I'M JANINE CLAYTON, THE DIRECTOR OF THE OFFICE OF RESEARCH ON WOMEN'S HEALTH HERE AT NIH. I'M DELIGHTED TO BE HERE TO BRING YOU BEYOND THE FIG LEAF, THE SCIENCE OF SEX AND GENDER DIFFERENCES, BROUGHT TO YOU BY THE OFFICE OF RESEARCH ON WOMEN'S HEALTH. AS I BEGIN, I WANT TO ACKNOWLEDGE OUR PLANNING COMMITTEE. THEY DID ALL OF THE HARD WORK IN PUTTING THIS SESSION TOGETHER AND I KNOW THAT YOU'RE GOING TO ENJOY THESE TRULY INFORMATIVE TALKS. THE RATIONALE BEHIND THIS PRESENTATION, OF THIS SYMPOSIUM, IS THAT AS PART OF IMPLEMENTATION OF THE NIH STRATEGIC PLAN FOR WOMEN'S HEALTH AND SEX DIFFERENCES RESEARCH. THAT STRATEGIC PLAN IS ENTITLED "MOVING INTO THE FUTURE WITH NEW DIMENSIONS AND STRATEGIES, A VISION FOR 2020 FOR WOMEN'S HEALTH RESEARCH." THERE ARE THREE VOLUMES TO THAT STRATEGIC PLAN. VOLUME 1 IS IT I 1 IS IN THE CENTER, CONSTITUTING THE STRATEGIC PLAN, AND IF YOU LOOKED ON YOUR PROGRAM, ON THE BACK OF YOUR PROGRAM, SO THIS IS THE FRONT. ON THE BACK OF YOUR PROGRAM, THE SIX GOALS OF THE STRATEGIC PLAN ARE LISTED THERE WITH THE HANDY DANDY PERFORATION-LIKE MARK FOR YOU TO CUT THOSE OUT, BECAUSE WE'D LIKE FOR YOU TO THINK ABOUT THOSE AS YOU GO FORWARD IN ALL YOUR AREAS AND SPHERES OF INFLUENCE IN TERMS OF CONSIDERING SEX AND GENDER APPROPRIATELY AND EXPANDING THE CONTEXT OF SEX AND GENDER IN SCIENCE RESEARCH AND CLINICAL PRACTICE. AS YOU KNOW, SEX IS A BASIC BIOLOGICAL VARIABLE, IT'S CRITICALLY IMPORTANT AND I THINK EVERYONE IN THE ROOM WOULD AGREE, IT CAN BE CRITICALLY IMPORTANT TO UNDERSTANDING SCIENCE AND TO CLINICAL CARE. PHYSICIAN DOESN'T TREAT A PATIENT, HE TREATS A FEMALE PATIENT OR A MALE PATIENT, IN ADDITION TO ALL THE OTHER VARIABLES THAT MAKE US DIFFERENT AND UNIQUE, AND PERSONALIZED CARE REALLY SHOULD BE AT A MINIMUM SEX-BASED AND SEX-INFORMED. SO WE ORGANIZED THIS WORKSHOP, THIS SYMPOSIUM, RATHER, TO HELP EXPLORE SOME OF THE AREAS RELATED TO SEX AND GENDER DIFFERENCES. WE KNOW THAT SEX DIFFERENCES ARE APPARENT ACROSS THE SPECTRUM OF HEALTH AND DISEASE. THEY IMPACT -- THE AFFECT NOT ONLY INDIVIDUAL HEALTH BUT ALSO PUBLIC HEALTH, RESEARCH AND HEALTHCARE DELIVERY. THAT GOES FROM THE MOST BASIC LEVEL TO DIFFERENCES IN GENE EXPRESSION AT THE CELLULAR LEVEL TO THE CLINICAL LEVEL TO MALE AND FEMALE DIFFERENCES, TO EPIDEMIOLOGIC IMPORTANCE AND SOCIETAL IMPORTANCE IN AREAS SUCH AS HEALTH -- RESEARCH -- HEALTH SERVICES RESEARCH AS WELL. SO WITHOUT FURTHER ADO, I WANT TO BRING UP OUR FIRST PRESENTER TO BEGIN OUR EXPLORATION BEYOND THE FIG LEAF. MEDICAL OFFICER IN THE CLINICAL APPLICATIONS AND PREVENTION BRANCH IN THE DIVISION OF CARDIOVASCULAR DISEASES AT NHLBI. SEPLEASE HELP ME WELCOME TO THE PODIUM DR. COOK. [APPLAUSE] >> GOOD AFTERNOON. IT'S A PLEASURE TO BE HERE TO TALK ABOUT SOMETHING THAT'S NEAR AND DEAR TO MY HEART, AND I THINK THIS IS A CRITICAL TOPIC OF IMPORTANCE BECAUSE IF WE'RE REALLY GOING TO TURN THE TIDE AGAINST THE TRENDS OF CARDIOVASCULAR DISEASE IN GENERAL IN THIS POPULATION, THEN WE'RE REALLY GOING TO NEED TO FOCUS ON HOW TO CHANGE THE MORBIDITY, MORTALITY AND ECONOMIC BURDEN OF CARDIOVASCULAR DISEASE AMONGST WOMEN, AND THAT'S WHAT I HOPE TO TALK A LITTLE BIT MORE ABOUT TODAY, IS SPECIFICALLY HOW SEX AND GENDER DIFFERENCES IN CARDIOVASCULAR DISEASE AND SPECIFICALLY HEALTHCARE DELIVERY DO EXIST AND WHAT WE CAN DO IN TERMS OF RESEARCH FOCUS GOING FORWARD. SO I THOUGHT I'D BEGIN JUST BY GIVING A LITTLE BIT OF AN OVERVIEW OF SEX AND GENDER DIFFERENCES IN THE CARDIOVASCULAR DISEASE BURDEN IN THIS COUNTRY, AS WELL AS IN THE RISK FACTORS FOR CARDIOVASCULAR DISEASE AND TALK A LITTLE ABOUT THE PRESENTATION THAT HAS SOME UNIQUE FEATURES TO WOMEN AS WELL AS TREATMENT OF CARDIOVASCULAR DISEASE AND THE DIFFERENCES IN TREATMENT FOR WOMEN AS COMPARED TO MEN, AND DIFFERENCES IN OUTCOMES THAT MAY RESULT FROM SUCH TREATMENT AS WELL AS GETTING INTO A LITTLE BIT AROUND INCLUSIONING CARDIOVASCULAR RESEARCH AND RESEARCH GAPS THAT MAY NEED FUTURE DIRECTION. WE MAY BE FAMILIAR WITH THIS CHART. THIS IS BASICALLY A LIFE EXPECTANCY TABLE BY RACE AND SEX BASED ON DATA IN THE UNITED STATES IN 2008, AND WHAT I WANT TO POINT OUT TO YOU IS THAT WE'VE MADE SIGNIFICANT STRIDES IN EXPANDING THE LENGTH OF LIFE LIVED BY U.S. AMERICANS, AND IF WE LOOK AT LIFE EXPECTANCY, WE KNOW THAT MEN, ON AVERAGE, LIVE TO ABOUT 75 1/2 YEARS OF AGE AND WOMEN ON AVERAGE LIVE FIVE YEARS LONGER, TO 80 YEARS OF AGE, BUT I THINK WHAT'S IMPORTANT HERE IS THE CONTEXT THAT THIS REPRESENTS WHEN WE TALK ABOUT CARDIOVASCULAR DISEASE, WHICH WE KNOW IS MANIFEST MUCH LATER IN LIFE. IF WE LOOK SPECIFICALLY AT DEATH FROM CARDIOVASCULAR DISEASE, OVER THE TIME PERIOD OF ABOUT 1900 THROUGH 2007, AS YOU CAN SEE, WE'RE ON A RAPID RISE IN DEATHS FROM CARDIOVASCULAR DISEASE FROM 1900 THROUGH ABOUT 1970, BUT THEN WE STARTED EXPERIENCING THIS DECLINE IN CARD VCARDIOVASCULAR SCEEZ DISEASE WHICH WE THINK MAY HAVE BEEN RELATED TO EXPLORATION OF RISK FACTORS FOR CAR CARDIOVASCULAR DISEASE, AND WE WERE AT RECORD LOWS IN 2007 IN TERMS OF THIS TREND. LET'S EXAMINE IT A LITTLE DEEPER WHEN WE WANT TO LOOK AT MORTALITY TRENDS FOR MALES AND FEMALE OVER THAT SAME TIME PERIOD. WHAT WE SEE IS THAT IN THE MID 198 EEs, THE GRAPHS FOR MEN AND WOMEN ACTUALLY CROSSED. AT THAT POINT, MORE WOMEN HAVE DIED FROM CARDIOVASCULAR DISEASE IN TERMS OF SHEER NUMBERS AS COMPARED TO MEN AND HAVE NOT EXPERIENCED THE SAME RATE OF DECLINE IN DEATHS OVER THIS TIME PERIOD. SO IT RAISES QUESTIONS ABOUT WHETHER THERE ARE SEX AND GENDER DIFFERENCES IN THE BURDEN OF CARDIOVASCULAR DISEASE AND HOW IS THAT REPRESENTED, AND IF WE LOOK AT THIS TABLE, WHICH IS BASE BASTEICALLBASICALLY LOOKING AT DIFFER ENT TYPES OF CARDIOVASCULAR DISEASE AND THE RELATIVE BURDEN IN MEN VERSUS WOMEN, WE SEE THAT ON AVERAGE, THE REMAINING LIFETIME RISK OF CARDIOVASCULAR DISEASE AT THE AGE OF 40 IN WOMEN IS ABOUT ONE IN TWO, COMPARED TO MEN, TWO IN THREE. AS WE LOOK DOWN THE CHART FOR WOMEN COMPARED TO MEN, WE SEE THE NUMBER OF DEATHS IN WOMEN EXCEED THAT OF MEN AND THIS IS DATA THAT'S BASED ON 2008 MORTALITY DATA, AND IF WE LOOK SPECIFICALLY AT CORONARY HEART DISEASE, WE ACTUALLY SEE A DIFFERING TREND WHERE MEANMEN ACTUALLY DIE MORE FREQUENTLY FROM CORONARY HEART DISEASE AS COMPARED TO WOMEN, BUT IF YOU LOOK AT THE RATES OF STROKE, WE SEE HIGHER RATES IN WOMEN AS COMPARED TO MEN, AND WE ALSO SEE HIGHER HOSPITALIZATIONS FOR STROKE AS WELL AS HOSPITALIZATIONS FOR HEART FAILURE IN WOMEN AS COMPARED TO MEN. SO WE START TO TEASE OUT THAT THERE ARE DIFFERENT COMPONENTS OF CARDIOVASCULAR DISEASE WHERE THE SEX AND GENDER DIFFERENCES ACTUALLY DO EXIST, WHICH ARE IMPORTANT IF WE REALLY WANT TO TRY TO FOCUS ON HOW TO CHANGE THIS TREND. I THINK IT'S ALSO IMPORTANT TO LOOK AT GRAPHS THAT SHOW US THE DEATH RATES, AND HERE I'M FOCUSING ON HEART DISEASE SPECIFICALLY AS ONE COMPONENT OF CARDIOVASCULAR DISEASE BECAUSE MUCH OF THE REMAINING -- BUT IF WE LOOK SPECIFICALLY AT FEMALES IN 2008 DATA ACROSS AGE GROUPS, WE ACTUALLY SEE THE RATES OF CARDIOVASCULAR DISEASE AND HEART DISEASE IN THIS SPECIFIC INCIDENT ARE HIGHER AS WE GET INTO THE OLDER POPULATION AND THIS IS IMPORTANT BECAUSE WE KNOW THAT WOMEN LIVE LONGER ON AVERAGE AND SO COMPLICATED BY THE FACT THAT HEART DISEASE TYPICALLY IS A DISEASE THAT OCCURRED MORE FREQUENTLY AS PEOPLE AGE, WE SEE THIS TREND OF THE INCREASED DEATH FROM HEART DISEASE IN THE OLDER POPULATION OF WOMEN. BUT THERE'S A SECOND POINT ON THIS GRAPH THAT I THINK IS VERY IMPORTANT, AND THAT IS THAT THIS DATA IS DIVIDED BY RACE AS WELL AS -- IT'S DIVIDED BY RACE WITHIN THE SEX CATEGORY, AND IF YOU LOOK AT THE GREEN BAR HERE REPRESENTING AFRICAN-AMERICANS OR BLACK, WE SEE THAT THE RATE OF DEATH FROM HEART DISEASE AMONGST BLACKS AT ALL AGE EXTRA TUM ISTRATUM IS HIGHER THAN ANY OF THE RACE ETHNICITIES HERE. SO NOT ONLY DO SEX AND GENDER DIFFERENCES EXIST BUT WE ALSO SEE THAT THERE IS AN INTERACTION HERE BETWEEN RACE AND SEX, WHICH ACTUALLY IS ALSO VERY IMPORTANT TO EXPLORE. SO ARE THESE DIFFERENCES OR ARE THEY DISPARITIES, WHEN WE TALK ABOUT DIFFERENCES IN RACE OF CARDIOVASCULAR DISEASE AMONGST WOMEN? AND I THINK THERE ARE A FEW INSTITUTE OF MEDICINE REPORTS THAT SHED SOME LIGHT ON THIS. IN 2001 AND UNTIL 2010, THERE WERE TWO REPORTS THAT FOCUSED ON SEX DIFFERENCES AND GENDER DIFFERENCES IN HEALTH AND HEALTHCARE AND I THINK THAT THOSE DEFINING REPORTS LET US KNOW THAT SEX DIFFERENCE REALLY DO REFER TO DIFFERENCES THAT ARE BIOLOGICAL IN NATURE. WHEREAS GENDER DIFFERENCES MAY MORE REFER TO THE SOCIAL CIRCUMSTANCES, ENVIRONMENTAL FACTORS AND THE KIND OF ECOLOGY OF HEALTH SYSTEMS THAT MAY ACTUALLY IMPACT THE OUTCOMES THAT WOMEN ACHIEVE. THUS, I THINK THAT DIFFERENTIATION BETWEEN SEX AND GENDER DIFFERENCES LAYS A GROUNDWORK, A FOUNDATION, BASICALLY, FOR US TO KIND OF CONSIDER WHEN WE'RE THINKING ABOUT RESEARCH THAT HAS TO DEAL WITH WOMEN. LASTLY, I WANTED TO POINT OUT THIS 2002 INSTITUTE OF MEDICINE REPORT ON UNEQUAL TREATMENT, THIS WAS A REPORT FOCUSED ON HEALTH OR HEALTHCARE DISPARITIES, BUT I THINK WHAT WAS IMPORTANT FROM THE DEAF DEFINITIONS IN THIS REPORT WERE REALLY THAT WE STARTED TO UNDERSTAND THAT DISPARITIES REALLY TALK ABOUT QUALITY OF HEALTHCARE, AND IT TALKS ABOUT QUALITY OF HEALTHCARE BETWEEN TWO POPULATIONS, WHERE THE DIFFERENCE IN QUALITY OF HEALTHCARE IS NOT RELATED TO THE CLINICAL APPROPRIATENESS AND NEED OR PATIENT PREFERENCES BUT IS MORE RELATED TO THE ECOLOGY OF HEALTHCARE SYSTEMS AS WELL AS ENVIRONMENTAL FACTORS. SO IN THIS SITUATION, WE'RE TALKING ABOUT DISPARITY AS OCCUPYING THIS ROUND WHEREAS DIFFERENCES REALLY DO OCCUPY THE FULL REALM HERE, SO WHAT I'M DESCRIBING A LOT OF TODAY HAS TO DO WITH DIFFERENCES BUT REMEMBER WHEN I TALK ABOUT DIFFERENCE, THERE MAY BE DISPARITY EMBEDDED WITHIN THAT. SO LET'S TALK A LITTLE ABOUT RISK FACTORS FOR CARDIOVASCULAR DISEASE AMONG WOMEN. THIS IS ONE PLACE WHERE WE KNOW WE CAN MAKE A DIFFERENCE. RISK FACTORS ARE MODIFIABLE IN MANY SITUATIONS TO UNDERSTANDING THE DIFFERENCES IN RISK FACTORS AMONGST WOMEN MAY BE AN IMPORTANT STEP IN TURNING THE TIDE. I THINK ONE OF THE MOST IMPORTANT THINGS WE SHOULD RECOGNIZE IS THAT THERE HAS TRADITIONALLY BEEN AN UNDERPERCEPTION OF RISK FOR WOMEN FOR CARDIOVASCULAR DISEASE, AND THIS BEARS OUT IN A STUDY THAT ACTUALLY SURVEYED WOMEN BUT THE AMERICAN HEART ASSOCIATION FUNDED THIS STUDY AND IF YOU LOOK OVER THE TIME PERIOD FROM 1997 TO 2009, THERE'S GENERALLY BEEN AN INCREASE IN AWARENESS THAT HEART DISEASE IS THE LEADING CAUSE OF DEATH AMONGST WOMEN BUT THAT AWARENESS IS ONLY AT THE 30% MARK IN 1997 AND ONLY AT THE 54% MARK IN 2009 SO WE'VE MADE PROGRESS BUT WE HAVE A WAY TO GO. AND YOU MAY BE AWARE THAT THE NHLBI HAS A HEART TRUTH CAMPAIGN WHICH IS ACTUALLY A NATIONAL AWARENESS CAMPAIGN TO TRY TO HELP WOMEN UNDERSTAND THEIR RISK OF HEART DISEASE AND TAKE ACTION TO REDUCE THEIR RISK. I THINK IT STILL HIGHLIGHTS THERE ARE MANY AREAS FOR US TO FOCUS, PARTICULARLY THAT WHILE WE HAVE A NATIONAL SYMBOL FOR HEART DISEASE, THIS RED DRESS WHICH BASICALLY KIND OF SYMBOLIZES THAT IT DOESN'T MATTER WHAT YOU WEAR, HEART DISEASE IS THE LEADING CAUSE OF DEATH IN THIS COUNTRY, BUT WE'RE TRYING TO INSPIRE WOMEN TO TAKE THAT KNOWLEDGE AND CONVERT IT INTO ACTION, BUT IN ORDER TO DO THAT, WE NEED RESEARCH THAT DRIVES THE ACTION THAT ACTUALLY WILL WORK. ANOTHER IMPORTANT FACTOR FOR RISK, THE OLD IR AGE OF PRESENTATION, WHICH WE TALKED ABOUT BRIEFLY. IF YOU LOOK AGAIN AT THIS GRAPH BY AGE STRATA, YOU SEE AS WE GET INTO THE 80-PLUS AGE GROUP, WOMEN EXCEED MEN IN TERMS OF PREVALENCE OF CARDIOVASCULAR DISEASE AND WE HAVE PREVIOUSLY TALKED ABOUT DEATHS THAT THE PREVALENCE AND MORTALITY ARE HIGHER AS WE GET INTO HIGHER AGE STRATA. OTHER ISSUES AROUND RISK FACTORS FOR WOMEN IS THAT TRADITIONALLY IT MAY UNDERESTIMATE RISK AMONGST WOMEN. AND FURTHERMORE THERE ARE EMERGING RISK FACTORS THAT WE'RE STARTING TO RECOGNIZE THAT ARE SPECIFICALLY UNIQUE OR HAVE A SPECIFIC BURDEN OF DISEASE AMONGST WOMEN, AND THOSE ARE PREGNANCY COMPLICATIONS WHICH WE'LL TALK ABOUT A LITTLE BIT MORE AND ROUGE THRO JIK DISEASES THAT HAVE A HIGHER RAIFT PRESENTATION AMONGST THE FEMALE SEX. SO THIS IS JUST A TABLE THAT I PULLED FROM A STUDY ON ONE OF THE COHORT STUDIES THAT