1. The document discusses approaches to disclosing individual genetic results to research participants. It proposes a result-evaluation approach where investigators and IRBs assess the analytic validity and clinical utility of results to determine if they should be offered. 2. The clinical utility of a result considers its clinical validity, the likelihood of a safe and effective clinical outcome, and the value of that outcome. A lower threshold of clinical utility is justified for disclosing results in research compared to clinical use. 3. The context of the study, like the investigators' capabilities and the participants' alternative access to results, also informs whether results should be disclosed. The same result may require different decisions in different research contexts.

1. Target Article
Disclosing Individual Genetic
Results to Research Participants
Vardit Ravitsky, National Institutes of Health1 and University
of Pennsylvania
Benjamin S. Wilfond, Social and Behavioral Research Branch,
National Human Genome Research Institute,
National Institutes of Health, Bethesda and Department of
Clinical Bioethics, The Clinical Center, National
Institutes of Health1 and University of Washington
Investigators and institutional review boards should integrate
plans about the appropriate dis-
closure of individual genetic results when designing research
studies. The ethical principles of
beneficence, respect, reciprocity, and justice provide
justification for routinely offering certain
results to research participants. We propose a result-evaluation
approach that assesses the
expected information and the context of the study in order to
decide whether results should
be offered. According to this approach, the analytic validity and
the clinical utility of a specific
result determine whether it should be offered routinely.
Different results may therefore require
different decisions even within the same study. We argue that
the threshold of clinical utility for
disclosing a result in a research study should be lower than the
threshold used for clinical use

2. of the same result. The personal meaning of a result provides
additional criteria for evaluation.
Finally, the context of the study allows for a more nuanced
analysis by addressing the investi-
gators’ capabilities for appropriate disclosure, participants’
alternative access to the result, and
their relationship with the investigators. This analysis shows
that the same result may require
different decisions in different contexts.
Keywords
Clinical Utility
Clinical Validity
Disclosure
Research Results
Genetic Research
Open Peer
Commentaries
Lynn G. Dressler
and Eric T. Juengst, 18
Mark A. Rothstein, 20
Lisa S. Parker, 22
Pilar N. Ossorio, 24
Christopher H. Wade

3. and Andrea L. Kalfoglou, 26
Leslie A. Meltzer, 28
Kelly E. Ormond, 30
Teri A. Manolio, 32
Robert Klitzman, 34
Kelly Fryer-Edwards
and Stephanie M. Fullerton, 36
Laura M. Beskow, 38
Flavia M. Facio, 40
Richard R. Sharp
and Morris W. Foster, 42
Conrad V. Fernandez
and Charles Weijer, 44
Robert R. Lavieri
and Samuel A. Garner, 46
Disclosure of individual results to participants in
clinical and epidemiologic research has emerged as
a complex and contentious issue. The approaches
and practices of investigators, institutional review
boards (IRBs) (Hull et al. 2004), and funding
agencies (Bookman et al. 2006) are quite diverse.
Some argue that disclosure should be the routine
practice in research, based on the principle of re-
spect for participants (Partridge and Winer 2002;
Fernandez, Kodish, and Weijer 2003; Shalowitz

4. and Miller 2005), while others emphasize the bal-
ance of benefits and harms and argue that disclo-
sure should be limited to certain situations (Fuller
et al. 1999; National Bioethics Advisory Commis-
sion 1999; Beskow et al. 2001; Clayton and Ross
2006). Furthermore, the federal regulations regard-
ing the conduct of clinical research do not pro-
vide clear guidance in this matter (Code of Federal
Regulations 1991). While there is an emerging
consensus in the literature regarding the disclosure
1. The opinions expressed in this article are those of the
authors and do not reflect the opinions or policies of the
National Human Genome Research Institute, the Na-
tional Institutes of Health, or the Department of Health
and Human Services.
of aggregate study findings (Beskow et al. 2001;
Partridge and Winer 2002; Fernandez, Kodish, and
Weijer 2003), individual genetic results raise chal-
lenging issues that require further analysis and
policy recommendations.
The development of ethically justified policies
regarding the disclosure of individual genetic re-
search results is important for several reasons. First,
genetic research is increasingly prevalent as the fo-
cus is shifting from studying rare diseases in isolated
families to determining the contribution of genetics
to common disorders such as cancer and heart dis-
ease (Collins et al. 2003). Second, the probabilistic
character of genetic information and the pleiotropic
nature of genes make accurate interpretation and
communication particularly challenging. Third,
the potential impact of genetic information on
family relationships, reproduction, and personal

