Slide 1. Research in the genetics of common complex
diseases shows tremendous potential to explain the role of genes as
causal factors in complex and common human diseases. Such understanding
is a necessary first step in realizing the promise of the Human Genome
Project (HGP) to revolutionize disease prevention, detection, and treatment.
As is true of all research, full realization of these benefits requires
careful attention to the ethical aspects of the research and how the
results are applied. This educational module, "Ethics and Genetics
Research in Populations", is made possible by a grant from the
Ethical, Legal and Social Issues program at the US Department of Energy.
Slide 2. Genetic epidemiology involves identifying
the potential genetic contribution to disease, including the interactions
between genes, and between genes and the environment. This depends
in part on analyzing DNA sequences from individuals who have or will
develop disease, using large-scale DNA databanks in attempts to uncover
genes that contribute to common illnesses in entire populations.
Slide 3. To date, many large scale databases have
been created and the discoveries already made give a hint of what is
to come. A population-wide DNA database in Iceland has been used to
map genes in 25 common diseases and identified genes in 81.
The past successes and future potential of genetic research into many
conditions have been documented: asthma2, diabetes3,
obesity4, arthritis5, and breast cancer6,
to name but a few. Therefore, it is not surprising that there is substantial
global scientific and corporate enthusiasm for extending this work.
Slide 4. Despite scientific success, several scholars
and professional groups have raised array of ethical concerns about
these efforts, including worries over confidentiality, informed consent,
and ownership of data. The Human Genome Organisation (HUGO)7,
the World Health Organization8, and the International Bioethics
Committee of UNESCO among others have released reports concerning these
issues9.
Some hypothetical case vignettes can help clarify the types of issues
confronted when designing and conducting genetics research in populations:
Slide 5. Researchers at a major university have access
to a large DNA bank. It includes samples from all patients at their
hospital who were admitted for the treatment of heart disease. The
researchers are approached by a neurologist who wants to use the DNA
bank to identify a genetic predisposition to major stroke. Is this
acceptable? What ethical issues does this case raise?
Slide 6. Working with a large population DNA bank,
researchers identify two different genes. One correlates with a predisposition
to developing an adult form of cancer that is essentially untreatable.
The other correlates with the likelihood of not being able to properly
metabolize a common drug. What responsibilities do the investigators
have to those whose DNA is in the bank?
Slide 7. Policy makers and scientists are enthusiastic
about creating an enormous DNA bank to help identify the genetic contribution
to common diseases such as high blood pressure and schizophrenia. They
are shocked by outcries from some religious groups and community groups
who object to moving forward with the plans for the bank. Why might
they be facing such objections?
Slide 8. Given cases such as these, this module
provides an overview of ethics in population genetics research. Upon
completing
this module, learners should be able to: (1) Recognize the major
ethical issues encountered in genetics research in populations; and
(2) Describe
strategies for minimizing possible harms related to these issues.
The emphasis in this module is on the ethical issues, not the related
legal
and regulatory considerations.
Slide 9. At least five general ethical obligations
are important for those involved with population-based genetics research:
(1) to avoid causing unnecessary harms; (2) maximize the benefits of
the research; (3) to be fair; (4) to respect the autonomy and liberty
of participants; and (5) to create and maintain a trustworthy endeavor.
Avoiding harm requires specifying the risks related to the research,
minimizing these risks through the design of the research and the procedures
used to handle data, and monitoring. Maximizing benefits includes considerations
of both individuals and groups that participate in the research, such
as providing important medical information to them. Fairness involves
broad considerations such as ensuring the appropriate choice of research
questions and subject populations as well as narrow considerations
such as choosing fairly among potential subjects. Respecting the autonomy
and liberty of participants typically requires obtaining their consent
for research and permission to use their medical information. Trustworthiness
of the endeavor is necessary to uphold the trust of those who participate
in the research. The ethical obligations for those engaged in population-based
genetics research are the same as those for research in other settings.
Nevertheless, these issues may manifest themselves in unique ways depending
upon the setting.
