Research Ethics and the Challenge of Whole-Genome Sequencing

Abstract

The recent completion of the first two individual whole-genome sequences is a research milestone. As personal genome research advances, investigators and international research bodies must ensure ethical research conduct. We identify three major ethical considerations that have been implicated in whole-genome research: the return of research results to participants; the obligations, if any, that are owed to participants' relatives; and the future use of samples and data taken for whole-genome sequencing. Although the issues are not new, we discuss their implications for personal genomics and provide recommendations for appropriate management in the context of research involving individual whole-genome sequencing.

Full text

Research ethics and the challenge of whole-genome sequencing
Amy L. McGuire, Timothy Caulfield, and Mildred K. Cho
Amy L. McGuire is at the Center for Medical Ethics and Health Policy, Baylor College of Medicine,
Houston, Texas 77030, USA.Timothy Caufield is at the Health Law Institute, University of Alberta,
Edmonton, Alberta T6G 2H5, Canada.Mildred K. Cho is at the Stanford Center for Biomedical Ethics,
Stanford University, Stanford, California 94305, USA
Abstract
The recent completion of the first two individual whole-genome sequences is a research milestone.
As personal genome research advances, investigators and international research bodies must ensure
ethical research conduct. We identify three major ethical considerations that have been implicated
in whole-genome research: the return of research results to participants; the obligations, if any, that
are owed to participants’ relatives; and the future use of samples and data taken for whole-genome
sequencing. Although the issues are not new, we discuss their implications for personal genomics
and provide recommendations for appropriate management in the context of research involving
individual whole-genome sequencing.
The recent publication of the first two individual human whole-genome sequences is significant
not only because it symbolizes a tremendous stride forward in our technological and scientific
ability to understand the genetic basis of disease, but because it provides a glimpse into the
future of genomic medicine. James Watson1 and Craig Venter2 are the first of many whose
genomes will be sequenced for research purposes and eventually as part of routine clinical
care3,4. This creates a unique opportunity to reflect on the ethical, legal and social challenges
that are associated with this next generation of personalized genomics. Privacy, confidentiality
and the potential for subsequent discrimination have been identified as major
considerations5–7, but other issues remain for those such as Watson, Venter and nine of the
‘Genome 10’ (REF. 8) who have agreed to have their genomes mapped non-anonymously.
We have identified three major ethical considerations that must be addressed in research
involving human whole-genome sequencing or the acquisition of large amounts of genome
sequence data: the circumstances under which research results are disclosed to research
participants; the obligations, if any, that are owed to participants’ close genetic relatives; and
the options regarding how future uses of samples and data taken for whole-genome sequencing
are dealt with. Although all of these issues have been implicated in past genetic research and
clinical practice, and may be resolved as genome sequencing takes on a more defined clinical
role, at this nascent stage, individual whole-genome research intensifies their significance and
the need for policy consideration. In many ways, the management of these ethical challenges
Correspondence to T.C., e-mail: tcaulfld@law.ualberta.ca.
FURTHER INFORMATION
Timothy Caulfield’s homepage:
http://www.law.ualberta.ca/centres/hli
23andMe: https://www.23andme.com
National Human Genome Project: http://www.genome.gov/10001772
International HapMap Project: http://www.hapmap.org
Us secretary’s Advisory committee on Genetics, Health, and society:
http://www4.od.nih.gov/oba/sacghs.htm
ALL LINKS ARE ACTIVE IN THE ONLINE PDF
NIH Public Access
Author Manuscript
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Published in final edited form as:
Nat Rev Genet. 2008 February ; 9(2): 152–156.
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can be simplified in the cases of Watson, Venter and the participants in the Harvard
Personalized Genome Project because of the unique knowledge, expertise and sophistication
of the research subjects9. However, these special circumstances will not apply to future
projects, creating the need for general guidance on how best to manage these important ethical
considerations. We propose specific recommendations for each of these ethically controversial
issues, which can be used to guide research practice and stimulate policy development (BOX
1).
Reporting back research results
When James Watson received a miniature hard drive with his entire genome sequence, it was
more than a mere symbolic gesture. Although Watson is a scientist with an individual and
academic connection to the personal genome initiative, at that moment he was also a research
participant receiving the raw data from a unique genetic research project.
