1 00:00:11,440 --> 00:00:13,640 Welcome to the Clinical Center Grand Rounds, 2 00:00:13,640 --> 00:00:17,440 a weekly series of educational lectures for physicians and 3 00:00:17,440 --> 00:00:20,080 health care professionals broadcast from the Clinical 4 00:00:20,080 --> 00:00:23,040 Center at the National Institutes of Health in 5 00:00:23,040 --> 00:00:24,840 Bethesda, MD. 6 00:00:24,840 --> 00:00:28,400 The NIH Clinical Center is the world's largest hospital totally 7 00:00:28,400 --> 00:00:32,080 dedicated to investigational research and leads the global 8 00:00:32,080 --> 00:00:35,040 effort in training today's investigators and discovering 9 00:00:35,040 --> 00:00:37,200 tomorrow's cures. 10 00:00:37,200 --> 00:00:46,600 Learn more by visiting us online at http://clinicalcenter.nih.gov 11 00:00:46,600 --> 00:00:48,320 I AM DELIGHTED TO INTRODUCE OUR 12 00:00:48,320 --> 00:00:51,840 SPEAKERS TODAY. 13 00:00:51,840 --> 00:00:54,560 DR. SWEE LAY THEIN AND DR. SAM 14 00:00:54,560 --> 00:00:55,200 MBULAITEYE. 15 00:00:55,200 --> 00:00:56,440 THEY WILL DELIVER A JOINT 16 00:00:56,440 --> 00:00:58,320 PRESENTATION SO I WILL INTRODUCE 17 00:00:58,320 --> 00:01:03,640 THEM BOTH AT THIS TIME. 18 00:01:03,640 --> 00:01:04,800 OUR FIRST SPEAKER, DR. SWEE LAY 19 00:01:04,800 --> 00:01:05,840 THEIN, IS SENIOR INVESTIGATOR 20 00:01:05,840 --> 00:01:08,000 AND CHIEF OF THE SICKLE CELL 21 00:01:08,000 --> 00:01:09,680 BRANCH AT THE NATIONAL HEART, 22 00:01:09,680 --> 00:01:13,920 LUNG, BLOOD, INSTITUTE SINCE 23 00:01:13,920 --> 00:01:16,120 MARCH 2015. 24 00:01:16,120 --> 00:01:18,440 PRIOR TO THIS TIME, SHE WAS 25 00:01:18,440 --> 00:01:19,640 PROFESSOR OF MOLECULAR 26 00:01:19,640 --> 00:01:21,600 HEMATOLOGY AND A CONSULTANT 27 00:01:21,600 --> 00:01:23,160 HEMATOLOGIST AT KINGS COLLEGE 28 00:01:23,160 --> 00:01:24,320 LONDON HOSPITAL, WHERE SHE 29 00:01:24,320 --> 00:01:25,680 SERVED AS CLINICAL DIRECTOR OF 30 00:01:25,680 --> 00:01:28,720 THE RED CELL CENTER. 31 00:01:28,720 --> 00:01:30,480 AT KCL, SHE WAS INVOLVED IN THE 32 00:01:30,480 --> 00:01:32,560 CARE OF 800 ADULT PATIENTS WITH 33 00:01:32,560 --> 00:01:33,760 SICKLE CELL DISEASE AND OTHER 34 00:01:33,760 --> 00:01:36,440 RED BLOOD CELL DISORDERS. 35 00:01:36,440 --> 00:01:37,880 SHE HAS PARTICIPATED AND 36 00:01:37,880 --> 00:01:39,640 DIRECTED A WIDE RANGE OF 37 00:01:39,640 --> 00:01:41,040 CLINICAL AND TRANSLATIONAL 38 00:01:41,040 --> 00:01:43,040 HEMATOLOGY RESEARCH ON INHERITED 39 00:01:43,040 --> 00:01:45,000 ANEMIAS, AND PARTICULARLY THE 40 00:01:45,000 --> 00:01:48,040 BETA HEMOGLOBIN DISORDERS. 41 00:01:48,040 --> 00:01:49,480 HER RESEARCH FOCUSES ON SICKLE 42 00:01:49,480 --> 00:01:50,680 CELL DISEASE TO BETTER 43 00:01:50,680 --> 00:01:51,880 UNDERSTAND HOW A SIMPLE MUTATION 44 00:01:51,880 --> 00:01:54,080 IN A SINGLE GENE CAN CAUSE 45 00:01:54,080 --> 00:01:56,360 DAMAGE IN MULTIPLE ORGANS AND 46 00:01:56,360 --> 00:01:58,840 THE EXTREME VARIABILITY IN 47 00:01:58,840 --> 00:02:00,320 SICKLE CELL DISEASE SEVERITY AND 48 00:02:00,320 --> 00:02:01,720 ALSO TO ACCELERATE TRANSLATION 49 00:02:01,720 --> 00:02:04,360 OF BASIC DISCOVERY TO THE 50 00:02:04,360 --> 00:02:05,880 THERAPEUTIC APPLICATION AND 51 00:02:05,880 --> 00:02:09,600 MANAGEMENT OF THESE DISEASES. 52 00:02:09,600 --> 00:02:11,640 IN 2022, DR. THEIN'S WORK IN 53 00:02:11,640 --> 00:02:13,640 SICKLE CELL DISEASE WAS CHOSEN 54 00:02:13,640 --> 00:02:15,600 BY SCIENTISTS AND AMONG THE 10 55 00:02:15,600 --> 00:02:17,920 BIGGEST SCIENCE STORIES AS 56 00:02:17,920 --> 00:02:19,120 PUBLISHED IN THE GUARDIAN IN THE 57 00:02:19,120 --> 00:02:20,120 U.K. 58 00:02:20,120 --> 00:02:22,520 THE STORY TITLED INCLUSIVE 59 00:02:22,520 --> 00:02:27,880 INRHODES FEATURES AN NIH STUDY 60 00:02:27,880 --> 00:02:33,560 OF METABABAT -- KINASE ACTIVATOR 61 00:02:33,560 --> 00:02:34,440 IN SICKLE CELL DISEASE AS PART 62 00:02:34,440 --> 00:02:37,480 OF A BROADER STORY ON INCLUSIVE 63 00:02:37,480 --> 00:02:40,560 SCIENCE WHERE GENDER, ETHNICITY 64 00:02:40,560 --> 00:02:41,960 AND LOCATION NEITHER PRIVILEGE 65 00:02:41,960 --> 00:02:42,640 NOR EXCLUDE. 66 00:02:42,640 --> 00:02:47,440 TURNING TO OUR SECOND SPEAKER, 67 00:02:47,440 --> 00:02:48,680 DR. SAM MBULAITEYE IS A SENIOR 68 00:02:48,680 --> 00:02:56,000 INVESTIGATOR IN THE INFECTIONS 69 00:02:56,000 --> 00:02:58,720 AND IMMUNOEPIDEMIOLOGY BRANCH AT 70 00:02:58,720 --> 00:02:59,360 THE NATIONAL CANCER INSTITUTE. 71 00:02:59,360 --> 00:03:00,600 HE CONDUCTS RESEARCH TO 72 00:03:00,600 --> 00:03:01,400 UNDERSTAND THE ETIOLOGY OF 73 00:03:01,400 --> 00:03:04,280 BURKITT LYMPHOMA, A CANCER THAT 74 00:03:04,280 --> 00:03:06,680 OCCURS WORLDWIDE BUT HAS ITS 75 00:03:06,680 --> 00:03:08,000 HIGHEST INCIDENCE RECORDED IN 76 00:03:08,000 --> 00:03:09,520 POPULATIONS OF SUB-SAHARAN 77 00:03:09,520 --> 00:03:10,000 AFRICA. 78 00:03:10,000 --> 00:03:12,160 HE IS A PRINCIPAL INVESTIGATOR 79 00:03:12,160 --> 00:03:14,480 OF A MULTI-COUNTRY CASE CONTROL 80 00:03:14,480 --> 00:03:16,760 STUDY CALLED THE EPIDEMIOLOGY OF 81 00:03:16,760 --> 00:03:21,600 BURKITT LYMPHOMA IN EAST AFRICAN 82 00:03:21,600 --> 00:03:25,200 CHILDREN IN SIX RURAL REGIONS IN 83 00:03:25,200 --> 00:03:30,840 AN UGANDA, TANZANIA AND KENYA. 84 00:03:30,840 --> 00:03:33,160 TO IDENTIFY AND ELUCIDATE 85 00:03:33,160 --> 00:03:34,680 INFECTIOUS, ET LOGICAL RISK 86 00:03:34,680 --> 00:03:35,680 FACTORS OF BURKITT LYMPHOMA. 87 00:03:35,680 --> 00:03:37,320 HIS STUDIES SHOW THE FEASIBILITY 88 00:03:37,320 --> 00:03:38,880 OF CONDUCTING HIGH IMPACT 89 00:03:38,880 --> 00:03:40,400 MOLECULAR STUDIES ON BURKITT 90 00:03:40,400 --> 00:03:43,560 LYMPHOMA IN AFRICA, GENERATE NEW 91 00:03:43,560 --> 00:03:45,400 DATA TO SUPPORT NEW DISCOVERIES 92 00:03:45,400 --> 00:03:47,280 AND COLLABORATIONS TO IMPROVE 93 00:03:47,280 --> 00:03:52,400 ITS DIAGNOSIS AND TREATMENT. 94 00:03:52,400 --> 00:03:54,480 DR. MBULAITEYE RECEIVED HIS 95 00:03:54,480 --> 00:03:56,600 PHYSICIAN TRAINING AT MAKERERE 96 00:03:56,600 --> 00:03:58,400 UNIVERSITY IN UGANDA, ADVANCED 97 00:03:58,400 --> 00:04:00,720 TRAINING IN EPIDEMIOLOGY AND 98 00:04:00,720 --> 00:04:01,440 BIOSTATISTICS FROM THE 99 00:04:01,440 --> 00:04:03,120 UNIVERSITY OF CAMBRIDGE U.K., 100 00:04:03,120 --> 00:04:04,560 AND SPECIALIST TRAINING IN 101 00:04:04,560 --> 00:04:10,680 INTERNAL MEDICINE FROM MAKERERE 102 00:04:10,680 --> 00:04:11,960 UNIVERSITY. 103 00:04:11,960 --> 00:04:15,720 MEASURING THE IMPACT OF HIV IN 104 00:04:15,720 --> 00:04:17,120 CANCER PATIENTS AND 105 00:04:17,120 --> 00:04:19,760 INVESTIGATING POPULATION TRENDS 106 00:04:19,760 --> 00:04:21,680 OF HIV IN EURL AND SOUTHWEST 107 00:04:21,680 --> 00:04:22,760 UGANDA. 108 00:04:22,760 --> 00:04:26,560 HE JOINED THE NCI IN 109 00:04:26,560 --> 00:04:28,520 DECEMBER 2000 TO FOCUS HIS WORK 110 00:04:28,520 --> 00:04:30,600 ON KAPOSI SARCOMA AND BURKITT 111 00:04:30,600 --> 00:04:31,440 LYMPHOMA AS A RESEARCH FELLOW 112 00:04:31,440 --> 00:04:34,320 AND THEN WENT ON TO OBTAIN 113 00:04:34,320 --> 00:04:35,280 SCIENTIFIC TENURE AND 114 00:04:35,280 --> 00:04:36,280 APPOINTMENT AS A SENIOR 115 00:04:36,280 --> 00:04:40,080 INVESTIGATOR IN 2013. 116 00:04:40,080 --> 00:04:41,600 IN 2022, HE WAS NAMED SCIENTIST 117 00:04:41,600 --> 00:04:43,000 OF THE YEAR BY THE LYMPHOMA 118 00:04:43,000 --> 00:04:45,240 FOUNDATION OF AMERICA. 119 00:04:45,240 --> 00:04:46,680 SO PLEASE JOIN ME IN WELCOMING 120 00:04:46,680 --> 00:04:50,040 OUR SPEAKERS FOR THEIR JOINT 121 00:04:50,040 --> 00:04:51,120 PRESENTATION TITLED "EXPLORING 122 00:04:51,120 --> 00:04:56,280 THE LINK BETWEEN SICKLE CELL, 123 00:04:56,280 --> 00:05:00,400 ALPHA THALASSEMIA, P FALCIPARUM 124 00:05:00,400 --> 00:05:01,080 MALARIA AND BURKITT LYMPHOMA IN 125 00:05:01,080 --> 00:05:01,560 AFRICA. 126 00:05:01,560 --> 00:05:02,960 I'LL TURN IT OVER TO YOU, 127 00:05:02,960 --> 00:05:03,040 DR. THEIN. 128 00:05:03,040 --> 00:05:05,160 SO THANK YOU, DR. CHUNG, AND 129 00:05:05,160 --> 00:05:06,760 THANK YOU TO THE COMMITTEE FOR 130 00:05:06,760 --> 00:05:10,680 GIVING SAM AND I THE OPPORTUNITY 131 00:05:10,680 --> 00:05:11,920 TO PRESENT OUR COLLABORATIVE 132 00:05:11,920 --> 00:05:13,560 WORK, WHICH IS ENTITLED 133 00:05:13,560 --> 00:05:14,840 EXPLORING THE LINK BETWEEN 134 00:05:14,840 --> 00:05:17,800 SICKLE CELL, ALPHA THALASSEMIA 135 00:05:17,800 --> 00:05:21,280 AND BURKITT LYMPHOMA IN AFRICA. 136 00:05:21,280 --> 00:05:22,640 SO THESE ARE OUR LEARNING 137 00:05:22,640 --> 00:05:24,840 OBJECTIVES. 138 00:05:24,840 --> 00:05:28,520 FIRST TO RECOGNIZE THAT MALARIA 139 00:05:28,520 --> 00:05:29,200 INFECTION AND BURKITT LYMPHOMA 140 00:05:29,200 --> 00:05:31,440 ARE CO-ENDEMIC, THAT MALARIA IS 141 00:05:31,440 --> 00:05:34,120 A RISK FACTOR FOR BURKITT 142 00:05:34,120 --> 00:05:35,320 LYMPHOMA. 143 00:05:35,320 --> 00:05:37,280 SECOND, TO RECOGNIZE THE 144 00:05:37,280 --> 00:05:38,560 INDEPENDENT PROTECTIVE EFFECTS 145 00:05:38,560 --> 00:05:41,760 OF SICKLE CELL TRAIT AND ALPHA 146 00:05:41,760 --> 00:05:45,240 THALASSEMIA AGAINST MALARIA AND 147 00:05:45,240 --> 00:05:46,440 THEIR PHYSIOLOGICAL IMPACT IN 148 00:05:46,440 --> 00:05:48,440 THE U.S. POPULATION. 149 00:05:48,440 --> 00:05:50,640 AND THIRDLY, TO EVALUATE THE 150 00:05:50,640 --> 00:05:52,480 INTERACTION OF ALPHA THALASSEMIA 151 00:05:52,480 --> 00:05:55,200 AND SICKLE CELL TRAIT ON THE 152 00:05:55,200 --> 00:05:55,720 PROTECTION AGAINST BURKITT 153 00:05:55,720 --> 00:05:59,680 LYMPHOMA. 154 00:05:59,680 --> 00:06:02,760 WE HAVE NOTHING TO DISCLOSE. 155 00:06:02,760 --> 00:06:07,360 SO I WILL SET THE SCENE FOR 156 00:06:07,360 --> 00:06:08,160 SAM'S PRESENTATION, STARTING 157 00:06:08,160 --> 00:06:10,200 WITH AN OVERVIEW OF THE GLOBAL 158 00:06:10,200 --> 00:06:11,960 DISTRIBUTION OF SICKLE CELL AND 159 00:06:11,960 --> 00:06:14,240 ALPHA THALASSEMIA IN RELATION TO 160 00:06:14,240 --> 00:06:15,440 MALARIA. 161 00:06:15,440 --> 00:06:17,040 AND THEN I'LL COVER A LITTLE ON 162 00:06:17,040 --> 00:06:19,560 THE PHYSIOLOGICAL IMPACT OF 163 00:06:19,560 --> 00:06:23,320 SICKLE CELL TRAIT AND ALPHA 164 00:06:23,320 --> 00:06:24,320 THALASSEMIA GENOTYPES IN THE 165 00:06:24,320 --> 00:06:25,200 U.S. POPULATION. 166 00:06:25,200 --> 00:06:27,480 AND FINALLY, TO COMPARE THE 167 00:06:27,480 --> 00:06:29,000 FREQUENCY OF ALPHA THALASSEMIA 168 00:06:29,000 --> 00:06:30,520 IN AFRICAN VERSUS THE U.S. 169 00:06:30,520 --> 00:06:33,280 POPULATION AND HOW COINHERITANCE 170 00:06:33,280 --> 00:06:35,720 OF ALPHA THALASSEMIA MODIFIES 171 00:06:35,720 --> 00:06:36,680 THE PHENOTYPE OF SICKLE CELL 172 00:06:36,680 --> 00:06:43,120 TRAIT. 173 00:06:43,120 --> 00:06:45,840 SO FIRST THE INHERITED DISORDERS 174 00:06:45,840 --> 00:06:48,720 OF HEMOGLOBIN LIKE ALPHA 175 00:06:48,720 --> 00:06:49,920 THALASSEMIA AND SICKLE CELL 176 00:06:49,920 --> 00:06:52,400 DISEASE, THEY ARE EXEMPLARS OF 177 00:06:52,400 --> 00:06:55,840 NATURAL SELECTION AND BALANCED 178 00:06:55,840 --> 00:06:58,320 POLYMORPHISM. 179 00:06:58,320 --> 00:07:01,480 HETEROZYGOUS -- ARE ASYMPTOMATIC 180 00:07:01,480 --> 00:07:03,880 AND PROTECTED FROM THE SEVERE 181 00:07:03,880 --> 00:07:05,200 FORMS OF MALARIA. 