Genomic investigations often produce more information than is initially expected. Several documents have addressed this issue. While the approaches to the management of incidental findings (IFs) vary, it is usually recommended that the information be disclosed if there is clinical utility and the possibility of prevention or treatment. This leaves unsolved fundamental issues such as the different ways of interpreting clinical utility and countless sources of uncertainty. Guidelines can offer indications but should not be allowed to relieve healthcare professionals of their responsibilities.

1. Unità di Bioetica
Managing incidental findings in
genomic investigations: ethical issues
Carlo Petrini
Head of the Bioethics Unit
Istituto Superiore di Sanità
Data Driven Innovation Summit
Rome, 24-25 February 2017

2. Unità di Bioetica
“IFs have been defined as findings having potential health or
reproductive importance for an individual, discovered in the course
of conducting a particular study (in research, clinical care or
screening) but beyond the aims of that study”
Christenhusz GM, Devriendt K, Dierickx K. To tell or not to tell? A systematic review of
ethical reflections on incidental findings arising in genetics contexts.
Eur J Hum Genet 2013;21(2):248-55
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Definitions

3. Unità di Bioetica
Incidental finding. “This term has been used in a variety of clinical
and research contexts to indicate unexpected positive findings. Other
terms have been used to describe these findings, particularly when
they are actively sought (rather than being unexpectedly discovered).
These terms include ‘serendipitous and iatrogenic’ findings, ‘non-
incidental secondary findings’, ‘unanticipated findings’. and ‘off-
target results’. We use ‘incidental findings’ (…) to indicate the
results of a deliberate search for pathogenic or likely pathogenic
alterations in genes that are not apparently relevant to a diagnostic
indication for which the sequencing test was ordered”
Green RC, Berg JS, Grody WW, Kalia SS, Korf BR, Martin CL et al. (American College of
Medical Genetics and Genomics).ACMG recommendations for reporting of incidental
findings in clinical exome and genome sequencing. Genet Med 2013;15(7) 565-74
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Definitions
ACMG

4. Unità di Bioetica
“The term ‘incidental finding’ is often applied inconsistently. Uses of
the term incidental finding include (i) unexpected positive findings,
and (ii) the deliberate search for pathogenic variants not related to the
primary diagnostic question (…). Other terms such as ‘unexpected’
or ‘secondary’ are equally problematic. Despite the fact that the term
‘unsolicited finding’ may be better terminology, ‘incidental finding’
is now commonly used”
Hehir-Kwa JY, Claustres M, Hastings RJ, Ravenswaaij-Arts C, Christenhusz G, Genuardi
M et al. (European Society for Human Genetics). Towards a European consensus for
reporting incidental findings during clinical NGS testing.
Eur J Hum Genet 2015;23(12):1601-6
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Definitions
ESHG

5. Unità di Bioetica
• “Anticipatable incidental finding is a finding that is known to be
associated with a test or procedure”
• “Unanticipatable incidental finding includes a finding that could
not have been anticipated given the current state of scientific
knowledge”
Presidential Commission for the Study of Bioethical Issues. Anticipate and communicate:
Ethical management of incidental and secondary findings in the clinical, research, and
direct-to-consumer contexts. 2013
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Definitions
US PC

6. Unità di Bioetica
• Primary findings: “results that are actively sought using a test or
procedure designed to find that result”
• Secondary findings: are those “actively sought by a practitioner”
but that are not the primary target
• Discovery findings: are those of a “broad or wide-ranging test
that was intended to reveal anything of interest”
Presidential Commission for the Study of Bioethical Issues. Anticipate and communicate:
Ethical management of incidental and secondary findings in the clinical, research, and
direct-to-consumer contexts. 2013
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Definitions
US PC

7. Unità di Bioetica
• “Pertinent findings are findings that have been generated or
sought with the purpose of answering a particular clinical or
research question either by genotyping specific areas of the
genome or by specifically interrogating those areas if the whole
genome has been sequenced”
• “Incidental findings are additional findings concerning a patient
or research participant that may, or may not, have potential
health implications and clinical significance, that are discovered
during the course of a clinical or research investigation, but are
beyond the aims of the original test or investigation”
Public Health Genetics Foundation. Managing incidental and pertinent findings from
WGS in the 100,000 Genome Project. April 2013
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Definitions
PHG

8. Unità di Bioetica
“While we acknowledge the distinction between these types of
findings, we believe that the most important ethical question
concerning WGS findings is not whether they belong to one or
other of these categories, but what we should do with them and the
normative framework that we apply to such a decision”
Public Health Genetics Foundation. Managing incidental and pertinent findings from
WGS in the 100,000 Genome Project. April 2013
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Definitions
PHG

9. Unità di Bioetica
“After the completion of the study, (…) individual subjects will be
informed of any finding that relates to their particular health status”
Council for International Organization of Medical Sciences (CIOMS). International
Guidelines for Biomedical Research Involving Human Subjects. 2002
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Recommendations
CIOMS

