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Separating the signal from the noise in metagenomic cell-free DNA sequencing.
Microbiome ( IF 15.5 ) Pub Date : 2020-02-11 , DOI: 10.1186/s40168-020-0793-4
Philip Burnham 1 , Nardhy Gomez-Lopez 2, 3, 4 , Michael Heyang 1 , Alexandre Pellan Cheng 1 , Joan Sesing Lenz 1 , Darshana M Dadhania 5 , John Richard Lee 5 , Manikkam Suthanthiran 5 , Roberto Romero 2, 6, 7, 8, 9, 10 , Iwijn De Vlaminck 1
Affiliation  

BACKGROUND Cell-free DNA (cfDNA) in blood, urine, and other biofluids provides a unique window into human health. A proportion of cfDNA is derived from bacteria and viruses, creating opportunities for the diagnosis of infection via metagenomic sequencing. The total biomass of microbial-derived cfDNA in clinical isolates is low, which makes metagenomic cfDNA sequencing susceptible to contamination and alignment noise. RESULTS Here, we report low biomass background correction (LBBC), a bioinformatics noise filtering tool informed by the uniformity of the coverage of microbial genomes and the batch variation in the absolute abundance of microbial cfDNA. We demonstrate that LBBC leads to a dramatic reduction in false positive rate while minimally affecting the true positive rate for a cfDNA test to screen for urinary tract infection. We next performed high-throughput sequencing of cfDNA in amniotic fluid collected from term uncomplicated pregnancies or those complicated with clinical chorioamnionitis with and without intra-amniotic infection. CONCLUSIONS The data provide unique insight into the properties of fetal and maternal cfDNA in amniotic fluid, demonstrate the utility of cfDNA to screen for intra-amniotic infection, support the view that the amniotic fluid is sterile during normal pregnancy, and reveal cases of intra-amniotic inflammation without infection at term. Video abstract.

中文翻译:

在宏基因组无细胞 DNA 测序中将信号与噪声分离。

背景 血液、尿液和其他生物流体中的无细胞 DNA (cfDNA) 为了解人类健康提供了独特的窗口。一部分 cfDNA 来自细菌和病毒,为通过宏基因组测序诊断感染创造了机会。临床分离物中微生物来源的 cfDNA 的总生物量很低,这使得宏基因组 cfDNA 测序容易受到污染和比对噪声的影响。结果 在这里,我们报告了低生物量背景校正 (LBBC),这是一种生物信息学噪声过滤工具,可通过微生物基因组覆盖的均匀性和微生物 cfDNA 绝对丰度的批次变化来获得信息。我们证明 LBBC 可以显着降低假阳性率,同时对 cfDNA 测试筛查尿路感染的真阳性率影响最小。我们接下来对从足月无并发症妊娠或伴有或不伴有羊膜内感染的临床绒毛膜羊膜炎患者采集的羊水中的 cfDNA 进行高通量测序。结足月无感染的羊膜炎症。视频摘要。结足月无感染的羊膜炎症。视频摘要。结足月无感染的羊膜炎症。视频摘要。
更新日期:2020-04-22
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