182 00:07:05,200 --> 00:07:07,640 THIS COMPENSATES FOR THE LOSS OF 183 00:07:07,640 --> 00:07:10,560 THE SEVERITY -- THE IMPROVED 184 00:07:10,560 --> 00:07:12,200 FITNESS OF HETEROZYGOUS ALLOWS 185 00:07:12,200 --> 00:07:14,920 THE FREQUENCY OF THESE DISORDERS 186 00:07:14,920 --> 00:07:19,200 TO INCREASE. 187 00:07:19,200 --> 00:07:21,240 THIS MALARIA HYPOTHESIS WAS 188 00:07:21,240 --> 00:07:27,840 FIRST PROPOSED BY JBS HALDANE IN 189 00:07:27,840 --> 00:07:31,680 1949 FOR THALASSEMIA AND ALISON 190 00:07:31,680 --> 00:07:32,640 IN 1954 FOR SICKLE CELL DISEASE. 191 00:07:32,640 --> 00:07:35,720 BOTH NOTED A STRIKING OVERLAP IN 192 00:07:35,720 --> 00:07:37,600 THE GEOGRAPHIC DISTRIBUTION OF 193 00:07:37,600 --> 00:07:41,520 MALARIA AND THESE DISORDERS. 194 00:07:41,520 --> 00:07:44,560 SOME IN VITRO STUDIES HAVE 195 00:07:44,560 --> 00:07:46,120 PROVIDED SUPPORT FOR THE 196 00:07:46,120 --> 00:07:48,200 PROTECTIVE ROLE OF HEMOGLOBIN S 197 00:07:48,200 --> 00:07:51,040 AGAINST THE MALARIAL PARASITE 198 00:07:51,040 --> 00:07:53,200 BUT IT WAS FRED PIEL IN OXFORD 199 00:07:53,200 --> 00:07:54,440 WHO FORMALLY INVESTIGATED AND 200 00:07:54,440 --> 00:07:56,080 PROVIDED THE GEOGRAPHICAL 201 00:07:56,080 --> 00:07:58,080 EVIDENCE IN SUPPORT OF THE 202 00:07:58,080 --> 00:07:59,560 MALARIAL HYPOTHESIS. 203 00:07:59,560 --> 00:08:02,640 HE SHOWED THAT GLOBALLY, THE 204 00:08:02,640 --> 00:08:06,160 HEMOGLOBIN S FREQUENCY INCREASES 205 00:08:06,160 --> 00:08:09,200 FROM EPIDEMIC TO HYPOENDEMIC AND 206 00:08:09,200 --> 00:08:12,680 THEN FROM MESOENDEMIC TO 207 00:08:12,680 --> 00:08:15,200 HYPERENDEMIC AND THEN TO 208 00:08:15,200 --> 00:08:15,520 HOLOENDEMIC. 209 00:08:15,520 --> 00:08:17,880 AND THE EVIDENCE WAS ACTUALLY 210 00:08:17,880 --> 00:08:19,520 DERIVED FROM MICRO MAPPING OF 211 00:08:19,520 --> 00:08:21,520 THE HEMOGLOBIN S ALLELE IN 212 00:08:21,520 --> 00:08:24,080 RELATION TO THE HISTORICAL 213 00:08:24,080 --> 00:08:27,760 DISTRIBUTION OF P FALCIPARUM. 214 00:08:27,760 --> 00:08:29,880 SURVIVAL ADVANTAGE OF THE AS OR 215 00:08:29,880 --> 00:08:33,160 THE CARRIERS IN THE MALARIA 216 00:08:33,160 --> 00:08:34,880 ENDEMIC REGIONS HAVE DRIVEN THIS 217 00:08:34,880 --> 00:08:39,840 GENE FREQUENCY UP TO 30% IN 218 00:08:39,840 --> 00:08:41,440 HISTORICALLY ENDEMIC REGIONS. 219 00:08:41,440 --> 00:08:43,880 SO CURRENTLY IT IS ESTIMATED 220 00:08:43,880 --> 00:08:45,960 THERE ARE ABOUT 5.5 MILLION 221 00:08:45,960 --> 00:08:49,320 BIRTHS OF AS ANNUALLY, AND 222 00:08:49,320 --> 00:08:51,120 300 MILLION PEOPLE ARE AFFECTED, 223 00:08:51,120 --> 00:08:52,920 WHICH IS ABOUT 5% OF THE WORLD 224 00:08:52,920 --> 00:08:56,360 POPULATION. 225 00:08:56,360 --> 00:08:59,520 AND HOW DID SICKLE ALLELE ARRIVE 226 00:08:59,520 --> 00:09:00,920 TO THE U.S. WAS PROBABLY 227 00:09:00,920 --> 00:09:01,360 IMPORTANT. 228 00:09:01,360 --> 00:09:05,040 FROM AFRICA WITH THE FIRST 229 00:09:05,040 --> 00:09:07,800 MIGRATION BETWEEN 16TH AND THE 230 00:09:07,800 --> 00:09:08,920 19TH CENTURY AND CURRENT 231 00:09:08,920 --> 00:09:11,080 ESTIMATE IS THAT THERE ARE ABOUT 232 00:09:11,080 --> 00:09:12,840 3 MILLION PEOPLE WHO ARE 233 00:09:12,840 --> 00:09:15,160 CARRIERS FOR SICKLE CELL, THE 234 00:09:15,160 --> 00:09:17,040 MAJORITY OF WHICH ARE BLACK 235 00:09:17,040 --> 00:09:18,080 AMERICANS, WHERE THE FREQUENCY 236 00:09:18,080 --> 00:09:23,040 IS ABOUT 7 TO 9%. 237 00:09:23,040 --> 00:09:24,680 SO WHAT IS SICKLE CELL? 238 00:09:24,680 --> 00:09:27,160 THE SICKLE HEMOGLOBIN OR 239 00:09:27,160 --> 00:09:29,880 HEMOGLOBIN S IS AN ABNORMAL 240 00:09:29,880 --> 00:09:33,320 STRUCTURE VARIANT, A RESULT 241 00:09:33,320 --> 00:09:34,760 OF -- SUBSTITUTION IN THE -- 242 00:09:34,760 --> 00:09:37,800 CHAIN OF HEMOGLOBIN TETRAMER AND 243 00:09:37,800 --> 00:09:39,480 CAUSE FOR SUBSTITUTION. 244 00:09:39,480 --> 00:09:41,080 CARRIERS OF THE SICKLE ALLELE 245 00:09:41,080 --> 00:09:44,080 ARE CLINICALLY ASYMPTOMATIC, BUT 246 00:09:44,080 --> 00:09:49,240 HOME SI ZYGOTES SUFFER FROM SICE 247 00:09:49,240 --> 00:09:53,000 CELL DISEASE, CHRONIC ANEMIA AND 248 00:09:53,000 --> 00:09:54,840 ACUTE EVENTS MOST OF WHICH ARE 249 00:09:54,840 --> 00:09:57,720 ACUTE SEVERE PAIN, SO SEVERE 250 00:09:57,720 --> 00:09:59,000 IT'S OFTEN REFERRED TO AS A 251 00:09:59,000 --> 00:10:00,000 CRISIS. 252 00:10:00,000 --> 00:10:01,960 AND WITHOUT TREATMENT, THE VAST 253 00:10:01,960 --> 00:10:08,880 MAJORITY OF HEMOGLOBIN SERS DAIS 254 00:10:08,880 --> 00:10:11,680 WE SEE IN SUB-SAHARAN AFRICA. 255 00:10:11,680 --> 00:10:14,560 AND HOW DOES THE SICKLE CELL 256 00:10:14,560 --> 00:10:15,640 TRAIT IMPACT PHYSIOLOGICAL 257 00:10:15,640 --> 00:10:19,680 FUNCTION? 258 00:10:19,680 --> 00:10:21,240 THERE ARE NUMEROUS STUDIES AND 259 00:10:21,240 --> 00:10:23,680 IT'S DIFFICULT FOR ME TO DO 260 00:10:23,680 --> 00:10:25,080 JUSTICE TO ALL OF THESE 261 00:10:25,080 --> 00:10:26,360 PUBLICATIONS, BUT THIS IS THE 262 00:10:26,360 --> 00:10:29,200 GIST OF WHAT WE HAVE GLEANED 263 00:10:29,200 --> 00:10:32,920 FROM THE PUBLISHED PAPERS IN A 264 00:10:32,920 --> 00:10:37,400 REVIEW THAT I AUTHORED WITH A 265 00:10:37,400 --> 00:10:38,960 CLINICAL FELLOW. 266 00:10:38,960 --> 00:10:40,760 SO IMPORTANT TO BARE IN MIND 267 00:10:40,760 --> 00:10:43,520 THAT SICKLE CELL TRAIT IS A 268 00:10:43,520 --> 00:10:44,840 BENIGN CARRIER STATE BUT 269 00:10:44,840 --> 00:10:46,600 NONETHELESS, IT'S IMPORTANT TO 270 00:10:46,600 --> 00:10:50,640 KNOW IF ONE IS A CARRIER FOR 271 00:10:50,640 --> 00:10:52,840 GENETIC COUNSELING PURPOSES AND 272 00:10:52,840 --> 00:10:55,680 ALSO EVALUATION OF RARE 273 00:10:55,680 --> 00:10:56,480 SICKLE-TYPE SYMPTOMS. 274 00:10:56,480 --> 00:10:57,680 LIFE EXPECTANCY IS NOT REDUCED 275 00:10:57,680 --> 00:11:00,080 WIBUT THOUGHT TO BE ASSOCIATED 276 00:11:00,080 --> 00:11:02,680 WITH HIGHER RISK FOR CERTAIN 277 00:11:02,680 --> 00:11:04,960 RENAL COMPLICATIONS LIKE 278 00:11:04,960 --> 00:11:06,600 HEMATURIA, CHRONIC KIDNEY 279 00:11:06,600 --> 00:11:08,560 DISEASE, RENAL MEDULLARY 280 00:11:08,560 --> 00:11:10,440 CARCINOMA, AND A RARE AND 281 00:11:10,440 --> 00:11:14,720 AGGRESSIVE RENAL TUMOR ALMOST 282 00:11:14,720 --> 00:11:17,640 EXCLUSIVELY DESCRIBED IN YOUNG 283 00:11:17,640 --> 00:11:18,840 ADULTS WITH SICKLE CELL TRAIT. 284 00:11:18,840 --> 00:11:19,720 THERE'S ALSO SOME ASSOCIATION 285 00:11:19,720 --> 00:11:21,160 WITH END STAGE KIDNEY DISEASE 286 00:11:21,160 --> 00:11:23,240 BUT EVIDENCE IS LOW. 287 00:11:23,240 --> 00:11:26,840 AND PLEASE NOTE SOMETHING I'LL 288 00:11:26,840 --> 00:11:28,480 COME BACK LATER, THE 289 00:11:28,480 --> 00:11:29,600 COINHERITANCE OF ALPHA 290 00:11:29,600 --> 00:11:31,320 THALASSEMIA IS AN ATTENUATING 291 00:11:31,320 --> 00:11:32,880 FACTOR FOR CHRONIC KIDNEY 292 00:11:32,880 --> 00:11:33,640 DISEASE. 293 00:11:33,640 --> 00:11:36,920 EVIDENCE FOR VENOUS THROMBOTIC 294 00:11:36,920 --> 00:11:38,520 EVENTS IS PARTICULARLY STRONG 295 00:11:38,520 --> 00:11:40,080 FOR PULMONARY EMBOLISM BUT NOT 296 00:11:40,080 --> 00:11:42,560 SO MUCH FOR DEEP VENOUS 297 00:11:42,560 --> 00:11:44,360 THROMBOSIS, AND THE RISK FOR 298 00:11:44,360 --> 00:11:46,080 THESE VTEs MAY BE MORE 299 00:11:46,080 --> 00:11:48,040 PRONOUNCED IN SOME SETTINGS, 300 00:11:48,040 --> 00:11:51,600 LIKE PREGNANCY AND POSTPARTUM. 301 00:11:51,600 --> 00:11:53,840 AND HERE IS ANOTHER SYNDROME 302 00:11:53,840 --> 00:11:55,280 WHICH IS A PRESENTATION IN 303 00:11:55,280 --> 00:12:01,960 ITSELF REFERRED TO AS ECAST, 304 00:12:01,960 --> 00:12:03,840 EXERCISE COLLAPSE ASSOCIATED 305 00:12:03,840 --> 00:12:06,440 WITH SICKLE CELL TRAIT, SUDDEN 306 00:12:06,440 --> 00:12:07,960 DEATH DURING STRENUOUS PHYSICAL 307 00:12:07,960 --> 00:12:09,080 ACTIVITY IN AS. 308 00:12:09,080 --> 00:12:11,480 IT'S UNCLEAR WHETHER THERE IS A 309 00:12:11,480 --> 00:12:13,200 RELATIONSHIP OR WHETHER THERE 310 00:12:13,200 --> 00:12:16,160 ARE ALSO COINHERITED GENETIC 311 00:12:16,160 --> 00:12:17,720 FACTORS, BUT DEHYDRATION IS A 312 00:12:17,720 --> 00:12:20,760 BIG, BIG FACTOR. 313 00:12:20,760 --> 00:12:23,960 AND RARELY YOU CAN SEE SICKLE 314 00:12:23,960 --> 00:12:33,040 CELL DISEASE -- OR THEY MAY HAVE 315 00:12:33,040 --> 00:12:36,640 THIS DOMINANT BETA S ALLELES 316 00:12:36,640 --> 00:12:38,600 LIKE HEMOGLOBIN JAMAICA PLAIN. 317 00:12:38,600 --> 00:12:40,680 THIS IS A GRAPHIC SUMMARY OF THE 318 00:12:40,680 --> 00:12:44,160 STRENGTH OF ASSOCIATION OF THE 319 00:12:44,160 --> 00:12:44,840 VENOUS SICKLE CELL TRAIT. 320 00:12:44,840 --> 00:12:48,760 SO THE STRONG EVIDENCE FOR CKD, 321 00:12:48,760 --> 00:12:50,760 PROTEINURIA, VTEs, IN 322 00:12:50,760 --> 00:12:56,440 PARTICULAR, PULMONARY EMBOLISM, 323 00:12:56,440 --> 00:12:57,760 HYPOSTHENURIA, AND RENAL 324 00:12:57,760 --> 00:13:00,240 MEDULLARY CARCINOMA. 325 00:13:00,240 --> 00:13:03,200 NOW ON TO ALPHA THALASSEMIA. 326 00:13:03,200 --> 00:13:05,960 SO THE EVIDENCE THAT ALPHA 327 00:13:05,960 --> 00:13:09,480 THALASSEMIA IS HIGHLY PROTECTIVE 328 00:13:09,480 --> 00:13:11,520 AGAINST MALARIA WAS PROVIDED BY 329 00:13:11,520 --> 00:13:13,360 JONATHAN FLINT, WHO COMPARED 330 00:13:13,360 --> 00:13:17,440 FREQUENCIES OF ALPHA THALASSEMIA 331 00:13:17,440 --> 00:13:20,280 IN THOSE EXPOSED TO THE 332 00:13:20,280 --> 00:13:23,200 DIFFERENT -- OF MALARIA AND ALSO 333 00:13:23,200 --> 00:13:25,160 THOSE IN NEW GUINEA LIVING AT 334 00:13:25,160 --> 00:13:25,920 DIFFERENT ALTITUDES. 335 00:13:25,920 --> 00:13:29,600 THIS IS PROBABLY THE MOST RECENT 336 00:13:29,600 --> 00:13:31,200 REPRESENTATION OF THE GLOBAL 337 00:13:31,200 --> 00:13:34,480 PRESENCE OF ALPHA THALASSEMIA. 338 00:13:34,480 --> 00:13:35,680 AND FIRST I WANT YOU TO SEE THAT 339 00:13:35,680 --> 00:13:37,440 THERE ARE MANY MORE DIFFERENT 340 00:13:37,440 --> 00:13:39,520 FLAVORS OF ALPHA THALASSEMIA 341 00:13:39,520 --> 00:13:41,640 COMPARED TO ONE SINGLE MUTATION 342 00:13:41,640 --> 00:13:46,080 FOR HEMOGLOBIN S. 343 00:13:46,080 --> 00:13:47,400 AND MOST OF THE ALPHA 344 00:13:47,400 --> 00:13:48,600 THALASSEMIA, HOWEVER, IS CAUSED 345 00:13:48,600 --> 00:13:53,640 BY A SINGLE DELETION, AND SINGLE 346 00:13:53,640 --> 00:13:55,040 ALPHA DELETIONS ARE MOST COMMON. 347 00:13:55,040 --> 00:13:56,800 AND NOTE HERE THAT THE ONES 348 00:13:56,800 --> 00:14:00,080 PRESENT IN AFRICA IS A SINGLE 349 00:14:00,080 --> 00:14:01,720 ALPHA GENE DELETION. 350 00:14:01,720 --> 00:14:05,560 AND AGAIN, IT'S MOST LIKELY THAT 351 00:14:05,560 --> 00:14:08,080 THE ALPHA THALASSEMIA WAS 352 00:14:08,080 --> 00:14:10,200 IMPORTED INTO THE U.S. WITH THE 353 00:14:10,200 --> 00:14:13,840 FIRST MIGRATION FROM AFRICA 354 00:14:13,840 --> 00:14:15,840 BETWEEN 14TH AND 19TH CENTURY. 355 00:14:15,840 --> 00:14:18,320 BUT FOR US IN THE U.S., THE 356 00:14:18,320 --> 00:14:20,520 SINGLE ALPHA GENE DELETION 357 00:14:20,520 --> 00:14:21,960 PREDOMINATES AS FOUND IN 358 00:14:21,960 --> 00:14:25,560 AFRICANS. 359 00:14:25,560 --> 00:14:30,800 SO THE QUESTION IS, DO THE 360 00:14:30,800 --> 00:14:34,120 DIFFERENT ALPHAS MATTER? 361 00:14:34,120 --> 00:14:35,800 -- WHICH IS HIGHLY DEPENDENT ON 362 00:14:35,800 --> 00:14:39,280 THE AMOUNT OF ALPHA GLOBIN CHAIN 363 00:14:39,280 --> 00:14:41,960 BUT IT'S ENCODED BY FOUR ALPHA 364 00:14:41,960 --> 00:14:42,840 GLOBIN GENES. 