>> GOOD AFTERNOON, EVERYBODY.
MY NAME'S CAROLYN HUTTER, I'M
DIVISION DIRECTOR FOR THE
DIVISION OF GENOME SCIENCES AT
NHGRI AND I WANT TO WELCOME
EVERYBODY TO TODAY'S WALS
LECTURE.
FIRST A COUPLE OF HOUSEKEEPING
NOTES.
I WANT TO THANK THE WALS TEAM,
PARTICULARLY DIANEA GOMEZ FOR
ORGANIZING TODAY.
IF YOU DIDN'T PICK IT UP ON YOUR
WAY IN, ON YOUR WAY OUT YOU CAN
PICK UP HANDOUTS ABOUT UPCOMING
WALS SPEAKERS, IT'S A VERY
IMPRESSIVE LINE UP.
I ALSO WANT TO THANK MY
COLLEAGUE LISA CHAD WICK WHO
NOMINATED DR. COX TODAY TO COME.
LISA IS A REMOTE WORKER SO SHE'S
WATCHING REMOTELY BUT I WANTED
TO THANK HER FOR HER WORK IN THE
NOMINATION AND IN ORGANIZING THE
DAY.
IF YOU ARE WANTING CME, THE CME
CODE IS 50111.
UP HERE ON THE SCREEN.
AND FOR WHEN WE GET TO THE Q&A,
PEOPLE IN THE ROOM, I WILL
ENCOURAGE TO USE 1 OF THE 2
MICs BUT WE WILL ALSO HAVE A
LARGE NUMBER OF PEOPLE
PARTICIPATING ONLINE TODAY, SO
ONLINE PEOPLE TO SUBMIT A
QUESTION FOR THE SPEAKER USE THE
SEND LIVE FEEDBACK BUTTON THAT
YOU WILL FIEBD ON THE VIDEOCAST
PAGE THAT YOU ARE WATCHING THIS
ON.
SO IN TERMS OF INTRODUCTION,
DR. NANCY COX, A PROFESSOR OF
MEDICINE AND DIRECTOR OF THE
DIVISION OF GENETIC MEDICINE
WITHIN THE DEPARTMENT OF
MEDICINE AT VANDERBILT
UNIVERSITY MEDICAL CENTER, A LOT
OF MEDICINE IN THAT TIELTS AND
FOUNDING DIRECTOR OF THE
VANDERBILT GENETICS INSTITUTE.
SHE HAD TRAINING AT YALE,
WASHINGTON UNIVERSITY, AND THE
UNIVERSITY OF PENNSYLVANIA,
BEFORE ANYTHING TO THE
UNIVERSITY OF CHICAGO WHERE SHE
WAS A DISTINGUISHED FACULTY IN
THE BIOLOGICAL SCIENCE PS
KIVISION, AND THEN MOVING TO
VANNEDDER BELT IN 2015.
SHE HAS AN ACTIVE RESEARCH
PROGRAM FOCUSED ON INTEGRATION
OF FUNCTIONAL GENOMIC
INFORMATION TOA AID AND
DISCOVERY OF AND INTERPRETATION
OF ASSOCIATIONS AND SHE'S DONE
BI PIONEERING PROGRAMS BAYOUS OF
THE VANDERBILT BIOBANK VENUE.
I COULD GO ON FOR HOURS, BUT
WILL CALL OUT THAT SHE'S THE
2008 RESEARCH LAND RON CANCER
RESEARCH AWARD, LEADER IN THE
2021 EPIDEMIOLOGY AWARD AND
RECENTLY THE 2023 HUMAN GENETICS
LEADERSHIP ARK WARD IN AKIGZ TO
HER RESEARCH, I JUST PERSONALLY
WANT TO NOTE THAT SHE HAS A VERY
STRONG FOCUS ON TRAINING,
MENTORING AND WORKFORCE
DEVELOPMENT, AND SHE'S BEEN AN
INSPIRATION TO MANY EARLY CAREER
GENETICISTS, PARTICULARLY WOMEN,
SEEKING INCREASING LEADERSHIP
ROLES IN THE FIELD SHE'S
CERTAINLY BEEN AN INSPIRATION TO
ME.
IN ADDITION TO THAT SHE'S HAD
MANY ACTIVE RESEARCH AND
ADVISORY ROLES IN GENOMIC
CONSORTIA, THAT'S WHERE I
CURRENTLY ISHT ACT WITH HER THE
MOST AND THIS INCLUDES HADDER
BEING A MEMBER OF THE N HGRI FOR
HUMAN GENOME RESEARCH.
SO IT'S TRULY AN HONOR TO
WELCOME NANCY COX TO GIVE
TODAY'S WALS LECTURE ON
PRIORITIZING GENETICS TO REDUCE
EXISTING HEGHT DISPARITIES.
NANCY?
[ APPLAUSE ]
NTHANKS SO MUCH FOR THAT
GENEROUS INTRODUCTION AND IT'S
SUCH A PLEASURE TO BE HERE AT
NIH, SUCH A STORIED PLACE FOR
RESEARCH IN THE UNITED STATES
AND I WAS A FREQUENT VISITOR TO
THE CAMPUS FOR MANY, MANY YEARS
AND WE'VE KIND OF GOTTEN AWAY
FROM THAT OVER TIME, AND THERE'S
A LOT MORE CAMPUS NOW, MANY OF
OUR NIH SPONSORED MEETINGS HERE
IN THE BETHESDA AREA AND
SATURDAY HOTELS AND SATURDAY NIH
BUILDINGS FURTHER OUT, IT'S NICE
TO BE ON CAMPUS IMEAN, I WAS
HERE FOR MANY, MANY KINDS OF
MEETINGS OVER MANY YEARS AND
ALSO, YOU KNOW, KNOW MANY
INTRAMURAL SCIENTISTS HERE SO
IT'S BEEN A REAL PLEASURE TO
CATCH UP ON ALL THE SCIENCE
BEING DONE HERE THAT IS SO
IMPORTANT AND WORKT WHILE, SO
I'M REALLY HAPPY TO BE HERE
TALKING ABOUT THIS TOPIC WHICH
IS TAKEN OVER MY LIFE AND SO I'M
REALLY GOING TO TALK ABOUT HOW
MUCH MORE HERITABILITY LAB
VALUES USED IN EVERY DAY
MEDICINE AND PHYSICIANS REALIZE
AND HOW THAT HAS LED TO REALLY
INSTITUTIONALIZED HELT
DISPARITIES THAT CAN'T BE FIXED
WITHOUT GENETICS.
AND IT'S--PART OF THIS IS THAT
BRINGING GENETICS INTO MEDICINE
IS CREATING NEW KINDS OF HEALTH
DISPARITIES AND WE ALL KNOW
THAT, IT'S--IT'S--THEY'RE
IMPORTANT NEW HEALTH DISPARITIES
IN BOTH THE COMMON VARIANT SPACE
WITH THINGS LIKE POLYGENIC RISK
SCORES FOR RISK PREDICTION AND
ALSO IN THE RARE VARIANCE SPACE
WITH HOW MUCH HARDER IT CAN BE
TO INTERPRET THE IME NOAMS,
FOR--GENOMES FOR ANYONE WHOSE
GENETIC ANCESTRIES ARE REALLY
OUTSIDE EUROPE.
IN CONTRAST, A LOT OF THE
LABORATORY VALUES WE USE IN
EVERYDAY MEDICINE ARE TRYING TO
CAPTURE PRIMARILY DYNAMIC
CHANGES THAT HAPPEN AS WE DEPART
FROM HEALTHY HOMEOSTASIS, INTO
EITHER A DISEASE STATE OR THAT
OUR MEDICATIONS ARE DRIVING US
IN THE WRONG WAY TO HAVE, BUT
THE PROBLEM IS THAT THESE
LABORATORY VALUES ARE MORE
HERITABLE THAN PHYSICIANS
REALIZE AND ESPECIALLY THE 1S
THAT ARE OLD AND MORE GENERAL
INDICATORS OF HEALTH THAN
SPECIFIC INDICATORS OF
PARTICULAR DISEASE.
THE GENETICS IS OFTEN COMPLETELY
NONPREDICTIVE OF THE OUTCOMES
WE'RE USING THE MEASUREMENTS
FOR, AND SO WHEN THOSE
LABORATORY MEASUREMENTS ARE
HIGHLY HERITABLE, AND THAT
GENETICS IS NOT PREDICTIVE OF
THE OUTCOMES, THE GENETICS IS
NOT JUST MISLEADING US BUT IT'S
CREATING A BARRIER TO THE
DYNAMIC PART OF THE MEASUREMENT
TELLING US THE RIGHT THINGS
ABOUT WHERE PEOPLE ARE IN THE
DISTRIBUTION.
THIS MAKE ITS AN OPPORTUNITY TO
USE GENETICS TO IMPROVE HEALTH
AND EQUITY, BOTH, NOT BY--NOT BY
USING THE GENETICS, TO CHANGE
THIS PREDICTION, BY REGRESSING
OUT THE GENETICS OF PLACES WHERE
IT'S MISLEADING US.
