Abstract This project aims to advance early screening procedures for autism spectrum disorder (ASD) in young children with Down syndrome (DS). Co-occurring ASD is a lifelong condition that impacts quality of life, adaptation, and cost of care for individuals with DS. A lack of systematic research on early development in young children with DS has significantly hindered efforts to identify those at heightened risk for ASD. The current lack of early detection means that children with DS+ASD do not benefit from developmentally informed, anticipatory early interventions that are available to the general population of young children with ASD. This project will identify markers of ASD risk in DS with an examination of two areas: (1) developmental presentation during early childhood in the areas of cognition, communication, motor skills, adaptive behavior, and other relevant developmental domains, and (2) the presence of candidate biomedical risk conditions including premature birth and low birth weight, infantile spasms (West syndrome), congenital heart defects, sleep dysregulation, and gastrointestinal conditions. We will characterize developmental profiles, biomedical conditions, and ASD symptom presentation comprehensively in a cohort of 225 young children with DS across three data waves (Wave 1: 18-21 months; Wave 2: 30-33 months; Wave 3: 42-45 months). We will then model the relationship between developmental and biomedical factors at Waves 1 and 2 and ASD presentation at Wave 3 via mixture modeling to identify the strongest early predictors of later ASD outcomes. Based on these analyses, we will generate recommendations for ASD screening protocols for children with DS ages 18 to 45 months. Findings from this study will directly address the NIH INCLUDE objective of improving health and well-being for people with DS.