Project Grant R43HL156685

USING MULTI-SPECTRAL IMAGING WITH MICROCHIP ELECTROPHORESIS TO ACCURATELY SCREEN NEWBORNS FOR SICKLE CELL DISEASE - PROJECT SUMMARY HEMOGLOBIN (HB) DISORDERS ARE AMONG THE WORLD'S MOST COMMON MONOGENIC DISEASES. NEARLY 7% OF THE WORLD'S POPULATION CARRY HB GENE VARIANTS. SICKLE CELL DISEASE (SCD) ARISES WHEN HB MUTATIONS ARE INHERITED HOMOZYGOUSLY (HBSS) OR PAIRED WITH ANOTHER SS-GLOBIN GENE MUTATION. GLOBALLY, AN ESTIMATED 400,000 BABIES ARE BORN ANNUALLY WITH SCD, AND 70%-75% ARE IN SUB-SAHARAN AFRICA (SSA). IT IS ESTIMATED THAT 50-90% IN SSA DIE BY THEIR 5TH BIRTHDAY, 70% OF THESE DEATHS ARE PREVENTABLE. EFFECTIVE MANAGEMENT OF SCD INVOLVES EARLY DIAGNOSIS, AND GENETIC COUNSELLING, AND, IMPORTANTLY, NATIONWIDE NEWBORN SCREENING (NBS). NBS PROGRAMS UTILIZING CENTRALIZED LABORATORIES HAVE DRAMATICALLY REDUCED SCD MORTALITY IN HIGH-RESOURCE COUNTRIES. NBS REQUIRES SENSITIVE DETECTION OF RELATIVELY LOW LEVELS OF HB VARIANTS IN THE PRESENCE OF HIGH FETAL HB (HBF). NORMAL HBA AND SICKLE HBS SHOULD BE ACCURATELY IDENTIFIED IN THE PRESENCE OF HIGH LEVELS (UP TO 90%) OF HBF. THE CURRENT GOLD STANDARD FOR HB VARIANT TESTING IS HIGH-PERFORMANCE LIQUID CHROMATOGRAPHY (HPLC), WHICH REQUIRES EXPENSIVE EQUIPMENT AND REAGENTS, HIGHLY TRAINED PERSONNEL, AND MODERN LABORATORIES. IN LOW- RESOURCE REGIONS, VERY FEW CENTRALIZED LABORATORIES CAN PERFORM COSTLY HB TESTING. TESTING IS NOT AVAILABLE TO THE LARGE PERCENTAGE OF INFANTS BORN OUTSIDE OF A MAJOR HOSPITAL OR CITY. THERE IS AN UNMET NEED FOR AFFORDABLE, PORTABLE, EASY-TO-USE, ACCURATE, POINT-OF-CARE (POC) TESTS TO FACILITATE DECENTRALIZED HB TESTING TO ENABLE NATIONWIDE NBS PROGRAMS. IN 2019, THE WORLD HEALTH ORGANIZATION (WHO) LISTED HB ELECTROPHORESIS AS AN ESSENTIAL IN VITRO DIAGNOSTIC IN LOW- AND MIDDLE-INCOME COUNTRIES. WE HAVE DEVELOPED A POC MICROCHIP ELECTROPHORESIS HB VARIANT TESTING SYSTEM, MICROCHIP ELECTROPHORESIS (MCE), UNDER THE PRODUCT NAME "GAZELLE HB VARIANT" BY HEMEX HEALTH, INC. MCE REPORTS HB PHENOTYPE, HB QUANTIFICATION (%HB), AND AN INTERPRETIVE STATEMENT SHOWING GENOTYPE (SUCH AS SCD, SICKLE CELL TRAIT, OR NORMAL). MCE HAS BEEN EXTENSIVELY VALIDATED FOR HEMOGLOBINOPATHIES, INCLUDING SCD, HEMOGLOBIN E DISEASE, AND THALASSEMIA. NEWBORNS AND INFANTS BELOW 6 WEEKS OF AGE HAVE VERY LOW CONCENTRATIONS OF HB VARIANTS OTHER THAN HB F WHICH IS HIGH, THEREFORE AN IMPROVEMENT TO LOWER THE LIMIT OF DETECTION (LOD) IS NEEDED TO SUPPORT NBS PROGRAMS WORLDWIDE. BY DECREASING THE LOD FROM THE CURRENT 10% TO 2%, NEWBORNS AND INFANTS CAN BE SCREENED WITH THIS AFFORDABLE SYSTEM. THE INNOVATION IN THIS SBIR PHASE I IS THE INTEGRATION OF MULTI-SPECTRAL IMAGING AND MACHINE LEARNING BASED DATA ANALYSIS CAPABILITY TO MCE TO DEVELOP MCE+ TO ACCURATELY SCREEN NEWBORNS FOR COMMON HB VARIANTS. WE PROPOSE THE FOLLOWING AIMS: AIM 1: INTEGRATE MULTI-SPECTRAL IMAGING AND MACHINE LEARNING ALGORITHM INTO THE MCE PLATFORM TO ENABLE IDENTIFICATION AND QUANTIFICATION OF HEMOGLOBIN VARIANTS IN NEWBORNS. AIM 2: PERFORM CLINICAL TESTING OF THE MCE+ MULTI-SPECTRAL NEWBORN SCREENING SYSTEM. SIGNIFICANCE OF THIS PROJECT IS THAT MCE+ IS THE ONLY AFFORDABLE POC SYSTEM FOR QUANTITATIVE AND OBJECTIVE HEMOGLOBIN VARIANT TESTING THAT ALLOWS SCREENING AT BIRTH.