Incidental Findings in Genetic Research and Clinical
Diagnostic Tests: A Systematic Review
Leigh Jackson,* Lesley Goldsmith, Anita O’Connor, and Heather Skirton
School of Nursing and Midwifery, Plymouth University, Plymouth, UK
Manuscript Received: 6 December 2011; Manuscript Accepted: 20 July 2012
Incidental findings arise when clinically relevant genetic infor-
mation about a research participant or patient is identified
outside the scope oftheoriginalresearchobjectiveor diagnostic
test being performed. These findings can relate to carrier status
for a heritable condition, misattributed paternity or increased
susceptibility to a medical condition. The decision whether to
disclose these findings to the research subject or patient is
underpinned by many ethical, moral, and potentially legal con-
siderations. There is an urgent need for definitive guidelines for
researchers and healthcare professionals. We performed a sys-
tematic review of the relevant literature concerning the disclo-
sure of incidental findings, based on the Preferred Reporting
Items for Systematic Reviews and Meta-Analyses recommenda-
tions, using the prescribed flowchart and checklist. At initial
screening, 473 articles were retrieved. The inclusion and exclu-
sion criteria aimed at obtaining data that were relevant and of
were identified, comprising 2,680 individual participants and
1,023 guidance documents. Major themes emerging from the
included articles include patient autonomy, patient welfare,
disclosure or non-disclosure of genetic incidental findings, and
researchers. ? 2012 Wiley Periodicals, Inc.
Key words: incidental findings; unexpected results; autonomy;
patient welfare; genetic literacy
testing has led to an exponential rise in the number of genetic tests
available for use by healthcare professionals in recent years. By the
single-gene disorders [House of Lords, 2009]. With nearly 2,000
genes involved in single-gene disorders in 2000 and a decade later
nearly 2,000 genetic tests in clinical usage and novel tests being
added atthe rate of20–30amonth [GeneTests, 2011]itis clearthe
demand for genetic testing is increasing at a significant rate.
As an example, in the United Kingdom, the numbers of reports
generated by National Health Service genetic testing laboratories
has risen in <20 years from approximately 20,000 to over
120,000 per annum [Clinical Molecular Genetics Society, 2009–
Wide Association Studies (GWAS) [Stadler et al., 2010b], Chro-
mosomal Microarrays (CMA) [Miller et al., 2010] whole exome
diseases outside the traditional monogenic disorders [GeneTests,
many areas of speciality outside genetics, such as for predicting
treatment efficacy [Weiss et al., 2008], has opened up debate as to
how the results are interpreted and communicated. With many
genes are currently thought to be associated with asthma, Rogers
et al., 2009], interpretation of results and abundance of personal
genetic data has become a major issue.
One particular concern is the issue of incidental findings (IF),
that has potential health or reproductive importance and is dis-
of the study’’ [Wolf et al., 2008, p. 219]. This definition relates to a
research setting but is applicable to a clinical setting with the
replacement of ‘‘participant’’ with patient and ‘‘study’’ with diag-
nostic test. With the increasing adoption of genomic technologies
in clinical applications, there is a strong possibility of discovering
genetic and genomic data outside the scope of the initial objective.
This acquisition of incidental data raises a number of ethical, legal
and clinically practical issues. The decision of whether and how to
and Midwifery, Plymouth University, 301 Hepworth House, Drake’s
Circus, Plymouth PL4 8AA, UK. E-mail: email@example.com
Article first published online in Wiley Online Library
(wileyonlinelibrary.com): 00 Month 2012
How to Cite this Article:
H. 2012. Incidental findings in genetic
research and clinical diagnostic tests:
A systematic review.
Am J Med Genet Part A 9999:1–9.
