Health and Biotechnology: Integrating Science and Infrastructure in Personalized Medicine

Joseph L. MintzerCoriell Institute for Medical Research

April 15, 2013

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

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.

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.

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

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

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

Organization of Coriell Biobanking Operations

BiobankingBiobanking

Courtesy: S. Madore

Health Disparity & Diversity CollectionsHealth Disparity & Diversity Collections

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Quality Management

Coriell’s Extensive Collections

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

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

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

www.cpmc.coriell.org

How the CPMC Study works

1 2

3

45

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

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

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

The CPMC uses two “GeneChips”

Affymetrix 6.0Affymetrix DMET Plus

• 2 million sites of variation

• 2,000 sites of known

relevance to drug action

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

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

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

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?

• 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.

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

Demonstrating Variants to CPMC Participants

Genetic and Non-Genetic Risk Assessments:Provided via CPMC Online Web Portal

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

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:

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%

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.

Perceptions of Benefits of CPMC

• % agreeing or strongly agreeing

• % agreeing or strongly agreeing

Perceptions of Risks of CPMC

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

Induced Pluripotent Stem Cell (iPS), a Reprogrammed Adult Cell

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

Potential Uses of iPS Cells

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

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

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

Coriell Institute

Acknowledgements:

Michael Christman Steven James MadoreCourtney Kronenthal Karen Fecenko-TackaKaren Fecenko-Tacka Christine BeiswangerCPMC Team