Informed Consent and Returning Results in Whole-Exome Sequencing Protocols - Julie Sapp


Uploaded by GenomeTV on 14.10.2011

Transcript:
>> CAN EVERYONE HEAR ME? GREAT.
TAU FOR STICKING AROUND UNTIL THE END.
BY THIS TIME, YOU MIGHT BE THINKING TO YOURSELF, HOW DO I
CONSENT, PARTICIPANTS AND RETURN RESULTS TO PARTICIPANTS IN THE
KIND OF EXOME SEQUENCING PROTOCOLS WE HAVE BEEN TALKING
ABOUT TODAY? I'M A GENETIC COUNSELOR IN THE
GENETIC DISEASE RESEARCH BRANCH AT NHGRI AND YOU MAY HAVE
ALREADY COME TO THE SAME CONCLUSION WE HAVE ABOUT
ANSWERING THIS QUESTION. THE RELATIVELY SIMPLE QUESTION
BUT IT'S A BIT OF A LESS THAN STRAIGHTFORWARD ANSWER SO I'M
HOW MUCHING TO SHED LIGHT ON THAT TODAY.
BECAUSE YOU'RE HERE, YOU SHOULDN'T HAVE QUESTIONS ABOUT
THE FACT THAT THE INFORMED CONSENT PROCESS PLAYS A CENTRAL
ROLE IN MANY CLINICAL RESEARCH PROTOCOLS.
ONE OF THE MOST COMMON QUESTIONS WE GET ABOUT OUR EXOME PROTOCOLS
IS WOULD BE WE SEE YOUR CONSENT FORM OR USE YOURS?
WE ARE MORE THAN HAPPY TO SHARE OUR FORM WITH ANYONE ON WHO
WANTS IT BUT AS ANY PARTICIPANTS CAN TELL YOU, CONSENTING TO OUR
PROTOCOLS ARE MORE INVOLVED THAN SIGNING A CONSENT FORM.
AND MAYBE BY THE END OF MY TALK, YOU'LL UNDERSTAND WHY.
I THINK THE REASON IS VERY TEMPTING FOR TO FIXATE OR FOCUS
ON THE CONSENT FORM WHEN THINKING ABOUT THE PROTOCOLS.
WE THINK OF THIS IS PART OF A LINEAL PROCESS.
WE SCIENTISTS DESIGN A STUDY AND WE ASK PEOPLE TO BE IN THE
STUDY, MAKE OR ASK THEM TO DONATE THEIR TIME OR SAMPLES TO
THE STUDY AND IF ALL GOES ACCORDING TO PLAN, WE ARE IN A
POSITION TO RETURN RESULTS TO THEM WITH THE BROADER SCIENTIFIC
COMMUNITY. WHEN PEOPLE ASK US TO SEE OUR
CONSENT FORM, THE REASON WHY THAT TURNS INTO A HOUR-LONG
CONVERSATION IN MANY INSTANCE SYSTEM IS BECAUSE WE THINK OF
THIS MORE ITERATIVELY AND WE THINK OF THESE RELATIONSHIPS NOT
SO LINEAR BUT INFORMING ONE ANOTHER.
AND I THINK THAT'S PART OF THE REASON THAT THERE IS A QUESTION
ABOUT WHETHER OR NOT WE SHOULD RETURN RESULTS IS NOT SOMETHING
THAT HAS COME UP. WE DECIDED ON AN A VERY ACTIVE
RESULT ITS DISCHLORRIER POLICY AND JENNIFER STARTED TO OUTLINE
THOSE REASONS AND I'LL GO INTO THAT A LITTLE BIT MORE.
SO I THINK THAT'S PART OF THE REASON WHY THIS HAS BECOME A
MORE INVOLVED PROCESS. THESE ARE COMING UP FOR US HOW
WE THOUGHT ABOUT GOING ABOUT CONDUCTING THESE KINDS OF
PROTOCOLS AND QUESTIONS WE TALK ABOUT OTHER INTERESTED
INVESTIGATORS ASK ABOUT. SO QUESTIONS LIKE, WHAT DO I
NEED TO KEEP IN MIND AS I APPROACH MY PROSPECTIVE
PARTICIPANTS? HOW DO I GET THEIR CONSENT?
I'LL GO OVER STRATEGIES WE HAVE EM PROVIDE.
WHAT ABOUT? I MEAN, WHAT ABOUT ENROLLING
KIDS? WHAT ABOUT ENROLLING HEALTHY
PEOPLE? WHAT ABOUT ENROLLING PEOPLE WITH
INTELLECTUAL IMPAIRMENTS? THESE ARE CHALLENGES THAT WE
ENCOUNTERED AND I'LL SPEND TIME HOW WE SPENT TIME OVER COMING
CHALLENGING SITUATIONS AND HOW DO WE RETURN RESULTS TO
PARTICIPANTS IF WE DECIDED TO DO THAT?
SO AGAIN AN OUTLINE FORMAT. I'M GOING TO GO OVER THE GENERAL
CONSIDERATIONS ON THE RATIONAL THAT WE EMPLOYED.
GIVE YOU A SPECIFIC EXAMPLE OF ONE APPROACH TO INFORMED CONSENT
WE USE IN OUR PROTOCOLS, REVIEW AGAIN HOW WE ADDRESSED THESE
CHALLENGING SITUATIONS AND PATIENT POPULATIONS AND TALK TO
YOU ABOUT SOME FINDINGS WE HAVE IN OUR EXPERIENCE IN RETURNING
RESULTS. SO, I THINK THAT FOR WHOLE EXOME
SEQUENCING, WE FOUND IT HELPFUL TO THINK OF INFORMED CONSENT NOT
SO MUCHS A ONE TIME ENCOUNTER BUT ONGOING PROCESS.
