>> WELCOME EVERYONE. IT'S MY PLEASURE TO INTRODUCE TODAY'S SPEAKER FOR THE NIH DIRECTOR'S FRIDAY AFTERNOON LECTURE SERIES. ANNE SUMNER WILL TALK TO YOU ABOUT SOME ISSUES UNDERSTANDING HEALTH DISPARITIES WITH RESPECT TO HEART DISEASE AND DIABETES MOSTLY IN AFRICAN AMERICAN POPULATIONS. IS THE CHIEF OF THE ETHNICITY AND HEALTH SECTION IN THE DIABETES AND END KRAWLG BRANCH. SHE GOT HER MEDICAL DEGREE AT THE UNIVERSITY OF PENNSYLVANIA HUNG AROUND PENNSYLVANIA FOR A WHILE IN TERMS OF HER MEDICAL TRAINING AND FELLOWSHIP IN ENDOCRINOLOGY AND DIABETES AND THEN BECAME AN ASSISTANT PROFESSOR AT THE UNIVERSITY OF HEALTH SCIENCES. BEFORE WE RECRUIT HER TO NIH TO BECOME A STAFF CLINICIAN. AND THEN VERY SHORTLY AFTER THAT SHE WAS RECRUITED TO THE TENURE TRACK AND LAST YEAR WAS TENURED AS A SENIOR INVESTIGATOR AT THE NIH. AS I MENTIONED, HER INTEREST HAS BEEN IN SOME REALLY CRITICAL AREAS THAT AFFECT HEALTH DISPARITIES AND PARTICULARLY BIOMARKERS IN INDIVIDUALS OF AFRICAN DESCENT OR AFRICAN AMERICANS IN THIS COUNTRY. SHE IS SHOWN SOME OF THE MUCH HIGHLY REGARDED MARKERS THAT WE USE ARE PROBABLY NOT VERY PREDICTIVE IN MANY PEOPLE OF AFRICAN DESCENT. I DON'T THINK YOU'RE GOING TO TALK ABOUT THE GLYCERIDE TODAY ANNE BUT FOCUS ON WORK ASSOCIATED WITH GLYCATED HEMOGLOBIN WHICH IS GENERALLY USED CLINICALLY AND MAY HAVE SOME LACK OF RELEVANCE IN CERTAIN POPULATIONS. SO WITHOUT FURTHER ADIEU, ANNE DELIGHTED TO INTRODUCE YOU AND THE TALK TODAY IS ENTITLED SICKLE CELL TRAIT INTERFERES WITH THE DIAGNOSIS OF GLUCOSE TOLERANCE STATUS BY A1C. >> THANK YOU VERY MUCH. [INDISCERNIBLE] [NO AUDIO] ARE WE OKAY NOW? CAN YOU HEAR ME NOW? OKAY. IN 2010, THE AMERICAN DIABETES ASSOCIATION AND THE INTERNATIONAL DIABETES FEDERATION SAID A1C COULD BE USED AS A TEST TO DIAGNOSE DIABETES. AS IT IS A SIMPLE TO OBTAIN, IT'S BEEN ADOPTED GLOBALLY. BUT WITH WIDE SPREAD APPLICATION, THE RESULTS ARE UNCERTAIN. AND I WOULD LIKE TO CONTRIBUTE TO THAT UNCERTAINTY. BECAUSE THEY ALSO STATED THAT A1C CAN BE USED AS A SCREENING TEST TO DIAGNOSE DIABETES IN PEOPLE WITH SICKLE CELL TRAITS. AND THAT I'M GOING TO QUESTION. AND I WILL PRESENT DATA WHICH SHOWS USING ATC AS A SCREENING TEST IN POPULATIONS WITH A HIGH PREVALENCE OF SICKLE CELL TRAIT WILL LEAD TO FAILURE OF DIAGNOSIS. AND THEREFORE THE LOST OPPORTUNITY FOR EARLY INTERVENTION. BECAUSE PEOPLE WITH SICKLE CELL TRAIT WILL BE TURNED AWAY AT WHICH SHOULD HAVE BEEN A POINT OF ENTRY INTO THE HEALTHCARE SYSTEM. I BELIEVE THAT IT IS ESSENTIAL TO HAVE THE RIGHT SCREENING TESTS BECAUSE THEY HAVE THE POTENTIAL TO ELIMINATE OR MINIMIZE MANY HEALTH DISPARITIES. AND THAT'S WHY SCREENING TESTS HAVE BECOME A MAJOR FOCUS OF MY SECTION, ETHNICITY AND HEALTH. SO THE SCREENING TEST I'M GOING TO FOCUS ON TODAY IS A1C. AND I'M GOING TO DISCUSS IT IN RELATION TO SICKLE CELL TRAIT. AND I'M GOING TO PRESENT DATA FROM 99BK0002 WHICH IS ALSO KNOWN AS DIABETES AND HEART DISEASE RISK IN BLACK. BUT IN ORDER TO PUT THIS TALK IN CONTEXT, I'M GOING TO START OUT WITH A DISCUSSION OF THE EPIDEMIOLOGY OF DIABETES IN AFRICA AND THE IMPORTANCE OF SCREENING TESTS IN AFRICA. THIS SLIDE SHOWS YOU THE GLOBAL PROJECTIONS FOR THE PERCENT INCREASE IN DIABETES BETWEEN 2010 AND 2030. IT WAS PREPARED BY STATISTICIANS AND MATHEMATICAL MODELERS FROM THE INTERNATIONAL DIABETES FEDERAL RACE. AND IN THEIR DIAGRAM, AFRICA APPEARS THE MOST BOLDLY BECAUSE IT IS ANTICIPATED THAT THERE WILL BE A 98% INCREASE IN THE PREVALENCE OF DIABETES BETWEEN 2010 AND 2030 COMPARED TO 42% WHERE YOU CAN HARDLY SEE IT IN CANADA AND THE UNITED STATES. SO DIABETES IS A MAJOR HEALTH THREAT IN AFRICA. YES, CERTAINLY THERE IS A WORLDWIDE PANDEMIC OF TYPE 2 DIABETES, BUT THE GENETIC RISK IS HIGHEST IN AFRICA. WHY IS DIABETES EXPRESSING ITSELF NOW? IT'S BECAUSE IT'S A COMPLEX DISEASE WITH AN ENVIRONMENTAL COMPONENT. AND WHAT IS THAT ENVIRONMENT? WELL, THIS IS A FAST FOOD RESTAURANT IN NIGERIA AND THEY'RE EATING APPROPRIATELY ENOUGH AT A RESTAURANT CALLED MR. BIG. I WOULD LIKE TO POINT OUT THAT I BELIEVE THAT THE OLDEN ARCHES ON THIS B ARE MEANT TO SIMULATE THE GOLDEN ARCHES ON OUR FRIEND MCDONALD'S. THIS IS HOW PEOPLE USED TO GET AROUND IN AFRICA, AND THIS IS LAGOS IN NIGERIA NOW. WITH THIS ENVIRONMENT, DIABETES IS EXPLODING AND THAT'S WHAT'S HAPPENING. ANOTHER PROBLEM IS DIABETICS, DIABETES UNAWARENESS. HALF THE PEOPLE WITH DIABETES IN THE WORLD DON'T KNOW THEY HAVE IT. BUT 80% OF THE PEOPLE IN HALF CAUSE WITH DIABETES DON'T KNOW THEY HAVE IT. AND THAT'S WHY SCREENING TESTS ARE SO IMPORTANT, BECAUSE THEY WILL ALLOW US TO CORRECTLY DETERMINE THE INCIDENCE AND PREVALENCE OF THE DISEASE, AND THEN HEALTHCARE RESOURCES CAN BE PROPERLY ALLOCATED, AND THEN WE'D HAVE IMPROVED HEALTHCARE ACCESS. AND FOR THE INDIVIDUAL, WE CAN IDENTIFY DISEASE EARLY AT A TIME WHEN INTERVENTION CAN AFFECT OUTCOME. AND WE WANT TO POSITIVELY AFFECT OUTCOME BECAUSE THE SCREENING TESTS FOR DIABETES, WE HAVE DEVASTATING COMPLICATIONS WHICH INCLUDE BLINDNESS AND AMPUTATION. AND THERE'S ALSO DEATH, DEATH FROM CARDIOVASCULAR DISEASE AND IT ACCOUNTS FOR 80% OF THE DEATHS IN DIABETICS. I WOULD LIKE TO REPEAT THAT. CARDIOVASCULAR DISEASE ACCOUNTS FOR 80% OF THE DEATHS IN DIABETICS. COMING TO NIH IN 1998, I HAVE FOCUSED ON HEALTHCARE DISPARITIES. IN THE AMERICAN COLLEGE OF PHYSICIANS IN THE INSTITUTE OF MEDICINE HAVE BEEN VERY CONCERNED BECAUSE BLACKS HAVE WORSE METABOLIC HEALTH THAN WHITES