I'M DIANA BIANCHI. I'M THE DIRECTOR OF NICHD. I'M COMING TO YOU TODAY BY -- MY HOME IN BOSTON WHERE I'M CURRENTLY REMOTELY WORKING AND THROUGH THE MAGIC OF ZOOM AND OUR RECORDING WE'RE ABLE TO JOIN EVERYONE AROUND THE WORLD IN DIFFERENT TIME ZONES SO THANK YOU FOR JOINING US TODAY. I THINK THAT WHEN WE DECIDED ON THIS DATE, DAVID I DON'T THINK WE CONSCIOUSLY REALIZED IT WOULD BE THE DAY AFTER MOTHER'S DAY AND WHAT MORE APPROPRIATE DAY TO START THIS WORKSHOP BECAUSE MOTHER'S DAY IS A CELEBRATION OF THE GREAT JOB OF THE WHAT 10 THAT. -- PLACENTA. WE WERE ALL CONNECTED TO A PLACENTA AND SOME OF US ARE MOTHERS SO WITH THAT IT'S MY PLEASURE TO KICK OFF THE FIRST TALK SO LET ME JUST GET MY SCREEN AND SHARE IT WITH YOU. GET ON THE PRESENTATION MODE. SO I WILL BE GIVING SOME IN PRO INTRODUCTORY REMARKS TO GET US GOING. AND I'D LIKE TO REMIND YOU ALL THAT WITH OUR REFRESHED MISSION STATEMENT WHICH WE SPENT A LOT OF TIME THINKING ABOUT THE PLACENTA IS EMBEDDED INTO ALL OF THESE WORDS. SO THE NICHD LEADS RESEARCH AND TRAINING TO UNDERSTAND HUMAN DEVELOPMENT, IMPROVE REPRODUCTIVE HEALTH, ENHANCE THE LIVES OF CHILDREN AND ADOLESCENTS AND OPTIMIZE ABILITIES FOR ALL. IF THE PLACENTA DOES ITS JOB WE WILL BE ABLE TO FULFILL OUR MISSION. LET'S TRY TO ADVANCE THE SLIDES. LET'S TRY IT AGAIN. OKAY. NOW WE SEEM TO BE CONNECTED. SO TODAY I'M GOING TO GIVE A BRIEF TALK WHICH WILL JUST BRIEFLY OUT LINE THE HISTORY OF THE HUMAN PLACENTA PROJECT. GIVE YOU SOME UPDATES ON THE NIH BUDGET. THE NICHD STRATEGIC PLAN AS WELL AS A NEW INITIATIVE THAT WE HAVE CREATED WITHIN OUR OWN INSTITUTE TO ADDRESS SOME OF THE ISSUES RELATED TO ACHIEVING EQUITY, DIVERSITY AND INCLUSION AND THAT IS KNOWN AS THE STRIVE INITIATIVE. STRATEGIES TO ENRICH INCLUSION AND ACHIEVE EQUITY AND THEN I'LL GET INTO WHAT IS OCCUPYING ALL OF US FOR THE PAST 14 MONTHS, COVID-19 RESEARCH. I'LL GIVE A BRIEF OVERVIEW OF NICHD STUDIES AND THE PLACENTAL STUDIES. IF YOU'RE NEW TO THIS HPP EXTRAVAGANZAS I THINK YOU'LL APPRECIATE THE FACT THAT WE CONSIDER TH PLACENTA AS NICHD'S ORGAN. I LOOKED AT THE NAMES OF THE 27 CENTERS AND CENTERS AT NIH FIVE HAVE AN ANATOMICAL SYSTEM IN THEIR NAME. NINE HAVE DISEASES IN THEIR NAME SUCH AS THE NATIONAL CANCER INSTITUTE AND FIVE HAVE POPULATIONS IN THEIR NAME SUCH AS THE CHILD HEALTH. OR NATIONAL INSTITUTE ON AGING AND THE REMAINDER 8 WERE A HODGEPODGE. THEY HAVE TECHNOLOGY OR BIOLOGY SUCH AS THE NATIONAL GENOME RESEARCH. BUT WE HAVE NOT GONE TOO ---- WITHOUT SHOWING THE PLACENTA PLATE THAT DAVID COMMISSIONED WAY BACK AT THE HUMAN FLORIDA FLORIDA PROJECT BACK IN 2014. THIS IS THE FIRST MEETING. THERE IS DAVID ON THE LEFT AND THERE IS ME ON THE RIGHT. ALTHOUGH I WAS A MEMBER OF THE NICHD COUNCIL AT THE TIME THE DIRECTOR OF NICHD IS RIGHT IN THE CENTER. AND IT WAS HIS BRAINCHILD TO DEVELOP THE HUMAN PLACENTA PROJECT AND THAT WAS BECAUSE MUCH ABOUT THE HUMAN FLORIDA HUMID -- PLAC ENTA REMAINS IN REALTIME. SO THIS PICTURE COMES FROM 2014. SEVEN YEARS AGO WHEN A NUMBER OF DIFFERENT THOUGHT LEADERS WERE CONVENED TO DISCUSS THE POSSIBILITY OF LAUNCHING THIS EFFORT. AND IT WAS REALLY AT THAT TIME THAT ADVANCES IN IMAGING AND OMEX MADE IT POSSIBLE TO IMAGINE THAT SAFE NONINVASIVE REALTIME ASSESSMENT OF THE HUMAN PLACENTA ACROSS PREGNANCY MIGHT BE POSSIBLE AND SOME OF YOU MIGHT RECOGNIZE YOURSELF. ALSO THERE WAS A NICE VIDEO PRODUCED FROM THIS MEETING. FAST-FORWARD SEVEN YEARS CHANGES IN TECHNOLOGY AND WE'RE VERY PROUD OF THE FACT THAT NICHD HAS SUPPORTED THE HPP WITH OVER $91 MILLION. AND THAT IS JUST THE HPP. IT IS NOT INCLUDING ADDITIONAL LARGE AND CONTINUED INVESTMENT IN BASIC WHAT 10 TALL RESEARCH. IN BASIC PLACENTAL RESEARCH. AND SOME OF THE ADVANCES TRANSLATE TO OTHER AREAS OF RESEARCH. SO FOR EXAMPLE SOME OF THE TECHNOLOGY THAT ZEB WILLIAMS LABORATORY DEVELOPED HAS BEEN USED FOR RAPID COVID-19 TESTING THAT IS UNRELATED TO TESTING THE PLACENTA. SO WHAT WE'RE GOING TO TRY TO DO TODAY IS TAKE A STEP BACK AND CONSIDER WE REALLY WANT TO BE REFLECTIVE AND CONSIDER WHAT HAVE WE ACHIEVED OVER THE PAST SEVEN YEARS. WHAT HAS THE $91 MILLION RESULTED IN TERMS OF IMPROVING CARE AND WHAT ARE THE GAPS GOING FORWARD BECAUSE THIS IS SOMETHING THAT I'M SURE THAT CONGRESS IS GOING TO BE VERY INTERESTED IN. THE U.S. CONGRESS THAT IS. IN TERMS OF CONTINUING FUNDING OR INTEREST IN THE SATISFACTORY. -- SATISFACTORY. ONE OF THE ADVANTAGES OF THE PANDEMIC IS THIS CONFERENCE IS VIRTUAL SO WE CAN LEVERAGE INFORMATION FROM ALL OVER THE GLOBE AND APPLICATIONS FOR TOOLS AND APPROACHES FOR APPLICATIONS AND CLINICAL RESEARCH. AND WHAT IS HAPPENED IN THE LAST YEAR OF COURSE HAS BEEN THIS INCREASED INTEREST AND COMMITMENT TO ENHANCING DIVERSITY AND INCLUSION WITH ALL VOICES HEARD AND ALL STAKEHOLDERS INVITED TO PARTICIPATE AND ONE OF THE THINGS THAT MANY OF YOU KNOW HAS BEEN USED TO PROVIDE PREMEETING INPUT AND DISCUSSION HAS BEEN THE IDEAL SCALE PLATFORM SO PRIOR TO THE MEETING I'LL SHOW YOU A SLIDE OF THAT. PEOPLE WERE ASKED TO COMMENT AND DISCUSS WHERE THEY THINK THE RESEARCH SHOULD GO TO MAKE THIS AS PRODUCTIVE AS POSSIBLE WITH THE LIMITATIONS OF THE VIRTUAL PLATFORM. AND WE ALSO ENCOURAGE YOU THAT DURING THE MEETING YOU SHOULD POST IDEAS, REACT, AFFIRM OR DISAGREE WITH WHAT IS POSTED SO THAT WE ALL BENEFIT AND I'D LIKE TO QUOTE HERE KENNETH BLANCHARD IN THE ONE MINUTE MANAGER. NONE OF US OR NO ONE OF US IS AS SMART AS ALL OF US PUT TOGETHER. SO HERE YOU SEE THE TOPICS FOR THE IDEA SCALE AND BY THE WAY ON THE VERY FIRST SLIDE BEFORE I STARTED THE LINK WAS GIVEN FOR THE IDEA SCALE. I'M NOT SURE IF THAT WILL BE SHOWN AGAIN. YOU MAY WANT TO WRITE IT DOWN. THIS GIVES YOU A BRIEF SENSE OF THE TOPICS THAT ELICITED THE MOST DISCUSSION SO THOSE WERE BY FAR BASIC RESEARCH AND THE FUTURE. BUT IN ADDITION CLINICAL BIOMARKERS AND DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE AS WELL AS CIRCULATING FACTORS GOT A LOT OF PROMISE. I WAS SURPRISED THAT CLINICAL TRIALS ONLY GOT ONE COMMENT SO YOU CAN LOOK TO SEE WHAT HAS BEEN SAID SO FAR AND YOU CAN SEE THAT PEOPLE ARE USING THEIR REAL NAMES. AND THEY ARE WRITING HOW THEY FEEL ABOUT THESE DIFFERENT TOPICS AND IT WAS QUITE INTERESTING TO READ SOME OF THOSE PRIOR TO THE MEETING. AND THEN IN ADDITION THERE WERE SOME PREMEETING MEETINGS WHERE PEOPLE WERE ASKED TO GIVE THEIR FEEDBACK IN TERMS OF POTENTIAL GOALS OR POTENTIAL GAPS OR WAYS TO MOVE FORWARD. SO YOU CAN SEE ON THE LEFT PARTICULARLY WITH REGARD TO IMAGING THIS WAS A GROUP THAT WAS MODERATED I THINK BY ELLEN GRANT. SOME OF THE QUESTIONS THAT CAME THROUGH ON THE RIGHT THE NUMBER OF IDEAS POSTED. THE COMMENTS ETC. AND I PUT THE IMAGE IN THE MIDDLE BECAUSE THERE IS OF COURSE NO SUBSTITUTE FOR BEING IN THE SAME ROOM WITH YOUR COLLEAGUES AND ACTIVELY DISCUSSING TOPICS IN BREAK OUT GROUPS BUT I THINK WE'VE ALL GOTTEN USED TO DOING THESE THINGS BY ZOOM OR VIRTUALLY AND I PARTICULARLY SELECTED THIS PICTURE BECAUSE SOME PEOPLE ARE DOING IT WITH THE PARTICIPATION OF THEIR CHILDREN OR GRANDCHILDREN AS WELL. SO WITH REGARD TO THE NIH BUDGET I THINK IT'S REALLY EXCITING FOR NICHD. I THINK WITH THE CHANGE IN THE ADMINISTRATION THOSE OF YOU WHO ARE IN THE PRESENCE PROBABLY RECOGNIZE THAT NICHD'S POPULATIONS ARE ON THE RADAR SCREEN IN A GOOD WAY. FOR THOSE OF YOU WHO ARE OUTSIDE THE UNITED STATES YOU MIGHT EXCLUDE THE SLIDE BUT PRESIDENT BIDEN'S PRELIMINARY BUDGET REQUESTED $51 BILLION FOR THE NIH WHICH WAS A 20% INCREASE BUT MUCH OF THAT INCREASES COMING TO FORM A NEW AGENCY. IT'S NOT A SEPARATE INSTITUTE BUT IT IS CALLED ARPA-H FOR RAPID TRANSITION TO THERAPEUTICS SO IT'S POSSIBLE IF THERE ARE PREGNANCY RELATED THERAPEUTICS WE WOULD MOVE IT OVER TO ARPAH. IN ADDITION THE PRESIDENT'S BUDGET PROPOSES $110 MILLION WHICH IS AN INCREASE OF $100 MILLION TO LOOK AT CLIMATE CHANGE AND HUMAN HEALTH AND I JUST WANTED TO POINT OUT THAT WE ARE ONE OF SIX INSTITUTES OR CENTERS THAT IS ON A EXECUTIVE COMMITTEE TO EXAMINE HOW CLIMATE CHANGA EFFECTS HUMAN * HEALTH IN OUR POPULATION. PREGNANT WOMEN AND CHILDREN AND PEOPLE WITH INTELLECTUAL DISABILITIES. THE FULL BUDGET WILL BE RELEASED IN A FEW WEEKS AND THEM WE'LL HAVE THE BUDGET APPROPRIATION HEARINGS. WITH REGARD TO MATERNAL HEALTH ON THE RIGHT I'M SHOWING KAMALA HARRIS. NICHD HAS BEEN VERY INVOLVED IN HIGH LEVEL TALKS . VICE PRESIDENT HARRIS REMAINS STRONGLY COMMITTED TO IMPROVING DISPARITIES IN MATERNAL HEALTH AND I WOULD SAY THAT THERE IS DEFINITELY BIPARTISAN INTEREST IN HOW VACCINES AFFECT PREGNANT WOMEN AND WHETHER OR NOT THERE ARE ADVERSE EFFECTS ON MENSTRUATION SO THIS IS ALL WITHIN NICHD'S PORTFOLIO. SO I THINK MANY OF YOU HAVE SEEN OUR STRATEGIC PLAN. IF YOU HAVE NOT YOU JUST NEED TO GOOGLE NICHD STRATEGIC PLAN AND YOU WILL SEE OUR STRATEGIC PLAN THAT WAS RELEASED IN 2019. THE END OF 2019 AND REALLY FOUR OF THE FIVE YOU COULD ARGUE ALL FIVE OF THE THEMES RELATE IN SOME WAY TO THE PLACENTA. THE PLACENTA IS NEVER FAR FROM OUR THOUGHTS. WHEN WE FIRST RELEASED THIS STRATEGIC PLAN REMEMBER THIS WAS BEFORE COVID, IT WAS BEFORE ALL OF OUR CONCERNS ABOUT RACISM AND -- I MEAN WE WERE VERY CONCERNED ABOUT HEALTH DISPARITIES BUT THEY WERE MAGNIFIED BY THE PANDEMIC. WE LISTED FIVE CROSSCUTTING THEMES OF WHICH TWO ARE THEIR IMPRESSION OF WHAT WAS GOING TO HALF IN 2020. SO HEALTH DISPARITIES LEADS ME TO THE STRIVE INITIATIVE. A LOT OF PEOPLE WANT TO KNOW WHAT IS NICHD DOING TO ADDRESS HEALTH DISPARITIES AS WELL AS INEQUITY IN THE WORKFORCE. WE KNOW THAT WE NEED TO DO MORE INCLUDING TACKLING STRUCTURAL RACISM. WE'RE VERY COMMITTED TO DIVERSIFYING THE SCIENTIFIC WORKFORCE. THERE IS A BROADER ANY INITIATIVE CALLED UNITE AND THAT IS GOING ON BUT WE FELT THAT WE NEEDED TO DO OUR OWN INITIATIVE TO ADDRESS OUR OWN WORKFORCE OUR OWN ISSUES INTERNALLY AS WELL AS BEING -- HAVING A LOT OF CONTROL AND BEING SURE THAT WE COULD ADDRESS SOME OF THE PRIORITIES PARTICULARLY AS THEY RELATE TO OUR SCIENTIFIC THEMES SO OUR EFFORT IS LED BY DR. CHARISSE LAMAR. AND WE'VE ESTABLISHED THREE COMMITTEES. ONE IS THE EQUITY, DIVERSITY AND INCLUSION IN NICHD'S WORKFORCE. THE IDEA IS TO RECRUIT AND RETAIN THE BEST TALENT ACROSS ALL CAREER PATHS TO MORE FULLY ACCOMPLISH OUR MISSION. AND THE SCIENTIFIC WORKFORCE GROUP IS LOOKING AT THE EXTRAMURAL RESEARCHERS SO THE PEOPLE ON THE CALL ARE VERY INTERESTED IN HOW DO WE DO THAT. AND WE ARE VERY COMMITTED TO TRAINING, SUPPORTING DIVERSE SCIENTISTS FOR THE FUTURE. FOR THE PRESENT AND THE FUTURE. AND THEN WE HAD ALREADY MADE THIS COMMITMENT TO HELP DISPARITY RESEARCH AND NOWHERE IS IT MORE OBVIOUS THAN IN THE RACIAL DISPARITIES IN THE MATERNAL MORBIDITY. SO NICHD BACK A YEAR AGO REALLY DID NOT HAVE A TARGETED APPROPRIATION SO OUR TARGETED STRATEGY WAS TO USE EXISTING NETWORKS AND PIVOT THEM TO STUDY OUR POPULATIONS. SO ONE OF THE INITIAL STUDIES WAS THE GRAVID STUDY. THOSE SITES TOO COMPARE MEDICAL RECORDS ANALYSIS OF WOMEN WHO HAD GIVEN BIRTH AT ONE OF THESE SITES IN THE YEAR PRIOR TO THE PANDEMIC COMPARED WITH ESSENTIALLY BETWEEN MARCH AND DECEMBER OF 2020. AND THE PRELIMINARY RESULTS THOSE OF YOU WHO ARE AT THE SMF MEETING HEARD THE PRESENTATION OF THE EARLY RESULTS FROM 1200 COVID POSITIVE PREGNANT WOMAN WITH WHO SHOWED THERE WAS COMPLICATIONS. AND THE WOMEN WHO HAD SEVERE DISEASE WERE AT HIGHER RISK FOR C-SECTION DELIVERY. POSTPARTUM HEMORRHAGE. HYPERTENSIVE DISORDERS OF PREGNANCY AND PRETERM BIRTH AND WE HAVE HAD A LOT OF INQUIRIES FROM PREGNANT PEOPLE. WE GOT ASKED ALL THE TIME THAT ARE YOU SURE PREGNANT WOMEN WANT TO PARTICIPATE IN RESEARCH. THEY WERE VERY INTERESTED IN PARTICIPATING IN THE RESEARCH. WE HAVE A GLOBAL HEALTH -- RESEARCH WHICH HAS SEVEN SITES. THEY ARE PARTNERED WITH SITES IN THE UNITED STATES AND THOSE SITES ARE DETERMINING THE PREVALENCE OF COVID-19 INFECTION DURING PREGNANCY. THEY ARE USING ANTIBODY TESTING AT DELIVERY TO DETERMINE THAT AND THIS IS A NETWORK THAT HAS A LONG HISTORY OF REGISTRY INFORMATION SO THEY HAVE A GOOD SENSE OF WHAT THE BASELINES ARE FOR THESE SITES IN BANGLADESH, INDIA, GUATEMALA AND KENYA AND THE DEMOCRATIC REPUBLIC OF THE CONGO AND ALSO ASSESSING KNOWLEDGE AND ATTITUDE AND PRACTICE OF PREGNANT WOMEN DURING THE PANDEMIC. HOWEVER WHEN THE VACCINES BECAME AVAILABLE IN THE UNITED STATES THERE WAS A REAL ISSUE FOR PREGNANT PEOPLE. INITIALLY EVEN THOUGH THE VACCINES WERE APPROVED FOR EMERGENCY USE THE DECISION REGARDING PREGNANT WOMAN WAS PUNTED TO HEALTH CARE PROVIDERS AND WOMEN WERE TOLD TO HAVE A DISCUSSION WITH THEIR PROVIDERS. UNFORTUNATELY THERE WAS NO DATA TO BE ABLE TO ADVICE THEM ALTHOUGH WE NOW KNOW THAT PREGNANCY INCREASES THE RISK OF HOSPITALIZATION AND THE ICU CARE -- COMPARED TO AGE MATCHED CONTROLS THAT ARE NOT PREGNANT. SO WE KNOW THAT IF YOU DON'T GET VACCINATED YOU HAVE A HIGHER RISK IF YOU'RE PREGNANT FOR BEING QUITE ILL. THE PROBLEM WAS THERE WAS NO INFORMATION. NOW WE SPENT ALMOST TWO YEARS WORKING ON RECOMMENDATIONS THROUGH OUR LAB TASK FORCE. RESEARCH ON PREGNANT AND LACTATING WOMEN SAYING THEY SHOULD BE PROTECTED THROUGH RESEARCH. NOBODY SEEMED TO APPLY THAT MESSAGE TO THE VACCINE CLINICAL TRIALS SO WE WROTE A COMMENTARY THAT WAS PUBLISHED IN JAMA AND SOME OF THE TAKE HOME MESSAGES INCLUDED REMINDING PEOPLE AND SOMETIMES WE EVEN NEED TO REMIND PEOPLE HERE AT THE NIH THAT PREGNANT PEOPLE ARE NO LONGER CONSIDERED AS A VULNERABLE POPULATION. AND WE CANNOT UNDO WHAT WAS DONE WITH THIS PANDEMIC BUT IT'S NOT TOO EARLY TO BEGIN PREPARING NOW FOR THE NEXT EPIDEMIC OR PANDEMIC. AND THERE WERE REASSURING ANIMAL STUDIES AND INITIAL PHASE I SAFETY DATA FOR OTHER POPULATIONS SO THEY SHOULD HAVE GONE AHEAD AND MADE A PLAN FOR INCLUSION OF PREGNANT PEOPLE INSTEAD OF THEM SAYING TALK TO YOUR HEALTH CARE PROVIDER ABOUT IT. I THINK THERE IS A LOT MORE COMFORT NOW WITH THE USE OF REGISTRIES AND THE CONTROL. HOW VACCINES ARE AFFECTING PREGNANT PEOPLE. THERE IS EXPERIENCE NOW ON OVER 90,000 PREGNANT PEOPLE WHO HAVE BEEN VACCINATED IN THE UNITED STATES. THE COMPLICATIONS WERE NO GREATER IN PREGNANT PEOPLE THAN IN NONPREGNANT PEOPLE ALTHOUGH THE LIMITATION WAS THAT MOST OF THE PEOPLE HAD BEEN VACCINATED IN THE THIRD TRIMESTER SO MORE DATA ARE NEEDED IN THE FIRST AND SECOND TRIMESTER. THERE IS ALSO THE IMPORTANCE OF SHARING DATA AND BIOSPECIMEN. SO AGAIN SO WE CAN BE READY FOR THE NEXT TIME. BUT ONE OF THE THINGS THAT WE HEARD A LOT BECAUSE REPRESENTATIVES OF INDUSTRY AND PHARMA WERE INCLUDED IN THE PREG LAC TASK FORCE WAS THAT PHARMA IS VERY CONCERNED ABOUT POTENTIAL LITIGATION AND RISKS BUT IT TURNS OUT THAT IN THE UNITED STATES THERE IS A COUNTER MEASURE INJURY COMPENSATION PROGRAM THAT PROVIDES BENEFITS TO PREGNANT AND NONPREGNANT PEOPLE WHO ARE INJURED BY PRODUCTS DESIGNED TO PREVENT PUBLIC HEALTH THREATS SO THAT PROGRAM COULD HAD BEEN USED TO PROTECT PREGNANT PEOPLE TO DO CLINICAL TRIALS ON THE VACCINE. SOME OF THE TRIALS ARE NOW ONGOING I THINK THAT SOME OF THE DATA FROM THE CDC HAVE REASSURED PREGNANT PEOPLE ESPECIALLY IN THE THIRD TRIMESTER BUT IT WAS AN OPPORTUNITY LOST. SO I'M GOING TO CLOSE WITH SOME OF THE PLACENTAL STUDIES WHICH WILL ALLOW US TO SEGUE INTO THE TOPICS OVER THE NEXT TWO DAYS AND I KNOW ROBERTA RAMIRO IS ON THE WEBSITE. AND THEY'VE BEEN INTERESTED IN THE MECHANISMS FOR WHY SO FEW FETUSES ARE INFECTED DURING PREGNANCY WHEN THE MOTHER IS INFECTED WITH SARS COVID 2. AND THEY DID A STUDY PUBLISHED IN E. LIFE LAST YEAR LOOKING AT MAINLY PREGNANT WOMEN WHO WERE INFECTED IN THIRD TRIMESTER AND THEY FOUND THAT THE PLACENTA LACKED THE MRNA REQUIRED TO MANUFACTURER THE RECEPTOR TO ENTER THE CELLS. THE PLACENTA ALSO WILL BEES THE MRNA TO MAKE THE ENVOLUME THAT COVID USES TO FINALIZE ENTRY INTO THE CELL. THEY ARE PRESENT IN MINUSCULE AMOUNTS -- CAN YOU PLEASE MUTE YOURSELF IF YOU ARE NOT SPEAKING. THANK YOU. SO SUGGESTING A POSSIBLE EXPLANATION WHY THE VIRUS HAS ONLY RARELY BEEN FOUND BUT IT HAS BEEN FOUND IN SOME FETUSES AND NEWBORNS. SO MORE RECENTLY THERE IS A PAPER THAT HAS NOT GULF THROUGH FULL PEER REVIEW BUT IT IS POSTED THAT SHOWS ACE 2 RECEPTORS ARE EXPRESSED IN HEALTHY PLACENTAS BUT RARELY AT TERM. AND THIS IS WORK DONE BY THE FIRST AUTHOR WHO'S SUPPORTED BY A TRAINING GRANT SO WE CAN CLAIM HER AS OUR OWN. SO INTERESTINGLY AND THIS DID NOT SURPRISE ME AT ALL BECAUSE SOME OF OUR LABORATORY WORK SHOWS THAT WEEK BY WEEK GENE EXPRESSION IS VERY DIFFERENT SO TERPLACENTAS -- IT'S THAT MATERNAL FEEL INTERFACE THAT WAS REALLY IMPORTANT IN TERMS OF EXHIBITING MARKERS THAT WERE ASSOCIATED WITH LATER PREGNANCY COMPLICATIONS AND ROBUST IMMUNE RESPONSES. THE BOTTOM LINE IN THIS STUDY SUGGEST THAT IT IS ASSOCIATED WITH IMMUNE ACTIVATION AT THE MATERNAL FIELD INTERFACE BUT THERE IS A PROTECTIVE MECHANISM THAT IS SHIELDING THE PLACENTA FROM ACTUALLY BECOMING INFECTED. SO WE CAN ADD SHIELD TO THE MANY ROLES THAT THE FLORIDA FLORIDA PLAYS. -- THAT THE PLACENTA PLAYS. WE ARE PARTICIPATING IN A MAJOR SO ANOTHER APPROPRIATION FROM OUR CONGRESS TO SPECIFICALLY STUDY LONG HALL COVID WHICH WE CALL PASC WHICH IS POST ACUTE -- SEQUELA OF COVID AND WE'RE VERY INTERESTED IN STUDYING PREGNANT WOMEN AND THE OFFSPRING OF THESE WOMEN WHO ARE IN THE WOMB WHEN THE WOMEN WERE INFECTED WITH SARS CO-V2. AND LASTLY AGAIN JUST VARIATION IN THE PLACENTA AND HOPING PEOPLE WILL ADDRESS THIS IN THE WORKSHOP A GROUP IN IRELAND HAS SHOWN THERE IS EXTENSIVE PLACENTAL DAMAGE THAT INVOLVES STILL BERTH AND THESE WOMEN HAD ONLY MILD OR NO SYMPTOMS AND DISPROPORTIONATE NUMBER OF THEM HAD THE B117 VARIENT WHICH MIGHT ENHANCE SPECIFICITY AND THAT IS LEADING TO THE PLACENTA. SO HOW DO THE VARIANTS AFFECT PLACENTA IS DIFFERENT AND ONGOING AND VERY INTERESTING WORK. SO JUST A COUPLE OF SLIDES ON THE WORKFORCE SO WE HAVE VERY AWARE OF THE CONSEQUENCES OF PANDEMIC ON PEOPLE WHO ARE IN THE MOST VULNERABLE PARTS OF THEIR CAREER AND WHO REALLY IN SOME CASES HAVE BEEN PUT ON PAUSE. AND A NUMBER OF WAYS THIS HAS HAPPENED IS THAT CLINICIAN SCIENTISTS MAY HAVE HAD TO DO MORE CLINICAL TIME BECAUSE IN PEDIATRICS FOR EXAMPLE THERE ARE HIGHER NUMBERS OF HOSPITALIZED CHILDREN OR COLLEAGUES WHO BECOME ILL SO THEY'VE TODAY STEP UP AND TAKE THEIR PLACES. I KNOW THAT AT NICHD WE'VE BEEN DEALING WITH AN INABILITY TO GET TO THE LABORATORY BENCH BECAUSE PHYSICAL WORK SPACES HAVE BEEN SHUT DOWN. SO THERE WAS A PERIOD OF THREE MONTHS WHERE NOBODY COULD GO TO THEIR LABS AND WE HAVE BEEN OPERATING AT SOMEWHERE BETWEEN A 25% AND 50% CAPACITY IN OUR PROGRAM. FURTHERMORE EVERYWHERE THERE HAS BEEN DECREASED RECRUITMENT IN CLINICAL TRIALS BECAUSE EITHER PEOPLE WERE NOT COMING TO THE HOSPITAL OR AFRAID TO COME TO THE HOSPITAL AND ALSO RESEARCH STAFF WERE PREVENTED OR UNABLE TO COME TO THE PHYSICAL WORK SPACE TO ENROLL PARTICIPANTS AND WE KNOW THAT THERE HAS BEEN A DISPROPORTIONATE AFFECT ON PEOPLE WITH FAMILIES. I SHOWED THAT PICTURE OF THE MAN AT THE COMPUTER WITH HIS CHILD WHICH RELATES A REALITY FOR WHAT I SEE ON ZOOM CALLS. PEOPLE ARE JUGGLING FAMILY NEEDS WITH THEIR OWN CAREERS AND THAT HAS TAKEN A TOLL. AND WE KNOW THAT WOMEN HAVE SHOULDER THE BIGGEST BURDEN COMPARED TO MALES SO WE'RE VERY AWARE OF THAT AND TRYING TO SUPPORT THAT. WE ARE SUPPORTING OUR OWN TRAINEES ON A CASE-BY-CASE BASIS. BUT THE NEWS IS NOT ALL BAD. I THINK THAT WE'VE LEARNED A LOT FROM DOING WORK VIRTUALLY. WE'VE SURVEYED OUR WORKFORCE AND PEOPLE ARE VERY HAPPY WORKING AT HOME IN MANY CIRCUMSTANCES. NOT THE BENCH PEOPLE BUT THE PEOPLE WHO ARE MANAGING YOUR GRANTS FOR EXAMPLE. THEY WOULD BE VERY HAPPY TO STAY AT HOME BUT I THINK THAT FROM THE PERSPECTIVE OF EDUCATION AND BEING ABLE TO INCLUDE GLOBAL COMMUNITY WE CAN DO THAT IN A WAY THAT IS COST EFFECTIVE AND MUCH MORE CONVENIENT TO TIME ZONES. ALL PRESENTATIONS ARE BEING RECORDED SO THAT THE PEOPLE IN AUSTRALIA DON'T HAVE TO WATCH THIS AT 4:00 IN THE MORNING. WE'VE TAKEN INTO ACCOUNT THE VARIOUS TIME ZONES BUT IT WILL BE KINDLER AND GENTLER TO SOME PEOPLE IF THEY WATCH THE RECORDINGS. SO IF THE PLACENTA DOES ITS JOB IF OUR RESEARCH CAN BE APPLIED TO THE PLACENTA AND WE ACTUALLY HAVE AN IMPACT WE WILL HELP TO ACHIEVE NICHD'S VISION WHICH IS HEALTHY PREGNANCIES, HEALTHY CHILDREN AND HEALTHY AND OPTIMAL LIVES. SO NOW IT IS MY GREAT PLEASURE AND I'M RIGHT ON TIME WHICH IS AMAZING IT'S MY GREAT PLEASURE TO INTRODUCE OUR VOICE OF THE PARTICIPANT SPEAKER. WE OFTEN LIKE TO INCLUDE SOMEONE WHO REALLY HAS PERSONALLY EXPERIENCED WHATEVER IT IS WE'RE TALKING ABOUT AND DANIELLA BLEI HAS A VERY IMPRESSIVE PROFESSIONAL HISTORY. SHE IS A WRITER. AN EDITOR OF BOOKS. HAS A PhD IN HISTORY. SHE ALSO ALSO THE VISITING FACULTY AT READE COLLEGE. AND HER WRITING HAS APPEARED IN THE ATLANTIC, THE CUT, SMITHSONIAN MARGIN AND ELSEWHERE. SHE LIVES IN * SAN FRANCISCO WITH HER FAMILY. BUT SHE IS HERE TODAY REALLY TO TALK ABOUT HER OWN PERSONAL EXPERIENCE WITH PREECLAMPSIA. SHE HAS ALSO WRITTEN ABOUT THE HUMAN PLACENTA PROJECT SO WE'RE VERY GRATEFUL TO DANIELLA FOR JOINING US TODAY AND TELLING US A LITTLE BIT ABOUT HER OWN PERSONAL STORY SO I WILL STOP SHARING MY SLIDE AND THANK YOU FOR YOUR ATTENTION. >> HI, EVERYONE. THANK YOU SO MUCH FOR HAVING ME HERE TODAY. IT'S AN HONOR TO JOIN YOU. I'M NOT A SCIENTIST. NOT A PHYSICIAN BUT I KNEW WHAT THE NIH WAS EVEN AT A VERY YOUNG AGE LIKE AT 3 BECAUSE MY FATHER WAS A LIVER RESEARCHER AND SO MANY OF THE RESULTS OF MY CHILD LIKE IF HE COULD TAKE ME TO A PLAYGROUND OR EVEN THE FAMILY VACATIONS ALL OF THIS EVOLVED AROUND NIH GRANT DEADLINES. SO WHAT I WANT TO DO IS SHARE A BIT OF MY STORY WHICH I WROTE ABOUT A COUPLE OF YEARS AGO AND IT'S HOW I FIRST MET DAVID WEINBERGER. WHAT I WANTED TO UNDERSTAND -- WHY I DEVELOPED PREECLAMPSIA FIVE DAYS AFTER MY SECOND CHILD. I'M HERE TODAY. MY SON IS TWO AND HE IS THRIVING * BUT I DO WANT TO TALK ABOUT THE MENTAL IMPACT AND THE POSTPARTUM PERIOD AND HOW IT SOMETIMES GETS NEGLECTED. I'M CONVINCED AFTER MY OWN EXPERIENCE BUT ALSO AFTER TALKING TO PEOPLE AND THERAPY THAT WHEN THINGS GO WRONG AT THIS EXTREMELY ESSENTIALSIVE MOMENT JUST AS THE MOTHER'S HORMONES ARE STARTING TO PLUMMET AND THERE IS THE STRESS OF KEEPING AN INFANT A LIFE AND THE FAMILY LIFE CHANGING AND TREMENDOUS SLEEP DEPRIVATION THERE IS THE POTENTIAL TO REALLY LOSE IT AND THAT IS PRECISELY WHAT HAPPENED TO ME. SO I SPENT NEARLY TWO WEEKS IN THE HOSPITAL. AFTER AN UNEVENTFUL C-SECTION BECAUSE I HAD PROTEIN IN MY URINE. MY SON WAS NO LONGER A PATIENT. SO HE COULD NOT BE IN THE HOSPITAL WITH ME. MEANWHILE ALL OF THIS HAPPENED DURING AN HISTORIC WILDFIRE SEASON IN CALIFORNIA WHICH MEANT NO ONE WAS GOING OUTSIDE UNLESS THEY ABSOLUTELY HAD TO. THE AIR WAS TOXIC AND THICK WITH SMOKE. SCHOOLS WERE CLOSED. PEOPLE LEFT TOWN OR WORKED AT HOME IF THEY COULD. SO DURING THIS TIME MY HUSBAND STAYED HOME. HE WAS TAKING CARE OF OUR NEWBORN AND DAUGHTER. OUR FRIENDS