Much has been written on when and how research participants should receive genetic research
results10–12. Knoppers and colleagues suggest that the scope of the duty to disclose will vary
depending on “the type of study, the clinical significance and reliability of the information,
and whether the study involves patients, genetically ‘at-risk’ families for a tested predisposition
or healthy volunteers.”13 Although these recommendations are informative, they were not
crafted with whole-genome sequencing in mind, and in most jurisdictions there are still no
definitive research ethics policies regarding the return of research results14.
Research ethics norms remain in constant flux. Nevertheless, convincing arguments have been
made for allowing research participants to be permitted access to their personal data if they so
choose12–15. Given the degree to which a whole-genome sequence implicates individual
integrity16, there is little reason to suppose that these arguments would not apply to research
participants in this context. Furthermore, as the media coverage intensifies1,17, the commercial
market for genome sequencing grows (for example, see the 23andMe web site) and direct-to-
consumer marketing for genetic tests become more common18, the desire for information and
the expectations of research participants for receiving their results are likely to increase. As
personal genome research moves forward, researchers should expect that research participants
will begin to assert their right of access. However, several important ethical and policy issues
regarding the form and process of disclosure must be addressed before any transfer of genome
data to research participants should occur.
First, what kind of data should be provided to research participants? Should participants simply
be given their raw sequence data? For most individuals, this form will be meaningless.
Participants are likely to want to learn more19,20. An annotated listing of potentially relevant
genes would provide more information, but this level of analysis would require validation in
an approved clinical laboratory (at least in the United States)21. Such a process would be
expensive and, without the appropriate expertise, the results could be subject to
misinterpretation. These concerns will be exacerbated if whole-genome sequencing is offered
in the commercial or clinical context, where appropriate research protections might not be
present. As such, at this early stage in the era of personal genomics, we propose the following:
all human whole-genome sequencing initiatives should be conducted under a formal research
protocol, and should include the development of a data return and counselling policy that can
be evaluated by the relevant research ethics board (recommendation 1.1). The second major
issue that deserves attention concerns the process of disclosure and follow-up clinical care.
The volume, complexity and clinical uncertainty of data generated in whole-genome
sequencing will make the communication of research results tremendously challenging.
Inevitably, the significance of the generated data will vary — from clearly clinically relevant
(for example, monogenetic disease information), to potentially relevant (for example, risk
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information), to data of unknown clinical significance. Expertise is needed for interpretation
and to ensure an adequate understanding of the health and social implications of the identified
genetic variation, both in the present and in the future. At present, there is no standard
mechanism for disclosing research results, and there are an inadequate number of physicians
who are specially trained to interpret and communicate this information and to provide follow-
up information and clinical care when new research findings are reported22,23. This suggests
an expanded role for geneticists and genetic counsellors, as well as physicians; we therefore
recommend that further training for primary-care physicians in genomics should be provided
to facilitate the communication of research results, and to provide follow-up information and
clinical care as new research findings are reported (recommendation 1.2).
Furthermore, genetic results of uncertain clinical validity will nevertheless generate potential
concern about disease risk among otherwise healthy individuals. This concern may potentially
lead to increased demand for more invasive follow-up diagnostics such as magnetic resonance
imaging (MRI) or computed tomography (CT) scans, raising questions about who should pay
for such services, and placing pressure on already stressed clinical providers. Even if wealthy
individuals choose to pay for themselves, issues of justice and equity arise as personal genome
sequencing will consume limited resources such as scanner, technician and physician time.
Before whole-genome sequencing is integrated into routine clinical care, the potential effects
on an already strained health-care system must be carefully considered3,4.
Finally, if research participants are given access to genetic data of variable present and future
clinical significance, the storage of that information and its integration into the health record
must be carefully considered. There are several groups that are actively working on developing
policy regarding the integration of genetic and genomic information into the electronic health
record24. This work should continue, and those involved must think progressively and
preventively about data generated from human whole-genome sequencing. It is recognized that
a process of determining what constitutes validated and clinically relevant data will be difficult
to implement. However, national advisory committees, such as the US Secretary’s Advisory
Committee on Genetics, Health, and Society (SACGHS), can provide useful guidance and set
standards for determining what the terms ‘validated’ and ‘clinically relevant’ mean. Whole-
genome sequence data should not be integrated into the health record until such detailed
guidance, appropriate security measures and comprehensive policies are developed and
ensured25,26. Of course, individuals retain the right to refuse genetic testing and can request
that individual research results are not included in their health record. We therefore make
several recommendations: only validated data of known clinical relevance should be included
in the health record; practice guidelines should be outlined for determining what constitutes
validated and clinically relevant data; and a process should be developed to update an
individual’s health record with additional genetic information as research progresses and as
new knowledge about the clinical relevance of specific gene loci is gained15 (recommendation
1.3).
