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

整合多组学数据：建模生物标志物和机制以减少细菌性阴道病复发

• 批准号: 10282850
• 负责人: Johanna B. Holm
• 金额: $ 9.29万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10282850
• 关键词: Affect; African; Age; American; Anaerobic Bacteria; Antibiotic Therapy; Archives; Atopobium vaginae; Award; Bacteria; Bacterial Vaginosis; Basic Science; Behavioral; Big Data; Bioinformatics; Biological Markers; Biometry; Case-Control Studies; Categories; Clinical; Clinical Research; Communities; Complement; Data; Diagnosis; Ecology; Epidemiologic Methods; Epidemiology; Ethnic Origin; Evaluation; Foundations; Funding; Future; Genes; Goals; Grant; HIV; Health; Hygiene; Immune Targeting; Immune response; Immunologic Markers; Infection; Inflammatory; Institutes; Intervention; Irrigation; K-Series Research Career Programs; Lactobacillus; Lead; Learning; Life Style; Longitudinal Studies; Maryland; Mentors; Metagenomics; Methods; Mission; Modeling; Molecular; Multiomic Data; Outcome; Participant; Pelvic Inflammatory Disease; Pelvis; Predisposition; Premature Birth; Prognostic Factor; Prognostic Marker; Quality of life; Race; Recurrence; Reporting; Reproductive Health; Research; Research Design; Research Personnel; Research Support; Resources; Risk; Sampling; Scientist; Sex Behavior; Sexually Transmitted Diseases; Source; Statistical Models; Symptoms; Training; Translating; United States National Institutes of Health; Universities; Vagina; Visit; Woman; Women' s Health; Work; aged; candidate marker; career development; certificate program; cervicovaginal; clinical Diagnosis; clinical translation; complex data; data integration; data modeling; data reduction; disorder risk; epidemiology study; genome sciences; improved; insight; machine learning method; medical schools; metabolome; metabolomics; metagenome; microbial; microbiome; model development; multiple omics; novel; personalized medicine; programs; reproductive; research study; screening; supervised learning; targeted treatment; therapeutic target; tool; vaginal microbiome; vaginal microbiota

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.

细菌性阴道（BV）的特征是阴道菌群，乳酸杆菌属的丰度低。和 厌氧细菌的较高丰度，影响近30％的北美妇女 接近撒哈拉以南非洲妇女的50％。 BV通过临床观察AMSEL诊断 标准（AMSEL-BV），但仅在报告症状时才建议治疗 未经治疗的妇女比例。即使进行治疗，BV复发率在6个月内范围为50-70％， 增加女性的后遗症风险。无论症状如何，BV都与严重的逆境有关 健康成果，包括早产和艾滋病毒，可能会严重影响女性的生活质量。理想的BV 治疗将消除复发。阴道微生物组和微环境共同提供 对BV状态的详细评估，并拥有关键的功能见解，以预测和理解AMSEL-BV 复发。该提案的目的是整合和操作微生物组（宏基因组）和 微环境（代谢组和免疫标记）数据以开发复发性BV的预后指标， 并确定候选生物标志物和因果机制，以减少复发。 PI的最新工作 在功能上将阴道微生物组分类用于大型临床研究（阴道宏基因组学 社区状态类型，MGCST）。该提议中的广泛假设是，并非所有微生物组 与阴道细菌相关的具有相同的复发潜力。初步数据表明 在含有BV相关细菌的9个MGCST中，仅观察到BV复发更常见。 这项研究提出了利用NIH 1999年阴道纵向研究的存档宫颈阴道样品 植物群在每季度每季度跟踪参与者一年。基线样品的多摩变分析将是 评估以鉴定微生物（宏基因组和代谢组学）和宿主（代谢组和靶向免疫） 标记）具有复发性BV的易感性签名。该建议的具体目的是：（1）进行 流行病学分析评估MGCST的人口和生活方式相关性，（2）采用 监督机器学习和因果推理建模，以识别预后因素和驱动因素 阴道微生物组和微环境的复发性BV。案件被定义为女性 AMSEL-BV处于基线，然后在3个月后清除，然后在六个月后复发。控件是 患有AMSEL-BV的妇女在9个月内不会经历复发。该赠款将支持PI的培训 临床研究证书计划的流行病学和生物统计学。 Pi的长期 术语目标是创建一个独立的研究计划，翻译阴道微生物组的基础科学 改善妇女的生殖健康结果。基因组科学研究所和大学 马里兰医学院独特地提供成功完成所需的资源和支持 该提案以及PI向独立调查员的过渡。