1. The University of Utah 9/4/20151 The Problem: Today’s Medicine The current system of health care delivery is inherently wasteful and driven more by tradition than by scientific principle. A new paradigm is needed to control costs and improve health (outcomes). Most of today’s medications are less than 50% effective in the intended population. Adverse drug reactions caused by the failure to predict toxicity in individuals and toxic drug-drug interactions now account for 100,000 patient deaths, 2 million hospitalizations, and $100 billion in health care costs in the United States every year. Current costs to bring a drug to market are astronomical (e.g. >$1B and 10 or more years).

2. The University of Utah 9/4/20152 The Consequences of Reactive Health Care Snyderman & Langheier, Genome Biology 2006; 7(2):104

3. The University of Utah 9/4/20153 Snyderman & Langheier, Genome Biology 2006; 7(2):104 The Consequences of Reactive Health Care

4. The University of Utah 9/4/20154 The Solution: Personalized Medicine Multiple names/similar concepts:  Predictive Medicine  Individualized Medicine  Information-based Medicine Common Goals:  Increase the efficacy of treatment  Minimize side effects  Improve cost-efficiency “The next ten years will be seen as a signal point of transition in healthcare. Medicine will be transformed from an instinctive art of alleviating symptoms to a science of personalized health care”. Secretary of Health and Human Services, Michael Leavitt (2006)

5. The University of Utah 9/4/20155 Why a Genetic Approach is Warranted Disease Heart Disease Cancer Stroke Lower Respiratory Disease Adverse Drug Reactions (est) Diabetes # of Deaths* 696,947 557,271 162,672 124,816 106,000 73,249 Genetic Susceptibility? Yes *National Vital Statistics Reports, Vol. 53, No. 17, March 7, 2005

6. The University of Utah 9/4/20156 Large Families Plus High Quality Clinical Information are Critical to Provide Insight into the Genetic Variations that Cause Disease Why Utah Provides a Unique Genetic Resource…

7. The University of Utah 9/4/20157 Utah Population Database (UPDB) University of Utah research resource Over 30 years of research About 9.0 million documents 65 approved projects http://www.hci.utah.edu/groups/ppr/

8. The University of Utah 9/4/20158 UPDB Resource Conduct studies that require individual and familial data Family histories (mainly Utah and SE Idaho families)  Genealogies: Family History Library, maintained by LDS Church  Family reconstitution: Create families from Utah’s vital records ◦ Create maternal and paternal birth histories  Link across generations - 11 generations for some families Medical information is linked to family histories  State wide cancer records  Vital records: cause of death and medical details from birth certificates  University of Utah Health Sciences medical records

9. The University of Utah 9/4/20159 Sources for Data UPDB Resource for Genetic & Epidemiologic Research

10. The University of Utah 9/4/201510 Documents Available in UPDB Genealogy (over 170,000 family group sheets)1,599,292 Utah birth certificates (1915-21, 1947-2005)2,088,389 Utah marriage and divorce (1978-2004) 783,993 Utah death certificates (1904-2005) 707,971 Social security death index 479,311 Utah Cancer Registry (in situ and invasive) 216,266 Cancer Data Registry of Idaho 124,079 Driver License 2,773,562 Total8.9 million Linked into 6.5 million “person records” and across generations

11. The University of Utah 9/4/201511 M F 102 7 3 12 8 4 1 5 Father (F), Mother (M) and children by birth order Married 1853, 12 Children, 3 Infant deaths (#6, 9, 11) Utah Family, Circa 1900

12. The University of Utah 9/4/201512 8 th of 15 children1 st of 5 children 1807180218171819 1889187018541850 CanadaNew YorkEnglandConnecticut MFMF 18371835 19171915 123456789101112 185418551857185918611863186418671869187018721874 193219401930193118921863193919521869190218721943 Utah Family in UPDB Spans 11 generations from 1807 to 2005 Couple (in picture): 4,289 descendants (3,821 living) Paternal side: 6,510 descendants (5,714 living) Maternal side: 19,350 descendants (16,973 living) 8 th of 15 children1 st of 5 children 18071802 1817 1819 18891870 1854 1850 Canada New York England Connecticut M F 1837 1835 1917 1915 1 2 34 5 6 7 8 9 10 11 12 1854 1855 1857 1859 1861 1863 1864 1867 1869 1870 1872 1874 1932 1940 1930 1931 1892 1863 1939 1952 1869 1902 1872 1943 Maternal side Paternal side

13. The University of Utah 9/4/201513 Utah: Extraordinary Research Opportunity Low inbreeding rate  Large initial founding population  High rates of immigration from diverse outside populations Extrapolate findings to broad spectrum of US and Western and Northern European populations Identify predisposition to disease  APC gene mutation in colon cancer  BRCA1 and BRCA2 breast cancer mutations  P16 gene mutation in melanoma cancer  Prostate cancer susceptibility gene