? 2012 Wiley Periodicals, Inc.
inform patients of complex potential risk factors for an unrelated
disease, carrier status or other, as yet functionally ambiguous,
mutations is far from trivial. The IF could have a potential impact
or other family members, which adds a further layer of complexity
Ness, 2008; Wolf et al., 2008], although little primary research has
been conducted. This aim of this review was to systematically
A search of the EMBASE, Medline, and CINAHL databases was
conducted covering the period from January 2000 to September
2011. These dates were chosen to coincide with publication of
sequence data generated by the Human Genome Project and the
resultant wealth of genetic information which could lead to IF in
research or the clinic [International Human Genome Sequencing
The search terms used to identify articles of interest were:
‘‘incidental finding*,’’ ‘‘off-target,’’ ‘‘unexpected,’’ combined
with ‘‘genetic counsel*,’’ ‘‘genetic*,’’ ‘‘clinic*,’’ and ‘‘research.’’
Inclusion and Exclusion Criteria
Papers were eligible if they satisfied the inclusion criteria. These
stated that papers must: specifically address the handling of inci-
dental findings in genetics or genomics in research or in a clinical
must be written in English.
the inclusion and exclusion criteria were used to eliminate papers
outside the scope of this review. Initially, this was achieved by
screening the title and abstract of each article but where there was
any ambiguity, the full text was obtained and assessed against the
identify any further articles that were not flagged up by the initial
search strategy. All articles considered for inclusion in the review
the Kmet quality scoring scale for qualitative and quantitative
research [Kmet et al., 2004]. Each paper is assigned a mark of 0
arethen totaled and used toderivea final score of between 0and 1.
Any disagreements about scoring of papers were discussed as a
group until consensus was achieved. We decided in advance that
relevant research in the review as possible, while maintaining an
appropriate levelof quality control, ensuring the robustness of any
if retained. After completing the systematic search and analysis of
papers only one paper was excluded from the review as a result of
this quality control.
Data Abstraction and Analysis
Initially, we extracted key data from each paper and these are
presented in Table I. As there was disparity between the methods,
participants and focus for each of the included papers, it was not
possible to conduct a meta-analysis. We therefore thematically
analyzed the findingsof each paper [Braun andClarke,2006]. This
included coding each relevant portion of the text, collating these
under categories and grouping the categories under over-arching
themes. The thematic analysis was confirmed by three authors.
The Preferred Reporting Items for Systematic Reviews and Meta-
Analyses PRISMA flowchart showing the consecutive methodo-
initial screening, 473 articles were detected, and after the inclusion
to exclude a further 23 articles, leaving four studies comprising
2,740 individual participants and 1,023 documents to be included
istics of the included studies are described in Table I. Four studies
wereidentifiedasbeingsuitableforinclusion inthereview. Twoof
these studies were concerned with IF in a clinical setting, two in a
research setting. Miller et al.  assessed the opinion of health-
care professionals to IF disclosure, Turney  investigated the
views of the public solely on IF related to misattributed paternity,
Lawrenz and Sobotka  evaluated the provision of guidelines
IF [Turney, 2005; Lawrenz and Sobotka, 2008; Miller et al., 2009].
No papers identified by our systematic research strategy examined
research participant or patient perspectives and experiences on the
return of genetic IF. Turney  incorporated lay opinions of
patients, however, this was in relation to a hypothetical scenario
using thematic analysis [Braun and Clarke, 2006] and the major
themes and sub-categories are presented in Table II.
The literature concerning incidental findings in genetic and
genomic research and clinical applications is largely composed
of opinion articles [Wolf et al., 2008], commentaries [Ballantyne,
2008], and ethical discussions [Scanlon, 2000; Richardson, 2008;
Van Ness, 2008] and supported by the fact we only identified four
papers, it is clear that there is a paucity of primary research [Oliver
et al., 2004]. The authors of a systematic review of the impact of
disclosing IF of carrier status identified by newborn routine blood
2 AMERICAN JOURNAL OF MEDICAL GENETICS PART A
TABLE I. MainQ1Characteristics of Included Studies
Country and setting
To identify whether IF
are addressed in
Content analysis study of
Documents taken from four
sources: 14 federal
societies, the top 100 NIH
funded universities and a
standard internet search.
