CAPTIONS BEGINS SOON. BEGINNING HERE IN 2004, THE FIRST -- THERE WAS A SLOW RISE, BUT AS WE POINT OUT, IT WAS SUBINFLATIONARY. THEN IN 2013, WE SEE THAT NOSEDIVE THAT ALL OF NIH TOOK, THEN IN 2014, THERE IS, FOR NIA, NIH WOULD NOT LOOK LIKE THIS, AN INCREASE ABOVE THE 2013 LEVEL TO ACTUALLY IN TERMS OF CURRENT DOLLARS HISTORICALLY HIGH APPROPRIATION FOR NIA, IF THAT CURVE OF HAD BEEN REPRODUCED FOR NIH, YOU WOULD HAVE SEEN THE BUMP UP NOT QUITE GETTING TO WHERE IT WAS FOR 2012. THEN IN THE MOST IMPORTANT CONSTANT DOLLARS LINE BELOW, YOU CAN SEE WE WERE DRIFTING GRADUALLY DOWNWARD WITH A PRECIPITOUS FALL IN 2013, AND AS I MENTIONED, THE INCREASE IN 2014 TO NIA NOW BRINGING US UP NOTABLY, REALLY VERY CLOSE TO THE LEVEL IT WAS IN 2012 ONLY, SO JUST RECOVERING FOR NIA FROM THE SEQUESTER. AT 2015, IT ILLUSTRATES RIGHT NOW THE PRESIDENT'S BUDGET, AND OF COURSE WE DON'T KNOW WHAT STANDS BETWEEN THIS AND A REAL APPROPRIATION, BUT THERE'S A VERY MARGINAL INCREASE OVERALL IN CURRENT DOLLARS, CONSTANT DOLLARS, YOU CAN SEE THIS WILL DROP US AGAIN TO A LEVEL IF THIS SHOULD BE THE BUDGET THAT WILL BE HISTORICALLY LOW, ONLY THE SEQUESTER LEVEL 2013 BEING LOWER. SO THERE'S A MIX OF VERY GOOD NEWS HERE, BUT A SOBERING CONTEXT, I THINK, FOR WHAT WE'VE SEEN. I WOULD NOTE, OF COURSE, IN PARTICULAR NIH SHOULD BE VERY GRATEFUL FOR THE INCREASE, WHICH WE DID RECEIVE THIS YEAR. THE WAY IN WHICH THIS IS BEING USED TO SUPPORT RESEARCH BY CATEGORIES IS A FAMILIAR PIE. NOT ANY SUBSTANTIAL CHANGE. STILL ABOUT TWO THIRDS OF THE ALLOCATIONS ARE IN RESEARCH PROJECT GRANTS WITH THE OTHER MECHANISMS INCLUDING CENTERS AND TRAINING CONTRACTS IN OUR INTRAMURAL PROGRAM IN PROPORTIONS THAT HAVE BEEN RELATIVELY SIMILAR YEAR BY YEAR. INTRAMURAL RESEARCH PROGRAM AT 10% IS ABOUT THE NIH OVERALL AVERAGE AS WELL. SO THIS IS 2013. 2014, I ANTICIPATE, WOULD BE VERY SIMILAR. SO WHAT DOES THIS DO TO OUR EXPECTED PAY LINES? FOR 2014, THIS IS WHAT WE HAD PROJECTED AND PUBLICIZE. CURRENTLY IT APPEARS TO BE WHERE WE WILL STAND. AS YOU KNOW FOR SOME YEARS NOW, WE'VE USED DIFFERENTIAL PAY LINES FOR THE LESS EXPENSIVE AND MORE EXPENSIVE AWARDS, THE MARGIN BEING $500,000 IN DIRECT COSTS BETWEEN THOSE TWO CATEGORIES. SO WE'RE EXPECTING 11% FOR ESTABLISHED INVESTIGATORS AND THE LESS EXPENSIVE, 8%, DIAL IN THE MORE EXPENSIVE GRANTS WITH 5 PERCENTAGE POINTS GREATER THAN THAT FOR THE EARLY STAGE MECHANISMS IN RO1 MECHANISMS ONLY, THEN 3% FOR THOSE WHO ARE NEW TO THE RO1 BUT NOT EARLY STAGE INVESTIGATORS. NOW THIS IS EXACTLY WHAT YOU SAW LAST YEAR. LAST YEAR WE HAD THE SEQUESTER, THIS YEAR WE'VE HAD AN IMPROVEMENT, WHY IS THE NUMBER THE SAME? LAST YEAR YOU MAY RECALL TO ACHIEVE THESE NUMBERS, WE HAD TO TAKE THE UNPRECEDENTED STEP OF CUTTING THE NONCOMPETING AWARDS SUBSTANTIALLY. SO THE COMMITMENTS WE'VE MADE, NONCOMPETING COMMITMENTS, HAD TO BE REDUCED IN ORDER TO ACHIEVE THESE NUMBERS. THIS YEAR WE ACHIEVED THESE SAME NUMBERS BUT WITHOUT THAT CUT SO THERE'S A RESTORATION IN THE SPECIFICS OF WHICH THERE ARE QUESTION, WE CAN ELABORATE, BUT MANAGED TO ACHIEVE THIS WHILE REVERSING THE CUTS MADE LAST YEAR. SO THAT'S WHY IT LOOKS THE SAME BUT IT IS A FAR MORE POSITIVE PICTURE OVERALL. KEVIN? >> REVERSING AS IN RE-ESTABLISHING, GOING BACK UP TO WHERE THEY WERE, OR JUST NOT CUTTING FURTHER? >> YOU WISH, RIGHT? [LAUGHTER] THE 2014 TYPE 5 AWARD WILL NOT BE CUT FROM THE 2014 EXPECTED COMMITTED LEVEL. >> AND NONCOMPETING? >> THAT'S A NONCOMPETING. >> OKAY. BUT EXPECTED LEVEL NOW, RELATE THAT TO, SAY, AN OLDER GRANT THAT HAD FUNDS IN 2012, 2013 TOOK A NONCOMPETING DROP AND 2014 WILL BE -- >> OKAY, HERE'S WHAT IT ALL IS. THE 2013 AWARDS THAT WERE CUT 5.5% IN 2013 WILL NOT BE CUT IN 2014. THEY WILL RECEIVE THEIR 2014 COMMITMENT LEVEL. >> SO THE PRESEQUESTER. SO IT IS A REVERSAL OF THAT CUT. >> BUT YOU DO NOT GET THE $2,013 BACK. >> RIGHT. >> THAT'S WHAT HE WAS ASKING. [LAUGHTER] JUST SOME OTHER CONGRESSIONAL ACTIVITIES. I WON'T READ THROUGH THIS BUT ILLUSTRATE THAT THERE HAVE BEEN A NUMBER OF HEARINGS AND BRIEFINGS SIBS WE LAST MET THAT HAVE FOCUSED ON ALZHEIMER'S DISEASE OR THE ACCELERATED MEDICINES PARTNERSHIP IN WHICH ALZHEIMER'S PARTICIPATES. AND WHERE AGING RESEARCH INCLUDING ALZHEIMER'S BUT NOT LIMITED TO THAT HAS BEEN A TARGET OF A GOOD BIT OF INTEREST OF LATE. AND ALTHOUGH I DON'T THINK I'VE GOT A SLIDE FOR IT, FOR THOSE OF YOU WHO FOLLOW FRANCIS COLLINS' BLOG, WHICH FEATURES NEWS WORTHY STORIES LATELY, IF YOU LOOK AT THE CURRENT ONE, IT'S INTERESTING, THERE WERE THREE OR FOUR NIA STUDIES THAT RANGE THE SPECTRUM OF RESEARCH, SO IT'S REFLECTIVE OF THE FACT THAT EVERYONE INCLUDING FRANCIS COLLINS IS NOTING THE SIGNIFICANT FINDINGS COMING THROUGH AND IT'S NICE TO SEE. GOOD READING. SOME OTHER MAJOR EVENTS, BETWEEN NIA AND PCORI, THE RFA WAS ISSUED LAST JULY, WE WENT THROUGH REVIEW, ROBIN AS OF TODAY -- WE THOUGHT WE'D MAKE IT BUT IT WON'T, I THINK WE'LL BE MAKING THE FINAL AWARD, JUST A MATTER OF CLARIFYING THE DETAILS OF THE AWARD. BUT THIS IS OR WILL BE A HISTORIC FIRST COLLABORATION OF ITS KIND BETWEEN, $30 MILLION, THE FULL COST OF FUNDING FOR THIS IMPORTANT INTERVENTION AT FALSE PREVENTION IN A REAL WORD SETTING. IT'S HOPED AND ANTICIPATE THIS HAD WILL BE A PRECEDENT FOR OTHER SUCH NIH-PCORI COLLABORATIONS COLLABORATIONS. IN THE CONTEXT OF THE INCREASED FUNDING NOTED FOR ALZHEIMER'S RESEARCH, WHICH BECAME EVIDENT ONLY IN FEBRUARY, HAVE MOVED, THEREFORE, TO TRY TO ALLOCATE THOSE FUNDS CONSISTENT WITH PRIORITIES THAT HAVE BEEN SET BY A LONG AND ONGOING PLANNING PROCESS, AND A PART OF THAT BALANCE IS ILLUSTRATED IN SOME OF THE SPECIFIC INITIATIVES HERE. YOU'RE WELL AWARE OF THEM BECAUSE YOU'VE APPROVED THEM ALL, BUT JUST WOULD POINT OUT, THEY RANGE, WHICH I THINK IS IMPORTANT, FROM MORE BASIC STUDIES SUCH AS REPROGRAM OF IBSLs AND -- GENETIC STUDY OF NEURAL SYSTEMS, AND CONTINUATION OF THE GENOME SEQUENCING PROJECT, THROUGH THE PLANNING GRANTS FOR ALZHEIMER'S TRANSLATIONAL CENTERS. I THINK WE'RE ALWAYS GOING TO BE LOOKING WITH YOUR HELP AND GUIDANCE AT THE RIGHT MIX OF RESEARCH THAT COMBINES MORE BASIC DISCOVERY WITH A VERY IMPORTANT NEED TO FIND NEW TARGETS, NEW APPROACHES, AS WELL AS TRANSLATING AS WE LEARN THOSE MOST PROMISING THROUGH VARIOUS STAGES OF TRANSLATION ULTIMATELY TO CLINICAL TRIALS AND INTERVENTIONS. THAT LATTER CATEGORY, SOME OF THE NEWLY FUNDED CLINICAL TRIALS HERE, THE DIANETU, TRIALS UNIT, IS THAT RIGHT, WE LEARNED YESTERDAY? THE APOE4 TRIAL AND A4 TRIAL, WHICH MOST OF US REFER TO JUST AS A4 RATHER THAN THE TONGUE TWISTER. THESE AGAIN ARE A PART OF THE COLLABORATION UNDER AMP, THE ACCELERATING MEDICINES PARTNERSHIP. AND HAVE BECOME THE BASIS FOR COFUNDING BY PHARMA TO ENHANCE THE BIOMARKERS INVOLVED IN THESE STUDIES, BOTH IMAGING AND LONG TERM PROJECTED USE OF FLUID BIOMARKERS. SO IT'S BEEN VERY WELL LEVERAGED AND ANOTHER EXCITING PUBLIC-PRIVATE PARTNERSHIP, WHICH I THINK NIA HAS BEEN AT THE FOREFRONT OF NIH EFFORTS OVER THE PAST YEARS, TURNING INTO DECADES. JUST A FEW RESEARCH UPDATES. THESE ARE JUST A SAMPLE PRESENTED BRIEFLY. WE'LL GET TO HEAR IN THE PRESENTATIONS OF OUR OUTSIDE SPEAKERS DURING THE FURTHER COURSE OF THE DAY IN MORE DEPTH BUT JUST TO ILLUSTRATE AGAIN SOME OF THE SPECTRUM OF INTERESTING FINDINGS. THIS IS A STUDY THAT LOOKED AT THE EFFECTS OF PROTEIN ON HEALTH AND WELL-BEING, IF YOU WILL, IN MICE, RODENTS, AND IN HUMANS, WITH THE IMPORTANT FINDING, NOT A SURPRISE TO MEN MANY O MANY OF US, THAT AGE MATTERS. SO IT TURNS OUT THAT IN ADULTS, LOW PROTEIN AT EARLIER AGES, IS ASSOCIATED WITH, THESE ARE ASSOCIATION STUDIES, NOT A RANDOMIZED MEDICAL TRIAL, WITH DECREASED OVERALL MORTALITY, CANCER MORTALITY, DIABETES MORTALITY, WHEREAS IN OLDER AGES, IT LOOKS AS THOUGH THE CIRCUMSTANCE IS NOT THE SAME, AND LOW PROTEIN INTAKE IN OLDER AGES ASSOCIATED WITH INCREASED OVERALL MORTALITY AND CANCER MORTALITY OR DIABETES MORTALITY REMAINS DOWN. PARALLEL DIFFERENCES HAVE BEEN SEEN IN ADULT VERSUS OLD ADULT RODENTS AS WELL, INDICATING WE JUST NEED TO BE COGNIZANT AS HOPEFULLY IN THIS IPS TEUT WE HAVE BEEN ALL ALONG DETERMINATIONS OF WHAT IS BEST INCLUDING DIETARY INTAKE MAY VARY DEPENDING ON AGE AND OTHER CIRCUMSTANCES AS WELL. WE HAVE BEEN SUPPORTING RESEARCH FOR SOME TIME LOOKING AT THE ABILITY TO INFLUENCE BEHAVIOR AND STRATEGIES TO DO THAT, AND THIS IS AN EXAMPLE OF THE NUDGE, THE RATHER GENTLE IN THIS CASE USE OF ENVIRONMENTAL QUEUES TO REINFORCE COMMITMENTS AIMED AT REDUCING INAPPROPRIATE ANTIBIOTIC PRESCRIPTIONS. THE INTERVENTION HERE SIMILARLY WAS THAT BY RANDOMIZING IN CLINICS THE USE OF POSTER-SIZE PRECOMMITMENT LETTERS IN EXAM ROOMS WHICH SIMPLY SAY WE'RE GOING TO DO OUR BEST NOT TO INAPPROPRIATELY PRESCRIBE ANTIBIOTICS, THAT IF YOU LOOK AT THE POSTER IN CONTROL GROUPS, THEY STARTED OUT ABOUT THE SAME IN TERMS OF BASELINE PROPORTION PERCENT PRESCRIPTIONS GIVEN, BUT THE POSTER GROUP, 34% VERSUS 53%, JUST BY HAVING THAT REMINDER AS A SYMBOL OF COMMITMENT AND ILLUSTRATES REPEATED THEMES THAT SOMETIMES CAN BE VERY SMALL INTERVENTIONS SUCH AS THIS WHICH CAN MAKE A DIFFERENCE WHEN WE KNOW WHAT BEHAVIOR IS THE APPROPRIATE ONE TO NUDGE, AND WE HAVE TO BE EVER, EVER MINDFUL OF THAT IMPORTANT CAVEAT. >> [INAUDIBLE] >> YEAH, YEAH. AN INTERESTING STUDY THAT CAME FROM HANDLES, THIS IS AN INTRAMURALLY SUPPORTED STUDY WITH MICHELLE EVANS AND ALAN PLAYING THE LEAD THAT YOU'VE BEEN HEARING ABOUT, PUBLISHED LAST YEAR IN THE NEW ENGLAND JOURNAL OF MEDICINE. THE FINDINGS AS SHOWN HERE, SOME OF THE LABELS MAY BE A LITTLE HARD TO SEE, BUT ON THE LEFT CURVE, THAT'S A TOTAL 25 HYDROXY VITAMIN D WITH THE ILLUSTRATION THAT THE DARKER RED, WHICH IS BLACK INDIVIDUALS, AFRICAN-AMERICANS, SHOW LOWER LEVELS OF VITAMIN D. OF COURSE THIS RAISES THE QUESTION OF WHETHER THAT MEANS THEY NEED TO BE TREATED BECAUSE THEY HAVE LOW LEVELS. ON THE RIGHT WHAT YOU SEE IS BIOAVAILABLE HYDROXY VITAMIN D AND HERE THERE IS NO DIFFERENCE. SO WHY THE DISTINCTION BETWEEN TOTAL AND BIOAVAILABLE LEVELS AS SHOWN HERE, BY VITAMIN D BINDING PROTEIN, WHICH BINDS VITAMIN D IN A FORM WHICH IS THEN IMMEDIATELY, AT LEAST, UNAVAILABLE, THOUGH AN EQUILIBRIUM -- YOU CAN SEE HERE LEVELS OF VITAMIN D BINDING PROTEIN ARE LOWER IN BLACKS, AND INTERESTINGLY AS NOTED IN THE TITLE, SOME 79% OF THAT DIFFERENCE IS ACCOUNTED FOR BY GENETIC POLYMORPHISM. SO A REALLY GREAT UNDERSTANDING IN TERMS OF GENETICS, GENETIC DETERMINATION OF A PROTEIN, AND EQUALLY IMPORTANT IF NOT MORE IMPORTANT WITH IMMEDIATE IMPLICATIONS FOR MANAGING OF INDIVIDUALS THEIR VITAMIN D NEEDS OR SUPPLEMENT REQUIREMENTS NOT TO BE BASED ON TOTAL VITAMIN D BUT ON MORE BIOLOGICALLY RELEVANT AND MEANINGFUL PARAMETERS HERE. THERE'S BEEN PROLIFERATION OF STUDIES USING TECHNIQUES INCLUDING PAIR BIOSIS INCLUDING CIRCULATING FACTORS THAT PLAY A ROLE IN AGING. THIS IS A SUMMARY OF PAPERS THAT CAME OUT THIS LAST MONTH IN NATURE MEDICINE AND A COUPLE IN SCIENCE THAT HAVE NOW LOOKED AT MULTIPLE SYSTEMS. THE YELLOW BOX IS ILLUSTRATING THE FUNCTIONS THAT ARE BEING AFFECTED BY THIS HETEROCHRONIC PAIR OWE BIOSIS, AND FOR THOSE WHO HAVEN'T GOTTEN MAYBE MORE FAMILIAR WITH THE TERM THAN THEY EVEN WANT TO BE, THIS INVOLVES JOINING CIRCULATION OF TWO ANIMALS, RODENTS, MICE IN THESE CASES, HETEROCHRONIC BECAUSE OLD AND YOUNG ARE COUPLED, THEN LOOKING AT THE IMPACT OF THAT COCIRCULATION ON THE OLD AND THE YOUNG ANIMAL. YOU MAY REMEMBER I THINK WE REPORTED A SESSION OR TWO AGO A SESSION THAT SHOWED REVERSAL OF AGE RELATED CARDIAC PIERP TROPHY IN OLDER RODENTS BY EXPOSURE TO -- THIS SHOWED CHANGES IN FUNCTION, OLE FACTION, REMODELING OF BLOOD VESSELS IN THE BRAIN, NEW CELL DIVISION, INCREASED BRAIN PLASTICITY, IMPROVED COGNITIVE FUNCTION, INCREASED POST INJURY REPAIR TO MUSCLES, AND MOVING BEYOND THE IMPORTANT PHENOMENONNOLOGY OF THE EXPERIMENT, THEN TO USE PROTEOMICS TO LOOK AT WHAT YEARS AGO WOULD HAVE BEEN A PRETTY FORMIDABLE CHALLENGE, KNOWING SOMETHING'S BEING CIRCULATED, HOW DO YOU FIND OUT WHAT IT IS IN THE LITERAL SEA OF PROTEINS? PROTEOMICS IDENTIFIED CANDIDATES THAT WERE DIFFERENT IN OLD AND YOUNG, IDENTIFIED GD IF 11 AS ONE OF THEM AND WENT ON, TGF BETA GROWTH FAMILY MEMBER, TO INJECT THEM AND FIND THAT IN THESE CIRCUMSTANCES, THE INTRODUCTION OF THAT PROTEIN MIMENT THMIMIC THE EFFECT OF CIRCULATION, SO THE OBVIOUS POTENTIAL FOR TRANSLATING THAT INTO AN INTERVENTION THAT MAY AFFECT MULTIPLE END POINTS. ANOTHER EXAMPLE OF HOW WE'RE LEARNING ABOUT COMPLEXITY OF BIOLOGIC INTERACTIONS, THIS FROM THE LABORATORY OF WILL BORE, INTRAMURAL PROGRAM, WHO HAS BEEN LOOKING AT SYNDROMES INVOLVED IN ALTERED DNA REPAIR, AND IN THIS PARTICULAR CASE, LOOKING AT ZERO DER MA PIGMENTOSA, AT LEAST ONE FAMILY THEREOF, A DEFECT NOTABLY AFFECTING DNA REPAIR FOUND THERE WERE ALSO ABNORMALITIES IN MITOCHONDRIAL FUNCTION. WHAT IS ILLUSTRATED HERE IS THE INTERACTION AND MECHANISM BY WHICH THAT OCCURS BETWEEN DNA APAIR AND MITOCHONDRIA, TWO AREAS THAT HAVE GOTTEN A LOT OF ATTENTION BUT THAT WE'RE LEARNING ONLY BY STUDIES LIKE THIS TO BE GREATER THAN PREVIOUSLY APPRECIATED, SO ANOTHER VERY BASIC STUDY THAT'S GOING TO UNDOUBTEDLY ENHANCE OUR ABILITY TO UNDERSTAND AND TRANSLATE THE MECHANISMS OF BIOLOGICAL AGING. SO JUST SOME UPDATES, TO POINT OUT THIS IMPORTANT CHANGE IN RESUBMISSION POLICIES, HAVING GONE FROM A FEW YEARS AGO ELIMINATION OF THE A2, SUBMIT A NEW APPLICATION, NEW MEANING THAT IT CONVINCED THE POWERS THAT BE, THE READERS AND REVIEWERS, THAT THIS WAS NOT THE SAME APPLICATION THAT HAD FAILED TWICE, NO LONGER THE CASE. NOW AFTER AN UNSUCCESSFUL A1, A NEW APPLICATION CAN BE SUBMITTED WITHOUT ANY REQUIREMENT THAT IT BE DIFFERENT OBVIOUSLY, INVESTIGATORS OUGHT TO BE INS NUNESED BY WHAT THEY LEARN FROM PEER REVIEW, BUT THERE IS NO SUCH REQUIREMENT. WHAT WE'RE WAITING TO SEE, MAYBE BY NEXT COUNCIL WE'LL HAVE AN IDEA, OF WHAT THIS IS GOING TO DO TO THE NUMBER OF APPLICATIONS. WHETHER AT THE EXTREME, MOST PEOPLE WHO HAVE HAD AN APPLICATION FAIL AS AN A1 WILL SIMPLY TURN THIS AROUND, GIVING US A BIG JUMP IN THE NUMBER OF NEW APPLICATIONS OR NOT, WE DON'T KNOW, LOTS OF SPECULATION, BUT WE'LL LET YOU KNOW IN OCTOBER. THE GERI -- SCIENCE INTEREST GROUP HAS CONTINUED TO MOVE FORWARD WITH ITS SUMMIT AND POST SUMMIT ACTIVITIES. POINT OUT NOW THAT THE OUTCOMES OR PIECES FROM THIS HAVE BEEN PUBLISHED, AND I DON'T THINK WE HAVE THE LINK ON HERE BUT IT'S AVAILABLE ONLINE AND WE CAN CERTAINLY PROVIDE THAT TO ALL OF YOU. SO THIS WILL SET THE STAGE FOR LOOKING AT SOME OF THE CATEGORIC MECHANISMS UNDERLYING AGING THAT WE HOPE WILL BE THE FRUIT OF MULTIPLE INSTITUTES NOW LOOKING AT AGE-RELATED CONSIDERATIONS IN THE STUDY OF MANY DISEASES, ORGANS AND CONDITIONS THAT ARE THE TOPICS OF NIH'S CENTERS. JUST TO POINT OUT AGAIN ANOTHER PLANNING EFFORT, THE ALZHEIMER'S SUMMIT NEXT PLAN FOR FEBRUARY 9TH THROUGH 11TH IN 2015. AT THIS STAGE, JUST ASKING PEOPLE TO HOLD THE DATE AND NOTE, ONCE AGAIN, THERE WILL BE NATIONAL, INTERNATIONAL EXPERTS BROUGHT IN TO HELP US CONTINUE TO HAVE THE MOST INFORMED PLANNING PERSPECTIVE FOR OUR EFFORTS IN THIS AREA. AND WHERE IS SHE? NOT HERE YET. WILL SHE BE HERE? ACCEPTING FOR. [LAUGHTER] >> WE WANTED TO THANK LINDA FOR HER SERVICE AS CHAIR OF FRIENDS OF NIA, PUT TOGETHER AT MAXIMUM ALLOWABLE GOVERNMENTAL COST. A BEAUTIFUL, SUITABLE FOR FRAMING, BUT WE COULDN'T FRAME IT FOR YOU, POSTER. IF YOU WOULD PLEASE PASS ON OUR THANKS. [APPLAUSE] AND WITH THAT, OPEN TO QUESTIONS OR DISCUSSION IF THERE'S ANY DESIRE. >> YESES THEN FOR DR. HODES. QUESTIONS. WHILE YOU'RE THINKING OF QUESTION, I'LL GET THROUGH THE MEETING DATES TO MAKE SURE YOU'VE GOT THEM IN YOUR CALENDAR. THE NEXT MEETING IS SEPTEMBER 16TH AND 17TH. THE ONE AFTER THAT IS JANUARY 27TH AND 28TH. I ALWAYS HAVE TO SAY "WEATHER PERMITTING" AT THAT POINT. AND THEN THE ONE A YEAR FROM NOW IS A LITTLE BIT EARLY. IT'S GOING TO BE MAY 12TH AND 13TH. THEY'RE ALL GOING TO BE IN THIS BUILDING, THE NACHER BUILDING. AND I CAN NOW SAY THAT WE CAN RETURN TO BUILDING 31 IN 2016. PRE SI LA HAS TWE HAVE TO RESERVE ROOMS TW O YEARS AHEAD. >> LET ME JUST -- AS USUAL, SHARE WITH YOU SOME OF THE PRESS COVERAGE THAT'S OCCURRED SINCE LAST COUNCIL, SO AS WE'VE DONE, PLEASE HAVE A LOOK AND THEN PASS IT ALONG. THANK YOU. >> I'LL ASK FOR A MOTION TO CONSIDER THE MINUTES FROM OUR JANUARY MEETING. THANK YOU. I SEE A SECOND. IS THERE A DISCUSSION OF THE MINUTES? SOMEDAY THERE WILL BE DISCUSSION OF THE MINUTES. ALL THOSE IN FAVOR? THANK YOU. ANYONE OPPOSED? ANY ABSTENTIONS? ALL RIGHT, THE MINUTES ARE APPROVED. ALL RIGHT. LAST CHANCE FOR QUESTIONS ON THE DIRECTOR'S STATUS REPORT. OKAY. THANK YOU. WE WILL MOVE ON THEN TO THE NEXT AGENDA ITEM, WHICH IS THE REPORT OF THE TASK FORCE ON MINORITY AGING RESEARCH, AND ELISEO PEREZ-STABLE IS GOING TO INTRODUCE THAT FOR US. >> GOOD MORNING. DID WE GET THE SLIDES UP? SO WE HAD OUR MEETING YESTERDAY, AND WE COVERED THREE TOPICS. THE FIRST -- I PUT UP THE AGENDA JUST TO GUIDE US IN A COUPLE OF THE SAMPLE SLIDES. SO FIRST WE HAD A PRESENTATION BY ANGELA BATES. DISCUSSED IN FEBRUARY AT OUR MEETING. THE IDEA HERE IS WHETHER THERE'S AN OPPORTUNITY TO REVIEW WHAT THE POLICIES ARE ABOUT INCLUSION OF MINORITIES AND WOMEN WHICH IS REALLY THE SET BY LAW. NIH IN GENERAL, BUT SPECIFICALLY REVIEWS OR LOOKS AT THESE REPORTS, MY PERCEPTION IS THAT MANY REVIEW COMMUNITIES, CHECK BOX, ADDRESS IT IN THEIR SUMMARY STATEMENT. THERE IS -- SO I THINK THERE IS AN OPPORTUNITY TO LOOK AT THIS AND WHETHER OR NOT THIS WOULD NOT BE INSTITUTE-SPECIFIC, WE SHOULD BE LOOKING AT WAYS TO CREATE INCENTIVES FOR INVESTIGATORS TO EITHER STAY COMMITTED TO THE TARGET RECRUITMENTS THAT THEY PROPOSE OR TO ENHANCE THEIR RECRUITMENT, BOTH FOR THERAPEUTIC AND ME MECHANISTIC OR OBSERVATIONAL STUDIES. WE DO GET A REPORT USUALLY IN THE FEBRUARY MEETING, WE HAD A REPORT ON THE INCLUSION OF MINORITIES, ALTHOUGH THERE IS A FLAW IN THE MECHANISM THAT INCLUDES ALL NON-U.S.-BASED STUDIES, AND SO FREQUENTLY WITH A LARGE STUDY IN EAST ASIA OR LATIN AMERICA, THE PROPORTIONS WILL BE DISTORTED. SO ONCE WE HAVE A BETTER HANDLE ON THAT, I THINK THAT WILL GIVE US A SENSE OF WHAT PROPORTION OF PARTICIPANTS IN ALL STUDIES AND THERAPEUTIC TRIALS SEPARATELY ARE FROM MINORITY GROUPS. PUT IN THE CONTEXT THAT IN 2010 CENSUS, ABOUT 35% OF THE U.S. POPULATION SELF-IDENTIFIED AS NOT WHITE OR NON-CAUCASIAN. AND THAT THIS PROPORTION IS LIKELY TO GROW AS DEMOGRAPHIC PROJECTIONS PRIMARILY OF THE LATINO AND ASIAN POPULATIONS CONTINUE TO SHOW INCREASES OVER THE NEXT 10 YEARS. THE ONE NOTABLE EVENT THAT WAS POINTED OUT BY ANGELA WAS THAT THERE'S AN INCLUSION MANAGEMENT SYSTEM THAT WILL BE ROLLED OUT IN THE FALL THIS YEAR, WHICH CHANGES HOW WE ARE REPORTING THE PARTICIPANTS IN STUDIES, AND I THINK IT ALLOWS US TO -- OR THE INVESTIGATORS TO DIRECTLY INPUT THE DATA, AND I WILL SEE HOW THAT WORKS. AT A MINIMUM, IT WILL HAVE GENDER, RACE, ETHNICITY. ONE COULD MAKE A REASONABLE ARGUMENT THAT THERE SHOULD INCLUDE SOME OTHER SELECTED SOCIAL DETERMINANTS LIKE SOME MEASURE OF SOCIAL ECONOMIC STA IT TUS WOULD BSTATUS WOULD BE WORTHWHILE, GEOGRAPHIC AREA, URBAN, RURAL, SOMETHING OF THAT NATURE, BUT I'M SURE THAT THAT CAN BE ADDRESSED LATER. JUST A COUPLE OF ANNOUNCEMENTS, THE NIA RECEIVED OVER 200 APPLICANTS FOR THE WILLIAM SCHOLARS PROGRAM, WHICH IS, THINK, A REAL INCREASE. THE SELECTION AND REVIEW IS ONGOING RIGHT NOW. THERE WERE A COUPLE OTHER BRIEF REPORTS FROM DIFFERENT GROUPS THAT HAVE BEEN PARTICIPATING IN THE TASK FORCE. WE DID ALSO HAVE A COMMENT ABOUT THE RESOURCE CENTERS FOR MINORITY AGING RESEARCH ANNUAL MEETING, WHICH WAS HELD MARCH MARCH 31, CARL HILL ATTENDED AS WELL AS LIZ NELSON FROM BSR, AND WE ACTUALLY BEGAN A CONVERSATION ABOUT POSSIBLY HOLDING A JOINT MEETING WITH PEPR IN A COUPLE OF YEARS WITH KEVIN, SO I'LL PROPOSE THAT TO THE DIRECTORS ABOUT AN OPPORTUNITY TO DO THAT. THERE WILL ALSO BE IN NOVEMBER AT THE GSA, A PLANNED MEETING BETWEEN RICK MARR PARTICIPANTS OR DIRECTORS, FACULTY, AND ADRC INVESTIGATORS WHO WILL BE ATTENDING THE GSA. SO I THINK THAT'S ALSO IN AN EFFORT TO ENHANCE COLLABORATION ACROSS NIA-FUNDED CENTERS. OUR SECOND PRESENTER WAS DR. CAN KIMBERLY JOHNSON, WHO IS ASSOCIATE PROFESSOR AT DUKE UNIVERSITY. SHE'S A GERIATRICIAN WHO FOCUSES ON PALLIATIVE CARE. SHE IS AFRICAN-AMERICAN, A PRODUCT SUPPORT FOR DIVERSE INVESTIGATORS AT NIA AT A CRUCIAL SORT OF POINT IN HER CAREER, THE TRANSITION TO ASSOCIATE AND HAVING BEEN FUNDED ON A -- AND NOW HAVING AN RO1. HER FOCUS HAS BEEN ON AFRICAN-AMERICANS' USE OF HOSPICE. THIS IS SORT OF AN EXAMPLE OF WHERE THE PROBLEM IS. YOU CAN SEE THE UNDERUSE OF HOSPICE, THIS IS FROM MEDICARE DECEDENTS WHO WERE ENROLLED IN HOS PIES. HOSPICE. THE NUMBER HAS INCREASED AND ALMOST TRIPLED FOR AFRICAN-AMERICANS, ALTHOUGH THE GAP IS, IN FACT, GROWING. SO MY OWN SPIN ON THESE KIND OF DATA ARE THAT I THINK THIS IS GOOD BECAUSE AT LEAST THINGS ARE MOVING IN THE RIGHT DIRECTION. KIM FOCUSED ON THE FACT THAT THE GAP IS REMAINING LARGER AND I THINK THAT'S STILL VERY IMPORTANT TO FIND OUT WHY. SHE'S DONE A NUMBER OF STUDIES AND SHE SHOWED US BOTH QUALITATIVE AND QUANTITATIVE REVIEW OF PARTICIPANTS OF WHY THEY HAD NOT USED HOSPICE. MUCH OF THEM HAD TO DO WITH LESS KNOWLEDGE, ALSO MORE UNFAVORABLE BELIEFS, AND SHE CREATED SORT OF A FRAMEWORK OF WHAT THE POTENTIAL CAUSES OF THIS ARE. INTERESTINGLY, I THINK SHE'S MORE DIRECTED NOW ON FOCUSING ON SYSTEMS. HER RO1, AS I UNDERSTOOD IT, IS GOING TO BE DOING A NATIONAL STUDY OF HOSPICES TO LOOK AT WHAT DIFFERENT ASPECTS OF THE SYSTEM MAY BE AFFECTING THEM. SO ORGANIZATIONAL AND SYSTEM CHANGE INTERVENTION THERE PRESUMABLY COINCIDING WITH IMPROVED EDUCATION AND ACCESS. ONE COMMENT THAT WAS MADE THAT WAS, I THINK, REMARKABLE, SHE SAID ONE OF THE PATIENTS -- OR IN THE DISCUSSION WOULD SAY, WELL, FOR YEARS, PATIENTS HAD NOT HAD ACCESS TO CARE BECAUSE THEY WERE KIND OF LEFT OUT OF THE SYSTEM, AND NOW THAT THEY DO HAVE ACCESS, THEY DON'T WANT TO BE TOLD THAT YOU'RE DECLINING MORE CARE AT THE POINT WHERE THAT WOULD BE MOST APPROPRIATE. SO I THINK THERE ARE MAJOR TRUST ISSUES AND INFORMATION/EDUCATION ISSUES PROBABLY INVOLVING ORGANIZATIONS WILL HELP GET OVER SOME OF THESE BARRIERS. AND FINALLY, WE SPENT THE LAST 20 MINUTES OR SO TALKING ABOUT A HEALTH DISPARITIES RESEARCH FRAMEWORK DISCUSSION TO REMIND THE COUNCIL, THIS WAS A RECOMMENDATION FROM OUR REVIEW OF THE NIH DISPARITIES AND DIVERSITY PORTFOLIO THAT WAS COMPLETED OVER A YEAR AGO. I SPECIFIC WILL POINT TO NORMAN ANDERSON AS THE ONE WHO PUT THIS IN THE RECOMMENDATIONS. IT MAY NOT BE NEEDED FOR A LOT OF PEOPLE WHO ALREADY THINK IN THESE TERMS, BUT CARL HAS TAKEN THIS ON AND WE HAD A COUPLE OF CONVERSATIONS BY PHONE AND THEN EMAIL COMAING EXAINGS, AND THIS IS STILL, I WANT TO SAY, A DRAFT. WE HAD A NUMBER OF THINGS THAT WE WOULD CHANGE ON THIS CURRENT VERSION AND AT SOME POINT, WE CAN CIRCULATE THIS. RICK MORIMOTO SUGGESTED WE SEND IT TO SORT OF SOME OF OUR TARGET AUDIENCE, RICK MAR DIRECTORS, OTHER INDIVIDUALS, ADRC DIRECTORS, TO SEE WHAT PEOPLE WOULD -- HOW PEOPLE WOULD REACT TO THIS AND TO USE IT FOR OUR TRAINEES. SO I THINK THAT IS. >> THANK YOU. ARE THERE QUESTIONS FOR ELISEO? I WILL MENTION THE NEW INCLUSION SYSTEM WHICH MAYBE YOU CAN CHANGE AT NIH. IT'S COMING IN LATER THIS YEAR ACTUALLY AND IS TIED TO THE FORM C APPLICATION THAT WAS INTRODUCED LAST SEPTEMBER, SO APPLICATIONS COMING IN SINCE THE OCTOBER SUBMISSION DATE HAVE BEEN IN A FORMAT THAT IS COMPATIBLE WITH THE INCLUSION SYSTEM THAT IS COMING ONLINE. THE DIFFERENCE IN IT IS THAT THE DATA ARE COMING IN IN A MANIPUTABLE FORMAT. PREVIOUSLY THEY WERE FROZEN. THAT MEANS WE CAN ADD THINGS LIKE RCDC TERMS TO THE DATA SO THAT WE CAN BEGIN TO PROBE WHAT THIS REALLY CLINICAL RESEARCH, WE CAN GET TO THAT QUICKLY IN THE DATA, AND THAT WILL ALLOW US TO HAVE MORE USEFUL TABLES FOR YOU WHEN WE PRESENT THEM SO YOU CAN ACTUALLY ASK QUESTIONS THAT ARE MEANINGFUL, LIKE IS CLINICAL RESEARCH REALLY RECRUITING SUFFICIENT NUMBERS OF MINORITIES, WHICH WE HAVEN'T BEEN ABLE TO GET FROM THE OLD TABLES. THE HOPE IN THE LONG TERM FOR THAT SYSTEM IS THAT IT WILL ALSO BE SOMETHING THAT INVESTIGATORS CAN USE TO WHAT