GOOD MORNING, EVERYONE. WELCOME TO NINR'S PRECISION HEALTH FROM OMICS TO SCIENCES BOOTH CAMP, I'M MARY ENGLER. I'M DELIGHTED TO BE YOUR PROGRAM CHAIR THIS WEEK. I HOPE YOU HAD GOOD TRAVELS TO BETHESDA AND THE NIH CAMPUS. THE COMPANY WE'RE WORKING ON. THE GOOD NEWS IS IT'S GOING TO BE 99 INSTEAD OF 100 I THINK TODAY BUT WE'RE IN GOOD CAPABLE HANDS WITH THE STATE OF THE ART AIR CONDITIONING HERE IN PORTER A SPECIAL WELCOME TO LIVE VIDEOCAST PARTICIPANTS AND VIEWERS TODAY. WE'RE JUST THRILLED TO SEE THE BIG TURNOUT AND HOW MUCH INTEREST AND POPULARITY THERE HAS BEEN FOR OUR PRECISION HEALTH BOOT CAMP. I APPRECIATE THE TIME ALL OF YOU ARE TAKING TO PARTICIPATE THIS WEEK, AS WELL AS THE TIME ALL OF OUR SPEAKERS HAVE TAKEN TO PREPARE FOR THIS GREAT EVENT. I ALSO WANT TO THANK SO MANY FOR THEIR TREMENDOUS HARD WORK AND PLANNING AND PREPARING OVER THE PAST YEAR FOR THIS WEEK'S BOOT CAMP INCLUDING OUR NINR'S DEPUTY TRAINING DIRECTOR DR. PAMELA TOMEZ AND THE FOUNDATION FOR ADVANCED EDUCATION IN SCIENCES, PROGRAM MANAGERS AND STAFF ESPECIALLY ASHANTI EDWARDS AND CHRISTINE FARRIOS, NIH EVENTS MANAGEMENT, AND THE VIDEO STAFF, OUR NINR DIVISIONS INCLUDING EXTRAMURAL SCIENCE PROGRAMS AND DIVISION OF SCIENCE POLICY AND PUBLIC LIAISON. I ALSO WANT TO THANK OUR NINR LEADERSHIP FOR THESE GREAT SUPPORT AS WELL. WE'RE SO ENERGIZED AND ENTHUSIASTIC WITH THE PROGRAM TOPIC AND OUTSTANDING EXPERT PRESENTERS JOINING US THIS WEEK. AS YOU KNOW, WE'RE IN THE MIDST OF AN EXCITING AND UNPRECEDENTED TIME IN SCIENC AND TECHNOLOGY DUE TO EXPLOSION OF MOLECULAR DATA. OUR KNOWLEDGE OF FUNDAMENTAL BIOLOGICAL MECHANISMS AND THE PROCESSES THAT DEFINE AND DRIVE PHYSIOLOGY IS RAPIDLY EXPANDING AS IS OUR UNDERSTANDING OF DISEASE PATHOGENESIS AND IMPROVING HEALTH. AS A RESULT, THE OMICS SCIENCE ERA HAS EVOLVED WITH FOCUS AREAS SUCH AS GENOMICS, EPIGENETICS, METABOLOMICS. THE A ND PROTEOMICS AND EXPANDED TO MICROBES, AND GENETICS AND DRUG RESPONSES, PHARMACOGENOMICS, WHICH WE HEAR MUCH MORE ABOUT THIS WEEK. PARALLEL ADVANCES IN INFORMATION TECHNOLOGIES ARE ALSO PROVIDING TRANSFORMATIVE OPPORTUNITIES TO USE HEALTH-RELATED BIOLOGICAL DATA TO ADVANCE BIOMEDICAL RESEARCH AND CLINICAL CARE. AS A RESULT OF THESE ADVANCES, TARGETED PREVENTIVE AND TREATMENT STRATEGIES WILL IMPLEMENT TIMELY AND EFFECTIVE INTERVENTION TO IMPROVE PATIENT OUTCOMES. THE PRECISION MEDICINE INITIATIVE IS PREDICTED TO PIONEER A NEW MODEL OF PATIENT-POWERED RESEARCH THAT PROMISES TO ACCELERATE BIOMEDICAL DISCOVERIES AND PROVIDE CLINICIANS CAN TOOLS, KNOWLEDGE AND THERAPIES FOR WHICH TREATMENT WILL WORK BEST WITH EACH PATIENT. IMPORTANTLY, SCIENTISTS, RESEARCHERS, CLINICIANS, EDUCATORS AND OTHER HEALTH CARE PROFESSIONALS WILL NEED TRAINING TO LEARN ABOUT THESE ADVANCES, EXPAND THEIR SKILLS AND TO DEVELOP NEW APPROACHES. SO TRAINING IS OUR GOAL WITH THE NINR 2016 2016 FROM PRECISION HEALTH TO OMICS BOOT CAMP. WE'LL ENGAGE WITH LEADERS IN THE AREAS OF OMICS SCIENCE AND DATA SCIENCE AS WELL AS INNOVATIVE HEALTHCARE SYSTEM MODELS. WE'LL ASSESS HOW INTEGRATING PATIENT PROVIDER COLLABORATIONS WITH OMICS AND DATA SCIENCE TECHNOLOGIES IS REDEFINING DEFINITIONS OF HEALTH AND ILLNESS AND THE ASSOCIATEED IMPLICATIONS OF ETHICAL, LEGAL AND SOCIAL ASPECTS. WE'LL HAVE INTERACTIVE DISCUSSIONS WITH BREAKOUT SESSIONS MODERATED BY OUR SCIENTIFIC EXPERTS, AND WE'LL PROVIDE NETWORKING OPPORTUNITIES WITH OTHER ATTENDEES AND SPEAKERS TO SHARE IDEAS, ASK QUESTIONS, AND FIND POTENTIAL COLLABORATORS. OUR HOPE IS INCREASE RESEARCH CAPABILITY, WHETHER YOU'RE A GRADUATE STUDENT, UNIVERSITY FACULTY, SCIENTIST OR CLINICIAN. TODAY'S PLAN THEN AS YOU CAN SEE ON YOUR AGENDA IS PROVIDE AN INTRODUCTION AND SIGNIFICANT OF PRECISION HEALTH AND OMICS SCIENCES. TOMORROW'S SESSION WILL FOCUS ON CLINICAL OMICS AND PRECISION MEDICINE. OUR THIRD DAY PRESENTATIONS WILL FOCUS ON ETHICAL, LEGAL AND SOCIAL IMPLICATIONS AND INFORMATICS. THEN ON THURSDAY, OUR FOURTH DAY, WE WILL FOCUS ON INNOVATIVE HEALTH, FROM GENOMICS TO HEALTHCARE SYSTEM MODELS. LASTLY, ON FRIDAY, WE WILL BE BRINGING IT ALL TOGETHER, PROVIDING YOU WITH INFORMATION ON NIH FUNDING OPPORTUNITIES FOR TRAINING, CAREER DEVELOPMENT, AND RESEARCH, AND WE WILL ALSO HAVE DATA SCIENCE METHODS TRAINING AND EXHIBITORS. SO WE HAVE AN EXCITING WEEK PLANNED AND I HOPE YOU HAVE A WONDERFUL EXPERIENCE. NOW BEFORE WE BEGIN OUR PROGRAM, I JUST WANT TO MENTION A FEW HOUSEKEEPING ITEMS. AS A COURTESY, PLEASE TURN OFF CELL PHONES OR SET THEM TO SILENT MODE DURING PRESENTATIONS. WE'RE VIDEOTAPING LIVE TODAY ONLY, AND ALL TODAY'S PRESENTATIONS WILL BE AVAILABLE FOR LATER ON-DEMAND VIEWING. WE'RE PLAN FIVE MINUTES OF QUESTIONS AND ANSWERS AT THE END OF EACH PRESENTATION. RESTROOMS ARE RIGHT OUTSIDE AT THE END OF THE LOBBY AREA. PLEASE NOTE WHERE THE EMERGENCY EXITS ARE IN THE LOBBY AREA. AS YOU MIGHT HAVE ALREADY SEEN, CAFETERIA AND COFFEE SHOP ARE RIGHT ACROSS THE LOBBY FROM OUR LECTURE HALL HERE, AND WE'RE SO LUCKY TO BE HERE IN THIS STATE-OF-THE-ART AND COOL PORTER NEUROSCIENCE BUILDING FOR OUR CONFERENCE. FINALLY, DRINK PLENTY MUCH FLUIDS. WITH THE EXTREME HEAT AND FOR THOSE WHO ORDER THE BOX LUNCHES ONLINE YOUR ORDERS WILL BE DELIVERED AT LUNCHTIME IN THE LOBBY AREA. SO NOW IT IS NOW MY DISTINCT HONOR TO OFFICIALLY HOPE OUR NINR 2016 PRECISION HEALTH FROM OMICS TO DATA SCIENCE BOOT CAMP AND INTRODUCE OUR FIRST SPEAKER, AND DIRECTOR OF NINR, DR. PATRICIA GRADY. [APPLAUSE] DR. GRADY WAS APPOINTED DIRECTOR IN 1995, SHE ISSUED HER UNDERGRADUATE DEGREE IN NURSING FROM GEORGETOWN UNIVERSITY IN WASHINGTON, D.C. AND PURSUED GRADUATE EDUCATION AT THE UNIVERSITY OF MARYLAND, RECEIVING A MASTER'S DEGREE FROM THE SCHOOL OF NURSING, RECEIVED A DOCTORATE IN PHYSIOLOGY FROM THE UNIVERSITY OF MARYLAND SCHOOL OF MEDICINE, DR. GRADY HAS AUTHORED AND CO-AUTHORED ARTICLES AND PAPERS ON HYPERTENSION, CEREBROVASCULAR PERMEABILITY AND STENOSIS, LECTURES AND SPEAKS ON A WIDE RANGE OF TOPICS INCLUDING FUTURE DIRECTIONS IN NURSING RESEARCH, DEVELOPMENTS IN NEUROLOGICAL SCIENCES, AND FEDERAL RESEARCH OPPORTUNITIES. OF NOTE, DR. GRADY WAS RECENTLY NAMED ONE OF THE TOP 100 MOST POWERFUL WOMEN IN WASHINGTON, D. C. [APPLAUSE] THIS MORNING DR. GRADY WILL PROVIDE WELCOME REMARKS AND AN OVERVIEW OF THE PROGRAM. PLEASE JOIN ME IN WELCOMING OUR DIRECTOR. [APPLAUSE] >> THANK YOU, MARY. INEVITABLY THAT ANNOUNCEMENT PRECEDES SOMETHING WHERE THERE WAS A COMPLICATION THAT DIDN'T GO WELL SO IT MAKES YOU FEEL LESS POWERFUL. SO THEY ARE WORKING ON GETTING MY SLIDES UP. THEY HAVE THEM BUT I'M NOT SURE THEY HAVE THEM QUEUED UP. LET ME SAY WELCOME TO ALL OF YOU. WE'RE DELIGHTED YOU'RE HERE. WE FEEL THIS IS GOING TON AN EXCITING AND INFORMATIVE WEEK FOR YOU. IT'S POWER-PACKED TO TRY TO GET AS MUCH AS WE CAN INTO A WEEK, BUT THIS IS SUCH AN IMPORTANT AREA, SUCH A BURGEONING AND FAST-DEVELOPING AREA THAT IT'S REALLY IMPORTANT FOR US IN THE SCIENTIFIC COMMUNITY TO TRY TO -- IT'S LATE FOR THE WHOLE OF US TO GET AHEAD OF THE CURVE BUT BASICALLY WE WANT TO BE ABLE TO GET AS CLOSE TO BEING ABLE TO MODIFY THINGS AND SHAPE OUR FUTURE USING THE NEW TECHNOLOGIES. WE'RE ALSO VERY LUCKY TO HAVE SOME OF THE VERY BEST SPEAKERS WE COULD GET, WHICH YOU'LL HEAR SEVERAL OF THOSE TODAY. AND WE APPRECIATE THE FACT THAT THEY ARE BRINGING THEIR EXPERTISE HERE AND ALSO MODIFYING IT TO THE CURRENT CIRCUMSTANCES. WE'RE VERY FORTUNATE AT NIH BECAUSE WE HAVE A COLLECTIVE LEVEL OF EXPERTISE IN HOUSE ON CAMPUS, BUT YOU'LL SEE THAT EVEN IN THIS AREA WHICH IS SUCH A FAST-MOVING AREA THAT YOU'LL EXPERIENCE HEARING FROM A NUMBER OF SPEAKERS, FROM ACROSS THE COUNTRY. SO WE'RE VERY EXCITED ABOUT THAT. LET ME TELL YOU A LITTLE BIT. I HAVE A FEW ONLY A FEW MINUTES BUT I WANT TO TOUCH ON OUR MISSION AND ITS INTERTWINING WITH THE NIH MISSION. THE FACT THAT WE AND NIH, OUR MISSION IS TO SEEK FUNDAMENTAL KNOWLEDGE ABOUT THE NATURE AND BEHAVIOR OF LIVING SYSTEMS AND TO APPLY THAT KNOWLEDGE TO ENHANCE HEALTH, LENGTHEN LIFE AND REDUCE ILLNESS AND DISABIY. THAT'S THE OVERALL NIH MISSION. EACH OF THE 27 CENTERS AND INSTITUTES AT NIH COMPLEMENT THAT MISSION. OUR MISSION FOCUSES MORE SPECIFICALLY ON THE HEALTH OF INDIVIDUALS, FAMILIES AND COMMUNITIES AND DOES ADDRESS ISSUES OF WELLNESS AND PREVENTION AND MANAGING HEALTH ACROSS THE LIFESPAN, ACROSS A NUMBER OF SETTINGS SO WE'RE NOT SPECIFICALLY RESTRICTED TO HOSPITAL SETTINGS BUT YOU WILL FIND OUR RESEARCHERS OUT IN THE COMMUNITIES AND A VARIETY OF EXTENDED CARE FACILITIES AS WELL. ALSO, OUR MAJOR EMPHASIS REALLY IS TO IMPROVE QUALITY OF HEALTH AND QUALITY OF LIFE FOR INDIVIDUALS AND FOR THEIR CAREGIVERS SO WE DO FOCUS A BIT MORE OR CARE GIVING THAN ON SOME OF THE OTHER INSTITUTES. 90% OF WHAT WE FUND IS CLINICAL ARENA SO WE DO HAVE A ROBUST PORTFOLIO OF 10% OF WHAT WE FUND THAT IS BASIC IN NATURE, BUT EVEN OUR BASIC SCIENCE IS TYPICALLY FRAMED FROM A CLINICAL PERSPECTIVE SO IF WE ARE -- IF OUR SCIENTISTS ARE LOOKING AT SOMETHING LIKE DIRECTION FINDING AND ORIENTATION THEY ARE LOOKING FROM THE CONTEXT OFTEN OF THE PATIENT WITH ALZHEIMER'S DISEASE OR CAREGIVERS. IT'S AN INTERESTING APPROACH. IF WE MOVE FORWARD THERE ARE A NUMBER OF FACTORS SUPPORTING THE NEED FOR THIS PARTICULAR DATA MARY SPOKE THIS MORNING ABOUT OMICS TO DATA SCIENCE, AND TO PRECISION MEDICINE, AND PRECISION MEDICINE IS SOMETHING THAT YOU'LL HEAR QUITE A BIT ABOUT WHILE YOU'RE HERE THIS WEEK. PRECISION MEDICINE IS A NEW INITIATIVE THAT IS ACTUALLY A WHITE HOUSE INITIATIVE. THIS IS SOMETHING THAT PRESIDENT OBAMA IS VERY INTERESTED IN, MENTIONED IN HIS STATE OF THE UNION ADDRESS, AND HAS BEEN VERY INVOLVED IN THE INITIATIVE AS IT'S BEEN DEVELOPING AND AS IT IS BEING TURNED OUT. THE PRECISION MEDICINE INITIATIVE IS DESIGNED TO PROVIDE INDIVIDUAL PERSONALIZED CARE FOR EVERY INDIVIDUAL ACROSS THE GLOBE. AND THE IDEA, THERE ARE TWO COMPONENTS CURRENTLY TO THIS. AND IT IS A VERY RAPIDLY CHANGING LANDSCAPE. THERE'S A SPECIFIC WEBSITE AND THAT DOES KEEP YOU INFORMED, NOT DAILY BUT WITH FREQUENT CHANGES AS THIS IS DEVELOPING. THE TWO MAJOR COMPONENTS, ONE DIRECTED AT PRECISION MEDICINE SPECIFICALLY IN THE AREA OF CANCER AND FINDING A CURE FOR CANCER, DEVELOPING PRECISION MEDICINE FOR INDIVIDUALS, AND THAT IS STRENGTHENING AND ENHANCING SOME EARLY INITIATIVES THAT HAVE HE ABOUT GUN -- BEGUN IN THIS AREA. YOU'LL BE HEARING MORE ABOUT THAT. THE MORE RECENT MOONSHOT WHICH WILL COMPLEMENT THAT. THE BULK OF PRECISION MEDICINE INITIATIVE IS DIRECTED ACROSS THE LIFESPAN AND AREAS OF WELLNESS AND POTENTIAL ILLNESS IN THE FUTURE. THE FIRST TASK IS COLLECT A COHORT OF LITERALLY A MILLION PEOPLE. WE'RE HOPING FOR MORE, TO PROVIDE A COHORT OF INDIVIDUALS WHO WILL BE AVAILABLE, FOR WHOM WE CAN CHARACTERIZE HEALTH STATUS AND WHO WILL BE AVAILABLE AS WE PLAY OUT IN THE FUTURE FOR POTENTIAL CLINICAL TRIALS AND FOR ADDRESSING ASPECTS, PARTICULAR ASPECTS OF THEIR HEALTH. THE EARLY RFAs HAVE GONE OUT, THE FIRST AWARDS HAVE NOW BEEN MADE. SO THERE'S A COORDINATING CENTER FOR THIS. THERE WILL BE A DATA REPOSITORY, AND IT IS GOING TO BE -- IT'S GOING TO BE A VERY EXTENSIVE INITIATIVE THAT WE EXPECT WILL SPAN OVER THE NEXT SEVERAL DECADES. SO FAST FORWARD CLOSER TO HOME, WE'RE VERY INVOLVED IN THE PRECISION MEDICINE INITIATIVE. BECAUSE IT WILL BE EARLY DAYS FOCUSING ON DISEASE BUT WILL ALSO BE FOCUSING ON THINGS OTHER THAN DISEASE SUCH AS BEHAVIOR, BEHAVIORAL INTERVENTIONS, LIFESTYLE CHANGES, ET CETERA. BUT SO WE WILL BE MUCH MORE INVOLVED AS THAT PLAYS OUT. WE'RE CURRENTLY WORKING WITH THE COMMUNITY COMPONENT OF THAT. BUT ANOTHER ASPECT THAT HAS SET THE STAGE FOR THIS IN WHICH NINR HAS BEEN INVOLVED IS THAT OF THE -- GENOMIC NURSING SCIENCE. AS WE KNOW THE AREA OF GENETICS AND GENOMICS HAS NOW BECOME FAIRLY COMMONPLACE IN THE FABRIC OF OUR EVERYDAY LIVES. THE TERMINOLOGY IS, YOU KNOW, EVERYWHERE YOU GO, WHETHER IT'S ABOUT ORGANICS AND NUTRITION AND FOOD IN THE GROCERY STORE OR IT'S ABOUT EVEN TO THE POINT OF (INDISCERNIBLE) BUT GENOMICS IS SOMETHING THE INSTITUTE HAS BEEN INVOLVED IN SINCE AROUND 1999 WHEN WE STARTED OFFERING SUMMER GENETICS COURSE. SUMMER GENETICS IN SITU WAS INTENDED TO PROVIDE THE BASIS FOR SCIENTIFIC COMMUNITY TO GET THE NECESSARY KNOWLEDGE, TO BE ABLE TO ENGAGE IN THE CONVERSATION, AND TO BE ABLE TO TAKE ADVANTAGE OF OPPORTUNITIES AS WELL AS CREATE NEW OPPORTUNITIES. AND SO THE IDEA WAS THAT PEOPLE WOULD TAKE THIS INFORMATION AND TO INCORPORATE IT IN THEIR RESEARCH PROTOCOLS IN THEIR PRACTICES, AND IN THE CLASSES THAT THEY WERE TEACHING. FLASH FORWARD, WE'VE NOW DEVELOPED OVER TIME THROUGH A DEVELOPED A BLUEPRINT FOR GENOMIC NURSING SCIENCE WHICH HAS BEEN PUBLISHED IN 2015. ACTUALLY THE UPDATE IS IN 2015, THE ORIGINAL BLUEPRINT WAS PUBLISHED IN 2013 AND THAT IS TIED TO OUR STRATEGIC PLAN AND DOES IDENTIFY A NUMBER OF OPPORTUNITIES AND NUMBER OF CHALLENGES IN THIS AREA. SO I WOULD SUGGEST FOR THOSE OF YOU THAT ARE PARTICULARLY INTERESTED IN THAT ASPECT, THAT PAPER WOULD BE A GOOD ONE TO GO TO. NOW, LOOKING AT SOME OF THE POTENTIAL OPPORTUNITIES IN DATA SCIENCE, AND THEY ARE NUMEROUS, YOU'LL HEAR MUCH MORE ABOUT THESE THROUGHOUT THE WEEK. WHAT YOU THOUGHT YOU KNEW WHEN YOU CAME WILL PALE IN COMPARISON TO WHAT YOU KNOW WHEN YOU LEAVE HERE, BUT JUST TO TAKE A FEW, AREAS THAT ARE PARTICULARLY RELEVANT ARE DATA VISUALIZATION, TAKING DATA AND CREATING MAPS, PROFILING COMPLEX CONDITIONS TO GUIDE THERAPY, TO GET DATA TO CHARACTERIZE WHAT'S HAPPENING TO CERTAIN POPULATIONS AND INDIVIDUALS AND PERSONALIZE FOR INDIVIDUALS TO PROVIDE INTERVENTIONS AND THERAPIES THAT WILL BE MOST HELPFUL TO THEM SPECIFICALLY. ALSO MINING SOCIAL MEDIA TO DISCERN TRENDS. THIS IS SOMETHING THAT WE'RE ALL LEARNING ON A DAILY BASIS AND WE'RE REALLY JUST BY -- SOME PEOPLE -- DESPITE SOME OF US BEING DRAGGED ARE GETTING BETTER AND BEGINNING TO APPRECIATE POSSIBILITIES. HOW DO YOU COLLECT THAT INFO? HOW DO YOU EVALUATE IT? HOW DO YOU SIFT THROUGH? SO THAT'S SOMETHING THAT WE WILL BE RELYING ON MUCH MORE AS WE FACE THE FUTURE. AND CERTAINLY THAT IS AN ENORMOUS SOURCE OF DATA. ALSO DEVELOPING LEARNING SYSTEMS TO MAXIMIZE USE OF LONGITUDINAL AND INTEROPERABLE DATA SETS AND THAT'S A CHALLENGE AS A NUMBER OF COMPANIES ARE DEVELOPING REPOSITORIES AND SO WE WILL BE ABLE TO DOWNLOAD SOME OF THOSE DATTS AS THEY WORK WITH US, BUT HOW DO YOU MAKE A GOOGLE DATASET INTERFACE AND INTERACT WITH ANOTHER DATASET? SO, AGAIN, THESE ARE THINGS THAT WE'RE FACED WITH AS CHALLENGES AND THINGS THAT WE WILL BE DEALING WITH AS WE GO FORWARD. SO WHAT ABOUT OUR PARTICULAR AREAS OF SCIENTIFIC FOCUS? THESE ARE OUTLINED IN OUR STRATEGIC PLAN BUT BASICALLY CENTER AROUND SYMPTOM SCIENCE WHICH IS PERSONALIZED MEDICINE, PERSONALIZED HEALTH, WELLNESS WHICH INVOLVES PREVENTION, SELF MANAGEMENT WHICH ADDRESSES THE AGING POPULATION IN OUR COUNTRY AND ACROSS THE GLOBE, THAT'S AGING WELL WITH CHRONIC ILLNESS, BUT REALLY IN THE SITUATION OF NEEDING TO MANAGE THE SYMPTOMS THAT THEY HAVE, YET LEAD ACTIVE LIVES. SO WORKING WITH THEM IN PARTNERSHIP IS SOMETHING WHICH IS VERY MUCH PART OF THE NEW HEALTH CARE PLAN AND SOMETHING WE HAVE BEEN FORESHADOWING AND ANTICIPATING FOR A WHILE. END OF LIFE AND PALLIATIVE CARE, WE'RE THE LEAD INSTITUTE AT NIH FOR THAT, WITH A UP IN OF SOCIALOLOGY CAL INFLUENCE, RELATIVELY UNDERSTUDIED AND INCREASING IN IMPORTANCE AND ATTENTION AND IMPACT IT CAN MAKE. SO JUST QUICKLY LOOKING AT A COUPLE EXAMPLES OF SOME SCIENCE IN THESE AREAS, FIRST LOOKING AT SYMPTOM SCIENCE, WE SAID OUR POPULATION IS AGING, SO WE HAVE A LARGE PROPORTION OF OLDER POPULATION NOW. THE HEALTH DATA OF OLDER ADULTS, A NUMBER OF DATASETS DO EXIST WE'RE ADDING TO THOSE. ONE OF THE CONTINUING PROBLEMS FOR OLDER ADULTS, WOMEN MORE THAN MEN, BUT BOTH SEXES, IS THAT OF FALLING AND BREAKING BONES, PARTICULARLY HIPS. SOMETIMES THAT IN PREVIOUS YEARS WAS A DEATH SENTENCE, AND NOW IT CERTAINLY IS SOMETHING THAT FORESHADOWS A PERIOD OF DISABILITY AND CAN BE LIFE-THREATENING. AND SO ONE OF OUR SCIENTISTS LOOKED AT LARGE DATASETS TO IDENTIFY THE DISABILITY OR MOBILITY OF OLDER ADULTS AND IDENTIFIED THAT THOSE WHO HAD THE -- WHO HAD EXPERIENCED FRACTURES, ALTHOUGH MANY PEOPLE HAD SOME MOBILITY ISSUES, THAT THOSE WHO EXPERIENCED FRACTURES WERE THOSE WHO HAD THE INCREASED MOBILITY IN THE PERIOD OF TIME CLOSEST TO WHEN THAT FRACTURE OCCURRED. THEY ALSO DID LOOK AT -- SO THAT CAUSED US TO LOOK AT REEVALUATION OF HOW LONG IS LONG TERM AND WHAT KIND OF MONITORING SHOULD OCCUR WITH THE ELDERLY, AT WHAT POINT SHOULD YOU BEGIN TO WORRY ABOUT DISABILITY WHICH MAY PUT THEM IN DANGER OVER THE EDGE TOWARD FALLING AND ULTIMATELY A FRACTURE. ALSO ANOTHER PERSISTENT PROBLEM OVER TIME IS THAT OF SEPSIS, INFECTION AND ACCEPT SITUATION, CHARACTERIZE THOSE AS HOSPITAL-BASED. THE IDEA IS STAY OUT OF HOSPITALS BECAUSE THAT'S WHERE YOU GET THE INFECTIONS. LOOKING AT SEVERAL VERY LARGE DATASETS, IT TURNED OUT THAT ABOUT 10% OF DISCHARGES FROM A GROUP OF ACADEMIC HOSPITALS AND THEIR AFFILIATES WERE INVOLVED IN SEPSIS BUT MAJORITY OF SEPSIS TURNED OUT TO BE COMMUNITY ACQUIRED, AND THE DIFFERENCE BEING THOSE WITH HOSPITAL-ACQUIRED SEPSIS HAD MORE SERIOUS INFECTION AND MORE NEGATIVE OUTCOMES, OF A MORE SERIOUS NATURE THAT PERHAPS THEY ARE MUCH MORE FRONT AND CENTER. I MENTIONED SELF MANAGEMENT EARLIER. SO ONE OF THE STUDIES USING LARGE DATASETS WE SPONSORED WAS LOOKING AT POST-MI INFARCTION MEDICATION ADHERENCE. UNFORTUNATELY WE KNOW MANY PEOPLE WHO EXPERIENCE CARDIOVASCULAR EVENTS SUCH AS STROKE AND MYOCARDIAL INFARCTION ARE PRONE TO HAVE RECURRENCE OF THOSE EVENTS, AND YET IT TURNS OUT THAT THE INTERVENTIONS THAT ARE PRESCRIBED THAT ARE PREVENTED FOR THOSE EVENTS TEND TO HAVE RELATIVELY LOW ADHERENCE IN MANY CASES. SO THESE DATASETS INTERESTINGLY POINTED OUT GEOGRAPHICAL DIFFERENCES AND ADHERENCE THAT AS YOU CAN SEE THE RED STATES, THESE ARE NOT RED AND BLUE STATES. [LAUGHTER] THIS IS A GOVERNMENT FACILITY. [LAUGHTER] BUT THOSE ARE THE STATES WITH POOREST ADHERENCE. BUT INTERESTINGLY ENOUGH, IN LOOKING AT THE VARIOUS FACTORS, IT REALLY WAS DIFFICULT TO POINT OUT THAT IT WAS, YOU KNOW, DIET OR LACK OF EXERCISE, ET CETERA, BUT ONE OF THE THINGS THAT WAS IDENTIFIED THAT IS THAT WERE A LOT OF FACTORS TO COORDINATE AND THERE WERE A NUMBER OF THINGS THAT INTERFERED WITH ADHERENCE THAT WERE IN FACT MODIFIABLE THROUGH COORDINATION AND BETTER CARE, AN INTERESTING AND UNEXPECTED FINDING. I MENTIONED ALSO THAT WE ARE LEAD FOR END OF LIFE. ONE OF THE BIG ISSUES IN THE AREA OF END OF LIFE AND PALLIATIVE CARE IS USE OF HOSPICE CARE, AND THIS STUDY LOOKED AT THE NATIONWIDE VARIATION AND USE OF HOSPICE CARE, AND THE ISSUE IS REALLY THAT HOSPICE CARE IS VERY VALUABLE FOR PEOPLE AT THE RIGHT TIME, AND MOST OFTEN WE FIND THAT PATIENTS ARE NOT REFERRED TO HOSPICE EARLY ENOUGH THAT IT COULD BE MORE THERAPEUTIC, OR SOMETIMES THEY ARE REFERRED EARLY AND THE TIME RUNS OUT, TRANSFERRING IN AND OUT IS DISRUPTIVE AND HAS POOR PROGNOSTIC -- IS A POOR PROGNOSTICATOR. THIS STUDY POINTED OUT WHICH AREAS ARE USING THESE FACILITIES MORE SUCCESSFULLY AND WHICH ARE NOT SO WE CAN THEN BURROW DOWN AND SEE WHAT ARE SOME OF THE FACTORS OTHER THAN STATE LAWS WHICH WE KNOW ARE A BIG ISSUE. AND EVEN IF THAT IS THE ISSUE THAT HELPS TO TARGET WHAT ARE THE STATES FOR THOSE WHO ARE TRYING TO CHANGE THE LAWS. WE ALSO LIKE OTHER INSTITUTES AT NIH HAVE AN SBIR PROGRAM AND THIS IS A VERY CLEVER STUDY THAT WHICH WOULD PREDICT READMISSION, AS WE KNOW IN THE NEW -- THE NEW ACA AND REIMBURSEMENT, THAT SO-CALLED UNPLANNED OR UNNECESSARY REHOSPITALIZATIONS ARE NOT REIMBURSED FOR SO THERE'S MORE OF A FOCUS FROM AGENCIES ON HOW TO PREDICT WHO REALLY NEEDS WHAT KIND OF -- WHO NEEDS FOLLOW-UP CARE AND WHAT KIND TO PREVENT REHOSPITALIZATIONS. WE'VE BEEN FOCUSING ON THAT FOR SOME TIME BUT IT'S NICE NOW THAT THE SOCIOLOGY OF THE HEALTHCARE SYSTEM IS FOCUSING ON IT AS WELL, ENHANCING OUR POTENTIAL FOR TRANSLATION OF THESE RESULTS. THIS INVESTIGATOR USING DATAS THAT EMBEDDED IN ELECTRONIC HEALTH RECORDS IDENTIFIED A NUMBER OF FACTORS WHICH COULD POTENTIALLY PREDICT WHO NEEDS FOLLOW-UP AFTER HOSPITAL DISCHARGE AND WHAT TYPE OF FOLLOW-UP, AND WAS ACTUALLY IN FIELD TESTING WAS SUCCESSFUL ENOUGH THEY WERE ABLE TO DEVELOP A SPECIFIC TOOL WHICH IS NOW BEING UTILIZED IN HOSPITALS ACROSS THE COUNTRY THAT IS VERY SUCCESSFUL IN IDENTIFYING WHICH PATIENTS NEED FOLLOW-UP AND WHAT TYPE OF FOLLOW-UP, AND AS A RESULT OF USING THIS DECISION SUPPORT SYSTEM, THERE ARE IMPROVED HEALTH OUTCOMES FOR THE POPULATIONS USING IT AND ALSO OF COURSE BECAUSE THERE ARE FEWER REHOSPITALIZATIONS, UNNECESSARY REHOSPITALIZATIONS, IT DOES ALSO REDUCE HOSPITAL READMISSION COST FOR OF THE HOSPITAL SYSTEM AND EXPENSES AND UNTOWARD OUTCOMES FOR PATIENTS. ONE OF THE ASPECTS OF SYMPTOM SCIENCE THAT THE STUDY OF SYMPTOMS AND HOW WE CAN COLLECT ENOUGH DATA TO BE ABLE TO DEVELOP SUCCESSFUL INTERVENTIONS TO DEAL WITH THOSE SYMPTOMS, ONE OF THE ISSUES IS THAT OF AMASSING LARGE ENOUGH SAMPLE SIZES. THAT'S ONE OF THE THINGS THAT THE PRECISION MEDICINE INITIATIVE WILL BE ADDRESSING, BEING ABLE TO COLLECT LARGE DATASETS BUT TO COMPARE DATA ONE MUST HAVE SIMILARITIES BETWEEN DATASETS AND DATA COLLECTED. WE'RE LOOKING AT COMMON DATA ELEMENTS. WHEN YOU'RE COLLECTING INFORMATION, IF YOU HAVE A NUMBER OF SMALL STUDIES COLLECTING SIMILAR -- COLLECTING DATA ON SIMILAR DATA ELEMENTS THERE'S THE POTENTIAL FOR COMBINING DATA SETS, POTENTIAL INCREASES, SO WE'RE IN OUR CENTERS PROGRAM ARE NOW EXPERIMENTING WITH COMMON DATA ELEMENTS IN THE DATA COLLECTION WITH CENTERS ACROSS THE COUNTRY, AND THOSE ARE ELEMENTS WHICH HAVE BEEN IDENTIFIED IN CONJUNCTION WITH THE COMMUNITY WITH A NUMBER OF REGIONAL MEETINGS, AND SO WE HAVE NOW IDENTIFIED A NUMBER OF CANDIDATES FOR THIS, AND ARE IT OUT, AND A PILOT IN OUR CENTERS PROGRAM. THIS WILL POTENTIALLY FACILITATE CONSOLIDATION OF DATA SETS, INCREASE STATISTICAL POWER AND BE ABLE TO HELP US TO IDENTIFY TRENDS AND POTENTIAL INTERVENTIONS WITH A GREATER FACILITY AND HOPEFULLY ONCE IT WILL BE VERY EFFECTIVE. I MENTIONED OUR STRATEGIC PLAN EARLY IN MY COMMENTS. WE ARE IN FACT DEVELOPING OUR NEW STRATEGIC PLAN, BUILDING ON THE CURRENT ONE, AND THAT WILL BE RELEASED IN SEPTEMBER OF THIS YEAR. THIS IS OUR 30th ANNIVERSARY AT NIH, AMAZINGLY, AND SO WE ARE RELEASING THE NEW STRATEGIC PLAN WITH THAT ANNIVERSARY IN SEPTEMBER. IT'S BEEN OUT FOR PUBLIC COMMENT, VETTED BY DIFFERENT GROUPS SO WE'RE VERY ENTHUSIASTIC. IT BUILDS VERY WELL ON THE EFFECTIVE PLAN WE'VE HAD BUT MOVES IT FORWARD AND MOVES US FORWARD FOR ANOTHER 5+ YEARS. I WOULD BE REMISS IF I DID NOT BRING THIS TO YOUR ATTENTION, THE NUMBER OF EVENTS THAT ARE OCCURRING, AND YOUR INVITATION TO ATTEND IN PERSON OR VIRTUALLY OVER THE NEXT SEVERAL MONTHS BEGINNING THE -- THE NEXT EVENTS IS OUR NINR DIRECTOR LECTURE SEPTEMBER 13 OF THIS YEAR, IT'S OUR LECTURE THAT INTERFACES MORE WITH SOME OF THE MORE PUBLIC ISSUES AND IT'S ELLEN GOODMAN SPEAKING ON END OF LIFE, "THE CONVERSATION WE'RE NOT HAVING" THAT SHOULD BE VERY INTERESTING, SHE'S BE A OUTSTANDING SPEAKER. SCIENTIFIC SYMPOSIUM IS SEPTEMBER 14 PRIOR TO THE COUNCIL FOR NURSING SCIENCE WEEK OF SCIENCE MEETINGS, AND FINISHING THE YEAR WITH THE DIRECTOR'S LECTURE ON NOVEMBER OF 2016. I INVITE ALL OF YOU TO ATTEND ANY OR ALL IN PERSON OR VIRTUALLY AND VISIT OUR WEBSITE. WE DO SPEND A LOT OF TIME REVISING AND TRYING TO DETERMINE THE BEST WAYS TO COMMUNICATE SO WE ALWAYS APPRECIATE FEEDBACK AND THE REASON YOU SEE MANY TWEAKS ALONG THE WAY IS BECAUSE WE DO IN FACT LISTEN TO ALL OF OUR PUBLIC ABOUT WHAT WORKS AND WHAT DOESN'T WORK, AND TRY TO KEEP YOU UP TO DATE WITH WHAT'S HAPPENING AND GIVE YOU HEADS-UPS, SORT OF AHEAD OF TIME, ANNOUNCEMENTS ABOUT THINGS IN THE PIPELINE AND THINGS YOU SHOULD LOOK FOR. WITH THAT I WILL CLOSE MY REMARKS AND AGAIN SAY THAT I'M DELIGHTED YOU'RE HERE. WE'RE LOOKING FORWARD TO HAVING YOU ALL WEEK AND YOU WILL SEE A NUMBER OF US SLIPPI IN AND OUT OF THE BACK DOOR BECAUSE WE'RE JUST AS INTERESTED IN HEARING MOST OF THE LECTURES AS YOU ARE. THANK YOU SO MUCH. [APPLAUSE] >> THANK YOU, SO MUCH, DR. GRADY. WE'RE MOVING RIGHT ALONG, AREN'T WE? WELL, I'M REALLY PLEASED TO INTRODUCE OUR NEXT SPEAKER, IF YOU WANT TO GO EARLY, IF THAT'S ALL RIGHT. WE HAVE THE GREATEST SPEAKERS, I HAVE IT TELL YOU, FIRST HAND. IT IS MY ESTEEMED PLEASURE TO INTRODUCE THIS MORNING'S KEYNOTE SPEAKER, DR. LEROY HOOD, PRESIDENT AND CO-FOUNDER OF INSTITUTE OF SYSTEMS BIOLOGY IN STATE OF WASHINGTON, WORLD RENOWNED SCIENTIST, INVENTOR, ENTREPRENEUR, AND VISIONARY. HIS DISCOVERIES HAVE PERMANENTLY CHANGED THE COURSE OF BIOLOGY AND REVOLUTIONIZED THE UNDERSTANDING OF GENETICS, LIFE AND HUMAN HEALTH. DR. HOOD'S OUTSTAND CONTRIBUTIONS HAVE HAD A RESOUNDING EFFECT ON THE ADVANCEMENT OF SCIENCE SINCE THE 1960s, HE HAS ADHERED TO ADVICE OF MENTOR DR. WILLIAM J. DRIER. IF YOU WANT TO PRACTICE BIOLOGY, DO IT ON THE HEEDING EDGE AND IF YOU WANT TO BE ON THE LEADING EDGE INVENT NEW TOOLS FOR DECIPHERING BIOLOGICAL INFORMATION. HE CREATED THE TECHNOLOGICAL FOUNDATION FOR SCIENCES OF GENOMICS, STUDY OF GENES, AND PROTEOMICS, STUDY OF PROTEINS, THROUGH INVENTION OF FIVE GROUND-BREAKING INSTRUMENTS AND INCREASING POTENTIAL OF GENOME AND PROTEOME RESEARCH INTO THE FUTURE THROUGH HIS PIONEERING WORK IN THE FIELDS OF SYSTEM BIOLOGY AND SYSTEMS MEDICINE. DR. HOOD'S INSTRUMENTS NOT ONLY PIONEERED DECIPHERING OF BIOLOGICAL INFORMATION BUT ALSO INTRODUCED THE CONCEPT OF HIGH THROUGHPUT DATA ACCUMULATION THROUGH AUTOMATION AND PARALLELIZATION OF PROTEIN AND DNA CHEMISTRIES. DR. HOOD WILL JOIN US AND PRESENT ON HOW SCIENTIFIC WELLNESS WILL TRANSFORM HEALTH CARE. PLEASE JOIN ME IN A WARM WELCOME FOR DR. LEROY HOOD. [APPLAUSE] >> IT'S A PLEASURE TO BE HERE. AND I'D LIKE TO TELL YOU ABOUT THREE THINGS. NUMBER ONE, SYSTEMS BIOLOGY IS REALLY TRANSFORMED HOW WE CAN PRACTICE MEDICINE AND I'LL TRY AND SHOW YOU WHAT THAT MEANS. IT'S LED TO SOMETHING WE CALL SYSTEMS MEDICINE, AND A CONCEPT OF HEALTHCARE THAT IS PREDICTIVE, PREVENTIVE, PERSONALIZED AND PARTICIPATORY, WE CALL THAT P-4 MEDICINE. P-4 MEDICINE HAS SAID THERE ARE TWO CENTRAL THRUSTS IN HEALTH CARE TODAY. ONE IS WELLNESS, AND THE OTHER IS DISEASE, AND WE ALMOST COMPLETELY IGNORE WELLNESS. AND WHAT I'LL SAY IS THERE IS A LOT OF WELLNESS THAT IS PSEUDOWELLNESS, AND I'M GOING TO TALK ABOUT SCIENTIFIC WELLNESS. AND FINALLY I'M GOING TO ALSO TALK ABOUT HOW IN ADDITION TO SYSTEMS BIOLOGY OF COURSE GENOMICS HAVE INTRUDED UPON MEDICINE AND TOGETHER THEY HAVE GIVEN US THIS CONCEPT CALLED TALK ABOUT WHAT PRECISION MEDICINE SHOULD BE AND TODAY IT'S A LONGER WAY FROM WHERE IT SHOULD BE. AND THEN FINALLY, I'LL SHOW YOU HOW THROUGH A RECENT AFFILIATION OF MY INSTITUTE WITH A VERY LARGE HEALTHCARE SYSTEM IN SEATTLE WHERE WE HAVE BECOME A RESEARCH ARM, WE FOR THE FIRST TIME HAVE THE ABILITY TO TAKE FUNDAMENTAL SCIENCE AND ITS TRANSLATIONAL MODIFICATIONS DIRECTLY TO THE PATIENT BEDSIDE, AND I'LL SHOW YOU SOME VERY EXCITING PROJECTS THAT WE'RE GOING TO BE WORKING ON. SO LET ME GIVE YOU A LITTLE HISTORIC CONTEXT FOR ALL OF THESE THINGS. WHEN I WENT AS A YOUNG ASSISTANT PROFESSOR TO CAL TECH IN 1970, I WAS REALLY IMPRESSED WITH THE ENORMOUS COMPLEXITY OF BOTH BIOLOGY AND DISEASE, AND WHAT I WAS CONVINCED IS WE DID NOT HAVE THE TOOLS OR STRATEGIES FOR REALLY DEALING WITH THAT COMPLEXITY, THE EARLY FORMS OF MOLECULAR BIOLOGY AND BIOCHEMISTRY AND CELL BIOLOGY HAD FOCUSED ALMOST ENTIRELY ON ONE GENE OR ONE PROTEIN OR ONE MOLECULE AT A TIME, AND YOU'LL NEVER SOLVE COMPLEXITY LOOKING AT THINGS ONE AT A TIME. BUT WHAT WAS ALSO MISSING WAS A WAY OF TALKING ABOUT BIOLOGICAL COMPLEXITY AND THAT'S WHAT SYSTEMS BIOLOGY LATER CAME TO BE CALLED. AND I REMEMBER THINKING AT THE TIME THAT THIS WHOLE ISSUE OF COMPLEXITY WAS VERY MUCH LIKE THE FABLE OF THE ELEPHANTS AND SIX BLIND MEN, EACH FEELING A DIFFERENT PART OF IT, AND THAT'S EXACTLY WHAT BIOLOGISTS WERE DOING IN THE EARLY '70s. THEY SPECIALIZED IN PROTEINS AND IN ONE OR TWO PROTEINS, OR GENES, AND THEN ONE OR TWO GENES, AND EACH OF THEM LOOKED AT THE ELEPHANT AND DECLAR FROM THEIR OWN POINT OF VIEW AS BLIND MEN, IT'S A ROPE, IT'S A TRUNK, AND WE NEEDED NEW TECHNOLOGIES THAT COULD ACTUALLY EXPLORE THE BIOLOGICAL DIMENSIONALITY OF THE ELEPHANT AND GIVE US A MORE COHESIVE VIEW OF WHAT IT REALLY WAS. SO THAT WAS ONE THING I STARTED THINKING ABOUT, AND THEN IN 1973 I REMEMBER READING A BOOK THAT REALLY REVOLUTIONIZED MY THINKING IN A LOT OF WAYS. IT WAS THOMAS KUHN'S "THE STRUCTURE OF SCIENTIFIC REVOLUTION" ABOUT PARADIGM CHANGES IN PHYSICS. A PARADIGM CHANGE IS A WAY OF DRAMATICALLY ALTERING HOW WE THINK ABOUT ONE PARTICULAR AREA OF SCIENCE. AND THE POINT KUHN MADE, TWO POINTS THAT WERE INTERESTING, ONE, PARADIGM CHANGE IS HARD TO ACHIEVE BECAUSE THEY REQUIRE PEOPLE TO THINK OUTSIDE THE BOX, AND MOST PEOPLE CAN'T DO THAT VERY WELL. BUT HE SAID EVEN MORE DIFFICULT IS ONCE YOU HAVE A PARADIGM CHANGE, IF PERSUADING YOUR COLLEAGUES THIS INDEED IS RIGHT, AND THAT'S BECAUSE SCIENTISTS TEND TO BE ENORMOUSLY CONSERVATIVE AND RELUCTANT TO GIVE UP LONG LEARNED LESSONS AND SO FORTH. SO I HAD THE GOOD FORTUNE TO BE INVOLVED IN A SERIES OF PARADIGM CHANGES OVER THE COURSE OF MUCH OF MY CAREER THAT DEALT WITH THIS BIOLOGICAL COMPLEXITY, AND WHAT WAS REALLY INTERESTING ABOUT THEM IS THEY REALLY KIND OF IRREVOCABLE PUSHED US TOWARDS THE IDEAS OF SYSTEMS MEDICINE AND NEW TYPES OF HEALTH CARE. THE FIRST YOU'VE ALREADY HEARD WE DEVELOPED AT CAL TECH FOUR INSTRUMENTS THAT LET YOU READ AND WRITE DNA AND PROTEINS, AND THEN TWO OTHER INSTRUMENTS LATER ON. AS YOU HEARD, WHAT THESE INSTRUMENTS INTRODUCED FOR THE FIRST TIME IS THE ABILITY TO MAKE VERY RAPID MEASUREMENTS IN BIOLOGY, SO-CALLED HIGH THROUGHPUT BIOLOGY. THE SECOND THING THESE INSTRUMENTS DID IS THEY PAVED THE WAY FOR BIG DATA AND ITS ANALYTICS, A CENTRAL PART OBVIOUSLY OF SYSTEMS MEDICINE AND PRECISION MEDICINE. NOW, ONE OF THE INSTRUMENTS THAT WE DEVELOPED WAS THE AUTOMATED DNA SEQUENCER, AND TALKING ABOUT CONSERVATIVE PEOPLE, THE FIRST TWO APPLICATIONS I PUT IN TO NIH TO FUND THIS NEW AUTOMATED DNA SEQUENCER WITH TURNED DOWN WITH ME OF THE WORST PRIORITY SCORES I EVER GOT, AND THE COMMENTS MADE WERE GRADUATE STUDENTS CAN DO IT MORE EASILY AND I REMEMBER ONE COMMENT SAID THIS IS UTTERLY IMPOSSIBLE. OF COURSE, THOSE ARE DIFFICULT COMMENTS TO RESPOND TO. [LAUGHTER] THE AUTOMATED DNA SEQUENCER GOT ME INVITED TO THE FIRST MEETING HEALTH ON THE HUMAN GENOME PROJECT IN THE SPRING OF 1985, TWELVE OF US WENT TO SANTA CRUZ TO TALK ABOUT THE MERITS OF THE GENOME PROJECT AND CAME TO TWO INTERESTING CONCLUSIONS. ONE IS IT WOULD BE TECHNICALLY FEASIBLE ALTHOUGH AT THAT TIME REALLY DIFFICULT, AND THE SECOND WHICH WAS FASCINATING, WE WERE SPLIT 6-6 ON WHETHER IT WAS A GOOD IDEA, AND IN FACT THE 6 AGAINST IT WERE FANATICALLY AGAINST IT. AND THE ESSENCE OF THEIR ARGUMENT WAS THE GENOME PROJECT WAS BIG SCIENCE AND BIG SCIENCE WOULD DESTROY SMALL SCIENCE. ARGUMENTS THAT TURNED OUT TO BE ENTIRELY SALACIOUS BECAUSE THEY ARE ENORMOUSLY COMPLEMENTARY. BUT WHAT THE GENOME PROJECT DID IS FOR THE FIRST TIME GAVE US A COMPLETE PARTS LIST OF ALL THE GENES AND BY INFERENCE PROTEINS AND HENCE WE COULD THINK FROM A SYSTEMS POINT OF VIEW ABOUT HOW TO ATTACK HUMAN BIOLOGY AND HUMAN DISEASE. NOW, THE AUTOMATED SEQUENCER WAS INTERESTING IN ANOTHER WAY IN THAT I HAD TO BRING TOGETHER AN ENGINEER, A COMPUTER SCIENTIST, REALLY GOOD CHEMIST, AND BIOLOGIST BEFORE WE COULD FIGURE OUT HAW TO DO AUTOMATED DNA SEQUENCING, AND WHAT THAT MADE ME REALIZE IS THAT LEADING EDGE BIOLOGY OUGHT TO ALWAYS OPERATE IN THE CONTEXT OF CROSS DISCIPLINARY ENVIRONMENT. IN THE LATE '80s I WENT TO PEOPLE AT CAL TECH, AND SUGGESTED I START AN APPLIED DEPARTMENT THAT HAD THAT KIND OF ENVIRONMENT. AND EVERYBODY AT CAL TECH LOVED THIS IDEA EXCEPT FOR THE BIOLOGISTS WHO VETOED IT. I'LL LEAVE THAT TO YOU TO FIGURE OUT WHY THEY MIGHT HAVE VETOED IT, BUT BILL GATES MADE IT POSSIBLE TO GO TO THE UNIVERSE OF WASHINGTON AND SET UP THE FIRST CROSS-DISCIPLINARY