Obligations to close genetic relatives
Data obtained from genome sequencing reveal information not only about the individual who
is the source of the DNA, but also probabilistic information about the DNA sequence of close
genetic relatives. This makes it possible to identify an individual by matching his or her DNA
to the sequence of a relative’s DNA27. The generation of whole-genome data significantly
increases the ability to match the DNA of close relatives, and to reveal predictive information
about relatives’ present and future health risks. This raises important questions about what
obligations, if any, are owed to the family members of individuals who consent to have their
genome sequenced as part of a research protocol.
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There are typically three activities associated with genomic research that can trigger questions
about obligations to third-party relatives: initial consent for research participation, data release
and data analysis. Third-party relatives are not generally considered to be research subjects of
a particular study, so their consent is not required for an individual to participate in genetic
research. In the united States, federal regulations define a human research subject as “…an
individual about whom the investigator … obtains data through intervention or interaction with
the individual, or identifiable private information.”28 As there is no direct interaction with
third-party relatives, the central question is whether, in the course of sequencing an individual’s
genome, scientists are simultaneously obtaining identifiable private information about that
person’s close genetic relatives29–31. It is generally accepted that, unless the third-party
relative is ‘readily identifiable’ (as distinguished from ‘potentially identifiable’), he or she
should not be treated as a research subject32. Of course, the identifiability of third-party family
members is a matter of degree, and as technology advances someone who is only potentially
identifiable today may become readily identifiable in just a few years.
Because identifiability and the associated risks vary over time, it is more appropriate to
conceptualize the obligations to third-party relatives as falling along a continuum. Ultimately,
the probability of, and risks associated with, identification must be balanced against the
scientific and clinical usefulness of the data and the autonomy-based rights of individuals to
participate in genetic research without interference from more risk-adverse family
members33–35. As the risks to relatives increase, the ethical obligations towards them
intensify.
At the point of initial informed consent for research participation, the individual research
subject is providing his or her autonomy-based consent to sequence his or her genome.
Applying traditional bioethics and health law principles, the individual research participant’s
consent is both necessary and sufficient. Although this research activity may generate
information about third parties that must be protected, it seems an inappropriate stretch of
autonomy-based consent principles to say that they have a right to deny its use. Following this
logic, we propose that during the initial informed consent process, investigators conducting
human whole-genome sequencing research should discuss the implications for family members
and encourage participants to include close genetic relatives in decisions about research
participation. As long as the risks associated with participation in genetic research can be
minimized by ensuring professional integrity, maintaining confidentiality and implementing
security measures to prevent unauthorized access to the data, additional informed consent from
close genetic relatives should not be required (recommendation 2.1).