SO ALL THIS WORK WAS DONE IN THE
CONTEXT OF THE BIOBANK OF
VANDERBILT UNIVERSITY WHERE WE
HAVE EHR DATA AND GOING BACK AN
AVERAGE OF 10-15 YEARS AND MORE
THAN 30 YEARS IN SUBSUBJECTS.
WE HAVE MORE THAN 300,000
SAMPLES, DNA SAMPLES IN THE
BIOBANK MAIL, AND HAVE GENOME
INTERROGATION ON ABOUT HALF OF
THOSE SUBJEKS IN VARIOUS WAYS,
GWAS, EXOHM SEQUENCING AND WHOLE
GENOME SEQUENCING BUT NOW
THERE'S AN ALLIANCE THAT WILL BE
SEQUENCING THE ENTIRE BIOBANK
AND PHARMA IS SEQUENCING THE
ENTIRE BIOBANK WHICH WILL REALLY
ALLOW US TO DO A BETTER
INTEGRATION OF THE COMMON AND
RARE VARIANT SPACE BUT WE'VE
ALWAYS ALSO USED THE GENOME
VARIATION TO IMPUTE OTHER OMICS
INTO THE DATA.
I THOUGHT 10 YEARS AGO, AS WE
WERE DOING MORE MULTIOMICS
STUDIES, AND THESE--THESE ARE
BIOMARKERS THAT ARE SO RICH,
THAT ALL OF THE MULTIOMICS DATA
IS VERY, VERY RICH FOR
PREDICTING FUTURE HEALTH STATUS.
THOSE THINGS WILL MAKE THEIR WAY
INTO MEDICINE AS BIOMARKERS THAT
WE WOULD USE COMMONLY IN
THINKING ABOUT HEALTH AND
DISEASE BUT EVERYTHING CHANGES
VERY SLOWLY IN MEDICINE AND FOR
SURE, TRANSCRIPT ORDER OF
MICRONSS, METRICS TAB O LOAMS,
PROTEOMES ARE NOT NEARLY AS
HARDENED IN TERMS OF INTER
IMAIGZ AS GENOMES HAVE BEEN AND
WE MEDE--WE NEED TO MOVE IN THAT
DIRECTION IN ORDER TO BE EVEN
THINKING ABOUT USING THESE IN A
CLINICAL CONTEXT.
BUT THE BIOMARKERS THAT WE USE
VERY ROUTINELY ARE OFTEN TELLING
US MUCH, MUCH MORE ABOUT VERY
LATE STAGE DEPARTURES FROM
HEALTHY HOMEOSTASIS AND I THINK
THE OPPORTUNITY MORE OF THE
OMICS MEASURES IS TO BE CATCHING
DEPARTURES FROM HEALTHY
HOMEOSTASIS POTENTIALLY MUCH
EARLIER.
ONE OF THE THINGS I HADN'T
APPRECIATED TILL I GOT TO
VANDERBILT IS THAT WHILE THE
PART OF THIS, THAT HAS THE
GENOMIC INTERROGATION IS A
FANTASTIC RESOURCE.
THE PART THAT DOES HAVE ANYTIME
GENOMIC INTERROGATION, THE
2.8 MILLION OTHER PEOPLE WITH
JUST 15-30 YEARS OF ELECTRONIC
HEALTH RECORDS DATA IS A
FANTASTIC ARK DITIONAL RESOURCE
FOR ENRICHING WHAT WE LEARNED
FROM THE GENETICS BUT ALSO FOR A
BIG SAMPLE THAT CAN LEAD TO
DISCOVERIES THAT WE ARE ABLE TO
TAKE INTO GENETICS TO VALIDATE
AND I THINK AS WE THINK MORE
ABOUT USING GENETICS TO DO
TARGET DEVELOPMENT FOR BETTER
THERAPEUTICS, THE OTHER THINGS
WE CAN DO WITH DATA LIKE THIS
ARE THINKING ABOUT THE MRI O
TROAPIC EFFECTS OF GENETIC
FACTORS EARLIER IN LIFE, SO THAT
WE USE BIOLOGICAL INFORMATION TO
THINK ABOUT SURROGATE END POINTS
THAT ARE NOT ALZHEIMERS BECAUSE
IT'S SO LATE IN ONSET, BUT ABOUT
SOME OF THE OTHER BIOLOGY DRIVEN
BY THE SAME GENETIC FACTORS THAT
ARE DRIVING AT LEAST PIECES OF
THE ALZHEIMER'S GENETIC PUZZLE
AND I THINK AS WE LEARN MORE AND
MORE, THINK ABOUT THE BIG
CONTRIBUTION THAT BIOLOGY
ATTRIBUTABLE TO MICROGLIA WHICH
ARE JUST MACROFAJS MIGHT BE
TELLING US ABOUT MUCH EARLIER IN
THE LIFE SPAN THAT WE COULD
PROFITABLY USE IN THINKING ABOUT
CLEVER DRUG DESIGNS TO WAIT
UNTIL PEOPLE HAVE COGNITIVE
DECLINE TO BE THINKING ABOUT
THERAPY RATHER LOOKING AT THE
SORT OF SAME KINDS OF FAILURES
IN OTHER CLASSES OF MACROFAJS
THAT MAY BE MANIFESTING EARLIER.
BUT EVERYBODY FULLY UNDERSTANDS
THAT INTRODUCING GENOMES INTO
MEDICINE HAS LED AND IS
CONTINUING TO LEAD TO NEW KINDS
OF HEALTH DISPARITIES AND PART
OF IT IS TOTALLY NOT IN OUR
CONTROL EXCEPT AS CITIZEN TO DO
ANYTHING ABOUT, THIS JUST SHOWS
THE INCREASE IN INCOME AND
EQUALITY IN THE U.S. IN FROM
1967 TO 2014.
AND THESE TRAJECTORIES GOT WORSE
AND IT WAS REALLY ONLY OVER
COVID WITH A DECREASE IN INEQUAT
TO REFLECT INVESTMENTS THAT WERE
MADE TO TRY TO KEEP PEOPLE
HEALTHY AND SAFE DURING THE
MIDST OF THE COVID OUTBREAKS.
THAT INEQUALITY OF ACCESS IS
THEN COUPLED TO HISTORICAL
FAILURES TO HAVE THE RIGHT DATA
FROM DIVERSE POPULATIONS TO
INVEST IN WITH GENETIC STUDIES.
IT MAKES SENSE TO USE CATATHAT
ARE VERY RICH AND HAVE A LONG
HISTORY OF INFORMATION, CLINICAL
INFORMATION, AND MEDICATION
INFORMATION TO USE IN INVESTING
IN THE FIRST GENETIC STUDIES BUT
BECAUSE THOSE STUDIES HAD MUCH
LESS DIVERSE DATA, LESS DIVERSE
WITH RESPECT TO REPRESENTATION
BY GENDER, LESS DIVERSE WITH
RESPECT TO REPRESENTATION OF THE
DIVERSITY OF THE HUMAN
POPULATION THAT WE--WE HAVE
SUBSTANTIALLY OVERSAMPLED
EUROPEAN GENOMES RELATIVE TO
GENOMES IN THE REST OF THE WORLD
AND THE PROBLEM IS THE VERY
SUCCESS OF THE SCIENCE IN
LEADING TO DISCOVERIES THAT HAVE
SOME GOOD OPPORTUNITIES FOR
CLINICAL TRANSLATION, MEANS THAT
POPULATIONS THAT CAN AFFORD TO
HAVE MORE GENETIC INFORMATION
USED IN OUR HEALTHCARE CONTINUE
TO DO THAT.
SO EVEN THOUGH WE ARE NOW
COLLECTING MUCH MORE IMENETTIC
DATA ON DIVERSE POPULATIONS THAN
WE EVER HAVE IT'S ACCUMULATING
FASTER, IT'S AN IMPRESSIVE WORLD
WIDE EFFORT.
WE ARE STILL ACCUMULATING
INFORMATION ON THE GENOMES OF
EUROPEANS EVEN FASTER.
I DON'T SEE A WAY TO CATCH UP
UNTIL EVERYBODY HAS GENOMES DONE
ROUTINELY FOR HEALTHCARE.
I REALLY DON'T THINK WE WILL
CATCH UP IN TERMS OF THE
REPRESENTATION OF WORLD
POPULATIONS IN INTERROGATED
GENOMES UNTIL THAT HAPPENS
BECAUSE EVEN WORLD WIDE, THERE
IS--THERE IS INEQUALITY OF
ACCESS TO INFORMATION AND
INEQUALITY IN THE ABILITY TO
INVEST IN THE RESEARCH
ENTERPRISES TO CREATE ALL THE
DATA THAT WOULD REALLY HAVE
VALUE FOR INTERPRETING.
SO WE KNOW THAT WE CAN'T MOVE
FORWARD WITHOUT CREATING NEW
KINDS OF HEALTH DISPARITIES, AND
SO THIS MAKES THE CASE EVEN NOW
THAT IN NOF 1 STUDIES IN
CHILDREN AND ADULTS FROM DIVERSE
POPULATIONS WERE LESS LIKELY TO
GET AN UNEQUIVOCAL SOLVE, WERE
MORE LIKELY TO BE DEALING WITH
VALID AND RELIABLE YABTS OF
UNKNOWN SIGNIFICANCE AND THAT
WOULD BE THE CASE FOR SOMETIME
YET.
