Clinical & Research GenomicsClinical & Research Genomics

Washington DC VA Medical CenterJack H. Lichy, M.D., Ph.D.Jack H. Lichy, M.D., Ph.D.

What is Genomic Medicine?

• DNA & RNA Testing: – Personalized Medicine

• An Accepted Standard of Care• Applications

– Sensitivity to Adverse Drug Reactions– Inherited Diseases & Syndromes– Cancer Diagnosis– Infectious Disease

Clinical & Research Genomics Core

The Concept

The same technologies used for clinically required DNA testing in the clinical laboratory are made available to support research in a single core laboratory facility.

• Clinical Laboratory directly meeting requirements of Veterans Healthcare

• CLIA Certified Laboratory for Research• Collaborative• Translational

Clinical & Research Genomics Core

Organization

• Start-up Grant from Office of Research and Development

• Clinical testing supported by clinical funds• Research supported by grant funds

Clinical & Research Genomics Core

Support

• FISH: Fluorescent in situ Hybridization• PCR, DNA Sequencing• Genotyping by Microarray Hybridization

Clinical & Research Genomics Core

Technologies

Current Testing CapabilitiesUrovysion:

A sensitive method for diagnosis of bladder cancer and early detection of recurrences.

Current Testing Capabilities

• Predicting Optimum Drug Dosage– Cytochrome P450’s:

• CYP 2C9, 2D6, 2C19, 3A4, 3A5

– Others:• VKORC1, UGT1A1

“Here’s my sequence . . .”

Current Testing Capabilities

• Prediction of Tumor Response to Therapy– K-ras Mutation Detection– Microsatellite Instability

• Diagnosis of leukemia and lymphoma– Gene Rearrangement Assays

• Risk factors for coagulation disorders– Factor V Leiden– Prothrombin G20210A

The Research Core

• Collaborative efforts to support a wide variety of research projects.

• Examples:– Evaluating Clinical Utility of Genetic Testing in

Warfarin Dosing– Pharmacogenomic assay validation– Neurotransmitter expression in PTSD model– Testing genomic markers of risk for mental health

disorders

• Too Little Thrombosis• Too Much Bleeding• Complications cause 43,000

ED visits/year in USA.• Wide variation in dose

requirements

Example: Warfarin Dosing

Warfarin Dosing: Clinical & Research Challenges

• Implement genetic testing data into Warfarin dosing decisions.

Clinical:

• Does genetic testing reduce the incidence of adverse reactions?

• Are there genetic markers of adverse reactions specific for minority populations?

Research:

Warfarin: Collaborations

• Clinical Staff• Pharmacy• ACOS Research• ACOS Informatics• Anticoagulation Research Lab

Warfarin: Accomplishments• Assay Development

– 3 well established markers

– 11 markers seen in minority groups

• Educational Activities• Software evaluations

– Incorporating genetic data into dosing– Interface with Electronic Medical Record

• Research Collaboration

Benefits to Veterans

• Tests already in use to support cancer diagnostics, clotting risk, Warfarin sensitivity.

• Reduced costs for clinical tests• Fewer days in the hospital• Fewer serious adverse drug reactions• More effective cancer treatments• Disease Prevention: Knowing the risk

HIV RESEARCH:HIV RESEARCH: Improving VeteransImproving Veterans’’ LivesLives

Washington VA Medical Center Washington DC • April 30, 2009

Melissa M. Turner, MSWMelissa M. Turner, MSW

HIV Research: Improving Veterans’ Lives

• A Veteran Participating in HIV Research– 42-year old man who presents to the AEC with swollen

lymph nodes, fever and fatigue and is offered HIV testing– After receiving positive test results in Yellow Team he is

escorted to ID Clinic and provided crisis management and further medical assessment

– His primary care is transferred to ID and during a regular visit, he is invited to participate in a randomized treatment trial for antiretroviral naïve volunteers

– He declines, but he is introduced to research team members and the informed consent process, and learns how research is integrated in and complementary to HIV primary care

HIV Research: Improving Veterans’ Lives

– Patient declines participation in the randomized trial but accepts an invitation to attend a meeting of the ID Clinic research advisory board