AND AS AN OPPORTUNITY FOR ONGOING RESEARCHER PARTICIPANT
DIALOGUE. IT'S A TWO WAY COMMUNICATION
WHERE PARTICIPANTS CAN TALK TO US ABOUT THEIR OWN GOALS AND
EXPECTATIONS AND PLANS FROM PARTICIPATING IN OUR RESEARCH
AND WE, AS INVESTIGATORS, CAN SHARE OUR GOALS AND OUR
EXPECTATIONS AND WHAT WE EXPECT TO FIND WITH PARTICIPANTS.
ACTIVELY ENGAGED OR FEEL THEY ARE ACTIVELY ENGAGED IN RESEARCH
PARTNERSHIP ARE MORE LIKELY TO REMAIN ENGAGED IN ONGOING
RESEARCH PROTOCOL SO WE LIKE TO KEEP THAT IN MIND AS WELL.
SO AGAIN, I THINK THAT WE VIEWED THISES IS A GOOD OPPORTUNITY TO
SHARE WITH PARTICIPANTS THE FACT THAT OUR RESEARCH GOALS DRIVES
HOW WE THINK ABOUT RETURNING THE RESULTS AND OUR INFORMED CONSENT
PROCESS. IT'S A GREAT OPPORTUNITY FOR US
TO TALK WITH THEM ABOUT THE INTERSECTION OF THEIR OWN GOALS
AND EXPECTATIONS WITH OURS AND HOW CLOSELY THOSE MATCH UP.
SO, AS PRETTY MUCH EVERYONE HAS SPENT TIME TALKING ABOUT TODAY,
THE DATA ARE THE INHERENT CHALLENGE IN THESE KINDS OF
PROTOCOLS AND THIS IS WHAT WE SPENT TIME THINKING ABOUT AND WE
SPENT A LOT OF TIME TALKING ABOUT.
SO IN TERMS OF VOLUME, AS YOU KNOW, IMMENSE NUMBER OF VARIANTS
CAN BE GENERATED FOR EACH PARTICIPANT AND THEY CAN FALL
ANYWHERE IN THE CONTINUUM FROM NOVEL AND NEVER BEFORE DESCRIBED
TO EXTREMELY WELL CHARACTERIZED AND FOR THOSE YOU CAN INTERPRET,
THEY FALL ON THIS CONTINUUM FROM BENIGN TO HIGHLY PENETRANT AND
LIKELY TO BE VERY DEL TEARUOUS. THE DATA ARE GENERATED AND
INTERPRETED ITERATIVELY AND SO WHAT YOU ARE --
OUR KNOWLEDGE OF THE GENOME IS EXPANDING AND THERE CAN BE
FURTHER DOWNSTREAM USES AND INTERROGATIONS THAT CAN TAKE
PLACE WITH ANY INDIVIDUAL EXOHM SEQUENCE.
I THINK THERE IS IN AREN'T UNCERTAINTY IN THE DATA WE ARE
GENERATING FROM WHOLE GENOME AND WHOLE EXOME SEQUENCING
PROTOCOLS. WHAT WE KNOW ABOUT THE GENOME IS
A MOVING TARGET. WE LIKE TO KNOW MORE ABOUT IT.
AND SO I WOULD LIKE TO ARGUE THAT FULLY AND ADEQUATELY
CONVEYING THE SCALE AND SCOPE OF GENOMIC INTERROGATION TO
PARTICIPANTS IN A REALLY SCIENTIFIC WAY IS NEITHER
PRACTICAL NOR POSSIBLE. SO I THINK IT IS IMPORTANT TO
THINK ABOUT THAT AND TO THINK ABOUT HOW THE IMPACT THAT THE
DATA THAT WE LEARNED AND THE IMPACT IT HAS ON INDIVIDUAL
PARTICIPANTS VARIES TREMENDOUSLY AND IT MAY VARY AND BE NONSTATIC
FOR US AS INVESTIGATORS. SO AS WE HAVE THE EXOME DATA AND
THINK ABOUT NEW WAYS TO INTERROGATE EXISTING DATASETS,
OUR INVOLVEMENT WITH THE DATA ARE MAYBE NOT TRIVIAL OVER TIME.
SO WITH THAT IN MIND, LET ME TALK TO YOU ABOUT OUR SPECIFIC
APPROACH TO THE CONSENT WE EMPLOYED WITH ONE OF OUR
PARTICULAR PROTOCOLS. SO WE HAVE TWO EXOME PROTOCOLS
THAT WE ARE ACTIVELY ONGOING RIGHT NOW IN OUR BRANCH.
CLIN-SEQUE, WHICH MANY PEOPLE MENTIONED IS A HYPOTHESES
GENERATING PROTOCOL. I'M NOT GOING TO SPEND A LOT OF
TIME TALKINGS ABOUT THAT. INSTEAD I'LL TALK WITH YOU ABOUT
OUR GENE DISCOVERY PROTOCOL. THIS HAS MORE IN COMMON WITH THE
MANY OF THE PROTOCOLS YOU'RE DESIGNING IN YOUR HEADS AS
YOU'RE LIFTYENING TO THE TALKS TODAY.
SO IT TELL YOU ABOUT THE STUDY, THE GOAL IS TO FIND GENES FOR
DISORDERS. WE ENROLL WITH RARE CONDITIONS.
