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Novel Methods to Test Precision(Personalized)
Medicine
CCC Forum 2015
Gordon R. Bernard MDVanderbilt University Medical Center
Nashville, TN
Organizing framework
PersonalizedPrevention
Personalized Diagnostics
Personalized Treatment
Risk prediction
preventative measures
Screening, early
detection, accurate
diagnoses
Therapy, monitoring,
pain management, life
plan, palliative care
<- Personalized Plan of Care ->
SNP Pharmacogenetics
Sequencing/dz susceptibility
Concurrent drugs, Comorbidities
psychosocial factors
Allergies
Much else
Evolutionary Plan
We are ~here
Social/family hx
It’s time to move forward
• Health System Formularies (BCBS, VUMC)• Clinical Practice Committee, P&T Committee • Advanced Informatics with decision support and
analytics:– StarPanel– VOOM with outpt decision support– HEO with inpt decision support– RxStar with decision support– MyhealthatVanderbilt
• Meaningful use improvements• Leadership unity and national thought leaders
Hand
washingFlu
vaccination
for all
healthcare
workers
Quality ImprovementTranslational SpaceClinical testingDiscovery
Clinical practice
Equipoise
Early concept of benefit:
but not sure when, for
whom, how, outcome
measures, or potential
risks.
Benefits
established,
learn how to
best
implement
Active Projects
Risk of: readmission
pressure ulcersChlorhexidine baths
N.S. vs. L.R.
Create Reusable Infrastructure
Ethics, regulatory and community
Biomedical informatics and IT infrastructure
Pharmacogenomics and clinical relevance
(evidence synthesis and review)
Clinical outcomes and health economics
Implementation/logistics/operations
Provider and patient communication
and education
PREDICT – Vanderbilt’s initial clinical foray into personalized medicine – prospective genotyping
MyCancerGenome – personalized cancer dx, treatment and clinical trials
Vanderbilt Institute for Clinical and Translational Research (VICTR)
Translational Space between research and clinical operations
National Problem
• 5.3% of hospital admissions due to adverse drug reactions
• Adverse drug reactions are 4th-6th leading cause of mortality in the US
• Over 200 drug labels now suggest pharmacogenomic testing to guide therapy – and the FDA has mandated testing for 4 of these (3 are cancer drugs)
Personalized Medicine 8:421, 2011
PREDICT Prognostic Model
• Implemented January 2012
• Predicts probability of patient receiving clopidogrel, a statin, or warfarin within three years based on information contained within a patient’s EMR:• Demographics
• Weight or BMI (where height is available)
• Hypertension
• Diabetes
• Coronary artery disease
• Atherosclerosis
• Congestive heart failure
• Atrial fibrillation
• Dialysis
• Previous clot
Schildcrout et al, CPT 2012
A Case for Prospective Genotyping
52,942 Vanderbilt “Medical Home” patients followed for up to 5 years….
How many patients received drug(s) that have
a recognized pharmacogenetic story? 1786
930
1454
2067
2870
3883
5244
6833
8247
9525
0 5000 10000
10+
9
8
7
6
5
4
3
2
1
Number of PatientsN
um
be
r o
f P
Gx
Me
ds
65% received ≥1 med within 5 years
Estimated number of severe adverse events mitigated : 383
Schildcrout et al, CPT 2012
• The PREDICT panel tests 184 SNPs within 34 genes known to impact drug therapy.