Slide 10. The module covers three broad areas related
to ethics in population-based genetics research: research design;
recruitment and consent; and dealing with results. In general, the
ethical obligations
related to each area will be described, followed by a description
of ways to minimize the ethical difficulties that may be associated
with
them. Each of the three case vignettes will be revisited in the relevant
portion of the module.
Slide 11. As the Council for International Organizations
of Medical Sciences (CIOMS) notes, scientifically unsound research
is, by definition, unethical: it places subjects at risk for no purpose.
Five specific topics related to research design will be described in
turn: delineating the research question; defining the trait; selecting
the study population;minimizing risks; and obtaining input from the
study population.
Slide 12. The first step in any research endeavor
is to delineate the research question. This raises important ethical
considerations. For instance, if the question itself is unanswerable,
it would be unethical to initiate or continue research because it would
expose participants to risk and their contributions would serve no
useful purpose. The question must also be appropriate with respect
to other pressing scientific questions in the field; and the extent
to which a particular population would then be under or over-studied.
Finally, consideration should also be given to whether it is affordable
to answer the question and whether answering it would divert resources
to answer other more urgent questions.
Slide 13. In studies of rare genetic conditions
family-based studies can be done effectively with little question
about the phenotypic
manifestations of the conditions. Defining the trait in population-based
genetics research can be more difficult, raising scientific and ethical
questions. For the science to be optimized, standard diagnostic criteria
are essential, and from the scientific perspective, broad thinking
about potential, scoreable outcomes to maximize statistical testing
is key. The gold standard for such studies is to have a committed
group of clinicians evaluate individuals in a consistent fashion
with specific
assessments of inter-rater reliability and procedures for adjudication
in place; but designs range from this gold standard to more practical
approaches such as medical record review. When practical considerations
require that medical records from multiple sources be obtained to
define the phenotypes of interest the study quality may be affected.
This
is compounded by the fact that many conditions have a complex genetic
contribution, the important genes may affect more than one disease
(for example, cancer in different sites) or may act in concert to
lead to disease. Furthermore, environmental exposure can mediate
expression of the underlying phenotype and complicate gene identification
studies.
Finally, traits that are controversial, stigmatizing, or lack uniformly
effective treatments, such as some forms of mental illness, may heighten
concerns for the participants.
Slide 14. Much debate exists as to whether social
criteria (e.g., race and ethnicity) used to define populations or "communities" adequately
reflect what researchers are seeking: an indicator of genetic homogeneity
(in studies with named populations, such as African-Americans) or heterogeneity
(in the International Haplotype Map10, 11). If defined too
broadly, the relevant features of a "community" or group
may classify coal miners and farmers as communities when these characterizations
have little to do with fundamental biological makeup12 (though
they may be important for gene-environment research). Researchers must
recognize the challenges involved in self-reporting, membership in
multiple groups, and the pitfalls of social labels, because all can
adversely affect or even invalidate research findings. Alternatively,
some studies are based in geographic communities, and require careful
assignment of underlying "groups" to allow potentially important
stratifications of data that may be key for accurate statistical analysis.
For instance, since high blood pressure is known to be more common
in African-Americans, it may be important to test associations between
genes and high blood pressure separately in African-Americans, Caucasian
Americans, and Asian Americans although all may live in the same identified
geographic region.
Slide 15. It is important to recall that well-intentioned
efforts in the past have led to appreciable harm to groups. For example,
the screening of African-Americans for sickle cell disease in the 1970s
resulted in highly visible employment discrimination whether or not
the individuals were afflicted with sickle cell anemia13.
In addition, the Ashkenazi Jewish population initially expressed concerns
over the study of "Jewish genes" in breast cancer and other
conditions14. Such experiences can undermine trust in the
research enterprise, perhaps destroying willingness to participate.
Slide 16. In all research it is essential for the
research to minimize risks to participants. While this is commonly
thought to involve physical risks, psychological, economic, and social
risks also should be considered and minimized. Physical risks may in
fact be limited to blood draws and biopsies, whereas psychological
risks may be related to receiving information about a genetic susceptibility
to a particular disease. Economic risks may relate to the loss of employment
or getting individual insurance in the future if such a predisposition
is detected. Social risks can be categorized as "external" and "internal".