HAD MOSTLY FLED THE BAY AREA IN SEARCH OF CLEANER AIR AND MY MOM OUR KEY SUPPORT PERSON TO HELP WITH EVERYTHING SUDDENLY TODAY FLY OFF TO ARGENTINA BECAUSE MY 95-YEAR-OLD GRANDMOTHER WHO LIVED THERE ACTUALLY DIED DURING MY DELIVERY. SO REALLY A PERFECT STORM. THERE I WAS ADMITTED FOR ALMOST TWO WEEKS NO BABY. NO FAMILY AND ALSO NO EXPLANATIONS. I ASKED ALL OF THE PHYSICIANS EVERY RESIDENT EVERY NURSE TAKING CARE OF ME WHY WAS THIS HAPPENING? AND THEY ALL SAID SOME VERSION OF THE SAME THING. YOU DON'T HAVE ROUTINE PLACENTA. IT'S NOT WELL UNDERSTOOD. DURING THIS TIME MY LIFE INVOLVED AROUND BLOOD PRESSURE CHECKS. THE GOAL WAS 24 HOURS OF SOMEWHAT NORMAL PRESSURE SO I COULD GO HOME AND BE WITH BABY AND WHEN I WAS DISCHARGED MY NUMBERS WERE STILL PRETTY BORDERLINE AND I WAS TAKING WHAT ONE DOCTOR SAID -- AND THIS WAS NOT VERY HELP. I WAS TAKING A NUCLEAR BOMBS WORTH OF MEDICATION SO AT HOME I WAS INSTRUCTED TO TAKE MY PRESSURES THREE TIMES A DAY AND TRYING TO BREASTFEED AND BOND WITH THE BABY I HAD BEEN SEPARATED FROM AND TRYING TO KEEP MY DAUGHTER HAPPY AND SWALLOW THE PILLS, I STARTED HAVING A LOT OF ANXIETY. USUALLY IT'S WHEN A MOTHER EXPERIENCES DARK INTRUSIVE THOUGHTS ABOUT HER BABY. SHE CANNOT SLEEP. AND COULDN'TLY CHECKS ON THE BABY AND WORRIES ABOUT HER BABY BEING HARMED OR EVEN DYING. IN MY CASE I HAD ANXIETY ABOUT MY OWN DEATH. I WORRIED CONSTANTLY ABOUT DROPPING DEAD. I HAD INTRUSIVE THOUGHTS ABOUT MY BLOOD PRESSURE WHICH SOUNDS BIZARRE. IT WAS BIZARRE. I WOULD BE PLAYING ON THE REGULAR WITH MY KIDS AND THINKING WHAT IS MY BP. AM I IN THE 160s. I HOPE I'M NOT IN THE 170s. DOOMSDAY SCENARIOS WOULD FLASH THROUGH MY HEAD. I THOUGHT ABOUT STROKES ALL OF THE TIME. I RESEARCHED MATERNAL DEATH. I STUDIED ON-LINE PREGNANCY FORUMS AND THESE ARE NEVER HELPFUL IN ANY CIRCUMSTANCES. I WAS BASICALLY CONSUMED BY MY ANXIETY AND OF COURSE THE KNOWLEDGE THAT THIS ANXIETY WAS MAKING MY BLOOD PRESSURE GO UP SO I COULD NOT GET OUT OF THE CYCLE. DURING ALL OF THIS I EXPERIENCED THE STRANGE VOID THAT IS POSTPARTUM CARE IN THE COUNTRY AND I SAY THIS AS A PERSON WITH QUITE A BIT OF PRIVILEGE AND PRETTY GOOD HEALTH INSURANCE. STILL SEVERAL WEEKS OUT I REALLY NO LONGER BELONGED TO MY OB ASIDE FROM THE ONE SIX WEEK POSTPARTUM VISIT WHERE YOU'RE CHECKED AND BASICALLY OKAY TO RESUME HAVING SEX WHICH BY THE WAY IS THE LAST THING ON ANY NEW MOTHER'S MIND BUT THAT IS ANOTHER CONVERSATION. THE POSTPARTUM PATIENT IS PRETTY MUCH ON THEIR OWN. THERE ARE ONE OR TWO MENTAL HEALTH SCREENINGS BUT THAT IS ABOUT IT. MOM IS LEFT TO HER OWN DEVICES TO MONITOR AND EDUCATE AND TAKE CARE OF HERSELF. THIS IS NOT WHAT IT LOOKS LIKE IN OTHER PARTS OF THE WORLD. IN IN YOUR OPINION THERE ARE THREE OR FOUR OF THEM -- THESE VISITS START AROUND 36 WEEKS OF PREGNANCY. SO POST NATAL CARE IS BUILT IN. SO IF YOU * LOOK AT SEVERAL COUNTRIES THERE IS REALLY JUST ONE MAJOR COMMONALITY WHERE MATERNAL MORTALITY IS LOW AND THAT IS ROUTINE COMPREHENSIVE POSTNATAL CARE. WHAT I LEARNED WHILE WRITING ABOUT MY EXPERIENCE AND TALKING TO DAVID WINE WEINBERGER -- -- YET WHEN I SHARE THIS WITH THE MANY NEW MOTHERS FRIENDS, COLLEAGUES AND NEIGHBORS SOME OF THEM HAVING HAD HYPERTENSION OR DIAGNOSIS IN PREGNANCY ABSOLUTELY NO ONE IS AWARE OF THE LONG-TERM PICTURE. I EVEN HAD A COUPLE OF PHYSICIAN TELL ME I'VE NEVER HEARD THAT BEFORE WHEN I EXPLAINED THIS INCREASED RISK THAT I NOW FACE. SO THE CULTURAL NORM PERSIST THAT PREGNANCY ENDS WHEN THE DELIVERY DOES AND THERE IS A REAL DISCONNECT BETWEEN WHAT EXPERTS YOU KNOW AND WHAT EVERYONE ELSE KNOWS. IT HAS BEEN SUCH A PRIVILEGE TO LEARN ABOUT THE HUMAN PLACENTA PROJECT AND TO UNDERSTAND JUST HOW FAR THE KNOWLEDGE HAS COME. BUT I HAVE SEEN IN REPORTING AND TALKING TO ORDINARY NONSCIENTISTS ABOUT PREGNANCY THAT MOST PEOPLE HARDLY KNOW ANYTHING AT ALL ABOUT THE PLACENTA. SO GIVEN ALL OF THIS IT DOES SEEM LIKE THE PLACENTA IS STILL SITTING IN A QUARTER OF WOMEN'S HEALTH OR REPRODUCTIVE HEALTH. AND OF COURSE CHANGING THIS IS PROBABLY LESS ABOUT THE SCIENCE AND MORE ABOUT WAYS THAT OUR SOCIETY THINKS ABOUT REPRODUCTION AND CHILD BEARING. SO AS I SEE IT THE URGENT TASK IS TO FRAME PLACENTAL HEALTH AS HUMAN HEALTH AND PREGNANCY NOT AS A SHORT-LIVED NINE OR 10 MONTH PROCESS BUT AS HAVING LONG-TERM IMPACTS. LONG LIFE IMPACTS. SO WITH THAT I'M GOING TO END AND SAY THANK YOU TO ALL OF YOU FOR EVERYTHING THAT YOU DO TO CREATE KNOWLEDGE WHICH HAS HELPED PEOPLE LIKE ME AND SO MANY OTHERS. AND THANK YOU SO MUCH FOR HAVING ME HERE TODAY. >> SO WOW! THAT WAS AMAZING. I WANT TO THANK YOU DR. BLEI FOR SHARING YOUR INCREDIBLE FRANKLY AAMAZING POWERFUL STORY AND I ALSO WANT TO GIVE A HEARTFELT THANK YOU TO DR. BIANCHI FOR A TRULY WONDERFUL KICK OFF TALK. WELCOME EVERYONE. MY NAME IS DR. DAVID WEINBERG AND TOGETHER WITH MY CO-ORGANIZER KATHRYN ADAMS AND YOU'LL SEE THE TWO OF US POPPING UP. WE WILL BE HELPING FACILITATE WHAT SHOULD BE A REALLY WONDERFUL COUPLE OF DAYS. WE WILL HAVE SCIENTIFIC TALKS. FROM A SERIES OF PREMEETING PLANNING CONVERSATIONS AND A PLANNING DISCUSSION. SO OUR FIRST SESSION ON MRI WILL BE LED BY DR. ELLEN GRANT. AND IF SHE IS WITH US I'LL ASK HER TO COME ON AND THEN WE'LL BEGIN WITH AN UP BRIEF OF THE PREMEETING PLANNING CONVERSATION. >> HI, DAVID. I'M HERE BUT I CANNOT TURN ON THE VIDEO. THERE WE GO. GREAT. SUPER. THANK YOU DAVID FOR THE INTRODUCTION. I'M GOING TO START SHARING MY SCREEN HERE. A SUMMARY OF THE DISCUSSION OF THE MRI GROUP AND I WANT TO THANK EVERYBODY FOR PARTICIPATING. WE HAVE 15-20 PEOPLE AND I POSTED A SUMMARY AND GOT FEEDBACK. SO A LOT OF PEOPLE CONTRIBUTED TO THE SUMMARY. SO FIRST WHAT WE STARTED TO TALK ABOUT IS WHAT ARE SOME THINGS THAT WE NEED AND WE DID ALL RECOGNIZE -- THE QUESTIONS AROUND MRI SAFETY IN THE FIRST TRIMESTER. MOST OF US ARE PRETTY CONVINCED IT IS SAFE BUT THERE IS STILL NEED FOR CONSENSUS STATEMENTS. IDEALLY IN A GROUP TOGETHER TO HELP IN A SCIENTIFIC WAY STATE THE SAFETY OF MRI IN THE FIRST TRIMESTER AND THIS IS REALLY IMPORTANT AS WE WANT TO EXPLORE PREECLAMPSIA AND OTHER ASPECTS OF PLACENTAL FUNCTION. SOME SITES ARE DOING RESEARCH AS EARLY AS 12 WEEKS BUT NOT ALL OF US CAN AND AGAIN IF WE BAN TOGETHER AND GET THE INFORMATION OUT THERE WE CAN HOPEFULLY BRING ALL OF THIS DOWN TO THE EARLIER OF WEEKS. DO WE NEED MORE STUDIES AS A QUESTION BEFORE WE MOVE TO TRYING TO SEE IF IT'S SAFE. OR DO WE NEED CLEAR TREATMENT INTERVENTIONS THAT WOULD ALTER CLINICAL MANAGEMENT. TO HAVE A BENEFIT TO BALANCE THESE EARLY SCANS. WE'RE HOPING THERE ARE ENOUGH THAT ARE HAPPENING ALREADY THAT WE CAN START TO GATHER THE DATA BUT IT WOULD BE USEFUL TO HAVE A GLOBAL OPINION. SO, THAT IS WHAT WE'RE HOPING TO GET IS A FORUM TO HAVE THAT KIND OF OPINION MOVE FORWARD. THE NEXT THING THAT CAME UP IS IT TIME FOR PROTECTIVE T2 CLINICAL TRIAL. -- PROSPECTIVE T2 CLINICAL TRIAL. * . JUST TO CALCULATE PLACENTAL AVERAGES OR DO WE NEED ONE NUMBER OR SOME OTHER ENOUGH TO GIVE US THE VALUE OF THE PET GET IN A TEE. -- HETEROGENEITY. * DO WE NEED PHANTOMS TO STANDARDIZE ACROSS SITES. WE WILL NEED AUTOMATED ACQUISITION THAT CALCULATES T2 * . ARE THERE PRIMARY AND SECONDARY CAUSES BECAUSE WE LOOK AT PRE PRE AS NORMAL SO HOW SPECIFIC ARE THOSE MEASUREMENTS. -- IF WE'RE GOING TO DO STUDIES DO WE NEED SOMETHING THAT IS ACTIONABLE. A TREATMENT THAT IS GOING TO HAPPEN IF THE T2 STAR IS TOO LOW. WHAT IS THE CLINICAL RELEVANCE AND IF IT'S ONLY GIVING US A MEASUREMENTS OF POTENTIAL PLACENTA AT RISK IS IT WORTH DOING IT WITHOUT A PLAN. IS IT ACTUAL OR JUST AN INDICATION TO MONITOR MORE CLOSELY. IT'S CHALLENGING TO ACCURATELY ASSESS THE PATHOLOGY. SO WHAT IS THE OPTIMAL OUTCOME MEASURE? THE PLACENTA PATHOLOGY OR SOMETHING ELSE. IT'S CHALLENGING. THERE IS A BIG SEPARATION IN TIME. SO, ITS A BETTER OUTCOME MEASURE -- OR PLACENTA PATHOLOGY OR BOTH. THERE IS A CONVERSATION AROUND THIS AND STARTING TO PUT TOGETHER A MULTI-SITE STUDY SUCH AS HAPPENING NOW. THERE IS ALSO I THINK A GOOD POINT THAT CAME UP IS WE'VE BEEN GATHERING A LOT OF DATA. SEVEN YEARS SINCE THE FIRST MEETING. THERE IS A LOT OF DATA OUT THERE SO WE NEED TO START SHARING THE DATA, PROTOCOLS AND TOOLS AND CLINICAL DATA ELEMENTS TO ENABLE SOME OF THE MACHINE LEARNING APPROACHES. THE HPP HAS GENERATED LOTS OF DATA SO WE NEED TO HAVE MORE DATA SHARING AND DISCUSSION. AND COMMON PROTOCOLS THAT CAN BE MADE AVAILABLE TO ALL AND HAVE DISCUSSIONS AROUND HARMONIZATION. CENTRALIZED SO EVERYONE CAN HAVE ACCESS. WE'RE STARTING TO PUT TOGETHER WEBSITES WHERE TOOLS CAN BE FOUND SO PEOPLE CAN GO AND HAVE AN EASY TO FIND PLACE SOME OF THE TOOLS. THE DIFFICULTY IS THAT THE SIZE OF SAMPLE SIZES IS LOW SO WE HAVE TO ENRICH FOR HIGH RISK PREGNANCIES DURING THE DEVELOPMENT AND VALIDATION OF THESE TOOLS AND FOR MACHINE LEARNING IT'S HARD TO TRAIN WITH NORMAL DATA. WE NEED TO FOCUS ON SPECIFIC CLINICAL PHENOTYPES AND BALANCE WITH LARGE NUMBERS OF BOTH NORMAL AND ABNORMAL. AND AGAIN TO THE POINT -- WITH HPP PRODUCT WE HAVE DATA FROM BOTH NORMAL AND ABNORMAL POPULATIONS THAT WOULD BE RIGHT TO START TO SHARE TO UNDERSTAND THE VARIANCE THAT IS DRIVEN BY THE PROTOCOL SELECTION. THERE IS ALSO A GOOD DISCUSSION TART STARTING TO COMBINE THE BLOOD TEST. * AND SEE THE IMPACT OF GENE EXPRESSION. TO HELP US BETTER INTERPRET THE BLOOD TEST. SO WE COULD DO PLACENTAL IMAGING TO SEE IF IT'S ALSO ALTERED. WE COULD SCREEN FOR DEVELOPING MRI SIGNATURES OR DO THE SICK BID SAMPLE FIRST IF THERE IS HIGH RISK TO SEE IF WE'RE STARTING TO SEE PHENOTYPES IN THE PLACENTAL STRUCTURE. THERE IS A POTENTIAL OF AI TO COMBINE MRI AND CLINICAL DATA ELEMENTS TOO BUT WE NEED TO MAKE SURE WE HAVE BALANCED DATASETS WITH BOTH NORMAL AND ABNORMALS. IT DOES OFFER SOME OPPORTUNITIES. THE MOST COME AND MOST ACCEPTABLE AND NEEDS TO BE DONE IN THE FIRST TRIMESTER. PERHAPS WE CAN LEVERAGE THIS NEED IN THE FIRST TRIMESTER AND BETTER ASSESS THE POTENTIAL -- STRESS TO FETUSES. WE NEED TO ADD MORE OF THE TEXTURE ANALYSIS TO OUR MRI APPROACHES IF WE CAN GET THESE SCANS PERFORMED IN THE FIRST TRIMESTER AND CONSIDER CONTRAST IMAGING. THERE IS A NUMBER OF MR SEQUENCES THAT ARE BEING DEVELOPED. THE T2 * WE NEED A STANDARDIZED. -- SOME OF US ARE STARTING TO COMPARE DATA AND A LARGE GROUP DISCUSSION ON THIS WOULD BE HELPFUL AND AGAIN AS WE MENTIONED BEFORE IS T2 * ACTIONABLE. -- IT WAS DISCUSSED AS WELL -- AND GIVING MOTHER OXYGEN. IS IT USEFUL TO UNDERSTAND PLACENTAL OXYGEN TRANSPORT. YOU DO ALTER METABOLISM BUT IT DOES FOR SOME OF OUR MEASURES WE LINE IT BECAUSE IF WE DO PICK UP A CHANGE WE THINK THAT OUR MEASUREMENTS ARE MORE ACCURATE SO WE WANT TO SEE A T2 MEASURE IF WE DON'T SEE THAT WITH OXYGEN THEN IT BECOMES QUESTIONABLE. WE KNOW THAT OXYGEN WILL NOT BE A LONG-TERM TREATMENT BUT IS IT USEFUL TO BETTER UNDERSTAND THE RESPONSE AND WE DON'T FULLY UNDERSTAND THAT. IT DOES SHIFT THE PLACENTA METABOLISM. WE DON'T KNOW IF THERE IS -- -- OKAY AGAIN DISRUPTS THE METABOLISM SO IT'S HARD TO UNDERSTAND THESE STUDIES BECAUSE WE'RE DISRUPTING METABOLISM BUT DO THESE TYPES OF TEST YIELD MORE INFORMATION BECAUSE WE'RE SHIFTING AND WATCHING RESPONSES WHERE IT RETURNS BACK TO NORMAL. NOT JUST MONITORING A BASELINE STATE. IVIM IS A DIFFUSION TECHNIQUE. THERE IS A NUMBER OF GROUPS WORKING IN THIS PARTICULAR SPACE. IT'S BEEN LABELED IN CONTRAST -- IT'S PICKING UP THE MATERNAL BLOOD FLOW. SO WE THINK IT'S MOST LIKELY WEIGHTED TOWARD THE MATERNAL SIDE. DOES IT DETECT ABNORMALITY. IS IT REPRODUCIBLE. SO THERE IS STILL SOME WORK IN GETTING ACCURATE METHODS FOR BOTH THESE TECHNIQUES. WITH THE LONG TRANSIT TIMES THAT WE SEE IN THE PLACENTA THERE IS A TECHNIQUE THAT LABELS THE BLOOD IN THE PLACENTA. WHEN YOU LABEL IT THERE ARE PROBLEMS WITH THE TRANSIT TIME BEFORE WE'RE ABLE TO MEASURE. SO WE'VE SETTLED TO THE VELOCITY SIDE OF ASL BECAUSE OF THE DELAYED TRANSIT TIME AND THAT HAPPENS WHEN WE USE THESE OTHER TECHNIQUES WHICH LABEL AND THEN YOU WAIT FOR THE BLOOD TO FLOW INTO PLACENTA BECAUSE OF THE LONG TIME SO THEY ARE SLOW AND AS A RESULT INACCURATE. WE'RE HOPING THAT THE HIGH BLOOD VOLUME MIGHT HELP MAKE UP FOR THE LOW SNR. HOPEFULLY WE CAN COME UP WITH FASTER MORE MOTION ROBUST TECHNIQUES THAT STILL ALLOW US TO CAPTURE INFORMATION AROUND THE FLOW. SO MORE DEVELOPMENT IS STILL NEEDED AND THE FOCUS WILL REMAIN IN VELOCITY SELECTED ASL. ANOTHER METHOD THAT IS DIFFERENT THAT ALLOWS CHARACTERIZATION OF THE SPACE AND A POTENTIAL ALTERNATIVE TO IDENTIFYING ABNORMALITIES. THIS IS LOOKING AT CHANGES IN PHASES OF SPIN AS A RESULT OF FLOW. RELAX OMETRY. IT HAS BECOME INTERESTING. BECAUSE IF YOU CAN QUANTIFY T1 AND T22349 BLOOD IT WOULD ENABLE DETERMINATION OF OXYGEN. -- WE CAN START TO CHARACTERIZE OXYGEN SATURATION IN THE MATERNAL BLOOD AND IN THE FEET PAL BLOOD. -- THE FETAL BLOOD. THE POTENTIAL FOR UNDERSTANDING OXYGEN EXCHANGE COMES WITH THESE TECHNIQUES BUT THERE IS STILL A LOT OF WORK IN TERMS OF IMPROVING ACCURACIES. THIS IS AN IV CONTRAST AGENT THAT IS A BLOOD COOL AGENT. IT MAKES THE BLOOD DARK. YOU CAN USE IT TO INJECT AND WAIT AND GET REALLY NICE ANGIO GRAMS, THAT INCREASES THE SIGNAL FOR ON 40 FLOW VISUALIZATION. AND IT'S CURRENTLY USED CLINICALLY SO THE BAR IS LOWER THAN SOME AGENTS TO GET THEM IN CLINICAL USE. THE DOSES THAT ARE NEEDED ARE VERY LOW. FETAL EXPOSURE IS NOT CLEAR BUT MAY BE IRRELEVANT SINCE ALREADY USED AS AN IRON SUPPLEMENT IN PREGNANT MOTHERS SO THIS IS A POTENTIAL IN MOVING FORWARD. ANOTHER CONTRAST AGENT THAT IS BEING DEVELOPED. NO TRANSFER INTO THE FETUS. IT'S THOUGHT TO BE MORE ACCURATE BUT THE DATA IS STILL PRELIMINARY SO THE JURY IS STILL OUT BUT SHOWS GOOD PROMISE. THERE IS WORK BEING DONE FOR WORK IN HUMANS. IT IS BEING USED NOW IN PRIMATES. ALL OF THESE METHODS WE STILL NEED TO ATTACH THOSE METHODS -- OR RESULTS OF VASCULAR BLOOD VOLUME COME PART END TO LOCATION AND ANATOMY. SO WE STILL NEED WAYS TO CHARACTERIZE THE 3-D PLACENTAL ANATOMY AND WORK WITH WHAT METRIC ON TO THE AND TOMORROW CALL GRID. -- ANATOMICAL. GRID. * SOME OF THE CHALLENGES ARE FETAL BLOOD OX EMPTY. OXYMETRY. SO THERE IS HOPE WITH THE VELOCITY SELECTIVE TO PROMOTE THE FLOW AND WITH IVIM -- BUT THAT IS STILL ONGOING WORK. WE NEED TO IMPROVE PLACENTAL STRUCTURE IMAGING AND STANDARDIZATION TO THE ANATOMY. SO HOW WE COME UP WITH A COMMON SYSTEM IS STILL ONGOING WORK. AND WE NEED TO BETTER MANAGE THE REGIONAL VARIATION AND SIGNAL BETTER DUE TO BOWEL AND NONUNIFORM FIELDS -- WHEN WE'RE DOING FETAL IMAGING. BECAUSE OF THE LARGE ABDOMEN. AND WE NEED TO BETTER UNDERSTAND THE INTERACTION BETWEEN FETAL HEART AND PLACENTAL EXCHANGE. IT WOULD BE WONDERFUL. THERE IT IS ONE DEVICE BUT IF YOU DON'T HAVE IT IN THE RIGHT PLACE IT WOULD BE CHALLENGING TO CONTINUE TO MONITOR THROUGHOUT THE ENTIRE MRI SESSION. THERE WAS RECOGNITION THAT MRI WILL BE SECOND LINE COMPARED TO ULTRASOUND DUE TO EXPENSE. THE MRI EXPENSE IS DRIVEN BY EQUIPMENT AND FACILITY NEEDS THAT ARE INESCAPABLE. THE LOW FIELD MAGNETS WHICH ARE PERMANENT MAGAZINE CUTS DECREASE CAUSE. BUT MAY BE OVERCOME WITH NANO PARTICLE CONTRAST AGENTS. WE MAY BE ABLE TO LEVER ANNUAL THE LOWER FIELD. SCAN COSTS -- THERE IS CONCERN THAT MRI WILL BE TOO EXPENSIVE. I THINK THAT IS UP FOR QUESTION. IF FAST SEQUENCES THAT ARE DEVELOPED THAT PROVIDE ONE OR TWO QUANTITATIVE METRICS THE SCAN TIMES MAY GO DOWN AND WE MAY NOT NEED A FULL HOUR SLOT. AND WE'RE DOING THAT RIGHT NOW WITH SOME OF OUR CHECKS AND PLACES WHERE WE'RE DOING THESE FASTER SCANS AND WE ALSO WANTED TO RECOGNIZE THERE ARE TWO ROLES OF MRI. ONE IS EXPLORING MECHANISMS THAT HAVE DIRECT IMPACT ON PATIENT CARE. MONITORING THE CHANGE WITH CONTRACTIONSES AND UNDERSTANDING THAT AS A STRESS TEST ON THE PLACENTA IT WOULD NOT BE USED FOR PATIENT CARE BUT HELP UNDERSTAND PLACENTAL PHYSIOLOGY. WHEREAS OTHER THINGS ARE BEING DEVELOPED. THERE ARE TWO ROLES OF MRI. ONE THAT HOPES TO GO TO DIRECT TRANSLATION AND ONE THAT HOPES TO ENRICH THE UNDERSTANDING THAT WILL FURTHER INFORM OUR DECISIONS OF WHAT DIAGNOSTIC TOOLS NEED TO BE DEVELOPED. ULTRASOUND -- HIGH SUCCESS IN DETECTING ACRETA. THERE IS ALSO A QUESTION ABOUT DO WE NEED NOVEL TECHNOLOGY TO BRING PLACENTAL MRI TO UNDERSERVED AREAS. SO I THINK AS OUR PROCEDURES MAY TIER IT WILL BE EASTER TO SAY IF SOMETHING CAN BE DONE WITH A PERMANENT MAGNET. >> MANY UNDER RESEARCHED AREA HAVE NO EXPERTISE SO WE DON'T NEED TO BRING NEW MRI'S. WE MAY HELP DEPLOY THE CURRENT MRIS THAT IS ARE ALREADY THERE. SO A LOT OF UNDER RESOURCED AREAS THAT HAVE 1.5 AND 3Ts. TO PROVIDE THEM WITH THE ACQUISITION STRATEGIES AND THEY TRANSMIT DATA TO EXPERIENCED SITES FOR DATA ANALYSIS. THE SECOND IS THE EASIER TO DEPLOY FOLLOWED BY THESE PERMANENT MAGNET SOLUTIONS IF WE FIND METRICS THAT CAN GUIDE CLINICAL MANAGEMENT. SO LAST SLIDE HERE TO SUM UP WHAT WE NEED TO DO IS BOTH DISTINGUISH AND ENCOURAGE BOTH HYPOTHESIS BASED RESEARCH. AND ALSO THESE HYPOTHESIS GENERATING RESEARCH TO GENERATE NEW METHODOLOGIES OR BETTER UNDERSTANDING OF THE UNDERLYING PHYSIOLOGY AND THE PATH OF THE PLACENTA. AND I JUST WANT TO COMMENT HOW HUGE OF AN INFLUENCE THE HUMAN PLACENTA PROJECT HAS MADE. I THINK THE COMMUNITY THAT HAS COME TOGETHER AROUND THIS HAS BEEN PHENOMENAL AND VERY COLLABORATIVE AND WITHOUT THE FOCUSED APPROACH WE WOULD NOT HAVE MADE IT TO WHERE WE ARE NOW AND WE'VE MADE TREMENDOUS STRIDES. THANK YOU. >> WOW. THAT WAS WONDERFUL. THANK YOU, DR. GRANT FOR THAT UP BRIEF. THERE ARE A LOT OF ISSUES TO THINK ABOUT IN THE MRI SPACE BOTH TECHNICALLY AND IN TERMS OF DATA SHARING AND COLLABORATION. AND I'LL PUT IN YET ANOTHER PLUG. I HOPE PEOPLE WILL WEIGH IN. THERE WERE A LOT OF THINGS PUT OUT THERE. SO WE'LL NOW HAVE TWO TALKS, THE FIRST TALK WILL BE BY DR. GRANT AND IT IS THE HUMAN PLACENTA PROJECT SAFETY SEQUENCE AND SERENDIPITY. >> THANK YOU, DAVID. BASICALLY THAT ENTIRE TALK IS POSTED. I REARRANGED THE ORDER BUT ALL OF THE TALKING POINTS ARE THERE. YOU CAN READ IT THERE IF YOU HAVE ANY QUESTIONS. AND THANK YOU DAVID FOR ASKING ME TO SUMMARIZE OUR EXPERIENCE WITH THE HUMAN PLACENTA PROJECT. THERE ARE A TON OF GROUPS DOING GREAT WORK. I REALLY HAD TIME TO FOCUS ON OURS BUT I AM ROUTINELY AMAZED AND INSPIRED BY OTHERS'S WORK TOO AND IT'S A WONDERFUL COLLABORATIVE COMMUNITY. I DO HAVE -- I'M ON THE SCIENTIFIC ADVISORY BOARD AND CONSULTANT FOR -- IMAGING. TO START -- WE HAVE DECIDE WE WANTED TO GET A BETTER HANDLE ON MR SAFETY AND WITH EVEN THE STANDARDS SCANNERS WORKING IN A STANDARD MODE THERE ARE NO GUIDELINES FOR LOCAL SAR. BECAUSE IT WAS HARD TO CALCULATE IT ACCURATELY BUT AS WE MOVE FORWARD WITH FETAL IMAGING WE WANT TO KNOW WHERE THERE WERE LOCAL SAR INCREASES AND WHAT CAUSES INCREASES. EZRA CREATED A BUNCH OF REALISTIC PREGNANT MODELS TO GET AN IDEA OF REALISTIC ANATOMY. SOME OF THE MODELS ARE -- FETUSES PUT IN A NONPREGNANT WOMAN OR OTHER SUCH NOT ACCURATE PLACENTAL OR FETAL MODELS SO WE WANTED TO HAVE AN ACCURATE ONE TO GIVE US AN IDEA. SO WITH THE LAST ONE WE ROTATED THE FETUS AROUND TO GET A SENSE OF HOW THINGS CHANGE. WE HAVE FETAL POSITIONS AS WELL TOO. WE HAD A RANGE OF BMIs FROM 20 TO 40 AND GESTATIONAL AGES FROM 27-35. AND WHAT WE FOUND -- THERE IS NO RANGE KNOWN AND NO REGULATED LIMITS SO WE WANTED TO KNOW WHAT THEY ARE. MATERNAL AND FETAL -- VARIES. IT WAS LOWEST FOR MODELS IN LEFT LATERAL AND ALSO LOWEST AT THE ARMS AT THE SIDE. WE FOUND THAT INCREASED BMI WAS ASSOCIATED WITH INCREASED WHAT TURNAL BUT NOT FETAL AND THIS IS SOMETHING THAT WE WANT TO LOOK INTO MORE. IT'S IMPORTAN-- THERE MAY BE SOME ROOM THE RE IF THERE IS NO CHANGES IN FETAL LOCAL SAR. >> DR. GRANT -- I'M SORRY. I DON'T THINK YOU'RE SHARING OR I DON'T THINK YOU'RE SHARING YOUR NEXT SLIDE DECK. SORRY. >> SORRY. YOU ARE GIVING A WONDERFUL TALK. IT WAS ALL CLEAR. >> SORRY TO WASTE PEOPLE'S TIME. THERE WE GO. AND THESE ARE THE DIFFERENT BIOMODELS AND YOU CAN SEE THE DIFFERENT BMPs AND THE GESTATIONAL AGE FROM 27-35 AND DIFFERENT FETAL POSITIONS AND AS YOU MENTIONED THERE IS NO PASSENGERS KNOWN OR NO REGULATED LIMIT. BUT WE DEFINED THAT IT VARIES WITH MODEL AND THE FETAL PEAK LOCAL STAR -- -- STAR. IF WE CAN USE THAT FACT THAT THE P LOCAL STAR IS NOT CHANGED IN FETUSES THERE MAY BE SOMETHING THAT WE CAN DO IF WE USE APPROPRIATE MODELS. AND SINCE THERE IS NO PEAK LOCAL STAR LIMITS -- WE USE WHAT WAS CURRENTLY FOUND IN THESE MODELS THAT WE USED HERE THAT PEAK LOCAL STAR -- IN STANDARD AM KNOWLEDGING AS A BENCHMARK. WHEN WE LOOK AT BODY MODELS USING THESE TWO CHANNEL PARALLEL TRANSMIT WHICH MEANS YOU CAN PUT IN THE -- TO CREATE THE IMAGE OUT OF PHASE SO YOU CAN PLAY A LOT WITH HOW THE ENERGY IS DEPOSITED IN THE MOTHER TO CREATE MORE UNIFORMED CAN DISTRIBUTION OF THE SIGNAL AND GET AWAY FROM THOSE BRIGHT AND DARK SPOTS THAT WE SEE TYPICALLY WITH THE STANDARD MODE OR CP MODE AND WHAT WE FIND IS THAT WHEN YOU FIX THE WHOLE BODY SAR -- USING THESE PTX APPROACHES YOU CAN GET BETTER DUTY CYCLES AND BETTER PERFORMANCE. HOWEVER AND WITH THAT TOO FOR THE MOTHER THE PEAK LOCAL SAR TENDS TO GO DOWN. HERE IS AN EXAMPLE HERE WITH A FETUS. WE SEE THE HIGHER LEVELS HIGHER SAR DEFINITION. WHEN YOU USE AN UNCONSTRAINED APPROACH TO RF SHIMMY WHEREAS WE ADD AN ADDITIONAL CONSTRAINT WHERE IT HAS TO BE AT OR BELOW THE WHOLE BODY AND PEAK LOCAL SAR WE CAN COME UP WITH -- ON THE DUTY CYCLE. AND ACTUALLY LOWER PEAK SARS TO CREATE SAFER IMAGING. THIS IS A BIT OF A COMPLEX SIDE BUT WHEN WE'RE DOING THESE TWO CHANNEL TRANSMITS WE CAN HAVE DIFFERENT RELATIVE PHASE IN AMPLITUDE. THE PURPLE IS THE STANDARDIZED GROUP AND THE YELLOW IS THE REGION YOU WANT TO BE IN. IN THE BOTTOM THIS IS A VARIANCE OF THE TRANSMIT FIELD AND YOU WANT IT TO BE VERY CONSISTENT. SO THE YELLOW IS A GOOD AREA TO BE IN. IN SOME CASES THE PTX APPROACH DOESN'T GIVE YOU ANY IMPROVEMENTS. BUT IN OTHER CASES SUCH AS BCH3 THIS DARK DASHED AREA WE CAN GET IMPROVEMENTS IN BOTH THE AVERAGE SIGNAL PUT IN AND THE UNIFORMITY AND NOT INCREASE THE SAR WITHIN THE FETUS IF WE STAY WITHIN THIS CONSTRAINED RANGE. WE CAN ACTUALLY COME UP WITH -- APPROACH THAT'S IMPROVE IMAGE APPROACHES FOR FIVE OUT OF THE SEVEN. WE WANT TO GET DOWN TO EARLY SECOND AND FIRST TRIMESTER. WE'RE STARTING TO ADD THESE MODELS TO OUR CURRENT MODELS AND AS I MENTIONED SAR IS A THEORETICAL CONCEPT. SIGNIFICANT ABSORPTION RATE. WE HAVE NEED TO UNDERSTAND TEMPERATURES. WE'RE MOVING TO TEMPERATURE MODELING TO ESTIMATE THE LOCAL TEMPERATURES. AND OUR FIRST APPROACH IS TO COMPARE 1.5 TO 3T WITH THE STANDARD MODE TO UNDERSTAND WHAT THE POTENTIAL LOCAL INCREASES IN TEMPERATURES THAT CAN RESULT. WE ARE IN NEED OF FIRST TRIMESTER IMAGES SO IF YOU'RE ONE OF THE SITES SCANNING IF WE CAN TAKE THEM AND DO 3-D RECONSTRUCTION -- WE CAN CREATE 3-D IMAGES THAT WE CAN SEGMENT AND PUT IN OUR SIMULATIONS AND BETTER LOOK AT TEMPERATURE DISTRIBUTION. SO IN SUMMARY MATERNAL -- AND FETAL POSITION -- WHAT DOES LOCAL SAR REALLY MEAN? WE DON'T KNOW SO WE NEED TO DO TEMPERATURE MODELING TO UNDERSTAND THE POTENTIAL OF HEATING PARTICULARLY WITH STARTING WHAT WE KNOW IS SAFE AND THEN MOVING FORWARD WITH SOME OF THE MORE SOPHISTICATED STRATEGIES TO IMPROVE OUR IMAGE QUALITY. MOVING ON TO SEQUENCES. SOME OF THE RESULTS TO DATE -- A LOT OF -- IS GOING TO BE TALKED ABOUT MAY THIGH YA LATER. MATHIAS LATER. WITH POSITION WE'VE GOT STATISTICAL SIGNIFICANCE SHOWING THASUPINE -- IS LOWER WITH MOTHERS IN SUPINE POSITION. THAT IS RELATED TO -- PRESSURE OF THE PLACENTAL. AND PARTIAL COMPRESSION. BREATHING CAN ALSO HAVE AN EFFECT. IT'S IMPORTANT TO KNOW WHETHER IT'S BREATH HELD OR NONBREATH APPROACH. AND WE'RE TRYING TO UNDERSTAND THAT THE RATES HAVE CHANGED WITH BREATH HOLDING. THE GREEN IS FREE BREATHING AND THE RED IS A BREATH HOLD. WE GET THE DECREASES WITH BREATH HOLDS. WE'RE LOOKING AT THE VELOCITY TO SEE IF IT GIVES US AN IDEA OF THE CHARACTERISTICS OF A PLACENTAL DIFFUSION. SO THERE IS A LOT OF PHYSIOLOGY OF THE POSITION AND BREATHING THAT WE DON'T FULLY UNDERSTAND. OR NOT -- WITH HOW VARIABLE IT IS FROM SCANNER TO SCANNER. IF WE DO CLUSTER -- WE CAN SEE THAT WITH CONTRACTIONS YOU GET CHANGES IN THE MATERNAL SIDE THAN IN THE FETAL SIDE OF THE PLACENTA. THIS IS A WAY TO NOT ONLY UNDERSTAND VARIANCE BUT ALSO TO UNDERSTAND THE PHYSIOLOGY OF THE PLACENTA AND THE STRESS AND RESPONSE OF THE PLACENTA TO THE CONTRACTIONSES THAT WE OBSERVE MORE OFTEN WITH GESTATIONAL AGE. CAN WE LEVERAGE THEM TO BETTER UNDERSTAND THE DYNAMICS AND POTENTIAL RISK. IMPORTANT METRICS. WE'VE BEEN TRYING TO GET THAT IN THE YOUNGER AGE AS THIS IS LOOKING AT WE'LL GET MEASURES. THE CHALLENGE COMES IN TRYING TO GET ACCURATE T2 AND T1 MEASUREMENTS. IT'S A REAL CHALLENGE WITH THE MOTION OF THE UMBILICAL ARTERY. AGAIN -- PULLING IT DOWN TO THESE LOWER GESTATIONAL AGE IS A CHALLENGE WITH THE MOTION THAT WE SEE. HOWEVER IF WE WANT TO GO TO THE PLACENTA MAYBE WE CAN DO A BETTER MEASURE. PREDOMINATELY BLOOD VOLUME. WE HAVE TO SEPARATE MATERNAL AND FETAL. THERE ARE MULTIPLE METHODS. BUT MOST ARE TIME INTENSIVE. ONE TAKES THREE MINUTES. AND ONE TAKES 36 SECONDS AND THAT IS A LONG TIME IN THE TERMS OF FETAL MOVEMENT. SO WE'VE BEEN LOOKING AT MRF WHICH IS RELATIVELY FAST AND YOU CIRCLE THROUGH ALL SORTS OF FLIP ANGLES. HERE IS A TIME COURSE OF A REGION OF INTEREST. YOU LOOK AT THAT TIME COURSE AND YOU'VE GOT A DICTIONARY OF WHAT SIGNAL -- IS. SO, ITS FAST AND SOMEWHAT PRO BOAST TO MOTION BUT IT REQUIRES ABOUT 12 MILLISECONDS TO GET THE ENTIRE PLACENTA. WE MIGHT BE ABLE TO REMOVE MOTION CORRECTION. AGAIN THE T1 AND T2 MAPS ARE SIMULTANEOUSLY ACQUIRED SO THERE IS NO REGISTRATION THAT NEEDED. IT'S A JOINT INFORMATION THAT IS NEEDED. HOWEVER WHEN WE LOOK AT COMPARISONS TO OTHER STUDIES WE FIND THAT OUR PLACENTA T1 IS IN AGREEMENT BULB THE T2 IS LOWER. AND THE BRAIN DECREASE WITH GESTATIONAL AGE ASPECTED SO, THAT IS ENCOURAGING IN THAT WE'RE STARTING TO GET RELIABLE MEASURES OF THE PLACENTA AND THE BRAIN. THERE IS STILL THE T2 THE MOTION IS DRIVING OUR MEASURES -- OF THE BRAIN AND THE PLACENTA DOWN AND THE FLOW IN THE PLACENTA IS ALSO DRIVING THESE MEASURES DOWN. SO WE'RE GETTING REASONABLE METHODS. AND TO GET TO THEIR REGIONAL CONTENT WE STILL NEED TO BE ABLE TO SEPARATE MATERNAL AND FETAL BLOOD VOLUMES. NOT JUST THE MRF APPROACHES WHICH ARE RELATIVELY FAST BUT A NEWER METHODS CALLED THE EPTI. THESE ARE 3.5 SECONDS. LESS MOTION PER I'M AM AND WE NEED ABOUT 10 TO 20 TO GET A WHOLE ESTIMATE. AND WE'VE BEEN LOOKING FOR SOMETHING THAT WE CAN DO AND MONITOR OVER TIME SO NOT ONLY CAN WE GET AVERAGES OF THE WHOLE PLACENTA BUT START TO UNDERSTAND SPACE, TEMPORAL CHANGES WITH OXYGEN PARADIGMS OR CONTRACTIONS TO BETTER UNDERSTAND A REGIONAL RESPONSES OF THE PLACENTA AND PLACENTA RESERVE. WE'VE USED AN APPROACH FIRST MOTION CORRECTION. YOU CAN SEE THE SLICES HERE. MOTION CORRECTED. THEY ARE SMOOTH AND NOT SO JAGGED. ONCE WE DO THE MOTION CORRECTED WE DO WITH AND WITHOUT FLOW COMPENSATION. WE GET MUCH BETTER CORRELATION VALUES. INCLUDING THE FLOW COMPENSATION AND THEN WE CAN GET WHOLE METRICS OF THE ENTIRE PLACENTA OR REGIONAL VALUES OF THE FLOW FRACTION AND WHAT WE THINK IS REPRESENTING IS A FLOW FRACTION OF THE FETAL BLOOD WITHIN THAT BOX HERE OR WITHIN THE ENTIRE PLACENTA. WHEN WE COMPARE IT THE FLOW FRACTION OF THE FRACTION IS LOWER WITH THE FLOW COMPENSATION. WE THINK IT WILL GIVE US SOME INSIGHT INTO THE VELOCITY OF FLOWS HAPPENING IN THE FETAL PHASE. THIS IS THE POTENTIAL TO GET AT CAPILLARY SIDE. LOTS OF GROUPS ARE DOING -- HERE IS WHAT IT LOOKS LIKE. THESE BRIGHT AREAS THAT WE THINK ARE AREAS OF FLOW IN THE INNER VILLA SPACE. BLOOD FLOW IS QUANTIFIED. SINCE THERE IS NO TRANSIT TIME -- IN VARIANCE. WE DON'T HAVE TO WORRY ABOUT ARRIVAL. THERE HAS BEEN MULTIPLE PARAMETERS EXPLORED IN OTHER PAPERS. WE FIND -- THIS IS A MUCH EASIER TO MEASURE THAN POST FROM SIGNAL TO NOISE AND WE'RE HOPING WITH MORE MODEL WE CAN GET MORE ACCURATE MEASURES OF WHAT THE FLOW OF VELOCITY IS HERE. GLUCOSE -- SETS IS SOMETHING THAT WE GOT INTERESTED IN. MOTHERS WITH DIABETES. SO WE FIRST VALIDATED THAT WE COULD PICK UP CHANGES. WE TOOK SPECIMENS OF THE PLACENTA AND SHOWED THAT WE COULD PICK UP DIFFERENCES. THE ONE THAT WAS SLIGHTLY ABNORMAL WAS ONE THAT ENDED UP HAVING A LOWER BLOOD VOLUME. AND WE DID AN INITIAL STUDY WITH ORAL GLUCOSE. THIS WOULD BE DONE IV SO YOU COULD GET A MORE RAPID ENTRANCE OF GLUCOSE INTO THE PLACENTA. WE DID SEE SOME EVIDENCE OF INCREASES IN GLUCOSE WITH THE TEST APPROACH. NOT YET REALTIME. WE HAVE NOT GOTTEN APPROVAL TO DO THESE WITH MOTHERS WITH DIABETES OR EVEN IV. IT'S A CHALLENGE TO GET IV APPROVALS TO MOVE FORWARD WITH SOME OF THESE APPROACHES. 7 WHAT HAPPENS WHEN YOU'RE NOT EXPECTING IT AND SOME OF THE DISCOVERIES -- THAT WE HAD NO IDEA. FIRST WE STARTED DOING THIS WORK INSPIRED BY WORK OF OTHERS. SHOWN HERE THAT COULD WE KEEP THE PLACENTA LIVE AND PROFUSE IT AND IMAGES IT AT THE SAME TIME. WE BUILT A PROFUSION CHAMBER AND A WHOLE CONTRAPTION TO PROFUSE THE VILLA SPACES AND YOU SEE THE CATHETER THAT COMES IN ON THE OTHER SIDE THAT PROFUSES THE MATERNAL -- THE UMBILICAL ARTERIES AND VEINS. AND WE HOOK UP OUR PUMPS AND PROFUSE AGAIN THROUGH THE ARTERIES AND VEINS AND ALSO THE PROFUSE THE MATERNAL SIDE. THIS IS A VIDEO OF 8 OF THOSE PLACENTAS AND WHAT WE FOUND THAT WAS NEVER REPORTED BEFORE IS THERE AN ARTERIAL BLUSH. THESE ARE THE CAPILLARY BLUSHES THAT YOU'RE SEEING AND IN REGIONS THAT ARE UNDER PROFUSED SOME SHUNTING FROM ARTERY TO VAIN WITHOUT GOING THROUGH THE CAPILLARY SYSTEM. WE THOUGHT THIS WAS INTERESTING AND BRINGS TO MIND A LOT OF LUNG ANATOMA NATIONAL--LUNG ANATOMY PHYSIOLOGY. AND NEXT WHEN DOING THIS -- ANOTHER INTERESTING DISCOVERY IS WHEN WE TOOK THE PLACENTAS AND DOING MRF OVER TIME. YOU CAN SEE THERE IS A T1 AND T2 SIGNAL AND SIGNAL CHANGE OVER TIME. THAT SHOWS WHERE INCREASING BLOOD VOLUMES SO THE T2 GOES UP AND WE FILL UP THE PLACENTA AND THEN WE SEE SUBTLE CHANGES IN THE SIGNAL INTENSITY AS WELL. DURING MRF WE'RE GET A FLOW EFFECT PROBABLY FROM THE PROFUSION IN THE CAPILLARY STAGE THAT IS DRIVING OUR T2 MEASURES DOWN. AND THIS IS REALLY THE FIRST EXAMPLE OF MR PHANTOM THAT I'M MICKS CAPILLARY FLOW. I LIKE TO SEE THINGS AND MAKE A JUDGMENT FIRST BY VISUAL INSPECTION AND THEN WE GO AFTER QUANTITATIVE METRICS AND INTERESTING -- -- HAS THE SAME PERCEPTION SO WE WANTED TO TAKE THESE AND FLATTEN THEM. WE HAVE HAD NO IDEA WHAT THE UNDERLYING T2 STARS SIGNALS LOOKED LIKE. YOU COULD SEE CLEAR DIFFERENCES BETWEEN THE BASELINE T2 SIGNAL WITH THE TWINS WITH THE LOWER T2 SCORE CORRESPONDING. THIS IS A VIDEO SHOWING THE FLATTENING TECHNIQUE AND HOW IT'S DONE TO TAKE THAT CURVED PLACENTA AND FLATTEN IT TO A MORE VISIBLE REGION TO COMPARE. THAT ALLOWS US TO MAP AN TOMORROW NATURAL SIGNALS AND THE GOAL IS TO VISUALIZE FIRST AND THEN GO AFTER METHODS. SO HERE NOW WE MAPPED AND SHOWED CONSISTENTLY -- AS WE GO FROM FETAL TO MATERNAL SIDE. T2 STAR INCREASES. AND WE CAN ALSO LOOK AT SPATIAL TEMPORAL DYNAMICS. SHOWING A CON TRANS HERE THAT WE CAN SEE MARKED DECREASES IN SIGNALS. TRYING TO GET A HANDLE ON WHAT KIND OF METRICS YOU WANT TO THROW ON THESE TIME COURSES TO PULL OUT RELEVANT SPATIAL TELL RALPH CHARACTERISTICS. IT'S A SUM OF A WHOLE SO WE DON'T WANT TO AGAIN COME OUT WITH THE CONCEPT OF PLACENTA RESERVE AND NOT JUST PLACENTA FAILURE. PART OF WHICH HAPPENS THROUGH PREGNANCY. AFTER DOING MANY THESE EXPERIENCE WE HELPS HELD WE HAVE HUNDREDS WHERE WE COULD SEE FETAL MOTION AND SEE FETAL KNEES AND HIPS AND WRISTS AND SO ON. SO WE STARTED TO DO THE MACHINE LEARNING TO TRACK, WE LABELED A TON OF ELBOWS, KNEES AND WRISTS AND HIPS AND BLADDERS AND -- EYES FOR THE HEAD. NOW WE'VE GOT A FAIRLY ROBUST ALGORITHMS. SO IT ALLOWS US TO QUANTIFY MOTION AND COME UP WITH WAYS TO PREDICT MOTION TO BETTER COME UP WITH BETTER STRATEGIES FOR IMAGE ACQUISITION AND BEING ABLE TO QUANTIFY MOTION SHOWS US THAT HYPER OXYGEN MAKES NO DIFFERENCE IN FETAL MOTION. WE SEE THAT ELBOW FLECKS VARIES WITH MORE VARIATION THAN I -- SUPINE. I JUST WANTED TO SAY ALL OF THIS TAKES A HUGE COHORT OF PEOPLE TO WORK WITH. WE'VE GOT A LARGE TEAM. OUR ENTIRE FACULTY AND MANY POSTDOCS THAT HAVE CONTRIBUTED TO ALL OF THIS WORK. THANK YOU TO EVERYONE WHO HAS HELPED WITH THE PROJECT AND THIS IS ONLY THE CURRENT PEOPLE. THERE ARE MANY IN THE PAST THAT HAVE CONTRIBUTED AS WELL. SO THANK YOU. >> THANKS SO MUCH, DR. GRANT. THAT WAS AN AMAZING AND COMPREHENSIVE. SO NOW WE HAVE ANOTHER TALK -- I'M PLEASED TO HAVE A TALK ABOUT >> WE WANTED TO SUMMARIZE A STUDY THAT WE PERFORMED AT TWO SITES PRIMARILY. AND CORRELATED WITH PREGNANCY OUTCOMES. THE GENESIS WAS SOME WORK THAT WE DID FIVE OR SIX YEARS IN PRIME -- MODEL OF PREGNANCY WHERE WE OBSERVED THAT EARLY CONTRAST UP TAKE IN DYNAMIC CONTRAST EXPERIMENTS CORRELATED ONE TO ONE WITH REGIONS OF ELEVATED T2 * IN THE PLACENTA SO THESE EARLY CONTRAST UP TAKE REGIONS ARE OUTLETS IN THE PLACENTA AND YOU CAN SEE HERE THAT THE REGIONS OF CONTRAST UP TAKE CORRESPOND WITH THE ELEVATED T2 * AND WE PERFORMED A NUMBER OF EXPERIMENTS IN THE PRIMATES THAT SHOWED IT GENERAL LILO BUT NOT ALWAYS. WHAT ARE WE TALKING ABOUT HERE? BOLD MRI FOR A QUICK REVIEW. IT'S BLOOD OXYGEN LEVEL DEPENDENTS. IT RELIES ON THE OBSERVATION THAT LARGE T2 * VALUES CORRESPOND TO OXYGENATED BLOOD AND SMALL T2 * VALUES IN BLOOD REFER TO HIGH OXYGENATED BLOOD. WE'RE LOOKING AT A BASELINE IN THE PLACENTA AND IN THIS CASE WE'RE NOT INDUCING MAY TURN TALL ---MATERNAL -- PLACENTAS. IT SHOULD BE CORRELATED WITH SOME ADVERSE PREGNANCY OUTCOMES AND THE PLACENTA AND THE PLACENTA FETAL SYSTEM IS COMPLEX AND CERTAINLY WILL BE PATHOLOGIES THAT ARE UNRELATED TO THIS PARTICULAR ASPECT OF MATERNAL PLACENTAL PROFUSION. THE STUDY WAS TO STUDY -- EVOLUTION OF PLACENTAL T2 * IN HUMAN PREGNANCIES. THE FIRST IS LOW RISK PREGNANCIES. NO HISTORY. SECOND GROUP IN ORDER TO ENRICH OR POPULATION IN AT LEAST POTENTIAL ADVERSE OUTCOMES WAS A HIGH RISK POPULATION WITH KNOWN RISK FACTORS AND THE THIRD GROUP WHERE WE WERE NOT ABLE TO ENROLL ENOUGH PARTICIPANTS TO ANALYZE THE DATA WAS IN TOBACCO AND MARIJUANA USERS. WE TARGETED THREE TIME POINTS ACROSS GESTATION. EARLY AND MID-AND LATE GUESS -- GESTATION. WE WANTED TO CHARACTERIZE DIFFERENCES BETWEEN UNCOMPLICATED AND AT RISK PREGNANCIES. THE STUDY ENROLLMENT LOOKED SOMETHING LIKE THIS. WE HAD MORE THAN 1300 ELIGIBLE POTENTIAL PARTICIPANTS AND MORE THAN 1600 AT UTAH. WE ENROLLED APPROXIMATELY 15% OF THEM AT OHSU AND 10% AT UTAH. CONSENTED 206 PATIENTS AT OHSU AND 165 AT UTAH. MOST CONSENTED TO MANAGE MAKE IT THROUGH THE MRI AT LEAST ONE MRI STUDY SO WE HAD 13% DROP OUT RATE. THEY WERE NOT ABLE TO COMPLETE AT LEAST ONE OF THE SCANS FOR EITHER REASONS OF CLAUSTROPHOBIA OR EXCESSIVE MATERNAL AND FETAL MOTION AND 17% AT UTAH SO WE STILL HAD A FAIRLY HIGH YIELD OF AT LEAST ONE STUDY. WE ENDED UP WITH 179 PATIENTS AT OHSU AND 137 AT UTAH AND ABOUT TWO-THIRDS WERE ABLE TO COMPLETE ALL THREE SCANS SO IN TOTAL THE DATA REPORTING IS IN 316 PATIENT PREGNANCIES AND 797MRI STUDIES. THE INITIAL FOCUS WAS ON THREE SEQUENTIAL SCANS IN DISCREET TIME WINDOWS. INDICATED BY THE BLUE BOXES AFTER A PLANNED ANALYSIS. STATISTIC REVIEW SUPPORTED TO MOVE INTO CONTINUAL ENROLLMENT SO WE WIDENED THE -- STUDY. ENROLLMENT HAS THREE PEAKS BUT WE CONTINUED ACQUIRING UP TO 11 WEEKS OF GESTATION. SO ROUGHLY I BELIEVE 14, 26 AND 32 WEEKS. AND THE PLACENTA AS INDICATED HERE IN BLUE. YOU CAN SEE HIGH PLACENTAL PROFUSION -- EARLY IN GESTATION. SOME DECREASE IN MID-GESTATION AND SIGNIFICANT DECREASE IN LATE GESTATION. IN CONTRAST IN THE CASE OF SEVERE PREECLAMPSIA IN MID-GESTATION WE CAN SEE THE SPIRAL ARTERY SOURCE CLEARLY. AND BY LATE GESTATION IT IS QUITE LOW THROUGHOUT. SO TO LOOK AT THE OUTCOMES WE PERFORMED ADJUDICATION INTO THREE CATEGORIES AND THIS WAS DONE BY TEAMS OF TWO DOCTORS AT EACH SITE. THIS WAS DONE AFTER DELIVERY. AND THEY WERE BLINDED TO THE MRI RESULTS. SO THEY DIDN'T KNOW WHAT PLACENTAL T2 * VALUES WERE. AND SIMILARLY THE MRI A NATURAL SAYS WAS ALSO BLINDED TO THE RESULTS OF THE ADJUDICATION AND THE THREE GROUPS THAT WE CATEGORIZED PREGNANCIES INTO WERE THE PRIMARY ADVERSE OUTCOMES WHICH WAS 70 OF THE 316 PREGNANCIES. ABOUT 22%. THAT INCLUDES HYPERTENSIVE DISORDERS OF PREGNANCIES, PREECLAMPSIA AND UNRELATED CONDITIONS. BIRTH WEIGHT BELOW THE 5th PERCENTILE. AND OR STILLBIRTH AND FETAL DEATH. WE HAD A SECONDARY ABNORMAL GROUP WHICH CONTAINED 48 OF THE 316 PREGNANCIES WHICH IS ABOUT 15%. AND THESE WERE CONDITIONS THAT WERE SLIGHTLY ABNORMAL BUT NOT EXPECTED TO NECESSARILY BE ASSOCIATED WITH PLACENTAL DYSFUNCTION. AND THEN THE REMAINING 198 PREGNANCIES ARE UNCOMPLICATED NORMAL GROUP SO HAD NONE OF THE CONDITIONS LISTED. AND THIS IS THE RESULT THAT WE OBTAINED IN OUR UNCOMPLICATED NORMAL PREGNANCIES. EACH GRAY DOT INDICATES THE T2 * VALUE AS A FUNCTION OF GESTATIONAL AGE AND THE BLACK LINES INDICATE A MODEL FIT WITH A SIG NOTICED MODEL SO IT HAS A PLATEAU EARLY IN GESTATION AND A RAPID PHASE IN DECLINE. -- OUR STANDARD DEVIATION WAS ABOUT 10 MILLISECONDS. HERE NOW WE'RE PLOTTING THE SAME THING BUT IN THIS CASE FOR THE SECONDARY ABNORMAL AND PRIMARY ADVERSE PATIENT GROUPS AND BECAUSE WE HAD SMALLER NUMBERS THE DATA IS A BIT NOISIER. WE WERE STILL ABLE TO FIT THOSE DATA WITH OUR SIGMOID MODEL. PLOTTED IN GREEN SHOWS BEHAVIOR THAT IS SIMILAR TO THE NORMAL ALTHOUGH AN EARLIER RATE OF DECLINE AND IT WAS NOT SIGNIFICANTLY DIFFERENT BASED ON THE OVERLAP OF THE INTERVALS. IN CONTRAST THE RED CURVE FOR ADVERSE PREGNANCY OUTCOMES IS DEFINITELY SIGNIFICANTLY DIFFERENT FROM THE NORMAL POPULATION. THE CONFIDENCE INTERVALS FOR THE MODEL REGRESSION ARE NONOVERLAPPING FROM 14 WEEKS TO 33 WEEKS. SO EARLY IN GESTATION AND LATE IN GESTATION THE NORMALS AND ABNORMALS CONVERGED BUT THERE IS A SIGNIFICANT DIFFERENCE WHERE THE AND NORMALS HAVE A LOWER T2 * LEVEL. TO COMPUTE Z SCORES WE CAN SHOW HISTOGRAMS OF THE Z SCORE VALUES. 7 OBVIOUSLY THE UNCOMPLICATED NORMALS LOOK LIKE A NORMAL CURVE. THE ABNORMAL SHOW A SLIGHT BUT MODERATELY SIGNIFICANT LEFT SHIFT HERE. AND THEN THE ABNORMAL PATIENTS HAVE A MEAN D SCORE WHICH IS BELOW MINUS ONE. SO AGAIN WE SEE THAT THE PLACENTAL T2 * IS LOWER. OTHER WAY OF LOOKING AT IT IS LOOKING AT THE DISTRIBUTIONS BY CATEGORY. AS YOU WOULD EXPECT THE BLUE HISTORIC GRAM BARS HERE FOR OUR UNCOMPLICATED NORMALS ARE UNIFORMLY DISTRIBUTED. ON THE OTHER HAND WE HAVE ABOUT 35 PERCENT OF ABNORMAL CASES LYING IN THE LOWEST 5th PERCENTILE. AND WE CAN PERFORM A RECEIVER OPERATING CHARACTERISTIC ANALYSIS. WE'LL SHOWING THE ROC CURVE FOR CATEGORIZING PREGNANCIES AS ADVERSE OUTCOME OR NO. BASED ON THE ENTIRE DATASET ACROSS ALL GESTATIONAL AGES. IF WE NOW STRATIFY ON THE THREE GESTATIONAL TIME -- WE SEE THAT EARLY AND LATE GESTATION WE STILL HAVE ELEVATED AUC AT .68. IN MID-IT'S HIGHER AT .76. ONE OF THE IMPORTANT POINTS THAT DR. GRANT EMPHASIZED IS THE QUESTION OF FEASIBILITY. OUR AVERAGE TOTAL SCAN TIME -- WAS BETWEEN 45 MINUTES AND AN HOUR GENERALLY DEPENDS ON GESTATIONAL AGE. THAT INCLUDED 15-30 MINUTES OF ECHO SCANNING WHERE WE COVERED THE ENTIRE PLACENTA WITH DENSELY PLACED SUPPLIESES. 1.5-MILLIMETER AND 3.5-MILLIMETER SLICES AND WE DID THESE SCANS BY REPEATED BREATH HOLDS LESS THAN 10 SECONDS LONG. OUR LOW DROP OUT RATE IN OTHER WORDS THE FACT THAT SIGNIFICANT PORTION OF THE PATIENTS CAME BACK FOR SUBSEQUENT SCANS SUGGEST THAT THE OVER-ALL SCANS WERE WELL TOLERATED. BUT IN THE NEXT SLIDE I'LL SHOW YOU WE LOOKED NOW AT SUB SAMPLING OUR DATA AND THAT SUGGEST THAT LARGE SCAN TIME REDUCTIONS ARE ACCEPTABLE. AND WE ALSO ARE GOING TO LOOK BRIEFLY AT SOME RESULTS THAT WERE DONE AT A THIRD SITE IN BARCELONA. THEY HELPED WITH DATA ANALYSIS AND GOT CONSISTENT RESULTS. HERE FIRST ALSO DR. GRANT KINDLY SHARED SOME OF HER MAPPING DATA. WE'RE PLOTTING THE DATE THAT THAT WE GOT FROM HER ON TOP OF OUR MODEL FITS. AND THEN WE HAVE A SECOND GROUP WHICH IS MOSTLY COMPRISED OF IDENTIFIED IUGR PATIENTS AT PARSE LONE A FETAL MEDICINE CENTER IN PURPLE AND AGAIN YOU CAN SEE CERTAINLY ALL OF THESE DATA POINTS LIE WITHIN. PREDICTION INTERVALS. IT GIVES US CONFIDENCE THAT THE RESULTS ARE REPRODUCIBLE WITH MINIMAL INTERVENTION AS FAR AS THE BARCELONA DATA AND ALSO ACROSS SITES THAT HAVE USED DIFFERENT BUT SIMILAR BUT DIFFERENT IMAGING PROTOCOLS IN THE CASE OF THE DATA FROM BOSTON. SO ONE OF THE THINGS THAT WE WERE ABLE TO DO WITH OUR DENSELY SAMPLED DATA WAS TO CONSIDER THE IMPACT OF ACQUIRING AFFIXED NUMBER OF SLICES THROUGHOUT THE PLACENTA AND IN THE PLOT ON LEFT WE LOOKED AT THE T2 * ERROR IN OVER-ALL POPULATION MEDIAN T2 * FOR SAMPLING WITH UP THROUGH 11 SAMPLES. AND THE BLACK CURVE SHOWS THE 25-50 -- 75-90 -- 95-5 AND 99 TO 1% QUAN TILES OF THE VALUES. SO YOU SEE SAMPLING RELATIVELY FEW SLICES CERTAINLY INCREASES THE UNCERTAINTY AND THE RED CAN HAVE SHOWS WHAT THE POPULATION STANDARD DEVIATION IS. BUT EVEN ONE SLICE 90% OF THOSE DATA POINTS LIE WITHIN THE DEVIATION. BY THE TIME YOU REACHED 10 SLICES THESE UNCERTAINTIES ARE RELATIVELY MODEST SO IT MIGHT BE POSSIBLE TO ACQUIRE THE DATA IN A HANDFUL OF BREATH HOLDS AND GET ACCURATE RESULTS. ON THE RIGHT HAND PANEL WE PLOTTED THEM IN THE AREA UNDER THE CURVE BY RERUNNING THE ENTIRE ANALYSIS PIPELINE FOR SUBSETS OF THE T2 * DATA SAMPLES FOR AFFIXED NUMBER OF SLICES. THE BLUE CURVE IS FOR THE FIRST GESTATIONAL. THE RED IS FOR THE SECOND AND THE GREEN IS FOR THE THIRD WINDOW AND AGAIN THE AUC VALUES FOR THESE CURVES SHOW RELATIVELY MODEST DEPENDENCE. MAYBE 15 MINUTES OR SO FOR THE STUDY. SO SOME OF THE ACCOMPLISHMENTS OF THE STUDY INCLUDED THAT WE EXCEEDED OUR PLANNED ENROLLMENT FOR CONTROL AND ADVERSE GROUPS. WE ESTABLISHED AN IMAGING PHENOTYPE FOR NORMAL PREGNANCIES FROM 11-38 WEEKS. LONGITUDINAL TRENDS FOR NORMAL AND ADVERSE PREGNANCIES. ESTABLISHED SENSITIVE AND SPECIFICITY VALUES. MID-GESTATION APPEARS TO BE THE SWEET SPOT. I DIDN'T DISCUSS THIS FOR REASONS OF TIME. BUT WE ALSO ASSESSED CONSISTENCY ACROSS SITES IN PARTICULAR LOOKING AT OHU VERSUS UTAH AND FOUND INTERESTING RESULTS AND ASSESSED THE IMPACT OF DATA SAMPLING AND THE POTENTIAL FOR ACQUIRING LESS DATA IN VIEW OF PLACENTAL MEASUREMENTS. SOME OF THE OPEN QUESTIONS THAT DR. GRANT BROUGHT UP CONFOUNDED PATHOLOGY IS ONE ISSUE WE DON'T EXPECT THAT PLACENTAL T2 * WILL CAPTURE EVERY ADVERSE OUTCOME. AND WE KNOW THAT INFLAMMATION OF THE FETAL VILLA CAN CAUSE A PARADOXAL INCREASE. SO IT MIGHT BE POSSIBLE FOR BOTH INSUFFICIENT MATERNAL INFUSION AND INFLAMMATORY CONCERNS IN PREGNANCY TO CAUSE CONFOUNDED OFFSETTING CHANGES IN T2 *. WE HAVE NOT INVESTIGATE ENDS MAGNETIC FIELD STRENGTH. IT WAS ACQUIRED AT THREE TEST LOADS WHICH SHOULD BE MORE SENSITIVE TO CHANGES. BUT IT CERTAINLY WOULD NEED TO BE INVESTIGATED. WE ALSO 7 HAVE NOT IN DETAIL STUDY THE DEPENDENCE ON DATA ACQUISITION APPROACH. SO WE'VE USED STRAND GRADIENT ECHO IMAGING. THERE ARE A NUMBER OF DECISIONS THAT NEED TO BE MADE IN TERMS OF ECHO TIMES, SPATIAL RESOLUTION AND A NUMBER OF OTHER THINGS. THOSE OUGHT TO BE WORKED OUT AND OUR DATA WAS OBTAINED ON SEMEN SCANNERS. THE DETAILS OF VENDOR DEPENDENTS HAVE NOT BEEN WORKED OUT YET AND FINALLY NEITHER POPULATIONS IN PORTLAND OR SALT LAKE CITY WERE DIVERSE. WE HAD HEAVY REPRESENTATION BY CAUCASIAN PATIENTS AND IT'S OF IMPORTANCE TO EXPAND OUR POPULATION STUDY. WE HAVE A PREPRINT OF THE MANUSCRIPT DESCRIBING THIS RESEARCH IN MORE DETAIL AVAILABLE ON RESEARCH SQUARE. AND WE'RE ALSO TESTING A CLOUD BASED SOLUTION TO TRY TO SOLVE THE ISSUE OF GENERATING T2 * MAPS AUTOMATICALLY. SO IT WOULD ALLOW SOMEONE TO UPLOAD -- MULTI-ECHO GRADIENT DATA. AND CONVERT THAT INTO SECONDARY CAPTURE FILES CONTAINING T2 * MAPS WHICH SHOULD BE COMPATIBLE WITH ANY SOFTWARE. ANYONE WHO'S INTERESTED IN TRYING TO DO THIS WITH THEIR OWN DATA SHOULD PLEASE CONTACT ME. WE WOULD BE HAPPY TO SHARE. AND FINALLY ACKNOWLEDGMENT. THIS STUDY INVOLVED MANY PEOPLE. FIRST AND FOREMOST THE MORE THAN 300 PREGNANT WOMEN WHO VOLUNTEERED TO COME BACK UP TO THREE TIMES DURING PREGNANCY AND WHO WERE KEY TO ACQUIRING THESE RESULTS. AND A LARGE GROUP OF PEOPLE WHO DID AN ENORMOUS AMOUNT OF WORK IN TERMS OF DATA ACQUISITION AND MANAGEMENT AND DEVELOPMENT AND PATIENT RECRUITMENT. SAMPLE ACQUISITION. ROI DRAWING AND THE ABOVE. AND OF COURSE WE HAVE TO GIVE CREDIT TO THE HUMAN PLACENTA PROJECT AND DAVID WEINBERG WHO HAVE BEEN VERY SUPPORTIVE OF THIS RESEARCH AND REALLY GOT IT KICK STARTED WITH THIS GRANT. THANK YOU VERY MUCH. >> THANK YOU SO MUCH. THAT WAS FANTASTIC. THANKS TO BOTH OF YOU FOR GREAT TALKS. THOSE WHO ARE WATCHING THE AGENDA -- WE'LL HAVE SEEN THAT WE'VE GOTTEN SIGNIFICANTLY BEHIND AND THE OUT BRIEF FOR MRI THAT DR. GRANT SUMMARIZED IS QUITE COMPREHENSIVE. SO TO KEEP US ON TIME FOR THE NEXT SESSION -- WE'RE GOING TO FOREGO PANEL DISCUSSION. HOWEVER WE REALLY ENCOURAGE YOU ALL TO GO TO THE IDEA SCALE PLATFORM AND TO CONTINUE THE DISCUSSION THERE. WE'RE GOING TO TAKE A BREAK. BREAKS ARE IMPORTANT AND WE'LL SEE YOU BACK AT 2: P.M. EASTERN TIME WHICH IS JUST UNDER 10 MINUTES SO WE'LL SEE YOU THEN. THANKS. -- IF WE CAN START USING THIS MORE AND MORE IT SEEMS TO BRING OUT THE BEST IN THE I'M AMENDING TECHNIQUES AND OF COURSE THERE IS ACTUAL NOVEL IMAGING TECHNIQUES. PROFESSOR CAR HILL WILL TALK ABOUT HER EXCITING RESEARCH IN THAT FIELD IN OUR LATER PRESENTATION. SO WE MOVED ON TO SAY DO WE THINK THAT THE MAJORITY OF ADVANCES FROM ULTRASOUNDS HAVE MOVED FROM ADVANCING ULTRASOUND HARD WORK TO JUST SOFTWARE SOLUTIONS AND THIS RAISED AN INTERESTING QUESTION THAT NONE OF US COULD ANSWER AND THAT IS DOES POST PROCESSING NEED TO BE REALTIME. IF IT MEANT THAT WE WERE GOING TO BE PROVIDING