managing incidental findings in genomic investigations: ethical issues - carlo petrini

Unità di Bioetica

Managing incidental findings in

genomic investigations: ethical issues

Carlo PetriniHead of the Bioethics Unit

Istituto Superiore di Sanità

Data Driven Innovation Summit

Rome, 24-25 February 2017

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

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

3DefinitionsACMG

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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DefinitionsESHG

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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DefinitionsUS PC

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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DefinitionsUS PC

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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DefinitionsPHG

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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DefinitionsPHG

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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RecommendationsCIOMS

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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RecommendationsACMG

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


recommendations for reporting of incidental findings in clinical exome and genome

sequencing. Genet Med 2013;15(7):565-74

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RecommendationsACMG

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


recommendations for reporting of incidental findings in clinical

exome and genome sequencing. Genet Med 2013;15(7):565-74

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RecommendationsACMG

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


recommendations for reporting of incidental findings in clinical

exome and genome sequencing. Genet Med 2013;15(7):565-74

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RecommendationsACMG

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

Unità di Bioetica

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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

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




April 2013

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




April 2013

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




April 2013

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


Managing incidental and pertinent findings from WGS in the 100,000

Genome Project.

April 2013

Unità di Bioetica

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Liberty rights (or licence)

Claim rights

Right to information

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

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 knowCoE

Unità di Bioetica

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“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

Unità di Bioetica

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“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

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 knowUNESCO

Unità di Bioetica

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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

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

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

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

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

Unità di Bioetica

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Unità di Bioetica

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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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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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Unità di Bioetica

Managing incidental findings in

genomic investigations: ethical issues

Carlo PetriniHead of the Bioethics Uni

Istituto Superiore di Sanità

Data Driven Innovation Summit

Rome, 24-25 February 2017

Unità di Bioetica

37

managing incidental findings in genomic investigations: ethical issues - carlo petrini

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