>> GOOD MORNING, EVERYBODY. IF YOU COULD TAKE YOUR SEATS, WE'RE READY TO GET STARTED. WE'RE HAVING A LITTLE BIT OF IT TECHNICAL PROBLEMS AND A FEW PEOPLE STILL DRIFTING IN, BUT WE STILL HAVE A VERY FULL AGENDA SO I'M EAGER TO GET STARTED. I'M TOM INSEL, THE CHAIR OF THE IACC. I WANT TO WELCOME ALL OF YOU TO THIS WORKSHOP. I'LL MAKE SOME INTRODUCTORY REMARKS, BUT MAYBE BEST JUST TO GET US ALL INTRODUCED TO EACH OTHER BECAUSE THERE ARE A NUMBER OF PEOPLE AROUND THIS U SHAPED TABLE WHO DON'T KNOW EACH OTHER, I SUSPECT, AND ALSO WE'LL GIVE YOU GOOD TRAINING IN HOW TO USE YOUR MICROPHONES. SO LET'S START OVER HERE WITH ALICE, AND WE CAN GO AROUND THE TABLE THAT WAY. THIS IS A NEW BUILDING AND A NEW P.A. SYSTEM SO YOU HAVE TO GET A LITTLE BIT USED TO IT. >> I'M ALICE, PROGRAM STAFF FROM EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT. I'M SITTING IN FOR OUR DIRECTOR, DR. ALAN GUTTMACHER. >> I'M ZACH FROM HARVARD. IF ALAN WAS HERE, I WOULD SAY THAT IF YOU DON'T LIKE ANYTHING I SAY, HE'S RESPONSIBLE BECAUSE HE INTRODUCED ME WHEN I WAS A MEDICAL STUDENT APPLYING FOR RESIDENCY PROGRAM, AND HE MADE THE MISTAKE OF ADMITTING ME TO THE CHILDREN'S HOSPITAL RESIDENCY PROGRAM. >> I'M MATT CAREY, PARENT OF AN AUTISTIC CHILD, PUBLIC MEMBER TO THE IACC FOR THE NEXT SEVEN DAYS. >> GOOD MORNING, I'M LISA CROWHEN, KAISER MERM NEN TEE. >> JUDEITY COOPER, NATIONAL INSTITUTE ON DEAFNESS AND OTHER COMMUNICATION DISORDERS HERE AT NIH. I'M SITTING IN FOR JIM BATTEY, OUR DIRECTOR, AND I ALSO COORDINATE THE AUTISM PROGRAM FOR NIDCD, PRIMARILY IN THE AREA OF LANGUAGE. >> GOOD MORNING. I'M BETH MALOW FROM VANDERBILT. I'M A NEWE NEUROLOGIST AND SLEEP SPECIALIST. >> GOOD MORNING. I'M ASSURE ASHURA BUCKLEY, CHILD NEUROLOGIST AND SLEEP SPECIALIST. >> GOOD MORNING. I'M SALLY BURTON-HOYLE, FROM EASTERN MICHIGAN UNIVERSITY. I RUN A MASTER'S PROGRAM TO TRAIN TEACHERS TO WORK WITH FOLKS WITH AUTISM AND A COLLEGE SUPPORT PROGRAM FOR INDIVIDUALS WITH AUTISM SPECTRUM DISORDERS. >> GOOD MORNING, JOHN HOPKINS UNIVERSITY, I AM A CLINICAL NEUROLOGIST AND NEUROPATHOLOGIST WORKING IN DIFFERENT ASPECTS OF CLINICAL -- >> HELLO, I'M JUDY VAN DE WATER, UNIVERSITY OF CALIFORNIA DAVIS, I'M AN IMMUNOLOGIST WORKING IN AUTISM. >> HELLO, I'M DONNA KIMBARK, I'M WITH THE DEPARTMENT OF DEFENSE, AUTISM RESEARCH PROGRAM. >> GOOD MORNING. I'M LAURA KAVANAUGH WITH THE HEALTH RESOURCES AND SERVICES ADMINISTRATION. >> GOOD MORNING. I'M ANSHU BATRA, DEVELOPMENTAL PEDIATRICIAN IN LOS ANGELES IN PRIVATE PRACTICE, AND I HAVE THREE KIDS, ONE OF WHOM IS ON THE SPECTRUM FOR AUTISM, HE'S 17, HAD HIS BIRTHDAY A MONTH AGO. I'M HAPPY TO BE HERE. >> I'M BO BOB NAVIAU MY TOE MITOCHONDRIAL SPECIALIST. >> LYN REDWOOD, VICE PRESIDENT OF COALITION FOR SAFE MINDS, ALSO MOM TO A 20-YEAR-OLD YOUNG MAN WHO PREVIOUSLY HAD PDD AND O.S. WHO'S IN HIS SECOND YEAR OF COLLEGE NOW. >> -- FROM BOSTON CHILDREN'S, CHILD NEUROLOGIST. >> I'M JOHN ROBISON, AUTISTIC ADULT. I'M AN IACC COMMITTEE MEMBER AND NEURODIVERSITY SCHOLAR AT WILLIAM AND MARY. >> -- FROM UY OF TORONTO, I'M A CHILD NEUROLOGIST. >> LARRY -- FROM EMORY UNIVERSITY, MARCUS CENTER, WHERE I RUN THE CLINICAL TRIALS PROGRAM. >> I'M DAN CORY, DEVELOPMENTAL BEHAVIORAL PEDIATRICIAN FROM NATIONWIDE CHILDREN'S HOSPITAL. >> GOOD MORNING. JOSE CORDERO, DEAN OF THE SCHOOL OF PUBLIC HEALTH, UNIVERSITY OF PUERTO RICO AND MEMBER OF THE IACC. >> GOOD MORNING. I'M ANG LEE JANZEN, PEDIATRICIAN AND HEALTH SERVICES RESEARCHER. >> GOOD MORNING. I'M SUSAN DANIELS, DIRECTOR OF THE OFFICE OF AUTISM RESEARCH COORDINATION AT NIMH AND I'M THE EXECUTIVE SECRETARY OF THE IACC. >> WE'VE GOT A REALLY DISTINGUISHED GROUP. DELIGHTED THAT ALL OF YOU COULD COME. FOR THOSE WHO HAVEN'T BEEN HERE BEFORE, THIS IS A NEW BUILDING, THE NEWEST BUILDING ON THE NIH CAMPUS, PORTER NEUROSCIENCE CENTER, WHICH WAS NAWG RATE IN INAUGURATED IN APRIL OF THIS YEAR, HOME TO SOME 80 DIFFERENT LABORATORY, MANY OF WHICH WORK ON PROBLEMS RELATIVE TO AUTISM. THIS IS ALSO THE DAY OF OUR ANNUAL SCIENCE FESTIVAL, SO THERE'S A LOT GOING ON ON THE NIH CAMPUS, US A PROBABLY SAW AS YOU CAME ON TO THE CAMPUS, BUT DELIGHTED THAT ALL OF YOU COULD MAKE IT HERE, SOME FROM QUITE FAR AWAY. MY CO-CHAIR FOR THIS SUBCOMMITTEE, JERRY DAWSON, WILL BE HERE, I THINK MOMENTARILY, BUT WE'LL GET STARTED WITHOUT HER. BY WAY OF INTRODUCTION, THE FIRST THING TO SAY TO THOSE OF YOU WHO ARE MY COLLEAGUES ON THE IACC, IS THAT THIS IS NOT AN IACC MEETING, SO EVEN THOUGH WE HAVE PLENTY OF ORAL AND WRITTEN COMMENTS FROM THE PUBLIC AND WE'RE WEBCASTING AND WE HAVE MANY OF THE SAME PEOPLE AROUND THE TABLE, THIS IT TRULY IS A WORKSHOP, AND THAT MEANS THAT THIS TIME FOR US IS MOSTLY FOR US TO LISTEN AND ASK QUESTIONS. THE WORKSHOP IT SELF WAS ORGANIZED BY THE BASIC AND TRANSLATIONAL RESEARCH COMIET EE THAT GERI AND I HAVE BEEN CO-CHAIRING FOR A COUPLE OF YEARS, AND WE HAVE BEEN WRESTLING WITH THIS GENERA TOPIC OF CO-MORBIDITIES FOR SOME TIME. PART OF THIS WAS DISCUSSED WITHIN THE IACC FULL COMMITTEE AND OTHER POINTS RAISED BY THE SUBCOMMITTEE, IT TOOK A WHILE TO FIX ON ACTUAL WHAT THE AGENDA SHOULD BE TO FRAME THAT A BIT FOR YOU. WE STRUGGLED WITH WHAT WE THOUGHT WERE THREE NEEDS THAT WE HEARD ABOUT, BOTH FROM THE PUBLIC AND FROM MEMBERS OF THE IACC. ONE BEING THE ABSENCE OF GUIDELINES TO GUIDE CLINICAL CARE FOR KIDS ON THE SPECTRUM AND FOR ADULTS ON THE SPECTRUM, BEYOND WHAT WE HAVE CURRENTLY FOR SLEEP, A LITTLE BIT FOR G.I. PROBLEMS AND FOR SEIZURES. AND AS WE TALKED ABOUT, THE WISH TO DEVELOP GUIDELINES IN THE IACC AND GETTING THE AMERICAN ACADEMY OF PEDIATRICS INVOLVED, OTHER GROUPS THAT COULD HELP WITH THIS, BECAUSE THE IACC IS NOT THE PLACE TO DEVELOP GUIDELINES, IT BECAME CLEAR THAT WE DON'T HAVE THE EVIDENCE BASE THAT PEOPLE WOULD NEED TO DO THAT. SO ONE ASPECT OF THIS MEETING WAS TO THINK ABOUT WHAT THAT EVIDENCE BASE COULD LOOK LIKE AND WHERE IT WOULD COME FROM AND WHAT SORTS OF STUDIES WOULD NEED TO BE DONE. THEN WE HAD TWO OTHER ISSUES THAT WE GRAPPLED WITH, ONE BEING THE SENSE THAT CAME TO THE FORE, I THINK, AS A MAJOR TOPIC, AND THAT WAS THE CONTINUING CHALLENGE OF SORT OF UNDETECTED OR UNDERRECOGNIZED CO-MORBIDITIES, AND CALLING THEM CO-MORBIDITIES BY ITSELF WAS A BIT OF A STRUGGLE, BECAUSE WE WEREN'T SURE TO WHAT EXTENT THESE WERE JUST SYMPTOMS OF CERTAIN ASPECTS OF AUTISM OR CERTAIN SUBTYPES, OR WHETHER THEY WERE LIKE THE RENAL COMPLICATIONS OF DIABETES, SOMETHING THAT OFTEN TRAVELS WITH AUTISM. WE TALKED A LOT ABOUT WHAT THOSE WOULD BE, AND AGAIN, THE CONCERN THAT WE HEARD FROM SO MANY PARENTS THAT WHEN THEIR KID WOULD DEVELOP ONE OR ANOTHER SERIOUS MEDICAL ISSUE, THAT IT WOULD BE TREATED AS -- IT WOULD BE IGNORED OR NEGLECTED BECAUSE THE CLINICIAN WOULD SAY, OH, BUT THEY HAVE AUTISM, SO IT MUST BE JUST PART OF AUTISM, RATHER THAN GETTING THE CARE THEY NEEDED. SO A LOT OF CONCERN WITH THAT. THEN THE THIRD ISSUE WAS THIS SENSE THAT SOME OF THE PEOPLE ON THE SUBCOMMITTEE HAD THAT BY ENGAGING IN A DEEP DISCUSSION ABOUT CO-MORBID ITS, WITIES, WE COULD GET INTO THE ETIOLOGY/PATHOPHYSIOLOGY OF AUTISM, PERHAPS NOT ALL OF AUTISM, BUT THAT CERTAIN KINDS OF AUTISM WOULD BE REVEALED BY TRYING TO UNDERSTAND SOMETHING AOUT THE BAYOLOGY AND THE CO-MORBID SYMPTOMS OR BIOMARKERS THAT MIGHT EMERGE OF STUDYING THIS GROUP BROADLY. SO WE KIND OF RES WER WRESTLED WITH ALL OF THESE ISSUES. YOU CAN SEE FROM THE AGENDA THERE'S A LITTLE BIT OF ALL THREE OF THEM. AGAIN, WE AREN'T GOING TO DO GUIDELINES BUT WHAT DO WE KNOW AN WHAT DO WE NEED TO MOVE FORWARD IN AREAS OTHER THAN THE THREE WHERE WE HAVE SOME GUIDELINES. THERE'S GOING TO BE MAJOR FOCUS ON THESE UNDETECTED OR UNDERREPORTED AND UNDERRECOGNIZED CO-MORBID ISSUES THAT COME UP THAT TRAVEL WITH AUTISM, AND THEN TOWARDS THE END OF THE DAY, HOPE IS THAT WE WILL HAVE MORE TIME ABOUT DOES THIS HELP US UNDERSTAND SOMETHING ABOUT MECHANISMS OF DISEASE OR ETIOLOGY. THE WAY WE'VE SET THIS UP IS HOPEFULLY TO HAVE RATHER BRIEF PRESENTATIONS, AND GERI, WELCOME, AS MY CO-CHAIR AND I WILL BE CAREFUL ABOUT THE TIME TO MAKE SURE THERE'S PLENTY OF TIME FOR DISCUSSION. AS I SAID, IACC IS REALLY HERE MOSTLY TO LISTEN AND ASK QUESTIONS AND TO DRAW YOU OUT AS EXPERTS SO WE CAN HAVE A DEEPER UNDERSTANDING OF THE PROBLEMS THAT DROVE US TO THIS WORKSHOP. SO IT WILL BE HOPEFULLY MORE OF A CONVERSATIONAL DAY AND WE'LL HAVE A CHANCE TO GET EACH OF YOU TO SAY A BIT MORE IN THESE DISCUSSION SECTIONS. SO TO JUST KIND OF ORGANIZE THE DAY A LITTLE BIT, ONE OF THE THINGS THAT THE PLANNING GROUP WANTED WAS AN OVERVIEW FROM SOME OF THE LARGE HEALTHCARE STUDIES AND LARGE POPULATION-BASED STUDIES OH GE TO GET A SENSE OF IT ISSUTHISISSUE FROM 30,000 FEET, WHAT ARE THE MAJOR ISSUES THAT WE SHOULD BE CONCERNED ABOUT IN THIS POPULATION. WE THOUGHT WE WOULD FOLLOW THAT WITH PERSPECTIVES FROM A WISE CLINICIAN, WHO WILL HOPEFULLY GIVE US SOME DIRECTION ABOUT HOW WE SHOULD BE THINKING ABOUT THE CLINICAL BURDEN AND THE CLINICAL OPPORTUNITY. I SHOULD MENTION AT THE OUTSET, BECAUSE I THINK IT WILL COME UP, THAT WE'RE LIKELY TO TALK QUITE A BIT ABOUT PSYCHIATRIC CO-MORBIDITIES. I KNOW THAT THESE USED TO BE CALLED BEHAVIORAL PROBLEMS, I JUST WANTED TO STRESS AT THE OUTSET AS THE HEAD OF NIMH THAT TODAY WE RECOGNIZE ANXIETY, DEPRESSION AND ADHD AS BRAIN DISORDERS AND NEURODEVELOPMENTAL DISORDERS EVERY BIT AS MUCH AS WE THINK THAT WAY ABOUT AUTISM ITSELF, SO PUTTING THEM INTO THAT CONTEXT, I THINK WILL BE IMPORTANT, THAT THEY'RE NOT SO MUCH MENTAL DISORDERS OR BEHAVIORAL PROBLEMS BUT ANOTHER ASPECT OF BRAIN CIRCUITRY NOT FUNCTIONING IN QUITE THE RIGHT WAY. WE'VE GOT A SECOND PANEL THAT WILL REVIEW SOME RECENT INSIGHTS ABOUT THOSE PARTICULAR CO-MORBIDITIES, AND THEN WE'LL BREAK FOR LUNCH. AFTER LUNCH, WE'RE GOING TO HEAR PUBLIC COMMENTS. YOU SHOULD HAVE ALL RECEIVED COPIES OF BOTH THE ORAL AND WRITTEN COMMENTS. I THINK SOME OF THESE WERE, IN FACT, INTENDED FOR THE IACC AND NOT SPECIFICALLY DIRECTED AT TODAY'S WORKSHOP. BUT AS YOU'LL SEE, MANY OF THEM ADDRESS SERVICE NEEDS AND SOME ADDRESS THE VACCINE ISSUES, SOME RECOMMEND SPECIFIC CAUSAL AND ENVIRONMENTAL FACTORS. THAT'S REALLY -- NONE OF THOSE ARE LIKELY OR SHOULD BE IN THE AGENDA TODAY. WHAT WE REALLY WANT YOU TO DO, THOUGH, IS TO LOOK CAREFULLY, AT LEAST MEMBERS OF THE IACC, SHOULD REVIEW THESE COMMENTS, EVEN IF WE DON'T HAVE TIME TO DISCUSS THEM TODAY, WE WON'T HAVE A LOT OF TIME GIVEN HOW MUCH WE WANT TO COVER WITHIN THE WORKSHOP. SO I HOPE -- AND I WANT TO IMPLORE YOU AND I THINK GERI WILL HELP IN THIS, TO REMAIN FOCUSED ON THE TOPIC OF CO-MORBIDITIES SO WE CAN FULFILL THE CHARGE WE HAVE FROM THE IACC TO BE ABLE TO RESPOND TO THAT PARTICULAR ISSUE OF THOSE THAT ARE ANDRECOGNIZE UNDERRECOGNIZED OR UNDERTREATED. WE'LL FOLLOW WITH PUBLIC COMMENT ON TWO PANELS ON SLEEP DISORDERS AND METABOLIC DISORDERS. HOPEFULLY WE'LL HAVE TIME FOR ABOUT AN HOUR AT THE END OF THE DAY FOR GENERAL DISCUSSION. JUST ONE OTHER COMMENT SINCE IT MAY BE ON SOME OF YOUR MINDS, WHAT HAPPENS TO THE IACC? THE MEMBERS OF THE IACC WILL FINISH THEIR TERM OF DUTY NEXT TUESDAY, IN ONE WEEK, SO THIS IS ACTUALLY THE LAST EVENT FOR THIS PARTICULAR COMMITTEE. THE CONGRESS HAS APPROVED AND THE PRESIDENT HAS SIGNED THE CARES ACT, WHICH WILL REINSTATE AN IACC, BUT WE'LL GO THROUGH THAT PROCESS OF NOMINATION AND CHARGE AND REFORMING COMMITTEE OVER THE NEXT FEW MONTHS. MY HOPE IS, OBVIOUSLY THERE WON'T BE TIME BETWEEN NOW AND NEXT TUESDAY TO DO JUSTICE TO THE MINUTES FROM TODAY AND TO ACTUALLY FORMULATE ANY KIND OF A SUMMARY OR REPORT, BUT WE CAN DO THAT EVEN AFTER SEPTEMBER 30TH AND WE'LL MAKE SURE THAT THAT'S AVAILABLE ON THE IACC WEBSITE, AND IT WILL COME BACK TO THE NEW COMMITTEE WHEN THAT NEW COMMITTEE CONVENES NEXT YEAR. SO I SHOULD JUST INTRODUCE OR HAVE HER INTRODUCE HERSELF, MY CO-CHAIR HERE, GERI DAWSON. DO YOU WANT TO SAY JUST A WORD ABOUT -- WE DID INTRODUCTIONS ALREADY. THAT'S THE MAIN REASON FOR DOING INTRODUCTIONS. >> WELL, WELCOME, EVERYONE. SO I'M GERI DAWSON, PROFESSOR OF PSYCHIATRY AND BEHAVIORAL SIGH EBBS AND NOW PSYCHOLOGY AND NEUROSCIENCE AT DUKE UNIVERSITY AND DIRECTOR OF THE DUKE CENTER ON AUTISM AND BRAIN DEVELOPMENT, AND I JUST WANT TO WELCOME EVERYONE HERE. WE'RE SO EXCITED ABOUT TODAY, AND JUST TO SAY THAT THIS IS A TOPIC THAT IS OF TREMENDOUS INTEREST TO PARENTS, WE'VE HEARD SO MUCH ABOUT THIS TOPIC, AND THE PUBLIC COMMENTS THAT WE'VE RECEIVED, AND ALSO THE IACC MEMBERS AND SO WE'VE REALLY BEEN LOOKING FORWARD TO THIS. I WAS JUST LOOKING AT THE GROUP OF PEOPLE THAT ARE PRESENTING TODAY, AND SO PLEASED THAT ALL OF YOU WERE ABLE TO COME AND I KNOW THAT IT'S GOING TO BE A REALLY EXCITING SET OF PRESENTATIONS AND DISCUSSION. WE HOPE TO LEARN MORE ABOUT HOW TO IMPROVE QUALITY OF LIFE BY ADDRESSING MEDICAL CO-MORBIDITIES, BUT ALSO HAVE BETTER INSIGHT INTO NEUROMECHANISMS AND FULL BODY MECHANISMS AND HOW THESE MAY PLAY A ROLE IN ETIOLOGY, BUT ALSO DEVELOPMENT IN AUTISM. SO WITH THAT, I THINK WE'RE READY TO BEGIN. >> ANY QUESTIONS BEFORE WE LAUNCH? OKAY. WELL, THANKS, ANJALI. LET'S MAKE SURE -- ARE ALL OF OUR TECHNICAL GLITCHES RESOLVED AND THIS POINT SO THE WEBSITE IS FULLY WORKING? CAN WE GET THAT? CONFERENCE CALL? THAT MEANS PEOPLE HAVE THE VIDEO BUT NOT AUDIO; IS THAT RIGHT? OKAY. DO WE HAVE ANY IDEA HOW LONG IT WILL TAKE TO GET THE CONFERENCE CALL WORKING? >> SO PEOPLE CAN JOIN BY WEBCAST. GIVEN -- THANKS, ZACH. GIVEN THE TIME, I THINK WE'D BETTER MOVE ON, AND THEN YOU CAN LET US KNOW. NOURISTHANK YOU. GREAT. PLEASURE TO INTRODUCE DR. ANJALI JAIN, WHO IS A GENERAL PEDIATRICIAN AND VICE PRESIDENT AT THE LEWIN GROUP, A HEALTH AND HUMAN SERVICES GROUP IN VIRGINIA. WE'LL TURN THIS OVER TO YOU. >> GOOD MORNING. THANK YOU FOR INVITING ME TO SPEAK HERE. I WANTED TO NOTE THAT WE HAD A HUGE DISCUSSION ABOUT WHAT TO CALL THESE CONDITIONS, AND ULTIMATELY SETTLED ONCOOCCURRING ON COOR KURRING CONDITIONS, SO THAT'S ONE POSSIBILITY. SO I'VE DISCUSSED OUR STUDY BEFORE AND I CAN CERTAINLY SPEND THE ENTIRE TIME TALKING ABOUT THE STUDY OVERALL, SO I'M GOING TO ASSUME THAT YOU'LL ASK QUESTIONS IF YOU NEED TO AND I'LL JUST GIVE A VERY BRIEF OVERVIEW OF WHAT WE AFFECTIONATELY CALL THE HEALTH OUTCOMES STUDY. IT CONSISTS OF FOUR TASKS. MOST OF WHAT I'M GOING TO BE PRETTINPRESENTING TODAY IS REALLY FROM THE FIRST TWO TASKS. TASK A IS TO REALLY JUST LOOK AT THE DATA. THIS IS A LARGE HEALTH INSURANCE CLAIMS DATA BAIT OR ADMINISTRATIVE DATABASE. THE FIRST PART WAS TO IDENTIFY CHILDREN WITH AUTISM AS WELL AS THEIR FAMILY MEMBERS, AND ALSO IDENTIFY A CONTROLLED GROUP OR COMPARISON GROUP OF CHILDREN AND THEIR FAMILY MEMBERS. PART OF THAT, OF COURSE, WAS TO VALIDATE THEIR A.C. DIAGNOSES USING A CHART STUDY. IN TASK B, WE COMPARED OVERALL VERY DESCRIPTIVELY THE HEALTH OUTCOMES OF CHILDREN WITH ASD AND WITHOUT ASD AS WELL AS THAT OF THEIR FAMILY MEMBERS. TASKS C AND D LOOKED AT ETIOLOGIC RISK FACTORS, WHICH I WON'T BE DISCUSSING HERE TODAY. SO THIS IS THE RESEARCH CLAIMS DATABASE. THE GROUP INVOLVED WAS US AS LEWIN AND OP TIM, OUR PARENT COMPANY NOW, AS WELL AS CRAIG SCHAEFER AND HIS COLLEAGUES AT DREXEL UNIVERSITY, WHO WAS THE MAIN CORE OF THE TEAM. SO WE HAD MEDICAL AND PHARMACY CLAIMS AND LINKED ENROLLMENT INFORMATION FROM 1993 TO PRESENT. FOR THIS PARTICULAR, THE RESULTS I'M PRESENTING TODAY, THE RESULTS ARE FROM 2001 TO 2010. THE DATABASE ITSELF IS GEOGRAPHICALLY DIVERSE ACROSS THE UNITED STATES, IT'S FAIRLY REPRESENTATIVE, HAS A LITTLE MORE IN THE NORTHEAST AND THE SOUTH COMPARED OH TO THE WEST, FOR INSTANCE, AND IT ALSO IS LINKED TO A SOCIODEMOGRAPHIC MARKETING DATABASE, SO WE WERE ABLE TO GET PERSON AND HOUSEH LEVEL DATA ON SOCIOECONOMIC CHARACTERISTICS, AS WELL AS A MATCH FOR SOME OF THE OTHER BASIC SOCIODEMOGRAPHIC CHARACTERISTICS FOR THE POPULATION. THIS JUST GIVES YOU A SENSE OF THE NUMBERS, WHICH ARE -- START OUT VERY LARGE AND GET SMALLER PRETTY QUICKLY, BUT STILL END UP QUITE SIZABLE. SO THE DATABA OVERALL DURING THIS TIME PERIOD HAS ABOUT 62 MILLION INDIVIDUALS, THIS IS ADULTS AND CHILDREN. AND IF ONCE YOU REQUIRE THEM TO HAVE ABOUT SIX MONTHS OF COVERAGE OR MORE, THAT NUMBER CUTS DOWN TO ABOUT HALF OR 30 MILLION. IT'S 9 1/2 MILLION OR SO OF THOSE ARE KIDS, MEANING THEY'RE IN THE DAY A BASE FROM AGE ZERO TO AGE 20. PLAWSH AT THE BEGINNINAT THE BEGINNING OF THEIR FOLLOW-UP PERIOD. WE WERE EXPLICITLY NOT STU EING RET'S SYNDROME AND ENDED UP WITH ABOUT 46,000 CHILDREN THAT HAD EVIDENCE OF ASD. WHAT I MEAN BY ASD IS THEY HAD AT LEAST ONE CLAIM WITH AN ICD9 CODE. FOR ONE OF THE ASPERGER'S, AUTISM AND ADDS CODE. WE ALSO POLLED THEIR SIBLINGS AND PARENTS AND AS WELL AS A 3 TO 1 COMPARISON GROUP. BECAUSE THEY WERE ON THE SAME HEALTH PLAN, WE WERE ABLE TO DO THAT AGAINST THE FAMILY LEVEL CHARACTERISTICS. I WILL BE PRESENTING A LITTLE BIT OF THAT DATA. BASED ON THE CHART, WE DECIDED FOR MOST OF OUR MULTIVARIABLE ANALYSIS AND MORE DETAILED ANALYSIS THAT WE WERE GOING TO STICK TO -- THOSE KIDS, WE'RE CALLING LIKELY AUTISM VERSUS THE O ARE PROBABLE OR POSSIBLE AUTISM. SO YOU'LL JUST SEE THAT TERM IT NOLTERMINOLOGY USE THE IN THE NEXT FEW SLIDES. SO TO LOOK AT CO-MORBID ITS OR CO-OCCURRING CONDITIONS, THE FIRST THING WE DID IS USED THE ARC CLINICAL CLASSIFICATION SOFTWARE WHICH BASICALLY GROUPS DOWN GROUPS OF ICD9 CODES INTO VARIOUS CATEGORIES, AND IN GENERAL, THIS SLIDE SHOWS CONTINUE WITH AUTISM EITHER LIKELY OR POSSIBLE, HAD GREATER RATES OF ALMOST EVERY GROUP OF CONDITIONS COMPARED TO THE COMPARISON GROUP. SOME OF THE CODES THAT FALL INTO THESE VARIOUS CATEGORIES ARE NOT VERY INTUITIVE, AND SO WE DID LOOK AT GROUPS OF CODE SEPARATELY AS WELL AS DEVELOPED OUR OWN SORT OF WORKING MODEL FOR A CLINICAL CO-MORBID IT INDEX TO USE HA IN CHILDREN, AND I'LL PRESENT THOSE RESULTS SHORTLY. SO LOOKING FIRST AT SOME OF THE MENTAL AND BEHAVIORAL HEALTH CO-MORBIDITIES, SO AS YOU CAN SEE HERE, THE LIKELY GROUP, AGAIN, THIS IS TWO CLAIMS, SO THEY'RE SORT OF -- MORE DEFINITELY HAVE AN AUTISM SPECTRUM DISORDER. POSSIBLE GROUP WITH THE ONES WITH ONLY ONE CLAIM, PROBABLE ARE THE GROUP ALL TOGETHER OR TOTAL ASD, AND THEN HERE'S THE COMPARISON GROUP. SO AS YOU CAN SEE, THE NUMBERS ARE LARGE, AND IF YOU JUST COMPARE TOTAL, TO COMPARISON, YOU CAN SEE THAT THE PREVALENCE IN THE DATASET OF ANXIETY, ATTENTION DEFICIT, BIPOLAR, ALL OF THESE DISORDERS ARE MUCH HIGHER PREVALENCE THAN IN THE COMPARE SOF GROUP. I DON'T THINK THERE'S ANY HUGE SURPRISES HERE. ONE THING YOU MIGHT NOTE IS THAT THE RATE OF INTELLECTUAL DISABILITY IS QUITE LOW COMPARED TO WHAT WE THINK IT PROBABLY IS, AND I THINK THAT'S A FUNCTION OF THESE BEING MEDICAL CLAIMS, SO INTELLECTUAL DISABILITY IS JUST NOT WELL CODED SO WE DON'T EXPECT THAT TO BE A VERY RELIABLE ESTIMATE. SO THIS IS -- WE WERE SEARCHING FOR AN APPROPRIATE INDEX OF CLINICAL CO-MORBIDITY IN CHILDREN AND ACTUALLY DIDN'T FIND MUCH, AND A LOT OF THAT HAS TO DO WITH CHILDREN NOT HAVING A LOT OF MORTALITY OR EVEN MORBIDITY AT A VERY HIGH RATE DURING CHILDHOOD. SO THE BEST THING WE FOUND WAS SOMETHING CALLED A CCC OR THE CLINICAL CO-MORBIDITY INDEX THAT WAS MOSTLY USED FOR CHILDREN WHO HAD SPENT A LOT OF TIME IN THE HOSPITAL ITSELF. SO WE DECIDE T DECIDED TO MODIFY THAT AND BREAK IT DOWN INTO AN ORDINAL SCALE FOR EACH OF THESE CATEGORIES, THERE WAS AN ADDITIONAL CATEGORY OF DEVELOPMENTAL DISORDERS, THAT WAS A DISEASE OF INTEREST, OF COURSE, AND WE LOOKED AT THE OVERALL CO-MORBIDITY. THIS WAS MOSTLY NEEDED AND USEFUL IN OUR STUDY SO THAT WE WERE ABLE TO CONTROL FOR SOME OF THESE OTHER CONDITIONS WHEN WE WERE LOOKING AT OTHER HEALTH OUTCOMES AND AS WELL AS UTILIZATION. SO HERE WE ALSO GROUPED CO-OCCURRING CONDITIONS OR CO-MORBIDITIES INTO SEVERAL DIFFERENT CATEGORIES, AND THESE HAVE THEIR OWN SET OF ICD9 CODES. I DO HAVE SOME HANDOUTS THAT LIST THOSE CODES. IF ANYONE IS INTERESTED. BUT FOR THESE MAIN GROUPS OF CONDITIONS, WE COMPARE CHILDREN WITH ASD TO COMPARISON GROUPS, AND AGAIN FOUND MUCH HIGHER RATES OF INFECTIOUS DISEASES, NEUROLOGICAL, NEURODEVELOPMENTAL DISORDERS, MENTAL HEALTH CONDITIONS, METABOLIC DYSFUNCTION, AUTOIMMUNE DISORDERS, CONGENITAL AND GENETIC DISORDERS, AND GASTROINTESTINAL NUTRITIONAL DISORDERS. ONE OF THE THINGS I THINK SUCH A LARGE AND HETEROGENUS DATASET DOES IT SORT OF NARROWS THE RANGE OF PREVALENCE FOR THESE CONDITIONS. IF YOU LOOKED AT THE LITERATURE PREVIOUSLY, YOU WOULD GET SOMETHING LIKE BETWEEN 9 AND 80% OF CHILDREN HAVE -- SO I THINK THIS GIVES US A LITTLE BIT MORE OF A HANDLE ON WHAT KIND OF THE NORM IS. SOMETHING LIKE INFECTIOUS DISEASES IS NOT IMMEDIATELY OBVIOUS WHY CHILDREN WITH AUTISM WOULD HAVE THEM IN SUCH A GREATER QUANTITY SO THOSE ARE SOME OF THE UNDERRECOGNIZED CONDITIONS THAT WE DON'T QUITE UNDERSTAND BUT MIGHT GIVE US A HANDLE OF WHAT'S GOING ON. THE CO-MORBIDITY SCORE WAS LOW ACROSS THE BOARD BUT STILL MUCH HIGHER IN CHILDREN WITH AUTISM COMPARED TO THE COMPARISON GROUP. SO THIS IS SIBLINGS, SO THESE ARE ALL THE SIBILITIES OF THE CHILDREN WITH ASD COMPARED TO THE SIBILITIES OF THE COMPARISON GROUP. SO THE CHILDREN THEMSELVES AS WELL AS THE CHILDREN IN THE COMPARISON GROUP WERE NOT INCLUDED IN THIS ANALYSIS. SO AS YOU CAN SEE, THE SIBLINGS ALSO HAVE HIGHER RATES OF JUST ABOUT EVERYTHING. NOT CLOSE TO WHAT THE CHILDREN WITH AUTISM HAVE, BUT STILL CONSIDERABLY HIGHER, AND I THINK THAT THIS KIND OF IS PROVOCATIVE IN THE SENSE THAT IT GIVES -- STARTS TO GIVE US A SENSE OF WHAT MIGHT BE BIOLOGIC, WHAT MIGHT BE ENVIRONMENTAL, WHAT MIGHT BE GOING ON AND ARE THESE THE SAME CONDITIONS THAT THEY'RE HAVING WITH THEIR SIBLINGS OR ARE THEY DIFFERENT CONDITIONS. SO I THINK THAT THIS DATA CAN BE EXPLORED. AND CERTAINLY THE IDEAS CAN BE. AND AGAIN, THEIR CO-MORBIDITY SCORE WAS ALSO HIGHER BUT ONLY A LITTLE BIT HIGHER. THIS IS ACTUALLY NOW PUBLISHED AS A PAPER, INCLUDING INJURIES IN CHILDREN WITH AUTISM. WE CONFIRMED WHAT'S FOUND IN THE LITERATURE IS THAT CHILDREN WITH AUTISM HAVE MORE INJURIES THAN CHILDREN WITHOUT. HOWEVER, WHAT WE FOUND IN OUR ANALYSIS IS A LOT OF THAT DIFFERENCE IS REALLY EXPLAINED BY CO-OCCURRING CONDITIONS. SO THAT REALLY MAKES YOU THINK TIES ABOUT HOW INTERVENTION AS WELL AS THE MECHANISM OF THE INJURY, AND FOR ANY INJURY EXPERTS, INJURIES VARY HUGELY BY AGE GROUP. SO WE DID DO A MORE DETAILED ANALYSIS ON INJURIES IN CHILDREN WITH AUTISM BY AGE GROUP COMPARED TO THOSE WITHOUT AND INDEED PO FOUND THAT INJURIES ARE MUCH HIGHER COMPARED TO YOUNGER KIDS, CHILDRN WITHOUT AUTISM, BUT THEY'RE ACTUALLY MUCH LOWER IN TEENAGERS. A LOT OF THAT IS EXPLAINED BY FEWER MOTOR VEHICLE ACCIDENTS. SO ONE OF THE THINGS THAT WAS REALLY PERPLEXING ABOUT HOW TO ADEQUATELY CONTROL IS THIS ISSUE OF SURVEILLANCE BIAS. SO CHILDREN WITH A CHRONIC CONDITION LIKE AUTISM OR GETTING MORE HEALTHCARE, SURE ENOUGH, OUR DATASET ON AVERAGE THE CHILDREN WITH AUTISM HAD -- HAD LONGER CONTINUOUS ENROLLMENT PERIODS, SO THEIR ENROLLMENT PERIOD ON AVERAGE WAS ABOUT THREE YEARS IN THE DATA, WHEREAS THE COMPARISON GROUP WAS ABOUT 2 YEARS. SO ONE OF THE PROBLEMS WITH ANY STUDY OF CO-OCCURRING OR CO-MORBID CONDITIONS, I THINK IS TRYING TO UNDERSTAND THE EXTENT TO WHICH THINGS ARE BEING PICKED UP VERSUS CO-OCCURRING. ONE OF THE THINGS WE DID IS -- THIS IS A VERY CRUDE MARKER BUT WE USE PREVENTL PREVENTIVE VISITS AS A MARKER OF HEALTHCARE USERS. WE FOUND AT LEAST FOR THE CHRONIC CONDITIONS, IT DIDN'T CHANGE THE RESULTS SIGNIFICANTLY. HOWEVER, WHEN WE LOOK AT THINGS LIKE OTITIS MEDIA, SURVEY LNS TENDED TO PLAY A HUGE ROLE IN TERMS OF HOW OFTEN THEY'RE PICKED UP. SO ANY SORT OF FURTHER RESEARCH OF CO-OCCURRING CONDITION, WE NEED TO PAY REALLY CLOSE ATTENTION TO THIS ISSUE, AND THE EXTENT TO WHICH WE'RE DIAGNOSING THINGS VERSUS ACTUALLY OCCURRING AT INCREASED RATES. TH IS JUST SOME OF THE GEOGRAPHIC DIFFERENCES I WANTED TO HAVE AVAILABLE IN CASE ANYONE HAS QUESTION, BUT YOU CAN SEE THE ENROLLMENT TIMES, FOR INSTANCE, VARY QUITE A BIT. JUST A COUPLE QUESTIONS. ONE OF THE THINGS THAT I THINK SUCH A LARGE AND HETEROGENEOUS DESCRIPTIVE DATABASE DOES IS IT ALLOWS US TO POTENTIALLY OBSERVE WHAT'S GOING ON IN TERMS OF THE OCCURRENCE OF CO-MORBID CONDITIONS AS WELL AS POTENTIALLY USE SOME OF THE NEWER DATA MINING TECHNIQUES TO TRY TO GET A SENSE WHICH THERE MIGHT BE CHILDREN WHERE CONDITIONS ARE CLUSTERING TOGETHER, AND THAT MIGHT HELP US TO UNDERSTAND BOTH AUTISM ITSELF AND ITS MANIFESTATIONS BUT ALSO PARTICULARLY HOW TO INTERVENE APPROPRIATELY IN DIFFERENT GROUPS OF CHILDREN. THEN I ALREADY BROUGHT UP EXTENT TO WHICH THE PATTERNS OF C CONDITIONS IN FAMILI MIGHT BE HELPFUL FOR US TO UNDERSTAND BOTH ETIOLOGY AND THE ABILITY TO INTERVENE. HOW AM I DOING ON TIME? >> YOU'VE GOT A MINUTE OR TWO LEFT. >> OKAY. THANK YOU. >> ALL SET? THANK YOU. [APPLAUSE] WE'LL COME BACK WITH QUESTIONS AT THE END, WHEN WE'VE GOT SOME TIME FOR THE WHOLE PANEL, SO -- OUR NEXT SPEAKER IS LISA CROEN, AND AS YOU HEARD LISA ALREADY INTRODUCED HERSELF AS SENIOR RESEARCH SCIENTIST AT THE DIVISION OF RESEARCH AT KAISER PERMANENTE OF NORTHERN CALIFORNIA. SHE'S DIRECTOR OF THE AUTISM RESEARCH PROGRAM AND WELL-KNOWN TO MOST OF THE PEOPLE IN THE ROOM THROUGH HER WORK ON EPIDEMIOLOGY AND MANY OTHER AREAS. WELCOME. >> THANK YOU. SO I'M GOING TO TALK -- THIS IS A NICE COMPANION TO THE LAST SPEAKER, A SIMILAR KIND OF STUDY DESIGN, CO-OCCURRING CONDITIONS, PSYCHIATRIC AND MENTAL CONDITIONS AMONG ADULTS WITH AUTISM, JUST A VERY QUICK BACKGROUND. WE KNOW CHILDREN AND WE'RE LEARNING TODAY AND MANY OF US KNOW ALREADY, CHILDREN WITH ASD HAVE INCREASED RATES OF MEDICAL AND PSYCHIATRIC CONDITIONS, EVERYTHING FROM G.I. PROBLEMS TO SLEEP DISTURBANCES TO SEIZURE, MITOCHONDRIAL CONDITION, INFECTION, ALLERGY, ASTHMA, AND PSYCHIATRIC DISORDERS. CDREN -- THE RATES OF AUTISM. THE PREVALENCE IS GOING UP DRAMATICALLY. LATEST FIGURE ARE 1 IN 68, AND KIDS BECOME ADULTS, AND SO WE NEED TO FIND OUT WHAT'S HAPPEN HAPPENING WITH AUTISTIC ADULTS. THERE'S NOT MUCH INFORMATION, THERE HAVE BEEN A FEW STUDY,E IN PARTICULAR THAT WAS LARGE THAT DR. COHANI, I THINK, WILL SPEAK ABOUT HIS STUDY THAT ID SOME ADULTS. MOST OF THE STUDIES IN ADULTS HAVE BEEN VERY LIMITED IN SIZE AND SCOPE AND AGE GROUP. THEY FOCUSED ON THE YOUNGER ADULTS. SO WHAT WE DID IS USED THE DATA THAT ARE COLLECTED ROUTINELY AS MEMBERS OF KAISER COME IN FOR THEIR ROUTINE CARE, AND IT'S A VERY LARGE DATASET, THE MEMBERSHIP IN NORTHERN CALIFORNIA IS ABOUT 3 1/2 MILLION, BOTH KIDS AND ADULTS WE L AT KIDS WITH AUTISM SPECTRUM DISORDER DIAGNOSIS. THIS STUDY ALSO LOOKED AT HEALTHCARE UTILIZATION, AND WE ALSO DID A SURVEY OF THE ADULT PROVIDERS, WHICH IN THOSE LAST TWO, I WON'T BE SPEAKING ABOUT. WHAT THE PROVIDERS TOLD US ABOUT THEIR KNOWLEDGE AND EXPERIENCE WITH AUTISM WAS VERY CRITICAL, I THINK, TO WHERE WE NEED TO MOVE THE FIELD FORWARD. SO I'LL BE FOCUSING ON THE HEALTH STATUS. THE STUDY WAS DESIGNED TO LOOK AT ADULT MEMBERS 18 OR OLDER WHO WERE MEMBERS OF KAISER PERMANENTE IN NORTHERN CALIFORNIA FOR AT LEAST NINE MONTHS PER YEAR OVER A FIVE-YEAR PER SO THIS ADDRESSES SOME OF THE SURVEILLANCE BIAS ISSUES THAT DR. JAIN JUST MENTIONED, SO WE ONLY FOCUSED ON PEOPLE WHO HAD THE SAME AMOUNT OF MEMBERSHIP, ALMOST FULL MEMBERSHIP OVER A FIVE-YEAR PERIOD AND WE IDENTIFIED ADULTS WITH SPECTRUM DIAGNOSIS. WE REQUIRED AT LEAST TWO DIAGNOSES IN THE MEDICAL RECORD ANY TIME THROUGH THE END OF THE STUDY PERIOD, AND WE RANDOMLY SAMPLED A CONTROL GROUP, A COMPARISON GROUP, THESE WERE THE SAME ADULT MEMBERS IN THE SAME STUDY PERIOD, WHO NEVER HAD AN ASD DIAGNOSIS RECORDED IN THEIR RECORD. THEY WERE MATCHED TO THE CASES ON THE TOTAL LENGTH OF KPNC MEMBERSHIP, SEX AND AGE. SO WE TRIED TO EQUALIZE AS MUCH AS POSSIBLE. IN TERMS OF DEFINING THEIR HEALTH STATUS, WE LOOKED AT ALL CONDITIONECONDITIONS RECORDED IN THE ELECTRONIC MEDICAL RECORD IN THIS FIVE-YEAR PERIOD BETWEEN 2008 AND 2012. WE USED A VARIETY OF DIFFERENT STRATEGIES TO COME UP WITH DIAGNOSTIC CATEGORIES, USING VALIDATED ALGORITHMS THAT USED A COMBINATION OF ICD9 CODES, LAB RESULTS AND MEDICATION THAT OTHER INVESTIGATORS HAD DEVELOPED FOR SPECIFIC CONDITIONS THAT THEY STUDY WITHIN OUR POPULATION, SO THESE HAD BEEN VALIDATED AGAINST OUR CHART REVIEW LOOKING AT MEDICAL RECORDS AND COMPARING TO CLINICAL EXAMS. WE ALSO HAVE A VERY LARGE AND LONG-STANDING CANCER REGISTRY AND DIABETES REGISTRY, SO FOR THOSE CONDITIONS, WE LINKED OUR STUDY POPULATION TO THOSE REGISTRIES TO DETERMINE CANCER AND DIABETES PREVALENCE. THEN FOR OTHER CONDITIONS, WE BASED GROUPINGS ON THE PHENOME WIDE -- TAKING THE ICD-9 CODES AND COMES UP WITH A WAY OF GROUPING THEM INTO SPECIFIC CONDITIONS. IN TERMS OF DETERMINING OBESITY, WE USED THE BODY MASS INDEX CALCULATED AT EACH OFFICE VISIT IN THIS FIVE-YEAR PERIOD AND TOOK THE HIGHEST ONE THAT HAD BEEN MEASURED OVER THIS FIVE-YEAR PERIOD. WE ALSO HAD SELF-REPORTED ALCOHOL AND SMOKING, AGAIN, THAT IS ASKED OF EACH PATIENT WHEN THEY COME IN FOR THEIR CARE SO THIS IS DO YOU CURRENTLY SMOKE, DO YOU CURRENTLY DRINK. SO A LITTLE BIT ABOUT THE POPULATION, WE IDENTIFIED ABOUT 1500 ADULTS WITH AN ASD DIAGNOSIS, AND 10 CONTROLS OR COMPARISON ADULTS FOR EVERY CASE, 15,000. THE MEAN AGE OF THIS POPULATION WAS ABOUT 29. BUT ABOUT A QUARTER WERE OVER 35 AND ABOUT 10% WERE OER THE AGE OF 50. SO I THINK THIS POPULATION IS ON THE -- IS OLDER THAN OTHER POPULATIONS THAT HAVE BEEN REPORTED ON IN TERMS OF ADULTS WITH AUTISM. WE HAVE A PRETTY DIVERSE GROUP IN TERMS OF RACE AND ETHNICITY. ABOUT THREERK, 75% WERE MEN, AND THE OTHER 25% WERE WOMEN, WHICH IS WHAT WE WOULD EXPECT EXPECT. IN TERMS OF THE PHENOTYPE OF THE AUTISM, ABOUT 37% HAD A DIAGNOSIS OF AUTISTIC DISORDER, ANOTHER 30% ASPERGER'S SYNDROME, AND THE OTHER THIRD, YOU COULDN'T TELL FROM THEIR RECORD, IT WAS A COMBINATION, YOU KNOW, OVER THE COURSE OF THE MANY DIAGNOSES, THERE WERE BOTH AUTISM AND ASD AND AUTISTIC DISORDER, SO IT JUST WASN'T CLEAR WHAT EXACTLY THE DIAGNOSIS WAS. IN THIS POPULATION IN TERMS OF INTELLECTUAL DISABILITY OF ALMOST 20%, 19% OF THIS POPULATION HAD IN THERE AN INDICATION IN THEIR MEDICAL RECORD OF INTELLECTUAL DISABILITY. AGAIN, I THINK THIS IS AN UNDERASCERTAINMENT FOR THE REA THAT DR. JAIN MENTIONED. THESE ARE MEDICAL RECORDS AND IS OFTEN NOT RECORDED IN THESE RECORDS. SO NOW I'M GOING TO SHOW YOU A SERIES OF BAR GRAPHS THAT LOOK LIKE THIS AND JUST TO ORIENT EVERYBODY TO THE GRAPH, WE HAVE PERCENT ALONG THE VERTICAL AXIS, THE Y AXIS, AND A SPECIFIC CONDITION ALONG THE HORIZONTAL OR X AXIS, AND SO THESE ARE BASICALLY THE RATE OR THE PERCENT OR THE PREVALENCE OF THE CONDITION. IN THE BLUE BAR IN THE ADULTS WITH ASD AND IN THE RED BAR, IT'S THE COMPARISON GROUP. AND THE OR IS THE ODDS RATIO, SO IN ADDITION TO COMPARING JUST THE STRAIGHT UPPER SENT OF THESE CONDITIONS BETWEEN THE CASE GROUP AND THE CONTROL GROUP, WE DID A MULTIVARIABLE ANALYSIS WHERE WE ESTIMATED AN ODDS RATIO, AND THIS IS AFTER ADJUSTING FOR SEX, AGE AND RACE ETHNICITY. SO THESE ARE ADJUSTED, SO AN OR OF 3.7 MEANS THE CASES ARE 3.7 TIMES AS LIKELY TO HAVE AN ANXIETY DIAGNOSIS RECORDED IN THEIR MEDICAL RECORD AS THE COMPARISON GROUP, AND THIS IS AFTER ADJUSTING FOR ANY DIFFERENCES BETWEEN THE TWO GROUPS, AGE, SEX AND RACE ETHNICITY. SO WHAT YOU'LL NOTICE AS I GO THROUGH THESE IS THAT THERE'S A SUBSTANTIAL EXCESS OR INCREASED RATE OF ALMOST EVERY CONDITION THAT WE LOOKED AT, IN THE AUTISTIC ADULTS COMPARED TO THE COMPARISON ADULTS. THIS FIRST SLIDE SUMMARIZES THE INDIVIDUAL PSYCHIATRIC CONDITIONS THAT WE LOOKED AT. THERE'S TWO TAKE HOME MESSAGES, ONE IS THE OVERALL -- LOOK AT THE HEIGHT OF THE BARS AND LOOKING AT THE PREVALENCE OF THE CONDITION IS REALLY STRIKINGLY HIGH. THESE AGAIN ARE BASED NOT ON SELF-REPORT BUT BASED ON MEDICALLY RECORDED DIAGNOSES BY PHYSICIAN. SO FOR EXAMPLE, ANXIETY OCCURRED -- WAS DIAGNOSED IN ABOUT 29% OF THE AUTISTIC ADULTS VERSUS MAYBE EIGHT, 9% IN THE NON-AUTISTIC ADULTS. SO 29% ANXIETY, 25, 26% DEPRESSION DIAGNOSIS, AND CAN YOU GO ON DOWN THE LINE HERE, SCHIZOPHRENIA, DISORDERS, WERE ABOUT 8, 9% DIAGNOSED IN THE AUTISTIC GROUP, ON SE SIEVE COMPULSIVE DISORDER, 8%. SUICIDE ATTEMPTS WERE ON THE ORDER OF ABOUT 3% IN THE AUTISTIC ADULT POPULATION. THIS IS ABOUT A FIVE FOLD HIGHER RATE COMPAR TO THE NON-AUTISTIC ADULT. SO QUITE HIGH BURDEN OF PSYCHIATRIC CONDITIONS. INTERESTING DRUG AND ALCOHOL USE, THESE ARE AGAIN DIAGNOSES OF ABUSE OR DEPEND WERE SIGNIFICANTLY LOWER IN THE AUTISTIC GROUP THAN THE COMPARISON GROUP. THE SAME CONDITIONS SHOW UP AS BEING IN EXCESS IN ADULTS. GASTROINTESTINAL DISORDERS, THIS WAS A WHOLE SLEW OF DIFFERENT CONDITIONS, I JUST GROUPED THEM INTO ONE BIG CATEGORY HERE. NEARLY 35% OF AUTISTIC ADULTS WERE DIAGNOSED WITH SOME KIND OF GASTROINTESTINAL DISORDER IN THIS FIVE-YEAR PERIOD. AND IT'S SIGNIFICANTLY ELEVATED COMPARED TO THE CONTROLS. ALLERGY WAS QUITE COMMON, AUTOIMMUNE DISEASES WERE COMMON, ASTHMA, SLEEP DISORDERS, WE'LL HEAR A LOT MORE ABOUT THAT LATER, WERE QUITE COMMON AND ALMOST TWO TIMES AS LIKELY TO BE DIAGNOSED IN THE AUTISTIC ADULTS AS THE NON-AUTISTIC ADULTS. AND THYROID DISEASE ALSO WAS SIGNIFICANTLY ELEVATED. AND THESE ARE -- SO THESE ARE ALL SIGNIFICANTLY ELEVATED, THE ONES I'VE SHOWN HERE STATISTICALLY SIGNIFICANT. IN TERMS OF METABOLIC CONDITIONS, AND I THINK THIS IS A SPECIAL INTEREST FOR THIS MEETING BECAUSE THESE ARE -- MOST OF THE DATA THAT ARE PUBLISHED HAVE NOT ADDRESSED OBESITY, THERE'S SOME GROWING BODY OF RESEARCH SHOWING OBESITY IS MORE COMMON IN CHILDREN AND ADOLESCENTS WITH AUTISM, WE FIND ALSO SIGNIFICANTLY HIGHER RATES OF OBESITY IN ADULTS AS WELL. THE HYPERTENSION, DYSLIPIDEMIA, DIABETES, THESE ARE OFTEN CONDITIONS THAT OCCUR AND ARE DIAGNOSED LATER IN LIFE AND WE DON'T HAVE MUCH DATA ON THIS YET. WE'RE FINDING THAT VERY HIGH RATES OF THESE KIND OF CHRONIC SERIOUS MEDICAL CONDITIONS THAT ARE OFTEN PRECURSORS TO OTHER MORE SERIOUS LIFELONG CONDITIONS. SIGNIFICANTLY HIGHER RATES IN ADULTS WITH AUTISM. THESE ARE OTHER MEDICAL CONDITIONS THAT WERE LESS COMMON, BUT AGAIN, SORT OF ACROSS THE BOARD, ACROSS EVERY SYSTEM, WE SEE SIGNIFICANTLY INCREASED RATES IN ADULTS WITH AUTISM. HERE IS NEUROLOGIC CONDITIONS, EPILEPSY, SEIZURE DISORDER WAS QUITE A BIT MORE COMMON IN THE AUTISTIC ADULTS. OTHER DISORDERS OF THE CENTRAL NERVOUS SYSTEM. STROKE, PARKINSON'S, AND DEMENTIA, ALL OCCURRED MUCH LESS FREQUENTLY, BUT AGAIN SIGNIFICANTLY ELEVATED IN THE AUTISTIC ADULTS. AGAIN, LIKE THE ALCOHOL ABUSE AND DEPENDENCY, THIS IS THE SELF-REPORTED ALCOHOL AND TOBACCO USE AND WE SEE SIGNIFICANTLY REDUCED RATES OF SMOKING AND ALCOHOL IN AUTISTIC ADULTS, WHICH IS VERY INTERESTING, AND WE KNOW THESE BEHAVIORS OR RISK FACTORS FOR HYPERTENSION, OBESITY, CHRONIC CONDITIONS, THESE BEHAVIORS WERE MUCH LESS COMMON IN THE AUTISTIC POPULATION. SO OF ALL OF THE CONDITIONS WE LOOKED AT, THESE WERE THE ONLY CONDITIONS THAT WERE SIGNIFICANTLY LESS COMMON, COMMONLY DIAGNOSED IN THE ADULTS WITH AUTISM. SO INFECTION WAS A LITTLE BIT LESS COMMONLY DIAGNOSED, MIGRAINE HEADACHES, GENITAL-URINARY DISORDERS AND CANCER. THE CANCER FINDING, I THINK IS VERY INTERESTING. I DON'T KNOW WHAT IT MEANS. THE NUMBERS WERE VERY LOW SO IT WAS HARD TO REALLY GO INTO THIS IN DEPTH. WE DID TRY TO LOOK AT AGE AT FIRST DIAGNOSIS OF CANCER AND STAGE AT FIRST DIAGNOSIS OF CANCER, AND THERE WAS A LITTLE BIT OF AN INDICATION THAT THE STAGE AT WHICH THE CANCER WAS FIRST DIAGNOSED WAS MORE ADVANCED IN THE AUTISM GROUP THAN THE NON-AUTISM GROUP, BUT THIS AGAIN IS -- TAKE THIS WITH A BIG GRAIN OF SALT BECAUSE THE NUMBERS WERE FAIRLY LOW, BUT I THINK THIS IS -- IN TERMS OF LOOKING FURTHER INTO ETIOLOGY AND WHAT MAY BE SHARED BETWEEN AUTISM AND NON-AUTISM, THIS MIGHT BE AN AREA TO LOOK AT. AM I RUNNING OUT OF TIME, GERI? OKAY. SO IN SUMMARY, THERE'S EVIDENCE FOR INCREASED RATES OF MANY OF THESE HEALTH CONDITIONS. WE DID KNOW THERE'S SOME EVIDENCE FOR COMMON BIOLOGIC CAUSES. THERE'S BEEN SOME NICE GENETIC WORK LOOKING AT SUSCEPTIBILITY, AND SNPs, POLYMORPHISM ACROSS SEVERAL PSYCHIATRIC DISORDERS INCLUDING AUTISM. WE KNOW OBESITY IS A RISK FACTOR FOR SEVERAL CHRONIC CONDITIONS, WE SEE OBESITY IS VERY HIGH IN THIS POPULATION. I THINK WE CAN SAY PRETTY CERTAINLY THAT THE COMMUNICATION AND SOCIAL IMPAIRMENTS AND SENSORY ISSUES MAY IMPEDE PREVENTIVE HEALTH, AND EARLY DIAGNOSIS AND TIMELY TREATMENT, AND THIS WOULD BE AN AREA FOR FURTHER RESEARCH. I THINK IT'S CLEAR THAT NUTRITION AND EXERCISE ARE VERY MUCH RELATED TO HEALTH AND THE NEED FOR HEALTH EDUCATION AND LIFESTYLE INTERVENTIONS EARLY ON IN LIFE TO MAKE SURE THAT CHILDREN ENTER ADULTHOOD WITH GOOD NUTRITION AND, REDUCE RISK FACTORS FOR CHRONIC ILLNESSES. THE BETTER INTEGRATION OF PEOPLE WITH ASD IN ALL ASPECTS OF SOCIETY TO REDUCE SOCIAL ISOLATION AND DISCRIMINATION, WHICH WE KNOW THE SOCIAL ISOLATION CAN BE RELATED TO MANY OF THESE DISEASES, ESPECIALLY ANXIETY, DEPRESSION AND THE PSYCHIATRIC PROBLEMS WE SEE. SO THESE ARE SOME RESEARCH OPPORTUNITIES THAT I THINK WE HAVE BEFORE US, UNDERSTANDING ALL OF THE DIFFERENT IMPLICATIONS, SOCIAL, HEALTHCARE AK CYST AND BIOLOGIC MECHANISMS THAT UNDERLIE THE INCREASED RATES OF THESE MEDICAL AND PSYCHIATRIC CONDITIONS, AND UNDERSTANDIN HOW PHYSICIANS MANAGE CHRONIC DISEASE IN ADULTS WITH ASD. THEN FINALLY COMING UP WITH IMPROVED STRATEGIES FOR DELIVERING HEALTHCARE TO THIS POPULATION IS VERY MUCH NEEDED. SO THANK YOU VERY MUCH. [APPLAUSE] >> THANKS VERY MUCH. A LOT MORE TO TALK ABOUT, SO LOOKING FORWARD TO THE DISCUSSION SECTION. PLEASURE TO INTRODUCE SAAC KOHANE FROM HARVARD MEDICAL SCHOOL, PROFESSOR OF PEDIATRICS IN HEALTH SCIENCES AND TECHNOLOGY, AS WELL AS DIRECTOR OF HARVARD UNIVERSITY'S COUNT COUNTWAY LIBRARY OF MEDICINE, DIRECTOR OF THE CHILDREN'S HOSPITAL INFORMATICS PROGRAM. MANY OTHER THINGS. >> THANK YOU VERY MUCH, I'M VERY EXCITED TO BE HERE. JUST ALREADY LISTENING TO THE FIRST COUPLE OF TALKS, I AM JUST FASCINATED TO BE ABLE TO PARTICIPATE IN THIS MEETING WHERE WE'RE LOOKING AT ALL DIFFERENT ASPECTS OF THIS BEAST, THIS BEAST, THIS COLLECTION OF SYMPTOMS AND PATHOLOGY THAT MAKE UP THIS THING THAT WE CALL AUTISM. AND I THINK IN SOME WAYS, WE'RE VERY MUCH LIKE WE WERE WHERE WE CALLED HEART FAILURE DROP SEED AND DID NOT UNDERSTAND IT WAS AN INFECTIOUS MYOCARDITIS, ATHEROSCLEROSIS BASED HEART FAILURE, TRAUMATIC HEART FAILURE, THAT THERE WAS STRUCTURAL PROTEINS THAT WERE ABERRANT, AND WE'RE ALL CALLING THAT HEART FAILURE. SIMILARLY WE CALL ALL THESE DIFFERENT THINGS AUTISM. JUST LISTENING TO ALL THESE TALKS ALREADY, I'M SURE THERE WILL BE MORE LIKE IT TODAY, TO GET THE FEEL FOR THESE OTHER ASPECTS. AND I SHOULD SAY BY TRAINING, I'M A PEDIATRIC ENDOCRINOLOGIST AND I HAVE A PH.D. IN COMPUTER SCIENCE, SO I WAS VERY BOTH ACTIVE IN THIS COMMITTEE, THIS NATIONAL SCIENCE COMMITTEE, THAT PUT OUT REPORT CALLED PRECISION MEDICINE, AND I WAS -- IT SAID IF WE CAN ACTUALLY