5. identity highlights the subjective value of ge-
netic results and may further complicate their
communication.
Challenging situations can be anticipated to
arise more frequently in both clinical trials and epi-
demiologic studies. Should investigators offer par-
ticipants results regarding the apolipoprotein (Apo)
The American Journal of Bioethics, 6(6): 8–17, 2006 ajob 8
Copyright c© Taylor & Francis Group, LLC
ISSN: 1526-5161 print / 1536-0075 online
DOI: 10.1080/15265160600934772
Disclosure of Genetic Results
e 4 allele in a clinical trial for the prevention of
Alzheimer’s disease (Petersen et al. 2005)? Should
they offer participants individual results of BRCA1
mutations in epidemiologic studies (Malone et al.
1998)? These examples show the importance of
choosing an approach to disclosure of individual
genetic results when planning the research, in or-
der to minimize ad hoc solutions to issues that may
emerge. Including a plan about disclosure in the
study design also allows IRBs to assess the appro-
priateness of the plan and could improve the ability
of investigators to communicate their intentions to
participants during the consent process.
We delineate a framework that will assist inves-
tigators and IRBs in deciding whether to offer indi-
vidual genetic results and, when needed, in choosing
an appropriate plan for their communication.

6. TWO POTENTIAL APPROACHES
When considering the appropriate approach to the
disclosure of individual genetic research results, two
opposite ends of a spectrum can be described. Both
polarized approaches are inadequate, because they
focus either solely on the perspective of an inves-
tigator or that of a participant, but fail to offer a
comprehensive balanced view.
The research-focused approach suggests that results
should generally not be offered because the primary
goal of research is not to provide individuals with
information about themselves but rather to pro-
duce generalizable knowledge (National Bioethics
Advisory Commission 1999). This approach is in-
adequate because even when the primary goal of
research is acknowledged, investigators still have
other responsibilities towards research participants
(Richardson and Belsky 2004). For example, benefi-
cence justifies offering participants information that
is of direct clinical utility and respect requires that
their preferences be taken into account.
The autonomy-focused approach suggests that all
results should be offered because participants have
a right to access information about themselves
(Shalowitz and Miller 2005). The recent legal cli-
mate created by the Health Insurance Portability
and Accountability Act (HIPPAA) Privacy Rule
(Neale and Schwartz 2004), which reinforces indi-
viduals’ control over much of their health-related
information, is consistent with this approach.
However, this approach does not distinguish
appropriately between research and clinical prac-

7. tice. In addition, even if a right to receive research
results is acknowledged, it is still unclear which raw
data count as “results.” It is not reasonable to require
that all data collected in the process of research be
accessible to participants, such as preliminary data
from a laboratory notebook.
Investigators who prefer not to disclose results
tend to rely on the research-focused approach. Other
investigators who prefer to disclose results tend to
rely on the autonomy-focused approach. This cur-
rent state of affairs is problematic because an ap-
proach should be adopted based on ethically appro-
priate criteria, not to satisfy a prior preference. It is
therefore important to develop an alternative sub-
stantive approach to address disclosure, which is the
main goal of this article. In addition, it is important
to involve independent evaluators, such as IRBs or
data monitoring committees, to review and com-
ment on the investigators’ chosen approach and to
provide advice when unanticipated results or new
interpretations of results must be considered.
AN ETHICAL FRAMEWORK FOR A
RESULT-EVALUATION APPROACH
We propose a result-evaluation approach according
to which the appropriate plan depends on the na-
ture of the information generated by the study and
on the context of the study. This approach is com-
prehensive because it allows investigators and IRBs
to consider multiple relevant values. We argue for
an ethical framework that is based on the princi-
ples of beneficence, respect, reciprocity, and justice,

8. which are fundamental ethical principles of research
(Emanuel, Wendler, and Grady 2000; Richardson
and Belsky 2004; Pelias 2005).
Beneficence requires that investigators offer re-
sults that are clinically useful, which means results
are expected to be valuable to participants’ physical
or psychological well being, to their reproductive
decision making or to their life planning. Respect
for participants requires that investigators provide
results that may be of interest to participants and
that have been acquired based on their participation.
Respect also requires that investigators respond to
participants’ preferences to receive, or not receive, a
certain result. Results should therefore be offered,
allowing participants to express their preferences, so
that even within one study individual participants
may be handled differently. Reciprocity requires
considering the nature of the relationship between
investigators and participants because the extent of
the obligation to offer results is influenced by the
duration and the intensity of this relationship. Fi-
nally, justice requires balancing participants’ prefer-
ences against considerations of prioritizing resource
November/December 2006, Volume 6, Number 6 ajob 9
The American Journal of Bioethics
utilization to maximize the benefits of research to
society.
CONSIDERING THE NATURE OF THE

