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Ethical issues raised by incorporation of genetics into the National Birth Defects Prevention Study.

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American Journal of Medical Genetics Part C (Seminars in Medical Genetics) 148C:40 –46 (2008)
A R T I C L E
Ethical Issues Raised by Incorporation of Genetics
Into the National Birth Defects Prevention Study
MARY M. JENKINS,* SONJA A. RASMUSSEN, CYNTHIA A. MOORE,
AND MARGARET A. HONEIN
Investigators involved in public health research must conduct high-quality studies that advance scientific
knowledge for the collective benefit of the public’s health, while at the same time ensuring that the individual
rights of human subjects are protected. Successful completion of the Human Genome Project provides greater
opportunity to incorporate the study of genetic factors into public health research. Integration of DNA specimen
collection into epidemiological studies of complex disorders, such as birth defects, is necessary to identify genetic
risk factors that affect susceptibility to potentially modifiable environmental risk factors, but collection of DNA
samples often heightens concerns about ethical issues. Some of these issues include ensuring informed consent in
an ongoing study as new genetic risk factors and novel genetic technologies for study continue to be identified,
achieving a balance between improving participation using incentives and avoiding coercion, ensuring
confidentiality of individual genetic data, and considering when and how to report research results to study
participants. We present a discussion of ethical issues addressed by investigators of the National Birth Defects
Prevention Study, a multisite, population-based, case–control study of risk factors for birth defects, which has
incorporated the study of genetic risk factors. Study participants include infants and young children whose
parents consent on their behalf, increasing the complexity of the ethical issues. Discussion of these issues and the
methods employed to ensure protection of human subjects might be helpful to other investigators working to
integrate genetics into large epidemiological studies. Published 2008 Wiley-Liss, Inc.{
KEY WORDS: birth defects; risk factors; public health; research ethics; genetic research
How to cite this article: Jenkins MM, Rasmussen SA, Moore CA, Honein MA. 2008. Ethical issues raised
by incorporation of genetics into the National Birth Defects Prevention Study.
Am J Med Genet Part C Semin Med Genet 148C:40–46.
INTRODUCTION
The goal of public health research is to
gain knowledge that will protect and
promote the health of society [Institute
of Medicine (IOM), 2002]. Investigators
involved in this type of research must
conduct scientifically sound studies that
provide robust results that can be used to
improve the public’s health, while simultaneously ensuring that the rights of
human subjects are protected. Research
studies that include analysis of genetic
risk factors provide additional ethical
challenges. However, population-based
genomic research is essential to ensure
The findings and conclusions in this report are those of the authors and do not necessarily
represent the views of the Centers for Disease Control and Prevention.
Mary M. Jenkins, Ph.D. is a Senior Service Fellow in the Birth Defects Surveillance and
Epidemiology Branch in the National Center on Birth Defects and Developmental Disabilities,
Centers for Disease Control and Prevention, Atlanta, GA.
Sonja A. Rasmussen, M.D., M.S. is a Pediatrician and Clinical Geneticist and currently serves as
Senior Scientist in the Birth Defects Surveillance and Epidemiology Branch in the National Center
on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention,
Atlanta, GA.
Cynthia A. Moore, M.D., Ph.D. is a Clinical Geneticist and Associate Director for Science in the
Division of Birth Defects and Developmental Disabilities in the National Center on Birth Defects
and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, GA.
Margaret A. Honein, Ph.D., MPH is an Epidemiologist and Chief of the Birth Defects
Surveillance and Epidemiology Branch in the National Center on Birth Defects and Developmental
Disabilities, Centers for Disease Control and Prevention, Atlanta, GA.
*Correspondence to: Mary M. Jenkins, 1600 Clifton Road, MS E-86, Atlanta, GA 30333.
E-mail: mmjenkins@cdc.gov
DOI 10.1002/ajmg.c.30157
Published 2008 Wiley-Liss, Inc.
