1. An Overview of Marshfield Clinics Research Program Exploring Opportunities for Collaboration in the Real World Dr. Humberto Vidaillet Director of Medical Research, Marshfield Clinic Director, Marshfield Clinic Research Foundation Clinical Professor of Medicine, UW SMPH September 14, 2011

2. Objectives: Purpose of Forum Provide an opportunity for research networks and other research groups to learn about each other and the projects they conduct. Learn about operational and project barriers, and successful methods to overcome barriers. Facilitate networking and connections between people and groups with similar interests.

3. 3 Welcome to Marshfield Clinic * * Ranked by Forbes in 2010 as the 5th best small city in the country to raise a family. Designated in 2008 by Demographics Daily as one of the nations top 20 Dream Towns

4. Marshfield Clinic Mission: To serve patients through accessible, high quality health care, research and education 501(c)(3) organization Largest private group practice in WI: 52 centers in >35 communities >770 physicians (102 family practice physicians) in >85 specialties 6,600 additional personnel ~3.5 million patient encounters/year ~365,000 unique patients/year Marshfield Labs (Human & Veterinary) Lakeview Medical Center, Rice Lake, WI Security Health Plan (HMO)

5. Why Marshfield Clinic Engages in Research & Education Core elements of Marshfield Clinics Mission, its status as a nationally recognized Academic Medical Center, and its Charitable Trust Contribute to knowledge leading to advances in patient care, quality metrics and public health, improves the quality of human existence and the lives of our patients and their loved ones Contribute to recruitment of high quality physicians and other professionals who want to work in an academic environment Differentiate Marshfield Clinic from competitors; patients rightly conclude that care is better at centers involved in research & education For clinicians who do research and teach, it adds another dimension to their contributions to medicine and improves their clinical practice; for virtually all Marshfield Clinic employees, a sense of shared pride! Research and Education have been integral to the Clinics culture, sustained growth and quality of care since 1916!

6. Research Program at Marshfield Clinic ~400 active studies ~125-150 clinical investigators and 30 MD/PhD scientists Major external sponsors: NIH, CDC, NIOSH, AHRQ, Industry, Philanthropy Academic structure: IRB, Research Comm., Research Compliance, Conflict of Interest, Biosafety, etc. Tenure program and Endowed positions Marshfield Clinic Research Foundation (MCRF) Mission: To discover and communicate scientific knowledge that substantially improves human health and well-being - 200 staff Main Clinic Building East Wing St. Josephs Hospital Laird Center for Medical Research Lawton Center for Research & Education

7. Research Program Structure Marshfield Clinic Research Foundation Humberto Vidaillet, MD, Director Steve Wesbrook, PhD, Deputy Director Clinical Research Center Steven Yale, M.D. Biomedical Informatics Research Center (BIRC) Simon Lin, M.D. Center for Human Genetics Murray Brilliant, Ph.D. Epidemiology Research Center Edward A. Belongia, M.D. National Farm Medicine Center (Rural, Agricultural Health & Safety) Barbara Lee, RN, PhD Research Centers Research Support Offices/Services Core Laboratory Research Integrity & Protections Scientific Writing & Publications Sponsored Programs & Fiscal Affairs Health Systems Research Associate Director Adedayo Onitilo, M.D.

8. Oversees MCRF, providing policy direction, financial oversight, and counsel to MCRF leadership in a wide range of areas associated with research structure, process, and resources MCRF Board of Trustees Physician Members Jaime Boero, MD. Vice - Chair Michael Caldwell, MD, PhD Christopher Cold, MD Rezwan Islam, MD Ram Pathak, MD Kent Ray, DO Shereif Rezkalla, MD, Treasurer Karl Ulrich, MD Matthias Weiss, MD Scientist Member Po-Huang Chyou, Ph.D. Community Members Rene Daniels John Hutchinson Brian Kief Patricia Kleine, Ph.D. John Laird Scott Larson, Secretary Mark T. Nelson Mark Nook, Ph.D., Chair Jim Schuh James Weber, PhD UW System, Interim Senior Vice President for Academic Affairs Mark Nook, PhD

9. 9 Publish Clinical Medicine & Research Publish Journal of Agromedicine With Division of Lab Medicine, part of State Laboratory Response Network and CDCs Select Agent Program; provide Laboratory Medicine facilities for its R&D With Clinic Information System, develop new clinical medical informatics tools Other Capacities

10. Research Strategy and Guiding Principles Integration of research into clinical practice and clinical practice into research. Collaboration with other top-tier medical centers, especially UWSMPH (now ICTR) and MCW. Dedication to achieving excellence in translational research, which requires close collaboration among physicians and scientists to bring scientific advances into clinical care and public health.

