>> WELCOME TO THE SECOND DAY OF OUR CLINICAL TRIALS DOWN SYNDROM FOR THE CONDITIONS ACROSS THE LIFE SPAN WORKSHOP TODAY WE ARE ACTUALLY GOING TO START OFF WITH A SESSION THAT'S GOING TO GO OVER THE INCLUDE FUNDED PROJECTS FOR 2019 FOR CLINICAL TRIAL READINESS AND CLINICAL TRIAL DEVELOPMENT SO THE WAY THIS IS GOING TO WORK IS I'M GOING TO INTRODUCE THE EACH PRESENTATION WILL BE ABOUT FIVE MINUTES LONG THEN WE'LL MOVE TO THE NEXT SPEAKER. WITH I'LL START WITH THE R21. READINESS. THEN WE'LL GO INTO THE R61, R33 CLINICAL TRIALS DEVELOPMENT GRANTS. SO I WOULD LIKE TO START BY INTRODUCING VOLNEY SHEEN. TAKE IT AWAY. >> CAN YOU HEAR ME? >> YES WE CAN. >> SO I WANT TO THANK NIH AGAIN FOR SETTING UP THIS WORK SHOT, THE TALKS YESTERDAY WERE QUITE INFORMATIVE, JUST KIND OF REITERATED TO ME THAT THE COMPLEXITY OF THIS DISORDER. ALSO WANT TO THANK ERICA FOR SETTING UP ALL THE GROUND WORK THAT'S BEEN NECESSARY TO GET THIS TO ACTUALLY WORK. MY LAB HAS BEEN WORKING ON DOWN SYNDROME FOR OVER 10 YEARS, WE INITIALLY HAD TAKEN A APPROACH OF LOOKING AT NEURAL STEM CELLS AND DOWN SYNDROME NEURAL STEM CELLS TO UNDERSTAND PATH LOGICAL MECHANISMS AND WE HAVE DONE MULTIPLE STUDIES AT TRANSCRIPTIONAL PROFILING METHYLATION PROFILING AND WHAT DAWNED ON US WAS THERE ARE ENUMERABLE PATHWAYS DISRUPTED. I REALIZE FROM THE TALKS YESTERDAY THERE'S COMMON THEMES ONE SEES IN DOWN SYNDROME IN TERMS OF NEUROLOGICALLY IN TERMS OF THE CELLS HAVING ISSUES WITH OX DAYTIVE STRESS OR CELL DEATH OR DIFFERENTIATION ISSUES BUT TO ME THERE WAS ALWAYS THE ISSUE OF WHICH PATHWAYS WERE THE MOTH RELEVANT AND HOW ONE COULD DETERMINE THE RELEVANT PATHWAYS TO TRY TO TARGET. THERE WASN'T AN EASY SOLUTION FOR ME. SO THERE WAS AN ENLIGHTNING PAPER PUBLISHED BACK IN 2013 BY JENNIE LAWRENCE AND NATURE WHERE SHE USED A NON-CODING RNA SOMETHING CALLED EXIST, EXIST IS FOUND BIOLOGICALLY USED FOR MAYBE FAMILIAR WITH ACTIVATION SO IN FEMALES THERE'S TWO X COPIES EXIST WILL BE ACTIVATED AT SOME POINT AND SHUT OFF ONE X CHROMOSOME. THEN VERY ELEGANT STUDIES HE WAS ABLE TO SHOW WHEN ONE IS ABLE TO INSERT EXIST INTO ONE COPY OF THE CHROMOSOME OF DOWN SYNDROME CHROMOSOME COPY, YOU ARE ABLE TO SHUT OFF THAT ONE COPY. THIS WAS A PROOF OF CONCEPT MEANING THERE CLEARLY TWO TECHNICAL ISSUES TO MAKE THIS TRANSLATIONALLY FEASIBLE MEANING THE ABILITY TO INSERT COPY OF ANY KIND OF GENETIC MATERIAL IS VERY DIFFICULT AND IT OCCURS VERY LOW EFFICIENCY. A LOT OF YOU HEARD ABOUT CHRIS PER CAS 9 AND POTENTIAL PROMISE FOR THIS BUT EVEN WITH USE OF CHRIS PER CAS 9 THE EFFICIENCY OF MOLECULE DIRECTED REPAIR IS TYPICALLY ON THE ORDER OF 1% OR LESS. THE SECOND HURDLE WE THOUGHT WAS PREVENTED FROM USING TRANSLATIONAL ASPECT IS HOW IS ONE ABLE TO TARGET ONE OF THREE HSA 28 COPIES. IN THAT PARTICULAR PAPER THEY BASICALLY SCREENED THROUGH THOUSANDS AND THOUSANDS OF CELLS TO FIND ONE WHICH HAPPENED TO HAVE THE EXIST INSERTED INTO THE APPROPRIATE LOCATION THEY WANTED AND AGAIN WAS -- WE ARE ABLE TO SHOW THAT IT DID INDEED LEAD TO SILENCING. TO UNDERSTAND THE EXPERIMENTS THAT I'M GOING TO GO THROUGH WITH YOU IN THE NEXT SEVERAL SLIDES YOU HAVE TO UNDERSTAND A LITTLE BIT ABOUT CHRIS PER CAS 9 AN ENDONUCLEASE SO IT CUTS DOUBLE STRANDED DNA, ITS REQUIREMENT IS FOR A PAN SIDE WHICH IS A LITTLE MOTIF, SPACER MOTIF WITH NGG SEQUENCE AND THEN YOU NEED A GUIDE RNA. SO WITH THE GUIDE RNA AND THE PAM SIDE YOU ARE ABLE TO CUT THE DNA. SO WHAT KIND OF APPROACH DID WE USE? WE HAVE BEEN WORKING ON A MODIFIED CHRIS PER APPROACH, THE MODEL IS TRYING TO INSERT GFP INTO 293 CELLS, INSERTION WITH FIVE PRIME ARM AND THREE PRIME ARM TO DIRECT HOMOLOGY DIRECTED REPAIR. WE MADE FOUR MODIFICATIONS AT THIS POINT. WE USED TWO GUIDE RNAs OF SINGLE GUIDE RNA TO CREATE THE TWO DOUBLE STRAND BREAKS. THE IDEA BEHIND THAT IS TO PREVENT DELAY TO ALLOW THE MOLECULE TO REPAIR. THEN WE USED A EXONUCLEASE FUSED TO CAS 9 WHICH IS AN ENDONUCLEASE. WHY USE THE EXOMU CREATION? YOU CAN SEE MY HAIR -- EXONUCLEASE? IT WILL START TO CUT THE ENDS OF THE DNA SO YOU CAN GET OVERHANG AND WE KNOW FROM USE OF SINGLE OLIGONUCLEOTIDES, YOU CAN GET HIGH EFFICIENCY DIRECTED REPAIR WITH SINGLE STRAND. SO THE IDEA BEHIND HERE IS USE EXONUCLEASE TO CREATES OVERHANGS THAT MIMIC A SINGLE STRAND OLIGONUCLEOTIDE TO ENHANCE HOMOLOGY DIRECTED REPAIR. WE THEN MODIFY EXONUCLEASE IN THE SENSE THEY ARE OFTEN SEEN IN PROKARYOTIC CELLS SO THEY ARE SEQUENCES ARE A LITTLE DIFFERENT, WE MODIFY THE SEQUENCES TO ENHANCE EXPRESSION IN EUKARYOTIC CELLS THEN A FOURTH MODIFICATION, WE INTRODUCED TWO ADDITIONAL GUIDE RNAs NOT DIRECTED TOWARD THE GENOMIC DNA WE ARE GOING TO CUT BUT RATHER THE DONOR SIDES SO THAT THE DONOR ARMS SPECIFICALLY MATCH UP TO THE REGIONS THAT WE WANTED TO INTEGRATE INTO THE GENOMIC SIDE. SO THIS IS THE PARADIGM WE ARE USING IN FIGURE A AND FIGURE B WHAT I'M TRYING TO SHOW YOU HERE BY WESTERN BLOT IS WE FUSE THE CAS 9 WITH MX, IT IS A LITTLE LARGER THAN THE TYPICAL CAS 9 AND THE EXPRESSION INCREASES WHEN WE -- FROM THE EXO TO MODIFIED EXO WHICH IS EXPECTED IN THE SENSE WE ARE MODIFYING THE SEQUENCE TO ENHANCE TRANSLATION. SO THIS IS JUST TO SHOW THAT IT CAN STILL BE EXPRESSED IN THE APPROPRIATE CONSTRUCTS AND THAT THE MODIFIED EXO INCREASES EXPRESSION. IN FIGURE C THIS IS AGAIN WESTERN BLOT TO SHOW WHEN WE TRANSFECT IN THE MODIFIED EXO PX 459 CONSTRUCT WITH SINGLE GUIDED RNA, WE CAN CAUSE DOUBLE STRAND EXPRESSION OF APP. YOU CAN SEE HERE OBVIOUSLY DIFFERENT GUIDE RNAs LEAD TO DIFFERENT EFFICIENCIES OF KNOCK DOWN THIS IS MORE OR LESS TO SHOW WITH MX YOU CAN KNOCK DOWN APP EXPRESSION WHICH SUGGESTS THAT YOU HAVE HAD A DOUBLE STRAND BREAK, CAUSED LOCALIZED DELETION, THAT FUSION OF MXO TO CAS 9 DOESN'T DISRUPT THE CAS 9 FUNCTION. IN FIGURE D, WE WENT FROM ONE GUIDE RNA TO A DUAL GUIDE RNA AND THIS IS TO SHOW YOU IN CERTAIN PAIRS OF GUIDE RNAS WE ARE ABLE TO INCREASE EFFICIENCY OF KNOCK DOWN AT THE APP SITE, THESE ARE WESTERN BLOTS FOR APP LOOKING AT EXPRESSION LEVELS SO WHAT YOU SEE HERE IN THE GREATEST DEGREE OF KNOCK DOWN USING THE APPROACH THAT -- THE DUAL GUIDE RNA THAT ACHIEVE IN LANE TWO USING TWO GUIDE RNAs ONE AND THREE, AND THEN LANE 5 WHICH IS WITH OUR MXO AND THE MODIFIED EXO FUSED TO THE CAS 9 AND TWO GUIDE RNAs, YOU ALSO SEE THAT DIFFERENT TYPES OF EXO NUCLEASES CAN LEAD TO KNOCK DOWN BUT IN THESE P 5 EXONUCLEASE WE INCREASE CELL DEATH SO WE SCREEN SEVERAL TYPES OF NUCLEASES TO IDENTIFY THE ONESES THAT HAVE THE LEAST NEGATIVE SIDE EFFECTS TO THE TARGETED CELLS AND ACHIEVE APPROPRIATE KNOCK DOWN. IN FIGURE E, WESTERN BLOT, SO FROM THESE WESTERN BLOTS WHICH ARE WHOLE ENUMERABLE LARGE VOLUMES OF CELLS, AND SCREENING THAT WAY WE HAVE TAKEN CLONES FROM THESE INDIVIDUAL CELLS, AND WHAT YOU CAN SEE IS THAT THIS IS JUST A REPRESENTATIVE EXAMPLE OF SEVERAL CLONE C 1, WHAT NOT, THERE'S LOSS OF EXPRESSION IN APP IN THESE INDIVIDUAL -- THERE'S A HIGH EFFICIENCY LOSS WITH THE APPROACH THAT WE HAVE TAKEN. SO THIS IS NOT SURPRISING IN THE SENSE THAT CHRIS PER CAS 9 SHOULD LEAD TO HIGH EFFICIENCY KNOCK DOWN ANYWAY, AND BUT THIS WAS MERELY TO SHOW THAT THE LOSS OF -- THAT THE IMPLEMENTATION OF THE MXO WOULD NOT AFFECT THIS PROCESS. NOW IN -- >> THIS IS LAURIE. WE NEED TO HAVE YOU WRAP UP YOUR LAST SLIDE SO WE CAN STAY ON TIME. >> SORRY ABOUT THAT. THIS IS THE MONEY SHOT IN SOME WAYS WITH THE PX 459 AND MXO WHAT YOU CAN SEE WITH THE MXO IS THAT EVEN WITH THE SINGLE GUIDE RNA WE START TO INCORPORATE GFP INTO A GENOMIC SIDE ALSO WITH SG RNA 3 AND WHEN WE INCORPORATE THE FOUR NUCLEOTIDE WITH DONOR SITE AS WELL WE GET EVEN HIGHER EXPRESSION. WE CAN DO THESE CLONALLY AND SHOW WE CAN GET A 30% INCORPORATION WHICH IS VERY VERY HIGH, THIS POTENTIALLY WILL HAVE TRANSLATIONAL FEASIBILITY, DEEP SEQUENCING TO SHOW THERE'S NOT INCRUISE MUTAGENESIS. LASTLY SINGLE TARGET COPY, ESSENTIALLY BECAUSE DOWN SYNDROME IS PRIMARILY DUE TO MYOSIS ON THIS JUNCTION ISSUE THE PAM SITES ARE DIFFERENT, SNPS ARE DIFFERENT SO WE CAN TARGET TAM PAM SITES DIFFERENTLY THIS IS TO SHOW YOU KNOCK DOWN AND THAT WE CAN GET AGAIN INCORPORATION OF EXIST INTO THESE CELLS AT HIGH EFFICIENCY. WE ARE REALLY EXCITED AT THIS POINT IN OUR TESTING LARGER CONSTRUCTS, AND IPS CELLS. THANK YOU. AGAIN THIS IS FUNDED THROUGH INCLUDE. >> THANK YOU. OUR NEXT SPEAKER IS NANCY RAITANO LEE. CAN YOU HEAR ME? >> YES. >> GREAT, LET ME PULL UP MY SLIDES. ARE YOU ABLE TO SEE MY SLIDES? >> YES. >> THANK YOU SO MUCH FOR HAVING ME, I'M PLEASED TO PRESENT ON BEHALF OF OUR TEAM, AND OUR STUDY THAT AIMS TO CHARACTERIZE EXECUTIVE FUNCTIN AND PREFRONTAL CORTICAL FUNCTION AND YOUTH WITH DOWN SYNDROME WITH VARYING DEGREES OF SLEEP DISTURBANCE. SO AS HIGHLIGHTED YESTERDAY, THE INCREASE OF CLINICAL TRIALS TO TREAT COGNITION TO DOWN SYNDROME AS WELL AS THOSE TARGETING SLEEP DIFFICULTIES A COMMON CO-MORBIDITY NECESSITATES DEVELOPMENT AND EVALUATION OF NEUROCOGNITIVE TESTS AND BIOMARKERS TO MEASURE TREATMENT OUTCOMES. FOR CLINICAL TRIALS TARGETING COGNITION AND SLEEP IN DOWN SYNDROME NEUROCOGNITIVE TEST AND BIOMARKERS MUST NOT ONLY BE SENSITIVE TO EFFECT OF DOWN SYNDROME BUT TO EFFECT OF SLEEP AS WELL AS CHANGES THAT RESULT FROM DIFFERENT INTERVENTIONS. IN MANY ADDITION THESE TESTS AND BIOMARKERS MUST BE VALIDLY RELIABLY MEASURED IN INDIVIDUALS WITH DOWN SYNDROME WITH RANGE OF MOBILITY LEVELS AND RANGE OF AGES. WE FOCUS ON MEASUREMENT OF EXECUTIVE FUNCTION AND CONCOMITANT PREFRONTAL FUNCTION FOR THE CURRENT STUDY, THIS WAS BASED ON OUR PRIOR RESEARCH, THE DOCUMENT IS SIGNIFICANT WEAKNESSES IN SEVERAL ASPECTS OF EXECUTIVE FUNCTION ALONGSIDE ATYPICAL PRE-PROBLEM TALL CORTICAL ANATOMY IN DOWN SYNDROME. IN ADDITION OUR TEAM WORK HIGHLIGHTED EXECUTIVE FUNCTION CHALLENGES AND REDUCTIONS IN PREFRONTAL CORTICAL VOLUME ARE GREATER AND YOUNG PEOPLE WITH DOWN SYNDROME AND CO-MORBID SLEEP DISTURBANCE, THUS MAKING THEM POSSIBLE TREATMENT TARGETS FOR CLINICAL TRIALS FOR BOTH SLEEP AND COGNITION IN DOWN SYNDROME. OUR PRIOR RESEARCH ON BRAIN DEVELOPMENT IN MANY DOWN SYNDROME WAS CHARACTERIZED BY SEVERAL LIMITATIONS THAT OUR CURRENT STUDY SEEKS TO ADDRESS. FIRST MANY CHILDREN WHO PARTICIPATED IN OUR STRUCTURAL NEUROIMAGING STUDY FROM 2016 ESPECIALLY THOSE WHO WERE YOUNGER, WERE NOT ABLE TO COMPLETE MRI PROCEDURES LIMITING THE GENERALIZABILITY OF THE FINDINGS. SECOND, OUR PRELIMINARY STUDY OF EFFECT OF SLEEP DISTURBANCE ON BRAIN AND DOWN SYNDROME RELIED UPON PARENT REPORT OF SLEEP DIFFICULTIES RATHER THAN OBJECTIVELY AND CONTINUOUSLY MEASURING SLEEP. THIRD OUR PRIOR RESEARCH DID NOT EXAMINE THE NEUROCORRELATES OF EXECUTIVE FUNCTION IN DOWN SYNDROME IN VIVO USING FUNCTIONAL IMAGING. THUS THE CURRENT RESEARCH SEEKS TO ADDRESS THESE LIMITATIONS. IN ONE SEEKS TO TEST FEASIBILITY OF USING A CHILD FRIENDLY NEUROIMAGING MODALITY, MAINLY FUNCTIONAL INFRARED SPECTROSCOPY WITH SAMPLE OF SIX TO 66 LEADER CHILDREN WITH DOWN SYNDROME AND TYPICALLY DEVELOPING CONTROLS. AIM 2 SEEKS TO EVALUATE EFFECTS OF DOWN SYNDROME AND SLEEP DISTURBANCE MEASURED USING ACTTY >> FEW ON PREFRONTAL NEUROEFFICIENCY DURING COMPLETION OF PSYCHO METRICALLY SOUND EXECUTIVE FUNCTION TEST BATTERY, PART OF DR. ARIZONA MEASUREMENT FOR PRE-SCHOOLERS IN SPECIAL POPULATIONS. WITH REGARD TO OUR PROGRESS TO DATE, WE WORKED WITH THE PROGRAMMER TO SYNCHRONIZE OUR iPAD BASED A MAP DATA COLLECTION WITH OUR F NEARS DATA COLLECTION. WE DEVISED A PROCEDURE TO CONSENT FREEIA PHONE TO PERMIT PREE VISIT COLLECTION AS WELL AS COLLECT QUESTIONNAIRE DATA VIA RED CAP TO REDUCE THE LIKELIHOOD OF MISSING DATA. WE COMPLETE STAFF TRAINING ON TASK ADMINISTRATION AND DATA COLLECTION, ONE OF THE THINGS WE SPENT TIME ON WAS TROUBLESHOOTING A WAY TO BRING F NEARS TO FAMILIES, WE DIDN'T WANT TO REDUCE EXPERIMENTAL CONTROL ASSOCIATED WITH COLLECTING DATA IN THE LAB SO WE ARE USING A MOBILE DATA COLLECTION BAND WE HAVE ACCESS TO AT DREXEL TO COLLECT F NEARS DATA CLOSE TO FAMILY HOMES WE ALSO KEYIATED A VIDEO -- CREATE AD VIDEO ABOUT THE STUDY PROCEDURES, WE THOUGHT THAT PARENTS MIGHT BE LESS FAMILIAR WITH F NEARS AS TECHNOLOGY SO WE WANTED TO SHOW THEM WHAT WAS INVOLVED AND HOW SIMPLE AND CHILD FRIENDLY IT IS. HERE IS PART OF THAT VIDEO, A VERY BRIEF CLIP THAT GIVES AN OVERVIEW WHAT IS INVOLVED WITH THE STUDY. THEN INTRODUCTION TO THE DEVICE. PUTTING ON THE DEVICE. HUE SIMPLE IT REALLY IS. -- HOW SIMPLE IT REALLY IS. AND THEN A CLIP OF THE TASK. SO WEARING THE BAND. WE DEVELOP MATERIALS TO PREPARE CHILDREN FOR F NEARS DATA COLLECTION SUCH AS CREATION OF PRACTICE OF F NEARS BANDS THAT CAN BE QUITE FUN, THAT WE PLAN TO SEND OUT TO CHILDREN IN ADVANCE OF THE VISIT SO THEY CAN PRACTICE WEARING THEM DURING TIME AT HOME. SO IN CLOSING OUR TEAM IS REALLY EXCITED ABOUT THE CURRENT STUDY POTENTIAL TO ADVANCE UNDERSTANDING OF NEURAL CORRELATES OF POOR SLEEP AND EXECUTIVE DYSFUNCTION IN DOWN SYNDROME IN PREP OPERATION FOR CLINICAL TRIALS RESEARCH. THE TEAM SCIENCE GREATLY BENEFITED FROM THE COMPLIMENTARY EXPERTISE OF THE INVESTIGATIVE TEAM MEMBERS. I ANTICIPATE OUR FUTURE RESEARCH WILL BENEFIT FROM A TEAM SCIENCE APPROACH. FOR EXAMPLE ONE POSSIBLE AVENUE IS JOIN FORCES WITH MEDICAL PROFESSIONALS TO EXAMINE PRE-PROBLEM TALL CORTICAL FUNCTION IN CHILDREN WITHIN THE CONTEXT OF A CLINICAL TRIAL TARGETING SLEEP APNEA. IT IS HOPE THE INCLUSION OF VALID BIOMARKER OF CORTICAL FUNCTION MAY SERVE AS INTERMEDIATE OUTCOME AND MAYBE SENSITIVE TO TREATMENT EFFECTS SOONER THAN COMMONLY USED BEHAVIORAL MEASURES. I WOULD LIKE TO END BY THANK YOUING YOU FOR YOUR ATTENTION AND OUR FUNDER, NICHD. >> THANK YOU NANCY, OUR NEXT SPEAKER IS IGNACIO TAPIA. >> HOW ARE YOU YOU? I'M GOING TO LOAD MY SLIDES. OUR PROJECT IS PERFORMANCE OF USED IN DOWN SYNDROME. >> IGNACIO, CAN YOU DO THE SLIDE SHOW -- (OFF MIC) >> CAN YOU JUST MAKE IT PRODUCE SLIDES? THERE WE GO. THANK YOU. MULTIPLE PET PROJECT PI, THE BACKGROUND AS WE -- WORKSHOP OSA COMMON IN CHILDREN AND ADULTS WITH DOWN SYNDROME, ALSO THERE'S SIGNIFICANT INSTRUCTIVE SLEEP APNEA -- WHICH IS PREFERRED TREATMENT, THAT'S VERY COMMON. QUALITY OF LIFE AND BEHAVIOR STILL IS NOT FULLY KNOWN. THE MAJOR CHALLENGE FOR THE DIAGNOSIS (INAUDIBLE) DIAGNOSIS. THIS CAN (INAUDIBLE) EXPENSIVE AND IS NOT ALWAYS -- MORE IMPORTANTLY IS NOT AVAILABLE ALL OVER THE UNITED STATES. ONLY SOME CENTERS HAVE PEDIATRIC SLEEP CENTERS. THEREFORE WE PLAN THIS RESEARCH WITH THE AIM ONE TO DESCRIBE FAMILY REPORTED PERCEPTION AND EXPERIENCE, AND FEASIBILITY OF (INAUDIBLE) TESTING. TWO IS TO EVALUATE DIAGNOSTICS OF HOME SLEEP APPROXIMATE PEEIA DIAGNOSIS -- INSTRUCTIVE SLEEP APNEA. WE DECIDEDDED TO CONCEPT TRAIT IN MODERATE TO SEVERE BECAUSE THIS MAYBE THE PORTION OF THE POPULATION THAT MAY NEED URGENT TREATMENT VERSUS MILD. THE N 2A ISEST MA IT SENSITIVITY OF H SAT FOR DIAGNOSING MODERATE TO SEVERE (INAUDIBLE) VERSUS SO SONOGRAPHY WITH (INAUDIBLE) INCLUDING AGE FOR EXAMPLE, MEDICAL CO-MORBIDITYIES, BEHAVIORAL PSYCHIATRIC DIAGNOSIS AND FAMILY FUNCTION. EXPLORATORY AIM RELATIONSHIP WITH OSA QUALITY OF LIFE. PARTICIPANTS AGE 10 TO 20 YEARS OLD THAT WILL HAVE BOTH (INAUDIBLE) AND ORDERS AND ALSO WILL FILL OUT QUESTIONNAIRE WILL FILL OUT MOST OF THEM (INAUDIBLE) QUESTIONNAIRE TO SEE THEM OR AUTHORITATIVE. QUESTIONNAIRES WHICH IS A QUESTIONNAIRE SPECIFIC FOR OSA. THIS IS THE DATABASE WE HAVE DEVELOPED SO YOU CAN SEE HERE (INDISCERNIBLE) WHETHER NASAL CANOLA WITH DIFFERENT OPTIONS FROM ONE TO FIVE, EXPERIENCE ANYTHING ABOUT SLEEPING ARRANGEMENTS AND ANYTHING ELSE THEY WOULD LIKE TO SHARE. ALSO (INDISCERNIBLE) WE ASK SPECIFIC (INDISCERNIBLE) TO ASK -- (INDISCERNIBLE) SO THEY CAN SELECT HOW WAS THAT THEY HAD WITH THE DEVICE. THIS REGARDS FEASIBILITY. IN ORDER OF SETTING UP THE DEVICE WE DEVELOP -- THAT I WANT TO SHOW YOU VERY, VERY LIKE A MINUTE OR IT SO LET ME TRY TO DO IT AGAIN. IF I HAVE TROUBLE I WILL CONTINUE WITH THE SLIDE SHOW. WE ALSO DEVELOP SOCIAL HISTORY TO EXPLAIN TO THE CHILDREN WHAT WOULD HAPPEN, WE LEARN YESTERDAY A LITTLE BIT ABOUT SOCIAL HISTORY AND HERE, WHICH WOULD BE THE NUMBER ONE AGE HISTORY, WE ARE GOING TO PUT THE PATIENT'S NAME HERE, EXPLAIN TO THEM HOW IT'S GOING TO HAPPEN WITH THIS SLEEP TESTENING THE HOSPITAL, WHAT THEY WILL ENCOUNTER THE HOSPITAL, THIS IS ALSO EXPLAINING THE VIDEO. THE PERSONNEL WE MEET HERE WITH THE DIFFERENT PICTURES THAT WILL CHANGE, (INDISCERNIBLE) SUGGEST THEY CAN WORK FOR EXAMPLE, HOW THIS DATA WILL BE -- THE MATERIAL WILL BE USED, THE LEADS HOW THEY WILL BE PLACED, AND BASICALLY STICKERS AND ALL THAT TYPE OF THING SO THEY ARE NOT SCARED WHEN THEY GO TO THE HOSPITAL. THIS IS A FAMILY BE DOWN SYNDROME OFFERED TO PARTICIPATE TO HELP US IN THIS STUDY. SO THIS IS THE SLIDES, I WANT TO E SHOW YOU BRIEFLY THE VIDEO SO LET ME TELL -- I WILL NOT SHOW IT ALL SO DON'T WORRY ABOUT THAT. LET ME GO BACK TO -- CAN I HAVE (INAUDIBLE) AGAIN? >> SORRY, GO AHEAD. I THINK YOU'RE NOTE SHARING YOUR FULL SCREEN OR IT MAYBE THAT IT'S BLOCKED. MAYBE IN THE INTEREST OF TIME WE CAN GO TO THE NEXT SPEAKER. >> OKAY, THAT'S FINE. >> YES. THANK YOU. THAT WAS EXCELLENT. >> SORRY, WE HAD A LITTLE DUALING MIKES SO OUR NEXT SPEAKER IS DEBRA FIDLER. DEBORAH FIDLER, I'M SORRY, NEXT SPEAKER IS EMILY DEBOER. I SKIPPED DOWN ON THE AGENDA THERE. >> NO WORRIES. THANKS LAURIE. I HAVE TO SAY THANKS FOR THE SUPPORT AND FOR INVITING US, IT'S BEEN REALLY VALUABLE FOR THOSE OF US, I SPEAK FOR OTHERS WHO ARE NEW TO THE COMMUNITY TO BE INVOLVED IN HERE'S SPECIALLY THE PANEL YESTERDAY. OUR RESEARCH IS PULMONARY MEASURES OF HEALTH IN CHILDREN WITH DOWN SYNDROME, AS DR. YEAR AGOER MENTIONED YESTERDAY MORNING LUNG DISEASE IS OVERLOOKED IN CHILDREN WITH DOWN SYNDROME AND THIS IS THE WAY I SUMMARIZE THE GREAT TALKS YESTERDAY MORNING. PNEUMONIA IS THE MOST COMMON CAUSE OF DEATH IN DOWN SYNDROME, IT IS REALLY A COMBINATION OF CO-MORBIDITIES THAT AFFECT PULMONARY HEALTH. WE INCLUDE THEM AS THE ARCs. SO MULTI-LEVEL AIRWAY OBSTRUCTION, WHICH CONTRIBUTES TO OBSTRUCTIVE SLEEP APNEA AND ASPIRATION. WE KNOW AUTO-IMMUNITY AND ABNORMAL INFLAMMATION CONTRIBUTE& AS WELL AS ALVEOLAR SUFFOCATION, LUNG HYPOPLASIA AND PULMONARY ARTERIAL HYPERTENSION. WE KNOW FROM LARGE STUDIES IN ASTHMA LUNG FUNCTION INCREASES THROUGHOUT CHILDHOOD AND THEN IT'S REALLY ALL DOWNHILL. SO LUNGS HEALTH OR LUNG DISEASE IN CHILDHOOD REFLECTS LUNG STATUS IN ADULTHOOD. BUT AGAIN, A THEME WE HEARD IS THAT OUTCOME MEASURES ARE NEEDED AND OUR PROBLEM IS THAT FORCED LUNG FUNCTION MANEUVERS ARE THE MOST ACCEPTED GOLD STANDARD OUTCOME IN PULMONARY FOCUSED CLINICAL TRIALS LIKE IN COPD AND ASTHMA. BUT THERE'S INCREASING EVIDENCE& THIS MAY NOT BE FEASIBLE IN PEOPLE WITH DOWN SYNDROME. SO OUR LONG TERM GOALS ARE TO IMPROVE PULMONARY HEALTH OF CHILDREN WITH DOWN SYNDROME AND FIND MARKs THAT APPROPRIATELY ASSESS PULMONARY HEALTH THAT WE CAN FOLLOW. OUR SHORT TERM GOAL IS O IDENTIFY ACCURATE FEASIBILITY MEASURES OF LUNG FUNCTION AIRWAY INFLAMMATION, TO ENABLE READINESS FOR RIGOROUS PULMONARY FOCUSED CLINICAL TRIALS IN CHILDREN BE DOWN SYNDROME. OUR HYPOTHESIS IS THAT OR ROW PHARYNGEAL ASPIRATION CAUSES MEASURABLE CHANGES IN LUNG FUNCTION INFLAMMATORY MARKERS AND CAREGIVER REPORTED OUTCOMES THAT ARE DISTINCT FROM ASTHMA. SO THESE ARE OUR AIMES. AIM ONE, DETERMINE EFFECT OF ASPIRATION ON LUNG FUNCTION IN CHILDREN WITH DOWN SYNDROME AND OUR PRIMARY OUTCOME IS FORCED OSCILLATION. THIS IS A PICTURE OF ONE OF OUR PARTICIPANTS. SHE HAS HER MOUTH ON THE MOUTHPIECE, HER HANDS ON HER CHEEKS, SHE'S WEARING THE NOSE CLIP AND SHE DOES PASSIVE BREATHING MA NEUROS. ONE BENEFIT IS -- MANEUVERS. FORCED OUTPUT IS NOT AEROSOL GENERATE WIG IS IMPORTANT DURING THE PANDEMIC AND SPIROMETRY IS AEROSOL GENERATING AND ALL OUR LUNG FUNCTION LABS ARE CLOSED OR JUST BECOMING TO OPEN. -- BEGINNING TO OPEN. FORCED OSCILLATION HAS BENEFITS, IT MEASURES LUNG RESISTANCE AND LUNG REACTANTS WHICH IS A MEASURE OF LUNG STIFFNESS. WE ARE ALSO DOING SPIROMETRY WITH OUR PATIENTS AND A SIX MINUTE WALK TEST, TO LOOK AT LUNG FUNCTION. AIM TWO IS TO ESTIMATE THE EFFECT OF ASPIRATION ON INFLAMMATORY MARKERS BOTH BLOOD BIOMARKERS, NASAL NITRIC OXIDE AND EXHALED HIGH NITRIC OXIDE, MEASURES OF LUNG INFLAMMATION SPECIFICALLY. THEN AIM THREE, DETERMINE AFFECT OF ASPIRATION ON CAREGIVER REPORTED RESPIRATORY SYMPTOMS AND QUALITY OF LIFE. SO I'M SO GLAD TO SEE EVERYONE'S VIDEOS AND PROGRESS CHARTS, WE HAVE OUR RED CAP ALREADY, WE PLAP TO START IN MARCH. OUR GOAL IS 75 SUBJECTS, 40 COME BACK FOR REPEATED MEASURES, CHILDREN 3 TO 18 YEARS OF AGE, SO WE ARE CURRENTLY ON HOLD. BUT THIS IS PILOT DATA FROM WHO LOOKED AT SPIROMETRY AND FORCED OSCILLATION AND THIS IS THE BAR CHART SHOWS BLUE IS SUCCESSFUL FORCED OSCILLATION MEASURES AND GREEN IS SUCCESSFUL SPIROMETRY MEASURES IN THREE AGE GROUPS. THE NUMBER, PERCENT SUCCESSFUL SO 76% OF KIDS, 34 PILOT STUDY WERE SUCCESSFUL COMPLETING FORCED OSCILLATION, NOW WITH THE NEW EUROPEAN RESPIRATORY GUIDELINES THAT ARE MORE LAX THAT FORCED OSCILLATION RESULTS WILL BE ACCEPTABLE IN MORE LIKE 85% OF OUR KIDS SO LOOKING REALLY PROMISING. WE FOUND NORMAL RESISTANCE IN THIS GROUP, BUT LOW REACTANTS 62% SO LUNGS WERE STIFFER. AND POSITIVE BRONCO DILATED RESPONSE IN 62% AS WELL. SO WE ARE EXCITED TO SHOW YOU MORE DATA AS WE GET THE STUDY UNDERWAY. BUT REALLY AS YOU CAN SEE WE ARE FOCUSED ON OUTCOME MEASURES, WE ARE WORKING ON WE HAVE BEEN WORKING ON MODIFYING OUR PROCEDURES AND WE WILL CONTINUE TO EVALUATE THAT AS WE MOVE FORWARD. AND AS DR. KISHNANI MENTIONED YESTERDAY WE AREK LOOK AT THE WHOLE STUDY VISIT TO MAKE SURE ALL MANEUVERS GET GOOD RESULTS TO MAXIMIZE EVERYBODY'S TIME. HEN WE NEED TO DEVELOP CONSISTENCY SO HE CAN EXPAND TO MULTIPLE SITES AND INTEGRATE MEASURES AMONG HEALTH INTO CLINICAL CARE LAKE IN ASTHMA, CYSTIC FIBROSIS AND MANY OTHER CHILDREN WE SEE SO WE CAN IMPLEMENT THEM IN THE LONGITUDINAL DATABASES AND REGISTRIES THAT EXIST. THEN AS DR. NOR WALK POINTED OUT YESTERDAY WE NEED TO BETTER UNDERSTAND THE RELATIONSHIP BETWEEN THE PULMONARY CO-MORBIDITIES, ALL THE As AND PNEUMONIA, MORBIDITY MORTALITY AND I WOULD ALSO ARGUE WITH QUALITY OF LIFE. THEN LOOKING FORWARD THERE'S NOT ANY CLINICAL TRIALS YET IN PULMONARY IN CHILDREN WITH DOWN SYNDROME AND IS THERE'S POTENTIAL TO EVALUATE VARIATIONS OF CURRENT CLINICAL PRACTICE, NOVEL THERAPIES, JACK INHIBITION, ET CETERA, THAT WE ARE LUCKY TO HAVE ON OUR CAMPUS. THEN WE NEED TO LOOK AT DEVELOPMENT OF BEST PRACTICE AS THINGS MOVE FORWARD IN THE PULMONARY FIELD. SO AGAIN, SO LUCKY TO BE PART OF THIS CENTER, PATIENTS AND THEIR FAMILIES, DR. HICKEY, BREATHING INSTITUTE AT CHILDREN'S AND THE -- CENTER UNIVERSITY OF COLORADO IS A GREAT PLACE TO DO RESEARCH IN DOWN'S SYNDROME. THANKS. >> THANK YOU, EMILY. SO ACTUALLY OUR NEXT IS DEBORAH FIDLER. D >> I'LL PLATEFUL TO PRESENT A PRE-- GRATEFUL TO PRESENT A DESCRIPTION OF OUR R21 READINESS PROJECT ADHD CHILDREN WITH DOWN'S SYNDROME. THIS PROJECT HOUSED AT COLORADO STATE UNIVERSITY AND OUR TEAM IS WITH DEVELOPMENTAL DISABILITIES RESEARCH LAB AND WE ARE REALLY GRATEFUL TO BE WORKING WITH A TERRIFIC TEAM OF COLLABORATORS ON THIS PROJECT INCLUDING NANCY LEE, WHO WE JUST HEARD FROM AT DREXEL UNIVERSITY, PA TELL AT CENTER FOR DOWN'S SYNDROME CHILDREN HOSPITAL COLORADO. JAMIE EDGEN UNIVERSITY OF ARIZONA AND ANNA ESBENSEN. WE HAVE A RANGE OF COGNITIVE BEHAVIORAL OUTCOMES, WE STUDY FOR THE UNDERSTANDING THAT NOTVE ALL INDIVIDUALS WITH DOWN'S SYNDROME WILL DEMONSTRATE EACH OUTCOME OF INTEREST AND IDENTIFYING SOURCES WITHIN DOWN'S SYNDROME VARIABILITY CAN BE A VERY IMPORTANT PART OF CHARACTERIZING OUTCOMES ASSOCIATED WITH DOWN'S SYNDROME AND IMPORTANTLY MITIGATING RISK FOR CHALLENGING CO-MORBIDITIES. OUR TEAM ALSO TAKES A LIFE SPAN DEVELOPMENTAL APPROACH WHERE WE ARE INTERESTED NOT ONLY IN CROSS SECTIONAL OUTCOMES IN MIDDLE CHILDHOOD ADOLESCENTS AND ADULTHOOD BUT INTERESTED IN EMERGENCE OF PATTERNS OF STRENGTH AND CHALLENGE DURING EARLY YEARS OF DEVELOPMENT, THIS TYPE OF APPROACH WE BELIEVE MAKES IT POSSIBLE TO ASK QUESTIONS ABOUT THE DEVELOPMENTAL ORIGIN OF ADAPTIVE AND MAL ADAPTIVE OUTCOMES AND CAN IMPROVE OUR ABILITY TO DETECT RISK FOR CO-MORBID CONDITIONS DURING EARLY STAGES OF DEVELOPMENT. THE OUTCOME OF INTEREST FOR OUR CLINICAL TRIAL READINESS PROJECT IS CO-OCCURRING ADHD AND ADHD SYMPTOMTOLOGY. RECENT ESTIMATES AS WELL DESCRIBED YESTERDAY BY DR. ESBENSEN CO-OCCURRING DOWN'S SYNDROME IN ADHD RANGE TO 44%, THAT MEANS THERE'S ALSO A GREAT YES OF HETEROGENEITY IN ADHD PRESENTATION IN THIS POPULATION BUT AT THIS TIME WE KNOW VERY LITTLE ABOUT THE MECHANISMS THAT UNDERLIE RISK FOR DEVELOPING ADHD SYMPTOMS IN THIS GROUP AND THEIR TREATMENT IMPLICATIONS. SO THE MAIN OBJECTIVES OF THIS PROJECT ARE TO IDENTIFY VERY EARLY INFANTS RISK FACTORS ASSOCIATED WITH LATER ADHD SYMPTOMTOLOGY IN YOUNG CHILDREN WITH DOWN'S SYNDROME AND THE ULTIMATE GOAL IS IMPROVE EARLY DETECTION AND TREATMENT OF CO-OCCURING CONDITION. OUR APPROACH INVOLVES A COMBINATION OF RETROSPECTIVE AND PROSPECTIVE RESEARCH DESIGN TO ALLOW US TO LEVERAGE A WEALTH OF EXISTING DATA ONCOHOTTER OF 76 INFANTS WITH DOWN'S SYNDROME WHO WE HAVE ALREADY COMPREHENSIVELY ASSESSED FOR FIRST WAVE OF DATA COLLECTION. OUR PLAN FOR THIS PROJECT IS TO LINK WAVE ONE INFANT DATA TO CURRENT PRESENTATION OF COGNITIVE CONTROL IN THE FORM OF EXECUTIVE FUNCTION AND ADHD SYMPTOMS AT 4 TO 5 YEARS FOR A WAVE 2. PARTICIPANTS AT WAVE 1 WERE 76 INSTANCES WITH DOWN'S SYNDROME AND CAREGIVERS RECRUITED BETWEEN 2015 AND 2019. APPROXIMATELY 50% FEMALE, AT WAVE 1 INFANTS HAD A MEAN CHRONOLOGICAL AGE OF TEN MONTHS AND COGNITIVE AGE EQUIVALENT DAILY OF APPROXIMATELY 7 MONTHS. MAJORITY OF REPORTED A TRISOMY NON-DISJUNCTION DIAGNOSIS, 40% PREMATURE, 40% CONGENITAL HEART DEFECT AND 70% REPORTED HISTORY OF SIGNIFICANT ILLNESS. AT WAVE 1 INFANTS WERE ASSESSED COMPREHENSIVELY ACROSS RANGE OF DOMAINS AND IN PARTICULAR FOR THIS PROJECT ADMINISTERED A SET OF INFANT LABORATORY MEASURES OF EARLY COGNITIVE REGULATION OR COGNITIVE CONTROL. WE ASSESSED EARLY VISUAL ATTENTION VIA EYE GAZE, EARLY LATENCY TO SHIFT ATTENTION, EARLY