RICHARD WAS TALKING ABOUT EARLIER, WHICH IS TO COMBINE DIFFERENT STUDIES, MINORITIES FROM DIFFERENT STUDIES, SO THAT YOU CAN DO AN ANALYSIS ACROSS STUDIES USING DATA FROM THOSE DIFFERENT STUDIES AND THAT REALLY IS THE PROMISE OF A MANIPUTABLE SYSTEM. I'M HOPING FOR A LATER USE FOR IT. SO IT IS AN IMPROVEMENT, WE WILL SEE, THEREFORE, IMPROVED DATA BEFORE COUNCIL AND I'VE GOT MY FINGERS CROSSED FOR IT. YES. >> I JUST WONDERED IF THE TASK FORCE, AS WE HAD THIS UNIT TO ADD DATA ELEMENTS POTENTIALLY THE INCLUSION REPORTS, IF WE COULD ASK FOR AGE GROUPS LOOKING AT 65, 74, 75, 84, 85 AND ABOVE. WE AT NIA ARE PARTICULARLY INTERESTED IN THAT. >> I THINK HE'LL DEFE I'LL DEFER TO SEE IF ANYONE CAN ANSWER THAT. I DON'T THINK THIS IS NIA-CONTROLLED. >> ANGELA WAS RAISING THE SAME POINT. THE PROBLEM IS THAT THE LEGISLATION ONLY -- IT WAS A 1995 LEGISLATION -- ONLY SPECIFIES RACE, ETHNICITY AND GENDER. IF THEY'D THROWN IN AGE, WE WOULD HAVE BEEN MUCH HAPPIER BUT THEY DIDN'T DO THAT. SO WE CAN'T REQUIRE IT AS ENTERED FROM ALL STUDIES BECAUSE THE LEGISLATION IS THE ONLY THING THAT ALLOWS THE REQUIREMENT. SO THE QUESTION IS WHETHER WE CAN FISH IT, PUT IT IN IN OTHER WAYS AND WE'LL LOOK INTO THAT, BUT IT'S GOING TO BE TRICKY, I KNOW. >> I CAN JUST ADD THAT I'VE BEEN SERVING ON THE SAME COMMITTEE THAT ANGELA BATES IS ON, THE EXTRA COMEUREXTRAMURAL INCLUSION ACTIVITY, AND THEY ARE VERY CONCERNED ABOUT THE ISSUE OF TRYING TO LOOK AT THE FULL RANGE. THE CHALLENGE THAT YOU RUN INTO IS JUST LOOKING AT PEOPLE IN AGE CATEGORIES DOES NOT NECESSARILY CAPTURE EVERYTHING THAT WE'RE INTERESTED IN BECAUSE OF THE ISSUES OF CO-MORBID IT, ET CETERA. FDA IS ALSO INTERESTED IN THESE ISSUES, SO WE ARE GOING TO CONTINUE TO WORK AT THAT, BUT AS ROBIN POINTS OUT, IT'S NOT THE A LEGISLATIVELY MANDATED THING SO IT'S GOING TO BE A LITTLE TRICKIER TO ACCOMPLISH. >> I THINK IF YOU PUT THE FIELD IN, A LOT OF INVESTIGATORS WILL COMPLETE IT. ESPECIALLY AGE, WHICH IS PRETTY SIMPLE. THAT WOULD BE MY SUGGESTION. >> THE OTHER THING THAT WAS EMPHASIZED AT THE TASK FORCE MEETING WAS THAT YOU HAVE TO ALIGN YOUR POPULATION WITH THE SCIENTIFIC GOALS OF THE STUDY, AND IF YOU LOOK AT POPULATION THAT HAS THIS DISEASE,, VERY OFTEN WE WILL BE PUSHING IT TO BE IN THAT REALM. SO I THINK THE MORE WE CAN PLAY THAT UP, THE BETTER WE'LL BE. >> THERE'S A LOT OF THINGS THAT WE EXPECT PEOPLE TO INCLUDE IN NIH PROPOSALS THAT ARE NOT MANDATED BY LAW. I THINK FOR US IN PARTICULAR, IT REALLY IS IMPORTANT TO KNOW WHAT AGE PARTICIPANTS ARE 75, 85 -- THAT'S THE FASTEST GROWING SEGMENT OF OUR POPULATION AND WE DON'T HAVE SIGNIFICANT DATA. IT'S REALLY IMPORTANT, I THINK, TO THE NATION, WE'VE GOT TO BE ADVOCATING FOR THAT. >> THANK YOU. I THINK INTERNALLY WE ARE ADVOCATING FOR IT. ANY OTHER QUESTIONS ON THE TASK FORCE MINORITY AGING REPORT? OKAY. WE'LL MOVE ON THEN TO THE REPORT FROM THE WORKING GROUP ON PROGRAM AND DR. MAYOR MO MORIMOTO WILL LEAD THAT. >> FIVE CONCEPT CLEARANCES WERE CONSIDERED YESTERDAY, PRESENTED BY STAFF, WITH DISCUSSION FROM COUNCILMEMBERS. TODAY WE'LL JUST GET A SUMMARY AND COMMENTS FROM COUNCILMEMBERS ON EACH OF THE FIVE TOGETHER WITH A DISCUSSION ON RENEWAL FOR A PROGRAM PROJECT THAT WILL COME AT THE END. THE FIRST BY DR. KEVIN HI WILL BE ON THE SARCOPENIA PHASE 2 VALIDATION OF CRITERIA FOR CLINICALLY RELEVANT MUSCLE WEAKNESS IN OLDER ADULTS WITH PHYSICAL LIMITATION. KEVIN? >> THANK YOU. THIS WAS A CONCEPT REVIEW FOR RFA TO SUPPORT ADDITIONAL WORK DETERMINING THE UTILITY OF MEASURES FOR WEAKNESS AND MUSCLE MASS TO PREDICT INCIDENT MOBILITY DISABILITY. THE CONCEPT OUTLINED THE NEED FOR BETTER CUT POINTS FOR VARIABLES THAT CAN BE USED TO STRATIFY SUBJECTS WHO WOULD PARTICIPATE IN CLINICAL TRIALS, AND PERHAPS FOR CLINICAL UTILITY TO DRIVE TREATMENT REGIMENS FOR REVERSAL OF SARCOPENIA AND WEAKNESS. PRIOR DEFINITIONS FOR CUT POINTS WERE DERIVED IN YOUNG ADULT POPULATIONS AND ARBITRARILY SET AT TWO STANDARD DEVIATIONS FROM THE MEAN. THEY WERE NOT DERIVED IN SENIORS, THEY WERE NOT DERIVED IN POPULATIONS WITH EVENT RATES OF A MOBILITY DISABILITY HIGH ENOUGH TO DETERMINE WHETHER THOSE CUT POINTS WERE APPROPRIATE, NOR WERE THEY EXAMINED IN STUDIES WITH ENOUGH DIVERSITY TO DRIVE CUT POINTS FOR SPECIFIC MINORITY POPULATION. SO THIS WAS A RESUBMISSION WITH THE MAJOR CHANGE FROM THE PRIOR SUBMISSION BE BEING THAT THE PRIOR PROPOSAL WAS FLAMED AS A VALIDATION STUDY TO BETTER VALUE -- MARKERS FOR MOBILITY DISABILITY. THE CURRENT PROPOSAL ACTUALLY SEEKS TO CLARIFY THOSE MARKERS AS VARIABLES TO BE USED -- THAT ARE LIKELY TO CAUSE A PATHWAY USED FOR STRATIFICATION OF SELECTION OF SUBJECTS RATHER THAN A SURROGATE MARKER. THE TITLE WAS MUCH CLEARER, EXPRESS -- DEVELOP THESE TWO VARIABLES IN THE CAUSATIVE PATHWAY TO SEPARATE THEIR INDEPENDENT FUNCTION IN PREDICTING MOBILITY DISABILITY. THE GOAL OF THE PROPOSAL WAS SORT OF TO PREPARE AN ROC CURVE, WHERE YOU WOULD LOOK AT DIFFERENT CUT POINTS AND SEE THEIR PERFORMANCE AND SENSITIVITY AND SPECIFICITY. AND IN THE END, THE COUNCIL WAS VERY FAVORABLE FOR THIS AND I RECOMMEND MOVING THIS FORWARD. >> THANK YOU, KEVIN. WERE THERE ANY OTHER COMMENTS? ELISEO, DID YOU WANT TO ADD ANYTHING TO THAT? >> NO. THAT'S FINE. >> ANY OTHER COMMENTS? WE NEED A MOTION. SECOND. ALL THOSE IN FAVOR? ANYONE OPPOSED? ANY ABSTENTIONS? THANK YOU. THE NEXT CONCEPT CLEARANCE, ALZHEIMER'S DISEASE TRANSLATION CENTERS FOR PREDICTIVE DRUG DEVELOPMENT. THIS IS A REQUEST FOR UP TO TWO CENTERS TAKING ADVANTAGE OF RECENT METHODOLOGIES AND QUANTITATIVE SYSTEMS PHARMACOLOGY TO TAKE AN INTEGRATED APPROACH INCORPORATING GENOMICS, PROTEOMICS, STRUCTURAL BIOLOGY, MATHEMATICAL MODELING, MULTIPLE CELL AND ANIMAL MODELS, BIOCHEMISTRY. THE PURPOSE IS TO MOVE WELL BEYOND THE CURRENT STATE OF KNOWLEDGE, THE STATE OF ART, IN DRUG DISCOVERY, WHICH TO DATE HAS GENERATED A LARGE NUMBER OF COMPOUNDS, ALL OF WHICH HAVE FAILED. COMING OUT OF VARIOUS MODEL SYSTEMS TOWARDS PATIENTS. THE STAFF HAS DONE AN OUTSTANDING JOB IN ADDRESSING SOME OF THE CONCERNS. THEY POINT OUT THAT THE REASON FOR FAILURE INCLUDE THE WRONG PATHOPHYSIOLOGICAL MECHANISMS, THE DRUGS DON'T ENGAGE THE INTENDED TARGET, DRUG INTERVENTION MAY OCCUR AT THE INCORRECT STAGE OF THE DISEASE, LACK OF TRANSLATABLE PHARMACODYNAMIC BIOMARKERS, AND PERHAPS MOST IMPORTANT, THE POOR PREDICTIVE POWER OF ANIMAL MODELS IN PRECLINICAL EFFICACY STUDIES. THE DISCUSSION WAS VERY ROBUST, AND I THINK THE ENTHUSIASM WAS VERY HIGH FOR THE HOPE OF THESE NEW TRANSLATION CENTERS TO BRING TOGETHER AND MOVE FORWARD EVEN BETTER TARGETS AND BETTER SMALL MOLECULES. SO IT MET WITH APPROVAL. OTHER DISCUSSION FROM PERHAPS ANA MARIA OR KEVIN? >> WE ALL PERCEIVE THIS AS SK VERY NECESSARY AND IT WAS VERY NICE TO SEE THIS INITIAL REQUEST FOR ACTION BECAUSE I THINK WE ARE GOING TO LEARN A LOT ABOUT THESE APPLICATIONS, CREATIVE WAYS TO JOIN EFFORTS. >> THANK YOU. MOTION TO APPROVE? AND A SECOND? ALL THOSE IN FAVOR? ALL THOSE OPPOSED? ANY ABSTENTIONS? THANK YOU. >> YOU'RE SUPPOSED TO ALLOW AT LEAST HALF A SECOND FOR DISCUSSION. [LAUGHTER] >> I'M FROM THE CITY OF CHICAGO. >> THANK YOU. SO NOTED. THE NEXT BIOMARKERS OF ALZHEIMER'S DISEASE AND DOWN'S SYNDROME. >> THIS IS A CONCEPT TO OBTAIN THE BIOMARKERS THAT WE'VE HAD SUCH RECENT ADVANCES IN OF ALZHEIMER'S DISEASE AND ANOTHER AT RISK POPULATION. THOSE INDIVIDUALS WHO HAVE DOWN SYNDROME, THE TRIPLCATION INCLUDES THE -- INDIVIDUALS WHO HAVE DOWN'S SYNDROME DEVELOP THE PATHOLOGY OF ALZHEIMER'S DISEASE, AMYLOID -- IN THEIR BRAINS BEGINNING IN THEIR 30s AND ALMOST INEVITABLY PROGRESS TO ALZHEIMER'S DISEASE DEMENTIA IN THEIR 50s AND WITH NEAR 100% PENETRANCE BY AGE 70. SO THE CONCEPT PRESENTED WAS TO START TO COLLECT IN VERY STANDARDIZED WAY THE SAME BIOMARKERS THAT WE'RE COLLECTING IN OTHER RISK POPULATIONS INCLUDING IMAGING, PET IMAGING, MRI, CEREBROSPINAL FLUID AND COGNITIVE TESTS THAT CAN HELP US LINK THE BIOMARKERS TO THE COGNITIVE CHANGES IN THESE INDIVIDUALS, BECAUSE THIS MAY BE A DIFFICULT POPULATION TO ASSESS COGNITIVE CHANGE. THIS WAS MET WITH A GREAT DEAL OF ENTHUSIASM YESTERDAY AMONG ALL OF THE DISCUSSANTS, OFFERS AN INCREDIBLE OPPORTUNITY TO PARTNER WITH THE NATIONAL INSTITUTE ON CHILD HEALTH AND DEVELOPMENT AS WELL AS NINDS, AND IT'S VERY COMPLEMENTARY TO THE EFFORTS THAT THE NIA IS ALREADY SUPPORTING IN AUTOSOMAL DOMINANT ALZHEIMER'S DISEASE AND AGE AT RISK INDIVIDUALS. SO THIS WAS STRONGLY SUPPORTED. >> THANK YOU VERY MUCH. RICHARD OR BRAD, DID YOU WANT TO ADD ANYTHING TO THAT DISCUSSION? VERY GOOD. WE NEED A MOTION TO APPROVE AND A SECOND? THANK YOU. ALL THOSE IN FAVOR, SAY AYE. THANK YOU. YOU NOTICE I PAUSED. [LAUGHTER] THE NEXT CONCEPT CLEARANCE FOR DISCUSSION, INTERDISCIPLINARY RESEARCH TO UNDERSTAND THE VASCULAR ETIOLOGY OF ALZHEIMER'S DISEASE AND RELATED DEMENTIAS. DR. RICHARD MAYUO. RICHARD? >> IT'S BEEN RECOGNIZED FOR A LONG TIME THAT THERE'S AN INTERPLAY BETWEEN VASCULAR DISEASE AND ALZHEIMER'S DISEASE AND THERE ARE SEVERAL COHORTS EXISTING THAT HAVE NOTED THE RELATIONSHIP, BUT WE NEED TO TAKE A STEP FURTHER TO UNDERSTAND HOW VASCULAR DISEASE CAUSES ALZHEIMER'S DISEASE, WHETHER THESE ARE PARALLEL OR BIOLOGICAL INTERACTION. THAT WOULD THEN PROVIDE SOME DATA THAT COULD THEN BE TAKEN TO THE LABORATORY TO LOOK AT MECHANISMS, AND THERE WAS A GREAT DEAL OF ENTHUSIASM. WE ALL RECOGNIZE IT AS A VERY IMPORTANT ASPECT TO STUDY. AND IT WAS ENTHUSIASTICALLY ENDORSED. >> THANK YOU, RICHARD. WOULD BRAD OR RISA, DID YOU WANT TO ADD ANYTHING FURTHER TO THAT? WOULD ANYONE ELSE LIKE TO MAKE A COMMENT? I NEED A MOTION TO APPROVE. SECOND? ALL THOSE IN FAVOR? THANK YOU. ANYONE OPPOSED? ANY ABSTENTIONS? THE LAST OF THE CONCEPT CLEARANCES, IMMUNE AND INFLAMMATORY MECHANISMS IN ALZHEIMER'S DISEASE. DR. ANA MARIA CUERVO? THIS IS A JOINT EFFORT, BASICALLY IT ATTEMPTS TO ADDRESS A VERY IMPORTANT POINT THAT IS THE ROLE OF THE INFLAMMATORY RESPONSE AND THE CONTRIBUTION TO ALZHEIMER'S DISEASE, SO IT BUILDS IN IMPORTANT OBSERVATIONS, THE FIRST ONE THAT CHRONIC INFLAMMATION HAS BEEN TRADITIONALLY -- OF COURSE INFLAMMATORY RESPONSE IS GOOD FOR A TIME BUT END RESULT CAN HAVE DETRIMENTAL CONSEQUENCES. RECENTLY THERE HAS BEEN GENETIC CONNECTION OF IDENTIFIED AS A RISK FACTOR OF AGING SOME OF THE INFLAMMATORY RELATED GENES AND IN ADDITION, THE DISEASE -- NEW PERCEPTION THAT THE IMMUNE SYSTEM MIGHT BE A VERY GOOD WAY OF COMMUNICATION OF THE BRAIN WITH THE OTHER SYSTEMS AND THERE IS GROWING EVIDENCE THAT HOMEOSTASIS OF THOSE ORGANS IS IN CONTROL ON -- IT HAS THE RATIONALE -- SUPPORTING THIS COMMUNICATION. SO THE REQUEST IS FOR FUNDING OPPORTUNITY AND SETASIDE MONEY, AND THE NEED IS JUSTIFIED BECAUSE THIS HAS TO BE -- IN A DIFFERENT WAY SINCE THIS IS -- INTEGRATE IMMUNOLOGY GISTS, NEUROSCIENTISTS, SYSTEMIC IN MANY ASPECTS. THEN IF FITS VERY WELL WITH THE MISSION THAT WE HEAR ABOUT ALZHEIMER'S RESEARCH AND THE NEED FOR CREATIVE AND DIFFERENT WAYS TO TACKLE THESE PROBLEMS. THERE HAS BEEN A LOT OF THINKING BEHIND THIS REQUEST AT THE LEVEL OF -- FOR ALZHEIMER'S AND THE GEROSCIENCE MEETING AND IS VERY WELL SUPPORTED. SO IT WAS RECEIVED WITH TREMENDOUS ENTHUSIASM BY THE COUNCIL AND BASICALLY THERE WAS DISCUSSION AND TWOS EVEN RECOMMENDED THAT EVEN FOCUSED MOSTLY ON ALZHEIMER'S STUDY, SIMILAR STUDIES -- MIGHT ALSO CONTRIBUTE AND -- THIS PROGRAM, SO OVERALL, IT WAS VERY WELL RECEIVED. >> THANK YOU, ANNA MARIA. BRAD, DID YOU WANT TO ADD ANYTHING TO THAT? THANK YOU VERY MUCH. ARE THERE ANY OTHER COUNCIL MEMBERS ON THIS CONCEPT CLEARANCE? OTHERWISE I NEED A MOTION TO APPROVE AND A SECOND. ALL THOSE IN FAVOR? THANK YOU. ANYONE OPPOSED? ANY ABSTENTIONS? THE FINAL ITEM ON THE DOCKET FOR US IS A DISCUSSION OF A RENEWAL FOR A PROGRAM PROJECT. ELISEO, WOULD YOU BE WILLING TO -- ROBIN. >> I'D BE GLAD TO DO IT, ELISEO, IF YOU WANT. START WITH -- THERE'S AN NIA POLICY ON PROGRAM PROJECTS WHICH ARE LARGE COLLABORATIVE PROJECTS ON A PROBLEM OF SOME SIGNIFICANCE, AND WE LIMIT THEM TO 1.5 MILLIONED A YEAR IN DIRECT COSTS, ALLOWING EXCEPTIONS BUT THE EXCEPTIONS MUST BE APPROVED BY SENIOR STAFF STAFF. THE PARTICULAR PROGRAM PROJECT WHICH WAS -- HAD EARLIER, I MEAN, FIVE YEARS AGO, BEEN APPROVED AT THAT TIME, WHERE THE BUDGET WAS, IN FACT, $3 MILLION IN DIRECT COSTS, WHICH WAS VERY SUBSTANTIALLY OVER $1.5 MILLION, AND IT IS FOR A LARGE SURVEY, THE MIDAS SURVEY, SO THERE WAS REALLY SOME JUSTIFICATION FOR DOING THAT. AT THE TIME THAT THEY CAME IN FOR REQUESTING PERMISSION TO SUBMIT THE RENEWAL, OBVIOUSLY THIS WAS IN 2013, WHEN WE HAD JUST BEEN CUT -- OUR BUDGET HAD BEEN CUT 5% AND WE WERE VERY HESITANT TO ACCEPT THE RENEWAL AT THAT TIME. SO WE ASKED AN OUTSIDE GROUP OF CONSULTANTS TO MAKE A RECOMMENDATION AND THEN BROUGHT THAT TO COUNCIL AND LAURA PRESENTED THE RECOMMENDATION AT THE WORKING GROUP YESTERDAY. IN FACT, THE GROUP RECOMMENDED THAT WE MOVE FROM A PROGRAM PROJECT TO A COOPERATIVE AGREEMENT, AND USE THE COOPERATIVE AGREEMENT MECHANISM TO SUPPORT THIS AWARD. THE FORMAL MECHANISM IS A U19, WE DON'T NEED TO KNOW THE DETAILS OF THAT, BUT WHAT THAT ALLOWS IS PROGRAM STAFF INVOLVEMENT IN THE WORK, IT ALLOWS THE STEERING COMMITTEE TO BE DEVELOPED THAT ALLOWS MORE VEGHTD TOREINVESTIGATORS TO HAVE INPUT INT O IT, WHICH IS IMPORTANT FOR THIS WORK BECAUSE PART OF THE VALUE OF THE SURVEY IS TO HAVE OUTSIDE INVESTIGATORS USE THE DATA OF THE SURVEY TO ACTUALLY EXPAND AND ENRICH THE FIELD THROUGH THAT, AND HAVING A STEER OOG COMMITTEE ALLOWS OUTSIDE INVESTIGATORS ALSO TO BE PART OF IT. SO THE RECOMMENDATION WAS DISCUSSED WITH THE WORKING GROUP, AND THE WORKING GROUP HAS RECOMMENDED TO COUNCIL THAT, IN FACT, WE ACCEPT IT AS A COOPERATIVE AGREEMENT RATHER THAN AS A PROGRAM PROJECT, AND THAT'S THE RECOMMENDATION BEFORE YOU NOW. >> JUST TO ADD TO THAT, THANK YOU, THIS PARTICULAR STUDY, COHORT STUDY, IS PERSONS IN MID LIFE. IT IS ESPECIALLY IMPORTANT GIVEN THE FOCUS ON REVERSIBILITY AND MODIFIABLE FACTORS FOR LATE LIFE EFFECT. AND STAFF AND THE SCIENCE BEHIND IT, I THINK HAS DEEMED IT VERY HIGH QUAL, SO THERE'S NO PERCEPTION IN THE CONSULTANTS' REPORT ABOUT THAT. IT'S ABOUT 7,000 PARTICIPANTS. THE ONE -- THERE WERE A NUMBER OF THINGS THAT WERE SUGGESTED AT THE DISCUSSION YESTERDAY, BUT I THINK WE'LL SEE HOW THE GRANT COMES IN. THE ONE POINT THAT I IN PARTICULAR WANTED TO MAKE IS THAT THERE WOULD BE AN INCREASE IN MINORITY PARTICIPATION, SINCE THIS WON'T BE A HALLMARK COHORT STUDY OF NIA LIKE THE HRS HOPEFULLY, BUT IN A COHORT STARTING AT A MUCH YOUNGER AGE AND FOCUS ON OTHER SOCIAL AND PSYCHOLOGICAL MECHANISMS OF LATE LIFE ADVERSITY. SO I THINK THAT'S THE ONLY POINT. >> THANK YOU, ELISEO. WERE THERE ANY OTHER DISCUSSION POINTS BY OTHER MEMBERS OF COUNCIL? OTHERWISE I THINK WE NEED A MOTION TO APPROVE THIS RECOMMENDATION. A SECOND? ALL THOSE IN FAVOR, PLEASE SAY AYE. GOOD. ANYONE OPPOSED? ANY ABSTENTIONS? THANK YOU. >> I THINK YOU'RE MOVING TOWARDS AN EARLY BREAK HERE, BUT BEFORE WE DO THAT, I'M GOING TO KEEP YOU FROM YOUR COFFEE JUST FOR A MOMENT TO ADVERTISE THE FACT THAT STATISTICAL PACKAGES AVAILABLE FOR VISITORS TO THE COUNCIL, WE TALKED ABOUT IT AT THE WORKING GROUP ON PROGRAM YESTERDAY. THE THING TO NOTE THAT IS OF PARTICULAR ATTENTION IS THAT OUR APPLICATIONS ARE STAYING UP. WE SAW A 30% INCREASE IN RESEARCH GRANT APPLICATIONS IN 2013 OVER 2012, IF YOU CORRECT FOR RFAs. IT WAS A 20% INCREASE. THIS WAS IN THE CONTEXT OF A 3% DECREASE IN APPLICATIONS ACROSS NIH, SO APPLICATIONS TO NIA WERE SOARING WHEN APPLICATIONS ACTUALLY FELL SLIGHTLY ACROSS NIH. WE'VE ANALYZED IT TO DEATH, AND THEY ARE SOARING ACROSS NIA. THAT IS TO SAY THERE ISN'T A PARTICULAR PATTERN IN WHERE IT IS, AND IN 2014, THE NUMBERS HAVE STAYED UP. THEY HAVEN'T GONE UP FURTHER, ANOTHER 20%, AND I'M GLAD OF THAT ACTUALLY. BUT THEY HAVE STAYED UP AT THE 2013 LEVELS. ANY QUESTIONS ON THE STAT PACK? ALL RIGHT. WE'LL TAKE A 15-MINUTE BREAK THEN BEFORE WE RECONVENE FOR DR. VALENTINE'S TALK. OUR NEXT ITEM IS DR. HANNAH VALENTINE, CHIEF OFFICER FOR SCIENTIFIC WORKFORCE DIVERSITY WILL TALK ON EXPANDING SCIENTIFIC WORKFORCE DIVERSITY, AND SHE WILL BE INTRODUCED BY DR. MARIE BERNARD. >> SO IT'S REALLY A PLEASURE TO BE ABLE TO INTRODUCE YOU TO DR. HANNAH VALENTINE, PROFESSOR OF CARDIOLOGY FORMERLY FROM STANFORD UNIVERSITY, AND WHO TOOK ON SIGNIFICANT LEADERSHIP ROLES AT STANFORD TO HELP CONSIDERATION OF DIVERSITY OF THE SCIENTIFIC WORKFORCE THERE. AS WAS MENTIONED THE WORKFORCE -- NIH HAS TAKEN SERIOUSLY THE SCIENCE REPORT IN AUGUST OF 2011 THAT DEMONSTRATED THAT WE ARE NOT DOING AS WELL WITH REGARDS TO SUCCESS FOR UNDERREPRESENTED MINORITY RESEARCHERS IN OUR RO. RO1 GRANTS AND OTHERS. PART OF OUR EFFORT TO DO BETTER ALONG THOSE LINES HAS BEEN TO NOT ONLY LOOK EXTERNALLY BUT ALSO LOOK INTERNALLY. SO WE LAUNCHED A NATIONWIDE SEARCH FOR A CHIEF OFFICER FOR SCIENTIFIC WORKFORCE DIVERSITY TO HELP ADDRESS ISSUES WITHIN NIH AND BEYOND, AND DR. VALENTINE WAS REALLY THE SUPERIOR CANDIDATE AND WE'RE REALLY DELIGHTED THAT SHE WAS ABLE TO ACCEPT THE OFFER FROM FRANCIS COLLINS O. SO DR. VALENTINE. >> THANK YOU VERY MUCH, MARIE. I'M REALLY DELIGHTED TO BE HERE, AND I'M JUST IN MY SIXTH WEEK OF THE JOB, AND LEARNING THE ROPES AND GETTING TO KNOW EVERYBODY HERE, BUT THIS IS A VERY IMPORTANT ISSUE TO ME, AND JUST A LITTLE BIT ABOUT HOW I GOT INTO THIS FIELD, I'M A CARDIOLOGIST BY TRAINING AND A CARDIAC TRANSPLANT PHYSICIAN AT THAT, WHO'S BEEN DOING RESEARCH IN BIOMARKER DEVELOPMENT TO IMOF PROVE THE OUTCOMES OF HEART TRANSPLANT RECIPIENTS, AND AS SUCH I'VE HAD AN ACTIVE RESEARCH PROGRAM AND CONTINUED TO DO SO BUT IN 2005, I WAS ASKED TO SET UP AN OFFICE THAT WOULD LEAD THE DIVERSITY EFFORTS TO DIVERSIFY THE FACULTY SPECIFICALLY AT STANFORD AT A TIME WHEN WE WERE REALLY QUITE LAGGING BEHIND, AND COUPLED WITH THAT, THE CHARGE WAS ALSO TO INCREASE OR IMPROVE FACULTY DEVELOPMENT PUT IN PLACE LEADERSHIP POGS AND GO DO THAT WAS THE CHARGE, SO AS YOU CAN IMAGINE, IT WAS QUITE CHALLENGING COMING FROM A PHYSICIAN WHO'S A CARDIOLOGIST WHO, QUITE FRANKLY, HAD BEEN IN THE TRENCHES THINKING MORE ABOUT SCIENCE AS OPPOSED TO THESE ISSUES, SO IT WAS VERY CHALLENGING BUT I EMBRACED IT, AND I WOULD SAY THE CORE OF MY WORK WHY THAT SPACE WAS TO REALLY HAVE FIRM EVALUATION ABOUT WHAT WORKS AND WHAT DIDN'T WORK, AND TO ROOT THE INTERVENTIONS IN THEORY SUCH THAT THE PROGRAMS COULD BE WELL DESIGNED AND FULLY EVALUATED. AND I THINK I GOT THAT A LITTLE BIT FROM THE FIELD OF CARDIOLOGY WHERE OF COURSE EVIDENCE BASE IS EVERYTHING. AND WE LIVE AND BREATHE ON IT. SO WHAT I'M GOING TO TALK TO YOU IN A MOMENT IS ABOUT A LOT OF THE PROGRAMS AND THE APPROACHES THAT I TOOK AT STANFORD, THEN WE'LL TALK A LITTLE BIT ABOUT WHAT THE DIRECTION WILL BE HERE. I THINK IT IS NOT REALLY NEEDED FOR ME TO EMPHASIZE TO YOU WHY WE'RE DOING THIS, WHAT IS THE IMPORTANCE OF DIVERSITY, AND IN PART, I THINK WE ALL AGREE TO THE EQUITY ARGUMENT THAT THERE SHOULD BE EQUAL ACCESS AND OPPORTUNITY FOR ALL OF OUR AMERICAN CITIZENS AND NATIONS TO EDUCATION, TO CONTRIBUTE TO BE PARTICIPATING IN THIS ACTIVITY. BUT I THINK IT GOES MUCH FURTHER. IT HAS NOW BECOME, I WOULD SAY, AN IMPERATIVE FOR SUCCESS OF THIS NATION. IT LINKS DIRECTLY TO ENSURING HOW WE RECRUIT, RETAIN AND ADVANCE THE ENTIRE INTELLECTUAL CAPITAL OF THIS NATION AND HOW WE GET THAT CAPITAL INVOLVED IN BIOMEDICAL RESEARCH FOR THE FUTURE. AND THAT, IN FACT, LEADS DIRECTLY TO MAINTAINING OUR COMPETITIVE EDGE AS A NATION. A LOT IS WRITTEN ABOUT THIS, SO I THINK THAT IN ADDITION TO THE EQUITY ARGUMENT, IT IS THIS COMPELLING ARGUMENT THAT IN ORDER TO BE ABLE TO SOLVE THE COMPLEX CHALLENGES OF HUMAN HEALTH AND DISEASE, WE NEED A DIVERSE WORKFORCE TO BE DOING THIS WORK. AND THERE'S ALSO THE EDUCATIONAL ACCESS. WE KNOW THAT THE NIH MISSION GOES BEYOND THE INNOVATIONS AND CREATING NEW APPROACHES TO HELP HEALTH AND DISCOVERIES. IT IS ALSO TO DO WITH TRAINING AND DEVELOPING THE NEXT GENERATION OF TALENT. AND GIVEN THE CHANGE IN THE THMOGRAPHIC OF THIS COUNTRY , SUCH THAT WE KNOW NOW THAT BY 2050, THE MINORITY GROUP WILL IMPACT THE MAJORITY, AND THAT HAS ALREADY HAPPENED IN THE AGES BETWEEN 15 AND 25. IF WE DO NOT PULL FROM THAT POOL OF PEOPLE, OUR CITIZENS, THEN WE WILL BE REALLY MISSING AN OPPORTUNITY. AND I THINK THIS IS A TIMELY OCCASION THAT THE NIH HAS ACTUALLY GOT TOGETHER TO GIVE THAT PUSH, THAT ADDITIONAL PUSH TO THIS EFFORT, AND IT WAS IN RECOGNITION OF THAT AND THE SERIOUSERIOUSNESS BEING AWARDED TO THIS ISSUE THAT I DECIDED TO, AFTER 28 YEARS AT STANFORD ON THE FACULTY, TO ACCEPT THIS POSITION HERE AT NIH. SO WHAT WERE WE TALKING WITH A LITTLE BIT ABOUT WHY THE DIVERSITY IS IMPERATIVE, AND WE'VE ALREADY TOUCHED ON THAT. I'LL SHOW YOU SOME DEPICKS OF WHAT THE DEMOGRAPHIC PROBLEM IS AS IT RELATES TO THE PIPELINE AND ATTRITION. THEN WE'LL TALK ABOUT INSTITUTIONAL PROGRAMS AND HOW LIMITED THEY ARE. THEY ARE NECESSARY BUT NOT SUFFICIENT FOR REACHING THE KINDS OF GOALS FOR DIVERSITY THAT I THINK WE ALL ASPIRE TO. THEN WE'LL TALK ABOUT WHAT ADDITIONAL THINGS, AND I THINK THOSE ADDITIONAL APPROACHES HAVE TO DO WITH INTERVENTIONS THAT TARGET THE CULTURE. I'VE TALKED A LITTLE BIT ABOUT THE IMPORTANCE OF DIVERSITY FOR EXCELLENCE. THE FACT THAT WHEN YOU HAVE A DIVERSE TEAM, THEY WILL COME UP WITH A BETTER AND MORE CREATIVE SOLUTION, PARTICULARLY FOR COMPLEX PROBLEMS. AND WHAT MORE COMPLEX THAN THOSE OF HUMAN HEALTH DISEASE ENVIRONMENT THAT WE ARE FACING. AND THIS IS NOT JUST SOMETHING PULLED OUT OF A HAT. THERE IS RESEARCH EVIDENCE THAT SHOWS THAT DIVERSITY TEAMS, IF MANAGED PROPERLY, BECAUSE THERE ARE CHALLENGES TO MANAGING, CAN RESULT IN BETTER SOLUTION TO COMPLEX PROBLEMS. THERE IS THE ISSUE OF NARROWING HEALTH DISPARITIES AND NARROWING THE GAPS TO WHICH WE THINK THAT BROADENING THE DIVERSITY IN THE BIOMEDICAL WORKFORCE WILL ACTUALLY HELP TO ADDRESS BY CREATING MORE RESEARCHERS THAT COME FROM DIVERSE BACKGROUNDS WHO WILL CONTRIBUTE TO SHAPING THE RESEARCH AGENDA, WILL HAVE MORE AFFINITY WITH RECRUITING PATIENTS INTO CLINICAL TRIALS AND TRANSLATING THAT KNEW KNOWLEDGE INTO ACTUAL CURES AND TREATMENT FOR PATIENTS. SO HERE'S THE PROBLEM. AND I THINK THIS IS PROBABLY ALL KNOWN TO YOU. WHAT IT TRIES TO DEPICT HERE IS THAT WHILE WE HAVE -- WE START OFF WITH A CERTAIN AMOUNT OF REPRESENTATION OF UNDERREPRESENTED GROUPS IN THIS BY DEFINITION AFRICAN-AMERICAN, NATIVE AMERICAN, HISPANIC, PACIFIC ISLANDER GROUP IN MEDICAL SCHOOL CLASS, FOR EXAMPLE, AS YOU GO UP THE CAREER PATH, YOU GET A SIGNIFICANT DROPOFF AND THIS ACTUALLY IMPLIES THAT WE NEED TO CONTINUALLY BE BUILDING THE PIPELINE. BUT THE PIPELINE ISN'T ALL THE ANSWER. THIS IS VERY NICELY DEPICTED BY THE STORY THAT WE CAN SEE WHEN WE THINK ABOUT GENDER DIVERSITY. AND WHAT YOU'RE SEEING HERE IS THE REPRESENTATION OF WOMEN IN READ AND MEN IN BLUE AS WE GO -- ADVANCE FROM MEDICAL STUDENT RIGHT UP TO LEADERSHIP POSITION. AND THIS AGAIN IS NOT NEW TO YOU, THIS DROPOFF, AND BY THE TIME WE'RE TALKING ABOUT LEADERSHIP POSITIONS, WE HAVE ONLY A 12%. AND THE REASON I SAY THAT THIS IS SOMETHING BEYOND THE PIPELINE, IS THAT WE HAVE BEEN GRADUATING 50% OF WOMEN IN CLASSES FROM MEDICAL SCHOOLS FOR THE LAST 10 YEARS. PH.D.s FOR EVEN LONGER. CLOSE TO 18 YEARS. THE PH.D. GRADUATE CLASSES HAVE BEEN MORE THAN 50% WOMEN. AND YET, AND YET, WE ARE NOT SEEING THEM HERE. AND THE SLOPE OF THE CURVES HAS BEEN DONE BY STATISTICIANS AND SHOWN THAT THIS IS NOT A COHORT EFFECT, IT IS ACTUALLY RELATED TO ATTRITION OR A LEAKY PIPELINE. SO OUR WORK IS CUT OUT TO INVOLVE MANY INTEGRATED INTERVENTIONS TO TRY AND ADDRESS THESE TWO ISSUES. LET ME JUST SAY A WORD ABOUT PIPELINE, AND AS AN EXAMPLE, SHOW YOU SOME OF THE WORK THAT HAS BEEN GOING ON AT STANFORD AND MANY OF YOU HERE WILL RECOGNIZE THIS KIND OF WORK THAT GOES ON IN MANY OF THE INSTITUTIONS. THAT IS TO SAY, TO HAVE PROGRAMS AT EVERY ONE OF THE TRANSITION POINTS THAT IS TARGETED TO ENABLE THE INCREASE OR THE EXPANSION OF DIVERSITY ACROSS THE ENTIRE PIPELINE OR PATH TO ACADEMIA. AND YOU CAN SEE HERE, WE HAVE THEM UNDE UNDERGRADUATE, GRADUATE AND SO FORTH. AND IT'S A LOT OF WORK. A KEY ELEMENT OF THIS NEW POSITION THAT I'VE TAKEN UP IS TO BE ABLE TO COME