DEPARTMENT AND IT LASTED FOR 8 YEARS, AND IT WAS UTTERLY SPECTACULAR. TWO OF ITS FACULTY DEVELOPED THE FIRST TWO KEY TECHNIQUES FOR THE NEWLY EMERGING FIELD OF PROTEOMICS, THIRD FACULTY WROTE ALL THE KEY SOFTWARE FOR ASSEMBLY AND QUALITY EVALUATION OF THE HUMAN GENOME. AT THAT TIME I INVENTED THIS TECHNOLOGY FOR SYNTHESIZING DNA TO GIVE YOU VERY LARGE SCALE DNA, AND ON AND ON. BUT WHAT WAS REAL INTERESTING IS I WENT THERE WITH A PROMISE FROM THE DEAN THAT AFTER 4 YEARS IN CREATING THIS CROSS-DISCIPLINARY DEPARTMENT I COULD BUILD ON TOP OF IT SYSTEMS BIOLOGY. AND, YOU KNOW, SERENDIPITY PLAYS REALLY INTERESTING ROLES IN ALL OF OUR LIVES, AND WHAT HAPPENED TO ME IS THAT YEAR 4, THE DEAN THAT MADE THAT PROMISE DIED IN AN AVALANCHE IN THE HIMALAYAS. AND THE NEW DEAN WHO CAME ON BOARD HAS TOTALLY DIFFERENT SET OF PRIORITIES. AFTER STRUGGLING FOR A FEW YEARS I DECIDED IT WOULD BE UTTERLY IMPOSSIBLE TO BUILD SYSTEMS BIOLOGY AT AL BUREAUCRATIC PLACE WHERE THE LEADERSHIP WASN'T IN SYNC WITH WHAT YOU WANTED TO DO. SO I RESIGNED AND STARTED THE INSTITUTE FOR SYSTEMS BIOLOGY IN THE YEAR 2000, AND IT WAS THE TOOK ON THE IDEA OF PIONEERING ON TO BOTH BIOLOGY AND SYSTEMS SCIENCE AND ITS TO MEDICIN AND OF COURSE THAT QUICKLY LED, AS I SAID EARLIER, TO SYSTEMS MEDICINE AND THIS THING WE CALL P-4 MEDICINE WHICH WE WILL TALK ABOUT IN SOME DETAIL. FINALLY IN APRIL WE HAD AFAILATION WITH PROVIDENCE, A LARGE HEALTHCARE SYSTEMS, I BECAME CHIEF SCIENCE OFFICER OF THE PROVIDENCE SYSTEM AND WAS IN A POSITION TO INITIATE A SERIES OF REVOLUTIONARY TRANSLATIONAL OPPORTUNITIES THAT WE'LL TALK ABOUT RIGHT AT THE VERY END OF THE LECTURE. WHAT I'D LIKE TO DO, JUST TO GIVE YOU AGAIN A CONTEXT FOR WHERE WE'RE GOING, IS, ONE, TALK ABOUT THE INSTITUTE FOR SYSTEMS BIOLOGY AND WHAT SYSTEMS BIOLOGY IS. NUMBER TWO, I'D LIKE TO TALK IN SOME DETAIL ABOUT WHAT SYSTEMS AND P4 MEDICINE ARE, AND THEN NUMBER THREE I WANT TO TALK ABOUT HOW WE CAN BRING REVOLUTIONARY IDEAS TO THE HEALTHCARE SYSTEM AND I THINK THERE ARE TWO INCREDIBLE OPPORTUNITIES FOR NURSING WHICH I'LL TALK ABOUT IN MY VERY LAST SLIDE. SO LET'S BEGIN BY TALKING ABOUT THE INSTITUTE FOR SYSTEMS BIOLOGY. SO WE'RE 16 YEARS OLD. WE HAVE ABOUT 200 PEOPLE, ROUGHLY 9 FACULTY AND ANNUAL BUDGET OF $35 MILLION A YEAR. WE REALLY HAVE BEEN A PIONEER IN KIND OF DEVELOPING SYSTEMS SCIENCE. BUT THE EASIEST WAY TO SHOW YOU WHAT SYSTEMS BIOLOGY IS IS TO USE THIS OLD RUBE GOLDBERG CARTOON ANALOGY. SO IN THIS CASE, RUBE GOLDBERG HAS PUT TOGETHER 14 GADGETS THAT WHEN CONNECTED ALLOW HIM TO COOL HIS SOUP. SO THE QUESTION WE CAN ASK IS HOW COULD YOU TAKE A SYSTEMS APPROACH TO UNDERSTAND THE NATURE OF THIS GADGET AND REALLY HOW IT WORKS. AND THAT'S OUTLINED HERE. PROJECT DID. WE GET A PARTS LIST AND FIND THE 14 PARTS AND THEN, TWO, WE DID WHAT A LOT OF EARLY BIOLOGY IS DOING, AND STILL DOING. WE TRY AND UNDERSTAND WHAT EACH PART DOES IN ISOLATION. THEN NUMBER THREE, WE TRY TO PUT THEM TOGETHER INTO A DEVICE IN A SENSE MECHANICAL NETWORK, IF YOU WILL, AND THEN NUMBER FOUR, WE'D LIKE TO UNDERSTAND THE DYNAMICS OF THIS NETWORK. AND THEN FROM ONE, TWO, THREE AND FOUR WE FORMULATE HYPOTHESES ABOUT HOW THIS DEVICE MIGHT WORK AND THE WAY YOU TEST TO SEE IF YOU'RE RIGHT IS PERTURB THE SYSTEM AND SEE IF IT BEHAVES IN WAYS THAT ARE PREDICTABLE ACCORDING TO YOUR HYPOTHESIS. SO THAT'S THE ESSENCE OF WHAT SYSTEMS BIOLOGY IS, EXCEPT THE DIMENSIONALITY OF LIVING ORGANISMS IS LARGER, THE AMOUNT OF DATA WE HAVE TO DEAL WITH IS LARGER. NOW, FROM A SYSTEMS POINT OF VIEW THERE ARE FOUR SPECIAL THINGS ABOUT DATA THAT WE WANT TO EMPHASIZE. ONE, WHEN YOU GENERATE DATA ON A BIOLOGIC OBJECT, YOU ALWAYS WANT IT TO BE AS COMPREHENSIVE AND GLOBAL AS POSSIBLE BECAUSE YOU NEVER KNOW WHICH PARTS ARE KEY TO WHATEVER YOU'RE LOOKING AT. NUMBER TWO, AS I SAID EARLIER, IN LIVING ORGANISMS WE MAY UNDERSTAND THE DYNAMICS OF HOW THEY OPERATE AND THE DYNAMICS OPERATE IN TIME, AND THEY OPERATE IN SPACE. AND WE ACTUALLY DON'T HAVE VERY GOOD TOOLS FOR UNDERSTANDING AND STUDYING DYNAMICS AT THIS POINT IN TIME. NUMBER THREE, WE HAVE TO BE ABLE TO INTEGRATE THIS DATA TOGETHER TO MAKE THESE COHERENT KINDS OF MODELS. AND THEN NUMBER FOUR, WHAT'S REALLY IMPORTANT TO UNDERSTAND IS ALTHOUGH BIG DATA IS ABSOLUTELY ESSENTIAL FOR SYSTEMS MEDICINE, WE HAVE TO UNDERSTAND ALL BIG DATA HAS ENORMOUS AMOUNTS OF NOISE IN IT, AND THE NOISES OF TWO TYPES, ONE IS THE TYPE THAT COMES FROM MAKING THE MEASUREMENTS THEMSELVES, AND THAT TECHNICAL NOISE IS PRETTY EASY TO DEAL WITH. THE SECOND TYPE OF NOISE IS THE NOISE THAT COMES FROM IRRELEVANT BIOLOGIES THAT YOU AREN'T INTERESTED IN CHANGING THINGS IN RESPONSE TO PERTURBATIONS. SO WHAT WE HAVE TO DO AS SYSTEMS BIOLOGISTS IS PRY AWAY THAT IRRELEVANT NOISE REQUIRING AN ENORMOUS AMOUNT OF DOMAIN EXPERTISE. I JUST WANT TO SAY ANYBODY WHO SAYS AS IBM DOES GIVE ME TONS OF DATA FOR WATSON AND I CAN TELL YOU ALL ABOUT MEDICINE IS SMOKING POT. [LAUGHTER] YOU NEED DOMAIN EXPERTISE TO SORT OUT SIGNAL FROM THE NOISE AND YOU'LL NEVER DO THAT WITH MACHINE LEARNING AND BIG COMPUTERS. ALL THE MAJOR I.T. COMPANIES HAVE FAILED TO DO EFFECTIVE THINGS IN HEALTH CARE SO FAR BECAUSE OF THAT REAL LIMITATION. NOW, THE OTHER IDEA WE HAVE AT THE INSTITUTE FROM THE VERY BEGINNING IS AS I SAID LEADING EDGE BIOLOGY SHOULD BE IN AN ENVIRONMENT WHERE IT COULD DRIVE THE KIND OF TECHNOLOGY IT NEEDS TO ANSWER ITS PARTICULAR QUESTIONS, AND THAT TECHNOLOGY AND ITS DATA THEN COULD DRIVE THE ANALYTIC TOOLS. SO IT'S KIND OF A TRIUMVERT. IF YOU CAN COMPLETE THAT TRIUMVERT YOU CAN REALLY DISCOVERY FUNDAMENTAL NEW THINGS ABOUT BIOLOGY AND YOU CREATE ENORMOUS OPPORTUNITIES FOR INNOVATION WITH NEW TECHNOLOGIES, NEW SOFTWARE, AND NEW SCIENTIFIC CONCEPTS. AND TO GIVE YOU AN IDEA OF INNOVATION IN THE 16 YEARS OF THE INSTITUTE'S EXISTENCE WE'VE STARTED 8 COMPANIES, ALL OF WHOM ARE DOING VERY WELL, SOME ARE GOING TO BE MAJOR COMPANIES. AT THE VERY END WE'LL TALK ABOUT ONE OF THOSE COMPANIES. BUT THE ESSENCE OF THIS CYCLE IS YOU HAVE TO HAVE THIS CROSS-DISCIPLINARY ENVIRONMENT WITH ALL OF THE SCIENTISTS THAT ARE LISTED THERE ON THE RIGHT-HAND PART OF THE SLIDE AND THERE ARE THREE THINGS THAT ARE ESSENTIAL FOR THOSE SCIENTISTS TO EXPERIENCE. ONE IS YOU WANT THEM IN CLOSE PROXIMITY WHERE THEY ARE INTERACT. TWO, THEY HAVE TO BE ABLE TO LEARN THE LANGUAGE OF THE OTHER DISCIPLINES SO THEY CAN COMMUNICATE. AND THREE, THEY HAVE TO LEARN TO WORK TOGETHER EFFECTIVELY IN TEAMS AND ACADEMICS DON'T DO ANY OF THOSE THINGS VERY WELL. SO TO GIVE YOU AN IDEA WHAT AN IMPACT SYSTEMS BIOLOGY HAS HAD OVER THE LAST 12 YEARS, THIS IS A STUDY BY AN INSTITUTE IN SPAIN THAT STUDIED 3300 RESEARCH INSTITUTES, AND IN 2012 PLACED ISB, OUR INSTITUTE, FOUR OUT OF 3300 IN THE IMPACT OF ITS PAPERS AND THEN MORE RECENTLY IT WAS THIRD OUT OF EVEN MORE ON HEALTHCARE TECHNOLOGIES, AND THE REALLY IMPORTANT POINT HERE IS SYSTEMS THINKING HAS REALLY TRANSFORMED BIOLOGY AND MEDICINE. SO YOU WANT TO REALLY COME TO UNDERSTAND IT IN IMPORTANT WAYS. I WOULD SAY THAT SYSTEMS BIOLOGY HAS MADE TWO ENORMOUS CNS TO THE IDEA OF SYSTEMS MEDICINE, THAT IS SYSTEMS MEDICINE BEING THE APPLICATION OF SYSTEMS BIOLOGY PRINCIPLE STUDY OF THESE. SO ONE IS THE IDEA OF DENSE, DYNAMIC PERSONALIZED DATA CLOUDS. AND I'M GOING TO SAY UNEQUIVOCALLY IN THE NEXT 10 NUMBERS OF PEOPLE WILL HAVE THESE DENSE, DYNAMIC DATA AND CLINICAL RECORDS WHICH IS MOSTLY WHAT PRECISION MEDICINE IS ABOUT NOW, BUT ALL OF THOSE OTHER KINDS OF DATA THAT ARE SO IMPORTANT FOR ASSESSING THE ENVIRONMENTAL AS OPPOSED TO GENETIC CONTRIBUTIONS TO HEALTH. AND THE IDEA IS WE OUGHT TO BE ABLE TO INTEGRATE ALL THOSE DIFFERENT TYPES OF DATA TOGETHER AND CREATE MODELS WHICH REVEAL ACTIONABLE POSSIBILITIES THAT LET ONE OPTIMIZE WELLNESS OR AVOID DISEASE AND WE'RE GOING TO TALK ABOUT THIS IN SOME DETAIL. AND OF COURSE WHAT'S INTERESTING IS THIS IS EXACTLY WHAT PRECISION MEDICINE IS. AND INTERESTINGLY ENOUGH, WE FIRST DEFINED THIS APPROACH TO WELLNESS IN 2012, A FEW YEARS BEFORE OBAMA CAME ALONG WITH PRECISION MEDICINE. AND WHAT I WILL SAY IS THESE DENSE, DYNAMIC PERSONALIZED DATA CLOUDS CONSTITE A PLATFORM THAT IS ABSOLUTELY GOING TO REVOLUTIONIZE HEALTH CARE, BOTH LETTING US COME TO UNDERSTAND WELLNESS BUT ALSO LETTING US COME TO UNDERSTAND DISEASE IN DAYS WE'VE NEVER BEEN ABLE TO THINK BIT BEFORE. I'LL EXPLAIN ALL OF THOSE IN JUST A MINUTE. THE SECOND THING SYSTEMS BIOLOGY CONTRIBUTED IS THE IDEA THAT THE INFORMATION CONDUITS THAT GOVERN DEVELOPMENTS AND PHYSIOLOGIC RESPONSES IN AGING ARE BIOLOGICAL NETWORKS THAT OPERATE AT A WHOLE SERIES OF HIERARCHICAL LEVELS AND THAT THEY ARE IN THE BODY SEAMLESSLY INTEGRATED. AND OF COURSE WHAT HAPPENS WITH DISEASE IS ONE OR MORE OF THESE NETWORKS BECOMES DISEASE PERTURBED AND IF YOU CAN UNDERSTAND HOW THAT DIFFERS FROM NORMAL COUNTERPART YOU CAN GET FUNDAMENTAL INSIGHTS INTO DISEASE MECHANISMS AND YOU CAN COME TO UNDERSTAND NEW APPROACHES FOR EARLY DIAGNOSIS AND THERAPY AND I'LL SHOW YOU AN MOUSE MODEL OF NEURODEGENERATION THAT IS PRION-INDUCED THAT WE STUDIED FOR THE LAST TEN YEARS OR SO, THE BASIC IDEA IS INJECT INTO THE BRAINS OF MICE ACTIVATED PRION PARTICLES AND FOR AT LEAST ONE STRAIN THE DISEASE PROGRESSED OVER A PERIOD OF ABOUT 22 WEEKS. SO THE EXPERIMENT THAT WE DID WAS TO ANALYZE THE TRANSCRIPTOMES OF THESE INFECTED MICE AT 10 TIMES ACROSS THE 22 WEEKS SO WE CAN SEE HOW THINGS WERE CHANGING, AFTER AT EACH OF THOSE 10-WEEK PERIODS WE TRANSCRIPTED FROM THE NORMAL ANIMAL AND LOOKED AT THINGS THAT CHANGED, DIFFERENTIALLY EXPRESSED GENES, AND TO OUR ENORMOUS HORROR IT TURNED OUT THAT 7400 GENES WERE DIFFERENTIALLY EXPRESSED, ON EXPRESSED, A THIRD OF THE MOUSE GENES, TURNS OUT ALMOST ALL WAS BIOLOGICAL NOISE AND WE FIGURED OUT CLEVER WAYS TO GET RID OF BIOLOGICAL NOISE AND ENDED UP WITH 300 GENES THAT MAPPED INTO 10 DISEASE PERTURBED NETWORKS. THE SECOND THING WAS DID WAS TO LOOK HISTOLOGICALLY IN SERIAL STUDIES AT THE MICE AND SO THERE WERE REALLY FOUR MAJOR BIOLOGICAL PHENOMENA THAT WERE THE ESSENCE OF WHAT NEURODEGENERATION SEEMED TO BE INDUCED IN THIS CASE BY PRIONS, PRION REPLICATION AND ACTIVATION, GLIAL ACTIVATION, INNATE IMMUNITY, AND TWO FORMS OF DEGENERATION. WE WERE ABLE TO FIND BIOLOGICAL NETWORKS THAT MAPPED TO EACH OF THESE FOUR PHENOMENA. WHAT WAS INTERESTING 200 OF THE 300 GENES MAPPED INTO THE FOUR MAJOR NETWORKS AND OTHER 100 IDENTIFIED SIX ADDITIONAL DISEASE-PERTURBED NETWORKS PEOPLE ARE NO IDEA WERE ASSOCIATE THE D WITH THE DISEASE BEFORE. HERE IS ONE THAT WORKS SCHEMATICALLY, RED INDICATES CHANGES THAT OCCUR ACROSS TIME AND YOU CAN SEE THAT THE NETWORKS BECOME DISEASE PERTURBED EARLY AND THEY CONTINUE TO CHANGE THROUGHOUT THE PROGREN OF THE DISEASE. BUT THE REALLY IMPORTANT POINT WAS IF YOU LOOKED AT THE DYNAMICS OF THOSE 10 DISEASE-PERTURBED NETWORKS THEY EXPLAIN VIRTUALLY EVERY ASPECT OF THE PATHOPHYSIOLOGY OF THIS DISEASE. THE REALLY IMPORTANT POINT IS THE ONE I'M GOING TO TELL YOU NEXT BECAUSE IT IS WHAT WE'RE TOTALLY MISSING IN BEING ABLE TO LOOK AT HUMAN DISEASE TODAY, AND THAT'S THE IDEA THAT IF WE LOOK JUST AT THE FOUR MAJOR NETWORKS THEY BECAME SEQUENTIALLY DISEASE PERTURBED IN AN ORDER THAT WAS INVARIATE. FIRST PRION ACCUMULATION, THEN GLIAL ACTIVATION AND THE TWO SIDES OF NEURODEGENERATION. WHY IS THIS IMPORTANT? THIS IS IMPORTANT BECAUSE BY LOOKING IN THE BRAIN WE CAN SEE THE FIRST SIGNS OF CHANGE AT 7 WEEKS, AND THAT'S 8 OR 9 OR 10 WEEKS BEFORE YOU GET ANY CLINICAL SIGNS WHATSOEVER. NOW, WHAT WE CLEARLY WANT TO DO IS NOT BE REQUIRED TO SAMPLE THE BRAIN TO SEE THIS NEURODEGENERATION PHENOMENA, BUT TO BE ABLE TO SAMPLE BLOOD. SO WHAT WE DID WAS TO DEVELOP A WHOLE NEW DIAGNOSTIC STRATEGY THAT WHAT CENTERED ABOUT THE IDEA THAT EACH ORGAN IN YOUR BODY HAS SPECIFIC PROTEINS AND SOME OF THOSE GET SECRETED INTO THE BLOOD AND THEIR LEVELS CAN BE FOLLOWED IN THE BLOOD BY MASS SPECTOMETRY. THE REALLY IMPORTANT POINT IS WE HAVE ALMOST 100 BRAIN-SPECIFIC BLOOD PROTEINS FOR HUMANS AND 80 FOR MICE, AND THOSE MAPPED BACK INTO MANY OF THE MAJOR NETWORKS PRESENT IN THE BRAIN. SO IF YOU HAVE A NORMAL BRAIN, THOSE 100 PROTEINS WILL BE ATNE SET OF LEV ELS, BUT IF YOU HAVE A DISEASED BRAIN THOSE NETWORKS THAT BECOME DISEASED PERTURBED WILL CHANGE THE CONCENTRATIONS OF THEIR COGNATE PROTEINS. N A SENSE YOU GET A FINGERPRINT THAT SEPARATES NORMAL FROM DISEASE AND IF YOU HAVE DISEASE, EACH DISEASE HAS A DIFFERENT SET OF DISEASE PERTURBED NETWORKS. SO YOU CAN GET UNIQUE FINGERPRINTS FOR ALL THE DIFFERENT BRAIN DISEASES. WHAT WE DID THEN WAS TO FIND IN THE MOUSE 11 BRAIN-SPECIFIC BLOOD PROTEINS THAT MAPPED PRETTY EVENLY INTO THE FOUR MAJOR NETWORKS, AND WERE ABLE TO SHOW IN THE BLOOD WHAT W SHOWED FROM THE BRAIN TRANSCRIPTOMES THAT FIRST THE PRION REPLICATION ACCUMULATION NETWORK WAS PERTURBED AND GLIAL ACTIVATION AND THEN THE TWO NEURODEGENERATION. AND THE REASONS THIS IS IMPORTANT IS BECAUSE WE NOW IN IN THEORY HAVE THE ABILITY TO LOOK AT THE VERY FIRST TRANSITION FROM WELLNESS TO DISEASE, TO THINK ABOUT CREATING EARLY DIAGNOSTICS FOR IT, AND TO THINK ABOUT THERAPEUTICS THAT CAN REVERSE AT THE EARLIEST STAGE RATHER THAN WAITING TILL THE PHENOTYPE MANIFESTS ITSELF. SO WE'RE GOING TO DO ALL OF THIS IN HUMANS AND I'LL SHOW YOU HOW WE'LL BE ABLE TO DO EXACTLY THE SAME KIND OF THINGS. SO THE EVOLUTION OF THE VISION FOR SYSTEMS BIOLOGY BY 2006 WE WOULD REALLY CLEARLY ARTICULATE WHAT SYSTEMS MEDICINE WAS AND P4 MEDICINE WAS. AND WE AT THAT TIME -- IT WAS VERY MUCH LINE THE ELEPHANT. WE NEEDED TO DEVELOP A LOT OF TECHNOLOGIES AND STRATEGIES AND WE HAD GREAT IDEAS FOR HOW TO DO THIS, BUT WHAT WE FOUND IS NIH HAS ALWAYS BEEN RESISTANT TO REALLY INNOVATIVE NEW TECHNOLOGIES. REMEMBER WHAT I TOLD YOU ABOUT SEQUENCING. AND YOU KNOW WHAT WE HEARD TIME AND AGAIN WAS, WELL, PROVE TO US THIS CAN WORK. AND OF COURSE YOUR GRANT IS TO SHOW THAT IT ACTUALLY CAN WORK. BUT IN 2007, SOMETHING REALLY FORTUNATE HAPPENED, TO ME AND TO THE INSTITUTE. THAT IS I MET THE MINISTER OF FINANCE FROM THE STATE OF LUXEMBOURG, AND HE WAS THE MOST POWERFUL POLITICIAN IN LUXEMBOURG AND HE HAD DECIDED TO TRANSFORM LUXEMBOURG'S ECONOMY FROM A 90% DEPENDENCE ON FINANCIAL SERVICE AND BRING IN HEALTHCARE AND BIOTECH. SO HE SAID WOULD YOU LIKE TO WRITE A PROPOSAL TO HELP US DO THIS? AND I JUST SAID, WHAT ARE THE CONSTRAINTS ON THE PROPOSAL? [LAUGHTER] AND HE SAID, THERE ARE NO CONSTRAINTS. SO I WROTE A PROPOSAL WHERE WE SET UP AN INSTITUTE LIKE OUR OWN AT THE UNIVERSITY OF LUXEMBOURG WHICH WAS THEN FOUR YEARS OLD AND HAD ESSENTIALLY NO BIOLOGY. AND THAT WAS ENORMOUSLY SUCCESSFUL. I WON'T TALK ABOUT THAT, BUT WHAT I ASKED IN RETURN FOR THAT WAS $100 MILLION TO INVENT THE TECHNOLOGIES AND STRATEGIES OF SYSTEMS BIOLOGY OF P4 MEDICINE. HE AGREED TO THAT. THAT PUSHED US TO A REALLY TIPPING POINT BECAUSE WE WERE ABLE TO DEVELOP NINE OR TEN DIFFERENT TECHNOLOGIES AND I'LL SHOW YOU SOME EXAMPLES OF THOSE IN A FEW MOMENTS. BUT ONCE WE GOT TO THIS TIPPING POINT IN 2012, 2013, I WENT BACK TO THIS IDEA OF WHAT WOULD BE THE IDEAL WAY TO BRING SYSTEMS MEDICINE INTO THE HEALTHCARE SYSTEM. AND WE MADE THE PROPOSAL AT THAT TIME, WHAT WE SHOULD DO IS TAKE 100,000 WELL INDIVIDUALS AND BUILD FOR EACH THEIR DENSE DYNAMIC PERSONALIZED DATA CLOUDS, COME TO UNDERSTAND WELLNESS, AND COME TO UNDERSTAND WELLNESS TO DISEASE TRANSITIONS. AND THAT REALLY WAS THE FIRST TIME THAT PRECISION MEDICINE WAS PROPOSED. AND THEN OBAMA CAME ALONG WITH HIS STATE OF THE UNION ADDRESS IN JANUARY OF 2015 AND THEN OF COURSE IN APRIL OF 2016 WE HAVE THE AFFILIATION WHICH WE'LL DISCUSS LATER. HERE ARE SOME OF THE TECHNOLOGIES, AND WE'VE PARTICIPATED IN MOST BUT NOT ALL OF THESE. AND I'M NOT GOING TO GO INTO ANY DETAIL EXCEPT TO GIVE YOU A FEW REAL TIME LINES. SO THIRD GENERATION SEQUENCING MEANS SINGLE MOLECULE SEQUENCING, USING NANOPORES OR DETECTION. AND BASICALLY WITH THIS TECHNOLOGY WE'RE GOING TO BE ABLE TO READ 10 TO 100,000 BASE PAIRS IN ONE RUN, IT MEANS YOU'LL BE ABLE TO DO DE NOVO ASSEMBLY OF HUMAN GENOMES WITHOUT REFERENCE TO A FAULTY PROTOTYPE SEQUENCE AND SO FORTH. BUT EVEN MORE IMPORTANT, WHAT WE'RE GOING TO BE ABLE TO DO IS TO PARALYZE THIS PROCESS TO THE POINT WHERE WE'LL BE ABLE TO DO A HUMAN GENOME IN 15 MINUTES, AND WE'LL BE ABLE TO READ OUT THE INDIVIDUAL BASES SO WE CAN IDENTIFY EACH OF THE 16 DIFFERENT TYPES OF MODIFICATIONS WE KNOW OCCUR IN DNA AUTOMATICALLY AS WE READ THE SEQUENCE. SO THAT'S A PART OF WHAT THIS IS ABOUT. IN A 5-8 YEAR PERIOD YOUR HUMAN GENOME WILL COST ABOUT $100. TODAY IF YOU'RE LUCKY YOU CAN GET IT FOR $10,000, THAT'S AN ORDER OF MAGNITUDE DIFFERENCE. THE PEPTIDE PROTEIN CAPTURE AGENTS ARE AGENTS -- I MEAN THEY ARE REALLY INCREDIBLE. THEY ARE ABSOLUTELY GOING TO REPLACE MONOCLONAL ANTIBODIES, INFINITELY STABLE. YOU COULD PUT IT IN AN ENVELOPE WITH THESE REAGENTS AND SEND IT TO AFRICA AND YOUR PROTEIN CAPTURE AGENTS, I.E. ANTIBODIES, WOULD BE PERFECTLY CAPABLE OF HAVING EXACTLY THE SAME AFFINITY AND SPECIFICITY. THE OTHER THING THESE REAGENTS CAN DO IS NOT ONLY DIAGNOSIS BUT THEY WILL BE THERAPEUTIC REAGENTS AS WELL. AND WE CAN ACTUALLY DESIGN THESE REAGENTS SO WE GET RID OF ALL THE CROSS-ITIES THAT PLAGUE ANTIBODIES AND PLAGUE ANTIBODIES AS THERAPEUTIC REAGENTS GIVING OFF TARGET HITS IN EVERYTHING, WE'LL BE ABLE TO PRECISELY TARGET THE DRUGS, THESE THINGS, TO JUST EXACTLY WHAT WE WANT. GLOBAL MASS SPECTOMETRY IS COMING. WE'LL BE ABLE TO DO 6000 PROTEIN MEASUREMENTS FROM THE BLOOD. AND I'LL JUST SAY SINGLE CELL ANALYSIS ARE UTTERLY GOING TO TRANSFORM HOW WE UNDERSTAND CANCER DEVELOPMENT, ALL SORTS OF DIFFERENT THINGS, BUT WE DON'T HAVE TIME TO TALK ABOUT THAT. FAMILY GENOME SEQUENCING WE'VE USED, THE MOST SPECTACULAR EXAMPLE IS WE'VE STUDIED 41 FAMILIES THAT HAVE MULTIPLE AFFECTIVS OF BIPOLAR DISEASE AGAINST CONTROLS, 125 GENES ASSOCIATED WITH DISEASE, IN THOSE INDIVIDUALS WE WENT TO 2000 SPORADICS AND SHOWED 25 OUT OF 25 FOUND IN SPORADIC BIPOLARS IN THE POPULATION, ALL OF THESE GENES FELL INTO ONE OF TWO FUNCTIONAL CATEGORIES, EITHER CALCIUM ION TRANSPORTERS OR GABA RECEPTOR RELATED KIND OF PROTEINS, BUT THE IMPORTANT POINT IS ALMOST ALL DISEASES IN THE FUTURE, CERTAINLY NEUROLOGIC DISEASES, ARE GOING TO BE COMPLEX AND WE HAVE TO DEVELOP TOOLS THAT WILL LET US LISTEN FOR MULTIPLICITY OF GENES THAT ARE GOING TO BE ASSOCIATED. WE TALKED ABOUT AN EXAMPLE OF BEING ABLE TO LOOKING IN MODEL ORGANISMS AT DISEASE AND THE FINAL THING I'LL TALK ABOUT IS WE'VE DEVELOPED SYSTEMS APPROACHES TO BE ABLE TO GO INTO THE BLOOD AND GENERATE DIAGNOSTIC REAGENTS. AND I'LL JUST TELL YOU ABOUT ONE REAGENT WE GENERATED. WE HAVE GENERATED NOW A TWO-PROTEIN PANEL FROM THE BLOOD THAT HAS THE ABILITY TO DISTINGUISH MORE THAN 50% OF BENIGN LUNG NODULES FROM THEIR NEOPLASTIC COUNTERPARTS, AND THAT'S IMPORTANT BECAUSE ALL OF THOSE DON'T GO THROUGH THIS GRUESOME WASTEFUL MORBIDITY-PRODUCING SURGERY. THAT SIMPLE ACT ALONE SAVES THE AMERICAN HEALTHCARE SYSTEM CLOSE TO $4.5 BILLION A YEAR. I'LL SAY WE'VE DONE EXACTLY THE SAME THING FOR PRE-TERM BIRTH AND AT 19 WEEKS WE CAN MAKE BEAUTIFUL DIAGNOSES ABOUT WHO IS GOING TO HAVE PRE-TERM BABIES AND YOU CAN GIVE THEM PROGESTERONE TO DELAY THE GESTATIONAL PERIOD. SO WE ARE GOING TO TALK ABOUT THE DYNAMIC PERSONALIZED DATA CLOUDS AND I JUST WANT TO LEAVE YOU WITH THIS IDEA BECAUSE, AGAIN, I THINK IT'S SO CENTRAL TO SCIENCE. NEW DIRECTIONS IN SCIENCE ARE LAUNCHED BY NEW TOOLS MUCH MORE OFTEN THAN NEW CONCEPTS. THE EFFECT OF CONCEPT-DRIVEN REVOLUTION IS TO EXPLAIN OLD THINGS IN NEW WAYS. THE EFFECT OF TOOL-DRIVEN REVOLUTION IS TO DISCOVER NEW THINGS THAT NEED TO BE EXPLAINED. THE GENOME PROJECT WAS A BEAUTIFUL EXAMPLE AND THE DYNAMIC PERSONALIZED DATA CLOUDS ARE GIVING US OTHER EXAMPLES. SO THE CONVERGENCE OF SYSTEMS MEDICINE OF ANALYTICS AND SOCIAL NETWORK ALLOWED US TO DEFINE MORE SHARPLY WHAT P4 MEDICINE IS PREDICTIVE, PREVENTIVE, PERSONALIZE AND PARTICIPATORY. P4 MEDICINE DELIVERS FROM CONTEMPORARY MEDICINE, PRO-ACTIVE NOT REACTIVE, ALL ABOUT FOCUSING ON INDIVIDUALS RATHER THAN POPULATIONS, IT'S ABOUT FOCUSING ON WELLNESS IN ADDITION TO DISEASE AND NOT JUST DISEASE. IT'S ABOUT CREATING THESE DENSE DYNAMIC PERSONALIZED DATA CLOUDS, AND THE REASON FOR THAT IS IT'S THE ONLY WAY THAT YOU CAN ASSESS FOR THE INDIVIDUAL THE RELATIVE CONTRIBUTIONS OF GENETICS AND ENVIRONMENT. THESE DATA CLOUDS DO THAT BEAUTIFULLY. AND IT'S ALSO IMPORTANT TO SAY THAT CLINICAL TRIALS ARE FUNDAMENTALLY GOING TO BE CHANGED NOW BECAUSE IF YOU TAKE 20,000 PATIENTS AND GIVE IT A DRUG AND/OR A PLACEBO AND EXACT OUT ALL THE INFORMATION, YOU SAY TO YOURSELF, GEE, ALL THESE PATIENTS ARE GENETICALLY UNIQUE ENVIRONMENTALLY UNIQUE. THEY SHOULDN'T BE AVERAGE. IF YOU AVERAGE THEM YOU ENORMOUSLY INCREASE THE NOISE AND BIG PHARMA SPENT BILLIONS TIME AND TIME AGAIN. WHAT WE DO FOR P4 MEDICINE IS WE'LL HAVE 20,000 INDIVIDUALS, EACH WITH THEIR OWN DATA CLOUD, AND THEN WE'LL STRATIFY THEM ACCORDING TO THE PROPERTIES THAT WE WANT, REACTION OR FAILURE, REACT TO A DRUG AND THE LIKE, AND THOSE STRATIFICATIONS COME FROM THE INDIVIDUAL UNIQUE PROPERTIES OF EACH INDIVIDUAL. AND THEN FINALLY WE CAN USE THE SOCIAL NETWORKS FOR EDUCATION, CROWD SOURCING, ADVOCACY AND THINGS LIKE THAT. LET ME TELL YOU, I WOULD SAY THERE ARE A LOT OF PEOPLE IN THE HEALTHCARE SYSTEM THAT ARE REALLY RESISTANT TO A LOT OF THESE IDEAS, AND IT'S THOMAS KUHN ALL OVER AGAIN, PEOPLE BEING RELUCTANT TO GIVE UP THE WAY THEY HAVE DONE THINGS MOST OF THESE LIVES. THIS IS A GREAT SLIDE, THE TOP TEN DRUGS SOLD IN THE U.S. TODAY, AND WHAT YOU SEE HERE IS THE RATIO OF PATIENTS THAT REACT EFFECTIVELY WITH THE DRUG TO THOSE THAT DON'T, IT VARIES FROM 1 IN 4 TO 1 IN 25. IF YOU LOOK AT THINGS AS POPULATION, YOU NEVER WILL BE ABLE TO DISTINGUISH FEATURES THAT DIFFERENTIATE REACTORS FROM NON-REACTOR, IF YOU DID EXPERIMENTS, DID 20,000 OF THEM WOULD READILY HAVE ALL THE DATA TO SORT OUT WHO IS GOING TO REACT, WHO ISN'T GOING TO REACT, THAT'S AN EXAMPLE OF WHAT WE CAN TALK ABOUT. SO AS I SAID EARLIER, CURRENT HEALTH CARE IS REALLY ABOUT WELLNESS, AND IT'S ABOUT DISEASE, AND OF COURSE 98% OF SOCIETY'S RESOURCES GO INTO DISEASE AT THIS POINT IN SCIENCE. AND I WOULD ARGUE THAT WE ARE CREATING NOW A SCIENTIFIC WELLNESS INDUSTRY THAT IS ABSOLUTELY GOING TO TRANSFORM HEALTH CARE IN INTERESTING WAYS. WE'LL TALK ABOUT THAT IN JUST A MOMENT. AND WHAT I WOULD ARGUE IS THIS SCIENTIFIC WELLNESS IS GOING TO CREATE AN INDEPENDENT SECTOR IN THE HEALTHCARE UNIVERSE AND THAT THAT WELLNESS SECTOR IN A 10-15 YEAR PERIOD WILL HAVE A MARKET CAP THAT FAR EXCEEDS THAT OF THE CURRENT INDUSTRY, WELLNESS HEALTH INDUSTRY, OR THE DISEASE INDUSTRY. SO HOW IS WELLNESS GOING TO TRA BOTH OUR UNDERSTANDING OF WELLNESS AND DISEASE AS WELL? IT'S THROUGH THE USE OF DENSE, DYNAMIC PERSONALIZED DATA CLOUDS. SO, ONE, WE'LL SEE HOW YOU CAN USE THOSE ON INDIVIDUALS TO OPTIMIZE WELLNESS. NUMBER TWO, AND THIS IS REALLY IMPORTANT, WITH A LOT OF INDIVIDUALS THAT ARE WELL IF WE FOLLOW OVER THE EXTENDED PERIODS OF TIME WE'LL SEE TRANSITIONS TO DISEASE FOR ALL OF THE WELL-KNOWN DISEASES AND WE'LL BE ABLE TO MAKE THE EARLY DIAGNOSTICS AND THERAPEUTICS, THAT IS WE WILL IN THE FUTURE BE ABLE TO REVERSE DISEASE AT ITS EARLIEST TRANSITION. AND THAT IS GOING TO BE THE ESSENCE OF WHAT PREVENTIVE MEDICINE WILL BE IN THE FUTURE. YOU REVERSE IT AT THE VERY EARLIEST TRANSITION. AND OF COURSE THESE DATA CLOUDS WILL LET US FOLLOW DISEASE RESPONSE TO THERAPY AND RETURN TO HEALTH. AND I'M JUST GOING TO SAY THAT n-OF-1 EXPERIMENTS ARE UTTERLY ESSENTIAL BECAUSE THEY ARE THE ONLY WAY WE'LL BE ABLE TO CHARTER OUR WAY THROUGH THE ENORMOUS COMPLEXITY OF MANY DISEASES. THE n-OF-1 WON'T GIVE YOU THE STATISTICS YOU NEED, BUT IT WILL TELL YOU THE RIGHT PATH TO PURSUE. OKAY. SO WHY IS WELLNESS IMPORTANT? WELL, AS WE ALL KNOW, CHRONIC DISEASE IS ABSOLUTELY SKYROCKETING. POPULATIONS ARE GETTING OLDER. AND IN FACT TO ILLUSTRATE THAT, IF WE TAKE ALL THE CHILDREN BORN IN THIS CALENDAR YEAR, YOU CAN DO A CALCULATION THAT 50% OF THEM WILL LIVE TO BE 100. THE QUESTION IS, WHAT IS THE QUALITY OF THEIR LIFE FOR THE LAST 30 YEARS? AND I'LL SAY UNEQUIVOCALLY, IF WE DON'T REALLY PUSH SCIENTIFIC WELLNESS, IT'S GOING TO BE EXACTLY LIKE THE QUALITY OF LIFE FOR MOST OF THE PEOPLE IN THAT AGE GROUP. HERE IS ANOTHER ABSOLUTELY FASCINATING IDEA. IF YOU TAKE THE DETERMINANTS OF HEALTH, AND THIS HAS BEEN PUBLISHED A NUMBER OF DIFFERENT PLACES NOW, 30% RESIDE IN GENETICS, 60% RESIDES IN BEHAVIOR AND ENVIRONMENT, AND 10% COMES FROM HEALTHCARE. THOSE ARE REALLY, REALLY STAGGERING RESULTS. WHAT I WOULD REMIND YOU IS THESE DENSE, DYNAMIC PERSONAL DATA CLOUDS ARE THE MEANS FOR GETTING ACCESS TO 90% OF WHAT WE'RE TALKING ABOUT, SO THEY ARE REALLY GOING TO BE THE KEY FOR THE FUTURE. IN 2014, I PERSUADED UNDER THE AID OF MY FRIENDS TO SUBMIT THESE CELLS OVER A YEAR TO CREATING THESE DENSE, DYNAMIC DATA CLOUDS. I'LL SAY 50% OF THEM WENT IN ENORMOUSLY SKEPTICAL BUT AGREEING TO DO IT BECAUSE I HAD TWISTED THEIR ARM, AND WE'LL SEE WHAT HAPPENED AT THE END. THIS IS SOMETHING I DID WITH NATHAN PRICE. HERE ARE THE DENSE, DYNAMIC PERSONALIZED DATA CLOUDS, WE DID A COMPLETE GENOME SEQUENCE, EVERY THREE MONTHS GOT BLOOD, URINE, SALIVA FOR CLINICAL CHEMISTRY, METABOLITES AND PROTEINS. ONCE AGAIN EVERY THREE MONTHS WE GOT A STOOL SAMPLE TO QUANTIFY THEIR GUT MICROBIOMES AND GAVE ACTIVITY, QUALITY OF SLEEP, PULSE AND OTHER KINDS OF THINGS. OF COURSE, THE IDEA ACROSS THE YEAR PERIOD WAS EVERY THREE MONTHS GATHER THE SAMPLES, AND THEN ESSENTIALLY EVERY MONTH WE HAD COACHES TALK TO THE INDIVIDUALS ABOUT THE ACTIONABLE POSSIBILITIES THAT CAME FROM THE INTEGRATION OF THESE DATA TOGETHER. AGAIN, ACTIONABLE POSSIBILITIES THAT LET YOU OPTIMIZE WELLNESS OR AVOID DISEASE, AND WE STARTED INITIALLY WITH ABOUT 600 ACTIONABLE POSSIBILITIES AND WE PROBABLY HAVE ABOUT 1200 NOW. SO AS THESE THINGS GO ON, YOU GENERATE MORE AND MORE ACTIONABLE POSSIBILITIES, SO KEEP THAT IN MIND. AND WE USED COACHES, WELLNESS COACHES, TO TALK WITH THE INDIVIDUALS AND THEIR JOB WAS TWO-FOLD. ONE, TO ENGAGE THEM AT THE VERY BEGINNING AND FIND OUT WHAT THEIR REAL HEALTH CARE OBJECTIVES WERE. AND, TWO, IT WAS TO BRING TO EACH MUCH THESE INDIVIDUALS EVERY MONTH SEVERAL ACTIONABLE POSSIBILITIES, EXPLAINING WHAT THEY WERE IN SIMPLE TERMS, AND PUTTING THEM IN THE CONTEXT OF THEIR OWN HEALTH CARE OBJECTIVES. AND THESE HAVE BEEN BEAUTIFUL FRAMED IN PSYCHOLOGY. SHE HAD A 70% ACCEPTANCE RATE OF THE ACTIONABLE POSSIBILITIES, AND THAT'S WHY COACHES ARE ABSOLUTELY ESSENTIAL FOR THIS. AND THIS IS GOING TO BE AN ENORMOUS OPPORTUNITY FOR NURSING IN THE FUTURE. AND I'LL TALK ABOUT THAT AT THE VERY END. THESE DATA ANALYSES OF THE DENSE DYNAMIC CLOUDS HAVE BEEN SPECTACULAR. I'LL SAY THE DATA IS EXACTLY LIKE THE HUBBELL TELESCOPE. THE HUBBELL TELESCOPE LET US LOOK AT THE UNIVERSE WITH RESOLUTION UNATTAINABLE, AND THE DENSE, DYNAMIC DATA CLOUDS LET US LOOK AT HUMAN BIOLOGY AND HUMAN DISEASE WITH RESOLUTION WE NEVER EVER BEFORE HAD. AND I'LL GIVE YOU AN EXAMPLE. THIS IS AN EXAMPLE OF TAKING OUR SIX MAJOR DATA TYPES AND FOR EACH INDIVIDUAL DATA TYPE, AND THIS HAS ONLY A SMALL FRACTION OF TOTAL DATA TYPES, FOR EACH INDIVIDUAL DATA TYPE WE DID A STATISTICAL ANALYSIS ASKING WHAT IT WAS CORRELATED WITH DATA TYPES IN ANY OTHER FIVE DATA TYPES, AND AT THE END WE FOUND 3500 STATISTICAL CORRELATIONS THAT WERE ACCEPTABLE AT THE POINT OF ONE LEVEL, AND WE WERE EW ACTIONABLE POSSIBILITIES,D THEY SHOWED US THE INTERACTIONS SYSTEMS WE HAD NO IDEA ABOUT BEFORE, THEY GAVE US FUNDAMENTAL INSIGHTS INTO DIAGNOSTIC CANDIDATES AND THERAPEUTIC CANDIDATES, AND UNFORTUNATELY THIS IS A HAIR BALL THAT HAS MOST OF THOSE STATISTICAL CORRELATIONS AND WE HAD A REALLY CLEVER PROGRAM WHICH SUCCESSIVELY CUT THE LINKS FOR JOINING THESE ENTITIES TOGETHER AT THE LOWEST PROBABILITY LEVELS. AND WHAT THAT DID IS IT DISSOLVED THE HAIRBALL INTO A BIG CONCENTRIC CIRCLE OF LITTLE CIRCLES, AND EACH OF THOSE LITTLE CIRCLES WAS BIOLOGICALLY RELEVANT IN CLINICAL OR BIOLOGICAL WAYS. AND HERE IS A REPRESENTATIVE EXAMPLE OF ONE OF THOSE CIRCLES. AND IF WE HAD THE SCHEMATICS I COULD TAKE ONE OF THESE AND SHOW YOU WHAT IT REVEALED. BUT WE LOOKED AT, FOR EXAMPLE, THAT'S NOT GOING TO THAT ONE, WAS A NUTRITION CLUSTER AND IT GAVE US A WHOLE SERIES OF NUTRITIONAL ASSOCIATIONS, A NUMBER OF WHICH HAD NEVER BEEN SEEN BEFORE. SO IT SHOWS YOU THE OLD THINGS WE KNEW AND SHOWS YOU MANY, MANY NEW THINGS WE DON'T KNOW. AND HERE IS A LIFETIME'S WORK FOR SMALL SCIENTISTS, AND WE AT THE VERY BEGINNING OF WHAT WE'RE TALKING ABOUT. NOW, WE CAN DETERMINE YOUR GENETIC RISK FOR ALL THE GWAS ASSOCIATED DATAS BECAUSE WE HAVE YOUR COMPLETE GENOME SEQUENCE, WE CAN USE THE GWAS DATA ASSOCIATED WITH PROBABILITIES TO SUM UP AND DETERMINE YOUR SUSCEPTIBILITY TO PARTICULAR KINDS OF DISEASES. AND FOR EXAMPLE WE WERE ABLE TO TAKE THE 108 INDIVIDUALS AND PUT THEM IN FIVE BINS FROM VERY LOW TO VERY HIGH WITH REGARD TO RISK FOR HIGH LEVELS OF LDL CHOLESTEROL, AND WHAT YOU CAN SEE IS THAT GENETIC PROPENSITY CORRELATES BEAUTIFULLY WITH THE DISEASE PHENOTYPE. AND THAT'S WHY WE'RE SURE THESE GENETIC ASSOCIATIONS ARE REAL AND SIGNIFICANT. WE'VE DONE THIS FOR FOUR OTHER DISEASES, WE'VE SEEN EXACTLY THE SAME, SO NOW WE CAN LOOK AT RELATIVE RISK FOR ANY ONE OF YOU FOR OF THE ORDER OF SIX YEARS OLD, DIFFERENT DISEASES. LET ME SHOW YOU WHY INTEGRATING DIFFERENT TYPES OF DATA IS REALLY IMPORTANT. SO WE HAVE GENETIC RISK HERE WITH HIGH RISK TO THE LEFT AND LOW RISK TO THE RIGHT FOR LDL SMALL PARTICLE CONCENTRATIONS. WE TOOK A FAMILY OF ABOUT 11 MEMBERS AND WE PLOTTED THEIR GENETIC RISK AGAINST THEIR LEVEL OF LDL, AND YOU GET A BEAUTI3 CORRELATION OF THE HIGH RISK HAVING HIGH LEVELS AND THE LOW RISK HAVING LOW LEVELS OF THE GENETIC PROFILE. YOU KNOW HDLs IS THE INVERSE, IT'S THE GOOD CHOLESTEROL. AGAIN, WE HAVE HIGH RISK AT THE LEFT, LOW RISK AT THE RIGHT. BUT THE CURVING GOES THE OTHER WAY BECAUSE OBVIOUSLY THE LOW RISK PEOPLE WILL HAVE THE HIGHEST LEVELS OF LDLS. AND YOU CAN SEE TWO INDIVIDUALS THAT FALL OFF THE CURVE. THE GREEN ONE IS WAY OFF THE CURVE ABOVE. HE'S THE TRIATHLON ATHLETE IN SUPERB SHAPE, KIND OF WHAT YOU'D EXPECT, OKAY? WHAT I THINK IS MOST INTERESTING IS THE GUY THAT'S OFF FROM THE RED CURVE, SO HE'S WAY, WAY BELOW HIS GENETIC POTENTIAL. AND IT ALMOST MEANS HE OR SHE HAS A HORRIBLE LIFESTYLE. BUT WHAT'S REALLY INTERESTING IS, LOOK, THIS PERSON'S CHOLESTEROL IS THE SAME AS THIS IF YOU WERE A PHYSICIAN AND DIDN'T KNOW THE GENETIC RISK, YOU WOULD TREAT THEM BOTH THE SAME WAY. AND CLEARLY THIS ONE SHOULD NEVER GET STATINS. HE SHOULD JUST BE TOLD TO SHAPE UP. [LAUGHTER] WHEREAS HE OR SHE, I DON'T KNOW WHAT IT IS, AND THE OTHER TWO CLEARLY YOU CAN THINK ABOUT STARTING WITH THEM. SO IF YOU JUST BEGIN TO PUT TWO PIECES OF DATA TOGETHER, YOU GET FUNDAMENTAL INSIGHT INTO WHAT'S GOING ON. WE'VE RANKED PEOPLE FROM VERY HIGH TO VERY LOW FOR CROHN'S DISEASE, AND THEN WHAT WE'VE BEEN ABLE TO DO IS MAP THE AVERAGE GUT MICROBIOME ON TOP OF EACH OF THESE, AND THE THING THAT COMES OUT IN A REALLY INTERESTING WAY HERE IS THERE IS A PARTICULAR INFLAMMATORY BUG IN THE GUT THAT IS -- INCREASES IN PROPORTION TO GENETIC RISK. AND ONE OF THE REALLY INTERESTING QUESTIONS IS, COULD WE GET RID OF THAT BUG WITH PROBIOTICS? AND THEN ACTUALLY MAKE THESE INDIVIDUALS LESS LIKELY TO GO ON TO HAVE CROHN'S DISEASE AND THE IMPORTANT POINT IS OUT OF THE 100 NAMES ONLY ONE WAS DIAGNOSED WITH CROHN'S DISEASE. CAN YOU USE THESE INSIGHTS TO MAKE PEOPLE WITH HIGH RISK AVOID POTENTIAL GENETIC FATE? HERE IS JUST A PARTIAL LIST OF GWAS DISEASES THAT WE CAN DO THESE KINDS OF GENETIC CALCULATIONS FOR, AND ONE OF THE THINGS WE'VE DONE BECAUSE WE HAVE 2000 NORMAL HUMAN GENOMES, WE CAN ACTUALLY MAP ANY GIVEN LIKE RISK FOR HIGH CHOLESTEROL LEVELS ACROSS THAT POPULATION AND WE GENERALLY GET A KIND OF A BELL-SHAPE CURVE BUT THEN WE CAN TAKE THE 108 INDIVIDUALS AND WE CAN ASSESS THEIR RISK RELATI TO A NORMAL WHITE CAUCASIAN POPULATION. AND WE'VE DONE THAT FOR FOUR DIFFERENT GENETICS DISEASES FOR THE 2000 INDIVIDUALS AND THE FASCINATING EXAMPLE IS THIS BIMODAL DISTRIBUTION FROM GOODS WAS MARKERS FOR ALZHEIMER'S DISEASE, BUT THE IMPORTANT THING IS WE CAN LOOK FROM THIS CURVE AT THOSE INDIVIDUALS THAT ARE REALLY AT HIGH RISK FOR ALZHEIMER'S AND WE'RE GOING TO USE THAT IN A LATER STUDY THAT I'LL TALK ABOUT, SO KEEP THAT IN MIND. WE ALSO CAN LOOK AT STATE TRANSITIONS, WELLNESS TO GREATER WELLNESS, AND WE FIND A NUMBER OF PEOPLE UNDERGO THIS TRANSITION, AND WHAT IS REALLY COOL IS WE WERE ABLE TO SHOW THAT A SET OF METABOLITES AND PROTEINS ACTUALLY PREDICTED THIS INCREASE IN WELLNESS VERY WELL. SO WE'RE CONFIDENT, ONE, THAT WE CAN GET ABSOLUTE OBJECTIVE QUANTITATIVE MARKERS FOR WELLNESS, AT THE PHYSIOLOGIC STATE BUT THINK WE CAN DO IT AT THE PSYCHOLOGIC STATE TOO AND I'LL TELL YOU WHY I THINK THAT'S SO BUT I WON'T NOW. WE CAN INVERSE, WELLNESS TO LESS WELLNESS, WELL NESS TO EARLIEST DISEASE AND PROGRESSION TO THERAPY AND HOPEFULLY BACK TO WELLNESS. I THINK THIS IS GOING TO BE A MAJOR TOOL IN THE STRATIFICATION OF REALLY COMPLEX DISEASES, BECAUSE WE HAVE TENS OF THOUSANDS OF FEATURES WE CAN USE TO STRATIFY IN DIFFERENT TYPES OF SCHIZOPHRENIA OR BIPOLAR DISEASE OR AUTISM OR WHATEVER COMPLICATING DISEASE YOU WANT TO TALK ABOUT. THE ONE TRANSITION THAT WORKED FOR OUR INDIVIDUALS BEST WAS FOLLOW ACTIONABLE POSSIBILITY AND SEE CHEMISTRY COME IN ACCORD WITH THE CHANGE IN YOUR BEHAVIOR. THAT WAS THE POSITIVE -- STRONGEST POSITIVE REINFOEMENT POSSIBILITY. WHAT WAS INTERESTING IN THE FIRST CLINICAL CHEMISTRY 91% OF THE INDIVIDUALS HAD NUTRITIONAL LIMITATIONS. A LARGE MAJORITY OF THOSE HAD TO DO WITH MUTATIONS IN THEIR GENES THAT COVERED THESE METABOLITES AND OF COURSE SUPPLEMENTS AND SO FORTH COULD BE USED TO FIX THEM. IN SUMMATION, ALMOST 70% OF THE INDIVIDUALS, IT WAS BOTH DIET AND IT WAS -- WE FOUND THREE DIFFERENT PEOPLE WITH INFECTIONS THEY HAD NO IDEA THEY HAD. AND MANY YOU CAN SEE CARDIOVASCULAR AND DIABETIC COMPLICATIONS. 