WE HAVE BROAD ELIGIBILITY CRITERIA.
SO WE ENROLLED PARTICIPANTS AS YOUNG AS ONE DAY OLD.
OUR OLDEST IS 83 OR 84 YEARS OLD.
IT RANGES FROM SEVERE NEONATAL ONSET CONGENITAL ANOMALY
DISORDERS TO MORE ADULT ONSET ENDOCRINE DISORDERS.
SO WE OFTEN EMPLOY A TRIO APPROACH BUT NOT ALWAYS.
IT'S NOT ALWAYS POSSIBLE. IT'S NOT ALWAYS PRACTICAL.
BUT WE GENERALLY THINK ABOUT A FAMILY PARTICIPATING IN OUR
STUDY AND GENERALLY THINK OF ENROLLING FAMILIES BECAUSE WE
ARE ENROLLING MOMS WHENEVER POSSIBLE BUT IT'S NOT ALWAYS
POSSIBLE AND NOT ALWAYS NECESSARY.
AS WAS MENTIONED EARLIER, FOR ONE OF THE DISORDERS WE STUDIED,
WE WERE ABLE TO FIND THE CAUSATIVE VARIANT WITH USING
JUST ONE TRIO. AND WE EMPLOY A DISCLOSURE
POLICY. THIS FALLS MORE IN THE THIRD
CATEGORY SARAH WAS MENTIONING WHERE WE HAVE A ROBUST RESULTS
DISCLOSURE POLICY. SO IN TERMS OF WHAT IT LOOKS
LIKE VERY PRACTICALLY SPEAKING WITH PARTICIPANTS, THIS IS WE
INITIATED CONTACT WITH PARTICIPANTS AND THEN I
GENERALLY HAVE A PHONE CALL WITH PARTICIPANTS DESCRIBING THE
STUDY AND THE GOAL OF THE CONVERCISION IS TO ALERT THEM TO
THE FACT THAT WE ARE ASKING THEM TO PARTICIPATE IN A
COMPREHENSIVE GENE SEQUENCING STUDY UNLIKE ANYTHING THEY
THOUGHT OF BEFORE. AND TO ALERT THEM ABOUT THE FACT
THEY MAY BE IN A POSITION TO MAKE DECISIONS ABOUT LEARNING
THINGS THAT THEY DIDN'T NECESSARILY ANTICIPATE.
THEN IF THEY ARE INTERESTED, THEY CALL US BACK AND LET US
KNOW THEY LIKE TO PARTICIPATE AND IF THAT IS TRUE, WE SCHEDULE
A VISIT TO THE NIH FOR FURTHER PHENOTYPING AND HAVE A
CONVERSATION ABOUT CONSENTING TO THE PROTOCOL.
SO WE THINK ABOUT THE TIMELINE HERE WITH THE ORANGE ARROW IS
THE TIMELINE OF THE PROTOCOL FOR PARTICIPANTS IT LOOKS LIKE THIS,
WE CALL THEM OR CONTACT THIS. WE HAVE THEM COME TO NIH WHERE
THEY SIGN OUR CONSENT FORM AND DO PHENOTYPING IMPORTANTLY IT'S
NOT CONCURRENT WITH THEIR DECISION ABOUT WHAT KINDS OF
RESULTS THEY LIKE TO RECEIVE FROM PARTICIPATING IN THE
PROTOCOL. BUT AT SOME POINT THEY MAKE A
DECISION ABOUT WHAT RESULTS THEY LIKE TO RECEIVE.
WE VALIDATE THOSE RESULTS AND RETURN THEM TO THE PARTICIPANTS
AT ANOTHER NIH VISIT IN PERSON AND THEN THERE IS ANING ON GO WE
LEAVE THE DOOR OPEN FOR REANNOTATION OF THE EXON
SEQUENCE AND FUTURE RECONTACT. AND WHILE THIS IS GOING ON
BETWEEN CONSENT AND THIS UNDETERMINED END POINT,
HOPEFULLY WE FIGURE OUT WHAT CAUSED THE DISORDER OF INTEREST.
WE ANNOTATED VARIANCE THAT MAKES SENSE TO US AND PARTICIPANTS AND
DESIGNED AND IMPLEMENTED RESEARCH QUESTIONS THAT WE CAN
USE THEIR EXOME SEQUENCE FOR. SO BECAUSE THIS IS REALLY KIND
OF THE MONEY POINT HERE. THAT'S WHAT I'LL SPEND TIME
TALKING ABOUT. MANY CONCEPTS DURING THE
PROCESS, ARE NOT REALLY THAT REVOLUTIONARY TO GENETIC
STUDIES. EVERYBODY SESSION CONTAINS SOME
INFORMATION ABOUT WHAT WE ARE ASKING PEOPLE TO DO AND WHAT
THEIR RISKS AND BENEFITS ARE. WE ARE FOCUSING ON HERE THE FACT
THAT THEY CAN LEARN A LOT OF INFORMATION SO LET ME BREAKDOWN
HOW WE GO THROUGH THAT WITH OUR PARTICIPANTS.
SO, I THINK THAT FOR MOST PARTICIPANTS, THE ANALOGY I FIND
THE MOST HELPFUL TO DESCRIBE THE DATA WE GENERATE FROM A FAMILY'S
EXOME SEQUENCE IS A TORRENT. SOME PEOPLE USED THE ANALOGY OF
LIKE GETTING A DRINK OF WATER FROM A FIRE HOSE.