COGNITIVE FLEXIBILITY. AND EARLY GOAL DIRECTED PLANNING AND EFFORTS FOR CONTROL. AT WAVE 2 FOR OUR CURRENT CLINICAL TRIAL READINESS R 21 WE ADMINISTER SEVERAL GOLD STANDARD MEASURES OF ADHD SYMPTOMS AND WE ARE ASSESSING DEVELOPMENTAL STATUS USING THE (INAUDIBLE) ALSO ADMINISTERING A DEVELOPMENTALLY APPROPRIATE PHENOTYPE SENSITIVE BATTERY OF EXECUTIVE FUNCTION MEASURES, INCLUDING ASSESSMENTS OF WORKING MEMORY, INHIBITORY CONTROL COGNITIVE FLEXIBILITY, AND PLANNING. IN ADDITION AT WAVE 2 WE EXAMINE MODERATING ROLE OF SLEEP AND BIOMEDICAL RISK IN THE RELATIONSHIP BETWEEN INFANT COGNITIVE CONTROL PRESENTATION AND PRE-SCHOOLER ADHD SYMPTOMS, WE ARE COLLECTING SLEEP ACTI >> FEW, DIARY AND HEALTH QUESTIONNAIRE DATA UNDER THE GUIDANCE OF DR. EDGEN AND HER TEAM AND WE ARE ALSO COLLECTING COMPREHENSIVE BIOMEDICAL RISK SURVEY DATA AS WELL. OUR ANALYTIC APPROACH INVOLVES MODELING THE RELATIONSHIP BETWEEN INFANTS COGNITIVE PRESENTATION AND ADHT SYMPTOMS AT FOUR TO FIVE YEARS AND TEST THE MEDIATING ROLE OF EXECUTIVE FUNCTION, AT FOUR TO FIVE YEARS IN THIS RELATIONSHIP AND WE ALSO AIM TO QUANTIFY AS I MENTIONED THE MODERATING EFFECT OF BIOMEDICAL RISK AND SLEEP ON COG MITIVE CONTROL AND ARCDHD SYMPTOMS AT FOUR TO FIVE YEARS. IN TERMS OF PROGRESS OUR TEAM HAS MET ALL PROJECTED MILESTONES TO DATE, AS OF APRIL WE HAD REENROLLED 65 OF THE 76 INFANTS FROM ORIGINAL COHORT AND VISITS SCHEDULED THROUGHOUT MARCH APRIL MAY AND JUNE. WE COMPLETED DATA COLLECTION FOR SIX PARTICIPANTS BEFORE THE PAUSE AND RESEARCH CAUSED BY COVID-19. ALL ENROLLED FAMILIES INDICATE WILLINGNESS TO PARTICIPATE IN THEIR RESEARCH VISITS ONCE SAFE TO DO SO AND WE PLAN TO CONTINUE TO RECRUIT THE REMAINING WAVE ONE PARTICIPANTS THROUGHOUT THE SUMMER OF 2020. WE BELIEVE THIS PROJECT WILL FACILITATE CLINICAL TRIAL READINESS BY HELPING TO ANSWER CRITICAL QUESTIONS. THAT IS HOW WE PROVIDE THE RIGHT TREATMENT TO RIGHT INDIVIDUAL AT THE RIGHT TIME. WE BELIEVE THAT A CAREFUL EXAMINATION OF EARLY INFANT PRE-SCHOOL PRESENTATION IN MANY DOMAINS HOLD IT IS KEY TO IMPROVED EARLY DETECTION AND MORE EFFECTIVE TREATMENT OF CO-MORBIDITIES LIKE ADHD AND DOWN SYNDROME AND OTHER NEUROGENETIC SYNDROME. WE BELIEVE THIS TYPE OF APPROACH ALLOWS FOR MORE ANTICIPATORY FRAME WORK FOR EARLY INTERVENTION WHICH CAPITALIZES ON EARLY NEURAL PLASTICITY WITH A SELECTION OF ENRICHMENT TO SUPPORT DEVELOPMENT IN TARGETED AREAS AND MORE ONSET OF MORE ADAPTIVE DEVELOPMENTAL CASCADES. OUR OVERARCHING GOAL IS TO WORK TOWARDS DEVELOPMENTAL APPROACH TO EARLY DETECTION THAT CAN HELP SHAPE MORE PERSONALIZED PRECISION AND EFFECTIVE TREATMENT THAT ARE DELIVERED JUST IN DEVELOPMENTAL TIME TO REDUCE THE PREVALENCE OF CHALLENGING CO-MORBIDITIES AND DOWN'S SYNDROME. WE ARE INCREDIBLY GRATEFUL TO FUNDERS FOR THIS PROJECT NICHD AND INCLUDE PROJECT AND ALSO GRATEFUL TO NIDLER FOR FUNDING WAVE ONE AS DATA COLLECTION. WE HAVE TREMENDOUS GRATITUDE THROUGH OUR COLLABORATORS WHO MADE THIS PROJECT TERRIFIC EXPERIENCE TO WORK ON TOGETHER. OUR VERY TALENTED PRODUCTIVE LAB MADE UP OF TERRIFIC TEAM LISTED HERE AND MOST IMPORTANTLY WE HAVE TREMENDOUS GRATITUDE TO THE PARTICIPANTS AND THEIR FAMILIES TO MAKE OUR RESEARCH POSSIBLE. >> ALL RIGHT. THANK YOU DEBORAH, WE ARE MOVING TO THE NEXT SPEAKER WHICH IS MICHAEL YEAGER. >> THANK YOU FOR GIVING US A CHANCE TO SHARE THIS, THIS HAS BEEN 'ALLY GREAT COUPLE OF DAYS. -- REALLY GREAT COUPLE OF DAYS. I WILL GO VERY QUICKLY OVER R21 FUNDED PROJECT LOOKING AT AT LYMPHOID TISSUE, TRYING TO ASK THE QUESTION IS IT FRIEND OR FOE IN DOWN SYNDROME SO THAT WE CAN PREPARE FOR CLINICAL TRIALS HOPEFULLY IN TARGETING THIS INTERESTING LUNG ORGAN IN THE SETTING OF INFECTIOUS RESPIRATORY DISEASE. I WON'T READ ALL THIS, DON'T WORRY, SIGNIFICANCE IS I THINK BECOMING MORE CLEAR EVEN IN THE LAST COUPLE OF DAYS THAT RESPIRATORY TRACT INFECTION AS EMILY MENTIONED TWO PRESENTERS AGO, THE MOST SERIOUS LIFE THREATENING HEALTH PROBLEM. MAJOR UNRESOLVED QUESTIONS THAT WE ARE GRAPPLING WITH, WE DON'T KNOW WHY IMMUNE RESPONSES ARE POOR IN DOWN'S SYNDROME, THAT'S SOMETHING WE NEED TO TAKE CARE OF. BECOME A LUNG PERSON AND PULMONARY VASCULAR PERSON I'M REALLY INTERESTED IN LOCAL LUNG IMMUNE RESPONSES, THAT'S BASIS OF WHAT WE DO IN OUR LAB SO OUR HYPOTHESIS IS THESE LYMPHOID TISSUES I WILL SHOW YOU IN A MINUTE ARE LIKE SMALL LYMPH NODES THAT APPEAR IN ALL MUCOSAL TRACKS. SO ALL DOWN THE AIRWAYS AND ALL DOWN THE GUT WITH PYRES PATCHES THESE LYMPHOID ORGANS ARE LOCAL REGULATORS OF A VARIETY OF IMMUNE RESPONSES AND THAT'S NO DIFFERENT IN THE LUNG. OR HYPOTHESIS GOING FORWARD IS THERE IS A PROBLEM, SO REDUCED BIOGENESIS OR AND/OR FUNCTION IN DOWN'S SYNDROME, IN PART IMMUNE SUPPRESSION AND PRE-DISPOSITIONS RESPIRATORY TRACK INFECTION, THAT'S SOMETHING WE CAN TARGET THERAPEUTICALLY. OUR TWO AIMS VERY SIMPLE IS JOAQIM SPOKE ON THIS YESTERDAY WE HAVE THE ABILITY IN OUR SENT TORE GO AFTER INTERFERENCE. SO -- INTERFERONS. IF WE ANTAGONIZE THEM OR AGONIZE THEM IN OUR CONTROLS AND LOOK AT BIOGENESIS WE SHOULD BE ABLE TO DETERMINE POTENTIAL ROLES FOR THIS INTERFERONOPATHY IN TERMS OF LUNG INFECTION. OUR SECOND ONE IS GO AT THE BALL ITSELF. WE HAVE GOT A LONG HISTORY IN OUR LAB OF LOOKING AT BALLS IN DIFFERENT CONTEXT ESPECIALLY PULMONARY HYPERTENSION. THOSE ARE OUR TWO AIMS. VERY QUICKLY, AS I SAID THE TOP LEFT THAT'S A BONA FIDE LYMPH NODE, ASSOCIATED LYMPHOID TISSUE HAS FEATURES OF LYMPH NODE SO THERE ARE LYMPHATIC SERVICES, HIGH ENDOTHELIAL VENUES THAT YOU CAN SEE HERE. THIS WOULD BE IS AIRWAY LIEU MEN HERE SO AS WE ALL BREATHE PARTICULATES AND ANYTHING THAT'S IN THE AIR, IS SAMPLED ESPECIALLY BY THESE M CELLS WHICH THEN TRANSPORT WHAT THEY ARE FINDING, WHAT THEY ARE SENSING INTO THIS BEAUTIFUL INNATE ACQUIRED IMMUNE SYSTEMS TO WORK TOGETHER AND FIGURE OUT WHAT IS THE APPROPRIATE RESPONSE. OBVIOUSLY IF IT'S JUST A LITTLE BIT OF DUST OR POLLEN YOU DON'T WANT TO MAKE A HUGE RESPONSE BUT SAY THERE ARE DANGEROUS ORGANIZE. S, -- ORGANISMS, THIS HAS TO REALLY BE RESPONSIVE. SO IT'S A VERY COMPLEX ORGAN, AS YOU CAN SEE HERE BY MY HOMEMADE DRAWING THERE IS AIRWAY OF PULMONARY ARTERY, THEN SPACE IN BETWEEN WHERE LYMPHOID TISSUE IS BIAS TOWARD THE AIRWAY. WE HAVE A LOT OF CELLS IN PLAY SO IT'S A COMPLICATED KIND OF DEVICE TO STUDY. BUT WE ARE INTENTIONSIVELY STUDYING IT AND WE THINK THAT WE HAVE GOT A GOOD HANDLE ON THIS. SO OUR OUTSET IS WE THOUGHT OKAY, LET'S LOOK AT THE POST INFLUENZA STATE IF THAT THAT'S WHAT WE HAVE, YOU HEARD MY TALK YESTERDAY, IN THE SETTING OF INFLUENZA YOU SEE LYMPHOID TISSUE DEVELOP. , THAT'S THE POINT OF THIS SLIDE. WE DON'T KNOW ABOUT INTERFERONS AND HOW THEY POTENTIATE OR ANTAGONIZE ASSOCIATED LYMPHOID TISSUE IN ANY SETTING, THAT'S NEVER REALLY BEEN LOOKED AT. TO THE MEAT OF IT, SO WHAT ABOUT THESE LYMPHOID TISSUES AND IMMUNE CELLS IN MOUSE MODELS OF DOWN'S SYNDROME BECAUSE WE ASK NOT GET LUNG SAMPLES READILY FOREPERSONS WITH DOWN'S SYNDROME. AS YOU CAN SEE HERE, IF WE LOOK AT CONTROLS, DP 60 AND DP 10 ARE TRIPLICATING INTERFERON PLAYERS, THESE ARE NOT. WHAT YOU SEE IS IN SALINE, THE LUNG LOOKS BEAUTIFUL. WHEN WE GIVE -- WE SEE DEVELOPMENT OF THESE BRONCHUS ASSOCIATED LYMPHOID TISSUES, THIS IS AN AIRWAY, THAT'S AN AIRWAY, YOU CAN SEE PULMONARY ARTERY, THE CLUSTER OF CELLS, AND THIS CORRELATES, CROFT THE CORRELATION DATA HERE BUT IT CORRELATES WITH THE EXTENT OF LUNG REMODELING AND THE CFU LUNGS -- COUNTS IN EACH LUNG LOBE SO YOU AND I WE HAVE THOSE BEAUTIFUL NICE RESPONSE WHERE WE DEVELOP LYMPHOID TISSUES AND EVENTUALLY WE CLEAR INFECTIOUS DISEASE. WHAT WAS REALLY CAUGHT OUR EYES FASCINATING IN THE SALINE SETTING, SO DP 60 BUT NOT TEN, LYMPHOID TISSUES ARE HERE, THEY ARE VERY ROBUST, AND THEN TO OUR SURPRISE THIS LARGELY GOES AWAY, YOU CAN SEE A LITTLE REMNANT LEFT OVER. THIS IS REALLY NEVER BEEN OBSERVED BEFORE, IT'S USUALLY THE OPPOSITE WITH PATHOGENS YOU GET DEVELOPMENT LYMPHOID TISSUE. WE HAVE IT ON BOARD AND THEN IT GOES AWAY. AGAIN, I DON'T HAVE THE CORRELATION DATA HERE, IT'S NOT QUITE THERE. WE ARE COUNTING THE NUMBER OF LYMPHOID TISSUES WE ALSO GO FOR SIDES AND WE WILL -- THE POINT OF THIS PRELIMINARY STUFF IS TO SAY THAT HEY, LYMPHOID TISSUE NUMBERS AND SIZE, DO THEY CORRELATE DIRECTLY. SO FAR IT LOOKS GOOD. SO THIS IS ALSO IN CONJUNCTION WITH A PAPER WE PUBLISHED WHERE WE LOOKED AT DIFFERENT BLOOD SUBPOPULATIONS AND WE THINK THIS ORGAN HERE IS NOW AT LEAST PARTIALLY RESPONSIBLE FOR SOME OF THESE HORRIBLE RESPONSES IN TERMS OF RESPONSE TO -- WE KNOW WHAT'S HERE, WE KNOW THERE ARE LYMPHOTOXIN BETA RECEPTOR POSITIVE CELLS, WE ALSO KNOW CD 11 CD POSITIVE DENDRITIC CELLS AND 11B MAX. THERE'S LYMPHATIC SERVICE BY SERVICE OF LYMPHATIC ENDOTHELIAL CELLS SO THE GOALS HERE WHICH WE ARE WRAPPING UP BEFORE THE COVID HIT WAS WE ARE LOOKING AT PROTEIN LOCALIZATION FOR ALL THE SPECIFIC CELL TYPES. WE ALSO LASER CAPTURE MICRODISSECTED LYMPHOID TISSUE HERE. THEN WE CAPTURED mRNA AND WE ARE LOOKING AT A VARIETY OF GENE EXPRESSION SO NOW WE ARE READY TO GOO DO THE EXPERIMENT WHERE WE SAY OKAY, IF WE BLOCK INTERFERENCE AS DESCRIBED YESTERDAY, THIS SHOULD DRIVE THIS ECTOPIC LYMPHOID TISSUE OR TERTIARY LYMPHOID TISSUE MAINTENANCE AND RESTORE INFLAMMATORY RESPONSE. IF WE TRIED TO BLOCK LYMPHOTOXIN BETA IS THIS SHOULD INHIBIT THIS, WE SHOULD LOSE THIS. SO THE CONTROLS HERE WHEN TREATED WITH THIS, SHOULD LOOK LIKE DP 16. DP 16 TREATED THIS WAY LIKELY WILL WORSEN. HOPEFULLY LOOK LIKE THE CONTROLS IF WE ARE CORRECT. THAT IS THE BULK OF OUR PROCESS, WE KNOW LOTS OF THE PLAYERS HERE. I WANT TO KEEP THIS NICE AND SHORT. LIKE TO GIVE THANKS AGAIN TO KELLY WHO MAKES ALL THIS POSSIBLE. YESTERDAY I WAS REMISS IN THANKING GLOBAL WHO FINANCES MUCH OF WHAT A LOT OF THE PRESENTERS AT THIS CONFERENCE DO AND I DID NOT MENTION THANK YOU TO MY SHE WOULD WHITMAN GLOBAL FOR FUNDING BOTH YESTERDAY'S WORK AND TODAY'S WORK. AND I WOULD LIKE TO CORRECT THAT NOW. THANK YOU. >> THANK YOU, MICHAEL. OUR NEXT SPEAKER IS JEFFREY CHANG. >> GEOFFREY CHANG. >> ALREADY CAN YOU GUYS HEAR ME? >> YES WE CAN. >> ALL RIGHT. THANK YOU, LAURIE FOR THE OPPORTUNITY TO SPEAK. IT'S A REAL PLEASURE TO PRESENT. I THANK ERICA FOR GETTING ME TO THIS POINT. I GET TO RUN A SMALL PROJECT WORKING WITH OPHTHALMOLOGY GROUP AT UC STEVEN STUDYING CATARACTS MAKING PROBES TO AMYLOID CONFORMERS IN THE EYE FOR CONTEXT FOR FOLKS WITH DOWN'S SYNDROME. THE PROSECOND IS FAIRLY SIMILAR -- PROJECT IS FAIRLY SIMPLE, THE FIRST GOAL IS TO REALLY PRODUCE A TYPE OF ANTIBODY LIKE PROBE DIFFERENT CONFORMERS OF AMYLOID. SELECTED FOR PARTICULAR CONFIRMATIONAL SPECIES. THE SECOND AIM IS THEN TO TEST THESE REAGENTS EYE TISSUE MOUSE MODELS RIGHT BEFORE THE BREAK DOWN'S SYNDROME EYE TISSUES WHICH IS RELATIVELY DIFFICULT TO OBTAIN. THE PROJECT LIKE I SAID A JOINT COLLABORATION WITH NEIGHBORING FOLKS AT UCSD. THE FOLKS IN MY LAB (INDISCERNIBLE) THEY ARE THE DRIVERS AND THEN I WORK WITH DAN AND JENNIFER WHO DOES THE IMMUNOSTAINING. FOR OUR PROBES. OKAY. SO I GUESS IN SOME WAYS THAT DISCLOSURE, I HAVE -- THAT'S ME ON THE LEFT. MY BROTHER RANDY ON THE RIGHT. HE HAS DOWN'S SYNDROME AND HE'S BEEN THENT OPERATION FOR MY STUDY. HE'S ABOUT TEN YEARS YOUNGER AND HE'S RELATIVELY HIGH FUNCTIONING, PRETTY HEALTHY, THIS IS MY PARENTS IN DELAWARE. HE HAS MENTAL DISABILITY OF COURSE LIKE ALL DOWN'S BUT HE'S PRETTY HIGH FUNCTIONING. HE GRADUATED HIGH SCHOOL IN REGULAR CURRICULUM, ACTUALLY COLLEGE DEGREE IN BIBLICAL STUDIES AS WELL, I DON'T KNOW IF THAT'S DUE TO PALACE AT THIS OF THE BRAIN OR WILL POWER OF MY PARENTS BUT OR COMBINATION OF THE TWO. BUT HE PLAYS PIANO VERY WELL. HE PERFORMS. WE A ARE A FAMILY OF MUSICIANS AND I THINK EVEN SOME ON THE CALL HAVE ACTUALLY EVEN SEE HIM SO I'M GRATEFUL FOR EVERYBODY WHO -- I'M IN THE TRANSITION OF BECOMING THE CAREGIVER WHICH I HEARD A LOT ABOUT IN THE WORKSHOPS HERE. BUT RELEVANTLY, TO MY TOPIC IS HE DEVELOPED SOME CATARACTS A FEW YEARS AGO AND HE PRETTY MUCH LOST 85 TO 90% OF HIS SITE, HE COULDN'T SEE THE MUSIC, HE COULD READ MUSIC JUST FINE BUT HE COULDN'T READ AT ALL. I DON'T KNOW HOW HE COULD -- THAT LONG AND IT WAS A LOT OF PROBLEMS GETTING HIM CARE. A LOT OF TRUST ISSUES. THERE WAS NOBODY IN DELAWARE THAT WOULD DO THE SURGERY SO HE ENDED UP GETTING THE SURGERY DONE JEFFERSON MEDICAL IN PHILADELPHIA. VERY GREAT CARE. TOOK A LOT OF WORK FROM MY PARENTS. SO THAT INSPIRED THE STUDY. BEING A RESEARCHER THE NEXT THING I DO IS I READ A LOT. I FIND OUT THERE'S HIGH PREVALENCE OF CATARACTS IN DOWN'S SYNDROME AND INTERESTINGLY IN CHILDREN AS WELL. AND OF COURSE THOSE IN THE ALZHEIMER'S FEEL ARE FAMILIAR WITH ADP, WHICH THEN CLEAVE TO AMYLOID, AND DEPOSITS AND THEN THERE ARE A LOT OF CONFLICTING STUDIES AND I THINK THAT IN SHORT, TO HAD A LOT TO DO WITH THE PROBES THAT THEY ARE USING AND THE TYPES OF STUDIES. SO OF COURSE WE WERE MAKING THESE TYPE OF PROBES AND PANELS PROBES OF BETA AMYLOID, SO WE DECIDED TO TRY TO MAKE A KIND OF REGULARIZE THE PROBES TO STANDARDIZED PROBES FOR THESE TYPE OF THINGS SO THIS HAS BEEN THE START OF THE PROJECT. LITTLE BIT ABOUT THE TECHNOLOGY WE USE, IT'S A FORM THAT WE DEVELOP IN THE LAB, THE LEFT HERE, YOU CAN SEE THESE ARE ANTI-BODIES AND THIS IS WHAT THEY LOOK LIKE. WE USE A TYPE OF MOLECULAR SCAFFOLD AS A PROBE THAT ORIGINALLY IS FROM CAMELS OR SHARKS. WE USE HUMANIZED CAMELS WE DON'T DO THAT ANY MORE, WE USE IN VITRO TO PRODUCE THESE NANOBODY PROBES, EFFICIENTLY ON THE RIGHT, I WON'T GO OVER ALL THIS DETAIL. BUT THIS IS A BASICALLY A IN VITRO SYSTEM FOR DISCOVERY OF THESE TYPE OF PROBES. SO WE AT THE MOMENT HAVE PANEL OF PROBES THAT BIND TO SPECIFIC CONFORMERS OF BETA AMYLOID. RIGHT BEFORE THE BREAK IT STARTED TO GET REALLY GOOD, SO THIS IS JUST SHOWING YOU SOME IMMUNOSTAINING UP HERE. WITH NB 136. THIS PARTICULAR ONE LEADS A FORM OF BETA THAT IS TOXIC IN SOME STUDIES THAT WE HAVE BEEN DOING WITH OTHER FOLKS AT UCSD THEN STARTED TO LOOK AT THESE IN EYES RIGHT BEFORE THE SHUT DOWN BUT WHAT WAS GETTING GOOD TOO IS WE FOUND PROBES THAT NOT ONLY BOUND BUT SEEM TO DISSOLVE DEPOSIT AMYLOID DEPOSIT AS WELL. THIS COULD LEAD POTENTIALLY TO WITH SOME DELIVERY WHICH IS BEING ABLE TO TREAT CATARACTS WITH EYE DROPS, THAT'S MORE AMENABLE FOR FOLKS BECAUSE THEY DON'T LIKE TO HAVE SURGERY. THAT'S A VERY BRIEF SUMMARY. I WANT TO THANK NEI, BARRAGE PROGRAM OFFICERS THAT WENT BACK AND FORTH AND WORKED WITH ME ON THIS, I WANT TO THANK NIH INCLUDE AND ALSO ALL THE RESEARCHERS HERE. I REALLY THANK YOU. YOU ARE MY HEROES. >> THANK YOU, ONE SECOND. >> SLEEP APNEA AND I WANT TO THANK THE NATIONAL INSTITUTES OF HEALTH FOR INVITING MEG TO TALK AS WELL AS UNDERSTOODING THIS PROJECT. IN DOWN'S SYNDROME WE TALK ABOUT THIS YESTERDAY, VERY COMMON, ENTER BETWEEN HALF AND 80% OF KIDS WITH IMPAIRED COGNITION QUALITY OF LIFE, THE STANDARD TREATMENT ARE PROBABLY EFFECTIVE IN MAYBE HALF OPTIMISTICALLY AND IMPORTANTLY (INAUDIBLE) APPEARS TO BE A REALLY IMPORTANT RISK FACTOR. SO THAT MIGHT BE WHY INSPIRE HAS NERVE STIMULATED IMPLANTED DEVICE THAT INCREASES AIRWAY MUSCLE DAMAGE, APPEARS REALLY EFFECTIVE. THE DOWN SIDE OF THAT, IT IS SURGERY, IMPLANTED DEVICE, I DON'T KNOW HOW FEASIBLE IT WOULD BE TO IMPLANT IT IN FIVE OR 6-YEAR-OLDS BECAUSE THEY WILL CONTINUE GROWING. THERE IS A PRIOR STUDY LOOKING AT -- AN ADHD MEDICATION Z AS WELL AS (INAUDIBLE) LADDER IN ADDITION THOSE ARE BOTH APPROVED FOR THOSE INDICATIONS AND KIDS DOWN TO AGE 6 BUT THEY TARGET AIRWAY HYPOTONEIA BY TARGETING NOREPINEPHRINE AS WELL AS (INAUDIBLE) EFFECTS. AND IN ADULTS WITH DOWN'S SYNDROME, CONSTRUCTIVE SLEEP APNEA, APPEARS EFFECTIVE, THEY GOT 76% IMPROVE IN SLEEP APNEA, INCREASE AIRWAY MUSCLE IN THAT SO THIS PROJECT IS R61 R33, R61 IS PILOT PHASE. SO AIM ONE OF THAT IS TO EVALUATE SHORT TERM EFFICACY OF (INAUDIBLE) ON DOWN'S SYNDROME. SO IT WAS EFFECTIVE IN TREATING LSA AND N 2 IS WE SEE IMPROVEMENT IN HEALTH RELATED QUALITY OF LIFE, THERE'S STUDY SHOWING QUALITY OF LIFE AS QUICKLY AS TWO OR THREE WEEKS AFTER SURGERY. SO DO WE SEE SHORT TERM BENEFIT. THIS IS SUCCESSFUL AT THE R33 PHASE WOULD BE A LONGER TERM ENABLE STUDY, WHERE AGAIN WE CONFIRM IT WORKS OVER LONG PERIOD OF TIME. QUALITY OF LIFE OVER LONG PERIOD OF TIME AND WE WANT TO RIGOROUSLY EVALUATE THE NEUROCOGNITIVE EFFECTS TO SEE IF TREATING LSA WITH THIS MIGHT LEAD TO IMPROVED COGNITION IN KIDS WITH DOWN'S SYNDROME. SO THE R61 ENROLLED TOTAL OF 27 PARTICIPANTS, AND LOOK AT TWO DOSES, GOING TO LOOK AT HIGH DOSE, DOSE USED IN PRIOR ADULT STUDY, AS WELL AS LOW DOSE WHICH IS THE FDA GROUP STARTING (INAUDIBLE) THEY GET RANDOM ORDER SO IT'S TWO WEEK WASH OUT BETWEEN ARMS CROSS DOUBLE BLIND STUDY, AND THEN OUTCOMESES ARE SLEEP STUDY AS WELL ON QUALITY AS WELL AS TREAT SLEEP APNEA DOESN'T IMPROVE THERE, QUALITY OF LIFE, TWO INSTRUMENTS, ONE LSA SPECIFIC IN KIDS AND THE OTHER MORE GENERAL QUALITY OF LIFE MEASURE. ACTUALLY THANKS TO SUPPLEMENTAL FUNDING FROM THE IDSC FOUNDATION WE ARE GOING TO ADD COGNITIVE MEASURES IN THE STUDY, TWO ARE REPORTING TO (INAUDIBLE) USED FOR ADHD AS WELL AS ADAPTIVE FUNCTION AS WELL AS USING THE DEVICE, WHICH IS A NATIONAL ENVIRONMENT LEARNING ASSESSMENT THAT'S ESSENTIALLY WHERE THE KIDS MICROPHONE OVER THE COURSE OF THE DAY AND WE DOWNLOAD THAT INFORMATION. SO CURRENT STATUS TO THE R61 IS IRB APPROVED, WE HAD INITIAL THE OTHER DAY IN APRIL, OPTIMISTICALLY WE WILL OPEN RECRUITMENT IN JUNE 2020 OBVIOUSLY COVID WILL DRIVE THAT. THEN R61 R33 WOULD BE A SIX MONTH OPEN LABEL STUDY WHERE AGAIN WE LOOK RIGOROUSLY AT COGNITIVE ASSESSMENT SO A NOER FORMAL OBJECTIVE COGNITIVE ASSESSMENT AS WELL AS EFFICACY AND QUALITY OF LIFE ONCE AGAIN. I DO WANT TO THANK THE NIH FOR FUNDING THIS. I THINK IT'S REALLY NEAT BECAUSE TYPICALLY DRUGS FOR KIDS WITH DOWN'S SYNDROME ARE FDA APPROVED IN ADULTS, IN HEALTHY KIDS WITH DOWN'S SYNDROME AND WORK THEIR WAY TO CHILDREN WITH DOWN'S SYNDROME, THIS SEEMS LIKE IT CAN PREFERENTIALLY BENEFIT CHILDREN WITH DOWN'S SYNDROME AND I APPRECIATE THE NIH TO BE TAKE THE RISK TO GO STUDYING KIDS WITH DOWN'S SYNDROME. THANK YOU VERY MUCH. >> THANK YOU, DAN. OUR NEXT SPEAKER IS ANNA ESBENSEN. I'M HAVING A TONGUE TWISTER MORNING. ESBENSEN. >> THAT'S OKAY. GOOD MORNING, EVERYBODY I MISSED SEEING YOUR FACES YESTERDAY, AT DINNER AND JUST GEEKING OUT AFTERWARDS IN THE LOBBY ABOUT YOUR AWESOME PRESENTATIONS FROM YESTERDAY BUT APPRECIATE THE NIH PULLING US TOGETHER IN THIS VIRTUAL FORMAT. I'M PRESENTING ON THE R 461 MANY THAT NICHD FUNDED FORD US EVALUATING ASSESSMENT OF METHYLPHENIDATE IN THE TREATMENT OF ADHD IN KIDS WITH DOWN'S SYNDROME AND IT'S ONE OF THOSE WONDERFUL OPPORTUNITIES OF HAVING A MULTI-PI PROJECT BECAUSE IT IS A GREAT COMBINATION OF MEDICAL ASPECT AND BEHAVIORAL SIDE OF IT DOING MEASUREMENT, I LOVE HOW MY SCREEN DOESN'T ADVANCE PERFECT. SO THE TALK YESTERDAY THAT I GAVE SET THE BACKGROUND FOR WHY WE ARE DOING THIS R61, SO JUST A BRIEF OVERVIEW OF FOLKS NOT ON YESTERDAY BUT RATES OF ADHD IN KIDS WITH DOWN'S SYNDROME ARE 3 TO 5 TIMES GREATER THAN WE SEE IN TYPICALLY DEVELOPING POPULATION. AND DESPITE HIGHER RATE WE ARE SEEING UNDERTREATMENT WITH USE OF MEDICATION, FOR KIDS WITH DOWN'S SYNDROME AND ADHD DESPITE THE FACT STIMULANTS ARE EFFICACIOUS IN TREATING ADHD AND THE RECOMMENDED AND GUIDELINES FOR TREATING CHILDREN WITH INTELLECTUAL DISABILITY, WHO HAVE ADHD, AS REVIEWED YESTERDAY THERE WERE LEGITIMATE REASONS FOR THAT, ONE THE POSITIONS ARE STRUGGLING HOW TO DIAGNOSE ADHD IN KIDS WITH DOWN'S SYNDROME, ATTRIBUTING ADHD ATTENTION OR HYPERACTIVITY TO THEIR DOWN'S SYNDROME RATHER THAN TO ADHD. SO ALSO CONCERNS THERE'S NO CLINICAL TRIALS DEMONSTRATING SAFETY EFFICACY OF THIS POPULATION GIVEN KIDS WITH DOWN'S SYNDROME HAVE GENERALLY BEEN EXCLUDED, TESTING METHYLPHENIDATE WITH TESTING ABILITY AND CONCERNS FOR CARDIAC SAFETY. GIVEN THE HIGH RISK CONGENITAL HEART DISEASE IN OUR KIDS WITH DOWN'S SYNDROME. IT PREFERS ME TO SHOW YOUR FACES WHICH I CANNOT SEE TO ADVANCE MY SLIDES. LOVE IT. SO FOR OUR R61 THERE'S TWO AIMS IN THE R61 THEN WE HAVE THREE OTHERS IN THE R33 BUT TWO AIMES ADDRESS THOSE CONCERNS, THAT PHYSICIANS HAVE FOR PRESCRIBING METHYLPHENIDATE IN DOWN SYNDROME ADHD. FIRST TO DIFFERENTIATE WHAT KIDS WITH AD -- DOWN'S SYNDROME LOOK LIKE WHEN THEY DO OR DON'T HAVE ADHD SO THE IS OUR PHENOTYPING STUDY WHERE WE ARE DOING -- WE ARE EVALUATING A HUNDRED KIDS WITH DOWN'S SYNDROME BETWEEN AGE 6 AND 17, BEING SEEN BOTH AT CINCINNATI BUT ALSO UC DAVIS SO YOU SEE CATHY AND LYNN UP THERE, THE PI FOR THE SUBCONTRACT. AND WE ARE EVALUATING KIDS WITH HOST OF MEASURES TO FIGURE WHICH MIGHT BEST DIFFERENTIATE KIDS WITH DOWN'S SYNDROME WITH OR WITHOUT ADHD SO THEY ARE RECEIVING A BRIEF TEST, COMPLETING A NURSE BATTERY, COMPLETING -- WE DOING BEHAVIORAL CODING ON MATH (INAUDIBLE) TO BE ABLE TO ASSESS FOR DIFFERENT SYMPTOMS BEHAVIORS OF INATTENTION AND HYPERACTIVITY. WE ARE DOING CLINICAL INTERVIEW, FOR BOTH ADHT SYMPTOMS AND OTHER MENTAL HEALTH DIAGNOSES AND ADAPTIVE FUNCTIONING, LOOKING AT FAMILY STRESS, DIFFERENT PARENT REPORTS AND TEACHER REPORT MEASURES OF ADHD, OTHER BEHAVIORS AND EXECUTIVE FUNCTIONING. THE PILOT CLINICAL TRIAL WE ARE PROPOSING IN OUR SECOND AIM IS BEING DONE SO THAT WE CAN BETTER INFORM WHAT THE SAMPLE SIZE SHOULD BE IN THE LARGER R33 TRIAL, WHAT WE ARE PROPOSING TO DO IS SEE 30 KIDS WHO HAVE DOWN'S SYNDROME AND ADHD. AND TO RUN THEM THROUGH THE PILOT TRIAL TO HELP INFORM WHAT SAMPLE SIZE REQUIRED LOOKING AT SOME PRIMARY OUTCOME MEASURES OF THE VANDERBILT AND SECONDARY OUTCOME MEASURES THAT ARE ONES ON THE PRIOR SLIDES. OUR STUDY IS TRIPLE BLIND, SO IF THE PARENTS, THE CHILD THE TEACHERS STUDY STAFF NONE OF US KNOW WHEN THE CHILD IS ON MEDICATION OR PLACEBO OR ON DIFFERENT DOSES. OF THE MEDICATION. I WILL SHOW YOU STUDY DESIGN IN A SECOND. EVERYBODY WHO IS GOING TO BE IN A STUDY IS GOING TO HAVE TO MEET INCLUSION CRITERIA FOR HYPERACTIVE AND ATTENDANT TYPE COMBINED USING X COMMUNITY SCHEDULE FOR EFFECTIVE DISORDERS AND VANDERBILT HISTORICALLY OR CURRENTLY BUT ON BOTH PARENTS AND REPORT BY ANOTHER INDIVIDUAL, SO THAT MIGHT BE TEACHER, THERAPIST. WHAT WE ARE RUNNING IN THE STUDY FROM METHYLPHENIDATE SINCE THERE'S MANY DIFFERENT FORMS OF METHYLPHENIDATE WE SELECTED (INAUDIBLE) EXTENDED RELEASE, WE ARE DOSING IS BASED TON CHILD WEIGHT, TO BE ABLE TO BE SUCCESSFUL TO KIDS WHO STRUGGLE WITH TAKING A PILL OR THE CAPSULES. SORRY SPRINKLES. HERE IS OUR STUDY DESIGN. SO RIGHT NOW WE ARE DOING THE PHENOTYPING VISITS WHICH IS THE BASELINE MEASURES, ADHD SCREENS TO DIFFERENTIATE CHILDREN SO EVERYBODY IN THE PILOT CLINICAL TRIAL WILL HAVE ALSO COMPLETED THAT PHENOTYPING VISIT. IF THEY DO HAVE ADHD THEY ARE GOING TO COMPLETE A THOROUGH MEDICAL SCREEN, OUR STUDY DID NOT ADD AS MANY PICTURES OF STUDY STAFF AS EVERYONE ELSE BUT WE HAVE CARDIOLOGISTS AND DEVELOPMENTAL PEDIATRICIANS ON THE TEAM WHO ARE GOING TO BE ASSESSING MEDICAL SAFETY, USING EKG, USING ECHOs AND DIFFERENT SIDE EFFECT RATING SCALES. IN OUR FIRST PHASE WHAT WE ARE DOING TO DO, EVERYONE WILL BE BLINDED BUT THE CHILD IS EACH WEEK GOING TO COME IN AND IN THAT BEAK PRIOR HAVE RECEIVED A DIFFERENT DOSE THAT WILL BE TITRATED OF THE MEDICATION. THERE'S GOING TO BE A RANDOM PLACEBO IN THERE SO WE CAN FIGURE WHAT OPTIMAL DOSAGE IS ON PARENT REPORT TEACHER REPORT CHILD BEHAVIORS AND WE WILL KNOW THAT IT'S WEAK 3 OF THE OPTIMAL DOSE, WE WON'T KNOW WHAT THE DOSAGE IS. ONCE WE ESTABLISHED THE OPTIMAL DOSE WE'LL MOVE TO PHASE 2 WHERE CHILD IS RANDOMIZED TO RECEIVE OPTIMAL DOSE OR PLACEBO. COME IN FOR POST ASSESSMENT AND THEN ON THE FOLLOWING WEEK WILL BE -- FLIP AND IF THEY RECEIVE PLACEBO THEY GO TO OPTIMAL DOSE OR VICE VERSA, SO EVERY CHILD IS GOING TO BE THEIR OWN CONTROL. AND WILL ALWAYS -- WE WON'T KNOW IF ON PLACEBO OR MEDICATION. OUR STUDY STATISTICIAN WILL KNOW, THERE WILL BE A SAFETY MONITORING SO AGAIN IF THAT COMMUNICATING TO FAMILIES THAT WE -- SOMEBODY DOES KNOW BUT PEOPLE THAT YOU ARE GENERALLY INTERFACING WITH DO NOT KNOW WE TRYING TO FIGURE HOW TO REVISE AND EVALUATING THE DRUG. ALL FAMILIES WILL BE INVITED TO PARTICIPATE IN THE SIX MONTH OPEN LABEL MAINTENANCE WHERE THERE'S MONTHLY VISITS AND FOLLOW-UP TESTING. BUT ALL OF OUR MEDICAL VISITS WE ARE ASSESSING FOR CARDIAC SAFETY, WE ARE ASSESSING FOR SIDE EFFECT IN ADDITION TO OPTIMAL IMPACT ON BEHAVIORS. IN IN TERMS OF OUR STATUS WE HAVE TWO SEPARATE IRBs ONE FOR DESCRIPTIVE PHENOTYPING AND ONE FOR THE PILOT CLINICAL TRIAL. BOTH RECEIVED IRB APPROVAL, WE RECEIVED FDA WAIVER EXEMPTION FOR THE (INAUDIBLE) ESTABLISHED IN INTELLECTUAL DISABILITY AND ADHT AND CONGENITAL HEART DEFECTS. IN TERMS OF PHENOTYPING, OUR GOAL IS 100 BUT IN TERMS OF MILESTONES BY END OF THE GRANT IS TO HAVE 50 INDIVIDUALS, WE WERE AT SCREENING 29 INDIVIDUALS, AND HAD ANOTHER 12 SCREENS SCHEDULED. AND WE ARE POSITIVE BECAUSE OF COVID. SIMILAR TO THE DANIEL'S CLINICAL TRIAL WE ARE RIGHT NOW GOING THROUGH THE DATA SAFETY MONITORING BOARD FOR APPROVAL AND HAVE RECRUITMENT GOALS FOR THE FOLLOWING JUNE. I WILL PASS THAT ON. >> THANK YOU. JOAQUIN ESPINOSA IS OUR NEXT SPEAKER. >> CAN YOU HEAR? >> WE CAN HEAR YOU. >> GREAT. LET ME SET UP A TIMER HERE FOR FIVE MINUTES MAKE SURE I DON'T EXCEED MY WELCOME. GREAT. SO I'LL PRESENT JAKE INHIBITION IN DOWN'S SYNDROME SAFE CITY AND EFFICACY FOR SKIN CONDITIONS IN DOWN'S SYNDROME ON BEHALF OF A LARGE TEAM OF INVESTIGATORS INCLUDING MY TWO CO-PIs. SO YESTERDAY WE TALK ABOUT THIS, THE MAIN RATIONALE FOR THIS IS THE WIDESPREAD OUT COMMUNITY IN DOWN'S SYNDROME, 60% ADULTS WITH DOWN'S SYNDROME HAVE BEEN DIAGNOSED WITH AT LEAST ONE CONDITION. SILL YAK DISEASE, THOSE CAN BE CONTROL WITH TITER HORMONE GLUE TIN FREE DIET. GLUTIN FREE DIET. THIS AREA HERE CONDITION CONDITIONS SOMETIMES CREATE CO-MORBIDITY AND THEY ARE NOT AVAILABLE OPTIONS THERE. THIS IS THE OVERARCHING HYPOTHESIS THAT COMMUNITY DRIVEN BY TRIPLICATION OF INTERFERON RECEPTORS LEADING TO JACK STAT SIGNALING. THIS DISREGULATION OF IMMUNE SYSTEM. SHOUGH VIABLE STRATEGY WOULD BE TO TARGET THIS JACK KINASE, ESPECIALLY