MY NAME IS DR. STEPHANIE GEORGE, PROGRAM DIRECTOR AND EPIDEMIOLOGIST IN THE DIVISION OF EXTRAMURAL RESEARCH AT THE NATIONAL INSTITUTE OF ARTHRITIS, MUSCULOSKELETAL AND SKIN DISEASES. ON BEHALF OF THE NHLBI WORKING GROUP ON OBESITY, I AM EXCITED TO SERVE AS THE MODERATOR TODAY FOR THE NINTH OBESITY NUTRITION AND PHYSICAL ACTIVITY SEMINAR. PAST PRESENTATIONS HAVE HIGHLIGHTED A VARIETY OF TOPICS SUCH AS TECHNOLOGY ASSISTED INTERVENTIONS FOR WEIGHT MANAGEMENT, FOOD INSECURITY, AND COVID-19. THE ROLE OF TEACHING KITCHENS IN TEACHING NUTRITION, DISPARITIES AND MANY OTHERS. TODAY'S PRESENTATION BY DR. KRAUSE IS ENTITLED M SCIENCE SUPPORTING PERSONALIZED LIFESTYLE MEDICINE WITH A FOCUS ON PHYSICAL ACTIVITY. WELCOME. SOME OF YOU ARE JOINING HERE FROM THE NIH, WHERE WE'RE JUST STARTING OUR WORK DAYS. SOME MAY BE JOINING ACROSS THE COUNTRY WHERE YOU'RE JUST WAKING UP. SOME EVEN ACROSS THE OCEAN, WHERE IT'S AFTERNOON OR EVENING AFTER YOUR WORK DAYS. SOME MIGHT EVEN BE TOMORROW, IF YOU'RE JOINING FROM THE FAR REGIONS. WHEREVER YOU ARE, YOU MIGHT BE HERE TO LEARN ABOUT THE LATEST RESEARCH IN THIS SPACE, OR MAYBE YOU'RE HERE BECAUSE OF THE TITLE, THAT IT CAUGHT YOU PARTICULARLY BECAUSE OF A PERSONAL INTEREST IN YOUR OWN PERSONALIZED MEDICINE FOR YOUR LIFE. WHILE VIRTUAL, WE MAKE UP A NETWORK HERE OF PEOPLE INTERESTED IN THIS SPACE, AND I PROMISE YOU AFTER THIS TALK, YOU WILL BE ENRICHED. AS YOU CAN TELL FROM BILL KRAUS' BACKGROUND, HE HAS A TRUE INTEREST IN ASTROPHYSIC. ACTUALLY HE MAJORED IN HAD ASTRONOMY AND ASTROPHYSICS AT HARVARD AS AN UNDERGRAD WAD. I'LL TELL YOU DESPITE THE FACT HE HAS TRAINING IN THIS SPACE HE'S ALSO EXCELLENT AT TAKING ONE THING, ONE FACT, AND PUTTING IT INTO A BIGGER PICTURE FOR US. SO AGAIN, WE'RE HERE FOR DIFFERENT REASONS, WE'RE ALL PART OF THIS NETWORK INTERESTED IN THIS SPACE TODAY. BEFORE WE BEGIN, I'D LIKE TO YOU TAKE A MOMENT, PERHAPS STAND UP, PERHAPS STRETCH AROUND, BECAUSE THAT'S WHAT WE'RE HERE FOR, TO TALK ABOUT PHYSICAL ACTIVITY, AND WHILE I CAN'T SEE YOU RIGHT NOW AND YOU CAN SEE ME, I WANT YOU ON A PIECE OF PAPER OR ON YOUR SCREEN ON YOUR COMPUTER, ON A WORD DOC, TO WRITE DOWN ONE PHYSICAL ACTIVITY THAT YOU DO THAT BRINGS YOU A LOT OF JOY. SO TAKE A MOMENT AND WRITE THAT DOWN. I'M GOING TO DO THE SAME. I'M GOING TO RETURN TO THAT WHEN WE CLOSE OUT THE TALK TODAY. BEFORE WE START, I WANT TO REVIEW A FEW HOUSEKEEPING ITEMS AS WELL. THROUGHOUT THE PRESENTATION AND DURING THE MODERATED Q & A, PLEASE SEND ANY QUESTIONS TO THE EMAIL ADDRESS LISTED ON THE SLIDES. OR CLICK THE LIVE FEEDBACK BUTTON AT THE BOTTOM OF THE VIDEOCAST SCREEN TO SUBMIT A QUESTION OR A COMMENT. AND WE WILL GET TO THOSE AFTER BILL'S TALK. AND NOW TO INTRODUCE THE FAMOUS BILL KRAUS. BILL IS A PHYSICIAN SCIENTIST AND AN INTEGRATIVE PHYSIOLOGIST. HE HAS SPENT HIS SCIENTIFIC AND CLINICAL CAREER DEVOTED TO THE STUDY AND IMPLEMENTATION OF PHYSICAL ACTIVITY AND EXERCISE FOR HEALTH AND ITS CURATIVE POTENTIAL. PERHAPS ONE OF THE REASONS WHY WE ARE ALL HERE TODAY TO HEAR MORE ABOUT THAT. HE IS THE RICHARD AND PAT JOHNSON DISTINGUISHED UNIVERSITY PROFESSOR OF CARDIOVASCULAR GENOMICS IN THE DIVISION OF CARDIOLOGY AND MOLECULAR PHYSIOLOGY INSTITUTE IN THE SCHOOL OF MEDICINE AT DUKE UNIVERSITY. IN 1996, HE RECEIVED HIS FIRST INTERVENTIONAL HUMAN STUDY TO STUDY THE DOSE-RESPONSE RELATIONS OF EXERCISE AND CARDIOVASCULAR RISK, WHICH WAS CALLED STRIDE. HE WAS SUBSEQUENTLY FUNDED FOR THREE LARGE NIH FUNDED EXERCISE TRAINING STUDIES THAT HAVE CONTRIBUTED SUBSTANTIALLY TO OUR UNDERSTANDING OF EFFECTS IN DIFFERENT INTENSITIES, AMOUNTS AND MODES OF EXERCISE ON CARDIOMETABOLIC HEALTH. HIS CENTER IS ONE OF SIX ADULT CENTERS FOR THE MOLECULAR TRANSDUCERS OF PHYSICAL ACTIVITY CONSORTIA, OTHERWISE KNOWN AS MOTOR PAC AND HE SERVED ON THE 2008 AND 2018 PHYSICAL BEING ATIVITY GUIDELINES ADVISORY COMMITTEE, THE LATTER OF WHICH I HAD THE PLEASURE OF WORKING WITH BILL ON. HIS CLINICAL FOCUS IS CARDIOVASCULAR PREVENTION WITH FOCUS ON LIFESTYLE MODIFICATION, CARDIAC REHABILITATION, AND SPORTS CARDIOLOGY. AND SO WITHOUT FURTHER ADO, I WOULD LIKE TO INTRODUCE DR. BILL KRAUS. >> THANK YOU, STEPHANIE, FOR THAT GENEROUS INTRODUCTION. SO LET'S JUST GET RIGHT TO IT. AS STEPHANIE SAID, I HAD THE PLEASURE OF SERVING ON THE PHYSICAL ACTIVITY GUIDELINES ADVISORY COMMITTEE THAT PROVIDES THE SCIENCE FOR THE DEVELOPMENT OF THE GUIDELINES WHICH IS DONE BY THE CENTERS FOR DISEASE CONTROL UNDER THE GUIDANCE OF DEPARTMENT OF HEALTH AND HUMAN SERVICES. AND AS PART OF THE LAST GUIDELINES, WE ASSEMBLED A TABLE TO SHOW THAT PHYSICAL ACTIVITY HAS A MYRIAD OF HEALTH BENEFITS, AND A MAJOR PROPORTION OF THOSE ARE LISTED HERE BUT THERE ARE MANY OTHERS. AND I WANTED TO MAKE THE POINT HERE ABOUT THE GREAT DISSIDENCE, WHAT I CALL THE GREAT DISSIDENCE. BEING A CLINICIAN WHO ATTEMPTS TO IMPLEMENT MECHANISMS TO INCREASE PHYSICAL ACTIVITY IN MY PATIENTS FOR THEIR HEALTH BENEFITS. I RECOGNIZE THAT ALTHOUGH THESE DATA MOSTLY COLLECTED IN LARGE POPULATIONS ARE EPIDEMIOLOGIC, YOU HAVE A PATIENT IN FRONT OF YOU. THE OTHER 999,000 OF THAT 10,000 COOR THE THAT COHORT THAT MIGHT HAVE CONTRIBUTED TO THAT DATA TO THAT PATIENT IN FRONT OF YOU REALLY DOESN'T MATTER. THEY WANT TO KNOW WHAT'S BEST FOR THEM AND THEY WANT TO KNOW WHAT WILL WORK FOR THEM. HENCE, THE EFFORT TO TRY TO DEVELOP A PRECISION-DIRECTED OR PERSONALIZED APPROACH TO LIFESTYLE MEDICINE, AND