365 00:14:42,840 --> 00:14:44,600 TWO ON EACH CHROMOSOME. 366 00:14:44,600 --> 00:14:50,400 SO A NORMAL PERSON SHOULD HAVE 367 00:14:50,400 --> 00:14:51,720 FOUR ALPHA GENE COPIES. 368 00:14:51,720 --> 00:14:53,480 DELETION OF A SINGLE COPY 369 00:14:53,480 --> 00:14:55,960 PRODUCES A PHENOTYPE THAT CANNOT 370 00:14:55,960 --> 00:14:59,040 BE DISTINGUISHED FROM NORMAL. 371 00:14:59,040 --> 00:15:01,440 LOSS OF TWO ALPHA GLOBIN GENES 372 00:15:01,440 --> 00:15:04,840 CAN BE FROM THE SAME CHROMOSOME 373 00:15:04,840 --> 00:15:08,640 OR ACROSS OPPOSITE CHROMOSOMES, 374 00:15:08,640 --> 00:15:09,880 AND THESE ARE ASSOCIATED WITH 375 00:15:09,880 --> 00:15:15,880 THE SAME PHENOTYPE OF -- ANEMIA. 376 00:15:15,880 --> 00:15:18,640 BECAUSE THE ALPHA THAL VARIANT 377 00:15:18,640 --> 00:15:20,200 IN AFRICANS AND BLACK AMERICANS 378 00:15:20,200 --> 00:15:22,040 IS A SINGLE ALPHA GENE DELETION, 379 00:15:22,040 --> 00:15:24,440 THE MOST SEVERE PHENOTYPE THAT 380 00:15:24,440 --> 00:15:27,880 ONE CAN GET IS ACTUALLY LOSS OF 381 00:15:27,880 --> 00:15:33,160 TWO ALPHA GLOBIN GENES, AND THIS 382 00:15:33,160 --> 00:15:43,440 IS -- ALSO LOSS OF FOUR CAUSES 383 00:15:43,440 --> 00:15:46,360 HEMOGLOBIN BART'S HYDROPS 384 00:15:46,360 --> 00:15:47,480 SYNDROME WHICH IS NOT COMPATIBLE 385 00:15:47,480 --> 00:15:48,360 WITH LIFE. 386 00:15:48,360 --> 00:15:50,640 THIS IS HOW YOU DESCRIBE IN 387 00:15:50,640 --> 00:15:52,000 AFRICAN AMERICANS OR BLACK 388 00:15:52,000 --> 00:15:53,640 AMERICANS FOR THE OBVIOUS 389 00:15:53,640 --> 00:15:55,160 REASONS THAT TWO ALPHA GENE 390 00:15:55,160 --> 00:15:57,880 DELETION IS NOT COMMON OR HIGHLY 391 00:15:57,880 --> 00:16:02,720 FOUND. 392 00:16:02,720 --> 00:16:04,320 -- MINIMAL CLINICAL IMPACT ON 393 00:16:04,320 --> 00:16:06,960 ITS OWN OR SO IT WAS THOUGHT, 394 00:16:06,960 --> 00:16:09,360 UNTIL THE APPEARANCE OF THIS 395 00:16:09,360 --> 00:16:16,280 NATURE ARTICLE IN 2012. 396 00:16:16,280 --> 00:16:18,440 SHOWING THAT ALPHA GLOBIN GENE 397 00:16:18,440 --> 00:16:21,800 IS EXPRESSING ALPHA THALASSEMIA 398 00:16:21,800 --> 00:16:23,680 CELLS AND REGULATES NITRIC OXIDE 399 00:16:23,680 --> 00:16:25,240 SIGNALING WHICH MEANS THAT THE 400 00:16:25,240 --> 00:16:27,520 NUMBER OF ALPHA GLOBIN GENES 401 00:16:27,520 --> 00:16:31,760 COULD HAVE A ROLE IN REGULATING 402 00:16:31,760 --> 00:16:32,760 VASCULAR TONE. 403 00:16:32,760 --> 00:16:35,480 THIS PAPER SPARKED UP A COUPLE 404 00:16:35,480 --> 00:16:35,960 OF STUDIES. 405 00:16:35,960 --> 00:16:39,120 WITH A QUESTION AS TO WHETHER 406 00:16:39,120 --> 00:16:40,960 THE FUNCTIONAL LOSS OF ALPHA 407 00:16:40,960 --> 00:16:44,040 GLOBIN INFLUENCED THE RISK OF 408 00:16:44,040 --> 00:16:46,880 HYPERTENSION. 409 00:16:46,880 --> 00:16:48,960 THE FIRST STUDY WAS CARRIED OUT 410 00:16:48,960 --> 00:16:50,600 ON KENYAN ADOLESCENTS LIVING IN 411 00:16:50,600 --> 00:16:55,200 THE FREE PART OF NYROBI, 412 00:16:55,200 --> 00:16:57,040 AMBULATORY BLOOD PRESSURE WAS 413 00:16:57,040 --> 00:17:00,000 MEASURED 24 HOURS USING A 414 00:17:00,000 --> 00:17:02,640 VALIDATED DEVICE THAT ALSO 415 00:17:02,640 --> 00:17:05,480 MEASURES -- WAVE VELOCITY. 416 00:17:05,480 --> 00:17:08,880 ALPHA GLOBIN GENOTYPE -- THE 417 00:17:08,880 --> 00:17:11,080 STUDY CONCLUDED THAT ALPHA 418 00:17:11,080 --> 00:17:13,000 THALASSEMIA GENOTYPE DOES NOT 419 00:17:13,000 --> 00:17:15,000 AFFECT BLOOD PRESSURE OR 420 00:17:15,000 --> 00:17:16,880 ARTERIAL STIFFNESS IN KENYAN 421 00:17:16,880 --> 00:17:18,960 ADOLESCENTS LIVING WITHIN 422 00:17:18,960 --> 00:17:24,800 NON-MALARIA ENDEMIC ENVIRONMENT. 423 00:17:24,800 --> 00:17:26,440 A MORE RECENT STUDY THAT IS MORE 424 00:17:26,440 --> 00:17:29,000 RELEVANT TO THE U.S. POPULATION 425 00:17:29,000 --> 00:17:33,160 CAME FROM HANS ECKERMAN AND HIS 426 00:17:33,160 --> 00:17:34,800 GROUP AT NIH. 427 00:17:34,800 --> 00:17:37,840 HANS AND HIS GROUP LEVERAGED 428 00:17:37,840 --> 00:17:41,680 RESOURCES OF THE REGRDS STUDY 429 00:17:41,680 --> 00:17:43,640 COHORT WHICH WAS DESIGNED TO 430 00:17:43,640 --> 00:17:46,160 ADDRESS THE REASONS FOR RACIAL 431 00:17:46,160 --> 00:17:51,320 DISPARITIES IN -- DECLINE IN 432 00:17:51,320 --> 00:17:52,880 BLACK AND WHITE AMERICANS AGE 45 433 00:17:52,880 --> 00:17:53,600 YEARS AND ABOVE. 434 00:17:53,600 --> 00:17:55,360 SO MORE THAN 30,000 COMMUNITY 435 00:17:55,360 --> 00:18:00,680 DWELLING SUBJECTS WERE 436 00:18:00,680 --> 00:18:01,920 RECRUITED, ENROLLED WITHIN 2003 437 00:18:01,920 --> 00:18:04,520 AND 2007, AND OF THESE, 41% WERE 438 00:18:04,520 --> 00:18:06,960 BLACK AMERICANS. 439 00:18:06,960 --> 00:18:10,240 ALPHA GLOBIN GENOTYPING WAS 440 00:18:10,240 --> 00:18:14,840 DETERMINED BY DIGITAL PCR, 441 00:18:14,840 --> 00:18:17,320 AND -- EXCLUSION CRITERIA 9,680 442 00:18:17,320 --> 00:18:19,320 FOWRP SAMPLES COULD BE ANALYZED 443 00:18:19,320 --> 00:18:22,800 FOR PREVALENT HYPERTENSION. 444 00:18:22,800 --> 00:18:24,200 BLOOD PRESSURE STATUS WAS 445 00:18:24,200 --> 00:18:25,960 DETERMINED USING A COMBINATION 446 00:18:25,960 --> 00:18:28,720 OF APPROACHES INCLUDING 447 00:18:28,720 --> 00:18:31,200 MEASUREMENT BY TRAINED PERSONNEL 448 00:18:31,200 --> 00:18:34,280 IN HOME VISITS. 449 00:18:34,280 --> 00:18:36,840 THE STUDY CONCLUDED THAT ALPHA 450 00:18:36,840 --> 00:18:39,320 GLOBIN GENE COPY NUMBER WAS NOT 451 00:18:39,320 --> 00:18:41,720 ASSOCIATED WITH RESISTANT, 452 00:18:41,720 --> 00:18:43,480 PREVALENT OR INCIDENT 453 00:18:43,480 --> 00:18:45,240 HYPERTENSION IN THE ADULT BLACK 454 00:18:45,240 --> 00:18:51,240 AMERICANS. 455 00:18:51,240 --> 00:18:55,600 THE NEXT QUESTION WAS, THIS DOES 456 00:18:55,600 --> 00:18:57,280 ALPHA GLOBIN GENE COPY NUMBER 457 00:18:57,280 --> 00:19:00,960 INFLUENCE RISK OF KIDNEYS 458 00:19:00,960 --> 00:19:02,600 DISEASE? 459 00:19:02,600 --> 00:19:03,800 TWO GENETIC VARIANTS THAT 460 00:19:03,800 --> 00:19:05,480 CONTRIBUTE TO THIS RISK INCLUDE 461 00:19:05,480 --> 00:19:12,200 SICKLE CELL TRAIT AND PROTEIN LN 462 00:19:12,200 --> 00:19:15,680 IN BLACKS BUT THEY'RE ONLY 463 00:19:15,680 --> 00:19:17,280 PARTLY EXPLAINED SOME DISPARITY. 464 00:19:17,280 --> 00:19:20,360 SO HANS AND HIS GROUP THEN ASKED 465 00:19:20,360 --> 00:19:23,560 IF COINHERITANCE OF ALPHA THAL 466 00:19:23,560 --> 00:19:24,640 PREVALENT IN BLACK AMERICANS 467 00:19:24,640 --> 00:19:26,640 COULD CONTRIBUTE TO THIS 468 00:19:26,640 --> 00:19:27,800 DISPARITY. 469 00:19:27,800 --> 00:19:29,760 THE STUDY AGAIN LEVERAGED 470 00:19:29,760 --> 00:19:33,600 RESOURCES OF THE REGARDS COHORT. 471 00:19:33,600 --> 00:19:35,920 INFORMATION ON VARIOUS VARIABLES 472 00:19:35,920 --> 00:19:38,040 INCLUDING PHYSICIAN DIAGNOSED 473 00:19:38,040 --> 00:19:39,320 CO-MORBID CONDITIONS ARE 474 00:19:39,320 --> 00:19:41,280 COLLECTED, BLOOD AND URINE 475 00:19:41,280 --> 00:19:43,880 SAMPLES AND VARIOUS VARIABLES 476 00:19:43,880 --> 00:19:45,240 SUCH AS HIGH WAVE BLOOD PRESSURE 477 00:19:45,240 --> 00:19:47,400 WERE COLLECTED BY TRAINED 478 00:19:47,400 --> 00:19:49,480 PERSONNEL DURING HOME VISITS, 479 00:19:49,480 --> 00:19:52,000 AND THE STUDY WAS ALSO -- 480 00:19:52,000 --> 00:19:55,600 ANALYSIS WAS ADJUSTED FOR 481 00:19:55,600 --> 00:19:58,560 COVARIATES INCLUDING 482 00:19:58,560 --> 00:20:00,080 HYPERTENSION, DIABETES, 483 00:20:00,080 --> 00:20:04,800 HEMOGLOBIN S, PRESENCE OF THIS 484 00:20:04,800 --> 00:20:05,960 APOL1 HIGH RISK GENOTYPE AND 485 00:20:05,960 --> 00:20:06,360 OTHERS. 486 00:20:06,360 --> 00:20:08,160 WHAT THEY SHOWED WAS THAT HAVING 487 00:20:08,160 --> 00:20:10,160 ALPHA THALASSEMIA ACTUALLY 488 00:20:10,160 --> 00:20:11,680 PROTECTS AGAINST CHRONIC KIDNEY 489 00:20:11,680 --> 00:20:13,760 DISEASE, AND THAT EACH 490 00:20:13,760 --> 00:20:15,960 ADDITIONAL COPY OF ALPHA GLOBIN 491 00:20:15,960 --> 00:20:19,720 GENE INCREASED CKD PREVALENCE BY 492 00:20:19,720 --> 00:20:21,760 14%, AND END STAGE KIDNEY 493 00:20:21,760 --> 00:20:29,840 DISEASE PREVALENCE BY 32%. 494 00:20:29,840 --> 00:20:32,800 SO DOES FUNCTIONAL LOSS OF ALPHA 495 00:20:32,800 --> 00:20:35,200 GLOBIN GENE INFLUENCE RISK OF 496 00:20:35,200 --> 00:20:35,520 HYPERTENSION? 497 00:20:35,520 --> 00:20:36,160 NO. 498 00:20:36,160 --> 00:20:37,960 DOES ALPHA GLOBIN GENE COPY 499 00:20:37,960 --> 00:20:39,160 NUMBER INFLUENCE RISK OF KIDNEY 500 00:20:39,160 --> 00:20:40,560 DISEASE? 501 00:20:40,560 --> 00:20:40,720 YES. 502 00:20:40,720 --> 00:20:42,600 INCREASING ALPHA GLOBIN GENE 503 00:20:42,600 --> 00:20:44,160 COPY NUMBER WAS ASSOCIATED WITH 504 00:20:44,160 --> 00:20:45,920 A GREATER PREVALENCE OF CKD AND 505 00:20:45,920 --> 00:20:50,080 INCIDENCE OF END STAGE KIDNEY 506 00:20:50,080 --> 00:20:51,840 DISEASE. 507 00:20:51,840 --> 00:20:54,880 SO IN THE PREVIOUS SLIDE, I 508 00:20:54,880 --> 00:20:56,640 MENTIONED THAT SICKLE CELL 509 00:20:56,640 --> 00:21:00,880 DISEASE COULD INFLUENCE -- 510 00:21:00,880 --> 00:21:01,880 FACTOR FOR KIDNEY DISEASE. 511 00:21:01,880 --> 00:21:04,600 THIS SLIDE REMINDS US OF THE 512 00:21:04,600 --> 00:21:07,320 EPIDEMIOLOGY OF THE HEMOGLOBIN 513 00:21:07,320 --> 00:21:12,520 DISORDERS THAT OVERLAP WITH 514 00:21:12,520 --> 00:21:13,160 MALARIA. 515 00:21:13,160 --> 00:21:17,960 THERE'IT IS NOT UNCOMMON FOR SOY 516 00:21:17,960 --> 00:21:19,640 WHO HAS SICKLE CELL TRAIT OR 517 00:21:19,640 --> 00:21:22,640 SICKLE CELL DISEASE TO HAVE 518 00:21:22,640 --> 00:21:23,960 COINHERITED ALPHA THALASSEMIA. 519 00:21:23,960 --> 00:21:26,240 AND THIS IS A VERY IMPORTANT 520 00:21:26,240 --> 00:21:27,680 POINT WHEN ANALYZING THE EFFECTS 521 00:21:27,680 --> 00:21:30,000 OF SICKLE CELL TRAIT OR SICKLE 522 00:21:30,000 --> 00:21:31,200 CELL DISEASE, BECAUSE THE 523 00:21:31,200 --> 00:21:33,320 PATHOLOGY OF THESE DISORDERS IS 524 00:21:33,320 --> 00:21:38,200 HIGHLY DEPENDENT ON THE -- S 525 00:21:38,200 --> 00:21:39,080 CONCENTRATION AND THIS IN TURN 526 00:21:39,080 --> 00:21:40,520 IS AFFECTED BY THE NUMBER OF 527 00:21:40,520 --> 00:21:43,200 COPIES OF ALPHA GLOBIN GENES. 528 00:21:43,200 --> 00:21:44,000 WHY? 529 00:21:44,000 --> 00:21:45,600 BECAUSE ALPHA GLOBIN GENES ARE 530 00:21:45,600 --> 00:21:47,360 POSITIVELY CHARGED. 531 00:21:47,360 --> 00:21:49,920 THEY FORM DIMERS THROUGH THE -- 532 00:21:49,920 --> 00:21:52,600 CHAINS THAT ARE NEGATIVELY 533 00:21:52,600 --> 00:21:53,960 CHARGED, AND BECAUSE BETA S 534 00:21:53,960 --> 00:21:56,440 CHAIN IS LESS NEGATIVELY CHARGED 535 00:21:56,440 --> 00:22:00,720 THAN BETA A OF HEMOGLOBIN A, 536 00:22:00,720 --> 00:22:03,680 ALPHA CHAIN WILL ALWAYS COMBINE 537 00:22:03,680 --> 00:22:05,200 MORE READILY WITH BETA A. 538 00:22:05,200 --> 00:22:07,960 SO YOU SEE HERE IN AS, THERE 539 00:22:07,960 --> 00:22:10,680 WILL ALWAYS BE MORE HEMOGLOBIN A 540 00:22:10,680 --> 00:22:14,360 AND THEN THE A DEFICIT IN ALPHA 541 00:22:14,360 --> 00:22:17,560 THALASSEMIA WILL LEAD TO FALL IN 542 00:22:17,560 --> 00:22:22,160 HEMOGLOBIN S, SHOWN VERY NICELY 543 00:22:22,160 --> 00:22:31,360 HERE -- WHO CORRELATED THE MEAN 544 00:22:31,360 --> 00:22:32,800 HEMOGLOBIN S FRACTION WITH THE 545 00:22:32,800 --> 00:22:37,160 NUMBER OF ALPHA -- GENE COPIES 546 00:22:37,160 --> 00:22:39,480 AND MORE -- THEY ARE THE HIGHEST 547 00:22:39,480 --> 00:22:42,080 HEMOGLOBIN S FRACTION. 