{
This article is a US Government work and, as such, is in
the public domain in the United States of America.
that recent research advances in genomics are translated to clinical and public
health applications [Gwinn and Khoury,
2006].
Birth defects are a leading cause of
infant mortality, accounting for more
than 20% of infant deaths in the United
States [Heron and Smith, 2007], and
they contribute significantly to hospitalizations in the newborn period and in
childhood [Yoon et al., 1997; Centers
for Disease Control and Prevention,
2007]. The causes of some birth defects
are known. For example, some birth
defects are caused by single-gene disorders or chromosomal abnormalities
[Murray, 2002; Pierpont et al., 2007],
while others are due to prenatal exposures to non-genetic (environmental)
factors, such as medications, infection,
and maternal illness [Jenkins et al.,
2007]. However, for most birth defects,
the etiology is unknown [Nelson and
Holmes, 1989], limiting opportunities
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AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS): DOI 10.1002/ajmg.c
for prevention. Most birth defects are
believed to be caused by a combination
of genetic and environmental factors
[Lidral and Murray, 2004; Willingham
and Baskin, 2007]. Understanding the
genetic component is critical [Khoury
et al., 2005] because this knowledge
(1) improves the accuracy of recurrence
risk counseling for affected families
[Wilkie et al., 2007]; (2) permits identification of genotypes that might increase
susceptibility to a particular environmental risk factor [Shi et al., 2007],
which could lead to targeted preventive
interventions [Khoury et al., 2005];
(3) could lead to identification of
modifiable risk factors weakly associated
with birth defects when examined in the
general population, but more strongly
associated when examined among individuals with a particular genotype
[Khoury et al., 1992a,b, 2005]; and
(4) might result in an improved understanding of pathogenesis and, subsequently, recognition of developmental
pathways potentially amenable to intervention [Khoury et al., 2005].
The National Birth Defects Prevention Study (NBDPS) is an ongoing
case–control study of major birth defects
whose goal is to identify genetic and
environmental risk factors for birth
defects. Incorporating the study of
genetic risk factors into the NBDPS
has presented investigators with several
challenges. Examples of these challenges
include ensuring informed consent in an
ongoing study as new genetic risk factors
and novel genetic technologies for study
continue to be identified, achieving a
balance between improving participation using incentives and avoiding coercion, ensuring confidentiality of individual
genetics data, and considering when and
how to report research results to study
participants. Sharing information about
these challenges and how they were
addressed might prove helpful to other
investigators working to integrate genetics into large epidemiological studies.
GENETIC STUDIES IN
THE NBDPS
Infants with one of more than 30 types
of NBDPS-eligible birth defects (case
infants) are ascertained through population-based birth defects surveillance
systems in nine study sites (Arkansas,
California, Georgia, Iowa, Massachusetts, New York, North Carolina, Texas,
and Utah). Infants with defects of known
etiology (i.e., recognized chromosomal
abnormalities or single-gene disorders)
are excluded. Infants without major
birth defects (controls) are randomly
selected from births in the same regions
from which case infants were ascertained, either through birth certificates
or hospital records. Information on
environmental risk factors (e.g., maternal medication use, nutrition, lifestyle,
occupation, and demographics) is obtained through an hour-long maternal
interview conducted by telephone, and
DNA for studies of genetic risk factors is
extracted from self-collected buccal
(cheek) cell samples from case and
control infants and their parents [Yoon
et al., 2001; Rasmussen et al., 2002].
NBDPS investigators initially
planned to use a candidate gene
approach focusing on genes for which
evidence from previous studies indicates
involvement with causation of birth
defects. However, in more recent years,
technological advances have led to
widespread use of genome-wide association studies, an approach that builds on
the recent availability of technologies
that allow genotyping of hundreds of
thousands of polymorphisms and holds
great promise for the identification of
genetic risk factors for complex diseases
[Christensen and Murray, 2007; Samani
et al., 2007]. No knowledge of prior
NBDPS investigators initially
planned to use a candidate gene
approach focusing on genes for
which evidence from previous
studies indicates involvement
with causation of birth defects.
