2018 Demystifying Medicine: Prenatal Genomics and Fetal Gene Therapy

WE HAVE A FAIRLY FULL AGENDA TODAY YOU MAY NOTICE THAT I'M NOT WIN ARIAS

WIN IS VERY HAPPY ABOUT THAT NO, WIN IS ACTUALLY VISITING IN EUROPE RECEIVING AN AWARD, I BELIEVE AND SO I'M JOHN HANOVER, I FILLED IN FOR HIM BEFORE BUT HE ASKED ME TO PRESIDE OVER THE SESSION TODAY AND I REALLY LOOK FORWARD TO THIS WEEK'S SESSION IT JIVES WELL WITH MY LONG-TERM INTEREST IN HUMAN GENETICS AND PATHOLOGY ASSOCIATED WITH CERTAIN CHROMOSOMAL ABNORMALITIES PARTICULARLY TURNER AND OTHER CHROMOSOME DISORDERS SO I WOULD BE COMING ANYWAY, SO IT'S WONDERFUL TO BE ABLE TO INTRODUCE 2 REALLY, REALLY GREAT SPEAKERS WE ACTUALLY HAVE 3 SPEAKERS TODAY, I LEARNED AND JESSICA WILL START US OFF BUT I WANT TO SAY AWE FEW WORDS ABOUT THE 2 SPEAKER WHO IS AGREED TO SPEAK TO US TODAY

THE FIRST IS DIANEA BIANCHI, I MET HER TODAY, IT'S A GREAT TREAT TO MEET HER BECAUSE I KNOW AND I READ ABOUT HER WORK SHE'S CURRENTLY THE DIRECTOR OF NICHD, AND I WILL GIVE YOU–I TOOK CRIB NOTES WHEN YOU HAVE PEOPLE WITH THIS KIND OF EXPERIENCE, YOU ACTUALLY NEED TO HAVE MATERIALS IN FRONT OF YOU SO, I'M GOING TO JUST TELL YOU QUICKLY SHE RECEIVED HER B A

AT THE UNIVERSITY OF PENNSYLVANIA AND M B AT STANFORD UNIVERSITY AND DID A PEDIATRIC RESIDENCY AT CHILDREN'S HOSPITAL IN BOSTON AND THEN DID A PROGRAM IN BOTH GENETICS AND PERINATAL DEVELOPMENT AT HARVARD MEDICAL SCHOOL SO THIS IS WHO REALLY SOME PEOPLE TALK ABOUT DOUBLE HITTER AND TRIPLE–BUT THIS IS A TRIPLE THREAT REALLY REMARKABLE TRAINING AND I LOOK FORWARD TO DIANEA'S TALK

IN THE SECOND TALK WE'LL BE HEARING FROM DR ALLANAND I WILL SCREW THIS UP BECAUSE I SCREWED IT UP WITH BILL TODAY BUT I WOULD SAY DE CHERNY WE'VE HAD LUNCH SEVERAL TIMES BUT ONCE AGAIN I LOOK FORWARD TO HEARING HIS TALK BUT HE HAS A REMARKABLE BACKGROUND HE GOT HIS M D

AT TEMPLE UNIVERSITY, INTURNOVERSHIP AT THE UNIVERSITY OF PENNSYLVANIA AND ENDED UP AT GYNECOLOGY IN THE UNIVERSITY, AND LONG-TERM INVOLVEMENT WITH NICHD AND YOU WERE IN LONDON AT AN IMMUNOLOGY VENUE SO ONCE AGAIN WE HAVE A REMARKABLY BROAD GROUP OF SPEAKERS TODAY, SO WITH NO FURTHER ADO, I WILL INVITE JESSICA TO COME FOURTH AND GIVE US A LITTLE PREAMBLE I'M JESSICA I'M AN REI FELLOW HERE AT THE NIH, SO PREGNANT WOMEN IN THE US ARE REQUIRED TO BE OFFERED THE OPPORTUNITY TO HAVE PRENATAL TESTING FOR THE MOST COMMON FETAL CHROMOSOMAL ANUE EMPLOYEDYS, THESE RISK OF THESE INCREASE AS MATERNAL AGE INCREASES CURRENT SCREENING FOR THESE CONDITIONS CONSIST OF MEASURING PROTEINS AND HORMONES IN THE BLOOD LIKE AFP AND INHIBIT A AND BETA SCG AND ALSO PERFORMING AN ULTRA SOUND OF THE BACK OF THE BABY'S NECK CALLED THE NUCLEOTRANSISTENCY, THESE ARE LOW IN THE GENERAL OBSTETRIC POPULATION, TODAY WE WILL DISCUSS AN EMERGING ALTERNATIVE SEQUENCING CIRCUTING CELL-FREE DNA MATERNAL PLASMA

THIS IS AN EXAMPLE OF A TRI SEEM 21 CARIO TYPE HERE CAN YOU SEE THE DUPLICATION OR TRIPLICATION OF TRI SEEMY 21, TO OBTAIN A CAR YOAT TYPE IN A PROCEDURE LIKE AN AMNIO SEN ILLEGALSEN TEASEIS, AND THESE ARE INVASIVE TESTS TO DECREASE THE RISK OF UNNECESSARY PROCEDURES, SCREENING TESTS THAT HAVE A LOW FALSE-POSITIVE RATE, A LOW FALSE-POSITIVE RATE ARE PREFERRED THIS IS A META-ANALYSIS OF DATA AND HIGH RISK OBSTETRIC POPULATION THIS ARTICLE WAS PUBLISH INDEED 2016 HERE YOU SEE THE DETECTION RATES FOR DOWNS SYNDROME, EDWARDS AND PTAOU SYNDROME

CELL-FREE DNA HAS A HIGH SENSITIVITY AND SPECIFICITY FOR DOWN'S SYNDROME WITH SLIGHTLY LOW OR FOR TAU AND EDWARDS SYNDROME IT'S BETWEEN 81-94% AND THE CHANCE OF A FALSE-NEGATIVE IS VERY LOW IT'S NOT A HUNDRED% ACCURATE AND SHOULD NOT BE USED AS A FINAL DIAGNOSIS FOR POSITIVE CASES >> THANK YOU JESSICA GOOD AFTERNOON TO EVERYONE

THANK YOU FOR COMING SO TODAY WE'RE GOING TO TALK ABOUT A REAL CASE HISTORY THIS IS A CASE THAT I'VE BEEN CONSULTED ON ELECTRONICALLY THEN WE WILL GO BACKWARDS AND SORT OF TELL YOU A LITTLE BIT ABOUT THE SCIENCE BEHIND PRENATAL GENOMIC TESTING, BUT THIS CASE IS REALLY GOING TO BE ABOUT THE INCIDENTAL FINDINGS THAT ARE BEING INCREASINGLY DETECTED AS A RESULT OF ROUTINE PRENATAL GENETIC TESTING FOR THE COMMON CHROMOSOME ANEUPLOYDES THAT JESSICA MENTIONED AND THEN WE WILL GET INTO THE ETHICAL ISSUES AND I WILL ALSO MENTION A SUMMARY OF ISSUES RAISED BY THE CASE I'VE WRITTEN ON NONINVASIVE PRENATAL TESTING WHICH IS ALSO KNOWN AS NIPT, OR NONINVASIVE PRENATAL SCREENING OR SCREENING USING CELL-FREE DNA SEQUENCING IN THE MATERNAL PLASMA AS THE VAN GUARD OF GENOMIC MEDICINE

WE JUST HAD A CONFERENCE LAST WEEK BETWEEN NICHD AND NHGRI THAT SPENT 2 DAYS DISCUSSING THE IMPLEMENTATION OF GENOMIC MEDICINE IN PRECONCEPTUAL PRENATAL PRENATAL CLINICAL CARE AND IT'S REALLY THE VAN GUARD FOR SEVERAL REASONS FIRST OF ALL, INDUSTRY RATHER THAN ACADEMIA HAS DRIVEN INNOVATION AND IN A VERY SHORT PERIOD OF TIME, THIS WENT FROM BENCH WORK AND THEN WITH THE RAPID AVAILABILITY OF COMMERCIAL GENOMIC SEQUENCING, IT BECAME IMPLEMENTED INTO CLINICAL CARE AND BECAUSE OF THAT TESTS THAT ARE CURRENTLY OFFERED TO PATIENTS HAVE BEEN INTRODUCED BEFORE CLINICAL UTILITY HAS BEEN ESTABLISHED SO IT'S KIND OF UNUSUAL THAT YOU WOULD BE OFFERING TESTS WITHOUT SHOWING THAT THEY ACTUALLY MAKE A DIFFERENCE IN TERMS OF PATIENT'S CLINICAL CARE FURTHER MORE, ALTHOUGH THERE HAS BEEN A LONG-TERM PROFESSIONAL STANDARD FOR OFFERING THIS PRENATAL SCREENING FOR ANUE EMPLOYEDY, THERE HASN'T BEEN A LONG-TERM PROFESSIONAL STANDARD FOR OFFERING SEX CHROMOSOME ANEUPLOYDY TESTING OR TESTING FOR THE GEORGE SYNDROME SO AS THE SEQUENCING AVAILABILITY HAS BECOME INCORPORATED INTO CARE NOW MORE AND MORE TESTS ARE BEING OFFERED PREINATEALLY

AND THERE'S ALSO BEEN AN IMPACT ON THE WHOLE FIELD OF MA MATERNAL FETAL MEDICINE SO THE FACT THAT THE SCREENING IS MORE PRECISE AND MORE ACCURATE MEANS THAT FEWER WOMEN NEED TO HAVE THESE CONFIRMAT SORRY TESTS SO SO IF THE NONINVASIVE PRENATAL SCREEN IS NEGATIVE FOR THE COMMON CHROMOSOME ANEUPLOYDYS, MOST PREGNANT WOMEN STOP THERE, THEY DON'T WANT TO HAVE A NEEDLE INTO THEIR UTERROUS SO THE CONSEQUENCE IS THAT 6 OR 7 YEARS THAT THE TESTING HAS BEEN AVAILABLE, THERE'S BEEN A 60-70% REDUCTION IN THE NUMBER OF INVASIVE PROCEDURES SO THAT HAS CONSEQUENCES FOR THE FIELD OF MATERNAL FETAL MEDICINE IN TERMS OF TRAINING AND CLINICAL EXPERIENCE AND IT ALSO HAS IMPLICATIONS FOR CYTOGENETIC LABORATORIES

THEY'RE NOT DOING AS MANY SAMPLES AS THEY USED TO DO BUT AN AREA THAT OUR LABORATORY IS QUITE INTERESTED IN AND BY THE WAY I'M NOT ONLY THE DIRECTOR OF NICHD, I HAVE A RESEARCH LABORATORY AT THE NATIONAL HUMAN GENOME RESEARCH INSTITUTE SO WE'RE VERY INTERESTED IN THE SEQUENCING OF THESE SAMPLES BECAUSE AS I'LL SHOW YOU IN A MOMENT, WHEN YOU DO THE SEQUENCING OF MATERNAL PLASMA, ABOUT 90% OF THE CIRCULATING CELL-FREE DNA IS FROM THE MOTHER AND 10% IS FROM THE PLACENTA SO YOU'RE NOT REALLY GETTING THE FETAL DNA, BUT YOU'RE GETTING THE PLACENTA DNA AS A PROXY FOR THE FETUS OKAY, SO THIS A REAL CASE I HAVEN'T SEEN THIS WOMAN BUT BECAUSE I HAVE WRITTEN EXTENSIVELY ON THESE FIND, I GET A LOT OF ELECTRONIC CONSULTS AND IT'S A WAY FOR ME TO KEEP IN TOUCH WITH MY CLINICAL SIDE SINCE I HAVEN'T YET SEEN PATIENTS IN THE CLINICAL CENTER

SO THIS IS A 41 YEAR-OLD WOMAN IN HER FOURTH PREGNANCY SHE HAD 2 PRIOR MISCARRIAGES AND SHE HAD A HEALTHY 2 YEAR-OLD CHILD AND SHE APPARENTLY UNDERWENT THIS NONINVASIVE PRENATAL TESTING IN HER PRIOR PREGNANCY AND THAT PREGNANCY HAD NORMAL RESULTS THIS PREGNANCY HOWEVER, HAD A RESULT THAT SAID THERE WERE NO RESULTS, IT'S ALSO KNOWN AS A NO CALL RESULT OR A TEST FAILURE RESULT NOW I'LL SHOW YOU WHAT THE ACTUAL RESULT HERE IT IS

