ArticlePDF AvailableLiterature Review

Incidental Findings in Data-Intensive Postgenomics Science and Legal Liability of Clinician–Researchers: Ready for Vaccinomics?

Authors:

Abstract

Vaccinomics encompasses a host of multiomics approaches to characterize variability in host-environment (including pathogens) interactions, with a view to a more directed or personalized use of vaccine-based health interventions. Although vaccinomics has the potential to reduce adverse effects and increase efficacy of vaccines, the use of high-throughput, data-intensive technologies may also lead to unanticipated discoveries beyond the initial aims of a vaccinomics study--discoveries that could be highly significant to the health of the research participants. How do clinician-researchers faced with such information have to act? What are the attendant legal duties in such circumstances and how do they differ from the duties of non-clinician researchers? Together with a critical analysis of the international laws and policies framing researchers' duties with regard to incidental findings, this article also draws from Quebec's civil law--with its rich jurisprudence on clinician and researcher liability--as a case study to evaluate the potential legal implications associated with vaccinomics investigations. Given previous lessons learned from other data-intensive sciences, the education of clinician-researchers with regard to their roles, limitations, and legal obligations remains an important strategy to prevent potential legal complications and civil liability in vaccinomics research in the postgenomics era.
Review Article
Incidental Findings in Data-Intensive Postgenomics Science
and Legal Liability of Clinician–Researchers:
Ready for Vaccinomics?
Ma’n H. Zawati, Matthew Hendy, and Yann Joly
Abstract
Vaccinomics encompasses a host of multiomics approaches to characterize variability in host–environment
(including pathogens) interactions, with a view to a more directed or personalized use of vaccine-based health
interventions. Although vaccinomics has the potential to reduce adverse effects and increase efficacy of vaccines,
the use of high-throughput, data-intensive technologies may also lead to unanticipated discoveries beyond the
initial aims of a vaccinomics study—discoveries that could be highly significant to the health of the research
participants. How do clinician–researchers faced with such information have to act? What are the attendant legal
duties in such circumstances and how do they differ from the duties of non-clinician researchers? Togethe r with
a critical analysis of the international laws and policies framing researchers’ duties with regard to incidental
findings, this article also draws from Quebec’s civil law—with its rich jurisprudence on clinician and researcher
liability—as a case study to evaluate the potential legal implications associa ted with vaccinomics investigations.
Given previous lessons learned from other data-intensive sciences, the education of clinician–researchers with
regard to their roles, limitations, and legal obligations remains an important strategy to prevent potential legal
complications and civil liability in vaccinomics research in the postgenomics era.
Introduction
W
ith scientists offering us the first draft of the human
genome in the beginning of the 21st century (Yamey,
2000), research aiming to develop new treatments and more
effective prevention measures for diseases with a genomics
component has thrived (Abdul-Rahman, 2010). Moreover,
with the subsequent creation of a map of human genetic
variations (International HapMap Project), our understand-
ing of health and disease has advanced, setting the pace for
what came to be known as personalized medicine (Collins,
2010). Vaccinomics is an example of research leading to such
development. In general terms, it refers to an emerging field of
research exploring the possibility of tailoring vaccination to
take genetic/genomic heterogeneity into account ( Joly et al.,
2010; Poland, 2007). Although being relatively recent, it
‘encompasses the fields of immunogenetics and im-
munogenomics as applied to understanding the mechanisms
of heterogeneity in immune responses to vaccines’ (Poland
et al., 2007). In fact, just as developments in pharmacoge-
nomics and pharmacogenetics have allowed for individual-
ized drug therapy, vaccinomics promises to allow
personalized vaccination. For that matter, Poland et al. state:
just as we now recognize that a variety of drugs [ . . . ]
may require different dosing based on individual genetic
differences and result in different side effect profiles
[ . . . ] we have now begun to recognize similar attributes
in terms of vaccine indications, dosing, side effects and
outcomes. (Poland et al., 2009)
Vaccinomics lies on the cutting edge of medical science and
promises to bring about immeasurable improvements in
disease prevention. The ‘omics’ sciences, in general, are a
notable example of postgenomics data-intensive science in the
21st century, allowing in-depth system level analysis of bio-
logical complexity and mechanism-based targeted health in-
terventions. Yet such data-intensive sciences also pose novel
challenges well beyond the technological, such as incidental
findings and the attendant legal liability. Considering that
human subject research—which relies on participant trust
and altruism (Knoppers and Zawati, 2010)—is required for
the development of vaccinomics, we must address the im-
portant legal issues associated with vaccinomics research.
For the field of vaccinomics to succeed in the near future, we
must effectively learn from the past lessons of other data-
intensive sciences.
Centre of Genomics and Policy, McGill University, Montre
´
al (Que
´
bec), Canada.
OMICS A Journal of Integrative Biology
Volume 15, Number &, 2011
ª Mary Ann Liebert, Inc.
DOI: 10.1089/omi.2010.0137
1
Cognizant of the multidisciplinary nature of vaccinomics
research—where both clinician and non-clinician researchers
collaborate—this article examines the clinician–researcher’s
duties when faced with one of the least discussed aspects of
research: incidental findings—or unanticipated discoveries
that go beyond the initial aims of the study (Wolf et al., 2008b).
This article’s primary aim is to provide guidance to clinician–
researchers conducting vaccinomics research with regard to
incidental findings. In order to do so, it will first examine the
intersection of vaccinomics research and incidental findings
and will identify the important issues that arise in this par-
ticular context. Second, pertinent norms that discuss the legal
duties of researchers with regard to incidental findings in
genomics will be compared and analyzed from an interna-
tional perspective. This will allow for a proper assessment of
the current state of the general guidance on this matter and
will permit the identification of the issues not yet addressed.
Third, this article will examine the legal duties of clinician–
researchers using Quebec’s civil law as a case model. Finally,
it will present the elements of potential legal liability, again
using Quebec law as a model.
