Prospective Genotyping and Pharmacogenomics in the Electronic Health Record

Josh Denny, MD MS

October 18, 2012

Case: A 57yo female with chest pain

First admission

for angina,

receives stent

Jan 2010 Dec 2010

9th admission, 5th

intervention, 9th stent placed

Recath, stent

“Plavix x 1 year minimum.

ASA life long.”

April

In-stent

thrombosis,

restent

In-stent

thrombosis,

restent

Angina, Cath, more stents

clopidogrel started

A perception of genomic medicine - pharmacogenomics

"Here's my sequence...”

New Yorker, 2000 Francis Collins, 9/16/2009

Discovery and Application using the EHR

VanderbiltBioVU

De-identified laboratory for

genomics and

pharmacogenomics

discovery In-house developed, web-

based EHR with CPOE,

patient portal, messaging,

etc.

BioVU: an Opt-Out DNA Biobank

Extracting DNA from left over blood samples

Jo

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ay h

ash

A7CCF99DE65732….

Jo

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e

1.7 million records

The Synthetic Derivative:

updated regularly from EMR

eligible Jo

hn

Do

e

On

e w

ay h

ash

A7CCF99DE5732….

A7CCF99DE65732….

Extract

DNA

A7CCF99DE65732….

Jo

hn

Do

e

1.7 million records

The Synthetic Derivative:

updated regularly from EMR

151,000 DNA samples

19,000 pediatric

0.5 5

Replicating known associations in BioVU

0.5 50.5 5.0 1.0

Odds Ratio

rs2200733 Chr. 4q25

rs10033464 Chr. 4q25

rs11805303 IL23R

rs17234657 Chr. 5

rs1000113 Chr. 5

rs17221417 NOD2

rs2542151 PTPN22

rs3135388 DRB1*1501

rs2104286 IL2RA

rs6897932 IL7RA

rs6457617 Chr. 6

rs6679677 RSBN1

rs2476601 PTPN22

rs4506565 TCF7L2

rs12255372 TCF7L2

rs12243326 TCF7L2

rs10811661 CDKN2B

rs8050136 FTO

rs5219 KCNJ11

rs5215 KCNJ11

rs4402960 IGF2BP2

Atrial fibrillation

Crohn's disease

Multiple sclerosis

Rheumatoid arthritis

Type 2 diabetes

disease gene /

region marker

2.0

Ritchie et al., AJHG 2010

observed published

Finding accurate cases • Billing codes alone only 50-80% accurate

– “Wrong” codes result from screening, misdiagnosis, or because “a certain code pays for a test/treatment”

• Negation terms

– “I don’t think this is MS”

• Context:

– “FAMILY MEDICAL HISTORY: positive for rheumatoid arthritis.”

– “Multiple Sclerosis Clinic Note: This is a 46yo seen for peripheral neuropathy…”

True

cases

Notes

(NLP or text

searches)

Billing

codes

Medications

& Labs

11

Coordinating

center

Vanderbilt

Marshfield Northwestern Mayo Group Health/UW

Mount Sinai

Geisinger

• Started in 2007 – 5 sites; now – 9 sites

• Each has ≥3000 GWAS EMR patients

• Goal: to perform GWAS for ~40

phenotypes with existing samples

• Translate to clinical practice

CHOP

Cincinnati

Partners

eMERGE GWAS to date

Site Primary phenotype Secondary Phenotypes

Group Health Dementia white blood cell counts

Marshfield Cataracts diabetic retinopathy

Mayo Clinic Peripheral Arterial

Disease

red blood cell counts

ESR levels

Platelet levels

Northwestern Type 2 Diabetes lipids and height

Vanderbilt PR Duration

QRS Duration

Phenome-wide association studies

(PheWAS)

Network Phenotypes

Autoimmune Hypothyroidism

Resistant hypertension =first description or

new findings

bold=GWAS completed

eMERGE-PGx: perform clinical sequencing to guide drug choice

• “Demonstration project” for pharmacogenomics:

– Clopidogrel and CYP2C19

– Warfarin and VKORC1 and CYP2C9

• Step 2 (Ongoing) - Discover/validate new associations

VESPA Vanderbilt Electronic Systems for Pharmacogenomic Assessment

Clopidogrel label revision March 2010

clopidogrel 2-oxoclopidogrel CYP2C19

16

Finding clopidogrel failures in the EMR

Survival analysis of all who

were on clopidogrel for at

least a year.

