I'M JIM KYLIE, DIRECTOR OF DIVISION OF LUNG DISEASES AT THE NATIONAL HEART LUNG AND BLOOD INSTITUTE, WELCOME TO THIS NIH SYMPOSIUM ON INNOVATIONS IN LUNG IMAGING FOR DIAGNOSIS TREATMENT AND MANAGEMENT OF LUNG DISEASE. THIS IS A VERY VERY SPECIAL SYMPOSIUM FOR YOU WILL IN NHLBI AND ACROSS THE NIH CAMPUS, THIS IS A GOLDEN ANNIVERSARY SINCE THE ESTABLISHMENT OF THE DIVISION OF LUNG DISEASE 50 YEARS AGO. SO TODAY WHAT WE WANT TO DO IS HIGHLIGHT SOME OF THE ADVANCES THAT OCCURRED OVER TIME BUT MORE IMPORTANTLY THINKING ABOUT WHERE ARE WE HEADED AND WHERE ARE SOME OF THE IMPORTANT NECESSARY AND INTERESTING AREAS THAT WE SHOULD PURSUE AND THE AREA WE CHOSE TO HIGHLIGHT IN THIS SYMPOSIUM IS IMAGING. WE THINK THERE'S BEEN QUITE A BIT OF PROGRESS OVER THE YEARS IN THIS AREA, WE HAVE A STELLAR LINE UP OF SPEAKERS FROM THE INTRAMURAL PROGRAM AND OUR EXTRAMURAL PROGRAM WHO WILL TELL YOU ABOUT WHAT THEY'RE DOING AND HOW THEY ARE APPLYING SOPHISTICATED IMAGING APPROACHES TO ADVANCE OUR KNOWLEDGE AT THE BASIC CELLULAR MOLECULAR MECHANISM LEVEL ALL THE WAY UP TO HOW IT TOUCHES THE PATIENT IN TERMS OF DIAGNOSIS AND MANAGEMENT OF DISEASE. WITHOUT TOO MUCH DELAY, I WANT TO LET US KICK OFF THIS SYMPOSIUM AND INTRODUCE THE DIRECTOR OF THE NATIONAL HEART LUNG AND BLOOD INSTITUTE T DR. GARY GIBBONS WHO WILL MAKE INTRODUCTORY COMMENTS. GARY. >> THANKS, FOR THAT INTRODUCTION. AND KICK OFF, WELCOME TO Y'ALL, THOSE IN THE ROOM AS WELL AS THOSE JOINING US BY WEBCAST. WE ARE VERY EXCITED ABOUT THIS MILESTONE IN THE HISTORY OF THE NATIONAL LUNG AND BLOOD INSTITUTE CELEBRATING THE 50th BIRTHDAY OF OUR NHLBI DIVISION OF LUNG DISEASES. AND CELEBRATING A PROUD LEGACY OF LEADERSHIP IN EXCELLENCE IN PULMONARY SCIENCE, SCIENCE THAT DISCOVERY THAT IS ENHANCED THE HEALTH OUR NATION. A BRIEF HISTORICAL NOTE WE JUST CELEBRATED THE 70th ANNIVERSARY OF THE NHLBI LAST YEAR AND NOT TO BE OUTDONE, THE DOD WANTED RECOGNITION OF ITS GOLDEN ANNIVERSARY ANNIVERSARY, 50, IT'S A PLEASURE TO DO THAT AND REFLECTS AGAINST THE LEGACY NHLBI AS THE NATION PIVOTED FROM FROM THE CONTROL OF INFECTIOUS DISEASES IN THE LAST CENTURY TOWARD THE NON-COMMUNICABLE DISORDERS BECOMING THE PUBLIC HEALTH PROBLEM. CLEARLY RECOGNIZING THAT TUBERCULOSIS AFFECTING THE LUNG STARTED TO DISSIPATE BUT INCREASE RECOGNITION OF PROBLEM OF CHRONIC LUNG DISEASE AND THE NEED TO ADD LUNG TO THE NATIONAL HEART INSTITUTE PORTFOLIO BACK IN 1969. SO IT'S WITH THAT RECOGNITION OF THAT TRANSITION OF DISCOVERY SCIENCE THAT -- TO ENHANCE THE NATION'S HEALTH, AGAIN THE DIVISION OF LUNG DISEASE WAS STARTED, ACTUALLY STARTED OFFICE. AND IT'S RESEARCH PORTFOLIO HAS HAD DRAMATIC IMPACT, TO DETAIL THAT I PRESUME DR. CRAPO MAY DO THAT IN SOME OF HIS REMARKS BUT CERTAINLY THE IMPACT ON INFANTS RESPIRATORY DISTRESS SYNDROME, RDS WHAT WE LEARNED, HOW WE EXPANDED THE LIFE OF PATIENTS LIVING WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE, EXTENDED THE LIFE SPAN OF THOSE WITH CYSTIC FIBROSIS, I WANT GO ON AND ON ABOUT A LOT OF ACCOMPLISHMENTS OF THE DIVISION TO PULMONARY SCIENCE OVER THE LAST 50 YEARS BUT WE ARE ALSO RECOGNIZING THAT WE HAVE UNFINISHED BUSINESS IN THIS AREA. THERE'S MORE -- FAR MORE TO DO IN ADDRESSING THE PROBLEMS WITH PARTICULARLY CHRONIC LUNG DISEASE. I WOULD SUBMIT THAT PART OF OUR TASK IS TO GET AWAY FROM THAT TERM OF CHRONIC LUNG DISEASE. WHAT ABOUT A FUTURE WHERE WE TAKE THE C OUT OF COPD? WE THINK ABOUT PREVENTION, PREEMPTION, REMISSION, REVERSAL. OF THESE DISORDERS. INDEED, A KEY PART OF THAT INVOLVES THE LUNG DIVISION AGENDA IN BASIC TRANSLATIONAL CLINICAL AND POPULATION SCIENCE IN HICH WE ARE COMMITTED WITH THE LUNG DIVISION LEADERSHIP. TO ADVANCING THE BASIC DISCOVERY SCIENCE HOW LUNG DEVELOPS. TODAY YOU WILL HEAR ABOUT NEW TECHNOLOGIES AND TOOLS THAT WILL ENABLE US TO RESOLVE A SINGLE CELL LEVEL THE MOLECULAR SIGNATURES OF THE CELLS THAT ARE DRIVING LUNG DEVELOPMENT AND CREATE THE LUNG RESERVE AND RESILIENCE THAT WILL LAST A LIFETIME. SIMILARLY, WE ARE EXCITED ABOUT THE OPPORTUNITY TO DISCOVER NEW TARGETS AND A NEW GENERATION OF THERAPEUTICS THAT GET BEYOND THE BRONCHODILATORS STEROIDS AND OXYGEN THAT CURRENTLY ARE PART OF THAT THERAPEUTIC ARMAMENTARIUM. THE LUNG DIVISION IS PLAYING AN ACTIVE ROLE THERE. WE ARE STARTING TO MOVE TOWARD A PATHWAY OF EARLIER DETECTION PRE-CLINICAL DETECTION, IN THE PATHOGENESIS AND PATHOPHYSIOLOGY OF THESE DISEASES. WE ARE EXCITED ABOUT THE WORK DONE IN OUR PRECISION MEDICINE TO DISCOVER THE MOLECULAR MEDIATORS OF THESE LUNG DISORDERS AND HOW THAT MAID FEED INTO ANKER RA OF PRECISION MEDICINE PERSONALIZED TREATMENT STRATEGIES FORGED IN LUNG DIVISION PRECISE PROGRAM WHERE WE CAN AGAIN ADVANCE UNDERSTANDING AND BETTER PREVENTION AND TREATMENT OF CHRONIC DISEASE. TODAY'S SYMPOSIUM WILL FOCUS ON TECHNOLOGY AND INNOVATION RELATED TO IMAGING AND THAT'S WHERE WE ARE EXCITED SEEING THOSE PRE-CLINICAL CHANGES THAT MAY BE MERGING SUCH THAT WE CAN GET EARLIER TO PREVENT PREEMPT REVERSE AND REMIT THESE CHRONIC LUNG DISORDERS. WITHOUT MUCH FURTHER ADIEU I WOULD LIKE TO PIVOT TO TODAY'S SPEAKERS WHO WILL BE ENGAGED FIRST WITH THE PERSPECTIVE OF DR. JAMES CRAPO FROM NATIONAL JEWISH HEALTH AND GIVEN ALL THE WHITE HAIR HE HAS, HE'S THE BEST PERSON POSSIBLE TO TELL US NOT ONLY ABOUT THE HISTORIC PART BUT HE'S A CRITICAL LEADER IN COPD GENE AND TOPIC PROGRAM AND SOME OF THE NEW IMAGING MODALITIES AND HOW THEY ARE TELLING MORE ABOUT THE PATHOGENESIS OF DISEASE THE OTHER SPEAKERS WOULD BE TELLING US ABOUT EXCITING INNOVATIONS THAT ARE OCCURRING IN IMAGING TECHNOLOGY AND THEIR POTENTIAL APPLICATIONS TO PULMONARY DISCOVERY AND INNOVATION. SPECIFICALLY ORDER YOU WILL HEAR FROM DR. SCAT FRASER, UNIVERSITY -- SCOTT FRASER, UNIVERSITY OF SOUTHERN CALIFORNIA, DR. SANJAY JAIN FROM JOHNS HOPKINS AND OUR VERY OWN DR. ADRIENNE CAMPBELL WASHBURN FROM THE NHLBI INTRAMURAL PROGRAM. YOU HAVE THEIR BIOS IN YOUR PROGRAM SO I WON'T DETAIL THEM HERE. EACH OF THEM WILL COME UP SEQUENTIALLY AND PRESENT THEIR TALKS. WITHOUT FURTHER ADIEU I WILL BRING O THE PODIUM DR. JAMES CRAPO. JAMES. [APPLAUSE] >> I WILL LIKE TO INTRODUCE THIS BY REVIEWING A LITTLE HISTORY OF DIVISION OF LUNG DISEASE AND HOW IT IMPACTED ON EVOLUTION OF PULMONARY DISEASE. OBVIOUSLY THE DIVISION OF THE DOD BEGAN WITH NOTICE CONGRESSIONAL ACTION NOTED FROM FEDERAL REGISTER IN 1969 AND HAS HAD THREE INCREDIBLE DIVISION DIRECTORS WHO LED THIS NOW WITH JIM FOR 50 FULL YEARS. I HAD THE WONDERFUL OPPORTUNITY OF WORKING WITH EACH ONE OF THEM. I WANT TO POINT OUT THAT THE -- THAT'S THE RIGHT BUTTONS HERE. THIS CHANGE OCCURRED IN THE MIDDLE OF MY THIRD YEAR MEDICAL SCHOOL UNIVERSITY OF ROCHESTER. SO I WATCHED THIS EVOLUTION, THIS IS THE PICTURE OF LUNG DISEASE I WAS TAUGHT AT THE BEGINNING. IT'S SMOKING BASICALLY SMOKING DROVE MOST OF LUNG DISEASE AND CHEST X-RAY WAS KING HOW WE DIAGNOSED IT. IT INTERESTING WHEN I JOINED THE FACULTY DUKE UNIVERSITY 1976, ALMOST ALL MY FACULTY SMOKED. THAT'S NOT TRUE ANY MORE BUT TREMENDOUS THINGS OCCURRED. LET ME SET A LITTLE BACKGROUND FOR WHAT WAS REALLY TAKING PLACE DURING THIS PERIOD. IF YOU LOOK BACK AT THE HISTORY AS GARY SAID, THE '60s WERE A WONDERFULFUL TIME TO START IF MEDICINE, VERY EXCITING PERIOD. IN THE CENTURY BEFORE THAT, LUNG DISEASE WAS ACTUALLY THE KING OF DISEASE IN THE MOST COMMON CAUSE OF HOSPITALIZATION. AND WE THOUGHT WE CONQUERED IT WITH INH AND RA FARM PIN. TB, THE SCOURGE WHITE MAKE WAS COMING UNDER CONTROL AND WE WERE CLOSING BEDS ALL OVER THE NATION FOR TB PATIENTS BUT AT THE SAME TIME OTHER THINGS WERE HAPPENING. SURFACTANT WAS DISCOVERED AT THE CBRI IN SAN FRANCISCO. ELECTROMICROSCOPY WAS BECOMING COMMON PLACE THAT ALLOWED US TO LOOK AT MOLECULAR AN CELLULAR LEVEL TRANSFORMING MEDICINE DURING THE 1960s. -- PUBLISHED THE BOOK THE NORMAL HUMAN LUNG. AND WE STARTED LOOKING AT MORE DETAIL OF LUNG ANATOMY. I THINK BACK TO THAT TIME T COMMON MEDICINE WAS ANTIBIOTICS, PENICILLIN, CEPHALOSPORINS WERE COMING INTO COMMON USE, BUT THE REAL BIG TWO MEDICINE FOR PULMONARY DISEASE WERE ISOPRIL AND (INAUDIBLE). TO TAKE A PATIENT WITH OBSTRUCTIVE LUNG DISEASE AND GIVE THEM AND PUSH THE DOSE UP UNTIL THEY VOMITED. AND THEN BACK OFF A DOSE TO KEEP THEM BRONCHODILATED WHY THEY DIDN'T SEIZE. SEEMS PRIMITIVE TODAY. THE BRONCHOSCOPE CAME INTO AMERICA IN THE 1970s, FIRST ONE AT DUKE OUTRANKED ON AS FELLOW AT THE SAME TIME MY FACULTY LEARNED. I LOOK DOWN THE SCOPE WITH THE TEACHER AT THE TIME HE FIRST SAW IT. IT'S HARD TO THINK OF THAT MOCH CHANGE OCCURRED IN LESS THAN 50 YEARS DURING THE TUITION OF LUNG DISEASE IT WAS -- DIVISION OF LUNG DISEASE IT WAS DEVELOPED. MY MEDICAL SCHOOL DIDN'T HAVE IT IN ROCHESTER. WHEN I WENT TO DUKE MICU IN 1976 ADS FACULTY MEMBER IT WAS A FIVE BED UNIT KNOCKED THE WALLS DOWN BETWEEN TWO PATIENT ROOMS OR THREE PATIENT ROOMS. AND WE HAD THE GREENBERG VENTILATORS, BY EYE BALL TRYING TO SET THE VENTILATION, CONTROLLING THE PRESSURE, ALL THE THINGS YOU WERE TRYING TO INVENT ON THE FLY. THAT'S THE SET. VERY EXCITING PERIOD, THINGS STARTING TO BREAK OPEN. BUT BEALSO SAW INCREASE IN COPD. CHRONIC LUNG DISEASE WAS NOW BECOMING A REAL PROBLEM TO DEAL WITH. MY FIRST EXPERIENCE AS INVESTIGATOR WITH THE DIVISION OF LUNG DISEASE WAS THEY FUNDED AN RFP TO LOOK AT MEMBRANE OXYGENATION FOR ARDS IN THE '70s. AS JUNIOR FACULTY MEMBER I JOINED PATHOLOGY CENTER AT DUKE TO LOOK AT THE CASES, IT ENDED UP WITH DISMAL RESULTS. THE SHOWN ON THE RIGHT 90% PATIENTS DIED AND WE SAW ALMOST ALL IN PATHOLOGY CENTER. THEIR LUNGS LOOKED LIKE LIVER. IT WAS A PRIMITIVE MACHINE WITH PRIMITIVE ATTEMPT AND IT DID NOT WORK. BUT DIVISION OF LUNG DISEASE KEPT GOING PUTTING OUT RFAs, STARTING SCORES TO LOOK AT THE PROGRAM AND THE NEXT YEAR WE SEE MULTIPLE PROGRAMS DEVELOP DIFFERENT THEMES PRESENTED BY DIVISION OF LUNG DISEASE THEY SPENT SEVERAL DECADES ON THIS, YOU SEE CHANGES IN ADVANCES IN MULTIPLE AREAS THAT IMPACT ON HOW WE TREAT CRITICAL LUNG INJURY. THEN BY TIME YOU GET ENINTO THE '90s YOU SEW IMPACT ON MORTALITY AND MULTIPLE STUDIES SHOW THE DECREASING MORTALITY OVER THE DECADES OF '90s AND EARLY 2000s. IF YOU LOOK TODAY AS MORTALITY NOW DROPS TO THE MAYBE AVERAGING 20% FROM THIS DISEASE, THE WE HAVE MULTIPLE NETWORKS EXPLORING THIS. MULTIPLE CLINICAL PHASE 3 TRIALS GOING FORWARD AND THE NHLBI DIVISION OF LUNG DISEASE IS GUIDING US AS EVIDENCE BY RECENT WORKSHOP TO PREPARE THE TRIALS FOR THESE PATIENTS. I'M HEARING THE ADULT -- NARYING THE ADULT, SIMILAR WITH INFANTILE RESPIRATORY DISTRESS SYNDROME, AND ITS DEVELOPMENT WE TALKED ABOUT. ONE THING I WANT TO COMPLIMENT THE DOD ON IS TREMENDOUS EMPHASIS ON TRAINING FROM THE VERY BEGINNING THEY SUPPORTED EVERY ASPECT OF TRAINING, YOUNG INVESTIGATORS, MID CAREER INVESTIGATORS AND SEEN YOUR INVESTIGATORS. LOOKING HOW TO KEEP THE WORK FORCE IN PLACE AND YOU HAVE SEEN IT TRANSITION FROM EMPHASIZING BASIC SCIENCE INTO THE CLINICAL AND ON INTO THE MODERN ERA AND TODAY WE HAVE PROGRAMS WIDE RANGING PROGRAMS LISTED ON THE RIGHT SIDE THAT RANGE FROM GRADUATE STUDENT TO VERY SENIOR INVESTIGATORS, WHOSE CAREERS ENCOURAGED BY APPROPRIATE SUPPORT FOR THE DIVISION OF LUNG DISEASE AND NHLBI. THE OTHER REALLY POWERFUL THING IS WATCHING THIS CHANGE OVER THE YEARS FROM BASIC SCIENCE INTO THE TRANSLATIONAL MEDICINE BEGINNING BACK IN THE '70s WE SEE LOTS OF PROGRAMS DEVELOPING, OBVIOUSLY I WON'T DETAIL ALL OF THESE BUT I TRY THE THINK OF WORDS TO CHARACTERIZE THE LEADERSHIP OF DLD AND WORDS WILL DO THAT. OPEN. CREATIVE. WILLING TO WORK HARD, WILLING TO IMPLEMENT PROGRAMS, THINKING ABOUT TRAINEES AND THINKING ABOUT WHICH PROGRAM CORRECT -- EVERY TIME WE SERVE IN A POSITION LIKE ON THE DISEASE ADVISE SRI COMMITTEE OR BOARD OF EXTERNAL EXPERTS QUESTIONS HOW TO DEVELOP A PROGRAM, WHAT IS NEEDED IN THE FIELD, WHAT CAN WE DO TO STIMULATE IT, WHERE IS THE OPTIMUM OPPORTUNITY TO GROW THIS AND THEN IT WAS IMPLEMENTED WITH INCREDIBLE EFFICIENCY. YOU SEE THAT THE FINAL FUNDING REACHES AS -- HAS HAD TREMENDOUS GROWTH. I WANT TO GO ON TO SAY ONE COMMENT THAT IMPRESSED ME, DURING THIS PERIOD OF TREMENDOUS ECONOMIC GROWTH OF THE DIVISION, I WATCHED WHOLE NHLBI CONTROL THE ADMINISTRATIVE COSTS OF MAXIMIZE TRANSFER OF FUNDS TO THE INVESTIGATOR. AS A PERCENTAGE OF THE FUNDING ADMINISTRATIVE TOLL KEPT SHRINKING AND I ALWAYS WONDERED HOW THEY DO THEIR JOB BECAUSE THE WORKLOAD FOR INDIVIDUAL WORKING IN ADMINISTRATION IS INCREASING DRAMATICALLY BUT THE QUALITY MAINTAINED AND THE WORK WENT FORWARD THE WAY GOVERNMENT PROGRAM OUGHT TO BE BASICALLY I WOULD SAY MODEL FOR US GOVERNMENT AND ONE I WISH WAS IN PLACE THROUGHOUT THE GOVERNMENT BUT THIS IS AN ABSOLUTE MODEL FOR IT. BACK IN THE '70s AND '80s IMPLEMENT WAS ON PROGRAM SCIENCE, PROGRAMS TO STIPULATE VARIOUS ELEMENTS THAT WOULD ESSENTIAL TO MOVE FORWARD BUT RAPIDLY TRANSLATED INTO CLINICAL NETWORKS AND AREAS THAT WOULD HAVE TRANSLATION OF PATIENT CARE AND TO THE BEDSIDE. I'M GOING TO AMONG THESE ARE QUITE A FEW, I DON'T HAVE TIME OR WOULDN'T BE APPROPRIATE TO GO THROUGH THEM BUT I WILL TAKE ONE IN BLUE AT THE BOTTOM RIGHT COP JAIN, THAT'S ONE I'M INVOLVED IN AND HIGHLIGHT WHAT'S TAKING PLACE WITH THAT PROGRAM. WHEN DOD WAS FORMED COPD WAS BECOMING A PROBLEM WITH MORTALITY AND THAT'S CONTINUED THROUGH THE PRESENT TIME. WE HOPE IT'S PLATEAUING BUT THE CHALLENGE IS HOW TO BEND THE CURVE DOWN AND MOVE PREVENTION. COPD GENE COHORT, COHORT OF 10,000 PEOPLE ACROSS 20 MEDICAL CENTERS NOW FOLLOWED INTO THEIR BEING FOLLOWED TEN YEARS OF FOLLOW-UP AND THE TOTAL WE HAVE TAKEN CLOSE TO 40,000 CHEST CTs ON THESE PEOPLE AS WELL AS CLINICAL HISTORY AND NHLBICS FUNDED THE ENTIRE HUMAN GENOME AND ALL OF THEM THE TRY TO UNDERSTAND THIS DISEASE. I WON'T HAVE TIME TO GO INTO ANY OF THAT DATA BUT THIS IS WHAT THEY LOOK LIKE AFTER FIVE YEARS. YOU SEE EACH OF THE SECTIONS OF THE COHORT ENJOYING TREMENDOUS CHANGE OF PROGRESSION, LOOK WHAT CAUSES THAT PROGRESSION? I WANT TO REALLY HIGHLIGHT ONE REAL FINDING THAT WAS KEY. YOU TOOK THIS MAMASIVE AMOUNT OF DATA AND ANALYZED IT USING MACHINE LEARNING AND KEY WE USE IS PRINCIPAL COMPONENTS SOMETHING AMAZING HAPPENING. THE TRADITIONAL PATHWAY WAS THOUGHT TO BE -- HOW IT WORKS HERE, OBVIOUSLY THOUGHT TO BE AN EMPHYSEMA PATHWAY, FROM GOAL 0 TO GOAL 1, 2, 3, 4, SO THIS WAS THOUGHT TO BE THE PRIMARY PATHWAY FOR DEVELOPMENT OF COPD AND IT WAS DEVELOPMENT FOR PEOPLE BELOW THIS LINE HERE FEC PONT RATIO OF .7. THERE'S ANOTHER PATHWAY PREDOMINATED WHICH AIRWAY DISEASE AND THEY HAD NO EMPHYSEMA IN THE EARLY FACES OF IT. -- PHASES AND THEY'RE SHOW SHOWING IN RED HERE HIGH RISK FROM AIRWAY DISEASE. WE LOOK AT MORTALITY OF THESE HIGH RISK GROUPS, THE AVERAGE WAS 5% FOR THE COHORT. DOUBLE FOR PEOPLE ON THE EMPHYSEMA PATHWAY. BUT IT WAS ALMOST DOUBLE THAT FOR THE PEOPLE IN THE AIRWAY DISEASE PATHWAY AND OF COURSE THE REALLY BAD DISEASE, A THIRD DIED AT END OF FIVE YEARS. WE NEED TO BLOCK THAT -- BOTH OF THESE PATHWAYS. WE TOOK A LARGE NUMBER OF CT, CT REPRESENTED THE MAJOR THING WE USE AND EARLY 2000s THIS IS STANDARD CT THAT ILLUSTRATES WHAT YOU CAN SEE, EMPHYSEMA HERE, YOU CAN SEE AIRWAY WALL THICKENING. YOU SEE CORONARY DISEASE HERE, LUNG CANCER THIS PERSON HAD AND YOU CAN SEE THE CAUSE FOR THE RIGHT (INAUDIBLE). THIS IS SIMPLIFYING A LOT OF WORK BUT I WANT TO EMPHASIZE THAT WE'RE GOING TO TODAY GO ON FROM THIS LEVEL OF CT ANALYSIS INTO ADVANCED IMAGING WILL BE THE NEXT PHASE. PEOPLE GOING THROUGH THE CLASSIC PATHWAY WITH EMPHYSEMA