• Clopidogrel, simvastatin, warfarin, tacrolimus, and thiopurine gene results are currently available in StarPanel
• Other drug-genome interactions (DGIs) will be added with no need to retest these patients
• Of 14,134 VUMC patients genotyped through PREDICT to date:
– 3,110 (22%) are at risk for reduced antiplatelet effect of clopidogrel
– 3,616 (26%) are at risk for simvastatin-induced myopathy
– 9,748 (69%) would benefit from genotype-guided tailoring of initial warfarin dose
PREDICT: Pharmacogenomic Testing to Tailor Drug Therapy
PREDICT implementation requires coordination across multiple domains
In press, Peterson et al., Genetics in Medicine 2013
Pre-Implementation Scientific Review
• Significant association between risk allele and adverse clinical event • Strength of evidence for drug-gene interaction• National guidelines from professional societies, FDA, etc.• Patients identifiable before they receive the drug• Alternative therapy or alternate strategy available• Internal validation of established DGI association (if possible)
• Assessment of genotype data as high quality in CLIA lab• High prevalence of drug utilization (≥3% of VUMC population)
Discovery:Preliminary genetic
associations
Replication:Replicate significant
associations
Clinical Implementation:Implement genetic testing via PREDICT
pipeline
BioVU Study:Identify subjects, phenotype and
genotype
State of the Evidence: 2013
* Scott et al. Clinical PharmacogeneticsImplementation Consortium Guidelines for CYP2C19 Genotype and Clopidogrel Therapy: 2013 Update
• 10 Meta-analyses summarizing hundreds of articles with primary data
– 6 report an impact on MACE: Major Adverse Coronary Events
– 4 report no significant impact
• Most recent systematic review:
Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines 2013 Update*
Clopidogrel - CYP2C19 “Loss of function” variants
PREDICT Informatics Architecture
In press, Peterson et al., Genetics in Medicine 2013
CYPC19 Genotype
*1/*1
*X = CYP2C19 Loss of Function Variant in set {*2, *3, *4, *5, *6, *7, *8}*17 = CYP219 Gain of Function Variant
Intermediate metabolizer*1/*X
Poor metabolizer*X/*X
Normal (Extensive) metabolizer
Uncharacterized genotype
PREDICT: Phenotype Assignment Algorithm
CYP2C19 - Clopidogrel
*1/*17
*17/*17
*X/*17Indeterminate
Drug Metabolism Phenotype
Other
Rapid metabolizer
PREDICT: Therapeutic Alternative Algorithm
Age > 75 years
Weight < 60 kg
History strokeor TIA
Prasugrel(10mg daily)
OrTicagrelor
(90 mg 2x daily)Or
Clopidogrel(150 mg daily)*Poor or
Intermediatemetabolizer?
Standard Prescribing Process
None
Normal, Rapid, Indeterminate or Uncharacterized
metabolizer?
CYP2C19 - Clopidogrel
Ticagrelor(90 mg 2x daily)
Severe Liver Disease
* Discontinued as Therapeutic Option
Intracranial Bleed
Contraindications
No liver or active
bleeding
Continue ClopidogrelOtherwise
PREDICT: Prognostic ModelIdentifying Candidates in the EHR
(1)
(2)
Drug-GenomeInteractionw/patient-
Friendly text
Validation of Clopidogrel-CYP2C19 Interaction in BioVU
Delaney, JT Clin Pharmacol Ther 2012 91:257
VUMC validation: 96% of cases are post-PCI
Normal Metabolizer
Poor or Intermediate Metabolizer
Ware et al CHEST 2010; 137(2):288–296
Clinical Markers:
• Age
• Etiology
• APACHE III
• Pplat
• No. organ failures
• A-a gradient
Biomarkers:
• ICAM
• IL-6
• IL-8
• TNFR
• Protein C
• PAI-1
• SP-D
• VWF
Full AUC 0.85
Biomarkers AUC 0.76
Clinical AUC 0.82
Reduced AUC 0.83
Predicted Probability of Death
Pro
port
ion
Dead
AUC Calculations for Various ModelsWare et al CHEST 2010; 137(2):288–296
Optimizing pain management in the ICU
“Pain management was the key issue in each patient’s lived experience.”
Words used to describe the experience of being intubated:
Clukey L et al. Discovery of unexpected pain in intubated and sedated patients.
Am J Crit Care. 2014 May;23(3):216-20..
PREDICT: CYP2D6 and pain management
(e.g., respiratory depression, changes in consciousness)
Subramanyam R1 et al. Future of pediatric tonsillectomy and perioperative outcomes.