11. Select Research Collaborations at MCRF (1)

12. Select Research Collaborations at MCRF (2)

13. Founded jointly in 2007 by UW and MC Has become framework of strengthening research ties between the two institutions Awarded a Clinical and Translational Science Award by NIH; now waiting for renewal Unprecedented level of collaboration: 14 funded pilot projects with UW-Madison investigators working together with 23 Clinic investigators from 16 different departments Likely to impact Clinics clinical and translational research for decades Institute for Clinical and Translational Research (ICTR) PARTNERSHIP Schools of Medicine and Public Health Pharmacy Nursing Veterinary Medicine and College of Engineering

14. Strength of the Marshfield Clinic - UW Research Partnership Collaboration & Integration of Administrative Activities

15. 15 The Marshfield-UW Partnership Foster Collaborations Leverage unique resources & shared Interests To Conduct research not otherwise possible …

16. 16 Purpose Facilitate collaboration among member institutions' Institutional Review Boards (IRBs) in order to provide more effective and efficient oversight of multi-site human subject research protocols In Wisconsin and reduce costs and duplication of effort among the Member institutions and affiliated investigators. One Agreement Allows any member institution to serve as the IRB of record for another, eliminating the need to draft individual, study-specific IRB authorization agreements for each study reviewed. WIC is in its development/pilot phase,and as such, is limited to the following participants: Aurora Health Care IRB, Milwaukee Marshfield Clinic IRB, Marshfield Medical College of Wisconsin IRB, Milwaukee University of Wisconsin-Madison Health Sciences IRB, Madison Wisconsin IRB Consortium (WIC)

17. Clinical Research Center Established in 1998 to provide centralized research support for clinician-led research throughout system Built on a strategy of integrating research and clinical practice More than 350 active clinical trials 125-150 clinician investigators >40 research coordinators and research nurses as well as other administrative support staff Community Clinical Oncology Program (CCOP) is the longest-running clinical research project

18. Type-2 Translational Research Study Goal To conduct a pilot test of a telepharmacy-based intervention to improve asthma control through medications and disease management in an underserved, rural patient population. Aims To assess the feasibility of providing a telepharmacy intervention To determine whether a telepharmacy intervention is acceptable To assess the interventions impact on patients asthma control, adherence to medications, and patient activation To examine the facilitators and barriers associated with implementing the intervention. The Role of Pharmacist Evaluation in Asthma Local PI Suzanne N. Havican, RN, RPh, BCPS PI Henry N. Young, PhD UW Madison

19. Type-2 Translational Research Tailored Approach to Genetic Counseling for Cystic Fibrosis Newborn Screening: A New Model Received additional/outside funding

20. Type-2 Translational Research Creating Healthy Workplaces: An intervention to Improve Outcomes for Providers and Patients Study Goal Test the impact of a novel quality improvement strategy on care quality. The quality improvement intervention (QIIs) will create healthy workplaces by addressing adverse primary care work conditions (workflow, work control, and organizational culture). Aims Increase clinician and staff interest in participating in QIIs by addressing primary care work conditions Improve care quality in hypertension and diabetes by improving work conditions Improve clinician and staff satisfaction, decrease stress, and reduce intention to leave Local PI Steven H. Yale, MD

21. Epidemiology Research Center Consequential epidemiology: focus on applied research questions that make a difference in the lives of people Vaccine safety & effectiveness Antibiotic resistance Cancer surveillance Cardiovascular care and outcomes Unique resources & network collaborations: Marshfield Epidemiology Study Area (MESA) HMO Research Network (HMORN) Cancer Research Network (NCI) Cardiovascular Disease Research Network (NHLBI) Vaccine Safety Datalink (CDC) In 2011, Dr. Laura Coleman joined as tenure-track scientist

22. Marshfield Epidemiologic Study Area (MESA) Key Features: Defined geographic region (24 zip codes) Nearly all residents choose to receive health care from Marshfield Clinic and affiliated hospitals Dynamic cohort tracked since 1991 Links to sophisticated electronic medical record system and data warehouse archive Low population mobility High population coverage and health event capture, in MESA Central: 97% population coverage 99% deaths captured 95% hospitalizations captures 90% outpatient visits captured 60,000 people 25,000 people

23. Marshfield Epidemiologic Study Area (MESA) There are more than 25 active consults in the current year, with many early and mid-career stage recipients, including: a UW Shapiro scholar, an ICTR scholar, UW Population-Health students, UW faculty and medical residents, & Marshfield faculty and medical residents.

