Introduction to the Medical Community Introduction to the Medical Community The Measurement to Understand Reclassification of Disease Of Cabarrus/Kannapolis Study The M.U.R.D.O.C.K. Study 22 Oct 2007

Agenda  Welcome and introductory comments Andrew Conrad PhD - CSO LabCorp and NCRC Lynne Scott Safrit - President Castle & Cooke Allan Dobson MD – VP Clinical Practice Development, CFM  Overview of study plan - Rob Califf MD  Overview of -omics study tools – Jessie Tenenbaum PhD  Example of liver project - John McHutchison MD  Community engagement plan - Lloyd Michener MD  Discussion - All  Timeline and next steps - Victoria Christian  Timeline and next steps - Victoria Christian

NCRC collectively improving human health Farming Practices Food Sciences Nutrition Effective Healthcare Disease Management Health Maintenance Medical Education Public Health Population Health Productivity Global Health

In 20 years…  All people in developed nations will have — An electronic health record Biological samples Digitized images  Healthcare will be personalized using an individual’s images, samples and clinical data.  The health of a community will be monitored using aggregate records.  Kannapolis — as hub of the Carolinas — could define this future through a public-private partnership.

 Build value using assets already in our reach.  Sub-classify major diseases into populations with specific risks and optimal therapy.  Apply new knowledge to the study of community health.  Re-define clinical research using the power of genomics and biomedical informatics.  Re-write the textbook of medicine. The MURDOCK Study will … Improvehumanhealth.

The MURDOCK Study will...  Fuel the financial success of the DHMRI Core Laboratory and Biorepository.  Foster breakthrough collaborations between NCRC schools with diverse and interconnected perspectives and expertise  Quickly increase the visibility and scientific impact of the DHMRI Lab.  Attract the scientific community.  Attract the biotechnology community.  Engage the local population in a high-impact, internationally recognized project. The modern equivalent of the Framingham Heart Study

Current data assets & DHMRI tools: Powerful once-in-a-lifetime value proposition

A new era of biomedical research  Novel research technologies have enabled the study of thousands of molecules at a time  Referred to as “high throughput” approach  These novel methods enable ‘-Omics’ scale research

What is ‘-Omics’?  The study of the totality of a type of biological data All genes: Genomics All transcribed genes: Transcriptomics All proteins: Proteomics All metabolites: Metabolomics  Omics scale research has enabled patient profiling at the molecular level

Continuum of -Omics Genes  mRNA  Proteins  Metabolites Genomics Transcriptomics Proteomics Metabolomics

Genomics and the media

Glass slide An example: DNA Microarrays Isolate mRNA, label Dr. Russ Altman, Stanford Univ. Cells of interest Reference sample Known DNA

DNA Microarray visualization: heatmaps Experiment 1 (e.g. Patient X) Gene 1 Gene 2 Expt 1 Gene 5 Gene 6 Gene 7 Gene 8 Gene 3 Gene 4 Gene 9

An opportunity   For the first time, diseases can be defined by molecular fingerprints or profiles   Mechanistic pathways of diseases can be elucidated   Symptomatic descriptors can be replaced by meaningful tools for stratification  These tools will enable truly personalized medicine

Medicine today   Drugs are developed to treat all patients with the same clinical diagnosis - “one size fits all”   Many drugs only work in less than half of the patients for which they are prescribed   Over 100,000 people die annually from drug related adverse events - a ‘top 10’ cause of death

‘-Omics’ technologies can help predict treatment response. Responder Adverse event Non-responder Cancer Excercise + Diet A Exercise + Diet B Exercise + Diet + Medication Diabetes -Omics Technologies

Combining clinical and molecular data will redefine disease management.  Quantify risks of developing diseases.  Apply preventive measures more effectively.  Establish diagnosis earlier.  Prevent disability by treating earlier.  Predict death and disability.  Use healthcare resources strategically.