AND THIS IS NOT--THIS IS A WORLD
WIDE PROBLEM AND WE--I MEAN
EVERYBODY IS TRYING TO INVEST IN
WAY TAC IMPROVE THOSE OUTCOMES
BUT IT WILL TAKE TIME AND IT
WILL BE HARD TO CATCH UP WITH
THE QUALITY OF INFORMATION.
IN THE COMMON VARIANT SPACE,
POLYGENIC RISK SCORES ARE BEING
DELIVERED TO DIVERSE POPULATIONS
EVEN NOW, BUT THE TRUTH IS WHAT
WE NEED TO LEARN FROM POLYGENIC
RISK SCORES WHAT WE HAVE ANY
OPPORTUNITY TO DELIVER INVOLVES
A LOT OF TAIL PROPERTIES, LIKE
MOST OF WHAT IS HAPPENING IN THE
MITSD OF THIS DISTRIBUTION
DOESN'T MATTER FOR UNDERSTANDING
RISK, YOU'RE AT THE SAME GENERAL
RISK AS THE GENERAL POPULATION.
WHAT WE GENERALLY TRY TO DELIVER
IS MORE INFORMATION FROM THE
TAILS AND IT CAN BE WILL HIGH
TALES OF RISK, WE NEED TO
UNDERSTAND LOW RISK AS WELL,
ESPECIALLY AS WE'RE ABLE TO
BETTER COMBINE RARE AND COMMON
VARIANTS IN A WAY THAT REALLY
HELPS DEFINE ACCURATELY, LARGE
SCALE GENETIC RISK TO DISEASE
BUT TAIL PROPERTIES OF NORMAL
DISTRIBUTIONS ARE THE LEAST
TABLE PART, RIGHT?
AND DIFFERENT WAYS OF
CALCULATING POLYGENIC RISK
SCORES HAVE THE MOST IMPACT IN
THE TALES OF DISTRIBUTION.
SO SMALL VARIATIONS IN HOW
CALCULATIONS ARE DONE IN THE
POPULATIONS IN WHICH THESE
PREDICTIVE MODELS ARE TRAINED
HAVE A BIG IMPACT IN WHO ENDS UP
IN THE TALE THAT GETS NFGZ THAT
THEY'RE AT HIGH RISK.
THAT'S NOT ATTRACTIVE FROM THE
STATISTICAL PERSPECTIVE BUT BOTH
OUR METHODS FOR CALCULATING THE
TRAINING OF THESE RISK SCORE
PREDICS ABOUT YOU ALSO THE
APPLICATION IGNORES THE REALITY
THAT ABOUT HALF OF THE U.S.
POPULATION IS
CONTINENTALLYAD-MIXED IN RECENT
GENERATION ANDS THAT THAT'S THE
FASTEST GROWING PART OF OUR
POPULATION, ALL OF WHICH IS
IGNORED AT SOME RISK OF FAILING
TO CAPTURE IMPORTANT ASPECTS OF
POPULATION LEVEL RISK FULLY
ACCURATELY.
AND SO, WE LOOK AT THOSE THAT
DEAL WITH THE LEVEL OF
COMPLEXITY THAT WE NEED TO DEAL
WITH IN TREATING POPULATIONS IN
THE U.S. AND DELIVERYING
IMENETTIC DATA TO POPULATIONS IN
THE U.S., IS GOING TO HAUNT US
FOR SOMETIME.
WE NEED TO IMPROVE METHODS THAT
ARE ALREADY BEING USED TO
DELIVER RESULTS TO OUR
POPULATIONS AND SO WE CAN HARDLY
DO THIS FAST ENOUGH BECAUSE IT'S
ALREADY HAPPENING.
SO WE KNOW BY TRANSLATING
GENOMIC DISCOVERIES, BUT WE HAVE
AN OPPORTUNITY IN THE LAB TO
SPACE THAT USE GENETICS IN A WAY
THAT WILL IMPROVE HEALTH AND
IMPROVE HEALTH EQUITY.
AND WE USE LABORATORY TESTS
EVERY DAY IN MEDICINE AND THE
FAILURE TO HAVE FULLY
APPRECIATED HOW DIVERSE HUMAN
POPULATIONS ARE IN THESE
MEASUREMENTS HAS CREATED A
NUMBER OF REALLY IMPORTANT
INSTITUTIONAL DISPARITIES WITHIN
MEDICAL CENTERS WHICH REALLY
HAVE TO BE ADDRESSED.
SO IN OUR CENTER IN VANDERBILT
GENETICS INNS TUITION, LEA DAVIS
LED THE EFFORTS TO CLEAN THE
LABORATORY VALUES IN A WAY THAT
IT COULD BE SHOWN THAT WE WERE
GETTING ESTIMATING WITH SAME
LEVELS OF HERITABILITY, GETTING
THE SAME GWAS SIGNALS AS STUDIES
DONE ON THOSE LABORATORY
MEASURES IN A RESEARCH CONTEXT.
THE REASON IT TAKES SO LONG AND
IT'S HARD TO CLAIM THESE VALUES
IS THAT OVER TIME WE ANY TO
DIFFERENT VENDORS FOR GETTING
LABORATORY TESTS RUN, OVER TIME
THEY CHANGE THE UNITS IN WHICH
LABORATORY VALUES GET REPORTED,
THERE'S MASSIVE BATCH EFFECTS
THAT CAN VERY BY PLACES WHERE
THE TESTS GET RUN AND ALL OF
THAT, YOU KNOW YOU WANT TO TRY
TO STANDARDIZE THAT WE CAPTURE
THE ESSENCE OF GENETICS THAT ARE
REALLY UNDERLYING THESE BY O
MARKERS BUT THEY SUCK
SEDENTARIED--SUCCEEDED IN THAT
AND YOU COULD SHOW THAT AT THE
END OF THIS PROCESS AND THAT
THEY PUBLISHED AND CREATE THIS
PIPELINE THAT'S USED BY LOTS OF
MEDICAL CENTERS NOW TO CLEAN AND
STANDARDIZE THEIR LABORATORY
VALUES FOR FURTHER GENETIC
STUDIES BUT YOU DO--YOU CAN GET
THE SAME ESTIMATES OF GWAS
SIGNALS.
WE ARE CAPTURING THE HEART OF
THE POLYGENIC ARCHITECTURE OF
LABORATORY VALUES IN THE
HOSPITAL SETTING IN THIS
CLINICAL SETTING.
SO WHAT PROPORTION OF THE THAT
PHYSICIANS ORDER AND INTERPRET
ON AT LEAST A MONTHLY BASIS AND
WE MIGHT SAY EVEN THAT WE HAVE
DAT ON AT LEAST A THOUSAND
PEOPLE IN OUR BIOBANK FOR WHAT
PROPORTION OF THOSE LAB VALUES
DO YOU THINK ARE 10% HERITABLE?
I ASK THESE QUESTIONS.
SO IF I ASK OR EVEN WHAT
PROPORTION OF LAB VALUES WOULD
BE SIGNIFICANTLY HERITABLE IN
THAT CONTEXT, IN A GROUP OF
PHYSICIANS IN A GRAND ROUNDS,
YOU KNOW IF I SAY HOW MANY
PEOPLE SAY 10% OF LABS YOU ORDER
WOULD BE SIGNIFICANTLY
HERITABLE, A LOT OF PHYSICIANS
WILL RAISE THEIR HAND AND 20%
AND HALF THE HANDS GO DOWN, AND
30% AND THEY'LL SAY, YEAH, IF MY
HUSBAND'S IN THE AUDIENCE, HE'S
THE ONLY 1 STILL RAISING HIS
HAND BECAUSE HE WERES I'M A
GENETICIST AND I WOULDN'T BE
ASKING OTHERWISE, BUT IT'S
2/3RDS OF LABORATORY VALUES
TAKEN--THEY HAVE--THAT WE HAVE
THAT MEAN PEOPLE ON THAT ARE
ORDERED AT LEAST ONCE A MONTH
ARE SIGNIFICANT LE HERITABLE IN
THE EHR, A SUBSTANDIAL FRACTION
OF THOSE, BETWEEN 30-40% OF
LABORATORY VALUES ARE
SIGNIFICANTLY HERITABLE, HAVE
HERITABILITYS IN EXCESS OF 40%
AND UP INTO THE 80, 90% RANGE.
SO IS THIS A PROBLEM BECAUSE
PHYSICIANS THINK OF THEM AS
DYNAMIC MEASURES OF DISEASE,
RISK AND PROGRESS AND THAT'S HOW
THEY ARE USED AS PRIMARILY
DYNAMIC MEASURES OF WHAT'S
HAPPENING RIGHT NOW, IN THIS
SYSTEM AND THE GENETIC SYSTEM
STATIC.