JUST LAYER MULTIPLE PERSPECTIVES ON THE PATIENT FROM THE MICROBIOME EXPOSURES TO THE GENOME TO CLINICAL DATA, WE'RE GOING TO MUCH BETTER UNDERSTAND MEDICINE AND BE ABLE TO DISSECT JUST LIKE HEART FAILURE A MULTITUDE OF DISEASES INTO THEIR HETEROGENEOUS COMPONENTS. MY OWN TAKE ON THAT SAME MESSAGE, WE RECENTLY PUBLISHED AS A VIEW POINT IN JAMA, WHERE I THINK IN AUTISM AND NEURODEVELOPMENT DISEASES, WE NEED TO TAKE THIS PERSPECTIVE, SO THIS FIGURE IS IN THIS JAMA ARTICLE WHERE THERE'S ACTUALLY A MUCH LARGER OF DATA SHOWN IN BLUE SHADED AREAS, IT'S STUFF THAT FALLS INTO OUR HEALTHCARE SYSTEM. WHICH IS IMPORTANT, SOME OF IT'S STRUCK EURD, SOF M IT'S INSTRUCTURED. IN MY OWN WORK, WE'VE DONE A LOT WITH THIS AND WE'VE HEARD FROM OTHER SPEAKERS, BUT THERE'S ALSO REGISTRY, CLAIMS DAY TA ALSO A NUMBER OF OTHER DATA SOURCES FROM AN SES TRY.COM TO ZILLOW TO FITNESS CLUB MEMBERSHIPS TO BLOGS AND TWEETS WHICH ARE INCREDIBLY REVEALING, AND BECAUSE ALTHOUGH I'M INTHEUS YAS TICK, I DON'T HAVE TIME TO TELL YOU THINGS SOME OF MY FACULTY HAVE DONE JUST IN CATEGORIZING AUTISM USING THE SOCIAL WEB. BUT THAT'S FOR ANOTHER TIME. THIS IS JUST TO THINK EXPANSIVELY ABOUT AVAILABLE DATA. IT'S NOT JUST THE 1% OF OUR LIVES THAT WE SPEND IN HEALTHCARE SYSTEMS, AS WE HAVE A MUCH BROADER MEMBERSHIP IN LIFE. MY VIEW OF PRECISION MEDICINE IS SIMPLY THIS. WHAT IS A PROBABILITY OF DISEASE GIVEN FINDINGS SM AND THE SMALLER THE AIR BARS AROUND THAT PROBABILITY ESTIMATE, THE MORE PRECISE WE ARE. THE MORE USEFUL IT IS, THE CLOSER IT IS TO ZERO OR ONE. THAT'S AN IDEAL PRECISION MEDICINE. NOW NOT BEING A SCIENCE RESEARCHER, WHEN I FIRST ENTERED THIS FIELD AT HARVARD, THIS IS WHAT THEY TOLD ME WAS AUTISM. THEY WERE NOT WRONG BECAUSE, IN FACT, WILL ARE A MULTITUDE OF SINGLE-FAMILIES WHERE YOU FOUND INDIVIDUAL PROBLEMS, MUTATIONS, IN THE SYNAPSE. THERE'S NO QUESTION THAT SYNAPSE IS INVOLVED IN MANY LEARNING DISABILITIES FOR MANY PATIENTS. THEY HAVE NOT ACCOUNTED FOR EVEN A SMALL PLURALITY OF CASES OF AUTISM. BUT NONETHELESS, THIS IS WHAT I SAW. SO WHEN I DID A GENE EXPRESSION STUDY, IN PATIENTS WITH AUTISM, LOOKING AT THE BLOOD, PUBLISHED MANY YEARS, MY GRAD STUDENTS STARTED MAKING FUN OF ME. NOT THAT THEY NEVER DO THAT FOR NO REASON AT ALL, BUT HERE THEY MADE SUPER FUN OF ME BECAUSE WE'RE LOOKING AT WHITE BLOOD CELLS, THEY SAID, SAAC, WHAT DID YOU EXPECT TO SEE, THERE'S A LOT OF HEMO KIENS AND ALL THESE IMMUNOLOGICAL SIGNALS, THIS IS AFTER ALL THE BLOOD. I SAID WAIT A SEC, WAIT A SEC. WE'RE ALSO SEEING LONG TERM POTENTIATION AND NEUROTROPHIC SIGNALING AS BEING DIFFERENTIALLY EXPRESSED, AND YES, IT'S THE BLOOD AND IT'S WHITE BLOOD CELLS, SO YEAH, YOU'RE GOING TO SEE IMMUNOLOGIC SIGNAL BUT IT'S DIFFERENT BETWEEN THE KIDS WITH AUTISM AND THE CONTROLS. AND WE DID SEVERAL STUDIES, BUT I WAS SO MYSTIFIED AND IRKED BY MY STUDENTS, SO I DID WHAT MY STUDENTS HAV SHOULD HAVE DONE BEFORE ATTACKING ME, WHICH IS READ THE LITERATURE. TURNS OUT THERE'S A WIDE LITERATURE THAT REFLECTS IMMUNE LOGICAL ASPECTS OF AUTISM IT. I'M NOT HERE TO SAY IT'S ONLY ASPECT BUT I WANT TO BROADEN OUR DISCUSSION. BACK HOME, ALL YOU HEAR ABOUT IS SIN APPS. I WAS VERY IMPRESSED OF THIS STUDY BY VARGAS IN 2006, WE LOOKED AT BRAINS OF KIDS WITH AUTISM VERSUS CONTROLS, UNFORTUNATELY ALL SUDDEN CAN DEATH BY CAR ACCIDENT, AND THEY SHOW THAT THE MICRO GLIA WERE MASSIVELY UPREGULATED. THEN I LOOKED INTO OTHER STUDIES AND IT SHOWED THAT THE EXPRESSION PROGRAM IN THE BRAIN, INCLUDING STUDIES -- SHOW IMMUNOLOGICAL SIGNATURE AS WELL AS A NEUROTROPHIC SIGNATURE. I SAW THE LATE PAUL PATTERSON WHO RECENTLY PASSED AWAY AT CAL TECH HAD A BEAUTIFUL MOUSE MODEL WHERE YOU PUT INTO THE MOTHER AGENTS WHICH CALLED A STERILE INFLAMMATION, THE PUPS THAT ARE BORN LOOK JUST AS AUTISTIC AS ANY MOUSE MODEL, GENETIC MOUSE MODEL OF AUTISM. AND IF YOU LOOK AT THE PERIPHERAL BLOOD, THERE'S A VERY INTERESTING IMKNEW MEU KNOW LOGICALLY DISTINCT SPHAL. ALSO IF YOU LOOK AT AWFUL ALL OF DENMARK, NOT MY WORK, MOTHERS WITH RHEUMATOID ARTHRITIS, FATHERS WITH TYPE 1 DIABETES ARE MUCH LIKELY TO HAVE KIDS WITH AUTISM. IF YOU LOOK AT ALL OF FINLAND THEE ARE COMPREHENSIVE, MOTHER WITH A HIGH GESTATIONAL CRP, MUCH MORE LIKELY, MEASURE OF INFLAMMATION, MUCH MORE LIKELY TO HAVE AUTISM. IF THERE'S INTRAAND PERIPARTUM INFECTION, MUCH MORE LIKELY TO HAVE AUTISM. AND I TOLD YOU ABOUT THE MOUSE MODELS. I'M A LIBRARIAN AT HARVARD MEDICAL SCHOOL. I WENT THROUGH THE LITERATURE LOOKING AT GENETIC IT DISORDERS, EITHER ASSOCIATED WITH THE SYNAPTIC FUNCTION OR ASSOCIATED WITH IMMUNOLOGICAL FUNCTION. THOSE ARE PAPERS, OPEN ACCESS LECTURE, THEY'RE NOTED N AND I. AS YOU CAN SEE, THEY'RE NON-OVERLAPPING, BUT EVEN WORSE, THE LITERATURE CITED BY THE IMMUNOLOGICAL GENETIC STUDIES AND CITED BY THE NEUROSCIENCE GENETIC STUDIES, ARE REALLY -- TENS OF THOUSANDS OF PAPERS THAT DON'T REFERENCE ONE ANOTHER. THIS TELLS YOU WHAT A SPLIT WE HAVE IN OUR COMMUNITY AND HOW BY NOT TAKING THE BIG DATA COMPREHENSIVE VIEW, WE ALLOW OUR COMMUNITIES TO ENGAGE IN SHOUTING MATCHES WITH EACH OTHER WITHOUT ACTUALLY HAVING LOOKED AT EACH OTHER'S OR AT LEAST WILLING TO ACKNOWLEDGE EACH OTHER'S LITERATURE. SO ONE OF MY ENDEAVORS OF THE PAST FEW YEARS HAD BEEN TO LOOK AT ELECTRONIC HEALTH RECORD DATA FROM LARGE HEALTHCARE SYSTEMS, I2B2, FREE SOFTWARE WHICH IS NOW USED BY OVER 100 ACADEMIC HEALTH CENTERS IN THE U.S. AND ABOUT THREE DOZEN INTERNATIONALLY. THIS WILL NOW ALLOW US ALSO TO CREATE REALTIME QUERIES ACROSS ACADEMIC HEALTH CENTERS. SO WE DID THIS QUICK STUDY WITH A4,000 PATIENTS WITH AUTISM. AND WE FOUND THAT THERE WERE ONLY ABOUT HALF A% OF THE POPULATION, SO PROBABLY AN UNDERESTIMATE, THEY HAD AN UNUSUALLY HIGH MALE TO FEMALE RATIO, I CAN'T EXPLAIN IT. BUT IMPORTANTLY, THEY HAD 5,000 DIAGNOSES OTHER THAN THE AUTISM-RELATED DIAGNOSES. AND I WANT TO POINT OUT THAT I'M NOT GOING OH SUMMARIZ TO SUMMARIZE THAT PAPER EXCEPT TO SAY THERE WERE RARE THINGS THAT ARE GREAT RESEARCH AGENDAS. WHY IS IT A FACT THAT 25% OF KIDS WITH DYSTROPHIN MUTATIONS HAVE AUTISM? I DON'T KNOW. IT'S AN INTERESTING -- BUT ALL THESE THINGS POPPED OUT. IN ADDITION TO ALL THE CO-MORBIDITIES YOU JUST HEARD ABOUT SO FAR. BUT WE SAW MANY, MANY SUCH FINDINGS. IN THIS DATASET, 3 MILLION MEASUREMENTS ON 3500 MEASUREMENT TYPES AND A BUNCH OF MEDICATIONS. BUT ONE OF MY POST DOCS, VINALI DOSHI, SHE GRADUATED TWO YEARS AGO WITH A PH.D. IN COMPUTER SCIENCE AT MIT, DID TWO YEARS OF POSTDOC WITH ME AND THEN IMMEDIATELY IN THAT PROCESS, BY THE WAY, HAD TWO KIDS, THEN JUST GOT ACCEPTED A TENURED POSITION AT A SCHOOL OF ENGINEERING APPLIED SCIENCES AT HARVARD. SO -- SUPERWOMAN. SO WHAT SHE DID WAS TO USE HER SAME INFORMATION THEE RE TICK TECHNIQUES, WHICH LOOKED A LOT LIKE GENE EXPRESSION CLUSTERING ON OUR DA DATA. SHE SAID GIVEN THE FACT WE HAVE 15 YEARS OF DATA ON THESE KIDS, I'M GOING TO LOOK AT THESE KIDS AS A TIME SERIES. IM GOING TO BREAK UP EACH OF THEIR SIX-MONTH BLOCKS IN THEIR LIFE, EACH OF THEIR 50 YEARS INTO SIX MONTH BLOCKS. WITH EACH SIX MONTH BLOCK, I'LL SIMPLY SAY DID THEY HAVE ONE OF THOSE 5,000 CO-MORBIDITIES. 1 IF THEY HAVE IT, ZERO IF THEY DON'T. SO YOU HAVE A LITTLE BIT STRING CORRESPONDING TO THEIR CO-MORBIDITIES IN THAT SIX MONTHS. THEN I'M GOING TO MARCH THAT OUT TO ALL 15 YEARS AND THEN I'M GOING TO CLUSTER THE PATIENTS TOGETHER, JUST LIKE YOU DO IN GENE EXPRESSES, ARE THERE CLUSTERS OF PATIENTS COMING TOGETHER? WHAT WE FOUND WAS PRETTY INTERESTING. SHOWING THE NETWORK OF HOSPITALS INVOLVED. SO THERE'S ONE SUBGROUP, WHEREAS IN OUR OTHER PREVIOUS STUDY, WE SHOW THAT WAS A 20%, 22% EPILEPSY SEIZURE PREVALCE, THERE WAS A SUBGROUP, DISTINCT SUBGROUP THAT HAD OVER 80% SEIZURES. SO THIS IS A GROUP THAT'S CHARACTERIZED BY SEIZURES. THERE WAS ANOTHER SUBGROUP THAT WAS CHARACTERIZED BY OTITIS MEDIA, YOU HEARD ABOUT IT, INFECTIONS, VIRAL INFECTION, NOT SHOWN HERE BECAUSE IT'S MUCH LOWER PREVALENCE, IT'S NOT ON THE SAME SCALE, HIGHLY INCREASED INFLAMMATORY BOWEL DISEASE AND A VARIETY OF G.I. DISORDERS. INCIDENTALLY, WHEN I TALKED TO MY TRULY BELOVED COLLEAGUES IN INTERNAL MEDICINE, WHAT THEY TOLD ME WAS, OH, YES, BRAIN IS BAD, TUMMY HURTS. WHICH AFTER THE FACT SEEMS INCREDIBLY DISMISSIVE. AND I'LL SHOW YOU WHAT WE LOOKED AT SUBSEQUENTLY. THEN THERE WAS ANOTHER SUBGROUP WHICH HAS A HUGE -- 60% PREVALENCE OF THINGS LIKE ADHD AND ANXIETY. CORROBORATING WHAT YOU JUST HEARD. THESE ARE INDEPENDENT STUDIES ACROSS MULTIPLE HEALTHCARE SYSTEMS, NOT SHOWN HERE BECAUSE IT'S A MUCH LOWER SALE, SCHIZOPHRENIA AS WELL. SO I WANT TO POINT OUT WHAT WE HAVE HERE, THREE DISTINCT GROUPS. NOW, THESE OVERLAP BUT THESE ARE THREE DISTINCT SUBGROUPS THAT HAVE DISTINTIVE BIOLOGICAL CLINICAL PATHOLOGIES. THEY LOOK LIKE DIFFERENT DISEASES. SO I WANT TO ASK YOU, WE POSTED IT IN PEDIATRICIAN DRIX EARLIER. THIS IS JUST TO SHOW THAT BETWEEN CHILDREN'S HOSPITAL AND WAKE FOREST, THE CO-MORBIDITIES LOOK THE SAME SO DESPITE THE CONFOUNDING DIFFERENT DOCTOR, DIFFERENT HOSPITALS, DIFFERENT PATIENTS, IT LOOKS THE SAME. IT'S AMAZINGLY REPRODUCIBLE. I CAN TELL YOU, THIS IS AMAZINGLY -- ESPECIALLY FOR SOMETHING THAT'S NOT RECOGNIZED. I SHOULD POINT OUT WHEN I FIRST PUBLISHED AN EARLIER PAPER, HI SOME EXPERIENCE WHICH I'D NEVER HAD BEFORE IN MY LIFE, WHICH IS ABUNCH OF PARENTS SENDING ME EMAILS BOTH POSITIVE AND NEGATIVE AND ALL SAID EITHER THANK YOU FOR IDENTIFYING WHAT I'VE ALWAYS KNOWN ABOUT MY KID OR WHY DEPARTMENT YO DIDN'T YOU FIND THIS SOONER? BECAUSE I'VE KNOWN THIS ALL MY LIFE. AND THAT WAS FOR ME FROM PRETTY PERSUASIVE, BECAUSE THE WAY I WAS TRAINED IS, PARENTS REALLY KNOW WHAT'S GOING ON WITH THEIR KID AND DOCTORS TEND TO BE ONE STEP REMOVED. LET'S SAY THE CAUSAL VARIANTS ARE 1% OF THE RELATIVE RISK IS IT 2, WHICH IS ON THE HIGH SIDE. THEN WITH 80% POWER, WE NEED 23,000 KIDS WITH AUTISM. THESE ARE ARGUMENTS WHICH ARGUE FOR LARGER AND LARGER COHORTS OF AUTISM. WHAT IF ASD IS REALLY 10 DISEASES? IF YOU SAW A THOUSAND KIDS WITH AUTISM, YOU'D ONLY SEE 10 WITH INFLAMMATORY BOWEL DISEASE. HIGHLY SIGNIFICANT. IF YOU HAD 10 PEDIATRICIANS, EACH WITH A THOUSAND KIDS, THEY'D NEVER SEE IT. SO MANY WOULD NOT BE CLINICALLY NOTICED, SO 10% FREQUENCY, SAME POWER, YOU'D ONLY HAVE -- SUBJECTS. BUT IF WEE TREAT AUTISM LIKE HEART FAILURE BEING ONE DISEASE, IN THE CASE CONTROL STUDY ON HEART FAILURE, SAY WHAT ARE THE CAUSE IF VARIANS CAUSE OF HEART FAILURE AND LUMPING ALL THE HEART FAILURES I TOLD YOU ABOUT INTO ONE, IT WOULD NEVER WORK. WE'RE TRYING TO GET SOME SIGNAL, LET'S USE THE BIOLOGY AND THE CLINICAL FINDINGS TO. I CAN'T SHOW YOU STUFF WE'RE DOING WITH IPS CELLS, BUT CAN WE FIND SUBGROUPS WHERE WE CAN ACTUALLY BOOST THE SIGNAL. WE ALWAYS THOUGH OF GENETICS BEING EXPENSIVE BUT THE AVERAGE PRICE FOR A GOOD PHENOTYPE TO NIH IS BETWEEN A THOUSAND AND $3,000. SO WE CAN USE ELECTRONIC HEALTH RECORDS AND, WE CAN NOW START DOING OM MILLIONS OF PATIENTS THESE ANALYSES THAT WERE PREVIOUSLY IMPOSSIBLE. SO HE SAID -- I WENT TO TALK TO LENNY RAPAPORT, HE DOESN'T THINK THIS IS A REAL THING, INFLAMMATORY BOWEL DISEASE. SO I SAID GO TO MY BUDDY THAT'S A G.I. SPECIALIST OF THE KIDS WITH IBD, AND WHAT SHE FOUND WAS NOT IBD DIAGNOSIS, BUT PATHOLOGY PROVEN IBBD, LIKE THE HIGHEST LEVEL DEFINITION, IBD WAS HIGHER. SO WE ACTUALLY LOOKED AT THE CASES. INTERESTING, THERE WAS ALSO ENRICHMENT FOR A SET OF CASES, INCREDIBLY HORRIBLE RANGING COLITIS AND EN ENTERITIS THAT DID NOT MEET THE CRITERIA FOR IBD SO WE HAVE A COLLABORATION WITH AETNA, USING WAKE FOREST OR BOSTON CHILDREN'S, WHATEVER WE WOULD LOOK AT, THE ENRICHMENT, THE PREF PREVALENCE OF IBD IS HIGHER THAN ANY. ESTIMATES OF THE CROHN'S FOUNDATION. NO MATTER HOW YOU SLICE IT, IT'S HIGHER. I ASSURE YOU WE'RE GOING TO SEE IT IN ALL THE OTHER DIFFERENT DISEASES BUT IT'S SO EASY TO IGNORE. SO IN SUMMARY, THE CONVENTIONAL WISDOM OF WHAT CAUSES AUTISM IS INCOMPLETE, DIVIDED AND OBSCURED BY THE FACT THAT WE ALL BY OUR HUMAN NATURE END UP DOWN THE RABBIT HOLE ONCE WE FIND A HYPOTHESIS. AND ALTHOUGH I'M A BIG FAN OF HYPOTHESIS DRIVEN RESEARCH, ON THE OTHER HAND, PREMATURE FOCUS CAN PUT IT ON BLINDERS. PHENOTYPE -- OF GENETIC ARCHITECTURE. THERE IS A LOT OF SHARED PATHOBIOLOGY ACROSS AUTISM AND I HAVEN'T HAD TIME TO SHARE IT, BUT FOR EXAMPLE, WE'VE LOOKED AT GENE EXPRESSION, CO-MORBIDITIES, MIGHTY INTERESTING. AROUN THE TOLL OF -- A TOLL-LIKE RECEPTOR PATHWAY. THERE'S A LOT OF UNDISCOVERED HETEROGENEITY WITHIN CONVENTIONALLY LABELED DISEASES OF WHICH AUTISM IS A GREAT EXAMPLE. SO WHAT WE'D ARGUE FOR IS AN AGGRESSIVELY ECUMENICAL APPROACH TO DATA ANALYSIS. THAT'S WHAT I THINK IACC ACTUALLY SEEKS TO PROMOTE, AND THAT'S WHY I'M SO EXCITED TO BE HERE, AND HERE'S A PLUG, SORRY FOR THE CHOPPING, SO NHGRI, BUT MOSTLY NIMH IN ITS WISDOM, OR WHATEVER, HAS DECIDED TO FUND A PROJECT THAT WE PUT IN FOR CENTER OF EXCELLENCE IN GENOMIC SCIENCE WITH ROY FROM MGH AND BASICALLY WE'RE GOING TO TAKE THIS SYSTEMATICALLY, ELECTRONIC HEALTH RECORD DEFINED PHENOTYPES, FOR WHICH WE HAVE -- AND WE'RE GOING TO DO BOTH CLASSICAL PHENOTYPING AND DMENGSAL PHENOTYPING, AND WE'RE GOING TO LOOK AT BOTH THOSE PATIENTS THAT WE HAVE IN A BIOBANK, A SPECIAL BIOBANK, AND ALL THE OTHER PSYCHIATRIC PATIENTS SO WE CAN COMPARE IT TO THEM. WE'RE GOING TO TAKE THOSE PATIENTS IN THE BIOBANK AND CREATE BOTH INDUCED NEURONS AND PLURIPOTENT NEUROPROGENITOR CELLS, AND WE'RE GOING TO LOOK AT THEIR TRANSCRIPTOME, WE'RE GOING TO LOOK AT THEIR EPIGENOME, WE'RE GOING TO DO CHIP SEEKS, AND WE'RE GOING TO LOOK AT NOT ONLY -- ALL THE NON-CODING TRANSCRIPTOME AS WELL AND WE'RE -- IN THESE NEURON CELLS AND NEURONS AND ACTUALLY COME UP WITH A MODEL THAT ATTEMPTS TO LINK BACK THE RESPONSES TO THE DRUGS IN THIS PRECISION MEDICINE STACK GOING ALL THE WAY FROM THE PHENOTYPE THROUGH THE TRANSCRIPTOME TO SEE IF IT CAN HAVE SOME EXPLANATORY/PREDICTIVE CAPABILITY. MEANWHILE, WE'LL HAVE MIKE GREENBERG WORKING ON THE SAME NEURONS, DEPO DEPOT LARRIZING THEM, TO SEE IF WE COULD ACTUALLY SEE AN AK TUFF-DEPEND CHANGE IN THE EP GEE NOLL AND TRANSCRIPTOME, WHICH IS A LONG WAY TO SAY WE FULLY BELIEVE IN THIS ECUMENICAL APPROACH, THANKS TO GENEROUS FUNDING BY NHGRI AND MOSTLY NIMH, WE'LL BE ABLE TO ATTACK THIS SYSTEMATICALLY. FOR THOSE INTERESTED, I'M GLAD TO TAKE MORE QUESTIONS LATER. SO I WANT TO THANK A FAIRLY LARGE CAST OF CHARACTERS. THANK YOU VERY MUCH. >> THANKS, SAAC. WE'LL GET BACK TO QUESTIONS VERY SOON AND OBVIOUSLY THERE'S A LOT TO TALK ABOUT. FINAL SPEAKER IN THIS SESSION WILL BE DR. DANIEL COURY, PROFESSOR OF PEDIATRICS AND PSYCHIATRY AT THE OHIO STATE UNIVERSITY COLLEGE OF MEDICINE. >> GOOD MORNING. IT'S A PLEASURE TO BE HERE. REALLY HAVE ENJOYED THE PRESENTATION SO FAR, EVERYONE IS GETTING A GOOD IDEA THAT AUTISM IS NOT A MENTAL OR NEUROLOGIC DISORDER, IT'S REALLY A WHOLE BODY DISORDER. I'M GOING TO SHARE SOME DATA WE HAVE FROM THE AUTISM SPEAKS, AUTISM TREATMENT NETWORK TO GIVE YOU A LITTLE MORE FEEL FOR THIS. YOU'VE HEARD FROM DR. JAIN ABOUT THE DATABASE FROM THE HEALTHCARE AIR, FROM DR. KOHANE FROM A LARGE MEDICAL DATABASE. WE ARE MORE OF A CROSS-SECTIONAL DATABASE, THE INFORMATION THAT WE HAVE FROM 14 SITES ACROSS NORTH AMERICA, AND THE NETWORK HAS AN EMPHASIS ON THE MEDICAL CONDITIONS THAT OCCUR IN CHILDREN WITH AUTISM SPECTRUM DISORDERS. THE BELIEF THAT IT IS MORE OF A WHOLE BODY DISORDER. WE ALSO HAVE GENEROUS FUNDING FROM HRSA TO SERVE AS THE AUTISM INTERVENTION RESEARCH NETWORK ON PHYSICAL HEALTH, WHICH HELPS US TO DO ADDITIONAL RESEARCH, AS WELL AS TO DEVELOP EVIDENCE BASED GUIDELINES FOR CARE. I ENCOURAGE YOU TO LOOK THAT OVER, IT HAS OPEN ACCESS AT THAT LINK THERE. WE HAVE OVER 6700 CHILDREN WITH DATA AT THIS TIME IN OUR NETWORK. I'M GOING TO BRIEFLY REPORT ON SOME OF THE CO-OCCURRING CONDITIONS AND SYMPTOMS AND YOU HEARD A LOT OF THIS IN DR. KOHANE AND DR. CROEN'S PRESENTATIONS. WE SEE A LOT OF G.I. DISORDERS, A LOT OF NUTRITIONAL SYMPTOMS PART LEA DUE TO VARIATIONS IN DIET PREFERENCES AND USE OF SUPPLEMENTS THAT THESE FAMILIES USE IN AN ATTEMPT TO TREAT OR IMPROVE THEIR CHILDREN'S HEALTH. WE HAVE A LOT OF COMPLAINTS ABOUT MOTILITY ISSUES FROM BOTH EXTREME, EITHER EXPLOSIVE DIARRHEA OR SEVERE CONSTIPATION AND IN SOME OF THE WRITTEN COMMENTS THAT WE'VE RECEIVED HERE TODAY, I SAW A NUMBER OF FAMILIES COMPLAINING ABOUT THAT AS WELL. EPILEPSY IS A CONCERN. SLEEP DISORDERS, WE'RE GOING TO BE HEARING BOTH OF THOSE IN A LOT MORE DETAIL LATER TODAY. IMMUNE CONDITIONS WHICH ARE ALSO GOING TO BE ADDRESSED, AND WE'VE HEARD A LITTLE BIT FROM DR. CROEN ABOUT MENTAL HEALTH CONDITIONS AS WELL. WHEN WE LOOK AT THE G.I. DISORDERS RECORDED ACROSS THE AUTISM SPEAKS, AUTISM TREATMENT NETWORK, AGAIN YOU SEE HERE SOME OF THE DATA, ANY PROBLEMS IN THE PAST THREE MONTHS, CHRONIC CONDITIONS CONTINUES TO HAVE SYMPTOMS DURING THE THREE MONTHS ACROSS THESE CATEGORIES. THERE'S A LOT OF PROBLEM WITH CONSTIPATION AND DIARRHEA, THE CHRONICITY OF THESE CONDITIONS, ABDOMINAL PAIN, OTHER G.I. ESTIMATES, NAUSEA, SYMPTOMS OF BLOATING, AND THEN OVERALL ANY G.I. PROBLEM BEING REPORTED IN OVER HALF OF THE PATIENTS. SO IT IS A SIGNIFICANT CONCERN. IT'S ALSO RAISING ANOTHER CONCERN OR A PROBLEM WITH ASSESSING THIS AND A PROBLEM THAT WE'VE HEARD FROM FAMILIES WHERE, AGAIN, THAT THEIR PHYSICIAN WAS DISMISSIVE ABOUT THIS. MY CHILD HAS ALL THESE G.I. PROBLEMS, YEAH, WE SEE THAT IN AUTISM, SO NOTHING IS DONE WHEN, IN FACT, A FAIR AMOUNT COULD BE DONE. THE OTHER PROBLEM WITH AUTISM, A COMMUNICATION DISORDER, PROBLEMS WITH SOCIAL INTERACTIONS, VERBAL AND NON-VERBAL COMMUNICATION, IS ACCURATELY IDENTIFYING ISSUES SUCH AS ABDOMINAL PAIN OR NAUSEA. MANY TIMES THIS IS NOT WELL EXPRESSED, IT RELIES ON PARENTAL BELIEF OR UNDERSTANDING OF THEIR CHILD, PATIENT PATIENTS ARE THE EXPERTS OF THEIR CHILD, BUT THESE CAN BE DIFFICULT TO INTERPRET AND UNDERSTAND. WE LOOKED AT NUMEROUS STUDIES THAT HAVE BEEN DONE OVER THE LAST 15 YEARS LOOKING AT G.I. PROBLEMS. IS IT REALLY MORE OF A PROBLEM IN AUTISM OR IS IT AS PREVALENT AND SIMPLY NOT RECOGNIZED COMPARED TO TYPICALLY DEVELOPING PEOPLE. A FEW OF THESE STUDIES HAVE COMPARISON GROUPS. IN THOSE THAT DO HAVE A COMPARISON GROUP, ALL OF THEM FIND THE RATE OF G.I. PROBLEMS FAR GREATER IN PEOPLE WITH AUTISM THAN IN THE COMPARISON GROUPS AND AT LEAST ONE OF THESE ALSO HAD A COMPARISON GROUP OF OTHER DEVELOPMENTAL DISABILITIES TO LOOK AT. AND AS DR. JAIN, I THINK, MENTIONED EARLIER, A RANGE OF 9 TO 90%, THAT'S VERY HELPFUL, ISN'T IT, IN MANAGING THIS AND ANSWERING THIS QUESTION. SO SOME OF THE THINGS THAT WE'RE HEARING HAD MORNING ARE GOING TO HELP US HOPEFULLY GET A BETTER UNDERSTANDING OF THAT. SEIZURE DISORDERS IN CHILDREN WITH AUTISM, AND AT THE TIME WE DID THIS, WE HAD 2500 CHILDREN IN THE REGISTRY. WE HAD ABOUT 16% AT THAT TIME WITH EPILEPSY, WE FOUND NO DIFFERENCES ACCORDING TO THEIR ASD DIAGNOSES, ASPERGER'S, AUTISM OR PDD NOS, NOR GENDER. W DID SEE HIGHER RATES AMONG WHITE CHILDREN AND LATINO POPULATIONS, AND HIGHER RATE IN CHILDREN WHO HAVE AN I.Q. LOWER THAN 70, WHICH WAS CONSISTENT WITH SOME PRIOR REPORTS IN THE LITERATURE. PARENTS ALSO REPORTED THAT THEIR CHILD HAD SKILL LOSS OR REGRESSION TO SOME EXTENT, THAT WAS HIGHER IN CHILDREN WITH SEIZURES. SO YOU START SEEING THAT THESE CHILDREN ARE HAVING A BIGGER PICTURE THAT IT'S NOT JUST NEUROLOGIC, BUT THERE MAY BE OTHER ASPECTS ASSOCIATED TO THIS, AND WHAT WE'VE ALSO SEEN IN OUR POPULATION IS THAT THE CHILDREN WITH SEIZURE DISORDERS AMONG A POPULATION OF CHILDREN WITH AUTISM HAVE A HIGHER RATE OF G.I. PROBLEMS AND OF SLEEP PROBLEMS. SO THIS IS DIFFICULT TO FULLY EXPLAIN UNLESS YOU TAKE A WHOLE LO BARACK OBAMA DEAPPROACBODY APPROACH TO THIS. THEY ALSO HAVE LOWER VINELAND ADAPTIVE SCORES AND CERTAIN SCALES WHICH PERTAIN TO ANXIETY AND OVERACTIVITY ARE ALSO DIFFERENT. SLEEP DISORDERS, I'M REALLY PLEASED WE'VE GOT A REALLY GOOD GROUP TALKING ABOUT SLEEP LATER TODAY. REPORTS HAVE RANGED FROM WELL OVER HALF TO 34TH OF CHILDREN WITH AUTISM HAVING SLEEP PROBLEMS, AND APPROXIMATELY HALF THAT RATE IN CHILDREN WITHOUT AUTISM. WE LOOKED AT ABOUT 1200 CHILDREN, WE CATEGORIZED THESE AS GOOD SLEEPER, MILD SLEEP PROBLEM, THEN MODERATE TO SEVERE SLEEP PROBLEMS, AND THAT WAS OCCURRING IN ABOUT -- OVER HALF WERE HAVING SOME DEGREE OF SLEEP PROBLEMS. WE DO SEE A LOWER INCIDENCE OF SLEEP PROBLEMS AS THEE CHILDREN GET OLDER, AND WE ALSO SEE THAT THE SLEEP PROBLEMS ARE ASSOCIATED WITH AN INCREASED RATE OF DAY TIME BEHAVIOR PROBLEMS. THIS IS ONE OF THE AREAS THAT WE ARE TRYING TO BETTER TEASE OUT. IF WE TREAT THE DAY TIME BEHAVIOR PROBLEMS, CAN WE HAVE BETTER SLEEP. IF WE BETTER ADDRESS THE SLEEP PROBLEMS, CAN WE IMPROVE DAY TIME MAY HAVE YOUR. I KNOW THAT MY OWN BEHAVIOR IMPROVES WHEN I GET GOOD SLEEP. WE BELIEVE THAT'S TRUE FOR PEOPLE WITH AUTISM AS WELL. PSYCHIATRIC SYMPTOMS, WE HEARD A LITTLE BIT ABOUT THIS, ADHD IS REPORTED IN 40 TO 78% OF CHILDREN WITH AUTISM IT AND WE GET A LOT OF REPORTS OF THIS IN OUR REGISTRY INFORMATION AS WELL, 37% SCORING IN THE CLINICAL RANGE ON THE ATTENTION SUBSCALE, 14% ON THE AGGRESSIVE SUBSCALE AND ABOUT 22% ON THE HYPERACTIVITY OF THE SUBSCALE OF THE CHILD BEHAVIOR CHECKLIST, WHICH IS A WELL VALIDATED INSTRUMENT. THIS IS A NON-COLOR VERSION OF DR. KOHANE'S OVERLAPPING BOXES AND SQUARES. IT MIGHT BE EASIER TO UNDERSTAND. THIS IS A SURVEY, THE PREVALENCE OF SYMPTOMS SUCH AS ADHD, BEHAVIOR CONDUCT PROBLEM, DEPRESSION AND ANXIETY, IN THE GENERAL POPULATION THROUGH THIS NATIONAL SURVEY OF CHILDREN'S HEALTH. SO WHEN WE LOOK AT HOW FREQUENT THESE OTHER CONDITIONS ARE, AND THEN HOW MANY OF THEM HAVE A CO-MORBID BEHAVIORAL CONDITION WE SEE THE AUTISM GROUP IS DRAMATICALLY DIFFERENT FROM OTHER GROUPS OF MENTAL HEALTH OR BEHAVIORAL HEALTH DISORDERS. SO AGAIN, THERE'S SOMETHING MORE HERE. AUTISM OR AUTISMS. WHEN WE LOOK AT THE IT USE OF MEDICATION, WHAT WE HAVE FOUND IS THE BEST PREDICTER OF MEDICATION USE IN CHILDREN WITH AUTISM IS THE PRESENCE OF ONE OF THESE CO-MORBID BEHAVIORAL OR PSYCHIATRIC DIAGNOSES. SO THE CHILDREN WHO HAVE ADHD AS A CO-MORBID DIAGNOSIS OR HAVE ANXIETY AS A CO-MORBID DIAGNOSIS ARE MORE LIKELY TO BE RECEIVING MEDICATIONS. WHEN WE LOOK AT OUR REGISTRY, AND AT THE TIME THAT WE LOOKED AT THIS, WE HAD ABOUT 2700 CHILDREN REVIEWED, THE NUMBER OF CHILDREN IN THE UNDER 6 AGE GROUP WAS ABOUT 1500, AND ABOUT 10% WERE ON SOME MEDICATION, A PSYCHOTROPIC MEDICATION. AS WE GET OLDER, WE HAVE HIGHER AND HIGHER RATES OF MEDICATION USAGE, AND THIS HAS BEEN SEEN IN OTHER REPORTS THAT HAVE BEEN DONE INDICATING THAT BY THE TIME WE HIT OUR TEEN YEARS, ABOUT TWO THIRDS OR MORE OF ADOLESCENTS ON THE SPECTRUM ARE RECEIVING MEDICATION. PSYCHOTROPIC MEDICATION DIRECTED AT TREATING SOME OF THEIR SYMPTOMS. WHEN WE LOOK AT -- IF YOU'VE SEEN SOME REPORTS OF OUR OVERALL FINDINGS IN THE REGISTRY, WHICH IS ROUGHLY 20%, IT'S FAR LESS THAN WHAT YOU SEE IN OTHER REPORTS BECAUSE WE ARE PICKING UP A LARGER PERCENTAGE IN OUR REGISTRY OF YOUNGER CHILDREN. MEDICATIONS THAT ARE USED ARE TYPICAL MEDICATIONS YOU MIGHT EXPECT FOR THESE SYMPTOMS OF HYPERACTIVITY OR ANXIETY, THEN THE ATYPICAL ANTIPSYCHOTICS USED TO TREAT WHICH IS REFERRED TO AS IRRITABILITY, ALPHA AGONISTS ARE ALSO USED TO TREAT ADHD SYMPTOMS. THE COEXISTING PSYCHIATRIC DIAGNOSES ARE A LOT SMALLER THAN YOU MIGHT HAVE EX-P PECTED. PART OF THAT, WE BELIEVE, IS AGAIN THE YOUNG AGE OF OUR POPULATION, WE DON'T DIAGNOSE DEPRESSION IN MANY 3-YEAR-OLDS. BUT ALSO UP UNTIL THE DSM5,, WE AREN'T ALLOWED TO GIVE ANY OF THESE OTHER DIAGNOSES BECAUSE IT WAS THE CHILD'S AUTISM, AGAIN ALMOST THE DISMISSIVE APPROACH TO THE PROBLEM. MANY OF THESE CHILDREN ARE TREATED WITHOUT HAVING A CLEAR DIAGNOSIS SO THERE IS A LOT OF SYMPTOMATIC TREATMENT IN OUR POPULATION. I DO WANT TO ACKNOWLEDGE FOLKS WHO ARE INVOLVED WITH THE ATN AND THE ARP THROUGH THE CLINICAL COORDINATING CENTER, MY COLLEAGUES LISTED HERE, AS WELL AS OUR HELP FROM AUTISM SPEAKS AND OUR FUNDERS. HAD A COUPLE OF OTHER COMMENTS I WANTED TO MAKE THAT REALLY FOLLOW UP WITH DR. KOHANE'S COMMENTS. PARENTS ARE THE EXPERTS ON THEIR CHILDREN, AND WE NEED TO LISTEN TO THEM, AND MANY TIMES WE SEE PARENTS SAYING MY PHYSICIAN HASN'T LISTENED TO ME. WE'VE SEEN SIMPLY TREATING THESE PROBLEMS AS YOU WOULD IN ANY OTHER CHILD CAN BE EFFECTIVE A GOOD NUMBER OF TIMES, BUT THEN WE RUN INTO THOSE PROBLEM ONES, ONES THAT ARE UNUSUAL THAT WE CAN'T FIGURE OUT. SO A LOT OF THIS IS VALIDATING COMMON WISDOM. PARENTS ARE THE EXPERTS, TRY NOT TO BE SO DISMISSIVE. ONE OF THE THINGS I LIKE TO REMEMBER IS WHAT YOGI BERRA ONCE SAID, IF I DIDN'T BELIEVE IT, I WOULDN'T HAVE SEEN IT. IF WE'RE NOT LOOKING AT THAT, WE'RE NOT LOOKING AT THE WHOLE PROBLEM. THANK YOU. [APPLAUSE] >> THERE WERE A FEW PEOPLE WHO JOINED US SINCE WE DID THE INTRODUCTION SO I WANT TO MAKE SURE WE CAPTURE EVERYBODY WHO'S HERE. ALLISON, I THINK YOU CAME IN LATER. MAYBE WE CAN GO AROUND AND THOSE WHO DIDN'T HAVE A CHANCE TO INTRODUCE THEMSELVES, THEY CAN DO THAT NOW. >> ALISON SINGER, AUTISM SCIENCE FOUNDATION, I AM THE MOTHER OF A 17-YEAR-OLD DAUGHTER WITH AUTISM, AND I ALSO SERVE AS LEGAL GUARDIAN FOR MY NOW 50-YEAR-OLD BROTHER WITH AUTISM. >> TIFFANY, ACTING DEPUTY DIRECTOR OF THE DIVISION OF PSYCHIATRY PRODUCTS AT FDA. >> I'M JOSIE BRIGGS, DIRECTOR AT THE NATIONAL CENTER FOR COMPLIMENTARY AND ALTERNATIVE MEDICINE. >> I'M JEFF WOOD, ASSOCIATE PROFESSOR OF EDUCATIONAL PSYCHOLOGY AND CHILD PSYCHIATRY AT UCLA. >> ROB RING, CHIEF SCIENCE OFFICER AT AUTISM SPEAKS. >> ALL RIGHT. LET'S OPEN THIS UP FOR DISCUSSION. WE'VE GOT ABOUT 15 MINUTES OR SO, SO WE'LL START WITH DR. NAVIAUX. >> I HAVE A QUESTION FOR LISA CROEN. RELATED TO THE CO-OCCURRING USE OF ATYPICAL PSYCHOTIC MEDICATIONS AND THEIR POTENTIAL CONFOUNDING ROLE IN THE PREVALENCE ESTIMATES OF OBESITY, DYSLIPIDEMIA AND DIABETES. >> THANKS FOR BRINGING THAT UP. I GOT THE SAME QUESTION FROM ROB AS I SAT DOWN. IT'S A VERY GOOD POINT. WE KNOW THAT MANY OF THESE MEDICATIONS THAT PEOPLE TAKE ARE KNOWN TO INCREASE WEIGHT GAIN AND HAVE LIPID PROBLEMS ASSOCIATED WITH THEM SO THAT'S SOMETHING WE HAVE TO LOOK AT. WE HAVE LOOKED SEPARATELY AT THE MEDICATION USE AMONG THE CASES AND CONTROLS, AND AS YOU'D EXPECT, THEY'RE MUCH HIGHER RATES OF PSYCHOTROPIC MEDS AND ANTISIGH TO KICK DRUGS, FOR EXAMPLE, AND WE NEED TO LOOK AT HOW MUCH OF THE INCREASED PREVALENCE OF THE MEDICAL CONDITIONS CAN BE ACCOUNTED FOR BY EXCESS MEDICATION USE. >> I THINK JOSE HAD HIS HAND UP. >> HI, LISA. QUESTION IS FOR YOU TOO. VERY INTERESTING DATA, GLAD THAT YOU HAVE SUCH A DISTRIBUTION IN TERMS OF RACE AND ETHNICITY. WONDER IF YOU CAN COMMENT IF YOU HAD A CHANCE TO LOOK AT DIFFERENCES IN TERMS OF CO-MORBID CONDITIONS. SOMETHING LIKE WHAT WAS DESCRIBED IN TERMS OF EPILEPSY, W AND LATINOS. ANY OTHER DIFFERENCES THAT MAY BE INTERESTING AND MAY SHED SOME LIGHT ON THE HETEROGENEITY WE OBSERVED HERE? >> YES, WE DID SEE SOME DIFFERENCES AND I'M NOT GOING TO BE ABLE TO -- THERE WERE SO MANY DIFFERENT CONDITIONS WE LOOKED AT AND THERE WERE DIFFERENCE, BUT IN DIABETES, FOR EXAMPLE, THERE WERE SOME DIFFERENCES IN PREVALENCE ACROSS THE DIFFERENT RACE ETHNIC GROUPS BUT I DON'T REMEMBER EXACTLY WHAT THEY ARE, BUT SURPRISINGLY, MANY OF THE CONDITIONS HAD SIMILAR PREVALENCE ACROSS RACE ETHNICITY, SO IT WAS THE CASE THAT MOST OF THE TIME IT DIDN'T MAKE MUCH DIFFERENCE, THERE WERE A FEW OCCASIONS WHERE THERE WAS QUI BIT OF VARIABILITY. >> FOR TYPE I DIABETES, OBVIOUSLY A VERY DIFFERENT PATHOPHYSIOLOGY, WE SAW AN INCREASED RATE OF TYPE I DIABETES IN THE KIDS, INCREASED RISK IN THE KIDS WITH AUTISM RELATIVE -- AND THAT'S HARD TO BE COMPOUNDED BECAUSE IF YOU DON'T TREAT IT, YOU GO DOWN. >> A ANJALI? >> THERE'S AN INCREDIBLY HIGH RAIFT POLYSCI COPHARMACY, SO IT'S NOT ONE MEDICINE WITH SIDE EFFECTS, IT'S OFTEN A COMBINATION OF MEDICATIONS. WE KNOW ALMOST NOTHING ABOUT THAT. >> WE'LL START WITH ANSHU AND JUST COME AROUND. >> I WANTED TO THANK ALL THE SPEAKERS, THIS WAS ABSOLUTE LIE WONDERFUL AND I WANT TO THANK SUSAN AND STAFF FOR ORGANIZING THE SPEAKERS TODAY. I AS A PEDIATRICIAN, THE DEVELOPMENTAL PEDIATRICIAN, THIS RESONATES WITH ME IN TERMS OF LOOKING AT THE WHOLE CHILD APPROACH, AND I'M VERY EXCITED ABOUT HAVING THE PRESENTATION. MY QUESTION IS TO ALL THE SPEAKERS, NOW THAT WE'VE IDENTIFIED THESE TENDENCIES, WHAT CAN YOU DO TO GUIDE ME AS A PEDIATRICIAN IN THE COMMUNITY TO NOW TREAT MY PATIENTS? WHAT GUIDELINES, WHAT APPROACHES CAN I TAKE HOME TO USE FOR MY PATIENTS? >> I'D LIKE TO JUST JUMP IN. I THINK THAT IF NOTHING ELSE, THIS IS JUST THE MODEL FOR OTHER -- DISEASE FOR KIDS. FOR EXAMPLE, KIDS WITH MILD IT DYSPLASIA, WHERE WE HAVE THE NEUROSURGEON -- WE HAVE A TEAM. AND I THINK THAT WHAT THIS DOES IS BOTH FOR THE PAYORS AS WELL AS THE PROVIDERS, IS START THINKING ABOUT WHAT ARE THE TEAMS WE NEED TO PUT IN PLACE SO PEDIATRICS ARE ALL ABOUT PARTS TRI GUIDANCE, RIGHT? SO LET'S DO IT FOR THE HEALTHCARE SYSTEM, WHICH IS THIS IS WHAT WE CAN EXPECT, DON'T LET THE PARENT BOUNCE AROUND WITH TUMMY ACHES ON THEIR KID UNTIL SOMETHING BAD HAPPEN, DON'T WAIT UNTIL THERE'S AN ANXIETY -- ASSESSMENTS, SO IT'S GOING TO BE CHEAPER AND CERTAINLY A BETTER EXPERIENCE IF THE MOTHER IS THE NOT FIRST ONE WHO HAS TO -- OR THE FATHER, PUSH THIS TO THE PEDIATRICIANS, INSTEAD HAVE THE PEDIATRICIANS BOTH RECOGNIZE IT AND HAVE A TEAM IN PLACE TO ACTUALLY TAKE CARE OF IT. I THINK IN TERMS OF HEALTHCARE ECONOMICS AND OUTCOMES, THAT'S WHAT WE NEED. AND WE HAVE A FEW BUT ONLY A FEW SUCCESSFUL MODELS OF THAT IN SOME COMPLEX DISEASES FOR KIDS. >> MY QUESTION WAS VERY SIMILAR, PRESENTATIONS WERE EXCELLENT, I COULD ASK EACH OF THE SPEAKERS AT LEAST AN HOUR'S WORTH OF QUESTIONS BUT WHAT WE REALLY NEED AS A COMMITTEE IS CONCRETE NEXT STEPS BECAUSE WE HEAR FROM THESE FAMILIES OVER AND OVER AND OVER AGAIN THAT THESE MEDICAL CONDITIONS ARE BEING IGNORED, THEY'RE NOT BEING ASSESSED, THEY'RE NOT BEING TREATED AND I THINK ALL OF US CAN AGREE THAT THE DATA THAT WAS PRESENTED TODAY IS JUST THE TIP OF THE ICEBERG. I KNOW WITH MY OWN SON, HE SUFFERED NEEDLESSLY WITH MANY OF THESE UNDERLYING CO-MORBIDITIES, AND MY CONCERN IS WE DON'T HAVE THIS ON THE RADAR SCREENS OF OUR GENERAL PEDIATRICIANS AND OUR PHYSICIANS AND CLINICIANS WHO ARE PROVIDING CARE, SO WHAT CAN WE DO AS A COMMITTEE TO GET THIS INFORMATION MORE WIDELY DISSEMINATED, HOW CAN WE DEVELOP CLINICAL PRACTICE GUIDELINES THAT JUST INCORPORATE ASSESSMENT TO ASK THAT QUESTION, IS YOUR CHILD SLEEPING DURING THE NIGHT, ARE THEY HAVING PROBLEMS WITH CONSTIPATION AND DIARRHEA, AND THEN WHERE DO WE GO FROM THAT TO REALLY EVALUATE THEM, BECAUSE MANY OF THESE ARE SUBTLE AND THEY'RE OVERLOOKED, AND WE SEE THE BEHAVIORS BUT WE'RE NOT LOOKING AT WHAT THE CAUSAL MECHANISMS MIGHT BE FOR THAT. SO THAT'S WHAT WE REALLY NEED TO KNOW TODAY. >> I WAS GOING TO BRING UP THE DISCREPANCY WHERE LISA CROEN SHOWED US IT WAS I THINK AN 18% SLEEP PROBLEM PREVALENCE IN THE CLAIMS DATA, BUT YOU POINTED OUT THE 50 TO 80% REPORT THAT PARENTS HAVE -- I DON'T THINK SLEEP IS UNIQUE, I THINK G.I. IS ANOTHER REALLY GOOD EXAMPLE. I THINK FIGURING OUT A WAY TO UNDERSTAND THAT DISCREPANCY, WE HAVE SOME IDEA IN SLEEP, IT MAY BE THE BEHAVIORAL PROBLEMS ARE ECLIPSING AND OVERSHADOWING, SO THE PEDIATRICIANS NEVER GET TO SLEEP BECAUSE THEY'RE HEARING ABOUT THE BEHAVIORAL ISSUES, BUT THOSE AND OTHER CO-OCCURRING CONDITIONS COULD ACTUALLY BE DRIVERS OF THE BEHAVIOR, AND THEN I THINK THE OTHER THING IS WE NEED TO FIGURE OUT TOOLS TO GIVE THE PEDIATRICIAN BECAUSE THEY'RE SO BUSY AND HAVE TO DO SO MANY DIFFERENT THINGS. THE LAST THING THEY WANT TO DO IS OPEN UP PANDORA'S BOX AND HEAR ABOUT SLEEP PROBLEMS OR G.I. PROBLEMS OR SOMETHING ELSE IF THEY'RE NOT EQUIPPED TO ACTUALLY TREETD THEM, SO I THINK WE NEED TO THINK ABOUT WHAT WE CAN DO TO HELP THE PEDIATRICIANS AND OTHER HEALTHCARE PROVIDERS ADDRESS THE ISSUES THAT ARE BROUGHT TO THEM. >> JOHN? >> I THINK THAT WE SHOULD, AT LEAST I WOULD HOPE WE WOULD ALL BE ABLE TO AGREE THAT THESE CO-OCCURRING CONDITIONS ARE THE RULE AND NOT THE EXCEPTION IN AUTISM, AND YET THEY ARE NOT A PART OF ANY OF THE RECOGNIZED DEFINITIONS OF AUTISM, AND I THINK ONE OF OUR FUNDAMENTAL PROBLEMS HERE IS THAT NOT ENOUGH MEDICAL PRACTITIONERS ARE AWARE OF HOW COMMON THESE CO-OCCURRING CONDITIONS ARE. I GUESS I'D LIKE TO SEE OUR COMMITTEE TAKE SOME KIND OF DEFINITIVE ACTION, MAYBE IN DOING SOMETHING WITH NIH OR HRSA O CDC, TO TAKE STEPS AND MAKE OUR MEDICAL PROFESSIONALS IN AMERICA MORE AWARE OF THE HIGH LIKELIHOOD OF THESE CO-OCCURRING C BECAUSE HERE, WE HAVE A SITUATION WHERE EFFECTIVE TREATMENTS FOR MANY OF THESE THINGS CURRENTLY EXIST, AND WHAT I TOOK AWAY FROM ALL OF THESE EXCELLENT PRESENTATIONS IS THAT A GREAT MANY CHILDREN AND ADULTS ARE SUFFERING NEEDLESSLY BECAUSE PEOPLE SAY THAT'S THEIR AUTISM OR THEY IGNORE IT, IT'S JUST NOT RECOGNIZED, AND YET WE HAVE TOOLS NOW TO HELP BUT WE ARE NOT DEPLOYING THEM. AND I THINK THAT'S A REALLY IMPORTANT POINT THAT I HOPE WE CAN ACT ON. >> I AGREE WITH YOU COMPLETELY, JOHN. THERE IS WORK GOING ON, AS I MENTIONED, THE AUTISM INTERVENTION RESEARCH NETWORK ON PHYSICAL HEALTH, THE FUNDING FROM HRSA AND MCHB FOR THAT, PART OF THAT IS SET ASIDE OR EARMARKED TO CONDUCT AND DEVELOP -- PRACTICE BEST PRACTICE GUIDELINES AND EVIDENCE BASED PRACTICE GUIDELINES. AS YOU'VE HEARD, THERE IS NO EVIDENCE. SO CURRENTLY THESE ARE CONSENSUS EXPERT GUIDELINES BASED ON WHAT THERE IS IN THE LITERATURE, AND THEN WHAT WE ARE DOING ACROSS THE NETWORK IS TESTING THESE GUIDELINES TO SEE HOW FREQUENTLY THEY DO WORK, AND SO FAR REGULAR STANDARD TREATMENTS WILL WORK, AS DR. ANSHU DOWN THE WAY HERE MENTIONED, A LOT OF IT IS KNOWING THAT THE PROBLEM IS THERE IN THE FIRST PLACE, SO WE ARE WORKING HARD TO GET PHYSICIANS TO ADD THESE TO THEIR REGULAR SCREENING IN EVALUATING THESE CHILDREN. JUST AS WE KNOW IN A CHILD WITH DOWN'S SYNDROME, THEY'RE AT INCREASED RISK FOR LOW THYROID, FOR DEVELOPING LEUKEMIA, AND SO PHYSICIANS MONITOR FOR THAT AS THEY FOLLOW A CHILD WITH DOWN'S SYNDROME, WE'RE PUSHING TO SPECIFICALLY ASK THOSE QUESTIONS ABOUT CONSTIPATION, DIARRHEA, ANY UNUSUAL SPELLS, SLEEP PROBLEMS AND SO FORTH, AND THEN WORKING ON THAT. SO THERE IS FUNDING AND THERE IS WORK CURRENTLY GOING ON THROUGH THE -- NETWORK. >> CAN WE JUST HAVE YOU UNPACK THAT A LITTLE BIT? I THINK WHAT YOU'RE HEARING FROM THE MEMBERS OF THE COMMITTEE IS THE INTEREST IN HOW DO YOU TAKE THIS TO SCALE. IT'S REALLY GREAT THAT IN THE FOUR PRESENTATIONS WE HEARD, YOU'RE SORT OF SEEING THE BEST CASE SCENARIO. ANJALI, YOU EVEN USED THE TERM SURVEILLANCE BIAS, LIKE THERE MIGHT EVEN BE TOO MUCH IN THE CASE BECAUSE THERE'S SUCH A KNOW CUSFOCUS ON HEALTHCARE FOR THESE KIDS. YET ALL OF US KNOW THAT IN FACT IN THE REAL WORLD OF PRACTICE, THESE THINGS ARE NEGLECTED. SO IF YOU COULD JUST GIVE US A BETTER SENSE OF WHAT'S THAT PATHWAY, MAYBE IT WAS FOLLOWED FOR DOWN'S SYNDROME, TO ACTUALLY GET THOSE KINDS OF SCREENING MATERIALS TO EVERY PEDIATRICIAN IN AMERICA, WHO DOES THAT, AND WHAT ARE THE STEPS TO MAKE THAT HAPPEN? >> SO IT'S A LONG ARDUOUS PATHWAY. IT DOESN'T HAPPEN OVERNIGHT. PHYSICIANS ARE NOTORI SLOW TO CHANGE. SO THE PRAWK IS THAT W PROBLEM IS WE HAVE TO HAVE EVIDENCE, IT HAS TO BE PRESENTED AS A BEST PRACTICE OR CLINICAL GUIDELINE, AND FOR THAT TO BE ACCEPTABLE TO PHYSICIANS, IT NEEDS TO COME FROM A CREDIBLE SOURCE. SO SUCH AS THE NIH OR FROM THEIR OWN PROFESSIONAL SOCIETIES, WHETHER IT'S PEDIATRICS, NEUROLOGY, OR WHATEVER, THE AAP, THE AAN AND SO FORTH, SO WE HAVE TO HAVE THAT STAMP OF CREDIBILITY FOR THEM TO DO THAT. THE NEXT THING IS DISSEMINATION. AS YOU'VE HEARD ME SAY, WE'VE BEEN DOING THE STANDARD DISSEMINATION ROUTINES OF PUBLISHING, HAVING CONFERENCES AND TRYING GET THE WORD OUT THROUGH THAT. THAT IS ALSO A SLOW PROCESS. WE'RE USING MORE TECHNOLOGICALLY SAVVY METHODS SUCH AS WEBINARS, BUT PEOPLE DON'T ALWAYS LOG IN TO THOSE. THE NEXT STEP IS REALLY GETTING OUT AND CHANGING PRACTICE. THE GOOD NEWS IS THAT ACROSS THE MEDICAL SPECIALTIES, MAINTENANCE OF CERTIFICATION IS IN PLACE, AND A REQUIREMENT FOR THAT IS QUALITY IMPROVEMENT, SHOWING THAT THE CLINICIAN IS ACTUALLY CHANGING THEIR CARE AND IMPROVING THEIR CARE. SO OUR NEXT STEP IS TRYING -- BECAUSE AUTISM HAS BECOME SUCH A PROMINENT CONCERN, TRYING TO GET PRACTICES TO CHANGE AND DEVELOPING WAYS THAT THEY CAN CHANGE HOW THEY ARE IDENTIFYING AND MANAGING THESE CHILDREN IN THEIR PRACTICE, SO WE'RE STARTING TO GET OUT IN THEIR HAND TO HAND RIGHT ON THE GROUND WITH THEM. >> I'D LIKE TO TAKE ISSUE WITH THAT A LITTLE BIT IN THE SENSE THAT I THINK THAT IT'S NOT OKAY TO -- WE NEED TO TAKE THOSE STEPS AND THEY DO TAKE A LONG TIME, BUT I ALSO THINK WE NEED ALALTERNATIVE PATHWAYS TO GET THERE. THE FACT IS THAT KIDS ARE GETTING TREATED, BUT THEY'RE NOT GETTING TREATED WELL, BUT NECESSARILY, BUT THEY'RE GETTING TREATED WITH MEDICATIONS, WITH TREATMENTS, SO THERE IS COLLECTIVE WISDOM OUT THERE THAT I THINK WE SHOULD WORK HARD TO MAKE AVAILABLE AS THE BEST AVAILABLE EVIDENCE UNTIL WE KNOW DIFFERENTLY. I ALSO THINK THAT SOME OF THE ADVOCACY ORGANIZATIONS AND THE GROUPS LIKE PATIENTS LIKE ME, WHERE PATIENTS ARE IN DIRECT COMMUNICATION WITH EACH OTHER ABOUT WHAT WORKS BEST FOR THEM CAN BE LEVERAGED TO GET MORE IMMEDIATE INFORMATION ABOUT WHAT IS THE BEST OF THE EVIDENCE TELLING US TO DO. >> ONE OF THE REALLY GREAT DELIVERABLES SO TO SPEAK THAT'S COME OUT OF THE AIRP ARE THE TOOL KITS FOR PHYSICIANS AND ALSO FOR FAMILIES, AND I WONDER ABOUT THE IDEA OF HAVING A TOOL KIT THAT REALLY IS FOCUSED ON PARTICIPATORY GUIDANCE ON THESE CONDITIONS FOR PEDIATRICIANS, AND OF COURSE YOU'RE LINKED TO A GREAT ADVOCACY ORGANIZATION, AND JUST TRYING TO GET THE INFORMATION OUT THROUGH THAT ROUTE. >> THAT IS ONE OF THE PATHWAYS, AND WE ARE WORKING ON THAT AND AMERICAN ACADEMY OF PEDIATRICS IS IN THE PROCESS OF REVISING THEIR GUIDELINES WHICH CAME OUT IN 2007, SO THEY'RE ALREADY BEING REVISED AS WE SPEAK. >> S WOULD IT BE FEASIBLE TO, ONCE THE AP OR SOME OTHER ORGANIZATION ENDORSES IT, TO ACTUALLY GENERATE A LITTLE CARD FOR PARENTS TO COME AND GIVE THE PEDIATRICIANS A -- THESE ARE THE ACADEMY GUIDELINES FOR AUTISM, BECAUSE I KNOW PARENTS DO THAT ALWAYS NOW WITH GENETIC TESTS, AND AFTER THE PEDIATRICIAN GETS OVER THE EMBARRASSMENT OF ACTUALLY BEING UP TO DATE ON THAT, THEY ACTUALLY DO WHAT THEY CAN TO HELP. SO I THINK PARENT-DRIVEN ADVOCACY FOR GUIDELINES, NOT GOING OVER THE ORGANIZATION BUT IMMEDIATELY ONCE THE ORGANIZATION ADOPTS IT, TO ACTUALLY HAVE THE PARENTS BE THE VEHICLE FOR THAT CHANGING BEHAVIOR OF THE CLINICIANS MIGHT BE THE BEST. >> I THINK T WOULD BE VERY HELPFUL. I THINK THE CHALLENGES IS THAT WE NEED A LITTLE BIT OF A SYSTEMS CHANGE ALSO BECAUSE WHAT HAPPENS IF YOU LOOK AT THE CO-MORBID CONDITION, SOME ARE G.I., SOME ARE PSYCHIATRIC AND