UP WITH A COORDINATED APPROACH TO DOING THESE PROGRAMS TO HAVE BETTER LINKAGES BETWEEN THESE PROGRAMS, AND MORE THAN ANYTHING, TO HAVE A COORDINATED EFFORT IN EVALUATING THESE PROGRAMS TO SEE WHAT REALLY DOES WORK, TO SUPPORT THOSE FURTHER AND DISSEMINATE THOSE FURTHER AND TO NOT PERSIST WITH PROGRAMS THAT WE CANNOT CONFIRM TO BE EFFECTIVE. THIS IS JUST ONE EXAMPLE, AND AGAIN, I THINK THOSE OF YOU ON THE BOARD MIGHT HAVE SIMILAR PROGRAMS IN YOUR INSTITUTIONS. THIS PROGRAM WAS STARTED BY A FACULTY MEMBER, MARILYN WINKELBEE OF STANFORD, AND HER GOAL WAS TO RECRUIT HIGH SCHOOL STUDENTS WHO ARE FROM VERY, VERY UNDER DISTURBED AREAS. AND IN FACT -- TO THE EXTREME AND WHO HAVE, IN FACT, BEEN EXPERIENCING INCREDIBLE SOCIAL CHALLENGES. AND WHAT MARILYN DESIGNED WAS THE STANFORD SUMMER PROGRAM THAT BRINGS A COHORT OF THESE STUDENTS, USUALLY IN THEIR JUNIOR YEAR, FOR A RESIDENTIAL PERIOD AT STANFORD FOR SIX WEEKS, THEY'RE PROVIDED WITH MENTORS, THEY HAVE LECTURES, THEY'RE ASSIGNED TO LABS OR TO CLINICS, AND THIS WORK OF MENTORSHIP THEN GOES ON AFTER THE PROGRAM IS COMPLETED SO THAT THEY GET SUPPORT FOR PREPARATION TOWARD THE SAT APPLICATION AND MANY OTHER THINGS. AND THE RESULTS ARE QUITE DRAMATIC, AND ONE OF THE REASONS I PARTICULARLY WANT THIS IS THAT MARILYN WIN KELBEE, BEING AN EP EPIDEMIOLOGIST, DESIGNED THESE PROGRAMS IN A WAY THAT SHE COULD DO LONG TERM FOLLOW-UP AND ASSESSMENT OF THESE PROGRAMS AND HAS PUBLISHED QUITE EXTENSIVELY ON IT, AND LAST YEAR RECEIVED THE PRECEDENTIAL AWARD FOR IT. BUT HERE'S SOME OF THE KINDS OF DATA THAT WE WOULD HOPE. THE FOUR-YEAR PROGRAM HERE, IF YOU SEE THE AFRICAN-AMERICAN 78 P% GRADUATION RATE, LATINO, 81% GRADUATE RATE, IN CONTRAST TO NATIONAL LEVELS WHICH ARE LESS THAN A THIRD COMPARED TO THIS PROGRAM. SO CLEARLY SOMETHING IS HAPPENING IN THIS PROGRAM. THIS IS THE KIND OF THING THAT SHOULD BE PICKED UP, DISSEMINATED, BOTH IN TERMS OF DESIGN AND APPLICATION. SO I MENTIONED TO YOU THAT IN 2005, BEN PISO ASKED ME TO SET UP AN OFFICE AT STANFORD WHOSE FOCUS WOULD BE TO EXPAND THE DIVERSITY, PARTICULARLY IN THE FACULTY AND TO HAVE THIS ALSO, THIS COORDINATING ROLE. AFTER A LOT OF SUPPORT, I DID A STRATEGIC PLANNING PROCESS AND CAME UP WITH A NUMBER OF GOALS, AND TO CUT A LONG STORY SHORT, THEY WERE AROUND RECRUITMENT, RETENTION, AND LEADERSHIP DEVELOPMENT. AND WHAT WE ACTUALLY DID AROUND THIS AREA OF RECRUITMENT WAS THAT WE CHANGED THE PROCESS SO THAT I WOULD ENGAGE VERY EARLY WITH SEARCH COMMITTEES. I WOULD REVIEW THE SEARCH COMMITTEE COMPOSITION FOR DIVERSITY, AND OF COURSE I BEING A LITTLE BIT NAIVE, MY FIRST RECOMMENDATION WAS THAT EVERY SEARCH COMMITTEE WOULD HAVE A PERSON FROM AN UNDERREPRESENTED GROUP AND A WOMAN. AND OF COURSE IT DIDN'T TAKE ME TOO LONG TO REALIZE THAT ALL 34 OF US UNDERREPRESENTED FACULTY AT THE TIME WOULD BE ON MULTIPLE COMMITTEES SO I EASED UP ON THAT REQUIREMENT BUT IT'S TRUE THAT EVERY SINGLE SEARCH COMMITTEE NOW HAS A WOMAN REPRESENTED ON IT. THE OTHER THING THAT WAS OUR FOCUS, AND IT'S SOMETHING I WANT TO DO EARLY HERE, IS TO PROVIDE SEARCH COMMITTEES WITH TOOLS TO SEARCH. AND TOOLS TO SEARCH MEAN KNOWING WHERE PEOPLE ARE AND KNOWING WHAT THEY'RE DOING AND HOW THEY CAN CONTRIBUTE TO THIS PARTICULAR APPOINTMENT IN THAT POSITION. ONE OF THE STRATEGIES IS TO LOOK AT THE WMC FACULTY ROSTER, SO I FORMED PARTNERSHIPS WITH THEM, AND THEY WOULD BE ABLE TO THEN GIVE ME INFORMATION ABOUT THE DEMOGRAPHICS IN A CERTAIN POOL, LET'S SAY WE'RE SEARCHING FOR A PROFESSOR OF CARDIOLOGY THAT WOULD BE ABLE TO TELL ME WHAT THE DEMOGRAPHICS OF THE PROFESSORS AND ASSOCIATE PROFESSORS THROUGHOUT THE HUNDRED 26, NOW 131, ACCREDITED SCHOOLS LOOKED LIKE, AND BREAK IT DOWN IN TERMS OF RACE, ETHNICITY AND GENDER. THE TRICK IS OF COURSE -- THEY WON'T GIVE YOU NAMES, BUT OF COURSE BY THE TIME YOU GET DOWN TO THE DATA IN A SELECTED POOL OF TOP 20 INSTITUTIONS, YOU PRETTY WELL KNOW WHO THOSE PEOPLE ARE AND WHERE TO FIND THEM AND HOW TO HOW TO DO THE NEXT STAGE, WHICH IS CRITICALLY IMPORTANT, WHICH IS OUTREACH. WOMEN AND UNDERREPRESENTED GROUPS ARE LESS LIKELY TO JUST RESPOND TO AN AD. THERE IS AN ADDITIONAL STEP THAT IS REQUIRED FOR ACTIVE RECRUITMENT HERE, AND THAT'S THE KIND OF THING THAT I WOULD TEACH THE SEARCH COMMITTEES. AND THE ADDITION -- I WOULD GO TO THE START OF EVERY SEARCH COMMITTEE MEETING AND THIS WAS QUITE BACK BREAKING BECAUSE AT ANY TIME AT STANFORD, THERE WOULD -- I WOULD TALK TO THEM ABOUT BEST PRACTICES, PROVIDE THEM WITH THESE TOOLS IN ADDITION TO PROMISE FOR ADDITIONAL FUNDING SHOULD THEY IDENTIFY A CANDIDATE WHO ADDED TO THE DIVERSITY OF THE INSTITUTION, BUT THEN WE WOULD ALSO TALK ABOUT SOME CHALLENGES IN SELECTING CANDIDATES. AND THESE CHALLENGES PARTICULARLY HINGE AROUND STEREOTYPES AND UNCONSCIOUS BIAS, AND HOW TO OVERCOME THEM AND WE'LL TALK ABOUT THAT IN A MOMENT. THEN FINALLY, WE DEVELOPED A DEFINITIVE PROCESS FOR EVALUATING LEADERSHIP ABILITY IN THE SEARCH PROCESSES. SO HERE'S THE KINDS OF THINGS THAT WE DID IN SUPPORT OF FACULTY RETENTION. THIS IS WHERE A NUMBER OF STRATEGIES ARE REQUIRED TO BE IN PLACE BECAUSE THE NEEDS DIFFER FROM ONE PERSON TO ANOTHER AND IN DIFFERENT STAGES OF A PERSON'S CAREER. SO FACULTY DEVELOPMENT WORKSHOP, YOU CAN SEE THERE THAT -- AIMED AND GIVING PROFESSIONAL DEVELOPMENT SKILLS, RESEARCH AWARD, BECAUSE OF THE STRESSES OF FUNDING, POLICIES AROUND CAREER FLEXIBILITY. THERE ARE A LOT OF THEM. THEY WERE AT STANFORD. BUT WHAT WE DISCOVERED IS THE FACULTY WAS EITHER UNAWARE OF THEM, OR EVEN WHEN THEY WERE UNAWARE OF THEM, WOULD NOT TAKE THEM. AND WHY? BECAUSE OF FEAR OF DEVIATING FROM WHAT THE NORMAL EXPECTATION IS AND BEING VIEWED AS NOT SERIOUS ABOUT THEIR CAREERS. AND THAT'S A KEY THING. AND THAT IMMEDIATELY, YOU CAN SEE, IS A CULTURAL ISSUE THAT WE BEGAN TO TACKLE BEFORE I GOT THERE. IT IS IMPORTANT TO SEND A KEY MESSAGE THAT THE LEADERSHIP CARES, SO WE MET WITH JUNIOR FACULTY, WE DEVELOPED MENTORING PROGRAMS, NETWORKING PROGRAMS AND LEADERSHI LEADERSHIP DEVELOPMENT PROGRAMS, AND ONE IN PARTICULAR WAS STRUCTURED TO CREATE A SENSE OF BELONGING, SO YOU TAKE A GROUP OF 20 FACULTY, PUT THEM THROUGH A YEAR-LONG PROGRAM SO THEY GOT TO KNOW EACH OTHER, THERE WAS A DINNER PRESENTATION ON A MONTHLY BASIS BY A KEY INSTITUTIONAL LEADER, LIKE THE PRESIDENT, THE PROVOST, THE DEAN, MANY OTHERS, WHO WOULD TELL ABOUT THEIR LEADERSHIP JOURNEYS. THEN THEY WOULD BE PUT INTO SMALL MENTORING GROUPS LED BY A SENIOR FACULTY MEMBER WHO HAD EXPERIENCE IN MENTORING, AND WITHIN THOSE GROUPS, THEY COULD BEGIN TO LEARN FROM EACH OTHER WHAT THE CHALLENGES WERE AND HOW TO OVERCOME THEM, GUIDED BY THE SENIOR PERSON WHO WAS EXPERIENCED IN MENTORING. THEN THERE WAS A THIRD COMPONENT WHICH WAS A CAREER DEVELOPMENT PLANNING PROCESS. THIS ISSUE OF -- WE ALSO DID A LOT OF EVALUATION, AND THIS, AS I MENTIONED WASHINGS THE CORE, WAS THE COR E ASPECT OF IT THAT I RAN. SO WE USED THE FACULTY SURVEYS TO INFORM US WHAT FACULTY WAS THINKING ABOUT, AND THEN WE DESIGNED PROGRAMS TO ACAN DRESS THEM. AND SO COMING OUT OF THEM DIRECTLY WITH A FACULTY CAREER, FLEXIBILITY PROGRAM, OUR CHILD CARE PROGRAM, AND PROGRAMS THAT ADDRESS THE SOCIAL PSYCHOLOGICAL ISSUES THAT LIMIT THIS PROBLEM. SO HOW DID WE DO WITH ALL OF THAT FLURRY OF ACTIVITY COMPARING 2004 TO 2012? AS YOU CAN SEE HERE, IF YOU LOOK AT THE RAW NUMBERS AND THE PERCENTAGES WITHIN THE BARS, YOU CAN SEE THAT THERE WAS SOME INCREASE. AND IN FACT, THE TOTAL UNDERREPRESENTED GROUP WENT FROM 34, AS I MENTIONED, TO OVER 100 OVER THIS PERIOD OF TIME. BUT UNFORTUNATELY, IT'S NOT THE PERCENTAGE REPRESENTATION THAT WE WOULD LIKE TO SEE, I THINK OVERALL, IT WORKED OUT TO BE ABOUT 6.8% OR SO UNDERREPRESENTED GROUPS. BUT THIS GIVES US A GREEN LIGHT MOVING IN DIRECTION BUT IT IS STILL NOT SUFFICIENT. HOW DID WE DO FOR WOMEN? SIMILAR STORY. SHOWING WOMEN INCREASING IN THE REPRESENTATION FROM 25% TO 36% OR SO, AND WE'VE PUT ALL OF THIS INFORMATION TOGETHER IN THE FORM OF A REPORT, WHICH WAS PUBLISHED LAST MONTH IN ACADEMIC MEDICINE, AND THE INCREASES HERE WERE QUITE INTERESTING. BECAUSE THE LARGEST PERCENT INCREASE WAS ACTUALLY IN THE FULL PROFESSOR RANK. WHICH IS THE RANK THAT IS JUST PRECEDING THE LEADERSHIP POSITION. SO WE WERE QUITE EXCITED ABOUT THAT PARTICULAR FINDING. HOWEVER, WHEN WE DID THE DETAILED ANALYSIS AND CALCULATED THE CHANGE OVER TIME OVER A 10-YEAR PERIOD, YOU CAN SEE THERE IS AN INFLECTION POINT HERE WITH A CARDINAL RED HERE, THE NATIONAL DATA, AND COMPARISON TO SIX PEER INSTITUTIONS IN BLUE. WHAT YOU CAN SEE HERE FOR STANFORD IS THAT THERE IS THE INFLECTION POINT HERE AT THE START COINCIDENT WITH THE START OF THE INTERVENTIONS FROM MY OFFICE, AND OF COURSE I'M TAKING FULL CREDIT FOR THAT. [LAUGHTER] HOWEVER, LOOK AT THIS INFORMATION HERE. THE TIME FOR 50% WOMEN FULL PROFESSOR, EVEN WITH THIS INCREASED SLOPE OF THE CURVE, IS 28 YEARS. AND 40 YEARS FOR PIERCE AND 48 YEARS FOR THE NATIONAL DATA. I DIDN'T KNOW ABOUT YOU, BUT AS AN IMPATIENT CARDIOLOGIST, THIS IS TOO LONG, FAR TOO LONG. SO WE'RE THINKING ABOUT, WHEN I LEFT, ABOUT OTHER APPROACHES, AND PARTICULARLY APPROACHES THAT ADDRESS THE KL TOUR. AND ONE OF THESE IS THIS INTERVENTION FOR UNCONSCIOUS BIAS OR IMPLICIT ATTITUDES THAT ARISE FROM STEREOTYPES THAT WE ALL HAVE. I'LL SHOW YOU A STUDY THAT WE DID WHICH WE WERE VERY EXCITED ABOUT THE RESULTS. THE OTHER IS THE FLIP SIDE OF THAT, WHICH IS STEREOTYPE THREAT, WHICH WAS FUNDED BY THE NIH DIRECTOR'S PATHFINDER AWARD, WHICH IS THE -- OF COMING TO A NEGATIVE STEREOTYPE IDENTIFIED WITH ONE'S IDENTITY GROUP, AND THAT FEAR AND ANXIETY AND LACK OF A SENSE OF BELONGING ACTUALLY DIMINISHES ONE'S PERFORMANCE. CAREER FLEXIBILITY, VERY IMPORTANT. I WON'T SAY MUCH ABOUT IT, BUT I CAN GIVE YOU MORE INFORMATION ABOUT IT, AND THAT WAS FUNDED IN PART BY AN AWARD FROM THE ALFRED SLOAN FOUNDATION, AND THE CORE OF THAT IS AN ATTEMPT TO SEND A CLEAR MESSAGE THAT THERE ARE MULTIPLE PARTS TO SUCCESS, THAT IT SHOULD BE INDIVIDUALIZED AND THE FACULTY AND SCIENTISTS IN GENERAL ARE GIVEN THE OPPORTUNITY TO SIT DOWN AND CREATE -- AND INSTITUTIONS ARE SUPPORTIVE OF THAT, THEN WE ARE MORE LIKELY TO HAVE SUCCESSFUL FACULTY WHO ENJOY THEIR WORK, AND THAT HYPOTHESIS IS STILL BEING TESTED. AND THEN SPONSORSHIP, WHICH I WON'T TALK ABOUT, OUR ACADEMIC COUPLES, TWO BIG AREAS THAT NEED TO BE ADDRESSED. NOW A LITTLE BIT ABOUT THIS UNCONSCIOUS BIAS. MOST OF US BELIEVE THAT WE KNOW SOMEBODY WHO HAS STEREOTYPES BUT WE DON'T CONSIDER OURSELVES TO BE ONE OF THOSE PEOPLE, BUT THE FACT IS THAT THESE STEREOTYPES OPERATE OUTSIDE OF OUR CONSCIOUS AWARENESS. WE KNOW THAT TONS OF LITERATURE AROUND THAT, AND AS I SHOW YOU THE SET OF DEMONSTRATION, YOU HAVE THE CITATIONS AT THE BOTTOM THERE TO EMPHASIZE THAT WHAT I'M TALKING ABOUT COMES FROM SCIENCE. IT'S NOT JUST BEING PULLED OUT OF THE HAT. SO HOW DOES IT HAPPEN? YOU KNOW? YOU GO -- THIS EXPERIMENT WAS CARRIED OUT WHERE THEY WENT TO -- FIRST TO KINDERGARTEN GRADE AND -- AND 58% OF THE KINDERGARTEN DREW THE TYPICAL SCIENTIST WHITE MALE. THE SADDENING THING IS, AS THEY WENT UP TO HIGHER GRADES, MORE OF THE STUDENTS HAVE THAT STEREOTYPIC IDEA OF WHO A SCIENTIST IS. THIS HAS HUGE IMPLICATIONS. NOT ONLY FOR THE SUPPORT AND THE ADVANCEMENT OF PEOPLE WHO DO NOT FIT THIS, BUT ACTUALLY THE PEOPLE THEMSELVES INTERNALIZATION AND FEELING THAT YOU ACTUALLY CAN BE A SCIENTIST, I THINK IS AS IMPORTANT AS THE INSTITUTIONAL AND OTHER RESPONSES TO THE INDIVIDUAL AS A SCIENTIST. SO DESPITE WELL INTENTIONS, WE ARE VULNERABLE TO MAKING COGNITIVE ERRORS, SO THESE STEREOTYPES CAN FEED INTO THIS PROPENSITY FOR US TO MAKE THE COGNITIVE ERRORS ABOUT PATIENTS, ABOUT DATA, AND THE CLASSIC ONE WHICH I'M SURE MANY OF YOU WILL HAVE SEEN THIS PUBLICATION LAST YEAR OR A COUPLE OF YEARS AGO WHERE AN IDENTICAL CV WAS SENT AROUND TO SCIENTISTS IN THE FIELD WHO -- AND THE STORY WAS GIVEN THAT THEY WERE TO SELECT THE APPLICANT FOR A LAB MANAGER POSITION, AND THE INFORMATION IN THE CDs WAS ABSOLUTELY IDENTICAL, AND THE ONLY DIFFERENCE WAS THE NAME. AND IN FACT, THESE ARE SCIENTISTS, THESE ARE PEOPLE WHO DEAL WITH DATA, WHO REGARD THEMSELVES AS OBJECTIVE, THAT MORE WERE THE -- THEY WERE MORE LIKELY TO SELECT THE CANDIDATE'S NAME WHEN THE CV WAS A MALE, THEY RATED THE CANDIDATE HIGHER, AND MOST DEPRESSINGLY, THEY OFFERED LESS MONEY TO THE FEMALE CANDIDATE. SO THAT TELLS YOU A LOT. BEFORE THAT WAS EVEN PUBLISHED, ONE OF THE AREAS THAT I GOT VERY INTERESTED IN EARLY WAS THIS ISSUE, SO WE DESIGNED A STUDY IN WHICH WE WERE ASKING A QUESTION, WELL, JUST A SHORT INTERVENTION, MEANING A TAUB, A STANDARDIZED TALK ABOUT UNCONSCIOUS BIAS WITH ABILITIES TO GUIDE HOW TO OVERCOME IT DOESN'T MAKE ANY DIFFERENCE, EITHER IN THE SHORT TERM OR THE LONG TERM. SO WE GOT 12 CHAIRS, DEPARTMENT CHAIRS, WHO BY DEFINITION UNFORTUNATELY -- UNFORTUNATELY WERE WHITE MALES AT STANFORD AND TAUGHT THEM ABOUT THIS AREA AND GOT THEM TO BE OUR CHAMPION TO GO OUT TO OUR DEPARTMENT AND GIVE THIS TALK. AND WE DID SOMETHING ELSE. BEFORE WE ACTUALLY GAVE THE TALK, WE GOT THE FACULTY MEMBERS TO DO AN IMPLICIT ATTITUDE TEST ALONG THE DIMENSION OF WOMEN IN LEADERSHIP. AND THE WAY THAT WORKS, IT'S A COMPUTER PROGRAM, AND YOU -- FEMALE SOUNDING WORDS ARE THROWN UP, MALE SOUNDING, LEADERSHIP SOUNDING WORDS, FOLLOWER WORDS, AND HOW QUICKLY YOU MATCH MALE WITH LEADER OR FEMALE WITH LEADER GIVES YOU A MEASURE, A SCORE OF YOUR DEGREE OF IMPLICIT ACTION. HERE'S WHAT WE FOUND. VERY MUCH TO OUR SURPRISE, THE DEGREE OF UNCONSCIOUS BIAS WAS GENERALLY LOWER FOR FEMALE FAFACULTY THAN FOR MAIL, MALE. WE DON'T KNOW WHY THAT IS BECAUSE THE SOCIAL SCIENCE LITERATURE WOULD NOT HAVE PREDICTED THIS RESULT AT ALL. WE THINK IT'S SOMETHING TO DO WITH JUST THE STAGE, THE CAREER STAGE OF PEOPLE. BUT THE MOST IMPORTANT FINDING IS THAT THERE IS A DECREASE IN EVERY CATEGORY IN TERMS OF THE LEVEL OF THE UNCONSCIOUS BIAS, THE READINESS FOR WHICH ONE LINKS LEADERSHIP WITH MALE AND AFTER THE INTERVENTION, AND THIS WORK HAS NEVER BEEN DONE BEFORE AND IT WILL BE PUBLISHED AND THE QUESTION IS WHAT NEXT. DO WE GO TO A RESEARCH COMMITTEE, EVERY DEPARTMENT, AND DO BOOSTER SHOTS RATHER LIKE VACCINES EACH YEAR TO KEEP THIS UP BECAUSE WE SUSPECT THAT THIS MIGHT NOT BE LONG LASTING, ALTHOUGH WE HAVEN'T DONE THAT EXPERIMENT EITHER. NOW LET'S TURN TO THE ISSUE OF STEREOTYPE THREAT, BECAUSE THAT IS AN AREA WHICH HOLDS POTENTIAL FOR INTERVENTION THAT MIGHT EXPAND THE DIVERSITY IN THE WORKFORCE. AND WHAT IT IS IS AT THE CORE OF THIS STEREOTYPE, THERE IS A SENSE OF NOT BELONGING. YOU WALK INTO A ROOM, YOU FEEL YOU DON'T BELONG, YOU BECOME ANXIOUS, AND YOUR PERFORMANCE GOES DOWN. AND THERE WAS A VERY NICE RANDOMIZED CONTROL TRIAL THAT WAS DONE WITH STUDENTS AT YALE THAT SHOW THAT THIS BELONGING INTERVENTION MADE A HUGE IMPACT ON THEIR GPAs. SO WE PROPOSED FOR THE PATHFINDER AWARD THAT INTERVENTIONS DESIGNED TO MITIGATE THE EXPERIENCE OF STEREOTYPE THREAT IN WOMEN MEDICAL SCHOOL PROFESSORS WILL IMPROVE THEIR ABILITY TO CAPITALIZE ON ALL THESE INSTITUTIONAL INTERVENTIONS THAT I'VE TALKED ABOUT, AND WE SET ABOUT BY IDENTIFYING AND CHARACTERIZING WHAT THOSE TRIGGERS ARE, AND THEN DESIGNED A RANDOMIZED CONTROLLED TRIAL OF A -- INTERVENTION. IN ADDITION TO THE BASIC SOCIAL SCIENCE STUDIES AROUND THAT, AS IT TURNS OUT, THAT THERE ARE KEY AREAS OF THE BRAIN THAT ARE RESPONSIBLE FOR THESE TRIGGERS OF THIS ANXIETY FEELING THAT IS A CONSEQUENCE OF THESE STEREOTYPE THREATS. AND THAT THROUGH FMRI IMAGING, YOU CAN BE ABLE TO PICK THOSE UP. SO WE CREATED VIDEOS FROM THE -- WHAT THE FACULTY TOLD US WAS A TRIGGER OF THIS STEREOTYPE THREAT, AND THEN IN OUR STUDY, THE MECHANISM TO SEE IF THOSE VIDEOS -- EXPOSED TO THOSE VIDEO SITUATIONS THAT TRIGGER STEREOTYPE THREATS, WHETHER THEY COINCIDENTALLY TRIGGER THE AREAS OF THE BRAIN THAT WE MIGHT EXPECT THEM TO DO. ALSO PART OF THAT EXPERIMENT, CAREER-RELATED WORDS, NEGATIVE WORDS, POSITIVE WORDS, NEUTRAL WORDS, AND AGAIN, ALL OF THIS CAN BE TESTED WITH AN APPROACH CALL ON THE FMRI, AND YOU CAN SEE THESE ARE AN EXAMPLE OF SOME OF THE IMAGES THAT HAVE BEEN OBTAINED AND THESE ARE BY -- DONE BY A NEUROSCIENCE COLLEAGUE WITH A HUGE COLLABORATIVE EFFECT EFFORT WITH SOCIAL SCIENTISTS, NEUROSCIENTISTS, AND FACULTY. SO IN -- I MENTIONED WE'RE DOING A RANDOMIZED CONTROL TRIAL OF AN INTERVENTION, BUT BEFORE THAT, WE HAD TO DO A BASELINE EVALUATION OF A SURVEY, AND THIS IS THE EXTENT, SOME OF THE SURVEY DATA WHICH SHOW SIGNIFICANT DIFFERENCES BETWEEN MALE AND FEMALE FACULTY, AND THESE WOULD SERVE AS END POINTS FOR OUR INTERVENTION. AND ONE OF THEM IS PERSONAL BELIEF IN YOUR POTENTIAL. AND THAT YOU CAN SEE THERE IS A SIGNIFICANT DIFFERENCE BETWEEN MEN AND WOMEN FACULTY, THESE ARE ALL ASSISTANT PROFESSORS. SIMILARLY, BELIEF IN CAREER ADVANCEMENT WHERE WE SEE THAT MEN ARE MORE READILY BELIEVED THAT THERE IS A POTENTIAL FOR CAREER ADVANCEMENT, AND VERY IMPORTANTLY, THESE FEELINGS OF ISOLATION, THE STANDARD SET OF QUESTIONS THAT WAS ASKED. AND THE QUESTION IS, WILL THE INTERVENTION NARROW THESE DIFFERENCES. AND I DON'T HAVE THE RESULTS TO SHOW YOU YET. YOU CAN SEE A PICTURE OF HOW THE APPLIED RESEARCH SHOULD, I BELIEVE, BE PUT INTO THE WHOLE RUBRIC OF DOING CHANGE TO IMPROVE DIVERSITY. LET ME JUST FINISH IN THE NEXT FEW MINUTES TO TALK ABOUT DIVERSITY EFFORTS AT THE NIH, BECAUSE THAT'S WHAT MY ROLE IS NOW, AND AS PA REMENTIONE AS MARIE MENTION ED IN RESPONSE TO THE GITNER REPORT DEMONSTRATED HOW THE RATE OF NIH AWARDS TYPICALLY RO1s, TO UNDERREPRESENTED GROUPS WAS REALLY LOW, AND IN AFRICAN-AMERICANS, 1%, AND IN RESPONSE TO THAT, THERE'S BEEN AN EXAGGERATED ACCELERATED ACTION ON THE PART OF LEADERSHIP HERE, DR. COLLINS PUT TOGETHER A NUMBER OF ADVISORY COMMITTEES TO ADVISE ON WHAT SHOULD BE DONE NEXT IN TERMS OF THE SCIENTIFIC WORKFORCE DIVERSITY, AND THERE ARE DOCUMENTS WITH 13 RECOMMENDATIONS, I'M NOT GOING TO GO THROUGH ALL OF THEM, BUT HERE IS SORT OF A SUMMARY OF THEM. HOUSING DIVERSITY IN THE NIH FUNDED WORKFORCE, AND IN PARTICULAR, FOCUSING ON ONE TRANSITION POINT, WHICH IS THE TRANSITION FROM UNDERGRADUATE TO POSTGRADUATE DEGREES IN THE BIOLOGICAL SCIENCES. THIS IS A FUNDING ANNOUNCEMENT THAT HAPPENED, THE FIRST ONE IS THE NIH BUILDING INFRASTRUCTURE, AND IT'S DEI DESIGNED FOR CREATING THE INFRASTRUCTURE FOR INSTITUTIONS THAT DO NOT HAVE THIS BANDWIDTH FOR RESEARCH AND HAVE NOT HAD IT BEFORE TO BUILD THAT CAPACITY SO THAT THEY CAN BE BUILDING AND CREATING THE NEXT GENERATION OF RESEARCHERS. NATIONAL MENTORING NETWORK IS ALSO PROPOSED, AND THERE'S A NUMBER OF PROPOSALS BEING REVIEWED AND KEY -- REALLY KEY TO ALL OF THIS IS A COORDINATING CENTER. THE CENTER WILL HAVE A COORDINATING ROLE TO OVERVIEW WHAT'S GOING ON, TO TRACK VERY EARLY METRICS OF SUCCESS, AND TO MAKE CHANGES IN PROGRAMS AS THEY OCCUR. THE SECOND IS ENSURING FAIRNESS IN THE REVIEW PROCESS. THIS IS UNDER A PROCESS RIGHT NOW, A LOT OF WORK GOING ON THERE, INCLUDING SOME PILOTS AROUND BLINDED REVIEW. THE THIRD BIG BUCKET IN WHICH I'M STANDING IS INCREASING ENGAGEMENT BY THE LEADERSHIP. FIRST OF ALL, THE CREATION OF THE NIH STEERING COMMITTEE WORKING GROUP ON DIVERSITY, THE WAY THE STRUCTURE OF THE INSTITUTION WORKS HERE AT NIH IS THAT THERE ARE THE STEERING COMMITTEE, AND THE STEERING COMMITTEE HAS WORKING GROUPS THAT THEN ADVISES THE DIRECTOR. THE DIVERSITY IS NOW BEING PART OF THE GOVERNMENT STRUCTURE. THE SECOND THEN WAS THE APPOINTMENT OF THE CHIEF OFFICE OF THE SCIENTIFIC WORKFORCE DIVERSITY, AND HERE I AM. AS I MENTIONED, I HAVE A COORDINATING ROLE FOR NIH INITIATIVES DESIGNED TO ENHANCE THE DIVERSITY OF THE NIH FUNDED RESEARCH WORKFORCE, AND THAT IMPLIES BOTH INTRAMURAL AND EXTRAMURAL. THIS WHOLE ISSUE OF RIGOROUS EVALUATION OF DIVERSITY PROGRAMS, ABSOLUTELY KEY. IT'S ALREADY BEGUN. THERE ARE MANY INSTITUTIONS -- INSTITUTES THAT HAVE DIVERSITY PROGRAMS THAT ARE EMBEDDED EXTRAMURALLY AND INTRAMURALLY, AND NOW WE REALLY NEED A SOLID IDEA OF HOW THEY'RE REALLY DOING. A THIRD ROLE IS TO COLLABORATE ACROSS THE NIH TO INCREASE THE DIVERSITY OF INTRAMURAL INVESTIGATORS, AND THAT IS ONE OF THE KEY THINGS. AND A VERY IMPORTANT AND STRATEGIC ROLE IS THAT THIS PERSON WAS REQUIRED TO THEN CONTINUE THEIR SCIENTIFIC RESEARCH PROGRAM. AND I WAS JUST MENTIONING HERE IN DISCUSSION OFFLINE THAT IT IS QUITE CHALLENGING BECAUSE IT FEELS LIKE TWO -- AT ONCE, BUT I THINK IT'S STRATEGICALLY IMPORTANT BECAUSE THIS IS A SCIENTIFIC INSTITUTION, THE CURRENCY IS ALL ABOUT SCIENCE, AND DOING THE SCIENCE OF DIVERSITY AND BEING A SCIENTIST GIVES ONE AN ABILITY TO ENGAGE BETTER WITH THE COMMUNITY. SO MY VISION IS TO BUILD THE SCIENTIFIC WORKFORCE ACROSS THE NIH AND MAKE IT INTO A MODEL FOR CAPTURING THE MOST TALENTED TO THE BIOMEDICAL RESEARCH ACROSS THE NATION. AND I'VE MADE THE POINT TO YOU ALREADY THAT, WE HAVE TO MAKE SURE THAT WE ARE TAPPING INTO THE ENTIRE INTELLECTUAL TALENT, AND THAT INCLUDES PEOPLE FROM BROAD DIVERSITY OF BACKGROUNDS. I HAVE BEEN MEETING IN MY INITIAL STEPS WITH ALL OF THE IC DIRECTORS, SCIENTIFIC DIRECTORS, TO GET A SCAN OF THE ENVIRONMENT TO SEE WHAT'S GOING ON AND WHAT REALLY ARE THE CHALLENGES. ESPECIALLY THOSE THAT MAY NOT BE ARTICULATED IN SURVEYS AND THAT KIND OF INQUIRY, AND TO LOOK FOR AREAS FOR EARLY SUCCESS, LOW HANGING FRUIT. AND I CAN SAY WITHOUT A DOUBT, AS I TALK TO EVERYBODY, THE KEY THING THAT PEOPLE ARE ASKING FOR IS TO FOCUS ON THE DIVERSITY OF THE INTRAMURAL PROGRAM, AND TO DO THAT, HELP THEM TO ENHANCE THE DIVERSITY IN THE APPLICANT POOL, SO I'LL BE USING SOME OF THE APPROACHES THAT I'VE ALREADY TALKED OH TO YOU ABOUT, AND THESE WILL COME IN THE FORM OF A SET OF TOOLS THAT CAN BE USED BY SEARCH COMMITTEES WITH ASSISTANCE, PEOPLE IN MY OFFICE, TO BE ABLE TO HELP THEM IDENTIFY WHERE THOSE CANDIDATES ARE. AND INJECTING MYSELF INTO THE SEARCH PROCESS SO THAT I CAN TALK TO THE SEARCH COMMITTEES ABOUT WHY DIVERSITY IS IMPORTANT AND HOW TO CONDUCT THE SEARCHES WITHOUT ACTUALLY BEING A MEMBER OF THE SEARCH COMMITTEE. THEN FINALLY, ONCE WE GET PEOPLE HERE, OR TO ANY INSTITUTION, YOU'VE GOT TO MAKE THEM FEEL THAT THEY LONG, THAT THEY ARE INCLUDED, THAT THEY ARE PART OF THE ENTERPRISE. AND I THINK THAT ONE OF THE PROGRAMS THAT WE HAD AT STANFORD CALLED THE FACULTY FELLOWS PROGRAM, DID JUST THAT. MANY OF THE PARTICIPANTS TOLD US FOR THE FIRST TIME IN 10 YEARS, I REALLY FEEL CONNECTED TO STANFORD UNIVERSITY. AND THAT'S THE KIND OF THING THAT I HOPE THAT THAT KIND OF FACULTY FELLOWS PROGRAM MIGHT BE INCORPORATED INTO THE FABRIC HERE AT NIH. SO TO CLOSE THEN, THIS IS TO PULL OUT -- THIS IS A BROADER CONTEXT OF THE STRATEGIC GOALS THAT I'M CONTEMPLATING, OF COURSE THIS WILL HAVE TO GO THROUGH ITS PHASES, BUT MY FIRST GOAL I ALREADY MENTIONED, DIVERSITY IN THE INTRAMURAL PROGRAM, CREATING THE CLIMATE OF INCLUSION AND SENSE OF BELONGING, AND THEN AN IMPORTANT ONE IS TO FACILITATE AND HELP NIH FUNDED INSTITUTIONS TO DO A BETTER JOB. AND, YOU KNOW, THE NIH HAS A LOT OF LEVERAGING POWER, THERE'S A LOT OF LARGE INSTITUTIONAL GRANTS THAT GO OUT AND I THINK THERE'S AN OPPORTUNITY THERE TO PARTNER WITH THESE INSTITUTIONS THROUGH PEER REVIEW, THROUGH SOME REQUIREMENTS, IN TERMS OF THE DIVERSITY WORK THAT IS GOING ON IN THESE INSTITUTIONS. THEN I REALLY SEE MY OFFICE AS BEING A CHART WHERE WE DESIGN INNOVATIVE DIVERSITY PROGRAMS, TEST THEM, AND GRADUALLY RODE THEM OUT, PILOT TEST THEM IN THE INTRAMURAL COMMUNITY AND THEN OUTSIDE OF NIH. AND THEN KEY OF ALL IS COORDINATING THE OUTPUT. SO I THANK YOU FOR YOUR ATTENTION. THIS IS THE WORK THAT WE ARE EMBARKED ON, AND I'M THINKING THAT ULTIMATELY WHAT I'D LIKE TO SEE IS SOMETHING LIKE TURNING DIVERSITY INTO HELP. THANK YOU. [APPLAUSE] >> [INAUDIBLE] -- TO RECRUIT MINORITIES IN THEIR RESEARCH. MINORITY RESEARCH AWARD GIVEN THREE YEARS OF SUPPORT UNDER THE PROGRAM IF YOU HAD AN EXISTING GRANT. THAT PROGRAM SEEMS TO HAVE DISAPPEARED. I WOULD LIKE TO KNOW IS THAT GOING TO BE REINSTATED? AT LEAST TWO OR THREE FACULTY A AT COLUMBIA HAD THEIR ORIGINS THERE. >> SO THIS IS A MINORITY SUPPLEMENT, WHICH AS YOU QUITE RIGHTLY SAID, IT WAS DESIGNED TO BE ADDED ON TO AN EXISTING RESEARCH AWARD, AND IT ACTUALLY