PROJECT SUMMARY – Project 1 (PR1) Immune development in early Life (IDEAL) involves complex processes with heterogeneous influences that establish immunologic trajectories and impart long-term health consequences1. While genetics play an important role, environmental exposures also substantially shape innate and adaptive immunity1, suggesting that IDEAL is modifiable. Historically, research has relied on clinical phenotypes to identify immune mechanisms, presuming that phenotypic similarity reflects common etiology2,3. While often true, this approach becomes increasingly complex with multifactorial etiology, as is the case with immune outcomes related to IDEAL. We contend that the considerable heterogeneity of mechanisms regulating immune ontogeny may best be identified via endotypes of IDEAL- subclasses of disease defined by distinct underlying mechanisms. Derived endotypes informed by multiOMIC systems biology capture complex biological processes4 that provide an integrated view of immunity and will identify biological mechanisms related to different immunologic trajectories. Our hypothesis is that clinically meaningful “IDEAL endotypes” exist and can be identified through the use of multiOMIC profiling, further informed by clinical phenotype. This approach further enables identification of actionable multiOMIC biomarkers that may be utilized in a precision medicine framework to classify, predict and/or optimize immune trajectories of specific IDEAL endotypes. Our approach in IDEAL Project 1 (PR1) considers integrated systems biology in conjunction with longitudinal follow-up for the select clinical outcomes of vaccine response (VR), respiratory infection proneness (IP), and asthma. To this end, we will utilize four large, ethnically diverse early-life cohorts with precise clinical phenotypes and longitudinal follow-up up thru 6 years (YR) of age. We capitalize on two cohorts with existing multiOMIC data for discovery: Vitamin D Antenatal Asthma Reduction Trial (VDAART; N=650), and the Expanded Program on Immunization Consortium- Human Immune Project Consortium (EPIC-HIPC; N=500); and two cohorts with dense biosample collection for replication, in which multiOMIC data will be generated via the proposed studies: the Rochester Combined Cohort (RCC; N=400) and the proposed prospective Rochester IDEAL cohort (RIC; N=200). We will define IDEAL endotypes and identify endotype-specific actionable biologic targets via the following Specific Aims (SAs): SA1) Identify multiOMIC variants of IDEAL clinical phenotypes; SA2) Define and characterize robust “IDEAL endotypes” through the synthesis of unbiased multiOMIC endotypes; and SA3) Using a multiOMIC framework, identify actionable biomarker targets for IDEAL endotypes that merit further functional interrogation in vitro in PR 3.