9. INFORMATION
Determinative Considerations: Analytic Validity
and Clinical Utility
In order to develop an appropriate disclosure plan
for a particular study, investigators and IRBs should
first evaluate the nature of the information that the
study is likely to generate. Different informational
considerations determine the approach to offering
results (Figure 1).
Analytic Validity
A result is analytically valid when it accurately and
reliably identifies a particular genetic characteristic,
such as a nucleotide sequence or a gene expression
profile. Accuracy and reliability must be achieved
both at the research stage of assay development and
at the clinical application stage in which labora-
tory proficiency and quality control are required.
Results should not be offered when they are not an-
alytically valid because such information is not re-
liable (Schulte 1991; Fuller et al. 1999). Incorrect
information may lead to harmful outcomes such as
Figure 1. Informational considerations.
unnecessary interventions, emotional distress, or a
false sense of security.
In the United States, analytic validity in clin-
ical laboratories is ensured by the Clinical Labo-
ratory Improvement Amendments (CLIA) of 1988
(Ehrmeyer and Laessig 2004). Research laboratories

10. are required to be CLIA certified when they offer
results to individual participants for the purpose of
assessing the health of the individual. In cases where
a research laboratory is not CLIA certified and in-
vestigators intend to offer clinically relevant results,
they should plan to send samples to a second, certi-
fied laboratory.
Clinical Utility
A result is clinically useful when it is analytically
valid and can be used to improve a participant’s
well-being. A judgment of clinical utility depends
on empirical data about the balance of clinical ben-
efits and risks related to the knowledge of a partic-
ular genetic result. Clinically useful results should
be offered to research participants. Furthermore, as
evidence for clinical utility becomes stronger, a test
may be appropriately considered for use in clinical
practice (Burke and Zimmern 2004). The assess-
ment of clinical utility is based on three consider-
ations: the association between the result and the
clinical condition (clinical validity), the likelihood
10 ajob November/December 2006, Volume 6, Number 6
Disclosure of Genetic Results
of a clinically effective outcome, and the value of
the outcome to the individual. These three consid-
erations should be considered as benchmarks to be
evaluated in decisions about disclosure. Together
they provide an assessment of clinical utility.

11. Clinical validity. Clinical validity refers to the
quality and quantity of empirical evidence regard-
ing the association between a genotype and a partic-
ular clinical outcome, such as increased or reduced
risk of a given condition (Holtzman and Watson
1999). Clinical validity begins to emerge with a
suspected association between genotype and clinical
condition and is strengthened when the association
is supported by a single publication and then many
publications. However, many reported associations
are not robust: a comprehensive review showed that
of 166 putative associations that have been studied
three or more times, only six have been consistently
replicated (Hirschhorn et al. 2002). Clinical valid-
ity is strengthened further when investigators gain
an understanding of the functional or causal rela-
tionship between genotype and clinical condition.
An appropriate threshold of clinical validity is nec-
essary to establish clinical utility because disclosure
of results that have very uncertain meaning has lit-
tle justification. Limited clinical validity can also
result in unnecessary procedures or anxiety. Differ-
ent investigators and IRBs may hold differing views
regarding the appropriate threshold for clinical va-
lidity.
The threshold of evidence for clinical validity
should be lower for offering an individual research
result than for general recommendations for rou-
tinely providing results in clinical practice. A result
may have enough clinical validity to be reliably in-
tegrated into an individual’s decision-making, even
before it is established enough in the literature to be
integrated into routine clinical practice and partic-
ularly when the other two considerations for estab-
lishing clinical utility are satisfied. A lower thresh-

12. old of clinical validity is justified also because of
participants’ contribution to the collection of data
and to the cumulative understanding of the infor-
mation. Finally, the ability to monitor any adverse
effects of misunderstood information is greater in
the research setting.
Likelihood of safety and effectiveness. The second
consideration is the likelihood that the clinical
outcome will be safe and effective. To assess the
likelihood, one should compare the safety and ef-
fectiveness of interventions that might follow the
disclosure with a situation in which no interven-
tion occurs. For example, a result regarding the
presence of the BRCA1 mutation may lead to in-
creased surveillance, which is likely to have the ef-
fective outcome of early diagnosis. Assessment of
likelihood should be based on review of the evi-
dence, as is now more routinely employed in mak-
ing broad recommendations for population-based
health care services.
Value of the outcome. The third consideration is a
normative assessment of the value of the outcome.
Information that reduces the risk of sudden death
is more valuable than, for example, information
about the genetic capacity for athletic endurance.
While clinical utility is generally framed as related
to medical intervention or prevention (Holtzman
and Watson 1999), results can be clinically useful
for reasons other than medical benefit. Provision of
genetic results may also reduce participants’ anxiety,
inform their reproductive decisions, or inform their
life plans in the case of late-onset conditions such as
Huntington’s disease. Such an expanded conception