NHLBI SPONSORS, WHERE THERE WAS AN ANALYSIS FOREMANNED THAT LOOKS AT WOMEN WHO WERE CLASSIFIED AS LOW FRAMINGHAM RISK, TRYING TO DETERMINE WHETHER THEY WERE DEVELOPING CARDIOVASCULAR EVENTS AND WHAT RATE. ALSO DID SCANNING TO DETERMINE WHETHER THERE WERE SUBCLINICAL ATHEROSCLEROSIS WHICH MAY NOT BE DETECTABLE BY PRESENTATION OR SYMPTOMS, BUT MAY BE PRESENT BY THE DEGREE OF CALCIUM THAT WAS REPRESENTED ON THOSE SCANS. AND WHAT THEY FOUND IS THAT ACTUALLY THERE WERE RATES OF EVENTS AMONGST WOMEN WHO WERE CLASSIFIED AS LOW FRAMINGHAM RISK WHILE THE NUMBERS AREN'T OVERWHELMING, THEY'RE DEFINITELY PRESENT, BUT WHAT I THINK IS MORE STRIKING IS ALMOST A THIRD OF THE WOMEN HAD SOME DEGREE OF CALCIUM IN THEIR CORONARY ARTERIES. WITH THE VARIATION OF CALCIUM AS YOU GET TO HIGHER SCORES WERE GREATER NUMBERS OF RISK FOR EVENTS BOTH CORONARY HEART DISEASE EVENTS AND CARDIOVASCULAR DISEASE EVENTS. SO THIS AGAIN CONFIRMING THAT PERHAPS THERE IS SOME UNDERESTIMATION OF RISK WITH FRAMINGHAM CLASSIFICATION ALONE. SO LAST YEAR, THE AMERICAN HEART ASSOCIATION IN CONJUNCTION WITH THE AMERICAN COLLEGE OF CARDIOLOGY PUT OUT GUIDELINES FOR CARDIOVASCULAR DISEASE IN WOMEN. THIS IS A CLASSIFICATION SCHEME THAT TRIES TO INCORPORATE SOME OF THE PLUSES OF THE FRAMINGHAM RISK SCORE BUT ALSO TRIES TO DELVE INTO SOME THINGS UNIQUE FOR WOMEN. IN ADDITION TO SOME OF THE TRADITIONAL RISK FACTORS AND FRAMINGHAM RISK QUALIFYING SOMEONE AS HIGH RISK, THEY ALSO STARTED TO INCLUDE SOME THINGS THAT MAY BE MORE SPECIFIC TO WOMEN SUCH AS SYSTEMIC AUTO I MEAN CARDIOVASCULAR DISEASE, AND SPECIFIC TO WOMEN, A HISTORY OF PREECLAMPSIA, GESTATIONAL DIABETES OR PREGNANCY INDUCED HYPERTENSION, AS FACTORS THAT MAY CONTRIBUTE AT LEAST MODERATE RISK FOR WOMEN. AND THEY ALSO INTRODUCED A VERY NEW CONCEPT CALLED IDEAL CARDIOVASCULAR HEALTH, WHICH IS THAT TEST WE WANT TO ALL OBTAIN IN ORDER TO REALLY MAKE A DIFFERENCE IN THE RATES OF HEART DISEASE AMONGST WOMEN AND THAT LOOKS AT ALL THE RISK FACTORS AT THEIR MOST OPTIMAL GOALS, SO THE IDEA BEHIND THESE GUIDELINES WERE, YES, WE KNOW WHAT PUTS PEOPLE AT HIGH RISK BUT MAYBE THE LOWER RISK CLASSIFICATION NEEDED A LITTLE MORE ADDITIVE INFORMATION IN ORDER TO CLASSIFY PEOPLE FOR BEING AT RISK WITHIN THAT, THEN PERHAPS WE NEED TO TRY TO REALLY AIM FOR SOMETHING THAT'S MORE IDEAL CARDIOVASCULAR RIS I.R.S. BEINGRISK, AND THAT'S SOMETHING THAT'S NEW IN THESE GUIDELINES THAT I THINK IS IMPORTANT TO HIGHLIGHT. SO OTHER ISSUES, WE KNOW WOMEN WHILE PRESENTING AT AN OLDER AGE PRESENTATION ALSO HAVE A HIGHER RISK FACTOR ON CO-MORBID IT BURDEN, AND IF WE LOOK AT THE RISK FACTORS FOR MEN VERSUS WOMEN HERE IN THIS TYPE OF TABLE, WE SEE THAT HYPERTENSION IS ABOUT THE SAME, 1 IN 3 U.S. ADULT AMERICANS HAVE HYPERTENSION AND THAT'S REPRESENTED IN MEN AND WOMEN WITH A SLIGHT INCREASE IN MEN. SO I THINK SOME OF THE THINGS THAT MAY NOT SEEM AS IMPORTANT IS THIS DIFFERENCE BETWEEN DIABETES IN WOMEN COMPARED TO MEN AND WE'LL TALK ABOUT HOW DIABETES MAY CONFER ACTUALLY A DIFFERENT RISK FOR WOMEN AS COMPARED TO MEN, SO A 1% DIFFERENCE ACTUALLY MAKES A BIG DIFFERENCE. TOTAL CHOLESTEROL GREATER THAN 240 HIGHER IN WOMEN AS COMPARED TO MEN, AND IF YOU LOOK AT RATES OF PHYSICAL INACTIVITY, HIGHER IN WOMEN AS COMPARED TO MEN. AND OBESITY TRENDS, WE KNOW HAVE BEEN JUST REALLY GROWING OVER THE POPULATION AND WHILE WOMEN HERE ARE NOT REPRESENTED AS HAVING MORE OBESITY THAN MEN, WHEN WE LOOK AT OVERWEIGHT AND OBESITY COMBINED, THE PROBLEM HERE ACTUALLY DOES SEEM TO BE MANIFEST IN OUR POPULATIONS OF RACIAL AND ETHNIC MINORITIES WITH AFRICAN-AMERICANS AND LATINO WOMEN ALMOST BEING IN THE 40% RANGE OF BEING CLASSIFIED AS OVERWEIGHT OR OBESE, SO WE SEE THE BURDEN OF THAT REPRESENTED IN MINORITY POPULATIONS. SPECIFICALLY HYPERTENSION BEING A RISK FACTOR WE HAVE TO PAY SPECIFIC ATTENTION TO BECAUSE WE SEE THE RATES OF HYPERTENSION AMONGST BLACKS ARE ACTUALLY RISING, AND OVER 50% OF THE POPULATION, THE BLACK POPULATION, HAS HYPERTENSION, AND THIS IS A REALLY IMPORTANT FACT WHEN WE KNOW THAT THOSE RATES OF DISEASE THAT WE TALKED ABOUT EARLIER ALREADY HAVE A RACE-SEX INTERACTION THAT MAKE BLACK WOMEN MORE AT RISK FOR CARDIOVASCULAR DISEASE AND COMBINED WITH RISING RATES OF HYPERTENSION AND CONTROL RATES THAT ARE LOW IN OUR POPULATIONS, WE'RE REALLY LOOKING AT A TREND TO SET UP FOR INCREASED RISK THAT WILL BE DIFFERENT BY RACE. SO A COUPLE OF OTHER RISK FACTORS I WANTED TO HIGHLIGHT. I MENTIONED JUST BRIEFLY THAT SOME OF THE RISK FACTORS WE SEE ACTUALLY HAVE A DIFFERING EFFECT BY SEX, AND IF WE LOOK AT FEMALE SMOKERS COMPARED TO MALE SMOKERS, THERE'S ACTUALLY A 25% INCREASED CORONARY ARTERY DISEASE RISK FROM FEMALES AS COMPARED TO MALES, AND A DISPRO FORGS NAT INCREASED CORONARY ARTERY DISEASE FOR DIABETIC WOMEN VERSUS DIABETIC MEN. THIS LOOKS AT FATAL HEART DISEASE EVENTS IN MEN AND WOMEN WITH DIABETES AS COMPARED TO THOSE WITHOUT DIABETES. WHAT WE SEE HERE IS THAT THE RATIO IS THREE FOLD FOR WOMEN AS COMPARED -- WOMEN WITH DIABETES AS COMPARED TO WOMEN WITHOUT DIABETES AND TWOFOLD. SO WE SEE AGAIN THAT WOMEN COMPARED TO MEN HAVE AN INCREASED RISK OF EVENTS RELATED TO DIABETES AS COMPARED TO MEN. SO JUST A BRIEF COMMENT OR TWO ABOUT CLINICAL PRESENTATION. WE TALKED ABOUT T E UNDERPERCEPTION OF RISK BUT THERE'S ALSO UNDERRECOGNITION OF SIEMENTS SIPTSYMPTOMS AND SIGNS WHEN WOMEN PRESENT WITH SYMPTOMS OF CARDIOVASCULAR DISEASE, AND THIS HAS BEEN DOCUMENTED IN SURVEYS OF HEALTHCARE PROFESSIONALS AS WELL AS IN EMERGENCY MEDICAL TECHNICIANS THAT RESPOND TO WOMEN. AND WE ALSO BELIEVE THAT THERE MAY BE DIFFERING MECHANISMS OF DISEASE. WE'RE STARTING TO SEE DOCUMENTATION OF PATTERNS OF DISEASE SUCH AS MICROVASCULAR DISEASE OR NON-OBSTRUCTIVE CORONARY DISEASE WITH WORSE PROGNOSIS FOR WOMEN AND WE ALSO BELIEVE THAT ANGINA IS A MAJOR PRESENTING SYMPTOM FOR CORONARY DISEASE AMONGST WOMEN AS COMPARED TO MYOCARDIAL INFARCTION IN MEN, SO WHILE A WOMAN MAY PRESENT WITH SYMPTOMS OF ANGINA AND NOT NECESSARILY HAVE A HEART ATTACK AT THAT MOMENT, THAT'S AN ACTUAL CARE OPPORTUNITY THAT IS BEING MISSED. 20% OF -- AMONGST WOMEN WHO PRESENT WITH ANGINA, THERE'S A 20% HIGHER RATE AS COMPARED TO MEN OF MYOCARDIAL INFARCTION, WHICH MEANS THAT EVEN IF IT'S NOT AT THAT MOMENT, THERE STILL SEEMS TO BE THE TIME WHERE THEY PRESENT WITH AN M.I. AT A HIGHER RATE WHEN THEY DO HAVE ANGINA, AND THE MORTALITY AND MORBIDITY RELATED TO WOMEN WHO HAVE ANGINA SEEMS TO BE DOUBLE THAT OF WHAT WE SEE IN MEN. AND IF WE LOOK AT POOLED ESTIMATES OF SEX RATIOS ACROSS ANGINA PREVALENT STUDY, WE SEE THAT OF THESE STUDIES THAT WERE POOLED, THAT HERE YOU SEE THAT OVERALL, ANGINA RATES ARE MUCH HIGHER AMONGST WOMEN AND MORE COMMON IN WOMEN AS COMPARED TO MEN. ACUTE CORONARY SYNDROME WHEN WOMEN ACTUALLY PRESENT WITH A MYOCARDIAL INFARCTION OR WITH UNSTABLE ANGINA, PERHAPS MORE -- IN FACT, WE KNOW WHEN WOMEN PRESENT WITH A HEART ATTACK, THE TYPE THAT REALLY WORRIES PEOPLE TO RUSH YOU OFF TO A CATH LAP, THERE ARE DIFFERENCES IN MORTALITY OF 10.2% OF THE POPULATION OF WOMEN DYING IN HOSPITAL AS COMPARED TO 5.5% OF MEN. I WANTED TO SHOW YOU THAT AMONGST WOMEN WHO ACTUALLY HAVE NO EVIDENCE OF OBSTRUCTION IN THEIR CORONARY ARTERIES AT THE TIME THAT THEY HAVE AN ANGIOGRAPHY WHEN THEY COME IN, THEY STILL HAVE A HIGHER EVENT RATE AS COMPARED TO THOSE WHO ACTUALLY DON'T HAVE ANY OBSTRUCTION -- I'M SORRY -- I SHOULD SAY THAT THOSE THAT DON'T HAVE ANY OBSTRUCTION STILL HAVE A HIGHER EVENT RATE THAN YOU WOULD ANTICIPATE AS COMPARED TO A CONTROL SAMPLE WHERE THERE'S NO CORONARY ARTERY DISEASE HISTORY OR SYMPTOMS. SO IF YOU SEE HERE THE EVENT RATES IN THE DARK BARS ARE STILL HIGHER THAN THOSE IN THE LIGHT BARS, WHERE THAT'S THE CONTROL POPULATION THAT HASN'T HAD ANY SYMPTOMS. AND THEN THE LAST THING I WANTED TO SAY IS THAT THEY ARE MORE LIKELY TO DIE OF CARDIAC ARREST BEFORE HOSPITAL ARRIVAL. TREATMENT DIFFERS. WE KNOW THERE ARE LOWER RATES OF STANDARD THERAPIES, HIGHER RATES OF REPEAT ANGR ANGIOGRAPHY, UNDERENROLLMENT IN CLINICAL TRIALS TO INVESTIGATE THIS. I'M GOING TO SKIP RIGHT DOWN TO THE PUNCH LINE AND SAY I THE OUTCOMES DIFFER AS WELL. THERE'S A HIGHER STANDARDIZED MORTALITY TO CORONARY HEART DISEASE WITH WOMEN AS COMPARED TO MEN. WOMEN ARE MORE LIKELY THAN MEN TO HAVE A RECURRENT MYOCARDIAL INFARCTION, AND WE KNOW THAT THIS HIGHER RATE OF MORTALITY SEEMS TO BE CONCENTRATED IN THIS SEGMENT OF MYOCARDIAL INFARCTIONS THAT ARE THE MORER JENT KINMOREURGENT KINDS, EVEN WHEN WE TRY TO GIVE OUR STANDARD REVASCULARIZATION THERAPIES AND OFTEN MORE TIMES COMPLICATED BY HEART FAILURE AS COMPARED TO MEN. AND WE KNOW THAT THE TRIALS THAT LOOK AT OUR CARDIOVASCULAR DEVICES REALLY HAVE UNDERENROLLED WOMEN. WE HAD A MEAN OF 67% MEN AND 78 CARDIOVASCULAR DEVICES, TRIALS THAT WERE INVESTIGATED AND 28% OF THE STUDIES DIDN'T REPORT SEX DISTRIBUTION IN THEIR FINAL PAPERS. SO WE HAVE FUTURE NEEDS. WE NEED TO EXAMINE YOUNGER WOMEN AND THIS PARADOX OF HAVING INCREASE ADVERSE OUTCOMES EVEN THOUGH THEY HAVE LESS OBSTRUCTIVE DISEASE. WE NEED TO UNDERSTAND DIFFERENCES IN PATHOPHYSIOLOGY AND WE NEED TO FOCUS ON SUBPOPULATIONS WITH GREATER RISK DISPROPORTIONATE DISEASE AND POOR OUTCOMES SUCH AS OUR RACIAL AND ETHNIC MINORITY AND WE NEED TO UNDERSTAND THESE DIFFERENCES AND PATTERNS OF CARE AND HOW THEY TRANSLATE INTO PREVENTION, DIAGNOSIS AND TREATMENT. THAT'S FROM ONE OF OUR RED DRESS COLLECTION FASHION SHOWS THAT I'LL END ON. THANK YOU FOR YOUR ATTENTION. [APPLAUSE] >> THANK YOU, DR. COOK. THAT WAS FANTASTIC. A LOT TO THINK ABOUT. LOTS OF DIFFERENCES AND I THINK THAT YOUR CAREFULLY DELINEATED SUM OF THE RACIAL AND ETHNIC DIFFERENCES AS WELL AS OTHER DIFFERENCES RELATED TO HEALTHCARE DELIVERY EXOWB AND THE MANY FACTORS THAT RESULT IN A DIFFERENCE IN HEALTH DATA FOR MEN AND WOMEN, SO THANKS FOR HIGHLIGHTING THAT IN AN AREA THAT'S CLEARLY OF IMPORTANCE TO US ALL. OUR NEXT PRESENTER IS DR. SETO, AND WE ARE DELIGHTED TO HAVE HER HERE. DR. SETO IS THE DEPUTY DIRECTOR OF THE NATIONAL INSTITUTE OF BIOMEDICAL IMAGING AND BIOENGINEERING. THE TITLE IS "SEX AND GENDER CONSIDERATIONS IN DEVICES AND THERAPEUTICS." PLEASE WELCOME DR. SETO. [APPLAUSE] >> GOOD AFTERNOON. THANK YOU VERY MUCH. IT'S ALWAYS MY PLEASURE TO INTERACT WITH THE ORWH. IT'S ONE OF MY FAVORITE OFFICES, JUST TO SHOW MY PREFERENCE. NOT SURPRISINGLY FOR MY INSTITUTE, THE EXAMPLES THAT I'M GOING TO SHOW YOU WILL INVOLVE IMAGING DEVICES AND TECHNOLOGY. I'M GOING TO SHOW YOU TWO PROJECTS. THESE ARE BY NO MEANS ALL THAT WE CAN SHOW YOU, BUT GIVEN THE TIME ALLOWED, I WANT TO HIGHLIGHT TWO PROJECTS. THE FIRST ONE IS FOR THE VERY OBVIOUS REASON THAT ORWH ACTUALLY COFUNDS THIS PROJECT WITH US. WE'RE VERY, VERY PLEASED FOR THAT. AS MANY OF YOU KNOW -- BREAST CANCER DISEASES INVOLVE HORMONE RECEPTOR BINDING, AND RECEPTOR HORMONE BINDING IS INVOLVED IN, FOR EXAMPLE, OVARIAN CANCER, UTERINE CANCER, FOR EXAMPLE. THIS PROJECT INVOLVED DEVELOPING AN MRI PROBE THAT IS BASED ON ITS FINDING TO PROGESTERONE RECEPTOR. (BINDING) NOW THIS IS A PROJECT THAT IS ONGOING. BESIDES THE FACT THAT I'M PLEASED THAT IT'S A PROJECT THAT WE COFUND, LAST WEEK I WAS AT A MEETING AT MIM AIM JING IN 2020, A VISIONARY MEETING, THINKING FORWARD ABOUT WHAT EMANLING IMAGING SCIENCE WOULD BE LIKE IN 2020. I HAD THE GREAT PLEASURE OF MEETING THE INVESTIGATOR WHO IS DOING THIS PROJECT. SHE'S A GRADUATE STUDENT AND AFRICAN-AMERICAN YOUNG WOMAN, YOUNG CERTAINLY BY COMPARISON TO ME. SHE IS VERY ENERGETIC, VERY SMART, AND SO I WANT TO ASSURE JANINE THAT HER MONEY, HER OFFICE MONEY IS GOING TO GOOD USE SUPPORTING ONE OF THOSE VERY RARE SUBSET OF AFRICAN-AMERICAN ORGANIC SYNTHETIC CHEMISTS INVOLVED IN RADIAL CHEMISTRY, SO I ACTUALLY TOOK MY VIDEO COMMUNICATION PERSON WITH ME, WE INTERVOODVIEWED HER, WE WILL PROMINENTLY DISPLAY HER STORY. IT'S REALLY VERY EXCITING LOOKING AT THE NEXT GENERATION. SO I DIGRESSED. ON THE TOP HERE, YOU SEE A CHEMICAL STRUCTURE OF PROGESTERONE. THESE ARE THE KEYS TO THE DIAGRAMS HERE. PROGESTERONE IS SHOWN AS BLUE DOTS AND AS MANY OF YOU KNOW, PROGESTERONE RECEPTOR IS ASSOCIATED WITH PROTEIN, WHEN THEY ENTER THE SITE OF THE CELL MEMBRANE. BUT ONCE IT ENTERS, THE PROTEIN IS RELEASED. THIS IS THE HEAT