53 OF THE INDIVIDUALS WERE PRE-DIABETIC. BY THE END OF THE STUDY SEVEN MOVED TO NORMAL, ALMOST ALL HAD MOVED SIGNIFICANTLY OVER TOWARDS NORMAL AND SO FORTH. A NICE EXAMPLE OF A DISEASE TO WELLNESS TRANSITION WAS HEMACHROMATOSIS. WE HAD AN INDIVIDUAL, YOUNG, EARLY '50s, CAME IN AND SAID, LOOK, I CAN'T GO HIKING WITH MY WIFE ANYMORE, IT'S WHAT I DEARLY LOVE BECAUSE I'VE GOT THIS ARTHRITIS IN MY ANKLES. I'VE HAD A CONCIERGE PHYSICIAN ON BOTH COASTS A LOOKED, NO ONE CAN FIND OUT WHAT'S WRONG. SO WE LOOKED AT HIS TRANSFERRIN LEVELS, THEY WERE HIGH. WE LOOK AT THE GENE FOR HEMACHROMATOSIS. WE SENT THAT TO HIS PHYSICIAN, THE EASIEST EARLIEST ACTIONABLE POSSIBILITY, TAKE A UNIT OF BLOOD FROM THE INDIVIDUAL EVERY MONTH UNTIL THE TRANSFERRIN OR ION LEVEL COMES DOWN TO NORMAL. HE WENT TO NORMAL WITHIN THE FIRST THREE MONTHS AND AT THE END OF THE TIME HIS ARTHRITIS WAS GONE AND HE WAS COMPLETELY NORMAL. LET ME JUST MAKE THE POINT, HEMACHROMATOSIS IS A DISASTEROUS DISEASE FOR SOCIETY TO PAY, STARTS WITH MINOR ARTHRITIS AND ATTACKS BETA CELLS, CIRRHOSIS AND CARDIAC DECOMPENSATION. THEY COME IN WHEN THEY DECOMPENSATE AND ARE CHRONIC INDIVIDUALS THE REST OF THEIR LIFE AND CAUSE SOCIETY A GAZILLION DOLLARS SO WE SAVE SOCIETY. WHAT YOU MAY NOT KNOW, THERE'S A GENETICS OF DIET. WE HAD EXAMPLES OF PEOPLE WHO FAILED THROUGH THEIR LIFE TO DIET, SHOWED THEM WHAT THEY HAD TO DO AND BOOM, THEY LOST WEIGHT JUST LIKE THAT. THERE'S GENETICS OF EXERCISE, AEROBICS AS OPPOSED TO POWER, GENETICS SHOW WHICH ONE IS MORE EFFECTIVE MOSH LOSING WEIGHT AND BURNING UP CALORIES AND THINGS LIKE THAT. WE'VE USED THAT, THERE ARE 300 GENETIC MARKERS FOR ATHLETIC INJURIES AND THOSE ARE IMPORTANT BECAUSE IF YOU KNOW YOU HAVE THEM, YOU CAN DO EXERCISES TO AVOID THEM AND SO FORTH. NUTRITION, INFLAMMATION, HEAVY METAL TOXICITY. WE HAD THREE INDIVIDUALS THAT HAD BLAZINGLY HIGH LEVELS OF ARSENIC, TWO OF THEM ATE ENORMOUS AMOUNTS OF TUNA SUSHI. WE PUT THEM ON SALMON SUSHI AND TO NORMAL. THE THIRD ONE HAD AMALGAM FILLINGS, WE HAD HIM GET THOSE REPLACED AND HE ZIPPED RIGHT DOWN TO NORMAL AGAIN TOO. SO THOSE ARE THE KIND OF THINGS YOU CAN DO WITH WELLNESS. SO CORRELATIONS, GENETIC DETERMINATION OF RISK, TRANSITIONS, THESE ARE REALLY CHANGING HOW WE THINK ABOUT MEDICINE IN MANY DIFFERENT WAYS. SO I WOULD SAY AT THE END OF THIS STUDY, ALMOST EVERYONE FELT IT WAS THE EXPERIENCE OF A LIFETIME AND THEY WERE REALLY THANKFUL THEY HAD DONE IT. SO THE 50% SKEPTICS REALLY DID DISAPPEAR. THEY ALL SAID I LOVE THE IDEA I CAN CONTROL MY HEALTH IF I'VE GIVEN SOME INFORMATION. I REALLY THINK THAT'S ONE OF THE KEYS TO LESSENING THE COST OF HEALTH CARE, GIVING PATIENTS THE ABILITY TO MAKE THEIR OWN DECISIONS. YOUR GENOME DOES NOT CONTROL YOUR DESTINY, JUST YOUR POTENTIAL. WITH MANY GENOME LIMITATIONS THERE ARE MANY WAYS TO GET AROUND THEM. NOT ALL, BUT MANY. AND OF COURSE WHAT THEY ALL FOUND IS THEY AREN'T NEARLY AS WELL AS THEY THOUGHT. IF WE HAD A SCALE FROM 1-100, I WOULD SAY MOST PEOPLE WERE PROBABLY IN THE 30-40 CATEGORY, IF YOU UP IN THE 80 CATEGORY EVERYBODY ELEVATED THEIR WELLNESS, INCLUDING THE HIGHEST ONES OVER THIS PERIOD OF TIME. AND THE OTHER POINT IS ALMOST EVERYBODY IN THE SALTS AREA WANTED TO GO INTO THE NEXT PHASE WELLNESS, AND THAT WAS WE CREATED A COMPANY CALLED ARIVALE THAT WAS ORIENTED SCIENTIFIC WELLNESS TOWARDS CONSUMERS. WE HOPE TO HAVE ON THE ORDER OF 10,000 INDIVIDUALS BY, SAY, THE END OF 2017. INTO IT THOSE 10,000 ANONYMIZED DATA CLOUDS ARE GOING TO TRANSFORM THE HEALTH CARE INDUSTRY, PHARMA, NUTRITIONAL COMPANIES, BIOTECH, DIAGNOSTIC COMPANIES, THERE ARE SO MANY WAYS WE CAN GIVE THEM CONTROL AND LET THEM DEAL WITH SIGNAL NOISE PROBLEMS PEOPLE HAVE NEVER SEEN BEFORE. OF COURSE, THE OTHER POINT IS ISB WITH OUR NEW AFIGURES -- AFFILIATION IS GOING TO USE THESE DATA CLOUDS, WE WANT TO DEVELOP VALID METRICS, DEVELOP BETTER DIAGNOSTIC TOOLS. THE BIG COSTS WITH THE ASSAYS AND WE LIKE TO TAKE THEM FROM 6000 TO 600 IN A PERIOD. WE NEED TO DEVELOP MORE ANALYTICS AND THEN USE THEM TO OPERATE THE WAYS WE ALREADY DISCUSSED. PROVIDENCE AND ISB AFFILIATION IS REALLY TRANSFORMATIONAL, THE FINAL DREAM FOR ME AND MY CAREER IN MEAN WAYS. PROVIDENCE IS IN SEVEN STATES, 50 HOSPITALS, 5000 PHYSICIANS, IT'S A $20 BILLION A YEAR KIND OF OPERATION, AND MOST IMPORTANT, WELL, IT'S THE THIRD LARGEST NOT FOR PROFIT HEALTHCARE SYSTEM IN THE U.S., BUT IT HAS 30 MILLION ELECTRONIC HEALTH CARE RECORDS AND WE ALREADY HAVE BEGUN TO LOOK AT THEM IN A WHOLE VARIETY OF WAYS THAT YOU CAN EASILY IMAGINE. BUT THIS IS AN ENORMOUS AMOUNT OF ABSOLUTELY FASCINATING MATERIAL. AND OF COURSE THE REAL CHALLENGE IN LOOKING AT HEALTHCARE RECORDS ARE THESE DATABASES LIKE EPIC, WHO ARE UNQUERIABLE. SO WHAT PROVIDENCE -- [LAUGHTER] FOR SCIENTIFIC THINGS. THEY GIVE YOU GOOD COST ESTIMATES. SO WHAT WE'VE DONE IS CREATED A COMPANY CALLED MULTI-SCALE THAT CAN SIT DOWN AND TALK WITH THESE ELECTRONIC DATABASES AND WE CAN ABSTRACT ANONYMIZED INTO THE CLOUD THOSE IN A FORM THAT WE CAN QUERY WITH CUBITER WORK STATIONS REALLY EASILY, THIS IS GOING TO LET US TRANSFORM A LOT OF THINGS. BUT THE OTHER THING THAT WE'VE DONE IS WE'VE CHOSEN FOUR TRANSLATIONAL PILLARS TO INTRODUCE INTO PROVIDENCE THAT HAVE THE ESSENCE AND VARIOUS WAYS OF SYSTEMS MEDICINE. THE FIRST IS ARIVALE IS GOING TO TAKE 2000 EMPLOYEES OF PROVIDENCE AND PUT THEM THROUGH THE SCIENTIFIC WELLNESS STUDY. THEY WILL HAVE 2000 CONTROLS. THEY ARE GOING TO DO IT FOR 3-5 YEARS AND WILL HAVE THE ECONOMIC PROOF THAT SCIENTIFIC WELLNESS SAVES AN ENORMOUS AMOUNT OF MONEY FOR EVERYONE. IT'S GOING TO BE ABSOLUTELY A TRANSFORMATIONAL STUDY. AND WHAT WE'RE ALSO DOING SINCE ARIVALE IS A CONSUMER-BASED COMPANY, IT CANNOT PRACTICE MEDICINE OR THE FDA WILL CLOSE IT DOWN, JUST AS THEY DID 23ANDME. SO WHAT WE'RE GOING TO TAKE IS 500 OF THESE PATIENTS THAT ARE ON THE ARIVALE STUDY AND WE'RE GOING TO GIVE THEM ALL THE GENETIC BENEFITS WE CAN'T DO WITH ARIVALE SO WE'LL HAVE ACTUALLY THREE ARMS AND WE'LL BE ABLE TO LOOK AT ALL THE DIFFERENT DIMENSIONS OF THIS, AND THAT AGAIN IS REALLY AN IMPORTANT STUDY. WOMEN DIAGNOSED WITH BREAST CANCER, PUTTING THEM ON THE DENSE DYNAMIC PERSONALIZED DATA CLOUD PROCEDURE, AND WE'LL FOLLOW THEM THROUGH TREATMENT AND POST-TREATMENT EXPERIENCES FOR A THREE-YEAR PERIOD OPTIMIZING THEIR WELLNESS. AND I THINK THIS IS GOING TO TRANSFORM THE HEALTHCARE EXPERIENCE. WE'LL DO THAT AGAINST CONTROLS AGAIN SO YOU CAN SEE WHAT THE DIFFERENCES ARE. ALZHEIMER'S, WE HAVE A COLLABORATOR THAT HAS LOOKED AT 100 EARLY ALZHEIMER'S PATIENTS, AND HE'S CREATED A 36-POINT REGIMEN CALLED MEN THAT HAS THE THE ABILITY TO REVERSE VIRTUALLY ALL HE HAD THE TIME TO SPEND TIME WITH, WE'RE GOING TO DO THE SAME THING AT PROVIDENCE, SET UP REVERSE EARLY ALZHEIMER'S. THAT'S ONE. NUMBER TWO, WE HAVE THE ABILITY NOW TO IDENTIFY 200 PEOPLE AT EXTREMELY HIGH RISK FOR ALZHEIMER'S, PUT THEM ON DENSE DATA CLOUDS, 45 AND UP, AND FOLLOW THEM, LOOKING FOR THE VERY EARLIEST TRANSITION TO ALZHEIMER'S AND THEN WE'LL FLIP THEM OVER TO THE REGIMEN TO REVERSE AT THE VERY EARLIEST STAGE. WE'LL TAKE AT LEAST 50 OF THOSE INDIVIDUALS AND WE'RE GOING TO PUT THEM ON THE REGIMEN BEFORE THEY EVER GET THE DISEASE AND THE INTERESTING QUESTION IS, CAN WE PREVENT THEM FROM EVER TRANSITIONING? SO WE CAN STUDY ALL THESE COMBINATIONS OF THINGS AND THEN THE GLIOBLASTOMA I WON'T GO INTO THE DETAILS. IT'S PART OF THE MOONSHOT PROJECT, AND MY BIG POINT IN CANCER IS I THINK CANCER IS EXACTLY LIKE AIDS. YOU SHOULD BE TREATING EVERY PATIENT FROM DAY ONE WITH TRIPLE DRUG THERAPY. OTHERWISE THEY WILL BE GREAT FOR EIGHT MONTHS BUT BACK WERE THEY WERE, RESISTANT TO ONE MORE DRUG, SO WE'RE GOING TO FIGURE OUT HOW TO DO THAT KIND OF THING. SO THE FUTURE OF HEALTHCARE I HOPE YOU CAN SEE. WE'RE BRINGING P4 MEDICINE TO HEALTHCARE. WE'RE GOING TO USE THE DENSE, DYNAMIC DATA CLOUDS TO BE ABLE TO ASSESS ENVIRONMENT AND GENETICS FOR THE INDIVIDUAL. WE'RE GOING TO OPTIMIZE WELLNESS THROUGH THE ACTIONABLE POSSIBILITIES AND LOOK AT THESE WELLNESS-TO-DISEASE TRANSITIONS AND REVERSE THEM FOR EARLY PREVENTION. SCIENTIFIC WELLNESS, A LIFETIME JOURNEY, WE'RE GETTING MORE AND MORE AND MORE NEW ACTIONABLE POSSIBILITIES AND THEY GIVE EVERYONE A POSSIBILITY OF ASPIRING TO EVEN HIGHER LEVELS OF WELLNESS. BUT I THINK THE REALLY INTERESTING POINT ABOUT A LIFETIME JOURNEY IS THE FOLLOWING. A THOUSAND INDIVIDUALS WERE STUDIED 90 YEARS OR OLD OLDER, NEVER BEEN SICK A DAY IN THEIR LIFE, NEVER TAKEN HAVE DRUG, THEY ARE FULLY FUNCTIONAL. REMEMBER THAT. POINT NUMBER TWO IS WE DID A STUDY SOME YEARS AGO OF 18 INDIVIDUALS, 115 OR OLDER, HOPING TO COMPLETE GENOME SEQUENCE ANALYSIS TO GET -- IDENTIFY GENES THAT PREDISPOSE TO AGING, AGAIN THE POWER WASN'T GREAT ENOUGH TO SAY VERY MUCH. BUT WHAT I DID LEARN WAS FASCINATING. THAT IS IF PEOPLE GET UP TO THEIR 100s, ALMOST ALWAYS YOU DIE VERY QUICKLY DUE TO A COMPLETE SYSTEMS FAILURE AND A RAPID SYSTEMS FAILURE. AND DEATH IS OFTEN PROMOTED AS YOU KNOW BY SLIPPING AND BREAKING SOMETHING, BUT WHEN YOU'RE 100 YOU DON'T LAST VERY LONG. SO THE IDEA ABOUT SCIENTIFIC WELLNESS IS, IF YOU CARRY THIS OUT FOR YOUR LIFETIME, ADDING ALL THE NEW ACTIONABLE POSSIBILITIES THAT COME ALONG, WHAT WE HOPE TO BE ABLE TO DO IS ELEVATE YOU TO THE STATUS OF THE WELLDERLY, SO YOU GO INTO THE 90s ALERT, PHYSICALLY CAPABLE, AND THEN WHEN YOU GET TO BE 100, YOU'RE ON YOUR OWN. [LAUGHTER] ANYWAY, I THINK THE HEALTHCARE COSTS WILL COME DOWN. WE REALLY THINK WE CAN TRANSFORM BIOTECH AND PHARMA. WHAT I REALLY LOVE IS IF WE CAN USE THE DIGITALIZATION OF MEDICINE TO BRING THE ASSAY COSTS DOWN, I CAN SEE TAKING SCIENTIFIC WELLNESS TO THE DEVELOPING AS WELL AS DEVELOPED COUNTRIES AND THIS RAISES A POSSIBILITY OF A DEMOCRATIZATION OF HEALTH CARE AND WELLNESS THAT WAS INCONCEIVABLE TO THINK ABOUT EVEN A FEW YEARS AGO. SO TWO OPPORTUNITIES FOR NURSING. I THINK YOU SHOULD START A NEW ACADEMIC CAREER IN NURSING TEACHING, CREATING COACHES FOR SCIENTIFIC WELLNESS. BECOME A BIG INDUSTRY AND FRANKLY I THINK THIS JOB WOULD BE MUCH MORE INTERESTING THAN BEING A PHYSICIAN IN A LOT OF WAYS. I MEAN YOU HAVE TO BE A GOOD COACH FOR THE THINGS WE'RE TALKING ABOUT HERE. POINT NUMBER TWO, THE WAY WE COULD EDUCATE NURSES AND FRANKLY MEDICAL STUDENTS IS PUT THEM THROUGH A YEAR OF SCIENTIFIC WELLNESS AND LET THEM USE THEIR OWN DATA TO FIGURE OUT HOW TO AND I PUT THEM THROUGH FOR EACH YEAR THEY WERE IN SCHOOL, AND YOU CAN COORDINATE EACH YEAR, NEW COURSES THAT TEACH AND INCREASINGLY SOPHISTICATED LEVELS SYSTEMS AND P4 MEDICINE AND THINGS LIKE THAT. SO SOMETHING TO THINK ABOUT, MANY PEOPLE WERE INVOLVED IN THE WELLNESS PROJECT, AND AGAIN NATHAN PRICE WAS MY COLLEAGUE IN THIS ENDEAVOR. AND THANK YOU FOR YOUR PATIENCE. [APPLAUSE] DO YOU WANT QUESTIONS? OKAY. WE'VE GOT TIME FOR A FEW QUESTIONS, SO IF ANYBODY HAS ANY. YES? >> THANK YOU, DR. HOOD, FASCINATING. I'M RACHEL WALKER. I'M CURIOUS IN ALL THIS WORK YOU'RE PIONEERING YOU TALKED ABOUT A LIFETIME JOURNEY, PEOPLE NOT BEING AS WELL AS THEY THOUGHT, AND I WAS WONDERING HOW GIVEN DATA CLOUDS AND (INDISCERNIBLE) HOW YOU'RE OPERATIONALIZING THE DEFINITION OF WHAT WELLNESS IS FOR THESE INDIVIDUALS AND HOW THAT IS PERSONALIZED IN THIS. >> WELL, THAT'S A GOOD QUESTION. HOW ARE WE GOING TO ASSESS WELLNESS FOR THE INDIVIDUAL? SO RIGHT NOW IF YOU LOOK UP WELLNESS, THERE ARE 50,000 DEFINITIONS AND THEY ARE ALL FUSSY AND PSYCHOLOGICAL. SO WHAT WE REALLY HOPE TO DO IN THE NOT-TOO-DISTANT FUTURE IS HAVE METRICS THAT GIVE US A REAL ASSESSMENT OF WELLNESS AND PARTICULARLY YOUR ABILITY TO INCREASE YOUR WELLNESS. I THINK THAT'S ONE REALLY IMPORTANT THING. RIGHT NOW I THINK THE MOST VALID WAY TO ASSESS WELLNESS IS TO COMPARE THE INDIVIDUAL WHEN THEY STARTED THIS OPERATION AGAINST THEMSELVES WHEN THEY FINISHED SENSE OF THE RELATIVE CHANGE OF EACH OF US, AND WE START AT DIFFERENT LEVELS. THERE ISN'T ANY WAY OF ABSOLUTE QUANTITATION RIGHT NOW SO I THINK WE DO IT JUST RELATIVE TO EACH INDIVIDUAL. BUT, AGAIN, AS I SAID, IF YOU WENT THROUGH THE 108, I WOULD SAY VIRTUALLY EVERYONE EXPERIENCED REALLY SIGNIFICANT INCREASED LEVELS OF WELLNESS, EVEN IF IN SOME CASES THEY WERE MORE RESISTANT AGAINST SOME OF THE ACTIONABLE POSSIBILITIES. I MEAN, YOU KNOW, ACTION POSSIBILITIESES VARY IN WHAT THEY DEMAND, SO YOU HAVE CHOICESES OBVIOUSLY ABOUT WHETHER YOU WANT TO DO THINGS. BUT I THINK ONCE PEOPLE START SEEING HOW THESE ACTIONABLE POSSIBILITIES, ONCE EXPERIENCED, CHANGE THEIR SENSE OF WELL-BEING, YOU REALLY GET HOOKED ON THIS. >> (INAUDIBLE). >> SO, THINK IT WILL BE A QUANTITATIVE EFFORT, OKAY? WE WANT QUANTITATIVE BLOOD METRICS BOTH FOR PHYSIOLOGIC WELLNESS AND PSYCHOLOGIC WELLNESS, AND WE HAVEN'T REALLY BEGUN TO DO THE PSYCHOLOGIC SIDE OF THINGS, AND THAT'S REALLY IMPORTANT AND WE'RE GOING TO GET INTO THAT THIS NEXT YEAR. YES? >> CINDY RUSSELL, GREAT PRESENTATION. I'M IN THE NURSING HEALTH STUDY, I WAS WONDERING IF THERE'S ANY OPPORTUNITY FOR NURSES TO BE INVOLVED (INAUDIBLE). >> UM ... [LAUGHTER] WELL, THE ONLY REASON I HESITATE IS ARIVALE IS ROLLING OUT -- WE STARTED IN SEATTLE, ACTUALLY WE GOT 1200 PEOPLE IN EIGHT MONTHS WITH NO ADVERTISING. AND WE'RE JUST STARTING TO ROLL OUT IN CALIFORNIA. SO THAT'S SAN FRANCISCO AND L.A. AND SAN DIEGO. AND THEN WE'LL BE COMING. SO IF YOU'RE NOT IN ONE OF THOSE TWO STATES, THAT'S WHY I HESITATED. IT WOULD BE A LITTLE HARDER. BUT IF YOU GOT A POPULATION OF PEOPLE THAT WERE REALLY INTERESTED AND COULD MAKE IT WORTHWHILE FOR ARIVALE, WE COULD SCHEDULE THAT, THAT KIND OF THING. WE'RE TALKING WITH A NUMBER OF GROUPS THAT ARE INTERESTED IN DOING THIS. ONE OF THE THINGS WE DID THAT WAS REALLY INTERESTING IS I WENT TO ABOUT 20 WEST COAST HIGH-TECH COMPANIES AND TALKED WITH CEOs AND PERSUADED THEM TO GO INTO SIX MONTHS FOR SCIENTIFIC WELLNESS AND IF IT WAS AS SUCCESSFUL AS WE THOUGHT IT WOULD BE WE WANTED THEM TO HELP BRING IN EMPLOYEES AND THAT'S WORKED EXTREMELY WELL. IN SOME OF THOSE CASES THEY WEREN'T ON THE WEST COAST SO WE HAVE TO THINK ABOUT THAT. BUT IF YOU'RE IN NEW YORK, THAT'S THE WORST PLACE TO BE BECAUSE IT'S THE HARDEST TO GET THROUGH THE KIND OF THINGS WE HAVE TO GET THROUGH. YES? >> (INAUDIBLE). >> I WAS CURIOUS, YOU MENTIONED THE CLINICALLY ACTIONABLE DIAGNOSTICS, AND I'M WONDERING IF THEY ARE COMMERCIALLY AVAILABLE DIAGNOSTICS, OR IF THEY ARE NEW ASSAYS THAT ARE BEING DONE? >> SO ALMOST ALL THE THINGS THAT WE'RE DOING COME FROM SEQUENCING HUMAN GENOME, CLINICAL CHEMISTRIES, METABOLITES, 400 OR SO PROTEINS, WE PUT THAT. THE GUT MICROBIOME IS GOING TO REALLY BE IMPORTANT, BUT IT'S IN THE EARLY DISCOVERY STAGE. IT'S PRETTY HARD TO HAVE ACTIONABLE THINGS THERE. AND THEN SOME OF THE QUANTIFIED SELF METRICS GIVE US AN INDICATION OF PEOPLE THAT ARE IN POOR SHAPE AND THINGS LIKE THAT. BUT THOSE ARE THE THINGS THAT WE'VE USED. AND, AGAIN, WHAT WE'RE -- AS WE DO THESE DATA ANALYSIS INTEGRATION, WE'RE DISCOVERING MORE AND MORE ACTIONABLE POSSIBILITIES AS WE PUT TOGETHER DIFFERENT KINDS OF DATA. REMEMBER HOW I SHOWED YOU THE LDL CHOLESTEROL FIRST AND HOW THE ONE INDIVIDUAL WAS WAY OFF LEVEL FOR HDL AND YOU'D HAVE HIM USE THE CHANGE IN LIFESTYLE AS OPPOSED TO STATINS, THOSE ARE THE KINDS OF THINGS WE'RE GETTING MORE SOPHISTICATED ABOUT. ONE OF THE -- THE SINGLE MINERAL THAT WE RAN INTO MOST EFFICIENT I THINK 91 OUT OF 108 WERE REALLY LOW IN VITAMIN D. AND THEN YOU CAN SAY, WELL, THEY DIDN'T GET ENOUGH SUN, BUT IT'S FAR MORE COMPLICATED THAN THAT BECAUSE THERE WERE SIX VARIANTS AND THREE GENES THAT BLOCKED UPTAKE OF VITAMIN D SO IF YOU HAVE MULTIPLE OF THOSE VARIANTS, YOU'LL NEVER GET TO A NORMAL LEVEL BY JUST TAKING WHAT ARE SUPPOSEDL NORMAL DOSES OF VITAMIN D. YOU HAVE TO TAKE 10X OR 20X THE DOSE OF VITAMIN D SO IT'S A LOT OF THOSE THINGS WE'RE BEGINNING TO LEARN AND MORE AND MORE GENECS ARE GOING TO TITRATE NUTRITION IN ABSOLUTELY FASCINATING WAYS. AND, YOU KNOW, I THINK THE KEY TO REALLY UNDERSTANDING NUTRITION IS GOING TO BE n-OF-1 STUDIES DONE IN REALLY LARGE POPULATIONS WHERE YOU'VE TRACKED THE NUTRIENTS THE INDIVIDUALS ARE TAKING IN. AND WE CAN REALLY SEE HOW IT'S STUDIED IN THE NOT TOO DISTANT FUTURE. OKAY. >> THANK YOU FOR A FASCINATING TALK. I GUESS MY QUESTION HAS TO DO WITH YOU SORT OF MADE I GUESS AN OFF-HANDED COMMENT ABOUT COMPARING THAT YOU HAD ABOUT 100 PEOPLE THAT WERE YOUR SORT OF NORMAL SAMPLE AND SORT OF MENTIONED THOSE WERE CAUCASIAN. YOU KNOW, A LOT OF THE DISEASES THAT YOU LISTED HAVE SIGNIFICANT HEALTH DISPARITIES AMONG DIFFERENT POPULATIONS, AND WE ANOTHER THERE ARE A LOT OF IMPORTANT TO CONSIDER, WE KNOW IN TERMS OF GENETICS AND OTHER BIOLOGICAL MARKERS THAT THERE ARE ETHNIC DISPARITIES OR RISK MARKERS AMONG DIFFERENT POPULATIONS. HOW MUCH OF YOUR WORK YOU'VE DONE WITH YOUR INSTITUTE HAS BEEN ABLE TO LOOK AT CERTAIN HEALTH DISPARITIES OR RISK MARKERS AMONG DIFFERENT ETHNIC POPULATIONS? >> WE HAVEN'T DONE THAT AT ALL. THE FIRST STUDY WAS FUNDED ENTIRELY ON PHILANTHROPY AND WE JUST HAD TO TAKE PEOPLE THAT WERE NEARBY. TWO STUDIES THAT I'M REALLY PUSHING NOW TO GET AT THOSE KINDS OF THINGS, I WAS IN AUSTRALIA ABOUT NINE MONTHS AGO, AND MET A COUPLE ABORIGINAL CHIEFS, AND PERSUADED THEM WE OUGHT TO COME DOWN THERE AND TAKE THE WHOLE ABORIGINAL TRIBE AND PUT THEM THROUGH A SCIENTIFIC WELLNESS REGIMEN. AND THE ISSUE IS FUNDING. SO THE GOVERNMENT WOULDN'T PAY FOR IT. THEY JUST REFUSED BUT MAY BE ABLE TO GET PHILANTHROPY TO PAY FOR IT AND THAT OF COURSE WILL LET US LOOK -- THAT'S AS FAR AWAY FROM US AS YOU COULD GET IN MANY WAYS, SO HOW THE COACHING WILL BE MANAGED, THEY WILL HAVE ABORIGINAL COACHES. IT WILL BE FASCINATING. WE'RE SETTING UP TO DO A SCIENTIFIC WELLNESS PROJECT DIRECTED AT DIABETES IN INDIA, AND THE BILLIONAIRE FUNDING IT WANTS TO TAKE HALF THE SUBJECTS FROM THE LOWEST SOCIOECONOMIC GROUP THERE AND THEN COMPARE THEM WITH UPPER MIDDLE CLASS KIND OF THINGS. SO THOSE WILL BEGIN TO GET AT SOME OF THOSE QUESTIONS. AS WE ROLL OUT TO DIFFERENT STATES, WE'LL OBVIOUSLY BEGIN TO GET SOME GEOGRAPHICAL DIVERSITY, BUT, YOU KNOW, THE ISSUE IS ALWAYS WHO IS GOING TO PAY FOR THE COST OF THESE THINGS, AND THAT'S -- I REALLY HOPE THAT WE CAN GET IN UNDER THE PRECISION MEDICINE PROGRAM, BUT WHAT THE PRECISION MEDICINE PROGRAM IS REALLY PUSHING, AND I THINK IT'S AN ENORMOUS MISTAKE, IS, LOOK, LET'S GET A MILLION PEOPLE AND KIND OF GET THE GENOME. I WOULD ARGUE LET'S GET 20,000 PEOPLE AND DEEPLY PHENOTYPE THEM AND REALLY KNOW WHAT'S GOING ON. BUT SO WE DIDN'T REALLY QUALIFY, EVEN WITH WHAT WE HAVE, TO GET IN PRECISION MEDICINE. SO WE HAVE TO FIGURE OUT HOW TO PAY FOR IT. BUT I AGREE WITH YOU COMPLETELY. OH, ONE OTHER STUDY WE HAVE THAT'S REALLY COOL IS WE -- NOT WE. WE SHOWED A FRIEND IN FINLAND HOW TO DO ALL OF THIS AND HE'S ABOUT SIX MONTHS INTO THE STUDY THERE. SO THAT WILL BE A VERY DIFFERENT POPULATION. AGAIN, IT'S NOT LOWER ECONOMIC. IT'S UPPER MIDDLE CLASS KIND OF THING. OKAY. ANY OTHER -- OR DO WE HAVE TO GO? >> I REALLY -- APPLAUSE PROS -- [APPLAUSE] >> I'M SORRY TO BREAK UP THE WONDERFUL DISCUSSION. THANK YOU SO VERY MUCH, DR. HOOD. WHAT AN INSIGHTFUL AND AMAZING PRESENTATION AND WE'LL LOOK FORWARD TO WHAT NEXT YEAR BRINGS. AT THIS TIME BEFORE WE BREAK, IF EVERYONE WOULD PLEASE JOIN US, WE HAVE A GROUP PHOTO WITH OUR NINR INSTITUTE DIRECTOR HERE IN THE LOBBY, IF YOU WOULD PLEASE JOIN US, AND WE'LL BREAK FOR 15 MINUTES AND CONVENE PROBABLY ABOUT TEN OF. OKAY? THANKS SO MUCH. >> WELCOME BACK FROM BREAK, EVERYONE. WHAT AN EXCITING START TO THIS MORNING. AND NOW I'M VERY DELIGHTED TO INTRODUCE OUR NEXT SPEAKER, DR. SUZANNE BAKKEN, DISTINGUISHED NURSE SCHOLAR IN RESIDENCE AT THE NATIONAL ACADEMY OF SCI3 HERE IN WASHINGTON, D.C. DR. BAKKEN IS THE ALUMNI PROFESSOR OF NURSING AND PROFESSOR OF BIOMEDICAL INFORMATICS AT COLUMBIA UNIVERSITY. SHE DIRECTS THE REDUCING HEALTH DISPARITIES THROUGH INFORMATICS, T32 TRAINING PROGRAM, AND LEADS A PROGRAM ON ADVANCING HEALTH EQUITY. DR. BAKKEN IS THE FELLOW OF THE AMERICAN ACADEMY OF NURSING, AMERICAN COLLEGE OF MEDICAL INFORMATICS, AND MEMBER OF THE NATIONAL ACADEMY OF MEDICINE. TODAY DR. BAKKEN WILL PRESENT ADVANCING PRECISION HEALTH, A NURSING INFORMATICS RESEARCH PERSPECTIVE. PLEASE JOIN ME IN A WARM WELCOME FOR DR. BAKKEN. [APPLAUSE] >> THANKS. IT'S MY GREAT PLEASURE TO BE HERE TODAY. THE MORNING HAS ALREADY BEEN SO STIMULATING. SO IT'S GREAT TO BE TALKING ABOUT SOME OF THESE SAME ISSUES PERSPECTIVE. SO FIRST I'M GOING TO -- THESE ARE THE OBJECTIVES FOR MY PRESENTATION. I WANT TO PROVIDE A BRIEF OVERVIEW OF AN ORGANIZING MODEL FOR NURSING INFORMATICS RESEARCH AND EL STRAIGHT ASPECTS OF FRAMEWORK WITH PRECISION APPROACHES FOR SELF MANAGEMENT FROM OUR RESEARCH AT COLUMBIA NURSING AND SHARE SOME THOUGHTS ON SOME FUTURE DIRECTIONS. SO THIS IS JUDDY EFFKEN'S ORGANIZING MODEL FOR NURSING INFORMATICS RESEARCH, HELPFUL IN TALKING TO PEOPLE THAT DON'T DO NURSING INFORMATICS RESEARCH BECAUSE I WANT TO POINT OUT WE SEE NURSING META PARATIME, ENVIRONMENT, CONTEXT IN THE MODEL, WE SEE INTERVENTIONS AND OUTCOMES, THINGS THAT WE SHARE IN COMMON BUT WHEN SOMEBODY IS PRACTICING INFORMATICS THINKING ABOUT WHAT ARE THE STRUCTURES OF DATA, HOW ARE YOU GOING TO MAKE THAT SYSTEM PERSISTENT, EXPAND AND, REUSABLE. WE SHARE THE CONCEPTS BUT THE NATURE OF RESEARCH INTERVENTIONS ENDS UP BEING DIFFERENT IN NATURE. I WANT TO -- I PROBABLY SHOULD HAVE STARTED WITH A DEFINITION OF WHAT NURSING INFORMATICS IS BEFORE GOING INTO THE ORGANIZING FRAMEWORK. THERE HAVE BEEN A NUMBER OF DEFINITIONS ABOUT INFORMATICS IN GENERAL AND BIOMEDICAL INFORMATICS, ET CETERA. THE DEFINITION OF NURSING INFORMATICS TAKE INTO ACCOUNT SOME COMBINATION OF COMPUTER SCIENCE, INFORMATION SCIENCE AND NURSING. AND THEN APPLYING THAT FOR UNDERSTANDING DIFFERENT PHENOMENA AND DEVELOPING TOOLS THAT COULD BE USED FOR CLINICAL PRACTICE, FOR RESEARCH, FOR DIFFERENT PURPOSES. BUT THE NURSING INFORMATICS DEFINITION WAS ONE OF THE FIRST INFORMATICS DEFINITION THAT TOOK INTO ACCOUNT REALLY THINKING ABOUT TOOLS THAT MIGHT BE MORE PATIENT-FACING OR CONSUMER-FACING AND THE NOTIONS OF FAMILY. SO LET'S MOVE ON WITH A COUPLE EXAMPLES. TODAY IN THIS PARTICULAR BOOT CAMP, THE TITLE SAYS FROM OMICS TO DATA SCIENCE, SO I WANT TO TELL YOU THAT DATA SCIENCE AND INFORMATICS ARE NOT THE SAME THING. THEY ARE NOT SYNONYMS, BUT PRECISION APPROACHES REQUIRE BOTH. THEY DO HAVE SOME OVERLAP IN THEM. SO IN LOOKING AT SOME -- THERE'S A LOT OF DIAGRAMS SIMILAR TO THIS THAT TALK ABOUT THE NOTION OF BIG DATA AND DATA SCIENCE, AND WE SEE THAT THERE ARE OVERLAPPING THINGS IN WHAT SUBJECT MATTER DOMAIN, WHAT WE NEED ON THE COMPUTATIONAL SIDE AND WHAT YOU NEED ON THE MATHEMATICAL OR BIOSTATISTICAL SIDE, AND THEY CALL THIS PERSON IN THE MIDDLE THE UNICORN, SOMEBODY WHO HAS GREAT SKILLS IN ALL THOSE THINGS. THERE ARE A FEW PEOPLE IN THE AUDIENCE THAT BELIEVE IN UNICORNS BUT THE POINT THAT UNICORNS REALLY DON'T EXIST, ALTHOUGH WHO KNOWS IF WE HAVE BETTER GENETICS MAYBE WE'LL FIND OUT THEY DO EXIST, MAYBE SOME OF US ARE UNICORNS AND WE DON'T KNOW IT, RIGHT? ANYWAY, IT IS IMPORTANT IN OUR NURSING SCIENCE AND IN OUR NURSING CURRICULA THAT WE'RE THINKING ABOUT WHAT ARE THE DATA SCIENCE SKILLS THAT ARE NEEDED, AND I DRAW THIS RED ARROW FOR WHERE I THINK THERE IS PRIMARY OVERLAP WITH NURSING INFORMATICS, AND MUCH OF OUR WORK ON THE COMPUTATIONAL SIDE HAS BEEN AROUND THINGS SUCH AS TERMINOLOGIES AND ONTOLOGIES AND REALLY TRYING TO GET AT NURSING LANGUAGE. A LOT OF THAT ACTUALLY HAS BEEN FUNDED BY NINR. BUT SOME OF THE THINGS THAT MIGHT BE PART OF WHAT SOMEONE WHO IS DOING NURSING INFORMATICS WILL DO THAT AREN'T INCLUDED IN DATA SCIENCE IS THINKING ABOUT THINGS LIKE TECHNOLOGY ACCEPTANCE, WHAT'S THE USER EXPERIENCE, WHAT'S THE HUMAN COMPUTER INTERACTION, AND SOME OF THOSE COMPUTER CLINICAL WORK FLOW TYPES OF THINGS THAT ARE IMPORTANT TO INTEGRATION. AND THIS IS TRUE WHETHER OR NOT YOU'RE DESIGNING TOOLS FOR PATIENTS, DESIGNING TOOLS FOR CLINICIANS, YOU'RE DESIGNING TOOLS FOR RESEARCHERS. SO FOR THOSE OF YOU WHO ARE DEANS, ONE OF THE POINTS IN THIS PARTICULAR PART THAT I WOULD MAKE IS IT'S -- YOU CAN'T NECESSARILY COUNT ON YOUR NURSING INFORMATICS FACULTY MEMBERS TO BE YOUR DATA SCIENTISTS BECAUSE THEIR RESEARCH MIGHT BE QUITE DIFFERENT FROM DATA SCIENTISTS, FROM DATA SCIENCE, AND IT MAY BE PEOPLE, A COMBINATION OF PEOPLE WHO ARE MORE COMFORTABLE WITH LARGE DATASETS AND THOSE TYPES OF THINGS THAT MIGHT EVOLVE TO DOING SOME DATA SCIENCE METHODS. WE'VE HEARD A LOT WILL PRECISION MEDICINE THIS MORNING AND PRECISION MEDICINE INITIATIVE. THE ONLY THING I WANT TO POINT OUT IS TO REMIND THE AUDIENCE THAT THIS IS VARIABILITY IN GENES AND LIFESTYLE AND DR. HOOD'S TALK POINTED THAT OUT. THE OTHER THING I WANT TO POINT INITIATIVE IS A DIVERSE COHORT. SO I WAS DELIGHTED THAT COLUMBIA, THE COALITION THAT COLUMBIA UNIVERSITY IS PART OF, WAS CHOSEN TO BE ONE OF THE HEALTH PROVIDER ORGANIZATION SIDES, PRIMARILY BECAUSE OUR MEDICAL CENTER IS SITUATED IN THE MIDDLE OF WASHINGTON HEIGHTS, PRIMARILY A LARGE LATINO COMMUNITY, PRIMARILY FROM THE DOMINICAN REPUBLIC, AND THEN WE ALSO ARE WORKING WITH HARLEM HOSPITAL AND CORNELL SO WE HAVE A LARGE VARIETY OF AFRICAN-AMERICANS AND LATINOS THAT WILL BE COMING IN, IN OUR PARTICULAR COHORT OVER THE NEXT FIVE YEARS. SO THAT'S REALLY EXCITING FOR US. SO IT'S BECOMING MORE POPULAR TO SAY PRECISION IN FRONT OF EVERYTHING. SO NOW PEOPLE ARE TALKING ABOUT PRECISION POPULATION HEALTH AND THAT'S HEALTH WITH HOT SPOTTING, SURVEILLANCE AND THOSE THINGS. I THINK A LOT OF WHAT DR. HOOD TALKED ABOUT REALLY FALLS INTO SOMETHING, PRECISION LIFESTYLE MEDICINE. THOUGHT OH MY GOD, THIS IS ANOTHER NAME FOR NURSING, BECAUSE IT WAS A LOT OF WHAT I FELT THE NURSING ROLE WAS. WE DIDN'T HEAR TOO MUCH ABOUT THE ENVIRONMENT, BUT AS WE'RE WELL AWARE AS WE LOOK AT STRUCTURAL INEQUITIES AND HEALTH DISPARITIES THAT ZIP CODE IS IMPORTANT AS WELL. AND SO JUST THINKING HOW WE'RE HAVING THAT COMBINATON OF VARIABLES, MAKING SURE WE'RE TAKING INTO ACCOUNT NOT ONLY THE PHYSICAL ENVIRONMENT BUT ALSO THE SOCIAL/CULTURAL ENVIRONMENT AND THOSE THINGS IN THIS ERA OF PRECISION APPROACHES. I'M GOING TO FOCUS ON THREE THINGS. THE FIRST IS TALKING ABOUT DATA-DRIVEN ENGAGEMENT THROUGH RESULTS REPORTING, TALKING ABOUT SOME DATA MINING FOR DISCOVERY OF SELF-MANAGEMENT AND TALKING ABOUT SOME TAILORED APPROACHES. THE FIRST PROJECT, AND MY DISCLAIMER, OTHER PEOPLE ARE DOING FABULOUS WORK. I TALK ABOUT WHAT WE DO BECAUSE I KNOW IT'S BEST SO ... [LAUGHTER] AND SO IT'S THE MOST FUN, OF COURSE. AND SO I WANT TO TALK ABOUT THREE DIFFERENT PROJECTS, TWO OF THEM ARE FUNDED, AND ONE OF THEM I THINK IS ALMOST FUNDED. AND SO THE FIRST I'M GOING TO TALK ABOUT IS OUR WASHINGTON HEIGHTS INWOOD INFRASTRUCTURE, A HUGE PROJECT FUNDED BY AHRQ. THE BASIC PROJECT AT INITIATION WAS TO GET A COMPREHENSIVE UNDERSTANDING OF OUR POPULATION IN WASHINGTON HEIGHTS SO WE COULD FACILITATE RESEARCH WITH THE POPULATION. WE'RE ALSO SUPPOSED TO DEMONSTRATE INFRASTRUCTURE FOR CAPABILITIES FOR COMPARATIVE EFFECTIVENESS RESEARCH. AS THE PROJECT EVOLVED, IT BECAME CLEAR THAT WE HAD SOME RELATE TO ESTABLISHING THE FABRIC OF TRUST FOR LEARNING HEALTH SYSTEM AND GRADE FOUNDATION FOR PRECISION MEDICINE AND I'M GOING TO TALK ABOUT SOME OF THOSE ASPECTS. THIS IS THE TOP OF MANHATTAN, THE SKINNY PART. IF YOU LOOK OVER THE EAST RIVER, YOU CAN SEE YANKEE STADIUM. BUT THE POINT IS THIS IS A COMMUNITY THAT HAS HIGH LEVELS OF HEALTH DISPARITIES, BOTH LOW SOCIOECONOMIC STATUS, IMMIGRANT POPULATION, OVER 2/3 LOTS OF DIABETES, LOTS OF CARDIOVASCULAR DISEASE, ET CETERA. AND THE BASIC IDEA BEHIND OUR WICER PROJECT, THE BRAIN CHILD OF ADAM WILL WILCOX, IMAGINE THE FRAMINGHAM STUDY IN A POPULATION PRIMARILY LATINO AND POOR, WITH TODAY'S TECHNOLOGY TO BRING TOGETHER DATA FROM ELECTRONIC HEALTH RECORD, FROM A LARGE COMMUNITY SURVEY, AND DATA FROM OTHER ORGANIZATION, PRIMARY ORGANIZATION FOR US WAS THE VISITING NURSE SERVICE OF NEW YORK AND PUT IT INTO A RESEARCH DATA WAREHOUSE AND THAT WITH A BROWSING TOOL, AND THEN ERS COULD HELP MAKE THE COMMUNITY BETTER. MY BABY WAS THIS ONE UP HERE. I SAID LET'S GIVE IT BACK TO THE PEOPLE IN THE COMMUNITY WHO ARE GENERATING THE DATA. AND SO THAT'S THE PART THAT I'M GOING TO PRIMARILY TALK TO YOU ABOUT. AND SO WE COLLECTED A LOT OF DATA. I'M NOT GOING TO READ THROUGH IT, ON 6000 PEOPLE IN THE COMMUNITY, MORE THAN 5500 WERE LATINO. SO YOU CAN SEE SOME OF THE DIFFERENT AREAS. WE HAVE SOME PROMIS TOOLS. WE DID RESEARCH QUALITY BLOOD PRESSURES, MEASURED HEIGHT AND WEIGHT TO DO BMI, ET CETERA. AND FOR A THIRD OF THE SAMPLE WE WERE ABLE TO COLLECT BIOSPECIMENS AS WELL. IN TERMS OF WHAT THE COMMUNITY CARED ABOUT, THIS WAS SOMETHING THAT WE SHOWED BACK TO THE COMMUNITY. IN ADDITION TO OUR STANDARDIZED SURVEYS WE HAD SOME -- WE HAD SOME OPEN-ENDED QUESTIONS AND ONE OF THEM WAS WHAT ARE THE THREE THINGS, THREE HEALTH PROBLEMS, YOU WORRY ABOUT THE MOST. SO THIS DOESN'T MEAN NECESSARILY THEY HAVE THE HEALTH PROBLEM, BUT THESE WERE THE CONCERNS. THE TOP ONES WERE NO SURPRISE TO US. WE SAW DIABETES, ALL THE ORANGE ARE CARDIOVASCULAR DISEASE, WE ALSO HAD CANCER, MORE THAN 4000 OF THE 6000 PEOPLE. THE PINK ONES WERE SURPRISING TO US, ALL ARE SOME FORM OF SEXUALLY TRANSMITTED INFECTIONS. SO PEOPLE WERE WORRIED ABOUT HIV/AIDS, HEPATITIS, SO WE DID MORE QUALITATIVE WORK TO FIGURE IN STUDYING THE COMMUNITY, OUT THAT. THE OTHER THING WE DISCOVERED WHICH WAS NO SHOCK TO US BUT WE HAV SEVERAL MEASURES OF HEALTH LITERACY WITH THE COMMUNITY HAVING QUITE LOW HEALTH LITERACY, WHETHER MEASURED BY NEWEST VITAL SIGNS OR ALSO THE THREE ONE-ITEM HEALTH LITERACY SCREENERS FOR FROM CHEW. BUT WE HAD THE QUESTIONS NEEDED IN OUR CONSENT FORM TO LOOK AT THE THREE THINGS YOU HAVE TO DO TO PARTICIPATE IN THE PRECISION MEDICINE INITIATIVE COHORT INITIATIVE, AGREE TO GIVE A SPECIMEN, AGREE TO SHARE YOUR DATA AND AGREE TO BE CONTACTED FOR FUTURE RESEARCH. POINT THAT I WANT TO MAKE OVER ALL OF THIS, WHEN WE LOOKED AT THE DIFFERENT PREDICTORS