– Patient’s interest in clinical trials increases as he learns more about treatment regimens, protocol development, informed consent, volunteer recruitment and retention strategies, and opportunities for veterans to collaborate with scientists in the VA protocol development process

– When an observational, non-interventional trial becomes available at the site, he joins the study

– Over time, patient’s interest in HIV science propels him to become a leader of the ID Clinic research advisory board and a prominent HIV treatment activist in multiple networks in DC and the nation

Veterans Living with HIV

• Largest single provider of direct HIV care in the United States

• Approximately 23,000 true unique patients with HIV infection

Washington VA Medical Center / Total Patients in Care 2008 939

Gender Age Race Source of Infection

Male 910 0 – 13 0 White 93 Injection Drug 178 Female 32 14-17 yrs 0 Black 693 Heterosexual 452 18 – 49 yrs 392 Latino 12 Same Sex 250 50 – 59 yrs 377 Asian 1 Mother-Infant 0 >= 60 yrs 170 Other 109 Other 23

Type of HIV Research

• Research is an integral part of the VA’s efforts to improve the diagnosis, treatment and prevention of HIV infection

• HIV Treatment Research• Optimizing clinical management of

HIV/AIDS, including co-infections and other HIV-related conditions

Major Collaborations• VA Cooperative Studies• Centers for Disease Control

– Tuberculosis Trials Consortium• National Institutes of Health

– Community Programs for Clinical Research on AIDS (CPCRA)

– International Network for Strategic Initiatives in Global HIV Trials (INSIGHT)

– HIV Prevention Trials Network (HPTN)– AIDS Clinical Trials Group (ACTG)

• Partnerships with Pharmaceutical Companies

TUESDAY, FEBRUARY 7, 2006

NIH Warns AIDS Patients Against Stopping Therapy

Study Finds People Who Forgo Continuous Treatment More Likely to Develop Other Illnesses or Die

A13

By

DAVID BROWN

Washington Post Staff Writer

People infected with the AIDS virus who periodically interrupt their drug treatment run a higher risk of falling ill and dying of both AIDS and other diseases compared with people who stay on the

medicines.

That is the conclusion of the largest and most expensive AIDS treatment study ever conducted….

Selected Publications on Non‐AIDS Events

How HIV Research Improves Veterans’ Lives

• Death Sentence Survival• Despair Hope/Optimism• Quantity and Quality of life• Thriving

– Achieving sobriety– Acquiring housing– Pursuing higher education/training/career advancement– Maintaining stronger Relationships– Addressing other health issues (smoking, obesity, etc)– Pursuing dreams, aspirations and a future

How HIV Research Improves Veterans’ Lives

• Altruism• Mental Health - "a state of well-being in which the

individual realizes his or her own abilities, can cope with the normal stresses of life, can work productively and fruitfully, and is able to make a contribution to his or her community”

• High Acceptance of Research Participation/Repeat Volunteers

• Enhances primary care• Advocacy

How HIV Research Shapes Healthcare Delivery

• Expanded treatment options• Increasing complexity• Outpatient management• Shorter hospitalizations • Development of a chronic disease

management paradigm for lifelong care of HIV infection

Impact on International Scope and Next Steps

• Emphasis on earlier intervention• Improve early detection of HIV infection• Expand and simplify HIV testing• Prevention education programs associated

with relevant VA programs: drug treatment programs, homeless programs, counseling programs, domiciliary facilities, STD programs and primary care clinics

HIV Research: Improving Veterans’ Lives

Many, many thanks to our nation’s veterans for

volunteering to participate in HIV research studies

Control of Hypertension and Control of Hypertension and Seasonal VariationSeasonal Variation

Location Washington DC • April 30, 2009

Ross Fletcher M.D.Ross Fletcher M.D.

VA Research: Improving Veterans’ Lives

Control of Hypertension and Seasonal Variation in a

Large VA Study 2000 - 2007

Progress Note Reminder Screen

VHA Doctor. 1

Demo Patient 1000-00-0001 001/01/1901 (00)

< 140, < 90 > 160, > 100

Improving HypertensivesWashington, DC VAMC

Perc

ent P

atie

nts

Perc

ent P

atie

nts

3,1333,133 6,5076,507 8,3578,357 9,4189,418 10,74510,745 12,60612,606 13,19813,198 12,78112,781 13,66813,668 13,48513,4850

10

20

30

40

50

60

70

80

90

1998 1999 2000 2001 2002 2003 2004 2005 2006 2007

Systematic ResponseSystematic Response

in Hypertensive Patientsin Hypertensive PatientsReminder Due should be addressed in all Reminder Due should be addressed in all

clinics.clinics.

