NEJM:万名妇女参与新型DNA唐筛 错误率比传统检测低百倍
2015/05/01
4月23日国际顶尖期刊《新英格兰医学》(NEJM)杂志比对了一项在遍布全球6个国家、35个地点、涉及19000个孕妇的标准的血液测试、“三重检测”及新型无细胞DNA测序(cfDNA)的产前筛查研究,发现无细胞DNA测序的新型DNA唐筛阳性误报率比传统检测低近100倍。

4月23日国际顶尖期刊《新英格兰医学》(NEJM)杂志比对了一项在遍布全球6个国家、35个地点、涉及19000个孕妇的传统标准测试、“三重检测”及新型无细胞DNA测序(cfDNA)的产前筛查研究,给怀孕待产的父母们带来了好消息:科研人员找到了一种能在产前极其精准检测唐氏综合症的基因检测方法。而且,这种基因检测方法简单易操作,只需要怀孕的妈妈血样就可以完成。

随着人们对产前基因检测的关注度越来越高,研究人员相继研发了一些可以在怀孕期间检测遗传疾病的方法。

传统的标准测试——羊水穿刺

在过去检测胎儿基因组成的唯一办法就是进行羊水穿刺。这是一种侵入式手术:医生将一根很长的针头直接插入孕妇的子宫,然后收集羊水样本用于分析检测。羊水穿刺手术不仅令孕妇不舒服,而且还有较小的几率导致流产。但是随着DNA测序技术的发展,这种落后的检测可能很快就会被淘汰了。



三重检测

在怀孕的早期阶段,少量胎儿的DNA会在孕妇的血液中循环流动。这一现象一直会持续到怀孕第十周。在新型技术的帮助下,我们只需要采集孕妇的血样就可以检测胎儿的DNA,查看胎儿是否存在三体综合征(胎儿因为遗传基因失调而引起的染色体倍性现象。以致身体细胞分裂时,某一对染色体得到了三条而不是正常的两条。)。新的研究主要观察第21对染色体三体变异,也就是导致唐氏综合症的元凶。但同时也会观察DNA筛选功能,以便筛查其他染色体的三倍体症。

目前采用的孕妇血清三重标记测试(Triplemarkertesting)虽然是非侵入性的,但因其敏感性和特异性较低,对21-三体诊断的准确率仅为60%

无细胞DNA测序(cfDNA)

去年, 美国波士顿儿童医院的Diana W. Bianchi教授等人发布了一篇类似的研究,其中涉及的患者有1914个,采用同样的DNA测试种类,研究结果也同期被发表在2015年2月27日的《新英格兰医学》杂志上。

与Diana W. Bianchi教授研究不同的是,4月23日《新英格兰医学》发表的新研究样本扩大了十倍,结果也更好,且所有的参与者都做了标准的筛选及DNA检测。研究涉及19000个妇女,35个地点,6个国家。研究主导是Mary Norton,受研究的所有妇女都曾做过常规产前筛查。该研究比对了标准的血液测试、“三重检测”及近期被罗氏收购的Ariosa Diagnostics 做的新型无细胞DNA测序(cfDNA)。

传统检测只能发现30例 DNA测序发现38例

该研究项目中同时接受了传统标准检测和DNA测序检测的孕妇数量为15841人(部分孕妇因为技术原因未能同时完成两种检测)。在这群人中,共有38例21号染色体出现染色体三体变异的情况。传统的标准检测发现了其中的30例,而DNA测序检测法发现了全部的38例。

DNA测序检测的误报率缩小了接近100倍

传统检测出现854例误报 DNA测序检测仅出现9例

更令人吃惊的是两种检测方法在假阳性误报方面的差异–传统检测出现了854例假阳性误报,而DNA测序检测仅仅出现了9例。这几乎将假阳性误报的规模缩小了100倍。

即在15841名孕妇中,传统检测结果共计报告884例“阳性”结果,其中仅有30例是正确的。如果你接受了传统检测并被报告为阳性,那么你的胎儿只有3.4%的几率患上唐氏综合症。为了确认结果,几乎所有的孕妇都会选择接受羊水穿刺手术,然后一面陷入焦虑,一面担心可能因为羊水穿刺导致流产。

DNA测序检测方法仅仅报告了47例“阳性”结果,其中38例是正确的。如果你接受了DNA测序检测并被报告为阳性,那么你的胎儿有高达81%的几率患上唐氏综合症。

另外,DNA测序检测方法在筛选13和18号染色体出现三体变异的检测中表现得也更精确。这两种染色体变异非常罕见,可能导致非常严重的健康问题。患有这两种疾病的婴儿一般在一岁之前就会死亡。

