Integrating multi-omics data: Modeling biomarkers and mechanisms to reduce bacterial vaginosis recurrence

细菌性阴道病(BV)的特征是阴道微生物群中乳杆菌丰度较低。和 厌氧细菌数量增加，影响了近30%的北美育龄妇女 接近50%的撒哈拉以南非洲女性。经Amsel‘s临床观察确诊BV 标准(AMSEL-BV)，但只有在报告症状时才建议治疗，留下显著的 未接受治疗的妇女比例。即使接受治疗，6个月内BV复发率也在50%至70%之间， 增加女性出现负面后遗症的风险。不管症状如何，BV都与严重的不良反应有关 健康后果，包括早产和艾滋病毒，并可能严重影响妇女的生活质量。理想BV 治疗可以消除复发。阴道微生物群和微环境共同提供 详细评估BV状态，并掌握关键的功能见解以预测和了解AMSEL-BV 复发。这项提议的目标是整合和运作微生物组(元基因组)和 微环境(代谢体和免疫标记物)数据，以开发复发BV的预后指标， 并确定减少复发的候选生物标记物和因果机制。国际和平研究所最近的工作 对阴道微生物组进行功能分类，用于大型临床研究(阴道元基因组学 社区状态类型、mgCST)。这项提议中的广泛假设是，并不是所有的微生物群 与细菌性阴道病相关的患者也有同样的复发可能性。初步数据显示， 在含有BV相关细菌的9个MgCST中，只有2个更常观察到BV复发。 这项研究建议利用1999年美国国立卫生研究院阴道纵向研究中的宫颈阴道样本 每季度对参与者进行为期一年的跟踪调查。将对基线样本进行多组学分析 评估以确定微生物(元基因组和代谢组)和宿主(代谢组和靶向免疫 标志)对复发性BV的易感性特征。这项建议的具体目的是：(1)进行 流行病学分析，以评估MgCST的人口学和生活方式相关性，以及(2)员工 有监督的机器学习和因果推理建模以识别预测因素和驱动因素 导致BV复发的阴道微生物群和微环境。病例被定义为女性 以Amsel-BV为基线，3个月后清除，6个月后复发。控件为 患有Amsel-BV的妇女在9个月内没有复发。这笔赠款将支持私家侦探的培训 完成临床研究证书课程的流行病学和生物统计学专业。私家侦探的长- 学期目标是创建一个独立的研究项目，翻译阴道微生物组的基础科学 以改善妇女的生殖健康成果。基因组科学研究所和加州大学 马里兰医学院独特地提供了成功完成 这项提议以及私家侦探向独立调查员的过渡。

Bacterial vaginosis (BV) is characterized by a vaginal microbiota with a low abundance of Lactobacillus spp. and higher abundances of anaerobic bacteria and affects nearly 30% of reproductive-age North American women and closer to 50% of sub-Saharan African women. BV is diagnosed by clinical observation of Amsel’s criteria (Amsel-BV), but treatment is only recommended when symptoms are reported, leaving a significant proportion of women untreated. Even with treatment, BV recurrence rates range from 50-70% within 6 months, increasing a woman’s risk of negative sequelae. Regardless of symptoms, BV is associated with serious adverse health outcomes, including preterm birth and HIV, and can seriously impact a woman’s quality of life. Ideal BV treatment would eliminate recurrence. The vaginal microbiome and microenvironment together provide a detailed evaluation of BV states, and hold key functional insights to predict and understand Amsel-BV recurrence. The goal of this proposal is to integrate and operationalize microbiome (metagenomes) and microenvironment (metabolomes and immune markers) data to develop a prognostic indicator of recurrent BV, and identify candidate biomarkers and causal mechanisms which reduce recurrence. Recent work by the PI functionally categorized the vaginal microbiome for use in large clinical research studies (vaginal metagenomic community state types, mgCSTs). The broad hypothesis in this proposal is that not all microbiomes associated with bacterial vaginosis have the same potential for recurrence. Preliminary data suggest that BV recurrence is more frequently observed in only two of the nine mgCSTs containing BV-associated bacteria. This study proposes to utilize archived cervicovaginal samples from the NIH 1999 Longitudinal Study of Vaginal Flora in which participants were followed quarterly for one year. Multi-omic analyses of baseline samples will be assessed to identify microbial (metagenomic and metabolomic) and host (metabolomic and targeted immune markers) signatures of susceptibility to recurrent BV. Specific aims of this proposal are to: (1) conduct an epidemiological analysis to evaluate the demographic and lifestyle correlates of mgCSTs, and (2) employ supervised machine learning and causal inference modeling to identify prognostic factors and drivers of the vaginal microbiome and microenvironment which lead to recurrent BV. Cases are defined as women with Amsel-BV at baseline, then clearance 3 months later, followed by recurrence at six months. Controls are women with Amsel-BV that do not experience recurrence within 9 months. This grant will support the PI’s training in epidemiology and biostatistics with the completion of a Certificate Program in Clinical Research. The PI’s long- term goal is to create an independent research program translating the basic science of the vaginal microbiome to improve women’s reproductive health outcomes. The Institute for Genome Sciences and the University of Maryland School of Medicine uniquely provide the resources and support required for successful completion of this proposal and the PI’s transition to an independent investigator.