IT SAYS NO RESULTS THEY COULDN'T DETERMINE THE FETAL SEX AND I'LL TELL YOU ABOUT THE FETAL FRACTION IN A MOMENT NOW WHAT'S INTERESTING, IT SAYS NO RESULTS DUE TO A DNA PATTERN THAT CANNOT BE INTERPRETED BY THIS ASSAY A REPEAT SPECIMEN IS NOT INDICATED SO YOU CAN IMAGINE HOW THAT'S VERY CONFUSING TO BOTH THE PATIENT AND THE PHYSICIAN BUT ALSO IN THIS SETTING OF TEST RESULTS, THEY SAY FURTHER GENETIC COUNSELING WITH THE EVALUATION OF COMPREHENSIVE DIAGNOSTIC TESTING SHOULD BE CONSIDERED BECAUSE OF AN INCREASED RISK OF ANEUPLOYDE WHEN THERE IS A NO CALL RESULT

SO NO RESULTS SO HOW DO WE GET TO THIS SPACE HERE? SO HERE'S THE FETUS AND HERE'S THE PLACENTA AND THE PLACENTA IS UNDERGOING APOPTOSIS AND THE RESULT OF THIS IS RELEASING LARGE AMOUNTS OF CELL FREE DNA INTO THE MATERNAL PLOOD STREAM BOTH THE MOTHER AND THE FETUS PRODUCE CELL FREE DNA FROM APOPTOTIC CELLS IN FACT EVERYBODY IN THIS ROOM HAS CELL FREE DNA IN THEIR PLASMA IF YOU'RE NOT PREGNANT IT'S EITHER COMING FROM YOUR OWN BONE MARROW OR SHOULD YOU HAVE CANCER IT COULD BE COMING FROM A SOLID TUMOR

BUT THE FETAL DNA COMES FROM THE PLACENTA SO THE MASSIVELY PARALLEL SEQUENCING IS PERFORMED ON THE MIXED DNA SAMPLE WE DON'T PHYSICALLY SEPARATE OUT A PLACENTA DNA AND THE PERCENT OF FETAL DNA OVER THE TOTAL DNA INCREASES AS THE PREGNANCY ADVANCES BUT THE AVERAGE SAMPLE AROUND THE TIME OF THE FIRST TRIMESTER OR SECOND TRIMESTER CONTAINS ABOUT 10% PLACENTA DNA AND YOU CANNOT DISTINGUISH–YOU SEQUENCE EVERYTHING, YOU CANNOT DISTINGUISH BETWEEN THE FETAL AND THE MATERNAL DNA, I SAY FETAL BUT I REALLY MEAN PLACENTA BUT IT'S A PROXY FOR THE FETUS

THE OHM WAY YOU CAN BE ABNORMALITIES SLIEWTLY SURE YOU'RE LOOKING AT FETAL DNA IS IF THE BABY IS A BOY AND THERE IS CLEARLY A Y-CHROMOSOME SO CLEAR THAT'S THAT IS NOT COMING FROM THE MOTHER, SO IN 1 ITERATION OF THE TECHNOLOGY, I WILL SHOW YOU WHAT A WHOLE GENOME SEQUENCING LOOKS LIKE SO, UNLIKE OTHER SITUATIONS WHERE YOU MAY HAVE TO FRACTIONATE YOUR DNA, IF YOU ARE WORKING WITH AN ORGAN SAMPLE FOR EXAMPLE, THE CELL FREE DNA IS ALREADY FRACTIONATED SO IT'S IN FRAGMENTS AND THE FRAGMENTS ARE SLIGHTLY DIFFERENT IN SIZE WHETHER IT'S ADULT DNA OR FETAL DNA THE SEQUENCING OCCURS ON THESE FRAGMENTS AND REALLY, YOU ONLY NEED TO SEQUENCE THE FIRST 25-36 BASE PAIRS

AND THAT IS UNIQUE ENOUGH TO THEN MAP THE ORIGIN OF THAT FRAGMENT TO A PARTICULAR CHROMOSOME OF INTEREST SO FOR SCREENING FOR TRISEME-21, YOU'RE INTERESTED IN THE RATIO OF THE NUMBER OF FRAGMENTS THAT MAP TO CHROMOSOME 21 COMPARED TO THE NUMBER OF FRAGMENTS THAT ARE MAPPING TO A NONTARGET CHROMOSOME THAT IS SERVING AS A REFERENCE CHROMOSOME SO IF A FETUS HAS A NORMAL CHROMOSOME COUNT OR IS EUPLOID, THERE SHOULD BE A 1 TO 1 RATIO DOES THAT MAKE SENSE TO EVERYBODY, BUT THIS TECHNIQUE IS SO SENSITIVE THAT IF THE FETUS HAS TRI SEMI21 FOR EXAMPLE, THERE WILL BE A SLIGHT EXCESS OF SEQUENCES THAT MAP TO CHROMOSOME 21 AND YOU WILL COME–IF THERE'S A FETAL FRACTION OF SAY 10%, YOU WILL COME UP WITH A RATIO OF 105 TO 1

AND THAT IS ENOUGH TO EXCEED THE Z-SCORES AND TRIGGER A SCREENING RESULT OF TRISSMI 21 SO THE PHYSICIAN WHO IS A FETAL MEDICINE SPECIALIST WHO CONTACTED ME SAID IN HER E-MAIL, I'M VERY WORRIED ABOUT CANCER THE PATIENT IS NOT NOW I'LL EXPLAIN WHY SHE'S WORRIED ABOUT CANCER SHE ALSO SAID I'VE REACHED OUT TO THE GENETIC COUNSELOR AT THE LABORATORY, SO THIS A COMMERCIAL LABORATORY THAT DID THE TEST AND A MEDICAL ONCOLOGIST WHO HAD NO IDEA WHAT I WAS TALKING ABOUT

IN THE MEAN TIME THE PATIENT HERSELF, THE PREGNANT WOMAN REQUESTED A REPEAT TEST FROM A DIFFERENT COMMERCIAL LABORATORY SO THE FIRST THING I ASKED HER ABOUT WAS WHAT'S THE FETAL FRACTION? BECAUSE WHEN THE FETAL FRACTION IS LOW, IT CAN TRIGGER A NO CALL RESULT SO WHAT IS THE FETAL FRACTION IN THE PLASMA SAMPLE ITSELF, YOU'RE LOOKING AT THE FETAL CELL FREE DNA OVER THE TOTAL AND WHAT CONTRIBUTES TO THE FETAL IS LARGELY AS I SAID A POPITOSEIS OF THE TROPOBLAST CELLS IN THE PLACENTA AND WHAT CONTRIBUTES TO THE MATERNAL IS THE MOTHERS HEMATOPOIETIC CELLS FROM HER BONE MARROW AND IF SHE IS OBESE, YOU ALSO GET A SIGNIFICANT COMPONENT OF APOPTOTIC ADIPOST CELLS NOW WHAT INFLUENCES THE FETAL FRACTION ARE GESTATIONAL AGE

SO THERE'S MORE IF THE GESTATION INCREASES, ALSO IF THERE'S TWINS MULTIPLE GUESTATION, THERE'S NOT TWICE AS MUCH BUT THERE'S LIKE 15 AS MUCH ALSO WITH CERTAIN ANEUPLOYDES, THERE'S LESS YOU WOULD EXPECT –AT ANY GUESTATIONAL AGE, THEY WERE LOOKING AT THE PERCENT FETAL FRACTION AND A GROUP OF WOMEN AT 13 WEEKS AND IT RANGED FROM 2

3% TO 30% SO, WITHIN WHAT'S CONSIDERED TO BE NORMAL, SOME WOMEN HAVE LOW FETAL FRACTIONS AND OTHER WOMEN HAVE HIGHER FETAL FRACTIONS THE ANSWER WAS IT WAS 12% IN THIS CASE, WHICH WOULD BE IN THE NORMAL RANGE SO A LOW FETAL FRACTION DIDN'T EXPLAIN WHY THERE WAS NO RESULT AND FETAL FRACTION IS IMPORTANT BECAUSE MORE TEST FAILURES DO OCCUR HERE THE BLUE BARS ARE FAILED TESTS SO THESE TEND TO OCCUR AT THE LOW FETAL FRACTURE AND EVERYBODY'S WORRIED ABOUT A CASE OF ANUE EMPLOYEDY

TESTING FOR CELL DNA, 1 IS THE TAG COUNTING APPROACH WHICH IS WHAT I SHOWED YOU BEFORE WHICH IT MAPPING THE TACTICS OR TAGS TO SPECIFIC CHROMOSOMES ANOTHER 1 IS THE SNIP BASED APPROACH WHERE YOU ARE LOOKING FOR SPECIFIC VARIATIONS IN SPECIFIC CHROMOSOMES OF INTEREST AND THEN YOU'RE COMPARING IT TO GENERALLY THE MOTHER'S WHITE BLOOD CELLS AND THEN THE THIRD IS A DIFFERENT, REALLY A MICRO ARRAY APPROACH I THINK THE TAG COUNTING APPROACH IS THE EASIEST TO EXPLAIN, BUT IN THIS CASE, THE FIRST TEST WAS DONE BY A SNIP BASED APPROACH AND THE SECOND TEST WAS DONE BY A TAG COUNTING APPROACH AND IT TURNS OUT THERE ARE DIFFERENCES IN TEST FAILURE RATES ACCORDING TO THE TECHNOLOGY USED NOW PEOPLE ARE VERY INTERESTED IN THE SNP BASED APPROACH AND TARGET BASED APPROACH BECAUSE THEY'RE MUCH CHEAPER THAN THE WHOLE GENOME SEQUENCING

BUT IT'S–IT'S LESS LIKELY TO GET A TEST FAILURE IF YOU ARE DOING THE MASSIVELY PARALLEL WHOLE GENOME SEQUENCING THE OTHER TECHNOLOGY ORGANIZATION IS THE SUGGESTED OR RESUMED ASSOCIATION WITH THE ANEUPLOIDY, THAT'S RECOGNIZED WITH THE TARGETED AND SNP,A PROACH NOT WITH THE MASSIVELY PARALLEL APPROACH AND THIS WILL ALL MAKE SENSE IN A FEW MINUTES WHEN I SHOW YOU PICTURES IT DOES CAUSE CLINICAL DILEMMAS BECAUSE WHEN YOU DO GET THIS TEST FAILURE MOST OF THE TIME IT IS RECOMMENDED THAT THE WOMAN SHOULD GO DIRECTLY TO A DIAGNOSTIC PROCEDURE SUCH AS AMNIO SEN ILLEGALSEN TEASEIS OR CORRIAN O SAMPLING THE PROBLEM IS THOSE PROCEDURES CAN CAUSE AN UNINTENDED MISCARRIAGE AND I HAVE TO ASSUME THAT THIS WOMAN WHO IS 41 WHO USED IVF TO GET PREGNANT MANY WOMEN IN THAT SITUATION DO NOT WANT TO HAVE AN AMNIO SENTISIS, BECAUSE THEY DON'T WANT TO RISK THEY MIGHT LOSE THIS WANTED PREGNANCY SO SHE DECLINED A PROCEDURE AND THAT'S WHY SHE SAID I'LL HAVE A TEST BY ANOTHER PROCIDER

AND THEN THESE TEST FAILURE RATES ARE GENERALLY EXCLUDED FROM INDUSTRY SUMMARY STATISTICS SO SOMETIMES THE SENSITIVITY LOOKS BETTER THAN IT IS NOW I'VE BEEN VERY INTERESTED IN THE FALSE-POSITIVE, THE TEST FAILURE CASES BECAUSE OF THE FACT THAT WOMEN DO NOT NECESSARILY UNDERSTAND THAT EITHER IF THERE'S BEEN A FALSE-POSITIVE OR THEY'RE TOLD THERE'S A TEST FAILURE WITH AN INCREASED RISK OF ANEUPLOYDY, THEY DECIDE THEY WANT TO HAVE A TERMINATION WHICH IS A NO-NO IT'S VERY CLEAR THAT THEY NEED TO HAVE CONFIRMATION THIS IS JUST A SCREENING RESULT THEY NEED A DIAGNOSTIC TEST

SO IT DOES NOT MEAN THAT THERE'S–YOU KNOW THE FETUS OR THE BABY HAS CHROMOSOME ABNORMALITY BUT IT'S BEEN A BIG CONCERN WITH THE TESTING I PRE'S FER TO THINK OF IT AS THESE FALSE-POSITIVE CASES AND THE TEST FAILURE CASES ARE REALLY AN OPPORTUNITY TO GENERATE NEW KNOWLEDGE REGARDING MATERNAL AND FETAL PLACENTA BIOLOGY SO YOU WILL HEAR ABOUT SOME OF THE CRAZY THINGS WE HAVE LEARNED ABOUT SO UP TO 2% OF HIGH RISK CASES, SOME PEOPLE SAY AS HIGH AS 10% ARE DISCORDANT SO THAT MEANS WHEN YOU GET A FALSE-POSITIVE RESULT OR A TEST FAILURE RESULT, THEN YOU DO THE DIAGNOSTIC TEST, THE FETUS IS NORMAL THE FETUS HAS NORMAL CHROMOSOMES, BUT YOU HAVE THIS WHACKY RESULT