JACK 1, TO TONE DOWN ATTENUATE INTERFERON HYPERACTIVITY. SO WE CAN DO THAT WITH FDA APPROVED JACK INHIBITORS APPROVED FOR ALL MEDICAL CONDITIONS SUCH AS ARTHRITIS. HOWEVER, WE WOULD LIKE TO GO BACK TO THE PHASE 2 SPACE TO REDEFINE SAFETY IN PEOPLE WITH DOWN'S SYNDROME. BECAUSE CHANCES ARE THE INDIVIDUALS WITH DOWN'S SYNDROME WERE NOT PART OF THOSE LARGE CLINICAL TRIALS THAT LED TO THE APPROVAL OF THIS DRUG FOR RHEUMATOID ARTHRITIS. THIS IS A PHASE 2 SINGLE ARM OPEN LABL TRIAL. FOUR MONTHS OF TREATMENT WITH THIS SPECIFIC JACK INHIBITOR TOFISITNIB. THE SAFETY DATA, TWO WEEK FOLLOW-UP AS PART OF THE TRIAL MAYBE A MUCH LONGER FOLLOW-UP ON OBSERVATION STUDY LATER ON. WHICH IS IND -- THE DRUG IS FDA APPROVED, WE WILL FOCUS ON ADULTS FOR THE TIME BEING. IT WILL BE TO THE FIRST TEN PARTICIPANTS DOING R61, ADDITIONAL R33. PARTICIPANTS HAVE TO HAVE AN ACTIVE AUTOIMMUNE CONDITION ONE OR MORE OF THIS LISTED HERE. THE (INAUDIBLE) ECTOPIC DETERMINE TIETIS, ALL CONDITIONS THEY HAVE BEEN CLINICAL TRIALS FOR JACK INHIBITION FOR POSITIVE RESULTS BUT NONE ARE FDA APPROVED YET SO THERE'S NO APPROVAL FOR ANY CONDITIONS YET. BUT VERY PROMISING RESULTS. SO THESE ARE FOUR AIMS THAT WILL GO INTO THEM IN A LITTLE BIT OF DETAIL. FIRST AGAIN REALLY FIND SAFETY PROFILE OF JACK INHIBITION IN PEOPLE WITH DOWN SYNDROME, VARIOUS EVENTS MADE SURE NUMBER AND TYPE OF ADVERSE EVENS ARE NOT CALL INTO QUESTION SAFETY OF INTERVENTION, SERIES OF ADVERSE EVENTS UNANTICIPATED PROBLEMS, PROTOCOL DEVIATION, LOTS OF MONITORING, SURVEILLANCE AND FOR JACK INHIBIT HUBS TO THERE'S MONITORING -- INHIBITORS THERE'S MONITORING LOGICAL FUNCTION. AIM TWO TO DETERMINE IMPACT OF IMMUNE DISREGULATION, YESTERDAY I WENT TO DETAIL ABOUT THIS, HOW TO BRING DOWN INTERFERON SCORES, CAN WE BRING DOWN CYTOKINES, HOW ABOUT NEUROTOXIN METABOLITES CAN WE BRING THOSE DOWN? PRIMARY END POINT, CYTOKINES ARE SECONDARY AND MET TAB LOAM IS A TERTIARY END POINT. GOING THROUGH THE SKIN. WE HAVE SOME PRELIMINARY DATA SHOWING THAT JACK INHIBITION CAN HELP DOWN'S SYNDROME, SKIN CONDITIONS, DEPENDING ON TYPE OF CONDITION THERE WILL BE DIFFERENT TOOLS USED TO ASSESS IMPROVING OUR RISK IN PATHOLOGY, FALLOW PEE SHA IS A POOL FOR -- THE -- REGARDLESS OF SPECIFIC CONDITION, EVERYBODY WILL GET THIS GLOBAL ASSESSMENT OF DETERMINE TO LOGICAL QUALITY OF -- DETERMINE LOGICAL QUALITY OF LIFE. LAST BUT NOT LEAST ARE EXPLORATORY AIM IS TO LOOK AT IMPACT ON COGNITION QUALITY OF LIFE. THIS HAS BEEN TALKED ABOUT A LITTLE BIT TODAY. DIFFERENT AREAS OF NEUROLOGICAL& FUNCTION THAT ARE IMPACTED IN DOWN'S SYNDROME TO FRONTAL CORTEX, HIPPOCAMPAL FUNCTION, CEREBELLUM SO WE ARE LOOKING FOR POTENTIAL IMPROVEMENTS IN EACH OF O THESE AREAS WITH APPROPRIATE TESTS. THIS WILL BE DONE IN COLLABORATION WITH CO-INVESTIGATOR DEBBIE FIDLER, WITH COMBINATION OF PAPER BASED AN TABLET BASED ASSESSMENT THAT WILL LOOK AT IMPROVEMENT IN RECEPTOR LUNG WHICH INHIBITS CONTROL EPISODIC MEMORY, PROCESS AND SPEED, WORKING MEMORY, SPECIAL PROCESSING, AND SO ON. SO WE ARE VERY EXCITED ABOUT THIS, I SAID YESTERDAY WE WILL MANAGE EXPECTATIONS, FOUR MONTHS MAY NOT BE ENOUGH TO SEE SIGNAL BUT HAVING BASELINE MEASUREMENT WILL BE GREAT. MY TIME IS UP. SO WE ARE HERE. THIS IS THE QUARTER. WE ARE SUPPOSED TO START ENROLLMENT DEPENDING ON COVID-19. WE HOPE SO THAT WE CAN ENROLL THIS SUMMER. SO CREDITS. I WANT TO DO -- GIVE CREDIT TO KEY PEOPLE AMANDA (INAUDIBLE) CO-PI DEBBIE AS CO-INVESTIGATOR AND THE TYPE AT GLOBAL DOWN'S SYNDROME FOUNDATION, STRONG RESEARCHERS, VERY INVOLVED IN RESEARCH ACTIVITIES HELPING US GET THE WORD OUT WITH THE COMMUNITY ABOUT THESE ACTIVITIES. THANK YOU VERY MUCH. IT'S BACK TO YOU NOW. >> THANK YOU, OUR NEXT SPEAKER IS MIKE RAFII. >> HI, LAURIE, THANKS, I HAVE BEEN PRIVILEGED TO JOIN PRESENTATIONS YESTERDAY AND TODAY AND I WILL UPDATE YOU ON OUR R61 PROJECT WHICH IS THE TRIAL READY COHORT FOR DOWN'S SYNDROME OR TRACK DS. I WORK AT THE ATCT AUTISM CLINICAL TRIALS CONSORTIUM WHICH RUNS CLINICAL TRIALS FOR AD IN THE TYPICAL POPULATION. WE KNOW FROM OUR EXPERIENCE THAT IT APPEARS DISEASE MODIFICATION NEEDS TO OCCUR EARLY ON IN ALZHEIMER'S DISEASE PRIOR TO EXTENSIVE NEURODEGENERATION TO HAVE AN EFFECT. WE THINK THAT THE SAME IS GOING TO BE TRUE FOR ALZHEIMER'S DISEASE AND DOWN'S SYNDROME. THIS IS A FIGURE I SHOWED YESTERDAY WHERE NEUROPATHOLOGY ASSOCIATED WITH ALZHEIMER'S DISEASE BEGINS VERY EARLY IN LIFE IN ADULTS WITH DOWN'S SYNDROME PROVIDES US WITH THE OPPORTUNITY AND FAIRLY WIDE WINDOW BETWEEN AGE 25 AND 55 WHERE THERE'S DYNAMIC CHANGE IN VARIOUS BIOMARKERS TO TARGET ALWAYS MIRE'S DISEASE. SO OUR PROJECTS AIMS INCLUDE DEVELOPING A TRIAL READY COHORT FOR DOWN'S SYNDROME THAT PROVIDE SHORTER RECRUITMENT PERIODS FOR CLINICAL TRIALS AND TO OBTAIN PARTICIPANT LEVEL RUN IN DATA ON MULTIPLE PARAMETERS INCLUDING RATES OF COGNITIVE DECLINE AND CHANGE ON THE STANDARD BIOMARKERS, RATES OF ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS, AS WELL AS UNDERSTANDING THE IMPACT OF APE 4 ON CLINICAL EXPRESSION AND BIOMARKERS AND POTENTIALLY STRATIFYING PARTICIPANTS ON VARIOUS MEASURES INCLUDING APOE 4. THIS TRACK WILL I ALLOW US TO ENSURE THAT PARTICIPANTS HAVE STABLE MEDICAL CONDITIONS AND ARE ABLE TO COMPLETE ALL THE STUDY PROCEDURES. WE AIM TO ENROLL 120 WELL CHARACTERIZED MEDICALLY STABLE NON-DI MEANTED PARTICIPANTS WITH DOWN'S SYNDROME BETWEEN AGE 35 AND 55, AGAIN THAT BEING THE AGE RANGE WHERE WE THINK IS EARLY ENOUGH BEFORE THERE'S EXTENSIVE NEURODEGENERATION BUT YET THERE IS ONSET OF PATHOLOGY. THE TRACK IS ESSENTIALLY HARMONIZED IN ITS PROCEDURES TO THE ABCDS MEASURES. THE GOAL IS TO ESTABLISH METHODS WITHIN THE TRIAL READY COHORT SO THAT WE ARE COLLECTING STUDY DATA THAT WOULD ADHERE TO THE CDER REQUIREMENT FORS THE FDA IN TERMS OF ANY SUBMISSION ACROSS A 15 INTERNATIONAL SITES. SO WE ARE CAPTURING THE STUDY DATA, AND ENSURING THAT IT IS ADHERED TO FDA REQUIREMENTS. TRIAL READY COHORT ON THE LEFT IS ONE PART OF THE LARGER STUDY, THE R61 PHASE PROVIDES SUPPORT FOR THE NEUROSITE TESTING PHYSICAL EXAM, NEUROEXAM, SOME BLOOD LABS, BIOMARKERS, ECG, BRAIN MRI AND AMYLOID PET ALL HARMONIZED WITH THE ABCDS PROJECT. THIS WILL SET THE STAGE FOR THE R33 PHASE, AN ANTI-AMYLOID THERAPY IN A PLACEBO CONTROLLED STUDY OVER NUMBER OF YEARS. THIS WOULD HAVE BOTH BASELINE VISITS INTERVENING VISITS AND A LAST VISIT SO THAT WE CAN POTENTIALLY GET PHASE 2 DATA AND PROCEED TO A LARGER PHASE 3 STUDY. STATUS. THE PROTOCOL IS SENTLY FINALIZED, APPROVED BY THE ACTCDSNB. PROTOCOL AND IBFs ARE SUBMITTED TO CENTRAL IRB LATER IN THE MONTH AND PROTOCOL DISTRIBUTED TO OUR SITES IN JUNE. WE HAVE VENDOR AGREEMENTS AND ENGAGEMENT WITH THE UNITS ONGOING. AND SITE AGREEMENTS ARE BEING SENT OUT TO THE 15 SITES NOW. WE EXPECT SITES START UP TO OCCUR SOMETIME IN AUGUST WITH FIRST PATIENT FIRST VISIT OCTOBER OF THIS YEAR WITH THE CAVEAT WE ARE NOT SURE HOW COVID WILL IMPACT STUDY ACTIVITIES BUT THIS IS OUR EXPECTED TIME LINE. SO I'LL SOP THERE. THANK YOU. >> THANK YOU MIKE. LAST SPEAKER OF THIS SESSION IS IGNACIO TAPIA. >> HI. I'M ON MUTE. HELLO. I WILL UPLOAD MY SLIDES. >> WE CAN HEAR YOU. >> GOOD. THANK YOU AGAIN, THIS IS OUR R 61, 33 FOR THE TREATMENT OF OBSTRUCTIVE SLEEP APNEA SYNDROME IN CHILDREN WITH DOWN'S SYNDROME. THIS IS A MILLION CENTER STUDY, WITH INVESTIGATORS MYSELF, MELISSA RESEARCH COORDINATOR, STUDY WE HAVE INVESTIGATORS STACYISHMAN AND (INAUDIBLE) BUYERS IN RESEARCH COORDINATORS SUSIE HIX. WE HAVE FROM DATA COORDINATOR CENTER IS (INAUDIBLE) WHAT WE HAVE HEARD IS O SA RESULTS IN A PORTION OF DOWN'S SYNDROME (INDISCERNIBLE) REFER FOR POSITIVE PRESSURE THERAPY INITIATION DUE TO PERSISTENT OSA. WE HEARD ALSO YESTERDAY FROM (INAUDIBLE) IT APPEARS IMPORTANT FEATURE OF EXPERIENCE LIVING WITH DOWN'S SYNDROME, IMPROVE OSA ASSOCIATED SYMPTOMS, (INAUDIBLE) STUDIED IN CHILDREN WITH DS. FROM MEASURING HERE POSTER PRESSURE WITH CPAP AND -- BY LEVEL POSITIVE AIR PRESSURE ASSUMPTION. (INAUDIBLE) IMPORTANT REPORTED OUTCOMES FOR IMPORTANT GAP -- AMONG THIS POPULATION. WE PLAN R61 33, R61 IS MIXED METHOD STUDY, THAT IMPACT ACCEPTABILITY AND IDENTIFY FAMILY CENTER OUTCOMES TO FORM R33 PHASE. THIS GRANT. R61 WE ARE ENROLLING A (INAUDIBLE) CHILDREN WITH DOWN'S SYNDROME SLEEP APNEA, WHO HAVE BEEN TREATED WITH (INAUDIBLE) OUR GOAL WAS TO ENROLL 20 PARTICIPANTS AND WE HAVE ALREADY ENROLL COMPLETED (INAUDIBLE). >> IGNACIO, YOUR SLIDES ARE NOT ADVANCING. WE ARE STILL ON MULTI-SLIDE 2 IT IS NOW ON BACKGROUND SLIDE NUMBER THREE. >> BACK TO FIRST ONE. IGNACIO? IF YOU LIKE WE CAN PRESENT YOUR SLIDES ON THIS END. AND JUST TELL ME WHAT SLIDE NUMBER YOU ARE ON. AND THEN YOU CAN SAY NEXT SLIDE. >> START WITH 4 PLEASE. >> OKAY. HOLD ON A SECOND. LET ME CHANGE THE -- >> HOLD ON, LET ME PULL UP THE SLIDE. YOU ARE ON SLIDE NUMBER FOUR. >> YES. >> I THINK WE MAY HAVE LOST YOU. >> I'M HERE. >> CAN YOU TELL ME NEXT SLIDE? IS THIS THE RIGHT SLIDE? >> YES. EXCELLENT. CAN YOU HEAR ME? IT IS THE RIGHT SLIDE. NEXT SLIDE. NEXT SLIDE. >> SO WE ARE ON THE AIMS FOR THE R33 SLIDE. >> NEXT SLIDE. NOT SHOWING UP ON MY SCREEN. WOMEN AND CHILDREN WITH DOWN'S SYNDROME, BEHAVIORAL INTERVENTION >> DO YOU MIND IF WE TAKE A QUICK BREAK? RIGHT HERE? BECAUSE WE WANT -- MAYBE FOR YOU TO HAVE YOU LOG OUT AND TRY DIALING BACK IN. I THINK THERE'S AN ISSUE AROUND CONNECTION. SO WE ARE GOING TO MOVE THE BREAK UP SO THE MORNING BREAK WILL TAKE ABOUT A FIVE MINUTE BREAK. AND THEN IF YOU CAN LOG BACK OUT AND RYE LOGGING BACK IN AND THEN AFTER THAT BREAK WE WILL THEN MOVE TO THE NEXT -- AFTER DR. TAPIA'S PRESENTATION WE WILL MOVE TO THE NEXT SESSION ON THE CLINICAL TRIAL INFRASTRUCTURE. INGS >> HI, IGNACIO. >> YES. >> WE CAN GET STARTED. >> SO WE WILL START FROM SLIDE THREE, WE WILL FAST FORWARD IN THE SLIDES. IF YOU CAN NOT SEE ME ADVANCING, CAN YOU TELL ME? I WILL SAY EVERY TIME I'M ADVANCING THE SLIDE. >> ABSOLUTELY. GO AHEAD. >> SO FOR BACKGROUND, WE BRIEFLY DISCUSSED THAT (INAUDIBLE) STUDY IN CHILDREN, WHAT WE KNOW ABOUT PRELIMINARY DATA IS NEUROBEHAVIORAL SYMPTOMS IMPROVE HOWEVER THIS MAY DEPEND ON ADHERENCE. ALSO WE NEED TO KNOW THE FAMILY AND PATIENT REPORTED OUTCOME IMPORTANT FOR THIS POPULATION. NEXT SLIDE. THE R61 IS THE MIX METHOD TRIAL, THIS MIXED METHOD STUDY TO IDENTIFY FACTORS THAT IMPACT ABILITY AND USE AND IDENTIFY FAMILY CENTER OUTCOMES TO INFORM THE R33 PHASE. PARENTS AND AIR GIVES OF CHILDREN WITH DOWN'S SYNDROME OSA WHO HAVE BEEN TREAT WITH PAP FOR SIX MONTHS ARE ENROLL. WE HAVE THE GOAL OF ENROLLING 20 PARTICIPANTS PER SITE WE COMPLETED 22 OF THESE INTERVIEWS. THESE INTERVIEWS WERE ALREADY PLANNED TO BE DONE REMOTELY AND NOT IMPACTED BY COVID AND WE CONTINUE THIS STUDY AS PLANNED. IS SUPPOSED TO LAST 18 MONTHS, WE CONTINUE WITH R33 PHASE, RAN TOMMIZE CONTROL TRIAL ABOUT ADHERENCE IN CHILDREN WITH DOWN'S SYNDROME, THAT ADHERENCE IS SIX MONTHS INTENSIVE BEHAVIORAL INTERVENTION THAT IS MULTI-COMPONENT FAMILY BASED INCLUDING BEHAVIORAL STRATEGIES, LEARNING AND CONTINGENCY MANAGEMENT, MOTIVATIONAL ENHANCEMENT AND ENGAGING IN STRATEGIES WITH EMPHASIS ON INVOLVEMENT. THE OUTCOMES THAT MEASURE AT SIX AND 12 MONTHS, INTERVENTION LASTS SIX MONTHS BUT WE WANT ALSO TO MEASURE 12 MONTHS TO SEE ANY CHANGES THAT WE MAY SEE. CONTINUE AFTER THE INTERVENTION. THE AIM OF THE R33 IS TO QUALITY OF LIFE NEUROBEHAVIORAL OUTCOMES AND CHARACTERIZATIONSES WE HYPOTHESIS WITH RESPECT TO STUDY ARM INCREASE ADHERENCE WILL BE ASSOCIATED WITH BETTER QUALITY OF LIFE, NEURAL BEHAVIORAL CHARACTERIZATIONS OUTCOMES. WE ALSO WANT TO EVALUATE EFFECTS OF PAP ADHERENCE IN CHILDREN WITH DOWN SYNDROME OSA ON PATIENT CENTER OUTCOMES AND FAMILY RELEVANT OUTCOMES, IDENTIFIED DURING THE R61 PHASE OF RESEARCH AND WE HYPOTHESIZE THIS WILL IMPROVE ADHERENCE. WE ALSO WANT TO DETERMINE EFFICACY OF INTENSIVE INTERVENTION TO CONTROL INTERVENTION UNDER STANDARD OF CARE PROMOTING PAP ADHERENCE. WE HYPOTHESIZE CHILDREN RECEIVING INTENSIVE INTERVENTION WILL SHOW SIGNIFICANT INCREASE OBJECTIVE MEASURE PAP ADHERENCE& AT SIX MONTHS COMPARED TO THOSE WHO RECEIVE CONTROL. WE WILL EVALUATE WHETHER IMPROVED ADHERENCE IS MAINTAINED OVER 12 MONTHS, SIX MONTHS AFTER INTERVENTION HAS FINALIZE. ALSO WE USE MIXED METHOD DURING RANDOMIZE CONTROL TRIAL AT SIX AND 12 MONTHS TO IDENTIFY FAMILY PERCEPTION NOT JUST -- EFFICACY, REGARDING PAP USE IN YOUTH WITH OSA AND DOWN'S SYNDROME. WE HYPOTHESIZE THAT THOSE RANDOMIZE TO THE INTENSIVE PATH INTERVENTION WILL HAVE BETTER POSITIVE RECEPTIONS COMPARED TO THOSE RANDOMIZE WITH CONTROL. THE INCLUSION CRITERIA ENROLLING DYADS OF CAREGIVER AND CHILD. CHILDREN AGE 6 TO 10 YEARS WITH DOWN'S SYNDROME REFER TO TREATMENT WITH PAP SO THIS WOULD BE THE FIRST TREATMENT WITH PAP, HAS TO BE -- TO TREATMENT WITH PAP. BOTH SEXES AND ALL RACES AND ETHNIC GROUPS ARE ELIGIBLE FOR PARTICIPATION. IN TERMS OF EXCLUSION CRITERIA, WILL EXCLUDE A CHILD WITH MAJOR ILLNESS SUCH AS LEUKEMIA, SIGH NOTTIC CONGENITAL HEART DISEASE LISTED FOR TRANSPLANT BUT MAY NOT BE ABLE TO COME TO THE VISITS. FAMILY PLANNING TO MOVE OUT OF AREA WITHIN A YEAR BECAUSE THEY WON'T BE ABLE TO COMPLETE STUDY. FORTUNATELY WE HAD TO EXCLUDE FAMILIES WHO DO NOT SPEAK ENGLISH WELL ENOUGH TO COMPLETE THE MEASURES. ALSO CHILD (INAUDIBLE) WE DON'T KNOW WHETHER THE CENTER WILL BE WITH THE CHILD FOR A YEAR, PREVIOUS DUE TO PAP BECAUSE THIS INTERVENTION IS INITIATION OF PAP. SO STUDY PARTICIPANTS WILL BE RECRUITED FROM BOTH SIDES SLEEP AND PULMONARY CLINICS AND SLEEP LABORATORIES. AND THIS IS THE DIAGRAM. YOU CAN SEE MY MOUSE HERE. WE HAVE PARTICIPANTS WITH PAP INITIATION, INTERVIEW CONSENT, WE DO IT IS BASELINE ASSESSMENTS THEN RANDOMIZE TO INTENSIVE IN RED AND IS THAT STANDARD OF CARE IN BLUE. THEY HAVE PRACTICALLY THE SAME VISITS BUT DISEASE INTERVENTION INCLUDES PSYCHOLOGY WHETHER THOSE STANDARD OF CARE DOES NOT ALSO IN TERMS OF INTERVENTION RECEIVE FREQUENT TECHNOLOGIES AT THE WEEKS LISTED THERE. AND TEXTING ON A NEEDED BASIS AND ALSO TO HAVE FULL CONTENT WITH RESEARCH COORDINATOR, THOSE STANDARD OF CARE, THEIR ALL OF OTHER CONTEXT BUT FAMILY WILL INITIATE PHONE CALLS ON AS NEEDED BASIS. WE WILL NOT BE INITIATING PHONE CALLS, OURSELVES. THEN WE HAVE WE EXPECT ALL CHILDREN TO HAVE TITRATION STUDY WITHIN THREE MONTHS AND AT SIX MONTHS HAVE VISIT WITH TEAM AND 12 MONTH WE WILL MEASURE THE OUTCOMES. FROM ARE THE THIS IS THE STUDY ASSESSMENTS THAT WE HAVE, THE TABLE IS YOU CAN SIGH BUT ALL WE ARE COLLECTING IN TERMS OF NEUROBEHAVIORAL TESTING THE CHILDREN WILL BE PERFORMING THEMSELVES THE TECH BOARD AND GO NO GO AS MEASURES OF EXECUTIVE FUNCTION WE HAVE BEEN USE THESE MEASURES IN THE -- OUR HEALTHY STUDY WHICH IS A SUPPLEMENTAL SELECTION STUDY. SO WE HAVE EXPERIENCE ALREADY ADMINISTERING THOSE MEASURES TO CHILDREN. THEY ARE VERY SHORT, LAST ABOUT 30 MINUTES BOTH TO COMBINE. RESPONDING TO QUESTIONNAIRES CALL OF LIFE OR SAY IN SLEEP QUESTIONNAIRE. WE ALSO WANT TO KNOW HOW THE FAMILY FUNCTIONS, IF STRESS, WHAT IS LITERACY MEDICINE, AND ET CETERA. THANK YOU, THAT'S IT. >> THANK YOU, OUR NEXT SESSION ON CLINICAL TRIAL INFRASTRUCTURE. I WILL HAND IT TO OUR SESSION MODERATOR, STEVE ABMAN. STEVE. >> HI, GOOD MORNING, EVERYBODY. REALLY DELIGHTFUL COUPLE OF DAYS HERE AND I WANT TO THANK LAURIE AND ERICA, DR. BIANCHI AND OTHERS, THIS IS A REMARKABLE MEETING, PULLING OFF SOMETHING THAT'S VIRTUAL, IT IS A CHALLENGE AND IT'S GONE VERY WELL. I'M ALSO IMPRESSED BY SO MANY PEOPLE ACROSS DIFFERENT DISCIPLINES AND BACKGROUNDS HAVE COME TOGETHER FOR THIS. I WANT TO THANK EVERYBODY FOR ALLOWING ME TO PARTICIPATE HERE. MY GOAL FOR TODAY IS TO DISCUSS THE DOWN'S SYNDROME PATIENT REGISTRY QUESTIONS RELATED SPECIFICALLY TO PULMONARY HYPERTENSION. AND I WOULD LIKE TO USE THIS, IT'S FOCUSED ON PH OR PULMONARY HYPERTENSION YET SOME OF THE PRINCIPLES OF WHAT WE ARE DOING THERE MAYBE RELEVANT TO MANY OF YOU WHO ARE NOT TYPELY ENGAGED -- DEEPLY ENGAGEDDED IN CARDIO PULMONARY DISEASE. SEE IF I CAN ADVANCE. FIRST DISCLOSURES, I HAVE PHARMACEUTICAL SUPPORT FROM UNITED THERAPEUTICS FOR LABORATORY RESEARCH. INVOLVED WITH DATA SAFETY MONITORING BOARDS FOR COUPLE OF PHARMACEUTICALS, UNITED AND BAYER, EDUCATIONAL GRANT FUNDING FOR YOUNG INVESTIGATORS FOR MELANCROFT, BUT WHAT I WOULD LIKE TO TO DO IS PRESENT UNIQUE FEATURES OF PULMONARY HYPERTENSION IN CHILDREN WITH DOWN'S SYNDROME WITH DATA FROM SINGLE CENTER AND MULTI-CENTER REGISTRIES. I WOULD LIKE TO THEN EXPLORE SOME OF THE UNDERLYING DISEASE MECHANISMS, THAT CONTRIBUTE TO THE INCREASE SUSCEPTIBILITY FOR PULMONARY HYPERTENSION IN CHILDREN WITH DOWN'S SYNDROME. DISCUSS POTENTIAL BIOMARKERS TO ENABLE MORE SUCCESSFUL RESEARCH TO HELP PREDICT OUTCOMES AND IMPROVE RISK STRATIFICATION OR DEFINE ENDOTYPES IN DOWN'S SYNDROME RELATED PH. FINALLY TO HIGHLIGHT ONGOING WORK FROM OUR PEDIATRIC PULMONARY HYPERTENSION NETWORK FOR PATIENT REGISTRY TO IMPROVE OUR CARE OF CHILDREN WITH DOWN'S SYNDROME IN PULMONARY HYPERTENSION. AS WE HEARD NICELY THE OTHER DAY PULMONARY HYPERTENSION CONTRIBUTES SIGNIFICANT MORTALITY AND HIGH MORBIDITY, IN CHILDREN WITH DOWN'S SYNDROME AND OCCURS IN 25 TO 30% OF CHILDREN WITH DOWN'S SYNDROME. IT CRIBS TO PROBLEMS ESPECIALLY SETTING OF HEART DISEASE AND LEADS TO FAR WORSE DEGREE OF PULMONARY HYPERTENSION THAT MAYBE OBSERVED IN NON-DOWN'S SYNDROME SUBJECTS, FOR A GIVEN CONGENITAL HEART DISEASE LESION. ALSO THEIR CARE IS MORE PROBLEMATIC. THEY HAVE POST-OPERATIVE MANAGEMENT ISSUES, LONGER DURATION OF MECHANICAL VENTILATION, GREATER NEED FOR ION TROPIC SUPPORT TO MAINTAIN CARDIAC SYSTEMIC HEMODYNAMICS. MORE DAYS IN THE ICU. BUT ALSO TALK ABOUT PULMONARY HYPERTENSION THERE'S SIGNIFICANT SUBGROUP OF INFANTS WITHOUT ANATOMIC HEART DISEASE, IN WHICH A SIGNIFICANT CO-MORBIDITY OF THAT LEADS TO THIS PROBLEM AND LEADS TO RECURRENT HOSPITALIZATIONS, PERHAPS POOR RESPONSES TO LUNG INFECTION THAT WE HAVE HEARD SO MUCH ABOUT. AND OTHER ITOLOGIES AND PROBLEMS. SO THE DIAGRAM I WILL INVESTIGATES WHEN WE THINK ABOUT THE MANY CAUSES OF PULMONARY HYPERTENSION, THERE ARE ELEMENTS IN EACH ISSUE, HEMODYNAMICS FROM HEART DISEASE, LUNG HYPOPLASIA, I'LL SPEAK MORE IN A MOMENT. END HEELIAL DYSFUNCTION WHICH IS DIRECTLY RELATED TO HIGH RISK FOR PH IN DOWN SYNDROME SUBJECTS AND ALSO ACQUIRED LUNG DISEASE AND OTHER KINDS OF ISSUES THAT LEAD TO THIS COMPLICATION. WHEN ONE LOOK AT THE CO-MORBID CONDITIONS LISTED HERE IN ADDITION TO CARDIAC ONE CAN SEE A NUMBER OF PULMONARY ISSUES. THAT IS LUNG HYPOPLASIA, OBSTRUCTIVE SLEEP APNEA, RECURRENT PNEUMONIA, RECURRENT ASPIRATION AND ASTHMA AND OTHER KINDS OF CONDITIONS ALL CONTRIBUTE TO PH IN PERSONS IN DOWN SYNDROME. AND THEY ALL LEAD TO THE SIGNIFICANT CLINICAL COURSE WE SEE. WE DID A SINGLE CENTER STUDY, THIS WAS DONE IN COLORADO, THANKS IN LARGE PART TO FAN HICKEY WHO RUNS THE CENTER THERE AND WE STARTED TO EXPLORE SOME OF THE PULMONARY HYPERTENSION PHENOTYPES IN CHILDREN WITH DOWN'S SYNDROME. YOU CAN SEE ON THE LEFT A LISTING OF CO-MORBIDITIES THAT ARE OFTEN ASSOCIATED WITH PULMONARY HYPERTENSION PERHAPS THE MOST VIKING FEATURE IS MANY FORMS OF PH, THEY CAN BE TRANSIENT IN EARLY IN MANY CHILDREN, OFTEN CONTRIBUTING TO PERSISTENT PULMONARY HYPERTENSION OF NEWBORN AFTER BIRTH. IT CAN RESOLVE OR PERSIST INTO INFANCY. OR MAY HAVE ONSET IN I HAVE BEEN FANCY THAT THEN PERSISTS LATER IN CHILDHOOD. WE HAVE MANY CHILDREN WITH DOWN'S SYNDROME WHO HAVE A PARENT RESOLUTION OF PULMONARY HYPERTENSION, ONLY TO HAVE IT RETURN LATER DUE TO SECONDARY CO-MORBIDITIES SUCH AS INFECTION, HYPOXIA, SLEEP APNEA AND OTHER ISSUES. SO THREE DIFFERENT PHENOTYPES IN MULTIPLE CO-MORBIDITIES HAVE MADE THE CARE OF CHILDREN WITH DOWN'S SYNDROME PULMONARY HYPERTENSION MORE PROBLEMATIC. SO CURRENT BEHAVIORS AND CURE OF CHILDREN ASSOCIATED WITH PULMONARY HYPERTENSION WE HAVE LIMITED UNDERSTANDING OF DISEASE SPECIFIC MECHANISM THIS IS THIS SETTING. WE KNOW THERE'S HETEROGENEITY OF CO-MORBIDITIES AS WE DISCUSSED. THERE'S BEEN A LACK OF ORGANIZED INTERDISCIPLINARY CARE FOR PH AT MANY SITES. IN OTHER WORDS OFTEN CARDIOLOGIST DEAL WITH PULMONARY HYPERTENSION BUT AS MENTIONED IT'S THE PULMONARY COMPONENTS THAT LEAD TO THESE ISSUES AND MANY OTHER INTERDISCIPLINARY GROUPS ARE NEEDED TO HELP TACKLE THESE PROBLEMS. EACH CENTER HAS SMALL NUMBERS OF PATIENTS TO DO SUFFICIENT RESEARCH. WE LACK WELL VALIDATED END POINTS FOR ASSESSING CLINICAL COURSE RESPONSE TO THERAPY. OUR CURRENT APPROACH IS BASED ON NOW DOWN'S SYNDROME SUBJECTS OR ADULT DATA. WE HAVE AN ABSENCE OF SYSTEMATIC AND CENTRALIZED DATABASE FOR CHILDREN WITH DOWN'S SYNDROME. AND WE HAVE THE LACK OF INFRASTRUCTURE FOR MULTI-CENTER TRIALS AND CLEARLY THERE IS NEED FOR GREATER INTERDISCIPLINARY TRAINING. SO YOU CAN SEE IN THE BOTTOM RIGHT IT SAYS PPH NET DENVER 2008. WE CALLED TOGETHER A GROUP OF LEADERS FROM MAJOR PULMONARY HYPERTENSION PROGRAMS FROM AROUND NORTH AMERICA AND ASKED THEM TO COME TO COLORADO TO ESTABLISH THE PPH NET. THE IDEA IS CLINICAL RATIVE MULTI-DISCIPLINARY NETWORK, CREATE LONGITUDINAL REGISTRY OR DATABASE TO FIND NATURAL HISTORY, THAT MAY INCLUDE ABILITY TO PERFORM OBSERVATIONAL STUDIES INTERVENTIONAL TRIALS, DEVELOP BIOMARKER, GENETIC GENOMIC AND PROTEOMIC STRATEGIES TO UNDERSTAND DISEASE PATHOBIOLOGY AND ESTABLISH A BIOREPOSITORY THAT CAN HELP ENRICH THE SCIENCE BEHIND OUR CLINICAL RESEARCH. FINALLY REALLY PURSUE THE MISSIONS OF EDUCATION, TRAINING AND ADVOCACY WORKING WITH THE FAMILY SUPPORT GROUPS LIKE PULMONARY HYPERTENSION WE ARE LAUNCHED BY PARENTS OF CHILDREN WITH PULMONARY HYPERTENSION, THIS WAS IN PART BY NIH AND I WANT TO THANK CAROL THE NHLBI LUNG DIVISION CHIEF AT THE TIME IN PEDIATRICS. SHE HELPED BRING TOGETHER ADULTS IN PEDIATRIC WORLDS AND DEVELOP WORKSHOP IMPROVING OUTCOMES FOR PULMONARY VASCULAR DISEASE. WE CLEARLY STATED FROM THAT WORKSHOP SUMMARY THE NEED TO DEFINE THE LONGITUDINAL COURSE NATURAL HISTORY, OF SPECIFIC PEDIATRIC POPULATIONS INCLUDING PREMATURE INFANTS, SETTING OF DEVELOPMENTAL LUNG DISEASE, HIGHLIGHTED DOWN SYNDROME AT THAT TIME. RECOGNIZING HOW OFTEN WE SEE CHILDREN WITH PH IN OUR CLINICS, AND HOW LITTLE IS REALLY UNDERSTOOD AT THAT TIME. HEART DISEASE AND OTHER DISORDERS AND WE REALIZE WE NEEDED TO DEVELOP A DISEASE CLASSIFICATION AND FUNCTIONAL CLASS SYSTEM THAT SPECIFIC FOR CHILDREN AS WELL AS UNDERSTANDING AGE RELATED AND DISEASE SPECIFIC END POINTS AND MARKERS. SO WE DEVELOP THIS NETWORK THAT WE GO THROUGH THREE DIFFERENT PHASES AS YOU CAN SEE HERE. THE UNFUNDED MANDATE, IN ORDER THIS DID NOT START WITH FUNDING FROM THE NIH OR OTHER SOURCES BUT JUST FROM THE COMPASSION AND RECOGNIZE NEED WE HAVE TO GET TOGETHER AS A GROUP TO BETTER UNDERSTAND KIDS WITH PH. SO WE BEGIN BY IDENTIFYING OUR NEEDS AND ESTABLISHING THE INFRASTRUCTURE THAT'S HIGHLIGHTED HERE. AND OVER TIME PROGRESS TO DEVELOP FAIRLY EFFECTIVE REGISTRY, STRONG WEBSITE, ORGANIZATIONAL RULES, COLLECTION OF OPTIMAL GUIDELINES FOR CARE OF THESE KIDS AND MANY OTHER CHALLENGES THAT ARE SHOWN HERE. SO WHAT REALLY HELPED US LAUNCH IN THIS EARLY PERIOD WAS RESPONSE TO NIH PROGRAM RFA, WE DECIDED TO ADDRESS THIS TO HELP DEVELOP OUR REGISTRY. SO WE CALL IT A DATA FUSION THAT IS DEVELOPING A SUSTAINABLE SCALABLE SOURCE REGISTRY FOR PEDIATRIC PULMONARY VASCULAR DISEASE, AND GOAL WAS TO DEFINE COMPUTABLE PHENOTYPES OF PULMONARY VASCULAR DISEASE USING INNOVATIVE INFORMATICS STRATEGIES WITH TRADITIONAL REGISTRY. TO CHARACTERIZE CO-MORBIDITIES AID ASSOCIATED WITH PEDIATRIC PULMONARY VASCULAR DISEASE, IDENTIFY SURROGATES AND END POINTS IN RESPONSES TO DRUG THERAPIES INCLUDING BENEFITS AND HARM. I WON'T GO THROUGH DETAILS BUT REALLY COMPARING ELECTRONIC HEALTH RECORD COLLECTION WITH REGISTRY DATA ITSELF. COMPARING AND CONTRASTING THE RELATIVE MERITS OF EITHER OF THOSE ALONE AS SOURCES OF INFORMATION AND DATA. AND WHETHER COMBINING THOSE COULD LEAD TO GREATER SUCCESS AND MORE ACCURATE INFORMATION. WE ARE BEGINNING TO WRITE PAPERS ON THIS, WE HAVE 1500 PATIENTS ENROLLED. THIS ILLUSTRATES THE BREAKDOWN OF THE GROUPS OF KIDS THAT WE HAVE HERE ACCORDING TO THE CLASSIC FIVE DIFFERENT TYPES OF PULMONARY HYPERTENSION. WHAT IS STRIKING HERE IN KIDS THAT HASN'T BEEN DESCRIBED BEFORE, IS THAT WHEN WE THINK OF SO CALLED GROUP ONE DISEASE ON YOUR RIGHT, WHICH CONSTITUTES NEARLY HALF OF THE POPULATION, EVEN MORE SIZABLE WAS THE GROUP 3, PULMONARY HYPERTENSION WITH LUNG DISEASE AND HYPOXIA, THAT INCLUDES BBD AND DIAPHRAGMATIC AND OTHER SETTINGS SO THIS IS ANAGRAM EXAMPLE HOW REGISTRIES INFORM US WHAT WE THOUGHT WE KNEW BEING ACTIVE IN THE CLINIC AND USING IT TO EXPLORE MANY DIFFERENT QUESTIONS. WHAT REALLY HELPED WAS SUPPLEMENT TO THE UO 1, AND PART OF THIS PROGRAM OVERALL IN WHICH WE CAN SPECIFICALLY LOOK AT DOWN SYNDROME. BECAUSE WE HAD A NUMBER OF SUBJECTS ENROLLED WITH DOWN SYNDROME AND THIS IS JUST SOME EARLY DATA UNPUBLISHED THAT WE ARE BEGINNING TO TEASE OUT FROM THE REGISTRY, AND IT REALLY SHOWS THAT WHEN WE LOOK AT THE CLASSIFICATION PATTERNS, ALTHOUGH GROUP ONE WITH CONGENITAL HEART DISEASE IS THE LARGEST COMPONENT, AGAIN THERE IS A SIGNIFICANT GROUP 3 COMPONENT WITH PRY MAY RECALL LUNG DISEASE. WE ARE BEGINNING TO QUANTIFY SOME OF THE CO-MORBIDITIES AS SHOWN ON THE TABLE ON THE RIGHT OF RESPIRATORY DISORDERS, EARWAY ISSUES, THE NEED FOR ENT PROCEDURES AND OTHER CONDITIONS THAT TRAVEL OR CO-TRAVEL WITH PULMONARY HYPERTENSION, THIS IS WHAT WE ARE DOING WITH THE REGISTRY AT THIS MOMENT TO BETTER EXPLORE DOWN'S SYNDROME RELATED PH. MECHANISTICALLY, WE WANT TO LINK IT WITH WHY ARE THESE KIDS MORE RISK FOR DEVELOPING PULMONARY HYPERTENSION? IT REALLY GOES BACK TO OLD STUDIES BY A PEDIATRIC SURGEON, A MARVELOUS GUY AT HARVARD, HE NOTICED THAT DOWN'S SYNDROME SUBJECTS OFTEN HAD LOWER RISK FOR SOLID TUMORS, AND HE HAD THIS IDEA THAT BLOOD VESSEL GROWTH TO CANCER REALLY LED TO THEIR DEVELOPMENT AND PROGRESSION. HE NOTEDDED THAT IN THE BLOOD OF PERSONS WITH DOWN'S SYNDROME THERE WERE ELEVATED LEVELS OF SOMETHING CALLED ENDOSTATIN WHICH IS A POTENT ANTI-ANGIOGENIC FACTOR. SO WE HAD DONE A NUMBER OF