548 00:22:42,080 --> 00:22:44,480 AND THIS CONCEPT WAS REALLY VERY 549 00:22:44,480 --> 00:22:46,560 NICELY SUMMARIZED IN THE 550 00:22:46,560 --> 00:22:49,120 BEAUTIFUL STUDY MORE THAN 30 551 00:22:49,120 --> 00:22:56,120 YEARS AGO INVOLVING -- IN NIDDK. 552 00:22:56,120 --> 00:22:57,200 INDIVIDUALS' ABILITY TO 553 00:22:57,200 --> 00:22:58,400 CONCENTRATE URINE, THIS IS DUE 554 00:22:58,400 --> 00:23:00,560 TO THE MOL MERRIZATION OF 555 00:23:00,560 --> 00:23:02,400 HEMOGLOBIN S IN THE HIGHLY 556 00:23:02,400 --> 00:23:03,640 CONDUCIVE ENVIRONMENT OF THE 557 00:23:03,640 --> 00:23:04,440 RENAL MEDULLA. 558 00:23:04,440 --> 00:23:07,320 BUT THIS IMPACT ABILITY IS 559 00:23:07,320 --> 00:23:10,200 HIGHLY VARIABLE. 560 00:23:10,200 --> 00:23:13,880 AND THEY ASKED THEN SINCE ALPHA 561 00:23:13,880 --> 00:23:14,880 THAL INFLUENCES THE 562 00:23:14,880 --> 00:23:16,640 CONCENTRATION OF HEMOGLOBIN S, 563 00:23:16,640 --> 00:23:17,720 COULD THIS BE ONE OF THE 564 00:23:17,720 --> 00:23:18,840 REASONS. 565 00:23:18,840 --> 00:23:22,120 AND ALPHA. 566 00:23:22,120 --> 00:23:23,960 THAL IS DETERMINED 567 00:23:23,960 --> 00:23:24,440 BY -- STATE OF THE ART 568 00:23:24,440 --> 00:23:24,960 TECHNOLOGY THEN. 569 00:23:24,960 --> 00:23:29,320 THEY SHOWED THAT ALPHA THAL 570 00:23:29,320 --> 00:23:31,280 REDUCED -- PERCENTAGE AS SHOWN 571 00:23:31,280 --> 00:23:34,000 EARLIER AND THAT THIS MAXIMAL 572 00:23:34,000 --> 00:23:35,240 URINE CONCENTRATING ABILITY 573 00:23:35,240 --> 00:23:36,840 ACTUALLY CORRELATED INVERSELY 574 00:23:36,840 --> 00:23:39,040 WITH A NUMBER OF HEMOGLOBIN 575 00:23:39,040 --> 00:23:41,440 ALPHA GENE COPY NUMBERS, AND 576 00:23:41,440 --> 00:23:43,440 THIS CONCENTRATING ABILITY 577 00:23:43,440 --> 00:23:47,040 ACTUALLY DECREASES THROUGH 578 00:23:47,040 --> 00:23:50,120 INCREASING HEMOGLOBIN S. 579 00:23:50,120 --> 00:23:53,320 SO GIVEN ITS PREVALENCE AND ITS 580 00:23:53,320 --> 00:23:55,720 MODIFYING EFFECTS ON SO MANY 581 00:23:55,720 --> 00:23:56,360 TRAITS, IT IS IMPORTANT TO 582 00:23:56,360 --> 00:23:58,320 ACCOUNT FOR ANY CONFOUNDING 583 00:23:58,320 --> 00:24:02,160 EFFECTS OF ALPHA THALASSEMIA TO 584 00:24:02,160 --> 00:24:03,560 RULE OUT --. 585 00:24:03,560 --> 00:24:06,280 MANY GROUPS HAVE ATTEMPTED TO 586 00:24:06,280 --> 00:24:12,000 DERIVE ALPHA THAL GINO TYPES. 587 00:24:12,000 --> 00:24:17,120 THIS PAPER HERE IS A TYPICAL 588 00:24:17,120 --> 00:24:19,560 EXAMPLE WHERE THEY CONCLUDE THAT 589 00:24:19,560 --> 00:24:23,040 IN FACT THE CAUSE OF THE COMPLEX 590 00:24:23,040 --> 00:24:25,960 HAPLOTYPE STRUCTURE ACROSS THE 591 00:24:25,960 --> 00:24:28,840 HEMOGLOBIN A GENE REGION BECOMES 592 00:24:28,840 --> 00:24:30,040 VERY CHALLENGING AND PREDICTION 593 00:24:30,040 --> 00:24:39,640 WAS NOT ACCURATE ENOUGH. 594 00:24:39,640 --> 00:24:41,600 SO SAM AND NCI FELT THEY WERE 595 00:24:41,600 --> 00:24:44,360 NOT CONFIDENT ENOUGH TO PREDICT 596 00:24:44,360 --> 00:24:47,320 ALPHA THAL FROM THE GENOME SCAN 597 00:24:47,320 --> 00:24:48,520 DATASET AND APPROACHED US TO 598 00:24:48,520 --> 00:24:51,880 HELP WITH THE ALPHA GENOTYPING 599 00:24:51,880 --> 00:24:54,680 AND IN EXCHANGE FOR THE SICKLE 600 00:24:54,680 --> 00:24:57,560 CELL BRANCH PERFORMING ALPHA 601 00:24:57,560 --> 00:24:59,320 GENOTYPING, NCI WILL GENOME SCAN 602 00:24:59,320 --> 00:25:01,320 SAMPLES FROM ANOTHER STUDY. 603 00:25:01,320 --> 00:25:03,520 AND OUR FIRST TASK WAS TO 604 00:25:03,520 --> 00:25:08,720 OPTIMIZE OUR DIGITAL DOPPLER PCR 605 00:25:08,720 --> 00:25:10,040 ASSAY. 606 00:25:10,040 --> 00:25:11,240 THEN ABLE RELIABLE RESULTS USING 607 00:25:11,240 --> 00:25:14,560 A MINIMAL AMOUNT OF DNA, AND 608 00:25:14,560 --> 00:25:18,600 SECONDLY TO -- AND THIS WAS 609 00:25:18,600 --> 00:25:22,960 METICULOUSLY CARRIED OUT BY OUR 610 00:25:22,960 --> 00:25:23,400 GROUP. 611 00:25:23,400 --> 00:25:24,840 HE TESTED DIFFERENT 612 00:25:24,840 --> 00:25:27,120 CONCENTRATIONS OF DNA AND THEN 613 00:25:27,120 --> 00:25:30,520 COMPARED THE WET DNA WITH DNA 614 00:25:30,520 --> 00:25:36,880 AIR DRIED, AND AS YOU CAN SEE, 615 00:25:36,880 --> 00:25:39,600 BELOW 6.5 -- RESULTS ARE 616 00:25:39,600 --> 00:25:43,840 QUESTIONABLE SO WE OPTED FOR 617 00:25:43,840 --> 00:25:46,280 20-NANOGRAMS DNA DRIED DOWN. 618 00:25:46,280 --> 00:25:50,640 SAM AND HIS GROUP THEN -- PLATES 619 00:25:50,640 --> 00:25:54,880 AND THIS WAS ACTUALLY TASKED 620 00:25:54,880 --> 00:25:57,320 TO -- STUDENTS, FRANCINE BAKER 621 00:25:57,320 --> 00:26:01,680 FROM THE NCI AND TEMI, A STUDENT 622 00:26:01,680 --> 00:26:02,760 IN OUR GROUP. 623 00:26:02,760 --> 00:26:06,720 THEY COLLECTED 5,000 SAMPLES. 624 00:26:06,720 --> 00:26:08,280 HERE YOU CAN SEE THE FREQUENCY 625 00:26:08,280 --> 00:26:09,720 OF ALPHA THALASSEMIA IN THE 626 00:26:09,720 --> 00:26:13,840 EMBLEM COHORT, VERSUS THE U.S. 627 00:26:13,840 --> 00:26:15,760 POPULATION, AND WHAT I'D LIKE TO 628 00:26:15,760 --> 00:26:17,240 POINT OUT IS THAT THE FREQUENCY 629 00:26:17,240 --> 00:26:20,000 OF ALPHA THALASSEMIA IN AFRICAN 630 00:26:20,000 --> 00:26:23,000 COHORT IS HIGHER THAN THAT IN 631 00:26:23,000 --> 00:26:25,240 THE SICKLE CELL DISEASE COHORT 632 00:26:25,240 --> 00:26:26,440 AS WELL AS THE REGARDS STUDY, 633 00:26:26,440 --> 00:26:33,240 AND THIS IS MOST LIKELY DUE TO 634 00:26:33,240 --> 00:26:33,760 RACIAL -- MIXTURE. 635 00:26:33,760 --> 00:26:35,280 WHICH IS CLEARLY SHOWN HERE WHEN 636 00:26:35,280 --> 00:26:37,720 WE LOOK AT AS INDIVIDUALS, NO, 637 00:26:37,720 --> 00:26:40,120 WE LOOK AT ANOTHER COHORT OF -- 638 00:26:40,120 --> 00:26:42,400 ANOTHER COHORT IN OUR PROTOCOL 639 00:26:42,400 --> 00:26:45,360 WHERE YOU COMPARED THE ALPHA 640 00:26:45,360 --> 00:26:46,680 GLOBIN -- ALPHA THALASSEMIA 641 00:26:46,680 --> 00:26:49,160 FREQUENCIES, AND HERE YOU CAN 642 00:26:49,160 --> 00:26:50,840 SEE THERE IS AN INCREASED 643 00:26:50,840 --> 00:26:56,440 FREQUENCY IN ALPHA THAT WILL THH 644 00:26:56,440 --> 00:27:01,640 EACH COPY O OF -- S. 645 00:27:01,640 --> 00:27:10,040 SO IT'S KUNDE INVESTIGATED A 646 00:27:10,040 --> 00:27:11,720 SIMILAR -- WHOLE GENE SEQUENCE 647 00:27:11,720 --> 00:27:14,280 DATA ON THE REFERENCE DATASET -- 648 00:27:14,280 --> 00:27:15,400 WE WERE QUITE EXCITED WHEN WE 649 00:27:15,400 --> 00:27:16,560 SAW THIS ALPHA THALASSEMIA BUT 650 00:27:16,560 --> 00:27:17,920 IN FACT IT DOES NOT SEEM SO 651 00:27:17,920 --> 00:27:19,680 SIMPLE. 652 00:27:19,680 --> 00:27:22,960 THE NON-DELETIONAL AND THE RARE 653 00:27:22,960 --> 00:27:24,800 4.2 DELETIONS -- SO WE REACHED 654 00:27:24,800 --> 00:27:28,000 OUT TO NHGRI AND NANCY HANSEN 655 00:27:28,000 --> 00:27:30,280 CAME UP WITH THE ANSWER 656 00:27:30,280 --> 00:27:33,560 GENERATING AN ALGORITHM USING AI 657 00:27:33,560 --> 00:27:37,720 AND MACHINE LEARNING FROM A 658 00:27:37,720 --> 00:27:39,480 WHOLE GENOME SEQUENCE DATASET 659 00:27:39,480 --> 00:27:40,680 DATA. 660 00:27:40,680 --> 00:27:42,880 AND SHE COMPARED HER MACHINE 661 00:27:42,880 --> 00:27:47,120 LEARNING METHOD TO OUR WET BENCH 662 00:27:47,120 --> 00:27:47,920 DDPCR. 663 00:27:47,920 --> 00:27:50,080 THE CONCORDANCE RATE WAS LIKE 664 00:27:50,080 --> 00:27:52,160 92%, AND WE ARE CURRENTLY 665 00:27:52,160 --> 00:27:53,920 REPEATING THE WET BENCH ASSAYS 666 00:27:53,920 --> 00:27:56,200 FOR THE SAMPLES THAT DO NOT 667 00:27:56,200 --> 00:28:00,480 AGREE, WHICH IS IN RED, TO 668 00:28:00,480 --> 00:28:02,120 VALIDATE THE ACCURACY. 669 00:28:02,120 --> 00:28:03,640 WHAT IS IMPORTANT USING THIS 670 00:28:03,640 --> 00:28:04,680 MACHINE LEARNING APPROACH IS 671 00:28:04,680 --> 00:28:06,840 THAT IT COULD PICK UP 672 00:28:06,840 --> 00:28:08,560 4.2 DELETION AND THE 673 00:28:08,560 --> 00:28:10,200 NON-DELETION ALPHA THAL 674 00:28:10,200 --> 00:28:11,720 VARIANTS, ALTHOUGH THESE ARE 675 00:28:11,720 --> 00:28:13,760 VERY UNCOMMON IN PEOPLE OF 676 00:28:13,760 --> 00:28:15,880 AFRICAN DESCENT. 677 00:28:15,880 --> 00:28:17,960 SO WITH THAT I'D LIKE TO HAND 678 00:28:17,960 --> 00:28:19,320 OVER TO SAM, BUT BEFORE THAT, I 679 00:28:19,320 --> 00:28:23,000 WOULD LIKE TO THANK THE PEOPLE 680 00:28:23,000 --> 00:28:25,520 WHO HELPED IN THIS PRESENTATION 681 00:28:25,520 --> 00:28:25,960 HERE. 682 00:28:25,960 --> 00:28:30,000 MY APPLAUSE GOES TO THE TWO 683 00:28:30,000 --> 00:28:33,400 STUDENTS, FRANCINE AND TEMI. 684 00:28:33,400 --> 00:28:36,560 ALSO TO XUNDE, WHO WAS A DIRECT 685 00:28:36,560 --> 00:28:39,520 MENTOR FOR TEMI, AND NANCY, WHO 686 00:28:39,520 --> 00:28:42,040 HELPED WITH THE ANALYSIS. 687 00:28:42,040 --> 00:28:45,680 SO OVER TO YOU, SAM. 688 00:28:45,680 --> 00:28:47,920 >>THANK YOU VERY MUCH, 689 00:28:47,920 --> 00:28:49,360 DR. THEIN, FOR INTRODUCING OUR 690 00:28:49,360 --> 00:28:50,920 RESEARCH. 691 00:28:50,920 --> 00:28:55,280 AND THANKS TO THE GRAND ROUNDS 692 00:28:55,280 --> 00:28:57,240 STAFF FOR INVITING US TO PRESENT 693 00:28:57,240 --> 00:28:58,960 AND ORGANIZING THIS GRAND ROUND. 694 00:28:58,960 --> 00:29:01,600 MY TALK WILL FOCUS ON BURKITT 695 00:29:01,600 --> 00:29:03,680 LYMPHOMA AS A PHENOTYPE OF 696 00:29:03,680 --> 00:29:07,520 MALARIA, AND SICKLE CELL TRAIT, 697 00:29:07,520 --> 00:29:11,840 AS WELL AS ALPHA THAL GINO TYP 698 00:29:11,840 --> 00:29:14,640 TYPES. 699 00:29:14,640 --> 00:29:18,680 WE'LL BE SHARING THE EMBLEM 700 00:29:18,680 --> 00:29:20,640 STUDY, MALAWI CHILDHOOD 701 00:29:20,640 --> 00:29:22,400 INFECTIONS AND CANCER STUDY 702 00:29:22,400 --> 00:29:24,720 WHICH I'LL REFER TO AS MALAWI. 703 00:29:24,720 --> 00:29:26,760 THE TWO QUESTIONS WE'LL BE 704 00:29:26,760 --> 00:29:28,840 ADDRESSING, DOES MALARIA CAUSE 705 00:29:28,840 --> 00:29:30,360 BURKITT LYMPHOMA AND DO THE 706 00:29:30,360 --> 00:29:32,440 SICKLE CELL TRAIT AND ALPHA 707 00:29:32,440 --> 00:29:39,360 THALASSEMIA ALEGA ALLELES PROTET 708 00:29:39,360 --> 00:29:42,200 AGAINST BURKITT LYMPHOMA, AND 709 00:29:42,200 --> 00:29:47,560 THEN CONCLUSIONS OF OUR DATA. 710 00:29:47,560 --> 00:29:51,080 PUBLICATION OF THIS REPORT BY 711 00:29:51,080 --> 00:29:54,080 DENNIS BURKITT. 712 00:29:54,080 --> 00:29:57,520 CHILDREN WITH MALIGNANT SARCOMAS 713 00:29:57,520 --> 00:29:58,280 IN AFRICA. 714 00:29:58,280 --> 00:30:00,320 THERE WERE TWO KEY INTERESTING 715 00:30:00,320 --> 00:30:01,480 FEATURES ABOUT THESE CASES. 716 00:30:01,480 --> 00:30:03,320 THE FIRST ONE WAS THE AGE 717 00:30:03,320 --> 00:30:04,720 DISTRIBUTION MOST CASES OCCURRED 718 00:30:04,720 --> 00:30:06,560 BETWEEN 2 AND 7 YEARS. 719 00:30:06,560 --> 00:30:08,360 WE SUGGESTED THAT THE MALIGNANCY 720 00:30:08,360 --> 00:30:12,400 WAS SUBACUTE IN THE CHILDREN. 721 00:30:12,400 --> 00:30:14,600 THE SECOND UNIQUE FEATURE WAS 722 00:30:14,600 --> 00:30:16,440 THE GEOGRAPHIC DISTRIBUTION 723 00:30:16,440 --> 00:30:17,840 INITIALLY NOTED IN UGANDA BUT 724 00:30:17,840 --> 00:30:19,720 ALSO ELSEWHERE IN AFRICA. 725 00:30:19,720 --> 00:30:23,200 THIS MAP SHOWS THE GEOGRAPHIC 726 00:30:23,200 --> 00:30:26,080 DISTRIBUTION OF CASES IN AFRICA. 727 00:30:26,080 --> 00:30:27,760 MOST WERE CONCENTRATED IN THE 728 00:30:27,760 --> 00:30:29,360 EQUATORIAL REGIONS, MOSTLY 729 00:30:29,360 --> 00:30:31,400 AROUND THE GREAT LAKES, LIKE 730 00:30:31,400 --> 00:30:34,120 LAKE VICTORIA IN KENYA, TANZANIA 731 00:30:34,120 --> 00:30:36,760 AND UGANDA. 