HERE WE'LL TALK ABOUT PHYSICAL ACTIVITY. SO TODAY I'M HOPING TO COVER IN THE BRIEF TIME I HAVE A BRIEF DISCUSSION ABOUT MY VIEW ABOUT WHAT PERSONALIZED OR PRECISION LIFESTYLE MEDICINE IS. TO TALK ABOUT LESSONS FROM CLINICAL TRIALS, AND I'LL FOCUS ON OUR FIRST OF THREE STRIDE TRIALS, TO TALK ABOUT WHAT WE KNOW ABOUT THE AMOUNT, INTENSITY AND MODE EFFECTS OF EXERCISE AND CARDIOMETABOLIC HEALTH, IN ORDER TO BETTER PRESCRIBE BY AMOUNT, INTENSITY AND MODE, EXERCISE FOR THE HEALTH BENEFITS OF OUR PATIENTS. TO TALK ABOUT WHETHER EVEN WITHIN THOSE GROUPS ORTHOS GENERALIZATIONS, INDIVIDUAL DIFFERENCES AND CLINICAL RESPONSES, AND WE KNOW THERE ARE AND WE'LL TALK ABOUT THAT. AND CAN THESE CLINICAL RESPONSES BE PREDICTED WITH SOME DEGREE OF PRECISION IN ORDER TO DIRECT THESE RECOMMENDATIONS TO OUR SPECIFIC PATIENTS, AND A NEW AREA THAT WE'VE GOTTEN INVOLVED IN IS WHETHER OR NOT WE CAN PREDICT PHYSICAL ACTIVITY BEHAVIOR. THAT IS, WHETHER INDIVIDUALS WILL CONTINUE WITH INITIATION OF A PROGRAM THAT THEY STARTED. AND HOW CAN WE USE SUCH INFORMATION CLINICALLY. AND FINALLY, WE'LL TALK ABOUT SOME UNANSWERED QUESTIONS AND KNOWLEDGE GAPS. SO MY VIEW OF WHAT PERSONALIZED LIFESTYLE MEDICINE IS. IT'S TAILORING LIFESTYLE INTERVENTIONS TO THE SPECIFIC MEDICAL NEEDS OF THE INDIVIDUAL, AND HOW CAN WE DO THAT. AND I WROTE A CHAPTER IN A TEXT BY WILLARD -- HUNT WILLARD AND JEFF BEGINS GINSBURG THAT IG TO HERE. SO LET'S TAKE THIS DIAGRAM HERE AND CONSIDER PERSONALIZED LIFESTYLE MEDICINE BEING THE UNION OF A DOMAIN THAT DEALS WITH GENETICS, PHARMACOLOGY, AND LIFESTYLE MEDICINE HERE FOCUSING ON PHYSICAL ACTIVITY. SO ACROSS THE TOP, WE KNOW ABOUT PHARMACOGENETICS. THAT IS, WHETHER OR NOT CERTAIN GENETIC VARIANTS CAN PREDICT RESPONSE TO A GIVEN PHARMACOLOGIC AGENT. WE'RE GOING TO TALK ABOUT -- A LITTLE BIT HERE ABOUT GENETIC LIFESTYLE MEDICINE, WHETHER GENETICS CAN PREDICT RESPONSES TO PHYSICAL ACTIVITY BEHAVIORS. AND EVEN A LITTLE BIT ABOUT WHETHER OR NOT PHARMACOLOGIC EXPOSURE CAN INTERACT WITH PHYSICAL ACTIVITY TO EFFECT RESPONSES. AND THERE ARE A COUPLE TRIALS GOING ON, FUNDED BY NHLBI AND NIDDK TO LOOK AT THIS, PARTICULARLY WITH METFORMIN. BUT WE'LL TALK ABOUT ANOTHER AGENT TODAY. BUT THE HOLY GRAIL WOULD BE ABLE TO PREDICT WHETHER OR NOT AN INDIVIDUAL WILL HAVE AN INTERACTION WITH PHYSICAL ACTIVITY AND WHETHER IT WILL BE IN A FAVORABLE OR UNFAVORABLE DIRECTION. SO LET'S TALK A LITTLE ABOUT OUR LESSONS FROM THE STRRIDE STUDIES. SO STRRIDE STANDS FOR STUDIES OF A TARGETED RISK REDUCTION WITH DEFINED EXERCISE. I AM PARTICULARLY PROUD OF THIS ACRONYM BECAUSE IT TAKES THE FIRST LETTER OF EACH OF THE WORDS IN THIS PHRASE, AND I NOTICE THAT SOME OF MY CARDIOVASCULAR COLLEAGUES WILL TAKE LETTERS RANDOMLY FROM WORDS AND PUT THEM INTO AN ACRONYM. IT TOOK US A WHILE TO DEVELOP THIS, BUT WE'RE PROUD OF THE STRRIDE ACRONYM. AND SO IN THE FIRST STRRIDE STUDY, WE RECRUITED INDIVIDUALS WITH ROUGHLY THESE CHARACTERISTICS. IN ORDER TO STUDY THE RESPONSE OF EXERCISE TRAINING, PARTICULARLY TO LIPIDS AND TO GLUCOSE HOMEOSTASIS. WE CHOSE TO TAKE INDIVIDUALS THAT WERE OVERWEIGHT OR MODERATELY OBESE, SO THE MI IS BETWEEN 25 AND 35 THAT WERE IN MIDDLE AGE, 40 TO 65, THAT HAD AN ABNORMALITY IN EITHER LDL OR HDL CHOLESTEROL. AND NOTICE AT THE TIME, THIS WAS 1996,s LDL UP TO 190 WAS CONSIDERED TO ARE APPROACHED FIRST WITH LIFESTYLE INTERVENTION. LIKEWISE FOR FASTING GLUCOSE, THAT WAS A TIME WHEN FASTING GLUCOSE OF 140 MILLIGRAMS PER DECILITER WAS CONSIDERED THE DIAGNOSTIC CRITERIA FOR DIABETES. BLOOD PRESSURE LIKEWISE, 160/90, 1ST APPROACH WOULD HAVE BEEN LIFESTYLE AT THAT TIME. SO YOU CAN SEE THIS DATES A LITTLE BIT THE POPULATION IN THE STUDY. BUT IT GAVE US THE OPPORTUNITY TO REALLY MEASURE RESPONSES, AND THE OTHER THING I WANT TO DRAW ATTENTION TO IS, THIS WAS A TIME IN WHICH INDIVIDUALS, WOMEN, WERE BEING PUT ON HORMONE REPLACEMENT THERAPY IF THEY WERE POST-MENOPAUSAL, FOR ACTUALLY CARDIOMETABOLIC HEALTH BENEFITS. IT WASN'T UNTIL LATER THAT THE WOMEN'S HEALTH INITIATIVE AND OTHER STUDIES IN CARDIOVASCULAR DISEASE SHOWED THAT, IN FACT, HRT, HORMONE REPLACEMENT THERAPY, WAS NOT BENEFICIAL AND IT'S NO LONGER USED AS A BASELINE PREVENTIVE THERAPY. BUT WE WERE FORTUNATE ENOUGH TO HAVE WOMEN ON HORMONE REPLACEMENT THERAPY AND ABOUT HALF WERE ON HORMONE REPLACEMENT THERAPY, WOMEN IN THIS GROUP, AND THEY HAD TO BE ON IT FOR ABOUT SIX MONTHS. THIS WILL BE PERTINENT LATER. SO IN STRRIDE ONE, WE RANDOMIZED INDIVIDUALS TO FOUR DIFFERENT GROUPS. AND I'M GOING TO OUTLINE WHAT THOSE GROUPS ARE HERE. AND THEY WERE CHARACTERIZED BY DIFFERENCES IN INTENSITY, A PERCENTAGE OF PEAK VO2 IN WHICH THEY WOULD BE EXERCISING, AMOUNT, KCAL PER WEEK THEY WOULD BE EXERCISING, AND THAT WOULD THOSE THEN DETERMINE THE MINUTES PER WEEK OF THEIR PROGRAM. SO FIRST WAS THE BRISK WALKING GROUP. WE CAN NOW CALL THIS THE PHYSICAL ACTIVITY GUIDELINES GROUP BECAUSE IT TURNS OUT THESE INDIVIDUALS WERE EXERCISING ABOUT 170 MINUTES PER WEEK, GUIDELINES SAY 150, AND IT'S A BRISK WALK, AND THE ENERGY EQUIVALENT OF 13 MILES PER WEEK IS WHAT THEY PERFORMED. THEN THERE WAS A JOGGING GROUP MATCHED ON A DISTANCE OR TOTAL ENERGY EXPENDITURE, AND PEAK VOS 60 TO EIGHT TEE 5% OF PEAK VO2 AND IT TOOK THEM ABOUT 120 MINUTES A WEEK TO DO THAT. THESE WERE BASICALLY THE GUIDELINES FOR MAINTAINING CARDIORESPIRATORY FITNESS THAT WERE FIRST ADVERTISED IN , SO S COULD BE THE