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>> GREAT. THANK YOU VERY MUCH.
SO THE SECOND ONE IS ALSO RELATED TO ALL OF THE THINGS
WE'VE BEEN TALKING ABOUT AND I IMAGINE YOU WILL SEE SOME
AREAS OF SNOERMG AND SOME AREAS OF OVERLAP AND WE'D
LOVE FOR YOU TO WARN US OF THE LATTER AND ENCOURAGE THE
FORMER. SO THIS IS AN EFFORT TO
BASICALLY UNIFY THE MANY EFFORTS ONGOING TO IDENTIFY
ACTIONABLE GENETIC VAERNS AND I'LL EXPLAIN WHAT WE
MEAN BY THAT. WE RECOGNIZE THE GENOMIC
STUDIES ARE IPCREASELY IDENTIFYING VARIANCE THAT
HAVE IMPLICATIONS FOR CLINICAL CARE.
THESE REALLY SEEM TO BE UNAVOIDABLE IN GENOMIC SCALE
RESEARCH AND ASSOCIATION STUDIES CHROMOSOMENAL
ANOMALIES AND SORT OF HIT YOU IN THE FACE, YOU CAN'T
MISS THEM. AND WE NEED TO COME UP WAY
WAY OF DEALING WITH THOSE, WHICH I THINK WE'VE DONE
NESHLELY, BUT MUCH MORE IS NEEDED.
CONSUMER TESTING ANDCLINATIONS
HAVE BEEN CHAMGD OR IGNORE IT COMPLETELY OR FIND WAYS
TO POTENTIALLY USE IT. AND SEQUENCING FOR CLINICAL
CARE IS GOING TO BE GENERATING EVEN MORE
VARIANCE THAT PEOPLE DON'T QUITE KNOW WHAT TO DO WITH.
IT'S ALSO FAIRLY CLEAR THAT, AS WE TRY TO MOVE TOWARD
IMPLEMENTATION, EVALUATION, AND HELP IT EFFECTIVE
IMPLEMENTATION, WE DO NEED SOME PARADIGM-SETTING
EXAMPLES. SO WHEN YOU RAISE THIS WITH
CHRIPGSS THEIR FIRST RESPONSE IS THIS IS I CAN'T
DEAL WITH THREE MEDICINES, EAT ALONE THAT SIZE OF A
DATA SET. AND REALLY, IF WE CAN PULL
OUT A COUPLE OF EXAMPLES THAT WILL HELP DRIVE SOME OF
THE DELIBERATIONS. IS THAT REALLY A GOOD
EXAMPLE? CAN WE DEBATE THE PROS AND
CONS OF THAT AND REALLY TAKE SOME OF THOSE PERHAPS
PERHAPS MORE STRAIGHTFORWARD? AND ALSO DEVELOP SOME OF THE
INFRASTRUCTURE FOR ACTUALLY DOING THIS IN THE CLINIC, AS
JILL HAD MENTIONED? THERE HAVE BEEN EFFORTS TO
TRY TO DO THIS OR AT LEAST RECOGNIZING THE FEED TO DO
THIS SORT OF THING FOR MANY YEARS.
THE FIRST CALL I HAVE SEEN IN PRINT COMES FROM MY
COLLEAGUE, A CONFERENCE REPORT FROM A WORKING GROUP
WITH 2004, SO IT'S NOW NEARLY EIGHT YEARS AGO.
NOTED WHEN GENETIC RESULTS ARE UNDER CONSIDERATION FOR
REPORTING THERE SHOULD BE GUIDELINES DEVELOPED AND
FOLLOWEDTO. TO OUR KNOWLEDGE, THIS HAS
NOT BEEN DONE IF LARGE PART AND A LIST OF TESTS THAT
MEET THESE CRITERIA SHOULD REVIEW.
NIHLBI UPDATED THIS, RECOMMENDING AN ADVISORY
COMMITTEE BE ESTABLISHED TO RUB EVIDENCE FOR GENETIC
RISK FACT USE AND OFFER GUIDANCE TO INSTITUTIONS IRBS
REGARDING WHEN A RESULT IS WELL UNDERSTOOD TO RETURN
RESULTS. OBLIGATION IS ANOTHER ONE OF
THOSE DIFFICULT WORDS AND PERHAPS WE MAY NOT BE ABLE
TO GO QUITE SO FAR AS IDENTIFYING THOSE AND WHICH
ONE IS OBLIMGD BECAUSE THOSE AALL SITUATIONS THAT DEPEND
SO MUCH ON LOCAL SETTINGS AND OTHER THINGS.
YOU HEARD ERIC DESCRIBE A NUMBER OF RELATED WORKSHOPS
THAT HAVE LED TO THIS. GENETIC AND HEALTH
INFORMATION TECHNOLOGY ORGANIZED FOR GREG FURROW IN
APRIL. IDENTIFIED A NEED FOR THIS
SORT OF THING. COLLOQUIUM CALLED FOR IT.
GENETIC INFORMATION CALLED FOR
IT AS WELL. NLLBI HAD A FORUM ON IT IS
IT CAME UP WITH VERY GOOD RECOMMENDATIONS FOR HOW ONE
MIGHT GO ABOUT DOING THAT. THE MEETING IF DECEMBER AND
WE ALSO HELD A DECEMBER MEETING THAT HOWARD WAS KIND
ENOUGH TO COME TO IN HIS NEW HOME IN BETHESDA TO ADDRESS
THE PROCESSES DATABASES AND OTHER RESOURCES TAMIGHT BE
NEEDED TO IDENTIFY CLINICICALLY RELEVANT
VARIANCE AND DECIDE WHAT THAT ACTION SHOULD BE AND
PROVIDE THEM FOR CONSIDERATION FOR CLINICAL
USE. SO NOT NECESSARILY THEY BE
USED BUT AT LEAST WE NARROW.UNIVERSE A BIT OF
THOSE THAT SHOULD BE CONSIDERED.
NOW, THERE ARE MANY WORDS IN THIS.
ONE THEM IS THIS TERM "ACTIONABLE."
MANY OF YOU HAVE HEARD OF CLINICAL VALIDITY A LOT OF
TIMES WE GET WELL, ISN'T THIS CLINICAL UTILITY AND
WHY JUST STICK WITH THAT TERM?
THIS REMINDS ME OF THE TASTE AGREE, LESS FILLING DEBATE
OF THE 70S AND IT MAY JUST BE TERMINOLOGY.
BUT IT MAY BE A LITTLE BIT MORE THAN THAT.
THE BEST DEFINITION I CAN FIND OF CLINICAL UTILITY
FROM THE GENTLEMAN WHO INVENTED IT CUREIE SF THE
EGAP REPORT METHODS PAPER IN 2009 AND EVIDENCE OF
IMPROVED MEASURABLE OUTCOMES AND USEFULNESS OF A GENETIC
TEST AND ADDED VALUE TO PATIENT MANAGEMENT DECISION
MAKING. SO TYPICALLY WHAT MOST ARE
EXPECTING WITH A VARIANT THAT HAS CLINICAL UTILITY IS
THERE IS A NET AND REAL BENEFIT TO A PATIENT FROM
ITS USE OVER NOT USING IT. IN GENERAL THESE KINDS OF
THINGS THEN MUST MEET A VERY BAR AND SOME SPECIALTIES
THAT'S EXPECTED TO BE FULL RANDOMIZED CHREPGAL TRIAL,
WHICH MAY NOT BE EITHER PRACTICAL NOR NECESSARY FOR
ALL VARPTS AND ALL DECISIONS TO BE MADE.
PERSPECTIVES DIFFER WIDELY ON THE OUTCOMES.
SOME OF THE SEQUENCING PERHAPS, PARTICULARLY THOSE
THAT HARVARD IS RUNNING AND THE COLLEGE OF WISCONSIN,
THERE HAS BEEN A TREMENDOUS BENEFIT TO PATIENTS.
EVEN FU CAN'T DO ANYTHING ABOUT IT, AT LEAST
KNOWING THAT THERE IS SOMETHING THAT IS WRONG AND
HAVING A NAME TO IT IS SOMETHING THAT HELPS
TREMENDOUSLY. MAKING REPRODUCTIVE
DECISIONS, OTHER THINGS.
SOME CHRIPGSS MAY NOT --CLINATIONS MAY NOT
CONSIDER THAT. SOME OF THESE VARIANTS MAY
BE VERY IMPORTANT IN ADVANCED STAGES IN PEOPLE
WITH PARTICULAR RISKS OR GIVEN FAMILY HISTORY.
MAY BE VERY UNIMPORTANT OR UNCLEAR HOW IMPORTANT THEY
ARE IN A CHILD, FOR INSTANCE OR SOMEONE WITHOUT RISK
FACTORS. MAY NEED TAILORING.
IF ONE CONSIDERS THE INFORMATION JUST TO BE
ANOTHER PIECE OF INFORMATION A CLINICIAN MAY USE IN
MAKING DIFFICULT DECISIONS ABOUT A PATIENT, ONE CAN
ARGUE THAT ISN'T MORE INFORMATION BETTER?
ON THE OTHER HAND, FU ARE NOT TALKING ABOUT A
DRAMATICALLY INVASIVE INTERSENSATION SUCH AS WHEN
YOU ARE ON A LONG PLANE FLIGHT, GET UP AND WALK
AROUND. THAT MAY BE A USEFUL THING
AND SOMETHING THAT MAY NOT REQUIRE QUITE AS MUCH
EVIDENCE AS SOMETHING ELSE. RECOGNIZING ADDRESSING
NUANCES LIKE THIS REQUIRES VERY CAREFUL CONSIDERATE AND
LOCAL DELIBERATION. THESE ARE LOCAL ISSUES.