BUT MORE DOMINANT WITH HIGHER MORBIDITY AND MORTALITY. SO WE'RE NOW PREPARED TO PROPOSE A MAJOR CHANGE IN DIAGNOSIS OF THIS DISEASE, AND WE ARE COMING OUT THIS WITH PROPOSAL -- THIS IS THE OLD DIAGNOSIS HERE, ALL THESE PEOPLE HAD COPD BUT DIAGNOSE PEOPLE THAT HAVE NORMAL SPIROMETRY SO TO SPEAK OR IN THIS QUADRANT AND INCLUDE THOSE IN THE DIAGNOSIS AND IMPORTANT THING IS IF YOU PREVENT THIS DISEASE, IT STARTS HERE, YOU HAVE TO STUDY THESE PEOPLE AND ADDRESS SIMPLES EARLY ON. THAT'S WHERE PREVENTION OCCUR, THAT'S THE FUTURE OF THIS DISEASE. FINALLY WHERE THE BIG DATA AND WE HAVE TALKED ABOUT NUMBER OF PROGRAMS DIVISION OF LUNG DISEASE ALLOW BIG DATA TO BE PUT TOGETHER, THIS BIG DATA REFERENCE BY SLIDE, IS TAKING PLACE IN MOTH DISEASES AND IS CLEARLY HAPPENING IN COPD AND FIELDS OF OKAY INSTRUCTIVE LUNG DISEASE. SO BACK TO THE PLD, I'M IMPRESSED THEIR VISION HAS BEEN TO DEVELOP PERSONALIZED MEDICINED TO LOOK FOR REGENERATION FORMS FOR THE LUNG TO LOOK AT PUBLIC HEALTH PREVENT AND PREVENTION OF DISEASE HAS BEEN PART OF THEIR STRATEGIC PLAN FOR THE WHOLE INSTITUTE. THERE THEY ARE SUPPORTING RESEARCH IN YOU KNOW INVESTIGATIVE PROGRAMS VERY BASIC SCIENCE TO GENOMICS TO DEVELOPMENT OF CLINICAL COHORTS AND APPLICATIONS TO THE BEDSIDE. I WANT TO END BY SAYING THAT I THINK THIS FUTURE IS VERY BRIGHT AND ACKNOWLEDGE THEIR ACTION PLAN FOR THIS DISEASE CALLS US TO BRING IN PEOPLE, PATIENTS, INVESTIGATORS AGENCIES, PROFESSIONAL SOCIETIES AND INTEGRATE THOSE INTO COMMON PLAN TO BE SUCCESSFUL, PEOPLE MAKING IT HAPPEN HERE AT THE DLD I WANT TO ACKNOWLEDGE WITH THIS PICTURE, THERE ARE LITERALLY HUGE DEDICATED STAFF, ABLELING THE PROGRESSION. SO THANK YOU VERY MUCH. [APPLAUSE] NEXT GOING TO INTRODUCE DR. FRASER TO TAKE US INTO ADVANCED IMAGING OF THE LUNG. >> WELL THANK YOU VERY MUCH FOR IS HAVING ME HERE. I'M REALLY EXCITE TO TELL YOU HOW I MOVED FROM MY DAY JOB INTO SOME INTEREST BY SARA LYNN AND DAVID WORK EVERYTHING TO WORK ON THE DYNAMICS THAT ARE INVOLVED IN LUNG BIOLOGY AND LUNG PATHOGENESIS. WHAT WE HAVE BEEN WORKING ON QUITE SOME TIME IS LOOKING AT EMBRYOS APPROXIMATE ALSO LOOKING AT EAT -- AND ALSO LOOKING AT THE FUNCTION OF THE LYMPH NODES YOU ARE SEEING OR EMBRYONIC ORGANS AS THAT I TAKE SHAPE. WHAT WE HAVE BEEN DOING AS OUR DAY JOBS IS THINK ABOUT ANALYZING COMPLEX EVENTS LIKE DEVELOPING EMBRYOS AS AN EXAMPLE OF A REALLY BEAUTIFUL SETTING FOR SYSTEMS BIOLOGY. SMALL ENOUGH TO FIT UNDER MICROSCOPE TO DO HIGH RESOLUTION STUDIES AND WATCH AS THOSE CHORIO GRAPHED EVENTS TAKE PLACE. AS WE ANALYZE WITH NORMAL SINGLE CELL ANALYSES, THAT PULL THE CELLS OUT OF CONTEXT, WE ARE REALLY STRUCK BY THE HETEROGENEITY AND VARIABILITY OF RESULTS AND WHILE THIS IS REALLY INTERESTING, IT MAKES IT QUITE CHALLENGING TO STUDY. WHAT WE WOULD LIKE TO DO IS TO TURN THE HETEROGENEITY AND THE VARIABILITY INTO AN ADVANTAGE, MAKE IT INTO THE THING WE STUDY BY DEVELOPING MULTI-DIMENSIONAL AND MULTIPLEX TECHNIQUES THAT LOOK AT DYNAMICS AND VARIANCE AND USE CORE VARIANT AS SIGNAL RATHER THAN THE NOISE WE HAVE BEEN DEVELOPING A NUMBER OF MULTIPLEX TOOLS TO SEE TECHNIQUE DEVELOPING TISSUE OR TISSUES AS THEY TAKE SHAPE. I WAS BROUGHT INTO THE LUNG IN PART BY SARA AND DAVID WARBURTON THROUGH INTERACTIONS AT CHILDREN'S HOSPITAL AND INTERACTIONS THROUGH THE SINGLE CELL NIH PROGRAM WHICH IS WHERE I FIRST INTERACTED WITH SARA. WHAT I WANT TO DO IS TRY TO TELL YOU A LITTLE BIT ABOUT THIS TRANSITION AND SHOW YOU THE LESSONS THAT WE HAVE BEEN GROWING. THE FIRST OF THESE IS RATHER THAN DOING SINGLE CELL TRANSCRIPT OMICS, WHERE WE TAKE THE CELLS OUT OF THE TISSUE, WHAT WE WANT TO DO IS SEE NOT CHANGES IN ISOLATED CELLS BUT CELLS IN THEIR CONTEXT. THE NORMAL WAY OF LOOK AT GENE EXPRESSION DOING IN SITU HYBRIDIZATION HAS VAGARIES TO IT BECAUSE OF THE ENZYME CHROMATIN SYSTEM. EVEN WITHIN THE SAME PAPER YOU CAN FIND THE SAME STAGE AND SAME GENE THAT LOOKED TREMENDOUSLY DIFFERENT. WE WORKED FOR SOME TIME TO MAKE A DNA SELF-ASSEMBLY TECHNIQUE THAT ALLOWS US TO LOOK AT THE TRANSCRIPTOME OF NOT ONLY FIXED CELLS BUT ALSO THE MICROBIOME AND OTHER THINGS THAT ARE THERE WITH THEM. BY HAVING A SET OF PROBES THAT BIND TO THE mRNA, THAT DAIRY INITIATORS THAT BRING ABOUT ASSEMBLY OF HAIR PINS INTO AN ASSEMBLY OF 200 DYES PER RNA. WE CAN BUILD IT SO WE GET PREDICTABLE RELIABLE DING AND IF WE USE THAT ON TISSUES LIKE MOUSE EMBRYOS, WE GET SOMETHING THAT GIVES QUANTITATIVE RESULTS THAT WE GET THE SIGNAL IF TWICE AS BREAK THERE'S TWICE AS MUCH MESSAGE PLUS OR MINUS 5% AND COLLEAGUES ALONG CAL TECH IN PARTICULAR, HAS BROUGHT THIS TO MORE THAN A 200 PLEX APPROACH BY SERIALLY STAINING THE TRANSCRIPTOME WITHIN THE TISSUE. SO PERMITTING QUANTITATIVE SPATIAL TRANSCRIPT OMICS. MORE RECENTLY WE HAVE REALIZED WE NEED TO MAKE THE NEXT GENERATION OF THIS SO THE NEXT GENERATION OF OUR HYBRIDIZATION CHAIN REACTION WE CALL MUSE, WHAT MUSE USES IS SIMILA HAIR PINS. INSTEAD OF PUTTING DYES ON IT DIRECTLY THEY HAVE HANGING OFF OF THEM THESE LONG OLIGONUCLEOTIDES, THOSE OLIGONUCLEOTIDES CAN BE SITES WE CAN STICK QUANTUM DOTS OR CONTRAST AGENTS OR METAL AGENTSES TO DO IMAGING, THIS ALLOWED US TO DO IMAGING AT 100 TIMES TO 200 TIMES SENSITIVITY AND ALLOWS US CARRY IT OVER AND USE IT AS A PROTEIN RECOGNITION REAGENT, EITHER DECORATING PROTEIN LIGANDS THAT BIND TO THINGS OR DECORATING ANTIBODIES. YOU CAN SEE A SINGLE HUMAN CELL, THESE ARE FLY EMBRYOS JUST TO SHOW SOME OF THE PATTERNS BUT BASICALLY WE CARRIED THIS FORWARD ABOUT 150 TO 200 FOLD IN ITS SENSITIVITY NOW. WHAT THIS ALLOWS US TO DO IS LOOK INTO INTACT TISSUES IF WE STRETCH THE HISTOGRAMS YOU CAN SEE IN THIS LIGHTING, WE CAN NOW SEE THE INDIVIDUAL DOTS THAT ARE INDIVIDUAL RECOGNIZED TRANSCRIPTS. WE CAN COUNT NOW WITHIN INTACT TISSUE FIXED AND STAIND WITH THESE REAGENTS, THE NUMBER OF TRANSCRIPTS WITH MUCH BETTER ACCURACY AND CAPTURE EFFICIENCY THAN WE HAVE WITH OUR PREVIOUS GENERATION. THE GOOD NEWS IS THESE TECHNIQUES WORK. THE REAGENTS PENETRATE VERY WELL INTO THICK INTACT TISSUES THAT HAVE BEEN FIXED LIKE INTACT BRAINS OR INTACT HUMAN BIOPSIES. WE GET THIS QUANTITATIVE SIGNAL. THE OTHER THING I GUESS THIS IS SOMETHING VERY ROBUST, THE INTENSITY OF THE PRODUCT IS NOT DEPENDENT ON THE DEVELOPMENT TIME AND THIS ONE SPENT TWO MONTHS IN THE REFRIGERATOR BEFORE IT WAS IMAGED SO IT'S STABLE OVER TIME. THE BAD NEWS IS ANOTHER TIME ASPECT WHICH IS THERE'S FIVE GIG VOXELS IN THAT MOUSE EMBRYO AND IF WE ARE TRYING TO LOOK AT A WHOLE HUMAN BIOPSY THOSE ARE QUITE A BIT BIGGER SO THAT'S TEN HOURS OF IMAGING ON THE MICROSCOPE. IF WE BLOW IT UP YOU CAN SEE BLEACH SPOTS WE DOUBLY IMAGE BECAUSE WE HAD TO DO IT IN A TILED FASHION. THAT'S WAY TOO LONG AND WE HAVE A PROBLEM OF NUMBER OF COLORS WE CAN SEE AT A TIME. SO WHAT I'M GOING TO DO IS TELL YOU HOW WE TRIED TO ADDRESS THOSE AND THEN SHOW YOU HOW WE HAVE BEEN APPLYING THESE OVER INTO LUNG RESEARCH. TO TRY TO GET FASTER, INSTEAD OF IMAGING TECHNIQUE THAT ACQUIRES EACH PIXEL IN SEQUENCE LIKE A CONFOCAL OR TWO PHOTON MICROSCOPE WE HAVE GONE OVER AS OTHERS HAVE TO HEIGHT SHEET IMAGING. LIGHT SHEET BRINGS FOR EXAMPLE THE EXCITING LIGHT BLUE LIGHT INTO THE SIDE AND ACQUIRES THE IMAGE IN PARALLEL. IT ALLOWS US TO THOUSAND FOLD FASTER COLLECT A WHOLE IMAGE PLAYING, AND TO DO IT WITHOUT BLEACHING THE SPECIMEN BY ILLUMINATING THE REGIONS ABOVE AND BELOW. IT'S MUCH MORE QUANTITATIVE MUCH MORE TOXIC. OUR ADVANCE IS TO MOVE TO TWO PHOTON EXITATION SO NOW IS THE LASER BEAM SHINES THROUGH THE SPECIMEN, INSTEAD OF THE BLUE EXITATION WHICH GIVES YOU THIS HOUR GLASS SHAPE, IF THERE'S ANY LIGHT SCATTERING YOU GET THINGS FAR OUT OF PLAYING TWO PHOTON DEPENDS ON INTENSITY SQUARED SO WITH GET A LIGHT SHEATHE AS DEFINED START DEFINE STOP AND HAS A VERY THIN CONTOUR IN THE SWEET SPOT OF THE LASER BEAM. THIS ALLOWS US TO IMAGE THINGS THAT ARE DYNAMIC AND IMAGING HOSTILE LIKE A BEATING HEARTED AND IN THIS CASE WE LABELED THE JUNCTIONAL PROTEINS THAT ARE BETWEEN THE CARDIO MYOSITES AND EACH ONE OF THE DARK OUTLYING IS A SINGLE CARDIOMYOCYTE IN INTACT ANIMAL AND INTACT BEATING HEART. SO THIS ALLOWS US TO CARRY IT INTO LIGHT IMAGING AND WE EXTENDED THE TIME TO IMAGE TO DAYS INSTEAD OF HOURS BECAUSE IT'S LESS PHOTO TOXIC BUT FOR PURPOSES HERE, THE TEN HOURS OF IMAGING BECOMES JUST A FEW MINUTES. THE SECOND PROBLEM I MENTION IS NUMBER OF COLORS WE CAN SEE. THAT'S E S I TO SEE WHAT THE PROBLEM IS BECAUSE NORMALLY FLUOROCHROMES THERE'S SPECTRA OVERLAPS SO MUCH IT'S HARD TO TELL ONE FROM THE OTHER CLEARLY. WHAT WE HAVE DONE IS BARRING THE REMOTE SENSING CROWD FROM JPL AND OTHER NASA STATIONS AND BASICALLY COLLECT A SPECTRUM OF EACH ONE OF THE PIXELS HERE IN Y AND X AND USE THAT SPECTRUM ACQUIRE WITH SPECTROMETER HOOKED UP TO CONFOCAL MICROSCOPE TO DECIPHER WHICH DYES WERE THERE. BASICALLY COLLECTING THE SPECTRUM AND WE CAN UNMIX THE SIGNALS. GOOD NEWS ABOUT THAT IS IT WORKS, THE BAD NEWS IS, IT'S CRITICALLY DEPENDENT THE SPECIMEN BE LABELED EQUALLY FOR THE DIFFERENT LABELS, TO GET A NICE IMAGE. WE HAVE BEGUN TO GET AROUND THAT PROBLEM BY INNOVATION TA CAME FROM THE WORK OF ENRICO GRETAN MOSTLY, AN AAPPROPRIATE AND WE APPLIED IT TO HYPERSPECTRAL DATA. SO THIS GREEN SPECTRUM FROM THIS REGION OF SPECIMEN, SO THE DOT BECOMES A SIGN AND COSIGN OF THAT SPECTRUM. THE RED SPECTRUM BECOMES THAT, IT GOES FROM THAT SPECTRUM TO THAT DYE AND IF WE GO TO A PLACE WITH THE TWO INTERMIXED IT'S DOT HALFWAY IN BETWEEN, WE CONVERTED A PROBLEM THAT'S INVERSE INTO SOMETHING THAT'S A FORWARD. IT MEANS SOMETHING THAT WOULDN'T HAVE WORKED WITH JUST GLASS FILTERS AND WORKS FAIRLY WELL WITH THE COMMERCIAL MICROSCOPE SOFTWARE, WORKS TREMENDOUSLY FASTER HOURS TO SECONDS SPEED UP AND WITHOUT THE BACKGROUND YOU CAN SEE HERE BECAUSE OF THE UNEQUALNESS OF THE LABELING. THIS ALLOWS US TO GO INTO A LIVE SPECIMEN THIS ONE HERE AND DO MULTI-SPECTRAL IMAGING OF DOZENS OF LABELS A TIME. THOUGH THEY OVERLAP TREMENDOUSLY TO CLEANLY SEPARATE THEM OUT, WHAT'S INTERESTING ABOUT THE DIFFERENT ONES YOU ARE SEEING IN THIS LIVE SPECIMEN IS SOME OF THESE ARE AUTOFLUORESCENCE SIGNALS AND ALL OF THEM ARE INFORMATIVE, THE SIGNAL WE CAN USE FOR FREE. THIS MAGENTA SIGNAL YOU ARE SEEING HERE IS METABOLISM OF THE ANIMAL, WE WILL COME BACK TO THAT LATER. FOR US LOOKING AT FIXED SPECIMENS LIKE BIOPSIES OR MOUSE EMBRYO, THE IMAGING THAT HAS BACKGROUND CONTRIBUTED ALMOST AS MUCH SIGNAL AS THE LABEL GETS INTO SOMETHING CLEAR TO SEPARATE. OUR BIG PROBLEM AS WE WANT TO JUMP FROM THESE EMBRYONIC PROBLEMS INTO THINGS MORE RELEVANT TO INTACT LUNGS AND INTACT ORGANS. IN GENERAL IS THAT WE HAVE A HORRIBLE WINDOWING PROBLEM THIS IS A MICROCT OF A BONE AFTER IMAGE THE MARROW INSIDE. FROM THAT IS THE LITTLE WINDOW WE ARE LOOKING AT HERE WITH THIS TWO PHOTON MICROGRAPH. GOOD NEWS IS WE CAN SEE INSIDE THE BAD NEWS IS WE SEE INSIDE IN A MINUSCULE FRACTION OF THE VOLUME WE NEED TO ASSESS THIS WHAT WE NEED SO SOME APPROACH TO JUMP BETWEEN MICROCT AND OTHER APPROACHES THAT YOU HAVE JUST SEEN IN HUMANS IN AUTOMATED SEGMENTATION PIPELINE, THAT'S WHERE COLLEAGUES AND LUNG MAP CONSORTIUM HAVE BEEN A REAL HELP SO WORKING TOGETHER WITH OUR COLLEAGUES IN CHILDREN'S HOSPITAL WE HAVE BEEN BUILDING THE TOOLS THAT LET US ACQUIRE THESE SORTS OF MICROCTs, THE TOOLS THAT ANALYZE THEM AND TOOLS TO PRESENT THEM TO YOU IN A WAY THAT THEY SORT OF SEE THE STORY. SO HERE WE ARE FLYING THROUGH A HYDRATED AND YOU CAN SEE MUCH OF THE STRUCTURES, YOU CAN SEE THIS SILLIAL BANDS, ALL SORTS OF THINGS INSIDE. WE NEED TO BE ABLE TO DO THIS IN COLOR, NOT JUST IN CT, AND WE ARE HOPING TO DO IT IN LIVE TISSUE EVENTUALLY. SO FIRST LET ME TELL YOU ABOUT ONE OF THE FIXED APPROACHES, AN APPROACH WE CALL VIBRASIM WHICH MAKES UP FOR THE FACT LIGHT CAN ONLY GO IN HUNDREDS OF MICRONS BEFORE IT GETS TOO SCATTERED TO COLLECT SO WE IMAGE THE SPECIMEN, REMOVE A HUNDRED MICRONS AND KEEP WHAT'S LEFT AND BUILD MACROSCOPIC VIEWS OF THE SPECIMEN THIS WAY. IF YOU DO THAT WE ARE ABLE TO SEE OVER CENTIMETER SCALES IN SOME CASES, FEATURES DOWN TO THE SUBMICRON. THIS ALLOWS US TO COMBINE ALL THE MOLECULAR TOOLS I TOLD YOU ABOUT EARLIER AND PUT THEM INTO EMBODIED CELLS, CELLS WITHIN THEIR NORMAL SETTING. THIS IS LET US UNDERSTAND THE FEATURE CONSIST IN THE DEVELOPING LUNG AND WE FOUND THE PARALOGS IN HUMAN SPECIMENS THAT WE HAVE LOOKED AT THAT SHOW MECHANISMS WE THOUGHT TEXTBOOK MECHANISMS MIGHT NOT BE THE WAY THE LUNG IS PATTERNING. WE HAVE BEEN ABLE TO TAKE THOSE DATA AND WITH THE BASICALLY INFORMING IT WITH THE MICROCT DATA, WE HAVE BEEN ABLE TO SEGMENT AND FOLLOW STRUCTURES INSIDE OVER DIFFERENT DEVELOPMENTAL TIME POINTS AND DIFFERENT TIMES IN MATURITY AND DIFFERENT DISEASE STATES AND BEEN ABLE TO SEE THE INDIVIDUAL UNITS FOR EXAMPLE BE ABLE TO SEE SOME OF THE BUILDING BLOCKS AND DEVELOPMENTAL INTERMEDIATES AND FAILURE INTERMEDIATES AREN'T QUITE WHAT WE WERE EXPECTING TO SEE. IN THE LAST COUPLE OF MINUTES WHAT I WOULD LIKE TO DO IS TURN TO A PROBLEM THAT WE HAVE GOT, IS THAT I HAVE THIS LOVELY SITUATION WHERE I CAN PUT SIX OR SEVEN DIFFERENT TRANSGENES INTO A ZEBRAFISH EMBRYO OR MOUSE OR CHICKEN EMBRYO AND HE CAN TAKE ALL OF THEM BUT FEW OF THE PATIENTS YOU TRY TO TREAT WILL COME IN WITH CONVENIENT GFP OR DIFFERENT FLUORESCENT PROTEIN MARKERS. AS I MENTION AS WE WENT BY, THERE'S AUTOFLUORESCENCE SIGNALS HERE THAT ARE STRUCTURAL, WHAT THE PURPLE THINGS ARE AN METABOLIC SUCH AS THE METABOLIC MARKER WE ARE SEEING HERE AND AUTOFLUORESCENCE SIGNAL. IF WE TRY TO LOOK AT UNLABELED ANIMALS, IN THIS CASE THE ZEBRAFISH, YOU CAN SEE METABOLIC MARKERS TO SEE THE -- VERSUS GLYCOLYTIC STATE OF THE TISSUE. WE CAN SEE MARKERS THAT ARE IMPORTANT FOR PATTERNING, MARKERS IMPORTANT FOR PHYSIOLOGY AND OTHER SIGNALING METABOLIC MARKERS. SO YOU CAN SEE SEVERAL OTHER OVER HERE IN THE PHASEAL SPECTRAL PLOT AND YOU CAN THINK THIS COULD BE A WAY AFTER THINGS WITHIN INTACT HUMANS AND WHILE ALIVE LIKE THIS ONE IS, BUT ONE OF OUR PROBLEMS IS SPECTRAL SIGNALS ARE PERTURBED. LIGHT SCATTERS THROUGH TISSUE AND SUCH. WHAT'S MUCH MORE DECISIONTANT TO THE IMPERFECT OPTICKINGS OF HUMAN TISSUE IS THE LIFETIME OF THE FLUORESCENCE, HOW LONG BETWEEN THE EXITATION AND EMISSION OF PHOTON. WE HAVE CREATED A HYBRID THAT BRINGS TOGETHER WORK OF TWO POST-DOCS IN THE LAB ONE WHO THINKS THE ENTIRE WORLD IS SPECTRAL AND ONE THAT THINKS IT'S A LIFETIME AND WE ARE ABLE TO NEGOTIATE WORKING TOGETHER ON THIS THAT NOW IS BEING FED THROUGH A BRONCO SCOPE AN ALLOWS A LIFETIME AND HYPER SPECTRAL TISSUE AN SEPARATE OUT MANY MARKERS THE STRUCTURAL AN CHEMICAL BASED ON THEIR SIGNATURE. THEY ARE STILL GETTING GOING ON THE HUMAN STUDIES, I WILL SHOW YOU MOUSE DATA, IN THIS CASE THE HYPERSPECTRAL IN THE PHLEGM AND HYPERSPECTRAL ALLOWS US TO SEE THE STRUCTURAL IN GREEN SHOULD BE COLLAGEN, I MIGHT HAVE GRABBED THE WRONG SLIDE. THERE'S THE COLLAGEN. HERE WE HAVE METABOLIC FROM GLYCOLYTIC TO OXIDATIVE. THIS IS IN MOUSE AND YOU CAN SEE THE PHYSIOLOGY OF THE CELLS DOWN TO A SINGLE CELL BASIS. WHAT WE TRYING TO SET UP TO DO NOW IS TO PUT THAT SAME INSTRUMENT THROUGH A BRONCHOSCOPE NOT INTO A MOUSE SPECIMEN BUT DOWN INTO A HUMAN SO FAR THE SIGNAL LOOKS LIKE IT'S THERE. WE HAVE GOT A GOOD NUMBER OF EXPERIMENTAL ANIMAL STUDIES, JUST SETTING UP NOW UNDER OUR FUNDING FROM OUR DOD GRANT TO DO THIS IN HUMAN STUDIES AND WE HOPE TO MAKE THIS ROBUST ENOUGH THAT IT DOESN'T REQUIRE THREE PHYSICISTS HANGING TO KEEP IT GOING. SO I'M GOING TO STOP AT