LABORATORY AND CLINICAL STUDIES IN PREMATURE NEWBORNS AND HAD THIS CONCEPT, THAT IF YOU DISRUPT ANGIOGENESIS, DISRUPT BLOOD VESSEL GROWTH IN DEVELOPING LUNG YOU ALSO IMPAIR ALVEOLAR AIR SPACE GROWTH LEADING TO HIGH RISK FOR PULMONARY HYPERTENSION AS WELL AS LUNG HYPOPLASIA. WORK FROM CHABA GALAMBOS AT COLORADO AS PART OF THE DOWN'S PROGRAM HIGHLIGHTS PULMONARY VASCULAR COMPONENTS OF DOWN'S SYNDROME. YOU CAN SEE THE EVIDENCE OF ALVEOLAR SIMPLIFICATION BY LUNG HISTOLOGY SHOWIN WIDE DILATED AIR SPACES THAT TOO OFTEN CONTRIBUTE TO MORBIDITIES IN OUR CHILDREN WITH DOWN'S SYNDROME. WITH OR WITHOUT HEART DISEASE. DELAYED VASCULAR DEVELOPMENT IS HIGHLIGHTED BY PROMINENT DOUBLE CAPILLARY NETWORK AND HERE YOU SEE A SLIDE THAT ILLUSTRATES THIS CLUSTER OF BASICALLY TWO TRACKS OF RED BLOOD CELLS GOING THROUGH VESSELS, THAT NORMALLY SHOULD BE ONE, THEY HAVEN'T FUSED YET SO THERE'S DELAYED DEVELOPMENT CONTRIBUTING. REMODELING IS SHOWN HERE WITH STRIKING CHANGES THAT OBSTRUCTIVE TO THE BLOOD VEES SELLS AND I WON'T GO INTO DETAIL BUT THEY ALSO SHOW THIS UNUSUAL PATTERN OF BLOOD VESSELS THAT LINK LUNG BLOOD VESSELS THAT NORMALLY PICK UP OXYGEN, WITH SYSTEMIC BLOOD VESSELS. THAT NORMALLY DON'T REALLY PROFUSE DISSAL LUNG. THE SHUNT VESSELS ARE VERY IMPORTANT BECAUSE THEY CAUSE LOW EXGENERAL TENSION WITHOUT SEVERE PULMONARY HYPERTENSION. SO KNOWING THAT HE HEN EXPLORED HUMAN LUNG TISSUE AND FOUND THAT FETUSES AND INFANTS WITH DOWN'S SYNDROME HAD A MARKED INCREASE IN ANTI-ANGIOGENIC FACTORS. THIS ILLUSTRATES THE MARKED INCREASE ENDOSTATIN mRNA, WE ALSO KNOW THAT ENDOSTATIN PROTEINS ELEVATED AS WELL AS OTHER FACTORS THAT ARE EXPRESSED ON CHROMOSOME 21. THESE INCLUDE COLLAGEN 18, ENDOSTATIC AMYLOID PROTEIN PEPTIDES, SCR 1, ALL ANTI-ANGIOGENIC FACTORS MARKEDLY UPREGULATE AND THE ANTI-ANGIOGENIC GENES LEAD TO A DELAYED VASCULAR GROWTH IN THE LUNG AND LUNG HYPOPLASIA MAKING OUR CHILDREN MORE SUSCEPTIBLE FOR DISEASE OVER TIME. THAT'S CORRELATE NICELY WITH CIRCULATING MARKERS WE HOPE TO USE PROFILES TO HELP FURTHER CHARACTERIZE OUR CHILDREN WITH DOWN'S SYNDROME TO SEE WHO IS AT RISK FOR PULMONARY HYPERTENSION TO ENABLE EARLY IDENTIFICATION OR RISK STRATIFICATION FOR CLINICAL TRIALS. FINALLY WE LEARN SO MUCH ABOUT DOWN'S SYNDROME FOR CHILDREN AND YOUNG ADULTS AND ADULTS WHO DEVELOP PULMONARY HYPERTENSION IN THAT SETTING BUT TURNS OUT IN ABSENCE OF DOWN'S SYNDROME, WHAT WE LEARN FROM DOWN'S SYNDROME INFORMS US OF OLDER CHILDREN OR ADULTS WITH PULMONARY HYPERTENSION. THIS PAPER CAME OUT OF HOPKINS THAT ILLUSTRATES WITH HIGHER LEVEL OF ENDOSTATIN THE ANTI-ANGIOGENIC FACTOR FIRST APPRECIATED IN DOWN'S SYNDROME, BUT MEASURE IN SUBJECTS WITHOUT DOWN'S SYNDROME IT CORRELATES WITH WORST FUNCTIONAL CLASS, WORST EXERCISE TOLERANCE BY SIX MINUTE WALK DISTANCE AND WORSE SURVIVAL. SO THIS IS AN EXAMPLE HOW WE LEARN SO MUCH THAT GOES BACK AND FORTH BETWEEN WHAT WE CAN LEARN ABOUT THE DISEASE COURSE IN DOWN'S SYNDROME THAT INFORMS PULMONARY HYPERTENSION MORE BROADLY. FINALLY WHEN WE LOOK AT THE SCHEMATIC YOU HAVE SEEN THIS BEFORE ON THE LEFT COLUMN, HIGHLIGHTING THESE ANTI-ANGIOGENIC FACTORS. AND THEY ARE LISTED THERE, ENDOSTATIN IS COLLAGEN 18, WE REPORTED BEFORE, LEAD TO SMALLER AND FEWER ALVEOLAR AIR SACKS DELAYED GROWTH IN ARTERIAL MODELING. WHICH MEANS MANY THE LUNG IF YOU HAVE ANY DEGREE OF SHUNT WITH CONGENITAL HEART DISEASE OR CONSTRUCTIVE SLEEP APNEA YOU ARE AT RISK FOR ACCELERATED PULMONARY HYPERTENSION THAT'S PART OF THE CLINICAL PROCESS. SO OVERALL PULMONARY FUNCTION IN NEONATES IN DOWN'S SYNDROME PRESENTS CHALLENGES, INSUFFICIENT CHARACTERIZATIONS OF DISEASE SPECIFIC PHENOTYPES AND BIOMARKERS, AND CLEARLY A NEED FOR SUFFICIENT INFRASTRUCTURE TO PROMOTE MULTI-SITE INTERDISCIPLINARY REGISTRIES TO OPTIMIZE CLINICAL CARE AND RESEARCH INCLUDNG CLINICAL TRIALS. I WANT TO ACKNOWLEDGE FOLKS IN COLORADO WE HARD FROM QOAKIN AND FAN HICKEY AND CHAVA THE PATHOLOGIST AND OTHERS AND PPH MEMBERS AND SITES AS SHOWN HERE. THEN FINALLY, ACKNOWLEDGMENTS FOR ALL THE SUPPORT, CAROL IN THE PAST, ARUN HAS BEEN A FANTASTIC ADVOCATE FOR PULMONARY HYPERTENSION IN WAS WITH DOWN'S SYNDROME AND HERE ARE SOME OF THE NIH GRANTS WE ARE USING AND THANKS FOR YOUR ATTENTION. >> YOU ARE MODERATOR FOR THIS SESSION. DO YOU WANT TO GO AHEAD AND INTRODUCE OUR NEXT SPEAKER? >> YES. THANK YOU. THE -- SO WE ARE GOING TO HEAR MORE ABOUT CLINICAL TRIALS INFRASTRUCTURE TRILLION BARTUNG A Ph.D. SCIENTIST AT NICHD AND SHE WILL TELL US ABOUT THE DOWN SYNDROME CONNECT REGISTRY. >> THANK YOU, CAN YOU HEAR ME? >> YES. >> CAN YOU SEE MY SCREEN? >> VERY NICELY, THANKS. >> OKAY. I KNOW THERE HAVE BEEN SOME ISSUES WITH ADVANCING THE SLIDES SO I'M JUST GOING TO TRY IT OUT HERE. SO LOOKS LIKE IT WORKS. GOOD MORNING, EVERYBODY. AND THANK YOU SO MUCH FOR THE OPPORTUNITY TO PRESENT ABOUT DS-CONNECT BUT FIRST KUDOS TO ERICA AND LAURIE FOR PIVOTING SO QUICKLY AND THIS HAS BEEN AMAZING TO BE DOING THIS VIRTUALLY IN SUCH A SHORT TIME AND IT'S WORKING GREAT SO FOR SO THANK YOU. I WOULD LIKE TO TALK ABOUT DS CONNECT, AN NIH SPONSORED AND DOWN'S SYNDROME CONSORTIUM SUPPORTED REGISTRY, ITS PRIMARY GOAL IS TO CONNECT FAMILIES TO RESEARCH OPPORTUNITIES THAT INCLUDES THEM SO HERE IS AN OUTLINE. IT WAS REALLY BACK IN 2011 THAT NIH LED THE CREATION OF THE DOWN'S SYNDROME CONSORTIUM AND HERE ARE THE INSTITUTES LISTED ON THE LEFT COLUMN. THERE ARE ABOUT 13 DIFFERENT INSTITUTES WITHIN NIH. THEY INCLUDE INITIATIVE INCLUDES 18 INSTITUTES. SO THE INCLUDE INITIATIVE DID BRING IN MORE INSTITUTES INTO THE WORKING TOWARDS DOWN SYNDROME OBJECTIVE AND RESEARCH GOALS. THERE ARE 16 PROFESSIONAL ORGANIZATIONS LISTED IN THE SECOND AND THE THIRD COLUMN. AND TOGETHER REALLY THE GOAL IS TO PROVIDE A FORUM FOR EXCHANGE OF INFORMATION ABOUT DOWN'S SYNDROME. TO REALLY IMPROVE THE QUALITY OF LIFE FOREPERSON WITH DOWN'S SYNDROME. AS YOU HEARD YESTERDAY, FROM MICHELLE THAT REALLY THIS HAS CREATED LOT OF COLLABORATIONS AMONG PROFESSIONAL ORGANIZATIONS. SO THE FIRST ACTIVITY OF THE DOWN'S SYNDROME CONSORTIUM WAS TO CREATE A REGISTRY, NIH TOOK LEAD AND SEVEN YEARS AGO LAUNCHED DS CONNECT DOWN'S SYNDROME REGISTRY, AN ONLINE SECURE CONFIDENTIAL WAY TO COLLECT BASIC DEMOGRAPHIC AND HEALTH INFORMATION ABOUT PEOPLE WITH DOWN'S SYNDROME. ALL THE INFORMATION IS ENTERED BY FAMILY MEMBER OR ACCOUNT HOLDER. A SELF-ADVOCATE WHO IS OVER 18 AND OVER CAN ALSO FILL OUT THE INFORMATION IN THE REGISTRY. THE REGISTRY IS ALSO RESPONSIVE TO INCLUDE COMPONENT TWO MENTIONED BY DR. BIANCHI YESTERDAY. THE GOAL IS TO BRING TOGETHER LARGE COHORT OF INDIVIDUALS WITH DOWN'S SYNDROME, THIS IS REALLY IMPORTANT TO FOLLOW THE DEVELOPMENT OVER TIME. AT DIFFERENT AGES ACROSS THE LIFE SPAN. THIS CAN ALSO HELP US TO AS CERTAIN THE AGE OF ONSET FOR VARIOUS CO-OCCURRING CONDITIONS AS WELL AS CRITICAL WINDOWS THAT CAN BE USED FOR INTERVENTION. SO THE REGISTRY HAS INITIAL HEALTH SURVEY WHICH HAS 50 QUESTIONS. WITHIN THE HEALTH QUESTIONNAIRE THERE ARE TEN TRIGGER QUESTIONS WHICH LEADS TO OTHER SURVEYS LISTED HERE, THYROID HEART SLEEP ET CETERA. ONLY IF PARTICIPANT RESPONDS YES TO SAY HAVING A CONGENITAL HEART DEFECT, THEY SEE ADDITIONAL 7 TO 8 QUESTIONS RELATED TO HEART. SO STREAMLINED NOT ALL PARTICIPANTS WILL SEE ALL THE QUESTIONS EMBEDDED IN THE REGISTRY. WE ALSO HAVE QUESTIONNAIRES FOR ADULTS. ADULTHOOD AND THEN MEN'S HEALTH AND WOMEN'S HEALTH AND WE ALSO HAVE TRANSITION TO ADULTHOOD SURVEY WHICH IS AVAILABLE FOR INDIVIDUALS AGE 30 OR 12 TO 30 YEARS OF AGE. WE WERE QUICKLY ABLE TO ADD COVID-19 RELATED QUESTIONS TO THE SURVEY AND TRYING TO CAPTURE EXPOSURES AT ALL TIME POINTS SO YOU CAN SEE WITHIN THE INITIAL HEALTH QUESTIONNAIRE WE HAVE ADDED IT TO THE HEALTH HISTORY AND ALSO THE PARTICIPANTS PRE-NATAL AND BIRTH HISTORY. AND FINALLY IN THE ADULTHOOD QUESTIONNAIRE AS WELL. SO THE REGISTRY IS BUILT AS TWO WAY STREET AND IT IS WITH GOAL OF PARTNERSHIP WITH FAMILIES. YOU HEARD YESTERDAY FROM EMILY CHESTNUT MENTIONING HOW FIRST YEAR IT ALMOST SEEMED LIKE GETTING A Ph.D. IN ALL MEDICAL TERMS RELATED TO DOWN'S SYNDROME FOR HER DAUGHTER NORA AS PART OF THE CLINICAL CARE. SO AT LEAST IN THE REGISTY WHAT WE ARE TRYING TO DO IS ALL OF THE MEDICAL HISTORY IS ONLINE AND THIS COULD BE A WAY FOR A FAMILY TO KEEP ALL OF THE MEDICAL INFORMATION IN ONE PLACE. THIS CAPTURES LONGITUDINAL HISTORY SO ANY CHANGE IS SAVED IN THE PROFILE. SO IF A FAMILY IS PART OF THE REGISTRY WE HIGHLY ENCOURAGE THEM TO COME BACK AND UPDATE THEIR INFORMATION SO WE CAN CAPTURE THAT CHANGE. YOU ALSO HEARD YESTERDAY FROM DR. KELLY ABOUT THE IMPORTANCE DEFINING OBESITY IN THE POPULATION AND UNDERSTANDING THE METABOLOMIC RISK FACTORS. WE WERE ABLE TO INCORPORATE THE CDC CHARTS DOWN'S SYNDROME INTO DS CONNECT WHERE FAMILY MEMBER CAN PLOT THEIR CHILD'S GROWTH SO WE ARE TRYING TO ADD THINGS TO THE REGISTRY, TO MAKE IT A PLACE WHERE FAMILIES CAN COME FOR DIFFERENT RESOURCES. ALL THE SURVEY QUESTIONS AND ANSWERS ARE AVAILABLE FOR FAMILIES TO VIEW. THEY ARE ALL DEIDENTIFIED AND AGGRATE DATA AS PIE CHART AND BAR GRAPH. AND IF THEY HOVER OVER EACH OF THE BARS IT SHOWS HOW MANY PEOPLE ARE RESPONDED TO A PARTICULAR QUESTION. THERE IS A HUGE LIST OF HEALTHCARE PROVIDERS THAT ARE PROVIDED BY FAMILIES. THIS IS NOT REALLY AT NIH WE ARE NOT RATING THE PROVIDERS BUT OBVIOUSLY FAP FAMILIES WHO LOVE PROVIDERS ARE PUTTING THAT INFORMATION IN HERE, IT IS A LIST THAT KEEPS GROWING. AND WE HAVE HEARD FEEDBACK FROM FAMILIES THEY LOOK AT THAT'S SPECIALLY WHEN MOVING TO A DIFFERENT CITY OR THEY NEED SOME SPECIALIST IN THEIR CITY THEY ARE LIVING. SO THIS IS A GREAT RESOURCE ON THE REGISTRY. AS I SAID, IT IS A PARTNERSHIP WITH FAMILIES WE TRY TO LINK TO OUR RESOURCES PROVIDED BY DS ON SOURCE YUM PARTNERS, HERE AVAILABLE ON THE WEBSITE ARE THE RESOURCES FOR HEALTHCARE GUIDELINES. IF SOMEONE HAS AN ACCOUNT AND THEY HAVE A CHILD WHO IS AGE 6 YEARS OLD ON THEIR DASH BOARD THEY SEE THE SPECIFIC AAP RECOMMENDED CHECKLIST FOR THEIR CHILD SO THAT HELPS TO STREAMLINE THIS INFORMATION FOR THIS INFORMATION WHO HAS INDIVIDUAL ACCOUNT ON TS CONNECT. WE ARE TRYING TO LAUNCH THIS PORTAL ON DS CONNECT WHERE WE WOULD PULL FROM INFORMATION FROM LAST.GOV SO FAMILIES GO TO REGISTRY AND LOOK AT NIH FUNDED STUDIES IN DOWN'S SYNDROME RECRUITING. WE WILL ALSO PROVIDE A LINK SO THAT IF THEY WANT TO KNOW MORE ABOUT OTHER STUDY OTHER CONDITION THEY CAN BE TAKEN. TO THE CLINICAL TRIALS WEBSITE. TO DO MORE SEARCH. JUST TO SHOW YOU A MAP OF THE REGISTRANTS, THIS IS THE US. THIS IS UPDATED REAL TIME, THIS IS A HEAT MAP SO NOT REALLY STREET ADDRESSES SHOWN, THE RED DOTS SHOWS WHERE CONSIDERABLE NUMBER OF PARTICIPANTS ARE LOCATED. YOU CAN SEE THERE ARE STILL LOTS OF GAPS AND WEAPONN'T REACHED THE FULL COUNTRY AND THERE'S LOT OF WORK TO DO IN THIS AREA. JUST WANTED TO SHOW THIS DATA, I JUST PULLED IT YESTERDAY BECAUSE WE HAVE BEEN TALKING ABOUT TRYING TO REACH EVERYBODY, DR. -- MENTIONED IT YESTERDAY. WE HAVE A ACTIVE COMMUNITY OUTREACH WORKING GROUP THAT CAME OUT OF THE SEPTEMBER INCLUDE WORKSHOP IN 2019. IN CLINICAL TRIAL READINESS, WORKING GROUP THAT IS HAVES COME UP WITH GREAT IDEAS AND NEXT STEPS TO TRY AND REACH DIVERSE POPULATION. BUT THIS IS HOW IT LOOKS. WE ARE SKEWED TOWARDS CAUCASIAN POPULATION AND HIGHER SOCIO ECONOMIC STATUS. AND WE DEFINITELY ARE AWARE OF IT AND ARE TRYING TO ADDRESS IT WITH FORMING THE WORKING GROUP, TRYING TO GET IDEAS AND OUTREACH IS A BIG PART OF WHAT WE DO AS WELL. WHEN I BEGAN THIS PRESENTATION I SAID WE NEED ONE OF THE MAIN GOAL IS TO CONNECT FAMILIES TO RESEARCH OPPORTUNITIES. SO ONE YEAR AFTER WE LAUNCHED THE REGISTRY WE ALSO LAUNCHED THE PROFESSIONAL PORTAL. AND BY PROFESSIONAL, ANYBODY WHO IS INTERESTED IN DOWN'S SYNDROME COULD BE RESEARCHER PROVIDER EDUCATOR, THEY CAN HAVE AN ACCOUNT ON DS CONNECT. WHAT THAT MEANS IS THAT THEY HAVE VIEW, THEY HAVE THE SAME VIEW AS FAMILY MEMBERS SO THEY CAN LOOK AT DEIDENTIFIED AGGREGATE DATA, WITHIN THE REGISTRY. THEY HAVE NO DIRECT CONTACT WITH ANY REGISTRY PARTICIPANTS. WE AS REGISTRY COORDINATORS OF -- AT THE GATEKEEPER AND WE ARE DOING THE CONTACTING, ON BEHALF OF THE PROFESSIONALS. PARTICIPANTS CAN CHOOSE WHETHER THEY WANT TO PARTICIPATE IN ANY RESEARCHING STUDY THEY GET NOTIFICATION OF. ON MY COVID-19 THIS IS A GOOD GRAPH WHERE WE SEE INCREASE OF RESEARCHERS WHO ARE GETTING APPLYING FOR ACCOUNTS ON DS CONNECT. SO FAR WE HAVE 447 RESEARCHERS. I WILL BRIEFLY MENTION LEVELS OF ACCESS THAT WE HAVE. THIS IS A VERY ACTIVE RESEARCH COMMITTEE, A LOT OF MEMBERS ON THIS CALL TODAY. THEY ARE REVIEW VERY THOUGHTFUL REVIEW OF ALL LEVEL THREE REQUESTS THAT COME IN. WE ARE GRATE GRATEFUL FOR THEIR INPUT INTO THIS PROCESS. THE THREE LEVELS, THE FIRST LEVEL AS I MENTIONED IS REALLY ALMOST SIMILAR TO A PARTICIPANT VIEW. SECOND LEVEL USED FOR MORE CUSTOMIZED SEARCHES AND IF THEY NEED -- PROFESSIONALS NEED SOME DATA FOR PUBLICATION OR PRESENTATION. AGAIN, THERE ARE NO IDENTIFYING INFORMATION THAT THEY CAN RECEIVE, THIS IS ALL DEIDENTIFIED AGGREGATE INFORMATION THAT THEY RECEIVE. LASTLY THE LAST LEVEL OF ACCESS IS REALLY FOR STUDY RECRUITMENT AND POSTING OF STUDY THROUGH DS CONNECT, THEY CAN ALSO PROPOSE NEW SURVEY MODULES AND THIS LEVEL REQUIRES IRB STATUS AND THIS REQUIRES REVIEW BY RESEARCH REVIEW COMMITTEE. IN THE PAST SIX YEARS THERE HAVE BEEN 21 APPLICATION, SO LEVEL 2, 54 STUDIES FOR LEVEL 3 ACCESS AND FIVE AND SIX PROJECTS THAT RECEIVE SUPPORT, THERE ARE A FEW MORE WE ARE WORKING ON RIGHT NOW. SO THIS IS DEFINITELY A RESOURCE THAT IS ALSO GOING TO HELP A LOT OF INCLUDE FUNDED PROJECTS. SO FOR FAMILY MEMBER, TAKING PART INTO RESEARCH STUDY CAN MEAN A LOT OF THINGS, THEY CAN TEAR A SURVEY, ANSWER QUESTIONNAIRE USING FIT BIT AS AN ACTIVITY TRACKER, OR THEY CAN PARTICIPATE IN A CLINICAL TRIAL. OR IN A INCLUDE FUNDED STUDY, BUT REALLY IT IS ANY OF THE CHOICE, AND THEY CAN ALSO DECIDE NOT TO PARTICIPATE IN ANY STUDIES AND CAN STILL BE PART OF DS CONNECT. HERE IS JUST AN EXAMPLE OF ONE OF THE STUDIES SUPPORTED THROUGH DS CONNECT. THIS WAS A STUDY DONE BY DR. AMY LUANDA LOOKING INTO NUTRITIONAL SUPPLEMENTS IN CHILDREN WITH DOWN'S SYNDROME. AND IF YOU CAN SEE THE GRAPH FEBRUARY 2017 TO ABOUT JUNE 2017 SHE WAS STRUGGLING TO MEET HER GOAL. SHE REALLY CAME TO DS CONNECT AS A LAST RESOURCE TO TRY THIS WAY OF TRYING TO RECRUIT. WITHIN TWO WEEKS POSTING THIS NOTICE, SHE NOT ONLY MET HER GOAL, SHE HAD TO GO BACK, SHE HAD TO STOP GO BACK TO IRB TO COMPLETE HER GOAL, SHE REACHED TO NOT SEND OUT NOTIFICATION. WE ONLY SENT ONE NOTIFICATION. THIS WAS THE RESULT. SO THIS IS A GOOD PROBLEM TO HAVE. AND I THINK IF WE CAN DO THIS FOR EACH AND EVERY STUDY THAT COMES TO DS CONNECT THAT WOULD BE FANTASTIC THAT WE CAN REALLY BE PLACE TO CONNECT RESEARCHERS TO ELIGIBLE AND WILLING PARTICIPANTS. THIS SAW FEW STUDIES WE ARE SUPPORTING. THERE ARE MANY MOTHER THAT WE ARE WORKING. WITH FOR THIS TOWARD THIS EFFORT. YOU HEARD FROM DR. ESBENSEN AND ESPINOSA ABOUT HAIR STUDY AND WE ARE HELPING RECRUIT. WE ARE ALSO WORKED WITH DR. -- AND THIS WAS FUNDED IN 2019. LASTLY, I WILL SAY WHAT IS REALLY NEEDED IS TO SPREAD THE WORD ABOUT DS CONNECT. AND AS WE ARE LEARNING FROM THE COMMUNITY OUTREACH EFFORT GROUP, WORKING GROUP, AND ALSO THE CLINICAL TRIAL READINESS WORKING GROUP WE HAVE TO KNOW OUR AUDIENCE. THERE ARE MANY STAKEHOLDERS IN THE DOWN'S SYNDROME COMMUNITY. AND WE NEED TO OUTREACH TO EACH AND EVERY ONE OF THEM AND IT HAS TO BE DONE, IT HAS TO BE TAILORED ACCORDING TO OUR AUDIENCE. THERE ARE MANY ELECTRONIC ITEMS AVAILABLE. WE HAVE DEVELOPED MANY MORE, WE TO REALIZE THAT BUT THESE ARE ALL AVAILABLE FREE OF CHARGE. WE HAVE A MODEST GOAL OF 10,000 AND WE ARE VERY CLOSE TO REACHING 5,000. SEEMS LIKE A BIG NUMBER BUT IN THE LAST SEVEN YEARS IT'S REALLY VERY SMALL PERCENTAGE, THOUGH WE HAVE BEEN ABLE TO HELP A LOT OF RESEARCHERS, WHO HAVE COME TO DS CONNECT FOR RECRUITMENT IN SUCH A SMALL NUMBER, IMAGINE WHAT WOULD HAPPEN IF YOU HAVE MANY, MANY PARTICIPANTS ON HERE, MUCH MORE HAHN 10,000 BE ABLE TO REALLY HELP RECRUIT FOR MANY MORE. HERE IS THE URL. AGAIN, THESE ARE ALL AVAILABLE ON THE WEBSITE. >> THANK YOU VERY MUCH. WONDERFUL PRESENTATION. WE HAVE TO MOVE FORWARD BECAUSE OF OUR SCHEDULE. BUT OUR NEXT SPEAKER WILL BE DR. MARA BECK ER, ASSOCIATE PROFESSOR AT DUKE UNIVERSITY AND SHE'S INVOLVED WITH THE PEDIATRIC TRIALS NETWORK WITH THE HUE CLINICAL RESEARCH INSTITUTE WHO WILL SPEAK ABOUT THE PTN DOWN'S SYNDROME CLINICAL PHARMACOKINETICS AND SAFETY TRIALS IN DOWN'S SYNDROME. THANK YOU, MARA. >> I WANT TO MAKE SURE I GET THE RIGHT -- AFTER MY PRACTICE. DR. BECKER YOU HAD IT UP, IF YOU GO BACK WHERE YOU WERE AND THEN SLIDE SHOW MODE. THERE WE GO. FROM >> IT'S AT THE TOP. LOOKS GOOD. >> THANKS, EVERYBODY. THANKS SO MUCH FOR GIVING ME THE OPPORTUNITY TO SPEAK TO YOU TODAY, IT'S BEEN REALLY INSPIRING LISTENING TO ALL THE WORK GOING ON OVER THE LAST DAY AND A HALF. I HAVE THE HONOR TO TALK TO YOU GUY ABOUT THE PEDIATRIC TRIALS NETWORK AND OUR PROJECT ENTITLED THE CLINICAL PHARMACOKINETICS AND SAFETY TRIALS IN DOWN'S SYNDROME WHICH HAS BEEN FUNDED BY THE INCLUDE INITIATIVE. SO TO GIVE YOU A LITTLE BIT OF BACKGROUND NOT THAT I NEED TO SPEAK TO THE CHOIR HERE BUT ONE OF THE BIGGEST DRIVING FORCES BEHIND CREATION OF THE PEDIATRIC TRIALS NETWORK IS FRANKLY THE DIFFICULTIES THAT WE FACE COMPLETING STUDIES IN CHILDREN IN GENERAL. SO A NUMBER OF THE REASONS ARE LISTED HERE AND NOT JUST MY DIFFICULT CHILD THAT I HAVE A PHOTO OF UP HERE BUT IT'S REALLY HARD TO ACTUALLY ACCOMPLISH AND COMPLETE STUDIES IN CHILDREN FOR A NUMBER OF REASONS. WE HAVE LIMITED NUMBERS OF PATIENTS, NO REAL HEALTHY VOLUNTEERS THAT WE CAN COUNT ON. LOW RATES OF PARENTAL INFORMED CONSENT. REALLY A LIMITED NUMBER OF PEOPLE WHO HAVE CLINICAL PHARMACOLOGY. PEDIATRIC SPECIFIC PHARMACOKINETIC AND FARM CO-DYNAMIC MODELING EXPERTISE. LET'S NOT EVEN TO COUNT THE DIFFICULTIES WE HAVE WITH LIMITED BLOOD VOLUME AND TIME SAMPLING THAT WE THINK ABOUT BEING QUITE NECESSARY FOR A LOT OF THE TRADITIONAL PHARMACOKINETICS STUDIESES THAT WE KNOW ABOUT. SO IN THAT VEIN, THE PEDIATRIC TRIALS NETWORK OR PTN WAS START WITH A VISION TO CREATE AN INFRASTRUCTURETOR INVESTIGATORS TO CONDUCT TRIALS THAT APPROVE PEDIATRIC LABELING IN CHILD HEALTH. IT'S ALSO BY THE NICHD UNDER THE BEST PHARMACEUTICALS FOR CHILDREN ACT. FOR THOSE LESS FAMILIAR WITH IT THAT WAS WRITTEN INTO LAW IN 2002 AND HAS BEEN RENEW AD NUMBER OF TIMES. IT HAS TWO REAL MAJOR GOALS. ENCOURAGE PHARMACEUTICAL INDUSTRIES TO PERFORM PEDIATRIC STUDYINGS, THEY DO IT OFFERING SIX MONTHS PATENT EXCLUSIVITY SO IF THOSE PHARMACEUTICAL INDUSTRY SPONSORS DO A PEDIATRIC STUDY THEY GET EXTRA PATENT EXCLUSIVITY TIME. WHICH IS QUITE LUCRATIVE AND HAS BEEN A HUGE IMPROVEMENT IN GETTING NEWER DRUGS LABELED FOR CHILDREN. SECOND HAVE NIH PRIORITIZE THERAPEUTIC AREAS AND SPONSOR CLINICAL TRIALS AND OTHER RESEARCH SPECIFIC SPECIFICALLY FOR OFF PATENT DRUG PRODUCTS THAT NEED FURTHER STUDY IN CHILDREN. AS YOU CAN IMAGINE SOME OLDER DRUGS MANY OF WHICH WE USE IN PRACTICE HAVE NEVER BEEN STUDIED SPECIFICALLY IN CHILDREN AND DEFINITELY NOT LABELED FOR CHILDREN SPECIFICALLY SO THERE IS A HUGE GAP THERE. THIS PTN IS A NETWORK DEVELOPED TO STUDY DRUG PRODUCT FORMULATION, EFFICACY, SAFETY AND DEVICE VALIDATION. TWO MAJOR COMPONENTS, INCLUDE THE CLINICAL COORDINATING CENTER RUN BY DUKE CLINICAL RESEARCH INSTITUTE AND THE DATA COORDINATING CENTER ONE BY THE MS CORPORATION. BPCA CONSORTIUM LOOKS LIKE THIS, IF YOU LOOK TO THE LEFT YOU HAVE THE CLINICAL COORDINATING CENTER RUN BY PTN AND DCRI, DATA COORDINATING CENTER, THE NICHD ALL KIND OF WORKING TOGETHER TO FORM THIS BPCA STEERING COMMITTEE. PRETTY REMARKABLE IS WHAT'S ABLE TO BE ACCOMPLISHED OVER LAST SEVERAL YEARS SINCE BEEN IN PRODUCTION. AND THOUGH THE CONTRACT FOR WORK IS TO THE LEFT INCLUDING 16 CLINICAL TRIALS OVER SIX THERAPEUTIC AREAS ENROLLING 1600 CHILDREN AND HOPING FOR FOUR PRODUCT SUBMISSIONS, IN FACT, THE GROUP HAS BEEN MUCH MORE SUCCESSFUL AND MUCH MORE EFFECTIVE MOVING THINGS FORWARD WHICH IS REMARKABLE IN ACCOMPLISHING OVER 38 TOTAL STUDIES IN PHASES FROM ONE TO FOUR AND OVER 13 THERAPEUTIC AREAS. GREATER THAN 7,000 CHILDREN ENROLLD IN STUDIES I FIND TO BE REMARKABLE AND THERE'S 21 PRODUCT SUBMISSIONS AND TEN LABEL CHANGES. WHICH IS A TERRIFIC ACCOMPLISHMENT. THE GOALS OF WHAT I CALL PTNDS PTN DOWN SYNDROME PROJECT IS CREATE A PEDIATRIC TRIAL INFRASTRUCTURE WHICH I AND OFF PATENT THERAPEUTIC ARE APPROVED TO CARE OF CHILDREN WITH DOWN'S SYNDROME. VIA TWO MAIN MECHANISMS OR TWO MAIN GOALS. FIRST DEVELOP A PEDIATRIC CLINICAL TRIAL NETWORK FOR PATIENTS WITH DOWN'S SYNDROME UNDER UMBRELLA PTN AND WE HOPE TO DO THIS VIA THESE MODALITIES, FIRST TO PARTICIPATE IN ALREADY ESTABLISHED WELL ESTABLISHED PTN STUDY, WHICH IS OPPORTUNISTIC PHARMACOKINETIC AND FARM CO-DYNAMIC STUDY. THE SECOND IS TO DEVELOP A PROSPECTIVE THERAPEUTIC TRIAL, SAFETY AND EFFICACY AND THERAPEUTIC IN CHILDREN WITH DOWN'S SYNDROME. SECOND MAIN GOAL, THIS PROGRAM PTNDS IS DEVELOP BIDIRECTIONAL RAINING PROGRAM FOR CLINICAL RESEARCHERS. FACT OF THE MATTER IS, PTN HAS OVER A HUNDRED CLINICAL PEDIATRIC SITES THAT ARE INVOLVED IN ITS STUDIES. IF WE CAN DO A BETTER JOB EDUCATING A NUMBER OF THOSE SITES WHO HAVE PATIENTS THAT HAVE DOWN'S SYNDROME, THEY WANTED TO ENROLL IN STUDIES OR INTERESTED IN WORK SPECIFICALLY IN THIS PATIENT POPULATION THAT'S A HUGE WIN. AND WE UNDERSTAND THAT THERE ARE THINGS THAT MANY OF THESE SITES JUST MAY NOT KNOW AND WE HAVE AN OPPORTUNITY TO IMPROVE BOTH OUR UNDERSTANDING OF HOW TO BETTER ACCOMPLISH TRIALS IN CHILDREN WITH DOWN'S SYNDROME. AND ALSO HOPEFULLY EDUCATE INVESTIGATOR WHOSE ARE INTERESTED IN DOING THIS TYPE OF CLINICAL PHARMACOLOGY BASED WORK. SO THE PROJECT SPANS THREE YEARS, SO WE HAVE A LOT TO GET DONE IN THOSE THREE YEARS SO MANY OF OUR GOALS OVERLAP ANDK AS YOU CAN SEE THOUGH SITES ARE GETTING ACTIVATED CURRENTLY TO GET INVOLVED IN THE STUDY WE EXPECT THAT TO RUN PROBABLY THROUGHOUT ALL LEE YEARS AND AT THE THE SAME TIME HOPEFULLY COLLECT INFORMATION TO PROVIDE OUR BIDIRECTIONAL TRAINING PROGRAM BOTH CAPTURING LESSONS LEARNED ALONG THE WAY AND INCORPORATING THEM INTO OPPORTUNITIES TO FEEDBACK. PROTOCOL DEVELOPMENT HAS STARTED AS WELL. THIS IS PROBABLY GOING TO BE THE LONGEST AND MOST DIFFICULT ROAD BUT AN OPPORTUNITY TO LEARN A LOT. FIRST THING FIRST, WE HAVE TO GET PARTNERS IN THIS WORK AND NONE CAN BE DONE WITHOUT THEM, WITHOUT QUESTIONS. MY INTEREST OR MY CLINICAL SPACE IS IN RHEUMATOLOGY SO I HAVE A CLINICAL INTEREST IN TREATING CHILDREN WHO HAVE ARTHRITIS, SOME OF THE WORK BEEN PRESENTED EARLIER IN THIS MEETING HAS BEEN INTERESTING AND REALLY INTERESTED IN DRUG VARIABILITY IN THE PATIENT POPULATION. WE NEEDED MORE EXPERTISE, THANKFULLY WHO PARTNER WITH THE ME AT DUKE TO ID FEW A NUMBER OF COLLEAGUES WE HAVE GREAT SLATE OF THOUGHT LEADERS. SO WE HAVE THOUGHT LEADERS FROM TALK INCLUDING DR. KISHNANI FROM KANSAS CITY CHILDREN'S MERCY, BOSTON CHILDREN, DR. FARMER, MASS GENERAL, AT UW MADISON, DR. STANLEY, KENNEDY KREIGER, WE HAVE A FAMILY REPRESENTATIVE WHO JOINS US, MICHELLE PFEIFFER WHO IS OUTSTANDING AND WONDERFUL ADVOCATE, AS WELL AS MEMBER FROM OUR ADVOCACY GROUP NDSS ASHLEY WHO ALSO TERRIFIC ADDITION. THESE FOLKS MEET WITH US ON CALLS, RESPOND TO QUERIES, THEY ARE INCREDIBLY ENGAGE AND B SO INSTRUMENTAL MOVING THIS WORK FORWARD. THE SITES IN GREEN WILL PARTICIPATE IN THE POP 2 SITE AND HOPEFULLY PARTICIPATE IN OUR PROTOCOL ONCE I GET FULLY DEVELOPED. SO YOU CAN TALK ABOUT POPO 2 BRIEFLY, IT'S FARM COPE KEN TICK DYNAMIC SAFETY PROFILE OF ADMINISTERED TO CHILDREN FOR CARE. THAT'S WHY WE JUST CALL IT POPO FOR SHORT. IT'S A SECOND IT RIGHT SO THERE WAS AMENDMENT THAT WENT THROUGH THIS YEAR AND WE WERE LUCKILY ABLE TO CAPITALIZE ON THAT AMENDMENT AND AMEND IN A COHORT OF FIVE SITES DOWN'S SYNDROME CLINICS. THE WHOLE POINT OF THE STUDY WHICH IS PRETTY BRILLIANT TO EVALUATE THE PK OF UNDERSTUDYING DRUGS BEING ADMINISTERED BY STANDARD OF CARE. SO WHEN THESE CHILDREN GET ADMITTED TO THE HOSPITAL, THIS IS HOW IT'S TRADITIONALLY BEEN DONE. THEY ARE IDENTIFIED, BLOOD SAMPLES OBTAINED WHILE ADMITTED. AND THEY ARE ABLE TO COLLECT SOME CLINICAL INFORMATION ON SAFETY, PARTICULARLY OF THESE STUDIES. BIT'S A REALLY PRETTY AWESOME COLLECT RANDOM PK SAMPLES, THEY USE A POPULATION PK PRACTICE TO BE ABLE TO START TO GET SOME INFORMATION ON THAT. OUR PATIENTS ARE AMBULATORY SO WE HAD TO MAKE AMENDMENTS TO THAT PROTOCOL TO BE ABLE TO -- AND REALLY THINK THROUGH THE PROCESS HOW WE ARE GOING TO TO AND COLLECT SAMPLES FROM AMBULATORY PERSPECTIVE. DRUGS OF INTEREST, THE GROUP HAS INFORMED US HAS WORKED WITH US TO IDENTIFYING FOOD, AMPHETAMINE, ANDREAS PER DONE TO START. THE GOAL OF UTILIZING THIS PLATFORM WHICH ARE REALLY USE IT AS AN OPPORTUNITY TO BOTH TRAIN THE CORE SET OF DOWN'S SYNDROME SITES WE HAVE IDENTIFIED, ON CLINICAL PHARMACOLOGY BASED RESEARCH AND CLINICAL TRIALS, TRAINING THEM PKPD AND REGULATORY GRADE DATA THROUGH PROCESS THE PTN HAS IN PLACE, GIVES US AN OPPORTUNITY TO LEARN FROM THESE SITES, WHAT ARE CHALLENGES UNIQUE TO THE POPULATION AN PHYSICIAN AND CLINICIANS THAT TREAT THEM. BUILD RELATIONSHIPS, THESE ARE PEOPLE I HADN'T KNOWN PREVIOUSLY AND IT'S BEEN TERRIFIC LEARNING FROM THEM AND THEIR SITE STAFF AS WELL. LASTLY, QUITE IMPORTANTLY, IT GIVES US AN OPPORTUNITY TO QUICK AND DIRTY START TO COLLECT SOME PK SAMPLES ON OUR PATIENTS TO START TO UNDERSTAND IN THE REAL WORLD SETTING WHAT THAT DRUG EXPOSURE LOOKS LIKE. SECOND COMPONENT OF THAT FIRST GOAL IS TO DEVELOP FREE STANDING PROTOCOL. WE ARE IN THE PROCESS OF WORKING THROUGH THIS. AT THIS POINT WE ARE THINKING AND MEETING WITH OTHER COLLABORATORS LIKE IGNACIO TAPIA WHICH I CAN'T BE MORE GRATEFUL FOR TALKING ME THROUGH SOME OF THEIR WORK AS WELL AND WE ARE LOOKING AT STUDYING A PROSPECTIVE MULTI-CENTER RANDOMIZE PLACEBO CONTROLLED TRIAL IN IMMEDIATELY RELEASE IN CHILDREN WITH DOWN'S SYNDROME. WITH ATTENTION DEFICIT HIVE ACTIVITY DISORDER, PRIMARILY