Ethical Issues in Genetic Testing for Complex Diseases and Traits

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Ethical Issues in Genetic Testing for Complex
Diseases and Traits

• Gail Geller, Sc.D., M.H.S.
• Professor
• Johns Hopkins University
• Berman Institute of Bioethics
• Department of Medicine
• Department of Health, Behavior Society

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Case Examples

• Breast cancer
• Smoking-related behaviors

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Main Arguments

• Genetic susceptibility testing is NOT, by itself,
  a form of disease prevention.
• Genetic susceptibility testing has the potential
  to harm (as well as benefit) people.
• In order to minimize these harms, testing must be
  offered and conducted in an appropriate and
  morally responsible way.
• There are several risk factors for
  inappropriate utilization of genetic tests.

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Risk Factors for Inappropriate Utilization of
Genetic Tests

• Exaggerations/inaccuracies in media coverage of
  genetic discoveries
• Direct-to-consumer marketing of tests by biotech
  companies/developers
• Misperceptions in the general public about the
  benefits and risks of genetic testing
• Misperceptions among clinicians about when
  testing is appropriate and the limitations of
  testing
• Difficulty communicating the uncertainties
  associated with testing

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Risk Factors for Inappropriate Utilization of
Genetic Tests

• Exaggerations/inaccuracies in media coverage of
  genetic discoveries
• Direct-to-consumer marketing of tests by biotech
  companies/developers
• Misperceptions in the general public about the
  benefits and risks of genetic testing
• Misperceptions among clinicians about when
  testing is appropriate and the limitations of
  testing
• Difficulty communicating the uncertainties
  associated with testing

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Media Coverage About the Gene Associated With
Colorectal Cancer (1997)

• In what the nations chief of genetic research
  is calling a landmark discovery, Johns Hopkins
  scientists say they have found a genetic mutation
  that causes one of the most common forms of
  cancerAnd theyve developed a test that could
  save tens of thousands of lives

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Media Coverage About the Gene Associated With
Colorectal Cancer (1997)

• In what the nations chief of genetic research
  is calling a landmark discovery, Johns Hopkins
  scientists say they have found a genetic mutation
  that causes one of the most common forms of
  cancerAnd theyve developed a test that could
  save tens of thousands of lives

1. Talking about causation instead of increased
   susceptibility reinforces genetic determinism.

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Media Coverage About the Gene Associated With
Colorectal Cancer (1997)

• In what the nations chief of genetic research
  is calling a landmark discovery, Johns Hopkins
  scientists say they have found a genetic mutation
  that causes one of the most common forms of
  cancerAnd theyve developed a test that could
  save tens of thousands of lives

1. Talking about causation instead of increased
   susceptibility reinforces genetic determinism.
2. Exaggerating the prevalence of familial forms of
   cancer plays on peoples fear of cancer and
   diverts attention away from non-familial causes.

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Media Coverage About the Gene Associated With
Colorectal Cancer (1997)

• In what the nations chief of genetic research
  is calling a landmark discovery, Johns Hopkins
  scientists say they have found a genetic mutation
  that causes one of the most common forms of
  cancerAnd theyve developed a test that could
  save tens of thousands of lives

1. Talking about causation instead of increased
   susceptibility reinforces genetic determinism.
2. Exaggerating the prevalence of familial forms of
   cancer plays on peoples fear of cancer and
   diverts attention away from non-familial causes.
3. Tests do not save lives. There are several
   necessary steps between genetic susceptibility
   testing and cancer prevention or control.

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From Brca1/2 Testing To PreventionOf Breast
Cancer Intervening Steps
Primary prevention
Women with a familyhistory of breast and/or
ovarian cancer
Change reproductive plans - PND abortion -
dont have children
Decreased incidence of breast cancer
Mutation carriers
BRCA1/2 testing
Secondary prevention
Screening/risk reduction - intensive
surveillance - prophylactic mastectomy -
chemoprevention - diet/exercise
???
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Assumptions Underlying The Link Between Genetic
Testing And Disease Prevention

• Inherited forms of the disease/trait are common
• Most at-risk people will undergo testing
• The test will detect a mutation in most people
  who are eligible for testing
• People who have a mutation will alter their
  screening or risk reduction behaviors
• Risk reduction efforts will be effective

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• These assumptions are reinforced by misleading or
  incorrect communication either by the mass
  media or by health care providers - about various
  uncertainties associated with testing

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Uncertainties Associated with Genetic
Susceptibility to Complex Diseases/Traits

• How likely is it that having an inherited
  susceptibility mutation will result in the
  development of the disease/trait?
• How likely is it that the test will identify an
  inherited susceptibility mutation if one exists?