WAS IN PLACE UNTIL VERY RECENTLY, AND AS PART OF THIS IT RUBRIC OF RE-EVALUATING EVERYTHING, I THINK IT'S BEEN -- BEFORE I STARTED, BEEN JUST PUT ON HOLD, BUT THE EXPERIENCE FROM THAT HAS BEEN A BIT MIXED, BECAUSE THIS IS, AGAIN, DATA, IT'S NOT CLEAR HOW EXTENSIVELY IT'S BEEN USED. AND IT'S BEEN VERY -- IN AREAS WE KNOW IT'S BEEN VERY PATCHY USE OF IT. AND I DID A SCAN ACTUALLY AT STANFORD, AND I FOUND THAT IT WAS NOT BEING USED VERY MUCH. SOME OF THE REASONS PEOPLE SAY, IT TAKES A LOT TO ACTUALLY CREATE THE APPLICATION AND THE MENTORING PROGRAMS AND SO FORTH, BUT YOU'RE RIGHT, SHOULD WE FIND THAT IT WAS EFFECTIVE, WE MAY LOOK AT HOW WE CAN SUPPORT IT EVEN FURTHER. AND I THINK WHAT HAS HAPPENED IS THAT OFTEN THE AWARD IS GIVEN AND THERE IS NO FURTHER SUPPORT FROM THE NIH TO EITHER MONITOR IT OR TO GET SOME GUIDANCE AS TO HOW TO ACTUALLY SUPPORT THESE PEOPLE. >> [INAUDIBLE] >> YOU CAN USE THE MICROPHONES NOW. HOLD ON. >> SO AS FAR AS I KNOW, THE DIVERSITY SUPPLEMENTS ARE STILL AVAILABLE, IN FACT, WE'VE GOT A RECENT EMAIL FROM OUR -- I THINK SOMEONE SAYING THE BUDGET IS ABOUT TO BE FINISHED ALLOCATED FOR THIS YEAR, SO THIS PROGRAM IS STILL IN PLACE. AND AS I WAS TELLING TALKING TO HANNAH BEFORE SHE STARTED, NIA WENT THROUGH A REVIEW OF ITS DIVERSITY AND DISPARITIES PORTFOLIO THAT WAS COMPLETED A YEAR AND A HALF AGO, THERE IS A REPORT THAT I ASSUME IT'S STILL ON THE WEBSITE, AND JUST SORT OF INFORMALLY I CAN SHARE THAT TO ME, ONE OF THE MOST SUCCESSFUL ASPECTS OF THE DIVERSITY PROGRAM THAT WE LOOKED AT WAS THE DIVERSITY SUPPLEMENT. THE DATA ON IT, YOU KNOW, DESPITE HAVING 10 YEARS OF DATA IN THE EXACT OUTCOMES NOT ALL BEING DEFINED, I THINK IT'S VERY PROMISING. FROM AN NIA PERSPECTIVE AND FROM OUR OWN SORT OF INSTITUTIONAL PERSPECTIVE, IT ALSO HAS BEEN, I THINK, VERY PROMISING. IT'S SORT OF THE FURTHER ALONG IN THE PIPELINE ASPECT OF INDIVIDUALS, SO WE SEE IT AS SORT OF A PREK AWARD. IT'S LIMITED TO TWO YEARS, BUT IT IS, I THINK, A FIXED AMOUNT THAT IS SUFFICIENT TO PROVIDE A BASE FOR SOMEONE TO DO RESEARCH UNDER MENTORSHIP OF AN RO1 OR IN OUR CASE, THE RICKMAR PROGRAM, IT WAS A P30. SO I THINK -- I'M NOT FAMILIAR WITH SORT OF A BROADER NIH ASSESSMENT OF THIS, BUT I'M SURE THAT WE CAN -- MARIE CAN SHARE ALL OF THE DETAILS WITH DR. VALENTINE FOR OUR EVALUATION, AND I WOULD SAY OF THE DIFFERENT THINGS THAT WE'RE DOING, AS AN INSTITUTE THAT IS ONE OF THE MORE PROMISING ONES. THE OTHER ONE IS THE RICKMAR PROGRAM, THE RESOURCE CENTERS FOR MINORITY AGING WHICH PROVIDE PILOT FUNDING FOR PREDOM NAPTLY MINORITY SCHOLARS, THAT'S LIMITED TO THE INSTITUTIONS THAT RECEIVE THE AWARD, BUT IT IS I THINK ALSO ANOTHER MODEL OF SUPPORTING DIVERSITY OF THE SCIENTIFIC WORKFORCE AT LEAST IN THE -- WELL, IT'S A BROAD RANGE, BUT PREDOMINANTLY NOT IN LABORATORY SCIENCE, BUT THAT COULD ALSO BE EXTENDED. WE ARE SORT OF IN NEED OF DOING MORE DETAILED EVALUATION OF THE OUTCOMES FOR THE RICKMAR PROGRAMS WHICH ARE NOW INTO THE FOURTH CYCLE OF FUNDING. >> DR. SPERLING. >> I WONDERED IF YOU HAD SOME DATA ON THOSE INDIVIDUALS WHO MAKE IT THROUGH MEDICAL SCHOOL, GO TO RESIDENCY AND THEN CHOOSE NOT TO COME INTO ACADEMICS. MY OWN SMALL EXPERIENCE IN MENTORING PEOPLE OF COLOR, THEY OFTEN FEEL THIS TENSION THAT THEY WANT TO GO BACK AND SERVE THEIR COMMUNITY. AND THEY SOMEHOW FEEL THAT THE RESEARCH ARM OF THAT IS NOT AS DIRECTLY IN THAT MISSION, AND SO SOMEHOW I FEEL THAT WE NEED TO HELP THEM REALIZE THAT THEY MAY EVEN BE ABLE TO HELP THEIR COMMUNITY, EVEN IN A STRONGER WAY, THROUGH SERVING AND RESEARCH, AND THIS IS PARTICULARLY AN ISSUE IN CLINICAL RESEARCH, AND I HAVEN'T EXPERIENCED AS MUCH WITH WOMEN BUT ABSOLUTELY IN TRYING TO MENTOR PEOPLE OF COLOR. SO DO YOU HAVE DATA ON THAT, AND WHAT WOULD YOU SUGGEST THAT WE COULD DO TO INTERVENE TO SHOW THEM HOW IMPORTANT THIS MISSION IS? >> THIS SPEAKS TO WHY IT IS PEOPLE DON'T GO ON TO ACADEMIC MEDICINE. AND OF COURSE WE SEE THAT THERE IS A GREATEST CHOICE TOWARDS NON-ACADEMIC CAREER TRACKS FOR UNDERREPRESENTED GROUPS. THAT'S WHERE WE LOSE THEM. AND I THINK -- I MEAN, I AGREE WITH YOU, WE PROBABLY DON'T PRESENT ADEQUATELY THE CASE FOR THE RESEARCH ARM, ESPECIALLY RESEARCH INTO HEALTH DISPARITIES, AND SO FORTH, AND THAT, AGAIN, THAT ISSUE LIES IN THE CULTURE, REALLY. AS THEY LOOK AROUND THESE INSTITUTIONS, THEY SEE WHAT IS MOST VALUED HERE, AND WE'RE NOT PRESENTING THIS AS WELL AS WE COULD. AND THERE IS DATA THAT HAS DOCUMENTED THE ATTRITION OF UNDERREPRESENTED GROUPS FROM ACADEMIA BECAUSE OF THIS CULTURE. THE LOOKING AND SEEING WHAT THE FACULTY ARE DOING AND NOT SEEING OTHERS LIKE THEMSELVES. SO WHAT CAN WE DO, THIS AGAIN IS A CULTURAL ISSUE TO CREATE AN ENVIRONMENT WHERE IT IS CLEAR THAT THAT KIND OF RESEARCH IS VALUED, EMBRACED, SUPPORTED, AND PROMULGATED. AND I THINK THAT MIGHT HELP. IN FACT, WE DID STANFORD WIDE SURVEY INTERVIEW STUDY, AND RESEARCH ISOLATION AM UNDERREPRESENTED GROUPS WAS FEATURED AS A MAJOR CONTRIBUTOR TO OVERALL SATISFACTION. AND WHAT THAT RESEARCH ISOLATION MEANT WAS SIMPLY THAT THEY FELT THE FIELD THAT THEY WERE IN WAS NOT REGARDED AS HIGH PRIORITY BY THE INSTITUTION. >> DR. MUTON, THEN DR. ANDERSON. >> I WAS JUST SITTING HERE THINKING ABOUT SOME OF THE PROGRAMS WE'VE USED SUCCESSFULLY, I WAS WONDERING IF SOME OF THESE CAN BE TRANSLATABLE TO NIH. I KNOW YOU HAVE A SUMMER RESEARCH PROGRAM FOR STUDENTS. BUT CERTAINLY HAVING AN EMPHASIS ON TRYING TO RECRUIT INDIVIDUAL UNDERREPRESENTED MINORITIES TO PARTICIPATE IN LABS AT NIH MAY BE SOMETHING SUCCESSFUL, PARTICULARLY AS YOU GET STUDENTS BETWEEN THAT FIRST AND SECOND YEAR OF MEDICAL SCHOOL, HAVING A LOT OF SCHOOLS HAVE A RESEARCH REQUIREMENT AND THEY USE THAT SUMMER FOR THAT EXPERIENCE. WE'VE HAD SEVERAL STUDENTS WHO EXPERIENCE OUR PROGRAM OF SUMMER RESEARCH AND THEN LOOK TO EXTEND THAT. OBVIOUSLY THE HOWARD HUGHES PROGRAM HAS BEEN ONE WAY OF DOING THAT. BUT THAT IS SO COMPETITIVE, IF NIH HAD A SIMILAR PROGRAM THAT AGAIN OCCURS, UNDERREPRESENTED MINORITIES, IN A HOWARD HUGHES-LIKE FASHION, TO PURSUE THAT KIND OF INVESTIGATION, WITH JUST A YEAR OFF OF MEDICAL SCHOOL, YOU MAY BE ABLE TO START TO ENERGIZE THE PIPELINE. A LOT OF THEM DON'T HAVE THE ABILITY TO TAKE OFF AND HAVE THE DESIRE TO TAKE OFF FOUR, FIVE, SIX YEARS TO GET A PH.D., THEY CERTAINLY ARE WILLING TO GIVE UP A YEAR TO DO SOME INTENSIVE RESEARCH IN THE LABORATORY. AND HAVING A -- LABORATORY FOR THEM TO WORK IN WOULD BE CRUCIAL. MANY OF THESE, AGAIN, THE SCHOOLS THAT I REPRESENT, DON'T HAVE SOME OF THAT ABILITY. SO HAVING THAT ACCESS TO NIH LABS WILL BE IMPORTANT. I REMEMBER WHEN I WAS AN UNDER DPS GRAD, IUNDERGRAD, IT WAS AN EXCHANGE PROGRAM, I REMEMBER COMING IN, TEACH FOR A YEAR, ET CETERA. IT WOULD BE INTERESTING TO SEE IF THERE WAS AN OPPORTUNITY TO DO THE REVERSE KIND OF THING AT NIH, WHERE FACULTY AT SOME OF OUR SCHOOLS PARTICULARLY UNDERREPRESENTED MINORITIES, IF WE CAN WORK OUT AN OPPORTUNITY FOR THEM TO SPEND SIX MONTHS, A YEAR, AT NIH DEVELOPING THEIR RESEARCH SKILLS, AND THEN BRINGING IT BACK TO THEIR HOME INSTITUTION AT TA TIME, THAT MIGHT BE SOMETHING AVAILABLE INSTEAD OF WAITING FOR THEM TO DEVELOP THE PROFESSORIAL 10-YEAR ABILITY AND HAVING THAT BE AN ADVANTAGE FOR THE SCHOOL IN SOME WAY WOULD MAKE A DEAN WANT TO SPONSOR THAT AS A FACULTY DEVELOPMENT ACTIVITY. THOSE ARE SOME OF THE THINGS THAT YOU CAN BE THINKING ABOUT TO TRY TO HELP ENGENDER A MORE DIVERSE WORKFORCE AROUND SCIENCE AND THE ENTIRE WORKFORCE ISSUE. >> THANK YOU FOR THE COMMENTS. I THINK YOU REALLY HIGHLIGHT THE IMPORTANCE OF THAT SCIENCE EXPERIENCE IN THE UNDERGRADUATE YEARS, AND THAT'S WHAT WE ARE HOPING THAT WE'LL BE SEEING A LOT IN THE BILL APPLICATIONS. I DON'T KNOW WHAT THEY'RE LIKE, BUT WE'RE HOPING THAT SOME OF THOSE WILL INCORPORATE THIS PARTNERSHIP IN INSTANCES WHERE INSTITUTIONS DON'T HAVE THE INFRASTRUCTURE FOR THAT DEEP SCIENCE EXPERIENCE, IF YOU COULD GET IT FROM SOMEWHERE ELSE WITH A PARTNER. >> DR. ANDERSON. >> HI, DR. VALENTINE. THANK YOU FOR THAT WONDERFUL PRESENTATION. IT'S REALLY GREAT TO HAVE YOU HERE. ONE OF THE THINGS THAT I WAS REALLY FASCINATED BY IN YOUR PRESENTATION WAS THE NOTION OF TAKING AN EVIDENCE-BASED APPROACH TO THE DESIGN AND IMPLEMENTATION OF DIVERSITY PROGRAMS. AND ACTUALLY USING NIH AS A LABORATORY, IF YOU WILL. , FOR THOSE TYPES OF EXPERIMENTS. SO CAN YOU TALK A LITTLE BIT MORE ABOUT HOW THAT MIGHT WORK? >> MY OFFICE WILL BE BUILT WITH AT LEAST TWO, PROBABLY THREE SOCIAL SCIENTISTS. SOCIAL SCIENTISTS WHO HAVE PARTICULAR INTEREST IN DIVERSITY IN EDUCATION, AND IN SOME OF THE SOCIAL PSYCHOLOGICAL ISSUES THAT I ALLUDED TO, AND THROUGH INCORPORATING THE SURVEYS THAT HAVE ALREADY BEEN DONE, MY MEETINGS WITH THE IC DIRECTORS, WE'LL BE ABLE TO IDENTIFY SOME PRIORITY AREAS AND SOME KEY QUESTIONS TO ASK. AND IN COLLABORATION WITH THIS SOCIAL SCIENTIST, WE WILL FIGURE OUT WHAT SOCIOPSYCHOLOGICAL THEORY ONE PARTICULAR QUESTION MIGHT FIT UNDER. AND THEN FROM THAT, WE'LL BE ABLE TO DESIGN THE BEGINNING EXPERIMENT TO FIGURE OUT FIRST OF ALL WHETHER OR NOT THAT THEE THEORY IS IN OPERATION, AND SECONDLY, WHAT WOULD BE THE INTERVENTION APPROPRIATELY FOR THAT. IN A WAY, IT'S SIMILAR TO THE TYPE OF THING WE'VE DONE WITH UNCONSCIOUS BIAS AND STEREOTYPE THREAT. BUT IT WILL NEED THIS CORE GROUP OF SOCIAL SCIENTISTS WHO ARE QUANTITATIVELY TRAINED, REALLY ADEPT AT DESIGN AND EVALUATION, TO BE ABLE TO FILL THAT INFRASTRUCTURE. >> DR. MORIMOTO? >> I ALSO WANT TO THANK YOU VERY MUCH FOR JOINING THIS ENDEAVOR. IT'S VERY IMPORTANT. I WANT TO RELATE TO YOU AN OBSERVATION. 13 YEARS AGO, MARION ZOTS, WHO IS IN NIGMS, AND I HELD THE FIRST WORKSHOP ON DIVERSITY. GM, AS YOU KNOW, IS HISTORICALLY THE MAJOR SUPPORTER OF TRAINING PROGRAMS AND FUNDS THE HISTORICALLY BLACK COLLEGES AND UNIVERSITIES AND THE HISPANIC SERVING UNIVERSITIES, AND THERE'S WONDERFUL PROGRAMS THAT HAVE BEEN OUT THERE FOR MANY, MANY YEARS. SO WE BROUGHT IN ALL THE DIRECTORS. THEN WE BROUGHT IN ALL OF THE NIGMS TRAINING DIRECTORS AT THE RESEARCH ONE UNIVERSITIES, AND WE PUT THEM -- WE SAID HOW MANY OF YOU ON ONE SIDE KNOW ANY OF YOU ON THE OTHER SIDE, AND THE 18 WAS ZERO. NOT ONE, NOT FIVE, IT WAS ZERO. THEY ALL KNEW EACH OTHER AND THEY ALL KNEW EACH OTHER. IT POINTS TOWARDS A CONCERN, AND I'M HOPING 13 YEARS LATER, MAYBE YOU CAN FIND THIS OUT, WHETHER PEOPLE NOW KNOW EACH OTHER, BECAUSE IF THERE'S GOING TO BE A PIPELINE, IT REALLY HAS TO BE AN AWARENESS FROM MOREHOUSE AS TO WHO ARE THE TRAINING DIRECTORS AT SCHOOLS THAT THEY MIGHT SEND THEIR YOUNG MEN TO, AND HAVING THAT RELATIONSHIP IS REALLY CRITICAL IN ENSURING THE SUCCESS OF THE STUDENTS. THE CARE FOR A STUDENT AT A MINORITY SERVING INSTITUTION IS VERY DIFFERENT THAN THE SENSE OF A STUDENT, NOT THAT WE DON'T CARE ABOUT OUR STUDENTS AT NORTHWESTERN, BUT THAT WE'LL CALL IT VERY CAREFUL HANDS-ON OFTEN DOESN'T EXIST AT THAT SAME LEVEL. BUT THAT RELATIONSHIP BETWEEN A TRAINING GRANT DIRECTOR COULD EXIST TO UNDERSTAND WHERE IS A BETTER PLACE WHERE THE STUDENT IS MORE LIKELY TO SUCCEED, BECAUSE YOU'RE TALKING ABOUT SUCH SMALL NUMBERS. IN TERMS OF THE PROFFESORIATE. IT REALLY COMES DOWN TO ONE AT A TIME. IF WE INCREASE BY 15, THE NUMBER WHO BECAME ASSISTANT PROFESSORS AT RESEARCH ONE UNIVERSITY, AND EVERY YEAR IT WAS ANOTHER 15, IT WOULD BE REMARKABLE AND WONDERFUL. SO PERHAPS YOU CAN LOOK INTO THAT AS WELL. I WAS STUNNED BY THE LACK OF FAMILIARITY ACROSS THE POND. >> AND THESE ARE BOTH SEVERAL GREAT POINTS YOU'VE MADE. THE FIRST POINTING TO THIS REALLY IMPORTANT IS BUILDING THE RELATIONSHIP. AND IT'S BUILDING NOT ONLY THE RELATIONSHIP OF THE PROPOSED STUDENT AND THE MENTOR, BUT AT A REALLY HIGHER LEVEL TO RECAPITULATE THAT KIND OF SUPPORT AND BELONGING THAT A STUDENT MIGHT FEEL IN ONE ENVIRONMENT, AND YES, I DON'T KNOW THE ANSWER, BUT IT'S CERTAINLY AN IMPORTANT THING TO BE LOOKING AT FOR SURE. >> I THINK WE'VE PROBABLY ASKED ENOUGH QUESTIONS DR. VALENTINE, SHE THOROUGHLY DESERVES A BREAK, SO THANK YOU VERY MUCH. [APPLAUSE] >> I'D LIKE TO PAUSE NOW TO GIVE AN OPPORTUNITY FOR INTRODUCTIONS, GUESTS THAT WOULD LIKE TO INTRODUCE THEMSELVES OR FOR A PROGRAM, WE'D LIKE TO INTRODUCE NEW STAFF WHO HAVE NOT MET COUNCIL BEFORE. WHO DO WE HAVE? >> I'D LIKE TO INTRODUCE A NEW MEMBER OF THE STAFF. [INAUDIBLE] [APPLAUSE] >> YOU LOOK FAMILIAR, TAYLOR. >> I'M OBVIOUSLY NOT JOHN WREN, I AM, HOWEVER, JANE FILLIE, SUBJECT MATTER EXPERT ON BRAIN HEALTH AND DEMENTIA FOR THE ADMINISTRATION FOR COMMUNITY LIVING AND IF PEOPLE DON'T KNOW WHAT THAT IS, IT'S A FAIRLY NEW PART OF HHS. I CAN EXPLAIN IT AT THE BREAK. >> ALL RIGHT. THANK YOU. WE'LL NOW MOVE ON TO THE PROGRAM HIGHLIGHTS SECTION OF THE MEETING. OUR FIRST SPEAKER IS GOING TO BE NORMAN SHARPLESS, WHO JUST REALIZED HE EIGHTS DOING THE INTRODUCTION. >> GOOD MORNING. IT'S REALLY A GREAT PLEASURE FOR DAB TO HAVE NORMAN SHARPLESS WITH US. AS YOU CAN SEE, HE'S FROM THE UNC CHAPEL HILL, AND HE HAS BEEN WORKING ON SENESCENCE AND AGING FOR A LONG TIME. AND WE ARE REALLY EXCITED ABOUT THE WORK HE'S DOING IN TERMS OF LOOKING AT BASIC BIOLOGY OF SENESCENCE, BUT ALSO WITH A POSSIBILITY OF USING THAT BASIC KNOWLEDGE IN TERMS OF TRANSLATION OF RESEARCH. DAB DOESN'T DO TRANSLATIONAL RESEARCH, BUT WE HOPE THAT THE RESEARCH THAT WE SUPPORT EVENTUALLY WILL LEAD TO THAT. AND THIS WILL BE A GOOD EXAMPLE IN WHICH HE HAS BEEN WORKING, HIS TEAM, IN LOOKING AT SENESCENCE AND THE CONSEQUENCE OF SENESCENCE, THE IMPLICATIONS FOR SENESCENCE IN HEALTH AND DISEASE, AND TODAY HE'S GOING TO TALK ABOUT HOW TO MEASURE SENESCENCE AND WHY THIS IS IMPORTANT, NOT ONLY IN ANIMAL STUDY, BUT ALSO IN HUMANS. SO NORM SHARPLESS. >> THANK YOU FOR THE OPPORTUNITY TO COME AND SPEAK TODAY. I'M VERY PLEASED TO BE ABLE TO SHARE OUR WORK IN THIS FIELD WITH THE NIA. SO USUALLY I TRY TO GET THROUGH MY DISCLOSURE SLIDE AS QUICKLY AS POSSIBLE BUT I THOUGHT I'D ACTUALLY DWELL ON IT FOR A MOMENT TODAY BECAUSE IT'S OF INTEREST. I BASICALLY STARTED TWO COMPANIES IN MY LIFE. ONE IS CALLED HEALTH -- DIAGNOSTICS, AN AGING COMPANY, AND ONE IS G1 THERAPEUTICS, A CANCER COMPANY. ONE HAS BEEN MUCH EASIER AND MUCH MORE ACCEPTED PATH AND MUCH BETTER UNDERSTOOD BY VENTURE CAPITALISTS IN WHAT HAS BEEN VERY, VERY DIFFICULT. AND I'LL LET YOU GUESS WHICH IS WHICH. SOME OF THE WORK I AM TALKING TODAY IS RELATED TO HEALTH SPAN. THE WORK IN SENESCENCE PROBABLY MEANS SOMETHING DIFFERENT TO YOU AND ME AND I'M SPEAKING ABOUT THIS PHENOMENA WHERE CELLS THAT ARE FORMERLY REPLICATION COMPETENT STOP DIVIDING -- DISCOVERED BY -- MANY YEARS AGO AND WE KNOW A LOT ABOUT IT NOW. IT HAPPENS IN SORT OF ALL MAMMALIAN SPECIES, IT'S ASSOCIATED WITH CHANGES IN THE MARKERS, THE BLUE DYES, THE CELLS EXPRESS A LOT OF DIFFERENT GENES, AND THE THINGS THAT ENFORCE SENESCENCE ARE THE -- AND -- PATHWAYS WHICH ARE ALL PRETTY MUCH -- WERE DISCOVERED BECAUSE THEY HAVE A ROLE IN CANCER SUPPRESSION. SO THEY WERE KNOWN TO CANCER BIOLOGISTS BECAUSE OF THEIR IMPORTANT ROLE IN PREVENTING -- WHEN HE DISCOVERED SENESCENCE IN THE 60s, HE TRIED TO PUBLISH IT IN THE JOURNAL OF EXPERIMENTAL MEDICINE AND HIS PAPER WAS REJECTED BECAUSE EVERYBODY KNEW THE LARGEST FACTS THAT HAVE COME OUT OF CELL CULTURE FOR THE LAST 50 YEARS, THE CELLS GIVEN THE RIGHT MOU WILL DIVIDE INDEFINITELY. IT WAS AN ARTIFACT OF HIS POOR TECHNIQUE. THE 1966 NOBLE LAUREATE IN PHYSIOLOGY MEDICINE. THIS IS IMPORTANT -- DISCOVERED ON GOONCOGENES. THIS IS THE WAY IT'S BEEN FOR TUMOR EXPRESSION THE ENTIRE TIME, IT'S SORT OF THE STEPCHILD OF ONG JEAN, BU ONCOGENE -- THAT'S SORT OF MY BACKGROUND IN THE FIELD. SO IT WAS KNOWN FOR WORK BY GORDON PETERS, DAVID BEACH AND OTHERS THAT THERE WAS THIS GENE CALLED P16 THAT'S INTIMATELY ASSOCIATED WITH SENESCENCE. SOME CELLS, MERELY THE EXPRESSION OF P16 IS ENOUGH TO TRIGGER THE WHOLE PHENOTYPE. JUST ABOUT EVERY SENESCENT CELL, WHETHER OR NOT IT NEEDS P15 TO UNDERGO SENESCENCE EXPRESSES P16. P16 IS MADE BY THIS VERY INTERESTING BIOLOGICAL LOCUST. THIS GENETIC LOCUST IS SPECIFIC TO ORGANISMS THAT HAVE LONG LIVING STEM CELLS. -- DON'T REALLY HAVE THIS SORT OF SENESCENCE INDUCING LOCUS, BUT MAMMALS AND FISH TO SOME EXTENT DO, AND IT ENCODES TWO INK PROTEINS, WHICH ARE VIRTUALLY THE SAME MOLECULE, THEY'RE BIOCHEMICALLY INDISTINGUISHABLE BUT THEY'RE REGULATED QUITE DIMPLE, AND THEY DIFFERENT LY, AND THAT AK VAITS TEASE RB PROTEINS WHICH PROMOTE SENESCENCE. THEN THERE'S ANOTHER PROTEIN MADE FROM THE SAME LOCUS BUT IT'S INTRICATE SORT OF SPLICING ARRANGEMENT THAT ACTIVATES THE GUARDIAN OF THE GENOME AND PERHAPS THE MOST FAMOUS EX-PRESSOR GENE. IN CONTRAST -- INDUCES SENESCENCE. IT'S IMPORTANT TO NOTE THAT P16 AND -- SHARE EXONS WITHIN NON- NON- -- MEANING IT'S A TOTALLY DIFFERENT PROTEIN. IT'S NOT AN ISOFORM. THIS ARRANGEMENT SORT OF ENCODING PROTEINS IN SEVERAL READING FRAMES IS COMMONLY FOUND IN VIRUSES BUT IT'S QUITE USUAL IN MAMMALS. THIS IS REALLY, I THINK, A SOLE EXAMPLE OF THE LOCUS LIKE THIS IN THE MAMMALIAN GENOMES. PDK AND 2B AND 2A, IF YOU READ THE GWAS LITERATURE WHERE THAT'S HAVE BECOME QUITE FAMOUS, THAT'S THE TERM THAT'S USED. BUT I REALLY DISLIKE THAT TERM BECAUSE YOU CAN NEVER KNOW FOR SURE IF YOU'RE TALKING ABOUT -- AND I'VE READ WHOLE PAPERS WHERE THE AUTHORS THEMSELVES HAD IT WRONG. SO HOW DID THE ONCOLOGISTS GET INTERESTED IN AGING AND THIS IS THE EXPERIMENT THAT DID IT. WHEN I WAS A POSTDOC AT HARVARD, I MADE MICE THAT DEPARTMENT HAVE P16, NOT SURPRISINGLY, THEY WERE HIGHLY TUMOR PRONE. THERE ARE PEOPLE THAT DON'T -- AND THEY'RE TOTALLY FINE, THEY'RE NORMAL UNTIL THEY ALL DIE ABOUT AGE 18 OF MELANOMA OR PANCREATIC CANCER. THAT'S TRUE OF THE MICE THAT DON'T HAVE P16, THEY'RE QUITE TUMOR-PRONE. THEN IF YOU CROSS THEM IN WITH PPD3 GENE, YOU MAKE ANIMALS THAT EFFECTIVELY CAN'T DO SENESCENCE, THEY LIVE ABOUT 10 TO 15 WEEKS. SO THEY DIARILY BEFOR DIE REALLY BEFORE TH EY CAN BREATHE. SO I THINK THIS ANSWERS THIS NOTION THAT CANCER IS SOMETHING THAT HAPPENS IN OLD AGE. THAT'S NOT TRUE. TUMOR SUPPRESSION IS SOMETHING THAT STARTS DAY ONE. WE CAN DEMONSTRATE THROUGH ONCOGENIC EVENTS THAT OCCUR THROUGH NEONATES, HA CAUSE LEUKEMIA, FOR EXAMPLE, SO TUMOR SPRE TORE MECHANISMS ARE NEEDED ALL THROUGHOUT LIFE AND NOT GETTING CANCER -- SO AS AN ONCOLOGIST, THERE WERE ALREADY PEOPLE IN THE FIELD THINKING THAT TUMOR SUPPRESSION AND AGING MIGHT HAVE SOME LINKS, THOSE PEOPLE ARE MOST PROBABLY FAMOUSLY -- BIOLOGISTS VERY INTERESTED IN THE IDEA THAT TUMOR SHORTENING COULD BE -- COULD ALSO PROMOTE AGING. WE THOUGHT THE SAME MIGHT APLAY PLOAPPLYTO P16 AND THAT LED TO THE SORT OF EXPERIMENT, WHAT IT WOULD MEAN TO THE FIELD. THIS IS AN EXAMPLE FROM SHAWN MORRISON'S WORK BUT IT APPLIES TO MANY OTHER TISSUES. I LIKE THIS IMAGE JUST BECAUSE IT'S PRETTY BUT YOU COULD DO THE SAME THING FOR OTHER TISSUES N YOUNG MAMMALS, THERE ARE THESE STEM CELLS, SOMATIC STEM CELLS, SELF ROOTING CELLS THAT DIVIDE QUITE WELL IN CERTAIN PLACES, AND IN OTHER ORGANS, THEY DON'T DIVIDE SO WELL, THEY LOSE THEIR ABILITY TO REPLICATE. THE GREEN MARKER IS THE RDU, AND THIS IS TRUE NOT CERTAINLY IN ALL CELLS, THE INTESTINAL STEM CELLS -- AND NEITHER DO TRUE HEMATOPOIETIC STEM CELLS, BUT THERE ARE LOTS OF REALLY INTERESTING IMPORTANT CELLS THAT DO THAT ARE QUITE RELEVANT TO THE BIOLOGY OF AGING. FOR EXAMPLE -- RED -- CELLS DIVIDE VERY NICELY IN YOUNG ANIMALS, NOT SO WELL IN OLD ANIMALS, MEMORY T CELLS, FOR EXAMPLE, ARE HOMEOSTATICLY COMPETENT OF REPLICATION IN SORT OF YOUNG NON-EXHAUSTED IMMUNE SYSTEMS BUT LOSE THAT ABILITY WITH TIME, WITH AGING. SO BEING CANCER BIOLOGISTS WHO HAVE BEEN VERY INTERESTED IN THE CELL CYCLE, IT SEEMED EASY TO LOOK AT WHAT THINGS ABOUT THE CELL CYCLE ARE DIFFERENT BETWEEN YOUNG AND OLD ANIMALS SINCE ALL THE GENES THAT REGULATE THE CYCLE ARE ESSENTIALLY KNOWN. WE ESSENTIALLY LOOKED AT THE EXPRESSION OF ALL REGULATORS OF THE CELL CYCLE IN MAMMALS WITH AGING IN BOTH MICE AND RATS, AND THESE RESULTS ARE SUMMARIZED HERE THAT -- TO SCALE SO -- OF THE RATIO OF EXPRESSION IN AN OLD VERSUS YOUNG MOUSE, THE ANSWER IS ON AVERAGE, P16 GOES UP ABOUT TENFOLD. SO SOME TISSUES IT GOES UP MORE, SOME IT GOES UP LESS BUT JUST IN ABOUT EVERY TISSUE, IT GOES UP TO SOME DEGREE. THE OTHER GENE IS A LOCUS RF HAS A VERY SIMILAR PATTERN, IT GOES UP IN MOST TISSUES AS WELL, SO THE LOCUS GETS ACTIVATED WITH AGING IN MOST MAMMALIAN TISSUES AND THAT'S IT. MOST OF THEM ARE NON-DYNAMIC, THEY DO NOT CHANGE WITH AGING, P15, P27, NONE OF THOSE CHANGE. THESE GUYS DO. SO IF YOU BELIEVE A FAILURE OF REPLITIVE CAPACITY IS IMPORTANT TO SOME ASPECT OF MAMMALIAN AGING, THESE WOULD BE YOUR BEST CANDIDATES FOR EFFECT BE THAT PHENOMENA. SO THAT'S CORE LATIVE DATA, THAT DOESN'T PROVE P16 HAS AN IMPORTANT ROLE IN THE AGING PHENOTYPES, SO WE DID THIS EXPERIMENT TO ADDRESS THAT, I PICKED BETA CELLS FOR REGIONS WE COULD TALK ABOUT FOR REASONS IF YOU'RE INTERESTED, BUT IT WAS A GOOD CANDIDATE TISSUE. YOU CAN BASICALLY TELL HOW OLD THE MOUSE IS BY DISSECTING ITS PANCREAS AND COUNTING THE NUMBER OF -- CELLS. SHARPLY DECLINE WITH AGING IN MICE. IT WAS THOUGHT AT ONE TIME TO NOT DO THIS IN PEOPLE BUT THAT'S OLD DATA. PANCREAS IS HARD TO EVALUATE IN PEOPLE. I THINK WITH GOOD WORK BY BUTLER AND OTHERS, IT'S VERY CLEAR THAT THIS SAME FEA NO, MA'AM NA OCCURS IN PEOPLE. AND IF YOU MAKE MICE THAT HAVE TOO MUCH P16, THIS IS ABOUT A FIVE FOLD EXCESS, THEIR BETA CELLS ARE OLD, EVEN WHEN THEY'RE YOUNG. THESE MICE ARE NOT TERRIBLY SYMPTOMATIC. THEY DON'T GET DIABETES AND THEY HAVE A NORMALLISH LIFESPAN. AND IF YOU MAKE MICE THAT ARE -- HAVE NO P16, THEIR BETA CELLS ARE YOUNG, EVEN WHEN THEY'RE OLD. BUT THAT'S NOT NECESSARILY A GOOD THING FOR THESE MICE. THEY ARE RESISTANT TO DIABETES, THEY ARE RESISTANT TO THINGS THAT WILL PROMOTE DIABETES IN BETA CELL FAILURE IN THIS STRENGTH, BUT THEY ALL DIE OF CANCER AT ABOUT 60 WEEKS, I ALREADY SHOWED THAT. SO THE TRADEOFF OF HAVING EXCESS ENHANCED BETA CELL FUNCTION AND -- T CELL FUNCTION AND MUSCLE STEM CELL FUNCTION IN P16 DEFICIENT ANIMALS IS THAT YOU DIE OF CANCER. I ALWAYS CALL IT THE JAMES DEAN IF HE NOPHENOMENA, LIVE FAST, DIE YOUNG AND LEAVE A GOOD LOOKING CORPS. I GOT A LOT OF PHONE CALLS ABOUT THIS ONE TIME FROM PHARMA COMPANIES BECAUSE LATER ON, AFTER SIX MONTHS AFTER WE PUBLISHED THIS, P16 WAS LINKED THROUGH GWAS TO TYPE~2 DIABETES IN PEOPLE BY FRANK VISCONE. WHEN FRANCIS COLLINS DISCOVERS YOUR GENE IS LINKED TO A COMMON HUMAN PHENOTYPE OF MORPHOLOGIC INTEREST, YOUR PHONE RINGS A LOT. YOU COULD TRY AND TURN P16 OFF AND HAVE IT DEACTIVATED AND PEOPLE NOT GET DIABETES BUT THEY MIGHT DIE OF PANCREATIC CANCER AND THAT WOULD SEEM TO ME TO BE WORSE. THAT ENDED THIS PHONE CALL. WHEN WE PUBLISH THIS IN 2006, WE BACK TO BACK PUBLISHED THIS WITH WORK WITH SHAWN MORRISON, DAVID AT HARVARD, SHAWN MORRISON AT MICHIGAN, HE'S AT SOUTHWESTERN -- THE RESULTS WERE BASICALLY THE SAME IN ALL THREE TISSUES, IS THAT IN ALL THREE OF THESE EMBRYOLOGICALLY DISTINCT TISSUES, THERE'S A -- IS RESCUED IN PART BUT NOT COMPLETELY BY P16 LOSS. IN EVERYIS EVERY TISSUE, THIS IS AN IMPORTANT PART OF WHY THESE CELLS FAIL WHEN YOU GET OLD. IF YOU EVER GET THE OPPORTUNITY TO TALK TO THE "NEW YORK TIMES" ABOUT YOUR SCIENCE, I RECOMMEND YOU NOT DO THIS, WHICH IS SAY THERE'S NO FREE LUNCH, BECAUSE YOU WILL GET A LOT OF STRANGE EMAILS IF YOU TELL "THE NEW YORK TIMES" THAT. I THOUGHT THE THREE STATEMENT -- HERE'S THE MODEL, IS WHEN YOU'RE YOUNG, AND AGAIN, WHAT I MEAN BY STEM CELL REALLY FOR THE PURPOSES OF MY DEFINITION IS SELF RENEWAL. SO -- IS UNIMPORTANT IN THE MODEL. A BETA CELL IN THE PANCREAS MEETS NO ONE'S DEFINITION OF A STEM CELL. IT REALLY CAN JUST TURN INTO MORE BETA CELLS. IT TURNS OUT TO BE REALLY IMPORTANT. IF YOU DON'T BELIEVE THAT, THE GWAS DATA HAS UNEQUIVOCALLY SETTLED THAT DISPUTE. SO STEM CELLS THEMSELVES RENEW, THEY DO IT PRETTY WELL WHEN YOU'RE YOUNG AND HEALTHY, IT MAKES SOME TISSUE THAT'S DI SIECIAL. AS YOU GET OLD, THEY BECOME DAMAGED, AND NATE TOUR OF THIS DAMAGE IS REALLY INTERESTING AND COMPLETELY UNKNOWN. I THINK THERE'S GOOD EVIDENCE THAT DNA DAMAGE CAN BE A TYPE OF DAMAGE, BUT I THINK THERE'S GOOD EVIDENCE THAT DNA IS NOT THE ONLY KIND OF DAMAGE THAT CAN BE A