Abstract Sickle-cell disease (SCD) is a life-threatening inherited blood disorder of the !-globin gene that affects over 300,000 newborns globally each year, over 90% of which occur in low- and middle- income countries. Early childhood mortality has been virtually eliminated in high-resource settings through the establishment of newborn screening programs that enable timely diagnosis and treatment. In contrast, up to 90% of affected infants born with SCD in low-resource settings will die before age five without ever receiving a diagnosis. Current diagnostic methods are expensive and require laboratory equipment and trained personnel, making them financially and technically inaccessible to the countries with the greatest burden of SCD. The development of a rapid, low-cost, and easy-to-use diagnostic test that can be implemented at the point-of-care (POC) could enable early diagnosis and prompt initiation of preventative treatment, potentially saving the lives of over 50 million infants born with SCD by 2050. Many in- expensive protein-based methods have been developed and piloted, but lack of sensitivity in the presence of high fetal hemoglobin, poor specificity in patients recently transfused, and lack of interpretability make these tests ineffective for newborn screening in settings that lack resources for confirmatory testing. Advances in isothermal amplification techniques and inexpensive paper- and plastic- based diagnostic platforms offer an opportunity to overcome existing limitations through the development of a DNA-based diagnostic that identifies the mutation in the !-globin gene encod- ing for sickled hemoglobin in an accurate, low-cost format that can be used in low-resource settings. In collaboration with an industrial partner that specializes in developing low-cost diagnostic platforms, Axxin Pty. Ltd., and a sponsor team based at Rice University and Texas Children's Hospital that specializes in POC diagnostic development, pediatric hematology, and evaluating technologies in low-resource settings, I will develop a novel, inexpensive (<$3/test), DNA amplification test to detect the point mutation responsible for SCD on an integrated platform, and eval- uate its performance and clinical utility in a low-resource setting. To accomplish this goal, we aim to (1) design and optimize a multiplexed isothermal amplification assay with lateral flow detection to detect and differentiate the genes encoding for normal and sickled !-globin chains, and integrate the assay into a paper- and plastic- cartridge; (2) develop a sample preparation procedure that is compatible with downstream amplification for a simple sample- to-answer workflow; and (3) evaluate performance and clinical utility in two pilot studies — one in Houston, TX and one in Lilongwe, Malawi. Completion of these aims will expand the ability of isothermal amplification methods to detect point mutations in DNA, provide the first demonstration of an integrated paper- and plastic- based nucleic acid...