Int J Pediatr Otorhinolaryngol. 2013 Feb;77(2):194-9.
Cumulative Oxycodone Consumption by PCA in Postoperative Patients
Stamer UM, Zhang L, Book M, Lehmann LE, Stuber F, et al. (2013) CYP2D6 Genotype Dependent Oxycodone Metabolism in Postoperative Patients. PLoS ONE 8(3): e60239.
Are we underestimating pain management needs in CYP2D6 PMs?
Plasma Concentrations of oxymorphone following initial dose
A 2013 study of 121 post-operative patients given oxycodone 0.05 mg/kg before emerging from anesthesia and patient-controlled analgesia (PCA) for the subsequent 48 postoperative hours suggests that CYP2D6 PMs require higher oxycodone doses for adequate analgesia.
My Cancer Genome
Mia Levy, MD, PhD
William Pao, MDVanderbilt University Medical Center
Mission of My Cancer Genome
To curate and disseminate knowledgeregarding the clinical significance ofgenomic alterations in cancer
Worldwide Collaboration
• 65 Contributors• 21 Institutions • 10 Countries
21 Cancers
56 Genes
428 Disease-Gene-Variant
Relationships
Clinical Trial Search
>40K Cancer Trials (PDQ)
150 Cancer Diagnoses
600+ Cancer Genes
500 Cancer drugs
>8,000 site visits per
week worldwide; visitors
from 186 countries
Personalized Lay LanguageHealth Profile
WEB: Full
Detail (MHAV)
Thank You!
PREDICT Results in Patient Web PortalMy Health at Vanderbilt
Drug-Genome Interaction w/patient-
friendly text
PREDICT Infrastructure
*Operational implementation of prospective genotyping for personalized medicine: the design of the Vanderbilt PREDICT project. Pulley JM, Denny JC, Peterson JF, Bernard GR, Vnencak-Jones CL, Ramirez AH, Delaney JT, Bowton E, Brothers K, Johnson K, Crawford DC, Schildcrout J, Masys DR, Dilks HH, Wilke RA, Clayton EW, Shultz E, Laposata M, McPherson J, Jirjis JN, Roden DM. Clin Pharmacol Ther. 2012 Jul;92(1):87-95. doi: 10.1038/clpt.2011.371. Epub 2012 May 16.
K-means cluster analysis (heat map) and gene ontologies of leukocytes when exvivo whole blood is stimulated with either lipopolysaccharide(LPS) or heat-killed Staphylococcus
aureus(SAC).
Robert J. Feezor et al. Clin Infect Dis. 2005;41:S427-S435
© 2005 by the Infectious Diseases Society of America
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2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015
PubMed mentions of Vanderbilt + Personalized Medicine
Cytokines Clinical Combined
Input parameters for network
% A
vera
ge
Pre
dic
tive
Accura
cy
*
Haplotype
(TCG)*
N ISS Sepsis, n
(%)
MODS
score
HMGB1
(ng/mL)
0 TOG 55 28 ± 10 29 (52) 7.3 ± 3.3 217 ± 98
1 TOG 303 25±8 105 (35) 6.0±2.6 178 ± 78
2 TOG 197 25 ± 8 77 (39) 5.7 ± 2.5 161 ± 48
Clinicl relevance of SNPs coding for
HMGB1 in patients with major trauma
Zeng et al Surgery 2012; 151:427-36
* 3 SNPs seem to act as “tag” SNPs for the entire HMGB1 gene
PheWAS plot:Estrogen Receptor - 1
Validations: Irregular menstrual cycle/bleeding Disorders of menstruation and other abnormal
bleeding from female genital tract Delay in sexual development and puberty NEC Noninflammatory disorders of vagina Dysmenorrhea Fibrosclerosis of breast Irregular menstrual bleeding
Novel associations: Systemic inflammatory response syndrome
(SIRS) Dependence on respirator [Ventilator] or
supplemental oxygen Acute and subacute necrosis of liver Shock Cardiac arrest and ventricular fibrillation Sepsis