Abstract Each year in the US, nearly a half million babies are born preterm ( <37 weeks of gestation). The significance of preterm birth (PTB) extends far beyond this huge number and the neonatal period. PTB affects ~14% of Black babies, which is ~50% higher than for White babies. There is growing evidence that PTB puts a child at significant risk for future cardiometabolic diseases, which are among the leading causes of death in the US and disproportionately impact Black populations. While the mechanisms underlying PTB-cardiometabolic risk remain largely unknown, we found that PTB was associated with differential maternal and cord circulating metabolites, some of which have been implicated in cardiometabolic diseases in adults. This competing renewal proposal aims to conduct a systematic investigation of the link between PTB and child long-term cardiometabolic health and the underlying biological pathways. Such an undertaking is critically needed to identify novel biomarkers for early risk assessment and targeted interventions to halt or reverse a PTB-induced adverse cardiometabolic trajectory over the life course. Built on the scientific discoveries we have made during the current funding cycle, we will leverage the rich resources of the Boston Birth Cohort (BBC), one of the largest and longest NIH-funded U.S. urban low- income predominantly Black birth cohorts, with ~3,500 mother-child pairs who were enrolled at birth and followed prospectively (at present, with a median follow-up of 13 years). This application will harness the cutting-edge Olink technology for a precise and high-throughput assessment of >1500 circulating proteins in BBC children at two time points (at birth and age 2 years). Our study design has been informed by a strong scientific premise and compelling preliminary data, including a proteomics pilot study that demonstrated feasibility, high quality of archived plasma samples and lab assays, and generated promising preliminary results. Specifically, we aim to (1) Examine prospective associations of PTB with cardiometabolic outcomes from birth to age 18 years using 3500 mother-infant pairs; (2) Identify differential plasma proteome profiles between 500 preterm and 500 term children; (3) Assess joint associations of PTB and plasma proteome with cardiometabolic outcomes of 1000 children; and (4) Integrate proteome with metabolome to gain a deeper understanding of metabolic dysfunctions due to PTB and implications for subsequent cardiometabolic outcomes using the same set of 1000 children. This proposal is strengthened by its prospective birth cohort design and a life course framework; focus on an under-represented, under-studied, high-risk minority population; and integration of proteomics with metabolomics data. By establishing PTB as an important early life risk factor of future cardiometabolic risk and by identifying novel cord and early childhood predictive biomarkers with long-term cardiometabolic implications, this study ...