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Returning genetic
research results in
neurodevelopmental
disorders:
Report and review
Working Group, ASD and return of results
Funded by Kids Brain Health Network (formerly NeuroDevNet)
Montreal, QC
September, 2015
2
Working Group
Emily Bell, PhD, Chair
Researcher, Neuroethics Research Unit
Institut de recherches cliniques de Montréal
Montreal, QC
Éric Racine, PhD, Co-chair
Director, Neuroethics Research Unit
Institut de recherches cliniques de Montréal
Montreal, QC
Co-PI, Neuroethics Core, NeuroDevNet
Melissa Carter, MSc, MD
Clinical Geneticist, The Hospital for Sick Children
Assistant Professor, Pediatrics, University of Toronto
Toronto, ON
Nina Di Pietro, PhD
Senior Research Fellow, National Core for Neuroethics
University of British Columbia
Vancouver, BC
Judy Illes, PhD
Director, National Core for Neuroethics
Canada Research Chair in Neuroethics
University of British Columbia
PI, Neuroethics Core, NeuroDevNet
Vancouver, BC
Lonnie Zwaigenbaum, MD, PhD
Developmental pediatrician, Stollery
Associate Professor, Pediatrics, University of Alberta
Project Team Lead, Autism Spectrum Disorder Project, NeuroDevNet
Edmonton, AB
3
About this report 5
Glossary 6
The complex etiologies of neurodevelopmental disorders as evidenced
by the genetics of ASD 7
Genetic research and the return of research results in children 11
Ethical guidance regarding the return of research results in
genetic studies and in pediatrics
Research ethics policies and guidelines for disclosure of genetic ndings 13
Perspectives from the academic normative literature on the ethics
of the return of research results
a) Underlying ethical considerations 18
b) Recommended approaches for adults 20
c) Recommended approaches for children 22
Researcher and parental perspectives regarding the return of
individual research results in genetic studies
a) Researcher perspectives 24
b) Research ethics board perspectives 26
c) Parent perspectives 27
The return of individual research results in genetic studies of autism
a) Researcher perspectives 28
b) Parent perspectives 29
Summary of ndings and issues for future study 32
1. Convergences and divergences between ethics policies, scholarly
perspectives and empirical data on the return of genetic results 33
2. Issues requiring consideration and or evidence to inform best practices
for return of genetic research ndings in neurodevelopmental disorders
The potential for researcher orientations towards genetics to impact
perspectives or practices in the return of genetic ndings of ASD 36
The potential for personal utility to meet the best interests standard
for disclosure of ASD-related ndings 36
The importance of risk communication in genetic studies of ASD 37
The role of the child or adolescent with developmental disability
in decision making 38
Conclusions 39
References 40
Table of Contents
Report and Review
4Returning Genetic Research Results in Neurodevelopmental Disorders: Report and Review
Box 1: Examples of genetic ndings related to ASD 7
Box 2: Three main issues complicate the interpretation of
genetics ndings in ASD 8
Box 3: Barriers to the return of individual research results 19
Box 4: Recommended approach for managing return of
individual research results 21
Box 5: Recommendations: Disclosure of incidental genetic ndings 33
Box 6: Recommendations: Disclosure of ASD-related genetic ndings 35
Table 1: Best practices for the disclosure of research results
in children and adolescents 16
Table 2: Parental perspectives on the return of research results
in genetic studies of ASD 30
Figure 1: Genetic research results relevant to the discussion of
return of individual ndings 10
Tables and Figures
5
Returning Genetic Research Results in Neurodevelopmental Disorders: Report and Review
This report originated from discussions at the Annual Brain Development Conference in
late 2013 between researchers in the Neuroethics Core and Autism Spectrum Disorders
Project of NeuroDevNet. Discussants felt that return of research results is a pertinent
issue but that researchers are missing a comprehensive picture of the recommendations,
approaches and empirical data related to the return of research results in genetics studies
in children, in neurodevelopmental disorders, and specically in autism.
This report provides an overview of recent genetic studies of autism spectrum disorder
(ASD), and reviews the ethical guidance (policies and peer-reviewed literature) and
best practices on the return of individual research results in adult and pediatric genetic
research. We focus on this case because of the wealth of genetic research being
carried out in families and cohorts to explain the etiology of ASD and because there is a
burgeoning literature on parental perspectives on the return of results in this case. The
empirical perspectives are collected and summarized and provide context with regard to
researcher and parent perspectives on the return of genetic results in ASD studies.
We conclude by making recommendations about the return of both incidental and
ASD-related ndings and highlight issues that merit further discussion, including the
role of the child or adolescent with developmental disability in decision-making, and
the importance of risk communication. We believe that the report will be of use not only
for those working in the area of ASD but more broadly in the eld of pediatric genetic
research and neurodevelopmental disorder research. For example, the publication of new
evidence showing that genetic alterations play an important role in the etiology of cerebral
palsy in some children means that genetic research may becoming increasingly common
in other areas of the study of neurodevelopmental disorders.
About this report
6Returning Genetic Research Results in Neurodevelopmental Disorders: Report and Review
General results: Aggregated ndings concerning a group or a cohort of persons, a
summary of the research.
Individual research results: Results directly concerning an individual participant that
are discovered during the course of research. Individual results can either be related to
the condition studied (i.e. Autism Spectrum Disorder) or be an incidental nding. It does
not include pre-existing personal information used during research, such as the medical
record of the individual.
Incidental ndings: Unanticipated discoveries that are outside of the research objectives
(i.e. that do not touch upon Autism Spectrum Disorder) but that may be relevant to the
individual participant. 1
ASD-related research ndings (or potentially relevant ndings): Results directly
concerning an individual participant discovered during the course of research, regarding
the presence of a variant implicated in Autism Spectrum Disorder.
Personal utility: Quality of the information that can be used on a personal level, namely
to understand better the origins of a condition (the why) and the reproductive implications
associated to the nding.
Clinical utility: Quality of results that provide meaning about the etiology of a child’s
condition and that are of use for clinicians and families. These results can be used on
a clinical level, towards better orienting prevention and therapeutic decisions for an
individual.
Clinical validity: Corresponds to the measurement of the accuracy with which a test
identies or predicts a clinical condition. It is dened in terms of clinical specicity,
sensitivity and predictive value. 2
Scientic validity (also called analytical validity): Represents the capacity of a test to
measure the characteristic it is designed to identify. In particular, this concept includes
the capacity that the test will be positive if the genetic characteristic is present (analytical
sensitivity), and negative if it is absent (analytical specicity). 3
Glossary:
1 Inspired by TCPS2, supra note 1 (glossary)
2 Inspired by Explanatory Report – Additional Protocol to the Convention on Human Rights and Biomedicine, concerning
Genetic Testing for Health Purposes, 27 November 2008, CETS 203, at art 5, s 49.
3 Inspired by Explanatory Report – Additional Protocol to the Convention on Human Rights and Biomedicine, concerning
Genetic Testing for Health Purposes, 27 November 2008, CETS 203, at art 5, s 48.
7
Returning Genetic Research Results in Neurodevelopmental Disorders: Report and Review
The involvement of genetic factors in the etiology of autism spectrum disorder (ASD) has
long been presupposed based on the increased concordance of autism among twins
and increased incidence in siblings.[1, 2] The chances of having a second child with ASD
may be as high as 18%.[3-6] However, the role of specic genetic factors in ASD is still
under investigation. In only about 25% of individual cases is a genetic factor present that
may explain the presence of ASD (See Box 1). This means that identiable genetic factors
alone are currently unable to account for approximately 75% of cases of ASD. In addition,
gene-environment interactions are increasingly recognized as playing a role in ASD.[7, 8]
Hence, the justication for advanced genetic research studies to identify the complex
relationships between risk, heritability, gene-environment interactions and ASD.