13. of utility is consistent with current clinical test-
ing practices that are justified based on psycholog-
ical well being and life-planning benefits. It is also
consistent with the ethical principle of beneficence
that includes benefits outside of a narrow medical
context.
The assessment of clinical utility of a research
result should include such broader personal bene-
fits. One example of this issue is whether to disclose
individual results of the Apo e 4 allele, which is
associated with increased risk for coronary artery
disease (Tiret et al. 1994; Stengard et al. 1996)
and for Alzheimer’s disease (Rubinsztein and Easton
1999).To date, the clinical utility of this result for
medical intervention or prevention remains uncer-
tain. However, knowing in advance that one is at
a higher risk of developing Alzheimer’s disease or
heart disease may have clinical utility if this infor-
mation is useful for decision making about future
living conditions.
Threshold of clinical utility. There are several
reasons why the threshold of clinical utility for jus-
tifying disclosure of results should be lower for
individual decision making between patient and
clinician in a research context (or a participant and
investigator) than for general recommendations for
routine clinical practice.
First, individual decision making, provides an
opportunity for nuanced decision making by ex-
amining the evidence and considering individual
goals and values. However, a policy recommenda-
tion for routine use may be interpreted as an en-
dorsement of the evidence and may lead to less

14. November/December 2006, Volume 6, Number 6 ajob 11
The American Journal of Bioethics
deliberative decision-making by a particular pa-
tient or clinician. Second, general policy recom-
mendation must go beyond evidence of individual
benefits/harms and consider other factors such as
budget constraints, and other service delivery issues
such as clinician capacity and service quality. For ex-
ample, although gene expression profiling has not
yet been recommended by policy makers for rou-
tine use in clinical oncology as a prognostic tool,
such profiling can still be useful to inform individ-
ual decision making, such as a treatment decision
regarding adjuvant chemotherapy (van de Vijver
et al. 2002). Finally, adverse outcomes resulting
from individual decisions will be limited to a few
specific individuals, whereas the impact will be
magnified when a policy recommendation is fol-
lowed by the general population.
Clinical utility and informed consent. The clinical
utility of a result is such an important considera-
tion that, even when it has not been anticipated
in advance, once it passes the appropriate threshold
it should still determine the course of action that
should be taken. For example, in a study that ex-
amined gene expression in breast biopsy specimens
(Hedenfalk et al. 2001), clinically meaningful re-
sults were not anticipated and therefore the IRBs
waived the requirement to obtain participants’ con-
sent to use their specimens, provided that investi-

15. gators would not contact them with any results.
However, the result from one participant was un-
expectedly suggestive of a BRCA mutation. Our
analysis suggests that because of the clinical utility
of a BRCA result, the investigators should make an
effort to facilitate communication with the affected
individual and offer this result, even in the absence
of an ongoing relationship, expectation of receiv-
ing such results, and informed consent. A similar
question was raised in a different study regarding
whether to disclose the result of a mutation in the
cardiac myosin-binding protein C gene, which is
associated with increased risk of hypertrophic car-
diomyopathy (Verweij and Hamel 2002). Investi-
gators arrived at a similar conclusion and offered
the result to the participant even in the absence of
prior consent.
A Guiding Consideration: Personal Meaning
Although results that have clear analytic validity
and clinical utility should be offered to partici-
pants, results that are analytically valid but have
less clinical utility are more contentious. For such
results, consideration of personal meaning should
guide investigators in determining the appropriate
approach. (Figure 1). Genetic results have the poten-
tial to affect participants’ relationships or personal
identity. Issues related to lineage can arise in family
studies, issues related to ethnic or cultural identity
can arise in ancestry studies (Behar et al. 2003) and
issues related to personal identity can arise in stud-
ies about genetic associations of behavioral traits
that are potentially modifiable, such as obesity or
addiction (Shields, Lerman and Sullivan 2004).