FITNESS GROUP. THEN THERE'S THE INDIVIDUALS THAT WERE ASKED TO DO VIGOROUS INTENSITY EXERCISE FOR ABOUT 22 MILES PER WEEK. IT TOOK THEM ABOUT 170 MINUTES PER WEEK TO DO THAT AMOUNT OF EXERCISE. I CALL THIS THE PATHENBARGER GROUP BECAUSE THE HARVARD ALUMNI STUDY SHOWED THIS WAS THE LATER OF THE RISK ASSOCIATED WITH PHYSICAL ACTIVITY IN THAT STUDY, 20 MILES PER WEEK OF JOGGING. SO -- AND THEN WE HAD AN INACTIVE GROUP THAT HAD NO INTERVENTION, WERE NOT GIVEN ANY PRESCRIPTION OR ALLOWED FREE LIVING TO CONTINUE TO DO WHAT THEY WERE DOING FOR ABOUT SIX MONTHS. NONE OF THESE GROUPS HAD A DIETARY COMPONENT INTRODUCED AT THIS TIME. HOWEVER, WE DID MONITOR DIET OVER THE COURSE OF THE INTERVENTION PHASE WITH MONTHLY EITHER DIETARY RECALLS OR THREE-DAY FOOD RECORDS, AND I'LL JUST SAY AT THE OUTSET, WE CAN SEE NO IMPACT ON THEIR DIETS DURING THE COURSE OF THESE INTERVENTIONS. SO YOU CAN SEE THE DESIGN ALLOWED US THEN TO UNDERSTAND THE INFLUENCE OF INTENSITY WHEN CONTROLLING FOR AMOUNT WHEN COMPARING THE FIRST TWO GROUPS. UNDERSTAND THE INFLUENCE OF AMOUNT WHEN CONTROLLING FOR INTENSITY IN THE SECOND TWO GROUPS. AND ALTHOUGH NOT DESIGNED TO LOOK AT FREQUENCY, YOU COULD ACTUALLY INFER SOME INFLUENCE OF FREQUENCY BECAUSE THOSE IN THE BRACKETING GROUPS, THE 170 MINUTES PER WEEK, CONDUCTED THEIR EXERCISE APPROXIMATELY FOUR SESSIONS PER WEEK WHEREAS THE MIDDLE GROUP DID THREE SESSIONS PER WEEK. SO THE INTERVENTION WAS THIS. THEY WERE ASKED TO PARTICIPATE WITH US FOR 9 TO 10 TO 12 MONTHS. ONCE RANDOMIZED TO THEIR GROUP, THEY THEN HAD THEIR BECAUSE LINE EXERCISE TEST ACTUALLY DONE BEFORE RANDOMIZATION, BUT THEN ONCE THE FIRST STUDY PERIOD WAS BEFORE INITIATION OF TRAINING, WE HAD A THREE-MONTH RAMP-UP PERIOD IN WHICH INDIVIDUALS WERE ASKED TO GO FROM DOING BASICALLY NOTHING TO THEIR TARGET EX-ER EE PROGRAM. WE DID THIS PARTICULARLY TO AVOID MUSCULOSKELETAL INJURIES THAT MIGHT HAVE INTERFERED WITH THEM CONTINUING IN THE PROGRAM. THEN THERE WAS A SIX-MONTH STEADY STATE TRAINING PROGRAM AND THERE WERE THREE ASSESSMENT PHASES STARTING 24 HOURS AFTER THE LAST BOUT OF EXERCISE. ONE THE DAY AFTER, 15 DAYS ONE S AFTER AND 115 DAYS AFTER. THOSE WERE USED SPECIFICALLY TO LOOK AT THE EFFECTS OF DETRAINING. I WON'T TALK ABOUT THOSE ASSESSMENTS TODAY. THEY'RE VERY INFORMATIVE ABOUT MECHANISM. AND THAT WAS THE PURPOSE OF DOING THOSE STUDIES. AND THEN WE OFFERED THEM RETRAINING UP TO THEIR STEADY STATE TRAINING LEVEL. AND THEN THEY WERE FREE TO GO ABOUT THEIR WAY. SO THE QUESTION IS, WHAT DID WE LEARN ABOUT THE AMOUNT, INTENSITY AND MODE EFFECTS OF THE EFFECTS ON CARDIO HEALTH. WHAT WE ACTUALLY PREDICTED IN OUR APPLICATION AS RESPONSE IN CARDIORESPIRATORY FITNESS TO THESE DIFFERENT EXERCISE PROGRAMS IS DEPICTED HERE. THE INACTIVE GROUP WILL ALWAYS BE IN YELLOW ON THE LEFT IN THE SUBSEQUENT SLIDES. THE LOW AMOUNT MODERATE INTENSITY GROUP, THE RISK WALKING GROUP WILL BE NEXT. OF THE LOW AMOUNT VIGOROUS INTENSITY WILL BE NEXT AND THE HIGH AMOUNT VIGOROUS INTENSITY WILL BE LAST ON THE RIGHT. AND YOU CAN SEE THEN TO JUST REITERATE BY COMPARING THE MIDDLE TWO GROUPS, YOU CAN UNDERSTAND THE INFLUENCE OF INTENSITY WHEN CONTROLLING FOR AMOUNT AND THE GROUPS ON THE RIGHT, THE INFLUENCE OF AMOUNT WHEN CONTROLLING FOR INTENSITY. SO THIS IS OUR ICONIC STUDY DESIGN FOR OUR THREE STRRIDE STUDIES. AND YOU CAN SEE THAT THERE IS AN INCREMENTAL EFFECT OF INTENSITY AND CARDIORESPIRATORY FITNESS AND INCREMENTAL EFFECT OF AMOUNT WHEN CONTROLLING FOR INTENSITY. EVERY ATHLETE KNOWS THIS, IN ORDER TO MAINTAIN OPTIMAL CARDIORESPIRATORY FITNESS FOR BEST PERFORMANCE, YOU EXERCISE AS MUCH AS YOU CAN DAILY, AND WHEN YOU ACTUALLY GET IN THAT COMPETITION, THAT 2% DIFFERENCE IN CARDIORESPIRATORY FITNESS CAN MAKE THE DIFFERENCE IN THE OLYMPICS BETWEEN A GOLD MEDAL AND NOT MEDALING AT ALL. SO THIS IS A GROUP INTERESTED IN OBESITY, SO I'M SHOWING A SLIDE ABOUT THE PERCENT CHANGE IN BODY MASS. THIS IS PERCENT CHANGE, SO FOR A 200-KILOGRAM MAN, A 1% CHANGE WOULD HAVE BEEN 2 POUNDS. AND YOU CAN SEE THAT OVER THE COURSE OF SIX MONTHS, CONTINUED TO LIVE THE LIVES THEY WERE LIVING BEFORE THE PROGRAM STARTED, IN THE INACTIVE GROUP, THEY GAINED 2 POUNDS, WHICH TRANSLATES TO 4 POUNDS IN A YEAR OR 40 POUNDS OVER 10 YEARS. AND WHEN I FIRST STARTED SHOWING THESE SLIDES, NO ONE BELIEVED THAT. AND FOR THOSE IN NORTH CAROLINA, I JUST REFERRED THEM TO THE AIRPORT OR THE BEACH, AND PEOPLE BEGAN TO REALIZE THIS IS EXACTLY WHAT'S HAPPENING TO THE U.S. POPULATION. THAT ARE INACTIVE. BUT WHEN YOU LOOK AT THE MIDDLE TWO GROUPS, YOU CAN SEE THAT ANY PHYSICAL ACTIVITY OR ANY EXERCISE ELIMINATED THAT WEIGHT GAIN, AND IN FACT, MATCHED FOR AMOUNT OR ENERGY EXPENDITURE WAS ABOUT THE SAME MODEST DEGREE OF WEIGHT LOSS. SO I ALWAYS STOP HERE AND SAY THAT EXERCISE IS NOT WHAT YOU DO TO LOSE WEIGHT. BUT AS YOU'LL SEE IN THE NEXT SLIDE, IT'S WHAT YOU DO TO MAINTAIN WEIGHT AT YOUR CURRENT LEVEL. HOWEVER, IN THE HIGH AMOUNT VIGOROUS INTENSITY GROUP, THOSE INDIVIDUALS LOST A SIGNIFICANTLY MORE AMOUNT OF WEIGHT BUT STILL, IT'S EQUAL TO 4 POUNDS IN A 20-POUND -- I DID WANT TO PLOT THIS OUT HERE. IF YOU ACTUALLY PLOT OUT EXERCISE DOSE IN KILLOMETERS HERE VERSUS THE WEIGHT CHANGE IN KILL KILOGRAMS FOR THESE FOUR GROUPS, YOU CAN SEE ACTUALLY THIS CURVE CROSSES THE ABCIS SA AT ABOUT 6 1/2 OR 7 KILOMETERS PER WEEK. EXERCISING A MODEST AMOUNT, BASICALLY 4 MILES A WEEK OF MODERATE