A platform contributing multiple insights into human health

In addition to the array typing conducted by the REDS-III program, whole genome sequencing (WGS) was performed through the successful application to include the Brazil SCD cohort in the NHLBI Trans-Omics for Precision Medicine (TOPMed) program. The TOPMed program aims to advance precision medicine by integrating WGS and other omics data (metabolomics, epigenomics, transcriptomics, and proteomics) with clinical, behavioral, and environmental data. The objective is to gain unprecedented insights into the fundamental biological processes that underlie heart, lung, blood, and sleep disorders and assess the predictive ability of omics data in health for these conditions. (see https://topmed.nhlbi.nih.gov/)

Currently TOPMed has WGS and associated phenotype data for ~200,000 individuals, including the REDS-III Brazil SCD cohort members as well as over 3000 other persons with SCD from other cohort studies. So far 17 manuscripts have been published using WGS data from the Brazil SCD cohort and other TOPMed cohorts. Several of these manuscripts have been led by the REDS Brazil team and have focused on SCD genetics related to outcomes, including ischaemic stroke, genetic modifiers of vaso-occlusive events, white blood cell counts, and the diversity of variant alleles encoding Kidd, Duffy, and Kell antigens1-5. The SCD cohort also contributes to a wider set of analyses ranging from human telomere length regulatory genes to factors driving clonal hematopoiesis.6-9

During REDS-IV-P, two additional clinical sites were included in the SCD cohort study. The cohort now has participation of patients from five states in Brazil. The REDS-IV-P Brazil SCD cohort includes 3059 members (2053 continuing participants from REDS-III with an additional 1006 new cohort participants). In addition to blood specimen collection during REDS-IV-P, we collected urine samples, expanding the types of analyses we can achieve to include renal function and disease. We also have completed array typing of the REDS-III new cohort members using the TMA, allowing us to continue our investigation of genetic factors associated with adverse events in SCD. Further in REDS-IV-P, members of the SCD cohort participated in the Red Blood Cell – IMProving trAnsfusions for Chronically Transfused Recipients (RBC-IMPACT) study which seeks to identify the blood donor, component manufacturing and recipient factors associated with red cell survival following transfusion among chronically transfused SCD and Thalassemia patients in the U.S. and Brazil10 and https://clinicaltrials.gov/study/NCT05255445). The Brazil SCD cohort study started with the specific objective to centralize detailed clinical, laboratory, transfusion, and medical history data to conduct studies of SCD pathogenesis and transfusion complications. From the inception the scope and complexity of the data collected have increased. The SCD cohort study has become a major contributor to transfusion, hematology, and human biology questions directly through the work of REDS investigators and through our collaboration with other researchers. Opportunities to further characterize SCD from patient quality of life to specific genetic modifiers and metabolomic factors that alter the trajectory of disease have stemmed from the wide and deep characterization of the cohort members and the health care they receive. This approach of capacity building and active collaboration serves as a model for the Big Data WP. The insights we have gained from array and WGS typing of the SCD cohort and array typing of blood donors whose units were transfused to patients coupled with clinical and laboratory data provide a relevant example for how complex data from international sources can be brought together to advance patient care.