AND IT GENERALLY IS DUE TO CONFINED PLACENTA MOSAICISM, NOW WHAT'S THAT THAT'S WHEN IN THE PLACENTA THERE IS A CHROMOSOME ABNORMALITY THAT IS NOT PRESENT IN THE FETUS SO THE FETUS IS NORMAL, PARTS OF THE PLACENTA HAVE MOSAICISM FOR TRISPEED 21 OR 13 NOT INFREQUENTLY WITH IVF, THIS WOULD VERY MUCH BE ON MY MIND IN THE DIFFERENTIAL IS THAT IT STARTED OUT AS A TWIN GUESTATION AND 1 OF THE TWINS DIED AND THE TWIN MIGHT HAVE HAD A CHROMOSOME ABNORMALITY AND THEN THE THIRD THING IS THAT THERE IS A MA MATERNALB NORMALITY –ABNORMALITY

NOW A FEW YEARS AGO, I WROTE A COMMENTARY IN NATURE WITH THE BIG PROBLEM WITH MATERNAL INCIDENTAL FINDINGS BECAUSE MOST PEOPLE ARE NOT COUNSELED WHEN THEY GET THIS BLOOD TEST THAT THIS COULD FIND OUT SOMETHING ABOUT YOUR OWN HEALTH STATUS OR YOUR OWN DNA SO I WAS CONCERNED ABOUT LACK OF INFORMED CONSENT I'M SURE ALAN'S GOING TO GO INTO THIS A LITTLE BIT AMAZING 3 AND JOHN MIGHT FIND THIS INTERESTING, WE ARE PICKING UP QUITE A NUMBER OF MATERNAL SEX CHROMOSOME ANEUPLOYIDIES THIS WAY, SO IF YOU ARE A WOMAN WITH TURNER SYNDROME YOU'RE INFERTILE BUT THERE ARE CONSIDERABLE NUMBER OF WOMEN WHO ARE TURNER SYNDROME MA ZAYICS OR WOMEN WHO HAVE 47 TRIPLE X AND THEY ARE PREGNANT SO THEY ARE FETTERILE BUT THEY SRO ENOUGH DNA WITH THE SEX CHROMOSOME ANEUPLOIDY CIRCULATION THAT IT THROWS OFF THE FETAL TESTING

IN ADDITION, WE'VE LEARNED ABOUT WOMEN WHO THEMSELVES ARE MOSAIC FOR AUTOSTUDIES OF MULTIPLE ENDOCRINAL ANEUPLOIDY, SO TRIEMATE 8 AND THE MOST COMMON OF THOSE SO YOU WOULD THINK IF I COUNSELED SOMEONE PRENATAL THAT THEIR FETUS HAD TRI SEMESTERRATE 8, I MIGHT GIVE A WORSE PROGNOSIS NOT KNOWING THAT WE'VE DISCOVERED ALL THESE WOMEN OUT THERE WHO ARE MOSAIC AND THEY'RE PERFECTLY NORMAL WE ALSO HAVE FOUND MATERNAL MICRODELETIONS OR COPY NUMBER OF VARIANTS THAT THROW OFF THE BIO-INFORMATICS AGAIN, I'LL BE EXPLAINING THIS AND WE KNOW OF A WHOLE SERIES OF MATERNAL MEDICAL COMPLICATIONS, FOR EXAMPLE, WOMEN WITH AUTOIMMUNE DISEASE WOMEN WITH B12 DEFICIENCY, INTERHEPATITIS EATIC COAL O STASEIS OF PREGNANCY, THESE ARE ALL CONDITIONS THAT THE MOTHER HAS THAT EFFECTS THE QUALITY OF THE DNA, AND EITHER MESSES UP THE WAY THE DNA LOOKS ON THE SEQUENCING PATTERN OR REDUCES THE FETAL FRACTION

I'M GOING TO GO STRAIGHT TO CANCER AS 1 POSSIBLE EXPLANATION BECAUSE THAT'S WHAT THE MFM WAS CONCERNED ABOUT THIS IS A COLLEAGUE OF MINE WHO IS A DUTCH GENETICIST WHO WAS JOKING AROUND AND SAID, NIPT REALLY SHOULD STAND FOR NONINCONTINUATIONAL PRESYMPTOMATIC TUMOR DIAGNOSIS AND WHEN I'VE TALKED TO NCI, BECAUSE WE'RE VERY INTERESTED IN WORKING UP WOMEN WHO HAVE A FALSE-POSITIVE RESULT DUE TO THE FACT THAT IT IS A TUMOR THEY HAVE THAT'S RELEASING DNA, NCI SAYS THIS IS SOME OF THE MOST COMPELLING DATA WE'VE SEEN ABOUT THE WAY A LIQUID BIOPSY FUNCTIONS SO IT'S AN UNINTENDED LIQUID BIOPSY, SO WE ACTUALLY, MY LABORATORY WHEN I WAS STILL AT TUSTS PUBLISHED ON THIS, WE DID A STUDY OF 10 WOMEN OF WHOM 8 ALLOWED US TO RETROSPECTIVELY ANALYZE THEIR DNA SO THESE ARE ALL WOMEN WHO WERE PREGNANT AT VARIOUS AGES AT VARIOUS GUESTATIONS BUT IF YOU LOOK DOWN HERE, THEY–THEY ALL HAD CANCER BUT WHAT HAPPENED WAS WHEN THEY HAD THIS TYPE OF TESTING THEY EITHER HAD TEST FAILURES OR THEY THEY HAD MULTIPLE ANEUPLOIDIES, SO HERE'S A WOMAN WHO THE TRIEMATE 13, 18, 21 AND MONOSTUDIES OF MULTIPLE ENDOCRINEY X THAT RESULT WOULD REALLY NOT BE COMPATIBLE WITH A LIVING FETUS SHE WENT ON AND HAD A FETAL DIAGNOSTIC PROCEDURE, THE FETUS WAS NORMAL

ALL THE FETUSES WERE NORMAL AND THE TIME THE TESTING WAS DONE IT WAS NOT KNOWN THEY HAD CANCER SO WE PUT A CALL OUT FOR THESE TYPES OF WOMEN WHO HAD CONFUSING RESULTS AND WE HEARD BACK FROM THESE 8 CASES THAT BASICALLY THEY WERE DIAGNOSED WITH CANCER AFTER THESE CONFUSING RESULTS AND THESE WOMEN GAVE US PERMISSION TO RETROSPECTIVELY OPEN UP THEIR DNA SEQUENCING RESULTS TO SEE WHAT WAS REALLY GOING ON NOW NOW IN THE TYPICAL SEQUENCING ANALYSIS, THE RESULTS ARE BLOCKED EXCEPT FOR CHROMOSOMES 13, 18, AND 21 SO YOU ONLY KNOW THAT SOMETHING IS GOING WRONG TO THOSE MAPPED CHROMOSOMES COMPARED TO THE REFERENCE CHROMOSOMES AND WHEN YOU OPEN UP THE RESULTS AND LOOK ACROSS THE WHOLE GENOME, WHAT YOU SEE IS GENOME WIDE IMBALANCE

SO, HERE ARE THE 8 CASES AND SOME OF THEM WE HAD MULTIPLE SAMPLES, BUT THERE WAS A CASE OF COLORECTAL CANCER AND SHE WAS INITIALLY SCREENED POSITIVE FOR TRIEMY 13, THE BLUE–IT'S ACTUALLY A VERY HIGH PEEK BUT WE CAN'T SHOW IT BECAUSE OF THE SCALE HERE SO IT'S THE BLUE BOX MEANS THERE'S EXCESS OF CHROMOSOME 13 AND THE SAMPLE WAS REPEATED WHEN SHE PRESENTED CLINICALLY AFTER DELIVERY WITH COLON CANCER AND BASICALLY HER WHOLE–ALL OF HER PARAMETERS WERE EXAGGERATED AND THEN AFTER TREATMENT, SHE'S COMPLETELY CLEAN WHAT THIS SLIDE IS MEANT TO SHOW IS THAT THERE ARE MULTIPLE AREAS OF IMBALANCE THAT ARE BEING INCORRECTLY INTERPRETED BY THE BIO-INFORMATICS ALGORITHMS BECAUSE THE ALGORITHMS ARE JUST REPORTING ON 13, 18, 21 SO WE KNOW THAT CANCER IS A REASON FOR FALSE-POSITIVE RESULTS AND THIS IS A DIFFERENT CASE

THIS IS A CASE FROM MICHIGAN THAT I WAS INVOLVED IN WHERE AGAIN THESE MULTIANEUPLOIDIES, ARE JUST GOING CRAZY, THESE ARE MONOSTUDIES OF MULTIPLE ENDOCRINEY 13, 18, 21 AND X AND IT'S INCOMPATIBLE WITH LIFE AND THIS WOMAN ALSO HAD AN ABNORMAL FETUS THIS IS HARD TO UNDERSTAND HER FIRST SAMPLE IF YOU LOOK AT THE GREEN LINE IT'S NOT THAT THERE'S MONOSTUDIES OF MULTIPLE ENDOCRINEY 21, 21 IS NORMAL, THIS IS THE IDENTITY LINE HERE, WHAT YOU'RE SEEING IS TRI SEMIOF CHROMOSOME 8, TRI SEMIOF CHROME SEMESTER 10, 20 AND THAT IS THROWING OFF THE BIO-INFORMATICS ALGORITHMS SO IT'S JUST–IN THIS CASE, 13, 18, 21 MUST BE USING 8 AND 10 AND 20 AS THE REFERENCE CHROMOSOMES THIS POOR WOMAN HAD A SIGNIFICANT DELAY IN HER CARE AND IT WAS MANY MONTHS LATER WHEN SHE HAD A SECOND SAMPLE AND YOU CAN JUST SEE HOW THESE PEEKS HAVE CHANGED OVER THAT INTERVAL OF TIME AND THAT CORRELATED WITH METASTASIS OF HER COLORECTAL CANCER AND GROWTH OF METASTASIS ON HER LIVER MRI

SO THERE'S INTEREST IN FOLLOWING THIS UP AND 1 GROUP IN BULGEIUM RECOMMENDED DOING WHOLE BODY MRIs AND WE'RE HOPING TO BE ABLE TO ADD THIS TO A PROTOCOL HERE AT THE CLINICAL CENTER BUT THIS CASE IS NOT ABOUT CANCER THE MFM JUMPED TO CONCLUSION SO IN FACT, THE PATIENT GOT IT RIGHT BECAUSE THE PATIENT SAID, I WANT MY TEST DONE BY ANOTHER LABORATORY SO THIS WAS DONE BY A DIFFERENT COMMERCIAL LABORATORY THAT NOW, INSTEAD OF JUST USING THE TARGETED APPROACH, IS DOING THE WHOLE GENOME SEQUENCING AND THE TEST RESULT IS NEGATIVE MEANING THERE'S NO ANEUPLOIDY, THE TEST IS NOT A FAILURE HERE, IT'S A FEMALE FETUS AND YOU KNOW IT'S BASICALLY ESSENTIALLY A NORMAL RESULT AT THE 7 MEGABASE LEVEL AND THAT IS GOING TO BE IMPORTANT LATER ON

YOU CAN SEA THIS PARTICULAR LABORATORY IS NOT ONLY LOOKING AT TRI STUDIES OF MULTIPLE ENDOCRINEYS AND FETAL SEX AND SEX CHROMOSOME ANEUPLOIDIES, BUT IT'S LOOKING FOR ANY IMBALANCES AT THE MEGABASE LEVEL AND SPECIFIC MICRODELETIONS THAT ARE ASSOCIATE WIDE CLINICAL SYNDROMES LIKE DEGEORGE AS I MENTIONED BEFORE SO, IT TURNS OUT THAT IT DOESN'T SAY IT ON THE RESULT BUT THEY DID SEE SOMETHING BELOW THE 7 MEGABASE LEVEL AND THEY RECOMMENDED THAT THIS WOMAN HAVE A CARIO TYPE DONE AND IN FACT HER PERIPHERALS, THIS IS THE MOTHER'S PLOOD CARIO TYPE NOW, SHOWS AN INVERSION OF CHROMOSOME 3 SO THE PRESUMED EXPLANATION IS THE MOTHER HAS AN UNBALANCED CARIO TYPE AT THE DNA LEVEL AND IF CHROMOSOME 3 WAS USED AS A REFERENCE CHROMOSOME FOR SEQUENCING RATIOS, THE RESULTS WOULD BE UNUSUAL AND END IN A NO CALL RESULT SO THAT'S WHAT I THINK HAPPENED BUT IT'S EVEN MORE EXTRAORDINARY BECAUSE THIS WOMAN WAS AN INFERTILITY PATIENT SO I JUST WANT TO MENTION THAT FALSE-POSITIVE RESULTS DUE TO MATERNAL COPY NUMBER VARIANTS AS I PRESUME OCCURS IN THIS CASE, AND HAS BEEN REPORTED AS A REASON FOR FALSE-POSITIVE RESULTS