THIS POINT AND JUST THANK THE LUNG MAP ORGANIZATION FOR BRINGING ME INTO THE FAMILY AND WARBURG CHILDREN'S HOSPITAL IN PARTICULAR REX MOTORS ONE OUR RING LEADERS, THAT HELPED US TO REALLY PULL TOGETHER TEAM THAT USE MICROCT AND OOZIER AS YOU ARE SEEING HERE, AND GAINING ALL SORTS OF TECHNIQUES, IN THIS LIGHT YOU MIGHT NOT SEE IT BUT AS YOU FLY THROUGH HERE THE MORE CONVENTIONAL DYE COUNT VIEWS ARE SHOWN THERE, THERE IS A MARKER YOU ARE HERE MARKER RIGHT THERE. I WILL USE THAT AND THANK YOU FOR YOUR ATTENTION. MOVE ON TO INVITE NEXT SPEAKER TO COME OUT. [APPLAUSE] OUR NEXT SPEAKER IS SANJAY JAIN. WHO IS GOING TO MOVE US IN YET ANOTHER DIRECTION. >> THANK YOU VERY MUCH, IT'S A PLEASURE TO BE HERE. I WILL HAVE TO FIGURE HOW TO SET MY SLIDES TOGETHER. SO I'M GOING CHAT IN THE INTEREST OF TEAM, I'M PEDIATRIC INFECTIOUS DISEASE PHYSICIAN AND I TAKE CARE OF CHILDREN WITH INFECTION. AS YOU HEARD CORRECTLY TODAY THE REST OF THE WORLD HAS DONE AN AMAZING JOB OF TREATING INFECTION, TB ALL TIME LOW IN THE UNITED STATES, THOUGH IN THE WORLD IT'S STILL ALL TIME HIGH. WHAT HAS HAPPENED INTERESTINGLY, WE HAVE GOTTEN RID OF BACTERIAL INFECTIONS. BUT WE ALSO CREATED MONSTERS AND THOSE ARE HIGHLY DRUG RESISTANT BACTERIA AND OTHER INFECTIONS THAT ARE VERY DIFFICULT TO TREAT. AND THE OTHER THING THAT'S EMERGING NOW IS ALSO THE INTERACTION OF WHAT THE MICROBES DO TO THE HUMANS. THERE'S A LOT OF DATA ON MICROBIOME SO YOU HAVE TO BE CAREFUL BUT GENERALLY THE RELATIONSHIP HOW THE BACTERIA INFLUENCE US AN CHRONIC DISEASE. I'M GOING TO TALK TB, THE FIRST PLOT I STARTED WORKING WITH BUT SHOW YOU DATA THERE IN TERMS OF WHAT WE CAN LEARN FROM TB TO TREAT INFECTION THAT WE HAVE LIKE STAPH AUREUS, MRSA NON-TB BACTERIA IN CYSTIC FIBROSIS PATIENTS AND PROVIDE SOME DATA THIS IS GOING TO BE INTERESTING TOOL FOR INFECTIOUS DISEASES IN THE U.S.. AND OBVIOUSLY GLOBALLY. SO QUICKLY I WILL START WITH THE REAL CASE, THIS IS A TWO-YEAR-OLD CHILD I TREATED, THIS IS A U.S. CHILD WHO TRAVELED TO INDIA AND THEN IN INDIA, GOT A VACCINE CALLED BCG NOT USED IN THE U.S. ANY MORE, THAT'S THE USE PREVENT TB. LAST WEEK OF HER VISIT SHE DEVELOPED FEVERS WHEN SHE RETURN TO THE U.S.. SHE WAS EVALUATED BY MY COLLEAGUE DR. NICHOLS AT JOHNS HOPKINS AN BASED ON CLINICAL DATA AND CT IMAGING, TB. YOUNG CHILDREN CANNOT BRING UP SPEW TA OR SPECIMENS USED TO DUST, THAT'S THE BANE OF WHAT WE USE TO TREAT DIAGNOSE INFECTION. SO WE PUT OUR TUBE DOWN THE NOSE INTO THE STOMACH AND IT'S FORM AD GASTRIC ASPIRATE, THAT WAS DONE CONSECUTIVELY FOR FOUR DAYS AND TRY TO ISOLATE THE BUG. SHE WAS STARTED BASED ON IMEN MAAING AND CLINICAL FINDINGS ON FIRST LINE TB TREATMENT WHICH IS FOUR DIFFERENT DRUGS. PARTIALLY GOT BETTER, SYMPTOMS GOT BETTER, TOOK US 12 WEEKS TO FIND OUT SHE HAD A HIGHLY DRUG RESISTANT FORM CALLED XTRTB. THIS IS A GRAPH SHOWING X AXIS, THINGS HAPPENING ON THE Y AXIS, CHILD FEVER RESOLVED WITH THE FIRST LINE TB TREATMENT SHOWN IN PINK, WHICH ULTIMATELY WAS INEFFECTIVE. WAS GAINING WEIGHT SO YOUNG CHILD THAT'S IMPORTANT THING TO LOOK AT AND A MARKER OF INFORMATION CALLED CRP WAS DECREASING. OBVIOUSLY WHEN WE FOUND THIS IS XTRTT WE INDIVIDUALIZED TREATMENT REGIMEN AND CHALLENGES CAME UP AFTER THAT. SO FIRST WE GAVE A BUNCH OF DRUGS THAT WE DIDN'T HAVE GOOD PHARMACOKINETIC DATA, IF YOU TAKE A DRUG ORALLY DOES IT WHERE SITE OF INFECTION IS. ONE OF THESE DRUGS HAD TO BE GIVEN BIP INJECTION AND CAUSES BOTH TOXICITY TO THE KIDNEYS AND TO THE EARS. AND THEN OFLY WE REALLY NEEDED TO KNOW THIS CHILD WAS GETTING BETTER OR NOT RAPIDLY. AND BECAUSE WE DIDN'T HAVE MICROBIOLOGY AND OTHER INDICATORS INCLUDING CLINICAL SCIENCE AND SYMPTOMS TO MONITOR BECAUSE OF THE PRIOR EXPERIENCE THAT IN EFFECTIVE REGIMEN HAS SHOWN IMPROVE, WE HAVE TO COME UP WITH SOMETHING. WE USED TO -- SOMETHING SIMPLE. WE USE CT IMAGING, YOU WILL HEAR MORE ABOUT HOW TECHNOLOGY HAS TRANSFORMED THE RADIATION DOSE TO REALLY LOW, I LEARNED A LOT DURING THIS CASE. VERY QUICKLY, AGAIN NOT TO BELABOR THIS FACT, CT IMAGING WAS INDEED USEFUL. WE ARE TOLD IN RADIOLOGY, IT LAX CLINICAL SYMPTOMS BUT IN THIS PATIENT WE CAN RAPIDLY SEE CHANGES WHEN WE STARTED TREATMENT SIX WEEKS INTO TREATMENT AND TEN WEEKS BEFORE WE HAD ANY OTHER CLAN OR UP TOM. VERY QUICKLY THIS CHILD HIGHLIGHTS SOME OF THE PROBLEMS WE ARE FACING NOW IN INFECTIOUS DISEASE IN THE HOSPITALS THAT WE HAVE HIGHLY DRUG RESISTANCE INFECTION, WE CAN'T USE EMPIRIC FIRST LINE ANTIBIOTICS. WE DON'T HAVE TOOLS TO DIAGNOSE OR MONITOR INFECTIONS. WE ALSO HAVE LIMITED LEVEL OF DATA. IN TERMS OF UNDERSTANDING HOW THE ANTIBIOTICS GET TO THE SITE OF INFECTION WHICH IS WHERE BACTERIA ARE. THIS CHILD RECEIVE 18 MONTHS OF MULTIPLE DRUGS AND THEN WE HAD TO MONITOR THIS CHILD FOR TWO YEARS AND WE ARE HAPPY TO NOTE THIS CHILD IS DEEMED TO HAVE A STABLE CURE. THISES A SUCCESS STORY, WE ALSO HAVE NOT A LOT OF SUCCESS STORIES. WITH THAT BACKGROUND I WANT TO TALK ABOUT WHAT THE FUNDAMENTAL PROBLEM IS. THE FUNDAMENTAL PROBLEM OF DIAGNOSING INFECTIONS IS, WE NEED A SPECIMEN, THIS IS THE LIGHT MICROSCOPY WHICH IS USED TO MAKE DIAGNOSIS WITH TB. WE HAVE FANCY TECHNOLOGY, AUTOMATED CULTURE TECHNOLOGY, WE HAVE PCR BASED TECHNOLOGY WE FUNDAMENTALLY NEED A CLINICAL SAMPLE SO THE PROBLEM IS YOU NEED TO GET TO THE BUG, YOU NEED TO BRING THEM OUT OR GO IN WITH A NEEDLE TO GET TO THEM. OFTEN INTRACTABLE -- YOU HAVE A BRAIN LESION IF YOU HAVE A LESION DEEP INSIDE THE LUNG IT COSTS MONEY TO DO A BIOPSY PLUS IT COULD BE DANGEROUS. THE OTHER FUNDAMENTAL PROBLEM, I THINK IT WAS REALLY NICELY POINTED OUT BY THE PRIOR SPEAKER IS THERE'S A LOT OF HETEROGENEITY IN DISEASE, THERE'S SAMPLING BIAS WITH SMALL NEEDLES TO TRY TO UNDERSTAND WHAT'S HAPPENING. IN A HUMAN PATIENT. SO THERE'S A SAMPLING BIAS. SO I'M A BIG FAN OF -- STAR TREK. ANYBODY WATCH STAR TREK HERE? I GREW UP IN INDIA, THE ORIGINAL FROM 1960s CAME IN THE '80s AND '90s AS A KID. I LOVE IT THE FLIP PHONES AN IPADS YOU ARE NOT PART OF IN THE 1960s AND NOW WE USE THEM. THIS IS DR. SPOC, IMAGING DEVICE FIX THINGS, FANCIER, NICE IMAGING NOW. THE FUNDAMENTAL THING WE CAN DO WITH MOLECULAR IMAGING WE LABEL A DRUG, WHICH EMITS ENERGY AND WE HAVE MACHINES CALLED SPEC THAT GIVE YOU THREE DIMENSIONAL INFORMATION FROM WHERE SIGNAL IS COMING. THERE'S A HUGE INVESTMENT ONCOLOGY NEUROLOGY CARDIOLOGY, CAN WE APPLY IT TO INFECTIOUS DISEASE. IN THE NEXT TEN MINUTES I WILL TRY TO GIVE YOU SOME DATA AND THANKS TO FUNDING FROM NHLBI SHOW THIS IS FEASIBLE, THAT'S WHAT I TRY TO PROVE TO YOU HOW WE APPLY THIS TO WHAT WE SEE IN OUR PARENTS IN THE U.S., ON A DAILY BASIS. SO I WANT TO HIGHLIGHT THIS THING ABOUT HETEROGENEITY. THERE'S A HUGE AMOUNT OF HETEROGENEITY, YOU SAW THAT IN MICROSCOPIC LEVEL EXISTS AS A MACRO SCOPIC LEVEL, THE CLINICAL SAMPLE TO MAKE DIAGNOSIS OR UNDERSTAND WHAT'S HAPPENING IN THE BODY ARE NOT ACCURATE REFLECTORS WHAT'S HAPPENING AT SITE OF INFECTION. S IS QUICKLY A MOUSE, THIS ONE MOUSE IS EXPERIMENTALLY INFECTED WITH TUBERCULOSIS AND YOU CAN SEE THE HISTOPATHOLOGY THERE, YOU CAN SIGH DIFFERENT LESIONS. I WILL TELL YOU NOT ONLY ARE THEY DIFFERENT, THEY LOOK DIFFERENT BUT THEY ARE ACTUALLY AT LEVEL ALSO DIFFERENT SO DIFFERENT MICROENVIRONMENTS. THIS IS A HUMAN PATIENT THAT WAS IMAGED AT JOHNS HOPKINS WHO ALSO HAS TB, YOU CAN SEE GABBA DISEASE, PNEUMONIA AND RADIOLOGISTS IN THIS BUT SOMETHING WHICH LOOKS MORE DENSE THAN PNEUMONIA AND GRAM DISEASE. THE RESPONSE TO DRUG TREATMENT WHAT THE BUGS SEE THERE ARE ALL DIFFERENT IN THESE DIFFERENT MILIEUS. VERY QUICKLY I SHOWED YOU SPATIAL HETEROGENEITY, THERE'S TEMPORAL HETEROGENEITY, THIS IS A MOUSE WITH TB AND THE PARIETAL THINGS ARE TB LEAGUES, WE ARE MEASURING METABOLIC ACTIVITY. YOU CAN SEE AS THE TREATMENT GOES ON, SOME LESIONS GET BETTER, SOME GET WORSE. WHAT DOES THIS MEAN,? WHY? THE INFLAMMATION IS DOWN IN CERTAIN AREAS, OVERALL THE ANIMAL DOES BETTER AND IS TREATED. I'M GOING TO TALK ABOUT THREE QUICK THINGS THAT I HAVE IN TERMS OF WHAT WE ARE TRYING TO UNDERSTAND IN BOTH ANIMALS BUT ALSO IN HUMANS. THE FIRST THING IS TRY TO DEVELOP SPECIFIC METHODS TO LABEL BACTERIA WILD TYPE BACTERIA, WE CAN LOOK AT IN HUMANS. THE FIRST THING I WANT TO POINT OUT WHICH I THINK MOST OF YOU KNOW IS THERE'S A EXACTLY ZERO BACTERIA SPECIFIC IMAGING AGENTS AVAILABLE IN INFECTIOUS DISEASE, WE USE CT MRI, ULTRASOUND, CHEST X-RAY NON-SPECIFIC. AND WE ARE UTILIZING ANTIBIOTICS LIKE WATER AND THAT'S WHAT'S CAUSING PARTLY THE DRUG EMERGENCE OF DRUG RESISTANCE. SO OUR FUNDAMENTAL HYPOTHESIS WAS THAT PATHOGENERAL SPECIFIC MOLECULES ARE DEVELOPED IF WE LOOK AT THE DIFFERENCES IN THE BIOLOGY OF -- BACTERIA FROM YOU CAREIOTS WHICH ARE HUMAN BEINGS. SO VERY QUICKLY, THREE GOALS, SPECIFIC DETECTION AND LOCALIZATION OF INFECTION, DEFINE BACTERIAL CLASS, SO THAT WE HAVE SOME IDEA OF WHAT EMPIRICALLY TREAT THESE PATIENTS WITH AND RAPIDLY DETECT THERAPEUTIC FAILURES I SHOW YOU THIS DATA TO PROVE THIS IS FEASIBLE. SO BEFORE ANYBODY DOES STUFF OBVIOUSLY I'M ONLY PRESENTING YOU MY SUCCESS, WE FAILED MULTIPLE TIMES. LET'S GO TO UNBIASED APPROACH SO WE SCREENED A THOUSANDS MOLECULES, THIS IS PUBLISHED BUT WE WERE TRYING TO LOOK FOR MOLECULES THAT WOULD BE SPECIFICALLY USEFUL TO DETECT BACTERIA. SO OUR BACTERIA SPECIFIC ACCUMULATING BACTERIA NOT METABOLIZED BY EUKARYOTIC SYSTEMS. SO WE HAVE A PLUS SCORE, PLUS THREE SCORE MINUS THREE SCORE, NOT GO INTO DETAILS OF MOLECULES FOUND I'LL TALK ONE MOLECULE TAKEN TO CLINIC TO SHOW PROOF OF CONCEPT THIS MAY BE FEASIBLE. WE PUBLISHED A PAPER AND MOLECULE CALLED SORBITOL, SUGAR. IT'S AN ISOMER OF GLUCOSE, IT CAN BE MADE FROM FTG, A COMMON PET TRACER. WE SHOWED THAT IT IS SPECIFICALLY TAKEN UP BY GRAM NEGATIVE BACTERIA FROM THE INTERBACK RESEE FAMILY E COLO AND KLEBSIELLA AND OTHERS, LOT OF RESISTANT BACK TOGETHER, WE SHOW SPECIFICALLY TAKEN OUT BY THE GRAM NEGATIVE BACTERIA AND NOT BY HUMAN CELLS OR CANCER CELLS YOU CAN SEE THE DARKER GRAY AS CONTROL WHICH IS FTG, THE LIGHT GRAY IS THE FDS IN THESE IMAGES. THIS IS A MECHANISTIC BASE, BACTERIA TAKING UP SPECIFICALLY THIS SUGAR SORBITOL, DESCRIBED IN THE 1970s. AND WE CAN PREDICT WHICH BACTERIA WILL TAKE IT UP BASED ON INFORMATICS THAT WE HAVE ON HOMOLOGY TO ENZYMES AND WE CAN TEST THAT IN VITRO. TO COMING TO SOME COOL IMAGES. THIS IS A MOUSE INJECTED WITH FLORAOXISOR BY TOLL --SORB TOLL. ON ONE SIDE THEY TEN TIMES HIGHER DEAD BACTERIA. THIS IS A THREE VERSION YOU CAN SEE SIGNAL FROM THE SIDE WHICH IS LIVE BACTERIA BECAUSE LIVE BACTERIA TAKE UPSORB TOLL -- SORBITOL. THIS IS I EXCLUDED THROUGH THE KIDNEYS. THIS BLADDER IS CATHERRIZED IN THIS ANIMAL. FTG GLUCOSE YOU CAN HAVE INFLAMMATION INDUCED BY DEAD BACTERIA AS LIVE BACTERIA. SO WE WENT BANANAS AFTER THAT. THIS IS AN ANIMAL GIVEN CYCLOPHOSPHOMIDE TO INDUCE NEUTROPENIA AS WE HAVE ONCOLOGY PATIENTS WHO DON'T HAVE GUT CELLS, MEASURING BACTERIA, NOT THE INFLAMMATION, YOU CAN SEE THE YELLOW ARROW, LIVE BACTERIA, NOTHING ON THE SIDE OF THE DEAD BACTERIA WHICH IS THE RIGHT ARROW. WE CAN CREATE A LUNG INFECTION MODEL, KLEBSIELLA PNEUMONIA, THAT CAUSES INFECTION, SO VENTILATOR PNEUMONIA, ARE LOT OF THEM ARE ENTEROBACK TIER'S MA. WE TREATED A BRAIN INFECTION MODEL, SO WE HAVE CREATED MODELS TO SHOW THIS WORKS IN MULTIPLE SIGNATURES. LASTLY -- SIGNATURESES. WE CAN -- SITUATIONS. THIS IS A DRUG SUSCEPTIBLE BACTERIA BEFORE WE GET ANTIBIOTICS WHICH KILLS THE FULLY SUSCEPTIBLE BACTERIA. YOU CAN SEE THE SIGNAL DISAPPEAR WITHIN 24 HOURS. CORRELATES WITHIN THE DECREASE IN BACTERIAL BURDEN. TAKE A HIGHLY DRUG RESISTANCE BACTERIA CALLED ESPL OR SPECTRAL BETA LACTAMASE PRODUCER 24 HOURS AFTER WORSE, ANIMALS SEPTIC SO DIAGNOSE PATIENT BEFORE THEY GET SEPTIC AND RAPIDLY. SO WE PUBLISHED THIS PAPER IN 2014, GROUP IN CHINA BY 2015 DONE FIRST IN HUMAN STUDYIER I WAS NOT HAPPY BUT IT WAS GREAT. UNRELATED GROUP DOES THE STUDIES, I DON'T HAVE TO PAY FOR THEM SO THE NIH DIDN'T PAY FOR ANY OF THESE STUDIES. SO WHAT THIS SHOWED IS CLEARLY THIS TRACER IS RAPIDLY ELIMINATEED FROM KIDNEY, GOT A METRIC WITH RADIATION NOT CAUSING RADIATION TO THE PATIENTS. FUNDED THROUGH THE NHLBI WE ENROLLED PATIENTS, CONTROL PATIENTS WHO HAVE A DISEASE BUT DON'T HAVE INFECTION PEDIATRIC PULMONARY FIBROSIS CANCER AND PATIENTS WITH INFECTION. I WANT TO SHOW THIS IS A PATIENT WITH PULMONARY FIBROSIS ONE HOUR AFTER TRACE INFECTION. SOME DISEASE IN LOWER PARTS OF THE LUNG IT DOES NOT ACCUMULATE. AT TWO HOURS YOU CAN SEE SUBSTANTIAL ELIMINATION WITH TRACER, SOME UPTAKE OF LIVER BEFORE THAT. THIS IS A PATIENT WHO HAS CANCER THEN HAD KLEBSIELLA PNEUMONIA INFECTION AND PSYCH IT ACCUMULATE BECAUSE OF NECROTIC TUMOR. THIS IS ANOTHER PATIENT WITH KLEBSIELLA INFECTION. DOESN'T HAVE CANCER BUT ALSO -- THIS IS SOMEBODY DATA, THESE ARE NOT A LOT OF PATIENTS SO TAKE MY DATA WITH GRAIN OF SALT ACCUMULATING MORE PATIENTS, THREE PATIENTS WITH INFECTED LUNG ONE WITH NEOPLASTIC LESION AND FOUR WITH INFLAMMATION AND THIS TRACER IS SPECIFICALLY ACCUMULATING IN THE LUNGS AT SITE OF INFECTION BECAUSE OF ANTEROBACTER. IF YOU TREAT WITH ANTIBIOTICS BEFORE AND AFTER TREATMENT YOU CAN FOCUS ON THE AREA ABOVE THE HEART. AND YOU CAN SEE THERE IS DECREASE IN SIGNAL, IF YOU QUANTIFY THIS YOU CAN SEE SIGNAL DECREASE IN INFECTED AREAS BUT NOT CANCER OUTSIDE AREAS BECAUSE TRACER DOESN'T GET THERE. I HAVE A FEW MORE MINCE, I WANT TO TALK ONE ANOTHER COOL THING WE ARE DOING WITH THIS TECHNOLOGY. THAT IS TO TRY TO UNDERSTAND IF THE ANTIBIOTIC WE GIVE GETS TO THE SITE OF INFECTION OR NOT. THAT'S CRITICAL BECAUSE NORMALLY WHEN WE TRY TO DEVELOP NEW DRUGS, ANTIBIOTIC WE CAN MEASURE BLOOD LEVEL BUT NOT THE LEVEL OF THE ANTIBIOTIC AT THE SITE OF INFECTION IN THIS SITUATION LUNG INFECTION. THIS IS MOUSE ROTATING. PEOPLE CALL 4D IMAGE OF A MOUSE THAT HAS RADIO LABEL WORKING RA FARM PIN, AS THE SAME CLASS OF DRUG FOR MRSA MTM, NON-BACTERIAL -- WE WANT TO USE THIS TO UNDERSTAND CON ENISSATION OF DRUG AT SITE OF INFECTION TO KILL BACTERIA WHERE THE INFECTION IS NOT IN THE BLOOD. THERE'S A LOT OF INFECTION NOT IN THE BLOOD. SO QUICKLY, WHAT YOU CAN SEE IS RA FARM PIN INTRAVENOUSLY GO TO ALL PARTS OF BODY, LIVER AND MIMICS HOW RA FARM PIN IS METABOLIZED THIS IS A MODEL OF TB MENINGITIS CAUSED BY TUBERCULOSIS AND WE SHOW THAT ONE THERE'S A HUGE AMOUNT OF HETEROGENEITY IN CONCENTRATION OF DRUG, SPATIAL BUT ALSO TEMPORAL, WITHIN TWO WEEKS OF STARTING TREATMENT BECAUSE OF BLOOD BRAIN BARRIER BECOME NICER THE ANTIBIOTIC DON'T GET INTO THE BRAIN. SO IF WE DECIDE TO USE ANTIBIOTIC LEVELS AT TIME OF START UP BUT MAY NOT BE DOING THE RIGHT THING. THE ANTIBIOTICS IS LOWER BECAUSE OF MULTIPLE REASONS. THERE'S TEMPORAL AS WELL AS PATIENT CHANGES HAPPENING IN PATIENTS. THE OTHER THING WE SHOWED HERE WAS THE CSF WE THINK WOULD BE A GOOD MARKER OF WHAT THE CONCENTRATION OF THE DRUG ARE, IS NOT HYBRID MARKER WHAT THE DRUG LEVELS ARE IN THE BRAIN, WHICH IS WHERE SOME OF THE INFECTION IS. WE HAVE DONE THIS SO WE RECRUIT ED ABOUT 13 PATIENTS. THIS IS DATA FROM COUPLE OF DAYS AGO SO DOESN'T INCLUDE NEW PATIENTS. WE HAVE CAVITY LEAGUES PNEUMONIC LESIONS AND WHAT WE SHOW IS THE GABBA TREE WALL HIGHEST NUMBER OF BACTERIA ALSO HAS LOWEST CONCENTRATION OF REAFAMPIN GETTING THERE SO SHOWS WHY LONG TREAT NEEDED FORD THIS. SO WE HAVE DONE IN ONE PATIENT WITH TB MENINGITIS, WE GOT LUCKY AND SHOWED DECREASE PENETRATION INTO THE BRAIN. WHAT DO WE DO WITH THE DATA? MODEL TO TRY TO SAY WHAT IS THE DRUG CONCENTRATION THAT WE NEED TO