Transcript Some Diversity Enables Us To Resist Infectious

Non-profit research institute and world’s leading biobank
Copying Leads to “Spelling Mistakes”
Some Diversity Enables Us To Resist Infectious Disease
Science magazine’s
“Breakthrough of the Year” in 2007
Most Genetic Variation is Shared Among Us All
Compare two chromosomes from any two people
Only ~ 1 in 1000 bases differ
Do these same sites show variation in other people?
90% chance that they do (freq. > 1%)
Gabriel et al. Science, 2002
Out of Africa
Measuring Genetic Variation is Now Possible,
Comprehensive and Cost Effective
Don’t we already know about many
Human Disease Genes?
Heart Disease, Diabetes
Cancer, Obesity
All known single
Gene diseases
~2,000
Multi-Gene Diseases
Impact on
Public 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
Plavix Must Be Activated in the Liver
Plavix
CYP2C19
Plavix*
liver
Alternative Drug
$8 Billion in
Annual Sales
Prasugrel
Just Approved by FDA
Tamoxifen is a Pro-Drug
7-10% of Women do not activate Tamoxifen
Alternative: aromatase inhibitors
Goal is to Determine Whether Using
Personal Genome Information
Will Be Useful In Medicine?
Genome-informed medicine will not be widely
Adopted 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?)
Correlations in Observational Data
Observational Data Can Be Useful
Dr. Francis Collins
“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
Free
Research study
The CPMC Uses Two “GeneChips”
2 million sites of variation
2,000 sites of known
Relevance to drug action
D-MET Coverage
Coriell Genome
Center
CLIA!
Education of Medical Professionals
“Don’t even tell me it’s a wart.”
Input From Medical Professionals
Who can participate and how
are they recruited?
Eligibility:
You must be at least 18 years old
You must have an email address and access to the internet
Recruitment Mechanisms:
Community-based recruitment
Cancer Clinic-based recruitment
Primary Care-based recruitment
Chronic
Disease
Community
and
Employer
Cancer
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 Information
Medical History
Medications
Family History
Lifestyle Information
Genetic Knowledge assessment
Cancer Cohorts:
Cancer Registry Data
Cancer-related health records
Prescribing Records
Primary Care Cohorts:
Electronic Health Records
Prescribing 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 to
all participants.
Actions completely transparent.
RNR Foundation
CPMC Risk Reporting
CPMC Process Overview
1. Selection of
Genetic Variant
&
Health Condition
2. Assessment &
Approval by
Independent
Advisory Board
(ICOB)
3. CPMC Risk
Reporting
Genetic
Risk
Reporting
NonGenetic
Risk
Reporting
Genetic Variant/Disease Selection
Search Public Databases for
published GWAS
NHGRI 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)
Selection of Health
Condition:
•Health conditions only (no Traits)
•Is disease potentially ‘actionable’?
•Assess by review of medical society policies
and recommendations
Final list of Health Condition/Genetic variants
Prepare Document with Health Condition and a Genetic Variant
Summaries for submission to ICOB
CPMC Risk Reporting
Objectives:
• Report findings directly
from the literature
• Apply as few assumptions
as possible; no reanalysis
• Report both genetic risks
AND non-genetic risks
Report Risks as Relative
Risk:
• Relative effects (OR, RR,
HR) more commonly
reported in the literature
• RR easier to interpret than
OR
• Very few prospective
studies reporting absolute
risk due to both genetic
and non-genetic factors
Risk Estimation
Step 1: Study Selection
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
Step 2: Risk Determination
 If study reports relative risk – report risks directly
 If study reports odds ratios – estimate relative risk and report
estimated risks
Study Selection
PubMed & HuGENetTM
Perform
Updated
Search for
ICOB
approved
SNPs
Hierarchy of Study
Designs
Meta-Analysis of
Prospective Studies
Individual Prospective
Study
Select
studies
from
highest
tier
Study Quality
• Disease Assessment
Carried out consistently?
Objective?
Clinically accepted definition?
• Genotyping
Are methods valid?
Carried out consistently?
•Population Stratification
Meta-Analysis of CaseControl Studies
Individual Population-Based
Case-Control Study
Individual Case-Control Study
(not population based)
Could risk estimates be biased?
If more than
one paper
qualifies then
select the
largest study
Select
Paper
Example: CAD and SNP rs1333049
Hierarchy of Study
Designs
Meta-Analysis of
Prospective Studies
no
Individual Prospective
Study
no
Meta-Analysis of CaseControl Studies
yes
Individual Population-Based
Case-Control Study
Individual Case-Control Study
(not population based)
(Circulation 2008; 117:1675-1684)
CDKN2A/CDKN2B
RR Estimates
rs1333049
(95% CI)
GG*
1
CG
1.29 (1.22 , 1.37)
CC
1.67 (1.48, 1.87)
*reference group
How do participants learn
about their results?
Participant Risk Summaries include
Non-genetic Risks
Potentially Actionable Conditions
Complex Disease
Drug Metabolism
Obesity
CYP2D6
Prostate cancer
VKORC1
Colon cancer
Melanoma
Coronary artery disease
CYP2C9
CYP2C19
Type 2 diabetes
Type 1 diabetes
Age-related macular degeneration
Hemochromatosis
Inflammatory bowel disease
Lupus
Rheumatoid Arthritis
As of
6-10-09
Pharmacogenomics Advisory Panel
Dr. Issam Zineh
FDA
Office of Clinical Pharmacology
CYP2D6-Tamoxifen
What Do My Results Mean?
Genetic Counselors available at no cost
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
PRWT and Cherokee Pharmaceuticals
Franklin Institute of Philadelphia
Reverend Floyd White of Camden, NJ
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 deidentified data for biomedical research.
Coronary Artery Disease Survey
Via Portal at 3 and 12 months
Surveys, Annual medical history updates,
And EMRs
Health Outcomes
Behavioral Outcomes
Newly diagnosed CAD
MI
Angina
Communication
Bypass surgery
Changes in behavior
Risk perception
Recent Federal Grants
CPMC Participant Behavior Upon Receiving Genome Info.
(Reed Peyritz at Penn)
Web-based educational content for physicians
(Mary Daly at Fox Chase)
•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
Perceptions of Benefits of
CPMC
% agreeing
or strongly agreeing
100%
97.3
92.6
90%
80%
87.3
69.1
70%
60%
50%
40%
24.3
30%
20%
11.6
10%
4.3
0%
The results will My participation
tell me about
may help
some of the
researchers
diseases I may
learn more
be at risk for.
The results will The results will The results will If I learn the
help me change tell me what tell me about all results I can
my behaviors medications to diseases I am at
have gene
and reduce my
avoid.
risk for.
therapy to
disease risk.
change my risk.
There are no
benefits.
Perceptions
of Risks of CPMC
% agreeing or strongly agreeing
35%
31.7
31.7
30.4
30%
25%
22.3
20%
15%
13.5
10%
5%
4.7
0%
The results may There are no risks. I may learn that I I may not be able I may learn that I I could lose my job
cause me to worry
have an increased to get insurance if have an increased if the results get
risk for a disease the results get out. risk for a disease
out.
that I did not want
that I can do
to know about.
nothing about.
CPMC Praised in Nature Article
Nature, November 6th, 2008
“Coriell study is leading by example…”
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
Recruitment of underserved minorities
Return of only potentially actionable results
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