External risks are imposed on a population, such as through racism,
discrimination, or perhaps via challenges to a culture’s history
(e.g., if genetic studies were to reveal unexpected ancestry that threatens
currently held land rights such as those involving Aboriginal land
claims in Australia). Internal or intra-community risks relate to discovering
shared or unshared ancestral identities.
Slide 17. Review by a proposed study population can
be beneficial both at the formative stages and throughout the research
process. Without sufficient knowledge about a particular population
under study, it may be difficult for researchers to anticipate harms
to the group, or individuals in the group, and to incorporate appropriate
protections into the research design. Such input may in turn led to
enhanced participation as well as provide important perspectives in
interpreting the results of the research. One way of thinking about
the process involves dialogue with members of the study population,
consultation about the research, approval of the research, and then
partnership through the research process.
The experience gained in the Human Genome Diversity Project highlights
the importance of obtaining group input.
Slide 18. Returning to the Case Vignette, "Resistance
to DNA Banking" described at the beginning of the module, it is
now clear that there are several reasons that groups might resist the
creation of an enormous DNA bank to study common diseases. These include
potential concerns of the study population regarding stigmatizing conditions
and the possibility of psychological, economic, and social risks. Since
the nature of the concerns are unclear, the researchers and sponsors
might do well to gain explicit input from the study population regarding
such concerns and perhaps identifying others. This in turn might suggest
means of addressing them.
Slide 19. While well designed research can address
ethical concerns, additional challenges can be encountered during recruitment
and informed consent. This section covers a brief overview of the process
of informed consent; the nature of "primary" and "secondary" research
subjects; the need for sensitivity to privacy and confidentiality during
recruitment and consent; and dealing with consent for the use of DNA
or information that was not anticipated at the time that initial consent
for research was obtained.
Slide 20. Informed consent is a means of meeting the
ethical obligation to respect the autonomy of persons and their right
to liberty, or the right in most circumstances to be left alone. These
rights preclude research and the use of one's personal information
without permission. In an ethical sense, informed consent is a process
of seeking informed permission for research. The process of informed
consent can only take place if a potential research subject has adequate
decision making capacity or competency to do so and is positioned to
make a voluntary choice about participation. If these threshold elements
are satisfied, the potential participant is given information about
the proposed research, including the procedures to be followed, and
alternatives to participating in the research. This information needs
to be given in a manner understandable to the potential participant.
Finally, a decision is made and authorized, usually by completing a
consent document.
Slide 21. Although it is clear that informed consent
needs to be obtained from research participants, population-based genetics
research can make it challenging to determine who in fact is a participant
from whom consent should be obtained. US federal regulations regarding
research define a human subject as: "a living individual about
whom an investigator… conducting research obtains (1) data through
intervention or interaction with the individual, or (2) identifiable
private information." While is is fairly easy to recognize a "primary" subject
in research on the basis of this definition, "secondary" subjects
can also be identified during the course of research. For example,
if a researcher has obtained a family history or pedigree, she or he
may have substantial "identifiable private information" about
secondary subjects. That is, individuals who have not given consent
to participate, may not know about the research, and may not want to
participate in it. Accordingly, in designing research and the informed
consent process for it, explicit attention should be paid to who constitutes
a participant from whom consent should be obtained.
Slide 22. Respecting autonomy also involves protecting
privacy and confidentiality. Privacy protections also may prevent social
and sometimes economic harm to participants. Protecting confidentiality
is arguably an expectation in most medical settings and recent legislation
(for example, HIPAA) requires careful attention to how and when data
are disclosed to others.
Slide 23. Recruiting primary subjects with specific
disease raises questions about who has legitimate access to private
medical information in order to recruit the patient to participate
in research. In general, it is better for treating clinicians to make
the initial contact with potential participants to notify them about
the possibility of participating, rather than having these persons
be contacted directly by the researchers. When recruiting secondary
subjects it may also become important to protect the privacy of the
primary subject.
Slide 24. Two additional measures can facilitate protecting
privacy. First, databases should be designed with attention towards
the need to protect privacy in mind. This includes building in appropriate
security and where feasible personal information from research findings
can be de-linked16 affording additional protections. De-linking
involves removing personal identifying information (such as name, date
of birth and social security number) from the participants' other data.