SHOCK PROTEIN 90. THEN IT BINDS TO ANOTHER RECEPTOR WHICH THEN TOGETHER GO INTO THE -- GO THROUGH THE NUCLEAR MEMBRANE AND BIND TO THE DNA. SO ALREADY, YOU CAN SEE THAT THE POSSIBILITY OF USING THIS NOT ONLY TO VISUALIZE WHERE THE DNA -- THE CHANGES ARE, BUT ONE CAN ALSO USE THIS AS A VEHICLE TO DELIVER THERAPY. SO THE IMAGES IN THE INFINITE WISDOM HAVE COINED A TERM CALLED SARA NO. OSTICS, ALSO DELIVERING THERAPY. AGAIN BECAUSE AS YOU KNOW WITH MRI, YOU HAVE TO USE SOMETHING THAT SHOWS UP IN THE MAGNETIC FIELD, IN THIS CASE, IT'S GADOLINIUM, AND WHAT THIS YOUNG LADY, MS. TOWNSEND DID, WAS TO SYNTHESIZE THIS GADOLINIUM MOITY THROUGH BOTA 2 PROGESTERONE. THIS IS BY NO MEANS TRIVIAL, EVEN THOUGH IT LOOKS SIMPLE HERE. SHE ACTUALLY HAS TO DO THIS AND PURIFY THIS. BUT ULTIMATELY SHE WAS ABLE TO SUCCEED IN THAT, AND WHAT SHE PRODUCED HERE ACTUALLY HAS TENFOLD HIGHER SENSITIVITY THAN RU486 GADOLINIUM. SO SHE NOT ONLY MADE PROGESTERONE GADOLINIUM, SHE ALSO MADE RU486 GADOLINIUM AS A COMPARISON. ALL OF US IN THIS AUDIENCE, I ASSUME, KNOW RU486 IS THE MORNING AFTER DRUG. AND THAT'S WHAT SHE USED FOR COMPARISON. NOT ONLY DOES IT HAVE A GREATER AFFINITY FOR THE DNA, IT ALSO HAS HIGHER CELLULAR RETENTION FOR THOSE CELLS THAT ARE PROGESTERONE-REACCEP RECEPTOR POSITIVE. ALSO FOR MR IMAGING, IT HAS GREATER SIGNAL RETENTION. SO JUST TO SHOW YOU, TO ORIENT YOU, THIS IS -- THESE ARE TWO PICTURES OF MICE BEFORE INJECTING THE GADOLINIUM PROGESTERONE. THIS IS A VIEW LAYING THE MICE ON ITS BACK TO SHOW YOU THE ANATOMY, THE MEMORY FAT PAD, THE OVER REHERE, THE UTERUS HORN. I POINT THESE OUT BECAUSE IN THE NEXT PICTURE, YOU WILL SEE THE SIGNALS FROM WHEN WE VIEWED THIS IN THE OVARY AND THE UTERINE HORN. SO TWO HOURS AFTER INJECTION, AFTER THE INJECTION THE MICE -- NOW THESE ARE DIFFERENT MICE, THE PREVIOUS MICE HAVE BEEN DISSECTED. DIFFERENT MICE TWO HOURS AFTER INJECTION, THE MICE ARE ALLOWED TO ROAM AROUND. THESE ARE ALL DONE, THE IMAGING IS DONE IN THE IN VIVO MR MACHINE, IT HAS A VERY TIE KNOW -- TINY BORE. THE ENGINEERING IS JUST LIKE THE HUMAN MRI MACHINE, BUT AGAIN TO ORIENT YOU, HERE IS THE UTERINE BODY, HERE'S THE OVARY AND THE UTERINE HORN. SO WHEN SHE EXCISED THE OVARY IN THE TOP, THESE ARE THREE DIFFERENT OVARIES. IN THE TOP IS WITHOUT THE ENHANCER, WITHOUT THE GADOLINIUM. THIS IS ONE WITH THE GADOLINIUM, THIS IS TH THE CONTROL WITHOUT THE PROGESTERONE. YOU CAN SEE EVEN FOR THOSE OF US WHO AREN'T IMAGERS THAT THIS IS REALLY BRIGHTLY LIT UP. THIS IS THAT SAME PICTURE IN THE PREVIOUS PANEL THAT I ISOLATED. JUST TO REMIND YOU, GADOLINIUM LINKED THROUGH TO PROGESTERONE, AND YOU CAN SEE AGAIN THE CONTROL IN THIS PICTURE, THIS IS LOOKING AT THE UTERINE HORN HERE AND THIS IS LOOKING AT A CORONAL VIEW LOOKING BACK AT THE OVARIES IN THE SAME PANEL WITHOUT THE ENHANCER, WITH THE ENHANCER AND THE NEGATIVE CONTROL. SO ONE THING THAT WE WANT TO DO, AND I WANT TO POINT OUT TOO, THAT ALL IS NOT WELL JUST BECAUSE SHE SYNTHESIZED THIS, AND FOR IT TO BECOME AN INJECTABLE DRUG USED IN HUMANS, IT IDEALLY NEEDS TO BE WATER-SOLUBLE. AND THE GADOLINIUM PROGESTERONE IS NOT VERY SOLUBLE IN WATER. AND AS YOU CAN SEE IN THE PARTITION COEFFICIENT IN PRO GLO IS WHAT SHE CALLED IT, IT'S MUCH -- IT'S VERY HYDROPHOBIC, SO SHE WANTS TO MAKE A COMPONENT, MAKE THIS COMPOUND MUCH MORE HYDRO -- SOIC IN ORDER TO BE SOLUBLE IN CLINICAL USE. WHAT SHE DID WAS TO TAKE THE PROGLO, THE DRUG THAT SHE DEVELOPED, AND LINKED CONGREGATED TO NANODIAMOND. SO PART OF OUR INSTITUTE PORTFOLIO ALSO INCLUDES NANO TECHNOLOGY, USED NOW IN COMMERCIAL USE, NOT SO MUCH FOR CLINICAL USE, NOT SO MUCH FOR THERAPEUTICS, BUT SHE WAS ABLE TO SUCCESSFULLY LINK THIS TO THIS COMPOUND TO A NANODIAMOND AND LOOK AT WHEN SHE DID THAT, WHAT THIS NANODIAMOND, IT IMMEDIATELY -- NOT ONLY DID IT IMPROVE THE BRIGHTNESS IN TERMS OF IMAGING BY MR, IT ALSO IMPROVED ITS WATER SOLUBILITY. SO SHE'S REALLY MOVING IN THE RIGHT DIRECTION OF HAVING THIS BEING USED AS A -- NOT ONLY AS A DIAGNOSTIC THAT ONE CAN IMAGE BY MAG NE TMAGNETIC RESONANCE IMAGING BUT ALSO AS A WAY OF LINKING THIS TO FOR EXAMPLE, ONE CAN CONGREGATE RNA TO BE OF THERAPEUTIC USE. SO I'M REALLY EXCITED, SHE'S ALREADY DONE THE PRECLINICAL, THE NEXT THING IS TO DO FURTHER CHEMISTRY AND AS I SAID TO LINK THOSE TO OTHER EXAMPLES AND FURTHER TEST IT IN CLINICAL USE. ANY QUESTION WITH THAT? OKAY. SO SECOND PROJECT THAT I'M GOING TO TALK TO YOU ABOUT IS A CT TECHNOLOGY FOR BREAST CANCER IMAGING. AGAIN, THIS IS A PROJECT THAT WE ARE VERY PLEASED TO BE ABLE TO SUPPORT FOR A NUMBER OF YEARS NOW. JOHN BOON IS AT THE U.C. DAVIS MEDICAL SCHOOL, AS ALL OF US WHO HAVE REACHED A CERTAIN AGE, WE HAD MAMMOGRAPHY DONE. NOW FOR THE LAST 30 YEARS,, MAMMOGRAPHY HAS IMPROVED, NONETHELESS, WHAT WE ARE DOING IS TAKING THREE-DIMENSIONAL PICTURES OF THE BREAST AND YET COMPRESS THE DATA INTO TWO-DIMENSIONAL CELL. SO IMAGINE HOW MUCH DATA IS LOST THERE. AND FURTHERMORE, IF WE'RE LOOKING AT A VERY, VERY SMALL LEAGUES, SUCH AS 2-MILLIMETER, IN THAT COMPRESSION OF THE DATA, IN PROCESSING THREE-DIMENSIONAL DATA INTO TWO DIMENSIONAL DATA FILM, ONE COULD EASILY LOSE A DETECTION OF A SMALL LEAGUES SO THAT'S WHY WE SUPPORT THIS VERY IMPORTANT INTERESTING PROJECT TO USE CT, SO RIGHT OFF THE BAT, YOU MIGHT ASK, GEE, TWO YEARS AGO, I READ A LOT ABOUT RADIATION RISK, THE DOSE OF EXPOSURE TO RADIATION FROM CT. THIS INVESTIGATOR, JOHN BOON, IS VERY MINDFUL IN ALL OF HIS DEVELOPMENT TO USE THE CURRENT RADIATION DOSE THAT WOMEN GET FROM MAMMOGRAPHY AS THE GOLD STANDARD. HE WOULD NOT PUSH THE TECHNOLOGY SUCH THAT THE RADIATION DOSE EXPOSURE FROM HIS CT TECHNOLOGY WOULD BE GREATER, SO YOU'RE GETTING NO MORE RADIATION DOSE THAN YOU WOULD FROM MAMMOGRAPHY, AND YET A BETTER DETECTION. NOW, ULTIMATELY, I WOULD BE CANDID TO TELL YOU THAT THIS IS NOT -- THIS TECHNOLOGY IS NOT MEANT FOR MASS SCREENING AS MAMMOGRAPHY IS, BUT FOR THOSE WOMEN WHO MIGHT HAVE A SUSPICIOUS FIRST READ FROM MAMMOGRAPHY, AND YOU'RE CALLED IN FOR A CONFIRMATORY OR IN ALL OF HIS CASES, AND I'LL GO INTO DESCRIBING THE CLINICAL TRIALS THAT HE IS INVOLVED IN NOW, WOMEN, TWO MINUTES, A FEW MINUTES BEFORE THEY GET A BIOPSY, THEY UNDERGO THE CT TEST. SO THIS IS REALLY FOR THOSE WOMEN WHO HAS ALREADY GOT A SUSPICIOUS READ FROM THE MAMMOGRAPHY AND SUCH THAT THEY NEED TO GO IN FOR BIOPSY. THIS WOULD BE BASICALLY A CONFIRMATORY TECHNOLOGY. SO THERE ARE THREE OPERATING SYSTEMS. GOES FROM LEFT TO RIGHT IN TERMS OF TIME OF DEVELOPMENT. THIS WAS -- ALBION WAS DEVELOPED IN 2004 AND 2007, 2012. SO HE HAS THREE PROTOTYPES. NOW, THIS FIRST ONE, AS YOU CAN SEE, THE WOMAN IS LAYING IN A PRONE POSITION. THE IMAGING ACTUALLY HAS TWO CUPS THAT FIT THE BREAST, SO THE GANTRY IS REVOLVED AROUND THE BREAST AREA ONCE. THE X-RAY TUBE, IN THIS BOTTOM HERE, YOU CAN SEE THERE IS A FLAT SCREEN DETECTOR. THE X-RAY TUBE IN THIS FIRST PROTOTYPE IS ABOUT 640 WATTS. HE THEN DEVELOPED A SECOND PROTOTYPE THAT HAS HIGHER WATTAGE, MORE POWER IS ABOUT A THOUSAND, AND IT'S ALSO LARGER SO THAT FOR THE RADIOLOGY TECHNICIAN, HE OR SHE CAN ACTUALLY STEP IN THIS. THIS IS RATHER DIFFICULT, IT'S VERY TIGHT QUARTER FOR THE TECHNICIAN TO GET INTO, BUT NONETHELESS, WITH THAT, HE WAS ABLE TO SCAN ABOUT ALMOST 400 PATIENTS IN THIS. ALL OF THESE PROTOTYPES HAVE BEEN UNDERGOING CLINICAL TESTING IN U.C. DAVIS AROUND THE SACRAMENTO MEDICAL SCHOOL AREA. AND SO 180 PATIENTS HAVE BEEN SCANNED USING THE SECOND ONE. THIS IS THE LATEST DEVELOPMENT. AND WHAT'S NEW ABOUT THIS IS THAT ALTHOUGH ONLY 10 PATIENTS HAVE BEEN SCANNED, HE CONTINUES TO RECRUIT PATIENTS FOR THIS. WHAT'S DIFFERENT ABOUT THE THIRD ONE IS THAT ONE CAN ACTUALLY DO IMAGE-GUIDED INTERVENTION WITH THIS MACHINE. SO IN OTHER WORDS, A PATIENT IS SCANNED AND YOU CAN ACTUALLY DO RESECTIONS, SO IT'S DESIGNED WITH ENOUGH ROOM AND USABILITY TO DO IMAGE GUIDED INTERVENTION. NOW FOR THOSE WHO ARE NOT FAMILIAR WITH THIS, IT'S NOTHING MORE IMPORTANT TO KNOW EXACTLY WHERE TO RESECT FOR THE SURGEON. THE SURGEON IS LOOKING AT THE IMAGE AND IS GUIDED BY THE IMAGE TO DO THE SURGERY, SO NONE OF US HAVE MORE TISSUE THAN WE CAN SPARE, SO YOU WANT TO MAKE SURE THAT THE SURGEON RESECTS AND CUTS OUT ONLY WHAT NEEDS TO BE CUT OUT, INDICATED BY THE CT SCAN PICTURES. SO THAT GOES TO SHOW YOU, THIS IS A COLLAGE OF DIFFERENT BREAST IMAGES, CLINICAL IMAGES. THE BOTTOM ROWS ARE CORONAL VIEWS, THESE ARE ALL SAGITTAL VIEWS. WHAT IS MOST IMPORTANT IS TO RECOGNIZE THAT BREAST TISSUES DIFFER FROM WOMAN TO WOMAN, ESPECIALLY FOR PREMENOPAUSAL YOUNG WOMEN, THEIR FIBRO GRANULAR TISSUES ARE HIGHER AND OFTENTIMES MAMMOGRAPHY CANNOT PICK UP LESIONS EASILY. CT, HOWEVER, IS SUCH THAT THEY CAN PICK OUT EVEN VERY SMALL LESIONS. THE PREVIOUS PICTURES, ALL OF THESE ARE WITHOUT ANY CONTRAST. SO YOU CAN IMAGINE IF YOU USE A CONTRAST AGENT, IT'S LIKE YOUR EVERYDAY PHOTOGRAPHY, IF YOU COULD SUPPRESS THE BACKGROUND, YOU CAN SEE THE SIGNAL HIGHER. WITH THE CONTRAST IN THE TOP ROW, YOU CAN SEE THE LESIONS VERY CLEARLY. WHAT PET DOES ARE THESE COLOR CODES, AND WHAT PET DOES IS TO SHOW THOSE CELLS THAT HAVE HIGHER METABOLISM FOR GLUCOSE, SO FTG PAD, THE UPTAKE SHOWS THESE RE CELLS ARE METABOLIZING HIGHER. WE ALL KNOW CANCER CELLS METABOLIZE HIGHER, AT A NORMAL RATE THAN NORMAL CELLS. WHAT HE DID IS TO OVERLAY THE PET PICTURES, THESE COLORED LESIONS, OVER THE GRAY, BLACK AND WHITE CT PICTURES. AND SO THIS IS A CASE OF A WOMAN, YOU CAN SEE WITH MULTIPLE LESIONS. CLINICAL RESULTS IN A PUBLICATION THAT JOHN BOONE PUBLISHED IN 2008 SHOW THAT THE BREAST CT CAN DETECT LESIONS BETTER, HOWEVER, IT IS NO BETTER THAN MAMMOGRAPHY. IN FACT, MAMMOGRAPHY IS BETTER PICKING UP MICROCALCIFICATION. SO WHATEVER THE TECHNOLOGY IS, ONE HAS TO RECOGNIZE ITS STRENGTH AND WEAKNESSES AND NOT ASSUME THAT IT IS A PANACEA FOR EVERYTHING. IN ANOTHER, HE CONFIRMS IN A PUBLICATION IN 201 2010 WITH CONTRAST ENHANCED BREAST CT IMAGING, IT'S STILL MUCH BETTER THAN MAMMOGRAPHY IN PICKING UP LESIONS. HOWEVER, IT IS NOT AS GOOD AS MAMMOGRAPHY WITH MICROCALCIFICATION. SO WITH THAT, I THANK YOU FOR YOUR ATTENTION. I THINK I STAYED WITHIN TIME. [APPLAUSE] >> THANK YOU, DR. SETO, FOR TRANSLATING NOW INTO SOME MORE APPLICATIONS AREA AND GIVING US A WHIRLWIND VIEW THERE OF SEVERAL IMAGING TECHNIQUES STWELS SWELS THASWELL AS THE BACKGROUND FO R SEX AND GENDER INFORMING THE FUTURE AND MAKING -- AND ITS RELEVANCE FOR DEVICES. THE NEXT PRESENTER IS DR. SUSAN TAMENS, PROGRAM DIRECTOR FOR REPRODUCTIVE JE TICS AND EPIGENETICS AT THE KENNEDY SHRIVER INSTITUTE. >> THANK YOU. [APPLAUSE] >> THANK YOU TO THE ORGANIZERS FOR INVITING ME HERE TODAY. THIS IS AN ENORMOUS TOPIC. I'M GOING TO TRY TO LEAVE YOU WITH TWO OR THREE KEY POINTS AND KIND OF A BROAD SURVEY. I WANTED TO START BY WITH THE BEGINNING OF GENERAL DIR DISPARITY, YOU GUYS MIGHT RECOGNIZE THESE TWO GENTLEMEN AS JAMES WATSON AND FRANCIS CHARACTERISTIC, THEY WERE GIVEN A NOBLE PRIZE IN 1962 FOR THEIR DISCOVERY OF THE DOUBLE HELICAL STRUCTURE OF DNA. THERE WAS ALSO A KEY WOMAN INVOLVED, DR. ROSALYN FRANKLIN, THE WOMAN WHO PRODUCED THE X-RAY CRYSTALOGRAPHY IMAGES THAT DROVE THE SUBSEQUENT BUILDING OF THE DOUBLE HELICAL MODEL, SO I JUST WANTED TO TAKE A SECOND TO RECTIFY THAT HISTORICAL OVERSIGHT AND GIVE DR. FRANKLIN HER DUE. IN LOOKING AT MEN AND WOMEN, CLEARLY WE LOOK VERY DIFFERENT. BUT WHAT DOES THAT TRANSLATE TO DOWN AT THE LEVEL OF A GENOME? THERE ARE 24 PAIRS OF CHROME ZONES IN THE HUMAN GENOME. 23 ARE IDENTICAL IN MEN AND WOMEN. THE DIFFERENCE LIES IN THE 24TH PAIR, MEN HAVE AN XY SEX CHROMOSOME COMPLEMENT AND WOMEN HAVE AN XX SEX CHROMOSOME COMPLEMENT. SO HERE YOU SEE THE X CHROMOSOME THAT'S IN COMMON BETWEEN THE TWO SEXES AND HERE IS THE LITTLE BITTY Y THAT IS ONLY FOUND IN MEN. SO WHEN HEAR THERE'S ONE WHOLE CHROME ZONE DIFFERENT BETWEEN THE SEXES YOU MIGHT THINK THAT'S AN ENORMOUS DIFFERENCE, BUT LET'S TAKE A LITTLE BIT OF A CLOSER LOOK, HOW DIFFERENT ARE THESE GENOMES REALLY? THE Y CHROMOSOME IS VERY SMALL. THAT ENCODES ABOUT 23 PROTEINS. 