SO IN THE NEW ENGLAND JOURNAL OF MEDICINE IN 2015, THERE WAS A REPORT OF SEVERAL PATIENTS WHO HAD FALSE-POSITIVE RESULTS FOR CHROMOSOME 18 AND WHAT THIS WAS IS CLINICALLY INSIGNIFICANT AREAS OF DUPLICATION OF THE DNA ON CHROMOSOME 18 THAT WAS TRIGGERING A FALSE-POSITIVE RESULT SO THERE ARE A NUMBER OF TEACHING POINTS FROM THIS CASE AS I SAID, THE MATERNAL AND PLACENTA DNA ARE SEQUENCED SO YOU'RE GETTING RESULTS ON BOTH THESE KIND OF UNUSUAL RESULTS, THESE SPECIAL EXPERTISE, SO YOU NEED GENETIC COUNSELORS INVOLVED, YOU NEED MATERNAL MEDICINE SPECIALISTS INVOLVED, YOU NEED MEDICAL GENETICISTS INVOLVED

A DIAGNOSTIC PROCEDURE SUCH AS AMNIO CENTEASEIS WILL SUGGEST THE FETAL STATUS AGAIN THIS WOMAN DIDN'T WANT THAT BUT SHE COULD HAVE HAD THAT AND THAT WOULD HAVE SHOWN THAT THE FEETSUS WAS NORMAL AND YOU COULD WORK UP EVERYTHING ELSE AFTER DELIVERY BUT SHE DID HAVE A PRIOR HISTORY AND MAYBE JESSICA WANTS TO COMMENT ON THIS, TOO, BUT SHE HAD 2 MISCARRIAGES AND AN INFERTILITY HISTORY AND THAT MIGHT HAVE PROMPTED PARENTAL CARIO TYPES AS PART OF THE WORK UP PRIOR TO PERFORMING INVITRO VERTALIZATION THE MATERNAL INVERSION IS RECORDED AS ASHES PARENTALLY BALANCED ON THE REPORT BUT I SLIGHTLY UNBALANCED WHICH YOU CAN FIND AT THE MOLECULAR LEVEL BUT YOU DON'T SEE IT UNDER THE MICROSCOPE SO IF THE MATERNAL INVERSION HAD BEEN FOUND EARLIER IT MIGHT HAVE CHANGED CLINICAL CARE AND IT MIGHT HAVE ALERTED US TO THE FACT THAT THE NON INVAIFIS PRENATAL SCREENING MIGHT HAVE HAD A PROGRAM OR WE MIGHT HAVE SAID DO THE WHOLE GENOME FIRST THE OTHER THING THAT WAS STRANGE IS THAT THE GENETICIST JUMPED IMMEDIATELY TO CANCER PARTLY BECAUSE IT'S MORE DRAMATIC BUT ALSO SHE HAD 1 OTHER CASE WHICH WAS CANCER SO SHE IMMEDIATELY WENT DOWN THAT LINE AND WAS TALKING TO THE PATIENT ABOUT, I THINK YOU HAVE CANCER WHEN THE PATIENT SAID I DON'T THINK I HAVE CANCER

SO THE ENTIRE DIFFERENTIAL DIAGNOSIS SHOULD HAVE BEEN CONSIDERED SO THAT'S MY ETHICAL FRAMEWORK DOES ANYBODY HAVE ANY QUESTIONS DID EVERYBODY HEAR THE QUESTION THAT THE LIQUID BIOPSY FOR CANCER IS ONLY ABOUT 20% SENSITIVE FOR SPECIFIC MUTATIONS LIKE KRASE MODEL, I ASSUME YOU'RE TALKING ABOUT, IN THIS CASE, YOU ARE NOT LOOKING FOR A SPECIFIC MUTATION YOU ARE LOOKING FOR GENOME WIDE IMBALANCE THE TUMOR IS UNDER GOING APOPTOSIS AND THROWING OUT A LOT OF CELL FREE DNA FRAGMENTS

AND THAT THROWS OFF THE BALANCE IN THESE RATIOS SO IT CAUSES THESE UNUSUAL RESULTS WE DON'T KNOW, AND THAT'S 1 OF THE THINGS WE HOPE TO STUDY IS WHETHER YOU CAN ACTUALLY IF THERE'S A SPECIFIC TYPE OF CANCER, WILL YOU DETECT THE SINGLE GENE MUTATION FOR EXAMPLE? >> [INDISCERNIBLE] >> CORRECT >> [INDISCERNIBLE]

>> NO IT'S NOT 10% OF THE FETAL GENOME IT'S 10% OF THE CIRCULATING DNA IS PLACENTA IT'S A HUNDRED% OF THE FETAL GENOME IS REPRESENTED AND THAT 10% INCREASES AS GESTATION ADVANCES >> THANK YOU >> YES? >> THE QUESTION WAS WHAT KIND OF OBSERVATION DOES THE OBSTETRICIAN HAVE, I PRESUME ALAN WILL TALK TO YOU ABOUT THIS BUT I SHOWED YOU THE EXACT REPORT SO THAT'S WHAT THE TEST RESULT LOOKS LIKE AND A BIG ISSUE IN CLINICAL CARE IS THERE'S NO STANDARD FOR HOW THESE TEST REPORTS ARE ISSUED

SO THIS IS VERY, YOU KNOW NEW IMPLEMENTATION OF GENOMIC MEDICINE AND THERE'S STILL NO STANDARDS SO THAT'S WHAT THEY GET AND IT'S COMPLICATED AND YOU DON'T KNOW NECESSARILY WHAT KIND OF GENETIC EDUCATION THE PRIMARY CARE PROVIDER HAS YES? >> CAN THE PATIENTS ORDER THE TEST THEMSELVES BECAUSE YOU KNOW THAT NOW PEOPLE CAN GO AND TAKE THE TEST FROM CPS? >> YEAH, THAT'S AN INTERESTING QUESTION TO MY KNOWLEDGE A HEALTHCARE PROVIDER HAS TO OFFER THESE PATIENT SIGNS A CONSENT FORM OR SOMETIMES THE PROVIDER SIGNS THE CONSENT FORNL >> I WAS GOING TO ASK ABOUT SOMETHING LIKE SWAGGER SYNDROME WHERE THE MOLECULAR DEFECT, IS THAT PART OF THE NORMAL SCREENING? >> IT'S NOT SCREENED BUT IT IS–I ACTUALLY HAVE REPORTED THAT AS 1 CASE OF FALSE-POSITIVES

SO A DIFFERENT KIND OF FALSE-POSITIVE IS WHEN THE GENETIC RESULT DIFFERS FROM THE ULTRA SOUND RESULT SO IN SWAGGER SYNDROME THERE'S A Y-CHROMOSOME SO THEY–THE RESULT ON THE BLOOD TEST WOULD HAVE BEEN NORMAL MALE AND THEN YOU GO TO THE ULTRA SOUND AND IT'S A FEMALE FETUS AND THAT HAPPENS MORE COMMONLY THAN YOU WOULD THINK SO I KNOW AT LEAST 1 CASE WHERE IT WAS SHOWN TO BE DUE TO THE FETUS HAVING SWAGGER–NO, ACTUALLY–SORRY IN THIS CASE IT WAS THE MOTHER HAD SWAGGERED SYNDROME AND SHE HAD HAD EGG DONATION SO IT WAS MORE COMPLICATED THAN THAT SO WE MADE RECOMMENDATIONS FOR A NUMBER OF QUESTIONS TO BE ASKED

BECAUSE IF A WOMAN NEEDS EGG DONATION TO CONCEIVE THEN YOU HAVE TO–YOU HAVE TO START THINKING ABOUT CAUSES OF INFERTILITY A LITTLE BIT DIFFERENTLY WOW >> SO JUST TO CLARIFY AN EARLIER POINT SO YOU CAN SEEQUENCE THE MOTHER'S D NA FOR HER OWN, CAN YOU DO THAT, AND THEN IS IT POSSIBLE TO GET A FULL SEQUENCE OF THE FETAL DNA FROM THE PLACENTA DNA AND THEN SEPARATE OUT BECAUSE THE MOTHER IS KNOWN A FULL PLACENTA SEQUENCE AND A FULL MOTHER'S MATERNAL SEQUENCE? >> YEAH, SO THANK YOU FOR RAISING THAT QUESTION

SO, JUST TO BE ABSOLUTELY CLEAR, THE SEQUENCING FOR THIS NONINVASIVE PRENATAL TESTING IS ONLY DONE FOR THE PURPOSE OF MAPPING YOU'RE NOT LOOKING IN THIS KIND OF TESTING THAT WE'RE TALKING ABOUT FOR SINGLE GENE DISORDERS SO WE WOULDN'T PICK UP SICKLE CELL ANEMIA FOR EXAMPLE, THIS WAY BUT OF COURSE, THE FIELD IS MOVING FORWARD SO THERE'S GREAT INTEREST CAN YOU NONINVASIVELY SEQUENCE THE FETUS AND WE'RE NOT THERE YET

IT HAS BEEN DONE IN DEMONSTRATION CASES BUT THERE WAS 1 REPORT IN TRANSLATIONAL MEDICINE IT COSTS $200,000 TO DO THAT 1 CASE I THINK ALAN WILL TALK ABOUT THIS, THERE'S A LOT OF INTEREST IN USING DIAGNOSTIC PROCEDURES TO GET PURE FETAL MATERIAL, SEQUENCE THAT TO DETERMINE THE WHOLE GENOME SEQUENCE OF THE FETUS SO THAT'S A WHOLE OTHER SET OF ETHICAL QUESTIONS WHERE YOU YOU HAVE A FETUS OR PREINATE AS WE HEARD LAST WEEK IN THIS DISCUSSION PEOPLE ARE PREFERRING THE TERM PREINATE IF YOU DO TREATMENT ON ON THE FETUS AND IF YOU HAVE THIS FETUS DO YOU WANT TO TELL THE PATIENTS ABOUT ALL THE THINGS YOU FIND AND ALSO HOW DO YOU INTERPRET THAT SEQUENCE IN THE CONTEXT OF A FETUS? WE MAY NOT KNOW WHAT SOME OF THESE MUTATIONS OR VARIATIONS MEAN >> SO IN A LOT OF MAMMALS, THE PLACENTA BECOMES POLYEMPLOYED WHICH HAS AN UNUSUAL CELL CYCLE SO DO YOU SEE ANY OF THESE THAT ARE SPECIFIC TO THE PLACENTA WHERE YOU HAVE GENOMIC INSTABILITY WHICH IS COMMON IN THEEND OF CYCLES WHERE THE FETUS LOOKS TO BE COMPLOATLY NORMAL

>> WELL MOLES ARLAN IS MORE OF AN EXPERT ON THIS >> WE HAVE TO USE THE MIC BECAUSE THERE'S ABOUT 4 TIMES AS PEOPLE PEOPLE HEARING THIS >> SO MOLES WOULD HAVE A VERY UNUSUAL TRIP LOID SEQUENCE FOR EXAMPLE, BUT IT'S–YOU WOULD CERTAINLY SEE THAT ON ULTRA SOUND THERE ARE CERTAIN FINDINGS THAT YOU WOULD SEE

>> SO, BASED ON THE TYPES OF CANCER THAT YOU SHOW, MOST OF THE CANCERS WERE BLOOD CANCERS LIKE LEUKEMIA, LYMPHOMA, DO YOU THINK IT HAS TO DO WITH THE FACT THAT YOU ARE COLLECTING THE CIRCULATING DNA SO YOU'RE MOST LIKELY TO GET CERTAIN TYPES OF CANCERS VERSUS OTHERS AND THEN FOR THE FETAL FRACTION, IF YOU ARE ABLE GET SOME OF THE–IRB GUESS THE HEPATOCYTE DNA, I JUST THINK OF LIKE COLON CANCER, USUALLY METRICS METASTASIZES TO THE LIVER, SO MY QUESTION IS, IF THESE TESTS ARE MOST LIKELY TO CAPTURE CERTAIN TYPES OF CANCER VERSUS OTHERS >> YEAH, SO WE DON'T KNOW ENOUGH YET WE HAVE OUR STUDY AND THEN THERE WAS ANOTHER STUDY DONE BY ANOTHER GROUP WHERE THEY REPORTED ON I THINK 40 CASES OF CANCER HALF OF THOSE WERE DUE TO UTERINE MYELOMAS, SO FIBROIDS THAT ARE UNDERGOING MALIGNANT CHANGE BUT WE SAW AN EXCESS OF LYMPHOMAS AND I STILL THINK LYMPHOMAS ARE AT THE TOP OF THE LIST BECAUSE OF THE AGE GROUP THESE ARE PREGNANT WOMEN AT A RELATIVELY YOUNG AGE