10. Unità di Bioetica
• The WG lists 56 genes associated with the risk of various
diseases; this list is subject to yearly updating
• “Constitutional mutations found in the genes on the minimum
list should be reported (…) regardless of the indication for
which the clinical sequencing was ordered”
Green RC, Berg JS, Grody WW, Kalia SS, Korf BR, Martin CL et al. ACMG
recommendations for reporting of incidental findings in clinical exome and genome
sequencing. Genet Med 2013;15(7):565-74
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Recommendations
ACMG

11. Unità di Bioetica
1) “Genetic exceptionalism”: rejected. When a genomic analysis is
carried out an attempt should be made to communicate all the
information of potential clinical interest, whether correlated
or not to the primary diagnostic question
Green RC, Berg JS, Grody WW, Kalia SS, Korf BR, Martin CL et al. ACMG
recommendations for reporting of incidental findings in clinical exome and genome
sequencing. Genet Med 2013;15(7):565-74
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Recommendations
ACMG

12. Unità di Bioetica
2) Genetic exceptionalism having been rejected, the subjects who
undergo a WGA, upon specific medical advice, are denied the
possibility to exercise the right to not know some secondary results
(IF), independently of their preferences and clinical condition. The
ACMG recognizes that this recommendation is in conflict with the
ethical and juridical norms that safeguard the patient’s autonomy, but
consider that the doctors and laboratory staff, have a more cogent
fiduciary duty, which is one of preventing any potential harm
(principle of beneficence) and to always inform patients about IFs of
potential interest for their health, even against their will
Green RC, Berg JS, Grody WW, Kalia SS, Korf BR, Martin CL et al. ACMG
recommendations for reporting of incidental findings in clinical
exome and genome sequencing. Genet Med 2013;15(7):565-74
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Recommendations
ACMG

13. Unità di Bioetica
3) The Working Group felt it best not to place arbitrary age
restrictions or limitations on the return of incidental variants because
such variants would likely have implications for others in the family
Green RC, Berg JS, Grody WW, Kalia SS, Korf BR, Martin CL et al. ACMG
recommendations for reporting of incidental findings in clinical
exome and genome sequencing. Genet Med 2013;15(7):565-74
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Recommendations
ACMG

14. Unità di Bioetica
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Public Health Genetics Foundation. Managing incidental and pertinent findings
from WGS in the 100,000 Genome Project.
April 2013

15. Unità di Bioetica
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16. Unità di Bioetica
16Non-disclosure of potential findings that might have an
impact on the health of an individual
•For:
Non-maleficence: disclosure could be harmful as the
(psychosocial, economic, clinical) benefits remain
unproven
Justice: disclosure has resource implications (trained
personnel to counsel; clinical validation of the
findings)
•Against:
Autonomy: non-disclosure of such findings may
violate the ability to determine the future
Non-maleficence: non-disclosure may result in
missed opportunities for prevention and treatment
Public Health Genetics Foundation.
Managing incidental and pertinent findings from
WGS in the 100,000 Genome Project.
April 2013

17. Unità di Bioetica
17Disclosing only clinically significant findings that are
severely and moderately life threatening AND clinically
actionable
•For:
Non-maleficence: is consonant with professional’s
obligation to do no harm
Beneficence: it has the potential for reducing the risk
of, or preventing, disease
•Against:
Autonomy: this approach undermines the autonomy
of persons who do not want to be informed about any
results
Justice: all options which support disclosure of such
findings will be more resource intensive
Public Health Genetics Foundation.
Managing incidental and pertinent findings from
WGS in the 100,000 Genome Project.
April 2013

18. Unità di Bioetica
18Disclosing all clinically significant findings regardless of
their severity AND actionability
•For:
Autonomy: enables individuals to have all the
available information
Beneficence: individuals may benefit from knowing
that they, or their putative offspring, are at risk of a
preventable disease
•Against:
Non-maleficence: could cause psychological (e.g.
anxiety, depression) and social (e.g. stigmatisation,
economic loss, discrimination) harm
Justice: all options which support disclosure of such
findings will be more resource intensive
Public Health Genetics Foundation.
Managing incidental and pertinent findings from
WGS in the 100,000 Genome Project.
April 2013

19. Unità di Bioetica
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Disclosing all variants (regardless of severity, clinical
significance and actionability)
•For:
Autonomy: information belong to individuals
•Against:
Beneficence and non-maleficence: such a policy
would abrogate the researcher/clinician from all
responsibility
Public Health Genetics Foundation.
Managing incidental and pertinent findings from
WGS in the 100,000 Genome Project.
April 2013

20. Unità di Bioetica
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Recommendation
Disclosing only research findings that are scientifically
significant and have been assessed by a competent
individual that are clinically significant AND severely or
moderately life threatening AND clinically actionable
Public Health Genetics Foundation.
Managing incidental and pertinent findings from WGS in the 100,000
Genome Project.
April 2013