95% OF THE GENES ON THE Y CHROMOSOME ARE COMPLETELY SPECIFIC TO MEN MOSTLY INVOLVED IN FORMING THE TESTES. FEMALES HAVE TWO X CHROMOSOMES. THE ONLY DIFFERENCE IS THE FEMALE HAS TWO. THE X CHROMOSOME IS LARGER, IT'S ABOUT 155 MILLION BASE PAIRS WORTH OF INFORMATION. THAT INCLUDES ABOUT 800 PROTEINS. SO THE DIFFERENCE HERE IS THAT IN THEORY, WOMEN HAVE A DOUBLE DOSAGE OF ANY GENE THAT OCCURS ON THE X CHROMOSOME. BUT IN ACTUALITY, MOST OF THAT SECOND X CHROMOSOME ISN'T ACTIVATED WITHIN THE CELL. MOST OF THAT INFORMATION IS SUPPRESSED IN WHAT'S CALLED DOSE SAJ COMPENSATION SO FOR THE MOST PART, THE INFORMATION COMING OFF THE X CHROMOSOME IS EQUAL BETWEEN MEN AND WOMEN. SO IN ADDITION TO THAT, EVEN THOUGH THE X AND Y CHROMOSOMES ARE VERY DIFFERENT, THEY HAVE TWO LARGE RENALES OF HEMOLOGY. GREEN ON THE X AND ON THE Y, PSEUDOAUTOSOMAL REGIONS. THEY ALLOW THE DIFFERENT CHROMOSOMES, THE X AND THE Y, TO PAIR AT MYOSIS. IS OVERALL, GIVEN THAT THE Y IS SMALL, GIVEN THAT THE SECOND COPY OF THE X IS PRETTY MUCH SUPPRESSED AND THAT THERE ARE REGIONS OF HEMOLOGY BETWEEN THE TWO CHROMOSOMES, OVER ALL THE XX AND THE XY GENOMES ARE VERY, VERY SIMILAR. THERE'S ABOUT A 2% DIFFERENCE OVERALL. SO CONSIDERING THAT, WHY DO WE END UP LOOKING AND BEHAVING SO DIFFERENTLY? WELL, I'D LIKE TO TELL YOU IN THE BEGINNING, WE'RE REALLY NOT VERY DIFFERENT. UP UNTIL ABOUT THE TENTH WEEK OF GESTATION, BOTH XX AND XY FETUSES ARE IDENTICAL. YOU CAN'T TELL THEM APART. THEY BOTH HAVE TWO BI POTENTIAL GOA IGONADS, TWO SETS OF PLUMBING, THERE'S A FEMALE AND A MALE SET IN ALL BABIES. ONE WILL GO ON TO DEVELOP AND THE OTHER WILL REGRESS. THE DIFFERENCE IS THAT IN AN XY FETUS, THE Y CHROMOSOME EXPRESSES A FACTOR CALLED SRY, ONLY FOUND ON THE Y CHROMOSOME. ONCE IT'S EXPRESSED, IT STARTS DRIVING THIS MALE DIFFERENTIATION PATHWAY SO THAT THE INDIFFERENT GONAD DEVELOPS INTO A TESTES. IN THE XX FETUS, THERE IS NO SRY AND IN THE ABSENCE OF THAT FACTOR, A FEMALE DIFFERENTIATION PATHWAY IS DRIVEN SO THAT THE INDIFFERENT GONAD DEVELOPS INTO AN OVARY. THERE ARE ALL KINDS OF PERMUTATIONS TO THIS PROCESS. I'VE MADE IT MUCH MORE STRAIGHTFORWARD THAN IT REALLY IS. YOU CAN GET CASES WHERE THE GENO TYPE AND THE PHENOTYPE DON'T MATCH. I DON'T WANT TO GO DOWN THAT ROAD, SO WHEN I'M TALKING FEMALE FOR THE REST OF THIS TALK, I MEAN XX, WHEN I'M TALKING MALE, I MEAN X WHY XY. I REALLY SHOULD HAVE TITLED THIS DIFFERENTLY BECAUSE I AM TALKING ABOUT BIOLOGICAL SEX AS A BIOLOGICAL PHENOMENON, NOT GENDER AS A SOCIAL PHENOMENON. SO TWO PROCESSES GOING ON HERE. YOU HAVE THE GENOMICALYY DETERMINED -- THE XX OR XY DICTATES THE PATH OF SEX DETERMINATION, WHETHER THE FETUS IS GOING TO DEVELOP TESTES OR OVARIES. ONCE THE GONADS ARE ESTABLISHED, THEY PRODUCE SEX-SPECIFIC HORMONES. THE HORMONES THEN ACT THROUGH THEIR NUCLEAR RECEPTORS TO TRIGGER EXPRESSION OF MANY, MANY HORMONE-SENSITIVE GENES IN A SEX-SPECIFIC MANNER. SO IT'S ACTUALLY THE EXPRESSION OF THE SEX HORMONE MOANS THAT CAUSES SEX DIFFERENTIATION, WHAT MAKES MEN AND WOMEN LOOK DIFFERENT. SO ONE OF THE THINGS THAT DIFFERENTIATES THE SEXES ARE DIFFERENCES IN RISK FOR VARIOUS DISEASES. I'VE JUST LISTED A FEW OF THEM AS COMMON DISEASES, THE DISEASES THAT HAVE THE GREATEST DISPARITY BETWEEN MALES AND FEMALES, SO AS DR. COOKE TOLD US, THERE'S CARDIOVASCULAR DISEASE ON THIS LIST, AUTOIMMUNE DISORDERS, OSTEOPOROSIS, DIABETES, OBESITY, IF YOU'RE REALLY ON TOP OF IT, YOU'VE PROBABLY ALREADY REALIZED THAT MANY OF THESE DISORDERS HAVE STRONG LINKS TO HORMONES AND MORE SPECIFICALLY SEX HORMONES. WE'RE GOING TO TAKE A LOOK HERE AT ONE SPECIFIC EXAMPLE, I DO MEAN BIOLOGICAL SEX DIFFERENCE IN THE RISK FOR LIVER CANCER. IT'S MORE COMMON IN MEN AND THAT'S BECAUSE ESTROGEN EXERTS A PROTECTIVE EFFECT AGAINST THE DEVELOP M OF THE LIVER CANCER. THESE DIFFERENTIAL HORMONE EFFECTS ARE MEDIATED THROUGH A TRANSCRIPTION FACTOR CALLED FOX A1/2 SO IF YOU TAKE A MOUSE AND DELETE THIS FOX A1/2 GENE, SUDDENLY THIS SEX RATIO FLIP-FLOPS TO WHERE FEMALES BECOME MUCH MORE SUSCEPTIBLE TO LIVER CANCER AND MALES BECOME PROTECTED FROM LIVER CANCER. THAT'S BECAUSE THIS ACTS AS A BINDING FACTOR FOR THE HORMONE RECEPTORS, SO ONCE YOU ABLATE THIS BINDING FACTOR, THE HORMONES ARE TAKEN OUT OF THE EQUATION. THIS WAS DONE IN MICE BUT THERE WAS ALSO A STUDY WHERE THESE SAME INVESTIGATORS LOOKED AT THE ACTUAL TUMOR TISSUE FROM WOMEN. THEY FOUND WOMEN WHO HAVE LIVER CANCER ARE MUCH MORE LIKELY TO HAVE THESE VERY SMALL GENETIC DIFFERENCES, NOT IN FOX A1/2 BUT IN THE PLACES WHERE IT BINDS ON THE GENOME. THESE DIFFERENCES MAKE IT DOESN'T BIND AS WELL ANYMORE AND IT KIND OF NEGATES THE HORMONAL EFFECT. SO THESE ARE DIFFERENCES IN THE GENOMES, NOT NECESSARILY IN A PLACE ENCODING THE GENE, NOT A PLACE AN INVESTIGATOR WOULD NECESSARILY THINK TO LOOK THAT CAN MAKE HUGE DIFFERENCES IN THE JGENDER RESPONSE TO A PARTICULAR GENETIC CHANGE. SO SWITCHING GEARS A LITTLE BIT. MOST OF THE GENETIC STUDIES AREN'T DONE ON A GENE BY GENE BASIS. YOU LOOK AT THE ENTIRE GENOME AS A WHOLE AND STUDIES THAT ARE CALLED GENOME WIDE ASSOCIATION STUDIES OR GWAS STUDIES. THIS IS A WAY TO LOOK AT THE WHOLE GENOME ACROSS A COHORT OF INDIVIDUALS WHO ARE AFFECTED AND COMPARE IT TO THE SAME INFORMATION IN INDIVIDUALS THAT ARE UNAFFECTED BY A PARTICULAR DISEASE. SO YOU'RE SURVEYING FOR VERY SMALL EFFECTS, YOU'RE MAKING SO MANY THOUSANDS OF COMPARISONS, YOU REALLY NEED HUGE NUMBERS OF INDIVIDUALS TO FIND A DIFFERENCE THAT'S STATISTICALLY SIGNIFICANT. SO THAT REQUIREMENT FOR REALLY LARGE COHORTS, ABOUT 5,000 OR SO AT LEAST, HAS DRIVEN A SCIENCE TO WHERE UNFORTUNATELY A LOT OF TIMES THESE STUDIES DON'T SEPARATELY LOOK AT MEN AND WOMEN WOMEN. WE KNOW THIS IS A PROBLEM BECAUSE WE KNOW SOME DISEASES ARE MORE PREVALENT IN ONE GENDER THAN THE OTHER. IF YOUR CASES AND CONTROLS AREN'T BALANCED BY GENDER, YOU CAN MISS RESULTS THAT YOU OUGHT TO HAVE SEEN IN ONE GENDER, YOU CAN WASH OUT EFFECTS THAT YOU OUGHT TO HAVE SEEN IN ONE GENDER AND YOU CAN GET FALSE POSITIVES THAT DON'T REALLY APPLY. IN ADDITION TO GENDER, WE KNOW DISEASE CAN OF COURSE VARY BY GENDER. WE KNOW THE INCIDENCE OF, SAY, CARDIOVASCULAR DISEASE INCREASES BY AGE, SO NOT ONLY DO YOU HAVE TO STRATIFY BY GENDER, YOU HAVE TO WITHIN THE GENDER TAKE INTO ACCOUNT CHANGES THAT OCCUR OVER AGE AND BALANCE YOUR COHORTS ON THAT AS WELL. THEN AS THE PREVIOUS SLIDE I SHOWED YOU ON LIVER CANCER SHOWED, WE KNOW THE SAME ALEAL CAN HAVE DIFFERENT EFFECTS IN MEN AND WOMEN. ALSO IN THE MAGNITUDE OF THE EFFECT, IF YOU'RE A WOMAN, MAYBE THIS CHANGE DOESN'T REALLY PREDISPOSE YOU TO THE DISEASE BUT IF YOU'RE A MAN, THE SAME CHANGE CAN MULTIPLY YOUR RISK. SO THE GOOD NEWS IS THAT RECENTLY PEOPLE HAVE STARTED TO LOOK FOR SEX DIFFERENCES WITHIN GWAS DATA AND THERE HAVE BEEN SOME RECENT REPORTS ON GENDER DIFFERENCES IN GWAS, FAT DISTRIBUTION, CROHN'S DISEASE OR BONE MINERAL DENSITY. A LOT OF THESE STUDIES WERE UNABLE TO REPLICATE THEIR DATA AND INDEPENDENT COHORTS, AND MOST OF THESE STUDIES DIDN'T CHECK THE SIGNIFICANCE OF THE SEX DIFFERENCE STATISTIC, SO AGAIN, WHEN YOU'RE MAKING THESE THOUSANDS OF COMPARISONS, YOU NEED TO RULE OUT THE POSSIBILITY THAT THERE'S A FALSE POSITIVE. MORE GOOD NEWS. SOME STUDIES RECENTLY HAVE PUBLISHED STATISTICAL METHODS THAT DO ALLOW RESEARCHERS TO RIGOROUSLY ANALYZE THEIR GWAS DATA BY GENDER. I'M NOT A STATISTICIAN, I CAN'T UNDERSTAND OR EXPLAIN THESE MODELS, THIS IS JUST TO LET YOU KNOW THEY'RE OUT THERE AND THEY'RE IN USE. FOR THESE MODELS TO BE USEFUL, FOR THESE METHODS TO BE USEFUL, THEY HAVE TO MAINTAIN THE POWER TO FIND VERY SMALL EFFECTS, THEY HAVE TO BE ABLE TO DETECT DIFFERENCES IN BOTH THE DIRECTION OF EFFECTS AND IN THE MAGNITUDE OF EFFECTS BY GENDER. SO SO FAR I'VE BEEN TALKING TO YOU ABOUT THE NUCLEAR GENOME, BUT THERE IS ANOTHER LEVEL OF COMPLEXITY IN THAT THAT'S NOT THE ONLY GENOME WITHIN OUR CELLS. EVERY CELL HAS A MY TOE CON DREE A AND IT HAS ITS OWN GENOME THAT'S SEPARATE AND DISTINCT FROM THE NUCLEAR GENOME. IT'S PASSED ONLY THROUGH THE MATERNAL LINE. ONLY WOMEN CAN PASS THEIR MITOCHONDRIA ON TO THEIR CHILDREN. MEN NEVER DO. THAT MEANS IF A WOMAN CARRY AS MUTATION, THERE ARE SEVERAL DISEASES THAT ARE CAUSED, IF A WOMAN CARRIES ONE OF THOSE, SHE'S GOING TO PASS IT TO HER CHILDREN, ONLY SHE CAN PASS IT TO HER CHILDREN. SHE'S GOING TO PASS IT TO ALL HER CHILDREN. HER SONS AND HER DAUGHTERS. IN ADDITION TO THAT, BECAUSE THERE'S NO SELECTION PRESSURE ON A MALE LINE, THERE'S NO SELECTION PRESSURE, THAT MEES THAT THERE'S A GENDER DISPARITY THERE AS WELL. WEE VERY PROGRAMMED TO THINK IN TERMS OF GENETICS BUT I'D ENCOURAGE YOU TO THINK OF THE GENOME AS LIKE A HARD DRIVE ON THE COMPUTER, AND IT'S REALLY THE SOFT CARE THA SOFTWARE THAT DOES THE W ORK. THE SOFTWARE OF THE GENOME IS CALLED THE EPIGENOME. THESE ARE MARKS THAT KIND OF SIT ON TOP OF THE GENOME LIKE MARKS ON DNA OR MARKS ON THE PROTEINS THAT WRAP UP THE DNA, THAT CHANGE THE DNA STRUCTURE. NOT AT SEQUENCE BUT ITS ACTUAL STRUCTURE. THESE MARKS CAN BE PASSED DURING CELL DIVISION, THEY CAN ALSO BE PASSED FROM GENERATION TO GENERATION. THESE MARKS AFFECT HOW GENES ARE EXPRESSED, WHAT TISSUES THEY'RE EXPRESSED IN, WHEN THEY'RE EXPRESSED, WHAT LEVEL THEY'RE EXPRESSED TO. THESE MARKS ARE RESPONSIVE TO ENVIRONMENTAL QUEUES. A MAJOR ONE BEING THE SEX HORMONE MILIEU. SO WE KNOW THERE ARE GENDER DIFFERENCES IN SOME OF THESE MARKS ASSOCIATED WITH A PARTICULAR DISEASE ASSOCIATED GENES BUT UNFORTUNATELY AGAIN, OVERALL, GENDER DIFFERENCES IN EPIGENETIC ANALYSES ARE NOT PERFORMED. AS FAR AS I KNOW TO DATE, THERE HAS BEEN NO GLOBAL SURVEY OF MALE VERSUS FEMALE EPIGENOMES. I DO NEED TO CUT THIS FIELD A BIT OF A BREAK BECAUSE UNLIKE THE A GENOME, WHICH IS ONE AND IT'S PRETTY STATIC, THERE ARE THOUSANDS OF EPIGENOMES BECAUSE EACH CELL EXPRESSES A DIFFERENT EPI GENOME AS EACH ONE OVER TIME, RESPONDING TO ITS ENVIRONMENT, WILL CHANGE THAT EPIGENOME. SO YOU'RE LOOKING AT A PARTICULAR SNAPSHOT IN TIME. THIS SLIDE IS JUST TO GIVE YOU AN IDEA WHEN I SAY THERE ARE SEX DIFFERENCES IN EXPRESSION LEVEL OF GENE, KIND OF THE MAGNITUDE OF WHAT I'M TALKING ABOUT. THESE ARE DIFFERENT HUMAN TISSUES, AND THIS MARK UP THE MIDDLE WOULD REPRESENT IF ALL THE GENES WERE EQUIVALENTLY EXPRESSED IN MEN AND WOMEN, THE PA TESH WOULD FALL ALONG HERE. THERE'S VERY LITTLE GENDER DIFFERENCE IN GENE EXPRESS, BUT IF YOU LOOK IN HYPOTHALAMUS OR IN MUSCLE, YOU CAN SEE THAT THERE ARE SOME GENES THAT ARE MUCH MORE STRONGLY EXPRESSED IN MALES THAN FEMALES AND SOME THE OPPOSITE. SO THIS IS PRETTY SIGNIFICANT DIFFERENCE IN SOME CELL TYPES AND IT CAN HAVE A PRETTY SIGNIFICANT EFFECT ON DISEASE. I AM WINDING UP. SO TO KIND OF SU SUMMARIZE THE CAUSE OF GENDER DIFFERENCES IN HEALTH, WE KNOW SOME GENETIC CONDITIONS AFFECT PRIMARILY ONE SEX LIKE X LINKED DISEASES THAT AFFECT PRIMARILY MALES BECAUSE THEY ONLY CARRY ONE COPY OF THE X CHROMOSOME. SOME DISEASES CAN ONLY BE PASSED THROUGH EITHER THE MATERNAL OR PATERNAL LINE, LIKE AN IMPRINTING DISEASE THAT WE DIDN'T DISCUSS TODAY CALLED ANGELMAN'S SYNDROME, OR LIKE A MITOCHONDRIAL DISEASE WHICH WE KNOW ONLY CAN BE PASSED FROM THE MOTHER. LIVER CANCER SHOWS US THE EXACT SAME ALLELE CAN HAVE DIFFERENT DOWNSTREAM EFFECTS IN MEN VERSUS WOMEN IN THE DIRECTION AND MAGNITUDE OF THE EFFECT. WE KNOW THERE CAN BE DIFFERENT SUSCEPTIBILITIES TO DISEASE BASED ON GENE BY GENDER INTERACTIONS AND ALSO GENDER BY ENVIRONMENT INTERACTIONS. AND FINALLY, WE KNOW THAT THE MITOCHON DMENT RIAL GENOME CAN ALSO PLAY INTO GENDER DIFFERENCES AND SUSCEPTIBILITY. I WANT TO LEAVE YOU WITH TWO MAJOR POINTS. THE GREATEST DIFFERENCE BETWEEN THE GENDERS IS NOT THE GENOME ITSELF, BUT RATHER WHEN, WHERE AND TO WHAT EXTENT THE GENES ARE ACTUALLY EXPRESSED. WHEN SCIENTISTS ARE DESIGNING GENETIC AND EPI J GENETIC STUDY, THEY NEED TO ROUTINELY CONSIDER GENDER AS A SOURCE OF VARIATION, DESIGN STUDIES TO TAKE THAT INTO ACCOUNT AND DISCOVER AND ADJUST FOR GENDER DIFFERENCES. THANK YOU VERY MUCH. [APPLAUSE] >> THANK YOU, DR. TAYMENS. WE'RE NOT THAT DIFFERENT, HUH? I DON'T KNOW ABOUT THAT. WE'RE LEARNING MORE AND MORE HOW DIFFERENT WE ARE, AND IF THERE ARE ALL THOSE EPID GENOMES, THERE'S ANOTHER OPPORTUNITY FOR US TO BE REALLY, REALLY DIFFERENT. WE'LL HAVE A TALK LATER THAT WILL MENTION SOME OF THE STA STATISTICAL CONCERNS THAT YOU TALKED ABOUT. BUT THANKS FOR THAT VERY, VERY INTERESTING PRESENTATION. PLEASE HELP ME WELCOME TO