TREAT A PATIENT EFFECTIVELY? THIS IS MODELK TO TREAT CHILDREN UNDER FIVE WHO WE NORMALLY GIVE ABOUT TEN TO 20-MILLIGRAMS OF RAFAMPIN BT DATA SUGGESTS 30 TO 35-MILLIGRAMS TO GET TO A CONCENTRATION WHICH IS HIGH ENOUGH TO KILL BUGS. SO YOU CAN USE THAT DATA. LAST IS INFLAMMATION. MAJOR ROLE IN INFECTION. WE HAVE FORGOT P IT CAN BE GOOD BUT ALSO BAD. NEW TRACER THAT LOOKS MORE SPECIFICALLY AT MACROPHAGE SPECIFIC INFLAMMATION. AND WE HAVE DONE THIS LOT OF WORK IN TB TO SHOW IT CAN BE PREDICTIVE OF TREATMENT OUTCOMES. SO WE HAVE TO WAIT FOR MONTHS TO YEARS AFTER WE FINISH TREATING PATIENT TO UNDERSTAND RELAPSE OR NOT. WE ALSO HAVE TAKEN INTO THE CLINIC. SO THIS IS DATA FROM DOSING METRIC DATA FROM PATIENTS, BUT THEN THE OTHER COOL THING IS NOT ONLY APPLYING THIS TO TB BUT ALSO TO SARCOIDOSIS WHICH IS A MACROPHAGE MEDIATED DISEASE. THIS IS A PATIENT WITH SARCOIDOSIS, YOU CAN SEE THESE SIGNALS. SO I WANT TO SUMMARIZE, I WANT TOENT PROOUT THAT BACTERIAL INFECTIONS ARE WORLD WIDE, NOW DEALING WITH DRUG RESISTANT BACTERIA HERE AT HOME IN THE UNITED STATES AND WE REALLY NEED SOME INTERESTING TOOLS TO BE ABLE TO CAPTURE THIS AND TREAT OUR PATIENTS APPROPRIATELY. THERE'S HETEROGENEITY, WE DON'T UNDERSTAND ALL THAT, WE BRUSH OFF AS BIOLOGICAL VARIABILITY BUT LAWS OF PHYSIC AND CHEMISTRY, THEY HOLE TRUE IN EVERYBODY. I TALKED ABOUT CERTAIN NEW TECHNOLOGIES WE ARE DEVELOPING TO UNDERSTAND BACTERIA AND MILIEU THAT IS HAPPENING AROUND ONE OF THE THINGS IS THIS ALLOWS PRECISION MEDICINE APPROACHES IN TRYING TO CLASSIFY PATIENTS WHO NEED LONGER TREATMENT OR OPTIMIZE TREATMENT, THINGS LIKE THAT. SO I WANT TO THANK ALL THE PEOPLE IN MY LAB WHO HAVE DONE THE TEST TEST TEST TEST TEST TEST TEST TEST TEST TEST TEST TEST TEST TEST TEST TEST TEST TEST TEST TEST OXYGEN IMAGES WE CAN SEE EXACTLY WHERE WE'RE GETTING SIGNAL ENHANCEMENT. SO THIS IS A TYPE OF VENTILATION MAPPING. SO HERE IS A HEALTHY VOLUNTEER, WHERE IF WE SUBTRACT THE UM IMAGINE YOU CAN SEE SIGNAL ENHANCEMENT MOSTLY IN THE LUNG, NOT VERY MUCH IN THE BACKGROUND TISSUE AND IT'S QUITE EVENLY SPREAD AROUND THE LUNG. AND BY COMPARISON, IF WE LOOK AT SUBJECTS WITH LUNG DISEASE, WE GET LOWER AMOUNT OF SIGNAL INTENSITY INCREASE, AND IT'S NOT EVENLY SPREAD AROUND THE LUNGS. SO CLEARLY THERE ARE REGIONS IN THESE PATIENTS THAT OXYGEN ISN'T REACHING SO WE DON'T HAVE GOOD VENTILATION. WE CAN START TO LOOK AT THESE MAPS TO LOOK AT THE REGIONAL OXYGEN DISTRIBUTION. WE CAN USE THE SAME EFFECT FOR BLOOD OXYGEN. IN HEALTHY VOLUNTEER IMAGE OF THE HEART, SO THE ORANGE COLOR IS THE DEOXYGEN IN THE BLOOD OPT RIGHT VENTRICLE SIDE AND PINKER COLOR IS THE OXYGENNATED BLOOD ON THE LEFT VENTRICLE SIDE. SO AS OXYGEN ENTERS THE BLOOD WE GET A CHANGE IN SIGNAL INTENSITY BETWEEN THE LEFT VENTRICLE AND THE RIGHT VENTRICLE. AND SUBJECTS WITH DISEASE, THIS DOESN'T HAPPEN AS CHARACTERISTICALLY SO WE SEE A HETEROGENEOUS POPULATION HOW BLOOD IS BEING OXYGENATED. TAKING THIS A STEP FURTHER WE CAN PERFORM PROFUSION MAPPING SO WE CAN LOOK AT PROFUSION DEFICITS IN THE LUNG SO FIRST PASS GADOLINIUM CONTRAST AGENT IN THE LUNG AND THE RESULTING QUANTITATIVE MAP SHOWING THE QUANTITATIVE PROFUSION THROUGHOUT THE LUNG. GOING BACK TO WHAT I SAID EARLIER, MR GIVES US THE OPPORTUNITY TO CHARACTERIZE THE LUNG TISSUE. NOT JUST VISUALIZE BUT CHARACTERIZE IT. AND SO A LONG TERM GOAL IS THINK CAN WE REPLACE SOME SURGICAL LUNG BUY I DON'T KNOW SIPS WITH M RI TISSUE CHARACTERIZATIONS. SO HERE ARE EARLY RESULTS IN RELATION TO SCARRING. YOU CAN SEE THE NODULE ON CT AND THE CORRESPONDING DIFFERENCE IN THE MRI SIGNAL IN THE BOTTOM. YOU CAN IMAGINE MOVING TOWARD A FUTURE TO DO A MULTI-DIMENSIONAL CHARACTERIZATIONS OF LUNG FUNCTION USING M RICS. SO WE HAVE ANATOMY, VENTILATION PROFUSION, TISSUE CHARACTERIZATIONS AND BLOOD OX GENERAL MEASUREMENTS ALL WITH NO IONIZING RADIATION IN A LOW FIELD MRI SO THE SECOND THING IS EVALUATION OF CARDIO PULMONARY DISEASE WITH MRI HEART CATHETERIZATION. I ALWAYS LIKE TO START WITH THIS VIDEO BECAUSE IT IS A HELPFUL ILLUSTRATION OF MRI GUIDANCE. SO IN THIS CASE THERE'S A PATIENT INSIDE THE BORE OF THE MRI SCANNER AND YOU CAN SEE THE FEET ARE STICKING OUT. AND THE INTERVENTIONISTS ARE USING ACCESS POINTS IN THEIR LEG, NAVIGATING DEVICE UP TO THE HEART. LOOKING AT IMAGES ON THE FRONT OF SCREEN AND USING THAT TO NAVIGATE FROM CHAMBER TO CHAMBER SO AT THE BOTTOM YOU CAN SEE EXAMPLE OF IMAGES LOOK LIKE REALLY A BOUNCING BALL WHICH IS A CONTRAST AGENT FILLED BALLOON BUT THEY NAVIGATE THROUGH DIFFERENT CHAMBERS OF THE HEART. THAT BALLOON IS USED TO MEASURE PRESSURE. THIS IS CATHETERIZATION PROCEDURE MEASURING PRESSURE ON THE RIGHT SIDE OF THE HEART. THE REASON FOR THIS MRI SCANNER IS TO COMBINE CHAMBER PRESSURE MEASUREMENTS USEFUL DIAGNOSTICALLY WITH MRI FUNCTION AND FLOW. AND THE IMPORTANT THING HERE IS THAT MRI IS THE MOST ACCURATE WAY OF MEASURING THE FUNCTION AND FLOW FOR BOTH RIGHT AND LEFT VENTRICLE. SO UNLIKE OTHER METHODS THEY CAN USE IN TRADITIONAL CATH LAB ENVIRONMENT, THIS WILL GIVE A MORE ACCURATE NUMBER REGARDLESS OF THE PHYSIOLOGICAL STATE OF THE PATIENT. FROM SO COMBINING THE TWO MEASUREMENT OF PULMONARY RESISTANCE IMPORTANT IN CLINICAL DECISION WHETHER OR NOT TO SEND A CHILD WITH CONGENITAL HEART DISEASE FOR SURGERY OR WHETHER OR NOT WE PRESCRIBE A DRUG. WE CAN ALSO DO PHYSIOLOGICAL PROVOCATION TO PROVOKE RESPONSE LIKE INHALING NITRIC OXIDE OR HAVING PATIENT EXERCISE IN MRI SCANNER. THIS IS DONE FOR A WHILE. THERE'S A TEN YEAR REVIEW FROM KINGS COLLEGE LONDON, IN CHILDREN'S NATIONALLED MANYCAL CENTER PUBLISHED IN 50 PATIENTS. SO IN OUR EXPERIENCE MOST PATIENTS EITHER HAD PULMONARY HYPERTENSION OR UNEXPLAINED DYSPNEA. AND 50% REQUIRED INHALATION NITRIC OXIDE FOR PHYSIOLOGICAL PROVOCATION. ALL THESE STUDIES WE ONLY EVERY USED PLASTIC CATHETERS SO HE CAN THESE ARE THREE COMMON CATHETERS, THAT IS NOT ALWAYS GOOD ENOUGH, IN FIVE% WE COULDN'T REACH ONE PULMONARY ARTERIES USING CATHETER ALONE WHICH MEANS PATIENT OUT OF SCANNER GO BACK TO CATH LAB, GUIDE WIRE THE SHELL AND DO IT UNDER X-RAY INSTEAD. THIS IS WHERE THE ROLE BECOMES OBVIOUS. THEY HAVE RACKS OF THESE DEVICES. THEY WILL USE FOR DIFFERENT ASPECTS OF DIFFERENT PROCEDURES DEPENDING ON THE MECHANICAL PROPERTIES AND MOST OF THESE HAVE METAL IN THEM. THEY CAN CREATE DANGEROUS AMOUNTS OF HEATING. IN A GEL PHANTOM DONE ON 1.5T SYSTEM WHERE WE START IMAGING WITH THE GUIDE WIRE BODY TEMPERATURE AND SECONDS BOILING THE GEL. SO OBVIOUSLY WE WOULDN'T WANT TO PUT THIS IN TO A PATIENT. IN ORDER TO DO ANYTHING MORE COMPLICATED FLOAT A BALLOON TO RIGHT SIDE OF THE HEART, WE NEED THESE DEVICES. IT IS A BIG MISSION TORY DESIGN TO MRI SAFE. SO WE WANT TO MOVE TO A SYSTEM WHERE THE MRI WAS INHERENTLY SAFE. I SHOWED THIS AT THE BEGINNING, AS MAGNETIC FIELD STRENGTH INCREASES HEATING INCREASES QUO DRATICALLY. BY GOING FROM 1.5T DOWN TO .55 WE HAVE A 7.5 FOLD REDUCTION IN HEATING. SO NOW WE CAN WALK INTO OUR CATH LAB, AND WE CAN TAKE SOME OF THESE OFF THE SHELF DEVICES AND USE THEM IN PATIENTS NOT ALL, SOME ARE -- BUT WE HAVE A SMALL FRACTION WE CAN USE. SO WE CAN TAKE THE SAME DEVICE THE INTERVENTIONIST IS USED TO USING X-RAY AND PUT IN THE MRI SCANNER AND USE FOR MRI GUIDED INVASIVE PROCEDURE. WE ARE DOING THIS NOW ON PATIENTS HERE AT THE NHLBI SO EVERY PATIENT WHO NEEDS A RIGHT HEART CATH WILL HAVE IT DONE UNDER MRI GUIDANCE WITH METALLIC GUIDE IRWIRE. THIS THIS OPENS THE DOOR TO MORE COMPLEX PRO E SO CURES WE CAN DO UNDER MRI -- PROCEDURES WE CAN DO UNDER MRU GUIDANCE WITH DEVICES. THIS RELIES ON BEING ABLE TO GENERATE GOOD QUALITY CARDIAC IMAGING SO TO DO THESE PROCEDURES WE NEED TO BE ABLE TO DO THE CARDIAC IMAGING TO GO WITH IT. SO HERE I'M SHOWING SOME EXAMPLES FROM A ROUTINE CARDIAC EXAM DONE ON HIGH PERFORMANCE LOW FIELD SYSTEM. SO I'M SHOWING RESULTS FROM IMAGING FLOW MEASUREMENTS, QUANTIFYING FAT, 3-D ANATOMY SCAR IMAGING AND THE PARAMETRIC TISSUE MAPPING. SO I THINK FOR ANY OF THE CARDIAC IMAGERS IN THE CROWD, IF I TOLD YOU THIS, IF I DIDN'T TELL YOU THIS WAS DONE AT LOW FIELD, YOU PROBABLY WOULD HAVE THOUGHT IT WAS 1.5T. WE ARE GETTING IMAGE QUALITY TO TRICK PEOPLE INTO THINKING THIS IS A REGULAR CONVENTIONAL MRI SYSTEM. SO THE HIGH PERFORMANCE LOW FIELD COMBINATION WORKS REALLY WELL FOR CARDIAC AND LUNG. SO SUMMARIZE, OUR NEW MRI SYSTEM COMBINED LOW FIELD WITH MODERN SYSTEM ENGINEERING AND IMAGING METHODS AND SHOWED YOU HUNDRED IMAGING IS BETTER AND ALSO OTHER NEAR IRIMIMAGING IS BETTER. OXYGEN IS USED AS CONTRAST AGENT AND PERFORMS BETTER LOW FIELD ALLOWS MRI GUIDED INVASIVE PROCEDURES. TWO OTHER POINTS I TIN TALK ABOUT MUCH IS PACEMAKER DEFILL BRING LAYTORS BECOMES EASIER AND SAFER AND LOW FEEL INHERENTLY COST EFFECTIVE MEANING INHERENTLY LOWER COST SYSTEM WHICH HAS IMPLICATIONS ON MRI IMAGING MORE BROADLY. SO WITH THAT I'LL THANK THE ENTIRE TEAM THAT I WORK WITH HERE AT NHLBI. THANK YOU FOR YOUR ATTENTION. [APPLAUSE] ALL THE SPEAKERS RETURN FOR A PANEL DISCUSSION. >> WE WILL KICK OFF THE Q&A SESSION AS YOU SAW IN THE PROGRAM WE HELD QUESTIONS AFTER EACH SPEAKERS PRESENTATION TO GIVE MAXIMUM AMOUNT OF TIME THE PRESENT THEIR DATA AND SHOW YOU SOME OF THE EXCITING FINDINGS OF THEIR WORK AND NOW WE WANT TO OPEN IT UP RANDOMLY, NOT IN ORDER. RAISE YOUR HAND OR WE ARE LOOKING AT VERY BRIGHT LIGHTS UP HERE SO IT'S A LITTLE TOUCH TO CATCH PEOPLE'S HANDS BUT NONETHELESS LET'S OPEN IT UP THERE'S MIKE -- MICS THAT CAN BE USED SO EVERYBODY CAN HEAR YOU. WITH THAT, WHY DON'T WE JUST SEE SCOTT, WHY DON'T YOU GO AHEAD? >> I LOOK THE LOW FIELD MRI, NOT SURE I WOULD LIKE THE DO THE TREADMILL OR BE RUNNING ON A TREADMILL WHILE ON MY BACK SO WHAT'S THE CHANCE OF GETTING TO ALLOW AN UP RIGHT POSTURE? >> GOOD QUESTION. NOW THAT WE ARE MOVING TO LOW FIELD WE HAVE THE OPPORTUNITY TO RETHINK DESIGNING MAGNETS. I AGREE, IT CAN BE VERY DIFFICULT TO BE RUNNING ON TREADMILL WITH A CHEST COIL ON WITH INVASIVE PROCEDURE, IT IS NOT PLEASANT, IT'S WORTH IT HOW TO REDESIGN T FOR LOWER FIELDS. HOW ABOUT IN THE AUDIENCE, QUESTIONS FROM THE GROUP? >> WHAT ABOUT MEASURING PULMONARY EXTRAVASCULAR WORK? I WORK WITH PATIENTS IN HOMES THAT IS EVIDENCE THAT THEY HAVE ACCUMULATION OF -- LUNGS AND -- >> THAT WOULD BE A REALLY INTERESTING THING TO DO TO MEASURE PULMONARY EXTRAVASCULAR WATER IN COMBINATION WITH A CATH PROCEDURE, IT COULD TELL A LOT ABOUT CARDIO PULMONARY PHYSIOLOGY. >> (INAUDIBLE) IS THAT? >> THERE'S STUDIES DONE ON OTHER MRI SYSTEMS AND SHOWING IT'S VERY ACCURATE FOR MEASUREMENTS PARTICULARLY IN HEART FAILURE PATIENTS THEY HAVE DONE THE STUDIES. >> THANK YOU. >> SCOTT, THE PICTURE YOU SHOW ARE PHENOMENAL AND ESPECIALLY THE MULTI-SPECTRAL WORK. WHAT'S THE HIT AND SIGNAL TO NOISE? WHEN YOU SPREAD YOUR MISSION LIKE FREQUENCY, THERE MUST BE A PRETTY SIGNIFICANT HIT IN TERMS OF YOUR ABILITY, THRESHOLD FOR SENSITIVITY BECOMES. >> THAT IS A GREAT QUESTION BECAUSE IN THE REMOTE SENSING WORLD, THEY MADE SPECTROMETERS THAT SPREAD OUT WITH TREMENDOUS RESOLUTION BECAUSE THEY WANTED TO BE ABLE TO SEE THINGS ABOUT EARTH OBSERVATION FOR EXAMPLE. BUT THERE'S WAY MORPHOTONS COMING BACK. >> AND MEASURE FOR A LONG TIME. >> FOR A LONG TIME. THE EARTH SITS STILL IN COMPARISON. SO WE HAVE CHOSEN TO SPREAD IT OUT INTO 16 OR 32 BANDS, BY GOING INTO THE PHASER APPROACH TURNS OUT THAT WE PICK UP A COUPLE OF ORDERS OF THE MAGNITUDE IN SENSITIVITY. THE OTHER THING WE GET THAT YOU MIGHT NOT EXPECT IS NORMALLY YOU HAVE TO THROW AWAY PART OF THE SIGNAL BECAUSE OF THE WAY THE REFLECTORS ARE BUILT AND OTHER -- AND THE BAND PASS FILTERS. IN THIS CASE WE ARE TAKING EVERYTHING. IN FACT MANY OF THOSE IMAGES WE ARE EXCITING WITH LASER LINES THAT ARE NOT THE ONES YOU WOULD NORMALLY CHOOSE TO, JUST TO KEEP THE EXITATION FAR AWAY FROM THE COLLECTION AND MAXIMIZE THE COLLECTION EFFICIENCY. WE END UP PICKING UP ALMOST ORDER OF MAGNITUDE MORE IN SIGNAL TO NOISE YOU GUESS THE BACK OF THE ENVELOPE CALCULATION. WE THINK IT'S GOING AFTER INTRINSIC SIGNALS LIKE THE BRONCHOSCOPE, THEY WERE LOOK AT WEAK ENDOGENOUS FLORACHROMES NOT OPTIMIZED BY CHEMISTS TO BE BRAVE, THAT'S PROVING TO MAKE IT MORE POSSIBLE TO DO. >> SO ON THE INTRINSICS, I WAS INTRIGUED TO SEE YOU ARE DESCRIBING LIFETIME TO GLYCOLYSIS FOR ADH, MAYBE TALK ABOUT THIS A LITTLE BIT BECAUSE THERE'S LONG LIFETIME MITOCHONDRIA AS WELL. >> I SHOULD MENTION, WHAT WE ARE TRYING TO DO IS SELECTIVELY LOOK AT THE NIDH AND THE FREE VERSUS BOUND NIDH WHAT WE ARE USING AS THE SURROGATE MARKER. IT'S FREE VERSUS -- GLYCOLYTIC VERSUS OX FOS AND READ IT OUT RIGHT ACROSS IN THAT SPECTRAL MAY HAVE SEEN NEE MUTT INTO A RAINBOW PLOT. THERE'S OTHER MARKERS WE CAN SEE OF METABOLISM WITH SPECTRAL AND WITH LIFETIME. SO WHAT WE ARE DOING IS SORT OF BELT AND SUSPENDERS SORT OF DETECTION. IT'S GOOD ENOUGH IN A PURE SYSTEM TO SEE IT JUST ONE MODALITY WITH BOTH OF THEM, FAR BETTER WHEN WE HAVE AUTOFLUORESCENCE AND THE IMPERFECT OPTICS TO USE THE TWO TOGETHER. THE OTHER THING I SHOULD SAY IS ONE OUR BIG CHALLENGES EXCITING IN THE UV BUT USING MULTI-PHOTON ACTIVATION TYPICALLY WHICH LETS US PIET THE TISSUE IN THE INFRARED AN LETS US CHECK THEM WITH THAT PULSED INFRARED LASER THE SECOND HARMONIC FROM THE STRUCTURAL FROM TEENS IN SIDE. WHAT WOULD BE BACKGROUND AGAIN IS SIGNAL WE CAN USE. >> OKAY. YES. (OFF MIC) >> RIGHT. I'LL REPEAT THE QUESTION. THE QUESTION IS ON OUR MULTIPLEX DETECTION HAVE WE TRIED TO GO AFTER NON-CODING RNAs. SOME OF THE OTHER DYNAMIC SPECIES THAT HAVE A SHORT LIFETIME AND LOW CONCENTRATION AMOUNT. PART OF THE REASON WE INCREASED THE GAME IS TO GET SENSITIVITY FOR THAT RELIABLY. FOR EACH PROBE WE GET 200 TIMES 200 DYES. SO THAT DOT BECOMES PRETTY INTENSE. WE CAN SEE NON-CODING RNAs OR SEE INTRONS AND EXONS AND USING SPECIFIC PROBES AS RNAs ARE TRANSCRIBED. WE ARE HOPING WE ARE GOING TO BE ABLE TO USE THESE BOTH TO LOOK AT -- AS YOU ARE MENTIONING SOME OF THE DISEASE MARKERS THAT COULD BE IMPORTANT BUT ALSO AS A FREEWAY OF SEEING SOME OF THE TRANSCRIPTIONAL CONTROL BECAUSE ENHANCERS HAVE THEIR OWN RNAs. IF WE ARE SENSITIVE ENOUGH WE CAN RECORD THOSE RNAs AND USE THOSE AS WAY TO SEE INTO THE 3-D ORGANIZATION OF THE GENOME. >> COOL. TONY. >> QUESTION FOR DR. CRAPO. A SLADE OF YOUR QUADRANTS, WE ARE SEEN END RESULT IN DISEASE PHYSIOLOGY AND CT CANCEL AND THEN YOU SHOW PROGRESSION. DO WE KNOW WHAT IS AT THE ORIGIN OF IT, DO WE KNOW IF THOSE POPULATION ACTUALLY ARE DISTINCT TO BEGIN WITH, GENETICS, IS THERE SOMETHING ELSE AND WOULD THAT BE AMENABLE TO THERAPEUTIC INTERVENTION? >> THE DATA TO ANSWER YOUR QUESTION IS BEING AT THE PRESENT TIME. BUT THERE HAVE BEEN ABOUT 80 GENES IDENTIFIED TO CORRELATE WITH RISK OF DEVELOPING COPD AND BIOMARKERS CORRELATEED BUT IN TERMS OF ANSWERING YOUR QUESTION, WHICH PEOPLE THAT DON'T HAVE OBSTRUCTION, ARE AT RISK OF PROGRESSION AND WHAT PATHWAYS ARE INVOLVED BUT THIS IS A CHALLENGE NOW FOR GATHERING MORE DATA ON THE WHOLE COHORT WHICH IS HAPPENING AS WE SPEAK AN BIG DATA ANALYSIS TO COME UP WITH THE ANSWERS. I'M TELLING YOU THERE'S -- YOU'RE RIGHT. WE NEED TO HAVE IDENTIFY BROAD SET OF PEOPLE AT RISK FOR COPD OR WITH IT, WE NEED TO DEVELOP SPECIFIC THERAPIES TO MODIFY THAT, IT'S NOT SUFFICIENT TO KNOW THEY HAVE -- THEY ARE PERSONS GOING TO DEVELOP SEVERE IMPAIRMENT WITHIN FIVE TEN YEARS. THE BIG CHALLENGE THE NEXT DECADE IS DEVELOP THOSE THERAPIES. FROM >> QUESTION FOR SANJAY. TRYING TO UNDERSTAND YOUR TECHNOLOGY AND THEY PULL IT OUT FROM INFECTIOUS