WATER REALLY LENDS ITSELF VERY WELL TO THESE KINDS OF
ANALOGIES. SO I THINK THAT WE HAVE A
DOWNPOUR OR TORRENT OF DATA. AND THAT OUR GOAL IS TOO TRY TO
ASSIST THROUGH THIS VAST AMOUNT OF DATA TO FIND SOMETHING THAT
WE ARE INTERESTED IN. SO TO MAKE SENSE OF ALL OF THIS
INFORMATION, WE FRAMED WHAT WE LEARNED IN TERMS OF THE GOAL OF
THE STUDY SO WE BROAD RECHARACTERIZE OUR RESULTS FOR
OURSELVES AND OUR PARTICIPANTS USING THIS TERMINOLOGY THEY MANY
PEOPLE HERE HAVE USED. SO USING THIS ANALOGY WITH
PARTICIPANTS, I TALK ABOUT HOW WE ARE REALLY AFTER HERE IS THIS
NUGGET OF GOLD. THE CLAUSE FOR THE DISORDER
UNDER INVESTIGATION IS A DISORDER AFFECTING THEMSELVES
AND THEIR CHILDREN. SO THIS IS US IN NIAGRA FALLS.
PANNING FOR GOLD IN THIS ENORMOUS RIVER TRYING TO FIND
THIS ONE GOLD NUGGET. AND WE FIND OTHER THINGS.
SO IN ADDITION TO THAT NUGGET OF GOLD, THERE IS OTHER INFORMATION
WE MAY FIND AND WE THINK OF THAT AS SECONDARY VARIANTS.
WE ARE CAREFUL TO LET THEM KNOW THIS PRIMARY AND SECONDARY
TERMINOLOGY SEBECAUSE OF THE RESULTS.
THE CLINICAL SIGNIFICANTS OF THE SECONDARY VARIANT MAY FAR
OUTWEIGH ANY OF THE CLINICAL SIGNIFICANTS OF A PRIMARY
VARIANT. BUT WE DEFINED THIS AS
EVERYTHING ELSE. AND WE ARE CAREFUL TO LET THEM
THAN FINDING THESE THINGS IS NOT THE GOAL OF THE STUDY.
THAT'S NOT IN WE ARE IN THIS BUSINESS.
NOT IN HERE TO FIND OUT ALL THE OTHER STUFF LURKING IN THE
GENOME. WE ARE AFTER ONE THING IN
PARTICULAR AND WE FIND THESE THINGS IS IN AREN'T TO
METHODOLOGY. THESE DATA ARE PRESENT AND WE
DON'T THINK THAT THE WAY WE DESCRIBED TO PARTICIPANTS IS WE
CAN'T DO THIS KIND OF AVERTING OF OUR EYES THAT THIS ENDS UP IN
THE -- IN OUR GOLD PAN UP AND WE HAVE TO MAKE SENSE OF IT FOR
PARTICIPANTS AND WE GO OVER MORE DETAIL ABOUT WHAT EXACTLY THESE
THINGS ARE. WE HAVE A COUPLE OF EXAMPLES
PRESENT IN OUR CONSENT FORM AND THEY DO REVIEW SOME OF EXAMPLES
WITH TAR PARTICIPANTS. THE REASON WHY WE GIVE EXAMPLES
AND THE REASON WHY WE CATEGORIZE THEM IS IT'S NOT POSSIBLE TO
GIVE PEOPLE A LIST OF ALL THE THINGS WE CAN FIND.
SO WE HAVE TO CATEGORIZE IT. SO WE TALK ABOUT CARRIER STATUS
OR RECESSIVE DISORDERS THE ONLY KIND OF GENOMIC VARIATION WE CAN
BE CERTAIN WE WILL FIND FOR ANY INDIVIDUAL THAT WE INTERROGATE.
AND MANY PEOPLE ARE FAMILIAR WITH SOME EXAMPLES OF CYSTIC
FIBROSIS, SICKLE CELL ANEMIA AND THESE KINDS OF THINGS.
AND GENETIC VARIANTS KNOWN TO CONTRIBUTE TO HUMAN DISEASE AND
WE TALK ABOUT THESE THINGS IN THREE GENERAL WAYS.
WE TALK ABOUT ONSET, MIGHT WE DIAGNOSIS YOU IF SOME CONDITION
YOU MAY BE HAVEN'T BEEN WORKED UP FOR OR SOME SYMPTOM YOU
HAVEN'T REALLY BROUGHT TO YOUR DOCTOR OR YOUR DOCTOR DISMISSED
AS NOT GENETIC BY THIS KIND OF INTERROGATION?
I'LL TELL THAT YOU HAS HAPPENED IN THE COHORT.
IS THIS DISORDER TREATABLE OR PREVENTABLE OR MANAGEABLE IN
SOME WAY OR NOT? AND THEN GIVING YOUR FAMILY
HISTORY IS SOMETHING YOU AS A PARTICIPANT MIGHT FIND
SURPRISING OR MORE OR LESS EXPECTED?
SO AGAIN, IT MIGHT REALLY NOT BE VERY SURPRISING FOR SOMEONE WHO
COMES A FAMILY WHERE THERE IS A LARGE PORTION OF PEOPLE WITH
HYPERCHOLESTEROLEMIA TO LEARN THEY HAVE A VARIANT THAT
INCREASES THEIR CHANCES TO HAVE HIGH CHOLESTEROL.