THE GENETICS IS HOLDING,
ANCHORING PEOPLE AT SOME PART OF
THAT DISTRIBUTION, TRYING AS
HARD AS POSSIBLE TO KEEP THEM
THERE, AND THAT'S WHERE IT'S
ACTUALLY A DRUG --DRAG ON THE
DYNAMIC PART OF THESE MEASURES.
CERTAINLY THERE COULD BE SOME
POSSIBILITY THAT ANY GENE BY
ENVIRONMENT INTERACTION, ANY
EXPOSURES THAT ARE CHANGING
THESE VALUES COULD BE
INTERACTING WITH THE GENETICS
BUT FOR THE MOST PART THE
GENETICS ARE STATIC AND
THAT--BECAUSE THEY'RE MUCH MORE
GENETIC THAN PHYSICIANS ARE
OFTEN GIVING THEM CREDIT FOR,
THAT MEANS THAT FIRST TIME
SOMEBODY ORDERS A CREATINE THAT
LOOKS LIKE IT'S PUTTING PEOPLE
INTO TAIJ 2 KIDNEY DISEASE
THEY'RE JUST WATCHING TO SEE
THAT PROGRESS BECAUSE THEY THINK
THAT PERSON IS IN STAGE 2 END
KIDNEY DISEASE BUT THE GENETICS
MAY BE PLACING THEM IN THE
GRIEWKS, THEY MAY BE AT STAGE 4
IN THE DISEASE, OR THEY MAY BE
HEALTHY.
I WILL SHOW YOU IN A MINUTE.
SO THEN IF YOU THINK ABOUT THESE
BEING HERITABLE AND MORE
HERITABLE THAN PHYSICIANS
REALIZE, WHAT PROPORTION OF THE
HERITABLE LAB VALUES HAVE MEAN
VALUES OR VARIANCES, THAT DIFFER
SIGNIFICANTLY BY EHR REPORTED
RACE ETHNICITY.
TEN%, A QUARTER OF THEM, HALF OF
THEM.
HALF OF THEM HAVE SIGNIFICANT
MEAN DIFFERENCES BY EHR REPORTED
RACE ETHNICITY AND NOT
INSUBSTANTIAL FRACTION DIFFERS
SIGNIFICANTLY IN THE VARIANCES
AND ESPECIALLY AMONG POPULATIONS
OF RECENT AFRICAN GENETIC
ANCESTRIES, THE FACT THAT
THERE'S A MUCH LONGER POPULATION
HISTORY LARGER AFFECTIVE
POPULATION SIZE, AND THOSE
POPULATIONS HAVE MUCH MORE
GENETIC VARIATION, THEY HAVE
MUCH MORE FUNCTIONAL VARIATION.
IT IS NOT UNCOMMON TO
OBSERVATION LABORATORY VALUES
WITH SIGNIFICANT MEAN
DIFFERENCES WHERE THE AFRICAN
AMERICANS IN OUR BIOBANK ARE
MORE LIKELY TO BE OUTSIDE
REFERENCE RANGES, OF COURSE, IN
THE DIRECTION WHERE THE MEAN HAS
CHANGED BUT ACTUALLY ARE MORE
LIKELY TO BE OUTSIDE REFERENCED
RANGES ON BOTH ENDS OF THE
GRIEWKS DESPITE THE FACT THAT
THERE'S A BIG MEAN DIFFERENCE.
IN SOME WAYS THIS IS A CRAZY
THING BUT THE TRUTH IS, MANY OF
THE REFERENCE RANGES WERE SET A
VERY ALONG TIME AGO IN NOW WE
WOULD NOW THINK OF RIDICULOUSLY
SAMPLES OF OLD WHITE MEN, SOME
OF THE LAB COMMONLY USED MEASURE
AMS HAVE UNDERGONE CHANGES OVER
TIME WITH RESPECT TO REFERENCE
RANGES, MOST HAVE NOT, MOST OF
THEM ARE NOT ADEQUATELY
CORRECTED FOR SEX DIFFERENCES IN
THE MEASURES OR FOR HOUR DIVERSE
THESE LABORATORY VALUES ARE
ACROSS POPULATIONS.
SO I WILL GO THROUGH A FEW
EXAMPLES OF STUDIES THAT HAVE
BEEN DONE ON COMMONLY USED LAB
VALUES, WHITE CELL COUNT,
NUTRIFILL COUNTS, XONLY USED TO
IN PEOPLE WHO TAKE DRUGS THAT
MIGHT BE CYTOTOXIC IN TRYING TO
IDENTIFY PEOPLE WHO MIGHT HAVE
THE DISEASE, THE DUFFY MORPHISM
IS A LOWER COMPOUND AND PEOPLE
HOMOZYGOUS FOR THISPOLOGYY
MORPHISM, MOST OF WHOM HAVE
RECENT GENETIC ANCESTRY FROM
AFRICA BECAUSE IT IS AN
ADAPTATION TO HIGH MALARIA
ENVIRONMENTS THAT IS EXTREMELY
EFFECTIVE, ALLELE FREQUENCIES
AND ENVIRONMENTS WHERE THE
PARTICULAR, THIS PARTICULAR
ADAPTATION IS EFFECTIVE.
ALLELE FREQUENCIES ARE NEARLY 1
FOR THIS--NEARLY EVERYONE IS
HOMOZYGOUS FOR THIS VARIANT IN
MOST PARTS OF AFRICA, SO ONA
AVERAGE AFRICAN AMERICANS IN THE
U.S. ARE--THE ALLELE FREQUENCY
.8, THAT'S ABOUT THE PROPORTION
YOU WOULD EXPECT GIVEN THE
AVERAGE ADD MIXTURE OF EUROPEAN
ALLELES IN AFRICAN--RECENT
AFRICAN ANCESTRY GROUPS IN THE
UNITED STATES, THAT MEANS 2/3RDS
OF AFRICAN AMERICANS ARE
HOMOZYGOUS FOR THIS ALLELE AND
WHEN A BONE MARROW BIOPSY IS
ORDERED IN A PATIENT HOMOZYGOUS
FOR THE DOVE ARK LEGAL, AND THE
ONLY REASON FOR THE BIOPSY IS
THE BONE MARROW WHITE COUNT.
IT'S NEVER POSITIVE, THERE'S NO
RETURN IN THE INVESTMENT OF THAT
BONE MARROW BIOPSY, IT IS NEVER
POSITIVE AND THAT WAS SHOWN AT
VANTER BUILT AND A GROUP OF
OTHER BIOBANKS, SO THERE'S
UNNECESSARY BONE MARROW
BIOPSIES, STILL BEING DONE
DESPITE THE FACT THAT THIS
BENIGN ETHNIC NEWT PENIA IS
SUPPOSED TO BE WELL KNOWN TO
PHYSICIANS.
BONE MARROW BIOPSIES ARE STILL
BEING ORDERED, NOT UNCOMMONLY IN
MEDICAL CENTERS, WHERE THE ONLY
INICATION IS A LOW WHITE CELL
COUNT.
NO ADDITIONAL SYMPTOMS AND WHEN
THOSE PEOPLE ARE DUFFY
HOMOSWROIG OATS THERE'S NO
RETURN ON THE BONE MARROW
BIOPSY.
THERE'S A LOT OF DRUGS THAT WE
GIVE THAT ARE CYTOTOXIC,
PHYSICIANS LOOK AT THE FIRST
WHITE CELL COUNT THAT HAPPENS
AFTER PATIENTS GET PUT ON THESE
DRUGS AND THEY ARE TAKING
PATIENTS WHO ARE DUFFY
HOMOZYGOTES OFF FIRST LINE MEDS
FOR AUTOIMMUNE CONDITIONS, FOR
CANCER CHEMO THERAPIES, YOU KNOW
DRUGS PEOPLE TAKE AFTER
TRANSPLANTATION, THEY'RE TAKING
DUFFY HOMOZYGOTES OFF THEIR
MEDS, WHEN THEY DON'T NEED TO
BE.
AFRICAN AMERICANS WHO ARE DUFFY
HOMOZYGOTES DON'T HAVE FEWER
WHITE CELLS, THERE ARE FEWER IN
CIRCULATION, THEY'RE HEANGING
OUT IN PERIPHERAL TISSUES AND AS
SOON AS THEIR'S AN INFEC, THEY
COME OUT, FIGHT THAT INFECTION
JUST FINE.
THE LOW COUNTS OF WHITE CELL
POPULATION ARE NOT INDICATIVE OF
INCREASED RISK FOR INFECTION.
SO, SO TAKING PEOPLE OFF THESE
IMPORTANT FIRST LINE DRUGS IS
DISADVANTAGING THEM IN THEIR
HEALTHCARE AND AGAIN, YOU SEE
THIS REALLY DRAMATICALLY FOR
DRUG WITHDRAWALS FOR HEMOPOETIC
TOXICITY BUT NOT FOR OTHER
REASONS THAT HAD TO DO WITH THE
INABILITY TO JUST TAKE THE DRUG,
OTHER KINDS OF SIDE EFFECTS
ENTIRELY, SO IT'S ALL ABOUT
DUFFY AND PEOPLE TAKEN OFF THE
DRUGS FOR TOXICITY AND ON
AVERAGE THEY GET TO TAKE ABOUT
20% OF THE FIRST LINE MEDS THAT
OTHER AFRICAN AMERICANS TAKE
WHEN THEY HAVE LUPUS AND WE'VE
ALWAYS KNOWN THAT PEOPLE WHO
HAVE LUPUS WITH RECENT AFRICAN
ANCESTRY DO WORSE WITH LUPUS
THAN WE SEE THIS OTHER
POPULATIONS BUT HOW MUCH OF THAT
IS TAKING A SUBSTANTIAL--2/3RDS
OF ATRICK AN AMERICANS ARE AT
RISK OF BEING TAKEN OFF THOSE
FIRST LINE MEDS VERY EARLY.