AND LOGISTIC REGRESS MODEL WHAT WAS CONSISTENT WAS LET LITERACY MADE A DIFFERENT, A FEW OTHERS MADE A DIFFERENCE FOR CON SENT. THAT GOT ME EXCITED. WHEN THEY HAD THE PRECISION MEDICINE INITIATIVE GROUPS AND WOULD LET ANYBODY IN THE DOOR I WOULD COME AND BE MOUTHY. BUT THEN I'M ALSO -- I HAPPEN TO BE ON THE INSTITUTE OF MEDICINE -- NATIONAL ACADEMY OF MEDICINE ROUNDTABLE IN HEALTH LITERACY, TALKED TO PEOPLE AND GOT MORE EXCITED. IF YOU'RE GOING TO DO PRECISION MEDICINE INITIATIVE RIGHT YOU REALLY NEED TO PAY ATTENTION TO HEALTH LITERACY OF THE POPULATION. SO WE BUSTED OUR BUTT TO GET THIS WRITTEN VERY QUICK BI, QUICKLY BECAUSE VARMUS AND COLLINS GOT THEIR ARTICLE IN THE NEW ENGLAND JOURNAL AND WE THOUGHT THAT THAT THIS WAS THE NEW PERSPECTIVE. THEY DISAGREED, NOT VARMUS AND COLLINS BUT THE NEW ENGLAND JOURNAL. WE PUT IT OUT AS NATIONAL ACADEMY OF MEDICINE PERSPECTIVE TO GET THINGS OUT ABOUT THE PRINCIPLES. BUT IT REALLY WAS THESE TWO THINGS. WANTING TO GIVE DATA BACK TO THE COMMUNITY WHO GENERATED IT AND KNOWING THAT THEY HAD LOW LEVELS OF HEALTH LITERACY. WE HAD TO BE VERY CAREFUL ABOUT HOW WE GAVE IT BACK. AND THIS HAS BIG IMPLICATIONS FOR THE PRECISION MEDICINE INITIATIVE COHORT BECAUSE THE INTENT IS THAT DATA IS GOING TO BE GIVEN BACK AND NOT JUST GENOMICS DATA BUT ALSO DIFFERENT TYPES OF DATA THAT ARE BEING COLLECTED. SO WE STARTED OUT BY DOING SOME PARTICIPATORY DESIGN WITH THE MEMBERS OF OUR -- WITH MEMBERS OF OUR RESEARCH SAMPLE. SO WE COLLECTED -- WE DID ABOUT 20 FOCUS GROUPS, MOST OF THEM IN SPANISH, TO DO THESE DESIGN SESSIONS. WE HAD PEOPLE LOOK AT THE DIFFERENT DESIGNS AND THEN WE ITERATED DESIGNS WITH MEMBERS OF THE COMMUNITY. WE DID SOME BASIC RESEARCH ABOUT -- THAT'S UNDERGOING NOW WHERE WE'RE DOING MORE OF EXPERIMENTAL DESIGN TO TEST ACTUAL COMPREHENSION. AND THEN THE EVENTUAL PLAN WILL BE THAT WE'LL TEST IT FOR ACTIONABILITY IN APPLICATIONS BUT WE'RE NOT QUITE THERE YET. WE HAVE LOTS OF PUBS ON IT, SO IT'S EASY TO FIND OUT MORE. I WANTED TO SHOW YOU A FEW DESIGNS AND TELL YOU A LITTLE BIT ABOUT SOME OF THE LESSONS THAT WE LEARNED IN GIVING THINGS BACK. AND THE THING I'LL MENTION NOW IS BOTH -- ALL OF THESE DESIGNS ARE FREELY AVAILABLE TO USE IN YOUR RESEARCH. SO JUST CONTACT ME. EVENTUALLY THEY ARE GOING TO BE ON A SITE I CAN SEND THE LINK TO BUT THEY ARE NOT THERE YET AND THE SOFTWARE WE'RE PUTTING INTO OPEN SOURCE. THIS IS A PROMIS ANXIETY SCORE SHOWING THE PERSON'S SCORE BEING 56, WHICH IS SLIGHTLY WORSE THAN AVERAGE. THIS IS AN EXAMPLE OF -- WE DID A COUPLE DESIGNS FOR DEPRESSION. THIS IS INTERESTING BECAUSE WE ORIGINALLY HAD A NICE PRIMARY COLOR PALLET PALETTE BUT ONE OF THE THINGS WE LEARNED IN TESTING WITH PARTICIPANTS THAT DEPRESSION NEEDED TO BE BLUE. AND SO WE CHANGED THE COLOR RELATED TO THAT. AND THEN WE ALSO WANTED TO CONVEY -- IN SOME INSTANCES WE WANTED TO SHOW A SINGLE PIECE OF INFORMATION LIKE THE ANXIETY. IN OTHER INSTANCES WE WANTED TO SAY THIS IS YOU, AND THIS IS AVERAGE SCORE FOR OTHER WOMEN IN YOUR AGE GROUP. WE ALSO HAD A LOT OF 30-DAY MEASURES. SO-- INCLUDING THIS IS ONE OF THE CDC MEASURES. SO THE BASIC IDEA BEHIND THIS WAS LET'S DO A CALENDAR, AND THIS IS PRETTY INTERESTING AS WELL BECAUSE THE MORE WE PUT, MADE IT LOOK LIKE A CALENDAR, THE MORE CONFUSING IT BECAME BECAUSE THE -- IT MADE PEOPLE THINK THOSE WERE THE ACTUAL DAYS OF THE MONTH. AND SO HOW WE DEALT WITH THAT TO TRY TO HANDLE THE COGNITIVE COMPLEXITY AND NOT HAVE PEOPLE DO THE MATH WAS TO JUST GO WITH THE BASIC 30-DAY BLOCK, BUT THEN TO GO AHEAD AND PUT THE NUMBER ON THE SQUARE SO YOU WOULDN'T HAVE TO DO A COMPUTATION TO FIGURE THAT OUT. BUT WE STILL DID RUN INTO SOME CONFUSION ABOUT MAYBE THAT WAS A SPECIAL DAY. AND IN SOME OF THE GROUPS THEY SAID, WELL, IS THAT THE BIRTHDAY? ONE OF THE DESIGNS THAT DID WORK REALLY WELL, ALTHOUGH NOT ALL ICONS DID, WAS THIS IS A FATIGUE MEASURE. THIS IS -- WE DID THE PROMIS MEASURE THAT HAD TO DO WITH FEELING RUN DOWN. AND THIS KIND MUCH BATTERY METAPHOR WORKED REALLY WELL IN OUR LOW LITERACY POPULATION. THIS DESIGN, AS I SAID, WE HAD DONE BODY MASS INDEX, CALCULATED FROM THINGS WE GOT, AND THEN HERE THOSE THAT PARTICULAR DESIGN WITH THAT. WE ALSO WANTED TO DO OVERALL HEALTH IN THIS INSTANCE ONCE AGAIN, SHOWING COMPARISON BETWEEN AN INDIVIDUAL AND OTHER WOMEN IN THE AGE GROUP. THIS IS AN EXAMPLE OF WANTING TO SHOW MULTIPLE MEASURES, AND SO THIS IS AN EXAMPLE OF MULTIPLE AND THIS IS SOMETHING THAT WAS -- THAT WAS WELL UNDERSTOOD ACROSS LEVELS OF LITERACY IN OUR PARTICIPATORY DESIGN GROUPS. THIS LAST ONE WAS NOT SO WELL UNDERSTOOD TO BEGIN WITH, BUT I JUST HAD THIS VISION OF WHAT I THOUGHT WAS KIND OF LIKE A FOUR-LEAF CLOVER, AND I WANTED TO BE ABLE TO SHOW IN AN EASY WAY WHAT SOMEONE'S OVERALL HEALTH WAS, EVEN IF DIMENSIONS WERE MEASURED ON INSTRUMENTS WITH DIFFERENT DENOMINATORS. SO WE WORKED AND WORKED ON THIS, UNTIL IT WORKED, AND MOST OF OUR PARTICIPANTS NOT BEING IRISH THOUGHT THIS WAS MORE LIKE A FLOWER THAN A FOUR-LEAF CLOVER. [LAUGHTER] IT'S A FLOWER. AND SO THERE WERE SOME THINGS THAT MADE -- THERE WAS SOME THINGS THAT MADE IT WORK. ONE WAS IT ENDED UP BEING IMPORTANT TO HAVE THESE DOTTED LINES AROUND IT, BECAUSE OTHERWISE PEOPLE HAD A HARD TIME KIND OF -- THEY WOULD KNOW IT WAS A DIFFERENT SIZE BUT WEREN'T QUITE SURE WHY IT MATTERED. AND SO BY ADDING THE DOTTED LINES AROUND IT TO THE U-DESIGN THAT PEOPLE WERE ABLE TO KIND OF GET WHERE THAT DEFICIT MIGHT BE. AND THIS TOOK A LOT OF KIND OF DATA TRANSFORMATION TO FIGURE OUT, OKAY, IF IT'S X AMOUNT ON THIS SCALE HOW MUCH OF THE CIRCLE SHOULD BE FILLED OUT. AND BETWEEN DOING THE DOTTED LINES ON THE -- DOING THE DOTTED LINES ON THE U AND SHOWING THE PRETTY GOOD TIME. IT WAS PRETTY EASY FOR THEM TO UNDERSTAND. BUT WE ALSO WANTED TO NOT JUST GIVE THE PEOPLE THEIR DATA BUT ALSO TO TRY TO BEGIN TO MOVE TOWARDS ACTIONABILITY OF THE DATA. AND SO IN THIS PARTICULAR DIAGRAM WE STARTED OUT WITH VERY SIMPLE LIKE STREET LIGHT METAPHORS, AND PEOPLE ACTUALLY ENDED UP NOT LIKING IT. LIKE THEY FELT IT WAS TOO SIMPLE. AND ONE OF THE BIG LESSONS WHICH I'LL REITERATE AGAIN IS SHOWING ON, JUST THEIR BLOOD PEOPLE A SINGLE PIECE OF PRESSURE VALUE WITHOUT ADDITIONAL STUFF, IT LACKS CONTEXT. SO AS OPPOSED TO SOME OF THE MAKE IT SIMPLE AS POSSIBLE, WE FOUND IN OUR PARTICULAR LATINO POPULATION THAT CONTEXT MADE IT REAL AND MADE IT MORE COMPREHENSIVE RATHER THAN CONFUSING. SO IN THIS PARTICULAR THING JUST IN THE BLOOD PRESSURE VALUE WE SHOW ONE OF THE WAYS BLOOD PRESSURE IS TAKEN WITH THE -- AND SHOWED THE NUMBER, BUT THEN WE ALSO HAD THOSE COLOR BARS THAT HAD THE NUMBER ON THEM, BUT ALSO HAVE THE COLORS FOR, YOU KNOW, FINE, BORDERLINE. BUT THEN WE ALSO WANTED TO SAY, WELL, THESE ARE SOME OF THE ISSUES THAT CAN HAPPEN, IF YOU HAVE HIGH BLOOD PRESSURE, AND SO IN THIS PARTICULAR ONE WE WANTED TO BE ABLE TO COMMUNICATE SOME OF THE RISKS IN WHAT WOULD BE A MORE COMMON LANGUAGE BUT ALSO WE ADDED THE PROFESSIONAL TERMS. AND WE FOUND FROM OUR PARTICIPANTS IN THE COMMUNITY WHO HELPED DESIGN THE THINGS WITH US THAT THAT WAS GOOD BECAUSE THEY KIND OF NEED TO KNOW BOTH WORDS BECAUSE THEY MAY RUN INTO THE CLINICIANS WHO ARE GOING TO USE THE PROFESSIONAL WORDS. SO WE DIDN'T -- IT WASN'T FOUND TO BE CONFUSING IN THAT REGARD. AND PEOPLE -- A NUMBER OF PARTICIPANTS IN THE DESIGN GROUPS, WE GAVE THEM EACH OF THESE DESIGNS ON VERY HIGH QUALITY KIND OF CARDBOARD MATERIAL AND A LOT OF PEOPLE TOOK THEM HOME. AND THIS WAS THE FAVORITE. THEY SAY I WANT TO PUT THIS ON MY FRIDGE. I KNOW IT'S NOT MY BLOOD PRESSURE BUT I KNOW PEOPLE WITH BLOOD PRESSURE SO IT'S A GOOD THING TO DO. THIS IS ANOTHER EXAMPLE. WE HAD A LOT OF ISSUES IN COMMUNICATING PHYSICAL -- TYPES OF PHYSICAL ACTIVITIES AND FRUITS AND VEGETABLE CONSUMPTION. ALTHOUGH THE ROWS OF ICONS LIKE THE STARS THAT YOU SAW WITH THE OVERALL HEALTH, THOSE WORK FINE, BUT WHEN WE TRIED -- DID THAT'S CALLED AN ICON ARRAY. WHEN WE TRIED ICON ARRAYS FOR THINGS LIKE FRUIT AND VEGETABLES, IF WE PUT ROW OF ORANGES THEN PEOPLE WERE SAYING I GET BORED EATING ORANGES. WE TRIED A FRUIT BASKET TRYING TO SHOW THE VARIETY OF FRUIT AND PEOPLE SAID OH MY GOD, BANANAS, ORANGES AND A PINEAPPLE TOO! [LAUGHTER] THIS IS TOO MUCH FRUIT! THIS IS TOO MUCH FRUIT! AND SO WE WENT TO -- WE ENDED UP GOING TO JUST MORE BAR GRAPHS ON BOTH FRUIT AND PHYSICAL ACTIVITY. FOR PHYSICAL ACTIVITY WE TRIED OUT SNEAKERS. WE TRIED OUT PEOPLE RUNNING, BUT THINK -- TAKE IT MUCH TOO LITERALLY. LIKE THIS IS THE SPECIFIC EXERCISE THAT YOU'RE WANTING ME TO DO. SO IN THIS INSTANCE WE WENT WITH SOMETHING SIMPLE. AND THEN WE WANTED TO PUT ALSO A LITTLE BIT ABOUT ACTUALLY THIS IS WHAT YOU'RE DOING, THIS IS WHAT THE MINIMUM RECOMMENDATIONS ARE. SO THAT WAS THE VISUALIZATION WORK FOR THE RESULTS REPORTING THAT WE DID IN WICER. NO MATTER HOW MUCH GRADUATE STUDENTS YOU HAVE, YOU CAN'T HAVE PEOPLE MAKE THESE WITH INDIVIDUAL VALUES ONE BY ONE. SO WE DEVELOPED SOMETHING WHICH WE CALL THE ENTICE SYSTEM, ELECTRONIC TAILORED INFO GRAPHICS FOR COMMUNITY ENGAGEMENT, EDUCATION AND EMPOWERED, SO BASICALY WHAT THE SOFTWARE DOES IS IT TAKES THIS INPUT, THE SURVEY DATA, AND WE HAVE A SET OF RULES THAT SAY THIS IS OF TYPE OF VISUALIZATION YOU SHOULD PRODUCE FOR THIS PARTICULAR SET OF DATA. AND SO IT HAS A DATABASE THAT HAS OTHER PEOPLE'S VALUES IN IT AS WELL SO YOU CAN DO COMPARATORS. THE INTENT HAS BEEN OPEN SOURCE, IT IS IN GITHUB, BUT WE HAVEN'T RELEASED IT TO THE PUBLIC YET BUT THE INTENT IS IT WOULD BE AVAILABLE FOR YOU TO EXTEND AND USE IN YOUR RESEARCH, BUT ALL THE DESIGNS ARE AVAILABLE NOW. AND I SHOWED YOU IN ENGLISH BECAUSE I ONLY SPEAK ENGLISH BUT EVERYTHING WE'VE DONE IS ALSO IN SPANISH. CERTAINLY YOU CAN FEEL FREE TO TRANSLATE AND TRY OUT DESIGNS AND EVOLVE WITH YOUR OWN POPULATIONS. SO IN TERMS OF SOME OF THE LESSONS WE LEARNED, CERTAINLY RATHER THAN LESS IS MORE, MORE IS MORE. WE FOUND WITH THE SLOW LITERACY POPULATION THAT DATA WITHOUT CONTEXT LACKED MEANING. THAT ICONS WERE INTERPRETED LITERALLY. WE HAD SOME DIFFICULTY DOING THE COMPARISONS TO OTHERS, BUT WE FINALLY FIGURED OUT HOW TO DO THAT. AND OBVIOUSLY IF YOU DO THIS IN BIG TIME LIKE THEY PLAN TO DO IN THE PRECISION MEDICINE INITIATIVE COHORT, IT'S IMPORTANT AUTOMATION IS THERE AS WELL. WE WANTED TO -- OUR INITIAL INTENT HAD BEEN -- AND WE DID ALL THE PROGRAMMING TO DO IT, IS WE WERE GOING TO GIVE ALL THE DATA BACK ELECTRONICALLY, BUT OUR INSTITUTION RECEIVED THE LARGEST HIPAA VIOLATION FINE IN HISTORY. I THINK STILL SO FAR. AND SO THEY WERE -- THEY DIDN'T ALLOW US TO DO THAT. BUT ON ON THE OTHER HAND IT WAS QUITE LOVELY. WE ENDED UP HAVING SIX PRECISION MEDICINE TOWN HALLS WITH THE COMMUNITY IN WHICH WE HAD PEOPLE COME IN, ALL THE TOWN HALLS WERE IN SPANISH EXCEPT FOR MY PRESENTATION, I USED SPANISH SLIDES BUT SPOKE IN ENGLISH. WE HAD THE OPPORTUNITY TO GIVE THE DATA BACK TO PARTICIPANTS. WE HAD NURSES THERE TO DO ANY EDUCATION OR ANY CLARIFICATION OF THE ANSWERS, ASK ANY QUESTIONS, IF SOMEBODY HADN'T ALREADY PROVED A BIOSPECIMEN THEY HAD OPPORTUNITY TO DO THAT. BUT WE HAD THE CHANCE TO FRAME WICER IN TERMS OF PRECISION MEDICINE, AND THIS ENDED UP BEING VERY IMPORTANT BECAUSE A LOT OF THE OTHER THINGS THAT HAD BEEN DONE IN THE COMMUNITY, AND WITH LESSER AMOUNTS OF PEOPLE, THEY FOUND THE COMMUNITY DIDN'T SEEM LIKE THEY WOULD BE VERY SUPPORTIVE OF DOING THINGS THAT WOULD INVOLVE GENOMICS, BUT WE FOUND IN DOING IT IN THE CONTEXT OF OUR RESEARCH TEAM THAT HAD BEEN IN THE COMMUNITY, WE'D GIVEN THEM BACK THEIR DATA, AND EXPLAINED THE IMPORTANCE OF HAVING DIVERSITY IN THE BIOBANKS, AND THERE ARE A NUMBER OF THINGS THAT DOMINICANS IN PARTICULAR HAVE SOME DIFFERENT PROPENSITIES TO, INCLUDING ALZHEIMER'S DISEASE, SO WHEN YOU TALKED ABOUT IT LIKE THAT PEOPLE IN FACT WERE VERY ENGAGED. 95% INDICATED THEY WOULD BE INTERESTED IN PRECISION MEDICINE INITIATIVE. SO NOW THAT WE'RE A RECRUITMENT CENTER WE SHALL BE GOING BACK TO THEM AND GETTING MORE SAMPLES AND RECONSENTING. WHEN I WAS HERE LAST YEAR IN THE BOOT CAMP WHICH WAS MORE BROADLY ON BIG DATA, I SHARED A LITTLE BIT OF MY FRUSTRATION IN THE DIFFICULTY OF GETTING RESEARCH FUNDED THAT HAD ANY DATA SCIENCE ASPECT TO IT. I FELT LIKE THINGS THAT WENT TO NURSING, PEOPLE DIDN'T LIKE THE DATA SCIENCE PARTS. IF I WENT TO A DATA SCIENCE STUDY SECTION THEY THOUGHT SELF MANAGEMENT WAS TOO NARROW. THIS YEAR I'M HAPPY TO REPORT ON A NUMBER OF GRANTS THAT WE DID GET IN THE LAST YEAR. SO WE HAD THE OPPORTUNITY TO, THROUGH A SUPPLEMENT TO AN EXISTING RO1 FOCUSED ON A FAMILY HEALTH INFORMATION SYSTEM FOR CAREGIVERS WITH ALZHEIMER'S, HAD A DIVERSITY SUPPLEMENT AND ARE EXPENDING VISUALIZATION WORK WE STARTED IN WICER AND WITH THAT WE'LL BE HAVING -- BE ABLE TO SHOW BOTH CAREGIVERS THEIR DATA AND ALSO DATA ABOUT THE PERSON THEY ARE CARING FOR, TO KIND OF LOOK AT THOSE TYPES OF THINGS AS PART OF OUR FAMILY HEALTH INFORMATION SYSTEM. AND THEN WE'RE ALSO STARTING TO BEGIN TO THINK ABOUT SOME VISUALIZATIONS IN THE GENOMIC SPACE. BOTH DOING SOME THINGS IN THE AREA OF ANCESTRY INFORMATIVE MARKERS, BECAUSE WE HAVE OUR -- OUR COMMUNITY IS HEAVILY LATINO, PRIMARILY DOMINICAN REPUBLIC, BUT THERE'S A LOT OF VARIATION IN ANCESTRY THERE AND ALSO PEOPLE FROM OTHER -- WHO ARE LATINO BUT FROM -- MIGHT HAVE A DIFFERENT ANCESTRY SO WE'RE BEGINNING TO DO THAT. WE'RE ALSO WORKING ON SOME RISK COMMUNICATION, SPECIFICALLY RELATED TO FAMILIAL RISK OF HYPER CHOLESTEROLEMIA AND VISUALIZE AND GIVE BACK TO INDIVIDUALS. THE SECOND AREA I WANT TO TALK ABOUT IS DATA MINING FOR DISCOVERY OF SELF MANAGEMENT INTERVENTIONS. AND SO IN OUR ORIGINAL WICER PROJECT WE HAD BEGUN TO DO SOME DATA MINING, BUT DOING IT WITH MORE STRUCTURED DATA. AND SO WE HAD A BUNCH OF VARIABLES ON EVERYONE, BUT STILL A SAMPLE SIZE THAT WAS ONLY OF 6000, SO IT REALLY DOESN'T MEET THE DEFINITIONS OF BIG DATA. BUT THROUGH SOME DATA MINING ACTIVITIES WE WERE ABLE TO -- THIS IS WORK DONE BY DR. SUN LEE YOON, THE DATA SCIENTIST THAT WORKS WITH US AT COLUMBIA, ABLE TO LOOK AT VARIABLES AROUND SOME OF THE PREDICTORS AND POSSIBILITIES OF WHERE WE MIGHT BE ABLE TO DO INTERVENTIONS. SECONDLY, WE HAVE THE OPPORTUNITY TO DO ANOTHER SUPPLEMENT, AND AS I SAID WE HAD THE GRANT ON THE FAMILY HEALTH INFORMATION MANAGEMENT SYSTEM FOR DEMENTIA CAREGIVING AND WE HAVE HAD SOME PREVIOUS EXPERIENCE IN DOING DATA MINING OF TWEETS TO LOOK AT ACTIVITIES RELATED, TO LOOK AT DIFFERENT ASPECTS OF PHYSICAL ACTIVITY. IN THIS PARTICULAR PROJECT, WHICH WAS FUNDED THROUGH A SPECIAL MECHANISM TO MORE DEEPLY UNDERSTAND THE MECHANISMS OF SOCIAL SUPPORT, AND SO WE BASICALLY -- THIS JUST SAYS A PIPELINE FOR MINING TWEETS. WE HAVE A PAPER ON THIS, THE PIPELINE IN THE AMERICAN JOURNAL OF PREVENTIVE MEDICINE THAT WALKS YOU STEP BY STEP HOW TO ANALYZE TWITTER DATA WITH SOME BASIC TOOLS THAT YOU DON'T NEED TO BE A PROGRAMMER TO DO. AND SO IN THIS PARTICULAR PROJECT WE'RE DOING BOTH SOME STRUCTURE MINING, TRYING TO LOOK -- WHEN YOU DO STRUCTURE MINING YOU CAN LOOK AT MACRO NETWORKS, MISO AND MICRO NETWORKS, LOOKING AT SOCIAL NETWORKS OF PEOPLE WHO ARE TWEETING ABOUT ALZHEIMER'S CARE GIVING. WE REALIZED NOT EVERYONE WHO IS A CAREGIVER TWEETS, WE FULLY REALIZE THAT, BUT WE HAVE DATA FROM OTHERS IN OUR -- WE HAVE QUALITATIVE DATA AND SURVEYS COMING FROM OUR COMPLETELY LATINO SAMPLE, BUT IN THIS PARTICULAR PROJECT WE WANTED TO SAY, OKAY, WE KNOW WE'VE GOT THAT MORE LOCALL BUT WHAT CAN WE FIND OUT WITH THE LARGE VOLUME OF TWEETS. THIS JUST SHOWS SOME OF THE MIDDLE LAYER, THE MESO LEVEL STRUCTURES OF PEOPLE WHO ARE TWEETING AND THEN WE ALSO LOOK AT MICRO LEVEL COMMUNICATION NETWORKS, THERE ARE 16 VARIETIES OF TRIADS IN THESE MICRO-LEVEL NETWORKS. IS IT SIMILARLY UNIDIRECTIONALLY WHERE SOMEONE IS SENDING SOMETHING OUT AND PEOPLE ARE ANYTHING ELSE WITH IT? JUST READING IT PERHAPS AND NOT OR ARE THERE -- BUT JUST THINKING ABOUT THE WAYS WE CAN POTENTIALLY SHORE UP SOME OF THESE COMMUNICATION PATTERNS TO HELP WITH THE SUPPORT. WE ALSO DO SOME CONTENT ANALYSIS, FREQUENTLY OCCURRING WORDS IN THE TWEETS AND MINE BOTH ENGLISH AND SPANISH TWEETS. SO THIS IS ANOTHER SLIDE OF A DIFFERENT SAMPLE OF TWEETS AS PART OF THE OVERALL PROJECT. AND FOR THIS PARTICULAR ANALYSIS, SOME OF THESE CATEGORIES MAY BE FAMILIAR TO YOU, IF YOU KNOW KATE LORD'S WOK, LOOKING AT THE DIFFERENT SELF-MANAGEMENT TYPES OF CATEGORIES. THE IDEA BEHIND THIS ANALYSIS WAS LET'S LOOK AT THEM FROM THE PERSPECTIVE OF THESE CATEGORIES AND LOOK AT WHAT PROPORTION OF THE TWEETS HAD TO DO WITH EMOTIONAL MANAGEMENT VERSUS MEDICAL MANAGEMENT VERSUS ROLE MANAGEMENT, AND THESE ARE THE ONES THAT PRIMARILY HAVE A SOCIAL SUPPORT ASPECT. THE OTHER THING THAT WE'RE LOOKING AT, AND THERE ARE A LOT OF TOOLS OUT THERE NOW FOR LOOKING AT SENTIMENT ANALYSIS, SO THESE ARE TOOLS THAT ALLOW YOU TO TAKE A SMALL BODY OF TEXT AND THEY -- IT'S PROCESSED AGAINST A DICTIONARY FOR THE AFFECT IN THE TWEET. AND SO AS YOU LOOK AT THESE PARTICULAR TWEETS YOU CAN ACTUALLY SEE THERE ARE A VARIETY OF BOTH POSITIVE, WHICH ARE GREEN, AND NEGATIVE SENTIMENTSES ASSOCIATED WITH THIS. YOU CAN DO THESE TO LOOK AT TEMPORAL RELATIONSHIPS, DAY OF WEEK AND TIME OF DAY AND THOSE TYPES OF THINGS. WE'RE FULLY DIGGING INTO THIS, AND WE WILL HAVE A FULL YEAR OF TWEETS, AND THE TWITTER RELEASES A PUBLIC SUBSET OF TWEETS, AND SO WE COLLECT THOSE IN BOTH ENGLISH AND SPANISH ING FOR DEMENTIA, ALZHEIMER'S DISEASE, CAREGIVING ASSOCIATED WITH THOSE TO DO THE CORPUS, BUT THIS STUDY IS -- GOES ON UNTIL DECEMBER SO WE HAVE A LOT MORE ANALYSES WE'RE DOING IN THIS PARTICULAR REGARD BUT IT JUST SHOWS YOU A LITTLE BIT OF POTENTIAL. I KNOW DR. HOOD IN HIS TALK THIS MORNING WAS TALKING SPECIFICALLY ABOUT WHAT ARE THEY GETTING OUT OF THESE DATA VERSUS THE OTHER DATA IN THE WELLNESS PROJECT. LASTLY, I JUST WANT TO MENTION A BIT ABOUT SOME TAILORED APPROACHES FOR SELF-MANAGEMENT INTERVENTION. AND SO WHEN WE THINK ABOUT -- WE HEARD THIS MORNING ABOUT VERY TAILORED APPROACHES FOR LIFESTYLE MANAGEMENT THAT WILL TAKE INTO ACCOUNT ALL OF THE VARIOUS OMES, AND WE'RE NOT THERE YET IN OUR PARTICULAR WORK. BUT IN THE AREA OF SELF MANAGEMENT, THERE ARE DIFFERENT TYPES OF TAILORS THAT ARE OCCURRING IN OTHER DIFFERENT RESEARCH PROJECTS. THE ONE ON SYMPTOM SEVERITY WAS SOMETHING FROM OUR -- ONE OF OUR P30 GRANTS THAT FOCUSED ON SELF-MANAGEMENT INTERVENTION FOR HIV, AND THIS HAS GONE ON TO A COUPLE OF RO1s SINCE THAT, AND THEN THE BOTTOM IS -- LOOK AT IT MORE FROM THE PERSPECTIVE OF THE INFORMATION MOTIVATION BEHAVIOR MODEL, CERTAIN TYPES OF VARIABLES THAT WE TAILOR OUR SELF-MANAGEMENT INTERVENTIONS ON. AND THEN I ALSO WANTED TO MENTION KATHLEEN HICKEY IS IN THE AUDIENCE, ALSO FROM COLUMBIA, AND THIS IS HER RO1, WHICH IS USING IPHONE TECHNOLOGY TO HELP EVALUATE AFIB. AND WE GOT A FEW MORE GRANTS IN THE WORKS. I WANT TO TALK ABOUT SOME FUTURE DIRECTIONS, AND ONE OF THE IDEAS OF DOING THIS IS JUST TO KIND OF MORE -- SHARE MY THOUGHT PROCESS, SCARY AS THEY MAY BE, SO YOU CAN REALLY THINK ABOUT, WELL, IF I HAD BEEN DOING A MORE TRADITIONAL PROGRAM OF RESEARCH, HOW CAN I EVOLVE MY SCIENCE TO DO SOMETHING THAT WOULD BE MORE PRECISION RELATED? SO THAT'S THE IDEA BEHIND THIS. I'M GOING TO GO BACK TO THE WICER STUDY. I TALKED ABOUT WHAT THE COMMUNITY WORRIED ABOUT. AND ALSO SOMETHING ABOUT THE HEALTH LITERACY AND WE'RE GIVING DATA BACK. BUT I DIDN'T MENTION THAT THE CLINICAL FOCUS OF OUR STUDY WAS AROUND HYPERTENSION. SO I'M GOING TO TALK A BIT ABOUT THAT PARTICULAR ASPECT OF THE PROJECT. AND IN THIS PARTICULAR SLIDE, THIS IS LOOKING AT WHETHER OR NOT SOMEBODY HAD BEEN TOLD THAT THEY HAD HYPERTENSION. AND SO THIS PART OVER HERE, AND SO THIS IS THE -- THE BLUE IS THE BLOOD PRESSURE AND MORE NORMAL RANGE. RED IS THE BLOOD PRESSURE IN THE HIGHER RANGE. AND YOU SEE THE DIVIDING THING IS 135 SYSTOLIC, AND THIS WAS -- THIS IS YES AND NO. SO A COUPLE THINGS BECOME VERY APPARENT. MOST IS THERE'S A LOT OF RED, REGARDLESS OF WHETHER YOU HAD BEEN TOLD OR NOT THAT YOU HAD HYPERTENSION, AND THIS WAS AUTOMATED BLOOD PRESSURE CUFFS, THREE READINGS, FIVE MINUTES APART, AVERAGE OF THE SECOND AND THIRD BLOOD PRESSURE READING. SO THEY WEREN'T JUST LOOSE READINGS OR SELF-REPORTED. THEY WERE WHAT'S CONSIDERED RESEARCH QUALITY READINGS IN THAT. SO, ONE, THERE'S EITHER A LOT OF UNDIAGNOSED -- THERE'S DEFINITELY UNDIAGNOSED HYPERTENSION AND ALSO HYPERTENSION THAT'S NOT WELL MANAGED. A SECOND FACT FOR THE GROUP OF PEOPLE THAT THIS IS LOOKING AT PEOPLE THAT STOP TAKING THEIR MEDICATION, HYPERTENSION MEDICATION, THAT THEY -- BECAUSE THEY FELT WORSE, OKAY? YOU SEE THERE'S A GOOD GROUP OF PEOPLE THAT DID THAT AND SOME OF THEIR BLOOD PRESSURE READINGS THAT ARE IN THE HYPERTENSIVE RANGE. THEN THIS IS INTERESTING. THIS IS BLOOD PRESSURE OVER AGE FROM 20-100. THE BLUE LINE IN THE MIDDLE IS PEOPLE FROM THE DOMINICAN REPUBLIC. THE ORANGE IS MEXICO. THE GREEN IS PUERTO RICO. AND SO THIS LOOKS POTENTIALLY INTERESTING, BUT YOU MAY NOT BE ABLE TO TELL THE -- I DON'T KNOW IF IT'S REGRESSION, MORE REGRESSION TO THE MEAN OR NOT BECAUSE IT MAY BE BECAUSE THE PEOPLE FROM THE DOMINICAN REPUBLIC WE HAVE A MUCH LARGER SAMPLE AND WE HAVE SO MANY FEWER PUERTO RICANS AND MEXICANS THIS MIGHT NOT HOLD UP IF WE HAD A LARGER SAMPLE. BUT ON THE FACE OF IT, IT'S KIND OF INTRIGUING THE WAY THE LINES CROSS AT ABOUT AGE 70. SO THIS MAKES US THINK ABOUT -- WE'VE BEEN ABLE TO GO THAT FAR WITH WHAT OUR TRADITIONAL APPROACHES HAVE GOTTEN US, SO OUR STANDARDIZED SURVEYS, OUR BLOOD PRESSURE, OUR BLOOD PRESSURE MEASUREMENTS, ET CETERA. BUT THEN WITH -- BUT THEN ONCE WE START THINKING ABOUT THIS, WE START THINKING ABOUT OTHER TYPES OF RESEARCH QUESTIONS THAT TAKE OTHER KINDS OF APPROACHES. ONE IS THINKING ABOUT TRIALS, WE HAVE THESE PEOPLE THAT HAVE BEEN TOLD THEY HAD HYPERTENSION THAT HAVE PROBLEMS, THEY SAY THEY STOP TAKING MEDICATION BECAUSE OF SIDE EFFECTS. SO WE NEED TO THINK ABOUT WHAT OTHER TYPE OF STUDIES WE CAN DO TO HAVE VERY FORMAL TRIALS FINDING OUT WHICH MEDICATIONS HAS THE BEST EFFECT FOR THE LOWEST SIDE EFFECT. AND SO THAT'S ONE OF THE RESEARCH QUESTIONS. CAN EFFICACY AND SIDE EFFECTS BE BALANCED TO IMPROVE MEDICATION ADHERENCE. AND THEN REALLY THINKING ABOUT THIS INTERESTING PATTERN WE SAW ABOUT LINES CROSSING, IS IT GENETICS, IS IT BEHAVIOR, IS IT CULTURE? AS I SAID, IT COULD BE JUST UNEQUAL SAMPLES BUT THOSE ARE INTERESTING THINGS THAT ARE INTRIGUING FOR MOVING US FORWARD. SO IN TERMS OF THINKING ABOUT THAT AND HOW DO YOU BEGIN TO GO FROM WHAT YOU'VE NORMALLY DONE TO THINKING ABOUT THINGS MORE IN THE WAY OF PRECISION HEALTH, YOU NEED TO BE THINKING, WELL, WE NEED MORE DATA SOURCES, SO, SURE, WE HAVE EVERYBODY'S ADDRESS AND SO WE CAN LOOK AT SOME BASIC ZIP CODE STUFF AND THAT'S BEING DONE IN A DISSERTATION WHERE WE'RE LOOKING AT BUILT FOOD ENVIRONMENTS, AND FRUIT AND VEGETABLE CONSUMPTION, BMI, BLOOD PRESSURE, HEALTH STATUS, ET CETERA, NEEDING TO KNOW ABOUT ENVIRONMENT BUT IN DIFFERENT WAYS, NOT JUST PHYSICAL AND BUILT ENVIRONMENT BUT THINKING ABOUT SOCIOECONOMIC, CULTURAL ENVIRONMENT, THINKING ABOUT WHAT MIGHT BE INTERESTING IN TERMS OF LOOKING AT ANCESTRY INFORMATIVE MARKERS MIGHT BE USEFUL NOT SO MUCH FROM AN INDIVIDUAL PERSPECTIVE BECAUSE WE REALLY DO NEED TO PAY ATTENTION TO WHAT ARE SOME OF THE DIFFERENCES IN THE ALLELES, BUT WHEN YOU'RE THINKING ABOUT THINGS AT THE POPULATION LEVEL IT CAN BE USEFUL TOE HAVE ANCESTRY-INFORMATIVE MARKERS. AND THEN EXTENDING IN THIS PARTICULAR POPULATION THE TYPE OF ANALYSES THAT WE HAD BEGUN TO DO IN PHYSICAL ACTIVITY IN A PRIOR PROJECT, NOW THE TYPE OF SOCIAL MEDIA MINING THAT WE'RE DOING IN -- THAT WE'RE DOING WITH OUR ALZHEIMER'S CAREGIVING, SO THINKING ABOUT SOME OF -- IT'S NOT JUST HAVING ALL THAT DATA. YOU NEED SOME DATA SCIENCE METHODS TO GO ALONG WITH THAT. AND SO DR. HOOD SHARED SOME OF THE TOOLS THAT THEY HAVE DEVELOPED PARTICULARLY FOR THE BIOLOGICAL SPECIMENS, BUT JUST THINKING ABOUT THE DIFFERENT TYPES OF STRATEGIES YOU NEED TO DO TO ACQUIRE THE DATA, TO DO YOUR PREPARATION AND DATA WRANGLING, WHAT TYPE OF ALGORITHMS DO YOU NEED TO APPLY, HOW DO THESE SOURCES GET INTEGRATED, HOW IS THE ANALYSIS. AND THEN IN BIG DATA, VISUALIZATION IS VERY IMPORTANT BECAUSE WE NEED VISUAL ANALYTICS THAT HELP US PINPOINT AREAS THAT MIGHT BE OF INTEREST. AND THEN OF COURSE A POINT THAT WAS MADE THIS MORNING BY DR. GRADY AND DR. HOOD, REALLY THINKING ABOUT THE IMPORTANCE OF INTERPRETATION. SO AS WE THINK ABOUT THESE NEW TYPES OF METHODS, DON'T FORGET THAT YOU ARE A DOMAIN EXPERT, AND YOU CAN HAVE SOME VERY SPURIOUS TYPES OF CORRELATION IN THESE TYPES OF THINGS, SO IT'S VERY IMPORTANT THAT YOU PUT ON THE HAT OF THE OF THE DOMAIN EXPERT AS YOU'RE DOING THESE KINDS OF THINGS. AND THEN LASTLY, AND I'M NOT GOING TO TOUCH ON IT MUCH, BUT AS WE GET INTO THESE TYPES OF THINGS WE REALLY HAVE TO BE PAYING ATTENTION TO THE BIOETHICS OF IT ALL BECAUSE WE COME UP WITH SOME UNIQUE CHALLENGES SUCH AS MODIFICATION OF DATA AND OTHER THINGS AND YOU'LL HEAR MORE ABOUT THAT FROM SOMEBODY WHO IS A REAL EXPERT IN THIS AREA IN A COUPLE OF DAYS SO I AM NOT GOING TO SAY MORE ABOUT ONE OF THE THINGS WHEN WE ARE TAKING THIS BACK, NOT ONLY TO THINKING ABOUT HOW WE WOULD EVOLVE OUR OWN NURSING SCIENTISTS BUT ALSO THINKING ABOUT THIS FROM THE PERSPECTIVE OF CURRICULUM, THESE ARE SOME OF THE THINGS THAT WE WANT TO BE THINKING ABOUT. MY TWO CENTS THAT I SAY -- I'M SURE THERE'S ONE OR MORE DEANS IN THE AUDIENCE, DATA SCIENCE IS NT A COURSE. IT IS SOMETHING THAT'S INTEGRATED THROUGH THE CURRICULUM. IT GOES INTO BIOETHICS. IT GOES INTO PHILOSOPHY OF SCIENCE. IT'S A WAY OF KNOWING THAT'S DIFFERENT FROM OUR TRADITIONAL WAY OF KNOWING THAT I KNOW THERE ARE SOME SCHOOLS THAT LOOK DOWN ON WHEN YOU DON'T PHYSICALLY COLLECT THE DATA FACE TO FACE IN FRONT OF A PATIENT, BUT THESE TYPES OF RESEARCH WHERE YOU'RE ACQUIRING DIFFERENT TYPES OF DATA SOURCES IS A NEW WAY OF KNOWING AND VALID AREA OF SCIENCE. WHERE WE'RE HOPING TO GO IS -- I SAY WE'RE NOT QUITE THERE YET. WE HAVE A COMPETITIVE GRANT WITH A SCORE OF 13 FOR A CENTER CALLED THIS, WHICH WE'VE NOT FINISHED, JUST IN TIME FOR, THE BASIC IDEA IN THIS IS TO COMBINE THINGS THAT WE KNOW ABOUT PRECISION APPROACHES BUT REALLY END UP FOCUSING ON SYMPTOM SELF MANAGEMENT, SPECIFICALLY IN -- THROUGH THE USE OF INFORMICS AND DATA SCIENCE METHODS, PRECISION AND CHARACTERIZATION OF GENOTYPE AND PHENOTYPE, THINKING ABOUT PRECISION AND IDENTIFICATION OF INTERVENTIONS TARGETS AND THEN PRECISION INTERVENTION DELIVERY. AND IN THIS ALTHOUGH THE NOTIONS ARE GENERAL AND OVER TIME WE WOULD LIKE TO DO IT IN DIFFERENT POPULATIONS, IN THIS PARTICULAR CENTER WE'RE EXPLICITLY FOCUSING ON LATINO BECAUSE THAT'S BEEN AN AREA OF EXPERTISE FOR US IN OUR PARTICULAR SCHOOLS. WE'RE WORKING ACROSS SYMPTOMS, PILOT INVESTIGATORS CHOSE FATIGUE, ONE OF FATIGUE IN HOME CARE, THE OTHER LOOKING AT FATIGUE IN PERSONS LIVING WITH HIV AND WILL USE THE NIH SYMPTOM SCIENCE MODEL AS A WAY OF INTEGRATING BIOMARKERS. INFORMICS AND DATA SCIENCE METHODS SUPPORT PRECISION APPROACHES FOR ADVANCING SCIENCE IN GENERAL. AS WE THINK ABOUT A NUMBER OF KEY AREAS OF THE NINR STRATEGIC PLAN, THINKING ABOUT SYMPTOM SCIENCE, THINKING ABOUT CAREGIVING RESEARCH AND SELF-MANAGEMENT AS WELL. I'M SURE -- WELL, PART OF THE END OF LIFE AND PALLIATIVE CARE HAS SYMPTOM SCIENCE IN IT, I'M SURE THERE'S OTHER WAYS I HAVEN'T THOUGHT ABOUT SINCE THAT AREA OF THE STRATEGIC PLAN WOULD TIE IN WELL WITH PRECISION APPROACHES, BUT IT'S REALLY ESSENTIAL THAT ALL NURSE SCIENTISTS ARE FAMILIAR WITH THE BASICS, AND SO IF WE HAVE A WAY TO GO TO FIGURING OUT WHAT THE BASICS ARE, BUT THAT ALSO THAT WE NEED TO BE PREPARING SPECIALISTS AT THE DOCTORAL LEVEL WHO WILL BE EXPERTS IN THESE VARIETY OF APPROACHES THAT YOU NEED TO REALLY USE PRECISION APPROACHES TO ADVANCE NURSING SCIENCE. AND SO WITH THAT, I WILL PUT UP MY ACKNOWLEDGMENT SLIDE AND TAKE THE FIRST QUESTION. I THINK I'M ALLOWED QUESTIONS. I DON'T KNOW WHERE THE TIME IS. YES, FIVE MINUTES. WE HAVE FIVE MINUTES FOR QUESTIONS. SO CAN I HAVE THE FIRST QUESTION? MARY, DO YOU HAVE A QUESTION FOR ME? IT'S BEEN A LONG TIME SINCE I'VE SPOKEN AND NOT GOTTEN A QUESTION. THERE'S ONE, GOOD. BE BRAVE. >> HI, I'M -- (INAUDIBLE) (OFF MICROPHONE, INAUDIBLE) >> YEAH, JUST REPEATING FOR THE VIDEOCAST, IT WASN'T SO MUCH A QUESTION BUT A COMPLIMENT ON THE VIDEOS, AND REITERATING IMPORTANCE OF WORKING WITH THE TARGET AUDIENCE ABOUT HOW YOU'RE GOING TO PRESENT DATA BACK TO THEM ENDS UP BEING REALLY IMPORTANT FOR THEIR COMPREHENSION. AND WE HAVE A QUESTION FROM DR. D. PLEASE. >> HOW MUCH BIOINFORMATICS -- (INAUDIBLE). >> YES, SO THE QUESTION IS HOW MUCH BIOINFORMATICS DO NURSES GET IN THEIR TRAINING. IT DEPENDS ON THE PARTICULAR -- IT DEPENDS ON THE PARTICULAR PROGRAM. SO THERE ARE A NUMBER OF TRAINING PROGRAMS, ONE AT THE UNIVERSITY OF PITTSBURGH, LED BY YVETTE CONLEY, THAT IS VERY STRONG ON THE GENOMICS COMPONENT, AND SO -- AND YOU CAN PROBABLY GET MORE DETAILS FROM THERESA -- DR. THERESA KOLAK IS A RECENT DOCTORAL GRADUATE FROM THERE AND NOW DOING A POSTDOC IN INFORMATICS WITH US AT COLUMBIA. AND SO IT REALLY DEPENDS ON THE PROGRAM. SO IN GENERAL, IF SOMEONE WAS NOT -- IF SOMEONE WAS NOT FOCUSING ON GENOMICS, THEY WOULDN'T GET MUCH IN THE AREA OF BIOINFORMATICS. THERE ARE GENERAL INFORMATICS COMPETENCIES THAT ARE PART OF THE NURSING DOCTORAL ESSENTIALS, AND SO DOCTORAL PROGRAMS 100% WILL HAVE SOME BASIC STUFF AND WILL HAVE SOME INFORMICS COMPETENCIES, IT JUST VARIES A LOT BY THE PROGRAM. ONE OF THE THINGS WE'RE TRYING TO FIGURE OUT, AND THIS IS TRUE IN GENOMICS AS IT'S TRUE IN INFORMATICS AND NOW TRUE IN DATA SCIENCE, WHAT IS IT THAT EVERY NURSE/SCIENTIST SHOULD KNOW VERSUS WHAT ARE WE GOING TO -- HOW ARE WE GOING TO TRAIN PEOPLE WHO WILL BE SPECIALISTS IN A PARTICULAR AREA AND WILL NEED A CERTAIN AMOUNT OF TRAINING IN TOOL USE AND PERHAPS -- BUT NOT TYPICALLY TOOL DEVELOPMENT, SO I STRONGLY BELIEVE SOMEBODY WHO IS A CARD-CARRYING BIOMEDICAL INFORMATICIAN AS WELL AS NURSE SCIENTIST THEY SHOULD BE GETTING A DOCTORATE NOT IN NURSING BUT IN OTHER FIELD AND APPLYING TOP NURSING PHENOMENA OF INTEREST. WE HAVE THREE LEVELS OF TRAINING AND DOCTORATE AND POST DOCTORATE LEVEL. I MIGHT BE A NURSE INTERESTED IN APPLYING TO NURSING SCIENTIST A DEGREE IN BIOINFORMATICS, COMPUTER SCIENCE, THESE DAYS DATA SCIENCE, WE'LL BE TRAINING PEOPLE WHO WILL BE NURSES, WHO WILL BE SPECIALISTS BUT NOT TOOL DEVELOPERS IN OUR DIFFERENT T32 TRAINING PROGRAMS, AND THEN WE'LL HAVE INTEGRATION OF SOME OF THESE CONCEPTS THROUGHOUT OUR CURRICULUM SO THAT EVERY NURSE/SCIENTIST WOULD KNOW SOME OF THE BASICS. I GUESS THE SHORT ANSWER IS IT VARIES BUT I THINK WE NEED THOSE THREE LEVELS IS HOW TO DO IT. I'D BE HAPPY TO -- OH, I GUESS -- ARE WE DONE, MARY? TIME FOR ONE MORE QUESTION? SHE SAYS NO MORE QUESTIONS. I'D BE HAPPY TO TALK TO YOU AT THE BREAK AT LUNCH. THANK YOU. [APPLAUSE] >> THANK YOU SO MUCH, SUE, FOR YOUR GREAT INSIGHT ON NURSINGTICS, RESEARC H, CONTEXT AS WE MOVE TO PRECISION APPROACHES. SORRY, I DIDN'T MEAN TO BE THE BAD GUY TO CUT OFF THAT LAST ONE THERE. I'M HAPPY WE'RE MOVING RIGHT ALONG AND WANT TO MAKE SURE WE'RE ON TIME WITH LUNCH AND THINGS SO NOTHING'S TOO LATE. BUT I'M VERY HAPPY AND OUR SPEAKERS ARE ANXIOUSLY WAITING, I'M HAPPY TO INTRODUCE OUR NEXT SPEAKER DR. JOSE ORDOVAS FROM THE USDA HUMAN NUTRITION RESEARCH CENTER ON AGING AT TUFTS UNIVERSITY IN BOSTON. HIS RESEARCH FOCUSES ON THE GENETIC FACTORS RELATED TO CARDIOVASCULAR DISEASE AND OBESITY AND THEIR INTERACTION WITH THE ENVIRONMENT AND BEHAVIORAL FACTORS WITH SPECIAL EMPHASIS ON DIET. HE HAS PUBLISHED OVER 700 SCIENTIFIC ARTICLES AND HAS WRITTEN BOOKS, A WORLD EXPERT ON GENE-DIET INTERACTION RELATED TO CARDIOVASCULAR DISEASE TRAITS AND RECEIVED NUMEROUS AWARDS. HE WILL BE PRESENTING ON NEUTRIGENOMICS AND PRECISION HEALTH. LET'S GIVE A BIG WELCOME TO DR. ORDOVAS. >> THANK YOU, MARY. I THINK THE EXPECTATION IS TOO HIGH. INDEED, IT'S A REAL PLEASURE TO BE HERE. IT'S A REAL PLEASURE TO SEE THE ROOM FULL, CONSIDERING THAT PROBABLY