DISEASE REALM TO CARDIOLOGIST. I WAS CURIOUS ABOUT WHERE SIGNAL TO NOISE FIDELITY IS OR SENSITIVITY IS MAJOR PNEUMONIA OR INFECTION TO SOMETHING A BIT MORE MOVING TOWARD SOMETHING FOR EXAMPLE LIKE PSEUDOMONAS AND CF PATIENTS OR A MICROBIOME. WHERE CAN THIS TECHNOLOGY GO TOWARD MORE CO-EXISTENCE SITUATIONS WITH INFECTIOUS DISEASE IN CHRONIC DISEASE. >> GREAT QUESTION. I WILL ANSWER THIS BECAUSE MULTIPLE DIFFERENT PARTS TO IT. THE FIRST QUESTION IS WHAT WOULD BE THE SENSITIVITY AND INHERENT SENSITIVITY SO ACUTE PNEUMONIA BACTERIAL BURDEN IS HIGH. ESTIMATES HAVE BEEN 10.9 BACTERIA PER ML, THIS TECHNOLOGY IS USEFUL FOR ALL ACUTE INFECTIONS. AND THE WORK THAT WE HAVE DONE IN ANIMALS WE HAVE NOT ACTUALLY DETERMINED THIS SENSITIVITY OF THE LOWER LIMIT OF DETECTION FOR BACTERIA, BUT SOMEWHAT 10 PAR 5, 10 PAR 6 WHICH IS GENERALLY CUT OFF FOR CONSIDERING A REAL INFECTION FROM COLONIZATION SO IF YOU DO LAVAGE AND SAY OKAY, IF THIS PATIENT HAVE PNEUMONIA OR NOT, IF YOU DO A URINE CULTURE THOSE ARE THE CUT OFFS. IT BECOME MORE COMPLICATED WHEN YOU LOOK FOR SMALLER NUMBER OF BACTERIA. THE ANSWER IS NOT STRAIGHT FORWARD BECAUSE IT DEPENDS ON THE BACTERIAL METABOLISM, A LOT OF THESE TRACERS ARE TAKEN UP SO FOR EXAMPLE, SORBITOL NEEDS TO BE PHOSPHORYLATED SO YOU NEED ATP. SO SMALL NUMBER OF SLOWLY DIVIDING BACK FEAR WHERE THE TECHNOLOGY WON'T WORK. THE OTHER HAND COOL THING IS WE ARE EXPLORING PROKARYOTIC TECHNOLOGY SO WE HAVE ATRAZINE THE TEST TUBE, NOT AFFECTED BY THE STAGE OF BACTERIA, SLOWLY DIVIDING BACTERIA TAKE UP THAT TRACER BECAUSE IT'S SO ESSENTIAL. ONE FINAL THING IN TERMS OF WHERE I THINK THIS TECHNOLOGY WILL FIT FOR EXAMPLE PSEUDOMONAS FOR CYSTIC FIBROSIS, PRETTY HIGH SO YOU WOULD BE ABLE TO DEDUCK IT, THE PROBLEM OBVIOUSLY IS TWO FOLD, ONE IS IT'S IN BIOFORMS AND THE SECOND IN THE AIRWAY. YOU GIVE SOMETHING INTRAVENOUS YOU GET THERE. THIS TECHNOLOGY IS UNDER DEVELOPMENT SO WE THINK IT'S GOING TO HAVE IMPLICATIONS IN ACUTE INFECTION AND HOPEFULLY IN UNDERSTANDING BIOLOGY. HETEROGENEITY THAT'S BEEN THERE, HOW LONG DO WE TREAT A PATIENT, MONITORING TREATMENT WHEN DO WE START ANTIBIOTICS AND THOSE KINDS OF THINGS. >> SANJAY, I WANT TO ASK A QUICK QUESTION. GO AHEAD. (OFF MIC) >> YOU SHOW THOSE SLIDES SHOWING THAT SUBJECTS WITHOUT A FLOW OBSTRUCTION INCREASE MORTALITY. IF YOU WANT MORE THAN 80%, IF ENVC, .7 OR BOTH. SO WHAT IS THE ATOMIC PATHOLOGIC SUBSTRATE OF THOSE PATIENTS? ARE WE GOING BACK TO RECALL THAT, IN ENGLAND, DIAGNOSING -- AND THERE'S NO -- EMPHYSEMA. THAT IS CHRONIC BRONCHITIS, (INAUDIBLE) INDEX. >> THAT'S A GOOD QUESTION, COMPLEX ANSWER SIMPLIFY IT, ONE IS DEFINITION OF OBSTRUCTION. OUR DEFINITION OF PREDICTED FEV1 OF LESS THAN 80%, OR RATIO LESS THAN 70% IS A POPULATION STATISTIC. WE NOW LOOKED AT THE THESE PEOPLE SO CALLED NORMAL WITHOUT OBSTRUCTION, SOME OF THOSE PEOPLE START AS MUCH AS 140% PREDICTED AND DROPPED DOWN TO 80 OR 90%, STILL CALLED NORMAL BUT LOST CLOSE TO 50% OF LUNG EXCULPATORY CAPACITY. SO THEY ARE OBSTRUCTED BUT WRONG TO APPLY A POPULATION NORMAL TO INDIVIDUALS. WHO HAVE A GREAT VARIABILITY IN STARTING POINT, WE FIND A LARGE FRACTION OF PEOPLE WE ARE TALKING ABOUT HAVE GREATER -- 2 TO 3 TIME IT IS ANNUAL RATE OF FALL APPROXIMATE FEV1, AND STILL REMAIN IN THAT QUADRANT OR MOVE TO THE PRISON QUADRANT WITH LOW FEV1s, NOT DIAGNOSED WITH COPD TODAY. I THINK WE'RE WRONG TO SAY THESE PEOPLE WERE NOT OBSTRUCTED. THEY ARE INDIVIDUAL ACCORDING TO THEIR OWN PHYSIOLOGY THEY ARE OBSTRUCTED. WE NEED TO FIND OUT THE MECHANISM DRIVING IT AND DEVELOP TREATMENTS TO PREVENT THAT. WHILE SO CALLED HEALTHY. >> THEY DIDN'T HAVE EF FA SEE MA, RIGHT? -- EMPHYSEMA, RIGHT? >> ALL CT SCANS SOME DO HAVE IT, DEVELOPED AS THE EMPHYSEMA PATHWAY TALKED AN'T DROPPING DOWN THROUGH A CLASSIC OBSTRUCTED PATTERN. THE ONES WHO MOVE TO THE UPPER LEFT PART OF THE DIAGRAM AND ARE ACTUALLY -- WE THROUGH OUT ANYBODY WITH INTERSTITIAL LUNG DISEASE SO NOT RESTRICTED PATIENTS. THEY ARE NOT DEVELOPING PULMONARY FIBROSIS. WHAT THEY ARE DOING IS GOING IN SEVERE COPD GO DIRECTLY TO UPPER LEFT QUADRANT AND OVER TEN YEARS OR FIVE AND TEN YEARS GO DIRECTLY TO SEVERE COPD BOTTOM LEFT QUADRANT. >> WE DON'T KNOW PATHOLOGY. >> WELL, WE ARE WORKING ON PATHOLOGY, WE DON'T KNOW, RIGHT NOW THE PATHOLOGY IS BY CT. THAT'S NOT CELLULAR LEVEL YET. YOU ARE DEFINING WHERE THIS HAS TO GO TO ANSWER THE QUESTION. OTHER QUESTIONS? >> FOR DR. JAIN, GETTING BACK TO CYSTIC FIBROSIS, ONE OF THE PROBLEMS WITH CHRONIC INFECTION LIKE MTM AND FOLLOWING THESE PATIENTS OVER TIME IS YOU SEE WAXING AND WANING ON CT SCAN OF A VARIETY OF LESIONS, DO YOU THINK IT'S POSSIBLE TO USE TRACERS SUGARS LIKE -- TRAIL LOADS THAT MIGHT BE SPECIFIC FOR MICROBACTERIA DIFFERENTIATION OF WHAT'S HAPPENING OVER TIME WITH TRACER IMAGING? >> SHORT ANSWER IS YES. WHAT I DIDN'T SHOW BEFORE WAS YOU CAN ALSO TRY TO DUAL TRAITSER IMAGING AND THAT'S OUTRAISESSER IMAGING, SOMETHING ON A SPEC TECHNOLOGY, ALSO YOU CAN DO BY COMBINING SHORT AND LONG HALF LIFE TRACERS WITH THAT. THE OTHER VERY IMPORTANT QUESTION THAT I'M NOT A PULMONOLOGIST BUT I GET SO MANY PATIENTS WITH CYSTIC FIBROSIS, I'M A PEDIATRICIAN AND WE'RE AT JOHNS HOPKINS SHIITIC FIBROSIS CENTER. ARE THESE SITTING THERE, ARE THEY CAUSING INFECTION? FUNDAMENTAL BIOLOGY LIKE THIS, IT'S ANSWERED SO INFLAMMATION IS A MAY JR. CAUSE OF DAMAGE, WE TRY TO KILL THE BUGS, ESSENTIALLY CREATE BUGS THAT ARE COMPLETELY RESISTANTS TO EVERYTHING. EVEN THOUGH WE HAVE A PATIENT WHO DIES OFSIS STICK FIBROSIS T. SO THE SHORT ANSWER IS YES, I THINK IT WOULD BE ABLE TO QUANTIFY LOAD AND THE OTHER THING IS MULTI-MODALITY IMAGING IS WHAT'S CRITICAL INFLAMMATION OF THE BUG. >> >> DR. JAIN. DO YOU THINK NEUROTRACERS COULD BE HIJACKED FOR THERAPY? ARE YOU THINKING ABOUT BUILDING ON THOSE MOLECULES? >> SO MANY YEARS A GRANT ON THIS TO THE GATES FOUNDATION, I SHOW EYE I DON'T KNOW SO THE WORK, THERE'S A LOT OF WORK IN (INAUDIBLE) MOLECULES THAT ARE MADE BY ALL LIVING ORGANISMS, IRON IS EXTREMELY IMPORTANT. THEY HAVE ABOUT A MILLION TIMES HIGHER, GOAL WAS TO ACTUALLY LABEL THEM AND USE ALPHA EMISSION AND TO KILL THE VERY DRUG BUGS DIDN'T FLY VERY WELL BUT IT'S A GREAT IDEA. Q. IN YOUR HUMAN STUDIES THE LIVER TOOK UP THE PROBE PROFICIENTLY, WHAT WAS THAT? FROM >> ORBIT OBVIOUSLY DIFFERENT PROJECTION TAKEN BY DIFFERENT ORAL. SO LIVER AT ONE HOUR OF IMAGING WHICH IS NOT IDEAL TIME POINT, THERE'S SECRETION. THERE'S ABOUT 95% ELIMINATION THROUGH KIDNEYS AND 5% IS METABOLIZED BY LIVER AND EXCRETED TO THE GALLBLADDER. >> I'M PUZZLED BECAUSE SORBITOL IS AN ORGANIC OS MOW LIGHT IN THE KIDNEY. USED TO BALANCE SODIUM IN THE PAPILLA. I BELIEVE THERE'S ENZYME PATHWAY TO PROCESS OTHERWISE IT WOULDN'T BE MILLIMOLAR CONCENTRATIONS IN THE KIDNEY. THERE MAYBE SOME INTERESTING PROBLEMS THERE. >> OBVIOUSLY SORBITOL IS EXCRETED THROUGH THE KIDNEYS BECAUSE IT IS A SUGAR NOT METABOLIZED. WHEN YOU ACTUALLY LABEL THE SORBITOL ON THE SECOND POSITION WITH FLUORIDE, IT'S NOT RECOGNIZED BY THE MAMMALIAN SYSTEMS AS WELL. SO IT'S WITH SHARE TWO FLUORODEOXYSO RBITOL. >> ANY FINAL QUICK ONES? WE ARE ABOUT THE END OF THE TIME FOR Q&A SESSION. THANK YOU ALL VERY MUCH FOR ASKING THE QUESTIONS AND PARTICIPATING IN THIS DISCUSSION. SPECIAL THANKS TO ALL THE SPEAKERS FOR THIS FIRST SESSION WHO HAVE DONE A TERRIFIC JOB AND HAVE SHOWN VERY EXCITING AND REALLY VISIONARY LOOKING SCIENCE. WE WILL MOVE TO THE NEXT GROUP OF SPEAKERS AND DON'T RUN OFF AT THE END BECAUSE WE DO HAVE ANOTHER Q&A SESSION, WE HOPE YOU WILL BE ABLE TO STAY AND ASK QUESTIONS IN THAT SESSION AS WELL. THANK YOU ALL. [APPLAUSE] OKAY. SO WE'RE GOING TO MOVE ALONG HERE TO THE NEXT GROUP OF SPEAKERS, REAL PRIVILEGE TO HAVE AN OPPORTUNITY TO INTRODUCE THEM, PROCEED LIKE WE DID EARLIER, EACH OF THE SPEAKERS WILL INTRODUCE THE NEXT BUT OVERALL WE'LL HEAR FROM DR. CARMEN PRIOLO, BRIGHAM AND WOMEN'S HOSPITAL HARVARD MEDICAL SCHOOL WHO WILL TALK ABOUT METABOLIC IMAGING AND PULMONARY DISEASE. WE WILL HEAR FROM MARCUS CHEN, IN THE INTRAMURAL PROGRAM HERE AT NHLBI. HE WILL TALK ABOUT ULTRA LOW DOSE CT IMAGING AND FINALLY HEAR FROM GRAHAM BARR, PROFESSOR OF MEDICINE AT COLUMBIA UNIVERSITY AND HE WILL TELL US ABOUT MACHINE LEARNING AND LUNG IMAGING. LET ME JUST GIVE A QUICK SHOUT OUT TO BOTH AID DEAN CAMPBELL AND MARCUS CHEN, ADRIENNE IS A AWARDEE THIS YEAR HIGH LEVEL FOR SCIENTIFIC ACHIEVEMENT IN THE NIH AND NHLBI. MARCUS IS ALSO AN AWARDEE BUT HE'S ALSO BEEN RECOGNIZED BY THE AMERICAN THORACIC SOCIETY AND HE RECEIVED THE RESEARCH INNOVATION AND TRANSLATIONAL ACHIEVEMENT AWARD THIS YEAR AT THEIR MAY MEETING. WE HAVE OUR RISING STARS HERE IN CARDIO PULMONARY AREA. PLEASURE TO INVOLVE THEM IN THIS SESSION. WITHOUT FURTHER DELAY, LET ME TURN IT OVER TO CARMEN AND MARCUS. SHE GIVE HER TALK ON CARDIAC AND PULMONARY DISEASE. >> THANK YOU. I FEEL HONORED TO BE PART OF THE SYMPOSIUM, THE CELEBRATION. SO THANK YOU VERY MUCH FOR INVITING ME. FIRST IS METABOLIC PULMONARY DISEASE. SPECIFICALLY METABOLIC IMAGING TECHNIQUE THAT'S OF GREAT INTEREST TO MY RESEARCH GROUP AND TEAM OF COLLABORATOR FOR THE LAST SEVERAL YEARS. THIS IS POSITRON EMISSION TOMOGRAPHY. PET. YOU ARE PROBABLY FAMILIAR WITH PET. THE BEAUTY IS IT IS VISUAL AND TRULY QUANTITATIVE AT THE SAME TIME. PROVIDING A SPATIAL TEMPORAL MAPS OF RAID GROW TRACER UPTAKE WITH THE GOAL OF MEASURING METABOLIC RATES OF NUTRIENT IN ORAL CANCER SPECIFICALLY LESIONS OR TUMORS. SO BRIEFLY THE DYNAMIC PROCESS OF RADIO LABEL UPTAKE IS ASSESSED THROUGH ASYME SERIES OF -- A TIME SERIES OF IMAGES DERIVED FOR ORGANS FOR TUMORS FOR LESION OF INTEREST, SO FOR EXAMPLE IN THE LUNG THIS IS OUR GOAL. THE MAIN DIFFERENCE BETWEEN DYNAMIC PET, IMAGE DYNAMIC OF PET IS IT ALLOWS FOR STUDIES WHICH IS IMPORTANT WHEN APPROACH RADIO TRACER FOR WHICH DISTRIBUTION AND METABOLISM FEATURES ARE NOT WELL KNOWN. SO HOW CAN WE TAKE ADVANTAGE OF THIS TECHNIQUE? AS A MEDICAL ONCOLOGIST IN THE CANCER BIOLOGY, FIRST THOUGHT IS LET'S CHOOSE THE BEST RADIO TRACER. WE HAVE BEEN TO US CANNED ON THE BENCH TO BEDSIDE MODEL, AS THE MOST VIEWED HERE AND OUR APPROACH IS FIRST APPLY OMICS TECHNIQUES METABALOMICS OR LIPIDOMICS TO BIOLOGICAL FLUID OR TISSUE FROM PATIENTS. TO IDENTIFY METABOLIC PATHWAYS THAT REALLY REVEAL SOMETHING ABOUT THE BIOLOGY OF THE DISEASE AND SECOND EVALUATE THROUGH MOLECULAR STUDIES AND ISOTOPE LABELING APPROACHES. AND NMR TO VALIDATE PHASE OF TASER OF INTEREST THEN WE MOVE TO CLINICAL TRIALS IMAGING TRIALS IN MICE, TRYING TO MIMIC WHAT WE DO IN PATIENT PERFORMING PET CT BUT ALSO USING DRUG TREATMENT, SENSITIVITY OF TRACERS. THE ULTIMATE GOAL IS OF COURSE FORM IMAGING CLINICAL TRIALS AND IDENTIFY TRACERS THAT CAN BE READILY TESTED IN PATIENTS. SO I WILL PROVIDE A COUPLE OF PROOF OF CONCEPT WHAT WE HAVE DONE, FIRST WILL INTRODUCE A PLATFORM FOR PRE-CLINICAL TESTING OF PET RADIO TRACERS WE HAVE IN COLLABORATION WITH MEDICAL IMAGING, THE MOST GENEROUS IN BOSTON IN ORDER TO STANDARDIZE THE PET ACQUISITION PROCEDURES AND ALSO SEPARATE SYSTEM TO FASTEN THE PROCESS OF DATA ANALYSIS. OUR COLLABORATORS TOGETHER WITH THIS PLATFORM AND GENERATED MET LAB SOFTWARE WE USE, OBTAINING DATA. WHICH EVENTUALLY ARE THE AVERAGE UPTAKE VALUE TIME ACTIVITY OR TAX FOR SPECIFIC GENERAL INTEREST. WE HAVE STARTED WITH DIFFERENT TYPE OF TUMORS, SOME ACUTE XENOGRAPH OF THIS MODEL I'M GOING TO SHOW YOU IN A SECOND. FOR THOSE THE ENTIRE LUNG AND OTHER ORGANS OF THE VARIOUS CONTROLS. SO OUR MAIN FOCUS IS (INDISCERNIBLE) OR LUNG. SO I BRING HERE THIS PERSPECTIVE. WHAT IS PARTICULAR ABOUT LUNG IS IT IS A LUNG DISEASE BUT AT THE SAME TIME A MULTI-ORGAN MULTI-SYSTEM DISEASE. CAN OCCUR AS SPORADIC DISORDER BUT BEING ASSOCIATED TO TUMOR SCLEROSIS COMPLEX WHICH IS AUTOSOMAL DOMINANT DISEASE, AFFECT ALMOST EXCLUSIVELY WOMEN AND THE LUNG LEVEL IS CHARACTERIZED BY CO-EXISTENCE OF CYSTIC LUNG DISTRACTIONS WHICH IS SEEN HERE IN THE CT SCAN IMAGE BELOW, AND THE PROLIFERATION OF DIFFUSE PROLIFERATION IN THE LUNG, MICRONODULES AROUND BRONCHI OF CELLS OF UNKNOWN ORIGIN, SO CALLED LUNG CELLS WHICH USUALLY POSITIVE FOR MUSCLE ACTING 45 BIOMARKERS. IN TERMS OF LESIONS THAT CAN BE IMAGES DETECTED IN LUNG PATIENTS IN THE CHEST SUCH AS RENAL BONE MUSCLE MYOMAS AND LESIONS SO WHAT IS RATIONAL FOCUSING ON THIS, THIS IS IN TERMS OF METABOLIC IMAGING. THE MICRO PATHOGENESIS OF THE LUNG. TC 1 OR 2 INACTIVITY MUTATIONS ARE OF THE ORIGIN OF PROLIFERATION OF LUNG CELLS. INACTIVATION OF THIS COMPLEX LEADS TO UNCHECKED ACTIVATION OF MAMMALIAN TARGET COMPLEX ONE, A TENNIS COMPLEX THAT IS A MASS REGULATOR OF GROWING METABOLISM, THE PHYSIOLOGICAL LEVEL. SO WHEN IT IS UNCHECKED THERE IS UNBALANCED ACTIVATION OF PROCESSES SUCH AS CHOLESTEROL SYNTHESIS AND NUCLEOTIDE SYNTHESIS AND PROTEIN SYNTHESIS AND SUPPRESSION OF ATO HAVE GIVE. IN A CLINICAL NEED IN LUNGS STILL NON-INVASIVE TECHNIQUE TO ASSESS RESPONSE TO RAPAMYCIN, THIS PATIENT TO FACILITATE DOSES AS WE MOVE TO PERSONALIZED MEDICINE AREA. THE FIRST PROOF OF CONCEPT BACKS TO THE MODEL OF THE BEDSIDE TO BENCH TO BEDSIDE, A FEW YEARS AGO THROUGH A PLASMA LIPID OMIC STUDY OF LUNG PATIENT, WE HAVE IDENTIFIED ANOTHER METABOLIC ABERRATION IN THIS CATEGORY OF PATIENTS, SPECIFICALLY THE CANDIDATE PATHWAY. MOVING TO IN VITRO IN VIVO STUDIES WE WERE ABLE TO TRACE USING -- THIS PATHWAY IN CELLS IDENTIFYING CRITICAL INCREASE INCORPORATION OF FORMING TO LIPIDS, PHOSPHOCHOLINE SPECIES IN DEFICIENT CELLS WHICH ARE THE ORIGIN OF LUNG, TO EXPRESSING CELLS. THE CANDIDATE WILL BE LABELED IN VIVO THROUGH PET IMAGING USING CALLING TRACERRER. THE APPROVED FOR PROSTATE CANCER METASTATIC PROSTATE CANCER WE ARE FOCUSED ON THE -- BECAUSE OF THE LONGER HALF LIFE WHICH CAN ACTUALLY PROVIDE HUGE ADVANTAGES IN TERMS OF PRODUCTION OF THE TRACER THROUGH THE SITE FOR CLINICAL PURPOSES. THE FLORACHOLINE OF VALIDATED METABOLIC FATE OF FLORAL CHOLINE, CONSISTENT WITH THROUGH NUCLEAR MAGNETIC RESONANCE WHERE WE HAVE SHOWN INCORPORATION OF TRACER SPECIFICALLY TO LIPIDS IS ALSO SUPPRESSED BY RAPAMYCIN. SO WE ARE LABELING THE PATHWAY AND PERFORM SERIES OF PRE-CLINICAL IN VIVO STUDIES, MICE, BARING DEFICIENT XENOGRAPH IN THE SKIN OR IN THE LUNG. IN THIS IMAGE YOU CAN SEE HOW THE DOCUMENTARY SHOW THE RAPAMYCIN TREATMENT TUMORS IN THE SAME MICE AFTER TREATMENT THAT DECREASING FLORAL CHOLINE UPDATE IS DRAMATIC ONLY THREE DOSES OF RAPAMYCIN IN THREE DAYS. THIS IS VALIDATED THROUGH THE ACTIVITY CREW SHOPE HERE ON THE BOTTOM. BOTH SUV MAIN SUV PEAK TUMORS ARE SHOWN IN DARK BLUE AND IN LIGHT BLUE WHICH CLEARLY PRESENTED DECREASE WHEREAS NO DECREASE IN SIGNAL WAS DETECTING MUSCLE OR IN THE BLOOD, WHICH IS THE RED PEAK. HERE SUMMARIZE DATA SHOWING DATA FROM THE THREE GROUPS, THE CONTROL GROUP OF MICE, MICE TREATED WITH RAPAMYCIN FOR 24 HOURS ONE DOSE OF DRUG RAPAMYCIN TREATED 72 HOURS, THERE IS DECREASE 24 HOURS BUT THE -- (INAUDIBLE) IS 72 HOURS. CONSISTENT WITH TO APOLOGY DATA DOWN HERE SHOWING THAT RAPAMYCIN PARTIALLY SUPPRESS SIGNALING TUMORS WHEREAS SIGNALING SHOWN 272 HOURS. IS INTERESTINGLY WE ALSO SAW NO CORRELATION BETWEEN TOW MORE SUV AND PROLIFERATION RATE OF THE TUMOR, MEANING WE ARE LABELING METABOLIC PATHWAY HERE SO WE ARE NOT JUST HEADING A READ OUT OF TUMOR SHRINKAGE OR PROLIFERATION. WE GENERATED LUNG MODEL THROUGH INJECTION OF THE DEFICIENT CELLS THROUGH THE -- OF THE MOUSE AND AS YOU CAN SEE WE ARE ABLE TO GENERATE MICRONODULES AROUND THE BRONCHI, SIMILAR TO WHAT HAPPENS IN