FOR SOMEONE WHO HAS A NEGATIVE FAMILY HISTORY IT MIGHT BE
SURPRISING. WE TALK ABOUT HOW THE VARIANT
RESULTS WE GENERATE WERE NOT NECESSARILY ABLE TO INTERPRET
RIGHT AWAY AND THAT MANY OF THE THINGS WE FIND FALL ON THE
SPECTRUM OF NORMAL VARIATION. WE GIVE PARTICIPANTS THE CHOICES
TO LEARN THE FIRST TWO CATEGORIES.
OUR THOUGHT IS THE GOAL TO DELIVER MEANINGFUL RESULTS TO
PARTICIPANTS THAT FALL INTO THE SECONDARY VARIANT CATEGORY.
IF WE ARE NOT GOING TO MAKE SENSE OF IT, WE ARE NOT IN A
POSITION TO RETURN IT TO PARTICIPANTS AT THIS TIME.
AND WE DON'T EXPLICITLY TELL THEM.
ONE COROLLARY WE TRY TO MAKE EXPLICIT IS THAT GOING THROUGH
THIS PROTOCOL IS NOT THE SAME THING AS GETTING THE CLEAN
GENETIC BILL OF HEALTH. SO AGAIN, I THINK THAT EVEN
THOUGH WE GO THROUGH SOME SPECIFIC EXAMPLES OF THE
SECONDARY VARIANTS, MOST IMPORTANT PART OF OUR
CONVERSATION IS SOME OF THE GENERAL CHARACTERISTICS ABOUT
SECONDARY VARIANTS OF HOW WE GENERATE THINGS.
IT'S REALLY PARTICIPANTS REALLY RESINATE WITH THE IDEA IN IS
ANCILLARY TO OUR RESEARCH GOAL AND WE CAN'T HELP BUT FIND THESE
THINGS AND WE WANT TO ENGAGE WITH THEM ABOUT HOW TO GET THIS
INFORMATION BACK TO THEM. I DO GENERALLY LET THEM KNOW
THAT ANNOTATING AN EXOME IS TIME CONSUMEING AND DONE BY PEOPLE
AND NOT BY COMPUTERS. IT'S AN ONGOING PROCESS.
IT DOES REPRESENT A DEPARTURE FROM TRADITIONAL PARADIGMS.
MANY HAVE HAD GENETIC TESTING AND HAVEN'T HAD EXOME OR GENOME
SEQUENCING. AND THE IMPACT WILL VARY HUGELY
ACROSS PARTICIPANTS AND ONE KEY POINT HERE IS THAT AS STUDYING A
PARTICULAR DISEASE COHORT, OUR IDEA IS TO GENERATE THESE KINDS
OF DATA BUT BECAUSE WE CAN FIND THIS OTHER STUFF AS WELL, WE
WANT TO GENERATE THESE DATA FOR AS FEW PEOPLE AS POSSIBLE.
SO IF WE CAN FIGURE OUT THE CAUSE OF WHATEVER DISORDER IT IS
WE ARE STUDYING BY LOOKING AT ONE TRIO, WE ARE NOT GOING TO
PROCEED TO EXOME SEQUENCING FOR EVERY PERSON WE HAVE IN OUR
COHORT. SO EVEN THOUGH PARTICIPANTS
CONSENT FOR A WHOLE GENOME SEQUENCING WHAT WE MAY DO WITH
THEIR SAMPLE RANGES FROM NOTHING ALL THE WAY THROUGH GENOME
SEQUENCING. SO EVEN THOUGH WE ARE HAVING
THIS LONG DRAWN OUT CONVERSATION, THEY MAY NOT EVEN
ABOUT -- NUMBER IN A POSITION TO MAKE
THESE DECISIONS. THE MAIN POINT IS THAT
PARTICIPANTS DO UNDERSTAND THIS ONCE WE GO THROUGH THE PROCESS
OF TALKING WITH THEM ABOUT WHAT THEY ARE AND HOW WE GO ABOUT
FINING THEM. SO PARTICIPANTS CAN CHOOSE TO
RECEIVE RESULTS OR NOT. THEY CAN CHOOSE WHETHER OR NOT
THEY WANT TO RECEIVE THE PRIMARY VARIANT OR SECONDARY VARIANTS BY
CATEGORY SO THEY CAN TELL US I'M NOT INTERESTED IN LEARNING
ANYTHING WHERE THERE IS NO TREATMENT AND IT WOULD BE
SURPRISING TO ME. EACH WHO PARTICIPATES IS AN
INDEPENDENT ACADEMIOR. EVEN THOUGH REENROLL MOMS AND
DADS AND KIDS, THEY CAN MAKE DIFFERENT CHOICES ABOUT WHAT
KINDS OF RESULTS THEY WOULD LIKE TO RECEIVE.
AND I'LL GO INTO A LITTLE BIT ABOUT WHY THAT IS A CHALLENGE
FOR US. AND THEN WE USUALLY TALK ABOUT
THE DUTY TO WARN AS THIS IDEA THAT WE WANT TO LEAVE THE DOOR
OPEN FOR SOME KINDS OF VARIANTS THAT WE WOULD REALLY LIKE TO
RETURN TO THEM REGARDLESS OF WHETHER OR NOT THEY HAVE GIVEN
US PERMISSION TO DO THAT. SO I THINK IT'S A FINE BALANCE
HERE TALKING TO THESE -- ABOUT THESE KINDS OF VARIANTS,
THE BREAST AND OVARIAN CANCER AND THINGS ON THAT CONTINUUM.
WITH PARTICIPANTS, BECAUSE THE GOAL IS NOT TO ALARM THEM.