Federal agency n¼154;
Internet consent forms
Content analysis. Coding
based on type of research, data handling, IF findingprotocol. Descriptive
statistics used to illustrate
frequency of IF related
9% of federal documents, 25% of
professional society, 11% of universityand37%ofweb-based
consent forms address IF (not
exclusively genomic); 1% of
federal, 0% of professional
societies, 4% of universities and
11% of web consent forms
advocate non-disclosure of IF;
0% of Federal, 0% of professional
societies, 1% of universities and
5% of web consent forms
suggest consulting with a
clinician before IF disclosure; 3%
of federal, 0% of professional
societies, 2% of universities and
4% of web consent forms rec-
0.8; A very well con-
ducted and rigorous
search of US IF
online. A useful paper
for assessing the
current status of IF
Meacham et al.
To assess researcher
perspectives on IF disclosure
study using thematic
analysis. Response to
vignette and semi-
interview; The vignette
new research shows that
10% of an existing study
sample may have a gene
variant linked to a high risk
of colorectal cancer. The
initial study did not
relevant results and as
such return or results was
notincluded inthe consent
process, however contactdetails were retained
2001; Hsieh and Shannon, 2005]. Atlas software was
used and transcripts were
at least two individuals.
Codes were grouped into
three broad categories:
how researchers would
respond, why they would respond in this way and
other recurring concepts
which did not fit into these
two discrete groups.
Frequency and order of
codes in the data was
analyzed and themes
The majority of researchers sup-
ported disclosure of the IF in the
given vignette. The three
of information suggesting
increased risk, welfare of the
participant and adherence to
rules. If the evidence of
increased risk was strong, it
could harm the participant andcontact could be made without
breaching confidentiality or
other IRB guidelines then
disclosure was favored.
used to support non-disclosuredecisions
0.8; A good study
generating rich data
disclosure decisions,however the
generalizability of the
findings is limited
somewhat by the
constraints of the
TABLE I. (Continued)
Country and setting
Miller et al. 
To assess attitudes
groups. To identify
underlying thepreference for disclosure or
Mixed methods study: (1)
cross-sectional self-completion postal survey.
five-point Likert scale
Random sample of healthcare
providers in Ontario,
Canada. Recruited fromCanadian medical
directory, association of
genetic counselors and
Ontario colleges of
midwives and nurses.
OB/GYN n¼206; midwives
n¼248; nurses n¼479;
FP n¼287; PED n¼270;
GEN n¼52; HEM n¼41
Descriptive statistics. x2
test for differences in
The majority of respondents were
found to support reasons for IF
disclosure and oppose reasons
against IF disclosure. However,geneticists stood out as a
to information were found to be
more supported than child
Quantitative 0.91; A very
broad range of participants were
useful comparisons,however there was a
slight issue with
identifying exact N
(2) Qualitative study using
modified grounded theory.
Data collected by
Purposive sample across
same healthcare provider
groups. Recruited via
indication of willingness to
participate on survey
returns and via snowball
Modified grounded theory
integrating iterative and
Reflexive approach based
on pre-existing concepts.
Dominant support for disclosure of
IF, motivated by clinical duty,
reluctance to keep secrets and
fear of litigation. Dissenters
wanted to avoid potential harms
of IF disclosure
Qualitative 0.85; The
addition of a
qualitative aspect to
the study increased the impact and depth
of the findings
To assess attitudes
Mixed methods study: (1)
(2) Focus groups. Face-to-
(3) Online focus group
Randomly selected sample
from respondents to large
national Australian study
on public perceptions of emerging technologies.
Tertiary educated men n¼7;
Tertiary educated women
educated men n¼7;
Fathers’ rights campaigners
n¼4; Women with
personal experience of
genetic testing. n¼6
ANOVA assessment of level of
comfort with disclosure of
non-paternity to the father.