AND GILL LIKES TO -- SOME GENETICS ARE LOCAL AND
MAKING THESE NEEDS TO BE DONE AT THE LEVEL OF THE
INSTITUTION. BUT THAT CAN BE INFORMED BY
EXPERT CONSENSUS. WHAT WE MEAN BY ACTIONABLE
AND WE'D WELCOME IPPUT ON THIS IS EVIDENCE THAT'S NOT
SUSPICION OR UTILITY -- SUFFICIENT BUT IS SUFFICIENT
TO DETERMINE HOW INFORMATION COULD BE USED IF A CLINICAL
CONTEXT. SOMEONE ELSE MAY NEED TO
DECIDE SHOULD IT BE USED AND ULTIMATELY THAT MAY BE USED.
BUT IT MAY BE AN INTERMEDIATE STAGE.
SORT OF ASKING THE QUESTION FU HAD THIS INFORMATION,
WOULD YOU USE IT AND HOW WOULD YOU USE IT?
IT MAY ALLOW CONSIDERATIONS OF THE ETHICS LAW AND POLICY
AND THE WHOLE RETURN OF RESULTS RESULTS ARENA TO BE
SCHIFFED TO THE APPROPRIATE EXPERTISE.
IT'S NOT CLEAR THAT CLINICIANS AND INSTITUTIONS
HAVE THE EXPERTISE TO BE ABLE TO MAKE THESE
DECISIONS. THERE NEEDS TO BE THOSE WITH
EXPERTISE IN THAT AREA MAKING THOSE DECISIONS.
IF THERE IS A WAY OF SEPARATING THEM OUT A LITTLE
BIT PERHAPS WORKING IN PARALLEL JUST LIKE THE BIG
JUMP, THE CHILDREN'S BOOK. YOU MAY DO A LITTLE BIT
BETTER THAN TRYING TO TACK IT ALL AT
ONCE. AND IT ALLOWS FOR CLINIXS --
CLINICIANS TO TAILOR IT. WE SEE THIS AS A SORT OF A
COMPLEX MATRIX OF MAKING DECISIONS.
WHAT IS RAILED TO CLINICAL OUTCOMES AND BESEE THAT AS
DATA RESOURCES WHICH CAESAR IS CERTAINLY GOING TO
GENERATE BUT THERE ARE OTHERS, CLIN VAR, THE EGAP
PROCESS, A WHOLE VARIETY OF DISCOVERY AND ASSOCIATION
DATABASES THAT THIS RESOURCE WOULD DEFINITELY NOT DO.
THERE IS ALSO THE QUESTION OF WHAT SHOULD BE DONE?
RETURN OF RESULTS CONSORTIUM AND EFFORTS LIKE IT WOULD
LAND ON THIS SIDE OF THE EQALINGS -- EQUATION.
AND BEHAVIORAL AND SOCIAL SCIENCES RESEARCH.
NORMATIVE RESEARCH IN DETERMINING WHAT WE BELIEVE
IS THE RIGHT THING TO DO HERE.
CAESAR SUBPROJECTS ARE ADDRESSING ETHICAL AND
PSYCHE SOCIAL SOME ISSUES. AND WE ARE TREG TO ADDRESS
THE QUESTION WHAT ARE THE OPTIONS THAT ARE AVAILABLE
AND THAT SHOULD BE EVALUATED AND THAT WOULD BE MORE WHERE
A CHILDRENITION WOULD SIT. BUT ALL OF THESE WOULD NEED
TO PROVIDE INFORMATION AND DON'T FORGET ONGOING THE
PATIENTS IN ORDER TO ACTUALLY DECIDE WHAT WILL BE
DONE WITH GIVEN INFORMATION. IT'S ALSO VERY IMPORTANT TO
ENSURE COORDINATION WITH RELATED EFFORTS.
THERE ARE A VARIETY OF THESE. PROBABLY THE OLDEST AND BEST
IS THE PGRN'S CLINICAL CONSORTIUM, WHICH IS DOING
THIS BASICALLY DRUDGING PAIR BY DRUDGING PAIR FOR
VARIANCE. AND WE WOULD HOPE WE COULD
LEARN FROM THAT PROCESS, MODEL ON IT, WHERE
APPROPRIATE, AND ABSORB THE KNOWLEDGE THAT HAS BEEN
GAINED THERE INTO ACTION. THERE IS ALSO THE CLINICAL
SEQUENCING EXPLORATORY RESEARCH EMERGE.
THE MERMG PROGRAM HAS ALREADY STARTED TO IDENTIFY
ACTIONABLE VARIANCE IN GENE TYPING STUDIES.
WE WOULD EXPECT EGAP WOULD HAVE IMPORTANT INFORMATION
TO PROVIDE, AS WITH THE F.D.A..
THE F.D.A. HAS A WEBSITE WITH OVER 100 VARIANTS LISTED
-- VARIANTS THAT ARE RELATED TO VARIOUS DRUGS.
PLUS THERE ARE OTHER GROUPS THAT ARE DOING IT.
PERSONALIZED MEDICINE CONSORTIUM HAS BEEN DOING
THIS BEFORE THE PGRN HAS. THAT ENTIRE GROUP SET ASIDE
IS LOOKING AT ACTIONABLE VARIANTS.
VANDERBILT IS DOING THIS AS WELL.
AND IN FACT, AS WE'VE HEARD AND TALKING WITH THE CENTERS,
EVERY ONE OF THEM IS DOING THIS KIND OF THING.
FOR THE MOST PART WITH THE SAME EVIDENCE, COMING
LARGELY TO THE SAME CONCLUSIONS ABOUT THE
EVIDENCE THAT'S AVAILABLE. BUT DECIDING DIFFERENTLY IN
TERMS OF HOW AND WHEN TO IMPLEMENT.
WOULDN'T IT BE WONDERFUL IF THERE WERE A WAY TO ACTUALLY
BRING THOSE TOGETHER? AND RECOGNIZING THAT THEY
ALL STILL EXIST AND NEED TO EXIST, CAN WE THEN BUILD ON
THEM, FEEDBACK SOME OF THE KNOWLEDGE THAT WE'VE GAINED
FROM THOSE EFFORTS SO THAT THEY CAN BASICALLY NOT HAVE
TO DUPLICATE WHAT EACH OF THEM IS DOING?
SO THE PROPOSAL HERE IS TO SUPPORT ACTIONABLE GENETIC
VARIANTS IN CLINICAL CARE TO IDENTIFY VARIANTS WITH
IMPLICATIONS FOR CLINICAL CARE, COLLECT THE EVIDENCE
AND DISSEMINATE IT RATHER THAN HAVING TO SEND A
GRADUATE STUDENT TO PULL YOU ALL THE EVIDENCE AVAILABLE.
DEVELOP SUPPORT SYSTEMS FOR INCORPORATING THESE INTO
CLINICAL CARE. BUILD UPON CLINICAL PROGRAMS
AND REDUCE DUPE CATIVE EFFORTS ACROSS ORGANIZATIONS.
THE SCOPE WE WOULD ANTICIPATE WOULD BE A SINGLE
AWARDEE TO COLLECT AND EVALUATE THE RELEVANCE WITH
TRAITS AND OBVIOUSLY ALL OF THOSE WOULD NEED TO BE
DEFINED. THIS IS JUST A CONCEPT AT
THIS LEVEL. WE WOULD ANTICIPATE A
MULTICOMPONENT APPROACH. PROBABLY THE TOUGHEST IS
GOING TO BE THE SEG, THE ONSENSUS GET.
. I DON'T THINK WE WOULD BE IN
A POSITION AT NHGRI TO SUPPORT SCREENING
RECOMMENDATIONS, RATHER PROVIDING THE EVIDENCE ON
WHICH THOSE RECOMMENDATIONS CAN BE MADE.
AND NHGRI IS RELATIVELY IN A GOOD POSITION BECAUSE WE ARE
NOT DISEASE-SPECIFIC. SO WE CAN ADDRESS THESE
ACROSS A VARIETY OF DISEASES AND A VARIETY OF INSTITUTES.
MANY OF WHOM I CAN TELL YOU ARE THRILLED THAT NHGRI IS
WELLING TO TRY TO TACKLE THIS PROBLEM AND ARE EAGER
TO COLLABORATE. THE QUESTION IS NOT WHETHER
CLINICIANS SHOULD BE ADVISED TO ORDER A PARTICULAR ASSAY
OR WHAT COULD BE CONSIDERED, RECOGNIZING THAT THIS IS
HAPPENING IN EVERY CLINIC BUT IS COMING AND SOMETHING
THAT WE NEED TO BE PREPARED FOR?
SO INTEGRATION PROCESS COULD WORK BY INVITING EXISTING
GROUPS THAT ARE ALREADY DOING THIS KINE OF WORK TO
JOAN OR TO INTERACT WITH THE RESOURCE, DEVELOPING A
FRAMEWORK FOR REVIEW AND EVALUATION.
GATHERING FROM ALL OF THESE DIFFERENT GROUPS THAT ARE
DOING THIS, HOW DO YOU GO ABOUT DOING THIS?
HOW DO YOU GO ABOUT COLLECTING IT AND REALLY
HELP CODIFYING THAT, NOT IN -- IN A WAY THAT KEEPS
OTHERS FROM HAVING TO BASICALLY REINVENT THE WHEEL.