THE PODIUM OUR NEXT PRESENTER, AND THAT IS DR. WEATHERINGTON, THE NATIONAL INSTITUTE OF DRUG ABUSE'S WOMEN AND SEX AND GENDER DIFFERENCES RESEARCH COORDINATOR. AND THE TITLE OF HER PRESENTATION IS "SEX AND GENDER DIFFERENCES IN PAIN." [APPLAUSE] >> THANK YOU, JANINE. SO TAGGING ON TO SOME OTHER COMMENTS ABOUT SEX VERSUS GENDER, MY TALK COULD EASILY HAVE BEEN SEX/GENDER, BUT AS WE MOVE ALONG, WE'LL SEE THAT IT'S OFTEN DIFFICULT TO MAKE THAT DISTINCTION BETWEEN WHETHER AN OUTCOME IS DUE TO SEX OR GENDER. SO MOST OF MY TALK FOR CONVENIENCE WILL USE THE WORD "SEX" TO GENERICALLY REFER TO MALE-FEMALE DIFFERENCES. SOME OF THE TOPICS THAT I'LL BE ADDRESSING ARE WHO'S MORE SENSITIVE TO PAIN, IS IT MEN OR IS IT WOMEN, WHAT ARE SOME OF THE FACTORS THAT AFFECT INDIVIDUAL DIFFERENCES AND PAIN SENSITIVITY, WHO RESPONDS BETTER TO WHAT TREATMENT OF PAIN, IS IT MEN, IS IT WOMEN, AND AS WE MOVE AL, WE'LL B ALONG, WE'LL BE HIGHLIGHTING PROGRESS THAT HAS BEEN MADE IN THE EXPERIMENTAL AND CLINICAL RESEARCH. IDENTIFYING RESEARCH GAPS AS WELL AS NEW DIRECTIONS. SO FIRST OF ALL, WHO IS MORE SENSITIVE TO PAIN, IS IT MEN OR WOMEN. AS YOU CAN SEE HERE IN THIS CARTOON, WHEN A DOCTOR, WHEN A PHYSICIAN WAS ASKED THIS QUESTION, HE SAYS, WELL, LET ME PUT IT THIS WAY, IF FATHERS GAVE BIRTH, YOU'D BE AN ONLY CHILD. SO THAT'S AN ANSWER FROM THE CARTOONIST. LET'S SEE WHAT CLINICAL RESEARCH HAS TO SAY FOR THAT QUESTION. THE ANSWER IS THAT PAIN DISORDERS ARE MORE PRE PREVALENT IN WOMEN. THIS CAN BE SEEN IN A TABLE WHICH IS LIKELY REFERRED TO IN THE LITERATURE AS THE BERKELEY LIST. THIS WAS PUBLISHED IN 1997 BY KAREN BERKELEY. YOU PROBABLY -- YOU MAY OR MAY NOT BE ABLE TO READ ALL OF THOSE CONDITIONS, BUT THE MAIN POINT IS THAT THE LIST FOR FEMALE PREVALENCE IS THE LONGEST LIST OF THE THREE. LONGER THAN MALE PREVALENCE AND LONGER THAN PREVALENCE OF DES ORDERDISORDERS FOR WHICH THERE'S NO SEX PREVALENCE. IN THE NEXT FEW SLIDES THAT YOU'RE GOING TO SEE, YOU'LL SEE THAT THE DEGREE OF SEX BIAS IN THE PREVALENCE OF PAIN DISORDERS VARIES OVER THE LIFESPAN. HERE IS THE PREVALENCE OF TEMPOROMANDIBULAR PAIN, AN INVERTED U SHAPED FUNCTION OF AGE. IT'S MORE PREVALENT IN FEMALES THAN IT IS IN MALES. THE DISPARITY IS GREATEST IN THE MIDDLE YEARS AND DECLINING WITH AGE. MIGRAINE HEADACHES, AGAIN AN INVERTED U-SHAPED FUNCTION, GREATER PREF LABS I PREVALENCE IN FEMALES, GREATER DISPARITY IN THE PEAK OF THE DISTRIBUTION AND DECLINES WITH AGE. CLUSTER HEADACHES ARE MOVE MORE PREVALENT IN MALES, INVERTED U-SHAPED FUNCTION, GREATEST DISPARITY IN THE 20s, AND IN THE 60s, THE DISPARITY DISAPPEARS. MID ABDOMINAL PAIN, NOT MENSTRUAL PAIN, THE PREVALENCE IS GREATER FOR FEMALES THAN FOR MALES. THIS DECLINES OVER THE YEARS WITH THE DISPARITY BEING APPROXIMATELY CONSTANT. NEXT SHOULDER PAIN INCREASES WITH AIRNLINGS GREATER IN FEMALES THAN IN MALE, AND THE DISPARITY BEING RELATIVELY CONSTANT. FINGER JOINT PAIN. THIS IS AN INTERESTING ONE. IN THE VERY EARLY YEARS, THERE'S NO SEX DIFFERENCE OR MAYBE A SLIGHT BIAS FOR MALES. INCREASES WITH AGE, ESPECIALLY FOR FEMALES, BUT FOR MALES IT LEVELS OFF. THE PREVALENCE OF THREE OR MORE OF FIVE PAIN COMPLAINTS LISTED THERE IN THE BOTTOM OF THE SLIDE IS GREATER FOR FEMALES THAN IT IS FOR MALES, BUT BY AGE 65, THE DISPARITY HAS DISAPPEARED. NOW WHAT ABOUT PAIN INTENSITY SCORES? IS THERE A SEX DIFFERENCE THERE? DATA FROM A STUDY PUBLISHED EARLIER THIS YEAR FINDS THAT THERE IS. THIS LISTS DATA FROM A HUGE DATABASE,S IT WAS THE ELECTRONIC MEDICAL RECORDS. FOR DATA ANALYSIS, THEY USED ICD9 DISEASE SECTIONS THAT HAD A MINIMUM OF 41 PATIENT ENCOUNTERS FOR BOTH MALES AND FEMALES, AND THIS WAS FOR PURPOSES OF STATISTICAL POWER. THAT ANALYSIS OR RATHER THAT CRY CRITERION RESULTED IN 47 DISEASE SECTIONS. 14 OF WHICH, THAT'S 30%, SHOWED A SEX DIFFERENCE. AND IT WAS ALWAYS IN THE DIRECTION OF FEMALES HAVING HIGHER INTENSITY SCORES THAN MALES. THERE WERE EIGHT MUSCULOSKELETAL DISEASE SYSTEM DISORDERS THAT WERE IDENTIFIED AS WELL AS ESSENTIAL HYPERTENSION, ACUTE SINUSITIS, AND H.I.V. SO THE STUDIES SHOW THE PAIN DISORDERS ARE MORE PREVALENT IN WOMEN THAN IN MEN AND HIGHER PAIN SEVERITY -- THAT HIGHER PAIN SEVERITY IS MORE PREVALENT IN WOMEN THAN IT IS IN MEN. NOW LET'S TURN TO EXPERIMENTAL STUDIES FOR ANSWERS TO THIS QUESTION. THE ANIMAL STUDIES ROUTINELY SHOW THAT FEMALES ARE MORE SENSITIVE. IN THE HUMAN STUDIES, AND THIS HAS BEEN LOOKED AT FOR A NUMBER OF YEARS NOW, AND THERE'S HISTORICALLY BEEN TWO COMMON OUTCOMES THAT ARE REPORTED. EITHER THAT FEMALES ARE MORE SENSITIVE OR THAT THERE'S NO DIFFERENCE BETWEEN MALES AND FEMALES. MORE RECENTLY WHEN THERE HAS BEEN REVIEWS, AND THERE'S BEEN SEVERAL REVIEWS IN THIS LITERATURE, RESEARCHERS OFTEN POINT TO SMALL SAMPLE SIZE AS BEING A BASIS FOR PERHAPS NOT FINDING DIFFERENCES BETWEEN MALES AND FEMALES IN THOSE STUDIES FOR WHICH THAT'S REPORTED. A STUDY THAT'S IN PRESS NOW, WHICH IS A LITERATURE REVIEW OF SEX DIFFERENCES AND PAIN THRESHOLDS AND TOLERANCE, FEMALES ARE SHOWN TO BE MORE SENSSENSITIVE THAN MALES IN THESE FIVE PAIN MODALITY AREAS THAT YOU SEE LISTED HERE. ISCHEMIC PAIN, HOWEVER, NO CONSISTENT SEX DIFFERENCES. AGAIN, THE AUTHORS POINT TO SMALL SAMPLE SIZES AS PERHAPS THE BASIS FOR THIS. SO THIS ISSUE OF SMALL SAMPLE SIZE, I THINK CAN BE ESPECIALLY SEEN IN THIS FREQUENCY DISTRIBUTION OF PRESSURE PAIN THRESHOLD. NOW, THIS STUDY IS ESPECIALLY IMPORTANT BECAUSE IT IS A VERY LARGE END STUDY, 697 MEN AND AN EQUAL NUMBER OF WOMEN. NOW WHAT YOU NOTICE IMMEDIATELY IS THAT THERE'S HUGE OVERLAP IN THE PAIN THRESHOLDS FOR MEN AND WOMEN. AND SO YOU CAN SEE THAT IF ONE HAS A RELATIVELY SMALL SAMPLE SIZE, IT WOULD BE EASY TO RANDOMLY SELECT YOUR MALES AND FEMALES IN SUCH A FASHION THAT YOU WOULD NOT SEE A DIFFERENCE IN THE PAIN THRESHOLDS, BUT WHEN YOU LOOK AT THE LEFT TAIL OF THE DISTRIBUTION AND PARTICULARLY I DRAW YOUR ATTENTION TO THE DOTTED LINE WHICH SHOWS THE 10TH PERCENTILE OF THE TOTAL POPULATION, WHAT IMMEDIATELY JUMPS OUT IS THAT YOU SEE MORE WOMEN IN THAT TENTH PERCENTILE THAN YOU DO MEN, AND AS A MATTER OF FACT, IN THAT TENTH PERCENTILE, WOMEN CONSTITUTE 83% OF THE DISTRIBUTION. SO WHO'S MORE SENSITIVE TO PAIN? A QUESTION WE MIGHT ASK IS, WHY DOES IT MATTER? IT'S INTERESTING, IT'S A QUESTION WE OFTEN ASK, BUT WHY DOES IT MATTER? ONE REASON WHY IT MATTERS IS THAT THERE'S EVIDENCE THAT EXPERIMENTAL PAIN MAY, IN FACT, PREDICT CLINICAL PAIN IN THE DEVELOPMENT OF CHRONIC PAIN. AND WHETHER OR NOT THIS EXPLAINS SEX DIFFERENCES IN THE PREVALENCE OF CLINICAL PAIN REMAINS TO BE DETERMINED, BUT IF IT DOES, THIS CLEARLY POINTS TO THE NEED FOR MORE RESEARCH TO UNDERSTAND THE FACTORS THAT AFFECT SEX DIFFERENCES AND PAIN SENSITIVITY. NOW GOING BACK TO THAT DISTRIBUTION, THE AUTHORS STATE ARGUABLY THIS SEGMENT OF THE POPULATION IS THE MOST SUSCEPTIBLE TO CLINICAL PAIN PROBLEMS BY VIRTUE OF FINDING NOXIOUS AND NEAR NOXIOUS EVENTS MORE PAINFUL THAN THE REST OF THE POPULATION. AS SUCH, IT MAY BE THAT THE TAIL OF THE DISTRIBUTION IS MOST RELEVANT TO THE GREATER FEMALE PREVALENCE OF MANY CLINICAL PAIN PROBLEMS DESPITE THE LARGE OVERLAP IN THE POPULATION AS A WHOLE. SO NOW LET'S TURN TO THE QUESTION OF WHAT ACCOUNTS FOR SEX DIFFERENCES IN PAIN. SO IN GENERAL, THERE'S BEEN A WEALTH OF RESEARCH ADDRESSING THE QUESTION OF WHAT ARE THE FACTORS THAT CONTRIBUTE TO INDIVIDUAL DIFFERENCES IN COMPARE MENTAL PAIN SENSITIVITY IN THAT RESEARCH IS SHOWING THAT SEX DOES MATTER. SO OBVIOUSLY NOCICEPTIVE PROCESSING IN THE NERVOUS SYSTEM, GENETIC FACTORS, HOR HORMONES, THEY ALL PLAY A ROLE AS DO INFLAMMATORY PROCESSES, AND THE GONADAL HORMONES INTERACT WITH ALL OF THESE. MORE RECENTLY, THERE'S BEEN A WHOLE HOST OF PSYCHOLOGICAL, SOCIOLOGICAL FACTORS THAT HAVE BEEN SHOWN TO PLAY A ROLE IN EXPERIMENTAL PAIN SENSITIVITY AND THEY INTERACT WITH THE EARLIER FACTORS IN THE SLIDE. AND A REALLY INTERESTING DIRECTION THAT RESEARCH IS BEGINNING TO TAKE IS QUESTIONS WILL MARKERSABOUT MARKERS, PAIN SENSITIVIT Y AND VARIOUS FACTORS THAT AFFECT PAIN SENSITIVITY, ARE THEY MARKERS FOR DEVELOPING CHRONIC PAIN DISORDERS, ARE THEY MARKERS FOR PAIN TREATMENT OUTCOMES, AND TO WHAT EXTENT ARE THESE MARKERS MODIFIABLE AND IF THEY CAN BE MODIFIED, CAN THEY BE MODIFIED IN SUCH A WAY SO AS TO PREVENT CHRONIC PAIN DISORDERS FROM OCCURRING AND CAN PAIN TREATMENT OUTCOMES BE ENHANCED O. OF COURSE THE BIG QUESTION IN THIS RESEARCH IS DOES SEX MATTER, AND OF COURSE THE DATA ARE NOT ANALYZED TO ANSWER THAT QUESTION, WE WILL NOT KNOW. SO NOW LET'S TURN TO THE TOPIC OF TREATMENT AND REQUESTS IF THERE'S A SEX DIFFERENCE IN RESPONSE TO PAIN TREATMENT. IN PARTICULAR, WE'RE GOING TO BE TALKING ABOUT OPIOD TREATMENT. STUDIES SHOW MALES GET MORE PAIN RELIEF THAN FEMALES DO. ON THE OTHER HAND, INTERESTINGLY, IN THE HUMAN STUDIES, BOTH THE EXPERIMENTAL AND CLINICAL STUDIES FIND WHEN THERE IS A SEX DIFFERENCE, IT FAVORS WOMEN, THAT WOMEN GET BETTER RELIEF. SO THIS QUESTION OF SEX DIFFERENCES WAS ADDRESSED IN THE META ANALYSIS THAT WAS PUBLISHED IN 2010 LOOKING AT THE HUMAN EXPERIMENTAL AND CLINICAL STUDIES. THEY FOUND THAT THE ANSWER TO THE QUESTION DEPENDED UPON WHETHER THE OPIODS WERE OPIODS THAT ACT AT THE NEW RECEPTOR VERSUS THE MU/KAPPA RECEPTORS. IT ALSO DEPENDED UPON WHETHER THE STUDIES WERE EXPERIMENTAL OR CLINICAL. I'M GOING TO FOCUS ON THE CLINICAL STUDIES. CONSIDERING THE 25 CLINICAL STUDIES THAT LOOKED AT THE NEW OPIOD ANALGESICS, THEY FOUND NO SEX DIFFERENCE. HOWEVER, WHEN THEY RESTRICTED THE ANALYSIS TO PATIENT CONTROLLED ANALGESIA, THERE WAS A SEX DIFFERENCE WITH WOMEN HAVING BETTER OUTCOMES THAN MEN. WHEN THEY FURTHER RESTRICTED THE ANALYSIS TO PCA THAT INVOLVED ONLY MORPHINE, THERE WAS AN EVEN STRONGER EFFECT GOING FROM A P VALUE OF .028 TO A POINT VALUE OF .003. THE LONGER THE DURATION OF THE PCA, THE DIFFERENCE BETWEEN THE SEXES INCREASED. NOW AN IMPORTANT CAVEAT HERE TO KEEP IN MIND IS THAT THERE ARE SEX DIFFERENCES IN THE SIDE EFFECTS OF MORPHINE WITH WOMEN SHOWING IN THIS STUDY GREATER SEDATION, DRY MOUTH AND NAUSEA AND OTHER STUDIES HAVE REPORTED VOMITING AS WELL. SO THIS ALSO RAISES A QUESTION WHEN THE PCA STUDIES WHEN WOMEN WERE TAKING IN LESS OPIATES, WAS THIS EFFECT POSSIBLY MODULATE RAITED BY THE SIDE EFFECTS. SO NOW LET'S TURN TO THE DATA, THE CLINICAL RESULTS LOOKING AT THE MU/KAPPA. SEVEN CLINICAL STUDIES WERE IDENTIFIED, INTERESTINGLY, SIX OF THEM WERE POSTOPERATIVE ORAL SURGERY PAIN STUDIES. HERE IN THESE SEVEN CLINICAL STUDIES, IT WAS CLEAR GREATER EFFICACY IN FEMALES THAN IN MALES. THIS SLIDE SHOWS INTERESTING DATA FROM ONE OF THOSE STUDIES ON WHICH TWO OF THE MU/KAPPA OPIODS WAS STUDIED. WHAT YOU IMMEDIATELY NOTICE IS FIRST OF ALL, ALL THE DATA POINTS ABOVE THE DASHED LINE INDICATE GREATER PAIN RELIEF AND THEN DATA POINTS BELOW THAT INDICATES INCREASING PAIN. THE HIGHER CURVES ARE FOR WOMEN SO WHAT YOU IMMEDIATELY NOTICE IS THAT THERE'S A MORE ROBUST RESPONSE IN WOMEN. IT LASTS LONGER. AND FOR MEN, AS WE SAID, IT WAS MUCH SHORT LIVED, THE RESPONSE WAS LESS ROBUST, AND NOTE THAT THE ANALGESIA IS FOLLOWED WITHIN AN HOUR OR SO BY AN INCREASE IN PAIN. SO CLINICALLY WHO HAS THE BETTER ANALGESIC RESPONSE TO OPIODS, MALES OR FEMALES? IN THE PCA STUDIES, WOMEN DID BETTER, FOR THE MU/KAPPA OPIODS, WOMEN HAD AN ADVANTAGE. SHOULD MENTION, HOWEVER, THAT THERE'S CONFLICTING OUTCOMES IN THE EXPERIMENTAL AND THE CLINICAL STUDIES, AND ALSO FOR THE MU OPIODS, THERE'S CONFLICTING STUDIES. THERE'S LOTS OF OPPORTUNITIES HERE FOR CLARIFYING THESE DISCREPANCIES. NOW I THINK THERE'S -- BASED UPON THIS STUDY THAT WE JUST SAW HERE, EMPHASIZING THESE DIFFERENCES BETWEEN MAIL MALES AND FEMALES AND THE ROBUSTNESS OF THE RESPONSES AND THE SHORT LIVED EFFECTS IN MALES AND THE INCREASE IN PAIN THAT WAS OBSERVED, I THINK THIS RAISES QUESTIONS THAT STUDY AS WELL AS THE OTHER STUDIES WE JUST SAW IDENTIFY SOME REALLY UNEXPLORED CLINICAL QUESTIONS AND THAT IS WHICH OPIOD IS BEST FOR MALES, WHICH IS BEST FOR FEMALES. AND FOR WHICH CONDITIONS. WITH A CONSIDERATION OF SIDE EFFECTS AND PATIENT ACCEPTABILITY. THIS, OF COURSE, REQUIRES COMPARE COMPARATIVE EFFECTIVENESS STUDIES WHICH JUST SIMPLY HAVE NOT BEEN DONE, SO THIS IS REALLY A HUGE GAP AREA. WE CAN ALSO HAVE