>> I WONDER TO WHAT EXTENT AND INFECTION, CAN SKEW THE RESULTS? >> SO THATIA A VERY INTERESTING QUESTION I DON'T KNOW, I DON'T THINK I EVER REALLY THOUGHT ABOUT THAT BUT INFLAMMATION IS GOING TO CHANGE THE BLOOD AND WHERE BLOOD IS GOING AND TRANSPORT OF DIFFERENT THINGS >> DO PEOPLE LOOK AT THAT AT ALL >> NOT THAT I KNOW OF, NO SO IT WILL BE AN INTERESTING OPPORTUNITY

>> [INDISCERNIBLE] >> SO CERTAINLY THERE ARE MORE FETAL CELLS INTACT FETAL CELLS IN WOMEN WHO HAVE PREECLAMPSIA BECAUSE OF THE ABNORMALITIES IN THE PLACENTA THERE'S SUCH A VARIATION IN FETAL FRACTION AND OTHERS HAVE DONE STUDIES TRYING TO FREE RADICALS DICT IF YOU HAVE A HIGH FETAL FRACTION, ARE YOU GOING TO HAVE MORE COMPLICATIONS BUT THE DATA ARE NOT CLEAR ON THAT AND I'M NOT AWARE OF A SPECIFIC COHORT THAT'S BEEN LOOKING AT PREECLAMP TICK WOMEN >> OKAY, I HATE TO CUT OFF THIS GREAT CONVERSATION BUT WE WILL HAVE TIME AFTER ALAN'S TALK TO ANSWER MORE QUESTIONS THANK YOU

>> OKAY, GREAT >> ALL RIGHT AND JUST SO YOU KNOW WHAT I WAS RECRUITED TO TUFTs, ALAN RECRUITED ME SO ALAN WAS MY BOSS AND NOW I'M HIS BOSS SO JUST BE CAREFUL >> [LAUGHTER] >> >> THANK YOU WELL FIRST OF ALL I HAVE A DISCLOSURE, I BORROWED THESE SLIDES FROM SOMEBODY, HALEY–IT'S PICKING UP HALEY SULLIVAN WHO IS IN THE BIOETHICS DIVISION GAVE A GREAT TALK ABOUT THIS SO I BORROWED SOME OF HER SLIDES WITH PERMISSION AND I WILL DESTROY THEM AS SOON AS I GIVE THIS TALK BUT WHAT I WANT TO TALK ABOUT IS THE PATIENT SIDE AND THE PHYSICIAN SIDE AS FAR AS THIS INFORMATION IS CONCERNED BECAUSE NOW THESE PATIENTS HAVE THIS TREMENDOUS AMOUNT OF INFORMATION AND THE OBSTETRICIAN GYNECOLOGYST AND THEY'RE HAVING A GREAT DEAL OF DIFFICULTY IN DEALING WITH THIS INFORMATION

YOU CAN SEE HOW COMPLEX THE SCIENCE IS AND HOW COMPLEX THE INFORMATION IS THAT THE PATIENT'S AND THE OBSTETRICIAN IS GIVEN SO JUST A BIT OF THE HISTORY ABOUT PRENATAL DIAGNOSIS, DATES BACK TO THE 50S AND THE FIRST THING WAS ULTRA SOUND, ACTUALLY IT WAS STILL ULTRA SOUND, NOT REALTIME ULTRA SOUND AND THEN ALTHOUGH IT SAYS 1877, ACTUALLY AMNIO SENTESIS, WAS FIRST WITH NORTHWESTERN IN 1966 AND THIS WAS PRETTY MUCH THE STANDARD UNTIL CORRIAN [INDISCERNIBLE] SAMPLING CAME ACROSS AND THAT WAS THOUGHT EITHER TRANSABDOMINALLY OR TRANSVAGINALLY WHERE A SMALL PIECE OF PLACENTA WAS TAKEN OFF AND ANALYZED AND THIS WAS ALL CHROMOSOMAL ANALYSIS, LOOKING MAINLY FOR TRI SEMIS OR SEX HORMONE DIFFERENTIATIONS AND NOW OF COURSE, WE'RE NOW IN THE ERA AND YOU CAN SEE HOW THINGS HAVE CHANGED DRAMATICALLY AS FAR AS CELL-FREE DNA IS CONCERNED AND JUST A BLOOD TEST AND OF COURSE, THE PATIENTS ARE HAPPY WITH THAT OPTION BECAUSE THEY DON'T DO SOMETHING THAT'S INVASIVE AND HAS EVEN A SMALL RISK OF MISTARRAGE, THEY STILL ARE CONCERNED ABOUT THAT, AND I MENTIONED EVEN IVF PATIENTS ARE EVEN MORE CONCERNED SO THIS IS TAKEN OFF DRAMATICALLY AS FAR AS THE PATIENTS ARE CONCERNED BUT THEN IT SET UP A NEW STANDARD OR A NEW PROBLEM AND AS FAR AS THE OBSTETRICIANS AND WE WILL TALK ABOUT THAT, IT'S EDUCATION IS THE PROBLEM

AND THE PATIENTS OF COURSE, IT'S THE DECISION TO GO ON WITH THE PREGNANCY OR TO TERMINATE THE PREGNANCY OKAY SO WHAT INFORMATION DO PARENTS WANT TO KNOW ABOUT THE FETUS AND YOU'LL SEE, SOME PATIENTS WANT TO KNOW NOTHING, AND SOME PATIENTS WANT TO KNOW EVERYTHING AND OF COURSE, THAT'S THE–THAT'S THE ETHICAL DILEMMA, AND WHAT DO PARENTS–WANT DO WITH THE INFORMATION AND MY CAREER I HAVE MANY EXAMPLES, I COULD SHARE 1, 1 OF MY IVF NURSES AT YALE HAD ABSENCE OF THE CORPUS COLOSEIUM, THE ABILITY TO GO ACROSS THE BRAIN FROM 1 HEMISPHERE TO THE OTHER, AND IT CARRIES A CHANCE THAT THE CHILD WOULD BE MARKEDLY RETARDED AND THE 90% CHANCE THAT THE THAT THE CHILD WOULD BE NORMAL YOU CAN SEE WHAT A TOUGH DECISION IT WAS AN OLDER WOMAN, IT WAS HER ONLY PREGNANCY

AND WHAT KIND OF GUIDANCE WOULD PATIENTS LIKE FROM THE MEDICAL TEAM REGARDING GENETIC TESTING RECENTLY A SPOKE AT THE UNIVERSITY OF PITTSBURGH LAW SCHOOL ABOUT THIS AND THERE ARE LOTS OF GENETIC COUNSELORS AND THEY SAID THERE'S NO PROBLEM HERE BECAUSE GENETIC COUNSELORS GIVE PATIENTS THE INFORMATION THAT THEY NEED THAT'S NOT TRUE THEY GIVE THE PATIENTS INFORMATION BUT THEY COME TO THE OBSTETRICIAN OR SOMETIMES THE PEDIATRICIAN AND WANT TO KNOW WHAT TO DO WITH THAT INFORMATION

SO ALTHOUGH THEY GIVE THEM INFORMATION, THEY REALLY WANT THE GUIDANCE FROM THE PHYSICIAN WHEN THEY HAVE TIME, WHEN THE TIME COMES TO MAKE IT DIFFICULT DECISION SO AS FAR AS THE PATIENTINGS THIS WAS–PATIENTS THIS WAS A SURVEY THAT WAS DONE IN THIS AREA, IT APPROVAL FROM SBA AN ONLINE SURVEY AND THE POPULATION WAS FROM ACTUALLY FAIR FIELD, AT FAIR FIELD COUNTY AND THERE WERE SPANISH SPEAKING WOMEN AND THERE WERE ENGLISH SPEAKING WOMEN AND IT WAS A BROAD SPECTRUM OF PATIENTS AS FAR AS WHO WAS STUDIED AND WHAT THEIR RESULTS AND WHAT THEIR FEELINGS WERE SO THIS JUST LOOKS AT THE DEMOGRAPHY AS FAR AS AGE IS CONCERNED OBVIOUSLY THE PEEK IS BETWEEN 31 AND 40 WHEN MOST WOMEN GO ON TO BECOME PREGNANT TODAY, 20 YEARS AGO IT WAS 21 TO 30, BUT THINGS HAVE SHIFTED DEMOGRAPHY WISE AND YOU CAN SEE THIS LOOKS AT ETHNICITY IN THIS GROUP AND YOU'RE FAMILIAR WITH FAIR FIELD COUNTY EQUALLY DIVIDED BETWEEN HISPANIC AND WHITE WHICH REALLY DOES REPRESENT WHAT THIS COUNTY WAS LIKE

AND THIS LOOKS AT EDUCATION, ALL SPANS OF EDUCATION, HIGH SCHOOL OR LESS AND GRADUATE DEGREE AND YOU WILL SEE THESE DEMOGRAPHIC PROFILES HAVE A LOT TO DO WITH THE DECISION THAT THE PATIENTS MAKE AND THIS JUST LOOKS AT INCOME AS FAR AS THESE PEOPLE WERE CONCERNED NOW HOW IMPORTANT IS RELIGION TO YOU? AND YOU CAN SEE HA IF YOU JUST CUT THE SLIDE IN HALF, RELIGION IS VERY IMPORTANT TO THIS GROUP OF PATIENTS THIS BECOMES IMPORTANT BECAUSE THE BOTTOM LINE IS TO HAVE AN ABORTION OR NOT TO HAVE AN ABORTION AND THAT'S THE DECISION THAT THE PATIENT REALLY HAS TO MAKE AT SOME POINT BUT THERE ARE OTHER DECISIONS THAT HAVE TO BE MADE AND WE'LL ILLUSTRATE THOSE IN JUST A MOMENT SO WHICH CATEGORIES OF INFORMATION WOULD PEASHTS WANT FROM PRENATAL DIAGNOSIS

WELL, THEY WANT TO KNOW ABOUT THE DISEASES THAT PATIENTS THAT THE INFANT WILL DIE IN THE FIRST 2 YEARS OF LIFE, THIS IS PRETTY EASY DECISION AND OF COURSE IN MY FIELD A LOT OF THESE PATIENTS ARE SCREENED OUT BEFORE CONCEPTION EVEN OCCURS BY TESTING ANOTHER IS THEY WANT TO KNOW ABOUT THE RISK OF VIELD HOOD CANCERS AND YOU'LL SEE WHY IT BECOMES IMPORTANT OVER TIME AND THEY'RE INTERESTED IN LEARNING DISABILITIES AND CAN THIS BE–CAN THIS BE PREDICTED, THEN MORE COMMON DISEASES, HEART DISEASES, HEART DISEASE AND ALZHEIMERS AND THEN THIS IS A SPINOFF OF 23 AND ME, LOOKING AT PREDICTING OF THINGS THAT ARE DIFFICULT TO PREDICT, THEY'RE COMMONLY AND THESE WERE POSSIBLE AS FAR AS BEING DIAGNOSIS IS CONCERNED AND THE CRITICAL PIECE, WELL THIS IS BRACKA 2 FOR TRAITS HOPKINS DID A STUDY A NUMBER OF YEARS AGO AND IT WAS SCREENED AT THE STANFORD LAW SCHOOL WHERE I ALSO SPOKE AND THEY HAD A–THEY HAD A PRIORITIZE GENETIC ENGINEERING SO THE FIRST WAS TAY-SACHS DISEASE OR THE SECOND WAS MUSCULAR DYSTROPHY, THE SECOND WAS BRACKA 2, AND THE THIRD–FOR BREAST CANCER, SCREENING FOR BREAST CANCER AND THE THIRD WAS EYE COLOR OR SEX DETERMINATION