However, in more recent years,
technological advances have
led to widespread use of
41
genome-wide association
studies, an approach that builds
on the recent availability of
technologies that allow
genotyping of hundreds of
thousands of polymorphisms
and holds great promise for
the identification of
genetic risk factors for
complex diseases.
association with outcome is needed for
genome-wide association studies. Both
of these approaches have advantages and
disadvantages [Green and Moore, 2006]
and may have different implications for
human subjects protection issues.
INFORMED CONSENT
ISSUES
Several issues arise regarding informed
consent for genetic studies of risk factors
for birth defects. Because children
represent a vulnerable population, in
the absence of a direct benefit to the
child, study participation can pose no
greater than minimal risk [Federal
Register, 1983]. Typically, questionnaire-based research is considered minimal risk. Although the collection of
buccal cells does not significantly add
to the risk for physical harm, parents
consenting for their children might have
concerns about use of the samples in
future research. To ensure that parents
are fully informed, the buccal cell
collection kit sent to NBDPS participants explains in detail what happens to
the buccal brushes and DNA samples
extracted from them. The explanations
clarify the use of code numbers for
sample labeling, the potential storage of
samples for many years until sample size
is adequate for analysis, assurance that
research on the genetic samples will be
limited to factors thought to be involved
in the causation of birth defects, and
information about return of research
42
AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS): DOI 10.1002/ajmg.c
results to participants. These explanations have helped to fully inform parents
of issues of concern related to collection
and analysis of DNA specimens.
Because many birth defects are
relatively rare, a multisite, multiyear
study is required to allow for collection
of sufficient numbers of specimens to
provide worthwhile analysis. However,
for ongoing studies, new genetic factors
and novel technologies for their assessment can be expected to become
available while the study is proceeding.
NBDPS investigators recognized this
issue early in the study and worked with
the CDC Institutional Review Board
(IRB) to develop a mechanism to ensure
that human subject protection issues
could be addressed appropriately. In
the informed consent form, rather than
provide consent for study of an extensive list of specific individual genetic
factors, participants are asked to provide
consent for studies of genetic factors
that might play a role in birth defects
causation, but for no other purpose.
To ensure human subjects protection,
detailed information on each genetic
factor proposed for study is reviewed by
the CDC IRB. Information required
for review includes a description of the
research; justification for studying the
factor; information on the ‘‘clinical
significance’’ of the factor proposed for
study (this issue will be discussed in
more depth in the section on reporting
research results to participants); and for
factors of clinical significance, a description of the additional efforts to ensure
human subjects protection. This information is submitted for IRB review as
an amendment to the overall study
protocol when a new genetic factor
is proposed for analysis. Approved
genome-wide association studies are
considered a screening tool for identification of genomic regions of interest
and specific candidate genes subsequently identified will also undergo
IRB review. Thus, the IRB serves
effectively as an independent review
panel to provide updated ‘‘consent’’ on
specific genetic studies, similar to what
has been proposed recently for studies
with large DNA biobanks [Shickle,
2006].
IMPROVING
PARTICIPATION USING
INCENTIVES
Low participation rates limit the numbers of specimens available for analysis,
therefore decreasing study power, but
also often introduce a selection bias
related to study participation that might
limit the capacity to identify genetic risk
factors for some racial and ethnic groups
with low levels of participation. Monetary incentives have been widely
reported to have a positive impact on
participation rates [Collins et al., 2000;
Shaw et al., 2001]. However, it is
important to ensure that the incentives
are not such that they could coerce
participants to disregard their concerns
about the study. Initially, the NBDPS
provided monetary incentives for the
buccal specimen collection but not the
maternal interview; however, participation rates were found to be lower than
desired and therefore monetary incentives were included in the initial interview mailing in an effort to improve
participation. At the Atlanta site of the
NBDPS, monetary incentives were
shown to be particularly effective at
improving buccal cell participation
among racial and ethnic groups with
the lowest participation rates [Crider
et al., 2006].