14. The University of Utah 9/4/201514 Inherited DisorderGene Colon Cancer (Familial Adenomatous Polyposis Coli)APC NeurofibromatosisNF-1 Breast CancerBRCA-1 BRCA-2 Melanomap16 Cardiac arrhythmias (Long QT Syndrome)KVLQT1 minK HERG MiRP1 Supravalvular Aortic StenosisELN Alport SyndromeCOL45A5 HypertensionXIB AGT Macular degeneration (Stargardt’s Disease)ABCR Ulnar-Mammary SyndromeTBX3 Williams SyndromeLIMK1 Porphyria Cutanea TardaURO-D Inflammatory SyndromesPAF-AH Chediak-Higashi SyndromeCHS-1 Neonatal EpilepsyKCNQ2 KCNQ3 Hyperkalemic Periodic ParalysisSCN4A Paramyotonia CongenitaSCN4A Potassium Aggravated MyotoniaSCN4A Hypokalemic Periodic ParalysisCACNA1S Periodic Paralysis 3KCNE3 Andersen’s SyndromeKCNJ2 Frings Audiogenic EpilepsyMass1 Spinocerebellar Ataxia Type 7SCA7 Familial Advanced Sleep Phase SyndromehPer2 Genetic Disorders in Which the Molecular Basis Was Discovered at the University of Utah

15. The University of Utah 9/4/201515 Sources of Medical Information Research Infrastructure - Master Subject Index U of U Health Sciences Center (UUHSC), Enterprise data warehouse (EDW)  Matched over 1.0 million (70%) patient demographic records  About 18 new projects Huntsman-Intermountain Cancer Care Program,  Link to Enterprise data warehouse  Developing an agreement to link data sets  5.3 million individuals in Enterprise Data Warehouse  Proposed to begin summer 2007  A use agreement has not be developed

16. The University of Utah 9/4/201516 New Research Opportunities Access to University of Utah Medical Records  Matched 1.0 million patient demographic records 16 new research projects, e.g.  Cardiovascular mortality in renal transplant patients  Fibromyalgia and chronic fatigue syndrome  Hereditary angioneurotic edema  Inflammatory bowel disease  Macular degeneration and other eye diseases  Polycystic ovary syndrome  Psoriasis  Rheumatoid arthritis

17. The University of Utah 9/4/201517 Examples of Types of Studies  Cancer Studies ◦ Cancer genetics: breast, colon, melanoma, pancreas, prostate ◦ Familial aggregation of cancers  Obstetric complications and childhood studies ◦ Preeclampsia and preterm births ◦ Birth defects, autism, juvenile idiopathic arthritis, developmental hip dysplasia  Chronic and other diseases and conditions ◦ Diabetes, psoriasis, rheumatoid arthritis, inflammatory bowel disease ◦ Macular degeneration, giant cell artiritis, interstitial lung disease, mullerian anomalies, ◦ Chronic pain, aneurysms, asthma, pelvic organ prolapse  Aging and mortality ◦ Longevity ◦ Memory in aging and Alzheimer’s Disease

18. The University of Utah 9/4/201518 Security and Confidentiality Not a public database – for research only  Researchers have no electronic access to identifying information State of the art database Policies and procedures on confidentiality  All projects are reviewed by IRB and data contributions Require researchers to sign confidentiality agreements Contact of potential subjects by an appropriate third party Wylie and Mineau, Biomedical databases: protecting privacy and promoting research. Trends in Biotechnology, March, 2003.

19. The University of Utah 9/4/201519 Unparalleled Discovery Assets Utah (USTAR PM) Iceland (deCODE) UK (UK BioBank) Wisconsin (Marshfield) Estonia (EGeen) Quebec (Galileo) Key advantages of Utah PM Assets  Most extensive genetic records  Extensively integrated medical records  Largest research institution

20. The University of Utah 9/4/201520 The goal of this proposed initiative is to develop a broad-based program that builds on Utah’s core strengths in human biology and genetics, and aims to further the molecular understanding of disease mechanisms to discover and direct diagnostic measures and therapeutic approaches to the right population of people, at the right time -ideally while they are still well. Personalized Medicine Initiative

21. The University of Utah 9/4/201521 Utah Genetic Reference Project  Access to genetic and phenotypic data on the genetic reference families used for the Human Genome Map and HapMap projects Utah Population Database (UPDB)  Tens of millions of records covering more than 7 million persons;  Dynamic integration of genealogic, demographic, and medical records Research Programs Clinical Trials Infrastructure University Hospital Medical Records (UUHSC) Utah Genetic Reference Project (UGRP) Utah Population Database (UPDB) Utah’s Natural Resource for Personalized Medicine UUHSC Medical Records  1.5 million person records have been Linked into core UPDB;  ICD9 Codes, pharmacy data, lab results Clinical Trials Infrastructure  Thought leaders participating in the development of new targeted therapies and molecular diagnostics Research Programs  Access to critical longitudinal data/samples  Robust prospective recruitment process