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Health and Biotechnology: Integrating Science and Infrastructure in Personalized Medicine
Joseph L. MintzerCoriell Institute for Medical Research
April 15, 2013
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Outline1. Introduction: Coriell Institute for Medical Research
2. Laboratory and Biobank Infrastructure
3. Coriell Personalized Medicine Collaborative: Methodology Genome Informed Medicine Participant Results
1. Establishment of the Induced Pluripotent Stem Cell Laboratory (iPSC)
2. Ethical Considerations
3. Summary and Concluding Remarks
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Coriell Institute for Medical Research, founded in 1953 and based in Camden, New Jersey, USA.
Pioneering programs in personalized medicine, cell biology, cytogenetics, genotyping, induced pluripotent stem cells, and biobanking drive our mission.
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501(c) non-profit biomedical research institute (NPO)
Ships and receives biomaterials from approximately 55-60 countries annually
“Custodian” of more than fifty (50) public and private biobank collections assuring
compliance to the wishes of the collection sponsor.
Recognized for its uncompromising commitment to quality.
Exceeds $35M in NIH biobanking contract renewals
Selected recently to build the iPSC biobank in California.
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Maintains an independent “Federalwide Assurance for
the Protection of Human Subjects,” including a
Department of Defense (DoD) Federal wide
Assurance Addendum
Research focus: “Genome Informed Medicine,”
through the “Coriell Personalized Medicine Collaborative (CPMC)” study
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Collection Types in the Coriell Biobank National Institutes of Health (NIH)
sponsored Collections
• National Institute of General Medical Sciences (NIGMS)
• National Institute of Aging (NIA)• National Institute of Neurological Disorders
and Stroke (NINDS)• National Human Genome Research Institute
(NHGRI)
Other important partnerships
• CHDI Foundation (Huntington’s Disease)
• Autism Research Resource
• National Science Foundation
• Centers for Disease Control and Prevention
• MJFox Foundation (Parkinson’s Disease)
• Congenital Heart Disease Genetic Network Study (CHD GENES)
Courtesy: S. Madore
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Basic Biobanking FunctionsBasic Biobanking Functions
Information TechnologiesInformation TechnologiesProject ManagementProject Management
Core ServicesCore ServicesScientific ExpertiseScientific Expertise
Sample collection kitsSample data captureProper consent
Laboratory Information Management System
Inventory Management and Catalogue System
Quality Management System Q9001-2008 compliant
Courtesy S. Madore
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Organization of Coriell Biobanking Operations
BiobankingBiobanking
Courtesy: S. Madore
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Health Disparity & Diversity CollectionsHealth Disparity & Diversity Collections
Ed
uca
tion
Ed
uca
tion
Bio
Ba
nkin
gB
ioB
an
king
Quality Management
Coriell’s Extensive Collections
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100% in-house, on-site administration and development
Leading edge technologies• Server Virtualization• Business Process Management Platform• LIMS managing ~12.0 million biosamples• Google Analytics and Collaborative Services• Standards driven architecture
• State-of-the-art Data Center (2009) with
Enterprise-class availability and disaster recovery• FISMA Compliant
Information Technology at Coriell
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Coriell Personalized Medicine CollaborativeResearch Study
Goals:
• Study the use of genome-informed medicine in a real-world clinical setting
• Determine the best mechanism to provide information to providers and participants/ patients
• Find correlations in observational data
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Exploring Best Practices
Conceived and pursued to guide the ethical, legal and responsible implementation of personalized medicine
• Study participants control information
• Genetic counseling offered
• Report quantitative non-genetic risk
• Web portal provides two-way communication with participants
• ICOB provides dynamic reassessment of genomic data
• Report only on “potentially actionable” conditions
• Seek expert advice on actionability (ICOB, PAG)
Coriell Personalized Medicine Collaborative
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www.cpmc.coriell.org
How the CPMC Study works
1 2
3
45
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CPMC RecruitmentEligibility:
• Be at least 18 years old• Hear informed consent
presentation• Have an email address and
access to the internet
Recruitment Mechanisms:• Community based• Cancer Clinic based• Heart Clinic based
Community and
Employer
Cancer
HeartDisease
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Coriell Genotyping and Microarray Center
• One of the largest microarray facilities in the U.S. offering genome-wide genotyping
• High-throughput platforms• Affymetrix SNP 6.0 and DMET Plus arrays• Illumina BeadXpress™ platform• mRNA and miRNA expression profiling• Copy number variation analysis • CLIA certified in all 50 states• Custom genotyping panels
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1.5 Gigabytes of Raw Data, per Participant• Combined genotyping raw data provides more than
1.2 gigabytes• Demographics, Family/Medical History, Survey
Results, Risk Reports• IBM XIV Grid Storage SAN and HP EVA SAN• Microsoft SQL Server Databases
Complete Genome Sequencing… Imminent• 3.2 Billion points of data• More than 1TB per subject• Multiple vendor platforms
Coriell Personalized Medicine Collaborative
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The CPMC uses two “GeneChips”
Affymetrix 6.0Affymetrix DMET Plus
• 2 million sites of variation
• 2,000 sites of known
relevance to drug action
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What information do we collect?All Cohorts:
• Demographic Information• Medical History• Medications• Family History• Lifestyle Information• Genetic Knowledge assessment
Cancer Cohorts:• Cancer Registry Data• Cancer-related health records• Prescribing Records
Heart Disease Cohorts:• Electronic Health Records• Prescribing Records
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Education:
Educating physicians and the public
Counseling:
Providing genetic counseling
Access to pharmacist network
Surveys:
Baseline and 3 month follow up
Outcomes Research
Coriell Personalized Medicine Collaborative
Where the CPMC Study Stands Apart
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1.Selection of
Genetic Variant
& Health
Condition
2.Assessment & Approval by Independent
Advisory Board (ICOB)
3.CPMC
Risk Reporting
Genetic Risk
Reporting
Non-Genetic
Risk Reporting
Coriell Personalized Medicine Collaborative
Risk Reporting Process
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Informed Cohort Oversight Board (ICOB), an external advisory board composed of scientists, medical professionals, ethicist, community members, who:
•Vote on whether conditions are potentially actionable.•Meet regularly to approve new conditions.•Urge results reporting all participants.