ATTENTION AND IMPULSIVENESS, IT IS DESCRIBED ELEGANTLY THE LAST TWO DAYS, THIS IS NOT SUPER EASY FOR A LOT OF REASONS AS FAR AS THE DEFINITION OF WHAT ADHD MEANS IN DOWN'S SYNDROME, THE FACT THAT (INAUDIBLE) ISN'T LABELED FOR ADHD MANY THE POPULATION NOR FOR CHILDREN AND HOW TO ADMINISTER THIS DRUG TO KIDS, SAFELY AND EFFECTIVELY AND ACCURATELY HAS BEEN DEFINITELY SUCH ENLIGHTNING PROCESS AS WE HAVE BEEN THINKING LIEU THIS PROTOCOL. ALL AGAIN OF COURSE LESSONS LEARNED ALONG THE WAY. OBJECTIVES AT THIS POINT WILL BE TO DETERMINE THE GUANTHA ISINE EFFECTIVENESS TO CHARACTERIZE THE EXPOSURE RESPONSE RELATIONSHIP TO CHARACTERIZE SAFETY PROFILE AND IF WE ARE LUCKY, ALSO THROW IN AN EXEMPLOYERTORY AIM WHICH WILL CHARACTERIZE -- EXPLORATORY AIM TO ACTTY >> FEW. SO THE SECOND GOAL FOR US IS TO CREATE AN -- PROBABLY THE MOST IMPORTANT I WOULD SAY WOULD BE CREATING THIS MULTI-DIRECTIONAL TRAINING PROGRAM. WHAT WE REALIZE IS THAT WE NEED TO BE ABLE TO GEAR THAT TRAINING TOWARDS THOSE INVESTIGATORS, THOSE GREATER THAN HUNDRED CLINICAL SITES WHO DON'T HAVE ANY EXPERIENCE OR MAYBE MINIMAL EXPERIENCE WORKING WITH INDIVIDUALS WITH DOWN'S SYNDROME IN THEIR FAMILIES. THIS IS REALLY GREAT OPPORTUNITY FOR US TO BE ABLE TO CREATE A PLATFORM TO INSTRUCT THEM. WE ALSO FIGURE THIS IS AN OPPORTUNITY TO TRAIN CLINICIAN WHOSE TREAT PATIENTS WITH DOWN'S SYNDROME WHO MAY HAVE LESS EXPERIENCE IN THE CONDUCT OF THESE CLINICAL PHARMACOLOGY BASED CLINICAL TRIALS. IF WE CAN UTILIZE THESE LESSON THE POPO 2 TRIAL FOR CLINICAL DEVELOPMENT TO INFORM TRAININGS WE MAYBE ABLE TO PREPARE NEW SITES FOR THAT PERSPECTIVE TRIAL A LITTLE BIT EASIER IN THE FUTURE. BUT THIS ALSO GIVES A REAL OPPORTUNITY TO CAPITALIZE ON THESE RELATIONSHIPS THAT WE HAVE BUILT WITH THE THOUGHT LEADERS IN THE SITES AS WELL AS COLLEAGUES FROM THE INCLUDE INITIATIVE AND ALL OF THE COLLABORATORS I HAVE MET ALONG THE WAY. BECAUSE AS YOU ARE DEVELOPING THIS GREAT NETWORK I THINK THAT THESE KINDS OF PROGRAMS YOU HAVE BEEN PUTTING ON LIEU INCLUDE HAVE HELPED FOR ME TO LEARN SOME OF THE MAIN PLAYERS IN THIS SPACE. WE HAVE PLANNED ON HAVING A FACE TO FACE MEETING AND THAT WENT KAPUT WITH COVID, WE MOVED OUR FIRST AT LEAST FOUNDATIONAL MEETING TO A VIRTUAL MEETING WHICH WE ARE GOING TO BE PLANNING FOR THE FALL. WE HAD A DRAFT AGENDA FOR THAT MEETING PRIMARILY SPEND AILING LITTLE BIT OF TIME TALKING ABOUT THE CLINICAL OVERVIEW WHICH I THINK WAS ALSO QUITE ELEGANTLY DISCUSSED YESTERDAY, SO MANY EXAMPLES OF THE THERAPEUTIC CHALLENGES THAT WE FACE IN CHILDREN WITH DOWN'S SYNDROME. A LOT OF TIME TALKING COMMUNITY ENGAGEMENT AND CLINICAL TRIAL READINESS WITH BOTH ADVOCACY PARTNERS, AND PATIENTS AND FAMILIES. AS WELL AS USING THIS AS AN OPPORTUNITY TO TO REVIEW DS CONNECT AS WELL. WE WILL SPEND TIME TALKING LESSONS LEARNED AND HAVE WE DEVELOPED BEST PRACTICES THAT WE CAN LEARN FROM FROM POPO 2 AS WELL AS PTN NETWORK AND HOPEFULLY SPEND AN HOUR TALKING ABOUT OUR PROTOCOL WHICH WILL HOPEFULLY HAVE FLESHED OUT BY THEN TO START TO GET FEEDBACK FROM OUR STAKEHOLDERS TO DETERMINE WHERE WE ARE GOING RIGHT WHERE WE HAVE ROOM TO GROW, MORE IMPORTANTLY HOW WE CAN HARMONIZE DATA ELEMENTS WE WANT TO COLLECT WITH BOTH INCLUDE INITIATIVES AS WELL AS OUR COLLABORATORS IN CINCINNATI. NEXT STEPS FOR MULTI-DIRECTIONAL TRAINING THAT I SEE WOULD BE PRIMARILY TO ESTABLISH STRENGTHEN RELATIONSHIPSES WITH INVESTIGATORS ANNIETIVES LIKE THIS ONE. -- INITIATIVES LIKE THIS. WE TALKED ABOUT INTENTIONALLY SPREADING THE WORDN'T WHAT -- WORD ABOUT WHAT THIS IS TRYING TO ACCOMPLISH AND VARIOUS ACADEMIC VENUES AND PTN NETWORK AND CREATING A REPOSITORY TO SHARE WITH INTERESTED INVESTIGATORS AND UTILIZE THAT FOR FUTURE STUDIES. MOST IMPORTANTLY, TO DEVELOP RELATIONSHIPS WITH THE NATIONAL ADVOCACY IMPAIRMENT GROUPS TO GEAR FEATURE TRIALS PRIMARILY TO AREAS THAT ARE IMPORTANT FOR THEM. I THINK WE CAN SPECULATE A LOT O OF WHAT WE THINK IS IMPORTANT FOR OUR PATIENTS BUT IF WE DON'T ENGAGE THEM UP FRONT IN THE PROCESS WE MAY BE MISSING THE MARK. LIKE TO THANK ALL OUR THOUGHT LEADERS THAT HAVE BEEN ALONG THE WAY WITH US ON THIS RIDE. OUR COLLEAGUES AT MS AND DCRI AND OUR INCLUDE SPONSORS AND COLLABORATORS, ACT THEMMIC PARTNERS WHO HAVE BEEN GRACIOUS WITH THEIR TIME FOR ME AS I HAVE BEEN TRYING TO GET THIS OFF THE GROUND. I'M GRATEFUL FOR ALL OF THEIR TIME AND ENERGY ALONG THE WAY. IF ANYBODY HAS ANY QUESTIONS I'M HAPPY TO ENTERTAIN THEM LATER OR FEEL FREE TO EMAIL ME OFFLINE. >> THANK YOU, OUTSTANDING PRESENTATION. GREAT WORK. AND HOPEFULLY WE'LL HAVE SOME TYPE TO RAISE SOME QUESTIONS SHORTLY OF OUR LAST TALKS THIS MORNING. OUR NEXT SPEAKER WILL BE JULIE MILLER FROM HEALTH CORPS WHO WILL SPEAK ON THE PEDIATRIC HEART NETWORK, AND LOOKING FORWARD TO THIS TALK. THANK YOU, JULIE. >> THANK YOU. HOPEFULLY YOU CAN HEAR ME. >> THANK YOU SO MUCH FOR INVITING ME TO SPEAK TODAY ABOUT THE PEDIATRIC HEART NETWORK. THIS IS ESPECIALLY IMPORTANT TO ME AS I HAVE A NEE VIEW WITH DOWN'S SYNDROME. SO I'M THRILLED TO BE PART OF THIS WORKSHOP. THERE'S SO MUCH GREAT INFORMATION SHARED OVER THE LAST COUPLE OF DAYS. THE PHN IS FUNDED BY NHLBE, STARTED IN 2001 WITH SEVEN SITES, DATA COORDINATING CENTER AND NHLBI AND AS YOU CAN SEE FROM THE HEART ON THE RIGHT, IN THE 19 YEARS LATER WE HAVE GOTTEN QUITE A BIT BIGGER, BEEN BUSIER AND ACCOMPLISHED QUITE A BIT NO THAT TIME. AS OF TODAY THIS IS A MAP OF WHERE OUR SITES ARE ACROSS THE UNITED STATES, WE ALSO HAVE SITES IN CANADA, AND IN SOUTH KOREA. WE HAVE EXPANDED TO INCLUDE NOT JUST OUR FUNDED CLINICAL SITES BUT AUXILLARY SITES ACROSS THE WORLD. THE OBJECTIVES OF THE PHN ARE TO IMPROVE HEALTH OUTCOME, DISSEMINATE COLLABORATIVE FINDINGS TO IMPROVE EVIDENCE BASED CARE. TRAIN NEW INVESTIGATORS, AND PROVIDE SUPPORT AND ADVOCACY DURING THE CONDUCT OF RESEARCHING. THE PHN IS RUN BY A LARGE STEERING COMMITTEE WHICH INCLUDES THE NHLBI PROGRAM OFFICE, OUR CLINICAL CENTERS, ALL OF OUR AUXILLARY SITES, THE DATA COORDINATING CENTER AND OUR CORE LABS. IT IS WE ARE GOVERNED BY EXECUTIVE COMMITTEE. THAT IS COMPRISED OF PIs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s, INVESTIGATOR INITIATED NEEDS AND EVERYTHING, CERTAINLY TO INFLUENCE THE FDA FOR APPROVAL WHAT IS NEEDED, HOW TO GET THERE. EARLY ENGAGEMENT WITH CLINICAL TRIAL DESIGN BY EXPERIENCE FOLKS SOUND LIKE A GREAT PIECE OF THIS TOO. THERE ARE COUPLE OF MESSAGES I RECEIVED AD CUP OF QUESTIONS ABOUT DO WE PLAN ON LINKING PEDIATRIC PULMONARY HYPERTENSION NETWORK WITH DS CONNECT I THINK IT'S A FABULOUS IDEA AND LOOKING PORED TO FUTURE OF TRYING TO MAKE SUCH ARRANGEMENTS. I THINK THAT WOULD BE A WONDERFUL OPPORTUNITY. ANOTHER QUESTION WAS, CAN I BREAK DOWN THE TYPE OF CONGENITAL HEART DISEASE SEEN IN CHILDREN WITH DOWN'S SYNDROME AND PAH, IT RUNS THE GAMUT BUT WE SEE DISPROPORTIONATE PULMONARY HYPERTENSION OR SEVERITY IN MANY OF THE LEFT TO RIGHT SHUNT LESIONS, ASDs, VSDs, AB CANALS ARE A BIG COMPONENT. DISPROPORTIONATE WITH WHAT SHOULD BE A SIMPLE ASD, WE SEE MORE PH IN DOWN'S SYNDROME SUBJECT THAN NONE. THERE'S NO DIFFERENCE. SO THERE'S SOME OF THE LESIONS BUT CERTAINLY THE IDEA OF HAVING SIGNIFICANT HIGH BLOOD FLOW INTO THE LUNG WHICH IS RELATIVELY UNDERDEVELOPED MAY LEAD TO MORE ACCELERATED PULMONARY HYPERTENSION. AND FOR FACTORS WE DISCUSSED IN THE TALK. BUT IT IS A GOOD QUESTION, WE WILL CONTINUE TO EXPLORE WHETHER THEY ARE LESION SPECIFIC DIFFERENCES IN THINGS LIKE THAT. ANOTHER QUESTION, MAYBE I CAN ASK SUE THE QUESTION HERE. HOW DO WE LINK REGISTRIES AS MUCH GO AHEAD. >> THANK YOU FOR THAT QUESTION. IN FACT WHEN THIS WAS SET UP, ONE OF THE THINGS THAT WE HAD ENVISIONED WAS DATA LINKAGE. SO WHEN THIS WAS BEING SET UP IN 2013 WHAT WE DID WAS INCORPORATED SOMETHING CALLED THE GLOBAL UNIQUE IDENTIFIER WHICH NOW FINDING MANY SOURCES TO GENERATE THAT. BUT WHAT DS CONNECT DOES IS USES FLASHNAL INSTITUTE OF MENTAL HEALTH RESOURCE, NDA, WHICH IS THE NATIONAL DATABASE OF AUTISM, WHICH HAS SOFTWARE ALGORITHM THAT GENERATES 200 CORD IF THEY HAVE FIVE ELEMENTS A PERSON, FIRST NAME AT BIRTH, LAST NAME AT BIRTH, DATE OF BIRTH, CITY OF BIT, AND GENDER. THAT ASSIGNS A UNIQUE COHORT TO THIS PERSON. SO WHENEVER ANYBODY REGISTERS ON DS CONNECT THAT CODE IS GENERATED BECAUSE WE DO COLLECT THESE FIVE ELEMENTS. THE GOAL IS ANY OTHER DATABASE IF THEY COLLECT THESE FIVE ELEMENTS AND USES THIS GOOD GENERATING SOFTWARE, THEN THEY WILL BE ABLE TO GENERATE THE SAME CODE AND WHEN WE EXPORT DATA OR LINK DATA IT CAN BE DONE USING THIS GRID. WE ARE IN THE PROCESS OF SETTING UP A COLLABORATION WITH A GROUP WHICH KIND OF WOULD BE OUR FIRST TEST CASE TO ACTUALLY MAKE THIS OPERATIONAL SO THERE'S A LOT OF BACK END WORK THAT NEEDS TO GO INTO CREATING THE DATA LINKAGES. I DO KNOW THAT DR. ESPINOSA'S GROUP STARTED COLLECTING THIS INFORMATION ON THEIR PARTICIPANTS WITH THE GOAL OF IN THE FUTURE LINKING OUR DATABASES. SO THERE'S ONE OF THE OUT OF THE INCLUDE WORKSHOP THERE WAS ONE -- THERE IS WORKING GROUP WHICH IS FOCUSED ON GRIDS AND ONE OF THE TASK IS TO AT LEAST KNOW HOW MANY ALGORITHMS ARE OUT THERE. THAT IS GENERATING THIS GRID. IN THEORY WE CAN DO THE LINKAGES, BUT RIGHT NOW WE ARE IN THE PROCESS OF MAKING IT HAPPEN AND SEEING WHAT ARE THE ACTUAL THINGS WE NEED TO DO TO MAKE THIS OPERATIONAL. THAT IS THE ULTIMATE GOAL TO BE ABLE TO LINK DIFFERENT DATA THAT ARE NOT ALL COLLECTING THE SAME INFORMATION. MORE EFFICIENT WITH THE TAXPAYER DOLLARS IN THE LONG RUN. >> SO I KNOW WE ARE TALKING INFRASTRUCTURE HERE FOR THE REGISTRIES, I THINK I WOULD BE REMISS IF I DIDN'T ASK YOU AN PERHAPS JULIE AND OTHERS WHAT ARE WE SEEING IN TERMS OF COVID AND DOWN'S SYNDROME SUBJECTS? IS THERE A STORY BREAKING YET FROM SUSCEPTIBILITY AND RISK THAT YOU ARE SEEING FROM EARLY REGISTRY DATA? >> WHAT I CAN SAY IS WE QUICKLY ADDED THE COVID-19 QUESTIONS WITHIN THE REGISTRY BUT EXISTING PARTICIPANTS CAN TAKE IT AND NEW PARTICIPANTS WILL BE ABLE TO TAKE IT AS WELL. I KNOW THROUGH THE REGISTRY THERE IS A T 21 THAT DR. SHOWMAN AND OTHERS HAVE BEEN -- THEY HAVE CREATED AND WHICH WE WILL BE PROMOTING THROUGH DS CONNECT. SO GIVEN THAT THE DS POPULATION IS IN THE HIGH RISK CATEGORY, THEY ARE VULNERABLE POPULATION ESPECIALLY THE COVID-19. BUT AT LEAST IN THE REGISTRY SINCE WE LAUNCHED THE -- THOSE QUESTIONS THERE HAVE NOT BEEN A LOT OF PEOPLE WHO HAVE TAKEN IT. AGAIN, WE HAVE TO MAKE SURE EVERYBODY KNOWS THOSE QUESTIONS ARE IN THERE. OCE T 21 IS OUT WE MAY BE ABLE TO GET MORE INFORMATION ABOUT HOW MANY INDIVIDUALS ARE BEING INFECTED AND HOW MANY ARE ACTUALLY BEING ABLE TO COME OUT OF IT. >> GREAT. WE ARE LOOKING FORWARD TO SEEING IT. ANY OTHER COMMENTS FROM JULIE OR MARA BEFORE WE END HERE? >> THIS IS MARA, MY ONLY COMMENT SO FAR IS WHAT WE SEE IN CHILDREN IS THAT -- NOT SPECIFIC TO CHILDREN WITH DOWN'S SYNDROME BUT CHILDREN IN GENERAL, THINGS AREK LOUING TERRIFIC FROM A COVID PERSPECTIVE SO WE ARE HOPING THAT IT CONTINUES TO BE MILD IN THIS POPULATION BUT I'M -- I'LL BE INTERESTED TO SEE WHERE THE NEXT SEVERAL MONTHS NEED LEAD US. AND I DON'T HAVE ANY SPECIFIC CHILDHOOD OR CHILDREN WITH DOWN'S SYNDROME DATA TO REPORT AT THIS POINT. BUT I'M HOPING THAT AT LEAST HAVING IN THE PEDIATRIC AGE GROUP MAYBE POTENTIALLY A BENCH -- A BENEFIT. >> AND THEN JULIE FROM THE PEDIATRIC HEART NETWORK, I KNOW YOU HAVE A STRONG INTEREST IN KAWASAKI AND THERE'S A LOT OF COVID INDUCED, MAYBE TOO EARLY TO HAVE DATA BUT IN YOUR NETWORK ARE YOU SEEING ANYTHING ABOUT COVID AND HEART DISEASE AND DOWN'S SYNDROME PATIENTS? >> SO IT IS SOMEWHAT A LATE BREAKING THING, SO IT IS BEING DISCUSSED, I DON'T HAVE ANY INFORMATION TO SHARE RIGHT NOW BUT IT IS SOMETHING OUR INVESTIGATORS ARE INVOLVED WITH. AND WE ARE MEETING IN THE NEXT COUPLE OF WEEKS TO DISCUSS FURTHER AND SEE WHAT INVOLVEMENT PHN MIGHT HAVE IN THAT AREA. >> VERY GOOD. I THINK IT'S TIME TO BREAK FOR LUNCHLESSER -- UNLESS THERE'S ANOTHER QUESTION. OF I DON'T HAVE ANY ADDITIONAL QUESTIONS ON THE EMAIL LIST. SHOULD WE BREAK OR OPEN IT UP? >> WE SHOULD DEFINITELY BREAK. WE DON'T HAVE ANY OTHER QUESTIONS THAT CAME THROUGH EITHER, STEVE SO WE WILL HAVE EVERYONE COME BACK AT 12:30. WE WILL START OUR AFTERNOON SESSION. >> I WANT TO THANK EVERYBODY FOR A WONDERFUL MORNING, IT'S BEEN FANTASTIC. LOOKING FORWARD TO MORE THIS AFTERNOON. >> HI, EVERYONE. I THINK WE'RE GETTING READY TO START THE NEXT SESSION ENTITLED "RECRUITMENT INTO CLINICAL TRIALS." >> HI, EVERYONE. CAN YOU ALL HEAR ME AND SEE MY SCREEN? >> YES, OUR FIRST SPEAKER IS GOING TO BE DR. ANNIE COHEN FROM THE UNIVERSITY OF PITTSBURGH. SHE'LL BE TALKING ABOUT RECRUITMENT OF DIVERSE POPULATIONS, LESSONS LEARNED AND IMPLICATIONS FOR DOWN SYNDROME RESEARCH. ANNIE. >> HI. THANKS VERY MUCH FOR THE INVITATION. I'M EXCITED TO TALK TO YOU GUYS TODAY A LITTLE BIT ABOUT THE LESSONS WE'VE LEARNED IN PITTSBURGH ABOUT RECRUITMENT OF DIVERSE POPULATIONS AND HOW WE'RE NOW BEGINNING TO APPLY THIS TO OUR DOWN SYNDROME RESEARCH STUDIES THROUGH A SUPPLEMENT TO OUR CTSI AND INCLUDE SUPPLEMENT TO OUR TCSI AND ALSO IN THE ABCDS STUDY THAT YOU'VE HEARD ABOUT A BIT OVER THE LAST COUPLE OF DAYS. SO THE FIRST EXPERIENCE IN WHAT I THINK IS BY FAR OUR MOST SUCCESSFUL EXPERIENCE IN PITTSBURGH WITH RECRUITMENT OF UNDERREPRESENTED COMMUNITIES IS THROUGH OUR COULD NECK TOE MIX AND BRAIN AGING STUDIES. SO THIS WAS A STUDY THAT WAS FUNDED THROUGH THE BRAIN INITIATIVE, A LONGITUDINA NEUROCOGNITION STUDY THAT HAD RECRUITMENT GOALS TO RECRUIT 400 PARTICIPANTS WHO WERE ACROSS THE SPECTRUM OF COGNITION FROM COGNITIVELY NORMAL, MILD COGNITIVE IMPAIRMENT, TO ALZHEIMER'S DISEASE WITH RECRUITMENT GOALS OF RECRUITING EQUAL PROPORTIONS OF INDIVIDUALS FROM THE AGINGS OF 50 TO 89 WITH HALF THE POPULATION BEING FEMALE AND HALF THE POPULATION BEING AFRICAN AMERICAN. AND WE FOCUSED ON AFRICAN AMERICANS FOR THIS STUDY BECAUSE THEY ARE THE LARGE EST ETHNIC MY MORTGAGE GROUP IN THE PITTSBURGH AREA. WE ACTUALLY HAVE VERY LOW PROPORTIONS OF BOTH HISPANICS AND ASIAN AMERICANS IN PITTSBURGH. TO DATE, WE'VE ENROLLED A LITTLE MORE THAN HALF THESE PARTICIPANTS AND WE'VE SURPASSED OUR GOALS IN TERMS OF DIVERSITY. WE'RE AT 52% OF OUR POPULATION IS AFRICAN AMERICAN, BUT WE DO HAVE A HIGHER REPRESENTATION OF FEMALES. THE AFRICAN AMERICAN GROUP ALSO TENDED TO BE YOUNGER THAN OUR WHITE GROUP, AND SOME OF THIS WAS RELATED TO OUR RECRUITMENT SOURCE, ONE OF THE PRIMARY RECRUITMENT SOURCES WAS OUR ALZHEIMER'S DISEASE RESEARCH CENTER WHERE MOST OF OUR CAUCASIAN PARTICIPANTS COME FROM AND THEY TEND TO BE OLDER. WHAT I WANTED TO TALK TO THIS GROUP ABOUT WAS ABOUT USE OF OUR COMMUNITY ONLINE REGISTRY, WHICH HAS REALLY BEEN A VERY SUCCESSFUL OUTREACH APPROACH FOR US IN THIS RESEARCH STUDY. SO WHAT HAVE WE LEARNED FROM THIS STUDY? WELL, THE FIRST THING -- SO THE FIRST FOCUS WAS OUR COMMUNITY -- SORRY, MY ANIMATIONS AREN'T SHOWING UP BUT THAT'S OKAY, I'LL JUST KEEP GOING. OUR COMMUNITY -- OUR COMMUNITY OUTREACH STRATEGY WITH THIS ONLINE REGISTRY CALLED PIT PLUS ME, WHICH IS RUN THREUL OUR THROUGH OUR CTSI. IT'S AN ONLINE REGISTRY THAT HAS BEEN VERY FOCUSED ON REACHING COMMUNITIES THAT DON'T TYPICALLY PARTICIPATE IN RESEARCH STUDIES. THEY'VE DONE LOTS OF TARGETED RECRUITMENT WITH BUS ALZHEIMER'S ALZHEIMER 'S BUS ADS AND SOCIAL MEDIA ADVERTISING, AND IT'S REALLY ALLOWED US TO REACH PARTICIPANTS WHO DON'T PARTICULARLY PARTICIPATE IN STUDIES. SO TYPICALLY OUR AFRICAN AMERICAN OUTREACH HAS BEEN AFRICAN AMERICANS WHO ARE MORE HIGHLY ED EDUCATED, ARE FROM HIGHER SOCIOECONOMIC GROUPS, AND PITT PLUS ME HAS ALLOWED US TO REACH PEOPLE WITH HIGH SCHOOL EDUCATION AND LESS, AFRICAN AMERICANS WITH LOWER SOCIOECONOMIC STATUS, AND SO IT'S BEEN VERY EXCITING BECAUSE WE FOUND THAT COMMUNITIES WHO TYPICALLY DON'T PARTICIPATE IN RESEARCH AND HAVE BEEN THOUGHT OF TO BE THE HARDEST TO REACH, WE'VE BEEN ABLE TO REACH THROUGH THIS APPROACH. IN FACT, WE WERE SO SUCCESSFUL IN THIS APPROACH THAT WE FOUND THAT OUR ALZHEIMER'S DISEASE RESEARCH CENTER COMPARISON GROUP WAS NO LONGER A GOOD COMPARISON GROUP BECAUSE THERE WERE SUCH DISPARITIES BETWEEN SOCIOECONOMIC AND EDUCATION, SO WE'RE NOW REACHING OUT TO CAUCASIANS THROUGH THIS STRATEGY AS WELL TO REACH LOWER EDUCATION CAUCASIANS TO BETTER MATCH OUR COMMUNITY GROUP. THE OTHER THING THAT WE'VE DONE THAT I THINK HAS TAUGHT US A LOT IS UTILIZING OUR COMMUNITY ENGAGEMENT CENTERS, AND SO THIS IS VERY DIFFERENT THAN GOING INTO A COMMUNITY CHURCH OR INTO A COMMUNITY CENTER, AND GIVING A SINGLE TALK AND THEN HOPING THAT PEOPLE ENROLL IN YOUR STUDY BASED ON THAT TYPE OF ADVERTISEMENT. THESE COMMUNITY ENGAGEMENT CENTERS HAVE MONTHLY DINNERS, THEY HAVE A VARIETY OF MEETINGS THROUGHOUT THE MONTH AND ONE OF THE THINGS THEY'VE REALLY ENCOURAGED INVESTIGATORS TO DO IS COME SPEND TIME IN THESE CENTERS AND INVEST IN THE COMMUNITY AND INVEST IN CONVERSATIONS WITH THE COMMUNITY. AND THIS HAS ALLOWED US TO BUILD LONGER TERM PARTNERSHIPS, AND ONE OF THE THINGS THAT WE'VE HEARD FROM THE COMMUNITY ENGAGEMENT CENTERS IS THAT THEY REALLY APPRECIATE THIS BECAUSE WE'RE NOT HITTING AND RUNNING, WE'RE NOT SAYING, COME TO OUR STUDY AND THEN THEY NEVER SEE US AGAIN. SO IT'S REALLY A LONG TERM PARTNERSHIP, AND WE'RE BEING BROUGHT INTO THAT PARTNERSHIP BY TRUSTED PARTNERS WITHIN THE COMMUNITY. AND SO I THINK LOTS OF INSTITUTIONS HAVE THESE SORT OF COMMUNITY ENGAGEMENT CENTERS, BUT THEY'RE TYPICALLY UNDERUTILIZED, SO THIS HAS REALLY BEEN A SUCCESS FOR US AS WELL. SO A COUPLE OF THE LESSONS THAT WE LEARNED FROM THIS OUTREACH. I THINK THIS IS SOMETHING THAT'S BEEN HIGHLIGHTED IN THIS MEETING THUS FAR, ONE IS FLEXIBILITY IN OUR RESEARCH STRATEGIES. WEE DISCOVERED THAT WE'VE DISCOVERED THAT LOTS OF OUR PARTICIPANTS DON'T HAVE CONSISTENT MEANS OF CONTACT. THEIR PHONE NUMBERS CHANGE, THEY DON'T HAVE CONSISTENT INTERNET ACCESS. SO WE'VE HAD TO BE CREATIVE IN HOW WE CONTACT PEOPLE AND REMINDING FOLKS, IF YOUR PHONE NUMBER CHANGES, WE WANT TO HEAR FROM YOU. IF YOU DON'T HAVE INTERNET FOR A WHILE, JUST GIVE US A CALL, LET US KNOW HOW WE CAN GET IN TOUCH WITH YOU. WE'VE ALSO HAD TO BE MORE FLEXIBLE AND CREATIVE IN OUR SCHEDULING OF RESEARCH PROCEDURES, PARTICULARLY THOSE œIN TO THE RESEARCH CENTER.OME SO ACKNOWLEDGING THAT PEOPLE HAVE HOURLY JOBS THAT THEY CAN'T TAKE OFF FROM OR THAT THEY MAY GET CALLED IN TO WITH VERY LITTLE NOTICE, SO BEING MORE FLEXIBLE IN OUR SCHEDULING, HAVING EVENING SCHEDULING, HAVING WEEKEND SCHEDULING. THE OTHER THING THAT WE'VE REALLY THOUGHT A LOT ABOUT AND THAT I THINK IS IMPORTANT AND I WAS REALLY EXCITED TO SEE SOMEONE MENTIONING THIS MOBILE NEARS UNIT THAT THEY'RE USING FOR THEIR DOWN SYNDROME STUDIES IS USING TRUSTED LOCATIONS FOR RESEARCH PROCEDURES THAT DON'T HAVE TO BE AT A RESEARCH CENTER. SO IF YOU HAVE THE ABILITY TO DO A BLOOD DRAW AT A COMMUNITY HEALTH CENTER WHERE THERE ARE TRUSTED PRACTITIONERS, IF YOU CAN DO NEUROPSYCHIATRIC TESTING IN THE HOME OR IN OTHER LOCATIONS, THESE ARE GREAT STRATEGIES FOR BUILDING TRUST AND GETTING RECRUITMENT. THE OTHER REALLY IMPORTANT THING THAT WE'VE DISCOVERED FROM THE STUDY AND THAT I THINK WAS REALLY EYE OPENING TO ME IN STARTING THESE RECRUITMENT EFFORTS WAS THAT WE ALL KNOW THAT WE NEED A RESPECTFUL EDUCATION PROCESS ABOUT OUR RESEARCH PROCEDURES. BUT I THINK WE ALSO COME INTO THESE STUDIES WITH A LOT OF ASSUMPTIONS ABOUT CERTAIN COMMUNITIES AND THE SORTS OF PROCEDURES THEY WILL AND WON'T BE WILLING TO DO. AND I THINK THAT WE HAVE TO THROW THOSE ASSUMPTIONS OUT THE WINDOW. ONE OF THE THINGS THAT WE'VE HEARD FROM PARTICIPANTS, ONE OF THE THINGS THAT WE INITIALLY DID WAS IN OUR AFRICAN AMERICAN OUTREACH, WE MADE THIS WOULD BE UNWILLING TO DO PET SCANS AND SO WE ALWAYS GAVE PEOPLE THE OPTION TO OPT OUT. WELL, THAT'S NOT A REQUIRED COMPONENT OF OUR STUDY, AND SEVERAL OF OUR ADVISORS FROM THE COMMUNITY ENGAGEMENT CENTER SAID THEN WHY ARE YOU ASKING US TO DO THIS? IF IT'S NOT IMPORTANT ENOUGH FOR US TO DO, WHY ARE YOU EVEN BOTHERING ASKING? THE MESSAGE WE GOT WAS THAT PART OF THIS TRUST BUILDING PROCESS IS REALLY TO SPEND THE TIME EXPLAINING WHY THE PROCEDURE IS NEEDED AND NOT JUST SAYING, OH, WELL, IF THIS IS OFF-PUTTING TO YOU, WE CAN FOREGO IT. HAVING THOSE DIFFICULT CONVERSATIONS AND ACKNOWLEDGING THAT THERE MAY BE SOME MISTRUST BUT THIS IS WHY WE'RE ASKING YOU TO DO THIS PROCEDURE THAT MAY BE MORE INVASIVE THAN YOU'VE TYPICALLY BEEN COMFORTABLE WITH. SO THE NEXT IN THE LAST COUPLE OF MINUTES I JUST WANTED TO TALK ABOUT HOW DOWN SYNDROME RESEARCHERS CAN ADDRESS THE RECRUITMENT OF UNDERREPRESENTED COMMUNITIES. ACKNOWLEDGING THAT IN DOWN SYNDROME, YOU REALLY HAVE TO THINK NOT ONLY ABOUT THE CHALLENGES AND THE HISTORY OF PROBLEMS WITH RESEARCH IN UNDERREPRESENTED COMMUNITIES, BUT YOU ALSO HAVE TO THINK OF THAT SECOND LAYER OF THE MISTRUST OF INDIVIDUALS WITH DOWN SYNDROME TO RESEARCH. SO THERE'S REALLY THIS KIND OF DOUBLE HIT THAT YOU HAVE TO ADDRESS. SO WHAT WE'RE REALLY WORKING ON RIGHT NOW BOTH IN OUR SUPPLEMENT AND ABCDS IS THAT ENSURES COMMUNITY MEMBERS WITH DOWN SYNDROME AND THEIR FAMILIES HAVE A SEAT AT THE TABLE. SO WE'RE DEVELOPING ADVERTISING MATERIALS, EDUCATION MATERIALS RELATED TO OUR PROCEDURES THAT WE'RE GETTING FEEDBACK ON AT EVERY STAGE OF OUR RESEARCH. AND THEN ONCE WE GET THAT SORT OF FEEDBACK, WE ALSO WANT FEEDBACK FROM THE COMMUNITY ABOUT THE SETTING AND LOCATION OF OUR RESEARCH. SO WOULD BLOOD DRAWS AT A MORE TRUSTED LOCATION RATHER THAN OUR RESEARCH CENTER BE PREFERRED? HOW CAN WE ADDRESS MAYBE SOME OF OUR TESTING IN SETTINGS WHERE INDIVIDUALS WITH DOWN SYNDROME ARE MORE COMFORTABLE AND NOT A HOSPITAL SETTING. SO THESE ARE THE QUESTIONS THAT WE'RE ASKING RIGHT NOW AND SEEKING FEEDBACK ON. WE ALSO HAVE TO ACKNOWLEDGE AND WE'RE WORKING VERY HARD TO UNDERSTAND OTHER SOURCES OF DOWN SYNDROME RECRUITMENT THAT THE TRADITIONAL SOURCES HAVE REALLY FAILED TO ENGAGE DIVERSE COMMUNITY MEMBERS. SO I THINK BRIAN YESTERDAY MENTIONED THAT THE SPECIALTY DOWN SYNDROME CARE SETTINGS, WHILE A GREAT SOURCE OF RECRUITMENT, THEY DON'T REACH THE ENTIRE DOWN SYNDROME COMMUNITY. TYPICALLY THE SUPPORT GROUPS HAVE NOT BEEN REAL SUCCESSFUL AT REACHING DIVERSE COMMUNITY MEMBERS AND AGAIN, CONFERENCES, THESE DOWN SYNDROME CONFERENCES, WHILE A GREAT SOURCE OF RECRUITMENT, THEY DON'T -- THEY ARE EXCLUDING INDIVIDUALS WHO CAN'T TAKE OFF WORK, WHO DON'T HAVE THE FINANCIAL MEANS TO ATTEND THOSE CONFERENCES, SO WE REALLY HAVE TO THINK ABOUT NEW SOURCES OF RECRUITMENT THAT CAN ENGAGE DIVERSE COMMUNITY MEMBERS. AND THEN FINALLY, I WANTED TO ALSO TALK AGAIN ABOUT HOW WE CAN MEET THE COMMUNITY WHERE THEY ARE, AND THIS IDEA OF THIS HIT-AND-RUN APPROACH. WE HEAR THIS CONSISTENTLY FROM LOTS OF OUR COMMUNITY MEMBERS WHO WE'VE QUERIED THAT THEY'RE ACUTELY AWARE OF THIS HIT-AND-RUN APPROACH, THIS IDEA THAT YOU COME IN AND YOU GET WHAT YOU NEED, AND THEN YOU LEAVE THE COMMUNITY, AND YOU'RE NOT PROVIDING ANY FEEDBACK OR ANY INFORMATION. AND SO WE'RE REALLY TRYING TO UNDERSTAND IN THE DOWN SYNDROME COMMUNITY HOW OUR RESEARCH CAN BE OF SERVICE TO THE COMMUNITY, WHAT CAN WE PROVIDE BACK FROM OUR RESEARCH STUDIES, EITHER IN SOME KIND OF COMPENSATION AND THAT DOESN'T NECESSARILY MEAN A FINANCIAL PAYMENT FOR THE RESEARCH PROCEDURE OR WITH INFORMATION FROM THOSE RESEARCH PROCEDURES THAT CAN BE OF USE. WE ALSO HAVE TO IDENTIFY IN THE DOWN SYNDROME COMMUNITY CHALLENGES AND BARRIERS TO PARTICIPATION. MANY OF OUR ADULTS WITH DOWN SYNDROME WHO WORK ARE WORKING AT OURLY POSITIONS THAT DON'T HAVE ANY KIND OF PAID LEAVE AND THEY'RE CONCERNED ABOUT LEAVING WORK TO GO PARTICIPATE IN A RESEARCH STUDY, SO AGAIN GOING BACK TO THAT IDEA OF FLEXIBILITY IN OUR SCHEDULING. THEN FINALLY, I THINK SOMEONE IN THE LAST SESSION MENTIONED THIS AND IT'S REALLY IMPORTANT TO ACKNOWLEDGE THAT THESE FACTORS ARE GOING TO DIFFER IN DIFFERENT TYPES OF DIVERSE COMMUNITY. AND SO WHENEVER WE DESIGN A RESEARCH STUDY, THAT DESIGN MEANS THAT WE HAVE TO BE AS INCLUSIVE AS POSSIBLE AND RECOGNIZE THAT DIRN DIFFERENT STRATEGIES WILL APPEAL TO DIFFERENT COMMUNITIES. SO IF YOU WANT DIVERSITY ACROSS ALL COMMUNITIES, THERE'S LIKELY GOING TO HAVE TO BE A WHOLE VARIETY OF STRATEGIES THAT YOU HAVE TO UTILIZE, NOT JUST A SINGLE OUTREACH STRATEGY. SO WHAT ARE WE DOING RIGHT NOW? SO WE ARE IDENTIFYING AND CONVENING A COMMUNITY ADVISORY BOARD TO IDENTIFY BARRIERS TO PARTICIPATION AND RESEARCH IN THE DOWN SYNDROME COMMUNITY. WE ARE FORMING FOCUS GROUPS TO GATHER INFORMATION ABOUT AGREEABLENESS TO A WIDE RANGE OF RESEARCH PROCEDURES, FROM THINGS AS LOW RISK AS NEUROPSYCHIATRIC TESTING AND A BLOOD DRAW, ALL THE WAY TO LUMBAR PUNCTURES AND BRAIN DONATION. AND WE'RE REALLY HOPEFUL THAT THESE FOCUS GROUPS WILL ALSO BE ABLE TO IDENTIFY THE NEEDS AND GOALS FOR RESEARCH IN THE DOWN SYNDROME COMMUNITY. WE KNOW WHAT OUR GOALS ARE, BUT WE DON'T -- WE AREN'T NECESSARILY CLEAR ON THE GOALS FOR INDIVIDUALS WITH DOWN SYNDROME AND THEIR FAMILY MEMBERS, ESPECIALLY IN DIVERSE COMMUNITIES. I ALSO WANTED TO MENTIO HERE THAT WHILE COVID-19 IS DIFFICULT IN THAT WE CAN'T BRING PEOPLE IN, IT'S REALLY CREATED A UNIQUE OPPORTUNITY FOR US TO ATTEMPT TO REACH A BROADER COMMUNITY. WHILE WE ALWAYS WANT TO TALK TO PEOPLE FACE TO FACE, THE PANDEMIC HAS REQUIRED US TO PIVOT TO ATTEMPT TO DO MORE OUTREACH FROM REMOTE STRATEGIES, SO WE'RE WORKING ON AN ONLINE SURVEY FORMAT THAT HAS A PHONE FOLLOW-UP COMPONENT RIGHT NOW, AND THIS MAY ALLOW US TO REACH INDIVIDUALS WE MIGHT NOT NORMALLY REACH. SO FOR EXAMPLE IN MORE RURAL COMMUNITIES, OR PEOPLE WHO HAVE LESS FLEXIBILITY TO COME IN AND SEE US. SO THEN FINALLY, WHEN ALL OF THIS IS DONE, WE ARE HOPEFUL THAT WE'LL HAVE EDUCATIONAL MATERIALS THAT HAVE GOTTEN LOTS OF FEEDBACK FROM THE COMMUNITY, AND THAT THESE MATERIALS CAN BE DISSEMINATED TO A WIDE VARIETY OF COMMUNITIES THROUGH SOCIAL MEDIA, THROUGH HANDS-ON COMMUNITY OUTREACH, AND THAT WE CAN SHARE THESE MATERIALS WITH YOU GUYS IN THE SCIENTIFIC COMMUNITY AS A WHOLE TO INCORPORATE INTO THINGS LIKE CLINICAL TRIALS. SO THANKS VERY MUCH FOR LISTENING, AND I'M HAPPY