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【资讯翻译】Detection of Fetal Subchromosomal Abnormalities by Sequenci...

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发表于 2015-4-8 10:34:31 | 显示全部楼层 |阅读模式
Detection of Fetal Subchromosomal Abnormalities by Sequencing Circulating Cell-Free DNA from Maternal Plasma


BACKGROUND: The development of sequencing-based noninvasive prenatal testing (NIPT) has been largely focused on whole-chromosome aneuploidies (chromosomes 13, 18, 21, X, and Y). Collectively, they account for only 30% of all live births with a chromosome abnormality. Various structural chromosome changes, such as microdeletion/microduplication (MD) syndromes are more common but more challenging to detect. Recently, several publications have shown results on noninvasive detection of MDs by deep sequencing. These approaches demonstrated the proof of concept but are not economically feasible for large-scale clinical applications.

METHODS: We present a novel approach that uses low-coverage whole genome sequencing (approximately 0.2×) to detect MDs genome wide without requiring prior knowledge of the event's location. We developed a normalization method to reduce sequencing noise. We then applied a statistical method to search for consistently increased or decreased regions. A decision tree was used to differentiate whole-chromosome events from MDs.

RESULTS: We demonstrated via a simulation study that the sensitivity difference between our method and the theoretical limit was <5% for MDs ≥9 Mb. We tested the performance in a blinded study in which the MDs ranged from 3 to 40 Mb. In this study, our algorithm correctly identified 17 of 18 cases with MDs and 156 of 157 unaffected cases.

CONCLUSIONS: The limit of detection for any given MD syndrome is constrained by 4 factors: fetal fraction, MD size, coverage, and biological and technical variability of the event region. Our algorithm takes these factors into account and achieved 94.4% sensitivity and 99.4% specificity.

信源地址:http://www.clinchem.org/content/61/4/608.abstract

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发表于 2015-4-9 01:39:26 | 显示全部楼层
领了。。。。。。。。。

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发表于 2015-4-9 23:55:37 | 显示全部楼层
利用孕妇血浆游离循环DNA测序鉴定胎儿亚染色体异常
背景:测序依赖的非损伤性胎儿测试(NIPT)的发展主要集中在全染色体的非整倍性(染色体12,18,21,X,Y)。他们总共只占活产婴儿染色体异常的30%。多种染色体结构改变,如染色体微缺失/染色体微重复(MD)综合征更常见也更难检测。最近,一些文章发表了利用深度测序技术进行非损伤性MDs检测的结果。这些方法只是作了概念证明,对大范围的临床应用不是经济适用的。
方法:我们在这里提出了一种新型的方法,这种方法在事先不需要了解MDs发生位点的情况下,使用低覆盖全基因组测序(接近0.2×)去检测全基因组MDs。我们开发了一种减少测序噪音的标准化方法,然后利用统计学方法搜索总体增加或减少的区域,最后用决策图表区分全染色体MDs事件。
结果:我们通过一项模拟研究表明:对于MDs≥9 Mb的事件,我们的方法和理论检测限之间的敏感性差异为5%。我们用一项盲法研究对其表现进行了测试,在该盲法测试中DMs从3Mb到40Mb不等。在这个研究中,我们的计算程序准确地鉴定出18例MDs中的17例,以及157不受影响案例中的156例。
结论:4个因素制约给定的MD综合征的检测极限,包括事件区域的胎儿碎片,MD大小,覆盖范围和生物及技术的变化性。我们的计算方法将这些因素考虑进来,并获得了94.4%的灵敏度和99.4%的专一性。(pxb译)

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 楼主| 发表于 2015-4-13 14:00:52 | 显示全部楼层
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