In the context of data release, there is an emerging ethical consensus that researchers have
greater obligations to address the concerns and protect the privacy of relatives when
information on family history is published33,34,36. This is analogous to the public release of
genomic sequence data. In both cases, privacy becomes more difficult to manage because of
the widespread distribution of the information. Decisions about data release, an emerging
policy norm31,37, should therefore ideally include family members whose privacy is most at
risk. However, it can be difficult to include third-party relatives in the decision-making process
if they are unknown to the investigators or if the family dynamics are less than perfect. We
therefore propose the following: participants should be encouraged to notify affected family
members, and investigators should take a family-centered approach to informed consent (an
approach that has already been embraced in many research ethics guidelines)38. The obligation
to include at-risk relatives increases with the degree of relatedness to the primary research
subject and, when inclusion is not practical, investigators should strongly encourage the
research participant to discuss the research with his or her relatives and make a family decision
about data release. The investigator should offer to help to facilitate this discussion and provide
genetic counselling when appropriate. Objections from family members should be investigated
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by a research ethics consultation team, if available, and should also be reviewed by the relevant
ethics review board (recommendation 2.2). Clinically relevant diagnostic and predictive
information about family members’ health risks can be revealed during the course of data
analysis. There is extensive literature on the obligation to warn at-risk family members of
genetic risk39,40. Although there is no legal consensus in the united States41,42, ethically, the
American Society of Human Genetics (ASHG) suggests that the unauthorized disclosure of
genetic risk is permitted only if “attempts to encourage disclosure on the part of the patient
have failed, the harm is highly likely to occur and is serious, imminent and foreseeable, the at-
risk relative(s) is identifiable and the disease is preventable, treatable or medically accepted
standards indicate that early monitoring will reduce the genetic risk.”32 These same general
principles apply in the research context43. We recommend that the ASHG guidance regarding
unauthorized disclosure of genetic risk to third-party relatives in the clinical context should be
expanded to the research setting. As long as the data are validated, the permissibility of
unauthorized disclosure will depend on the clinical relevance of the information and the
potential to avert or alleviate known health risks (recommendation 2.3).
Future uses of samples and data
Secondary uses of samples and data from genetic studies are common, but the informed consent
processes that are used in the original collection of these samples have often not predicted their
future uses in research. Often, no mention of secondary uses was made, or ‘blanket consent’
to any research use was obtained. The proliferation of electronic databases for genetic and
associated information37,44 and the international commitment to broad data sharing in
genomic research45,46 have made blanket consent increasingly desirable. However, the many
possible uses for this information increases as whole-genome sequencing becomes more
widespread, creating the potential for research to be conducted that is far outside the scope of
the research for which the samples were originally collected. This heightens the legal and
ethical issues that are already associated with the use of a blanket consent approach in other
contexts47,48.
Indeed, the secondary use of samples and data pose not only privacy and confidentiality issues,
as discussed above, but also potential threats to the autonomy of individual research subjects
and groups49. Individuals who willingly gave samples for the purpose of studying a disease
of interest might be at risk of having their sample used to study other phenotypes, such as
personality traits, IQ, behaviour or evolution and natural selection. As whole-genome
sequencing becomes more common, these data become much more amenable to the study of
complex traits. Although the study of other phenotypes might potentially be more useful to the
research community, some might be less acceptable to the research subjects.
Although there is a long history of using biological material for research beyond the scope of
the original study for which it was collected50, the practice of broad data sharing in publicly
accessible electronic databases emerged in the context of large-scale sequencing studies, such
as the National Human Genome Project (USA) and the International HapMap Project. For
these studies, unrestricted data release was essential because the primary purpose of the
research was to create a reference genome or catalogue of genetic variation that was easily
accessible and freely available to use for a host of other research purposes. In the early years
of human whole-genome sequencing, the goals are similar: to advance technology and increase
our understanding of genetic variation in humans. Thus, there are rationales supporting the
position that individual human whole-genomes sequenced in the context of federally funded
research ought to require consent for broad data sharing and unspecified research uses.
However, such an approach might challenge traditional ideas of informed consent, which, in
general, require that consent is obtained for each study that links to identifiable information.
Can a person consent to something that they have no details about? This tension between the
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desire to support research in the public good and the need to protect individual rights and
established ethics norms has become a major policy issue in other domains, particularly
biobanking51–53.
Given the importance of consent in research ethics, resolving this and other consent dilemmas
(such as the scope of the right to withdraw) seems essential for the future of this work. Indeed,
as the field advances and personal genomes are generated in the context of disease-association
studies (for which the primary goal is to study a particular disorder(s)) and as more complete
genomic data can increasingly be used to make inferences about a wide range of other traits
(including non-disease traits), the challenges associated with consent seem likely to intensify.
At a minimum, individuals ought to be able to participate in a particular genome-wide
association study without having to consent to more extensive data sharing or broader research
use.
For existing samples, data sharing and future use must be consistent with the original informed
consent. Databases will need to be designed to restrict certain uses for which there is no consent,
and secondary users must exercise professional integrity by ensuring that their research does
not go beyond the scope of the participant’s original consent. In some circumstances in which
the participant has agreed to re-contact, re-consent might be warranted. Therefore, policy work
should focus on developing consent mechanisms that can be reconciled with existing consent
norms, including the analysis of the appropriateness of a broad future-use consent model. In
the meantime, genome researchers must ensure that research remains within the spirit of the
original informed consent, or re-consenting should be considered (recommendation 3.1).