BOX 1: Examples of genetic ndings related to ASD
Rare and de novo copy number variants
Features: incomplete penetrance, variation in the phenotype (overlap with disorders
such as schizophrenia, Bipolar Disorder), may be inherited but not necessarily inherited
in the case of de novo variants, and rare in the general and ASD population (any single
variant is only found in 1% of cases of ASD). Found in approximately 10-20% of
individuals with ASD
Coding sequence variations in neuronal synaptic genes
Features: mutations of candidate genes found in areas of the genome responsible for
specic functions thought to be dysregulated in ASD, such as synapse function. Found
in 5-10% of individuals with ASD
Genetic disorders where ASD is secondary
Features: genetic disorders where ASD is secondary (i.e., Fragile X or Rett syndrome)
Informed by Heil and Scha (2013) [1] and Huguet et al. (2013) [2]
The complex etiologies of neurodevelopmental
disorders as evidenced by the genetics of ASD
8Returning Genetic Research Results in Neurodevelopmental Disorders: Report and Review
Results from a recent large multi-center study of families aected by ASD have conrmed
the increased likelihood of rare copy number variants in individuals with ASD compared to
controls.[9] The results implicate many candidate genes responsible for neuron signaling
and synapse function. These and other data suggest strong endorsement for clinical
genetic testing in autism[10, 11] because it may identify needed interventions or provide
early awareness of related medical issues where specic genetic factors are recognized.
In return, increased clinical genetic testing and the addition of more genetic data from
individuals with ASD into clinical genetics databases may also further elucidate genetic
components of the disorder. Three persisting issues complicate the interpretation of
genetic ndings in ASD (See Box 2).
Box 2: Three main issues complicate the interpretation of genetic ndings in ASD
Incomplete penetrance of currently identied genetic factors associated
with ASD
i.e., the presence of a genetic factor associated with ASD does not necessarily indicate
the etiology of ASD (a small set of the population will have the same genetic factor and
no ASD)
Variation in phenotype expressivity
i.e., the same genetic variants associated with ASD are associated with other psychiatric
disorders and individuals with the same variant may express dierent phenotypes, for
instance schizophrenia or bipolar disorder
Variation in inheritance with de novo variants
i.e., the inheritance of genetic variants may only be understood as a potential cause of
ASD in light of information about the role played by the gene in neurodevelopmental
processes or in light of the pedigree and phenotype expression of other members of
the family
Informed by Heil and Sha (2013) [1]
The complex etiologies of neurodevelopmental
disorders as evidenced by the genetics of ASD continued
9
Returning Genetic Research Results in Neurodevelopmental Disorders: Report and Review
Genetic research in the area of ASD seeks to gain broader knowledge about the etiology
of the spectrum of ASD and the discovery of genetic factors that predict earlier detection
of autism, or to identify those at high risk of developing ASD. Data are often gathered
from children with ASD and their families through large multi-national projects such as
the International Autism Genome Project. The fact that many genetic ndings are rare or
de novo justies the collection of large data sets and the study of various members of
the family.
Some of the important considerations emerging with the discovery of ASD-relevant
genetic research ndings are:
1. A new rare copy number variant is dicult to ascribe meaning to;
2. Detection of a copy number variant associated with ASD may be meaningful
beyond the research participant (either because of sibling risk, reproductive risk,
or under-diagnosed ASD or psychiatric disorders in family members);
3. Families or individuals involved in research may or may not have already received
clinical genetic testing.
These issues indicate the wide-ranging implications of participation in genetic research
for families and siblings and hint that the full scope of the meaning of genetic ndings in
the child may not be understood without context from the family’s genetic and phenotypic
pedigree (see Figure 1). Furthermore, any genetic research has the potential to generate
incidental ndings (IFs) that in pediatric participants could reveal genetic ndings that are
actionable in childhood or that indicate adult-onset disorders or carrier status (Figure 1).
The discovery of incidental ndings is common with the advent of exome and whole-
genome sequencing. There is always a possibility that some genetic variants may be
present but remain undetected by a research team.
The complex etiologies of neurodevelopmental
disorders as evidenced by the genetics of ASD continued
10 Returning Genetic Research Results in Neurodevelopmental Disorders: Report and Review
Figure 1: Genetic research results relevant to the discussion of return of individual ndings
Individual genetic
research results
ASD-relevant ndings
(or potentially relevant ndings) Incidental ndings
Variant is
signicant
Variant is of
uncertain
signicance
Clinically
meaningful
Not
signicant
Childhood
disorder
Adult-onset
disorder
Carrier
status
Implications for
individual:
� Finding denotes
health implications
and potential
therapeutic options
Implications for
parents and siblings:
� Could indicate
suspected
reproductive risks
for the child/
parents or siblings
� Could indicate
presence of a
related phenotype
in parents
Implications for
individual:
� Finding may
denote uncertain
or unclear health
implications or
therapeutic options
Implications for
parents and siblings:
� May necessitate
more study of
family to understand
meaning
� Could lead to
genotype-driven
research where
ndings encourage
study of family
and investigation of
phenotypes in family
members
The complex etiologies of neurodevelopmental
disorders as evidenced by the genetics of ASD continued
11
Returning Genetic Research Results in Neurodevelopmental Disorders: Report and Review
Generally, clinical genetic testing in children for adult-onset conditions has been
endorsed only when the results would lead to altered medical management in childhood,
emphasizing the importance placed on actionability and the fact that preferences of
the adolescent/child should guide decisions about testing once they reach adulthood.
[12] Even in the clinical context, recommendations surrounding the return of secondary
ndings have been followed by intense discussion and even some reversal of position.
In 2013, guidelines by the American College of Medical Genetics (ACMG)[13] for genome-
scale sequencing suggested that a requisite number of pathogenic genetic mutations had
to be tested for and disclosed in adults and in children. This approach brought forward
questions about the alignment of ACMG’s own policies for predictive testing in children
and allowing children to consent to testing at adulthood. General objections soon followed
along with criticism that the recommendations set aside patient autonomy.[14] The ACMG
has since updated the recommendation such that it is acknowledged that patients should
be given the option to opt out of the routine analysis of this predetermined set of genes at
the time of sending the sample.[15] With this update, parents also have the opportunity to
opt out of testing for their child during the consent process.
In the research setting, researcher obligations and the ethical rationale for returning
individual research results have been the focus of thorough discussion, especially in
light of the fact that there are important dierences between the clinical and research
environments (i.e., quality of genetic testing) and obligations towards individual
participants (and their families). Many open questions remain such as how are the
preferences of parents and children taken into account (at the time of consent and
afterwards); to whom should disclosure be made and when, and what are the obligations
of researchers to disclose. Challenges, which have been much debated in the eld of
genetic research, include how to balance researcher obligations for the disclosure of
individual research ndings with the need to protect participants and parents from undue
related harm (e.g., privacy, anxiety). These challenges become more complex in the
pediatric context where researchers must take into account the expectations of parents
and minors to know, or not know, about these ndings.
Genetic research and the return of research
results in children
12 Returning Genetic Research Results in Neurodevelopmental Disorders: Report and Review
In this report, we review the ethical foundations for and against the return of research
ndings and the positions put forward in international guidelines for best practices and
by other collaborative or interdisciplinary eorts. The perspectives of researchers and
parents, as well as empirical studies of researchers and parents regarding ASD studies
specically are reviewed in an eort to establish the degree of overlap or disagreement
with the normative literature about the return of research results. Our review is based
primarily o literature searches conducted in July 2013, was informed by ethics policy
documents that were already in our library, and was expanded when external peer
reviewers with an expertise in this area identied important reference documents.
We summarize the ndings including the convergences and divergences of these
perspectives and policies; and discuss four issues requiring consideration and or evidence
to inform best practices for return of genetic research ndings in neurodevelopmental
disorders:
1. How researcher orientations impact perspectives or practices in the return of
genetic ndings;
2. How personal utility might meet the needs of the best interest standard for
disclosure;
3. The importance of risk communication in neurodevelopmental disorders;
4. The role of the child or adolescent with developmental disability in decision
making.
When possible, we describe in detail the applicable Canadian policies and studies.