732 00:30:36,760 --> 00:30:39,520 AND LAKE MALAWI IN MALAWI. 733 00:30:39,520 --> 00:30:41,680 THERE WERE CASES CLUSTERED ALONG 734 00:30:41,680 --> 00:30:45,600 THE COASTAL REGIONS AS WELL. 735 00:30:45,600 --> 00:30:49,360 MOSTLY ALONG THE GREAT RIVERS. 736 00:30:49,360 --> 00:30:51,520 THESE KEY TEE FEATURES SUGGESTED 737 00:30:51,520 --> 00:30:52,840 THIS CONDITION WAS MOSTLY 738 00:30:52,840 --> 00:30:54,160 PEDIATRIC, IT WAS ENDEMIC IN 739 00:30:54,160 --> 00:31:01,920 AFRICAN REGIONS WHERE MOSQUITOES 740 00:31:01,920 --> 00:31:03,800 WERE COMMON AND IT COULD BE 741 00:31:03,800 --> 00:31:05,720 CAUSED BY A PATHOGEN -- BY 742 00:31:05,720 --> 00:31:06,320 HOSPITALS. 743 00:31:06,320 --> 00:31:08,040 THOSE INFERENCES ATTRACTED 744 00:31:08,040 --> 00:31:09,920 INTEREST WORLDWIDE, AND LED TO 745 00:31:09,920 --> 00:31:11,960 THE DISCOVERY OF EPSTEIN-BARR 746 00:31:11,960 --> 00:31:13,600 VIRUS AS A FIRST HUMAN VIRUS 747 00:31:13,600 --> 00:31:16,040 LINK TO THE HUMAN CANCER. 748 00:31:16,040 --> 00:31:18,360 THERE WAS OTHER RESEARCH ABOUT 749 00:31:18,360 --> 00:31:20,080 THIS DISEASE INCLUDING WHETHER 750 00:31:20,080 --> 00:31:22,600 IT COULD BE CURED BY 751 00:31:22,600 --> 00:31:29,240 CHEMOTHERAPY. 752 00:31:29,240 --> 00:31:30,600 TODAY WE KNOW BURKITT LYMPHOMA 753 00:31:30,600 --> 00:31:31,240 OCCURS GLOBALLY. 754 00:31:31,240 --> 00:31:33,680 IN THIS SLIDE I'M SUMMARIZING 755 00:31:33,680 --> 00:31:38,320 DATA FROM 64 COUNTRIES FROM THE 756 00:31:38,320 --> 00:31:40,800 INCIDENCE IN -- REPORT PRODUCED 757 00:31:40,800 --> 00:31:41,800 BY THE WORLD HEALTH 758 00:31:41,800 --> 00:31:43,160 ORGANIZATION. 759 00:31:43,160 --> 00:31:46,560 THE MAP SHOWS THAT THE 760 00:31:46,560 --> 00:31:47,560 DISTRIBUTION OF BURKITT LYMPHOMA 761 00:31:47,560 --> 00:31:50,720 RANGES FROM LESS THAN 1 TO 762 00:31:50,720 --> 00:31:52,680 2 CASES PER MILLION, MOSTLY IN 763 00:31:52,680 --> 00:31:53,200 ASIA. 764 00:31:53,200 --> 00:31:54,840 COUNTRIES LIKE INDIA, CHINA, 765 00:31:54,840 --> 00:31:59,800 JAPAN AND SOUTH KOREA, RATES ARE 766 00:31:59,800 --> 00:32:01,240 INTERMEDIATE BETWEEN 2 AND 767 00:32:01,240 --> 00:32:03,720 4 CASES PER MILLION PEOPLE IN 768 00:32:03,720 --> 00:32:06,040 EUROPE, NORTH AMERICA AND LATIN 769 00:32:06,040 --> 00:32:07,040 AMERICA. 770 00:32:07,040 --> 00:32:08,320 AND COUNTRIES IN AFRICA HAVE 771 00:32:08,320 --> 00:32:11,080 HIGHER RATES RUNNING FROM 4 TO 772 00:32:11,080 --> 00:32:13,480 OVER 10 CASES PER MILLION. 773 00:32:13,480 --> 00:32:15,640 DISTRIBUTION IN AFRICA REALLY 774 00:32:15,640 --> 00:32:17,760 MIRRORS WHAT DENNIS BURKITT 775 00:32:17,760 --> 00:32:18,840 REPORTED FIVE DECADES AGO. 776 00:32:18,840 --> 00:32:21,360 ON THE RIGHT, I'M SHOWING A BAR 777 00:32:21,360 --> 00:32:23,640 GRAPH WHICH SHOWS THE INCIDENCE 778 00:32:23,640 --> 00:32:25,600 BY SEX, AND YOU CAN SEE ALMOST 779 00:32:25,600 --> 00:32:28,560 IN ALL COUNTRIES WHERE BURKITT 780 00:32:28,560 --> 00:32:30,440 LYMPHOMA HAS BEEN STUDIED, CASES 781 00:32:30,440 --> 00:32:32,960 OCCUR MORE IN MALES THAN 782 00:32:32,960 --> 00:32:33,480 FEMALES. 783 00:32:33,480 --> 00:32:34,800 WE DON'T KNOW WHY THAT IS THE 784 00:32:34,800 --> 00:32:36,760 CASE. 785 00:32:36,760 --> 00:32:38,440 BUT IT DOES SUGGEST THAT IN 786 00:32:38,440 --> 00:32:42,040 ADDITION TO MALARIA AND 787 00:32:42,040 --> 00:32:43,320 EPSTEIN-BARR VIRUS, THERE ARE 788 00:32:43,320 --> 00:32:44,680 OTHER RISK FACTORS YET TO BE 789 00:32:44,680 --> 00:32:48,720 DISCOVERED. 790 00:32:48,720 --> 00:32:50,360 THE TWO STUDIES THAT I SUES HAVE 791 00:32:50,360 --> 00:32:55,360 CLOSE TO FI 5,500 PARTICIPANTS 792 00:32:55,360 --> 00:33:01,680 ENROLLED INCLUDING CLOSE TO 200 793 00:33:01,680 --> 00:33:05,120 BURKITT LYMPHOMA CASES. 794 00:33:05,120 --> 00:33:07,200 CLOSE TO 5,000 PARTICIPANTS OF 795 00:33:07,200 --> 00:33:07,960 WHOM 800 ARE CASES. 796 00:33:07,960 --> 00:33:10,160 THE MAJORITY OF THE DATA COME 797 00:33:10,160 --> 00:33:14,720 FROM THE EMBLEM STUDY, WHICH -- 798 00:33:14,720 --> 00:33:18,560 WITH CLOSE TO 5,000 SUBJECTS AND 799 00:33:18,560 --> 00:33:19,120 ABOUT 900 BURKITT LYMPHOMA 800 00:33:19,120 --> 00:33:19,880 CASES. 801 00:33:19,880 --> 00:33:24,480 THE EMBLEM STUDY IS IN THE AREAS 802 00:33:24,480 --> 00:33:26,440 SHOWN ON THAT MAP. 803 00:33:26,440 --> 00:33:27,880 IT'S POPULATION-BASED. 804 00:33:27,880 --> 00:33:29,520 CASES COME FROM THE DEFINED 805 00:33:29,520 --> 00:33:32,440 GEOGRAPHIC AREAS AND THE 806 00:33:32,440 --> 00:33:34,680 CONTROLS WHERE -- FROM 300 807 00:33:34,680 --> 00:33:35,960 RANDOM VILLAGES. 808 00:33:35,960 --> 00:33:38,360 WE HAVE QUESTIONNAIRE, LAB 809 00:33:38,360 --> 00:33:40,320 RESULTS AND VILLAGE-LEVEL DATA, 810 00:33:40,320 --> 00:33:47,760 AS WELL AS BIOSPECIMENS FOR 811 00:33:47,760 --> 00:33:50,080 STUDIES. 812 00:33:50,080 --> 00:33:53,760 600 SUBJECTS IN THE MALAWI 813 00:33:53,760 --> 00:33:58,360 STUDY, CASES WERE ENROLLED AT A 814 00:33:58,360 --> 00:34:02,560 TERTIARY LEVEL HOSPITAL, TH WE 815 00:34:02,560 --> 00:34:04,520 CHARACTERIZE THEM AS CASES AND 816 00:34:04,520 --> 00:34:06,920 OTHERS I USED AS CONTROLS. 817 00:34:06,920 --> 00:34:08,440 WHOLE BLOOD SPECIMENS FOR OUR 818 00:34:08,440 --> 00:34:13,240 GENETIC STUDIES. 819 00:34:13,240 --> 00:34:16,680 IN ADDRESSING THE QUESTION DOES 820 00:34:16,680 --> 00:34:17,520 MALARIA INCREASE BURKITT 821 00:34:17,520 --> 00:34:20,360 LYMPHOMA RISK, I'LL FOLLOW THREE 822 00:34:20,360 --> 00:34:20,680 STRATEGIES. 823 00:34:20,680 --> 00:34:23,880 THE FIRST ONE IS TO USE PUBLIC 824 00:34:23,880 --> 00:34:25,920 HEALTH METRICS AS INDICATORS OF 825 00:34:25,920 --> 00:34:28,120 MALARIA BURDEN AND SEEK 826 00:34:28,120 --> 00:34:29,120 ASSOCIATION WITH VARIOUS 827 00:34:29,120 --> 00:34:30,000 INDICATORS. 828 00:34:30,000 --> 00:34:33,320 THE SECOND ONE IS TO CORRELATE 829 00:34:33,320 --> 00:34:35,040 MALARIA BURDEN WITH BURKITT 830 00:34:35,040 --> 00:34:37,120 LYMPHOMA RISK WITHIN DEFINED 831 00:34:37,120 --> 00:34:39,400 GEOGRAPHIC AREAS OF EMBLEM. 832 00:34:39,400 --> 00:34:44,000 AND THE THIRD ONE, THIS IS WHERE 833 00:34:44,000 --> 00:34:49,560 MY COLLABORATION WITH DR. SWEE 834 00:34:49,560 --> 00:34:51,880 LAY -- ASKS THE QUESTION WHETHER 835 00:34:51,880 --> 00:34:53,240 IT DOES PROTECT AGAINST BURKITT 836 00:34:53,240 --> 00:34:57,320 LYMPHOMA AS WELL. 837 00:34:57,320 --> 00:34:59,320 SO IN THIS SLIDE I'M SHOWING YOU 838 00:34:59,320 --> 00:35:01,280 MY FIRST RESULTS USING THE FIRST 839 00:35:01,280 --> 00:35:02,600 STRATEGY. 840 00:35:02,600 --> 00:35:05,200 WHERE WE ASKED INDIVIDUALS ABOUT 841 00:35:05,200 --> 00:35:07,840 VARIOUS HEALTH METRICS THAT 842 00:35:07,840 --> 00:35:11,200 INDICATE FROM THE GOVERNMENT 843 00:35:11,200 --> 00:35:13,200 PERSPECTIVE THAT WE LIVE IN AN 844 00:35:13,200 --> 00:35:14,200 AREA WHERE MALARIA BURDEN IS 845 00:35:14,200 --> 00:35:14,720 HIGH. 846 00:35:14,720 --> 00:35:19,320 I SHOW IN THE FIRST PART OF THAT 847 00:35:19,320 --> 00:35:20,200 TABLE, BURKITT LYMPHOMA CASES 848 00:35:20,200 --> 00:35:23,920 WERE MORE LIKELY TO REPORT THAN 849 00:35:23,920 --> 00:35:25,880 CONTROLS BEING IN AN AREA WHERE 850 00:35:25,880 --> 00:35:29,600 THE GOVERNMENT HAD DISTRIBUTED 851 00:35:29,600 --> 00:35:31,040 MOSQUITO BED NETS WHERE THEY HAD 852 00:35:31,040 --> 00:35:35,080 THEM BUT DID NOT USE THEM, OR WE 853 00:35:35,080 --> 00:35:36,520 WHERE THEY HAD THEM AND USED 854 00:35:36,520 --> 00:35:38,360 THEM, OR WHERE THEY LIVED IN 855 00:35:38,360 --> 00:35:41,080 HOUSES THAT HAD BEEN SPRAYED BY 856 00:35:41,080 --> 00:35:43,400 THE GOVERNMENT WITH RESIDUAL 857 00:35:43,400 --> 00:35:46,120 SPRAYING OR THEY USED REGULAR 858 00:35:46,120 --> 00:35:48,840 INSECTICIDE SPRAYS RANGING FROM 859 00:35:48,840 --> 00:35:49,400 3 TO 9. 860 00:35:49,400 --> 00:35:52,240 WE ALSO ASKED WHETHER THE 861 00:35:52,240 --> 00:35:55,080 CHILDREN HAD HAD A HISTORY OF 862 00:35:55,080 --> 00:35:56,200 MALARIA 12 MONTHS BEFORE 863 00:35:56,200 --> 00:35:57,600 ENROLLMENT IN THE EMBLEM STUDY. 864 00:35:57,600 --> 00:35:59,960 AND THE INTEREST HERE WAS 12 865 00:35:59,960 --> 00:36:01,080 MONTHS BEFORE ENROLLMENT BECAUSE 866 00:36:01,080 --> 00:36:02,760 WE WERE AWARE THAT BURKITT 867 00:36:02,760 --> 00:36:04,720 LYMPHOMA IS A SUBACUTE 868 00:36:04,720 --> 00:36:06,560 CONDITION, NOT AN ACUTE 869 00:36:06,560 --> 00:36:09,760 COMPLICATION OF MALARIA SO WE'RE 870 00:36:09,760 --> 00:36:11,600 LOOKING FOR -- HISTORY OF 871 00:36:11,600 --> 00:36:14,680 MALARIA EXPOSURE. 872 00:36:14,680 --> 00:36:17,640 MORE LIKELY TO REPORT INPATIENT 873 00:36:17,640 --> 00:36:18,960 MALARIA TREATMENT AS WELL AS 874 00:36:18,960 --> 00:36:20,160 OUTPATIENT MALARIA TREATMENT. 875 00:36:20,160 --> 00:36:22,680 THESE RESULTS INDICATE A VERY 876 00:36:22,680 --> 00:36:24,760 STRONG ASSOCIATION BETWEEN 877 00:36:24,760 --> 00:36:28,520 EXPOSURE TO HELY MALARIA AND 878 00:36:28,520 --> 00:36:30,200 BURKITT LYMPHOMA RISK. 879 00:36:30,200 --> 00:36:31,840 IT DOESN'T GIVE US A QUALITATIVE 880 00:36:31,840 --> 00:36:33,600 VALUE OF HOW MUCH MALARIA IS 881 00:36:33,600 --> 00:36:35,000 NEEDED TO INCREASE BURKITT 882 00:36:35,000 --> 00:36:44,760 LYMPHOMA RISK. 883 00:36:44,760 --> 00:36:46,120 TO TRY AND GET AT THAT QUESTION, 884 00:36:46,120 --> 00:36:49,360 WE USED OUR GEOGRAPHIC DATA FROM 885 00:36:49,360 --> 00:36:51,800 EMBLEM FIRST TO ESTIMATE BURKITT 886 00:36:51,800 --> 00:36:52,800 LYMPHOMA INCIDENCE IN 49 887 00:36:52,800 --> 00:36:54,800 DISTRICTS WHERE WE HAD COMPLETE 888 00:36:54,800 --> 00:36:57,040 LOCATION DATA FOR THE CASES AS 889 00:36:57,040 --> 00:36:59,440 WELL AS POPULATION BASED DATA. 890 00:36:59,440 --> 00:37:02,480 ON THE LEFT, I SHOW THE MAP OF 891 00:37:02,480 --> 00:37:05,480 THE STUDY AREA WITH THE BURKITT 892 00:37:05,480 --> 00:37:07,960 LYMPHOMA INCIDENCE DATA SHADED 893 00:37:07,960 --> 00:37:09,160 THERE AS COLORS. 894 00:37:09,160 --> 00:37:13,320 THE INCIDENCE RANKED FROM ZERO 895 00:37:13,320 --> 00:37:15,800 TO 60, WITH MORE INTENSE COLORS 896 00:37:15,800 --> 00:37:16,920 INDICATING HIGHER INCIDENCE. 897 00:37:16,920 --> 00:37:19,360 AND THEN FOR THE SAME REGIONS, 898 00:37:19,360 --> 00:37:22,520 WE WERE ABLE TO CALCULATE THE 899 00:37:22,520 --> 00:37:25,640 NUMBER OF INFECTIONS, OF MALARIA 900 00:37:25,640 --> 00:37:26,760 INFECTIONS A CHILD HAD BY YEAR. 901 00:37:26,760 --> 00:37:29,480 TO DO THAT, WE USED DATA FROM 902 00:37:29,480 --> 00:37:31,800 THE MALARIA ATLAS PROJECT. 903 00:37:31,800 --> 00:37:34,200 THE MALARIA ATLAS PROJECT 904 00:37:34,200 --> 00:37:36,840 COMPILES MALARIA INFECTION DATA 905 00:37:36,840 --> 00:37:39,320 GLOBALLY AT A VERY HIGH 906 00:37:39,320 --> 00:37:43,160 RESOLUTION OF -- OF AREA. 907 00:37:43,160 --> 00:37:45,520 SO WE WERE ABLE TO EXTRACT DATA 908 00:37:45,520 --> 00:37:47,680 FOR THE 49 DISTRICTS AND USED 909 00:37:47,680 --> 00:37:49,520 MATHEMATICAL FORMULAE TO CONVERT 910 00:37:49,520 --> 00:37:52,920 IT INTO THE NUMBER OF INFECTIONS 911 00:37:52,920 --> 00:37:53,680 BY CHILD BY YEAR. 912 00:37:53,680 --> 00:37:57,720 ON THE RIGHT, I SHOW THE DATA 913 00:37:57,720 --> 00:37:58,760 FOR MALARIA BURDEN. 