PERHAPS THE DOMAIN TO GROUPS FOR EVALUATIONS.
WOULDN'T IT BE COOL IF WE COULD DIVIDE UP SOME OF
THESE? NOT EVERYBODY HAS TO LOOK AT
IT BUT SOME COULD LOOK AT VARIANTS IN ONE AREA AND
SOME IN ANOTHER. APPLYING THE FRAMEWORK AND
REACHING CONSENSUS ON VARIOUS ACTIONS COULD BE
RECOMMENDED. AND CHOOSING PEOPLE TO BE
PART OF THIS THAT ARE CONSENSUS BUILDERS BUT
RECOGNIZING THAT SOMETIMES DELIBERATIONS CAN'T BE
BROUGHT TO A CENSUS. BUT IT WOULD BE IMPORTANT TO
ADDRESS THAT AND TO MAKE IT CLEAR WHETHER THERE WAS NOT
A CONSENSUS AND WHY NOT. OBTAKEN INPUT FROM A VARIETY
OF STAKE HOLDERS, PROFESSIONAL ORGANIZATIONS,
PATIENTS, ON DRAFT RECOMMENDATIONS, AND
ENSURING CONSIST-EY OF DOMAIN-SPECIFIC
RECOMMENDATIONS WITH THE FRAMEWORK.
IF WE SET OUT A FRAMEWORK CRITERIA AND GUIDANCE THAT
NHI CALLED FOR MAKING SURE THAT IS CONSISTENT.
ONE COULD CONSIDER THESE DIFFERENT GROUPS AS PERHAPS
TAKING A GIVEN AREA. IT MIGHT MAKE PEST SENSE TO
CONTINUE TO FOCUS ON IT. MAY BE THERE WOULD BE ONE
GROUP THAT HAD A G.I. CLINIC THAT WAS INTERESTED IF THAT
BECAUSE THEY HAD A CHAMPION IN THAT AREA OR MAYBE THE
RHEUMATOLOGIST OR THE EITHER PEDIST.
MAYBE BUN GROUP WOULD WANT TO ATTACK A SINGLE DISEASE
OR MIGHT WANT TO CUT THE PIE IN DIFFERENT WAYS.
JUST LOOK AT THOSE THAT ARE IMPORTANT IN ASIAN PACIFIC
ISLANDERS OR PORP IN HISPANIC LATINOS OR IN THE MILITARY.
WHATEVER IT MIGHT BE. THERE COULD BE A WAY OF
DIVIDING UP THIS WORK RATHER THAN DUPLICATING IT.
THE DISMISS SUPPORT SEEMS MUCH MORE STRAIGHTFORWARD
AFTER CONSIDERING THE CONSENSUS BUT THIS IS A
CHALLENGING AREA AS WELL. IT WOULD BE IMPORTANT TO
PROVIDE DOCUMENTATION OF THE CONSENSUS PROCESS, AND THEN
TO DEVELOP AND DISTRIBUTE CLINICAL DECISION SUPPORT
RULES, WHICH WOULD BE KIND OF A DESCRIPTION OF WHAT ONE
WOULD DO IN C.D.S WITHOUT HAVING SPECIFIC SOFTWARE
PROGRAMS OR THE TOOLS SPECIFIC SOFTWARE FOR
ADOPTION IN THE EMRS AND OTHER CLINICAL SYSTEMS.
IT WOULD BE GREAT IF WE COULD FIND FOOLS AND
DISTRIBUTE THEM TO OTHER HEALTH SYSTEMS, ESPECIALLY
NON-U.S. SYSTEMS. THE WORKSHOP WE HELD WAS
CO-SPONSORED BY THE WEALTH AND TRUST.
THEIR RECORDS ARE QUITE DIFFERENT FROM OURS.
ANTICIPATED FUNDING WOULD BE TWO MILLION IN FISCAL 13 AND
WE WOULD ANTICIPATE FOUR MILLION FOR THE FOLLOWING
THREE YEARS. WE WOULD HOPE TWO TO THREE
DOMAINS COULD BE TACKLED IN THE FIRST YEAR AND PERHAPS
FIVE TO EIGHT DOMAINS AFTER THAT ANNUALLY WE WOULD
CONSIDER A CONTINUATION AND IF THE RESOURCE WAS
INCREASINGLY USED MIGHT RECONSIDER THAT THREE TO
FIVE YEARS. THIS WOULD USE COOP RATIB
AGREEMENT AND SEEK SUPPORT AND ENTHUSIASM FROM OTHER
ICS. AND AGAIN, THANKS TO THE
SHALL THOSE WHO PARTICIPATED IN THE WORK SHOP AND
PLANNING GROUP MARK AND ESPECIALLY RAMOS, WHO WOULD
BE PREPPING THIS, WERE IT NOT FOR AN INITIATIVE OF HER
OWN, WHO HAPPENS TO BE IN THE BACK.
HOLDING HER INITIATIVE. SO I THINK WITH THAT, I'LL
BE HAPPY TO TAKE ANY QUESTIONS.
>> AS YOU GET TOWARDS SPECIFIC VARIANCE, ARE
MALPRACTICE LAWYERS GOING TO BE DROOLING AT THIS?
IF IT'S CLINICAL CARE, YOU GET SUED FOR NOT DOING IT
BUT IF IT'S RESEARCH, YOU GET SUED.
MY FEAR IS WE ARE ALREADY -- >> DROOLING.
SOMETHING WILL BE COMING OUT OF THEIR MOUTHS.
>> I THINK THEY DROOL, TOO. >> THEY DO ALL OF THAT.
AND ONE OF THE BIG BARRIERS IS THAT CLINICIANS ARE
SAYING I DON'T KNOW -- I DON'T WANT TO HAVE THESE
RESULTS BECAUSE I HAVE TO ACT ON THEM.
ONE OF THE THINGS DISCUSSED AND HOWARD AND REX AND JIM
KNOW IS WE WILL ONLY PULL OUT A FEW OF THOSE VARIANTS
AND WILL KEEP THE RESULTS IN SOME DATABASE AND THE
CLINICAL DECISION SUPPORT WILL ONLY
PULL OUT THOSE THINGS WE AGREE WITH RELEVANT AND
APPROPRIATE. SO THE CLINICIAN MAY NEVER
SEE THE 500,000 RESULTS BUT THEY WILL SEE THE
INSTITUTION AGREE. WOULD THAT ADDRESS THAT
CONCERN? >> YOU ALSO WENT THROUGH HOW
THIS IS LOCAL. EVERYTHING IS LOCAL.
WE ALL KNOW FU HAVE A SODIUM OF 150, YOU SHOULD DO
SOMETHING. BUT FU HAVE THIS VARIANT,
WHERE DOES THAT FILTER OUT? >> IT'S A GOOD POINT AND I
THINK ONE OF THE CHALLENGES HERE IS GOING TO BE
INSTITUTIONS FIGURING OUT WHERE THEY HAVE FLEXIBILITY
OR WHERE THE EVIDENCE IS SO STRONG AND HOWARD CAN SAY
THIS BETTER THAN I THAT THEY DON'T HAVE A CHOICE AND THEY
NEED TO PURSUE IT. >> WE ALREADY HAVE THAT
SITUATION WITH THE CHANGES. AND MANY OF US ARE GETTING
CALLS BY LITIGATION ATTORNEYS SAYING HEY, WE
HAVE ASIAN PATIENTS WHO GOT THE SYNDROME AND CHANGE
THREE YEARS AGO, LET'S GO. SO THAT SORT OF THING IS
ALREADY OUT THERE IN A WAY. WITH FORM COGENETICS BEING A
COMPONENT OF THAT. SOMEONE MIGHT BRING SOME
CLARITY TO THAT. I HOPE THAT IT WOULD REMAIN
VISIBLE TO THE PEOPLE. >> I THINK, PEARL, YOUR
POINT IS ACTUALLY A VERY IMPORTANT DRIVER OF THIS.
I THINK THIS IS A VERY IMPORTANT INITIATIVE BECAUSE
IT CUTS ACROSS THE ENTIRE RANGE OF COMMUNITIES THAT
ARE CONCERNED WITH WHOLE EXON AND GENOME SEQUENCES
WHETHER YOU ARE CONCERNED WITH THE LEGAL ASPECT.
THERE HAS TO BE SOME KIND OF SNARL GUIDANCE ABOUT THE
THINGS THAT SHOULD BE CONSIDERED.
AND I THINK YOU'RE RIGHT TO BRING UP THE TERM LIKE YOU
DID ON ONE OF YOUR SLIDES OBLIGED.
I'M SURE IT WOULD BE PROMULGATED AS HERE IS THE
FINAL ENDALL AND BEALL LIST, BUT IT WILL INFORM THE
RESPONSIBILITIES THAT EVERYBODY HAS DOING THIS AND
IT WILL MAKE THEIR LIFE EASIER BECAUSE ALL THE LOCAL
GROUPS CAN USE THAT AS A STARTING POINT.
>> GREAT. REX AND THEN MIKE?
