Transcript Santayanas Lament Fost

Santayana’s Lament: Ethical
Issues in Genetic Screening
Norman Fost MD MPH
Professor, Pediatrics and Bioethics,
University of Wisconsin
Treuman Katz Center for Pediatric Bioethics - 2008 Conference
“Those who do not study history
are doomed to repeat it.”
George Santayana
Treuman Katz Center for Pediatric Bioethics - 2008 Conference
“In genetics, even those who
study history are doomed to
repeat it.”
Norman Fost
Treuman Katz Center for Pediatric Bioethics - 2008 Conference
Purposes of genetic screening
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Treatment (PKU)
Counseling (SCD, TSD)
Research (XYY)
Forensics (Paternity, Crime)
Exclusion (Insurance, employment)
Treuman Katz Center for Pediatric Bioethics - 2008 Conference
Screening for Rx: The PKU Story
• 1:10,000 births
• Profound MR
• PA -------> good stuff
PKU
Bad stuff
Treuman Katz Center for Pediatric Bioethics - 2008 Conference
PKU story
• Dx inefficient, late
• Diet expensive, unpalatable
• 1960
– Guthrie test: cheap, simple, sensitive
– Lofenalac
– JFK
• PKU lobby: mandatory newborn
screening
Treuman Katz Center for Pediatric Bioethics - 2008 Conference
PKU story
• Assumptions of PKU program
– Positive test (confirmed) --> MR
– Diet --> 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 --> 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 -->
acidosis --> death
• Usher regimen: screen for acidosis --> treat with bicarbonate
• Odell: Makes no sense; makes rats
worse
• Simmons: Placebo controlled RCT
(“unethical”) --> rx harmful -->
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 (1:208 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/counseling:Sickle 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
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No children
Adopt
ART (AID, egg donation, surrogacy)
Illegitimacy
Prenatal dx --> 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:
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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
Treuman Katz Center for Pediatric Bioethics - 2008 Conference
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
Treuman Katz Center for Pediatric Bioethics - 2008 Conference
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)
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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 -->
– 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
– Can’t screen for all
– 10-20 Most common = 90% sensitivity
• “Limbo” couples
– +/- or -/+
– 1:70 = 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-->50
• Time for education/counseling:1 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 --> 13 weeks
• NIH, IOM, ACOG --> High standards
for informed consent
• 5T story
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5T Story
• Present in 1:20 normal population
• Only  CF if paired with rare
mutation (R117H)
• 40-200 amnio’s 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 --> prophylactic mastectomy?
– Huntington’s Disease
– Alzheimer’s disease
– Li Fraumeni syndrome --> 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 > 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
Treuman Katz Center for Pediatric Bioethics - 2008 Conference