All patients had stent or MI

as first event

Cases =

MI/stroke/revascularization/

Death and compliant with

clopidogrel

Controls = None of the

above

Delaney et al. CPT. 2012

Use of EMR data to predict drug response

Normal metabolizer

Poor or intermediate

metabolizers

clopidogrel failure=MI, stroke, revascularization, death following MI or PCI

n=225 cases, 468 controls

Delaney et al. Curr Pharm Ther. 2012

Warfarin Pharmacogenetics Using genetics to predict effective dose

SNP (Gene) Beta P

rs1057910 (CYP2C9*3) 0.83 2.70x10-26

rs9934438 (VKORC1) 0.87 4.48x10-61

Ramirez et al. Pharmacogenomics. 2012

FDA’s role • FDA began including pharmacogenomic (PGx)

effects in labels in 2007

• Now lists 83 medications with germline variants

– >100 germline and somatic

Gene Drug

Other Germline Variants

VKORC1 warfarin

HLA-B*1501 carbamazepine

HLA-B*5701 abacavir

CCR5 maraviroc

Familial

hypercholesterolemia

atorvastatin

G6PD deficiency rasburicase, primaquine

Protein C deficiency warfarin

urea cycle disorder valproate

Gene Drug Drug Metabolism Pathways

TPMT azathioprine

UGT1A1 irinotecan, nilotinib

CYP2D6 atomoxetine, fluoxetine

CYP2C19 clopidogrel, proton pump

inhibitors

CYP2C9 celecoxib, warfarin

N-acetyl transferase rifampin, isoniazid,

pyrazinamide

DPD capecitabine

http://www.fda.gov/Drugs/ScienceResearch/ResearchAreas/Pharmacogenetics/ucm083378.htm

Traditional PGx testing

• test ordered at the point of care when initiating a treatment

regimen

• one-genotype-at-a-time

• dose/med adjusted retrospectively after results returned

• Prospectively collect genotypes and embed in the electronic

medical record (EMR)

• Couple with decision support

• Genotypes available at the time of prescribing

Alternative vision – our vision

How should we implement genetic testing?

Medication initiation: warfarin1

Why Prospective? Risk of Side Effects highest at drug start

1 month 3 months 6 months 9 months 12 months

Medication initiation: simvastatin2

Medication initiation: azathioprine3

Medication initiation: tacrolimus4

Medication initiation: abacavir5

1 month 3 months 6 months 9 months 12 months

1 month 3 months 6 months 9 months 12 months

1 month 3 months 6 months 9 months 12 months

1 month 3 months 6 months 9 months 12 months

1. Ferder et al, Journal of Thrombosis and Haemostasis, 2010

2. The SEARCH Collaborative Group, NEJM 2008

3. Higgs et al, Pharmacogenomics 2010

4. Hesselink et al, 2008; Zhang et al, 2010

5. Mallal et al, NEGM 2008

Finding drug exposures in the EMR

• Found ~53,000 patients who met a “medical home”

definition

• Medications extraction from EMR data

– All inpatient meds (structured)

– ePrescribing (~30-50% outpatients scripts)

– Natural language processing of clinical documentation

using MedEx

MedEx

Clinical Text

“warfarin 5mg tablets,

1.5 tabs daily”