TYPE OF DAMAGE THAT CONTRIBUTES TO -- KREF SELF RENEWAL. I THINK PROTEIN MISHOLDING -- MAY BE A VERY IMPORTANT COMPONENT. THE HERITABLE DAMAGE TO THESE CELLS IS UNKNOWN OR MAYBE A VARIETY OF KIND OF DAMAGE BUT IT LEADS TO -- THEN WHAT HAPPENS TO THESE CELLS IS SORT OF ONE OF THREE THINGS. THEY CAN EITHER DIE AND THE CONSEQUENCES OF THAT WITH REGARD TO AGING I THINK ARE LARGELY UNKNOWN, THEY CAN LEARN HOW TO DIVIDE TOO FAST AND BECOME A MALIGNANT CELL, THAT'S A FAMILIAR PROBLEM, THE OTHER THING IS THEY CAN UNDERGO EFFECTIVE AND PERMANENT SENESCENCE. WE BELIEVE THAT PROMOTES AGING. SENESCENCE, WE THINK IS BAD FOR TWO REASONS. ONE IS I SORT OF ALLUDED TO, THAT CELL NO LONGER DOES WHAT IT USED TO DO. SO IF IT USED TO MAKE MORE BETA CELLS AND YOU LOSE THE ABILITY TO DO THAT, THAT HAS CONSEQUENCES. I THINK THE OTHER REASON WE BELIEVE THEY'RE BAD IS BECAUSE THEY RELEASE HORMONES, THERE ARE VERITIABLE -- THIS IS THE SENESCENCE ASSOCIATED PHENOTYPE THAT JUDY AND DANIEL AND OTHERS HAVE WORKED ON. I THINK THAT'S A LIKELY IMPORTANT TOO SO THERE'S BOTH A LOSS OF FUNCTION OF SENESCENT CELLS AND A GAIN OF FUNCTION TOXICITY OF SOMATIC CELLS, I HAVE TO SAY FOR MY POINT OF VIEW, IT SEEMS LIKE A LOSS OF FUNCTION DATA A BIT STRONGER ARE PRESENT. THE UNBIASED HUMAN GENETICS -- SO THERE'S BEEN A LOT OF EVIDENCE FOR THIS MODEL IN 2006. I WON'T BELABOR IT, LYMPHOCYTES ACCORDING TO KEN -- OTHER INTERESTING WORK -- BETA CELL AGING HAS NOW BECOME QUITE THE RAGE, IN FACT, PEOPLE ARE TRYING TO DRUG P16 SPECIFICALLY IN BETA CELLS, THAT'S WORK FROM KIM IN STANFORD, MUSCLE AGING, SARCOPENIA, TWO PAPER PAPERS IN 2014 ON THIS TOPIC EXPLICITLY. A VERY INTERESTING PAPER FROM MICHAEL CLARKE ON DOWN'S SYNDROME AS A PROGERIA, EXCESS COPY INVOLVES REPRESSING THE LOCUS, AND LASTLY A PAPER IN 2011 THAT I THINK MANY OF YOU ARE PROBABLY FAMILIAR WITH WHERE JOHN VAN DURZEN -- TOXIC MOLECULE THAT'S PHARMACOLOGICALLY TOK IK SO WHEN HE FEEDS THE MOUSE THE DRUG, ALL THE CELLS DIE. IN A -- STRAIN OF ANIMALS, THE P16 KILLED CELLS, KILLED ANIMALS, LOOKED MUCH HEALTHIER THAN THE P16 NON-KILLED CELLS -- WITHOUT KILLING OFF -- SO SENESCENT CELLS CLEARED, NOT CLEARED, AND THE EFFECTS PARTICULARLY PRONOUNCED ON BONE AND SARCOPENIA. SO LOOKS LIKE THIS IS INDEPENDENT CONFIRMATION FROM A VARIETY OF DIFFERENT EXPERIMENTS, IT'S NIEK TO TALK ABOUT THE HUMAN SIDE. SWHOWN WANTS THEIR SCIENCE TO BECOME AT SOME POINT TRANSLATIONAL, SORT OF MAKES TWO PREDICTIONS ABOUT PEOPLE THAT I'D NOW LIKE TO TALK B PREDICTION ONE IS, SINCE THERE'S HETEROGENEITY OF ALL HUMAN PHENOTYPES, IF PEOPLE WHO HAVE EXCESS OR TOO LITTLE SENESCENCE OUGHT TO AGE DIFFERENTLY, IF SENESCENCE REALLY HAD SOMETHING TO DO WITH AGING. THE FACT THAT IT HAS SOMETHING TO DO WITH CANCER -- THE OPPOSITE PREDICTION SHOULD BE TRUE AS WELL. YOU SHOULD BE ABLE TO FIND LINKAGE TO SENESCENCE RELATED GENES. I MADE A LIST OF SUCH GENES, I SENT IT TO ONE OF MY COLLEAGUES AND WE BEGAN THINKING ABOUT HOW TO DO THIS, AND WE BASICALLY GOT SCOOPED, 3 MILLION PATIENTS OF DATA FROM THE SORT OF GWAS REVOLUTION, THEY WERE CURRENTLY IDENTIFIED IN IP21 -- AS BEING ASSOCIATED WITH A VARIETY OF AGE ASSOCIATED DISEASES. WE WERE SO STRUCK BY THAT THAT WE JUST DOWNLOADED ALL THE AVAILABLE GWAS DATA FROM NHGRI, THREE YEARS AGO, WE FILTERED THEM SO WE THREW OUT ALL THE NON-DISEASED TRAITS AND THINGS LIKE RED HAIR, THINGS THAT MAPPED BY GWAS BUT JUST KEPT DISEASES. THEN WE LOOKED AT THE HITS AND MAPPED THEM INTO 200 -- WE'RE ASKING IF THEY'RE ASSOCIATED WITH NOT ONE DISEASE BUT MULTIPLE DISEASES, ARE THERE HOT SPOTS FOR WELLNESS, IF YOU WILL. THE ANSWER IS THEY VERY CLEARLY ARE. THERE'S ONE AT 6Q PRETTY FAMOUS AND IT'S FOUR BINS, SO FOUR DOTS ALL BESIDE EACH OTHER, 800KB LOCUST, THERE ARE ABOUT A THOUSAND GENES THERE. THERE ARE ABOUT 25 DIFFERENT LOCUSTS THAT MAP TO THAT -- THINGS LIKE THAT. SO THIS IS CLEARLY A MAJOR DETERMINANT OF HOW YOUR IMMUNE RESPONSE BEHAVES IN HUMAN. THEN THE SECOND BEST -- THERE WERE FOUR MORE OF THESE, ALL OF THOSE ARE THINGS THAT ENCODE -- THEN THERE WAS ONE FINAL HIT HERE AT 5P WHICH IS TURF. SO BASICALLY AT THIS ANALYSIS, WE ONLY UNCOVERED TWO PATHWAYS AS BEING ASSOCIATED WITH HUE MAB MULTI-DISEASE ACCESSIBILITY, IMMUNITY INFLAMMATION LOOKS REALLY IMPORTANT FROM THIS ANALYSIS, AND SENESCENCE. TWO DIFFERENT WAYS OF REGULATING -- SO THAT, I FIND VERY CAPTIVATING. THERE ARE A BUNCH OF PATHWAYS FOR M MODEL ORGANISMS WE DIDN'T IDENTIFY, THERE MAY BE VERY GOOD EXPLANATION FOR WHY WE DIDN'T FIND THAT APPROACH BUT IT IS AN INTERESTING OBSERVATION. IF ONE WERE TO ALLOCATE RESOURCES FOR FUTURE RESEARCH IN MODEL ORGANISMS, I WOULD THINK THESE DATA WOULD SUGGEST THE FOCUS ON THINGS THAT HAVE AN IMMUNE SYSTEM THAT LOOK SOMEWHAT LIKE A MAMMAL, LIKE MAYBE MACROPHAGES AND T CELLS AND MAYBE SOMETHING THAT HAS STEM CELLS THAT UNDERGO SENESCENCE. FISH, MAMMALS, PRIMATES, ET CETERA. THE THINGS THAT MAP THERE ARE MAY OWMYOCARDIAL INFARCTIONS -- THE OTHER ONES I THINK WERE VERY SURPRISING, PARTICULARLY THE ATHEROSCLEROSIS. THE DIABETES WAS ABOUT THE THIRD STRONGEST IN THE HUMAN GENOME BUT FOR ATHEROSCWHRAIROSIS, THIS IS THE STRONGEST COMMON DETERMINANT. VERY SURPRISING BECAUSE IT'S NOT LINKED TO LIPIDS OR HYPERTENSION OR ANY OF THE CLASSIC RISK FACTORS FOR ATHEROSCLEROSIS. SO THAT WAS VERY SURPRISING TO MANY PEOPLE. I THINK IT SHOULD BE SAID -- WAS THE CELL CYCLE -- CLINICAL TRIAL WITH HER HUSBAND TRYING TO -- P16 TO -- PLAQUE BACK IN THE 90s, SO THERE CERTAINLY WERE SOME OF THE SCIENTISTS THINKING ABOUT THE CELL CYCLE BUT THERE WERE NOT VERY MANY. IT WAS REALLY VERY SURPRISING TO MOST OF THE FIELD. IF YOU LOOK AT WHERE THESE HITS MAP TO, THEY DON'T REALLY MAP TO CODING P16 OR ARF, THEY MAP TO WHAT'S CLEARLY AN ENHANCER AWAY FROM THE LOCUS. A NUMBER OF GROUPS MOST RECENTLY RECENTLY -- WHAT LOOKS TO BE A PRETTY STRONG ENHANCER IN EXACTLY THE SPOT WHERE ALL THESE MAP TO, EXPRESSION OF P15, P16 AND ARF. THERE REALLY AREN'T MANY GENES AROUND BEYOND -- SO PREDICTION NUMBER TWO IS THAT YOU OUGHT TO BE ABLE TO MEASURE AGING. SENESCENCE IS THE THING THAT CAUSES ASPECT OF AGING, ONE SHOULD BE ABLE TO MEASURE THAT, THIS HAS SORT OF ALREADY BEEN TRIED WITH TEE LOW MERES, BUT THEY ONLY CHANGE ABOUT 30%. S BEST ASSAYS COST ABOUT $1,000 A SAMPLE WHICH IS REALLY DIFFICULT TO MAKE THAT WORK IN A CLINICAL TRIAL. SO WE THOUGHT WE COULD TAKE ADVANTAGE OF THIS BY USING THE PROMOTER TO SORT OF MAKE A MOUSE REPORTER THERE'S THIS DORIAN GRAY BOOK, OSCAR WILD'S GOTHIC NOVEL ABOUT A GUY WHO PARTIES IN CROWDS, HE LOOKS GREAT BUT HIS PICTURE LOOK OLD AND TIRED. WE KNOCKED FIRE FLY -- GOES UP ON AVERAGE AND IN MANY TISSUES MUCH MORE THAN THAT, WE USED HAIRLESS MOUSE WHICH TURNS OUT TO BE KIND OF IMPORTANT AS THE ANIMALS AGE, THEY GLOW. THESE ANIMALS ARE NOT VERY OLD, AT EE WEEKS IS SOR80 WEEKS IS LATE MIDDLE AGE FOR A MOUSE. IF YOU LOOK REALLY INTERESTINGLY, THE AVERAGE OF THE COHORT GOES UP AND IT ACTUALLY GOES UP EXPONENTIALLY IF YOU TRUST ME ON THAT. BUT YOU SEE THERE'S A LOT OF HETEROGENEITY. SOME MICE HAVE QUITE A LOT OF EXPRESSION, SOME MICE HAVE VERY LITTLE, EVEN AT THE SAME AGE. THESE ARE SINK NEIGHBORING MICE, LITTER MICE HOUSED IN THE SAME COLONY. WE DOND UNDERSTAND THAT. I CAN TELL YOU IT BREEDS DREW, THIS DOT HERE IS GOING TO BE ONE OF THESE DOTS HERE, BASICALLY THE ANIMALS ABOVE THE SORT OF AVERAGE AT ANY TIME POINT AND THE ONES THAT ARE BELOW STAY BELOW. ALSO SOMEWHAT DISAPPOINTINGLY, THE AP MALLS THAT HAVE THE HIGHEST EXPRESS DON'T DIE WITH ANY GREATER FREQUENCY THAN ANIMALS THAT HAVE A LOWER EXPRESSION. DEATH IN OUR KO COLONIES ALL -- DIED OF CANCER, THAT REALLY HAS NOTHING TO DO WITH THE BURDEN OF SENESCENT CELLS. WE'VE BECOME VERY INTERESTINGLY CAPTIVATED WITH USING THIS AS A WAY TO TEST FOR TROT GENERALS. THE IDEA THAT THERE'S AN ENVIRONMENTAL EXPOSURE UNSHARED AMONG US THAT PROMOTES AGING. A KEY FOR CARCINOGEN TESTING AS MANY YOU HAVE MAY KNOW ARE STRAINS LIKE IN MUTA MOUSE, BIG BLUE, REPORTERS FOR REVERSE -- WE THOUGHT A REPORTER FOR GERONTOGEN WOULD BE A NICE ONE AS WELL. YOU CAN SEE THE HIGH FAT FED ANIMALS ARE ACTUALLY FATTER THAN THE REGULAR CHOW MICE BUT THEY DON'T GLOW ANYMORE. BUT CIGARETTE SMOKING ON THE OTHER HAND WAS QUITE A GOOD GERONTAGEN. VERY BRIEF EXPO SEU FIVE HOURS A DAY, FIVE DAYS A WEEK, THAT INVOLVES A GRAD STUDENT LIGHTING A CIGARETTE ABOUT EVERY 10 MINUTES. ONLY A FEW WEEKS OF THAT, THEN WE STOP AND THERE'S A LIFELONG INCREASE IN EXPRESSION OF THE MARKER. IT'S ONLY CONFINED TO THE AREA WHERE THE DOSE OF TOBACCO IS SIGNIFICANT, WHICH IS THE NASOFEHRING INASOPHARYNX IN MICE. THEY DON'T REALLY INHALE. THIS IS ANATOMIC -- WE THINK OF CIGARETTE SMOKE -- WE'VE USED THIS ALLELE TO LOOK FOR LOTS OF JE RONG GENERALS. WE'VE YET TO FIND A REALLY GOOD ONE IN THE SYSTEM THAT DOESN'T BREAK DNA. BUT I'M SURE OTHER THINGS THAT DON'T CAUSE DNA DAMAGE WOULD BE INTERESTING BUT WE HAVE YET TO IDENTIFY A REALLY POTENT THING -- IT MAY BE WE HAVEN'T TRIED SOME OF THE RIGHT THINGS. LASTLY I WANT TO TALK ABOUT HOW WE DO IT IN PEOPLE. SO WE TRIED A NUMBER OF DIFFERENT CELLS AND EVENTUALLY HIT ON T CELLS AS WHAT WE HAVE TO DO, THEY'RE READILY AVAILABLE, ONE CAN MAIM RNA FROM THEM, AND THEY'RE HIGHLY ABUNDANT AND -- IMPORTANT CELL. IT'S HARD TO GET TO THEM, WHERE T CELLS ARE READILY AVAILABLE. TO WE MEASURED AGAIN P16 AND A COUPLE HUNDRED NORMAL DONORS HERE AND SHOWED AGAIN THERE'S THIS EXPONENTIAL INCREASE, A LINE MEANS AN EXPONENTIAL INCREASE IN GROWTH OF THE MARKER WITH AGE. 16 FOLD OVER EIGHT DECADES. EXCEPT IN HUMANS, IT TAKES 80 YEARS, IN MICE, IT TAKES TWO, AND THE INCREASE IS SEEN WELL BEFORE AGING IS IMPORTANT, WHICH IS AN IMPORTANT CHARACTERISTIC OF AN AGING BIOMARKER. WE'VE SHOWN SMOKING ACCELERATES AGING IN PEOPLE, WE'VE SHOWN EXERCISE IS PROTECTIVE, AND LASTLY CHRONIC HIV INFECTION IS BAD. AND LASTLY THIS STUDY WHICH WE JUST STUDIED WHICH IS TO MEASURE MOLECULAR AGE BEFORE CHEMOTHERAPY, AND THREE TIME POINTS AFTER. THEY'RE ALL THE SAME SO WE AGGRAVATE THEM. WE CAN SEE EVERYBODY -- HAS A FAIRLY SIGNIFICANT INCREASE IN THEIR MOLECULAR AGE, AT LEAST OF THEIR T CELL ORGAN, SO ONE THING WE CAN MEASURE. THERE'S ONE PATIENT WHO DOESN'T CHANGE. THIS IS AN INTERESTING PATIENT. SHE'S THE YOUNGEST PATIENT IN THE COHORT, YET HER P16 IS THE HIGHEST TO BEGIN WITH, WHICH IS SURPRISING. SHE SURVIVED HER BREAST CANCER AND DIED A YEAR LATER OF PANCREATIC CANCER AND FOUND LATER TO HAVE A -- I SUSPECT THAT'S WHY HER P15 IS HIGH TO BEGIN W I HAVE -- EVERYBODY ELSE HAD A SIGNIFICANT INCREASE, 1.9 FOLD ON AVERAGE -- THIS IS NOT SURPRISING ONCOLOGISTS. WE ALL KNOW IF WE GET PEOPLE ON -- THERAPY, THEIR BONE MARROW GETS TIRED AND OLD AND WE INCREASE THE RISK OF LEUKEMIA, BOAB MARROW FAILURE, THINGS LIKE THAT WITH AGING. SO SUMMARY, A PERSON'S MOLECULAR AGE CAN BE MEASURED AND I THINK IN MY LIFETIME WE WILL HAVE A GOOD SET OF TESTS. I DON'T THINK IT WILL BE ONE TEST BUT A GOOD SET OF TESTS OF TO MEASURE MOLECULAR AGE. GENETIC DIFFERENCES IN SENESCENCE MACHINERY REGULATE HUMAN AGE OR AT LEAST RESPONSE TO HUMAN AGING, SMOKING, PHYSICAL INACTIVITY, CHRONIC HIV INFECTION AND CANCER CHEMOTHERAPY ACCELERATE AGING. AND MEASURING MOLECULAR AGE IS FIRST STEP TO TREATING AGING. REALLY CRITICAL AND I THINK POSH. WITH THAT, I'LL BE HAPPY TO TAKE ANY QUESTIONS AND POINT OUT TO PEOPLE WHO HAVE DONE THE WORK IN MY LAB AND WITH COLLABORATORS. THANK YOU. [APPLAUSE] >> THANK YOU VERY MUCH, DR. SHARPLESS. WE HAVE A FEW MINUTES FOR QUESTIONS. DR. RANDOLPH. >> GREAT INTERESTING WORK. I'M THINKING IN TERMS OF THE REPORTER MOUSE P16 -- YOU'RE LOOKING FOR -- THINGS THAT WOULD MAKE IT WORSE. HAVE YOU LOOKED FOR THINGS, EXERCISE, ANYTHING LIKE THAT? >> EXERCISING MICE TURNS OUT TO BE HARDER THAN YOU WOULD THINK. WE LOOKED INTO THAT. THOSE CAGES DO EXIST, WE HAVE ACCESS BUT ONLY FOR TWO WEEKS AT A TIME. LONGITUDINAL STUDY HAS NOT BEEN TRIVIAL. WE DISSECTED THE ANIMALS AND MEASURED OF P16 AND A VARIETY OF TISSUES AND RESULTS WERE INTERESTING AND SURPRISING. THE ANSWER IS THAT IN SOME TISSUES -- ALMOST COMPLETELY ABLATED THE INCREASE, AND IN OTHER TISH EU THERE WAS NO EITHER AT ALL. FOR THE UTERUS, IT WENT UP JUST THE SAME SO THERE WAS THIS SORT OF PATCHY EFFECT OF CALORIC RESTRICTION. IT WASN'T THE SAME IN ALL TISSUES, BUT IN MOST, IT WAS AT LEAST A TWOFOLD REDUCTION. >> VERY NICE. WHEN I'VE LOOKED AT YOUR DATA BEFORE, IT LOOKS TO ME, AND I'M JUST EYEBALLING IT, LIKE THERE'S A MORE AGGRESSIVE CHANGING P16 AROUND PUBERTY, AROUND SEXUAL MATURATION AND THEN IT FLATTENS OUT A LITTLE BIT, IS THAT JUST SORT OF LOOKING AT THE DATA WITHOUT A STATISTICIAN OR IS THERE A CHANGE AT SEXUAL MATURITY THAT SEEMS TO ACTUALLY CORRELATE WITH A CHANGE IN SLOPE THERE? >> WELL, WE DON'T KNOW THE ANSWER IN PEOPLE, BECAUSE OUR IRB APPROVAL DIDN'T ALLOW PATIENTS UNDER 18. SO IN HUMANS, ALL WE'VE EVER DONE IS STARTING AT AGE 18. THE OTHER PROBLEM WITH PEOPLE IS BECOMES QUITE HARD TO MEASURE BELOW 20 YEARS OF AGE. P16 IS A TRANSCRIPT THAT -- IT'S VERY HARD TO ACCURATELY MEASURE IT IN YOUNG PEOPLE, WHICH HAS BEEN A BIT OF A PROBLEM. IN MICE, HARDER TO SAY. GENERALLY I TELL PEOPLE IN MY LAB TO IF HLAB TO FOCUS -- THERE ARE THING S THAT HAPPEN EARLIER IN DEVELOPMENT THAT WE CAN'T EX-PLAIP. IN THE FEW INSTANCES WHERE WE LOOKED IN YOUNGER ANIMALS, YOU MAY BE RIGHT, THERE MAY HAVE BEEN EVEN A FASTER PACE AT THE EARLIER AGES. THAT'S CERTAINLY TRUE WITH TELOMERES. IT MAY BE THE SAME, THAT MAY BE BOTH KINDS OF SENESCENCE ARE HAPPENING FASTER AND SORT OF DEVELOPING ANIMALS BUT HE WOULDN'T BE SHOCKED BY THAT. I DON'T THINK OUR DATA ARE CLEAR CLEAR. >> ONE THING THAT'S REMARKABLE INTRIGUING HETEROGENEITY -- IT'S REALLY REMARKABLE, I'M SURE YOU GUYS ARE BEATING THAT TO DEATH. JUST WONDERING HOW DOES IT CORRELATE FOR INDIVIDUAL ANIMALS IN -- GROUP WITH THE RESISTANT TO A STRESS OR EVEN I KNOW THE HIGH FAT DIET DOESN'T MAKE IT FOR THAT BUT IS THERE ANY RELATION ON THE ROBUSTNESS OF THESE ANIMALS AND THE HETEROGENEITY? THAT WAS REALLY REMARKABLE. >> WE DID A LOT WITH IT, AND I'M AFRAID ALL THE GOOD STUFF I ALREADY TOLD YOU. SO WE -- FIRST I WAS CONCERNED IT WAS JUST THE ASSAY THAT DIDN'T WORK VERY WELL, IT WAS JUST NOISE, BUT THAT'S REALLY IT. IF YOU TRACK THE SAME ANIMALS, THIS IS PUBLISHED BY THE WAY, THIS UPDATE IN THAT PAPER, YOU CAN SEE THERE REALLY ARE SORT OF ONES THAT ARE ALWAYS HIGH OR ALWAYS LOW, SO IT SEEMS TO BE A REPRODUCIBLE FINDING THROUGHOUT -- WE ALSO THOUGHT MAYBE IT'S THE RATE OF CHANGE OR THE EXPRESSION AT SOME AGE THAT'S REALLY IMPORTANT, BECAUSE WE LOOKED AT ONE PHENOTYPE, DEATH, LONGEVITY, WITH A VARIETY OF END POINTS, NOT JUST HIGH-LOW AT ONE TIME POINT BUT HIGH-LOW IF AN AGGREGATE WAY, NONE OF THEM CORRELATED WITH THAT, SO IT REALLY DIDN'T APPEAR THAT YOUR RISK OF DYING IF YOU'RE A MOUSE IS RELATED TO YOUR TOTAL BODY BURDEN OF SENESCENT CELLS. THAT'S A LITTLE TROUBLING. I THINK MOST OF US WHO THINK ABOUT HUMAN CANCER, THIS IS JUDY'S WORK LARGELY, BUT WE BELIEVE SENESCENT CELLS RELEASE HORMONES THAT PROMOTE MALIGNANCY MALIGNANCY. I GUESS I COULD STILL LIVE WITH THOSE THINGS BEING TRUE, IF YOU THINK ABOUT HUMAN CANCER, IT SORT OF HAPPENS OVER 10 YEARS OR 20 YEARS, MUCH SLOWER PROCESS. THESE CANCERS THAT MICE HAVE ARE VERY QUICK AND THEY'RE MORE LIKE PEDIATRIC CANCERS, DRIVEN BY ONE OR TWO GENETIC EVENTS. IN TERMS OF OTHER AGING PHENOTYPES, WE HAVEN'T LOOKED SO MUCH. MOSTLY BECAUSE WE'RE NOT GOOD AT THEM. I TRY TO AVOID DOING THINGS THAT I'M NOT REALLY COMFORTABLE DOING, SO WHAT MY PLAN THERE HAS BEEN IS TO DISTRIBUTE THE ALLELE AS WIDELY AS POSSIBLE, AND I BELIEVE WE SENT IT TO 50 LABS AND COUNTING IN ASIA AND EUROPE AND LET THEM DO IT. SO SOMEBODY WANTED ME TO DO CADMIUM LEVELS, I'M LIKE THAT'S A GREAT EXPERIMENT, I KNEW NOTHING ABOUT CADMIUM, HERE ARE THE MICE. THIS FURLESS THING IS A BIT OF A PROBLEM, SO I'M TRYING NOW TO GIVE EVERYONE WHO'S INTERESTED IN SERIAL IMAGING, IF YOU WANT AN IMAGE OF THE SAME ANIMAL FOR TWO YEARS, THE HAIRLESS ANIMALS ARE MUCH BETTER. SO HOPEFULLY WE'LL HAVE A LOT OF THE ANSWERS TO THESE KINDS OF THINGS AS THE ALLELE GETS USED MORE. I CAN ALSO SAY THERE'S BEEN PICKUP IN PHARMA. HOPEFULLY THERE WILL BE SOME SORT OF GERONOGENE TESTING IN INDUSTRY AS WELL. >> THANK YOU VERY MUCH, DR. SHARPLESS. [APPLAUSE] >> HI, I'D LIKE TO INTRODUCE DR. RICHARD MAYEUX, OUR COUNCILMEMBER. THE GERTRUDE H. SERGIEVSKY PROFESSOR OF NEUROLOGY, PSYCHIATRY AND EPIDEMIOLOGY, THE CHAIR OF THE DEPARTMENT OF NEUROLOGY AND COAT DIRECTOR OF THE TAUB INSTITUTE ON ALZHEIMER'S AND THE AGING BRAIN AT COLUMBIA UNIVERSITY. RICHARD HAS DONE A LOT OF WORK OVER MANY YEARS IN EPIDEMIOLOGY AND GENETIC EPIDEMIOLOGY, AND HE'S GOING TO TALK TO US THIS MORNING ABOUT SOME OF THAT WORK. RICHARD, THANK YOU. >> THANKS, IT'S AN HONOR TO BE HERE. I THINK I'VE BEEN FUNDED FOR HALF OF MY LIFE BY THE NATIONAL INSTITUTE OF AGING, STARTING WITH A FIRST AWARD WHEN I WAS A FELLOW AND PROBABLY GOING TO REMEMBER MOST OF YOU ARE PROBABLY TOO YOUNG TO REMEMBER THEY HAD SOMETHING CALLED A FIRST AWARD. SO I'M GOING TO TALK TO YOU A LOT ABOUT THE GENETIC ANALYSIS AND THE CARIBBEAN, HISPANIC AND AFRICAN-AMERICAN POPULATION, BUT MORE IMPORTANTLY, I'M GOING TO SORT OF PUT THAT IN THE CONTEXT OF WHERE WE ARE WITH GENOMICS AND WHY IT'S IMPORTANT TO INCLUDE THESE GROUPS. FOR THOSE OF YOU WHO AREN'T FAMILIAR WITH ALZHEIMER'S GENETICS, IT'S EXCEEDINGLY COMPLEX BECAUSE THE PHENOTYPE IS NOT SO PRECISE. THERE ARE LONG PERIODS OF TIME WHERE WE DON'T HAVE ANY SYMPTOMS, WE KNOW THAT NOWSM THE MANIFESTATIONS AND RATE OF PROGRESSION VARIES IN PATIENTS, AND WE DO KNOW THAT IT AFFECTS EVERY ETHNIC GROUP THAT WE'VE LOOKED AT, OF COURSE FOR LATE ONSET DISEASE, THEY HAVE TO LIVE A LONG TIME, SO WE HAVE TO SEE POPULATIONS THAT ARE IN 60s AND 70s. IT'S ALSO GENETICALLY COMPLEX, I'VE ILLUSTRATED THAT ON THE RIGHT SIDE OF THE SLIDE. WE'VE KNOWN FOR A LONG TIME THAT THERE ARE THESE AUTOSOMAL DOMINANT -- THESE RARE AUTOSOMAL DOMINANT FAMILIES, AUTOSOMAL DOMINANCE BEING THAT EVERY GENERATION IS AIIVETTED BOTH MOTHERS AND FATHERS CAN TRANSMIT THE DISEASE TO THE SUBSEQUENT GENERATION, AND A CHILD OR OFFSPRING OF A PARENT THAT'S AFFECTED HAS A 50/50 CHANCE OF DEVELOPING THE DISEASE. THERE ARE NO KNOWN AS YET RECESSIVE FAMILIES, BUT THERE IS SOME EVIDENCE FROM A COUPLE OF STUDIES IN THE POPULATION I'M GOING TO TALK ABOUT OF RUNS OF HOMOSEGOCITY. THERE ARE ALSO A NUMBER OF FAMILIES LIKE THIS. I HAVE TO CREDIT TONY PHELPS FOR GETTING THIS THING STARTED. WE KNEW AS A GROUP THAT THERE WERE FAMILIES THAT HAVE LATE ONSET DISEASE THAT WERE NOT MENDELIAN LIKE THIS. WE KNEW THEY WERE AROUND BUT EVERYBODY HAD TWO OR THREE BUT NOVEMBER HAD ENOUGH TO MAKE ANY DIFFERENCE WITH, SO IN 2002, TONY ASKED ME TO ORGANIZE AN NIA LOAD, LATE ONSET FAMILY STUDY, AND THAT HAS PRODUCED ABOUT 1500 FAMILIES. I'LL TALK A LITTLE BIT MORE ABOUT THOSE LATER. IT'S PROBABLY THE MOST WIDELY USED AVAILABLE COHORT FOR ALZHEIMER'S DISEASE GENETICS IN THE WORLD. I THINK EVERYBODY FROM THE GET-GO, YOU COULD GET ACCESS TO THE DATA AND THE CLINICAL INFORMATION, AND WE'RE DOING ONGOING FOLLOW-UP OF THE FAMILY MEMBERS, BECAUSE THEY CONVERT AT A RATE THAT'S PRETTY ASTOUNDING. THEN THERE ARE THESE. THESE ARE THE KINDS OF PATIENTS THAT ALL NEUROLOGISTS SEE IN THEIR OFFICE. THEY SEEM TO BE SPORADIC, PU MY BUT MY FRIEND PETER REMINDED ME SPORADIC DOES NOT MEAN THAT IT'S GENETIC. THE REASON IS IF YOU GO BACK FAR ENOUGH, YOU FIND OUT THAT AN UNCLE OR AN AUNT HAD THE DISEASE AS WELL, AND SORT OF GAVE US THE IDEA THAT WE REALLY HAVE TO LOOK AT THESE PEOPLE VERY CAREFULLY, BECAUSE THERE PROBABLY ARE CRYPTIC GENETIC INFLUENCES THAT WE CAN DETECT ONLY BY A SERIOUS INVESTIGATION. SO TO PUT THIS IN THE CONTEXT, I FIRST WANT TO INTRODUCE YOU TO WASHINGTON HEIGHTS, WHERE I HAVE LICHED FOR THE LAST 35 YEARS, AND IF YOU JUST GOOGLE WASHINGTON HEIGHTS, THIS PICTURE WILL COME UP. IT'S AN IDEAL COMMUNITY, WAS FIRST FUNDED IN 1989, WAS ORIGINALLY A PROGRAM PROJECT AND THEN WE MOVED INTO AN RO1. THE REASON I LOVE THE COMMUNITY WAS BECAUSE WHEN WE STARTED THE STUDY, IT WAS ONE-THIRD HISPANIC, ONE-THIRD AFRICAN-AMERICAN, ONE-THIRD CAUCASIAN. BY THAT TIME EVERYBODY HAD PUBLISHED RISK FACTORS IN MOST CAUCASIAN POPULATIONS SO WE CAME IN WITH THE IDEA OF LOOKING ACROSS THE THREE DIFFERENT GROUPS TO SEE IF WE COULD DETECT DIFFERENCES. AND THAT WAS REALLY THE ORIGIN OF THIS STUDY, AND IT'S ACTUALLY STILL GOING ON. I THINK WE'VE STUDIED IN THREE WAYS CLOSE TO 8,000 MEDICARE RECIPIENTS. THE SAMPLING FRAME IS ALWAYS THROUGH WITH THE HELP OF CMS. IT'S A WONDERFUL COMMUNITY, IT'S SURROUNDED BY THE RIVER, THE HUDSON RIVER ON ONE SIDE, EAST RIVER ON THE OTHER. WE DON'T SEE CORPSES FLOATING ON THE EAST RIVER, WHICH YOU MAY THINK, BUT IT'S ACTUALLY A BEAUTIFUL COMMUNITY. IT'S KIND OF ISOLATED. THERE'S NO INDUSTRY THERE, THE HOUSING IS PRETTY INEXPENSIVE. THERE ARE 35,000 PEOPLE OVER 65 THAT LIVE IN THE COMMUNITY, AND THEY ARE VERY EAGER TO PARTICIPATE IN STUDIES. THERE ARE 22 AGING CENTERS THAT FREELY ALLOW US TO GO UP AND TALK TO THE PEOPLE WHO GO THERE FOR LUNCH AND THINGS LIKE THAT, SO WE'VE BEEN ABLE TO RECRUIT AND STUDY PATIENTS THERE FOR A LONG TIME. WE DO MOST THINGS BY CHOICE EITHER IN THEIR HOME, THEY WANT US TO, AND WE DO NUMEROUS PHENOTYPES. WE DRAW BLOOD, IF THEY HAVE A MEDICAL PROBLEM, THEY COME TO SEE US. WE'VE ACTUALLY HELPED OUT ON A LOT OF STUDIES REGARDING DIET. GENETIC STUDIES WHICH I'LL TALK ABOUT, CARDIOVASCULAR STUDIES, AND WE'VE ACTUALLY JUST FINISHED IMAGING 1300 OF THE HEALTHY NORMAL PEOPLE, AND THOSE DATA ARE AVAILABLE AS WELL. I ALSO WORK IN THE DOMINICAN REPUBLIC. HOW DID I WIND UP THERE? IT TURNS OUT THAT MOST OF THE HISPANICS IN MY COMMUNITY WERE FROM THE DOMINICAN REPUBLIC, AND WE HAD NOTED EARLY ON THAT THEY HAD A LOT OF -- THEY WERE MORE OFTEN THAN THE CAUCASIANS OR AFRICAN-AMERICANS IN THE COMMUNITY, HAD A FAMILY MEMBER WITH ALZHEIMER'S DISEASE. IN ABOUT 1990, I WAS LUCKY ENOUGH TO GET ONE OF THESE LEAD AWARD, AND ONE OF THE PILOTS WAS TO GO TO THE DOMINICAN REPUBLIC AND IDENTIFY THE FAMILIES WE ORIGINALLY IDENTIFIED IN NEW YORK. WE DISCOVERED THAT TO AB GOLD MINE. SO FOR THE LAST 16 YEARS, I'VE BEEN TRACKING FAMILIES IN THE DOMINICAN REPUBLIC, WE HAVE A JAIR TON GIST IN SANTO DOMINGO AND A COUPLE IN SANTIAGO, WERE THE TWO MAIN CITIES, AND OVER THE LAST 16 YEARS, WE'VE HAD ABOUT 700 FAMILIES THAT ARE MULTIPLEX FAMILIES WITH ALZHEIMER'S DISEASE AND WE DO THE SAME ASSESSMENTS WE DO IN WASHINGTON HEIGHTS IN THE DOMINICAN REPUBLIC. FOR A LONG TIME WE DIDN'T HAVE IMAGING. THERE WAS NOT A CAT SCAN EVEN ON THE ISLAND. THERE IS NOW 1.5 AND A 3.0 TESLA MAGNET, AND ACTUALLY AT THE END OF THIS MONTH, I'M GOING DOWN TO THE CLINIC BECAUSE WE'RE GOING TO START DOING BRAIN IMAGING THERE, OR THEY'RE GOING TO START DOING BRAIN IMAGING THERE. FOLLOWING FAMILIES THERE, THEY TYPICALLY ARE VERY HAPPY TO HAVE YOU COME. YOU HAVE TO HAVE COFFEE AND SOMETHING TO EAT BEFORE YOU DO ANYTHING. DON'T EAC EVEN TRY TO GO RIGHT INTO WHY YOU'RE HERE AND GET THE CONSENT. IT'S A TRADITION. SO YOU DRINK A LOT OF COFFEE AND YOU EAT A LOT OF FOOD. AND THEY BRING -- EVERYBODY GETS DRESSED UP AND THEY COME OUT TO GREET YOU AND YOU DO A LOT OFT% THINGS IN THE FIELD. SOMETIMES YOU HAVE TO GO IN TO SANTIAGO AND TRYING TO FIND A PARKING PLACE THERE WITH OUR VAN IS NEARLY IMPOSSIBLE, OR YOU TRACK A FAMILY MEMBER OUT INTO THE COUNTRY, AND WE HAVE NEVER -- JUST ONE, THEY USUALLY ACCEPT WHATEVER THE COLUMBIA UNIVERSITY IRB HAS ACCEPTED IT, THEY USUALLY ACCEPT THAT, BUT WE DO HAVE TO PRESENT EVERY YEAR TO THEIR INSTITUTIONAL REVIEW BOARD BOARD. WE TRIED AT ONE POINT TO GET INTO HAITI AND WE REALLY WERE NOT SUCCESSFUL, THEY DIDN'T WANT US TO BE THERE, SO WE GAVE UP AND STAYED IN THE DOMINICAN REPUBLIC. THESE ARE SOME OF THE PATIENTS THAT WE'VE SEEN. THAT'S DOLLY, SHE'S A KEY PERSON ON OUR TEAM, ANGEL WHO'S A NEUROLOGIST. THIS IS REALLY FIELD WORK. YOU CAN SEE. SOMETIMES IT GETS A LITTLE DICEY. THIS IS OUR TRUCK. THE ROAD WAS CLOSED BECAUSE IT WAS MUDDY BUT THE FAMILIES WERE WAITING FOR US IN THE VILLAGE SO THEY TOOK US IN BY HORSEBACK. WE WENT