Genetic research and the return of research results in children continued
13
Returning Genetic Research Results in Neurodevelopmental Disorders: Report and Review
Research ethics policies and guidelines for disclosure of
genetic ndings
A review of international research ethics policies on the return of individual research results
demonstrates a wide variability of recommendations.[16] A common anchor of existing
policies is the potential health benets that may be accrued by the return of clinically
signicant research ndings. Several international policies, but not all, recommend that
individual results (or incidental ndings) be obligatorily disclosed when relevant to health or
quality of life. Guidance issued by the World Health organization on the specic disclosure
of individual genetic results further denes that disclosure should be made on the basis
of a clear demonstration of clinical benet and communicated in a way that averts or
minimizes harm so long as there is no evidence that the individual would prefer not to
know.[16] Levesque and colleagues’ (2011) describe how some international guidance
leaves room for return of results as an option rather than an obligation.
Canadian research ethics guidelines for human genetic research, as laid out in the
Tri-Council Policy Statement (2010), require that researchers plan for managing
information revealed through their research. This requirement includes a plan for sharing
individual ndings with participants.[17] When planning to share ndings, researchers are
compelled to oer participants the opportunity to indicate their preferences regarding the
receipt of such information, and the sharing of this information with family or others.[17]
The adult participant must be allowed an informed choice about disclosure, and current
guidance reects that preferences should be respected. The following guidance is oered
by the The Network of Applied Genetic Medicine’s “Statement of principles on the return
of research results and incidental ndings” (Quebec):
1. That material ndings should be oered to an adult participant when, additional
considerations and exceptions have been weighed (i.e., anonymization,
expectation of participants), REB approval has been obtained, the participant has
consented to the return, and the research result has been conrmed;
2. That non-material ndings may be oered to adult participants, so long as they
meet criteria for scientic and clinical validity, REB approval is obtained, the
benets of return surpasses the risks, the participant has consented to the return,
and the research result has been conrmed;
3. That results that do not meet generally accepted criteria of scientic and
clinical validity should not be returned to participants. [18]
Ethical guidance regarding the return
of research results in genetic studies
and in pediatrics
14 Returning Genetic Research Results in Neurodevelopmental Disorders: Report and Review
A review of TCPS guidelines can be found in Table 1, including those provisions laid out
in the newest edition of the TCPS (2014).[19, 20] The most signicant changes include
detailing of the unintended harms that may result from disclosing incidental ndings such
as needless concern, including anxiety, costs or burdens of follow up or aect insurability,
and the opportunity that some researchers may request an exemption from the obligation
to return material incidental ndings (See Table 1).
How the above guidance applies to children participating in research is important.
The Network of Applied Genetic Medicine oers the following recommendations when
returning results about minors:
1. That results should be returned (and parents should not be able to refuse return)
when they meet the generally accepted criteria of scientic and clinical validity,
and they have signicant implications for the health of the minor, including that
there are treatment or prevention strategies available that should be initiated
during childhood or adolescence, REB approval has been obtained and the
research result has been conrmed.
2. That results concerning the future adult health of a minor should not be oered
except in exceptional circumstances where the validated results are important for
the immediate health of a parent or adult-aged sibling. In these cases the assent
of the minor should be obtained, and parent consent must have been obtained.
[18]
Ethical guidance regarding the return of research results
in genetic studies and in pediatrics continued
15
Returning Genetic Research Results in Neurodevelopmental Disorders: Report and Review
In an eort to draw together best practices for pediatric research, Avard and colleagues
(2011) have reviewed international research ethics guidance for policies and practices
relevant to children, including the return of research results. The resulting Best Practices
for Health Research Involving Children and Adolescents provides a summary of suggested
best practices for the return of individual research results in pediatric studies.[21] These
best practices are positioned next to the current TCPS guidelines in Table 1. Best
practices also include the ways that researchers acknowledge or balance the rights of
parents and children not to know about genetic ndings. Avard and colleagues (2011)
suggest that these include:
(1) respecting parents and children when they indicate not wanting to know
about results;
(2) overriding preferences not to know when the results have signicant health
implications for the child;
(3) extending the right not to know to relatives.[21]
Ethical guidance regarding the return of research results
in genetic studies and in pediatrics continued
16 Returning Genetic Research Results in Neurodevelopmental Disorders: Report and Review
Table 1: Best practices for the disclosure of research results in children and adolescents
Research ethics guidance
(TCPS(2010) [17]; TCPS(2014) [19])
Genetic research:
� Researchers conducting genetic research shall: a) in their proposal, develop a plan for managing information that may be
revealed through their genetic research; b) submit their plan to the REB, and c)advise prospective participants of the plan
for managing information revealed through the research (Article 13.2, TCPS (2010) and TCPS (2014))
� When researchers plan to share ndings with individuals, researchers shall provide participants with an opportunity to:
a) make informed choices about whether they wish to receive information about themselves; and
b) express preferences about whether information will be shared with a biological relative, or others with whom the
participants have a family, community or group relationships (Article 13.3, TCPS (2010) and TCPS (2014))
� Where researchers plan to share results of genetic research with participants, the research proposal should make genetic
counselling available at that time, where appropriate (Article 13.4, TCPS (2010) and TCPS (2014))
TCPS (2010)
� Researchers have an obligation to disclose to the participant any material incidental ndings discovered in the course of
research (Article 3.4, TCPS (2010))
� Material incidental ndings include those ndings that have been interpreted as having signicant welfare implications for
welfare for the participant, whether health-related, psychological or social (Article 3.4, TCPS (2010))
� When material incidental ndings are likely, researchers should develop a plan indicating how they will disclose such
ndings to participants, and submit this plan to the REB (Article 3.4, TCPS (2010)
� If researchers are unsure of how to interpret ndings or uncertain whether ndings are material, they should consult
colleagues or refer to standards in the discipline. If researchers are unsure of the most appropriate method for disclosing
material incidental ndings to participants, they should consult with their REB or with colleagues (Article 3.4, TCPS(2010))
� Researchers should exercise caution in disclosing incidental ndings that may cause needless concern to participants.
When necessary, researchers should direct participants to a qualied professional to discuss the possible implications of
the incidental nding for their welfare (Article 3.4, TCPS (2010))
� In some cases, incidental ndings may trigger legal reporting obligations and researchers should be aware of these
obligations (Article 3.4, TCPS (2010))
TCPS (2014)
� Researchers have the obligation to disclose to the participant any material incidental ndings discovered in the course of
research (Article 3.4, TCPS (2014))
� Incidental ndings are considered to be material incidental ndings if they have been interpreted as having signicant
welfare implications for the participant . Material incidental ndings may appear at any stage of the research
(Article 3.4, TCPS(2014))
� If researchers are unsure of how to interpret ndings or uncertain whether ndings are material, they should consult
colleagues or refer to standards in the discipline. (Article 3.4, TCPS(2014))
� Researchers should exercise caution in disclosing incidental ndings that may cause needless concern to participants
such as participant anxiety, unnecessary costs and burdens of follow-up; or may aect eligibility for employment
or insurance. When necessary, researchers should direct participants to a qualied professional to discuss the possible
implications of the incidental nding for their welfare (Article 3.4, TCPS (2014))
� When material incidental ndings are likely, researchers should develop a plan indicating how they will disclose such
ndings to participants, and submit this plan to the REB (Article 3.4, TCPS (2014))
� A researcher may request an exception to the obligation to disclose material incidental ndings, based on the
impracticability or impossibility of disclosing such ndings to the participant. The onus is on the researcher to justify to the
REB the need for the exception (Article 3.4, TCPS (2014))
DISCLOSURE OF INDIVIDUAL RESULTS
DISCLOSURE OF INCIDENTAL FINDINGS
17
Returning Genetic Research Results in Neurodevelopmental Disorders: Report and Review
Table 1: Best practices for the disclosure of research results in children and adolescents continued
Best practices
(Taken from Best Practices for Health Research Involving Children and Adolescents (Avard et al., 2011 [21]))
� Individual results should be communicated when they are clinically valid and reliable and where there are signicant
implications for the health of the participant and either prevention or treatment is available
� When parents refuse to know the results, researchers should oer the results to the child when s/he reaches maturity
or majority
� When the research involves young children, the information should be disclosed to the parents
� When the research involves school-age children and adolescents, the information should also be delivered to them
in a manner appropriate to their development, level of understanding and degree of maturity
� When returning such results, counselling should be oered to the parents and, if appropriate, to the child
� Researchers should also discuss the following considerations: the choices available, the limitations of available clinical
services, the accessibility of counselling services, and the familial implications of the information
� Researchers should discuss with potential participants and/or parents the likelihood of incidental ndings being discovered
in the course of research during the informed consent process
� The method of disclosure of these ndings should be detailed in the consent form
� If appropriate and possible, incidental ndings should be discussed with the REB and, if appropriate, oered to the child
and/or parents
� Incidental ndings with clear and proximate clinical importance should be disclosed to the child and/or parents
� Non-paternity should be disclosed to the mother only
� When communicating such ndings, counselling should be oered to the child and/or parents
DISCLOSURE OF INDIVIDUAL RESULTS
DISCLOSURE OF INCIDENTAL FINDINGS
18 Returning Genetic Research Results in Neurodevelopmental Disorders: Report and Review
a) Underlying ethical considerations
Generally, recommendations for the return of results imply that the actual return of general
(e.g., summaries) or individual research results is supported by three ethical principles.[16]
1. Principle of justice: reciprocity (fairness) is owed to the participant for the
knowledge gained during research
2. Principle of benecence: the benets of research should be returned more globally
to society and to participants through the communication of research results
3. Principle of respect for persons: the communication of results acknowledges the
importance of participants as persons in research
Based on these principles, most authors believe that researchers have an obligation to
return at least aggregate results but researcher obligations to return individual or incidental
ndings results have been debated. At a minimum, it may be ethically acceptable for
researchers to consider a range of issues such as the actionability of ndings discovered,
the severity and age of onset of the genetic risk, the eect on the subject of receiving
the information and potential structural conditions in place for disclosure (e.g., expertise
of the team and access to follow up care) with an emphasis on returning results that are
clinically signicant or accurate and that lead to important health benets.[16, 22] Part
of the controversy stems from the acknowledgement that there are many practical and
conceptual issues that complicate the return of individual research results (see Box 3).
