Methodology:
This PGA utilizes a DNA registry focused on individuals and families with
congenital cardiovascular disease. The registry provides the groundwork for
multiple ongoing resident and collaborative investigations.
The registry is responsible for coordinating clinical care / research efforts
in genetic cardiology (identifying collaborators in cardiology, genetics, and
genetic research within Children’s Hospital / Enders Research community,
identifying potential joint projects), preparing educational materials,
developing resources for physician education, and creating patient/donor
information pamphlet or newsletters as appropriate.
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Patient Selection / Recruitment
Initially patients and families have been recruited from one of several
categories. These include individuals affected with abnormalities of development
including conotruncal maldevelopment, hypoplastic left heart structures,
abnormalities of visceral sidedness (heterotaxy) or those with a family history
of recurrent cardiovascular abnormalities. Individuals are ascertained through
the general cardiology and cardiovascular genetics clinics, as well as those who
are undergoing elective operative procedures or cardiac catheterization.
Potential participants are selected by diagnosis and/or by report of familial
clustering or syndromic associations without regard to gender, race, ethnicity,
or age. Because we also serve a population of adults with congenital heart
disease, some adults are included in this generally pediatric cohort. Patients
meeting inclusion criteria are added to an ongoing list of individuals who are
approached in a generally consecutive manner. Actual enrollment is dependent
multiple factors including stability of proband health, familial availability,
and availability of recruitment staff. Ethnicity and sex ratio are tracked to
ensure appropriate representation. Families are not approached if in active
crisis. Patients approached by the registry are offered basic information about
the registry. If a patient indicates a general interest in participating, an
informed consent process is initiated, and if completed, an extensive
medical/family history is taken including a three-generation pedigree. Finally,
blood and/or tissue samples are obtained from the proband, parents (if
possible), and other available affected relatives. Most donors provide
peripheral blood samples only. Discarded skin, tissue, and/or muscle samples may
be obtained when the donor is undergoing a surgical procedure for clinical
purposes.
The Registry places a high premium on the participant’s time and resources
and provides the necessary ingredients to guarantee the efficient and effective
use of donations. These include: assessing the participant’s interests and
concerns (including desire to learn of significant results), gathering all
appropriate medical and family history, offering general information and
answering participant questions and concerns while providing for an adequate
informed consent process. (See Risks and Benefits)
In most instances, the completed informed consent process is separated from
additional information gathering sessions by at least 1 full day, often several
days to weeks. This intervening time allows for participants to more fully
assess their desire for participation and to begin to formulate questions and
concerns that can be most effectively addressed in a face to face counseling
session. It also provides participants the opportunity to gather additional
medical and family information.
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Phenotype Development
Detailed histories of all maternal pregnancies are elicited with a focus on
the affected pregnancies. Potential maternal factors and/or teratogenic
exposures are explored as well as history of infertility, miscarriage,
termination, neonatal death, SIDS, premature death.
Clinical phenotype assessment of the proband includes both cardiac and
non-cardiac findings. Details of medical and developmental history are explored
with an emphasis the development of a precise cardiac phenotype. This includes
analysis of echocardiograms, MRIs, catheterization and operative reports.
Additional medical records are obtained to explore possible developmental
abnormalities in other organ systems as well as developmental milestones. This
history is comprised of both family reported and medically/developmentally
(non-cardiac subspecialties, primary care, early intervention, OT, PT, speech
therapy, IEP) verifiable information. Full three-generation pedigrees are
obtained with special emphasis on details described above including cardiac and
non-cardiac abnormalities. “Release of medical information” forms are obtained
from all appropriate family members to obtain medical records if necessary.
These records may include genetic or biochemical testing results, as well as
products of conception and autopsy reports.
The registry seeks to establish a relationship with participants
where there is an expectation of ongoing contact. Families have the opportunity
to update us on evolving medical and family histories or to inquire about
potential new developments. This dynamic process permits a more substantial and
evolving phenotype development.
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Participant Privacy
While participant’s cardiologists and cardiovascular surgeons are aware of
the potential for their patients to be involved in the registry, they are not
apprised of specific family participation. Records of participation are kept in
locked files separate from the medical record system. All data is kept in a set
of interactive password-protected databases housed in within the research
computer system.
While identifiers are maintained within the databases, each
family/participant is assigned a unique study number. This number is attached to
samples and records (see Sample Integrity) to
help protect participant privacy.