SO AS I DAY DUFFY IS A BENIGN
POLYMORPHISM EXCEPT FOR HOW IT
EXECUTES HEALTHCARE IN THE
UCARIOT.
SO IT IS NOT A GENETIC HEALTH
DISPARITY, IT IS SOMETHING ELSE,
IT SHOULD NEVER LEAD TO A HELT
DISPARITY BUT IT LEADS TO A LOT
OF REPEAT TESTING, UNNECESSARY
BONE MARROW BIOPSIES,
UNDERTREATMENT IN LUPUS, THAT I
JUST SHOWED YOU, BUT UNDER THE
HOOD, I MEAN THE THRESHOLD FOR
WHITE CELL COUNT TO GET INTO
CANCER THEME O THERAPY TRIALS
WAS FOR MANY YEARS GOING TO KEEP
HALF OF ALL AFRICAN AMERICANS
OUT OF CLINICAL TRIALS BECAUSE
2/3RDS OF THEM WHO ARE DUFFY
HOMOZYGOTES END YOU FALLING
BELOW THE THRESHOLDS ALL THE
TIME AND THEY SET THOSE
THRESHOLDS BECAUSE THEY DON'T
WANT TO LOOSE PEOPLE IN THE
WORSE OF CLINICAL TRIALS WHO ARE
ALREADY STARTING TO HAVE
CYTOTOXICITY FROM THE TREATMENTS
THEY'VE HAD BUT OF COURSE, WITH
HOMOZYGOTES THEY WILL BE LOWER,
IT WAS AN INAPPROPRIATE
THRESHOLD FOR AFRICAN AMERICANS
AND I--WHILE THAT'S BEING
CHANGED NOW, THAT'S PART OF THE
REASON WHY IT'S SO
UNDERREPRESENTED IN CHEMO
THERAPY TRIALS FOR SO MANY
YEARS.
AND FOR TRANSPLANT, PEOPLE ARE
LOOKING AT BUT IT'S NOT ANYTHING
IMD, I CAN TELL THAT NOW.
HOW BAD IT IS, WE ARE STILL
LOOKING AT BUT YOU CAN SEE IT IN
THE RATES AT WHICH AFRICAN
AMERICANS ENDED UP HAVING BURST
APPENDIXES BECAUSE MANY OF THE
RUBRICS FOR WHEN YOU DO SURGERY,
WHEN YOU SHOULD DO SURGERY, TO
KEEP THE APPENDIX FROM BURSTING
REQUIRED REACHING A CERTAIN HIGH
WHITE CELL COUNT THAT PEOPLE
WITH, WHO ARE DUFFY HOMOZYGOTES
WILL NOT GET TO.
THEY WILL BE--THEY WILL BE RIGHT
AT OTHER POPULATIONS AFRAMMINGS
WHEN THEY'RE WHITE CELL COUNTS
HAVE REALLY GOTTEN DANGEROUSLY
HIGH.
AFRICAN AMERICANS HAVE JUST HAD
MORE SERIOUS HEALTH DISPARITIES
REFLECTING BURST APPENDIX.
RISK BASED REF FERENCE RANGES
CANNOT SOLVE THIS PROBLEM.
ONE-THIRD OF AFRICAN AMERICANS
ARE NOT DUFFY ZYGOTES, THEY ARE
DISTRIBUTION OF THEIR WHITE CELL
COUNTS LOOKS LIKE EVERYBODY'S
EXPWRIEWKS OF WHITE CELL COUNTS,
IT'S NOT ABOUT THE SOCIAL
CONSTRUCT OF RACE, IT'S ABOUT
WHAT ALLELES YOU HAVE AND COMMON
ALLELES WITH BIG EFFECTS DRIVE
HUGE HERITABILITYS.
THE HERITABILITY OF WHITE CELL
COUNTS IN POPULATIONS OF RECENT
AFRICAN ANCESTRY IS MUCH HIGHER
ABOUT THE HERITABILITY OF WHITE
CELL COUNTS IN OTHER POPULATIONS
BECAUSE IN PART OF THIS ALLELE
IT HAS A BIG IMPACT ON AVERAGE
CELL COUNT, AND IS VERY COMMON
IN THAT POPULATION, MOST ALLELES
THAT HAVE BIG EFFECT SIZES ARE
RARE, THIS IS AN EXAMPLE OF HOW
SELECTION HAS DRIVEN ALLELE, AN
ALLELE TO VERY HIGH FREQUENCY
THAT'S BENIGN FOR HEALTH BUT NOT
BENIGN WHEN WE THINK OF HOW IT
INFLUENCES HEALTHCARE.
SO WHAT DO YOU EVEN CALL THIS
DISPARITY?
IT'S NOT REALLY A DISPARITY,
IT'S AN IGNORANT DISPARITY.
IT'S 1 THAT CAN BE FIXED WITH
GENETIC COUNTS.
WHILE CELL COUNTS ARE USEFUL
MEASUREMENTS WE SHOULD BE
RECOGNIZING AND YOU KNOW THESE
ARE STUDIES THAT ARE ABOUT TO BE
PUBLISHED, THE POLYGENIC
BACKGROUND FOR WHITE CELL COUNTS
IS NOT PREDICTIVE FOR ANY OF THE
OUTCOMES THAT WE USE IT, IT'S
NOT PREDICTIVE OF WHO WILL
DEVELOP INFECTIONS WHEN THEY
TAKE MEDICATIONS, JUST THE PURE
POLYGENIC BACKGROUND, EVEN IN
EUROPEAN POPULATIONS, WHAT'S
VALUABLE ABOUT WHITE CELL
COUNTS, NUTRIFILL COUNTS IN
THESE CONTEXT IS THAT DYNAMIC
NATURE.
WILL WAY GENETIC INFLUENCE WHERE
YOU ARE IN THE DISTRIBUTION IS
NOISE FOR HOW WE USE THAT
MEASURE AND THAT MEASURE WILL BE
MORE INFORMATIVE, IF WE REGRESS
ALL THE GENETICS OUT FOR
EVERYBODY, IT WILL BE A BETTER
MORE EFFECTIVE BIOMARKER FOR THE
WAYS THAT WE USE IT.
--HOW WELL THE CONTROL FOR BLOOD
FLUICOSE LEVELS IS IN PEOPLE
WITH DIABETES.
IT IS NOW NOT INFREQUENTLY
USEDDAs A WAY OF DIAGNOSE
DIABETES IN HEALTHCARE SYSTEMS.
BUT G6 PEOPLE WHO CARRY GSPD
ALLELES, MUTATIONS, AGAIN THAT
HAPPEN TO BE ADAPTATIONS TO
MALARIA ENVIRONMENTS THIS IS A
VERY COMMON ADAPTATION THAT HAS
RISEN OVER AND OVER AGAIN
INDEPENDENTLY AT DIFFERENT
ALLELES AT G6 PD, WHICH IS ON
THE X-CHROMOSOME, SO MALES ARE
HOMOZYGOUS FOR THESE ALLELES,
THESE ARK LEGALS HAVE ARISEN ALL
OVER THE WORLD WHERE IT'S
INDEMMIC AND THEY'RE NOT RARE IN
POSE POPULATIONS, COLLECTIVELY
G6 PD MUTATIONS THAT CAN HAVE
THIS EFFECT ON HEMOGLOBIN
IEE, AUDIENCE 1 C RANGE FROM
25%, WE CARRY AROUND THOSE
VARIANTS IF ARE A LONG TIME
AFTER THE PATHOGENS ARE NO
LONGER DRIVING THEM EMPLOY THE
REASON THIS AFFECTS A1C LEVEL
SYSTEM THAT THERE'S RED CELL
HOMOLOGY SIS WHICH AFFECTS TD
AVERAGE LIFE SPAN OF THE RED
CELL WHA. WE'RE DOING IS
MEASURING THE GLUE
MARIOUSICATION OF HEMOGLOBIN ON
RED CELLS AND IN PEOPLE WITHOUT
G6 PD VARIANCE LEADING TO RED
CELL HOMOLYSIS, WE ARE GETTING A
SNAPSHOT OF THE AVERAGE
CIRCULATING GLUCOSE LEVELS IN
ABOUT THE PAST 3 MONTHS WHICH IS
THE RATE OF RED CELL TURNOVER
AND PEOPLE WITH G6 PD VARIANTS,
THERE'S MORE RAPID TURNOVER, RED
CELLS BECAUSE OF THE HOMOLYSIS
AND YOU'RE LOOKING AT SOMETHING
CLOSER TO A MONTH OR A MONTH AND
A HALF OF LIFE OF THAT
HEMOGLOBIN MOLECULE IN ITS GLUE
MARIOUSICATION, THE 1 WHO YOU
DON'T KNOW WHO'S A CARRIER AND
WHO'S NOT YOU CAN'T TAKE THAT
INTO ACCOUNT AND ON AVERAGE WITH
DIABETES, THOSE CARRYING G6 PD
ALLELES HAVE ABOUT A 1 POINT
LOWER HEMODPLOABIN A1C LEVELS
FOR MALES AND YOU CAN SEE THE
PROGRESS IN FEMALES, EVEN THE
HETEROZYGOTES HAVE A LOWER LEVEL
AND HOMOZYGOTES MORE SIMILAR TO
WHAT WE SEE IN THE MALE
HOMOZYGOTES.
