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Santayanas Lament: Ethical Issues in Genetic Screening

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Simmons: Placebo controlled RCT ('unethical') -- rx harmful -- stopped everywhere ... Gene therapy still more hope than reality ... – PowerPoint PPT presentation

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Title: Santayanas Lament: Ethical Issues in Genetic Screening


1
Santayanas Lament Ethical Issues in Genetic
Screening
Norman Fost MD MPH
Professor, Pediatrics and Bioethics, University
of Wisconsin
2
Those who do not study history are doomed to
repeat it. George Santayana
3
In genetics, even those who study history are
doomed to repeat it. Norman Fost
4
Purposes of genetic screening
  • Treatment (PKU)
  • Counseling (SCD, TSD)
  • Research (XYY)
  • Forensics (Paternity, Crime)
  • Exclusion (Insurance, employment)

5
Screening for Rx The PKU Story
  • 110,000 births
  • Profound MR
  • PA -------gt good stuff

PKU
Bad stuff
6
PKU story
  • Dx inefficient, late
  • Diet expensive, unpalatable
  • 1960
  • Guthrie test cheap, simple, sensitive
  • Lofenalac
  • JFK
  • PKU lobby mandatory newborn screening

7
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

8
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

9
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

10
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

11
Screening/rx examples
  • Prematures screened for low oxygen
  • Rx with high oxygen
  • Patz
  • severe damage to retina
  • dose response curve

12
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)

13
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

14
Screening/counselingSickle Cell Disease (SCD)
  • Severe anemia, painful crises, strokes, early
    death
  • Autosomal recessive
  • 8 African Americans carriers
  • No effective treatment

15
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

16
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

17
Problems with sickle screening
  • Stigmatization Unwanted psychosocial effects
  • Self
  • Wash DC telethon
  • Others
  • Life, disability insurance

18
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

19
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

20
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

21
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

22
Cystic fibrosis
  • The Gene
  • 1,000 mutations
  • Cant screen for all
  • 10-20 Most common 90 sensitivity
  • Limbo couples
  • /- or -/
  • 170 28,000/year

23
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

24
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

25
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

26
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

27
Alternatives
  • Dispense with informed consent
  • Generic consent
  • Non-human education/counseling
  • Pamphlets
  • Interactive computer programs
  • BRCA1 testing
  • Computer skilled counselor

28
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

29
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

30
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

31
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
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