One of the more substantial challenges is the fact that genetic ndings may not at rst
appear to be clinically signicant but may become so as research progresses. These and
other barriers challenge the sequence of responsibilities of researchers.
Perspectives from the academic normative
literature on the ethics of the return of
research results
19
Returning Genetic Research Results in Neurodevelopmental Disorders: Report and Review
In pediatric genetic research, additional issues have been acknowledged such as the
potential for the return of results to lead to unnecessary and costly investigations or
medical interventions, increased parental anxiety or guilt, family stress related to identifying
other members of the family who may be at risk, and potential psychological harm when
altering a parent’s perception of their child.[23] In children particularly, one concern is
removing the right to an open future by returning individual genetic results to parents,
especially where conditions are adult-onset or have no accepted treatment.[23, 24] These
barriers are sometime juxtaposed against the potential benets to children and families of
identifying a potentially serious, medically actionable genetic nding.[23]
BOX 3: Barriers to the return of individual research results
Practical barriers
Burden and cost of returning results
Which to return, how and when
Incorporating participant preferences (which can change over time)
Secondary use of biobank data is not linked to information about the participant
Inconsistent ethics guidance on the topic
Theoretical barriers
Incoherence between the goals of research to create generalizable knowledge
and the return of individual ndings
Uncertain psychological and medical eects of returning results
View that genetic results are not predictive
Inconsistent perspectives about researcher obligations
Examples pulled from: Levesque et al. (2011) [16]; Hens et al. (2011) [22]; Knoppers et al. (2014) [23];
Di Pietro and Illes (2013) [27]
Perspectives from the academic normative literature
on the ethics of the return of research results continued
20 Returning Genetic Research Results in Neurodevelopmental Disorders: Report and Review
b) Recommended approaches for adults
Recommended approaches for the return of research results in capable adults have
been developed. Levesque (2011) describes the strengths of an approach that deals
with scientically-oriented concepts rather than vague or confusing ethical principles
(Box 4). For the researcher in genetics, such a model may also take into account the
broader range of scientic factors that inuence ethical decisions and options about
the return of research results. Importantly, what becomes clear by looking at this
recommended approach is that there is almost no situation where patient preferences
or any other ethical, legal, and social (ELSI) issue would override an important clinically
signicant nding. However, this feature seems to align with other views on the balance
of patient autonomy and benecence; most recommendations state that it would be
appropriate to override patient or parent preferences for results that are medically
important and actionable.[21, 25] While most academic reections on the topic have
focused on the validity of ndings and how to reconcile these with personal preferences
for disclosure, an important early reection oered by Ravitsky and Wilfond (2006) draws
attention to how personal meaning can be incorporated into decisions about returning
genetic results. In the absence of clear clinical utility, the authors suggest that researchers
may consider the personal meaning of results when making decisions about disclosure,
although they acknowledge that the broad implications of disclosures for personal utility
requires more study.
Perspectives from the academic normative literature
on the ethics of the return of research results continued
21
Returning Genetic Research Results in Neurodevelopmental Disorders: Report and Review
Perspectives from the academic normative literature
on the ethics of the return of research results continued
Box 4: Recommended approach for managing return of individual research results
Rationale:
A exible framework is needed that recognizes that in many cases disclosure is
permissible or advisable, in few it is an obligation.
Criteria for consideration during disclosure:
� Analytic validity (including accuracy of the result)
� Clinical validity (including accuracy with which we can detect the clinical outcome)
� Clinical utility (including how likely the result will impact health)
� ELSI issues (including participant preferences, investigations that may be
undertaken, potential for anxiety)
Outcome:
According to the degree to which all four criteria are fullled by the ndings,
return of results:
� Is not recommended (i.e., ndings that are uncertain, dicult to interpret or about
a benign condition)
� May be recommended
� Is highly recommended (i.e., ndings that indicate a high probability of developing
a serious illness where there is available treatment)
Levesque et al. (2011) [16]
22 Returning Genetic Research Results in Neurodevelopmental Disorders: Report and Review
c) Recommended approaches for children
In pediatric research studies, the controversies about which ndings to return and when
are complex due to consideration of the ways that children benet or not from ndings
that may be medically signicant (e.g., actionable or not in childhood). In adults, autonomy
is respected by considering patient preferences for disclosure of individual results.
However, parental authority does not necessarily dictate the appropriate boundaries of
return of results for children.[22, 23] A parent’s preference not to know about results may
be overridden in the case of clinically meaningful and actionable ndings in childhood, and
similarly, results may be withheld from parents in cases where the developing autonomy of
children may allow them the opportunity to participate in decisions about what they want
to know about themselves and when.[22]
Recommended approaches in children favor the return of genetic variants predicting
a strong probability of the child being at risk for early-onset treatable or preventable
disorders that reect consideration of the child’s best-interests.[22, 23] Parents should not
be able to opt out of the return of these ndings.[26] In spite of guidance that scientically
valid and clinically useful results should be returned, much more caution should be
used when disclosing ndings that lack clinical accuracy or condence and when
disclosed these should be accompanied by warnings about acting on ndings that are
not clinically validated (i.e., possibility of undergoing unnecessary medical tests) as well
as other information about what role the researcher can or will play after disclosure.[24]
Additional thorny questions arise in considering whether parents have a right to receive
all of their child’s genetic research results. Although much of the guidance assumes
that parents act in their child’s best interest in seeking out information that may impact
the family, reproductive decisions, and psychosocial wellbeing, the rights of the child or
adolescent to voice their own opinion about the disclosure of research results must be
given due attention.[23, 26] For this reason, Knoppers et al., (2014) suggest that ndings
that predispose a child to an adult onset disorder should generally not be returned and
decisions surrounding return of results should be delayed until the child can make this
decision. This aligns with proposals that recognize the right of the child to an open future.
Perspectives from the academic normative literature
on the ethics of the return of research results continued
23
Returning Genetic Research Results in Neurodevelopmental Disorders: Report and Review
Perspectives from the academic normative literature
on the ethics of the return of research results continued
“Consensus exists ... that indicate parents should not have
access to genetic data about their children if there are no known
treatments or preventative therapies of immediate benet to
the child”[24]
Other concerns for the return of individual research results in children[22] continue to be
reected upon, including:
• The consideration that should be given to the age of sexual majority in
determining when to disclose or when to seek preferences of the participant when
it relates to adult onset disorders or reproductive risks.