A QUESTION ABOUT SEX DIFFERENCES IN OPIOD, NON-OPIOID TREATMENTS. IT WAS FIRST PUBLISHED BY KAREN BERKELEY IN 1997 AND SHE'S BEEN ADDING TO IT, UPDATED IT BACK IN AUGUST OF THIS YEAR, AND FOR MANY OF THESE, SEX DIFFERENCES HAVE NOT BEEN EXAMINED SO THERE'S QUESTIONS AGAIN OF WHICH OF THESE TREATMENTS ARE BEST FOR MEN AND WOMEN FOR WHICH CONDITIONS, AND AGAIN, ISSUES OF SIDE EFFECTS AND ACCEPTABILITY. SO LOTS OF PROGRESS HAS BEEN MADE AND I THINK WE'RE JUST AT THE TIP OF THE ICEBERG, BUT THE GOOD NEWS IS THAT THERE'S LOTS OF SIGNS SHOWING THE PROGRESS THAT HAVE BEEN MADE, SUCH AS A FORTHCOMING BOOK ENT TITLED PAIN IN WOMEN, CURRENT CONCEPTS IN THE UNDERSTANDING AND MANAGEMENT OF COMMON PAINFUL CONDITIONS IN FEMALES. THERE'S A SECTION LISTED HERE, YOU SEE FOUR CHAPTERS DEVOTED TO THAT TOPIC. ANOTHER GROUP OF CHAPTERS, BIOSOCIAL FACTORS CONTRIBUTING TO SEX DIFFERENCES, ANOTHER GROUP OF CHAPTERS, FEMALE-SPECIFIC PAIN, ANOTHER GROUP OF CHAPTERS, PAINFUL CONDITIONS WITH FEMALE PREVALENCE. SO LOTS OF PROGRESS HAS BEEN MADE, WHICH IS FURTHER SHOWN IN THIS SLIDE HERE, WHICH SHOWS THE PERCENTAGE INCREASE IN PUBLICATIONS COMPARED TO 1980 THAT DEAL WITH THE HIGHER CURVE SHOWING THE HUGE INCREASE IN STUDIES SHOWING GENDER DIFFERENCES IN PAIN COMPARED TO PAIN OVERALL. BUT THERE IS SORT OF A DARK NOTE IN ALL OF THIS GOOD NEWS AND THIS GOES TO A STUDY PUBLISHED IN 2005 ANALYZING ARTICLES PUBLISHED IN THE JOURNAL "PAIN" BETWEEN THE 10 YEARS OF 1996 AND 2005. LOOKING AT THE WHOLE ANIMAL STUDIES OF WHICH 540 WERE IDENTIFIED, 79% OF THOSE WAS MALE-ONLY. ONLY 5% INCLUDED BOTH MALES AND FEMALES AND CONDUCTED A GENDER ANALYSIS OF THE DATA. OF THOSE 5%, HOWEVER, 72% REPORTED A SEX DIFFERENCE, WHICH REALLY RAISES QUESTIONS AS TO WHAT WOULD HAVE HAPPENED IN THE 428 MALE ONLY STUDIES, WE DON'T KNOW IF SEX DIFFERENCE WOULD HAVE BEEN FOUND OR NOT, BUT IF 72% DID FIND A SEX DIFFERENCE, THEN THAT WOULD HAVE CONTRIBUTED 338 ADDITIONAL STUDIES IN THE LITERATURE TELLING US SOMETHING ABOUT SEX DIFFERENCES. SO THEY STATE IN THE ARTICLE, THERE MAY BE A MORAL IMPERATIVE AT WORK HERE. THERE ARE ROBUST SEX DIFFERENCES IN THE FREQUENCY AND INTENSITY OF CHRONIC PAIN IN HUMANS WITH WOMEN COMPRISING THE BULL OF CHRONIC PAIN SUFFERERS. ONE MIGHT ARGUE T THAT BASIC SCIENTISTS ARE SHIRKING THEIR RESPONSIBILITIES TO HALF OF THE HUMAN POPULATION BY AVOIDING THE USE OF DIRECT ANIMAL MODELS OF THEM. WE SIMPLY DO NOT SEE ANY VALID EXCUSES REMAINING FOR THE CONTINUED EXCLUSION OF FEMALE RODENTS FROM BASIC SCIENCE STUDIES OF PAIN. SO THE HOPE HERE IS THAT ROUTINE ANALYSIS OF OUTCOMES BY SEX IN BOTH ANIMAL AND HUMAN RESEARCH WILL LEAD TO BETTER PAIN THERAPIES FOR BOTH MEN AND WOMEN, AND WITH THAT, I DO WANT TO ACKNOWLEDGE ALL THE PAIN RESEARCHERS WHO HAVE ANALYZED THEIR DATA BY SEX GENDER AND STUDY FEMALE SPECIFIC PAIN AND I ESPECIALLY WANT TO THANK THESE RESEARCHERS IN THE FIELD FOR PROVIDING ME WITH SOME SLIDES AND SEW PREPRINTS AND SOME GOOD CONVERSATION AND OF COURSE ALL THE NIH INSTITUTES WHO REPORT -- WHO SUPPORT RESEARCH IN THIS AREA AND JANINE AND HER ORGANIZING COMMITTEE FOR INVITING ME. SO THANK YOU VERY MUCH. [APPLAUSE] >> THANK YOU VERY MUCH. THAT WAS INSPIRING AND ALSO SPEAKS TO THE CHALLENGES WE HAVE AHEAD OF US. OUR NEXT PRESENTATION IS BY DR. LAW A LEE JOHNSON. DR. JOHNSON IS A BIOSTATISTICIAN WITH THE NATIONAL CENTER FOR COMPLEMENTARY AND ALTERNATIVE MEDICINE. THE TITLE OF HER PRESENTATION IS TRAPS WHEN DESIGNING STUDIES IN EVALUATING SEX AND GENDER DIFFERENCES. PLEASE WELCOME DR. JOHNSON. [APPLAUSE] >> MY OFFICE IS ACTUALLY ACROSS THE HALL, SO I WAS THRILLED TO BE ASKED AND I'M SORRY I WAS A LITTLE LATE IN THE BEGINNING, EVERYONE IS GETTING READY FOR OUR NEXT ROUND OF FUNDING SO IT'S ALWAYS FUN. I AM A BIOSTATISTICIAN. WE ACTUALLY DO TEACH A COURSE HERE AT THE CLINICAL CENTER ON THE PRINCIPLES AND PRAIK TISES OF CLINICAL RESEARCH. THE LAST DAY TO SIGN UP IS TODAY. SO GO CHECK ON THE COMPUTER SYSTEM UNDER THE CLINICAL CENTER AND YOU CAN LEARN A WHOLE HOST OF INFORMATION ABOUT THIS. NOW, ONE THING THAT I THINK IS REALLY IMPORTANT AND THAT I WAS ASKED TO TALK ABOUT ISN'T JUST ABOUT PHASE 3 STUDY, BUT ACTUALLY TALK ABOUT WHAT WE CAN DO WITH SOME OF THESE SMALLER STUDIES. SO WE'RE GOING TO START OFF WITH SOME QUESTIONS AND DESIGNS AS IS A STA TISH TISH, PEOPLE THINK THEY BRING THE DATA AND I BRING THEM A MIRACLE. WHAT I WANT TO ENCOURAGE PEOPLE TO DO IS SPEND A LOT OF TIME PLANNING STUDIES, NOT JUST YOUR OWN BUT AS A FIELD LOOKING AND TALKING TO OTHER FOLKS TO FIGURE OUT HOW YOU CAN ACTUALLY CO BINE INFORMATION ACROSS A LOT OF SMALLER STUDIES TO ACTUALLY ANSWER SOME OF THE QUESTIONS THAT ARE VERY PER PERTINENT. THEN WE'LL GO THROUGH SOME OF THE DEFINITIONS AND WHY THOSE CAN BE SO IMPORTANT AS YOU'RE ACTUALLY TRYING TO DO THIS WORK AND A FEW ANALYSIS TRICKS. NOW, A FEW THAINGS I'LL BRING UP, I'M GOING TO TRY TO TALK ABOUT SOME TRAPS I SEE PEOPLE FALL IN PRETTY REGULARLY, AND A LOT OF WHAT I'M GOING TO TALK ABOUT IS TRUE FOR MANY TYPES OF SUBGROUP ANALYSES, NOT ONLY WHEN YOU'RE LOOKING EITHER AT SEX, GENDER OR BOTH. SO IF ANYBODY'S TAI WEN A CLASS FROM ME KNOWS I TALK A LOT ABOUT ANALYSIS FOLLOWS YOUR DESIGN. THE RESEARCHERS QUESTION REALLY IS ONE OF THE MOST IMPORTANT THINGS THAT WE CAN TALK ABOUT HERE AND THE HIGH POTASSIUM CEASE ARHYPOTHESES AREGOING TO FLOW FROM T HERE. SOMETIMES IT'S HARD TO EXPRESS THE QUESTIONS THAT ARE ORIGINALLY ASKED IN TESTABLE HYPOTHESES. SO WE HAVE TO GO BACK AND FORTH A LITTLE BIT TO FIGURE OUT HOW WE'RE GOING TO HAVE SOMETHING THAT WE CAN ACTUALLY TEST. BUT YOUR EXPERIMENTAL DESIGN IS DERIVED FROM THOSE HIGH POTASSIUM CEASE AND WE'RE GOING HYPOTHESES . THE DATA COMES FROM ALL THOSE SAMPLES AND WE'RE ANALYZING THE DATA AT THE END. AND THEN DRAWING THE CONCLUSIONS AND USUALLY MAKING ANOTHER CIRCLE. THE PROBLEM HERE IS THAT IF YOU HAVE ANALYSES OR YOU DECIDE TO COLLECT DATA THAT DON'T MATCH SO IF YOU HAVE ANYTHING THAT'S NOT FLOWING HERE, YOU HAVE A PROBLEM YOU'RE NOT GOING TO BE ABLE TO GET AN ANSWER TO THE ACTUAL QUESTION THAT YOU HAVE. SO DON'T BRING IN YOUR STATISTICIAN AT THE END BECAUSE WE MAY NOT BE ABLE TO HELP YOU. GET TO THE CONCLUSIONS. BUT THE MOST IMPORTANT PART IS, WHAT IS YOUR QUESTION, HOW ARE YOU GOING TO TRY TO ANSWER THAT QUESTION, AND ARE YOU EVEN GOING TO BE ABLE TO ANSWER IT. A LOT OF TIMES WE HAVE REALLY INTERESTING QUESTIONS BUT IT'S HARD TO MAKE IT INTO A STUDY THAT WE CAN ADEQUATELY IMPLEMENT WITH THE RESOURCES WE HAVE AND THEN ALSO BE ABLE TO HAVE SOMETHING THAT'S TESTABLE IN THE END. SO IT'S REALLY IMPORTANT TO FOCUS NOT ONLY YOUR RESEARCH QUESTION NOW BUT ALSO ALL THE QUESTIONS THAT ARE COMING UP NEXT, SO WHEN YOU'RE TRYING TO DESIGN A STUDY, YOU NEED TO BE THINKING ABOUT THREE STUDIES AHEAD. AT LEAST THAT'S WHAT I FIND. I TEND TO SAY, OKAY, WHAT IS IT THAT I NEED TO KNOW TO PLAN MY NEXT STUDY. KIND OF REGARDLESS OF HOW IT WORKS OUT, WHAT AM I LEARNING TO MOVE FORWARD, ESPECIALLY IF YOU HAVE SMALL STUDIES, THEY'RE GOING TO HAVE REALLY LIMITED ABILITIES TO ANALYZE A LOT OF COVARIANTS. THAT'S WHERE UNLESS YOU'RE DOING A STUDY SPECIFICALLY FOCUSED ON SEX OR GENDER DIFFERENCES, A LOT OF TIMES WE'RE BASICALLY MOVING AROUND IN OUR COVAIR YACHT LAND. ALSO IF YOU WANT TO LOOK AT ADVERSE EVENTS THAT MAY BE DIFFERENTIAL, YOU HAVE EVEN LESS POWER AND LOWER ABILITIES TO LOOK AT THAT. THAT MEANS YOU NEED TO HAVE REALLY CAREFUL PLANNING. WHEN YOU DO SMALL STUDY, THE IOM HAS TALKED ABOUT THIS, THE FDA HAS TALKED ABOUT IT, WE TALK ABOUT T YOU HAVE TO REALLY, REALLY THINK ABOUT WHAT YOU WANT TO DO. FOCUS ON WHAT YOUR QUESTION OF INTEREST IS. NOW, A LOT OF TIMES SEVERAL BULLETS DOWN, I BURIED IN THE MIDDLE, WHEN WE TEACH GENERAL 101 HOW TO DO BIOSTATISTICS AND EPIDEMIOLOGY, WE'RE GENERALLY LOOKING AT DIFFERENCES BETWEEN GROUPS IN A STUDY. BUT REALLY WHAT MOST STUDIES TEND TO BE DOING, THEY TEND TO WANT TO TRY TO INTERPRET WORK IN A NEW POPULATION. THEY WANT TO TRY TO HELP CLINICIANS OR PROVIDERS MAKE A DECISION ABOUT AN INDIVIDUAL CASE THAT IS BEING PRESENTED TO THEM. SOMETIMES WE'RE LOOKING AT MAKE CHANGES IN SHIFTING POPULATION DISTRIBUTIONS, YOU SEE A LOT OF THIS NOW IN DIABETES MANAGEMENT STUDIES, WHERE IT'S NOT TRYING TO GET EVERYBODY BELOW A CERTAIN HVA1C, IT'S TRYING TO SHIFT THE POPULATION. SOMETIMES THEY WANT TO DO BIOMARKER DEVELOPMENT. IN WHICH CASE I SAY VERY FANCY, NICE TERM EVERYBODY LIKES RIGHT NOW BUT WHAT KIND OF BIOMARKER? WHAT EXACTLY ARE YOU LOOKING FOR? AND THAT CAN BE A HUGE PLACE WHERE YOU COULD FIND DIFFERENTIATIONS. DEVELOPING A NEW OUTCOME. I WORK WITH THE PATIENT REPORTED OUT COME INFORMATION SYSTEM AND A MEUJ ISSU HUGE ISSUE, OUR VERY EARLIEST QUANTITATIVE RESEARCH, YOU HAVE PEOPLE THAT ARE INVOLVED THAT COME FROM A VARIETY OF DIFFERENT BACKGROUNDS AND MAKING SURE YOU HAVE MALES AND FEMALES SHOWING UP TO TALK AND TO BE INVOLVED IN THAT EARLY RESEARCH. THERE ARE A LOT OF OUTCOMES THAT I HAVE WORKED WITH IN MY RESEARCH CAREER THAT HAVE BEEN USED IN WOMEN OR USED IN MEN THAT DEVELOPED WITH VERY FEW OF THEM INVOLVED IN THAT. SO YOU REALLY NEED TO THINK ABOUT THESE OUTCOMES AND IF YOU'RE DEVELOPING ONE, FROM THE VERY EARLIEST POINT. DON'T TELL ME YOU TESTED A THOUSAND WOMEN IF NONE OF THEM WERE INVOLVED IN TRYING TO ACTUALLY DECIDE WHAT THE QUESTIONS WERE OR YOU HAD ONE OUT OF 30 PEOPLE. THAT'S NOT ENOUGH. THE LEVEL OF EVIDENCE, WHAT IS IT THAT YOU'RE TRYING TO LOOK AT? ARE YOU TRYING TO ESTABLISH A LEVEL OF EVIDENCE OR ARE YOU TRYING TO DO A META ANALYSIS AND EVALUATE A LARGE SET OF EVIDENCE? AND THINK ABOUT THIS IN YOUR POPULATION. IF YOU'RE THINKING ABOUT DEPRESSION, ONE OF THE FIRST STUDIES I WORKED IN, WE ACTUALLY NOTICED THAT THE COMPOSITION OF PEOPLE IN THE INTERVENTION GROUP IS A GROUP INTERVENTION STUDY ACTUALLY MATTERED. SO THERE COULD BE A LOT OF DIFFERENT WAYS THAT GENDER COULD BE INFLUENCING YOUR STUDIES. AND WHEN YOU THINK ABOUT BIOMARKERS AND HORMONE, I WORKED IN A LOT OF POST AND PREMENOPAUSAL ALCOHOL STUDIES IN WOMEN, THERE, WE HAD ALL SORTS OF INTERESTING THINGS HAPPENING. SO THINK ABOUT WHAT IT IS THAT YOU WANT TO LOOK AT AND SEEP IF PERHAPS MAYBE SEX OR GENDER MIGHT BE CAUSING AFFECT MODIFICATIONS OR MAY BE IMPACTING YOUR OUTCOMES. SO HOW ARE WE GOING TO START DESIGNING OUR STUDIES? WE NEED TO THINK ABOUT YOUR STUDY AIMS AND YOUR BACKGROUND BUT ALSO THINK ABOUT THE POPULATIONS YOU'RE BASING AND GAINING THIS BACKGROUND INFORMATION ON. THINK ABOUT THOSE END POINTS, THE OUTCOME VARIABLES, WHAT ARE THE SPECIFIC VARIABLES. DON'T TELL ME YOU WANT TO MEASURE SLEEP. TELL ME EXACTLY WHAT YOU WANT TO MEASURE. HOW YOU'RE GOING TO MEASURE IT. AND THEN MAKE SURE THAT HOW YOU'RE MEASURING IT IS GOING TO BE SENSITIVE IN THE POPULATION YOU'RE CARING TO STUDY AND THE CHANGES YOU EXPECT TO SEE. KIND OF THE CRUDE WAY I TALK ABOUT THIS, YOU KNOW THOSE LITTLE WOODEN OR PLASTIC RULERS YOU GIVE THE KIDS IF THEY'RE GOING TO ELEMENTARY SCHOOL, OR ARE YOU GOING TO MEASURE IT WITH A CALIPER? LIKE KIND OF HOW CAREFULLY ARE YOU MEASURING SOMETHING? WHAT IS THE RELIABILITY AND VALIDITY OF THE MEASURE IN THE POPULATION YOU'RE LOOKING AT. IS IT SOMETHING THAT CAN BE VALIDATED BUT NOT IN THE POPULATION YOU CARE ABOUT, YOU MAY NEED A SMALL PILOT STUDY FIRST TO MAKE SURE THAT YOUR END POINTS AND OUTCOMES MAKE SENSE FOR YOUR POPULATION, AND TO LOOK AT KIND OF WHAT TYPES OF DIFFERENTS AND WHAT VARIABILITY ARE YOU GOING TO SEE IN THE POPULATION YOU WANT TO STUDY BEFORE YOU LAUNCH A LARGER STUDY. WE NOW AND CAN MANY TIMES HAVE BEEN TELLING OUR INVESTIGATORS AND THEY AGREE WITH US TO KIND OF TAKE A STEP BACK AND MAKE SURE WE HAVE ALL OF OUR DUCKS IN A ROW BEFORE WE START MOVING INTO EVEN A PHASE TWO STUDY. YOUR INCLUSION EXCLUSION CRITERIA REALLY MATTER HERE, SO THINK ABOUT YOU DON'T WANT TO EXCLUDE TOO MANY PEOPLE, BECAUSE THEN YOU HAVE NOBODY TO GET YOUR DATA ON. BUT IF YOU INCLUDE A VERY LARGE GROUP OF PEOPLE, YOU COULD HAVE A VERY HETEROGENEOUS GROUP, SO YOU HAVE TO REALLY THINK WHEN IS IT TIME TO BE HOMO GENIUS AND WHEN IS IT TIME TO ACTUALLY BE BROAD, BECAUSE IF YOU WANT TO ACTUALLY DESCRIBE SOMETHING THAT HAPPENS ACROSS THE LIFESPAN BUT IT'S EASIER TO TAKE ONLY POST-MENOPAUSAL