EVEN AFTER ADJUSTMENT FOR SOCIO-ECONOMIC STATUS AND HEALTH INSURANCE. IT'S THE POSITION OF OUR GROUP THAT FAILURE OF SCREENING CONTRIBUTES TO THIS DISPARITY. AND THE REASON SCREENING TESTS FOR DIABETES AND CARDIOVASCULAR DISEASE FAIL IS BECAUSE MOST OF THEM REQUIRE TRIGLYCERIDE LEVELS TO BE HIGH TO TRIGGER INTERVENTION. BLACKS HAVE PARADOXICALLY LOW TRIGLYCERIDES HAVE HIGH RISK FOR CARDIOVASCULAR DISEASE. AS OUR GROUP WAS WORKING TO EXPLORE THE MECHANISMS FOR WHY LOW TRIGLYCERIDE ACTUALLY LEADS TO OBESITY, DIABETES AND HEART DISEASE IN BLACKS. WE EXTENDED OUR COHORT IN 2008 TO INCLUDE AFRICAN IMMIGRANTS LIVING IN THE UNITED STATES. IN 2010, WHEN THE AMERICAN DIABETES ASSOCIATION AND THE INTERNATIONAL DIABETES FEDERAL ACE RECOMMENDED AC1 OF THE SCREENING TEST, WE INCLUDED IT. NOW I INCLUDED IT NOT BECAUSE I WAS INTENDED TO CHALLENGE IT, BUT BECAUSE I'M A THOROUGHLY MODERN KNOWING AND I WANTED TO STAY UP TO DATE. BUT BY 2011, I BEGAN TO FEEL THIS TELLS WAS NOT WORKING AS A SCREENING TEST. AND I HAD A SUMMER STUDENT AND I ASKED HIM TO SYSTEMATICALLY ANALYZE OUR DATA. SO THAT'S THE BACKGROUND FOR HOW THIS STUDY GOT STARTED. AND NOW I NEED TO GIVE YOU BACK GROUND TO, IN ORDER FOR YOU TO INTERPRET OUR DATA. SO I NEED TO TELL YOU ABOUT HUMAN GLOBIN IN A1C BY HEALING YOU ABOUT HEMOGLOBIN. IT'S IN THE BLOOD CELLS AND ITS MAIN FUNCTION IS TO CARRY OXYGEN. THE STRUCTURE OF HEMOGLOBIN A FEW ALPHA GLOBIN AND BETA GLOBIN GENES. THOSE TWO NORMAL BETA CHAINS ARE MOST IMPORTANT TO OUR DISCUSSION TODAY AND THERE WILL BE MORE ON THAT LATER. NOW GLYCATED HEMOGLOBIN MEANS GLUCOSE IS BOUND TO HEMOGLOBIN BUT THE LOCATION IS NOT SPECIFIED. EVERYONE HAS GLYCATED HEMOGLOBIN. IT'S A QUESTION OF DEGREE. UNCONTROLLED DIABETICS HAVE VERY HIGH LEVELS OF GLYCATED HEMOGLOBIN. CONTROLLED DIABETIC AND THOSE OF US WITHOUT DIABETES HAVE LOW LEVELS OF GLYCATED HEMOGLOBIN BUT WE ALL HAVE GLYCATED HEMOGLOBIN. A1C IS A FORM OF GLYCATED HEMOGLOBIN. GLUCOSE IS ALWAYS FOUND IN THE END TERMINUS OF THE DATA CHAIN IN A1C. ITING EXPRESSED THE PERCENT AND IN THE DENOMINATOR IS TOTAL HEMOGLOBIN. NORMAL A1C LEVELS ARE 4 TO 5.6%. HYPOGLYCEMIA OR LOW GLUED SUGAR IS ASSOCIATED WITH A1C BELOW 4 AND HYPERGLYCEMIA IS ASSOCIATED WITH GREATER THAN 4.6%. LET'S TALK ABOUT THE FORMATION OF A1C. THIS IS A HEMOGLOBIN MOLECULE. THAT'S THE EVEN TERMINAL OF THE BETA CHAIN AND HERE IS THE GLUCOSE. THEY BECOME LINKED AT THAT NUMBER ONE CARBON. IF YOU LOOK AT THAT DOUBLE BOND, IT BECOMES A SINGLE BOND, HAT HYDROXYL BECOMES A KETONE. YOU HAVE ERROR REVERSIBLE RELATIONSHIP NOW BETWEEN HEMOGLOBIN AND GLUCOSE. YOU HAVE HEMOGLOBIN A1C. WHICH IS A FERMENT OF GLYCATED HEMOGLOBIN. THE FACTORS WHICH AFFECT THE INTRACELLULAR GLIE INDICATION RATE OF HEMOGLOBIN WHICH IS FAST OR SLOW AND IS GENETICALLY DETERMINED PROVIDED YOU BELIEVE IN THIS CONTROVERSIAL TOPIC AT ALL. THE GLYCATION OF HEMOGLOBIN IS DEPENDENT ON THE CELL LIFE SPAN WHICH IS 120 DAY. THE LONGER THE LIFE SPAN OF THE RED BLOOD CELL THE GREATER THE CHANCE FOR GLYCATION. NOW THE HISTORY OF A1C ON AS A DIAGNOSTIC TEST IS THIS. IN 1997, IT WAS ALREADY IN USE TO MONITOR THERAPY BUT THAT'S WHEN IT WAS FIRST PROPOSED TO USE DIAGNOSTICALLY. BUT IT WAS REJECTED, BECAUSE THE ASSAYS ARE NOT STANDARDIZED AND THE RESULTS COULD BE, COULD NOT BE UNIFORMLY APPLIED TEMPORALLY OR CROSS POPULATIONS. BUT IN 2010, IT WAS RECOMMENDED AS A DIAGNOSTIC ALTERNATIVE TO THE ORAL GLUCOSE TOLERANCE TEST. SO WHAT HAPPENED IN 2010? STANDARDIZATION COMMITTEES MET AND THEY AGREED ON A WORLDWIDE HARMIZATION FOR THE ASSAY. ONCE THAT WAS DONE, THE ADA AND THE INTERNATIONAL EXPERT COMMITTEE RECOMMENDED A1C TO DIAGNOSE GLUCOSE TOLERANCE, AND AS AN ALTERNATIVE TO THE ORAL GLUCOSE TOLERANCE TEST. WHY DO WE WANT AN ALTERNATIVE TO THE ORAL GLUCOSE TOLERANCE TEST? BECAUSE YOU HAVE TO GO TO THE CLINIC AT 8:00 A.M. IN THE MORNING. YOU HAVE TO FAST FOR EIGHT HOURS. YOU HAVE TO GET A BLOOD STICK AND DRINK A MEASURED AMOUNT OF SUGAR WATER AND GET ANOTHER BLOOD STICK TWO HOURS LATER. IT'S TIME CONSUMING. TIME IS MONEY. PATIENTS HATE IT. AND A1C IS SO MUCH EASIER TO DRAW. IT'S ONE BLOOD DRAW ANY TIME OF DAY. SO TO DIAGNOSE GLUCOSE TOLERANCE STATUS BETWEEN 1979 AND 2009, YOU HAD TO HAVE A RANDOM GLUCOSE GREATER THAN 200 WITH SYMPTOMS, OR AN ORAL GLUCOSE TOLERANCE TEST WOULD BE THRESHOLDS. WHERE DO THOSE THRESHOLDS COME FROM? THEY CAME FROM THE ASSOCIATION BETWEEN DIABETIC RETINOPATHY AND GLYCEMIA. AND DIABETIC RETINOPATHY IS MICRO VASCULAR DISEASE. THE DATA COMES FROM NINE STUDIES IN KNIFE COUNTRIES WITH 45,000 PARTICIPANTS. THE 45,000 PARTICIPANTS HAD GRADED RETINAL PHOTOGRAPHS AND THAT'S WHY THEY COULD BE INCLUDED. AND THE FIVE COUNTRIES FROM WHICH THEY OBTAIN ARE AUSTRALIA, INDIA, JAPAN, SINGAPORE AND THE UNITED STATES. SO THESE THRESHOLDS WERE ACTUALLY SET IN WHITES AND ASIANS. NOW THESE ARE THE THRESHOLDS FOR FASTING AND TWO HOUR GLUCOSE THAT PREDICT PRE DIABETES AND DIABETES BASED ON RETINOPATHY. WITH THE INCLUSION OF A1C, A1C THEN WAS ADDED TO THE -- AT THESE THRESHOLDS THAT THEY ALSO PREDICTED RETINOPATHY. SO FROM FASTING GLUCOSE, TWO HOUR GLUCOSE AND A1C PREDICT MICRO VASCULAR DISEASE RETINOPATHY BUT THERE'S CORONARY HEART DISEASE. AND THIS MACROVASCULAR DISEASE IN PRE DIABETES PRECEDES THE ONSET OF THE MICRO VASCULAR DISEASE IN DIABETES. HOW LONG HAVE WE KNOWN THAT THE CORONARY HEART DISEASE PRECEDES THE MICRO VASCULAR DISEASE. SINCE 