• If parents could be the gatekeepers for genetic information about their children,
and strategies to ensure that parents pass on appropriate information to their
children and when.
• What can we do to manage new scientic evidence and follow up over a long
term with children and adolescents with evolving capacity to consent to the return
of ndings?
• How do we manage ndings that may have reproductive implications for siblings,
parents and child participants?
Di Pietro and Illes (2013) propose a framework for dealing with the disclosure of incidental
ndings to competent minors in brain research. They recommend that IFs that are
of uncertain signicance or of clinical signicance be disclosed to both parents and
minors, in a manner sensitive to the developmental stage of the participant, without the
opportunity to opt out of such ndings. In the case of ndings of low clinical signicance,
they suggest that preferences of a competent minor could overrule those of parents for
disclosure of the information although researchers should try to reconcile the perspectives
of parents and minors.[27]
Perspectives oered from normative ethics and guidelines are helpful, but we must
also turn to researcher and parent perspectives on the return of individual results to
understand their relationship to recommended best practices.
24 Returning Genetic Research Results in Neurodevelopmental Disorders: Report and Review
a) Researcher perspectives
A handful of empirical studies conducted in the United States have assessed the broad
perspectives and experiences of genetics researchers, with an emphasis on the reporting
of incidental ndings.[28-33] Together, these studies show that researchers are inclined
to report the discovery of IFs when they are of clear or probable medical signicance[28]
or when they are highly penetrant and have immediate medical implications [29].
Researchers typically feel that the return of those ndings hinges on a moral obligation
to disclose information that could negatively impact participants’ health or a right of
the participant to the information.[29, 31, 32] In contrast, researchers became more
uncomfortable with the return of research results when the medical signicance was
unknown and this and other reasons formed the basis of decisions to withhold results.[28,
29] Other inuential factors reported include:
• Appraisal of the clinical signicance of the nding and the information to support
this interpretation of signicance;
• Availability of expertise to return results appropriately;
• Quality of sequencing results not obtained from a certied clinical genetics
laboratory;
• Potential burden imposed on researchers which can hinder the progression of
research;
• Possibility that participants may not understand the results;
• Potential loss of condentiality as a result of disclosure;
• Potential for emotional burden for participants.[28,30,31]
In-depth analysis of the perspectives of researchers reveals that many complex factors
shape their views about the return of incidental ndings, including the genetic variant
identied, the associated disease and penetrance of the variant, actionability of the
nding, participant wellbeing, researcher responsibility, and input from institutional ethics
bodies.[30]
Researcher and parental perspectives
regarding the return of individual research
results in genetic studies
25
Returning Genetic Research Results in Neurodevelopmental Disorders: Report and Review
More specically in pediatric cases, researchers suggested that they would
overwhelmingly support (91%) returning research ndings in children if it showed a highly
penetrant condition that was clinically actionable before adulthood. The ndings were not
so strong for those conditions that were not actionable until adulthood, where only 68%
of researchers would return these ndings. Compared to return of incidental ndings in
adults, researchers were more cautious in general about the return of ndings in children.
[29]
Generally questions persist about the denition of dierent concepts such as actionability,
high penetrance or risk.[29] Following from this, and other challenges listed above,
researchers used dynamic problem solving to deal with individual cases [31]; what
Klitzman et al., 2013b describe as judgment calls.[30] Researchers often erred on the side
of caution in reporting incidental ndings because they feared that participants might take
overly aggressive action based on these ndings. Their decision-making was complicated
by ndings that were less published, de novo or rare variants.[30]
“If it’s never been seen before, does that guarantee it’s important?”
(Participant as reported by Klitzman et al., 2013b)
Most researchers in Klitzman et al.’s study (approximately 82%) believed that participants
should be oered the opportunity to express whether or not they want IFs returned.
However, respecting this choice was sometimes hampered by numerous competing
obligations; for instance a highly penetrant but treatable condition.[29, 30] Respecting
patient preferences was also challenged by the fact that participants were perceived not
always to have fully considered the impacts of knowing (or not), or the perceived likelihood
that they could change their minds about disclosure according to dierent ndings.
Nonetheless, patient preferences were often taken into account. However, when these
preferences were overridden, researchers and ethics review boards felt justied in doing
so.[28-30] In contrast, some researchers felt that they should not be obligated to report
results or IFs as long as this is expressly stated in the informed consent form and agreed
to by participants.[33]
Researcher and parental perspectives regarding the return of
individual research results in genetic studies continued
26 Returning Genetic Research Results in Neurodevelopmental Disorders: Report and Review
b) Research ethics board perspectives
Studying the perspectives of 34 institutional review board (IRBs) chairs about the
management of genomic incidental ndings, Williams and colleagues (2012) report a focus
of IRB chairs on procedure and study protocols. For instance, one IRB chair suggested
that many issues associated with how IFs were to be managed could be dealt with by
ensuring that protocols and consent documents were clear on the expected process,
leaving researchers to enact the approved process.[28] However, as Kiltzman et al.’s
(2013) study of researcher perspective’s reveals, researchers often seek IRB members’
views on whether and when to return such ndings. This emphasizes one dierence
that Williams et al., (2012) observed between researchers and IRB chairs; researchers
viewed the return of IFs on a case by case basis (and may look to IRBs to help them
navigate these decisions) and IRBs viewed their return driven by existing policy, study
protocol or consent. The variation in institutional policies surrounding IFs is important, and
leads to signicant variation in the return of IFs that is especially obvious in multicenter
research trials.[30] Williams et al. 2012 describe that some IRB chairs reported that the
same IF policy is applied to any IF while other IRBs reported having no policy about IF
return. Similarly, in a review of a sample of informed consent documents for magnetic
resonance imaging research in Canada, Palmour et al. (2011) report various strategies
disclosed in consent documents for dealing with IFs in neuroimaging research. These
include variations in who will be informed (the participant directly or their physician), and
how participant preferences will be taken into account in disclosure (i.e., “subject has the
choice to be informed of IF”, “subject has the choice for the physician to be informed”).
[34] Signicant evidence gaps exist for IRB decisions (and decision-making processes)
about disclosure of research results or IFs.
Researcher and parental perspectives regarding the return of
individual research results in genetic studies continued
27
Returning Genetic Research Results in Neurodevelopmental Disorders: Report and Review
c) Parent perspectives
Two studies, one Canadian and one American, have examined the perspectives of parents
of children with rare diseases regarding the return of genetic research ndings. These
studies revealed important insights into how parents view the obligations of researchers
and their own rights over information about their child. Kleiderman and colleagues (2013)
found that most parents wanted genetic incidental ndings returned to them and believed
that they had a right to be informed of all results about their child’s health status. However,
parents were less condent about wanting to know about adult-onset life limiting and/
or untreatable conditions or the carrier status of their child.[35, 36] Knowing about the
carrier status of their child was seen as useful for the future of the child, although most
parents felt that they should be able to choose whether to receive this information or
not.[35] Similarly, Sapp et al. (2014) found that parents wanted to receive information
about ndings that indicated an increased risk of preventable or treatable conditions in
childhood.
In general, these studies demonstrate that parents see themselves
as the guardians of health information about their child, regardless
of its uses or severity, and perceive the information as important to
maintaining control over their child’s health.
Kleiderman et al. (2013) further describe that parents perceived that it was their own
responsibility to share information with their child at a time that was appropriate and
sensitive to the child’s understanding of it. This also included information inuencing
future planning or reproductive risks and the control of communicating health risks with
other family members. Parents considered that researchers had an obligation to divulge
incidental ndings and expected disclosure as a result of their child’s participation.
Parental views reected that information sharing should change with evolving capacity;
parents felt that later on their child should be able to decide whether or not they wanted
to know about incidental ndings.[35] In this case, that seemed to mean that parents
should respect the fact that they may know about a child’s incidental nding but that the
child at maturity has a right to tell the parent they do not want to know about it.