INTENSITY EXERCISE, ONE CAN MAINTAIN ONE'S WEIGHT. WHICH IS A USEFUL CLINICAL PARAMETER FOR PATIENTS. NOW THIS WAS THE MOST SURPRISING FINDING WE HAD IN OUR STRRIDE 1 STUDY. WE DID NOT PREDICT THIS, BUT IT TURNED OUT TO BE VERY INFORMATIVE. SO WHAT THIS IS IS A PLOT OF CHANGE IN SI, CHANGE IN INSULIN SENSITIVITY INDEX DETERMINED BY A FREQUENTLY SAMPLED INTRAVENOUS GLUCOSE TOLERANCE TEST, WHICH TARGETS MUSCLE INSULIN SENSITIVITY. SO JUST THINK WE'RE TALKING ABOUT MUSCLE INSULIN SENSITIVITY HERE. UP TO 80% OF THE GLUCOSE THAT IS CONSUMED IN A MEAL ACTUALLY GETS STORED IN SKELETAL MUSCLE. AND THIS IS WHAT THIS TEST BASICALLY MEASURES. SO WE ADMINISTERED GLUCOSE INTRAVENOUSLY. THERE IS A LITTLE BIT OF INSULIN RELEASED FROM THE PANCREAS WHICH PROMOTES THAT GLUCOSE UPTAKE IN MUSCLE, AND THEN WE ADMINISTER A LITTLE BIT MORE OF INSULIN INTRAVENOUSLY AND THAT THEN COMPLETES THE UPTAKE. THAT'S MODELED USING THE SO-CALLED BERGMAN MODEL, AND REVEALS A ITEM CALLED THE INSULIN SENSITIVITY INDEX. SO WHAT WE SAW HERE IS THAT THE INACTIVE GROUP DIDN'T LOSE ANY MUSCLE INSULIN SENSITIVITY BY CONTINUING TO BE INACTIVE. THEY'RE ALREADY IN THE BASEMENT. BUT YOU CAN SEE THAT ANY EXERCISE HAD A VERY ROBUST IMPROVEMENT IN INSULIN SENSITIVITY BUT THE MOST INTRIGUING THING WAS THAT COMPARING THE MIDDLE TWO GRAPHS, YOU CAN SEE THAT ACTUALLY THERE IS A STATISTICALLY SIGNIFICANTLY BETTER IMPROVEMENT IN INSULIN SENSITIVITY IN THOSE THAT DO THE MODERATE INTENSITY EXERCISE CONTROLLING FOR AMOUNT THAN THOSE THAT DO THE VIGOROUS INTENSITY EXERCISE, IMPLYING THAT THERE MAY BE SOME COUNTER REGULATORY EFFECTS GOING ON WITH VIGOROUS INTENSITY EXERCISE THAT INHIBITS THE FLOW RESPONSE TO EXERCISE. IN FACT, THE INDIVIDUALS HAD TO DO 50% MORE VIGOROUS INTENSITY EXERCISE IN THE GROUP ON THE RIGHT TO EQUAL THE INSULIN SENSITIVITY RESPONSE WITH MODERATE INTENSITY EXERCISE. THIS IS GREAT NEWS FOR, FOR EXAMPLE, PRE-DIABETIC POPULATIONS SUCH AS THIS, OR EVEN THOSE THAT HAVE DIABETES, BECAUSE WHAT IT SAYS IS YOU DON'T HAVE TO DO VIGOROUS HIT EXERCISE TO IMPROVE YOUR INSULIN SENSITIVITY, IN FACT, IT MAY BE BEST FOR YOU TO BE DOING BRISK WALKING IN THAT DISEASE GROUP. SO THERE WERE SOME DOUBTS ABOUT WHETHER OR NOT THIS WAS A REAL FINDING IN THE STRRIDE STUDY. I CAN SAY THAT IN STRRIDE 3, WE REPRODUCED THOSE FINDINGS. I DON'T HAVE TIME TO SHARE THOSE DATA WITH YOU HERE. WE CALL THAT STUDY STRRIDE PRE-DIABETES. BUT WHAT WE DID DO IS WE LOOKED AT THE CHAIK CHANGE IN TRIGLS IN THE SAME POPULATIONS, THE SAME INDIVIDUALS, AND WE CAN SEE A ROBUST DECREASE IN TRIGLYCERIDES IN THE MODERATE INTENSITY GROUP. ONCE AGAIN, IN FACT, THE CURVES FOR TRIGLYCERIDES ALMOST REPRODUCES THAT AS THE INVERSE OF THAT INSULIN SENSITIVITY INDEX. AND SERUM TRIGLYCERIDES ARE ALSO INSULIN RESPONSIVE PARAMETER, EXCEPT IN THIS CASE, IN ADIPOSE TISSUE. SO WE REALLY THINK THIS IS REAL BIOLOGY AND IT REALLY POINT TO SOMETHING THAT IS A REALLY IMPORTANT CLINICAL MESSAGE HERE. SO THESE ARE THE GROUP RESPONSES. WHAT YOU GUYS HAVE BEEN LOOKING AT, I DARE SAY, UNLESS YOU'RE A STATISTICIAN, IS ACTUALLY THE HEIGHT OF THE BARS. AND WE TEND TO PUT IN OUR BACKGROUND THESE AIR BARS. WHAT THESE AIR BARS INDICATE IS THAT THERE'S A SIGNIFICANT DIFFERENCE IN RESPONSIVENESS AMONG THESE -- IN THIS GROUP. IN THE SUBGROUPS. SO ONE CAN USE -- I'M SORE S, LET'S GO BACK AGAIN. ONE CAN USE THESE DATA TO ACTUALLY PERSONALIZE EXERCISE PRESCRIPTION IN THE CLINIC, AND I DO THIS ALL THE TIME. I TELL MY PRE-DIABETIC PEOPLE, YOU KNOW, BRISK WALKING IS GOOD. JUST DO STEPS AND MEASURE THE STEPS AND LET'S FOLLOW THAT. AND THAT'S OBVIOUSLY MUCH MORE TENABLE FOR SOME INDIVIDUALS. HOWEVER, NOT EVERYBODY IS GOING TO BE AT THE SAME RESPONSIVENESS, SO I HAVE TO KEEP THAT IN THE BACK OF MY MIND. NOW WE'RE GETTING TO WHAT I CALL THE GREAT DISSIDENCE, RIGHT? SO HOW DO WE KNOW IF YOU COME TO ME THAT YOU'RE GOING TO BE A HIGH RESPONDER OR LOW RESPONDER OR UNRESPONDER TO ALL THAT EXERCISE YOU'RE GOING TO DO? SO LET'S TALK A LITTLE BIT ABOUT DRUG EXERCISE INTERACTIONS FIRST BEFORE WE GO THERE. AND SO THIS IS A PLOT OF INSULIN SENSITIVITY CHANGE IN STRRIDE 1 JUST THE SAME DATA THAT YOU SAW BEFORE, BUT IT'S NOW BROKEN OUT BY WOMEN AND MEN IN THE UPPER BARS. AND YOU CAN SEE THE MEN ARE IN THE BLUE, AND THE WOMEN ARE IN THE GREEN. AND BASICALLY THERE'S NO STATISTICALLY SIGNIFICANT DIFFERENCE BETWEEN THE RESPONSE IN THE WOMEN AND THE MEN. THERE'S A HINT IN THAT -- THE WOMEN MIGHT BE A LITTLE LESS RESPONSIVE IN GENERAL, BUT YOU CAN'T REALLY MAKE A LOT ABOUT THAT IN A STUDY OF THIS SIZE. HOWEVER, KIM HUFFMAN, A COLLEAGUE FOR MANY YEARS, HAS HAD A BRILLIANT IDEA AND SHE SAYS, WHY DON'T WE BREAK OUT THE WOMEN BY WHETHER THEY'RE ON HORMONE REPLACEMENT THERAPY OR NOT? IT TURNED OUT ABOUT HALF OF THE WOMEN WERE ON HRT AND HALF NOT. AND WE FOUND SOMETHING VERY REMARKABLE. THERE IS INTERACTION BETWEEN EXERCISE AND HORMONE REPLACEMENT THERAPY. AND IN FACT, IN THE WOMEN IN THE LOW AMOUNT MODERATE INTENSITY GROUP, THERE'S BASICALLY NO DIFFERENCE. THE WOMEN ON HRT DID A LITTLE BETTER, THEY'RE IN GREEN, THAN THE WOMEN IN THE YELLOW BARS THAT WERE NOT ON HORMONE REPLACEMENT THERAPY. HOWEVER, WHEN YOU LOOK AT VIGOROUS INTENSITY EXERCISE, IF YOU ARE A WOMAN IN STRRIDE 1 ON HORMONE REPLACEMENT THERAPY, YOU HAD ALMOST NO IMPROVEMENT IN INSULIN SENSITIVITY. WITH VIGOROUS INTENSITY EXERCISE, WHEREAS THOSE THAT WERE ON HRT