16. In some circumstances, results that have per-
sonal meaning may also have clinical utility. For ex-
ample, a misattributed paternity result may mean
that a child is not at risk because she should not
have a mutation that has been suspected based on
a certain pedigree. In many other circumstances,
however, the benefits and risks of learning such in-
formation may be difficult to assess or predict, be-
cause its meaning and value vary among individu-
als and their families or communities (Davis 2000).
Whereas some individuals may prefer to learn infor-
mation of this nature, others may not want to know
because of the possible harms of disclosure. For ex-
ample, information about misattributed paternity
can have an adverse impact on a family, and infor-
mation about the genetic basis of tribal affiliation
may lead to exclusion of certain members and thus
have an adverse impact on the excluded individuals
and on the community as a whole.
Potential harms of this kind can justify a plan
not to routinely offer results. Investigators should
carefully evaluate the benefits and risks of offering
such results and exercise caution in planning their
approach. They can also assess participants’ pref-
erences empirically by using preliminary conver-
sations with potential participants, focus groups,
or community meetings (Fernandez, Skedgel, and
Weijer 2004). When participants express interest
in results that have personal meaning, these results
should be offered, depending on the study context
as described later in the text. There is a need for
more empirical research to help guide decisions re-
garding whether to offer results that have complex
implications.

17. CONSIDERING THE STUDY CONTEXT
Genetic research includes studies that investigate a
range of patterns of inheritance in a range of pop-
ulations. These different contexts affect the appro-
priateness of offering results because they influence
investigators’ capabilities for appropriate disclo-
sure, participants’ alternatives for accessing the in-
formation, and the relationship between investiga-
tors and participants. When clinical utility is high,
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Disclosure of Genetic Results
Figure 2. Contextual consideration when analytic validity and
clinical utility are established.
contextual considerations help determine the ap-
propriate strategy for making results available
(Figure 2). When clinical utility is not as high, con-
textual considerations help determine the extent of
the obligation to offer results (Figure 3).
Investigators’ Capabilities
The capabilities of investigators to appropriately com-
municate results should be considered. Capabilities
primarily include maintaining a satisfactory level of
quality control in the laboratory and ensuring effec-
tive communication by providing genetic counsel-
ing when needed.

18. When the result in question has sufficient clini-
cal utility, there is greater justification for ensuring
that results are offered within the framework of the
study, and the study budget should be designed ap-
propriately to include such elements as testing in
a CLIA-certified laboratory (Figure 2). Moreover,
although a clinician-investigator may feel fully ca-
pable of communicating the information, a basic
scientist-investigator may not be as able to commu-
nicate results appropriately. In these cases, a genetic
counselor should then be available as a part of the
research team.
In some cases, results are clinically use-
ful but resources are limited. For example, an
investigator whose laboratory is not CLIA-certified
may find that the budget cannot include testing in a
CLIA-certified laboratory because the cost will be
too high and then the study cannot be performed
(Fuller et al. 1999; Fernandez, Skedgel, and Weijer
2004). In such a case, the ethical responsibility to of-
fer results can be met by providing participants with
appropriate referral information regarding clinical
services for testing and counseling. However, if clin-
ically useful results are not otherwise available out-
side the context of the study, then the investigators
have an obligation to develop their capabilities. Al-
though developing these capabilities will divert re-
sources from other research objectives, the fact that
participants have no other access to this useful in-
formation can justify this reallocation of resources.
In other cases, results may not have a clearly
established clinical utility. In such cases, routinely
offering results may not be justified. For example,
in a population study of a large cohort, the cost of

19. routinely offering all the results can be so high that
planning to do so may impede or hinder the re-
search. Such a plan would strain already limited re-
sources for research that should be invested in a way
November/December 2006, Volume 6, Number 6 ajob 13
The American Journal of Bioethics
Figure 3. Contextual considerations for results that have
personal meaning, but clinical utility is not established.
that creates generalizable knowledge and benefits
the public.
The issue of resource allocation is complex be-
cause it is relevant both at the level of the researcher,
who is managing a fixed research budget and must
prioritize between different research aims, and at
the level of the research sponsor or funding agency,
who has a fixed (but larger) budget and must priori-
tize between a number of research projects and their
scope. In both cases, different approaches to disclo-
sure will affect the research budget and therefore
will affect other research activities. There is a ten-
sion between obligations to provide results to par-
ticipants and obligations to achieve other research
objectives. Because neither obligation trumps the
other, at both levels a decision has to be made after
careful ethical deliberation regarding the balance
between these two obligations.
Participants’ Alternative Access