1990, WHEN USING DATA FROM THE PROSPECTIVE SAN ANTONIO HEART STUDY. THESE INVESTIGATORS ASK DOES A CLOT FOR CORONARY HEART DISEASE START BEFORE THE TICKING, START TICKING BEFORE THE ONSET OF CLINICAL DIABETES. AND THE ANSWER WAS YES. SO IT TURNS OUT THAT FASTING GLUCOSE AND TWO HOUR GLUCOSE PREDICTS CORONARY HEART DISEASE. AND TWO HOUR GLUCOSE DOES A MUCH BETTER JOB THAN FASTING GLUCOSE AND PREDICTING CORONARY HEART DISEASE. THAT'S VERY IMPORTANT BECAUSE 80% OF THE DEATHS IN DIABETICS ARE FROM CORONARY HEART DISEASE. WE HAVE NO DATA WHETHER A1C WILL PREDICT CORONARY HEART DISEASE. IF A1C REPLACE THE ORAL GLUCOSE TOLERANCE TEST, WE HAVE TO ASK WILL THE ABILITY TO PREDICT CORONARY HEART DISEASE BE LOST? NOW, INFORMATION ABOUT A1C AS A DIAGNOSTIC TEST. NOW WE NEED TO TALK ABOUT HEMOGLOBIN A1C IN POPULATIONS WITH A HIGH PREVALENCE OF HEMOGLOBINOPATHY. PARTICULARLY SICKLE CELL DISEASE AND TRAITS. SO IN HEMOGLOBIN A1C IT REQUIRES HEMAGLOBIN A. WELL THAT'S PROBLEMATIC IN THE PRINCIPAL OF SICKLE CELL DISEASE AND SICKLE SELL TRAITS. IN SICKLE CELL DISEASE HEMOGLOBIN A IS ABSENT AND IN SICKLE CELL TRAIT HEMOGLOBIN A IS DECREASED. SICKLE CELL DISEASE AND SICKLE CELL TRAIT AFFECT AFRICA BUT IT'S NOT THE ONLY AREA OF THE WORLD WHERE SICKLE CELL TRAIT AND DISEASE REIGN. THIS IS HEMOGLOBIN JUST TO GIVE YOU AN EXAMPLE. HEMOGLOBIN A IS NOT ACTUALLY A HUNDRED PERCENT. HEMOGLOBIN S IS ZERO PERCENT. FOR PEOPLE WITH SICKLE CELL TRAIT HEMOGLOBIN A IS NOT 50% IT'S BETWEEN 50 AND 60% AND HEMOGLOBIN S IS MUCH CLOSER TO 40%. THE PREVALENCE OF SICKLE CELL TRAIT IS 7 TO 8% IN AFRICAN AMERICANS. BUT IN EQUITORIAL AFRICANS IT'S 10-40%. SO IF THERE'S A CHALLENGE IN RELATIONSHIP TO USING A1C IN POPULATIONS WITH SICKLE CELL TRAITS, AFRICA WILL BE DISPROPORTIONATELY EFFECTIVE. NOW THIS IS THE DNA SEQUENCE OF THE BETA CHAIN OF HEMOGLOBIN A ON CHROMOSOME 11. THIS IS THE BETA CHAIN AND THIS IS FOR HEMOGLOBIN S. YOU CAN SEE THERE'S A SINGLE NUCLEOTIDE CHANGE SO THAT ACID BECOMES -- NOW IN SICKLE CELL DISEASE THERE'S NO HEMOGLOBIN A. A1C IS UNMEASURABLE AND [INDISCERNIBLE] [NO AUDIO] ARE AWARE OF THE DIAGNOSIS, OKAY. BUT IN SICKLE CELL TRAITS YOU HAVE 55% OF HEMOGLOBIN IS HEMOGLOBIN A. A1C IS MEASURABLE BUT IT'S LOWER THAN NORMAL BECAUSE YOU HAVE LESS HEMOGLOBIN A AND YOU HAVE SMALLER RED BLOOD CELLS. MOST PEOPLE WITH SICKLE CELL TRAIT ARE UNAWARE THAT THEY HAVE IT. SO I REPEAT, A1C IS LOWER THAN NOW BECAUSE THEY HAVE LESS HEMOGLOBIN A. THEY ALSO HAVE SMALL RED BLOOD CELLS, AND MOST PEOPLE WITH SICKLE CELL TRAIT ARE UNAWARE THAT THEY HAVE IT. NOW WE NEED TO LOOK AT THE RELATIONSHIP BY RACE OF GLYCEMIA TO A1C BECAUSE THESE THRESHOLDS WERE SET IN WHITES AND ASIANS. SO IS THERE A RACE DIFFERENCE, IS THERE EFFECT OF SICKLE CELL TRAITS AND IS THE ASSAY ACCURATE IN THE PRESENCE OF SICKLE CELL TRAITS? THIS HIGHLY QUOTED STUDY THEY EXAMINED THE RELATIONSHIP BETWEEN GLYCATED HEMOGLOBIN ON THE Y AXIS AND GLUCOSE ON THE X AXIS. THE ORANGE ARROW REPRESENTS WHITE PEOPLE AND THE ORANGE ARROW REPRESENTS AFRICAN AMERICAN PEOPLE AND THE BLUE ARROW REPRESENTS WHITE PEOPLE. AND YOU CAN SEE AT EVERY LEVEL OF GLYCEMIA, GLYCATED HEMOGLOBIN IS HIGHER IN BLACKS THAN WHITES. SO YES THERE ARE RACE DIFFERENCES IN THE RELATIONSHIP OF A1C TO GLUCOSE. NOW, IN THIS STUDY BY THE SAME GROUP, THEY INCLUDED AFRICAN AMERICANS WITH AND WITHOUT SICKLE CELL TRAITS. SO AGAIN THE BLUE ARROW REPRESENTS WHITE PEOPLE. THIS BIG RED ARROW REPRESENTS AFRICAN AMERICANS WITH SICKLE CELL TRAITS, AND THIS OTHER RED ARROW ALSO REPRESENTS AFRICAN AMERICANS WITHOUT SICKLE CELL TRAITS. AND YOU CAN SEE THAT THE LINES OVERLAP 100%. SO AFRICAN AMERICANS WITH OR WITHOUT SICKLE CELL TRAITS HAVE NO DIFFERENCE IN THE RELATIONSHIP OF GLUCOSE TO A1C. SO IS THERE A RACE DIFFERENCE? YES. AND MAYBE DIFFERENT THRESH HOLDS WILL BE NECESSARY. IS THERE AN EFFECTIVE SICKLE CELL TRAIT? NO. IS THE ASSAY ACCURATE IN THE PRESENCE OF SICKLE CELL TRAIT? WE STILL HAVE TO ASK THAT QUESTION BECAUSE HISTORICALLY THE ASSAY HAS FAILED IN SICKLE CELL TRAITS. SO PHYSICAL CHEMISTS AND CLINICAL CHEMISTS HAVE WORKED ON THIS PROBLEM. AND IN THIS FIGURE FROM THE CLINICAL PATHOLOGY LITERATURE. THE GOLD STANDARD IS ON THE Y AXIS AND IF THE MEASURE OF THE PHYSICAL CHEMISTRY CHARACTERISTICS OF HEMOGLOBIN A1C. AND ON THE X AXIS ARE MEASURES USED IN LABORATORIES AND HOSPITALS AND THEY'RE BASED ON CHARGE. AND YOU CAN SEE AS BY 2008, PEOPLE WITH HEMOGLOBIN, SICKLE CELL TRAITS THAT THOSE ASSAYS COULD CRAFT ACCURATELY MATCH UP WITH THE GOLD STANDARD THAT'S WHY THEY MATCH UP ON THE DOTTED LINE. I PUT THE SEA CUR KULZ HERE TO SHOW YOU THE ASSAYS USED AT THE NIH CLINICAL CENTER. IT'S NOT JUST CLINICAL LABS THAT ARE AGREEING THAT A1C IS ACCURATE IN PEOPLE WITH SICKLE CELL TRAIT. THE GOVERNING BODY THE NATIONAL GLYCOHEMOGLOBIN STANDARDIZATION PROGRAM IS BASICALLY AUGUST 2012 HAVE SAID ALL OF THOSE ASSAYS ARE CORRECT IN TELLING YOU WHAT A1C IS IN PEOPLE WITH SICKLE CELL TRAIT. AND THE TWO RED ARROWS ARE AGAIN TO SHOW YOU WHAT IS USED IN THE NIH CLINICAL LAB. NOW WE'RE ALL SET. A1C ASSAYS ARE VALID AND THEY CORRECTLY REPORT A1C IN SICKLE CELL TRAITS. SO WE CAN PROCEED WITH OUR ANALYSIS. AND ASK THE QUESTION, CAN A1C REPLACE THE ORAL GLUCOSE TOLERANCE TEST FOR THE DIAGNOSIS OF GLUCOSE TOLERANCE STATUS IN AFRICANS. WE HAVE AT THIS TIME 154 AFRICANS LIVING IN THE UNITED STATES. THEY ARE SELF IDENTIFIED AS