TO ANSWER QUESTIONS VIA EMAIL OR LATER IN THE SESSION. >> THANK YOU, ANNIE. THAT WAS TERRIFIC. OUR NEXT SPEAKER IS DR. SHARON KRINSKY KRINSKY-MCHALE FROM THE NEW YORK STATE INSTITUTE FOR BASIC RESEARCH IN DEVELOPMENT DISABILITIES, "OBTAINING CONSENT IN CLINICAL TRIALS, STATE-SPECIFIC POLICIES AND SHARON? >> HELLO. >> HI, SHARON, AND MIKE, BEFORE YOU BEGIN, SHARON, CAN YOU MAKE SURE WHEN YOU SHARE YOUR SCREEN, YOU'RE SHARING FROM THE TOP RIBBON? >> THAT'S WHAT I DID. DO YOU SEE IT NOW? >> YES, YOU CAN SEE IT. I JUST WANTED TO MAKE SURE BECAUSE IT'S ALSO STREAMING THROUGH THE VIDEOCAST SO I WANT TO MAKE SURE IT CAPTURES IT. THANK YOU. >> OKAY. VERY GOOD. I'D LIKE TO JUST TAKE THIS OPPORTUNITY TO THANK NIH, LAURIE AND ERIKA FOR PULLING OFF WHAT SEEMED -- FLAWLESSLY PULLING OFF WHAT SEEMED ALMOST IMPOSSIBLE TO DO, TO HOLD THIS WORKSHOP AS A VIRTUAL PRESENTATION. WHILE I MISS MEETING MANY OF YOU AND DOING THAT INFORMAL TALKING THAT IS SO VALUABLE TO ALL OUR WORK, I'M JUST SO GLAD THAT YOU'VE ASKED ME TO BE PART OF THIS. TODAY I'M GOING TO TALK ABOUT RECRUITING AND OBTAINING CONSENT OF ADULTS AND CHILDREN WITH DOWN SYNDROME IN CLINICAL TRIALS. I JUST ALSO WANT TO POINT OUT THAT I AM ALSO ONE OF THE RESEARCHERS ON THE ABCDS PROJECT AND I WORK ALSO WITH MIKE ON THE ACTCDS. SO ONE OF THE THINGS THAT WE HAVEN'T DISCUSSED IS ALL OF US UNDERSTAND THAT SCIENTIFIC ADVANCES CAN IMPROVE THE LIVES OF ADULTS WITH DOWN SYNDROME, YET CONCERNS THAT RESEARCH PARTICIPATION MAY IMPOSE HARM IMPEDES SCIENTIFIC PROGRESS. WHAT COUNTS AS HARMFUL CAN BE VERY SUBJECTIVE, WHAT I LEARNED IN DOING RESEARCH FOR THIS TALK, AND PERCEPTIONS OF HARM MAY VARY AMONG THE VARIOUS STAKEHOLDERS THAT WE WORK WITH. SO IN THIS PRESENTATION, I WILL ANSWER, DO STATES DIFFER IN THEIR POLICIES AND REGULATIONS REGARDING MEDICAL RESEARCH FOR CHILDREN AND ADULTS WITH INTELLECTUAL AND DEVELOPMENTAL DISABILITIES. AND THE SHORT ANSWER IS YES, REGULATIONS FOR SURROGATE CONSENT AND BIOMEDICAL RESEARCH DIFFER ACROSS STATES. THE LONG ANSWER IS THAT THIS IS SOMEWHAT MORE A MORE COMPLICATED PICTURE. BECAUSE OF THE HISTORY OF CONTROVERSIAL RESEARCH IN PATIENTS WITH ID/DD, RIGOROUS RESEARCH PRO PROTECTIONS FOR RESEARCH PARTICIPANTS ARE CURRENTLY MANDATED IN SOME STATES. SO TO HELP HIGHLIGHT THIS, I WILL PRESENT SOME HISTORY OF MEDICAL RESEARCH THAT HAS BEEN CONDUCTED WITH INDIVIDUALS WITH ID/DD IN NEW YORK STATE, AND THEN I WILL PRESENT SOME POLICIES AND REGULATIONS FROM THREE STATES: NEW YORK, NEW JERSEY, WHICH IS OBVIOUS AS STATEN ISLAND WHERE I WORK IS IN NEW YORK AND I LIVE IN NEW JERSEY. NEW MEXICO WAS JUST SORT OF A SERENDIPITOUS FIND. SO I DON'T KNOW VERY MUCH IN DETAIL, BUT I'LL PRESENT TO YOU WHAT I DO KNOW. SO THERE ARE COMPETING FACTORS AT WORK HERE. SO INDIVIDUALS WITH INTELLECTUAL DEVELOPMENTAL DISABILITIES ARE POTENTIALLY A RISK FOR EXPLOITATION WITHIN THE RESEARCH PROCESS BECAUSE OF THEIR LIMITATIONS AND RELATIVE SOCIAL POWERLESSNESS. BUT AVOIDING THESE ISSUES VIA BLANKET EXCLUSION FROM RESEARCH DENIES SUCH INDIVIDUALS THE OPPORTUNITY TO CONTRIBUTE TO AND BENEFIT FROM SCIENTIFIC RESEARCH, AND I THINK MAYBE YOU MIGHT REMEMBER THAT FRANK STEVENS' PRESENTATION YESTERDAY, HE HIGHLIGHTED HOW HE THOUGHT IT WAS VERY IMPORTANT FOR PEOPLE WITH DOWN SYNDROME TO PARTICIPATE IN RESEARCH. AND I FOUND THAT VERY TOUCHING. SO THIS IS JUST FROM LOOKING AT VARIOUS STATES, I'VE COME UP WITH SORT OF A HIERARCHY OF POLICIES AND REGULATIONS, AND I LIKED THIS PARTICULAR WAY TO REFER TO ALL THE VARIOUS PEOPLE THAT WE HAVE TO GO THROUGH AS GATE KEEPERS. SO WHAT WE'RE DOING IS WE'RE RECRUITING THROUGH GATE KEEPERS. SO I DON'T HAVE ON HERE THE FEDERAL REGULATIONS BECAUSE I'M JUST GOING TO BE DOING THE STATE AND LOCAL IRBs AND VARIOUS DEVELOPMENTAL DISABILITIES OFFICE, BUT THIS IS WHAT IT SORT OF LOOKS LIKE. SO IN SOME STATES, THERE ARE LAWS ON THE BOOKS WHICH AFFECT WHO CAN PARTICIPATE IN RESEARCH, AND EVEN IF THEY SAY THIS PERSON OR THIS GROUP OF PEOPLE CAN PARTICIPATE IN RESEARCH, YOUR LOCAL IRBs MIGHT SAY NO, WE ARE UNCOMFORTABLE WITH THAT, AND WE HAD SOME OF THAT WHEN WE FIRST RECRUITED FOR ADDS, THE LOCAL IRB AT COLUMBIA UNIVERSITY WAS JUST NOT EXPERIENCED ENOUGH WITH THE POPULATION WITH DOWN SYNDROME, SO THEY WERE A BIT MORE CAUTIOUS. NOW THEN AT LEAST IN THE TWO -- IN MY TWO STATES, WE HAVE -- THERE ARE STATE OFFICES FOR PEOPLE WITH INTELLECTUAL -- IN NEW YORK IT'S KNOWN AS OPWDD, THE OFFICE FOR PEOPLE WITH DEVELOPMENTAL DISABILITIES, AND IN NEW JERSEY, IT'S THE DIVISION -- THE NEW JERSEY DIVISION OF DEVELOPMENTAL DISABILITIES. SO IT'S REALLY THE ATTITUDES OF RESEARCHERS AND IRB MEMBERS AND THOSE IN CHARGE OF CONDUCTING AND MONITORING RESEARCH THAT PLAY A SUBSTANTIAL ROLE IN SHAPING THE KNOWLEDGE BASE ABOUT THE TREATMENT OF INDIVIDUALS WITH INTELLECTUAL AND DEVELOPMENTAL DISABILITIES. WHEN I FIRST SAW THE AGENDA FOR THIS MEETING, I WAS WONDERING WHY THEY THOUGHT ABOUT ME TO PRESENT STATE-SPECIFIC POLICIES AND REGULATIONS FOR ENROLLING AND CONDUCTING CLINICAL TRIALS. I STILL HAVEN'T ASKED THEM BUT I THINK A LITTLE HISTORY OF THE NEW YORK STATE COMPLEX WHERE I HAVE WORKED FOR THE LAST 25 YEARS MIGHT PRESENT SOME ANSWERS. SO I WORK ON THE CAMPUS OF WHAT WAS THE WILLOW BROOK STATE SCHOOL WHICH SITS ON ABOUT 375 ACRES OF LAND LOCATED IN THE WILLOW BROOK SECTION OF STATEN ISLAND IN NEW YORK CITY. AND IT WAS USED AS A NEW YORK STATE-RUN FACILITY TO CARE FOR APPROXIMATELY 3,000 INTELLECTUALLY DISABLED CHILDREN FROM THE GREATER NEW YORK METROPOLITAN AREA WITH, QUOTE-UNQUOTE, A HIGH DEGREE OF TENDERNESS AND ATTENTION. WILLOWBROOK OPENED IN 1947 AND FULLY AND PERMANENTLY CLOSED IN 1983, AND IN FACT, MY RENOVATED BUILDING WITH THE BUILDING WHERE -- WAS THE BUILDING WHERE THE INFANTS USED TO BE HOUSED. OUTSIDE, WE CAN STILL SEE SOME OF THE OUTDOOR TOYS THAT THEY HAD USED. THE RESIDENTS OF WILLOWBROOK WERE THE MOST SEVERELY DISABLED AND THE MOST HELPLESS AND IT WAS ONLY SUPPOSED TO HOUSE 4,000. AT THE END OF THE TIME, THEY HAD OVER 6,000 INDIVIDUALS HOUSED AT WILLOWBROOK. AND THUS THE CONDITIONS WERE OPTIMAL FOR THE TRANSMISSION OF HEPATITIS, RESPIRATORY INFECTIONS AND PARASITIC INFECTIONS. BETWEEN 1963 AND 1966, MORE THAN 700 CHILDREN WERE INVOLVED IN THE STUDIES. SOME WERE INJECTED WITH THE HEPATITIS VIRUS. EARLY SUBJECTS WERE FEDEX TRACTS FROM STOOLS OF INFECTED INDIVIDUALS AND LATER SUBJECTS RECEIVED INJECTIONS OF MORE PURIFIED VIRUS PREPARATION. I DO WANT YOU TO KNOW THAT THE RESEARCH PROTOCOL WAS REVIEWED AND APPROVED BY STATE, UNIVERSITY AND FEDERAL REVIEW BOARDS. THE PRACTICE WAS DEFENDED BY SAYING THAT THE VAST MAJORITY OF CHILDREN WOULD ACQUIRE THE INFECTION ANYWAY, AND IT WAS BETTER FOR THEM TO BE INFECTED UNDER CONTROLLED RESEARCH CONDITIONS. BUT IT WAS A PRIME EXAMPLE OF COERCION AND ENROLLED CHILDREN MOVED UP ON THE LIST TO BE ELIGIBLE FOR THIS SCHOOL. IT WAS CLOSED TO NEW RESIDENTS BUT THERE WAS THIS SPECIAL WING FOR CHILDREN THAT WERE INVOLVED IN THE STUDY. DR. KRUGMAN, WHO YOU SEE HERE ON THE LEFT, HE SAID THE FACT THAT THE CHILDREN WERE MENTALLY RETARDED WAR RELEVANT ONLY TO THE EXTENT THAT SOCIETY PLACED THEM IN AN INSTITUTION WHERE HEPATITIS WAS PREVALENT. THE PRIMARY OBJECTIVE OF OUR STUDIES WAS TO PROTECT THE CHILDREN AND EMPLOYEES WHILE ACQUIRING NEW KNOWLEDGE IN THE PROCESS. THIS HAD THE EFFECT OF FOREVER CHANGING THE WAY SOCIETY VIEWED PEOPLE WITH INTELLECTUAL AND -- NATIONWIDE TO REFORM SERVICE DELIVERY SYSTEMS AND RECOGNIZE THE INALIENABLE CIVIL RIGHTS OF PEOPLE WITH DEVELOPMENTAL DISABILITIES. BECAUSE OF THE NECESSITY TO CONCENTRATE, THOUGH, ON BASIC PROGRAM IK NEEDS OF WILLOWBROOK RESIDENTS IN THE HISTORY OF EXPERIMENTATION AT WILLOWBROOK, IT WAS SAID THAT NO PHYSICALLY INTRUSIVE, CHEMICAL, OR BIOMEDICAL RESEARCH OR EXPERIMENTATION SHALL BE PERFORMED AT WILLOWBROOK OR UPON MEMBERS OF THE PLAINTIFF CLASS. THIS STANDARD, HOWEVER, ONLY RECOGNIZES THE POSSIBILITY THAT SUCH RESEARCH OR EXPERIMENTATION UNDER PROPER SAFEGUARDS MAY BE APPROPRIATE FOR PERSONS WHO WERE NOT MEMBERS OF THIS WHAT THEY CALLED THE WILLOWBROOK CLASS. SO BACK IN 1972, THERE WAS THIS WILLOWBROOK DECREE, AND IN 1993, THE WILLOWBROOK PERMANENT INJUNCTION WAS SIGNED WHICH REPRESENTS THE CURRENT STANDARDS OF SERVICE FOR CLASS MEMBERS. WHILE THIS WAS MEANT TO ONLY APPLY TO WILLOWBROOK CLASS MEMBERS FOR THE DURATION OF THEIR LIVES, THERE WERE ADDITIONS TO IT, AND ONE IS IN APPENDIX JA. PARAGRAPH 3 AND 4 WHICH DISCUSSES SPECIFICALLY BEHAVIOR MODIFICATION RESEARCH AND HAZARDOUS OR EXPERIMENTAL TREATMENT AND IT'S BEEN WIDELY INTERPRETED AND APPLIED BY OPWDD AND EXTENDED TO ALL NEW YORK STATE RESIDENTS WITH IDD WITH EXCEPTION. WHAT IT SAID IS -- THE SPECIFICS SAID THAT YOU CAN, IN PARAGRAPH 3, CONDUCT THESE EXPERIMENTAL TREATMENTS ONLY AFTER APPROVAL HAS BEEN OBTAINED, AND THAT'S FROM THE RESIDENT OR IF HE OR SHE IS CAPABLE OF GIVING INFORMED CONSENT FROM A PARENT OR GUARDIAN OR FROM A THREE PERSON SPECIAL COMMITTEE, WHICH I WON'T GO INTO HERE. AGAIN, NO PHYSICALLY INTRUSIVE, CHEMICAL OR BIOMEDICAL RESEARCH OR EXPERIMENTATION SHALL BE PERFORMED ON WILLOWBROOK CLASS MEMBERS. IT WAS THOUGH RECOGNIZED, AGAIN, THAT IT MAY BE APPROPRIATE FOR SOME PEOPLE WHO ARE NOT MEMBERS OF THIS CLASS. SO WHAT WE HAVE IS THAT ALL FACILITIES OR ENTITIES WHICH WILL CONDUCT RESEARCH INVOLVING PARTICIPANTS WITH DEVELOPMENTAL DISABILITIES MUST SUBMIT TO THE COMMISSIONER OF OPWDD A COPY OF THEIR FEDERALLY APPROVED ASSURANCE OF COMPLIANCE WITH REGULATIONS FOR THE PROTECTION OF HUMAN SUBJECTS. MOVING ON TO NEW JERSEY, NEW JERSEY HAS HAD EVEN MORE STRINGENT LAWS IN PLACE, AND UP UNTIL 2012, INDIVIDUALS WITH INTELLECTUAL AND DEVELOPMENTAL DISABILITIES COULD NOT BE PARTICIPANTS IN ANY RESEARCH WITHOUT A COURT-APPOINTED GUARDIAN AD LITEM. SO WHAT WE WOULD HAVE HAD TO HAVE DONE WAS TO GO TO COURT AND HAVE AN APPOINTMENT MADE BY A JUDGE FOR EACH PARTICULAR INDIVIDUAL IN OUR STUDY. IT DID SAY THAT THEY BE ADMINISTERED ANY MEDICATION EXCEPT UPON THE WRITTEN AUTHORIZATION OF A PHYSICIAN WHEN NECESSARY AND APPROPRIATE, AND THAT THEY COULD NOT BE SUBJECT TO MEDICAL, BEHAVIORAL OR PHARMACOLOGICAL RESEARCH WITHOUT THE EXPRESS AND INFORMED CONSENT WITHOUT SUCH PERSON'S GUARDIAN AD LITEM. SO WHAT WE DID IS AT THE TIME THAT WE STARTED -- OH, I THINK IT WAS OUR LEGACY STUDY, OUR PROGRAM PROJECT GRANT, AT THAT TIME, I WAS LIVING IN A VERY SMALL TOWN IN NEW JERSEY AND I WAS ACTIVE IN THE POLITICAL PARTIES THERE, AND I KNEW MY LOCAL ASSEMBLY WOMAN AND I ASKED HER IF SHE WOULD SPONSOR A BILL THAT WOULD ELIMINATE THIS CONFUSION AND POTENTIAL STATUTORY CONFLICT WITH THE ACCESS TO MEDICAL RESEARCH ACT. SO ASSEMBLY BILL NUMBER 1291, AND SENATE BILL NUMBER 941 DEALS SPECIFICALLY WITH THIS ISSUE. IT PERMITS A BROADER RANGE OF RESEARCH AND AUTHORIZES SPECIFIED INDIVIDUALS OTHER THAN A GUARDIAN AD LITEM TO PROVIDE SURROGATE CONSENT FOR MEDICAL RESEARCH WHEN SPECIFIC PROTECTIVE CRITERIA ARE MET. MEDICAL RESEARCH SHALL ALSO BE APPROVED BY THE INTERDISCIPLINARY RESEARCH COMMITTEE, MEMBERS THAT ARE APPOINTED BY THEIR OFFICE FOR DEVELOPMENTAL DISABILITIES. IT GOES ON TO SAY THAT THE IRC WOULD INDEPENDENTLY DETERMINE WHETHER THE PROTECTIVE MEASURES AND CONSENT REQUIREMENTS HAVE BEEN MET, AND THAT THEY COULD IMPOSE SUCH OTHER CONDITIONS ON APPROVAL AS IT DETERMINES TO BE NECESSARY. AND AS IT CURRENTLY STANDS, IN NEW JERSEY, WE ARE ONLY ABLE TO CONDUCT MINIMAL RISK PROCEDURES. SO THEREFORE, IN THE ABC-DS PROJECTS, THE PROCEDURES THAT ARE CURRENTLY PROHIBITED ARE PET SCANS AND LUMBAR PUNCTURES. WE'RE HOPING THAT MAYBE WE CAN GO BACK AND TRY TO PLEAD THE CASE HOW THIS IS VERY IMPORTANT FOR THE LIVES OF PEOPLE WITH DOWN SYNDROME. AND JUST VERY BRIEFLY IN NEW MEXICO, I CAME ACROSS THIS TALE OF DR. CECILIA YI. AROUND 2014, SHE FIRST SAW GEORGE IN HER CLINIC AT THE UNIVERSITY OF NEW MEXICO CANCER CENTER THAT SHE THOUGHT WOULD BE AN IDEAL CANDIDATE FOR A NATIONWIDE REGISTRY STUDY. HE'D BEEN SUCCESSFULLY TREATED FOR LEUKEMIA IN HIS 30s BUT LATER DEVELOPED PANCYTOTEEN CYTOPENIA. AS IT TURNED OUT, GEORGE WAS NOT ELIGIBLE TO PARTICIPATE IN THE STUDY BECAUSE HIS INTELLECTUAL DISABILITY MADE HIM UNABLE TO COMPLETE THE STANDARDIZED QUALITY OF LIFE MEASURES REQUIRED OF THIS STUDY PROTOCOL. THEY ALSO COULDN'T ENROLL HIM IN AN INTERVENTION TRIAL EVEN THOUGH HIS SISTER AND HIS FATHER WERE HIS LEGAL REPRESENTATIVES AND WANTED HIM TO PARTICIPATE. WHAT SHE FOUND WAS THAT IN THE PEDIATRIC SETTING, PARENTS OF PARENTS CAN MAKE THE DECISION TO ENROLL THEIR CHILDREN IN CLINICAL TRIALS, BUT ADULTS, IF PARENTS ARE UNABLE TO CONSENT -- BUT IF THE PATIENTS, I'M SORRY, ARE UNABLE TO CONSENT OR FULFILL THE PROTOCOL REQUIREMENTS, THEY CANNOT BE ENROLLED, EVEN IF THE TREATMENT IS POTENTIALLY LIFE SAVING. IF YOU WANT TO LOOK AT SOME OF THE RESEARCH INTO THE PERCEIVED HARMS AND BENEFITS OF RESEARCH WITH THIS POPULATION, KATHRYN MCDONALD AT SYRACUSE UNIVERSITY HAS EXTENSIVELY STUDIED AND PUBLISHED ON THESE ISSUES FOR ADULTS WITH INTELLECTUAL AND DEVELOPMENTAL DISABILITIES. AND SHE COMPARES THEIR SYSTEMATIC EXCLUSION FROM CLINICAL TRIALS TO THE EXCLUSION THAT USED TO OCCUR OF WOMEN AND ETHNIC MY MORTGAGES FROM RESEARCH IN THE PAST. FEDERAL FUNDING AGENCIES NOW MANDATE INCLUSION OF THESE GROUPS TO ENSURE STUDIES ARE REPRESENTATIVE OF LARGER POPULATION, HOWEVER, NO SUCH MANDATES EXIST REGARDING PEOPLE WITH INTELLECTUAL AND DEVELOPMENTAL DISABILITIES. SO THIS IS GOING TO SEGUE INTO BEN HANDEN'S TALK, SO PARTICIPATION IN CLINICAL TRIALS FOR PEOPLE WITH INTELLECTUAL AND DEVELOPMENTAL DISABILITIES, THIS NECESSITATES THE DEVELOPMENT OF METHODS TO IMPROVE THE INFORMED CONSENT PROCESS. DR. JEFFREY SPIKE SAYS CONDUCTING ETHICAL TRIALS IN THIS POPULATION MEANS STRIKING A BALANCE BETWEEN PROTECTING POTENTIAL PARTICIPANTS WHO MIGHT BE EASILY MANIPULATED AND RESPECTING THEIR ABILITY TO MAKE THEIR OWN DECISIONS LIKE ANYONE ELSE. AND DR. RAYMAKER WENT ON TO SAY JUST BECAUSE SOMEONE IS NOT ABLE TO MAKE GOOD DECISIONS ABOUT HIS OR HER FINANCES OR HEALTH DOES NOT NECESSARILY MEAN HE OR SHE CAN'T GIVE INFORMED CONSENT ABOUT PARTICIPATING IN A RESEARCH TRIAL. AND JUST BECAUSE AN INDIVIDUAL HAS SOMEONE WHO HOLDS POWER OF ATTORNEY DOES NOT MEAN THAT HE OR SHE CAN'T PARTICIPATE IN SHARED DECISION-MAKING OR EVEN BE ABLE TO GIVE INFORMED CONSENT HIM OR HERSELF. SO VALID CONSENT IS A TENACIOUS CHALLENGE FOR US, BUT WE MUST FIND ALTERNATIVE MEANS TO PROMOTE UNDERSTANDING AS THERE IS LITTLE SUPPORT FOR EXCLUSION FROM RESEARCH OF THIS POPULATION. SO JUST IN SUMMARY, I THINK WE HAVE TO BECOME FAMILIAR WITH EACH OF OUR STATE'S POLICIES AND REGULATIONS. WE HAVE TO DISCUSS THE STUDY DESIGN AND PROCEDURES WITH OUR LOCAL IRB, AND VERY IMPORTANTLY, WE ALL HAVE TO KNOW IF WE HAVE A STATE'S LOCAL OFFICE FOR PEOPLE WITH DEVELOPMENTAL DISABILITIES AND WHAT THEIR ROLE IS IN DETERMINING WHO AND WHO CANNOT PARTICIPATE IN RESEARCH. THANK YOU. >> THANK YOU, SHARON. THAT WAS VERY INFORMATIVE AND ENLIGHTENING ABOUT WILLOWBROOK. AND IT'S IMPORTANT THAT WE NOW HAVE THE INCLUDE INITIATIVE THAT GOES RIGHT INTO THE FACE OF ALL OF THE EXCLUSIONS THAT HAVE BEEN IN THE FIELD FOR PEOPLE WITH DOWN SYNDROME. THANK YOU. OUR NEXT SPEAKER IS DR. BEN HANDEN FROM THE UNIVERSITY OF PITTSBURGH WHO WILL BE SPEAKING ABOUT OBTAINING CONSENT OR ASSENT. >> OKAY. LET'S SEE IF I CAN PULL THIS OFF. CAN EVERYBODY SEE MY SCREEN YET? >> JUST CLICK ON SLIDE SHOW. >> IF YOU CAN PULL YOUR SLIDES BACK UP AND THEN GO TO SLIDE SHOW. >> WE'LL SEE HOW IT GOES. OKAY. I'M BEN HANDEN FROM THE UNIVERSITY OF PITTSBURGH SCHOOL OF MEDICINE. I'M GOING TO BE THE FOLLOW-UP FOR SHARON'S PRESENTATION. I'M GOING TO BE TALKING ABOUT CONSENT AND ASSENT. I HAVE A COUPLE OF CONFLICTS OF INTEREST. SO I THOUGHT I'D START WHEN I FIRST DID THIS SLIDE, FIRST I THOUGHT WELL, MAYBE IT ISN'T ROCKET SCIENCE AND AFTER THINKING A LITTLE BIT MORE ABOUT IT AND LISTENING TO CHRISTA'S TALK YESTERDAY AND A LOT OF THE PRESENTATIONS, I REALIZED, THIS IS ROCKET SCIENCE. THIS IS A TOUGH THING TO DEAL WITH CONSENT AND ASSENT WITH SPECIAL POPULATIONS. MANY OF US IN THIS CONFERENCE HAVE BEEN DOING THIS FOR DECADES. BUT WE STILL HAVE A LOT TO LEARN AND A LOT TO SHARE WITH EACH OTHER. SO I THINK IT'S AN IMPORTANT TOPIC. SO I THOUGHT I WOULD USE AS AN EXAMPLE PART OF OUR ABC-DS STUDY, ESPECIALLY HOW WE DO THIS AT THE UNIVERSITY OF PITTSBURGH, AND I THINK THAT WILL KIND OF LAY THE GROUNDWORK FOR THE KIND OF ISSUES THAT HAVE TO BE ADDRESSED AND HOW WE MIGHT ADDRESS THEM. SO THE ABC-DS STUDY IS REALLY COMPLEX, AND WHEN WE DO CONSENT OR ASSENT, WE'RE REALLY GETTING APPROVAL AND AGREEMENT FOR A LOT OF DIFFERENT INTERVENTIONS, AND IT INCLUDES BLOOD DRAWS, PHYSICAL AND NEUROLOGICAL EXAM, GENETIC TESTING, MRI SCANS, DATA SHARING, PET SCANS, NEUROPSYCHOLOGICAL TESTING, AN OPTIONAL LUMBAR TONGUE TOUR AND PUNCTURE A ND EVEN A DISCUSSION OF BRAIN DONATION. SO SOME OF THESE THINGS ARE MINIMAL RISK PROCEDURES AND SOME ARE GREATER THAN MINIMAL RISK, AND AS SHARON ALREADY MENTIONED, THERE ARE SOME OF THESE INTERVENTIONS THAT IF YOU'RE FROM NEW JERSEY AND YOU WANT TO PARTICIPATE, IT'S JUST NOT AVAILABLE TO YOU. SO THESE ARE REALLY COMPLEX THINGS TO EXPLAIN TO OUR POTENTIAL PARTICIPANTS, AND THEIR CAREGIVERS AND FAMILIES. SO WHEN I THINK ABOUT THE CONSENT PROCESS, IT REALLY STARTS AT THE BEGINNING, EVEN BEFORE A FAMILY AND A PARTICIPANT OR CAREGIVER AND A PARTICIPANT COME IN TO YOUR CLINIC FOR THE CONSENT. IT REALLY STARTS PROBABLY WITH EVEN THE MATERIALS THAT WE PUT OUT ON WEBSITES, THAT MAY ATTRACT A FAMILY INTO A STUDY. BUT THE MOST IMPORTANT PART FROM OUR PERSPECTIVE IS THAT TELEPHONE SCREEN. IT REALLY HAS TO BE DETAILED ENOUGH TO DETERMINE WHETHER IT MAKES SENSE TO HAVE THE FAMILY COME IN, TAKE A DAY OFF FROM WORK, TWO DAYS OFF OF WORK TO ASK A PARTICIPANT TO TAKE TIME OFF OF WORK TO COME IN, IN OUR CASE, THIS IS A TWO DAY, 2 1/2 DAY ASSESSMENT. SO WE WANT TO DO IT RIGHT, EXPLAIN THINGS TO THE CAREGIVER. TWO THIRDS OF OUR FAMILIES DRIVE AT LEAST THREE HOURS TO COME FOR ASSESSMENTS AND STAY OVERNIGHT WITH US. SO THE LAST THING WE WOULD WANT IS TO HAVE THEM GET IN THE CAR AND DRIVE THREE HOURS, SHOW UP IN OUR CLINIC AND 20 MINUTES INTO THE CONSENT REALIZE, OH, THIS ISN'T GOING TO WORK, THANKS FOR COMING. THAT'S JUST NOT THE WAY TO RUN THINGS. SO HERE'S THE KINDS OF THINGS THAT WE DO FOR THIS STUDY OVER THE PHONE. WE CLEARLY TALK ABOUT WHAT KIND OF HISTORY THE INDIVIDUAL HAS HAD WITH SCANS. OBVIOUSLY IF WE LEARN THAT THEY'VE NEEDED TO HAVE FULL SEDATION TO DO AN MRI IN THE HOSPITAL, THEY'RE PROBABLY NOT GOING TO BE A GOOD CANDIDATE FOR THE STUDY, WHERE WE CAN'T REALLY SEDATE FOLKS. WE NEED TO KNOW ABOUT ANY PROBLEMS WITH BLOOD DRAWS, BECAUSE THAT'S AN INTEGRAL PART OF THE STUDY, MRI CONTRAINDICATIONS LIKE METAL IN THE BODY, PHYSICAL LIMITATIONS THAT WE MIGHT HAVE TO CONSIDER SOME MODIFICATIONS FOR LIKE PROBLEMS WITH VISION OR HEARING OR MOTOR, COGNITIVE LIMITATIONS THAT WE NEED TO KNOW ABOUT, FOR INSTANCE, IF THE INDIVIDUAL HAS VERY LIMITED EXPRESSIVE LANGUAGE, THAT WILL IMPACT OUR ABILITY TO TEST, TO USE CERTAIN PSYCHOLOGICAL TESTS, AND LEGAL ISSUES, WHICH REALLY COVERS A LOT OF WHAT SHARON MENTIONED. IN FACT, SHE DIDN'T TALK ABOUT PENNSYLVANIA, BUT I WILL TELL YOU PENNSYLVANIA HAS THE OPPOSITE POLICY THAT NEW JERSEY HAD. IN PENNSYLVANIA, IF AN INDIVIDUAL WITH DOWN SYNDROME, AN ADULT HAS A LEGAL GUARDIAN, THAT GUARDIAN IS NOT ALLOWED TO SIGN THAT INDIVIDUAL INTO A RESEARCH STUDY. SO WE CLEARLY NEED TO KNOW THAT WHEN WE DO THE PHONE SCREEN. NEXT THING IS WE HAVE TO IDENTIFY A POTENTIAL STUDY PARTNER. WE NEED SOMEONE WHO KNOWS THE ADULT WITH DOWN SYNDROME WELL, SEES THEM ON A REGULAR BASIS AND CAN COME IN AT OUR VISITS TO GIVE US THE INFORMATION. AND IF THEN ALL THAT CHECKS OUT, THEN WE REALLY NEED TO HEAR FROM THE PARTICIPANT THEMSELVES. WHAT WE'VE DONE IN THIS STUDY IS WE'VE DEVELOPED A DVD, IT'S AN 11 TO 12-MINUTE DVD THAT REVIEWS THE PROCEDURES THAT WE'RE GOING TO BE ASKING THE PARTICIPANT TO BE INVOLVED IN, AND WE ASK THE CAREGIVER, THE FAMILY MEMBER, THE STAFF PERSON TO SIT DOWN WITH THE INDIVIDUAL AND WATCH THIS DVD TOGETHER AND DISCUSS IT. SO WE'LL EITHER MAIL IN THE DVD OR IF THEY'RE SAVVY, WE'LL GIVE THEM THE LINK. IF WE'RE GOOD, I'M GOING TO SHOW YOU A FEW MINUTES OF THIS DVD, WE'LL SEE IF EVERYTHING WORKS AND IF YOU CAN HEAR IT. BUT THIS IS AN ABBREVIATED VERSION SO YOU CAN GET A FEEL FOR WHAT OUR PARTICIPANTS AND THEIR CAREGIVERS WOULD SEE. >> HELLO. THANK YOU FOR YOUR INTEREST IN THE DOWN SYNDROME RESEARCH STUDY. WE HOPE THAT YOU'LL TAKE A FEW MINUTES TO WATCH THIS DVD. IT SHOWS THE MRI AND PET SCANS THAT ARE USED IN THE STUDY. WE WANT TO YOU WATCH THE DVD WITH YOUR FAMILY OR CAREGIVER AND SEE IF YOU THINK YOU'LL BE ABLE TO DO THESE TWO TESTS. THEY'RE AN IMPORTANT PART OF OUR STUDY. IN FACT, YOU MAY HAVE ALREADY HAD ONE OF THESE TESTS BEFORE. IF YOU PLAN TO COME TO OUR PITTSBURGH STIET FOR THIS STUDY, YOU MAY MEET SOME OF THE PEOPLE IN THE DVD. HOWEVER, IF YOU GO TO A DIFFERENT SITE, THE ROOMS AND PEOPLE WILL BE DIFFERENT BUT THE TESTS WILL STILL BE THE SAME. TALK WITH YOUR FAMILY OR CAREGIVERS ABOUT JOINING THE STUDY. PLEASE FEEL FREE TO CONTACT US IF YOU HAVE ANY QUESTIONS. WE LOOK FORWARD TO MEETING YOU. THE RESEARCH STUDY PARTICIPANT IS GREETED IN THE WAITING ROOM. >> I'M GOING TO DO YOUR SCAN TODAY. IS THIS YOUR DAD? >> YES. >> HI, NICE TO MEET YOU, DAVE? >> YES. >> EDDIE, HAVE YOU EVER HAD AN MRI BEFORE? >> YEAH, A COUPLE TIMES. >> A COUPLE TIMES? OKAY. DID THEY GO OVER ALL THE SCREENING QUESTIONS WITH YOU? >> YES. >> IT'S REAL NOISY, WE ASK YOU TO KEEP NICE AND STILL. THAT'S ABOUT IT. IT'S EASY. >> ALL RIGHT. >> OKAY. COME ON BACK. THIS IS THE ROOM WHERE I'M GOING TO BE. THIS IS THE MRI SUITE. >> YES. >> I'M JUST GOING TO TYPE YOUR NAME IN. THIS IS THE SCREEN. I CAN HEAR AND SEE YOU ALL THE TIME. I CAN SEE YOU IN THERE. HEY, EDDIE, HOW ARE YOU DOING? YOU'LL SAY, FINE, REAL GOOD. NOW I NEED YOUR HEAD RIGHT IN THIS LITTLE BASKET. ON YOUR BACK. JUST SLIDE UP A LITTLE BIT. I'M GOING TO RAISE THE TABLE. HOW'S THAT? OKAY. >> LET'S SEE IF I CAN GET BACK TO THE SLIDES. OKAY. SO CAN EVERYBODY HEAR ME AGAIN? OKAY. SO IT WAS A PROFESSIONALLY DONE VIDEO EXCEPT FOR THE ANNOUNCER. HE DIDN'T HAVE MUCH IN THE WAY OF BEING VERY PROFESSIONAL. BUT I TRIED MY BEST. SO AFTER THAT VIDEO, WE THEN GET BACK IN TOUCH WITH THE CAREGIVER AND THE FAMILY, AND FIND OUT WHAT THE PARTICIPANT SEEMED TO THINK AND WHETHER HE OR SHE SAID, OH, YEAH, I CAN DO THIS, AND IF WE GET TWO THUMBS UP, WE SCHEDULE THE APPOINTMENT. DURING THE CONSENT PROCESS OR THE ASSENT PROCESS, WHETHER THE INDIVIDUAL ENDS UP SIGNING THE CONSENT OR SIGNING AN ASSENT, THE PROCESS IS ESSENTIALLY THE SAME, AND IN PENNSYLVANIA UNLIKE SOME OF THE OTHER STATES, THE ASSUMPTION IS THAT AN ADULT WITH A DEVELOPMENTAL DISABILITY IS ASSUMED TO BE COMPETENT TO SIGN A CONSENT FOR RESEARCH UNLESS PROVEN OTHERWISE. SO WE APPROACH THIS THAT THEY'RE GOING TO ASSIGN SIGN THE CONSENT FOR THEMSELVES UNLESS WE FEEL WE DON'T UNDERSTAND, IN WHICH CASE WE WOULD ASSIGN PROXY CONSENT. SO ALL OF THE INFORMATION ON THE CONSENT IS CONTAINED IN A NUMBER OF FLIP CHARTS, WHICH I'M SURE A LOT OF YOU USE. WE USE A LOT OF VISUALS, WHICH SHOULDN'T BE SURPRISING, SO THAT WE CAN EXPLAIN THINGS EASILY TO THE PARTICIPANT AND THEIR CAREGIVER AS WELL. ON ONE SIDE OF THE FLIP CHART IS THE INFORMATION FOR THE PARTICIPANT TO SEE, ON THE OTHER SIDE IS A LITTLE MORE DETAIL FOR THE INVESTIGATOR, I'M USUALLY THE ONE DOING THE CONSENT, AT LEAST IN PITTSBURGH, TO PROMPT ME NOT TO MISS ANYTHING. AND HERE'S JUST SOME OTHER EXAMPLES OF SOME OF OUR FLIP CHARTS. WE COVER EVERYTHING FROM WHAT'S AMYLOID, WHERE DO YOU SEE IT IN THE BRAIN, HOW DOES IT GET THERE, SO WE NEED TO EXPLAIN ALL OF THESE THINGS. OBVIOUSLY, YOU KNOW, WE'RE GOING TO TALK ABOUT THE MRI, INCLUDE A DESCRIPTION OF THAT AND WHAT THAT WILL BE LIKE. FLEURN AND THEN WE HAVE AN OPTIONAL LP, I THINK YOU'VE HEARD THAT MENTIONED A NUMBER OF TIMES IN OUR STUDY. SO IF WE DO AN LP CONSENT, WE PROVIDE SOME VISUALS WITH THAT AS WELL, IT EXPLAINS WHAT THE PROCESS IS AND WHAT WE'RE EXPECTING OF THE INDIVIDUAL. ONE OF THE LAST THINGS WE TALK ABOUT IN THE CONSENT PROCESS IS THE CONCEPT THAT THE PARTICIPANT CAN CHANGE THEIR MIND, THAT THEY CAN STOP AT ANY TIME. TO ME, SURPRISINGLY OVER THE YEARS, THIS HAS BEEN THE TOUGHEST PART OF THE CONSENT TO COVER, BECAUSE THE PARTICIPANTS WHO COME AND JOIN US WANT TO BE IN THE STUDY, WHEN I EXPLAIN TO THEM THEY CAN CHANGE THEIR MIND ANY TIME, WE CALL THEM AT 16 MONTHS TO COME BACK, THI THEY CAN SAY, I DON'T WANT TO GO BACK TO PITTSBURGH, THEY LOOK AT ME AND SAY I WANT TO BE IN THE STUDY. WE HAVE A NEW STUDY THAT'S STARTING AND WE'VE ALSO DECIDED TO SIMPLIFY OUR CONSENT FORMS AND ARE WORKING ON THAT. AS WE SPEAK. AND CLEARLY THE BEST WAY TO DO THAT TO MAKE THE CONSEN USEABLE TO BOTH THE FAMILY CAREGIVER AND THE PARTICIPANT IS ALSO TO USE AS MANY VISUALS AS WE CAN, SO HERE'S SOME EXAMPLES OF THINGS WE'VE BEEN PLAYING AROUND WITH. SO THE CONSENT FORM WHICH ENDS UP BEING THIS RIDICULOUSLY LONG FORM CAN BE REALLY USEFUL TO EVERYONE. SO JUST SOME EXAMPLES, AGAIN, A SUMMARY OF HOW LONG EACH OF THE PROCEDURES WILL BE, SO WE'RE STILL KIND OF WORKING ON THIS, AND CERTAINLY WE'D LOVE TO HAVE ANY INPUT OR EVEN SHARE EXAMPLES FROM OTHER FOLKS DOING RESEARCH, WHO MAYBE HAVE ALREADY THOUGHT OF THIS. THIS IS, AGAIN, NOTHING NEW. BUT I THINK NECESSARY FOR WORKING WITH CHILDREN AND WITH ADULTS WITH DEVELOPMENTAL DISABILITIES. IN THE NIA SITES INCLUDING PITTSBURGH, WHAT WE DO AT THE END OF THE CONSENT IS WE TYPICALLY WILL HAVE THEM WATCH THIS 11 MINUTE DVD AGAIN THAT YOU SAW AND ONE OF US, USUALLY ME, I'LL SIT WITH THE PARTICIPANT AND MAKE SOME COMMENTS AND A MAKE SURE THEY UNDERSTAND WHAT'S GOING ON. AND AT THE END OF THE DVD, I ASSESS THEIR UNDERSTANDING BECAUSE, AGAIN, MY JOB, AT LEAST IN PENNSYLVANIA, IS TO DETERMINE, DOES THIS INDIVIDUAL