ABSTRACT Beginning early in life, metabolic dysregulation related to the triplication of chromosome 21(e.g. decreased energy expenditure, increased leptin, hypotonia, increased inflammation, and autonomic dysfunction) as well as lifestyle (e.g., poor diet, sedentary behavior, reduced and disrupted sleep, and stressors) are thought to contribute to the 2 times greater prevalence of obesity in people with Down syndrome (DS) as compared to the general population. In the general population, metabolic health, obesity, and lifestyle have strong associations with health conditions including obstructive sleep apnea, Alzheimer’s disease, cardiometabolic diseases, and cognitive impairments. However, the relationship between these factors in people with DS is not well understood. The Metabolic Health, Lifestyle, and Risk of Co-Occurring Health Conditions in Down Syndrome (MET-DS) study is a five-year, longitudinal study of factors that alter the risk and severity of co-occurring health conditions in children, adolescents, and young adults with DS. The study involves a rigorous deep-phenotyping protocol to better understand the complex interplay between trisomy 21, metabolic dysregulation, obesity, lifestyle, and the development of co-occurring health conditions. This effort will enroll 200 participants (ages 6- 24 years of age) with DS from four clinical performance sites, and follow them annually across 3 data collection cycles to address the follow aims: 1) Deeply characterize and establish normative data on metabolic health, obesity, and lifestyle factors of a large cohort (N = 200) of children, adolescents, and young adults with DS (aged 6-24 yrs.); 2) Measure the stability and change in profiles of metabolic health, weight status, and lifestyle factors across 2 years (3 time points; 12 months apart) and during transitional periods of development; 3) Establish the relation between metabolic health, obesity, and lifestyle factors on co-occurring health conditions (e.g., obstructive sleep apnea, cardiometabolic diseases, autoimmune diseases, and early biomarkers of Alzheimer’s disease) and cognitive development across 2 years (3 time points; 12 months apart); 4) Collaborate with the other DS-CRS sites and the DS-4C on the development, implementation, and data harmonization of common core measures across domains (e.g., clinical, cognitive, behavioral, imaging, and multi-omics) and sites, and lead the DS-CRS sites in collection of metabolic and lifestyle measures.

Project Narrative The Metabolic Health, Lifestyle, and Risk of Co-Occurring Health Conditions in Down Syndrome (MET-DS) study is a five-year, longitudinal deep-phenotyping study of factors driving the risk and severity of co-occurring conditions in children, adolescents, and young adults with Down syndrome, funded by the NIH INCLUDE Project (INvestigation of Co-occurring conditions across the Lifespan to Understand Down syndromE). The study involves a rigorous protocol for understanding the complex interplay between trisomy 21, metabolic dysregulation, obesity, lifestyle, and the development of co-occurring conditions across childhood, adolescence, and into young adulthood in people with Down syndrome. This effort will enroll 200 participants (ages 6-24 years of age) with Down syndrome from four clinical performance sites, and track conditions and variables across 3 data collection cycles.