USEFUL INFORMATION. HAVE WE WILL BEING SO USED TO ULTRASOUND BEING PRESENTED REALTIME BECAUSE THAT IS HOW WE'VE ALWAYS DONE THAT. WE DIDN'T ANSWER THAT ONE SO I OPEN THAT TO THE FLOOR FOR ANY THOUGHTS AND DISCUSSION THAT MAY ARISE FROM THAT. ONE OF THE MAJOR THEMES AS WELL THAT CAME THROUGH IS WE ARE NOT GOING TO BE ABLE TO MOVE OUR ADVANCES FROM HARDWARE TO SOFTWARE SOLUTIONS ESPECIALLY WITH AI AND DEEP LEARNING. IF WE DON'T IMPROVE STANDARDIZATION BECAUSE WE'RE ALL RECORDING ULTRASOUNDS SCANS WITH DIFFERENT DATA, DIFFERENT SETTINGS THAN OUR DATA THAT CAN'T BE SHARED AND NOVEL TECHNIQUES CAN'T BE SHARED. ONE OTHER THING WAS THE POST PROCESSING DATA -- SUCH AS FRACTIONAL LIMB VOLUME WHICH IS ALLOWING US TO VISUALIZE WHAT WAS GOING ON IN TERMS OF THE AMOUNT THAT A FAT THAT THE FETUS IS LAYING DOWN. 7 SO ONE OF THE MAJOR THINGS THAT CAME OUT OF THAT DISCUSSION IS THE NEED TO STANDARDIZE. WE TALKED AS WELL ABOUT ROOM FOR NOVEL HARDWARE. WE'RE HAVING TO STITCH TOGETHER IMAGES TO TRY TO INCREASE THE SIZE OF THE THREE DIMENSIONAL VOLUME. WE CANNOT CAPTURE 3-D VOLUME OF THE WHOLE PLACENTA AT TERM. BUT COULD THIS BE IMPROVED BY HARDWARE THAT HAS SPATIAL MONITORING SO IT DOCUMENTS WHERE THE PROBE IS OR COULD WE GO ONE STEP FURTHER AND HAVE SENSORS ON THE BODY SURFACE MAYBE CONTOURED LIKE A NET OF SENSORS OVER THE ABDOMEN. AND THIS IS AN IDEA -- THAT HAS BEEN AROUND SINCE THE '80s. IT'S SO DATA DEMANDING AND DIFFICULT TO DO THAT IT HAS NOT GONE AS FAR AS IT COULD AND GIVEN THAT WE'RE NOW SO MUCH FURTHER AHEAD IN THE FIELD OF COMPUTATION THERE MIGHT BE A WAY FORWARD WITH THAT AND COULD WE CONSIDER HOW THE ULTRASOUND PROBLEM COULD BE CHANGED. WE HAVE A HAND-HELD PROBLEM BUT MAYBE WE CAN GENERATE A HALF PIPE ARRANGEMENT. WE TALKED ABOUT THE MAJOR BARRIERS TO CLINICAL TRANSLATION. I MENTIONED LACK OF STANDARDIZATION. WE NEED TO GET TOGETHER AND STANDARDIZE. WE NEED TO EDUCATE. LACK OF UNDERSTANDING OF THE PHYSICS OF ULTRASOUND MEAN THAT WE DON'T ALWAYS GET THE BEST DATA COLLECTION AND OTHER THING THAT WAS HIGHLIGHTED WAS THE TOTAL LACK OF COOPERATION FROM MANUFACTURERS. THEY WON'T SHARE THE RAW DATA. AND YET SHARING HAPPENS WITH OTHER IMAGING MODALITIES. AND OF COURSE LACK OF GROUND TRUH GOLD STANDARDS ARE ALL BARRIERS. WE DISCUSSED ANIMAL MODELS AND THIS TOO CAME UP ON IDEA SCALE. SHOULD WE BE USING THE SMALLER CHEAPER ANIMALS OR SHOULD WE BE USING LARGER ANIMALS -- SHEEP WITHSTAND ULTRASOUND MACHINES SO, ITS DIRECTLY TRANSLATABLE AND THIS WAS COMMENTED ON BY ANNA DAVID. HIGHLIGHTED THE AMOUNT OF ULTRASOUND WORK THEY'VE DONE IN SHEEP MODELS AND HOW WELL IT WORKS. WE CAN USE ANIMALS TO VALIDATE TECHNIQUES AND MEASURES AS WAS DONE RECENTLY WITH RADIOACTIVE MICRO PARTICLES. WE ASK TALKED ABOUT A ROLE FOR THESE TECHNOLOGIES IN LOW-INCOME COUNTRIES AND THE PANEL FELT THAT AI ASSISTED PAT EXCEPT RECOGNITION WHICH CAN BE USED WOULD BE THE MOST USEFUL. I HOPE THAT WAS A USEFUL 10 MINUTE TROT THROUGH -- TWO HOURS OF EXCELLENT DISCUSSION AND I JUST WOULD LIKE TO SAY A HUGE THANK YOU TO THE PANEL -- THEIR TIME AND EXPERTISE AND ENTHUSIASM AND REALLY INTERESTING INSIGHTS MADE IT A VERY USEFUL WAY TO SPEND TWO HOURS. SO FOR THAT I THINK WE SHOULD MOVE ON. -- >> THANK YOU SO MUCH DR. COLLINS. I WANTED TO THANK YOU FOR A FANTASTIC SYNOPSES AND TAKE A BRIEF MOMENT TO INTRODUCE OUR FIRST TALK IN THIS AREA FROM DR. CAHILL. TAKE IT AWAY. >> THANK YOU FOR THE INTRODUCTION AND YOU CAN SEE MY SCREEN HOPEFULLY. I'M COMING TO YOU FROM ST. JOHNS IN NEWFOUNDLAND AND LABRADOR IN CANADA. I MOVED HERE A YEAR AGO AND STARTED A POSITION AS AN ASSISTANT PROFESSOR AT MEMORIAL UNIVERSITY AND I'M VERY HAPPY TO TALK TO YOU TODAY ABOUT SOME OF OUR WORK FUNDED BY THE HUMAN PLACENTA PROJECT. I WOULD START BY ACKNOWLEDGING THE WONDERFUL TEAM THAT I GOT TO WORK WITH ON THIS PROJECT. SO THE PROJECT WAS LED BY JOHN SLED AT THE HOSPITAL FOR CHILDREN. AND THAT IS WHERE I WAS PREVIOUSLY. AND JOHN AND CHARISMA GO WANT LED THE TEAM AT SICK KIDS. ALSO DONE IN COLLABORATION WITH THE TEAM AT THE MOUNT SINAI HOSPITAL AND A TEAM AT JOHN'S HOPICS. * SO JUST A BRIEF INTRODUCTION TO THE IMPORTANT ROLE OF ULTRASOUND IN PREGNANCIES. IT'S A POWERFUL TOOL AND TO EVALUATE BOTH THE STRUCTURE AND THE FUNCTION OF THE PLACENTA AND IT'S ROUTINELY USED TO GUIDE THE TIMING OF DELIVERY IN GROWTH RESTRICT FETUSES. SO AS SALLY SAID IT'S CURRENTLY THE GOLD STANDARD FOR DETECTING PLACENTAL PATHOLOGY. WE USELY MEASURE THE UMBILICAL ARTERY. THE INDEX IS MEASURED AS THE DIFFERENCE BETWEEN THE -- HERE SHOWN AN EXAMPLE -- JUST A NORMAL WAVE FORM AND YOU CAN SEE HOW IT CHANGES WITH THE PULSE INCREASING. PULLS TILT. -- AND IT IS THE STANDARD OF CARE BUT DESPITE THIS IT'S BEEN SHOWN TO HAVE ONLY MODERATE DIAGNOSTIC UTILITY PARTICULARLY IN LATE GESTATION. AND ONE OF THE REASONS IS THAT THE PULSATILITY INDEX IS CONFOUNDED BY A NUMBER OF FACTORS. THE BASELINE FETAL HEART RATE SO OUR IDEA WAS TO DEVELOP A METHODOLOGY TO ISOLATE THE COMPONENT OF THE DOPPLER SIGNAL THAT IS SPECIFIC TO THE PLACENTA PLACENTA. TO PROVIDE A MORE SPECIFIC MARKER OF PLACENTAL VASCULAR PATHOLOGY. AND THIS IDEA CAME FROM THE FACT THAT WE KNOW UMBILICAL ARTERY WAVE FORMS VARY BECAUSE OF INTERFERENCE BETWEEN THE FORWARD AND REFLECTED DYNAMIC WAVES. IT'S BEEN WELL-KNOWN. BUT IT HAS YET TO BE APPLIED TO THE PLACENTA. SO OUR RESEARCH PROGRAM HAD TWO AMS TO IT. THE FIRST WAS IN THE MOUSE WHICH WE USED FOR METHOD DEVELOPMENT. WE LOOKED AT MODELS OF PLACENTAL DYSFUNCTION AND WERE BEES ABLE TO CORRELATE TO PLACENTAL MORE FOLLOW GEE. *. AS SALLY EXPLAINED ANIMAL MODELS HAVE AN IMPORTANT PLACE IN PREGNANCY RESEARCH. THERE ARE MANY BENEFITS. THEY PRODUCE MANY OF THE FEATURES OF HUMAN PREGNANCY AND VERY EFFICIENT FOR RESEARCH. THEY HAVE RAPID GESTATION. 19-20 DAYS. LARGE LITTER SIZES UP TO 20 FETUSES AND THE PATHOLOGY IS REPRODUCIBLE. THEY HAVE THE SAME VASCULAR AND CELLULAR STRUCTURE. YOU CAN SEE ON THE LEFT THE MAXIMUM INTENSITY IMAGE OF A MOUSE PLACENTA. AND YOU CAN COMPARE IT TO THE HUMAN PLACENTA AND SEE THE SIMILARITIES. THE SCALE BARS ARE VERY DIFFERENT BETWEEN THE TWO. ANOTHER BENEFIT OF USING MICE IS THAT YOU CAN TEST EXPERIMENTAL THERAPIES. YOU CAN EXPLORE GENETIC FACTORS AND YOU CAN -- [ AUDIO DIFFICULTIES ] SO I'LL TELL YOU ABOUT THE METHODOLOGY TO MeSH WAVE REFLECTIONS IN THE MOUSE. THIS IS DESCRIBED IN THIS PAPER BY A TALENTED STUDENT. HERE IN THE MOUSE YOU CAN DO ULTRASOUND IN THE SAME WAY YOU DO CLINICAL SYSTEM. WE HAVE A HIGH FREQUENCY TRANSDUCER WHICH ALLOWS YOU TO GET THE INCREASED SPATIAL RESOLUTION. SO WE'RE ABLE TO MEASURE CHANGES IN AREA OF THE UMBILICAL ARTERY OVER TIME USING 40 MEGA Hz TRANSDUCER. YOU CAN SEE WHAT IS OUTLINED IN RED ARE THE VESSEL WALLS OF THE ARTERY AND YOU CAN SEE HOW THEY CHANGE WITH TIME. SO WE MEASURE THE ARTERY AS WELL AS THE DOPPLER WAVE FORM IN THE SAME POSITION. AND THEN SEPARATE THESE INTO THEIR INDIVIDUAL CARDIAC CYCLES BASED ON THE ON-SITE -- WHICH IS MARKED WITH THE YELLOW CROSSES AND ARROWS AND WE ALIGN THE TRACES AND THEN AVERAGE THEM WHICH IS WHAT IS SHOWN IN RED SO THIS IS HOW THE DATA IS ACQUIRED. I'VE ILLUSTRATED THIS A BIT FURTHER WHERE THE VELOCITY AND -- ARE COLLECTED AT THE FETAL END OF THE CORD. THEY ARE REFLECTED SO THAT THESE TWO REPRESENT THE SUPER POSITION OF THE FORWARD AND BACKWARD TRAVELING WAVES SO THE FORM IS INVERTED. AND THIS PROVIDES THE BASES TO UNIQUELY DECOMPOSE THE WAVE FORMS INTO THEIR FORWARD AND REFLECTIVE WAVES WHICH YOU CAN SEE IN ORANGE AND IN GREEN. WE USE THE PULSE WAVE VELOCITY WHICH IS THE SPEED AT WHICH THOSE PULSE PRESSURE WAVES PROPAGATE ALONG THE VESSELS TO DECOMPOSE THE WAVE FORMS TO THE FORWARD REFLECTED COMPONENTS. ONE WAY THAT WE SUMMARIZED THE REFLECT END WAVE FORMS WAS IN TERM OF A REFLECTION CO-EXHIBITER -- THE TUT PEEK TO PEEK RESOLUTION BETWEEN THE REFLECTIVE WAVE AND THE FORWARD WAVE. WE WANTED TO ANSWER TWO QUESTIONS. THE FIRST IS WHAT IS THE RELATIONSHIP BETWEEN THE CHANGES IN THE WAVE REFLECTION METRICS. AND ALSO CAN WE DETECT CHANGES IN WAVE REFLECTION IN ESTABLISHED MOUSE MODEL OF FETAL GROWTH RESTRICTION. FOR THE FIRST QUESTION WE LOOKED AT A MOUSE MODEL WHERE WE DELIVERED COMBINATION INTO RETROVIRAL THERAPY. THIS IS THE SAME TREATMENT THAT ARE GIVEN TO PREGNANT WOMEN WHO ARE HIV POSITIVE. AND PREVIOUSLY IN OUR LAB AT THE UNIVERSITY OF TORONTO HAS SHOWN THAT THIS TREATMENT RELATES IN ABNORMAL PLACENTA ATION. SO THE TWO IMAGES ARE MICRO CT IMAGES. THEY ARE PREPARED BY PROFUSING X VIVO THE PLACEBO AND THEN SCANNED. YOU CAN SEE THE CURRENT PLACENTA AT THIS LATER GESTATIONAL TIME POINT HAS AN INCREASE IN THE VESSELS. SO WE PERFORMED OUR WAVE REFLECTION -- -- THE CO-EXHIBITER INCREASED IN BOTH GROUPS WITH GESTATIONAL AGE AND THIS IS CONSISTENT WITH THE ESTABLISHED GROWTH IN THE VASS COULD YOU LAYER NETWORK THAT WE'VE CHARACTERIZED PREVIOUSLY IN OUR LAB. BUT FOR THIS PRESENTATION IF YOU LOOK AT THESE LAST TWO BARS YOU CAN SEEP THAT THE REFLECTION COEFFICIENT INCREASED. WE ARE WANTED TO EXPLORE THIS FURTHER AND TO DO THIS -- WE KNOW THE ARTERIAL TREE HAS A REGULAR STRUCTURE. WE ANTICIPATED THAT THE GEOMETRIC RELATIONSHIPS OF THE PLACENTA COULD ABSORB. SO IF THE VALUE WAS ONE THEN IT WOULD BE COMPLETELY ELIMINATED. >> SO WE DID THIS. WE CALCULATED THE AREA OF RATIO AT THE UMBILICAL ARTERY USING THE MICRO CT DATA AND WE CAN FIT THIS TO A MODEL. THE MINIMUM IS NOT ZERO BECAUSE THIS AVERAGE IS THE SUM OF ALL OF THE REFLECTIONS SO THE SUBSEQUENT REFLECTIONS ARE GOING TO BE NONZERO. THERE IS ONGOING WORK IN JOHN SLED'S LAB LOOKING AT COMPUTATIONAL MODELING TO TRY TO DETERMINE WHAT OTHER SITES IN THE PhD ARE CONTRIBUTING TO THE MEASURE OF REFLECTIONS AND WE'VE SEEN THAT THE TERMINAL VESSEL SEEMED TO PLAY A SIGNIFICANT ROLE AS WELL. SO HAVING ESTABLISHED THAT WAVE REFLECTIONS ARE ASSOCIATED WITH THE VASCULAR MORE OF ALLERGY OF THE TREE. THIS INVOLVES EXPOSING THE PREGNANT MICE. STARTING AT 14 AND A HALF DAYS OF GESTATION IN A CONTROLLED ENVIRONMENT ARE PUT INTO A CHAMBER AT 11% OXYGEN UNTIL WE DO OUR FINAL MEASUREMENT JUST BEFORE TERM AND YOU CAN SEE THAT THERE IS AN OBVIOUS LARGE DECREASE IN FETAL WEIGHT IN THE MICE EXPOSED. SO THE RESULTS FROM THE WAVE REFLECTION ANALYSIS WE SEE THIS LARGE INCREASE IN REFLECTION COEFFICIENT IN THE GROWTH RESTRICT MICE. WHAT WAS INTERESTING WAS THAT THE PULSATILITY INDEX THE GOLD STANDARD MEASURE WAS NOT DIFFERENT BETWEEN THE CONTROL AND THE CHRONIC HYPOXIA MICE. 7 IT WAS SHOWING INCREASED SENSITIVITY. TO SUMMARIZE WE WERE ABLE TO SHOW THE WAVE REFLECTION MEASUREMENTS ARE ALTERED. THE REFLECTIONS ARE ASSOCIATED WITH THE GEOMETRY OF THE ARTERIAL TREE. AND THAT THERE SEEMS TO BE AN INCREASED SENSITIVITY. SO THESE WERE PROMISING RESULTS TO LAY THE GROUND WORK TO INTERPRET THE RESULTS THAT WE FOUND IN OUR HUMAN CLINICAL STUDY. I JUST SHOWED A DIAGRAM OF THE FLOW OF THE PARTICIPANTS. WE ENROLLED 427 WOMEN AT EITHER MOUNT SINAI HOSPITAL OR JOHNS HOPICS UNIVERSITY. WE HAD TO EXCLUDE 126 BECAUSE SOME PATIENTS WITHDREW AND THERE WERE A LARGE UP IN OF PLACENTAS THAT WERE NOT SENT IN FOR PATHOLOGY. WE HAD THE PREGNANCY OUTCOMES AND THE PLACENTAS WERE ASSESSED FOR PATHOLOGY. 40 WOMEN MET THE CRITERIA FOR CONTROLS. SO WE HAD A FAIRLY STRICT EXCLUSION CRITERIA FOR THE CONTROLLED POPULATION SO NO MATERNAL CO-MORBIDITIES. A TERM BIRTH AND A BIRTH WEIGHT GREATER THAN THE 25th PERCENTILE. WE USED THE AMSTERDAM CRITERIA AND WE WORKED WITH TONY PARKS IN THE PATHOLOGY DEPARTMENT AT THE MOUNT SINAI HOSPITAL. WE HAD 36 WOMEN WHO SHOWED EVIDENCE. ONE OF OF THE MOST COMMON COMPLICATIONS AND 16 WOMEN WITH FETAL VASCULAR -- WHICH IS A RARE OCCURRENCE BUT BOTH ARE IMPORTANT. SO THE METHODOLOGY IN THE HUMAN IS A BIT DIFFERENT. AND THE REASON IS THAT WE CANNOT MEASURE AN M MODE TRACE OF THE UMBILICAL ARTERY. [ AUDIO DIFFICULTIES ] BECAUSE OF THE RESOLUTION -- DESCRIBED IN DETAIL IN THIS PAPER BY ONE OF MY COLLEAGUES. SO WE MEASURED DOPPLER ULTRASOUND AT BOTH ENDS OF THE CARD. WE THEN MODELED THE PLACENTAL VASCULAR RESISTANCE WITH A RESPONSE FUNCTION AND THIS IS COMPOSED OF TWO REFLECTIONS. ONE THAT IS GENERATED WHEN THE PULSE ENTERS THE PLACENTA AND THEN A DECAYING -- OF REFLECTIONS. SO WE HAVE FOUR SETS OF DOPPLER WAVE FORMS. TWO ARTERIES AND TWO SITES. AND THIS ALLOWS US TO UNIQUELY DECOMPOSE THESE WAVE FORMS NOT FORWARD WAVE IN GREEN AND REFLECTIVE WAVE IN ORANGE. SO WHILE THIS IS AN ADDITIONAL NUMBER OF MEASURES THAT NEED TO BE COLLECTED COMPARED TO A TYPICAL CLINICAL SCAN ALL OF THE DATA COLLECTED WAS COLLECTED ON STANDARD ULTRASOUND EQUIPMENT AND THEN PUT THROUGH OUR ANALYSIS SO IT CAN BE EASILY TRANSLATED TO OTHER CENTERS. HERE IS THE RESULTS. ON THE LEFT PANEL WE HAVE A REFLECTION CO-EXHIBITER SO IN WHITE IS OUR CONTROLLED PATIENTS. IN BOTH CASES WE SAW A HIGH REFLECTION WHICH SUGGESTS THAT ONE OR WHO SITES HAVE HIGH IMPEDE ANNES OR A VERY LARGE MISMATCH. WHEN WE COMPARED THIS THIS WAS ONLY ELEVATED IN THE MVM CASES. SO BASED ON THIS DATA I HOPE THAT YOU CAN IMAGINE THAT WE HAVE A DIFFERENTIAL DIGITAL DIFFERENCE DIA GNOSES. THE RESULTS JUST CAME OUT LAST WEEK. IT HAS MODERATE PREDICTIVE PERFORMANCE. WE BELIEVE THAT COMBINING THE WAVE REFLECTION CO-EXHIBIT WITH OTHER METHODS. THAT COMBINING ALL OF THESE TOGETHER HAVE THE POTENTIAL TO IMPROVE DIAGNOSIS OF PLACENTAL BIOLOGIES. WE'VE DEVELOPED A ROBUST METHODOLOGY USING DOPPLER ULTRA SOUND. WE'VE EYWE HAVE ISOLATED THE PART. WE BELIEVE THESE FINDINGS HAVE A POTENTIAL TO EXTEND THE UTILITY -- TO IMPROVE DIAGNOSES AND WE WERE EXCITED ABOUT THIS IN THE CASES OF FETAL VASCULAR MALL PROFUSION WHICH THERE IS NOT A GREAT DIAGNOSTIC TEST. AND OFFER ONLY DIAGNOSED UPON PLACENTAL PATHOLOGY SO WE FOUND THIS PARTICULARLY EXCITING. WE HOPE THAT EMERGING TECHNOLOGIES SUCH AS ULTRA FOUND ULTRASOUND IMAGING WILL HAVE THE ABILITY TO IMPROVE THE MEASUREMENTS. THANK YOU VERY MUCH. >> THANK YOU SO MUCH. OUR NEXT TALK WILL BE BY DR. DR. ABUHAMAD. >> IT'S A PLEASURE TO PRESENT FROM OUR STUDIES. LET ME DESCRIBE OUR STUDY FIRST. THIS IS A COLLABORATION BETWEEN -- THE MEDICAL SCHOOL, THE UNIVERSITY OF TEXAS MEDICAL BRANCH -- WITH CANON MEDICAL AND ILUMNANA CORPORATION. 610 PREGNANCIES. WE DID THE LONGITUDINAL ULTRASOUND -- STUDY AND 8 ULTRASOUND EXAMS PER PREGNANCY AND ANY DELIVERY AT LESS THAN 37 WEEKS AND THE GOAL WAS TO LOOK AT NOVEL ULTRASOUND TOOLS AND WHETHER WE'RE ABLE TO PREDICT PREGNANCY COMPLICATIONS. THIS IS THE SCHEMATICS AT THE TIME WHEN THE ULTRASOUND WERE PERFORMED. THE FIRST HALF OF PREGNANCY TRYING TO IDENTIFY CHANGES EARLY ON THAT COULD PREDICT LONG-TERM OUTCOME. 610 WERE OUR TOTAL COHORTS. WE LOOKED AT THE SPIRAL ARTERIES, THE FETAL PLACENTAL THE MATERNAL URINARY ARTERIES STARTING FROM THE FIRST TRIMESTER. SO OUR ULTIMATE GOAL WAS TO TRY TO CREATE A PLACENTAL INDEX IN EARLY GESTATION THAT COULD PREDICT PREGNANCY OUTCOME AND BY COMBINING NOVEL ULTRASOUND TOOLS AND OTHER AVAILABLE TOOLS TO US. SO WE HAD 610 PREGNANCIES. OUR CONTROLS WERE 511 PREGNANCIES THAT DELIVERED AT OUR LATER THAN 37 WEEKS AND OUR CASES WERE 99 PREGNANCIES THAT DELIVERED AT LESS THAN 37 WEEKS. FROM OUR CONTROLS WE ALSO IDENTIFIED 90 PREGNANCIES THAT HAVE NORMAL MATERNAL FETAL AND NEONATAL OUTCOME AND WE CALL THEM AS THE REFERENCE GROUP THAT IS HELPFUL FOR US TO DEVELOP NORMAL GRAMS FOR THESE NOVEL TOOLS. THE CONTROLS EVEN THOUGH WE DEFINE CONTROLS AT DELIVERY AT OR 37 WEEKS WE WANT TO DEVELOP OUR NORMAL GRAMS FOR A GROUP THAT IS TOTALLY NORMAL. THIS IS THE CASE IS 99 PATIENTS I'M SHOWING YOU THE ABOUT 37% DELIVERED SPONTANEOUSLY AT LESS THAN 37 WEEKS AND 63% INDUCED. IF YOU LOOK AT THE TIME FOR DELIVERY ABOUT 10% DELIVERED AT LESS THAN 28 WEEKS. AND CLOSE TO 80% BETWEEN 32 AND 37 WEEKS. IF YOU LOOK AT THEM INDICATED DELIVERIES YOU'LL SEE THE MAJORITY WERE HYPERTENSIVE DISORDERS OF PREGNANCIES INCLUDING PREECLAMPSIA OR COMPLICATED HYPERTENSION. 18% WITH PR PRERUPTURED MEMBRANES. I'M GOING TO TALK ABOUT THE SPIRAL ARTERIES. WAND HERE YOU SEETHE SPIRAL ARTERIES WITHI N THE PLACENTA. WE LOOK AT HOW MANY COULD WE SEE STARTING IN EARLY GESTATION AT THE 13 WEEKS ULTRASOUND. THESE ARE THE THE NINE PREGNANCIES THAT ARE TOTALLY NORMAL. HERE IS OUR CONTROL GROUP THAT DELIVERED AT OR GREATER THAN 37 WEEKS. AND THESE ARE OUR CASE THAT'S DELIVERED AT LESS THAN 37 WEEKS. I'M GOING TO GO THROUGH THESE OUR DATA AND THEN I'LL SHOW YOU SOME STATISTICAL ANALYSIS TO COMPARE CASES AND CONTROLS. THEN WE LOOKED AT THE PEEK SYSTOLIC ARTERIES. STARTING FROM EARLY GESTATION. HERAND FOR EVERY DATA POINT IS THE AVERAGE OF SIX MEASUREMENTS OBTAINED AT THE TIME. AND HERE WE'RE LOOKING AS THE POSITIVITY INDEX AND THIS IS OUR REFERENCE GROUP AGAIN OUR CONTROL GROUP, DELIVERY GREATER AT 37 CASE. NOW IF YOU LOOK AT THE DATA THAT WE HAD I'M GOING TO SHOW YOU THE CHANGE BETWEEN EARLY GESTATION SO AT 12 WEEKS AND YOU SEE THE SPIRAL ARTERIES HAVE A FAIRLY HIGH -- INDEX AND AS YOU GO INTO MID-GESTATION AND TOWARD THE END OF GESTATION AND YOU SEE THE ADAPTATION THAT HAPPENS CLOSE TO TERM. THIS IS AT 32 WEEKS GESTATION. IF YOU LOOK AT THE DATA AGAIN WHAT I THINK BECAME OBVIOUS FROM OUR DATA THESE ARE THE CONTROLLED GROUP. THE 510 PATIENTS ALL GROUPED TOGETHER. YOU SEE THAT WE DEMONSTRATED THAT THE INDEX DECREASES FROM THE FIRST TRIMESTER ONWARD AND THIS IS IN KEEP WITH WHAT WE KNOW FROM THE SPIRAL ARTERY THE MODELING THAT STARTS IN THE FIRST TRIMESTER AND EXTENDS INTO THE SECOND TRIMESTER. BASED ON OUR DATA IT DOESN'T BEGIN TO LEVEL OFF UNTIL AFTER THE SECOND TRIMESTER BETWEEN 20-25 WEEKS GESTATION. IF YOU ALSO LOOK AT THE MAKE SYSTOLIC VELOCITY YOU SEE THERE IS A DOWNWARD TREND AS EXPECTED. THEY START A BIT HIGH AND THEN DROPS IN PREGNANCY AND THIS IS IN KEEPING WITH THE REMODELING THAT HAPPENS IN THE MAIN GOAL OF PROTECTING THE PLACENTAL TISSUE. NOW IF WE COMPARED THE ARTERIES BETWEEN CASES AND CONTROLS WE SEE THAT WHEN WE LOOK AT THE NUMBER OF SPIRAL ARTERIES THAT WE SEE WE SAW A SIGNIFICANT DIFFERENCE AT THESE GESTATIONAL AGE. BETWEEN CASES YOU CAN SEE ON THE SPIRAL ARTERY NUMBER THAT'S WE SEE THE HIGHEST NUMBER IN OUR REFERENCE GROUP FOLLOWED BY OUR CONTROLS AND THEN BELOW THAT IS OUR CASES. SO IT'S REFLECTIVE OF WHAT WE ANTICIPATED TO SEE BASED ON THE CHANGES IN PREGNANCY. NOW WE LIKE THE AT THE UTERINE ARTERY. THIS IS OUR REFERENCE GROUP. AND THESE ARE OUR CASES. WHEN YOU LOOK AT THE UTERINE ARTERY WE SAW SOME SIGNIFICANT DIFFERENCES IN THE FIRST ULTRASOUND THAT WAS DONE AT 12-1 WEEKS AND THEN LATER ON BETWEEN 20-24 WEEKS. AND WHEN COMPARED THE DATA IT WAS VERY HIGH CORRELATION BETWEEN THE TWO AND YOU CAN SEE VISUALLY THE SPIRAL ARTERIES PI AS I'VE SHOWN EARLIER DROPS UNTIL MID-GESTATION AND THEN LEVELS OFF SIMILAR CURVE PATTERN. THEN WE LOOKED AT THE FETAL VESSELS AND AGAIN HERE LOOKING AT THESE -- HERE IS THE NUMBERS THAT WE WERE ABLE TO DOCUMENT IN THE FIRST TRIMESTER IN OUR REFERENCE GROUP IN OUR CONTROLS AND IN OUR CASES. THEN WE LOOKED AT THE MAKE SYSTOLIC VELOCITY AND YOU SEE THE DATA HERE PRESENTED BETWEEN THE THREE GROUP. AND WE LOOKED AT THE PI OF THE PLACENTAL ARTERIES. HERE TO SHOW UP THE CHANGE IN THE POSSIBILITY INDEX YOU CAN SEE THAT EARLY IN PREGNANCY AT 12 WEEKS THERE IS HIGH CIRCULATION AND THEN THIS IS MID-GESTATION AND THEN COMING CLOSER TO TERM THIS IS AT 36 WEEKS AND YOU CAN SEE SIGNIFICANT REDUCTION WITHIN THE PLACENTA BASED ON THE MEASUREMENT. AND AGAIN WHAT WE HAVE DOCUMENTED IS DECREASING PLACENTA IMPEDE ANC STARTING FIRST TRIMESTER ONWARD. THAT IS PROBABLY RELATED TO THE NUMBER OF ARTERIES THAT WE WERE ABLE TO SEE AS WE DOCUMENTED HERE. WE HAVE DATA ON CARDIAC FUNCTIONS THAT WE WILL BE ANALYZING TO ASSESS. YOU CAN SEE A HIGH CORRELATION. AND WHEN YOU LOOK AT THE COMPARING CASES AND CONTROLS WE SEE THAT WE CAN ONLY DOCUMENT STATISTICAL DIFFERENCE IN THE 20-21 WEEKS ULTRASOUND. WE WILL BE ANALYZING THAT SHORTLY AND NO DIFFERENCE BETWEEN CASES IN CONTROLS FOR THE PEEK SYSTOLIC VELOCITY AND THEN ONE WINDOW AT 28-29 WEEKS WHERE WE WERE ABLE TO FIND STATISTICAL DIFFERENCES. THEN WE WANTED TO LOOK AT PLACENTAL TISSU CHARACTERIZATION. THIS IS NOT RELYING ON THE OPERATOR PUTTING ANY PRESSURE ON THE TISSUE ANALYZED. THIS RESULTS IN INCREASE OF SPEED OF THE PULSE THAT CAN BE QUANTIFIED AND MEASURED. AND THIS IS RELYING ON FOR INSTANCE THERE ARE TWO OUTPUTS THAT COME OUT FROM THE SYSTEM. ONE IS THE RELIABILITY INDICATOR THAT ALLOWS YOU TO CONFIDENTLY MEASURE AN AREA OF INTEREST WITHIN THE PLACENTA AND THEN YOU GET THE STIFFNESS MEASUREMENT WHICH IS DISPLAYED IN SPEED METERS PER SECOND AND THE HIGHER SPEED THE MORE DENSE THE TISSUE OR CONVERT IT TO A FORMULA. AND THE CONCEPT OF IT IS REALLY TO RELY ON THE RELIABILITY OF THE MEASUREMENTS. THIS IS WHAT NEED TO SEE AND EVEN PROPAGATION OF THE ECHO THAT SHOWS ALL LINES ARE SMOOTH. IF YOU HAVE A CO-ON THEIC PROPAGATION THIS IS ANNIE REASON YOUR MEASUREMENTS THAT CAN INTRODUCE ERRORS. HERE IS AIRPLAY AT 13 WEEKS. -HERE IS A PLACENTA AT 13 WEEKS. THERE IS MINIMAL CHANGE WHICH WE DOCUMENTED IN OUR STUDY AND HERE IS OUR CONTROLS AND OUR CASES THAT DELIVERED AT LESS THAN 37 WEEKS. ALSO WE WANTED TO ASSESS WHETHER THERE ARE CHANGES. WE WANTED TO LOOK WAS THERE ANY DIFFERENCE BETWEEN THE CENTRAL PORTION OF THE PLACENTA AS YOU CAN SEE HERE AND WE FOUND THERE WASN'T. THE SHEER WAVE MEASUREMENTS WERE SIMILAR IN THE THREE AREAS OF THE PLACENTA. WE WANTED TO COMPARE. AND WHAT WE FOUND WAS THAT IN EARLY GESTATION UP TO 17 WEEKS THERE IS VERY GOOD CORRELATION. AS YOU GO BEYOND THAT GESTATIONAL AGE THEY TEND TO PRODUCE DIFFICULTY BECAUSE OF THE DISTANCE BECAUSE OF THE PULLSATION SO IT BECOMES LESS RELIABLE. SO HERE IS THE DATA FOR THE TOPOGRAPHY AND WE COULD NOT SEE ANY STATISTICAL DIFFERENCES BETWEEN CASES AND CONTROLS. WE CAN DISCUSS WHY THAT MAY BE THE CASE PROBABLY RELATED TO THE LOW INCIDENCE OF PREECLAMPSIA AND GROWTH RESTRICTION. REMEMBER OUR ULTIMATE GOAL WAS TO TRY TO COME UP WITH A PLACENTAL INDEX LOOKING AT VARIOUS ULTRASOUND NOVEL TOOLS WITH THE HOPE THAT WE CAN -- PREDICT PREGNANCY OUTCOMES. THESE ARE THE SIGNIFICANT DIFFERENCES THAT WE'VE SEEN AT VARIOUS ULTRASOUND EXAMINATIONS. SO IF WE START TO COMBINE PARAMETERS. FOR INSTANCE LOOKING AT THE UTERINE ARTERY PI OVER THE SPIRAL ARTERY NUMBER WE CAN SEE THAT THIS RATIO SHOWS SIGNIFICANCE FROM EARLY GESTATION COMPARING THE CASES WITH THE CONTROLS AS YOU SEE HERE. BUT WHAT I HAVE SHOWN YOU AND SHARED WITH YOU TODAY IS JUST THESE ELEMENTS OF OUR STUDY. SO WE'RE IN THE PROCESS OF LOOKING AT PLACENTA -- -- AND EARLY ON AND CERTAINLY LOOKING AT THE CALCIUM CONTENTS AND HOPEFULLY INCLUDING DATA TO SEE IF WE'RE ABLE TO APPROVE ON OUR ABILITY TO PREDICT COMPLICATIONS FROM EARLY ON GESTATION. SO I'M HOPEFUL THAT DURING THIS PRESENTATION I HAVE CONFIRMED THE ABILITY OF ULTRASOUND -- FROM