If the research carries social or legal risks to participants, one
means of providing additional protections is through a Certificate
of Confidentiality can be obtained which protects the research data
from subpoena.
Slide 25. DNA banks with associated personal information
that provide the foundation for important research can be expensive
and time-consuming to construct, making them a valuable resource. It
is not uncommon that researchers cannot and do not anticipate the types
of research questions they or other researchers will want to ask in
the future. However, informed consent requires that participants have
a sense of the research question and the potential risks and benefits
of participating. When the research question cannot be specified in
advance, there can be tension between the need to respect the limits
of an initial informed consent and the scientific desire to address
other issues. Recognizing this problem, in some research settings participants
are now given the option of providing consent for a number of different
possibilities such as the specific study, related studies, unrelated
studies, or additional studies only with re-consent, etc. Such preventive
approaches should be considered to avoid subsequent difficulties in
determining the use of specimens and data.
Slide 26. Returning to the Case Vignette, "Hearts,
Brains, and Banks" described at the beginning of the module, in
determining whether the neurologist should be granted access to the
DNA bank in large part depends upon what the original consent process
was for the bank. If the subjects gave permission for such uses, then
it would be acceptable for the bank to grant this access. Absent such
consent it might be possible to grant access by obtaining additional
consent or perhaps providing anonymized data17 to the neurologist.
Nevertheless, such options would require review and approval by the
responsible Institutional Review Boards.
Slide 27. The findings of population-based genetics
research can pose an additional set of challenges for researchers.
Of special importance is determining when it is appropriate to contact
participants regarding these results and how to appropriately share
the benefits of this research.
Slide 28. The need to contact participants with some
of the results of some population genetics research is based in the
ethical obligation of beneficence: the results may provide a direct
and tangible benefit to the participants. The National Bioethics Advisory
Commission, or NBAC, suggested that it is appropriate to contact participants
when four conditions are met: the findings are valid and confirmed;
they have significant implications for subject's health; a course of
action is available; and an appropriate referral is given. Of course,
letting potential participants know when and if results will be given
is an important component of the informed consent process. When considering
the possibility of contacting individual participants with results,
there should be a careful assessment of whether the specimens, results,
and person are indeed the same since a chain of custody that is standard
for most clinical tests may not have been followed in the research
setting. Regardless, it is important to try to identify a clinically
appropriate condition under which to do testing and counseling.
Slide 29. Regardless of whether data emerges from
the study that would meet these criteria for contacting individual
participants, there is an obligation to provide the results of the
study to participants, both individuals and populations, that desire
this information. Providing these results recognizes the important
role that participants play as partners in the research enterprise.
In addition, this information may be useful to members of the population
as they make health-related decisions related to it. Study results
may be disseminated in a variety of ways including distribution of
published articles, newsletters, meetings, websites, and list serves.
Slide 30. Returning to the Case Vignette, "Finding
Genes, Now What?" described at the beginning of the module, based
on the NBAC criteria, the investigators have an obligation to notify
those that may not be able to metabolize the common class of drugs,
but not those predisposed to the unpreventable and untreatable form
of cancer. However, it remains unsettling that they have this information
that might help some persons make important decisions about their lives.
Accordingly, how and when participants want to be notified about such
results is best incorporated into the informed consent process, by
explicitly eliciting preferences regarding notification. Nonetheless,
even when participants desire such information at the time consent
is obtained, their opinions may change over time and they may be difficult
to locate.
Slide 31. Sharing the benefits of research with the
participants and their communities helps to meet the ethical obligation
of justice, by recognizing their contributions to the scientific endeavor.
While a complete coverage of this topic is beyond the scope of this
module, advance agreements about how benefits will be shared should
be discussed prior to initiating research. The sponsor of the research
may influence the nature of benefit sharing, although government funded
research would be expected to be shared most broadly.
Slide 32. In conclusion, a range of ethical issues
may be encountered throughout the process of population-based genetics
research. Fortunately, simple measures sometimes can be used to avert
the problems that can be associated with these issues. It is incumbent
upon those sponsoring, designing, overseeing, and conducting this research
to be able to recognize these issues and deal properly with them.
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