HEALTHY, AND YOU CAN SEE THEIR AFRICAN REGION OF ORIGIN. THEY'RE ALL FROM EQUITORIAL AFRICA. EVERYONE HAD A GLUCOSE TALL RUN TEST IN A FREQUENTLY SAMPLED INTRAVENOUS GLUCOSE TIMES TEST. I ALREADY TOLD YOU WHAT AN ORAL GLUCOSE TOLERANCE TEST IS SO LET ME BRIEFLY TELL YOU ABOUT FREQUENTLY SAMPLED INTRAVENOUS CALL TRUNS TEST. GLUCOSE IS GIVEN, 20 MINUTE INSULIN INJECTION IS GIVEN. YOU GET 32 BLOOD DRAWS IN THREE HOURS. YOU PUT IT IN A MATHEMATICAL MODEL AND YOU KNOW WHAT IT IS FOR THAT INDIVIDUAL. SO EACH PARTICIPANT HAD AN ORAL GLUCOSE TOLERANCE TEST OF FREQUENTLY SAMPLED INTRAVENOUS GLUCOSE TOLERANCE TEST, AN A1C BY A CERTIFIED METHOD. AND SO NOW WE WILL DETERMINE THE EFFICACY OF A1C WITH ORAL GLUCOSE TOLERANCE AS A GOLD STANDARD AND WE'LL RELATE A1C TO MACRO VASCULAR RISKS. IN OUR RESULTS WE SHOWED THAT THE PREVALENCE OF SICKLE CELL TO BE OF 20%. THAT'S GOOD BECAUSE WE PREDICTED BETWEEN 10 AND 40%. THE ENTIRE COHORT THERE WAS ABSENCE OF ANEMIA HIGHER DEFICIENT HYPER -- AND UREMIA. THAT'S IMPORTANT BECAUSE THOSE FOUR FACTORS CAN CHANGE A1C INDEPENDENT OF THE LEVEL OF GLYCEMIA. JUST TO SHOW YOU HOW SIMILAR THE TWO GROUPS WERE, I'D LIKE YOU TO SEE THAT THERE WAS NO DIFFERENCE IN SIX, DISTRIBUTION AGE OR BMIIN THE TWO GROUPS. NEITHER GROUP WAS ANEMIC BUT THE SICKLE CELL TRAIT HAD SMALLER RED BLOOD CELL CONSISTENT WITH SICKLE CELL TRAIT. NEVER GROUP WAS IRON DEFICIENT. THE GROUP WITH SICKLE CELL TRAIT DID HAVE HIGHER BILIRUBIN LEVELS. THEY HAD HIGHER BILIRUBIN LEVELS WITHIN THE NORMAL RANGE. AND NEITHER GROUP YEW REAMIC. THE PERCENT GLUCOSE INTOLERANCE MEANS FASTING GLUCOSE -- AND DIABETES WAS IDENTICAL. YOU'RE NOT GOING TO GET MUCH BETTER THAN.95 IN TERMS OF BETA CELL FUNCTIONS THERE'S NO DIFFERENCE IN THE TWO GROUPS. SO WE EXPECT NO DIFFERENCE IN A1C. BUT THESE ARE OUR RESULTS FOR A1C IN A BOX AND WHISTLE CUR CLOT WITH NORMAL HEMOGLOBIN ON THE LEFT AND SICKLE CELL TRAIT ON THE RIGHT. IN THIS BOX YOU CAN SEE THE 50TH, 5TH AND 90 PERCENTILE. THE DIFFERENCE WAS CLEAR BY THE FIGURE THAT SICKLE CELL TRAIT PEOPLE HAVE LOWER A1C, EVEN THOUGH THE LEVEL OF GLYCEMIA WAS EXACTLY THE SAME. COME JOIN US. AND SO WHAT ABOUT THIS DATA THAT I SHOWED YOU THAT'S QUOTED OVER AND OVER AGAIN. AFRICAN AMERICANS WITH OR WITHOUT SICKAL CELL TRAIT HAVE THE SAME RELATIONSHIP BETWEEN A1C AND GLUCOSE. WHAT ACCOUNTS FOR THE DIFFERENCE BETWEEN MY DATA AND THIS PUBLISHED DATA? WELL, THEY EXCLUDED EVERYONE WITH A1C LESS THAN 5%. THEY SAID THAT THAT WAS KEPT WITH HYPO GLYCEMIA. BUT NORMAL A1C ACCORDING TO THE NIH CLINICAL CENTER IS 4.8 TO 6.4%. AT THE MAYO CLINIC THEY CONSIDERED 4.5 TO 6%. THE AMERICAN DIABETES ASSOCIATION AND WEB MD SAYS THAT NORMAL A1C, GOT TO GET YOUR DATA SOMEWHERE, IS 4 TO 5.6%. THIS IS A1C DISTRIBUTION ON A POPULATION BASIS FROM M HAINES POPULATION BASE DATA COLLECTED BY THE CENTERS FOR DISEASE CONTROL, NON-DIABETIC NON-HISPANIC WHITES, MEXICAN AMERICANS AND NON-HISPANIC PLAQUES. IN THESE NORMAL PEOPLE, IF I PUT THE LINE THERE AT 5, THEY WOULD BE EXCLUDING ALL OF THESE NORMAL PEOPLE FROM THEIR ANALYSIS. SO BY EXCLUDING ANYONE WITH A1C LESS THAN 5%, THEY WERE EXCLUDING MANY NORMAL PEOPLE. AND THEY WERE EXCLUDING MANY PEOPLE WITH SICKLE CELL TRAIT WAS SICKLE CELL TRAIT IS ASSOCIATED WITH LOWER A1C BECAUSE THEY HAVE LOWER LEVELS OF HEMOGLOBIN A. NOW THIS IS MY DATA WITH UNRESTRICTED A1C. WHAT ABOUT IF I ONLY INCLUDED PEOPLE WITH AN A1C GREATER THAN FIVE. IT'S PRETTY IDENTICAL TO ME. NOW THEY PREDICTED A1C BASED ON A MULTIPLE REGRESSION ANALYSIS. SO I DID THE SAME MULTIPLE REGRESSION ANALYSIS. THE RELATIONSHIP BETWEEN A1C AND GLUCOSE WAS IDENTICAL AS LONG AS I EXCLUDED THE PEOPLE WITH A1C GREATER THAN 5. BECAUSE WHEN I HAD UNRESTRICTED A1C LEVELS, THEN THERE WAS A SIGNIFICANT DIFFERENCE IN THE RELATIONSHIP BETWEEN A1C AND GLUCOSE. NOW THEY'VE PROVIDED US WITH GRAPHS OF PREDICTED A1C INSTEAD OF ACTUAL DATA. I THINK ACTUAL DATA'S BETTER BUT THEY USED PREDICTED A1C, SO DID I. DOING THE SAME ANALYSIS, PREDICTED A1C VERSUS FASTING DPLOO COAST AND THE TWO LINES OVERLAP. WHAT ABOUT IF I USED UNRESTRICTED A1C. THERE'S A DISTINCT DIFFERENCE BETWEEN THOSE WITH AND WITHOUT SICKLE CELL TRAITS. SO BY EXCLUDING PEOPLE WITH A1C LESS THAN 5%, ARE THEY SIGNIFICANTLY DECREASE THE AT RISK POPULATION THAT INTRODUCE SYSTEMIC BIAS AND THEY DISSEMINATED MISINFORMATION. NOW THAT IS STRONG LANGUAGE BUT I BELIEVE SHOWING YOU DATA FROM 99BK0002 AND POPULATION-BASED DATA FROM M HAINES THAT EXCLUDING PEOPLE WITH A1C LESS THAN 5 WAS NOT VALID. AND THE CONSEQUENCES THAT PEOPLE WITH SICKLE CELL TRAIT AND EITHER PREDIABETES OR DIABETES WILL HAVE A LOW A1C. AND THIS WILL BE INTERPRETED AS NORMAL AND THEIR DOCTOR WILL NOT OFFER THEM MEDICAL CARE. THEY WILL NOT BE OFFERED MEDICAL CARE AT A TIME WHEN INTERVENTION COULD IMPROVE OUTCOME. SO THAT'S A PROBLEM. BUT HAVING RECOGNIZED IT, WE CAN PROCEED WITH THE ANALYSIS OF OUR DATA. SO, EVEN WHEN THE DEGREE OF GLYCEMIA IS THE SAME, A1C IS LOWER AND AFRICANS WITH SICKLE CELL TRAITS THAN AFRICANS WITHOUT SICKLE CELL TRAITS. BUT WE STILL DO NOT KNOW IF A1C CAN DIAGNOSE GLUCOSE TOLERANCE STATUS IN EITHER GROUP. BUT WHEN WE ASK THE QUESTION NOW, CAN A1C REPLACE THE ORAL GLUCOSE TOLERANCE TEST FOR THE DIAGNOSIS OF GLUCOSE TOLERANCE STATUS IN AFRICANS, I'M GOING TO DIVIDE THE PARTICIPANTS INTO TWO GROUPS. THOSE WITH AND WITHOUT SICKLE CELL TRAITS. AND I'M GOING TO USE THE STANDARD METHODOLOGY