SO WHAT HAPPENS AS A CONSEQUENCE
OF THIS?
CERTAINLY PEOPLE WITH DIABETES,
SEEING THEIR PHYSICIANS ON A
REGULAR BASIS, AND HAVING THIS
MEASURED NOT BEING TREATED AS
AGGRESSIVE LOAMACYY BECAUSE
THEIR PHYSICIANS AND THEY
THEMSELVES THINK THEY ARE DOING
BETTER AT CONTROLLING THEIR
BLOOD DPLUICOSE LEVELS THAN THEY
ACTUALLY ARE, A FULL POINT LOWER
ON AVERAGE IN MALES.
THIS MEEPS IN OUR BIOBANK ON
AVERAGE, CARRIERS OF G6 PD
ALLELES HAVE A 1.2 FOLD DIABETIC
RISK COMPLICATION IN ANY
SITUATION EMPLOY IT IS SERIES
FOR DIABETIC RETINAL LOCATIONIN
OPEN MEETINGATHY, AND IT'S IN
EARLY CLINICAL TRIALS TO
UNDERSTAND HOW WELL, BLOOD
GLUCOSE CONTROL WOULD REDUCE THE
RISK OF COMPLICATIONS, DIABETIC
RETINAL LOCATION NUMBER OF
PATIENTSATHY WAS THE SENTINEL 1
BECAUSE IT'S 1 OF THE FIRST
COMPLICATIONS TO ARISE, SO
HUGELY SIGNIFICANT EMPLOY 1.8
FOLD INCREASED RISK IFA BETTIC
RETINAL LOCATIONIN OPEN
MEETINGATHY, HIGHLY SIGNIFICANT,
BUT BIOBANKS ARE SEEING THIS
TOO.
WE ARE WORKING IN PRIMED IN A
CONSORTIUM TO LOOK AT THIS IN A
SERIOUS WAY.
IT'S THE SAME EVERYWHERE, AND WE
HAVE GOOD INFORMATION FROM
SINGAPORE AND TAIWAN--AND STILL
IS ENDEMIC IN SOUTHERN PARTS OF
EUROPE.
IT AFFECTS THIS MEASUREMENT OF
GLUE MARIOUSICATED HEMOGLOBIN
THAT IS A RELATIVELY INEXPENSIVE
AND EFFECTIVE ASSAY.
IN POPULATIONS THAT HAVE THE
KIND OF HEALTHCARE SYSTEM WHERE
HEMODPLOAGIN A1C IS TESTED EVERY
WHY TO IDENTIFY DIABELTICS, IT'S
AN AVERAGE 7 YEAR LATER
DIAGNOSIS OF THE DIABETES IN THE
G6 PD CARRIERS.
SO IT'S NOT JUST THAT THEY'RE
NOT BEING TREATED AGGRESSIVELY
ENOUGH, BUT IF YOU USE
HEMODPLOABIN A1C TO DIAGNOSE THE
DIABETES, THEY WILL HAVE IT FOR
MANYIERS BEFORE YOU RECOGNIZE
AND TREAT IT.
THE COST OF DIABETIC
COMPLICATIONS IS 1 OF THE
REASONS WHY THE NATIONAL
INSTITUTES OF DIGESTIVE
DISORDERS AND KIDNEY DISEASE
EXIST.
DIABETES IS A HUGE PUBLIC
HEALTHCARE PROBLEM EXCLUSIVELY
BECAUSE OF THE COMPLICATIONS
THAT IT CAUSES AND THE EXPANSE
AND DIFFICULTY OF TREATING THOSE
COMPLICATIONS AND THE MORBIDITY
AND MORTALITY THAT ARISE BECAUSE
OF THESE COMPLICATIONS.
WE HAVE ALWAYS RECOGNIZED THAT
MINORITY POPULATIONS HAVE MORE
DIABETIC COMPLICATIONS AND IT'S
EASY TO SAY, WELL, THEY CAN
ACCESS HEALTHCARE LESS, THEY
HAVE LESS ACCESS TO THINGS LIKE
FLUICOSE METERS THAT GIVE
CONTINUOUS FEEDBACK ON HOW WELL
THEY'RE DOING?
BUT PART OF IT ARE THESE KINDS
OF THINGS AND REMOVING THIS 1
HEALTH DISPARITY, USING GENETICS
WOULD PAY FOR THE GENETICS FOR
EVERYTHING ELSE.
IT'S HUGELY CONSEQUENTIAL IN
COST TO HAVE PEOPLE GO BLIND.
AND AS I SAY, THESE ALLELES ARE
NOT RARE IS ON THIS PARTICULAR
BIOMARKER THEY HAVE A BIG
EFFECT.
THEY HAVE EFFECTS ON OTHER
BIOMARKERS, TOO BECAUSE OF THE
RED CELL HOMOLYSIS.
BLOOD BORNE PATHOGENS, THE
ADAPTATIONS TO BLOOD BORNE
PATHOGENS WILL HAVE A LOT OF
EFFECTS ON THINGS WE MEASURE IN
BLOOD.
WE HAVE IGNORED THOSE THINGS IN
INTERPRETING LABORATORY VALUES
IN WAYS THAT ARE TRULY
DISADVANTAGING A LOT OF THE
WORLD'S POPULATIONS AND WE CAN
FIX THIS AND WE WOULD IMPROVE
HEALTHCARE IN GENERAL AND HEALTH
EQUITY IF WE DO.
I'M GOING TO GO FAST THRU A
KIDNEY STORY BECAUSE THIS IS
JUST A CRAZY WAY THAT
GENETICISTS AND NEPHROLOGIST
HAVE TALKED PAST EACH OTHER FOR
A LONG TIME.
YOU CAN MAKE DIRECT MEASURE AMS
OF KIDNEY FUNCTION THROUGH GLUE
MARRIAL FILTRATION, BUT IN
GENERAL WE ESTIMATE GLUE HERRIAL
FILTRATION THAT ARE FILTERED
THROUGH KIDNEYS, 1'S A
METABOLITE, 1'S A PROACTIVE TEEN
AND THE EQUATIONS FOR USING THIS
TO ESTIMATE GLUE MARULAR
FILTRATION REALLY TAKES SEX AND
AGE INTO ACCOUNT AS IF THE
CIRCULATING AND VARIABILITY OF
CIRCULATING LEVELS OF THESE
BIOMARKERS WAS ONLY ATTRIBUTABLE
TO KIDNEY FUNCTION.
THE HERITABILITY OF SIS AT THAT
TIMEIN C HAS BEEN ESTIMATED IN
THE RANGE OF 70-80% AND A HUGE
PROPORTION OF THAT HERITABILITY
IS ATTRIBUTE AUTOMOBILE TO THE
STRUCTURAL LOCUST VERSUS STATIN
C GENES WHERE THERE'S A HUGE
EFFECT OF QTLs, SO THERE'S A
BIG GENETIC INFLUENCE ON WHERE
PEOPLE ARE GOING TO SIT IN THAT
DISTRIBUTION FOR
[INDISCERNIBLE].
CREATINE IS JUST POLYGENIC, IT'S
NOT BIG EFFECT ALLELES BUT IT'S
60% HERITABLE.
THE ONLY PART OF THE ACTUAL
GENETIC VARIATION IN THAT SPACE
THAT'S TELLING US ABOUT KIDNEY
FUNCTION IS THE PART THAT'S
SHARED BETWEEN THE 2 OF THESE.
THEY HAVE NOTHING INTRINSIC TO
DO WITH KIDNEY FUNCTION, THEY'RE
JUST CHEAP AND EASILY MEASURED
PROTEINS OR METABOLITES THAT GET
FILTERED THROUGH KIDNEYS AND
USING THEM AS IF THE ONLY THING
AFFECTING THEIR LEVELS IS KIDNEY
FUNCTION IS SELLING SHORT WHAT
THE BIOLOGY OF THESE THINGS
ACTUALLY IS, THEY HAVE THEIR OWN
GENETIC REASONS FOR BEING
PRESENT IN CIRCULATION AND
AFFECTING KIDNEY FUNCTION ISN'T
1 OF THEM.
THEY'RE JUST WAYS WE ASSAY
KIDNEY FUNCTION.