Structured Output

DrugName: warfarin

Dose: 1.5 tablets

Strength: 5 mg

Route: po

Frequency: daily

Xu et al. JAMIA 2010; 17:19-24

Doan et al. JAMIA 2010; 17: 528-31

5-year Medication Exposures in 52,942 “Medical Home” patients

Schildcrout et al. Curr Pharm Ther. 2012

1786

930

1454

2067

2870

3883

5244

6833

8247

9525

0 10000

10+

9

8

7

6

5

4

3

2

1

Number of Patients

Nu

mb

er

of

PG

x M

ed

s

65% received ≥1

med within 5 years

Genotyping may prevent ADEs

Medication

Adverse Event

Gene Nmed Overall Event

Probability

Number of events

prevented

abacavir Reaction within first

6 weeks of treatment

HLA-B*5701 87 -- 3 (3, 3)

azathioprine Myelosuppression TPMT activity 878 0.098 17 (13, 21)

clopidogrel MI, stroke, or death CYP2C19*2 or *3

or *4 or *5 6361 0.089 79 (19, 143)

simvastatin Myopathy SLCO1B1

rs4149056 17631 0.003 18 (5, 32)

tamoxifen breast cancer

recurrence

CYP2D6 540 0.186 15 (1, 29)

warfarin Any bleeding events carrier of

CYP2C9*2 or *3 6651 0.13 251 (91, 408)

Total 383 (212, 552)

Schildcrout et al. Curr Pharm Ther. 2012

Event Cost

Warfarin-related subdural hematoma $35,904

Myocardial infarction $72,446

That first event is just a start…

drug eluting stent

statin

warfarin

time

Cumulative number of

times genetic data are used

1

2

3

4

5

6

0

Prozac

Imuran, tamoxifen….

PREDICT: Pharmacogenomic Resource for

Enhanced Decisions In Care and Treatment

• Multiplexed genotyping

with Illumina ADME chip

• Prospective identification

of those at risk to receive

candidate medications

• Coupled with EMR-based

Decision Support

PREDICT: Genotype preemptively

CYP2C19

(rs4244285)

clopidogrel

poor metabolizer

CYP2D6

(many…)

tamoxifen,

antidepressants

poor metabolizer

SLCO1B1

(rs4149056)

statin myopathy

CYP2C19

(rs12248560)

clopidogrel

Rapid metabolizer

CYP2C9

(rs1799853)

warfarin

slow metabolizer

CYP2C9

(rs1057910)

warfarin

ultra slow metabolizer

VKORC1

(rs9923231)

warfarin dose

Selection of PREDICT Drug-Gene Interactions

Review and Approval by P&T

Committees

Implementation including

automated decision support

Guidance: Professional

Societies, FDA

Evidence Review

Replication in Vanderbilt population

(BioVU)

29

PREDICT Pipeline

DRUG: Clopidogrel Simvastatin Warfarin Thiopurines Phase 1: Peds

Heme/Onc

Thiopurines Phase 2: All

Specialities

GENE: CYP2C19 SLCO1B1 CYP2C9, VKORC1

TPMT TPMT

ADVERSE OUTCOMES: stent thrombosis/

MACE* myopathy/

rhabdomyolysis bleeding/

out of range INR myelosuppresion myelosuppresion

EVENT RATE: 1% / 9% <1% 13% / 45% 7% 7%

FDA/POLICY: black box none recommended recommended recommended

SUMMARY STATUS: Live Live Live Est. Go Live

Oct 2012

Est. Go Live

Nov 2012

ST

EP

S IN

TH

E P

RE

DIC

T P

IPE

LIN

E

Clinical impact of negative outcomes significant

High prevalence of drug utilization (≥5% of VUMC population)

Scientific evidence for drug-gene effect

Patient target identifiable before they receive the drug TBD

Alternative therapy available

Internal validation of established association in VUMC pop not feasible

Assessment of genotype data as high quality in CLIA lab

Completion of DGI summary of evidence (bundle)