Researcher and parental perspectives regarding the return of
individual research results in genetic studies continued
28 Returning Genetic Research Results in Neurodevelopmental Disorders: Report and Review
a) Researcher perspectives
Qualitative and quantitative survey studies assessing researcher perspectives on the
topic of the return of individual genetic research results in the context of ASD reveal
that several practical and conceptual elements factor into researchers’ appraisals of the
appropriateness of disclosure and the goals of disclosure. All of the following studies were
conducted in Canada by the same research group.
Hayeems and colleagues (2011) report that 80% of respondents
in their sample of international researchers in the areas of cystic
brosis and autism spectrum disorder believed that clinically
signicant ndings warranted reporting, while a majority
believed that disclosure of provisional ndings or ndings
with uncertain clinical signicance was not recommended and
could in fact be harmful.
Their research reveals that the majority of researchers endorsed the obligation to ensure
access to clinical services required as a consequence of receiving results, and to
updated information about these genetic ndings as new research becomes available.
[37] Importantly this study revealed several key judgments made by researchers about
the clinical signicance of genetic ndings that impact on willingness to disclose genetic
results. Less condence in the clinical signicance of ndings was ascribed to/by:
• Less well-replicated ndings;
• Less robust ndings (those that indicate only a small risk of ASD or CF);
• Incidental ndings;
• ASD genetic ndings in general, when compared to genetic ndings in CF studies;
• Researchers who work in the area of ASD;
• Researchers who don’t have a clinical interpretative role.[38]
The return of individual research results
in genetic studies of autism
29
Returning Genetic Research Results in Neurodevelopmental Disorders: Report and Review
Interestingly, researchers who reported that the return of clinically signicant ndings was
warranted were more likely to feel condent in the clinical signicance of hypothetical
genetic ndings provided. This is in line with research in the context of ASD that shows
that researchers’ beliefs about returning individual research results are inuenced by their
own orientations towards the role of genetics in autism[39] (see below table for more
information). As expected, when hypothetical scenarios contained elements diminishing
condence about the clinical signicance of ndings were presented to researchers,
they were less likely to support the disclosure of research results, including half as likely
to support reporting ASD ndings compared to CF ndings.[38] Irrespective of the fact
that fewer researchers endorsed the return of ASD genetic ndings, they believed that
researchers have a duty to follow up any disclosure with updated information about
the genetic variation and provide participants access to clinical services.[37] This
demonstrates that researchers endorse strong cascading commitments beyond the
disclosure of research results, even in the face of potential barriers to accessing clinical
care.[37] Earlier research demonstrates that researchers rely on judgments about sucient
“proof” and “truth” of genetic ndings in ASD to dictate the appropriateness of disclosure.
Some researchers supported the disclosure of individual research ndings if it could help
to ascertain the meaning of uncertain results, atypical cases or if disclosure would help
initiate genotype-driven research within families. Other respondents however, felt that
individual results should not be returned based on the assumption that individual case
meaning would only exist once statistical evidence had accumulated in populations.[39]
b) Parent perspectives
Studies from the US and Canada on parent perspectives on the return of the individual
genetic research results in autism reveal that there are two key drivers to the desire for
disclosure [39-41]:
• Genetic research results may answer the question of “why?”, provide relief from
guilt or better understanding of the etiology of their child’s condition;
• Genetic research results could be used for reproductive planning and planning for
the future.
Not all parents endorsed these views, with some expressing concerns about the impact
of genetic ndings on self-blame or the potential for genetic ndings to lead to fear, stress
and depression among parents without the ability to improve the day-to-day care of their
child with ASD. Studies conducted with parents in the context of genetic research in
autism are described in further detail in Table 2 and the key ndings are reviewed.
The return of individual research results in genetic studies of autism continued
30 Returning Genetic Research Results in Neurodevelopmental Disorders: Report and Review
Opinions and intentions of parents
of an autistic child toward genetic
research results
Baret L and Goddard B
Table 2: Parental perspectives on the return of research results in genetic studies of ASD
Article
What is a meaningful result?
Disclosing the results of genomic
research in autism to research
participants
Miller FA, Hayeems RZ and Bytautas JP
Parent perspectives on pediatric
genetic research and implications for
genotype-driven research recruitment
Tabor H, Brazg T, Crouch J,
Namey EE, Fullerton SM,
Beskow LM and Wilfond BS
Study population
158 parents of an autistic child
34 parents of minor or adult
children with autism spectrum
disorders (focus groups)
26 parents of minor or adult
children with autism spectrum
disorders (interviews)
23 researchers (interviews)
17 parents of children enrolled in
genetic studies of autism
6 parents of children enrolled in
genetic studies of diabetes
Type of study
Survey
Focus group
and interview
Interview
Publication
year
2011
2010
2011
31
Returning Genetic Research Results in Neurodevelopmental Disorders: Report and Review
� Return of research results, as they were, had priority over returning them only once validated and before a prevention or
treatment became available
� 37% of parents thought individual research ndings would allow them to make better decisions for the future, 19% to
allow them to better inform their family circle
� 14% would do nothing with genetic results returned but still wished to receive them
� Impact of receiving positive or negative results was generally positive or neutral (i.e., provided relief or understanding
(14%), allowed parents to be prepared for the future (37%))
� Two proles of parents in favor of returning individual results were found:
A. Those who wanted the knowledge to make reproductive choices and prepare for the future (20% of participants)
B. Those who “want to know” (have no intentions about doing anything with the information) (15% of participants)
� Parents and researchers emphasized non-clinical benets of genetic results (i.e., identify reproductive risks, provide an
answer to question of “why?”) over any direct clinical benets
� Some respondents believed that answering the question “why?” would bring relief or reduce sentiments of blame while
others questioned whether genetic ndings could increase feelings of self-blame
� Researchers emphasized that individual results should only be reported if there is sucient evidence of the result’s
importance or signicance (including that returning the result would aid in understanding uncertain results and advance
knowledge generally as well as provide rationale for studying phenotypes in other members of the family)
� Researchers have non-uniform beliefs about the genetic factors in autism (i.e., some believe that genetic characterization
of autism is possible, while others support the use of genetic factors to understand how the disorder inuences
neurodevelopment)
� Beliefs about the role of genetics in autism inuenced researcher perspectives on the return of individual research results
and the meaning of genetic research ndings
� Parents anticipated that improved treatment may result from genetic research
� Parents were not hesitant to participate in more research related to their child’s disease although they expressed a
preference that their children only participate in genetic research that was relevant to their family
� None of the parents felt that there was any possible negative psychological impact of the return of genetic results on
their child
� Parents described the negative psychological impact in general on parents of returning ndings with uncertain meaning
or where no treatments were available
� Some parents of children with autism (and not parents of children with diabetes) identied self-blame and guilt as potential
negative factors accompanying genetic result disclosure. Other parents discussed opposing perspectives that genetic
results removed guilt, provided relief about genetic conditions that were not present, and were empowering
� Most commonly parents suggested that receiving results could be accompanied by worry, stress, fear and depression
� Parents desired to choose whether or not they wanted individual research results returned to them
� Parents of children with diabetes were more likely to discuss direct clinical utility of genetic results. Parents of children
with autism discussed more vague clinical uses for the information. Regardless, parents saw genetic ndings as
knowledge that could be useful now or in the future
� Parents of children with autism alone stressed the potential of results to inform reproductive planning, although some
parents worried that, when used to inform reproductive risks, this information could be harmful to their own children
or society
� Parents of children with autism alone felt that returning genetic research results would be an incentive to participate in
future studies. For this reason, some parents expressed a strong desire for disclosure of research ndings
Table 2: Parental perspectives on the return of research results in genetic studies of ASD continued
Key ndings
32 Returning Genetic Research Results in Neurodevelopmental Disorders: Report and Review
We acknowledge several limitations to this report. Our report is an overview of the
literature, both normative and empirical, with regards to the disclosure of genetic ndings.
Advancements in the study of genetics such as the development of whole genome
sequencing are expected to provide more extensive genetic information as well as to
increase the possibility of incidental ndings being discovered. At the same time, as
more genetic variants are identied across research studies generally, the possibility that
research participants will feel falsely reassured despite the presence of undetected genetic
ndings is also increased. In order to be eective in oering guidance to researchers, we
must keep in mind the primary goals of research to contribute to generalizable knowledge.