LUNG AND THE DISEASE LUNG HERE SHOW HOT SPOT WHILE WE GENERATE WHOLE LUNG VOLUME OF INTEREST IN THE DYNAMIC FASHION STILL SEE SIGNIFICANT INCREASE COMPARED TO AS THE LUNG SHOWS BELOW SO WE ARE EXCITED ABOUT THIS BECAUSE THE GOAL IS TO IMAGE LUNG LESIONS. AND THE SECOND PROOF OF CONCEPT I WANT TO SHOW HERE JUST TO SHOW NOT EVERY TRACER ARE THE SAME WAY, IS METABOLIC BIOMARKER MITOCHONDRIAL ACTIVITY. FLORAACETATE IS BEHAVES SLIGHTLY DIFFERENT THAN ACETATE IN TERMS OF METABOLIC FATE. IT IS METABOLIZING TO FLORAL CITRATE WHICH IS IRREVERSIBLE INHIBITOR, KEY ENZYME OF THE KREB CYCLE. SO WHAT HAPPENS IS THE NEVER GET OXIDIZED TO -- WHICH IS A FINAL PRODUCT OF KREB CYCLE, REALLY IMPORTANT FOR LUNG IMAGING BECAUSE THE RADIO ACTIVITY IN THE AIR TRAPPED IN THE LUNG CAN CAUSE BACKGROUND SO FLORAL ACETATE DECREASE THE AMOUNT OF REDACT TISSUE TO THE DISEASE RELEASED. FIRST AGAIN VALIDATED THE BIOMARKER MITOCHONDRIAL ACTIVITY, WE ARE USING ANALYZER TO SHOW FLORAACETATE TREATMENT OF LUNG CELLS IN THE PRESENCE OR ABSENCE OF RAPAMYCIN IS ABLE TO SUPPRESS OXYGEN CONSUMPTION RATE. THEREFORE, AS IMPACT ON MITOCHONDRIA, ALSO ACCUMULATION OF CITRATE, WHICH IS A SUBSTRATE SHOWING IRREVERSIBLE INHIBITION OF AN ENZYME. WE HAVE FURTHER COMPARE ACETATE IN FLORAACETATE FOR THE PURPOSE OF CHOOSING NEW RADIO TRACER. WE HAVE FOUND THAT CELLULAR INCORPORATION OF ACETATE SIGNIFICANTLY SUPPRESS RAPAMYCIN, THEREFORE MY WORK AS BIOMARKER RAPAMYCIN ACTIVITY FLORAACETATE INCORPORATION IS NOW IMPACTED BY RAPAMYCIN TREATMENT. WE LIVE IN COOPERATION FLORAACETATE IS NOT INCORPORATING THE LIPIDS AT ALL WHEREAS ACETATE IS INCORPORATED AT HIGH LEVELS. LOOKING IN VIVO FLORAACETATE PET, WE WERE PLEASANTLY SURPRISED TO FIND DESPITE NO CHANGE RANMYCIN IN VITRO, YOU CAN SEE SUV TUMORS FOR FLORAACETATE WERE REMARKABLY HIGH SO WE THINK IN TERMS OF IMAGING IN TERMS OF DISEASE PROGRESSION OR NEW TUMOR BURDEN, THESE TRACERS COULD BE IDEAL. ADS BIOMARKER MITOCHONDRIAL ACTIVITY THEREFORE CAN BE SUPPLY TO OTHER DISEASE. HERE THE ACTIVITY SHOWED DECREASE IS MINIMAL, ABOUT 10%, PROBABLY NOT CLINICALLY. RELEVANT, THE MUSCLE DID NOT SHOW CHANGE, BLOODIED NOT SHOW CHANGE. HERE DATA SUM RIDES DATA FOR FOR ALL MICE. I WOULD LIKE TO SUMMARIZE A MESSAGE RELATED TO LUNG, WE THINK METABOLISM OF DEFICIENT CELLS PROVIDE OPPORTUNITIES FOR METABOLIC IMAGING IN LUNG. AND IDENTIFY FLORAL CHOLINE MARKERS FOR ACETATE ACTIVITY, WHEREAS UPTAKE OF FLORAL ACETATE MITOCHONDRIAL ACTIVITIES ARE HIGH IN LUNG FOR CLINICAL MODELS AND MEASURING DISEASE PROGRESSION T WHOLE BODY TUMOR BURDEN. ON A MORE GENERAL LEVEL QUANTITATIVE IMAGING MAY PROVIDE NON-INVASIVE TECHNOLOGIES TO ASSESS LUNG, DISEASE BURDEN AND ME AT THAT TIME LIMB AND RESPONSE THERAPEUTIC TREATMENTS IN NON-PROLIFERATIVE DISORDERS. FROM THE BENCH TO BEDSIDE TRANSLATIONAL PERSPECTIVE PROUD TO START THE FIRST FEASIBILITY STUDIES FOR 11C ACETATE, AS INDICATOR OF EARLY RESPONSE TO LUNG PATIENTS AND CLINICAL STUDIES IRB APPROVAL FUNDED THROUGH THE GRANTS LATE LAST YEAR. FOR PERSPECTIVE WITH METABOLIC IMAGING FOR LUNG DISEASE IN PRECISION MEDICINE, WE CAN THINK OF CELLULAR POTENTIAL METABOLIC IMAGING BIOMARKERS IN THE FIELD CAN BE MOVE TO THE CLINIC. BUT I THINK WE CAN LEARN A LOT FROM LUNG CANCER FIELD AND THERE ARE AREAS THAT CAN REALLY PROBABLY FOR THE NEXT TEN YEARS AND ONE AREA INTEGRATING GENOMIC METABALOMICS LANDSCAPE, LARGE BODY OF IT HAS BEEN INJURED IN THE LAST FEW YEARS. AND I THINK THE INTEGRATING THIS DATA THAT WOULD BE KEY TO UNDERSTAND PATHOGENETIC MECHANISM OF DISEASE THAT CAN BE EXPLOITED FOR IMAGING BIOMARKERS AND ALSO IDENTIFYING METABOLIC HALLMARKS OF THE LUNG MICROENVIRONMENT WHICH WOULD BE THE TUMOR MICROENVIRONMENT, THESE WOULD BE ANOTHER GREAT, ESPECIALLY NOW WITH ALL IMMUNE THERAPIES. I WOULD LIKE TO CLOSE HERE BUT NOT WITHOUT ACKNOWLEDGING THE WONDERFUL PEOPLE I WORK WITH AND THE LARGE TEAM FOR BEING ABLE TO HELP US HELP US GET TO THIS POINT FIRST IMAGING TRIALS IN LUNG PATIENTS. SO MY COLLABORATORS AT MASS GENERAL HOSPITAL (INAUDIBLE) AND COLLABORATORS AT BRIGHAM WOMEN'S HOSPITAL TO MIT AND THE BROAD INSTITUTE. THANK YOU VERY MUCH. THANK YOU VERY MUCH AND TURN THE MICROPHONE TO THE NEXT SPEAKER. DR. MARCUS CHEN. [APPLAUSE] >> GREAT. IT'S AN HONOR TO BE HERE AND BEING AMONG THESE DISTINGUISHED SPEAKERS. I WILL TALK ULTRA LOW DOSE CT IMAGING. SO I'LL START WITH A CASE. THIS IS AN 18-YEAR-OLD WHO THIS WAS AROUND THANKSGIVING COME HOME FOR THANKSGIVING BREAK, HAD A QUESTION WITH DIAGNOSIS OF LAMB AND DOES REFER TO THE NIH BY (INAUDIBLE) TO SEE WHETHER OR NOT SHE HAD LAMB. UNFORTUNATELY SHE HAD BILATERAL PNEUMOTHORACES, AND THAT WAS REASON FOR SHORTNESS OF BREATH, SHE HAD CHEST TUBES PLACED IN AND BASED ON CHEST X-RAYS THEY MADE A CHEST TUBE FROM THE LEFT SIDE, AND ON THE CHEST FILM HERE, THERE'S A LITTLE BIT OF A NEW MEDIASTINUM ON THE LEFT SIDE, THEY REQUESTED LOW DOSE CT, TO SEE HOW MUCH RESIDUAL PNEUMOTHORAX WAS THERE. SO HERE IT IS. SO THIS IS A CROW MOW IMAGE OF THE CT. AND WE GET SO MUCH MORE INFORMATION FROM CROSS SECTIONAL IMAGING THAN FROM A 2D PROJECTION FROM CHEST X-RAY, WOULDN'T IT BE GREAT IF WE ARE ABLE TO DO A FULL CHEST CT AT THE RADIATION DOSE OF A CHEST X-RAY? THAT'S WHAT WE'LL TALK ABOUT TODAY. CT IMAGING IN THE U.S. HAD BEEN INCREASING AT ASTRONOMICAL RATE. THIS IS DATA THAT IS ONLY UP TO 2011, SINCE 1993 TO 2011 THE NON-CT IMAGING IN THE U.S. HAVE BEEN GOING UP MORE THAN 10%. THIS IS DESPITE POPULATION OF THE U.S. ONLY INCREASING LESS THAN 1%. PUT THIS IN PERSPECTIVE IN 2011 THERE'S 85 MILLION CT SCANS DONE, U.S. POPULATION IS 300 BILLION SO THIS IS ONE IN FOUR PEOPLE GET CT. OBVIOUSLY OLDER PATIENTS ARE GET MORE FREQUENT CTs VERSUS YOUNGER, THIS PUTS IT IN IN PERSPECTIVE. IN 2011 NIH FUNDED FILE WAS THE LOOKING AT SCREENING FOR LUNG CANCER, THIS IS A HUGE, OVER 54,000 PATIENTS THEY GET RANDOMIZED TO CHEST X-RAY OR CT FOR SCREENING FOR LUNG CANCER. THE TAKE HOME MESSAGE IS THAT BY SCREENING BY CT, DECREASE MORTALITY BY 20%. YOU DECREASE OVERALL MORTALITY BY PUT THAT IN PERSPECTIVE ROUTINE SCREENINGS SUCH AS MAMMOGRAPHY, SCREEN OVER A THOUSAND PEOPLE TO SAVE A LIFE FROM CANCER OR HAVING A COLONOSCOPY WHEN 50 YOU NEED TO HAVE OVER A HUNDRED PATIENTS IN ORDER TO DETECT ONE. SO BASICALLY WHAT THIS LAND MARK TRIAL IT WAS NOW RECOMMENDED TO DO SCREENING CT FOR PATIENTS AT HIGH RISK LUNG CANCER. SO LOOK AT SCREEN TEST REQUIREMENTS, YOU NEED TO BE ABLE TO DETECT THE DISEASE, HAS TO BE REASONABLE COST. YOU HAVE TO DEMONSTRATE IMPROVED HEALTH OUTCOMES DUE TO THE SCREENING, NEEDS TO BE WIDELY AVAILABLE, ALSO SAFE TO ADMINISTER. IF YOU LOOK AT LUNG SCREENING LIMITATION THE ONE MAJOR LIMITATION NUMBER OF FALSE POSITIVES. 40% PATIENTS HAD AT LEAST ONE FALSE POSITIVE RESULT. OVER THREE YEARS. THE REASON IS THAT THE CRITERIA USED AT TIME OF FLYER NEAR CRITERIA SO INTERMEDIATE NODULE, BASED ON THE INTERMEDIATE NODULE YOU CAN HAVE UP TO THREE OR FOUR CT SCANS WITHIN THAT FOLLOWING YEAR TO SEE IS THAT LESION STABLE, GOING TO GROW LIKE A CANCER OR IS IT A GRANULOMA IN THE BENIGN LESION? LAST YEAR THE UPDATED THESE GUIDELINES IN THE RECOMMENDATION HAS BEEN TO DECREASE THE AMOUNT OF FOLLOW-UP SCREENING. HOWEVER, THERE HAS BEEN STUDIES DONE TO SEE WHAT IS THE RISK FROM THESE ADUGGAL CT SCANS FROM LUNG CANCER SCREENING? IF YOU SEE LUNG SCREENING TRIAL, 50 TO 75-YEAR-OLD HIGH RISK PATIENTS, WE GET ANNUAL CT SCAN, IT'S 50% COMPLIANCE RATE IF YOU MODEL THE RADIATION RISK-BASED ON SURVIVORS OF ATOMIC BOMBS AN EXTRAP LATE DOWN TO ZERO, BASED ON THESE ASSUMPTIONS YOU WOULD -- THERE WOULD BE ABOUT 36,000 ADDITIONAL LUNG CANCER INDUCED BY CT EXAMINATION, WHICH LEADS TO ABOUT 2% OVERALL INCIDENCE. EVERY YEAR IN MEDICAL LITERATURE THERE'S AN ARTICLE ABOUT THIS, TWO YEARS AGO REPORTS HAD A REPORT ABOUT DANGERS OF CT SCANS, NEW YORK TIMES HAS ARTICLE THIS IS BOTH MEDICAL LITERATURE AND ALSO LAY PRESS. PATIENTS ARE ASKING WHAT ARE THE RISKS. SO OUR GOAL IS TO REALLY MAINTAIN THE DIAGNOSTIC ACCURACY OF CT EXAM BUT REDUCE AMOUNT OF RADIATION LEVEL BY PROFOUND AMOUNT OF LEVEL OF CHEST X-RAY. SO THERE ARE MULTITUDE OF DIFFERENT CHARACTERISTICS THAT END UP FOR FORMING CT IMAGE. AND THE REAL REASON I GOT INVOLVED IS I HAVE SUCCESSFUL REDUCING RADIATION FOR CURRENT CT AND BEING IN THE HEART LUNG AND BLOOD INSTITUTE, COLLEAGUES IN THE PULMONARY DIVISION SAY HEY THIS IS GREAT, FOR HEART WHAT ABOUT MY PATIENT. THEY SEE A PATIENT WHO ARE YOUNG DIAGNOSE WOMEN AND GET FREE CHEST CT EXAMS. THE BIGGEST ADVANTAGE WE HAVE FOR INDUCE REDUCING RADIATION IS IMAGERY CONSTRUCTION. UNTIL VERY RECENTLY, CT IMAGE CONSTRUCTION WAS BASED ON TECHNOLOGY WHEN INVENTED IN LATE '60s, EARLY '70s. MATHEMATICAL SHORT CUTS WERE TAKEN BECAUSE COMPUTING POWER AT THAT TIME WAS LIMITED. SO WE NOW USE CONSTRUCTION WHERE WE PROGRAM THE SCANNER AND WE HAVE BASICALLY THERE'S A MODEL OF WHAT THE IMAGE LOOK LIKE. AND SCANNER TO INITIAL CONSTRUCTION AND IF NOT -- WE'LL DO IT AGAIN AND AGAIN AND AGAIN. THESE MULTIPLE ITERATIONS OVER TIME. THE BEST ANALOGY OF THIS IS WHEN I WAS IN HE WILL MEN TEAR SCHOOL BE IT SCHOOL CAFETERIA, LUNCHTIME, TALKING ABOUT YOUR FRIENDS WHEN YOU'RE DONE EATING AND YOU HAVE PORK AND ON THE BACK OF THE PORK IS A NUMBER AND WE GUESS THE NUMBER OUR FRIEND HAD ON IT. NUMBER WAS 52, HIGHER OR LOWER AND YOU EVENTUALLY GET TO THAT NUMBER. THIS IS WHAT WE DO WITH IMAGERY CONSTRUCTION. AND THIS HAS BEEN LEVERAGED BY INCREASES IN COMPUTING POWER. SO GORDON MOORE WAS FOUNDER AT INTEL AND HE HYPOTHESIZED COMPUTING POWER WOULD DOUBLE EVERY TWO YEARS. TO PUT IN PERSPECTIVE 40 YEARS AGO TO TAKE A FLIGHT FROM HERE TO LONDON COSTS A THOUSAND DOLLARS, AND SEVEN HOURS SO IF YOU DECREASE THAT BY HALF EVERY TWO YEARS HOW LONG WILL THAT FLIGHT TAKE? IT WILL TAKE LESS THAN A SECOND. ACROSS LESS THAN A PENNY. IT STILL COST IT IS SAME AMOUNT, STILL TAKES THE SAME AMOUNT OF TIME. THIS SHOWS YOU HOW STRONG COMPUTING POWER IS NOW NOWADAYS. COMPUTING POWER IS RATED IN OPERATIONS PER SECOND. SO IF I SAY WHAT'S SEVEN TIMES SEVEN, THE ANSWER IS 49, HOW LONG DID IT TAKE YOU? PROBABLY A FRACTION OF A SECTION. TO GIVE AN IDEA, THESE WE USE GRAPHIC BOARDS USED TO RENDER PIXAR MOVIES LIKE TOY STORY, TRILLIONS OF OPERATIONS PER SECOND. WE HAVE EIGHT THAT WORK IN PARALLEL, PUT IN PERSPECTIVE, WORKING IN PARALLEL IS 40 TRILLION PHLOX, YOU HEARD IBM WATSON SUPER COMPUTER THIS IS ABOUT HALF AS STRONG AS A SUPER COMPUTER. THIS IS ON CT SCANNER. HOW DO WE GO ABOUT VALIDATING THIS? FOR LUNG IMAGING WE USE A STANDARD PHANTOM OR PLASTIC REPRESENTATION OF LUNGS. YOU CAN PLACE INSIDE OF IT SIMULATED LUNG NODULES. WE WENT AND STARTED IMAGING SO THIS IS STANDARD CHEST CT IS, USING STANDARD CLINICAL PARAMETERS THERE'S TWO LUNG NODULES WITH APE SEIZE OF THE LUNGS. THERE AND THERE. IF WE REDUCE RADIATION DOWN TO THAT OF A CHEST X-RAY AND USE STANDARD IMAGERY CONSTRUCTION IS NOW DIFFICULT TO SEE THESE TWO LESIONS. YOU CAN SEE THAT. OTHER LESION IS QUITE DIFFICULT BUT IF WE USE KNEWER IMAGERY CONSTRUCTION METHODS WE CAN BUY BACK RESOLUTION AND SEE THE LESION. I'LL BLOW IT UP FOR YOU HERE. HERE IS A QUESTION FOR YOU. SO ONE OF THE THESE -- ONE SCAN IS STANDARD CT AND THIS IS PATIENT WITH LAMB. OTHER IMAGE IS A RESEARCH ULTRA LOW DOSE CT. AS CARMEN SHOWS YOU THE PATIENTS WITH CYSTIC LUNG DISEASE, MULTIPLE CYSTS, SO IN THE AUDIENCE ON THE LEFT SIDE OF YOUR SCREEN WHO THINKS THAT'S A RESEARCH SCAN? HOW ABOUT ON THE RIGHT? SOME PEOPLE. WHO CAN'T TELL? ALL RIGHT. THE ONE ON YOUR RIGHT IS A RESEARCH SCAN, DONE AT THE SAME TIME SAME PATIENT, THAT REPRESENTED SIX CHEST X-RAYS WORTH OF RADIATION AND 90% REDUCTION RADIATION SO WE'RE GETTING THE SAME CLINICAL INFORMATION. SO WHAT WE DID WITH IRB APPROVE PROTOCOL, WE TOOK PATIENTS REFERRED FOR CLINICAL CT SCAN BUT THEN WE IMPLEMENTED CHANGES SCANNER USING A ULTRA LOW DOSE METHOD. AND BASICALLY EVERY PATIENT IS THEIR OWN CONTROL, THEY HAVE A STANDARD DOSE SCAN AND RESEARCH ULTRA LOW DOSE SCAN. COMPARED THE FINDINGS FOR THE TWO. WE USED A COMPUTER TO DO QUANTITATIVE ANALYSIS TO MEASURE THE AMOUNT OF CYSTS IN THE VOLUME OF CYSTS THAT WERE CONTAINED IN THE LUNGS. THIS IS HELP ELIMINATE ANY BIAS BY READER. THIS WAS RECENTLY PUBLISHED LAST MONTH IN CHEST. WHAT WE FOUND IS THERE'S A NEAR PERFECT CORRELATION USING ULTRA LOW METHODS. ON THE X AXIS IS STANDARD CT, ON THE Y AXIS IS ULTRA LOW DOSE METHOD. R VALUE IS NEARLY ONE, IF YOU LOOK AT THE PLOT TO SEE WHAT THE SYSTEMATIC DIFFERENCE IS, IT'S THE DIFFERENCE WAS ONLY ONE PERCENT WHICH IS CLINICALLY INSIGNIFICANT. HERE IS ONE EXAMPLE PATIENT, PATIENT WITH -- HERE IS AUTOMATIC QUANTITATIVE ANALYSIS DONE BY COMPUTER AND THE IMAGE ON THE LOWER ROW IS 93% DOSE REDUCTION. PUT THIS IN PERSPECTIVE, IF YOU GO TO THE STORE AND BUY SOMETHING ON SALE, YOU ARE HAPPY TO GET 20% OFF, IF THEY -- IF THE STORE IS GOING OUT OF BIDS, IF THERE'S A FIRE SALE, YOU GET 50% OFF SAVINGS. WHAT WE RE-- BEARE TALKING IS 9 -- WE ARE TALKING IS 9% SAVINGS. TEN CTs FOR AMOUNT OF RADIATION OF ONE STANDARD CT. HERE IS THE LUNG RADIATION WE DID OVER TIME AND BASICALLY WE ARE GIVING AMOUNT OF RADIATION EQUIVALENT TO ONE CHEST X-RAY. SO PUT IN PERSPECTIVE, EVERYONE IS EXPOSED TO RADIATION BACKGROUND RADIATION FROM THE SUN, THE GROUND, IT'S ABOUT THREE TO FIVE MILLISECONDS PER YEAR. I RADIATION WORKER, SUCH AS RADIOLOGIST OR NUCLEAR POWER PLANT, OCCUPATIONAL LIMIT IS 15 MILISIEVERTS IN ONE YEAR, STANDARD CHEST CT IS FIVE TO 8 MILISIEVERTS. LOW DOSE LUNG SCREENING CT, LUNG SCANNING TRIAL WAS ABOUT ONE AND A HALF TO TWO MILISIEVERTS OF RADIATION. THAT'S LOW DOSE. CHEST X-RAY, GIVE YOU IDEA ABOUT 10% OF THAT, SO.