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Morally Relevant Considerations in Genetic Testing

• Clinical validity of results
• Clinical utility of results - Availability of
  effective interventions
• Collateral (social and psychological) implications

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Clinical Validity of the Test

• Sensitivity probability that the test will be
  positive in people with the disease
• Specificity probability that the test will be
  negative in people without the disease
• Positive Predictive Value probability that
  people with positive test results will get the
  disease

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Clinical Utility of Results Availability/Efficac
y of Interventions

• Do interventions exist?
• If so, how effective are they?
• If effective, how available/accessible are they?
• How good are the data about the
  availability/efficacy of interventions

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Collateral Implications

• Potential for psychological distress
• Implications for reproductive decisions
• Implications for life planning decisions
• Implications for other family members
• Relationships with other family members
• Misattributed parentage
• Potential for employment/insurance problems
• Implications for other conditions in the proband
  (pleiotropy)

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Morally Relevant Characteristics of Different
Types of Genetic Tests
HD
Penetrance of mutation(s)? 100 Clinical
Validity of test? High Is there an
effective preventive intervention? No
Variable prevalence of genotype?
No Pleiotropy No

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Facts About Inherited Susceptibility to Breast
Cancer

• 5-10 of breast cancer is due to inherited
  mutations on BRCA1/2 genes
• Inherited form is usually
• early onset
• present in several family members
• associated with ovarian cancer

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Facts About Inherited Susceptibility to Breast
Cancer

• Women from families with a mutation, who
  themselves have the mutation, have a 50-85
  lifetime risk of developing breast cancer
• Women from families with a mutation, who
  themselves do not have a mutation, have the same
  lifetime risk (1/9) as women in the general
  population
• Risk-reducing interventions exist but are not
  perfect, are expensive and have risks of their
  own
• prophylactic surgery (mastectomy or oophorectomy)
• chemoprevention (e.g., tamoxifen)

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Facts About Smoking Behavior (in the U.S.)

• Smoking is the leading cause of preventable death
• Most adult smokers begin smoking before the age
  of 18
• 2/3 of adolescents engage in smoking behaviors a
  substantial proportion exhibit symptoms of
  nicotine addiction
• Efforts to prevent smoking, or to help
  adolescents quit, have met with limited success

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Facts About the Science of Genetics and Smoking

• Genes in the serotonin pathway linked to
• the likelihood of smoking initiation
• the age at which smoking begins
• Genes in the dopamine reward pathway - linked to
  the ability to quit, including nicotine addiction
• Genetic variants interact with psychological and
  social factors
• Pleiotropy the same genes are implicated in
• other addictions (cocaine, alcohol)
• many behavioral/psychiatric conditions
• There may be racial/ethnic variation in the
  frequencies of relevant variants/polymorphisms

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Morally Relevant Characteristics of Different
Types of Genetic Tests
Cancer Susceptibility
Smoking-Related Behaviors
HD
Penetrance of mutation(s)? 100
50-85 Very low Clinical Validity of
test? High Moderate Low
Is there an effective No Not
perfect Exists but preventive intervention?
and risky ?
efficacy Variable prevalence No
Higher in Higher in of genotype?
Ashkenazi?
African-Amer? Pleiotropy No
Yes Yes
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Ethical Question

• Should there be population-based genetic
  screening for susceptibility to
• Breast cancer
• Smoking-related behaviors

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Ethical Considerations in Genetic Screening

• Availability of accurate genetic tests
• Whether an at-risk population can be determined
  for targeted screening
• Whether screening should be mandatory or
  voluntary
• Who has access to the screening program
• Whether there exists an effective and affordable
  treatment for the condition
• Whether the public is willing to accept the
  screening program
• Hodge JG. Ethical issues concerning genetic
  testing and screening in public health. AJMG
  2004125C66-70.

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Ethical Question

• Should certain subgroups of the population be
  targeted for screening?
• e.g. screening adolescents and young adults for
  enrollment in targeted smoking prevention and
  cessation programs

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Potential Risks

• Genetic information about susceptibility to
  substance abuse and psychiatric disorders may be
  far more stigmatizing to individuals than
  information about susceptibility to smoking
• Labeling people (particularly adolescents and
  young adults) as being at-risk for addiction or
  for health consequences of smoking may be
  particularly damaging to their self-image and
  perceived ability to shape their future.
• Create a false sense of security among those who
  are told that their genotype is associated with
  reduced likelihood of addiction or adverse health
  outcome if they smoke

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Ethical Questions

• If susceptibility testing is only offered to
  at-risk families (i.e., those in which a mutation
  or risk-conferring polymorphism has already been
  identified)
• Should children and adolescents be tested?
• Should physicians notify at-risk family members
  about a mutation in the family?