To decrease the possibility of providing an incentive that has undue
influence on participants while conveying that the information and samples
provided by participants are of value
to the investigators, incentive amounts
offered to NBDPS participants have
been devised to be consistent with the
amounts offered by comparable studies
[Singer and Bossarte, 2006]. Currently,
mothers eligible for the NBDPS are sent
a $20 monetary incentive with the
introductory study material (before the
telephone interview). When the interview is completed, each family is sent a
buccal cell collection kit with a second
$20 as a monetary incentive. Some
participants likely view this second
incentive as a reward for completing
the interview, while others might view it
as incentive to complete the buccal
collection. Eight study sites currently
ARTICLE
send a third monetary incentive of $20
to families with a thank you letter after
return of the completed buccal cell
collection kit. While these incentives
have resulted in relatively high participation rates for the interview portion of
the study (70%), participation rates for
collection of buccal specimens remain
low (56% of those interviewed). Better
understanding of the reasons that families are reluctant to participate in buccal
collection is needed to minimize selection bias, without providing incentives
that could be coercive.
ENSURING DATA
CONFIDENTIALITY
An important area addressed in the
consent process is data confidentiality.
Parents might have particular concerns
about the future disclosure of genetic
information and what this disclosure
might mean for their child’s insurability
or employment opportunities. Although
public concern about genetic discrimination is widespread, a review of the
literature pertinent to discrimination in
life insurance resulted in few reported
cases of validated genetic discrimination
[Joly et al., 2003]. Further reassurance
in this area could be provided by the
Genetic Information Non-Discrimination Act (GINA), legislation currently
passed by the U.S. House of Representatives (H.R.493) and under consideration by the U.S. Senate (S. 358; http://
www.ornl.gov/sci/techresources/human
genome/elsi/legislat.shtml). This Act
would prohibit access to genetic information by insurance companies and
prohibit companies from discriminating
against an applicant based on genetic
information, previous genetic testing, or
refusal to submit genetic information.
Additionally, the Act would prohibit
employers from using or collecting
genetic information for employment
decisions.
Given the current popularity of
DNA forensics in the entertainment
media, parents might also be concerned
about the potential disclosure of their
child’s genetic information for legal proceedings [Burke and Diekema, 2006].
To assure NBDPS participants of data
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AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS): DOI 10.1002/ajmg.c
confidentiality, a certificate of confidentiality was obtained for the study [Public
Health Service Act, 1988a]. This certificate protects the legal rights of study
participants under section 301[d] of the
Public Health Service Act 42 U.S.C.
241[d] and prevents study staff from
being forced under a court order or other
legal action to identify study participants. This protection exists in perpetuity for any persons who were participants
in the research during any time the
certificate was in effect.
Data confidentiality is of particular
concern when the number of polymorphisms assessed is large, for example,
genome-wide association studies, because the results could potentially be
used to identify study participants. To
ensure data confidentiality, genetics data
will be stored in a limited-access database, and only investigators who are
protected by the NBDPS certificate of
confidentiality will have access to the
data for use in analyses.
REPORTING RESEARCH
RESULTS TO PARTICIPANTS
Whether or not to report research results
to study participants has engendered
much discussion over recent years
[Bookman et al., 2006; Knoppers et al.,
2006; Manolio, 2006]. These discussions
have centered on the issues of clinical
significance, analytic validity, and an
individual’s right to not know results.
Guidelines to assist investigators in
deciding what research results to provide
to research participants were developed
by the National Heart, Lung, and Blood
Institute (NHLBI) Working Group on
Reporting Genetic Results in Research
Studies [Bookman et al., 2006]. These
include that (1) the risk for disease is
significant and has been replicated, (2)
the disease has important consequences
for health (i.e., increased morbidity or
mortality), and (3) interventions of
proven benefit for treatment or prevention are available [Bookman et al., 2006].