BASICALLY YOU'RE TALKING ABOUT DIFFERENT PEOPLE THAT TRADITIONALLY ARE IN DIFFERENT PLACES AND WE NEED TO FIND A WAY TO HAVE MORE OF A MULTIDISCIPLINARY APPROACH FOR PARENTS INSTEAD OF HAVING TO GO TODAY AND SAY LINE ONE OF THE CARD, I NEED TO GO TO THE NEUROLOGIST, LINE TWO, TO THE G.I. PERSON, THAT EVERYONE WILL BE MOUNTAIN SAME PLACE. I THINK SOME OF THE GROUPS ARE TRYING TO DO THAT, BUT WE NEED TO SORT OF HAVE A MORE COMPREHENSIVE MULTIDISCIPLINARY APPROACH FOR THE MILLIONS THAT HAVE AUTISM. >> I'M MINDFUL. TIME, AND WE'RE RIGHT AT OUR BREAK TIME. OBVIOUSLY THERE'S A LOT MORE TO IT TALK ABOUT. THINK WE'LL COME BACK TO MANY OF THESE ISSUES. LIKE LYN, VI ABOUT AN HOUR OF QUESTIONS THAT I'VE ALREADY SCRIBBLED DOWN, BUT WE'LL HAVE TIME AT THE END OF THE DAY TO CIRCLE BACK TO SOME OF THOSE. LET'S TAKE A BREAK AND RECONVENE RIGHT AT 11:00 FOR THE NEXT SESSION. I'M GOING O TO TURN THIS OVER TO GERI DAWSON. >> WELCOME BACK, EVERYONE. NOW WE'RE BEGINNING THE PART OF THE DAY WHERE WE'RE GOING TO DELVE MORE DEEPLY INTO A FEW OF THESE AREAS, WE'RE GOING TO START WITH PSYCHIATRIC DISORDERS. WE'VE GOT A REALLY GREAT GROUP OF COMPLEMENTARY SPEAKERS. OUR FIRST SPEAKER WILL BE LARRY SCAHILL, WHO IS A PROFESSOR OF PSYCHIATRY AT THE MARCUS AUTISM CENTER. LARRY? >> HOW DO YOU DO? I WASN'T NERVOUS UNTIL I GOT HERE. THOSE FIRST FOUR TALKS WERE OUTSTANDING, AND SO DATA-DRIVEN. I DON'T HAVE MUCH DATA. I HAVE LOTS OF DATA, BUT THAT'S NOT THE PRESENTATION FOR TODAY. AND FOR THE SAKE OF MY CHAIR, I HAVE -- BARBARA STOL, I'M PROFESSOR OF PEDIATRICS, I'VE CHANGED, I'M NOW IN PEDIATRICS. >> SO IT'S WRONG ON HERE. >> THE MARCUS AUTISM CENTER IS A RATHER REMARKABLE PLACE. WE SEE ABOUT 5,000 CHILDREN A YEAR. VERY HIGH PERCENTAGE OF THEM, AUTISM SPECTRUM, AND THE REST OF THEM HAVE VARIOUS TYPES OF DEVELOPMENTAL DISABILITIES. IT'S A WONDERFUL, WONDERFUL PLACE. AND WE ARE GROWING THE RESEARCH PORTFOLIO OVER THE PAST FEW YEARS. DISCLOSURE, I'VE JUST GOTTEN USED TO DOING THIS. THESE ARE COMPANIES THAT, BELIEVE IT OR NOT, HAVE AN INTEREST IN AUTISM, AND THAT'S WHY WE TALK TO THEM. MOST OF OUR FUNDING COMES FROM THE NIMH. SO BRIEFLY WHAT I'M GOING TO TALK ABOUT IS OUTCOME MEASUREMENT, BECAUSE I'M A VERY PRACTICALLY ORIENTED PERSON. CLINICAL TRIALS PERSON. AND I'M VERY INTERESTED IN OUTCOME MEASUREMENT. IF YOU CAN'T MEASURE IT, YOU CAN'T REALLY STUDY IT. AND THEN A LITTLE BIT ABOUT OUR AUTISM SPEAKS TASK FORCE. AND A BIG INTEREST OF MINE IS PATIENT OR IN OUR WORLD PARENT REPORTED OUTCOMES. THEN A LITTLE WORK WE'RE IN THE MIDST OF, AN NIMH GRANT TO DEVELOP ANXIETY MEASURES IN CHILDREN WITH AUTISM. NOW DIRECTOR INSEL SAID IT RIGHT AT THE BEGINNING, I'M A LITTLE SHAKY ON THIS CO-MORBIDITY, ANXIETY IN CHILDREN WITH AUTISM FOR THE PAST 14 YEARS OR SO. I CAME TO THAT THROUGH WORK THAT I HAD BEEN DOING AT YALE UNIVERSITY IN TURRETT'S SYNDROME. IT'S DEFINED BY TICKS BUT THERE'S OFTEN REPETITIVE BEHAVIORS, ADHD, AND A LOT OF TIMES THOSE OTHER COMPONENTS WERE A BIGGER DEAL THAN THE TICS THEMSELVES. SO WE DIDN'T TALK TOO MUCH ABOUT CO-MORBID IT, WE TALKED ABOUITY, WE TALKED ABOUT WHAT'S THE BIGGEST PROBLEM. SO I KIND OF BROUGHT THAT NOTION TO THE WORK IN AUTISM. TO UNDERLINE OUR PRACTICAL CHARGE HERE IS WE'VE BEEN STUDYING MOST LE MOSTLY THROUGH THE RESEARCH UNITS -- OUR FIRST PUBL WAS BACK IN 2002, AND YOU SEE THE TARGETS HERE. THESE ARE TARGETS THAT WE HAVE MEASURES FOR. IF WE HAD SOME BRILLIANT OTHER DRUGS OUT THERE, WE'D HAVE A CHALLENGE HOW TO MEASURE IT. SO WE REALLY HAVE TO KEEP OURSELVES WORKING ON OUTCOME MEASUREMENT. WHAT MAKES A GOOD OUTCOME MEASURE? IT'S GOT TO BE RELEVANT RG, THAT'S REALLY OBVIOUS. IT SHOULD MEASURE A SEPARATE AND MEASURABLE CONSTRUCT, AGAIN, OBVIOUS, BUT YOU'D BE SURPRISED IF YOU START LOOKING AT MEASURES, THEY OFTEN DO NOT ACCOMPLISH THOSE SIMPLE TWO TASKS. THE DISTRIBUTION SHOULD BE ORDERLY. THAT MEANS WE SHOULD BE ABLE TO TALK ABOUT THE MEAN AND THE STANDARD DEVIATION. BECAUSE WHEN WE TALK ABOUT CHANGE, WE'RE TALKING ABOUT OFTENTIMES STANDARD DEVIATION UNITS, SO WE NEED TO UNDERSTAND SOMETHING ABOUT THE MEAN AND THE STANDARD DEVIATION. WE'VE DONE SOME WONDERFUL WORK WITH OBSERVATIONAL MEASURE, AND WHAT DO WE FIND? THE STANDARD DEVIATIONS ARE BIGGER THAN THE MEANS. THAT'S NOT TOO GOOD. IT WOULD BE GREAT TO HAVE NORMATIVE DATA. WHEN I SAY NORMATIVE, I MEAN IN DEVELOPMENTAL DISABI I DON'T MEAN IN THE GENERAL POPULATION. BECAUSE THAT'S GOING TO HELP US INTERPRET THOSE MEANS AND STANDARD DEVIATIONS. OTHERWISE WE'RE HARD PRESSED TO KNOW WHAT THEY MEAN. INTERNAL CONSISTENCY, MUCH IS MADE OF THIS. PROPER SORPROFESSOR CROENBOX IS PROBABLY THE MOST CITED PAPER IN ALL OF PSYCHOLOGY AND PSYCHIATRY, BUT IT'S IMPORTANT, BUT A LITTLE NOISE IS OKAY. GOOD TESTS AND RE-TESTS. WE LEARNED FROM THE AUTISM SPEAKS TASK FORCE THAT SURPRISINGLY, WE DON'T KNOW A WHOLE LOT ABOUT COMMONLY USED MEASURES, HOW DO THEY BEHAVE IN THE ABSENCE OF INTERVENTION. THAT'S TEST AND RE-TEST. IF YOU DON'T HAVE GOOD TEST AND RE-TEST, YOU'VE GOT A VERY NOISY MEASURE. YOU'VE GOT TO HAVE THAT. SORT OF THE GOLDILOCKS THING, IT CAN'T BE TOO LONG, TOO SHORT, TOO NARROW. IT'S GOT TO BE JUST RIGHT. IT'S GOT TO HAVE COVERAGE BUT IT CAN'T TAKE AN HOUR. WE WANT HANDY DANDY BUT WE ALSO WANT COVERAGE. SENSITIVITY TO CHANGE, THAT'S OBVIOUS. BUT YOU REALLY DON'T KNOW UNTIL YOU'VE GOT A GOOD TREATMENT TO TEST BECAUSE IF IT DOESN'T CHANGE, YOU DON'T KNOW IF IT'S THE TREATMENT. AUTISM SPEAKS TASK FORCE, THERE WERE THREE OF THEM. THIS IS THE PAPER IT WAS PUBLISHED IN JAD, SOME OF THE FOLKS ON THAT COMMITTEE ARE HERE RIGHT NOW TODAY. IT WAS A VERY INTERESTING ENTERPRISE. THE ISSUE OF CO-MORBIDITY WAS THREADED THROUGHOUT THAT DISCUSSION. I COMMEND YOU TO THAT ARTICLE. SO THE COMMITTEE COULD NOT IDENTIFY A MEASURE THAT WAS READY FOR PRIME TIME. SO WE IDENTIFIED THREE THAT LOOKED LIKE THEY HAVE SOME PROMISE. SO CALLED APPROPRIATE WITH CONDITIONS. THE COMMENT ON YOUR FAR RIGHT IS THE CONDITIONS. THAT KIND OF EMERGED. IF A MEASURE IS GOING TO WORK IN THIS POPULATION, IT'S GOT TO WORK ACROSS A FULL RANGE OF I.Q. I SHOULDN'T SAY IT HAS TO. IT WOULD BE GOOD IF IT DID. AND IF IT DOESN'T, THAT NARROWS THE SCOPE OF THIS APPLICATION. SO NO GOOD MEASURES JUST YET. THIS FORTUNATELY HAS HELPED US FOCUS ON THIS AND MOVE FORWARD. WE LEARNED A LOT FROM THIS MONOGRAPH, FROM THE FDA. IF YOU HAVEN'T STUMBLED ON THIS, THIS IS WELL WORTH LOOKING FOR. THEY DON'T MENTION AUTISM IN THIS WHOLE MONOGRAPH. THIS IS REALLY ABOUT OUTCOME MEASUREMENT. IT IS -- IT SAYS IF YOU WANT TO HAVE A CLAIM OF A DRUG OR A DEVICE AND YOU HAVE A NEW OUTCOME MEASURE, YOU'D BETTER DEVELOP IT ALONG THESE LINES OR YOU'RE GOING TO HAVE A HARD SELL AT THE FDA. AND WHAT'S GOOD ABOUT IT IS IT'S ON THE MONEY. IT IS -- THEY REALLY HAVE OFFERED A ROAD MAP ON HOW TO BUILD AN OUTCOME MEASURE. SO HERE'S THE CONCEPTUAL PROBLEM FOR ME. IF IT IS THE CASE THAT ANXIETY DISORDERS ARE NO DIFFERENT IN CHILDREN WITH AUTISM OR TYPICALLY DEVELOPING CHILDREN, THEN JUST MEASURE ANXIETY AND IF YOU'RE GOING TO DEVELOP A MEDICATION OR A TREATMENT FOR IT, IT SHOULD BE RELEVANT TO TYPICALLY DEVELOPING CHILDREN, CHILDREN WITH AUTISM AND SO FORTH. BUT IF IT'S NOT THE CASE. IF IT'S NOT SIMPLY THAT THIS CHILD IS UNLUCKY AND HAS TW CONDITIONS, WE NEED TO THINK A LITTLE DIFFERENTLY ABOUT IT. AND THIS MAY BE WHAT I'VE CALLED THE COMPLICATION MODEL, WHICH IS THAT THE PRESENCE OF AUTISM INCREASES THE RISK OF EVOLVING CONDITION THAT WE COULD LABEL ANXIETY. IT'S SORT OF LIKE IF YOU PLAY FOOTBALL AND YOU HAVE A BAD KNEE AND YOU START WALKING FUNNY AND THEN SUDDENLY YOU'VE GOT A HIP PROBLEM. IT'S RELATED, IT'S NOT AN ACCIDENT. AND THAT'S A SORT OF BLENDED AMPLIFICATION TYPE OF SITUATION. MORE AND MORE, THAT'S THE WAY I'M THINKING ABOUT IT. CONVERGENT MODEL, THERE ARE PEOPLE THAT WONDER AND I DON'T THINK WE CAN DISMISS IT OUT OF HAND, ANXIETY MIGHT ACTUALLY BE A PART OF AUTISM. THIS IS A COMMENT GOING RIGHT BACK TO LEO CONNOR, THAT HE USED SUCH TERMINOLOGY. WHAT I CAN TELL YOU, I DON'T HAVE TIME TO PRESENT THE DATA, ON MEASURES OF ANXIETY, WE HAVE CHILDREN WITH AUTISM IN FAIRLY LARGE SAMPLES WHO ARE LOW ON ANXIETY. SOME WHO ARE IN THE MIDDLE AND SOME ARE HIGH. SO I'M NOT REALLY CONVINCED ABOUT THE BOTTOM, BUT I DON'T THINK WE SHOULD DISMISS IT. SO A PRACTICAL PROBLEM. WE HAVE TO DISENTANGLE ANXIETY FROM ASD. SOCIAL AVOIDANCE, FOR EXAMPLE, BECAUSE PEOPLE -- SOME PEOPLE WITH AUTISM MAY NOT BE THAT INTERESTED IN INTERACTING WITH OTHER PEOPLE. SO THEY'RE AVOI DANT. IS THAT THE SAME THING AS BEING ANXIOUS ABOUT INTERACTING WITH OTHERS? COULD IT BE THAT SOCIAL AVOIDANCE OVER TIME MAKES A PERSON NOT VERY GOOD AT SOCIAL INTERACTION SO THEN IT BECOMES A SOCIALLY ANXIOUS KIND OF A THING. COGNITIVE LANGUAGE DELAY. I WAS INTERESTED THAT IN THE WONDERFUL TALKS WE HEARD EARLIER, I DIDN'T HEAR MUCH ABOUAL DISABILITIES LIKE LANGUAGE DELAY. BUT I SUSPECT ESPECIALLY WITH A NEW FRAME IN DMS5, THAT LANGUAGE DISORDERS WILL EMERGE AS AN IMPORTANT AREA. B EVEN CHILDREN WHO DON'T HAVE COGNITIVE DELAYS MAY NOT HAVE THE BEST USE OF LANGUA SO GETTING THE CHILD TO TELL BUT THEIR INTERNAL EXPERIENCE MAY BE DIFFICULT. IT MAY BE THAT THERE IS SOME BLENDING OF ANXIETY IN CHILDREN WITH ASD. SO FOR EXAMPLE, I HAD ONE MOTHER EXPLAIN TO ME THAT HER CHILD IS VERY INSISTENT ON ROUTINES AT BREAKFAST, AND VARIOUS ROUTINES THROUGHOUT THE DAY. AND I THOUGHT, YEAH, I'VE HEARD THAT BEFORE. BUT THE MOM WENT ON TO SAY THAT IT'S NOT JUST THAT SHE IS INSISTENT ON THESE THINGS. SHE'S ALWAYS ON THE THE LOOKOUT FOR WHETHER THIS IS GOING TO BE SOME DEVIATION IN THE ROUTINE. THAT'S STARTING TO SOUND A LITTLE MORE LIKE ANXIETY TO ME. BLURRY BOUNDARIES. THIS IS TRUE AS WELL. CHILDREN WITH SEPARATION ANXIETY OFTEN HAVE GENERALIZED ANXIETY. CHILDREN WITH GENERALIZED ANXIETY OFTEN HAVE SOCIAL ANXIETY. SO THAT'S TRUE WITH TYPICALLY DEVELOPING CHILDREN. GIVEN SOME OF THE ISSUES WE JUST TALKED ABOUT IN CHILDREN WITH ASD, THOSE BLURRING BOUNDARIES ARE PROBABLY GOING TO EVEN A BIGGER DEAL. I'LL TELL YOU MY WISH. MY WISH IS THAT WE ARE NOT GOING TO FOE CAN CUSS ON SPECIFIC ANXIETY DISORDERS IN CHILDREN WITH ASD, THAT WE'RE GOING TO FOCUS ON ANXIETY. AND WE COME UP WITH AN OUTCOME MEASURE THAT IS NOT SEVEN ITEMS OF THIS AND FOUR ITEMS OF THAT. SO WE HAVE THIS WONDERFUL NIMH GRANT, AND WE USE THE FDA MONOGRAPH AS A TEMPLATE. WE STARTED WITH SIX FOCUS GROUPS WITH PARENTS. WE ASKED THE PARENTS TO TELL US ABOUT WHAT THEY THOUGHT WERE MANIFESTATIONS OF ANXIETY. IT'S BEEN SAID HERE A COUPLE TIMES, PARENTS ARE THE EXPERTS OF THEIR CHILDREN. THEY TOLD US A LOT. WE LEARNED A LOT FROM THEM. WE HAVE NOW TAKEN THOSE 600 PAGES OF TRANSCRIPTS AND WE'VE PULLED OUT ITEMS. MORE ABOUT THAT IN A MINUTE. WE'RE NOW GOING TO TAKE THOSE ITEMS AND PUT THEM ON THE WEB AND HOPEFULLY WE'LL GET 900 FAMILIES TO FILL THEM OUT, AND WE'LL START DOING A FACTOR ANALYSIS AND THE LIKE. ONCE WE'RE DONE WITH THAT, WE'RE GOING TO BRING IN ABOUT NIE 90 TO 100 CHILDREN, WE'LL HAVE FACE TO FACE EVALUATIONS TO LOOK AT THAT MEASURE AND ALSO A REVISED INTERVIEW MEASURE THAT'S BEEN AROUND FOR TYPICALLY -- CHILDREN WITH ANXIETY. FINALLY, WE'RE GOING TO TRY TO TAKE THE CHILDREN WITH HIGH ANXIETY, COMPARE THEM TO CHILDREN WITH LOW ANXIETY, AND LOOK AT BIOMARKERS LIKE HEART RATE VARIABILITY. SO WHAT DID THE PARENTS TELL US? THEY TOLD US MANY, MANY THINGS, AND I'VE BOYLEED THIS DOWN REALLY TO ONE SLIDE, PERHAPS UNFAIRLY. THEY TOLD US THAT THEY NOTICED CHANGES IN THEIR CHILD'S BEHAVIOR IN CERTAIN SITUATIONS. I REALLY APPRECIATED THEIR OBSERVATION THAT THEY WERE TALKING ABOUT CHANGE IN THE CHILD'S BEHAVIOR. AND YOU CAN SEE WHAT IT SAYS ON THE SLIDE. WE ASKED HEMITO TELL US ABOUT THEM TO TELL US ABOUT THE BEHAVIORS, NOT JUST THE TRIGGERS. THEY TOLD US THINGS LIKE REQUESTING FOR REASSURANCE. NOW THAT'S IN TYPICALLY DEVELOPING CHILDREN AS WELL. AVOIDING BEHAVIORS BECAUSE OF THE SITUATIONS WHERE DISTRESS WAS OBSERVED. AND WHAT WE CAME TO CALL CHILD COPING BEHAVIOR. SO THESE ARE THE BEHAVIORS THAT THE CHILD RESORTED TO WHEN THEY ENCOUNTERED THESE TRIGGERING SITUATIONS. IN OUT COME MEASURE, THE MONEY IS MOST HEE IN OBSERVABLE BEHAVIOR, I THINK YOU'LL AGREE. SO WE TOOK THOSE 600 PAGES AND I'M ONLY SHOWING A FEW, YOU CAN READ THEM, I WON'T READ THEM OUT, I'LL JUST GIVE YOU AN EXAMPLE OF HOW YOU GO FROM TESTIMONY FROM THE PARENTS THAT WAS OFTEN, YOU KNOW, RAMBLING, SOMETIMES RIGHT ON THE MONEY, SOMETIMES -- WE HAD TO BOIL IT DOWN TO SIMPLE ITEMS THAT COULD BE READ OFF AND SCORED ON ZERO TO 3. THIS IS JUST A FEW EXAMPL I WENT TO THE MIDDLE OF THE PACK OF THE 52 ITEMS AND JUST MADE A SLIDE OUT OF IT. WE'LL HAVE ALL TOGETHER 71 ITEMS THAT WE'RE GOING TO ASK PARENTS TO COMMENT ON. ON A SIMPLE ZERO TO 3 SCALE. SO PUT THOSE ON THE WEB, WE'RE HOPING WE GET A DIE MENTIONAL PARENT RATED MEASURE. WE'RE HOPING IT IS IN THE NEIGHBORHOOD OF 30 TO 35 AT BEST ITEMS. WE ARE THEN GOING TO DO AN ASSESSMENT OF THE CHILDREN, AND LOOK IN A MORE FINE GRAINED WAY, AND THEN WE'RE GOING TO DO THIS HEART RATE VARIABILITY. THE HEART RATE VARIABILITY, WE NOW COLLECTED PILOT DATA. WE CAN MEASURE THIS IN CHILDREN WITH AUTISM, IT'S, I THINK, A VERY COOL POSSIBILITY. THESE ARE COLLABORATORS AT EMORY. KAREN BARRES, A PSYCHOLOGIST THAT MOVED DOWN FROM YALE TO EMORY WITH ME, OUR GOOD FRIENDS AT OHIO STATE, AND OUR GOOD FRIENDS AT CHOP IN PHILADELPHIA. THANK YOU VERY MUCH. [APPLAUSE] >> THANK YOU, LARRY. I'M SURE THERE WILL BE MANY QUESTIONS AT THE END. OUR NEXT SPEAKER IS JEFF WOOD, AND HE'S AN ASSOCIATE PROFESSOR AND A CLINICAL CHILD PSYCHOLOGIST FROM UCLA. I KNOW JEFF HAS DONE A LOT OF WRK IN THE AREA OF TREATMENT OF ANXIETY, SO WE'RE LOOKING FORWARD TO HEARING YOU. >> WELL, THANKS FOR HAVING ME TODAY, AND NICE TO SEE YOU ALL, AND I'D LIKE TO START BY FIRST THANKING THE ORGANIZATIONS THAT HAVE HELPED TO FUND MY RESEARCH, AUTISM SPEAKS, NICHD AND NIMH, WITHOUT WHICH I CERTAINLY WOULD NOT BE HERE. WE HAVE ALREADY DISCUSSED THE ISSUE OF PSYCHIATRIC CO-MORBIDITY IN DETAIL TODAY, AND I AM CITING YET ONE MORE SLIDE OF PREVIOUS RESEARCH BY LEFUR AND COLLEAGUES WHICH SHOWS IN THEIR STRUCTURED DIAGNOSTIC STUS DI THAT CHILDREN WITH ASD GENERALLY HAD AT LEAST ONE CO-MORBID PSYCHIATRIC DIAGNOSIS, ONLY 27% IN THE STUDY DID NOT. SO TODAY I WANT TO TALK FIRST CONCEPTUALLY ABOUT SOME EMERGING THINKING IN MY LAB ABOUT THE POSSIBLE REASONS FOR SOME OF THOSE CO-MORBIDITIES, AND THEN MOVE ON IN THE SECOND HALF TO DISCUSS THE TREATMENT RESEARCH THAT WE'VE BEEN WORKING ON. ONE OF THE REALLY PUZZLING CHARACTERISTICS TO ME IN MY WORK IN THE CO-MORBIDITY OF ANXIETY AND ASD HAS BEEN WHY THE RATE OF ANXIETY IS SO HIGH IN CHILDREN WITH ASD. IN SEARCHING FOR REASON, ULTIMATELY WE'VE BEEN LOOKING FOR BOTH ENVIRONMENTAL AS WELL AS INTERPERSONAL FACTORS THAT MIGHT EXPLAIN THE LINKAGE. ONE INTERESTING POSSIBILITY WHICH WE'VE BEEN EXPLORING WITH OUR DATA WITH CHILDREN WITH ASD IS THAT POSSIBLY EXECUTIVE FUNCTIONING DEFICITS ARE RELATED TO THE ANXIETY ISSUES THAT ARE EXPERIENCED WITH SOME CHILDREN WITH ASD. IN GENERAL, EXECUTIVE FUNCTIONS ARE RELATED TO BASIC COGNITIVE ABILITIES SUCH AS INHIBITING IMPULSIVE RESPONSES, IN SHIFTING COGNITIVE SETS AND THINKING ABOUT STIMULI IN A DIFFERENT WAY AND IN AN ADAPTIVE SENSE, AND EXECUTIVE FUNCTIONS DEFICITS HAVE GENERALLY BEEN LINKED WITH MANY PSYCHIATRIC DISORDERS, ESPECIALLY ADHD, BUT ALSO SCHIZOPHRENIA, MOOD DISORDERS, AND ANXIETY DISORDERS IN THE GENERAL POPULATION. THESE DEFICITS ARE MORE PRONOUNCED IN PEOPLE WITH ASD AS WELL, AND IT SEEMS THERE MAY BE A COMMON LINKAGE EXPLAING WHY THERE IS SUCH AN EXTENT OF CO-MORBIDITY IN CHILDREN WITH ASD IN TERMS OF THESE EXACT SAME DIAGNOSES. SO PRELIMINARY RESEARCH IN MY LAB HAS BEEN LOOKING AT THESE LINKAGES AND INDEED FINDING CORRELATIONS BETWEEN EXECUTIVE FUNCTIONS AS MEASURED BY SIMPLE TASKS SUCH AS REVERSED NUMBER RESPONDING AND OTHER TYPES OF COGNITIVE PATHS, AND SCORES ON PARENT REPORTED MEASURES SUCH AS THE CASI ON ANXIETY, ADHD SEVERITY, MOOD SYMPTOMS AND SO FORTH. AND SEEMINGLY THERE MAY BE SOME IMPORTANT LINKAGES THAT SHOULD BE FURTHER INVESTIGATED. THERE'S SOME OTHER RESEARCH THAT'S BEEN PUBLISHED IN THE LITERATURE ALREADY IN ASD I, WHICH LINKED EXECUTIVE FUNCTIONING DEFICITS WITH PSYCHOTIC SPECTRUM DISORDER SYMPTOMS SUCH AS ILLOGICAL THOUGHT IN CHILDREN WITH ASD, IN OTHER WORDS, GREATER DEFICITS IN CHILDREN WITH ASD THAT HAVE MORE PSYCHOTIC SYMPTOMS IN THE FORM OF ILLOGICAL THOUGHTS. SO THIS IS A VERY PRELIMINARY SET OF FINDINGS. THESE ARE NOT PUBLISHED IN MY LABORATORY YET, BUT AGAIN, IN SHARING SORT OF OUR THINKING ABOUT HOW TO UNDERSTAND THESE CO-MORBIDITIES, THIS IS ONE IMPORTANT DIRECTION THAT WE FEEL THE FIELD MAY NEED IT TO GO IN. IT'S ALSO INTERESTING TO COVER THAT THIS NOTION OF AUTISM AS A MULTITUDE OF VARIABLY CAUSED DISORDERS MAY BE VERY HELPFUL IN UNDERSTANDING WHY SOME PEOPLE DO AND OTHERS DO NOT HAVE CERTAIN CO-MORBIDITIES IN AUTISM. A PARALLEL AND VERY INTERESTING SET OF WORK HAS BEEN DONE IN THE FIELD ON A PSYCHOPA THEE PARTICULARLY IN ADULTS WHICH HAS USED PHENOTYPING AND BASICALLY PERSONALITY TRAIT PSYCHOLOGY TO UNDERSTAND -- ONE OF WHICH INVOLVES ESSENTIALLY EXTREMELY LOW LEVELS OF FEARFULNESS AND THE OTHER OF WHICH INVOLVES VERY HIGH EMOTIONALITY, EYE NEUROTICISM AND POOR EMOTION -- BRAIN CORRELATES HAVE BEEN MAPPED ON TO THESE SORT OF SUBTYPES OF PSYCHOPATHY AND DIFFERENT CLINICAL OUTCOMES THAT ARE LINKED AS WELL. SO AN ADDITIONAL AREA OF INTEREST, I THINK, IS TO IDENTIFY AT A PHENOTYPIC LEVEL, ARE THERE PATTERNS OF TRAITS THAT INDIVIDUALS WITH ASD HAVE, WHICH MAY ULTIMATELY HELP TO EXPLAIN WHY CERTAIN PEOPLE HAVE HIGH RISK FOR SOME CO-MORBIDITIES, PARTICULARLY PSYCHIATRIC ONES, AND OTHER PEOPLE HAVE RISKS FOR OTHERS OR NO CO-MORBIDITIES WHATSOEVER. ALONG THESE LINES, SOME INITIAL GENETIC RESEARCH HAS BEEN SUGGESTING THAT SOME OF THE SAME MARKERS FOR CO-MORBID PSYCHIATRIC DISORDERS SUCH AS ANXIETY AND DEPRESSION, WHICH ARE PRESENT IN PEOPLE WITHOUT ASD, ARE ALSO PRESENT IN PEOPLE WITH ASD WHO HAVE THE SAME CO-MORBIDITIES, AND I WOULD POINT TO GENERAL GABOW'S WORK AS EXCELLENT RESEARCH IN THAT FIELD. AT ANY RATE, A MODEL THAT KEN AND I PUBLISHED A FEW YEARS AGO IN TRYING TO UNDERSTAND SOME OF THE CO-MORBIDITY EFFECTS ALSO LOOKS AT ENVIRONMENTAL FACTORS. HAD HAD IS THE MODEL, AND IN SHORT, WE'RE FOCUSING ON ASD-RELATED STRESSORS WHICH MAY PRODUCE GREATER SUSCEPTIBILITY TO, IN PARTICULAR, ANXIETY BUT OTHER KINDS OF MOOD SYMPTOMS TOO SUCH AS ANG GER AND DEPRESSION. THE BASIC IDEA IS THAT HAVING ASD OFTEN PRODUCES VERY SPECIFIC DAILY STRESSORS FOR INDIVIDUALS THAT OTHER PEOPLE DON'T NECESSARILY EXPERIENCE. SOME EXAMPLES ARE SOCIAL CONFUSION, UNPREDICTABILITY OF SOCIAL ENCOUNTERS, PEER REJECTION, VICTIMIZATION EXPERIENCES, PREVENTION OF ACCESSING PREFERRED ACTIVITIES, FOR INSTANCE, DURING SCHOOL. SO THE IDEA IS THAT THERE'S A LONG -- DECADES LONG BODY OF RESEARCH SHOWING THAT DAILY STRESSORS THAT ARE FRUSTRATING TO PEOPLE INCREASE ANXIETY, ANGER, AND OTHER NEGATIVE MOOD SYMPTOMS, AND IF PEOPLE WITH ASD ARE EXPERIENCING A HIGH LEVEL OF DAILY STRESSORS, THEN IT MIGHT FOLLOW THAT THERE IS HEIGHTENED ANXIETY AND OTHER TYPES OF MOOD SYMPTOMS THAT ARE CORRELATED WITH THIS. SO A DISSERTATION STUDY THAT'S RECENTLY BEEN COMPLETED IN MY LAB HAS FOUND BOTH MEASURING STRESS AT THE PARENT REPORT LEVEL AND AT THE CORTISOL LEVEL IS INDEED LINKED WITH HIGHER LEVELS OF THESE TYPES OF MOOD SYMPTOMS AS REPORTED BY BOTH CHILDREN AND PARENTS, AND THE INTERESTING QUESTION TO ASK IS, IS THERE A LINKAGE THEN BETWEEN THIS INCREASED LEVEL OF EMOTIONALITY AND NEGATIVE MOOD AND SOME OTHER MORE DISTAL EFFECT SUCH AS INCREASED SOCIAL AVOIDANCE, AND AVOIDING COPING AND REACTIVE AND AGGRESSIVE COPING ON THE PART OF CHILDREN THAT MAY EXPLAIN EVEN A BROADER SWATH OF PSYCHIATRIC SYMPTOMS, FOR INSTANCE, THOSE IN THE DISRUPTIVE BEHAVIOR DOMAIN. THIS HAS YET TO BE DETERMINED, BUT OUR MODEL WOULD PREDICT IT, AND WE'RE TRYING TO INVESTIGATE THAT FURTHER. VERY BRIEFLY, WE'VE ALSO BEEN INTERESTED IN THE IDEA THAT DR. SCAHILL BROUGHT UP ABOUT THE DIFFERENTIATION BETWEEN ANXIETY AND AUTISM SYMPTOMS, PER SE, SO IN A PAPER PUBLISHED IN MY LAB USING -- MODELING, WE ESSENTIALLY FOUND THAT THE SEVERITY OF ASD SYMPTOMS AS INDICATED BY THINGS LIKE THE ADOS AND THE ADIR AND SRS HAD ESSENTIALLY ALMOST ZERO CORRELATION WITH CONSTRUCTS RELATED TO ANXIETY, SEPARATION ANXIETY, SOCIAL PHOBIA AND TOTAL ANXIETY BASED ON CHILD, PATIENT AND CLINICIAN REPORT. SO THIS WAS DONE MAINLY TO INVESTIGATE THE IDEA THAT THERE IS THIS OVERLAP, AND YET TO WHAT EXTENT DO ANXIETY SEVERITY AND AUTISM SEVERITY ACTUALLY TRAVEL TOGETHER IN THE AUTISM POPULATION. THIS ONE STUDY SUGGESTED IT MAY BE A FAIRLY LOW LEVEL OF COVARIANCE. MOVING ON TO THE TREATMENT RESEARCH THAT I'VE BEEN DOING, AND I REALIZE I DON'T HAVE MUCH TIME, WE'VE BEEN STUDYING COGNITIVE BEHAVIORAL THERAPIES FOR BOTH THE CO-MORBID IT OF ANXIETY AND OCD IN CHILDREN WITH AUTISM, AND YOUTH WITH AUTISM, BUT ALSO MORE RECENTLY, CBT OR CORE AUTISM SYMPTOMS THEMSELVES, AND WE HAD FOUND IN EARLIER WORK THAT CBT, WHEN ADAPTED CAREFULLY IN PEOPLE WITH ASD, SEEMED THAT IT WAS HAVING SOME IMPACT ON PARENT REPORTED AUTISM SYMPTOMS, SO WE FOLLOWED THESE EARLY STUDIES UP WITH LARGER STUDIES USING OBSERVATIONAL MEASURES OF AUTISM SYMPTOM SEVERITY WHETHER TO DETERMINE IT MIGHTING USEFUL IN ACTUALLY ADDRESSING COURT FEATURES OF AUTISM SUCH AS PERSPECTIVE TAKING, LOW SOCIAL MOTIVATION, REPETITIVE BEHAVIORS AND SO FOR. IN DOING SO, WE HAVE BEEN CONCURRENTLY DEVELOPING A MEASURE TO TRY TO PERSONALIZE MEASUREMENT OF OUT COME, AND THE IDEA HERE IS THAT PARENTS IDENTIFI TOP PROBLEMS THAT THEIR CHILDREN ARE EXPERIENCING WITHIN THE REALM OF AUTISM SYMPTOMS, AND THEN THEY RATE THESE PROBLEMS CONTINUOUSLY THROUGHOUT TREATMENT AND ULTIMATELY WE WANT TO KNOW IF THESE THREE TOP PROBLEMS CAN BE IMPROVED, PERSONALIZED TO EACH TILED WITH CBT, AND IF THAT IS -- LIKE THE SRS AND THE ADOVE AND SO FORTH. WE'VE BEEN USING VIDEOTAPING IN THE HOME TO TRY TO VALIDATE THIS PARTICULAR MEASURE AND OUR REPORT IS DUE TO AUTISM SPEAKS IN A FEW WEEKS AND FORTUNATELY THERE'S GOOD NEWS, THERE'S A LOT OF CONVERGENCE BETWEEN INDEPENDENT CODING OF TEASE BEHAVIORS AND PARENTS' CODING OF THE BEHAVIORS ON A DAILY BASIS. SO THE MEASURE LOOKS PROMISING, WE DON'T KNOW HOW IT'S GOING TO PERFORM AS A TREATMENT MEASURE YET BUT THAT IS COMING UP. SO IN THE FUTURE, IT FEES LIKE CBT MAY BE A WORTHWHILE TREATMENT APPROACH TO CONTINUE TO ASSESS AND POTENTIALLY DISSEMINATE. I RECENTLY HAVE PUBLISHED AN ARTICLE ON POTENTIAL IMPLEMENTATION PLANS FOR ANY EVIDENCE BASED INTERVENTION IN THE SCHOOLS AND COMMUNITY HEALTH CLINICS DUE TO THE DIRE NEED OF CREATING ACCESS TO GOOD QUALITY INTERVENTIONS IN OUR COMMUNITIES AND NOT JUST DEEP IN OUR RESEARCH CENTERS, SO THIS IS IMPRESSED IN BEHAVIOR THERAPY, AND I FEEL THAT CURRENTLY, THE TREATMENTS THAT I'VE BEEN DEVELOPING, ARE TOO PRELIMINARY TO ACTUALLY BE MOVING TO AN IMPLEMENTATION STAGE. HOWEVER, WITH THE HELP OF NICHD, WE ARE CURRENTLY TESTING CBT IN A MORE STRINGENT CLINICAL TRIAL VERSUS AN ACTIVE ALTERNATIVE CBT TREATMENT FOR THE ANXIETY CAN CO-MORBIDITY SPECIFICALLY, AND THIS IS A THREE-SITE TRIAL AND WE MAY HAVE A CLEARER IDEA OF HOW BENEFICIAL CBT FOR CHILDREN WITH AUTISM MIGHT BE AT THE END OF THIS TRIAL, AS WELL AS THE ONES FUNDED BY NIMH AND AUTISM SPEAKS FOR CORE AUTISM SYMPTOMS. MY FINAL POINT IS THAT I THINK LOOKING FORWARDS THE FUTURE, INVESTIGATING GENETIC, NEUROLOGIC, NEUROPSYCHOLOGICAL AND PERSONALITY SUBSTRATES OF CO-MORBID PSYCHIATRIC DISORDERS IN ASD MAY BE VERY BENEFICIAL IN UNDERSTANDING BETTER HOW SIMILAR ARE THESE CO-MORBIDITIES TO THE SAME TYPES OF SYMPTOMS THAT ARE IN THE GENERAL POPULATION, AND TWO EXAMPLES OF HAD TYPE OF RESEARCH MIGHT BE FUNCTIONAL NEUROIMAGING, PEOPLE WITH AND WITHOUT HIGH ANXIETY, AND IN THE CONTEXT OF ASD -- SECOND, PURSUING THIS IDEA THAT EXECUTIVE FUNCTIONING DEFICITS AND STRESS MAY PREDICT GREATER CO-MORBIDITY CONCURRENTLY AND OVER TYPE, SEEMS LIKE PERHAPS A FRUITFUL DIRECTION TO PURSUE. SO THANK YOU FOR YOUR TIE. [APPLAUSE] YOUR TIME. >> THANK YOU, JEFF. SO OUR LAST SPEAKER FOR THIS SECTION IS EVDOKIA ANAGNOSTOU. EVDOKIA IS A SENIOR CLINICIAN SCIENTIST AND ASSOCIATE PROFESSOR AT THE BLOORVIEW RESEARCH INSTITUTE AND UNIVERSITY OF TORONTO. EVDOKIA. >> MY JOB TODAY -- IT'S A PLEASURE TO BE HERE. MY JOB TODAY SO TO TALK A LITTLE BIT ON THE DEFINITIONS OF CONSTRUCT. I WANT TO DISCLOSE MY BIAS. I MY FUNDING IS IF FIGURING OUT WHAT IT WOULD TAKE TO TAKE THE EMERGING GENOMIC FINDINGS, THE EMERGING BASIC SCIENCE FINDINGS AND GET TO NOVEL COMPOUNDS OR ALL COMPOUNDS THAT WE HAVE THAT WOULD ACTUALLY TARGET THOSE MECHANISMS. SO THIS IS MY BIAS AND HAD IS THE LENS BY WHICH I SEE THESE ISSUES, SO YOU'LL SEE HOW THIS BECOMES A LITTLE TRICKY IN EFFECT. SO THERE'S BEEN LOTS OF NICE DATA PRESENTING ON PREVALENCE. I JUST HAVE THIS ONE UP JUST TO REMIND US THAT IT MATTER WHEN IS WE LOOK, SO FOR THE FIRST TWO TALK, YOU SAW THE DISCREPANCY PREVALENCE IN O C D AND IN ANXIETY. IF WE LOOK AT A 30-YEAR-OLD, THIS IS THAT COHORT THAT UCLA -- FROM THE 80s THAT HAD BEEN FOLLOWED AND CLASSIFIED WITH DSM-IV CRITERIA, THEN THE RATES OF THOSE CO-MORBIDITIES LOOK MUCH HIGHER. IT ALSO MAKES A DIFFERENCE A LITTLE BIT ABOUT WHETHER WE LOOK AT CODES, WHICH ACTUALLY MAKE IT POSSIBLE TO DO VERY LARGE SIZED RESEARCH, OR WHETHER WE ACTUALLY USE EXPERT CLINICIANS WHO ADMINISTER STRUCTURED INTERVIEWS, AND ACTUALLY MAKE EXPERT DIAGNOSIS, WHICH WAS IN THIS CASE. SO YOU'LL SEE A LITTLE BIT OF A DISCREPANCY, ALTHOUGH NOT THAT MUCH, SO YOU SEE THAT ADULTS WITH ASD WHO HAVE CHILDHOOD DIAGNOSIS OF ASD, WE HAVE ALMOST 70% CHANCE OF A LIFETIME OCCURRENCE OF A CO-MORBID NEUROPSYCHIATRIC DISORDER, WITH ANXIETY DISORDER LEADING IN TERMS OF NUMBERS FOLLOWED BY OCD, THESE ARE 30-YEAR FOLLOW-UPS, THESE ARE 30-SOMETHING-YEAR-OLDS IN TERMS OF THE MEANS. SOME INCREASED PREVALENCE IN EXTENSIVE MOOD PROBLEMS IN SIGH TO TICK DISORDERS BUT STILL REMAIN LOWER THAN THE OTHER PROBLEMS AND DEPRESSION DATA HAS BEEN CHALLENGED A LITTLE BIT, IT'S AN INTERESTING DISCUSSION TO HAVE. THIS PARTICULAR STUDY DID NOT LOOK AT ADHD CO-MORBIDITY JUST BECAUSE IT'S NOT PART OF THE INSTRUMENT THAT THEY USE TO IDENTIFY CO-MORBID CONDITIONS. THE OTHER THING THAT HAS BEEN REPORTED BEFORE AND PEOPLE IN THE ROOM HAVE ACTUALLY AVOIDED THEAREPORTEDTHEM BEFORE, AGE IS NOT THE ON LY THING THAT MATTER, I.Q. AND LANGUAGE ABILITY ALSO MATTERS. SO IN THIS PARTICULAR COHORT, VERY CONSISTENT WITH PREVIOUS, THERE IS A MUCH LOWER PREVALENCE OF ANXIETY AND DEPRESSION IN PEOPLE WHO HAVE LOWER IQs OR WHO HAVE LANGUAGE DIFFICULTIES. THIS BRINGS ME TO THE ISSUE THAT I'M GOING TO START DISCUSSING BECAUSE I'M NOT GOING TO GIVE YOU A PREVALENCE TALK. THE PEOPLE WITH INTELLECTUAL DISABILITY HAVE NEUROLOGY DISTINCT FROM PEOPLE WHO DON'T HAVE INTELLECTUAL DISABILITY BUT MAKES THEM LESS LIKELY TO HAVE INTERNALIZING DISORDERS, OR IS IT THAT THE WAY WE MEASURE INTERNALIZING DISORDERS IS MORE LIKELY TO IDENTIFY THOSE DISORDERS IN PEOPLE WHO HAVE HIGHER IQs AND HIGHER LANGUAGE ABILITY, AND, THEREFORE, WE ARE MISSING PEOPLE WITH THE SAME BIOLOGICAL CONSTRUCT IN THE GROUP OF PEOPLE WHO HAVE IQs BELOW 70. SO THIS BECOMES THIS DISCUSSION OF CONSTRUCT. IS IT THAT THE CONSTRUCTS WE HAVE FOR THIS DIAGNOSTIC -- I DON'T MEAN TO BE FACETIOUS, BUT IS IT THAT THEY DO NOT MAP ON THE BIOLOGICAL CONSTRUCTS, THEREFORE WHEN WE LOOK AT COCONCURRENCE, THIS IS A MOOT POINT BECAUSE THE CONSTRUCTS THAT WE ARE LOOKING AT ARE NOT ADDITIVE BECAUSE THEY'RE NOT DISTINCT BIOLOGICAL ENTITIES. IS IT THAT OUR MEASUREMENT PRODUCES CONFUSION BECAUSE QUEER NOWE'RENOT QUITE CLEAR WHAT WE'RE CALLING ANXIETIES IN THE POPULATION DEPENDING ON THEIR IQ, THEIR LANGUA AND BIOLOGICAL SUBSTRATE, AND WITH WHAT DOES ALL THIS CONFUSION MEAN FOR TENT DEVELOPMENT? MY BIAS WOULD BE NEW MEDICATION DEVELOP M, HOW DO YOU TRANSLATE FROM BASIC SCIENCE TO TREATMENT KNOWING THIS. SO I'M JUST GOING TO BRING A COUPLE OF EXAMPLES. MOST OF OUR FUNDING IS CANADIAN, AND WHAT WE HAVE ARGUED WITH THE CANADIAN FUNDING AGENCIES IS TO GIVE US THE ROOM TO CONSIDER THAT OUR DIAGNOSTIC CONSTRUCTS ARE NOT VALID, PERIOD. SO THEN WE HAVE -- WE BASICALLY WERE ABLE TO GET FUNDING TO CREATE A LARGE BIOMARKER CORE THAT RECRUITS CHILDREN WHO HAVE ASD, OCD, INTELLECTUAL DISABILITY, IN EVENT OF RARE SYNDROMES WE TYPICALLY ASSOCIATE WITH AUTISM AND CREATE A SERIES OF PLATFORMS FOR CHARACTERIZATION THAT ARE DIAGNOSIS AGNOSTIC, SO ALL THE KIDS GET THE SAME GENOMICS, THE SAME IMAGING, THE SAME PHENOTYPING FOR BEHAVIOR AND COGNITION, AND THEN THE QUESTION BECOMES, ARE WE VALIDATING USING T BIOLOGICAL SYSTEM THE EXISTING CONSTRUCT OR ARE WE SAYING THAT BIOLOGY DOES NOT MAP TO THIS CONSTRUCT. TO LOTS OF DATA NOW TO SUGGEST THAT ADHD AND ASD HAVE OG GENOMIC ARCHITECTURE. THIS IS -- WHICH IS AN INTERESTING GENE BECAUSE IT'S IMPORTANT FOR MIGRATION -- GUIDED MIGRATION, SO THE ORIGINAL CASES WERE REPORTED UNDER INTELLECTUAL DISABILITY, A COUPLE OF CASES WERE REPORTED AND THEY WERE ASD. SO WE COMBINED OUR COHORT WITH THE LARGE GENOMIC COHORTS WE HAVE ACCESS TO AND LOOKED AT WHAT OTHER PHENOTYPES ARE DESCRIBED FOR THIS VARIANT. WE'RE GETTING OVERLAPPING -- THERE WAS SOME DEBATE AT SOME POINT WHETHER THEY WOULD PREDICT DIFFERENCE IN -- AND WE'RE NOT GETTING THAT, SO OVERLAPPING, WE GIVE YOU IN OUR HANDS -- A LITTLE BIT OF SCWIZ FREN YA A BIT OF PIE POLAR, WITH EPILEPSY. RESPONSIVE DATA ACROSS A VARIETY OF THOSE GENES. SO WHAT DOES IT MEAN TO HAVE CO-OCCURRING ADHD AND ASD WHEN THE SAME GENETIC VARIANTS WILL PRODUCE BOTH SYNDROMES? THIS CO-OCCURRING CONTEXT -- CONCEPT IS BECOMING DIFFICULT TO INTERPRET. IN ADDITION, WHEN WE LOOK AT THE RARE CASES, WE HAVE 46 NOW CASES ACROSS, AND WE LOOK AT WHAT CLINICIANS PUT THAT IN THE DATABASE, THE MOST COMMON DIAGNOSES -- LANGUAGE DELAY, ANXIETY AND OCD. SO -- CAPTURED BY A SINGLE TYPE OF MUTATION. AND THERE ARE VARIATIONS IN THE EXPRESSION OF THIS PARTICULAR MUTATION DEPENDING ON WHERE THE CUT POINTS ARE AND ALL OF THAT, BUT THE POINT IS, IT'S VERY EASY TO START FROM A VERY -- FROM A SINGLE OR SIMILAR EARLY GENETIC DIFFERENCE AND END UP WITH A VARIETY OF THOSE NEWER DEVELOPMENTAL DISORDERS. SO ONE PROBLEM. SECOND PROBLEM I IS A MEASUREMENT PROBLM, AND I'M A NEUROLOGIST, I'M A LITTLE BIT CRUDE THERE, SO THIS IS THE CLINICAL DILEMMA IN THE NEUROLOGY CLINIC. THAT'S THE KID WHO COMES IN WITH GENERALIZED ANXIETY FROM THE GENERAL POPULATION, WHO HAS PERSISTENT WORRIES THAT HE CANNOT CONTROL, BUT THAT MAY BE UNREASONABLE, HAVE THE SAME ANXIETY WITH A LOW FUNCTIONING -- WHOSE PARENTAL REPORT IS THAT HE'S SPACING, HE'S HYPERAROUSED BOTH GET AN ANXIETY DIAGNOSIS, BUT IS THE BIOLOGICAL CONSTRUCT OF THOSE TWO ANXIETIES THE SAME THING, AND HOW DO WE DO TRANSLATION IF WE CALL BOTH ANXIETY BUT WE DO NOT KNOW THAT THE BIOLOGICAL CONSTRUCTS IS THE SAME THING. AND THEN IN AN EFFORT TO CLARIFY THAT, WE'RE ASKING WHETHER BIOLOGY STUDIES CAN CLARIFY THOSE QUESTIONS, AND AGAIN, I'LL SHOW YOU A LITTLE BIT OF EARLY DATA AND I DON'T MEAN TO BE SIMPLISTIC, THIS IS JUST TO SEE OUR THOUGHT PROCESS IN THIS BIOMARKER CORE. SO IT HAS ALREADY BEEN NOTED, THERE IS A KNOWN SIGNATURE AND THAT SIGNATURE FOR INSIDE THE GENERAL POPULATION. YES, THE DIFFERENT ANXIETIES HAVE A SLIGHTLY DIFFERENT SIGNATURE. BUT YOU KNOW, GOING WITH GENERALIZED ANXIETY CONCEPT FOR THE PURPOSE OF THIS DEMONSTRATION, WE KNOW THAT WE HAVE ANOTHER -- WE HAVE INCREASED SWEATING, INCREASED HEART RATE, CUTANEOUSCONSTRICTION, SO WE CAN LOOK AT HEART RATE AND HEART RATE VARIABILITY AND ELECTRODERMAL ACTIVITY TO MEASURE THESE THINGS. SO OUR QUESTION IS IF WE DESCRIBE ANXIETY IN TERMS OF SELF-REPORT WHERE AUTISM IS IMPAIRED BECAUSE OF COMMUNICATION DIFFICULTIES AND -- DIFFICULTIES, A AND IF WE MEASURE ANXIETY BASED ON BEHAVIOR, WHICH IS A BIT ALSO PROBLEMATIC, BECAUSE BEHAVIOR WE USED TO CALL ANXIETY COMES FROM ALL DIFFERENT KINDS OF CONSTRUCTS FROM ASD, CAN WE USE -- WE DO THE SAME TNG WITH IMAGING. WE HAVE A SIMILAR PIPELINE THAT WE DO WITH IMAGING. SO THIS IS A LITTLE BIT OF OUR DATA. IF YOU LOOK AT HEART RATE, COMPARE ASD TO CONTROL, ABOUT 40 AND 40 KIDS AT THIS POINT IN THE SAMPLE. SO YOU GET INCREASED HEART RATE COMPARED TO CONTROLS WITH ASD AND YOU GET A BIT OF -- SO THIS IS A PARADIGM WHERE THE KIDS DO TWO TASKS THAT ARE ANXIETY PROVOKING, IT GETS FASTER AND FASTER AND EVERYBODY GETS REALLY ANXIOUS. THEY'RE DOING A SERIES OF TASKS, THEY ARE NOT PARTICULARLY ANXIETY PROVOKING. SO YOU'LL SEE ACROSS THESE TASKS, YOU GET HIGHER HEART RATES IN THE KIDS WITH ASD VERSUS CONTROLS. BUT YOU GET THE STATISTICALLY SIGNIFICANT DIFFERENCE AT BASELINE, AND YOU GET THE DAMPENED RESPONSE IN THE PUBLIC SPEAKING TASKS. YOU SEE ALTHOUGH THERE'S A TREND ACROSS, THIS IS NOT THE GENERAL PHENOMENON. YOU DON'T GET IT ACROSS ALL DOMAINS, YOU GET IT AROUND THE ANXIETY TASKS AND BASELINE. FOR HEART RATE -- RIGHT NOW WE'RE NOT GETTING VERY MUCH YET. IT COULD BE THAT WE SEPARATE THIS LATER. I'LL SHOW YOU THAT. BUT HEART RATE VARIABILITY SEEMS TO BE PULLING OUT AT A COGNITIVE LOW TASKS. THEN IF YOU LOOK AT THE ELECTRODERMAL ACTIVITY, YOU GET CONTROLS AND YOU GET ASD YOU AND GET AGAIN THIS PATTERN THAT'S CONSISTENT WITH INCREASING -- LOWS. SO THE QUESTION IS IF WE SPLIT THE CASE WITH ASD TO HIGH ANXIETY AND LOW ANXIETY KIDS, WOULD WE SEE A DIFFERENCE IN A PATTERN LIKE THAT? NOW, WE HAVE A MEASUREMENT HERE, I'M NOT GOING TO GO THERE BECAUSE I'D LIKE TO TALK ABOUT IT IN DETAIL. WE'RE AS GOOD AS OUR MEASURE, BUT WE'RE TAKING -- 65 AND WE'RE LOOKING AT KIDS WHO ARE HIGH ANG SIT VERSUS LOWER ANXIETY PLUS CONTROL. SO CLEARLY THE KIDS WHO HAVE HIGHER ANXIETY LOOK DIFFERENT THAN THE CONTROLS, AND THIS IS A SIGNATURE THAT WE SEE IN THE GENERALIZED ANXIETY LITERATURE. THERE'S NOTHING ATYPICAL PER SE WITH THE PATTERN EXCEPT THE KIDS WHO HAVE AUTISM WHO ARE NOT SUPPOSED TO BE HAVING ANXIETY STILL HAVE THIS INCREASED AROUSAL PATTERN, INSO NOW WE HAVE A CONCEPT PROBLEM AGAIN. IS IT THAT OI OUR MEASURE IS NOT SENSITIVE ENOUGH TO PICK ALL THE KIDS WHO HAVE ANXIETY, OR IS IT THAT THE MEASURE IS DOING JUST FINE, BUT THAT THE PATTERN WHICH IS THE SIGNATURE OF ANXIETY IN THE GENERAL POPULATION ISN'T PARTICULARLY SPECIFIC FOR ANXIETY IN ASD, IN WHICH CASE WE HAVE A BIOLOGICAL CONSTRUCT PROBLEM. IN EITHER CASE, WE HAVE A CONSTRUCT PROBLEM. SO WHAT WE'RE DOING RIGHT NOW IS WE ARE ADDING -- WE HAVE ALL THE KIDS IN THE GENERAL POPULATION WITH ALL THE DIFFERENT ANXIET TO FIGURE OUT WHAT THEIR PATTERNS LOOK LIKE, AND WE'RE ADDING NUMBERS, AND WE HAVE AN IMAGING CORE THAT GOES AT THE SAME TIME. BUT THIS IS AGAIN TO HIGHLIGHT, WE CAN TALK ABOUT MEASUREMENT, WE CAN TALK ABOUT TREATMENT, BUT WE ARE NOT QUITE SURE WHAT OUR CONSTRUCTS ARE. WE'RE NOT QUITE SURE WHAT THE CONSTRUCT OF ANXIETY IS IN THIS POPULATION. SO THIS IS MY LAST SLIDE. I WOULD ARGUE THIS IS A CRITICAL PROBLEM FOR DRUG DEVELOPMENT, AND AGAIN, THIS IS MY BIAS, BUT TAKE IT AS IS. SO P IF, LET'S SAY, ANXIETY IN THE GENERAL POPULATION AND ANXIETY IN ASD IS THE SAME BIOLOGICAL CONSTRUCT, WE DON'T HAVE A PROBLEM OF MEDICATION DEVELOPMENT. THERE ARE PLENTY OF MEDICATIONS THAT ARE EFFECTIVE FOR GENERALIZED ANXIETY IN THE DMEUNT, AND THE MAIN PROBLEM WE HAVE THAT WE HAVE TO DEAL WITH IS HOW DO WE GET KIDS WITH AUTISM INTO THE MENTAL HEALTHCARE SYSTEM? SAME THING, YOU CAN THINK COGNITIVE CONSTRUCTS TOO, SO IN THE CASE OF ADHD, I LIKE THIS BECAUSE I SEE IT IN CLINIC, IF THE ATTENTION DEFICITS OF ADHD IN GENERAL POPULATION WOULD STAND TO BE DIFFICULT IN SUSTAINING ATTENTION AND STOPPING, ARE THE TYPES OF ATTENTION DEFICITS WE GET IN ASD, WE'RE GOOD. BUT FOR THE ATTENTION DEFICITS IN ASD ARE SHIFTING AND ORIENTING AND OTHER TYPES OF PROBLEMS IN THE ATTENTION PATHWAY THAT THEY'RE NOT TYPICAL OF ADHD, THEN WE HAVE A CONSTRUCT PROBLEM THAT WOULD MAKE IT UNLIKELY WITH OUR MEDICATIONS THAT WERE DEVELOPED FOR ADHD IN THE COMMUNITY WILL ACTUALLY BE AS EFFECTIVE FOR KIDS WITH ASD. SO I WOULD SAY WE NEED TO RESOLVE THIS ISSUE, THIS IS THE GAP IN THE LITERATURE OF CO-OCCURRING CONDITIONS, IF YOU WANT TO CALL THEM THAT, BECAUSE WE NEED TO FIGURE OUT WHETHER WE NEED DRUG DEVELOPMENT FOR THIS CO-OCCURRING CONDITION BECAUSE THE CONCEPTS ARE BIOLOGICALLY DISTINCT OR WHETHER WE ACTUALLY DEALING WITH A COMMON BIOLOGICAL CONSTRUCT THAT EXISTS IN THE COMMUNITY THAT WE HAVE TREATMENT FOR, AND IT'S ABOUT SERVIC DELIVERY. THE LAST, LAST THING I'M GOING TO PUT THERE FOR FOOD FOR THOUGHT, ESPECIALLY IN THE PRESENCE OF REGULATORY AGENCIES, IS IS WHAT DO WE DO WITH THIS PROBLEM WHERE OUR GENOMIC INFORMATION HAS NO SENSITIVITY FOR DIAGNOSTIC CONSTRUCT OR VICE VERSA, THAT DIAGNOSTIC CONSTRUCT IS NOT SHOWING SPECIFICITY FOR THE BIOLOGICAL PATHWAY. SO IF WE'RE THINKING DRUG DEVELOPMENT, WE HAVE TO, BASED ON THE CURRENT REGULATORY CON CONTEXT, THINK ABOUT DEVELOPING DRUGS FOR SPECIFIC DISORDERS, RIGHT? BUT IF THE BIOLOGY WE ARE TARGETING WITH THE DRUG DEVELOPMENT IS NOT SPECIFIC OR SENSITIVE FOR A SPECIFIC DISORDER, THEN -- THE RIGHT CONTEXT TO DEVELOP EFFECTIVE DRUGS THAT MAKE BIG CHANGES IN KIDS AND ADULTS -- FUNCTION OF LIFE AND -- OF LIFE. AND I'LL STOP THERE. [APPLAUSE] >> THANK YOU TO ALL THREE SPEAKERS. IT'S A VERY INTERESTING SESSION BECAUSE YOU REALLY GET A SENSE OF THIS FIELD BEING AT A AN EARLY STAGE WHERE WE'RE REALLY GRAPPLING WITH SOME BASIC CON VUCTS AND LOTS OCONSTRUCTS AND LOTS OF QUESTIONS. I'M SURE THE GROUP HAS MANY QUESTIONS SO I'LL OPEN IT UP. YES, LYN. >> I'M SORT OF CONFUSED, ONE OF THE QUESTIONS I HAD WAS WITH REGARD TO THESE OUTCOME MEASURES, ES PUBLISH THE HEART RATE VARIABILITY, WITH THE STUDIES THAT WE HAVE FOUND THAT ABNORMAL IN AUTISM ALREADY, WHETHER OR NOT YOU'RE ACTUALLY MEASURING DYSFUNCTION IN THE YOU A NAUTONOMIC NERVOUS SYSTEM OR IF YOU'RE MEASURING ANXIETY. IF SOMEBODY COULD ADDRESS THAT ISSUE. THE SECOND WAS THE USE OF BETA-BLOCKERS IN ASD, WHICH THERE'S BEEN A FEW SMALL TRIALS AND IT'S BEEN VERY HELPFUL IN TERMS OF SOCIAL SKILLS, AND I'M WONDERING WHETHER OR NOT THAT MIGHT ALSO BE A WAY TO REDUCE ANY OF THE ANXIETY AND IF ANYONE IS LOOKING AT THAT AS WELL, IF IT IS SOMETHING THAT IS OF PHYSIOLOGICAL ABNORMALITY THAT'S DRIVING THE ANXIETY. >> SO TO COMMENT ON THE HEART RATE VARIABILITY, A FEW THOUGHTS. ONE IS, I DO THINK THAT THE STUDIES THAT HAVE BEEN PUBLISHED ALREADY DIDN'T NECESSARILY MANAGE THE ANXIETY QUESTION VERY WELL. THERE IS ONE RECENT ONE THAT I THINK DOES A LITTLE BIT BETTER JOB. OUR TAKE ON IT IS THAT WE'RE GOING TO TRY TO DO A BETTER JOB OF DECLINING ANXIETY AND THEN SEE HOW IT MAPS TO HEART RATE VARIABILITY. NOT THE OTHER WAY AROUND. IF IT DOES, THEN HEART RATE