Supported by the RNR Foundation
Who decides what genetic information is reported?
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• Review in vivo PK/PD evidence or in vitro functional analysis supporting effect on protein function (e.g. enzymatic activity,plasma concentrations, etc.), if available
• Review clinical outcome data supporting drug metabolizing phenotype, including adverse events or reduced efficacy
Strength of Evidence Code
PK: PharmacokineticPD: Pharmacodynamicn: null mutationscd: mutation located in known important substrate-binding or catalytic domainse: mutation leading to splicing errorae: mutation leading to altered gene expression.
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Complex Disease• Age-related macular degeneration• Breast cancer• Bladder cancer• Chronic obstructive pulmonary disease• Colon cancer• Coronary artery disease• Inflammatory bowel disease• Hemochromatosis• Lupus• Melanoma• Obesity• Prostate cancer• Rheumatoid arthritis• Testicular cancer• Type 1 diabetes, and Type 2 diabetes
Potentially Actionable Conditions Currently Approved to be Reported by the CPMC Study®
Drug Metabolism
•CYP2D6
•VKORC1
•CYP2C9
•CYP2C19
•UGT1A1
•CYP4F2
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Demonstrating Variants to CPMC Participants
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Genetic and Non-Genetic Risk Assessments:Provided via CPMC Online Web Portal
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Coronary Artery Disease: Outcome Survey
Respondent Characteristics N = 472 %
Mean Age 51 years
Female 315 68.9
Caucasian 433 94.8
Bachelors Degree or higher 328 71.7
Occupation
Healthcare providers (all) 122 26.7
Life, Physical, Social Scientists 24 5.3
All other Occupations 311 68.1
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Distribution of Participants by Number of CAD Risk Factors
N = 430 %
No Risk Factors 55 12.8
One Risk Factors 197 45.8
Two Risk Factors 161 37.4
Three - Four Risk Factors 17 4.0
Participants reporting somewhat/very high perceived risk
No Risk Factors 1 / 55 1.8
One Risk Factor 63 / 197 32.0
Two Risk Factors 75 / 161 46.6
Three to Four Risk factors 14 / 17 82.4
Coronary Artery Disease: Outcome Survey cont’d:
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Outcomes by Risk Group
Tests/Procedures received since receiving CPMC CAD results:
Electrocardiogram 95 20.8%
Echocardiogram 42 9.2%
Stress Test 31 6.8%
Nuclear Stress Test 17 3.7%
Electron Beam CT 5 1.1%
MRA 4 0.9%
Balloon angioplasty and stent placement
2 0.4%
Other 34 7.4%
Don’t Know 2 0.4%
No tests or procedures
296 64.8%
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Tests or Procedures by Risk Group
Tests received associated with age and positive family history of CAD. No strong association between genotype and tests received.
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Perceptions of Benefits of CPMC
• % agreeing or strongly agreeing
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• % agreeing or strongly agreeing
Perceptions of Risks of CPMC
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What is an induced pluripotent stem cell (iPS) and how is it generated?
• The iPS cell is
– self-renewing (retains ability to make more cells like it)
– pluripotent (retains ability to differentiate into many tissue types)
http://www.cellulardynamics.com/images/ips_process.jpg
“Reprogramming factors”-Txn regulators
-[DBPs, miRNAs, siRNAs]- Small molecules
2 Properties of Stem CellsSelf renewalPluripotency
Courtesy S. Madore
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Induced Pluripotent Stem Cell (iPS), a Reprogrammed Adult Cell
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Colony of Undifferentiated
stem cells
Shows that the stem cells can
produce all types of cells
Nerve CellsCardiac Cells
Pancreatic Cells
Undifferentiated Stem Cells are Unspecialized Cells
They can be tested for their ability to
become specialized cells
They can be tested for their ability to
become specialized cells
Courtesy C. Beiswanger
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Potential Uses of iPS Cells
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iPSCs for Studying “Disease in a Dish”
Compare with matched
“normal” cells
iPSCs in Coriell’s collection include Huntington’s Disease, Spinal Muscular Atrophy, and “apparently healthy” controls.
Courtesy S. Madore
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1. Informed Consent, is it truly informed?2. Information Management, are we really managing?
a. Personal health recordsb. Data compromise: discovery is possible
3. Genomic Eraa. Are we prepared for what is being revealed about
ourselves and others?b. Are we prepared for what may be possible? c. Is Society?
4. How and what do we teach; who is ready to learn?5. Who decides?
Ethical Considerations
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1. The CPMC initiative is integrated seamlessly into the Coriell infrastructure.
2. The integration of research and biobanking has promulgated cutting edge laboratory investment, e.g. iPSC.
3. The “appetite” for genome informed health care is in its infancy.
4. Information technology sustains and promulgates the scientific enterprise
5. The genome era is challenging our understanding of science and raising new ethical issues, yet to be truly revealed or understood.
Concluding Remarks
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Coriell Institute
Acknowledgements:
Michael Christman Steven James MadoreCourtney Kronenthal Karen Fecenko-TackaKaren Fecenko-Tacka Christine BeiswangerCPMC Team