VARIANTS ARE RARE OVERALL. IT'S NOT OUR INTENT TO DISCOVER
THIS KIND OF INFORMATION. BUT IT'S REALLY HARD
PARTICULARLY WITH SOME OF THE CANCER PEDIGREES THAT JENNIFER
SHOWED. SOMETIMES IT'S IMPOSSIBLE FOR US
TO PREDICT WHO THESE VARIANTS WILL SHOW UP IN.
AND SO IT'S IMPORTANT TO ALERT PARTICIPANTS TO THIS
POSSIBILITY. WE DO TALK ABOUT HOW THIS IS NOT
WHY WE ARE DOING THIS BUT IT COULD BE A POTENTIAL BENEFIT FOR
SOME OF THE PEOPLE WHO PARTICIPATE IN OUR STUDIES.
SO I THINK MOST PARTICIPANTS IDENTIFY WITH THIS.
I MENTIONED THIS EARLIER, ANY TIME A PROTOCOL EMPLOYS GENETIC
TESTING, IT'S IMPORTANT TO CONSIDER THE FAMILIAL
IMPLICATIONS AND GO BEYOND THE MISATTRIBUTED BOILERPLATE
LANGUAGE AND INCLUDED IN ALL CONSENT FORMS AND MOST PEOPLE
USE ON CONSENTING PARTICIPANTS TO GO INTO A LITTLE MORE DETAIL.
NOT ALL FAMILY MEMBERS MAY UNDERGO THE SAME LEVEL OF
GENOMIC OR EXOMIC TEARIGATION. WE ENROLL A TRIO AT THE TIME OF
CONSENT BUT WE MAY ONLY SEND THE PRO BAND OFF FOR SEQUENCING.
AND AS WE TALK ABOUT SECONDARY VARIANTS, WE SPEND TIME JUST
ASKING PARTICIPANTS WHETHER THEY MENTIONED TO THE EXTENDED FAMILY
THEY ARE ARE HAVING THEIR GENOME SEQUENCE OF THE ARED.
THEY MAY BE IN A IMPORTANT POSITION TO SHARE INFORMATION
WITH OTHER FAMILY MEMBERS. SOME APPROACHES REQUIRE
COMMUNICATION AMONG FAMILY MEMBERS.
SOMETIMES IT'S CRITICAL TO HAVE A TRIO OR A TRIO AND ANOTHER
SIBLING FOR THOSE WHO HAVE SOLE CUSTODY OF HER CHILD AND DAD IS
NOT INVOLVED. WE MAY NOT BE ABLE TO PROCEED
UNLESS WE CAN GET THE PATERNAL SAMPLE.
SIMILARLY, IT'S POSSIBLE FOR ANY TWO MEMBERS OF A TRIO TO TRY ANG
LATE THE GENETIC INFORMATION OF THE THIRD MEMBER OF THE TRIO.
SO AGAIN, EVEN THOUGH EVERYONE WHO PARTICIPATES MAKES THEIR OWN
DECISIONS IF A MOM AND CHILD COMPARE NOTES THEN THEY
AUTOMATICALLY KNOW WHAT IS GOING ON WITH DAD.
AND AGAIN, WE DO EMPLOY THIS PROTOCOL WITH MINOR CHILDREN AND
I'LL GET INTO THAT MORE SPECIFICALLY IN A MINUTE.
WHY AM I GOING INTO SO MUCH DETAIL?
TO RETURN MEANINGFUL RESULTS TO PARTICIPANTS AND BECAUSE WE WANT
TO ENABLE OUR PARTICIPANTS TO MAKE INFORMED DECISIONS ABOUT
RESULTS. AND I THINK THAT THE THEME THAT
KIND OF UNDERLIES THESE TWO POINTS IS IS THIS IDEA THAT I
DISCUSS WITH MOST, ONCE YOU CHOOSE TO KNOW SOMETHING, IT'S
IMPOSSIBLE TO RETURN TO A STATE OF IGNORANCE.
AND I THINK IT'S SOMETHING THAT IS IMPORTANT FOR BOTH
PARTICIPANTS AND INVESTIGATORS TO KEEP IN MIND AS WE ARE
THINKING ABOUT GENERATING THESE KINDS OF DATA.
THIS IS NOT LIKE OTHER GENETIC TESTING PEOPLE HAVE HAD DONE.
EVEN THOUGH CLINICALLY AVAILABLE.
WE DO THIS IN A -- SO THERE ARE ALTERNATIVES.
THIS IS CURRENTLY AVAILABLE ON A RESEARCH BASE.
WITHDRAWING MAY NOT BE A STRAIGHTFORWARD PROCESS.
SO WE ALERT PARTICIPANTS TO THE IDEA IF THEY CHANGE THEIR MIND
AND WE ALREADY GENERATED SEQUENCE DATA, WE NEED TO HAVE A
CONVERSATION WITH THEM ABOUT HOW WE ARE GOING TO MANAGE THOSE
DATA. AND I THINK ANOTHER INTERESTING
POINT TO CONVEY IS THAT WE ARE ALL HOPING THIS ENTERS CLINICAL
PRACTICE SO EACH THOUGH WE ARE MAKING A BIG DEAL ABOUT ALL THE
INFORMATION THAT WE CAN FIND NOW WITHIN THE LIFE TIMES OF MANY
PARTICIPANTS, THIS TESTING IS SOMETHING THEIR CLINICIANS WILL
ORDER ON A ROUTINE BASIS. I THINK MANY PEOPLE UNDERSTAND
THAT. BUT ARE YET EXITED TO BE GETTING
IN ON THE GROUND FLOOR OF THIS KIND OF TECHNOLOGY.
SO SOME CHALLENGING PROPALATIONS AND SITUATIONS.