In addition to these criteria, the NHLBI
Working Group emphasized the need to
document analytic validity of the laboratory test under consideration (i.e., the
test must accurately and reliably measure
the genetic factor of interest) [Burke
et al., 2002]. One way that analytic
validity is assessed in clinical laboratories
is through regulations of the Clinical
Laboratory Improvement Amendments
(CLIA), passed by Congress in 1988
[Ehrmeyer and Laessig, 2004]. The goal
of CLIA is to establish quality standards
for laboratory testing in the United
States, and CLIA certification is required
for any laboratory examining ‘‘materials
derived from the human body for the
purpose of providing information for
the diagnosis, prevention, or treatment
of any disease or impairment of, or the
assessment of the health of, human
beings’’ [Public Health Service Act,
1988b, p. 222]. The NHLBI Working
Group recommendations concluded
that if results are to be provided to
research participants, the studies should
be performed in a CLIA-certified
laboratory.
As discussed earlier, for each genetic
factor to be studied using NBDPS
specimens, the CDC IRB will review
information including whether the factor is of ‘‘clinical significance.’’ The
inclusion of this criterion was to ensure
that the issue of reporting research results
from which participants could benefit be
carefully considered. Most research
studies of genetic risk factors currently
planned for the NBDPS will assess
genetic polymorphisms of unknown
clinical significance. For those studies,
reporting the genetic results will be of
no potential benefit to the participants.
However, studies of some risk factors
of clinical significance are planned.
Most research studies of genetic
risk factors currently planned
for the NBDPS will assess
genetic polymorphisms of
unknown clinical significance.
For those studies, reporting the
genetic results will be of
no potential benefit to the
participants. However, studies
43
of some risk factors of clinical
significance are planned.
Because the term ‘‘clinical significance’’
could be subject to interpretation,
guidelines to assess clinical significance
of a genetic factor were developed by
NBDPS investigators with assistance
from the CDC IRB. These guidelines
are consistent with those developed by
the NHLBI Working Group (i.e., significant risk for disease is reliably associated with the genetic factor, the disease
has important consequences for health,
and interventions of proven benefit for
treatment or prevention are available)
[Bookman et al., 2006]. For genetic
factors that meet these criteria of clinical
significance, discussion of whether
results will be provided to research
participants must be included in the
amendment submitted to the IRB.
Additionally, when analysis of a particular genetic factor deemed to be of
clinical significance is performed on
specimens collected by the NBDPS,
CLIA certification will be sought.
There has been considerable debate
about whether participants’ right to not
know extends to genetic information
[Malpas, 2005; Wilson, 2005]. The
issues are particularly complex when
the genetic risk information is about a
child, and parents might be choosing not
to know genetic information that has
clinical significance to the child [Swartling et al., 2007]. If knowledge of the
genetic results would change the medical
care or treatment of the child, provision
of this information is clearly of strong
benefit to the family and health care
providers. However, learning about
genetic risk factors can negatively affect
family relationships [Gilbar, 2007;
Stroup and Smith, 2007]. Knowing
about genetic risk factors might interfere
with parent–child bonding when that
knowledge is learned very early in the
child’s life, even if results turn out to be
incorrect, such as with false positive
newborn screening results [Gurian et al.,
2006]. Some families experience increased stress or symptoms of depression
after receiving genetic risk results [Yu
44
AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS): DOI 10.1002/ajmg.c
Learning about genetic risk
factors can negatively affect
family relationships. Knowing
about genetic risk factors might
interfere with parent–child
bonding when that knowledge is
learned very early in the child’s
life, even if results turn out to be
incorrect, such as with false
positive newborn screening
results. Some families
experience increased stress or
symptoms of depression after
receiving genetic risk results.
et al., 1999; Bennett Johnson et al.,
2004; Hood et al., 2005].