PRESERVED THEIR RESPONSE. AND IN FACT, THEY'RE ACTUALLY BETTER THAN THE MEN. SO THIS WAS OUR FIRST FORAY INTO WHAT WE MIGHT CALL PHARMACOLIFESTYLE MEDICINE. AND THE INTERACTIONS BETWEEN DRUGS THAT WE TAKE FOR OUR CONDITIONS AND THE EXERCISE WE'RE PRESCRIBING FOR THE SAME CONDITIONS. AND I THINK -- I'LL GET TO THE END, BUT THIS IS A BIG RESEARCH GAP AND IT REALLY NEEDS TO BE ADDRESSED IF WE'RE GOING TO BE ABLE TO PERSONALIZE EXERCISE FOR INDIVIDUALS. SO LET'S GO BACK TO THIS CHANGE IN P PO2 AND THE VARIOUS RESPONSES. SO WHAT WE DID IS WE TOOK THESE INDIVIDUALS AND CREATED WATERFALL PLOTS IN EACH OF THE GROUPS, AND THOSE ARE SHOWN HERE. AND YOU CAN SEE THE CONTROL GROUP IS IN THE UPPER LEFT, AND YOU CAN SEE THE MEAN CHANGE IS ABOUT ZERO, THE MILD INTENSITY HAS A VARIATION RESPONSE, THE MODERATE ALSO, AND THE HIGH AMOUNT, HIGH INTENSITY, HIGH AMOUNT VIGOROUS INTENSITY GROUP HAD THE MOST ROBUST CHANGE. AND THESE BLACK LINES ACROSS THE THING ARE THE TECHNICAL VARIATION OF THE TEST. SO YOU EXPECT SOME VARIATION WITHIN THOSE AND YOU CAN SEE THAT THE VIGOROUS GROUP HIGH AMOUNT HAD THE MOST ROBUST RESPONSE. HOWEVER, YOU'RE COMING TO ME IN CLINIC AND YOU SAY, I WANT TO INCREASE MY PPO2, THAT'S MY AREA, I WANT TO GET MORE FIT, THERE ARE SOME PEOPLE THAT WITH THAT PROGRAM WON'T, AND THERE ARE SOME THAT WILL HAVE VERY ROBUST RESPONSE. THE QUESTION IS, IF THAT'S YOUR CONDITION YOU WANT TO IMPROVE, DON'T YOU WANT TO KNOW IF YOU'RE A RESPONDER OR NOT? LIKEWISE FOR INSULIN SENSITIVITY RESPONSE. YOU DO THE WATERFALL PLOTS HERE, YOU CAN SEE THERE'S A LARGE VARIATION WITHIN EACH GROUP IN RESPONSES. NOW, SOME OF MY COLLEAGUES SAY, WELL, FITNESS IS JUST A SURROGATE FOR HEALTH AND SO ALL WE NEED TO REALLY DO IS IMPROVE PEOPLE'S FITNESS AND THEN THEY'LL GET HEALTHIER. AND SO THIS IS AN ATTEMPT TO PUT THAT TO REST. SO WHAT I'VE DONE HERE, WE CREATED A TABLE WHERE WE TAKE THE LOWEST RESPONDERS IN FITNESS, WE'VE PUT ALL OUR EXERCISERS IN THIS ANALYSIS, AND I'VE SHOWN YOU THE TOP OR THE BOTTOM RESPONDERS, MAYBE THERE'S 25 HERE. -- 37, THERE WAS A PERSON IN THE LOW DOSE VIGOROUS GROUP THAT ACTUALLY DECREASED THEIR FITNESS USING OUR MEASURES DURING THE STUDY. AND I PLOTTED THE DELTA, THE CHANGE IN ADIPOSE TISSUE, THE CHANGE IN HDL CHOLESTEROL, THE CHANGE IN TRIGLYCERIDES AND THE CHANGE IN FASTING INSULIN HERE AS A SURROGATE FOR INSULIN SENSITIVITY. AND WHAT YOU CAN SEE IS, EVEN NON-RESPONDERS IN FITNESS, THIS GROUP, THIS GUY HERE, THE THIRD ONE DOWN IN THE LOW VIGOROUS RESISTANCE GROUP IN STRRIDE 2, IMPROVED ALL FOUR OF THOSE CARDIOMETABOLIC MEASURES, SIGNIFICANTLY. EVEN THOUGH THERE WAS A DECREASE IN FITNESS. IN CONVERSE, THE SAME IS TRUE. SO WE'VE ORDERED THEM BY THE GREATEST FITNESS RESPONSE AND YOU CAN SEE THIS PERSON IN THE LOW MODERATE GROUP, GREAT IMPROVEMENT IN FITNESS, HAD A ADVERSE RESPONSE, INCREASED THEIR VISCERAL ADIPOSE SIGNIFICANTLY, DECREASED THEIR HDL CHOLESTEROL WITH BASICALLY NO CHANGE IN DELTA TRIGLYCERIDES AND FASTING INSULIN. SO THERE IS NO CORRELATION. SO THE MESSAGE HERE IS THAT YOU PRESCRIBE THE EXERCISE FOR THE CONDITION NOT ONLY THE PERSON IS TRYING TO ADDRESS, BUT IF WE COULD PREDICT RESPONSIVENESS, WE WOULD LIKE TO BE ABLE TO DO THAT. SO THAT'S PHYSIOLOGIC RESPONSIVENESS, AND MY COLLEAGUE LEEANNE ROSS HAS FOCUSED ON THAT AS HER AREA OF INVESTIGATION, BUT WE HAVE KATIE COLLINS WHO HAS COME ON AND IS REALLY INTERESTED IN BEHAVIOR, AND SO WE HAVE BEEN TACKLING THAT OVER THE LAST COUPLE YEARS, AND WE'RE LOOKING AT DROPOUT AND VARIATIONS IN ADHERENCE TO AN EXERCISE PROGRAM. SO THE BACKGROUND IS, ABOUT 30 TO 33% OF INDIVIDUALS WHO COME INTO OUR STRRIDE PROGRAM DON'T FINISH. THEY DROP OUT. WHAT WE'VE PLOTTED HERE, THIS IS PUBLISHED RECENTLY IN THE TRANSLATION JOURNAL OF THE ACSM, IS REASONS THEY GIVE US FOR DROPPING OUT. THESE ARE PEOPLE WE REMOVE, THESE ARE PEOPLE THAT VOLUNTARILY REMOVED, AND YOU CAN SEE THAT 40% IDENTIFY TIME, THEY DON'T HAVE THE TIME TO CONTINUE TO PARTICIPATE. AND IF YOU BREAK OUT THOSE REASONS ON THE RIGHT, THESE ARE ALL THE TIME PEOPLE ON THE RIGHT. STILL, A MAJORITY OF THOSE PEOPLE SAY IT'S JUST TIME, BUT SOME IDENTIFY OTHER THINGS LIKE WORK AND TRAVEL LIMITS MY TIME, MY WORK AND MOTIVATION, TRAVEL, ET CETERA, ET CETERA. SO THERE ARE ALL KINDS OF REASONS PEOPLE GIVE YOU FOR DROPPING OUT. IT TURNS OUT MOST OF THIS OCCURS EARLY IN THE PROGRAM. SOME DURING BASELINE VISITS. BUT MOST OF THEM ACTUALLY DURING THAT EARLY RAMP PERIOD. AND THEN ONCE THEY GET GOING, WE GET VERY FEW DROPOUTS. THESE ARE ALL ON-SITE TRAINING PROGRAMS. AND IF YOU ACTUALLY BREAK OUT THOSE REASONS BY THE TIME TO SEE IF IT MAKES A DIFFERENCE, THE REASONS THEY GIVE YOU FOR WHEN THEY DROP OUT DURING THAT EARLY PERIOD, IT TURNS OUT MOST OF -- WE CAN'T REALLY DETECT THAT THE REASON ACTUALLY DETERMINES WHEN DURING THAT EARLY PERIOD THEY'RE DROPPING OUT. SO WHAT WE'VE DONE, WE DECIDED TO TAKE OUR GENETICS TOOLS AND SEE IF WE COULD APPLY TO BEHAVIOR. SO THIS WAS A STUDY THAT WAS DEVELOPED A NUMBER OF YEARS AGO. I HAD A COLLEAGUE INTERESTED IN INSULIN SENSITIVITY IN MUSCLE, POSTDOCTORAL FELLOW, AND HE ACTUALLY HAD A MAP. HE WANTED TO DO GENETICS FOR PROTEINS OR ENZYMES THAT WERE INVOLVED IN ENERGY METABOLISM IN MUSCLE AND SEE IF THEY COULD PRO DICTIONARY PREDICT RESPONSIVENESS IN OUR PROGRAM. SO WE TOOK TWO GENES INVOLVED IN TRIGLYCERIDE OR FATTY ACID SYNTHESIS TO THREE ACTUALLY FOR FATTY ACID