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 1264 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.

Conclusion

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提高了无创产前筛查的分析性能

目的

来自胎儿的母体游离 DNA (cfDNA) 样本（胎儿分数；FF）的百分比是无创产前筛查 (NIPS) 灵敏度和特异性的关键驱动因素。在某些 NIPS 平台上，超过 20% 的体重指数高的女性（总体上 >5%）由于 FF 低（<4%）而导致测试失败。

方法

一项可扩展的胎儿分数扩增 (FFA) 技术在 1264 个接受基于全基因组测序 (WGS) 的 NIPS 的样本上进行了分析验证。所有样品都在有和没有 FFA 的情况下进行了测试。

结果

使用 FFA 筛查时，零样本的 FF < 4%，而在 25 名相同患者中，有 1 名的 FF < 4% 没有 FFA。FF 值低的样品平均增加了 3.9 倍（总体为 2.3 倍），而 99.8% 的样品在 FFA 中的 FF 值更高。对于在 NIPS 上筛查的所有异常，阳性样本的z分数平均增加了 2.2 倍，而在阴性样本中保持不变，从而提高了 NIPS 的灵敏度和特异性。

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关于整个基因组中广泛的潜在胎儿染色体异常的可靠结果。