A PARENT MACON SENT ON BEHALF OF THEIR MINOR CHILD.
WE EMPLOY A SPECIFIC CONSENT FORM FOR PARENTS TO SIGN ON
BEHALF OF THEIR CHILDREN. WE WILL RETURN RESULTS FOR MINOR
CHURN UNDER CERTAIN CIRCUMSTANCES.
THERE ARE GUIDELINES ABOUT WHETHER OTHER RESULTS ARE ABLE
TO RETURN FOR PEOPLE WHO CAN'T MAKE THEIR OWN DECISION BUSY
WHAT KIND OF GENETIC INFORMATION THEY WANT TO KNOW ABOUT
THEMSELVES. SO REALLY, IDEALLY THE ONLY KIND
OF RESULT THAT WE WOULD FEEL REALLY GOOD ABOUT RETURNING ARE
MEDICALLY ACTIONABLE VARIANTS IN CHILDHOOD AND ALTER THAT HEALTH
OF THE PEDIATRIC POPULATION. SOMETIMES WE ONLY HAVE DATA ON A
MINOR PRO BAND. WE ARE OKAY WITH RETURNING
CARRIER STATUS FOR MINOR CHILDREN.
BECAUSE IT COULD HAVE HEALTH IMPLICATION PHYSICAL FOR THAT
FAMILIAR IF THE PARENTS WOULD LIKE TO RECEIVE THAT.
THERE ARE VERY SPECIAL CIRCUMSTANCES UNDER WHICH WE
WOULD PREFER TO RETURN THAT INFORMATION EVEN THOUGH IT IT IS
ON A MINOR. WE TALKED TO PARENTS ABOUT HOW
WE WOULD LIKE FOR THIS CHILDREN TO RECONTACT US ON THE AGE OF
MAJORITY. OR WHEN THEY GET CLOSE TO 18, TO
TALK TO US ABOUT THE FACT THAT THEIR PARENTS ENROLLED THEM IN
THE SEQUENCING STUDY WHEN THEY WERE 5 OR 6 OR 10 OR HOWEVER OLD
THEY WERE AND WOULD THEY LIKE TO LEARN THIS INFORMATION?
WE CAN ENROLL PEOPLE WITH INTELLECTUAL IMPAIRMENT, THIS
HAPPENS A FAIR I. AND WE HAVE DRAWN ON THE
SERVICES TO HELP US SORT THROUGH THIS WHEN APPROPRIATE.
IN THE CASE OF INTELLECTUALLY IMPAIRED MINORS IS ANOTHER
CIRCUMSTANCE THAT WE HAVE FOUND OURSELVES IN AND IT INVOLVES A
THOROUGH AND NUANCE DISCUSSIONS AT THE TIME OF CONSENT BECAUSE
REALLY THE RATIONAL FOR WITHHOLDING SOME KIND OF
VARIANTS FOR PEDIATRIC POPULATIONS IS VERY CLOSELY TIED
TO A CHILD'S DECISION-MAKING CAPACITY AND WANTING THEM TO
ACHIEVE THEIR OWN DECISIONS AT AN APPROPRIATE TIME.
BUT FOR SOME SEVERELY INTELLECTUALLY IMPAIRED MINORS,
THIS IS MAYBE NOT NECESSARILY GOING TO BE IN THEIR FUTURE AND
WE TALK WITH PARENTS OF HOW WE ARE WILLING TO SHARE RESULTS FOR
THEIR MINOR CHILD, ANY KIND, ACCORDING TO THEIR PREFERENCE.
BUT IT'S NOT SOMETHING THAT WE EASTERLY --
USUALLY SPECIFICALLY STATE TO PARENTS BUT WE WAIT FOR PARENTS
TO RAISE WITH US THEIR CHILD'S INTELLECTUAL IMAIRPORT AND
FUTURE DECISION-MAKING CAPACITY. SO THIS WHOLE CONVERSATION
SHOULD HOPEFULLY MAKE YOU THINK THAT THIS KIND OF RESEARCH IS
MAYBE NOT APPROPRIATE FOR EVERYONE AND THAT INDEED SOME
PARTICIPANTS ARE KIND OF TURNED OFF BY THIS FROM OUR INITIAL
CONVERSATION. SO WE ARE REALLY HOPING AND
LOOKING FOR PEOPLE WHO ARE LOOKING TO ENGAGE WITH US OVER A
PERIOD OF YEARS WHERE THERE ISN'T A FAMILY STRUCTURE THAT
WILL IMPOSE ADDITIONAL BURDENS ON PARTICIPANTS AS THEY ARE
TRYING TO MAKE DECISIONS ABOUT WHAT KINDS OF RESULTS THEY WOULD
LIKE TO RECEIVE AND SOME DISCUSSION OF MEDICAL AND SOCIAL
RESOURCES THAT ARE MABYE AVAILABLE TO THESE FOLKS OR IT'S
IMPORTANT FOR US TO CONSIDER. SO HOW DO WE GET RESULTS BACK TO
FOLKS? SO, THERE ARE MANY DIFFERENT
RESULTS DISCLOSURE POLICIES SO THERE IS AN IDEA YOU CAN NOT
GIVE PEOPLE ANY RESULTS, BUT YOU CAN GIVE THEM EVERYTHING YOU
FIND OR YOU CAN CHOOSE. I WOULD SAY THAT IS WHAT WE
EMPLOY. SO AGAIN, THIS IMPORTANTLY
HAPPENS NOT HERE. BUT HERE.
