Non-profit research institute and world’s leading biobank

Copying Leads to “Spelling Mistakes”

Some Diversity Enables Us To Resist Infectious Disease

99.6%identical

0.4%unique

Science magazine’s “Breakthrough of the Year” in 2007

90% chance that they do (freq. > 1%)Gabriel et al. Science, 2002

Compare two chromosomes from any two people

Only ~ 1 in 1000 bases differ

Do these same sites show variation in other people?

Most Genetic Variation is Shared Among Us All

Out of Africa

Measuring Genetic Variation is Now Possible, Comprehensive and Cost Effective

Heart Disease, Diabetes Cancer, Obesity

All known single Gene diseases

~2,000

Don’t we already know about many Human Disease Genes?

Multi-Gene Diseases

Impact onPublic Health

GWAS Studies

Manolio et al. (2008) J. Cli. Inv. 118(5):1590

Maher, B. (2008) Nature 456

Many Differences in the Way Individuals Respond to Rx Drugs are Clear Already

CYP2C19

$8 Billion inAnnual Sales

Prasugrel Just Approved by FDA

Plavix Plavix*

liver

Plavix Must Be Activated in the Liver

Alternative Drug

Tamoxifen is a Pro-Drug

7-10% of Women do not activate Tamoxifen

Alternative: aromatase inhibitors

Genome-informed medicine will not be widelyAdopted until it is demonstrated to work in the clinic

How data are provided to patient and doctor will Be critical determinants of successful adoption (i.e. what’s the right system?)

Goal is to Determine Whether Using Personal Genome Information Will Be Useful In Medicine?

Correlations in Observational Data

Observational Data Can Be Useful

“American Family Study”

“We desperately need, in this country, a large-scale, prospective, population-based cohort study. And we need to enroll at a minimum half a million people. We would need to have their environmental exposures carefully monitored and recorded, their DNA information recorded, their electronic medical records included, and have them consented for all sorts of other follow-ups.”

June 6, 2008 Interview with Science Magazine

Dr. Francis Collins

FreeResearch study

2 million sites of variation

2,000 sites of knownRelevance to drug action

The CPMC Uses Two “GeneChips”

D-MET Coverage

Coriell GenomeCenter

CLIA!

Education of Medical Professionals

Input From Medical Professionals

“Don’t even tell me it’s a wart.”

Who can participate and how are they recruited?

Eligibility:You must be at least 18 years oldYou must have an email address and access to the internet

Recruitment Mechanisms:Community-based recruitmentCancer Clinic-based recruitmentPrimary Care-based recruitment

Community and

Employer

Cancer

ChronicDisease

The CPMC Web Portal

cpmc.coriell.org

Jane Doe

Collection of Detailed Family, Medical History, Medication, Lifestyle and Demographic Info

What information do we collect?All cohorts: MFLQ

Demographic InformationMedical HistoryMedicationsFamily HistoryLifestyle InformationGenetic Knowledge assessment

Cancer Cohorts:Cancer Registry DataCancer-related health recordsPrescribing Records

Primary Care Cohorts:Electronic Health RecordsPrescribing Records

Who decides what genetic information is reported?

Informed Cohort Oversight Board (ICOB), an external advisory board. Composed of scientists, medical professionals, ethicist, community members.

Vote on whether conditions are potentially actionable.

Meet at least twice a year. New results then reported toall participants.

Actions completely transparent. RNR Foundation

CPMC Risk Reporting

CPMC Process Overview

Genetic Variant/Disease SelectionSearch Public Databases for

published GWASNHGRI GWAS catalogue; HuGENet™; PubMed

Generate list of Health Condition/Genetic variant papers

Selection criteria for Genetic Variant:

•Replicated associations•Adequately sized studies•On Affymetrix 6.0 GeneChip (currently)

Final list of Health Condition/Genetic variants

Selection of Health Condition:

•Health conditions only (no Traits)•Is disease potentially ‘actionable’?•Assess by review of medical society policies and recommendations

Prepare Document with Health Condition and a Genetic Variant Summaries for submission to ICOB

CPMC Risk Reporting

Risk Estimation

Evaluate Study Design and Size Select study that will provide most representative and valid risk estimates

Assess Study Quality Evaluate methods used for determining phenotype and genotype

If study reports relative risk – report risks directly

If study reports odds ratios – estimate relative risk and report estimated risks

Step 1: Study Selection

Step 2: Risk Determination

Study Selection

PubMed &

HuG

ENet TM

Select studies

from highest

tier

If more than one paper

qualifies then select the

largest study

Hierarchy of Study Designs

Meta-Analysis of Prospective Studies

Individual Prospective Study

Meta-Analysis of Case-Control Studies

Individual Population-Based Case-Control Study

Individual Case-Control Study (not population based)

Study Quality • Disease Assessment Carried out consistently? Objective? Clinically accepted definition?