Quantification of effects of
education and gender of
Identification of key themes
and concepts underlying
the opinion of different
groups of interest
No universal consensus on
non-paternity disclosure. Key
themes identified related to
rights of the father, the mother
and the child. Arguments were
found to be individualistic and
of the necessity of carrier
screening and a campaign to
educate the public in basic lawsof hereditary (sic)
0.7; Combined with the
survey data, thefocus
groups gave an
interesting insight to
towards IF disclosure
in the specific case of
paternity. The paper
also gives a detailedappraisal of theethical issues
however being a mix between a
made it difficult to
follow at times
OB, obstetricians; GYN, gynecologists; FP, family physicians; PED, pediatricians; GEN, genetics professionals; HEM, hematologists.Quality score is measured using standard quality assessment criteria for evaluating primary research papers from a variety of fields [Kmet et al., 2004].
spot screening to parents in 2004 found no studies worthy of
inclusion [Oliver et al., 2004]. The aim of the current review was
to give an updated overview on genetic IF research and has been
driven by improving technology that allows affordable whole
genome analysis for research projects, clinical diagnostics and
direct-to-consumer services [Miller et al., 2010; Stadler et al.,
There was disparity in research questions, for example Turney
 discussed misattributed paternity, whilst Lawrenz and
Sobotka  conducted a literature search. These disparities
mean that a meta-analysis of the data is inappropriate, however a
thematic analysis identified some overlap in the findings, resulting
in common key themes which we will now discuss.
Meacham et al. , Miller et al. , and Turney 
discuss the concept of autonomy with regards to the issues sur-
rounding IF disclosure. The majority opinion elucidated by the
study of Miller et al.  was in favor of disclosure of IF to the
patient by the clinician. A duty to disclose was perceived by
clinicians as they felt the test results belonged to the patient and
FIG. 1. PRISMAflowdiagramofstudyselection.Thescreeningprocessidentifiedfourstudiesfromaninitialpoolof473asbeingrelevanttothecurrent
review, of sufficient quality and having satisfied the inclusion criteria. This PRISMA flow diagram demonstrates the process of identifying and
screening relevant studies.
TABLE II. Major Themes Emerging From Included Papers
Test results belong to the patient
Participants should benefit from research
Who is the patient?
Disclosure allows participants to seek
Avoid paternalistic attitude
Avoid harm and distress if not clinically
Keeping IF secret could endanger health
Potential to be destructive/harmful
Moral/legal obligation to disclose
Understanding of the patient/participant
Understanding of the clinician/researcher
Ramifications of misinterpretation
JACKSON ET AL.
they were not prepared to remove this ownership and thus
autonomy from them. There were a number of different reasons
expressed for favoring disclosure by researchers studied by Mea-
cham et al. , one of which was to allow the participant to
benefit from having taken part in the research study. Researchers
considered that by withholding IF and thus preventing participant
autonomy then they may be breaking an obligation to the partic-
ipant. The rationale for this was that research participants had
already inconvenienced themselves by agreeing to take part in the
study and the least they should expect from the researchers was
honesty when a clinically relevant IF was discovered.
complex. Allowing for conflicting viewpoints on who to tell, and
who was defined as the patient, the participants in the Turney
child was being screened for carrier status and was therefore the
patient. However, the results were to be communicated to the
was entitled to be told if misattributed paternity was uncovered.
Consensus opinion in the wider field of IF would suggest that the
child should have the option of being told when they are old
enough, as the issue does not pose a serious medical problem in
childhoodor necessarily at all [Pediatrics, 2001;Borry et al., 2006].
Turney  states that the ethical argument for IF disclosure on
information. The disclosure of misattributed paternity may never
and this perceived right to autonomy may be secondary to the
adverse social effects on the welfare of the patient that disclosure
may cause [Garfinkel, 1956; Hirczy, 1994; d’Agincourt-Canning,
2001; Lucast, 2007].