SO DURING THE CONSENT SESSION, WE AGAIN REVIEW ALL OF THE
POSSIBILITIES WITH PARTICIPANTS AND ASK THEM TO THINK ABOUT WHAT
THEY MIGHT SAY AT THAT FUTURE CONSERVATION.
AT A DON'T COMMIT TO A RESULTS DECISION AT THE TIME OF CONSENT.
AND THERE ARE NO BOXES THAT THEY CHECK ON OUR CONSENT FORMS
SAYING THEY WANT ONE CATEGORY OR ANOTHER OF RESULTS.
SO AGAIN, THE PROCESS HERE IS THAT WE REVIEW THEIR RESULTS
PREFERENCES THAT WE COME TO TOGETHER DURING INFORMED CONSENT
PROCESS AND WE NOTE THOSE IN OUR CHARTS.
NO COMMITMENT TO A PREFERENCE WITH THE TIME OF CONSENT BECAUSE
WE RECOGNIZE THAT PEOPLE'S PERCEPTIONS ABOUT WAKINDS OF
RESULTS THEY LIKE TO RECEIVE MAY CHANGE OVER TIME.
AND SO, AFTER THEY LEAVE ANNOTATION PROCEEDS PER THE
STUDY GOAL SO WE DO AGAIN THE BUSINESS IS TRY TO UNCOVER THAT
PRIMARY VARIANT AND PARTICIPANTS ARE RECONTACTED WHEN RESULTS ARE
AVAILABLE. WE REVIEW THE BROAD CATEGORIES
WE TALKED ABOUT AT THE INITIAL CONSENT SENSION AT THAT TIME.
MAKE AN ELECTION ABOUT WHAT KINDS OF RESULTS THEY LIKE TO
RECEIVE. WE VALIDATE THOSE AND THEN ASK
THEM TO COME BACK TO NIH FOR IN PERSON REVIEW OF RESULTS.
THIS MAY HAPPEN MORE THAN ONCE AS WE REANNOTATE THEIR SEQUENCE.
JUST A FEW ANECDOTES QUOTES I HAVE UP HERE FROM OUR
PARTICIPANTS. SO, ONE FATHER OF A CHILD WITH A
RARE DISORDER SAID ABOUT SECONDARY VARIANT RESULTS FOR
HIMSELF AND FOR HIS CHILD: [READING]
SO IT MIGHT BE UNSETTLING WE HAVE THAT INFORMATION AND THEY
ARE NOT PRIEF TOW IT. ANOTHER PARTICIPANT ASKED:
[READING] SO I THINK THAT AGAIN THESE ARE
THE TYPES OF RESPONSES THAT WE GET FROM PARTICIPANTS WHEN WE
TALK TO THEM ABOUT THIS INFORMATION.
BUT REALLY AT THE END OF THE DAY, MOST PEOPLE SAY THAT THEY
WANT TO LEARN ABSOLUTELY EVERYTHING AND THAT INCLUDES
PARENTS WANTING TO LEARN ANY AND ALL RESULTS THAT ARE AVAILABLE
FOR THEIR CHILDREN AND SOME PARENTS HAVE BEEN UNCOMFORTABLE
WITH SOME OF THE ETHICAL DISTINCTIONS THAT WE HAVE DRAWN
BETWEEN DIFFERENT KINDS OF VARIANT RESULTS AND THIS IDEA
THAT WE WANT THEIR CHILDREN TO REAPPROACH US WHEN THEY CAN MAKE
THEIR OWN DECISIONS. SO IN CONCLUSION, I THINK THAT
WE FEEL VERY FORTUNATE BECAUSE DURING THESE CONVERSATIONS IT
BECOMES CLEAR THAT OUR GOALS ARE CLOSELY ALIGNED.
THESE ARE PARENTS AND PEOPLE AFFECTED WITH RARE DISORDERS.
PEOPLE WHO ARE AFFECTED WITH RARE DISORDERS AND THEY ARE VERY
MOTIVATED TO HELP US FIND THE MOLECULAR ETIOLOGY FOR THESE
DISORDERS. IN GENERAL, PATIENTS UNDERSTAND
THE COMPLEXITIES INVOLVED IN THIS PROCESS.
AND THEIR PREFERENCES ABOUT WHAT THEY LIKE TO RECEIVE OR THE WAY
THEY APPROACH THOSE RESULTS OR THE MEANING THEY ASCRIBED TO
RESULTS ARE AVAILABLE VARIES TREMENDOUS ACROSS PARTICIPANTS.
I HOPE THAT TODAY I LEFT YOU WITH THE IMPRESSION THAT THESE
CAN BE ITERATIVE RELATIONSHIPS, THAT THERE CAN BE RELATIONSHIPS
THAT GO BOTH WAYS BETWEEN THE DESIGN OF OUR PROTOCOLS, HOW WE
COMMUNICATE WITH OUR PARTICIPANTS AND HOW WE RETURN
RESULTS AND THAT MORE TRANSPARENTS BETHIS PROCESS CAN
GO A LONG WAY TOWARDS ACCOMPLISHING OUR REACH GOALS.
WITH THAT, I'LL THANK MANY PEOPLE IN OUR LAB PARTICULARLY
MY COLLEAGUE, CLAUDIA WHO IS VERY THE CLIN-SEQUE EXPERT.
ALL MY CONVERSATIONS WITH PEOPLE FROM OUR GROUP, JENNIFER AND
SARAH AND THE PARTICIPANTS IN OUR RARE DISORDER PROTOCOL AND
THE CLIN-SEQUE PARTICIPANTS. THANK YOU.