of cell-free DNA (cfDNA) in the mother's peripheral blood that is of fetal origin, which plays a pivotal role in noninvasive prenatal screening (NIPS). We present a method that can reliably estimate FFs by examining autosome single-nucleotide polymorphisms (SNPs).
Even at a very low sequencing depth, there are plenty of SNPs covered by more than one read. At those SNPs, we define read heterozygosity and demonstrate that the percent of read heterozygosity is a function of FF, which allows FF to be inferred.
We first demonstrated the effectiveness of our method in inferring FF. Then we used the inferred FF as an informative alternative prior to computing Bayes factors to test for aneuploidy, and observed better power than the Z-test. In analysis of clinical samples, we were able to identify female-male twins thanks to the accurate FF inference.
Knowing FF improves efficacy of NIPS. It brings a powerful Bayesian method, allows "no call" for samples with small FFs, renders screening for XXY syndrome simpler, and permits an adaptive design to sequence at a higher depth for samples with small FFs.
胎儿分数（FF）是母亲外周血中游离 DNA（cfDNA）中源自胎儿的百分比，它在非侵入性产前筛查（NIPS）中起着关键作用。我们提出了一种通过检查常染色体单核苷酸多态性（SNP）来可靠估计 FF 的方法。
即使在测序深度非常低的情况下，也有大量 SNP 被多个读取覆盖。在这些 SNP 处，我们定义了读取杂合性，并证明了读取杂合性的百分比是 FF 的函数，这使得可以推断 FF。
我们首先证明了我们的方法在推断 FF 方面的有效性。然后，我们将推断出的 FF 作为在计算贝叶斯因子以测试非整倍体之前的信息替代物，并观察到比 Z 检验更高的功效。在对临床样本的分析中，我们能够识别出女性-男性双胞胎，这要归功于准确的 FF 推断。
了解 FF 可提高 NIPS 的效果。它带来了一种强大的贝叶斯方法，允许对 FF 较小的样本进行“无调用”，简化了对 XXY 综合征的筛查，并允许对 FF 较小的样本进行自适应设计以更高的深度进行测序。