Similarly, our understanding of the genetics of neurodevelopmental disorders is in ux
as each new large set of genetic data is analyzed and published. These discoveries may
impact our understanding of which genetic ndings are clinically signicant and should
be disclosed in studies seeking to directly identify their presence. Lastly, important
international perspectives of researchers and parents are missing from the predominately
North American literature on the return of research ndings. We must acknowledge that
international teams are often involved in large scale studies of genetics and this implicates
dierent international research ethics policies guiding return of results as well as suggests
that we need a better understanding of cross-cultural perspectives on the return of
research ndings.
Summary of ndings and issues for
future study
33
Returning Genetic Research Results in Neurodevelopmental Disorders: Report and Review
Summary of ndings and issues for future study continued
Box 5: Disclosure of incidental genetic ndings: major recommendations and
observations from ethics policies, literature, and empirical studies
A. Disclosure of actionable and material ndings (meeting clinical and
scientic validity criteria) is generally supported
� TCPS (2010, 2014) describes an obligation to return material incidental ndings, and
other international policies identify that ndings relevant to a participants’ health
status should be disclosed (CIOMS, Council of Europe) [16]
� Other policies generally support the oer of disclosure (rather than obligation) of
material research results, including incidental ndings under certain conditions [18]
� In pediatric participants, an obligation to disclose results that have signicant health
implications, and that could lead to prevention or treatment is emphasized
[18, 21-23]
� Some guidance and authors recommend that parents should not be able to opt
out from receiving such information (that which has signicant health implications or
is actionable in childhood) [18, 26]
� Research on parental perspectives generally supports the return of research results,
without specically dealing with the issue of incidental ndings [35, 40, 41]
1. Convergences and divergences between ethics policies,
scholarly perspectives and empirical data on the return
of genetic results
Box 5
Disclosure of incidental genetic ndings: major recommendations
and observations from ethics policies, literature, and empirical studies
continued on next page
34 Returning Genetic Research Results in Neurodevelopmental Disorders: Report and Review
1. Convergences and divergences between ethics policies,
scholarly perspectives and empirical data on the return of
genetic results continued
Summary of ndings and issues for future study continued
Box 5: Disclosure of incidental genetic ndings: major recommendations and
observations from ethics policies, literature, and empirical studies
B. Disclosure of non-actionable or non-material ndings is debated
� Generally, ndings with unclear scientic or clinical validity should not be returned
[18] and the TCPS (2014) urges researchers to exercise caution in returning results
which may cause needless concern[19]
� For non-material incidental research ndings, researchers may consider actionability,
participant preferences, and clinical signicance in deciding whether or not an
incidental nding will be disclosed [18] 4
� In pediatric studies, results concerning the future health adult health (non-actionable
in childhood) of the minor should generally not be disclosed [18, 24], although it
has also been suggested that ndings without clear and proximate clinical
importance should be discussed with the REB and, if appropriate oered to the
child/or parents [21]
� Researchers should consider the possibility that in longitudinal research, incidental
ndings that are non-material or non-actionable in childhood could be withheld until
such a time that participants reach the age of maturity and can oer their
preferences about disclosure [21]
� Empirical evidence shows that researchers are inclined to report incidental ndings
when they are of clear or probable medical signicance or are highly penetrant
and have immediate medical implications. Those results where medical signicance
is unknown are subject of more case by case analysis, and may be consulted on by
REBs [28-30]
� Parents have described the negative psychological eects of returning ndings with
uncertain meaning or where no treatments are available [41], and are not entirely
certain that they want to know about fatal adult-onset conditions or the carrier
status of their child [35, 36]
4 Best-practices highlight a graded strategy as it relates to the disclosure to young children, school-aged children,
and adolescents where developing capacity is acknowledged and disclosure practices aligned (for young children
disclosure should be to parents, for school aged children they should be included in developmentally appropriate ways
and when results have not been provided to parents they may be provided at the age of maturity to the participant)
(Avard best practices). In the case of neurodevelopmental disorders, researchers will want to consider the potential
for participants, at the age of maturity, to participate in a developmentally appropriate manner to discussions about
disclosure preferences, and the ramications of withholding such information from parents at an earlier time if they are
already intricately involved in their child’s care (i.e., would the patient be able to enact their own preferences without the
parent being involved and therefore is anything gained by waiting to determine the child’s preferences). Depending on
this reection, and the nature of the relationship with the research team and the recruited families, it may be appropriate
to use parent preferences to guide the return of non-actionable, non-signicant incidental ndings. In these cases,
parents should act with their child’s best interests in mind when requesting or refusing information.
35
Returning Genetic Research Results in Neurodevelopmental Disorders: Report and Review
Summary of ndings and issues for future study continued
1. Convergences and divergences between ethics policies,
scholarly perspectives and empirical data on the return of
genetic results continued
Box 6: Disclosure of ASD-related genetic ndings: major recommendations and observations
from ethics policies, literature, and empirical studies
A. Disclosure of general research results overwhelmingly supported in a way that is
accessible to adult participants, parents, and if appropriate children [16, 18, 21]
B. Disclosure of individual research results depends on context
� Participants should be asked about their preferences related to the disclosure of individual research
results [18, 19]
� Material results should be oered to adults when additional considerations are weighed (including
their preferences and practical considerations such as the availability of genetic counselling support)
[18]
� Disclosure of pediatric individual research results is encouraged when individual research results are
reliable and valid and have important implications for the participant’s health [21] 5
� Researchers hold diering views on the denitions of concepts such as actionability, high penetrance
and risk, that lead them to case-by case analysis when considering disclosure of research results [29]
� Researcher decision-making about the return of IRR is complicated when results are less published,
de novo or rare variants [30]
� Researchers generally support the return of clinically signicant ndings but not of uncertain or
provisional ndings [38]
� Researchers have diering views themselves about the role that genetic information plays in ASD
and that impacts their views on disclosure [39] 6
� Disclosure of individual results in autism might be seen as appropriate if it allows for genotype-driven
research with families or clarication of uncertain variants [39]
� Parents whose children participate in ASD genetic research, generally desire that results be returned.
They justify this on the basis that it provides personal utility in the form of assisting reproductive
decisions and answering questions about why the child has ASD [39-41]
� Parents describe that returning individual research results creates an incentive to participate in
genetic studies [41]
5 Although guidance related to the return of incidental ndings may be a starting point for considering the appropriate return of
ASD-related genetic ndings, the fact that many ASD-related genetic ndings have uncertain meaning, or are non-actionable, puts a
greater emphasis on the challenges facing researchers in dealing with decisions about the disclosure of non-material or uncertain ndings.
6 Researchers of ASD studies expressed a reluctance to disclose results relative to medical conditions that have stronger genetic links,
for instance more penetrance. This is discussed further below but there is a need for researchers in the eld of ASD to engage in further
deliberation about their own diering views about the genetics of ASD and the meaning of genetic research results. As is identied generally
by genetic researchers, questions of certainty and actionability are still active and ongoing but this can seem to conict with research ethics
policies and REB practices that treat the issue as very routine with seemingly clear guidance (i.e., if X is uncertain than do not disclose).
It is not a surprise then that researchers report seeking REB advice to deal with individual cases; particularly because issues of context are
important (i.e., what expertise is on the team, are genetic counsellors available). This underlines what Eriksson and colleagues (2008) have
described as the interpretation problem, the fact that “there will always be a gap between the rules and the practice they are meant
to regulate” and “an agent must always interpret the rules in order to assess their applicability in a particular situation”. [42]
36 Returning Genetic Research Results in Neurodevelopmental Disorders: Report and Review
The potential for researcher orientations towards genetics to impact
perspectives or practices in the return of genetic ndings of ASD
The return of research results is inuenced heavily by context and not all genetic ndings
are considered equal. For instance, researcher perspectives on the return of results are
highly contingent on factors such as the accurateness of the result, or clinical utility of the
result. Importantly, beliefs about the role of genetics in ASD also inuence perspectives
about disclosure. Contextual elements impacting the disclosure of research results are
impossible to capture in general ethics policies, and there is likely to be a lack of specic
contextual expertise to contribute to decisions made by REBs about when to disclose
results.