24. Collaborations: MESA Goal: To examine the actual mortality burden and rates of cardiovascular events among a rural population-based cohort of lupus patients Mortality & Cardiovascular Events Among Rural Systemic Lupus Erythematosus Patients

25. HMO Research Network Focus is on cancer, cardiovascular disease, diabetes, genomics, vaccine safety, medical product surveillance, health care quality, and comparative effectiveness. MCRF co-hosted the National HMORN meeting in 2008, at which the NCRR Director was a plenary keynote speaker. Mission: Use collective scientific capabilities to integrate research and practice for the improvement of health and health care among diverse populations. Consortium of 16 HMO organizations MCRF leveraged the MESA cohort and Security Health Plan enrollees to facilitate membership in the HMORN. MCRF investigators are currently leading efforts on more than 20 active collaborative research projects within the HMORN.

26. Survey of the Health of Wisconsin First statewide research survey to systematically gather data on health status and health disparities among Wisconsin adults. Marshfield Clinic became the home of a new, third recruitment and enrollment center for SHOW, joining Madison (Middleton) and Milwaukee. MCRF assists SHOW data collection, including: face-to face interviews, self administered questionnaires, and physical exams. In the first year of the MCRF, 30 scheduled weeks of rural Wisconsin data collection were completed in three months due to Marshfield Clinics presence in rural WI communities. The data collected from SHOW will address critical and novel research questions to accelerate translation into evidence-based policies and health care practices, and improve health and reduce health disparities in Wisconsin.

27. Center for Human Genetics A long history of important discoveries in human genetics (short tandem repeat polymorphisms, Marshfield linkage maps) Mission: To conduct translational research in medical genetics that substantially improves patient care In 2009, recruited Dr. Murray Brilliant (Center Director, tenured Senior Research Scientist and James Weber Endowed Chair) in 2010, recruited Dr. Steve Schrodi and Dr. Deana Cross as tenure-track scientists In 2011, joint recruitment of Dr. Brautbar Major programs and unique resources: Personalized Medicine Research Project (PMRP) Wisconsin Genomics Initiative (WGI) Electronic Medical Records and Genomics (eMERGE) Network

28. Personalized Medicine Research Project (PMRP) In September 2002, Governor McCallum and the leadership of MC and MCRF announced enrollment of the first research subject Initial funds: State government ($2 million), Federal government ($800K), and Marshfield Clinic ($1 million) Ultimate Goal: Translate genetic data into specific knowledge about disease that is clinically relevant & will enhance patient care Key Features: Nations largest population-based biobank Stable population of approximately 20,000 adults DNA, plasma and serum samples on each subject Access to longitudinal electronic health record 99% of PMRP cohort has agreed to be re-contacted All genotyped for 50 medically relevant markers, ~5K high-density genotyped samples

29. PMRP Community Advisory Group The Community Advisory Group (CAG) provides advice and guidance from the community perspective on the continued development, implementation and on-going operations of the Personalized Medicine Research Project

30. Ongoing Studies Pharmacogenetics Efficacy and safety of statins Efficacy of metformin in patients with type II diabetes Pharmacogenetics of tamoxifen for breast cancer Pharmacogenetics underlying response to beta blockers in patients with glaucoma Pharmacogenetics of warfarin metabolism Sulfa hypersensitivity ACE and angioedema Genetic Basis of Disease Atrial fibrillation/flutter Cataracts Endometriosis Hypertensive heart disease Low HDL Macular degeneration Multiple sclerosis Myocardial infarction Obesity, genetics and risk of diabetes and abnormal lipids Prostate cancer Venousthromboembolism Dz.

31. Wisconsin Genomics Initiative (WGI) Announced by Governor Doyle in October 2008 Received $2 million in State FY10-11 budget A historic collaboration of Wisconsins three academic medical centers and its major urban university created to advance predictive and personalized health care Vision: to be able to predict for individual patients in a clinical setting the risk of disease susceptibility and treatment response using the combined power of cutting edge genetic, phenotypic, and environmental analyses

32. MCW Genetic & Genomic Analysis Diverse Urban & Pediatric Patient Populations High Through-Put Genotyping UW-Milwaukee Urban & Environmental Health Community Engagement School of Nursing Marshfield Madison Milwaukee UWSMPH Regenerative Medicine Statistical & Computational Analysis Super-Computing Capability MCRF Rural Cohort Comprised of 20,000 Adults Biomedical Informatics Phenotyping Wisconsin Genomics Initiative

33. Building Accurate Predictive Models Complex combinations of variables are required for accurate prediction The more we know about individual patients, greater the probability of prediction ( + & ) = P EC G