The interactive databases are linked through the assigned study number but
separate demographic, phenotypic and family history from genetic information.
Each database has it’s own password protection. Access to the databases is
restricted solely to registry staff.
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Sample Integrity
Samples may be obtained in a variety of settings including cath lab, O.R., or
clinic and placed in designated repository for CVG Registry samples. Samples are
drawn from family members by registry staff (sometimes with the assistance of
research nursing staff.) Occasionally samples are drawn by the hospital
phlebotomy service. Rarely, samples are mailed in from outside sources. While we
ask that they be appropriately labeled, we cannot be completely assured of their
integrity. After pick up, the samples are brought to the lab. Pending
processing, blood samples are stored in a dedicated -20°C refrigerator in a
locked laboratory; tissue is stored in dedicated -80°C or -120°C freezers. In
general, blood samples are split, with aliquots frozen for later verification
purposes. Depending on sample size, a proportion of the sample is used for DNA
extraction/quantitation, while a portion may be used to generate immortalized
cell lines. Blood samples are often split into several batches to protect
individual donations from lab error. Once a sample has entered the processing
phase, they are given new labels with unique identifiers including CVG #, sample
date, and diagnosis. (See Providing Results.)
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Individual Investigations
The objective of the Cardiac Genetic Registry is to provide a more systematic
approach and protection for patients who choose to participate in genetic
cardiac research. For patients who elect participation, the Registry process
allows access to an evolving set of appropriate studies including those
contained within the PGA. While many studies may not provide a direct
therapeutic benefit for a given participant, many offer important information to
the field of cardiovascular genetics, some provide meaningful information for
counseling purposes, while others help to improve the medical management of the
participant’s healthcare concerns. The types of research that can be anticipated
from use of this element of the PGA include mutation analysis of newly
identified candidate genes that are believed to play a role in cardiovascular
development and/or cardiac function. Given the rapidly evolving nature of our
knowledge and technical ability, such a registry serves the patient’s interest
by enabling multiple scientific inquiries without repeated solicitation.
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Providing Results
Participants have multiple opportunities to indicate whether or not they
would like to be contacted with information generated from their participation.
However, they always retain the right to decline such information at any point.
If a participant has requested information and a preliminary mutation
identified, the participant is re-contacted. They are advised that a preliminary
result exists and must be confirmed before the result can be released. If
interested, a new blood sample is drawn and sent to a CLIA (Clinical Laboratory
Improvement Amendments) approved lab to be verified. Participants are made aware
of these government guidelines at the time of consent. Within the legal limits
dictated by hospital policy, the data is protected from third parties. In terms
of disclosure, each participant is viewed as independent of any other donors.
Results are reported only at the prerogative of the donor. Records are assigned
a study number and referred to by number only. Identifiers are not maintained
during any subsequent investigations; non-identifying phenotypic information is
available as deemed necessary by individual protocol. The principal investigator
maintains the only record linking study numbers to other identifiers. Links to
identifying information are maintained primarily to allow donors to be contacted
when relevant information arises, or to further delineate phenotypic
characteristics.
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Risks and Benefits
While the physical risk is negligible, participants are encouraged to
consider potential psychological and social risks. These are the characteristic
risks associated with genetic testing. In addition, emphasis is placed on the
fact that testing of samples will be performed on a research basis, rarely
yielding direct benefit. The risk/benefit balance of participation is explored
with each participant. The discussion includes but is not limited to the
possibility of being included in multiple studies (consecutively or
simultaneously), and the potentially unknown nature of evolving testing. Efforts
are made to assure a non-coercive, well-considered, and supportive decision
making process. Precautions are taken to provide adequate security to protect
the privacy and confidentiality of both registry participation and particular
results. A genetic counselor with expertise in congenital cardiovascular disease
is directly involved in the consent process and in ongoing registry related
patient contact.
The tests performed on the samples are genetic in nature and carry all the
risk factors associated with genetic testing. Results could impact on the future
health care and liability of the donor and could theoretically influence hiring
decisions. By providing a centralized source of DNA linked to pertinent medical
and family histories, the registry dramatically enhances the ability to
efficaciously search for a better understanding of the interplay between genetic
etiologies and anomalous cardiovascular development. Ultimately this may lead to
better prevention, detection, and treatment for individuals affected with these
disorders.
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For questions or feedback, please e-mail us: Cardiovasculargenetics@cardio.chboston.org
Participants
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