Quantitative Metagenomics and the Vaginal Microbiome of Preterm Birth

项目摘要/摘要 卡拉汉实验室开发了提高精度的定量和计算方法， 标记基因和元基因组测序方法的准确性和重复性，并实现了这些 方法在开源和积极支持的软件中。卡拉汉实验室与其他 研究小组调查宿主相关微生物群落在各种健康问题中的作用， 特别关注阴道微生物群在早产中的作用。 标记基因和元基因组测序方法彻底改变了对人类微生物组的研究， 但通过这些技术测量的微生物类群的相对丰度被系统性地扭曲了(或 “有偏见的”)从真实的相对丰度通过实验和分类群特定的因素，我们不知道。 在接下来的五年里，我们打算通过多个部分来解决元基因组测序中的偏差问题 包括开发和验证元基因组学中偏倚的解释性机制模型的计划 实验，量化下游分析方法对元基因组学偏差的敏感性，并创造 不受偏见影响的新分析方法，并开发开放源码软件，允许研究人员 纠正有偏见的标记基因和元基因组学测量，使其达到真实值。 最近，标记基因测序和元基因组测序方法揭示了沙门氏菌阴道微生物群 孕妇可以预测早产的风险。然而，关于具体问题的研究之间存在分歧 目前，早产风险的微生物签名限制了这些结果的翻译。我们打算开发密集的 数百种阴道微生物区系的亚种分类分辨率纵向剖面 怀孕。我们将在怀孕早期定义准确的早产风险生物标记物，并确定 候选分类群可作为降低早产率的治疗干预措施的一部分。 我们将综合这一主题的更大证据基础，同时控制不同的元基因组学 不同研究中的偏差，以确定早产风险的可重复生物标记物。我们将整合 阴道微生物区系的纵向分布与宿主反应的其他组学测量 阴道微生物区系紊乱和早产之间潜在致病途径的证据。 通过开发计算和统计方法，将微生物组的测量结果修正为真实的 价值，卡拉汉实验室致力于提高更广泛研究的精密度和准确度 群落可以表征人类微生物群，从而加速我们对微生物群的理解-- 相关的健康状况和改善人类健康的微生物组疗法的发展。

Project Summary/Abstract The Callahan laboratory develops quantitative and computational methods that improve the precision, accuracy and reproducibility of marker-gene and metagenomics sequencing methods, and implements those methods in open-source and actively supported software. The Callahan laboratory collaborates with other research groups to investigate the role of host-associated microbial communities in various health problems, with a particular focus on the role of the vaginal microbiome preterm birth. Marker-gene and metagenomic sequencing methods have revolutionized the study of the human microbiome, but the relative abundances of microbial taxa measured by these technologies are systematically distorted (or “biased”) from the true relative abundances by experiment- and taxa-specific factors we do not understand. Over the next five years we intend to solve the problem of bias in metagenomic sequencing via a multi-part program that includes developing and validating an explanatory mechanistic model of bias in metagenomics experiments, quantifying the sensitivity of downstream analysis methods to metagenomics bias and creating new analysis methods unaffected by bias, and developing open-source software that allows researchers to correct biased marker-gene and metagenomics measurements to their true values. Recently, marker-gene and metagenomic sequencing methods have revealed that the vaginal microbiome of pregnant women can predict risk of preterm birth. However, disagreements between studies on the specific microbial signatures of preterm risk currently limit translation of these results. We intend to develop dense longitudinal profiles with sub-species taxonomic resolution of the vaginal microbiota in hundreds of pregnancies. We will define precise biomarkers of preterm risk as early in possible in pregnancy, and identify candidate taxa that could be targeted as part of therapeutic interventions to reduce the rate of preterm birth. We will synthesize the larger evidence base on this topic while controlling for the different metagenomics biases in different studies in order to identify reproducible biomarkers of preterm birth risk. We will integrate the longitudinal profiles of the vaginal microbiota with other omics measurements of host response to build evidence for potential causative pathways between disturbances in the vaginal microbiota and preterm birth. By developing computational and statistical methods that correct measurements of the microbiome to their true values, the Callahan laboratory seeks to improve the precision and accuracy with which the wider research community can characterize the human microbiome, thereby accelerating our understanding of microbiome- related health conditions and the development of microbiome therapies that improve human health.