Looking forward
As the cost of human whole-genome sequencing decreases, important questions will arise about
whether this technology should be generally available, and if and how it should be integrated
into routine clinical care3,4. Concerns about privacy and the complexities of informed consent
will persist and intensify. Economic issues will relate to who will have access to the benefits
of personal genomics, and whether public and private health-care systems will pay for the
generation of an individual genome, follow-up clinical care or recommended preventive
treatment to decrease genetic risk. We need to better understand, through empirical study, what
the effects of data sharing are on research subjects, what types of use are acceptable and how
to best determine, communicate and respect subjects’ wishes about the use of the samples and
data. Such studies should start on a small scale before moving towards a wide availability of
data on a large scale. We are currently able to generate an enormous amount of genomic data,
but we have relatively little appreciation for its function or significance. As a better
understanding of the contribution of genetic variation to human diversity develops, more
challenging questions will come to the fore; for example, questions about personal identity,
the limits of genetic determinism and the value in human diversity. This is an exciting time for
the field of genomic science; however, it is essential that, as we move forward, we do so with
some caution and with conscious consideration, critical reflection and careful study of the many
ethical and social implications of new developments at each step along the way.
Box 1 Summary of recommendations
Returning research results
Recommendation 1.1—All human whole-genome sequencing initiatives should be
conducted under a formal research protocol, and ought to include the development of a data
return and counselling policy that can be evaluated by the relevant research ethics board.
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Recommendation 1.2—Further training for physicians should be provided to facilitate the
communication of research results, and to provide follow-up information and clinical care as
new research findings are reported.
Recommendation 1.3—Only validated data of known clinical relevance should be
integrated into the health record. Practice guidelines should be developed for determining what
constitutes validated and clinically relevant data. A process should be developed to update an
individual’s health record with additional genetic information as research progresses and new
knowledge about the clinical relevance of specific gene loci is gained.
Obligations to third-party relatives
Recommendation 2.1—During the initial informed consent process, investigators
conducting human whole-genome sequencing research should discuss implications for family
members and encourage participants to include close genetic relatives in decisions about
research participation. As long as the risks associated with participation in genetic research
can be minimized by ensuring professional integrity, maintaining confidentiality and
implementing security measures to prevent unauthorized access to the data, additional
informed consent from close genetic relatives should not be required.
Recommendation 2.2—In the context of data release, participants should be encouraged
to notify affected family members, and investigators should take a family-centered approach
to informed consent. The obligation to include at-risk relatives increases with the degree of
relatedness to the primary research subject and, when inclusion is not practical, investigators
ought to strongly encourage the research participant to discuss the research with his or her
relatives and make a family decision about data release. The investigator should offer to help
facilitate this discussion and should provide genetic counselling when appropriate. Objections
from family members should be investigated by a research ethics consultation team, if
available, and reviewed by the relevant ethics review board.
Recommendation 2.3—American Society of Human Genetics guidance regarding
unauthorized disclosure of genetic risk to third-party relatives in the clinical context should be
expanded to the research setting. As long as the data are validated, the permissibility of
unauthorized disclosure will depend on the clinical relevance of the information and the
potential to avert or alleviate known health risks.
Future uses
Recommendation 3.1—Policy work should focus on developing consent mechanisms that
can be reconciled with existing consent norms, including the analysis of the appropriateness
of a broad future-use consent model. In the meantime, genome researchers must ensure that
research remains within the spirit of the original consent, or re-consenting should be
considered.
Acknowledgements
Research is supported by the Greenwall Foundation Faculty Scholars Program, The Gillson Logenbaugh Foundation
and The ARCO Foundation Young Teacher–Investigator Award, Genome Alberta, the Ethical, Legal, and Social
Implications (ELSI) Research Program, Genome Canada, Alberta Heritage Foundation for Medical Research, National
Human Genome Research Institute (NHGRI-ELSI) and US National Insitutes of Health grants R01HG004333 and
5P50HG003389. Thanks to A. Adair.
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