• Genotyping Are methods valid? Carried out consistently?

•Population Stratification Could risk estimates be biased?

Select Paper

Perform Updated

Search for ICOB

approved SNPs

Example: CAD and SNP rs1333049

no

no

CDKN2A/CDKN2B rs1333049

 RR Estimates (95% CI)

GG* 1 CG 1.29 (1.22 , 1.37) CC 1.67 (1.48, 1.87)

(Circulation 2008; 117:1675-1684)

Hierarchy of Study Designs

Meta-Analysis of Prospective Studies

Individual Prospective Study

Meta-Analysis of Case-Control Studies

Individual Population-Based Case-Control Study

Individual Case-Control Study (not population based)

*reference group

yes

EXAMPLE

How do participants learn about their results?

Participant Risk Summaries include Non-genetic Risks

Potentially Actionable Conditions

Prostate cancer

Colon cancer

Melanoma

Coronary artery disease

Type 2 diabetes

Type 1 diabetes

Age-related macular degeneration

Hemochromatosis

Inflammatory bowel disease

Obesity CYP2D6

As of6-10-09

Lupus

Rheumatoid Arthritis

CYP2C9

CYP2C19

VKORC1

Complex Disease Drug Metabolism

Pharmacogenomics Advisory Panel

Dr. Issam Zineh

Office of Clinical Pharmacology

FDA

CYP2D6-Tamoxifen

Genetic Counselors available at no cost

What Do My Results Mean?

In person or by phone

Nearly all states represented in the CPMC

10,000 Participants by 2010

Ultimate goal of 100,000

Minority Participation and Outreach

U.S. Senator Robert Menendez

Franklin Institute of Philadelphia

Reverend Floyd White of Camden, NJ

PRWT and Cherokee Pharmaceuticals

What do participants do after viewing their results?

• They can invite their physician or members of their family to register to view their personal risk information through the web portal

• They may decide to make changes to their lifestyle to try to lower their risk of the health condition.

• They may decide to talk to their physician about their risk of the health condition.

• They can request genetic counseling at CPMC to discuss their risks, at no charge

• CPMC will send them period emails asking them to log onto their web portal account and complete short questionnaires about what they did with their results

What research will be done with CPMC data?

• CPMC scientists, health researchers and biostatisticians will determine whether giving people information about their genetic risk alters their health behavior or their health.

– Outcome surveys, annual MFLQ, medical records

• CPMC scientists will assess the genetic knowledge of CPMC participants during the course of their participation in the study.

– Voluntary genetic knowledge survey

• The broader scientific community will have access to genotypic and phenotypic data from those individuals who opt to release their de-identified data for biomedical research.

Coronary Artery Disease Survey Via Portal at 3 and 12 months

Health Outcomes Behavioral Outcomes

Communication

Risk perception

Changes in behavior

Newly diagnosed CAD

MI

Angina

Bypass surgery

Surveys, Annual medical history updates, And EMRs

Recent Federal Grants

Web-based educational content for physicians (Mary Daly at Fox Chase)

CPMC Participant Behavior Upon Receiving Genome Info. (Reed Peyritz at Penn)

•U01 trial will examine patient lifestyle changes and physician behavior

(assessed by coded tests/procedures/referrals) when the physicians have

or have not received training in genomic medicine.

Study Aims• Assess motivations to participate in the CPMC and

perceptions of the utility of personalized medicine– Recruit potential “early adopters” to complete an anonymous survey

from among those who sign up to attend a CPMC enrollment event

• Explore participant understanding of personalized genomic disease risk results, intended and actual use of information and educational needs of individuals receiving results– Interview with CPMC participants (n=60)

• Develop possibly recommendations for the ethical offering of personalized genomic disease risk assessment

Perceptions of Benefits of CPMC

% agreeing or strongly agreeing

Perceptions of Risks of CPMC% agreeing or strongly agreeing

Nature, November 6th, 2008

“Coriell study is leading by example…”

CPMC Praised in Nature Article

HHS Visits Coriell“pioneers in the field of personalized medicine”

Federal HHS Secretary Michael Leavitt Commissioned white paper

For-Profit Personal Genome Companies

Will profile your genome for $1000 - $2500

Contrasts between the CPMC study and some for profit DTC companies

No charge to study participants

Genetic counseling provided

A research study to determine whether genome Data is useful clinically

Direct engagement of hospital partners

Risk reporting based on family history, Demographics, lifestyle and genetics

IRB approved and monitored

Return of only potentially actionable results

Recruitment of underserved minorities

Collection of rich set of medical data over time

Difficult Ethical, Legal and Social Issues

Ensuring genetic privacy

Anxiety associated with a genetic prognosis

How will doctors use the information?

Education of Participants, Doctors, Nurses and genetic counselors

Insurance Companies

EMRs!

The Alternative

cpmc.coriell.org