AND THE PUBLIC WAS OPPOSE TO EYE COLOR, TRAIT SELECTION AND OBVIOUSLY, PEOPLE IN THE AUDIENCE OR 200 PEOPLE IN THE AUDIENCE THAT WERE 5 PHYSICIANS PHYSICIANS AND 195 LAWYERS AND SOCIAL WORKERS AND STUFF THEY WERE NOT–THEY COULDN'T DECIDE ABOUT THE PATIENTS WITH BRACKA 2 BECAUSE THE BABIES WERE NOW WITH BRACKA 2, 30 YEARS OR 40 YEARS FROM NOW WHEN THAT BREAST CANCER WOULD SHOW UP, PERHAPS THERE WOULD BE CURES OR SOMETHING, SO THERE WEREN'T–THEY COULDN'T DECIDE ON THAT BUT THEN A WOMAN GOT UP WHO HAD A WIG ON WHO OBVIOUSLY HAD BREAST CANCER THAT WAS METASTATIC AND SHE SAID, I WOULD DO ANYTHING SHE SAID IT'S HELL OR DIAGNOSIS WOULD BE ON THE NEXT GENERATION AND THAT CHANGED PEOPLE'S VOTES IN THE AUDIENCE AND THEY DECIDED THAT FETUSES SHOULD BE SCREENED FOR BRACKA 2 OR ACTUALLY RENATAL–IN FERTILITY PATIENTS SO WHAT CATEGORIES OF INFORMATION WOULD PATIENTS WANT INFORMATION IS RED IS THEY WOULDN'T WANT INFORMATION AND YOU CAN SEE TRAITS TO LOOK AT THAT END

I THINK IT'S STRANGE THEY WOULDN'T WANT EVIDENCE ON ALZHEIMER PATIENT'RE ALZHEIMERS AND PENNING TONS AND HOW THEY WERE CANC OWLED AS FAR AS THAT'S CONCERNED BUT THE LAST THING THERE MIGHT BE MANY REASONS WHY THEY WOULD WANT TO LEARN BUT SELECTED SINGLE MOST IMPORTANT AND YOU CAN SEE IF YOU LOOK AT CHILDHOOD CANCER, THEY COULD PREPARE FINANCIALLY BECAUSE THE PATIENT WOULD HAVE TO BE TREATED AND IF YOU LOOK AT THE OTHER END, THE ALZHEIMER'S IT'S THE SAME IF YOU LOOK AT THINGS THAT WERE NOT SO INTERESTING, AND PEOPLE–IN THE GRAFT IN THE RED SPECTRUM, YOU COULD SEE LIKE BREAST CANCER DID NOT HAVE THE SAME INTENSITY AS FAR AS PATIENTS WANTING TO KNOW –THIS IS PRETTY MUCH–YOU SEE THIS A LOT IN OB PRACTICE, AS FOR AS JUST LOOKING FOR TRI SEMI21, BECAUSE MANY PATIENTS WILL SAY THEY DON'T WANT TO BE SCREENED BECAUSE IF THE PATIENT IS GOING TO BE EFFECTED WITH TRIEMY 21 THEY WOULDN'T HAVE AN ABORTION ANYWAY THEY WOULD RAISE THE CHILD AND OF COURSE, YOU TRY TO COUNSEL THEM THAT IT'S HELPFUL TO KNOW THAT THE CHILD WILL HAVE THAT SO YOU CAN PREPARE FOR THAT, BUT MANY PATIENTS WILL SAY–WILL SAY NO IN FACT ONLY 75% OF THE PATIENTS THAT HAVE A DIAGNOSIS OF DOWN'S SYNDROME WILL GO ON WILL GO ON TO ABORT, 25% AND THOSE THAT KNOW THEY HAVE DOWN'S SYNDROME WILL NOT ABORT THE CHILD

AND THEY'RE THE PEOPLE THAT HAVE TO IRPT ACT WITH THE PATIENT AS FAR AS THIS INFORMATION IS CONCERNED –SO INFORMATION WANTED TO PREPARE MEDICALLY, PSYCHOLOGY, WAS IMPORTANT TO THE PATIENT, TRESS OR WILLING KNOW TO NOT TERMINATE ARE MOST CITED REASONING FOR NOT WANTING GENETIC INFORMATION SO LET'S JUMP TO THE OBSTETRICIAN FOR JUST A MOMENT AND ACTUALLY THIS–I DON'T HAVE TO DISCLOSE SO MUCH BECAUSE I HELPED [INDISCERNIBLE] DO SOME OF THIS POLING BUT THIS IS A BIG PROBLEM FOR US, FOR OBSTETRICIAN-GYNECOLOGYST BECAUSE WE'RE NOT WELL EDUCATED AS FAR AS THIS INFORMATION IS CONCERNED I MEAN THE REPORT THAT DIANEA SHOWED IS PRETTY EASY BUT WE GET REPORTS THAT ARE COMPLICATED AND DIFFICULT TO INTERPRETINAL LOCATION AND IT'S HARD TO COUNSEL THE PATIENTS AND YOU CAN SEE HERE, WHERE IT SAYS PREPAREDNESS FOR RETURNING GENETIC TEST RESULTS, THE RESULTS ARE PRETTY–PRETTY GRIM AS FOR AS HOW COMFORTABLE OBLIGATIONS STETRICIANS FEEL AND REFER TO GENETIC COUNSELOR FOR CLINICAL, YES, THEY USUALLY HAVE THOSE COUNSELORS BUT AS I SAID, THEY DON'T PROVIDE–THEY PROVIDE INFORMATION BUT NOT HELP MAKING A DECISION

WILL YOUR PRACTICE HAVE SUFFICIENT RESOURCES TO INTERPRET, COMMUNICATE THESE RESULTS AND YOU CAN SEE, I THINK IT'S HIGHLIGHTED THAT ONLY A LITTLE MORE THAN 25% OF THE OBSTETRICAL PRACTICES FEEL THEY CAN HANDLE THESE PATIENTS SO THIS IS A REAL CRISIS NOW IT MIGHT TURN OUT WHICH WOULD BE SAD THAT THE FIELD TURPS IT OVER TO THE PEDIATRICIANS WHO ARE MORE FACILE WITH GENETIC MATERIAL BUT FOR ME THAT WOULD BE A SHAME BECAUSE THAT WOULD BE THE OBSTETRICIAN GIVING AWAY AN RESPONSIBILITY IS TAKING CARE OF PATIENTS –THE RESPONSIBILITY OF TAKING CARE OF PATIENTS NOW THIS STARTED WITH MICHELLE AND I AND ALL THE OBSTETRICIANS AND I DON'T REMEMBER HOW MANY TESTS OR QUESTIONS THERE WERE, ROUGHLY 20 QUESTIONS ABOUT GENETIC LITERACY AND FEELINGS ABOUT THE GENETIC PRENATAL DIAGNOSIS WITH DETAILED MATERIAL, NOT JUST CHROMOSOMES AND YOU CAN SEE THAT THE SCORES WERE PRETTY SAD AND THIS IS NOT CHANGED

THERE ARE COURSES BUT THE COURSES ARE NOT ADEQUATE TO TEACH TO OBGYNs, SO THIS A CRITICAL PROBLEM AND YOU CAN SEE HERE LOOKING AT THE COMFORT RANGE OF PHYSICIANS AS FAR AS COUNSELING IS CONCERNED THEY ARE COMFORTABLE WITH THE OLD TESTING BUT NOT COMFORTABLE AT ALL WITH THE NEW TESTINGS SO WHAT ROLE SHOULD PROFESSIONAL SOCIETIES PLAY IN ADOPTION OF THIS CERTAINLY THEY HAVE TO EMBRACE THIS, THIS IS WONDERFUL TECHNOLOGY THAT GIVES US LOTS OF INFORMATION, BUT IT'S A PROBLEM BECAUSE WE'RE NOT EDUCATING OUR OBSTETRICIAN GYNECOLOGYST AND I'M NOT SO SURE THEY UNDERSTAND THE IMPORTANCE OF THIS SO ON THAT NOTE I'LL STOP AND IF YOU HAVE ANY QUESTIONS FOR BOTH OF US YOU'LL BE HAPPY TO ANSWER MORE QUESTIONS

>> I ALSO DON'T WANT PEOPLE TO FEEL LIKE THE ONLY OPTION IS TO CONTINUE OR NOT CONTINUE THE PREGNANCY ISSUES THE WOMEN ARE USING INFORMATION FIRST OF ALL, TO HELP THEM DECIDE WHERE THEY WILL DELIVER SO IF THERE IS A GENETIC PROBLEM FOR EXAMPLE, IF IT'S TRI SEMI21, IT'S VERY HELPFUL TO KNOW THAT SO THAT YOU DELIVER IN A TERTIARY HOSPITAL WHERE THERE IS FOR EXAMPLE PEDIATRIC CARDIOLOGYST SO 50 OF BABIES HAVE HEART DISEASE, THEN A WOMAN DELIVERS IN THE HOSPITL, SHE WILL BE SEPARATED FROM THE BABY, SO WE COUNSEL WOMEN WHO ARE CONTINUING THEIR PREGNANCY THAT THIS IS A BENEFIT OF KNOWING AHEAD OF TIME PLUS MOST WOMEN NOWADAYS USE THE INFORMATION TO EDUCATE THEMSELVES AND IT'S KIND OF INTERESTING BECAUSE THE EARLY ADOPTION OF NONINVASIVE PRENATAL TESTING WAS NOT WHERE YOU WOULD THINK ON THE COASTS, IT WAS A LOT IN THE SO CALLED RED STATES AND WOMEN WANTED THE INFORMATION BECAUSE THEY WANTED TO KNOW ABOUT THEIR BABIES

THEY HAD NO INTENTION OF TERMINATING THE OTHER THING IS, IN OUR LABORATORY AT NHGRI, WE ARE WORKING ON RENATAL TREATMENT FOR DOWNS SYNDROME I REALIZE THE TITLE INCLUDED FETAL TREATMENT AND WE HAVE IN A MOUSE MODEL SHOWN THAT APOGENERATEDIN WHICH A NATURALLY OCCURRING COMPOUND THAT EXISTS IN LEAVEY GREEN VEGETABLES AND CITRUS FRUITS IF YOU GIVE IT TO THE PREGNANT DAM, FROM CONCEPTION ONWARDS BASICALLY THAT WE CAN SHOW THAT ACQUISITION OF DEVELOPMENTAL MILESTONES IS SHORTENED IN THE MOUSE MODELS DOWNS SYNDROME SO SO IT'S PROOF OF PRESENCE PEL THAT PRENATAL TREATMENT AT LEAST IN MOUSE MODEL IS LOOKING PROMISING >> QUESTIONS? >> OUT OF THE PERCENTAGE OF PEOPLE WHO WANT TERMINATION DEPEND ON THE AVAILABILITY OF HEALTHCARE, SO YOU COMPARE NORWAY, SWEDEN, UNITED STATES, HOW DOES THAT INFORM THE DECISION

>> I CAN'T ANSWER THAT >> WELL COMPARISONS AMONGST DIFFERENT COUNTRIES WHICH HAVE A HEALTHCARE OR NONHEALTHCARE AVAILABLE? >> I DON'T KNOW IT'S A BIG SOCIAL QUESTION AS WELL SO I DON'T KNOW– >> DO YOU HAVE THE ANSWER? >> I WOULD SAY IT'S NOT SO MUCH THE AVAILABILITY OF HEALTHCARE IT'S THE MICRO ENVIRONMENT OF THE CULTURE LIKE ALAN SAID, RELIGION EFFECTS DECISION MAKING

IT'S VERY DIFFERENT EVEN NEXT DOOR NEIGHBORS SCANDINAVIAN COUNTRIES SO NORWAY IS MUCH MORE CONSERVATIVE THAN SWEDEN THEY BOTH HAVE VERY SIMILAR HEALTHCARE SYSTEMS BUT NORWAY VERY FEW WOMEN TERMINATE FOR A PRENATAL DIAGNOSIS OF DOWN SYNDROME WHERE IN SWEDEN IT'S THE OPPOSITE YOU KNOW PEOPLE ASK ME ALL THE TIME BECAUSE I'VE BEEN WORKING IN NONINVASIVE PRENATAL TESTING FOR MUCH OF MY CAREER, YOU KNOW, SO WHEN YOU MOVE TO A LIVE-BASED SCREENING EMPLOY FOR ANEUPLOIDIES, BECAUSE THEY HAVE FEWER STAGES UPON CAN WHICH TO REFLECT ON WHAT THE RESULTS MEAN AND THERE'S NOW 8 STUDIES THAT HAVE LOOKED WORLD WIDE ABOUT THE INFLUENCE OF THE CELL-FREE DNA TESTING ON THE TERMINATION RATE FOR FETAL ANEUPLOYIDES, AND THERE'S BEEN NO EFFECT THE UNITED STATES, ABOUT 40% OF WOMEN CONTINUE THEIR PREGNANCIES WITH A KNOWN DIAGNOSIS OF DOWNS SYNDROME IT'S SOMEWHAT DEPENDENT ON WHERE YOU ARE LIKE NEW YORK CITY HAS 1 EXTREME, UTAH HAS ANOTHER EXTREME BUT OVERALL IT'S ABOUT 40%