>> AND I THINK YOU MIGHT THINK OF THIS IN THE SAME
WAY YOU THINK OF HOW CLINICAL STANDARDS RECOMMENDATIONS
GET MADE ALL ALONG. THEY TYPICALLY ARE MADE BY
DOMAIN EXPERTS AND EXPERTS PUBLISH THEM AND WHAT
HAPPENS IS EACH LOCAL SITE THERE IS A CLINICAL
IMPLEMENTATION OR QUALITY IMPROVEMENT GROUP THAT
REVIEWS THEM AND DECIDES WHETHER OR NOT THEY'RE GOING
TO INCLUDE THEM IN THEIR CLINICAL PRACTICE GUIDELINES
AT THAT LOCAL SITE AND SO ULTIMATELY IT'S BEEN THROUGH
A VARIETY OF LEVELS OF EXPERT CLINICAL DECISION
MAKING AND I THINK THE KEY FOR US TO THINK ABOUT IS
THAT THIS IS SIMPLY -- I AM UNDERSTATING -- BUT SORT OF
A DATABASE IN WHICH THAT KIND OF INFORMATION CAN BE
HELD AND DISSEMINATED AND LOCAL PLACES CAN FILTER IT
HOWEVER THEY WANT TO. >> MIKE?
>> TWO VERY NAIVE QUESTIONS BUT ONE IS HOW MANY
ACTIONABLE VARIANTS ARE THERE RIGHT NOW?
AND TWO, WILL WHATEVER GROUP THIS IS BE VIEWED IN THE
FIELD AS HAVING SUFFICIENT STANDING THAT ALL THESE
DIFFERENT GROUPS WHO ARE DOING THIS WILL ACTUALLY PAY
ATTENTION TO WHAT THIS GROUP SAYS?
>> YEAH. GOOD POINTS.
THE FIRST. THERE ARE DEBATES AND I
HEARD THIS DEBATED AT HOWARD.
SOMEWHERE LESS THAN A DOZEN IS WHAT I HAVE HEARD, BUT
WOULD YOU CARE TO OPINE? >> ABOUT A DOZEN FOR THE
THINGS THAT YOU WOULD ACT ON RIGHT NOW.
BUT THE PUBLIC LEVEL WE HAVE A LITTLE BIT LARGER NUMBER
BECAUSE THERE YOU ARE CHOOSING AMONGST A MENU OF
AVAILABLE DRUGS FOR POPULATION.
SO IT'S A LITTLE BIT DIFFERENT DWE.
YOU WOULD INCLUDE -- INCLUDE SOME DISEASE ASPECTS AND
THINGS LIKE THAT WHERE THERE IS SPECIFIC DATA.
>> YEAH. I CAN GIVE YOU A PRECISE
NUMBER. SO IN GOING THROUGH OMAM AND
LOOKING AT EVERY GENE, OUR GROUP CAME UP WITH 161
CANDIDATES WHERE THERE SEEM TO BE REASONABLE EVIDENCE
THAT KNOWLEDGE OF THIS WOULD TRIGGER SPECIFIC
RECOMMENDATIONS. NOW, 161 GENES AND THIS IS
GENE-BASED AND THAT IS THE IMPORTANT POINT.
GENES ARE FINEITE, WHERE AS VARIANTS ARE INFINITE,
RIGHT? MANY OF THOSE COLLAPSE INTO
THE SAME CONDITION. SO FOR EXAMPLE, THERE ARE.
THOSE THAT ARE PREDISPOSED TO SAY ANEURYSMS WHERE THERE
IS CLEAR RECOMMENDATIONS THAT YOU SHOULD GET ECHOS,
ET CETERA. SO I AM NOT BY ANY MEANS BY
COMING UP WITH A NUMBER -- I DO THAT A BIT TONGUE AND
CHEEK -- TRYING TO SAY END OF STORY SO YOU DON'T NEED
THOSE. THE POINT IS THAT IT'S A
MANAGEABLE NUMBER AND THEN YOU CAN DEBATE.
SO WE HAD A LONG CONFERENCE CALL WITH THE UNIVERSITY OF
WASHINGTON PEOPLE BECAUSE I AM ON THEIR COMMITTEE FOR
DECIDING THESE KINDS OF THINGS AND THERE WAS A LOT
OF CONSENSUS AND AGREEMENT FROM MOST OF THOSE AND THEN
WE FARMED OUT TO VARIOUS PEOPLE ON THAT CALL.
LET'S LOOK CLOSELY AT MATURITY, UNFIT DIABETES AND
THE YOUNG. THAT WOULD BE SOMETHING YOU
WOULD BE OBLIGATED TO REPORT.
BUT IT'S A TRACTABLE NUMBER OF GENES.
>> I WONDER -- I THINK THIS IS A SUPER IMPORTANT AREA,
BUT GIVEN THE NUMBER OF GROUPS THAT ARE CURRENTLY
WORKING ON THIS IN VARIOUS CONTEXTS, I WONDER IF THIS
WOULD BE AN RFA FOR A NEW INITIATEIVE OR CONCEPTULIZE
MORE OF A COORDINATION EFFORT TO GET THE PEOPLE IN
THE ROOM TO KIND OF HATCH IF OUT AND SAY THESE ARE OUR
METHODS AND THIS IS WHAT WE FOUND AND WEIBE DONE THIS
AND THESE WERE OUR METHODS AND HAVE A CONVERSATION
ABOUT IT? IT SEEMS LIKE YOU ARE GOING
TO HAVE ONE MORE OF MANY. >> ABSOLUTELY.
YEAH SO THAT'S WHY THE GOAL IS REALLY TO GATHER THOSE
EFFORTS TOGETHER. REALLY THAT'S THE
ANTICIPATION IS THAT THIS GROUP WOULD BE THE ONE THAT
WOULD BE THE CONVENE AND/OR BRING THEM TOGETHER AND
THAT'S NOT GOING TO BE AN EASY THING TO DO.
WHY WOULD THIS GROUP BE VIEWED AS BEING THE BODY
THAT DECIDES ON THESE? AND WHAT WE WOULD WANT TO DO
WOULD BE TO HAVE THEM -- AND AGAIN MAYBE INTO THE DETAILS
-- SO I DON'T WANT TO GO TOO FAR DOWN THAT PATH MANY BUT
IT MAY MAKE SENSE TO CONTACT THE ORGANIZATIONS THAT ARE
ALREADY DOING THIS AND SAY WHAT IS IT WOULD IT BE FOR
YOU TO BE HAPPY THAT THIS IS A GROUP THAT YOU COULD
FOLLOW OR THAT SORT OF THING?
I AM AFRAID I CAN'T GIVE YOU SPECIFICALLY HOW ANY
PARTICULAR APPLICANT WOULD CHOOSE TO ADDRESS THAT.
I AGREE COMPLETELY WHAT THIS IS A CONVENING FUNCTION.
IT'S NOT JUST ANOTHER ONE OF THESE.
>> IT SEEMS LIKE -- THIS IS REALLY, REALLY IMPORTANT.
I'D LOVE TO SEE THIS AP. I DON'T KNOW -- I DON'T SEE
HOW IT WORKS AS AN RFA AND I'M REPEATING WHAT THE LAST
TWO QUESTIONERS BROUGHT UP. THIS IS A VERY IMPORTANT
INITIATIVE, BUT IS IT SOMETHING WHERE YOU NEED TO
ASK FOR RESEARCH APPLICATION RATHER THAN SOMEHOW
FACILITATING -- IT'S PRETTY OBVIOUS WHAT NEEDS TO
HAPPEN. YOU NEED TO GET PEOPLE
TOGETHER TO MAKE DECISIONS ON THE 161 OR WHATEVER THE
NUMBER IS. >> THIS WOULD BE TAI
RESOURCE APPLICATION AND WE FUND A NUMBER OF RESOURCES.
SO I THINK FROM THAT FIF, -- POINT OF VIEW THE RESEARCH
ASPECTS ARE LESSER THAN THEY WOULD BE IN TERMS OF A
REGULAR RESEARCH GRANT. ON THE OTHER HAND, WITHOUT
THIS KIND OF GLUE AND THIS IS NOT A HUGE AMOUNT OF GLUE,
OUR EFFORTS ARE STYMIED. AND ONE OF THE THINGS WE'D
LIKE TO DO IS FIND WHERE THE OBSTACLES ARE AND DEAL WITH
THEM AND THIS SEEMS TO BE A WAY OF DOING THAT.
YES? >> I GIS I DON'T WAP TO
REPEAT THE CONCERN BUT I HAVE THE SAME ONES.
THAT IT'S A GNARLY SET OF ISSUES THAT WE ALL THINK ARE
REALLY IMPORTANT AND MY CONCERN IS THAT FU CALL
FOR A SINGLE GRANTEE PROPOSAL WITH A REALLY
GNARLY SET OF ISSUES, THAT NO ONE GROUP WILL ACTUALLY
BE ABLE TO ACHIEVE THE CONSENSUS THAT YOU WANT
BECAUSE THE UNFUNDED GROUPS WILL STILL THINK THEY HAVE A
BETTER ANSWER THAN THE FUNDED GROUP.
AND I AM NOT SURE FOR THIS SET OF ISSUES THAT A SINGLE
AWARDEE IN A RAPIDLY CHANGING AREA WHERE THERE IS
A DIVERSITY OF OPINIONS AND THE ISSUES ARE VIEWED BY
EVERYBODY AS INCREDIBLY IMPORTANT IS GOING TO
ACHIEVE THE GOALS THAT YOU WANT TO ACHIEVE.
>> NO. AND I AGREE.
IT'S AN IMPORTANT CONSIDERATION.