# 1 TO .15. WE ARE TALKING ABOUT AT THE NIH OUR DOSES LOWER THAN THE TYPICAL AVERAGE, OUR AVERAGE IS JUST OVER MILISIEVERTS, ULTRA LOW DOSE CT IS LESS THAN ONE MILLIONLY SIEVERT. WHAT I SHOWED YOU IS ACTUALLY ALMOST 10% OF WHAT LOW DOSE IS. WE ARE TALKING .14 MILL HI SIEVERTS TO FULLY DIAGNOSTIC CHEST CT. SO WE TALK ABOUT LAMB. NIH WE STUDIED RARE DISEASE, THE LESSONS WE LEARNED FROM LAIN ARE TRANSLATABLE TO OTHER LUNG DISEASE SUCH AS COPT EMPHYSEMA, CYSTIC FIBROSIS, LUNG KNOWLEDGE INTERSTITIAL LIGHT LUNG DISEASE, TB AND BRONCHIAL. HERE IS A PATIENT WITH EARLY LUNG CANCER, THE STANDARD CT, IF YOU GO AHEAD AND DIAL DOWN USED SINGLE CHEST X-RAY VERY DIFFICULT TO DETECT THIS CANCER HERE, BOTH NOW USE THESE NEW CONSTRUCTION METHODS, WE ARE ABLE THE BUY BACK THE RESOLUTION AND BE ABLE TO DETECTION THAT CANCER. HERE ARE EXAMPLES OF LOWER, THIS IS A LARGE RATHER -- NODULE, ZOOM UP ON THAT. ON THE LEFT IS STANDARD IMAGE, ON THE RIGHT HERE IS THE RESEARCH IMAGE OF ONE CHEST X-RAY WORTH OF RADIATION. HERE IS A FOUR MILLIMETER BASED NODULE, TO DETECT THAT. HERE IS WHAT A SMALL NODULE AND SCARRING LOOKS LIKE. ON THE RESEARCH SCAN ON THE RIGHT, ONE CHEST X-RAY WAS ABLE TO VISUALIZE AND NOT MISS DISEASE. FROM ONE HOT TOPIC IS ARTIFICIAL INTELLIGENCE. MACHINE LEARNING OR AI. THERE'S TONS OF ARTICLES EVERY DAY ANT THIS. THIS IS THE NEW FRONTIER. -- ABOUT THIS. THIS IS THE NEW FRONTIER. DR. BARR IS GOING TO TALK ABOUT THIS. BUT I WANT TO TALK ABOUT ARTIFICIAL INTELLIGENCE FOR IMAGERY CONSTRUCTION. WHAT WE DO HERE IS THIS IS WHERE THE FUTURE IS, WE CAN TAKE A CT SCAN, WE CAN ADD NOISE TO IT TO SIMULATE A LOWER AMOUNT OF RADIATION WE CAN TRAIN THE COMPUTER -- TRAIN DEVELOP ALGORITHMS SUCH AS COMPUTER CAN BUY BACK THE RESOLUTION. KNOWING WHAT IT SHOULD LOOK LIKE. SO YOU HAVE LOW DOSE IMAGE, YOU HAVE STANDARD DOSE IMAGE FROM THE SAME PERSON, COMPUTER OVER THOUSANDS OF DATA SETS. DEVELOP THE ALGORITHMS TO THEN USE LOW DOSE DATA AND BUY BACK RESOLUTION. HERE ARE EXAMPLES WE ARE WORKING ON, LEFT IS STANDARD RECONSTRUCTION, ON THE RIGHT IS DEEP LEARNING RECONSTRUCTION, OVERALL WHAT WE ARE ABLE TO DO IS ABLE TO MAINTAIN FINE STRUCTURES BY ABLE TO DECREASE IMAGE NOISE. SO OVERALL IN SUMMARY, ULTRA LOW DOSE CT CLEARLY HAS BENEFITS. CHANGES PATIENT SAFETY, CHANGES THE BENEFIT RATIO. WE ARE NOW DECREASING THE AMOUNT OF RISK. BY LOWERING THE DOSE WE CAN NOW ENABLE MORE FREQUENT FOLLOW-UPS, BASICALLY PHENOTYPE AND DISEASE, WE CAN NOW INSTEAD OF THREE MONTHS OR SIX MONTHS ASSESS CHANGE. WE CAN PERHAPS LOOK EARLIER AND SEE IF THERE'S EARLIER CHANCE OF RESPONSE. POTENTIALLY WE CAN REPLACE ADDITIONAL CHEST X-RAY BY USING THESE ULTRA TECHNIQUES SINCE THE RISK IS MITIGATED. WHY DON'T I SPEND THE LAST TWO MINUTES ON IS BY REDUCING THE AMOUNT OF RADIATION, MAYBE WE CAN NOW USE SOME OF THESE NEWER IMAGING TECHNOLOGIES, PRETTY EXCITING TO HELP PHENOTYPE THE LUNGS. CONVENTIONAL CT, IS BASICALLY BLACK AND WHITE. SO WE USE THESE ENERGY INTEGRIN DETECTORS SO A FULL X-RAY SPECTRUM HAS MULTIPLE DIFFERENT ENERGIES AND THE DETECTORS CURRENTLY JUST INTEGRATE ALL -- WHATEVER ENERGY HITS IT, REGISTERS AND WE BASICALLY GET BLACK AND WHITE IMAGE. SPECTRAL IMAGING WHERE WITH FANCY I DETECTORS OR YOU MAY HAVE HEARD PHOTON DETECTORS WHICH ARE PROTOTYPE, WE ARE ABLE TO INDIVIDUALLY MEASURE INDIVIDUAL ENERGY EVENTS DIFFERENT TISSUES HAVE DIFFERENT ABSORPTIONS. SO WE MAY HAVE POTENTIAL TO DIFFERENTIATE FOR EXAMPLE POLYNODULE, BENIGN VERSUS MALIGNANT, BECAUSE OF AMOUNT OF ENERGY ABSORBS COULD BE DIFFERENT. ONE OF MY COLLABORATORS IS HUNG WEN AND WHAT HE DEVELOPED IS NOVEL, HE WANTS TO PUSH RESOLUTION OF CT SCANNER AND THIS IS THE SAME PATIENT, ON THE LEFT CONVENTIONAL CT, ON THE RIGHT IS WHAT YOU CAN CALL ZOOM CT, WE ARE ABLE TO GET MORE RESOLUTION OUT OF THE CT. SO THIS IS AT THE EXPENSE OF MORE RADIATION BUT IF WE ARE ABLE TO REDUCE RADIATION WE ARE ABLE TO BASICALLY SEE THESE SMALL CYSTS WHICH ARE NOT VISIBLE BEFORE. IN OPENING TALK BY DR. CRAPO, HE TALKED THE NEW CATEGORY OF COPD. THAT PERHAPS WITH IMAGING WE CAN DIAGNOSE IT AT EARLIER STAGE. WE CAN PERHAPS DIAGNOSE SUBCLINICAL DISEASE AND WITH I THINK IN THE NEXT TALK HERE ABOUT NEW MACHINE LEARN TECHNIQUES, MIGHT BE ABLE TO LOOK AT THOSE IMAGES, SEE THINGS IN IT THAT WE WEREN'T ABLE TO RECOGNIZE BEFORE AND IDENTIFY DISEASE AT EARLIER STAGE AND START TREATMENT EARLIER. SO WITH THAT, ALL THIS WORK DONE WITH NUMEROUS COLLABORATORS. I'LL INVITE UP DR. BARR TO TALK ABOUT MACHINE LEARNING. THANK YOU FOR YOUR ATTENTION. >> THANK YOU VERY MUCH FOR THE OPPORTUNITY TO GIVE THIS TALK. I NOTICE THERE ARE NO AV GLITCHES SO FAR TODAY. THIS IS THE LAST TALK. WE SHALL SEE. IF ALL GOES WELL. GREAT. SO I WANT TO THANK AGAIN NHLBI FOR ASKING ME TO GIVE THIS TALK. ON OPPORTUNITIES, MACHINE LEARNING AND LUNG IMAGING. I HAVE GIVEN A LITTLE BIT OVERVIEW BUT WITH SPECIFIC SETS OF MACHINE LEARNING WORK THAT WE HAVE BEEN DOING. AND I HAVE A COUPLE OF DISCLOSURES. FIRST GRANT FUNDING FROM THE ALPHA ONE COPD FOUNDATION IN ADDITION THE NHLBI. SECONDLY, NEITHER RADIOLOGIST NOR ENGINEER, LOOKING FOR FINAL ANSWERS HERE YOU MAY GO AND GET DRINKS. THE OUTLINE, I THINK THERE ARE REMARKABLE OPPORTUNITIES THIS REALLY UNIQUE MOMENT IN TIME. WHEN IT COMES TO LUNG IMAGING BECAUSE WE HAVE CONFLUENCE OF TECHNOLOGIES, MANY WHICH ARE OUTSIDE MEDICINE THAT ALLOW US TO DO THINGS WE COULDN'T DO TWO OR THREE YEARS AGO CERTAINLY TEN YEARS AGO. THE LAST TALK WAS ONE EXAMPLE OF THEM. THIS PROVIDES OPPORTUNITIES FOR DISEASE DEFINITIONS AND DIAGNOSIS THAT WE CAN COMPLETELY RETHINK IN A UNBIASED WAY AND MOVE INTO THE CLINIC QUICKLY. AND PROVIDES ITSELFMATION OF TREATMENT BENEFITS AND IMPORTANTLY IN THE CURRENT TIME HARM AND THEN QUICKLY COVER SOME CHALLENGES IN TERMS OF WHERE WE ARE. WHY THINK ABOUT MACHINE LEARNING AND AI FOR THE LUNG? SPECIFICALLY CT IMAGING AND THE ANSWER IS THIS IS WHERE THE DATA ARE. HOW MUCH DATA DO WE HAVE? IF RADIOLOGIST IS LOOKING STANDARD CT SCAN SHOWN HERE WHICH PROJECTS WELL, HE IS LOOKING AT .3 MEGA PIXEL IMAGE. NOT SURE IF YOU WOULD BUY A MEGA PIG SEVERAL CAMERA IN YOUR PHONE, THAT WAS A LITTLE WHILE AGO. MINE IS AROUND .5 OR SOMETHING. BUT IT'S A LONG WAY TO GO. BUT WHEN YOU DO A RESEARCH CT SCAN, AS EF DONE IN COPD GENE IN PIR -- SPIRO MICKS YOU ARE TALKING 20 TO 30 MEGA PIXEL IMAGE. EACH GOES FROM NEGATIVE THOUSAND TO POSITIVE THOUSAND SO IT'S MORE THAN FOUR LETTERS. AND IF YOU DO THE MATH IT'S ABOUT THE SAME AS ONE ENTIRE GENOME SEQUENCED. FULL GENOME SEQUENCE. OF COURSE, WE DON'T JUST DO IT ONCE, HERE IS ONE, HERE IS ANOTHER SCAN AT FUNCTIONAL RESIDUAL VOLUME AND ONE AT RESIDUAL VOLUME SO WE DID ACQUIRED THREE OF THESE IMAGES FOR EXAMPLE IN THE LUNG STUDY AND A THOUSAND PEOPLE IN ABOUT FIVE MINUTES OF SCANNING. THAT'S HOW MUCH DATA WE HAVE JUST FROM ONE EXAM IN THE LUNG STUDY. SAME TRUE IN COPD GENE, SAME IS TRUE IN SPIRO MICKS. SO HOW MUCH DATA ARE WE TALKING ABOUT? THIS SHOWS THE LUNG STUDY SINCE 2000 WHICH WAS MESO, THROUGH 2019, WE HAVE ABOUT 21,000 CT SCANS, SOME OF THIS WAS DOUBLED ON THE CARDIAC SIDE. SO WE ARE TALKING ABOUT A VERY LARGE AMOUNT OF DATA AND IN A WAY THE MOST DATA WE HAVE REQUIRED IN ANY STUDIES AFTER WE INCLUDE ALL THE GENOME WIDE SEQUENCING. FROM FURTHERMORE THIS IS POTENTIALLY UNBIAS DATA ARE, MEANING THAT WE CAN ACQUIRE. IMAGINES FIRST OF ALL STEREO TACTICALLY THROUGHOUT THE LUNG SO IF YOU THINK ABOUT BIOPSYING ON A BRONCHOSCOPY OR AUTOPSY OR SECTIONS OF THE LUNG YOU ARE IMAGING THE WHOLE LUNG SO YOU HAVE UNBIAS SAMPLE, IF HE CAN DO IT IN POPULATION BASED SAMPLE LIKE ME IS A FRAMINGHAM SO FORTH WE HAVE UNBIASED REPRESENTATION OF WHAT'S GOING ON AT POPULATION LEVEL WHICH I THINK PROVIDES GREATER INFERENCES. AND THE FINAL COMPONENT IS WE CAN DO THIS IN PEOPLE STILL LIVING NOT WHO ARE DEAD OR HAVE BEEN COME TO THE HOSPITAL FOR A BIOPSY SO THEREFORE AGAIN NOT BIAS BY SEVERAL FACTORS AND WE CAN LEARN MORE ABOUT PROGRESSION. THIS IS ALSO AN OPPORTUNITY WITH CURRENT STATE-OF-THE-ART MACHINE LEARNING APPROACHES TO USE ALL THE DATA IN THIS SCAN. SO THIS IS AN EXAMPLE OF SHOWING HIGH ATTENUATION AREAS FOR THE LAST ITEM OF 30 YEARS WE CAN LOOK LOW AND HIGH ATTENUATION AREAS IN CT SCAN FOR QUANTITATIVE LUNG IMAGING. WHAT THIS MEANS, IS THAT ON THE SCAN WE PLOT THE HOUSE FEEL UNITS OR ATTENUATION OF EACH SCAN AND WE GET A DISTRIBUTION, USUALLY WE DRAW ONE LINE, THAT GIVES US ONE NUMBER THAT WAS WHAT WE SPENT 30 YEARS OF DOING. VALIDATED AGAINST HISTOLOGY, SO FORTH, PREDICTS DEATH, IT'S A HELPFUL NUMBER BUT REALLY ONE DIGIT OUT OF 20, 30 TERABYTES AND MEGA BYTES OF DATA. SO LOOK MORE RADIOLOGIST AT INTERSTITIAL LUNG ABNORMALITIES OBVIOUSLY INTEGRATE MORE THAN ONE DATA THAT'S ALSO PREDICTIVE BUT WE CAN START TO USE MACHINE LEARNING APPROACHES FIRST TO MIMIC THE RADIOLOGIST WHICH CAN BE HELPFUL SO THIS IS BASICALLY COMPUTER IDENTIFYING INTERSTITIAL LUNG ABNORMALITIES ON THE CT SCAN BUT MORE IMPORTANTLY SHOW YOU IN A FEW SLIDES, WE CAN USE THE DATA OF WHAT THE RADIOLOGIST IS TELLING US. RADIOLOGISTS ARE GREAT BUT NOT ALWAYS REPRODUCIBLE AND LOOK AT THE SAME THING AGAIN AND AGAIN. THERE'S EQUAL PROBLEM WHEN WE THINK ABOUT THE AIRWAYS. SO HOW DO WE DESCRIBE THIS AIRWAY TREE. FRANKLY WE WERE SCRATCHING OUR HEAD AROUND THIS FOR A LONG TIME, YOU CAN USE A FRACK TILE DIMENSION, IT'S HARD TO SUMMARIZE THE ENTIRE AIRWAY TREE. IN CONTRAST MACHINE LEARNINGS USES A NODAL TREE BASED APPROACH OR SOME MACHINE LEARNING DOES, IT'S PERFECT FOR THIS KIND OF A PROBLEM SO WE HAVE WAYS TO THEN START UNITING ALL THE DATA IN THE SCAN RATHER THAN JUST A BIT. THE OTHER I THINK VERY LARGE PROMISE HERE IS IT'S RELATIVELY EASY TO TRANSLATE ACROSS SPECIES AND ACROSS SCALE. THIS IS AN EXAMPLE OF A NORMAL AIRWAY RECONSTRUCTED FROM A CT IMAGE IN THE ME IS A LUNG STUDY. WHAT WE FOUND IS THIS PERSON IS NORMAL ANATOMY AND WE DID THIS ACROSS 3,000 PEOPLE IN THE GENERAL POPULATION REMARKABLY ONLY 75% HAVE READ THE TEXTBOOK ALLUDED TO EARLIER. THE OTHER 25% HAD VARIABLE ANATOMY, INCLUDING MISSING A LOBE, SORRY ABOUT THE POINTER, MISSING AN AIRWAY HERE. THIS IS EQUIVALENT MISSING YOUR PINKY FROM SOME OTHER POINT OF VIEW, AND SOME HAD EXTRA -- COMMON IN POPULATION, IT WAS ASSOCIATED WITH DISEASE, ASSOCIATED WITH ALTERED ARCHITECTURE OF THE LUNG THROUGHOUT THE LUNG, AND VERY STRONG GENETIC HIT FOR FGF 10. YOU CAN GO QUICKLY INTO A KNOCK OUT MOUSE, AND FIND EXACTLY THE SAME AIRWAY VARIANT, IMAGE THE CT SCAN AND START TO APPLY THE SAME ALGORITHMS IN THE MOUSE AND THE HUMAN AND IT RATE BACK AND FORTH. ANOTHER EXAMPLE IS FOR -- GALVAN IN TERMS OF USING FUNCTIONAL MALARIA IMAGING. THE PROBLEM ON THE IMAGE HERE IS YOU CAN SEE IT'S CUT OFF YOU LOSE RESOLUTION OF THIS SCAN, THIS ALLOWS US TO LOOK AT IMAGES OF THE CT SCAN, CO-REGISTER THEM TO ESTIMATE WHAT'S GOING ON AT THE LEVEL OF SMALL AIRWAYS THAT YOU CAN'T SEE ON THE CT SCAN. THIS IS RECENTLY BEEN VALIDATED BY THE SAME GROUP AGAINST MICROCT. NOTICE IS ACTUALLY WE ARE LOOKING AT THE SAME IMAGE HERE AS HERE ON DIFFERENT SCALE AND NOW WE'RE VALIDATION IN AUTOPSY SPECIMENS, BIOPSY SPECIMENS IS AGAIN IMAGING CONSTRUCT. WE CAN MOVE BACK AND FORTH, EASIER AS WE ARE USING STANDARDIZE METHODS ACROSS SCALE AND SPECIES TO MOVE QUICKLY. ADDITIONAL EVOLUTION SHOULD WE SAY NOT SO MUCH MEDICAL FIELD BUT HELPFUL IN THIS AREA DEEP LEARNING, A LOT OF HYPE ABOUT THIS AND SO FORTH, I'M NOT GOING THROUGH IN DETAIL BUT JUST TO SAY IF WE ARE THINKING ABOUT TRYING TO SEGMENT THE LUNG ON CT SCAN. THERE'S PROBABLY A COUPLE OF DECADES OF ENGINEERS WHO HAVE WRITTEN CODE TO DO THIS. YOU TAKE THE RAW CT SCAN AND GET TO NICELY SEGMENTED LUNG HERE. NOTICE CUTTING OUT THE HEART I SHOULD POINT OUT, THE CARDIOLOGIST WILL DO THE OPPOSITE THING ON THE SAME SCAN. REMARKABLE. AND THEY SPENT DECADES WRITING THIS CODE, REPLACE IT WITH A NEURAL NETWORK WHICH IS SHOWN HERE. IT RUNS A COUPLE OF TIMES, THIS WAS RECENTLY PUBLISHED. AND IT WORKS, COMPLETELY OUTPERFORMANCE AND LEARNS BASED ON THE NEURAL NET WORK LOOK OF THE SCAN AND SEGMENTS EXTREMELY WELL,'S NOT PERFECT BUT BETTER THAN THE PRIOR CODE AND IT CUTS OUT 90% OF THE HUMAN SUPERVISION COMPONENT TO DOUBLE CHECK WORKING WELL. THE REMARKABLE THING IS YOU CAN THEN TAKE THE SAME CODE AND RUN IT TO FIND FISHSURE AND PUT THE FIVE LOBES TOGETHER AND IT'S EXACTLY THE SAME CODE LEARNING DIFFERENT THINGS, WORKED SO WELL THAT YOU CAN SPIN IT AROUND, AND TAKE CT IMAGES FROM OTHER SPECIES, RUNNING THE SAME CODE AND YOU HAVE SEGMENTED THE LUNG IN THESE ANIMALS. THIS IS NOT TRUE OF THE PRIOR CODE. SO WE HAVE TANKEN 20 YEARS OF -- TAKEN 20 YEARS OF WORK AND MOVED TO ABOUT SIX TO NINE TO 12 MONTHS OF WORK TO ACCOMPLISH THE SAME THING. THIS ALLOWS US TO MOVE VERY, VERY QUICKLY. THE OTHER MAJOR ADVANTAGE OF THIS DEEP LEARNING APPROACH IS THAT IT TAKES -- ALLOW US TO TAKE CT RESEARCH SCANS HIGHLY PROTOCOLIZED BATE DONE ON SPECIFIC SCANNERS AND TRANSLATE TO CLINICAL SCANNERS IN THE HOSPITALS. THE BIG PROBLEM WITH QUANTITATIVE IMAGING SO FAR IS IT'S PROTOCOL DEPENDENT IN THE LUNG AND WE CAN DEEP LEARN ACROSS, GO STRAIGHT INTO CLINICAL SCANS IN A VERY RAPID PROGRESSION PROBABLY WITHIN THE NEXT COUPLE OF YEARS. IN CONTRAST WE DEEP LEARNED STATE-OF-THE-ART CT SCANS AND ME IS A BACK TO CT SCANS IN 2000 THROUGH 2002, WHICH IS A COMPLETELY TECHNOLOGY IN THE TRASH HEAP, ALMOST AS WELL, REALLY REMARKABLE. THE OTHER THING THAT IS A HUGE BOON RIGHT NOW IS IMPLEMENTING WORKING WITH OUR IMAGING COLLABORATORS TO IMPROVE ACQUISITION AND ANALYSIS, THESE ARE JUST A FEW EXAMPLES REALLY POOLED OFF CT SCANS JUST IN EITHER PROCESS OR ACQUIRED IN SOMEWHAT UNUSUAL WAYS. TO ANSWER BIOLOGICAL QUESTIONS. THIS IS -- FIRST ONE SHOWS CO-REGISTRATION OF SCANS IN THE CPD GENE STUDY, WHERE YOU CAN LOOK AT STRAIN SPECIFIC TYPES OF LUNG MECHANICS THROUGHOUT THE LUNG ON REPEATED BASIS YOU CAN DO THIS, ESSENTIAL VOLUME AND TOTAL LUNG CAPACITY. THE SMALL AIRWAY DISEASE STORY IS BECOMING MORE AND MORE ROBUST, RECENT VALIDATION, WE CAN SPLIT THE CT SCAN INTO AREAS OF EMPHYSEMA FUNCTIONAL SMALL AIRWAY DISEASE WHICH PRECEDES SPIRO METICALLY DEFINED COPD IN SOME PEOPLE AT LEAST BUT WE HAD INTEREST IN THE PULMONARY VASCULATURE, FROM COPD GENE STUDY, NONCONTRAST CT SCAN, WHERE USING DEEP LEARNING SPLIT ARTERIES FROM THE VEINS AND THEN IN ME IS A BECAUSE WE HAVE BEEN INTERESTED IN THE MICROVASCULATURE WE GAVE ELEVATED CONTRAST AND ABLE TO MEASURE THE PULMONARY BLOOD VOLUME DIRECTLY. SO THIS IS -- THE NICE THING ABOUT THIS IMAGING IS YOU CAN DO IT IN A LARGE SCALE. SO THIS AUTOMATED CONTRAST PROTOCOL AT ME IS A WAS 750 PEOPLE, THE ARTERY AND VEIN SPLITTING CURRENTLY UP TO ALMOST 10,000 PEOPLE IN THE ME IS A COPD GENE. WE ARE STARTING TO BE ABLE TO UNDERSTAND POPULATION LEVEL WHAT IS GOING ON, I POINT OUT THE PULMONARY VASCULATURE WAS PREVIOUSLY ONLY ACCESSIBLE THROUGH CARDIAC CATHETERIZATION AS WE SUGGESTED BEFORE AND IT PROBABLY MATTERS IF WE THINK ABOUT ALLOWING US AND HELPING US STUDY THE LUNG AND THE HEARTS TOGETHER. CHEATING SLIGHTLY BECAUSE I SUPERIMPOSED CT SCAN WITH 40 FLOW MR. THIS IS A PATIENT WHO IS A NORMAL EJECTION FRACTION, I HOPE YOU WOULD AGREE PROBABLY NOT GETTING SIX LITTERS OF BLOOD -- LITER OF BLOOD PER MINUTE AND DIRECT IN TERMS OF WHAT'S GOING ON LUNGS AND CARDIAC FUNCTION, WE'RE IN THE PROCESS OF REDOING THIS NOW WITH FIVE DEFLOW MRI THAT NOT JUST TAKES IT, MEASURE BLOOD FLOW THROUGHOUT THE TEST NOT ACCOUNTING FOR THE CARDIAC CYCLE BUT ALSO RESPIRATORY CYCLE. WE ARE PRETTY SURE IN PATIENTS WITH LUNG DISEASE INFECTION, THIS IS WELL DESCRIBED IN THE PAST. THIS IS A QUOTE FROM BALDWIN CORNSERS AND RICHES WHO YOU MAY KNOW FROM WHO CAME ONE THE ORIGINAL COPD CRITERIA. TWO GOT THE NOBEL PRIZE FOR CARDIAC CATHETERIZATION. REALLY DOING IT TO MEASURE PULMONARY BLOOD FLOW AND BACK IN 1949 THEY SAID OBVIOUS THE PULMONARY DELIVERY UP TO ONE UNIT SO WE ARE LOOKING FORWARD TO REDISCOVERING ARE THAT. I THINK AGAIN IMAGING IS THE WAY WE ARE MOST ABLE TO DO IT ON A LARGE SCALE WE ARE NOT GETTING BIAS SAMPLES. THERE ARE OPPORTUNITIES FOR UNSUPERVISED LEARNING, THIS IS AN EXAMPLE THAT WE HAVE BEEN WORKING ON IN SPIRO MICKS. DEEP LEARNING REQUIRES GOLD STANDARD, LABEL DATA WE NEED TO KNOW THE ANSWER TO LEARN. IN LUNG DISEASE WE HAVE A PROBLEM WITH EMPHYSEMA SUBTYPES IN THAT THE ORIGINAL STUDIES TO CENTRAL LOBULAR DISEASE AND PARACEPTIVE DISEASE BASED ON AUTOPSIES 65, 75 AND TWO PATIENTS, PERIOD. RADIOLOGISTS TRIED TO MIMIC THOSE AND IT'S TOUGH, WE HAVE ALGORITHM THAT TRIES TO MIMIC THE RADIOLOGIST AND THAT'S ALSO TOUGH SO YOU MAY THINK MAYBE IT'S TIME TO THROW OUT AND RESTART AND USE UNSUPERVISED MACHINE LEARNING FOR POTENTIAL NEW SUBTYPES. WE DID THIS WORK IN SPIRO MICKS WHICH IS 3,000 SUBJECTS T ME IS A LUNG WITH 3,000 WITH A HIGHLY STANDARDIZED CT PROTOCOL BUT VERY DIFFERENT POPULATION, SPIRO MICKS COPD AND CONTROLS, HEAVY SMOKERS, ME IS A LUNG POPULATION BASE 50% NEVER SMOKERS. SO TAKE THE CT SCAN, IDENTIFY EMPHYSEMATUS REGIONS OF INTEREST. THE IMPORTANT THING HERE IS IN 3,000 SUBJECTS IN SPIRO MICKS WE GET ABOUT 6 OR 700,000 OF THESE REGIONS OF INTEREST. SO NOW WE CAN START TO DO REAL LEARNING. THAT'S ENOUGH TO GET SOMETHING ROBUST. WE DO TEXT ON FEATURES TO -- THIS IS BASED ON FACIAL RECK NIX. YOUR PHONE DOES THIS, NOT