Prediction of Fetal Maturity and Neonatal Morbidity Using Novel Biomarkers from Cell-Free Amniotic Fluid Transcriptome

使用无细胞羊水转录组的新型生物标志物预测胎儿成熟度和新生儿发病率

• 批准号: 9922947
• 负责人: DANIEL, T (MD) Todd Swarr
• 金额: $ 19.62万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9922947
• 关键词: 37 weeks gestation; Address; Adrenal Cortex Hormones; Amniotic Fluid; Biological Markers; Blinded; Blood; Cells; Clinical; Complex; DNA; Data; Decision Making; Detection; Development; Diagnostic tests; Discipline of obstetrics; Exhibits; Expression Profiling; Fetal Development; Fetal Lung; Fetal Organ Maturity; Fetal Tissues; Fetus; Gene Expression Profile; Genes; Genetic Transcription; Gestational Age; Goals; Hospitals; Human; Individual; Infant; Intervention; Investigation; Life; Link; Liquid substance; Lung; Maternal-fetal medicine; Methods; Molecular Target; Morbidity - disease rate; Mothers; Neonatal; Neonatal Mortality; Organ; Pattern; Personal Satisfaction; Physiological; Physiological Processes; Population; Positioning Attribute; Pregnancy; Premature Birth; Premature Infant; Process; Proteins; Public Health; RNA; Readiness; Research; Resources; Risk; Risk Assessment; Sampling; Sensitivity and Specificity; Serum; Source; Specialist; Specificity; Steroids; Testing; Time; Tissues; Translations; Uncertainty; Urine; Validation; Work; age related; antenatal; biobank; body system; candidate identification; candidate marker; cell free fetal DNA; cell type; clinical database; clinical practice; clinical risk; cohort; feeding; fetal; high risk; high risk population; improved; maternal serum; molecular diagnostics; neonatal morbidity; neonatal outcome; noninvasive diagnosis; novel marker; postnatal; potential biomarker; predictive marker; predictive test; premature; prenatal; programs; recruit; respiratory morbidity; transcriptome; transcriptome sequencing; transcriptomics; validation studies

PROJECT SUMMARY Multiple research agencies addressing the complex public health problem of preterm birth have emphasized conducting research to identify biomarkers that could improve clinical risk assessment for preterm birth. Late- preterm infants (34 to <37 weeks gestation) comprise 74% of premature births, and are most responsible for the increased rates of premature deliveries in the U.S. During this time, obstetricians struggle to make delivery- planning decisions where uncertainty exists regarding benefit vs. risk for mother and baby, and the only currently available fetal maturity testing focuses on the lung. For this high-risk late-preterm population, identification of fetal biomarkers that predict physiologic readiness for postnatal life is critical for obstetrical and neonatal risk assessment, particularly when maturational processes have different trajectories for individual infants. Amniotic fluid (AF) both contributes to and reflects fetal well-being, and contains an abundant proportion of cell- free fetal DNA and RNA that can be targeted quantitatively for ease of application, specificity, and broader representation of cell types than protein or metabolites. Our preliminary work has demonstrated that this cell- free fetal RNA/DNA can be isolated and analyzed to produce a snapshot of overall fetal maturity, thereby making analysis of amniotic fluid a practical first step to discovery of novel biomarkers that can then be identified in maternal serum. This R21 will continue our discovery driven preliminary work by further elucidating the following hypothesis: The AF RNA transcriptome will exhibit RNA expression patterns that identify the state of fetal organ maturity, and will predict neonatal morbidity. Aim 1 will describe differences in the amniotic fluid transcriptome at 4 different time points in pregnancy to describe the trajectory of physiologic processes occurring with advancing gestation. Aim 2(a) will identify candidate biomarkers for lung and other organ maturity by determining differences in amniotic fluid RNA expression between preterm infants (32 to <38 weeks) with and without common adverse neonatal outcomes. Aim 2(b) will then test the predictive capacity of the candidate biomarkers identified using a separate validation cohort, and compare the specificity and sensitivity for predicting fetal maturity, compared to current methods of fetal lung maturity testing. The proposed research has the potential impact to illustrate the transcriptomic profiles that are dynamically changing across fetal development and to inform the timing of non-indicated deliveries, significantly reducing maternal complications and neonatal morbidity resulting from prematurity, or to allow for other interventions to be administered to ameliorate fetal maturity (antenatal corticosteroids). By better informing the timing of late- preterm deliveries, we can reduce maternal and neonatal complications resulting from prematurity, a major public health concern.

项目摘要 针对早产这一复杂的公共卫生问题，多个研究机构强调， 开展研究，以确定可以改善早产临床风险评估的生物标志物。晚- 早产儿（妊娠34至<37周）占早产儿的74%，并且是导致早产的主要原因。 美国早产率的增加。在这段时间里，产科医生努力分娩- 在母婴受益与风险方面存在不确定性的规划决策，以及目前唯一的 可用的胎儿成熟度测试集中在肺上。对于这一高危晚期早产人群， 预测产后生理准备的胎儿生物标志物对产科和新生儿风险至关重要 评估，特别是当个别婴儿的成熟过程有不同的轨迹时。 羊水（AF）有助于并反映胎儿的健康，并含有大量的细胞， 游离胎儿DNA和RNA，可以定量靶向，便于应用，特异性和更广泛的 比蛋白质或代谢物更能代表细胞类型。我们的初步研究表明这个细胞- 可以分离和分析游离胎儿RNA/DNA，以产生总体胎儿成熟度的快照，从而使 羊水分析是发现新的生物标志物的第一步， 母体血清这个R21将继续我们的发现驱动的初步工作，进一步阐明 以下假设：AF RNA转录组将显示RNA表达模式， 胎儿器官成熟状态，并将预测新生儿发病率。目标1将描述 在妊娠的4个不同时间点，羊水转录组描述生理性 随着妊娠的进行而发生的过程。目标2（a）将确定肺和其他组织的候选生物标志物。 通过测定早产儿（32至<38岁）之间羊水RNA表达的差异， 周），有或无常见的不良新生儿结局。目标2（B）将测试 使用单独的验证队列鉴定候选生物标志物，并比较特异性和灵敏度 与目前的胎儿肺成熟度检测方法相比， 拟议的研究具有潜在的影响，以说明动态的转录组学概况， 在胎儿发育过程中发生变化，并告知非指征分娩的时间， 早产导致的产妇并发症和新生儿发病率，或允许其他干预措施， 给药以改善胎儿成熟度（产前皮质类固醇）。通过更好地告知晚些时候的时间- 早产，我们可以减少早产造成的产妇和新生儿并发症， 公共卫生问题。