20. Another contextual consideration is whether partic-
ipants have other alternatives to obtain the specific
results in question. In some cases, tests are commer-
cially available even if there are no policy recom-
mendations for routine clinical use. In other cases,
alternative access is not possible if no other labora-
tory has the expertise to perform the test.
Whereas investigators’ responsibility to offer re-
sults diminishes when tests are available in other
settings, they still have an obligation to inform
participants about the clinical availability of testing
(Figure 2). This responsibility is particularly im-
portant if participants are unaware of the existence
of results that may be meaningful to them, which
could occur in epidemiologic studies in which asso-
ciations are confirmed long after initial enrollment.
In such cases, sending participants newsletters that
update them about aggregate study findings is an
appropriate and cost-effective way of fulfilling this
obligation. However, when access to results is not
otherwise available, and clinical utility has been es-
tablished (as may happen with a rare condition),
investigators are obligated to offer the results and,
if necessary, to develop the necessary capabilities
(Figure 2).
Information about clinical availability is only
sufficient when participants have the ability to
pay for testing and counseling elsewhere. How-
ever, when a test is clinically useful and participants
cannot afford testing, investigators should refer
participants to available social support services that
may provide funding.

21. Relationship Between Investigator
and Participant
The obligation to offer results increases when the
interaction with a research participant is more ex-
tensive because a more intense relationship creates
14 ajob November/December 2006, Volume 6, Number 6
Disclosure of Genetic Results
a stronger requirement for reciprocity (Figure 3).
The nature of the relationship is defined by the level
of involvement (e.g. does the investigator have per-
sonal contact with the participant?), the duration of
the interaction (e.g. does the reaction extend over
many years?), and the nature of the contribution of
a participant to the research (e.g. does participation
entail discomfort or a time commitment?).
For example, an epidemiologic study of samples
that entails no personal contact with participants at-
tenuates justifications to directly communicate re-
sults that do not exceed a high threshold of utility.
In such a case, it is adequate to send participants
a newsletter informing them of the aggregate find-
ings and, when relevant, of the existence of alter-
native access to testing. In contrast, in a longitudi-
nal study of families with multiple affected mem-
bers that involves an ongoing engaged relationship
with participants, the ethical duty to offer results is
amplified because participants who are actively in-
volved in the research process deserve to be offered

22. even more preliminary results whose interpretation
is less clear. In addition, the frequent contact can
facilitate the communication of the result.
CONCLUSION AND RECOMMENDATIONS
Informational and contextual considerations should
guide investigators and IRBs regarding the choice
of an appropriate plan for offering or not offering
a specific result. Cases of clear analytic validity and
substantial clinical utility are relatively easy to re-
solve. In the research context, however, most results
are likely to have less clinical utility and the de-
cision about disclosure requires further evaluation
involving personal meaning and contextual consid-
erations. The same result can therefore be handled
differently in different studies. Table 1 shows that
these considerations may point in the direction of
Table 1. Contextual Considerations in Deciding Whether to
Offer Apolipoprotein e4 Test Results.
Study Feature Study A Study B
Type of study Family-based, longitudinal,
epidemiologic
Population-based, cross-sectional,
epidemiologic
At-risk population Yes No
Participants Preference of prefer to know Yes Unknown
Investigators–participant relationship Prolonged and intense
One-time
Investigators have capabilities for appropriate Yes No

23. disclosure (eg, laboratory and counseling)?
In These Two Hypothetical Studies of a Result (Apolipoprotein
e4) with Moderate Clinical Utility (Moderate Clinical Validity
and Moderate Likelihood
of an Outcome of Moderate Value), the Context of Study A
Points Towards Offering Disclosure of Results and the Context
of Study B Points Towards
Non-Disclosure.
disclosure in study A and in the direction of non-
disclosure in study B for Apo e 4 results.
No matter which approach is chosen, it is impor-
tant to inform participants about the plan during
the consent process. Consent forms should explic-
itly articulate the plan regarding aggregate find-
ings, regarding specific results that have probable
implications for participants, and regarding other
results that are preliminary and have less meaning.
Moreover, the offering of individual results should
involve effective communication and address issues
such as study limitations, interpretation of data,
and the place of the study in the general scientific
framework.
In some contexts disclosure is controversial. It
is important therefore to conduct trans-disciplinary
research on people’s interest in receiving results and
on their responses to them. Conducting more stud-
ies such as the Risk Evaluation and Education for
Alzheimer’s Disease (REVEAL) study (Roberts et al.
2004), which offers Apo e 4 testing, can be useful in
providing opportunities to learn more about partic-
ipants’ actual preferences and evaluate the benefits
and harms of offering specific results. When results