THIS IS NOT THE BEST PLACE TO BE AT THIS TIME OF THE YEAR, RIGHT? I WAS SURPRISED LAST NIGHT. THE WEATHER, I MEAN. YEAH, I AM GOING TO FOCUS FOR THE NEXT FEW MINUTES ON THE NUTRITION HUB OF THE DISCUSSION, WHICH CAME OUT MUST BE TIMES ALREADY, AS MARY WAS SAYING THE OBJECTIVES FOR THE LAST, OH, SINCE THE EARLY '80s HAVE BEEN PRECISELY TO WORK ON THE GENETICS OF CHRONIC DISEASES. OUR INSTITUTION IS DEDICATED TO AGING, IT'S PART OF THE USDA AND ALSO TUFTS. WHAT WE'VE BEEN DOING IS INTEGRATE PRECISELY THE GENETICS, THE DIET, AND SO ON, IN ORDER TO SLOWLY BUT HOPEFULLY SURELY GET TO THAT GOAL, THAT BRINGS MOST OF US HERE, WHICH IS THE PERSONALIZED NUTRITION, EXCUSE ME, PERSONALIZE THE HEALTH. WE'VE BEEN DOING SOMETHING ALSO IN PHARMACOGENETICS BUT THAT'S NOT OUR MAJOR FOCUS. AS I SAY, FROM MY PERSPECTIVE, DIET IS OF THE HUB. WE'RE LOOKING FOR THAT PERSONAL HEALTH, OBVIOUSLY IT'S VERY COMPLEX. AND NUTRITION PLAYS A ROLE. NUTRITION IS JUST BEYOND PERSONAL HEALTH, PART OF OUR CULTURAL IDENTITY, PART OF SOCIAL INTERACTIONS, AND THE LAST MAYBE 20 OR 30 YEARS WE HAVE BEEN ABLE TO MOVE FORWARD IN TERMS OF HOW NUTRITION RELATES TO THAT PERSONAL HEALTH. THANKS TO A NUMBER OF TECHNOLOGIES, THAT WERE MENTIONED ALREADY, EARLIER THIS MORNING, I MEAN WE PRESENTED SAME ESSENCE BUT WITH DIFFERENT TYPE OF ART. SO THIS IS WHAT WE HAVE SEEN WITH LARRY HOOD, THIS GENOMICS, TRANSCRIPTOMICS, METABOLOMICS, PROTEOME IS, NOT ONLY IN TERMS OF INDIVIDUAL BUT ALSO IN TERMS OF THE ENVIRONMENT BECAUSE OBVIOUSLY WE HAVE TO PAY ATTENTION, ALSO THE GENOMICS OF THE FOODS THAT WE PUT IN OUR MOUTH. SO THE NECKLACE ENDS IN THAT CENTRAL PIECE, THE BIG DATA THAT BRINGS US HERE. WE SHOULD NOT FORGET WE'RE NOT BY ANY MEANS STATIC AND ALL THESE THINGS ARE HAPPENING IN THE CONTEXT OF OUR RHYTHM, BIOLOGICAL RHYTHM, CIRCADIAN RHYTHM, SO ON AND SO FORTH, TAKING A POSITION IN OUR RESEARCH TO LOOK AT BIOLOGICAL RHYTHMS BECAUSE THEY PLAY A ROLE IN HEALTH. OKAY. SO NEXT I'M GOING TO GO OVER THE GENETIC COMPONENT OF ALL THIS, AND JUST BRING IN SOME HISTORY. AS I SAY, WE'VE BEEN DOING THIS KIND OF RESEARCH SINCE THE '80s, OBVIOUSLY WE HAVE IN FRONT OF US A TOTAL MAZE, AND THE TECHNOLOGY IS THAT WE HAD A AVAILABLE AT THAT TIME, THEY WERE NOT REALLY STATE OF THE ART. WELL, THEY WERE STATE OF THE ART THEN BUT IT WAS A LAUGHING MATTER TODAY. AND WE HAVE THE PIECE, THE TECHNOLOGY WE USED TO STUDY THE FEW POLYMORPHISMS WE COULD STUDY IN THE GENOME. THEN THE REVOLUTION OF THE PCR AND WE WERE ABLE TO THINK ABOUT DOING GENETICS IN LARGE POPULATIONS AND ALSO IN LARGE NUMBER OF VARIANTS. AND OBVIOUSLY THAT REALLY MATERIALIZED LATER ON. AT THAT POINT WITH LIMITED TECHNOLOGY, YOU'VE SEEN THIS CARTOON WITH PARKING LOT, LOOKING FOR THE KEYS, BUT IN THIS CASE THIS GUY IS LOOKING FOR SOMETHING, THE POLICEMAN ASKS WHAT YOU'RE LOOKING FOR. QUARTER. DID YOU LOSE IT HERE? NO, BUT THIS IS WHERE THE LIGHT IS. I'VE LOST THE QUARTER A FEW BLOCKS BACK. BUT AGAIN, WE WERE TOTALLY LOST. FINALLY, WITH THE COMING OF THE CENTURY WE'RE ABLE TO HAVE A ROAD MAP OF OUR GENOME AND THE DEVELOPMENT OF THE TECHNOLOGIES THAT YOU KNOW. WE HAVE THE GWAS, POPULATING IN TERMS OF LOCUS, OR LOCI, WHERE DIFFERENT PHENOTYPES WERE ASSOCIATED AND WITH ALL THAT CAME THE FACT THAT OVER 200 -- I DON'T REMEMBER HOW MANY MILLION DOLLARS FOR THE FIRST GENOME BUT KNOW FOR $2000 AS WAS MENTIONED BEFORE, AND LARRY WAS TALKING ABOUT $100, IN THE NEAR FUTURE BUT IF YOU TALK TO THE PEOPLE IN THE GENOME INSTITUTE THEY SAY IT WILL BE $10, YOU KNOW. WE'LL SEE. DIFFERENT OPINIONS. IT DEPENDS ON THE ECONOMY OF CHINA I GUESS. WE HAVE NOW OUR GENOME TOTALLY FILLED UP WITH DIFFERENT PHENOTYPES OF EVERYTHING THAT WE CAN MEASURE AND GENETIC COMPONENT. AND THIS IS THE REFLECTION OF THE FIRST. SO THANKS TO ALL THIS COMBINATION WHAT WE HAVE IS WE THOSE GENE SeqS, HOPEFULLY IN THE RIGHT PLACE, -- GENE CHIPS, AND IN FACT WE HAVE SO MANY QUARTER WE DON'T KNOW WHAT TO DO WITH THEM. THAT'S PRECISELY WHERE THE BIG DATA COMES, DURING THIS PROCESS NOT ONLY THE TECHNOLOGY EVOLVED BUT ALSO THE WAY WE CONDUCT THE STUDIES, IN PART BECAUSE OF THE TECHNOLOGY, IN PART BECAUSE OF SCIENTIFIC MENTALITY. WHEN WE STARTED IN THE '80s, WELL, THIS IS THE KIND OF STUDIES THAT WE WERE ABLE TO DO. 140 PEOPLE, IT TOOK FOREVER, YOU WERE EXPOSED TO LARGE AMOUNTS OF RADIOACTIVITY IN THE PROCESS. THAT LASTED FOR A WHILE. THE TURNING POINT PRECISELY THE CHIPS, DNA TECHNOLOGY, ABLE TO STARTING LOOKING AT SERIOUS NUMBERS, 40,000, 100,000. EVEN THAT WE DON'T HAVE ENOUGH STATISTICAL POWER TO DEAL WITH COMPLEX DECISIONS. OF COURSE WE CAN DO IT WITH MONOGENIC DISEASES BUT NOT WITH THE KIND OF GOALS, OBJECTIVES WE HAVE, GLOBAL HEALTH. AND THEN WE HAVE TO LOOK FOR SOMETHING MORE SERIOUS IN TERMS OF NUMBERS LIKE THE ONE MILLION COHORT, THAT IS HOPEFULLY CREATED HERE. ALL THE THE EFFORTS IN EUROPE, FOR EXAMPLE THE U.K. BIOBANK. NOW THE PAPERS CONTAIN MORE AUTHORS THAN AT THE BEGINNING WE HAD SUBJECTS, PART OF THIS PEOPLE FROM THE DIFFERENT AREAS OF KNOWLEDGE THAT BEFORE WERE COMPETING BUT NOW WE KNOW WE CANNOT COMPETE. WE HAVE TO JOIN EFFORTS. EXAMPLES OF WHAT WE CAN DO NOWADAYS, WE HAVE TO EDUCATE THE NUMBERS. (INDISCERNIBLE) SO WE CAN TALK. INDEED WHENEVER WE KEEP READING, WE USED TO READ IN THE NEWSPAPERS, OH, SUCH AND SUCH GROUP, USUALLY IN HARVARD, FOUND THE GENE FOR OBESITY, THAT IS OBVIOUSLY NOT THE CASE. FOR THIS CHRONIC DISEASE, AGE-RELATED DISEASES, WE DON'T HAVE A GENE. WE HAVE MULTIPLE GENES. AND THIS IS WHAT WE HAVE BEEN HARVESTING FROM THE GENOME FOR THE LAST 30 YEARS AND MUCH MORE SUCCESS IN THE LAST 10 YEARS AS YOU HAVE SEEN. THIS IS A MAP OF THE OBESITY GENES THAT ARE KNOWN. THE QUESTION IS, WELL, IF YOU HAVE THIS, WHATEVER, THIS GENE OR THIS GENE OR THIS GENE, ARE YOU GOING TO BE OBESE? A BALANCE IN YOUR GENOME, IT DEPENDS ON HOW MANY GENES YOU THAT PREDISPOSE YOU TO OBESITY OR HOW MANY GENES YOU HAVE THAT PROTECT YOU FROM OBESITY. AND AT THE END OF THE DAY, FROM THE GENETIC POINT OF VIEW, THE BALANCE IS GOING TO DEFINE YOUR PREDISPOSITION TO OBESITY. LET ME BEFORE GOING OR MOVING FORWARD IN TERMS OF ASSOCIATION AND INTERACTION, JUST IN CASE ANY OF YOU ARE NOT FAMILIAR WITH GENETIC STUDIES, LET'S GO OVER THE MOST SIMPLE SCENARIO, THE ONE THAT'S BEEN USED FOR THE GENOME WIDE ASSOCIATION STUDIES, OR ASSOCIATION STUDIES THAT WE'VE BEEN USING OR DOING FOR MANY YEARS. FOR A GENETICIST THIS WILL BE THE FRAME OF THE WINDOW LOOKING AT THE GENOME. AND THEN YOU HAVE POLYMORPHISM IN WHICH YOU MAY HAVE THE NORMAL HOMOZYGOTES AND THE HETEROZYGOTES, THE ONES THAT CARRY THE LESS COMMONALITY. AND I MEAN THESE ALLELES CAN SAY, OKAY, ARD AACCORDING TO THE STUDY IF THE HAVE YOU G ALLELE YOU'RE GOING TO HAVE HIGHER CHOLESTEROL OR LOWER LDS IN THE EXAMPLE MENTIONED BEFORE, MORE OBESITY OR MORE BMI, WHATEVER. THAT'S SUCCESSFUL. THIS IS A GENE THAT CAN BE USED AS A PREDICTOR FOR OBESITY. ON THE OTHER HAND, IF A GENETICIST FINDS SOMETHING LIKE THIS, CARRIES OF THE NORMAL GENOTYPE AND CARRIERS OF G ALLELE, POLYMORPHISM, THEY DON'T HAVE ANY DIFFERENCE, THIS GENE IS USELESS, NOT GOING TO BE INFORMATIVE FROM THE POINT OF VIEW OF THE OBESITY. SO THAT'S APPARENTLY THE END OF THE STORY FOR SOME. GOING BACK TO THAT KIND OF STORY, THIS IS WHAT YOU HAVE IN TERMS OF OBESITY, THOSE ARE STUDIES THAT THOSE ARE DATA FROM SOME STUDIES, THE ONES WE CONDUCTED, IN SALT LAKE CITY AND MINNEAPOLIS. WHAT WE DID WAS TO BUILD A GENETIC RISK SCORE IN WHICH WE LOOK AT PEOPLE WHICH OUT OF THIS NUMBER OF GENES THAT ARE MARKERS OF OBESITY THAT YOU FOUND IN TWO SLIDES AGO, IF PEOPLE DON'T HAVE THE VARIANT ALLELE THAT PREDISPOSED YOU TO OBESITY YOU ARE GIVEN ON A SCORE OF ZERO, IF YOU'RE A HETEROZYGOUS SCORE OF 1 AND HOMOZYGOUS FOR NORMAL ALLELE GIVEN A SCORE OF 2. 63 VARIANTS, FROM 0-126. THERE IS NOBODY, CONSIDERING THESE ARE COMMON VARIANTS, RISK NOBODY WAS A RISK SCORE OF 0, NOBODY WITH A RISK SCORE OF 126. NOBODY IS THAT UNLUCKY. THESE ARE THE PEOPLE WITH A LOW RISK SCORE, MEANING BETWEEN 45 OR 66 OF THESE VARIANTS IN YOUR GENOME. THIS IS THE ENTIRE MEDIATE AND THIS IS THE UPPER TERTILE. AS YOU HAVE MORE GENES, YOU HAVE A DIFFERENT PHENOTYPE, SO THIS WILL BE IN THE FIRST TERTILE, THE SECOND AND THIRD TERTILE. THE MEANING IS IF YOU'RE BORN WITH THIS GENETIC LOAD YOU'RE GOING TO DEVELOP THIS OBESITY. THE ANSWER WILL COME IN A FEW SLIDES. THE ANSWER IS NO. OBESITY IS NOT ONLY GENETIC, IT'S ALSO ENVIRONMENTAL, GENETIC 30, ENVIRONMENT WAS 60%. THAT'S WHERE THE GENE/DIET INTERACTIONS ENTER INTO THE GAME. WE HAVE SEEN THIS BEFORE, THAT WAS THE PLAIN ASSOCIATION, WITHOUT TAKING INTO CONSIDERATION ANYTHING AROUND THE INDIVIDUAL, JUST THE GENES AND THE RESULTS, PHENOTYPES. BUT WHAT HAPPENS IF PEOPLE ARE EXPOSED TO DIFFERENT WE HAVE A SIMPLE SITUATION, REMEMBER THIS POLYMORPHISM WAS ASSOCIATED WITH OBESITY. IS THAT TRUE FOR EVERYBODY? THESE PEOPLE ARE TAKING LET'S SAY DIET 1, ONE OF THESE PROVEN DIETS THAT ARE RECOMMENDED BY DIETARY GUIDELINES, AND SEE WHAT HAPPENS. YOU CAN HAVE THE NORMAL GENOTYPE OR YOU CAN HAVE THE LESS COMMON GENOTYPE THAT WAS ASSOCIATED IN THEORY WITH PHENOTYPE, LET'S SAY HIGHER LDL CHOLESTEROL LEVELS, NO DIFFERENCE BETWEEN THE TWO GROUPS. AND THIS IS BECAUSE UNDER THAT SPECIFIC ENVIRONMENTAL CONDITION, YOU DON'T TRIGGER THE EFFECT OF THE GENOTYPE. SO YOU CAN HAVE THE PREDISPOSITION BUT IT'S NOT EXPRESSED. HOWEVER, IF YOU ARE CONSUMING DIET 2, MAYBE HIGHER SATURATED FAT, THEN THAT'S WHERE THINGS ARE REALLY TRIGGERED. AND THEN YOU CAN SEE THE LARGE DIFFERENCE BETWEEN THOSE THAT ARE NOT PRE-DISPOSED AND THOSE THAT ARE PRE-DISPOSED. IN FACT, NOT ONLY THEY ARE PRE-DISPOSED, THEY EXPRESS THE PHENOTYPE. WHY? IT'S BECAUSE THEY ARE IN THE WRONG ENVIRONMENT, AT LEAST FOR THE GENOME. HERE WE HAVE SOMETHING THAT IS TELLING US THAT IF YOU ARE JUST DOING PURE GENETICS, YOU CAN BE FOOLED AND CAN JUST THROW TO THE GARBAGE INFORMATION THAT IS VERY IMPORTANT. WHY? BECAUSE YOU MAY HAVE AN INTERACTION THAT IS ACROSS, WELL IN FACT THAT SHOWS HERE, THIS INFORMATION THAT YOU SEE IN THE PREVIOUS FRAME. TAKEN THE DATA AS CONTINUOUS. SO HERE WHAT YOU SEE IS THAT UNDER THESE CONDITIONS, DIET NUMBER, HIGHER LEVELS SAY OF CHOLESTEROL THAN THESE OTHER PEOPLE THAT ARE SUPPOSED -- MEANING WE DON'T KNOW THAT THAT COULD HAPPEN IF WE WERE LOOKING JUST AT THIS DATA, WITHOUT TAKING INTO CONSIDERATION THE ENVIRONMENT, IN THIS CASE DIET. BUT IF YOU HAVE PEOPLE CONSUMING DIET 2, THE EFFECT CAN BE TOTALLY REVERSED, AND WE'RE GOING TO SEE AN EXAMPLE OF THIS, JUST FROM THE POINT OF VIEW LIPID METABOLISM, YOU'LL SEE THE ILLUSTRATION MUCH BETTER. SO WHAT WE HAVE IS THAT OUR GENES ARE NOT SOMETHING THAT JUST LIKE A LIGHT THROUGH A WINDOW THAT YOU HAVE IN A STRAIGHT LINE. IT JUST REFLECTS, ACCORDING TO THE SITUATION, IN YOUR LIFE. SO IT'S LIKE THE LIGHT DIFFRACTING IN A PRISM. SO WHAT WE HAVE IS SITUATIONS IN WHICH YOU MAY HAVE TOTALLY OPPOSITE EFFECTS, AS I MENTIONED BEFORE, DEPENDING ON THE ENVIRONMENTAL FACTORS, FOR A GENETIC VARIANT. AND I'M NOT GOING TO STOP ON THIS BECAUSE I WILL BE THE TOPIC OF THE NEXT SLIDE IN MUCH MORE DETAIL. AND THEN THE GENETIC MAKEUP, AND THIS IS A GENE/DIET THAT'S WELL KNOWN, IT MAY DEPEND ON NUTRITIONAL NEEDS, MAY DEPEND ON YOUR GENETIC MAKEUP. LET'S SAY FOR EXAMPLE THAT MTHFR, PEOPLE WITH THIS NEED MUCH MORE FOLIC ACID THAN WITHOUT THIS MUTATION. LET'S FOCUS ON THIS AND GO BACK TO THE LIPIDS. THIS IS -- THAT WAS SOMETHING THAT WE PUBLISHED QUITE A FEW YEARS AGO, AND THAT WAS THE CLASSICAL BOOK EXAMPLE OF GENE/DIET INTERACTION, THIS IS IN THE FRAMINGHAM POPULATION, FRAMINGHAM STUDY, AND WHAT WE HAVE HERE IS A POLYMORPHISM IN THE LIPC GENE, HEPATIC LIPASE, VERY IMPORTANT. THIS MUTATION IS MINUS 514CT IN THE PROMOTER REGION, MEANING THE REGION OF THE GENE THAT DEFINES HOW THE EXPRESSION OF THE GENE IS REGULATED. AND WE CALL IT FUNCTIONAL. SO WE KNOW VERY WELL THE SIDE EFFECTS OF LDL THAT MAKES CARE OF MAKING ARTERIES DIRTY, AND THE HCL THAT HAS TO DO THE CLEANING. IN ADDITION TO TRADITIONAL LDL AND HDL MEASURE THAT PEOPLE ARE USING IN THE CLINIC, THERE IS ALSO THE RATIO, WHAT IS BEING USE IS QUITE INFORMATIVE IN TERMS OF FUTURE CARDIOVASCULAR RISK. SO IF WE HAVE A GOOD BALANCE BETWEEN THE HDL AND HDL WE'RE IN THE GREEN ZONE. IF WE HAVE ELEVATION OF LDL AND HDL CANNOT KEEP UP, WE'RE IN THE YELLOW REGION. LDL AND HDL GOES DOWN WE ENTER IN THE RED AREA OF HIGH RISK OF CARDIOVASCULAR DISEASE. OBVIOUSLY WE CAN MAKE THESE MUCH MORE REFINED, AND IF WE GO TO WHAT YOU SAW BEFORE, THE LDL SIZE OR HDL SIZE, THAT ARE PHENOTYPES EVEN CLOSER TO THE RISK, BUT FOR THE TIME BEING LET'S JUST LOOK AT THE TRADITIONAL VALUES THAT WE HAVE BEEN LOOKING FOR MANY YEARS. OKAY. SO THIS IS AS I MENTIONED DATA FROM THE FRAMINGHAM STUDY, AND HERE THIS IS WHAT EACH ONE OF THESE DOTS REPRESENT, ONE INDIVIDUAL IN FRAMINGHAM, AND THIS IS WHAT HAPPENS WHEN CC INDIVIDUALS, CC INDIVIDUALS ARE THE SO-CALLED NORMALS, IF WE GO MENTIONED, PUT FORWARD EARLIER ABOUT WHAT HAPPENED IN OTHER ETHNIC GROUPS, THERE ARE MANY THINGS THAT HAPPEN IN OTHERETHNIC GROUPS AND WE HAVE TO STUDY IN MORE DETAIL. SO ANYWAY, CCs, WHEN PEOPLE ARE CONSUMING LOW FAT OR HIGH FAT DIET, IF YOU ARE A CC, LIPID METABOLISM IS ABLE TO MAINTAIN A VERY GOOD HOMEOSTASIS. WHAT HAPPENS WHEN YOU INCREASE THE LEVELS OF FAT IN THE DIET? SATURATED FAT ESPECIALLY. YOUR LDL CHOLESTEROL GOES UP. HOW YOUR METABOLISM CAN KEEP UP WITH WITHOUT INCREASING LDL, DOING THIS, INCREASING HDL, SO HDL CONSTANT. SO PEOPLE THAT HAVE THE CC, THEY HAVE VARIOUS MARKED HOMEOSTASIS, THINK EAT HAPPILY, EITHER LOW FAT DIET OR HIGH FAT DIET, AT LEAST FROM THE POINT OF VIEW OF CARDIOVASCULAR RISK. OTHER THINGS MAY HAPPEN. WHEN YOU CONSUME HIGH SATURATED FAT. WHAT HAPPENED TO THE CTs? THE ONES THAT ARE HETEROZYGOUS? THEY ARE IN THE MIDDLE, DON'T HAVE TOO MUCH EFFECT, MEANING THAT, WELL, IF THEY CONSUME A HIGH SATURATED FAT DIET THE LDL IS GOING TO GO UP AND THE HDL TRIES TO FOLLOW BUT IT CAN NOT MAKE IT SO THEY WILL GO INTO THE YELLOW AREA. AND WHAT HAPPENS TO THE TTs? THOSE ARE HOMOZYGOUS FOR POLYMORPHISM, THEY WERE DOING VERY BAD. SEE THE CCs? LDL, HDL AND LOW FAT CONDITIONS. HERE LDL, HDL AND HIGH FAT CONDITIONS, RATIO IS THE SAME. LOOK WHAT HAPPENS TO THE PEOPLE WITH TT. AND THE LOW FAT CONDITIONS, LDH AND HDL ALMOST PERFECT RATIO OF ONE. IF THESE PEOPLE MOVE TO A HIGH-FAT DIET, HDL GOES DOWN, LDL GOES UP, THEY GO FROM GREEN TO REALLY RED AND TO A VERY HIGH RISK OF CARDIOVASCULAR DISEASE. THEN THIS IS WHAT WE ARE TALKING ABOUT IN TERMS OF PERSONALIZED NUTRITION, TO IDENTIFY WHO CAN BENEFIT OF WHAT. LET'S REMEMBER THE WOMEN'S HEALTH INITIATIVE IN WHICH PRACTICALLY NOTHING WORKED, OF THE INTERVENTIONS. WELL, USING THE FAT IN THE DIET, THEY DIDN'T DO ANY GOOD. IT'S BECAUSE EVERYBODY WAS PUT IN THE SAME PILE AND IF YOU HAVE MORE OF THESE PEOPLE, AS IS THE CASE IN THE GENERAL POPULATION, WHEN YOU DO STATISTICS OF EVERYBODY, THIS IS GOING TO BE DRIVING THE RESULTS BECAUSE YOU HAVE LESS OF THESE PEOPLE SO YOU ARE NOT GOING TO SEE THAT DIETARY FAT IS HARMFUL BECAUSE THESE RESULTS GET BURIED BY TAKING EVERYBODY IN THE SAME POT. SO IN THE FUTURE, THE IDEA IS WE'LL BE ABLE TO IDENTIFY THESE PEOPLE AND, YES, THESE PEOPLE WILL REALLY BENEFIT WITH A LOW-FAT DIET, VERSUS THESE PEOPLE IT WILL BE PRACTICALLY THE SAME THAT THEY FOLLOW ONE DIET OR ANOTHER. ALL RIGHT. SO WHAT HAPPENS WHEN YOU FOLLOW THE PUBLIC HEALTH RECOMMENDATIONS, THE GUIDELINES? NOTHING. EVERYBODY'S IN THE MIDDLE. YOU CANNOT JUST SAY PUBLIC HEALTH VERSUS PERSONAL NUTRITION. NO, FOR MOST PEOPLE DIETARY GUIDELINES DON'T WORK. THE EXTREMES OF BEHAVIOR, EXTREMES OF GENETICS WHEN YOU REALLY NEED THE PUSH OF THE PERSONALIZED NUTRITION, BUT I MEAN IF YOU JUST FOLLOW THE COMMON SENSE AND PROVEN DIET, PRACTICALLY DOESN'T MATTER TOO MUCH YOUR GENETIC MAKEUP, FOR MOST OF THE POPULATION. NOW, REMEMBER THAT WE WERE LOOKING AT THE FEWER SLIDES AGO TO THE GENETIC RISK SCORE FOR OBESITY. SO PEOPLE THAT HAVE THE FIRST TERTILE OR SECOND OR THIRD TERTILE HAD DIFFERENT PREDISPOSITION. CAN YOU FIGHT YOUR GENETIC PREDISPOSITION FOR OBESITY? THE ANSWER IS YES. THESE ARE THE SAME PEOPLE, SAME DATA, GENETIC SCORE VERY HIGH, VERY LOW GENETIC RISK SCORE, SO IF YOU ARE IN THE LOW RISK SCORE PRACTICALLY ANY DIET, YOU CAN EAT ANY DIET, DOESN'T MAKE ANY DIFFERENCE. IF YOU HAVE HIGH GENETIC RISK SCORE FOR OBESITY, THEN ONLY IF YOU HAVE THE HIGH FAT DIET OR HIGH SATURATED FAT DIET IT'S GOING TO TRIGGER YOUR GENETIC PREDISPOSITION AS YOU CAN SEE BASED ON THESE DATA. BUT EVEN IF YOU HAVE A HIGH GENETIC RISK SCORE BUT YOU HAVE A PROVEN DIET, YOU CAN FIGHT OBESITY AND YOU CAN SEE HOW DIFFERENT IS YOUR BMI. THESE PEOPLE HAVE THE SAME GENETIC RISK SCORE. THEY FOLLOW DIFFERENT DIETS. AND THEN HERE YOU HAVE 29 HERE, YOU HAVE 34 OR 35 OF BMI. IT IS TRUE YOU CANNOT -- IF YOU HAVE SUCH HIGH GENETIC RISK SCORE IT WILL BE HARD TO GO TO 24 OR 25 BUT YOU ARE ABLE TO REMAIN IN THE AREA WITH NORMAL DIETARY INTERVENTION, IN THE AREA OF OVERWEIGHT AND NOT GET INTO THE AREA OF OBESITY WHICH IS IMPORTANT, RIGHT? NOW, THIS IS SOMETHING THAT I LIKE, EVEN THOUGH THE BIOLOGY MAY NOT BE REPRESENTED HERE. IT'S JUST FOR YOU TO REALIZE, YOU ALREADY KNOW, THAT'S WHY YOU'RE HERE, BUT THE IMPORTANCE OF EDUCATION. THERE'S BEEN MENTION ALREADY A FEW TIMES ONE WAY OR ANOTHER. IN TERMS OF THE GENES THAT PREDISPOSE PEOPLE TO OBESITY, THE FTO IS THE ONE WITH THE STRONGEST EFFECT IN THE GENERAL POPULATION. SO IF YOU HAVE THESE THREE GENOTYPES AND FTO YOU DON'T HAVE HIGH RISK. IF YOU ARE HETEROZYGOUS YOU HAVE MORE RISK, AND IF YOU'RE AA, POLYMORPHISM, HIGH RISK FOR OBESITY, JUST ISOLATING ONE OF THE MANY GENES THAT PREDISPOSE EXAMPLE TO SEE HOW IMPORTANT IS THE ENVIRONMENT. IN THIS CASE THE CULTURAL ENVIRONMENT. WHAT'S THE DIFFERENCE BETWEEN THESE PEOPLE AND THESE PEOPLE? THESE PEOPLE HAVE THE SAME GENETIC PREDISPOSITION IN TERMS OF FTO. THEY ARE RED AND THEY ARE GREEN. THE DIFFERENCE IS THIS. EDUCATION. ALL RIGHT? SO IF YOU ARE -- IF YOU HAVE MORE EDUCATION, THAT SOMETIMES IS ALSO DIFFICULT TO DIFFERENTIATE FROM SOCIOECONOMIC STATUS, FIRST YOUR LEVEL OF OBESITY IS MUCH LOWER, BMI IS LOWER IN GENERAL. BUT ALSO YOU ARE ABLE TO FIGHT YOUR GENETIC PREDISPOSITION. WHY? BECAUSE BY THAT KNOWLEDGE, BY THAT EXPOSURE, THAT EDUCATION, YOU TEND TO HAVE PRECISELY THAT PROVEN DIET, YOU KNOW THAT YOU ACTIVITY, IF YOU'RE HIGHLY EDUCATED YOU HAVE ACCESS PROBABLY TO BETTER FOODS OR HEALTHIER FOODS, THOUGH THIS IS A MATTER OF DISCUSSION. THE CASE IS THAT OVERALL YOUR OBESITY IS LOWER AND YOU'RE ABLE TO TOTALLY ELIMINATE THE PREDISPOSITION TO OBESITY THAT YOU MAY HAVE BECAUSE OF YOUR GENES, GENETIC RISK SCORE, WHATEVER. THEREFORE IT IS IMPORTANT FOR PEOPLE TO EDUCATE, NOT ONLY IN TERMS OF PEOPLE AT RISK BUT PEOPLE LIKE YOU THAT ARE THE ONES THAT ARE GOING TO EDUCATE THE POPULATION AT LARGE. SO THIS IS VERY INTERESTING. OBVIOUSLY THESE PEOPLE KNOW FTO GENE OR ANY OTHER GENE, IT'S JUST THAT NATURALLY THEY ARE ABLE TO FIGHT OBESITY BY THEIR BEHAVIOR, WHICH COMES AGAIN TO THE MOST TRAIT WHEN IT COMES TO OBESITY OR ANY OTHER CHRONIC DISEASE, GENETICS IS NOT BY ANY MEANS EVERYTHING, BUT IT'S JUST ONE OF THE COMPONENTS THAT IS GOING TO DRIVE THE PHENOTYPE. ANYWAY, SO THE BOTTOM LINE IS THAT WHEN IT COMES TO RESEARCH, SCIENTISTS IN THAT CONNECTION BETWEEN GENETICS AND NUTRITION, BETWEEN THE ROCK AND A HARD PLACE, BECAUSE IF YOU ARE LOOKING AT DIET JUST PURE DIETARY DATA, YOU ARE NOT EXAMINING, AT LEAST IT HAS NOT BEEN DONE, UNTIL THE PERSON, GENETIC VARIATION, AND THE PEOPLE LOOKING AT GENETIC POLYMORPHISMS USUALLY DON'T LOOK AT DIETARY FACTORS AND THAT'S WHY YOU HAVE ALL THE CONFOUNDERS IN THE LITERATURE. AND TALKING ABOUT PRECISION MEDICINE, IF EVERYBODY KNOWS A CLASSICAL EXAMPLE OF NON-PRECISION MEDICINE IS PRECISELY COLLECTING DIETED BASED ON QUESTIONNAIRES, MEMORY, CHEATING, BECAUSE I KNOW WHAT IS GOING FOR ME BUT I'M NOT GOING TO SAY -- [LAUGHTER] NO, IT'S TRUE. WHEN IT COMES TO REPORTING, I AS AS YOU KNOW, WOMEN REPORT ACCURATELY WHAT THEY EAT WITH THE EXCEPTION OF CHEATING BECAUSE YOU HAVE GOOD MEMORY. BUT WHEN IT COMES O MALES, WE DON'T KNOW -- NO, REALLY, WE DON'T KNOW WHAT WE EAT. THERE ARE DIFFERENT -- I DON'T HAVE TO TELL YOU BECAUSE MANY OF YOU ARE REALLY MUCH MORE EXPERT THAN I AM IN COLLECTING THIS INFORMATION BUT I MEAN, YEAH, WE HAVE THE FOOD FREQUENCY QUESTIONNAIRE, DIET HISTORIES, EACH ONE OF THEM HAS BENEFITS AND ALSO MANY PROBLEMS. WE REALLY HAVE TO IMPROVE THAT BECAUSE IN ORDER TO REACH THAT GOAL OF PERSONALIZED MEDICINE, PERSONALIZED NUTRITION, WE NEED TO COLLECT THAT INFORMATION. WE NEED TO COLLECT BIG DATA. AND WHEN IT COMES TO GENETIC INFORMATION, WE'RE ABLE TO DO THAT. AND WE ARE ABLE TO DO THAT WITH PRECISION. WHEN WE BRING DIFFERENT COHORTS LIKE HERE YOU HAVE SOME EXAMPLES, LIKE ARIC, GOLDEN, CHS, FRAMINGHAM, SO MANY COHORTS PARTICIPATE IN THE META ANALYSIS WE DO NOW, WE CAN MERIT GENETIC DATA BUT WE'RE HAVING A HARD TIME MERITING THE NUTRITIONAL DATA WHICH IS MENTION IF WE WANT TO LOOK AT THIS GENE ENVIRONMENT INTERACTION. THIS IS OUR BOTTLENECK IN TERMS OF BEING ABLE TO GENERATE TRANSLATIONAL INFORMATION THAT CAN BE APPLICABLE TO THE FUTURE OF PERSONALIZED MEDICINE. NOW, BY SAYING THAT, ONE WAY TO GET A LITTLE BIT ASIDE OF THIS INCONVENIENCE OF THE COLLECTING DIETARY INFORMATION IS INTERVENTION. WHEN YOU DO AN INTERVENTIONAL STUDY MORE OR LESS YOU KNOW WHAT PEOPLE ARE EATING. THE OTHER THING IS THAT IF YOU DESIGN THE STUDY PROPERLY, YOU CAN FIND INFORMATION BEYOND THE RISK FACTOR BECAUSE ALL THAT I HAVE SHOWN TO YOU SO FAR IS, OKAY, HOW THIS GENE AND THIS ENVIRONMENT INTERACT TO GIVE YOU HIGHER OR LOWER LEVELS OF A RISK FACTOR LIKE LDL OR HDL OR EVEN OBESITY. THAT IS BOTH A DISEASE BY ITSELF BUT ALSO A RISK FACTOR. SO WHAT WE WANT TO DO AT THE END OF THE DAY, OR OUR LIVES, IS TO SEE, OKAY, IF WE APPLY THIS PERSONALIZATION ARE WE GOING TO GET TO THE BOTTOM LINE, WHICH IS ARE WE GOING TO BE ABLE TO DECREASE THE INCIDENCE OF DISEASE IN THE INDIVIDUALS THAT WE INTERVENE OR WE RECOMMEND DIETARY INTERVENTION? AND I'M GOING TO GIVE YOU AN EXAMPLE OF THIS IN TERMS OF THE DIFFERENCE OF WHAT WE'VE BEEN DOING SO FAR, CARDIOVASCULAR RISK FACTORS AND WHAT WE WANT TO ACHIEVE WHICH IS PREVENT THE EVENTS AS THE BOTTOM LINE. FOR THAT I'M GOING TO USE THE EXAMPLE OF PREDIMED, BROUGHT UP TO THE MAP SOMETHING THAT WAS MISSING FROM LITERATURE, MEDITERRANEAN DIET, GREAT. IF YOU LOOK AT WHAT PEOPLE EAT IN THE MEDITERRANEAN, IF YOU LOOK AT WHAT PEOPLE EAT IN CARIBBEAN COUNTRIES AND THE U.S., WELL, PEOPLE EAT DIFFERENT. THEY HAVE DIFFERENT RATES OF DISEASE. WHEN IT COMES TO CARDIOVASCULAR DISEASE AND OTHER DISEASES, APPARENTLY MEDITERRANEAN ENVIRONMENT OR PEOPLE THAT FOLLOW THE MEDITERRANEAN DIET THEY HAVE LESS PREVALENCE OF THESE DISEASES. BUT WHEN IT COMES TO OBSERVATIONS YOU CAN MAKE A LOT OF ASSUMPTIONS THAT ARE NOT TRUE. HOW YOU CAN DEMONSTRATE SOMETHING IS REALLY DOING WHAT YOU THINK IT'S DOING, JUST BY RANDOMIZED TRIAL AS WE DO FOR EXAMPLE IN PHARMA. AND IN THIS CASE THIS WAS A MULTI-CENTER STUDY IN DIFFERENT PLACES IN SPAIN, OVER 7000 PARTICIPANTS, TREE ARMS TO THE STUDY, ONE THAT WAS, YEAH, MEDITERRANEAN DIET BASED ON EXTRA VIRGIN OLIVE OIL, THE OTHER MED MEDITERRANEAN INSTEAD OF OLIVE OIL NUTS USED TO PROVIDE HEALTHY FATS, AND THEN THE OTHER CONTROL GROUP, THAT WAS CONSUMING HIGH SATURATED FAT DIET WOULD HAVE BEEN QUITE EASY, LOWER FAT ACCORDING TO AMERICAN GUIDELINES. WHEN IT COMES TO RISK OF CARDIOVASCULAR DISEASES, THIS WAS THE ACCUMULATION OF EVENTS IN THOSE PEOPLE CONSUMING CONTROL DIET, LOW FAT DIET, AND IT WAS SIGNIFICANTLY HIGHER, IN THIS CASE SIGNIFY LOWER, IN THOSE THAT WERE CONSUMING EITHER EXTRA VIRGIN OLIVE OIL OR THE NUTS, RIGHT? WALNUTS, PRIMARILY. SO BASED ON THIS INTERVENTION STUDY, IT SEEMS LIKE THAT CONCEPT OF THE MEDITERRANEAN DIET BEING HEALTHY, THAT WAS TRUE, ESPECIALLY IF YOU DO IT IN SPAIN. WHICH IS A MEDITERRANEAN COUNTRY. [LAUGHTER] IT HAS TO BE DEMONSTRATED THAT'S THE CASE HERE. NOW THE QUESTION IS, IS THAT GOOD FOR EVERYBODY? THE PANACEA, EVERYBODY SHOULD RUN AFTER THE MEDITERRANEAN DIET. AND THAT'S SOMETHING WE'RE CURRENTLY STUDY BECAUSE IT MAY FOR SOME PEOPLE IT'S BENEFICIAL AND SOME PEOPLE MAY NOT BE SO BENEFICIAL BASED ON THEIR GENOME. THIS IS SOMETHING THAT DEMONSTRATES FOR SOME PEOPLE MEDITERRANEAN DIET WITH BE ESPECIALLY BENEFICIAL. AND THE EXAMPLE IS WITH THE GENE PCF7L2 WAS THE FIRST GENE IDENTIFIED USING THE GENOME WIDE ASSOCIATION STUDIES FOR DIABETES. SO IS THE EQUIVALENT FOR DIABETES OF WHAT WE SAW BEFORE FOR OBESITY WITH THE FTO GENE, THE ONE WITH THE STRONGEST EFFECT FOR COMMON OBESITY IN THE CASE OF FTO, COMMON DIABETES IN THE CASE OF PCF7L2. IT DOES MANY THINGS, AND IT'S EXPRESSING MANY THINGS, IT'S AN IMPORTANT GENE. IT WAS NOT KNOWN UNTIL THE GENOMIC EFFORT BROUGHT THIS TO THE SURFACE, TO THE MAP, THIS GENE. IT WAS NOT AMONG THE CANDIDATE GENES WE STUDIED FOR OVER 20 YEARS SO IT WAS A NICE SURPRISE. LET'S BRING THE SURPRISE TO THE STUDY THAT WE STUDIED AND FOCUS ONED STROKE RISK. NOW, THE SAME ALLELE THAT PRE-DISPOSED PEOPLE TO DIABETES, PRE-DISPOSED PEOPLE ALSO TO A STROKE, AND SOMEHOW THEY ARE RELATED, YOU KNOW. SO IN THE CASE OF THE PREDIMED STUDY THEY WERE FREE OF DISEASE, AT HIGH RISK BUT FREE OF DISEASE, CARDIOVASCULAR DISEASE. THIS IS FOR PEOPLE THAT HAVE THE NORMAL GENOTYPE, THIS WAS THE INCIDENCE OF A STROKE. LOW, MEDIUM AND HIGH. OKAY. SO WHAT YOU EXPECT, PEOPLE WERE PRE-DISPOSED TO CERTAIN DISEASE, DESPITE THE FACT THEY WERE CONSUMING A PROVEN LOW-FAT DIET. LOOK AT THE PEOPLE FOLLOWING THE MEDITERRANEAN DIET INTERVENTION. EITHER WITH OLIVE OIL OR WALNUTS. WELL, WHAT HAPPENED IS IN GENERAL, YOU CAN SEE THE INCIDENCE OF THE DISEASE, STROKE IN THIS CASE, WAS MUCH LOWER, BUT WHO BENEFITED MORE OF THE MEDITERRANEAN DIETED? THE PEOPLE THAT WERE PRE-DISPOSED TO HAVE A STROKE. IN THE SAME WAY YOU SAW YOU COULD REMOVE RISK OF OBESITY LET'S SAY WITH EDUCATION, RIGHT? YOU CAN -- YOUR ADDITIONAL RISK OF A STROKE THAT COMES FROM THIS SPECIFIC GENE, YOU CAN REMOVE IT ENTIRELY BY FOLLOWING THE SPECIFIC DIET, IN THIS CASE MEDITERRANEAN DIET. SO HOW THAT TRANSLATES? THIS NUMBER OF PEOPLE BECAUSE THEY WERE PUT IN THE RIGHT DIET FOR THEIR GENE, FOR THEIR GENOTYPE, THESE DON'T HAVE STROKE DURING THE FIVE YEARS THAT LAST THE INTERVENTION. I DON'T KNOW HOW MANY PEOPLE ARE HERE. THIRTY PEOPLE OR SO. OKAY, 30 PEOPLE IN FIVE YEARS, TAKE THAT TO THE POPULATION OF SPAIN, THEY HAVE 90,000 STROKES PER YEAR, 9000 COULD HAVE BEEN PREVENTED BY PUTTING THEM IN THE RIGHT DIET. NOW YOU KNOW VERY WELL THE NUMBERS IN THE U.S., AND ACCORDING TO WHAT I LOOK THIS MORNING IT WAS ABOUT 870,000 CASES OF STROKE EVERY YEAR. MADE A MAP, 10% OF THEM COULD BE PREVENTED BY PLACING PEOPLE IN THE RIGHT DIET, JUST USING ONE GENE. THE WHOLE IS TO BRING WHOLE GENOME INFORMATION IN ORDER TO NOT JUST BE ABLE TO PREVENT 10% BUT 50, 60, 70% AS WE GAIN MORE SCIENTIFIC INFORMATION ABOUT WHAT WE HAVE IN OUR HANDS. SO MEDITERRANEAN DIET WHEN YOU LOOK AT THE ENTIRE GROUP OF PARTICIPANTS IN THE PREDIMED STUDY WAS GOOD, EVEN BETTER FOR THOSE PRE-DISPOSED TO HAVING A STROKE. SHOULD WE FORGET EVERYTHING THAT THE AMERICAN HEART ASSOCIATION AND PANEL SAID ABOUT LOW FAT AND LET'S JUST EVERYBODY START USING OLIVE OIL AND WALNUTS AND SO ON? NO. THE SAME WAY THAT WE HAVE FOUND SPECIFIC MARKERS, GENOTYPIC MARKERS THAT IDENTIFY PEOPLE THAT BENEFIT FROM THE MEDITERRANEAN DIET WE'RE FINDING ALSO OTHER MARKERS IN OTHER GENES THAT IDENTIFY PEOPLE THAT ARE GOING TO BENEFIT FROM THE LOW FAT DIET BUT NOT FROM THE MEDITERRANEAN DIET. SO THERE IS NO UNIQUE ANSWER. WE JUST HAVE TO FIND AND PUT IN PRACTICE THE SPECIFIC ANSWERS FOR EACH ONE OF US. ALL RIGHT. HOW ARE WE DOING WITH TIME? TEN MINUTES, OKAY. IN ONE OF THE FIRST SLIDES I WAS MENTIONING THE IMPORTANCE OF BRINGING TIME INTO THE EQUATION. WHEN IT COMES TO NUTRITION, OUR BEHAVIOR IN GENERAL IS NOT ONLY WHAT WE EAT OR HOW MUCH WE EAT. IT'S WHEN WE EAT IT, WHAT IS ALSO IMPORTANT. AND HERE ARE SOME EXAMPLES OF THE WORK THAT WE HAVE BEEN DOING. AS YOU KNOW, WE HAVE A VERY COMPLICATED CLOCK IN OUR BRAINS. IN FACT WE HAVE CLOCKS IN EVERY ORGAN OF OUR BODY BUT THE CENTRAL CLOCK IS HERE IN THE BRAIN, AND THERE IS FOUR OR FIVE GENES THAT ARE THE CORE CLOCK GENES THAT ARE REALLY ORCHESTRATING HOW WE WORK AT DIFFERENT HOURS OF THE DAY. G POLYMORPHISMS IN THE AND IN THE SAME WAY THAT WE WERE LIPID GENES, LIPID-RELATED GENES THAT WERE DEFINING LEVELS OF HDL OR LDL, IN OTHER GENES DIABETES OR OBESITY, WHEN IT COMES TO CLOCK GENES THEY DEFINE WHETHER WE'RE LARKS OR OWLS. THERE MAY BE A CULTURAL COMPONENT IN TERMS OF WHETHER YOU ARE MORE -- YOU FEEL BETTER TO WORSE AT THE END OF THE DAY, MEANING IF YOU ARE A LATE PERSON OR NIGHT PERSON OR MORNING PERSON, BUT MOST OF THAT IS IN OUR GENES. WHETHER YOU ARE MORNING OR EVENING OR LATE PERSON. AND THAT IS NOT ONLY THAT WE FEEL BETTER IN THE NIGHT OR IN THE MORNING AND WE DO OTHER THINGS BETTER BUT ALSO DEFINES WHAT WE EAT, WHEN WE EAT IT, THE FIRST CLOCK GENE THAT WAS DISCOVERED. AND IF YOU HAVE THE NORMAL GENOTYPE, WELL, THIS IS THE AMOUNT OF CALORIES YOU CONSUME PER DAY. IF YOU'RE A HOMOZYGOUS OR HETEROZYGOUS FOR THE ALLELE THAT'S GOING TO DEFINE YOUR BEHAVIOR, YOU EAT MORE. SO WHEN THAT HAPPENS, DAY AFTER DAY, MORE OBESITY AND FOR EXAMPLE OTHER FACTORS THAT HAVE BEEN ASSOCIATED WITH A CHRONIC DISEASE, FOR EXAMPLE YOU HAVE ELEVATED CYTOKINES, MEANS YOU'RE MORE INFLAMED, YOUR SLEEP HAS LESS QUALITY, THAT IF YOU HAVE THE POLYMORPHISM, SO YOU WENT UP HAVING HIGHER RISK OF DISEASE IN GENERAL. THE OTHER THING INDEPENDENTLY OF THE GENES, DEPENDING ON WHAT YOU EAT, YOU ARE GOING TO RESPOND DIFFERENTLY TO WHAT YOU EAT. THIS IS ANOTHER PAPER THAT WE PUBLISH ALREADY THREE YEARS AGO, IN WHICH THESE ARE PEOPLE THAT WERE OVERWEIGHT, OR OBESE, AND THEY WERE FOLLOWING A DIET TO LOSE WEIGHT AND THAT'S WHAT HAPPENED TO PEOPLE THAT ATE BEFORE 3:00 P.M. TS WAS OBVIOUSLY IN EUROPE, PEOPLE HERE USUALLY EAT MUCH -- [LAUGHTER] AND THESE ARE PEOPLE THAT EAT AFTER 3:00 P.M., SAME AMOUNT OF FOOD, SAME FOOD PRACTICALLY, BUT IT DEPENDS IF YOU WERE EATING LATE, LATER OR EARLIER, YOUR SUCCESS IN TERMS OF LOSING WEIGHT WAS DIFFERENT. SO IT'S BETTER TO EAT EARLIER THAN TO EAT LATER FROM THIS PERSPECTIVE. THIS IS JUST GOING OVER SIMILA NOW INTEGRATING THE INFORMATION ABOUT THE CLOCK GENE YOU HAVE THE SAME SITUATION. THIS IS THE AMOUNT OF WEIGHT YOU LOSE IN THE SAME PROGRAM, IF YOU ARE TT, BUT IF HAVE THE VARIANT YOU LOSE LESS WEIGHT. YOU DROP OUT OF THE STUDY MUCH EASILY. YOU HAVE A ELEVATION OF GHRELIN, YOU PREFER CERTAIN AMOUNT OF -- CERTAIN TYPES OF FOODS VERSUS OTHERS. YOU SLEEP LATE IF YOU HAVE THE POLYMORPHISM, SIMILAR TO WHAT WE SAW BEFORE, AND YOU FEEL BETTER AT DIFFERENT TIMES OF THE DAY. SO NOW LET'S MOVE SLIGHTLY OUTSIDE FROM THE VARIATION AND LOOK AT THE EPIGENETICS. AS YOU KNOW, THERE ARE TWINS, WE HAVE EXAMPLES HERE. AND WHEN THEY ARE BORN, THEY HAVE THE SAME EPIGENETICS MARKS, BUT THAT IS PEOPLE GET -- AS TWINS GET OLDER BECAUSE OF DIFFERENT EXPOSURE TO ENVIRONMENT THEY START TO GET DIFFERENCE AND DIFFERENCE AND THEY MAY LOOK QUITE DIFFERENT. LOOK AT THIS, FOR EXAMPLE, RIGHT? SO EPIGENETICS PLAY AN IMPORTANT ROLE, AND WE HAVE TO PUT THAT INTO THE EQUATION WHEN WE'RE TALKING ABOUT SYSTEMS BIOLOGY, INTEGRATION AND SO ON, EPIGENETICS IS GOING TO BE VERY IMPORTANT. THE PROBLEM IS THAT WHEN IT COMES TO THE GENES WE HAVE 25,000 GENES TO DEAL WITH. WHEN IT COMES TO EPIGENETIC THE COMPLEXITY IS PROBABLY 100 TIMES LARGER AND MORE DIFFICULT TO STUDY SO WE HAVE A BIG CHALLENGE IN FRONT OF US BUT EPIGENETIC RULES EVERYTHING, THE BRIDGE BETWEEN THE ENVIRONMENT AND HOW OUR GENES ARE EXPRESSED. BY ENVIRONMENT WE'RE TALKING ABOUT REAL ENVIRONMENT, IN TERMS OF AIR, WATER, BUT ALSO EXPOSURE TO OUR MICROBIOME, PHYSICAL ACTIVITY, THE DIET, BIOLOGY INDICATED BEFORE, ALSO EMOTIONAL HEALTH. EVERYTHING IS GOING TO IMPACT OVER OUR EPIGENETIC MARKS AND THAT'S GOING TO DEFINE OUR POINT OF