TO DETERMINE THE EFFICACY OF A1C WITH THE ORAL GLUCOSE TOLERANCE TEST AT THE GOLD STANDARD. WE'RE GOING TO USE THESE TESTS LISTED ON THE RIGHT. JUST TO GIVE YOU AN IDEA FOR HOW THEY WORK. IN THE BOX I HAVE COMPARISON TESTS ON THE Y AXIS AND GOLD STANDARD ON THE TOP. SO A1C IS THE COMPARISON TEST, AND THE ORAL GLUCOSE TOLERANCE IS THE GOLD STANDARD ON THE TOP. NOW, IF THE A1C SAYS DIABETES AND THE OGTT SAYS DIABETES IT'S A TRUE POSITIVE IT'S YELL OVAL IF THE A1C SAYS DIABETES BUT THE OGT SAYS NO IT'S A FALSE POSITIVE IT'S GREEN. IF THE A1C SAYS IT'S NOT DIABETES BUT THE OGT SAYS IT IS DIABETES, ARE IT IS DIABETES AND THAT'S A FALSE NEGATIVE. IF THE A1C SAYS NO AND THE OGT SAYS NO, THAT'S A TRUE NEGATIVE. SO THOSE ARE THE ABBREVIATIONS FOR THE FORMULAS AND BASICALLY THOSE ARE GOOD BECAUSE THEY'RE TRUE AND THOSE ARE BAD BECAUSE THEY'RE FALSE. THESE ACTUAL NUMBERS, AND I PROVIDE YOU WITH THE ACTUAL NUMBERS SO YOU KNOW YOU HAVE TRUTH IN ADVERTISING ABOUT OUR SAMPLE SIZE. BASICALLY THESE ARE GOOD BECAUSE THEY'RE TRUE AND THOSE ARE BAD BECAUSE THEY'RE FALSE. NOW THE SENSITIVITY IN THE NORMAL HEMOGLOBIN GROUP WAS 54%. AND IN THE SICKLE CELL TRAIT GROUP, IT WAS 40%. SO THAT'S NOT GOOD IN EITHER GROUP BUT IT IS CERTAINLY BETTER IN THE NORMAL HEMOGLOBIN GROUP. SO LET'S LOOK AT DATA THAT'S PUBLISHED AND HOW OUR RESULTS BACK UP TO WHAT'S IN THE LITERATURE. IT TURNS OUT THAT THESE STUDIES HAVE BEEN DONE SINCE 2010 WHEN THE RECOMMENDATION WAS MADE AND THE SENSITIVITIES ONLY AND ALL THE OTHER POPULATIONS TESTED BETWEEN 50 AND 60%. THAT'S TERRIBLE SENSITIVITY PERCENTAGE. IF YOU WANT TO USE THIS TEST FOR SCREENING, YOU WANT TO HAVE A SENSITIVITY OF 70, 80 OR 90%. NOW THIS IS DISCUSSED AT THE AMERICAN HEART ASSOCIATION MEETING THE FIRST WEEK IN NOVEMBER. AND THEY HAVE, TO BE PUBLISHED, A1C LEVELS ON THOUSANDS OF PEOPLE FROM STORED SAMPLES FROM LARGE COHORTS AND THEY SAY THAT DIABETES WILL BE MISSED IN 30 TO 50% OF THE PEOPLE THAT HAVE IT, IF WE USE A1C. BUT IT'S OKAY. IT'S OKAY BECAUSE WE'RE GOING TO BE IDENTIFYING SO MUCH MORE PEOPLE BECAUSE WE'RE GOING TO BE TESTING SO MUCH MORE PEOPLE. WELL, I SUGGEST IT'S NOT REALLY OKAY AND THAT IN SEVEN TO 10 YEARS A1C WILL NOT BE USED AS A DIAGNOSTIC TEST FOR DIABETES. AT LEAST WHAT I CAN SAY NOW IS THAT IN AFRICAN IMMIGRANTS IT'S NO BETTER OR WORSE THAN IN OTHER POPULATIONS. BUT I CONSIDER IT CONTROVERSIAL THE USE OF A1C, THE PEOPLE WITH NORMAL HEMOGLOBIN. LIKE I SAID IT IS BEING HOTLY DEBATED IN THE DIABETES LITERATURE. IN TERMS OF AFRICANS WITH SICKLE CELL TRAIT, YOU HAVE A SENSITIVITY OF 40%. YOU'RE MORE OFTEN WRONG THAN RIGHT. YOU CAN REJECT THAT NOW AND IT WOULD NOT BE A CONTROVERSIAL STATEMENT. SO CLEARLY A1C AND SICKLE CELL TRAITS IS NOT REFLECTING GLYCEMIC STATUS. BECAUSE AFRICAN IMMIGRANTS WITH OR WITHOUT SICKLE CELL TRAIT HAVE THE SAME DEGREE OF GLYCEMIA BUT A1C IS LOWER IN PEOPLE WITH SICKLE CELL TRAITS. SO IF A1C IS NOT AN EFFECTIVE DIAGNOSTIC TEST IN SICKLE CELL TRAIT IS THE ASSAY, THE ANSWER IS NO. BECAUSE IF YOU TAKE A BLOOD SAMPLE FROM SOMEONE WHO HAS SICKLE CELL TRAITS AND YOU MEASURE IT BY CHEMICAL PHYSICAL METHODS OR BY CHARGE, YOU'RE GOING TO GET THE SAME ANSWER. SO A1C ASSAYS THAT ARE CERTIFIED THAT ARE USED IN HOSPITAL LABORATORIES ARE CORRECTLY REPORTING WHAT A1C IS IN THOSE INDIVIDUALS. SO THE ASSAY'S OKAY. SO IF IT'S NOT THE ASSAY, THEN A1C IS NOT REFLECTIVE OF GLUCOSE TOLERANCE STATUS IN THIS POPULATION. WHY IS A1C NOT REFLECTIVE OF GLUCOSE TOLERANCE? THAT REMAINS TO BE DETERMINED. THERE ARE A NUMBER OF HYPOTHESES THAT COULD BE ADDRESSED. BUT THE KEY IS, THAT ONCE PEOPLE SAW THAT THE A1C ASSAY WAS CORRECT, THEY NEVER WENT BACK AND CHECKED. WHETHER THE A1C AND THAT POPULATION WAS REFLECTIVE OF GLUCOSE TOLERANCE STATUS. AND THAT'S WHAT WE'VE DONE. AND THAT'S THE LOOP THAT WE'VE CLOSED. SO IF THE POPULATION HAS A HIGH PREVALENCE OF SICK AL CELL TRAITS SUCH AS EQUATORIAL OF COMES YOU HAVE TO OBTAIN PHORESIS RESULTS -- I AGREE, THAT'S A DEAL BREAKER. SO THE SENSITIVITY OF A1C WITH ORAL GLUCOSE TOLERANCE AS A GOLD STANDARD BASED ON OUR DATA WE CAN SAY THAT THE SENSITIVITY'S UNACCEPTABLE IN THE PRESENCE OF SICKLE CELL TRAITS. BUT NOW LET'S RELATE A1C TO CARDIOVASCULAR DISEASE. THE WAY THAT'S TRADITIONALLY DONE IN CROSS SECTIONAL STUDIES IS TO LOOK AT CORRELATIONS BETWEEN A1C AND FASTING AND TWO HOUR GLUCOSE. SO THIS IS THE CORRELATION BETWEEN FASTING GLUCOSE AND A1C IN PEOPLE WITH SICKLE CELL TRAIT. IN OTHER WORDS THERE'S THOUGH CORRELATION. SAME THING WITH TWO HOUR GLUCOSE. THERE IS NO CORRELATION. SO WE CANNOT USE A1C IN SICKLE CELL STRAIGHT PEOPLE TO DIAGNOSE GLYCEMIC OR VASCULAR RISK. WHAT ABOUT THE NORMAL HEMOGLOBIN GROUP. IN THE NORMAL HEMOGLOBIN GROUP, THERE IS A SIGNIFICANT CORRELATION BETWEEN FASTING GLUCOSE AND A1C PERCENT. NOW YOU CAN SAY YES, IT'S SIGNIFICANT. BUT THAT'S NOT THE BEST R VALUE YOU'VE EVER SEEN, AND I'VE SHOWN YOU THE DATA SO YOU CAN EVEN ATTACK IT YOURSELF. ON MY BEHALF. BUT WHAT I WANT TO SAY IS THAT OTHER GROUPS ARE ALSO REPORTING A CORRELATION BETWEEN FASTING GLUCOSE AND A1C. AND THIS IS THE QUALITY OF THE DATA THAT'S BEING PUBLISHED. THIS IS THE SAME IN OF -- AFRICANS AS OTHER GROUPS. THERE'S NO CORRELATION BETWEEN TWO HOUR GLUCOSE AND A1C. LET'S RELATE A1C TO TRADITION OF CARDIOVASCULAR RISK FACTORS. THIS TABLE WAS TAKEN FROM THE REFERENCE ON THE BOTTOM OF THE SLIDE. IN WHICH THEY LOOKED AT THE