CATABOLISM, TWO INVOLVED IN CERAMIDE METABOLISM, TURNS OUT CERAMIDE IS AN INHIBITOR OF INSULIN SENSITIVITY, AND WHEN IT CONVERTS TO SPHINGSEEN, IT ACTUALLY REMOVES CERAMIDE AND ALLOWS FOR GREATER INSULIN SENSITIVITY RESPONSE. AND THEN WE HAD TWO TRANSCRIPTION FACTORS. SO WE TOOK COMPLETE GENETIC VARIANTS ACROSS THESE GENES, THERE'S ABOUT 67 TOTAL VARIANTS, AND AS A FIRST FORAY, WE ACTUALLY SAID, CAN WE PREDICT DROPOUT? THAT'S AN EASY BINARY VARIABLE, IT'S AN EASY STATISTICAL ANALYSIS, AND LO AND BEHOLD, OH, MY GOODNESS, WE WERE SURPRISED THAT THERE WAS ACTUALLY ONE OF THESE PROTEINS THAT COULD PREDICT DROPOUT. AND THIS IS THE 3810 VARIANT, AND IF YOU HAVE THE TT MINOR ALLELE AND YOU'RE HOMOZYGOUS FOR IT, YOU ACTUALLY HAD A 50% DROPOUT, WHEREAS IF YOU HAD A GG, THE MAJOR ALLELE, YOU ONLY HAD ABOUT A 25% DROPOUT. THIS IS STATISTICALLY SIGNIFICANT. AND IF YOU ACTUALLY LOOK AT THE TWO STRRIDE STUDIES THAT WE WERE STUDYING AT THAT TIME, STRRIDE U ACTUALLY PLOTTED OUT THE VARIANTS IN THE GENE, YOU ACTUALLY SEE WE COULD PRODUCE AN ODDS RATIO OF DROPOUT WHICH IS AS GREAT AS 2, IF YOU HAVE THE VARIANT. ACROSS THOSE TWO STUDIES. SO AGAIN, WE THINK THAT'S A REALLY REAL FINDING, SO WE SAID WHAT COULD BE THE REASON FOR THAT? IS THERE A BIOLOGICAL CORRELATE FOR THIS? SO WE MEASURE GENE EXPRESSION IN MUSCLE ACCORDING TO GENOTYPE IN THESE PARTICIPANTS AND, IN FACT, IF YOU HAD A HOMO HOMOZYGOUSE GENE EXPRESSION WAS SIGNIFICANTLY LESS THAN THAT OF THOSE THAT HAD AT LEAST ONE OF THE G ALLELES. AND THERE'S A CORRELATE WHERE ACTUALLY RESPONSIVENESS TO THE TRAINING FOR THIS VARIANT. IN FACT, WE THINK THIS MAY BE SOME REASON PEOPLE ARE DROPPING OUT, THAT THEY'RE JUST NOT GETTING AS GOOD A RESPONSE ON THE TREADMILL AND WHEN HE WAKES UP IN THE MORNING, IT'S SNOWY OUT, IT'S FREEZING AND THEY HAVE TO COME IN FOR TRAINING, THEY TURN OVER IN BED AND SAY I'M NOT GOING TODAY, THEN THEY DON'T GO THE NEXT DAY AND BEFORE YOU KNOW IT, THEY'RE NOT PARTICIPATING ANYMORE. SO WE THINK THERE MAY BE A SUBCONSCIOUS COMPONENT OF THIS BUT THAT'S YET TO BE PROVEN. BUT YOU SEE IS THOSE THAT HAD THE MINOR ALLELE, HOMO ZYGOTE, THEY HAD -- SO THIS PROMPTED US TO DO A WHOLE GENOME STUDY ACROSS ALL THREE STRRIDE STUDIES. THIS IS A MANHATTAN PLOT OF THIS GWAS AND WE SEE A REGION ON CHROMOSOME 16 THAT ALMOST REACHES GENOME-WIDE STATISTICAL SIGNIFICANCE HERE. AND IF YOU BLOW UP THAT GENETIC REGION AND YOU LOOK AT THE GENES UNDER THIS, THIS IS A BLOW LN UP OF -UP OF THAT REGION AND YOU CAN SEE THE R SQUARED ASSOCIATED WITH A DROPOUT HERE, ASSOCIATED WITH THESE VARIANTS, AND YOU CAN SEE THE GREATEST ONE IS 722069 AND YOU LOOK AT THE GENES UNDERNEATH THAT PEAK, AND YOU LOOK AT VARIANTS -- WHETHER VARIANTS ACTUALLY PREDICT GENE EXPRESSION IN MUSCLE, WE CAN IDENTIFY USING GTECHS, YOU CAN IDENTIFY THREE GENES THAT HAVE METABOLIC COMPONENTS SUPPORTING OUR INITIAL FINDING. SO WE CONTINUE WITH THIS WORK AND FIND IT VERY INTERESTING. SO WHAT IS PERSONALIZED MEDICINE? I'M BRINGING YOU BACK TO THIS PLOT. AND I'VE SHOWN YOU THAT WE'VE TALKED A LITTLE BIT ABOUT THE GENETICS OF RESPONSE TO PHYSICAL ACTIVITY, AND A LITTLE BIT ABOUT THE INTERACTION BETWEEN DRUGS AND LIFESTYLE MEDICINE AND REALLY THINK THE WAY FORWARD IS ACTUALLY TO COMBINE ALL THESE THREE AND TRY TO LOOK AT WHETHER OR NOT WE CAN, FOR OUR PATIENTS, IDENTIFY WHETHER PHYSICAL ACTIVITY OF DIFFERENT MODE INTENSITY AMOUNT IS BETTER FOR THEM WHETHER THEY'D BE MOST RESPONSIVE IN THE AREA FOR WHICH THEY NEED WORK, OR WHETHER OR NOT WE SHOULD LOOK AT AN ALTERNATIVE TREATMENT FOR THEM. SO I'VE BEEN ASKED TO ADDRESS WHAT I THINK ARE THE KNOWLEDGE GAPS AND I'M NOT GOING TO ADDRESS THEM AS DECLARATIVE STATEMENTS BUT ASK QUESTIONS. CAN WE DEVELOP A MOLECULAR MODEL THAT CAN PREDICT PHYSICAL ACTIVITY BEHAVIOR WITH AN ROC BETTER THAN 85%? THAT WOULD BE AWESOME, BECAUSE IF WE COULD THEN TARGET PEOPLE THAT ARE GOING TO BE PARTICULARLY AT RISK TO NOT CONTINUING THEIR BENEFICIAL BEHAVIOR, THEN MAYBE WE COULD TARGET COUNSELING, INTERVENTION, HEALTH COACHING MODALITIES TOWARDS THEM AND THOSE THAT ARE JUST GOING TO HAPPILY CONTINUE, LET THEM CONTINUE WITHOUT EXPENDING THOSE RESOURCES. CAN WE DO BETTER WITH INDIVIDUALIZING ADHERENCE. THAT WAS BASICALLY WHAT I WAS JUST TALKING ABOUT AND WE'VE COINED THAT IN OUR GROUP BEHAVIORAL LIFESTYLE MEDICINE. AND WHAT ROLE DOES PREDICTION OF INDIVIDUALIZED RESPONSIVENESS PLAY IN LIFESTYLE MEDICINE? THIS IS AN OPEN QUESTION. REMEMBER THE GREAT DISSIDENCE, ALL RIGHT? SO RIGHT NOW, WE'RE DEALING WITH GROUP RESPONSES IN CLINIC WE KNOW THIS HAPPENS AT A GROUP LEVEL OR EPIDEMIOLOGICALLY, BUT DOES THAT MEAN ANYTHING FOR THE PERSON SITTING IN FRONT OF YOU? WHAT IS THE ROLE OF GOOD CIRCADIAN HYGIENE IN CARDIOMETABOLIC HEALTH? I'VE BECOME MORE CONVINCED IN THE LAST FIVE YEARS THAT KEEPING A GOOD DAILY TEMPORAL PATTERN OF ONE'S BEHAVIORS HAS VERY PROFOUND EFFECTS ON OUR CARDIOMETABOLIC HEALTH AND WE NEED TO DEFINE BETTER WHAT THE ROLE IS OF COUNSELING IN THAT REGARD IN OUR CLINICAL SETTINGS. CAN WE LEARN MORE FROM DRUG EXERCISE INTERACTIONS? I THINK THIS IS A REALLY OPEN SPACE AND REALLY AN OPPORTUNITY TO LEARN A LOT MORE ABOUT NOT ONLY BIOLOGY AND POTENTIALLY NEW THERAPEUTICS, BUT HOW WE CAN BETTER TREAT OUR PATIENTS. AND FINALLY, WHEN WOULD WE IDENTIFY -- IF IN FACT THIS IS AN IMPORTANT THING TO DO THIS MAY TAKE TIME IN LARGE POPULATIONS TO DO. SO WITH THAT, I THINK