VIEW FOR ANTI-ININFLAMMATORY, OXIDATION, ALL THE WAY AROUND. WHEN IT COMES TO JUST BY ADDING ANOTHER EXAMPLE OF THE CLOCK GENES, IT'S NOT ONLY THE VARIANTS THAT WE HAVE IN THE CLOCK GENES THAT ARE GOING TO DEFINE HOW MUCH WE EAT AND WHEN WE EAT. WHAT WE HAVE FOUND IS THAT THERE ARE EPIGENETIC MARKS, METHYLATION IN THE CLOCK GENE THAT'S GOING TO DRIVE PRECISELY WHETHER WE JUST EAT ALL THE TIME, SNACKING ALL THE TIME, WHETHER THE ANSWER TO BEING BORED IS LOOK FOR SOMETHING TO EAT, AND WHEN WE'RE EXPOSED TO FOOD WE GO AFTER THE LARGER SIZE. SO THIS IS PRECISELY SOMETHING THAT WE HAVE BEEN ABLE TO IDENTIFY IN THE METHYLATION MARKS. THE ADVANTAGE IS METHYLATION MARKS CAN BE CHANGED, CHANGED WITH DIET, UNLIKE THE GENOME, THE VARIANTS WE HAVE IN THE GENOME THAT WE CANNOT DO ANYTHING, AT LEAST ETHICAL ABOUT THAT. NOW, THAT APPLIES TO ANYTHING. WHEN IT COMES TO CHRONO BIOLOGY, IT'S ABOUT EVERYTHING WE DO. HOW MANY OF YOU LIKE TO EXERCISE IN THE MORNING? IN THE EVENING? I THINK THERE ARE MORE PEOPLE THAT LIKE TO EXERCISE IN THE MORNING THAN IN THE EVENING. LET'S SEE. LOOKING IN THIS CASE YOUNG WOMEN, THEY WERE DOING PHYSICAL ACTIVITY, THEY WERE FUTBOL PLAYERS, RUGBY IN REALITY, EUROPEAN FUTBOL, AND LOOKING IN THIS CASE IT WAS IS THERE EVENING PHYSICAL ACTIVITY, IS IT AS GOOD OR BETTER THAN MORNING PHYSICAL ACTIVITY? AND THIS IS WHAT HAPPENED IN WHEN THEY WERE NOT DOING PHYSICAL ACTIVITY, AND THIS IS THE NORMAL CHANGES THAT YOU SEE DURING THE DAY IN TERMS OF CORE BODY TEMPERATURE AND THE MORE PRONOUNCED ARE THE CHANGES THE BETTER. OBVIOUSLY, AS YOU KNOW, ONE OF THE -- EVERYTHING CHANGES DURING THE CIRCADIAN RHYTHM. YOUR BLOOD PRESSURE, HORMONES, ALSO YOUR BODY TEMPERATURE. AS YOU KNOW, IT'S LOWER IN THE NIGHT AND HIGHER IN THE AFTERNOON AND SO ON. BUT ONE -- WHAT YOU WANT IS BIG CHANGES, THAT'S A SIGN OF HEALTH. NOT FEVER, OF COURSE, THAT'S NOT A SIGN OF HEALTH, BUT IN THE NORMAL ROUTINE, WHAT YOU WANT IS CHANGES BETWEEN THE LOWER AND THE UPPER TEMPERATURE. THIS IS WHAT HAPPENS WHEN YOU EXERCISE IN THE MORNING. WHAT YOU SEE, YOU SEE WHAT YOU OBSERVE IN THE CONTROL SITUATION, BUT EVEN THE CHANGES ARE OF HIGHER MAGNITUDE. SO THIS IS SOMETHING ASSOCIATED WITH GOOD HEALTH. SEE WHAT HAPPENS IN THE CASE OF THE EVENING PHYSICAL ACTIVITY, YOU DISRUPT THE NORMAL EFFECTS. THE DIPS OR HIGHS DISAPPEAR, SO EVERYTHING SEEMS TO BE QUITE DISRUPTED. THESE CHANGES IN BODY TEMPERATURE, CIRCADIAN BODY TEMPERATURE, ARE SIMILAR TO THE ONES YOU FIND IN OBESE PEOPLE. SO I AM NOT GOING TO SAY IT'S BETTER JUST TO LIE FLAT AND DO NOTHING RATHER THAN DOING PHYSICAL ACTIVITY IN THE EVENING. [LAUGHTER] BUT SOMEHOW IF YOU WANT TO GET THE MAXIMUM OUT OF PHYSICAL ACTIVITY, IT'S BETTER TO DO IT IN THE MORNING THAN TO DO IT IN THE EVENING. AND THE SAME APPLIES ALSO TO, FOR EXAMPLE, EATING. IT'S BETTER TO EAT EARLY IN THE MORNING THAN TO PUSH YOUR DINNER LATE IN THE EVENING. SO THESE ARE EXAMPLES OF THE IMPORTANCE OF WHAT WE EAT IS IMPORTANT, HOW MUCH WE EAT IS IMPORTANT, BUT WHEN WE DO THINGS LIKE EATING OR PHYSICAL ACTIVITY IS ALSO GOING TO BE VERY RELEVANT FOR OUR HEALTH. AND OF COURSE WHETHER YOU DO THINGS IN THE MORNING OR IN THE EMBEDDED IN YOUR GENOME. SO THE PERSONALIZED BEHAVIOR IS ALSO IMPORTANT IN TERMS OF REACHING THAT PERSONALIZED HEALTH THAT WE'RE LOOKING AT. I THINK WE'RE GETTING TO THE PE THESE THINGS.RREL SO I SHOULD OH, YEAH, WHEN IT COMES TO BIG DATA THIS IS IN REALITY WHAT WE HAVE IN OUR HANDS. YEAH, BIG COHORTS, 3000 HERE, BUT IN REALITY WHAT WE HAVE IS P ATCHWORK, A STUDY THAT HAS A DESIGN, ANOTHER STUDY THAT HAS ANOTHER DESIGN. IT'S A LITTLE BIT LIKE THIS. SO JUST BY THINKING THAT PUTTING ALL THESE DATA TOGETHER AS LARRY WAS SAYING BEFORE, WITHOUT REALLY KNOWING OR HAVING THE HEART OF DISTINGUISHING THE NOISE FROM THE SIGNAL IS NOT GOING TO GIVE YOU THE ANSWER. YOU NEED THE EXPERTISE OF A LOT OF PEOPLE TO BRING UP THE BEAUTY OF THE PATCHWORK AND THEN END UP PRECISELY WITH THESE KIND OF DESIGNS THAT ONLY A REAL ARTIST OR ONLY SCIENTISTS WORKING TOGETHER WORK TOGETHER RATHER THAN ISOLATE PIECES THAT CAN BE DISCOVERED, RIGHT? SO THE NEXT GOAL WILL BE PRECISELY AS IT HAS BEEN MENTIONED A FEW TIMES, IN THIS KIND OF NUMBERS, WHO IS GOING TO PAY FOR THESE NUMBERS? BUT INFORMATION IS ALREADY EMBEDDED, IN WHAT WE DO EVERY DAY IN TERMS OF THE ELECTRONIC HEALTH RECORDS AND SO ON. IN THE FUTURE, WELL, IN THE PRESENT IN FACT, WHAT PLE ARE STARTING TO DO IS TO MOVE FROM THE GWAS IN WHICH WHAT YOU ARE FINDING, TRYING TO FIND THE GENES ASSOCIATED WITH ONE DISEASE, TO THE pheWAS, USING ELECTRONIC DATA TO LOOK AT ONE SPECIFIC GENE, ONE SPECIFIC POLYMORPHISM AND SEE WHAT KIND OF DISEASES ARE ASSOCIATED WITH THESE SPECIFIC LOCUS AND SO ON, AND THERE ARE EXAMPLES THAT YOU CAN INTERPRET AS PARTLY SUNNY OR PARTLY CLOUDY DEPENDING HOW OPTIMISTIC YOU ARE ABOUT DATA COMING OUT OF THESE INITIAL STUDIES. BUT THE PROBLEM IS THAT IN THE ELECTRIC HEALTH RECORDS YOU CAN NOT CAPTURE THE AMOUNT OF INFORMATION THAT YOU NEED IN ORDER TO BRING OUT THE ENVIRONMENT. YOU MAY HAVE INFORMATION ABOUT SMOKING, ABOUT ALCOHOL, BUT WHAT WE'RE STILL LACKING IS SOME VERY IMPORTANT COMPONENTS OF THIS EQUATION THAT YOU HAVE TO TIE THE KNOT WITH GENOMIC INFORMATION IN ORDER TO BRING THE INTERACTIONS THAT ARE GOING TO BE INFORMIC FOR THE PRECISION INFORMATION. IN THE FUTURE, WE ARE GOING TO COMBINE -- WE ALREADY ARE COMBINING INFORMATION ABOUT THE GENETIC VARIATION WITH DIETARY INTAKE IN ORDER TO BRING THIS PERSONALIZED RECOMMENDATIONS, SO THAT RESEARCH WILL BE ABLE TO DISCRIMINATE, BUT TO INDULGE WE NEED ONE TYPE OF DIET OR ANOTHER TYPE OF DIET, OUR CHALLENGE AS I MENTIONED EARLIER IS THAT WE ARE UNABLE YET TO CAPTURE PROPERLY THE NUTRITION INFORMATION WE REALLY NEED TO COME OUT WITH PRACTICAL ANSWERS, AND THAT WE ALSO NEED TO TAKE INTO CONSIDERATION THE CURRENT BIOLOGY ASPECT SO WHEN IT COMES TO MY PLATE IT'S VERY NICE, THIS IS WHAT YOU NEED PROBABLY TO EAT DURING THE DAY, BUT IT WOULD BE NICE TO HAVE INFORMATION ABOUT WHAT YOU SHOULD BE EATING, AS AN INDIVIDUAL, DURING THE DIFFERENT MEALS THAT WE HAVE DURING THE DAY. ALL RIGHT. SO THIS IS WHAT IS HAPPENING NOWADAYS. THESE ARE THE BABIES, IN THE PRESENT WE DON'T KNOW THE GENOMES. THEY ARE EXPOSED TO AN ENVIRONMENT, THE PREDISPOSITION WILL BE EXPRESSED. IN THE FUTURE, NEAR FUTURE, WE'LL BE ABLE TO HAVE INFORMATION ABOUT GENOME, PERSONALIZE THE ENVIRONMENT, AMONG OTHER THINGS THE DIET. YOU SEE FROM PREVIOUS AVAILABLE WILL BE ABLE TO CONTROL GENETIC PREDISPOSITION. NEEDLESS TO SAY IN THE FUTURE WE NEED TO GAIN KNOWLEDGE IN EPIGENOME. THIS IS WHAT NEUTRIGENOMICS IS ABOUT. THIS IS NOT THE ONLY TIME NEUTRIGENOMICS WILL COME TO THE TABLE THIS WEEK. YOU WILL HAVE OTHER SPEAKERS TALKING ABOUT THIS FROM A DIFFERENT PERSPECTIVE, MORE COMMERCIAL. THANK YOU VERY MUCH FOR YOUR ATTENTION. IF ANYBODY HAS ANY QUESTIONS I WOULD BE HAPPY TO TRY TO ANSWER. [APPLAUSE] >> I HAVE A QUESTION. (INAUDIBLE). >> THAT WAS AN EXCELLENT TALK. IN LIGHT OF WHAT YOU SAID ABOUT THE (INAUDIBLE) MANY IN OUR EARLY CAREERS WORKING SHIFT WORK, I WORK 12 HOURS, 15 YEARS ON 12-HOUR NIGHTS. DO YOU HAVE ANY THOUGHT, I WOULD EAT MY LUNCH AT TWO IN THE MORNING. DO YOU HAVE ANY THOUGHTS? >> WELL, THE QUESTION IS ABOUT THE -- IF ALL THIS IS TRUE, WHICH I DON'T KNOW. [LAUGHTER] NO, REALLY, REALLY. KEEP IN MIND EVERYTHING I HAVE PRESENTED IS BASED ON STATISTICS. AND YOU CAN DO ANYTHING WITH STATISTICS. SO TO MY STUDENTS I ALWAYS SAY THIS. ALL THAT I CAN SAY, I'M TELLING YOU WHAT I KNOW WHAT WE KNOW TODAY. TOMORROW, WHO KNOWS. BUT THE QUESTION WAS ABOUT SHIFT WORK. AND WHAT WE KNOW SO FAR IS THAT BASED ON THE SCENARIO FROM THE POINT OF VIEW OF LET'S SAY MORE EXPOSURE TO CARDIOVASCULAR DISEASE, MORE RISK FOR CARDIOVASCULAR DISEASE, DIABETES, CANCER, BUT ALSO IN TERMS OF BEHAVIORAL ASPECTS, RIGHT? BASED ON THE OBSERVATIONS THAT WE HAVE, IT'S NOT THE BEST CASE SCENARIO BUT SOMEBODY HAS TO DO IT, RIGHT? WHAT IS BETTER OR WHAT IS WORSE? WE ARE LOOKING AT FOR EXAMPLE FACTORY WORKERS, AND WHAT WE ARE DOING IS PEOPLE THAT ARE ALWAYS ON THE SAME SHIFT, LET'S SAY NIGHT SHIFT, PEOPLE THAT EVERY MONTH THEY GO REGULAR AT NIGHT, AND THE RANKING WE GET IN TERMS OF INFLAMMATION, IN TERMS OF RISK FACTORS IS PEOPLE THAT ARE ONLY DOING THE NORMAL SHIFTS, THEY DO WELL. PEOPLE THAT ALWAYS STAY ON THE SAME ONE SOMEHOW PHENOTYPIC FLEXIBILITY, YOU GET USED TO THAT AND YOU TRAIN YOUR METABOLISM TO DO IT. BUT THE PEOPLE THAT FLIP-FLOPS ARE THE ONES THAT TEND TO FARE WORSE IN TERMS OF RISK FACTORS. AND THAT APPLIES AGAIN TO -- I MEAN NURSES, PHYSICIANS, FACTORY WORKERS, ALL THE PEOPLE THAT HAVE BEEN EXAMINED SO FAR. BUT, AGAIN, THAT'S CURRENT KNOWLEDGE. >> (INAUDIBLE). >> OH, SORRY. KNOWING YOU DIDN'T TAKE A GENETIC TEST TO KNOW YOUR PREDISPOSITION TO DIABETES AND STROKE, KNOWING FOR EXAMPLE THE TT GROUP DID SO MUCH BETTER THAN THE CC GROUP, WOULDN'T YOU JUST RECOMMEND SOMEONE WHO HAVE LIKE LET'S SAY A FAMILY HISTORY OF DIABETES AND STROKE TO GO AHEAD AND GO ON THE MEDITERRANEAN DIET KNOWING NOT EVERYBODY CAN DO THE GENE OH TEST -- GENOME TEST AT THIS POINT IN TIME? >> THAT'S AN EXCELLENT QUESTION. THE GENETIC PREDISPOSITION, YOU CAN MEASURE IT, PAY FOR IT, OR YOU CAN JUST LOOK AROUND YOU. AND THE FAMILY HISTORY IS EXTREMELY REVEALING. SO BASED ON WHAT THE KNOWLEDGE THAT WE ARE ACCUMULATING, IF I HAVE TO ADVISE SOMEBODY, FOR ONE REASON OR ANOTHER DOES NOT HAVE ACCESS TO GENETIC TEST THAT'S WHAT I WILL DO. I WILL SAY, WELL, LOOK AT YOUR PARENTS OR BROTHER OR UNCLE AND SO ON. OBVIOUSLY, YOU MAY NOT HAVE INHERITED THAT SPECIFIC ALLELE BUT THIS ONE NOTCH UP IN TERMS OF PERSONALIZATION BASED ON THE FAMILY HISTORY, SOW IT'S INFORMATIVE. AND IN FACT THERE ARE PAPERS THAT HAVE COMPARED INFORMATION FROM THE GENETIC TEST AND INFORMATION FROM THE FAMILY HISTORY. UH-HUH. >> THANK YOU SO MUCH, DR. ORDOVAS. [APPLAUSE] THANK YOU VERY MUCH FOR YOUR EXPERT AND ENTERTAINING PERSPECTIVE ON THE BENEFITS AS WELL AS THE CHALLENGES OF NEUTRIGENOMICS AND PRECISION HEALTH. I'VE SEEN A LOT OF HUNGRY FACES AND IT'S COME TO THIS TIME, I WANT TO ESPECIALLY THANK ALL THIS MORNING'S OUTSTANDING SPEAKERS FOR A WONDERFUL AND ENGAGING START TO THE PRECISION HEALTH CONFERENCE. DR. GRADY, DR. HOOD, DR. BAKKEN, AND DR. ORDOVAS, HOW ABOUT A BIG ROUND MUCH APPLAUSE FOR OUR EXCELLENT SPEAKERS TODAY. [APPLAUSE] SO NOW WE'LL BREAK FOR LUNCH, AND WE'LL RECONVENE ABOUT 2:00, OKAY? SO HAVE A GREAT LUNCH, AND DON'T GET IN THE HEAT NOW, OKAY? I HOPE YOU HAD A GOOD LUNCH AND ARE STAYING COOL. HOPEFULLY A LITTLE BIT. AND ARE REENERGIZED FOR THIS AFTERNOON'S PRESENTATIONS. I'M REALLY -- IT'S TRULY A PLEASURE FOR ME TO INTRODUCE OUR FIRST AFTERNOON SPEAKER. DR. DEANNA KROETZ. DR. KROETZ IS A PROFESSOR IN THE DEPARTMENT OF BIOENGINEERING AND THERAPEUTIC SCIENCES IN THE SCHOOL OF PHARMACY AT THE UNIVERSITY OF CALIFORNIA SAN FRANCISCO. AND THE DIRECTOR OF THE PHARMACEUTICAL SCIENCES AND PHARMACOGENOMICS GRADUATE PROGRAM. SHE RECEIVED HER BACHELORS DEGREE IN PHARMACY FROM OHIO STATE UNIVERSITY. AND HER Ph.D. IN PHARMACEUTICS FROM THE UNIVERSITY OF WASHINGTON. DR. KROETZ WAS A PROUD FELLOW HERE IN THE LABORATORY OF MOLECULAR CARCINOGENESIS AT NCI OR THE NATIONAL CANCER INSTITUTE SO IN MANY WAYS YOU'RE COMING BACK HOME, AREN'T YOU? HER RESEARCH INTERESTS ARE BROADLY IN THE AREA OF DRUG METABOLISM, DRUG TRANSPORT, AND PHARMACOGENETICS. DR. KROETZ WILL PRESENT PHARMACOGENOMICS, AND PRECISION HEALTH. SO PLEASE JOIN ME IN A WARM WELCOME AFTER LUNCH. [APPLAUSE] DR. KROETZ. [APPLAUSE] >> THANK YOU, MARY, FOR THAT INTRODUCTION AND THE OPPORTUNITY TO SPEAK HERE TODAY. SO WHAT I'M GOING TO DO IN THE NEXT 45 MINUTES OR SO IS TO GIVE THE FRAMEWORK FOR WHAT IS GOING ON IN THE FIELD OF PHARMACOGENOMICS. I WILL TELL YOU ABOUT SOME OF THE THINGS THAT ARE REALLY ACTIONABLE TODAY AND HOPEFULLY A FEW OF YOU IN THIS ROOM HAVE SEEN THOSE BEING PUT INTO ACTION. BUT WE'RE A LITTLE SLOW IN THE IMPLEMENTATION. I WILL ALSO TELL YOU ABOUT SOME OF THE DISCOVERY WORK AND HOW THIS IS FEEDING INTO DRUG DISCOVERY AND HOW WE ACTUALLY TEST DRUGS TO BRING THEM TO THE MARKET IS WHERE IT REALLY IS WHAT THE FUTURE IS FOR PHARMACOGENOMICS. I SHOULD ALSO MENTION I HAVE SPOKEN WITH THE SPEAKER TOMORROW, DR. BAUM WILL BE SPEAKING SO HOPEFULLY WE HAVE COORDINATED SO I GIVE YOU THE BACKGROUND AND HE'LL GO INTO DETAIL ABOUT THE CLINICAL IMPLEMENTATION AND THE GREAT WORK THEY HAVE DONE AT MAYO. SO THIS IS AN OVERVIEW OF WHAT I'M GOING TO DO. I THINK PROBABLY AS NURSES, EVERYBODY REALIZES THE NEED FOR PHARMACOGENOMICS. I'M GOING TO SPELL THAT OUT. GIVE YOU A LITTLE HISTORICAL PERSPECTIVE WHICH IS ALWAYS INTERESTING. AND THEN GIVE YOU SOME OF THE AREAS WHERE WE HAVE MADE ADVANCES AND THERE ARE WHAT ARE CONSIDERED CLINICALLY ACTIONABLE. ASSOCIATIONS. TELL YOU A LITTLE BIT ABOUT DISCOVERY USING MY OWN WORK, MY OWN LAB AS AN EXAMPLE. THEN TALK ABOUT PHARMACOGENOMICS AND DRUG DISCOVERY. LET ME START BY JUST EMPHASIZING WHY WE REALLY NEED TO DO PHARMACOGENETICS, RESEARCH AND IMPLEMENTATION. I THINK THIS ILLUSTRATES IT QUITE WELL. TYPICALLY WHAT WE DO, A PATIENT GETS DIAGNOSIS, THEY GET A STANDARD OF CARE. THEY'RE GIVEN THE DRUG THAT MOST PEOPLE START WITH AND GIVEN AT A SINGLE DOSE. THE STARTING DOSE, THE TYPICAL STARTING DOSE. THAT'S REALLY HOW MEDICINE IS DONE. LARGELY STILL TODAY. WE KNOW THAT DOESN'T WORK. SO WHAT YOU SEE IS A LOT OF VARIATION IN RESPONSE. YOU HAVE PATIENTS WHERE THE DRUG IS TOXIC AND YOU GET NO BENEFIT OR JUST HARMING OUR PATIENT. SOMETIMES YOU GET DRUGS THAT YOU HAVE NO TOXIC EFFECT OR NO BENEFICIAL EFFECT. THAT'S NOT ALSO HELPING THE PATIENT GET BETTER. WHAT WE WANT TO DO IS FIND THIS GROUP OF PATIENTS WHERE THE DRUG HAS NO TOXICITY OR AT LEAST VERY MINIMAL TOXICITY AND IS BENEFICIAL. SO THIS IS THE GROUP THAT WE WANT TO PICK OUT FOR THIS DRUG THERAPY AND OF COURSE WE WANT TO DO THAT BEFORE WE START THERAPY. WE DON'T WANT TO HAVE TO GO THROUGH ITERATIONS OF TRIAL AND ERROR TO TRY TO GET THE BEST DRUG FOR THE PATIENTS THAT YOU'RE TREATING. SO FOR ANYONE WHO IS WORKING IN THE HEALTHCARE FIELD, YOU HAVE REALIZED THAT WE DOSE WITH A LOT OF DRUGS THAT ACTUALLY DON'T WORK IN A LARGE NUMBER OF PEOPLE. THIS IS LOOKING AT THE RESPONSE RATE OVER DIFFERENT DISEASE CATEGORIES. YOU CAN SEE THAT FOR THINGS LIKE ALZHEIMER'S DISEASE AND ONCOLOGY, THE RESPONSE RATE HOW MANY PEOPLE DO THESE DRUGS WORK IN IS QUITE LOW ON THE ORDER OF 20, 25%. SO AS YOU SAW EARLIER, IN THE FIGURES THAT WERE PUT UP THERE, WE'RE DOSING A LOT OF PEOPLE WITH THESE DRUGS TO GET BENEFIT IN JUST A FEW. OTHERS WE DO QUITE WELL. AND OTHER THERAPEUTIC AREAS AS WELL. THE OTHER REASON WE SHOULD BE THINKING HOW GENOMICS CONTRIBUTE TO DRUG RESPONSE IS WE ALSO HAVE A LARGE PROBLEM WITH ADVERSE DRUG EVENTS. SO IT'S ESTIMATED BETWEEN TWO AND 4 MILLION PEOPLE A YEAR EXPERIENCE A SERIOUS ADVERSE DRUG EVENT, THESE ARE ESTIMATED CAUSE OVER 700,000 EMERGENCY ROOM VISITS PER YEAR IF YOU LOOK, THE MEDIAN RATE OF ADVERSE DRUG EVENTS IS ABOUT 2.4 PER 100,000 INDIVIDUALS, YOU CAN ALSO SEE THAT AS YOU GO UP IN AGE, OF COURSE THESE ARE THE PATIENTS TAKING MANY DRUGS, YOU CAN SEE THAT THIS IS QUITE A BIT HIGHER. SO THESE ARE SERIOUS PROBLEMS, DRUGS AREN'T WORKING IN EVERYONE THE WAY WE WANT THEM TO AND THEY ARE CAUSING ADVERSE EVENTS AND THAT'S THE REASON WE NEED TO TRY TO FIGURE OUT CAN GENOMICS GUIDE OUR USE OF DRUGS. SO THE GOAL OF PHARMACOGENOMICS THEN IS TO FIRST OF ALL PICK THE RIGHT DOSE OF THE RIGHT DRUG FOR THE RIGHT INDICATION FOR THE RIGHT PATIENT AT THE RIGHT TIME. SO THAT'S WHAT YOU HEAR ALL THIS PERSONALIZED MEDICINE THINKING SPECIFICALLY ABOUT DRUGS. I'M SURE YOU RECOGNIZE THAT ALTHOUGH THAT SOUNDS GREAT IT'S NOT SO EASY TO GET TO THAT. I ALSO WANT TO POINT OUT THIS HAS BEEN POINTED OUT ALREADY THIS MORNING, IS DRUG RESPONSE IS ONE OTHER EXAMPLE OF A COMPLEX PHENOTYPE. IT'S NOT JUST GENETICS. SO WE KNOW THAT GENETICS IS IMPORTANT FOR SOME DRUGS BUT THERE'S A LOT OF OTHER ENVIRONMENTAL FACTORS, THE PATIENT DISEASE STATE, ALL THESE VARIABLES CONTRIBUTE TO HOW A PATIENT IS GOING TO RESPOND TO A DRUG BOTH PHARMACOLOGICAL AND A TOXIC RESPONSE. SO WHEN WE'RE THINKING ABOUT HOW WE'RE GOING TO IMPLEMENT PHARMACOGENOMICS OR HOW USEFUL THE INFORMATION WE FIND IN DISCOVERY IS, WE HAVE TO REALLY APPRECIATE THE FACT THIS IS JUST ONE MORE MARKER OF HOW PATIENTS WILL RESPOND AND WE HAVE TO CONSIDER GENETICS IN THE CONTEXT OF THESE OTHER ENVIRONMENTAL EXPOSURES AND DISEASE FACTORS AND OTHER THINGS THAT AFFECT DRUG RESPONSE. SO JUST A COUPLE OF SLIDES ON WHERE THIS FIELD START? IF YOU PAID ATTENTION TO THE LAY PRESS YOU WOULD THINK IT WAS A NEW FIELD. THAT STARTED WITH THE HUMAN GENOME PROJECT, THAT'S NOT TRUE AT ALL. IF YOU LOOK, THE FIRST EXAMPLE OF A CLEAR INDICATION WHERE THERE'S VARIABILITY WITHIN A POPULATION TO A RESPONSE WAS REPORTED BY (INDISCERNIBLE) IN 510 BC HE REPORTED THERE WAS A SUBSET OF PEOPLE WHO WHEN THEY INGESTED BROAD BEANS SO FAVA BEANS DEVELOPED A POTENTIALLY FATAL HEMOLYTIC ANEMIA. THAT WAS OBVIOUSLY -- SORRY THIS THING IS NOT GOING OFF. OBVIOUSLY QUITE A WHILE AGO. AND IT'S ABOUT 2000 YEARS TO UNDERSTAND WHAT IS THE MOLECULAR BASIS FOR THIS VARIATION IN RESPONSE TO FAVA BEANS? IT WAS FOUND TO BE RELATED TO A GENETIC DEFECT IN G-6 GLUCOSE 6 PHOSPHODIE HYDRONASE ACTIVITY. SO THIS LED TO THIS HEMOLYTIC ANEMIA. THIS IS THE SAME POLYMORPHISM RESPONSIBLE FOR VARIATION IN RESPONSE, ANTI-MALARIAL. A LITTLE MORE RECENTLY IF YOU LOOK, MOST OF THE EARLY PHARMACOGENETICS BEFORE WE HAD GENOME SEQUENCE DATA, SO IN THE 60s AND 70s AND 80s, MOST OF THESE WERE DISCOVERED BECAUSE THERE WAS ALWAYS A SUBSET OF PEOPLE WHO HAD A VERY UNUSUAL RESPONSE. VERY DRAMATIC RESPONSE. SO IT WAS EASY TO IDENTIFY THE PATIENTS IN THE POPULATION. SO FOR EXAMPLE WITH THE VERY SOB PLAN, THIS IS AN ANTI-HYPERTENSIVE THAT DIDN'T CAME ON THE MARKET IN U.S. BUT DID IN EUROPE. THERE ARE PEOPLE NOW WE KNOW ARE DEFICIENT COMPLETELY DEFICIENT IN SIB 2B 6 ACTIVITY METABOLIZING ENZYME THAT HAD A SUCH A PROFOUND RESPONSE BECAUSE THEY CANNOT ELIMINATE THE DRUG THEY DEVELOPED HYPERTENSION. THESE ARE REALLY DRAMATIC RESPONSES. SO THESE WERE THE FIRST EXAMPLES OF PHARMACOGENETICS. SIMILARLY WITH PPMT DEFICIENCY, YOUNG PATIENTS, PEDIATRIC PATIENTS GIVEN SIX PURINE FOR TREATMENT OF ALL DEVELOPED SEVERE HEMOTO LOGICAL TOXICITY. NOW WE CAN ATTRIBUTE THAT TO A SINGLE GENE. AND OFTEN A SINGLE SNP. BUT THESE ARE THE EASY ONES TO FIND. BECAUSE YOU HAVE THESE DRAMATIC PHENOTYPES. THIS IS REALLY NOT WHAT DEFINES PHARMACOGENETIC RESPONSES FOR MOST DRUGS. THEN THE HUMAN GENOME PROJECT CAME ALONG. IT WAS REALLY RECOGNIZED VERY EARLY ON THAT THE DATA THAT WAS COMING OUT OF THE HUMAN GENOME PROJECT AS WELL AS ALL THE TECHNOLOGIES THAT CAME ABOUT BECAUSE OF THE HUMAN GENOME PROJECT CAN REALLY ADVANCE OUR UNDERSTANDING OF DRUG RESPONSE. THIS SEEMS TO MAKE IT IN THE LAY PRESS IN A PRETTY REGULAR FASHION. IT'S ALSO SOMETHING THAT PATIENTS RESPOND TO. IF YOU TALK TO A PATIENT ABOUT UNDERSTANDING THEIR GENOME SO WE CAN GIVE THEM BETTER DRUG TREATMENT MORE EFFECTIVE AND LESS TOXIC DRUG TREATMENT IT'S ALSO SOMETHING THAT THEY CAN RELATE TO AS WELL. SO WHAT I'M GOING TO DO NEXT IS TELL YOU ABOUT SOME OF THESE EXAMPLES JUST TO SHOW YOU WHERE THESE PHARMACOGENETIC DISCOVERIES CAME FROM AND REALLY FOCUS ON ONES THAT MOST OF US IN THE FIELD BELIEVE ARE CLINICALLY ACTIONABLE TODAY. SO THESE ARE GOING TO BE BOTH GERM LINE POLYMORPHISMS AS WELL AS SOME THAT ARE SEMATIC MUTATIONS IN TUMORS WHERE DRUGS ARE BEING DEVELOPED SPECIFICALLY FOR A MUTATION. SO MOST OF THE EARLY PHARMACOGENETIC STUDIES THAT HAVE TO DO WITH GERM LINE POLYMORPHISMS ARE FOCUSED ON DRUG METABOLIZING ENVIRONMENTS AND DRUG TRANSPORTERS. THIS IS JUST RELATED TO DRUG EXPOSURE. SO INDIVIDUALS WHO CANNOT METABOLIZE THE DRUG AS RAPIDLY AS WHAT'S CONSIDERED THE NORMAL PERSON, WILL THEN HAVE HIGHER DRUG LEVELS. THIS IS WHY WE WERE SEEING THOSE EARLY EXAMPLES OF PHARMACO GENETICS WHERE PATIENTS DEVELOP TOXICITY. SO THAT'S A COMMON SCENARIO IF YOU LOOK AT THE WELL DEVELOPED PHARMACOGENETIC EXAMPLES. I WILL TALK ABOUT CODING WHICH IS IMPORTANT FOR EFFICACY AND TOXICITY AND GIVE YOU AN EXAMPLE WITH PEDIGRIL AND ABACAVIR. MORE RECENTLY WHAT YOU HAVE SEEN IS THAT WE HAVE -- WE'RE DISCOVERING A LOT OF MUTATIONS IN TUMORS THAT DETERMINE WHETHER YOU'RE GOING TO RESPOND TO A DRUG. SO NOW WE KNOW THAT IF WE SEQUENCE A TUMOR THAT WE CAN IN SOME CASES TO THE DRUG THERAPY THAT'S GOING TO BE SPECIFIC FOR THAT MUTATION. I WILL GIVE YOU A COUPLE OF EXAMPLES OF THAT AS WELL. THEN THERE'S ALSO DRUGS THAT ARE DEVELOPED BASED ON INDIVIDUAL'S EXPRESSION LEVEL OF A SPECIFIC PROTEIN. THIS IS MOSTLY IN THE AREA OF ONCOLOGY, THE EXAMPLE I WILL GIVE YOU IS HERCEPTIN WHICH IS ONE OF THE FIRST OR PROBABLY THE FIRST EXAMPLE WE DEVELOP A DRUG AND WHEN WE STARTED USING IT NEW THAT IT WOULD ONLY WORK IF YOU OVEREXPRESS A PROTEIN. SO THERE WAS A DIAGNOSTIC TO GO ALONG WITH THAT. SO THIS IS THE LIST OF WHAT IS CONSIDERED CLINICALLY ACTIONABLE GERM LIEN GENETIC VARIANTS -- GERM LINE GENETIC VARIANTS TODAY AND THE MEDICATIONS AFFECTED BY THESE GERM LINE VARIATIONS. AND MOST OF THESE ARE DRUG METABOLIZING ENZYMES. THERE'S HLA ALLELES SO WE KNOW IMMUNE RESPONSE CAN INFLUENCE DRUG TOXICITY AND A FEW TARGET GENES AS WELL. TRY NOT TO SHINE THIS LIGHT IN ANYONE. I APOLOGIZE. THIS IS FROM A REVIEW ARTICLE BY MARY RELLING AND SAINT JUDE WHO ARE LEADERS IN THIS FIELD, THEY LOOKED AT THESE CLINICALLY ACTIONABLE POLYMORPHISMS AND THEY LOOK AT WHAT PERCENTAGE OF THE FEA APPROVED MEDICATIONS WERE AFFECTED BY THESE PHARMACO GENES. AND IT WAS ABOUT 7% IF YOU LOOK AT WHAT ABOUT THE PRESCRIPTIONS THAT ARE FILLED IN THIS COUNTRY, IN ALMOST 20% OF PRESCRIPTIONS THAT ARE FILLED IN THIS COUNTRY ARE FOR DRUGS THAT ARE ASSOCIATED WITH THESE CLINICALLY ACTIONABLE GERM LINE POLYMORPHISMS. SO THIS IS THE BASIS OF THE CLINICAL PHARMACOGENETICS IMPLEMENTATION COB SOURCE YUM OR CPIC. THIS WAS STARTED BY MARY RELLING AS PART OF THE NIH SPONSORED PHARMACOGENOMICS RESEARCH NETWORK. AND DR. BAUM WILL SPEAK MORE ABOUT HOW THEY USE THIS DATA FOR IMPLEMENTATION TOMORROW. BUT THIS WAS ACTUALLY -- THIS IS DESIGNED NOT TO TELL ANYONE WHAT POLYMORPHISMS THEY SHOULD BE TESTING FOR BUT INSTEAD IF YOU DO HAVE THIS GENETIC INFORMATION, HOW YOU USE IT. BECAUSE WHEN MARY AND HER COLLEAGUES WENT OUT AND ASKED PRACTITIONERS WHY YOU NOT USE THIS INFORMATION, THE MOST COMMON RESPONSE WAS I DON'T KNOW WHAT TO DO WITH IT. I GET IT AND I DON'T KNOW WHAT TO DO WITH IT. SO THEY HAVE PUT TOGETHER THESE GUIDELINES FOR HOW TO ACTUALLY DOSE A DRUG BASED ON THIS GENOTYPE THAT IS AVAILABLE AND THEY WERE ALSO HOPEFUL THAT EVENTUALLY PEOPLE WILL PREEMPTIVELY GENOTYPE PATIENTS AND THIS INFORMATION WILL BE PART OF THE ELECTRONIC HEALTH RECORD. WE WILL GET THERE PROBABLY NOT AS SOON AS MANY OF US WOULD HOPE. JUST FOR YOUR INFORMATION, THESE CPIC GUIDELINES ARE AVAILABLE AT A NUMBER OF PLACES, POSTED ON THIS WEBSITE, FARM GKB. THEY'RE ALSO PUBLISHED WHEN THEY BECOME AVAILABLE IN CLINICAL PHARMACOLOGY AND THERAPEUTICS WITH UPDATES EVERY THREE YEARS. IF YOU ARE ON PUBMED YOU CAN USE THE PRACTICE GUIDELINES FILTER AND FIND THEM THERE AS WELL. SO I ENCOURAGE ANYONE WHO IS INTERESTED TO ACCESS THIS INFORMATION. SO I'M GOING TO FOCUS ON THESE THREE GENES, SO 2D 62C 19 AND HLAB. I WANT TO START WITH ONE OF THE OLDEST POLYMORPHISMS CYTOCHROME P 450. THIS IS A DRUG METABOLIZING ENZYME, METABOLIZING SOMEWHERE BETWEEN 25 TO 35% OF MOST DRUGS ON THE MARKET AT LEAST TO SOME DEGREE. IT'S VERY IMPORTANT FOR THE METABOLISM OF CODEINE. AND IN FACT, CODEINE REQUIRES METABOLISM BY CYTOCHROME P 4502D 6 TO SEPARATE MORPHINE, WHAT WE GET OUR ANALGESIC AFFECT FROM. THERE IS A COMMON POLYMORPHISM IN CAUCASIAN POPULATIONS WHERE THESE INDIVIDUALS IN SOME CASES ACTUALLY HAVE NO COPIES AT ALL, THE GENE IS COMPLETELY DELETED, AND IN OTHER CASES, HAVING REDUCED FUNCTION ALLELE OF CITE CHROME P 4502D 6 SO THEY'RE LESS ABLE TO CONVERT CODEINE TO MORPHINE SO THEIR MORPHINE LEVELS ARE GOING TO BE MUCH LOWER. OF COURSE THIS IS GOING TO AFFECT THEIR RESPONSE TO THE DRUG. THIS IS ILLUSTRATED HERE LOOKING AT EXPOSURE TO MORPHINE RELATIVE TO CODEINE. SO THESE INDIVIDUALS WITH THE HIGHEST ACTIVITIES ULTRA METABOLIZERS HAVE THE HIGHEST LEVEL MORPHINE AND WE CAN SEE POOR METABOLIZERS HAVE THESE DEFECTIVE ALLELES MAKE LITTLE MORPHING AT ALL SO GIVING THEM CODEINE IS NOT GOING TO GIVE THEM ANALGESIC EFFECT. BUT WE CAN ALSO THINK ABOUT WHAT ABOUT THESE INDIVIDUALS? THEY HAVE MUCH HIGHER LEVELS OF MORPHINE THAN WHAT THE DRUG WAS DESIGNED TO WORK IN WHICH ARE THEY METABOLIZERS HERE. SO THIS IS CONSIDERED THE NORMAL POPULATION. SO IF YOU HAVE A LOT OF ACTIVITY OF 2D 6 YOU WILL MAKE HIGH LEVELS OF MORPHINE. THIS IS GOING TO BE ASSOCIATED WITH TOXIC EFFECTS. IN FACT IN THESE INDIVIDUALS YOU'RE GOING TO HAVE A HIGHER INCIDENCE OF RESPIRATORY DEPRESSION. THIS BECAME REALLY APPARENT. IN ABOUT TEN YEARS AGO NOW WHERE THERE WAS A CASE IN CANADA OF A FATAL OVERDOSE OF A NEWBORN INFANT WHO WAS INGESTING MORPHINE FROM THEIR MOTHER THROUGH THE BREAST MILK. AND THIS CASE REPORT HAS SHOWN HERE, THIS IS LOOKING AT MORPHINE CONCENTRATION, IN THE BLOOD AND THE MILK IN A PERSON WITH A NORMAL 2D 6 GENOTYPE AND IN THIS PATIENT WHOSE MOTHER HAD AN ULTRA RAPID METABOLIZER PHENOTYPE SO SHE MADE A LOT OF MORPHINE. SO YOU CAN SEE THE MILK LEVELS OF MORE PHONE WERE MUCH HIGHER THAN TYPICALLY EXPECTED. UNFORTUNATELY THIS LED THE DEATH OF THIS INFANT AND THIS WARNING THAT CODEINE SHOULDN'T BE CONSIDERED A SAFE DRUG FOR INFANTS DURING BREAST FEEDING WITHOUT FURTHER INFORMATION. THIS IS WHAT THE CPIC GUIDELINES SAY ABOUT SIP 2D 6 AND CODEINE. THEY SAY IF YOU'RE ULTRA RAPID METABOLIZER YOU SHOULD AVOID CODEINE USE SO YOU'RE NOT INCREASE RISK FOR RESPIRATORY DEPRESSION. AND IF YOU'RE A POOR METABOLIZER YOU SHOULD ALSO HAVE A DIFFERENT THERAPY BECAUSE YOU'RE NOT GOING TO GET THERAPEUTIC BENCH THIS IS AN EXAMPLE OF WHAT THESE GUIDELINES LOOK LIKE. THEY SPECIFICALLY TELL YOU WHAT TO DO FOR ALTERNATIVES. SO IT ACTUALLY GETS OPTION FOR CLINICS TO ACT ON THIS GENOTYPE AND PHENOTYPE INFORMATION. A SECOND EXAMPLE IS CLOPIDAGRIL. AND THAT IS A PRODRUG. SO IT ACTUALLY NEEDS TO BE METABOLIZED LARGELY BY CYTOCHROME P 4502C 19 SHOWN HERE IN THE RED CIRCLE. TO THIS ACTIVE METABOLITE. AND THIS ACTIVE METABOLITE IS WHAT'S RESPONSIBLE FOR THE ANTI-PLATELET EFFECT OF CLOPEDAGRIL. LOOK AT THE LEVELS OF THIS ACTIVE METABOLITE, THIS IS WHAT THE DRUG IS DEVELOPED FOR, PEOPLE WITH A NORMAL GENOTYPE AND THESE ARE INDIVIDUALS WHO HAVE ONE OR TWO COPIES OF THIS COMMON VARIANT ALLELE. THEY HAVE MUCH LOWER LEVELS OF THIS ACTIVE METABOLITE. THIS IS IMPORTANT, THIS IS JUST MEASURED IN VITRO ON PLATELET AGGREGATION. THESE INDIVIDUALS DO NOT GET THE SAME EFFECT AS YOU WOULD EXPECT BASED ON NORMAL POPULATION. MORE IMPORTANTLY THIS TRANSLATES INTO A CLINICAL PHENOTYPE AND THIS CASE, DEATH OR ACUTE MI STROKE IN INDIVIDUALS WHO CARRY, LOOK AT THE RED LINE HERE, THESE ARE INDIVIDUALS WHO CARRY 2 COPIES OF A VARIANT ALLELE OF SIP 2C 19. SO THESE INDIVIDUALS ARE MUCH MORE LIKELY TO HAVE ONE OF THESE SERIOUS ADVERSE EVENTS, WHEN TREATED WITH CLOPIDIGRIL WHICH IS WHAT IT'S SUPPOSED TO PREVENT FROM HAPPENING. SO HERE AGAIN ARE THE CPIC GUIDELINES THEY SAY IN POOR METABOLIZERS WHO HAVE TWO COPIES OF A VARIANT ALLELE OF SIP 2C 19 YOU SHOULD HAVE ALTERNATIVE ANTI-PLATELET THERAPY, UNLESS THERE'S OTHER STRONG INDICATIONS NOT TO. THIS IS THE SPECIFIC TO INDIVIDUALS WHO ARE GETTING STINT AFTER ACUTE CORONARY EVENTS. AND JUST TO ILLUSTRATE, AND DR. WINSHELL BAUM WILL ILLUSTRATE MORE TOMORROW HOW HARD TO IMPLEMENT THESE TYPES OF RECOMMENDATIONS, THERE WAS THIS IS JUST A HANDFUL OF EDITORIALS AND COMMENTARIES THAT CAME ON BOARD AFTER THE FDA PUT THIS IN A BLACK BOX WARNING SIP 2C GENOTYPE BEFORE TREATING WITH CLOPINAGRIL CLEARLY NOT EVERYONE CARDIOLOGISTS IN IN PARTICULAR THOUGHT IT WAS A GOOD IDEA. THOUGH PEOPLE LIKE OURSELVES MIGHT SAY THAT LOOKS LIKE STRONG EVIDENCE. AND IF YOU WERE TAKING IT YOU WOULD WANT TO KNOW. BUT IT'S REALLY BEEN DIFFICULT TO GET THIS ADOPTED BY CLINICIANS BROADLY. I THINK YOU WILL HEAR MORE ABOUT THAT TOMORROW. FROM THE LAST EXAMPLE OF GERM LINE POLYMORPHISM IS WITH ABACAVIR. SO ABAKAVI,R IS ONE OF MANY DRUGS THAT'S RECOMMENDED TO BE USED FOR THE TREATMENT OF HIV AIDS THESE ARE FROM THE GOVERNMENT GUIDELINES FOR INITIATION OF TREATMENT OF HIV. SO ABACAVIR IS ABBREVIATED HERE ABC, IT'S FOUND IN BOTH THE FIRST LINE RECOMMENDATIONS AS WELL AS ALTERNATIVE RECOMMENDATIONS INTEGRATION INHIBITOR BASED OR PI BASED COMBINATIONS THAT ARE PROPOSED FOR USE ON -- IN INITIAL TREATMENT. SO ABACAVIR IS ONE OF THOSE -- ONE OF A HANDFUL OF DRUGS THAT CAUSE SEVERE HYPERSENSITIVITY REACTIONS. THIS IS RECOGNIZED EARLY ON, INCIDENCE AND CAUCASIAN POPULATIONS IS ABOUT 5%. LESS THAN AFRICAN AMERICAN POPULATIONS. IS RELATIVELY DOSE INDEPENDENT. TYPICALLY OCCURS IN FIRST SIX WEEKS AND OCCURS IN FIRST THREE WEEKS. THIS IS IMPORTANTLY A VERY SERIOUS ADVERSE REACTION THAT CAN LEAD TO MULTIPLE ORGAN FAILURE AND DEATH. CLINICIANS WERE AWARE OF THIS EARLY ON IN THE MARKET AND RELUCTANT TO USE THE DRUG BECAUSE OF IT. IT REQUIRES IMMEDIATE ATTENTION AND OBVIOUSLY STOPPING THERAPY. THIS WAS ACTUALLY A GOOD GRIP OF CLINICIANS TO HAVE THIS TYPE OF PROBLEM BECAUSE THEY'RE FAMILIAR WITH GENETICS, THEY THINK ABOUT VIRAL GENETICS ALL THE TIME. SO THERE WAS A PRETTY GOOD RECEPTION OF THIS DATA. THEY QUICKLY DISCOVERED THERE WAS A SPECIFIC HLA ALLELE, 5701. THAT WAS LARGELY RESPONSIBLE FOR THE HYPERSENSITIVITY REACTION. YOU CAN SEE PROBABLY MOST IN THIS ROOM WHERE NEVER SEE ODDS RATIO OF 117 BUT THIS WAS A REALLY STRONG ASSOCIATION, INDIVIDUALS WHO CARRY THOSE HLAB 5701 ALLELE IN THIS ONE COPY OF ALLELE, WERE MUCH MORE LIKELY TO HAVE A HYPERSENSITIVITY REACTION. SO THIS WAS A REALLY GOOD INDICATION OF RISK FOR DEVELOPING THE HYPERSENSITIVITY REACTION. THIS LED TO A RANDOMIZED CONTROL TRIAL WHICH IS VERY UNUSUAL IN PHARMACOGENOMICSMENT AND ONE REASON WHY I THINK THEY WILL TOUCH ON THIS TOMORROW, ONE REASON IT'S BEEN HARD TO ADOPT THIS CLINICALLY IS CLINICIANS WANT RANDOMIZED CONTROL TRIAL. THEY ACTUALLY DID DO ONE IN AUSTRALIA TO ACTUALLY GENOTYPE AHEAD OF TIME. AND THEN DOSED BASED ON WHETHER YOU HAVE THIS ALLELE OR NOT. THEY COULD COMPLETELY PREVENT THIS HYPERSENSITIVITY REACTION, BY TREATING -- GENOTYPING AHEAD OF TIME AND JUST NOT GIVING THE DRUG. SO THIS CLEARLY WORKS. THIS IS AN EXAMPLE THAT'S BEEN ADOPTED COMPLETELY AND NO ONE WOULD NOW GIVE ABACAVIR AT LEAST IN THE U.S. WOULD NOT GIVE ABACAVIR WITHOUT GENE TYPING FIRST AND THEY OBSERVED THEY DON'T HAVE THIS ALLELE. THERE ARE MANY PEOPLE EFFECTIVELY TREATED WITH ABACAVIR THAT'S NEVER BEEN GENOTYPED, THAT'S RECOGNIZED AS OKAY ALSO BECAUSE OF THE WAY WE KNOW THAT THIS HYPERSENSITIVITY PRESENTS. SO YOU CAN SEE IF YOU GO BACK TO THESE GUIDELINES, THAT IT SAYS THESE COMBINATIONS THAT HAVE ABACAVIR ONLY HLAB 5701 NEGATIVE. THESE ARE INCLUDED IN THE GOVERNMENT GUIDELINES AS WELL AS IN THE FDA LABEL FOR THE DRUG. MOVING ON TO SEMATIC VARIATION. A LOT OF INTEREST IN TARGETED DRUG THERAPY IN THE AREA OF ONCOLOGY. A LOT OF TUMOR SEQUENCING BEING DONE TRYING TO UNDERSTAND CAN WE SEQUENCE TUMORS AND CAN WE DIRECT THERAPY PERSONALIZED THERAPY FOR PATIENTS TUMOR. THE SHORT ANSWER IS WE HAVE A LONG WAY TO GO TO GET THERE BUT WE ARE GENERATING A LOT OF SEQUENCE DATA, NOW IT'S A MATTER OF UNDERSTANDING WHICH DRUGS WORK FROM WHICH MUTATIONS. SO THIS IS AN EVER EXPANDING LIST. THIS IS RELATIVELY UP TO DATE ON SEMATIC GENETIC VARIATION. AND THESE GENES WE KNOW SPECIFIC MUTATIONS RESPOND DIFFERENTLY TO PARTICULAR DRUGS. I'M GOING TO GIVE YOU A COUPLE OF EXAMPLES OF THIS. THE FIRST EXAMPLE OF THIS WAS WITH JEFITANIB. THIS WAS NOT DEVELOPED WITH THIS IN MIND BUT DURING THE COURSE OF EARLY USE OF IT, A TYROSINE KINASE INHIBITOR IN NON-SMALL CELL LUNG CANCER, CLINICIANS NOTICED THERE WAS A SUBSET OF PATIENTS THAT JUST DID NOT