IN AND WERE ABLE TO COMPLETE ALL THE ASSESSMENTS. THERE ARE TWO FEDEX DROPOFFS SO WE USUALLY OBTAIN BLOOD AND SHIP EVERYTHING BACK, AS LONG AS YOU GET IT THERE BY 3:00, IT'S USUALLY PRETTY SUCCESSFUL. SO HOW DOES THIS FIT INTO THE OVERALL STRATEGY? I KIND OF DID THIS WHAT I CALL THE PIPELINE FOR DISCOVERING GENETIC VARIANTS. THERE'S AN INTERNATIONAL GROUP AND I'LL SHOW YOU IN A MINUTE, THESE COMBINED ENTITIES HAVE IDENTIFIED MOSTLY IN CAUCASIANS 24 VARIANTS THAT ARE CONSIDERED COMMON VARIANTS. I WAS SORT OF INTERESTED IN CONDUCTING THE AFRICAN-AMERICAN AND HISPANIC GROUP AND SO WE WERE ABLE TO PUT TOGETHER 6,000 AFRICAN-AMERICANS, AND DETECTED TWO GENES THAT WE KNEW ABOUT FROM THE CAUCASIAN GWAS AND I'LL SHOW YOU THE DATA THERE. AND THE CARIBBEAN HISPANIC, I'M GOING TO SHOW YOU UNPUBLISHED DATA BUT IT'S PRETTY INTERESTING FOR WHAT WE GET IN THE CARIBBEAN HISPANIC. I'LL THEN MENTION WHAT'S GOING ON WITH THE WHOLE EXOME STUDY. THIS IS THE NIA LOAD STUDY, THERE'S SOME INTERESTING RESULTS FROM THE WHOLE EXOME STUDY. I'VE BEEN DOING WHOLE EXOME SEQUENCING IN THE HISPANIC, THEN I'LL BRIEFLY TALK ABOUT IN A MOMENT, AND WHOLE GENOME SEQUENCING IS STARTING AND I'LL TALK A BIT MORE ABOUT THAT IN A MOMENT. SO WHAT ABOUT THE GWAS HIT? THIS IS THE RESULT, IT WAS IN NATURE GENETICS NOT TOO LONG AGO, THIS IS AN INTERESTING STORY. SO THE ALZHEIMER'S DISEASE GENETIC CONSORTIUM PUT TOGETHER DNA FROM ALL OF THE ALZHEIMER'S CENTERS FROM THE NIA LOAD STUDY FROM EPIDEMIOLOGICAL COHORTS, AT THE TIME WE WERE PRESENTING THE PAPER AT THE INTERNATIONAL ALZHEIMER'S MEETING, WE GOT WIND THAT OUR COLLEAGUES IN EUROPE AND FRANCE HAD SIMILAR FINDINGS. IT DIDN'T TAKE A GENIUS TO KNOW THAT IF WE COULD SOMEHOW GET THESE TWO GROUPS TO TALK TOGETHER, THAT WE COULD DOUBLE THE SAMPLE SIZE AND WE HAD THE SAME HIT, SO WITH A LITTLE HELP FROM OUR FRIENDS AT THE ALZHEIMER'S ASSOCIATION, THEY GAVE US MONEY FOR STARTING TO TALK TO EACH OTHER, AND THAT IS NOW GOING ON AT THE INTERNATIONAL GENETICS OF ALZHEIMER'S PROJECT, AND THIS IS THE FIRST PAPER, THE GWAS. IN RED ARE NEW GENES, IN BLACK ARE GENES THAT ARE SNIPS NEAR GENES THAT WE HAD DETECTED BEFOREHAND. THERE ARE NOW 24 VARIANTS ASSOCIATED WITH ALZHEIMER'S DISEASE. THE ODDS RATIOS VARY CONSIDERABLY. COURSE APOE IS A STRONG PLAYER. THOSE ARE THE ONES WE'RE SEEING PREVIOUSLY BEFORE THE COMBINED ANALYSIS. HERE'S THE AFRICAN-AMERICAN STUDY. I GOT TO TAKE THE LEAD, THIS WAS MY YOUNG COLLEAGUE, APOE IS OF COURSE A VERY STRONG PLAYER. ABCA7 IS ALMOST AS STRONG AS APOE. THE ALLELE FREQUENCY HERE WAS ABOUT 11%, FOR APOE IT'S ABOUT 21%, SO THE ODDS RATIO THEN BECOMES VERY STRONG AND I ATTRIBUTABLE RISK FOR ABCA7 APPLIES HIGH. NOW THIS VARIANT DOES APPEAR IN CAUCASIANS, BUT IT'S MUCH LOW ALLELE FREQUENCY, AND SO THOSE WERE THE TWO TOP HITS. YOU'LL NOTICE THERE ARE A LOT OF THINGS UNDER THE SURFACE HERE, SO MY GUESS IS IF WE HAD A LARGER SAMPLE SIZE, THAT WE'LL DETECT MORE OF THESE COMMON VARIANTS. IN CAUCASIANS, 75,000 PEOPLE, YOU CAN DETECT PRETTY MUCH EVERYTHING YOU NEED TO DETECT. WITH 6,000, WE'RE AT A DISADVANTAGE BECAUSE WE DON'T HAVE ENOUGH PHYSICIAN POWER TO DETECT ALL THE VARIANTS. THERE'S NOTHING EVEN CLOSE TO THIS HIT, BUT YOU CAN SEE IT'S AT THE SAME L%VEL AS THE ABCA7. AND OF COURSE THIS AREA IS BEING SEQUENCED AS WE SPEAK. SO I THINK THERE'S MUCH MORE TO BE GAINED BY DOING THIS BUT TRYING TO PUT TOGETHER A LARGE ENOUGH SAMPLE SIZE TO DO THIS IS REALLY THE TASK AT HAND. I'M SHOWING YOU UNPUBLISHED DATA FROM THE CAR CARIBBEAN HISPANIC. OF COURSE APOE, AGAIN THIS IS IN 6,000 CARIBBEAN HISPANICS THAT WE'VE BEEN ABLE TO PUT TOGETHER, AND WE FEEL, AGAIN, THAT WE COULD DETECT MORE IF WE HAD A LARGER SAMPLE SIZE BUT AT LEAST WE'RE MOVING IN A GOOD DIRECTION DIRECTION. WHAT ABOUT THESE VARIANTS? THESE ARE ASSOCIATED SNIPS. AS YOU KNOW, THE SNIPS ARE GENERALLY CAUSAL. EVERY ONE OF THESE HAS TO UNDERGO TARGETED RESEQUENCING TO FIND THE TRUE VARIANT. THE ADVANTAGE OF HAVING OTHER ETHNIC GROUPS, AS THEY SHOW UP, GENERALLY THERE ARE DIFFERENCES IN THE ALLELE FREQUENCY IN CAUCASIANS AND OTHER ETHNIC GROUPS. THIS GIVES YOU AN IDEA OF WHICH REGION OF THE GENE IS IMPORTANT, IN TERMS OF DRIVING THE FACTOR. SO QUESTION IS, DO WE DO WHOLE GENOME, DO WE DO EXONS ONLY, DO WE TRY TO GET IN SOME OF THE REGULATORY REGIONS, WE KNOW THOSE ARE ARE GOING TO BE CRITICALLY IMPORTANT, BUT WE ARE GOING TO NEED LARGE SAMPLE SIZES BECAUSE THE VARIATION, EVEN IN SMALL STUDIES, YOU GET A LOT OF MUTATIONS, YOU DON'T KNOW WHETHER ANY OF THOSE MUTATIONS ARE RELATED TO DISEASE UNTIL YOU HAVE ENOUGH SAMPLE SIZE, YOU NEED BIOINFORMATICS ANALYSIS TO HELP SORT HA OUT, AND IMPORTANTLY, IF YOU HAVE 24 HITS TO TAKE THEM INTO THE LAB TO LOOK AT THE FUNCTION OF HAD GENE, YOU NEED TO GIVE OUR COLLEAGUES IN THE LAB SOME IDEAS ABOUT WHICH PROTEINS OR WHAT ASSAYS ARE NEEDED, SO WE'VE BEEN SORT OF USING OUR SYSTEMS BIOLOGY FOLKS TO GIVE US SOME BIOPHYSICAL EVALUATIONS TO KNOW WHAT THE MUTATION WOULD DO TO THE STRUCTURE OF THE PROTEIN AND HOW THAT WOULD AFFECT PROTEIN-PROTEIN INTERACTION SO THEY CAN THEN ADVISE THE ANALYSIS THEY NEED TO DO. SO THE BIOLOGICAL AND FUNSAL ASSAY TO DETERMINE THIS ROLE, WE HAVEN'T EVEN STARTED TO DO THAT YET. SO THAT'S THE NEXT STEP AFTER WE IDENTIFY ALL THE GENES. SOME EXAMPLES OF SUCCESSFUL WORK HAS BEEN ON -- SO WHAT ABOUT THE WHOLE EXOME SEQUENCING? AGAIN, HERE'S THE PIPELINE. THIS IS WHAT'S BEING DONE IN THE NIA LOAD STUDY ALREADY. I'LL SHOW YOU SOME WORK WE'VE DONE AND THEN I'LL MENTION WHAT THE ADSP IS GOING TO BE UP TO. SO THE NIA LOAD WAS CREATED OVER ABOUT A 10-YEAR PERIOD. THERE ARE 1600 FAMILIES. ACTUALLY IT'S A LITTLE BIT MORE NOW BECAUSE THE OTHER GROUPS THAT HAD ORIGINALLY DECIDED NOT TO CONTINUE, WE'VE ACTUALLY BEEN ABLE TO CONVINCE THEM TO COME BACK IN AND WE GOT MORE PEOPLE WHO HAVE ORIGINALLY CONTRIBUTED FAMILIES. WE ALSO RECRUITED CONTROLS THAT WERE NOT PART OF THE FAMILY, THEY WEREN'T MARRIED IN, BUT THEY WERE FROM THE SAME COMMUNITY. FLOWSH ABOUT MID-WAY THROUGH, WE PUT IN A COMMON NEUROPSYCHOLOGICAL TESTING AND PSYCHIATRIST ASSESSMENT. WE'RE NOW FOLLOWING THE AFFECTED AN UNAFFECTED. THE REASON FOR THIS WAS THAT EVERYBODY'S BANKING ON THESE FAMILIES BECAUSE THEY ASSUME THEY'RE AT HIGHER RISK, BUT NO ONE HAD ACTUALLY EVER DONE THE WORK TO SAY WELL ACTUALLY IS IS THEIR INCIDENCE RATE REALLY HIGHER THAN WOULD YOU EXPECT BECAUSE OF THEIR AGE? IT TURNS OUT THEY'RE ABOUT THREE FOLD HIGHER INCIDENCE OF CONVERSION TO ALZHEIMER'S DISEASE, AND THAT WAS A PAPER JUST RECENTLY PUBLISHED. WE FREQUENTLY COLLECT AUTOPSIES. SOME OF THEM WERE AUTOPSIES TO BEGIN WITH. WE HAVE -- BECAUSE OF THE EXPENSE, WE'VE JUST DONE ALL THE AUTOPSIES AT COLUMBIA. SO IF SOMEBODY IN THE COHORT DIES, WE'LL BE HAPPY TO DO THE AUTOPSY FOR THEM. -- STO INVESTIGATORS. I ACTUALLY CALL THE FAMILIES MYSELF TO TALK TO THE FAMILY MEMBERS BECAUSE THAT ALSO ENCOURAGES THE FAMILY MEMOER ABOUTS TO CONTINUE PARTICIPATING. WE HAD EXOME CHIP ON ONE MEMBER OF EACH FAMILY. AND THIS IS THE MOST WIDELY USED COHORT OF PATIENTS FOR GENETICS IN THE WORLD. THERE HAVE BEEN SOME INTERESTING PAPERS. THIS IS ONE THAT CARLOS -- DID. WE NOTICED THAT SOME OF THE FAMILIES WERE LARGE A AGAIN THESE ARE LATE ONSET FAMILIES. SOME OF THEM ARE QUITE LARGE, ALMOST LOOKING MENDELIAN. SO WE DECIDED TO LOOK AT THE EARLY ONSET MUTATIONS AND SURE ENOUGH, THERE WERE MUTATIONS IN THE APP AND -- 1. YOU CAN SEE THE NUMBER OF CARRIERS. THIS IS A COMMON ONE. D2 OH206A. THAT PERSON DID NOT HAVE ALD DISEASE, THEY HAD FTD. THEY HAD AN ALZHEIMER'S PHENOTYPE. THE REASON WE KNOW THAT IS BECAUSE ONE OF THE MEMBERS OF THAT FAMILY WAS PART OF A TEACHING TAPE TO TEACH PEOPLE HOW TO DO THE COGNITIVE TESTING. SO ALL OF THE WISE NEUROLOGISTS LOOKED AT THIS VIDEOTAPE AND SAID THIS IS ALZHEIMER'S DISEASE DISEASE. OF COURSE THE PATHOLOGIST WAS THE FINAL PERSON WHO SAID NO, THIS IS SOMETHING ELSE. WE THOUGHT THIS WAS MAYBE JUST UNIQUE TO THAT FAMILY, THAT GROUP OF FAMILIES, SO WE DID IT IN THE CARIBBEAN HISPANIC FAMILY FAMILIES. WE FOUND MUTATIONS -- GRANULIN AND TAO. I THINK THERE'S ONE FAMILY NOW THAT I'M AWARE OF THAT HAS A -- MUTATION AND AD PATHOLOGY BUT MOST OF THE ONES THAT HAVE -- HAVE FTD PATHOLOGY. THIS WILL BE PRECISION MEDICINE, LOOKING AT PHENOTYPES BUT GETTING THE MOLECULAR GENETIC CHARACTERISTICS. THE TRM2 PAPER, THE ORIGINAL FAMILIES CAME FROM THE NIA LOAD STUDY. AGAIN, BECAUSE WE MADE IT AVAILABLE RIGHT FROM THE GET-GO, IT USES EVERY NIA RESOURCE POSSIBLE. THE BLOOD IS ACTUALLY SENT TO NICRED, THE CLINICAL DATA ALL COMES TO COLUMBIA. PEOPLE APPLY TO GET ACCESS TO THE DNA AND WE USUALLY SHIP THEM THE CLINICAL DATA. WE THEN TOOK THE TREM 2 BECAUSE IT WAS MOSTLY DONE IN WHITE AND SAID COULD WE SEE IT IN AFRICAN-AMERICAN, AND WE SHOWED THAT THE ORIGINAL VARIANT IN THE WHITE IS MONO MORPHIC IN AFRICAN-AMERICANS SO IT'S NOT A PLAYER. WE THEN IDENTIFIED A LOCUS IN THE SAME LINKAGE -- CARLOS AT WASHINGTON UNIVERSITY IS TRYING TO PUT TOGETHER A LARGE ENOUGH COHORT TO IDENTIFY THE GENETIC MUTATION IN TREM 2 AND AFRICAN-AMERICAN, AND AGAIN, WE'RE STRUGGLING TO GET ENOUGH -- A LARGE ENOUGH SAMPLE SIZE TO DO THAT, BUT THAT WOULD TELL US AN IMPORTANT ROLE FOR THAT CHANGE. I MENTIONED THAT I'D DONE SOME -- THIS IS PRELIMINARY DATA AGAIN IN 31 CARIBBEAN HISPANIC FAMILIES. WE TOOK FAMILIES THAT HAD FOUR OR MORE AFFECTED. WE'VE DONE WHOLE EXOME SEQUENCING. THESE ARE SOME OF THE GENES THAT ARE IMPORTANT. OF COURSE I'VE BEEN SORT OF VERY PARTICULAR ABOUT THAT GENE. IN 2007, PETER HISLOFF AND I PUBLISHED THIS IN NATURE GENETICS USING SNIPS. BUT WE HAD A HECK OF A TIME WITH THE LARGE GENE SEQUENCING IT, SO WE HAVE JUST FINISHED IT. THAT PAPER IS UNDER REVIEW NOW. WE FOUND 54 INDIVIDUALS, I THINK THEY WERE IN ABOUT 12 FAMILIES, LARGE MISSENSE MUTATION, THERE ARE TWO RARE MUTATIONS, AND THEY CORRESPOND VERY CLOSELY TO WHERE THE SNIPS WERE IN THE ORIGINAL PAPER, SO WE WERE HAPPY ABOUT THAT. THEN WE'VE DONE SOME BIOLOGICAL ASSESSMENT, THIS IS THE REAL COMMON ONE. IT DOESN'T AFFECT A BETA 40 BUT IT DOES AFFECT A BETA 42 SIGNIFICANTLY COMPARED TO WILD TYPE, AND THIS MUTATION IS VERY INTERESTING, BECAUSE WE COULDN'T FIND IT ON THE CELL SURFACE OR IN THE CELL. THE BIOPHYSICAL ASSESSMENT, I WENT TO BARRY HOENIG, A SYSTEMS BIOLOGIST AND COMPUTATIONAL BIOLOGIST AND HE MODELS THE GENE AND WHAT HAPPENS IS, IN THE 947M THERE'S A HYDROGEN BRIDGE THAT CLOSES THE RECEPTOR FOR THE LIPOPROTEIN RECEPTOR, SO THAT THEN TOLD US THAT WE HAD TO DO A DIFFERENT TYPE OF ASSAY TO REALLY FIGURE OUT WHAT THE FUNCTION OF THAT MUTATION IS. SO I THINK THAT'S REALLY WHAT WE'RE GOING TO HAVE TO BE DOING FOR MANY OF THESE GENES. SO I JUST WANT TO TOUCH A LITTLE BIT ON THE ALZHEIMER'S DISEASE SEQUENCING PROJECT, I PLAYED A PRETTY GOOD ROLE THERE TOO. LET ME START AT THE BOTTOM. THE WHOLE GENOME SEQUENCING, THERE ARE 566 PEOPLE FROM -- I WISH IT WAS -- 111 MULTIPLEX FAMILIES. THEY'RE UNDERGOING WHOLE GENOME SEQUENCING. 21 ARE NIA LOAD AND THEN THERE ARE SEVERAL OTHERS FROM OTHER COHORTS. THAT EXPERIMENT IS DONE. WE'RE LOOKING AT SORT OF PILOT TESTING THE RESULTS OF THAT EXPERIMENT AND I'LL SHOW YOU SOMETHING INTERESTING IN A MOMENT. THE WHOLE EXOME SEQUENCING, 5,000 CASES UNRELATED, SELECTED BECAUSE THEY'RE UNLIKELY TO EVER GET ALZHEIMER'S DISEASE, AND 5,000, THE CASES WERE SELECTED LIKELY NOT TO HAVE APOE AND THE CONTROLS WERE LIKELY NOT TO GET DISEASE. THEN WE HAD A BUNCH OF FAMILIES WE HADN'T INCLUDED IN THE WHOLE GENOME EXPERIMENT SO WE DECIDED TO TAKE ONE PERSON FROM EACH OF THOSE FAMILIES AND PUT THEM IN AS ANOTHER CASE GROUP. AND THEN WE'VE ACTUALLY FIGURED OUT WHO ELSE IS DOING EITHER WHOLE GENOME OR WHOLE EXOME SEQUENCING THAT'S NOT PART OF THIS STUDY, AND THEY'VE ALL AGREED TO HELP PUT TOGETHER THE DATA FOR THE ANALYSIS. AND THIS IS ABOUT HALFWAY THROUGH IT. THIS WHOLE EXOME SEQUENCING PROJECT. THIS IS AN INTERESTING FAMILY, IT'S BILINEAL, SO THIS PERSON IS AT VERY, VERY HIGH RISK. THESE ARE THE TYPES OF FAMILIES THAT WE HAVE. SOMETIMES YOU CAN SEE THE APOE GENOTYPE. WE PREFERRED TO HAVE FAMILIES THAT LACKED APOE4, BUT THEY WERE MULTIPLEX. THIS IS A LOAD FAMILY. SOME OF THE FAMILIES ALREADY HAD SEQUENCING SO WE CHOSE THE OTHER INDIVIDUALS, THEN WE CONTACTED THE INVESTIGATOR WHO WAS DOING THE SEQUENCING AND SAID WOULD YOU BE WILLING TO COMBINE YOUR DATA WITH OURS SO WE'RE GOING TO BE SEQUENCING OTHER FAMILY MEMBERS. AND THIS IS SOME EXCITING DATA, SO IT WAS ACTUALLY DONE BECAUSE NOW WE HAVE WHOLE GENOME DATA COMING IN THESE FAMILIES, WE DECIDED, WELL, MOST OF THOSE FAMILIES HAVE HAD GWAS, SO WE DID A LINKAGE ANALYSIS TO FIGURE OUT WHICH REGIONS WE WANT TO LOOK AT FIRST, AND THESE ARE THE DOMINICAN FAMILIES ON TOP AND THESE ARE THE CAUCASIAN FAMILIES ON THE BOTTOM, AND YOU CAN SEE ANYTHING -- THESE ARE SCORES IN THE RANGE OF OVER 5, SO THESE ARE REGIONS WHERE WE'RE GOING TO START LOOKING AND IT'S VERY EXCITING, THERE'S AT LEAST -- THERE'S SEVERAL LOOKING AT A DOMINANT MODEL, WHERE THERE ARE SEVERAL REALLY INTERESTING CANDIDATE AGENTS TO LOOK AT MUTATIONS. SAME THING IN THE CAUCASIANS, AND WE'RE ESPECIALLY INTERESTED IN AREAS WHERE THEY OVERLAP. SO JUST TO CONCLUDE, I THINK THERE ARE LIKELY TO BE MULTIPLE GENETIC VARIANTS THAT EXIST THAT RAISE THE RISK OF LOAD. THE FUNCTIONAL ANALYSIS IS INCOMPLETE. SO FAR EVERYTHING SEEMS TO AFFECT AMYLOID PROCESSING OR CLEARANCE. GENETIC VARIATION IN SORL1 AND VPS GENE, THEY ALTER -- THERE ARE NOW A HALF DOZEN GENES INCLUDING MANY OF THE GENES IN THE GWAS THAT ALL ARE INVOLVED IN THE INTRACELLULAR TRANSPORT SYSTEM, WHICH I THINK IS A VERY ROBUST AREA FOR FURTHER INVESTIGATION. IT'S ALL PART OF THIS THING CALLED THE RETROMR COMPLEX. THIS BRINGS UP THE WHOLE ISSUE ABOUT GENETIC COUNSELING AND THOSE LATE ONSET FAMILIES BECAUSE THESE ARE HIGH RISK MUTATIONS. PATHOGENIC MUTATIONS TYPICALLY SEEN IN FTLD, PARTICULARLY -- MAY BE PRESENT IN SOME FAMILIES WITH A SO CALLED AD PHENOTYPE, SO WE'RE GOING TO HAVE TO SORT OF FIGURE THIS ONE OUT. CAUSAL VARIANTS IN GENES THAT OCCUR IN ALL ETHNIC GROUPS BUT THEY DIFFER IN FREQUENCY AND EFFECT SIZE, AND THAT'S PROBABLY NO SURPRISE TO THOSE OF YOU WORKING OTHER ETHNIC GROUPS, BUT I THINK IT STRESSES THE IMPORTANCE OF INCLUDING ADDITIONAL ETHNIC GROUPS IN THESE STUDIES. IT'S VERY IMPORTANT. AND I THINK ONLY WHEN WE CAN DO THE GENETIC AND MOLECULAR CHARACTERIZATION CAN WE HOPE TO IDENTIFY NEW TARGETS FOR TREATMENT AND PREVENTION. IT TAKES MORE THAN A VILLAGE, IT TAKES A LOT OF CENTERS TO DO THIS. ALL THE GROUPS. THIS IS THE THING WHERE WE DECIDE TO DO AN ANALYSIS, WE CALL UP EVERYBODY. EVERYBODY IS ON THE PHONE AND WE CAN PULL THESE GROUPS TOGETHER AND GENERALLY EVERYBODY WANTS TO PARTICIPATE. THESE ARE THE KEY PEOPLE THAT I WORK WITH. SOME OF YOU KNOW ALL OF THESE PEOPLE. POT YOUNG PEOPLE THAT STARTED OFF AS POST DOCK DOCK DOCS WITH ME, GREAT ADDITION TO OUR ST STUDIES. THIS IS WHERE I WORK. BEAUTIFUL CITY. GOOD STAFF. DOLLY DOES REALLY ACTUALLY EVERYTHING. SO I DON'T DO MUCH. THANK YOU VERY MUCH. [APPLAUSE] >> [INAUDIBLE] >> FIRST OF ALL, I THINK THAT I WOULD DISAGREE STRONGLY WITH THE FIRST THING YOU SAID. SO WE'VE COMPARED THE RATES OVER ABOUT A 25 YEAR PERIOD AND LOOKED AT RECURRENT TRENDS, AND WHILE WE'VE SEEN SORT OF A FLATTENING IN THE CAUCASIAN GROUP, THE RATES OF ALZHEIMER'S DISEASE ARE GOING UP IN HISPANICS AND AFRICAN-AMERICANS, AND WE'VE ALWAYS FOUND THAT IN THE SAME COMMUNITY, THIS IS A POPULATION BASED STUDY THAT WE'VE DONE SINCE STARTING IN 1989, A COUPLE OF DIFFERENT WAYS, SO FREQUENCY OF ALZHEIMER'S DISEASE IS ACTUALLY TWICE AS MUCH IN AFRICAN-AMERICANS AND A LITTLE BIT MORE THAN TWICE AS MUCH IN THE CARIBBEAN HISPANICS. NOW IT MAY BE DIFFERENT IN CENTRAL SOUTH AND MEXICAN-AMERICANS, BUT CERTAINLY FOR THAT COHORT, IT'S THE SAME. AUTOPSY FINDINGS ARE PRETTY MUCH THE SAME. WHEN WE DO AUTOPSIES, WE SEE THE SAME TREND. IN THE -- I DIDN'T -- I FAILED TO MENTION THAT YES I HAVE FOCUSED ON FAMILIES, AND THE REASON I DID WAS BECAUSE THE AVERAGE DEGREE OF INBREEDING IN THE DOMINICAN REPUBLIC IS ABOUT LIKE SECOND COUSINS. IT'S A LITTLE BIT MORE IN SOME FAMILIES THAN OTHERS, AND IT'S PARTICULARLY PRESENT IN THE OLDER POPULATIONS. THE YOUNGER POPULATIONS WAS MUCH LESS INBREEDING, AND WE HAVE A PAPER THAT SHOWS SIGNIFICANT RUNS OF HOME MOA SIGH GOSS IT AND WE'RE ACTUALLY FOCUSED ON THAT RIGHT NOW. IN THE SELECTION USING CMS AS OUR SAMPLING BASE, THE FREQUENCY OF ALZHEIMER'S DISEASE AGAIN, AND TEASE ARE SPORADIC, YOU KNOW, SORT OF PEOPLE LIVING IN THE COMMUNITY, THE RATES ARE STILL MUCH HIGHER NOW IS IT ALL ALZHEIMER'S DISEASE? WE THINK SO. WE'VE DONE NOW IMAGING, WE'RE NOW DOING PET SCANS WITH AMYLOID PET. WE'RE ACTUALLY NOW THINKING ABOUT TRYING TO DO LUMBAR PUNCTURES TO GET -- THAT MIGHT BE CHEAPER AND EASIER TO DO. TRYING TO GET THAT THROUGH A COMMUNITY STUDY IS GOING TO BE A LITTLE TOUGH, BUT WE'VE GOT IT THROUGH IRB, SO THE NEXT STEP IS TO TRY TO DO A FEW OF THOSE. SO I THINK THE RATES ARE STILL HIGHER. THAT'S MY OPINION. >> DR. MORIMOTO. >> RICHARD, THAT WAS JUST WONDERFUL. AS YOU MIGHT IMAGINE, I LIT UP WHEN I HEARD YOU TALK ABOUT MAPPING SOME OF THE MISSENSE MUTATIONS TO PROTEIN STRUCTURE. THERE'S SOME STUDIES OUT THERE NOW WHERE PEOPLE ARE LOOKING AT WHAT PROTEINS MIGHT BE AT RISK FOR AMPLIFYING PROTEIN DAMAGE. THERE'S A SERIES OF ALGORITHMS THAT CAN LOOK AT SEQUENCES AND ACTUALLY MAKE PREDICTIONS OF THE LIKELIHOOD OF INSTABILITY MISFOLDING AND ACTUALLY FURTHER AM MI FYING THE AMYLOID PHENOTYPE. SO IT MIGHT BE VERY INTERESTING TO TAKE YOUR -- ONE COULD EVEN TAKE THE GWAS BECAUSE IT'S A FINITE NUMBER OF GENES, BUT IN PARTICULAR, WHEN YOU'RE DOWN TO LOCI AND ALLELES, TO ACTUALLY TAKE IT TO THESE ALGORITHMS TO EVEN TEST THE HYPOTHESIS, BECAUSE EITHER OF THESE PROTEINS ARE AT HIGHSER RISK FOR MISFOLDING OR THEY'RE NOT. AT LEAST WE CAN START TO TEST SOME HYPOTHESES THAT MAYBE IT'S PART OF CUMULATIVE DAMAGE THAT STARTS TO EXPLAIN SOME OF THESE. OR AT LEAST SOME OF THE ALLELES. >> WELL, I COULDN'T AGREE WITH YOU MORE. WHEN WE DID THE SORL1 AND WE HAD THE STRAIGHTFORWARD EFFECT ON BETA 40 AND 42, WE WANTED TO KNOW IS THIS A BAY A BINDING AND IS IT APP? TURNS OUT THAT TWO OF THEM WE COULD ACTUALLY SEE HOW THEY WERE BINDING TO APP AND WE COULD SEE THAT THEY WEREN'T BINDING EFFICIENTLY INTRACELLULARLY. BUT THAT ONE MUTATION, WE COULDN'T FIGURE OUT, SO THAT'S WHEN I WENT TO BARRY AND I SAID YOU GUYS MUST KNOW HOW TO LOOK AT PROTEINS, THERE'S SOMETHING WRONG WITH THIS VARIANT BECAUSE WE CAN'T MEASURE IT ANYWHERE. AND THAT'S WHEN THEY GOT VERY INTERESTED, SO NOW I'VE GOT THEM LOOKING AT EVERY MUTATION THAT WE HAVE TO LOOK AT WHAT -- THEY CAN TELL US WHAT PROTEINS IT INTERACTS WITH AND HOW THE MUTATION -- THEY DIDN'T WANT TO DEAL WITH THE SNPs BECAUSE THEY DIDN'T FEEL THOSE WERE EFFECTIVE, BUT THEY SAID IF YOU GIVE US A MUTATION AND WE CAN MODEL THE SEQUENCE AND PREDICT WHAT EFFECT THAT WOULD HAVE ON PROTEIN INTERACTION OR PROTEIN-PROTEIN INTERACTION, AND HE SHOWED US THE NORMAL PROTEIN STRUCTURE FOR SORL-1 AND THEN SHOWED US THE EFFECT OF THIS MUTATION IS JUST CLOSING THIS -- I MEAN, I COULD EVEN SEE, THERE WAS A BIG GAP THERE NORMALLY, THIS BIG GREEN THING COMES OVER THE TOP OF IT AND IT'S NOT GOING TO BIND. PRETTY CLEAR. THAT'S WHY WE PROBABLY CAN'T MEASURE IT. SO I PERSONALLY THINK WE'RE GOING TO HAVE TO DO THIS FOR ALL THESE VARIANTS, AND TO GET THE SYSTEMS PEOPLE IN EARLY WOULD BE REALLY A FUN THING TO DO, BECAUSE IT WILL HELP DEVICE THE ASSAYS. BRAD AND I HAVE TALKED ABOUT THIS A LOT. RIGHT NOW WE'VE GOT 24 ASSOCIATIONS. THAT ISN'T GOING TO HELP ANYBODY. WE HAVE TO FIGURE OUT WHAT EACH OF THESE GENES DO AND HOW THEY DO IT, AND WHETHER WE CAN DO ANYTHING ABOUT IT. >> FOLLOWING UP ON YOUR SUGGESTION OF THE IMPORTANCE OF NETWORK ANALYSIS. SOME VERY PRODUCTIVE -- SEEMS TO BE OCCURRING LOOK AT OMICS AS GENE EXPRESSION IN THE BRAINS. WHAT'S THE SITUATION FOR AVAILABILITY OF MATERIALS FROM SOME OF THESE GROUPS? >> WE HAVE -- I PERSONALLY CONTROL ABOUT 200 OF THE BRAINS. JEAN PAUL, IF YOU JUST FILL OUT THE FORM, YOU GET MORE -- I DON'T CONTROL THE OTHER 500 BRAINS IN THE LOAD STUDY. THE WAY WE SET UP THE LOAD STUDY WAS THAT AS A P.I., I WOULD BE -- I DON'T HAVE NAMES OR IDENTIFICATION AT THE SITE. ALL I HAVE IS THAT THE SITE AND THE SITE P.I. AND THEIR CODE NUMBER. SO WE TALK ABOUT THIS A LOT, ABOUT WHETHER WE COULD GO BACK AND GET ALL THOSE BRAINS INTO ONE LOCATION. AND FRANKLY FOR MOP E MONEY AND TIME, IT WAS A BIG EFFORT AND WE JUST DIDN'T HAVE THE TIME TO DO IT. IT'S DOABLE, BECAUSE MORE AND MORE PEOPLE ARE DYING, AND THEY USUALLY -- WE GET THE BRAIN THEN BUT WE KEEP IT AT COLUMBIA THEN. BUT WE COULD DO IT. >> THANK YOU VERY MUCH, DR. MAYEUX. WE'LL TAKE A SHORT BREAK NOW TO GET LUNCHES AND COME BACK FOR THE FINAL TWO TALKS. HOT FLASHES AND NIGHT SWEATS, SOME OF THE ONGOING WORK WE'RE DOING AND PLANNING TO DO RELATES TO OTHER COMMON SYMPTOMS OF MENOPAUSE AND THE POST MENOPAUSE WHICH INCLUDE INSOMNIA AS WELL AS VAGINAL DRYNESS AND OTHER VAGINAL SYMPTOMS. SO TO ORIENT A LITTLE BIT TO WHAT WE'RE TALKING ABOUT HERE IN TERMS OF THESE SYMPTOMS, HOT FLASHES ARE HIGHLY PREVALENT, UP TO 88% OF WOMEN WILL GET HOT FLASHES AT SOME POINT DURING THE MENOPAUSE TRANSITION. THEY ARE THE MAJOR REASON WHY WOMEN WILL SEEK MEDICAL ATTENTION, SO THE COSTS AND MEDICAL BURDENS ARE SUBSTANTIAL. THEY INTERFERE WITH WOMEN'S LIVES BECAUSE THEY'RE DISRUPTIVE DURING THE DAY, INTERFERE WITH SOMEBODY'S ABILITY TO CONTINUE ON WITH WHAT SHE'S DOING, THEY'RE BOTHERSOME, PHYSICALLY UNCOMFORTABLE WITH THIS EPISODIC AND REPEATED SENSATION OF HEAT, AND THEY ALSO HAVE A MAJOR EFFECT ON SLEEP AND SLEEP FRAGMENTATION. HOT FLASHES HAVE ALSO BEEN IDENTIFIED BY SOME OF THE INTERESTING WORK THAT'S COME OUT OF OUR OTHER UL1 SUPPORTED NIA FUNDED NETWORK, WE'VE IDENTIFIED EPIDEMIOLOGIC STUDY THAT HOT FLASHES ARE ALSO CORRELATED WITH AND A MARKER OF OTHER HEALTH OUTCOMES IN WOMEN, INCLUDING CORONARY ARTERY DISEASE AND OTHER ADVERSE CONDITIONS. SO THIS IS AN IMPORTANT SYMPTOM TO STUDY FOR A VARIETY OF REASONS. FOW AFTER THE WOMEN'S HEALTH INITIATIVE RESULTS REPORTED THAT HORMONE THERAPY HAD IMPORTANT RISKS ASSOCIATED PARTICULARLY WITH LONG TERM USE, THE USE OF HORMONE THERAPY WHICH HAS ALWAYS BEEN THE PRIMARY TREATMENT FOR HOT FLASHES WENT DOWN SIGNIFICANTLY. AND THERE ARE A LOT OF WOMEN WHO ARE QUITE SYMPTOMATIC AND AT THAT TIME, GROWING OUT OH OF SOME EARLIER WORK IN THE BREAST CANCER POPULATION WHERE HORMONES HAD NOT BEEN AN OPTION FOR THOSE WOMEN, THERE WAS A LOT OF INTEREST IN NON-FORM ENCLOSE JIK NON-PHARM ACOLOGIC TREATMENT, BEHAVIORAL INTERVENTION AS COMPLEMENTARY TREATMENT. HOWEVER, NONE OF THESE -- FEW OF THESE INTERVENTIONS HAVE BEEN STUDIED IN LARGE TRIALS, THEY'RE VERY SYSTEMATICALLY -- SO OUR MISSION WAS TO UNDERTAKE THOSE INVESTIGATIONS. SO TO GIVE YOU A LITTLE BIT OF A SUMMARY OF WHAT WE'VE DONE TO DATE, WE'VE DONE THREE RANDOMIZED TRIALS ON HOT FLASHES. THIS INCLUDES ABOUT 900 WOMEN IN THE THREE TRIALS TOGETHER. THROUGH THIS, WE TESTED SIX INTERVENTIONS. THESE INCLUDE THREE PHARMACOLOGIC INTERVENTIONS, SFRI, SEROTONIN -- SELECTIVE SEROTONIN UP TAKE INHIBITOR, AND LOW DOSE -- WE'VE ALSO INVESTIGATED ONE COMPLEMENTARY INTERVENTION WHICH IS OMEGA-3, AND TWO BEHAVIORAL INTERVENTIONS, EXERCISE AND YOGA. WE'VE ALSO COMPLETED ONE PILOT STUDY INVESTIGATING OBJECTIVE HOT FLASH MONITORS TO PHYSIOLOGICALLY QUANTIFY THESE SYMPTOMS THAT ARE PERCEIVED AND REPORTED, AND WE'VE BEEN CONDUCTING TWO ANCILLARY STUDIES LOOKING AT HOT FLASH CORRELATES WITH HEART RATE VARIABILITY AS AN INDEX OF AUTONOMIC PERTURBATION, AND ALSO BONE TURNOVER MARKERS IN RELATION TO SEROTONIN REUPTAKE INHIBITORS. IN TERMS OF SOME OF THE ONGOING WORK THAT WE'RE DOING NOW, WE HAVE TWO ACTIVE PILOT TRIALS. ONE IS BOTH ACTIVE NOW AND RECURRING. ONE IS FOR A COGNITIVE BEHAVIORAL INTERVENTION FOR INSOMNIA THAT'S BEING STUDIED FOR THE FIRST TIME IN MENOPAUSE ASSOCIATED INSOMNIA, AND WE'RE MORE THAN HALFWAY THERE. AND SMALLER TRIAL LOOKING AT NIGHTTIME ONLY DOSING OF GABAPENTIN STUDIED IN A THREE TIMES A DAY DOSING, WE'RE LOOKING