914 00:37:58,760 --> 00:38:00,920 WHAT WE FOUND WAS WITHIN THE 915 00:38:00,920 --> 00:38:03,200 STUDY AREA, CHILDREN WERE 916 00:38:03,200 --> 00:38:06,360 GETTING BETWEEN 100 AND 400 917 00:38:06,360 --> 00:38:08,240 INFECTIONS BY CHILD BY YEAR. 918 00:38:08,240 --> 00:38:11,200 THAT'S AN ENORMOUS NUMBER, IF 919 00:38:11,200 --> 00:38:14,280 YOU USE COVID AS AN EXAMPLE, IF 920 00:38:14,280 --> 00:38:16,680 SOMEBODY HAD 20 INFECTIONS OF 921 00:38:16,680 --> 00:38:18,240 COVID THAT WOULD BE ENORMOUS, 922 00:38:18,240 --> 00:38:21,040 BUT THIS IS 100 TO 400 923 00:38:21,040 --> 00:38:22,480 INFECTIONS BY CHILD BY YEAR. 924 00:38:22,480 --> 00:38:24,760 WHAT WAS INTERESTING IS WE 925 00:38:24,760 --> 00:38:27,960 CORRELATED THE MALARIA BURDEN TO 926 00:38:27,960 --> 00:38:28,920 BURKITT LYMPHOMA INCIDENCE, WE 927 00:38:28,920 --> 00:38:33,000 FOUND A STRONG CORRELATION, 928 00:38:33,000 --> 00:38:36,360 CLOSE TO .6, THAT IS 929 00:38:36,360 --> 00:38:37,040 STATISTICALLY SIGNIFICANT. 930 00:38:37,040 --> 00:38:39,960 THESE ARE THE CLEAREST DATA 931 00:38:39,960 --> 00:38:42,800 INDICATING THAT AS THE NUMBER OF 932 00:38:42,800 --> 00:38:43,880 MALARIA INFECTIONS INCREASE IN A 933 00:38:43,880 --> 00:38:45,560 POPULATION, SO DOES THE BURKITT 934 00:38:45,560 --> 00:38:49,360 LYMPHOMA RISK IN THAT POPULA 935 00:38:49,360 --> 00:38:49,680 POPULATION. 936 00:38:49,680 --> 00:38:51,000 THE WEAKNESSES HERE ARE WE STILL 937 00:38:51,000 --> 00:38:54,920 DON'T KNOW WHAT THE -- RISK FOR 938 00:38:54,920 --> 00:38:56,280 BURKITT LYMPHOMA IS SO WE WANTED 939 00:38:56,280 --> 00:39:00,960 TO ALSO GET TO THAT. 940 00:39:00,960 --> 00:39:02,960 IN THIS SLIDE, I'M SHOWING YOU 941 00:39:02,960 --> 00:39:07,000 RESULTS WHERE WE ATTEMPTED TO 942 00:39:07,000 --> 00:39:08,160 ESTIMATE THE INFECTION RISK FOR 943 00:39:08,160 --> 00:39:08,960 BURKITT LYMPHOMA IN OUR 944 00:39:08,960 --> 00:39:11,240 POPULATION. 945 00:39:11,240 --> 00:39:15,440 AND WHAT WE DID, WE ESTIMATED 946 00:39:15,440 --> 00:39:18,080 THE NUMBER OF INFECTIONS A CHILD 947 00:39:18,080 --> 00:39:20,760 IN A GIVEN LOCATION OR A GIVEN 948 00:39:20,760 --> 00:39:23,400 EDGE WOULD HAVE HAD AT A GIVEN 949 00:39:23,400 --> 00:39:23,840 TIME. 950 00:39:23,840 --> 00:39:27,360 AND THEN COMPARED WHAT CHILDREN 951 00:39:27,360 --> 00:39:31,280 WHO DID NOT HAVE GIVEN EDGE FROM 952 00:39:31,280 --> 00:39:32,720 THE SAME LOCATION WOULD HAVE 953 00:39:32,720 --> 00:39:33,040 HAD. 954 00:39:33,040 --> 00:39:35,880 AND WHAT THE RESULTS IN THE LEFT 955 00:39:35,880 --> 00:39:39,920 GRAPH SHOW, BEGINNING WITH THE X 956 00:39:39,920 --> 00:39:42,880 AXIS, I'M SHOWING YOU 957 00:39:42,880 --> 00:39:43,760 ACCUMULATED NUMBER OF 958 00:39:43,760 --> 00:39:46,160 INFORECASTS WE CALCULATED AND ON 959 00:39:46,160 --> 00:39:48,200 THE Y AXIS I'M SHOWING THE 960 00:39:48,200 --> 00:39:50,760 BURKITT LYMPHOMA INCIDENCE 961 00:39:50,760 --> 00:39:51,640 RATIO. 962 00:39:51,640 --> 00:39:54,280 WHEN YOU COMPARE THE CHILDREN 963 00:39:54,280 --> 00:39:57,320 THAT HAD 50 INFECTIONS, EACH 964 00:39:57,320 --> 00:40:01,320 ADDITIONAL 100 INFECTIONS AFFECT 965 00:40:01,320 --> 00:40:02,680 9% INCREASE IN BURKITT LYMPHOMA 966 00:40:02,680 --> 00:40:04,200 WHICH WAS STATISTICALLY 967 00:40:04,200 --> 00:40:04,560 SIGNIFICANT. 968 00:40:04,560 --> 00:40:08,040 THIS IS THE FIRST PART INFECTION 969 00:40:08,040 --> 00:40:09,120 ESTIMATE THAT IS AVAILABLE. 970 00:40:09,120 --> 00:40:11,080 WE WERE INTERESTED IN FINDING 971 00:40:11,080 --> 00:40:14,280 OUT IF THE INTENSITY OF 972 00:40:14,280 --> 00:40:17,040 INFECTION, IF THE NUMBER OF 973 00:40:17,040 --> 00:40:19,440 INFECTIONS A CHILD SABAWI 974 00:40:19,440 --> 00:40:26,280 IBRAHIM AL-HHAS, HAS --ON THEIR. 975 00:40:26,280 --> 00:40:27,880 ON THE RIGHT IS THE THREE 976 00:40:27,880 --> 00:40:29,000 INFECTION LEVELS. 977 00:40:29,000 --> 00:40:31,360 ONE INFECTION A YEAR, 10 978 00:40:31,360 --> 00:40:32,640 INFECTIONS PER YEAR AND 20 979 00:40:32,640 --> 00:40:33,600 INFECTIONS PER YEAR. 980 00:40:33,600 --> 00:40:36,000 THE Y AXIS SHOWS THE INCIDENCE 981 00:40:36,000 --> 00:40:38,120 RATIO AS BEFORE, BUT THIS TIME 982 00:40:38,120 --> 00:40:40,400 THE X AXIS IS SHOWING THE RISK 983 00:40:40,400 --> 00:40:41,520 BY AGE. 984 00:40:41,520 --> 00:40:43,000 AND WHAT YOU CAN SEE VERY 985 00:40:43,000 --> 00:40:45,560 CLEARLY AS THE NUMBER OF 986 00:40:45,560 --> 00:40:47,280 INFECTIONS A CHILD IS EXPOSED TO 987 00:40:47,280 --> 00:40:53,000 IN THAT AREA INCREASES, SO DOES 988 00:40:53,000 --> 00:40:55,040 THE -- RISK INCREASE, WITH THE 989 00:40:55,040 --> 00:40:58,880 RISK BEING HIGHEST IN -- 990 00:40:58,880 --> 00:41:01,840 COMPARED TO THOSE EXPRESSING ONE 991 00:41:01,840 --> 00:41:06,960 INFECTION PER YEAR. 992 00:41:06,960 --> 00:41:10,240 WE WERE THEN ABLE TO ASK ANOTHER 993 00:41:10,240 --> 00:41:12,680 QUESTION, WHETHER THERE WERE 994 00:41:12,680 --> 00:41:14,160 DECREASING TRENDS IN MALARIA 995 00:41:14,160 --> 00:41:18,360 INFECTION RATES WITHIN OUR STUDY 996 00:41:18,360 --> 00:41:19,080 POPULATION -- AND WE WERE ABLE 997 00:41:19,080 --> 00:41:22,720 TO SHOW THAT BETWEEN 2000 AND 998 00:41:22,720 --> 00:41:27,520 2015, WHERE WE ANALYZE DATA, P 999 00:41:27,520 --> 00:41:32,720 FALCIPARUM INTUCKS RATES FELL BL 1000 00:41:32,720 --> 00:41:33,160 BY 50%. 1001 00:41:33,160 --> 00:41:34,600 WHAT WAS INTERESTING IN THE SAME 1002 00:41:34,600 --> 00:41:37,880 PERIOD WHEN WE ENROLLED CASES, 1003 00:41:37,880 --> 00:41:39,720 BURKITT LYMPHOMA RISK FELL BY 1004 00:41:39,720 --> 00:41:43,560 10%, SHOWING FOR THE FIRST TIME 1005 00:41:43,560 --> 00:41:49,920 DECLINING RATES OF P 1006 00:41:49,920 --> 00:41:51,200 FALCIPARUM -- THESE RESULTS 1007 00:41:51,200 --> 00:41:52,640 INDICATE A -- CORRELATION 1008 00:41:52,640 --> 00:41:54,400 BETWEEN MALARIA AND BURKITT 1009 00:41:54,400 --> 00:41:55,120 LYMPHOMA. 1010 00:41:55,120 --> 00:41:57,000 THE LIMITATIONS OF THE DATA ARE 1011 00:41:57,000 --> 00:41:58,560 THAT WE REALLY DON'T KNOW 1012 00:41:58,560 --> 00:41:59,640 WHETHER IT IS THE BURKITT 1013 00:41:59,640 --> 00:42:02,280 LYMPHOMA CASES WHO ARE 1014 00:42:02,280 --> 00:42:04,160 EXPERIENCING THE HEAVY MALARIA 1015 00:42:04,160 --> 00:42:11,800 BURDEN BECAUSE WE CONDUCTED 1016 00:42:11,800 --> 00:42:14,000 THESE -- PRESENT BEFORE MALARIA 1017 00:42:14,000 --> 00:42:15,960 AND IF SOMEBODY HAS THAT MARKER 1018 00:42:15,960 --> 00:42:17,840 THEY'VE HAD LESS MALARIA THAN 1019 00:42:17,840 --> 00:42:19,680 ONE WHO DOESN'T HAVE THE MARKER. 1020 00:42:19,680 --> 00:42:21,280 AND THAT'S WHEN WE TURNED TO THE 1021 00:42:21,280 --> 00:42:22,400 SICKLE CELL TRAIT AND ASKED THE 1022 00:42:22,400 --> 00:42:24,720 QUESTION, IS THE CORRELATION 1023 00:42:24,720 --> 00:42:26,800 BETWEEN CARRYING THE SICKLE CELL 1024 00:42:26,800 --> 00:42:29,120 TRAIT AND BURKITT LYMPHOMA? 1025 00:42:29,120 --> 00:42:31,560 TO BE HONEST, WE'RE NOT THE 1026 00:42:31,560 --> 00:42:32,720 FIRST TO THINK ABOUT THIS IDEA, 1027 00:42:32,720 --> 00:42:34,160 WHEN WE LOOKED IN THE 1028 00:42:34,160 --> 00:42:34,960 LITERATURE, WE FOUND THERE ARE 1029 00:42:34,960 --> 00:42:36,320 FIVE STUDIES THAT HAVE LOOKED AT 1030 00:42:36,320 --> 00:42:37,440 THIS IDEA IN THE PAST. 1031 00:42:37,440 --> 00:42:40,480 BEGINNING WITH THE FIRST ONE IN 1032 00:42:40,480 --> 00:42:43,320 1966, IN A STUDY CONNECTED IN 1033 00:42:43,320 --> 00:42:45,960 NIGERIA, WHERE THEY FOUND THAT 1034 00:42:45,960 --> 00:42:49,240 CHILDREN WITH SICKLE CELL TRAIT 1035 00:42:49,240 --> 00:42:51,360 WERE SIGNIFICANTLY LESS LIKELY 1036 00:42:51,360 --> 00:42:54,640 TO HAVE BURKITT LYMPHOMA. 1037 00:42:54,640 --> 00:42:56,280 THAT WAS A STATISTICALLY 1038 00:42:56,280 --> 00:42:57,200 SIGNIFICANT RESULT. 1039 00:42:57,200 --> 00:42:58,680 HOWEVER, FOUR OTHER STUDIES THAT 1040 00:42:58,680 --> 00:42:59,800 WERE CONDUCTED AFTERWARDS HAD 1041 00:42:59,800 --> 00:43:03,720 MIXED RESULTS WITH SOME FINDING 1042 00:43:03,720 --> 00:43:05,840 DECREASED RISK THAT WAS NOT 1043 00:43:05,840 --> 00:43:06,520 STATISTICALLY SIGNIFICANT AND 1044 00:43:06,520 --> 00:43:09,640 ONE STUDY FOUND FINDING AN 1045 00:43:09,640 --> 00:43:12,280 INCREASED RISK THAT WAS NOT 1046 00:43:12,280 --> 00:43:12,880 STATISTICALLY SIGNIFICANT. 1047 00:43:12,880 --> 00:43:15,080 SO WE KNEW THE QUESTION WAS 1048 00:43:15,080 --> 00:43:16,200 STILL VERY MUCH OPEN AND 1049 00:43:16,200 --> 00:43:17,920 DESERVED A CAREFUL LOOK TO SEE 1050 00:43:17,920 --> 00:43:19,280 WHAT THE ACTUAL RELATIONSHIP 1051 00:43:19,280 --> 00:43:28,000 WAS. 1052 00:43:28,000 --> 00:43:30,840 SO THEN WE HAVE USED OUR EMBLEM 1053 00:43:30,840 --> 00:43:33,240 MALAWI STUDIES, ESPECIALLY THE 1054 00:43:33,240 --> 00:43:35,560 GENOMES AND SUBSET, WHERE WE 1055 00:43:35,560 --> 00:43:41,480 HAVE CLOSE TO FIVE THOWL -- DATA 1056 00:43:41,480 --> 00:43:43,640 TO ASK THE QUESTION, THE 1057 00:43:43,640 --> 00:43:46,080 MODIFICATION WE DID IN OUR STUDY 1058 00:43:46,080 --> 00:43:48,600 WAS -- WE DECIDED TO LOOK AT ALL 1059 00:43:48,600 --> 00:43:50,120 LOCI THAT HAVE BEEN PUBLISHED IN 1060 00:43:50,120 --> 00:43:52,640 THE LITERATURE AS HAVING AN 1061 00:43:52,640 --> 00:43:54,320 EFFECT ON MALARIA INCLUDING THE 1062 00:43:54,320 --> 00:43:56,040 SICKLE CELL. 1063 00:43:56,040 --> 00:43:58,560 AND WHILE WE'RE DOING THIS, WE 1064 00:43:58,560 --> 00:44:00,960 WANT TO ALSO INCLUDE THE ALPHA 1065 00:44:00,960 --> 00:44:01,560 THALASSEMIA GENOTYPES, AND THAT 1066 00:44:01,560 --> 00:44:05,320 IS WHEN WE DISCOVERED THAT WE 1067 00:44:05,320 --> 00:44:08,320 COULDN'T PREDICT WHAT THOSE 1068 00:44:08,320 --> 00:44:10,520 GENOTYPES BE USING OUR GENOME 1069 00:44:10,520 --> 00:44:12,600 SCAN DATA AND WE MOVED TO 1070 00:44:12,600 --> 00:44:14,320 COLLABORATION WITH DR. THEIN SO 1071 00:44:14,320 --> 00:44:15,920 SHE COULD HELP US TO GENOTYPE 1072 00:44:15,920 --> 00:44:26,080 OUR SUBJECTS. 1073 00:44:26,080 --> 00:44:28,040 SO I'D LIKE TO COMMENT ABOUT THE 1074 00:44:28,040 --> 00:44:29,520 UNIQUE STRENGTHS OF OUR STUDY TO 1075 00:44:29,520 --> 00:44:32,200 USE GENETIC MARKERS TO ADDRESS 1076 00:44:32,200 --> 00:44:33,360 THIS QUESTION. 1077 00:44:33,360 --> 00:44:35,000 THE FIRST GENETIC STRENGTH IS 1078 00:44:35,000 --> 00:44:37,560 THAT WE ALREADY KNOW THE MALARIA 1079 00:44:37,560 --> 00:44:40,920 BURDEN IN AFRICAN NATION FOR 1080 00:44:40,920 --> 00:44:42,600 EXAMPLE, EVERY CHILD LIVING IN 1081 00:44:42,600 --> 00:44:44,120 THIS AREA WILL EXPERIENCE 1082 00:44:44,120 --> 00:44:46,640 BETWEEN 100 AND 400 INFECTIONS 1083 00:44:46,640 --> 00:44:47,200 BY YEAR. 1084 00:44:47,200 --> 00:44:50,680 SO THAT'S AN ENORMOUS BURDEN OF 1085 00:44:50,680 --> 00:44:52,120 MALARIA THAT WE HAVE TO DEAL 1086 00:44:52,120 --> 00:44:54,520 WITH, AND THOSE WHO HAVE 1087 00:44:54,520 --> 00:44:56,840 GENOTYPES THAT PROTECT THEM 1088 00:44:56,840 --> 00:44:58,800 WOULD HAVE AN ADVANTAGE. 1089 00:44:58,800 --> 00:45:00,000 THE SECOND APPROACH THAT WE USED 1090 00:45:00,000 --> 00:45:03,640 TO VERIFY THAT ASSUMPTION WAS 1091 00:45:03,640 --> 00:45:05,160 SAMPLING 100 OF OUR SUBJECTS. 1092 00:45:05,160 --> 00:45:08,120 50 CASES AND 50 HEALTHY 1093 00:45:08,120 --> 00:45:09,560 CHILDREN, RANDOMLY SELECTED FROM 1094 00:45:09,560 --> 00:45:10,800 THE ENTIRE STUDY. 