In fact, due tothe lack of medical ramifications, many clinicians
decide not to disclosemisattributed paternity to any party in order
to preserve the integrity of the family unit and current social
circumstances in the best interests of the child [Ross, 1996; Soder-
dahl et al., 2004; Lucast, 2007]. This option is not as acceptable
though in the wider IF field. Outside genetics, when clinically
relevant IF are uncovered, for example tumors being observed
patient and preservation of patient autonomy. Although it may be
controversial, It could be argued that these obligations should
be equally applicable in the context of genetic IF. In accordance
with this view, Miller et al.  found that a majority of health-
care professionals supported the reasons for IF disclosure and
disagreed with the reasons opposing disclosure. Despite the differ-
due to the logistical difficulties of providing anonymity, distance,
consent process, may not necessarily be duty bound to report
clinically significant IF but the Meacham et al.  findings
indicate a perceived moral or ethical obligation to disclose
for non-disclosure. This is an interesting finding as they could be
and interpretation of the genetic IF. It could be that a lack of
completeunderstanding of the precise results and consequences of
that even among healthcare professionals the issue of whether or
is any ambiguity as to the understanding of healthcare professio-
will be able to interpret and process results from complex genetic
tests. It was primarily for reasons concerning patient welfare that
the geneticists cited withholding genetic IF. However, patient
welfare was also one of the foremost reasons given by other health-
care professionals in support of IF disclosure. These findings were
confirmed by the Meacham et al.  study, where participant
welfare emerged as the most cited reasons for both disclosing and
withholding IF. Reasons for disclosing IF on the grounds of
participant welfare centered on allowing the participant to seek
keeping. Reasons for withholding information on the grounds of
participant welfare centered on the avoidance of harm and distress
relevant upon further investigation.
Secrets are Harmful
Many participants in the studies included in this review expressed
discomfort with the idea of secrets being kept. This ranged from
of participants [Meacham et al., 2010], healthcare professionals
being wary of the fact that secrets ‘‘are destructive, are potentially
destructive or harmful’’ [Miller et al., 2009, p. 629] or worrying
about the implications for other family members [Turney, 2005].
is a very specific example of IF (and is not addressed in any of the
other included papers), the idea that the clinician had a moral and
possibly legal obligation to inform the patient of IF was consistent
with the findings of Miller et al. . Non-disclosure of IF was
feared by both clinicians and members of the public to affect the
crucial bond of trust that exists between patient and clinician. This
perceived obligation to disclose is intertwined with the concept of
patient and participant autonomy discussed previously.
The idea of secrets and particularly family secrets being harmful
is well established in the literature [Karpel, 1980; Vangelisti and
Caughlin,1997; Wismeijer, 2011]. In a study ofparentsof children
conceived as a result of egg donation, Hahn and Craft-Rosenberg
theme driving parents who disclosed to their children. The case of
professional/researcher and the patient/participant as well as
6 AMERICAN JOURNAL OF MEDICAL GENETICS PART A
between the patient/participant and their family members. This
brings an additional layer of complexity to the decision of whether
to disclose IF and if so then who to disclose to and also to the
requirement for informed consent. If an IF occurs that couldaffect
family members, the healthcare professional or researcher is faced
with a number of ethical dilemmas. Parker  suggests that
undertaking a genetic test that could have repercussions for other
confidentiality of that affected individual has also been compro-
clinically relevant genetic IF, should the patient/participant be
professional is faced with the decision to either breach patient
principles of non-maleficence to the potentially affected family
member by respecting the patients confidentiality. Whilst this may
not seem like a common problem, a US study of 206 geneticists by
Falk et al.  showed that 60% of those surveyed had experi-
enced a patient reluctant to disclose results to family members and
with the burgeoning number of genetic tests being carried out this
problem is only going to increase [Falk et al., 2003]. The study also
showed that 25% of these geneticists considered breaching patient
this extreme course of action, having decided that the secrets were
the US, (Genetic Information Nondiscrimination Act GINA 2008,
www.genome.gov), this finding demonstrates the depth of feeling
amongst geneticists. The ambiguity over the disclosure of genetic
lack of guidelines and legal precedents. With the anticipated
of Lawrenz and Sobotka  presented in this review. They
found that there were very few guidance documents from uni-
versities, federal bodies or professional societies concerning IF and
those that did exist did not suggest non-disclosure.