24. are offered in a research context, feedback from the
IRB may enhance subject protection. �
ACKNOWLEDGMENTS
This research was supported by the Intramural Re-
search Program of the National Human Genome
Research Institute, National Institutes of Health.
We would like to thank David Shalowitz for his
input and for suggestions that helped shape this
paper. We would like to thank Ezekiel Emanuel,
Colleen McBride, Barbara Biesecker, John Barton,
Frank Miller, Mildred Cho, and Caryn Lermann
for their constructive comments on earlier drafts
of the paper, and Leslie Biesecker, Lawrence Brody,
November/December 2006, Volume 6, Number 6 ajob 15
The American Journal of Bioethics
and Elaine Ostrander for helpful discussions on this
topic.
REFERENCES
Behar, D. M., M. G. Thomas, K. Skorecki, M. F. Hammer,
E. Bulygina, D. Rosengarten, A. L. Jones, K. Held, V.
Moses, D. Goldstein, N. Bradman, and M. E. Weale.
2003. Multiple origins of Ashkenazi Levites: Y chromo-
some evidence for both Near Eastern and European
ancestries. American Journal of Human Genetics 73(4):
768–779.
Beskow, L. M., W. Burke, J. F. Merz, P. A. Barr, S. Terry,

25. V. B. Penchaszadeh, L. O. Gostin, M. Gwinn, and M. J.
Khoury. 2001. Informed consent for population-based
research involving genetics. Journal of the American
Medical Association 286(18): 2315–2321.
Bookman, E. B., A. A. Langehorne, J. H. Eckfeldt, K. C.
Glass, G. P. Jarvik, M. Klag, G. Koski, A. Motulsky, B.
Wilfond, T. A. Manolio, R. R. Fabsitz, and R. V. Luep-
ker. 2006. Reporting genetic results in research studies:
Summary and recommendations of an NHLBI working
group. American Journal of Medical Genetics. Part A
140A(10): 1033–1040.
Burke, W., and R. L. Zimmern. 2004. Ensuring the ap-
propriate use of genetic tests. Nature Reviews Genetics
5(12): 955–959.
Clayton, E. W., and L. F. Ross. 2006. Implications of dis-
closing individual results of clinical research. Journal
of the American Medical Association 295(1):37.
Code of Federal Regulations. 1991. Title 45 Part
46. Protection of human subjects, Available at
http://www.hhs.gov/ohrp/humansubjects/guidance/45
cfr46.htm (accessed August 9, 2006).
Collins, F. S., E. D. Green, A. E. Guttmacher, and M.S.
Guyer. 2003. A vision for the future of genomics re-
search. Nature 422(6934): 835–847.
Davis, D. S. 2000. Groups, communities, and contested
identities in genetic research. Hastings Center Report
30(6): 38–45.
Ehrmeyer, S. S., and R. H. Laessig. 2004. Has compli-
ance with CLIA requirements really improved quality

26. in US clinical laboratories? Clinica Chimica Acta 346(1):
37–43.
Emanuel, E. J., D. Wendler, and C. Grady. 2000.
What makes clinical research ethical? Journal of the
American Medical Association 283(20): 2701–2711.
Fernandez, C. V., E. Kodish, and C. Weijer. 2003. Inform-
ing study participants of research results: An ethical
imperative. IRB 25(3): 12–19.
Fernandez, C. V., C. Skedgel, and C. Weijer. 2004. Con-
siderations and costs of disclosing study findings to
research participants. Canadian Medical Association
Journal 170 (9): 1417–1419.
Fuller, B. P., M. J. Kahn, P. A. Barr, L. Biesecker, E.
Crowley, J. Garber, M. K. Mansoura, P. Murphy, J. Mur-
ray, J. Phillips, K. Rothenberg, M. Rothstein, J. Stopfer,
G. Swergold, B. Weber, F. K. Collins, and K.L. Hudson.
1999. Privacy in genetics research. Science 285(5432):
1359–1361.
Hedenfalk, I., D. Duggan, Y. Chen, M. Radmacher, M.
Bittner, R. Simon, P. Meltzer, B. Gusterson, M. Esteller,
O. P. Kallioniemi, B. Wilfond, A. Borg, and J. Trent. 2001.
Gene-expression profiles in hereditary breast cancer.
New England Journal of Medicine 344(8): 539–548.
Hirschhorn, J. N., K. Lohmueller, E. Byrne, and K.
Hirschhorn. 2002. A comprehensive review of genetic
association studies. Genetics in Medicine 4(2): 45–61.
Holtzman, N. A., and M. S. Watson. 1999. Promot-
ing safe and effective genetic testing in the United
States. Final report of the Task Force on Genetic Test-