HAVE THE ABILITY TO ACTUALLY CONSENT FOR THEMSELVES? SO THE WAY I ASSESS WHAT THEY UNDERSTAND, AT LEAST ONE WAY, IS JUST WITH PICTURES. AND I'LL DOLL A LITTLE TEST DO A LITTLE T EST WITH TWO PICTURES. HERE'S AN EXAMPLE, I MIGHT SAY TOMORROW WHEN YOU GO OVER TO THE HOSPITAL, ARE YOU GOING TO BREATHE IN A TUBE OR ARE YOU GOING TO GO INTO AN MRI AND HAVE A PICTURE OF YOUR BRAIN TAKEN? AND HOPEFULLY THEY WILL PICK THE CORRECT ANSWER. I WON'T TEST ANYBODY HERE. AND THEN WE'LL DO ANOTHER ONE LIKE THIS TOMORROW WHEN YOU GO TO THE HOSPITAL, IS SOMETHING GOING TO EXERCISE YOUR LEG OR IS SOMEONE GOING TO PUT A NEEDLE IN YOUR ARM TO DRAW SOME BLOOD? AGAIN, THIS IS A WAY FOR US TO ASSESS WHETHER THE INDIVIDUAL UNSTANDS WHAT WE'RE ASKING THEM AND WHAT'S GOING ON. SO A COUPLE THINGS BEFORE I FINISH IS, I WANT TO TALK ABOUT WITHDRAWING CONSENT AND ASSENT. THIS REALLY IS -- CONSENT REALLY IS AN ONGOING PROCESS THROUGHOUT THE WHOLE COURSE OF THIS PARTICULAR LONGITUDINAL STUDY, AND I EXPECT IT'S THE SAME FOR A TREATMENT STUDY. AND YOU KNOW, IDEALLY AN INDIVIDUAL WOULD SAY, NO, I DON'T WANT TO BE IN THE STUDY ANYMORE, BUT OUR PARTICIPANTS, EVEN IF THEY'RE NOT GOING TO TELL US, THEY'RE GOING TO VOTE WITH THEIR FEET. THEY'RE GOING TO SHOW US WHETHER THEY STILL ARE AGREEING TO BE IN THE STUDY. AND THERE'S SO MANY OPPORTUNITIES REALLY AT EVERY PROCEDURE. SO OBVIOUSLY IF WE'RE DOING COGNITIVE TESTING AND AN INDIVIDUAL CROSSES THEIR ARMS AND PUTS THEIR HEAD DOWN AND ESSENTIALLY SAYS, I'M DONE, I'M FINISHED, WELL, THEN THEY'RE DONE, THEY'RE FINISHED. AND THEY'VE ESSENTIALLY DECIDED THEY DON'T WANT TO CONTINUE WITH THAT PROCEDURE AND WE STOP. SOMEONE CAN'T STAY IN AN MRI SCANNER FOR 30 MINUTES, WHICH IS ASKING A LOT FOR MANY OF US, THEY'RE GOING TO PRESS THE BUTTON AND ASK TO LEAVE, OBVIOUSLY THAT'S THEIR CHOICE AND WE ACCEPT THAT. SOMEONE GETS UP IN A PET SCAN, THEY'RE TELLING US THEY'RE DONE WITH THE PET SCAN. COOPERATION WITH THE BLOOD DRAW CERTAINLY REQUIRES COOPERATION, SO WE HAVE TO JUDGE THAT VERY EASILY. AND REFUSING TO FOLLOW DIRECTIONS DURING AN LP PROCEDURE IS HIGHLY IMPORTANT IF WE CAN'T GET SOMEONE TO FOLLOW DIRECTIONS, THEN WE'RE GOING TO ASSUME THAT THAT'S KIND OF THE WITHDRAWAL OF ASSENT OR CONSENT. SO IT IS AN ONGOING PROCESS. FINALLY, I GUESS I'LL END WITH SOME RULES OF THE ROAD. I'VE BEEN DOING THIS FOR A FEW YEARS. IN TERMS OF AT LEAST THIS CURRENT STUDY, ANY STUDY I'VE EVER DONE, WHETHER IT'S WITH CHILDREN OR ADULTS, IS WE HAVE TO OBTAIN FAMILY SUPPORT. EVEN IF I DON'T NEED FAMILY TO SIGN THE CONSENT FORM, WE WOULD NEVER INVITE A PARTICIPANT IN THIS PARTICULAR STUDY AND DO A STUDY WITHOUT TALKING TO THE FAMILY, WITHOUT THERE BEING FAMILY AGREEMENT THAT THIS MAKES SENSE FOR THE ADULT WITH DOWN SYNDROME TO DO, AND IF THERE'S SOME DISAGREEMENT AMONG THE FAMILY, THEN THEY HAVE TO WORK THAT OUT AND HELP US FIGURE OUT THE BEST WAY TO PROCEED. THE CONSENT PROCESS ITSELF, AS I'M SURE EVERYONE ELSE DOES, WE WOULD NEVER MEET ALONE WITH AN ADULT WITH DOWN SYNDROME. IDEALLY WE WANT TO HAVE A FAMILY MEMO ABOUT THERE OR MEMBER OR ADVOCATE, AN LAR. PHYSICALLY, WE WILL HAVE THEM JOIN BY PHONE OR VIDEO SO THEY CAN BE WITH US AT THAT POINT, THE FAMILY GETS A COPY OF THE CONSENT TO LOOK AT AS WELL SO WE CAN WALK THROUGH IT WITH THEM. OBVIOUSLY THE STUDY PARTNER, WHETHER IT'S A STAFF PERSON AT A GROUP HOME OR A SIBLING OR ROOMMATE, WHOEVER IT'S GOING TO BE, WE WANT THEM THERE AS WELL. AND FINALLY, I GUESS I WOULD SAY TAKE PLENTY OF TIME. THERE'S NO REAP TO REASON TO RUSH THROUGH THE CONSENT PROCESS. FOR OUR PARTICIPANTS, THIS IS REALLY THE FIRST TIME THAT WE MAY HAVE MET THEM, MOST OF THEM ARE NOT FAMILIES THAT WE'VE WORKED WITH CLINICALLY BEFORE. SO IS THIS IS A CHANCE TO DEVELOP A RELATIONSHIP TO GET TO KNOW EACH OTHER BECAUSE WE'RE GOING TO WANT THEM BACK EVERY 16 MONTHS FOR A NUMBER OF YEARS. SO THIS IS KIND OF A MAKE OR BREAK HOUR, HOUR AND A HALF THAT WE HAVE TO REALLY GET TO KNOW EACH OTHER, TO BUILD THAT TRUST, AND TO HAVE SOME BUY-IN FOR THE IMPORTANCE OF THE RESEARCH AND THE WILLINGNESS TO DO THE INTERVENTIONS. SO I WILL LEAVE IT AT THAT, OTHER THAN SPECIAL THANKS TO ALL OF OUR ABC-DS PARTICIPANTS AND THEIR FAMILIES. THANKS. >> THANKS, BEN. WE'VE BEEN VERY FORTUNATE TO BE ABLE TO UTILIZE A LOT OF THE LEARNINGS AND EXPERIENCES FROM ABC-DC, PARTICULARLY WITH THE INFORMED CONSENT. ONE QUESTION THAT I HAVE ACTUALLY FOR ANNIE, SHARON AND BEN IS THE USE OF REMOTE CONSENTING. WE HAVE THE REGISTRY, AND AT LEAST ENGAGING REMOTELY, PARTICULARLY NOW DURING THE TIME OF COVID, CERTAINLY FAMILY MEMBERS OR LEGALLY AUTHORIZED REPRESENTATIVES THAT COULD ENGAGE ON A DEEPER LEVEL WITH RESEARCHERS TO INDICATE WHETHER THE PARTICIPANT WOULD BE WILLING OR WOULD BE INTERESTED, ANY THOUGHTS ON MOVEMENT IN THAT E-CONSENT KIND OF FRAMEWORK? REMOTE CONSENT IS PROBABLY REASONABLE FOR SOME OF THE EARLY BASIC PARTS OF THIS STUDY, BUT I THINK IT'S HARD FOR US, I WOULD GUESS, TO ASSESS THE UNDERSTANDING OF THE ADULT WITH DOWN SYNDROME REMOTELY. I SUPPOSE WE COULD. I'M JUST THINKING OUT LOUD HERE, SURE, IF I COULD HAVE A REMOTE CONVERSATION WITH THE INDIVIDUAL, WE COULD LOOK AT THE -- SHARE THE DVD TOGETHER AND TALK ABOUT IT, ASK SOME QUESTIONS ABOUT -- TO MAKE SURE HE OR SHE UNDERSTANDS WHAT WE'RE GOING TO BE ASKING OF THEM. YEAH, I SUPPOSE THAT WOULD BE THE CASE. IF IT WAS SOMEONE WHO WAS A LITTLE SHIER, MORE RETICENT TO TALK TO US, I WOULDN'T WANT TO MAKE AN ASSUMPTION THAT THEY DIDN'T UNDERSTAND. SO SHARON, WHAT DO YOU THINK? >> -- THE CAREGIVER OR THE PERSON THAT'S GOING TO SIGN FOR THE INDIVIDUAL, AND THEN WE SEND TO THEM BY MAIL. SO FOR US REMOTE WOULDN'T BE ALL THAT DIFFERENT. IT'S AT THAT POINT RECRUITING NEW PARTICIPANTS IS THE DIFFICULTY BECAUSE IT INVOLVES A LOT OF THE LOCAL AGENCIES, AND THERE'S NOBODY THERE AT THE MOMENT. SO THAT WOULD BE THE PART THAT'S DIFFICULT FOR US. THAT WE JUST CAN'T GO TO PARTICIPANTS THEMSELVES UNLESS THEY COME TO US FROM DS CONNECT, BUT OTHERWISE WE HAVE TO DO EVERYTHING THROUGH THE VARIOUS SERVICE AGENCIES. >> I THINK ONE OPPORTUNITY HERE THAT IS SORT OF SEPARATE FROM CONSENT BUT IT GOES INTO KIND OF WHAT BEN WAS TALKING ABOUT THAT YOU START WITH INTRODUCING THE STUDY AND WORKING THROUGH THOSE FLIP BOOKS IS THAT IT CAN GIVE YOU THE OPPORTUNITY TO GET TO KNOW THE PARTICIPANT AND THEIR FAMILY A LITTLE BIT BEFORE THEY ACTUALLY COME IN AND SO RIGHT NOW WHEN WE'RE NOT ABLE TO BRING PEOPLE IN, ONE OF THE FOCUSES CAN SORT OF BE ON INCREASING THIS COMFORT LEVEL WITH PARTICIPANTS AND THEIR FAMILIES, AND SO THEY'RE SEEING THE INVESTIGATORS' FACES, SO THE FIRST TIME THEY COME IN THE SORT OF DISTRESS FULL HOSPITAL SETTING, THEY NOW KNOW WHO THEY'RE LOOKING FOR AND WHO THEY'RE SEEING. SO I THINK IT MIGHT BE A REALLY NICE OPPORTUNITY. >> YEAH, AND BRIAN MADE A GREAT COMMENT ABOUT HIS EXPERIENCE USING FACEBOOK, AND I FEEL THERE MAY BE KIND OF A MISSED OPPORTUNITY HERE WHERE YOU COULD SET UP A VIDEO CHAT WITH INDIVIDUALS WHO ARE INTERESTED IN LEARNING MORE THROUGH FACEBOOK AND OTHER SOCIAL MEDIA, BECAUSE THERE DOES SEEM TO BE A HEAVY PRESENCE. AND I THINK THAT WOULD BE AT LEAST LAYING THE GROUNDWORK FOR FUTURE CONTACT, IN PERSON EVEN. >> I LIKE THAT IDEA, MIKE, ESPECIALLY IF WE'RE BRINGING IN FAMILIES FROM A LONG DISTANCE. YOU JUST REALLY DON'T WANT TO BRING SOMEONE IN FIVE HOURS WITHOUT BEING REALLY SURE THAT IT'S GOING TO BE A GOOD MATCH, AND YEAH, I THINK IT MAKES SENSE. AND WE CERTAINLY HAVE LEARNED A LOT IN THE LAST TWO MONTHS, AT LEAST THOSE OF US RUNNING CLINICS, BECAUSE EVERYTHING IS DONE ONLINE NOW. AND IT SEEMS TO BE WORKING, SO IT'S A GREAT FEUNT TO TRY IT OPPORTUNITY TO TRY IT OUT. >> I THINK IT'S ALSO DEPENDENT ON THE AGE OF YOUR RESEARCH PART PANTS. OURS TEND TO BE OLDER THAN YOURS, BEN, SO AS I TOLD YOU, WE TRIED THE NIH TOOLBOX AND IT WAS JUST IMPOSSIBLE TO GET THEM TO UNDERSTAND THE PROCESS. BUT GIVEN THE CLIMATE NOW, IT WOULD CERTAINLY BE WORTH A TRY TO SEE HOW WELL WE DO. >> IT WOULDN'T SURPRISE ME IF A LOT OF OUR PARTICIPANTS WHO AREN'T LIVING AT HOME AT THIS POINT HAVE BEEN SKYPING AND TALKING TO THEIR FAMILIES AND SO THIS TECHNOLOGY, THEY'RE PROBABLY DOING IT MORE THAN WE ARE AT THIS POINT, AR PROBABLY NOT SITTING LIKE WE ARE EIGHT HOURS A DAY IN FRONT OF A COMPUTER BUT YEAH, IT WAS A GOOD QUESTION, MIKE. I THINK IT'S SOMETHING WE SHOULD DEFINITELY -- >> ANOTHER QUESTION I HAVE MOSTLY FOR SHARON, IS THERE A CENTRALIZED REPOSITORY OF THESE LEGAL STATUTES, OR IS THERE A NEED FOR THIS THAT SOMEONE COULD COMPILE -- IT SOUNDS LIKE YOU HAD TO DO SOME RESEARCH YOURSELF FOR YOUR PRESENTATION, BUT I WONDER IF THIS IS SOME KIND OF INITIATIVE THAT WE COULD PUT TOGETHER TO GENERATE SUCH A REPOSITORY. I HAVE TO SAY THAT GLOBAL DOWN SYNDROME FOUNDATION HAS A WEBSITE THAT LISTS THE MEDICAL CLINICS AROUND THE COUNTRY, AND I'VE HAD MANY, MANY, MANY INDIVIDUALS WHO HAVE REFERRED TO THAT IN HAVING A FAMILY MEMBER, HAD A CONCERN, JUST NOT GETTING THE CLINICAL CARE THEY NEED AND REFERRING TO THAT. IT'S REALLY BECOME A CENTRAL DEPOT FOR INFORMATION DISSEMINATION. I WONDER IF, FOR RESEARCHERS, WE COULD HAVE THAT TYPE OF A SETUP WHERE IF YOU WANTED TO CONDUCT A CLINICAL TRIAL OR A LONGITUDINAL STUDY, YOU'D BE ABLE TO REFER TO THAT AND UNDERSTAND WHAT ARE THE LEGAL REQUIREMENTS BECAUSE YOU'RE JUST REINVENTING THE WHEEL EACH TIME YOU DO THIS, AND IT SEEMS VERY -- >> DEFINITELY. I AGREE WITH YOU, IT WOULD BE NICE TO HAVE SOME KIND OF CENTRALIZED DATABASE THAT A RESEARCHER IN HAWAII CAN LOOK UP, WHAT WOULD I NEED TO DO IN ORDER TO GET CONSENT TO DO THIS RESEARCH STUDY? AND YOU KNOW, TO KNOW THE FULL VARIETY, BECAUSE IT'S DIFFERENT IF THEY'RE PARTICIPATING, OF COURSE, IN MINIMAL RISK RESEARCH VERSUS CLINICAL TRIALS. THE OTHER THING THAT I DIDN'T FIND OUT, AND IT WAS JUST IMPOSSIBLE, WAS, IS THERE A DIFFERENCE IN CONSENT IF IT'S A PHASE ONE OR A PHASE TWO OR A PHASE III? THAT WAS A QUESTION THAT I JUST COULD NOT FIND ANYWHERE, EVEN FOR NEW YORK AND NEW JERSEY. SO A CENTRALIZED DATABASE THAT HAS THIS INFORMATION, AND THAT KEEPS UP WITH IT, BECAUSE AS YOU CAN SEE, WE HAD SOME LEGISLATION IN NEW JERSEY PUT IN PLACE JUST A FEW YEARS AGO. THAT WOULD BE INVALUABLE TO ALL OF US, ESPECIALLY AS WE START HAVING ALL THESE MULTISITE STUDIES. >> ONE QUESTION THAT'S NOT COMING FROM ME IS, HOW ARE RESULTS SHARED WITH THE PARTICIPANTS AND WHICH TYPES ARE SHARED AND WHICH ARE NOT AND WHY? AND BEN, MAYBE YOU COULD TAKE THIS ONE. >> RIGHT. SURE. A LOT OF THAT IS DETERMINED BY LOCAL IRB REQUIREMENTS AND SO ON, SO I CAN SPEAK TO PITTSBURGH AND SHARON MAY BE ABLE TO SPEAK TO COLUMBIA AND SOME OF THE OTHER SITES. WE'RE NOT ALLOWED TO SHARE PET SCAN RESULTS, THOSE ARE CONSIDERED TO BE, YOU KNOW, SOMEWHAT EXPERIMENTAL, WE DON'T KNOW WHAT THEY MEAN. YOU KNOW, IT WOULDN'T MAKE A LOT OF SENSE TO TELL A PARTICIPANTS WHO'S 45 YEARS OLD THAT THEY HAVE A LOT OF AMYLOID BASED ON THEIR PET SCAN BECAUSE ANYONE WHO'S 45 WITH DOWN SYNDROME PROBABLY HAS AMYLOID. WE DON'T KNOW WHAT IT MEANS. THAT'S WHY WE'RE DOING THE STUDY. BUT WE DO TELL THEM WE WILL SHARE IF WE FIND CLINICALLY SIGNIFICANT OR MEANINGFUL FINDINGS ON AN MRI, ALL OF OUR MRIs ARE EXAMINED BY A NEURORADIOLOGIST AND WE WILL TALK WITH THEM AND TALK WITH THEIR PCPs IF . IF WE GET ANY LAB WORK THAT'S OF CONCERN, WE WILL LET THEM KNOW AND SHARE THAT. IN PITTSBURGH, A LOT OF OTHER SITES DON'T NECESSARILY DO IT, WE PROVIDE KIND OF A SUMMARY OF NEUROPSYCH FINDINGS. MOSTLY BECAUSE OUR PARTICIPANTS ARE A LITTLE YOUNGER AND IT'S KIND OF -- SERVES AS A BASELINE SHOULD THERE BE A PROBLEM, CHANGE IN FUNCTIONS 10 YEARS DOWN THE LINE. SO WE GIVE THAT TO OUR FAMILIES. NOT EVERY SITE DOES THAT, SO IT'S WHAT INDIVIDUALS -- INDIVIDUAL SITES MAKE THAT DECISION. BUT THOSE ARE THINGS THAT WE THINK FAMILIES SEEM TO APPRECIATE. SO SHARON, I DON'T KNOW WHAT -- IF YOU HAVE ANY MORE TO ADD? >> NO, EXACTLY THE SAME THING. IF WE FIND A LEVEL 2 OR A LEVEL 3 FINDING ON AN MRI, WE DO NOTIFY THE LAR. WE DON'T TYPICALLY GIVE THE RESULTS OF THE NEUROPSYCH UNLESS THEY'VE ASKED US. THEN USUALLY IN THOSE CASES, IT'S BECAUSE THERE IS SOMEONE THAT'S BEGINNING TO SHOW THE SIGNS AND SYMPTOMS OF DEMENTIA, AND THEY JUST WANT AN EXTRA PIECE OF INFORMATION TO TAKE WITH THEM TO THEIR NEUROLOGIST. SO IN THAT CASE, WE DO IT, BUT WE VERY CLEARLY SAY THIS IS A RESEARCH STUDY, THIS IS NOT REALLY, YOU KNOW, A CLINICALLY RELEVANT FINDING BUT AS PART OF THEIR PARTICIPATION IN THAT RESEARCH STUDY, THIS IS OUR IMPRESSIONS. >> GREAT. THAT COULD CHANGE, MIKE, YOU KNOW, IF THE LAWS CHANGE. SO FOR INSTANCE, IF IT BECAME STANDARD TO SHARE APOE RESULTS, FOR EXAMPLE, WE MIGHT FEEL OBLIGATED TO DO THAT, I WOULD SUPPOSE. , AT THE MOMENT. THAT'S WHAT WE DO. >> GREAT. WELL, THANK YOU TO THE PRESENTERS. THIS WAS REALLY A FABULOUS SESSION, AND WE'LL CLOSE OUT THE Q & A SESSION. I THINK WE'RE MOVING ON NOW TO THE REPORT FROM THE BREAKOUT TELECONFERENCE SESSIONS. >> YES. HI. THIS IS LAURIE. SO ABSOLUTELY. SOL IF WE WERE MEETING IN PERSON, WE WOULD HAVE HAD ACTUAL BREAKOUT SESSIONS SO WHAT WE DID IS A COUPLE WEEKS AGO, WE HAD A TELEPHONIC OR WEB-BASED BREAKOUT SESSIONS FOR BOTH THE PEDIATRIC ISSUES AND CONSIDERATIONS AND FOR THE ADULT ISSUES AND CONSIDERATIONS, SO THIS NEXT SECTION -- SESSION, RATHER, WE WILL HAVE REPORTS BACK FROM THE CO-CHAIRS FOR BOTH OF THOSE, AND WE'LL START WITH PEDIATRICS AND THEN WE'LL MOVE TO ADULT, AND THEN WE WILL HAVE THE OPPORTUNITY FOR QUESTIONS RELATED TO THAT. SO FOR THE BREAKOUT SESSIONS, WHAT THE CHARGE WAS, REALLY WE WANTED TO TALK ABOUT WHAT ARE THE GAPS IN RESEARCH FOR MOVING AHEAD FOR CLINICAL TRIALS IN INDIVIDUALS WITH DOWN SYNDROME AND WHAT ALSO ARE THE OPPORTUNITIES, WHAT THINGS CAN WE TAKE ADVANTAGE. SO WE'LL GO AHEAD AND START OFF WITH PEDIATRICS, SO STEVE AND PRIYA? >> LAURIE, COULD I SHARE MY SCREEN? >> SURE. >> HI, THIS IS PRIYA. STEVE IS GOING TO BE PRESENTING ON OUR BEHALF. STEVE VERY KINDLY PUT THE SLIDES TOGETHER. SO HE WILL BE PRESENTING FOR US AND FOR THE BREAKOUT. THANK YOU. >> FIRST AGAIN, I WANTED TO THANK LAURIE AND ERIKA FOR A BRILLIANT JOB ON THE SESSION, AND ALL THE ORGANIZERS. IT'S BEEN REMARKABLE THAT WE COULD PULL THIS OFF IN THE VIRTUAL WINDOW THAT WE ARE. THESE BREAKOUT SESSIONS I SORT OF CONSIDER REALLY AS THE WARMUP FOR THE ACTUAL MEETING ITSELF. MANY OF THE TOPICS HAVE ALREADY BEEN DISCUSSED IN FAR GREATER DETAIL BUT I THOUGHT I WOULD JUST PRESENT FOR PRIYA AND MYSELF SORT OF AN OVERVIEW OF SOME OF THE POINTS THAT WERE MADE ON OUR DISCUSSIONS. AND I THINK WHEN WE -- AS PHYSICIANS, AS CARE PROVIDERS, AS FAMILY MEMBERS, WE REALLY WANT TO MAKE THE RIGHT DECISIONS FOR OUR CHILDREN, OUR PATIENTS AND OUR FAMILIES, AND I TOOK THIS FROM THE IMPORTANT SCIENTIFIC JOURNAL CALLED THE "THE NEW YORK TIMES" A WHILE AGO BECAUSE IT REALLY REFERS TO MEDICAL SOURCES, WHO TO TRUST, ADVISE TO FOLLOW, ET CETERA. AND THEY HAVE SOMETHING FOR A GOOD DOCTOR BUT IT'S REALLY MOM, I THINK, THAT WE REALLY LISTEN TO MOSTLY FOR OUR BEST ADVICE. PERHAPS IT SHOULD BE CLINICAL TRIALS, AND I THINK THAT'S REALLY WHY WE'RE MEETING HERE, TO DISCUSS MANY OF THESE ISSUES. AND SO WHEN YOU THINK ABOUT THE RATIONALE FOR DEVELOPING A MULTICENTER CLINICAL CLINICAL TRIALS CONSORTIUM FOR CHILDREN WITH DOWN SYNDROME, THERE ARE SEVERAL REASONS BEHIND IT THAT WE DISCUSSED. FIRST THERE REALLY LIMITED UNDERSTANDING OF DISEASE-SPECIFIC MECHANISMS FOR MANY ASPECTS OF DOWN SYNDROME. WE SPOKE ABOUT THE HETEROGENEITY AND DIVERSITY OF CO-MORBIDITIES. THE LACK OF ORGANIZED MULTIDISCIPLINARY CARE OUTSIDE OF MAJOR CENTERS IS AN ISSUE. THE RELATIVELY SMALL NUMBERS OF PATIENTS AT EACH CENTER TO PROVIDE THE NUMBERS REQUIRED FOR MULTICENTER TRIALS. MOST OF OUR CURRENT STRATEGIES OR PRELIMINARY DATA ARE OFTEN BASED EXCLUSIVELY ON CASE REPORTS OR FOR THOSE OF US WHO ARE PEDIATRICIANS, WE RELY ON ADULT DATA, AND THE LACK OF CARE GUIDELINES AND AGE RELEVANT AND DISEASE-SPECIFIC END POINTS FOR ASSESSING CLINICAL COURSE AND THE RESPONSE TO THERAPY. SO INDEED WE'RE IN THE ERA OF PRECISION MEDICINE AND WE NEED TO THINK ABOUT EVIDENCE-BASED PRACTICE AND THERE ARE MANY CHALLENGES HERE. FIRST WE KNOW THERE ARE A LOT OF INHERENT DIFFICULTIES IN PERFORMING MULTICENTER RANDOMIZED CLINICAL TRIALS, AND WE DISCUSSED ABOUT ALL OF THESE ASPECTS OVER THESE PAST COUPLE DAYS. SYSTEMATIC REVIEWS OF SMALLER STUDIES. ANALYSES OF THE WONDERFUL REGISTRIES WITH HE HAVE ALREADY OR BIG DATA ARE REALLY NOT SUFFICIENT COMPARED TO WHAT WE MUST ACHIEVE THROUGH CLINICAL TRIALS, BECAUSE THEY DON'T NECESSARILY ACCOUNT FOR KEY STUDY DESIGN DIFFERENCES. THE PATIENTS WHO ARE ENROLLED REGARDING DISEASE HETEROGENEITY, VARIABILITY BETWEEN CENTERS IN TERMS OF EVALUATION MANAGEMENT AND OTHER THINGS. AND ALSO THERE'S A POTENTIAL PROBLEM WITH ECK EQUIPOISE. REALLY BEFORE YOU GET RELIGION, BEFORE YOU HAVE TOO MUCH EXPERIENCE AND HAVE BIAS, YET WE OFTEN LACK THE PRELIMINARY DATA NEEDED ON DISEASE MECHANISM WE'RE TARGETING, SUBJECT SELECTION, DRUG DOSE AND OTHER ISSUES. AND THEN FINALLY AGAIN, AS A PEDIATRICIAN, ALWAYS TRANSLATING THE ADULT EXPERIENCE TO A PEDIATRIC DISEASE AND I OFTEN SEE ONLY EVIDENCE AVAILABLE FOR DECISION-MAKING. AND THEN FINALLY, CLINICALLY, OF COURSE, AVOIDING WHAT I CALL THERAPEUTIC PARALYSIS, IS THAT EVIDENCE-BASED PRACTICE OR EVIDENCE-BASED MEDICINE IS IMPORTANT AND YET SOMETIMES WE STILL HAVE ISSUES WE MUST MANAGE, MANAGE THEM URGENTLY AT TIMES, SO WE STILL HAVE TO FIGURE OUT THE BEST WAY OF UNDERSTANDING OUR APPROACHES. SO CERTAINLY WE TALK A LOT ABOUT PHENOTYPE AND ENDOTYPE. PHENOTYPES ARE THE OBSERVABLE CHARACTERISTICS THAT ARE REALLY THE INTERACTION BETWEEN GENETIC MAKEUP, ENVIRONMENT AND OTHER ISSUES. ENDOTYPE IS REALLY THE ADDITION OF SPECIFIC BUY LO YIK PATHWAY DATA, AND THAT'S WHERE COMBINING PHYSIOLOGIC PHENOTYPING, AWARENESS OF COMORBIDITIES AND DISEASE MODULATORS WITH LABORATORY BIOREPOSITORIES, WHERE WE PERFORM SUFFICIENT PROTEOMICS, PK AND PD STUDIES, GENOMICS AND GENETICS, AND REALLY OUR GOAL SHOULD BE TO PERHAPS KNOW WHAT WE'RE STUDYING AND HOW TO UNDERSTAND DISEASE BY ESTABLISHING PHENOTYPES MORE CAREFULLY. SO WE THINK ABOUT CHALLENGES IN CLINICAL TRIALS IN PERSONS WITH DOWN SYNDROME, CERTAINLY THE INCLUDE PROGRAM HAS BEEN FANTASTIC. THERE ARE THREE CATEGORIES THAT ARE OUTLINED IN THE PROGRAM THAT IS FIRST BASIC SCIENCE OR LABORATORY-BASED GENERALLY HIGH RISK/HIGH REWARD PROJECTS, AND YET WITHOUT THE BASIC SCIENCE WHEN WE TALK ABOUT CLINICAL TRIALS, I THINK WE WOULD LOSE MUCH, SO I THINK IT'S IMPORTANT TO REMEMBER THAT INTERFACE. WHAT I MENTIONED ABOUT DEEP PHENOTYPING, HOW IMPORTANT IT IS TO GET OUR SUBJECTS AND OUR QUESTIONS RIGHT WHEN WE LAUNCH OUR STUDY DESIGNS AND OUR PROJECTS IS KEY, AND FINALLY HAVING CLINICAL TRIAL NETWORKS TO REALLY ENSURE THE BEST PRACTICES AND MANY THINGS THAT WERE DISCUSSED THROUGHOUT THE DAY IN THE PREVIOUS SESSION ABOUT CONSENT AND ASSENT AND RECRUITMENT AND RETENTION ARE REALLY KEY FEATURES AS WELL. SO THESE ARE OVERALL COMPONENTS BUT THEY ALL WORK HAND IN GLOVE WITH IMPROVING OUR DESIGN AND IMPLEMENTATION OF SUCCESSFUL CLINICAL TRIALS. SO THERE ARE IMPORTANT RULES FOR ESTABLISHING OR ESTABLISHED REGISTRIES, TO BETTER ENABLE STUDY DESIGN AND BUILD A CLINICAL TRIALS CONSORTIA, DEVELOPMENT OF LONGITUDINAL DATABASES WILL ESTABLISH PRECISE PHENOTYPES AND ENDOTYPES, ESTABLISHING LONG TERM OUTCOMES, NATURAL HISTORY, AND THEN LINKING WITH BIOREPOSITORY, I THINK ARE IMPORTANT. SO IN GENERAL, IT'S IMPORTANT TO HAVE A NETWORK OF EXPERT INVESTIGATORS AND I THINK CLINICAL TRIALS CONSORTIA OFFER THAT. LARGER CLINICAL PROGRAMS WITH RELATIVELY LARGE POPULATIONS FOR STUDIES WOULD BE KEY, I THINK, FOR SOME OF THE SUCCESS, AND YET REMEMBERING THAT BEING MORE INCLUSIVE FROM EVEN LOCAL SITES IS KEY AND HOW TO MEET THOSE GOALS AND NEEDS HAS BEEN DISCUSSED EARLIER TODAY. IMPORTANT ROLES FOR COMPREHENSIVE REGISTRY, DATABASE FOR CHARACTERIZING AND OPTIMIZING OUR TARGET STUDY POPULATION, DISEASE PREVALENCE, COMORBIDITIES, POWER ANALYSES, ALL THESE THINGS WOULD ENABLE BETTER CLINICAL TRIALS. SO OVERALL THIS WORKSHOP REFLECTED THE DIVERSITY OF DISCIPLINES AND CLINICIANS AND SCIENTISTS ARE ENGAGED IN THIS PROCESS, AND THESE ARE JUST SOME OF THE ARENAS THAT WE WERE TALKING ABOUT. AND NOT ONLY ACUTE PROBLEMS AND NARROW WINDOWS OF PROBLEMS BUT REALLY DISEASE ACROSS THE LIFESPAN IS SO IMPORTANT IN EACH OF THESE AREAS. WE ALSO HAVE FOUND FROM THIS WORKSHOP THE VITAL MORNS OF IMPORTANCE OF STRONG COLLABORATIONS. I'VE BEEN SO IMPRESSED ABOUT THE TRANS-NIH APPROACH WHERE WE HAVE THE HEART DIVISION, THE LUNG DIVISION, NICHD. SO MANY GROUPS ARE COMING TOGETHER TO REALLY ADDRESS THIS TO DEVELOP PARTNERSHIPS BETWEEN FAMILIES, FOUNDATIONS, ACADEMICS AND INDUSTRIES. AND OF COURSE THE IDEA OF LINKING ALL THIS TOGETHER WITH A DIVERSE POOL OF FOLKS WHO ARE INVOLVED, THE IDEAS OF NEW PATHWAYS TO DISCOVERY FROM THE BENCH FROM THE BASIC SCIENTISTS, LEADING TO THE RESEARCH TEAMS OF THE FUTURE, WHICH I THINK THIS WORKSHOP REALLY BRINGS OUT NICELY, AND RE-ENGINEERING THE CLINICAL RESEARCH ENTERPRISE, WHICH IS ONE OF THE GOALS OF THIS WORKSHOP. SO OTHER CHALLENGES, AND THERE ARE MANY THINGS THAT HAVE ALREADY BEEN COVERED, I REALLY WANT TO GIVE KUDOS TO MICHELLE WHEN I 10 WHITTEN AND OTHERS WHO HAVE ALREADY RAISED SOME OF THESE THINGS. DEVELOPING CLINICAL TRIAL NETWORKS, CLINICAL TRIALS CONSORTIUMS, IMPROVE COMMUNICATION AROUND RESEARCH BY PROVIDING INFORMATION FOR STUDY PARTICIPANTS. ROLES FOR TELEHEALTH, VIRTUAL MEETINGS AND IMPROVED COLLABORATIONS WITH LOCAL PROVIDERS, THE COVID-19 STUDIES HAVE ACCELERATED OUR LEARNING CURVE, BUT ALSO WE NEED TO LEARN MORE ABOUT SUCCESSFULLY INCORPORATING PATIENT-REPORTED OUTCOMES ASCII METRICS OF HEALTH AND CLINICAL STATUS, AND AGAIN, WE HEARD SOME NICE DISCUSSION THESE LAST COUPLE DAYS ABOUT HOW GROUPS ARE ACHIEVING THAT. DEVELOPING AND SUSTAINING THE TRUST OF OUR CHILDREN AND FAMILIES AND OTHERS, MOTIVATING SUBJECTS FOR STUDY RECRUITMENT AND RETENTION HAS BEEN COVERED, NEED FOR RESOURCES, TO HAVE THE PERSONNEL TO REALLY DO HIGH QUALITY MRCT WORK IS VITAL. WE NEED TO DEVELOP SUITABLE AND WELL -- EMILY SPOKE ABOUT HOW HARD IT IS TO PERFORM LUNG FUNCTION TESTING AND PROVIDES US WITH SOME NICE LEADS OF HOW TO THINK ABOUT THAT AS ONE METRIC, BUT CERTAINLY WHETHER IT'S BEHAVIORAL, COGNITION, IMMUNOLOGIC RESPONSES, HAVING THESE END POINTS FOR CLINICAL TRIALS SWR TO BE MORE CLEARLY DEVELOPED. AROUND CERTAINLY COLLABORATING WITH OTHERS AROUND THE DOWN SYNDROME SPHERE WILL BE IMPORTANT FOR SUCCESS AND LONG TERM OUTCOMES ACROSS THE LIFE CYCLE. WE TOUCHED BASE ON RACE, ETHNICITY, SOCIOECONOMICS, EXTENSIVE PHENOTYPING FOR CLINICAL TRIAL SUCCESS, MANY REGULATORY ISSUES WERE BEAUTIFULLY DISCUSSED IN THE PREVIOUS SESSION, AND MANY OTHER ISSUES IN TERMS OF WHAT WE WANT TO ACHIEVE. BUT I WANTED TO HIGHLIGHT THISPOINT OF TRAINING NEXT GENERATION CLINICAL SCIENTISTS TO DEVELOP STRONG CLINICAL TRIAL EXPERTISE AND FOR PURPOSES OF THIS WORKSHOP, PARTICULARLY FOCUSED IN DOWN SYNDROME, AND THAT'S WHERE INTEGRATING PROGRAMS IS SO IMPORTANT, LOOKING AT INSTITUTIONS OUTSIDE OF OUR OWN THAT HAVE THE FORMATS ALREADY ESTABLISHED, BUT SPECIFICALLY BEING ABLE TO ACHIEVE RESEARCH OBJECTIVES AS PART OF THEIR TRAINING WILL REALLY ENHANCE THE CORE OF FOLKS THAT CAN WORK IN THE FIELD. FINALLY OTHER ISSUES OF BUILDING COLLABORATIVE NETWORKS, CERTAINLY THE PRINCIPLES OF SHARED LEADERSHIP AND DISSECTION DECISION-MAKING, DEFINING CLEAR MISSION GOALS WITH SHORT AND LONG TERM STRATEGIES, ESTABLISHING ORGANIATIONAL STRUCTURE AND RULES OF THE ROAD FOR WORKING TOGETHER, THE DEVELOPING OF REGULAR MEETINGS, CONFERENCES AND WORKING GROUPS, EXPRESSING VALUE TO CONTRIBUTIONS FROM DIVERSE DISCIPLINES OUTSIDE OF OUR OWN, RESPECTFUL COMMUNICATIONS AND SUPPORT FOR OUR COLLEAGUES, UNDERSTANDING ISSUES THAT ARISE REGARDING TEAM SCIENCE ARE VITAL. SO I HOPE THAT SORT OF CRYSTALLIZED MANY OF THE DISCUSSIONS WE HAD IN OUR BREAKOUT SESSION THAT PRECEDED THIS MEETING, BUT I THINK THE MEETING ITSELF REALLY HIT ON THESE IN FAR GREATE DETAIL AND I REALLY WANT TO THANK EVERYBODY, AND I ALSO WANT TO THANK LAURIE, ERIKA AND OTHERS FOR ALLOWING ME TO PARTICIPATE. SO THANK YOU VERY MUCH. >> THANK YOU VERY MUCH, STEVE. THAT WAS WONDERFUL. SO WE'LL GO TO THE ADULT ISSUES AND CONSIDERATIONS FROM ANNIE AND MIKE, AND THEN WE'LL HAVE TIME FOR QUESTIONS. >> I'M GOING TO SHARE MY SCREEN AND TALK ABOUT THE FIRST PART OF THIS, AND THEN I'M GOING TO SWITCH OVER TO MIKE. WE THOUGHT THAT WOULD SORT OF UTILIZE OUR RELATIVE EXPERTISE IN THE BEST WAY. SO IN OUR BREAKOUT SESSION, WE REALLY -- THE THEMES THAT EMERGED FROM THIS WERE, WE SPENT A LOT OF TIME TALKING ABOUT CHALLENGES FOR RECRUITMENT AND TALKING ABOUT LOGISTICAL CHALLENGES INCLUDING TRIAL SETTING, AND SOME OF THE REGIONAL DIFFERENCES IN REGULATORY ISSUES THAT SHANNON -- OR SORRY, SHARON HIGHLIGHTED, AND THEN WE ALSO TALKED A BIT ABOUT THERAPEUTICS AND TARGET ENGAGEMENT, BIOMAKERS AND OUTCOME AGENTS AND LABS AND SAFETY ISSUES RELATED TO CLINICAL TRIALS AND DOWN SYNDROME. SO RECRUITMENT WAS REALLY, I THINK, THE THING WE SPENT THE LONGEST AMOUNT OF TIME ON. OBVIOUSLY WE ALL ARE FAMILIAR WITH LOTS OF CHALLENGES RELATED TO THIS, INCLUDING CONSISTENCY OF CAREGIVERS, ESPECIALLY WITH ADULTS WITH DOWN SYNDROME. OFTEN THEY HAVE AN OLDER PARENT WHO IS THEIR LAR, AND OFTEN THIS LEADS TO A TRANSITION IN LAR TO A SIBLING OR SOMEONE ELSE, AND OUR GROUP REALLY COMMENTED ON THE IDEA THAT SIBLINGS ARE OFTEN MORE CONSERVATIVE ABOUT PARTICIPATING IN RESEARCH COMPARED TO PARENTS, SO THIS CREATES CHALLENGES IN KIND OF CONTINUED PARTICIPATION AMONG ADULTS WITH DOWN SYNDROME. THERE ARE ALSO CHALLENGES RELATED TO THE GROUP HOME SETTING, WHETHER THERE IS A CONSISTENT LAR OR A CONSISTENT INFORMANT WHO CAN PROVIDE INFORMATION. WE SPENT A BIT OF TIME TALKING ABOUT THE LACK OF REPRESENTATION FROM DIVERSE COMMUNITIES AND A NEED FOR TRUST. THE OTHER SORT OF INTERESTING THING WAS THAT PARTICIPANTS