personalized medicine in the era of genomics wylie burke md phd department of medical history and...
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Personalized Medicine in the Era of GenomicsPersonalized Medicine in the Era of Genomics
Wylie Burke MD PhDWylie 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 medicineOne view
Personalized medicineOne view
The right treatment, for the right patient, at the right time
The right treatment, for the right patient, at the right time
Personalized medicineAnother view
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
– 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 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
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
Pathways from genetic research to clinical benefit
Research
on genetics
& disease
Research
on genetics
& disease
Testing to diagnose or identify riskTesting to diagnose or identify risk
Innovative therapyInnovative therapy
Improved disease classificationImproved disease classification
Medullary thyroid cancer & RET mutation testing:
Multiple Endocrine Neoplasia 2 (MEN2)
Medullary thyroid cancer & RET mutation testing:
Multiple Endocrine Neoplasia 2 (MEN2)
Medullary thyroid cancerMedullary thyroid cancer
Medullary thyroid cancer, RET mutation +Medullary thyroid cancer, RET mutation +
If RET +, offer prophylactic thyroidectomyIf RET +, offer prophylactic thyroidectomy
Predicting toxicity from chemotherapy
Retrospective analysis of clinical trial data
Predicting toxicity from chemotherapy
Retrospective analysis of clinical trial data
020406080
100
Low High
JNCI 1999;91: 2001JNCI 1999;91: 2001
% with toxicity in children with leukemia% with toxicity in children with leukemia
Thiopurine methyltransferase (TPMT) activityThiopurine methyltransferase (TPMT) activity
Pathway from test to benefitPathway from test to benefit
Test Test Health benefitHealth benefit+ Result+ Result
ACTIONACTION
Spectrum of genetic contribution to diseaseSpectrum of genetic
contribution to disease
Mostly GeneticMostly Genetic
Genes and Environment Genes and
Environment Mostly
EnvironmentMostly
Environment
Cystic fibrosisCystic fibrosis
DiabetesAsthma
DiabetesAsthma
Chicken poxChicken pox
Gene variants associated with common complex diseases
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 asthmaMultiple 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, -30-50 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, -30-50 others -diesel fuel
Asthma
Can genetic test results provide a threshold for clinical intervention?Can genetic test results provide a threshold for clinical intervention?
Genetic test
USUAL CARE
ACTIONImproved outcome
No reduction in outcome
+
-or
NO ACTION
Estimate of lifetime diabetes risk Based on presence/absence
of disease-associated mutation
Estimate of lifetime diabetes risk Based on presence/absence
of disease-associated mutation
020406080
100
PPARG CAPN10 TCF7L2
No copy
1 copy
2 copies
Janssens & Khoury, It J Pub Health 2005; 3:35-41Janssens & Khoury, It J Pub Health 2005; 3:35-41
%
Risk of age-related macular degenerationEffect of population variation in 3 genes
Risk of age-related macular degenerationEffect 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 averageNat Genet 2006; 38:1055-9Nat Genet 2006; 38:1055-9
Data gapsData 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
Policy questions if benefit is present
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?