OUR GOVERNMENT BUT THE CHINESE GOVERNMENT DOES THIS REALLY WELL. WE KNOW, THIS IS MATURE TECHNOLOGY, IT WORKS WELL. FURTHERMORE WE KNOW THERE IS DIFFERENT PARTS OF THE LUNG DIFFERENT THINGS HAPPEN SO WE KIND OF WANT TO STANDARDIZE KNOW WHERE EACH REGION OF INTEREST IS IN THE LUNG. SO WE DISCOVERED AND LOOKED AT HALF OF SPIRO MICKS WE CAME UP AND IN A COMPLETELY UNSUPERVISED WAY THERE WERE TEN SUBTYPES AND SEE PATTERN LOOKS SIMILAR, THESE ARE DEFINITELY EMPHYSEMA, THESE FIBROTIC EMPHYSEMATUS DISTRIBUTION, THIS IS INFERIOR, THIS IS SUPERIOR. THIS ONE IS MUCH MORE DIFFUSE. SO THIS SEEMED LIKE IT WORKED. THEN WE REPEATED IN THE OTHER HALF OF SPIRO MICKS AND STRIKINGLY GOT VISUALLY SAME ANSWER WITH THE SAME DISTRIBUTION AND IF WE COMPARED THE TWO AND CROSS VALIDATION CROSS LEARNING, THE REGIONAL INTERLEARNER REPRODUCIBILITY WAS .82, IN OTHER WORDS, 80% -- 82% OF THE TIME THE COMPUTER LEARNED SAME PATCH OF LUNG ALONG THE SAME WAY. THE SUBJECT LEVEL GREATER THAN .95. SO WE IDENTIFIED IMPAIRED DOWN OVER TIME AND WITH DATA REDUCTION WE ARE REALLY SIX OF THESE SUBTYPES, I WON'T GO THROUGH ALL OF THEM IN THE INTEREST OF TIME. BUT JUST THE FIRST IS AN APICAL DISTRIBUTION, THIS IS WHAT IT LOOKS LIKE AND REMARKABLY THIS WAS THE ONLY ONE THAT WAS ASSOCIATED WITH CHRONIC BRONCHITIS ALLUDED TO EARLIER. IT IS A CLASSIC COPD SUBTYPE, LOWER FEV1, NO CHANGE IN THE TOTAL LUNG CAPACITY, INCREASED HEMOGLOBIN AND IF YOU ARE READING ARTICLES FROM 1966 THIS IS VERY, VERY, VERY CLOSE TO THE ORIGINAL DESCRIPTION OF BRITISH COPD SUB-PHENOTYPE. THE DIFFUSE ONE, WAS THE NEXT MOST COMMON, VERY DIFFUSE AS YOU CAN SEE, ARE DIFFERENT PHYSIOLOGY, NO RELATIONSHIP TO THE FEV 1, INCREASE FEC RESULTING IN A LOWER RATIO MAKING COPD CRITERIA. INCREASE TOTAL LUNG VOLUME, LOSS OF ELASTICITY IN THE LUNG. HYPOXEMIA AND SO FORTH, QUITE CLOSE TO TYPE A AMERICAN COPD FROM 1960s. THE OTHER ONES, I WON'T GO THROUGH IN THE INTEREST OF TIME BUT ALSO MATCH PREVIOUS DESCRIPTIONS TO THE LITERATURE WITH MUCH MORE SPECIFICITY. I WILL GO THROUGH THE LAST COUPLE OF SLIDES QUICKLY BECAUSE WE ARE SHORT ON TIME. TO POINT OUT OF THE THERAPIES THAT WE HAVE IN EMPHYSEMA, THE ONLY ONE THAT IS REALLY PERSONALIZED IS ALPHA ONE ANTITRYPSIN DEFICIENCY IDENTIFIED OPT BASIS OF IMPROVED PHENOTYPING, CHEST X-RAY AND ALPHA GLOBULINS OVER ABOUT 50 YEARS, CLINICAL TRIALS SHOW BENEFIT AND LUNG DENSITY, AND NOW WE CAN START TO REDO THIS, WE HOPE, WITH HYPOTHESIS GENERATED END POINTS FOR BENEFIT AND POTENTIALLY FOR HARM IN TERMS OF eCIGARETTES AND EFFECTS ON VENTILATION. THERE ARE A NUMBER OF CHALLENGES IN THIS AREA AND PART OF THIS IS VERY MULTI-DISCIPLINARY WORK, IN TERMS OF ENGINEERS EPIDEMIOLOGISTS AND CLINICS, FALSE POSITIVE RESULTS WE NEED TO THINK REPRODUCIBILITY IN SEPARATING DISEASE FROM NORMAL WHICH MEANS YOU HAVE TO STUDY NORMALS. GP POWERS OF -- IN FACT MAYBE NIH HAS NON-EXTRAMURAL COMPONENT. WITH OUR -- THIS IS JUST A PHOTO OF HUTCHINSON FROM 1846. NOTABLE FOR INVENTING THE SPIROMETER WHERE HE NAILED EVERY ONE OF THESE IN ONE PAPER AND DID SPIROMETRY IN 4,000 PEOPLE BEFORE ROLLING OUT SPIROMETER TO UNDERSTAND WHAT IT WAS DOING. WE DISCOVERED PROBABLY 90% SPIROMETRY AND I GUESS H INDEX IS ONE PAPER BUT IMPACT IS HUGE AND YOU HAILY WENT THROUGH THESE STEPS. WE ARE AT A TIME WHEN THERE ARE HUGE OPPORTUNITIES TO REALLY REDO HUTCHINSON WORK WITH MODERN METHODS IN TAKING ADVANTAGE OF COMPUTER SCIENCE IMAGING, AND WE KNOW ABOUT BIOLOGY TO REDEFINE LUNG DISEASE TESTING OF NEW TARGETED THERAPIES AND RAPID TRANSLATION. WITH THAT I'LL THANK THE VERY MANY COLLABORATORS AND THE NIH FOR FINDING THIS WORK -- FOR FUNDING THIS WORK. [APPLAUSE] >> THANKS THIS GROUP OF SPEAKERS FOR OUTSTANDING PRESENTATIONS AND LET'S GO AHEAD AND OPEN UP THE SESSION FOR QUESTIONS FROM THE AWED YENS. WE CAN REDO THE LIGHTS AGAIN, IT WILL HELP US. RIGHT IN FRONT. CAN'T SEE YOU. SANJAY. SORRY. (OFF MIC) >> THIS IS A QUESTION FOR DR. MARCUS CHEN, TWO QUESTIONS, QUESTION ONE, THE AMOUNT OF (INAUDIBLE) (OFF MIC) RADIATION (INAUDIBLE) BY -- WHAT CAN WE DO TO CHANGE THAT PERCEPTION? THAT'S (INAUDIBLE) EACH QUESTION SEPARATELY. FIRST QUESTION, CAN YOU USE THE SAME IMAGING TECHNIQUES FOR TRADITIONAL X-RAY IN TERMS OF REDUCING RADIATION? ANSWER IS NO. BECAUSE CT WE ARE SAMPLING SO WE ARE TAKING BASICALLY 2D PROJECTIONS FROM ALL THE WAY AROUND THE PATIENT AND RECONSTRUCTING IMAGE AND FORMING WHAT WE END UP SEEING AS AXIAL IMAGE. WITH TRADITIONAL X-RAY ALL THIS IS PIECE OF FILM MIND THE PATIENT AND X-RAY (INAUDIBLE) SO UNFORTUNATELY NO WE CAN'T DO IT FOR TRADITIONAL X-RAY. SECOND QUESTION WAS IN TERMS OF PERCEIVED RISK OF MEDICAL IMAGING. SO THAT BRINGS UP A GOOD POINT. SO THERE'S AN OVER INFLATING RISK OF ACTUAL CHANCE CHAINESS OF DEVELOPING A CANCER FROM CT SCAN OR MEDICAL IMAGING. THE WHOLE IDEA IS THAT IONIZING RADIATION YOU CAN POTENTIALLY MUTATE A DNA THAT DOESN'T GET REPAIRED BY THE DNA REPAIR MECHANISMS AND THAT ONE MUTATION CAN MANIFEST AS A CANCER AFTER YEARS AND YEARS OF CELL DIVISION. IF YOU ACTUALLY LOOK AT ABSOLUTE RISK, THE ABSOLUTE RISK OF DEVELOPING CANCER FROM ONE CT SCAN IS QUITE LOW. IT'S LOWER THAN THINGS THAT WE TAKE FOR GRANTED FOR EXAMPLE DRIVING IN THE CAR T. OR WALKING DOWN THE STREET MORE LIKELY TO GET CAR ACCIDENT OR HIT BY A CAR OR BE AIRPLANE THAT CRASHES THAN HAVING CANCER FROM A CT SCAN. WHAT CAN WE DO TO HELP EDUCATE PEOPLE. BASICALLY I THINK YOU NEED TO TELL PEOPLE WHAT THE RISKS ARE IN PUTTING CONTEXT, WHAT IS OVERALL RISK OF GETTING A CANCER VERSUS THINGS WE TAKE FOR GRANTED IN DAILY LIFE. AUDIENCE, TONY I SEE A HAND. >> THIS IS FOR YOU. I WAS IMPRESSED FROM THE LIPID DATA I DIDN'T KNOW, SAME QUESTION I ASKED YOU, YOUR SELECTIVE -- IT'S NOT SELECTIVE BUT DEFINITELY INCREASE UPTAKE OF THE LIPID TRACER YOU TAKE CARE OF USING OR IS SOMEBODY USING THE LIPID COMPOUND AS POSSIBLE TARGET IN CYTOTOXIC MECHANISM FOR THE CELLS? >> IN TERMS OF THERAPEUTICS LIPIDS MAY HAVE A TOXIC EFFECT ON THE CELLS. THE SPECIFIC WHAT WE HAVE LABELED IS SYNTHETIC PATHWAY OR BIOSYNTHETIC PATHWAY, THAT'S BEING USED IN PROSTATE CANCER NORMALLY MUCH IN THE UNITED STATES, ON THE EXTENT USE IN EUROPE. IN TERMS OF THERAPEUTICS I THINK WE CAN THINK OF LIPID (INAUDIBLE) FOR EXAMPLE, CYTOTOXIC EFFECT, THE PROBLEM IS INJECTING SPECIFIC TO THE TUMOR, PRETTY DIFFICULT BECAUSE ADULTS SHOULD BE REALLY HIGH. I THINK IT COULD BE POSSIBLY OPPORTUNITIES FOR THERAPEUTICS BUT WE NEED TO DESIGN SPECIFIC WAY TO REALLY GET VERY HIGH CONCENTRATION TO THE TUMOR. THROW TRANSPORTERS. >> SERENA. >> FIRST I WANT TO THANK DR. -- AND COLLEAGUES PUTTING UP A WONDERFUL SESSION. I'M A VISUAL PERSON SO THIS WAS THE FIRST VISUAL FOCUS THAT VERY ATTRACTED TO I HAVE A QUESTION FOR DR. BARR SPECIFICALLY BEYOND COMPLIMENTS, I'M VERY INTERESTED IN IMAGING LUNG VASCULATURE. SO THERE IS SUCH AN INTIMATE RELATIONSHIP BETWEEN CAPILLARIES AND ALVEOLI AND I'M SURE SUPER IMPORTANT IN MANY DIFFERENT DISEASE AND NOT EVEN TRYING TO ENUMERATE THAT. IT'S DIFFICULT TO FIND LITERATURE IN ANYWAY OF RECONSTRUCTING THE SMALL VASCULATURE OF THE LUNG. IS THERE A BARRIER, IS THERE A GAP? CAN YOU TELL MOUSE ABOUT THAT? YOU SHOWED A COUPLE OF IMAGES. >> THE THERE IS A HUGE GAP BECAUSE IT'S AN ENTIRE CIRCULATION THAT WE HAVE NOT HAD GOOD METHS TO ACCESS AT LEAST -- METHODS ON AT LEAST A POPULATION LEVEL OR IN CLINICAL WAY OTHER THAN BUYING BASIC METHODS. AND SO THIS IS A REALLY JUST FIRST STROKES IF YOU LIKE IN TERMS OF FIRST RECONSTRUCTING THE NON-CONTRAST CT SCANS WHICH ARE VENUS IMAGES AND SHOWING BEING DONE ON LARGE SCALE. SECONDLY USING NOVEL METHODS THE ACCESS IN TERMS OF DIVISION. CERTAINLY CT IS EXTREMELY GOOD AND I WAS VERY HAPPY WE WERE ABLE TO DO IT SAFELY IN 750 PEOPLE IN ME IS A. AND SIMILARLY CONTRAST, WE BOTH SHOWED IMAGES OF GADOLINIUM ENHANCED MR FOR THE PULMONARY VASCULATURE WHICH IS REALLY EASY, I I SHOULDN'T SAY REALLY EASY BUT ABLE TO DO IT IN 300 PLUS PEOPLE ON MULTI-CENTER BASIS AND REPEATING IT. NIECE THING BECAUSE THERE'S NO RADIATION CURRENT LEVEL YOU CAN REPEAT IT QUICKLY. SO A LOT OF IMAGES ARE FROM TWO DIFFERENT BOLUSES IN THE SAME IMAGING SESSION. >> SAME VARIABILITIES LIKE IN THE AIRWAYS IN TERMS OF VASCULATURE BRANCHING? >> WE HAVEN'T LOOKED AT THEM YET BECAUSE DATA ARE FRESH OFF THE PRESS IF YOU LIKE AND WE ARE FIGURING OUT THE BEST WAY TO ANALYZE IT. THERE ARE NO COMMERCIAL SOFTWARE TO DO THIS. WE HAVE A PROCESS INSTEAD OF WORKING IT OUT. THE ARTERIES AND THE VEINS FOLLOW THE AIRWAYS, THERE MUST BE VARIABILITY AND WHEN YOU SPEAK WITH -- SORRY? >> MAYBE THE OTHER WAY AROUND. >> Q. OR THE OTHER WAY AROUND. CERTAINLY EVEN JUST INVASIVE CARDIOLOGISTS WILL TELL YOU TRYING TO GET INTO PULMONARY ARTERY AND THEY DON'T KNOW WHERE THEY ARE BECAUSE THEY DON'T KNOW THE ANATOMY AND YOU CAN DEFINE IT ON CT EASILY. >> DR. MENSA. >> JIM, THANK YOU. I AGREE WITH SERNA, A FANTASTIC SESSION. THANK YOU VERY MUCH. I ENJOYED THESE LAST THREE AND I HAVE A QUESTION FOR DR. CHEN. I'M DEFINITELY SOLD ON THE ULTRA LOW DOSE CT AND I'LL SIGN UP WITH A STUDY ANY DAY. I KEPT WAITING THE HEAR YOU SAY SOMETHING ABOUT THE DOWN SIZE AND I DON'T THINK I HEARD ANYTHING ABOUT THE DOWN SIZE OF THIS, AND THE REASON I'M ASKING IS I REMEMBER MY OLD RADIOLOGY PROFESSOR TELLING ME YOU CAN TELL LOT FROM THE CHEST X-RAY NOT JUST THE LUNG PARENCHYMA, YOU CAN TELL BONY STRUCTURES ARTERIES IN THE VEINS. ARE YOU LOSING ANYTHING THERE? AND ANY DOWN SIZE AT ALL? >> THE BIG DOWN SIDE IS COST. SO TO BE ABLE TO PUSH IMAGE OR CONSTRUCTION YOU NEED GPUs. YOU NEED THESE IMAGERY BOARDS AND THAT DRIVES UP THE COST OF THE RECONSTRUCTION UNIT. THE GOOD THING IS THAT CT MANUFACTURERS RECOGNIZES, THEY RECOGNIZE THE FUTURE REDUCING THE PERCEIVED RISK OF RADIATION. SO THEY ARE NOW INTEGRATING THESE HIGH NGPUs INTO THEIR NEW SCANNERS. IF YOU HAVE AN OLD CAR WITHOUT AN AIR BAG, WE TAKE FOR GRANTED AIR BAGS IN THE CAR BUT IF YOU WANT TO PUT AN AIR BAG IN THE OLD CAR, THAT'S EXPENSIVE BUT COMPUTERS ARE GETTING CHEAPER AND CHEAPER, EVERY YEAR APPLES SAMSUNG COMES OUT WITH NEW PHONE FASTER AND CHEAPER SO THE NEW SCANNERS BEING SOLD NOW HAVE THAT TECHNOLOGY IT WILL TAKE TIME BECAUSE LIFE CYCLE OF CT SCANS PROBABLY RUN TEN YEARS SO IT WILL TAKE THAT AMOUNT OF TIME BEFORE IT GETS FULLY IMPLEMENTED IN THE IMMUNITY. >> IF I CAN FLOW ON THAT, CAREFULLY SELECTING SITES, THE IMAGES SHOWED FOR ME IS A WHERE WE DID THREE CT SCANS, IN THESE SUBCHECKS ARE REQUIRED FOR LESS THAN 2 MILISIEVERTS ACROSS A THOUSAND PEOPLE. THE STUDY WE ARE PROPOSING NOW BY 3 CT ONE MILLIONLY SIEVERT WITH COMMERCIAL SCANNERS, EVEN WITH EXISTING MULTI-SCANNERS YOU CAN GET RIGHT NOW. >> QUESTION FOR DR. PARK T. WHAT KIND OF MACHINE LEARNING SOME KIND OF RECOMBINANT PHENOTYPE CT DATA? AS A TRAINING DATA SET, ARE USING JUST THE OWN TRAINING DATA, PRETTY OVERLAP FEATURE AT THE END? >> I THINK IT DEPENDS ON WHAT YOU ARE TRYING TO DO WITH MACHINE LEARNING AND SO THE MOST COMMON ARCHETYPE IS DEEP LEARNING APPROACH WHERE THERE IS -- ASSUMES GOLD STANDARD, ASSUMES VALID LABELING AND THEN YOU CAN LEARN AND THERE'S CLEARLY LARGE PROBLEMS WITH FALSE POSITIVES, AND THERE'S A NEED TO MOVE ACROSS. THIS GOES BACK TO WHAT WE NEVER THOUGHT OF AS MACHINE LEARNING. BUT JUST STRAIGHT LOGISTIC REGRESSION AND DATA DRIVEN APPROACHES WHICH YOU COULD OVERFIT THE MODELS AND OVERFIT THE STATISTICAL ANALYSES, THIS IS EQUALLY TRUE FOR DEEP LEARNING. SO THERE IS A NEED TO MOVE ACROSS DIFFERENT DATA SETS AND MAKE SURE THAT THE RESULTS ARE VALID. FROM I THINK FOR THE WORK IN TERMS OF UNSUPERVISED, DIFFERENT PROBLEM, DIFFERENT QUESTION, THE MORE STANDARDIZATION THAT YOU HAVE IN THE PROTOCOL, PROBABLY THE BETTER FOR LEARNING TO COME UP WITH NEW GOAL STANDARD AND WORK TO TRANSLATE THEM ACROSS MODALITIES. >> DAVID. >> SO JIM, I WANT TO ADD MY CONGRATULATIONS ON A REALLY WONDERFUL AFTERNOON, THIS SESSION HAS BEEN FANTASTIC AND REALLY DOES HIGHLIGHT THE PARTNERSHIP BETWEEN HEART AND LUNG THAT'S BEEN GOING ON NOW FOR OVER 50 YEARS WHICH IS REALLY GREAT. SO TO KIND OF TRY TO CONTINUE ON THAT THEME, GRAHAM, YOU RAISED THE ISSUE OF TRYING TO EXTEND THE DEEP LEARNING TO THE COUPLING OF THE HEART AND LUNG THAT YOU ARE ABLE TO DO WITHIN MESA LUNG SO WONDERING IF YOU'RE ABLE THE USE DEEP LEARNING TECHNIQUES TO GIVE US IDEAS ABOUT WHICH OF THE PATIENTS WITH COPD MAYBE GREATEST RISK FOR PROGRESSING TO RIGHT HEART FAILURE OR OTHER CARDIOVASCULAR CONDITIONS RELATED TO THE DYSFUNCTION OF A PULMONARY SIDE? >> THANK YOU FOR THE QUESTION. YOU HAVE A GRANT ON THIS AT THE MOMENT. WHICH SCORED WELL. >> GO TO DIVISION OF LUNG DISEASE OR DIVISION OF CARDIOVASCULAR SCIENCES? >> SO REMARKABLE AS WE KNOW THE LITERATURE ON THE OLD PHENOTYPES, BLUE BLOODERS PINK -- 19 # 2 SHOWED THE CARDIOVASCULAR CONSEQUENCES OF LUNG PHENOTYPES WHICH ARE AT THIS POINT DISCARDED LUNG PHENOTYPES. THE REMARKABLE THING TO US IS LEARNING ONLY ON THE LUNG CT SCANS, WE DISCOVERED SOME GENETICS THAT I DIDN'T HAVE TIME TO TALK ABOUT. THE POINT TO CARDIOVASCULAR CORRELATES AND ABLE TO BASICALLY FIND USING CARDIAC MRI IN THE MESA COPD STUDY, THE FIRST THAT BLUE BLOATER QUOTE UNQUOTE IS ASSOCIATED WITH BIGGER RV TO LV RATIO IN THE MESA DATA. THE OTHER ONE NEXT I SHOWY IS DIFFUSE PHENOTYPE SEEMS TO BE ONE MEASURING MORE PERCENT EMPHYSEMA SINGLE DIGIT LUNG SCAN PUBLISHED IN THE NEW ENGLAND JOURNAL NINE YEARS AGO, ONE OF THE MAJOR CORRELATES IN THE GENERAL POULATION AND THERE'S COUPLE MORE WHERE GENOTYPIC HITS LOOK AT SPECIFIC CARDIOVASCULAR PHENOTYPES AND YES THEY SEEM TO REMARKABLY LINE UP, WE WANT MORE REPLICATION AND TAKE THE NEXT STEPS BUT I THINK THERE'S A VERY STRONG SIGNAL THERE. >> DID THE NEURAL NETWORK PICK UP CALCIUM IN ITS AS A FEATURE OR SOME OTHER HINT ABOUT THE POTENTIAL OVERLAP? >> I HATE TO SAY IT BUT WE EXPLICITLY EXCLUDED THE HEART. SO WE WERE INTERESTED IN LEARNING NEW SUBTYPES OF EMPHYSEMA, THEREFORE ONLY LOOKED IN THE LUNG. THERE WAS OTHERS WHO HAVE TAKEN APPROACH LOOK AT THE WHOLE CT SCAN, TO -- THAT AND I HAVE COME UP WITH DIFFERENT RESULTS, INCLUDING CALCIUM. >> OKAY. WE ARE RIGHT AT THE END OF OUR TIME. AND I WANT TO EXTEND A VERY, VERY DEEP THANKS AND GRATITUDE TO ALL OF OUR SPEAKERS FOR DOING NOT ONLY SUPERB JOB PRESENTING THEIR DATA AND THE NEW ESIGNEDDINGS AND GIVING US A HINT OR AT LEAST A WINDOW INTO FUTURE FOR PULMONARY IMAGING AT ALL LEVELS, I THINK IT WAS A PHENOMENAL DISPLAY OF A LOT OF WORK GOING ON BY A LOT OF PEOPLE ACROSS THE COUNTRY. I WANT TO SAY THANK YOU FOR THEM TO -- FOR -- TO ALL OF THEM FOR BEAUTIFULLY SUM RIDING THAT DATA. ALSO FOR STAYING ON TIME, WHICH I KNOW IS REALLY, REALLY DIFFICULT. [APPLAUSE] >> NO ONE EXCEEDED IT AND IT WAS REALLY OUTSTANDING AND I THINK WE WANT TO THANK YOU AND FOR ALL THOSE WHO TUNED IN THROUGH THE VIDEOCAST, FOR SPENDING THE AFTERNOON WITH US, LEARNING A LITTLE BIT ABOUT THE LUNG AND GETTING AGAIN A LOOK WHERE WE MAYBE HEADING GOING FORWARD. WE ARE EXCITED THIS IS A TERRIFIC YEAR FOR DLD AS WE CELEBRATE OUR 50th ANNIVERSARY, WE HAVE A LOT OF EVENTS TEED UP FOR THE REST OF THE YEAR AND STAY TUNED BECAUSE IN DECEMBER WE WILL HAVE A YEAR IN REVIEW WHICH WE HOPE WILL BE THE FINALE TO OUR PROGRAM, THE FOURTH OF JULY FIREWORKS WE WILL DO MANY THANKS TO OUR COLLEAGUES BY LENOIR JOHNSON FRONT ROW HELPING IMMENSELY PLANNING AND NOT ONLY THIS EVEN BUT THOSE TO COME. THANK YOU FOR YOUR PARTICIPATION. WE WILL CALL THIS SESSION TO A CLOSE AND WE WISH YOU A GOOD NIGHT. [APPLAUSE]