Methodology for Literature Search and Synthesis
The various international norms analyzed in this article
were retrieved from the HumGen International database, an
on-line resource specializing in legal and socioethical issues in
human genetics. For general documentation on the ethical,
legal, and social issues in genomics research, the keyword
‘research’ was used. As for the more specific documents on
incidental findings, the keywords ‘communication of results’
and ‘confidentiality’ were chosen. For both types of docu-
ments, the time line covered ranged from the year 1990 to the
present. The relevant literature on vaccinomics and incidental
findings was retrieved using PubMed. The search terms used
were ‘incidental findings,’ ‘vaccinomics research,’ and each
of the following keywords: ethics, liability, responsibility,
researcher, unexpected, duties. For the literature search, no
date range was specified and no other limitations were cho-
sen. Finally, when researching the legal duties of clinician–
researchers and the elements of liability from the Quebec
perspective, legal databases such as REJB (Re
´
pertoire E
´
lec-
tronique de Jurisprudence du Barreau), CanLii (Canadian
Legal Information Institute), LexisNexis, and Westlawe-
Carswell were used to find relevant legislation and case law.
Searches in these databases were limited to the jurisdiction of
Quebec and the following keywords were used: physician,
liability, research, duty, malpractice, and civil law.
Vaccinomics research
Vaccinomics research is based on the idea that the benefits
of vaccination would be maximized, and its risks minimized,
by a personalized approach as opposed to uniformly ad-
ministering vaccination to everyone in the population (Poland
et al., 2008). Vaccinomics relies on the premise that, due to
genetic heterogeneity, not everyone is equally susceptible to a
given disease, not everyone requires the same dose to develop
immunity, and some people are more likely to experience
adverse reactions to vaccination than others (Poland et al.,
2008).
Personalization in the context of vaccination refers to ‘the
targeting of vaccine antigens outcome (maximizing immu-
nogenicity and minimizing the risk of either vaccine failure or
vaccine reactogenicity and side effects in a host at risk of
serious disease or complications)’ (Poland et al., 2008). Per-
sonalization may take place at either the individual, gender,
racial/ethnic, or subpopulation levels: at the individual level,
an individual’s known genetic makeup would be taken into
account; at the gender level, vaccination would be based on
the known responses to antibody levels among males and
females; at the racial/ethnic level, vaccination would take into
account known genetic traits affecting immune responses
among different racial/ethnic groups; and at the subpopula-
tion level, vaccination would be based on the known effects
that certain environmental factors (such as prescription drug
consumption) have on immune response genes (Poland et al.,
2008). It should be noted, however, that gender and racial/
ethnic distinctions in research typically generate thorny ethi-
cal issues (Caulfield et al., 2009; Lawrence and Rieder, 2007),
but discussing them here would exceed the scope of this
article.
Incidental findings
Why are incidental findings an important issue in vacci-
nomics research? To effectively answer this question and to
better understand the intrinsic relationship between these two
topics, a proper definition and a brief overview of incidental
findings is in order.
The term ‘incidental finding’ generally refers to ‘a finding
concerning an individual research participant that has po-
tential health or reproductive importance and is discovered in
the course of conducting research but is beyond the aims
of the study’ (Wolf et al., 2008b). Incidental findings should
theoretically be differentiated from research results, although
regulatory documents (i.e., laws, guidelines, and recommen-
dations) do not efficiently distinguish between the two. As to
their prevalence, incidental findings are endemic to human
subjects’ research but the likelihood of coming across inci-
dental findings increases proportionately with the quantity of
information gathered during the course of research.
The potential for incidental findings is significant in the
context of genomic research, which has made major strides
over the last 10 years (Cho, 2008). Large-scale research of the
human genome has been made possible by increasingly
powerful technologies: genomic microarrays, scanning tech-
nologies, and other research instruments now generate mas-
sive amounts of information (Wolf et al., 2008a). The problem,
however, is that ‘some of that information is the data that the
researchers are seeking in order to answer their research
question and achieve the aims of their study, but much of that
information is incidental’ (Wolf, 2008).
The same could be said for vaccinomics research, where
large omics datasets are required for discovery science and
statistical power for ‘analysis, discovery, replication, valida-
tion, and interpretation’ (Poland and Oberg, 2010). Indeed,
when trying to find associations between ‘variations in vac-
cine immune responses and polymorphisms of immune re-
sponses genes’ (Poland et al., 2008), high-dimensional
genome-wide sequencing (Poland and Oberg, 2010) becomes
essential. Although such data might not necessarily be perti-
nent to the research at hand, it might yield a panoply of ge-
netic information, such as misattributed paternity, other
misattributed lineage, or ‘unanticipated genetic or chromo-
2 ZAWATI ET AL.
somal variant beyond the genes or chromosomes being
studied’ (Wolf et al, 2008a). Unanticipated information be-
comes less of an issue at later, more detailed stages of analy-
ses, such as when using a focused candidate gene approach.
Consequently, incidental findings call into question the
researcher’s legal obligations (Miller et al., 2008). Because
vaccinomics research has multiple settings—(individual,
ethnic, populational)—such obligations could very well be-
come multilateral in scope. Does the clinician–researcher have
a duty to disclose potentially medically significant informa-
tion to research participants? Could the clinician–researcher
breach his duty to uphold secrecy in order to warn at-risk
relatives of a genetic predisposition incidental to the research
conducted? These questions are more easily answered in the
context of research results, where the information in question
is actually under investigation (Wolf, 2008) and where a
specific mention of the steps to be taken is usually included in
the consent form. Incidental findings, however, pose a unique
problem, because researchers may not only lack the expertise
to properly interpret these findings (Wolf, 2008)—after all,
these findings are beyond the aims of the study—but there
might not be plans to address them if/when they arise.
Moreover, having a clinician in the research team brings an
interesting variable into the equation, especially when par-
ticipants are also his/her patients. Can the general duties that
apply in the clinical setting be transposed to the research
setting?
The nature of genomic information complicates matters
further. Most disease predictions based on genomics are
probability estimates, where genetic modifiers can increase
the likelihood of disease often depending on exposure to en-
vironmental factors (Van Ness, 2008). Indeed, ‘most re-
searchers understand that results that may show genetic
associations with an outcome are not precise, but rather shift
the probability of an outcome’ (Van Ness, 2008). How should
such imprecision affect the way we treat incidental findings in
genomics research? Should findings that lack accuracy be
returned and how should this question depend on the ex-
pertise of the clinician–researcher?