27. ing. Journal of Child and Family Nursing 2(5): 388–390.
Hull, S. C., H. Gooding, A. P. Klein, E. Warshauer-Baker,
S. Metosky, and B. S. Wilfond. 2004. Genetic research
involving human biological materials: A need to tailor
current consent forms. IRB 26(3): 1–7.
Malone, K. E., J. R. Daling, J. D. Thompson, C. A.
O’Brien, L. V. Francisco, and E. A. Ostrander. 1998.
BRCA1 mutations and breast cancer in the general pop-
ulation: Analyses in women before age 35 years and in
women before age 45 years with first-degree family
history. Journal of the American Medical Association
279(12): 922–929.
National Bioethics Advisory Commission. 1999. Re-
search involving human biological materials: Ethical
issues and policy guidance. Rockville, MD: National
Bioethics Advisory Commission.
Neale, A. V., and K. L. Schwartz. 2004. A primer of
the HIPAA Privacy Rule for practice- based researchers.
Journal of the American Board of Family Practice 17(6):
461–465.
Partridge, A. H., and E. P. Winer. 2002. Informing clini-
cal trial participants about study results. Journal of the
American Medical Association 288(3): 363–365.
Pelias, M. K. 2005. Research in human genetics: The
tension between doing no harm and personal auton-
omy. Clinical Genetics 67(1): 1–5.
Petersen, R. C., R. G. Thomas, M. Grundman, D.
Bennett, R. Doody, S. Ferris, D. Galasko, S. Jin, J. Kaye,
A. Levey, E. Pfeiffer, M. Sano, C. H. van Dyck, and L. J.

28. Thal. 2005. Vitamin E and donepezil for the treatment
of mild cognitive impairment. New England Journal of
Medicine 352(23): 2379–2388.
Richardson, H. S., and L. Belsky. 2004. The ancillary-
care responsibilities of medical researchers. An ethical
framework for thinking about the clinical care that re-
searchers owe their subjects. Hastings Center Report
34(1): 25–33.
16 ajob November/December 2006, Volume 6, Number 6
Disclosure of Genetic Results
Roberts, J. S., M. Barber, T. M. Brown, L. A. Cupples,
L. A. Farrer, S. A. LaRusse, S. G. Post, K. A. Quaid,
L. D. Ravdin, N. R. Relkin, A. D. Sadovnick, P. J. White-
house, J. L. Woodard, and R. C. Green. 2004. Who seeks
genetic susceptibility testing for Alzheimer’s disease?
Findings from a multisite, randomized clinical trial.
Genetics in Medicine 6(4): 197–203.
Rubinsztein, D. C., and D. F. Easton. 1999. Apolipopro-
tein E genetic variation and Alzheimer’s disease.
A meta-analysis. Dementia and Geriatric Cognitive
Disorders 10 (3): 199–209.
Schulte, P. 1991. Ethical issues in the communication of
results. Journal of Clinical Epidemiology 44: 57S–61S.
Shalowitz, D. I., and F. G. Miller. 2005. Disclosing in-
dividual results of clinical research: Implications of re-
spect for participants. Journal of the American Medical
Association 294(6): 737–740.

29. Shields, A., C. Lerman, and P. Sullivan. 2004. Trans-
lating emerging research on the genetics of smoking
into clinical practice: Ethical and social considerations.
Nicotine and Tobacco Research 6(4): 675–688.
Stengard, J. H., J. Pekkanen, C. Ehnholm, A. Nissinen,
and C. F. Sing. 1996. Genotypes with the apolipoprotein
epsilon4 allele are predictors of coronary heart disease
mortality in a longitudinal study of elderly Finnish men.
Human Genetics 97(5): 677–684
Tiret, L., P. de Knijff, H. J. Menzel, C. Ehnholm, V. Nicaud,
and L. M. Havekes. 1994. ApoE polymorphism and
predisposition to coronary heart disease in youths of
different European populations. The EARS Study. Euro-
pean Atherosclerosis Research Study. Arteriosclerosis
and Thrombosis 14(10): 1617–1624.
van de Vijver, M. J., Y. D. He, L. J. van’t Veer, H.
Dai, A. A. Hart, D. W. Voskuil, G. J. Schreiber, J.
L. Peterse, C. Roberts, M. J. Marton, M. Parrish, D.
Atsma, A. Witteveen, A. Glas, L. Delahaye, T. van der
Velde, H. Bartelink, S. Rodenhuis, E. T. Rutgers, S.
H. Friend, and R. Bernards. 2002. A gene-expression
signature as a predictor of survival in breast can-
cer. New England Journal of Medicine 347(25): 1999–
2009.
Verweij, M. F., and B. C. Hamel. 2002. Unexpected
findings in identifiable stored blood samples after
analysis without consent: Moral arguments for and
against disclosure. Genetic Counselling 13(2): 115–
121.

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