34. WGI Funded Demonstration Projects (1) Integrating Genomic Data into a Computational Model for Improved Breast Cancer Diagnosis PIs: Elizabeth Burnside, MD 4 ; David Page, PhD 4 Collaborators: Cathy McCarty, PhD, MPH 1 ; Peggy Peissig, MBA 1 ; Adedayo Onitilo, MD 1 Improving the Predictive Modeling of Atrial Fibrillation/Flutter (AF/F) and Its Outcomes PI: Humberto Vidaillet, MD 1 Collaborators: Bess Berg, MS 4 ; David Page, PhD 4 ; Peggy Peissig, MBA 1 ; Percy Karanjia, MD 1 Feasibility of Modular High Throughput Electronic Phenotyping PI: Peggy Peissig, MBA 1 WGI Infrastructure Project Proposal: Expand the Current Informatics Architecture in Order to Capitalize on the Available EMR and Genetic Data PI: Justin Starren, MD, PhD 1 WGI Exome Sequencing to Identify Coding Variants for Myocardial Infarction PI: Ulrich Broeckel, MD 2 Collaborators: Cathy McCarty, PhD, MPH 1 ; David Page, PhD 4 1 MCRF 2 MCW 3 UW-Milwaukee 4 UWSMPH

35. WGI Funded Demonstration Projects (2) Risk Modeling Post-Hospitalization Venousthromboembolism in a Population-Based Cohort PI: Steve Yale, MD 1 Collaborators: Mark Craven, PhD 4 ; Deanna Cross, PhD 1 ; Stephen Talsness, BA 1 ; Peggy Peissig, MBA 1 ; Joseph Mazza, MD 1 Sustained Community Engagement in Genetics and Genomics Research to Improve Health and to Increase Health Equity PIs: Aaron Buseh PhD, MPH 3 ; Sandra Underwood, PhD, RN, FAAN 3 Development of a Predictive Algorithm for Age-related Macular Degeneration PI: Murray Brilliant, PhD 1 Collaborators: David Page, PhD 4 ; Joe Carroll, PhD 4 ; Cathy McCarty, PhD, MPH 1 ; Gary Pesicka, MD 1 ; Robert Valenzuela 1 Investigation of Genomic Association Between Heart Failure & Diabetes Mellitus PI: Nancy Sweitzer, MD, PhD 4 Collaborators: Cathy McCarty, PhD, MPH 1 ; Orly Vardeny, PharmD 4 ; Zhan Ye, PhD 1 Membrane Metaloproteinase-9 Genotype and Aortic Aneurysm PI: Jay Yang, MD, PhD 4 Collaborators: Sijan Wang PhD 4 ; Martha Wynn MD 4 ; Charles Acher, MD 4 ; Peggy Peissig, MBA 1 ; Ulrich Broeckel, MD 2 1 MCRF 2 MCW 3 UW-Milwaukee 4 UWSMPH

36. WGI Project: Development of a Predictive Algorithm for Age-Related Macular Degeneration

37. WGI Project: Sustained Community Engagement in Genetics & Genomic Research to Improve Health & to Increase Health Equity Study Purpose Determine effective ways to engage members of diverse urban communities in genetic and genomics research designed to improve health and achieve health equity. Aims Determine how characteristics of diverse ethnic, racial urban communities are related to their potential engagement in genetics and genomics research; Describe knowledge and attitudes of members of diverse ethnic, racial urban communities toward genetics and genomics research for health; Identify facilitators and barriers to sustained engagement of members of diverse ethnic, racial urban communities in genetics and genomics research for health. PI: Aaron Buseh UW Milwaukee

38. 38 Collaboration with UW Waisman Center Genetic/Complex Disorders 1) To estimate the prevalence of premutation of FMR1 using the Wisconsin longitudinal Study (WLS) cohort (PMRP in the Marshfield cohort 2) To describe natural history of premutation into adulthood and into old age (18 through 70 yrs.) with respect to family background, academic achievement, IQ, marital history, fertility, childbearing patterns, menopause, occupational stability, depression and anxiety, health and physical symptoms and cognition. 3) To compare men and women with the premutation with a closely matched comparison group of WLS unaffected age peers. Because of the small size of the sample with the permutation, this will be an exploratory aim. Murray H. Brilliant, PhD MCRF Marsha Seltzer, PhD Waisman Center

39. Vanderbilt QRS duration Group Health Cooperative Dementia Mayo Clinic Peripheral artery disease Marshfield Clinic Cataracts Northwestern Type II diabetes Coordinating center

40. 40 MCRFs Oral & Systemic Health Research Project (1) Goals: Understand the causes of oral diseases, such as periodontal disease and caries (e.g., determining the effect of genetics, diet, water source [well/city + fluoridation], and microbiome). Understand the connections between oral and systemic health, (e.g., mutual enhancement of periodontal disease and diabetes). Understand how improving oral health aids systemic health (comparative effectiveness) and bring PHC to the dental arena.