In brief, there is general uncertainty about what to do with
incidental findings (Wolf, 2008) and even more uncertainty
when it comes to incidental findings in the hands clinician–
researchers. Therefore, identifying the duties of clinician–
researchers pursuant to international norms will allow for a
better assessment of the state of the legal and ethical guidance
on the issue and will set the stage for an in-depth analysis of
the clinician–researcher’s duty as analyzed from the Quebec
civil law perspective.
Clinician–researcher
and the physician–patient relationship
The term clinician–researcher refers to practicing physi-
cians performing research in vaccinomics. Analyzing their
duties with regard to incidental findings will be important
due to their (not always reconcilable) dual role. Indeed, as
clinicians, they are bound by their professional responsibili-
ties of care and, as researchers, their primary objective is to
answer their study question while minimizing the risks and
maximizing the benefits (Miller et al, 2008).
Although some authors have posited that the physician–
patient relationship does not present a useful model for the
investigator–patient relationship when it comes to incidental
findings (Miller et al, 2008), they do not thoroughly consider
the important issues that arise when a physician takes on the
role of researcher. Moreover, even though authors have re-
cently highlighted core responsibilities for researchers when
managing incidental findings (Wolf et al., 2008b), they
assumed—for the purpose of their study—that the researcher
is not also a clinician. In the same vein, authors have offered
recommendations on the management of incidental findings
aimed at researchers generally without deliberating in great
depth the particular issues associated with researchers
who are also clinicians (Wolf et al., 2008a). Consequently,
exploring the topic of incidental findings in vaccinomics re-
search from the clinician–researcher perspective will help
identify the unique issues facing clinicians conducting re-
search for nonclinical purposes (i.e., not for diagnostic or
therapeutic purposes).
Additionally, clinician–researchers usually benefit from
well-established norms governing their clinical and research
activities, which could be used to clarify some of their obli-
gations and concretize their legal liability. In order to do so,
Quebec’s civil law will be used as a case model.
Indeed, Quebec, with its rich case law on clinicians’ and
researchers’ duties and liability, will be used to provide a
concrete liability model and to explore the jurisprudential
application of such duties. Although liability remains a legally
private jurisdictional matter (i.e., differs from jurisdiction to
jurisdiction on an international level), taking Quebec as a
model will allow for an in-depth discussion of the elements
underlying any potential legal liability that could later be
adapted in other jurisdictions. Moreover, it will allow us to
determine whether the core responsibilities proposed by
previous authors are helpful in the context of vaccinomics
research conducted by clinician-researchers.
Legal duties of the researcher:
an international perspective
Genetics professionals, bioethicists, and policymakers are
increasingly expanding the scopeoftheinformationtheybelieve
is critical for informed consent in the context of genetics research
to include the possibility of incidental findings (Michigan
Commission, 1999). Where regulatory documents impose some
kind of duty on researchers to address incidental findings in the
informed consent process, however, they seem to differ on
whether the decision to disclose these findings should be left to
the research participants themselves or to researchers.
It is important to mention that two types of regulatory
documents will be used in this section. The first type function
as legal norms: documents that bind their subjects, such as
laws and regulations. The second type of document is of the
non-binding nature. In other words, they are those that typi-
cally function as guideposts for ethical conduct. Examples of
non-binding regulatory documents are guidelines, policies,
recommendations, opinions and consultation papers, to name
a few. As nonbinding norms, they are usually flexible (i.e.,
easier to modify than laws and regulations) and play an im-
portant complementary role.
As mentioned above, some regulatory documents would
allow participants to preemptively determine whether they
wish to be informed of any incidental findings as an element
of informed consent. Although crystallizing the researcher’s
INCIDENTAL FINDINGS IN DATA-INTENSIVE POSTGENOMICS SCIENCE . . . 3
duty to inform, such an approach seems to privilege the
participant’s autonomy and right to self-determination over
any ethical or legal obligations possibly held by researchers to
warn participants of potentially significant health risks.
An example of such a trend appears in the Ethical, Legal and
Social Issues in Genetic Testing: A Consultation Paper published
by the Bioethics Advisory Committee of Singapore, which
states that ‘where appropriate, it may be beneficial to [ . . . ]
take into consideration [ . . . ] [the] possibility of unexpected
findings [ . . . ] and whether the [participant] will want to
know such findings.’ In the same vein, the Recommendation on
the Ethical Aspects of Collections of Samples or Human Tissue
Banks for Biomedical Research of the Ethics Committee of the
Rare Disease Research Institute (2007) of Spain suggests that
‘subjects must be offered the possibility of deciding whether
or not they wish to receive [research results and incidental
findings].’ Finally, paragraph 5 of the Statement on the Prin-
cipled Conduct of Genetics Research by the Human Genome
Organization (HUGO) states that ‘choices to be informed or
not with regard to results or incidental findings should [ . . . ]
be respected.’ In fact, this regulatory document goes the
furthest, adding that the participant’s decision whether to be
informed of incidental findings should even ‘bind other re-
searchers and laboratories’’—presumably those that have ac-
cessed archived samples—and that ‘in this way, personal,
cultural, and community values can be respected.’
On the other hand, some regulatory documents hold the
researcher responsible for deciding whether incidental find-
ings should be disclosed. This approach seems to acknowl-
edge the existence of either an ethical or legal obligation owed
by the researcher to the participant. In these cases, when
confronted with an incidental finding, the researcher is either
permitted, encouraged, or obligated to inform the participant,
having taken into consideration the potential risk of harm
associated with nondisclosure (see examples below). Also,
where regulatory documents empower the researcher to
make disclosure decisions in this way, they generally demand
prior consultation with research ethics committees (e.g.,
Spanish Law 14/2007 and TCPS 2, 2010).
An example comes from the Spanish Law 14/2007, of 3 July,
on Biomedical Research, a nationally binding document, which
confirms the existence of the participant’s right ‘not to know’
about incidental findings, but:
when this information, according to the criteria of the
doctor in charge, is necessary in order to avoid serious
damage to his health or that of his biological family
members, a close family member or a representative
shall be informed.
It is clear from this section that this law puts important
weight on disclosing such findings to family members when
serious damage to the health of the participant or a family
member could be avoided. Indeed, the law establishes two
necessary conditions for disclosure: (1) that serious damage to
the health of an individual is possible and (2) that such
damage would be avoided with disclosure.