CORRELATION BETWEEN A1C FASTING GLUCOSE AND TWO HOUR GLUCOSE IN THESE TRADITIONAL CARDIOVASCULAR FACTORS IN THE IRISH COHORT. WHAT THEY FOUND WAS IDENTICAL TO WHAT WE FOUND. WHY IS THERE A SIGNIFICANT CORRELATION BETWEEN A1C AND FASTING GLUCOSE, THERE WAS NO OTHER CORRELATION BETWEEN A1C AND THE OTHER CARDIOVASCULAR RISK FACTORS BUT MANY CORRELATION, SOMETHINGANT CORRELATIONS WITH FASTING AND TWO HOUR GLUCOSE. BUT LET'S SAY LOOKING AT FASTING GLUCOSE BEING THE ONLY SIGNIFICANT CAUSE THAT THE ONLY PREDICTOR OF MICRO VASCULAR DISEASE IS THAT SUFFICIENT IN THE NORMAL HEMOGLOBIN GROUP OR DO WE NEED AN ALTERNATIVE TO FASTING GLUCOSE. AND I SAY WE NEED A TEST THAT SUBSTITUTES FOR TWO HOUR GLUCOSE. BECAUSE TWO HOUR GLUCOSE IS A BETTER PREDICTOR OF CARDIOVASCULAR DISEASE, THAT WHICH KILLS PEOPLE. AND IT'S A BETTER PREDICTOR OF PROGRESSION TO DIABETES. AND 73% OF THE OF COMES WITH PREDIABETES OR DIABETES IN MY STUDY AND 74% OF AFRICAN AMERICANS WITH PREDIABETES OR DIABETES IN MY OTHER STUDIES WERE NOT IDENTIFIED BY FASTING BLOOD GLUCOSE. THEY WERE IDENTIFIED ONLY BY ISOLATED ELEVATED TWO HOUR GLUCOSE. SO THEIR RISKS FOR MAX INCLUDE VASCULAR DISEASE WOULD NOT BE DETECTED UNLESS WE HAVE A MEASURE FOR THE TWO HOUR GLUCOSE. IT'S VERY INTERESTING HOW SIMILAR THE AFRICANS AND AFRICAN AMERICANS IN PEOPLE. SO WHILE THE CONTROVERSY AND UNCERTAINTY ABOUT A1C RAGES, I AM SURE YOU WANT TO ASK ME SO I THANK YOU FOR THE QUESTION, IS THERE AN ALTERNATIVE. MY GROUP IN COLLABORATION WITH DAVID -- IS WORKING ON AN ALTERNATIVE. THE ALTERNATIVE WE'RE PROPOSING IS GLYCATED ALBUMIN. IT'S A FORM OF FRUCTOSEMEAN. REMEMBER A C IS HEMOGLOBIN BOUND TO GLUCOSE. IT'S IRREVERSIBLE. IF YOU REPLACE THAT HEMOGLOBIN WITH AN ALBUMIN IRREVERSIBLY LINK TO THE GLUCOSE YOU'RE GOING TO HAVE GLYCATED ALBUMIN. FRUCTOSEMINE IS ANY SENIOR PROTEIN. GLYCATED ALBUMIN IS A FORM OF FREQUENT TOASTMEAN. ALBUMIN IS IRREVERSIBLY BOUND TO GLUCOSE. IT'S EXPRESSED AS PERCENT OF TOTAL GLUE TOAST. IT REFLECTS GLUCOSE CONTROL FOR 14-21 DAYS BECAUSE THAT'S THE LIFE SPAN OF ALBUMIN AND IT IS OUTSIDE THE RED BLUE CELL. NOW A1C TO REMIND YOU SO WE CAN COMPARE AND CONTRAST IS A FORM OF DPLIE INDICATED HEMOGLOBIN. HEMOGLOBIN IS IRREVERSIBLY BOUND TO GLUCOSE. IT'S EXPRESS OF TOTAL HEMOGLOBIN AND IT REFLECTS GLUCOSE CONTROL FOR 120 DAYS WHICH IS THE LIFE SPAN OF THE RED BLOOD CELL AND IT IS INSIDE THE RED BLOOD CELL. THIS IS OUR DATA FROM THE NEXT PHASE. WE HAVE EXTRACELLULAR GLYCATION AND INTRACELLULAR GLYCATION. OUTSIDE THE REMEMBER BLOOD CELL. HEMOGLOBIN INDEPENDENT IS GLYCATED ALBUMIN WHEREAS A1C REPRESENTS INTRACELLULAR GLYCATION SO INSIDE THE RED BLOOD CELL AND IT IS HEMOGLOBIN DEPENDENT. SO SICKLE CELL TRAIT SHOULD HAVE NO IMPACT ON GLYCATED ALBUMIN. AND WE CAN DETERMINE THE CORRELATIONS WITH FASTING AND TWO HOUR GLUCOSE. AND WE CAN DETERMINE IF EITHER CAN REPLACE THE ORAL GLUCOSE TOLERANCE TEST. SO THIS IS MY DATA WITH A1C. AND YOU CAN SEE THAT EVEN THOUGH THE LEVEL OF GLYCEMIA WAS IDENTICAL, SICKLE CELL TRAIT PEOPLE HAD LOWER A1C. BUT WHAT ABOUT GLYCATED ALBUMIN. THEY HAVE A SIMILAR DEGREE OF GLYCEMIA AND IDENTICAL LEVELS OF GLYCATED ALBUMIN. .92 IS PRETTY GOOD. SO THEREFORE WE CAN COMBINE THE AFRICANS WITH AND WITHOUT SICKLE CELL TRAIT INTO A SINGLE GROUP. WE CAN LOOK AT THE CORRELATION BETWEEN GLYCATED ALBUMIN AND FASTING GLUCOSE, AND THERE IS NONE. BUT WHAT ABOUT THE CORRELATION BETWEEN GLYCATED ALBUMIN AND TWO HOUR GLUCOSE. THAT'S A PROBLEM WE REALLY WANT TO SUBSTITUTE FOR. OUR SAMPLE SIZE, WE ARE SEEING A SIGNIFICANT CORRELATION. SO I SHOW YOU THE DATA OF THE R AND P VALUE FOR YOU TO INTERPRET. WE LOOKED BEFORE AT THE CORRELATIONS OF A1C WITH CARDIOVASCULAR RISK NARCOTICS. AND NOW WE NEED TO LOOK AT THOSE CORRELATIONS WITH GLYCATED ALBUMIN. WE CAN LOOK AT THOSE CORRELATIONS WITH ALL THE PARTICIPANTS. AND THERE ARE SIGNIFICANT CORRELATIONS WITH MACROVASCULAR DISEASE. SO GLYCATED ALBUMIN MIGHT BE ABLE TO PREDICT MACROVASCULAR DISEASE. THERE'S NO DATA ON WHETHER GLYCATED ALBUMIN WILL PREDICT MICRO VASCULAR DISEASE, SPECIFICALLY RETINOPATHY. BUT SINCE BOTH A1C AND GLYCATED ALBUMIN SHARE COMMON FEATURES, WE CAN BE HOPEFUL. AS GLYCATED ALBUMIN CAN BE USED IN POPULATIONS WITH HEMOGLOBINOPATHY, IF GLYCATED ALBUMIN IS SHOWN TO PREDICT MICRO AND MACRO, THERE'S A SPELLING ERROR THERE, MACROVASCULAR DISEASE, IT MIGHT SUPPLANT A1C. NOW SUPPLANT DOES NOT MEAN REPLACE. SAW PLANT MEANS OVERTHROW WITH TREACHERY. I'M NOT LOOKING FOR THE TREE REA PART BUT LOOKING TO OVERTHROW. I TOLD YOU ABOUT HEMOGLOBIN A1C. SICKLE CELL TRAIT I SHARED MY DATA WITH AFRICAN IMMIGRANTS AND I PRESENTED AN ALTERNATIVE TO A1C. SO IN THE CLOSING SECTION OF MY TALK, I'D LIKE TO SAY DIABETES IS AN ENORMOUS HEALTH THREAT IN AFRICA. THAT 80% OF AFRICANS WITH DIABETES ARE UNDIAGNOSED. SO EFFECTIVE SCREENING TESTS ARE IMPERATIVE. NOW THE PROJECTED NUMBER OF OF COMES AFFECTED BY DIABETES IN THE YEAR 2030 MAY BE 23.9 MILLION. IN THE NUMBER OF PEOPLE WITH PRE DIABETES WILL BE 47.3 MILLION. AND I RECOGNIZE THAT MY STUDY IS SMALL. IN THE 154 PEOPLE, ONLY 31 OF WHOM HAS SICKLE CELL TRAITS. HOWEVER I WOULD LIKE TO SUGGEST WITH A JOURNEY OF A THOUSAND MILES BEGINS WITH A SINGLE STEP. AS THIS STUDY IS NOW DESIGNED TO ANSWER THE QUESTION OF WHAT TESTS WILL PREDICT DIABETES IN AFRICANS. SO WE WILL CONTINUE TO COLLECT DATA FOR GLYCATED ALBUMIN. WE WILL DEVELOP THRESHOLDS OF RISK FOR GLYCATED