REALLY -- AND THEIR FAMILIES REALLY WANT TO SEE A DIRECT BENEFIT, SO IT SEEMS TO BE EASIER TO RECRUIT INTO TRIAL SORT OF STUDIES RATHER THAN OBSERVATIONAL STUDIES, BUT OF COURSE THE OBSERVATIONAL STUDIES ARE NECESSARY FOR US TO GET TO THE TRIALS. WE HAD A LOT OF DISCUSSION ABOUT LONGITUDINAL STUDIES AND HOW DO WE AVOID ATTRITION, PARTICULARLY GIVEN SOME OF THE CONCERNS THAT I'VE ALREADY LISTED LIKE CAREGIVER CONSISTENCY AND GROUP HOME CHALLENGES. AND THE NEED FOR TRUSTED CLINICS AS SITES THAT CAN PULL OFF CLINICAL TRIALS AND SO THIS AGAIN GOES BACK TO THIS IDEA THAT THE SPECIALTY DOWN SYNDROME CLINICS ARE THIS INCREDIBLE RESOURCE, BUT THERE ARE NOT THAT MANY OF THEM, THEY DON'T PROVIDE CARE TO THE ENTIRE DOWN SYNDROME COMMUNITY, AND SO IDENTIFYING OTHER TRUSTED CLINICS THAT CAN REACH DOWN SYNDROME PARTICIPANTS AND CAN PULL OFF CLINICAL TRIALS IS REALLY A CHALLENGE, AND THEN THE NEED TO IDENTIFY SORT OF TRUE INCENTIVES FOR THE COMMUNITY. MICHELLE FROM THE GLOBAL DOWN SYNDROME SOCIETY MENTIONED THEIR REACH OUT AND READ INITIATIVE, THAT THEY PROVIDED A BOOK TO PARTICIPANTS FOR RETURN VISITS AND THIS ENDED UP BEING SURPRISING TO THEM AS SOMETHING THAT WAS REALLY AN INCENTIVE FOR PEOPLE TO COME BACK FOR SOMETHING AS SIMPLE AS A BOOK. AND THEN WE REALLY SPEND A LOT OF TIME TALKING ABOUT THIS KNEELED FOR RESEARCHER CARE PROVIDER PARTICIPANT PIPELINE, WHERE CARE PROVIDERS AND RESEARCHERS WORK TOGETHER TO IDENTIFY POTENTIAL PARTICIPANTS, AND THIS COULD BE THE OPPORTUNITY TO BUILD RELATIONSHIPS. SO IN TERMS OF OPPORTUNITIES IN RECRUITMENT, WE TALKED ABOUT WORKING WITH SELF ADVOCATES TO ENGAGE INDIVIDUALS THROUGHOUT THE PROCESS, AND IN PARTICULAR, GOING BACK TO SOMETHING THAT WAS DISCUSSED A LOT AND PRESENTED YESTERDAY, AND THAT BEN FOCUSED ON A GOOD BIT, IS THIS NEED FOR SIMPLE, ACCURATE INFORMATION THAT'S UNDERSTANDABLE TO INDIVIDUALS. AND PROVIDING INFORMATION THAT CAN IMPACT CLINICAL CARE. THERE IS IS SOMETHING HIGHLIGHTED BY THE GROUP, IS THAT THE DOWN SYNDROME COMMUNITY IS VERY FOCUSED ON ALZHEIMER'S DISEASE, SO THIS IS REALLY AN OPPORTUNITY TO RECRUIT INDIVIDUALS INTO STUDIES WITH ALZHEIMER'S DISEASE AND THAT THERE'S ALSO THIS NEED TO IDENTIFY MORE NON-PHARMACOLOGICAL INTERVENTIONS. THIS IS SOMETHING THAT THE COMMUNITY IS VERY INTERESTED IN. AND THE LAST OPPORTUNITY THAT WE REALLY FOCUSED ON IS THIS HUGE RESOURCE OF DOWN SYNDROME ADULT CLINICS, THAT THESE LOCATIONS REALLY MATTER. THEY'RE IMPORTANT FOR PULLING OFF CLINICAL TRIALS, THEY'RE OFTEN TRUSTED SOURCES OF INFORMATION FOR THE COMMUNITY, AND THIS CAN ALSO ALLOW SORT OF A DESENSITIZATION PROCESS FOR FEAR OF MORE INVASIVE PROCEDURES, SOMETHING THAT THE MIND HAS REALLY PIONEERED. IN TERMS OF LOGISTICS, WE TALKED A LOT ABOUT THE CONSENT CHALLENGES AND THE STATE TO STATE DIFFERENCES AND RISKS OF PROCEDURES THAT SHARON HAS ALREADY HIGHLIGHTED. AND THEN WE TALKED A LOT ABOUT TRIAL SETTING. SORE HOW DO SO HOW DO WE REDUCE THE NUMBER OF VISITS FOR A TWRIEL TRIAL TO REDUCE BURDEN? CAN WE ADDRESS TELEHEALTH AND HOME HEALTH CHALLENGES? SO THE IDEA THAT THERE MAY BE DIFFICULTIES WITH TECHNOLOGY THAT WE WERE DISCUSSING IN THE LAST Q & A, THAT THERE MAY NOT IN A GROUP HOME BE A LOCATION THAT'S CONDUCIVE TO SOMETHING LIKE COGNITIVE TESTING. SO WE TALKED A LOT ABOUT THE POTENTIAL FOR INCREASING THAT FLEXIBILITY TO IMPROVE OVERALL RECRUITMENT AND RECRUITMENT OF DIVERSE POPULATIONS. AND TRYING TO STRIKE A BALANCE BETWEEN COMMUNITY CARE PROVIDERS WHO ARE OFTEN THE MOST TRUSTED INDIVIDUALS IN THE LIVES OF DOWN SYNDROME PARTICIPANTS AND THEIR FAMILIES, AND SITES THAT CAN RELIABLY EXECUTE CLINICAL TRIALS. SO REALLY THINKING ABOUT HOW DO WE BEST STRIKE THAT BALANCE. NOW I'M GOING TO SWITCH OVER TO MIKE TO TALK ABOUT THERAPEUTICS AND TARGET ENGAGEMENT. >> LET ME JUST SHARE MY SCREEN. I WILL PICK UP WHERE YOU LEFT OFF. THANKS, ANNIE. THE OTHER ISSUES THAT CAME UP IN TERMS OF GAPS AND OPPORTUNITIES INCLUDED WHAT METHODS CAN WE USE TO BEST ASSESS TARGET ENGAGEMENT. IN THE REALM OF ALZHEIMER'S DISEASE, WE'VE BEEN TALKING ABOUT IMAGING, BLOOD AND CSF. SRNLY IN OTHER DISEASE CONDITIONS, IT WILL BE CRITICAL TO MAKE SURE WE HAVE THE IDEAL BIOMARKERS THAT ARE AVAILABLE. ONE QUESTION, CAN THE SAME MEASURES BE USED IN DOWN SYNDROME AS IN TRIALS WITH TYPICAL ADULTS AND WE ARE PRETTY CERTAIN THAT THAT IS NOT THE CASE AND THAT BEGS THE QUESTION, SENSITIVE TO WHATEVER MECHANISM OF ACTION THAT WE'RE TARGETING. WE ALSO NEED TO DEVELOP METHODS TO ASSESS TARGET ENGAGEMENT ITSELF, SO NOT JUST EFFICACY AND EFFECTIVENESS, BUT REDUCTION IN A PARTICULAR BIOMARKER. SO MANY OF THE LAB RESULTS THAT WE ORDER IN CLINICAL TRIALS, WHEN WE GET THEM BACK FROM OUR LAB VENDOR, IN DOWN SYNDROME STUDIES, THEY ARE OFTEN MARKED AS OUT OF RANGE. AND ABNORMAL. AND THOSE ABNORMALITIES MAY, IN FACT, BE NORMAL IN THE PHYSIOLOGY OF A PERSON WITH DOWN SYNDROME. SO WE CERTAINLY HAVE SOME GAPS THERE. WE REALLY NEED TO CREATE A FORUM WHERE RESEARCHERS, CLINICIANS, PHARMA PARTNERS, REGULATORS AND ADVOCACY GROUPS CAN COME TOGETHER TO DISCUSS POTENTIAL THERAPEUTICS AND TO MOVE THE FIELD FORWARD IN BRINGING SO MANY OF THE THERAPIES THAT ARE IN THE TYPICAL POPULATION INTO THIS GROUP. THERE'S A NEED FOR VALIDATED COGNITIVE OUTCOMES THAT BALANCE BOTH EARLY DETECTION OF DECLINE BUT ARE ALSO SENSITIVE TO CHANGE. MORE IMPORTANTLY, THEY NEED TO BE INCLUSIVE OF PEOPLE WITH THE ENTIRE SPECTRUM OF INTELLECTUAL DISABILITY. SO WHAT WE WOULD HATE IS FOR US TO ALLOW ADULTS WITH DOWN SYNDROME TO SCREEN FOR STUDIES BUT THEN BEGIN TO EXCLUDE PEOPLE WITHIN THE DOWN SYNDROME COMMUNITY FROM PARTICIPATING, AND THAT STARTS WITH OUR OUTCOME MEASURES. WE ALSO NEED KNOWLEDGE OF THE NATURAL HISTORY OF THOSE OUTCOME MEASURES BECAUSE THEY WILL VERY MUCH SERVE AS THE PLACEBO ARM, AND WE'VE BEEN BURNED BY THIS IN SO MANY SPORADIC ALZHEIMER'S TRIALS THAT IT NEEDS TO BE ADDRESSED EARLY ON IN THE DESIGN OF OUTCOME MEASURES FOR THIS POPULATION. CAREGIVER MEASURES NEED TO BE VALID AND RELIABLE IN THE CASE œWHICH IS WHAT ANNIE JUSTGIVERS, MENTIONED EARLIER ABOUT THERE CAN BE FREQUENT CHANGE IN STAFF AT RESIDENTIAL CARE FACILITIES AND GROUP HOMES, AND WE NEED TO BALANCE RESPECT FOR ADULTS WITH ADULT EXPERIENCES AND USE MEASURES AND QUESTIONNAIRES AND IMAGES THAT ARE APPROPRIATE FOR ADULTS WITH INTELLECTUAL DISABILITY AND NOT TO TREAT THEM AS CHILDREN. AND WE WANT TO DESIGN CLINICAL TRIALS THAT MEASURE CLINICALLY MEANINGFUL IMPACT. WHETHER IT'S AN EARLY STAGE OF A DISEASE OR A LATER STAGE OF A DISEASE, IN ALZHEIMER'S DISEASE, WE HAVE THE PRE-CLINICAL STAGE, AND WE REALLY NEED TO FIGURE OUT HOW CAN WE ASSESS AN OUTCOME MEASURE THAT'S MEASURING COGNITION IN FOLKS WHO AREN'T HAVING A PROGRESSIVE DECLINE DUE TO DEMENTIA, AND WHAT WOULD BE THE DURATION OF TREATMENT AND SAFETY FOLLOW-UP. I'VE MENTIONED EARLIER THAT THE NORMATIVE DATA FOR DOWN SYNDROME, PARTICIPANTS NEED TO BE BROADLY UNDERSTOOD AND AVAILABLE FOR ALL CLINICIANS AND ALL RESEARCHERS. THERE NEEDS TO BE DISCUSSION AND SHARED RESOURCES OF WHAT THE PRIOR CLINICAL TRIALS HAVE FOUND IN TERMS OF LAB QUOTE-UNQUOTE ABNORMALITIES. THE ABC-DS PROJECT AND THE HUMAN TRISOME PROJECT WILL GO A LONG WAY IN PROVIDING THIS KIND OF INFORMATION. WE ALSO NEED TO THINK ABOUT APPROPRIATE INCLUSION/EXCLUSION CRITERIA THAT ARE SPECIFIC TO DOWN SYNDROME AND WHAT IS ABNORMAL IN THE CONTEXT OF DOWN SYNDROME, PARTICULARLY WITH REGARDS TO SAFETY LABS. AND WE'D LIKE TO UNDERSTAND LONGITUDINAL DYNAMICS AND CHANGE OVER TIME IN THESE BIOMARKERS. CLINIC SETTING IS IMPORTANT. ANNIE BRIEFLY TOUCHED ON THIS, BUT THERE ARE CHALLENGES BOTH TO SPACE AND STAFF EXPERIENCE. SO IT'S NOT JUST SIMPLY BEING A BUSY DOWN SYNDROME CLINICALLY NICHE WHERE THE DECISION IS YOU CAN START RUNNING TRIALS. THE STAFF NEEDS TO BE EXPERIENCED AND NEEDS TO HAVE THE BACKGROUND AND THE ABILITY TO PROVIDE THE SAFETY OVERSIGHT NEEDED. SO THERE HAVE BEEN SUGGESTIONS MADE FROM THE MEETING THAT WE HAD PRIOR TO THIS THAT THERE WOULD BE AN EXPLORATION OF SPECIFIC TRAINING FOR CLINICIANS WHO ARE PARTICIPATING IN CLINICAL RESEARCH THAT WOULD PROVIDE, PERHAPS, CME CREDITS FOR THEM. THERE IS THE ECHO MODEL, WHICH PROVIDES TRAINING AND OUTREACH TO PROVIDERS IN RURAL AND UNDERSERVED COMMUNITIES, AND THE ACHC HAS THE IMPACT-AD HAS THE TRAINING MODEL FOR THE NEXT GENERATION OF RESEARCHERS FOR ALZHEIMER'S DISEASE. WE REALLY NEED TO MAKE SURE THAT DATA COLLECTION IS HARMONIZED AND VALIDATED ACROSS NOT JUST SITES BUT ALSO STUDIES. FINALLY, I THINK PARAMOUNT TO THIS ENTIRE UNDERTAKING OF CLINICAL TRIALS, BEING SOMEONE WHO DEALS WITH MEDICAL SAFETY ISSUES AND ONGOING STUDIES, WE NEED EXPERTISE IN OBTAINING INFORMED CONSENT AND ASSENT BUT ALSO THE CLEAR DESCRIPTION OF THE RISKS THAT ARE ASSOCIATED. WE NEED TO HAVE REPORTING STRATEGIES FOR ADVERSE AND SERIOUS ADVERSE EVENTS. WE KNOW THAT THESE CAN DIFFER ACROSS SITES AND WE NEED TO HAVE COHESIVE REPORTING STRATEGIES FOR STUDIES ACROSS ALL THE SITES, AND WE NEED SITES THAT ARE EXPERIENCED IN CONDUCTING INTERVENTIONAL TRIALS AND CAN MANAGE ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS AND HAVE EXPERIENCE IN TRIALS, IN INDIVIDUALS WITH INTELLECTUAL DISABILITY, WHERE PARTICIPANT REPORTING OF ADVERSE EVENTS MAY MOVE FORWARD. WE NEED ADDITIONAL KNOWLEDGE ON THE COMORBIDITIES AND THE IMPACT ON THE DOWN SYNDROME PHYSIOLOGY ON SAFETY AND TOLERABILITY AND THE KNOWLEDGE OF A PARTICULAR DRUG, SO DOSING, PK AND PD, SO MUCH THAT'S BEING DONE IN THE PTN NETWORK. SO THERE'S A UNIQUE OPPORTUNITY TO EDUCATE FAMILIES ABOUT SAFETY OF TRIALS AND TRIAL PROCEDURES. THIS STILL REMAINS A GAP. IN ADDITION, WE NEED CLARITY ON THE REGULATORY PATHWAY FOR NEW DRUGS. AND I MENTIONED EARLIER PHARMACEUTICAL COMPANIES IN PARTICULAR ARE INTERESTED IN UNDERSTANDING WHETHER ACCELERATED APPROVAL OR ORPHAN CLASSIFICATION IS APPLICABLE TO DRUGS THAT ARE BEING EVALUATED AND IN PEOPLE WITH DOWN SYNDROME AND THIS IS SOMETHING WE NEED TO KNOW TO BRING THOSE INDIVIDUALS AND THOSE COMPANIES TO THE TABLE SO THAT WE CAN WORK TOGETHER. I'LL STOP THERE. >> THANK YOU, MIKE. ANNIE. I THINK WE HAVE A COUPLE QUESTIONS THAT CAME THROUGH. WE HAVE -- ERIKA HAS SENT OUT. YOU ALL HAVE THE QUESTIONS OR DO YOU NEED US TO READ THEM? >> I HAVE THE FIRST ONE THAT ERIKA SENT ME WHICH IS, HOW CAN WE HAVE CLINICAL TRIAL CENTERS TO SERVE THE DOWN SYNDROME COMMUNITY. I THINK MIKE TOUCHED ON THIS WHEN WE TALKED ABOUT THE IDEA FOR THESE MODELS THAT HAVE BEEN USED IN ALZHEIMER'S DISEASE, LIKE IMPACT-AD AND THEN THIS ECHO MODEL THAT HAS BEEN USED TO REACH OUT TO PROVIDERS WHO HAVEN'T NECESSARILY BEEN INVOLVED IN THESE TYPES OF STUDIES THAT WE REALLY NEED TO THINK ABOUT WAYS TO REACH OUT AND TRAIN CLINICAL CARE PROVIDERS WHO MAY BE PROVIDING CARE TO THE COMMUNITY BUT AREN'T NECESSARILY IN A SPECIALTY CENTER BECAUSE AS MIKE SAID, THERE ARE SO MANY ISSUES ASSOCIATED WITH PULLING OFF A CLINICAL TRIAL THAT WE NEED TO BE VERY THOUGHTFUL ABOUT HOW WE TRAIN THESE INDIVIDUALS. AND THEN I THINK SECONDLY RELATED TO THAT IS THAT -- [PLEASE STAND BY] >> HI, ANNIE, ARE YOU STILL THERE? >> HI, ANNIE, ARE YOU STILL THERE? >> IT CUT ME OFF AND NOW I'M BACK. >> OKAY, GOOD. >> SO I WAS JUST SAYING THAT I THINK THAT PIPELINE FROM PARTICIPANT TO CARE PROVIDER TO RESEARCHERS IS GOING TO BE REALLY IMPORTANT, SO IT MAY NOT BE THAT THESE CLINICAL CENTERS HAVE TO BE A RESEARCH -- HAVE TO BE A CLINICAL TRIAL SITE, BUT IF WE ESTABLISH RELATIONSHIPS WITH THOSE AND BECOME A TRUSTED PARTNER WITH THEM, THAT'S ANOTHER OPPORTUNITY FOR US TO HAVE RESEARCHERS SORT OF SERVING THE DOWN SYNDROME COMMUNITY. >> GREAT. STEVE OR PRIYA, DID YOU WANT TO ALSO HAVE ANYTHING -- >> I JUST WANTED TO MENTION REALLY BRIEFLY, THOSE ARE GREAT COMMENTS. THAT'S SORT OF ONE OF THE MAJOR ROLES AT MANY OF THE NIH'S CTSIs, THE CLINICAL TRANSLATIONAL SCIENCE INSTITUTES, IS TO REALLY SERVE AS THE HUB, TO INTERACT WITH OTHER SITES THROUGHOUT THE REGION TO ACTUALLY ENCOURAGE COMMUNITY ENGAGEMENT IN RESEARCH MORE BROADLY, AND I THINK HAVING THE DOWN SYNDROME COMMUNITY MORE AWARE OF THAT OR UTILIZING THOSE PROGRAMS, I THINK WILL BE VERY, VERY HELPFUL BECAUSE A LOT OF THESE COMMUNICATIONS AND FORMATTING OF THESE RELATIONSHIPS HAS ALREADY BEEN ESTABLISHED THROUGH THE CTSI PROGRAM. >> GREAT. AND THE OTHER QUESTION WE HAD IS HAD ON THE LAST SESSION, WHAT ARE THE ISSUES AND HOW DO WE ADDRESS RETURN OF NOT INDIVIDUAL TESTS THAT WERE BEING TAKEN DURING A STUDY BUT THE ACTUAL OVERALL STUDY RESULTS. WE HEARD SOME OF THAT YESTERDAY AS WELL. THERE MAY BE DIFFERENCES FOR PEDIATRIC VERSUS ADULTS. SO STEVE OR ANNIE? >> THAT'S A REAL GREAT QUESTION. IT'S SO VITAL THAT WE DO THIS. I KNOW ALL OF ACADEMICS IS TRYING TO FACE THIS CHALLENGE, JOURNAL EDITORS AND EVERYONE, AND THEN WE AS REVIEWERS FOR THE JOURNALS AS WELL ALL PLAY A ROLE IN THIS, IS THAT SOMETIMES IF THERE ARE NEGATIVE RESULTS IN A STUDY, WE DON'T REPORT THEM, WE DON'T HAVE THE TIME COMMITMENT, SOMETIMES TIME HAS GONE ON SO FAR THAT WE NO LONGER HAVE THE RESOURCES TO REALLY FINALIZE THAT, BUT I THINK THERE ARE MANY AVENUES OF APPROACHES, BUT THESE KINDS OF THINGS SHOULD BE ENCOURAGED, AND THE SECOND PIECE, OF COURSE, IS HOW TO GET IT OUT TO THE PARTICIPANTS, I THINK IS AN ETHICAL ROLE THAT WE MUST PLAY, THAT IF SOMEONE REALLY PARTICIPATE IN THE STUDY, IT'S OUR ETHICAL DUTY TO MAKE SURE THAT THEY DO HEAR THE RESULTS OF THE INVOLVEMENT. THE OUTCOME OF THEIR ENGAGEMENT IN IT IN SOME WAY. SO VERY IMPORTANT THAT WE ADDRESS THESE ISSUES. >> HI THIS, IS PRIYA. I JUST WANTED TO ADD A COMMENT TO THIS, STEVE. IT ALMOST SEEMS TO ME THAT THERE SHOULD BE SOME KIND OF MANDATE, YOU KNOW, FOR CLINICAL TRIALS, WHETHER THEY'RE POSITIVE OR NEGATIVE. THERE NEEDS TO BE, YOU KNOW, BEYOND JUST THE CSR OR THE CLINICAL STUDY REPORT, WHICH IS SOMETHING THAT ENDS UP WITH THE FDA, BUT IT STILL DOES NOT GET OUT TO THE OTHER INVESTIGATORS AND TO THE BROADER SCOPE OF THE FIELD. USUALLY THIS OCCURS IN THE SITUATION OF PEDIATRIC EXCLUSIVITY WHEN YOU'RE REQUESTING FOR THAT ADDITIONAL SIX MONTHS, AND IF YOU HAVE THAT CHECK BOX, YOU GET THE BENEFIT BUT YOU NECESSARILY ARE NOT EVEN PUBLISHING THE DATA. SO TO ME, IT REALLY NEEDS TO BE THOUGHT ABOUT. >> THANK YOU, PRIYA. ANDY OR MIKE, DID YOU WANT TO COMMENT? -- ANNIE OR MIKE, DID YOU WANT TO COMMENT? >> THIS IS MIKE. I THINK THAT THE CLINICALTRIALS.GOV DOES HAVE REPORTING REQUIREMENTS, ALL ALTHOUGH THOSE ARE VERY MINIMAL AND THE NIH MANDATE FOR FUNDED PROJECTS TO PRESENT TOP LINE DATA WITHIN A YEAR OF DATA LOCK IS ALSO VERY HELPFUL. I'M NOT SURE HOW THEY COULD MANDATE INDUSTRY SPONSORS FOR PURELY INDUSTRY SPONSORED STUDIES TO BE REQUIRED TO SORT OF DIVULGE THOSE DATA, BUT IT WOULD BE VERY HELPFUL TO SEE HOW THINGS WERE DONE, HOW THEY WORKED AND HOW THEY DIDN'T WORK. AND MAYBE THERE IS SOME FEDERAL MANDATE THAT COULD COME TO DO THAT. >> I BELIEVE THERE'S ANOTHER QUESTION CAME THROUGH THAT IS IN THE CHAT. CAN YOU ALL SEE THAT? >> YES. SO THE ROLE FOR DOWN SYNDROME SELF ADVOCATES IN COMMUNICATING WITH THE DOWN SYNDROME COMMUNITY. DO WE SEE A ROLE FOR DOWN SYNDROME SELF ADVOCATES IN COMMUNICATING WITH THE DOWN SYNDROME COMMUNITY. SO I THINK THAT'S A GREAT QUESTION AND IT'S AN EXCELLENT POINT THAT I THINK THAT'S GOING TO BE REALLY IMPORTANT, IS THAT WE IDENTIFY SELF ADVOCATES WITH DOWN SYNDROME WHO CAN TALK ABOUT THEIR RESEARCH EXPERIENCES AND REACH OUT TO THE COMMUNITY. I'M REALLY HOPEFUL THAT IN OUR OUTREACH STRATEGIES, THAT THE PARTICIPANTS FROM OUR RESEARCH STUDIES WILL BE WILLING TO COMMUNICATE WITH THE COMMUNITY AND BE INVOLVED IN THAT PROCESS, BECAUSE I THINK THAT'S A REALLY, REALLY IMPORTANT THING, AND THEY'RE GOING TO BE SOME OF OUR MOST IMPORTANT ADVOCATES AND PARTNERS IN THIS. >> GREAT. SO I'M NOT SEEING ANY OTHER QUESTIONS COME THROUGH. I DON'T KNOW IF YOU ALL HAVE ANY LAST WORDS HERE, IF YOU DON'T, WE'RE GOING TO GO AHEAD AND -- WE'LL GO TO DR. GIBBONS AFTER THIS, AND THEN I WILL WRAP UP AT THE END, BUT ANNIE, MIKE, ANY LAST WORDS ON THIS? >> JUST TO SAY THANK YOU AGAIN TO YOU GUYS FOR ORGANIZING A REALLY GREAT MEETING. >> THANK YOU. AND PRIYA AND STEVE, ANYTHING? LAST WORDS? >> JUST AMEN TO THAT. THANK YOU SO MUCH. >> ABSOLUTELY. THANK YOU ALL SO MUCH. AND TRULY, YOU KNOW, THE FACT THAT WE COULD COME TOGETHER AND BE SO PRODUCTIVE IN A VIRTUAL MEETING TELLS US THAT WE ARE TRAIL BLAZING A COMPLETELY NEW WORLD. THANK YOU ALL. BE SAFE. >> WE'LL HEAD OVER TO OUR COLLEAGUE FROM NHLBI. >> THANKS, EVERYONE. I'M DELIGHTED TO HAVE THE OPPORTUNITY TO PARTICIPATE IN THIS WONDERFUL WORKSHOP OVER THE PAST COUPLE OF DAYS. I'M FURTHER DELIGHTED TO INTRODUCE DR. GARY GIBBONS TODAY. DR. GIBBONS IS THE DIRECTOR OF THE NATIONAL HEART, LUNG AND BLOOD INSTITUTE, CO-CHAIR OF THE NIH INCLUDE STEERING COMMITTEE ALONG WITH DR. BIANCHI. DR. GIBBONS IS A CARDIOLOGIST AND ALSO AN ACCOMPLISHED INVESTIGATOR, THE RELATIONSHIP BETWEEN CLINICAL PHENOTYPES, BEHAVIOR, MOLECULAR INTERACTIONS, SOCIAL DETERMINANTS OF GENETICS AND CARDIOVASCULAR DISEASE. THIS IS A MULTIDISCIPLINARY APPROACH THAT ALSO HAS RELEVANCE TO RESEARCH IN DOWN SYNDROME. MOST IMPORTANTLY FOR TODAY, HE HAS BEEN AN ENTHUSIASTIC AND ENGAGED SUPPORTER OF THE INCLUDE PROGRAM. DR. GIBBONS, I'LL TURN IT OVER TO YOU NOW. >> THANK YOU, GAIL. HOPEFULLY EVERYONE CAN HEAR ME OKAY? >> YES. >> GOOD. OKAY, GREAT. JUST CHECKING. I GO FROM ZOOM TO WEBEX AND BACK AND FORTH THESE DAYS, SO I JUST WANTED TO BE SURE. IT'S REALLY A PLEASURE TO BE WITH THIS COMMUNITY. AS GAIL MENTIONED, THIS IS AN IMPORTANT PRIORITY FOR US, AN IMPORTANT COLLABORATIVE PARTNERSHIP. IT'S TERRIFIC THAT THIS IS A CONVENING OF THOSE INDIVIDUALS LIVING WITH DOWN SYNDROME, THEIR FAMILIES, CARE PROVIDERS, RESEARCHERS, ADVOCATES, AND IT REALLY TAKES THIS WHOLE CIRCLE OF PARTNERS, THIS VILLAGE, IF YOU WILL, OF ALL WHO ARE COMMITTED TO THE GOAL OF ENHANCING THE LIVES OF THOSE LIVING WITH DOWN SYNDROME, AND IT TAKES US ALL WORKING COLLABORATIVELY AS PARTNERS TOGETHER. I BELIEVE THAT'S COME THROUGH IN THE THEMES OVER THE LAST TWO YEARS -- TWO DAYS THAT I'VE HEARD ABOUT. MAYBE IT SEEMS LIKE TWO YEARS, BUT THE LAST TWO DAYS WHERE YOU'VE HAD A VERY ENGAGED DISCUSSION AND THE DEBRIEFS I'VE HAD, I WAS ABLE TO CATCH A LITTLE BIT OF THE LAST PART OF THE MEETING TODAY, AND I KNOW MY COLLEAGUE AND CO-CHAIR, DR. BIANCA FROM CHILD HEALTH BIANCHI FROM CHILD HEALTH GAVE OPENING REMARKS, . WE SHOULD BE PROUD COLLECTIVELY ABOUT WHAT HAS BEEN ACCOMPLISHED HERE WITH INCLUDE, THAT IT CAME INTO BEING JUST TWO YEARS AGO AS PART OF THIS COLLABORATIVE PARTNERSHIP WITH STRONG ADVOCACY IN THE FROM THE COMMUNITY AND STRONG COMMITMENT FROM THE NIH AND GENEROUS SUPPORT BY OUR REPRESENTATIVES IN CONGRESS. WE'VE MADE SUBSTANTIAL PROGRESS, TWO YEARS OLD, WE'RE NOT IN THE BABY CARRIAGE ANYMORE. WE'RE ACTUALLY GONE FROM CRAWLING TO WALKING AND WE HAVE A VERY EXCITING PORTFOLIO OF PROGRAMS, PARTICULARLY RELEVANT TO THE LAST TWO DAYS ABOUT CLINICAL TRIALS. AS WE CERTAINLY TRY TO UNDERSTAND THE BASIC SCIENCE, WE'RE DEVELOPING A FULL PORTFOLIO THAT SPANS THAT WHOLE SPECTRUM, THAT IT'S INCLUSIVE OF CLINICAL RESEARCH. AND THAT PORTFOLIO HAS INDEED BEEN DEVELOPED WITH VARIOUS SORTS OF PROJECTS, THE ONES I'VE NOTED, PARTICULARLY RELEVANT OBVIOUSLY TO NHLBI, WILL RELATE TO HEART DISEASE AND SLEEP IN PARTICULAR, WITH OUR CLINICAL TRIALS, AND WHERE IMPORTANT INSIGHTS ARE BEING GAINED. WE'RE EXCITED ABOUT THAT. IN ADDITION, THE CAPACITY BUILDING THAT THIS PROGRAM HAS ENHANCED AND ACCELERATED GIVES US A LOT OF HOPE AND CONFIDENCE ABOUT THE TRAJECTORY OF RESEARCH THAT'S GOING TO BE RELEVANT ENHANCING THE LIVES OF INDIVIDUALS WITH DOWN SYNDROME. IN PARTICULAR, THE TRAINEES, THE NEXT GENERATION, PROMOTING A CADRE OF INVESTIGATORS WHO REALLY ARE GOING TO SPUR THE FUTURE AND REALLY ADVANCE THE FIELD, AND I THINK THAT'S A KEY PART OF MAKING TRANSFORMATIVE CHANGE, IS INVESTING IN THE NEXT GENERATION. SO WE'RE VERY EXCITED ABOUT WHAT HAS HAPPENED SO FAR, AND WHAT WE ANTICIPATE WILL CONTINUE TO EVOLVE. IT'S CLEAR THAT YOU'VE HAD A VERY RICH DIALOGUE AND DISCUSSION. I WAS ABLE TO HEAR A LOT OF THE SUMMARIES FROM THE BREAKOUT SESSIONS THAT YOU'VE BEEN HAVING OVER THE LAST PERIOD OF TIME, ALBEIT VIRTUALLY, BUT IT'S CLEAR THAT YOU'VE HAD AN INTERACTION THAT'S IDENTIFIED SEVERAL MAJOR ISSUES, KEY ISSUES, AND IT'S NOTABLE THAT IN MANY WAYS, WE'RE ALL CAUGHT UP BY THIS COVID PANDEMIC THAT'S DISRUPTED ALL OF OUR LIVES, CERTAINLY HERE AT NIH, IT SEEMS LIKE IT'S 24/7. AND WHAT IT KIND OF REINFORCES, I THINK, IS HOW INTERDEPENDENT WE ALL ARE, HOW IMPORTANT IT IS FOR US TO FUNCTION AS A COLLECTIVE, AND I THINK THAT'S COME THROUGH, EVEN IN YOUR DISCUSSIONS AND HOW IMPORTANT IT IS TO HAVE THAT OUTREACH AND ENGAGEMENT, THAT BUILDING OF TRUST WHICH I THOUGHT RESONATED WITH ME. THIS NOTION THAT WE HAVE TO BE SO MUCH MORE INCLUSIVE IN WHO WE STUDY, HOW WE STUDY, HOW WE ENGAGE IN THOSE RESEARCH TOPICS AS PARTNERS. WE HEAR YOU, THAT THERE'S BEEN A PERIOD OF A HISTORY OF EXCLUDING INDIVIDUALS WITH DOWN SYNDROME. AND THAT HISTORY HAS TO CHANGE. I'M FAMILIAR WITH THAT FROM OTHER POPULATIONS THAT HAVE FELT NEGLECTED OR UNDERSERVED OR MARGINALIZED, AND WE'RE COMMITTED TO BEING SURE THAT THAT IS A PAGE OF HISTORY THAT WE TURN. SO WE LOOK FORWARD TO WORKING WITH YOU, AS PARTNERS, TO DEVELOP THOSE CLINICAL RESEARCH PLATFORMS, COLLABORATIONS, CONSORTIA, THAT WORK WITH THE COMMUNITY OF INDIVIDUALS WITH DOWN SYNDROME, THEIR FAMILIES, TO FIGURE OUT BETTER STRATEGIES TO DO THIS MORE EFFECTIVELY. SIMILARLY, WE HEAR YOU ABOUT SOME OF THE ISSUES RAISED IN APPRECIATING THE VARIABILITY OF THE INFLUENCE OF TRY TRISOME 21 AND INDIVIDUALS IN DOWN SYNDROME. WE RECOGNIZE VARIATION IN TERMS OF ITS PRESENTATION BUT THE VARIATION IN EACH INDIVIDUAL, AND AGAIN, AS WAS POINTED OUT, THE NEED FOR PRECISION MEDICINE, THE NOTION OF WHAT WAS SOPHISTICATEDLY CALLED ENDOPHENOTYPES, APPRECIATING THAT INDEED WE MAY NEED TO TAILOR OUR APPROACH AND UNDERSTANDING THE NATURAL HISTORY MORE EFFECTIVELY. SO THAT MEANS WE HAVE TO BUILD UP THE REGISTRIES AND THE CAPABILITY OF BIOREPOSITORIES TO DO THAT. WE ALSO RECOGNIZE THAT THAT WILL BE IMPORTANT IN BUILDING THE CLINICAL SCIENCE QUESTIONS ABOUT HOW WE CAN INTERVENE AND HOW WE CAN INTERVENE MORE EFFECTIVELY. I KNOW IN OUR PORTFOLIO, THAT'S COME UP WITH APPROACHES TO SLEEP APNEA, AND THERAPEUTICS FOR SLEEP APNEA, THAT MAY INDEED NEED TO BE ADAPTED AND ALTERED IF, INDEED, THEY'RE GOING TO BE MOST HELPFUL FOR INDIVIDUALS WITH DOWN SYNDROME. AND APPRECIATING THE DISTINCTNESS OF THE PHYSIOLOGY THAT MAY BE RELEVANT IN INDIVIDUALS WITH DOWN SYNDROME RELATIVE TO OTHERS WITH SLEEP APNEA. SO AGAIN, IT'S REALLY PERSONALIZING AND BEING MORE PRECISE WITH OUR MEDICINE. AND CREATING THE RESOURCES TO MAKE THAT HAPPEN. CERTAINLY IN NHLBI, WE HAVE A PROGRAM IN PRECISION MEDICINE CALLED TOP MED THAT DOES INDEED TRY TO UNDERSTAND THE MULTIPLE DIMENSIONS THAT INFLUENCE HEALTH AND VARIABILITY, AND WE SEE THIS PROGRAM LINKING WITH THAT AS WELL AS DS CONNECT AND OTHERS AS WE FURTHER UNDERSTAND IT. SO JUST TO CONCLUDE, WE HOPEFULLY HAVE HEARD THAT THIS IS A HIGH PRIORITY, THERE'S FIRM COMMITMENT BY NIH, THIS IS A TRANS-NIH EFFORT THAT, AGAIN, I'M PRIVILEGED TO CO-CHAIR WITH DIANA BIANCHI, BUT IT INVOLVES A NUMBER OF INSTITUTES AND CENTERS AND THAT'S REFLECTIVE OF A GREAT COMMITMENT TO MAKE A DIFFERENCE IN THE LIVES OF THOSE INDIVIDUALS LIVING WITH DOWN SYNDROME AND IT'S REALLY TO THANK THE ORGANIZERS, THE STAFF, THE PARTNERS, MICHELLE, JOAQUIN AND OTHERS SO INSTRUMENTAL IN PUTTING THIS TOGETHER, AND WE APPRECIATE THE CONTRIBUTIONS OF ALL THE SPEAKERS THAT HAVE PUT TOGETHER A TERRIFIC PROGRAM.& IT WAS A HISTORIC ONE TO FOCUS IN ON CLINICAL TRIALS, AND I THINK IT APPEARS TO HAVE HAD A RICH PRODUCT THAT WILL GIVE US GUIDANCE ABOUT HOW WE CAN CONTINUE TO ENHANCE OUR RESEARCH PORTFOLIO IN A WAY THAT TURNS DISCOVERY INTO ENHANCING BOTH HEALTH AND WELL-BEING OF INDIVIDUALS WITH DOWN SYNDROME. SO WITH THAT, AGAIN, I SAY THANK YOU, AND WE LOOK FORWARD TO ONGOING PARTNERSHIP AND TURN IT BACK OVER TO GAIL AND OTHERS. >> ALL RIGHT. CAN EVERYONE HEAR ME? >> YES. >> OKAY. BECAUSE I WAS -- THE SCREEN KIND OF WENT BLANK THERE. OKAY. GOOD. SO I AM JUST GOING TO WRAP UP BY FIRST OF ALL SAYING, REALLY, THIS HAS BEEN A TREMENDOUS, TREMENDOUS ALMOST TWO FULL DAYS, JAM-PACKED, COULDN'T HAVE DONE IT WITHOUT YOU ALL, THE PARTICIPANTS. THE VIRTUAL REALM IS NOT EASY, WE HAD A FEW TECHNICAL GLITCHES BUT WE OVERCAME THOSE, AND REALLY THANK YOU ALL. AND I ALSO WANT TO THANK ALL OF MY COMPONENT THREE, THE CLINICAL TRIALS WORKING GROUP, EVERY ONE OF US, OUR TRANS-NIH DOWN SYNDROME WORKING GROUP, AND OF COURSE THIS WOULD NOT BE COMPLETE AND YOU'VE HEARD A LOT ABOUT ERIKA, YOU'VE EVEN SAW A LITTLE ABOUT HER, THIS COULD NOT HAVE BEEN PULLED OFF AT ALL WITHOUT MY COLLEAGUE ERIKA TARVER BECAUSE SHE IS AMAZING, ORGANIZED, GOT EVERYBODY PREPARED, OBVIOUSLY I COULDN'T HAVE DONE IT WITHOUT HER, WE ARE A PARTNERSHIP, SO THANK YOU, ERIKA, I DON'T KNOW IF YOU CAN TURN YOUR CAMERA ON -- SHE WON'T TURN HER CAMERA ON, SO I JUST WANT TO SAY THANK YOU TO ERIKA BUT WE WOULDN'T BE ABLE TO DO THIS WITHOUT HER. THE LAST THING, I WANT TO MENTION, I THINK WE'RE GOING TO SHOW A SLIDE ABOUT THE RFI THAT YOU HEARD A LITTLE BIT ABOUT YESTERDAY ON THE DOWN SYNDROME RESEARCH PLAN, AND I THINK ERIKA IS GOING TO SHOW -- THERE IT IS -- SHOW THE LINK. THERE WAS SOME QUESTIONS YESTERDAY ABOUT THE 2014 PLAN THAT DIDN'T MAYBE INCLUDE ENOUGH ABOUT LUNG DISEASE, SO REALLY, THIS IS YOUR CHANCE, HELP US, YOU KNOW, WE WANT YOUR INPUT ON THE NEXT RESEARCH PLAN FOR DOWN SYNDROME AND THERE'S THE LINK THERE. SO PLEASE, PLEASE, DO GIVE US YOUR THOUGHTS. AND WITH THAT, WE WILL END. THANK YOU ALL AGAIN, AND I'M SURE WE'LL BE HAVING MORE INCLUDE AS I KNOW WE WILL ACTUALLY, I SHOULD MENTION GAIL IS GOING TO BE LEADING ONE WE'RE GOING TO HAVE ON MORE BASIC SCIENCE, SO WE'LL GET TOGETHER AGAIN, MAYBE WE'LL BE ABLE TO BE IN PERSON THEN. THANK EVERYONE, STAY SAFE.