Although specifying that the criteria of necessity should
be assessed by a doctor, the Spanish law does not address
the possible tensions created by such an approach. In
particular, it is unclear how the clinician–researcher would
discharge his duty to uphold professional secrecy while
adopting such an approach. Also, what happens if the
relative is not identifiable? These issues will be revisited in
Part III of this article.
The Council for International Organizations of Medical
Sciences’ (CIOMS’) International Ethical Guidelines for Biome-
dical Research Involving Human Subjects states that ‘subjects
will be informed of any finding that relates to their particular
health status.’ In the same vein, the 2nd Edition of the Tri-
Council Policy Statement (TCPS 2, 2010) published by the In-
teragency Advisory Panel on Research Ethics of Canada
(2010) states that ‘researchers have an obligation to disclose to
the participant any material incidental findings discovered in
the course of research.’ Material incidental findings are de-
fined as having ‘significant welfare implications for the par-
ticipant, whether health-related, psychological or social.’
Moreover, the TCPS 2 states that researchers should develop a
plan outlining how they will disclose incidental findings.
Such a plan should, then, be provided to prospective partici-
pants.
In light of these regulatory documents, two conclusions can
be drawn. First, there is a clear lack of uniformity in the ter-
minology employed. Depending on the document, incidental
findings are referred to as ‘unexpected findings,’ ‘unantici-
pated results,’ and are sometimes qualified as ‘material’ in
nature. This diversity in terminology calls for standardization
or the development of a lexicon that will effectively impose
uniformity in the use of terms relating to incidental findings.
Indeed, standardization will allow for international norms to
be more easily compared and analyzed, and will aid re-
searchers as they draft research protocols and informed con-
sent forms.
The second conclusion relates to the lack of specificity with
regard to clinician–researchers’ duties. The norms reviewed
above do not adequately express the duties of the clinician–
researcher and fail to consider the intrinsic legal tensions
between these duties and the clinician’s professional respon-
sibilities. This is precisely what we will endeavor to accom-
plish in the following section (Part III) using Quebec’s legal
framework as a model.
Legal duties of the clinician–researcher:
Quebec’s civil law perspective
Pursuant to the Constitution Act of 1867, legislative powers
are divided in Canada between the provinces and the central
federal government. Medical liability legislation is considered
a provincial matter as the constitution grants provinces ju-
risdiction over civil rights. Accordingly, each Canadian
province has enacted legislation on civil rights and legal lia-
bility in general. Quebec is not an exception, and with its rich
case law on medical liability and on researchers’ duties, it
represents an interesting example for analysis.
The two most relevant pieces of legislation of general ap-
plication that bind physicians, as any other professionals, in
Quebec are the Civil Code of Quebec and the Professional Code.
Physicians are also bound by the Medical Act and the Physician’s
Code of Ethics, both specific to the medical field. Most profes-
sionals in Quebec are bound by similar field-specific legislation
(e.g., Code of Ethics of Nurses, Code of Ethics of Dentists).
Case law in Quebec has identified four major duties ap-
plicable to physicians in the context of their profession: the
duty to inform, the duty to care, the duty to follow-up, and the
duty to uphold secrecy (Philips-Nootens et al., 2007). Al-
4 ZAWATI ET AL.
though not wanting to address the issues of contractual
(consensual agreement to provide care) versus extra-
contractual (where consensual agreement is not possible,
e.g., the unconscious patient) professional relationships be-
tween the physician and the patient, it is important to mention
that the legal literature has highlighted the prominence of
the above-mentioned duties in both relationships (Philips-
Nootens et al., 2007).
The intensity of these duties is modified for physicians
engaging in research. In the research setting—where the
exercise is not necessarily therapeutic or diagnostic–the
duty to care, for example, is limited in its scope. Indeed,
when conducting research without diagnostic ambitions,
the physician cannot follow standard clinical guidelines
because these typically govern the diagnostic process
(Philips-Nootens et al., 2007). Moreover, the duty to follow-
up reinforces the physician’s role in continuously evaluat-
ing the treatment provided to the patient (Philips-Nootens
et al., 2007; Legault v. Parentau, 1988) and is therefore ir-
relevant in the research setting.
The following sections will address two duties that also
apply to the research setting: the duty to inform (1), and the
duty to uphold secrecy (2), both from the perspective of in-
cidental findings in vaccinomics research.
Duty to Inform. Wolf et al. (2008b) propose five core re-
sponsibilities for researchers when managing incidental
findings. Indeed, they posit that researchers have a duty to: (1)
plan for incidental findings in the research protocol; (2) dis-
cuss the possibility of discovering incidental findings with the
participants; (3) address incidental findings in a responsible
way; (4) to effectively evaluate incidental findings when dis-
covered; and finally (5) to offer to disclose, in certain cases,
incidental findings to research participants. The same authors
consider these duties as emanating from the general ethical
and legal principle of minimizing risk to the participant. Al-
though justifiable, this approach—intended for researchers at
large—presumes that the incidental findings are problematic
(hence, the need to address them, evaluate them and offer to
disclose some of them to research participants).
When it comes to addressing this issue from the perspective
of the clinician–researcher in Quebec, it is the duty to inform,
and not the duty to minimize risk, that is the primary trigger
for the need to discuss the possibility of discovering incidental
findings. Indeed, this is all the more true given that clinicians
are best placed to communicate any medical results to par-
ticipants.
There is abundant literature and case law in Quebec ad-
dressing the physician’s duty to inform in the clinical setting
(Letendre and Lancto
ˆ
t, 2007; Hopp v. Lepp , 1980; Reibl v.
Hughes, 1980). Indeed, physicians are required to inform their
patients of the diagnosis, the nature and scope of the medical
intervention, as well as the therapeutic choices available
(Fournier v. Caron; 1995; Labrie v. Gagnon, 2003; Philips-Noo-
tens et al., 2007) so that patients may provide free and in-
formed consent. As for the risks, physicians are required to
inform patients of risks that are, among other criteria:
1. ‘Probable and predictable;
2. Rare, if serious and particular to the patient;
3. Known to all, if particular to the patient’ (Philips-
Nootens et al., 2007).
Importantly, as will be discussed below, the intensity of this
duty is heightened in the research setting. It is first necessary
to review the pertinent laws on the physician’s duty to inform
in the research setting before exploring this issue, however.
