PROJECT SUMMARY There is a fundamental gap in the availability of cognitive outcome measures that are reliable and sensitive to detecting change among children with Down syndrome (DS). Lack of such outcome measures represents an important problem to interpreting clinical trials aimed at improving the lives of individuals with DS. Without evidence-based cognitive outcome measures, future treatment trials in this population will remain suboptimal due to poor study measures. Despite some promising findings in currently recommended assessment batteries, the evidence base for cognitive outcome measures in DS is limited. Multi-site studies evaluating the reliability and validity of outcome measures are the needed next step towards supporting the evaluation of new pharmaceutical and clinical interventions for children with DS. Working groups convened by NICHD of leading experts in DS led to recommendations of promising measures for use in this population. The prior R01 HD093754 began evaluating the psychometric properties of recommended promising measures and expanded upon those recommendations by evaluating individual variability and accounting for the method of assessment (verbal, nonverbal, computer, parent-report) to support our understanding of performance within a cognitive domain. The proposed renewal continues evaluating the psychometric properties of measures that fill the gaps in cognitive domains (Study 1), extends the natural history of change in performance on measures with annual follow-up visits (Study 2), and refines the measurement of individual variability to include co-occurring medical and mental health conditions across both Studies. The overall objective of this application is to establish the psychometric properties of individual clinical outcome measures in children with DS across the cognitive domains of episodic memory, executive functioning (set-shifting, inhibitory control, working memory), learning and memory, and processing speed. Our rationale for working with this population is that DS is associated with a distinct pattern of cognitive strengths and weaknesses related to their neuroanatomy. Thus, the selection of outcome measures to be evaluated needs to take into account the DS behavioral phenotype. We propose three specific aims: 1) To examine the psychometric properties of selected cognitive outcome measures with children with DS. 2) To evaluate differences in the psychometric properties of the measures as a function of variations in demographics and co-occurring medical and mental health conditions. 3) To characterize the developmental trajectories of cognition and executive functioning. To achieve these aims, 200 children in Study 1 ages 6-17 years with DS will participate in repeated neuropsychological assessments with follow-up evaluations at 2 weeks, 6 months, and 1 year. We will continue to follow at minimum 120 children from R01 HD093754 annually in Study 2. We anticipate that this measurement study will provide...