Elevated Blood pressure should be Elevated Blood pressure should be repeated two or three times. The lowest one repeated two or three times. The lowest one counts. counts.

Treatment change should follow continued Treatment change should follow continued elevations.elevations.

RemeasureRemeasure BP in nurse run or other clinics BP in nurse run or other clinics in less than 2 weeks.in less than 2 weeks.

Increase the availability of subspecialty Increase the availability of subspecialty clinics for those who have continued clinics for those who have continued elevations.elevations.

HTN BP < 140 / 90 2005 – Q3 2007

0102030405060708090

100

VISN

4

VISN

8

Mar

tinsb

urg

VISN

2

VISN

3

VISN

12

VISN

1

VISN

6

VISN

7

VISN

15

VISN

16

VISN

19

VISN

23

VISN

11

VISN

17

VISN

21

VISN

9

VISN

10

VISN

22

VISN

5

VISN

18

VISN

20

Bal

timor

e

Was

hing

ton

Nat

iona

l

0102030405060708090

100

Was

hing

ton

Mar

tinsb

urg

VISN

4

VISN

1

VISN

10

VISN

8

VISN

6

VISN

3

VISN

12

VISN

5

VISN

7

VISN

11

VISN

16

VISN

17

Bal

timor

e

VISN

21

VISN

20

VISN

22

VISN

2

VISN

9

VISN

19

VISN

15

VISN

18

VISN

23

Nat

iona

l

20052005

Q3 2007Q3 2007

HTN BP > 160 / 100 2005 – Q3 2007

0022446688

1010121214141616

VISN

4VI

SN 4

VISN

19

VISN

19

VISN

23

VISN

23

Mar

tinsb

urg

Mar

tinsb

urg

VISN

1VI

SN 1

VISN

6VI

SN 6

VISN

8VI

SN 8

VISN

12

VISN

12

VISN

16

VISN

16

VISN

21

VISN

21

VISN

2VI

SN 2

VISN

3VI

SN 3

VISN

7VI

SN 7

VISN

11

VISN

11

VISN

15

VISN

15

VISN

18

VISN

18

VISN

22

VISN

22

VISN

9VI

SN 9

VISN

10

VISN

10

VISN

17

VISN

17

VISN

20

VISN

20

VISN

5VI

SN 5

Was

hing

ton

Was

hing

ton

Bal

timor

eB

altim

ore

Nat

iona

lN

atio

nal

20052005

0022446688

1010121214141616

Was

hing

ton

Was

hing

ton

Mar

tinsb

urg

Mar

tinsb

urg

VISN

1VI

SN 1

VISN

8VI

SN 8

VISN

12

VISN

12

VISN

2VI

SN 2

VISN

7VI

SN 7

VISN

5VI

SN 5

VISN

17

VISN

17

VISN

3VI

SN 3

VISN

16

VISN

16

VISN

4VI

SN 4

VISN

10

VISN

10

VISN

6VI

SN 6

VISN

22

VISN

22

VISN

11

VISN

11

VISN

19

VISN

19

Bal

timor

eB

altim

ore

VISN

9VI

SN 9

VISN

20

VISN

20

VISN

18

VISN

18

VISN

21

VISN

21

VISN

23

VISN

23

VISN

15

VISN

15

Nat

iona

lN

atio

nal

Q3 2007Q3 2007

Analysis at 4 month IntervalBalt

imore

Martinsb

urgWas

hington

Baltim

oreMart

insburg

Washington

0

20

40

60

80

100

Perc

ent o

f Pat

ient

sSeptember 20, 2001 January 3, 2002

0

20

40

60

80

100

High(> 160 / 100 )

Moderate(140 - 159 / 90 - 99 )

Normal(< 140 / 90 )