The Physician’s Code of Ethics is the only Quebec statute that
includes sections explicitly written for clinician–researchers.
On their duty to inform, it states:
28. A physician must, except in an emergency, obtain
voluntary and informed consent from the patient or his
legal representative before undertaking an examina-
tion, investigation, treatment or research.
[. . .]
29. A physician must ensure that the patient or his
legal representative receives explanations pertinent to
his understanding of the nature, purpose and possible
consequences of the examination, investigation, treat-
ment or research which he plans to carry out. He must
facilitate the patient’s decision-making and respect it.
30. A physician must, with respect to research subjects
or their legal representative, ensure:
(1) that each subject is informed of the research pro-
ject’s objectives, its advantages, risks or disadvantages
for the subject [ . . . ]
Although it is clear that both sections 28 and 29 are appli-
cable to both the clinical and research settings, case law pro-
vides more precision as to the nature of the clinician–
researcher’s duty. For instance, in Weiss v. Solomon (1989), the
Quebec Superior Court cites a judgement dating back to 1965
which asserted that:
[ . . . ] the duty imposed upon those engaged in med-
ical research [ . . . ] to those who offer themselves as
subject for experimentation [ . . . ] is at least as great as,
if not greater than the duty owed by the ordinary
physician or surgeon to his patient. There can be no
exceptions to the ordinary requirements of disclosure
in the case of research as there may well be in ordinary
medical practice [ . . . ] The subject of medical experi-
mentation is entitled to a full and frank disclosure of
all the facts, probabilities and opinions which a rea-
sonable man might be expected to consider before
giving his consent.
Because incidental findings are more likely to arise in ge-
netics research (Van Ness, 2008)—such as misattributed pa-
ternity and pleiotropy (Wolf et al., 2008a)—it seems clear,
based on the above-mentioned legislation and case law, that
clinician–researchers have a duty to inform their participants
of the possibility of discovering incidental findings in the
course of research. Although such findings cannot be pre-
dicted, they are nonetheless expected, and full and frank
disclosure of all reasonable probabilities is required in re-
search.
For example, in the course of vaccinomics research, a ge-
netic variant that goes beyond the genotype: phenotype as-
sociations studied more specifically can be discovered.
Although it is not possible to predict the exact type of variant,
such a discovery can nevertheless be reasonably expected,
especially when using high-throughput technology. Even
more specific to vaccinomics research is the possibility of
INCIDENTAL FINDINGS IN DATA-INTENSIVE POSTGENOMICS SCIENCE . . . 5
coming across a genetic immune response profile that signals
vulnerability to a disease not amenable to vaccination. The
primary focus of vaccinomics research involves scanning
through immune response genes to uncover genetic suscep-
tibility to diseases that may be prevented through immuni-
zation. However, immune response genes determine
susceptibility to all forms of disease, not only those prevent-
able through immunization. What if a vaccinomics researcher,
in scanning through immune response genes, comes across
genetic susceptibility to a disease or condition that cannot be
vaccinated against (e.g., susceptibility to certain pathogenic
bacteria)? Such information would be considered ‘incidental’
to the research aim of tailoring vaccination based on genetic
heterogeneity, but could nonetheless be of great medical im-
portance to the participant.
This duty to inform about the likelihood of discovering
incidental findings cannot, as some regulatory documents
studied earlier have pointed out, be limited to findings that
have significant implications for the participant’s health. This
is mainly because neither their nature nor their repercussions
can be predicted at the onset of research. Clinician–research-
ers in vaccinomics research therefore have a duty to inform
participants of the probability of discovering such findings in
a general sense. As to whether they have a duty to allow
participants to decide whether they would like to receive in-
cidental findings or not, there are no legal requirements to that
effect, although it is encouraged by different non-binding
documents, namely the 2008 Joint Statement on the Process of
Informed Consent for Genetic Research, which states that ‘prior
consent should be obtained with regard to the research par-
ticipant’s wish to be informed of [ . . . ] unanticipated results.’
Not having a legal duty to allow participants to decide
whether or not they would like to receive incidental findings
does not mean that researchers do not have a duty to return
some types of incidental findings to research participants
(discussed below). Moreover, if the consent form states that
incidental findings will be returned to participants, the clini-
cian-researcher has to abide by it, since it is the crystallization
of his duty to inform (Philips-Nootens et al., 2007).
Do clinician–researchers in Quebec have a duty to plan for
all incidental findings in the research protocol as re-
commended by some authors (Wolf et al., 2008b)? Not quite.
The 2nd edition of the Tri-Council Policy Statement (a docu-
ment that binds a large number of research institutions in
Canada) posits that researchers (including clinicians) should
‘develop a plan indicating how they will disclose such find-
ings [incidental findings that have significant welfare impli-
cations] to participants and submit this plan to the REB’
(TCPS 2, 2010). Therefore, the plan will only focus on how to
disclose significant incidental findings and not on how they
will manage all types of incidental findings. This is because
clinician–researchers will not be obliged to return all inci-
dental findings to the research participants (discussed below).
Indeed, the duty to inform of the likelihood of incidental
findings is general in scope, but can the scope of the re-
searcher’s duty to return incidental findings be similarly
general? Wolf et al. 2008b recommend that the consent form
should mention only categories of incidental findings with a
strong net benefit and findings with a possible net benefit. The
first category, which the authors believe should be offered to
participants, includes information about conditions that can
likely be life-threatening. The second category, which the
authors believe may be offered to participants, includes in-
formation about nonlife-threatening conditions that can likely
be grave or serious or can be helpful for reproductive decision
making (could be offered) (Wolf et al., 2008b).
For clinician–researchers in Quebec, the issue will be lim-
ited to knowing how critical this information might be.
Quebec’s Charter of Human Rights and Freedom states that:
Every human being whose life is in peril has a right to
assistance.
Every person must come to the aid of anyone whose
life is in peril, either personally or calling for aid, by
giving him the necessary and immediate physical as-
sistance, unless it involves danger to himself or a third
person, or he has another valid reason.