One way to address this issue is to
ask parents during the original consent
process to indicate their desire to
receive—or not receive—genetic test
results, and then respect their decision
[Beskow et al., 2001]. However, families
of children with major birth defects are
often overwhelmed by the hospitalizations and other medical procedures
needed to meet their child’s immediate
medical needs. The stress, exhaustion,
and emotional strain might create some
specific time periods when parents
are unwilling or unable to cope with
receiving results of genetic tests. Because
participants’ views might change
over time, NBDPS has a procedure in
place to make results available to participants if desired, considering both the
right to know and the right not to know
genetic research results. A newsletter is
mailed to participants each year updating
them on the status of the study. Results
of genetic tests of clinical significance
will be reported in summary form in the
annual participant newsletter. Participants will be able to contact the study site
and request genetic test results after
publication in the study newsletter.
When clinical tests are available, participants will be encouraged to have the
tests repeated in a clinical lab setting.
Participants will also be provided the
opportunity to speak to a clinical
geneticist at each site who can answer
their questions on the appropriate interpretation of the genetic test results.
The informed consent document for
NBDPS DNA specimen collection
informs parents of the option to receive
results of clinical significance; however,
the document emphasizes that (1) studies
on buccal samples are not meant to test
medical status, (2) results are not planned
to be provided, and (3) if families desire
information about genetic testing, they
should contact their health care provider. No testing of genetic risk factors
of clinical significance has yet been
performed, so these procedures have
yet to be tested.
A Case Study: Identifying Children
With 22q11.2 Deletion
One genetic risk factor planned for
NBDPS analysis, 22q11.2 deletion, has
presented a particular challenge regarding provision of research results to
participants. The term ‘‘22q11.2 deletion’’ refers to loss of about 3 Mb of
DNA and more than 20 genes from the
long arm of chromosome 22 [McDonald-McGinn et al., 2005]. In clinical
studies, 22q11.2 deletions have been
associated with several problems, including cleft palate, congenital heart defects,
cognitive impairment, schizophrenia,
hypocalcemia, and increased risk for
infections.
The study of 22q11.2 deletions as
part of the NBDPS is important for two
reasons. First, some defects (e.g., certain
congenital heart defects) have been
clearly associated with 22q11.2 deletions
in previous clinical and epidemiological
studies [Goldmuntz et al., 1998; Botto
et al., 2003; McElhinney et al., 2003].
Because defects of known etiology (e.g.,
chromosome abnormalities, including
22q11.2 deletions, when recognized) are
excluded from the NBDPS, a child with
a 22q11.2 deletion identified clinically
would be excluded. However, wide
variation exists in the frequency of
clinical testing for this deletion across
study sites. Thus, based on regional
ARTICLE
clinical practices, some sites will readily
be able to exclude case infants with
22q11.2 deletions, while others will not.
If a child with this deletion was not tested
or the information was not ascertained,
he or she could be included in the study
inappropriately, and inclusion of cases
with known etiology could lessen the
opportunity to identify non-genetic risk
factors [Khoury et al., 1992a]. In addition, some of the evidence for association between 22q deletions and certain
defects (e.g., imperforate anus, hypospadias, craniosynostosis [McDonaldMcGinn et al., 2005], radial aplasia
[Digilio et al., 1997], and esophageal
atresia [McDonald-McGinn et al.,
2005]) is based primarily on case reports;
thus, testing of children with these
defects is uncommon in current clinical
practice.
Testing for 22q11.2 deletion meets
several NHLBI criteria for reporting of
genetics research results [Bookman et al.,
2006]. First, 22q11.2 deletion testing has
established analytic validity; fluorescence in situ hybridization (FISH) testing for this deletion is performed in
clinical laboratories across the country
and is considered ‘‘standard of care’’ for
patients with certain defects. Because of
the specimens available for study, we
plan to use a different methodology
(i.e., quantitative PCR, rather than
FISH testing [Weksberg et al., 2005,
2007]), but implications of the results
will not change. To document analytic
validity of the testing, CLIA certification
will be sought before 22q11.2 testing of
NBDPS specimens is initiated.