WOMEN OR WOMEN WHO ARE ON A VERY CERTAIN TYPE OF BIRTH CONTROL, YOU LOST YOUR GENERALIZABILITY. SIMILARLY WITH RETENTION ISSUE, WE DO TALK TO PEOPLE QUITE FREQUENTLY, YOU KNOW, IF THEY HAVE CAREGIVER STATUS, THEY MAY NEED SOMEBODY TO BE PROVIDING THAT CAREGIVER IF YOU WANT THEM TO PARTICIPATE IN YOUR STUDY. THERE ARE A LOT OF THINGS TO BE THINKING ABOUT IN THE DESIGN AND PLANNING AND IMPLEMENTATION OF A STUDY THAT HAVE NOTHING TO DO WITH THE DATA TO A CERTAIN EXTENT, BUT IT IS GOING TO BE DETERMINANT OF WHO YOU'RE GOING TO BE GETTING YOUR DATA ON. THESE TREATMENTS AND PARTICIPANT IMPLICATIONS, WHEN WE EVALUATE A LOT OF THESE PRODUCTS, SO WE DO A LOT OF DISRANGING STUDIES AND WE ALSO THINK ABOUT THE QUALITY OF THE INTERVENTION, BUT THINK ABOUT THE TRAINING, THINK ABOUT DO YOU CARE ABOUT WEIGHT, MUSCLE MASS AS YOU'RE TRYING TO DO DOSING, HORMONES, AGAIN, WHERE IN THE LIFESPAN ARE PEOPLE, THINK ABOUT THAT AS YOU'RE TRYING TO THINK ABOUT WHAT TREATMENTS, WHAT INTERVENTIONS YOU WANT TO MOVE FORWARD. YOU NEED TO ALSO CONSIDER AND KEEP YOUR MINDS OPEN AND ENCOURAGE ALL THE INVESTIGATORS YOU'RE WORKING WITH, A LOT OF THEM, WHEN WE TALK TO THEM THEY GO, OH, YEAH, THAT MAKES A LOT OF SENSE, BUT IT JUST WASN'T -- THEY WERE VERY FOCUSED ON THEIR SCIENTIFIC QUESTION, SO I THINK FOR ALL OF US, THE REASON I'M HERE TODAY AND NOT SITTING IN MY OFFICE IS BECAUSE I THINK THIS IS A GREAT LEARNING MOMENT AND OPPORTUNITY FOR ALL OF US TO KEEP SHARING AND THINKING ABOUT THESE ISSUES. IF YOU EXPECT YOUR INTERVENTION IS GOING TO BE DIFFERENT IN MALES OR FEMALES, MEN OR WOMEN, THEN YOU NEED TO REALLY CONSIDER THAT AND ROLL IT INTO YOUR ANALYSIS, ROLL IT INTO YOUR DESIGN. NOW ALSO ANOTHER THING TO THINK ABOUT IS CONSISTENTLY DEFINING SEX AND GENDER. SO I WILL SAY THIS IS TRUE FOR EVERY SINGLE VARIABLE THAT YOU ARE COLLECTING AND IN FACT YOU WILL SEE IT ON THE NEXT PAGE. SO WHEN I MENTIONED TO MY DIRECTOR THAT I WAS GOING TO BE GIVING THIS TALK, AND WE WERE TALKING IN THIS GROUP AND SOMEBODY SAID YOU'RE TALKING ABOUT GENDER NOT SEX AND GENDER AND I SAID, OH, NO, NO, NO, I WAS THRILLED, THRILLED TO SEE IT WAS BOTH SEX AND GENDER. AND SO THIS IS A REALLY IMPORTANT ASPECT. WHAT EXACTLY IS IT THAT YOU'RE USING TO DECIDE? SO WHEN SOMEBODY SAYS I'M GOING TO LEAVE PEOPLE OUT WHO ARE DEPRESSED, I SAY, HOW DO YOU FIGURE OUT IF THEY ARE DEPRESSED? IF THAT'S YOUR INCLUSION CRITERIA, FINE, BUT HOW DO YOU DEFINE IT? SAME THING HERE. HOW ARE YOU DEFINING SEX? HOW ARE YOU GOING TO TEST TO DECIDE WHAT SEX SOMEBODY IS? SAME THING FOR GENDER. IS IT WHAT THEY'RE SELF IDENTIFYING, IS IT THAT IN FACT YOU'RE GOING TO RUN A TEST, WHAT IF YOU FIND OUT THAT SOMEBODY IS XXY, HOW ARE YOU GOING TO HANDLE THIS? YOU'VE GOT TO REALLY THINK ABOUT HOW YOU'RE DEFINING IT AND ALSO HOW OTHER PEOPLE ARE GOING TO DEFINE IT FOR YOU BECAUSE EVENTUALLY YOU MAY COME UP WITH A DECISION INSIDE OF YOUR STUDY THAT YOU'RE GOING TO TO PUBLISH THIS AND OTHER PEOPLE ARE GOING TO BE COMPARING YOUR WORK. SO REALLY THIS KIND OF CONSISTENCY CAN BE VITAL. NOW, ACTUALLY ONE OTHER POINT I WANT TO MAKE HERE IS THINK ABOUT HORMONE THERAPIES THAT PEOPLE ARE ON WHEN WE START WORRYING ABOUT HORMONES. LIFESPAN AND WHAT ELSE PEOPLE ARE TAKING. IF YOU THINK THAT HORMONE IS GOING TO BE YOUR DRIVER INSTEAD, AGAIN, MEASURE IT, KNOW HOW YOU'RE DEFINING IT AND WORK WITH IT THAT WAY. REPRODUCIBLE MEASUREMENTS. THE BIG BUZZ WORDS RIGHT NOW, REPRODUCIBLE SCIENCE, REPRODUCIBLE RESEARCH, THIS IS VERY IMPORTANT. THE OTHER PART HERE IS REALLY YOU WANT SCIENCE THAT CAN BE REPLICATED. AND AS WE'VE ALREADY HEARD TODAY, SOMETIMES THAT SCIENCE HAS NOT BEEN REPLICATED. HOW YOU DEFINE AND HOW YOU MEASURE EVERYTHING IN YOUR STUDY IS REALLY IMPORTANT. AND I WOULD ENCOURAGE PEOPLE, ESPECIALLY IF YOU WANT TO TRY TO DO METAREGRESSION, SO ACTUALLY NOT JUST TAKING THE OUTPUT THAT'S IN THE MANUSCRIPT, ACTUALLY SAYING WE AS A GROUP OF SCIENTISTS ARE GOING TO POOL OUR RAW DATA TOGETHER, THAT MEANS YOU HAVE TO BE THINKING ABOUT IT, TO MAKE SURE THE IRBs ARE HAPPY WITH HOWEVER YOU'RE DOING THIS, BUT THERE ARE MORE AND MORE GROUPS DOING THIS TO SAY WE ARE GOING TO DO METAREGREXES AND WE ARE GOING TO ESTABLISH DATA DICTIONARIES, LIBRARIES AND INFORMATION IN OUR CONSENT TO BE ABLE TO POOL TOGETHER DATA WE ARE GOING TO SET UP A SET OF CORE DATA ELEMENTS EVEN, INDS HAS DONE THIS, OTHER GROUPS HAVE, TO SAY WE'RE GOING TO MEASURE EVERYTHING IN THIS WAY, CONSISTENTLY ACROSS ALL THESE PROTOCOLS, AND THEN TOGETHER WITH THIS, WE'RE GOING TO HAVE A WELL-DEFINED COHORT AND WE'RE GOING TO BE ABLE TO ANSWER SOME OF THESE QUESTIONS. THAT'S A GREAT WAY TO TRY TO DO THIS, BUT AGAIN, YOU HAVE TO HAVE CONSENSUS AND THE ABILITY TO DO IT. BUT IN ANY SINGLE STUDY, HAVING A REALLY WELL-DEFINED COHORT, HAVING TIGHT INCLUSION EXCLUSION CRITERIA THAT PEOPLE CAN ACTUALLY REPLICATE, WHEN I SIT ON THE STUDY, I USED TO JOKE, I'M YOUR BIOSTATISTICIAN, I NEED TO BE ABLE TO READ IN YOUR MANUALS, KNOW HOW TO TAKE ALL YOUR BLOOD AND BE ABLE TO GET THE SAME PEOPLE IN YOUR STUDY THAT YOUR RESEARCH NURSE IN THE P.I. AND OTHER PEOPLE CAN DO IT. YOU WANT OTHER PEOPLE TO BE ABLE TO REPEAT THIS WORK. SAME THING FOR THE STUDY CONDUCT, WHEN ARE PEOPLE BEING MEASURED HOW ARE THEY BEING MEASURED, ALL OF THIS. THERE ARE A LOT OF PLACES TO ANNOTATE YOUR DATA, YOUR ANALYSES, THINGS LIKE THAT, SO THAT PEOPLE CAN RE-RUN IT. A LOT OF INSTITUTIONS AND JOURNALS THAT ARE ACTUALLY ASKING FOR WHERE IS THE CODE, AND WE ARE GOING TO RE-RUN IT. SIMILAR TO WHAT THE FDA DOES. IF YOU HAVE A REALLY SMALL STUDY, AGAIN, IN THE PLANNING, AGREE TO WORK WITH OTHER TEAMS. SOMETIMES INSTEAD OF DOING A BUNCH OF SMALL UNDERPOWERED STUDIES, WE NEED TO SAY, NOPE, IT'S TIME TO PUT UP. PUT IT UP, EVERYBODY DO THE LARGER STUDY AND ANSWER THE QUESTION THAT'S IMPORTANT, OR AGREE AS A WHOLE THAT WE'RE ESSENTIAL PUTTING OUR DATA TOGETHER TO ESSENTIALLY CREATE THAT STUDY. THERE ARE PROBLEMS WITH IT BUT IT CAN BE VERY HELPFUL. SO WHAT ARE SOME OF THE HIDDEN BIAS? THEY HAVE A LOT OF BIASES. TIMING OF MEASUREMENTS, ESPECIALLY IF YOU'RE TRYING TO TAKE BLOOD MEASURES AND YOU HAVE PREMENOPAUSAL WOMEN, CAN YOU HAVE ALL SORTS OF EXCITEMENT. WHO IS MEASURING IT? I WORKED IN ONE STUDY WHERE, IN FACT, THE DATA CHANGED BASED ON WHETHER WE HAD A MALE TAKING THE INFORMATION OR A FEMALE TAKING THE INFORMATION. NOW THAT CAN HAPPEN FOR A LOT OF THINGS. I'VE ALSO SEEN IT HAPPEN BY THE COLOR OF YOUR SKIN. BUT THINK ABOUT WHERE YOU CAN HAVE BIASES IN YOUR INFORMATION AND ALSO THINK IF YOU ARE PURPOSEFULLY OR ACCIDENTALLY EXCLUDING A VERY LARGE PORTION OF YOUR POPULATION. NOW WHAT I WANT TO END WITH IS THE FACT THAT A LOT OF PEOPLE LOOK AND THEY MAY SAY, OH, THE P VALUE IS NOT SIGNIFICANT, I TESTED FOR SEX, I TESTED FOR GENDER, EVERYTHING IS FINE, IT'S NOT SIGNIFICANT. SO AB ACCEPTS OF EVIDENCE DOES NOT EQUAL EVIDENCE OF ABSENCE T-SHIRT? IT'S REALLY IMPORTANT -- AND THE SAME THING ACTUALLY GOES IF THE P VALUE IS LESS THAN .05 OR WHATEVER CUTOFF VALUE YOU WANT TO LOOK AT. ESPECIALLY IN SMALLER STUDIES, YOU HAVE REALLY HIGHLY VARIABLE SETS OF INFORMATION. AND ALSO PEOPLE HAVE THIS TENDENCY TO DO VERY SIMPLE ANALYSES WITH VERY COMPLICATED DATA. YOU SEE THESE EPIDEMIOLOGIC STUDIES, THEY COLLECT A LOT OF DATA, AND YET THEY USE A 2 BY 2 TABLE AND TALK ABOUT VERY SIMPLE COMPARISONS. INSTEAD OF TAKING INTO ACCOUNT THE REALLY RICH DATA THAT'S BEEN COLLECTED. SO THINK ABOUT DON'T OAF FIT OVERFIT YOUR MODELS BUT REALLY THINK ABOUT WHAT ARE THE INTERACTIONS, WHERE IS THAT, IN FACT, YOU WILL SEE DIFFERENCES THAT THOSE TREATMENTS BEHAVE DIFFERENTLY IN MEN AND WOMEN AND IMPACT THE OUTCOMES DIFFERENTLY? SOMETIMES THDY MAY JUST HAVE VERY DIFFERENT MECHANISMS BUT THE OUTCOME IS THE SAME. SO YOU HAVE TO REALLY THINK AND TEST, ARE WE SEEING INTERACTIONS, ARE WE SEEING COULCONFOUNDING. THERE ARE A LOT OF DIFFERENT METHODS FOR THESE SMALL SAMPLES AND THERE'S AN ENTIRE FDA COURSE COHOSTED BY NIH, THINK YOU CAN STILL FIND IT ONLINE, TALKING ABOUT THIS. JOHN POWERS GIVES A LECTURE AND I ACTUALLY GAVE YOU THE LINK TO LAST YEAR'S LECTURE BECAUSE IT'S COMPLETELY OPEN ONLINE RIGHT NOW FOR THAT, WHERE HE TALKS ABOUT KIND OF THESE STUDY DESIGNS, BUT A BIG ISSUE HERE IS THAT YOU NEED TO RECOGNIZE IF YOU HAVE POWER AND IF YOU DON'T, HOW YOU'RE GOING TO GET IT. I SEE PEOPLE WHO P POWER FOR MAIN EFFECT BUT FORGET TO LOOK AT THE INTERACTION. MAYBE YOU SET THAT TYPE I ERROR RATE, I DON'T SET IT PINT 05. I SET IT AT .1. I'M LOOKING FOR A TREND AND I WANT TO SEE IF THERE'S SOMETHING THERE. BUT I HAVE BEEN KNOWN TO POWER ENTIRE STUDIES BASED ON THE INTERACTION. YOU CARE TO SEE THAT, YOU GO FOR IT. THAT'S YOUR QUESTION, POWER YOUR STUDIES FOR THE QUESTIONS THAT MATTER. IT'S NOT JUST THE PRIMARY OUT COME BUT WHATEVER OUTCOMES ARE OF IMPORT TO YOU. AND DON'T TELL ME THAT MEN AND WOMEN, THAT THE OUTCOMES ARE EQUIVALENT UNLESS YOU ACTUALLY BOTHER TO DO A TEST OF EYE QIF LENS, IN WHICH CASE YOU NEED TO DEFINE THE MARNL AS TO PLUS OR MINUS WHAT MAKES THINGS EQUIVALENT, AND IT'S NOT USUALLY COMING WITH A VERY SMALL SAMPLE SIZE. SO A LOT OF PEOPLE TALKED ABOUT STRATIFICATION. DON'T STRATIFY TYPICALLY. BUT I'M GOING TO TELL YOU WHAT YOU SHOULD DO. TYPICALLY WHEN PEOPLE ARE TRYING TO STRATIFY, THEY SEPARATE THEIR DATA. IT COMPLETELY KILLS YOUR POWER. NOW, MAYBE WHAT YOU WANT TO DO IS ACTUALLY DO A STRATIFIED RANDOMIZATION. AND SO YOU'RE GOING TO STRATIFY, AGAIN, YOU HAVE TO DECIDE, IS IT SEX, IS IT GENDER OR WHAT. BUT YOU STRATIFY SO YOU END UP WITH EQUIVALENT NUMBERS OF MEN AND WOMEN -- OR WOMEN IN EACH GROUP AND OF MEN IN EACH GROUP, BUT YOU ALSO MAY NEED TO OVERSAMPLE IN ORDER TO MAKE SURE THAT YOU HAVE ENOUGH MEN AND/OR WOMEN IN YOUR STUDIES. BUT STRATIFICATION IS YOUR BIGGEST TRAP. WHAT YOU WANT TO DO INSTEAD IS ACTUALLY ADD THE VARIABLES INTO YOUR MODEL, USE THOSE INTERACTIONS OR AFFECT MODIFICATION SO WHEN YOU JUST ADD THE VARIABLE IN THE MODEL, THEN YOU'RE ESSENTIAL TESTING AND YOU CAN LOOK AT CONFOUNDING, BUT REALLY WHAT YOU WANT TO DO IS TRY TO REDUCE THE UNDERLYING VARIABILITY IN THE DATA TO MAKE MORE PRECISE COMPARISONS AND THEN INTERACT THAT VARIABLE WITH YOUR TREATMENT VARIABLE OR WHATEVER OTHER ITEM YOU WANT TO LOOK AT IN ORDER TO SEE IF MAYBE YOU DO HAVE INTERACTIONS AND AFFECT MODIFICATION. BUT AGAIN, YOU'RE GOING TO HAVE TO TRY TO GET SOME INFORMATION FIRST ABOUT THAT TO THEN POWER A STUDY IN ORDER TO REALLY EVALUATE IT. BUT WHEN YOU LEAVE IT IN AN ENTIRE LARGER REGRESSION MODEL, YOU'RE GOING TO HAVE A LOT MORE POWER. SO IN CONCLUSION, WHAT I WANT TO TELL YOU IS TO NOT BE AFRAID. I ALSO WANT TO TELL YOU TO PREPLAN. START THINKING ABOUT YOUR CURRENT YOU A FUTURE STUDIES, HOW YOU'RE GOING TO COLLECT IT, HOW YOU'RE GOING TO TALK TO YOUR FRIENDS, OTHER FOLKS AND MAYBE YOUR FOES TO TRY TO GET THAT INFORMATION. CONFIDENCE INTERVALS, THEY ARE WHAT'S USEFUL. THE POINT ESTIMATES ARE NOT USEFUL. BECAUSE THAT TELLS YOU MANY TIMES THE MIDDLE TENDENCY, YOU NEED TO THINK ABOUT WHAT COULD BE HAPPENING ON THE EDGES. THOUGH LARGER STUDY MIGHT BE NEEDED, THAT'S OKAY, YOU CAN PLAN DO IT, BUT DON'T DECIDE TO STICK YOUR HEAD IN THE SAND AND NOT LOOK AT ANYTHING JUST PAUSE YOU DON'T THINK THAT YOU'RE POWERED FOR IT. AT THE SAME TIME I'M GOING TO TELL YOU NOT TO OVERINTERPRET WHAT YOU DO SEE. SO DON'T TAKE GROUP A, GROUP B, THEY LOOK DIFFERENT, SO I THINK THEY'RE DIFFERENT. YOU WANT TO TEST. BUT REALLY, THE STATISTICALLY SIGNIFICANT OUTCOMES MAY NOT BE GENERALIZABLE, THE ONES THAT YOU DO SEE, SO YOU REALLY HAVE TO BE CAREFUL. THINK ABOUT T PLA IT, PLAN IT INTO YOUR PHASE 2 AND PHASE 1 DESIGN, LOOK EARLY. AM I OUT OF TIME NOW? OKAY. TAKE CARE. [APPLAUSE] >> THANK YOU, DR. JOHNSON. LOOK EARLY. ALL RIGHT. SO OUR LAST PRESENTATION BEFORE WE'LL HAVE A LITTLE BIT OF TIME FOR SOME QUESTIONS IS FROM DR. SHARE, A FAIR AWART AWARD RECIPIENT. THE TITLE OF HER PRESENTATION IS OBESITY RELATED HORMONES AND ENDOMETRIAL CANCER RISK. [APPLAUSE] >> GOOD AFTERNOON, EVERYONE. THANK YOU TO THE ORGANIZERS FOR THE OPPORTUNITY TO PRESENT MY RESEARCH. I'M GOING TO BEGIN WITH A BRIEF NOTE ON OBESITY AND POTENTIAL SEX DIFFERENCES FOLLOWED BY SOME BACKGROUND ON THE EPIDEMIOLOGY OF ENDOMETRIAL