VARIABILITY COULD SERVE AS A EARLY MARKER IN EARLY DRUG STUDIES THAT WILL BE MORE PRECISE THAN SOME OF OUR MEASURES. ON THE ISSUE OF BETA-BLOCKER, RIGHT NOW I WOULD SAY WE HAVE A CHALLENGE TO MEASURE THE OUTCOME. BUT IT'S NOT A BAD IDEA. >> JOHN? >> GO AHEAD. >> I WAS JUST GOING TO MAKE A VERY BRIEFLY COMMENT ON THE BETA-BLOCKERS, BUT I THINK THAT'S THE QUESTION. SO IF THEY LOWER FUNCTION INTAKE, WALKING AROUND, TOUCHING, HAS EXTREMELY -- HEART RATE AND HIGH BLOOD PRESSURE, HAS A DIFFERENT ANXIETY THAN THE --, THE EVIDENCE FOR THE -- FOR THE LOWER FUNCTIONING KID WOULD NOT BE VERY GOOD AND YOU WOULD THINK ABOUT MECHANISMS OF MANIPULATING -- TO TREAT THAT CHILD. SO WE NEED TO GET OUT IF THE ANXIETY IS THE SAME AS THE ANXIETY OF THE CHILD WHO HAS WORRIES AND THOUGHTS AND ALL OF THAT. >> I'D LIKE TO OFFER A PERSPECTIVE FROM BEING AN AUTISTIC CHILD. YOU KNOW, MY GRANDFATHER ALWAYS SAID TO ME, BOY, IT'S EASIER BEING DUMB, BUT AT THE SAME TIME, YOU KNOW, I KNOW NOW WHEN I WAS GROWING UP, PEOPLE SAID HORRIBLE THINGS ABOUT ME. AND THEY WENT RIGHT OVER MY HEAD AND ALL THIS CHILD ABUSE STUFF, YOU KNOW, AND ALL THAT WAS IN MY FAMILY, MUCH TV PASSED ME RIGHT BY AND NOW I THINK IT'S BECAUSE I WAS AUTISTIC AND IT PROTECTED ME FROM THE WORST OF IT, BUT AT THE SAME TIME, WHAT I DID PERCEIVE HURT ME TERRIBLY TERRIBLY. THE IDEA THAT HE'S OBLIVIOUS TO IT SO IT'S NOT A PROBLEM WAS ABSOLUTELY WRONG IF MY PAIN IS A GUIDE. I WANT TO MAKE CLEAR THAT WE CAN BE AUTISTIC AND OBLIVIOUS, WE CAN BE DUMB AND OBLIVIOUS, WE CAN BE WHATEVER YOU WANT TO SAY, BUT THAT DOESN'T MEAN THAT WE CAN'T SUFFER TREMENDOUSLY. AND I THINK THAT'S A REALLY IMPORTANT POINT WHEN WE TALK ABOUT THESE KINDS OF TREATMENTS. IT'S ONE THING TO SAY WE DON'T SUFFER FROM AUTISM. WE ARE AUTISTIC AND WE ARE DIFFERENT. BUT WHEN WE TALK ABOUT DEPRESSION AND ANXIETY, PEOPLE ABSOLUTELY SUFFER FROM THOSE THINGS AND THEY END THEIR LIVES OVER IT. THAT WHINGS ME TO THE NEXT POINT I WANT TO MAKE ABOUT WHAT YOU SAID WHICH I THOUGHT WAS VERY SIGNIFICANT, IT'S A GOOD QUESTION TO ASK IF THE BIOLOGICAL FOUNDATION OF ANXIETY OR DEPRESSION IS THE SAME IN AUTISTIC PEOPLE AS IT IS IN THE REST OF THE POPULATION. BUT WE COULD JUST AS WELL ASK THAT QUESTION OF MANY OTHER POPULATION SUBGROUPS WITH RESPECT TO PSYCHIATRIC DISORDERS, AND THAT'S NOT A REASON FOR INACTION. AND ONE THING THAT REALLY TROUBLES ME IS THAT IT'S VERY EASY TO GO FROM RAISING A PERFECTLY VALID RESEARCH QUESTION, AND ABSOLUTELY AGREE WE SHOULD STUDY IT, TO SAYING, WELL, WE'RE NOT READY TO TELL THE CLINICIAN COMMUNITY THAT THEY SHOULD BE LOOKING OUT FOR ANXIETY AND DEPRESSION IN AUTISTIC PEOPLE. JUST BECAUSE WE DON'T KNOW WHAT THE FOUNDATION -- DOES NOT MEAN WE SHOULD NOT BE TAKING ACTION, ABSOLUTELY TIME TO ACT IN MY OPINION. EVEN IF I'M DUMB, I SEE THAT. SO -- >> WELL, WE KNOW YOU'RE NOT DUMB, JOHN, THAT'S FOR SURE. >> MY GRANDFATHER SAID SO ANYWAY. >> OKAY. AND I DO WANT TO JUST EMPHASIZE THE POINT THAT YOU MADE BECAUSE I THINK IT CAME UP IN A NUMBER OF THE SPEAKERS' TALKS, WHICH IS THE IDEA OF EARLY STRESS AS A RISK FACTOR FOR LATER ANXIETY. AND THINK WHAT YOU'RE TALKING ABOUT IS THAT PEOPLE WITH AUTISM DO EXPERIENCE A LOT OF STRESS IN LOTS OF DIFFERENT WAYS, AND THIS COULD CONTRIBUTE TO LATER ANG SIE. >> I THINK THAT'S THE THING. IT'S VERY EASY TO LAUGH AT PEOPLE AND SAY, YOU KNOW, WE'RE JUST LIKE DOGS OR WE DON'T KNOW THE DIFFERENCE. YOU CAN TELL A DOG YOU'RE GOING TO EAT IT FOR DINNER AND HE WAGS HIS TAIL, BUT AT SOME LEVEL, WE SOAK THIS STUFF UP AND IT HURTS, AND IT REALLY DOES, AND IT'S FOLLOWED ME ALL MY LIFE. AND EF ONE WHO CONSIDERS YOU KNOW, I THINK WE SHOULD BE AWARE OF THAT, BECAUSE I THINK IT'S CRAZY TO THINK SOMEONE WHO'S LESS VERBAL THAN ME IS IMMUNE TO THOSE FEELINGS. >> RIGHT. AND I DO THINK THAT IS ONE OF THE POINTS THAT A COUPLE OF THE SPEAKERS WAS MAKING, IS THE CHALLENGE OF THESE INTERNALIZING KINDS OF DISORDERS, WHETHER IT'S ANXIETY OR DEPRESSION, OFTEN HAVE RELIED ON INTRO SPECS AND SELF-REPORT, AND SO BAW PEOPLE ARE AUTISM HAVE TROUBLE TALKING ABOUT THEIR OWN FEELINGS, PERHAPS, WE ASSUME THAT THEY'RE NOT EXPERIENCING THESE, AND THAT IS REALLY A MISJUDGMENT. I KNOW YOU HAVE A POINT TO MAKE. NO? OKAY. >> IT SEEMS THAT THE SPEAKERS TODAY ARE -- WHAT WE'RE ALL STRUGGLING WITH IS THE CONCEPTS OF HOW WE ACTUALLY KNOW WHAT IS AN EMERGENT PROPERTY OR A COMPLICATION OF AUTISM, OR IF IT'S JUST AN ACCIDENTAL CO-OCCURRING PHENOMENON, AND I'LL BRING A METAPHOR OF DIABETIC KIDNEY DISEASE TO THE TABLE. PATIENTS WITH DIABETIC KIDNEY DISEASE -- WELL, WITH DIABETES ARE AT INCREASED RISK OF HAVING KIDNEY DISEASE. WE CAN TREAT THAT KIDNEY DISEASE IN A COUPLE WAYS. WE CAN TREAT IT WITH A CHANGE IN -- IN THE FUNDAMENTAL PROCESS THAT'S INVOLVED IN THE PATHOGENESIS OF DIABETES AND CHANGE DIET AND EXERCISE, AND THAT WILL IMPROVE KIDNEY DISEASE, OR WE CAN TREAT THE F WITH ANTIFIBROTICS THAT ARE DIRECTED SPECIFICALLY AT THE KIDNEY DISEASE. BOTH HAVE SOME VALIDITY, BOTH ARE SUPPORTED BY SCIENTIFIC EVIDENCE, BUT IF WE CAN GET AT SOMETHING THAT'S FUNDAMENTALLY INVOLVED IN INCREASING THE ODDS RATIO OF COMPLICATIONS OF AUTISM, THEN WE'RE DOING SOMETHING MORE -- WE'RE CHANGING THE WHOLE FIELD OF THINGS THAT A CHILD MIGHT HAVE TO FACE OVER THE COURSE OF THEIR LIFETIME. SO I GUESS -- SO THIS IDEA OF CONSTRUCT VALIDITY IS INCREDIBLY IMPORTANT, BECAUSE IF WE JUST CALL IT SOMETHING SIMILAR -- SO ANXIETY IS JUST THIS ISOLATED CONCEPT LIKE KID FE KIDNEY FIBROSIS, THEN WE TREAT IT JUST LIKE KIDNEY FIBROSIS WITH A DRUG DEVELOPED TO DO THAT. BUT IF WE THINK OF IT IN THE BROADER CONTEXT OF THE AUTISM SPECTRUM DISORDERS AND WE DO MORE FOR OUR CHILDREN CHILDREN. >> I WANTED TO BUILD ON THAT BECAUSE I AGREE THAT THE SPEAKERS WERE FASCINATING, AND IT GOT ME THINKING, BECAUSE I'M GOING TO TALK IN MY TALK ABOUT THE AROUSAL DISREGULATION POTENTIALLY BEING A TRIGGER AND FEEDING INTO ANXIETY, G.I. PROBLEM, INSOMNIA, AND DAN ALREADY BROUGHT UP THE CONNECTION BETWEEN G.I. AND INSOMNIA AND WHAT MIGHT BE DRIVING THAT, AND I THINK YOU'RE ABSOLUTELY RIGHT, BECAUSE IF THAT IS TRUE AND IF WE DO SHOW THERE'S A POTENTIALLY AUTONOMIC DRIVER, THEN WE CAN FOCUS TREATMENT ON -- I THINK THAT'S WHAT YOU'RE GETTING AT. SO IT MIGHT BE TBTT MAY BE CERTAIN DRUGS, BUT REALLY UNDERSTANDING AND TEASING OUT WHAT THE DRIVER IS, I THINK IS EXTREMELY IMPORTANT IN TERMS OF PLANNING THERAPIES. >> I THINK THE IMPORTANCE OF THIS DISCUSSION TRANSLATES TO EDUCATION, AND THINGS MUST BE QUANTIFIED FIRST IN MEDICINE BEFORE SCHOOLS EVER PAY ATTENTION TO THEM, AND I CAN'T TELL YOU HOW MANY TIMES SERVICES HAVE BEEN DENIED TO AN INDIVIDUAL ON THE SPECTRUM BECAUSE IT WAS SAID THAT THEY WERE TOO LOW TO HAVE ANXIETY OR TOO LOW TO EXPERIENCE DIFFERENT SORTS OF CONSTRUCTS THAT YOU ALL ARE WORKING HARD TO QUANTIFY, SO KEEP IT UP. THANK YOU. >> I WANTED TO THANK THE SPEAKERS, ALL OF THEM WERE WONDERFUL IN DEMONSTRATING HOW COMPLICATED THIS ISSUE S I WANTED TO TOUCH ON A COUPLE THINGS IN TERMS OF THE AGE, EVEN THOUGH AGE SHOULDN'T MATTER BUT IT DOES, BECAUSE IN MY WORLD OF PEDIATRICS, AS ONE THE SPEAKERS MENTIONED, WE DON'T DIAGNOSE LITTLE ITTY BITTY ONES WITH ANXIETY TRADITIONALLY. AND IT SURPRISED MESSY AFTER DR. CAHILL'S TALK THAT AS THE AGE RISE, THE INCREASED INCIDENCE OF MEDICATION RISES, BECAUSE AS THESE KIDS GET OLDER, THE DEMANDS ARE MORE AND THEY DEMONSTRATE IT BEHAVIORALLY. SO ONE OF THE KEY THINGS HEERYLY STARTING TO IDENTIFY A TOOL TO HELP US FIGURE OUT, QUANTIFY THE CHIEF COMPLAINT, THE PARENTS COME TO US WITH, WHICH IS MY CHILD, IS ANXIOUS, AND IT'S VERY DIFFICULT FOR US TO TEASE APART WHAT DOES ANXIETY MEAN AS HE MENTIONED. IS IT RESISTANCE TO TRANSITION, IS IT SEPARATING FROM PARENTS, NOT WANTING TO DO SOMETHING THAT'S NOVEL, SO THE OBSERVABLE BEHAVIOR, I THINK IS REALLY KEY HERE, BECAUSE THAT IS WHAT WE'RE SEEING. THAT'S WHETHER IT'S A SCHOOL DISTRICT OR WHETHER IT'S IN A DOCTOR'S OFFICE AND QUANTIFYING THAT. NUMBER ONE. NUMBER TWO, I JUST WANTED TO SORT OF MORE FROM A PHILOSOPHICAL STANDPOINT WHEN WE TALK ABOUT DRUGS, I HOPE WE'RE USING THAT AS A TERM IT FOR INTERVENTION BECAUSE, AGAIN, IN PEDIATRICS, AND I THINK ACROSS THE BOARD MOST OF US WOULD AGREE THAT MEDICATION MAY NOT BE THE APPROPRIATE FIRST STEP FOR TREATMENT FOR IN AND THAT THERE IT ARE SOME OTHER TREATMENTS THAT CAN BE USED, INCLUDING DIET, NUTRITION, ET CETERA, ET CETERA. AS WELL AS DRUGS. THANK YOU. I JUST WANTED TO DWELL A LITTLE BIT ON THE CONSTRUCT IDEA AND I WONDER IF WE WOULDN'T GET FURTHER PERHAPS BY THINKING ABOUT RESPONSE TO STIMULUS OR JUST REGULATORY RESPONSE TO STIMULUS IN A SENSE THAT IT'S BEING POTENTIALLY EXPRESSED DIFFERENTLY AND TRIGGERED DIFFERENTLY IN KIDS WITH AUTISM BUT IT'S KIND OF THE SAME THING IN THE SENSE OF THE BIOLOGICAL CONSTRUCT, ALMOST AS IF IT'S A LANGUAGE OF EXPRESSION OR THE KINDS OF TRIGGERS AND I JUST AM NOT BEING VERY ARTICULATE, BUT WHAT CAME TO MIND WAS IN DR. TALK, RESPONSE TO NOISES, CROWDS, THAT KIND OF THING, POTENTIALLY SIMILAR ACROSS KIDS AFTER CERTAIN AGE GROUP WHO ARE GETTING EXPOSED TO THESE KINDS OF ENVIR BUT THEN HOW DO THEY SORT OF PROCESS THAT AND EXPRESS IT DIFFERENTLY. OFTEN I FIND WITH MY DAUGHTER AS WELL AS A LOT OF THE KIDS I'VE SEEN IN PRACTICE THAT IT'S REALLY A MATTER OF DEGREE IN TERMS OF HOW THESE THINGS GET BOTH TRIGGERED AS WELL AS EXPRESSED. YOU WONDER IF WE MIGHT BE ABLE TO KIND OF THINK ABOUT WHAT A CONSTRUCT MEANS A LITTLE BIT DIFFERENTLY AS A MATTER OF THRESHOLD OR DEGREE AS OPPOSED TO SOMETHING ALL TOGETHER DIFFERENT. >> YOU'RE RAISING TO ME I THINK A REALLY CENTRAL ISSUE, THIS IDEA OF CATEGORIES VERSUS DIE MENTIONS, AND TO ME, IT WOULD BE MORE USEFUL FOR UNDERSTANDING THE RANGE OF THESE PROBLEMS IN CHILDREN WITH ASD P IF WE THOUGHT ABOUT A DIE MENTIONAL. WHETHER IT WILL REALLY COME OUT THAT WAY, I DON'T REALLY KNOW, BUT THERE' LOT OF SCALES OUT THERE THAT HAVE LOTS TO BACK THEM UP BUT THEIR PRACTICALITY RUNS INTO A PROBLEM BECAUSE THEY HAVE MULTIPLE FACTORS THAT BARS YOU FROM USING THE TOTAL SCORE BECAUSE THE FACTORS COLLIDE, AND THE INDIVIDUAL FACTORS ARE FEW IN NUMBER, AND SO THEN THEY DON'T WORK AS INDIVIDUAL FACTORS. I HOPE WE DON'T FIND OURSELVES PAINTED IN THAT CORNER BUT INTERESTING DIE MENTIONS. >> I WOULD CONCUR THE IMPORTANCE OF GETTING AWAY FROM THESE CURRENT CATEGORIES AS ESSENTIAL. I WAS REALLY PLEASED THAT EACH OF THE SPEAKERS SORT OF TALKED ABOUT ANXIETY MORE GENERICALLY AND DIDN'T BOTHER TO INVOKE ANY OF THE NINE OR 12 OR 15 DIFFERENT CATEGORIES THAT ARE IN THE DIAGNOSTIC MANUALS NOW, BECAUSE IT'S CLEAR, THERE'S NO BIOLOGICAL VALIDITY TO ANY OF THOSE, AND THOSE HAVE TO BE REDONE SORT OF FROM THE BIOLOGICAL DATA TO TELLS WHERE THE CLASS FIRES WOULD BE. BUT THE SAME IS TRUE FOR AUTISM, WE DON'T KNOW HOW MANY DISORDERS AUTISM WILL TURN OUT TO BE. THIS GOES BACK TO SAAC'S QUESTION ABOUT AUTISM. THE QUESTION I HAD FOR THE THREE OF YOU ON THE PANEL, TO WHAT EXTENT IS THE PRESENCE OF SEVERE ANXIETY HELP US AS A CLASS FIRE? DOES IT IDENTIFY A SUBGROUP IN TERMS OF PROGNOSIS, IN TERMS OF OTHER ASPECTS OF THE DISORDER, IN TERMS OF TREATMENT RESPONSE, ARE THESE THE KIDS WHO RESPOND BETTER OR WORSE TO BEHAVIORAL INTERVENTIONS, TO MEDICATION? CAN YOU GIVE US ANY SENSE, OR MAYBE IT'S NOT A USEFUL CLASS FIRE BUT IT WOULD BE HELPFUL TO KNOW THAT. >> I'M INTERESTED IN IT BECAUSE I THINK THAT THERE PROBABLY ARE MEDICATIONS THAT WE SHOULD BE PURSUING FOR CHILDREN THAT ARE TEENAGERS THAT ARE ON THAT UPPER END OF THE DIE MENTION, SO I THINK IT IS FINDING OUT WHO'S LOW, WHO'S MEDIUM, WHO'S HIGH. RIGHT NOW IT'S A LITTLE BIT COMPOUNDED BY LANGUAGE, BECAUSE MOST OF THE MEASURES REQUIRE LANGUAGE. AND THEY ARE BIASED AGAINST CHILDREN WITH LANGUAGE DISABILITIES AND INTELLECTUAL DISABILITIES. SO THAT'S WHY I FEEL THERE'S A NEED FOR A NEW RATING. I'M VERY INTERESTED IN MEDICATIONS. >> ON THE CBG SIDE, I THINK UNFORTUNATELY THE RESEARCH IS TOO PRELIMINARY BECAUSE THE STUDIES ON CBG FOR ANXIETY AND AUTISM HAVE FOCUSED ONLY ON THE SUBGROUP OF THOSE WITH ANXIETY IN AUTISM AND HAVEN'T BEEN MORE BROADLY DISTRIBUTED ACROSS THE RANGE OF ANXIETY, WHICH PRECLUDES US FROM REALLY UNDERSTANDING WHAT DOES ANXIETY TELL US ABOUT THE POTENTIAL OF TREATMENT RESPONSE. NOW, THERE HAS BEEN SOME CONCEPTUAL WORK THAT HAS SUGGESTED THAT ANXIETY MIGHT BE A MARKER OF GREATER TREATMENT RESPONSIVENESS IF ONLY BECAUSE CHILDREN MAY BE MORE IN SOME CASES WITH ANXIETY RESPONSIVE TO REQUESTS TO ENGAGE IN CERTAIN TYPES OF INTERVENTIONS DUE TO THEIR HARM AVOIDANCE CHARACTERISTIC, AND THIS IS A COMPLETE CON JE CONJECTURE, BUT IN OUR EXPERIENCE WITH THE SUBGROUP CHILDREN WITH ANXIETY DISORDER AND ASD, THERE DOES TEND TO BE A VERY SIMILAR LEVEL OF COMPLIANCE WITH THERAPEUTIC TASKS AS COMPARED TO CHILDREN WITH JUST ANXIETY AND NOT ASD, WHICH IS AN IMPORTANT ONLY CLINICAL OBSERVATION BUT POTENTIALLY IMPORTANT. >> JUST AS A FOLLOW-UP, WE KNOW IN SO CALLED TYPICALLY DEVELOPING CHIRCH, NOT A VERY GOOD TERM, THAT PREPS OF ANXIETY, SEVERE ANXIETY AT AGE 8 IS A VERY GOOD PREDICTER FOR DEPRESSION AT AGE 28. I WAS THINKING ABOUT LISA'S DAY A TA FROM EARLIER THIS MORNING, STRIKINGLY HIGH RATES OF DEPRESSION IN AUTISM AND THE SUICIDAL EVENTS OR THOUGHTS IS REALLY REMARKABLE IF YOU JUST LOOK AT THE ODDS RATIO. DO WE KNOW ANYTHING ABOUT THE LINK WITHIN THE AUTISM DIAGNOSIS, WHETHER THE KIDS WITH ANXIETY OR THE ADULTS WITH AUTISM HAVE DEPRESSION, STA ACTUALLY KNOWN OR ANYBODY LOOKED AT THAT? OKAY. >> THERE IS OM RESEARCH IN THE LITERATURE THAT CORRELATES EARLY SENSORY SENSITIVITIES WITH LATER ANXIETY OR THE DEVELOPMENT OF ANXIETY BUT ALSO CORRELATES IT WITH THE DEVELOPMENT OF G.I. RELATED CONDITIONS. I DON'T KNOW WHETHER THIS WAS SPECIFIC TO ABDOMINAL PAIN, WHICH OFTEN DOES GO WITH ANXIETY, BUT I WONDER ABOUT THAT CLUSTER OF SYMPTOMS AND WHETHER THAT MIGHT BE A TYPE OF SUBTYPE? >> SO SINCE THE QUESTION WAS DIRECTED TO ME, UNFORTUNATELY I CAN'T GIVE YOU A POSITIVE ANSWER BECAUSE YOU'RE TALKING ABOUT TWO DIFFERENT SOURCES OF DATA. ONE IS MEASURES OF SENSITIVITY, AND I'D HAVE TO FIGURE OUT WHETHER THERE WAS EVIDENCE IN THE CLINICAL NOTES ABOUT THAT, PEDIATRICIAN NOTES THAT MAY OR MAY NOT WORK, RATHER THE G.I. ONES SEEM TO JUMP OUT, WHICH I'LL TELL YOU, AS I HEAR ALL THESE DISCUSSION, IT'S GREAT THAT WE SORT OF RAISED THE GAME OF EVERYBODY BY LOOKING AT THE DATABASES, SEEMS TO ME THAT WAS MISSING FOR ALL OF US. ALTHOUGH WE CAN PUSH A LITTLE BIT FURTHER TOWARDS IT AS LONGITUDINAL INFORMATION, JUST WHO ARE THE KIDS WHO ARE GOING TO GET BETTER NO MATTER WHAT WE DO, WHO ARE THE KIDS WHO ARE GOING TO GET BETTER IF WE DO CERTAIN THINGS, AND WHO ARE THE KIDS THAT STAY OR GET WORSE REGARDLESS OF WHAT WE DO AND SO ON. I THINK THAT'S HUGELY IMPORTANT, AND I THINK IT WILL GIVE US EVEN BETTER STRATIFICATION OF SUBGROUPS. SO I THINK YOUR QUESTION IS A SUBSET OF THAT QUESTION, OF THAT CHALLENGE, I THINK IT'S HARD UNTIL GET BETTER AT -- SO I'LL SPEAK FOR MYSELF, I AM GOING TO TRY TO UNDERSTAND THOSE INTERMEDIATE MEASURE, BUT I SUSPECT WE'LL HAVE GOOD SPECIFICITY IN THE SENSE OF WE'LL BE ABLE TO FIND CASES WHERE THERE'S HIGH SENSITIVITY AND TRACK THOSE ALONG, WE'RE NOT GOING TO HAVE GOOD -- HIGH SPECIFICITY, WE'RE NOT GOING TO HAVE GOOD SENSE ITTIVITY OF KIDS WOULD HAVE SENSITIVITY ISSUES, WHICH WE WON'T PICK UP BECAUSE NO ONE ACTUALLY BOTHERED TO NOTE IT ANYWHERE IN ANY EITHER PROSPECTIVE DATABASE OR ELECTRONIC MEDICAL RECORD. >> WERE YOU ASKING IF THERE WAS SUCH A STUDY OR -- BECAUSE WILL IS ONE -- >> THERE IS -- SO I WAS MENTIONING THERE IS SOME REALLY NICE LITERATURE ON ANXIETY AND G.I. AND SENSORY, AI JUST REALLY HADN'T HEARD THE SPEAKERS TALK ABOUT THAT CLUSTER OF SYMPTOMS AND ALSO SOME DEVELOPMENTAL MODELS ABOUT HOW EARLY SENSORY SENSITIVITIES COULD LEAD TO LATER DEVELOPMENT OF ANXIETY DISORDERS AND AS WELL AS G.I. RELATED CONDITIONS. >> I JUST WANTED TO GO BACK WITH THAT COMMENT TO THE AUTONOMIC NERVOUS SYSTEM AGAIN BECAUSE THAT'S ALSO VERY IMPORTANT IN CONTROLLING G.I. FUNCTION AS WELL. SO I'M WONDERING WHETHER OR NOT YOU'RE SEEING A PATTERN HERE WITH THIS SORT OF ABNORMAL FIGHT OR FLIGHT RESPONSE, TO ME ABNORMALITIES IN THE AUTONOMIC NERVOUS SYSTEM, THAT WE REALLY HAVEN'T FULLY INVESTIGATED. AND I THINK THAT'S AN AREA THAT WOULD BE REALLY RIPE FOR R BECAUSE IT CAN EXPLAIN SOME OF THESE VERY DISPARATE CO-MORBIDITIES WE'RE SEEING WITH ONE UNDERLYING MECHANISM, WHICH COULD BE REALLY NICE IF THAT IS THE CASE TO START DEVELOPING TARGETS FOR TREATMENT. SO I REALLY HOPE THAT WE CAN BRING A LOT OF THESE ABNORMALITIES TOGETHER USING MAYBE SYSTEMS BIOLOGY TO TRY TO UNDERSTAND WHAT IS THE DRIVER AND THEN THAT, I THINK, IS ALSO GOING TO HELP US TO DETERMINE IN A WAY WHAT IS CAUSING THESE ABNORMALITIES IN OUR CHILDR AND WHAT THE ACTUAL ETIOLOGY FOR THIS DISORDER. SO I JUST -- I CAN'T BEG ANYMORE TO PLEASE DO THAT AS FAST AS POSSIBLE. >> JIER EE BROUGHT UP A REALLY INTERESTING POINT, THE SENSORY, SENSITIVITY, MAY BE A SUBTYPE WITHIN THE BROADER TERM. I THINK ONE OF THE ISSUES GOES BACK TO NOT HAVING A TOOL, AND OUT COME MEASURE THAT'S VALIDATED IN THAT WORLD, WE HAVE OUR SENSORY SCREENERS, OUR PROFILES, BUT THEY ARE NOT AS -- THEY'RE NOT USED IN PRACTICE OR ESPECIALLY TO, AGAIN, GENERATE THESE -- TO ASSESS CHANGES IN OUT COME MEASURES, AND I THINK THAT WOULD BE ANOTHER GOOD THING TO LOOK AT IN TERMS OF DEVELOPING TOOLS TO DRIVE THERAPY. >> I JUST WANT TO CLARIFY SOMETHING, I DON'T THINK WE HAVE ANY EVIDENCE FOR AN AUTONOMIC C AT LEAST WITH THE DATA WE HAVE SO FAR, WE DON'T HAVE EVIDENCE FOR -- BUT YOU CAN GET -- FROM SENSORY VISION EARLY MOST OF THE TIME WHERE WE GET DYSFUNCTION, IT IS NOT -- [INAUDIBLE] IT'S -- DRIVING AUTONOMIC DYSFUNCTION. WE HAVE SOME EVIDENCE FOR THAT, G BACK TO THE IDEA THAT SUBPHENOTYPE, THERE WAS MIXED FINDING -- UP AND DOWN, AND NOW THE DATA THAT I HAVE SEEN THAT'S COMING OUT, LONGITUDINAL -- LOOKS LIKE THE -- THEY LOOK LIKE A DISTINCT -- THEY LOOK LIKE THEY'RE GOING TO ULTIMATELY DEVELOP ANXIETY, SO SOME OF THE STUFF, WE -- I DON'T THINK IT'S CLEAN BUT I THINK BETWEEN CNS MEASUREMENTS, AUTONOMIC SERVICE SYSTEM MEASUREMENT AND WHATEVER WE MANAGE TO DO WITH CLINICAL CONSTRUCTS OF ANXIETY, I DO THINK -- IT LOOKS LIKE IT MAY BE SEEN AS A DISTINCT SUBGROUP. ALSO IT'S A BIT TOO EARLY TO MAKE A BIG STATEMENT ABOUT WHETHER SOCIAL MOTIVATION PREDICTS ANXIETY, BUT WE NOW HAD SO FAR KIDS WHO HAVE SCORED LOW ON SOCIAL -- NOT SEEM TO BE HAVING HIGH SCORES OF ANXIETY, SO IT SEEMS TO BE ANOTHER, AGAIN, KIND OF SUBGROUP OF KIDS, AND THE KIDS WHO DON'T CARE IF LOWER RATES OF ANXIETY PROVIDED THAT WE KNOW WHAT ANXIETY -- >> WE HAVE ONE MORE COMMENT. >> I WAS JUST GOING TO SAY ONE THING, YOU KNOW, WE SHOULD ALSO JUST NOT FORGET THAT THE RESPONSE TO ANXIET AND HOW IT'S DEALT WITH IS PLAYING A HUGE ROLE WITH A GREAT DEAL OF VARIATION AS WELL IN TERMS OF THE PARENTS AND THE FAMILY AND THE SCHOOLS AND THE SOCIAL MILIEU, SO THAT'S ANOTHER HUGE VARIABLE IN THE MIX. >> ALL RIGHT. WE'RE GOING TO BREAK FOR LUNCH UNTIL 12:45, IS THAT RIGHT, TOM? >> RIGHT. SO WE'LL NEED YOU RIGHT BACK HERE AT 12:45. IF YOU NEED TO, BRING YOUR LUNCH BACK IN WITH YOU. I THINK WE'RE ALLOWED TO EAT IN HERE. IF NOT -- WE'LL FIND OUT IF WE BREAK THE RULE, BUT WE DO WANT TO START PUBLIC COMMENT RIGHT AT 12:45. >> WE NEED TO RECONVENE, WE'RE A BIT BEHIND SCHEDULE. AND WE WANT TO GET INTO THE PUBLIC COMMENT PERIOD. SO THIS IS A REALLY CRITICAL PART OF THE MEETING FOR THOSE OF YOU NOT ON THE IACC WE'RE HAPPY TO HAVE YOU SIT IN, NOW CHANCE FOR PUBLIC TO TALK ABOUT IN THIS CASE TOPIC OF THE SYMPOSIUM ONCO OCCURRING DISORDERS. WE HAVE A LIST OF FIVE PEOPLE WHO HAVE SIGNED UP FOR GIVING PUBLIC COMMENT AND I WANT TO REMIND YOU WE HAVE BOTH WRITTEN VERSION OF THIS IN YOUR PACKAGE AS WELL AS A LOT OF OTHER WRITTEN COMMENTS THAT CAME IN. THAT'S 52 PAGES OR SO WRITTEN COMMENTS FROM THIS MEETING. WE ASK THE COMMENTERS TO KEEP THEIR REMARK A0L BRIEF A POSSIBLE, WON'T BE ABLE TO READ THE ENTIRE THING BECAUSE WE WON'T HAVE THE TIME BUT PRESUMABLY COMMITTEE MEMBERS HAVE READ THAT THEN WE'LL HAVE SOME TIME FOR DISCUSSION THEREAFTER. SO THE FIRST PUBLIC COMMENTER IN CAROLYN CAMIIA. CAN EITHER USE THE PODIUM HERE OR YOU CAN COME TO THE TABLE IF YOU WOULD BE MORE COMFORTABLE WITH THAT. >> SORRY ABOUT THAT. JOHN. FROM >> AT THE LAST MEETING I HEARD -- I READ OFF THE NAMES AND TOPICS OF THE WRITTEN PUBLIC COMMENTERS. AND WE MIGHT JUST TALK A COUPLE OF MINUTES SINCE WE LOST ONE OF OUR OTHER FOLKS, COULD RENIGH THE PEOPLE WHO HAVE WRITTEN TO US? >> PLEASE DO. GO AHEAD. >> SO THE FOLKS HAVE WRITTEN PARDON ME IF I GET YOUR NAMES WRONG HERE. WE HAVE THERESA AARONS WHO IS WRITTEN IN ABOUT CONCERNS WITH LIFE, WE HAVE (INDISCERNIBLE) MECHANANDI, WHO HAS WRITTEN IN ABOUT THE SPECTRUM. MARTIN FACE, EDUCATION. THERESA (INAUDIBLE), ABOUT THE NEED FOR US TO HELP AUTISTIC PEOPLE GET EDUCATION AND GET JOBS, SOMETHING THAT I HAVE A PERSONAL INTEREST IN. MARY ANN DARR TALKING ABOUT THE CHALLENGES OF LIFE AS WE TRY TO BECOME INDEPENDENT ADULTS. MARIA FERER,A TALKING ABOUT HEALTH ISSUES AND WHY WE DON'T DO OUR JOBS HERE. BEVERLY FROST TALKING ABOUT HER SON, ADULT SOP AND LIFE WITH AUTISM. FROM ANN BOWER WHO WANTS TO TALK ABOUT THE PUBLIC HEALTH CRISIS OF NON-VACCINATION. EILEEN SIMON WHO OFFERED QUITE A NUMBER OF WRITTEN COMMENTS AND IS ALSO HERE AS A PUBLIC COMMENTER. THERESA AGAIN ON THE ASSISTANCE TO A COLLEGE STUDENT. SHANNON ROSA HA WRITTEN IN TO ASK WE RECOGNIZE THE CAPABILITY OF AUTISTIC PEOPLE AND OUR NEED FOR SUPPORTS AND SHE ASKS THAT WE STOP ACCOMMODATING PSEUDOSCIENCE AND AND SPECIFICALLY VACCINE AND MERCURY CAUSATION THEORY. THEN AFTER THAT, WE HAVE DAWN -- I'M EMBARRASSED I WAS JUST TALKING TO HER TO GET HER NAME WRONG BUT -- I'M SORRY, I GOT IT WRONG, SHE'S HERE TOO. MIKE HOOVER HEATHER PRICE, MICHELLE SCHNEIDER KATHLEEN LEVINSTEIN, CAROL PERSELLA JOYCE AARON, RAFAEL (INAUDIBLE), THE PRINCIPAL THEME OF THESE COMMENTS IS THE OPPOSITE OF THOSE OF SHANNON ROSA THAT WE ARE IGNORING VACCINE CAUSATION AND I CAN REALLY SAY IS IT SHOWS HOW HARD IT IS TO TRY TO BE IMPARTIAL WHEN WE HEAR COMPLETELY THINGS FROM PEOPLE AND WE HAVE TO JUST DO OUR BEST, KRISTEN KAUFFMAN, JOSEPH JACKSON AND I WOULD LIKE TO JUST SAY ONE THING IN RESPONSE TO MR. JACKSON'S COMMENT, HE'S TALKING ABOUT THE CONSEQUENCES OF WHAT WE HAVE DONE TO CAUSE AUTISM AND THAT HIS SON BORN IN 2008 DID NOT HAVE TO HAVE AUTISM. I DON'T PROFESS TO KNOW WHY I AM AUTISTICKER WHY MY SON IS AUTISTIC BUT I HAVE YET TO MEET AN AUTISM ADULT -- AN AUTISTIC ADULT WHO CARES A GREAT DEAL HOW HE CAME TO BE THIS WAY, THE FACT IS THIS IS WHERE WE ARE AND I WISH PARENTS WOULD REMEMBER THAT ONE DAY CHILDREN WHO ARE THESE DESCRIBED AS DISEASE THINGS WE WILL RELUCTANTLY LOOK AT THESE COMMENTS BUT AT THE SAME TIME I WOULD WANT TO SAY AS AN AUTISTIC ADULT THAT I FEEL YOUR PAIN AND I KNOW HOW HARD IT IS BUT WE HAVE THE VIEW TOO. KATIE HARRIS, EILEEN NICOLE SIMON HA WRITTEN IN AGAIN. SUSAN WHAT WOULD ABOUT THE AUTISM EPIDEMIC. LESLIE PHILLIPS ABOUT THE TROUBLES OF HER TWO SONS WITH AUTISM. SHANDA JACKSON WHO WRITES ABOUT OUR FRAUD AS A DIRECTOR AND WHO SHE IS. I DON'T KNOW WHO SHE IS BUT MS. JACKSON KNOWS. I'M NOT BEING CYNICAL, IT'S NOT MENTIONED HERE. COURTNEY REED HA WRITTEN IN ABOUT THE STATEMENTS FROM WILLIAM THOMPSON THE CV WHISTLE BLOWER. TARA MCMILLAN, WRITING ABOUT HER VACCINE INJURED CHILD. MIKE HOOVER, MR. HOOVER IS WRITING ABOUT HIS VACCINE INJURED CHILD. CHRISTINE MARSHALL ABOUT WHAT WE ARE GOING TO DO WITH AUTISM IN SCHOOLS. HAVEN DELAY ON WHAT AUTISM REALLY IS AND HOW IT IS A VACCINE PROBLEM. SHANNON STRAYHORN, WE HAVE OUR LACK OF ACTION AND OUR CONSPIRACY WITH PHARMACEUTICAL COMPANIES. AND DAVE WALSH. I GUESS AND FINALLY WE HAVE CONNIE YOUNG. I JUST I WISH I KNEW WHAT TO SAY TO SETTLE THIS BY OF VACCINE BECAUSE IT IS THE MOST COMMON SOURCE OF COMMENTARY HERE AND AS AN AUTISTIC ADULT, I WOULD JUST LIKE TO SAY THAT I WISH THAT WE COULD MOVE FORWARD TO DEVELOP THERAPIES TO MAKE OUR LIVES BETTER INSTEAD OF BEING HUNG UP ON HOW WE GOT THAT WAY, BUT I KNOW SO MANY PEOPLE SEE IT DIFFERENTLY, ALL I CAN REALLY DO IS RECOGNIZE ALL OF YOU WHO WROTE IN AND THAT WE RESPECT YOUR OPINIONS AND WE READ THEM AND I NAMED THEM HERE. >> LET'S GO AHEAD WITH COMMENTS OF THE PEOPLE WHO ARE HERE, CASSANDRA OLDEN. >> I JUST WANT TO THANK YOU FOR THE OPPORTUNITY TO BE ABLE TO SPEAK TODAY AND BEFORE I READ WHAT I HAVE WRITTEN I JUST WANT TO SAY IF MY CHILDREN PUT COULD ARTICULATE SO WELL WHAT THIS GENTLEMAN DID I WOULD SLEEP BETTER AT NIGHT. I HAVE NON-VERBAL CHILDREN THAT I'M TALKING ABOUT. I LIKED IT AT A CAUSE BECAUSE I WANT TO STOP IT FROM HAPPENING TO OTHER PARTS AND CHILDREN. THE NUMBERS OF CHILDREN DIAGNOSED CONTINUE TO RISE WITH LITTLE BEING DONE TO FIND THE CAUSE OR THE CURE. EVEN IS MOVING SUCH A LEISURELY PACE. WE NEED TO CALL THIS THE EPIDEMIC IT IS. MY CHILDREN ACQUIRED ONSET OF VIA TOXINS. S. WE KNOW BASED ON MEDICAL TEXT AND THESE TOXINS WERE VACCINES. SOMETHING NEEDS TO BE DONE TO PREVENT OTHER CHILDREN FROM SUCH INJURIES. I KNOW THAT AT LEAST ONE OF MY CHILDREN'S DOCTORS HAS SPOKEN HERE IN THE PAST AND HAS MENTIONED MEDICAL TESTS THAT CAN BE DONE STARTING AT THE PEDIATRICIAN OFFICE. IN CASE YOU FORGOT WHAT THESE TESTS ARE, I WON'T TAKE THE TIME TO GO INTO THEM, I BROUGHT A COUPLE OF JOURNEY GUIDE THAT PUT THEM FORWARD, I WOULD LIKE TO GIVE ONE TO THE PEDIATRICIAN A SOON AS I'M DONE, IF ANYBODY ELSE WANTS ONE I WILL PROVIDE ONE FREE OF CHARGE, LET ME KNOW, GIVE ME YOUR NAME AND NUMBER AND I WILL GET THAT TO YOU. I HAVE WRITTEN MY NAME AN PHONE NUMBER ON THE INSIDE COVER SO IF YOU HAVE ANY QUESTIONS CALL ME AND I'LL GO THROUGH ANYTHING WITH YOU. MY CHILDREN HAVE NO FUTURE. THEY'RE EXTREMELY AFFECTED, THEY DO NOT TALK. THAT NEEDS TO STOP. IT WAS BROUGHT TO MY ATTENTION THAT SOME OF THE STUDIES THIS COMMITTEE USES TO MAKE CERTAIN OPINIONS WERE FALSIFIED AND CORRECTION WAS TAKING PLACE. PEOPLE NEED TO BE HELD ACCOUNTABLE BECAUSE CHILDREN CONTINUE TO GET HARMED. ALSO ANY OF THE NUMBERS YOU READ ON VACCINE INJURY DON'T INCLUDE MY VOICE. ANY NUMBERS YOU READ ON AUTISM DON'T INCLUDE MY VOICE. IF THEY DON'T INCLUDE THESE BOYS HOW MANY THOUSANDS OF CHILDREN ARE YOU LEAVING OUT OF THESE NUMBERS? THESE ARE PEOPLE AND THEY DESERVE A CHANCE. AS THESE STUDIES HAVE BEEN SKEWED WE NEED TO QUESTION THE VALIDITY OF THEM, BY GAINS FINANCIAL TIMES AN CONFLICT OF INTEREST. I WAS PERSONALLY ASKED TO REMOVE MY SON FROM A STUDY AT KENNEDY KREIGER WITH [PII redacted] BECAUSE MY SON WAS NEGATIVELY AFFECTING THE FINDINGS. DURING THAT TIME PERIOD A GENETICIST AT HOPKINS WHO STUDIED MY BOYS TOLD ME HE WAS NOT PUBLISHING SOME PAPERS ON AUTISM BECAUSE HE WAS SCARED OF THE REPER DUGS. HE TOLD ME CERTAIN KEY ASPECTS OF MY SON'S MEDICAL CONDITIONS WERE GOING TO BE ADMITED FROM THEIR FILE, NOT BECAUSE THEY WERE NOT ACCURATE BUT BECAUSE HE SAID H DIDN'T KNOW WHO I WAS GOING TO SHOW THEM TO. NOT ONLY DO MY CHILDREN NOT COUNT THEY SUFFER SO THE BENEFIT OF THE GREATER GOOD. SO COMMITTEE MEMBERS HAVE SAID THAT I'M A PARENT GRASPING FOR FALSE ANSWERS AND LOOKING TO BLAME. I WISH I HAD THE LUXURY TO GO TO BED BUT PIECE OF MIND MY CHILDREN WERE BORN WITH AUTISM IS LIKE DOWN'S SYNDROME BUT I KNOW BETTER. I DID NOT SEEK A MITOCHONDRIAL DIAGNOSIS. I WALKED INTO A HOSPITAL WITH A CHILD WHO DEVELOPED NORMAL, GOT SICK, REGRESSED, DEVELOPED AUTISM, THEY TOLD ME TOXINS CAUSED IT. NOW I KNOW BETTER AND I MUST SPEAK FOR FUTURE GENERATIONS. YOU HAVE THE POWER AND AUTHORITY TO MOVE ON CHANGE. SIT AND THIS WHERE YOUR MORAL COME PASS IS. ARE WE PART OF THE PROBLEM OR PART OF THE SOLUTION. MY CHILDREN SUFFER DAILY. ONE LITTLE THING I WOULD LIKE TO SUGGEST FOR FURTHER MEETINGS THAT IS A HUGE HINDRANCE FOR MY FAMILY IS MY CHILDREN CONTINUE TO BE TREATED LIKE FIFTH CLASS CITIZENS. I CAN'T TAKE THEM OUT IN PUBLY. HERE ARE THREE EXAMPLES. MY NINE-YEAR-OLD LOST HIS FINGER DOING SPECIAL NEED HOCKEY, WE WERE WE WERE IN THE ER THEY STAID THAT BECAUSE HE HAD AUTISM, IT WASN'T WORTH SEWING BACK ON BUT NORMALLY THEY DO A GRAPH. THIS WAS AT VIRGINIA HOSPITAL CENTER. MY SIX-YEAR-OLD WHEN TRAVELING WALK THROUGH TSA HE HAS A TRACKER ON HIM GIVEN DIBITHE SHERIFF'S OFFICE. HE SET OFF THE ALARMS AND BECAUSE HE DIDN'T HAVE THE VERBAL UNDERSTANDING I WAS NOT ALLOWED TO TOUCH HIM TO BE TOLD TO GO OVER TO THE SIDE HE WAS TREATED A HOSTILE AN THROWN IN A BOX BY TSA AGENTS. I WROTE A LETTER OF COMPLAINT BUT TSA INVESTIGATES TSA COMPLAINT AND THEY FOUND THEY WERE NOT AT HARM. ONE MORE THING. I HAD THREE THERAPISTS TELL ME THAT ONE OF THE THERAPISTS HAD BEEN ABUSING MY CHILDREN. I CALLED THE CPS AND THE POLICE AND THOUGH I HAD THREE WITNESSES NO CHARGES WERE FILED BECAUSE MY CHILD COULDN'T DESCRIBE WHAT HAPPENED AND HE DIDN'T LOOK TRAUMATIZED. THE ABUSE AND THE BASIC HUMAN RIGHTS TRAMPLING FOR THESE CHILDREN AND OTHERS NEEDS TO STOP. FROM PLEASE CONSIDER TALKING ABOUT THAT AND TRY TO MAKE CHANGE. THANK YOU. >> THANK YOU. ALLISON HOFFMAN. NOT HERE. EILEEN NICOLE SIMON. >> MY FIRST TWO SONS SUFFERED TRAUMA AND OXYGEN INSUFFICIENCY AT BIRTH. PEDIATRICIANS REAINSURED US THAT OUR CHILDREN WOULD OUTGROW THEIR DEVELOPMENTAL DELAYS. THEY DID MOSTLY. BUT PROBLEMS WITH LANGUAGE AND DEVELOPMENT REMAINED A SERIOUS IMPEDIMENT FOR COGNITIVE GROWTH. IN MY WRITTEN COMMENTS I DISCUSSED AUDITOR DEFICITS AND PROBLEMS WITH SPEECH PRODUCTION. I ALSO DESCRIBE RESEARCH WITH MONKEYS ON ASPHYXIA AT BIRTH. DAMAGE WAS MOST PROMINENT AND NUCLEI OF THE BRAIN STEM AUDITORY PATHWAY, BUT THEN MATURATION OF CEREBRAL CORTEX DID NOT PROCEED NORMALLY. AUTISM IS THE RESULT OF MANY DIFFERENT CAUSES. IN MY WRITTEN COMMENTS I POINTED OUT SOME OF THESE AND WHY ALL ARE LIKELY TO AFFECT SUBCORTICAL SITES. NUCLEI IN THE BRAIN STEM AUDITORY PATHWAY ARE SUSCEPTIBLE TO DAMAGE BY ALL OF AUTISM'S KNOWN CAUSES. FROM DURING GESTATION, DURING BIRTH AND FROM SOME NEONATAL INTERVENTIONS. PLEASE DISCUSS THE POSSIBILITY THAT CO-OCCURRING CONDITIONS IN AUTISM MAY ALL RESULT FROM INJURY OF BRAIN STEM SITES AND SUBSEQUENT DISRUPTION OF MATURATION. PLEASE DOES CUSS ALSO ANY EVIDENCE THAT LANGUAGE DISABILITY AND CO-OCCURRING CONDITIONS MIGHT BE MERE DIFFERENCES ON THE SPECTRUM OF NEURODIVERSITY. FROM THANK YOU. >> THANK YOU. [APPLAUSE] >> MEGHAN DAVENHALL. >> HELLO. I'M HERE REPRESENTING THE THINKING MOMS REVOLUTION AND I HAVE A STATEMENT CRAFTED BY OUR ORGANIZATION. WHAT WE'RE HERE TO SAY IS ABSOLUTELY NOTHING NEW. NOTHING THIS COMMITTEE HASN'T HEARD BEFORE FROM MULTIPLE OTHER PUBLIC COMMENTERS OVER THE YEARS. THAT'S A HUGE SUBSET OF INDIVIDUALS WITH THE AUTISM THAT THEY WERE NOT BORN WITH AUTISM. THESE CHILDREN YOUNG ADULTS AND ADULTS TYPICALLY DEVELOPING HEALTHY CHILDREN AND THEN REGRESSED INTO AUTISM. THIS IS NOT THE AUTISM THAT YOU SEE IN HIGHLY FUNCTIONING DEVELOPED THE WAY MR. ROBINSON DESCRIBED HIMSELF. THIS IS NOT WHAT WE'RE TALKING ABOUT BUT WE DON'T HAVE ANOTHER WORD. WE HAVE AUTISM. SO WE ARE TALKING ABOUT HIGH FUNCTIONING ADULTS, PEOPLE WHO LOVE WHO THEY ARE, AND SHOULD CELEBRATE WHO THEY ARE, AND WE'RE TALKING ABOUT KIDS WHO ARE SICK. THEY ARE TWO DIFFERENT THINGS AND WE CALL IT ALL AUTISM. THIS AUTISM IS EXTREMELY DIFFERENT, IT'S A DIFFERENT EXPERIENCE FOR THESE INDIVIDUALS. IT'S PAIN, IT'S BOWEL DISEASE, IT'S MITOCHONDRIAL DYSFUNCTION, SEIZURES. FROM IMNEURON DEFICIENCY, IN MANY CASES IT IS A SILENT PLEA FOR HELP THROUGH HEAD BANGING AND SELF-INJURIOUS BEHAVIORS AND AGGRESSION. FROM PARENTS HAVE BEEN SEARCHING FOR TREATMENT FOR THESE CO-CONDITIONS FOR YEARS WE PAY OUT OF POCKET BECAUSE THE INSURANCE WON'T PAY THE STAGGERING COSTS THAT OUR CHILDREN SUFFER FROM, OUR KIDS WHO FALL INTO THIS MODEL OF AUTISM, THE ONES HEALTHY AND BECOME URGENTLY ILL NEED TO BE TREATED WITH RESPECT AND LIKE HUMAN BEINGS THAT ARE SICK. THEIR PHYSICAL SYMPTOMS NEED TO BE ADDRESSED BY MEDICAL PROFESSIONALS IN THE SAME WAYS THAT THEY WOULD BE HANDLED BY -- IN A PERSON WITHOUT AUTISM. NEVER AGAIN SHOULD A PARENT HAVE TO HEAR FROM A DOCTOR OR PSYCHIATRIST THAT A PHYSICAL PROBLEM SUCH AS DIARRHEA OR CONSTIPATION AS WE DISCUSSED EARLIER, THAT IS JUST PART OF THEIR AUTISM BUT IT STILL HAPPENS. THAT IS WHAT PARENTS ARE HEARING. WHEN YOU GO TO THE PEDIATRICIAN THE SPECTRUM HAVE DIARRHEA, THEY HAVE CONSTIPATION, IT'S PART OF AUTISM. I TALKED ABOUT MY SON'S REGRESSION AT THE PEDIATRICIAN. A REGRESSION, TYPICALLY DEVELOPING CHILD REGRESSED INTO AUTISM AND I WAS TOLD THAT'S THE VERY DEFINITION OF AUTISM. WE NEED TO REWORK HOW WE'RE TALKING ABOUT THESE THINGS IN PEDIATRICIANS IN OFFICES ACROSS THE COUNTRY AND YOU NEED TO BE THE CHANGE FOR THAT HAPPENING. PARENTS HAVE BEEN TELLING YOU FOR YEARS THAT THERE WERE SOME TRIGGER THAT SAID SENT THEIR HEALTHY CHILD INTO A PHYSICAL DEVELOPMENTAL TAIL SPIN. THEY WATCH THIS HAPPEN TO THEIR KIDS AND WE'RE IGNORED. YOU IGNORE FIRSTHAND WITNESS ACCOUNTS OF DAMAGE TO OUR CHILDREN. YOU HOLD THESE MEETINGS THAT ACCOMPLISH NOTHING. AND GIVE US THE MIC A FEW TIMES A YEAR AND WE TELL YOU AUTISM IS MEDICAL. THIS VERSION OF AUTISM THAT THE PARENTS COME HERE AND TALK TO YOU ABOUT, LET ME BE CLEAR ON THAT. OUR CHILDREN GET BETTER WHEN WE TREAT THE MEDICAL PROBLEMS THEY HAVE, THEIR BEHAVIORS THAT LAND THEM ON THE SPECTRUM IN THE FIRST PLACE IMPROVE WHEN THEY GET HEALTHIER. AND YOU DON'T HEAR US YOU GIVE US 15 MINUTES OF YOUR DAY AND INTERRUPT PARENT WHOSE TRAVEL ON THEIR OWN DIME TO COME HERE AND SPEAK TO YOU. IF THEY GO OVER THEIR ALLOTTED THREE MINUTES, THEY GET INTERRUPTED. AS LONG AS WE END THE MEETING BY 5. I WANT TO THANK DR. CORRY FOR RECOGNIZING ONE THING I HAVEN'T HEARD HERE IN ALL THE TIME I HAVE BEEN LISTENING AND WATCHING AND COMING TO THE MEETINGS. I HEARD THE PHRASE THE PARENTS ARE THE EXPERTS ON THEIR CHILDREN. I HEARD IT FROM OTHER PEOPLE IN THE ROOM TODAY TOO. AND BOTTOM LINE, WE ARE. WE ARE THE EXPERTS ON OUR CHILDREN. WE SEE WHAT THEY'RE LIVING WITH DAY IN AND OUT, THE MEDICAL CONDITIONS WE ARE TRYING SO DESPERATELY TO FIND ANSWERS FOR. BUT WE RECEIVE NONE. I HOPE TODAY THAT YOU HEAR IT AS WELL. TREATING THE CO-OCCURRING CONDITIONS IS CRITICAL. BUT IT IS ABSOLUTELY NOT ENOUGH. THIS COMMITTEE NEEDS TO START GETTING SERIOUS ABOUT PREVENTION. YOU NEED TO START INVESTIGATING THE DANGERS OF VACCINES, PESTICIDE EXPOSURE, OF ANTIBIOTIC OVERUSE. CHEMICALS THAT ARE IN OUR FOOD SUPPLY, THAT WE KNOW CAUSE NEUROLOGICAL DYSFUNCTION. WE HAVE A MEDICAL SYSTEM THAT IS RUN BY PHARMACEUTICAL COMPANIES WHO DON'T CARE ONE BIT IF OUR KIDS ARE HEALTHY OR NOT. THIS COMMITTEE NEEDS TO START WORKING WITH OUR GOVERNMENT TO LESSEN THE TOXIC BURDEN OUR CHILDREN ARE EXPOSED TO. WE PARENTS ARE WATCHING AND WE DON'T SEE THIS COMMITTEE DOING MUCH OF ANYTHING. THE AUTISM NUMBERS CONTINUE THE CLIMB WITH NO END IN SIGHT AND WE HAVE BEEN SCREAMING INTO THE ABUSINESS. WE HAVE BEEN TELLING YOU WHAT IS HAPPENING, WE HAVE GIVEN -- WE'RE GIVING YOU CREW CLUES TO STUDY BUT YOUING KNOW US. -- IGNORE US. ARE YOU AFRAID OF WHAT YOU WILL FIND? AFRAID OF DOING THE RIGHT THING UNTIL IT'S TOO LATE? IT'S QUICKLY BECOMING TOO LATE. HOW MANY MORE KIDS WILL DIE IN PONDS OR IN POOLS BECAUSE THEY WANDERED OFF AND DROWNED? HOW MANY MORE DIAGNOSED WILL IT TAKE FOR YOU TO ACT? THIS EPIDEMIC AND THE US GOVERNMENT INACTION IS CREATING A VOCAL INTELLIGENT PASSIONATE ARMY OF LOVED ONES THAT REACHED A CRITICAL MASS IN NUMBER AND WILL NOT BACK DOWN. WILL BE AT EVERY ONE OF YOUR MEETINGS. WE WANT TO HEAR WHAT YOU OOH GOING TO DO ABOUT CO-OCCURRING CONDITIONS AND WHAT YOU'RE GOING TO DO TO PREVENT THIS RISE IN AUTISM. IT CAN'T BE IGNORED ANY LONGER. WE HAVE BEEN TELLING YOU THESE THINGS FOR WELL OVER TEN YEARS, WHAT I WANT TO KNOW TODAY IS WHO IN THIS ROOM IS GOING TO BE A CHAMPION FOR THIS? WHO WILL STAND UP AND FORCE THE INDEPENDENT STUDY, LOOKING AT CAUSATION OR SPEARHEAD VICTIMIZED EFFECT -- INDIVIDUALIZEDDED EFFECTIVE TREATMENT FOR CHILDREN. IF THAT PERSON IS IN THE ROOM, NOW IS TIME TO STAND UP. THANK YOU FOR YOUR TIME. ON A SEPARATE NOTE, I WOULD LIKE TO THANK LYNN REDWOOD FOR ALWAYS BEING A VOICE FOR FAMILIES THAT HAVE BEEN SCREAMING THIS. SHE ASKED THE HARD QUESTIONS AND SHE'S NOT GIVEN UP ON THAT JOB. THANK YOU. [APPLAUSE] >> TAKE A FEW MINUTES FOR DISCUSSION. JOHN. >> I JUST SEE SO MUCH -- SO MUCH ANGER AND FRUSTRATION THAT WE HAVE NOT DELIVERED VALUE TO OUR COMMUNITY. I JUST -- I HAVE SAID THIS SO MANY TIMES NO MATTER WHERE YOU THINK THIS AUTISM COMES FROM, WE HAVE A DUTY TO DELIVER TOOLS TO MAKE OUR LIVES BETTER. I'D SAY TO THE PERSON WHO JUST SUGGESTED HOW MUCH WORSE HER OWN CHILD WAS, THE SAD TRUTH IS MY END OF THE SPECTRUM WHERE MOST AUTISTIC PEOPLE KILL THEMSELVES. I HAVE LIVED WITH ENOUGH COMPLICATIONS MYSELF THAT I KNOW THE PAIN OF THIS IS VERY REAL EVERYWHERE ON THE AUTISM SPECTRUM AND THINK FRANKLY ALL OF US ARE EQUALLY DESERVING OF RESPECT AND RECOGNITION THAT OUR PROBLEMS AS AUTISTIC PEOPLE ARE LEGIT MET AND REAL AND ALL OF US -- LEGITIMATE AND REAL AND WE ALWAYS SHOULD PULL TOGETHER TO HELP, NOT FIGHTING. ONE THING I GUESS I HAVE TO SAY, TOM, ABOUT THIS VACCINE BUSINESS AND THIS CAUSATION BUSINESS, IS THAT I WONDER IF WE NEED TO DO SOME KIND OF EXPLORATION OF WHAT THESE VIEWS ARE THAT PEOPLE ARE BRINGING TO US BECAUSE CONSISTENTLY I COME HERE TO THE IACC AND HALF THE COMMENTARY I SEE IS AQUEUIZATIONS THAT WE ARE NOT DOING OUR JOB OR NOT ADDRESSING THE VACCINE AND CAUSATION QUESTIONS AND I JUST HAVE TO ASK MYSELF IS THIS AN INCREDIBLY VOCAL MINORITY? AND I'M IN LEFT FIELD OR IS THIS TRULY AN OPINION THAT IS HELD BY A GREAT MANY FAMILIES IN THE AUTISM COMMUNITY. IF IT'S TRUE THAT OPINION IS HELD BY A GREAT MANY FAMILIES IN THE COMMUNITY WHETHER I PERSONALLY AGREE WITH THAT OR NOT, I WOULD HAVE TO SAY AS A MEMBER OF A PUBLIC COMMITTEE IF THAT'S A VIEW OF A SIGNIFICANT PERCENTAGE OF CONSTITUENCY WE SERVE WE HAVE A DUTY TO THEM. I WISH I KNEW THE ANSWER TO THAT QUESTION BUT I'M HEARING IT SO, SO MUCH THAT I GUESS I HAVE TO ASK WE SHOULD QUANTIFY A WIDESPREAD THE VIEW IS AND CONSIDER WHAT WE'RE GOING TO DO. BUT I ALSO THINK IF WE DELIVERED VALUE TO MAKE LIVES BETTER WHICH WE COULD FOCUS ON WITH REDETECTION OF OUR EFFORTS WE WOULD DO A GREAT DEAL TO MEET -- AMELIORATE THE CRITICISM OF OUR COMMITTEE AND I JUST INCREASINGLY, I SEE, IT'S FOUNDED IN A LACK OF DELIVERABLES. >> OTHER >> I WANTED TO FOLLOW-UP ON JOHN'S STATEMENT. I HAVE A SON ALMOST 21 YEARS OLD AND WHEN I FIRST -- MY SON WAS FIRST DIAGNOSED AND THERE WAS CONCERNS ABOUT VACCINES I THOUGHT AT THE TIME I'M A NURSE PRACTITIONER BY PROFESSION. I HAVE ADMINISTERED VACCINES, I SIT ON THE BOARD OF HEALTH FOR COUNTY VACCINE THERAPEUTICS PROGRAM. IT WASN'T UNTIL I STARTED LOOKING AT THE SCIENCE THAT I REALIZED THIS IS BIOLOGICALLY PLAUSIBLE. SO I HAVE BEEN LISTENING TO THESE