PROJECT SUMMARY/ABSTRACT The overarching goal of the proposed INCLUDE Clinical Cohort Coordinating Center (DS-4C), co-led by investigators at RTI International and Emory University, is to improve the health and well-being of individuals with Down syndrome (DS) by supporting the INCLUDE Project’s DS Cohort Development Program (DS-CDP). In this capacity, the DS-4C will serve as the central hub for orchestrating and integrating all components of the DS-CDP, including overseeing the development and implementation of a common protocol to guide harmonized data collection across multiple DS Cohort Research Sites (DS-CRS) in the DS-CDP and facilitating data transfer into the INCLUDE Data Coordinating Center (DCC) and Data Hub for availability to researchers. The complex structure of the DS-CDP requires the DS-4C’s expert leadership and coordination to generate an effective, integrated, unified network to achieve the goal of generating deep phenotyping data and collecting biospecimens in a large, diverse cohort of individuals with DS across the lifespan to support future research efforts to improve DS-associated co-morbidities. The four cores of the DS-4C (Administrative, Cohort, Outreach, and Data Management) will leverage the expertise of core staff and work collaboratively to provide administrative support to facilitate collaboration and communication across the DS-CDP; ensure seamless implementation of the protocol; implement and support inclusive outreach efforts to facilitate inclusion and representation in recruitment; and manage the flow of data and biospecimens from the DS-CRS to the INCLUDE DCC and Data Hub and DS-Biorepository, respectively. Our specific aims are as follows: Aim 1: Implement tools and systems to foster seamless integration and operational efficiency within the DS-4C and across the DS-CDP. Aim 2: Provide expertise and resources to develop and implement the common protocol across the DS-CDP while enhancing the scientific rigor of DS-CRS studies to maximize the scientific impact of the INCLUDE Project. Aim 3: Enhance community engagement, facilitate recruitment of participants and team members from typically underrepresented groups, advance health equity goals, and promote awareness of the INCLUDE Program. Aim 4: Manage the flow of data from DS-CRS into the INCLUDE DCC and Data Hub for access by the DS research community. The DS-4C will be led by Multiple Principal Investigators, Dr. Hunter at RTI and Dr. Rosser at Emory, with a collaborative history and extensive expertise in elucidating health outcomes of individuals with DS through phenotypic protocol development, biospecimen collection, multi-site recruitment efforts, and data harmonization. The proposed DS-4C is immediately and amply prepared to support its mission to develop clinically meaningful findings that positively impact those affected by DS.