Santayanas Lament: Ethical Issues in Genetic Screening

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Santayanas Lament Ethical Issues in Genetic
Screening
Norman Fost MD MPH
Professor, Pediatrics and Bioethics, University
of Wisconsin
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Those who do not study history are doomed to
repeat it. George Santayana
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In genetics, even those who study history are
doomed to repeat it. Norman Fost
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Purposes of genetic screening

• Treatment (PKU)
• Counseling (SCD, TSD)
• Research (XYY)
• Forensics (Paternity, Crime)
• Exclusion (Insurance, employment)

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Screening for Rx The PKU Story

• 110,000 births
• Profound MR
• PA -------gt good stuff

PKU
Bad stuff
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PKU story

• Dx inefficient, late
• Diet expensive, unpalatable
• 1960
• Guthrie test cheap, simple, sensitive
• Lofenalac
• JFK
• PKU lobby mandatory newborn screening

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PKU story

• Assumptions of PKU program
• Positive test (confirmed) --gt MR
• Diet --gt reduce severity of MR
• Problems with PKU program
• 95 false positive (normal children)
• Dietary restriction as harmful as excess

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PKU story

• Consequences of false assumptions
• False impression that diet was working
• Harm to normal children/mild variants
• Mental retardation
• Harm to PKU children
• Malnutrition ? kwashiorkor
• Excessive restriction ? retardation
• 10 year delay in understanding
• 1973 NAS-NRC Committee

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Lessons from the PKU story

• Genetic disorders are heterogeneous
• Screening/rx programs are experiments --gt trials,
  IRB review, consent
• Mandatory programs hard to stop
• Zeal clouds critical thinking
• AAP 1965

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Screening/rx examples

• Prematures with RDS/HMD --gt acidosis --gt death
• Usher regimen screen for acidosis ---gt treat
  with bicarbonate
• Odell Makes no sense makes rats worse
• Simmons Placebo controlled RCT (unethical) --gt
  rx harmful --gt stopped everywhere

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Screening/rx examples

• Prematures screened for low oxygen
• Rx with high oxygen
• Patz
• severe damage to retina
• dose response curve

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Screening for Rx

• Genome project has identified 1000 genes
  associated with disease
• Gene therapy still more hope than reality
• Molecular defect in sickle disease was discovered
  in 1945
• ACMG 2005 Add 54 newborn tests
• 25 No defined disease or rx
• 24 Test accuracy unknown or rx unproven
• UK Added 1 disease (MCAD)

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Newborn screening MBADD

• Severe MR, FTT, seizures
• 2004 8 cases, 1/8 normal
• 2001-2005 (Wisc) 23 cases
• All of Hmong descent (1208 births)
• 22/23 normal 1 speech delay
• Rx Low protein diet, carnitine
• Compliance poor
• All children labelled with life-threatening
  illness ? ? vulnerable child syndrome

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Screening/counselingSickle Cell Disease (SCD)

• Severe anemia, painful crises, strokes, early
  death
• Autosomal recessive
• 8 African Americans carriers
• No effective treatment

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Options for sickle carrier

• No children
• Adopt
• ART (AID, egg donation, surrogacy)
• Illegitimacy
• Prenatal dx --gt selective abortion
• Informed gamble
• Others of little interest/unavailable

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Problems with sickle screening

• Confusion
• Self
• 20 irrational reproductive decisions
• Washington DC Greece
• Others
• Dupont Corp
• 12 life insurance companies
• Massachusetts public schools
• Defense Department

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Problems with sickle screening

• Stigmatization Unwanted psychosocial effects
• Self
• Wash DC telethon
• Others
• Life, disability insurance

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Lessons from the sickle story

• Genetic labels can have serious psychosocial
  effects
• Difficult to prevent
• Screening programs are experiments with unknown
  benefits and risks
• Reproductive decisions are personal ? high
  standards for consent

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Lessons from the sickle story

• Education/counseling before testing
• Mispaternity surprises
• Public unprepared for genetic information
• Probability not taught in schools
• Medicine/politics inseparable
• R Nixon hugging Sammy Davis Jr
• Black Panthers promotions

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Other counseling programs

• Successful
• Tay Sachs Disease (US)
• Highly educated population
• Preceded by educational programs
• Uniformly dread disease
• Community involvement
• Thalassemia (Greece, Sicily)
• Supported by church

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The cystic fibrosis story

• Most common lethal genetic disorder in North
  America
• Sticky mucus --gt
• pancreatic obstruction
• lung infections
• Median age of death 31 years
• Gene discovered 1989
• 1997 NIH recommends carrier screening

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Cystic fibrosis

• The Gene
• 1,000 mutations
• Cant screen for all
• 10-20 Most common 90 sensitivity
• Limbo couples
• /- or -/
• 170 28,000/year

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CF story

• What is cystic fibrosis?
• 75 public knows little/nothing
• Obstetricians not experienced
• Normal IQ, life expectancy 30--gt50
• Time for education/counseling1 hr
• Time for office visit 5 minutes
• Insurance reimbursement low-0

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CF story

• Genetic counselors
• ca 2000 in US
• each spend 50 weeks on CF
• If 15 minutes --gt 13 weeks
• NIH, IOM, ACOG --gt High standards for informed
  consent
• 5T story

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5T Story

• Present in 120 normal population
• Only ? CF if paired with rare mutation (R117H)
• 40-200 amnios based on 5T alone
• Quest Labs 41/250 samples 5T alone
• Uncertain number of abortions

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Screening for reproduction

• 1000 tests
• BRCA1 --gt prophylactic mastectomy?
• Huntingtons Disease
• Alzheimers disease
• Li Fraumeni syndrome --gt 30 risk of cancer by
  age 30
• 1,000 genome ? 100 genome

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Alternatives

• Dispense with informed consent
• Generic consent
• Non-human education/counseling
• Pamphlets
• Interactive computer programs
• BRCA1 testing
• Computer skilled counselor

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XYY Story Screening for Research

• XYY more common in prisoners
• Publicized killers (Richard Speck)
• Male chromosome ? aggression
• Legal implications
• Defense excused crime
• Prosecution predicts dangerousness
• Walzer Prospective study (1968)
• Existing newborn blood spots
• Screening without consent

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Walzer XYY study

• Confusion
• My son is not a Mongol
• Stigmatization
• Pygmalion effect
• In the classroom
• In Walzer study
• Study stopped in 5 yrs under pressure
• Familiar features
• No IRB review no consent adverse effects not
  anticipated

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Conclusions

• Genetic news different from other medical news
• Number new tests unprecedented
• Testing proliferating gt treatment
• Affects others besides patient
• Whether to be tested is a value judgment, for
  patient to decide

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Conclusions

• Screening programs are experiments, with
  uncertain benefits and risks, until measured in
  well designed studies
• Studies need not be randomized controlled
  trials
• Mandatory registries minimum