CANCER AND AN INTRODUCTION TO TWO IMPORTANT AND THEN I'LL DESCRIBE MY PROJECT WITHIN THE COHORT WHICH EVALUATED IN RELATION TO CANCER RISK AMONG POST-MENOPAUSAL WOMEN. ACCORDING TO DATA FROM THE CDC, RECENT DATA FROM 2009 TO 2010, APPROXIMATELY 35% OF U.S. ADULTS ARE CLASSIFIED AS OBESE DEFINED AS HAVING A BMI OF GREATER THAN OR EQUAL TO 30 KILOGRAMS METERS SQUARED SO THE BIG QUESTION FOR TODAY IS WHETHER OR NOT THERE ARE SEX DIFFERENCES IN THE PREVALENCE OF OBESITY. USING RECENT DATA, 2009-2010, ACTUAL SEX DIFFERENCES IN OBESITY PREVALENCE HAVE ALMOST LEVELED OFF. THERE ARE NO STRIKING DIFFERENCES IN THE OVERALL OBESITY PREVALENCE BETWEEN MEN AND WOMEN. HOWEVER, SEX DIFFERENCES HAVE BEEN NOTED WHEN LOOKING AT THE DISTRIBUTION OF ADIPOSE TISSUE WITH MEN HAVING A GREATER TEND TEND SEE TO CARRY EXCESS ADIPOSITY IN THE ABDOMEN AREA, WHEREAS WOMEN ARE GENERALLY CLASSIFIED OR CARRY EXCESS WEIGHT IN THE HIPS AND THIGHS, WHICH IS KNOWN AS THE PEAR SHAPE. SO WE ALL KNOW, OBESITY HAS BEEN SHOWN TO LEAD TO VARIOUS ADVERSE HEALTH OUTCOMES. ONE OF WHICH IS AN INCREASE IN CANCER AT NUMEROUS SITES. FOR EXAMPLE, OBESITY IS ASSOCIATED WITH INCREASED COLORECTAL CANCER RISK AND INCREASED RISK OF RENAL CANCER. HOWEVER, WHEN ANALYSES STRATIFIED BY SEX, WE SEE A GREATER INCREASE IN RISK BETWEEN -- AMONG OBESE MEN COMPARED TO NON-OBESE MEN WHEREAS FOR RENAL CANCER, THE RISKS ARE STRONGER A AMONG WOMEN. SO FOR TODAY I'LL BE FOCUSING ON WOMEN AS ENDOMETRIAL CANCER OCCURS IN WOMEN AND RELATIONSHIP BETWEEN OBESITY AND ENDOMETRIAL CANCER IS QUITE STRONG. PREVIOUS EPIDEMIOLOGICAL STUDIES HAVE SHOWN INCREASE IN RISK RANGING FROM 3 TO 5 FOLD. SO CANCER AS IN THE LINING OF THE UTERUS, SHOWN HERE IS AN AGE-SPECIFIC INCIDENT CURVE USING DATA FROM 2000 TO 2008 AND AS YOU CAN SEE, THE RISK OF ENDOMETRIAL CANCER INCREASES WITH AGE UNTIL ABOUT AGE 70. IN ADDITION TO AGE -- VARIOUS EP DEEJ DEEM LOGICAL RESEARCH IDENTIFIED THE RISK FACTORS THAT I'VE TRIED TO SUMMARIZE FOR YOU HERE. THE MOST NOTABLE RISK FACTORS FOR ANY REGIONAL CANCER INCLUDE UNOPPOSED ESTROGEN THERAPY AND OBESITY. POTENTIALLY PROTECTIVE FACTORS ALSO BEEN SUGGESTED AND THOSE INCLUDE ORAL CONTRACEPTIVE USE AND PHYSICAL ACTIVITY JUST TO NAME A FEW. SO WHAT ARE SOME POTENTIAL BIOLOGICAL MECHANISMS UNDERLYING THE STRONG OBSERVED ASSOCIATION BETWEEN OBESITY AND ENDOMETRIAL CANCER CHRI RISK? MULTIPLE PATHWAYS HAVE BEEN SUGGESTED AND MOST OF THEM ARE INTERRELATED, ONE OF WHICH IS THE SEX STEROID HORMONE PATHWAY WHICH INVOLVES THE CONVERSION OF ANOF -- IN ADDITION TO THE PATHWAY, INSULIN, INFLAMMATION, GROWTH FACTORS AND -- HAVE ALSO BEEN SUGGESTED TO PLAY A ROLE. SO FOR TODAY I'LL BE FOCUSING ON THE POTENTIAL ROLE TO CANCER RISK. ADIPOSE TISSUE IS AN ACTIVE ENDOCRINE ORGAN. IT ACTIVELY RELEASES NUMEROUS BIOLOGICAL PEPTIDES, WHICH ARE SHOWN HERE ON THE SCHEMATIC. SO WHAT DO THESE TWO DO? LEPTIN IS POSITIVELY CORRELATED WITH BMI AND FAT MASS AND SHOWN TO PREDICT WEIGHT GAIN AND INSULIN RESISTANCE. ADD POE NECK TIN HAS BEEN SHOWN TO BE NEGATIVELY CORRELATED WITH TYPE~2 DIABETES. IN TERMS OF BIOLOGICAL PROPERTIES, HELP TIN INHIBITS APOP PTOSIS, ALL OF WHICH ARE IMPORTANT PROCESSES IN CAR SIN OWE GENESIS. ADD POADIPONECTIN -- ANTI-INFLAMMATORY PROPERTIES TO INHIBIT SELF PROLIFERATION. ADDITIONALLY WHAT' WHAT'S INTERESTING IS THERE ARE DIFFERENT ISOMERS BASED UPON ITS MOLECULAR WEIGHT. IN TERMS OF SOURCES OF VARIATIONS, INTERESTINGLY ENOUGH, THE RESEARCH IN THIS AREA IS SOMEWHAT LIMITED BUT STUDIES HAVE SHOWN SEX DIFFERENCES IN THE LEVELS OF BOTH LEPTIN AND ADIPONECTIN, AS I MENTIONED EARLIER, THE ASSOCIATION WITH OBESITY IS OPPOSITE FOR EACH MARKER. LEPTIN HAS BEEN SHOWN TO HAVE HIGHER -- OR -- ADD POE KIENS. I PUT DASHES FOR ADIPONECTIN BECAUSE STRANGELY ENOUGH, IT'S HARD TO FIND SUMMARY INFORMATION IN HEALTHY POP LAYING POPULATIONS THAT'S CONSISTENT BUT SOME STUDIES HAVE SHOWN THERE'S JUST BEEN SOME INCONSISTENCY IN TERMS OF THE VARIATION OF ADIPONECTIN ACROSS THESE FACTORS. WHAT WE'RE DOING NOW IN TERMS OF THESE ADIPOKINES WITH REGARD TO ENT MEE TREEL CANCER RISK, OVERALL THE NUMBER OF PRIOR STUDIES IN THE FIELD HAS BEEN SOMEWHAT LIMITED. THREE STUDIES HAVE EVALUATED LEPTIN LEVELS, ALL OF WHICH SUGGEST THAT HIGHER LEPTIN LEVELS INCREASE RISK. HOWEVER, IT'S IMPORTANT TO NOTE THAT ALL OF THOSE PRIOR STUDIES ASSESS LEPTIN USING POST DYING NICDIAGNOSTIC SERUM SAM SAMPLES. SO IN TERMS OF THE RATIO OF BOTH MARKERS, THERE'S ONLY BEEN ONE STUDY THAT HAS EVALUATED THE RATIO OF LEPTIN TO ADIPONECTIN AND RECENT EVIDENCE HAS SUGGESTED THAT MAYBE THE RATIO WOULD ALSO BE INFORMATIVE BEYOND EACH OF THE INDIVIDUAL MARKERS ALONE. HIGHER LEPTIN TO ADIPONECTIN RATIO INCREASES RISK BY APPROXIMATELY SIX FOLD. HOWEVER, MY DISCLAIMER IS IT IS A CASE CONTROLLED STUDY WITH POST DYING TIC DIAGNOSTIC MEASURE. IN TERMS OF THE HIGH PLEAK PLEK LAR WEIGHT ISOFORM, NO -- HAVE EVALUATED THIS MARKER. SO THIS BRINGS ME TO MY PROJECT WITHIN THE B FIT STUDY. IT INCLUDES ABOUT 15,000 OF THE 22,000 WOMEN THAT WERE ONCHLY SCREENED FOR THE INTERVENTION TRIAL DURING THE PERIOD OF 1990 TO 1993. WOMEN WERE POST MENOPAUSAL FROM AGES 55 TO 80 AT BASELINE OR SCREENING. THEY WERE RECRUITED FROM 10 CLINIC CENTERS ACROSS THE UNITED STATES. THE FIT TRIAL WAS A RANDOMIZED CONTROL TRIAL AND THE AIM OF THE TRIAL WAS TO ASSESS FRACTURE RISK REDUCTION IN WOMEN WITH LOW BONE MARROW DENSITY. WOMEN PROVIDED A BASELINE QUESTIONNAIRE, UNDERWENT A BONE MINERAL DENSITY SCAN AND MEASUREMENTS, AND THEY ALSO PROVIDED FASTING SERUM SAMPLE. WOMEN WERE FOLLOWED FOR AN AVERAGE OF 10 YEARS AND CANCER STATUS WAS ASCERTAINED BY THE SOURCES LISTED. SO THE MAIN AIM OF THIS ANALYSIS WAS TO EVALUATE CIRCULATING PREDIAGNOSTIC ADIPOKINES AMONG POST-MENOPAUSAL WOMEN. WE EVALUATED LEPTIN ADIPONECTIN, HIGH MOLECULAR WEIGHT ADIPONECTIN AS WELL AS THE RATIO OF EACH MEASURE TO LEPTIN. OUR HYPOTHESIS INCLUDED THE FOLLOWING, THAT HIGHER LEPTIN LEVELS WOULD BE ASSOCIATED WITH AN INCREASE IN ENDOMETRIAL CANCER RISK BASED ON THE BIOLOGICAL PROPERTIES THAT I MENTIONED ON THE PREVIOUS SLIDE, AND THEN HIGHER LEVELS OF ADD POADIPONECTIN AND HIGH -- WOULD BE INADVERTENTLY ASSOCIATED WITH ENDOMETRIAL CANCER RISK. WE DESIGNED A CASE CONTROL STUDY WITH ONE TO TWO MATCHING TWO CONTROLS PER CASE, AND WE MEASURED THESE MARKERS IN PREDIAGNOSTIC FASTING SERUM SAMPLES. TO BE ELIGIBLE FOR THE STUDY, WOMEN NEEDED TO HAVE AN AVAILABLE BASELINE SERUM SAMPLE, TO HAVE COMPLETED THE QUESTIONNAIRE, TO HAVE NOT REPORTED ESTROGEN PILL USE WITHIN FOUR MONTHS OF THE BLOOD DRAW, NO NOT HAVE REPORTED PRIOR HISTORY OF CANCER OTHER THAN NON-MELANOMA SKIN CANCER AND TO NOT HAVE REPORTED A HYSTERECTOMY. CONTROLS WERE RANDOMLY SELECTED FROM AN EXISTING SUBCOHORT OF WOMEN THAT WE DESIGNED FOR AN ONGOING STUDY AND THEY WERE MATCHED ON THE FOLLOWING FACTORS INCLUDING AGE AT BLOOD DRAW WITHIN FIVE YEARS, TIME OF BLOOD DRAW, GEOGRAPHICAL CLINIC SITE AND TRIAL PARTICIPATION STATUS. SO THE FINAL STUDY POPULATION INCLUDED 186 CAUCASIAN POST-MENOPAUSAL WOMEN, 62 CASES AND 124 MATCH CONTROLS. IN TERMS OF OUR ANALYTIC APPROACH, WE USE -- CATEGORIES WERE BASED ON THE DISTRIBUTION OF THE CONTROL POPULATION. WE ALSO CONSIDERED ADDRESSING FOR KEY FACTORS SUCH AS BODY MASS INDEX, C PEPTIDES TO TRY TO ACCOUNT FOR THE INSULIN PATHWAY AN CIRCULATING ESTRADIAL. LABORATORY ASSAYS WERE CONDUCTED FOR THE -- USING A STANDARD COMMERCIAL ALIZA ESSAY. SO ON TO THE RESULTS. I'VE TRIED TO SUMMARIZE HERE SOME KEY CHARACTERISTICS FOR THE STUDY POPULATION. AS YOU CAN SEE, AGE AT BLOOD DRAW WAS SIMILAR FOR BOTH CASES AND CONTROLS WHERE WOMEN WERE ON AVERAGE 67 YEARS ON BLOOD DRAW WHICH WAS IMPORTANT BECAUSE THAT WAS A MATCHING FACTOR. IN TERMS OF BODY MASS INDEX, CASES HAD A HIGHER BMI AS COMPARED TO CONTROLS AND WE SAW THIS WHEN WE ANALYZED OR LOOKED AT THE MI CONTINUOUSLY AS WELL AS WITH THE STANDARD BMI CUP POINTS OF 30 AND 35 AND ABOVE. CASES WILL ALSO MORE LIKELY TO REPORT A HISTORY OF DIABETES AND A HISTORY OF HYPERTENSION. THERE WERE NO DIFFERENT DIFFERENCES -- MEDIUM LEPTIN LEVELS WERE HIGHER VERSES CASES IN CONTROL. SOWM RISED HERE ARTHIS IS THE FOURTH PLOT WHERE TER TILES ARE COMPARED TO -- ARE EACH COMPARED TO THE LOWEST TERTILE NOT DEPICTED ON THE PLOT. AS YOU CAN SEE, HIGHER LEPTIN LEVELS WERE ASSOCIATED WITH AN INCREASE IN ENDOMETRIAL CANCER RISK WHEN COMPARING WOMEN IN THE THIRD TERTILE TO THE FIRST, IT'S NOT SHOWN HERE BUT THE TREND WAS ALSO SIGNIFICANT. WE DID NOT SEE STATISTICALLY SIGNIFICANT ASSOCIATIONS WITH EITHER ADD P ADIPONECTIN MARKER, HOWEVER, WHEN LOOKING AT THE RATIO OF THESE ADIPONECTINS TO LEPTIN, WE SEE SIGNIFICANT REDUCTIONS IN RISK WHICH, OF COURSE, ARE IN PART DRIVEN BY THE ASSOCIATION WITH LEPTIN. WE ALSO ADJUSTED OUR ANALYSES FOREST GENERAL ANFOR ESTROGEN AND C PEPTID E. THE RATIO OF TOTAL ADIPONECTIN TO LEPTIN AND HIGH MOLECULAR WEIGHT ADIPONECTIN TO LEPTIN WERE ALSO SUGGESTED -- AFTER TRYING TO ADJUST FOR THESE PATHWAYS. SO WHAT I'M GOING TO TRY TO ADDRESS IN THE NEXT COUPLE SLIDES IS THE POTENTIAL ROLE OF BMI AND HOW DOES THAT FIT IN TERMS OF THESE ASSOCIATIONS SO SHOWN HERE ARE CORRELATIONS ADJUSTING FOR AGE, AND EACH AN OWE LIGHT -- THERE'S LOTS OF STATISTICALLY SIGNIFICANT CORRELATIONS HERE BUT THE KEY POINT I WOULD LIKE TO DRAW ATTENTION TO IS THAT LEPTIN AND BMI ARE STRONGLY CORRELATED AND THAT IS DEFINITELY EXPECTED. YOU MAY ALSO BE WONDERING IF THE EFFECT OF BMI STUDY ON THE POPULATION. WHEN ANALYZING -- WOMEN IN THE HIGHEST CATEGORY OF BODY MASS INDEX HAD APPROXIMATELY THREE FOLD INCREASE IN THE RISK AS COMPARED TO NORMAL WEIGHT WOMEN AND THIS IS PRETTY CONSISTENT WITH PRIOR EPIDEMIOLOGICAL RESEARCH. SO ALTHOUGH I'M NOT A FAN OF THESE ANALYSES, I ADJUSTED FOR BMI BECAUSE THAT'S WHAT EVERYBODY DOES. HOWEVER, I WANTED TO SHOW THE STRONG CORRELATION BECAUSE IN TERMS OF EVALUATING ITS APPROPRIATENESS, WE HAVE TO SORT OF THINK ABOUT IF IT REALLY MAKES SENSE ADJUSTING FOR BMI WHEN THERE'S SUCH A STRONG CORRELATION PARTICULARLY WITH LEPTIN, SO NO BIG SURPRISE, LEPTIN -- THE ASSOCIATION WITH LEPTIN IS ATTENUATED AFTER ADJUSTMENT FOR BODY MASS INDEX AS WELL AS BOTH RATIO MEASURES. SO AS WITH ANY STUDY, THERE ARE BOTH LIMITATIONS IN STRENGTHS, THE KEY ONE BEING SAMPLE SIZE, ALSO POTENTIAL ISSUES WITH GENERALIZABILITY GIVEN THAT THESE ARE WOMEN WHO VOLUNTEER FOR CLINICAL TRIAL, AND WE HAVE LIMITED INFORMATION ON SOME CHARACTERISTICS. THE KEY STRENGTHS ARE THAT WE WERE ABLE TO MEASURE MULTIPLE ADIPOKINES IN PREDYING IK LEVELS PREDIAGNO STIC LEVELS. WE ALSO TRIED TO ACCOUNT FOR INTERRELATED PATHWAYS. SO IN SUMMARY, HIGHER LEPTIN LEVELS -- THIS IS CONSISTENT WITH THE PRIOR CASE CONTROL STUDIES, AND MAY SUGGEST THAT LEPTIN OPERATES DIRECTLY ON RISK INDEPENDENT OF THOSE PATHWAYS. WE DO NOT OBSERVE -- WITH EITHER ADIPONECTIN MARKER, AND GIVEN OUR FINDINGS WITH THE RATIO OF HIGH MOLECULAR WEIGHT TO ADIPONECTIN, FUTURE STUDIES MAY WANT TO CONSIDER -- RATHER THAN HISTORICALLY ONLY MEASURING ONE, AND LASTLY THE QUESTION OF TOTAL VERSUS HIGH MOLECULAR WEIGHT ADIPONECTIN, GIVEN THIS IS THE FIRST STUDY TO TRY TO ADDRESS T I THINK MORE RESEARCH IS NEEDED BEFORE WE CAN REALLY DETERMINE WHRB IT IS A BETTER MEASURE TO BE USED. THAT'S T THANK YOU FOR YOUR TIME AND ATTENTION. [APPLAUSE] >> THANK YOU. SO WE'RE AT OUR TIME. SO SO IF THERE IS ONE QUESTION, A BURNING QUESTION FOR ANY OF THE SPEAKERS, WE COULD TAKE TIME FOR THAT BUT WE DON'T HAVE TIME FOR THE PANEL BECAUSE WE'RE OVER TIME HERE. OR IF ANY OF THE SPEAKERS WANTED TO MAKE A LAST COMMENT OR SOMETHING THAT CAME UP. KAREN, DID YOU WANT TO ASK -- >> I WAS WONDERING WHETHER YOU THOUGHT THAT WAS ACTUALLY A BIOLOGICAL DIFFERENCE BETWEEN THE HUMANS AND THE RODENTS, SO WHETHER THAT WAS ACTUALLY THE EFFECT OF GENDER COMING OUT IN THAT WAY. >> SO WHAT SOME RESEARCHERS HAVE SUGGESTED THIS MIGHT BE A DIFFERENCE FOR THE NEW OPIOIDS, THAT IT COULD BE BIOLOGIC, AND I GUESS THIS HASN'T BEEN THOROUGHLY EXPLORED, BUT THE THOUGHT IS THAT THERE MAY BE DIFFERENCES IN THE ACTIVE METABOLITES IN HUMANS VERSUS ANIMALS. >> THANK YOU. >> ANY OTHER BURNING QUESTIONS? WELL, PLEASE JOIN ME IN THANKING OUR SPEAKERS AND THANK YOU FOR ATTENDING THIS SYMPOSIUM. [APPLAUSE]