PROJECT SUMMARY The Human Leukocyte Antigen (HLA) region on human chromosome 6p21 is the most medically important region of the human genome. Over 100 infectious, autoimmune and pharmacological disease phenotypes and cancers are associated with genetic variation of HLA, and matching of HLA genotypes is required for bone marrow and solid organ transplantation. HLA molecules have functional interactions with Killer cell Immunoglobulin-like Receptor (KIR) molecules, also recognized to play critical roles in transplantation and disease. The genes encoding these molecules are highly polymorphic and display extensive structural variation relative to other genomic regions. Recognizing the need to consolidate complex data from a broad field, in the prior project periods we developed a suite of tools and programs for the standardized analysis, collection, exchange and storage (ACES) of all current and future immunogenomic data. These tools serve to fill gaps in genomic data- management and analysis tools, which are primarily designed for use with single nucleotide polymorphism (SNP) and whole-genome and whole-exome sequence (WG/ES) data, and do not support the highly polymorphic genetic data characterized by the immunogenomic loci and other highly polymorphic genetic systems. Our standards and tools have been widely adopted by the immunogenomics community, but there remains an urgent and unmet need for integrated, easy-to use, clinical-grade tools that unify immunogenomic genotype, SNP and WG/ES data, while anticipating future genomic data formats. In the previous project periods, we have made substantial progress on the development of these tools and resources, which are designed to maximize the ongoing utility of immunogenomic data for clinical and basic research science. In the proposed project period, we will advance the development of these tools, expanding their scope and improving ease of use, centralizing their availability and enabling interoperability with electronic medical record (EMR) systems, and making them available adjacent to these highly complex datasets for application in translational medicine. We will expand the utility of our tools and services to accommodate additional data types and analytical methods, as well as integrating across methods. Building on our development of an infrastructure to support transmission of HLA data using HL7 FHIR resources, we will work to incorporate these resources into our data management tools and pipeline. Finally, we will build on an infrastructure developed to support aggregation and standardized analysis of HLA data in the context of COVID-19 to support additional data types and disease phenotypes for immunogenomic disease association studies. By integrating these resources, and other tools and services we have developed, and empowering them to generate FHIR messages, the products of these immunogenomic ACES resources can be made available and accessible to researchers and within health systems, i...