>> YEAH, I'M SORT OF INTERESTED ABOUT THE MECHANICS OF THE INTERPRETATION AND THE WHAT YOU WOULD DO FROM THERE SO I'M WONDERING IN THE SURVEY IT SAID THAT MAYBE HALF THE OBSTETRICIANS WOULD JUST GO TO A GENETIC COUNSELOR AND SO I HAVE 2 RELATED QUESTIONS ONE IS WHY WOULDN'T YOU JUST DO THAT ALL THE TIME WHY ISN'T THAT A CRUTCH YOU COULD LEAN ON ALL THE TIME? AND THE OTHER 1 IS, WHAT PERCENTAGE OF THESE TESTS ARE SOMETHING THAT ARE NOT JUST COVERED BY SOME FDA GIED LEAN OR SOMETHING LIKE THAT THAT YOU WOULD FEEL COMFORTABLE SAYING HERE'S THE ANSWER I'M NOT A DOCTOR OBVIOUSLY THERE'S A CHART SOMEWHERE IN THE DOCTOR'S HAND BOOK THAT SAYS GO LOOK AT THIS AND HOW OFTEN IS IT THAT YOU REALLY SAY I DON'T KNOW WHAT'S GOING ON AND I DON'T FEEL COMFORTABLE WITH AN ANSWER

>> THE SECOND QUESTION, THERE IS NO HAND BOOK >> THAT'S WHAT I THOUGHT >> BUT I WOULD–I WOULD GUESS, 1 OF THE CURES FOR THIS FOR THE OBLIGATIONS STITRICIAN, EVENTUALLY WHEN THERE'S ENOUGH OF A LIBRARY IT WILL BE ON AND YOU CAN GO IN AND YOU CAN LOOK UP SOME OF THESE THINGS AND COME OUT WITH EXPERIENCE BASED ON BUILDING A LIBRARY BUT THIS IS RELATIVELY NEW TECHNOLOGY SO, THERE'S NOT A LOT OF IT AND THE FLOW IS ACTUALLY FROM THE GENETIC COUNSEL

YOU SEND THE PATIENT TO THE GENETIC COUNSELOR, THE GENETIC COUNSELOR INFORMS THEM ABOUT STATISTICS AND THEN THEY COME BACK TO THE DOCTOR AND THEN THEY WANT TO THE DOCTOR TO HELP INTERPRET, NOT HELP, REALLY INTERPRET THAT FOR THEM AND ACTUALLY YOU CAN SEE THE DIFFERENCE BETWEEN AN OBSTETRICIAN AND A PEDIATRICIAN >> OR A GENETICIST >> BUT YOU'RE A PEDIATRICIAN >> YEAH >> AND SHE'S WILLING–SHE'S INTERESTED IN ADAPTING THE CHILD, THE CHILD ADAPTING AND WE'RE INTERESTED IN YOU KNOW DELIVERING THE BEST BABY POSSIBLE FOR THE COUPLE

>> SO I JUST WANT TO POINT OUT NONE OF THESE TESTS ARE FDA APPROVED THEY'RE ALL LABORATORY DEVELOPED TESTS NUMBER 1 NUMBER 2, THE TIMELINE HAS BEEN INCREDIBLY QUICK SO, REMEMBER THAT YOU COULD ONLY–AN INDIVIDUAL LABORATORY COULD ONLY BUY A MASSIVELY PARALLEL SEQUENCING MACHINE AROUND 2008-209

THAT'S WHEN THE LARGE SCALE CLINICAL TRIALS STARTED AND THE TESTING BECAME AVAILABLE IN THE UNITED STATES AT THE END OF 2011 SO WE BASICALLY ONLY HAVE 6 YEARS EXPERIENCE SO IT'S BEEN THE FASTEST GROWING GENETIC TEST IN HISTORY SO IT'S HARD TO EDUCATE PEOPLE SO WHO'S TAKEN UP THE SLACK HAS BEEN THE COMPANIES AND THAT'S BEEN AN ISSUE AND YOU KNOW THE OBSTETRICIANS THEN TURN TO THE COMPANY REPRESENTATIVES, SOME OF WHOM MAY BE GENETIC COUNSELORS BUT MAYBE NOT, MAYBE THEY'RE MARKETING REPRESENTATIVES THEY ARE PROVIDING THE INFORMATION ON THE STATISTICS SO THATIA A LITTLE DIFFERENT FROM SOME OTHER AREAS OF MEDICINE YES ARE YOU A GENETIC COUNSELOR? >> NO, I HAVE SOMETHING TO SHARE WITH YOU ALL

I'M ACTUALLY A MEDICAL TECHNOLOGYST WITH THE NOVA FAIRFAX HOSPITAL AND I WOULD JUST LIKE TO SAY THAT THIS IS REALLY INTERESTING BECAUSE I'M DOWN THERE IN THE LAB BUT 70% OF THE DIAGNOSIS ARE MADE FROM LAB TESTS LABORATORIES, MEDICAL DIRECTORS AND MATHOLOGYSTS AND ANATOMICAL PATHOLOGISTS ARE THE 1S WHO MAKE ALL THE MONEY, YOU KNOW IF YOU HAVE A UTERINE FIBROID AND YOU GO GET IT EXAMINED BY A RADIOLOGYST THEY GET $600 A CLINICAL PATHOLOGIST IN THE LABORATORY GETS $25 ON GIVING A CONSULT ON ANYTHING THEY HAVE TO A ABOUT THIS THIS IS DEVELOPING WITH DR MIKE LAPP A CADA, FROM TEXAS IS DIAGNOSTIC TEAMS SO THEY'RE DEVELOPING THE CLINICAL PATHOLOGIST WHO WILL BE THERE FOR YOU AS A CLINICIAN TO INTERPRET THESE LAB TESTS BECAUSE THERE ARE SO MANY LAB TESTS RIGHT NOW LIKE WE'RE SAYING, THE EXPLOSION OF THEM, AND ESPECIALLY IF YOU GO IT A GYNECOLOGYST AND THE GENETICISTS BUT ALSO, THE CLINICAL PATHOLOGISTS IN THE LABORATORY, THERE ARE MANY OF THEM THAT HAVE GREAT EXPERTISE IN THIS, AND SO THEY'RE GOING TO DEVELOP THIS THING CALLED THE DIAGNOSTIC MANAGEMENT TEAM AND THIS IS A LITTLE OFF THE SIDE, BUT SAY A PATIENT COMES IN THE EMERGENCY ROOM AND THEY'RE PREGNANT BUT THEY ALSO HAVE LUPUS AND THEY HAVE SICKLE CELL ANEMIA

AND NOW THEY HAVE HISTORY OF INFLUENZA A 3 WEEKS AGO AND YOU'RE WORRIED ABOUT THEIR PNEUMONIA AND COMPLICATED CASES SO THIS ISN'T SOMETHING THAT CAN BE COVERED BY 1 SPECIALTY SO YOU HAVE A DIAGNOSTIC MANAGEMENT TEAM THAT IS ORDIBLE TEST OUT OF THE GATE RIGHT OUT OF THE GATE, HAVE YOU A MEETING ON THURSDAY THE LABORATORY PUTS TOGETHER EVERYBODY AND YOU GET ON SKYPE, YOU GET ON THE PHONE, THE PATIENT'S JUAN WALKING DOWN THE STREET, THEY'RE ON THEIR IPHONE, HAVE YOU A MEETING WITH EVERYBODY AT THE SAME TIME TO GO OVER WHAT IS GOING ON WITH THIS PATIENT AND THE INTERPRETATIONS OF WHAT IS THE CORRECT TEST TO ORDER SO, A LOT OF TIMES CLINICIANS DON'T EVEN KNOW WHAT'S THE RIGHT TEST TO ORDER

THEY ORDER THE TEST, THEY GET THE ANSWER LIKE YOU'RE SAYING AND THEY LOOK AT THIS, IT SAYS NO RESULTS OR NO TEST, WHAT DOES THAT MEAN? SO YOU HAVE EVERYBODY INVOLVED IN THE ANSWER FOR THE PATIENT TALKING AT THE SAME TIME RADIOLOGY, HEMEATOLOGY, ONCOLOGY AND YOU ALSO HAVE PEOPLE AT ALL DIFFERENT LEVELS NOT JUST THE PHYSICIAN BUT ME WHO WORKS AT 10:00 O'CLOCK AT NIGHT IN THE LAB THAT YOU KNOW AND LOOKING AT BLOOD AND HAS ANSWERS >> THANK YOU FOR SHARING THAT BUT IT DOES REMIND ME THAT THE REPORTS ARE SIGNED BY BOARD CERTIFIED USUALLY CLINICAL MOLECULAR GENETICIST WHICH IS A BOARD CERTIFIED SPESHT BY GENOMICS AND GENOMICS >> SO I'M CURIOUS IN TERMS OF WHAT TIME DURING PREGNANCY THAT THIS IS [INDISCERNIBLE]

SO TO LARGE EXTENT I THINK THE SMALLER CAN KD–SALLY WAFETAL [INDISCERNIBLE] WHICH IS ACCESSIBLE FOR THE ANALYSIS >> RIGHT >> THE EARLY PROBLEMS CAN BE DIAGNOSE EDUCATIONAL AND THE MORE WOMEN PRESUMABLYILY BE OPEN TO IT? >> SO WE SAY THE EARLIEST IS 9 WEEKS BUT MOST PEOPLE RECOMMEND AFTER DEN WEEKS FROM GUESTATION SO THAT'S STARTING FROM THE LAST DATE OF THE LAST MENSTRUAL PERIOD THE TEST GETS PROGRESSIVELY MORE ACCURATE AS GUESTATION ADVANCES SO CAN YOU ACTUALLY DO THE TEST, THE DAY BEFORE YOU DELIVER AND GET INFORMATION SOMETIMES THAT'S HELPFUL

IF YOU SEE SOMETHING UNUSUAL ON ULTRA SOUND AND YOU WANT TO MANAGE A CASE, LET'S SAY THAT YOU THINK THAT IT'S TRI SEMI18 AND YOU HAVE TO DECIDE WOULD YOU DO AN EMERGENCY SESARRIAN SECTION ON THIS WOMAN YOU WILL USE THAT INFORMATION AND IT SHOULD BE ACCURATE EVEN LATE IN THE PREGNANCY >> DO YOU SEE REGIONAL DIFFERENCES IN THE FAIL RIGHT THAT MIGHT SUGGEST YOU'RE HAVING QUALITY CONTROLS IN THE LABORATORIES? >> NO, IT'S NOT THAT, IT'S MORE RELATED TO THE SPECIFIC TECHNOLOGY >> OKAY , IT'S NOT REGIONAL

ALTHOUGH, UP UNTIL–SO BETWEEN 2011 AND 2015 ALL OF THE TESTS WERE DONE ESSENTIALLY BY 6 MAJOR COMMERCIAL ORGANIZATIONS, SO SEQUEN OHM, ILLUMINA, NATARA, ARE–ADMINISTRATIVEIOSA AND 2 COMPANIES IN CHINA, BARRY GENOMICS AND BGI AND IN 2015 THOSE COMPANIES STARTED TO SUBLICENSE TO OTHER LABORATORIES SO, WHEN THE BIG 6 WERE DOING IT, THEY HAD EXPERIENCE IN HUNDREDS OF THOUSANDS OF CASES THEIR QUALITY WAS GENERALLY VERY GOOD BUT AS THEY BEGAN TO SUBLICENSE IT TO OTHER SMALLER LABORATORIES, THEN WITH LESS EXPERIENCE, LABORATORIES BEGAN TO HAVE SOME DIFFICULTIES >> WHAT DETERMINES THE RATE OF PLACENTA APOPTOSIS >> SO I THOUGHT AT 1 POINT– >> I THOUGHT–WE THOUGHT IT WAS RELATED TO VOLUME