I WANT TO ACKNOWLEDGE MY GROUP. THIS IS THE STRRIDE 1 GROUP, THERE'S A BIGGER GROUP FOR THE OTHER STRIDES STRRIDES BUT THESE ARE THE FOLKS THAT REALLY GOT US STARTED. THERE'S THE DUKE TEAM HERE IN GREEN AND OUR ECU COLLABORATORS WHO TRAINED THE SUBJECTS, THEY'VE BEEN LONG TERM COLLEAGUES, AND ERIC HOFFMAN AND HIS GROUP, NOW DUSTIN, MONICA, STARTED US ON THE GENETIC PATHWAY AND THEN MORE RECENTLY WE HAD LEANNA ROSS AND KATIE COLLINS. LEANNA FOCUSED ON GENETICS OF RESPONSIVENESS AND KATIE ON GENETICS AND OTHER MOLECULAR PREDICTORS OF BEHAVIOR. AND SO THIS IS THE BEHAVIOR GROUP THAT'S NOW WORKING WITH US IN THIS PARTICULAR AREA AND YOU RECOGNIZE SOME OF THESE NAMES, AND AGAIN, I LIST KATIE AND LEANNA. SO WITH THAT, I THINK I'LL END, AND I WILL -- I GUESS WE HAVE OPPORTUNITY FOR QUESTIONS. >> THANK YOU SO MUCH, BILL, FOR THE EXCELLENT PRESENTATION. IT'S SO TIMELY, IT'S SO RELEVANT, AND ESPECIALLY GIVEN NHLBI'S RESEARCH PRIORITY ON PRECISION MEDICINE AND PRECISION PREVENTION, WHICH WE KNOW PHYSICAL ACTIVITY HAS A HUGE ROLE IN. SO I'M GOING TO OPEN UP THE FLOOR FOR QUESTIONS. PLEASE REMEMBER IF YOU HAVEN'T SUBMITTED A QUESTION AND YOU HAVE ONE, TO SUBMIT LIVE FEEDBACK OR TO THE EMAIL ADDRESS THAT WAS GIVEN. SO I'LL KICK US OFF WITH THE MANY QUESTIONS THAT HAVE STREAMED IN. THE FIRST ONE IS, BILL, WHAT ARE THE IMPLICATIONINGS OF A PERSONALIZED PHYSICAL ACTIVITY PROGRAM WITH RESPECT TO CURRENT POPULATION-BASED PHYSICAL ACTIVITY GUIDELINES? >> I THINK I ALLUDED TO THAT. I THINK THAT WE KNOW -- WE BASICALLY KNOW ABOUT AMOUNT FROM THE PHYSICAL ACTIVITY GUIDELINES. THEY'RE BASICALLY BASED UPON ENERGY EXPENDITURE AND THE MESSAGES WE GET FROM THE GUIDELINES IS THAT MORE ENERGY EXPENDITURE WITH PHYSICAL ACTIVITY IS BETTER. AFEMENTS ATTEMPTS TO LOOK ATY AND AMOUNT COMBINED IN EPIDEMIOLOGIC STUDIES IS FRAUGHT WITH HAZARD UNTIL WE ACTUALLY HAVE OBJECTIVE MEASURES OF THOSE, SO I THINK WHAT WE CAN TAKE IS FROM THESE SMALLER STUDIES, SOME HINTS AT BREAKING DOWN THAT. AND SO AGAIN, WHAT I WOULD SAY IS FOR MY INDIVIDUALS THAT NEED TO FOCUS ON INSULIN SENSITIVITY OR GLUCOSE CONTROL, MODERATE INTENSITY EXERCISE. BUT GO WITH THE GUIDELINES. WITHIN THAT CONTEXT. >> EXCELLENT. I THINK ONE OF YOUR EXAMPLES THAT YOU GAVE WHERE YOU HAD SOME PATIENTS THAT DID BETTER ON WALKING, FOR EXAMPLE, THAN, YOU KNOW, GOING TO THE STRAIGHT VIGOROUS ACTIVITY HIGHLIGHTED THAT WELL. THANKS. HOW CAN WE ADAPT THIS APPROACH TO ENHANCE THE HEALTH OF WOMEN OF REPRODUCTIVE AGE, INCLUDING DURING PREGNANCY? IN ALIGNMENT WITH GOALS OF ADDRESSING HEALTH INEQUITIES AND ENHANCING INFANT AND CHILD HEALTH TOO? >> YES, SO THIS IS ANOTHER AREA WHERE I THINK THE MESSAGE -- THE GREATEST -- ONE OF THE GREATEST RISKS IN PREGNANCY IS CART YOE CARDIOMETABOLIC DISEASE. YOU HAVE GLUCOSE CONTROL, HYPERTENSION, PREECLAMPSIA, ET CETERA. AND I WOULD JUST TAKE THE -- AND WE HAVE MORE DATA, I WISH I HAD MORE TIME TO TALK ABOUT OUR REUNION AND THE 10-YEAR FOLLOW-UP, BUT WHAT REPEATEDLY COMES OUT IN OUR WORK IS THAT MODERATE INTENSITY WORKS. AND IF WE CAN JUST GET WOMEN TO WALK DURING PREGNANCY, ESPECIALLY IN THOSE LATER STAGES, WHEN YOU SAY EXERCISE OR PHYSICAL ACTIVITY, WOMEN OFTEN THINK ABOUT HAVING TO GET IN SPANDEX AND GET IN THE GYM AND WE'VE GOT TO GET PAST THAT. SO I WOULD SAY WALK, WALK, WALK. >> I LOVE THAT. AND HAVING HAD THREE CHILDREN OF MY OWN, I'VE BENEFITED FROM HAVING CLINICIANS THAT KNEW THE VALUE OF PHYSICAL ACTIVITY, BUT I THINK FOR A WHILE, THERE'S BEEN THIS MAYBE PHYSICAL ACTIVITY IS BAD, IT'S HARMFUL, IT'S SCARY, AND I'M GLAD TO SEE AT LEAST IN OUR LAST ITERATION OF THE GUIDELINES, A LITTLE BIT OF A FOCUS ON THIS IS GOOD, THIS IS HEALTHY FOR PREGNANCY. >> YEP. >> SO THE NEXT QUESTION IS -- I'M GOING TO READ ONE THAT'S RELEVANT TO YOUR SLIDES AND SKIP AROUND HERE. I WONDER IF PEOPLE WITH THE TT ALLELE WHO SHOW LESS VO2 IMPROVEMENT WITH EXERCISE FIND EXERCISE MORE PAINFUL, DUE TO LESS RESPIRATORY ADAPTATION AND, HENCE, DROP OUT FOR THAT REASON. HOW DO YOU EXPLAIN THESE GENETIC DIFFERENCES IN DROPOUT? >> SO THAT'S A REALLY GOOD QUESTION. THE GENETIC WORK WAS RETROSPECTIVE. WE DIDN'T DESIGN THE STUDY, LOOKING AT GENETICS. THIS WAS 1996, AND, OH, MY GOODNESS, THAT'S JUST THE TIME WE'D START COLLECTING ENOUGH SAMPLES TO ACTUALLY DO ANYTHING IN MOLECULAR BIOLOGY. BUT WE REALLY NEED TO DO A PROSPECTIVE STUDY LIKE THIS AND COLLECT THOSE DATA GOING FORWARD. SO DO A STRRIDE-LIKE STUDY, AND THEN ACTUALLY DO SOME INTERVIEWING OF WHAT PEOPLE ACTUALLY FEEL SO THAT WE CAN THEN -- AT THE SAME TIME WE'RE ALL DOING ALL THE MOLECULAR WORK, TO UNDERSTAND MORE ABOUT WHAT PEOPLE ARE ACTUALLY FEELING. BUT I THINK THAT'S A REALLY INSIGHTFUL COMMENT, AND I THINK THERE'S A LOT TO IT. >> AWESOME. WE HAVE TWO QUESTIONS THAT WERE RELEVANT TO THE MEDICAL PHARMACOLOGY PIECE THAT YOU WERE DISCUSSING WITH RELATION TO INSULIN SENSITIVITY. SO I'M GOING TO POSE THEM BOTH HERE BECAUSE THEY'RE BOTH KIND OF RELEVANT TO THE TOPIC. THE FIRST WAS, WITH REGARD TO INSULIN SENSITIVITY, THE LOW AMOUNT OF VIGOROUS ACTIVITY SHOWN IS FAIRLY LOW, WAS THE FREQUENCY LOWER? WAS THAT FREQUENCY THAT WAS -- >> THE FREQUENCY WAS -- SO THE FREQUENCY IN THE MODERATE INTENSITY -- YES. SO IF YOU COMPARE THE FREQUENCY IN THE LOW AMOUNT VIGOROUS AND THE LOW AMOUNT MODERATE, THE LOW AMOUNT MODERATES EXERCISE MORE TIME AND MORE FREQUENTLY. >> PER PERFECT. CAN YOU EXPLAIN WHY THE MODERATE