Rules development complete (clinical + genotype to identify high risk)

CDS language developed for VGR and RxStar

Pediatric evaluation - Sub P&T Peds Committee

Pediatric P&T approval

Sub P&T Committee endorsement and approval

Main P&T Committee approval of decision support rules

Clinician and provider education and outreach

Algorithm technical development complete

Go live

Results available via MHAV patient portal

Surveillance infrastructure established

Rules refinement based on evolving evidence

Evaluation of quality improvement underway

PREDICT Results Appear in Patient Summary

30

Drug Genome Interactions in the Patient Summary

Point-of-care Decision Support

Prospective Genotyping Using the Prognostic Model

• Model identifies patients who are highest risk for starting warfarin, clopidogrel, or simvastatin therapy within the next three years as candidates for preemptive genotyping

• Used medical home population not on a target med previously (N~18000)

• Factors include:

– Age, gender, race, and BMI when height is available (or weight

when BMI is not available)

– History of…Diabetes, coronary disease, atrial fibrillation,

hypertension, atherosclerosis, congestive heart failure, previous

DVT/PE, and end stage renal disease 32

AGE BMI DM HTN CAD CHF Probability of being placed on Simvastatin, Warfarin, or Clopidogrel

>80

>25 1

<25 1

60-80

>30

1 1 1

1 1

1

1 1

1

25-30

1 1

1

1 1

1

18-25

1 1

1

1 1

1

<18 1

40-60

>30

1 1 1

1 1

1

1 1

1 1

1

25-30

1 1

1

1 1

1 1

1

Patient comes in,

selected for

genotyping (cardiac

cath, predictive

algorithm, etc)

Genotype

DB Select variants put into

EMR (currently ~18 variants)

• Validated

• CDS

• P&T review

184 variants

Drop variants that

don’t work well

New research for drug-

genome interaction

discovery

P&T Committee

PREDICT research team

~130 other variants

validated of unknown

significance

PREDICT is Live

Effect Total

normal risk 7040

intermediate risk 2303

indeterminate 217

high risk 185

9745

Clopidogrel DGI by Genotype Simvastatin DGI by Genotype

Effect Total

normal metabolizer 6491

intermediate metabolizer 1847

indeterminate 693

hypermetabolizer 453

hypometabolizer 263

9747

43% of patients have a variant in SLCO1B1 and/or CYP2C19

Our case: What personalizing medicine really means

57yo with

admitted for

angina, receives

stent

Jan 2010 Dec 2010

9th admission, 5th

intervention, 9th stent

PREDICT: CYP2C19*2/*2

Recath, stent

“Plavix x 1 year minimum.

ASA life long.”

April

In-stent

thrombosis,

restent

In-stent

thrombosis,

restent

Cath, more stents

Switched to prasugrel

clopidogrel started

Future PGx: Variable drug response is common

--41 %41 %

Distribution of Changes in LDL

Cholesterol with Simvastatin 40 mg/d

Percent changePercent change

00

2020

4040

6060

8080

100100

--100100 --8080 --6060 --4040 --2020 00 2020

nn

Changes not related to compliance or changes in other lipids

Simon et al., Am J Cardiol 2006Simon et al., Am J Cardiol 2006

LDL cholesterol changes by

simvastatin 40 mg

QT changes with ibutilide

Therapeutic Warfarin dose

Patients

, %

%FEV1, from baseline

0

10

20

30

40

<-20-20 to -10

-10 to 0

0 to 10

10 to 20

20 to 30

30 to 40

>40

study #1

study #2

study #3

Change in FEV1 with inhaled

corticosteroids in asthma

Summary

• EMR-linked DNA biobanks can be used for

genomic and pharmacogenomic discovery

• Clinical, prospective genetic testing is

feasible and may improve patient outcomes

• Informatics infrastructure is key, but many

challenges remain

The Team

…and many more…