Hypertensive Patients Returning to < 140 / < 90

Months

0.3

0.35

0.4

0.45

0.5

0.55

0.6

Perc

ent P

atie

nts

Jan 99 Jul 99 Jan 00 Jul 00 Jan 01 Jul 02 Jan 03 Jul 03 Jan 04Jul 01 Jan 02

Hypertensive Patients with BP > 160 >100

MonthsJan 99 Jul 99 Jan 00 Jul 00 Jan 01 Jul 02 Jan 03 Jul 03 Jan 04Jul 01 Jan 02

0.1

0.15

0.02

0.25

0.3

Perc

ent P

atie

nts

Hypertensive Patients with BP > 160 >100Hypertensive Patients with BP > 160 >100

VistA/HDR: Vital Sign History

Anchorage, AL

Honolulu, HI

Boston, MS

Washington, DC

Baltimore, MD

Miami, FL

Los Angeles, CA

Houston, TX

Fargo, ND

Chicago, IL

San Juan, PR

Philadelphia, PA New York, NY

Minneapolis, MN

Portland, OR

Controlling Hypertension Showing Seasonal Variation15 Cities –

522,264

patients

Hyp

erte

nsiv

es R

etur

ned

to N

orm

al (%

)

50

55

60

65

70

75Ja

n-00

Jun-

00

Dec

-00

Jun-

01

Dec

-01

Jun-

02

Dec

-02

Jun-

03

Dec

-03

Jun-

04

Dec

-04

Jun-

05

Dec

-05

Jun-

06

Dec

-06

Jun-

07

Dec

-07

Month

Hypertensives Returning to NormalSeason Effect by City Rank

Perc

ent B

P Va

riatio

n w

ith S

easo

n

Cities

0

2

4

6

8

10

12PH

IB

AL

DC

AA

NC

LAX

FRG

BO

S

HST

HO

N

MIA CH

I

SJA

MIN

POR

NYC

Latitude and Seasonal Variation4 Cities with the Highest vs. 4 with the Lowest Latitude

Percen

t Returning

 to Normal

High Latitude CitiesAnchorage/Fargo/Portland/Minneapolis

Lowest Latitude CitiesSan Juan/Honolulu/Miami/Houston

45

50

55

60

65

70

75

80

Jan-

00

Jun-

00

Dec

-00

Jun-

01

Dec

-01

Jun-

02

Dec

-02

Jun-

03

Dec

-03

Jun-

04

Dec

-04

Jun-

05

Dec

-05

Jun-

06

Dec

-06

Jun-

07

Dec

-07

BP Seasonal VariationHypertensives vs. Normotensives

105

110

115

120

125

130

135

140

145

Month

Mea

n S

ysto

lic B

P

66

68

70

72

74

76

78

80

82

Mea

n D

iast

olic

BP

HTN‐SYSTOLIC

NORM‐SYSTOLIC

HTN‐DIASTOLIC

NORM‐DIASTOLIC

Jan-

00

Jun-

00

Dec

-00

Jun-

01

Dec

-01

Jun-

02

Dec

-02

Jun-

03

Dec

-03

Jun-

04

Dec

-04

Jun-

05

Dec

-05

Jun-

06

Dec

-06

Jun-

07

Dec

-07

Controlling Hypertension by Age

Month

45%

50%

55%

60%

65%

70%

75%

Hyp

erte

nsiv

es R

etur

ned

to N

orm

al (%

)

<55 55-<70 70-<80 80+

Jan-

00

Jun-

00

Dec

-00

Jun-

01

Dec

-01

Jun-

02

Dec

-02

Jun-

03

Dec

-03

Jun-

04

Dec

-04

Jun-

05

Dec

-05

Jun-

06

Dec

-06

Jun-

07

Dec

-07

15 Cities –

522,264

patients

15 Ci15 Cities ties –– 522,264 hypertensive patients522,264 hypertensive patientsSystolic and Diastolic BP by Age

130

135

140

145

1999

-10

2000

-4

2000

-10

2001

-4

2001

-10

2002

-4

2002

-10

2003

-4

2003

-10

2004

-4

2004

-10

2005

-4

2005

-10

2006

-4

2006

-10

2007

-4

2007

-10

Month

Syst

olic

BP

65

70

75

80

85

Dia

stol

ic B

P

<55 55 - <70 70 - <80 80+

Systolic and Diastolic BP by Age

Controlling Hypertension by Race

45%

50%

55%

60%

65%

70%

75%

80%

Months

Hyp

erte

nsiv

es R

etur

ning

to N

orm

al (%

)

