Personalized Medicine in the Era of Genomics

1. Personalized Medicine in the Era of Genomics Wylie Burke MD PhD Department of Medical History and Ethics Center for Genomics and Healthcare Equality University of Washington

2. Personalized medicineOne view The right treatment, for the right patient, at the right time

3. Personalized medicineAnother view • Attending to the whole person, in context of personal & medical history and life circumstances Safran 2003 Ann Intern Med 138:248 • “Working alliance” of doctor & patient • Agreement on goals of treatment • Collaboration • Liking and trust Fuertes et al 2006 Pat Ed Counsel 66:29

4. Newborn screening for PKU Screen for newborn for elevated phenylanaine  Identify affected newborns  Diet to prevent mental retardation

5. Personalized care for children with PKU • Cost of diet • Social barriers to maintaining diet • Child’s commitment to lifetime diet

6. Pathways from genetic research to clinical benefit Research on genetics & disease Testing to diagnose or identify risk Improved disease classification Innovative therapy

7. Medullary thyroid cancer & RET mutation testing:Multiple Endocrine Neoplasia 2 (MEN2) Medullary thyroid cancer Medullary thyroid cancer, RET mutation + If RET +, offer prophylactic thyroidectomy

8. Predicting toxicity from chemotherapyRetrospective analysis of clinical trial data %withtoxicity in children with leukemia JNCI 1999; 91: 2001 Thiopurinemethyltransferase (TPMT) activity

9. Pathway from test to benefit Test ACTION Health benefit + Result

10. Spectrum of genetic contribution to disease Genes and Environment Mostly Environment Mostly Genetic Cystic fibrosis Diabetes Asthma Chicken pox

11. Low relative risk (most <2.0) Polygenic Often account for only a small percentage of disease cases Gene variants associated with common complex diseases

12. Multiple contributors to asthma GeneticsEnvironment -beta-adrenergic -mites receptor -cockroaches, -GSTM1, GSTT1 -pollens -IL-4, IL-4RA, IL-13 -animal danders, -TNF-alpha -cigarette smoke, -30-50 others -diesel fuel Asthma

13. Can genetic test results provide a threshold for clinical intervention? Genetic test ACTION Improved outcome + USUAL CARE No reduction in outcome - or NO ACTION

14. Estimate of lifetime diabetes risk Based on presence/absence of disease-associated mutation % Janssens & Khoury, It J Pub Health 2005; 3:35-41

15. Risk of age-related macular degeneration • Effect of population variation in 3 genes 1% have > 50% risk of AMD MOST have risk close to average • Nat Genet 2006; 38:1055-9

16. Data gaps Often not known: • Whether testing leads to improved health outcome • Whether testing influences management decisions • Whether testing is associated with direct or indirect harms

17. Policy questions if benefit is present • Does the benefit outweigh potential harms? • Who participates in decisions about appropriate use? • How is equitable access assured?

18. Guiding principle (After Osler) “More important to know the patient who has the genotype than the genotype that has the patient”