RESPOND AT ALL TO THIS DRUG. IN LOOKING AT THE TUMORS OF THESE PATIENTS, WHAT THEY FOUND IS THAT INDIVIDUALS WHO HAD A SPECIFIC MUTATION IN EGFR, THE TARGET FOR THIS INHIBITOR RESPONDED MUCH BETTER THAN THOSE WHO DO NOT HAVE THE MUTATION. WHICH IS SHOWN DOWN HERE. THESE ARE MUTATION NEGATIVE. SO THESE INDIVIDUALS WITH THE EGFR MUTATION HAD A GOOD RESPONSE, THEY ACTUALLY DID WORSE, THEY DID WORSE IF YOU DIDN'T HAVE THIS MUTATION. SO THIS IS AN EXAMPLE WHERE TUMORS SEQUENCE WAS DETERMINING WHETHER YOU WOULD RESPOND TO DRUG OR NOT AND CLEARLY WE SHOULD NOT BE GIVEN GEFITNIB TO THESE INDIVIDUALS, THAT WON'T HELP, WE NEED SOMETHING DIFFERENT. THIS IS ANOTHER EXAMPLE WITH THE KIT GENOTYPE AND IN THIS CASE YOU CAN SEE IF YOU HAVE SHOWN HERE WITH THIS YELLOW LINE, PROGRESSION FREE SURVIVAL, A MUTATION IS EXON 11 OF KIT, MEANS YOU ARE GOING TO HAVE A MUCH POORER RESPONSE TO TREATMENT WITH SENITANIB. SO YOU CAN SEE THESE ARE QUITE DIFFERENT IN PROGRESSION FREE SURVIVAL. AS WELL AS OVERALL SURVIVAL. THESE INDIVIDUALS YOU ARE NOT GOING TO WANT TO BE TREATING WITH FETINITIB. PROBLEM IS WHAT DO YOU TREAT WITH, THAT'S BEEN THE CHALLENGE. IT'S OFTEN EASY TO FIGURE OUT WHAT DOESN'T RESPOND BUT WE OFTEN DON'T HAVE YET DRUGS AVAILABLE OR DON'T HAVE THE KNOWLEDGE ABOUT THOSE DRUGS TO WHAT TO DO NEXT. MORE COMPLICATED HIGHLY DEPENDENT MUTATION SPECTRUM IN THESE TUMORS IS DEPENDENT ON THE DRUGS THEY ALREADY HAD. SO PATIENTS COME TO STUDIES LIKE THIS WITH VERY DIFFERENT PRE-THERAPY, SO YOU REALLY END UP WITH A SPECTRUM OF MUTATIONS. SO NOW THE EFFORTS ARE IN TRYING TO UPHOLD THOSE APART AND TRYING TO FIGURE IF YOU CAN COME UP WITH GENERAL DOSING DIED LINES BASED ON MUTATIONS. FOR FINITIN,B, FOR INDIVIDUAL WHOSE HAVE BEEN TREATED HEMATOANYBODY HAVE DIFFERENT MUTATIONS. SO IN THIS CASE THIS EXON 1718 MUTATION IN KIDS RESULTS IN A MUCH POORER RESPONSE BOTH AGAIN WITH RESPECT TO PROGRESSION FREE AND OVERALL SURVIVAL. SO THIS ILLUSTRATING THE COMPLEXITY OF THIS GENOMIC LANDSCAPE AND TUMORS THAT WE'RE REALLY TRYING TO PERSONALIZE THERAPY FOR. SO I THINK YOU WILL SEE THIS CHANGE A LOT IN THE NEXT COUPLE OF YEARS. BUT THERE'S STILL A LOT OF WORK TO BE DONE. WE'RE STILL LIMITED BY DRUGS THAT ARE AVAILABLE. AND WE DON'T ALWAYS HAVE DRUGS FOR THESE DIFFERENT MUTATIONAL PHENOTYPES. SO I ALSO MENTIONED THAT WE HAVE BEEN DEVELOPING DRUGS THAT ARE SPECIFIC FOR PEOPLE THAT OVEREXPRESS OR UNDEREXPRESS IN SOME CASE A SPECIFIC PROTEIN. THIS IS THE FIRST EXAMPLE, THIS IS HERCEPTIN OR TRASTUZIMAB. IT WAS NOTICED THAT THERE WERE BREAST CANCER -- BREAST TUMORS THAT OVEREXPRESS THIS HER 2 PROTEIN. FOR THOSE SUBSET OF BREAST TUMORS YOU CAN TARGET THE HER 2 OVEREXPRESSION. THAT THAT WOULD BE VERY EFFECTIVE IN THIS SUBGROUP OF PATIENTS. SO THIS DRUG HERCEPTIN WAS DEVELOPED WITH THIS IN MIND AND REPRESENTS WHAT THE TREND IS NOW IS TO UNDERSTAND THESE UNDERLYING GENOMIC PRETTIES POSITIONS EARLY DURING DEVELOPMENT AND AT THE SAME TIME DEVELOP DIAGNOSTICS THAT CAN IDENTIFY WHICH TUMORS ARE ACTUALLY OVEREXPRESSING FOR EXAMPLE HERCEPTIN. YOU WOULD USE THAT TO DECIDE WHO WILL RECEIVE THIS THERAPY. THAT WAS DONE, THIS HAS BEEN ON THE MARKET ALMOST 15 YEARS NOW. AS YOU CAN SEE IN THE EARLY STUDIES THIS IS COMPARING CHEMOTHERAPY ALONE, STANDARD OF CARE, FOR METASTATIC BREAST CANCER IN 2000 WITH CHEMOTHERAPY PLUS TRASTUZIMAB ONLY IN THOSE INDIVIDUALS WHO OVEREXPRESS THE HER-2 PROTEIN. YOU CAN SEE WITH RESPECT TO PROGRESSION-FREE SURVIVAL YOU GET A VERY NICE RESPONSE, AS WE OFTEN SEE IN ONCOLOGY, WE OFTEN DON'T, THAT DOESN'T ALWAYS TRANSLATE INTO OVERALL SURVIVAL. THIS IS UNFORTUNATELY QUITE TRUE. SO WHAT ABOUT DISCOVERY? SO THERE IS A LOT OF WORK BEING DONE IN PHARMACOGENETIC DISCOVERY. IN SOME WAYS MOST OF THE EXAMPLES I GAVE YOU ARE STRAIGHT FORWARD, THERE WERE OFTEN A SINGLE GENE SOMETIMES THE DRUG METABOLIZING ENZYME A SINGLE VARIANT THAT'S ASSOCIATED WITH A VERY WIDE RESPONSE. THAT DOESN'T EXPLAIN MOST COMPLEX DRUG RESPONSE PHENOTYPES. SO THIS IS WHERE WE HAVE BENEFITED FROM THE TECHNOLOGIES THAT DR. HOOD WAS TALKING ABOUT EARLIER. IN PARTICULAR, THE USE OF GENOME WIDE GENOTYPING AND NEXT GENERATION SEQUENCING HAS REALLY MOVED THIS AREA PHARMACO GENOMIC DISCOVERY ALONG. IT ALLOWS US A MEEK NICKICING OF DRUG RESPONSE AND TOXICITY SO YOU DON'T HAVE TO KNOW ANYTHING A AHEAD OF TIME ABOUT YOUR DRUG. IT'S PROVIDING A NEW BIOLOGICAL CLUES ABOUT MECHANISM, IT ALSO IS GENERATING A LOT OF DATA WHICH YOU ARE ALL INTERESTED IN, BUT WE CAN THEN MINE FOR FURTHER INFORMATION RELATED TO DRUG RESPONSE AND TOXICITY. I WOULD LIKE TO ILLUSTRATE THIS WITH JUST BRIEFLY WITH AN EXAMPLE FROM MY LABORATORY. WHEN WE HAVE BEEN USING GENOME WIDE ASSOCIATION STUDIES AND MORE RECENTLY DOING EXON SEQUENCING TO IDENTIFY NEW GENETIC MARKERS OF VARIATION AND DRUG RESPONSE. I BELIEVE YOU SAW THIS IN THE PREVIOUS TALK AS WELL, THIS IS THE LATEST GREEN SHOT FROM THE GWAS CATALOG. WHAT I WANT TO POINT OUT IS ONE CATEGORY THESE HITS ARE CATEGORIZED AS IS RESPONSE TO DRUG. BUT IF YOU LOOK AT ALL THESE GENOME WIDE ASSOCIATIONS THAT HAVE BEEN PUBLISHED, 2% ARE RELATED TO PHARMACOGENOMICS. SO WE'RE LAGGING BEHIND IN THE WHOLE HUMAN GENETICS FIELD AND THIS IS RELATED TO AVAILABILITY OF SAMPLES. WE DON'T HAVE LARGE ENOUGH SAMPLES TO BE DOING THESE STUDIES SO THAT'S REALLY WHY WE'RE SO FAR BEHIND JUST DISEASE GENETICS. SO THE APPROACH THAT WE TAKE IS START WITH PATIENTS. GET SAMPLES, PHENOTYPE AND BLOOD SAMPLE EITHER DO GENOME WIDE ASSOCIATION USING THESE GENE CHIPS YOU SAW EARLIER OR EXOME SEQUENCING. THIS INVOLVES A LOT OF COMPUTATIONAL ANALYSIS, BUT THEN BRINGING THIS BACK INTO THE LAB TO REALLY UNDERSTAND WHAT DO THESE GENES THAT WERE IDENTIFYING, HOW DO THEY RELATE TO DRUG TOXICITY? AND EVENTUALLY BACK TO THE PATIENT. WE ARE WORKING ON CHEMOTHERAPY INDUCED NEUROPATHY. THIS IS A IMPORTANT TOXICITY AND ON COG PATIENTS, 30 TO 40% OF CANCER PATIENTS BOTH VARIANT PERIPHERAL NEUROPATHY AT SOME TIME DURING THEIR TREATMENT IS IMPORTANTLY ONE OF THE MOST COMMON REASONS THAT PATIENTS STOP THEIR THERAPY. AND WE KNOW THAT IF YOU STOP YOUR THERAPY EARLY THAT THAT'S EFFECTING YOUR RESPONSE RATE AS WELL. IT ALSO AFFECTS QUALITY OF LIFE. FOR EXAMPLE IN EARLY BREAST CANCER THIS IS COMMONLY TREATED WITH CYTOTOXIC AGENTS AND IT'S A RELATIVELY HEALTHY BUT WE AGAIN END UP HARMING THEM IN THE COURSE OF TRYING TO HELP THEM. THERE'S COURSE OF DRUG THERAPIES AND WE MANAGE SYMPTOMS IN THESE PATIENTS WITH PERIPHERAL NEUROPATHY. THE INTENT IS TO -- WAS TO DEFINE NEW GENETIC MARKERS FOR THIS TOXICITY, WHO IS AT RISK. THAT COULD INFORM WHETHER WE GET THESE DRUGS OR HOW WE GET THESE DRUGS TO THESE PATIENTS. BUT WE ALSO HOPE THAT WE MIGHT BE ABLE TO USE THIS INFORMATION TO DESIGN MORE EFFECTIVE WAYS TO TREAT THIS TOXICITY. I THINK IT'S FAIR TO SAY NOWHERE IN THE FORESEEABLE FUTURE WE STOP USING CYTOTOXIC AGENTS IN ON DOG SO WE NEED TO THINK ABOUT HOW DO WE DEAL WITH THIS TOXICITY. WE KNOW THERE IS A NUMBER OF RISK FACTORS FOR SENSORY PERIPHERAL NEUROPATHY, HOW WE GIVE THE DRUG, THE DOSE WE GIVE, HOW OFTEN AFFECTS THE PATIENT RISK OF DEVELOPING THIS. WE KNOW IT'S CUMULATIVE DOSE DEPENDENT TOXICITY. IF YOU HAD PRIOR NEUROTOXIC DRUG THERAPY YOU'RE INCREASED RISK. WE ALSO KNOW THIS IS BECOMING INCREASINGLY IMPORTANT, PATIENTS WHO MIGHT HAVE NEUROLOPOTHYS FOR OTHER REASONS FOR EXAMPLE DIABETES ARE ALSO INCREASE RISK OF DEVELOPING WORSENING NEUROPATHY WHEN WE GIVE THEM THESE AGENTS. SO WE KNOW ALL THESE CHIN FACTORS, -- CLINICAL FACTORS BUT WE ALSO KNOW THIS DOES NOT ALONE EXPLAIN INCIDENCE OF TOXICITY. SO WE AND OTHERS HAVE BEEN LOOKING AT WHAT ARE THE GENETICS MIND THIS TOXICITY. SO JUST TO HIGHLIGHT SOME OF THE FINDINGS, I DON'T HAVE TIME TO GO INTO ALL THE WORK THAT WE HAVE BEEN DOING OVER THE LAST TEN YEARS OR SO, BUT WE WERE ABLE USING THESE GENOME WIDE APPROACHES TO IDENTIFY NEW GENES THAT MAYBE A GRADUATE PHENOTYPE DOWN FOR A YEAR THOUGHT THROUGH ALL THE PROCESSES THAT COULD BE INVOLVED YOU MIGHT COME UP WITH THESE CANDIDATE GENES. THIS ALLOWS YOU TO GO IN AND DO THIS DISCOVERY WITH VERY LITTLE KNOWLEDGE OF THE UNDERLYING BIOLOGICAL MECHANISMS OF THE TOXICITY. SO HERE ARE TWO EXAMPLES, WE FOUND FOUR MAJOR FINDINGS SO FAR THAT WE HAVE BEEN ABLE TO REPLICATE FOR EXAMPLE THIS SNP AND GENE FGD 4 OR EPAK 5 MY E YOU CAN SEE INDIVIDUALS IN THE GREEN LINES HERE HOLD TWO COPIES OF THIS VARIANT ALLELE. AND THEY'RE MUCH MORE LIKELY TO DEVELOP SENSORY PERIPHERAL NEUROPATHY AT LOWER CUMULATIVE PACK LA TACK SOL DOSE, THAN REFERENCE PHENOTYPE OR ONE COPY. SO THESE ARE THE TYPES OF FINDINGS YOU CAN GET OUT OF THESE GENETIC PHARMACOGENETIC DISCOVERY STUDIES. IMPORTANTLY, THESE ARE MAKING SENSE. WE FOLLOWED UP, THERE WAS A -- ORIGINALLY DATA IN THE LITERATURE THAT SUGGESTED WE MIGHT BE ON TO SOMETHING AND WE HAVE SINCE BROUGHT THIS INTO THE LAB. AT UCSF AS WELL. FOR EXAMPLE THIS EFFERENT A 5 GENE WAS ONE OF A HANDFUL OF GENES THAT IS KNOWN TO HAVE DIFFERENTIAL EXPRESSION. THIS IS LOOKING AT RNA, FOLLOWING A PERIPHERAL NERVE INJURY IN A MOUSE MODEL. AND IN RESPONSE TO THAT PERIPHERAL NERVE INJURY, EPHA 5 TYPICALLY GOES UP TO HIGH LEVELS RIGHT AWAY, IN A MOUSE DEFICIENT IN REPAIR, YOU DON'T SEE THIS CHANGE. SO THIS WAS QUITE INTERESTING AND MADE SENSE WITH OUR PERIPHERAL NEUROPATHY PHENOTYPE, WHAT WE ARE WORKING ON NOW TO TRY TO UNDERSTAND OUR WORKING HYPOTHESIS IS INDIVIDUALS WITH AN EPHA 5 GENETIC VARIANT THAT LEADS TO LOSS OF FUNCTION WILL HAVE POOR RECOVERY FROM THOSE NERVE INJURY. AND WE HAVE SOME PROMISING STUDIES IN THE LAB RIGHT NOW THAT ARE SUPPORTING THAT HYPOTHESIS. WE FOUND THIS SNP IN FDG 4, ALSO ASSOCIATED WITH INCREASE RISK OF DEVELOPING PERIPHERAL NEUROPATHY. THIS HAPPENED TO BE ONE OF THE GENES, THERE'S ABOUT 50 THAT CAUSE CHAR CO-TOOTH DISEASE, CONGENITAL NEUROPATHY. THESE ARE RARE MUTATIONS NOT FOUND IN THE GENERAL POPULATION. SO FOR EXAMPLE, THIS AMINO ACID CHANGE OR FRAME SHIFT MUTATION, WHERE YOU SEE VERY SIGNIFICANT CHANGES IN MYELINATION IN THESE NERVE BIOPSIES. SO YOU CAN SEE IN THE DARK BANDS HYPERMYELINATION, RIGHT NEXT TO COMPLETE DEMYELINATION. SO VERY UNUSUAL PATTERNS OF MYELINATION, HERE YOU SEE THIS UNUSUAL ARRANGEMENT OF THE MYLEN SHEATHE AROUND THE PERIPHERAL NERVE. SO AGAIN IT MADE SENSE, PEOPLE HAD MORE COMMON VARIATION IN THIS GENE MIGHT NOT HAVE ANY PHENOTYPE UNTIL YOU DOSE THEM WITH THE DRUG THEN YOU'RE GOING TO BE MORE SENSITIVE. SO WE'RE FOLLOWING UP WITH STUDIES ALONG THOSE LINES. WE HAVE ALSO BEEN ABLE TO USE THIS DATA TO TRY TO GET A BETTER FEEL FOR PATHWAYS WHAT PATHWAYS ARE INVOLVED. THERE'S SO MANY TOOLS OUT THERE THAT ALLOW YOU TO DO THIS TYPE OF ANALYSIS. WE WERE ABLE TO SHOW THAT MOST OF THE HERITABILITY SIGNAL WE SEE WERE RELATED TO GENES THAT ARE INVOLVED IN AXON EXTENSION AND REGULATION AND SPECIFICALLY THE OVERLAP BETWEEN THESE TWO PATHWAYS. WHEN YOU LOOK AT WHAT GENES ARE IN THIS OVERLAP OF THESE TWO PATHWAYS, A NUMBER OF GENES COME OUT THAT ALREADY ARE ASSOCIATED WITH SOME TYPE OF PERIPHERAL NERVE PHENOTYPE. SO AGAIN, THESE DATA SETS ARE RICH, THEY CAN BE MINED FOR MANY DIFFERENT PHENOTYPES AND TO GIVE YOU AGAIN BETTER IDEA OF BIOLOGY, SO THAT YOU CAN THEN TAKE THAT BACK TO IN OUR CASE INTERESTED IN DRUG DEVELOPMENT TOWARDS THESE TARGETS. LET ME END BY TALKING ABOUT PHARMACOGENOMICS AND DRUG DISCOVERY AND DEVELOPMENT, AND THIS WAS IMPORTANT FOR NEW DRUG TARGETS AS WELL AS HOLDS PROMISE IN STRATIFYING PATIENTS FOR CLINICAL TRIALS. SO THERE'S BEEN A LOT OF INTEREST IN USING GENETICS TO IDENTIFY NEW DRUG TARGETS. THIS IS ILLUSTRATING THE GENERAL IDEA WHERE YOU TAKE PATIENTS WITH A SPECIFIC DISEASE AND CONTROL PATIENTS WHO DON'T HAVE THAT DISEASE, DO THESE GENOME WIDE SNP ANALYSES LOOK FOR DISEASE SPECIFIC SNPS. FROM THOSE GENES WITH THESE POLYMORPHISMS RESIDE YOU CAN HAVE SOME IDEA ABOUT POTENTIAL TARGETS FOR TREATING THESE DISEASES. I THINK PROBABLY MANY OF YOU ARE AWARE, THESE THE BEST EXAMPLE OF THIS WITH DRUGS COMING ON THE MARKET IN THE LAST YEAR. THESE ARE WITH PSCK 9 MUTATIONS, AND IT WAS NOTED ABOUT A DECADE AGO THAT THERE WERE INDIVIDUALS WHO HAD MUTATIONS IN THESE GENES OR POLYMORPHISMS IN THESE GENES THAT HAVE MUCH LOWER LEVELS OF LDL CHOLESTEROL THAN THE GENERAL POPULATION. SO THIS OF COURSE MADE PEOPLE WONDER COULD YOU MOVE POPULATION DOWN TO LOWER LEVEL BY INHIBITING PSCK 9. WHAT REALLY DROVE THIS IS THAT LOOK AT CORONARY HART DISEASE, THE RISK WAS MUCH HIGHER INCIDENCE WAS HIGHER IF YOU DID NOT HAVE THE MUTATION COMPARED TO THOSE WHO DID. SEW INTERESTING CARDIOVASCULAR TARGET. NUMBER OF COMPANIES WORKED ON THAT, THIS WAS THE FIRST TO SHOW IF YOU INHIBITED PSCK 9 WITH THIS ANTIBODY, YOU CAN LOWER LDL CHOLESTEROL. THESE ARE DIFFERENT DOSE LEVELS. GIVEN INTRAVENOUSLY AND SUBCUTANEOUSLY. THE FIRST PSCK 9 INHIBITOR CAME ON THE MARKET LAST SUMMER SOMETIME. THIS IS A CLEAR EXAMPLE, THEY STARTED WITH GENETICS, THEY LOOKED AT PEOPLE AND LOOKED AT WHAT GENOTYPE WERE ASSOCIATED WITH A PARTICULAR PHENOTYPE AND USE THAT INFORMATION TO MOVE FORWARD. IT WAS MENTIONED ON THE PREVIOUS TALK ABOUT CWAS STUDIES, THESE ARE ALSO BEING USED NOW TO GUIDE DRUG DISCOVERY AND COMING UP WITH THESE NEW TARGETS. NOW THAT WE HAVE THE DATABASES FULL OF GENOTYPE DATA, AND WHERE THEY ARE CONNECTED AT LEAST WITH THE ELECTRONIC HEALTH RECORDS WHICH UNFORTUNATELY AREN'T AS MANY PLACES AS WE LIKE, THE LEADERS IN THIS FIELD HAVE BEEN INVESTIGATORS IN THE EMERGE NETWORK LED BY VANDERBILT WHO REALLY PIONEERS THIS AREA OF CWAS STUDIES. SO YOU CAN DO IS TAKE IN IN THIS CASE GENETIC POLYMORPHISM A SNP AND LOOK AT WHAT DOES IT ASSOCIATE WITH IN YOUR ELECTRONIC HEALTH RECORD. YOU CAN LOOK AT VARIOUS DISEASES OR, THESE ARE ICD 9 CODES THAT HAVE A STRONG ASSOCIATION SO YOU CAN SEE THIS SNP IN THIS TRANSCRIPTION FACTOR IRF-4 ASSOCIATED WITH A NUMBER OF CONDITIONS RELATED TO THE SKIN. SO THIS THEN SUGGESTS THAT YOU MIGHT CONSIDER SOMETHING RELATED TO IRF 4 OR TRANSCRIPTIONAL REGULATION PATHWAY AS A WAY TO TREAT SOME OF THESE CONDITIONS. AS MORE GENETIC DATA IS ASSOCIATED WITH ELECTRONIC HEALTH RECORDS, THIS HOLDS GREAT PROMISE FOR DISCOVERING NEW DRUG TARGETS SO THERE'S A LOT OF INTEREST IN THIS FIELD. FINALLY, GENOTYPE GUIDED CLINICAL TRIALS. THIS IS BEEN TALKED ABOUT FOR A LONG TIME. AND WE HAVE CASES DOING TRIALS BASED ON OVEREXPRESSION LIKE HERCEPTIN EXAMPLE BUT THERE'S ALSO AN INTEREST IN DOING PRE-CLINICAL STUDIES SO THAT YOU CAN A GOOD IDEA OF WHAT TYPE OF PERSON GIVES THIS GOOD RESPONSE BASED ON GENETICS EARLY ON. ONLY DO STUDIES IN THOSE INDIVIDUALS. PROBABLY MANY TRIALS FAIL JUST BECAUSE THERE'S NO PATIENT SELECTION. MANY DRUGS THAT WE SAY DON'T WORK ACTUALLY PROBABLY WORK OR WE KNOW THEY WORK IN HUMANS IN POPULATION. BUT COULD WE IDENTIFY THAT SUBPOPULATION OF PATIENTS EARLIER, IF WE CAN DO THIS THIS WOULD PROBABLY GREATLY INCREASE THE SUCCESS RATE OF DRUG DEVELOPMENT. I THINK WITH THE HIGH COST OF DRUG DEVELOPMENT AND THE NEED FOR BETTER DRUGS, YOU WILL SEE THIS USED MORE OFTEN. IT'S REALLY JUST GETTING ENOUGH GENETIC INFORMATION EARLY ON IN THE PRE-CLINICAL WORK YOU CAN APPLY IT. SO I JUST WANT TO END WITH I HOPE -- HOPEFULLY LEFT YOU WITH A FEW TAKE HOME MESSAGES THAT I TRIED TO SUMMARIZE HERE. I BELIEVE PHARMACOGENOMICS HOLDS GREAT PROMISE FROM PROVING DRUG TREATMENT, I THINK WE HAVE LOTS OF ROOM TO GO, WE HAVE IMPROVED BOTH RESPONSE TO DRUGS AS WELL AS PREVENT TOXICITY E WE CAUSE WITH DRUG THERAPY. AS YOU WILL SEE MORE ABOUT TOMORROW CLINICAL IMPLEMENTATION OF THESE FINDINGS EVEN WHEN VERY OBVIOUS REMAINS A CHALLENGE. YOU WILL SEE A GREAT EXAMPLE OF THE MAYO CLINIC AND HOW THEY HAVE BEEN ABLE TO DO THIS, AND THERE ARE A NUMBER OF OTHER REALLY ONLY A HANDFUL OF OTHER INSTITUTIONS THAT HAVE REALLY IMPLEMENTED THESE PHARMACOGENETIC TESTING IN THE COUNTRY BUT WHERE THEY HAVE THEY HAVE BEEN ABLE TO SHOW THEY'RE BENEFICIAL NOT ONLY TO THE PATIENT BUT ALSO TO THE HEALTHCARE SYSTEM IN TERMS OF COST. HOPEFULLY EVENTUALLY THIS WILL BE ADOPTED MORE. CLEARLY MODERN GENOMIC TECHNOLOGIES WITH SEQUENCING BEING MORE COMMON NOW, THIS WILL ONLY MAKE THIS BETTER. THIS IS REALLY FUELING PHARMACO GENOMIC DISCOVERY. WE'RE UNDERSTANDING MORE AND MORE ABOUT DRUG RESPONSE AND TOXICITY BY USING THESE TECHNOLOGIES. YOU WILL SEE A LOT MORE INTEREST IN USING GENOMICS USING GWAS AND CWAS STUDIES FOR THE IDENTIFICATION OF NEW DRUG TARGETS. AND CLEARLY COMPANIES ARE VERY INTERESTED AND SOME ARE DOING GENOTYPE BASED PATIENT STRATIFICATIONS IN ORDER TO IMPROVE THE DRUG DEVELOPMENT PROCESS AS WELL. SO WITH THAT I'M HAPPY, I THINK DO I HAVE TIME FOR -- I HAVE TIME FOR A FEW QUESTIONS. PHI LAST SLIDE. I THINK WE'RE MOVING CLOSER. >> I'M CINDY RUSSELL, UNIVERSITY OF MISSOURI, I'M NEW TO THIS AREA. THE SLIDE ON THE GENOME WIDE I ASSOCIATION STUDIES, CAN YOU EXPLAIN THAT SLIDE IN A LITTLE MORE DETAIL? IT'S NUMBER 44 AND IT HAD THE DIAGRAM OF THE 17 CATEGORIES. >> THE CWAS STUDY? >> YES. >> TITLED GENOME WIDE ASSOCIATION STUDY. SO IT'S BACK ABOUT -- IT'S QUITE A BIT FARTHER BACK, SEEMED LIKE AN IMPORTANT SLIDE AND I DIDN'T UNDERSTAND EXACTLY WHAT IT WAS SHOWING. THAT ONE. YES. >> DO SO WHAT THIS IS, THIS IS -- THESE ARE AVAILABLE IF YOU GO TO THIS WEBSITE. AND WHAT THIS IS, IS SHOWING ON EACH CHROMOSOME WHERE SIGNIFICANT STATISTICALLY SIGNIFICANT ASSOCIATIONS WITH A SNP IN THESE LOCATIONS, SO SOME POLYMORPHISM, SOMETIMES NOT ALWAYS ASSOCIATED WITH A GENE BUT SOMEWHERE IN THE REGION AROUND THE GENE, MANY OF THESE BECAUSE OF TECHNOLOGY AND THE WAY THAT WE DO THESE, SOMETIMES THEY END UP BETWEEN GENES AND WHAT'S CALLED GENE DESSERTS. BUT THIS IS SHOWING WHERE THEY'RE AT ON THE CHROMOSOME FOR EXAMPLE THIS IS CHROMOSOME 1. THEN BY THE COLOR IT'S TELLING YOU WHAT IT'S BEEN ASSOCIATED WITH. SO MOST OF THESE ARE FOR DISEASE SUSCEPTIBILITY. BECAUSE THAT'S WHERE MOST OF THE HUMAN GENETICS WORK HAS BEEN DONE IS DISEASE SUSCEPTIBILITY. SO THEY'RE CATEGORIZED INTO 17 TRAITS, ONE OF WHICH IS DRUG RESPONSE. SO OF THESE THAT ARE ON HERE, ALMOST 6,000 SO FAR, FOR SUMMER, THEY'RE UPDATED ALL THE TIME SO THIS IS JUNE. OF THESE 6,000 ASSOCIATIONS THAT ARE REPORTED, TWO PERCENT ARE RELATED TO DRUGS. IT'S EASIER TO GET HUNDREDS OF THOUSANDS OF PATIENTS WITH DIABETES THAN TO GET A THOUSAND PATIENTS TREATED WITH THE SAME DRUG UNDER SOMEWHAT CONTROL CONDITION WHICH IS WHY WE LAG SO FAR BEHIND. SO IT'S LOOKING FOR DOES THIS SNP ASSOCIATE, ARE YOU MORE LIKELY TO HAVE THIS DISEASE IF YOU HAVE THIS SNP. THESE ARE ALL I SHOULD SAY THESE ARE GENOME WIDE. SO THAT MEANS IT'S LOOKING AT ANYWHERE FROM 500,000 TO UPWARDS OF SEVERAL MILLION DIFFERENT GENETIC MARKERS ACROSS THE GENOME. >> WHAT YOU'RE LOOK AT GENETIC TESTING FOR WORK AROUND, DOES THE INSURANCE COMPANIES ARE NOT APPROVING GENETIC TESTING FOR THEM. AND DO YOU HAVE ANY SUGGESTIONS ON HOW WE CAN GET THESE INSURANCE COMPANIES TO DO GENETIC TESTING? >> THAT'S A GREAT QUESTION, I THOUGHT ABOUT INCLUDING WARFARIN BUT IT'S ALSO CONTROVERSIAL. AND SOMEWHAT DIFFICULT BECAUSE IT'S AN EXAMPLE WHERE THERE'S TWO GENES THAT ARE INVOLVED, SO YOU HAVE TO GENOTYPE TWO GENES AND IT'S A COMBINATION OF TWO SNPS THAT DETERMINE IT. I BELIEVE PROBABLY PAYERS WILL BE WHAT REALLY MAKES THIS STUFF GET IMPLEMENTED SO EVENTUALLY AS THESE CENTERS THAT ARE DOING THIS NOW, I DON'T ACTUALLY REMEMBER, DAVE WILL TALK ABOUT WARFARIN TOMORROW OR NOT, BUT AS THESE CENTERS DEVELOP MORE AND MORE EXPERIENCE WITH THIS GENOTYPING, THEY'RE GOING TO -- THEY ALREADY ARE, THERE'S PUBLICATIONS SHOWING THAT IS COST EFFECTIVE. LIKE IN THE CASE OF WARFARIN, IT'S COST EFFECTIVE BECAUSE PATIENTS DON'T END UP IN THE HOSPITAL BECAUSE OF BLEEDING EVENT OR WORSE, THAT THEY HAVE CARDIOVASCULAR EVENT BECAUSE OF NOT HAVING EFFECTIVE THERAPY. WITH THAT DATA THAT WILL MOVE IT FORWARD. THIS HAS BEEN -- WE HAVE KNOWN ABOUT THE EXAMPLE WITH WARFARIN AND SIP 2C 9 WE HAVE KNOWN ABOUT A WHILE, A LONG TIME, MORE THAN TEN CLEARS. (OFF MIC) HAS A WONDERFUL ARTICLE ABOUT WHY THEY ARE NOT APPROVING IT. THEY HAVE GOT -- AND EVERYTHING ELSE AND -- >> INTERESTING. >> GOOD INFORMATION, SOME ARE NOT APPROVING. >> SO THE OTHER -- SO THE OTHER ISSUE WITH THAT, THE REASON I WAS AVOIDING IT ACTUALLY, IT WAS -- NO, NO, IT'S GREAT. IT IS THE ONE OTHER EXAMPLE WHERE THEY HAVE DONE A RANDOMIZED CONTROL TRIAL AND SO YOU MIGHT KNOW THIS IS PROBABLY WHAT THEY'RE REFERRING TO, UNFORTUNATELY THERE WERE THREE RANDOMIZED CONTROL TRIALS THAT WERE DONE TWO FUNDED BY NHLBI, ONE DONE IN EUROPE, AND THE EUROPEAN ONE SUGGESTS IT'S USEFUL AND THE ONES HERE SUGGEST IT'S NOT USEFUL. YOU CAN CRITICIZE ALL OF THOSE. THAT'S COMPARING APPLES AND ORANGES AND SO THERE'S SOME ISSUES WITH THE WAY ALL OF THOSE STUDIES WERE DONE. IT IS DEFINING DEFINING WHO BENEFITS AND WHAT SUBSET BENEFITS. WITH PEDIGRIL, YOU ONLY DO THIS IF YOU'RE USING CLOPIDIGRIL FOR -- AFTER AT THIS PARTICULAR TIMES BECAUSE THAT'S WHERE THE DATA WAS THE STRONGEST AND SO THEY WENT WITH THAT, BECAUSE DATA WAS CLEAR THERE, EVEN WITHOUT THERE'S SOME HUGE CONTROVERSY, SO YEAH. YOU WILL HEAR MORE ABOUT PROBLEM CHALLENGES LIKE A PLACE LIKE MAYO YOU CAN DO IT BECAUSE THEY CAN TELL THEIR PHYSICIANS WHAT TO DO. THAT DOESN'T WORK FOR MOST PEOPLE. (OFF MIC) >> IS IT MORE UNIVERSITY DRIVEN? THE UNIVERSITY IS DOING THE RESEARCH SO THERE'S A HOPE THAT IT WILL BE PUBLIC VERSUS WHAT PHARMACEUTICAL COMPANIES MIGHT BE DOING INTERNALLY. BUT AREN'T BEING RELEASED NECESSARILY. >> THE GOOD QUESTION. SO THE PHARMACEUTICAL, MOST DRUGS THAT I WAS TALKING ABOUT, DRUGS ON THE MARKET FOR A LONG TIME, MOST OF THAT WORK IS DRIVEN BY ACADEMICIANS. WITH THE SUPPORT OF THE FDA GOING -- PEOPLE MAKE THIS THEIR PASSION TO GO TO THE FDA AND GET LABEL CHANGES. SO THAT'S KIND OF WHAT HAS LED THAT SO FAR. NOW A NEW DRUG DISCOVERY, I WOULD TELL YOU WHEN WE FIRST STARTED ACTIVELY DOING PHARMACOGENOMICS RESEARCH 20 YEARS AGO, THEY PHARMACEUTICAL INDUSTRY WAS VERY RELUCTANT TO LIMIT THEIR POPULATION THAT THEY MIGHT PRESCRIBE A DRUG FOR. SO THEY WERE NOT VERY INTERESTED IN SUBDIVIDING THEIR POPULATION INTO THOSE WHO RESPOND AND THOSE WHO WON'T FROM A FINANCIAL STANDPOINT. THEY HAVE COMPLETELY REVERSED COURSE WITH ALL THIS EMPHASIS ON PRECISION MEDICINE AND REALLY TRYING TO MAKE SURE THAT WE'RE DEVELOPING DRUGS THAT WORK FOR INDIVIDUAL PATIENTS OR NOT REALLY INDIVIDUAL PATIENTS BUT GROUPS OF PATIENTS WHO LOOK ALIKE. SO THAT -- THEY HAVE CHANGED FROM A DISCOVERY SIDE. SO WHAT YOU WILL SEE IS THAT THEY ARE REALLY THE DRIVERS OF USING GENOMICS FOR DRUG DISCOVERY. THEY'RE REALLY VERY INTERESTED, THEY DON'T HAVE ACCESS TO THE ELECTRONIC HEALTH RECORD DATA SO BUT THEY'RE VERY INTERESTED IN THE DATA COMING OUT OF THE EMERGE NETWORK WHERE ELECTRONIC HEALTH RECORDS ARE LINKED TO GENOTYPES AND REALLY TRYING TO USE THAT AS A WAY TO DEVELOP NEW TARGETS, I THINK MOST PEOPLE AGREE NOW THAT STARTING USING ANIMAL MODELS IS NOT THE WAY GET A GOOD TARGET, WE NEED TO START WITH PATIENTS AND LOOK FOR THESE DIFFERENCES LIKE YOU SAW WITH THIS MUTATION THAT I GAVE YOU AN EXAMPLE OF AND THEN WE DO NEED TO GO BACK AND DO RESEARCH OBVIOUSLY IN OTHER MODELS BUT JUST START WITH THE PATIENT TO GET THAT INFORMATION. SO THEY HAVE REALLY COMPLETELY CHANGED GEARS NOW. [APPLAUSE] >> THANK YOU SO VERY MUCH DR. KROETZ FOR HIGHLIGHTING THE IMPORTANT IMPLICATIONS OF VARIATION IN DRUG RESPONSE AND PHARMACOGENOMICS AND THE GREAT EXAMPLES AS WE MOVE TO OUR PRECISION HEALTH. SO OUR IDEA GOAL IS EVERYBODY ALL TOGETHER NOW, THE RIGHT DRUG, THE RIGHT TIME, THE RIGHT INDICATION, THE RIGHT DOSE. ONE MORE. AND THEN THE RIGHT PATIENT. WE ARE REALLY DELIGHTED NOW AS WE'RE MOVING ON THIS AFTERNOON TO INTRODUCE OUR NEXT SPEAKER, DR. ZHONGMING ZHAO. DR. ZHAO IS THE DR. DORIS L. ROSS PROFESSOR AND FOUNDING DIRECTOR OF THE JOINT CENTER FOR PRECISION HEALTH AT THE SCHOOL OF BIOMEDICAL INFORMATICS AND SCHOOL PUBLIC HEALTH AT THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON. UT HEALTH. BEFORE DR. ZHAO JOINED UT HEALTH IN 2016, HE WAS THE INGRAM PROFESSOR OF CANCER RESEARCH AND PROFESSOR OF BIOMEDICAL INFORMATICS AD VANDERBILT MEDICAL CENTER AND CHIEF BIOINFORMATICS OFFICER VANDERBILT INGRAM CANCER CENTER IN NASHVILLE, TENNESSEE. HE HAS MORE THAN 18 YEARS OF BIOINFORMATICS AND SYSTEMS BIOLOGY RESEARCH EXPERIENCE AND HAS CO-AUTHORED 256 PAPERS IN THE AREA. DR. ZHAO WILL PRESENT TRANSLATIONAL BIOINFORMATICS. PLEASE JOIN ME IN A REALLY NICE WELCOME FOR DR. ZHAO. >> HELLO, CAN YOU HEAR ME? BETTER? OKAY. THANKS TO THE ORGANIZERS FOR THE INVITATION. IT IS MY GREAT HONOR TO TALK ABOUT CONSOLATION OF BIOINFORMATICS, IT'S A VERY EXCITING EVENT. AS BIOINFORMATITION, I LEARN FROM OTHER PEOPLE, SO TODAY I ENJOY ALL TALKS SO FAR, VERY EXCITING, VERY COOL. ACROSS THE COUNTRY NOW EVERYWHERE SO MAKES ME FEEL HAPPY, FEEL COMFORTABLE FROM NASHVILLE TO TEXAS BECAUSE TEXAS IS ALWAYS HOT. TRILLION DOLLAR LET'S CONTINUE ON THAT. AND SEE WHETHER I CAN BRING YOU ADDITIONAL COOL STUFF TODAY. SO MY TALK IS I WOULD SUGGESTED TO HAVE THIS BIG TITLE, TRANSLATIONAL BIOINFORMATICS BUT REALLY I LIKE TO BE SPECIFIC SO TODAY I MAINLY TALK ABOUT THE SUBTYPE OF USING INFORMATICS APPROACH, ESPECIALLY THE GENOMICS DATA. THE DATA MINING TO IDENTIFY THE MUTATIONS ON A GENE SPECIFIC TO THE DRUG REPOSITIONING. SO A LOT OF WORK BEING DONE IN VANDERBILT BECAUSE RESENTENCELY I MOVED TO TEXAS SO I STILL USE MY PREVIOUS WORK TO TALK ABOUT -- TO PRESENT HERE. SO MY FIRST SLIDE IS BASICALLY I WOULD LIKE TO SHARE WITH EVERYONE MOST OF YOU ALREADY KNOW THIS. SEVERAL SPEAKERS ALSO MENTION ESPECIALLY AMAZING LIKE GENOME SEQUENCING, I HOPE I CAN DO IT SOME TIME SOON BUT AS A HUMAN GENOME SEQUENCING, A MAJOR GOAL HAS BEEN FOR A WHILE TO HOW -- THOUSAND DOLLARS GENOME SEQUENCING. UNDER THIS GOAL ESSENTIALLY RICH ABOUT A -- REACHED A YEAR AGO AND SEVERAL YEARS AGO LIKE THREE OR FOUR YEARS AGO THERE WAS A BIG PRIZE LIKE HUNDRED MILLION DOLLARS FOR THOSE PEOPLE WHO CLAIM THEY WANT DOLLARS FOR GENOME SEQUENCING. BASICALLY THEY HAY NOUNSED THEIR SYSTEM, -- ANNOUNCED THEIR SYSTEM, JUST FACT, THE HIGH SEQ EXTRINSIC SYSTEM, THEY CLAIM THEY CAN DO AVERAGE $1,000 PER GENOME SEQUENCING. AND ALSO THEY RELEASE THE OTHER GENOME SEQUENCING. ANOTHER CASE I WOULD LIKE TO MENTION HERE BECAUSE A LOT OF THE WORK I'M TALKING, I'M GOING TO TALK IS RELATED TO THE DATA AND HOW WE UTILIZE THE MASSIVE AMOUNT OF DATA. WE CAN DO ADDITIONAL DATA MINING. ANOTHER CASE IS THE ARMED DIAGNOSIS DISEASE NETWORK. TODAY WHEN I -- SOMEONE MENTIONED, JUST -- HE TRIED TO INTRODUCE TO OTHER PEOPLE SAY THIS IS THE NIH CLINICAL CENTER UNDER THIS DIAGNOSIS DISEASE NETWORK IS PART OF IT. SO I WAS FORTUNATE TO PARTICIPATE IN THIS NETWORK WHEN I WORKED IN VANDERBILT. SO THAT NETWORK WHEN IT WAS FOUNDED, THAT'S 2014, THE -- ONE OF THE -- ADVANTAGE, THEY OFFERED IT TO THE PATIENT INVOLVED IN THE SYSTEM, IS TO DO THE GENOME SEQUENCING AND PRIZE $1,100 PER GENOME SEQUENCING. WHOLE GENOME SEQUENCING OR WHOLE EXOME SEQUENCING. THIS IS VERY IMPORTANT BECAUSE ONCE WE REACH THIS GOAL, WHAT WE EXPECT, RIGHT NOW EVERY DAY WE SEE THESE HAPPENING, MASSIVE AMOUNT OF GENOMIC SEQUENCING DATA. HOW CAN WE TAKE IT ADVANTAGE OF IT. THIS IS ANOTHER SLIDE SHOW THE DATA HAVE CHANGED, MENTIONING IN NATURE, THEY COVER FOR SEVERAL PAPERS TO TALK ABOUT THE BIG DATA SCIENCE. ONE SLIDE HERE GENOME SEQUENCING. MAYBE YOU CAN SEE THIS ONE, AS YOU CAN SEE, THIS IS HISTORICAL AND BY THE TIME THE PAPER WAS PUBLISHED THIS WAS A LAW CALLED -- LAW EXPONENTIAL GROWTH. PEOPLE EXPECT NOT LIMITATION OF THE GROWTH. HOWEVER, IF YOU LOOK AT THE -- BASED ON HISTORICAL GROWTH, IT'S ACTUALLY MUCH FASTER THAN THE MOORE'S LAW AND THEY ARE RIGHT NOW MAJOR GENOME SEQUENCING MANUFACTURER SO -- BOTH OF THEM AS YOU CAN SEE MUCH FASTER THAN THE LIMIT OF WHICH WAY WE CAN WE CAN IMAGINE ON THAT. THIS SUGGESTS WE WILL SEE MORE FUTURE MORE AND MORE DATA, IT'S NOT NEWS TO ME BUT -- CRAIG WINTERS GENOME SEQUENCE CENTER. HE IS DOING LONGEVITY PROJECT UNDER THE NEW SPACE, EVERY 15 MINUTES, THEY FINISH ONE WHOLE GENOME SEQUENCING. 