Abstract This Competing Revision will expand the scope of R01HD099150-0, a five-year project that involves extensive data collection on cognition and executive function in young children with Down syndrome (DS). The focus of R01HD099150-0 is outcome measure validation for future treatment work in DS, and the proposed revision will provide funds to support the collection and analysis of blood samples concurrently with cognitive assessment. Supplementing the parent project data with blood sample collection and multi-omics analyses will leverage the wealth of cognitive phenotyping data on this cohort of young children with DS, and make it possible to preliminarily test a model of executive dysfunction in DS that can inform the development of novel treatments. Blood samples will be collected from 60 children who enroll in Wave 1 of the parent R01 project during project years 3 and 4. All children will have chronological ages between 2.5-7.99 years. Proposed analyses will seek to identify multi-omics signatures of executive dysfunction in the transcriptome, proteome, metabolome, and immune profile. The ultimate goal of this Competing Revision will be to identify endotype features associated with variable executive dysfunction in DS. This integrated biobehavioral examination of executive dysfunction in DS is novel, and has the potential to transform treatment science for young children with DS and promote healthy developmental outcomes and well-being in this population.

Narrative This Competing Revision aims to identify biosignatures associated with executive dysfunction in individuals with Down syndrome. Leveraging parent R01 data collection that includes evaluation of executive function in a cohort of young children with Down syndrome, this project will examine the association between cognitive phenotypic presentation and multi- omics signatures in the transcriptome, proteome, and metabolome. This work will have important translational relevance, and will provide essential information to allied health providers, interventionists, and researchers aiming to transform treatment for executive dysfunction in children with Down syndrome.