THE MAGNITUDE OF GENETIC
EFFECTS, SO THIS IS UK BIOBANK
DATA, SIS STATIN C LEVELS, HUGE
EFFECTS AND WE TOOK OUT THE
CHROMOSOME 20 REGION BECAUSE WE
WANT TO KEEP SIS STATIC C AND
CREATININE ON THE SCALE AND THE
VALUE FOR THE LOCUST IS LIKE 10
TO THE MINUS 5000, IT'S SUCH A
BIG EFFECT AND OF COURSE THEY'RE
IDEBTICAL WHETHER YOU USE RAW
SIS STATIN C OR KRAW
CREATEININE, SO THE GENETICS IS
THE SAME FOR THE RAW BIOMARKER
AS THE ESTIMATED TBLOR MARULAR
FILTRATION AND WHEN I TALK ABOUT
THIS WITH NEPHROLOGIST THE FIRST
THING THEY IS WELL, NO, WE ONLY
CARE ABOUT THE CHANGES, THAT'S
THE ONLY THING THAT MATTERS,
IT'S THE CHANGES THAT TELL US,
EXCEPT MANY PEOPLE WITH THEIR
FIRST CREATEININE LEVEL ARE IN
SOME STAGE OF KIDNEY FAILURE.
SO WE'RE USING ABSOLUTE VALUES,
NOT JUST CHANGES IN THE WAY WE
LABEL PEOPLE AND FOLLOW THEM.
AND SOMEBODY SAID TO BE AT STAGE
2 KIDNEY DISEASE, MAY BE
PERFECTLY HEALTHY OR MAYBE AT
STAIM 4 JUST FROM THE DISTANCE,
THE GENETICS THAT HAVE NOTHING
TO DO WITH KIDNEY FUNCTION TAKES
THEM, SO IT LEADS TO THE
HERITABILITY CAN LEAD TO
MISSTAGING, THIS CONTRIBUTES TO
WHAT WE SEE AS FAILURE TO
PROGRESS, BUT IT ALSO IS
SOMETHING THAT IS PROBABLY, I
MEAN BASED ON OUR DATA WOULD BE
SOMETIMES MISLABELINGED AS CUTE
KIDNEY INJURY THAT LEADS PEOPLE
TO EARLY DEATH.
THESE 2 BIOMARKERS HAVE NOTHING
IN COMMON EXCEPT FOR WHAT THEY
DO AND THEY'RE RECYCLED THROUGH
THE KIDNEYS.
SO KIDNEY FUNCTION IS IMPORTANT
FOR SHARED BIOLOGY, SO THE TOP
IS SERUM CREATEININE, THE
BOTTOM'S THE SIS STATIN C BUT
THEY ALSO HAVE, ABSOLUTELY
UNIQUE BIG EFFECTS AND OF COURSE
THIS IS STATIN C ON CHROMOSOME
20 IS A HUGE EFFECT IN SIS
STATIN C THAT'S NOT IN CREATINE,
WE COULD ESTIMATE GFR BETTER BY
REIMRESESSING OUT THE GENETIC
PARTS THAT ARE NOT ABOUT KIDNEY
FUNCTION.
WE WOULD HAVE A BETTER MEASURE
OF THE TRULY DYNAMIC PART OF
WHAT'S HAPPENING WHEN KIDNEYS
START TO FAIL, AND SO, YOU KNOW
YOU COULD DO A PRS THAT'S JUST
ABOUT THAT SHARED GENETIC
ARCHITECTURE THAT REALLY IS
TELLING BUT THE LIKELIHOOD OF
FUTURE KIDNEY FAILURE BUT YOU
COULD DO AN EGFR, ESTIMATED GLUE
MARRIAL FILTRATE VERSUS
STATINNING AND REMOVE EVERYTHING
THAT ISN'T SHARED WITH--ACROSS
THESE BIOMARKERS AND SO, YOU
KNOW YOU WOULD JUST REMOVE ALL
THE HERITABILITY AND USE THE
GENETICS AS GENETICS, OR YOU
COULD DO THESE OTHER KINDS OF
REGRESSIONS THAT FOCUS IN ON
JUST THE DYNAMIC PART THAT
MATTERS.
I'M GOING TO STOP TALKING ABOUT
THIS NOW, SO WE CAN HAVE
QUESTIONS, BUT SEX IS A PROBLEM,
TOO.
WOMEN HAVE BEEN DISADVANTAGED IN
LIVER TRANSPLANT FOR A LONG TIME
BECAUSE THE SEX DIFFERENCES IN
MEASURES OF LIVER FUNCTION WERE
NEVER TAKEN APPROPRIATELY INTO
ACCOUNT.
THERE ARE NO SIMPLE SOLUTIONS TO
COMPLEX PROBLEMS AND THE WHOLE
BUSINESS OF THE HERITABILITY OF
COMMONLY USED LABORATORY VALUES
IS A TIP OF THE ICEBERG PROBLEM.
AS I SAID, HALF OF THESE HAVE
POPULATION DIFFERENCES IN
ACHERAGE VALUES, HALF OF THE
HERITABLE MEASURES AND MOST OF
THE MEASURES ARE HERITABLE, IF
WE EVEN FOCUS ON IN ON THE
HIGHLY HERITABLE 1S THAT HAVE
DIFFERENT POPULATION DIFFERENCES
WE HAVE DOZENS MORE IMPORTANT
BIOMARKERS THAT THAT WE HAVE TO
ADDRESS AND AND YOU CAN'T--I
MEAN YOU JUSTICE CAN'T GO
FORWARDOT SAME PATH ONCE YOU
KNOW ABOUT THIS.
WHEN YOU KNOW ABOUT HARMS THAT
YOU ARE DOING EVERY DAY IN
MEDICINE, WE HAVE TO FIGURE OUT
HOW WE CAN FIX THESE AS FAST AS
POSSIBLE, AND SO WE'RE BECAUSE
WE'VE USED GENETICALLY PREDICTED
GENE EXPRESSION SO MUCH, WE'RE
REALLY USED TO THE IDEA OF
SEPARATING OUT THE GENETIC
COMPONENT FROM ALL OF THE OTHER
THINGS THAT INFLUENCE GENE
EXPRESSION.
AND I THINK AS IMENET CYSTS
WE'RE FOCUSED ON THE VASE VERY
HEAVILY BUT WE CAN USE THE
GENETICS TO SEE MUCH BETTER THE
CONSEQUENCES OF THINGS LIKE
ENVIRONMENTAL EXPOSURES AND
SOCIAL DETERMINANTS OF HEALTH
AND LEARN THAT BIOLOGY AND WHEN
THE GENETICS IS NOISE FOR HOW WE
USE A LABORATORY VALUE IN
MEDICINE, WE SHOULDN'T HESITATE
TO REMOVE IT.
WE DO A LOT OF THINGS WITH
LABORATORY VALUES UNDER THE HOOD
O WHAT COMES BACK FROM THE
LABORATORY THAT'S ORDERED OFTEN
GOES THROUGH SOME EQUATION
BEFORE THAT IS SUBMITTED TO THE
PHYSICIAN TO INTERPRET.
ALL WE WOULD BE DOING IS
REGRESSING OUT THE GENETICS THIS
THAT SAME KIND OF EQUATION.
SO YOU COULD THINK ABOUT THIS AS
INDIVIDUALIZING GENETIC
DIFFERENCES, CHANGES IN THE
INDIVIDUAL REFERENCE RANGES THAT
ARE PROVIDED TO PHYSICIANS AND
OUR PHYSICIAN SCIENTISTS THINK
THAT IS THE BEST WAY TO DO IT,
BECAUSE IT WOULD HELP PHYSICIANS
INTERNALIZE HOW DIVERSE THEIR
POP EULOGIES ACTUALLY ARE WITH
RESPECT TO THESE MEASURES, THEY
WOULD LEARN AND UNDERSTAND MORE
ABOUT GENETIC DIVERSITY IN
LABORATORY MEASUREMENTS BUT I
HAVE TO TELL YOU PHYSICIANS WHO
HAVE 9 OR 10 CLINICS A WEEK,
HEAR THAT AND THEY'RE LIKE, ARE
YOU NUTS?
I DON'T WANT TO SEE A MILLION
DIFFERENT REFERENCE RANGES FROM
MY PATIENTS, NO.
IF YOU THINK THIS IS DESTROYING
MY ABILITY TO INTERPRET
LABORATORY VALUES, TAKE THAT
GENETICS OUT, BLOW THE
DISTRIBUTION BACK UP TO WHAT I
EXPECT AND LET ME USE THE
REFERENCE RANGES THAT I'M
FAMILIAR WITH AND KNOW HOW TO
DEAL WITH.
SO I THINK WHAT WE NEED TO DO IS
STUDY TO REALLY LOOK AT
PHYSICIANS AND THINK ABOUT HOW
WE TRY TO FIX THIS BUT IT HAS TO
BE DONE UNDER THE HOOD, IT HAS
TO BE DONE IN A WAY THAT DOESN'T
REQUIRE PHYSICIANS TO KNOW AND
UNDERSTAND THE GENETICS OF DUFFY
IN ORDINANCE NUMBERER TO
INTERPRET A WHITE CELL COUNT.