ACTIVITY HAD BETTER EFFECTS THAN THE VIGOROUS ACTIVITY? >> THAT'S AN INTERESTING QUESTION. WE HAVE ACTUALLY SEEN HINTS, I HAVE SEEN EMPIRICALLY AS WELL AS ACTUALLY FOCUSING ON PUBLISHED PAPERS THAT WITH RESPECT TO GLUCOSE LEVELS, JUST FASTING GLUCOSE LEVELS, OR GLUCOSE LEVELS IN GENERAL, VIGOROUS INTENSITY ATHLETES TEND TO RUN HIGHER GLUCOSE LEVELS. AND WE THINK IT'S PROBABLY BECAUSE THEY HAVE TO REPLACE THE GLYCOGEN IN THEIR MUSCLE FOR THE NEXT BATTLE. SO THE BODY IS ADAPTING TO HAVE MORE GLUCOSE AVAILABLE TO ACTUALLY REPLETE THOSE STORES, AND SO IT MAY BE A PROTECTIVE, IF YOU WILL, OR ADAPTIVE RESPONSE. AND WE KNOW AT LOWER INTENSITIES OF EXERCISE, ONE IS ACTUALLY PREFERENTIALLY METABOLIZING FATS, AND WE THINK THOSE FATS MAY RELEASE AN INHIBITION IN SKELETAL MUSCLE THAT WE'RE NOT SEEING WITH THE VIGOROUS INTENSITY EXERCISE. >> REALLY INTERESTING. THE NEXT QUESTION IS ABOUT -- I THINK IT'S IN THE BUCKET OF ONE OF YOUR RESEARCH FACTS ABOUT INDIVIDUALIZED BEHAVIORAL COUNSELING. SO AS YOU THINK ABOUT AGING POPULATIONS, THAT COULD MEAN NOT NECESSARILY, YOU KNOW, 55 OR 60 AND OLDER, WE'RE TALKING ABOUT AS PEOPLE AGE THROUGH ADULTHOOD. WHAT IS THE POTENTIAL TO PRESCRIBE PRECISION PHYSICAL ACTIVITIES THAT ALSO TAKE INTO ACCOUNT AVOIDING VARIOUS INJURIES THAT MAY OCCUR MORE READILY WITH AGING? >> I THINK THAT'S A VERY GOOD POINT AS WELL. I HATE TO POUND ON THE MODERATE INTENSITY, BUT WHEN YOU'RE TALKING ABOUT INJURIES IN OLDER INDIVIDUALS, OBVIOUSLY A LESS INTENSIVE PROGRAM MAY BE MORE BENEFICIAL. THE OTHER THING THAT WE STRUGGLED WITH, STEPHANIE, I THINK YOU KNOW THIS IN THE PHYSICAL ACTIVITY GUIDELINES IS WHEN YOU'RE COMPARING ENERGY ACROSS POPULATIONS, WITH WALKING, OLDER INDIVIDUALS ACTUALLY SPEND MORE ENERGY WALKING THAN YOUNGER INDIVIDUALS. THEY'RE LESS EFFICIENT WITH THEIR STEPS, AND SO WHEN COMPARING STEP COUNTS AND NEEDS FOR STEP COUNTS IN OLDER INDIVIDUALS, IT MAY BE ACTUALLY LESS. AND IN FACT, THE PAPER FROM AMANDA POLLACK AND OTHERS RECENTLY PUBLISHED LOOKING AT STEPS IN MORTALITY. IT'S A META-ANALYSIS, ACTUALLY SHOWED FOR OLDER INDIVIDUALS, THEY REQUIRE FEWER STEPS THAN YOUNGER INDIVIDUALS FOR THE SAME BENEFIT. >> NOW I'M GOING TO ASK YOU TO PUT YOUR CLINICAL HAT ON. AS A CLINICIAN, HOW DO YOU SEE PREDICTIONS OF LIFESTYLE BEHAVIOR FITTING IN TO CLINICAL CARE? WHAT DOES THAT LOOK LIKE? WHAT WOULD YOU LIKE THAT TO LOOK LIKE IN AN IDEAL WORLD? >> I WOULD LIKE TO HAVE AN ADDITIONAL CLINICAL TOOL TO BE ABLE TO DIRECT MY THINKING ABOUT WHETHER OR NOT THE PROGRAM, LET'S JUST SAY THE EXERCISE PROGRAM THAT I'M GOING TO SUGGEST THEY BE INVOLVED IN IS GOING TO BE TARGETING THEIR PARTICULAR NEED. AND SO THAT'S A BIG ASK, BECAUSE I SEE FIVE DIFFERENT CONDITIONS IN CARDIOMETABOLIC CLINIC, AND EACH ONE MIGHT HAVE A DIFFERENT RESPONSE. AND SO I DON'T THINK THERE'S AN ANSWER HERE. IT'S KIND OF LIKE HOW ARE WE GOING TO GET TO MARS. WE HAVE SOME IDEAS BUT WE REALLY DON'T KNOW FOR SURE. >> THANK YOU. I'M GOING TO GIVE A LAST QUESTION HERE AND THEN WRAP US UP. I'M SO GLAD TO HEAR THAT MODERATE ACTIVITY IS AS GOOD IF NOT BETTER THAN VIGOROUS ACTIVITY. IN TERMS OF TAILORING LIFESTYLE MEDICINE, HOW IMPORTANT DO YOU THINK IT IS FOR PEOPLE TO FIND A PHYSICAL ACTIVITY THAT THEY ACTUALLY ENJOY? >> OH, IT'S ABSOLUTELY ESSENTIAL. IT'S ABSOLUTELY ESSENTIAL. BECAUSE I THINK WHAT WE'RE GOING TO FIND -- WHAT WE KNOW IS THAT PEOPLE DO WHAT THEY ENJOY DOING. AND WHETHER IT BE IN THE CONTEXT OF GAMING OR WHETHER IT BE IN THE CONTEXT OF GOLFING OR WHETHER IT BE IN CONTEXT OF COMPETITION OR WHETHER JUST BECAUSE IT MAKES THEM FEEL AND THINK BETTER, THAT'S WHAT GIVES PEOPLE SATISFACTION AND ALLOWS THEM TO TAKE CARE OF THEIR HEALTH AS WELL IS GOING TO BE ESSENTIAL. WHEN WE MAKE IT A CHORE, IT'S JUST NOT GOING TO WORK. >> THANK YOU SO MUCH, BILL. SO I FEEL LIKE THE PERSON WHO ASKED THIS QUESTION MUST HAVE KNOWN POSSIBLY WHAT I MIGHT SAY AT THE END, BUT I ASKED YOU ALL AT THE BEGINNING TO TAKE A MOMENT AND WRITE DOWN A PHYSICAL ACTIVITY THAT YOU DO OR HAVE DONE THAT YOU'VE YOU REALLYD I WANT YOU TO TAKE ANOTHER MOMENT, REVISIT WHAT THAT WAS AFTER HEARING BILL'S RESPONSE TO THAT LAST QUESTION. AND HOW IMPORTANT THAT IS TO FIND SOMETHING YOU ENJOY. NOW, WHEN I ASKED BILL ABOUT SOME FUN FACTS, HE SHARED SOMETHING REALLY WONDERFUL WITH ME THAT HE LOVES PRIME NUMBERS. WELL, WE HAVE A VERY IMPORTANT PRIME NUMBER COMING UP ON THE 19TH OF JUNE, WHICH IS JUNETEENTH. AND SO I WANTED TO SHARE WITH ALL OF YOU HERE THAT ARE GATHERED HERE TODAY ABOUT PERSONALIZED LIFESTYLE MEDICINE, I WANT TO SHARE WITH YOU AND INVITE YOU TO JOIN ME AND OTHERS AT NIH IN A CHALLENGE, SO ON JUNETEENTH AS WE CELEBRATE THIS PIVOTAL MOMENT IN HISTORY, I'D LIKE TO INVITE YOU TO SPEND 19 MINUTES DOING THAT PHYSICAL ACTIVITY THAT YOU WROTE DOWN, THAT YOU ENJOY. FEEL FREE TO DO IT THAT DAY OR SPREAD IT OVER A COUPLE DAYS. BILL, I KNOW YOU'VE RUN 17 MARATHONS AND 11 BOSTONS, WHICH IRONICALLY ARE BOTH PRIME NUMBERS. MAYBE YOU'LL TAKE ON RUNNING AS THAT THING. I THINK I'M GOING TO BE PADDLING TO DO MY ACTIVITY. BUT I REALLY WANT TO THANK YOU TODAY FOR SUCH AN EXCELLENT TALK WITH ALL OF US WHO HAVE JOINED FROM AROUND THE WORLD TO HEAR ABOUT THIS, AND THANK YOU TO LORI AND ALL THE ORGANIZERS AT NHLBI THAT SET UP THIS EXCELLENT SEMINAR. WE CERTAINLY LEARNED A LOT TODAY. >> THANK YOU FOR HAVING ME. I REALLY ENJOYED IT. >> EXCELLENT. THANK YOU ALL.