ARGUMENTS FOR 20 YEARS NOW, TOM, AND THE COMMENTS RECEIVED THIS MEETING REFERRED TO A GENTLEMAN RESEARCH SCIENTIST AT CDC WILLIAM THOMPSON WHO AS YOU MAY OR MAY NOT HAVE HEARD IS RECENTLY COME FORWARD, WHISTLE BLOWER AND IN A STATEMENT REROLLED BY HIS ATTORNEY HE ACKNOWLEDGES QUOTE, THAT HE ADMITTED STATISTICALLY SIGNIFICANT INFORMATION LINKING MMR VACCINE TO INCREASED RISK OF AUTISM IN A 2004 STUDY. HE SAID DECISIONS KEN QUOTE WERE MADE WHICH FINDINGS TO REPORT AFTER THE DATA WAS COLLECTED. THIS IS TIP OF THE ICEBERG. IN EARLY 2000 MY ORGANIZATION FILED FOIA REQUESTS WE RECEIVED THOUSANDS OF PAGES OF DOCUMENTS, WE LOOKED AT MANY CDC STUDIES ONE BY DR. STATIN USING ADVERSE NEURAL DEVELOPMENTAL OUTCOMES IN THEIR FIRST RUN OF THAT DATA THAT WAS NEVER REPORTED RECEIVED BY FOYA THEY FOUND THAT IN CHILDREN WHO RECEIVED HIGH LEVEL EXPOSURE COMPARED TO NO EXPOSURE AN INCREASE RISK OF AUTISM THAT WAS 7.6 TO # # .4 TIMES -- 11.1 TIMES THAT OF CHILDREN NOT RECEIVED THE EXPOSURE. THEY ALTERED THE CRITERIA MAKING IT MANDATORY TO BE IN THE STUDY YOU RECEIVED TWO PORTFOLIO OWE VACCINES SO THE NEXT RUN OF THE DATA THEY HAD NO CONTROL GROUP. THEY HAD NO ZERO EXPOSURE LEVELS SO IT WAS A COMPARISON BETWEEN ANALOGY IS A TWO PACK A DAY SMOKER VERSUS FOUR PACK A DAY SMOKER AND LUNG CANCER. THESE ARE THE REASONS THE PARENTS HAVE CONCERNS. THAT PARTICULAR DATA WAS ALTERED FOUR MORE TIMES BEFORE IT WAS PUBLISHED. OTHER ASSOCIATIONS THAT STILL FOOD WERE SPEECH AND LANGUAGE DELAYS NEURAL DEVELOPMENTAL DELAY, ADD ADHD, DELAYED TICK DISORDERS. MISERY DISORDERS WERE THE FINDINGS IN THAT PARTICULAR SET OF DATA. SO THESE PROBLEMS HAVE BEEN GOING ON FOR YEARS NOW. I CAN CITE THREE OTHER STUDIES TWO AUTHORED BY DR. THORS OBJECTIONN NOW ON THE MOST WANTED LIST BY INSPECTOR GENERAL'S OFFICE FOR FRAUD AND MONEY LAUNDERING WHO AUTHORED TWO STUDIES, THESE WERE USED BY THE INSTITUTE OF MEDICINE TO DATA THERE WAS NO ASSOCIATION BETWEEN VACCINES AND AUTISM. SO I THINK THIS COMMITTEE SHOULD ASK THE SECRETARY, ONE CHARGE IS TO REPORT TO THE SECRETARY CONCERNING. THIS SHOULD BE REPORTED TO THE SECRETARY AND ASK FOR SPECIAL (INAUDIBLE) TO INVESTIGATE THE ALLEGATIONS BECAUSE THEY DIRECTLY AFFECT WHAT WE DO HERE AT COMMITTEE. SO THAT WOULD BE MY RECOMMENDATION, JOHN IN TERMS OF HAVING THIS INVESTIGATED TO GET TO THE TRUTH. IN TERMS OF COMORBIDITIES I HOPE THE WORKSHOP TODAY WILL CONTINUE AND THIS WORK GROUP WILL CONTINUE AND THAT THIS WILL PROGRESS RAPIDLY, IT'S BEEN TOO LONG IN THE COMING. >> I WANT MOST OF ALL, I WANT TO RESPECT THE VIEWS OF THE PEOPLE WHO HAVE GONE TO THE TROUBLE TO COME HERE EVEN WHEN SOMETIMES I DISAGROW BUT I HOPE WE CAN PULL TOGETHER AND TAKE AN OPPORTUNITY LIKE THIS TO RECOGNIZE THAT WE NEED TO MAKE OUR MISSION INTO THE DELIVERY OF TOOLING TO HELP WITH THESE COMORBIDITIES. WHAT WE NEED NO MATTER HOW WE BECAME AUTISTIC IS TOOLS TO HAVE A BETTER QUALITY OF LIFE. >> I WOULD LIKE TO PREGNANT GIVE BACK WHAT JOHN SAID BEFORE THAT, ID -- >> LIKE TO PIGGY BACK. >> I WOULD LIKE TO THANK THE PUBLIC SPEAKERS AS WELL AS WRITTEN SPEAKERS TAKE THE TIME AND HAVE COURAGE TO COME UP AND SPEAK. IT'S NOT NEW, IT'S REPEATED, AGONIZING AS A PARENT. AND TIME IS (INAUDIBLE) WHEN DEALING WITH YOUR CHILD (INAUDIBLE) THIS CONFERENCE AS A LOVELY (INAUDIBLE) AUTISM AND LOVE EVERY SPEAKER SO FAR HAS AUTISM AND HAS REFERRED TO THE FACT THERE ARE SEVERAL TYPES AND ONCE WE DO THAT WE CAN DEVELOP A THERAPEUTIC. MODALITY TO INDIVIDUALIZE AND PERSONALIZE THE THERAPIES. I HOPE THAT IS A SHINING -- A SMALL RAY OF HOPE AS WE MOVE FORWARD. THANK YOU. >> OTHER COMMENTS? OR RESPONSES? >> >> FULL DISCLOSURE I'M A FRIEND OF SHANNON ROADS. ONE OF HER STATEMENT -- ONE IS VERY DIRECT WHAT WE'RE DOING HERE. FOCUS ON RESEARCH AND HELP AUTISTIC PEOPLE WHO ARE ALREADY HERE. WE NEED MORE ABOUT AUTISM AND SENSORY ISSUES, AUTISM AND ANXIETY AN CO-OCCURRING MEDICAL ISSUES AND SO ON. SHE GOES ON TO SAY THIS SHOULD BE HIGHER PRIORITY THAN RESEARCH INTO CAUSATION. IF WE CAN FOCUS THE FIRST PART, WITHIN REASON I BRING UP SHANNON HER STATEMENT NOT ONLY JUST HIGHLIGHT THAT BUT BECAUSE MOST OF THAT IS ALREADY -- THE IDEA TO FOCUS ON CO-OCCURRING MEDICAL CONDITIONS IS WHAT WE'RE DOING. BUT SHANNON'S WE LIVE ABOUT 30, 40-MILES APART. SHANNON EES SON IS PUT ON A BUS DRIVES -- MY SON IS DRIVEN WE DRIVE HIM ACTUALLY UP TO HER CITY. WE ALWAYS JOKE THE KIDS ARE PASSING ON THE FREEWAY EVERY DAY. IF YOU STRATIFY KIDS BY HIGH FUNCTIONING, LOW FUNCTIONING TERMS I DON'T LIKE BUT IF YOU DO THAT, YOU WOULD SAY THESE TWO KIDS ARE THE SAME BUT THERE'S A BIG REASON WHY ONE KID GOES 30-MILES ONE WAY, ONE GOES THE OTHER WAY, BIG REASON BOTH KIDS GO 30-MILES. THEY'RE VERY UNIQUE THOUGH YOU MIGHT STRATIFY THAT TOGETHER. MEDICAL, ANXIETY, EVERYTHING ELSE, WE TEND TO ALWAYS GROUP BY INTELLECTUAL LEVEL IT'S IMPORTANT TO LOOK AT EPIDEMIOLOGY AND WHO HAS MORE PROBLEMS AN MORE ISSUES AND WHERE -- WHAT COMMUNITIES ARE GOING TO HAVE THEM. EVEN WITHIN THESE GROUPS THEY'RE VERY DIVERSE. AND KEEP THE FOCUS ON THAT. THANKS. >> ANY OTHER COMMENTS? >> I WOULD FOLLOW-UP WITH THAT FOR A MINUTE. I THINK WHAT WE SHOULD TAKE A LESSON FROM APPLIED BEHAVIORAL ANALYSIS AND THINK ABOUT PART OF THE REASON IT'S SO EFFECTIVE IS IT'S HIGHLY CUSTOMIZED. AND IT'S FOCUSED ON ACTUAL BEHAVIORS THAT ARE CAUSING ISSUES AND SO IT'S A DOWNSTREAM IMPACT OF SOMETHING THAT HAS -- EFFECTS THE UNDERLYING CONDITIONS. SO IF WE CAN BEGIN TO THINK ABOUT TREATMENTS MORE IN THAT WAY, AND REALLY INDIVIDUAL WAY, DEAL WITH WHAT IS BOTHERING THE PATIENT, AND THE FAMILY, I THINK WE COULD ALSO MAKE SOME HEADWAY. >> QUICK COMMENT. >> FIRST I WOULD LIKE TO RECOGNIZE JOHN FOR HAVING CREATED THE ROCKETS AND THE GUITARS THAT CAME OUT OF -- ROCK BAND MEMBERS. [APPLAUSE] VERY IMPRESSIVE. SOMETHING I SEE HERE AS A BIOMEDICAL STATISTICIAN I SEE BROADLY IT'S HARD NOT DISCLOSE MANY DISEASES TO TALK RATIONALLY ABOUT THERAPY OR PROGNOSIS WHEN WE DON'T EVEN KNOW THE BEGINNINGS OF WHAT ARE THE COMPONENTS OF IT. AND IT'S TRULY HEART WRENCHING TO HEAR A MOTHER SAY I HAVE A VERY -- KID WITH A VERY DIFFERENT KIND OF AUTISM. AND THE FACT IS, I DON'T THINK WE KNOW WHAT ARE THE NATURAL TRAJECTORIES OF THESE DISEASES ABOUT HOW THEY RELATE TO FUNCTIONING, WHICH 30-MILES THEY HAVE TO GO ALONG. AND SO WHAT IS INSPIRING BY ABOUT THE MEETING, TOM AND THE COMMITTEE, CO-MORBID IS ANOTHER DIMENSION WE'RE ABLE TO UNDERSTAND BETTER WHAT THESE INDIVIDUALS HAVE THAT WE'RE ALL LUMPING TOGETHER. ONE FEAR AS I LISTEN TO THIS, IF WE END UP AS LIKELY TO BE THE CASE, VERY DIFFERENT DISEASES, THEY SHOULD GET A BROAD SUPPORT THAT HAVING A NICE LARGE COMMUNITY THAT IS LABELED BY PERHAPS INCORRECTLY BY THE SAME LABEL IT CURRENTLY PROVIDES. I THINK WE KEEP ON THE DIRECTION THIS WORKSHOP IS GOING, IT'S A REASON FOR OPTIMISM. >> MAYBE I CAN USE TO IT SUM UP BECAUSE WE NEED TO GO ON WITH THE REST OF THE AGENDA. I ALSO WANT TO THANK THAT PEOPLE WHO MADE ORAL COMMENTS AND THOSE IN WRITTEN COMMENTS, CLEARLY AS JOHN SAID, THE FRUSTRATION AND ANGER ESPECIALLY AT THE COMMITTEE, THE FRUSTRATION MORE GENERALLY AT THE STATE OF CARE IS PROFOUND, THERE'S NO QUESTION ABOUT THAT. I THINK YOUR COMMENT IS TO THE POINT, WE'RE AT A VERY EARLY STAGE HERE. IT'S AS IF AUTISM, IF YOU WANT AN ANALOGY LIKE FEVER, WHAT CAUSES FEVER, SOME HAVE EBOLA, SOME HAVE STREP THROAT AND SOME KIDS HAVE SOMETHING VERY DIFFERENT. THE ONLY THING THEY SHARE IS THE TEMPERATURE. AND EVEN THAT, RANGES FROM 101 TO 105. SO WE HAVE A REAL PROBLEM THAT THIS EARLY STAGE THIS FIELD, AND IT IS EARLY, THIS IS A FIELD THAT'S DEEPLY INVESTED IN BIOMEDICAL RESEARCH FOR A COUPLE OF DECADES. THERE'S FEW PARTS OF THE NIH THAT ARE THAT YOUNG IN TERMS OF THEY HAVE BEEN EXPECTED TO GO. I CAN'T HELP BUT SAY PART OF THE FRUSTRATION IN THE COMMITTEE IS CONTINUED MISUNDERSTANDING OF WHAT WE CAN DO, WHAT OUR AUTHORITY IS, WHAT OUR RESOURCES HAVE, WE HAVE NO MONEY, WE HAVE NO ABILITY TO FUND ANYBODY TO DO ANYTHING. WE ARE A BULLY PULPIT AND THE BEST WE CAN DO IS TRY TO INSPIRE SOME OF THE FUNDERS AROUND THE ROOM, THE NIH, CDC, AUTISM SPEAKS THE SIMONS FOUNDATION AND OTHERS, AUTISM SCIENCE FOUNDATION TO MAKE APPROPRIATE INVESTMENTS IN THE ISSUES IN THE STRATEGIC PLAN. BUT THERE IS NO MANDATE TO DO THAT EITHER. WE HAVE NO RECOURSE IF SOMEONE DOESN'T. I THINK IF THE COMMITTEE UNDERSTANDS THIS, I'M SURE THE PUBLIC TRULY UNDERSTANDS AND I CAN TELL FROM WRITTEN COMMENTS THERE'S A CLEAR MISUNDERSTANDING ABOUT WHAT ARE ACTUAL AUTHORITY IS IN TERMS OF WHAT WE CAN ACCOMPLISH. WE CAN HAVE THESE VERY HONEST EXCHANGE OF VIEWS, U THINK IT IS USEFUL TO TRY TO FIND A WAY TO ALIGN THE COMMUNITY NOW POLARIZED. AND JOHN, I THINK YOUR COMMENTS HELP IN SOME WAYS TO PUT IT ALL OUT ON THE TABLE TO SAY AT LEAST WE CAN BEGIN TO LISTEN FOR MORE CAREFULLY AND REALIZE THIS IS A MULTIFACETED PROBLEM, PEOPLE WITH DIFFERENT EXPERIENCES. >> DR. INSEL, THIS IS JANUARY CANDY ON THE LINE. >> THANKS FOR JOINING US. >> I WOULD LIKE TO MAKE A SHORT COMMENT. THIS IS -- I WOULD I WISH OUR COMMITTEE WOULD ACKNOWLEDGE HOW JOHN STATED THE WHISTLE BLOWER THEME, BECAUSE WHAT'S HAPPENING IN OUR COMMUNITIES IS PARENTS ARE OPTING OUT OF VACCINES IN CALIFORNIA. >> I'M SORRY TO INTERRUPT YOU BUT THIS ISN'T AN IACC MEETING. >> RIGHT. >> THAT TOPIC IS -- IF YOU WANT TO TAKE UP AT THE MEETING THIS WORK GROUP IS NOT THE PLACE TO DECIDE WHAT TO DO ABOUT THAT. IF ANYTHING. SO >> I'M NOT ASKING US TO DO SOMETHING, I'M SAYING I DON'T THINK THE COMMITTEE WE'RE HEARING PUBLIC COMMENT TODAY THAT IT SHOULD BE STATED THE WHISTLE BLOWER THING, I THINK I WOULD APPRECIATE IF YOU MADE A COMMENT TO ADDRESS THE PUBLIC IN THE PUBLIC COMMENT THIS ISSUE BECAUSE IT IS POLARIZING OUR COMMUNITY, FAMILIES CONTINUE TO NOT VACCINATE THEIR CHILDREN, THE DATA SHOWS IN THE LAST SEVEN YEARS DOUBLED OPTING OUT OF VACCINES. THAT'S A PROBLEM FOR OUR COMMUNITY BECAUSE IF WE CAN'T TRUST THE CDC HOW (INAUDIBLE) TRUST AND VACCINE? >> I'M HAPPY TO RESPOND TO THE QUESTION ABOUT THAT PARTICULAR ISSUE BUT AGAIN, THIS IS NOT THE PLACE FOR THE IACC SINCE THE COMMITTEE NOT HERE IN FULL, THIS IS NOT A MEETING TO DECIDE ON ANYTHING WITH RESPECT TO POLICY. I WISH I KNEW MORE ABOUT THAT PARTICULAR INSTANCE. I CAN TELL YOU THE 2004 PEDIATRICS PAPER WAS ONE OF 14 PAPERS FOR THE IOM REVIEWED AND THERE'S ANOTHER MULTIPLE PAPERS SINCE THEN. ALL WHICH IN 20 # 1 WERE CONSISTENT IN NOT FINDING A RELATIONSHIP BETWEEN VACCINATION AND AUTISM. WHAT THE IOM DOESN'T SAY AND NOBODY HAS SAID IN A WAY I FIND COMPELLING IS THAT THERE COULD STILL BE RARE CASES THAT COKE OCCUR. -- COULD OCCUR. AND WHAT WE NEED TO THINK IS HOW ONE INVESTIGATE THAT IF THAT WERE THE CASE. THAT'S ANOTHER TOPIC THAT I DON'T THINK THAT'S A CO-OCCURRING QUESTION, I WANT TO REALLY MAKE SURE WE USE THE DAY FOR WHAT WE SET OUT FOR TO DEFINE THE CO-OCCURRING ISSUES. JOHN, LAST WORD. >> >> I WOULD SAY WITH RESPECT TO WHAT WE SHOULD DO WITH THIS COMMUNITY AND IN THIS WORKSHOP, I THINK THAT WE WOULD BE WISE IN RESPONDING TO OUR CONSTITUENTS THE SATISFACTION -- DISSATISFACTION TO ASK IF THE PURVIEW OUR COMMITTEE MIGHT BE EXPANDED TO MOVE MORE INTO RECOMMENDATIONS FOR SERVICES AND TREATMENTS. BECAUSE IT SEEMS LIKE THE IACC WAS ORIGINALLY CHARTERED TO OFFER GUIDANCE IN THE DIRECTION OF RESEARCH AND WHAT WE HEAR ALMOST EXCLUSIVELY FROM OUR COMMUNITY IS THEY WANT US TO OFFER GUIDANCE AND ACTION -- IN DELIVERABLES APPROXIMATE SERVICES WHICH IS DIFFERENT FROM WHAT WE WERE -- >> THAT'S GOING TO COME OUT OF THE AIR CARES ACT IN THE NEXT VERSION OF THE COMMITTEE, THERE IS CLEAR LANGUAGE ABOUT MANDATE FOR THIS COMMITTEE WHEN REFORMED TO FOCUS ON SURFACES AS WELL AS RESEARCH, IT'S COMPLICATED BECAUSE SERVICES ARE DONE AT THE STATE LEVEL, RESEARCH IS DONE AT FEDERAL LEVEL SO IT'S EASIER TO THE EXTENT WE CAN DO ANYTHING TO BRING PEOPLE AROUND THE TABLE WHO CAN HAVE IMPACT ON RESEARCH. THE 50 DIFFERENT SYSTEMS THAT ARE SUPPORTING SERVICES AREN'T IN THE ROOM AND THAT BECOMES MORE COMPLICATED FOR US TO HAVE AN IMPACT THERE EXCEPT THROUGH CMS OR SOMETHING LIKE THAT. WE NEED TO GO ON. AND I WANT TO TURN THIS OVER TO JERRY TO START THE AFTERNOON SESSION. SLEEP AND NEUROLOGICAL DISORDER. >> OKAY. SO WE'RE GOING TO BEGIN WITH BETH MALOW AND SHE IS A PROFESSOR OF NEUROLOGY AND PEDIATRICS IN THE SCHOOL OF MEDICINE VANDERBILT UNIVERSITY. WELL KNOWN RESEARCHER IN THE AREA OF SLEEP. >> THANK YOU. THERE WE GO. I WANT TO THANK THE IACC COMMITTEE AND JERRY FOR HAVING ME AND RECOGNIZING THE IMPORTANCE OF CO-OCCURRING CONDITIONS IN AUTISM. I ALSO WANTED TO THANK AUTISM SPEAKS AN NECHD FROM FUNDING SUPPORT THEY PROVIDED ME, I WANT TO GIVE A LITTLE BACKGROUND, I'M A SLEEP SPECIALIST, AN WHEN MY CHILDREN WERE BORN AND DIAGNOSED WITH AUTISM I WAS ENCOURAGED TO MOVE INTO THE FIELD OF SLEEP AND AUTISM AND I'M EXCITED TO BE PART OF VIBRANT COMMUNITY. SO I WANT THE START OUT WITH A CASE, TO PAINT A PICTURE HOW DISRUPTIVE SLEEP DISTURBANCE CAN BE FOR CHILDREN AND THEIR FAMILIES. ALEX IS A 6-YEAR-OLD BOY WITH AUTISM SPECTRUM DISORDER, HE TAKES HOURS TO FALL ASLEEP, HIS PARENTS SAY HE CAN'T SHUT HIS BRAIN DOWN, HE DRINKS MOUNTAIN DUE AFTER DINNER, HE CAN'T SETTLE DOWN TO GO THE SLEEP AND LEAVES HIS ROOM REPEATEDLY TO FIND HIS PARENTS. AND ONCE ASLEEP HE WAKES UP MULTIPLE TIMES DURING THE NIGHT SOMETIME ACE WAKENS PARENTS OTHER TIMES WANDERS AROUND THE HOUSE, GOES TO THE KITCHEN TO EAT, FALLS ASLEEP IN A DIFFERENT ROOM. AND IT'S NEARLY IMPOSSIBLE TO AWAKEN ALEX IN THE MORNING FOR SCHOOL. HIS PARTS ARE EXHAUST, OVERWHELMED. HIS TEACHER DESCRIBES HIM BEING HYPE ACTIVE AND DISRUPTIVE IN CLASS. AND EVEN AFTER TAKING AWAY VIDEO GAMES AND MOUNTAIN DUE, KIDS LIKE ALEX MAY STILL NOT FALL ASLEEP. SO WE CAME ONE FRAMING QUESTIONS FOR THE PRESENTATION TODAY I WILL TALK ABOUT WHAT WE KNOW ABOUT SLEEP AND AUTISM, THE EVIDENCE LINKING BIOLOGICAL CAUSES OF SLEEP DISTURBANCE WITH FEATURES OF ASD WHICH MAYBE A WINDOW FOR BIOMARKERS WE CAN DEVELOP. WHAT WE NEED TO LEARN IN ORDER TO TREAT SLEEP DISTURBANCE IN ASD, I'LL TRY LISTEN TO COMMENTS MADE AND BE PRACTICAL HERE AS WELL, TALK ABOUT GAPS, TALK ABOUT OPPORTUNITIES AND TALK ABOUT THE AUTISM SPECIFIC FEATURES CAN AFFECT DIAGNOSIS AND TREATMENT AND GET IN THE WAY. I PUT TOGETHER A BIBLIOGRAPHY SO IF YOU SEE A REFERENCE THAT INTRIGUES YOU YOU CAN LOOK IT UP ON THE SHEET. THIS SHOULD BE IN YOUR PACKET. SO WHAT HAVE WE LEARNED? THERE IS A HIGH PREVALENCE OF PARENT REPORTED SLEEP CONCERNS IN ASD ACROSS COGNITIVE LEVELS, THESE ARE STUDIES THAT COMPARE ASD WITH TYPICALLY DEVELOPING POPULATIONS THE STORY FROM THE CHARGE STUDY AND LISA POUND SPOKE EARLIER WAS ABOUT AUTHOR ON THAT. SLEEP DISTURBANCES ALSO ASSOCIATED WITH CHILD BEHAVIOR AND FAMILY FUNCTIONING. THIS MAYBE BIDIRECTIONAL. MANY ASPECTS INCLUDING REPETITIVE BEHAVIOR, INATTENTION, HYPERACTIVITY, PARENTING STRESS ASSOCIATED WITH POOR SLEEP. INSOMNIA APPEARS THE MOST PREVALENT SLEEP DISTURBANCE, IT MAY TAKE THE PROLONGED TIME THE FALL ASLEEP, PREFERENCE FOR DELAYED BEDTIME, BEDSYME RESISTANCE, INCREASED AROUSALS AN AWAKENINGS AND DECREASED SLEEP DURATION. WE HAVE ALSO LEARNED MULTIPLE CAUSES OF INSOMNIA AND MANY ARE TREATABLE. THIS IS WHERE WE CAN GET PRACTICAL ASPECTS, WE WANT TO BE VIGILANT HUNTING FOR MEDICAL CAUSES SUCH AS BE CAUSES OR NEUROLOGIC CAUSES SUCH AS EPILEPSY, WE ALREADY HEARD A LOT ABOUT THE PSYCHIATRIC CAUSES TODAY THAT CAN AFFECT SLEEP, MEDICATIONS THAT WE USE TO TREAT MEDICAL PSYCHIATRIC CAUSES CAN AFFECT SLEEP. AND THEN OTHER SLEEP DISORDERS CAN ALSO PLAY A ROLE IN RESULTING IN INSOMNIA. AND A BEHAVIORAL CATEGORY IS VERY IMPORTANT AS WELL, WE THINK ABOUT POOR SLEEP HABITS LIKE MOUNTAIN DUE, LIKE VIDEO GAMES BUT FEATURES THAT ARE RELATED TO ASD SUCH AS DIFFICULTY WITH TRANSITIONS, SENSORY SENSITIVITIES ALSO CONTRIBUTE TO BEHAVIORAL ISSUES WITH SLEEP AND EXHAUSTED PARENTS MAY SLEEP POOR SLEEP IS PART OF AUTISM, WE HEARD A LOT TODAY, AND BEHAVIORAL APPROACHES THAT CAN HELP. OTHER CAUSES RELATED TO ASD NEUROTRANSMITTER ABNORMALITIES MELATONIN PATHWAYS GABBA AN SEROTONIN CAN PLAY A ROLE AS WELL, IF YOU LOOK AT BIOLOGICAL CLAUSES AND DO GENETIC STUDIES IT'S IMPORTANT TO KEEP THE WHOLE LIST IN MIND BECAUSE YOU MAY HAVE THE GENE THAT CAUSES SLEEP DISTURBANCE IN AUTISM IF THE CHILD IS INVOLVED WITH VIDEO GAMES OR GETTING CAFFEINE OR OTHER ENVIRONMENTAL OR MEDICAL ISSUES GOING ON, THAT MAY CONFOUND YOUR RESULTS. SO I WOULD LIKE TO TAKE A MOMENT TO DISCUSS EVIDENCE LINKING BIOLOGICAL CAUSE OF SLEEP DISTURBANCE WITH FEATURES OF ASD. I WOULD LIKE TO DISCUSS EMOTIONAL REGULATION FOR A MOMENT AND WE ALL KNOW WHAT IT'S LIKE TO NOT SLEEP WELL AND FEEL CRABBY AN CRANKY THE NEXT DAY. THERE'S ACTUALLY A BIOLOGY UNDERLYING THIS AND IT LINKS SLEEP AND ASD. SO WE KNOW SLEEP DEPRIVATION AFFECTINGSES THE NEURONAL CIRCUITRY UNDERLYING THE EMOTIONAL REGULATION INCLUDING HOW THE AMYGDALA AND PREFRONTAL CORTEX ARE CONNECTED. FEAR PROCESSING THE PRE-FRONTAL CORTEX IS INVOLVED IN REASONING AND IN PROCESSING FROM THE AMYGDALA IN SUCH A WAY THAT IS HEALTHY, THAT IS UNDER CONTROL. WE KNOW THAT WHEN THIS GOES AWRY WE CAN HAVE EMOTIONAL REGULATION PROBLEMS BEHAVIORAL DISTURBANCE, THIS ABNORMALITY, THIS ABNORMAL CONNECTIVITY ALSO EXISTS IN ASD, YOU CAN THINK OF IT AS IF YOU ALREADY HAVE ABNORMAL CONNECTIVITY BETWEEN THE AMYGDALA AND PRE-FRONTAL CORTEX AND ASD AND THEN SLEEP DEDRIVE PRIEVED YOU ADD SLEEP PROBLEMS ON TOP, THAT CAN MAKE THE BRAIN GO EYE AWRY, THIS IS ONE EXAMPLE FROM A FUNCTIONAL FMRI STUDY AND SLEEP DEPRIVED HEALTHY PARTICIPANTS WERE COMPARED TO THOSE. THOSE SLEEP DEPRIVED SHOWED INCREASE SIGNAL IN AMYGDALA, INCREASED PEAK AMYGDALA SIGNAL AND ACTIVATED. WHEN THEY WERE VIEWING IMAGES THAT WERE EMOTIONALLY AVERSIVE. THE FUNCTIONAL CONNECTIVITY WAS STRONGER IN THE SLEEP CONTROL GROUP, THE PRE-FRONTAL CORTEX IN THE AMYGDALA WERE COMMUNICATING NORMALLY, THERE'S A GOOD HEALTHY THING. IN THE SLEEP DEPRIVED GROUP THE AMYGDALA WAS ACTUALLY COMMUNICATING WITH AUTONOMIC BRAIN STEM REGIONS. AND THIS COULD BE VIEWED MORE PRIMAL OR PRIMITIVE REACTION SO THE BOTTOM LINE HERE IS AUTISM MAY ALREADY BE VULNERABLE TO EMOTIONAL REGULATION AND SLEEP DEPRIVATION CAN MAKE IT THAT MUCH WORSE. WE HEARD ABOUT AROUSAL REGULATION, THIS IS REALLY INTERESTING TO ME BECAUSE I WONDER IF ONE THEORY IS THAT HYPERAROUSAL OR AROUSAL DISREGULATION MAY TIE SEVERAL FEATURES OF ASD INCLUDING ANXIETY, SENSORY OVER RESPONSIVITY AND FUNCTIONAL GI PROBLEMS, AND THESE WERE FOUND HIGHLY ASSOCIATED IN A STUDY OF ALMOST 3,000 CHILDREN ENROLLED IN THE AUTISM TREATMENT NETWORK. IN ADDITION, YOU CAN PUT INSOMNIA IN THE MIX. SO YOU CAN LOOK AT SOME WORK THAT'S BEEN DONE WITH THE HPA AXIS THE HYPERTHALAMIC PITUITARY ADRENAL AXIS AND DISREGULATION IN INSOMNIA AN ASD IN ASSOCIATION WITH DAYTIME STRESSORS. SO YOU CAN POSTULATE A MODEL WITH STRESSORS DURING THE DAY, THEY LEAD TO INSOMNIA AT NIGHT AND WHAT HAPPENS WITH NORMALLY CORTISOL LEVELS FALL AT NIGHT AND THEN WE CAN GO TO SLEEP. BUT IN HPA AXIS DISREGULATION AND THE ACCUMULATION OF THESE STRESSORS YOU HAVE ELEVATED LEVELS OF CORTISOL WHICH CAN RESULT IN INSOMNIA AND YOU'RE NOT SLEEPING WELL AT NIGHT SO MORE HYPERAROUSAL AND DISREGULATION AND THEN BEHAVIORAL CHALLENGES DURING THE DAY, IT'S A VICIOUS CYCLE. THEN WE ALREADY HEARD FROM ADOKIA ABOUT FUNCTIONAL STUDY INCLUDING ELEVATED BASELINE HEART RATE AND ALSO ELECTRODERMAL ACTIVITY WHICH CERTAINLY REQUIRE MORE STUDY BUT ARE VERY PROVOCATIVE. AND THE ARGUMENT I WOULD MAKE WE HAVE BEEN HEARING WE NEED TO DO SOMETHING NOW, WE NEED TO UNDERSTAND BIOMARKERS BETTER, I WOULD SAY WHY NOT WE DESIGN INSOMNIA TREATMENT STUDIES EITHER WITH MEDICATIONS OR WITH BEHAVIORAL TECHNIQUES AND BEHAVIORAL STRATEGIES TO TRY TO TARGET HYPERAROUSAL AND WHILE WE'RE AT IT MEASURE BIOLOGICAL MARKERS OF AUTONOMIC HPA DYSFUNCTION INCLUDING HEART RATE VARIABILITY, ELECTRODERMAL ACTIVITY, AND CORTISOL. ONE OTHER AREA -- THAT LINKS SLEEP DISTURBANCE IN ASD IS MELATONIN ENDOGENOUS BY THE PINIAL GLAND PROMOTES SLEEP AND STABILIZES RHYTHMS THROUGH ACTIONS ON THE SUPER NUCLEUS. AND APART FROM HYPNOTIC AND CIRCADIAN PROPERTIES MELATONIN INHIBITS HTA RESPONSES IN THE HUMAN ADRENAL GLAND SO IT MAY BE MITIGATING HYPERAROUSAL. MEL TONE ANYONE PROCESSING APPEARS ALTERED IN ASD, IT'S ACTING IN SLEEP, AUTISM, IT'S COMPLICATED BUT IT'S WORTH REVIEWING THE PATHWAY SO THE SEROTONIN IS CONVERTED TO MELATONIN THROUGH ASMT, THIS ENZYME, AND THEN SIF 1A 2 IS INVOLVED IN BREAK DOWN OF MELATONIN TO MAJOR URINARY METABOLITE, INACTIVE METABOLITE MELATONIN. AND SEVERAL STUDIES HAVE HOOKED AT THAT TIME MELATONIN PATHWAY, (INAUDIBLE) AND COLLEAGUES SHOWED ASD MELATONIN LEVELS WERE LOWER THAN CONTROLS AND THEN THE ASMT ACTIVITY WAS LOWER IN ASD AND THEY POSTULATED THAT THIS IS ENZYMATIC BLOCK SO TO SPEAK THAT'S LIMITING PRODUCTION OF MELATONIN, THE STUDY WAS LIMITED IN THEY DID MELATONIN LEVELS IN THE MORNING IN BLOOD AND MELATONIN PEAKS AT NIGHT. WE RECENTLY FOUND THAT MELATONIN LEVELS WERE NORMAL, THAT WE DOCUMENTED NORMAL PROFILES OF ENDOGENOUS MELATONIN IN TERMS OF RISE TIME PEAK AND RELATIONSHIP TO SLEEP ONSET SHOWN HERE IN BLUE AND SAMPLE OF CHILDREN WITH AUTISM WITH SLEEP ON SIT, PARTICIPATING IN NICHD TRIAL SUPPLEMENTAL MELLITE ANYONE, THIS IS ONE PARTICIPANT SHOWN HERE. TO ADD TO THE MIX SIX SOUL FOXY MELATONIN IN URINE IS LOWER IN AUTISM THAN CONTROL ADJUSTING FOR PUBERTAL STATUS. SO HOW DO YOU PUT THIS TOGETHER, HOW DO YOU RECK SIZE NORMAL MELATONIN LEVELS WE FOUND WITH THE ASMT LEVELS THAT ARE ABNORMAL AND MELKE WORK AND THE LOW SIX FM AND THE APPROACH IS EXAMINE MELATONIN SYNTHESIS AND DEGRADATION PATHWAYS TOGETHER WITH BIOCHEMICAL AND MOLECULAR APPROACHES MAYBE ENLIGHTNING, OLIVEIA REACH IN OUR LAB RECENTLY SHOWED GENETIC STUDY IN A SAMPLE OF CHILDREN RESPONSIVE TO SUPPLEMENTAL MELATONIN, THAT DYSFUNCTIONAL GENOTYPES THAT WERE RESPONSIBLE FOR BOTH DECREASED MELATONIN PRODUCTION AND DECREASE OF 1A 2 SHOWN HERE AFMT AND SIP 1 A 2, MAY APPEAR CORRELATED. SO THIS IS ALLOWING US TO GENERATE A HYPOTHESIS THAT CHILDREN MAY HAVE NORMAL LEVELS OF ENDOGENOUS LEVELS OF MELATONIN BECAUSE SIP 1A 2 IS DEGRADING THE MELATONIN THEY HAVE AVAILABLE. THIS WOULD BRING TOGETHER MELKE WORK WITH ASMT AND (INAUDIBLE) WORK WITH SIX FM WITH FINDINGS. WE NEED TO DO MORE STUDIES, THIS IS IMPORTANT AND RELEVANT BECAUSE IF WE CAN IDENTIFY SOME BIOMARKERS FOR WHICH CHILDREN HAVE ABNORMAL MALADIES IN MELATONIN PATHWAYS AND ENZYMES IT MIGHT HELP US IDENTIFY WHICH CHILDREN MAYBE MORE RESPONSIVE TO BEHAVIORAL THERAPIES VERSUS MELATONIN VERSUS MORE POTENT MEDICATIONS. AND THEN THAT'S A SEGUE WHAT I WANT TO DO IN THE LAST MINUTE OR TWO WITH THE GAPS AND THE OPPORTUNITIES. SO I WANTED TO BRING UP THE SUPPLEMENT THAT DAN CORRY MENTIONED EARLIER IN THE PRACTICE PATHWAY AND PEDIATRICS, TAKE HOME MESSAGES, CLINICIANS NEED TO ASK ABOUT SLEEP, WE OFTEN TIMES FORGET TO ASK EVERYTHING ELSE ECLIPSES THAT. WE NEED TO LOOK AT THESE MEDICAL -- COKE OCCURRING CONDITIONS IDENTIFY AND TREAT THEM. BEHAVIORAL EDUCATION WORKS WORKING WITH FAMILIES ON IMPLEMENTING BEDTIME ROUTINES TAKING AWAY ELECTRONS CLOSE TO BEDTIME DO WORK AND IMPROVE CHILD BEHAVIOR AND FAMILY FUNCTIONING. WE NEED TO UNDERSTAND SLEEP MEDICATIONS BETTER. I WANTED TO MENTION THAT IMMEDIATE RELEASE MELATONIN HAS LIMITATIONS, IT ONLY WORKS FOR ABOUT AN HOUR BUT THERE ARE LONGER AGENTS THAT ARE BEING PROLONG AGENTS AND AGONISTS BEING STUDIED. THERE MAY ALSO NEED TO LOOK AT MEASUREMENTS OF BASELINE SLEEP STATUS TREATMENT RESPONSE INCLUDING ACTI GRAPHY WHICH IS NOT WELL TOLERATED IN KIDS. WE HAVE TOOLS THAT -- THAT CAN BE PRACTICALLY USED. TO SUM UP WE KNOW SLEEP DISTURBANCE IS COMMON, IT CAN BE ASSOCIATED WITH CHILD BEHAVIOR AND FAMILY FUNCTIONING, THERE'S MANY TREATABLE CAUSES. WE THINK WE KNOW IMPROVING SLEEP IMPACTS FAVORABLY BUT WE NEED TO DO MORE RESEARCH, THESE ARE THE THINGS THAT I THINK WE STILL NEED TO KNOW. I APPRECIATE YOUR ATTENTION. THANK YOU. [APPLAUSE] >> THANK YOU VERY MUCH, OUR NEXT SPEAKER IS -- ASHURA BUCKLEY, SHE'S A CLINICAL INVESTIGATOR AT THE NATIONAL INSTITUTE OF MENTAL HEALTH. >> GOOD AFTERNOON. THANKS FOR THE INVITATION. I'M GOING TO BE DISCUSSING EPILEPSY AND ASD IN THE NEXT 15 MINUTES. SO MAYBE I'LL Q. A LITTLE QUICKLY BUT BEAR WITH ME AND I'M HAPPY TO ANSWER ANY QUESTIONS I CAN AFTERWARDS. SO THE OBJECTIVES FOR THIS TALK WE'RE GOING TO DEFINE WHO WE'RE TALKING ABOUT IN THIS CO-OCCURRING -- CAN YOU HEAR ME? CONDITION, WHAT ARE THE CLINICAL BIOLOGICAL RELATIONSHIPS BETWEEN ASD AN EPILEPSY THAT WE KNOW ABOUT AND WHERE DO WE GO FROM HERE? SO I WANT TO FIRST START BY SAYING THAT THE FRAMEWORK FOR THIS TALK COMES FROM A WONDERFUL WORKSHOP THAT IS PUT TOGETHER BY FENDS NENDS TWO YEARS AGO AND DR. DEBRA HERTZ AND DR. (INAUDIBLE) PUT TOGETHER A FABULOUS WORKSHOP BRINGING LEADERS IN THE FIELD REALLY JUST TO DISCUSS CUSS CO-OCCURRENCE ASD AND MANY OF YOU IN THE ROOM WERE THERE AND IT WAS GREAT, IT WAS SPONSOR BY NIC HEALTHCARED AUTISM SPEAK, CITIZENS UNITE FOR RESEARCH AND EPILEPSY AND THREE OBJECTIVES THAT WE TALK ABOUT COME FROM WONDERFUL DISCUSSION FROM THAT WORKSHOP, THERE ARE MORE, FOUR OUR FIVE OR SIX SEVEN DIRECTIONS PEOPLE WANTED TO GO, PROCEEDS WHERE THAT WERE PUBLISHED LAST FALL IN NEUROLOGY TO 13 IF PEOPLE WANT TO REFERENCE THEM FURTHER. WHO ARE WE TALKING ABOUT? WE NEED TO START BY ACKNOWLEDGING DEFINITION REALLY MATTERS AND WHERE YOU LOOK FOR DATA REALLY MATTERS SO HOW YOU DEFINE EPILEPSY IS GOING TO REALLY IMPACT WHERE OWE FIND PREVALENCE RATES OR WHAT THEY LOOK LIKE. SO THE INTERNATIONAL LEAGUE AGAINST EPILEPSY DEFINED AS CHRONIC NEUROLOGIC CONDITION CHARACTERIZED BY RECURRENCE SEIZURES AND OTHER FOLKS USE LESS STRINGENT DEFINITION, SOME PAPER THAT INCLUDE IN EPILEPSY GROUP PEOPLE WHO HAVE EVIDENCE ON EEG BUT MAYBE NOT SEIZURES OR LOSS OF CON SHE ISNESS, WE NEED TO KNOW WHAT YOU'RE LOOKING AT AND I PULL TWO META ANALYSES JUST TO GET A GOOD IDEA WHAT THE PREVALENCE RATE MIGHT BE. THE FIRST WAS PUBLISHED IN 2008, IT WAS REALLY ONLY LOOKING AT CROSS SECTIONAL STUDIES THAT LOOKED AT THE PREVALENCE OF EPILEPSY IN ASD IF THEY COULD ALSO LINK IT TO THE PREVALENCE OF INTELLECTUAL DISABILITY. THEY FOUND THIS WAS VERY -- FOUR DECADES OF WORK THAT THEY LOOKED AT AND THEY CHOSE REALLY GOOD STUDIES AND THEY FOUND SOMETHING INTERESTING IF INTELLECTUAL DISABILITY WAS PRESENT WE HA HAD HIGHER RATE OF EPILEPSY THAN IF WE HAD NORMAL IQ. IQ OVER 7 SO ABOUT A THIRD. THE NEXT I LOOKED ATE@WAS ONE FROM 2012, IT WAS ONLY ONE STUDY HERE. AND THIS WAS FROM 1984 TO 2010 WAS THE LAST PAPER THEY LOOKED AT, THEY FOUND THE SAME THING AND THEY HAD AN INTERESTING DICHOTOMY THAT WAS AGE RELATED SO LOWEST PREVALENCE WAS FOR CHILDREN LESS TAN 12 WHO DID NOT HAVE INTELLECTUAL DISABILITY, THAT RATE WAS 2% HIGHEST WAS PEOPLE LOOKED AT AFTER ADOLESCENTS AND INTO ADULTHOOD WITH INTELLECTUAL DISABILITY AND THAT WAS 25%. SO NUMBERS ARE SIMILAR. HIGH EYESORESK WAS PEOPLE WITH ID AND WHEN YOU LOOK AT PREVALENCE OF ASD AND EPILEPSY THE HIGHEST RISK WAS PEOPLE WITH BELL SELECT ACTUAL DISABILITY. THESE ARE INTERESTING PAPERS AS WELL, I PUT REFERENCES TO LOOK AT, THIS WAS TWO LARGE PROSPECTIVE STUDIES IN PEDIATRIC POPULATIONS THE RATE WAS 4 TO 5% OF ASD IN EPILEPSY AND THIS WAS A LARGE COHORT STUDY OUT OF ENGLAND LOOKING AT JUST ADULTS WITH PEOPLE 16 YEARS OLDER, 16 YEARS OR OLDER WHICH FOUND A SEVEN FOLD INCREASE IN ODDS OF ASC IF YOU HAVE EPILEPSY, THE OTHER THING TO NOTE IS IT DOESN'T PUT PEOPLE APART, IT DOESN'T SAY, NONE OF THESE SAY WE EXCLUDE PEOPLE WITH SYNDROME OR ONLY MEAN PEOPLE WHO HAVE WHAT WE THINK IS IDIOPATHIC AUTISM, THESE ARE ALL COMERS BUT AN IDEA WHO WE MIGHT BE TALKING ABOUT. SO WHAT CAUSES THEM TO OCCUR TOGETHER? THAT'S WHAT WE WANT TO KNOW. IT'S A GREAT DEAL OF PEOPLE, THAT WE'RE TALKING ABOUT HERE SO EARLY NEURAL DEVELOPMENT IS THIS TIME OF REALLY INCREASED EXITATION. THAT'S A GOOD THING, WE NEED THAT BECAUSE EXITATION IS WHAT NEEDS TO GET NEURONS GOING AND PROCESSES THAT HAVE TO OCCUR, THAT'S GREAT, WE HAVE HIGHEST RATES OF SOMATOGENESIS, RAPID MATURATION OF PLASTICITY MECHANISMS, OVERLAP, WE'RE PRIMED FOR ACTIVITY DEPENDENT PROCESSES TO HAPPEN. BUT WHAT HAPPENS BECAUSE OF THAT IS WE ARE ALSO UNIQUELY VULNERABLE FOR ANY INSULT DURING THAT VERY EXCITABLE TIME TO HAVE CELL TEARIOUS EFFECTS THAT MAYBE CASCADE AND CONTINUE TO CAUSE NEURAL DISRUPTION FOR TIME PERIODS MONTHS, YEARS, DOWN THE LINE. SO THE THINKING FROM THIS WORKSHOP WAS THAT THERE ARE A COUPLE OF PATHWAYS THIS COULD TAKE, WHEN WE HAVE EPILEPSY AND INTELLECTUAL DISABILITY IN THE SAME PERSON THIS MAY REPRESENT A PRIMARY DISRUPTION IN SENATE TOE GENESIS, COULD BE A GENETIC ABNORMALITY, EARLY INSULT LIKE H IE AND NEONATE YOU GET THE PRIMARY INSULT CAUSING BOTH ASD AND SEIZURE. YOU CAN HAVE SOME GENETIC PRE-DISPOSITION TO HAVE A SEIZURE OR COULDN'T BE GENETIC AT ALL HICSE AND WE HEARD FROM ONE OF THE PUBLIC SPEAKERS ABOUT THAT AND HER SONS. AND THAT'S THE PRIMARY DISRUPTION. THAT RESULTS IN COGNITIVE IMPAIRMENT AND ASD. YOU CAN HAVE SOME KIND OF PREDISPOSITION GENETIC PROGRAM TO HAVE IMPAIRMENT AND ASD AND SEIZURES FURTHER EXACERBATE THAT CONDITION. SO THERE'S A LOT OF MODELS THEY'RE PROBABLY ALL RELATED, BEGINNING TO MAKE STRIDES PIECING OUT WHICH IS WHAT, THIS IS THE DRIVE HOME THAT POINT. THE ASSOCIATION BETWEEN EPILEPSY AND AUTISM SPECTRUM DISORDERS IS RECOGNIZED. IT'S JUST BEGINNING TO BE WELL UNDERSTOOD. BETTER UNDERSTOOD. THAT'S EXCITING. DEVELOPING BRAIN WE CAN GO THIS WAY, THIS SO DRIVE THIS HOME, PLASTICITY, THIS COULD BE ABNORMALITIES IN RECEPTORS, MOLECULES AN NEUROTROPE IN, ANYTHING FUELING FUELING THAT SCAFFOLDING PICTURE. THAT LEADS TO EPILEPSY. THESE ONGOING SEIZURES ARE REALLY WHAT'S DRIVING THE COGNITIVE DEFICIT IN THE AUTISM SO THAT'S ONE PATHWAY. YOU CAN HAVE PEOPLE WHO HAVE A DISRUPTION HERE IN SIMILAR MOLECULES SIMILAR DISRUPTION, YOU GET THE COGNITIVE DEFICIT AUTISM AND DON'T SEE THE ADEQUACY. SO THIS IS FROM AMY BROOKS -- THIS IS A CARTOON THAT JUST DISTORT SOFT UNDERLINE THE FACT THE INITIAL INSULT COULD BE HERE, ANYWHERE IN HERE BUT ONCE YOU GENERATE THE SEIZURE, THE SEIZURES ONGOING EFFECT, WHEN YOU HAVE A SEIZURE THERE'S IMMEDIATE RESPONSES IN THE BRAIN. GET TURNED ON ALL SORTS OF THING THERE'S A DELAYED EFFECT, THERE'S EVEN LONGER EFFECT DOWN THE LINE, CHARACTERIZE INFLAMMATION, GLIOSIS AND NEURAL REORGANIZATION. THIS IS SHOWING HERE THE INITIAL EFFECT THAT MAYBE HITS ONE OR TWO OR THREE OF THESE PROCESSES. THEN YOU HAVE ON GOING PROCEDURES AND YOU EAR DISRUPTING PRUNING LATER ON IN LIFE, DENDRITIC AND AXONAL REFINEM, RECEPTOR AND ION CHANNEL MATURATIONAL CHANGES. THESE ARE ONGOING CHRONIC DISORDERS. YEAH SO WHERE DO WE GO AND WHAT'S THE WAY TO GET INTO THAT AND START UP PACKING IT. WE'RE LUCKY WE HEAR FROM MUSTAFA SAHIN REALLY SHORTLY ABOUT TSC BUT WE DO IS MAYBE ONE APPROACH THAT WORKS OUT THE LOOK AT SINGLE GENE DISORDERS THAT HAVE A HIGH OCCURRENCE OF ASD AN EPILEPSY AND ALSO IN FACT INTELLECTUAL DISABILITYND AND THE THREE THAT STOOD OUT WERE COMPLEX PREVALENCE IN RED SO THESE ARE DISORDERS THAT HAVE ALL THREE OF THOSE THINGS. NTSC IS 50% KIDS MAY HAVE ASD, 80 TO 90% WILL THEN GENERATE SEIZURES. WILL HAVE EPILEPROCY. FRAGILE X, 30% OF BOYS WILL HAVE ASD. 10 TO 15 OR 25% WILL DEVELOP SEIZURES AS WELL AS EXACTLY AUTISM THERE'S A LOT OF PHENOTYPIC OVERLAP HERE AND THE INTERESTING THING ABOUT THE SEIZURE GENERATION INTERACTIVE DISORDER IS SEIZURE TYPE CHARACTER IN THESE GIRLS IS -- IT'S VERY DEVELOPMENTALLY MEDIATE SOD IF YOU'RE A GIRL FIVE AND YOU SEIZURE DISORDERS LOOKS DIFFERENT THAN AD LESS SUSPECT AND MORE DIFFERENT THAN OLDER PERSON AND PREVALENCE RATES ARE DIFFERENT SO THOSE MAYBE ALL CLUES. THE OTHER THING ABOUT IN PARTICULAR IS THE GENE IS KNOWN, THE GENE PRODUCT IS KNOWN AN MORE AND MORE WE CAN TRY TO DIG DOWN AND FIGURE OUT WHAT THAT GENE PRODUCT IS DOING IN TERMS OF ROLE IN SYNAPTIC PLASTICITY AND WHAT IS THE DEAN PRODUCT DOING IN THIS ROLE IN IMBALANCE OF EXCITATORY INHIBITOR BRAIN CIRCUITS THAT'S HAPPENING. WE'RE FIGURING OUT THEY'RE OVERLAP HERE BETWEEN GENE PRODUCTS AND PROCESSES. THAT'S REAL EXCITING. SO IN SUMMARY WHAT WE KNOW, ASD AND -- ARE SPECTRUM DISORDERS,. EPILEPSY IS AS WELL, AND MORE PEOPLE ARE IN THE FIELD BEGINNING TO SAY THAT. PEOPLE WHO HAVE EPILEPSY HAVE INCREDIBLE PSYCHIATRIC DISORDERS AND OTHER ABNORMALITIES. EPILEPSY IS A SPECTRUM DISORDER AS WELL. BOTH CONCEPTUALIZED AS DISORDERS OF THE NEURAL CONNECTIVITY. RESULTING FROM THE PRIMARY REGULATION OF SYNAPTIC PLASTICITY AND THIS IS REALLY IMPORTANT. IF YOU HAVE ONE, AND YOU ALSO HAVE ID, YOUR RISK IS GREATLY INCREASE OF HAVING THE OTHER. SO WHAT DO WE WANT TO KNOW MORE ABOUT? WE HAVEN'T TALKED MUCH ABOUT THIS AT ALL. WE SHOULD BE THINKING MR. CXFC ABOUT BETTER CHARACTER RIDING THE SEIZURE PATTERNS LIKE THE CHILDREN WHO HAVE RAT -- WHO HAVE -- ABOUT PEOPLE WHO HAVE ASD AND SEIZURE, THERE MAYBE KNOWLEDGE THAT WE'RE NOT GLEANING. WHAT IS THE ROLE OVERLEAPTY FORM EEG WHO HAS A FRANK SEIZURE, DISRUPTION AN LOSS CONSCIOUSNESS BUT WHAT ABOUT REALLY UGLYING EEG, WE DON'T KNOW WHAT THAT MEANS. THEY HAVE BEHAVIORAL ABNORMALITIES SO WE'RE IN THE SURE WHAT THIS MEANS WE NEED TO CHARACTERIZE BETTER. THE OUTCOMES IN THE PHENOTYPE, WE DON'T HAVE A HANDLE ON THAT. NEAR AND DISEASE TO MY HEART, WHICH IS THEIR CRITICAL WINDOW FOR INTERVENTION THAT CAN AROUSE DYSFUNCTION THAT WE ANY IS GOING ON IN -- THINK IS GOING ON IN NEURAL CIRCUITRY. HOW DO WE DO THAT? SO I'M GOING TO START WHAT WE NEED FOR NEXT STEPS FROM THE BOTTOM UP. WE REALLY NEED MODELS THAT BETTER IDENTIFY NEURAL DYSFUNCTIONS IN ORDER TO BE ABLE TO INTERVENE AND CORRECT THEM. POPULATIONS THAT HAVE ASD AN EPILEPSY AND INCLUDE PEOPLE WITH ID, VERY INTERESTING PAPER AT THE END OF THIS WORKSHOP ONE THING THAT PEOPLE TALK ABOUT WOULD BE A GREAT MODEL WOULD BE THIS MODEL OVEREATERS SYNDROME. SO IT'S A -- MODEL LET'S -- ROTE SYNDROME. IT'S CLINICALLY CHARACTERIZED BY INFANTILE SPASMS AND BY EEG, I CAN SEE PEOPLE NODDING AROUND THE ROOM, VERY COMFORTABLE WITH THAT. SO THERE'S A REALLY INTERESTING PAPER JUST THIS MONTH IN SEIZURE BY GREG HOLMES WHO IS AT UVM NOW AND SCOTT (INAUDIBLE) AT DARTMOUTH WHERE THEY LOOK AT SLEEP AND COHERENCE PATTERNS SO REALLY USING A WAY COHERENCE AS WAY TO LOOK AT NEURAL CONNECTIVITY IN DIFFERENT GROUPS OF KIDS, 12 WHO HAVE THE SYNDROME AND MATCHED TO TYPICALLY DEVELOPING CONTROLS WHAT THEY FOUND IS THE ADHERENCE PATTERNS IN THESE CHILDREN CHILDREN WERE DIFFERENT FROM ONE WHO HAD RHETT SYNDROME, THIS IS SLEEP, THIS IS DEFAULT STATE AND THEN TYPICALLY DEVELOPING KIDS. WHICH IS REALLY INTERESTING AND THEY WERE DIFFERENT IN WAYS THEY HADN'T ANTICIPATED. AND A LITTLE TEASER IN THIS, BRIEF COMMUNICATION AND ALSO READ IT, IT WILL TAKE YOU TEN MINUTES WHEN THEY DID A FOLLOW-UP A YEAR LATER, THE KIDS WHO DIDN'T HAVE ARRHYTHMIA, BUT DID HAVE EEG THEY WERE DEVELOPMENTALLY DELAYED. THE CHILD IS ONE CHILD BUT STILL EXCITING WHO'S BEHAVIOR HAD NORMALIZED DEVELOPING NORMALLY THAT CHILD DID NOT HAVE ABNORMALITIES IN THE NEURAL CIRCUITRY. SO THAT'S THE MODEL AN INNOVATIVE THINKING WE NEED TO DO TO IDENTIFY WINDOWS WHERE AND HOW TO MEASURE THAT. WE NEED THIS AND THAT STARTS WITH ALL THESE DEFINITIONS OR PEOPLE TALKING, BETTER ANIMAL MODELS, AND YOU CAN READ THAT ONE OPT TOP. THAT'S IT. THANKS. -- ON THE TOP. THAT'S IT. THANKS. [APPLAUSE] >> THANK YOU. THE LAST SPEAKER IN THIS SESSION IS MUSTAFA SAHIN, DIRECTOR OF TRANSLATIONAL NEUROSCIENCE CENTER BOSTON CHILDREN'S HOSPITAL AND ASSOCIATE PROFESSOR OF NEUROLOGY AT HARVARD MEDICAL SCHOOL. >> THANK YOU VERY MUCH FOR HAVING ME, I LEARNED A TON IN THIS WORKSHOP. ONE THING THAT'S COME UP A LOT DURING DISCUSSION AS WELL AS TALKS IS HOW HETEROGENEOUS AUTISM SPECTRUM DISORDER CAN BE BOTH IN TERMS OF THE ETIOLOGY AND ALSO HOW IT PRESENTS. AND THERE ARE DIFFERENT APPROACHES TO THIS OBSTACLE THAT AUTISM SPECTRUM DISORDER PRESENTS TO US. ONE IS TO START WITH HETEROGENEOUS GROUP OF INDIVIDUALS LIKE ZACK IS DOING AND OTHERS ARE DOING. TRYING TO IDENTIFY POTENTIAL OVERLAP BIOLOGICAL SIGNATURES THAT ALLOW US TO SUBDIVIDE THAT DISORDER TO BE ABLE TO TREAT IT BETTER. ALTERNATIVE AND COMPLIMENTARY APPROACH IS TO START WITH DEFINED BIOLOGICAL ENTITY POTENTIALLY GENETIC DISORDER THAT IS HIGH INCIDENCE AUTISM SPECTRUM DISORDER AND USE AS A MODEL TO UNDERSTAND AUTISM SPECTRUM DISORDER AND NEURAL CIRCUITRY BETTER. WHAT I WOULD LIKE TO DO TODAY IS PRESENT THE USE OF WORK GOING ON, NOT JUST MY LAB BUT MY COLLABORATORS AROUND THE COUNTRY USING TUBULE SCLEROSIS AS A MODEL. , A STORY FROM 12 YEARS AGO. [PII redacted from slide] DIAGNOSEDIA NCI UTERO, 20 WEEKS [PII redacted from slide] OF ULTRASOUND, SHOWING TUMORS [PII redacted from slide] GROWING IN HIS HEART AND FMRI [PII redacted from slide] SHOWED THAT THERE WERE TUMORS IN [PII redacted from slide] HIS BRAIN SO THE COMBINATION OF [PII redacted from slide] THOSE TWO FINDINGS MADE [PII redacted from slide] DIAGNOSIS OF TUBULE SCLEROSIS. [PII redacted from slide] HE WAS BORN FULL TERM SOON AFTER [PII redacted from slide] BIT WEENIE COUNSEL THE PARENTS [PII redacted from slide] THAT WE MAY HAVE HIGH INS DENSE [PII redacted from slide] ESPECIALLY ADULT SPASMS WHICH [PII redacted from slide] MIGHT BE DIFFICULT TO IDENTIFY, [PII redacted from slide] MENTIONED PRESENTERS USED TO BE [PII redacted from slide] CALLED WET SYNDROME. [PII redacted from slide] HE STARTED HAVING INFANTILE -- [PII redacted from slide] THREE MONTHS OF AGE, LUCKILY [PII redacted from slide] CALLED OUT IN FIRST DAYS OF PRESENTATION, WE STUDY MEDICATION CALLED (INAUDIBLE) THE SEIZURES STOPPED AFTER TWO OR THREE DAYS, HE HAS NOT HAD ANY SEIZURES SINCE THEN. HOWEVER HE'S HAD MULTIPLE ISSUES. HIS FOLLOWED BY OUR [PII redacted from slide] MULTI-DISCIPLINARY TUBULE [PII redacted from slide] SCLEROSIS AT CHILDREN'S [PII redacted from slide] HOSPITAL, SEEN BY NEPHROLOGIST, [PII redacted from slide] CARDIOLOGIST, OPHTHALMOLOGIST, [PII redacted from slide] UNDER VERY GOOD CONTROL. [PII redacted from slide] HE DOES HAVE SIGNIFICANT SLEEP [PII redacted from slide] PROBLEMS AS MENTIONED EARLIER. [PII redacted from slide] TUBULE SCLEROSIS HAVE [PII redacted from slide] [PII redacted] SEEMS TO BE A CIRCADIAN RHYTHM ABNORMALITY, HE WAKES UP AT 2 NOT MORNING, HIS PARENTS AND IT'S QUITE DISRUPTIVE TO HIS SCHEDULE AS YOU CAN IMAGINE. IMPORTANTLY HE WAS DIAGNOSED WITH AUTISM SPECTRUM KISS ORDER. AT THE AGE OF 12 HIS'S NON-VERBAL, HE HAS SELF-INJURIOUS BEHAVIOR, ONLY ONE TOY HE PLAYS WITH AND HIS PARENT VERSUS BOUGHT 50 COPIES OF THE SAME TOY SO HE DOESN'T LOSE THEM. SO TUBULE SCLEROSIS HAS HIGH INCIDENCE OF AUTISM SPECTRUM DISORDERS, I LIKE TO ARGUE THAT WE CAN USE TUBULE SCLEROSIS AS A MODEL TO STUDY ASD. HERE ARE SOME OTHER REASONS