相比于传统检测方法,DNA测序检测的误报率缩小了接近100倍。因此,利用DNA检测进行产前筛查的优越性就显而易见了。

虽然目前为止可以检测出来疾病的数量并不多,但是这一领域的发展速度非常快,科学家希望开发更多的可检测出来疾病的数量,并尽快淘汰传统的检测方法,让怀孕父母从假阳性带来的焦虑和羊水穿刺手术带来的风险中解脱出来。

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  • Cell-free DNA Analysis for Noninvasive Examination of Trisomy

    BACKGROUND Cell-free DNA (cfDNA) testing for fetal trisomy is highly effective among high-risk women. However, there have been few direct, well-powered studies comparing cfDNA testing with standard screening during the first trimester in routine prenatal populations. METHODS In this prospective, multicenter, blinded study conducted at 35 international centers, we assigned pregnant women presenting for aneuploidy screening at 10 to 14 weeks of gestation to undergo both standard screening (with measurement of nuchal translucency and biochemical analytes) and cfDNA testing. Participants received the results of standard screening; the results of cfDNA testing were blinded. Determination of the birth outcome was based on diagnostic genetic testing or newborn examination. The primary outcome was the area under the receiver-operating-characteristic curve (AUC) for trisomy 21 (Down's syndrome) with cfDNA testing versus standard screening. We also evaluated cfDNA testing and standard screening to assess the risk of trisomies 18 and 13. RESULTS Of 18,955 women who were enrolled, results from 15,841 were available for analysis. The mean maternal age was 30.7 years, and the mean gestational age at testing was 12.5 weeks. The AUC for trisomy 21 was 0.999 for cfDNA testing and 0.958 for standard screening (P=0.001). Trisomy 21 was detected in 38 of 38 women (100%; 95% confidence interval [CI], 90.7 to 100) in the cfDNA-testing group, as compared with 30 of 38 women (78.9%; 95% CI, 62.7 to 90.4) in the standard-screening group (P=0.008). False positive rates were 0.06% (95% CI, 0.03 to 0.11) in the cfDNA group and 5.4% (95% CI, 5.1 to 5.8) in the standard-screening group (P<0.001). The positive predictive value for cfDNA testing was 80.9% (95% CI, 66.7 to 90.9), as compared with 3.4% (95% CI, 2.3 to 4.8) for standard screening (P<0.001). CONCLUSIONS In this large, routine prenatal-screening population, cfDNA testing for trisomy 21 had higher sensitivity, a lower false positive rate, and higher positive predictive value than did standard screening with the measurement of nuchal translucency and biochemical analytes.

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  • DNA Sequencing versus Standard Prenatal Aneuploidy Screening

    BACKGROUND In high-risk pregnant women, noninvasive prenatal testing with the use of massively parallel sequencing of maternal plasma cell-free DNA (cfDNA testing) accurately detects fetal autosomal aneuploidy. Its performance in low-risk women is unclear. METHODS At 21 centers in the United States, we collected blood samples from women with singleton pregnancies who were undergoing standard aneuploidy screening (serum biochemical assays with or without nuchal translucency measurement). We performed massively parallel sequencing in a blinded fashion to determine the chromosome dosage for each sample. The primary end point was a comparison of the false positive rates of detection of fetal trisomies 21 and 18 with the use of standard screening and cfDNA testing. Birth outcomes or karyotypes were the reference standard. RESULTS The primary series included 1914 women (mean age, 29.6 years) with an eligible sample, a singleton fetus without aneuploidy, results from cfDNA testing, and a risk classification based on standard screening. For trisomies 21 and 18, the false positive rates with cfDNA testing were significantly lower than those with standard screening (0.3% vs. 3.6% for trisomy 21, P<0.001; and 0.2% vs. 0.6% for trisomy 18, P=0.03). The use of cfDNA testing detected all cases of aneuploidy (5 for trisomy 21, 2 for trisomy 18, and 1 for trisomy 13; negative predictive value, 100% [95% confidence interval, 99.8 to 100]). The positive predictive values for cfDNA testing versus standard screening were 45.5% versus 4.2% for trisomy 21 and 40.0% versus 8.3% for trisomy 18. CONCLUSIONS In a general obstetrical population, prenatal testing with the use of cfDNA had significantly lower false positive rates and higher positive predictive values for detection of trisomies 21 and 18 than standard screening. (Funded by Illumina; ClinicalTrials.gov number,

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