Santayana’s Lament: Ethical Issues in Genetic Screening

1. Santayana’s 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 • 1:10,000 births • Profound MR • PA -------> 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) --> MR • Diet --> 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 --> trials, IRB review, consent • Mandatory programs hard to stop • Zeal clouds critical thinking • AAP 1965

10. 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

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 (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”

14. Screening/counseling:Sickle 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 --> 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 --> • 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 • Can’t screen for all • 10-20 Most common = 90% sensitivity • “Limbo” couples • +/- or -/+ • 1:70 = 28,000/year

23. 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

24. 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

25. 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

26. 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

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 > 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