41. 41 Microbiome contribution to heath is an NIH priority and our investigators will be among the first to utilize oral microbiome data in personalized healthcare Will create a unique research infrastructure to support the OSHRP: Initial cohort of 2,000 participants with electronic dental and health records coupled with a comprehensive biobank (DNA, plasma, serum, urine and periodontal microbiome) Questionnaire data on environment, diet, etc OSHRP builds upon the Personalized Medicine Research Project (PMRP) >1,000 participants in PMRP who are also dental patients of Marshfield Clinic; 2 MC dental facilities in PMRP recruitment area have been operating for 1 year As the Clinics Electronic Health Record contains medical and dental care information, this research sub-cohort of PMRP can be used today to study the connections between oral and systemic health in a population-based cohort National Institute of Dental and Craniofacial Research (NIDCR) Collaborative Grant: Data Extraction using Electronic Dental Record in Dental Practice Based Research Network Collaborating with University of Pittsburgh MCRFs Oral & Systemic Health Research Project (2)

42. Plans for 2011 and 2012 Improve user interface for PMRP Sequence 10 subjects Stakeholders plan incorporation of genetic data in EHR Pilot/Develop a clinically actionable predictive algorithm (Age-related Macular Degeneration - AMD) Pilot/Develop Oral-Systemic Health Research Project (OHRP) and plan recruitment of a large OSRP cohort Goals for the next 5 years Searchable PMRP database Sequence all 20,000 subjects in PMRP Sequence genetic data linked to iEHR with decision making tools Pilot Personalized Health Care to clinical standard of care (AMD) Create enhanced Personalized Health Care Resource Networks Planned Transition to Personalized Health Care Current cost $4K

43. 43 To visit the Marshfield Clinic, a longtime innovator in health information technology, is to glimpse medicines digital future. Across the national spectrum of health care politics there is broad agreement that moving patient records into the computer age, the way Marshfield and some other health systems have already done, is essential to improving care and curbing costs. By: Steve Lohr Published: December 26, 2008

44. 44 Biomedical Informatics Research Center (BIRC) Established in 2005 7 PhDs and 38 other staff Mission: to accelerate improvements in human health and well being through informatics research while providing integrated tools, services and reliable management of information assets in support of Marshfield Clinic missions Organizational Structure: Administrative Informatics Support Biostatistics Usability/ICDI (Interactive Clinical Design Institute) Informatics Research Infrastructure & Central Resource Research Data & Analytics Management

45. 45 BIRC: Multiple Missions BIRC Researchers Foundation Administration Clinic IS Design Data Analysis Strategy Prototyping Evaluation IT Planning Infrastructure Backoffice External Funders Research Outcomes

46. 46 BIRC Personnel Growth Does not include short term students

47. Cost: $980,000 Accommodates 25 additional people in BIRC, increasing its staff to 65 by end FY 2012 Provides enhanced Biomedical informatics infrastructure support for increased collaboration with internal & external investigators BIRC expansion will house personnel to support: MCRFs new tenure track hires & grants they will generate Collaboration w/ MCs IS (R&D: usability, decision support, etc.) New Networks in Personalized Care and Population Research Dental Informatics & Oral Systemic Health Research Networks BIRC Expansion

48. 48 Dental Informatics Research l It is a sub-discipline of biomedical informatics. l Dental informatics is the application of computer and information science to improve dental practice, research, education and management. * Eisner J. The future of dental informatics. Eur J Dent Educ. 1999;3 Suppl 1:61-9.

49. 49 Major Dental Informatics Research Projects A Standard Information Model for General Dental Records - Funded by National Institute of Dental and Craniofacial Research, NIH - Goal is to develop a comprehensive, consensus-based Electronic Dental Record Information Model (EDRIM) as a reference standard for the content and structure of Electronic Dental Records Multi-institutional Consortium for Comparative Effectiveness Research in Diabetes Treatment and Prevention - Funded by Agency for Healthcare Research and Quality, DHHS - Goal is to build a national research network and a multi-system distributed database for conducting comparative effectiveness research (CER) in the treatment and prevention of diabetes mellitus Personnel: Dr. Amit Acharya Collaboration: University of Pittsburgh

50. Objectives: Purpose of Forum Provide an opportunity for research networks and other research groups to learn about each other and the projects they conduct. Learn about operational and project barriers, and successful methods to overcome barriers. Facilitate networking and connections between people and groups with similar interests.