1095 00:45:10,800 --> 00:45:19,120 AND WE MEASURED -- 1,000 PEOP 1096 00:45:19,120 --> 00:45:20,640 PEOPLE -- PROTEINS BECAUSE THE 1097 00:45:20,640 --> 00:45:23,240 NEW RESPONSE -- HAD DIFFERENT 1098 00:45:23,240 --> 00:45:24,880 PATHOGENS. 1099 00:45:24,880 --> 00:45:27,480 AND IN THIS SLIDE I'M SHOWING 1100 00:45:27,480 --> 00:45:28,160 TWO HEAT MAPS. 1101 00:45:28,160 --> 00:45:30,360 I'LL JUST EXPLAIN EXACTLY HOW 1102 00:45:30,360 --> 00:45:32,360 THEY'RE ARRAYED. 1103 00:45:32,360 --> 00:45:36,160 THE COLUMNS ARE INDIVIDUAL 1104 00:45:36,160 --> 00:45:40,440 SUBJECTS, THEIR -- 1,000 1105 00:45:40,440 --> 00:45:40,760 PROTEINS. 1106 00:45:40,760 --> 00:45:41,920 I HAVE SORTED THE PROTEINS 1107 00:45:41,920 --> 00:45:44,280 ACCORDING TO THE STAGE OF 1108 00:45:44,280 --> 00:45:46,800 MALARIA WHERE THOSE PROTEINS ARE 1109 00:45:46,800 --> 00:45:47,400 EXPRESSED. 1110 00:45:47,400 --> 00:45:51,040 SO FOR EXAMPLE, THE LITTLE GREEN 1111 00:45:51,040 --> 00:45:53,120 BARS ON THE SIDE INDICATES 1112 00:45:53,120 --> 00:45:55,640 PROTEINS EXPRESSED IN THE -- 1113 00:45:55,640 --> 00:45:56,280 STAGE. 1114 00:45:56,280 --> 00:45:57,880 THE YELLOW BARS INDICATE THOSE 1115 00:45:57,880 --> 00:46:02,320 IN THE -- STAGE, THE BLUE ONES, 1116 00:46:02,320 --> 00:46:06,600 THE -- STAGE AND THE -- AND THEN 1117 00:46:06,600 --> 00:46:08,720 WITHIN EACH HEAT MAP OF CERTAIN 1118 00:46:08,720 --> 00:46:10,120 INDIVIDUALS BUT COUNTRY, SO WE 1119 00:46:10,120 --> 00:46:12,840 HAVE UGANDA, TANZANIA AND KENYA 1120 00:46:12,840 --> 00:46:14,800 AND WITHIN EACH COUNTRY I'VE 1121 00:46:14,800 --> 00:46:16,240 SORTED INDIVIDUALS BY AGE SO THE 1122 00:46:16,240 --> 00:46:17,200 YOUNGEST ARE ON THE RIGHT AND 1123 00:46:17,200 --> 00:46:20,840 THE OLDEST ARE ON THE LEFT. 1124 00:46:20,840 --> 00:46:23,000 WHAT YOU CAN SEE IS IF YOU STAND 1125 00:46:23,000 --> 00:46:24,120 BACK AND LOOK AT THESE HEAT 1126 00:46:24,120 --> 00:46:25,880 MAPS, SO THE HEAT MAP ON THE 1127 00:46:25,880 --> 00:46:27,560 LEFT IS FOR HEALTHY CHILDREN AND 1128 00:46:27,560 --> 00:46:28,520 THE ONE ON THE RIGHT IS FOR 1129 00:46:28,520 --> 00:46:30,640 CASE, YOU CAN SEE VERY CLEARLY 1130 00:46:30,640 --> 00:46:31,920 YOU CANNOT DISTINGUISH THE CASES 1131 00:46:31,920 --> 00:46:33,280 OR THE CONTROLS OR EVEN THE 1132 00:46:33,280 --> 00:46:33,560 COUNTRIES. 1133 00:46:33,560 --> 00:46:35,320 SO THAT WAS ANOTHER REASSURANCE 1134 00:46:35,320 --> 00:46:37,000 THAT OUR POPULATION IS HEAVILY 1135 00:46:37,000 --> 00:46:37,840 EXPOSED TO MALARIA AND 1136 00:46:37,840 --> 00:46:44,640 APPROPRIATE FOR THIS APPROACH. 1137 00:46:44,640 --> 00:46:45,760 ANOTHER STRENGTH IS HAVING 1138 00:46:45,760 --> 00:46:47,800 GENOME SCAN DATA BECAUSE WE 1139 00:46:47,800 --> 00:46:48,480 BECAME AWARE THAT BECAUSE WE 1140 00:46:48,480 --> 00:46:51,880 WERE USING GENETIC MARKERS, 1141 00:46:51,880 --> 00:46:54,600 THERE WAS POSSIBILITY OF 1142 00:46:54,600 --> 00:46:57,200 CONFOUNDING BY ANCESTRY IN THE 1143 00:46:57,200 --> 00:47:02,200 DIFFERENT POPULATION FOR AFRICAN 1144 00:47:02,200 --> 00:47:06,680 COUNTRIES BUT OUR COLLEAGUES AT 1145 00:47:06,680 --> 00:47:10,920 NHGRI -- AND CONTROL FOR -- IN 1146 00:47:10,920 --> 00:47:16,080 OUR ANALYSES. 1147 00:47:16,080 --> 00:47:19,240 AND THEN WE THOUGHT THAT COULD 1148 00:47:19,240 --> 00:47:21,240 BE GENETIC RELATIONSHIPS BUT WE 1149 00:47:21,240 --> 00:47:24,600 WEREN'T SURE, BUT AGAIN GENOME 1150 00:47:24,600 --> 00:47:26,720 SCAN DATA WERE ABLE TO -- 1151 00:47:26,720 --> 00:47:29,200 QUANTITATIVELY AND WE IDENTIFY 1152 00:47:29,200 --> 00:47:31,200 THAT WE HAD GENETICALLY RELATED 1153 00:47:31,200 --> 00:47:33,120 INDIVIDUALS IN OUR UGANDAN SET 1154 00:47:33,120 --> 00:47:36,600 OF SAMPLES, SLIGHTLY FEWER IN 1155 00:47:36,600 --> 00:47:39,880 KENYA AND TANZANIA AND THIS 1156 00:47:39,880 --> 00:47:41,080 ALLOWED US ALSO TO INCORPORATE 1157 00:47:41,080 --> 00:47:42,080 JE NE AT THIS TIME RELATED LESS 1158 00:47:42,080 --> 00:47:45,920 IN THE MODELS. 1159 00:47:45,920 --> 00:47:47,440 SO THIS SLIDE SUMMARIZES THE 1160 00:47:47,440 --> 00:47:49,640 BASE MODEL THAT WE HAVE USED TO 1161 00:47:49,640 --> 00:47:51,400 DRAW GENETIC ANALYSIS. 1162 00:47:51,400 --> 00:47:55,000 WE CONTROL FOR AGE, SEX, 1163 00:47:55,000 --> 00:47:57,560 COUNTRY-SPECIFIC PCs, COUNTRY, 1164 00:47:57,560 --> 00:48:03,360 AND GENETIC RELATEDNESS. 1165 00:48:03,360 --> 00:48:06,240 SO THIS IS THE RESULT THAT WE 1166 00:48:06,240 --> 00:48:10,760 IDENTIFIED IN THE LITERATURE. 1167 00:48:10,760 --> 00:48:12,600 THE FIRST ON THE RIGHT -- FOR 1168 00:48:12,600 --> 00:48:17,520 THE EFFECT OF EACH LOCUS FROM 1169 00:48:17,520 --> 00:48:17,960 INFECTION. 1170 00:48:17,960 --> 00:48:19,400 IN THE FIRST PLOT ON THE LEFT 1171 00:48:19,400 --> 00:48:25,360 SHOWS THE EVENT OF EACH LOCUS IN 1172 00:48:25,360 --> 00:48:25,760 BURKITT LYMPHOMA. 1173 00:48:25,760 --> 00:48:27,960 WHEN WE CORRELATED THESE EFFECTS 1174 00:48:27,960 --> 00:48:30,680 WE FOUND THEY WERE SIGNIFICANTLY 1175 00:48:30,680 --> 00:48:33,640 CORRELATED WITH -- .4. 1176 00:48:33,640 --> 00:48:35,400 WHAT THAT MEANS IS IF THE EFFECT 1177 00:48:35,400 --> 00:48:39,560 OF THE LOCUS IS TO DECREASE -- 1178 00:48:39,560 --> 00:48:41,120 INFECTION, THAT LOCUS WILL ALSO 1179 00:48:41,120 --> 00:48:44,480 TEND TO HAVE A -- EFFECT TO -- 1180 00:48:44,480 --> 00:48:45,800 THE RISK FOR BURKITT LYMPHOMA. 1181 00:48:45,800 --> 00:48:48,240 HOWEVER, WHAT WAS EVEN MORE 1182 00:48:48,240 --> 00:48:50,000 INTERESTING, WE HAD TWO LOCI 1183 00:48:50,000 --> 00:48:52,720 THAT STATISTICALLY PROTECTED 1184 00:48:52,720 --> 00:48:54,280 AGAINST BURKITT LYMPHOMA RISK. 1185 00:48:54,280 --> 00:48:56,320 ONE LOCUS WAS IN THE -- REGION 1186 00:48:56,320 --> 00:48:58,000 AND THE OTHER WAS -- THE SICKLE 1187 00:48:58,000 --> 00:49:02,800 CELL ALLELE. 1188 00:49:02,800 --> 00:49:06,440 SO THIS SLIDE SUMMARIZES THE -- 1189 00:49:06,440 --> 00:49:06,680 EFFECTS. 1190 00:49:06,680 --> 00:49:11,880 SO THE TWO LOCI DECREASE THE 1191 00:49:11,880 --> 00:49:15,280 RISK BETWEEN -- TO 40%. 1192 00:49:15,280 --> 00:49:17,400 WE LOOKED AT THE EFFECTS BY 1193 00:49:17,400 --> 00:49:20,560 COUNTRY AND WE FOUND THAT THOSE 1194 00:49:20,560 --> 00:49:21,840 VARIATION, SO BEGINNING WITH THE 1195 00:49:21,840 --> 00:49:23,160 FIRST PLOT ON THE LEFT, THAT'S 1196 00:49:23,160 --> 00:49:24,840 FOR THE SICKLE CELL ALLELE. 1197 00:49:24,840 --> 00:49:28,320 WE FOUND THAT EFFECTS WERE 1198 00:49:28,320 --> 00:49:29,760 SIGNIFICANT IN UGANDA AND MALAWI 1199 00:49:29,760 --> 00:49:40,320 BUT NOT SIGNIFICANT IN TANZANIA. 1200 00:49:44,720 --> 00:49:47,200 SO THE VARIATION OF EFFECT BY 1201 00:49:47,200 --> 00:49:50,560 COUNTRY MADE US REMEMBER WHAT 1202 00:49:50,560 --> 00:49:55,280 DR. SWEE LAY HAS PRESENTED WITH 1203 00:49:55,280 --> 00:49:57,720 THE EPISTATIC EFFECTS THAT WE'RE 1204 00:49:57,720 --> 00:50:00,720 SEEING BUT NOT CONTROLLING FOR 1205 00:50:00,720 --> 00:50:04,080 BETWEEN ALPHA THALASSEMIA AND 1206 00:50:04,080 --> 00:50:08,840 SICKLE CELL ALLELE SO WE LOOKED 1207 00:50:08,840 --> 00:50:12,360 FOR ALPHA THALASSEMIA AND 1208 00:50:12,360 --> 00:50:15,840 THEN -- BY SICKLE CELL STATUS. 1209 00:50:15,840 --> 00:50:18,080 SO IN THIS SLIDE I'M SHOWING THE 1210 00:50:18,080 --> 00:50:23,320 RESULTS THAT WERE GENERATED BY 1211 00:50:23,320 --> 00:50:25,720 DR. THEIN, FRANCINE BAKER AND 1212 00:50:25,720 --> 00:50:28,080 TEMI AND WE WANTED TO SEE IF -- 1213 00:50:28,080 --> 00:50:30,120 BETWEEN THE NUMBER OF ALPHA 1214 00:50:30,120 --> 00:50:31,120 GLOBIN GENES WITH BURKITT 1215 00:50:31,120 --> 00:50:32,760 LYMPHOMA RISK. 1216 00:50:32,760 --> 00:50:34,960 COMPARED TO INDIVIDUALS WITH 1217 00:50:34,960 --> 00:50:36,360 FOUR COPIES, THOSE WITH FIVE 1218 00:50:36,360 --> 00:50:41,440 COPIES HAD AN ELEVATED RISK -- 1219 00:50:41,440 --> 00:50:43,880 1.86, WHEREAS WHEN WE LOOK AT 1220 00:50:43,880 --> 00:50:45,400 THOSE WITH TWO COPIES, THEY HAD 1221 00:50:45,400 --> 00:50:48,640 A DECREASED -- RATIO ALTHOUGH 1222 00:50:48,640 --> 00:50:50,080 THAT WAS NOT STATISTICALLY 1223 00:50:50,080 --> 00:50:50,400 SIGNIFICANT. 1224 00:50:50,400 --> 00:50:54,240 WITH RESPECT TO WHERE THOSE -- 1225 00:50:54,240 --> 00:50:55,440 EFFECTS BY SICKLE CELL STATUS, 1226 00:50:55,440 --> 00:50:58,840 WE DID A STRATIFIED ANALYSIS. 1227 00:50:58,840 --> 00:51:03,320 AND THESE RESULTS SUMMARIZE THE 1228 00:51:03,320 --> 00:51:06,000 ASSOCIATIONS STRATIFIED BY THE 1229 00:51:06,000 --> 00:51:07,400 SICKLE CELL STATUS. 1230 00:51:07,400 --> 00:51:10,000 SO THE FIRST PART OF THE TABLE 1231 00:51:10,000 --> 00:51:12,560 SHOWS THE RESULTS FOR ALPHA THAL 1232 00:51:12,560 --> 00:51:14,400 IN INDIVIDUALS WHO DO NOT HAVE 1233 00:51:14,400 --> 00:51:17,160 THE SICKLE CELL ALLELE. 1234 00:51:17,160 --> 00:51:20,640 AND THOSE INDIVIDUALS WITH FIVE 1235 00:51:20,640 --> 00:51:24,160 COPIES HAD AN INCREASED RISK 1236 00:51:24,160 --> 00:51:27,160 WITH A -- OF 1.9 WHICH IS -- 1237 00:51:27,160 --> 00:51:29,120 WITH WHAT WE OBSERVED BEFORE 1238 00:51:29,120 --> 00:51:31,280 WHEREAS THOSE WHO HAD TWO COPIES 1239 00:51:31,280 --> 00:51:33,280 HAD A RISK OF .78 WHICH IS ALSO 1240 00:51:33,280 --> 00:51:34,480 STRONGER THAN WHAT WE OBSERVED 1241 00:51:34,480 --> 00:51:34,840 BEFORE. 1242 00:51:34,840 --> 00:51:39,640 NOW WHEN WE LOOK AT THE 1243 00:51:39,640 --> 00:51:40,440 STRUCTURE -- THE SICKLE CELL 1244 00:51:40,440 --> 00:51:42,080 ALLELE, WE SAW THE EFFECTS 1245 00:51:42,080 --> 00:51:44,360 TENDED TO BE ATTENUATED, SO 1246 00:51:44,360 --> 00:51:46,240 THOSE WITH FIVE COPIES HAD AN 1247 00:51:46,240 --> 00:51:48,640 INCREASED RISK BUT NOW THE -- IS 1248 00:51:48,640 --> 00:51:50,960 1.3, AS OPPOSED TO 1.9. 1249 00:51:50,960 --> 00:51:53,240 AND THOSE WHO HAD TWO COPIES, 1250 00:51:53,240 --> 00:51:57,320 THEY HAD A DECREASED RISK -- 1251 00:51:57,320 --> 00:51:58,520 .83. 1252 00:51:58,520 --> 00:52:02,040 SO THESE RESULTS DID NOT 1253 00:52:02,040 --> 00:52:03,240 INDICATE STATISTICAL 1254 00:52:03,240 --> 00:52:05,080 INTERACTION, BUT WE ACTUALLY 1255 00:52:05,080 --> 00:52:07,960 WERE CONSISTENT WITH THE -- THAT 1256 00:52:07,960 --> 00:52:10,920 DR. SWEE LAY HAD TOLD US ABOUT. 1257 00:52:10,920 --> 00:52:12,560 SO I WILL NOW MAKE A FEW 1258 00:52:12,560 --> 00:52:15,520 CONCLUDING REMARKS. 1259 00:52:15,520 --> 00:52:17,760 FIRST QUESTION WAS, DOES THE 1260 00:52:17,760 --> 00:52:19,720 SICKLE CELL ALLELE PROTECT 1261 00:52:19,720 --> 00:52:20,240 AGAINST BURKITT LYMPHOMA? 1262 00:52:20,240 --> 00:52:24,760 WE SHOWED THAT TO BE THE CASE. 1263 00:52:24,760 --> 00:52:24,920 IN 1264 00:52:24,920 --> 00:52:26,200 AFRICA, AND WE THINK THAT'S 1265 00:52:26,200 --> 00:52:28,480 BECAUSE THE SICKLE CELL ALLELE 1266 00:52:28,480 --> 00:52:33,400 DECREASES MALARIA BURDEN -- AND 1267 00:52:33,400 --> 00:52:35,640 INFLAMMATION AND THROUGH THAT, 1268 00:52:35,640 --> 00:52:37,120 IT DECREASES BURKITT LYMPHOMA 1269 00:52:37,120 --> 00:52:37,480 RISK. 1270 00:52:37,480 --> 00:52:38,920 WITH RESPECT TO ALPHA 1271 00:52:38,920 --> 00:52:40,240 THALASSEMIA, OUR DATA SUGGESTS 1272 00:52:40,240 --> 00:52:42,240 THAT THE COPY NUMBERS OF THE 1273 00:52:42,240 --> 00:52:43,880 ALPHA GLOBIN GENES ASSOCIATED 1274 00:52:43,880 --> 00:52:46,280 WITH BURKITT LYMPHOMA RISK. 1275 00:52:46,280 --> 00:52:49,240 WE THINK THAT THE COPY NUMBERS 1276 00:52:49,240 --> 00:52:50,200 MIGHT INFLUENCE BURKITT LYMPHOMA 1277 00:52:50,200 --> 00:52:51,680 RISK BY MODULATING MALARIA 1278 00:52:51,680 --> 00:52:52,880 BURDEN. 