ALBUMIN USING THE ROC CURVES AND INDEX. WE'LL HAVE JUSTIFICATION TO INVEST RESOURCES TO MEASURE GLYCATED ALBUMIN IN STORED SAMPLES FROM M HAINES THE RESISTANCE AND SCLEROSIS STUDIES AND THE SAAB ANTONIO STUDY. THOSE STUDIES ARE IMPORTANT BECAUSE THEY ALREADY HAVE DATA ON ORAL GLUCOSE TOLERANCE TESTS, RETINAL EXAMS AND PROSPECTIVE DATA ON CARDIOVASCULAR DISEASE. IN COLLABORATION WITH MY FRIEND AND COLLEAGUE CHARLES ROTINI, WE CAN USE DATA FROM THE AFRICA AMERICAN DIABETES STUDY WHICH IS PEOPLE FROM GHANA AND NIGERIA. WE CAN STUDY PEOPLE THROUGHOUT SUBSAHARA AFRICA. WE WANT TO CLOSE THE LOOP AND IDENTIFY SCREENING TESTS THIS AFRICA. NOW THE USUAL PARADIGM FOR SCREENING TESTS IS THAT THEY CAN'T SEE THE UNITED STATES BUT BELIEVE ME IT'S OVER THERE. THAT'S WHERE THEY COME FROM AND THEY'RE EXPORTED AROUND THE WORLD. BUT MAYBE SCREENING TESTS SHOULD BE OUT OF AFRICA. AND I SUGGEST TO YOU THAT IF GLYCATED ALBUMIN REPLACES HEMOGLOBIN A1C BECAUSE OF THE WORK THAT WE DID, IT WAS IN FACT OUT OF AFRICA. SO IN CLOSING, SCREENING TESTS FAIL GLOBALLY BECAUSE THEY ARE DEVELOPED AND INVALIDATED IN WELL DEFINED HOMOGENEOUS COHORTS WORLDWIDE. BUT THE POPULATION OF THE WORLD IS HETEROGENEOUS AND SCREENING TESTS APPLY TO POPULATIONS IN WHICH THEY WERE NOT VALIDATED MEANING HEALTHCARE RESOURCES ARE GOING TO BE INVESTED WITHOUT BENEFIT. AND THERE'S GOING TO BE HARM FROM MISDIAGNOSIS. THOSE IN NEED WILL NOT GET TREATMENT AND THOSE WITH NO RISK WILL BE GETTING UNNECESSARY TREATMENT. SO RAISING AWARENESS OF THE IMPORTANCE OF THE SCREENING TEST IS THE SECTION IN ETHNICITY AND HEALTH WILL MAKE A DIFFERENCE. I WOULD LIKE TO THANK -- WHO IS THE ASSOCIATE CHIEF OF THE SECTION OF ETHNICITY AND HEALTH AND SHE MAKES OUR STUDIES POSSIBLE. I HAVE EXCELLENT POST BACK -- WORKING WITH ME, MICHELLE O'CONNOR AND NATALIE RAMSEY AND ALFRED R ROVMENT TINI DID AN EXCELLENT JOB. I WOULD LIKE TO THANK RITA -- FOR HER WORK ON THE ALBUMIN ASSAY AND I WOULD LIKE TO THANK MY NIH COLLABORATORS. [NO AUDIO] THANK YOU FOR YOUR ATTENTION. [APPLAUSE] >> I'M SURE ANNE WILL BE HAPPY TO TAKE QUESTIONS AND I ASK THAT YOU GO TO THE MICROPHONE BECAUSE WE'RE BROADCASTING THIS TO OTHER SITES. AND IF YOU CAN'T, WE'LL JUST REPEAT THE QUESTION. MAYBE I SHOULD START. OKAY. THERE'S A QUESTION THERE. >> NO, BUT IT WON'T GO TO NORTH CAROLINA, TRUST ME. >> SO MICHELLE ALBERT. TWO QUESTIONS. WELL A STATEMENT AND A QUESTION. SO THIS GETS TO THE ISSUE OF SURROGATE BIOMARKERS AND DISEASE RISK. AND THERE IS ALWAYS THE ARGUMENT THAT AS YOU LOOK AT SURGOVERNMENT BIOMARKERS YOU NEED TO LOOK AT DISEASE COURSE. AND I WOULD LIKE YOU TO COMMENT ABOUT YOUR SUGGESTED BIOMARKER AS IT RELATES TO DISEASE COURSE IN THE SICKLE CELL POPULATION AND ITS POSSIBILITY FOR PREDICTION OF RISK, CERTAINLY FOR CARDIOVASCULAR RISK. THE NEXT QUESTION HAS TO DO WITH, IT'S A CLINICAL QUESTION. THERE HAVE BEEN SEVERAL WELL THERE'S BEEN A LARGE CLINICAL STUDY IN DIABETIC WHERE THEY LOOK ADD HEMOGLOBIN A1C LEVELS AND LOOKED AT THE REDUCTION OF HEMOGLOBIN A1C IN GLUCOSE LEVELS AND PATIENTS DIDN'T DO WELL WITH VERY LOW GLUCOSE OR THE HEMOGLOBIN A1C WAS NORMALIZED. I JUST WONDER HOW THAT FITS INTO THE CONTEXT OF YOUR CURRENT TALK. >> WELL, TAKING YOUR -- THOSE ARE TWO DIFFERENT ISSUES. HOW TO CONTROL PEOPLE THAT ARE ESTABLISHED DIABETICS AND WHAT LEVEL OF GLUCOSE THEY HAVE TO MANAGE THEM ONCE THEY HAVE ESTABLISHED CORONARY HEART DISEASE -- AS A SCREENING TEST TO DETECT EARLY DISEASE [NO AUDIO] LIKE YOU'RE DESCRIBING. SO THAT IS NOT RELEVANT TO THIS DISCUSSION, RELATIVE TO USING -- AS A SCREENING TEST. IN REGARD TO THE FIRST QUESTION, WE NEED MORE INFORMATION. THIS GLYCATED ALBUMIN HAS ONLY BEEN AVAILABLE FOR ABOUT 10 YEARS. THE ASSAY IS NOW STANDARDIZED OR IS BECOMING STANDARDIZED. IT'S NOT ACTUALLY EVEN FDA APPROVED. BUT WE NEED TO PROVIDE, LOOK AT GLYCATED ALBUMIN RELATIVE TO THOSE RETINAL PHOTOGRAPHS, THOSE 45 THOUSAND RETINAL PHOTOGRAPHS. WE ALSO NEED TO GET GLYCATED ALBUMIN IN POPULATIONS OF AFRICAN DESCENT. I DON'T BELIEVE GLYCATED AL BILLION WILL BE IN PEOPLE WITH OR WITHOUT SICKLE CELL TRAIT. IT WILL ELIMINATE THE PROBLEM OF HEMOGLOBINOPATHY. IT'S POSSIBLE THE GLYCATED ALBUMIN COULD REPLACE A1C BECAUSE IT WOULD BE BETTER INDEPENDENT OF HEMOGLOBINOPATHY TO PREDICT CORONARY HEART DISEASE. WE DON'T HAVE THE DATA. THIS IS JUST THE FIRST SHOT AT THE STUDY. THIS IS THE FIRST RUN THROUGH. NO ONE IS PREVIOUSLY REPORTED AN ASSOCIATION BETWEEN GLOW INDICATED AL -- GLYCATED ALBUMIN IN GLUCOSE. WE'RE COLLECTING THAT DATA TO FIND OUT WHAT IT IS. WE WANT TO GO FORWARD AND LET YOU KNOW AND HAVE YOU HELP US DESIGN STUDIES. >> VERY NICE TALK. MARK REDMAN. I WAS GOING TO ASK THE SAME QUESTION JUST ASKED IN A SLIGHTLY DIFFERENT WAY WHICH IS YOU'VE USED AS YOUR CARDIOVASCULAR RISK THE TWO HOUR GLUCOSE WHICH IS NOT -- PEOPLE PRODUCE A PRETTY GOOD PREDICTOR THAT WE KNOW THAT. SO THE QUESTION I WAS GOING TO ASK IS IF YOU CONSIDER TEST REPRODUCIBILITY FOR THINGS LIKE THE NEW A1C THAT'S BEEN VALIDATED FOR TEST REPRODUCIBILITY ON TWO HOUR GLUCOSE, COULD AN A1C IN A NON-SICKLE CELL POPULATION ACTUALLY BE A BETTER PREDICTOR OF TRUE CARDIOVASCULAR RISK, DEATH, YOU KNOW HARD ATTACK, STROKE OR CARDIOVASCULAR DEATH. >> THE DATA IN LARGE EPIDEMIOLOGICAL, IT'S JUST LIKE A1C AS A SCREENING TEST MISSES 30 TO 50% OF THE PEOPLE WITH DIABETES. IT'S ALSO BEING SHOWN IN THE LARGE STUDIES NOT TO DO AS WELL WITH