The potential for personal utility to meet the best interests standard
for disclosure of research results
Return of research ndings related to ASD for reasons of personal utility requires us to
think more about the ways that this meets the obligation of parents to act in their child’s
best interest. Because personal utility (i.e., answering the question of why), rather than
clinical utility, seems to be important to many parents participating in genetic studies of
ASD, disclosure of individual results on that basis respects the values upheld by parents
but it is unclear how they relate this to the best interests of their children. Provided that
there is transparency about what the return of research results achieves, a disclosure
for reasons of personal utility may be appropriate as long as the parents’ desire for
information is aligned with best interests of the child. The Network of Applied Genetic
Medicine, for instance, suggests that under exceptional circumstances a genetic result
that is not actionable in childhood may still be returned based on a favorable balance
between benets and risks (i.e., where the information has signicant consequences
for the health of the parent’s, the siblings). In general, policies about the disclosure of
research results lack broad consideration of issues of personal utility. Rather clinical utility
has often been the standard by which disclosure and best interests have been established
based on immediate health benets. Furthermore, clinical utility has often been described
in a narrow fashion (i.e., results that are clinically actionable or indicate the need for
treatment or monitoring). A broader conception of clinical utility would be results that
provide meaning about the etiology of a child’s syndrome and are of use for clinicians and
families. When clinical utility is seen broadly, and where we remain sensitive to a family
centered model of best interests, personal and clinical utility are evidently more closely
related.
2. Issues requiring consideration and or evidence to inform
best practices for return of genetic research ndings in
neurodevelopmental disorders
Summary of ndings and issues for future study continued
continued on next page
37
Returning Genetic Research Results in Neurodevelopmental Disorders: Report and Review
Summary of ndings and issues for future study continued
2. Issues requiring consideration and or evidence to inform
best practices for return of genetic research ndings in
neurodevelopmental disorders continued
Some may argue that disclosure for reasons of personal utility – with increased potential
for feelings of guilt or anxiety when ASD is genetically “explainable” (see below for further
discussion of the importance of risk communication) – pose substantial risks to the child
and family unit. Further, as it relates to reproductive knowledge, some parents fear that
genetic ndings could discourage their child with ASD from later having biological children
of their own. This hints at unintended harms that may accompany disclosure. One study
has shown that regardless of receiving results, families participating in ASD genetic
research still found the act of participating valuable.[43]
The importance of risk communication in genetic studies of
neurodevelopmental disorders
Dierent philosophies about the return of research results pit a protective/restrictive
model (“only disclose results that are actionable and clinically signicant in childhood”)
against a more libertarian model of communicating risk information with parents or even
minors. As in other instances of risk communication, inadvertent harms are thought
to be inherently important to evaluate. These include arousing fear and worry, causing
blaming or stigmatizing reactions or inciting guilt, suggesting that actions be taken that
are not in an individual’s best interests, and detrimentally impacting on the individual’s
identity.[44] The magnitude of these harms is important in evaluating the appropriateness
of policies surrounding return of research results although empirical data might be
lacking to demonstrate clearly if there are resulting harms. In addition, the magnitude
of harms associated with communicating risk related to an “expected” nding (related
to ASD) might be signicantly dierent than the magnitude of harms associated with
communicating risk related to an incidental or unexpected nding. Empirical evidence
suggests that many parents, at least, nd the return of research ndings useful for reasons
of personal utility when they relate to explaining (or not) the presence of ASD. At the
same time, researchers have shared with us their personal experiences suggesting that
communicating the meaning of a genetic nding related to ASD can be extremely dicult,
complex and thorny because of issues identied early on in this review (i.e., incomplete
penetrance, non-Mendelian genetics, de novo mutations, dierences in phenotypic
expression). In empirical studies, parents express more worry about the disclosure of
incidental ndings, particularly when they indicate life-limiting diseases of adult-onset that
lack eective therapy. However, the fact that parents are outwardly more positive about
wanting the disclosure of ASD related ndings may not reect the true experience of
parents when they are on the receiving end of results that may be confusing, complex,
and nuanced, and that may lead to unanswered questions about risk (or heredity,
phenotype) for other family members. Additional philosophical and empirical work is
needed to further understand harms as a result of risk communication as well as to devise
rational explanations that favor one model over another.
38 Returning Genetic Research Results in Neurodevelopmental Disorders: Report and Review
The role of the child or adolescent with developmental disability
in decision making
Current best practices regarding the inclusion of the minor participant in disclosure
practices stresses the need for dierent levels of involvement based on the child’s
developmental maturity. For young children, information should be disclosed to parents,
and parent preferences for disclosure respected, where they are presumed to make these
decisions in the best interests of their child. For school-aged children and adolescents,
information about ndings should be communicated in a way that is developmentally
appropriate with consideration of their level of understanding and maturity. However,
when to involve or respect minor’s preferences with regards to disclosure of research
results has seen less attention. Di Pietro and Illes (2013) describe that as long as a minor
has capacity, he or she should be involved in decisions about whether to disclose/share
results or not. In these cases, they should be asked to consent to the disclosure of results
and their preferences should be respected for ndings that are of low signicance. For
minors with ASD who may lack capacity or developmental maturity, parental preferences
may guide disclosure. However, an emphasis should be placed on the right of the child to
participate actively in these decisions by giving assent or dissent, and parents should be
encouraged to revisit disclosure preferences in light of their child’s expressed preferences.
Moreover, parents should be encouraged to think about future disclosure to the child
at the age of maturity or in a developmentally appropriate manner at the time that, for
instance, reproductive decisions may become important. An evidence-base relative to
the developing capacities of youth with ASD to consent to research does not exist to
our knowledge. Without such important empirical questions answered, there will be an
evidence gap in understanding eective and appropriate ways to involve youth with ASD
in research decisions. The practical implication of such a gap might be a high burden
placed on the researcher (i.e., directive to involve youth in developmentally appropriate
ways that are time consuming and may not even be eective), or paternalistic practices
that exclude the potential involvement of youth with ASD despite their ability to be
involved in meaningful ways (i.e., paternalistic restriction placed on vulnerable persons
participating in research). These concerns should be examined in more detail.
2. Issues requiring consideration and or evidence to inform
best practices for return of genetic research ndings in
neurodevelopmental disorders continued
Summary of ndings and issues for future study continued
39
Returning Genetic Research Results in Neurodevelopmental Disorders: Report and Review
Conclusions
Although in some areas there is little debate (i.e., that parents should not be able to opt-
out of receiving information about actionable, material research ndings), in many more
areas there exist variations in recommended best-practices for the return of research
results in pediatric studies (i.e., who should be asked about preferences for disclosure,
how and when should ndings be disclosed, should parents be oered all genetic results
about their child). In many instances, this variation reects sensitivity to the fact that
researchers have dierent proximity to patients involved in their research, have dierent
systems in place to handle disclosure, and operate under dierent institutional bodies
granting ethical approvals. By reviewing the international ethics policies, normative
literature and stakeholder perspectives on this topic, we have discussed convergences
and divergences regarding best practices for the return of genetic research results and
examined unresolved issues in the return of genetic ndings in neurodevelopmental
disorders. We remain cognizant of the fact that new evidence or argument about a range
of issues could sway or impact best practices in the future. Families who participate in
research are leading the charge in the development of new knowledge and treatment
options and in doing so they shoulder a signicant burden when considered alongside the
day to day challenges they may encounter. For this reason it demonstrates deep respect
to consider how research can fulll the broad goals of families participating in research.
One way to fulll these goals may be to return individual research results.
Summary of ndings and issues for future study continued
40 Returning Genetic Research Results in Neurodevelopmental Disorders: Report and Review
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43
Returning Genetic Research Results in Neurodevelopmental Disorders: Report and Review
Returning genetic
research results in
neurodevelopmental
disorders:
Report and review
Working Group, ASD and return of results
Funded by Kids Brain Health Network (formerly NeuroDevNet)
Montreal, QC
September, 2015