Purpose The percentage of a maternal cell-free DNA (cfDNA) sample that is fetal-derived (the fetal fraction; FF) is a key driver of the sensitivity and specificity of noninvasive prenatal screening (NIPS). On certain NIPS platforms, >20% of women with high body-mass index (and >5% overall) receive a test failure due to low FF (<4%). Methods A scalable fetal-fraction amplification (FFA) technology was analytically validated on 1,264 samples undergoing whole-genome sequencing (WGS)-based NIPS. All samples were tested with and without FFA. Results Zero samples had FF<4% when screened with FFA, whereas 1 in 25 of these same patients had FF<4% without FFA. The average increase in FF was 3.9-fold for samples with low FF (2.3-fold overall) and 99.8% had higher FF with FFA. For all abnormalities screened on NIPS, z-scores increased 2.2-fold on average in positive samples and remained unchanged in negative samples, powering an increase in NIPS sensitivity and specificity. Conclusions FFA transforms low-FF samples into high-FF samples. By combining FFA with WGS-based NIPS, a single round of NIPS can provide nearly all women with confident results about the broad range of potential fetal chromosomal abnormalities across the genome.

中文翻译：

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高通量胎儿分数扩增可提高无创产前筛查的分析性能

目的胎儿来源的母亲无细胞DNA（cfDNA）样本（胎儿分数； FF）的百分比是无创产前筛查（NIPS）敏感性和特异性的关键驱动因素。在某些NIPS平台上，由于FF低（<4％），> 20％的女性具有较高的身体质量指数（且总体> 5％）接受测试失败。方法对1264个样本进行了基于全基因组测序（WGS）的NIPS的分析验证性可扩展胎儿分数扩增（FFA）技术。在有和没有FFA的情况下测试所有样品。结果进行FFA筛查时，零样本的FF <4％，而这些患者中有25分之1的患者FF <4％，而没有FFA。FF低的样品的FF平均增加3.9倍（总体为2.3倍），FFA样品的FF平均增加99.8％。对于在NIPS上筛选的所有异常，z得分增加了2。阳性样品的平均含量是普通样品的2倍，阴性样品的平均含量却没有变化，从而提高了NIPS的敏感性和特异性。结论FFA将低FF样本转换为高FF样本。通过将FFA与基于WGS的NIPS相结合，单轮NIPS可以为几乎所有女性提供有关整个基因组潜在的胎儿染色体异常范围广泛的自信结果。