WE HAD A SIMILAR SORT OF SITUATION WHEN WE WERE
TRYING TO DEFINE PHENOTIPIC MEASURES AND OTHER GENETIC
STUDIES. AND THE SAME KINDS OF ISSUES
CAME UP IN TERMS OF WELL, WHO ARE WE TO TELL PEOPLE
WHAT THE PHENOTYPE SHOULD BE, AND THE PHOENIX PROJECT, HAS
ACTUALLY BEEN REMARKABLY SUCCESSFUL IN IDENTIFYING
THOSE WHO ARE MOST KPID TO A GIVEN DOMAIN, A GIVEN AREA
WOHAVE PHENO TYPIC MEASURES THAT NEED TO BE CONSIDERED.
AND REALLY BRINGING THEM INTO THE CONVERSATION AND I
THINK WE WOULD EXPECT AN APPLICANT TO DO THE SAME
SORT OF THING HERE. WHETHER THIS IS EXACTLY THE
MODEL THAT WILL BE DONE. BECAUSE THIS IS A CONCEPT
AND WE WOULD RELY ON APPLICANTS TO PROPOSE THEIR
APPROACH AND THEY MAY CHOOSE A DIFFERENT APPROACH FROM
THE ONE THAT I'VE DESCRIBED OR THAT YOU HAVE DESCRIBED.
I DON'T THINK WE ARE -- I THINK FU HAVE
SUGGESTIONS THAT ARE AT THE CONCEPT LEVEL RATHER THAN AT
THE APPLICATION LEVEL AS TO WHAT ELSE MIGHT BE
CONSIDERED, THAT WOULD BE VERY HELPFUL TO HAVE.
>> BUT I THINK PEOPLE ARE TRYING TO MAKE SUGGESTIONS
AT THE CONCEPT LEVEL AND NOT THE INDICATION LEVEL.
THEY ARE SUGGESTING THIS CONCEPT WILL DRAW THE WRONG
KIND OF APPLICATION. I THINK THESE POINTS ARE
REALLY GOOD. I GUESS TO ME THE STRENGTH
OF THIS IS THAT IF IT IS KOUCHED VERY MUCH IN TERMS
OF -- COUCHED NEPS OF TRYING TO BRING IN THE VERY EFFORTS
IS IT GET THEIR INPUT AND MAKE THEM PART OF THE
PROCESS, WITHOUT THIS, WOULD I -- WHAT I WORRY ABOUT IS
THAT YOU'VE GOT THE UNIVERSITY OF WASHINGTON,
THE UNIVERSITY OF NORTH CAROLINA AND YOU'VE GOT
CAESAR AND THESE OTHER THINGS THASH ALL GOING TO
KIND OF COME UP WITH SIMILAR OVERLAPPING LISTS WITH USING
SIMILAR BUT NOT QUITE THE SAME CRITERIA.
AND THE FIELD WILL BE LEFT WITH INSUFFICIENT GENS,
WHERE AS IF THIS IS DONE RIGHT, ONE COULD --
GUIDANCE. HERE IS A REASONABLE
TEMPLATE THAT TOOK INTO ACCOUNT MANY DIFFERENT
APPROACHES AND HERE IS A LIST NOW GO TO IT AND APPLY
IT LOCALLY, ET CETERA. I GUESS THAT WOULD BE MY
DEFENSE OF THIS KIND OF IDEA.
ALTHOUGH YOUR POINTS ARE I THINK REALLY WELL TAKEN.
>> YES. >> SO THERE IS A NEED FOR
THIS. WHAT I CAN'T THINK OF THE AT
THE MOMENT IS WHO ELSE WILL DO IT.
EVEN THERE ARE A BUNCH OF WARTS ON THIS THING OR IT'S
GNARLY -- I ALWAYS USE GNARLY IN THE CONTEXT OF
SURFING -- SO IT DOES HAVE THAT.
SOMEHOW WE NEED TO COME UP WITH SOME APPROACH TO
FORWARD. IN THE ABSENCE OF ANOTHER
BETTER BODY TO DO THIS, WE NEED -- TO DO IT AND I LOVE
-- IF WE HAD AN ADMINISTRATIVE MINISTRY OF
HEALTH, THEY WOULD HAVE DONE IT.
WE DON'T HAVE ONE, SO WE'RE STUCK.
IF THE NIH CAN'T DO IT AS A WHOLE -- I GUESS I LOOK AT
IT AS THERE IS A NEED, AND IF NO ONE ELSE IS GOING TO
STEP UP, THEN WHY NOT NHGRI? >> ARE ANY OTHER NIH
INSTITUTES DOING THIS FOR THEIR OWN DISEASES?
>> THEY'VE HAD A COUPLE OF WORKSHOPS AND NCI IS VERY
INTERESTED AND PGRN. AND
>> THEY ACTUALLY HAVE PAYING FOR A FAIR AMOUNT OF EFFORT
AND PRODUCING THIS EVIDENCE. BUT YOU CAN'T HAVE -- I
DON'T THINK WE WANT FIVE OR SIX DIFFERENT GROUPS DOING
THIS. >> JUST TO CLARIFY, I AM NOT
SAYING THAT NHGRI SHOULDN'T DO IT AND I THINK WE ALL
AGREE IT NEEDS TO BE DONE. SOME OF US ARE HAVING
TROUBLE SEEING HOW FUNDING ONE GROUP COULD DO THIS IS
GOING TO ACCOMPLISH THE GOALS.
AND -- >> SO I WOULD SUGGEST A WAY
TO THINK ABOUT IT IS THIS IS THE RECORDER.
THIS IS NOT NECESSARILY THE DECIDER.
THEY ARE GOING TO TAKE THE EVIDENCE THAT FROM WHEREVER
THE EVIDENCE CAN COME FROM. A PLACE WHERE THE EVIDENCE
GETS RORED FOR WHATEVER IS AVAILABLE, IT WOULD BE MOST
LIKELY TO BE SUCCESSFUL. SO THAT ANYBODY ELSE CAN GO
TO THAT RESOURCE AND SEE WHAT VARIANTS ARE OUT THERE,
WHAT GENES HAVE BEEN IDENTIFIED AS IMPORTANT IN
PRODUCING DISEASE OR IN PRODUCING A SUCCESSFUL
THERAPEUTIC OUTCOME FROM A DRUG OR AN ADVERSE EVENT FOR
THAT MATTER. TO THE EXCEPT THERE IS SPLIM
SIMPLY A REPOSITORY FOR THAT INFORMATION -- BUT --
[INDISCERNABLE] THAT PUSHES SOME BUTTONS.
I THINK IT SHOULD BE THOUGHT OF THAT WAY, MAYBE AND THAT
MAY HELP YOU. >> SURE, THAT WOULD BE
REALLY GREAT AND IT BRINGS TOGETHER MANY EFFORTS THAT
ARE ONGOING. I WAS HEARING, THOUGH, THAT
THIS IS GOING -- WHOEVER GETS FUNED IS GOING TO COME
UP WITH THE LIST OF ACTIONABLE VARIANTS.
AND I AM JUST NOT HEARING -- I CAN'T SEE HOW THAT LATTER
THING IS GOING TO HAPPEN. BUT IT REALLY NEEDS TO
HAPPEN. >> HOW SHOULD IT HAPPEN
OTHERWISE THEN? >> A CONFERENCE OR SOMETHING?
>> YOU NEED GLUE MONEY. AND FUNDING ONE GROUP OUT OF
FIB OR SIX WHO WANT IT IS NOT GLUE.
IT DRIVES THEM APART AND I DON'T KNOW A CONFERENCE
WHERE YOU CAN'T LEAVE UNTIL YOU'VE DECIDED?
[LAUGHTER] >> I STRONGLY SUPPORT THE
IDEA OF A DATABASE WITH SUPPORTING EVIDENCE FOR
VARIANTS THAT THE MALLEABLE OVERTIME THAT SOMEBODY KEEPS
UP. I THINK THAT'S A REALLY,
REALLY GOOD CONCEPT FOR THIS.
I AGREE THAT -- I DON'T THINK IT'S APPROPRIATE FOR
NIH TO SET CLINICAL STANDARDS.
I THINK THAT'S THE ROLE OF PROFESSIONAL SOCIETY TO PUT
FORTH WHAT THE CLINICAL STANDARDS OUGHT TO BE.
SO TO COME UP WITH A DEFINITIVE LIST I WOULD ECHO
PEARL'S CONCERNS ABOUT THAT SET STANDARD OF CARE THAT
HAS LEGAL IMPLICATIONS AND I WOULD FROM A CONCEPT
PERSPECTIVE, I WOULD SHY AWAY FROM THAT MORE TOWARDS
SORT OF A DATABASE OF WAWE THINK OF OVER TIME AS
CLINICALLY ACTIONABLE VARIANTS AND THE EVIDENCE TO
SUPPORT THAT AS IT BUILDS OR.
>> THIS IS THE UNIVERSE OF WHAT YOU MIGHT DO.
BUT IT'S NOT JIM'S LIST OF HERE IS WHAT WE'RE GOING TO
IMPLEMENT AT UNC. IS THAT FAIR?
>> YEAH, TO ME. ONE THING THAT I THINK IT
SOUNDS TRIVIAL BUT I THINK IT'S A REALLY IMPORTANT
POINT OF I THINK IT'S CRITICAL
TO NOT GET BURIED IN THE ISSUE OF VARIANTS FIRST.
WHAT YOU FIRST HAVE TO ADDRESS ARE WHAT ARE THE
GENES IN WHICH, FU HAVE A DELETERIOUS MUTATION, THAT
IT IS -- THERE IS A GENERAL CONSENSUS THAT SOMETHING IS
ADVISABLE THAT YOU DO, RIGHT?