AND HERE'S A RECEIPT PUBLICATION
THAT SHOWS THE DISTRIBUTION MUCH
WHITE CELL COUNTS IN DUFFY
HOMOZYGOTES RELATIVE TO THE
MEANS FOR THE POPULATION AT
LARNG.-
-LARGE.
SO IT'S A BIG EFFECT ON A SINGLE
ARK LEGAL ON A COMMONLY USED
BIOMARKER.
AND I DO WANT TO SHOUT OUT TO MY
COLLEAGUES IN THE HEALTH
DISPARITIES RESEARCH THAT WE DO,
I'VE BEEN WORKING WITH CONSWALA
WILKINS, SHE WAS THE FITTER
NONGENETICIST TO ASK ME TO
COLLABORATE ON STUDIES SHE WAS
DOING AND SHE ALWAYS TELLS THE
FUNNY STORY THAT SHE HAD TO WORK
UP THE COURAGE TO SAY TO ME
WHILE WE'RE PLANNING OUR FIRST
GRANT, NANCY, I DON'T REALLY
THINK GENETICS HAVE VERY MUCH TO
DO WITH HEALTH DISPARITIES, I
WAS LIKE OH YEAH, ME EITHER, BUT
THEY'RE MOSTLY ABOUT OTHER
THINGS ABOUT YOU WE DON'T WANT
TO LEAVE ON THE TABLE ANYTHING
THAT WE COULD FIX USING
GENETICS.
AND SO THAT'S BEEN OUR MANTRA
THROUGH--NOW 2 GENERATIONS OF
STUDIES AND THEN OUR EPIC PRS
GROUP THAT'S PART OF THE PRIMED
CONSORTIUM, WE WERE ALL OVER
THIS, IN THIS GRANT AND THEY
REALLY HAVE THOUGHT OF VERY
CLEVER WAYS OF TRYING TO GET AT
SOME OF THESE THINGS AND IT'S
BEEN A REAL PLEASURE TO WORK
BOTH IN THAT CONSORTIUM AND IN
THIS GROUP AND MY FUNDING AND
HAPPY TO TAKE QUESTIONS.
I THOUGHT I WOULD LEAVE MORE
TIME BUT DO I GET CARRIED AWAY
WITH THIS STUFF.
REALLY, APOLOGIZE, I SHOULD HAVE
LEFT MORE TIME FOR QUESTIONS.
[ APPLAUSE ]
>> SO WHILE WE'RE WAITING FOR
HER TO FIND QUESTIONS ONLINE,
ARE THERE QUESTIONS FROM THE
AUDIENCE.
>> I WAS GOING TO SAY, WE DO
HAVE A FEW MINUTES, PLEASE COME
TO THE MICROPHONE AND PEOPLE
HERE IN PERSON, THERE WILL BE A
RECEPTION RIGHT AFTER THIS, SO
JUST IF 5 MINUTES WE CAN DO
QUESTIONS THEN.
AND PEOPLE ONLINE, PLEASE FEEL
FREE TO SUBMIT YOUR QUESTIONS
AND WE WILL SEE WHAT WE CAN DO.
SO GO AHEAD.
NTHANK
--
>> THANK YOU VERY MUCH, NANCY I
AM [INDISCERNIBLE] FROM NIMHD
AND I WOULD LIKE TO ASK YOU DO
YOU THINK THAT HAVING REFERENCE
VALUES FOR DIVERSE POPULATIONS
OR FOR LET'S SAY DIFFERENT
GENDERS AND DIFFERENT TIMES,
DIFFERENT AGES WILL DO AS
OPPOSED TO WHAT WE'RE USING
RIGHT NOW BEFORE WE HAVE TO GET
TO THE POINT THAT YOU'RE TALKING
ABOUT WHERE YOU HAVE--
>> ACTUALLY NO.
SO I'M UNEASY THAT THAT'S
A--ONE-SIZE-FITS-ALL KIND OF
SOLUTION THAT WON'T FIT ANYBODY.
AND I MEAN THAT SINCERELY FOR
THE SUBSTANTIAL FRACTION OF
LABORATORY VALUES THAT ARE
HERITABLE, THE IDEA OF REFERENCE
RANGES THAT TRY TO USE JUST
POPULATION LEVEL INFORMATION, IS
GOING TO BE AT BEST MISLEADING
AND MOSTLY WRONG FOR EVERYBODY.
BUT IS IT GOING TO BE BETTER
THAN WHAT WE HAVE RIGHT NOW?
>> I DOUBT IT.
I MEAN BECAUSE I'LL SAY, WE USED
TO USE RACE IN THE CREATEININE
CALCULATION OF ESTIMATED
GLOMULAR MARULAR FILTRATION AND
THAT WAS NOT BETTER BECAUSE IT
WAS NOT ABOUT THE ACTUAL
BIOLOGY.
IT DISADVANTAGED POPULATIONS OF
RECENT AFRICAN ANCESTRIES, AND
REALLY PROMINENT WAYS THAT
ALMOST CERTAINLY KEPT PEOPLE WHO
NEEDED KIDNEY TRANSPLANTS FROM
GETTING THEM.
TAKING RACE OUT OF THAT
EQUATION, DOESN'T REMOVE THE BIG
MEAN DIFFERENCES THAT ARE THERE.
PEOPLE ARE STILL DISADVANTAGED
BY THE GENETICS BUT
THEY'RE--THEY'RE NOT
DISADVANTAGED IN A PARTICULAR
RACE BASED WAY, THEY'RE
DISADVANTAGED BY THE GENETICS
THAT WE FAIL TO ADEQUATELY
ACCOMMODATE IN THE WAY WE DO THE
CALCULATIONS.
I THINK THAT MORE INDIVIDUALIZED
REFERENCE RANGES FOR THINGS LIKE
SEX AND AGE, MAKE A LOT OF
SENSE.
BUT I'M UNEASY ABOUT POPULATION
BASED REFERENCE RANGES THAT
WOULD CAPITALIZE ON ALLELE
FREQUENCY DIFFERENCES AMONG
POPULATIONS BECAUSE THOSE REALLY
DON'T WORK FOR ANY INDIVIDUAL.
YOU HAVE TO KNOW THE ALLELES,
AND SO, I THINK, YEAH, WOULDN'T
THEY BE BETTER?
IN MOST CASES I'M SKEPTICAL THEY
WOULD BE BETTER.
MAYBE FOR THINGS LIKE AGE AND
SEX WHEN THOSE HAVE A PROMINENT
ROLE IN THE INTERPRETATION OF
THE BIOMARKER BUT, YOU KNOW IF
IT'S REALLY JUST ABOUT AGE AND
REALLY JUST ABOUT GENDER, YEAH,
WE SHOULD BE DOING THINGS LIKE
THAT.
>> OKAY, THANK YOU.
NSO WE HIT THE 3:00 MARK.
ARE YOU COMING DOWN FOR A
QUESTION?
SO WE'LL UNFORTUNATELY HAVE THIS
BE OUR LAST QUESTION, BUT AGAIN,
AVAILABILITY IN THE--FOR THE
RECEPTION OUTSIDE.
GO AHEAD.
>> I WANT TO THANK YOU FOR A
BEAUTIFUL TALK EMPLOY I'VE BEEN
TRYING HERE AT NIH THE PAST 2
YEARS TO GET PEOPLE HERE TO GET
THEMSELVES A WHOLE GENOME
SEQUENCE INCLUDING ALL THE RNA,
ET CETERA, AND EXPRESSION.
YOUR EXAMPLES, YOU'RE USING A
LOT OF EUPHEMISMS IN YOUR
EXAMPLES BUT BASICALLY IT COMES
DOWN TO YOU HAVE TO DIAGNOSE
FIRST, TREAT SECOND, NOT THE
OTHER WAY AROUND AND SO JUST
THANK YOU AGAIN FOR YOUR TALK.
>> THANK YOU.
>> SO HAPPY TO ANSWER QUESTIONS
USED AND IF ANYBODY LISTENING IN
HAS QUESTIONS THAT THEY DIDN'T
GET TO ASK OR THINK OF LATER,
I'M HAPPY FOR THEM TO E-MAIL AND
WE'LL DEFINITELY RESPOND.
>> SO WONDER.
SO LET'S THANK DR. COX AGAIN.
[ APPLAUSE ]
AND I WILL NOTE TO THE SIDE,
NANCY IF YOU CAN POINT FOR ME,
WE HAVE A WALS PLAQUE WHICH WE
WILL MAIL TO HER AND NOT MAKE
HER CARRY ON HER CARRY HOME, BUT
THANK YOU GANNA FOR EVERYONE WHO
CAME IN, PLEASE PICK UP THE LIST
OF UPCOMING WALS, I WAS LOOKING
AT IT, VERY IMPRESSIVE LINE UP
ON YOUR WAY OUT AND PLEASE YOIN
US FOR THE RECEPTION AND
EVERYBODY PARTICIPATING ONLINE,
WE APPRECIATE YOURCANDIDATES
JOINING US THIS AFTERNOON. 1470 01:02:08,958 THANK YOU.