Oneof the practicalconsiderations when considering disclosure of
genetic IF is the perceived genetic literacy of the patient, or indeed
the genetic literacy of the healthcare professional interpreting the
results. This issue was discussed in various contexts across the
papers includedinthereview. Turneyfoundthat in regards
to the issue of misattributed paternity; ‘‘the Mendelian science of
genetics was poorly understood, particularly among the general
arose.’’ The author went on to conclude that ‘‘given the prevalence
people on basic laws of hereditary’’ (sic). This displayed concerns
about poor public understanding having an influence on clinical
decision making even in the context of a relatively simplistic
dichotomous situation. In the context of genetic research, Mea-
cham et al.  state in their conclusions ‘‘this study also points
to a need for a better understanding of genetic information on the
part of researchers, the media, and the public-in particular, the
arise from sharing and acquiring personal genetic information.’’
We believe that this reflected their uncertainty that the researchers
a clinical viewpoint, one of the most intriguing findings of Miller
incidental carrier status results across many medical specialties
apart from one, genetics [Miller et al., 2009]. As geneticists are the
group who should best understand the ramifications of these
results, their reluctance to disclose suggests that members of the
the genetics or are more confident that the patients will be suffi-
ciently equipped to deal with the information.
and Japan found that they were not routinely achieving the basic
competencies in genetics, nor were they confident in their under-
standing of genetics and suggested that this may have an effect on
the antenatal screening decisions of women [Skirton et al., 2010b].
Lea et al.  hasQ3described the challenges facing nurse
network of excellence have devised a set of core competencies to
prepare healthcare professionals for dealing with the ever-increas-
There has been some very informative work carried out into
assessing the genetic literacy of the general public. With direct
relevance to the Turney  study presented in this review,
Taylor  investigated the perceptions of genetic risk and
predictive genetic testing in Australia and the implications for
valued genetic information positively and whilst risk information
was less appreciated than certain information, women valued
genetic risk information significantly more highly than men. The
participants were evenly split between concern (44%) and no
concern (47%) about potential misuse of genetic information. In
to assess the public understanding of basic genetics [Lanie et al.,
2004]. The authors summarized that despite conversational famil-
genetic knowledge which could impact on routine healthcare
decisions. More recently, Christensen et al.  investigated
the basic genetic understanding of a cohort of US citizens. While
and 24% linked single-gene influences to behavior. The results of
this study indicate a generally poor public genetic literacy but the
another studydidfindsignificantage-relateddifferences ingenetic
be inversely proportional to age and this resulted in the oldest age
group preferentially attributing causes of body weight to genetic
factors, as opposed to behavioral factors such as diet and exercise.
JACKSON ET AL.
Increasing public understanding of genetics is essential to allow
this reason, the National Human Genome Research Institute
identified ‘‘improving the public’s genetic literacy in order to
enhance consumer skills’’ as one of their main priorities for
communication, behavioral and social sciences research [McBride
t al., 2010, p. 556].
methodologically diverse. This, coupled with the limitations of the
For example, the Turney  study examined a very specific
example of IF in attitudes to paternity results in the Australian
public, the Miller et al.  study of genetic professionals was
limited to one geographical setting in Ontario, the Meacham et al.
 study relied entirely on hypothetical situations and the
Lawrenz and Sobotka  study was an audit of current US
guidance documents on IF management but clearly cannot seek to
common themes we have identified and considered, the general-
emphasizes the urgent need for empirical research into the field of
genetic IF. Healthcare professionals and researchers alike are cur-
are unsure of their obligations in relation to clinical and ethical
practice. None of these papers focused on research participant or
patient perspectives. Whilst the issue of genetic IF has been widely
discussedintheethical literature, thereisapaucityofdatapertain-
ing to the views of the most interested stakeholders. The views of
patients, health professionals, researchers, and ethics committees
need further investigation with a view to establishing a robust
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