This duty for assistance requires that the person’s life be in
peril and that the danger be imminent, thus requiring im-
mediate assistance. Some liability authors in Quebec have
been doubtful on the use of this duty in the genetics domain
(Philips-Nootens et al., 2007). Stating that genetic disease
cannot be transmitted between living individuals (in an
analogy to HIV), they conclude that there exists no immediate
threat to anyone’s life, unless the information would be per-
tinent to reproductive decisions. In the same vein, if clinician–
researchers conducting vaccinomics researches find mis-
attributed paternity or other misattributed lineage (e.g., un-
revealed adoption), providing such information to the
participant would not satisfy the above-mentioned criteria.
For more guidance on the issue, a recent court decision
where a physician and a clinician–researcher were sued for
not informing a patient and her relatives of critical genetic
information (Liss v. Watters, 2010) has set a precedent on the
matter by determining that clinician–researchers have a duty
to disclose critical genetic findings. The Court states:
Dr. Watters had specific, important, conclusive
knowledge of a grave danger looming over that fam-
ily. Moreover, an important part of this knowledge
was based on research made possible thanks to
Edythe’s written permission. Having consented to the
research, Edythe was, in a very real sense, already in
the loop.
It also states:
The Court understands that not just any facts would
create such a duty. They must be sufficiently impor-
tant, meaning that they are of serious enough conse-
quence, that a reasonable person would deem that they
ought to be communicated to appropriate persons.
Where facts of that nature are to a physician’s
knowledge, then an obligation to inform exists.
The court’s rationale is that there is nothing in the law that
impedes the clinician–researcher from disclosing critical in-
formation to the research participants. Although this case is
presently being appealed by both parties, it remains reflective
of the current trend of the courts with regard to the issue of
returning critical genetic information. According to the court,
the obligation to inform is triggered only if the information is
specific, important, and conclusive so as to allow for the
prevention of a grave danger. Applying this reasoning to
vaccinomics research, information extracted from unantici-
pated genetic variants that are discovered must be specific as
6 ZAWATI ET AL.
to their nature, important as to their effect (i.e., risk out-
weighed by benefits) and conclusive as to their accuracy.
Moreover, this type of information must lead to the preven-
tion of an identifiable grave danger. If these elements are not
satisfied, the clinician–researcher will not have a duty to
inform.
The remaining question relates to the participants’ rela-
tives. What if the genetic variant discovered incidentally could
have implications for biological relatives? Can clinician–
researchers disclose such information without breaching
their duty to uphold secrecy? The following section will
attempt to provide some guidance on this issue.
Duty to uphold secrecy. The clinician’s duty to uphold
secrecy derives from three pieces of legislation: the Physi-
cian’s Code of Ethics, the Quebec Charter of Human Rights
and Freedoms and the Professional Code.
More importantly, the Quebec Charter of Human Rights and
Freedoms states:
Every person has a right to non-disclosure of confi-
dential information.
No person bound to professional secrecy by law [ . . . ]
may, even in judicial proceedings, disclose confidential
information revealed to him by reason of his position
or profession, unless he is authorized to do so by the
person who confided such information to him or by an
express provision of law.
[. . .]
Both the Physician’s Code of Ethics as well as the Professional
Code provide that clinicians have a duty to uphold profes-
sional secrecy. The Professional Code offers an exception to this
general duty when preventing ‘an act of violence, including a
suicide, where he has reasonable cause to believe that there is
an imminent danger of death or serious bodily injury to a
person or an identifiable group of persons.’ As for the Phy-
sician’s Code of Ethics, it states that the general duty to uphold
secrecy can be set aside if ‘compelling and just grounds re-
lated to the health or safety of the patient or of others’ exist.
However, when communicating such information, the same
Code of Ethics requires that the physician takes several factors
into account, one of them being the imminence of the violent
act he aimed to prevent. This puts into question the scope of
such a breach and whether disclosing critical genetic infor-
mation to relatives is legal.
Here again, Liss v. Watters provides some guidance by
stating that two criteria must be satisfied in order to disclose
such information to relatives: (1) the information in question
must be critical and (2) the clinician–researcher must be
within a ‘radius of contact.’ As for the first criterion, it refers
to the gravity of the condition reflected in the information—
clinician–researchers owe a duty to inform to the extent that
the findings reflect serious health risks. As mentioned above,
the findings must be specific, important, and conclusive al-
lowing for the prevention of grave danger. It goes without
saying that the relatives must also be at risk. As for the ‘radius
of contact’ criterion, this refers to the intensity of the rela-
tionship, either existing or possible, between the clinician–
researcher and the relative in question. If both criteria are met,
disclosure is the norm and it should be done by the clinician–
researcher since he/she is best fit to ‘understand the conse-
quences of the case’ (Liss v. Watters, 2010).
However, if clinician–researchers decide to inform relatives
of findings that are not considered critical, they could be sued
for breach of professional secrecy. More concretely, clinician–
researchers in vaccinomics research cannot, for example,
discuss misattributed paternity with the spouse of the par-
ticipant, as it may have ‘health, legal and financial implica-
tions’ (Van Ness, 2008) and it might do more harm than good.
After having discussed these two duties and their scope, it
is pertinent to concretize their use or misuse as a basis for any
potential legal liability. In order to do that, a brief look at the
elements of liability and how they pertain to such duties in the
context of incidental findings in vaccinomics will be under-
taken.
Potential legal liability: what are the elements?
In Quebec, there are three elements necessary to prove civil
liability of an individual: (1) a fault, (2) an injury, and (3) a
causal link between the two.
In the case of a clinician–researcher, the notion of fault re-
fers to the breach of one of the duties owed to his participant.
Such a breach must be proven objectively by seeking the ex-
pertise of a similarly-situated clinician–researcher (Philips-
Nootens et al., 2007), who will testify that such behavior is not
in keeping with the norms of the practice. In the case of inci-
dental findings in vaccinomics, failing to inform the partici-
pant of the possibility of discovering incidental findings—if
reasonably expected—can be considered as a breach of their
duty to inform. Likewise, failing to warn participants of
critical genetic information can also be considered as a
breach of the same duty.
If clinician–researchers decide to refrain from disclosing
critical genetic information to at-risk relatives, it might be
considered a civil fault. In fact, satisfying their duty to uphold
professional secrecy in such circumstances could be consid-
ered as violating the norms established in the case law.
