Treuman Katz Center for Pediatric Bioethics - 2008 Conference Santayana’s Lament: Ethical Issues...

Treuman Katz Center for Pediatric Bioethics - 2008 Conference

Santayana’s Lament: Ethical Issues in Genetic

Screening

Santayana’s Lament: Ethical Issues in Genetic

Screening

Norman Fost MD MPHNorman Fost MD MPHProfessor, Pediatrics and Bioethics, University of Wisconsin


“Those who do not study history are doomed to repeat it.”

George Santayana


“In genetics, even those who study history are doomed to repeat it.”

Norman Fost


Purposes of genetic screeningPurposes of genetic screening

• Treatment (PKU)

• Counseling (SCD, TSD)

• Research (XYY)

• Forensics (Paternity, Crime)

• Exclusion (Insurance, employment)

• Treatment (PKU)

• Counseling (SCD, TSD)

• Research (XYY)

• Forensics (Paternity, Crime)

• Exclusion (Insurance, employment)


Screening for Rx: The PKU StoryScreening for Rx: The PKU Story

• 1:10,000 births

• Profound MR

• PA -------> good stuff

• 1:10,000 births

• Profound MR

• PA -------> good stuff

PKU

Bad stuff


PKU storyPKU story• Dx inefficient, late

• Diet expensive, unpalatable

• 1960– Guthrie test: cheap, simple, sensitive– Lofenalac– JFK

• PKU lobby: mandatory newborn screening

• Dx inefficient, late

• Diet expensive, unpalatable

• 1960– Guthrie test: cheap, simple, sensitive– Lofenalac– JFK

• PKU lobby: mandatory newborn screening


PKU storyPKU 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

• 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


PKU storyPKU 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

• 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


Lessons from the PKU storyLessons 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

• Genetic disorders are heterogeneous

• Screening/rx programs are experiments --> trials, IRB review, consent

• Mandatory programs hard to stop

• Zeal clouds critical thinking– AAP 1965


Screening/rx: examplesScreening/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

• 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


Screening/rx examplesScreening/rx examples• Prematures screened for low oxygen

• Rx with high oxygen

• Patz– severe damage to retina– dose response curve

• Prematures screened for low oxygen

• Rx with high oxygen

• Patz– severe damage to retina– dose response curve


Screening for RxScreening 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)

• 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)


Newborn screening: MBADDNewborn 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”

• 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”


Screening/counseling:Sickle Cell Disease (SCD)

Screening/counseling:Sickle Cell Disease (SCD)

• Severe anemia, painful crises, strokes, early death

• Autosomal recessive

• 8% African Americans carriers

• No effective treatment

• Severe anemia, painful crises, strokes, early death

• Autosomal recessive

• 8% African Americans carriers

• No effective treatment


Options for sickle carrierOptions for sickle carrier• No children

• Adopt

• ART (AID, egg donation, surrogacy)

• Illegitimacy

• Prenatal dx --> selective abortion

• Informed gamble– Others of little interest/unavailable

• No children

• Adopt

• ART (AID, egg donation, surrogacy)

• Illegitimacy

• Prenatal dx --> selective abortion

• Informed gamble– Others of little interest/unavailable


Problems with sickle screening 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

• Confusion– Self

• 20% irrational reproductive decisions– Washington DC; Greece

– Others: • Dupont Corp• 12% life insurance companies• Massachusetts public schools• Defense Department


Problems with sickle screeningProblems with sickle screening

• Stigmatization: Unwanted psychosocial effects– Self

• Wash DC telethon

– Others• Life, disability insurance

• Stigmatization: Unwanted psychosocial effects– Self

• Wash DC telethon

– Others• Life, disability insurance


Lessons from the sickle storyLessons 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

• 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


Lessons from the sickle storyLessons 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”

• 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”


Other counseling programsOther 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

• Successful– Tay Sachs Disease (US)

• Highly educated population• Preceded by educational programs• Uniformly dread disease• Community involvement

– Thalassemia (Greece, Sicily)• Supported by church


The cystic fibrosis storyThe 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

• 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


Cystic fibrosis 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

• “The Gene”– 1,000+ mutations– Can’t screen for all– 10-20 Most common = 90% sensitivity

• “Limbo” couples– +/- or -/+ – 1:70 = 28,000/year


• 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

• 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

CF storyCF story


CF storyCF 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

• 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


5T Story5T 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

• 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


Screening for reproductionScreening 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

• 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


AlternativesAlternatives• Dispense with informed consent

– Generic consent

• Non-human education/counseling– Pamphlets– Interactive computer programs

• BRCA1 testing– Computer ~= skilled counselor

• Dispense with informed consent– Generic consent

• Non-human education/counseling– Pamphlets– Interactive computer programs

• BRCA1 testing– Computer ~= skilled counselor


XYY Story: Screening for Research

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

• 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


Walzer XYY studyWalzer 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

• 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


ConclusionsConclusions• 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

• 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


ConclusionsConclusions• 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

• 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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