EARLY GESTATION ON. WE HAVE DEVELOPED NORMAL GRAMS THAT ARE USEFUL FOR OTHERS. AND WE HAVE SHOWN SOME SIGNIFICANT DIFFERENCES BETWEEN NORMAL AND ABNORMAL PREGNANCY BASED ON THE PARAMETERS THAT WE'VE OUTLINED THUS FAR AND HOPEFULLY TO DEFINE OUR RESULTS -- THIS WAS A STUDY THAT INVOLVED MORE THAN 600 PREGNANCIES WITH A LOT OF WORK SO REALLY IT IS THE TEAM BOTH AT UTMB AND EDMS THAT HAVE CONTRIBUTED SUBSTANTIALLY TO OUR ABILITY TO COMPLETE THE STUDY. CERTAINLY OUR PREGNANT WOMAN WHO VOLUNTEERED THEIR TIME AND EFFORT TO PARTICIPATE IN THE STUDY. AND OUR RESEARCH TEAM THAT YOU SEE HERE ESPECIALLY ANGELA WHO HAS SUPERB STATISTICAL SUPPORT THAT IS HELPING US THROUGH THE ANALYSIS OF THIS COMPLEX DATABASE. THANK YOU VERY MUCH. THANK YOU, DAVID ALSO FOR HIS SUPPORT THROUGHOUT THE YEARS AND HELPING US AND TRYING TO ASSESS HOW USEFUL THIS IS. THANK YOU FOR YOUR ATTENTION. >> THANK YOU SO MUCH FOR A GREAT PRESENTATION. AT THIS TIME I WOULD LIKE TO INVITE DR. COLLINS BACK TO LEAD OUR PANEL DISCUSSION. ALONG WITH THE OTHER ULTRASOUND EXPERTS WHO ARE WITH US TODAY. >> THANK YOU. FROM THE QUESTIONS -- IN THE CHAT I HAVE TO SEND ONE TO PROFESSOR ABUHAMAD. HELEN JONES HAS ASKED WHAT VESSELS ARE YOU ACTUALLY IDENTIFYING? >> THANK YOU, SALLY. SO OF COURSE WE DON'T KNOW WHAT THESE VESSELS ARE BUT WE'RE BRANCHING OFF THE UMBILICAL ARTERIES AS THEY GO INTO THE PLACENTA. >> AND WHAT A -- ANATOMICAL LANDMARK DID YOU USE? >> ABOUT A CENTIMETER FROM THE ENTRANCE OF THE CORD INSERTION INTO THE PLACENTA VESSELS. >> SO THESE ARE THE VESSELS THAT RUN ALONG THE SURFACE OF THE PLACENTA. >> CORRECT. AND THE FIRST TRIMESTER IT'S HARD TO SEE THEM. WE'RE PROBABLY MORE INTO THE PLACENTA THAN LATER ON IN PREG -- IN PREGNANCY. >> THANK YOU. ANOTHER QUESTION FROM ANTONIO FRIAS. DID YOU COLLECT DATA ON THE RADIAL ARTERIES? >> NO. WE DID NOT. >> ANYONE ANTONIO IF YOU'RE ON THE LINE -- HAVE YOU PARTICULARLY SEEN ANYTHING INTERESTING IN THE RADIAL ARTERIES WITH YOUR MRI WORK OR IS THIS BASED ON THE MICRO BUBBLE WORK IF YOU WANT TO COME ON THE LINE AND CHAT? >> I WAS COMMENTING BASED ON THE MICRO BUBBLE WORK AND THE MODEL MODELING WORK. >> I THINK THE DIFFICULTY -- ALFRED WOULD YOU PROPOSE THERE WOULD BE A WAY OF MEASURING THE RADIAL ARTERIES? BECAUSE THE MICRO BUBBLE WORK IS ABSOLUTELY FASCINATING SAYING THAT MIGHT BE WHERE THE PATHOLOGY LIES. >> IT'S REALLY HARD TO SEPARATE THEM AND MEASURE THEM ON ULTRASOUND BECAUSE OF ALL OF THE COMPLEXITY OF THE NETWORK THAT WE SEE. I DON'T THINK IT'S EASY TO ISOLATE THEM AND SEPARATE THE SPIRAL FROM A RADIAL ARTERY COULD BE DIFFICULT BASED ON THE IMAGE. NOW WE'RE GROUPING -- ALL ARTERIES BASED ON THE -- COMING DOWN ON THE PLACENTA BUT IT'S HARD TO DIFFERENTIATE. WE HAVE DATA ON THE LARGE VESSELS COMING INTO THE PLACENTA IT'S REALLY HARD TO SEE BUT WE HAVE THIS DATA THAT WE HAVE NOT ANALYZED YET. >> BUT YOU'RE USING THE STANDARDIZED METHOD. >> CORRECT. >> DIANE HAS ASKED HOW ARE YOU CAPTURING THE VOLUMES IN THE LATE SECOND AND THIRD TRIMESTER. BECAUSE THAT IS ONE OF THE THINGS THAT CAME UP IN OUR DISCUSSION. >> THEY WERE ONLY IN THE FIRST TRIMESTER. AND VOLUME OF THE PLACENTA WERE ONLY IN THE FIRST TRIMESTER. LATER ON IT BECOMES DIFFICULT. >> LOVELY. THANK YOU. IF ANYONE HAS ANY QUESTIONS FOR PROFESSOR CAR HILL COULD YOU EITHER RAISE YOUR HAND OR POP IT IN THE CHAT BOX. BECAUSE WE'RE INUNDATING -- >> DID YOU NOTICE REGIONAL DECREASES IN DENSITY WITH PLACENTAL AGE? >> GREAT QUESTION. WE HAVE THE ABILITY TO DO SO. WE HAVE NOT BECAUSE THE DATA IS THE AVERAGE OF THE SPIRAL ARTERIES THAT WE'VE SEEN AND WE'VE DIVIDED THE PLACENTA INTO THE CENTRAL PORTION WHICH IS AROUND A CORD INSERTION ABOUT A THIRD AND THEN THE LOWER SEGMENT. SO FOR THIS DATA WE'VE USED THE AVERAGE BUT WE'RABLE TO ANALYZE IT BUT WE'VE NOT DONE THAT YET. >> THAT HAS BEEN SOMETHING THAT I THINK GRANT BURTON AND I HAVE DISCUSSED WHEN WE TALKED ABOUT THE SPIRAL ARTERIES. DO THEY START IN THE MIDDLE AND THEN GO OUT AS THE PLACENTA GROWS OUT OR DOES THE PLACENTA GROWS AS THE UTERUS IS EXPANDING. I DON'T THINK ANYONE HAS GOTTEN THAT ANSWER. DID YOU GET ANY INSIGHT. >> I DON'T KNOW, SALLY. >> SORRY. I'M INTERROGATING YOU. >> I DON'T KNOW -- I THINK WE'RE ABLE TO IDENTIFY ABOUT 7-8 SPIRAL ARTERIES IN THE FIRST 13 WEEKS SO WE SHOULD BE ABLE TO DEFINE ANY DIFFERENCES BETWEEN THE PA RIFF RALPH ONES AND THE CENTRAL ONES. >> COOL. OKAY. THERE IS A QUESTION FROM WESLEY LEE. DID YOU NOTICE ANY DIFFERENCE IN THE ELASEING ON FREE WHEN THERE WAS MATERNAL OBESITY. ANY EFFECT? >> VERY GOOD QUESTION. I WAS HOPEFUL THAT THE TOPOGRAPHY BASED ON THE DATA THAT IS GOING TO BE A STRONG MARKER OF PLACENTAL DISEASE. BECAUSE THERE ARE SEVERAL STUDIES LOOKING AT PREECLAMPSIA AND DIABETES AND SO FORTH THAT FOUND SIGNIFICANT DIFFERENCES BETWEEN CASES AND CONTROLS LIKE THREE TO FOUR FOLD DIFFERENCE. WE DID NOT FIND ANY DIFFERENCE AS YOU CAN SEE AS I'VE SHOWN YOU FROM THE DATA. I DON'T KNOW IF OUR SAMPLE SIZE FOR DISEASE IS LOW AND THERE MAY BE A NUMBER OR BASED ON OUR DATA BUT WE ARE GOING TO LOOK AT THESE PREGNANCIES THAT HAVE SIGNIFICANT -- PREECLAMPSIA AND SO FORTH TO ISOLATE THEM AND SEE IF WE'RE ABLE TO SEE CHANGES AND THAT COULD BE IMPORTANT TO INFORM FUTURE STUDIES. SO WE HAVE NOT ANALYZED THE DATA BY MATERNAL WEIGHT. THAT'S AN IMPORTANT THING. WE CAN DO THAT TO SEE IF THERE ARE DIFFERENCES. >> ONE LAST QUESTION BEFORE WE MOVE ON TO PROFESSOR CAR HILL. IN TERMS OF LOOKING AT YOUR OUTCOME DATA DID YOU FIND YOU HAD SIGNIFICANTLY LESS CASES. Preeclampsia than you were anticipating because this actually seems to be a fairly common finding for ultrasound studies and that raises a whole interesting question. >> WE DEFINED LESS EVEN THOUGH IN OUR RECRUITMENT WE HAD TWO ARMS. RECRUITING NORMAL PREGNANCIES AND PREGNANCIES WITH PRIOR COMPLICATIONS. I WAS SURPRISED AND WE EXTENDED THE STUDY. INITIALLY IT WAS CLOSE TO 500 PATIENTS. BUT ANOTHER 100 PATIENTS INCREASED THE NUMBERS OF PREGNANCIES WITH COMPLICATIONS. IT IS ON THE LOWER SIDE TO FIND CLOSE TO 100 PATIENTS OUT OF 600 WITH COMPLICATIONS. WE MODELED THE STUDY BASED ON THE NEW STUDY DESIGN AS CONSTITUTING CASES TO BE ABLE TO HAVE A NUMBER OF PREGNANCIES IS REASONABLE TO STUDY WITHIN THE TIME PERIOD FOR THE GRANTS. >> GREAT. THANK YOU SO MUCH. >> THANK YOU, SALLY. >> PROFESSOR CAR HILL. A COUPLE OF QUESTIONS. ONE FROM HELEN JONES WHO SAID WONDERFUL PRESENTATION. WHAT WOULD YOU EXPECT THE IMPACT OF IMPAIRED FETAL HEART FUNCTION TO BE ON YOUR UMBILICAL COLLECTION. >> WE USED A SUB GROUP. HOPING THAT THERE IS NOT AN IMPACT OF IMPAIRED HEART FUNCTION AND WE HAVE ABOUT 20 PREGNANCIES WITH CON AGAIN THE TALL HEART DEFECTS. I HAVE NOT LOOKED AT THE DATA SO I DON'T KNOW THE ANSWER BUT IT'S SOMETHING THAT WE WANT TO LOOK AT MORE CLOSELY. AND THE NEXT QUESTION -- MATERNAL BLOOD PRESSURE. I DON'T THINK BASED ON HOW OUR METHODOLOGY WORKS THAT THE MATERNAL BLOOD PRESSURE ITSELF WOULD IMPACT THE PULSE PRESSURE WAVES BUT IT'S SOMETHING THAT WE HAVE QUITE A FEW WOMEN WHO THEY HAD PREECLAMPSIA AS WELL AS -- PATHOLOGY SO, ITS SOMETHING THAT WE CAN LOOK AT. A GOOD QUESTION. >> AND THINKING ABOUT THE WAVE REFLECTION. YOU CAN SEE THERE WAS A CORRELATION WITH POSITIVITY INDEX. ARE THESE TWO FEATURES INDEPENDENT? DO YOU HAVE OTHER THINGS. THE AREA UNDER THE CURVE AND YOU COULD IMPROVE THAT. DO YOU HAVE ANY IDEAS -- HAVE YOU DONE THAT. DO YOU HAVE ANY PILOT DATA ON THAT. >> FROM THE DATA I PRESENTED -- ADDING UMBILICAL CORD PULLS SERVE IT INDEX -- WE HAVE A WHOLE SET OF PATIENT THAT'S HAD MORE MILD PATH ALLERGY. -- DO YOU THINK THIS WILL BECOME OR BECOME THE MEASURE THAT WE WILL BE DOING TO TRY AND WORK OUT A TIME OF DELIVERING IN A POTENTIALLY GROWTH RESTRICT FETUS? >> THERE IS STILL A LOT OF WORK TO BE DONE IN TERMS OF THE VARIABILITY AND REPEATED MEASUREMENTS. THERE IS A LOT THAT WE WOULD NEED TO DO. BECAUSE WE'RE ALSO COLLECTING THIS -- WE HAVE TO MOVE THE TRANSDUCER FROM END-TO-END ON THE CORD THERE IS A TIME DELAY SO THINGS ARE CHANGING. WE'RE HOPING WITH NEW TECHNIQUES THAT WILL GET BETTER QUALITY DATA SO YES I THINK IN THE LONG RUN BECAUSE OF THE FACT THAT IT'S JUST CLINICAL SYSTEMS RIGHT NOW WE WOULD HOPE TO ABLE TO INCLUDE IT. THERE IS A BIG DEMAND FOR HIGH QUALITY DATA. THE WAVE FORMS NEED TO BE AND WE HAD TO GET RID OF A LOT OF WAVE FORMS WHEN WE FIRST STARTED THIS STUDY SO, THAT IS SOMETHING THAT WOULD NEED TO BE MADE. IT'S VERY IMPORTANT FOR THE SO NOTHING OFFICERS TO KEEP IN MIND. -- >> -- LIKE THE AORTA. IS THAT POTENTIALLY GOING TO BE ABLE TO AFFECT WHAT YOU'RE SEEING WITH THE POSTERIOR PRESENTER. >> SORRY IS THAT A QUESTION FOR ME? >> YES. SORRY. I DIDN'T MAKE IT CLEAR BECAUSE IT CAME FROM PROFESSOR -- >> ARE WE SEEING ANY MATERNAL VASS COULD YOU LAYER TEE THAT COULD IMPACT ON THE WAVE REFLECTION. >> I'M NOT SURE. >> WHETHER MAYBE LINDSEY MAYBE THAT PULLS ASIANS FROM THE AORTA ARE PRESENTED. >> IT'S NOT SOMETHING I'VE THOUGHT OF BEFORE BUT IT'S A GOOD POINT. I DON'T THINK WE I'LL HAVE TO THINK ABOUT THAT A BIT FURTHER. >> FANTASTIC. THANK YOU. >> I THINK WE'VE GOT NINE MINUTES LEFT. AND WE CAN OPEN THE FLOOR TO DISCUSSIONS FROM THE ULTRASOUND GROUP. DAVID HAS SUGGESTED WE ASK WHAT IS THE LOW HANGING FRUIT FOR THE USE OF ULTRASOUND. IS IT TRAINING? LOWER COST DEVICES? DOES ANYONE WANT TO HOP IN WITH THIS ONE? >> I CAN TRY SALLY TO ANSWER THAT. THE MAIN ISSUE IS TRAINING AND HAVTRAIN --INGAND SUSTAINABILITY AND HAVE STRONG DATA THAT ULTRASOUND IMPACTS OUTCOMES. SO I WOULD SAY TRAINING IS KEY AND -- AS THEY'VE DONE THROUGH THEIR OUTREACH PROGRAM HAS WORKED IN INTRO INTRODUCING ULTRASOUNDS IN SETTINGS WHERE THAT COULD BE HELPFUL AT LEAST SCREEN FOR HIGH RISK PREGNANCIES AND DIRECT THOSE TO A PLACE WHERE RESOURCES ARE AVAILABLE. BUT IT'S COMPLICATED. IT'S VERY COMPLICATED BECAUSE THERE ARE A LOT OF CULTURAL ISSUES. A LOT OF SOMETIMES HINDRANCES AS MOM HAS TRANSPORTATION TO GET TO THE BIRTHING CENTER. IS SHE AVAILABLE TO HAVE BABY-SITTING. THERE ARE MANY FACTORS. BUT IN MY EXPERIENCE CERTAINLY TRAINING IS KEY. BECAUSE THE AVAILABILITY OF THE EQUIPMENT IS MORE AVAILABLE NOW THAN IT WAS 10-15 YEARS GO. BUT YOU HAVE TO MAKE SURE THE TRAINING AND THE SUSTAINABILITY OF THE EQUIPMENT OVER TIME. >> YES. ANY OTHER ULTRASOUND GROUP PARTICIPANTS WHO WOULD LIKE TO WITH A IN, COMMENT ON THIS? -- WHO WOULD LIKE TO WEIGH WEIGH IN OR COMMENT ON THIS. *. THE HAND-HELD ULTRASOUND WHERE YOU CAN TURN YOUR SMARTPHONE INTO A MONITOR IS FANTASTIC AND IF WE CAN COMBINE THAT WITH THE AI TECHNOLOGY THAT IS ALLOWING RECOGNITION, AUTOMATED FETAL -- RECOGNITION OF A PLACENTA WOULD POTENTIALLY UNDIAGNOSED -- FETAL -- AND ENABLE WOMEN T GET THE HELP. ANYONE ELSE WANT TO COMMENT ON THAT OR ANY OF THE OTHER THINGS THAT WERE RAISED. WE HAD A FASCINATING CONVERSATION ABOUT WHY WE DO ULTRASOUND THE WAY THAT WE DO IT. WE'RE SO USED TO HAVING A HAND-HELD PROBE AND GIVING THE PATIENT THE DIAGNOSIS. AND THE IDEAS THAT CAME UP FOR MULTIPLE IT WILL TRANSDUCERS SPATIALLY RANGED. SORT OF ULTRASOUND COMPUTER. AND IT MAY TAKE LONGER BUT THERE WAS AN EXPERIENCE THAT WOMEN MAY BE PREPARED TO WAIT FOR THAT AND CERTAINLY IN PRIVATE CONVERSATIONS I THINK ANNA DAVID WAS SAYING THAT SHE FELT FROM HER PATIENT PARTICIPATION GROUPS THAT PEOPLE WOULD BE PREPARED TO WAIT LONGER. ANNA DID YOU WANT TO SAY SOMETHING ABOUT THAT? >> THANKS, SALARY. THIS WAS SOMETHING THAT WE WERE DOING AS PART OF A GROUP, TWO STUDIES WHICH HAVE BEEN TWO PROJECTS FUNDED BY THE UK. DEVELOPING A SYSTEM OF TWO OR THREE ULTRASOUND PROBES THAT SIT AROUND THE MOM'S ABDOMEN AND PRODUCE SIMULTANEOUS CANS AND THE IDEA IS TO IMPROVE PARTICULARLY CARDIAC ASSESSMENT AND THE WORK THAT I'VE BEEN DOING ON FETAL SURGERY AND WE WERE PART OF A PUBLIC DIALOGUE ABOUT WHAT DO PATIENTS THINK ABOUT HAVING A POTENTIAL DIAGNOSES AND DOING OFF-LINE PROCESSING RATHER THAN HAVING THE SEE NOTHING FOR GIVING THE DIAGNOSIS. YOU NEED TO HAVE SOME OF KIND OF HUMAN INTERACTION BUT IT MIGHT FREE UP SO NOTHING OFFICERS AND GIVE FEEDBACK. 7 -- FREE UP SONOGRAPHERS AND GIVE FEEDBACK. FOR MRI SOMETIMES WE HAVE TO WAIT FOR A DIAGNOSIS. WE DON'T THINK BY THE WITH ULTRASOUND. >> I THINK THIS REALLY HIGHLIGHTS ONE OF THE THINGS THAT CAME VERY STRONGLY OUT ABOUT OUR DISCUSSION AND THAT IS ULTRASOUND IS SOMETHING THAT WE'VE ALL USED. WE GOT USED TO IT AND HOW IT FUNCTIONS. BUT ACTUALLY FROM ANNA IS TALKING ABOUT THE FINDS THE TOMOGRAPHY RESEARCH AND THE FACT THAT PATIENTS WOULD BE MORE PREPARE TO WAIT FOR RESULTS THAT MAYBE THE SINGLE BIGGEST THING THAT WE NEED TO DO TO PUSH RESEARCH FORWARD IS TO STOP ASSUMING THAT JUST BECAUSE WE'VE ALWAYS DONE IT THAT WAY IT'S THE RIGHT WAY AND THAT MAYBE WE NEED TO START THINKING ABOUT THINKING OUTSIDE THE BOX. WHY SHOULD IT BE A SINGLE PROBE. WHY NOT A WHOLE ARRAY OF PROBES. AND GOING BACK TO SOMETHING THAT ELLEN SAID ABOUT USING MRI FOR PLACENTA A CRETE. MAYBE THE FUSION THAT WE'RE SEEING IN SO MANY OTHER SPECIALTIES -- MAYBE THAT CAN BE USED WITH PLACENTA ACRETA TO IMPROVE OUR UNDERSTANDING. TO POTENTIALLY MAKE ULTRASOUND BETTER. I DON'T KNOW. THESE ARE JUST IDEAS. WE HAVE ABOUT A MINUTE LEFT. IF ANYONE WOULD LIKE ANY OTHER QUESTIONS -- ELLEN IS JUST AGREED. YES. POTENTIAL OF COMBINED ULTRASOUNDS AND MRI AND WE'VE GOT THE PERFECT EXCUSE IN PLACENTAL RESEARCH TO DO MORE MRI'S BECAUSE THE STAKES ARE SO HIGH. I THINK ON THAT NOTE WE'RE APPROACHING WELL IT'S 8:15 IN THE UK TIME. I THINK IT'S 3:15 WITH YOU AND I THINK DAVID AND KATHRYN PROBABLY WON'T NEED TO DRAW THIS TO A CLOSE AND THANK EVERYONE WHO WAS INVOLVED IN THE PANEL DISCUSSION AND OUR TWO FABULOUS SPEAKERS TODAY. THANK YOU. >> THANK YOU SO MUCH SALLY. THAT WAS FANTASTIC AND THAT WAS SUCH A GREAT PANEL DISCUSSION. YOUR WORK HAS BEEN AMAZING BRINGING THIS ALL TOGETHER AND BRING ALL OF THESE GREAT IDEAS INTO OUR FOREFRONT. WE WILL NOW GO ON A BRIEF BREAK AND INVITE YOU TO RETURN AT ABOUT 3:25 EASTERN. AND WE'LL HAVE THE SLIDE UP WITH THE LINK FOR IDEA BUT IF YOU'RE ON THE VIDEO CAST AND YOU LOOK DOWN IN THE DESCRIPTION IT'S RIGHT THERE AS WELL SO THAT WE CAN HELP SOLICIT ALL OF THE WONDERFUL IDEAS AND WHETHER IT'S YOUR OWN NEW IDEA OR A COMMENT ON SOMETHING THAT IS ALREADY THERE. ENJOY YOUR BREAK. >> WELCOME BACK EVERYBODY. THE NEXT SESSION WILL BE FOCUSED ON CIRCULATING FACTORS. AND WE'LL BEGIN WITH AN OUT BRIEF OF THE PREMEETING -- PLANNING DISCUSSION AND THIS WILL BE GIVEN BY DR. LESS MYATT AND DR. IRINA BUHIMSCHI. >> THANK YOU, DAVID. I'M GOING TO START ON THE CIRCULATION FACTORS. AND I WOULD LIKE TO THANK ALL OF THE PARTICIPANTS WHO TOOK PART IN THE PREMEETING DISCUSSIONS AND I'M GOING TO SHARE THIS PRESENTATION NOW. WE WANT TO OUTLINE WHAT THE GROUPS RECOGNIZED AS KIA ACHIEVEMENTS AND BREAKTHROUGHS. * SO THE FIRST IS A DESCRIPTION OF POTENTIAL ROLES OF PLACENTAL EXTRA CELLULAR VESICLES. A FIELD THAT IS NOT WITHOUT ISSUES CURRENTLY. OBVIOUSLY DUE TO DEFINITION OF SIZE OF THE ROLES. ADVANCES IN CIRCULATING RNAs. AND THE DESCRIPTION OF THE EXISTENCE OF ROLES WITH VARIOUS ESSENTIAL MICRO RNAs. CONSTANT ADVANCES IN GENOMICS, SEQUENCING TECHNOLOGIES, AND NOW WE HAVE SINGLE CELL TECHNOLOGY SPATIAL -- ETC. AND THE CHALLENGE IS TO KEEP THESE ADVANCE IN TECHNOLOGIES AND APPLY THEM TO THE PLACENTAL FIELD. OBVIOUSLY MANY DIFFERENT STUDIES OF THE PLACENTA ACROSS THE PAST FEW YEARS AND WE ARE NOW STARTING TO SEE ADVANCES THAT INTEGRATE THE INFORMATION ACROSS THESE DIFFERENT STATUSES. WE'RE ALSO AWARE OF THE ROLE OF PLACENTA SEXUAL DIMORPHISM. THE DETROIT GROUP SEVERAL YEARS AGO DESCRIBED PLACENTAL CELLS THAT WERE SHED INTO THE CERVIX AND THE CAPABILITY OF USING THESE FOR PREDIAGNOSTICS. AND THIS IS TRANSLATED THROUGH THE USE OF -- FAILURES AND BIOMARKERS. WE'VE ALSO LEARNED HOW WITH GAUGE OUR SUCCESSES AGAINST ADVANCES IN OTHER FIELDS SO WE CAN USE THE CANCER FIELD AND THE CARDIOVASCULAR DIAGNOSTIC FIELD AS A YARD OF STICK TO GAUGE OUR SUCCESSES AND FAILURES IN OUR OWN STUDIES AND WE'VE LEARNED ALONG THE WAY FROM OUR VALIDATION STUDIES LOOKING AT THE BIOMARKERS -- AND WE'VE OBVIOUSLY LEARNED VALUABLE LESSONS FROM THE VALIDATION STUDIES THAT CAME OUT AFTER THE PLACENTAL MICRO BO MICROBIOME WAS DISCOVERED. THE BIOLOGICAL NOISE ACROSS GESTATION. AND THE FACTORS THAT INFLUENCE THIS. AND THE ALSO THE VARIABILITY WITH THE INDIVIDUAL LENGTH OF GESTATION ANY MEASUREMENTS. WE'RE STILL HELD BACK BY THE RELATIVELY POOR CLINICAL DEFINITION OF PREGNANCY DISEASES AND THE PET AGAIN IN A TEE AND WE'RE TRYING TO TAKE STEPS TO ADDRESS THIS. THAT SAID WE HAVE AN INCOMPLETE UNDERSTANDING OF THE SOURCE AND SIGNIFICANCE OF EXTRA -- OF CELL FREE RNA AND THE POTENTIAL USE AS BIOMARKERS AND THIS IS NOT HELPED BY THE REALLY LACK OF MEASUREMENTS DURING AND OUR UNDERSTANDING OF THE FIRST TRIMESTER. THIS STILL REMAINS A BLACK BOX AND WE'VE HEARD IN BOTH THE MRI AND THE ULTRASOUND DISCUSSIONS THIS MORNING. WE'RE LIMITED BY ITS VERY EASY TO GET PLACENTAL TISSUE AT DELIVERY BUT WE'RE STILL LACKING THE ABILITY TO STUDY PLACENTAL FUNCTION ADEQUATELY IN THE FIRST TRIMESTER. GET HOLD OF SAMPLES. WE ALSO HAVE A RELATIVELY POOR UNDERSTANDING OF HOW THE PLACENTA ADAPTS TO THE ENVIRONMENT AND THAT COULD BE THE EXTRA CELLULAR ENVIRONMENT SO THE EXPOSURE OF PREGNANT WOMEN TO ENVIRONMENTAL TOXINS. CHEMICALS ETC. BUT ALSO THE MATERNAL ENVIRONMENT ITSELF. AND OFTEN WHEN WE SEE CHANGES IN THE PLACENTA FROM THE NORMAL SCENARIO WE THINK THESE ARE INDICATE I HAVE OF SOME PATHOLOGY BUT THEY MAY BE ADAPTIVE. -- IF WE'RE TO INCLUDE THESE WE ARE GOING TO HAVE TO BE ABLE TO DO MULTIPLE ADJUSTMENTS FOR ALL OF THESE VARIOUS FACTORS THAT POTENTIALLY IMPACT PLACENTAL FUNCTION. ALSO AN INCOMPLETE UNDERSTANDING OF HOW PLACENTAL HEALTH INFORMS LONG-TERM OUTCOMES. THIS IS NOT JUST LONG-TERM MATERNAL OUTCOMES BUT ALSO LONG-TERM FETAL OUTCOMES UNDER THE DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE HYPOTHESIS AND AGAIN A FIELD THAT NEEDS FURTHER EXPANSION AN. SO WHAT ARE THE OPPORTUNITIES TO FILL THE GAPS IN KNOWLEDGE? THERE IS ALMOST OTHER THAN VERTICAL AGREEMENT -- -- UNIVERSAL AGREEMENT -- TO DISCUSS THIS THAT WE * NEED TO DEVELOP LARGE LONGITUDINAL COHORTS TO ALLOW UNBIASED DISCOVERY. WE NEED TO PAY ATTENTION TO PATIENT AND DISEASE HETEROGENEITY. WE NEED A BIG COHORT TO DEVELOP UNBIASED APPROACH TO UNDERSTAND THE BASICS OF PREGNANCY OUTCOMES BUT A LONG WITH THIS WE NEED TO COLLECT THE CORRESPONDING COMMITTAL DATA IN A STANDARDIZED HARMONIZED FORMAT. WE ALL HAVE DATA THAT IS VERY DIFFICULT TO COMBINE BECAUSE IT'S COLLECTED IN DIFFERENT FORMATS AND DIFFERENT DATA DICTIONARIES. THAT IS OBVIOUSLY OUR ABILITY TO DO THAT -- IN A STANDARDIZED HARMONIZED FORMAT FROM THE GET-GO AND THE DATA THAT WE COLLECT IS LIMITED. WE NEED TO EXPAND THE TYPE AND AMOUNT OF CLINICAL DATA THAT WE COLLECT. ONCE WE COME TO TRANSLATE BIOMARKER DISCOVERIES WE NEED TO PROVIDE A ROAD MAP FOR THE DISCOVERY FOR THE QUALIFICATION AND VALIDATION THAT PEOPLE CAN REFER TO AND SET UP A STANDARD FOR THE QUALIFICATION VALIDATION AND PERHAPS WE NEED ALSO TO PROVIDE A FAIL FAST REPRODUCIBILITY PIPELINE OF PROMISING BIOMARKERS. BUT FOR THIS EFFORT WE NEED TO ALSO INVEST IN HUMAN CAPITAL. SO THE FIRST THING WE IDENTIFY WE NEED TO PROVIDE INDIVIDUALS WITH VERY STRONG TRAINING. IT'S OBVIOUS THERE IS MORE AND MORE APPLICATION TO EVERYTHING THAT WE DO FROM EXAMINING THE DATASETS TO INTEGRATING EVERYTHING SO WE'VE GOT TO PROVIDE MORE AND MORE INDIVIDUALS WITH THAT SORT OF TRAINING AND WE ALSO NEED TO PROVIDE INDIVIDUALS TRAINED IN MULTI-DISCIPLINARY COLLABORATIONS IN TEAM SCIENCE. NONE OF US ARE TRAINED IN THE WIDE RANGE OF DISCIPLINES THAT WE NEED NOW TO TACKLE THIS PROBLEM SO WE'LL TO HAVE PROVIDE INDIVIDUALS TRAINING. I'D LIKE TO HAND OVER TO MY CO-PRESENTER. >> THANK YOU, LES. AND THANK YOU EVERYONE WHO PARTICIPATED IN OUR PANEL. IT'S BEEN QUITE AN INTERESTING AND VERY ENTERTAINING DISCUSSION SO I WILL CONTINUES WITH THE TECHNICAL GAPS. AMONG THESE -- THE INCONSISTENCY -- METHODS OF ISOLATION AND CHARACTERIZATION HAS BEEN AT THE FOREFRONT. BUT ALSO THE -- THE ABILITY TO HOLD IMPORTANT BIOMARKERS. SO THERE NEEDS TO BE MORE CONSISTENCY IN IDENTIFYING THE METHODS THAT WORK. IMPORTANT ABOUT MOVING FORWARD ON PROTEIN BIOMARKERS -- THAT ARE ABLE TO MEASURE LOWER LEVELS HAVE RAPID RESULT TURN AROUND AND ARE COST EFFECTIVE. THERE ARE LESSONS THAT COULD BE LEARNED FROM OTHER BIOMARKERS. WHERE BIOMARKERS HAVE BEEN MADE IMPORTANT -- SUCH AS CANCER OR PRIMARILY CANCER WHERE MOST OF THE RESEARCH AND BIOMARKERS HAS BEEN. SO THE RULES OF THE FIVE Rs IS THE RIGHT TEST, TIMING, PATIENT, COST AND CLINICAL PURPOSE. AND IMPORTANT IN THE FIVE Rs IS THE COST AND RECOGNITION THAT THINKING ABOUT LOW COST DIAGNOSIS IS ALSO IMPORTANT. ANOTHER THING THAT CAME IN OUR DISCUSSION WAS THE CHALLENGES IN THE LINING -- LACK OF STANDARDS. WHICH COULD BE CLASSIFIED AS PREANALYTICAL GAPS AND THEN LACK OF UNDERSTANDING. HOW SAMPLE PROCESSING AND SAMPLE AGE SO DURATION FROM COLLECTION TO ANALYSIS COULD CHANGE. PREANALYTICAL ISSUES. AND ALSO THE ABILITY TO LINK CLINICAL DATA. THE OPPORTUNITIES TO FILL THESE GAPS FOR EXAMPLE PROVIDING HOMO GET IN A TEE. -- ABILITY TO USE MULTI-MODEL APPROACHES. TO INTEGRATE DATA FROM DIFFERENT BIOMARKERS AND THE STATISTICS THAT GO ALONG WITH THAT. THEN MODELS FOR LOW COST NONINVASIVE SAMPLING. FOR EXAMPLE SUCH AS THE ONE DEVELOPED WITH THE CERVICAL CELLS THAT SHOWS PROMISE AND THE NEED FOR WELL DEFINED SAMPLES FOR GESTATIONAL AGE AND THE THINKING TO USE DIFFERENT SPECIMEN TYPES SUCH AS URINE AND SALIVA. SO WHAT THE GROUPIE FIND AS CHALLENGES. THE IDEA THAT WE NEED FIRST TO UNDERSTAND THE -- PATHOLOGY AND THEN LOOK AT CLINICAL ABILITY. ALTHOUGH THERE HAVE BEEN EXAMPLES WHERE ONE DOES NOT NEED TO FULLY UNDERSTAND. THE PHYSIOLOGY TO MOVE FORWARD WITH CLINICAL USE. THE FACT THAT THERE ARE FRAGMENTED KNOWLEDGE -- IT'S USUALLY HELD BY DIFFERENT PEOPLE SO INTEGRATING REQUIRES MULTI-TEAM APPROACH AND MULTI-PI APPROACH WHICH ARE DIFFICULT. MANUFACTURERS -- FEW OF THESE QUALIFY BIOMARKERS SO THERE ARE CERTAIN CHARACTERISTICS FOR PROTEIN OR RNA. THE NOTION OF BIOLOGICAL VARIABILITY AGAIN CAME OVER AND OVER IN OUR DISCUSSIONS AND THE FACT THAT THE PLACENTA ESPECIALLY I IN THE ANALYTES THAT IT PRODUCES THERE COULD BE WIDE RANGE OF VARIABILITY WITHIN THE NORMAL RANGE AND THE RATIONAL OF BIOMARKERS IN THE ABSENCE OF EFFECTIVE TREATMENTS AGAIN IT WOULD BE PROBLEMATIC TO THINK ABOUT. THE NEED FOR BIOREPOSITORIES -- WITH SAMPLES AND ARM ONIZED CLINICAL DATA AND -- * THE NEED FOR CONSENSUS OF CLINICAL PRIORITIES. THE RIGHT PATIENT IN THE RIGHT CLINICAL USE SO PERHAPS IF WE WERE THINKING THAT THAT COULD BE THE FIRST PLACE TO START WOULD BE A CONSENSUS OF LINES ON WHAT IS THE CLINICAL PRIORITY. SO BASICALLY THE WHO DO WE NEED