1279 00:52:52,880 --> 00:52:57,720 AND WE ALSO SHOWED THAT THE COPY 1280 00:52:57,720 --> 00:53:01,000 NUMBERS OF THE ALPHA GLOBIN 1281 00:53:01,000 --> 00:53:02,760 GENE, THE EFFECT ON BURKITT 1282 00:53:02,760 --> 00:53:05,400 LYMPHOMA VARY BY COINHERITANCE 1283 00:53:05,400 --> 00:53:07,000 OF THE SICKLE CELL ALLELE BUT 1284 00:53:07,000 --> 00:53:10,240 FEPHENOTYPIC INTERRUPTIONS ARE 1285 00:53:10,240 --> 00:53:10,720 WEAK. 1286 00:53:10,720 --> 00:53:14,240 THE RESULTS ARE PRESENTS THE 1287 00:53:14,240 --> 00:53:17,080 STRONGEST SUPPORT FOR MALARIA 1288 00:53:17,080 --> 00:53:19,160 BASED ON LARGE SAMPLE SIZE, 1289 00:53:19,160 --> 00:53:20,880 MULTICENTER DESIGN AND 1290 00:53:20,880 --> 00:53:21,840 MULTIVARIATE ADJUSTMENT BUT WE 1291 00:53:21,840 --> 00:53:24,000 ALSO NOTED WEAKNESSES IN TERMS 1292 00:53:24,000 --> 00:53:28,080 OF SUBGROUP RESULTS -- IN TERMS 1293 00:53:28,080 --> 00:53:29,600 OF THE MECHANISMS THAT 1294 00:53:29,600 --> 00:53:30,600 GENERATING THOSE EFFECTS. 1295 00:53:30,600 --> 00:53:32,880 WE ALSO BECAME AWARE THAT THERE 1296 00:53:32,880 --> 00:53:34,000 ARE COFACTORS THAT HE WITH NEVER 1297 00:53:34,000 --> 00:53:34,480 THOUGHT ABOUT. 1298 00:53:34,480 --> 00:53:38,120 IN PARTICULAR, THERE IS THIS P 1299 00:53:38,120 --> 00:53:39,320 FALCIPARUM SICKLE CELL ALLELE 1300 00:53:39,320 --> 00:53:42,920 THAT WAS RECENTLY DESCRIBED. 1301 00:53:42,920 --> 00:53:48,880 SO IN THIS PAPER, BAND, ET AL. 1302 00:53:48,880 --> 00:53:50,960 AT OXFORD REPORTED THAT MALARIA 1303 00:53:50,960 --> 00:53:52,720 PROTECTION DUE TO SICKLE CELL 1304 00:53:52,720 --> 00:53:54,520 HEMOGLOBIN DEPENDS ON THE 1305 00:53:54,520 --> 00:53:55,800 PARASITE GENOTYPE. 1306 00:53:55,800 --> 00:53:57,320 SO THERE ARE SOME PARASITES THAT 1307 00:53:57,320 --> 00:54:01,360 HAVE ALLELES THAT SUCCESSFU 1308 00:54:01,360 --> 00:54:03,640 SUCCESSFULLY -- AND IF THOSE ARE 1309 00:54:03,640 --> 00:54:06,360 PREVALENT IN AN AREA, THEY WILL 1310 00:54:06,360 --> 00:54:09,640 REDUCE THE EFFECT ON THE SICKLE 1311 00:54:09,640 --> 00:54:13,800 CELL AND BURKITT LYMPHOMA. 1312 00:54:13,800 --> 00:54:15,200 SO IN THIS SLIDE, I WOULD JUST 1313 00:54:15,200 --> 00:54:18,040 LIKE TO ACKNOWLEDGE MANY 1314 00:54:18,040 --> 00:54:18,520 COLLABORATORS WHO HAVE 1315 00:54:18,520 --> 00:54:19,560 CONTRIBUTED TO THE DATA THAT I 1316 00:54:19,560 --> 00:54:24,880 HAVE SHOWED YOU IN UGANDA, 1317 00:54:24,880 --> 00:54:33,280 TANZANIA, MALAWI, INCLUDING THE 1318 00:54:33,280 --> 00:54:40,680 U.K., NIH, NH TB. RI, NHLBI. 1319 00:54:40,680 --> 00:54:45,840 THANK YOU. 1320 00:54:45,840 --> 00:54:48,200 >>THANK YOU BOTH. 1321 00:54:48,200 --> 00:54:49,520 >>I'LL STOP SHARING NOW? 1322 00:54:49,520 --> 00:54:55,280 >>YES, YOU CAN. 1323 00:54:55,280 --> 00:54:56,800 TWO PEOPLE ACTUALLY ASKED THIS 1324 00:54:56,800 --> 00:54:57,680 QUESTION. 1325 00:54:57,680 --> 00:55:00,320 PEOPLE WERE QUITE INTERESTED IN 1326 00:55:00,320 --> 00:55:03,160 EP TEEN BAR VIRUS AND THAT WAS 1327 00:55:03,160 --> 00:55:04,160 MENTIONED IN THE TALK. 1328 00:55:04,160 --> 00:55:06,160 AND ALSO I WONDERED IF THERE WAS 1329 00:55:06,160 --> 00:55:09,120 SOME WAY TO DISCUSS THE ROLE OF 1330 00:55:09,120 --> 00:55:13,720 EPSTEIN-BARR VIRUS? 1331 00:55:13,720 --> 00:55:17,000 >>SO WE HAVEN'T INCORPORATED 1332 00:55:17,000 --> 00:55:19,040 EPSTEIN-BARR VIRUS INTO THIS 1333 00:55:19,040 --> 00:55:19,640 ANALYSIS YET. 1334 00:55:19,640 --> 00:55:21,840 WE PLAN TO DO THAT. 1335 00:55:21,840 --> 00:55:26,760 WE'VE MEASURED EP SE EPSTEIN-BAR 1336 00:55:26,760 --> 00:55:30,080 VIRUS -- AND WE WILL INCORPORATE 1337 00:55:30,080 --> 00:55:31,520 THOSE RESULTS IN OUR ANALYSIS 1338 00:55:31,520 --> 00:55:32,720 AND PROVIDE AN UPDATE. 1339 00:55:32,720 --> 00:55:34,120 WE THINK IT'S AN IMPORTANT 1340 00:55:34,120 --> 00:55:37,200 COFACTOR THAT WE HAVEN'T YET 1341 00:55:37,200 --> 00:55:39,560 CONSIDERED IN OUR ANALYSIS. 1342 00:55:39,560 --> 00:55:41,160 >>GREAT. 1343 00:55:41,160 --> 00:55:43,560 CAN YOU ALSO ADDRESS THE ISSUE 1344 00:55:43,560 --> 00:55:47,280 OF POTENTIAL IMPACT IF THERE IS 1345 00:55:47,280 --> 00:55:48,960 A SUCCESSFUL VACCINE FOR 1346 00:55:48,960 --> 00:55:52,040 MALARIA? 1347 00:55:52,040 --> 00:55:55,840 >>SO OUR DATA INDICATE CLEARLY 1348 00:55:55,840 --> 00:55:59,600 THAT IF MALARIA BURDEN IS GOING 1349 00:55:59,600 --> 00:56:01,440 DOWN, THE BURKITT LYMPHOMA RISK 1350 00:56:01,440 --> 00:56:05,840 SEEMS TO BE ALSO SUPPRESSED. 1351 00:56:05,840 --> 00:56:08,480 AND, THEREFORE, TO THE EXTENT OF 1352 00:56:08,480 --> 00:56:10,760 THAT SUCCESSFUL INTERVENTIONS 1353 00:56:10,760 --> 00:56:12,400 AGAINST MALARIA INCLUDING -- I 1354 00:56:12,400 --> 00:56:14,400 THINK THEY WOULD REDUCE THE RISK 1355 00:56:14,400 --> 00:56:15,320 FOR BURKITT LYMPHOMA. 1356 00:56:15,320 --> 00:56:16,520 WHAT THE DATA SHOW CLEARLY IS 1357 00:56:16,520 --> 00:56:18,520 THAT YOU HAVE TO BE FOCUSING ON 1358 00:56:18,520 --> 00:56:22,560 THE POPULATIONS THAT -- HIGH 1359 00:56:22,560 --> 00:56:23,800 MALARIA BUT IS MORE THAN 20 1360 00:56:23,800 --> 00:56:25,280 INFECTIONS PER YEAR TO 1361 00:56:25,280 --> 00:56:26,840 SIGNIFICANTLY HAVE AN IMPACT ON 1362 00:56:26,840 --> 00:56:33,360 BURKITT LYMPHOMA RISK. 1363 00:56:33,360 --> 00:56:36,480 >>ANOTHER QUESTION IS, WHAT IS 1364 00:56:36,480 --> 00:56:38,800 THE ROLE OF MOSQUITOES AS THE 1365 00:56:38,800 --> 00:56:40,560 COMMON TRANSMITTER OF BOTH, 1366 00:56:40,560 --> 00:56:43,960 AGAIN, EBV AND MALARIA? 1367 00:56:43,960 --> 00:56:46,920 I THINK YOU MENTIONED, YOU KNOW, 1368 00:56:46,920 --> 00:56:49,680 HIGH MOSQUITO BURDEN REGIONS, 1369 00:56:49,680 --> 00:56:50,800 CORRECT? 1370 00:56:50,800 --> 00:56:53,760 >>YEAH, SO THE MOSQUITO 1371 00:56:53,760 --> 00:56:57,400 CONNECTION WAS LIKE -- IT'S THE 1372 00:56:57,400 --> 00:56:59,680 ONE THAT LED TO THE DISCOVERY OF 1373 00:56:59,680 --> 00:57:01,000 EPSTEIN-BARR VIRUS, BUT WE THEN 1374 00:57:01,000 --> 00:57:03,200 DISCOVERED THAT EPSTEIN-BARR 1375 00:57:03,200 --> 00:57:05,520 VIRUS IS NOT TRANSMITTED BY 1376 00:57:05,520 --> 00:57:07,280 MOSQUITOES, IT IS TRANSMITTED BY 1377 00:57:07,280 --> 00:57:11,200 CONTACT WITH SALIVA THAT IS -- 1378 00:57:11,200 --> 00:57:12,240 PERSON TO PERSON. 1379 00:57:12,240 --> 00:57:13,520 HOWEVER, WE NOW KNOW FROM THE 1380 00:57:13,520 --> 00:57:15,160 MALARIA LITERATURE THAT 1381 00:57:15,160 --> 00:57:16,720 DIFFERENT MOSQUITOES HAVE 1382 00:57:16,720 --> 00:57:19,600 DIFFERENT EFFICIENCIES IN 1383 00:57:19,600 --> 00:57:21,960 TRANSMITTING MALARIA PARASITES, 1384 00:57:21,960 --> 00:57:24,320 AS WELL AS BITING -- SOME BITE 1385 00:57:24,320 --> 00:57:26,400 INSIDE THE HOUSE, SOME BITE 1386 00:57:26,400 --> 00:57:30,120 OUTSIDE THE HOUSE, SOME BITE 1387 00:57:30,120 --> 00:57:31,760 ANIMALS, SO THERE IS AN INTEREST 1388 00:57:31,760 --> 00:57:33,560 IN HOW DIFFERENT MOSQUITOES 1389 00:57:33,560 --> 00:57:35,000 MODIFY THE PHENOTYPES THAT WE'RE 1390 00:57:35,000 --> 00:57:36,520 LOOKING AT. 1391 00:57:36,520 --> 00:57:38,280 WE'VE NOT COLLABORATED WITH AN 1392 00:57:38,280 --> 00:57:38,920 ENTOMOLOGIST BUT THAT'S 1393 00:57:38,920 --> 00:57:39,880 SOMETHING WE'RE REALLY, REALLY 1394 00:57:39,880 --> 00:57:42,080 INTERESTED IN. 1395 00:57:42,080 --> 00:57:45,720 >>OKAY MAYBE A QUESTION FOR DR. 1396 00:57:45,720 --> 00:57:49,480 CAN YOU ADDRESS THE RELATIVE 1397 00:57:49,480 --> 00:57:51,120 CLINICAL IMPACT OF ALPHA 1398 00:57:51,120 --> 00:57:54,520 THALASSEMIA VERSUS SICKLE CELL, 1399 00:57:54,520 --> 00:57:55,760 AND WHETHER OR NOT THE 1400 00:57:55,760 --> 00:57:58,920 COMBINATION OF THE TWO ARE 1401 00:57:58,920 --> 00:58:00,440 IMPORTANT TO NOTE IN TERMS OF 1402 00:58:00,440 --> 00:58:07,280 CLINICAL PRESENTATIONS? 1403 00:58:07,280 --> 00:58:11,000 >>THE FIRST MODIFYING EFFECTS 1404 00:58:11,000 --> 00:58:12,960 ON THE SICKLE CELL DISEASE 1405 00:58:12,960 --> 00:58:15,160 ITSELF, AND -- IS BASED ON THE 1406 00:58:15,160 --> 00:58:17,560 FACT THAT ALPHA THALASSEMIA 1407 00:58:17,560 --> 00:58:20,680 INCREASES THE HEMOGLOBIN S 1408 00:58:20,680 --> 00:58:24,600 CONCENTRATION, SO THE 1409 00:58:24,600 --> 00:58:25,480 MODIFICATION EFFECTS ARE 1410 00:58:25,480 --> 00:58:26,480 SLIGHTLY DIFFERENT. 1411 00:58:26,480 --> 00:58:29,240 SOME ARE FAVORABLE AND SOME, YOU 1412 00:58:29,240 --> 00:58:32,080 KNOW, THEY CAUSE MORE SYMPTOMS 1413 00:58:32,080 --> 00:58:34,040 ASSOCIATED WITH MICROVASCULAR 1414 00:58:34,040 --> 00:58:34,400 OCCLUSION. 1415 00:58:34,400 --> 00:58:37,160 THIS IS IN SICKLE CELL DISEASE. 1416 00:58:37,160 --> 00:58:42,240 SO IN TRAIT, AS SHOWN EARLIER, 1417 00:58:42,240 --> 00:58:44,400 WHEN YOU HAVE ALPHA THALASSEMIA, 1418 00:58:44,400 --> 00:58:46,640 IT ACTUALLY REDUCES THE AMOUNT 1419 00:58:46,640 --> 00:58:48,160 OF HEMOGLOBIN S CONCENTRATION. 1420 00:58:48,160 --> 00:58:51,080 THIS TURNS OUT TO BE ACTUALLY 1421 00:58:51,080 --> 00:58:52,720 QUITE FAVORABLE, WHERE IT 1422 00:58:52,720 --> 00:58:54,000 IMPACTS THE SICKLE CELL TRAIT, 1423 00:58:54,000 --> 00:58:59,120 AS WE'VE SHOWN IMPAIRMENT IN 1424 00:58:59,120 --> 00:59:00,320 CONCENTRATING URINE IS LESS WHEN 1425 00:59:00,320 --> 00:59:05,040 YOU HAVE ALPHA THALASSEMIA. 1426 00:59:05,040 --> 00:59:11,080 AND THEN -- SO THAT'S THE MOST 1427 00:59:11,080 --> 00:59:13,040 OBVIOUS THING. 1428 00:59:13,040 --> 00:59:15,760 ALSO IMPACT THE RISK OF CHRONIC 1429 00:59:15,760 --> 00:59:18,680 KIDNEY DISEASE, IT LESSENS THE 1430 00:59:18,680 --> 00:59:18,880 RISK. 1431 00:59:18,880 --> 00:59:19,680 >>OKAY. 1432 00:59:19,680 --> 00:59:21,560 SO ONE LAST QUESTION, DR. ECKER 1433 00:59:21,560 --> 00:59:25,360 MADR. ECKERMAN ASKED SAM WHETHER 1434 00:59:25,360 --> 00:59:27,240 OR NOT THE ASSOCIATIONS WITH THE 1435 00:59:27,240 --> 00:59:29,120 ABOL GROUP DATA WERE THE 1436 00:59:29,120 --> 00:59:32,880 OPPOSITE DIRECTION FOR BURKITT'S 1437 00:59:32,880 --> 00:59:33,520 AND MALARIA. 1438 00:59:33,520 --> 00:59:34,960 HOW WOULD YOU INTERPRET THIS 1439 00:59:34,960 --> 00:59:35,160 RESULT? 1440 00:59:35,160 --> 00:59:42,160 >>SO IT IS UNCLEAR, BUT THE 1441 00:59:42,160 --> 00:59:47,560 EFFECTS OF ONE AN ARE NOT ALWAYS 1442 00:59:47,560 --> 00:59:48,560 EQUAL OR EXACTLY THE SAME 1443 00:59:48,560 --> 00:59:49,000 DIRECTION. 1444 00:59:49,000 --> 00:59:53,320 AND IT'S BECAUSE THE LOCI WERE 1445 00:59:53,320 --> 00:59:55,160 SELECTED FOR SEVERE MALARIA 1446 00:59:55,160 --> 00:59:56,680 WHEREAS WE WERE STUDYING THEM 1447 00:59:56,680 --> 00:59:57,800 FOR CHRONIC MALARIA. 1448 00:59:57,800 --> 01:00:00,920 SO WE'RE NOT SURE ABOUT THE 1449 01:00:00,920 --> 01:00:01,760 DIFFERENCES THERE BUT THERE 1450 01:00:01,760 --> 01:00:02,760 MIGHT BE SOME DIFFERENCES. 1451 01:00:02,760 --> 01:00:03,920 >>THANK YOU VERY MUCH, BOTH OF 1452 01:00:03,920 --> 01:00:05,120 YOU, FOR A WONDERFUL TALK. 1453 01:00:05,120 --> 01:00:08,840 AND WITH THAT, OUR SESSION IS 1454 01:00:08,840 --> 01:00:09,120 CONCLUDED. 1455 01:00:09,120 --> 00:00:00,000 >>THANK YOU.