THAT MAKE TUBULE SCLEROSIS A GOOD MODEL. HALF THE PATIENTS ARE AFFECTED WITH AUTISM SPECTRUM IT IS ORDER. IMPORTANTLY MANY PATIENTS [PII redacted] CAN BE DIAGNOSED BEFORE BEFORE BIRTH. DUE TO WORK I'M GOING IN VARIOUS LABORATORIES AROUND THE WORLD, SEVERAL ARE BEGINNING TO BE UNDERSTOOD AND FORTUNATELY THE INHIBITORS OF THESE CELLULAR MECHANISMS THAT ALLOW US TO REPURPOSE THOSE INHIBITORS FOR CLINICAL TRIALS RELATIVELY RAPIDLY. SO THE COMBINATION OF THESE FOUR FACTORS I THINK MAKE TSC A GOOD MODEL TO STUDY FOR AUTISM. VERY BRIEFLY WHAT IS TUBULE SCLEROSIS? A MULTI-SYSTEM DISEASE THAT AFFECT IT IS BRAIN OBVIOUSLY ALSO AFFECTS THE SKIN, KIDNEY AND THE HEART. AND ALL THESE ORGANS CAUSES BENIGN TUMORS P. TSC PATIENTS PRESENT THE CHILD NEUROLOGIST LIKE MYSELF BECAUSE 90% HAVE L HAVE SEIZURES IN THEIR LIFE, HALF OF THEM HAVE AUTISM. THE INCIDENCE OF THE DISEASE IS ABOUT ONE IN 6,000 SO WE THINK THERE ARE ABOUT 50,000 PEOPLE IN THIS COUNTRY ABOUT A MILLION PEOPLE WORLDWIDE AFFECTED WITH TSC. THE GENES HAVE BEEN KNOWN SINCE 1990s, TSC-1 AND 2. WHAT THESE GENES DO IS CONTROL CELL SIZE, HERE IS AN EXAMPLE FROM THE BRAIN OF A PATIENT WITH TUBULE SCLEROSIS, -- TISSUE WAS TAKEN AT TIME OF EPILEPSY SURGERY, THE BRAIN SHOWS THE GIANT CELLS ABOUT TEN TIMES THE SIZE OF NORMAL NEURON, EVERY ORGANIZE. WHICH THEY'RE MESSING YOU SEE CELLS AN ORGANS, THIS IS FROM THE FRUIT FLY, THE FRUIT FLY EYE IS BIGGER HAIR CELLS ARE BIGGER. WHY DOES THIS HAPPEN? IT TURNS OUT THERE'S A PATHWAY IN CELLS, IT'S EXTREMELY (INAUDIBLE) PROTEIN SYNTHESIS THE MORE PROTEIN YOU MAKE THE BIGGER THE CELL GETS UNDER CONTROL OF ENZYME CALLED MTOR OR MAMMALIAN TARGETED (INAUDIBLE) BUT THC GENES IS CLOSELY RELATED TO -- THEY BREAK ON MTOR, AS YOU CAN IMAGINE -- MTOR BECOMES -- IT MAKES TOO MUCH PROTEIN SYNTHESIS AND THE CELL GROWS. THE ADVANTAGE OF THIS CONNECTION BETWEEN (INAUDIBLE) WAS MADE BY FIVE DIFFERENT LABS AROUND THE WORLD IN 2002, IT HAS CHANGED THE LANDSCAPE OF TUBULE SCLEROSIS RESEARCH AND CARE SINCE THEN. WE HAVE SPECIFIC INHIBITORS OF THIS ENZYME. THEY'RE IN THE FAMILY OF PROTEINS CALLED RAPAMYCIN AND RAP LOG AND THOSE ARE BEING USED IN RESEARCH AND MORE RECENTLY IN CLINICAL SETTING. IN THE PAST BEFORE CLOSER UNDERSTANDING OF ROLE OF TSC GENES IN THE BRAIN RESEARCH FOCUSED ON BENIGN TUMOR PATIENTS WITH TUBULE SCLEROSIS DEVELOPED IN THE BRAIN AND SOME STUDY SUGGESTED CORTICAL TUMORS ESPECIALLY TEMPORAL LOBE NECESSARY FOR DEVELOPING AUTISM BUT SEVERAL OTHER STUDIES HAVE CONTRADICTIVE EVIDENCE AND SUGGESTED FRONTAL LOBES ARE TO SUGGEST CEREBELLUM IS CAUSE OF AUTISM, MY LAB AND SEVERAL OTHERS HAVE RECENTLY TURNED TO ALTERNATIVE HYPOTHESIS. THAT MISWIRING OF NEURAL CONNECTIVITY MAY CONTRIBUTE TO PATHOGENESIS OF TSC, WE HAVE DONE WORK IN THE AXON AND DENDRITES OF NERVE CELLS, AND SHOWN THAT TSC MISSING DEFICIENT NERVE CELLS HAVE ABNORMALITIES WITH AXONAL CONNECTIONS AN DENDRITIC CONNECTIONS. I DON'T HAVE TIME TO GO INTO THOSE, I WANT TO DESCRIBE ONE PROJECT, LOOKING AT THE NEURAL CIRCUITRY OF AUTISM. WE WANT TO CHOOSE PARTS OF THE BRAIN WHICH WE THOUGHT PARTICULARLY IMPORTANT IN THE CIRCUITRY ON THE AUTISTIC LIKE BEHAVIOR AND USE MOUSE MODEL TO TEST THE HYPOTHESIS. AS YOU KNOW, CEREBELLUM PART OF THE BRAIN IMPLICATED IN MOTOR COORDINATION BUT WORKING MEMORY AND LANGUAGE HAS ALSO BEEN IMPLICATED IN AUTISM. THE MOST CONSISTENT FINDING ON BRAIN PATHOLOGY IN ASD PATIENTS IS REDUCTION PURR KINK CELLS AND MORE RECENTLY (INAUDIBLE) AND COLLEAGUES AT CHILDREN OOH HOSPITAL BOSTON SHOWED IF YOU HAVE A NEWBORN WITH ISOLATED HEMORRHAGE BLEEDING IN CEREBELLUM YOU HAVE 37% CHANCE OF DEVELOPING AUTISM SPECTRUM DISORDER. THESE FINDINGS SUGGEST CEREBELLUM IS PARTICULARLY IMPORTANT FOR DEVELOPING POTENTIALLY DEVELOPING AUTISM FEATURE. THERE'S SOME STUDIES PRIOR THE OUR WORK IN THE WORK OF HARRY (INAUDIBLE) AND COLLEAGUES LOOKING AT PET SCANS OF INDIVIDUALS OF TUBULE SCLEROSIS AND THEY SHOW THE CEREBELLAR NUCLEI IN THE BRAIN STEM OF INDIVIDUALS WITH TUBULE SCLEROSIS AND AUTISM SHOWS HYPERMETABOLISM. THIS IS COMPLICATED BY BASE OF CEREBELLUM IN THE NUCLEI. SUGGESTS THE CEREBELLUM IS HYPOFUNCTIONING, FUNCTIONING LESS. BASED ON THIS PRELIMINARY OBSERVATIONS WE DECIDED TO TEST WHETHER DELETING A TSC GENE IN ONE PARTICULAR CELL IN THE MOUSE RESULT IN SOCIAL PHENOTYPE. AND WE USE TO (INAUDIBLE) DEVELOPED BY JACKIE YOULY AT NIMH AND HERE WHAT THEY'RE DOING IS PUT MOUSE IN MIDDLE CHAMBER ALLOWING TO EXPLORE ANOTHER LIVE MOUSE VERSUS OBJECT AND TYPICALLY DEVELOPING MOUSE MOUSE USUALLY SPEND MORE TIME EXPLORING THE LIVE MOUSE VERSUS THE OBJECT AND THAT'S WHAT'S IN OUR CONTROL GROUP. MORE EXPLORATION OF THE MOUSE VERSUS THE OBJECT. OUR MUTANTS OF TSC IN JUST THIS ONE PARTICULAR CELL TYPE IN THE CEREBELLUM MADE NO DIFFERENCE, THEY HAD SHOWN NO PREFERENCE OF THE MOUSE VERSUS THE OBJECT. SO WE THEN ASKED THE QUESTION IF WE TREE THESE FROM EARLY ON IN LIFE RAPAMYCIN WE PREVENT THE BEHAVIOR IN THE MOUSE MODEL? THE ANSWER SEEMS TO BE YES. SO TREATED MICE WITH RAPAMYCIN AND THIS IS CONTROL RAP RAPAMYCIN AND THIS IS MUTANT RAPAMYCIN BASED ON MORE TIME WITH LIVE MOUSE THAN WITH THE OBJECT. NOW WE'RE STARTING TO ASK WHETHER WE TREAT THESE MICE, THEY START SHOWING AUTISTIC LIKE FEATURES, WHERE WE CAN TREAT THESE, WE'RE GETTING TO THOSE RIGHT NOW. I DON'T HAVE ENOUGH DATA TO TALK ABOUT THAT YET. EVERYTHING I TOLD YOU SO FAR HAS TO DO WITH MOUSE MODELS, BUT I THINK IT PROVIDES US WITH PROOF OF PRINCIPAL TO TEST THE SAME HYPOTHESIS IN OUR PATIENTS. ALSO HERE AUTISM SPECTRUM FIELD IS THAT AUTISM SPECTRUM REPRESENTS DEVELOPMENTAL DISCONNECTION SYNDROME, IT IS THE CASE OUR WORK ON TUBULE SCLEROSIS IS CONGRUENT WITH THIS HYPOTHESIS. AND IN FACT WE HAVE ONE PARTICULAR ADVANTAGE STUDYING PATIENTS WITH TUBULE SCLEROSIS COMPARED TO OTHER TYPES OF AUTISM. THAT ADVANTAGE IS MANY OF THE PATIENTS WITH TUBULE SCLEROSIS DIAGNOSE BEFORE OR AT TAME OF BIRTH. ONE OF MY COLLEAGUES BOSTON SHOWN AMONG FETUS AND NEWBORNS FORM CARDIAC TUMORS THE CHANCES OF HAVING TUBULE SCLEROSIS IS 95% SO A BIOMARKER TELLS YOU A FETUS OR NEWBORN IS LIKELY TO DEVELOP TUBULE SCLEROSIS. COMBINE IT WITH THE FACT THAT A CHILD WITH TUBULE SCLEROSIS HAVE A 50% CHANCE OF DEVELOPING AUTISM, WE ASK WHETHER TO USE THAT TOOL TO ANSWER A SIMPLE QUESTION. CAN WE DETECT WHICH INFANT BORN WITH TUBULE SCLEROSIS DEVELOPS AUTISM. THIS IS WHAT WE STARTED AT BOSTON CHILDRENS USING NEUROCOGNITIVE ASSESSMENT, DIFFUSION TEST IMAGE AND NEUROLOGICAL ASSESSMENT OF OTHER SOCIAL PARADIGMS. AND NOW WE HAVE SOME PREALMOSTNARY DATA FROM THAT STUDY THAT WE PUBLISHED A FEW YEARS AGO. HERE ARE SOME DIFFUSION TEST IMAGING ADVANCE FORM OF MRI IMMA'AMING IN THREE GROUPS OF PATIENTS. IN A TYPICAL DEVELOPING CONTROLS, TUBULE SCLEROSIS PATIENTS WITH NO SIGNS OF AUTISM AND NO ON THE SPECTRUM. WHAT WE LOOK AT HERE ARE CONNECTIONS WITH A MAIN CONNECTIVITY, WITH CORPUS CALLOSUM, THERE'S NO SIGNIFICANT DIFFERENCE BETWEEN THESE TWO GROUPS. IN FACT BY QUANTIFICATION WE DON'T SEE A SIGNIFICANT DIFFERENCE BETWEEN THESE TWO GROUPS. CSC PATIENTS ON THE SPECTRUM HAVE CONNECTIVITY BETWEEN THE TWO HEMISPHERES. THIS IS ACTUALLY A FINDING SHOWN IN (INAUDIBLE) POPULATION IN THE PAST AS WELL. SO THIS ALLOWS US FOR THE FIRST TIME TO TAKE A GENETICALLY DEFINED GROUP OF PATIENTS AND DIFFERENTIATE THEM HAVE AUTISM BASED ON DIFFUSION TENSOR MRI. SO THIS WAS A SINGLE STUDY OF ABOUT 40 PATIENTS. WE WERE LUCKY ENOUGH TO GET FUNDING FROM THE NIH TO ASK THIS QUESTION PROSPECTIVELY, GROUP OF SENSORS SO WE NOW HAVE CONSORTIUM CENTER OF EXCELLENCE NETWORK OF 5 -- GEOGRAPHICALLY DISTRIBUTED AROUND THE COUNTRY, ANALYZING PATIENTS FOR TUBULE SCLEROSIS THE SAME WAY USING EEG AND NEUROCOGNITIVE TESTING. THE STUDY IS HALFWAY DONE, WE ENROLLED 500 PATIENTS AND HAVE THE RESULT IT IS NEXT COUPLE OF YEARS. AT THE SAME TIME A PARALLEL STUDY FUNDS BY THE NINDS LOOKS AT PREDICTIVE VALUE OF EEG TO PREDICT EPILEPSY IN CHURN WITH TUBULE SCLEROSIS, THAT STUDY IS ALMOST COMPLETED. ONE OF THE THINGS OF COURSE WE WANT TO PREDICT WHO IS LIKELY TO HAVE AUTISM, WHO SNOT LOOKLY TO HAVE AUTISM BUT REALLY BASIC QUESTION IS CAN WE INTERVENE IN SOME WAY. IS THERE SOME INTERVENTION THAT CHANGE THE COURSE OF DISEASE AUTISM DEFICIT IN CHILDREN WITH TUBULE SCLEROSIS. IN THE MOUSE MODEL THE DRUG -- THE GROUP OF DRUGS CALLED RAP LOGS LOOK PROMISING. THEY CAN IMPROVE CONNECTIVITY IN TERMS OF MYELINATION, THEY CAN PREVENT SEIZURES. THEY CAN IMPROVE LEARNING, AS I SHOWED YOU THEY CAN PREVENT AUTISTIC LIKE FEATURES IN THE MOUSE MODEL. SO AS A RESULT OF THAT WE SHOW THAT PHASE 2 TRIALS IN PATIENTS WITH TUBULE SCLEROSIS BETWEEN 6 AND 21, WE LOOK AT NEUROCOGNITIVE FEATURES AT PRIMARY ENPOINT BUT WE'RE ALSO LOOKING AT AUTISM SEIZURES AND SECONDARY ENPOINTS. -- END POINTS. WE HAVE ENROLLED 50 PATIENTS FROM TWO SIDES AND THE LAST PATIENTS WILL BE DONE WITH THE TRIAL AT THE END OF DECEMBER SO I HOPE TO HAVE SOME RESULTS BY EARLY NEXT YEAR. WE COMPARE NEUROCOGNITIVE TESTING AT BASELINE THREE MONTHS AND SIX MONTHS OF TREATMENT VERSUS TREATMENT VERSUS PLACEBO IN THIS GROUP OF PATIENTS. I THINK EVERYTHING WE HAVE DONE WITH TUBULE SCLEROSIS BEGS THE QUESTION, HOW MANY OF THE FINDINGS THAT WE HAVE IN TUBULE SCLEROCITYSIS ARE SPECIFIC TO TUBULE SCLEROSIS, OF PATIENTS WITH TUBULE SCLEROSIS. SO TO BE ABLE TO ANSWER THAT QUESTION, WE FORMED A CONSORTIUM, A RARE DISEASE RESEARCH NETWORK CONSORTIUM THAT JUST GOT FUNDING BY COMBINED EFFORT AT THE NIH AND THAT CON SR. SUM WILL LOOK AT NOT JUST TUBULE SCLEROSIS PATIENTS BUT ALSO SHANK 3 MUTATIONS IN THE POPULATION AND P-10 MUTATIONS AS WELL, KNOWN CAUSES OF AUTISM AND INTELLECTUAL AT THIS ABILITY. AND WHAT ARE THE SIMILARITIES AND DIFFERENCES BETWEEN THREE DIFFERENT SYNDROMES. WE ASK PATIENTS WITH P-10 TREATED WITH MTOR INHIBITORS TO IMPROVE COGNITION IN THOSE PATIENTS AS WELL. SO I THINK COMPARATIVE ANALYSIS OF SINGLE GENE DEFECTS INTELLECTUAL AUTISM CONVERGENCE BIOLOGY AND AUTISM SPECTRUM DISORDERS. I WOULD LIKE THE STOP HERE AND THANK THE COLLABORATORS AND FUNDING RESOURCES. THANK YOU VERY MUCH. [APPLAUSE] >> THANK YOU, MUSTAFA. TOW MIND IF I START WITH A QUESTION? >> TAKE OVER IF YOU WANT. SO I'M TRYING TO UNDERSTAND MUSTAFA, I LOVE YOUR FININGS USING DIFFUSION SENSOR IMAGING TO SHOW DIFFERENCE IN FIBER TRACKS BETWEEN CHILDREN WITH TSC WITH AN WITHOUT AUTISM. SO I JUST WOPPEDDER WHEN YOU DO THE STUDIES WITH RAPAMYCIN, WHERE YOUR INSERT PATHWAY, AND YOUR MOUSE MODEL IS AFFECTING THE AUTISM OUTCOME, YOBBO YET MY UNDERSTANDING IS ALSO -- DOES IT AFFECT TUMOR GROWTH WHEN YOU GIVE IN THE MOUSE MODEL? I'M WONDERING WHETHER YOU THINK, IS IT MEDICATION INFLUENCING THE AUTISM OR THE TUBULE SCLEROSIS ARE BOTH, HOW DO YOU THINK ABOUT THAT? >> I GUESS I THINK OF THEM AS A CONVERGENT DISORDER. I THINK THE BEHAVIORAL DEFICITS WE SEE IN THE INDIVIDUALS AFFECTED WITH TSC THEY MAYBE ANXIETY OR ADHD ARE COMING FROM THE SAME ABNORMALITY IN THE MTOR PATHWAY. AND THEY MAY HAVE HAVE DIFFERENT NEURAL CIRCUITS BUT DEFICITS SO THE MAIN -- ABNORMALITY IN THE (INAUDIBLE) MAY OCCUR BECAUSE THERE MIGHT BE OTHER ABOUT NORMALITIES IN (INAUDIBLE) SIX SYNAPSES APT DIFFERENT SURFACE MIGHT BE AFFECT BUD THE UNDERLYING BIOLOGICAL FEEDBACK IS THE HYPERACTIVATION SO POTENTIALLY WE WOULD BE AFFECTING ALL OF THOSE SYMPTOMS AT THAT TIME SAME TIME. IN A SENSE PSC IS A COMPILATION OF SYMPTOMS AND EXAMPLE TOM WAS GIVING ABOUT FEVER IF THE FEVER WAS CAUSED BY SEPSIS, INFECTION IN THE LUNG AND BRAIN WITH SEPSIS, THAT WE -- ATTACK THE VACCINE IN ALL THOSE PATHWAYS. I THINK THERE'S (INAUDIBLE) TRANSFORMATIVE THERAPY THAT HAVE UNDERLYING ABNORMALITY AND ALSO SURFACE. I THINK THAT IS TRUE SO WE HAVE MOUSE MODELS FOR INSTANCE EPILEPSY. T HEALTHCARES THAT CAUSES EPILEPSY, WE SEE ABNORMALITIES IN THE MYELIN DEPOSITION IN THOSE MICE AND WE TREAT THEM WITH THE MYELINATION IMPROVES. I DON'T THINK SEIZURES ARE PART OF THE MYELINATION -- BUT BOTH SYMPTOMS IMPROVE. DOES THAT ANSWER YOUR QUESTION? >> CLINICAL THAT SAME TRACK FOR BOTH ASHURA AND YOU TALKED ABOUT. CAN YOU GET ANY USE ANY APPROACH TO GET LOCALIZATION. IF YOU COMPARE KIDS WITH TSC WITH AND WITHOUT AUTISM, BESIDES -- YOU SHOW THE ONE WHITE MATTER TRACK BUT FOR INSTANCE ARE TUMORS MOST LIKELY IN ONE PARTICULAR PART OF THE BRAIN? THEY'RE THE MOST LIKELY GRANTED MOLECULAR DEAF IS EVERYWHERE BUT IS THERE SOMETHING ABOUT ONE AREA THAT SEEMS TO BE AFFECTED THAT WILL TRULY INCREASE THE RISK FOR ASD IN THIS POPULATION. THE SAME THING WHEN YOU LOOK AT SEIZURES. WHAT IS THE FOCUS THAT MATTERS MOST FOR HAVING ASD WITH EPILEPSY? >> SEVERAL GROUPS LOOKED AT THAT QUESTION BECAUSE TUMORS ARE RELATIVELY EASY TO IDENTIFY, CAT SCAN AND WHERE TUMORS ARE. THERE DOESN'T SEEM TO BE GOOD CORRELATION BETWEEN TUMOR SIZE, TUMOR LOCATION OR TUMOR LOAD, THE WAY YOU CALCULATE, AUTISM SPECK TRIM DISORDER THAT'S WHY WE TRY TO DO MORE TO ADVANCE IMAGING TUMORS WHICH ARE OBVIOUSLY ON CONVENTIONAL MRI BUT DIFFUSION TENSOR IMAGING TO GET CONNECTIVITY. ALONG THOSE LINES, YOU THINK THE LANGUAGE PATHWAY MIGHT BE AFFECTED IN PATIENTS WITH AUTISM. WE DO SEE THAT SIMILAR TO WHAT I SHOW WITH CORPUS CALLOSUM, MORE DISORGANIZED IN ASD PATIENTS WITH TSC. >> WHAT ABOUT ANY FUNCTIONAL MEASURES LIKE JUST LOOKING AT RESTING STATE OR SOMETHING LIKE THAT. >> THOSE ARE DIFFICULT TO DO IN OUR POPPINGS -- POPULATION OF PATIENTS. WE DON'T HAVE GOOD FUNCTIONAL MRI. WE TRIED TO DO FUNCTIONAL MRI IN YOUNG KIDS THAT DON'T NEED SEDATION UNDER GOOD SLEEP BUT -- >> VERY RARELY, THINK SEE AS WE THINK WE KNOW THE REASON THEY SEE SO WE RARELY GET LPs ON CHILDREN. >> ON EPILEPSY AND SEIZURE FOCUS? >> I THINK PART OF WHAT I LIKE LOOKING AT AT THE SLEEPING BRAIN, IF YOU CAN SORT OF RECREATE A LOT OF THOSE COHERENCE THE WAY FUNCTIONAL ASSOCIATION BETWEEN GROUPS OF NEURONS, WHAT THEY LOOK LIKE IN DIFFERENCE POPULATIONS WITHOUT HAVING TO WORRY ABOUT EXTERNAL STIMULATION WHERE THE CHILD ATTENTION IS, OR IF THEY'RE HOPING STILL GREAT COLLEAGUE VERSUS TAKEN AS WELL AND THE EXAMPLE THAT I BRIEFLY OUTLINED LOOKING AT KIDS WITH SPASMS. SO YOU CAN RECREATE SO WHAT I DIDN'T MENTION IN THAT STUDY IS THAT PARTICULAR TYPE OF ABNORMALITY AND COHERENCE WHEN COMPARED WITH TYPICAL KIDS WITH VERY INTENTION WHAT WE CALL LONG IT IS ANSWER COHERENCE OR VERY HIGHLY HIGH CORRELATION BETWEEN POSTERIOR BRAINS AN ANTERIOR PARTS OF THE BRAIN, SURPRISING FOR THEM TO FIND, IT WASN'T WHAT THEY EXPECTED. AND AUTHORS INTERPRETED THAT TO MEAN FAILURE OF GROUP DIFFERENTIATION THAN A TYPICALLY DEVELOPING BRAIN. THIS IS LIKE AN INFLEXIBLE STATE, WHAT'S INTERESTENING THAT STUDY IS THAT A PAPER PUBLISHED BY DUFFY ET AL TWO YEARS PRIOR FOUND SIMILAR COHERENCE LONG DISTANCE BUT INTERPRETING OF FAILURE DIFFERENTIATION AND DIFFERENT NEURAL CIRCUITS IN THE BRAIN IN POPULATIONS OF PEOPLE WHO ARE AWAKE WHO HAVE ASD. SO SO YOU CAN LOOK AT TEMPORAL ORGANIZATION AND SHORT DISTANCE ELECTRODES SO YOU CAN GET CLOSER TO AREAS YOU MIGHT FIND FUNCTIONAL ABNORMALITIES. SO MAYBE NOT PINPOINT WITH FMRI AND NOT LOOKING FOR LOCALIZE ABNORMALITIES, YOU'RE LOOKING FOR NEURAL CIRCUITS AND PATHWAYS. SO I LIKE THAT APPROACH BETTER. >> REAL QUICK, TWO QUESTIONS. FIRST IS FROM THE PRESENTATION THERE WAS SOMETHING LIKE 21.5% INCIDENCE OF SEIZURE ACTIVITY AND INTELLECTUAL DISABILITY CHILDREN. MY FIRST QUESTION IS WHETHER OR NOT YOU SHALL BE BRINGING THOSE CHILDREN EARLY ON. I HEAR PARENT TELL ME FROM TIME TO TIME THAT THEIR CHILD WAS HAVING WHAT THEY CALL SILENT SEIZURES AND ONCE STARTED SEIZURE MEDICATION, THERE WAS A BOOSTING COGNITION, WHETHER WE DO A BETTER JOB IDENTIFYING THAT, TWO, THIS SEGUES TO THE IMMUNE PRESENTATION LATER ON, I WAS READING A MICROGLIAL CELLS CAN ALSO ACTIVATE SEIZURE ACTIVITY AND WHEN THEY MOVE IN TO AREA OF THE BRAIN INJURED AND THEY RELEASED CYTOKINES THAT THOSE CYTOKINES CAN ACTIVATE THE NEURONS AND ACTUALLY TRIGGER SEIZURES AN THIS IS SOMETHING THAT IS RELATIVELY NEW. SO ONE INTERESTING THING ABOUT THAT, I SEE IT IN POST TRAUMATIC HEAD INJURY AND SOMETIMES AFTER INFECTION YOU CAN GET THE DRUG THAT CAN BLOCK THAT IMMUNE RESPONSE IN THE BRAIN AND ACTUALLY PREVENT SEIZURES. SO SINCE WE KNOW CARLOS, I'M SURE YOU WILL ADDRESS THIS YOU SPEAK THERE IS MICROGLIAL ACTIVATION GOING ON, CAN THAT LATER BE A TARGET FOR TREATMENT ESPECIALLY IN CHILDREN WITH REFRACTORY SEIZURES THAT ARE NOT RESPONDING TO YOUR TYPICAL ANTI-SEIZURE MEDICATION? >> (INAUDIBLE) FOR ME. SO I'M JUST GOING TO PUNT TO CARLOS THE SECOND QUESTION BECAUSE I THINK HE'S A BETTER PERSON TO ANSWER THAT. THIS REALLY -- A QUESTION WITH A LOT OF LAYERS THERE AND WE CAN DISCUSS AFTER HIS TALK BUT I WILL ADDRESS THE FIRST QUESTION WHICH IS THAT, YES, THAT'S SOMETHING THAT WE HEAR ALL THE TIME AND I ALLUDED TO IT A LITTLE BIT IN MY VERY BRIEF TALK ABOUT WHAT DOES THAT LOOK LIKE. ARE THERE BEHAVIORAL MANIFESTATIONS THAT ARE PART OF THE EPILEPSY SPECTRUM THAT MAY HAVE SHARED ORIGIN WITH THE ASD SPECTRUM THAT MANIFESTS AS SOMETHING OTHER THAN WHAT WE'RE USED TO CALLING SEIZURE ACTIVITY. THAT'S SOMETHING THAT PEOPLE IN THE FIELD REALLY HAVE BEEN THINKING ABOUT, CAME UP AT THE WORKSHOP, SOMETHING THAT I KNOW COLLEAGUES WORKING AT (INAUDIBLE) SIMONS FOUNDATION, THEY'RE ACTUALLY DOING THAT, THEY'RE TRYING TO BETTER CHARACTERIZE WHAT IF ANY ARE BEHAVIORAL MANIFESTATIONS OF THE SILENT SEIZURES YOU ARE MENTIONING, YOU NEED TO SORT OF GET A GOOD WELL DESCRIBED COHORT OF KIDS AND BOTH AWAKE AND ASLEEP WHICH WE KNOW LOWERS SEIZURE THRESHOLD AND DO THE INTERVENTION. SO (INAUDIBLE). >> SHOULDN'T WILL BE A GUIDELINE IN PLACE IF A CHILD HAS AUTISM INTELLECTUAL CAPABILITY THEY AUTOMATICALLY GET EEG AWAKE AN SLEEP IN THAT'S MY QUESTION. SHOULD THERE BE A GUIDELINE? I THINK WE'RE COLLECTING EVIDENCE ABOUT THE PREVALENCE OF THOSE THINGS, LEFT TO THE PRACTITIONER, WHAT IS THEIR BEST -- THE BEST -- THAT'S YOUR CRITICISM YOU LEFT UP TO AN INDIVIDUAL PRACTITIONER WHETHER THEY BEST GUESS WHEN THE CHILD SHOULD HAVE THE EEG. AND SHOULD IF YOU HAVE INTELLECTUAL DISABILITY GET EEG LOOKING FOR SEIZURES. >> THE ATM AND THEIR P MECHANISM HAS COME UP WITH OR IS IN THE PROCESS OF COMING UP WITH GUIDELINES RELATED TO DIFFERENT COMORBIDITIES AND EEG EPILEPSY. DID YOU WANT TO SPEAK TO CURRENT GUIDELINE IN THAT AREA? >>S IS SOMETHING TRYING TO DEVELOP PARTLY ACROSS THE COUNTRY, A LOT OF EEGs ARE ORDERED PRIA BIPRIMARY CARE PROVIDERS NEUROLOGISTS IN TERMS OF ACCESS TO -- FOR THEM TO ORDER THAT. ESPECIALLY BECAUSE PRIMARY CARE PROVIDERS DON'T HAVE THE LEVEL OF SUSPICION REGARDING SOME OF THESE BEHAVIORAL MANIFESTATIONS AND SO THEY'RE NOT AWARE WHAT I JUST SAW MIGHT BE A SEIZURE SO THEY AREN'T ORDERING IT AS FREQUENTLY AS THEY SHOULD BE SO WE ARE WORKING TO TRY TO BROADEN THAT. >> BEFORE WE MAKE A GRIND WE HAVE TO HAVE EVIDENCE WHAT'S HAPPENING. THAT'S WHY I THINK I -- THE HEAD ON YOUR ANSWER -- HEDGED ON YOUR ANSWER. PART OF THE ONGOING DR. BRONZE WAS TRYING TO DO. >> REALLY GOOD ISSUE FOR THIS AFTERNOON. THIS IS IN FACT AN UNDETECTED CO-OCCURRING SYNDROME WHICH IS WHETHER TO CALL THEM SILENT SEIZURES WE TONE KNOW, IN TERMS OF NUMBER TWO UP THERE, GETTING A LOT MORE INFORMATION ABOUT WHAT THOSE LOOK LIKE, AND HOW TO MANAGE THEM WOULD BE INCREDIBLY IMPORTANT. CARLOS, GO AHEAD. >> JUST A BRIEF COMMENT, COMING FROM NEUROPATHOLOGY POINT OF VIEW, IN THE BRAIN OF PATIENT WITHOUT DISEASE PREVALENCE TO SEE COURTCLE DISARRANGEMENT, A LOT OF ABNORMAL ABNORMALITIES. THAT WILL TRANSLATE IN A NORMAL ELECTRICAL SIGNAL THAT WON'T BE AFFECTED BY EEG. SO I GUARANTEE IF YOU'RE GOING TO USE EEG AS A TOOL YOU HAVE HAVE A LOT OF ABNORMALITIES IN THOSE CASES AND CLINICIANS NEED TO DECIDE WHAT IS GOING TO BE THE APPROACH TO TREAT CLINICAL SYNDROME, CLINICAL SEIZURE OR TO TREAT THE EEG. SO I THINK THAT I BELIEVE AT THIS MOMENT WITH QUITE BEHIND IN UNDERSTANDING THE VALUE OF THE EEG FOR THOSE PATIENTS AND I WONDER THAT BECAUSE YOU'RE NOT GOING TO USE A LOT OF DISEASE MEDICATIONS IN PATIENTS THAT HAVE SOME NEUROLOGICAL SO THAT IS (INAUDIBLE). >> I THINK THE USE OF EEG IN A PATIENT THAT'S SEIZURE WISE ASYMPTOMATIC IS A CONTROVERSIAL AND I THINK OVERALL GENERALIZE IN THIS COUNTRY WOULD NOT BE DOING THAT BECAUSE THE YIELD LOW AND THE INFORMATION IS NOT THERE. WE ARE ALL CONCERNED ABOUT GETTING RESULTS FROM THAT WE DON'T KNOW WHAT TO DEAL WITH AT THIS POINT. WHAT WE'RE TRYING TO DO WITH THE COMMUNITY IS TO DO A PROSPECTIVE STUDY TO SEE HOW PREDICTIVE IS THE EEG. AND WHAT EEG IS CORRELATED WITH FIRST OF ALL EPILEPSY AND SECOND OF ALL, AUTISM SPECTRUM DISORDER AND SINCE THE PATIENTS TUBULE SCLEROSIS WITH HIGH RISK GROUP KIND OF LIKE INDIVIDUALS WITH ASD WHICH WE USE THAT GROUP AS WAY TO TEST THE HYPOTHESIS AND I THINK IN TERMS OF EPILEPSY, THE RESULTS ARE VERY PROMISING THAT WE HAD SOME PARENTS THAT PREDICT EPILEPSY SO THE FIRST PIECE OF EVIDENCE RESULTS FROM AUTISM WE DON'T HAVE THOSE YET. >> I GUESS (INDISCERNIBLE) DISCUSSION. SO ACTUALLY THIS IS A VERY (INAUDIBLE) SO DON'T -- YES SO THE CRITICAL QUESTION IS WHETHER THE ONLY CLINICAL OUTCOME OF (INAUDIBLE) SEIZURE AN ADDED CLINICAL OUTCOMES ARE THERE AND THEREFORE SHOULD BE TREATED. THE CRITICAL TEST IS IF YOU SUPPRESS ACTIVITY, DO YOU IMPROVE OUTCOME? AND THAT TEST HAS NOT BEEN DONE. PART OF THE STUDY TRYING TO DO THAT. THAT'S -- IF IT'S SUPPRESSED, YOU GET IMPROVED OUTCOMES AND YOU DON'T KNOW IT'S HARD TO MAKE A RECOMMENDATION WITHOUT HAVING (INDISCERNIBLE). >> THIS IS CELL BIOLOGICAL QUESTION MUSTAFA. BECAUSE OF ROLE OF NTORND INNATE IMMUNITY IN GRAHAM POSITIVE AND IMMUNITY, HAVE YOU ENCOUNTERED ANY DOSE LIMITING IMMUNOSUPPRESSION IN THE CHILDREN TREATED WITH RAPAMYCIN? >> SO IT TURNS OUT MILD IMMUNOSUPPRESSANTS BY THEMSELVES. MOST COMMONLY USED IN OTHER CHEMOTHERAPY AGENTS, MORE BETTER RESPONSE. WE HAVE BEEN USING PATIENTS RAP LOGS FOR A WHILE FOR TREATING REAL TUMORS AND CYTOMAS WITH NO TCP PROPHYLAXIS AND ADVERSE REACTIONS. IN PHASE 2 AND 3 TRIALS PLACEBO CONTROLLED THERE WAS STRIKING INCREASE IN INTERCURRENT INFECTION. IN -- DRUG GROUP VERSUS PLACEBO GROUP. THERE WAS NONE. >> IT DOESN'T SEEM TO BE A MAJOR PROBLEM IN TERMS OF THAT. >> FIRST I WOULD LIKE TO THANK FOR PUTTING THIS TOGETHER. HAD SOME ENPUT WITH ME BUT FOR BRINGING L IN THE EPILEPSY DAY ONE, WHEN I CAME IN TO THE IACC, THREE THINGS (INAUDIBLE) AUTISM, ONE OF THE QUESTIONS I HAD THEN AND I STILL HAVE NOW, WE TALK ABOUT THE OVERLAP OF EPILEPSY AND AUTISM AN SYSTEM LAYERTIES, ONE THING THAT STRUCK ME SINCE THE BEGINNING IS THERE A CONFERENCE IN EPILEPSY AND AUTISM AND HOW CAN WE BRING THAT BACK TO TREAT FOR TREATMENT, CAN WE DO THE SAME MEDICATIONS HAVE THE SAME EFFECT IN AUTISM. DO THEY HAVE THE SAME ADVERSE EFFECT OR ARE THEY WORSE? THIS IS VERY MUCH PROMPTED -- PERSONAL ANECDOTE OUT WHEN MY SON DEVELOPED EPILEPSY, GOT TWO APPROACHS FROM TWO NEUROLOGISTS, WE DON'T LIKE KEPRING A, LOGISTICS CREATE BEHAVIOR PROBLEMS IN OUR EXPERIENCE AND OTHER IMMUNOLOGIST WHO SAID -- KEPRA HAS NEVER KILLED ANYBODY BECAUSE THE MEDICINE YOU PRESCRIBE HAS ALLERGIC REACTION WITH SOME PATIENTS AND NOT IN A LONG TIME BUT HAS DONE THAT. SO WITHIN YOU'RE FACED WITH THAT AS A PARENT YOU LIKE TO HAVE DATA RATHER THAN I LIKE THIS, I LIKE THAT. YOU'D LIKE TO HAVE SOMEBODY SAY FOR KID LIKE YOURS WE KNOW IT'S NOT SPECIFIC BUT MOST OFTEN THIS ONE WOULD PROBABLY BE BETTER. GOING BY BEST NEEDS THEY HAVE OF THEIR OWN EXPERIENCE. I WOULD LIKE TO SEE IN AUTISM IS IT DIFFERENT AND MAYBE I DON'T LOOK THROUGH THE DATABASES OF PRESCRIPTION DRUGS TO SEE WHERE DO KIDS LAND. AFTER A LONG TIME, DO MORE LAND ON KEPRA IF AUTISM OR OR SOME OTHER DRUG IF NOT AND WE CAN PLAY BACK TO HA AND GET AN IDEA. THANK YOU FOR THE WORK YOU'RE DOING. APPRECIATE IT. >> JERRY WILL ASK THE LAST QUESTION THEN WE'LL BREAK. GO AHEAD. >> I'M WONDERING WHAT WE KNOW ABOUT THE LONGITUDINAL COURSE OF EPILEPSY AND AUTISM AND I KNOW I SAW INCREASE IN AD LESSENS, I THINK FROM THE FIRST PRESENTATION. BUT WHAT DO WE KNOW ABOUT MOVING INTO ADULTHOOD AND AND WHETHER SEIZURES TEND TO GET WORSE WITH TIME, WHAT DO WE KNOW ABOUT THE LONGITUDINAL COURSE? >> I PUT THAT ON THE NEED TO KNOW SLIDE. WE NEED BETTER DATA. I THINK WHAT COMPLICATES THAT IS PEOPLE GET PRESCRIBED ALL SORTS OF MEDICATIONS FOR OTHER CO-OCCURRING NEUROPSYCHIATRIC CONDITIONS IN PARTICULAR IS THEY'RE GETTING A LOT OF MEDICATIONS SO WHAT HAPPENS NATURAL HISTORY PART OF THE EPILEPSY AND ADULT PATIENTS WITH ASD YOU DON'T KNOW ABOUT IT BUT IT WILL TAKE AN EXTRA SECOND TO MAKE A PLUG FOR THINKING ABOUT THE FACT THAT ID INTELLECTUAL DISABILITY MAYBE A DIFFERENT ANIMAL AND WE NEED TO THINK ABOUT INCLUDING PEOPLE WITH INTELLECTUAL DISABILITY MORE OFTEN IN STUDIES WHERE WE'RE STUDYING ASD AND EPILEPSY AND WE HAVE DONE A GOOD JOB OF THAT. >> WE LOOKED INTO THIS QUESTION A LITTLE BIT IN OUR STUDY AND IT WAS MOSTLY ANECDOTAL BUT PEOPLE SEEM TO THINK THERE MIGHT BE A BIMODAL DISTRIBUTION IN TERMS OF SEIZURES EARLY ON OR IN ADOLESCENTS AND THAT'S THE BEST I CAN GATHER. >> I WAS LOOKING AT YOUR DAYTIME FROM THIS MORNING, 16 FOLD ODDS RATIO OF 16 FOR EPILEPSY, WHAT IS THE -- DOES THAT LOOK ANYTHING LIKE THE 21% OR 8%? >> I DEN SHOW THE RATES OF CO-OCCURRING CONDITIONS BUT INTELLECTUAL DISABILITY BUT I HAPPEN TO HAVE IT HERE AND IN FACT IT'S RIGHT ON EXACTLY WHAT YOU'RE SAYING. ADULT POPULATION THE RATE OF EPILEPSY OR RECURRENT SEIZURE WAS 27, 28% IN THE GROUP AND 8% IN THE NON-AUTISTIC GROUP SO EXACTLY WHAT -- AND YEAH, THERE'S A HUGE -- I DON'T KNOW WHAT TYPE OF SEIZURE, WE PROBABLY COULD LOOK AT THAT IN OUR DATE BASE. NOT SO MUCH IN LONGITUDINAL BUT BIG GROUP OF KIDS, BIG GROUP OF ADULTS SEEING SEIZURE TYPES ARE DIFFERENT. THAT'S SOMETHING THAT I PUT ON MY NOTES HERE. >> INCREDIBLE ALL THE INFORMATION IS AROUND THE TABLE. GREAT. >> SO QUICK CLARIFICATION. YOUR DIVISION WAS BY INTELLECTUAL DISABLE, NOT AUTISM. >> OKAY. >> DR. INSEL, THIS IS JAN CANDY, I DON'T MEAN TON -- CRANDY, I DONE MEAN TO BE THE CONTROVERSIAL ONE BUT NEVADA PASSED THE MEDICAL MARE WHAT N PARENTS ARE WANTING TO ADDRESS SEIZURE ACTIVITY UTILIZING THAT. IS THERE STUDIES OR IS THAT TOO YOUNG NOW? >> ANYBODY HERE CAN FEEL THAT, MUSTAFA? THERE'S NOT ENOUGH INFORMATION THAT AMERICAN EPILEPSY SOCIETY MADE THIS STATEMENT WE DON'T HAVE ENOUGH INFORMATION IN THE CLINICAL POPULATION OF PATIENTS WITH EPILEPSY THAT MEDICAL MARIJUANA IS EFFECTIVE OR SAFE IN SMALL GROUP OF PATIENTS WE HAVE LESS DATA SO WE FEEL LIKE THIS IS A REALLY IMPORTANT AREA OF PRIORITY AND WE'RE TRYING TO STUDY IN MOUSE MODELS WHERE WE KNOW THE MOUSE MODELS REPLICATE THE EPILEPSY FOR TSC QUITE WELL TO SEE WHICH -- IF ANY COMBINATION TREATMENTS RASH YES TREATMENTS WOULD BE EFFECTIVE IN MOUSE MODELS. >> GO AHEAD. >> (INAUDIBLE) I THINK THAT'S -- CLINICAL TRIAL IN RETT SYNDROME, THEY SHOW SOME DATA WITHIN A COUPLE OF YEARS, THE ONLY QUESTION WITH ANIMAL MODEL IS THE (INAUDIBLE) SYSTEM SEEMS TO BE OF INTEREST TO US THROUGHOUT THE GROUP BUT -- WOULD BE TO (INAUDIBLE) ABNORMALITIES. WHETHER SOME KIDS WE NEED AGONIST OR ANTAGONIST REMAINS TO BE SEEN SO WE HAVE TO BE CAREFUL. WHEN WE PUT THESE INTO -- >> SOUNDS LIKE THE JURY IS OUT ON THAT ONE BUT IT'S ANOTHER QUESTION TO BE STUDIED. >> LEGALIZING MARIJUANA THAT A CERTAIN PERCENT OF THE PROCEEDS FROM THE SALES WILL GO INTO MEDICAL RESEARCH, IF THERE'S RESEARCHERS AROUND TABLE TO LOOK AT THAT, I KNOW PARENT REPORTS especially with the CDP type strain, that's been very, very beneficial, it's something that would be great, if someone would apply for some funding to look at it. >> TIFFANY. >> I WAS GOING SAY AS LONG AS MARE WHAT REMAINS SCHEDULE ONE DA IT'S RELATIVE TO DO THOSE CLINICAL TRIALS, WE HAVEN'T FIGURED OUT HOW WE CAN REVIEW THEM AS LONG AS -- THOUGH IT'S LEGAL IN CERTAIN STATES FEDERAL LEVEL WE HAVE PROBLEMS. IT'S SOMETHING WE ARE LOOKING INTO AND WORKING ON THIS SO THAT WAY THOSE TRIALS SOMEBODY CAN DO THEM. >> SOUND LIKE AUTISM SPEAKS WOULD FUND IT NOT THE FEDERAL GOVERNMENT. >> IT'S NOT SO MUCH THE FUNDING ISSUE AS MUCH AS GETTING AN IND IN ORDER TO STUDY A NEW INDICATION FOR THAT PRODUCT. IT WOULD BE A MEDICAL USE TO MITIGATE -- >> PRE-IND COULD STILL BE -- >> ANIMAL STUDIES SURE BUT HUMANS, GOING TO GET MORE DIFFICULT. >> ON THAT NOTE, WE'VE EARNED A BREAK. LET'S MAKE IT BRIEF BECAUSE WE'RE FAR BEHIND LET'S TAKE TEN MINUTES AND RECONVENE BY 3:00. SO LET'S TAKE TEN MINUTES AND RECONVENE BY 3:00. >> LET'S RECONVENE. WE'RE RUNNING PRETTY FAR BEHIND ON THIS SCHEDULE. WE HAVE SOME DISCUSSION TIME AT THE END THAT WE CAN ABSORB. SO WE'RE GOING TO MOVE INTO THE FINAL SESSION FOR PANELS, PANEL 4 METABOLIC IMMUNE DISORDERS AND WE'RE GOING TO DO SOMETHING A LITTLE UNUSUAL, WHICH IS WE'LL DO A TANDEM PRESENTATION. BETWEEN CARLOS PARKO AND JUDY SANDER WATER, IN THE SPIRIT OF A COORDINATING COMMITTEE TO COORDINATE THEIR PRESENTATIONS AND DO THEM TOGETHER. SO THIS CARLOS, YOU WILL BE STARTING. >> YEP. >> WELCOME. >> CARLOS PARDO-VILLAMIZAR. >> SO MY MAIN GOAL IS TO KEEP YOU A WAKE. YOU WILL SEE TWO PEOPLE TRYING TO KEEP YOU AWAKE AND A LOT OF SLIDES WITH COLORS. THE MAIN MESSAGE WE HAVE FOR YOU IS TO UNDERSTAND WHAT THE ROLE OF THE THE. MINE SYSTEM IN -- IMMUNE SYSTEM IN AUTISM, THIS IS A VERY INTERESTING CHALLENGE AND BOTH JUDY AN MYSELF ARE COMMITTED TO WORK IN THE LAB, TRYING TO UNDERSTAND THE ROLE OF THE IMMUNE SYSTEM PATHOGENESIS OF AUTISM. I NEED TO MENTION PART OF THE BACK GROUND THE CENTRAL NERVOUS SYSTEM IN THE BRAIN IS IN CONSTANT COMMUNICATION WITH IMMUNE SYSTEM. THE MAIN REASON OF THIS COMMUNICATION IS THIS IMPORTANT PART OF THE HUMAN BEINGS IS TO MAINTAIN EQUILIBRIUM, BASICALLY THE IMMUNE SYSTEM IS VERY IMPORTANT FOR MAINTAINING HOMEOSTASIS IN THE HUMAN BODY. MANY OF THE CONCEPTS THAT WE LEARN IN THE 20th CENTURY ARE FOR THE IMMUNE SYSTEM ARE STILL VALID, A LARGE PERCENTAGE OF DOGMAS AND OTHER CONCEPTS THAT HAVE BEEN CHANGING DRAMATICALLY IN THE PAST TEN YEARS AND WHILE I LIKE TO GIVE YOU IS AN UPDATE ABOUT WE UNDERSTAND THE ROLE OF THE IMMUNE SYSTEM IN BRAIN DISORDERS IN PARTICULAR FUNCTION IN THE CENTRAL NERVOUS SYSTEM. THE MAIN QUESTION WE HAVE FOR THIS MEETING IS WHERE WE STAND AUTISM BETWEEN THE SYSTEMIC FUNCTION AS WELL AS THE CENTRAL NERVOUS SYSTEM ACTUALLY START FROM THE BEGINNING BECAUSE THE MATERNAL (INAUDIBLE) IS PROVIDING AN IMPORTANT IMMUNOLOGICAL MILIEU TO THE DEVELOPING BRAIN AND THAT VITAMIN IS TRANSLATED IN THE FUTURE WHAT IS GOING TO BE THE OUTCOME IS THE BRAIN -- DEVELOPED BRAIN THAT IS SUSCEPTIBLE NOT ONLY TO GENETIC FACTORS BUT TO THE ENVIRONMENT AND THAT IS EXACTLY WHERE THE IMMUNE SYSTEM IS GOING THE PLAY A SIGNIFICANT ROLE. IN OTHER WORDS, THIS SYSTEM IS GOING TO KEEP STARTING THE BEGINNING DURING PREGNANCY AND AT THE END WHEN THE CHILD IS BORN AND IS GROWING AN GROWING. SO FOLLOWING THE GUIDELINES FOR THIS MEETING, ONE THING WE LIKE TO DISCUSS IS WHAT IS THE (INAUDIBLE) WE HAVE ABOUT ROLE OF IMMUNE SYSTEM IN PATHOGENESIS OF AUTISM AND THE FUTURE IS HOW WE ARE GOING TO APPLY THIS EVENTUALLY FOR DIAGNOSIS AN TREATMENT. AS PART OF THE MY (INAUDIBLE) I WOULD LIKE TO INTRODUCE IMPORTANT TOPICS ABOUT THE ROLE OF THE IMMUNE SYSTEM FOR MAINTAINING HOMEOSTASIS. AND THIS IS IMPORTANT BECAUSE I -- WE BELIEVE THAT UNDERSTANDING THE ROLE OF THE IMMUNE SYSTEM WILL ALLOW US TO UNDERSTAND HOW THE BRAIN IS WORKING AND HOW THE BRAIN IN PATIENTS WITH AUTISM IS WORKING. THE IMMUNE SYSTEM IS THERE FOR MAINTAINING HOME YOUSTASIS. THIS HOMEOSTASIS IS AFFECTED BY DIFFERENT FACTOR, GENETIC FACTORS HAPPENING ANY TRAUMA, INFECTION, MALIGNANCY, ANY METABOLIC DISTURBANCE IS GOING TO AFFECT THIS HOMEOSTASIS. AND THAT'S WHERE THE IMMUNE SYSTEM IS GOING TO PLAY AN IMPORTANT ROLE WITH TWO MAJOR BRANCHES, A BRANCH THAT IS RAPID RESPONSE PART OF THE IMMUNE SYSTEM THAT IS THE ENNATE IMMUNITY THAT DOESN'T HAVE ANY MAY MAJOR OF DEGREE OF SPECIFICITY, THIS IS THE FIRST LINE OF CELLULAR IMMUNOLOGIC RESPONSES THAT CHARACTERIZE INFLAMMATION. BUT THERE IS ANOTHER BRANCH IN ACAPTIVE IMMUNE SYSTEM WHICH IS A SELECTIVE PRODUCTION OF CELLS, VERY SELECTED PRODUCTION OF ANTIBODIES THAT IS GOING TO MAINTAIN AN CONTROL SOME OF THE FACTORS THAT EVENTUALLY ARE DAMAGING HOMEOSTASIS IN THE BODY. THIS PROCESS IS ACTUALLY INVOLVE MANY CELL TYPES INVOLVES MANY CHEMICAL IMMEDIATE MEAD YEAHTORS INCLUDING CYTOKINES, CHEMOKINE, T-CELL, B CELL, EVENTUALLY PART OF THAT SYSTEMIC REACTION WHEN ALL THESE FACTORS ARE AFFECTING HOMEOSTASIS. THE BRAIN AND CENTRAL NERVOUS SYSTEM IS ACTORS OF IMMUNE SYSTEM ARE DIFFERENT IN THE BRAIN. IN OTHER WORDS, CENTRAL NERVOUS SYSTEM CONTAIN AND IS COMPRISED BY COMPLEX NET WORK OF CELLS, T-CELLS OR B CELLS GLIAL CELLS NETWORK THAT ARE IN CONSTANT CONTACT AND INTERACTION WITH (INAUDIBLE) FACILITATE THAT COMMUNICATION THAT EVENTUALLY IS PART OF THE IMMUNE SYSTEM. ONE OF THE MAIN ACTORS IS THE MICROGLIAL CELL POPULATION, THE AUSTRIA GLIAL CELL POPULATION AND ENDOTHELIAL CELL PART OF THE BLOOD BRAIN BARRIER. THESE ARE VERY IMPORTANT FOR NEURONAL FUNCTION, AGAIN, THESE ARE THE MAJOR CELL POPULATIONS THAT KEEP THIS CRITICAL ELEMENT OF THE CENTRAL NERVOUS SYSTEM IN NORMAL FUNCTION. IMMUNE SYSTEM IN THE BRAIN IS COMPRISED, AGAIN, BY TWO MAJOR BRANCHES, INNATE IMMUNITY, THAT IS COMPRISED BY MICROGLIA AND ASTRO GLIA AND PORTION OF THE NEURAL GLIAL CELL COMPARTMENT WITH ADAPTIVE COMMUNITY THAT IS BASICALLY THE RESPONSE THAT IMMUNE SYSTEM HAS COMPRISED MOSTLY BY SPECIFIC T-CELL POPULATIONS TRAFFICKING IN THE CENTRAL NERVOUS SYSTEM AND EVENTUALLY WHEN THERE IS A CHALLENGE BY PRODUCTION OF ANTIBODIES. THIS INTERACTION IS MAINTAINING EQUILIBRIUM BUT THIS ELEMENT THAT IS BLOOD BRAIN BARRIER, THIS BLOOD BRAIN BARRIER IS BASICALLY -- THE DOOR IS OPENING AND CLOSING ALL THE TIME TO DIFFERENT ELEMENTS OF THE IMMUNE SYSTEM FOR MAINTAINING THE NORMAL COMMUNICATION BETWEEN SYSTEMIC EVENTS AND CENTRAL NERVOUS SYSTEM. AND IT'S VERY INTERESTING BECAUSE MANY OF THE DELINEATORS OF THAT COMMUNICATION, PARTICULARLY NEUROTRANSMITTERS ARE SHARED BY NEURONAL CELL POPULATION, NEURAL GLIA AND IS EVENTUALLY GOING TO BE EXPRESSED IN TWO TYPE OF CELLS IN THE IMMUNE SYSTEM. SO IN THE PAST TEN YEARS FOR EXAMPLE WE HAVE LEARNED THAT GLUTAMATE RECEPTORS AND OTHER TYPE OF NEUROTRANSMITTER RECEPTORS ARE ALSO EXPRESSED IN CELLS OF THE IMMUNE SYSTEM LIKE T-CELLS OF MONOCYTES, AND THAT'S A VERY IMPORTANT CONCEPT BECAUSE WE ARE GOING TO SEE A LOT OF SHARED COMMUNICATION BETWEEN THE TWO SYSTEMS. THE MAJOR ISSUE FOR US IS WHAT IS GOING TO HAPPEN WITH IMMUNOLOGICAL REACTIONS AND ROLE OF IMMUNE SYSTEM IN THE PROCESS OF BRAIN DEVELOPMENT LATER IN THE PROCESS OF SYNAPTOGENESIS OR PROCESS OF LEARNED INTERACTIVE BRAIN FUNCTION. THIS IS ONE OF THE ISSUES WE NEED TO SOLVE. WHAT IS THE ROLE OF SIGNIFICANT COMPONENT OF ADAPTIVE IMMUNITY OR MOST OF THE RESPONSES THAT WE SEE IN BRAIN DEVELOPMENT IS PART OF INNATE IMMUNITY. WE HAVE IN THE PAST 20 YEARS OR MORE IS BROKING EVIDENCE THERE IS A VERY CLOSE INTERACTION BETWEEN CENTRAL NERVOUS SYSTEM AND IMMUNE SYSTEM IN PATIENT WITH AUTISM AN THIS IS DERIVED FROM STUDY LINKING IMMUNOGENETIC STUDIES, DERIVED FOR MANY STUDIES EVALUATING THE ROLE OF THE BRAIN, COMING FROM STUDIES OF SYSTEMIC IMMUNOLOGICAL RESPONSE IN WHICH ASSESSMENT OF CELL ANTIBODY CELL POPULATIONS ARE EXPLAINED, ALSO A LOT OF INFORMATION COMING FROM ANIMAL MODELS THAT EVALUATE INTERACTION OF THOSE TWO SYSTEMS. I LIKE TO EXPLAIN IN THE NEXT COUPLE OF SLIDES IS THE PROCESS OF BRAIN DEVELOPMENT, THIS PROCESS UNCOLLUDE STEPS IN TERMS OF NEWSPAPERRAL MIGRATION, SYNAPTOGENESIS, GLIAL PROLIFERATION AND MYELINATION INVOLVE SEVERAL ELEMENTS OF THE IMMUNE SYSTEM, THIS IS THE PERIOD IN WHICH WE UNDERSTAND THAT ALL OF THE PROCESSES DEALING WITH SYNAPTOPHRASETY ARE CURED AND THESE ELEMENTAL PERIOD IS BASICALLY THE PERIOD OF CRITICAL EVENT FOR PATHOGENESIS AN AUTISM. SO WE BELIEVE AND UNDERSTAND THE GENETIC FACTORS THAT INVOLVE THE PROCESS OF SYNAPTOGENESIS AN BRAIN ORGANIZATIONS ARE BASICALLY ASSOCIATED WITH A CONCERT OF IMMUNOLOGY THAT IS GOING TO AFFECT THESE PROCESS AND EVENTUALLY THIS IS PART OF THE PATHOGENIC PERIOD IN BRAIN DEVELOPMENT AN LATER ONCE THE BRAIN IS PARTIALLY DEVELOPED, THERE'S A CONTINUING ACTIVITY THAT LEADS TO SYNAPTIC FORMATION AND SYNAPTIC ELIMINATION THAT IS BASICALLY THE PROCESS OF ADAPTIVE SYNAPTIC PLASTICITY AND PART OF THE LEARNING PROCESS. MATERNAL ENVIRONMENT IS CRITICAL AND MATERNAL ENVIRONMENT IS CRITICAL BECAUSE THE MOIETY IS EXPOSED TO NOT ONLY INFECTION BUT MAYBE EXPOSED EVENTUALLY TO OTHER POTENTIAL RISK LIKE AUTO-IMMUNITY, THIS IS ONE OF THE PROCESS THAT WE ARE IN PROCESS, WE ARE TRYING TO UNDERSTAND IN AUTISM. AS I MENTION BEFORE, THIS CRITICAL PERIOD PATHOGENESIS INVOLVE MANY ELEMENTS OF THE NEURAL GLIA AND INVOLVE MANY ELEMENTS OF THE IMMUNE SYSTEMMENT LET ME GIVE A FEW EXAMPLES. MICROGLIA, NEURAL GLIA ARE PRESENT IN THE BRAIN DURING BRAIN DEVELOPMENT TO FACILITATE THIS IMPORTANT ROLE. THE MODELING OF THE CEREBRAL CORTEX AND DIFFERENT STRUCTURE OF THE CENTRAL NERVOUS SYSTEM. AND ALONG THIS NEURAL GLIA ROLE, THERE ARE SEVERAL ELEMENTS OF THESE IMMUNOLOGICAL CHEMOKINE AN CYTOKINE AND TOLL HIKE RECEPTORS AND ME -- MEDIATORS WE RECOGNIZE VERY WELL IN IMMUNE SYSTEM BUT IN THE BRAIN PLAY DIFFERENT ROLE AND PERHAPS A VERY CRITICAL ROLE FOR USE IN THIS BEAUTIFUL PROCESS OF BRAIN DEVELOPMENT THIS IS GROSSLY ASSOCIATED WITH THIS DEVELOPMENTAL PLASTICITY THAT EVENTUALLY IS GOING TO DEFINE THE NEURAL BIOLOGICAL TRAJECTORY OF CORTICAL ORGANIZATION, AND GOING TO HAVE THE NICE OUTCOME OF DISEASE BEHAVIORAL TRAJECTORIES INCLUDING LANGUAGE COMMUNICATION AND SOCIABILITY. ON THE OTHER HAND DURING THE (INAUDIBLE) THERE IS THIS PROCESS OF ADAPTATION IN WHICH DIFFERENT IMMUNE FACTORS ARE GOING TO PLAY ALSO CRITICAL ROLE AND AGAIN, THE SAME ACTORS THAT WERE PRESENT HERE IN BRAIN DEVELOPMENT ARE GOING TO CONTINUE PLAYING AN IMPORTANT ROLE IN THE PROCESS OF ADAPTING SYNAPTIC PLASTICITY. SO THESE PROCESSES, THESE TWO PERIODS ARE GOING TO BE AFFECTED BY DIFFERENT FACTORS. PARTICULARLY PRESENCE OF NEURAL TOXINS, PRESENCE OF MATERNAL IMMUNITY, PRESENCE OF MATERNAL INFECTION, AND EVENTUALLY THESE FACTORS ARE GOING TO DISRUPT THIS BRAIN ORGANIZATION AND WILL PRODUCE DESTRUCTION OF THIS TRAJECTORY ON NEUROBIOLOGYCAL BEHAVIOR. SO I WILL PASS THE TORCH TO JUDY WHO WILL EXPLAIN THE ANTIBODY WORK IN MATERNAL COMMUNITY SHE IS (INAUDIBLE). >> WE'RE GOING TO BE UP AND DOWN SO MAKE SURE YOU'RE AWAKE. THANK YOU. SO WE JUST THOUGHT WE WOULD TRY TO GET EVERYBODY ON THE SAME PLAYING FIELD, FOR A LOT OF TERMINOLOGY THAT WE USE. SO IN LIGHT -- I'M GOING TO GIVE ONE EXAMPLE OF WORK THAT WE'RE DOING IN HOW MATERNAL IMMUNE ENVIRONMENT CAN AFFECT NEURAL DEVELOPMENT AND I WILL TALK SPECIFICALLY ABOUT AUTOANTIBODIES PRESENT IN THE SELECTIVE PERCENTAGE OF MOTHERS THAT HAVE CHILDREN WITH AUTISM THAT WE DON'T SEE IN MOTHERS OF TYPICALLY DEVELOPING