AT SELECTIVE DOSING FOR NIGHTTIME SYMPTOMS AND FOR INSOMNIA, BUT PRIMARILY LOOKING AT TOLERABILITY TO SEE IF THIS IS AN INTERVENTION THAT WE CAN INVESTIGATE GOING FORWARD. IN TERMS OF OUR PUBLICATIONS, WE HAVE 15 PUBLICATIONS THAT ARE AVAILABLE OR IN PRESS, FIVE THAT ARE CURRENTLY IN REVIEW, AND 12 THAT ARE ACTIVELY IN PREPARATION. I DON'T HAVE THE TIME TO GO OVER ALL OF THEM, BUT WE'VE BEEN REPORTING THE MAIN TRIAL RESULTS FROM OUR THREE TRIAL, WE'VE BEEN LOOKING AT A NUMBER OF IMPORTANT SECONDARY END POINTS INCLUDING SLEEP DISTURBANCE, INSOMNIA, SEXUAL FUNCTION, QUALITY OF LIFE, RECURRENCE OF SYMPTOMS, AND SO ON. SO QUITE A BIT OF ONGOING WORK, OF COMPLETED WORK, AND ALSO ONGOING WORK. SO THE RESULTS OF OUR FIRST TRIAL WERE PUBLISHED A FEW YEARS AGO IN JAMA, THE LEAD AUTHOR WAS ELLEN FREEMAN. THIS STUDY WAS AVAILABLE IN GENERIC -- SSI, OFF LABEL AT THE TIME WE INVESTIGATED, NO NON-HORMONAL TREATMENTS WERE PROVED BY THE FDA FOR HOT FLASHES. SINCE THEN, THERE HAS BEEN ONE APPROVED LAST YEAR. SO WE INVESTIGATED THIS IN A TRIAL OF ABOUT 200 WOMEN. HERE ARE THE MAIN RESULTS FROM THE PAPER. YOU CAN SEE IT'S AN 8-WEEK TRIAL. THE MAIN END POINT HERE IS THE NUMBER OF HOT FLASHES REPORTED PER DAY. SO WE USED DIARIES IN WHICH WOMEN REPORT CONTINUOUSLY OVER THIS PERIOD OF TIME HOW MANY SYMPTOMS THEY'RE HAVING, AND THEY START WITH AN AVERAGE OF -- HERE THE MEAN IS 10. AND THE REDUCTION WITH BOTH INTERVENTIONS IS PARTIAL. THERE'S ALWAYS A PLACEBO RESPONSE WITH ALL OF THESE TRIALS. BUT IHE EFFICACY OF THE DRUG HERE IS GREATER THAN THE EFFECT OF PLACEBO. THE OTHER THING WE SAW IN THE TRIAL IS ONCE UNDER DOUBLE BLIND CONDITIONS, THE INTERVENTION WAS DISCONTINUED. THE RECURRENCE WAS QUITE SWIFT. SO THESE ARE NOT -- THESE INTERVENTIONS DON'T HAVE SUSTAINED BENEFIT AFTER THEY'RE DES CONTINUED. DISCONTINUED. IN TERMS OF CATEGORICAL DEFINITION OF CLINICAL BENEFIT, A 50% REDUCTION FROM BASELINE, BOTH AT FOUR WEEKS AND ALSO AT EIGHT WEEKS, YOU CAN SEE THAT THE -- IN THE RED, THAT THE WOMEN ASSIGNED TO ESOTALAPRAM WERE MUCH MORE LIKELY TO HAVE A CLINICALLY SIGNIFICANT RESULT. I MENTIONED EARLIER 50% OF THE WOMEN IN THIS TRIAL WERE AFRICAN-AMERICAN AND 50% WERE CAUCASIAN, AND WE DID NOT SEE ANY DIFFERENCES IN RACE OR ANY OTHER MAJOR DEMOGRAPHIC CHARACTERISTIC OR SYMPTOM CHARACTERISTIC IN TERMS OF RESPONSE. THE SECOND TRIAL WAS A THREE BY TWO FACTORIAL DESIGN IN 355 WOMEN. THIS SHOWS YOU THE OVERVIEW OF HOW THE TRIAL WAS IMPLEMENTED. WE HAD THREE BEHAVIORAL APPROACHES. YOU CAN SEE YOGA EXERCISE AND THEN NO BEHAVIORAL INTERVENTION, AND THEN EACH OF THOSE THREE GROUPS WAS CROSS RANDOMIZED TO OMEGA-3 OR PLACEBO, SO ALTHOUGH THE USUAL ACTIVITY GROUP DID NOT HAVE A BEHAVIORAL INTERVENTION, THEY HAD THE EXPECTANCY EFFECT OF BEING ON A DRUG OR PLACEBO. AND IN THIS -- THESE WERE THREE SEPARATE REPORTS THAT CAME OUT LAST YEAR OF EACH OF THESE INTERVENTIONS, AND WE FOUND NONE OF THESE THREE INTERVENTIONS WERE MORE EFFECTIVE THAN THE CONTROL ARM. SO THIS BEEN IMPORTANT, WE ENCOURAGE PEOPLE TO EXERCISE AND STAY HEALTHY, BUT TO SPEND MONEY MONEY -- THIS WOULD NOT BE EXPECTED TO BE EFFECTIVE FOR THEM. NOW TO SPEND THE MAJORITY OF OUR TIME ON THE THIRD TRIAL TO TALK TO YOU ABOUT THE STUDY MOTIVATION HERE WAS THAT VERY COMMONLY USED MEDICATIONS TO TREAT HOT FLASHES OFMOTOR SYMPTOMS HAVE BEEN ESTRADIOL,S, ALSO THE NON-HORMONAL PHARMACOLOGICAL INTERVENTIONS HAVE BEEN USED OFF LABEL PRIMARILY. THE MAGNITUDE OF THE EFFECT OF THESE INTERVENTIONS HAS NOT BEEN VERY WELL UNDERSTOOD RELATIVE TO THE OTHER IN THAT THERE'S BEEN THIS CLINICAL IMPRESSION THAT THE -- DRUGS IN PARTICULAR ARE LESS EFFECTIVE THAN ESTROGEN THERAPY, AND THE POPULATIONS IN THESE DIFFERENT TRIALS HAVE BEEN QUITE DIFFERENT. SO THE MAJORITY OF THE WOMEN IN THE ESTROGEN TRIAL, BECAUSE THESE WERE FDA REGISTRATION TRIALS, HAD SEVEN OR MORE MODERATE TO SEVERE HOT FLASHES PER DAY, AND IN CONTRAST FOR THE SEROTONERGIC DRUGS, THEY WERE TWO OR MORE PER DAY. THE ESTROGEN TRIAL POPULATION WAS A BIT OF AN OUTLIAR WHEN YOU LOOK AT THE DISTRIBUTION OF HOT FLASH FREQUENCY. SO THE POPULATIONS WERE DIFFERENT, THE APPROACHES, THE WAY THE END POINTS WERE EXAMINED WERE ALSO DIFFERENT. THE OTHER IMPORTANT THING IS THAT THE MAJORITY OF THE ESTROGEN STUDIES USED A HIGHER DOSE THAN HAS BEEN USED PRIMARILY NOW AFTER THE WHR RESULTS CONCLUDED THAT -- OR THE RECOMMENDATION THROUGH THE FDA WAS TO USE THE LOWEST DOSE POSSIBLE AND ALSO TO USE ESTROGEN FOR THE SHORTEST TIME POSSIBLE. AND SO LOW DOSES WHICH HAVE HAD VERY LITTLE INVESTIGATION HAVE NOT BEEN -- THE EFFICACY HAS NOT BEEN UNDERSTOOD QUITE AS WELL. SO WE KNOW THESE ARE BOTH PREMEDS FOR WOMEN WHO ARE ABLE TO TAKE BOTH AS ALTERNATIVES, THEY BOTH HAVE BENEFITS, THEY BOTH HAVE SIDE EFFECTS, THEY BOTH HAVE RISKS, BUT IN ORDER TO GUIDE WOMEN MORE SPECIFICALLY, WE PLAPPED AND INITIATED A THREE ARM TRIAL TO INVESTIGATE HERE OUR PRIMARY AIM TO DETERMINE THE EFFECT OF EACH ACTIVE TREATMENT RELATIVE TO PLACEBO. WE HAD HYPOTHESIZED SUPERIORITY OVER PLACEBO. WE HAD -- THIS WAS ON THE PRIMARY END POINT OF HOT FLASH FREQUENCY. WE ALSO LOOKED AT SECONDARY OUTCOMES OF THE EXTENT TO WHICH THESE SYMPTOMS ARE BOTHERSOME, THE SEVERITY INDICATORS, AND ARE QUESTIONING OUR BASE HOT FLASH INTERFERENCE, THE EXTENT TO WHICH THEY INTERFERE WITH DAILY AND NIGHT FUNCTION. WE ALSO HYPOTHESIZE THAT THERE MIGHT BE BASELINE CHARACTERISTICS THAT MIGHT DIRECT SOMEBODY TO BE MORE RESPONSIVE TO ONE INTERVENTION VERSUS ANOTHER, AND THAT WAS EXAMINED HERE. SO JUST A LITTLE BIT ABOUT OUR POPULATION. WE TOOK WOMEN WHO ARE MOST LIKELY TO GET HOT FLASHES WHO ARE BETWEEN THE AGES OF 40 AND 62, ALTHOUGH SWAN DATA NOW SHOW THE LONGER WE FOLLOW WOMEN, THE MORE WE LEARN THAT WOMEN CONTINUE TO HAVEVASO MOTOR SYMPTOMS WELL INTO THEIR 60s AND BEYOND BUT PEAK PRE PREVALENCE PREVALENCE. WE REQUIRED A MINIMUM OF TWO SYMPTOMS PER DAY, WHICH WOULD TRANSLATE INTO FOUR OR MORE -- 14 OR MORE PER WEEK, BUT AS YOU'LL SEE OUR BASELINE LEVEL IS MUCH HIGHER, SO ON AVERAGE, WE HAD WOMEN COME IN WITH EIGHT OR MORE PER DAY, SO THEY'RE QUITE SYMPTOMATIC. ONE IMPORTANT THING WE DID TO TRY TO MINIMIZE THE PLACEBO RESPONSE WHICH HAS PLAGUED A LOT OF THESE TRIALS IS WE GOT TWO WEEKS OF DIARY READINGS TO ASCERTAIN A SYMPTOM LEVEL THRESHOLD AND STABILITY OF SYMPTOMS AND THEN EVEN A THIRD WEEK OF DIARY READINGS TO MAKE SURE THAT SYSTEMS DIDN'T DECLINE, SO WE TRIED TO GET A POPULATION WHERE THEY HAD STABLE SYMPTOMS THAT WEREN'T BOUNCING AROUND OR AGRESSING. WE OF COURSE EXCLUDED ANY WITH CONTRAINDICATIONS TO EITHER INTERVENTION, CONVENTIONAL ESTROGEN, CONTRAINDICATIONS, PSYCHIATRIC DISORDERS, SUBSTANCE ABUSE THAT WOULD BE POTENTIALLY CONTRAINDICATION FOR USE OF AMALOF LAX INE, ALSO WITH CONTRAINDICATED MEDICATIONS AND WE REQUIRED THAT BLOOD PRESSURE BE CONTROLLED IF THERE WAS HYPERTENSION. AND OF COURSE THEY WERE NOT PREGNANT. HERE IS THE OVERALL SCHEMA OF WHAT YOU CAN SEE THAT WE'VE CONDUCTED AN 8 WEEK INTERVENTION TRIAL AND BEFORE THAT, AS I MENTIONED, WE HAD A PRETTY EXTENSIVE SCREENING PROCESS. THERE WAS A PARALLEL THREE ARM RANDOMIZATION. IT WAS A 2 TO 2 TO 3 RANDOMIZATION SO WE HAD A LARGER PLACEBO GROUP IN ORDER TO HAVE A STABLE ESTIMATE AND PROVIDE EFFICIENCY FOR THE STATISTICAL ANALYSIS FOR THE TWO COMPARISONS. THE ESTRADIOL, WE USED WITH PURE 17 BETA, WE USED ORAL WHICH IS STILL MORE WIDELY USED THAN TRANSDERMAL. THAT IS THE LOWER DOSE. THAT IS NOT THE LOWEST DOSE BUT LOWER DOSE THAT'S TYPICALLY USED. THE VENLAFAXINE DOSE IS ALSO THE LOWEST DOSE TO BE EFFECTIVE, WE TITRATED THEM ON, AND AFTER THE TRIAL, WE TITRATED THEM OFF AND THEY WERE THE PLACEBO ARMS. WE UNBLINDED AT THE END OF THE # WEEKS IN ORDER T8 WEEKS IN ORDER TO GIVE T HE POST TRIAL TREATMENT FOR WOMEN WHO HAD A UTERUS AND ALL OF OUR DATA COLLECTED WERE UP THROUGH THAT EIGHT WEEKS AND WERE DOUBLE BLINDED, AND WE ALSO TITRATED WOMEN OFF OF VENLAFAXINE TO AVOID A DISCONTINUATION TREATMENT EMERGENT SYMPTOM. BUT HERE WE ARE, JUST TO SHOW THAT WE HAD A DIARY THROUGHOUT. THIS IS A DAILY SYMPTOM -- SIMPLE SYMPTOM REPORTING DIARY, AND WE HAD STANDARDIZED QUESTIONNAIRES THAT WERE ANALYZED BEFORE AND AFTER. SO I'M GOING TO BE PRESENTING THE DOUBLE BLINDED PART OF THE RESULTS HERE. HERE'S A SCHEME OF OUR CONSORT DIAGRAM. WE SCREENED OVER 4,000 WOMEN WHO CALLED. WE EXCLUDED ABOUT HALF OF THEM AT THE TIME OF THE INITIAL SCREEN. WE SENT THESE QUESTIONNAIRES AND DIARIES TO ALMOST A THOUSAND WOMEN IN ORDER TO GET 339 WOMEN ENROLLED. I HAVE TO SAY, WE WERE ALL QUITE NERVOUS ABOUT WHETHER WE'D BE ABLE TO ENROLL WOMEN INTO THIS TRIAL, GIVEN THE EXTENT OF THE FEAR OF WOULD WOMEN BE WILLING TO TAKE ESTROGEN, AND WE ACCRUED MUCH FASTER THAN WE PROJECTED. SO FAST THAT WE ENDED UP TAKING A FEW EXTRA WOMEN THAN WE HAD THOUGHT AT OUR MINIMUM BECAUSE THEY WERE ALREADY ALL IN PROCESS. SO IT WAS REALLY AN INTERESTING LESSON AND SEEING A LOT OF THESE WOMEN, THEY ARE OF A SLIGHTLY DIFFERENT GENERATION THAN THE WOMEN WHO HAD BEEN IN THE MENOPAUSE AGE AT THE TIME THAT THE WHI RESULTS CAME OUT. AND MANY OF THEM SAID THESE ARE OBVIOUSLY A SELECTION OF THE PEOPLE WHO CAME IN TO THE TRIAL, AND THEY SAID YOU KNOW, I HEARD ABOUT THAT, BUT I'M REALLY BOTHERED BY THESE SYMPTOMS AND I WANT TO UNDERSTAND HOW I CAN FEEL BETTER. SO WE HAD PRETTY WONDERFUL PEOPLE COMMITTED TO THIS TRIAL. IT ENDED UP BEING HERE, VERY FEW NON-COMPLETERS. THE MAJORITY OF WOMEN COMPLETED THE TRIAL. AND THE ANALYSIS WAS INTENT TO TREAT ANALYSIS. IN TERMS OF OUR PARTICIPANTS, THE MEAN AGE HERE IS ABOUT 54, 55 WAS EXPECTED. I MENTIONED THAT WE HAD 60% CAUCASIAN, 34% AFRICAN-AMERICAN. THE BMI HOT FLASHES ARE KNOWN TO OCCUR MORE COMMONLY IN WOMEN WHO ARE OVERWEIGHT OR OBESE. AND AS WE DIE COT MIEZ THE BMI HERE, YOU CAN SEE THAT THE MEAN BMI WAS 28, AND TWO THIRDS WERE EITHER NORMAL WEIGHT OR OVERWEIGHT. THE MAJORITY WERE NOT CURRENT SMOKING, SMOKING CERTAINLY EXACERBATES HOT FLASHES. THE MAJORITY WERE MARRIED, IT WAS A COLLEGE EDUCATED POPULATION. IT WAS A MIXTURE OF WOMEN IN THE POST MENOPAUSE AND LATE MENOPAUSE, BUT PRIMARILY THEY WERE IN THE POST MENOPAUSE, 75%. WE INCLUDED SOME PEOPLE WHO WERE OVER 10 YEARS FROM THEIR FINAL MENSTRUAL PERIOD, AND AS I MENTIONED, THE SWAN DATA AND OTHERS MENTIONING THE LONGER YOU FOLLOW PEOPLE, THE LONGER THEY STAY SYMPTOMATIC. AND DOES FREQUENCY OF SYMPTOMS, AS I SAID, 8 -- ON AVERAGE 8 PER DAY. THESE ARE SOME OF THE QUESTIONNAIRES JUST TO SHOW YOU, WE KERIK HE TERRIZED THE POPULATION BOTH ON SLEEP MEASURES. ISIs, INSOMNIA, PS -- PHQ9 IS MOOD AND JAD7 ARE ANXIETY MEASURES, AND IT SHOWS YOU THAT WE EXCLUDED WOMEN WHO WERE TREATED FOR DEPRESSION OR ACTIVELY ON A MEDICATION, AND ANYBODY WHO HAD A SIGNIFICANTLY HIGH SCORE ON THEIR DEPRESSION SCALE, BUT THESE WERE NOT PRIMARILY -- THESE WERE VERY LOW -- VERY LOW LEVELS OF SYMPTOMS IN TERMS OF MOOD OR ANXIETY. BUT QUITE HIGH IN TERMS OF SLEEP DISRUPTION AND INSOMNIA. THE SUBTHRESHOLD, YOU LOOK AT THE ISI, THE SUBTHRESHOLD MODERATE AND SEVERE CLINICAL INSOMNIA WAS THE VAST MAJORITY OF WOMEN, AND THAT'S PRETTY MUCH WHAT WE'VE SEEN IN ALL OF OUR TRIALS. SO HERE ARE THE PRIMARY RESULTS FOR OUR HOT FLASH FREQUENCY. THE RED IS THE ESTRADIOL, THE GREEN IS THE VENLAFAXINE AND THE BLUE IS PLACEBO. WHAT YOU'LL SEE IS THAT OVER THE EIGHT WEEK INTERVENTION PERIOD, IT ALL STARTED AT ABOUT 8, THE VENLAFAXINE AND ESTRADIOL GROUP BOTH WERE REDUCED MORE THAN PLACEBO OVER THE 8-WEEK PERIOD OF TIME. THE MEAN FREQUENCY REDUCTION FROM THAT 8 WEEK TO THAT TIME POINT IS LISTED HERE, SO THERE WAS A 53% REDUCTION FROM BASELINE ON ESTRADIOL, A 48% REDUCTION ON VENLAFAXINE, AND A 29% REDUCTION ON PLACEBO. SO THAT TRANSLATES HERE INTO THE ESTRADIOL INTERVENTION, THE WOMEN ASSIGNED TO ESTRADIOL HAD TWO -- THE EXCESS NUMBER OF REDUCTION OVER THOSE REDUCED ON PLACEBO WAS 2.3 MORE PER DAY, THAT WAS THE POINT ESTIMATE WITH CONFIDENT INTERVALS HERE, AND THAT WAS STATISTICALLY SIGNIFICANT, AND SIMILARLY THE VENLAFAXINE GROUP HAD 1.8 MORE HOT FLASHES REDUCED PER DAY RELATIVE TO THE PLACEBO GROUP. SO BOTH OF THEM WERE SOMEWHERE AROUND THAT TWOFOLD DIFFERENCE WHICH HAS BEEN CONSIDERED MODERATE BUT MEANINGFUL DIFFERENCE IN TERMS OF SOMEBODY'S QUALITY OF LIFE. JUST BRIEFLY THE JOURNALS ASKED US TO CONDUCT -- WE DID NOT POWER THIS FOR NON-INFERIORITY STUDY. THE SAMPLE SIZE WASN'T LARGE ENOUGH FOR THAT. IT WAS A SUPERIORITY DESIGN, BUT ONE OF THE REPORTS IN THE JOURNAL WILL BE WHEN WE COMPARE THE EFFECT OF THE ESTRADIOL RELATIVE TO THE VENLAFAXINE, THE ESTRADIOL REDUCED HOT FLASHES BY HALF A HOT FLASH MORE PER DAY THAN THE VENLAFAXINE. THAT WAS NOT STATISTICALLY SIGNIFICANT, SO THERE IS A SLIGHT SUPERIORITY, AND THE QUESTION FOR PEOPLE WILL BE WHETHER THAT TRANSLATES TO SOMETHING THAT'S CLINICALLY MEANINGFUL. IN TERMS OF THE SECONDARY END POINTS, WE HAVE BOTH SEVERITY AND BOTHER MEASURES, BOTH SHOWING THE TOP OF THE FIGURE, THE P VALUES HERE SHOWING BENEFIT OF THE INTERVENTION OVER PLACEBO. VENLAFAXINE BOTHER AT THE THRESHOLD OF P EQUALS 0.5. THE OTHER SECONDARY END POINT OF THIS INTERFERENCE SCALE SIMILAR BOTH DRUGS WERE MORE EFFECTIVE THAN PLACEBO AT REDUCING THE EXTENT TO WHICH SYMPTOMS INTERFERE WITH SOMEBODY'S DAY TIME AND NIGHTTIME LIFE, SLEEPING INCLUDED. WHEN WE LOOKED AT THE CATEGORICAL END POINT OF CLINICAL IMPROVEMENT THIS, IS A 50% REDUCTION FROM BASELINE. THE ESTROGEN THERAPY GROUP 50% HAD SIGNIFICANT REDUCTION, VENLAFAXINE IF WITH ON 51 VERSUS THE PLACEBO AT 31. THEN WHEN WE LOOKED AT TREATMENT SATISFACTION, THE ESTROGEN GROUP HAD MORE TREATMENT SATISFACTION THAN PLACEBO AND AS VENLAFAXINE BORDERLINE HERE, BUT IT'S AN INTERMEDIATE FINDING. ALL OF THE BASELINE DEMOGRAPHIC MENOPAUSE SYMPTOM CHARACTERISTICS THAT WE HYPOTHESIZE AND A PRIORI THAT MIGHT DIRECT AND HELP GUIDE PEOPLE TOWARDS WHICH INTERVENTIONS MAY BE MOST EFFECTIVE ON OUR INTERACTION ANALYSES WERE NON-SIGNIFICANT. THERE WAS NOTHING THAT WE LOOKED AT HERE THAT WOULD SAY THAT ANY OF THESE CHARACTERISTICS WOULD INFORM LIKELIHOOD OF BENEFIT. TOLERABILITY WAS HIGH. ALMOST 94% COMPLETED THE PROCEDURES, ONLY 11 STOPPED BECAUSE OF ADVERSE EVENTS, AND THERE WAS NO DIFFERENCE BETWEEN GROUPS IN THE NUMBER OF TREATMENT EMERGENT ADVERSE EVENTS. YOU CAN SEE IN THE SECOND GROUP OF BARS FATIGUE AND AROUSAL, THOSE WERE THE MOST COMMON SIDE THEESKTS WERE REPORTED BY ALL THREE GROUPS. NO DIFFERENT FROM THOSE. INSOMNIA WAS THE MOST FREQUENT ADVERSE EVENT ON ESTRADIOL. ESTROGEN THAIR THERAPY AND OTHER STUDIES HAVE BEEN BENEFICIAL FOR SLEEP IN WOMEN WITH HOT FLASHES BUT THIS WAS AN ADVERSE REPORT, FATIGUE ON -- AND PLACEBO. SUICIDAL IDEATION WHICH HAS BEEN REPORTED IN INDIVIDUALS UNDER 24 AS A POTENTIAL TREATMENT EMERGENT RESPONSE TO SERATONERGIC DRUGS, WE MONITORED CAREFULLY TO MAKE SURE THAT WAS NOT A CONCERN, AND YOU CAN SEE THAT NONE OF THE WOMEN ON VENLAFAXINE DEVELOPED ANY SUICIDAL IDEATION AFTER STARTING ON THE DRUG WHEREAS WE DID HAVE A FEW NOT THOUGHT TO BE DRUG-RELATED, BUT OCCURRING ON THE OTHERS. WE MONITORED BLOOD PRESSURE CLOSELY. VENLAFAXINE IS KNOWN TO INCREASE BLOOD PRESSURE, BOTH SYSTOLIC AND DIASTOLIC BLOOD PRESSURE, AND WE DID OBSERVE THAT. SO THERE WAS A SLIGHT REDUCTION IN SYSTOLIC AND DIASTOLIC BLOOD PRESSURE ON ESTRADIOL AND PLACEBO BUT A SLIGHT INCREASE IN BOTH SYSTOLIC AND DIASTOLIC ON VENLAFAXINE, AND WE LOOKED AT THE CUTOFFS FOR HYPERTENSION CUTOFFS THAT WE USE HERE, WE DID SEE THAT MORE WOMEN HAD DEVELOPED THIS ON VENLAFAXINE, AND WE LOOKED AT WHO ARE THESE WOMEN WHO DEVELOPED THIS, THEY STARTED WITH HIGHER BLOOD PRESSURES TO BEGIN WITH, ALTHOUGH WITHIN OUR ELIGIBILITY CRITERION, AND THEY WERE ALMOST UNIVERSALLY OBESE OR OVERWEIGHT. AS EXPECTED, ESTROGEN THERAPY LED TO ABNORMAL BLEEDING PATTERNS WHICH WERE MONITORED CLOSELY. 8% OF WOMEN DEVELOPED SOME CHANGE IN BLEEDING, EITHER ANY BLEEDING IN A POST-MENOPAUSAL WOMEN ARE SOME CHANGE FROM BASELINE AND THE PERIMENOPAUSAL WOMEN, AND SO WE CONDUCTED TRANSVAGINAL ULTRASOUNDS TO LOOK AT THE ENDOMETRIAL STRIPE, WHICH WAS THEN HIGH IN HALF OF THOSE WOMEN AND THEY UNDE UNDERWENT BIOPSIES BUT FORTUNATELY NOBODY HAD ANY IN THIS 8 WEEK STUDY, WE WOULDN'T EXPECT IT, BUT OF COURSE WE WERE VERY CAREFUL. SO TO SUMMARIZE THESE RESULTS, WE SHOWED THAT LOW DOSE ESTRADIOL AND LOW DOSE VENLAFAXINE ARE BOTH EFFECTIVE TREATMENTS FOR VASOMOTOR SYMPTOMS ASSOCIATED WITH MENOPAUSE, THAT THERE WERE NO DEMOGRAPHIC OR MENOPAUSE SYMPTOM CHARACTERISTICS THAT WOULD PREDICT A DIFFERENTIAL RESPONSE, THAT THE EFFICACY OF THE LOW DOSE ESTRADIOL SLIGHTLY SUPERIOR TO VENLAFAXINE BUT THE DIFFERENCE IS SMALL, UNCERTAIN CLINICAL SIGNIFICANCE. BOTH TREATMENTS WERE WELL TOLERATED WITH KNOWN AND DIFFERENT AND DISTINCT ADVERSE EFFECT PROFILES THAT ARE ESTABLISHED AND CONSISTENT WITH THEIR MECHANISM OF ACTION. AND WE EXPECT AND HOPE THAT THESE WILL BE USEFUL INFORMATION TO CLINICIANS IN MID LIFE WOMEN TRYING TO MAKE A DECISION. I WANTED TO BRIEFLY TELL YOU ABOUT OUR RENEWAL APPLICATION WHICH IS UNDERWAY, A REVISION NOW. WE'RE SHIFTING TO LOOK AT ANOTHER VERY IMPORTANT SYMPTOM RELATED TO MENOPAUSE, PARTICULARLY INCREASING IN PREVALENCE WITH AGE FOR MENOPAUSE, SO IT'S AN OLDER POST POST-MENOPAUSAL SYMPTOM, AND THAT IS VAGINAL DRYNESS, WHICH IS REPORTED BY 45 PES 45% OF POST-MENOPAUSAL WOMEN AND IT GOES HAND IN HAND OFTEN WITH OTHER SYMPTOMS INCLUDING SEXUAL DYSFUNCTION AND OTHER BURNING AND OTHER PHYSICAL DISCOMFORT SENSATIONS. THE PREVALENCE OF THESE SYMPTOMS INCREASES FROM MENOPAUSE AS OPPOSED TO HOT FLASHES WHICH ULTIMATELY DECREASE OVER TIME THE PREVALENCE. SO WE WILL BE LOOKING IN THIS TRIAL AT AN OLDER POPULATION. WE WILL BE INVESTIGATING A VERY, VERY LOW DOSE ESTROGEN TABLET AND ALSO IN A THREE-ARM TRIAL LOOKING AT ANOTHER HYDROFILLING GEL CALLS REPLE NSE, WHICH HAS -- RELATIVE TO PLACEBO TABLET AND GEL ON SUBJECTIVE SYMPTOMS, AND THIS IS IMPORTANT BECAUSE THE VAST MAJORITY OF DATA WITH THESE VAGINAL ESTROGEN STUDIES HAVE BEEN ON PH AND VAGINAL MATURATION INDEX AND THEY HAVE LOOKED AT THE MOST BOTHERSOME ESTIMATE BUT WE'RE GOING TO BE LOOKING AT SUBJECTIVE SYMPTOMS MOST COMPREHENSIVELY BECAUSE THAT'S WHAT GETS SOMEBODY, YOU KNOW, INTO TREATMENT. IN TERMS OF SOME OF THE SECONDARY AIMS, WE'RE GOING TO LOOK AT OTHER VAGINAL SYMPTOMS IN SEXUAL FUNCTION MEASURES, WE WILL LOOK AT THE MATURATION AND VAGINAL PH, AND WE'RE GOING TO BE CREATING A BIO REPOSITORY OF VAGINAL SPECIMENS AS WELL AS BLOOD SPECIMENS. THESE ARE FROM SIMPLE VAGINAL SWABS TO LOOK AT SOME OTHER MECHANISTIC PILOT STUDIES GOING FORWARD. THE SECOND MAJOR AIM OF OUR RENEWAL APPLICATION IS TO LOOK AT DATA DISSEMINATION. WE ARE VERY COMMITTED TO TRY AND HELP AND EDUCATE AND INFORM PEOPLE ABOUT SOME OF THESE TREATMENT DECISIONS USING THE DATA THAT WE'VE COLLECTED FROM OUR TRIALS AS WELL AS THOSE FROM OTHER TRIALS. THERE ARE VERY FEW RESOURCES AVAILABLE AND A LOT OF MISINFORMATION PEOPLE GET. WE TEND TO DEVELOP IN COLLABORATION WITH OTHER ADVOCACY GROUPS COMPREHENSIVE STATE OF THE ART TAILORED MATERIALS THAT WILL HELP PEOPLE MAKE DECISIONS. SO GOING BACK TO THE INVESTIGATIVE TEAM, IT'S A LARGE -- VERY LARGE VILLAGE, AND WE'VE WORKED VERY WELL TOGETHER, IT'S BEEN INCREDIBLY PRODUCTIVE AND VERY MUCH APPRECIATED THE SUPPORT FROM NIA AND THE OTHER NIH COFUNDERS AND WE LOOK FORWARD TO OPPORTUNITIES TO CONTINUE TO INFORM MENOPAUSE SYMPTOM MANAGEMENT. SO THANK YOU VERY MUCH. [APPLAUSE] >> [INAUDIBLE] >> MEDICATIONS WERE INITIATED IN THE MORNING. THAT'S BECAUSE VENLAFAXINE MAY BE ACTIVATING IN SOME PEOPLE, BUT IF THEY HAD ANY SEDATION, THEY HAD THE OPTION TO FLOP TO THE EVENING. ESTROGEN THERAPY COULD BE DOSED AT ANY TIME. VENLAFAXINE AND ESTROGEN -- ESTRADIOL -- ARE DOSED DAILY, YOU KNOW, WITH CONTINUOUS EFFICACY. WE'VE SEEN BENEFIT FOR DAY AND NIGHT SYMPTOMS WITH THESE INTERVENTIONS. SO THEY'RE NOT SHORT ACTING ENOUGH THAT THAT WOULD BE AN EFFECT. THE SECOND QUESTION ABOUT SLEEP, TO QUANTIFY AT BASELINE AND ALSO WITH THE INTERVENTION? >> SO AT BASELINE, THEY HAD A LOT OF SLEEP DISTURBANCE. MAYBE I MISSED IT, BUT DID YOU GIVE THE IMPROVEMENT IN THAT SLEEP DISTURBANCE? >> I DIDN'T REPORT THAT. THAT IS A PAPER IN REVIEW BUT WE DID SEE IMPROVEMENT WITH BOTH INTERVENTIONS ON BOTH THE INSOMNIA SCALES AND THE SLEEP QUALITY SCALES. THE MAGNITUDE OF THE EFFECT WAS RELATIVELY SMALL, BUT THERE WAS SOME IMPROV IMPROVEMENT. >> DID YOU HAVE ANY COGNITIVE OUTCOMES OR SUBJECTIVE COGNITIVE OUTCOMES? >> WE DID NOT. >> ALL RIGHT. THANK YOU VERY MUCH. >> THANK YOU. [APPLAUSE] >> OUR FINAL SPEAKER WILL BE DR. BRENT ROBERTS, WHO WILL BE INTRODUCED BY DR. NIELSEN. >> SO IT'S MY PLEASURE TO INTRODUCE BRENT ROBERTS TO THE NIA COUNCIL. PRESENT ROBERTS IS PROFESSOR OF PSYCHOLOGY AT THE DEPARTMENT OF PSYCHOLOGY AT THE UNIVERSITY OF ILLINOIS IN URBANA, CHAMPAIGN. HE'S THE RECIPIENT OF NUMEROUS AWARDS IN THE FIELD OF PERSONALITY PSYCHOLOGY, INCLUDING THE AWARD IN PERSONALITY PSYCHOLOGY FROM THE FOUNDATION FOR PERSONALITY AND SOCIAL PSYCHOLOGY AND MOST RECENTLY, THE 2012 HENRY MURRAY AWARD FROM THE SOCIETY FOR PERSONALITY AND AMERICAN PSYCHOLOGICAL ASSOCIATION. DR. ROBERTS' PRIMARY LINE OF RESEARCH IS DEDICATED TO UNDERSTANDING PATTERNS OF CONTINUITY AND CHANGE IN PERNLTD ACROSS THE DECADES OF ADULTHOOD AND THE MECHANISMS THAT AFFECT THESE PATTERNS, AND HE HAS A SECONDARY LINE ON PERSONALITY ASSESSMENT THAT PARTICULARLY FOCUSES ON STUDIES OF THE MEANING AND SCOPE OF THE TRAIT OF CONSCIENTIOUSNESS AND THE RELATIONSHIP BETWEEN CONSCIENTIOUSNESS AND THE HEALTH PROCESS. DR. ROBERTS' PRESENTATION TO COUNCIL TODAY COINCIDES WITH THE PUBLICATION THIS MONTH OF A SPECIAL SECTION OF THE APA JOURNAL OF DEVELOPMENTAL PSYCHOLOGY ON CONSCIENTIOUSNESS AND HEALTHY AGE, A COPY OF WHICH WAS DISTRIBUTED TO ALL THE COUNCIL MEMBERS AT THIS MEETING. THIS SPECIAL SECTION IS THE CULMINATION OF A 2 1/2 YEAR INTENSIVE REVIEW BY THE BEHAVIORAL AND SOCIAL RESEARCH DIVISION AT NIA. THE SCIENCE SURROUNDING THIS PERSONALITY PHENOTYPE, MOBILIZING A BROAD SCOPE OF EXPERTS IN CLINICAL AND DEVELOPMENTAL SCIENCE, GENETICS AND BEHAVIOR CHANGE, AND IT REPRESENTS OUR EVIDENT TO ADVANCE THADD --A FIELD THAT HAS RECEIVED CONSIDERABLE INVESTMENT BY NIA BOTH IN THE INTRAMURAL AND EXTRAMURAL DIVISIONS. OUR GOAL WITH THIS EFFORT HAS BEEN TO ACHIEVE A BERT UNDERSTANDING OF THE MECHANISMS RESPONSIBLE FOR WELL DOCUMENTED ASSOCIATIONS BETWEEN PERSONALITY, PARTICULARLY CONSCIENTIOUSNESS AND MORTALITY AND HEALTHY AGING, AND ULTIMATELY TO LEVERAGE THIS MECHANISTIC UNDERSTANDING TO INFORM THE DESIGN OF THE NEXT GENERATION OF GENERATIONS FOR HEALTHY AGING. DR. ROBERTS PLAYED A CENTRAL ROLE IN THIS EFFORT CONTRIBUTING HIS EXPERTISE FROM THE OUTSET AND IN SEVERAL OF THE MANUSCRIPTS AND HIS PRESENTATION IS A MARKER OF HEALTH AND LONGEVITY WILL EXPLORE SOME OF HIS WORK AROUND THESE THEMES. >> THANK YOU FOR THE OPPORTUNITY TO SPEAK TODAY. I GREATLY APPRECIATE THE CHANCE TO SEE YOU AND GET TO KNOW YOU. I'M GOING TO GIVE YOU AN OVERVIEW BROADLY SPEAKING OF WHAT THE WORKING GROUP HANDLED AND ALSO MORE BROADLY THE DOMAIN OF STUDIES ON CONSCIENTIOUSNESS THAT HAVE OCCURRED OVER THE LAST TWO OR THREE DECADES, MANY OF WHICH HAVE OPINIO BEEN SUPPORTED BY NIA. I HAVE TO BEGIN THE STORY AT THE END OF THE I THINK THE MAIN REASON WHY I'M HERE IS BECAUSE BACK IN 1993, HOWARD FRIEDMAN REPORTED A RATHER PROVOCATIVE FINDING THAT CHILDHOOD RATINGS OF CONSCIENTIOUSNESS PREDICTED MORTALITY, AND I HAVE TO ADMIT AND I'M GOING TO CONFESS THAT IT IS A PUBLIC VENUE AND IT'S GOING TO BE RECORDED THAT I AT THE TIME WAS QUITE SKEPTICAL OF THIS FINDING. IT WAS AN ODD STUDY. IT WAS DETERMINE LONGITUDINAL STUDY, THEY'RE ALL GENIUSES, THEIR RATING WAS TOGETHER QUITE NEATLY IN CHILDHOOD SO I THOUGHT IT WOULD BE A TYPE I AI ERROR I'D LIKE TO GO ON RECORD SAYING I WAS UTTERLY AND COMPLETELY WRONG. SINCE THAT TIME, THERE HAVE BEEN NUMEROUS STUDIES, THREE SEPARATE METAANAL SEIZE NON-OVERLAPPING BETWEEN -- MEN -- FUNDED BY NIA. AND I CAN REPORT TO YOU THAT THIS WEEK, I WAS JUST SHOWN DATA FROM THE LONGITUDINAL STUDY IN WHICH A SINGLE ITEM RATING DONE BY TEACHERS OF MIDDLE SCHOOL STUDENTS OF HOW INDUSTRIOUS THE STUDENT IS PREDICTS MORTALITY 40 YEARS