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 Department of Medical History and Ethics Center for Genomics and Healthcare Equality University of Washington

Personalized medicine One view The right treatment, for the right patient, at the right time The right treatment, for the right patient, at the right time

Personalized medicine Another 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 –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

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

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

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

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

Predicting toxicity from chemotherapy Retrospective analysis of clinical trial data JNCI 1999; 91: 2001 JNCI 1999; 91: 2001 % with toxicity in children with leukemia Thiopurine methyltransferase (TPMT) activity

Pathway from test to benefit Test Health benefit + Result ACTION

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

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

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

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

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

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

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 Often not known: –Whether testing leads to improved health outcome –Whether testing influences management decisions –Whether testing is associated with direct or indirect harms

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

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