CHILDREN. THERE'S A LOT OF WORK GONE INTO THIS SO WE STARTED THIS I THINK OUR FIRST PAPER CAME OUT IN 2007 ON THIS. AND THIS IS WHAT IT ALL BEGAN WITH DEFINING THESE TWO -- THIS PARTICULAR PATTERNS WE SAW FETAL BRAIN INTHE A WESTERN BLOT AND WE (INAUDIBLE) AS A MATTER OF FACT ALL OF OUR STUDIES DEVELOPMENTAL DELAY CONTROLS AS WELL. WE HAVE MOTHERS -- MOTHERS CHILDREN WITH DEVELOPMENTAL DELAY WITHOUT AUTISM. MOST OF THE WORK THAT WE SEE, THE DEVELOPMENTAL DELAY POPULATION LOOKS THE SAME AS TYPICALLY DEVELOPING POPULATION IMMUNOLOGICALLY WHICH IS INTERESTING. THEY DISTINGUISH FROM THE POPULATION AT THE IMMUNE LEVEL IN BOTH MOTHERS AND KIDS. THESE ANTIBODIES ASSOCIATED WITH CHANGE IN BEHAVIOR INCLUDING REGRESSION WHICH IS COUNTER INTUITIVE YOU WOULDN'T HAVE EXPECTED AUTOANTIBODY THROUGHOUT DEVELOPMENT NOT ASSOCIATED WITH LATER ONSET FORM OF AUTISM. WE ACTUALLY DO SEE THAT MORE FREQUENTLY IN THAT POPULATION THAN THE EARLY ONSET SO IT'S VERY DEFINITELY COUNTER INTUITIVE. WE DO SEE DEFICITS IN LANGUAGE AND THIS IS PROBABLY THE MOST SIGNIFICANT INCREASE IN STEREOTYPIC BEHAVIOR IN THIS POPULATION. WE SEE THAT THE MET VARIANT THAT PAT LOVETT AND DAN CAMPBELL DESCRIBE IS ASSOCIATED WITH THE PRESENCE OF THESE ANTIBODIES AND MET IN THIS CONTEXT IS AN IMMUNE CONTROL GENES OR IMMUNE CONTROL PROTEINS, DOWN REGULATOR OF IMMUNE SYSTEM, INNATE IMMUNE SYSTEM, THAT VARIANT CAUSES LESS REGULATION, SO SPEAKING TO WHAT CARLOS IS TALKING ABOUT DURING GESTATION THAT CAN HAVE AN IMPACT. INTERESTING WE SEE IN -- I'LL TALK ABOUT THAT MORE IN A MINUTE. THE BIG THING FOR US IS IDENTIFYING WHAT THESE PROTEINS ARE. BECAUSE BY UNDERSTANDING WHAT THEY ARE WE CAN POTENTIALLY INTERVENE IN THESE PATHWAYS. WE HAVE SEVERAL ANIMAL MODELS NOT JUST US BUT ANDY AND (INAUDIBLE) ANDY WAS AT JOHNS HOPKINS, ALSO HAD A MOUSE MODEL SHOWING THAT WHEN WE PASSIVELY TRANSFER MEANING WE TAKE HUMAN ANTIBODIES AND PUT THEM IN ANIMAL DURING GESTATION THEY HAD CHANGES IN BEHAVIOR. SO THAT SPEAKS TO PATHOLOGIC SIGNIFICANCE OF THESE, WE'RE LOOKING AT ANIMAL TISSUES, UNDERSTAND WHAT THE PATHOLOGY IS, I CAN TALK ABOUT THAT BUT BECAUSE THESE SLIDES ARE PUBLIC AND THAT DATA ISN'T OUT I'M NOT GOING TO GO INTO THAT. I THINK THE TRANSLATIONAL POTENTIAL FOR THIS IS THAT WE CAN IDENTIFY CHILDREN PRIOR TO CONCEPTION, WE CAN IDENTIFY ANTIBODIES PRIOR TO CONCEPTION SCREENING WOMEN AT RISK. THIS IS NOT -- I WOULD SAY THIS IS A GOOD MARKER FOR RISK OF HAVING CHILD WITH AUTISM, I WOULDN'T GO DOWN ROAD OF DIAGNOSTIC OR -- I CERTAINLY A BIOMARKER OF RISK. I THINK MORE IMPORTANTLY WE FINE PATHOPHYSIOLOGY AN DEVELOP INTERVENTIONS SPECIFIC TO THIS TYPE OF INTERVENTION, THAT'S THE DIRECTION MY RESEARCH IS GOING. SO NOW THAT WE KNOW WHAT THEY ARE, WHAT WE UNDERSTAND IS EACH OF THESE PROTEINS ARE THE SEVEN SPECIFIC TARGET AUTOANTIGENS THAT WE FOUND, LDH HAS A ABOUT B SUBTYPE THAT ARE IMPLICATED. WE WILL NEVER SEE CHANGES HERE BECAUSE ANTIBODIES DON'T CROSS THE PLACENTA UNTIL THAT DAY GESTATION SO THE ANTIBODIES DON'T HAVE ACCESS DURING THAT EARLY DEVELOPMENTAL PERIOD BUT THEY DO ACCESS DURING DENDRITIC BRANCHING. ESPECIALLY THE KREBS CYCLE PARTICULARLY INTERESTING, FROM SEVERAL STANDPOINT. BUT THIS IS JUST GIVES YOU A BREAK DOWN, SO REALLY IT ISN'T ONE PARTICULAR PROTEIN, IT'S THE COMBINATION OF THEM AND THEY'RE ADDITIVE FROM EVERYTHING THAT WE HAVE LOOKED AT TITERS THAT ARE IMPORTANT SO HOW STRONG THEIR RESPONSE IS, IS VERY IMPORTANT FOR THE OBVIOUS REASON THAT THE MORE ANTIBODIES THE MORE IMPACT THE SYSTEM. BUT ALSO THE COMBINATION. IT'S THIS PARTICULAR COMBINATION WHAT WAS DEFINED IN OUR ORIGINAL PAPER BUT THE TWO BANDS I SHOWED YOU IT TURNS OUT THAT'S WHAT THESE ARE MY LITTLE HOLY TRIAD THERE, THE BIG PROTEINS MOST SIGNIFICANT AT THAT TIME, THIS IS THE PATTERN IS REALLY ASSOCIATED WITH STEREOTYPIC BEHAVIOR. WHEN YOU PUT (INAUDIBLE) IN THE MIX YOU END UP WITH LETHARGY SO THERE IS A BEHAVIOR DIFFERENCE IN BEHAVIOR PHENOTYPE THAT'S ASSOCIATED WITH THE PRESENCE OF THESE. AND AS I MENTION WE HAVE SEVERAL ANIMAL STUDIES, THIS IS THE BIG QUESTION BECAUSE IT'S -- IF THEY HAVE PATHOLOGIC SIGNIFICANCE THAT'S IMPORTANT FOR GOING TO TRY TO DO SOMETHING IN THE THERAPEUTIC REALM WITH THEM. WE NEED TO UNDERSTAND WHAT THEY IMPACT. SO THIS IS STUDY THAT WAS CHRISTINE AT -- WITH MY GROUP AND THAT WE HAD CHILDREN IN 2 TO 4 YEARS OLD, 2 TO 4 YEARS OF AGE, MALES IN STUDY OR IN THIS PARTICULAR DATA I'M GOING TO PRESENT WHERE WE LOOKED AT TOTAL BRAIN VOLUME. AND WE NOTICED THAT BOYS FROM WHOSE MOTHERS HAD THESE PARTICULAR AUTOANTIBODIES HAD A MORE EXTREME ABNORMAL BRAIN GROWTH. SO MEANING THEIR BRAINS WERE ACTUALLY LARGER THAN THE LARGER -- THAN THE BOYS WITH ELEVATE BRAIN SO I WILL SHOW THAT, THE GRAPHIC IS MORE TELLING HERE, THESE ARE THE ONES WHOSE MOTHERS HAVE ANTIBODY AND THESE ARE THE LARGE IN DEVELOPING POPULATIONS. THEY ARE DISTINGUISHED EVEN FROM THE REST OF THE ASC POPULATION. THERE'S A PHYSIOLOGIC EFFECT OF HAVING THESE ANTIBODIES THAT WE CAN MEASURE ACTUALLY BY MRI. THIS IS JUST A LISTING, I DIDN'T WANT TO GO THROUGH THIS IN DETAIL BE A LISTING OF ALL THE ANIMALS WITH THE MOST RECENT WHERE WE ACTUALLY INJECTED, I HAVE A COLLEAGUE WHO IS VERY GOOD INJECTING THE DEVELOPING MOUSE EMBRYO ON DAY 14 AND DIRECTLY IN VENTRICLES BECAUSE WE'RE PUTTING HUMAN ANTIBODY IN SO WE BYPASS THE CIRCULATION HAVING THEM REMOVED BY MOUTH OF IMMUNE SYSTEM AND THEY DEVELOP PERFECTLY FINE AND WE SAW INCREASED STEREOTYPIC BEHAVIOR IN THE REALM OF SPONTANEOUS GROOMING AND RESPONSE TO NOVEL ENVIRONMENT. SO THAT IS WHERE WE ARE ON THE MATERNAL IMMUNE, WE DO KNOW -- I DON'T HAVE A PUBLISHED BUT YET BUT THESE ANTIBODIES DO GET INTO THE CELLS, THEY GET INTO THE RADIO GLIAL CELLS, THEY SEEM TO BE CHANGING NEURONAL PROLIFERATION SO THAT'S WHAT WE'RE LOOKING AT NOW SO WE CAN SEE A AT CELLULAR LEVEL THAT THEY DO GET INTO THOSE CELLS AN SEEM TO IMPACT MIGRATION. (LOST AUDIO) THE CHALLENGE OF THE MATERNAL ENVIRONMENT, WE ARE MOVING TO (INAUDIBLE) WHEN THE BRAIN IS ALREADY DEVELOPED AND DURING CHILDHOOD AND ONE OF THE CHALLENGE THAT WE HAVE IS TO UNDERSTAND WHAT IS GOING ON IN THE BRAIN OF PARENTS IMMUNE SYSTEM INTERACTION WITH SYSTEMIC RESPONSES. COUPLE OF METABOLIC APPROACHES, THE IMMUNE SYSTEM, BRAIN SYSTEM INTERACTION MAYBE STUDY EXVIVO WITH NEURONEURAL PATHOLOGICAL STUDY, THIS IS A GAP WE NED TO CHECK MORE BRAIN FOR UNDERSTANDING BETTER HEPATOLOGY OF THE IMMUNE SYSTEM THE WAY THE APPROACH IN VIVO IS BRAIN IMAGE ANALYSIS. USING MET -- IMMUNE SYSTEM IN THE BRAIN, THAT'S MICROGLIA BUT WE ARE STILL BEHIND HAVING A GOOD TECHNOLOGY TO DO IMMUNOLOGICAL REACTIONS IN THE BRAIN. WE ARE LEFT WITH STUDIES OF BLOOD, WE ARE LEFT WITH STUDIES OF CSF. THIS IS A GAP, NO SPINAL FLUID ANALYSIS WITH AUTISM, WE HAVE ACCESS TO BLOOD, I WILL DEMONSTRATE LATER BLOOD STUDIES ARE NOT EQUIVALENT TO THE SPINAL FLUID ANALYSIS. MANY STUDIES FROM PATHOLOGY DERIVE VERY FEW BRAIN OBTAINED FROM THE ATP AND THEN THE COLLECTION DERIVED FROM AUTISM SPEAKS. THESE STUDIES HAVE FOCUSED MOSTLY IN EVALUATION OF NEURAL GLIA RESPONSES ON BEHALF OF THE FIRST DEMONSTRATION OF IMMUNE SYSTEM HYPERREACTION IN THE BRAIN STUDY IN 2005 THAT DEMONSTRATE MEET COMPLETELY NEURAL GLIAL CELL POPULATIONS WERE ACTIVE IN MANY AREAS OF THE BRAIN IN PATIENTS WITH AUTISM AND LATER HAVE BEEN VALIDATED BY OTHER STUDIES THAT USED MORE SOPHISTICATED HISTOLOGICAL TECHNIQUE DEMONSTRATED IN POPULATIONS AND REALLY INCREASE IN AREAS OF THE (INAUDIBLE) AREAS OF WHITE MATTER IN THE BRAIN OF PATIENTS WITH AUTISM. IN ADDITION TO OBSERVATIONS THAT THERE ARE GLIAL REACTIONS WE HAVE ALSO OBSERVED THAT MANY CYTOKINE CHEMOKINES ARE SELECTIVELY EXPRESSING AREAS TO HAVE BRAIN PARTICULARLY THE FRONTAL LOBE OR CEREBELLUM AN THESE ARE IMMUNOLOGICAL FUNCTION LIKE THE ROLE OF MICROPHAGOPROTEIN OR SOME OF THE FROM INFLAMMATORY KITEKINES LIKE IL-6. THOSE CHEMOKEENS ARE NOT DERIVEED FROM THE BLOOD, THEY -- THE CENTRAL NEURONAL CELL POPULATIONS GLIAL CELL POPULATIONS ARE CHARGED WITH USE MANAGE CYTOKINES AND CHEMOKINES. THAT IS INTERESTING BECAUSE ONE OF THE MOST RELEVANT STUDIES IN THE PAST FEW YEARS FOR ANALYSIS OF TRANSCRIPTOME IN BRAINS OF PATIENTS WITH AUTISM, THAT DEMONSTRATE THAT THERE ARE OBVIOUSLY ABNORMALITIES IN THE TRANSCRIPTOME OF SYNAPSES BUT ONE SURPRISING FINDING FOR HIS STUDY IS THERE WASN'T PRESENCE OF IMMUNOLOGICAL GENES OR IMMUNE RELATED GENES, THAT WERE VERY PROMINENT TO BE PRESENT IF BRAIN IN THOSE AREAS OF THIS PARTICULAR COHORT OF BRAINS SO THIS DEMONSTRATE INTERACTION BETWEEN SYNAPTIC APPROXIMATE I WILL MINE FUNCTION OF CENTRAL NERVOUS SYSTEM GENES AND IMMUNE GENES, THIS IS THE LEAST OF THE MOST RELEVANT GENES AND AGAIN YOU ARE ABLE TO RECOGNIZE THAT SOME OF THE IMMUNE MEDIATOR GENES ARE VERY PROMINENT IN THE BRAIN OF PATIENT WITH AUTISM. MORE RESEASONLY THERE'S UNDERSTANDING FROM IMAGING POINT OF VIEW WHAT IS EXPRESSION OF MICROGLIA, AGAIN THIS IS WHICH IS A GAP BECAUSE WE DON'T HAVE GOOD TOOLS. THIS IS A PAPER THAT WAS PUBLISHED A COUPLE OF YEARS AGO, DEMONSTRATED ASSUME TO BE A RELATIVELY FAIR LIGAND FOR DETECTING MICROGLIA, DEMONSTRATE ONCE AGAIN AREAS OF THE BRAIN APPEAR TO BE WITH INCREASE PRESENCE OF MICROGLIAL CELL. LATION. THIS LIGAND, MY UNDERSTANDING IS THERE ARE SEVERAL NEW LIGANDS PRODUCED FOR BETTER UNDERSTANDING OF MICROGLIA. THE QUESTION NOW IS WHAT IS THE EVIDENCE THAT WE HAVE WHAT THE CAUSE OF THE PROBLEM? MANY YEARS AGO WHEN WE PUBLISHED OUR FIRST PAPER, WE NEVER COMMITTED TO EXPLAIN WHY THE REASON THE NEURAL GLIAL ACTIVATION MICROGLIAL PRESENT BUT THERE ARE SEVERAL EXPLANATIONS BUT HAVE RELATED WITH BRAIN DEVELOPMENT, PERHAPS RELATED WITH DEVELOPMENT OF SOME IMMUNOLOGICAL RESPONSES. ONE INTERESTING FINING IN THE LAST COUPLE OF YEARS IS DEMONSTRATION THAT IS SYNAPTIC ORGANIZATION FOLLOW A PATTERN IN WHICH THERE IS A VERY IMPORTANT ROLE FOR ELEMENTS OF ELIMINATION, THIS IS A BEAUTIFUL PAPER THAT WAS PUBLISHED A COUPLE OF WEEKS AGO THAT DEMONSTRATE ALL OF MTOR DEPENDENT AMERICA AUTO PHAGOY IN BRAINS OF PATIENTS WITH AUTISM, THIS IS DEMONSTRATION THAT IN MANY OF THOSE BRAIN THERE IS AN AMOUNT OF SYNAPSIS AND THIS IS A VERY NICE DEMONSTRATION BECAUSE THIS IS PROBABLY ONE OF THE SUSPECTS THAT MAY INVOLVE THE ROLE OF MICROGLIA. SO ONE HYPOTHESIS THAT I HAVE RAISED IN THE PAST IS MICROGLIA RESPONSE, IN BRAIN OF PATIENT WITH (INAUDIBLE) ALSO RESPONDS TO MAINTAIN HOMEOSTASIS AND PERHAPS TO MAINTAIN NORMAL SYNAPTIC ACTIVITY HAPPEN IN THE BRAIN OF THESE PATIENTS. ANOTHER PUBLISHED A COUPLE OF YEARS AGO IS A PAPER FROM (INAUDIBLE) CHILDREN HOSPITAL IN BOSTON THAT DEMONSTRATE THE CRITICAL ROLE OF COMPLIMENT AS WELL AS ELEMENTS OF MICROGLIA IN THE PROCESS OF SYNAPTIC PRUNING AND SYNAPTIC BY MICROGLIA. SO THIS COME TO THE CONCLUSION THAT MANY OF THOSE ELEMENTS OF MICROGLIA ARE PERHAPS ASSOCIATED WITH NEURONS FOR MAINTAINING THIS EQUILIBRIUM OF DENDRITIC ORGANIZATION SYNAPTIC ACTIVITY AND THIS COMMUNICATION INTERESTING IS MEDIATED BY MANY IMMUNOLOGICAL METED YEAHTOR WE MENTION BEFORE IN PRESENCE OF CYTOKINE, IN ELEMENTS OF THE OMPLIMENT CASCADE INCLUDING EVIDENCE OF CYTOKINES NETWORKS. THIS IS A DEMONSTRATION THAT THE ROLE OF THE IMMUNE SYSTEM IN THE BRAIN IS MORE HOMEOSTASIS FOR HOMEOSTASIS THAT DRIVES IMMUNOLOGICAL RESPONSE. I WILL MOVE QUICKLY IN SOME RESEARCH THAT'S BEEN DONE IN REFERENCE TO PRESENCE OF BLOOD REACTIONS AND SPINAL FLUID. THIS IS IN CLOSE COLLABORATION WITH (INAUDIBLE) AN NATIONAL INSTITUTE OF MENTAL HEALTH HERE AT NIH, THIS GROUP WAS LED BY DR. SWEDO HAVE SELECT CHECKED A VERY IMPORTANT COHORT OF PATIENT IN WHICH MANY ELEMENTS OF THE IMMUNE SYSTEM HAVE BEEN EVALUATED PARTICULARLY FOR UNDERSTANDING THE ROLE OF THIS COMPARTMENT THE SYSTEMIC COMPARTMENT VERSUS SPINAL FLUID COMPARTMENT, WE HAVE LEARNED THIS IS (INAUDIBLE) INFORMATION IS A COMPARTMENT OF IMMUNOLOGICAL PROTEINS IN SPINAL FLUID VERSUS THE COMPARTMENT IN THE BLOOD IS COMPLETELY, COMPLETELY DIFFERENT. SO THERE'S SOMETHING WE CAN USE THE BLOOD FOR UNDERSTANDING ELEMENTS OF THE CENTRAL NERVOUS SYSTEM AND REFLECT IN THE BRAIN WHAT IS WRONG. SO EXPRESSION OF IMMUNE IN THE BLOOD COMPARTMENT IS DIFFERENT TO EXPRESSION IN SPINAL FLUID, INTERESTINGLY MANY OF THOSE ELEMENTS OF THE IMMUNE RESPONSE IN THE CEREBRAL SPINAL FLUID ARE VERY WELL RECOGNIZED TO BE ELEMENTS ASSOCIATED WITH ENNATE IMMUNE ACTIVITY PARTICULARLY BECAUSE MANY OF THESE CYTOKINES AND CHEMOKINES ARE CRITICAL FOR PROCESSING OF MONOCYTE AND PROCESSING MICROGLIAL ACTIVATION IN THE BRAIN OF PATIENTS. SO WE NEED TO MOVE VERY QUICKLY, WE HAVE ONLY 30 SECONDS NOW. SO JUST TO WRAP UP WHERE WE ARE, WHAT WE KNOW, I THINK AUTISM IS THE PERFECT EXAMPLE OF HOW MUCH DIFFERENCE THERE IS AMONG KIDS WITH AUTISM. WHEN I LOOK AT THEM WE SEE I WANT TO SEE GO THROUGH THIS QUICKLY THESE ARE THE NUMBER OF STUDIES, I HIGHLIGHTED, THERE'S A LOT OF BETWEEN LABS DOING -- SOME EARLY, BUT ONE INTERESTING THING, THIS IS A SERINE CYTOKINE CHEMOKINE LEVEL, WE'RE STARTING TO RELATE IT TO BEHAVIOR ANDNESS THAT CHANGES IN PARTICULARLY INTERESTING TGF BETA THAT LOW TGF BETA IS AN ISSUE WHEN IT COME IT IS BEHAVIOR, HYPERACTIVITY, WHEN WE ACTIVATE THE CELLS, THIS IS A BETTER MEASURE THAN MEASURING PLASMA CYTOKINES, ASKING THE CELLS TOCOSOMETHING GIVES US A BETTER PICTURE OF WHAT THE CELLS LOOK LIKE. AND THAT WE AGAIN SEE CHANGES IN BEHAVIOR ASSOCIATED WITH -- THIS IS A NUMBER OF DIFFERENT GROUPS THAT WE SEE CHANGES IN BEHAVIOR THAT ARE RELATED TO SOME OF THESE CHANGES IN CYTOKINES AND CHEMOKINE LEVELS. AND I'M NOT GOING TO GO THROUGH THAT MORE. WHAT I DO WANT TO SHOW YOU IS AN EXAMPLE OF SOMETHING WE'RE DOENING THE CHILDREN'S CENTER AT DAVIS AND WE ACTUALLY SEE A DIFFERENTIAL IMMUNE RESPONSE IN THE PRESENCE OF TOXICANT BD 49 WHERE WE HAD CHILDREN, SIX SUBJECTS AND CO-CULTURE WITH THIS PARTICULAR -- WHICH IS A FLAME RETARDANT. AND USE THIS AS AN EXAMPLE OF GENETIC SUSCEPTIBILITY THERE'S SOMETHING WE DON'T UNDERSTAND THAT IS CREATING THIS VERY, VERY DIFFERENTIAL PICTURE, WE HAVE TAKEN THE CELLS INCUBATED FOR FOUR HOURS WITH BD 49 WE HAVE DONE NOTHING ELSE TO THE CELLS EXCEPT LET THEM GO 48 HOURS AFTER THAT AND GATHER THE CHECK FOR CYTOKINES AND YOU CAN SEE THE AU GROUP RESPONDS VERY -- RESPOND ABSOLUTELY APPROXIMATE SIT FOR SEVERAL CYTOKINES AN CHEMOKINES THAT WE HAVE LOOKED AT. THIS IS A SMALL PICTURE. BUT NOT ONLY DO THEY HAVE DIFFERENCE, THEY GO IN THE OPPOSITE DIRECTION. SO THERE'S SOMETHING FUNDAMENTALLY DIFFERENT ABOUT HOW THE KIDS IMMUNE SYSTEMS SEE THESE PARTICULAR EXPOSURES AND SO WHAT WE'RE DOING IN THE CHILDREN CENTER IS TRYING TO UNDERSTAND GENETICALLY WHAT IS IT THAT DIFFERENTIATES THESE TWO POPULATIONS SO DRAMATICALLY? SO THAT'S JUST TO GIVE YOU AN IDEA OF SORT OF SOME OF THE THINGS WE'RE LOOKING AT TO UNDERSTAND THE FUNDAMENTAL DIFFERENCES. >> IT'S OKAY IF WE GO FOR TWO MORE MINUTE? ALL RIGHT. WHY DON'T THEY ISSUE WHAT IS TRIGGERING IMMUNOLOGICAL RESPONSE? ONE OF THE QUESTIONS THAT ACTUALLY WE OUTLINE HERE WITH NIMH GROUP UNDER DR. SWEDO IF THERE ARE ANY ELEMENT OF GASTROINTESTINAL PATHOLOGY INCREASING CYTOKINE RESPONSE AN EVENTUALLY PRODUCING ABNORMALITIES, IN THE BRAIN FUNCTION. THIS IS A WORK IN PROGRESS BUT ONE QUESTION WE ASK WAS IS THERE ANY ELEMENT OF GASTROINTESTINAL SYSTEM TRANSLOCATING INTO A SYSTEM THAT IS GOING TO BE RECOGNIZED BY THE IMMUNE SYSTEM AND GENERATING IMMUNOLOGICAL RESPONSE, THAT IS CALLED MICROBIAL TRANSLOCATION, IN OTHER WORDS, IF THERE IS INTESTINAL INFLAMMATION, IS THERE ANY WAY THAT INTESTINAL INFLAMMATION MAY TRIGGER SYSTEMIC RESPONSES THAT EVENTUALLY ARE GOING TO TRIGGER IMMUNOLOGICAL HYPERACTIVITY IN THE BRAIN. TO STUDY THAT, WE HAVE SEVERAL TOOLS IN IMMUNOLOGY, WE CAN STUDY THE EXPRESSION OF LPS OR LPS PROTEIN OR CD 14 OR ALL ELEMENTS OF MICROBIAL TRANSLOCATION. SO WE NEED THAT IN STUDY IN NATIONAL INSTITUTE OF MENTAL HEALTH, WHAT WE FOUND IS THAT THIS ABSOLUTELY NO EVIDENCE THAT ELEMENTS OF MYKREBIAL TRANSLOCATIONS ARE PRESENT IN PATIENTS WITH AUTISM. THIS IS BASICALLY COMPARING A GROUP OF PATIENTS WITH AUTISM AND GROUP OF PATIENTS THAT REPRESENT CONTROLS. COMPARING THE PATIENTS WHO ARE LABELED AUTISM WITH REGRESSION VERSUS NEURAL REGRESSION. SO THERE IS NO DIFFERENCE IN PRESENCE OF THAT. WE WENT TO MORE SPECIFIC TECHNOLOGY, WE KID ANALYSIS OF THE 16 S RNA, LOOKING FOR BACTERIA IN PLASMA AND AGAIN WE FOUND NO EVIDENCE OF THAT TYPE OF REACTION. SO IN OTHER WORDS THE HYPOTHESIS THAT THERE ARE ELEMENTS OF MICROBIAL TRANSLOCATION TRIGGER IMMUNOLOGICAL REACTIONS IS NOT DEMONSTRATED IN THIS COHORT OF PATIENTS. BUT THE RATIONALE FOR USE IN ANTIBIOTIC IN PATIENTS WITH THE HYPOTHESIS THAT THERE IS A LEAKY GUT ON OPPOSING SECTIONS IS NOT PROVEN IN THESE COHORT OF PATIENTS. LET ME FINISH MY PRESENTATION, WITH THIS SLIDE BECAUSE THIS IS A SLIDE RELATED WITH TREATMENT. SO THERE HAS BEEN A LOT OF CONCERN ABOUT IMMUNOLOGICAL REACTIONS IN PATIENT WITH AUTISM. AND THERE IS AND USE OF TREATMENT OR SUGGESTION OF TREATMENT WITH IMMUNOSUPPRESSIVE MEDICATION. WITH ASSUMPTION THAT WE ARE GOING TO BE TREATING SOME ELEMENTS OF THE CENTRAL NERVOUS SYSTEM. I THINK THAT IN MY VIEW CLINICIAN WORKING IN IMMUNOLOGY, THIS IS A DANGEROUS WORLD. WILL IS NO EVIDENCE THAT WE ARE DEALING WITH AUTOIMMUNE DISORDER IN AUTISM AND THERE IS NO EVIDENCE THAT THE BRAIN ABNORMALITIES THAT WE ARE SEEING IN AUTISM ARE RELATED WITH ANY PROCESS THAT INVOLVE PRESENCE OF HYPERACTIVITY IMMUNE SYSTEM IN THE BRAIN. ADDRESSING CONCEPT, THE USE OF IVIG, WE MAY NEED TO UNDERSTAND THIS BETTER BECAUSE ICIG MODULATE COMPLIMENT TASK CASE. BASED ON (INAUDIBLE) THE ROLE OF COMPLIMENT IN THE PROCESS OF SYNAPTOGENESIS. THIS IS SOMETHING FOR THE FUTURE POTENTIAL ROLE OF THESE IMMUNOLOGICAL MODULATORS. (LOST AUDIO) SO IN OTHER WORDS, CONCLUSION THAT WE HAVE AT THIS MOMENT IS MUCH BETTER TO WAIT AND HAVE A BETTER UNDERSTANDING OF THE IMMUNE AUTISM JUNCTION USE MITIGATION THAT WE DON'T KNOW WHAT IS THE OUTCOME. IN OTHER WORDS, MY MOTTO IS DON'T MESS UP WITH. MINE SYSTEM. THE CONCLUSION IS YES WE HAVE AREAS OF INNATE IMMUNE RESPONSE IS PRESENT IN PATIENTS WITH AUTISM. WE HAVE MATERNAL AND THIS IS RELEVANT AS A RISK. WE KNOW THAT THERE IS AN AUTOIMMUNE PROCESS AN RATHER THAN THE SYSTEM IS NOT PATHOGENIC PROCESS. THE IMMUNE SYSTEM IN AUTISM PERHAPS IS FOLLOWING A PATTERN OF DISREGULATION AND FUNCTION PROVIDED PATHOGENIC EFFECT THAT IS PRODUCING DAMAGE OF THE BRAIN. AGAIN, WE MAY NEED TO WORK MORE IN THE GASTROINTESTINAL PATHOLOGY THE MAIN CONCLUSION AS IMPINGES BEFORE AT THIS TIME THERE IS NO ROLE FOR IMMUNOLOGICAL THERAPIES OR TREATMENT OF TREATMENT WITH IMMUNOSUPPRESSIVE PATIENTS WITH ANTIBIOTICS. THANK YOU. [APPLAUSE] >> WE ALL HAVE A LOT OF QUESTIONS. LET'S GO TO THE FINAL PRESENTATION THEN WE'LL TAKE TIME THEN TO ASK QUESTIONS OF ALL THREE OF YOU. >> THANK YOU VERY MUCH. TOM AN INJURY AND JOHN AND THE MEMBERS OF THE ORGANIZING COMMITTEE IT'S AN HONOR TO SPEAK TO YOU TODAY ABOUT WHAT I'M TASKED TO SPEAK TO YOU, WHICH IS OUR RECENT FINDINGS IN THE METABOLIC DISTURBANCES IN AUTISMEN ANIMAL MODELS AND COMPARISON TO HUMAN STUDIES. SO THE OVERALL SUMMARY TO MY TALK TODAY IS TO EXPRESS THE VIEW THAT AUTISM IS A WHOLE BODY, DISEASE, ULTIMATELY CONTROLLED BY CHEMISTRY. LEAVES TO ALTERED NEURAL DEVELOPMENT GI ABNORMALITIES AN FUNDAMENTAL DISTURBANCES IN INNATE IMMUNITY. AND CELL DEFENSE PATHWAYS. THE SECOND POINT IS, THE BRAIN CAN ULTIMATELY BE CONSIDERED A CELL DEFENSE AND SURVIVAL ENGINE THAT REGULATES THESE PROCESSES. SO SO THE SUMMARY OF THE TALK, IN OTHER WORDS IS -- WILL ALL AUTISM SUBJECTS THAT HAVE BEEN EXAMINED TO DATE HAVE METABOLIC ABNORMALITIES. MOST MITOCHONDRIAL DYSFUNCTION IN AUTISM IS SECONDARY AND NOT THE RESULT OF SINGLE GENE MENDELIAN OR MITOCHONDRIAL DNA DEFECTS THOUGH FURTHER TO SAY THAT THE MITOCHONDRIAL DYSFUNCTION THAT WE SEE IS AN ACTIVE SUPPRESSION OF THE MITOCHONDRIAL FUNCTION THAT LEAVES THE CELL WITH THE ABILITY TO EXPLODE -- REACT EXPLOSIVELY TO ENVIRONMENTAL STIMULI. REDOX GLUTATHIONE DISTURBANCES ARE MORE THAN HALF KIDS AND I WAS ASKED BY LYNN TO TUCK ABOUT PIONEER IN THIS FIELD, DR. JILL JAMES AND SOME WORK IN ASD BIOCHEMISTRY. EEL INTRODUCE THE CELL DANGER HYPOTHESIS. FROM Z WE'LL TALK A LITTLE BIT ABOUT HOW AUTISM LIKE BEHAVIOR METABOLISM AND SYNAPTIC DEFECTS DESIGNED TO ADDRESS THE CELL DANGER RESPONSE. METABALOMICS USING MASS SPECTROMETRY THAT THE DISTURBANCES AN MOUSE MODELS AND HUMANS WITH AUTISM HAVE THE SAME CORE METABOLIC PATHWAY ABNORMALITIES. AND THAT PREVIOUSLY IDENTIFIED DEFECTOR PATHWAYS OF THE CELL DANGEROUS ARE THESE PATHWAYS. COMMUNICATION WITH DR. JAMES, AND WHAT SHE SPECIFICALLY ASKED ME TO SAY PLEASE DO NOT PLACE MY WORK IN THE CATEGORY OF OXIDATIVE STRESS SCHOOL OF AUTISM, THAT IS REACTIVE OXYGEN SPECIES CAUSE DISEASE. SO SHE WAS A PIONEER AND FINDING SOME OF THE FIRST OKAY DAYTIVE CHANGES IN GLUE TATHIONE AND MAJORITY OF CHILDREN WITH AUTISM IN 2004 AND RECENT PAPER PUBLISHED LAST YEAR SHE USED METHYL B-12 THALAMIC ACID TO RESTORE THE GLUE TATHIONE IMBALANCE AND THAT WAS CORRELATED WITH SOME BENEFITS AND WE'LL TALK ABOUT THAT. SO THIS IS A PICTURE FROM A RECENT PUBLICATION OF RICHARD FRY AND JILL JAMES, THAT TALKS ABOUT THE METABOLIC CYCLE OF FOLATE CYCLE INVOLVED IN PURINE AN PRIM DEAN SYNTHESIS HOW THE METHYLATION CYCLE IS INVOLVED WITH ME THIONEINE AND HOW THAT ULTIMATELY FEEDS INTO TRANSALTERATIONSIS SEEN AND GLUTATHIONE METABOLISM. SO I'LL INTRODUCE DR. JAMES WORK BY FIRST PUBLICATION IN THIS AREA WAS 2004 THAT IDENTIFIED A DECREASED RATIO OF REDUCED OXIDIZED GLUTATHIONE IN THE PLASMA OF CHILDREN WITH AUTISM. AND SHE FOLLOWED THIS UP WITH ABOUT OPEN LABELED CLINICAL TRIAL, THERE WAS PUBLISHED THIS LAST YEAR IN AUTISM RESEARCH TREATMENT. THE DESEEN OF THAT STUDY IS OPEN LABEL TREATMENT WITHOUT PLACEBO, THERE'S 65 SCREENS ELIMINATED THOSE WITH WITHOUT GLUTATHIONE ABNORMALITIES AND ENROLLED 48. GAVE TREATMENT METHYL B-12 AND THALAMIC ACID FOR THREE MONTHS. AND OBTAINED THE FOLLOWING RESULTS USING THE ADAPTIVE BEHAVIORAL SCALES AS BEFORE AND AFTER. AND SAW A SIGNIFICANT INCREASE IN IMPROVEMENT IN THE VAVS SCALE SCORES. AND CORRELATIONS IN IMPROVEMENT IN GLUTATHIONE REDOX STATUS WERE ASSOCIATED WITH EXPRESSIVE COMMUNICATION SCORES AND OTHERS. THE IMPORTANT -- I WILL FOLLOW THIS WITH AN IMPORTANT CAUTIONARY TALE FROM MY FIELD OF MITOCHONDRIAL MEDICINE. IS THAT IN A RECENT PUBLICATION BY NATURE REVIEW IN NEUROLOGY IN 2013, WE LOOK AT OUR COMMUNITY LOOKED AT OVER A THOUSAND CLINICAL TRIALS IN MITOCHONDRIAL MEDICINE, ONLY 35 OF THOSE CLINICAL TRIALS DESCRIBED IN SUFFICIENT DETAIL TO GIVE WHAT'S KNOWN AS A SCORE CLINICAL TRIAL QUALITY. THE HADAD SCORE IS CHARACTERIZED, YOU GET TWO POINTS RANDOMIZED TWO POINTS DOUBLE BLINDED PLAT BOW CONTROL AND ANOTHER POINT FOR PAYING ATTENTION TO HOW -- WHY THE SUBJECTS DROPPED OUT OF THE STUDY AND NOT LOSING THEM FROM THE DENOMINATOR OF THE STUDY. AND THE MITOCHONDRIAL MEDICINE WHEN LOOK AT THE LOW HADAD SCORE TREATMENT TRIAL, WE FOUND MANY SUCCESSFUL AT -- PASSED THE .05 CONCLUSION THRESHOLD. IN THE STUDIES PER SPECK TVLY RANDOMIZED AND DOUBLE BLINDED PLACEBO CONTROLLED, NONE OF THEM PASSED THE EFFECTIVE TREATMENT CONCLUSION. SO THIS IS A HEART FELT MESSAGE TO EVERYONE AND ACTUALLY MOST INVESTIGATORS KNOW THIS. IS WE CAN IDENTIFY MAYBE SAFETY AND TOXICITY IN OPEN LABEL TRIALS BUT WE CAN'T DETERMINE EFFICACY. WHICH IS WHAT EVERYBODY REALLY WANTS SO IF WE WANT TO MOVE FORWARD WITH TREATMENT WE HAVE TO BE DOING PERSPECTIVELY RANDOMIZED PLACEBO CONTROL CLINICAL TRIALS. HADAD SCORE AROUND 5. IN ORDER TO UNDERSTAND THE METABOLISM YOU HAVE TO UNDERSTAND HOW CELLS SMELL THE WORLD. HOW THEY SEE AND SMELL, SEE IS NOT A BAD METAPHOR BECAUSE IT ALL STARTED WITH WILL THE RECEPTORS TO LIGHT. SO THEIR G PROTEIN COUPLED RECEPTORS SEVEN TRANSMEMBRANE DOMAIN, IMAGINE AN ANGEL WITH SIZE OF CELL, HOW DO YOU KNOW WHAT'S GOING ON IN YOUR ENVIRONMENT. TURNS OUT THERE WERE RECEPTOR THAT ACT LIKE THE CELLULAR MASS SPECTROMETERS. THAT LITERALLY MEASURE THE MOLECULES USED FOR -- CELLS USE BUILDING BLOCKS FOR CELL GROWTH, METABOLISM AND FUNCTION. SO WE HAVE FOUR DIFFERENT RECEPTOR, 388 ODOR RECEPTORS, HUMANS ONLY HAVE TWO PHEROMONE RECEPTORS, WE HAVE 25. BUT INTERESTINGLY THE CLASS OF MOLECULE DESIGNED TO INTERROGATE THE METABOLIC MILIEU OF THE CELL CONNECTS ALL OF THESE -- ALL OF THESE CHEMOSENSORY RECEPTORS. SOME OF THE MOST FUNDAMENTAL ONES ARE SIMILAR GROUPS. CHEMOKINES, ATP SHORT CHAIN FATTY ACIDS, NICOTINE ORAL IN ONE LITTLE GROUP, DOWN HERE I HAVEN'T INDICATED BUT WE HAVE REACCEPT TOTORS ACETYL CO-LYNERGIC ROLE CELLULAR RESPONSES ARE TIGHTLY INTIMATELY TIED TO CHEMOSENSORY INTEGRATION OF THE CELL. SO WE FORM THIS CYTOKINE RECEPTORS, WITH OLDER RECEPTORS, THESE ARE IN EVERY SINGLE CELL OF THE BODY. AND SEVEN TRANSMEMBRANE G PROTEIN COUPLED RECEPTORS THAT RESPOND TO ATP, UTP, SHORT CHAIN BEAUTY RATE, BETA HYDROXY BEAUTY RATE, PHOSPHATE, A LOT OF IMPORTANT ACTORS THAT PEOPLE KNOW ABOUT, THESE ARE RELATED PHYLOGENETICALLY INTERESTING THE PURENERGIC RECEPTORS THAT RESPOND TO KNEW LEO TIDES, ATP AND UTP ARE THE MOST DIRIGHT TO REMAIN SILENTLY DISTRIBUTED IN ALL CELL TYPES OF THE BODY. SO WE ASKED THE QUESTION TIED TO HOW DOES THE CELL KNOW SAFETY AND DANGER? I'LL SAY THAT AT THE ONSET, SAFETY AND DANGER ARE NOT ANTHROPOMORPHIC CONSTRUCTS IN THE WAY I USE THEM. THEY ARE CHEMICAL DEFINITIONS OF THE INSTANTANEOUS CONCENTRATION OF METABOLITES MATCHING THE COLLECTIVE KMs AND KE OF CELLULAR RECEPTORS AND ENZYMES VERSUS BEING TOO HIGH OR TOO LOW. BELOW KB AN KM OF THE COLLECTIVE RECEPTORS RESPONDING TO THEM. WE STARTED LOOKING FOR WAYS TO UNDERSTAND HOW CELLS RESPOND TO DANGER. WE NOTICE THAT THE CELLS SEEM TO RESPOND DIFFERENTLY ACCORDING TO ULTIMATELY THE AVAILABILITY OF ELECTRON. WORLD OF CHEMISTRY IS WRITTEN WITH ELECTRONS I REFER YOU THIS LITTLE PAPER WE'RE PLEASED REMARKABLY POPULAR CELL DANGER RESPONSE TO MITOCHONDRIAL 6,000 DOWNLOADS AN 30,000 VIEWS IN LESS THAN A YEAR. BASICALLY WE TALK ABOUT CONDITIONS OF SCARCE CALORIES, IT HAPPENED EVOLUTIONNARILY OVER THE WINTER. WE IDENTIFIED ABOUT 30 DIFFERENT PIVOTAL METABOLITES. THAT CAN BE TREATED IN ONE DIRECTION UNDER CONDITIONS OF LOW ELECTRON AVAILABILITY. AND MOVE DOWN ANOTHER PATHWAY, UNDER CONDITIONS OF (INAUDIBLE) ELECTRONS CREATE TO CARBON, CARBON, CARBON OXYGEN BONDS. MITOCHONDRIA TURN OUT TO RESPOND INSTANTANEOUSLY WITH A VOLTAGE TROUGH WHENEVER AN INFECTION OCCURS WHEN ELECTRONS ARE DIVERTED FROM THEM, THEY WILL DECREASE OXYGEN CONSUMPTION AN OXYGEN CONSUMPTION BEGIN TO RISE IN THE CELL. THAT RESULT IN INCREASE IN OXIDATION THAT RESULTS IN THE OPENING OF CHANNELS IN THE CELL RELEASE ATP SO THE OUTSIDE OF THE CELL, SO THIS ALSO LEADS TO CASCADE OF EVENTS, THAT INCLUDE CHANGES IN SULFUR AND GLUTATHIONE METABOLISM, FOLATE B-12, CELL CELL ME THIONEINE BUT WE WANTED O FOCUS ON WHAT IS IT THAT MIGHT BE CONSIDERNATING THIS OR MAINTAINING THE PATHOLOGICAL PERSIS TENSE OF WHAT IS -- PERSISTENCE OF WHAT IS UNIVERSAL. IN RESPONSE TO ANY KIND OF CELL INJURY. SO THE DANGER RESPONSE IS A METABOLIC RESPONSE THAT'S UNIVERSAL BUT IN SOME CASES CAN BE PATHOLOGICALLY PRESERVED. SO LOOKING FOR, ATP SIGNALING ON THE OUTSIDE OF THE CELL, SO ANOTHER POINT OF THE TALK, ATP HAS TWO AND A HALF MINUTES. HAS A ENERGY CARRIER FUNCTION UNSIDE THE CELL BUT AN INFORMATIONAL FUNCTION OUTSIDE THE CELL. SO WE FOUND THAT THERE IS ONE COMPOUND IN THE WORLD THAT'S AVAILABLE THAT HAVE HA -- WAS A COMPETITIVE ANTAGONIST OF ATP USED BOTH IN ANIMALS AND IN HUMANS THAT COMPOUND THE SERMON, ONE THAT CANNOT BE USED FOR ANY OTHER FUNCTION OTHER THAN THE TREATMENT OF AFRICAN SLEEPING SICKNESS AN RIVER BLINDNESS CURRENTLY. BUT WE ARE USING IT AS A LEAD COMPOUND TO OPEN UP A CLASS OF DRUGS THAT CAN BE MADE SAFER AND BETTER. WHEN WE TREAT ANIMALS WITH MATERNAL IMMUNE ACTIVATION MODEL, ONE THAT'S INVOLVED THE TREATMENT OF PREGNANT ANIMALS WITH SIMULATOR VIRUS INFECTION WITH POLYIC DOUBLE STRAND RNA, THAT THE RESULTING OFFSPRING HAVE BEHAVIORS AND THEY LOOSE PURR KINK CELLS POSTNATALLY, LOST BUT IF WE GIVE DRUG WE CAN COMPLETELY PREVENT THAT. WE CAN ALSO -- THESE ARE ABOUT NORMAL SENATE TOESOMESOMES WITH HYPOMORPHIC POST SYNAPTIC DENSITY AND ELECTRON DENSE MATRICES, WE CAN PREVENT THAT. IN TREATING ANIMALS WITH ANTI-PURENERGIC THERAPY. FRAGILE X MODEL WITH ELECTRON DENSE MATRIX AND HYPOMORPHIC POST SYNAPTIC DENSITY AND WE CAN RETURN THIS TO NORMAL WITH ANTI-PERINERGIC THERAPY. THE ANIMALS WITH THE M,A MODEL ARE LESS SOCIABLE AS YOU SAW EARLIER,WE CAN RESTORE H WITH PURENERGIC THERAPY AND FRAGILE X LESS SOCIAL, WE CAN RESTORE THAT WITH ANTI-PURENERGIC THERAPY, IF WE GET DOWN TO WHAT CELLS DO BUT RELATIVELY NOT AS EASY TO DO FOR HUMANS ANIOUS A MASS SPECTROMETER TO INHERIT SEGREGATE CELLULAR CHEMISTRY WE CAN IDENTIFY 700 ENDOGENOUS METABOLITES AND 63 BIOCHEMICAL PATHWAYS AND CHARACTERIZE THE METABOLIC DISTURBANCES BY SYSTEMS ANALYSIS. WHEN WE DO THAT WE HAVE SEEN IN THE FRAGILE X MODEL I MISSED ONE. SO IN THE MIA MODEL WE CAN MOVE ABNORMAL AUTISM PHENOTYPE METABOLITE IN THE DIRECTION OF CONTROL FROM RED TO GREEN HERE. IN THE FRAGILE X MODEL WE CAN MOVE IN THE DIRECTION OF THE RED BEING AUTISM LIKE FRAGILE X TO -- TOWARD THE CONTROL. WHAT WE SEE WHEN WE ANALYZE THIS, THAT THE MOST INFLUENCED PATHWAY OR THOSE BIOSYNTHESIS, THERE'S MICROBIOME COMPONENT AND FRAGILE X, THE FATTY ACID OXIDATION COMPONENT. I'LL POINT OUTPOURERNERGIC SIGNALING GENE EXPRESSION ABOUT NORMALITIES WERE IDENTIFIED BY MARK NADOWITZ IN PAPER THAT WE HER ABOUT ACTUALLY FROM SPHEREIA CALLED MORERY KNOW SO INVOLVED IN THIS, BUT THAT'S A HUMAN STUDY THAT IDENTIFIED PURENERGIC SIGNALING GENE EXPRESSION ABNORMALITIES WERE HIGHLY CORRELATED WITH BEHAVIORAL ABNORMALITIES IN CHILDREN WITH AUTISM IN THE BRAINS OF CHILDREN WITH AUTISM. SO IF WE CORRELATE THE BIOCHEMICAL PATHWAYS IDENTIFIED OVER THE LAST 50 YEARS AND CHILDREN WITH AUTISM, THERE ARE ABOUT TWO DOZEN PATHWAYS, BUT IT TURNS OUT 75% ARE SHARED WITH MA TERM IMMUNE ACTIVATION MODEL AND ANOTHER 75% ARE SHARED WITH THE FRAGILE X MODEL AND 50% ARE ACTUALLY SHARED BY ALL ACROSS ALL GROUPS. THOSE INCLUDE DISTURBANCES IN PURINE METABOLISM OR MICROBIOME,S IF FOE LIPIDS, CHOLESTEROL GLYCOLYSIS, KREBS CYCLE, NIACIN, ME THIONEINE AND GLUTATHIONE METABOLISM. THAT'S IT. THESE ARE FEATURES OF THE METABOLIC CELL DANGER RESPONSE AND BASICALLY THESE METABOLIC PATHWAYS ARE COORDINATE FANTASTICALLY REGULATED, -- THEY ACTUALLY TELL WHICH -- TELL US WHICH PROTEIN EXPRESS. SO THE SMALL MOLECULES ARE FIRST -- CHANGES IN SMALL MOLECULES THAT TELL THE CELL PROTEINS TO EXPRESS AND TRIGGERED BY A REDISTRIBUTION OF ELECTRON FLOW AND OXYGEN AND SUBSTRATE CONCENTRATIONS. AND SO FAR WE HAVE SEEN IT HYPERPURINASIA AND METHODS ARE BRAIN CONTROL METABOLISM. ALL BRAIN DISORDERS HAVE MET BOLLK DISTURBANCES. SO SMELL THE WORLD THROUGH A CONSERVED REACCEPT TO THAT CONTINUOUSLY MONITORED. PURE ANERGIC SIGNALING IN MITEKINES CONTROL CELLULAR RESPONSE TO SAFETY AND DANGER THOUGH NOT APPROXIMATE THOUGH POE MORPHIC CONSTRUCTS BUT MISMATCH OF THE INSTANTANEOUS CHEMICAL CONCENTRATION OF EFFECTOR MOLECULES MALL MOLECULES AN RECEPTOR, EVOLVE KB AND KB AND A DOZEN CORE METABOLIC PATHWAYS SHARED BY ENVIRONMENTAL MICA MODEL, FRAGILE X MODEL AND HUMAN AUTISM. THAT'S IT. THANKS. [APPLAUSE] >> THANK YOU TO ALL THREE OF YOU TERRIFIC SET OF PRESENTATIONS, LET'S OPEN THIS UP FOR DISCUSSION. >> FASCINATING PRESENTATION. I HAVE LOTS OF QUESTIONS BUT LIKE TO GO DO JUST ONE. IMMUNE CHANGES THAT YOU ON RELATED TO AUTISM, ARE THEY SPECIFIC FOR AUTISM OR SEEN IN OTHER CONDITIONS LIKE INTELLECTUAL DISABILITY. I'M THINKING OF WORK THAT WAS DONE GOING BACK I THINK NELSON NEURAL PEPTIDES USING BLOOD SPOTS FROM NEWBORN SCREENING AND LOOKING AT CHILDREN THERE WERE SOME ELEVATED NEURAL PEPTIDES LIKE IN AUTISM BUT NOT (INAUDIBLE) I'M CURIOUS TO SEE WHETHER DESCRIBING SPECIFIC FOR AUTISM OR SPECTRUM OF OTHER CONDITIONS? >> I DIDN'T HEAR THE ANTIBODIES PART OF THAT. IT'S VERY SPECIFIC, THIS IS ACTUALLY -- DEVELOPMENTAL DELAY, THERE'S ONE PATTERN WE FOUND THAT MAY CORRELATE WITH ADHD. BUT (INAUDIBLE) CORRELATE WITH SPECIFIC BEHAVIOR BUT THAT WAS VERY AUTISM SPECIFIC. >> SO I'M REMINDED OF THE GREAT COUNTRY WESTERN SONG IT'S A SHAME ALL BLAME FALLS ON THE WIN. >> ALONG LINES OF JOSE'S QUESTION, SOMETHING THAT HAS CONFUSED ME, THEY'RE ALSO BEEN REPORTS OF MATERNAL INFLAMMATION AS IN MOTHERS WHO HAD SOMETHING LIKE THE FLU DURING THEIR PREGNANCY OR SOME OTHER ILLNESS WITH FEVER AND THE QUESTION OF HOW THAT MIGHT BE RELATED TO AUTISM, THE WORK THAT YOU'RE SHOWING WITH THE CYTOKINES AND SUCH, HOW DO I KNOW THAT THAT'S AUTOIMMUNE GENERATED AS OPPOSED TO GENERATED BY SOMETHING LIKE INFECTION THE MOTHER IS HAVING? WHOEVER CAN ANSWER THIS. >> (INAUDIBLE) >> MARRY THE BRAIN AND IMMUNE SYSTEM. SO I THINK THAT'S A VERY GOOD QUESTION THOUGH. SO THERE HAVE BEEN A NUMBER OF STUDIES LOOKING AT INFLAMMATION IN SCHIZOPHRENIA AND IN INFLAMMATION IN AUTISM DURING GESTATION. SO WHAT THE IMPORTANT CAVEAT IS, IF THERE A LOT OF PEOPLE WHO DON'T HAVE A CHILD WITH AUTISM SO THAT MEANS THERE'S UNDERLYING SUSCEPTIBILITY OR WAY THE IMMUNE SYSTEM IS REGULATED. THAT LIKELY CONTRIBUTES TO THAT, SO IT'S NOT AS SIMPLE AS INFECTION. I THINK IT'S A NICE -- INTERESTING MODEL. WHETHER IT'S SCHIZOPHRENIA OR AUTISM DEPENDS ON WHEN THAT OCCURS. AND WHEN YOU ASK FOR MEASURING, THE CYTOKINE DISCUSSION THAT I WAS TALKING ABOUT, THAT WAS CYTOKINES I WAS PRESENTING WAS GOING ON IN THE CHILDREN. WE DO HAVE STUDIES LOOKING AT WHAT'S GOING ON IN GESTATION IN WOMEN AND WE HAVE HAD THE STUDY LISA CRONIN AND I DID RECAPITULATING IN A LARGER STUDY SO WE'RE WRITING THAT UP NOW. IT'S NOT AS -- A SIMPLE ANSWER. CAN YOU TELL WHAT THEIR REACTING TO? THAT WILL SAY FOR CHILDREN THAT COME -- THE CHILDREN THAT COME THROUGH CHARGE WE ONLY WILL HAVE -- THEY CAN'T BE SICK WHEN THEY COME FOR BLOOD DRAW AND THEY CAN'T WITHIN TWO WEEKS SO WE TRY THE GET THEM AT A BASELINE AS BEST WE CAN. WE ALL KNOW KIDS CAN BE DEATHLY ILL THE NEXT DAY AND INCUBATING IN THERE. SO IT'S QUICK FOR THEM. YOU CAN'T RULE OUT WHEN WE DO THE MEASURES, I DON'T THINK THEY'RE GOOD MEASURE FOR BIOMARKERS, BUT MORE I LIKE TO USE HOW THEY RESPOND TO THINGS WE DO TO THEM, THE CELLS. MIGHT BE WRONG, WHAT PATHWAYS ARE DISREGULATED. I'M NOT SURE IT CAME OUT IN THE PRESENTATION, IMMUNE CELLS OF NEURONS IMMUNE CELLS OF NEURONS SHARE MANY PATHWAYS MTOR IS CRITICAL FOR HEALTHY IMMUNE CELL DEVELOPMENT AS WELL. MANY PATHWAYS WE THINK MIGHT BE DISREGULATED IN BOTH ARMS. SO THAT'S WHY WE'RE ANY KIND OF MEASURE OF BIOMARKERS AS FAR AS IMMUNE MOLECULE INVOLVED. >> SO IN THE CASE OF MATERNAL INFECTION OR ANY TOXIC EXPOSURE TO MOTHERS, WOMEN NEED TO BE A LITTLE BIT CAUTIOUS GERMINATED FROM BLOOD. VERY ACTIVE IMMUNE ORGAN ANY TYPE OF CHALLENGE O THE MOTHER LATINO CYTOKINES AND CHEMOKINES. EVENTUALLY THAT IS GOING TO BE AFFECTING THE FETUS, WE ARE GOING TO SEE THAT -- WON'T SEE THAT TOO MUCH IN THE BLOODSTREAM FROM THE MOTHER. SO I THINK IN THE FUTURE ANIMAL MODEL RELEVANCE WILL HELP OUT UNDERSTAND A LITTLE BIT OF STUDIES DEFINITELY MATERNAL INFECTION FROM EPIDEMIOLOGICAL POINT OF VIEW, AN INTERESTING TOPIC FOR AUTISM AND I (INAUDIBLE) PROVIDE SOME INFORMATION, INVOLVED IN SOME OF THE EPIDEMIOLOGICAL STUDIES IN MATERNAL INFECTION IN RISK FACTOR IN AUTISM. >> EPIDEMIOLOGIC DATA DO SUGGEST THAT MATERNAL INFECTION OR FEVER DURING PREGNANCY IS ASSOCIATED WITH INCREASED RISK FOR AUTISM, THE TYPES OF ORGANISMS AND TIME PERIOD THAT HAVE BEEN ASSOCIATED WITH INCREASE RISK FOR AUTISM DIFFER ACROSS STUDYND AND SOMETIMES THERE'S AN INCONSISTENCY BUT THERE'S A BODY OF EVIDENCE THAT SHOWS SOME KIND OF RELATIONSHIP, WHAT HASN'T BEEN DONE TO MY KNOWLEDGE IN SOME OF THESE NEW PERSPECTIVE PREGNANCY COHORT STUDIES WILL BE ABLE TO DO THIS IS LINK THE BIOMARKERS IN THE BLOOD OR PLACENTA, AND LEVEL OF CYTOKINES AND OTHER IMMUNE MOLL COOLS WITH THE CLINICAL IN THE FEVER IN THE MOM OUTCOME IN THE CHILD. BRINGING THOSE THREE PIECES TOGETHER, I THINK WILL BE INFORMATIVE HOW THE RESULTS FIT TOGETHER. >> LYNN? >> GREAT PRESENTATION. THANKS TO EVERYONE. WITH REGARD TO IMMUNE ACTIVATION I WAS THINKING AN'T THE WORK OF PAUL PATTERN SON AND ANIMAL MODELS WHERE HE ACTUALLY FOUND IT WAS NOT THE INFECTION ITSELF BUT IT WAS THE RELEASE, THE IMMUNE ACTIVATION, THE RELEASE OF THE CYTOKINES THAT ACTUALLY CAUSE THE NEUROLOGICAL INJURY AND THE OFFSPRING. SO FOLLOWING THAT LINE OF WORK ONE OF THE QUESTIONS THAT I HAVE IS ADMINISTERING FLU VACCINE AND NOW DTEP VACCINES DURING PREGNANCY SO THERE'S RECOMMENDATION NOW FOR DEPENDING ON STAGE OF PREGNANCY TWO FLU VACCINES AND A DTAP VACCINE WE KNOW CAUSES IMMUNE RESPONSE. AND SO WHETHER OR NOT THAT SHOULD BE SOMETHING THAT WE SHOULD BE LOOKING AT AS WELL, ALSO THE EFFECT THAT VACCINATION IS KNOWN TO RESULT IN THE ELEVATED C REACTIVE PROTEIN LEVELS WHICH IN THE NORWEGIAN STUDY WAS A RISK FACTOR IN THE DEVELOPMENT OF AUTISM AND ONE STUDY THAT LOOKED WHEN THEY HAVE A HISTORY OF DEPRESSION, AND THEY FOLLOW THE C REACTIVE PROTEIN LEVELS AFTER FLU VACCINE THEY FOUND THEY HAD A MUCH -- VERY PROLONGED ELEVATED C REACTIVE PROTEIN LEVEL AND IT LASTED LONGER THAN WOMEN THAT DID NOT HAVE HISTORY OF DEPRESSION. SO THAT FEEDS INTO WHAT WITH KNOW ABOUT AUTISM 2 IN TERMS OF STRONG FAMILY HISTORY TO MOTHERS ALSO HAVING DEPRESSION, SO PUTTING A PLUG FOR THAT TO BE LOOKED AT AND TO GET INPUT FROM THE COMMITTEE ON THAT AS WELL. WITH REGARDS TO DR. JAMES' RESEARCH THAT YOU MENTION, SHE ACKNOWLEDGED CLEARLY THIS INTERVENTION REQUIRES FURTHER STUDY AND DOUBLE BLIND PLACEBO CONTROL TRIAL, TO ELIMINATE THE POTENTIAL BIAS ASSOCIATED WITH OPEN LABEL STUDY. SO I THINK IT IS IMPORTANT THAT IT MOVE FORWARD AND WE DO MORE TYPES OF INVESTIGATIONS LOOKING AT CORRECTING SOME OF THESE IDENTIFIED METABOLIC ABNORMALITIES IN CHILDREN ESPECIALLY THE RESULTING IN IMPROVED BEHAVIORS AND I WAS WONDERING IF DR. NAVARO COULD TALK ABOUT THE MITOCHONDRIAL ABNORMALITIES AND INDIVIDUAL AUTISM. >> SO IT WAS ACTUALLY THE DISCONNECT BETWEEN WHAT WE OBSERVED IN CHILDREN WITH INHERITED FORMS OF RESPIRATORY CHAIN DISORDER OXIDATIVE PHOSPHORYLATION, MITOCHONDRIAL DISEASE CHILDREN CLINICALLY AND THE CLINICAL FEATURES OF AUTISM THAT GOT ME INTO AUTISM AND MAYBE THIS IS THE APPROPRIATE TIME TO THANK AUTISM SPEAKS FOR GIVING US OUR START IN AUTISM FUNDING OF THE TRAILBLAZER AWARD. SO THE CHILDREN WITH INHERITED FORMS OF MITOCHONDRIAL DISEASE COME IN WITH MULTI-ORGAN SYSTEM INVOLVEMENT, DECREASE IN HEARING SITES SKIN SENSATION, TASTE, THEY RESPOND ACTUALLY WITH A BLUNTED IMMUNE RESPONSE TO MOST IMMUNIZATION SO THE ACTUAL PERCENTAGE OF IMMUNE CONVERSION TITER CONVERSION AFTER PNEUMOVAX IS DECREASED IN CHILDREN WITH AUTISM. EXCUSE ME. WITH MITOCHONDRIAL DISEASE. WHEN WE LOOK AT CHILDREN