15 MINUTES, THAT'S A LOT OF DATA TO GENERATE EVERY DAY. SO AGAIN THIS IS THE DIAGNOSIS DISEASE NETWORK SITE SO THIS ONE ALSO TRY TO COLLECT THE PATIENTS AND ALSO I LEARNED A LOT, THE DATA IS NOT ENOUGH. THE GENOMIC DATA, IT'S MOSTLY THE PHENOTYPE DATA AND GENOMIC DATA AND SO KIND OF LONGITUDINAL DATA. SO EVERYTHING TOGETHER WHICH IS MEANINGFUL, WE CAN DO MORE TO -- FOR HEALTHCARE, NUTRITION, FOR EVERY KIND OF MEDICAL RESEARCH. I MENTION THIS, I'M NOT GOING TO TALK ABOUT THE DETAILS ABOUT MANY PROJECTS I'M GOING TO MENTION. ALSO MENTION SEVERAL TIMES, I WOULD LIKE TO -- AUDIENCE HERE PRESIDENT OBAMA MENTIONED IN JANUARY 2017 ABOUT PMI INITIATIVE. I LIKE THIS, THAT'S WHY I TRY TO HIGHLIGHT THIS BECAUSE IT'S VERY NEAT. ONLY ONE SENTENCE SUMMARIZE EVERYTHING WE WANT TO DO. OR SCIENTIST MEDICAL RESEARCHER THIS IS VERY IMPORTANT, TRY TO DELIVER THE RIGHT TREATMENT AT RIGHT TIME EVERY TIME TO RIGHT PERSON. SO THIS IS VERY IMPORTANT. AS YOU CAN SEE THE LAST TWO MONTHS, SERIES OF NIH TRY TO PMI INFRASTRUCTURE PART OF $55 MILLION PMI EVENTS, THE GRANTS TO DEVELOP PMI. PROGRAMS. NOT ONLY THE AGENCY, FUNDING AGENCY TRY TO PUSH FORWARD THIS PHARMACEUTICAL BIOMEDICAL PHARMACEUTICAL INDUSTRY DOING HIGHER LEVEL, I THINK FOR EXAMPLE ONE COMPANY ASTRA ZENECA IS FAMOUS FOR DELIVERING GENOMIC MEDICINE APPROACHES TO DRUG DISCOVERY, THEY ANNOUNCED IN APRIL, SEQUENCE TWO TOO MANY GENOMES. IN ADDITION TO THOUSANDS OF THE GENOMES WE ALREADY HAVE DONE. THIS IS VERY IMPORTANT SOMATIC MUTATIONS THAT'S GOING TO TARGET SEMATIC MUTATIONS, OBVIOUSLY THERE ARE MANY PHARMACEUTICAL COMPANIES DOING SIMILAR TO DEVELOP MOLECULES THERAPEUTIC STRATEGY UNDER DRUGS TO TARGET ON MUTATION IN THE HUMAN GENOME. I WAS LUCKY TO WORK WITH A FEW CANCER ALSO IN OTHER AREAS, ESPECIALLY IN CANCER AREA I WORKED WITH DR. WILLIAM POWELL AND OTHER ONCOLOGISTS TO DEVELOP VANDERBILT CANCER CENTER PRECISION MEDICINE INITIATIVE CALLED PCMI SO WE HAVE DONE A SERIOUS WORK INCLUDING DEVELOP APOSTROPHE NICHE POST WHOLE GENOME SEQUENCING IN VANDERBILT UNIVERSITY MEDICAL CENTER AND ALSO I USE THIS AS AN EXAMPLE, WE ALSO DID A SERIOUS GENOME SEQUENCING FROM WHOLE GENOME WHOLE EXOME TRANSCRIPTOME TARGETED SEQUENCING AND DEVELOP CANCER PANEL RIGHT NOW ALMOST MAJOR -- ALL THE MAJOR CENTERS CANCER CENTERS, THE CANCER PANEL TO SCREEN CANCER PATIENT, IDENTIFY CANDIDATES THE PATIENTS WHETHER THEY ARE LEGIBLE FOR THE MOLECULAR THERAPIES. SO THIS IS VERY IMPORTANT. I THINK MUCH BETTER TECHNOLOGY USE TO PEOPLE USE CYTOGENETICS OR TRADITIONAL GENETIC METHOD. THIS IS VERY HIGH TO TAKE POTENTIAL MUTATION IN CANCER PATIENTS. WE ALSO USE DEVELOP RESEARCH APPROACH TO IDENTIFY THOSE POTENTIAL MUTATION DURING THE DRUG TREATMENT AND IF THE PATIENT FINALLY DEVELOP DRUG RESISTANCE. THIS IS UNFORT MATILY FOR THE KINASE INHIBITOR TYPICALLY USED FOR PATIENT TO DEVELOP DRUG RESISTANCE. MENTIONED FOR THE PATIENT CARE, WE HAVE TO BE CAREFUL AT THE BEGINNING SO HOW TO UNDERSTAND DRUG RESISTANCE MECHANISM, WE ALSO TRY TO DEVELOP RESEARCH PROGRAMS, TRY TO ADDRESS THAT, I WILL USE SOME ONE EXAMPLE TO SHOOT IT. WE ALSO TAKE CARE OF -- INFORMATICS TEAM, MY TEAM DEVELOP PIPELINES AND METHODS AS WELL AS DATABASE TO HAVE OTHER INVESTIGATORS TO IMPROVE THE QUALITY OF THE RESEARCH. SO HERE, BACK TO MY SUBTITLE, I USE A FEW EXAMPLES, I ALSO SUMMARIZE WHAT WE CURRENTLY THE FIELD IS GOING TO DO. ABOUT THE BIG DATA GENOMIC MEDICINE AREAS, HOW AS INFORMATICS ALSO INFORMATICS LAB, HOW WE CAN TAKE ADVANTAGE OF THAT. AND OTHER PEOPLE, I ALWAYS -- WE ARE NOT LIKE -- WE CAN'T SOLVE EVERYTHING, WE TRY TO HELP PEOPLE TO REACH ANOTHER GOAL QUICKLY. SO WE USUALLY INFORMATICS IS CAN TAKE LIKE STATEMENT OF -- BUT WE ARE VERY IMPORTANT, ALWAYS PART OF OTHER PEOPLE'S RESEARCH. SO HERE I SHOW YOU A FEW EXAMPLES HOW WE CAN HAVE OTHER PEOPLE TO SOLVE PROBLEMS BY -- MORE ACCURATE. SO I USE THE CANCER DATA PRIMARY TO TALK ABOUT THE TRANSLATIONAL BUY INFORMATICS UNDER GENOMIC -- BIOINFORMATICS. SO BEFORE I TALK ABOUT THE REAL CASE I WOULD LIKE TO TALK A FEW -- A FEW SLIDES TO TALK ABOUT SOME BACK GROUNDS BECAUSE THEY ARE ALREADY TO MY TALK TODAY. FIRST IS HERE AT NUTRIGENOMICS, CANCER GENOME ATLAS, AND BASICALLY TRY TO FIND ALL MOLECULAR PROFILES BASICALLY FROM GENOME SEQUENCING TO TRANSCRIPTOME METHYLATION, MICRORNA, AND FOR ALL THE MAJOR TISSUE SITES FOR CANCER AS WELL AS PEDIATRIC CANCER, TRY TO IDENTIFY ALL THE MUTATIONS AS WELL AS OTHER MIXED PROFILES. OMICS PROFILES. SO TWO MAJOR FUNDINGS SO FAR, OBVIOUSLY MANY OR FUNDINGS AS QUELL, SO FIRSTLY THIS PROJECT ALLOWS US TO SYSTEMATICALLY INVESTIGATE THE GENOMIC PROFILE LIKE INFORMATICIAN LANDSCAPE ACROSS ALL THE MAJOR CANCER TYPES IN MANY THOUSANDS OF CANCERS GENOMES. SECOND THROUGH THIS PROJECT, IT'S NOT SURPRISING, IT'S DEMONSTRATE CANCER IS COMPLICATED DISEASE, ICE NOT ONE MUTATION, IT'S INVOLVED IN THE PATHWAY ON THE NETWORK AND THEY ARE DYNAMIC INTERACTION WHICH CAN ALSO THE ENVIRONMENTAL FACTORS CAN CAUSE THE DISEASE, DISEASE CANCER. SO THIS APRIA TRIBUTE ON THE THE FOUNDATION, I DEVELOP MY INFORMATICS APPROACH TO IDENTIFY THE POTENTIAL GENES AND ALSO THOSE GENES RELATED TO THE DRUG DEVELOPMENT OR POSITIONING. SO I WILL MENTION LATER ON, TCGA PROJECT WAS COMPLETE, RIGHT NOW IT'S MOST JOINT EFFORT ICE AGENCY INTERNATIONAL GENOMICS CONSORTIUM, THE AMBITION MUCH -- THE GOAL IS MUCH LARGER, THEY WANT TO STUDY MORE THAN 25,000 HUMAN GENOMES ON MORE THAN 50 CANDIDATE TYPES OR SUBTYPES AND CANCER GENOMES. TO ME I THINK ONE OF THE -- I'M VERY INTERESTED IN THIS NUMBER, RIGHT NOW IT'S MORE THAN THAT. SOMATIC MUTATION IN VARIOUS TYPE OF CANCERS. HOW CAN WE USE INFORMATICS APPROACH TO IDENTIFY ONE OR ONLY A FEW WHICH CANCER TYPE. IN TERMS OF CLINICAL IMPLICATION. MANY OTHER PEOPLE LOOK AT MANY OF THEM PICK OUT SOME POTENTIALLY CAN BE USEFUL BY LIKE GAMBLING. SO THIS SLIDE SUMMARIZE THE MOTIVATION, I BOUGHT FROM A COMPANY BUT NOT ALLOWED ME TO USE THAT. EVERY HUMAN GENOME FROM NORMAL TISSUE THROUGH THE WHOLE GENOME SEQUENCING, MY TEAM CAN DO THAT, WE IDENTIFY THE MUTATION, WHEN WE COMPARE THE REFERENCE GENOME. IF YOU LOOK AT NORMAL TISSUE, IF YOU WHOLE GENOME SEQUENCING DATA, SURPRISINGLY OR NOT SURPRISINGLY WE EXPECTED TO SEE ABOUT SINGLE NUCLEOTIDE POP MORPHISM. MOST OF THEM ARE HERE, DON'T CAUSE ANY PROBLEMS FOR US. SOME OF THEM, IT'S TREATMENT RELATED LIKE PREVIOUS SPEAKERS TALK ABOUT A LOT OF TREATS. WHAT WE REALLY WANT TO KNOW IS AMONG THOSE LARGE AMOUNT OF GENOMIC POLYMORPHISM DATA HOW CAN WE IDENTIFY ONLY A FEW IDEALLY ONLY ONE MUTATION INVOLVED IN THIS, NOT VERY CHALLENGING BECAUSE EVERYONE SAY I CAN DO THAT BUT IN REALITY, IT'S VERY DIFFICULT. SO NOT MANY PEOPLE ARE DOING -- TRYING TO FIND A BIOLOGICALLY RELEVANT CLINICALLY COURSE OF VARIANTS FROM LARGE AMOUNT OF GENOMIC DATA, GENETIC VARIATION DATA. BEFORE I TALK ABOUT THE REAL STORY I WOULD LIKE TO MAKE COON SEPTEMBER CLEAR TO YOU, IF YOU'RE NOT FAMILIAR WITH SO I WILL USE A LOT OF TIME, THE DRIVER MUTATION, ACTIONABLE MUTATION LIKE OTHER SPEAKERS MENTION, SO THE DRAMA MUTATION IS DEFINE AS DOSE MUTATIONS INVOLVED IN THE ABNORMAL GROWTH AND FINALLY TO DEVELOP TUMOR. AXONAL MUTATION IS MORE CLINICALLY RELEVANT, THEY HAVE POTENTIALLY INVOLVED IN THE DIAGNOSIS -- DIAGNOSTIC, PROGNOSTIC OR THERAPEUTIC IMPLICATION. SUBSET OF CANCER PATIENTS OR SPECIFIC THERAPIES. AND ALSO IN COMPUTATIONAL APPROACH, WHEN WE DEAL WITH LARGE AMOUNT OF SOMATIC MUTATION OR GERM LINE MUTATION AS WELL, SO WE ALWAYS USE STATISTICAL METHOD TO SEE THIS MUTATION UNLIKELY BY CHANCE WHICH MEANS THEY ARE ASSOCIATED STATISTICALLY ASSOCIATED WITH THE DISEASE. SO WE ALSO CALLED A SIGNIFICANT LY WE CALL STATISTICALLY ASSOCIATED MUTATION. THAT'S ANOTHER TERM USED IN LITERATURE. I TALK ABOUT WHAT CAN WE DO TO DEAL WITH LARGE AMOUNT OF GENETIC VARIATION DATA, AS I MENTION EARLIER TCGA THE CANCER GENOME ATLAS, HAD -- HAVE INVESTED THE LANDSCAPE OF MUTATION IN SEVERAL THOUSAND CANCER GENOMES AND YOU CAN SEE THESE ARE THE ONES TWO EXAMPLES. THE FIRST EXAMPLE IS ONCOGENE. YOU CAN SEE THE MUTATIONS, THEY OCCUR VERY HIGH FREQUENCY AMOUNT OF PATIENTS TO INVESTIGATE. LIKE THIS ONE, THE IDEA BUT IF YOU LOOK AT BOTH OF THESE TWO GENES YOU CAN SEE THEY ALSO HAVE A LOT OF MUTATION BUT DISTRIBUTED EQUALLY ACROSS THE GENE REGION, MANY OF THEM HIGHLIGHTED HERE THE TRUNCATION MUTATION. WHICH MEANS THEY COST STOP CO-DON. SO THESE ARE TUMOR SUPPRESSOR GENES, SO MUTATION PATTERN ON FREQUENCY OCCURRENCE PATTERN IS QUITE A DIFFERENT IN CANCER GENOMES. SO WE HAVE TO DEAL WITH, DIFFERENTLY WHEN WE USE INFORMATICS APPROACH NOT SURPRISINGLY WHEN THE DATA BECOMES MORE AND MORE BECAUSE OF GENOME SEQUENCING IS CHEAP. WE HAVE SEEN A LOT OF DATA. LAST ABOUT TWO YEARS. MAINLY MOST OF THE THE TOOL HERE DEVELOPED THE LAST TWO YEARS, SOME -- LAST THREE YEARS, IDENTIFY THOSE MUTATIONS OR CANCER GENOMES, SO MY POST DOC SPENT SEVERAL MONTHS REVIEW ARTICLE TO SUMMARIZE METHODS AND TOOLS BASED ON FEATURES. SOME OF THE METHODS USE MULTIPLE FEATURES, SO THIS IS FOR EACH SQUARE HERE, THE METHOD AND TOOLS WE -- NOT SPECIFIC FEATURE. MUTATION FREQUENCY, FUNCTIONAL IMPACT, STRUCTURE GENOMICS, AS PROTEIN STRUCTURE, AND ALSO THE NETWORK PATHWAY, THAT'S WHY I HAD EARLY ON, THE DATA INTEGRATION BECAUSE WE ALWAYS HAVE A MULTIPLE DIMENSIONAL DATA WE CAN INTEGRATE TO IMPROVE POWER SOMATIC MUTATION INVOLVING CANCER. HERE, MY VERSION BEFORE I TALK WITH HIM SAY YOU WRITE ARTICLE TO SUMMARIZE WHAT HAS HAPPENED RECENTLY, THIS IS MY SLIDE, I GIVE TO HIM, LOOK AT THIS DISEASE, THAT'S WHAT I TALK ABOUT. BUT I STILL LIKE TO USE THIS ONE. SO THIS IS A -- I SUMMARIZE BY THREE MAJOR APPROACH, APPROACH ONE, DISTINGUISH MUTATION FROM MUTATION, A MUTATION THEY UPGRADE NEUTRAL, THEY DON'T HAVE MAJOR ROLE TO CONFER THE ABNORMAL GROWTH, SO THE FIRST ONE IS BASED ON IF YOU HAVE LARGE AMOUNT OF SEQUENCE -- SAMPLE DUE TO SEQUENCING YOU FIND DOSING MUTATION WITH HIGH FREQUENCY OR MODULAR FREQUENCY, THE MORE LIKELY INVOLVED IN CANCER AND FUNCTIONAL IMPACT OF MUTATION, THEY ARE SEVERAL OR MANY TOOLS BEGIN ASSESS THE FUNCTION OF IMPACT LIKE CHANGE THE FUNCTIONAL DOMAIN OF THE GENE AND ALSO BIOLOGICAL IMPLICATIONS BECAUSE CANCER ESPECIALLY IN SINGLE PATHWAY INVOLVING -- I USE ONE EXAMPLE LATER ON. THE SECOND APPROACH IS EARLY ON USE THE NETWORK. PATHWAY HAVE BEEN RIGHT NOW FREQUENTLY USED TO DEVELOP METHOD AND TOOL TO DETAIL MUTATION UNDER -- THEY HAVE QUITE A FEW AND HIGHLIGHT IN BOLD CAME FROM MY LAB. SO I WILL USE THE ONE EXAMPLE, TO DEMONSTRATE HOW IT WORKS. AND A THIRD APPROACH IS, AS BIOINFORMATITION WE LEARN FEATURES FROM EXISTING DATA AND PREVIOUS WORK AND WE APPLY TO THE NEW DATA TO HELP OTHER PEOPLE PREDICTED CANCER MUTATION. SO THIS IS FEATURE ORIENTED OR MACHINE LEARNING METHOD TO LEARN FEATURES WE ALREADY LEARN CANCER RESEARCH DATA THERE ARE QUITE A FEW, ONCO DRIVER TCGA CONSORTIUM WE FEEL PUBLISHED TO DO THESE FEATURES, REGARDING MUTATION. IN CANCER GENOMES. SO I ALSO HAVE ONE EXAMPLE TO DEMONSTRATE HOW IT WORKS. SO HERE FOR THESE THREE APPROACH, I TALK ABOUT APPROACH ONE USE ONE CASE STUDY. I HOPE THIS CAN BE HELPFUL FOR IF YOU HAVE SIMILAR SAMPLE AND THINK ABOUT THIS APPROACH MAY WORK WELL. THIS IS ACTUALLY ONE PATIENT THROUGH INTERDISCIPLINARY RESEARCH, SHORT TIME, SHORT TIME IS ONLY ONE YEAR. UNDER THIS MUTATION, ACTIONABLE MUTATION, SENSITIVE TO MAKE INHIBITOR IS AVAILABLE TO TREAT PATIENT. FINALLY WE DEMONSTRATED THIS MUTATION ONCOGENE CALLED A BMAP, THIS IS FROM ONCOLOGIST, PHYSICIAN SCIENTISTS AND ALSO BIOINFORMATICS LAB, LABORATORY SCIENTIST AND CLINICAL TRIAL. WE WORK TOGETHER TO MAKE THIS STORY. TO MAKE THIS HAPPEN IN SHORT TIME. AS A VERY BRIEF INFORMATION, FROM THIS DISEASE, MOST DANGEROUS SKIN CANCER, IT HAS FIVE SUBTYPES AND EACH SUBTYPE YOU ALREADY FIND DRIVER GENES MUTATION. THE FREQUENCY OF THE GENES OCCURS IN SUBTYPE AND THIS MUTATION POTENTIALLY MAY HAVE SOME DRUG CALLED KINASE INHIBITOR SPECIFICALLY ON MUTATION. ACTUALLY ON THE SLIDE, THESE SMALL MOLECULE KINASE INHIBITOR CAN COMBINE PROTEIN AND INHIBIT PROTEIN FUNCTION. THAT'S HOW IT WORKS. THEY CONFOUND SUBTYPE, MANY PATIENTS DON'T HAVE MUTATION, HOW WE DEAL WITH THIS CASE STUDY SO THE PATIENT IS -- HE DEVELOP MELANOMA, HAVE A TYPICAL CLINICAL TREATMENT WITH LYMPHO NODES. AND HAVE LOCAL RECURRENCE FOUR MONTHS LATER AND HAD SURGERY AND RADIATION TREATMENT. AT THAT TIME THE VANDERBILT CENTER THE PATIENT HAD A GENETIC SCREENING, UNFORTUNATELY THIS PATIENT IS ALL NEGATIVE FOR THE NON-DRIVER GENE MUTATION. NOT GENE MUTATION IN MELANOMA. SO B 6, (INAUDIBLE) ALSO MENTION DRUG SPECIFIC TARGET IN VIVO IN PREVIOUS TALK. SO LIKE THIS, WE ALREADY HAVE A DRUG CALLED (INAUDIBLE) BUT UNFORTUNATELY THESE PATIENTS DIDN'T HAVE NON-MUTATION. THE PATIENT UNFORTUNATELY HAD A METASTASIS. 14 DAYS LATER H E PASSED AWAY. WHEN HE PASS AWAY -- WE COULD OFFER SOLUTION WHAT HAPPENED IN HIS TUMOR GENOME WHETHER WE CAN IMPROVE THE TREATMENT OF THIS KNOWLEDGE. SO THE PHYSICIANS IN CANCER CENTER, OFFERED HIM WHY NOT WE TO THE WHOLE GENOME SEQUENCING. FOUND NOVEL MUTATION GENOME. THE PATIENT AGREED. AFTER HE PASSED AWAY, THE FAMILY OBSERVED HIS WILLINGNESS TO MEASURE THE PATIENT, HIS TISSUE AS WELL AS CONTROL THE WAY THE WHOLE GENOME SEQUENCING. VERY FORTUNATELY THE TUMORS ARE QUALITY IS QUITE HIGH. SO THIS IS THE GENOME SEQUENCING, WE DID A TUMOR GENOME OF THE PATIENT AND USE HIS BLOOD CONTROL TO DO IN PARALLEL FOR THOSE SINGLE NUCLEOTIDE POLYMORPHISM SMALL INHIBITION, COPY NUMBER VARIATION AND STRUCTURE VARIANTS. WHAT WE DID IS SUMMARIZE ALL THE INFORMATION IN A PLOT CALLED A CIRCUS PLOT AND OUTSIDE ACROSS CHROMOSOME 1, 2, 22 AXON Y EVERY IS SINGLE NUCLEOTIDE POP MORPHISM. AND -- POLYMORPHISM. IF YOU HAVE SAMPLE DO GENOME SEQUENCING, YOU CANNOT MAKE IT DATA QUALITY BECAUSE RIGHT NOW YOU HAVE A COLLABORATIVE TOOL NOW BECOMES BETTER THAN BEFORE. THEN YOU LOOK AT ACROSS THE CHROMOSOME, CALLED A INTER-- THOSE KIND OF CHANGES TRANSLOCATION AND ALSO CAN BE WITHIN CHROMOSOME INTRATRANSLOCATION AND COPY NUMBER VARIATION AND LOSS IN THE MIDDLE. SO WHAT WE DID, YOU HAVE MODELING SINGLE NUCLEOTIDE POLYMORPHISM AND COPY NUMBER VARIATION. HOW WE CAN IDENTIFY ONLY ONE OR A FEW WHICH RELATE TO THIS PATIENT. TUMORIGENESIS, THAT'S WHY IN THE BEGINNING I USE THAT TRIANGLE REVERSE TRIANGLE TO ASSURE HOW WE CAN FIND IT. SO WHAT WE DEVELOP APPROACH IS VERY STRAIGHT FORWARD HERE, IS BASED ON FREQUENCY, FUNCTIONAL IMPACT AND ALSO THE ACCURACY OF THE MUTATION BECAUSE MANY MUTATION IN CANCER GENOME HAVE LOW FREQUENCY, WE MAYBE NOT TRUE. SO WHAT WE DID IS LOOK AT THOSE FUNCTIONAL MUTATION, USUALLY THE PROTEIN CODING REGION, THEN LOOK AT -- TO DO THE VALIDATION. AND SOME OF THEM, THIS ON CO-GENE, FOR SPECIFIC SIDE WE FOUND IT'S HIGH QUALITY AND ALSO HAVE THE HIGH (INAUDIBLE) SO IN THIS MUTATION ALSO VALIDATE WE MAYBE POTENTIALLY TRUE AND POTENTIALLY IMPORTANT. THEN WE LOOK AT SCREEN THOSE MUTATION AND TRY TO PHENOTYPE BASED ON FUNCTIONAL IMPORTANCE, ONE WAY TO LOOK AT THIS BIOLOGICAL PATHWAY ONCOGENE RELATED PATHWAY LIKE RAS PATHWAY, PEOPLE CONSIDER ONE OF THE KINASE PATHWAYS, ESPECIALLY THE MELANOMA, THE V 600 BRAF IN THIS PATHWAY ALREADY IDENTIFY TARGET SPECIFIC MUTATION. SO IF WE USE MUTATION IN SUCH PATHWAY SUGGESTING THEY ARE POTENTIALLY CLINICAL RELEVANT. SO THE THIRD ONE FREQUENCY YOU DON'T WANT TO SEE A MUTATION ONLY OCCURS ONCE BECAUSE MOST ARE LIKELY PASSENGER MUTATION, JUST BY CHANCE. SO FORTUNATELY A TUMOR BANK, SO WE ARE SCREENING 650 GENOME SEQUENCING, NOT THAT WE HAVE MANY TO DO THAT, GENOTYPING TECHNOLOGY AND FROM THOSE MUTATIONS WE FIND ABOUT THIRD OF THEM DIDN'T HAVE ANY NULL MUTATION IN THIS DRIVER GENE MELANOMA, SO WE CALLED NEGATIVE AMONG THOSE PATIENT OR TUMOR SAMPLES WE FOUND TWO TUMORS SAME MUTATION AT SAME LOCAL SUGGESTING THIS MUTATION MAYBE VERY IMPORTANT. ALSO ANOTHER TWO BIOSITES SUGGESTING CLINICALLY RELEVANT. SO WHAT WE DID NEXT IS INTRODUCE MUTATION FOR THE CANCER CELL LINE AND TREAT THOSE DRUGS AND USE IT AS A POSITIVE CONTROL BECAUSE PEOPLE ALREADY KNOW THIS, THIS IS A 600E POSITIVE CONTROL, THIS IS THE NEW MUTATION. AND THIS -- MEEK INHIBITOR WE TRY TO ATTEST THE WAY TO HAVE A SIMILAR DRUG SENSITIVITY. SO YOU CAN SEE FOR EXAMPLE LIKE HERE, WHEN THE DRUG DOSE INCREASE THE CELL GROWS DRAMATICALLY INCREASE OR CELLS WILL KILL. SUGGESTING THE DRUG, POTENTIALLY CAN BE RELATED TO THIS CANCER TREATMENT. WHAT MAKES THIS, WE IDENTIFY THE PATIENT UNFORT MATILY PASSED AWAY. SO WE IDENTIFY THE PATIENT, UNDER THE SAME MUTATION OF THE SAME SITE, FROM CLINICAL TRIAL, THIS PATIENT ALREADY HAD -- WAS IN METASTASIS AND HAD STRONG LESION LEVEL AND KIDNEY AND UP THE TREATMENT SIX MONTHS LATER, IT WAS ALMOST GONE, THE LESION WAS ALMOST GONE MUCH SMALLER AND WE HAD VALIDATION MUTATION IN THIS SITE SUGGESTING THIS DRUG POTENTIALLY TREATED THE PATIENT WITH SPECIFIC MUTATION. RIGHT NOW THIS MUTATION IS INCLUDED IN SCREENING IN BIOMEDICAL CLINIC COUNSELING CLINIC. SO FROM ONE STUDY -- SORRY. HOPEFULLY WORKS. BASICALLY ONE STUDY SUGGEST THROUGH THIS INTERDISCIPLINARY RESEARCH WE WERE ABLE TO FIND CLINICALLY RELEVANT MUTATION, UNDER THIS EXAMPLE APPLIED TO SOME SIMILAR RESEARCH IN VITRO. SO WORK WAS AS A COVER STORY IN CANCER DISCOVERY AND ALSO RECEIVE PRETTY GOOD FEEDBACK INCLUDING THE CHIEF EDITORS OF THE DISCOVERY COMMENTARY. I LIKE THIS WAY BECAUSE WHICH TALK ABOUT A LOT ABOUT PRECISION MEDICINE, THIS IS A WAY FROM CLINICAL SCIENTIST TO -- LABORATORY SCIENTISTS A LOT OF PHARMACOLOGY STUDY BACK TO THE PATIENT SIDE BECAUSE EVENTUALLY WE SHOULD HELP PATIENT CARE AND GET FEEDBACK FROM THE PATIENT. SO THIS IS FROM PATIENT SIDE. WE HEAR THE STORY WITH THE FAMILY, THEY WERE VERY ONE SIDED, VERY HAPPY, ON THE OTHER HAND FEEL SAD. IF WE WERE ABLE TO FIND THESE THINGS BEFORE WE CAN'T HELP THE PATIENT AT LEAST LIVE A LITTLE LONGER. BUT ON THE OTHER HAND THEY NEED MORE MONEY TO (INAUDIBLE) THE CENTER, THAT'S WHAT THE PATIENT RESPONSE COMMENT ON OUR WORK, THEY HIT A HOME RUN. SO ONCE AGAIN THROUGH ONE SINGLE INDIVIDUAL STUDY WE WERE ABLE TO FIND THIS MUTATION. ADS I MENTION ALSO, OTHER SPEAKERS FOR THIS KINASE INHIBITOR TO TREAT PATIENT UNFORTUNATELY, PATIENT CAN BE SURVIVE, LIVE LONGER, THE CANCER DRUG RESISTANCE. SO HOW CAN WE USE THE NEXT GENERATION SEQUENCING TECHNOLOGY, GENOMIC APPROACH -- TO BETTER UNDERSTAND WHAT HAPPENED IN DOING THE DRUG RESISTANCE APPROPRIATION. WE CAN IMPROVE AND DEVELOP A BETTER APPROACH TO AVOID ALL THE DRUG RESISTANCE OPPORTUNITY. THIS IS ONE STUDY, THERE ARE MANY KINDS OF APPROACHES TO DEVELOP SO THIS ASSURE WE USE A CANCER CELL LINE AN THOSE CANCER CELL LINE THIS IS A MOUSE MODEL LUNG CANCER, THEY ARE SENSITIVE TO THE TIE ROW SEEP KINASE INHIBITOR AND THEN THEY TREAT CELL LINE TREATED AS DRUG VERY WELL, LUNG CANCER TREATMENT, HEMATOANYBODY, THOSE KINDS OF DRUGS, THE CELL LINE EVENTUALLY DEVELOP DRUG RESISTANCE. THEN WE CAN MONITOR WHAT HAPPENS IN THOSE CELL LINE GENOMES WHICH MUTATION THE CELL LINE GAIN OR LOST. SO THAT'S THE KIND OF APPROACH. WHAT WE DID. SO WE PUBLISH A LOT -- THIS IS A PILOT STUDY IN THIS RESEARCH, WE HAVE A LOT OF DETAIL RESULTS BUT HERE I JUST USE ONE SLIDE TO SUM RIDES WHAT WE LEARN. SO THE AMPLIFICATION IS VERY IMPORTANT IN TWO SINGULAR PATHWAY. ONE IS THE RAS PATHWAY I MENTION. ALSO ANOTHER IS MTOR PATHWAY. THIS IS A -- AS YOU CAN SEE HERE WE HAVE SEVERAL DRUG RESISTANCE CELL LINE HIGHLIGHTED HERE. THE THREE. THE FIRST ONE CALLED THE CYTOGENETICS VERY LOW RESOLUTION. THE STYLE. AMPLIFICATION. THEY WANT TO KNOW THIS -- AMPLIFICATION DATA. THROUGH NEXT GENERATION SEQUENCING WE WERE ABLE TO FIND LOCATION AT COPY NUMBER CHANGES. UNDER THESE TWO DRUG RESISTANCE CELL LINES THIS HAS A STRONGER COPY NUMBER CHANGES. VERY INTERESTINGLY FOR THIS CANCER CELL LINE DRUG RESISTANCE CANCER CELL LIEN, THE COPY NUMBER CHANGE ACROSS THE CELL LINE GENOME IS ALMOST FOUR FOLD MORE COPY NUMBER CHANGES WHEN YOU COMPARE WITH OTHER DRUG RESISTANT CELL LINES. INTERESTINGLY WHEN YOU LOOK AT THIS CELL LINE DID NOT OBSERVE ANY CHANGES SUGGESTING IS QUITE A DIFFERENT HIGHLY HETEROGENEOUS, EVERYBODY PATIENT IT SHOULD BE CONSIDER FROM BEGINNING TO THE END OF THE TREATMENT. TUMOR -- EVERY TUMOR IS DIFFERENT USING MOLECULAR PROFILING WITH CLINICAL DATA WITH PHARMACO LOGICAL DATA PUT TOGETHER TO DEVELOP PRECISION APPROACH TO TREAT A PATIENT. SO THAT'S WHAT WE CAN SEE HERE. NOW TO THE SECOND APPROACH TO DETECT THE CANCER MUTATION CLINICALLY RELEVANT MUTATION. SO AS I MENTION EARLIER, THE NETWORK PATHWAY, IS A MAJOR FEATURE, INVOLVED IN CANCER DEVELOPMENT. SO WE USE SEVERAL TYPE OF NETWORK LIKE A PROTEIN PROTEIN INTERACTION NETWORK, WHICH IS A POPULAR -- AND KINASE INTERACTION NETWORK BECAUSE IN CANCER A LOT OF GENES WITH POTENTIAL FOR MOLECULAR THERAPY INVOLVING KINASE DOMAIN SO WE LOOK AT THAT, ALSO 3-D PROTEIN STRUCTURE. AMELIORATED FEATURES NETWORK. LIKE THE PREVIOUS TWO SPEAKERS, THEY MENTION THAT GWAS DEVELOP, YOU'RE PROBABLY HAVING SPECIFICALLY PAY ATTENTION TO LOCI 6P, THERE ARE MANY SIGNIFICANT GWAS HITS, BECAUSE MANY INFLAMMATION IN IMMUNE SYSTEM AND CHROMOSOME 6P HAS A LOT OF IMMUNE INFLAMMATION WITHIN GENES. SO IF WE PUT ALL TOGETHER, WE CAN CATEGORIZE ALL GENES BY DISEASE TO DIFFERENT TYPE OF CANCER GENE TUMOR SUPPRESSING ONCOGENE AND WE CAN PUT THIS ESSENTIAL GENE PUT ALL TOGETHER, VERY COMPREHENSIVE NETWORK THEN THIS FORM LIKE A RESOURCE, WE HAVE THE REAL DATA, YOU CAN GO INSIDE TO CHECK WHETHER THEY FORM SOME INTERACTION IN LISTENING TO OTHER SPECIFIC DISEASE. SO THAT'S THE KIND OF IDEA SO WHAT WE DID AS ONE EXAMPLE HERE, WE USE VERY FAMOUS LAW CALLED A NEWTON'S LAW OF GRAVITY. VERY INTERESTING. SO IT JUST -- YOUR OBJECT TO SEE HOW IT WORKS AND HOW TO APPLY TO CANCER GENOME DATA OR MAYBE THE DATA POTENTIALLY SO THIS IS HYPOTHESIS OR SCENARIO. THE TWO GENES IN THE GENOME, IF THEY HAVE A HIGH MUTATION RATE AND SUGGESTING THE DOSE INVOLVED IN DISEASE AND ALSO WE WANT TO SEE HOW THEY INTERACT. THERE ARE TWO GENES THAT HAVE HIGH GENE CO-EXPRESSION WHICH MEANS THEY CHANGE DIFFERENTLY. WHEN THEY COMPARE THE CONTROL SAMPLE, SO WE THEN SUGGEST THESE TWO GENES HAVE A SYNERGISTIC INTERACTION IN THE NETWORK. SO WHAT WE SPECIFICALLY DO IS LOOK AT LIKE A CANCER DATA DIFFERENT TYPE OF CANCER HERE IS MORE THAN TEN TYPE OF CANCER BUT EACH TYPE OF CANCER LOOKING AT THOSE GENES FOR EVERY PAY OFF GENE, WHETHER THEY HAVE HIGH MUTATION RATE AND GOES TO CANCER DATA THE GENE EXPRESSION DATA, WHETHER THEY ALSO FORM THE GENE CO-EXPRESSION CO-EXPRESSION GENE CO-EXPRESSION INTERACTION NETWORK. YOU THEN JOIN TWO NETWORKS BECOMES MORE ADVANCED NETWORK, LOOK AT SUBUNIT FROM THE VERY SPECIFIC PATH AND THEN USE GENE GRAVITY LAW, IF BOTH GENES HAVE HIGHER MUTATION RATE HERE, IF THEY HAVE CO-EXPRESSION, THEY DIVIDE BY THIS, AND THE HIGH EXPRESSION MEANS SMALLER AND YOU HAVE A HIGHER G SCORE AND TRY TO MEASURE. BECAUSE OF TIME I'M NOT GOING TO GIVE THE DETAILS BUT THIS IS THE CONCEPT TO APPLY TO ANY KIND OF BIOMEDICAL DATA. BEHAVIORAL ENVIRONMENTAL FACTORS AS WELL SO THE CONCEPT IS HOW THEY INTERACT, MORE DYNAMIC WAY AND ALSO SYNERGISTIC WAY SO WE LOOK AT CANCER DATA, MORE THAN TEN TYPES, THIS IS ABOUT 3,000 CANCER JONES. USE GENE GRAVITY SCORE SCREEN HIGHER TOP CANDIDATES AND SOME OF THE RESULTS IS INTERESTING, THESE TOP CANDIDATES SEVERAL IS ON EX-CHROMOSOME. ONE EXAMPLE STAG 2 GENE HERE, THIS STAG 2 GENE THE UTERINE CANCER, IF THE PATIENTS MUTATION RATE IS BASICALLY BY LOG SCALE, SO IF THE PATIENT HAS STAG 2 MUTATION BASED ON GENE GRAVITY SCORE, THE OVERALL HAVE MUCH HIGHER MUTATION RATE ACROSS THE GENOME WHEN YOU COMPARE TO THE CONTROL SAMPLE, THOSE PATIENTS CANCER PATIENT GENOME THEY DID NOT HAVE THE STAG 2 MUTATION. SO SUGGESTING THROUGH THIS APPROACH YOU CAN IDENTIFY PATIENT AFFECTED BY ONE MUTATION IN CANCER GENE. AND AFFECTED DRAMATICALLY ACROSS THE GENOME. THIS KIND OF NEW PRIORITY. UNDER THIS GENE REPORTED A SIMILAR FEATURE IN GLIOBLASTOMA. SO THE SORT OF FEATURE -- THE THIRD FEATURE, THIRD APPROACH IS FEATURE BASED, AS INFORMATICIAN WE HAVE MORE DATA. ESPECIALLY LIKE THE COMPLEX DATA. THEN WE CAN LEARN FEATURE FROM MULTIPLE TYPE OF INFORMATION AND THEN TRY TO FEED TO THE -- USE THE FEATURE WE LEARN TO APPLY TO THE NEW DATA. IN CANCER RESEARCH, PEOPLE IDENTIFY MAJOR FEATURES LIKE POSITIVE SELECTION, REVISIONS HOT SPOT, DELETERIOUS IMPACT AND FUNCTIONAL DOMAIN. AND FOR EACH WE DEVELOP AN APPROACH TO ADDRESS THIS PUBLISHED PAPERS HERE BUT I USE ONE EXAMPLE RELATED DRUG BECAUSE RIGHT NOW I TRY TO SHIFT A LITTLE BIT FROM GENOMIC STUDY TO -- TOWARDS TRANSLATIONAL SIDE. SO FOR INHERITED DISEASE ALMOST ALL MUTATION INVOLVED IN THAT DISEASE OCCURS IN A POCKETED REGION OF THE PROTEIN STRUCTURE, THIS IS A SIMPLE WAY TO SUM RIDES THE PROTEIN STRUCTURE. THREE SURFACE FEATURES. ONE IS CALLED A POCKET. THAT'S WHAT WE LEARN FROM TARGET, SPEAKER WHEN WE TALK INFORMATICS APPROACH TO BETA REGION, SINCE I ANALYZE SEMATIC MUTATION ONE LOOK AT SEMATIC MUTATION, IN A POSITIVE REGION WHETHER WE HAVE CHANCE TO IDENTIFY DRUGGABLE OR ACTIONABLE MUTATION, THAT'S THE MOTIVATION. BECAUSE OF TIME I HAVE TO SUMMARIZE HERE WE LOOK SYSTEMATICALLY THE CANCER TYPE THE GENOMES, LOOK AT MUTATION CHANGE ACROSS THE DIFFERENT PROTEIN STRUCTURE, IN A POCKETED REGION. SO THEN WE HIGHLIGHT A FEW EXAMPLES, MUTATION IN -- CAN BE TARGET FOR THIS DRUG BECAUSE THE POPULAR REGION IS AWARE OF THE ENZYME OF THE SMALL MOLECULE LIKE THE DRUG COMBINED SO WE CAN USE INFORMATICS APPROACH TO FIND THIS DRUG POTENTIALLY TOGETHER WITH THE MUTATION. SEMATIC MUTATION WITH THE DATA WE IDENTIFY. SO ONE EXAMPLE, AKT 1 WE FIND 1, MUTATION, POTENTIALLY IS DRUGGABLE SITE. SO BASICALLY, APPROACH, I HAD A BRIEF TALK ABOUT SECOND AND THIRD APPROACH. HERE I USE ANOTHER EXAMPLE BACK TO WHOLE GENOME SEQUENCING OF THE GENOME AND WE CAN IDENTIFY THE ACTIONABLE MUTATION OR POTENTIALLY THE MUTATION CAN BE RELATED TO THE PATIENT. SO THIS IS ANOTHER EXAMPLE, IT'S ALSO SHORT TIME LIKE ONE YEAR OR SOMETHING WE CAN FINISH. IT'S ALSO PART OF THE VANDERBILT PRECISION CANCER PREVENTION INITIATIVE. SO WE REQUEST PROPOSAL, PEOPLE RESPONDED AND WE OFFERED A FREE SEQUENCING FREE DATA ANALYSIS. ONE PROJECT WE SPONSOR, WE WERE ABLE TO FIND THESE MUTATION CLINICALLY RELEVANT. SO THIS IS A CUTANEOUS TCR INFORMANT. THIS IS ONE OF THE SUBTYPE CALLED MYCOSIS, A RARE CANCER, WE WERE ABLE TO COLLECT THE FIVE PLAYERS THAT DID WHOLE GENOME SEQUENCING AND BEFORE NOTING BIOMARKERS TO DIAGNOSIS AND TREATMENT. SO THIS IS A SUMMARY OF THE FIVE PATIENTS, CLINICAL STAGE AND WE DID A WHOLE GENOME SEQUENCING. SO THIS IS A PIPELINE FROM THE CLEANING PROCESSING, DATA, QUOTA MUTATION, IT'S PRETTY STANDARD BUT WE IMPROVE -- ENHANCE A LITTLE BIT. THIS, HERE, AGAIN THE CANCER HIGHER CANCER HETEROGENEITY, FIVE PATIENTS, SUPPOSEDLY WE HAVE SAME PHENOTYPE, LOOK AT MUTATION DISTRIBUTION, THIS IS A CHROMOSOME 1 TO 22 XY, EACH INDIVIDUAL GENOME, AS YOU CAN SEE MUTATION RATE, THE FIRST INDIVIDUAL GENOME YOU CAN SEE THE MUTATION RATE IS DRAMATICALLY HIGHER THAN INDIVIDUAL TWO AND THREE AND FOUR. BUT FIFTH INDIVIDUAL GENOME YOU CAN HIGH MUTATION RATE. SUGGESTING AGAIN EACH PATIENT IS QUITE DIFFERENT. WHEN YOU TRY TO DEVELOP MOLECULAR STRATEGY TO TARGET MUTATION, WE SHOULD BE VERY CAREFUL. SO OBVIOUSLY WE ARE -- WE DID A LOT OF ANALYSIS, HERE JUST HIGHLIGHT MAJOR FINDINGS. FIRST WE FIND A LOT OF GENES, THEY HAD A MUTATION IN WE OBSERVE IN THIS COMPLEX CALLED SWI, VERY FAMOUS IN CANCER. THE SECOND ONE IS CHROMATIN THE SECOND ONE IS JAK3 RADIO PATHWAY. WE FIND THIS MUTATION IS ALSO VERY INTERESTING, OCCURS MULTIPLE TIMES, TWICE IN FIVE OF THE PATIENTS SO WHAT WE'RE SPECIFICALLY LOOKING AT IS JAK3 MUTATION. WE FIRST SOMATIC MUTATION WE NEED TO VALIDATE, WE FIRST VALIDATE NORMAL SKIN, NOT THE PATIENT, AND ALSO CATCH LINE FROM THE PATIENT. WE VALIDATED THE PATIENT, THEN WE WERE ABLE TO CONNECT THE THREE CTC CELL LINES, AVAILABLE IN A COMMUNITY AND WE LOOK AT CELL LINE HAD A SIMILAR MUTATION WE IDENTIFY IN THIS THIS JAK3, 573 MUTATION FIVE. AMONG THIS CELL LINE WE FIND ONE OF THEM HAD A MUTATION. SO THIS PROVIDE US MAYBE FURTHER, FREQUENCY. POTENTIALLY THIS MUTATION IS RELATED TO THE CTC BECAUSE TWO OUT OF FIVE PATIENTS HAD THAT MUTATION AND OTHER CELL LINE, ACQUIRED THIS MUTATION LATER ON. WHAT WE DID IS GO A LITTLE FURTHER FOR TRANSLATIONAL, THIS IS A DRUG RECENTLY APPROVED BY FDA TO SPECIFIC TARGET ON JAK3 AND WE WANT TO SEE WHETHER THIS MUTATION SENSITIVE TO THIS DRUG. SO WE LOOK AT AGAIN THESE THREE CANCER CELL LINE, TREATED THE (INAUDIBLE) AND WHEN THE DRUG DOSE INCREASE YOU CAN SEE THE SURVIVAL FOR THIS MUTATION HOVERING CELL LINE, SURVIVAL RATE IS SHORTER, THE DRUG POTENTIALLY CAN INHIBIT OR KILL CELL QUICKLY. SO THE RESULTS STILL FROM MEMORY, WE NEED TO DO A LOT OF WORK BUT WE SUGGEST THIS MUTATION IS TRANSLATIONAL, IS POTENTIALLY CAN BE USEFUL FOR DRUG TREATMENT. THROUGH THIS VERY COMPARING VERY -- A LOT OF LARGE SCALE STUDY, THIS IS SMALL. WHOLE GENOME SEQUENCING OF THESE SPECIFIC CANCER MYCOSIS. SO WE FIND LAST MUTATION WE LOOK AT MUTATION SIGNATURES BECAUSE OF TIME I'M NOT GOING TO TALK BUT DISEASES ARE CUTANEOUS SO WE FIND UV RELATED SIGNATURE, MUTATION SIGNATURES IN THE GENOME. FINALLY HOW MANY MINUTES I HAVE? THREE MINUTES. MAYBE I'M TOO EXCITED TALKING TOO LONG. WE HAVE RESEARCH HERE SO WE USE BIOINFORMATICS APPROACH TO DEVELOP A PIPELINE FRAMEWORK TO DO THE POSITIONING AND WE TALK A LOT ABOUT CELL LUNG CANCER WE TEST ONE DRUG SO INITIALLY IT WAS USED FOR THE ANTIDEPRESSANT CALLED (INAUDIBLE) AND WE FOUND SENSITIVE TO THE NON-SMALL CELL LUNG CANCER. BECAUSE OF TIME, THIS IS A GENE DISEASE INTERACTION NETWORK. YOU HAVE A MINI DATABASE HERE AND HERE, TRY TO CONSOLIDATE AND PURIFY THE DATA AND WE HAVE A LOT OF DATA HERE. A LOT OF DATA HERE, THAT'S CALLED BIG DATA COME HERE. AND WE DEVELOP A FRAMEWORK INFORMATICS BASED ON DRUG GENE GENE TO DISEASE, BASICALLY USE A GENE AS COMMON FEATURE TO MATCH THE MOLECULAR PROFILE WITH THE DISEASE. SUGGESTING WHETHER THERE'S SOME GENE THE DRUG TARGET ON THOSE GENE INVOLVED IN THE DISEASE. AND THE DRUG INITIALLY INVOLVED IN OTHER DISEASE BECAUSE OF SIMILAR PROFILE, WE CAN SUGGEST FOR THE OTHER DISEASE. THEY HEAR THE MOLECULAR PROFILES. THAT'S THE KIND OF CONCEPT. FOR NON-SMALL CELL LUNG CANCER WE HAVE 95 DRUG STATISTICALLY SIGNIFICANT, WE ALSO SCREEN ALL KIND OF DISEASE ALL KINDS OF DRUGS SO IT'S A LOT OF WORK HERE BUT WE ONLY ISSUE ONE. THIS IS A DRUG (INAUDIBLE) WITH LUNG CANCER THEY ARE SENSITIVE COMPARED TO THE HEMATONIB IN LUNG CANCER BUT JUST NEED SMALL DOSES TO REACH THOSE KIND OF OUTCOMES FOR THE CELL GROWTH INHIBITION. ALSO RIGHT NOW ALWAYS DRUG COMBINATION THROUGH STAGE ONE PHASE 1, PHASE 2 PHASE 3, PEOPLE USE SECOND GENERATION DRUG, PEOPLE USE COMBINATION OF DRUGS SO (INAUDIBLE) MUCH BETTER PERFORMANCE IN TERMS OF SERO INHIBITION. YOU CAN SEE MUCH SMALLER WHEN COMBINATION. ANIMAL MODEL IF YOU HAVE BOTH DRUG IN TUMOR GROWTH VERY SMALL, AND THIS IS -- WHEN YOU HAVE A POST DRUG THE TUMOR SURVIVAL IN MICE MUCH LONGER -- CAN LAST MUCH LONGER. SO JUST THERE MAYBE IMPORTANT IN NON-SMALL CELL LOPING CANCER FOR DRUG SUPPOSEDLY DEVELOPED FOR ANTI-DEPRESSION. SO WE DEVELOP A LOT OF TOOLS ESPECIALLY (INAUDIBLE) WE USE TO IDENTIFY THE VITAL -- THE FINAL INFECTED HUMAN GENOME OR ANY GENOME AND ALSO WE CAN DETAIL THE WAY THE VIRUS INTEGRATED HOST THE GENOME AND IT'S ALREADY USING A GENOME NEXT GENERATION SEQUENCING DATA. ALSO I'M RUNNING CONFERENCE CALLED INTERNATIONAL CONFERENCE ON INTELLIGENT BIOLOGY AND MEDICINE, A LOT OF INFORMATICS APPROACH, TRANSLATIONAL SITE, WE HAVE SPECIAL ISSUES, SOME INTERESTING PAPER, WE ALSO HAVE PMC MEDICAL INFORMATICS SPECIAL ISSUE. SO ESPECIALLY FOR THAT, YOU CAN CONSIDER THAT. THE WORK ACTUALLY IT'S NOT MY WORK IT'S MAINLY A TEAM, I'M RUNNING A BIOINFORMATICS PLATFORM SEVERAL YEARS, BIG TEAM, REALLY APPRECIATE THOSE PEOPLE ALWAYS DEVELOP A NOVEL APPROACH. MY COLLABORATOR IN THE CANCER CENTER, WILLIAM POWELL, JEFF ALWAYSMAN, OTHER PEOPLE, CHRIS LOVELY, AND MANY OTHER COLLABORATORS. THANK YOU FOR YOUR ATTENTION. HOPEFULLY I HAVE TIME. [APPLAUSE] >> IT'S MAYBE DIFFERENT FROM WHEN (INAUDIBLE) TO RESEARCH BUT I HOPE THIS KIND OF APPROACH YOU CAN THINK ABOUT THE -- HOW TO POTENTIALLY EXTEND THROUGH YOUR WORK AND WE CAN COLLABORATE. I COLLABORATE WITH MANY PEEP SOL SMILE WITH ME, SAY I WANT TO WORK WITH YOU. I WILL ALWAYS WORK WITH YOU. MAYBE ONE QUESTION. (OFF MIC) >> WHAT YOU MAY KNOW OF THE SIOPS PROGRAM THAT'S OUT THERE? >> IT IS COMMERCIAL BIG DATA. >> TODAY I HAVE -- DO WE HAVE A SUGGESTION? >> I WAS JUST CURIOUS TO GET YOUR THOUGHTS. >> THERE ARE MANY PROJECTS AND DATA LIKE ALSO MY LAB WORK WITH (INAUDIBLE) DOING (INDISCERNIBLE) PHARMACOLOGICAL RELATED VARIANTS. WE DO A LOT OF PROJECTS, SMALL SCALE, NOT LIKE HIGH LEVEL BUT DATA SCALE IS ALWAYS THE LAST. YEAH. (OFF MIC) >> VERY GOOD QUESTION. USUALLY WE ASK A SIMILAR QUESTION, CAN YOU DO WHOLE GENOME SEQUENCING, DNA SEQ. AND TRANSCRIPTIONOME CALLED RNA SEQ. CAN YOU DO BOTH? THIS IS VERY IMPORTANT BECAUSE ESPECIALLY CANCER, THE SOMATIC, MUTATION CAN OCCUR AT THE DNA LEVEL, TRANSCRIPTION LEVEL, IF YOU CAN DO BOTH YOU CAN IMPROVE THE POWER TO DO MORE MUTATION. THE REALITY IS ONCE THE THICKEN THE SAMPLE THE TISSUE, A LOT OF TIME YOU DON'T HAVE TISSUE FOR RNA SEQUENCING. WHOLE GENOME AND EXOME SEQUENCING WE HAVE RIGHT NOW HAVE A ADVANTAGE ON THIS HERE SOMETIME LATER. RIGHT NOW, THOUGH YOU CAN SAY DOLLARS FOR WHOLE GENOME SEQUENCING WHY STILL USE WHOLE EXOMESIS QUEENING MAINLY IT'S THE COVERAGE. FOR WHOLE EXPOEM SEQUENCING YOU CAN DO HIGHER COVERAGE. FOR SOMATIC MUTATION ESPECIALLY, THIS IS VERY IMPORTANT. FOR EXAMPLE, IN OUR PROJECT, WE WILL DETECT THREE COPIES A THOUSAND READS, IF YOU USE WHOLE GENOME SEQUENCING APPROACH, YOU CAN'T. BECAUSE YOU NEED HIGHER COVERAGE. WE HAVE 2000 COVERAGE, IT'S TARGETED SEQUENCING. SO DEPENDS ON PROTECT SOMEWHERE. WE TALK WITH THE COLLABORATOR AND MAKE A BETTER DESIGN, WHETHER IT'S WHOLE GENOME, WHOLE EXOME RNA SEQ OR BOTH. >> WHEN YOU (INAUDIBLE) PROTOCOL HOW DO YOU DECIDE WHICH BIOINFORMATICS (INAUDIBLE)? Q. VERY IMPORTANT QUESTION. THERE'S NO ANSWER. THAT'S WHY WE RUN A BIG BIOINFORMATICS LAB BECAUSE FOR SOME STANDARD APPROACH, ESPECIALLY GERM LINE BASED MUTATION DETECTION, THE LINEUP BECOMES MORE STANDARD. LIKE SOMATIC OR SOME TISSUE, VERY SPECIFIC YOU HAVE TO ALWAYS DEVELOP YOUR OWN PIPELINE. DOESN'T MEAN EVERYTHING IS NEW BUT YOU ENHANCE OR SIGHTLY ADJUST TO MEET THE PROJECT NEED. SO THAT'S WHY BIOINFORMATICS LAB RIGHT NOW IS VERY IMPORTANT, IN ALMOST EVERY RADIO CENTER. ONE MORE QUESTION. >> I HAVE A VERY BIG PICTURE QUESTION. SO THE AS TRAY SENECA PAPER, ARE GENOMES PRIORITIZED FOR EXPLORATION? YOU HAVE 2 MILLION, WHERE DO YOU START AND HOW -- WHAT KIND OF DECISIONS GO INTO DECIDING WHAT'S GOING TO BE LOOKED AT FOR A SECOND AND THE 2 MILLION? >> I DID THIS IN MY CURRENT UNIVERSITY, WE HAVE A WORKING GROUP TRANSLATIONAL BIOINFORMATICS AND PRECISION MEDICINE, I TRIED TO FIND OUT WHAT EXACTLY ARE THEY GOING TO DO. FIRST ASTRA ZENECA AS DONE A WHOLE GENOME, WE ACTUALLY WORK WITH THEM LIKE ADD 90 TO 91, RECENTLY APPROVED BY FDA. WHAT WE PROPOSE IS THEY DON'T HAVE A TIME LINE, MANY YEARS, SECOND IS THE DISEASE, THEY COVER ALL KINDS OF DISEASE, OBVIOUSLY CANCER IS THERE ONE OF THE MAJOR FOCUS. BUTLY ALSO DO OTHER DISEASE. WHAT IS OTHER THING? OBVIOUSLY THE TRANSLATIONAL, TRY TO FIND MUTATION CAN BE CLINICALLY USEFUL, NOT WHAT I RECALL. BASED ON THIS FROM OTHER SITE, I THINK I LEARNED THIS FROM A JOURNAL PRECISION MEDICINE, LOOKS LIKE I DO A LOT OF ADVERTISEMENT BUT I'M NEUTRAL. THEY HAVE A LOT OF DISCRETION ABOUT WHAT THEY ARE GOING TO DO. IT'S A NEWS FROM NATURE. A FEW RELATED IN THAT NATURE ISSUE. I HOPE I ANSWERED YOUR QUESTION. BUT SEND ME EMAIL, I HAVE TWO SLIDES TO TALK ABOUT THAT. I CAN SEND YOU ALL OF THEM. YEAH. [APPLAUSE] >> THANK YOU SO VERY MUCH, DR. ZHAO. SO EXCITING TO SEE THE ADVANCES IN TRANSLATIONAL BIOINFORMATICS APPLICATIONS AND CANCER. AND USING BIOINFORMATIC TOOLS TO IDENTIFY DRIVER MUTATIONS. WE APPRECIATE YOUR BIOINFORMATICS EXPERTISE AND SEE HOW COLLABORATION IS SO IMPERATIVE.