However, if clinician–researchers disclose genetic information
that is not specific, important, and conclusive to the relatives
of a participant, this could be considered as a breach of their
duty to uphold professional secrecy.
However, such wrongful behaviour alone is not enough to
establish liability—there must also be an injury. Quebec’s civil
law recognizes three types of injury: moral, material, and
bodily. What is meant by bodily injury needs no explanation.
Material injury refers to expenses incurred and loss of reve-
nue. As for moral injuries, they refer to psychological suffer-
ing such as emotional stress and loss of joy (Liss v. Watters,
2010).
The research participant might be injured in each of these
three ways should a physician–researcher breach his duty to
inform. The same could be said of at-risk relatives who have
not benefited from critical genetic information that could
have been considered in reproductive decisions. The par-
ticipant or the at-risk relative might suffer from moral and
bodily injuries if it is proven that clinician–researchers failed
to return critical incidental findings that contain information
on life-threatening conditions, such as accurate information
on predisposition to a chronic disease. Any monetary loss
associated with this failure would be considered material
injury.
A breach of professional secrecy would likely bring about
moral injury, where the individual in question resents the lack
INCIDENTAL FINDINGS IN DATA-INTENSIVE POSTGENOMICS SCIENCE . . . 7
of professionalism from the researcher’s part and becomes
emotionally burdened. Moreover, this will also have the
negative effect of undermining the individual’s trust in the
research endeavour and in the researchers undertaking it.
Finally, it is important to prove a causal link between the
breach of the duty/norms of practice on one hand and the
injury on the other. Otherwise, liability cannot be established.
Indeed, if a clinician–researcher does not inform a participant
of the possibility of discovering incidental findings, he cannot
be considered liable if no linkable injury exists and if no in-
cidental findings are discovered. The same can be said if the
clinician–researcher refrains from disclosing incidental find-
ings of a critical nature and where it is later proved that the
participant already knew of the content of such information
from an earlier diagnosis.
Conclusions and Outlook
Vaccines are one of the most significant realizations of
modern medicine and are among the most cost-effective in-
struments in public health ( Jagannath et al., 2009). Indeed, as
a result of their widespread use, vaccine-preventable diseases
in many developing and developed countries have been re-
duced by 98–99% (Salmon et al., 2006). Compulsory vacci-
nation programs have contributed to the achievement of high
rates of immunization. Compared with pharmaceutical
products, the number of lives saved per dollar invested in
vaccines is substantial.
Genomics could have a major impact on disease prevention
through its application to the design and development of
novel vaccine strategies. In fact, genome sequencing projects
of both common and emerging pathogens have provided
scientists with the tools to rapidly screen and identify prom-
ising molecular targets for vaccine development against a
background of human and pathogen genomic variation. Our
improved understanding of genomic differences underlying
individual immune responses and toxicity will lead to the
development of more effective and safer vaccine (Thomas and
Moridani, 2010). On a more translational level, physicians will
also be able to adjust the inoculation dosage of both old and
new vaccines according to individual (or more likely group)
genotypes to achieve optimal results while minimizing the
risk of reactogenicity and vaccine failure ( Joly et al., 2010). As
some authors proclaim, we are on the cusp of the second
golden age of vaccinology (Poland et al., 2008).
However, the use of high-throughput sequencing technol-
ogies in these research initiatives may lead to unanticipated
discoveries that go beyond the initial aims of the study. Such
discoveries, or incidental findings, can be highly significant to
the health of the research participant. Indeed, because they
can be so significant, incidental findings create an important
legal dilemma for researchers in general and clinician–
researchers in particular.
The available international regulatory guidance on the
issue is limited in scope and only poorly addresses the major
tensions inherent to the decision on whether or not to disclose
incidental findings when it comes to clinician–researchers.
This is why the study of clinician–researchers’ duties from the
Quebec civil law perspective was deemed beneficial, because
clinicians in Quebec are bound by well-established norms.
Indeed, Quebec’s legislation and case law can serve to com-
plement the international norms on the issue and has allowed
for a better understanding of the recurring tensions and how
they might be attenuated.
Actually, international regulatory documents differ on
whether the decision to disclose incidental findings should be
left to the research participants themselves or to researchers.
First, when it comes to research participants, the norms are
vague and general in scope, allowing the participants to
choose whether or not to receive incidental findings at large
(Bioethics Committee of Singapore; Rare Disease Research
Institute of Spain). This is particularly problematic in vacci-
nomics research, where not all findings can be interpreted and
their utility proven even by clinicians. Therefore, leaving the
decision whether or not to receive incidental findings to par-
ticipants will be too much of a burden on them. It will also be a
burden on researchers if they have to return any incidental
finding discovered during research. Second, as to documents
that posit that the decision to disclose incidental findings
should be left to researchers, they do not all reflect the intrinsic
tensions facing clinician–researchers who are generally bound
by professional secrecy as well as the limitations on their duty
to inform in research. In order to clarify the elements of such
duties and to understand their limitations, they were both
analyzed from Quebec’s civil law perspective (see Table 1).
In Quebec, clinician–researchers have a general duty to
inform participants of the likelihood of discovering incidental
findings in vaccinomics research. They are not obliged to
provide all existing incidental findings; however, only those
that are specific, important, and conclusive allowing for the
prevention of a grave danger. This also differs with previous
recommendations by authors positing that researchers should
offer to disclose incidental findings to participants when they
are likely to contain life-threatening information. For clinician–
researchers, such a recommendation might be too broad.
Having clinician–researchers only return specific, important,
and conclusive incidental findings reflects the exceptional
nature of such an approach, delimits its scope and helps dis-
sipate any therapeutic misconception (where the research par-
ticipant mistakenly believes that he will benefit from research).
Moreover, clinician–researchers will also be bound by their
duty to uphold professional secrecy unless they have critical
information that could benefit at-risk relatives that are in the
researcher’s radius of contact. The issue of relatives was sel-
dom mentioned in the regulatory documents discussing in-
cidental findings, although it plays an important role in
genetics research.