African American Caucasian Hispanic

Jan-

00

Jun-

00

Dec

-00

Jun-

01

Dec

-01

Jun-

02

Dec

-02

Jun-

03

Dec

-03

Jun-

04

Dec

-04

Jun-

05

Dec

-05

Jun-

06

Dec

-06

Jun-

07

Dec

-07

Controlling Hypertension by Race

15 Ci15 Cities ties –– 522,264 hypertensive patients522,264 hypertensive patients

Seasonal Variation in Weight

190

192

194

196

198

200

202

Month

Wei

ght (

lbs.

)

92

93

94

95

96

97

98

99

100

Ave

rage

BP

Avg WT Avg BP

Jun-

00

Dec

-00

Jun-

01

Dec

-01

Jun-

02

Dec

-02

Jun-

03

Dec

-03

Jun-

04

Dec

-04

Jun-

05

Dec

-05

Jun-

06

Dec

-06

Jun-

07

Dec

-07

Jan-

00

HTN Showing Improved Winter Treatment

Washington, DC

40

50

60

70

8020

01‐12

2002

‐220

02‐4

2002

‐620

02‐8

2002

‐10

2002

‐12

2003

‐220

03‐4

2003

‐620

03‐8

2003

‐10

2003

‐12

2004

‐220

04‐4

2004

‐620

04‐8

2004

‐10

2004

‐12

2005

‐220

05‐4

2005

‐620

05‐8

2005

‐10

2005

‐12

2006

‐220

06‐4

2006

‐620

06‐8

2006

‐10

2006

‐12

2007

‐220

07‐4

2007

‐620

07‐8

2007

‐10

2007

‐12

Perc

ent H

yper

tens

ives

Ret

urne

d to

Nor

mal

40

50

60

70

8020

01‐12

2002

‐220

02‐4

2002

‐620

02‐8

2002

‐10

2002

‐12

2003

‐220

03‐4

2003

‐620

03‐8

2003

‐10

2003

‐12

2004

‐220

04‐4

2004

‐620

04‐8

2004

‐10

2004

‐12

2005

‐220

05‐4

2005

‐620

05‐8

2005

‐10

2005

‐12

2006

‐220

06‐4

2006

‐620

06‐8

2006

‐10

2006

‐12

2007

‐220

07‐4

2007

‐620

07‐8

2007

‐10

2007

‐12

Perc

ent H

yper

tens

ives

Ret

urne

d to

Nor

mal

40

50

60

70

8020

01‐12

2002

‐220

02‐4

2002

‐620

02‐8

2002

‐10

2002

‐12

2003

‐220

03‐4

2003

‐620

03‐8

2003

‐10

2003

‐12

2004

‐220

04‐4

2004

‐620

04‐8

2004

‐10

2004

‐12

2005

‐220

05‐4

2005

‐620

05‐8

2005

‐10

2005

‐12

2006

‐220

06‐4

2006

‐620

06‐8

2006

‐10

2006

‐12

2007

‐220

07‐4

2007

‐620

07‐8

2007

‐10

2007

‐12

Perc

ent H

yper

tens

ives

Ret

urne

d to

Nor

mal

VA Research: Improving Veterans’ Lives

Fitness Lowers Mortality in Fitness Lowers Mortality in Veterans with Type 2 DiabetesVeterans with Type 2 Diabetes

Peter Kokkinos, PhDPeter Kokkinos, PhD

Veterans Affairs Medical Center Washington DC • May 1, 2009

Special Thanks to All Veterans for Making this study possible!