TO TREAT. AND WHY. AND THEN THERE WOULD BE A CONSENSUS OF STAKEHOLDERS. WHO ARE THE STAKE HOLDERS. WHO WOULD BENEFIT THE MOST FROM THE CIRCULATING FACTORS IF THEY MOVE ON AS CLINICAL BIOMARKERS. MOST OF THE BIOMARKERS DISCOVERED ARE USED TO FACILITATE TREATMENTS OR BETTER TREATMENTS OR TOXICITY TO PREDICT TO BE -- TOXICITY. NO ONE PERSON CAN HOLD THIS KNOWLEDGE. AND AN IMPORTANT FACTOR TO CONSIDER IS MANUFACTURERS ARE CONSIDERED BUT VERY FEW ARE SUBJECT TO -- APPLICATIONS AND THAT'S AN IMPORTANT PART OF MOVING SOMETHING FORWARD INTO CLINICAL USE. SO AGAIN THERE WAS A LOT OF DISCUSSION ON OPPORTUNITY AND WHERE ARE THE LOW HANGING FRUIT. THE IDEA BLUE SKIES RESEARCH BASICALLY FOCUSED ON UNDERSTANDING MORE ABOUT PATHOPHYSIOLOGY OF THE PROCESSES THAT ARE OF INTEREST TO THE NLM VERSUS A BLIND RESEARCH APPROACH. CLINICAL RESEARCH. MOVING FORWARD WHAT WE KNOW AND THE CONCLUSION WHICH WAS UNANIMOUS IS BOTH HAVE -- MERIT. BUT WE SHOULD FOCUS ON CLINICAL PROBLEMS. BUT THAT SUCCESSES WITHOUT BIOLOGICAL UNDERSTANDING HAVE BEEN POSSIBLE. WE NEED TO LEARN FROM MISTAKES IN OTHER FIELDS AND WE NEED TO THINK ABOUT THE FDA FRAMEWORK OF QUALIFICATION, METHOD AND MEASUREMENT. THINK ABOUT THE PLACENTA AS THE WINDOW TO FEATURE HEALTH AND INCENTIVISE THE PRIVATE SECTOR. THANK YOU. >> FANTASTIC. THANK YOU. THAT WAS A GREAT SUMMARY. SORRY. GOT A LITTLE STRESSED OUT. WENT A LITTLE OVER TIME. AND IT IS OKAY SO I INVITE PEOPLE TO RESPOND TO THIS AND REFLECT ON WHAT WAS SAID ON IDEA SCALE AND NOW WE'LL HAVE TWO PRESENTATIONS AND THE FIRST WILL BE BY DR. PAHEMSIA. >> THANK YOU, DAVID. * >> THANK YOU SO MUCH FOR THE INVITATION TO PRESENT ON THE CONGO RED TEST. I HAVE SOME DISCROWS US. -- DISCLOSURES. SO I WILL TALK A LITTLE BIT VERY SHORT ABOUT OUR LAB APPROACH TO BIOMARKER -- AND WHY THAT HAS BEEN ABLE TO LEAD US TO SOMETHING NEW. A PATHWAY THAT WE DEVELOPED AND HELPED LINK TO PREECLAMPSIA. A LITTLE BIT ON THE STORY OF THE CONGO RED TEST AND WHY THAT IS RELEVANT TO PLACENTA AND PREGNANCY OUTCOME AND HUMAN HEALTH. SO OUR LABS APPROACH OF WHICH WE PUBLISHED STARTS WITH -- COMEICS. HOW THESE BIOMARKERS CAN IMPROVE DIAGNOSTICS IN THE CURRENT STATE OF CLINICAL PRACTICE. SO WE CALL THAT CHALLENGE PHASE. AND THE GOAL OF THAT IS TO IDENTIFY SUBGROUPS WHICH WILL BENEFIT FROM DIFFERENT APPROACHES. SHOULD THOSE BECOME AVAILABLE. IN PARALLEL OUR LAB WORKS ON UNDERSTANDING HOW THESE BIOMARKERS HELP UNDERSTAND WHAT IS NEW IN PATHO PHYSIOLOGY. WHY THEY OCCUR AND HOW THEY LINK WITH WHAT WE ALREADY KNOW. THE TRANSITIONAL PHASE. IF WE UNDERSTAND THAT WE COULD PROVIDE BETTER TREATMENT TARGETS FOR FUTURE CLINICAL TRIALS THAT TOGETHER WITH WHAT WE LEARN FROM OUR CHALLENGE IN THE FUTURE COULD LEAD US TO WHAT IS CALLED THE -- APPROACH. WE PUBLISHED ON THIS WORKFLOW. MORE THEORETICAL LEVEL. BUT WHAT IS IMPORTANT IS THAT IN THIS PHASE WE USE CAREFULLY SELECTED PATIENTS. AND AIM FOR 100% ACCURACY. WE LOOK FOR MOLECULES THAT ARE EXPRESSED IN HIGH LEVELS THAT SEGREGATE TWO 100% ACCURACIES. WHEREAS IN THE CHALLENGE PHASE WE LOOK AT UNSELECTED CONSECUTIVE PATIENTS. BASED ON INTENT TO DIAGNOSE AND WE ONLY LOOK FOR 70%. THE IDEA BEING THAT CURRENT DIAGNOSTIC PRACTICE IS IMPERFECT SO IF YOU REACH 100% THE DIAGNOSTIC TEST IS NOT NEEDED WHEREAS WITH 70% ACCURACY YOU WOULD BE ABLE TO FIND BETTER SUBGROUPS. IN THE TRANSLATIONAL PHASE WE GROUP PATIENTS BY MOLECULAR FENO TYPES. OUR COMPLETE PIPELINE APPROACH STARTS WITH PATIENT COLLECTION WHICH WE'VE STARTED ABOUT 20 YEARS AGO AND ACQUIRING HIGH QUALITY REPOSITORY AND ACCESS TO CLINICAL SAMPLES TO WHICH WE HAVE ACCESS TO PATIENT'S RECORDS THAT WE CAN GO BACK AND LOOK FOR OUTLIERS FOR TEXAS. -- EXAMPLE. A LOT OF OUR NEEDS WE OFTEN ASK WHAT DO YOU THINK -- YOU'RE UNSURE. WHAT DO YOU THINK COULD BE DONE BETTER? WE PRIORITIZE MARKERS FOR VALIDATION AND WE FILE FOR DISCLOSURE AND AFTERWARDS WE PUBLISH. AND THEN AT THE SAME TIME WE MOVE TOWARDS THE TRANSITIONAL PHASE WHERE WE TRY TO UNDERSTAND THE PATHWAYS AND WHAT ARE THE BIG PICTURE APPLICATIONS AND POTENTIAL TREATMENTS. AT THE SAME TIME HOW CAN WE SIMPLIFY THE METHODS AND WE ASK ABOUT USABILITY AND HUMAN FACTORS. IN THE SAME TIME WE COLLABORATE WITH PRIVATE SECTOR TO MOVE TOWARDS LICENSING -- AND A LOT HAS TO DO WITH COOPERATE WITH THE OFFICE OF TECHNOLOGY -- AT THE ACADEMIC INSTITUTIONS WHICH HAVE BEEN CRITICAL IN OUR SUCCESS SO FAR. AND WE LOOK FORWARD TO VALIDATION BY OTHERS WHICH ULTIMATELY IS THE PROOF THAT SOMETHING VALUABLE IS THERE WHEN OTHERS CAN REPEAT WHAT YOU HAVE DONE. SO I WILL TELL THE STORY HOW IT STARTED. MORE THAN 10 YEARS AGO. WE WERE CONDUCTING STUDIES OF -- ON FLUID AND WE WERE INTERESTED IN URINE. BY APPLYING SIMILAR -- THESE ARE TWO TRACINGS OF PRO HOMEIC BIOMARKERS. WE OBSERVED THAT CERTAIN SIGNALS WERE PRESENT AND EXTREMELY HIGH WITH WOMEN WITH PREECLAMPSIA AND THEY WERE INCREASING WITH DISEASE SEVERITY. SO WE WERE INTERESTED IN WHAT THOSE WERE AND WE IDENTIFIED THOSE USING -- TOF AS FRAGMENT. SO WE BASICALLY FOUND THE DEGRADATION. SO THAT MAY NOT HAVE SEEMED AS INTERESTING BECAUSE CERTIFY PINA 1 -- ANOTHER IMPORTANT OBSERVATION IS THERE WERE TWO FRAGMENTS THE TWO FRAGMENTS THAT WERE BIOMARKERS WHICH WAS THIS AND THIS FACTOR. WHERE CLEAVAGE WITHIN THE -- -- HELP TIED -- THERE WERE TWO RIGHT HERE. AND BASICALLY THERE IS NO OTHER COMBINATION IN THE HUMAN PROTEOMIC. -- SO WE REALIZED THAT THESE MAY MEAN -- COAGULATED FORMS. SO WHICH LED US TO THE IDEA THAT PERHAPS WHAT WE WERE SEEING WAS AGGREGATED MISS FOLDED STATE. WITH THAT CORROBORATED WITH THE IDEA THAT PERHAPS WHAT WE WERE SEEING MAY NOT ONLY -- SEE THIS -- BUT PERHAPS -- WHETHER THIS MISS FOLDING WAS MORE OF A GENERAL FEATURE IN PREECLAMPSIA OR LINKED JUST TO SERPINA 1 BECAME AN INTERESTING QUESTION. ONE EXPERIMENT WE WERE THINKING OF WAS PERHAPS WHAT WE WERE HAVING HERE WAS THE DEFECTIVE PROTEIN HOMO STATION US -- HOMEOSTASIS. THEY NEED TO BE IN A PROPERLY FOLDED STATE. HOWEVER IF THIS GOES ARRAY THEY TURN INTO AGGREGATES OR WHAT IS KNOWN AS MISS FOLDED STATE. WHICH ARE PRONE TO AGGREGATION IN PROPER CELL TRAFFICKING, CELL TOXICITY, CELL DEATH. AND THEY OCCUPY SPACE AND WHAT DOES THIS HAVE TO DO WITH PREECLAMPSIA? WELL THAT WAS NOT REALLY KNOWN AT THAT TIME BUT WHAT WAS KNOWN WAS THAT THIS PROCESS IS AT THE BASES OF MANY DISEASES SUCH AS OF WHICH THE MOST WELL-KNOWN AND MOST STUDIES IS ALZHEIMER'S DISEASE. THE PROTEIN -- AND OTHERS ARE NOW INVOLVED. IN OUR WORK -- IS NOW FOCUSED ON IDENTIFYING THE PROTEINS THAT MISS FOLD IN PREECLAMPSIA. ONCE WE HAVE MADE THIS CONNECTION A WHOLE NEW UNIVERSE HAS OPENED. SO PART OF THIS WAS THE RECOGNITION THAT THERE IS A COMMON FEATURE OF MISS FOLDED PROTEINS. IT'S A DYE THAT WAS SYNTHESIZED FOR CELL YOU ON LOWS. CONGO FILL YA. IF WE APPLY IT AND THEN WASH AWAY -- ALL THAT WOULD BE LEFT -- AS YOU CAN SEE HERE. THEREFORE ONE COULD DEVICE A VERY QUICK TEST FOR MEASURING YOU ARE ONE CONGOPHILIA BY LOOKING AT THE RATIO BETWEEN THE OPTICAL DENSITIES OF THE DOTS AFTER THE WASH VERSUS THE ONE BEFORE THE WASH AND WE CALL THAT THE CRR. 7 SO WE PUBLISHED THIS IN 2014 IN A PAPER WHERE WE AMOUNTED SEVERAL LINES OF EVIDENCE THAT PREECLAMPSIA IS A PROTEIN MISS FOLDING DISEASE SIMILAR TO A PROCESS PREVIOUSLY DESCRIBED IN ALZHEIMER'S AND WE'VE ALSO SHOWN THAT THE PLACENTA HAS THE APPARATUS TO GENERATE -- AS WELL AS THE PLACENTA WITH PREECLAMPSIA -- SO I WOULD BE VERY INTERESTED TO WORK WITH THE MRI GROUP OR ULTRASOUND GROUP. THAT IS FOR THE FUTURE. SO NOW THINKING ABOUT THE FOUNDATION PHASE. THESE ARE THE RESULTS FROM THE FIRST CONSECUTIVE ENROLLMENT WHERE WE SCREENED OVER 500 WOMEN SHOWING THAT WOMEN WHO DELIVERED FOR PREECLAMPSIA HAD LIAR CONGOPHILIA LEVELS. -- IT WAS SUPERIOR THAN OTHER URINE ANALYZES. AND NEXT -- IN ORDER TO SIMPLIFY THIS MEASUREMENT WE FOUND THAT ACTUALLY IF ONE INSTEAD OF PUTTING THE URINE MIXED -- ONE WOULD PUT IT ON A PLANE MILES PER HOUR BUT NOT ANY PAPER SO A SPECIFIC PAPER WITH CERTAIN QUALITIES IN ABSORB ANCE. AS I MENTIONED EARLIER CONGREGATE WAS DISCOVERED AS A RED DYE. IN NEGATIVE -- ONE WOULD GET A TIGHT DOT. IN THIS CASE IT HAS ALREADY BOUND THE AGGREGATES. AND AGAIN WE FILED FOR A PATENT AND WE MADE A LITTLE KIT WHICH WE NAMED IT THE CONGREGATE DOT KIT WHICH WAS MADE IN OUR LAB AT THAT TIME. AND LATER WHEN MY LAB MOVED TO NATIONWIDE CHILDREN'S HOSPITAL WE PUBLISHED IN COLLABORATION WITH OHIO STATE A STUDY OF OVER 300 PROSPECTIVE WOMEN WHERE WE'VE CLINICALLY TRAINED RESEARCH NURSES, TESTED PATIENTS AT POINT OF CARE -- AND WE'VE SEEN SENSITIVITIES AROUND -- BETWEEN 90-92 PERCENT. IN THIS UNSELECTED COHORT. OTHERS HAVE -- REPLICATED WHAT WE'VE SEEN. MOST OF THE STUDIES IN THE RESEARCH LAB DIRECT FORMAT -- THERE WERE SEVERAL PAPERS AND ONE PAPER WHO ALSO REPEATED WHAT WE REPORTED ON THE POINT OF CARE. AND MOST EXCITINGLY THE STUDY IN INDIA WHERE THEY CONCLUDED THAT IT CAN BE USED TO IDENTIFY PREECLAMPSIA WOMEN. MY LAB HAS CONTINUED TO WORK ON THIS TO IDENTIFY WHAT EXACTLY IS CONGOPHILIA. WE'VE DEVELOPED A METHOD IN WHICH WE CAN PURIFY PROTEINS -- TO IDENTIFY WHAT WE CALL THE MISS FOLD. SO WE COULD IMAGE IT AND IDENTIFY -- AND WE CAN ASK WHAT PROTEINS CONTRIBUTE? WHETHER THEY ARE THE BAD GUYS, CHAPERONES THE GOOD GUYS OR BYSTANDERS. PROTEINS THAT HAVE NOTHING TO DO BUT THEY ARE CAUGHT IN THE STORY. WHAT IS THEIR ORIGIN. CAN WE UNDERSTAND ANYTHING BASED ON THIS AND DOES IT TELL US ANYTHING ABOUT WHERE THIS CASE CAN GO TOWARDS HELP -- TOWARDS SEVERE PREECLAMPSIA OR IS THIS JUST A PREGNANCY COMPLICATED BY HYPERTENSION. WE HAD USED CONGOPHILIA -- FOR MOLECULAR PHENOTYPING. WE IDENTIFIED IN THE URINE -- A COMBINATION OF ABOUT 700 PROTEINS BUT THE COMBINES OF THESE PROTEINS TELL US SOMETHING ABOUT THE CLINICAL PHENOTYPES. SO WOMEN WITH SEVERE -- PREECLAMPSIA ARE CLUSTERED TOGETHER. THOSE WILL HELP CLUSTER TOGETHER AS WELL. AS YOU CAN SEE THERE IS CONTROLS AND -- THIS IS FAR AWAY AND IN MILD PREECLAMPSIA IS ON A TRAJECTORY BETWEEN CONTROLS AND SEVERE PREECLAMPSIA. AND SO DEPENDING ON HOW YOU INVOLVE THE CLINICAL CLASSIFICATION AND INTERSECT THAT WITH THE BIOCHEMICAL CLASSIFICATION YOU HAVE INFORMATION ON WHAT PROTEINS COULD BE USED TO COMBINE THESE INTO A MORE PRECISE MARKER OF TRAJECTORY. ANOTHER QUESTION IS WHERE ARE THESE MISS FOLDED PROTEINS COMING FROM. WE KNOW THAT THEY COME FROM A COMBINATION OF SOURCES. SO IN THE COMBINED -- MULTI-NAMEICS -- COMING FROM THE PLACENTA. SO THERE IS 47 THAT I THAT I THAT ARE PLACENTAL -- OR AGAIN. SOME WERE KIDNEY ORIGIN AND SOME ARE ALSO THE -- ORIGIN AND THAT IS IMPORTANT BECAUSE IT TELLS US THAT THE MUMBO JUMBO THAT WE FIND IN THE URINE COULD BE A COMBINATION OF FETAL PROTEINS CO-AGGREGATED AT THE LEVEL OF COMPLEXITY WHICH IS A BIT MIND BOGGLING. BY THE COULD BE WORKED AROUND. SO WHAT WOULD BE THE NEXT STEPS? CAN WE USE IN CLINICAL PRACTICE WHAT WE'VE SEEN? CAN WE USE FOR EXAMPLE THE CONGO RED TEST. WITH THE ASSISTANCE OF A COLLABORATOR WHO WAS ABLE TO MOVE -- THE INTELLECTUAL PROPERTY -- SO THE DIAGNOSTIC TEST HAS BEEN LICENSED FOR COMMERCIAL DEVELOPMENT -- INITIALLY BY YALE AND THEN THEY RAISED FUNDS AND HAVE RAISED FUNDS TO PERFORM CLINICAL STUDIES IN PREPARATION FOR -- REGULATORY CLEARANCE. SO I THINK THAT IS ONE STEP WHERE THIS COULD BE MOVED TO A DEVICE THAT HOPEFULLY WILL BE USED CLINICALLY. MY ROLE IS TO MAKE THAT ACCESSIBLE TO EVERYONE. EQUITABLE. SO WITH ASSISTANCE AND HELP FROM -- PARTNERS I WAS FORTUNATE TO RECEIVE A GRANT FROM -- TO TAKE THE CONGO RED TEST INTO LOW-INCOME COUNTRIES AND THE RESULTS HAVE BEEN PUBLISHED BUT WE'VE SHOWN THAT THIS TEST CAN BE PERFORMED ANYWHERE IN THE WORLD. EVEN IN LOW RESOURCED COUNTRIES AND THAT WAS VERY EXCITING US TO. THIS STUDY WAS CONDUCTED IN TERTIARY CARE FACILITIES. THERE IS A TREMENDOUS DIFFERENCE ON HOW PREECLAMPSIA IS DIAGNOSED BETWEEN COUNTRIES AND THERE IS LOTS TO IN TERMS OF CLINICAL ACCESSIBILITY IN DIFFERENT SETTINGS. AND NEXT STEP IS WE WERE FORTUNATE TO RECEIVE HERE A GRANT TO TAKE THE TEST TO THE CLINICS IN UGANDA SO THAT WOULD MOVE IT TO -- CARE AND HOPEFULLY WE CAN FIND WOMEN WHO ARE NOT PICKED UP BY HEALTH SYSTEM. SO I HOPE THE STORY WILL BE LITERALLY UNFOLDING. IN THE MATTER OF THE CONTEXT OF USE OF THE CONGO RED TEST BOTH IN HIGH AND LOW-INCOME COUNTRIES. WHAT WOULD BE THE USABILITY -- MAXIMUM IMPACT? CAN WOMEN THEMSELVES USE IT? WHAT WOULD BE THE TYPE OF TEST WOMEN WOULD WANT? WHAT WOULD BE THE IMPLICATION -- FOR INDEX PREGNANCY. THERE ARE WINDOWS OPENED BECAUSE DRUGS HAVE BEEN DEVELOPED FOR ALZHEIMER'S THAT COULD PERHAPS BE USED FOR PREGNANT WOMEN AND WHAT -- -- FOR PREVENTION? THERE ARE LOTS OF THINGS TO DO. IF WE WOULD JUST HAVE TIME. THANK YOU AND I WILL TAKE QUESTIONS. >> THANK YOU SO MUCH DR. BUHIMSCHI. AND SO WE'LL MOVE ON AND OUR NEXT SPEAKER IS DR. >> THANK YOU VERY MUCH. FOR REALLY MAKING THIS A GREAT PLATFORM FOR COLLABORATION -- AS WE CAN EMBARK FROM THIS MEETING. I REALLY HOPE THAT NEXT YEAR WE WILL BE ABLE TO BE IN PERSON BUT IT'S GREAT TO HEAR EVERYBODY AND SEE THE PICTURES OF MANY US. IN A SHORT PRESENTATION I'M GOING TO TALK ABOUT PLACENTAL EXTRA CELLULAR VESICLES. WHY WE HAVE THEM AND WHAT THEY DO AND WHAT ARE THE CHALLENGES AND OPPORTUNITIES IN THE FIELD. SO IF YOU WANTED TO SEND A BIOLOGICAL PACKAGE IN THIS CASE A MOLECULE OF RNA FROM CELL A TO CELL B AND WANTED TO COMBINE IT MORE EFFICIENTLY WITH A SMALL RNA MOLECULE OR PROTEIN OR OTHER SIGNALING MOLECULES AND WE WANT THEM ALL TO BE PROTECTED SO WE PUT THEM IN A PACKAGE. 7 WITH A BAR CODE TO BE ABLE TO TARGET OUR PACKAGE THAT WE'RE GOING TO SEND FROM THIS CELL TO THIS CELL. AND USING THIS BAR CODED PACKAGE WE'RE GOING TO TRY TO REACH OUR TARGET AND TRANSMIT THE BIOLOGICAL SIGNAL. THIS IS WHAT IT'S GOING TO LOOK LIKE IN TRANSMISSION AND THAT IS WHAT IT'S GOING TO LOOK LIKE WHEN WE SEND THOSE PACKAGES FROM THIS CELL TO THE NEXT CELL. I'M GOING TO TAKE US ALL ON A BUS TOUR OF WHAT HAPPENS TO VESICLES AND WHAT ARE THE CHALLENGES IN THE FIELD WHEN WE SEND THEM FROM THE ORIGINATING CELL TO THE RECIPIENT CELL. I'M TAKING ADVANTAGE OF A PLATFORM THAT DR. -- MARGOLIS HAVE PUBLISHED AS A REVIEW PAPER AS YOU CAN SEE HERE. SO IMAGINE THIS IS THE DONOR CITY OR DONOR CELL IN OUR CASE AND THIS IS THE RECIPIENT CELL AND WE'LL HAVE 8 DIFFERENT BUS STOPS ALONG THE WAY TO TALK ABOUT THE CHALLENGES AND OPPORTUNITIES ABOUT WHAT WE KNOW ABOUT EXTRA CELLULAR VESICLES. SIZE DIVERSITY. YEARS WHEN THE FIELD EMERGEED MANY OF US IN OUR OWN WORK WE'VE BEEN THINKING ABOUT THREE MAJOR TYPES OF EXTRA CELLULAR VESICLES AND THIS IS THE WORK AND THE REVIEW. WE'VE BEEN THINKING ABOUT -- MICRO VESICLES -- AND THE SMALLER ONES. AND EACH ONE IS MADE IN ITS OWN WAY. HOWEVER RECENT WORK FROM OTHERS -- THIS IS A PAPER BY A GROUP -- WITH THE USE OF NEW TECHNIUES THAT ARE NOT COMMONLY USED. AND THEY CHARACTERIZED NUMEROUS TYPES FAR EXCEEDING. YOU CAN SEE SOME OF THE SIZES AND THE NAMES. SO NOW WE KNOW THAT IN THE FIELD SHOULD NOT JUST THINK ABOUT TWO OR THREE OR FOUR TYPES BUT A MUCH BROADER LANDSCAPE OF EXTRA CELLULAR VESTIBLES THAT MAY MEDIATE ACTIVITY. OUR NEXT STOP IS WITHIN THE CELL ITSELF AND THAT IS PROBABLY ONE OF THE BIGGEST CHALLENGES AND TO PURELY DEFINE -- EXTRA CELLULAR VESICLES. ISOLATE BEFORE THEY PRODUCE BECAUSE ONCE THEY ARE PRODUCED WE USE SIZE TO DEFINE THE VESICLES. BUT IF THERE IS A WAY TO IDENTIFY THEM BEFORE THEY ARE ACTUALLY RELEASED FROM THE CELL TO THE EXTRA CELLULAR OR -- BLOODSTREAM -- THE ANALYSIS WOULD BE MUCH MORE ROBUST HOWEVER THIS IS NOT TECHNICALLY FEASIBLE AT THE CURRENT STAGE. WE DO KNOW THAT THE EXTRA CELLULAR VESICLES THEY CONTAIN DIVERSE REPERTOIRE OF MANY TYPES OF MOLECULES. AND YOU CAN SEE THE DIFFERENT TYPES OF RNAs. IN A TYPICAL SIZE IN THIS CASE THIS IS THE NUMBER THAT WE CAN GET IN THE BLOODSTREAM AND THIS IS OUR NUMBER OF VESICLES THAT WE CAN GET -- THIS IS ROUGHLY THE DIAMETER -- AND HAS BEEN CONCURRED BY OTHERS THAT THIS KIND OF VESICLE CONTAIN ABOUT 25,000 SMALL RNA SPECIES. THERE IS A GREAT DIVERSITY OF NUMBER OF MOLECULES IF YOU FACTOR THIS INTO PRO TEAMS AND OTHER MOLECULES THAT CAN BE HARBORED WITHIN A VESICLE. OUR THIRD BUST STOP IS ON THE CARGO LOADING AND IT HAS BEEN CONTROVERSIAL. THERE IS SELECTIVE LOADING OR IS THE LOADING REFLECTIVE OF WHAT YOU CAN FIND. THIS IS BY RANDY -- FROM THE UNIVERSITY OF CALIFORNIA AT BERKELEY WHERE HE SHOWED THAT THIS LINE -- CAN SELECTIVELY LOAD -- INTO EXOH ZOOMS. * THIS IS CONTROVERSIAL. WE COULD NOT FIND IT. WE MEASURED THE CARGO -- WE FOUND THAT WHATEVER -- WHATEVER WE FOUND IN THE CELLS WERE EXPRESSED IN A SIMILAR MANNER. AND YOU CAN SEE HERE THE VERY NICE CURVE. IT'S ALSO FOUND IN THE -- CELLS. HERE YOU CAN SEE THE CARE OF COMPARING THOSE TWO -- THE CURVE IS A BEAUTIFUL CORRELATION. SO THIS REMAINS A CONTROVERSIAL ISSUE IN THE FIELD ABOUT SELECTIVE PACKAGING INTO -- EXTRA CELLULAR VESICLES. OUR NEXT IS ON THE TRAFFICKING AND PROBABLY ONE OF THE HOTTEST AREAS OF RESEARCH BECAUSE WHEN YOU HAVE ACCESS TO THE BLOOD OR TO THE ACCESS TO THE FLUID THEN YOU CAN MEASURE EXTRA CELLULAR VESICLES AND THE CARGO AND USE IT AS A BIOMARKER FOR DISEASE. WE HAVE BEEN USING A MOUSE MODEL TO TRY TO DECIPHER THE TRAFFICKING OF EXTRA CELLULAR VESICLES AND IN THIS CASE -- HOW THEY TRAFFIC BETWEEN THE PLACENT, THE MOTHER AND THE FEET THAT SIDE. TO SUMMARIZE WE FOUND BEAUTIFUL TRAFFICKING FROM THE PLACENTA TO THE MOTHER'S SIDE. SOME FROM THE MOTHER INTO THE PLACENTA AND ALSO SOME FROM THE PLACENTA INTO THE FETAL COMPARTMENT. THIS WAS VERY INTERESTING TO US AND WE'LL CONTINUE THESE STUDIES. HOWEVER I HAVE TO ADMIT THAT THE FIELD OF EXTRA CELLULAR FLUID -- AND BLOOD ASSESSMENT IS BASED ON THE NOTION OF THESE VESICLES THAT ARE PRODUCED CAN BE USED AS A BIOMARKER FOR DISEASE AND LITERATURE PROBABLY MORE THAN 95% OF THE LITERATURE IN OUR FIELD CENTERS ON USING -- AS BIOMARKERS FOR DIFFERENT DISEASES SO I WOULD NOT FOCUS ON THESE STUDIES RIGHT NOW BUT THIS IS ONE OF THE RICHEST AREAS OF RESEARCH. I DO WANT TO MOVE ON TO THE NEXT BUS STOP WHICH CENTERS ABOUT VESICLES AND COMPARED TO VIRUSES. THIS IS AN INTERESTING AND FOOD FOR THOUGHT FOR US. BECAUSE WHEN YOU THINK ABOUT EXTRA CELLULAR VESICLES AND VIRUSES THEY ARE SIMILAR. THE MEMORIES ARE SIMILAR. PROTEINS THAT ARE EXPRESSED IN BOTH ARE SIMILAR. EVEN THE CARGO IS SIMILAR AND THIS IS A CARTOON -- WHERE WE CAN SEE THAT THE VESICLES AND VIRUSES GET INTO THE CELLS THROUGH THE SAME PATHWAYS GETTING TO THE ZONES AND THEY LEAVE THE ZONES WHERE THEY RELEASE THE CARGO TO HAVE SOME BIOLOGICAL FUNCTION WITHIN THE CELLS -- AND THEN GET EXTRUDED FROM THE CELL TO INFECT THE NEXT CELL. THIS IS PARTICULARLY INTERESTING FOR US BECAUSE WE'VE DONE SOME WORK AS A TOOL TO PROTECT THE PLACENTA IN THE PREGNANCY AGAINST DIFFERENT VIRUSs. THIS WAS A VERY FRUITFUL GRANT FOR OUR RESEARCH. SO THIS SIMILARITY -- AND THIS IS FROM THE FUNCTIONAL POINT OF VIEW AND VERY INTERESTING FOR US AND WE CONTINUE TO PURSUE THIS STYLE OF RESEARCH. OUR NEXT BUS STOP NUMBER SIX IS ON CELL DELIVERY. DO THEY GET INTO THE CELLS AND CAN THEY DO THEIR BIOLOGICAL FUNCTIONS WITHIN THE TARGET CELLS. USING DIFFERENT TOOLS WE HAVE BEEN USING LABELED -- -- ONE OF THE KEY PROTEINS WHICH IS DOUBLE LABELED AND WE CAN TRACE HOW THEY ARE GET INTO CELLS AND NOW PURSUING THE BAR CODE THAT MEDIATES THE INTERRUPTION OF THE EXTRA CELLULAR VESICLES WITH THE TARGET CELLS. THEY'VE PURSUED THE DIFFERENT PATHWAYS THAT THEY USE TO GET INTO TARGET CELLS AND THE BOTTOM LINE WAS -- USING DIFFERENT RNAs WE FOUND THAT THE NAME OR PATHWAYS THAT MEDIATE THE -- ARE AND -- AS YOU CAN SEE HERE AND THE OTHERS -- PROBABLY PLAY A MINOR ROLE IN THE -- PLACENTAL -- -- THE TARGET OF PROCESSING. VERY NICE THAT THE -- GETTING TO CELLS BUT ARE THEY PROCESSED. HERE THE WORK OF -- AND OTHERS FOCUS ON SHOWING SPECIFICALLY SHOWING HOW THOSE EXOH ZOOMS -- CAN LOCALIZE * AND HERE BY COLLABORATION -- THEY WERE ABLE TO QUANTIFY THE ENTRY OF THE EXOH ZOOMS INTO DIFFERENT COMPARTMENT WITHIN THE EARLY -- ZONES AND LATER -- WERE ABLE TO QUANTIFY HOW THE HUMAN -- LOCALIZE IN DIFFERENT COMPARTMENTS IN THE TARGET CELLS. NOT ONLY CAN WE SHOW THEY GET INTO THE CELLS BUT THEY GET INTO THE RIGHT TARGETS AND PROCESSED IN THE RIGHT WAY. THIS IS GREAT BUT ARE THESE ABLE TO LEAVE THE -- AND -- THIS IS OUR LAST BUS STOP IN OUR TOUR HERE WHERE WE TRY TO LOOK AT INTEREST CELLULAR FUNCTION -- *. JUST TO REMIND US THIS IS A DIFFERENT CARTOON TO BE ABLE TO EXECUTE THE FUNCTION THOSE -- -- -- END ZOOM. BUT TO INTERACT WHICH IS CALLED P BODY. TO DEGRADE MRNAs OR INHIBIT TRANSLATION INTO THE MATURE PROTEINS AND IN THIS STUDY I WAS ABLE TO SHOW THAT THOSE MICRO RNAs -- CAN BIND PROTEINS AND WE SEE NICE ENRICHMENT WHERE THEY ARE DELIVERED THROUGH PLACENTAL EXZOOMS. THIS IS THE END OF THE BRIEF BUS TOUR. WE TALKED ABOUT HOW THE VESICLES ARE BEING PRODUCED. WE TALKED ABOUT THE DIVERSITY IN CARGO LOADING. WE TALKED ABOUT THE EASIEST TARGET FOR OUR RESEARCH WHICH IS IDENTIFYING BIOMARKERS THROUGH THE TAKING ADVANTAGE OF THE TRAFFICKING OF THOSE MICRO RNAs WITHIN VESICLES AND WE TALKED ABOUT THE POTENTIAL ACTION OF THOSE VESICLES AND THEIR BIOLOGICAL CARGO ON CELL ENTRY, PROCESSING AND POTENTIAL BIOLOGICAL FUNCTION. SO I'M NOT SURE THERE IS A FIELD CALLED VES ICU LOMICS BUT I THINK THIS FIELD IS RIPE FOR INVESTIGATION. STARTING FROM IDENTIFYING BIOMARKERS BUT GOING INTO MUCH MORE PROFOUND BIOLOGICAL ACTION IN HEALTH AND DISEASE. THANK YOU VERY MUCH. I'LL JUST MENTION THE PEOPLE THAT CONTRIBUTED TO OUR STUDIES WHICH I SHOWED THROUGHOUT MY BRIEF PRESENTATION. THESE ARE PEOPLE FROM OUR LAB WHO PARTICIPATE IN OTHER STUDIES. COLLABORATORS. >> EVERYBODY YOU HEARD IT HERE FIRST. I LOVE IT. THANK YOU FOR THIS TALK ON A SET OF MOLECULES THAT HAVE MORE COMPLEXITY THAN MIGHT SEEM OBVIOUS AT FIRST LOOK. WE HAVE TIME FOR A SHORT PANEL DISCUSSION LED BY DR. BUHIMSCHI. WE INVITE YOU TO TURN ON YOUR CAMERAS IF YOU LIKE. CHIME IN ON THE TALK ON SOMETHING THAT THEY HEARD OR THE SUMMARY OF THE PREMEETING DISCUSSION THAT YOU HEARD ABOUT AT THE BEGINNING AND AGAIN I ALWAYS INVITE PEOPLE TO GO TO IDEA SCALE TO GET IN A LOT OF ACTION -- TODAY. I TURN IT BACK OVER TO YOU. >> THANK YOU, DAVID. SO IF YOU COULD PUT ANY QUESTIONS IN CHAT I WILL GET TO THEM. WE HAVE ONE COMMENT FROM DR. BIANCHI REGARDING THE NIH'S -- EFFORTS ON COVID. THAT HAVE LED TO -- COMBINATION OF DATA ELEMENTS. I THINK THAT IS IMPORTANT AND WE ARE HOPING TO UNFORTUNATELY WE DIDN'T NEED COVID FOR THAT BUT WE'RE HOPING THAT RESEARCH WILL PROGRESS DUE TO THIS HARMONIZATION. I HAVE A QUESTION REGARDING THE CARGO OF THE RNA THAT GO TO THE FETUS AS OPPOSED TO THE PLACENTA. DO YOU KNOW IF IT'S CARGO DRIVEN OR -- TAG DRIVEN? >> IF IT'S CARGO DRIVEN? >> THE VESICLES THAT GO TO THE FETUS VERSUS THE ONES THAT GO TO THE MOM. ARE