PROJECT SUMMARY The overarching goal of the INCLUDE Data Hub is to serve all people with Down syndrome (DS) by accelerating the pace of discoveries into the mechanisms by which trisomy 21 (T21) predisposes these individuals to a wide range of comorbidities that shorten their life expectancy and diminish their quality of life. Over the last few decades, the life expectancy for people with DS has significantly increased, and epidemiological studies reveal that T21 causes a different disease spectrum, protecting these individuals from developing certain conditions, such as most solid malignancies (1,2), while strongly predisposing them to others, such as Alzheimer’s disease (AD) (3), congenital heart disease (CHD) (4), leukemias (1), autoimmune disorders (5–17), and neurological conditions such as autism and seizure disorders (18–22). With the exception of their increased risk of developing AD, which has been linked to the presence of the APP gene on chromosome 21 (3), little is known about the mechanisms underlying this differential clinical profile. Moreover, there is massive phenotypic variation among individuals with T21, which suggests the existence of factors modulating the effects of the extra chromosome, such as genetic variation, epigenetic modifiers, varying endotypes modulating the transcriptome, proteome and metabolome, lifestyle and environmental factors, or even perhaps the microbiome. Therefore, elucidating the mechanisms driving and modulating DS comorbidities will serve not only the six million people worldwide with DS alive today, but also millions of individuals affected by these comorbidities in the typical population. The INCLUDE Data Hub has reached a significant milestone of an MVP launch featuring both open-access and controlled data (via Kids First Gen3) on 21 March 2022. Here, we propose “Advancing the cloud-based data access and interoperability infrastructure of the INCLUDE data ecosystem” to empower more authorized researchers to access controlled INCLUDE data. This capability is beyond the scope of what we envision in the original INCLUDE DAPI proposal. Our focus is to develop and implement Clearinghouse software and integrate it with the DRS Server already developed for INCLUDE. The Clearinghouse receives and interprets the RAS Passport, and the custom visas contained, to ascertain the ability of a user to access controlled data (importantly, authorization continues to be governed by dbGaP). We will also provide feedback and advance the GA4GH specification pertinent to this effort, to drive these standards towards alignment with the INCLUDE Data Hub strategy.

PROJECT NARRATIVE The INCLUDE Data Hub has reached a significant milestone (MVP launch) featuring both open-access and controlled data. Investing in INCLUDE infrastructure that can serve controlled access data directly will empower more researchers with richer data; increasing the probability of advancing DS research. We will design, build, and integrate a Clearinghouse with the INCLUDE DRS Server and the NIH Researcher Auth Service (RAS) to create a secure and compliant system to serve controlled data within the INCLUDE Data Hub.