THAT HAS TO BE THE FIRST QUESTION AND I WOULD NOT
CONFLATE THIS WITH THE ISSUE OF VARIANCE THAT IS THAT IS
A TRULY INTRACTABLE PROBLEM AT REPRESENT.
WHERE AS COMING UP WITH GENE LISTS IS INTRACTABLE AND I
LIKE THE IDEA OF THIS BEING A RECORDING-TYPE THING WHERE
THIS EFFORT COULD SAY HERE ARE THE VARIOUS LISTS THAT
HAVE BEEN ARRIVED AT BY USING THESE KINDS OF
CRITERIA, ET CETERA. >> AND HERE IS THE OVERLAP,
RIGHT? >> YEAH, OR THE PROCESSS BY
WHICH YOU DECIDE ON VARIANTS, RIGHT?
>> SO EVEN THE GENES PART, JIM, SEEMED LIKE IT IS A LOT
OF -- THERE IS SOME ROOM FOR SUBJECTIST OR ARE PEOPLE
CHOOSING THEIR FAVORITES OR YEAH, AND SO WHAT DO YOU
REALLY MEAN BY ACTIONABLE? >> SO WHAT I NOTICED IS
THERE IS TREMENDOUS AGREEMENT WHEN JUST
INFORMALLY WHEN I TALK ABOUT THIS ON A WHOLE VARIETY OF
GENES. I THINK I'VE NEVER YET RUN
INTO SOMEBODY WHO DOESN'T FEEL LEC A LYMPH ASSOCIATED
GENE WOULD NOT BE ON THIS LIST.
ON THE OTHER HAND, THERE ALWAYS ARE A HANDFUL OF
RATHER PREDICTABLE ONES THAT THERE IS SOME DEBATE ABOUT.
YOU ARE ALWAYS GOING TO HAVE THIS DEBATE.
AND TO ME, A SIMILAR EFFORT, BUT ONE THAT HAS TRACTION
HAS BEEN ABLE TO HAVE BEEN APPLIED TO IS NEWBORN
SCREENING. NOT EVERYBODY AGREES ON
WHETHER CRAB A DISEASE SHOULD BE A CAPPEDAT.
BUT FOR MOST DISORDERS, MOST PEOPLE CAN AGREE ON A CORE
SET. AND THEN STATES ARE FREE TO
SWALE, WE THINK WE SHOULD DO CRAB K, WHATEVER.
I THINK THIS IS A VERY SIMILAR KIND OF THING.
AND I AM VERY COGNIZANT OF THE PROBLEMS WITH THIS, BUT
I FEEL LIKE KIND OF LIKE HOWARD SAID, SOMEBODY'S GOT
TO DO IT AND STEP UP AND SAY THIS IS HOW WE'RE GOING TO
-- THIS IS THE LIST THAT THERE SEEMS TO BE SOME
AGREEMENT ON AND HERE ARE ONES THAT SEEM TO BE CLOSE
CALLS AND. >> THE FRAMEWORK.
WE DON'T EVEN HAVE A FRAMEWORK.
>> THE FRAMEWORK'S CRITICAL. >> IT REMINDS ME A LITTLE BIT
OF THE DRUGABLE TARGETS THAT
FARMA HAS BEEN TALKING ABOUT FOR 20 YEARS AND THAT'S
LIMITING PROBABLY HAS BEEN LIMITING.
SO ONE OF THE QUESTIONS IS -- I THINK FU DO
ANYTHING HERE THAT WORKS, IT'S GOOD.
IT DOESN'T HAVE TO COVER EVERY ACTIONABLE ONES.
THAT STRIKES -- HOW DO YOU KNOW THAT A LOSS OF FUNCTION
OR A DOWNREGULATION OR SOMETHING OF GENE -- USUALLY
YOU KNOW THAT MOUSE MODEL BUT YOU ALSO KNOW FROM --
>> ACTUALLY, AND AGAIN THIS GETS INTO THE VARIANCE AND
THAT'S FAIRLY STRAIGHTFORWARD BECAUSE
WE'RE TALKING HERE ABOUT REALLY INCIDENTAL RESULTS.
WE'RE TALKING ABOUT RESULTS THAT BUBBLE UP WHEN THERE IS
A LOW A PRIORITY RISK, THAT THAT VEGE ACTUALLY HAS THIS
DISEASE AND THEREFORE, YOU SET A VERY HIGH BAR FOR WHAT
KIND OF VARIANT YOU ARE GOING TO CAUSE BECAUSE WHAT
YOU HAVE TO AVOID AT ALL COSTS IN A SITUATION LIKE
THIS ARE AN INFINITE NUMBER OF FALSE POSITIVES.
SO YOU SET A REAL HIGH BAR AND THAT'S APPROPRIATE
BECAUSE THE A PRIORITY PROBABILITY THAT SOMEBODY
HAS LYNCH SYNDROME IS LOW. THEREFORE, YOU SAY ONLY
EITHER FRAME SHIFT MUTATIONS OR MUTATIONS THAT HAVE BEEN
REPORTED AND CONFIRMED TO BE DELETERIOUS.
>> REALLY ONLY FOR RARE DISEASE, AM I UNDERSTANDING?
IT'S NOT. >> NO.
>> ON THE LIST THAT YOU HAVE GOT TO DECIDE AND THIS IS
ONE OF THOSE ONES THAT PEOPLE, ARGUE ABOUT.
A LITTLE WILL BE SOMETHING LIKE HEM CHROMATOSIS.
YOU GOT TO MAKE THESE CALLS AND THEN -- ONE OF THE MAYBE
IN THIS RFA YOU COULD PROPOSE THAT PEOPLE TRY TO
GENERATE EVIDENCE THAT WOULD ADDRESS SOME OF THE MORE
CONTENTIOUS. >> THIS MAY NOT BE BIG
ENOUGH TO BE ABLE TO DO THAT AND BEING A RESOURCE, IT'S
LIKELY TO BE THE SORT OF THING THAT THAT GROUP
WOULDN'T DO. I THINK THAT WOULD BE
TREMENDOUSLY HELPFUL FOR THEM TO SAY WE REALLY NEED
MORE EVIDENCE ON X, Y, Z. >> THE COMMUNITY SHOULD GO
AT IT AND TRY TO FIGURE OUT WHAT'S THE DOCTOR
>> AND WE CAN HELP FACILITATE THAT IF WE'RE AT
THE TABLE. >> PEARL?
>> ONE THING I'VE BEEN LISTENING TO THE TALK ABOUT
AND GOING TO THE RIGHT SIDE OF THE DIAGRAM.
WAWE'RE FENGED IS IRBS AND WONDER WHAT DO I DO?
SO WHILE I THINK A REPOSITORY OF THE DATA IS HELPFUL TO
MANY OF PEOPLE SITTING AROUND THIS TABLE, I THINK
THE HUMAN CRY IS MORE YEAH, THAT'S NICE, BUT HOW DO I
READ THOSE 58 ARTICLES? WHETHER THAT IS A SEPARATE
ACTIVITY, BUT I FEAR THAT JUST HAVING A REPOSITORY IS
GOING TO PUSH US FURTHER TO THE LEFT.
>> AND FU WILL NOTICE IN THE OBJECTIVES, IT'S ALSO TO
IDENTIFY THE ACTIONS THAT COULD BE TAKEN.
SO IT'S NOT JUST HERE ARE THE VARPTS BUT THERE SHOULD
BE -- THIS SHOULD BE PART PROBABLY CAN'T RESIDE IF A
DATA RESOURCET PROBABLY NEEDS TO BE DECIDED AT THE
LEVEL OF AN INSTITUTION. >> COULD BE IS A STEP AWAY
FROM JUST A REPOSITORY. >> WELL, AND THAT'S FINE.
I THINK WE ARE HOPING THAT THEY'LL DO THE COULD BE
STUFF. >> DAVID, LAST WORD.
>> I THINK THAT I REPEAT FACE ISSUE IS A LITTLE BIT
OF MY DISCOMFORT WITH CALLING FOR THIS AT THIS
TIME BECAUSE REALLY F YOU THINK ABOUT THE SLIDES THAT
YOU REPRESENTED, IT'S A COMBINATION OF PULLING
TOGETHER INFORMATION ON WHAT IS ACTIONABLE.
BUT THERE WAS ALSO A DESCRIPTION OF TRYING TO
COME UP WITH THE INTERFACE THAT IS GOING TO REPRESENT
THAT INFORMATION TO USER GROUPS.
AND I JUST THINK THIS IS A VERY FLUID FAST-MOVING AREA,
AND I AM STILL NOT CONVINCED THAT A SINGLE GROUP AT A
RAPIDLY MOVING TIME IS GOING TO BE THE BEST MECHANISM TO
PUT TOGETHER ONE DATABASE AND THE INTERFACE THAT
PRESENTS THAT INFORMATION TO THE VERY DISPRATT GROUP OF
CLINICAL APPLICATIONS AND USERS THAT WILL PROBABLY
TAKE ADVANTAGE OF THIS KIND OF INFORMATION OVER THE NEXT
FIVE OR TEN YEARS. AND WHILE I AGREE THAT
SOMETHING IS OSHLY BETTER THAN NOTHING, I'VE ALSO SEEN
FOR MANY ORGANISM DATABASES AND OTHER THINGS THAT THERE
IS A TENDENCY TO ONCE SOMETHING IS SET UP, THAT IT
BECOMES THE PLACE WHERE OTHER THINGS GET ADDED ON
LATER AND DECISIONS MADE AT AN EARLY STAGE GET
PROPAGATEED. AND YOU MIGHT NOT MAKE THE
SAME DECISION IF THERE WAS A WIDER BASE OF OPTIONS THAT
WERE PRESENTED AT THE STAGE WHERE THE INITIAL STRUCTURES
AND INTERFACES AND MECHANISMS OF HANDLING IT
MIGHT HAVE BEEN CONSIDERED. >> SO WOULD YOU BE MORE
COMFORTABLE THEN TO THREE OR FOUR AWARDEES THAT WOULD
WORK COLLABORATEIVELY? WOULD THAT ADDRESS YOUR
CONCERN? >> YES, IT WOULD.