CORONARY HEART DISEASE AND THAT IN THESE LARGE STUDIES LIKE SAN ANTONIO HEART STUDIES THE FASTING GLUCOSE BASELINE DID BETTER PREDICTING CORONARY HEART DISEASE AT A LATER TIME. BUT WE CAN ONLY DO CROSS SECTIONAL DATA AT THIS TIME WITH OUR SAMPLE SIZE. BUT ONCE WE PROVE THAT IT IS ASSOCIATED IN A CROSS SECTIONAL WAY, THEN WE CAN MOVE THE STORED SAMPLES THEN WE WOULD HAVE THE REASON TO ASK FOR MONEY IN THIS TIGHT CLIMATE OF MONEY, TO PROCEED WITH THESE OTHER STUDIES. THIS IS JUST THE FIRST STEP. >> THANK YOU. >> IS THERE ANYTHING KNOWN ABOUT GENETIC VARIATION IN ALBUMIN SEQUENCE? >> WELL, THAT'S A QUESTION VERY GOOD QUESTION AND THERE WILL BE PEOPLE THAT HAVE ABNORMAL ALBUMINS THAT YOU WILL NOT BE ABLE TO USE ALBUMIN AS A MARKER OF DIABETES RISK. BUT THE NUMBER OF PEOPLE WITH KNEE OF NEPHROTIC SYNDROME OR OTHER ISSUE RELAYED TO ALBUMIN IS GOING TO BE A LOT SMALLER THAN 10 TO 40% FOR EXAMPLE ON THE OF CONTINENT. >> I UNDERSTAND THAT YOUR GLYCATED ALBUMIN IS A PROPORTION OF TOTAL ALBUMIN. >> RIGHT. >> I'M A LITTLE CONCERNED BECAUSE THERE ARE SO MANY FACTOR THAT DETERMINE NORMAL ALBUMIN LEVEL INCLUDING NUTRITION WHICH MIGHT BE AN ISSUE IN CERTAIN POPULATIONS WHERE YOU'RE DOING THE SCREENING TESTS. BUT ARE YOU GOING TO HAVE TO, ARE YOU GOING TO HAVE TO VALIDATE WHETHER OR NOT THAT PROPORTION OF GLYCATED ALBUMIN HOLDS UP DIAGNOSTICALLY ACROSS DIFFERENT LEVELS OF BASELINE ALBUMIN IN TERMS OF DETECTING DIABETES. IS THAT CLEAR ENOUGH? >> YES, THAT'S CLEAR ENOUGH. THANK YOU. THANK YOU FOR THE QUESTION. WELL, I THINK AS A FIRST RUN-THROUGH, WE'RE LOOKING AT DIABETES IN THESE ARE HEALTHY NORMAL PEOPLE WHO DON'T KNOW THEY HAVE DIABETES. LOOKING FOR DIABETES IN MALNOURISHED ISSUE IS A COMPLETELY DIFFERENT STUDY. I DON'T HAVE AN ANSWER AT THIS TIME. I LIKE DAVID SACKS WALKING TO THE MICROPHONE. >> YOU HAVE NUTRITION, LIVER DISEASE ALL OF WHICH [INDISCERNIBLE] >> THANK YOU. >> DAVID SACKS. I HAVE A COMMENT ON THE PREVIOUS QUESTION AND THIS LAST ONE. SO THAT THE QUESTION ABOUT ALBUMIN VARIANCE IS ACTUALLY A VERY GOOD QUESTION. THEY ARE MUCH RARER THAN HEMOGLOBIN VARIANCE AS FAR AS WE KNOW. THERE HAVE BEEN SOME DESCRIBED AND ACTUALLY THE PIMA INDIANS WHO HAVE A EYE PREVALENCE OF TYPE TWO DIABETES HAVE A HIGH PREVALENCE OF AL BOOMEN VARIANCE. IT'S A SINGLE -- RESULTS IN A SUBSTITUTION THAT'S NOT A LYSINE. ALBUMIN GETS GLYCATED A LYSINES. WHETHER THIS MUTATION IN THE INDIANS -- IS NOT KNOWN. AND THERE ARE OTHER SEVERAL GLYCATED, SEVERAL OTHER ALBUMIN POINT MUTATIONS THAT HAVE BEEN DESCRIBED. BUT AGAIN IT'S NOT CLEAR HOW THEY WOULD AFFECT ALBUMIN GLYCATION. SO THE SECOND QUESTION RAISED IS A VERY GOOD QUESTION. AND THE GLYCATED ALBUMIN ASSAY WAS DEVELOPED IN JAPAN. IT'S BEEN USED VERY WIDELY IN JAPAN. IN FACT THEY USE IT, I DISCOVERED THAT THE JAPANESE GOVERNMENT WILL PAY FOR ONE GLYCATED ALBUMIN ASSAY A MONTH IN PEOPLE THAT ARELY DIAGNOSED WITH DIABETES FOR SIX MONTHS. THEY USE IT ON ALL THEIR PATIENTS. AND THEY HAVE EVALUATED PATIENTS IN WHOM IT'S NOT VALID AND CLEARLY PATIENTS WHO HAVE NEPHROTIC SYNDROME ALBUMIN AND CERTAIN OTHER PATIENTS THERE'S SOME OTHER RARE CONDITIONS. BUT OBVIOUSLY THE DETAILS HAVE TO BE EVALUATED IN TERMS OF PEOPLE WHO ARE MALNOURISHED AND SO WHETHER THIS WOULD BE VALID. EVEN CORRECTING FOR TOTAL ALBUMIN WHICH THE ASSAY DOES WOULD BE HELPFUL. CERTAINLY IF OBVIOUSLY THE LIFE SPAN OF ALBUMIN IS REDUCED THEN THE GLYCATION WILL BE REDUCED AND IT WILL BE TOO LOW SO YOU'LL HAVE THE SAME ISSUE. >> SO SPEAKING ABOUT THE LIFE SPANISH OR IN ONE OF YOUR EARLIER SLIDES YOU POINTED OUT THAT ONE REASON FOR REDUCED GLYCATED HEMOGLOBIN WOULD BE MORE RAPID TURNOVER OF RED CELLS. IF I REMEMBER MY MEDICINE CORRECTLY PEOPLE WITH SICKLE CELL TRAIT HAVE A POPULATION OF CELLS THAT IS SOMEWHAT ABNORMAL. YOU POINTED OUT THEY ARE SMALLER.' THERE'S BEEN EXTENSIVE STUDIES, LIFE SPAN STUDIES IN PEOPLE WITH SICKLE CELL TRAIT SAYING THEY DON'T HAVE DECREASED RED BLOOD CELL TURNOVER. IT'S A CONTROVERSIAL IN THE LITERATURE BUT I THINK THESE QUESTIONS, IT'S TURNS OUT THAT THE AMERICAN SOCIETY IS [NO AUDIO] EVERYONE ASSOCIATED [NO AUDIO] AT THIS HOSPITAL INSTITUTION OR AT THAT MEETING. AND THEY WOULD CONTRIBUTE TO A LIVELY DISCUSSION ON THAT TOPIC. SO THE ANSWER IS IT'S NOT COMPLETELY SETTLED. BUT WE WILL PROBABLY DISCUSS THAT AGAIN IN FEBRUARY BECAUSE I'M GIVING CLINICAL CENTER GRAND ROUNDS THEN. I'M GOING TO HAVE A LOT MORE GLYCATED ALBUMIN DATA AND WE'LL HAVE THE HEMATOLOGY PEOPLE HERE TO HELP US WITH THOSE ISSUES. >> ONE OF THE REASONS I'M ASKING I'M WONDERING HOW GENERALIZABLE THE ISSUE IS. ARE THERE PEOPLE WITH OTHER HEMOGLOBINOPATHIES THAT MAY BE CARRIERS DO THEY HAVE THE SAME PROBLEM. >> YES, EXACTLY. SICKLE CELL TRAIT WITH THE LIFE SPAN IS IN DEBATE. BUT IN OTHER PEOPLE WITH OTHER HEMOGLOBINOPATHIES THEY HAVE HIGH RED BLOOD CELL TURNOVER AND THEY CANNOT USE A1C, THAT'S CORRECT. >> I'M GOING TO GUESS THAT YOUR DATA IS ACTUALLY IN SUPPORT OF THE IDEA THERE'S SOME INCREASE TURNOVER OF RED CELLS IN SICKLE CELL TRAITS. >> WE DON'T DIRECTLY STUDY -- >> I UNDERSTAND. >> IT'S NOT IN [NO AUDIO] >> ANY OTHER QUESTIONS? OKAY, IF NOT, LET'S THANK ANNE. [APPLAUSE] SHE TOLD YOU ABOUT HER GRAND ROUNDS COMING UP, RIGHT. WHAT'S THE DATE FOR THAT? >> IT'S IN MID FEBRUARY. IT MIGHT BE FEBRUARY 15TH OR 16TH, WHATEVER THAT WEDNESDAY IS. >> WE'LL KEEP AN EYE ON THAT. >> THANK YOU VERY MUCH. THANK YOU TO EVERYONE.