THEY THE SAME OR DIFFERENT? >> I DON'T THINK WE HAVE ENOUGH INFORMATION PRODUCTION OF VESICLES THAT GO TO THE FETAL SIDE BUT QUITE A BIT OF INFORMATION THAT GOES TO THE MATERNAL SIDE BECAUSE OF EASE OF ACCESS AND NUMBER OF PEOPLE IDENTIFYING BIOMARKERS. MORE LIKELY THE TWO THINGS THAT WILL DETERMINE SHUTTLING TO THE MOTHER'S SIDE OR THE FETAL SIDE WOULD BE "A" WHICH CELLS PRODUCE THE VESICLES. IT'S EASY TO SHED VESICLES INTO THE MOTHER'S SIDE. WHEREAS -- FOR A VESICLE AR -- TO CROSS TO THE FETUS SIDE -- THE SECOND PART THAT IS CRITICAL IS MOLECULES ON THE SURFACE OF THE VESICLES. WITH WE LIKE TO CALL SOMETHING CAN BE BAR CODED OR OTHER PROTEIN EMBEDDED IN THE COME PART MEANT THAT DEFINES THE VESICLE. THESE ARE THE TWO MAJOR COMPONENTS THAT DEFINE THE DIRECTIONALITY OF THE TRAFFICKING. >> THANK YOU. QUESTION FROM -- TARA MARGON. -- COULD THEY BE DUE TO SELF-FRAGMENTS MISTAKEN AS EXOH ZOOMS. *. >> IF THE QUESTION IS CELL FRAGMENTS -- COULD CONTAIN MICRO -- THE ANSWER IS YES. WE MEASURE THEM AND CAN SEE THEM. WE DON'T KNOW IF IT'S A TARGETED PACKAGING. BUT IT IS CLEAR TO US BASED ON THE STUDIES THAT OTHER VESICLES -- AND POTENTIALLY OTHER IMPORTANT SIGNALING MOLECULES. >> THANK YOU. FROM HELEN JONES. WILL THE METHOD OF ISOLATION OF THE VESICLES WILL IT RESULT IN DIFFERENT PROFILES? SHOULD METHODS BE MORE STANDARDIZED? >> THERE ARE DIFFERENT METHODS RIGHT NOW IN THE FIELD TO ISOLATICE.BECAUSE THE PUREST OPERATION MAY LEAD TO THE BETTER FINISH OF THE CARGO. WHEREAS IF YOUR METHOD IS NOT VERY PURE THEN THE LIKELIHOOD OF CONTAMINATION IS GOING TO BE MUCH HIGHER. THERE'S NO DOUBT THAT THE BEST ISOLATION OF THE TECHNOLOGY COULD NOT BE ONLY ACCURATE AND PRECISE BUT ALSO FAST AND AS I MENTIONED WE'RE WORKING WITH BIOENGINEERS TO TRY TO COME UP WITH A SYSTEM -- AND TONY WHO'S AT DUKE HAS BEEN A COLLABORATOR ON THE HPP GRANT COME UP WITH A SYSTEM WHERE WE CAN ISOLATE RAPIDLY -- FROM WHOLE BLOOD AND COME UP WITH A GOOD EVALUATION OF THEIR CARGO. I THINK THIS WORK IS STILL IN PROGRESS. >> THANK YOU. WE KNOW THAT THINGS MAY SEEM DIFFICULT AT THE BEGINNING BUT AS TECHNOLOGY ADVANCES IT'S IMPORTANT TO PUSH TECHNOLOGY SO THAT IT'S MADE SO IT ACTUALLY FOLLOWS PATHOPHYSIOLOGY. I HAVE A QUESTION REGARDING THE CONGO RED TEST. REGARDING HOW EARLY IT WILL WORK IN PREG MANSE. -- PREGNANCY. WE HAVE * TESTED PREGNANCIES EARLY ON TO LATE PREGNANCY AND WE DON'T SEE -- -- OBVIOUSLY WITH PREECLAMPSIA WE -- DETECT AT 20 WEEKS. VERY FEW NORMAL WOMEN ARE CONGO -- ACTUALLY ALMOST NONE ARE IN NORMAL PREGNANCY. SO IF THERE IS ONE SAMPLE THAT IS -- THERE IS HIGHER RISK OF COMPLICATIONS AND WE HAVE THE DATA. BUT WE HAVE A QUESTION WHETHER PREDICTION EARLY ON IN PREECLAMPSIA IS ACTIONABLE IN THE ABSENCE OF TREATMENT. AND THAT IS A SUBJECT OF DISCUSSION IN THE PRELEADING SESSIONS WHERE SHOULD WE FOCUS OUR ATTENTION. SO WITH RESPECT TO THE CONGO RED TEST WE THINK THE ACTIONABLE POINT WITH NOW IN THE CURRENT STATE OF PRACTICE -- -- RULE OUT PREECLAMPSIA. BUT TO ANSWER YOUR QUESTION IT DOES -- SO CONGOPHILIA STARTS BEFORE THE MANIFESTATION OF THE DISEASE. MORE QUESTIONS -- WE HAVE IN THE CHAT LINE. SO MORE QUESTIONS RELATED TO INCREASING SIZE -- SO WOULD SIZE -- IS THE DETECTION SCALE A LIMITING FACTOR IN THE SIZE OF THE VESICLES? >> IF THE QUESTION BUT IS THE DIFFERENT SIZES OF VESICLES I THINK THE ANSWER IS YES AND I THINK RIGHT NOW WE IN COLLABORATION WITH TONY AND OTHERS IN THE FIELD ALSO IN THE CANCER FIELD WHICH IS I'M OOOH, NOT GEE FIELD ARE VERY MUCH INTERESTED IN DEVELOPING NEW TECHNOLOGIES -- ESPECIALLY THE SUBTYPES OF EXOH ZOOMS AND TRY TO IDENTIFY DIFFERENT BAR CODES AND POTENTIALLY DIFFERENT MECHANISM OF ACTION. THIS FIELD IS JUST BEGINNING BUT IT'S CRITICALLY IMPORTANT. IN THE CANCER FIELD EXOH ZOOMS HAVE KEY FUNCTIONS IN DETECTING IN DIRECTING METASTATIC SPREAD. SO I THINK THE FIELD OF EXOH ZOOMS WILL GO FAR BEYOND JUST BIOMARKERS AND THE DEFINITION IS CRITICAL. >> SO ACTUALLY WE'RE RIGHT AT TIME. THERE WAS LOTS OF GOOD THINGS IN THE CHAT AND PEOPLE OUT ON THE VIDEO CAST DON'T SEE IT. I HOPE PEOPLE WILL TAKE COMMENTS THAT WERE NOT COVERED IN THE CHAT ARE AND PUSH THEM TO IDEA SCALE. WE'RE CLOSING IN ON OUR LAST SESSION. BREAKS ARE IMPORTANT. AND WE'LL RECONVENE IN JUST ABOUT 10 MINUTES AT 4:35 P.M. EASTERN TIME. THANK YOU EVERYBODY. >> WELCOME BACK. WE WILL START WITH AN OUT BRIEF BY DR. TONG FROM THE PREMEETING PLANNING PHASE. THE FLOOR IS YOURS. >> OKAY. THANK YOU. CAN YOU SEE ME? >> WE SEE YOU AND HEAR YOU. >> OKAY. THANK YOU. >> THANK YOU VERY MUCH FOR THE INVITATION AND THE OPPORTUNITY TO CHAIR THIS SESSION. I HAD THE PLEASURE AND PRIVILEGE OF CHAIRING THE -- AND IT WAS AN ESTEEMED GATHERING THERE WITH INCREDIBLE NAMES. SO THE SUMMARY OF THE PANEL DISCUSSIONS I SUPPOSE COULD BE GROUPED IN TO TWO SECTIONS. WE PUT IT TO THE GROUP WHAT WAS THE KEEL -- IN DEVELOPING THE BIOMARKER WITH THE CLINICAL CONTEXT IN MIND. THE GROUP AGREED THAT THERE SHOULD BE A FOCUS ON CLINICAL UTILITY. SIMILAR TO THE FIVE RS THAT IS WERE PRESENTED IN THE PREVIOUS PANEL SESSION AND IT'S IMPORTANT TO NOTE THAT LET THE CLINICAL NEED INFORM THE DEVELOPMENT AND GUIDANCE OF NEW BIOMARKER TESTS AND IT WAS NOTED AND PROBABLY QUITE WIDESPREAD IN OUR CURRENT FIELD THAT A LOT OF RESEARCHERS FIND A TEST FIND A MARKER THAT HAS AN ASSOCIATION WITH A DISEASE AND GET EXCITED ABOUT IT WHERE WE SHOULD BE WEARY OF CHASING A MOLECULE MERELY BECAUSE THEY HAVE AN ASSOCIATION WITH THE DISEASE. IT SHOULD BE CLINICALLY USEFUL FOR THE OUTCOME. THE SECOND POINT WHICH WAS NOTED ESPECIALLY BY THE KING'S GROUP -- IS THAT OBESITY, ETHNICITY, SEX AND REGIONAL DIFFERENCES CAN AFFECT THE PERFORMANCE OF A BIOMARKER WHEN APPLIED TO DIFFERENT POPULATIONS. IT WAS NOTED IN THE KING'S EXPERIENCE -- TO SCREEN FOR EARLY ON PREECLAMPSIA AND THEY HAVE TO REJIG THE TEST BECAUSE THERE ARE REGIONAL DIFFERENCES APPARENT EVEN WITHIN THE UK AND SO THEY SHOULD BE TAKING AND DEVELOPING A BIOMARKER. IF YOU OVER SANITIZE YOU COULD BE IN TROUBLE BECAUSE VALIDATION MIGHT FALL SHORT. THE THIRD IS THAT GENERAL VALIDATION AND THE GROUP AGREED THAT VALIDATION OF A BIOMARKER TEST IS USEFUL. THE LITERATURE IS REPLETE WITH PAPERS PROPOSING A BIOMARKER AND THEY'VE IDENTIFIED IT IN ONE POPULATION. AT BEST THAT IS HYPOTHESIS GENERATED. YOU MUST VALIDATE IT IN A DIFFERENT POPULATION. AND A GOOD EXAMPLE AND WILL BE DELIGHTED TO HEAR SOON IS PROFESSOR LEONA FROM HONG KONG AND SHE IS ATTEMPTING TO VALIDATE THE -- TEST IN HONG KONG AND IS COMING UP WITH SOME PERFORMANCE VARIATIONS WHICH SHE IS ATTEMPTING TO OVERCOME BY REWORK THE RANG OF THE TEST. -- POPULATION * VARIANCE AND RELATED TO THE VARIATION -- VALIDATION IS IMPORTANT. POINT FOUR IS KEEP IN MIND THAT TESTS CAN BE MULTI-MODEL AND THAT MAY ENHANCE YOUR DIAGNOSTIC TEST PERFORMANCE. YOU MAY COMBINE WHAT IS CIRCULATING IN THE BLOOD WITH CLINICAL CHARACTERISTICS -- AND MAYBE EVEN IMAGING FINDINGS. PRINCIPALLY ULTRASOUND TESTS. AND INTEGRATE LOTS OF INFORMATION. AND THIS LAST POINT WITH REGARD TO CONSIDERATION IN DEVELOPING A CLINICALLY RELEVANT BIOMARKER TEST RESONATES WITH OUR TEAM. IT'S THAT TEST SHOULD BE DEVELOPED WHERE SPECIFIC TEST PERFORMANCES AND PERFORMANCE THRESHOLDS SHOULD BE KEPT IN MIND TARGETS WHICH WOULD MAKE THE TEST CLINICL USED FOR AND THEREFORE THE CLINICIANS OR THE RESEARCH PROGRAM SHOULD DECIDE WHAT IS THE OPTIMAL SENSITIVITIES -- AND SPECIFICITIES. IF YOU SET IT AT 90% IT'S A 10% POSITIVITY RATE. AND YOU NEED TO KEEP IN MIND THE POSITIVITY PREDICTIVE VALUE OR NEGATIVE PREDICTIVE VALUE. AND ONCE YOU'VE DECIDED WHAT MIGHT BE USED FOR YOU GO OUT AND AIM FOR THOSE TARGETS AND THRESHOLDS ARE LIKELY TO BE DIFFERENT FOR DIFFERENT DISEASES. THE FETAL MEDICINE FOUNDATION I BELIEVE HAS A PREDICTIVE -- OF 15%. THAT IS PRETTY EXCELLENT -- 15% FOR PREECLAMPSIA BUT THAT IS SLEPT GIVEN THAT THE BASELINE INCIDENCE IS ABOUT 1% OR LESS. BUT IF YOU HAD A TEST FOR SGA AND PERFORMED WITH A POSITIVE PREDICTIVE VALUE MAY NOT BE GOOD. IT'S THRESHOLD TARGETS SHOULD VARY ACCORDING TO WHAT DISEASE AND WHAT THE CLINICAL CIRCUMSTANCES IS. SO IN THE NEXT SET -- NEXT FOCUS OF THE PRECLINICAL DISCUSSION WAS REALLY JUST BROAD RANGING QUESTIONS. DOES THE GROUP HAVE ANY THOUGHTS, IDEAS, CONCEPTS REGARDING THE DEVELOPMENT OF BIOMARKERS. AND THE FETAL MEDICINE FOUNDATION GROUP SUGGESTED THAT IT MAY BE VERY PRAGMATIC TO CONSIDER BIOMARKER DEVELOPMENT AT ASY POX ACROSS * PREGNANCY. AS AN EARLY ON SET PREECLAMPSIA 12 WEEK TEST. IN THE MIDDLE 20 WEEK TEST AND THEN 26 WEEK TEST. IT MAY BE USEFUL TO IDENTIFY EARLY ON SET DISEASE AND THAT IS BEING SHOWN WITH SUCCESS IN THE FETAL MEDICINE FOUNDATION TESTING FOR PRETERM PREECLAMPSIA. AT 20 WEEKS AN ULTRASOUND AND THE INFORMATION. AND NOTING THAT A LOT OF TERM DISEASE OR CLINICAL DISEASES SUCH AS FETAL GROWTH PREECLAMPSIA DOES INCREASE SHARPLY IN THE LAST LITTLE BIT OF PREGNANCY OF 36 WEEKS. THERE MAY BE A VALUE OF A 36 WEEK TEST BECAUSE SGA WHERE THE INCIDENCE INCREASES TOWARD THE END OF PREGNANCIES HAS A -- WITH STILLBIRTH. TEST FOR GESTATIONAL DIGITAL. IT WAS PROPOSED THAT THERE WAS A NEED THERE. AND THE DISEASE HAD BEEN BREWING FOR MONTHS. WHILE CHALLENGING IT WAS NOTED THAT IT MAY BE USEFUL TO DEVELOP A BIOMARKER SCREENING TEST TO IDENTIFY THOSE AT RISK OF DISEASES IN LATER LIFE. JUST LOOKING AT THE DOE HEAD CONCEPT. THAT WOULD BE CHALLENGIN CHALLENGE CHALLENGING. -- * AND JUST FROM OUR GROUP AND YOU'LL HEAR LATEYOU WILL HEAR LATER WE'VE BEEN LOOKING AT OTHERS -- WHO ARE TRYING TO DEVELOP A 36 WEEK BIOMARKER. PICK BABIES AT RISK. IT'S NOT THOUGHT TO BE HARMFUL AND THAT MAY DECREASE THE RISK OF STILLBIRTHS FOR BABIES THAT ARE NOTED TO HAVE AN ELEMENT OF PLACENTAL INEFFICIENCY. THE GROUP SPENT TIME AND USING A BOLD CONCEPT WHICH I PROMISE TO JUST PUT IT TO THE NIH MEETING. IT WAS -- PRESENTED STRONGLY. THE CONCEPT A BOLD NEW INITIATIVE OF A MAJOR COHORT -- THE GROUP WAS UNANIMOUS IN PRODUCING THIS. A VERY LARGE COLLECTION CALLED A PREGNANCY MOONSHOT. TENS OF THOUSANDS WHERE THERE WILL BE DEEP PHENOTYPING, AGREED PROTOCOLS. MULTI-PRONG AND THEN SHARED WITH ALL RESEARCHERS. IT WAS NOTED THAT THESE LARGE COHORTS HAVE BEEN DONE BEFORE AND HAVE NOT SHOWN ANYTHING USEFUL BUT THAT COULD BE OVERCOME IF IT WAS A CLEVER EXECUTIVE TEAM AND THE FACT THAT -- THIS IS IN EXCESS OF -- BUT IF WE ALL CAMPAIGNED THEN THAT MIGHT BE SOMETHING THAT CAN GAIN LEGS AND LEAD TO A LOT OF DISCOVERIES. SO, THAT IS A SUMMARY OF WHERE WE'RE UP TO AND I THINK IT'S MY PLEASURE TO INTRODUCE OUR TWO SPEAKERS. AND THE FIRST ONE IS DR. DR. TUUHEVAHA KAITJU-LINO. >> THANK YOU. >> THANKS, DAVID AND THANK YOU TO KATHRYN AND DAVID FOR THE INVITATION TO SHARE SOME OF OUR WORK HERE TODAY. I'M PRESENTING FROM MELBOURNE IN AUSTRALIA SO I WOULD LIKE TO START OFF BY ACKNOWLEDGING THE TRADITIONAL OWNERS OF THE LAND FROM WHICH I'M PRESENTING. AND PAY RESPECTS TO THEIR ELDERS PAST, PRESENT AND EMERGING. SO TODAY I'M PRESENTING AS HEAD OF DIAGNOSTICS DISCOVERY AND THE REVERSE TRANSLATION IN PREGNANCY GROUP. I'M A BASIC SCIENTIST BUT I WORK CLOSELY WITH SOME WONDERFUL CLINICIAN SCIENTISTS IN THE SPACE AS WELL AS ENGINEERS AND DATA ANALYSIS EXPERTS. SO TODAY THE IDEAS AND THE DASHES THAT I'M SHARING ARE FROM THE ENTIRE TEAM. SO TODAY I WILL PRESENT ON PLACENTAL INSUFFICIENCY AND STILLBIRTH AND OUR SEARCH FOR BIOMARKERS IN THIS SPACE. ALSO FOR BIOMARKERS IN PREECLAMPSIA. SO I JUST WANTED TO QUICKLY MENTION CONFLICTS OF INTEREST. SO THE CLINICAL IMPERATIVE TO IDENTIFY SMALL BABIES COMES FROM THE FACT THAT WE KNOW FETAL GROWTH RESTRICTION IS ONE OF THE SINGLE RESPECTERS FOR STILLBIRTH AND THIS IS SHOWN IN THIS GRAB HERE WHERE WE'RE LOOKING AT STILLBIRTH RISK. AND YOU CAN SEE FROM THE RED LINE WHICH REPRESENTS THE SMALL GESTATIONAL AGE -- LESS THAN TENTH PERCENTILE. THAT SMALL BABIES HAVE A TWO TO THRETHREEFOLD RISK. NOW WE KNOW IN ORDER TO REDUCE STILLBIRTH THE KEY REALLY IS BEING ABLE TO DETECT THESE SMALL BABIES AND THIS IS SHOWN HERE. HERE AGAIN LOOKING AT STILLBIRTHS PER THOUSAND PREGNANCIES. IMPORTANTLY WE KNOW FROM THIS WORK THAT IF WE LOOK AT WHETHER THE PREGNANCIES WERE IDENTIFIED OR NOT YOU CAN SEE THAT SIMPLY DETECTING WHICH BABIES WAS SMALL EFFECTIVELY HALVESES THE NUMBER OF STILLBIRTHS HAPPENING. IT'S VERY IMPORTANT IF WE'RE WANTING TO REDUCE STILLBIRTH THAT WE'RE ABLE TO DETECT WHICH BABIES ARE SMALL. THERE ARE TESTS THAT ARE BEING USED EACH AND EVERY DAY. PERHAPS MOST COMMONLY IS FUNDAL HEIGHT MEASURES. AS WELL AS THE SUES OF SERIAL FETAL BIOME TREE. * NEITHER PERFORM WITH HIGH ACCURACY AT IDENTIFYING SMALL BABIES. FUNDAL HIGH MEASURES ONLY PICK UP AROUND 20% TO 30% AND WE KNOW THAT THESE NUMBERS ARE BECOMING WORSE AS WE SEE INCREASING BMIs. AS WELL AS SERIAL FEATURE BIOME TREE CAN ONLY PICK UP ABOUT 50%. SO OUR TEAM HAS BEEN INTERESTED IN IDENTIFYING PLACENTAL POSSIBLE COOLS THAT COULD BE MEASURED BY A SIMPLE BLOOD TEST. A WINDOW INTO WHAT IS HAPPENING WITHIN THE PREGNANCY AND WE KNOW THAT MICRO MRNAs AND PROTEINS ARE RELEASED IN ABUNDANCE WITHIN THE PLACENTA. OF COURSE THE IDEA THAT THERE MIGHT BE CIRCULATING PROTEINS FROM THE PLACENTA MEASURABLE DURING PREGNANCY IS NOT NEW AND WE SEE THERE ARE MANY REPORTS OF DIFFERENT PROTEINS THAT PERHAPS ARE CHANGED IN DISEASES OF PLACENTAL INSUFFICIENCY. IN REGARD TO FETAL GROWTH RESTRICTION THE BEST MARKER -- THE FOCUS OF OUR TIME IS TRYING TO IDENTIFY NOVEL PROTEINS THAT MIGHT BE USEFUL AS PREDICTORS OF THESE DISEASES. SO WE WENT BACK TO THE DRAWING BOARD AND TRIED TO THINK ABOUT AN APPROACH TO BIOMARKER DISCOVERY AND THE APPROACH THAT WE'VE CHOSEN TO FOCUS ON IS TO TARGET MOLECULES THAT ARE HIGHLY EXPRESSED IN THE PLACENTA. WITH THIS IDEA BEING THAT IF WE FIND PROTEINS -- THAT ARE PERHAPS SPECIFIC TO THE PLACENTA -- -- WE'VE BEEN LOOKING AT WHETHER WE CAN IDENTIFY MOLECULES LOCATED ON THE PLACENTAL SURFACE. WE ASKED IF WE CAN IDENTIFY SOME OF THE PROTEINS COULD THEY BE NOVEL BIOMARKERS. WE HAVE ABOUT 350 CANDIDATES THAT WE'RE WORKING THROUGH. THE TEAM THAT OUR TEST HOPES TO DEVELOP AND THE ONE THAT I'LL SPEAK TO TODAY IS A TEST THAT IS UNDERTAKEN AT 36 WEEKS OF GESTATION TO TRY TO IDENTIFY THOSE PREGNANCIES THAT ARE SMALL TOWARDS TERM SO THAT THE INTERVENTION OF DELIVERY COULD OCCUR TO REDUCE THE RISK OF STILLBIRTH. WHEN WE THINK ABOUT THE TEST WE'RE INTERESTED IN THE PRODUCTIVE VALUE AS WELL AS THE SPEAKSIVITY. WE WANT TO KNOW HOW THE SENSITIVITY SO WHAT THE PICK UP RATE IS -- AND THE SPECIFICITY -- HOW MANY NORMAL SIZE BABIES ARE BEING RULED OUT BY OUR TEST. WE'VE COME UP WITH A LEVEL THAT WE HOPE TO ATTAIN WHEN TRYING TO DEVELOP OUR BLOOD TESTS. 7 IN REGARDS TO POSITIVE PREDICTIVE VALUE WE'RE AIMING FOR OVER 20%. ULTRASOUND PERFORMS AT 35% AND WE NOTE THAT FALSE POSSIBLESSIVES MAY RESULT IN A LIGHTLY -- DELIVERIES. NEGATIVE PREDICT I HAVE VALUE WE'RE HOPING TO GO AS HIGH AS POSSIBLE. SO I GUESS THESE ARE OUR OVER-ALL THOUGHTS AS FAR AS HOW WE HOPE TO DEVELOP THE BLOOD TEST THAT WE'RE WORKING ON. NOW I JUST THOUGHT I WOULD STOP AND INTRODUCE THE TEAM THAT WE'RE WORKING WITH AS WELL AS THE COHORTS OF SAMPLES. THESE THREE PHOTOS OF THREE OF THE WONDERFUL CLINICIAN SCIENTISTS THAT I'M LUCKY ENOUGH TO WORK WITH. DR. TERESA McDONALD WHO RECENTLY COMPLETED HER PhD. PROFESSOR SUE WALKER. ALONG WITH PROFESSOR STEPHEN TONG. AS PART OF THE PREMEETING DISCUSSION THE GROUP DISCUSSED THE FACT THAT BIG COHORTS ARE NEEDED TO OVERCOME POPULATION VARIATION AS WELL AS TO ENSURE GOOD VALIDATION. THE COHORTS THAT WE'RE WORKING HERE WITH ARE THE FLAG COHORT -- A COLLECTION FROM 2000 WOMEN WHERE WE COLLECTED SAMPLES AT 28 AND 38 WEEKS OF GESTATION WHICH ARE CONVENIENT TIME POINTS BECAUSE WOMAN ARE ALREADY COMING IN FOR CLING -- CLINICAL VISITS AT THIS TIME. THE SECOND COHORT -- IS THE BUMPS COHORT. TO MINIMIZE PREVENTABLE STILLBIRTHS. APPROXIMATELY 4,000 WOMEN. AGAIN AT SO TO HAVE A LOOK AT SOME OF THE BIOMARKERS CURRENTLY BEING EXAMINED. OF COURSE THE MOST COMMONLY STUDIED MOLECULE IS PLACENTAL GROWTH FACTOR. AS PART OF THE FLAG STUDY AND AS PART OF TERESA'S PhD. THIS IS JUST THE DATA FOR PIGF. WE DEFINE SGA AS BABIES BORN LESS THAN THE TENTH PERCENTILE. AGAIN AT 36 WEEKS OF PREGNANCY. YOU CAN SEE IT'S QUITE A BIT SOUTH OF ULTRASOUND WHEN LOOKING IN OUR SPECIFIC COHORT IN MELBOURNE AND THIS IS IN LINE WITH WHAT OTHERS IS FROM AROUND THE WORLD ARE ALSO REPORTING. THIS IS DATA IN 2015 LOOKING AT THE PREDICTION OF LESS THAN TENTH PERCENTILE AGAIN. AND YOU CAN SEE THE SENSITIVITY AT AFFIX SPECIFICITY AGAIN AT 35%. WHILE WE DO SEE SLIGHT IMPROVEMENTS IN THE DETECTION RATES WHEN CONSIDERING LESS THAN 5th PERCENTILE. SO PIGF PERFORMED REASONABLY BUT NOT BETTER THAN ULTRASOUND MEASURES AND THIS IS WHERE OUR FOCUS IS TO TRY TO IDENTIFY OTHER BIOMARKERS THAT PERHAPS COULD BE USED ALONE OR EVEN IN COMBINES WITH MARKERS SUCH AS PBGF. ONE THAT WE'VE HAD A FOCUS ON IS A PROTEIN CALLED SPINT1. IT'S HIGHLY EXPRESSED IN THE PLACENTA. WE DO KNOW THAT WE CAN MEASURE IT IN THE PLASMA ALTHOUGH WE HAVE TROUBLES MEASURING IT IN SERUM. IT FUNCTIONS TO INHIBIT -- THAT APPEAR TO BE NORMAL IN NORMAL PLACENTAL DEVELOPMENT AND THIS HAS COME FROM SOME EXCELLENT STUDIES. SO WE'VE HAD A LOOK AT IT AND YOU CAN SEE HERE SOME DATA DEMONSTRATING A REDUCTION IN SPINT1. AND OUR STATISTICAL TIM HAAS GENERATED THE DATA. *. SPIN ONE. WE'VE PUBLISHED THIS IDEA OF PERHAPS A FOUR TIER RISK MODEL USING SPINT1. SO, I'LL JUST TRY TO WALK YOU THROUGH THIS TABLE AS IT CAN BE A LITTLE BIT CONFRONTING WHEN LOOKING AT IT WITHOUT EXPLANATION. IF WE SAT HERE -- I GUESS IT'S HIGHLIGHTING THAT THE POPULATION RISK OR ANY PREGNANT PERSON WHO COMES INTO THE CLINIC CAN BE INFORMED THAT THEIR BACKGROUND RISK OF DELIVERING ARE LESS THAN -- IS OF COURSE 3, 5, 10 OR 20 PERCENT. WE CAN ASSIGN PATIENTS INTO A DIFFERENT LEVEL OF RISK ACCORDING TO WHAT THEIR SPINT1 LEVELS WERE. I'LL START OFF HERE WITH THE HIGHEST RISK COHORT. THE PATIENTS THAT HAD THE LOWEST LEVELS IN THEIR CIRCULATION AND YOU CAN SEE BY USING A CUT OFF AS SHOWN HERE THAT WE CAN ACTUALLY REDEFINE THE RISK FOR THESE PATIENTS. SO YOU CAN SEE FOR THE LESS THAN THIRD -- ABLE TO INDICATE THEY HAVE A 5 FOLD INCREASE RISK OF HAVING A SMALL BABY AND YOU CAN SEE THE REASSIGNMENT OF RISK IS AROUND 3-4 FOLD INCREASE AT LESS THAN 10 PERCENTILE. IF WE THEN HAVE A LOOK AT THE GROUP THAT USE THE FOURTH TIER YOU CAN SEE THIS IS THE GROUP THAT HAD THE HIGHEST LEVELS AND PATIENTS WITHIN THIS COHORT REALLY HAVE A VERY LOW RISK OF DEVELOP ERRING A BABY THAT WAS LESS THAN THE TENTH PERCENTILE. NOW THE SECOND TIER WHICH WE REFER TO AS NORMAL RISK WE WERE NOT ABLE TO ADJUST THE RISK RATING BEYOND WHAT WAS APPARENT IN THE POPULATION RISK. HOWEVER IN THE LOWER RISK GROUP THE THIRD TIER WE WERE THEN AGAIN ABLE TO SEE A HALVING IN THE RISK. SO YOU CAN SEE BY UTILIZING THE MODEL THAT WE ARE ABLE TO REASSIGN THE RISK FOR JUST UNDER HALF OF THE POPULATION TO TRY TO IDENTIFY HOW LIKELY IT WOULD BE FOR THOSE PATIENTS TO DELIVER A SMALL BABY AND THIS IS A MODEL THAT WE'RE HOPING TO VALIDATE AS WE MOVE INTO THE FUTURE. THE OTHER I GUESS ASPECT OF OUR RESEARCH IS TRYING TO DEVELOP A MULTI-MODEL TEST AND THIS WAS AN IMPORTANT ASPECT OF THE PREMEETING DISCUSSION. THE IDEA THAT PERHAPS MULTI-MODEL TEST MIGHT BE A STRONG OPTION AND CERTAINLY THE MATERNAL FETAL MEDICINE FOUNDATION TESTS HAS SHOWN THAT THIS CAN BE THE CASE. WE ARE FOCUSED ON IDENTIFYING BLOOD BIOMARKERS AND EXAMINING WHETHER WE CAN COMBINE MORE THAN ONE BIOMARKER TO IMPROVE THE SENSITIVITY OF OUR BLOOD TEST. WE'RE ALSO AS PART OF THE BUMP STUDY AND THE FLAG STUDY CREATING ULTRASOUND INFORMATION TO SEE IF WE CAN COMBINE THAT DATA. AS WELL AS EXAMINING MATERNAL CHARACTERISTICS. TRYING TO BRING TOGETHER LOTS OF INFORMATION TO PRODUCE THE MOST SENSITIVITY ALGORITHM TO PICK OUT WHICH WOMEN ARE AT THE GREATEST RISK. SO JUST A LITTLE BIT OF DATA ON OUR ABILITY TO COMBINE BLOOD BIOMARKERS. THIS IS FROM THE BUMP STUDY. THE DATA LOOKING AT SPINT1 ALONE. IF WE COMBINE SPINT1 WITH OTHER PROTEIN BIOMARKERS WE'RE SEEING THAT WE CAN SHIFT SENSITIVITY AND POSITIVITY PREDICTIVE VALUE AND SUDDENLY WHILE WE ACKNOWLEDGE PERHAPS THE EASIEST TEST WOULD BE ONE WITH A SINGLE BIOMARKER OR PERHAPS A LOWER NUMBER IT DOES SEEM IF WE ADD IN ADDITIONAL BIOMARKERS WE CAN START TO SEE IMPROVEMENTS IN SENSITIVITY. SO, ITS THIS IDEA THAT PERHAPS BIOMARKER COMBINATIONS MIGHT OUT PERFORM SINGLE BIOMARKERS. SO WHAT IS NEXT FOR SPINT1 IN OUR SIDE OF THE WORLD? WE'RE VALIDATING OUR OWN IN-HOUSES SAY THAT WILL HOPEFULLY SEE IMPROVEMENTS. WE'RE WORKING WITH COLLABORATORS AROUND THE WORLD AND FROM THE PREMEETING DISCUSSIONS THAT IS AN IMPORTANT ASPECT. THE IMPORTANCE OF BEING ABLE TO VALIDATE IN DIFFERENT POPULATIONS BEYOND WHERE THE BIOMARKERS WERE DISCOVERED. AND A REALLY IMPORTANT ASPECT OF THE WORK THAT I'M INTERESTED IN AS A BASIC SCIENTISTS IS TO CONTINUE LABORATORY STUDIES TO BETTER UNDERSTAND THE BIOLOGY AND NOT JUST STICKING TO THE HUMAN OR THE MOUSE BUT WE'VE INITIATED COLLABORATIONS. WHAT IS NEXT BEYOND SPINT1? WE'RE CONTINUING TO SCREEN AND WORK THROUGH THAT LIST OF 350 CANDIDATE MARKERS TO SEE IF WE CAN IDENTIFY OTHER LEARNED BIOMARKERS OR BIOMARKERS THAT CAN BE COMBINED? OTHER -- WORKING WITH OTHERS AROUND THE WORLD SO THAT WE CAN EXAMINE PERHAPS THEY COULD BE COMBINED WITH THE BIOMARKERS THAT WE'RE IDENTIFYING AND OF COURSE AS HAVING ARTIFICIAL INTELLIGENCE EXPERTS AS PART OF OUR TEAM WE'RE INTERESTED IN USING THEIR EXPERTISE TO SEE IF WE CAN START TO DEVELOP THESE MULTI-MODEL TESTS USING LARGE DATASETS NOT JUST PROTEIN BIOMARKERS ON THEIR OWN. SO, THAT IS IT FOR ME. I WANTED TO ACKNOWLEDGE THAT NONE OF THIS RESEARCH IS POSSIBLE WITHOUT AN AMAZING TEAM OF PEOPLE SURROUNDING MYSELF AND SO OF COURSE THE MEMBERS OF MY TEAM BUT WE HAVE A FANTASTIC RESEARCH MID-WIFE TEAM WHO WORK REALLY HARD TO COLLECT THE SAMPLES. WE'RE WORKING WITH SOME WONDERFUL TEAMS AND COHORTS FROM AROUND THE WORLD AND OF COURSE THE FUNDING THAT IS NEEDED TO ENSURE THIS RESEARCH IS POSSIBLE. THANKS SO MUCH FOR YOUR TIME. >> THANK YOU VERY MUCH. A BRILLIANT RUNDOWN. THANK YOU VERY MUCH. IT'S MY PLEASURE TO NEXT INTRODUCE SOMEONE WHO'S WELL-KNOWN INTERNATIONALLY AND REALLY VERY MUCH A BRILLIANT MIND AND THAT IS PROFESSOR LEONA POON WHO'S NOW IN HONG KONG. >> THANK YOU, STEPHEN AND THANK YOU DAVID AND KATHRYN FOR PUTTING THIS MEETING TOGETHR. THIS IS A GREAT OPPORTUNITY FOR ME TO SHARE MY EXPERIENCE IN HONG KONG AND IT IS 5:00 A.M. HERE IN HONG KONG AND STILL PITCH BLACKOUT SIDE. -- I'LL COVER MORE CLINICAL IMPLEMENTATION ASPECTS OF BIOMARKER USE FOR THE PREDICTION OF PREECLAMPSIA. FIRST HERE ARE MY DISCLOSURES. WE WERE ALSO USING A SIMILAR APPROACH FOR SCREENING BUT THIS METHOD IS OBVIOUSLY QUITE SIMPLE BUT ITS PREDICTIVE VALUE IS ONLY ACHIEVING 30%. ANOTHER ISSUE THAT WE HAVE DISCOVERED IS SUCH AN APPROACH OF SCREENING HAS LED TO A RATHER POOR UPTICK. ONLY 23%. SO IT WAS CLEAR THAT WE NEEDED TO IMPROVE THE METHOD OF SCREENING FOR PREECLAMPSIA AND ALTERNATIVE APPROACH AS MENTIONED BY BODES STEPHEN AND THE PREVIOUS SPEAKER. THIS APPROACH THAT ASSUMES THAT THE PREGNANCY WOULD CONTINUE INDEFINITE ALL WOMEN WOULD EXPERIENCE PREECLAMPSIA. BY MOVE ON I WANT TO PAUSE AND ASK A QUESTION. WHAT IS A BIOMARKER? MANY ASSUME THAT IT'S A MEASURABLE BLOOD MARKER BUT THAT IS NOT THE CASE AS IT'S A MEASURABLE INDICATOR OF THE SEVERITY OR PRESENCE OF SOME DISEASE STATE. SO EVEN BLOOD PRESSURE IS CONSIDERED A BIOMARKER. SO THROUGH OUR RESEARCH FOR THE EFFECTIVE PREDICTION OF PREECLAMPSIA WE HAVE NARROWED IT DOWN TO THREE. AND I'M SURE THIS IS NOT THE END AND THERE WILL BE MORE MARKERS TO COME. THE FIRST IS THE MEASUREMENT OF -- HERE IS THE PROTOCOL. YOU CAN SCAN THIS CODE HERE FOR A MORE DETAILED DESCRIPTION. HYPEHYPE YOU CAN SCAN THIS CODE FOR MORE DETAILED DESCRIPTION. -- MEANS THAT NEW MARKERS CAN BE ADDED BY EXTENDING AN EXISTING MODEL. SO THE TEST OF MATERNAL FACTORS -- THIS SLIDE SHOWS THE DIFFERENCE. AND YOU CAN SEE THAT THE BEST MODEL IS A COMBINES. -- COMBINATION. I WOULD LIKE TO DRAW YOUR ATTENTION TO SEVERAL KEY FACTORS. THE FIRST POINTS TO THE DISEASE ITSELF. THE SECOND RELATES TO VARIATION. SO WE RECOMMEND NOT TO USE A SINGLE MEASUREMENT. SO IT IS CRITICAL TO BE COMPLIANT WITH A WELL DEFINED PROTOCOL. WHEN I FIRST CAME BACK TO HONG KONG FIVE YEARS AGO I WAS TOLD BY MY TEAM THAT MY PREDICTION MODEL DID NOT WORK BUT I WAS KEY TO FIND OUT WHY. WE CONDUCTED THIS SIMPLE STUDY TO DETERMINE -- -- DIFFERENCES. 