• Dr. Jon Myers Palo Alto VAMC• Dr. Eric Nylen DC VAMC• Dr. Marc Blackman DC VAMC• Dr. Charles Faselis DC VAMC• Dr. Steven Singh DC VAMC

Fitness and All-Cause Mortality in Veterans

0.8

0.51

0.31

0.2

0.4

0.6

0.8

1

Relative R

iskn=15,660

Kokkinos et al. Circulation 2008; 117:614-622

Very-Low-Fit Low-Fit Moderate-High High-Fit

* * P<0.001

Fitness Levels and Mortality

0.8

0.57

0.46

0.290.33

0.27

0.2

0.4

0.6

0.8

1

Relative Risk

n=15,660

Kokkinos et al. Circulation 2008; 117:614-622

≤2 METs 4.1-6 6.1-8 10.1-12

* P<0.001

12.1-142.1-4 8.1-10 >14

Questions• Does fitness reduce mortality risk

(improve survival) in veterans with DM? • Is fitness effective if DM co-exists with

other risk factors? • Is it effective in both young and older

diabetics?• Are the health benefits similar for African-

Americans and Caucasians?

Fitness Categories are Based on Peak Exercise Time Achieved on the Treadmill

Using a Standardized Protocol.

Low-FitLowest 25%

Moderate-Fit 26%-75%

High-Fit >75%

3,148Veterans with

type 2 DM

n=762n=934 n=1,452

Question 1

Does fitness reduce mortality risk (improve survival) in

veterans with DM?

Exercise Capacity and Mortality in Diabetics

0.63

0.41

0

0.2

0.4

0.6

0.8

1Relative Risk

*

*

Low- Fit Moderate- Fit High-Fit

* p<0.001

Kokkinos P, et al. Diabetes Care 2009

n=3,141

Log Rank=147.4; p<0.001

≥8 METs

(n=934)

5.1-7.9 METs (n=1452)

≤5 METs (n=762)

Cum

ulat

ive

Surv

ival

0.00 5.0 10.0 15.0 20.0 25.0

Years of follow-up

1.0

0.6

0.4

0.2

0.0

0.8

Survival According in Diabetic Veterans According to Fitness

Question 2

Is fitness effective if DM co-exists with other

risk factors?

Fitness and Mortality in Diabetics with Hypertension

Relative Risk

0.62

0.36

0

0.2

0.4

0.6

0.8

1

Mod-FitLow-Fit High-Fit

Mortality in Diabetics According to Fitness and Fatness

Relative Risk

0.59

0.41

0.58

0.36

0.48 0.46

0

0.2

0.4

0.6

0.8

1 Low-Fit

Mod-Fit

High-Fit

Normal WT (BMI <25) Over-Wt (BMI 25-29.9) Obese (BMI ≥30)

Question 3

Is fitness effective in both young and older diabetics?

Fitness and Mortality in Diabetics 50-69 Years of Age

0.53

0.31

0

0.2

0.4

0.6

0.8

1

*

*

* p<0.001

n=2086 481 deaths

Relative Risk

Low-Fit Moderate-Fit High-Fit

Fitness and Mortality in Diabetics 70 Years and Older

0.58 0.57

0

0.2

0.4

0.6

0.8

1

Relative Risk

* *

Low-Fit Moderate-Fit High-Fit

* p<0.001

n=669287 deaths

Question 4

Does fitness have similar beneficial effects for African-Americans

and Caucasians?

An intriguing finding of some studies is that African-American diabetics exhibit

significantly lower exercise capacity than do Caucasian diabetics.

Fitness and Mortality in Veterans with Type 2 Diabetes

0.57

0.33

0.66

0.54

0

0.2

0.4

0.6

0.8

1

Caucasians African-Americans

Relative Risk

*

*

*

*

<=5 METs

Mod-Fit

>8 METs

High-Fit

5-8 METs

p=0.24

p=0.03

Low-Fit Mod-Fit High-FitLow-Fit

What does it Take to become Moderate to High-Fit?

Low-Fit Moderate-Fit High-Fit

20-40 min of Brisk walk/jog most days of the Week

Summary of Our Findings

• Increased fitness is associated with reduced risk of mortality for all diabetics regardless of age, risk factors or race.

• Mortality rates were lower by at least 40% and up to 70% in some cases, for Moderate and High-Fit diabetic veterans

• The risk was reduced by 17% for every one unit increase in the level of fitness.

Thank You!

VA Research: Improving Veterans’ Lives