21. Unità di Bioetica
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Liberty rights (or licence)
Claim rights
Right to information

22. Unità di Bioetica
• Until 1977 the supranational and international documents of
normative importance did not mention the possibility of
guaranteeing a right not to know in healthcare
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Right not to know

23. Unità di Bioetica
Article 10 – Private life and right to information
“1. Everyone has the right to respect for private life in relation to
information about his or her health.
2. Everyone is entitled to know any information collected about his
or her health. However, the wishes of individuals not to be so
informed shall be observed.
3. In exceptional cases, restrictions may be placed by law on the
exercise of the rights contained in paragraph 2 in the interests of the
patient.”
Council of Europe. Convention for the Protection of Human Rights and Dignity of the
Human Being with regard to the Application of Biology and Medicine: Convention on
Human Rights and Biomedicine. 4 April 1997
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Right not to know
CoE

24. Unità di Bioetica
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Right not to know
CoE
“Article 10 – Private life and right to information”
“68. In some circumstances, the right to know or not to
know may be restricted in the patient’s own interest or else
on the basis of Article 26.1”
Council of Europe.
Explanatory Report.
Convention for the protection of human rights and dignity of human being with
regards to the application of biology and medicine: Convention on Human
Rights and Biomedicine.
4 April 1997

25. Unità di Bioetica
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Right not to know
CoE
“Article 27 – Duty of care”
“If research gives rise to information of relevance to the
current or future health or quality of life of research
participants, this information must be offered to them. That
shall be done within a framework of health care or
counselling. In communication of such information, due
care must be taken in order to protect confidentiality and to
respect any wish of a participant not to receive such
information”
Council of Europe.
Additional Protocol on the Convention on
Human Rights and Biomedicine Concerning Biomedical Research.
25 January 2005

26. Unità di Bioetica
Article 5
“(a) Research, treatment or diagnosis affecting an individual’s genome shall be
undertaken only after rigorous and prior assessment of the potential risks and
benefits pertaining thereto and in accordance with any other requirement of
national law.
(b) In all cases, the prior, free and informed consent of the person concerned
shall be obtained. If the latter is not in a position to consent, consent or
authorization shall be obtained in the manner prescribed by law, guided by the
person’s best interest.
(c) The right of each individual to decide whether or not to be informed of the
results of genetic examination and the resulting consequences should be
respected.”
United Nations Educational, Scientific and Cultural Organization (UNESCO). Universal
Declaration on the Human Genome and Human Rights. 11 November 1997
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Right not to know
UNESCO

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Rehmann-Sutter C, Müller H (eds.).
Disclosure dilemmas.
Ethics of genetic prognosis after the 'Right to know / non to know' debate.
Farnham: Ashgate, 2010

28. Unità di Bioetica
Interpretations
1) What has value and is worthy of protection, is the
noninterference by others in the most person
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Right not to know

29. Unità di Bioetica
Interpretations
2) People have the right and duty to know as much information as
possible about their own state of health, genetic make-up included,
to be able to exercise selfgovernance
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Right not to know

30. Unità di Bioetica
Interpretations
3) Emergence of a new moral right, that is, a right to the ignorance
of one’s own future, which in certain situations (for example, in the
case of predictive information on late-onset non-preventable and
untreatable) genetic diseases), can be considered as a precondition
of the free construction and definition of self-identity (Hans Jonas)
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Right not to know

31. Unità di Bioetica
Interpretations
Nevertheless, if one passes from the philosophical-moral level to
the factual one of the concrete dilemmas that doctors and doctors-
researchers can be faced with when they find themselves before IF,
the above mentioned do not help to resolve the question of the
decision to be taken
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Right not to know

32. Unità di Bioetica
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33. Unità di Bioetica
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34. Unità di Bioetica
“The NBC recommends that the traditional distinction between
adults and minors be maintained in medicine and research alike,
and that the ‘best interest’” of the subject not yet able to give their
own consent should be particularly and carefully evaluated”
Comitato Nazionale per la Bioetica. Managing “incidental findings” in genomic
investigations with new technology platforms. 17 March 2016
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35. Unità di Bioetica
“The interest and/or right not to know must be safeguarded as
much as possible, even though it is never absolute insofar as it can
come across limitations, in factual circumstances, for reasons that
surpass it and which must therefore be convincingly argued each
time. A certain degree of discretion can never be completely
avoided since it ultimately lies with the responsibility of the doctors
and doctors-researchers, with the help of other consultants, to
decide on the ‘exceptions’, bearing in mind the relevance of the
typology of information at stake”
Comitato Nazionale per la Bioetica. Managing “incidental findings” in genomic
investigations with new technology platforms. 17 March 2016
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36. Unità di Bioetica
Managing incidental findings in
genomic investigations: ethical issues
Carlo Petrini
Head of the Bioethics Uni
Istituto Superiore di Sanità
Data Driven Innovation Summit
Rome, 24-25 February 2017

37. Unità di Bioetica
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