The Quebec case model has also shown that a breach of the
norms of practice alone is not enough to establish liability—
injury and causation must also exist. As for clinician–
researchers, the intensity of their legal duties or potential legal
liability will not increase just because they are performing
vaccinomics research. As a matter of fact, their liability could
be challenging to prove for one reason: the limitation existing
on their duty to inform. Indeed, as this article has shown,
three major conditions dictate whether clinician–researchers
should return incidental findings: they have to be specific,
important and conclusive. This is not always the case in
vaccinomics research, where the clinical significance of the
results that are powered by high-throughput sequencing
technologies are largely unknown (Cho, 2008) and where
other types of information (misattributed paternity for ex-
ample) do not satisfy the above-mentioned criteria. Generally,
in research using high-throughput sequencing technology,
8 ZAWATI ET AL.
probability is the norm rather than the exception, whereas
conclusiveness is the keyword with respect to incidental
findings.
In brief, as Liss v. Watters has shown, not just any facts
would create a duty to inform. They must be sufficiently im-
portant (serious enough in consequences) that a reasonable
person (expert) would deem that they should be communi-
cated to appropriate persons. Because much of the discovered
information during genomics research does not appear in the
day-to-day standard of care procedures, it will be more dif-
ficult to demonstrate the clinical utility of this information
(Cho, 2008). In sum, there could be an injury, but the fault
(breach of a duty) will be hard to prove, bearing in mind that
vaccinomics research requires high levels of expertise. Thus,
an important condition needed to demonstrate general civil
liability is more likely to be missing.
Finally, the education of clinician–researchers involved in
the use of vaccinomics (Collins, 2010) with regard to their
roles, limitations and legal obligations will remain the best
avenue to prevent any undesirable legal complications and
to prevent potential civil liability. This avenue will prove
safer and more beneficial in the long term. To succeed, local
physician associations around the world should take a leaf
out of the World Medical Association’s Medical Ethics
Manual (WMA, 2005) and initiate information workshops
and publish clear, jurisdictionally specific guidelines for their
members to help guide them to adapt and cope with what is
now recognized as the future of their practice: personalized
medicine.
Acknowledgments
The authors acknowledge the financial contribution of
Ge
´
nome Que
´
bec through its Genomics and Proteomics platforms
for vaccines and immune therapeutics discovery and development
project. The authors also thank Michael Le Huynh and Ame
´
lie
Rioux for their assistance in the editing of this article.
Author Disclosure Statement
The authors declare that no conflicting financial interests
exist.
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!
The use of high-throughput sequencing technologies in vaccinomics research may lead to unanticipated discoveries that go
beyond the initial aims of the study.
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Because they can be significant to the health of the participant, incidental findings create an important legal dilemma for
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the study.
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An analysis of Quebec’s civil law reveals two important duties relevant to the issue of incidental findings: (1) the duty to
inform and, (2) the duty to uphold professional secrecy.
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relatives who are in the researcher’s radius of contact.
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causation must also exist.
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and legal obligations remains a viable strategy to prevent legal complications and to prevent potential civil liability.
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Address correspondence to:
Ma’n H. Zawati
Centre of Genomics and Policy
McGill University
740, Dr Penfield Avenue, Suite 5200
Montre
´
al (Que
´
bec), Canada H3A 1A4
E-mail: man.zawati@mcgill.ca
10 ZAWATI ET AL.
... Given the recent proliferation of genetic testing, research and personalized medicine, local physician associations should abide by the World Medical Association"s Ethics Manual (2009) and initiate "workshops […] for their members to help guide them to adapt and cope with what is now recognized as the future of their practice: personalized medicine" (Zawati et al., 2011). Such policy initiatives will ensure that human genetics is not only at the forefront of medical science, but is also ethically and morally just. ...
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Advancements in genomic technology and genetic research have uncovered new and unforeseen ethical and legal issues that must now be faced by clinician-researchers. However, lack of adequate ethical training places clinician-researchers in a position where they might be unable to effectively assess and resolve the issues presented to them. The literature demonstrates that ethics education is relevant and engaging where it is targeted to the level and context of the learners, and it includes real-world based cases approached in innovative ways. In order to test the feasibility of a combined approach to ethics education, a conference was held in 2012 to raise awareness and familiarize participants with the ethical and legal issues surrounding medical technology in genetics and then to have them apply this to reality-based case studies. The conference included participants from a variety of backgrounds and was divided into three sections: (i) informative presentations by experts in the field; (ii) mock REB deliberations; and (iii) a second mock-REB, conducted by a panel of experts. Feedback from participants was positive and indicated that they felt the learning objectives had been met and that the material was presented in a clear and organized fashion. Although only an example of the combined approach in a particular setting, the success of this conference suggests that combining small group learning, practical cases, role-play and interdisciplinary learning provides a positive experience and is an effective approach to ethics education.
... 8 With next-generation sequencing technology producing vast amounts of data, the debate has become more complex due to the ensuing increase in incidental findings (IFs) in research. 9 IFs are defined as findings concerning a research participant that have potential health or reproductive importance and are discovered during the course of research but are outside the objectives of the project. 10 The rise of data-intensive science stemming from the use of high-throughput technology has led to a debate on the pertinence of returning IRRs and IFs in genomic biobanks. ...
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Managers of genomic biobanks constantly face ethical and legal challenges ranging from issues associated with the informed consent process to procedural concerns related to access by researchers. Yet, with the availability of next-generation sequencing technologies, one topic is emerging as the focus of ongoing debate: the return of individual research results and incidental findings to participants. This article examines this topic from an international perspective, where policies and guidelines discussing the matter in the context of genomic biobanks and genomic research are analyzed and commented. This approach aims to highlight the shortcomings of these international norms, mainly the danger arising from both the therapeutic misconception and the conflation of research results with incidental findings. This article suggests some elements to consider in order to complement available guidance at the international level. Genet Med 2012:14(4):484–489
... Indeed, although communicating generalizable knowledge to the public is essential, there are limits to what can be returned on the individual level. First, with data-enabled sciences producing vast amounts of incidental and—in most cases— nonvalidated information (Zawati et al., 2011 ), it is consequently crucial to emphasize that ''data'' do not necessarily amount to ''knowledge,'' and that there are limits to what can be returned to participants (Hayeems et al., 2011). Second, it is important to recognize the difficulty of adjudicating results at the scientific level, where ''distinctive cultures with respect to interpreting and reporting results'' exist, thus making it more difficult to provide homogeneous ethical guidance to scientists in a field of scientific uncertainty (Hayeems et al., 2011). ...
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