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 U.S. 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
1.05 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
1.5 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.
 