IT WOULD MAKE SENSE THAT IT'S RELATED TO VOLUME BUT IT'S NOT WE DID A STUDY LOOKING WITH ULTRA SOUND TO VERY PRECISELY MEASURE, MAYBE NOT BY TODAY'S STANDARDS THIS WAS DONE MAYBE 8 OR SO YEARS AGO, BUT WE TRY TO CORRELATE PLACENTA VOLUME WITH FETAL FRACTION, IT DIDN'T CORRELATE AT ALL SO I DO THINK IT'S A MARKER OF PLACENTA HEALTH AND THAT'S WHY YOU'RE SUGGESTED STUDY OF PREELAMPSIA WOULD BE A GOOD IDEA >> AND ALSO, ARE THERE ANY KNOWN GENETIC CHANGES THAT OCCUR UPON FOR EXAMPLE, THE [INDISCERNIBLE] FORMATION IN THE PLACENTA? IN THE NUCLEIR? >> IT'S A MATTER OF FUSION BUT I DON'T KNOW THAT ANYBODY'S REALLY LOOKED AT THE UNDERLYING MECHANISM BEHIND PLACENTA MOSAICISM OTHER THAN IT'S USUALLY A POST FERTILIZATION, AND THEN, BUT ARE THERE OTHER FACTORS THAT ARE PROMOTING THAT, I DON'T KNOW? >> WE SEE MOSAICISM IN OUR EMBRYO BIOPSIES SO HOW WILL THAT REFLECT IN THE FETAL DNA? >> SO, THAT'S A GREAT QUESTION BECAUSE IT'S A BIG ISSUE NOW IN IVF, DO YOU TRANSFER CHROMOSOMEALLY MOSAIC EMBRYO AND I MEAN YOU TELL ME, BUT I THINK THE–THE USUAL WISDOM IS OBVIOUSLY, YOU WILL TRANSFER A UPLOID EMBRYO FIRST BUT WHAT IF SHE'S 40 YEARS OLD AND ONLY HAS 3 EMBRYOS LEFT OR 1 EMBRYO LEFT THAT HAS A CHROMOSOMAL ABNORMALITY SO THERE'S INCREASING DISCUSSION ABOUT WHETHER YOU SHOULD TRANSFER THOSE EMBRYOS SO WHAT WE'RE FINDING IN THESE WORK UP OF THESE UNUSUAL FALSE-POSITIVE RESULTS ARE THERE ARE RARE TRI STUDIES OF MULTIPLE ENDOCRINEYS THAT I AS A PEDIATRICIAN ARE GENETICIST NEVER THOUGHT WAS COMPATIBLE WITH LIFE OR CERTAINLY NOT WITH A PREGNANCY THAT WOULD GET UP TO THE THIRD TRIMESTER SO WE'RE INCREASINGLY SEEING THESE UNUSUAL TRI STUDIES OF MULTIPLE ENDOCRINEYS SOME OF WHICH ARE JUST IN THE PLACENTA

SO THAT–YOU KNOW, WE DON'T KNOW SOME OF THOSE MIGHT HAVE BEEN MOSAIC EMBRYOS IF WE HAD KNOWN, IF WE BIOPSIED THEM SO I THINK THAT A LOT OF THE CONVENTIONAL WISDOM, THE FACT THAT WOMEN WITH TURNER INDROAM THAT ARE INFERTILE ALL THE TIME OR THESE RARE TRI STUDIES OF MULTIPLE ENDOCRINEYS ARE GOING TO MAKE IT THROUGH THE PREGNANCY ALL OF THAT IS QUESTIONED BY THE TECHNOLOGY BEN, YOU LOOK CONCERNED YOU'VE BEEN VERY QUIET

[LAUGHTER] >> CAN YOU SPEAK TO YOUR STUFF >> SO HOW MANY TESTS AND WHO'S PAYING FOR IT AND HOW MUCH DOES IT COST? >> OKAY, SO HOW MANY TESTS? THERE HAVE BEEN SOMEWHERE BETWEEN 4 AND 6 MILLION DONE SINCE 2011 I ACTUALLY KEPT COUNT HIGOOD RELATIONS WITH THE 6 COMPANIES AND THEY GAVE ME THEIR NUMBERS ONCE THEY WERE PUBLICLY RELEASED SO WE COULD GET AN IDEA OF WHAT WAS HAPPENING BUT WHEN IT BECAME DISSEMINATED GLOBALLY WE LOST TRACK SO WE CAN ONLY ESTIMATE NOW, BUT IT HAS HAD A SIGNIFICANT IMPACT ON PRACTICE THE WAY IT'S HANDLED IN DIFFERENT COUNTRIES IS DIFFERENT

SO THE UNITED STATES IT'S ALL OVER THE PLACE IF YOU ARE HIGH RISK FOR A FETAL ANEUPLOIDY SO IF YOU'RE OVER AGE 35 AT THE TIME OF DELIVERY, IF YOUR FETUS HAS A MAJOR SEWNOGRAPHIC ABNORMALITY IF YOU HAD A PREVIOUS CHILD WITH A CHROMOSOME ABNORMALITY OR IF YOUR SERUM SCREENING OR TRANSLUCENCY TESTS LOOK ABNORMAL, MOST INSURERS IN THE UNITED STATES ENCLUEDING SOME STATE PROGRAMS WILL PAY FOR THIS TEST WHAT IT COSTS, IT'S ALL OVER THE PLACE THE STATE OF CALIFORNIA WILL OFFER YOU EVERYTHING FOR $207

IT CAN BE UP TO A THOUSAND DOLLARS IN OTHER PLACES BUT WHAT'S REALLY INTERESTING IS THE WAY OTHER COUNTRIES ARE DOING THIS SO THE BIG DEBATE IS WHETHER TO OFFER THIS TO ALL PREGNANT WOMEN OR JUST WOMEN AT HIGH RISK WE JUST SHOWED YOU THE DATA, THE META-ANALYSIS DATA, JESSICA SHOWED YOU THIS ON THE THIRD SLIDE ON HIGH RISK WOMEN BUT AT THE END OF THE DAY ASK WE PUBLISHED ON THIS IN THE NEW ENGLAND JOURNAL OF MEDICINE, THIS PERFORMS MUCH BETTER AS A FIRST TEARED TEST SO IT'S 10-20 TIMES BETTER THAN THE CURRENT STANDARD OF CARE WHY NOT OFFER THAT TO EVERYONE

WELL IT'S A BIT MORE EXPENSIVE RIGHT NOW BUT CERTAINLY WE EXPECT THOSE COSTS TO GO DOWN THERE'S EDUCATION ISSUES THERE ARE COUNSELING ISSUES WE DON'T HAVE ENOUGH GENETIC COUNSELORS THAT WAS 1 OF THE QUESTIONS, IS WE DON'T HAVE THE WORKFORCE CAPACITY

BUT IN SMALLER EUROPEAN COUNTRIES, LIKE BULGEIUM IS OFFERING IT TO ALL PREGNANT WOMEN AS A FIRST TEAR TEST AS PART OF THEIR NATIONAL HEALTH SERVICE, NO RAEXTRA CHARGE THE NETHERLANDS IS COMPARING JUST FOCUSED TRI SEMI131821 RESULTS COMPARED TO EVERYTHING IN THE U K THEY WILL OFFER IT AS A SECONDARY SCREEN AS PART OF THE NATIONAL HEALTH SERVICE TO WOMEN AT HIGH RISK SO IT'S A BIT ALL OVER THE PLACE

BUT EVERYBODY AGREES THAT IT IS FOR SURE THE MOST ACCURATE SCREEN FOR DOWNS SYNDROME YES? >> [INDISCERNIBLE] >> IN BELGIUM, THE ALGORITHM THAT'S PUBLICLY AVAILABLE CALLED WISE COPPEDDOR SO THEY ARE LOOKING AT ALL OF THE CHROMOSOMES AND I BELIEVE THEY ARE REPORTING ON ALL OF THOSE RESULTS BECAUSE A LOT OF THE EXPLANATIONS FOR THE FALSE-POSITIVE CASES ARE COMING FROM BELGIUM I DON'T KNOW THEIR EXACT STUDY DESIGN BUT I BELIEVE THEY ARE REPORTING ON EVERYTHING >> YEAH, YEAH, YEAH, WELL IN A SMALLER COUNTRY, THEY HAVE WELL-ORGANIZED CENTERS EXPERTISE AND THOSE ARE THE GROUPS THAT ARE RERESPONSIBLE FOR BOTH STANDARDIZING THE REPORTING OF THE RESULTS AND EDUCATING THEIR PHYSICIAN WORKFORCE

>> I HAVE A 2 PORT QUESTION THINKINGBACK TO THE ISSUE OF CANCER YOU DESCRIBED, YOU COULD GET A BASE LINE PRECONCEPTION OR VERY, VERY EARLY IN PREGNANCY AND IN THEORY THOSE THINGS–THOSE ANOMALIES WOULD BE THERE EVEN YOU KNOW AT THAT EARLY STAGE IS THAT'S SOMETHING THAT'S BEING TALKED ABOUT AND THE SECOND PART IS ARE THERE SEGMENTS OF DNA FROM A PRIOR PREGNANCY THAT STICK AROUND >> SO LET ME ANSWER THE SECOND 1 FIRST SO THE CELL FREE DNA IS FROM THE PLACENTA AND IF THE PLACENTA DELIVERS NORMALLY LIKE THERE'S NO RETAINED PLACENTA THEN MOST OF IT IS GONE WITHIN 2 HOURS OF DELIVERY

SO I THINK IT'S FAIRLY SAFE TO SAY THAT PRINCESS KATE DOESN'T HAVE ANY Y-CHROMOSOMAL DNA CIRCULATING FROM THE LATEST BABY BUT IF THERE'S A RETAINED PLACENTA OR–WE'VE ACTUALLY STUDIED IN THE CASE OF MEDICAL TERMINATIONS WHERE THE EXPULSION OF THE PLACENTA WAS NOT COMPLETE, YOU DEFINITELY STILL SEE THE Y-CHROMOSOME SEQUENCE IF IT'S A MALE THE FIRST QUESTION WAS ABOUT THE CANCER WOULD WE– >> SCREEN BEFORE? >> YEAH, I DON'T THINK WE'RE THERE YET I MEAN WE'RE BASICALLY RIGHT NOW AT A VERY EARLY STAGE WHERE WE–WE WANT TO UNDERSTAND ARE THERE SPECIFIC PATTERNS IN THE DNA SEQUENCING THAT WOULD LEAD US TOWARDS A CANCER WORK UP VERSUS SOMETHING ELSE AND ALSO UNDERSTANDING WHAT'S GOING ON WITH FIBROIDS

>> BUT IT'S SUCH A LOW RISK GROUP >> YOU MEAN IN GENERAL? >> YEAH, PRENATAL SCANNING TO RULE OUT MALIGNANCY, BECAUSE IT'S A LOW–SUCH A LOW INCIDENCE GROUP OF PEOPLE >> YEAH, IT PROBABLY WOULDN'T BE AN APPROPRIATE USE OF RESOURCES BUT ONCE YOU SEE THAT SAW TOOTH PATTERN THAT'S WHAT WE'RE INTERESTED IN >> AND TECHNOLOGICALLY DO YOU SEE A CONVERGENCE ON SHORT READS ILLUMINATED SHORT READS SHOTGUN SEQUENCING OR THERE'S A BIG PUSH FOR LONGER, HIGHER REDEPOSITION AND LONGER READS, THE MIKE SEQ TYPE? DO YOU SEE CONVERSIONOT SHORT READS, I CAN SEE ADVANTAGES TO THE LONGER READ TECHNOLOGY

>> YEAH, I'M NOT IN THE COMMERCIAL LABS BUT I KNOW THEY'RE LOOKING AT PRECISION BUT REDUCING COSTS SO THERE ARE SOME LABS THAT ARE LOOKING AT BENCH TYPE APPROACHES IF YOU'RE JUST INTERESTED IN 131821 THERE'S THE POSSIBILITY OF MORE RAPID BENCH TOP APPROACHES , AND FOR US THE IVF STUFF THEY LOOK FOR 200 DISEASES SPECIFICALLY AND TAKEN–THEY'S WHAT THEY LOOK FOR BESIDES ANEUPLOIDY >> FOR YOUR TEST DO YOU SEE ANY DIFFERENCE IN TERMS OF WHAT PATIENTS WITH THAT THEY SAY PLACENTA CRETE PREVENTIVIA OR ANY PLACENTA ABNORMALITIES DO YOU GET A DIFFERENCE IN TERMS OF THE RESULTS >> YEAH, SO UNFORTUNATELY, THE COMMERCIAL LABS THAT TRULY HAVE DATA ON HUNDREDS OF THOUSANDS OF CASES AND I COLLABORATED WITH SOME OF THEM TO GET INFORMATION

THEY'RE NOT GETTING THE KIND OF RICHLY DETAILED OBSTETRICAL HISTORIES YOU WOULD LIKE TO& INTERPRET THAT EVEN SOMETHING AS SIMPLE AS FIBROIDS WHICH ARE MUCH MORE COMMON IN AFRICAN AMERICAN WOMEN, THEY'RE NOT EVEN CAPTURING RACE SO IT'S VERY HARD TO KNOW BECAUSE I'VE BEEN ASKED, YOU KNOW IS IT MORE COMMON? WOULD YOU EXPECT MORE COMMONLY A FALSE-POSITIVE RESULT IN AN AFRICAN AMERICAN WOMEN DUE TO THE HIGH PREVALENCE OF FIBROIDS? AND THE LABS, I DON'T KNOW, IT WOULD BE A REASON TO DO A RESEARCH STUDY >> OKAY, IF THERE ARE NO FURTHER QUESTIONS, LET'S THANK BOTH OUR SPEAKERS TODAY! [ APPLAUSE ] AND I ASSUME THEY MAY BE AROUND FOR A FEW MINUTES TO ANSWER ADDITIONAL QUESTIONS SO THANK YOU

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