Second, the risk for disease associated with 22q11.2 deletion is significant,
based on available data. For example, in
one study, about 80% of infants with
22q11.2 deletion had a congenital heart
defect [Botto et al., 2003], although
22q11.2 deletions were identified in
that study as part of clinical care so this
number could represent an overestimate.
In addition, 22q11.2 deletions have
important consequences for health;
some manifestations of 22q11.2 deletion
(e.g., hypocalcemia, congenital heart
defects) have serious health implications
if not treated promptly. Information
from 22q11.2 deletion testing is also
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AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS): DOI 10.1002/ajmg.c
routinely used to counsel families about
the child’s prognosis and parents’ recurrence risk (i.e., 50% if one of the parents
also carries the deletion).
However, the criterion that
requires the availability of interventions
of proven benefit for treatment or
prevention is not clearly met; often,
testing would be performed too late to
institute interventions for what are
typically early manifestations of the
disorder. There are also potential risks
of reporting research results of 22q11.2
deletion testing. Information on the
presence of a 22q11.2 deletion could
change the family’s perception of the
child, given that affected children are at
risk for problems such as cognitive
impairment and schizophrenia. Persons
identified with a deletion could face
insurance and employment discrimination and social stigmatization. Thus, we
recognize that some families might not
desire this information.
Because of these complex issues, we
will give parents the option to receive
22q11.2 deletion results, but we will not
provide results to those who choose not
to receive them. General information on
22q11.2 deletion testing has already
been shared with participants through
the newsletter. When 22q11.2 deletion
results become available, we plan to
publish summarized results of these
studies in the annual newsletter sent to
study participants. In the newsletter,
parents will be given the option of
receiving individual test results. Families
who choose to receive research results
will be encouraged to repeat testing in a
clinical laboratory and to meet with a
genetic counselor to discuss the results.
When requesting genetic results,
parents of infants with major birth
defects might suspect a genetic cause
(such as the 22q11.2 deletion) contributed to their child’s defect. However, any
positive results among control infants or
unaffected parents are likely to be
unanticipated. The risk of identifying
22q11.2 deletion in a control infant is
presumed to be very low, but given the
lack of population-based data on the
frequency of such deletions in the
absence of a recognized phenotype, we
cannot assume that no control infants in
the study will have this clinically significant risk factor or another genetic result
of concern. Appropriate referrals to
genetics clinics will be especially critical
for the families of any control infants
with positive results because these families are much less likely than case
families to have already connected with
genetic evaluation and counseling services as part of their routine medical care.
CONCLUSIONS
We and other NBDPS investigators have
addressed several ethical challenges as
analysis of genetic risk factors has been
incorporated into the study; however,
these challenges are unlikely to be
unique. We hope the discussion of these
issues and how they were addressed
proves beneficial to other large epidemiological studies that incorporate the
collection and analysis of genetic samples. To address these issues, the NBDPS
investigators (1) strive to provide complete and transparent disclosure of possible risks and benefits to potential study
participants during the informed consent process; (2) use a mechanism by
which each genetic factor proposed for
analysis using NBDPS specimens undergoes IRB review; (3) provide monetary
incentives in amounts that decrease
selection bias while avoiding coercion;
(4) obtained and maintain a certificate of
confidentiality to help ensure protection
from forced disclosure of identifiable
study data; (5) follow established guidelines to determine if research results
should be reported to study participants;
and (6) plan to release aggregate study
results in a newsletter to respect each
participant’s right to know and not know
clinically significant results. Given that
the NBDPS is ongoing, we will likely
face additional challenges in the future as
we continue to learn more about the
causes and prevention of birth defects,
while ensuring the protection of the
rights of human subjects.
ACKNOWLEDGMENTS
The authors thank the families who
participate in the National Birth Defects
Prevention Study as well as the NBDPS
45
staff and scientists from all collaborating
sites. We also acknowledge staff of the
CDC IRB for their efforts in helping us
to carefully consider these ethical challenges.
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