I REALIZE THERE IS SCALE ISSUES AND WHAT YOU ARE
TRYING TO ACHIEVE IS CONSENSUS.
BUT I JUST THINK IN THIS AREA THAT A SINGLE GROUP
APPROACH IN A RAPIDLY MOVING AREA I THINK IS UNLIKELY TO
BE SUCCESSFUL. >> GREAT.
THAT'S VERY, VERY HELPFUL BECAUSE WE'RE STRUGGLING
WITH THIS AS WELL. HOW DO YOU SORT OF ATONIGHT
IN ONE GROUP THAT IS GOING TO BE THE LEAD AND TAKE THIS
OVER? WE NEED TO BE A RELATIVELY
SMALL NUMBER OF AWARDS AND PROBABLY NEED TO INCREASE
THE BUDGET SOME. WE CAN LOOK AT WHETHER WE
COULD DO IT WITHIN THIS BUDGET.
IF NOT, WE MIGHT NEED TO BRING IT BACK TO YOU.
>> DOES THAT MEAN WE'RE IN A POSITION TO TAKE A VOTE?
>> WELL, I THINK WHAT WE WOULD PROPOSE THEN WOULD BE
A SMALL NUMBER OF AWARDS THREE TO FIVE TO DO THE SAME
WORK? >> BUT THERE WOULD BE CHANGE
IN THE BUDGET? >> WELL, I GUESS THAT'S A
QUESTION. >> YEAH.
>> WOULD YOU BE SUPPORTIVE OF -- WE'D NEED TO LOOK AT
WHAT WE CAN AFFORD BASICALLY. ERIC,ION HOW YOU'D LIKE TO
PROCEED. >> THE EMPHASIS IS NOT TO
WAIT AND NOT DO ANYTHING. I AM HEARING CONFLICTING
THINGS, TOO, THAT THIS IS AN IMPERATIVE AND NEED TO GET
GOING. IF WE IN PERFECT CAST WITH
ONE, BUT IF WE WAIT TO FIGURE OUT THE PERFECT, THEN
-- >> THE REALITY IS IT IS
BEING DONE, RIGHT? I DON'T THINK WAITING TO TRY
TO HONE THIS WOULD JUNDS MINE THE FACT THAT IT'S
BEING DONE. THE PLACES THAT ARE DOING
SEQUENCING ARE COMING UP WITH THEIR LISTS.
THEY HAVE TO. BUT THE PEOPLE --.
>> I MEAN, I HEAR JUST LOTS OF CONFUSION.
YOU'VE GOT TO HELP ON THIS. I'VE HEARD THIS FROM LOTS OF
PEOPLE YOU'VE GOT TO HELP ON THIS BECAUSE IT'S A WILD
WILD WEST OUT THERE. THIS WAS OUR ATTEMPT TO DO
THAT. WE CAN BICKER ABOUT WHETHER
IT'S REALISTIC TO BE ONE GROUP OR WITH IT OR THREE.
BUT I AM A LITTLE WORRIED ABOUT COMPLETE INACTION.
>> THE PEOPLE AT THIS TABLE HAVE A BACKUP PLAN.
BUT IT'S NOT THE PEOPLE AROUND THE TABLE THAT ARE
CALLING YOU. >> WELL, IT SEEMS THAT PART
OF THE AWARD HAS TO GO TOWARDS DEVELOPING A SET OF
STANDARDS TOWARDS FIGURING OUT WHAT ARE ARE GOING TO BE
THE ENTRIES INTO THE DATABASE STWRRX SIMILAR TO
THE DATABASE -- IT HAD TO HAVE BEEN REPLICATED ACROSS
POPULATIONS AND WE'RE TALKING ABOUT SIZES THAT ARE
BIGGER THAN THE CATALOGS. THAT IS A QUESTION OF
AGREEING ON A SET OF STANDARDS OF WHAT POPULATION
DATABASE AND WITH EVERY DATABASE IT'S NOT GOING TO
BE PERFECT BUT AT LEAST THAT'S TRANSPARENT AND
PEOPLE KIND OF KNOWS WHAT GOES INTO IT.
I SORT OF AGREE WITH THE VIEW, THOUGH, THAT YOU
SHOULDN'T AWARD A SINGLE -- I DON'T THINK A SINGLE AWARD
IS THE WAY TO GO. YOU ARE GOING TO END UP
HAVING A LOT OF BOTH COMPANIES AND UNIVERSITIES
TRY TO VIE FOR THAT WITH A LOT OF POTENTIALLY GOOD
IDEAS AND FINDING A COUPLE OF THOSE TO WORK
COLLABORATEIVELY MIGHT BE THE BEST APPROACH.
>> PERHAPS MAYBE IF -- >> COULD YOU GET NEAR THE
MICROPHONE, I'M SORRY, DIDI? >> MOVE FORWARD WITH ONE
THAT'S A RECORDER AND GETTING EVERYTHING ALL
TOGETHER AND THEN WAIT TILL THE NEGS COUNCIL MEETING TO
FIGURE OUT HOW WE GO ABOUT IN TERMS OF THE DECISION
MAKING PART OF IT. >> JUST AS A POINT OF
INFORMATION, I USE IT ALL THE TIME AS A REPOSITORY OF
INFORMATION WITH A LOT OF RESULTS COMING IN ON ALMOST
A DAILY OR WEEKLY BASIS. WHAT WAS THE PROCESS AT
NHGRI THAT LED TO THE ESTABLISHMENT OF WHAT
CURRENTLY EXISTS ON THE WEB AS THE G WAS DATABASE AND MY
GUESS IT WAS NOT A TWO TO FOUR MILLION DOLLARS A YEAR
BY ONE GROUP OR FOR OR FIVE YEARS TO COME UP WITH A
MECHANISM TO PULL THE DATA TOGETHER.
>> THE G WAS CATALOG IS AN INTERNAL PRODUCT OF NHGRI
LED BY MY GROUP AND STARTED AS A TABLE IF A PUBLICATION
IN THE JCI AND WE BASICALLY SAID IT WOULD BE NICE TO
EXPAND THIS. WE ARE NOT IN A POSITION TO
BE ABLE TO DO THAT FOR THIS AREA.
PLUS THAT WASN'T CONTROVERSIAL.
THAT DIDN'T NEED REALLY A DECISION TABLE.
WHAT WE WERE DOING WAS GATHERING INFORMATION AND WE
STUCK THEM IF A TABLE. THAT'S ESSENTIALLY HOW THAT
WORK. THE WAY IT BECAME THE LEAD
IS WE STUCK WITH IT AND OTHERS LOOK TO IT NOW AND
SAY THIS IS VALUABLE. DO YOU KEEP IT UPDATED?
I HAVE TWO STAFF MEMBERS FOCUSING ENTIRELY ON THIS,
LOUISA AND HEATHER. >> BUT ALSO, I THINK THE
FACT THAT IT CAME FROM NHGRI ALSO HAD SOMETHING TO DO
WITH THE UPTAKE, RIGHT? >> WHICH IS ONE OF THE
REASONS WE REALLY WANT TO MOVE ON THIS BECAUSE WE WILL
GET UPTAKE. IF WE'RE FUNDING IT AND
COORDINATING IT AND OVERSEEING IT.
>> BUT IT SEEMS LIKE THE PROBLEM IS THAT -- I AGREE
WITH DAVID ABOUT HOW STUFF GETS PROPAGATEED?
ONCE YOU PUT IT IN AND EVEN FU HAVE LOTS OF CAVEATS,
THIS IS GOING TO CHANGE. WE'RE GOING TO LEARN THAT WE
SHOULDN'T HAVE PUT THIS ONE ON, BUT SO WHATEVER YOU DO,
I THINK YOU HAVE TO SCREEN THAT FROM THE TREETOPS
BECAUSE PEOPLE -- >> DEFINITELY.
>> I JUST WANT TO PUT MY TWO CENTS IN.
I THINK THAT OBVIOUSLY PEOPLE REALLY WANT TO DO
THIS, AND I THINK IT'S VITAL. I DON'T THINK THAT DELAYING
FOR FIVE MONTHS IS GOING TO MAKE THAT BIG OF A
DIFFERENCE THAT MORE THOUGHT SHOULD NOW BE PUT INTO THIS.
THIS IS EXTREMELY CONTENTIOUS, AND I DON'T
THINK THAT EVEN IF IT'S FUNED BY NHGRI, IT IS A SINGLE RFA
AND IS GOING TO BE IDENTIFIED WITH THE
INSTITUTION THAT CREATES IT AND NO MATTER HOW GOOD THEY
ARE,INOT SURE THEY ARE GOING TO BE ABLE TO DRAW ON THE
DIVERSITY OF OPINIONS AND CONTEXTS THAT THEY ARE GOING
TO NEED IN ORDER TO CREATE SOMETHING THAT IS REALLY
GOING TO BE A USEFUL PRODUCT.