LATER ABOVE AND BEYOND SOCIOECONOMIC STATUS AND COGNITIVE FUNCTIONING. SO I WAS VERY, VERY WRONG WHEN I WAS SKEPTICAL OF FRIEDMAN'S FINDING. AND I THINK WHAT HAPPENED IN OUR FIELD AND IN THE FIELD MORE BROADLY SPEAKING IS WOULD THESE FINDINGS SLOWLY AND SURELY TOOK HOLD AND TOOK NOTICE AND STARTED ASKING ABOUT WHAT'S GOING ON THERE, THIS SEEMS TO BE SOMETHING SIGNIFICANT IF WE CAN PREDICT SOMETHING AS CONCRETE AS MORTALITY AND THE WORKING GROUP REFLECTED THAT, THEY TRIED TO BRING TOGETHER DECADES OF RESEARCH THAT SYNTHESIZED THE BASIC QUESTION WHY IS THERE THIS IT RELATIONSHIP. IT BOYLEED DOWN TO A NUMBER OF QUESTIONS THAT WE TRIED TO ADDRESS, WHAT IS CONSCIENTIOUSNESS, WHAT ARE THE DEVELOPMENTAL ANTECEDENTS TO IT, WHAT MECHANISMS EXPLAIN THE RELATIONSHIP BETWEEN CONSCIENTIOUSNESS AND LONGEVITY AND THEN HOW TO AGE AND EXPERIENCE OR CONTEXT-MODERATE THESE TYPES OF ASSOCIATION, AND I'LL GO THROUGH EACH OF THESE QUESTIONS IN PART IN THE PRESENTATION I'LL SHOW YOU. THE FIRST QUESTION IS WHAT IS CONSCIENTIOUSNESS? IT'S A PERSONALITY TRAIT THAT EMERGES OUT -- SCREENTLY OUT OF THE BIG FIVE TAXONOMY OF PERSONALITY TRAITS THAT EXISTED BEFORE THAT TAXONOMY WAS DISCOVERED, AND IT'S BEEN INVESTIGATED FOR MANY, MANY DECADES. THIS IS A WORKING MODEL, IT'S NOT A SINGLE THING. IT'S ACTUALLY A GROUP OF THINGS THAT ARE RELATED IMPORTANTLY. AND UNRELATED IN SOME DISTINCT WAYS TOO, SO THE FACETS ARE IMPULSE CONTROL, WHICH IS OF COURSE THE ABILITY TO INHIBIT THE PREPOTENT RESPONSE WHETHER YOU EAT THAT COOKIE AFTER LUNCH, RESPONSIBILITY IS THAT PROPENSITY OH TO FOLLOW THROUGH WITH OBLIGATIONS AND FULFILL YOUR PROMISES. ORDERLINESS IS HOW MUCH YOUR DESK IS NEAT AND CLEAN, WHICH IS I GUESS NO LONGER THE CASE NOW THAT WE HAVE PDF BUT MAYBE IT SHOULD BE QOWR DESKTOP IS NEAT AND CLEAN. INDUSTRIOUSNESS IS KIND OF THE STEREOTYPICAL CORE KIND OF IDEA THAT WHEN PEOPLE INVOKE CON CONSCIENTIOUSNESS, WILLINGNESS TO PERSIST IN THE FACE OF CHALLENGES, CONVENTIONALITY IS AN UNUSUAL FINDING, IT'S YOUR WILLINGNESS TO ADHERE TO AND SUPPORT NORMS AND RULES OF SOCIETY. PUNCTUALITY IS THANK GOD SOMETHING I DID TODAY WHICH IS SHOW UP ON TIME. WE LIKE THE FAMILY APPROACH FOR A NUMBER OF REASONS. ONE IS THAT MANY OF THESE FACETS HAVE DIFFERENTIAL RELATIONSHIPS TO IMPORTANT OUTCOMES AND THEY TELL DIFFERENT STORIES. OBVIOUSLY IMPULSE CONTROL IS HIGHLY RELATED TO CLINICAL ISSUES, ESPECIALLY DRUG AND ALCOHOL ABUSE. CONVENTIONALITY TURNS OUT TO BE RATHER PROFOUND FOR HEALTH BEHAVIORS. PEOPLE WHO LISTEN TO YOU TELL THEM TO EXERCISE IF THEY'RE CONVENTIONAL ARE MORE LIKELY TO DO THAT. ORDERLINESS TENDS TO ARE RATHER BORING UNTIL WE FOUND OUT IN LATE ADULTHOOD, IT'S ACTUALLY A MORE PROFOUND FACET FOR PREDICTING MORTALITY THAN OTHER FACTORS, SO OLDER PEOPLE WHO KEEP THINGS IN ORDER TEND TO LIVE LONGER THAN OTHERS. IT HELPS US ORGANIZE ON GOING RESEARCH THAT COMES DOWN THE PIPELINE AND GET RID OF THE JINGLE JANGLE EFFECT IN OUR FIELD. SOCIAL PSYCHOLOGY IS A CONSTRUCT OF SELF CONTROL, AND THAT'S SYNONYMOUS WITH WHAT WE CALL IMPULSE CONTROL. SO WE HAVE TWO PARALLEL LINES OF RESEARCH THAT COULD BE QUITE INDEPENDENT BUT IN THIS CASE ACTUALLY DO SIMILAR THINGS, THEN OF COURSE ANGELA STUDIES GRIT AND GRIT IS QUITE CLOSE TO WHAT WE THINK OF AS INDUSTRIOUSNESS. SO THIS APPROACH HELPS US TO KEEP THINGS IN ORDER. SO TO SPEAK AS NEW IDEAS COME DOWN THE PIPELINE. WHEN IT KOSMS T COMES TO THE ANTECEDENTS TO CONSCIOUSNESS, WE HAD A NUMBER OF PEOPLE ON THE PANEL AND WORKING GROUP AND A NUMBER OF INDIVIDUALS IN ADDITION TO THAT CONTRIBUTING TO AT THE STORY IS RELATIVELY BRIEF LIKE ALL PHENOTYPES IN PSYCHOLOGY, THERE IS A GENETIC AND AN ENVIRONMENTAL COMPONENT TO CONSCIENTIOUS NUSS AND IN THIS CASE, I'LL HAVE IT PLAYING OUT THROUGH -- CONTROL, WHICH IS THE -- THAT THEY AGREED UPON TEM PERMT IN CHILDHOOD THAT LINKS UP TO ADULT LEVELS OF CONSCIENTIOUSNESS. IN TERMS OF THE ENVIRONMENTS TO DATE, W WE KNOW OF WHO THAT ARE SIGNIFICANTLY LINKED TO HIGHER LEVELS THAN LOWER LEVELS. IF YOU'RE BORN INTO A SECURE ATTACHMENT SITUATION WITH A CAREGIVER, YOU TEND TO BE HIGHER. IF YOU WERE BORN INTO A FAMILY SITUATION WHERE THERE'S A LOT OF CONFLICT, WHETHER IT BE PHYSICAL, VERBAL CONFLICT, YOU WILL TEND TO BE A LITTLE BIT LOWER ON CONSCIENTIOUSNESS. THAT'S IT SO FAR. LINKING UP THE TEM PERMT RESEARCH, FAMILY CONTEXT RESEARCH AND THEN ADULT PERSONALITY IS AN AREA OF GREAT NEED. WHEN IT COMES TO TELLING YOU THE STORY OF HOW CONSCIENTIOUSNESS PLAYS OUT IN TERMS OF HEALTH AND LONGEVITY, I'M GOING TO USE A RELATIVELY SIMPLISTIC MODEL ADAPTED FROM ADLER AND MATTHEWS THAT SAYS ESSENTIALLY CONSCIENTIOUSNESS ENDS UP AFFECTING MORTALITY THROUGH THE LIFE STRUCTURES THAT PEOPLE BUILD, THROUGH HEALTH BEHAVIORS THEY PARTICIPATE IN THROUGH PHYSICAL HEALTH ITSELF, AND I'LL GO THROUGH EACH OF THESE PATHS IN ORDER WITH SOME EXAMPLE. SO THE LIFE STRUCTURES ASPECT IS ONE OF MY FAVORITES, BEING A VERL MENTAL PSYCHOLOGIST. IT TELLS THE STORY THAT PEOPLE THAT ARE CONSCIENTIOUS BUILD DIFFERENT LIFE STRUCTURES THAN PEOPLE WHO ARE NOT CONSCIENTIOUS. BY THAT BUILDING, THEY CREATE CONSEQUENCES THAT PLAY OUT ACROSS A LIFE COURSE THAT ARE RATHER PROFOUND FOR THEIR HEALTH. THESE LIFE STRUCTURES, THESE LIFE PATHS ARE ALSO AGE GRADED. THEY HAPPEN AT CERTAIN TIMES IN THE LIFE COURSE AND THAT HAS I THINK SERIOUS IMPLICATIONS FOR HOW AND WHETHER WE INTERVENE. SO HERE'S ONE EXAMPLE. IN TERMS OF CONSCIENTIOUSNESS, THE CLASSIC THING IS RELATED TO ACHIEVEMENT. ONE OF THE MOST CONSISTENT FINDINGS NOW IN THE EDUCATIONAL RESEARCH IS THAT CONSCIENTIOUSNESS CONTRIBUTES TO HIGHER ACHIEVEMENT IN HIGH SCHOOL AND COLLEGE ABOVE AND BEYOND ALL OF YOUR TYPICAL BACKGROUND FACTORS LIKE IQ MEASURES, IT'S A SMALL BUT REALLY CONSISTENT EFFECT, SEVERAL METAANALYSES TO THIS EFFECT AND YOU SEE IN THIS CASE KIDS WHO ARE MORE CONSCIENTIOUS TEND TO HAVE HIGHER GPAs. YOU GET INTO COLLEGE. HERE IS A STUDY THAT WAS IN -- WELL, IT WAS IN ONE OF JIM HECKMAN'S TOMES THAT HE PUBLISHES, AND HE SHOWED USING GSOP DATA THAT INDIVIDUALS WERE MORE CONSCIENTIOUS THAT NOT ONLY GET INTO COLLEGE BUT THEY PERSIST AND GET MORE YEARS OF EDUCATION THAN OTHER PEOPLE, AND THE LEVELS OF SIGNIFICANCE OF IMPACT FOR CONSCIENTIOUSNESS IS EQUAL TO MANY OF THE OTHER THINGS LIKE BACKGROUND FACTORS AND IQ. SO THERE YOU HAVE ONE OF THE FIRST PATHWAYS IN THE LIFE COURSE THAT WE KNOW PLAYS OUT IN TERMS OF POSITIVE HEALTH OUTCOMES, INDIVIDUALS ARE DOING BETTER IN SCHOOL AND THEY'RE GETTING INTO COLLEGE AND FINISHING COLLEGE, WHICH WE KNOW HAS PROFOUND INFLUENCE ON HEALTH AND AGING LATER. WHAT HAPPENS AFTER COLLEGE, OF COURSE, IS THE WORK WORLD. THIS IS THE LITTLE SNIPPET FROM TIMMY MOFFET, PRESENTED HERE I BELIEVE A FEW YEARS AGO SHOWING THE RELATIONSHIP BETWEEN CHILDHOOD RATINGS OF SELF CONTROL AT AGE 10 LINKED UP TO FINANCIAL AND OCCUPATIONAL OUTCOMES AT AGE 32. IN THIS FIGURE, YOU SEE THAT KIDS WHO WERE MORE SELF CONTROLLED AT AGE 10 TENDED TO BE BETTER OFF IN TERMS OF INCOME AT AGE 32, IN HIGHER SCS JOBS AND THEY WERE PLANNING FOR THEIR FINANCIAL FUTURE ALREADY AT AGE 32, WHICH WE KNOW IS REALLY IMPORTANT FOR THINGS LIKE RETIREMENT. THEN OF COURSE THEY WERE SUFFERING FEWER FINANCIAL STRUGGLES BUSTRUGGLES BOTH ACCORDING TO THEMSELVES AND THEIR FRIENDS. SO YOU SEE EDUCATION, COLLEGE, THEN THE WORK WORLD ALL PLAYING OUT IN A WAY THAT ARE, AGAIN, THINGS WE KNOW ARE IMPORTANT FOR HEALTH. DR. MOFFITT ALSO LOOKED AT SOME OF THE REASONS WHY THESE INDIVIDUALS MIGHT BE DOING BETTER IN ADULTHOOD, AND SHE SHOWED QUITE INTERESTINGLY INDIVIDUALS WHO ARE HIGH IN SELF CONTROL AVOID SNARES THAT OCCUR IN ADOLESCENCE THAT CAN BE QUITE PROBLEMATIC. SO KIDS WHO ARE LOW ON SELF CONTROL AT AGE 10 WERE MORE LIKELY TO START SMOKING BY AGE 15, THEY'RE MORE LIKELY TO LEAVE SCHOOL WITHOUT EVER GETTING A DEGREE, AND THEY WERE ALSO MORE LIKELY TO EXPERIENCE AN ON TIME PREGNANCY. ALL OF THESE AS YOU KNOW ARE PROW FOUNDLY IMPORTANT TO THE STRUCTURES OF LIFE GOING FORWARD. IT TAKES A LOT OF EFFORT BY INDIVIDUALS AND SOCIETY TO OVERCOME THESE TO GET AN EDUCATION AND TO EXPERIENCE POSITIVE AGING. IF WE WERE ONLY WORK, I SUSPECT IT WOULD BE FINE BUT IT'S WORSE THAN THAT, IT GOES OFF INTO LOVE TOO. SO CONSCIENTIOUSNESS NOT ONLY AFFECTS THE WORK WORLD AND ACHIEVEMENT WORLD, BUT IT AFFECTS HOW WE STRUCTURE OUR MARRIAGES. SO THIS IS FROM A META-ANALYSIS OF LONGITUDINAL PROSPECTIVE STUDIES WE DID BACK IN 2007, IN THIS CASE WE WERE SIMPLY PREDICTING WHETHER PEOPLE GOT DIVORCED. AND YOU SEE HERE THAT CONSCIENTIOUSNESS PREDICTS PEOPLE STAYING TOGETHER MORE OFTEN THAN NOT. AND THIS IS ALONG WITH OTHER DISPOSITIONS BUT NONETHELESS IT'S A NICE CONSISTENT FINDING, PEOPLE WERE MORE CONSCIENTIOUS, DON'T GET DIVORCED. WE ALSO KNOW FROM EPIDEMIOLOGICAL STUDIES THAT GETTING DIVORCED IS QUITE BAD FOR MEN. THEY SUFFER QUITE SIGNIFICANTLY AS A CONSEQUENCE, FOR WOMEN, THEY SUFFER FINANCIALLY. SO THIS IS A PUBLIC HEALTH ISSUE. AND AT THE ROOT OF THAT IS IN PART PERSONALITY. WHEN IT COMES TO HEALTH BEHAVIORS, I'LL SHOW YOU ONE STUDY WE DID A DECADE AGO LINKING CONSCIENTIOUSNESS TO ALL OF THE MAJOR BEHAVIORAL REGIONS WHY PEOPLE EXPERIENCE PREMATURE MORTALITY IN THE WEST, SO THERE ARE EIGHT REASONS FOR WHY WE DIE YOUNG, THOSE ARE ALONG THE X AXIS. IT'S IMPRESSIVELY SIGNIFICANT FOR ALL OF THESE. WHAT I LIKE ABOUT THIS FINDING MORE THAN ANYTHING ELSE IS KIND OF THE AGE GRADED ME NATURE OF IT, PEOPLE ARE LOW ON CONSCIENTIOUSNESS FIND WAYS OF DYING AT LATE AND EARLY AGES. SO WE KNOW YOUNG PEOPLE ARE GOING TO EXPERIENCE MORTALITY BECAUSE OF THINGS LIKE UNSAFE DRIVING, UNSAFE SEX, DOING TOO MANY DRUGS AND OF COURSE GETTING IN FIGHTS, AND CONSCIENTIOUSNESS IS A PROTECTIVE FACTOR FOR THOSE. WE DO KNOW WHEN WE REACH MIDDLE AND OLD AGE IT'S DEGENERATIVE DISEASES THAT AFFECT US MOSTLY. YOU SEE IT'S A PROTECTIVE FACTOR THERE TOO, PEOPLE WHO ARE MORE CONSCIENTIOUS ARE EATING BETTER, EXERCISING MORE, NOT DRINKING ALCOHOL AND EXPERIENCING BETTER AGING LATER ON. IN TERMS OF MORBIDITY, THERE ARE DOZENS OF STUDIES SHOWING CONSCIENTIOUSNESS IS LINKED TO SELF-REPORTED HEALTH. WE KNOW SELF-REPORTED HEALTH IS ONE OF THE BEST PREDICTORS OF MORTALITY BUT WE'RE DOING A MUCH BETTER JOB PREDICTING WHAT WE MIGHT THINK OF AS OBJECTIVE HEALTH INDICES. THIS IS A STUDY THAT WAS JUST PUBLISHED LAST MONTH AGAIN FROM THE STUDY LINKING CONSCIENTIOUSNESS RATED AT AGE 26 BY OBSERVERS TO PHYSICAL HEALTH OUTCOMES AT AGE 38. THE INDEX OF PHYSICAL HEALTH INVOLVED THE FOLLOWING QUALITIES: METABOLIC ABNORMAL NORMTS, PULL KNOW MARE FUNCTION, PAIR DONE TA DISEASE, SYSTEMATIC INFLAMMATION, THOSE ARE THE RATES THAT INDIVIDUALS AT AGE 38 WERE SUFFERING FROM THESE THINGS. WE ADDED THEM UP IN A SINGLE DIMENSION AND INDIVIDUALS MORE CONSCIENTIOUS WERE EXPERIENCING FEWER OF THESE AS EARLY AS AGE 38. THAT HELD UP EVEN WHEN CONTROLLING FOR OTHER HEALTH FACTORS, SOCIOECONOMIC STATUS AND IQ. THIS IS A FINDING THAT IS ALSO SURPRISING, IT WAS TO ME WHEN IT STARTED EMERGING OUT OF DAVID BENNETT'S LAB IN 2007, BUT IS NOW ACTUALLY PRETTY CONSISTENT. CONSCIENTIOUSNESS IS A PROTECTIVE FACTOR FOR ALZHEIMER'S DISEASE. THIS IS A FINDING JUST PUBLISHED LAST WEEK BY ANTONIO WHO USED TO WORK OF COURSE AND STILL WORK FOR THE BLSA, WHICH IS SUPPORTED BY NSA, AND THIS SHOWS PEOPLE WHO ARE LOW IN CONSCIENTIOUSNESS TEND TO EXPERIENCE ALZHEIMER'S AT A HIGHER RATE. THERE ARE ENOUGH STUDIES THAT TONY PUBLISHED METAAMAL CYST I META-ANALYS IS, THERE'S NO LINK TO PHYSIOLOGY. WHEN THEY DO THE BRAIN AUTOPSIES AFTERWARDS, YOU'RE NOT SEEING A LINK TO THE GEOLOGY SO QUESTIONS -- ARE AVOIDING ALZHEIMER'S DISEASE AS OPPOSED TO NOT. SO THERE YOU SEE A STRONG RELATIONSHIP WITH HEALTH MARKERS -- YOU SEE ANOTHER REASON WHY YOU END UP WITH STRONGER MORTALITY, I NOTED THAT THE WORKING GROUP -- IT'S JUST THIS UNITARY D MONOLITHIC IMPACT POSITIVE OR NEGATIVE. ARE MODERATED BY -- I'LL GIVE YOU ONE EXAMPLE OF THAT WITH PEGGY CONCERN'S 2009 STUDY WHERE SHE LOOKED AT THE INTERACTION BETWEEN CONSCIENTIOUSNESS AND CAREER SUCCESS. AND FOUND THAT DEPENDING HOW YOU LOOK AT IT, CAREER SUCCESS IS MORE PROBLEMATIC FOR PEOPLE WHO ARE LOW ON CONSCIENTIOUSNESS OR CONVERSELY PEOPLE WHO ARE HIGHER ON CONSCIENTIOUSNESS WHO ARE SOMEWHAT PROTECTED FROM THE IMPACT OF LOW CAREER SUCCESS ON MORTALITY ITSELF. SO IT'S NOT JUST A SIMPLE THING THAT IT'S ALL GOOD OR IT'S ALL BAD. WE CAN EMBED IT WITHIN THE LIFE COURSE AT DIFFERENT AGES AND DIFFERENT CONTEXT AND UNDERSTAND THAT ROLE WILL BE MODERATED BY THOSE EXPERIENCES. YOU MIGHT HAVE NOTICED THAT IN MY MODEL, I PUT DOUBLE HEADED ARROWS BETWEEN THE FACTORS THAT CONSCIENTIOUSNESS CONTRIBUTES TO IN TERMS OF HEALTH, AND THAT ASSUMES THAT THOSE THINGS NOT ONLY ARE CAUSE BID CONSCIENTIOUSNESS BUT ARE IN TURN CAUSING CONSCIENTIOUSNESS WHICH BEGS THE QUESTION, OF COURSE, IS IT FIXED OR CHANGEABLE. I'M OF COURSE A PROPONENT OF THE IDEA THAT IT'S CHANGEABLE. WE PUBLISHED THIS IN 2006, WE TRACKED APPROXIMATELY 100 LONGITUDINAL STUDIES LOOKING AT CHANGES IN PERSONALITY ACROSS A LIFE COURSE. THIS FIGURE SHOWS YOU THAT INDIVIDUALS INCREASE IN CONSCIENTIOUSNESS NOT ACTUALLY IN ADOLESCENCE, WHICH IS INTERESTING, BUT MORE OFTEN IN YOUNG ADULTHOOD. THEY CONTINUE TO DO SO IN MID LIFE AND THEY EVEN SHOW SIGNIFICANT MEAN LEVEL INCREASES IN OLD AGE, WHICH IS WHY I ACTUALLY STARTED STUDYING CONSCIENTIOUSNESS, INTERESTING DEVELOPMENTAL CONSTRUCT THAT IS NOT STUCK IN PLACE OR PLASTER AND CONTINUES TO DEVELOP IN A RATHER PROFOUND WAY ALL THE WAY THROUGH THE LIFE COURSE, SO IT DOES CHANGE. THAT BEGS CERTAIN QUESTIONS LIKE IF IT DOES CHANGE, WHY DOES IT CHANGE. WE HAVE LOTS OF STUDIES AND I'LL GIVE YOU TWO THAT I THINK ARE MOST RELEVANT TO THIS COMMITTEE. THE FIRST LOOKED AT THE EXPERIENCE OF SOCIAL SUPPORT IN OLD AGE IN A SHORT-TERM LONGITUDINAL STUDY TRACKS INDIVIDUALS FOR ABOUT FIVE MONTHS. THIS IS -- STUDY ACTUALLY, PAT HILL WAS THE FIRST AUTHOR. WE FOUND IN THE STUDY THAT NOT ONLY IS SOCIAL SUPPORT AND CONSCIENTIOUSNESS POSITIVELY RELATED, BUT INDIVIDUALS WHO EXPERIENCE MORE SOCIAL SUPPORT INCREASED ON CONSCIENTIOUSNESS OVER THIS PERIOD AND THOSE WHO WERE EXPERIENCING LESS SOCIAL SUPPORT DECREASED. SHOWING TWO THINGS THAT ARE IMPORTANT. ONE, THAT IT'S CHANGEABLE EVEN IN OLD AGE, AND TWO, THAT IT'S LINKED TO HEALTH FACTOR THAT WE ALL KNOW IS QUITE IMPORTANT FOR POSITIVE AGING SUCH AS SOCIAL SUPPORT. HERE IS THE MORE RECENT ANALYSIS WE JUST PERFORMED ON A REPRESENTATIVE SAMPLE ON U.S. CITIZENS LINKING CHANGES IN CONSCIENTIOUSNESS TO CHANGES IN STRESS. CHANGES IN STRESS IS ONE OF THE LEADING PROBLEMATIC EXPERIENCES FOR PEOPLE WHEN IT COMES TO HEALTH AND WHEN WE FOUND IN THIS STU DISI IS THAT PEOPLE WHO EXPERIENCE DECREASES IN STRESS ACTUALLY EXPERIENCED INCREASES IN CONSCIENTIOUSNESS OVER TIME. SO TAKE THE FOOT OFF THE GAS PEDAL AND PEOPLE CAN ACTUALLY GET BETTER. THIS CAME OUT OF GERMANY, MARITAL STABILITY, IF YOU STAY MARRIED LONGER, YOU TEND TO INCREASE IN CONSCIENTIOUSNESS, THIS HAS BEEN SHOWN THREE OR FOUR TIMES NOW. DOING OR NOT DOING DRUGS, THEY'VE DONE VERY NICE WORK ON THIS. PEOPLE WHO PARTICIPATE IN DRUG ABUSE OF ANY SORT TEND TO EXPERIENCE WHAT WE MIGHT THINK OF AS ARRESTED DEVELOPMENT. THEY DON'T INCREASE ON CONSCIENTIOUSNESS LIKE OTHER PEOPLE DO. THEN WE TRACK CHANGES IN PHYSICAL HEALTH AND CHANGES IN CONSCIENTIOUSNESS AND FOUND IT WAS RELATED TO CHANGES IN CONSCIENTIOUSNESS AND THIS WAS NOT AGE GRADED, IT HAPPENED AT ANY TIME OVER THE LIFE COURSE. OF COURSE THESE STUDIES SHOW THAT CONSCIENTIOUSNESS CHANGES AND IT SHOWS THAT THOSE CHANGES ARE LINKED UP TO RELATIVELY REASONABLE THINGS. YOU MIGHT HAVE SEEN MORE CHANGING CONSCIENTIOUSNESS, OBVIOUS FOLLOW UP QUESTION IS CAN WE CHANGE CONSCIENTIOUSNESS. NOT ONLY AM I HERE TO SAY YES, I'M HERE TO SAY WE'VE ALREADY DN DOING IT -- NOT WE, CLINICIANS HAVE BEEN DOING IT FOR A LONG TIME. I'M NOT SURE WHETHER THEY KNEW IT, BUT I'LL SHOW YOU THE DATA. SO WE'VE BEEN DOING A META-ANALYSIS OF CLINICAL INTERVENTION CHANGES THAT HAPPEN TO TRACK CHANGES IN PERSONALITY TRAITS ALONG WITH TYPICAL INDICATORS THEY'RE CONCERNED WITH, LIKE DEPRESSION AND ANXIETY. 200 STUDIES INTO THE META-ANALYSIS, WE'RE PRETTY CONFIDENT THE EFFECT SIZES WILL REMAIN WHERE THEY ARE, THESE ARE CHANGES IN THE BIG FIVE PERSONALITY TRAITS THAT RESULT FROM APPROXIMATELY FOUR WEEKS OF THERAPEUTIC INTERVENTION AND YOU SEE INCREASES IN EX-TROA VERSION, INCREASES IN CONSCIENTIOUSNESS AND MOST APPROPRIATELY, INCREASES IN EMOTIONAL STABLE. THIS WAS TRUE IN THE EXPERIMENTAL STUDIES, IN THE SIMPLE PREPOE STUDIES, TRUE IN STUDIES THAT TRACK THE EFFECT OF MED KAIGS LIKE SSRIs, IT WAS TRUE OF COGNITIVE BEHAVIORAL THERAPY, SUPPORTIVE THERAPY, AND EVEN PSYCHOANALYTIC THERAPY. IT'S QUITE INTERESTING. SO I'M HERE TO TELL YOU THAT THE CLINICIANS HAVE ALREADY BEEN CHANGING PERSONALITY TRAITS FOR A LONG TIME. THESE DATA GO BACK QUITE FAR INTO THE HISTORY OF PSYCHOLOGY. AND WE MIGHT NOT HAVE NOTICED IT, I SUSPECT. SO YES, PERSONALITY INCLUDING CONSCIENTIOUSNESS IS CHANGEABLE AND CAN BE CHANGED THROUGH INTERVENTION. BETTER QUESTIONS THAT WERE IN PART ADDRESSED BY THE AUTHORS OF SEVERAL OF THE PAPERS AND THE SPECIAL ISSUE, WHEN SHOULD WE INTERVENE? IF YOU KNOW JIM HECKMAN, NOBEL PRIZE WINNING ECONOMIST, HE'S QUITE SUPPORTIVE OF THE IDEA OF INTERVENING VERY EARLY. HE LOOKS AT THESE RESULTS AND HE SAYS THERE'S ABSOLUTELY NO REASON TO WAIT, IF WE CAN GET KIDS TO BE A BIT MORE SELF CONTROLLED WHEN THEY'RE YOUNG, THIS COULD HAVE QUITE POSITIVE IMPACTS ON THEIR LIFE COURSE GOING FORWARD. THERE'S SOME CONTRAINDICATIVE RESULTS FROM PSYCHOLOGISTS THAT BECOMING TOO CONSCIENTIOUS TOO EARLY MIGHT BE TOO PROBLEMATIC. YOU MIGHT HAVE BEEN EXPERIENCED BEING BULLIED AS A TEENAGER BECAUSE YOU WERE QUITE NERD-LIKE, PEOPLE WHO ACCELERATE IN -- TEND TO HAVE TROUBLE AS ADOLESCENTS. THEY'RE GREAT AS YOUNG ADULTS. ON WHOM SHOULD WE INTERVENE IS A FAIR QUESTION. SHOULD WE ONLY INTERVENE ON THOSE PEOPLE WHO ARE ON THE LOW END OF THE SPECTRUM, SHOULD WE AVOID TRYING TO GET PEOPLE WHO ARE MODESTLY CONSCIENTIOUS MORE CONSCIENTIOUS? THESE ARE THINK QUESTIONS WE NEED TO ADDRESS AND DEAL WITH. HOW BEST TO INTERVENE IS A TOPIC THAT WE ADDRESSED IN SEVERAL OF THE PAPERS SHOULD WE TAKE A BOTTOM UP APPROACH AND USE COGNITIVE BEHAVIORAL THERAPY, OR MEDICATION? THESE ARE IDEAS THAT I THINK NEED TO BE TESTED FURTHER. AND OF COURSE YOU COULD IGNORE THIS ENTIRELY AND ARGUE THAT YOU CAN USE CONTEXT TO MAKE THIS INDIVIDUAL CONTEXT IRRELEVANT. I THINK THAT'S A FAIR QUESTION, I WOULD ARGUE WHY THERE'S NO REASON WHY WE CAN'T DO BOTH. MOVING FORWARD, RECOMMENDATIONS FROM THE WORKING GROUP ARE THAT WE OF COURSE IMPROVE THE MEASUREMENT OF CONSCIENTIOUSNESS. I'M A PHENOTYPIST, SO I KNOW AND I DO MYSELF, I DO GENE EXPRESSION AND GENETICS WORK AND I TRIED FOR YEARS TO GET INTO THE MAGNET BECAUSE THAT IS THE MOTIVATIONAL SYSTEM WE HAVE IN PLACE, AND I'M NOT GOING TO ARGUE AGAINST THAT, BUT I WILL ARGUE THAT TO DO THAT WELL, WE REALLY DO NEED TO KNOW WHAT IT IS THAT WE'RE MEASURING. AND EVEN THOUGH WE'VE BEEN DOING THIS FOR A WHILE, WE CAN ALWAYS DO IT BETTER, AND THERE'S LOTS OF STUFF WE CAN IMPROVE ON AND THE MEASUREMENT OF CONSCIENTIOUSNESS, AND I THINK WE SHOULD DEDICATE OURSELVES TO THAT. ONE THING THAT WOULD FALL OUT IS WHAT ARE THE COGNITIVE AND BIOLOGICAL SUBSTRATES THAT LINK TO THAT, WHICH OF COURSE WOULD HELP IDENTIFY THE DEVELOPMENTAL ANTECEDENTS TO CONSCIENTIOUSNESS. AS I NOTED EARLIER, WE DON'T HAVE A LOT OF INFORMATION ON THAT. THEN OF COURSE IT WOULD BE THEN GOOD TO EXAMINE THE GENETIC AND NEUROLOGICAL ASSOCIATES OF CONSCIENTIOUSNESS WHICH MANY PEOPLE ARE STARTING TO DO BUT WE'RE LIKE 10 YEARS BEHIND ON PEOPLE WITH ALZHEIMER'S ACCORDING TO OUR DATASET. IT WOULD BE SLEPT IF WE CONTINUED TO UNDERSTAND THE MANIFESTATION OF THIS FAMILY OF PHENOTYPES WITHIN AN AGE-RELATED AND CONTEXT-BASED SYSTEM WHICH WAS PUT OUT BY PEOPLE LIKE HOWARD FRIEDMAN AND MICHAEL SHANAHAN AND DAVID REESE, WHICH I THINK WERE EXCELLENT CONTRIBUTIONS. FROM A PUBLIC HEALTH PERSPECTIVE, A FAIR QUESTION THAT I THINK IS JUST STARTING TO BE ASKED AND NEEDS TO BE ASKED IN A MORE POINTED FASHION IS WHETHER CHANGES IN CONSCIENTIOUSNESS ACTUALLY DO CONTRIBUTE TO PUBLIC HEALTH, SO IN MOFFITT'S PAPER, SHE SHOWED IN ONE ANCILLARY ANALYSIS THAT KIDS WHO INCREASE FROM AGE 10 TO 18 SHOWED EVEN BETTER OUTCOMES AT AGE 32 ABOVE AND BEYOND WHERE THEY STOOD AT AGE 10. AND WE NEED MORE STUDIES LIKE THAT THAT ARE REALLY PRAGMATIC IN ORIENTATION. HOW MUCH GAIN TO DO YOU GET, HOW MANY YEARS OF ADDED LIFE WOULD YOU GET IF YOU INCREASED A QUARTER DEVIATION, A QUARTER STANDARD DEVIATION. WE STARTED THAT BUT WE NEED TO DO IT MORE. THEN OF COURSE THE CON TRAIRIAN AT THE END, ARE THERE TIMES OR CIRCUMSTANCES WHERE THIS MIGHT BE A LESS THAN GOOD THING. SO FOR EXAMPLE, ONE OF THE NEGATIVE CORRELATES OF CONSCIENTIOUSNESS HAPPENS TO BE EATING DISORDERS. SO PEOPLE WHO ARE HIGHER IN CONSCIENTIOUSNESS WILL HAVE A HIGHER PROPENSITY TO EXPERIENCE THINGS LIKE ANOREXIA. SO IT'S NOT ALWAYS GOOD TO BE EXTREMELY HIGH, GOOD THING TO KEEP THAT IN MIND, WHERE IT IS NOT ALWAYS GOOD. WITH THAT, I AM DONE. THANK YOU. [APPLAUSE] >> QUESTIONS FOR DR. ROBERTS? >> THANK YOU. THAT WAS GREAT. A COUPLE TIMES YOU ALLUDED TO ADJUSTMENTS FOR SCS. YOU MUST HAVE TEMPERATURE FIED DATA BY RACE ETHNICITY SOCIAL CLASS. IS THIS A CONSTANT PERSONALITY MARKER, DOES IT VARY WITH REGARDS TO THOSE DETERMINANTS? >> THERE ARE NO PROFOUND OR STRONG RELATIONSHIPS TO SES OR ETHNICITY OR RACE. SO IT REALLY DOES NOT DISTINGUISH RACES OR ETHNICITY. IN FACT, IT'S NOT EVEN STRONGLY RELATED TO GENDER. WOMEN ARE, OF COURSE, A LITTLE HIGHER. I THINK PEOPLE EXPECT WOMEN TO BE MUCH HIGHER ACTUALLY. THEY'RE USUALLY HIGHER IN THE LIFE COURSE THAN MEN ARE. BUT IN TERMS OF RACE AND ETHNICITY AND SES, THE DEMOGRAPHERS HAVE NOT REALLY LOOKED AT THIS AS SYSTEMATICALLY AS THEY COULD, BUT THE DATA THAT I SEE COMING OUT OF THE PSYCHOLOGICAL LITERATURE, THERE'S NOT A SINGLE THING THERE THAT I WOULD PUT MONEY ON. >> THANKS, DR. ROBERTS. THAT WAS WONDERFUL. >> DR. ANDERSON. >> THE SCS QUESTION A LITTLE BIT MORE, YOU TALKED ABOUT ANTECEDENTS. PARENTAL SES RELATED TO CONSCIENTIOUSNESS IN KIDS -- >> I JUST LOOKED AT THIS FOR OUR PRESENTATION, AND I'D LIKE TO SAY THAT IT'S THERE, BUT YOU HAVE TO HAVE THE RIGHT DATA, REALLY GOOD CHILDHOOD SES AND YOYOU HAVE TO HAVE SERIOUS OUTCOMES LATER IN THE LIFE COURSE. THERE ARE VERY FEW STUDIES. THE DENNY DEN STUDY IS ONE, PROJECT TALENT DATASET WHICH YOU MIGHT HAVE SEEN AT TIMES, THERE'S A POSITIVE RELATIONSHIP BUT SMALL. THE ADD HEALTH DATASET, IT'S ZERO. SO IT DESERVES MORE ATTENTION, I AGREE, BUT IN TERMS OF, I THINK, THE WAY PEOPLE MIGHT IDENTIFY THAT RELATIONSHIP, WE HAVEN'T IDENTIFIED IT YET. IT THE CONDITIONS YOU -- IT'S NOT THE CONDITIONS YOU ARE BORN INTO AS IT IS WHAT YOU DO WITH THEM. IF YOU HAVE CONFLICT IN YOUR FAMILY, IT IS RELATED TO POF POVERTY, IT WILL PLAY OUT IN TERMS OF CONSCIENTIOUSNESS. THE INTERNAL CONFLICT IN THE FAMILY I THINK IS MUCH MORE IMPORTANT. >> WHAT'S THE RELATIONSHIP BETWEEN ANXIETY AND CON CONSCIENTIOUSNESS? >> ONE OF THE BURDENS OF MY CAREER IS TRYING TO SAY THAT WORD OVER AND OVER AGAIN. STILL DRIVES ME CRAZY BECAUSE I DO CONSCIOUSNESS AND CONSCIENTIOUSNESS ALL THE TIME. OSTENSIBLY IT'S PART OF THE BIG FIVE SO IT SHOULD BE INDEPENDENT OF IT. THERE ARE SOME FASCINATING INTERRELATIONSHIPS, I WOULD SAY. SO LARGELY IT'S INDEPENDENT. I THINK THE COMBINATION IS REALLY INTERESTING. ONE STUDY, FOR EXAMPLE, WHERE WE FOUND IF YOU'RE MARRIED TO SOMEBODY WHO IS BOTH HIGH ON CONSCIENTIOUSNESS AND NEWER OT SISM, THIS COMES OUT OF THE HEALTH AND RETIREMENT STUDY, MIND YOU, YOU HAVE BETTER HEALTH. [LAUGHTER] THAT MAKES SENSE. YOU MIGHT HAVE AN UNHAPPY MARRIAGE, BUT THAT PERSON IS CHECKING UP ON YOU, RIGHT? SO I THINK THOSE TYPES OF COMBINATIONS TEND TO BECOME MORE INTERESTING. WHEN IT COMES TO HEALTH, THOSE ARE THE BIG TWO. BOTH IN MENTAL AND PHYSICAL HEALTH, CONSCIENTIOUSNESS AND NEWER OT SISM ARE THE THINGS THAT HAVE THE LARGEST INFLUENCE OVER EVERYTHING THAT WE LOOK AT. [APPLAUSE] >> TIME TO USE THAT GAVEL. WE ARE ADJOURNED.