Three horizons of MURDOCK Study Horizon 1 Use assets on hand to generate molecular data Generate hypotheses by leveraging bioinformatics Horizon 1.5 Engage community Build community registry Horizon 2 Validate hypotheses prospectively Apply new knowledge to local community through partnership with local medical community Improve human health

Outcomes of Hepatitis C virus infection Spontaneous clearance (~25%) Chronic infection Treatment RespondersNon-responders (>50%) Hepatic Fibrosis Steatosis Insulin resistance Dyslipidemia Increased risk of diabetes Unknown consequences

Reclassification of HCV disease  Use genomic technologies to subset patients based on their molecular signature  This signature may become a useful marker of: Treatment response – therapeutic decision-making Development of fibrosis or steatosis - non-invasive diagnostic alternative Insulin resistance or dyslipidemia – may have broader relevance for diagnosing and treating non- HCV patients with these conditions

Selection of biomarkers for HCV profiling  Standard available assays: inflammatory, lipid metabolism, glucose metabolism, etc.  Novel protein biomarkers – proteomic discovery  Novel protein biomarkers – genetic approaches

Novel biomarker discovery strategies  Proteomic discovery  Genetic discovery gt1gt2gt3 R NR  Open discovery platform allows for discovery of novel protein biomarkers (host or viral-specific) that may be associated with treatment response and/or HCV genotype  These biomarkers, along with others, will be typed in a large HCV patient cohort  Unbiased discovery platform tests for association of >500,000 gene variants with HCV outcomes and/or quantitative traits (protein markers)  Genes discovered in this way may become useful protein biomarkers or remain as DNA diagnostics

Molecular profiling of HCV patients  Type large number of biomarkers in ~1000 chronic HCV patients from the Duke Hepatology Research Clinic cohort Tx response Fibrosis Steatosis Diabetes Dyslipidemia  Use statistical modeling to subset HCV patients based on common biomarker signatures  Correlate molecular signatures with outcomes in HCV patients and similar traits in non-HCV patients

Deploy assets for maximum potential benefit to communities.  Uncover new knowledge in diseases that afflict large patient populations. Epidemics — obesity, diabetes, depression Diseases of aging — arthritis, dementia  Use this new knowledge in clinical practice. Make decisions based on breakthroughs in the individualized treatment of breast cancer and depression  Make new discoveries with commercial potential. Contributory drug-able pathways Novel biomarkers

Challenge of biomedical informatics: Turning data into knowledge DATA Knowledge

Groundwork for successful community engagement  Transparency of efforts  Advice from appropriate community groups Questions to ask: how are citizens best reached? where do they gather? how do they prefer to receive information?  Preparation of documents and study plans in iterative process with feedback from community  Communication strategy based on community groups’ advice  Formation of Community Advisory Group

Possible modes of engagement  Interactive website  Community surveys  Posters, brochures, other written materials  Educational presence at community events (e.g., health fairs)  Targeted cable television programs Local physician and patient with 15 min on specific topic (living with osteoarthritis, managing diabetes, etc.)  Videos for doctors’ offices  Interactive kiosks  Open communication with local media outlets  Meetings with community groups (health related and non-health related)

Community Registry Accelerating Discovery:  Suppose we identify a Biomarker that distinguishes a sub-population of patients correlating with new insulin resistance  If this is true, we’d treat differently to achieve better patient outcomes  We need to test this to assure improved patient outcomes  Positive result would drive creation of the diagnostic and care guidelines. Finding Application Translation into Practice Confirm

Community Registry  Allow patients to declare interest in research participation  Store information People interested in research participation Summary level health information Permission to contact Primary physician  Accelerate discovery by having this information when discoveries are ready to be tested

Summary  We are committed to building transparent, open partnership with local community.  We will seek to maximize opportunities to have meaningful impact on local human health and local economy.  The MURDOCK Study offers an opportunity for the local community to have global impact by generating knowledge that improves health and alleviates disease.