WITH AUTISM, IN THE RAIL BLOOD WE SEE AN INCREASE IN MITOCHONDRIAL DNA COPY NUMBER AMONG THE WHITE BLOOD CELLS. HOWEVER, WHEN YOU LOOK AT THE CELLULAR FUNCTION WITH CELL MEMBRANES AND TACT, IT APPEARS THAT THE MITOCHONDRIA ARE ACTUALLY RESPIRING LESS, THEY HAVE WHAT WE CALL AN INCREASE RESERVE CAPACITY. WHEN YOU UNCOUPLE THEM THEY CAN REACT EXPLOSIVELY AND ALSO WHEN YOU PLACE THEM UNDER LOAD THEY CAN DRAMATICALLY INCREASE THE LEVEL OF REACTIVE OXYGEN PRODUCTION. CAN YOU CLARIFY, GO BACK TO JOSE'S QUESTION? HOW SPECIFIC ARE ANY OF THESE FINDINGS FOR AUTISM STRUCK BY YOURSELF COME AT THE END, ALL BRAIN DISORDERS HAVE METABOLIC DISTURBANCES. WHAT'S UNIQUE ABOUT AUTISM? >> THE RANK ORDER OF THE METABOLIC PATHWAY DISTURBANCES. WE SEE THERE IS AN OVERLAP WITH SOMETHING FOR EXAMPLE WE STUDY IN POST TRAUMATIC STRESS DISORDER IN MARINES ARE FROM IRAQ AND AFGHANISTAN SO THERE'S SOME OVERLAPPING ABNORMALITIES THAT'S HAVE -- ARE DIFFERENT BECAUSE THOSE DIDN'T AFFECT NEURAL DEVELOPMENT. BUT DO AFFECT FUNCTION OF INDIVIDUALS WITH THE DISTURBANCES. SO IN TERMS OF THE HOW BROAD YOU'RE ASKING HOW BROAD FOR EXAMPLE, THE METABOLIC DISTURBANCE IS ASSOCIATED WITH CELL DANGER RESPONSE ARE, IT'S VERY BROAD. BUT IF YOU'RE ASKING IS THERE A SPECIFIC SIGNATURE IN AUTISM, I WOULD SAY IT'S PROBABLY PREMATURE TO SAY, JUST HOW SPECIFIC IT IS. BUT WE SEE IF WE LOOK AT COHORTS OF SUFFICIENT NUMBER, MY TRAINING IN HUMAN GENETICS HAS TAUGHT ME TO EXPECT SUBCLUSTERS WITHIN THE SUPER CLUSTER. SO WHEN WE LOOK AT THE DOTS THAT SEPARATE THE METABOLITES OF CONTROLS AND CHILDREN WITH AUTISM GLUTATHIONE SUBCLUSTERS OF DIFFERENT SLIGHT DIFFERENCES IN CHILDREN WITH FOR EXAMPLE (INAUDIBLE) BEING DIFFERENT THAN THOSE WITH LEATHER JOY. POTENTIALLY -- LETHARGY, BUT OVERALL THE MESSAGE IS PRESERVE THERE'S A METABOLIC SEPARATION BETWEEN -- THE METABOLIC SEPARATION. >> SUE SWEDO WILL JOIN US HER WORK IS CITED HEAVILY IN THIS SESSION. >> I WANT TO FIRST ASK ABOUT THE ASSUMPTION ON ALL BRAIN DISORDERS AND METABOLIC DISORDERS BECAUSE THE BRAIN CONTROLS THE METABOLISM IT DOESN'T CONTROL THE METABOLISM OF THE THE ENTIRE BODY IN EVERY CELL. AT THE POINT YOU TAKE VERY BROAD SYSTEM AND YOU FIND LINKS IN ONE QUARTER THREE QUARTERS WE WERE COMING IF YOU EXPAND BROAD ENOUGH, IT HAS WATER, CAR BEEN DIOXIDE AND OTHERS, THE QUESTIONS OF SPECIFICITY, I WOULD LIKE TO SEE THE EVIDENCE FOR YOUR INITIAL ASSUMPTION THAT INDIVIDUALS WITH AUTISM HAVE ABNORMALITIES METABOLISMS. SUBCONSCIOUSLY OUR BRAIN STEM IS CONTINUOUSLY MONITORING THE CHEMISTRY OF THE BODY. A BIG PART OF AUTONOMIC TONE IS GENERATED IN RESPONSE TO THE CHEMOSENSORY MONITORING OF NEURONS IN EIGHT DIFFERENT VENTRICULAR ORGANS NOT BLOOD BRAIN BARRIER INCLUDING THE FLOOR -- THE FOURTH VENTRICLE AND THE AREA BUT OTHERS AS WELL. AND THAT WHAT'S INTERESTING TO ME, I'LL ANSWER THAT BY -- FIRST WE DON'T HAVE THE DATA TO BE ABLE TO FULLY DEMONSTRATE THAT, BECAUSE WE HAVEN'T TESTED ENOUGH CHILDREN. NOR HAVE WE TESTED ALL CASES OF PTSD BUT IN THE CASES THAT WE HAVE, SEE THE ABNORMALITIES. >> WHAT KIND OF ABNORMALITIES? WE TEST AD LARGE NUMBER OF CHILDREN. >> YOU HAVE TO -- PROGRAM WE HAVEN'T FOUND ANY MEANINGFUL ABOUT NOR FAULTY. >> ALLOWSES TO LOOK IN A BROAD-BASED WAY 700 METABOLITES. SO IT'S NOT POSSIBLE WHEN YOU FOCUS ONE THING OR ANOTHER, YOU SEE THOSE ONE THINGS OR ANOTHER BUT IF YOU BROADEN THE LENS, SO YOU'RE INTERROGATING MANY PATHWAYS AS YOU CAN WITHOUT BIAS OR ASSUMPTION IN THE BEGINNING. >> THAT'S IN BLOOD OR CSF? >> PALACE M&A MA IT TURNS OUT. SO EVEN THOUGH THE MAPPING IS NOT ONE TO ONE, THERE IS THERE IS A SIGNATURE IN PLASMA THAT CORRELATES WITH A DIFFERENT SIGNATURE IN CSF. >> WHAT WE SAW FROM CAR LESS'S PRESENTATION WAS THIS STRIKING DIFFERENCE IN HEAT MAPS. >> BECAUSE YOU'RE ASKING TNF ALPHA ASKING BE CORRELATED WITH TNF ALPHA IN CSF, THAT DOESN'T HAPPEN. BUT WHAT WE SEE IS FOR PAM EXAMPLE TRIPTOPHANE LEVELS ON THE OUTSIDE CORRELATED WITH SEROTONIN LEVELS ON THE INSIDE. THERE WILL BE METABOLIC CORRELATIONS THAT ARE NOT THE SAME METABOLITE, OUTSIDE AND INSIDE. >> I APOLOGIZE FOR BEING THE ENTERLOPER BUT I JUST WANTED TO MAKE A COMMENT ON DR. SANDER WATER'S GORGEOUS DATA AND ASK HER FOR HER COMMENTS BECAUSE YOU FREQUENTLY USE THE TERM RISK FACTOR AND IT COULD BE A BIOMARKER AND EVERY PAPER I HAVE BEEN ABLE TO FIND FROM YOUR GROUP AND FROM OTHERS WE DO NOT YET HAVE PROSPECTIVE DATA. WHERE MOTHERS ARE FOLLOWED THROUGH PREGNANCIES, OTHER THAN THE CYTOKINE CHEMOKINES WHICH THERE WERE ACTUALLY NO GROUP DIFFERENCES. WE DON'T KNOW THAT MATERNAL ANTIBODIES ARE PRESENT DURING GESTATION, WE ONLY KNOW THAT THEY WERE HIGHER IN A GROUP OF MOMS WHOSE CHILDREN HAD AUTISM WHEN THOSE CHILDREN WERE 6 TO 12 YEARS OLD. >> YOU MEAN THERE WERE 2 TO 5. THEY DO HAVE THE DATA, I DON'T PRESENT THEM IN A PUBLIC FORUM BECAUSE -- IT LOOKS REALLY GOOD ACTUALLY, AS FAR AS BEING VERY IN THE MARBLE STUDY O FAR, SO IT HOPE IT HAPPENS FAST BECAUSE WE HAD A PATIENT WHO GOT THE PROFILE AND TERMINATE AD PREGNANCY ON THE BASIS THAT SHE HAD A QUOTE 96% RISK OF HAVING A CHILD WITH AUTISM AND I'M JUST CONCERNED ABOUT THAT KIND OF INTERPRETATION OF DATA. >> WHERE WAS SHE FROM? >> SHE MUST HAVE BEEN. MAY HAVE BEEN. IT'S ALL RESEARCH AND THEY KNOW THAT. FIRST WE DON'T ACTUALLY DO IT DURING PREGNANCY BECAUSE WE DON'T HAVE (INAUDIBLE). SO SOMEBODY WHO I -- >> SHE HAS IT IN HER BLOOD. >> RIGHT. SO ANYBODY -- WE TESTED -- WE DO HAVE TESTS DURING PREGNANCY WE DON'T TELL THEM ACTUALLY. SO NONE OF THE MOTHERS IN THE STUDY FOR OBVIOUS REASONS, WE DON'T ACTUALLY EVEN TEST UNTIL THEY'RE THROUGH THE STUDY. I DON'T RUN THEM. BUT NO, IT'S A TRICKY, TRICKY THING. THE DATA COMING OUT ON PERSPECTIVE IS VERY GOOD, ACTUALLY BETTER THAN THE RETROSPECTIVE. BECAUSE ONE THING IN THE TYPICALLY DEVELOPING MODEL, DID THE POSTNATALLY, NO IDEA WHAT THE NEXT CHILD LOOK LIKE. SO I THINK I AGREE, THE STUDIES TAKE A LONG TIME BECAUSE WE BRING THEM IN BEFORE PREGNANCY, WE DON'T EVEN DO A FINAL DIAGNOSIS UNTIL THREE. >> WE TALKED BEFORE ABOUT GAP MS. THE RESERGE LITERATURE AND I THINK USING THE COHORT AND THE DANISH COHORT AND SOME OF THE OTHERS WHERE THERE WERE MATERNAL SAMPLES OBTAINED DURING PREGNANCY AND NOW THOSE CHILDREN ARE OLD ENOUGH THEY HAVE PASSED THROUGH THE AGE AT RISK, IF I WERE STILL HERE I WOULD BE PUTTING THAT AS HIGHEST PRIORITY FOR THAT GROUP TO FUND THEM TO GET DONE. >> SO THIS -- I WANT TO ADD THE STUDY WE'RE DOING WITH BANK SERUM FROM MID PREGNANCY FROM MSA OUTCOMES RETROSPECTIVE COHORT STUDIES ANTIBODY TESTING AND WE'RE IN THE PROCESS OF ANALYZING THAT SOON. >> CAN YOU -- A COUPLE OF CLARIFICATIONS ABOUT HOW THIS WILL -- SO AFTER THE PREGNANCY YOU'RE COLLECTING BLOOD TO FIND MATERNAL ANTIBODIES. A QUESTION IS DO SUBSEQUENT CHILDREN, DO THEY HAVE A HIGHER RATE OF AUTISM IN THOSE MOMS? >> THIS IS ORIGINALLY TO THE CHARGE STUDY AND IT WAS DO THEY EXIST. SO THE DATA WAS BASED ON JUST FINDING THEM. IN THE FIRST PLACE. WE DID GO BACK TO A GROUP OF MOMS AND ACTUALLY INQUIRED, INTERESTINGLY SOME OF THEM WOULDN'T ANSWER. THEY WOULDN'T ANSWER WHETHER THEY WERE OR WERE NOT BUT WE ACTUALLY IT WAS PREDISTINCTIVE IN THAT COHORT. WE DIDN'T DO THAT IN A WAY WE PUBLISH IT SO WHEN MARBLES BEGAN THAT'S WHERE WE REALLY LOOKED AT AS WE MEASURED BEFORE THOSE ARE HIGH RISK MOMS MIND YOU BUT WE ALSO HAVE JUST BEGUN ENROLLING 100 MOMS IN THAT POPULATION. SO YES, IT WAS THE ORIGINAL STUDY WAS BASED ON SEEING IF THOSE ANTIBODIES EXIST. >> PEOPLE ARE STARTING TO DRIFT OUT AND I'M WATCHING THE CLOCK BUT THERE ARE STILL QUESTIONS AN I WANT TO GET THEM ON THE TABLE. >> A SPECIFIC QUESTION, I THINK FOR CARLOS, SO WHEN YOU THINK ABOUT THE NEUROIMMUNE HYPOTHESIS IN AUTISM PARTICULARLY FROM AN ETIOLOGICAL PERSPECTIVE OR DEVELOPMENTAL PERSPECTIVE AS YOU SHOWED SHOWED IN YOUR DIAGRAM, DO YOU THINK OF THIS AS A COMMON PATHWAY MANY FORMS OF AUTISM OR DO YOU THINK THIS IS A MODEL THAT APPLIES TO A SUBGROUP, SETS OF WHAT SIZE SUBGROUP? HOW DO YOU THINK ABOUT THIS IN THE CONTEXT OF THE BROADER POPULATION OF AUTISM? >> THAT APPLIES TO ALL FORMS OF AUTISM. THE FUTURE BASICALLY NEEDS TO FOCUS, FUTURE STUDIES FOCUS NCI FOR EXAMPLE COMBINING DIFFERENT RISK FACTORS LIKE MATERNAL INFECTION OR ENVIRONMENTAL FACTORS OR DIFFICULT PREGNANCY IES OR EVEN DIFFICULT DELIVERY BECAUSE (INAUDIBLE) PROCESS, THEY TART REACTING DIFFERENTLY, THE TIMENING BRAIN DEVELOPMENT IS GOING TO BE (INAUDIBLE) THE TARGET MAYBE DIFFERENT. BECAUSE EVERY REGION OF THE BRAIN FOLLOW VERY WELL (INAUDIBLE) ORGANIZATION SO I BELIEVE THERE ARE MATERNAL INFECTION OF AGE 28 OF GESTATION, COMPARED WITH 36. THE SAME MAY HAPPEN FOR POTENTIAL NEUROTOXICANTS. ANY TOXIC MATERIAL DEPENDS ON AGE OF EXPOSURE SO I THINK IT THE MODEL APPLY TO EVERYTHING CRITICAL STEPS IN FUTURE, A GOOD CLINICAL EPIDEMIOLOGICAL STUDY TO ANALYZE THAT TIME, PERHAPS ANIMAL MODELS THAT (INAUDIBLE) BEFORE WE GO TO GENERAL DISCUSSION. LYNN. >> JUST WITH REGARD TO IMMUNE SYSTEM ACTIVATION CARLOS AND COMMENTS YOU WERE MAKING, THAT IT WAS THE TAKE HOME MESSAGE WAS DON'T MESS WITH IT AND THERE'S JUST SO MANY OF THESE OTHER ABNORMALITIES THAT COME UP LIKE MYELIN ABLATIVE PROTEIN ANTIBODIES IN CHILDREN, THESE ELEVATED CYTOKINE LEVELS, WHAT DO WE DO WITH THAT INFORMATION, HOW DO WE FOLLOW-UP ON IT, WHAT'S THE NEXT STEPS WITH REGARD TO RESEARCH TO DETERMINE WHETHER OR NOT IT'S SOMETHING WE NEED TO SUPPORT OR SOMETHING WE NEED TO (INAUDIBLE) WE KNOW PARENTS OUT THERE NOW ARE USING TREATMENTS, FOR MICROGLIAL ACTIVATION, AND THEY DON'T NOBODY KNOWS BECAUSE OF ABSENCE OF THAT INFORMATION THEY'RE ACTING ON THEIR OWN SO WHAT ARE NEXT STEPS TO GET THAT VITAL INFORMATION AND THEN DISSEMINATE IT TO THE PUBLIC? >> THE MAIN ISSUES WE NEED TO UNDERSTAND COMPLETELY HOW THE PROCESS IS. WE NEED -- WE HAVE A LOT OF PIECES FLOATING AROUND, WE NEED TO MOVE PIECES TOGETHER. MICROGLIAL ACTIVATION IS A VERY GOOD EXAMPLE OF THAT. TEN YEARS AGO WE ARRIVED WE WERE WRITING THE PAPER WE NEVER COMMITTED TO SAY MICROGLIAL -- WE NEVER HAD EVIDENCE OF THAT. VERY GOOD APPROACH BECAUSE RIGHT NOW IN THE PAST TWO YEARS WE ARE LEARNING TONS ABOUT MICROGLIA AND LEARNING THE CRITICAL SYNAPTIC -- WE KNOW THAT THERE ARE VERY IMPORTANT FOR PROCESS OF PROGENITORS, ET CETERA. SO I THINK THAT THAT ELEMENT IS AN ELEMENT THAT ALL OF THOSE IS BUSINESS INFORMATION NEED TO COME IN A VERY GOOD EXPLANATION OF PATHOGENESIS, ANTIBODIES. IF YOU SCREEN THE POPULATION OF THE UNITED STATES AT AGE 15 YOU ARE GOING TO FIND 50% OF THAT POPULATION WOULD HAVE ANTI-BOYS. ARE THOSE ANTIBODIES PATHOGENIC? PROBABLY NOT. THE IMMUNE SYSTEM HAVE THE ABILITY TO ENCOUNTER MANY ANTIGENS AND GENERATE IMMUNOLOGICAL RESPONSES INITIALLY WE'RE GOING TO GO AWAY WITHOUT ANY IMPACT ON THE CLINICAL OUTCOME. I BELIEVE THAT WE LOOK FOR ANTIBODIES, WE NEED TO FOCUS ON ANTIBODIES RELEVANT FOR DISEASE PROCESS AND WE NEED TO BE CRITICAL AND VALIDATE THAT PROCESS FOR UNDERSTANDING ANTIBODY. IN ADULT POPULATION YOU LOOK AT ANTIBODIES AGAINST HORMONES, WE'RE GOING TO HAVE THAT 25% OF THE POPULATION OF THE PATIENTS THAT HAVE ANTIBODIES (INAUDIBLE) SO WE NEED TV A BETTER UNDERSTANDING OF THE CLINICAL IMPLICATION OF SMALL FINDINGS. >> I JUST HAVE A GENERAL OBSERVATION. ARE WE GOING TO MOVE IN TODAY, PANEL DISCUSSION? >> ABSOLUTELY. WILL THE'S DO IT. YOU CAN KICK IT OFF. GO AHEAD. >> I'M JUST TRYING TO BE GENERAL HERE. I THINK IT'S FAIRLY AMAZING MEETING. I THINK AGAIN REINFORCES, REMIND ME THE IMPORTANCE OF HAVING VERY MULTI-DISCIPLINARY TYPES OF GROUPS BECAUSE BRINGING TOGETHER PEOPLE WORKING IN WHAT SEEMS TO BE QUITE DIFFERENT DISTANT RESEARCH FROM ONE ANOTHER IS ALL CONNECTS ON AUTISM AND TAKES PARTICULAR -- FROM MITOCHONDRIA TO IMMUNE SYSTEM JUST BEEN TERRIFIC, I THINK WE NEED TO HAVE MORE OF THIS KINDS OF DISCUSSIONS, OPPORTUNITIES FOR PEOPLE FROM VERY DIFFERENT DISCIPLINES CAN INTERSECT AND CONNECT AND SEE WHERE THE CONNECTIONS ARE THAT ACTUALLY REALLY NEW IDEAS. >> THANK YOU. THAT SETS AN INVITATION FOR EVERYBODY TO JOIN INTO A GENERAL DISCUSSION. ALLISON. >> I HAD A QUESTION FOR DR. KOHANE, HE LEFT SO I'LL PUT IT TO THE GENERAL GROUP BUT HE BROUGHT UP THE IDEA OF PHENOTYPE FIRST APPROACH AND MY QUESTION WAS RELIABILITY OF PHENOTYPE FIRST APPROACH. BECAUSE IT SEEMS TO ME ALL THE SUSPECTED CAUSES OF AUTISM OR MAJORITY, NOT ALL BUT MAJORITY, THE ONLY THING I CAN THINK OF ADVANCED MATERNAL AGE OR GENETICS THE RECENTLY REPORTED WITH REGARD TO 16 P 11 THERE WERE DIVERSE PHENOTYPES, IRONICALLY DIVERSE PHENOTYPES. SO WHAT IS THE BENEFIT OF THE PHENOTYPE FIRST STRATEGY? >> I WOULD BE HAPPY TO TAKE THAT ON IF NO ONE ELSE WANTS TO. NIMH IS DEEPLY INVOLVED IN THAT QUESTION FOR ABOUT THREE YEARS OR FOUR YEARS. AND WE FINALLY GAVE IT -- LAUNCHED THE RESEARCH DOMAIN CRITERIA PROJECT. ESSENTIALLY TO SAY THAT THE FUTURE HAS TO BE GETTING BEYOND SYMPTOM BASED DIAGNOSIS FOR ANY OF THESE BRAIN DISORDERS. AND TO THE EXTENT WE'RE LIMITED TO SYMPTOMS, WE'LL NEVER HAVE BUY MARKERS BECAUSE THEY DON'T MAP TO SYMPTOM CLUSTERS IN A CONSISTENT WAY. WE KNOW THAT AS YOU SAID. 16 P 11 IF YOU CAN PICK YOUR FAVORITE, THING LOU THAT LOOKS LIKE A CAUSATIVE GENE YOU GET DIFFERENT KINDS OF OUTCOMES. WHAT DO YOU DO IN THAT CASE? YOU DO AN ACTUALLY ZACK TALKED ABOUT IT. HE HAD A SLIDE OF WHAT'S HAPPENING IN THE WORLD OF ONCOLOGY USING PRECISION MEDICINE AND THE CONCEPT THERE IS TO BUILD AN INFORMATION COMMONS, A HUGE DATABASE WHICH YOU BRING IN ALL KINDS OF STUFF. IMMUNE FACTORS, NEUROIMAGING, GENETICS, YOU DO BRING IN CLINICAL SYMPTOMS, TREAT THE RESPONSE, PUT IT ALL ON THE TABLE. YOU BEGIN TO SORT DATA TO COME UP WITH THE ENTITIES. WE DID THIS FOR ALL THE PSYCHOTIC DISORDERS. IT TURNS OUT WE PUT IN BASICALLY THREE OR FOUR THAT FORM THE REALM OF PSYCHOSIS IN ADULTHOOD, WE CAME OUT WITH THREE OR FOUR CATEGORIES BUT THEY WEREN'T IN ANYWAY MAPPED ON TO THE ONE WE WENT IN WITH. THEY'RE NOT THE DIAGNOSTIC CATEGORIES THAT WE HAVE, YET THOSE ARE THE ONES THAT SEEM TO HAVE SOME BIOLOGICAL VALIDITY BECAUSE THEY FOLLOW NOT JUST THE GENES BUT CONNECTOME, COGNITIVE FUNCTION AND OTHER THINGS. THAT'S A KIND OF WAY FORWARD HERE. THAT WE OUGHT TO THINK ABOUT, IT WASN'T IN THE STREAM PLAN TO TO CREATE AN INFORMATION COMMONS BUT YOU CAN IMAGINE WITH NDAR AND OTHER THINGS, IT WOULDN'T BE DIFFICULT TO PUT THE DATA IN A POOL AND SEE HOW IT SORTS OUT. BUT IT'S NOT GOING TO HAPPEN BASED ON THE PRESENCE OR ABSENCE OF ONE OR TWO OR THREE SYMPTOMS, THAT'S JUST NOT THE WAY ANY BRAIN DISORDER WORKS IN THAT WE HAVE SEEN SO FAR. >> YEAH. >> I THINK THAT ACTUALLY FROM PEOPLE LIKE ME WORK IN THE PREVIOUS CENTURY, I THINK THE EXAMPLES OF WHAT HAPPENED WITH CLINICAL GENETICS AND SYNDROMES, AND MORPHOLOGY ACTUALLY A GOOD PAM EXAMPLE, WE STARTED TRYING TO SPECIFY THAT HELP, WHEN WE WENT INTO THE MOLECULAR BASIS OF THE ACTUALLY BEGINNING TO IDENTIFY SPECIFIC GENES AND AFTER THAT WAS DONE WE FIND GENES ARE THE SAME GENES THAT ACTUALLY CAUSES THE PHENOTYPES. ACTUALLY WAS VERY HELPFUL, BUT IT'S A NARROW GROUPS MORE MANAGEABLE TO LOOK INTO WHAT IS BASIC BIOLOGY BUT ALSO GENETICS. >> ALL THE BASHING DSM-5, IF YOU READ THE AUTISM SECTION IN DSM-5, IT SAYS THIS, IT SAYS WE DON'T KNOW ENOUGH YET TO KNOW HOW TO BREAK THE CATEGORIES. SO IT'S ESSENTIALLY A REALLY WELL WRITTEN SECTION. I HAVE A HUNCH THAT SUE SWEDO WROTE IT BUT I'M NOT SURE ABOUT IT. BUT IT SAYS GIVEN THE STATE OF OUR IGNORANCE IN AUTISM, LET'S NOT EVEN TRY TO PRETEND THAT WE KNOW WHERE TO BREAK IT INTO PARTS. LET'S PUT EVERYTHING INTO THIS BUCKET THAT WE WILL CALL AUTISM SPECTRUM DISORDER BUT THE CHARGE TO THE FIELD IS TO DECONSTRUCT THIS OVER THE NEXT FEW YEARS. AND TO COLLECT THE DATA IN SUCH A WAY THAT WE CAN DECIDE ABOUT THE AUTISM WHETHER THAT'S 8 OR 10 OR 15 DISORDERS. AND IT MAY FEEL HIKE HYPERTENSION 5% OF THE TIME, I'LL START TO PEAL OFF AS WE GET GOOD CONNECTOMES AS WE GET GOOD GENETICS AND MORE INFORMATION ABOUT THE IMMUNE METABOLIC FACTORS, THIS LEADS TO THE QUESTION THAT INHERENT IN EVERYTHING WE HEARD TODAY, HOW MUCH OF WHAT WE'RE HEARING THAT WE'RE CALLING CO-OCCURRING IS REALLY THAT CAN HELP US TO UNTANGLE THIS HETEROGENEOUS GROUP, WE'RE STILL NOT THERE, IT'S STRIKING HOW THERE ARE LOTS OF CLUES AND INTERESTING LEADS BUT IT'S NOT -- I'LL PUT THE QUESTION OUT ON THE TABLE, ARE WE AT A POINT NOW WHERE ANY OF THIS HELPS US TO IDENTIFY THAT SUBGROUP THAT NOW HAS A NEW NAME LIKE FRAGILE X, WE CAN PUT NEIGHBOR AROUND IT, WE DON'T HAVE GENETICS BECAUSE WE KNOW ABOUT CAUSE, MECHANISM, SYNDROME, AND TREATMENT RESPONSE >> FROM THE POINT OF VIEW OF FAMILIES LOOKING FOR TREATMENT, POINT OF CARE, WHAT MANY FAMILIES WANT IN FOR SOMEONE TO BE ABLE TO SAY TO US YOUR CHILD PRESENTS WITH SYMPTOM A, B AND SYMPTOM C. AND THEREFORE SHOULD HAVE THIS TREATMENT AND THAT PERSON SHOULD HAVE THIS TREATMENT. SO TREATMENTS THAT ARE EVIDENCE BASED BASED ON THE PRESENTATION I GUESS MY QUESTION IS DOES THE PHENOTYPE FIRST STRATEGY LEAD THAT WAY OR DOES A MORE TRADITIONAL STRATEGY LEAD IN THAT DIRECTION? ULTIMATELY THAT IS GOING TO EFFECT TREATMENT AT POINT OF CARE. >> PHENOTYPE FIRST COULD DO THAT INCLUDE IN THE PHENOTYPE IS TREATMENT RESPONSE, THAT'S ONE WAY TO DEFINE YOUR SYNDROME. IF YOU DON'T LIMIT YOURSELF TO SYMPTOMS IF YOU COLLECT LOTS OF DIFFERENT KINDS OF DATA, YOU COULD GET THERE. AND THAT'S WORKED, IN LOTS OF OTHER AREAS. SO IT COULD WORK HERE. WE DO HAVE TO HAVE A WAY TO COLLECT THAT DATA IN AN AGGRAVATED WAY SO IT MOVES QUICKLY SO THIS ISN'T A SERIES OF PAPERS OVER 20 YEARS BUT THAT THERE IS A COLLECTIVE EFFORT TO DRIVE THIS HOME. OVER A SHORT PERIOD. IT'S NOTS DONE JET IN QUITE THAT WAY BUT COULD BE. >> TWO PURPOSES FOR THE PHENOTYPE. THE PHENOTYPE BACK TO CAUSATION. I THINK MAYBE NOT, MAYBE NOT SO FRUITFUL, THE PHENOTYPING FOR NAMING TARGETS SYMPTOMS THAT ARE THE OBJECT OF TREATMENT, THAT'S I STILL THINK IS WORTHWHILE. >> FEW RESPONSES, ONE IT'S IMPORTANT THE KEEP IN MIND WHEN WE THINK ABOUT TREATMENT IN FAMILIES THAT MANY OF THE COMORBIDITIES THAT INDIVIDUALS WITH AUTISM ARE PRESENTING WITH ARE TREATABLE WITH COMMON KINDS OF TREATMENT. SO I THINK THAT WE CAN MAKE VERY RAPID PROGRESS BY GETTING THE INFORMATION OUT TO PEDIATRICIAN THAT YOU CAN LOOK AT SLEEP HYGIENE OR PRESCRIBE MELATONIN FOR CONSULTATION THE TREATMENT IS HOW YOU WOULD TREAT ANOTHER CHILD WITH CONSTIPATION, CORRECT? SO THAT'S SOMETHING WE CAN DO IMMEDIATELY IS GET THOSE THINGS OUT THERE. THE OTHER THING I WANT TO UNDERSCORE WHAT YOU WERE SAYING ANT THE IDEA OF TRYING TO DO A PHENOTYPE FIRST KIND OF APPROACH BY LOOKING AT WHO RESPONDED TO THE TREATMENT AND WHO DOESN'T AND IF WE WERE NIH WOULD MANDATE THAT IN ADDITION TO COLLECTING I DON'T KNOW WHETHER CHECKING GENETIC INFORMATION NOW FOR THOSE KINDS OF TRIALS ALWAYS? BUT THEY MAY SHOULD COLLECT COMORBIDITIES, SO IN A VERY SYSTEMATIC WAY. AND IT GOES INTO NDAR SO WE START TO COLLECT LOTS OF DATA ON WHETHER THERE'S CERTAIN TYPES OF SUBTYPES THAT RESPONDING TO TRIALS IN A DIFFERENT WAY. SO THAT MAKES -- >> GO AHEAD. >> SO JUST TO BUILD ON JERRY'S COMMENT. FOR EXAMPLE, IF I WERE GOING TO DO A SLEEP TRIAL AFTER TODAY I WOULD BE EXCITED ABOUT COLLECTING PHENOTYPE DATA SO DOES THE CHILD HAVE A BIPOLAR PHENOTYPE WITH SHORT DURATION. IN OTHER WORDS CAN OTHER PHENOTYPE INFORMATION TOGETHER THAT I MIGHT NOT NORMALLY HAVE THOUGHT TO COLLECT SO I THINK THAT'S AN OPPORTUNITY IN OUR TREATMENT TRIAL THINK ABOUT THESE OTHER THINGS, THINK ABOUT YOUR ANXIETY MEASURES FOR EXAMPLE. OTHER THING SAYING SEVERAL OF US MENTIONED HYPER AROUSAL, ELECTRODERMAL ACTIVITY, HEART RATE, HEART INVESTIGATE VARIABILITY AND THINK -- HEART RATE VARIABILITY AND AUTONOMIC MEASURES DOING THE TREATMENT TRIAL BECAUSE JERRY'S POINT IS WELL TAKEN, THAT'S WHAT THE PUBLIC WANTSK WHAT OUR FAMILIES WANTS, THEY WANT THE TREATMENT. THEY DON'T WANT TO WAIT TO DO THE TREATMENT UNTIL WE FIGURE OUT WHAT'S DRIVING THE PATHOLOGY. BUT IN THE PROCESS OF DOING THE TREATMENT COLLECT THOSE DATA SO THAT IT WILL INFORM WHO IS GOING TO BE RESPONSIVE TO THOSE TREATMENTS. >> PHENOTYPE FIRST TO UNDERSCORE THEIR DIMENSIONS OF PHENOTYPE AND AS WE WERE SO OFTEN WE COLLECT WHAT WE CAN SEE AND WITH THE TOOLS THAT WE HAVE, IT'S IMPORTANT TO TRY TO UNPACK THE PHENOTYPE FROM AS MANY LAYERS AS WE CAN SO LOOKING FROM CHEMISTRY TO ELECTROPHYSIOLOGY TO FUNCTIONAL IMAGING TO BEHAVIOR SO IT TURNS OUT THOSE STUDIES ARE HARD TO DO METABALOMICS WITH DIFFUSION TENSOR IMAGING AND INTERVENTIONS STUDY, BUT THE FUTURE WHAT WE HAVE TO DO IN ORDER TO UNDERSTAND THE INTERCONNECTEDNESS OF ALL THOSE LAYERS OF PHENOTYPE. >> TO UNDERSCORE BRING IT BACK TO ALLISON'S COMMENT, IT'S IMPORTANT TO DO A MULTI-LAYER KIND OF WAY, MULTI-DIMENSIONAL BECAUSE IN THE END IT MAY NOT BE THIS CONSOLATION OF SYMPTOM A, B, C, IT MAYBE SYMPTOM A AND BIOMARKER H AND MOLECULAR SOMETHING OR OTHER J THAT REALLY HELPS US FIGURE OUT WHAT TREATMENT VERY IMPORTANTLY DEVELOP NEW TREATMENTS, IT'S VERY IMPORTANT JERRY'S POINT WE USE THOSE TREATMENTS WE KNOW NOW ON A SOMEWHAT EMPIRICAL BASIS WORK FOR A CERTAIN CHARACTERISTIC OF KIDS THAT WE CAN FIGURE OUT OR WHATEVER BUT THEY TEND TO WORK BUT WE THINK ABOUT MORE BIOCHEMICALLY BASED OR OTHER KINDS OF TREATMENTS, WE HAVE TO PA BREAK IT DOWN ON A VERY -- I THINK SOME WE TALK ABOUT PHENOTYPE PEOPLE THINK ABOUT MANIFEST SYSTEM TIMES, WE WANT TO EVENTUALLY MAKE IT MUCH RICHER THAN THAT, THE CHALLENGE IS FIGURING OUT THE MULTI-DIMENSIONAL KINDS OF THINGS WHICH ONES ARE REALLY GOING TO PAY OFF, WHICH ONES, SO WE HAVE TO CAST A WIDE NED WHICH MAKES IT MORE COMPLICATED, MORE EXPENSIVE. IF WE DO THIS I THINK PARTICULARLY FOR ASC WE NEED TO CAST A FAIRLY WIDE NET AND CERTAINLY PEOPLE WHO ARE COOING STUDIES NOW IN PARTICULAR -- DOING NOW IN PARTICULAR OF PHENOTYPE WE WANT TO -- ONE LARGE DEEP PHENOTYPE STUDY, WE WANT TO GO DEEP AS WE CAN, OTHER STUDIES AND TRY TO COLLECT AS MUCH INFORMATION AS WE CAN. >> WONDERFUL PAPER OUT LAST WEEK OR TWO WEEKS AGO IN CELL WHICH WE CAN DISTRIBUTE HERE. THIS THING FOR CANCER, IT'S THE CANCER GENOME ATLAS PROJECT. THEY TOOK 12 CANCERS FROM DIFFERENT PARTS OF THE BODY, THEY TRIED TO CHARACTERIZE THEM 6 OR 8 PLATFORMS TO FIGURE OUT HOW TO DEFINE THESE DIFFERENT CANCERS THAT THE NECK CANCER WAS IDENTICAL TO BLADDER CANCER, COMPLETELY DIFFERENT PHENOTYPE CELLS LOOK DIFFERENT, CANCER LOOKS DIFFERENT BUT MOLECULAR CELLULAR AN TREATMENT RESPONSE LEVEL, IDENTICAL TOUR, WHEREAS WITHIN THE BLADDER, THEY'RE COMPLETELY THREE COMPLETELY DIFFERENT KINDS OF CANCERS THAT WERE PRESENT. IT IS THIS IDEA OF PULLING ALL OF THESE PIECES TOGETHER AND I THINK ONCOLOGY HAS GOTTEN THERE FIRST AND HELPING TO SHOW THE IMPORTANCE OF USING THAT KIND OF INFORMATION MOLECULAR CELLULAR TREATMENT RESPONSE INFORMATION USING THAT TO SORT OUT YOUR DIAGNOSTICS AS THEY SAY IN ONCOLOGY, THE BEST PATH TO BETTER TREATMENT BETTER DIAGNOSIS AND WE NEED TO DO THAT HERE AS WELL. BECAUSE WE'RE DESYLING WITH HETEROGENEOUS CATEGORY. LISA. >> I THINK THIS IS THE WAY TO GO BUT PRACTICALLY HOW DO IMPLEMENT THIS, WE'RE TALKING ABOUT A BEHAVIORALLY DEFINED DISORDER WITH A LOT OF PHYSICAL AND BIOCHEMICAL AND SOME HARD -- SOMETHING YOU CAN MEASURE BUT WE DON'T TYPICALLY IN CANCER BIOPSY AND HAVE A SPECIMEN AND LOOK AT GENETICS AND YOU CAN LOOK AT IT'S EASIER TO COLLECT THE DATA, IN OTHER WORDS ON LARGE NUMBERS OF PEOPLE THAN IN OUR AUTISM STUDIES WHERE WE'RE OFTEN STUDYING CHILDREN NUMBER ONE AND WE'RE LOOKING AT BEHAVIORS AND WE DON'T -- AND DOING BRAIN IMAGING AND COLLECTING BIOSAMPLES AND MOLECULAR CELLULAR AND GENETIC, IT'S -- HAVING BEEN INVOLVED IN STUDIES THAT WHERE WE'RE COLLECTING LOTS OF DATA AT DIFFERENT LEVELS, IT IS INCREDIBLY EXPENSIVE AND HARD TO GET FUNDED AND YOU CAN'T LOOK AT LARGE NULLS NUMBERS SO I'M WONDERING IMPRACTICALLY HOW WE IMPLEMENT A STRATEGY OF COLLECTING INFORMATION AT THESE DIFFERENT LEVELS OF PHENOTYPE AND (INAUDIBLE). >> THIS IS PERHAPS WHERE THE ZACK COHANE APPROACH IS IMPORTANT. IF YOU CAN TAKE LARGE DATE SETS AND SAY OKAY, WE'RE FINDING THAT KIDS WITH GI ARE ALSO HAVING INFECTION DISTINCT OTHER GROUPS THAT HAVE EPILEPSY, SO YOU HAVE THIS LARGE DATA SET AND IT LOOKS LIKE THEY'RE GOING TO DO IT EVEN MORE, IF THINGS POP OUT AS RELEVANT SUBTYPES THOSE MIGHT BE THINGS TO PRIORITIZE NIH, FOR EVERY CLINICAL TRIAL WE FUND WE WANT TO KNOW DOES THE KID HAVE SEIZURES, DOES THE KID HAVE D GI DISORDERS HISTORY OF INFECTION BUT SOME WAY TO PRIORITIZE, BUT THE ANALYSES POINT IN DIFFERENT DIRECTIONS. >> ONE OF THE SURPRISING THINGS ABOUT PEOPLE WHO DO AUTISM RESEARCH IS THEY DON'T APPRECIATE SUCCESSES. I TALK TO PEOPLE IN THE DEMENTIA FIELD. THERE ARE NO INTERVENTIONS FOR ALZHEIMER'S. >> THERE'S NOTHING THAT WILL MOVE DEMENTIA 10% BUT WE MAYBE HAVE JUST PURE LUCK AND SERENDIPITY HAVE ENDED UP WITH PRETTY GOOD OUTCOMES FOR A LOT OF KIDS WHO DO ACTUALLY PRETTY WELL. AND WHEN IT COMES TO THE CO-OCCURRING CONDITIONS WE CAN DO REALLY WELL, SO IT'S WORTHYING ABOUT. HOW THESE WILL PREDICT WHO ARE THE KIDS THAT DO BEST. SO YOU CAN HELP SELECT TREATMENTS. EVEN AS GREAT AS IT IS TO HAVE THESE BIOMARKERS AND HAVE TISSUE FOR CANCER, GOOD LUCK WITH PANCREATIC CANCER, IF YOU CAN GET AT 21 DAY LONGER SURVIVAL THAT'S CONSIDERED A FANTASTIC SUCCESS. WE'RE IN A MUCH BETTER PLACE IN TERMS OF TREATMENTS AND THE FACT THAT IS WE HAVE GOT A LOT OF SYMPTOMS THAT ARE RELATIVELY MALLABLE, I DON'T THINK WE APPRECIATE THAT NEARLY ENOUGH HERE. AND THE QUESTION THAT'S OPTIMIZE IT. >> I THINK JERRY JUST HIT SOMETHING VERY IMPORTANT AND IT BUILDS OFF OF SOMETHING A THEME EMERGING HERE IN THIS CONVERSATION WE'RE FACING IT WITH OUR 10,000 GENOMES PROGRAM WHICH IS BUILDING A GIANT CLOUD BASED DATABASE WITH GOOGLE ALL ON ALL GMC SEQUENCING, WHAT WE'RE RUNNING INTO THAT NEED FOR STANDARDIZATION ON THE COLLECTION OF DATA. I THINK WE CAN BE CREATIVE ACROSS THE FUNDING ECOSYSTEM IF YOU WILL AND REGARDLESS OF WHERE THAT FUNDING ORIGINATES CREATING REQUIREMENTS FOR THE COLLECTION OF DATA AND THE COLLECTION OF BIOSAMPLES ON TOP OF EXISTING RESEARCH SEEMS LIKE A VERY QUICK WAY TO START TO BUILD UP A REPOSITORY OF INFORMATION AND MEANS TO COLLECT THE ADDITIONAL INFORMATION BUT I WILL ALL FALL DOWN UNLESS THE STANDARDIZATION OF THAT COLLECTION IS NOT ACHIEVED. WE HAD WE AS A FIELD HAVE REACHED SOME CONSENSUS ON STANDARDIZATION FOR CORE COLLECTION ACTIVITY. THAT STARTS WITH THE FOUNDATION ON WHICH THE HARMONIZATION MIGHT BE BASED FOR CASES ON THE DIAGNOSIS BUT I THINK THAT THAT'S A HUGE CHALLENGE, I KNOW TOM, WE HAVE DEALT WITH THIS AROUND THE BIOMARKERS CONSORTIUM ACTIVITIES CAN WE AGREE ON WHAT THAT CORE SET OF END POINT WOULD BE WHETHER OR NOT YOU LEAD IN ON FEE NO, MA'AM OR GENOME OR WHATEVER THE OMICS PREFERENCE IS, STANDARDIZATION STANDARDIZATION IS -- REALLY BE ABLE TO ACHIEVE THE SCALE NECESSARY FOR ALL OF US TO MINE IT IN AN OPEN ACCESS KIND OF WAY AND ANSWER SOME OF THESE QUESTIONS. THIS IS A REALLY IMPORTANT POINT FOR THE AFTERNOON SESSION HERE. WE DON'T HAVE THAT YET FOR MOST MEASURES THAT FLOATED UP FOR SLEEVE, IT SHOULD BE RELATIVELY EASY TO STANDARDIZE. >> I THINK ONE OF THE CHALLENGES, I'M SORRY, I DIDN'T SEE YOUR HANDS, CAN I JUST FOLLOW-UP ON THE -- I THINK ONE OF THE CHALLENGES PARTICULARLY IN FIELD LIKE SLEEP IS AS I SHOWED, WE CAN HAVE A PARTICULAR GENE THAT PREDICTS SHORT SLEEP DURATION AND ALL THE ENVIRONMENTAL THINGS AND IT'S REALLY HARD TO SORT OUT THE ENVIRONMENTAL INFLUENCES AND I'M TALKING ABOUT SIMPLE THINGS LIKE iPAD USE. BUT ONE OF THE THINGS I THINK WE'RE TRYING TO DO AND OTHERS ARE TRYING TO DO IS LOOK AT SOME OF THESE QUESTIONNAIRES LIKE THE CSHQ INCLUDED IN AUTISM SPEAKS DATA COLLECTION AND SAY WHAT ARE THE MOST ROBUST. SO FOR EXAMPLE, A KID WHO SLEEPS THREE HOURS IS PROBABLY GOING TO SLEEP THROW HOURS WHETHER THEY'RE USING THE iPAD OR NOT, IN OTHER WORDS THERE MAYBE SOME STRONG PREDICTORS. AND I THINK THAT NOT JUST THE SLEEP BUT OTHER FIELDS AND OTHER COMORBIDITIES AS WELL SO FOCUSING ON THOSE AREAS, MIGHT BE FRUITFUL AND REALLY DIGGING INTO THOSE QUESTIONNAIRES. >> I WAS GOING TO SAY THAT I THINK WE SEEM TO BE NOT TALKING ABOUT BIG DATA SETS AND GENOME DATA SETS AND CLAIMS AND CLINICAL INFORMATION, IT SEEMS LIKE A LOT OF THIS RISK IS ABOUT LINKING THESE DIFFERENT LEVELS OF INFORMATION, AND KINDS OF DATA TOGETHER AROUND THE CHILDREN THEMSELVES OR THE ADULTS. WITH AUTISM. I LIKE THE CANCER MODEL BECAUSE AT LEAST FOR CHILDHOOD CANCER THERE AREN'T A LOT OF KIDS IN ANY PARTICULAR CENTER BUT IT'S IN THE -- IN DEVELOPING A REGISTRY THAT THEN YOU BEGIN TO STANDARDIZE NATURALLY, HAVING KIDS COLLECTED AND DEATH WITH IN THE SAME WAY WHERE ALL THAT INFORMATION IS AVAILABLE AT THE CHILD LEVEL. SO I WONDER IF WE CAN EXPAND ON THAT MODEL BECAUSE A LOT OF THESE KIDS ARE GETTING WORKED UP, THEY ARE GETTING -- THEY AREN'T GETTING MRI TO BEGIN TO PUT THEM IN ONE PLACE. THAT WE CAN DRAW FROM THE COLLECTIVE EXPERIENCE AND LINK IT TO CLAIMS, THE GENOME BIG DATABASES AS WELL. >> NDAR IS NOW THE 35 TO 40,000 SUBJECT LEVEL FOR AUTISM, AND WELL OVER 100,000 FOR TOTAL SUBJECTS SO THAT'S AN ATTEMPT TO DO THAT. MAYBE DOESN'T HAVE EVERYTHING IN IT BUT IT HAS A LOT OF LEVELS WE'RE TALKING ABOUT GENETICS IMAGING CLINICAL FEATURES WHOLE RANGE OF THINGS, IT HAS BEEN WITH FAIR AMOUNT OF STANDARDIZATION. THE CHALLENGE IS WE STILL HAVE ALL THE RIGHT MEASURES BUT NOT SURE WHAT THOSE MEASURES SHOULD BE IN THE FUTURE. >> SOME OF THE -- GO AHEAD. >> I GUESS MY (INAUDIBLE) (INAUDIBLE) AROUND THE WORLD, THAT I AGREE WITH THAT IDEA, RIGHT? SO WE HAVE A CLINICAL TRIAL NETWORK BIOMARKER ACLOSE MULTIPLE SITES. THE (INAUDIBLE) PROJECT IN EUROPE, HAS CLINICAL TRIAL NETWORK IMAGE BIOMARKER CORE ACROSS EUROPE, RIGHT? (INAUDIBLE) PROGRAM HAS SEVERAL SITES CLINICAL TRIALS BIOMARKER PRECEDENT SIGNALING RESPONSE. SO ACROSS MULTIPLE NETWORKS WE HAVE BEEN THINKING IN SIMILAR WAYS BUT WE HAVEN'T GOT THEM TOGETHER TO SAY IS THERE A BARE MINIMUM ARE THE BIOMARKERS CORE, WITH WE ALL HAVE A INTEREST BUT IS THERE -- OTHER CONSENSUS, NOT VACATION WITH DIFFERENT REGULATORY RESPONSIBILITIES AN FUNDING AGENCIES, WE'RE ALL GOING TO COLLECT AND ARE WE GOING -- IN FACT ALL OF US HAVE OBLIGATIONS PUBLIC DOMAIN SO YOU GUYS HAVE ONE, DIFFERENT PUBLIC DOMAIN OBLIGATION. WE IN THE PUBLIC DOMAIN WE ARE GOING TO COMBINE ACROSS DOING FROM THE BEGINNING I LIKE TO CONSTANTLY THINK ABOUT HOW WE COMBINE THIS DATA. >> WE HAVE HAD SEVERAL MEETINGS ABOUT THAT AND INITIATIVE WITH SIGH MOPS FOUNDATION AUTISM SPEAKS AN NIH IS LAUNCHING SO THAT WILL BE ORGANIZED BY THE FOUNDATION FOR NIH AND EU AIMS HAS BEEN AS PART OF THAT AS WELL. SO WE NEED TO GET THE CANADIAN PIECE TO BE PART OF THAT AS WELL. WE'D LOVE TO DO THAT BUT THERE'S A LOT OF MEETINGS AND CONVERSATION, ONE MIGHT ASK WHETHER THIS SHOULD BE SUCH A FORUM AND WHETHER THE IACC SHOULD BE THE PLACE TO DO THAT BUT IT HASN'T BEEN THE PLACE TO BRING THE SCIENCE TOGETHER IN THAT WAY. IT'S BEEN I THINK A LITTLE TOO POLARIZED FOR THAT. >> I WONDER IF WE'RE COMING UP WITH BEST PRACTICE GUIDELINES IF THAT COULD INCORPORATE SIMPLE STANDARD WORK UP TESTING THAT SHOULD BE DONE. AS PART OF THAT. >> I FEEL COMPELLED TO SAY THIS, WHICH IS I THINK ONE OF THE REASONS WHY IT'S BEEN SO DIFFICULT BESIDES HETEROGENEITY AND SO MANY AUTISMS, IS THIS FACT THIS IS A DEVELOPMENTAL AT THIS ORDER AND THAT'S SOMETHING WE HAVE TO KEEP IN MIND ESPECIALLY, I THINK I LOVE THE BIG DATA APPROACH AND THE BIOMARKER APPROACH IN RESPONSE TO TREATMENT. ULTIMATELY THAT HAS TO BE COMPLIMENTED WITH VERY -- STUDIES THAT UNDERSTAND DEVELOPMENT. AND WE BELIEVE NOT ONLY HUMAN DEVELOPMENTAL STUDIES BUT ALSO ANIMAL MODEL STUDIES BECAUSE A LOT OF THE ACTION AND INTERESTING THINGS THAT ARE BEING FOUND OUT NOW ABOUT HOW TOXINS EFFECT THE IMMUNE SYSTEM DURING FETAL CELL -- ALL OF THAT REALLY HAS IMMEDIATE IMPLICATIONS THAT IT COMES THROUGH ANIMAL STUDIES BECAUSE OF DEVELOPMENTAL DISORDERS. >> WE'RE COMING TO THE VERY END OF OUR MEETING, AND THE END OF THE CURRENT IACC. SO I WANT TO LEAVE ABOUT FIVE MINUTES FOR PEOPLE TO REFLECT IF THERE'S ANYTHING WE SHOULD TALK ABOUT FROM TODAY'S PROCEEDINGS. SUSAN AND HER TEAM WILL BE WORKING ON A MEETING SUMMARY THAT WILL BE SHARED SO YOU WILL HAVE A CHANCE TO SEE THAT. THIS IS A RICH DAY, SO THERE WILL BE A LOT TO DESCRIBE IN WHAT WE HAVE HEARD. LET ME OPEN UP TO OTHERS FOR THEIR COMMENTS. >> WE COULD HAVE DONE EVERYTHING WE DID -- WE COULD PROBABLY KEEP TALKING A LONG TIME SO I'LL BE QUICK, KEEP IT TO ONE THING, WE'RE STILL TALKING A LOT ABOUT GETTING THE TOOLS INTO THE HANDS OF PEDIATRICIANS SO THAT THEY CAN HELP THE CHILDREN. AND WE NEED TO CHANGE OUT INTO GETTING THE HANDS -- GETTING THE TOOLS INTO DOCTORS TO HELP ALL THE (INAUDIBLE) WE HAVE TO INCLUDE MORE -- WE LEARNED A LOT TODAY ABOUT -- FELT SPECIFIC AND ESPECIALLY THESE THINGS LIKE INCREASED PARKINSONS AND DEMENTIA. THOSE ARE EXACTLY THE KIND OF THINGS THAT FRANKLY SCARE THE HECK OUT OF ME AND I WOULD LIKE TO KNOW MORE ABOUT. AND KNOW THERE'S SOMETHING ON THE HORIZON I NEED TO KNOW ABOUT AND IF THERE'S A WAY TO INTERVENE WITH ADULTS. >> THIS IS REALLY EXCITING TO COMMENT, I GUESS WHAT I HEARD THE PUBLIC WANTS TREATMENT NOW AND WE SHOULD GO WITH THINGS THAT WE HAVE AND THEN POTENTIALLY COLLECT DATA SUCH THE BIOMARKERS AS WE'RE DOING THE TREATMENTS EVEN IF THEY'RE INCORRECT AND LOOK AT WHAT WE HAVE IN OUR BEST SHOT AND MOVE FORWARD. I ALSO HEARD TRY TO INCORPORATE THE AUTISM COMMUNITY AND THE PUBLIC IN PUTTING TOGETHER OUTCOMES MEASURES SO THEY FEEL LIKE THEY'RE WORKING HAND IN HAND WITH THE SCIENCE. THAT'S REALLY IMPORTANT AND IT IT BUILDS BRINGS SO THOSE ARE THE TWO MESSAGES THAT I CAME AWAY WITH. >> I AGREE, WE ALSO HEARD WHAT MATTHEW AND ANGELA HAVE SAID IS THE NEED FOR BETTER PRACTICE GUIDELINES AND THERE ISN'T A LOT OF EVIDENCE FOR MORE SPECIFIC TREATMENT AS THIS POINT. BUT AS WE CONTINUE TO GET MORE CLINICS TO USE THE BASICS WE KNOW ALREADY WORK A FAIR NUMBER OF KIDS WITH CONSTIPATION DO RESPOND TO TREATMENT, IT'S MORE DIFFICULT BECAUSE THEIR BEHAVIORS IN TERMS OF GETTING THEM TO TAKE THE MEDICATIONS AND LAXATIVES AND SO FORTH. WE'RE AT THE POINT NOW WE DON'T HAVE NECESSARILY NOVEL TREATMENT BUT THE MORE WE CAN TREAT WITH TREATMENTS THAT WE KNOW WORK YOU FIND THE ONES LEFT ARE THE TRUE RESISTANT CASES WHERE WE START GETTING INTO MORE SPECIFIC OR INNOVATIVE TREATMENTS. THE SAME IS TRUE WITH SLEEP. WE STILL FIND A NUMBER OF THESE KIDS WILL RESPOND TO BEHAVIORAL STRATEGIES THAT WORK IN TYPICALLY DEVELOPING KIDS AND WHERE WE HAVE IMPLEMENTED THAT AND EXHAUSTED THAT, THAT'S WHEN WE GET TO THE ONES WHERE THERE MUST BE SOMETHING ELSE GOING ON AND WE START LOOKING AT WHETHER IT'S SMT GENES AND ABNORMAL MELATONIN METABOLISM OR OTHER PROBLEMS THAT THEN ARE GOING TO REQUIRE DIFFERENT STRATEGIES AND THE INNOVATIVE STRATEGIES WE'RE WORKING ON. BUT RIGHT NOW AS LONG AS WE HAVE GOT REALLY THE KIDS WHO DON'T HAVE THAT PROBLEM MIXED IN BECAUSE THEY'RE NOT GETTING THE BASIC TREATMENTS, THEN WE REALLY MISS THEM AND THAT'S WHERE WE GET CONFUSED AS TO WHAT WORKS AND WHAT DOESN'T. PART IS KNOWING UP FRONT THEN YOU ARE RESISTANT AND MORE BIOMARKERS MORE GENETIC STUDIES UNFORTUNATELY ARE STILL PART OF THAT. ONE MESSAGE FROM TODAY IS WHAT DROVE US INTO THIS DAY IS THE FACT THAT SO MANY OF THESE PROBLEMS WHICH ARE IN FACT TREATABLE ARE UNDETECTED OR KNOW ONE EVEN IDENTIFIES THEM AS BEING SEPARATE FROM HAVING THE CORE OF AUTISM ITSELF SO THINKING ABOUT A WAY TO GET THAT MESSAGE OUT, I THOUGHT ZACK'S IDEA OF HAVING A LITTLE CARD THAT GOES OUT TO PARENTS IS WAY INCREASING MAYBE DRIVING A BIGGER CHANGE THAN ANYTHING WE TRY TO DO THROUGH THE MEDICAL SYSTEM. INTERESTING POINT. >> I THINK WE ALSO HAVE TO PAY ATTENTION TO TIME AND REIMBURSEMENT THAT'S ALLOWED FOR PRIMARY CARE DOCS TO REALLY LOOK AT THIS STUFF. AND THAT'S A HUGE BARRIER IN THEIR ABILITY TO PICK UP ON ANYTHING MUCH LESS -- >> TO THE CAPACITY, I HEARD THIS FROM SOMEBODY SITTING AROUND THE ROOM THAT AS A PEDIATRICIAN, IF YOU SEE THE PROBLEM AND YOU WANT TO REFER FOR GETTING A REALLY GOOD REFERRAL FOR GI PROBLEMS IN A KID WITH AUTISM, THERE'S NOT A LONG LIST OF PEOPLE TO REFER TO AND THEY ARE ALL VERY BUSY. THERE IS A CAPACITY PROBLEM AS WELL. HINSHU. >> I WANT TO THANK SUSAN AND STAFF FOR SETTING THIS UP. IT'S BEEN WONDERFUL TO SIT HERE ALL DAY AND LISTEN TO SOMETHING THAT IS REALLY WILL HELP ME IN PRACTICE. ONE THING THAT DAN MENTIONED THAT RESONATED WITH LACKING AT THE WHOLE CHILD WHOLE BODY APPROACH, NICE TO HEAR EVERYTHING ECHOING THAT. NUMBER TWO, DISSEMINATION OF INFORMATION (INAUDIBLE) FOLLOW UP ON THAT MR. HELP US IN IMMUNITIES. AND THE OTHER KEY COMPONENT THAT I HER WAS THE NEED TO SUBTYPE. DIFFERENT AUTISMS BECAUSE IN ANSWER TO ALLEY SOPS QUESTION, BECAUSE THAT HELPS DRIVE CUSTOMIZE THERAPY WHICH IS WHAT THE FAMILIES, I WANT THE COMMUNITY WANTS AND OF COURSE WE WANT TO KNOW ETIOLOGY, OF COURSE, BUT AS JOHN SAID BEING ADULT WITH AUTISM, THAT THIS POINT HE WANTS THE TREATMENT AND MOST ADULTS WITH AUTISM DON'T -- THEY NOT FOCUS ON WHY BUT REALLY ONE CAN HAVE A BETTER FUNCTION IN LIFE. THAT'S WHAT AS A PHYSICIAN AS A PARENT THAT IS EXACTLY WHY MY TO CUTS AND OUR FOCUS IS TO HELP DO THE BEST WE CAN TO HELP BETTER THE LIFE OF THE INDIVIDUAL WITH AUTISM. >> THANK YOU FOR THAT. I ALSO WANT TO ECHO A REALLY IMPORTANT COMMENT BAD BY ONE OF OUR PUBLIC COMMENTERS ABOUT IMPORTANCE OF PREVENTION. WE CAN'T DUCK THAT. IT'S TRUE WE HAVE TO DEAL WITH THE NEEDS OF PEOPLE TODAY BUT ALSO AT THE IACC YOU WANT TO BE THINKING 10, 20 YEARS OUT AND HOW WE BEND THE CURVE THE MAKE SURE THAT FEWER PEOPLE ARE GOING TO BE STRUGGLING WITH THE SAME ISSUES F. -- WE'RE AT THE CLOTHING HOUR AND I WANT TO SAY THIS HAS BEEN REALLY A TERRIFIC DAY OF DISCUSSION, LOTS OF INTERESTING IDEAS, GREAT SCIENCE, SOME ISSUES THAT WERE HERE AN NOW AS WELL AS ISSUES FOR MORE RESEARCH. THANKS TO ALL OF YOU WHO CAME FAR AND WIDE, ESPECIALLY EXPERTS WHO CAME IN. YOU'RE PART OF A REALLY IMPORTANT PROCESS GOING ON FOR MANY YEARS. THROUGH DEPARTMENT OF HEALTH AND HUMAN SERVICES AND OTHER FEDERAL AGENCIES, THE IACC. AND FOR THE IACC MEMBERS, MY GOODNESS, THANK YOU FOR YOUR PUBLIC SERVICE. WHICH WILL TERMINATE, HOPEFULLY MANY WILL BE BACK THE NEXT ROUND OF THIS COMMITTEE, THAT'S UP TO THE SECRETARY. EXCEPT FOR THOSE WHO ARE FEDERAL MEMBERS, THAT'S UP TO ME. SO YOU'RE THE RUN ONES WHO ARE LIKELY TO GET CALLED. IT'S BEEN GREAT EXPERIENCE TO SERVE WITH ALL OF YOU AND EVEN IF WE'RE NOT WORKING TOGETHER ON THE COMMITTEE I HOPE WE WILL BE INTERACTING AGAIN IF THE KNEWTURE SO I WANTED TO THANK YOU DEEPLY ON BEHALF OF THOSE OF US IN FEDERAL SERVICE YOU BECAME WHAT ARE CALLED TEMPORARY GOVERNMENT EMPLOYEES FOR THE DAYS THAT YOU WERE HERE AND IT'S BEEN GREAT TO HAVE YOUR DEDICATION AND YOUR COMPASSION AND YOUR SMARTS, WHICH MADE ALL OF US FEEL REALLY WELL. SO WE ARE ADJOURNED. THANK YOU.