7 SO THE MEASUREMENTS WERE PERFORMED BY TWO SONOGRAPHERS. I DID MEASUREMENT AT THE LEVEL -- AT ONE, TWO AND THREE CENTIMETERS AWAY AND MY COLLEAGUE AT THE -- AND IT WAS VERY CLEAR THAT MY COLLEAGUE WAS MEASURING AT 2 CENTIMETERS AWAY FROM MY MEASUREMENTS. THIS LED TO A DROP AND IT COULD HAVE REDUCED THE DETECTION BY 8%. SO THE CONCLUSION WAS THAT MEASUREMENT -- IS SOMETHING SITE DEPENDENT. DESPITE THE AVAILABILITY OF A PRESTRICT I HAVE PROTOCOL AND WE RETRAINED EVERYONE IN THE DEPARTMENT. WE WERE CURIOUS TO FIND OUT IF THE PREDICTION MODEL WORKS IN ASIA. WE AIMED TO EVALUATE FOR PREECLAMPSIA IN SEVERAL ASIAN POPULATIONS. WE HAD ELEVEN SITES ACROSS SEVEN REGIONS OF ASIA. BUT BEFORE WE EVALUATED THE SCREENING PERFORMANCE -- IN ASIA WE WANTED TO EVALUATE THE -- [ INDISCERNIBLE ] WE USED TWO ASSESSMENT TOOLS. THE FIRST WAS THE TARGET PLOT. THE SECOND WAS A TEST -- THAT ALLOWED US TO -- DEVIATION -- OVER TIME. YOU CAN SEE HERE THE TARGET PLOTS, THE DIFFERENT SYMBOLS REPRESENT DIFFERENT SITES. ON THE LEFT YOU CAN SEE THAT THE MAP VALUES WERE WITHIN 10% BUT THAT THE MAP TENDED TO BE LOWER IN ASIAN WOMEN. IN THE MIDDLE YOU CAN SEE THAT THE NA MAJORITY -- WERE WELL WITHIN THE BOX OF 10% LIMIT. AND ON THE RIGHT YOU CAN SEE THAT THE -- -- SHIFTED TO THE LEFT AS WELL EXCEPT FOR ONE SITE. HERE ARE THE CUSUM PLOTS. THIS PAPER HAS DEMONSTRATED THAT THE TARGET AND CUSUM PLOTS CAN BE USED TO EVALUATE VARIATIONS IN COMPARISON. WITH A LOWER MAP -- MOM THE FALLS POSITIVE RATE WOULD HAD BEEN AFFECTED. SO THERE IS NEED TO ADJUST TO BRING THE MOMS TO ONE. HERE I SHOW YOU THE PLOTS. THERE ARE TWO . THE BLUE ONES REPRESENT THE DATA AND THE PINK REPRESENTS OUR DATA. IN THE ASIAN STUDY CALIBRATION OF RISK WAS GENERALLY GOOD. IT WAS ONE IN 100. SO THE CALIBRATION OF THE MODEL IN ASIA WAS ALSO VERY GOOD AND HERE ARE THE RESULTS ON THE SCREENING PERFORMANCE. I WON'T DWELL ON THIS. BY FOLLOWING ADJUSTMENTS OF THE BIOMARKERS WE CAN SEE THAT THE RESULTS IN ASIA WERE COMPARABLE IN COMPARISON TO THE DATABASED ON EAST ASIAN FROM THE EUROPEAN DATA. AND HERE YOU CAN SEE THE DETECTION RATE ACCORDING TO THE RESPECTFUL FALSE POSITIVE RATE OF 10% AND 20% AND OUR ASIAN STUDY PERFORMED EQUALLY WELL. AND WE'VE ALSO OF CONFIRMED THAT THE TRIPLE TEST IS SUPERIOR -- EVEN IN THE ASIAN SETTING. WHAT IS MORE WITH OUR COLLABORATION WITH CANADA WE'VE LEARNED THAT VARIATIONS -- ALSO HAPPENS ELSEWHERE. THESE GRAPHS ARE SIMILAR . THE DIFFERENT COLOR ZONES REPRESENT 5% AND 10% AND BEYOND. THE GREEN ZONES MEAN GOOD. YELLOW MEANS OKAY AND THE RED ZONES MEAN BAD. SO FOR THE CANADIANS THEY WILL NEED TO ADJUST THE VALUE TO BRING THE MOM VALUE TO ONE. SO WHILE I'M RAISING THE POSSIBILITY OF DIFFERENCES I ALSO WANT TO LOOK AT DIFFERENCES AND RISK FACTORS BETWEEN POPULATIONS. WE USED THE CRUDE NUMBERS TO COMPARE EACH RISK FACTOR FOR PREECLAMPSIA BETWEEN STUDIES AND WE SHOWED CLEAR SIMILARITIES. WHILE COMBINING BOTH STUDIES FROM CHINA AND SPAIN RISK FACTORS -- WERE LOW MATERNAL AGE AND NORMAL MATERNAL WEIGHT. ALTHOUGH THERE ARE SMALL DIFFERENCES BETWEEN RISK FACTORS THERE ARE MORE SIMILARITIES THAN DIFFERENCES WHICH RAISES THE QUESTION ON HOW DIVERSE POPULATIONS DIFFER FROM EACH OTHER IN THE CONTEXT OF PREECLAMPSIA SCREENING. I'VE SHOWN YOU DIFFERENCES BETWEEN BIOMARKERS -- AND NOW I SHOW YOU SIMILARITIES IN RISK FACTORS IN THE CONTEXT OF PREECLAMPSIA SCREENING. THE COMPLEXITY OF DEVELOPMENT FOR PREDICTION OF PREECLAMPSIA. I JUST WANT TO RAISE THE THREE ASPECTS FOR CONSIDERATION WITH REGARD TO THE USE OF BIOMARKERS. THERE SHOULD BE STANDARDIZATION IN RELATION TO TRAINING AND QUALITY ASSURANCE. AND RECOGNIZE THE DIFFERENCES IN VALUES OF BIOMARKERS. AND THANK YOU FOR YOUR ATTENTION. HAPPY TO TAKE QUESTIONS. >> OKAY. THANK YOU VERY MUCH. I THINK WE'RE UP TO PANEL DISCUSSION. >> THAT IS TRUE. KATHRYN IS THE LEAD ON THIS. >> SORRY, KATHRYN. >> ABSOLUTELY. STEPHEN. IT'S TIME TO CALL THE PANEL DISCUSSION AND -- WITH YOUR ABLED GUIDANCE AND LEAD TO INVITE OUR SPEAKERS TO SHARE AND CONVERSE ON THEIR INPUT INTO THESE IDEAS AS WE MOVE INTO THIS OPEN CONVERSATION TIME. >> OKAY. SO I INVITE EVERYONE ON THE -- ALL OF THE PARTICIPANTS HERE TO COME UP WITH YOUR QUESTIONS AND ASK THE TWOS STEAMED PRESENTERS. WHILE WE'RE WAITING FOR A FEW QUESTIONS I MIGHT ASK LEONA IS -- DO YOU KNOW AND ANYONE ON THE PANEL IF THERE IS ANY INTEREST IN THE U.S. IN ADOPTING THE FMF ALGORITHM AND IF NO, THEN WHY NOT? >> I'M AWARE THAT SEVERAL GROUPS HAVE REALLY EVALUATED THE MODEL. AND CERTAINLY IN THOSE PLACES THEY HAVE SHOWN THAT THE PREDICTION MODEL WORKS. AND SO I SUPPOSE IN RELATION TO IMPLEMENTING SUCH A MODEL HAS BEEN RELATING TO THE DEVELOPERS OF THE BIOMARKERS. MY MODEL INCORPORATES TWO MARKERS THAT ARE READILY AVAILABLE. THE MEASUREMENT OF BLOOD PRESSURE. AND THE MEASURE OF -- AND A THIRD MARKER IS MORE CHALLENGING. THAT IS THE PLACENTAL GROWTH FACTOR. WHILE EVERYONE IS KEEN TO IMPLEMENT THE MERCEDES MODEL AND I THINK ONE COULD ALSO START THINKING WITH A FIAT MODEL. MAYBE YOU CAN START WITH COMBINING -- BLOOD PRESSURE WITH MATERNAL RISK FACTORS. I THINK THAT IS THE STARTING POINT BUT YES CERTAINLY HAPPY TO HEAR WHY THERE IS MAYBE NOT THE LACK OF INTEREST BUT CERTAINLY WHY IT'S NOT SO EASY FOR OTHER PEOPLE TO IMPLEMENT SUCH A PREDICTION MODEL. >> THANK YOU. IF WE COULD HEAR FROM THE CHAT ANYONE FROM THE U.S. IN TERMS OF THEIR PERSPECTIVE AS TO WHY IT'S NOT BROUGHT INTO THE U.S. THAT WOULD BE GREAT. BRIAN -- RAISES A QUESTION. -- GLOBAL COLLABORATIVES. WHICH IS RELEVANT. HOW WOULD THIS BE ACHIEVED? THROUGH INTERNATIONAL AGENCIES -- SO THAT IS A QUESTION FOR DAVID. >> I JUST THREW THE QUESTION OUT THERE. I WOULD LIKE TO HEAR THE THOUGHTS OF THE PEOPLE FROM THE DISCUSSION. WHAT THEY THINK. WHAT THEY THINK WOULD BE NECESSARY. I CANNOT SPEAK TO NIH BUT I CAN SAY THAT WE ARE LISTENING. WE WANT TO HEAR WHAT PEOPLE THINK NEEDS TO BE DONE LIKE WHAT YOU JUST MENTIONED ABOUT LOOK IN TO TEST LEONA'S MODEL TEST IN THE STATE AND I'M NOT A CLINICIAN SO I'M NOT THE RIGHT PERSON TO SPEAK TO IT. >> IT'S ADJUST A GENERAL POINT THAT BRIAN HAD RAISED AND I THINK IT RESONATES FOR ME, WE HAD THE OPPORTUNITY TO PRESENT IN OUR BIOMARKER APPROACH AND EVEN THIS FORUM TODAY IS VERY INTERESTING FIRST STEP BUT EVEN -- AT OTHER CONFERENCES -- WOULD BE USEFUL IN TERMS OF NOTING WHAT EVERYONE IS DOING. OKAY. IS THERE ANYONE ELSE WHAT WOULD LIKE TO CONTRIBUTE TO THE CHAT OR DISCUSSION? HAPPY TO HEAR ANY THOUGHTS AT ALL. >> STEPHEN, JUST TO COME BACK TO THE LAST POINT. WE TALK ABOUT COLLABORATION AND STANDARDIZATION AT TWO DIFFERENT LEVELS. WE'RE SITTING HERE MAINLY AS RESEARCHERS TODAY. PREDOMINATELY RESEARCHERS. WHEN WE TALK ABOUT COLLABORATION IT'S EASIER TO TALK ABOUT COLLABORATION AND ADOPTION STANDARDS. BECAUSE IN THE CLINICAL WORLD WE HAVE NATIONAL AND LOCAL ORGANIZATIONS THAT SET STANDARDS OF PRACTICE ETC. SO THERE IS TWO DIFFERENT LEVELS. IF WE'RE GOING TO ADOPT LIONA'S TEST THEN IT'S THE REGULATORY BODIES THAT HAVE TO BE INVOLVED AS OPPOSED TO THE SCIENTISTS AND THE RESEARCHERS. SO JUST A COMMENT ON IT. >> OKAY. SO I WILL MENTION THIS -- JACKIE -- THANK YOU FOR YOUR CONTRIBUTION. THE ADDED VALUE OF THE SCREENING APPROACH IN THE U.S. REMAINS UNCLEAR. A LARGE NUMBER OF PATIENTS HAVE STARTED ON -- FOR PREECLAMPSIA PREVENTION. WE DON'T HAVE OTHER INTERVENTIONS FOR THE PEOPLE WHO WE IDENTIFY AS HIGH RISK. I MIGHT LET IONA ANSWER THAT. WE DON'T KNOW WHETHER IT'S VALIDATED IN THE U.S. BUT I WOULD ANTICIPATE IT HAS A HIGH SENSITIVITY. LIONA. >> THANK YOU, STEPHEN AND THANK YOU FOR THIS QUESTION. THE CHALLENGE I SEE IS THAT SUCH RECOMMENDATIONS BY ACOC CAME ALONG IN EARLY 2010 AND THAT MAKES IT MUCH HARDER BECAUSE IN MY OPINION THE RECOMMENDATION IS NOT ENTIRELY BASED AROUND MUCH CONTROLLED TRIALS OF SCREENING USING ALTERNATIVE RISK FACTORS BY GIVING -- -- THIS IS TRUE. I DON'T SEE ANY EVIDENCE SUGGESTING THAT THE SUGGESTION IS BASED ON ESPECIALLY BEAM LOGICA--EPIDEMIOLOGICAL DATA. *. THE SECOND IS THAT YES IN OUR SETTING AS YOU HAVE SEEN APPLY THE ACOC RECOMMENDATION ACHIEVES MUCH LOWER DETECTION RATE AS I SHOWED IN ONE OF MY SLIDES. HALF OF THE DETECTION RATE OF WHAT THE MODEL CAN ACHIEVE. SO OBVIOUSLY YES I WOULD ENCOURAGE OTHER PEOPLE TO EVALUATE AND SEE HOW WELL THE MODEL WORKS IN YOUR POPULATION. BUT I THINK WE MUST BE OPEN MINDED. WE MUST ACCEPT THAT THERE ARE BETTER MODELS OUT THERE. NOT JUST BASED ON MATERNAL RISK FACTORS. AND SO I THINK BEFORE YOU ASK WHETHER THERE IS ANY ADDED VALUE WE NEED TO EVALUATE AND SEE WHETHER THAT IS INDEED THE CASE IN YOUR SETTING. >> THANK YOU VERY MUCH. DR. BUHIMSCHI MAY I INVITE YOU BACK. >> I WAS TRYING TO TYPE BUT THEN I THOUGHT I WOULD ASK. ONE THING THAT I'M NOT SURE MAYBE THE PANEL KNOWS MORE THAN ME IS WHAT HAPPENED TO THE PLGF POINT OF CARE TEST. I DON'T THINK IT WAS BROUGHT TO THE FDA. I DON'T KNOW WHAT HAPPENED. ONE THING THAT WILL NEED TO HAPPEN IS THAT THERE WILL NEED TO BE IN COUNTRY STUDIES OF THIS. SO THE IDEA THAT ACCURACY VARIES ESPECIALLY IN THE U.S. WHERE THE MAJORITY OF PREECLAMPSIA WOMEN ARE TERMED PREECLAMPSIA WILL RENDER THE -- A LITTLE BIT OF COLD FEET I THINK BUT I DON'T REALLY KNOW WHAT HAPPENED TO THE PLGF. BECAUSE I THINK THERE WERE A NUMBER OF STUDIES WITH THE POINT OF CARE TEST THAT NEVER MATERIALIZED HERE. >> THANK YOU. I MIGHT JUST MENTION AND APOLOGIZE FOR THE ELECTRONIC SYSTEM. THERE IS JUST TOO MANY SHEETS OF PARTICIPANTS THAT I CANNOT SEE HANDS RAISED SO IF YOU COULD TYPE THE CHAT AND THEN WHEN IT COMES TO YOU FEEL FREE TO FLICK YOUR CAMERA ON. I DO APOLOGIZE FOR THAT. ANNA DAVE I HAD HAS A QUESTION. HOW MANY POPULATION VARIATIONS DOE LIONA THINK THERE IS LIKELY TO BE. LESS OR OVER 10 FOR EXAMPLE? >> STEPHEN I'M NOT FOLLOWING THIS QUESTION. >> I'M NOT EXACTLY EITHER. ANNA -- COULD YOU -- >> SURE. THANK YOU SO MUCH. GREAT TALK. I WAS REALLY WONDERING ABOUT -- ARE WE LOOKING AT VERY BASIC GROUPINGS OR IS IT LIKELY THAT CERTAIN ETHNIC GROUPS WITHIN OTHER POPULATIONS ARE GOING TO NEED TO IDENTIFY AND BE TREATED. HAVE DIFFERENT TEST RESULTS DEVELOPED FOR THEM AND HOW DIFFICULT IS THIS GOING TO BE? >> TO PERHAPS ANSWER THE LAST PART IS NOT VERY DIFFICULT BECAUSE JUST TO MAKE THINGS CLEAR. I APPLIED THE EUROPEAN BASED MOM FAMILY. SO WHAT IS A MOM FORMULA. WE KNOW THAT BIOMARKERS ARE HEAVILY INFLUENCED BY MATERNAL FACTORS. SO ONE MUST CORRECT THESE BIOMARKERS AND EXPRESS THEM AS MULTIPLES OF MEDIAN. SO BACK IN ASIA I APPLIED THE EUROPEAN BASE AND WE DISCOVERED THAT THE BLOOD PRESSURE IS A BIT LOWER IN ASIANS. THAT IS EXPECT BECAUSE WE'RE SMALLER BUILT AND HAVE LOWER RATE OF CO-MORBIDITIES. SO THE LOWER BLOOD PRESSURE IS EXPECT SO YOU NEED TO UNDERSTAND YOUR POPULATION AS WELL AND SEE IF THESE DEVIATIONS ARE EXPECT. THE LOWER -- IS RELATED TO POPULATIONS AS WELL. SO -- THAT BOILS DOWN TO UNDERSTANDING YOUR POPULATION. THE BLOOD PRESSURE FROM M CANADIAN COLLABORATORS IS EXPECTED TO BE LOWER AS WELL. IT'S AN APPLICATION OF THE TARGET PLOTS -- AND TESTS AND SEE. ONCE YOU RECOGNIZE THESE DEVIATIONS AND I WOULD NOTIFY THE SOFTWARE PROVIDERS THAT HAVE BUILT IN THESE -- CALCULATORS TO APPLY THESE CORRECTION FACTORS TO BRING THE MOM DOWN TO ONE MOM OR UP TO ONE MOM. >> CAN I JUST JUMP IN BEFORE I GO TO THE NEXT QUESTION. ALSO JUST SAY I KNOW WITH THE -- I MIGHT BE MISTAKEN WAS VERY LITTLE SO DO YOU THINK CONCEPTUALLY THAT AS YOU COMPARE WITH DIFFERENT POPULATIONS CIRCULATING BIOMARKERS MIGHT HAVE A BETTER CHANCE OF HAVING LESS VARIATION OR YOU DON'T THINK SO. >> WAS THE QUESTION FOR ME? >> WAS THE VARIATION MUCH LESS BETWEEN POPULATIONS AND DO YOU THINK CONCEPTUALLY CIRCULATING BIOMARKERS MIGHT -- >> I LOST YOU COMPLETELY. >> I'LL GIVE UP AND GO TO BRIAN. 7. >> THANKS. I THINK LIKE SOME OF THE THINGS THAT CAME UP IN CONVERSATIONS -- WE HAD IS A DISCUSSION GROUP ABOUT THE AND THEY WERE MENTIONED IN YOUR INTRODUCTION SOME OF THE INTRODUCTIONS -- AROUND MODALITY AND WE HAVE NOT TRIED TO ADDRESS THAT. THERE IS A COST BURDEN AND A WORKLOAD BURDEN. THERE IS NOT A -- THAT IS GOING TO TAKE ON A MULTI--- PROJECT. WHAT WE HAVE SEEN IS THERE ARE LOTS OF LABS WITH EXCELLENT SKILL AND RESOURCE IN PARTICULAR MODES OF ANALYSIS AND WHAT WE WANT TO TRY TO DO IS I THINK TRY TO LINK UP THESE TYPE OF LABS TO CREATE THESE MOONSHOT STYLE EXPERIMENTS WHERE WE CAN SPREAD SAMPLES AND DISTRIBUTE THEM. AND THAT IS A WAY OF BUILDING AN INTERNATIONAL COMPONENT TO IT. AND I THINK THAT IS WHAT GAMING AT WHEN I SAY A MOONSHOT EXPERIMENT. I DON'T EXPECT ONE ENTITY TO FUND IT. HOW DO WE TAKE SOMETHING LIKE THE HUMAN PLACENTA PROJECT -- AND TURN IT INTO SOMETHING THAT CAN HELP US BUILD BETTER BASIC BIOLOGY AND PATHOLOGY UNDERSTANDING OF THE PLACENTA AND OF PREGNANCY IN GENERAL AND I THINK -- IT WAS BROUGHT UP IN UNDERSTANDING NORMAL. WHAT DOES A BASELINE PREGNANCY LOOK LIKE. AND THERE IS A LARGE VARIATION. IF WE DON'T ENGAGE IN THE STUDIES -- I THINK IT'S GOING TO BE DIFFICULT TO SOLVE A LOT OF THESE PROBLEMS BECAUSE WE STILL TAKE A VERY BI MODEL LOOK. YOU'RE EITHER HEALTHY OR SICK AND EVEN EARLY ON SET PREECLAMPSIA -- AND IT'S VERY UNCLEAR HOW THOSE TRANSLATE INTO A SUB SAHARAN AFTER COUNTRY OR ASIAN COUNTRY SO WE NEED TO TRY TO USE HPP TO LINK THIS INTERNATIONAL COLLECTION OF EXPERTS TO REALLY DEEPLY UNDERSTAND PREGNANCY AND PLACENTA SO WE CAN BUILD BETTER TREATMENTS AND DETECTION METHODS. >> I THINK THAT IS A VERY WELL SAID, BRIAN. JUST MY HUMBLE OBSERVATION. THE FORUM PROBABLY EXIST. A LOT OF US GO TO SRI AND THE CLINICIANS GO TO CLINICAL CONFERENCES. A LOT HAVE COME DOWN TO A FORMULA WHERE EACH SPEAKER IS INVITED TO SPEAK ON THE ABSTRACT AND A BIT OF DISCUSSION. BUT FORUMS LIKE THIS WHERE THERE IS A DEEPER DISCUSSION SEEM TO NOT HAPPEN TO CURRENT MODERN CONFERENCES. BUT WITH GROUPS OF RESEARCHERS THAT MEET TOGETHER BUT HAVE A COMMITMENT WITH SAMPLES TO WORK TOGETHER IF THE CIRCUMSTANCES ARE GOOD. IF THAT COULD BE PULLED OFF THAT MAY BE ONE FORUM -- FOR EXISTING CONFERENCES MIGHT DO THAT BUT WE NEED A VISION IN HOW THEY ARE RUN. I THINK DAVID HAS DONE A GOOD JOB IN DOING SOMETHING THAT MOVES US IN THAT DIRECTION. ENOUGH FROM ME P. LEONA HAS JUMPED IN AND ANSWERED THIS ON THE CHAT. BUT I MIGHT STILL PUT VOICE TO THIS. A QUESTION. ETHNIC -- I HOPE SHE CAN HEAR ME NOW. IS IT STRICTLY ETHNIC VARIATIONS ARE IS THERE AN ENVIRONMENTAL CONTRIBUTION AS WELL. DOES THE MODEL OPTIMIZE FOR ASIAN FEMALES IN HONG KONG -- AND FOR ASIAN FEMALES ELSEWHERE. >> YES. I CAN HEAR YOU. IT'S A COMBINATION OF BOTH BUT OBVIOUSLY I HAVE NOT LOOKED AT THAT AT THE MOLECULAR LEVEL AND I'VE ALREADY ANSWERED PARTLY TO THE QUESTION IN THE CHAT BOX SO ESSENTIAL LEAP WE HAVE VALIDATED THIS MODEL ACROSS SEVEN REGIONS IN ASIA SO, THAT IS ALSO NOT ENTIRELY SPEAKING CHINESE WOMEN. AND WE'RE EXPANDING TO THREE OTHER REGIONS IN ASIA INCLUDING INDONESIA AND THE PHILIPPINES AND VIETNAM. ANOTHER POINT THAT WE NEED TO RECOGNIZE IS THAT WHILE WE DO RECOGNIZE THE VARIATIONS -- THE BIOMARKERS THEMSELVES VARY FROM DAY-TO-DAY AS WELL. SO I THINK ONE CHALLENGE THAT WE'VE BEEN SEEING WITH THE MEASUREMENT THAT IS EVEN WITH LOT TO LOT CHANGE WE HAVE SEEN MASSIVE VARIATIONS AND -- IN RELATIONSHIP THE RESULTS. ONE MUST PUBLIC VERY CAREFUL WHEN WE'RE IMPLEMENTING BIOMARKERS. WE NEED TO ACKNOWLEDGE BETWEEN POPULATION VARIATIONS BUT ALSO THE VARIATION AS WELL AS LOT TO LOT VARIATION. SO I DO AGREE THAT IMPLEMENTATION OF SUCH A PREDICTION MODEL CAN BE CHALLENGING ESPECIALLY WHEN WE'RE BRINGING IN A BLOOD BIOMARKER. >> THANK YOU FOR THAT. PROFESSOR ROBERTS -- FROM SOUTH AUSTRALIA, SHE JUST FIRSTLY MAKES OF THE POINT TO SUPPORTING BRIAN'S COMMENTS AND ASKED LEONA ARE YOU MOVING ANY CLOSER TO PREDICTION FOR TERM PREECLAMPSIA? >> I THINK STEPHEN ALREADY BROUGHT THIS ISSUE UP. PRE DICTION AT DIFFERENT STAGES OF THE PREGNANCY AND IT'S CLEAR TO US THAT WE CANNOT PREDICT THIS TYPE OF PREECLAMPSIA WHILE IN THE FIRST TRIMESTER BUT IT DOESN'T MEAN I'LL STOP LOOKING FOR BIOMARKERS BUT THE WORK IS STILL ONGOING. IN RELATION -- THERE IS HOPE PUSHING FOR A LATER PREDICTION PERHAPS 5-37 WEEKS YOU WOULD GET MUCH BETTER DETECTION RATE BUT THE TROUBLE IS WHAT CAN WE DO? ALL WE HAVE IS TO CONSIDER INDUCTION OF LABOR IF YOU FIND SOMEONE IS AT HIGH RISK BEYOND 35 WEEKS. BUT AS STEPHEN HAS HIGHLIGHTED INDUCTION LABOR IS RELATIVELY BENIGN IN TERMS OF NOT INCREASING THE RATE OF C-SECTION AND IT COULD PRODUCE THE OVER-ALL INCIDENCE -- DISORDER. SO AROUND 35 WEEKS. AND INDUCING THESE WOMEN AT 37-38 WEEKS WOULD REDUCE THE RISK OF TERM PREECLAMPSIA. THAT WOULD BE THE FOCUS OF OUR WORK AS WELL. >> THANK YOU. AND IN CONTINUATION OF BRIAN'S COMMENTS WE GET TWO CONTRIBUTIONS FROM TWO HEAVYWEIGHTS IN THE FIELD. LESLIE WANTS TO NOTE THAT HE HAS PUT A POST ON IDEA SCALE RELATED TO -- CO-LAB ABOUT BUILDING BIOBANKS AND SHARING SAMPLES. AND I COMPLETELY AGREE WITH THAT. WE FOLLOW PROTOCOLS AND ENCOURAGE EVERYONE WHO IS LOOKING FOR LARGE BIOBANKS TO LOOK THAT UP AND JUST NOTED THAT THE NICHD -- THEY HAVE REGISTRY STARTED FROM 180 STUDIES FROM 49 DIFFERENT TOP EASE. -- STUDIES. * AND THAT IS SOMETHING ELSE THAT OTHERS CAN LOOK UP. THAT IS VERY INTERESTING AND NONE OF THIS WOULD -- WELL I WOULD NOT HAVE KNOWN ABOUT DASH. SO, THAT IS VERY USEFUL CHAT THERE. SO THANK YOU TO BOTH. >> STEPHEN I CAN JUST SAY THAT IT'S QUITE INEXPENSIVE. EVEN IN AUSTRALIA YOU CAN GET ACCESS TO THE SAMPLES SO IF YOU WANT TO TEST THE HYPOTHESIS THAT A CERTAIN BIOMARKER -- -- YOU COULD PULL THEM OUT OF THE REPOSITORY AND MAIL THEM TO AUSTRALIA SO THAT COMPARED WITH GEARING UP A CLINICAL TRIAL AND TRYING TO ENROLL 4,000 PREGNANT PEOPLE IT'S MUCH MORE COST EFFECTIVE. ONE THING I'M TAKING AWAY IS EVERYONE IS COMMENTING ON THE NEED FOR LARGE STUDIES. BUT WE'RE INTERESTED IN REPURPOSING STUDIES IN WHICH WE'VE INVESTED A SIGNIFICANT AMOUNT OF MONEY AND MANY OF THESE STUDIES ARE FROM THE MATERNAL FETAL MEDICINE NETWORK. SO JUST LOOK IT UP ON-LINE. AND YOU'LL SEE ALL OF THE STUDIES THERE. ESPECIALLY PEOPLE ENTERING THE FIELD. ENABLE THEM TO TEST HYPOTHESIS. >> THAT IS VERY INFORMATIVE. SHE IS FINALIZING DASH -- APPLICATION NOW THAT WE HAVE HEARD IT. WE'LL DEFINITELY LOOK INTO THAT. IRINA HAD MENTIONED THAT IT'S HER VIEW OR HER SUGGESTION THAT THE ANALYTICAL VARIATIONS IN THE PLATFORM ARGUABLY NEEDS TO BE RESOLVED BEFORE THE TEST COULD BE USED CLINICALLY FOR PREDICTION AND THAT'S AN INTERESTING COMMENT GIVEN THAT IT HAS BEEN ROLLED OUT IN SPAIN. AUSTRALIA USES IT AND UK HAVE ALREADY USED IT CLINICALLY. WHAT IS YOUR THOUGHTS ON THAT LEONA. SHOULD WE PAUSE THE TEST UNTIL THE SA VARIABILITY -- BEFORE WE USE IT? >> OBVIOUSLY THE ANSWER IS NO. AND IT'S JUST A MATTER OF REALLY DOING YOUR QA ON A REGULAR BASIS. IT'S NOTHING DIFFERENT AND THIS IS SOMETHING THAT HAS BEEN ONGOING FOR YEARS FOR THE -- LIMITATION OF DOWN SYNDROME SCREENING. THE LAB PERFORMS THE QA DATA ON A MONTHLY BASES AND THIS IS EXACTLY THE SAME PRINCIPLE. AS LONG AS YOU RECOGNIZE THESE VARIATIONS AND THE ASSAY VARIATIONS YOU WILL BE ABLE TO HANDLE THAT BUT YOU NEED TO BE ON TOP OF IT JUST TO MAKE SURE THAT YOU'RE AWARE AND CORRECT FOR DEVIATIONS ACCORDINGLY. >> WE HAVE RUN OUT OF TIME AND THERE IS A FEW MORE CONTRIBUTIONS ON CHAT SO I'M SO SORRY WE'RE NOT GOING TO REACH THEM ALL. JUST A COMMENT FROM HELEN JONES WHICH WAS SECONDED SO I'LL VOICE THAT. I THINK IT IS AN IMPORTANT COMMENT. AND IT'S A -- THAT MANY EXISTING BIOBANKS -- OR DATA BANKS DO NOT CONTAIN A PERFECT NORMAL SAMPLE PREGNANCY -- THERE ARE MORE THAT DO BUT THE MORE EXPENSIVE STUDIES ARE. HELEN'S COMMENTS ARE WELL MADE AND THAT IS SOMETHING TO CONSIDER. AND MAYBE THE LAST QUESTION -- FROM JACKIE. DO YOU THINK THAT RELIABLE PREDICTION OF LOW RISK INDIVIDUALS MAY BE USEFUL. PATIENTS WHO ADMITTED FOR PRETERM PREECLAMPSIA OR PRETERM BIRTH PERHAPS. BULB THE DIAGNOSIS SEVERITY IS UNCERTAIN. SO, ITS TO PICK THAT SOMEONE HAS A LOW RISK OF DEVELOPING SEVERE FEATURES ETC. I MIGHT JUST PUT A FEW THOUGHTS THAT I THINK THE ANSWER IS DEFINITELY YES AND THERE ARE SOME THAT ARE TRYING TO DO THAT. LAURA McGEE AND -- HAS COME UP WITH A MODEL SO IF SOMEONE IS ADMITTED WITH A DIAGNOSIS OF PREECLAMPSIA THEY'VE COME UP WITH AN ALGORITHM THAT MIGHT PREDICT. AND THAT WOULD BE ONE EXAMPLE. ONE IS ANDY'S GROUP IN THE U.K. HAVE DEVELOPED IF YOU'VE COME IN WITH CERTAIN PRETERM LABOR YOU MIGHT BE ADMITTED AND WE DON'T KNOW WHETHER OR NOT THE UTERUS WILL GO INTO FULL BLOWN BIRTH AND YOU CAN DO A SWAB TEST OF THE VAGINA AND THAT COULD RULE IT OUT. SO, THAT IS A GOOD RULE OUT TEST FOR AN EXAMPLE. THAT CONCEPT IS EXCELLENT ALSO FOR WOMEN WHO ARE AT LOW RISK OF DISEASE AND HAPPY IF LEONA HAS ANY COMMENTS TO THAT. OKAY. I THINK WE SHOULD PERHAPS WRAP THIS UP KATHRYN. >> ABSOLUTELY. IT'S ABOUT THAT TIME. I JUST WANTED TO TAKE A BRIEF MOMENT TO THANK OUR PANELISTS AND SPEAKERS TODAY. YOUR CREATIVITY AND COMMITMENT TO RESEARCH MADE THIS POSSIBLE. THANK YOU TO EVERYONE WHO HAS OFFERED QUESTIONS AND I INVITE ALL OF OUR ATTENDEES TO DAY TWO TOMORROW STARTING AT 3:00 P.M. EASTERN. THANK YOU SO MUCH.