AND IF DELAYING FIVE MONTHS, THEN PAYS OFF IN A MUCH
BETTER PRODUCT, I THINK IT'S A RISK THAT IT WOULD BE
WORTH TAKING. >> I AM GOING TO ASK A
QUESTION ABOUT WHAT PEOPLE ARE LOOKING FOR BECAUSE IT
SEEMS TO ME THAT AS LONG AS WE'RE NOT KOUCHING THIS AS
CREATING A DEFINITIVE LIST ABOUT WHAT TO LOOK FOR, BUT
INSTEAD SORT OF PRIORITYIZES THINGS TO LOOK FOR AND THEN
PROVIDES THE CLINICAL DECISION SUPPORT, WHICH I
THINK IS THE KEY. THAT'S WHAT I'VE HEARD
PEOPLE SAY WE REALLY NEED. THAT PIECE SEEMS A LITTLE
BIT LESS CONTENTIOUS TO ME IN TERMS OF WHAT A GROUP
DOES. IS THAT CLINICAL DECISION
SUPPORT OR IS IT THE DEFINITIVE LIST THAT YOU ARE
HEARING PEOPLE -- >> BOTH.
>> MY UNDERSTANDING OF IT AND JIM MAY BE ABLE TO
ANSWER -- IS PEOPLE WHO DON'T HAVE THE NECESSARY
EXPERTISE, SAY WE FOUND THIS.
NOW WHAT DO I DO WITH IT AND HOW DO I GO ABOUT THINKING
ABOUT IT? A DECISION TREE.
>> TO ME, THE UTILITY OF A LIST IS THAT IT GIVES
GUIDANCE TO EVERYBODY WHO IS GENERATING GENOMIC DATA
ABOUT WHAT IS IT AND I'LL USE THE TERM THAT TERRY USED
-- WHAT IS IT THAT I'M OBLIGATED TO LOOK FOR?
WE JUST DID A WHOLE GENOME SEQUENCING ON THESE PEOPLE,
AND WHAT ARE THE GENES THAT I NEED TO LOOK IN AND REPORT
SOMETHING IF IT MEETS A CERTAIN BAR?
THAT IS THE SINGLE QUESTION THAT I THINK PEOPLE ARE
ASKING AND WHY THEY'RE CLAMORING.
>> JUST IN TERMS OF CLINICAL DECISION SUPPORT.
CLINICAL DECISION SUPPORT. TAS A WHICH TO FEED
INFORMATION TO ACLINATION WHEN THEY NEED IT AND NOT
BEFORE. SO YOU WOULDN'T HAVE TO KNOW,
FOR EXAMPLE FOR INSTANCE, ABOUT A VARIANTS TO GO BACK
TO THAT ONE, UMS YOU ARE GOING TO PROSCRIBE THE DRUGS
THAT THAT GENE IS INVOLVED IN AND THAT IT HAS AN EFFECT
ON OUTCOME SO THAT'S PROVIDING A RULE.
>> AND I DO THINK WE NEED TO --
>> SO THERE ARE CONSENSUS THAT COME OUT ON A PERIODIC
BASIS. MAYBE NOT AS DYNAMIC AS
TERRY HAD IN MIND. NCI PUTS THEM OUT ON A
REGULAR BASIS FOR SCREENING MAIN.
ANOTHER OPTION WOULD YOU TO HAVE AN RFA FOR A GROUP THAT
FEEDS THE ENGINE BUT ACTUALLY COMES OUT FROM
NHGRI. AND DAVID'S POINT THE FACT
THAT IT WAS ON AN NHGRI WEBSITE THAT GAVE IT EXTRA
CREDIBILITY, NOT THE FACT THAT YOU FUNDED IT.
>> IS THERE A POSITION FROM THE COLLEGE MEDICAL
GENOMESIS ON THESE ISSUES AND IF NOT, COULD NHGRI AND
THAT BODY, MAYBE SHG PUT TOGETHER A PAPER AND ONCE
THAT PAPER IS DEFINED, THAT WOULD GIVE THE SET OF
GUIDELINES FOR THIS DATABASE?
>> SO MIKE WATSON WAS HERE THIS MORNING, THE EXECUTIVE
DIRECTOR OF ACMG. THERE IS AN EFFORT RIGHT NOW
THAT SOME OF US ARE INVOLVED WITH AT THE BOARD OF ACMG TO
BEGIN TO COME UP WITH THIS. I REALLY LIKE THE IDEA THAT
I THINK HOWARD ALLUDED TO THAT YOU ARE ALLUDING TO,
CARL, THAT HAVING THE IMPRIM TOUR OF FHG WOULD BE A VERY
USEFUL THING. AGAIN, NOT IN A BINDING WAY
THAT SAYS HERE IS THE ABSOLUTE LIST.
BUT HERE IS A LIST THAT HAS BEEN FORMED BY SOME TYPE OF
CONSENSUS. AND THAT WOULD BE GREAT,
BECAUSE IT WOULD GET AWAY FROM THIS ADMITTED
SIGNIFICANT PROBLEM OF YOU'VE GOT ONE INSTITUTION
THAT'S NOW THE GO-TO PLACE AND PEOPLE AREN'T GOING TO
LIKE THAT. >> ERIC, DEW POINT SHALL DID
YOU WANT TO MAKE A COMMENT? >> CAN YOU HEAR ME?
>> NO. >> I WAS JUST GOING TO SAY
THE COMMENTS ABOUT THE INTERFACE THAT IF WE PUT
THIS LIST TOGETHER, AND THINKING BACK TO THE CATALOG
HOW IT STARTED AS A TABLE, YOU COULD ENVISION THE
INTERFACE THAT THIS GROUP DEVELOPS SORT OF THAT
EXPAPDED TABLE BUT WE'VE TALKED ABOUT
HAVING STANDARD FORMATING SO THE MORE SOPHISTICATED
INSTITUTIONS CAN TAKE THAT THROUGH WEB SERVICING TO
DEVELOP WHAT THEY NEED TO WORKS BEST WITH THEIR
INSTITUTION. WE CAN PACKAGE THE
INFORMATION IN A WAY THAT WORKS FOR A BROAD NUMBER OF
PEOPLE BUT AT THE SAME TIME ALLOWING AT LEAST THERE TO
BE A CLEAN, SIMPLE INTERFACE FOR THOSE THAT DON'T HAVE
THE GROUPS TO BUILD SYSTEMS. THEY COULD AT LEAST COME HERE
AND USE THE INFORMATION AS IT'S PLAYED.
>> LET'S SEE IF WE CAN BUILD A CONSENSUS HERE.
IS THERE A CONSENSUS THAT IT WOULD BE A MISTAKE TO GO
FORWARD WITH FUNDING ONE GROUP?
THERE IS A CONSENSUS THAT YOU WANT TO SEE MULTIPLE
GROUPS -- MULTIPLE AWARDS COME OUT OF THIS OR THE
POSSIBILITY OF MULTIPLE AWARDS?
SHOW OF HANDS. >> ISN'T THAT TIED IN WITH
THE CONCEPT THAT EITHER MULTIPLE AWARDS OR SOME BODY
LIKE ACMG OR NHGRI? RIGHT?
>> I AM TRYING TO DECIDE WHETHER WE'RE GOING TO VOTE.
ARE WE GOING TO TAKE AN UP OR DOWN VOTE OR YOU ARE
GOING TO MAKE SOME SET OF RECOMMENDATIONS AND VOTE ON
THAT CHANGE TO THE DOCUMENT? IS THAT CLEAR?
OKAY. SO SHOW OF HANDS ALL THOSE
IN FAVOR OF HAVING MULTIPLE AWARDS ASSOCIATED WITH THIS.
HANDS UP. ONE, TWO, THREE, FOUR, FIVE,
SIX. THOSE OPPOSED?
A LOT OF ABSTAINERS? A LOT OF ABSTAINERS.
NOW, THE ABSTAINERS, WOULD YOU VOTE DOWN ON THIS NO
MATTER WHAT FORM OR FLAVOR WE BRING TO YOU?
[INDISCERNABLE] SO AS THERE A MOTION HERE
TO DEFER THIS CONCEPT TILL MAY COUNCIL?
SHOW OF HANDS? THOSE IN FAVOR?
THOSE OPPOSED? SORRY, HOWARD.
NO CHOCOLATE FOR YOU. [LAUGHTER]
>> OKAY. >> ARE WE OKAY WITH THAT?
SO WE'LL DEFER THIS. GO AHEAD, LISA.
>> [INDISCERNABLE] A QUESTION ABOUT HOW THE
MULTIPLE AWARDS WOULD WORK AND YOU ARE TALKING ABOUT
HAVING THESE MULTIPLE GROUPS THAT COME UP WITH THEIR OWN
STANDARDS OR CRITERIA. SO I DOUBT THAT YOU ARE
TALKING ABOUT HAVING FUNDING MULTIPLE GROUPS TO COME UP
WITH THEIR OWN CRITERIA AND THEN HAVING THOSE GROUPS
WORK IT OUT THEMSELVES? OR ARE YOU TALKING ABOUT
HAVING DIFFERENT GROUPS OR DIFFERENT DISEASE DOMAINS?
>> I THINK THAT'S GOING TO GET REPRESENTED AT MAY
COUNCIL. >> PERHAPS TALKING WITH
COUNCIL MEMBERS OR SOMETHING? >> SURE.
>> OKAY. THAT WAS INFORMATIVE.
SO LET'S MOVE ALONG TO ANASTASIA