Ethical Issues in Personalized Medicine

1
Ethical Issues in Personalized Medicine

• Jeffrey R. Botkin, M.D., M.P.H.
• Professor of Pediatrics and Medical Ethics
• Associate Vice President for Research

2
The Human Genome
February, 2001
3
Consequences of Human Genome Project

• Technology available for detailed sequencing
• Normal and abnormal sequence information
  available
• Proliferation of genetic tests for DNA sequences
  associated with clinical conditions
• Testing available before effective treatments or
  prevention available

4
ELSI Issues in Genetic Halfway Technologies

• Challenges for genetic tests
• Genome research many new tests
• 1715 diseases for which there are tests
• 1435 clinical tests
• 280 research tests
• Limited FDA oversight
• Rapid transition from bench to bedside
• Direct marketing of recreational genetic tests
• Public/professional confidence in benefits of
  medical technology

5
Ethics and Genetics

• 1990 Dr. James Watson announces that 3 - 5 of
  new human genome project budget will be devoted
  to ethical, legal, and social implications
• ELSI Program
• Why this allocation in genetics research?

6
Why the public concern over genetic technology?
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Genetic Concepts

• Genetic determinism
• The notion that our genes determine our biology
  and behavior
• Generally false even for Mendelian conditions
• Genetic exceptionalism
• The notion that genetic knowledge is different
  than other forms of knowledge in biology and
  medicine
• Differences Family relationships, a history of
  abuse, beliefs in genetic determinism (genes as
  the blueprint)

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Lewis Thomas, M.D.

• The Technologies of Medicine
• Non-technologies
• Decisive technologies or high technologies
• Immunizations
• Halfway technologies
• Dialysis
• Human Genetics?

(1913-1993)
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High Technology Power?

• Gene therapy
• Somatic
• Germline
• Designer babies
• Reproductive cloning
• Tissue engineering
• Personalized medicine

Chris Blair
10
Single Gene vs Complex Diseases

• Successful identification of genes associated
  with Mendelian disorders
• Diagnostic testing
• Predictive testing
• Carrier testing
• Prenatal diagnosis
• Limited success with identifying major genes
  associated with complex conditions

11
Genetic Determinants of Obesity

• Researchers Discover New Genetic Risk Factors
  Involved in Adult and Childhood Obesity
• Comprehensive Study Uncovers Six Genetic Variants
  Associated With Body Mass Index

http//www.genome.gov/27529231 December 2008
12
Obesity Study

• 32,000 individuals of European ancestry
• 15 genome wide association studies identified
  and analyzed
• 35 genetic variants identified that are
  associated with BMI
• Results
• The 1 of the population with the most
  obesity-causing variants estimated to be 10 lbs
  heavier than the 1 with the least number of
  variants

13
Common, Complex Conditions

• To date, limited progress on identifying single
  genes or small gene sets that are strongly
  associated with common, important health
  conditions
• Genetic tests may not provide valuable
  predictive information for these conditions
• Genetics may provide better understanding of
  pathophysiology and therapeutic targets

14
Systems Biology

• Institute for Systems Biology, Seattle
  Washington
• Systems biology is the study of an organism,
  viewed as an integrated and interacting network
  of genes, proteins and biochemical reactions
  which give rise to life.

http//www.systemsbiology.org
15
Social and Policy Issues

• Challenges will emerge from the complexity of
  individual technologies as applied in specific
  research, clinical, social, and public health
  contexts

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ELSI Issues in Genetic Non-technologies

• Information management -- Social and Policy
  Issues
• Education and standards for MDs
• Genetic counselors
• Implications for family members
• Responsibilities of physicians/counselors
• in clinical care
• Responsibilities of investigators in research
• Privacy of genetic information

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Evaluation of Genetic Tests

• ACCE Framework
• Analytic validity
• Does the test detect what it is designed to
  detect?
• Analytic sensitivity and specificity
• False positives and false negatives
• Clinical Validity
• Does the test correctly identify those with the
  condition and those without the condition?
• False positive and false negatives
• Clinical Utility
• Does screening/testing for the condition improve
  the outcome for the individual?
• ELSI considerations
• EGAPP initiative (CDC)

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Validity/Utility
From Burke et al. AJMG 2001106233
Clinical Utility
Yes
No
MEN2
HD
Clinical Validity
High
HFE
ApoE
Low
MEN2 multiple endocrine neoplasia type 2 HD
Huntington disease HFE hereditary
hemochromatosis ApoE apoliproprotein alleles to
predict Alzheimer
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Research Challenges

• Development of research protocols to demonstrate
  the clinical validity and clinical utility of
  genetic tests
• Requires an assessment of the impact of
  information on behavior and secondary impacts on
  morbidity and mortality
• Questions about whether information per se, or
  non-patient impacts, have sufficient value to
  justify testing or screening
• Newborn screening context

20
ELSI Concerns over Predictive Testing

• Concerns over negative psychological impacts
  from genetic testing have not been borne out in
  research to date
• Individual situations may justify concern
• Individuals generally use genetic information in
  appropriate ways
• The risk of insurance and employment
  discrimination is low
• Fears over risks are a significant barrier to
  use of genetic tests

21
Insurance Discrimination

• Long-standing concern of policy makers that
  predictive genetic testing will lead to insurance
  discrimination
• The single most consistent concern expressed by
  those declining genetic testing
• Health insurance a primary concern
• Life and disability insurance also a concern
• Isolated instances of insurance and employment
  discrimination

22
Insurance and Employment Discrimination

• Genetic Information Non-discrimination Act
  (GINA) passed in 2008
• Protects against use of genetic information in
  insurance and employment
• HIPAA had protected against group discrimination
• Federal employees protected
• Many state laws in place
• Efficacy of GINA remains to be demonstrated

23
Genetic information vs Privacy
Lin Z, et al. Science 2004305183
24
Re-Identification based on DNA sequence
information

• Sequences are not intrinsically identifiable
• Necessary to have a reference database that links
  sequence information to individual identifiers
• Re-identification only important if sequence
  information carries important health information
• Important health information must be revealed to
  someone who can use the information to harm the
  source individual

25
Group Discrimination/Stigma

• Concerns about impacts of genetic information on
  social groups
• Stigmatizing clinical conditions associated with
  defined social groups (Jewish mutations)
• Return to genetic explanations for social
  problems
• Poor mans pharmacogenomics presuming
  genotypes based on racial or ethnic background

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ELSI for Genetic Testing

• Genetics currently has limited power for the
  prevention and treatment of disease
• Likely to provide more contributions over time
  perhaps through a systems approach
• High value in better understanding basic biology
• Expanded use of poorly validated tests due to
  limited oversight
• Test validity and utility are serious concerns
• Group impacts from genetic research