Leigh F. Callahan - US grants

NUSCOR will serve six primary functions: (1) methodological construction and review, (2) development and maintenance of patient databases, (3) data entry and management, (4) biostatistical consultation and technical support, (5) education and (6) computer technology support. These services, which are described in more detail below, are available to all faculty, staff, and students conducting musculoskeletal research at UNC- CH. In addition to providing support for ongoing projects, a central goal of NUSCOR is to stimulate new research initiatives. In the past, the Core has been instrumental in developing projects that resulted in extramural funding and in undertaking studies that would not have been feasible given the level of funding available from other sources. Although NUSCOR was designed primarily to support E/E/HSR research efforts, the Core also provides services to biomedical investigators and facilitates collaborative research efforts via the maintenance of patient databases (a function shared with the Biomedical Component); biostatistical support; shared educational activities; and computer support, which serves to coordinate the hardware and software used by investigators in both components to enhance investigators' ability to share data and other resources.

Low levels of formal education are associated with increased prevalence, morbidity and mortality of most common chronic diseases. Several studies suggest that formal education level may be a surrogate for behavioral/psychosocial variables, which are also independently correlated with health status and outcomes. While circumstances associated with lower levels of formal education and poor SES cannot be altered through medical intervention, certain behavioral variables may be amenable to improvement, at least in part. The set of behaviors an individual uses to cope with a chronic condition is known as self-management. Individuals with a chronic disease negotiate the specific practices in their self-management strategies based on their needs and resources. Formal education level may be a marker for the capacity of individuals with a chronic disease to develop optimal self-management strategies. The objective of this study to examine self-management strategies of individuals with rheumatoid arthritis (RA) in the context of measures of disease activity, perceived control, and formal education level vis a vis health outcomes. The objective will be approached through the following specific aims: 1) to characterize self-management in individuals with RA; 2) to examine associations between self-management and formal education level in individuals with RA; 2) to examine associations between self management and formal education level in individuals with RA; 3) to determine whether the domains and frequency of use of self-management strategies reported by individuals with RA vary over time with changes in measures of disease activity; and 4) to define the relative contribution of self-management strategies and formal education level to health care utilization and health-related quality of life over a three year period in individuals with RA. If associations between level of formal education and health status can be accounted for, at least in part, by psychological status and self- management strategies, health care providers might more effectively target patient education interventions to effect an improvement in health status. In addition, there is emerging evidence that helping patients manage not just their disease, but also common underlying needs, is cost effective. Therefore, clinicians, health care policy-makers, public health planners and voluntary health agencies could all benefit from a better understanding of possible mechanisms.

[unreadable] DESCRIPTION (provided by applicant): The long-term goal of this proposed project is to better clarify the role of both individual and community social determinants with health outcomes in 4337 non-Hispanic African-Americans and non-Hispanic Caucasians with OA. This will be accomplished in a unique, prospective, population-based study of knee and hip OA in Johnston County, a predominantly rural county in North Carolina. This goal will be accomplished using multi- methodology through the following aims: 1) to determine whether there is an independent association between community and individual SES with knee and hip OA prevalence; 2) to determine whether there is an independent association between community and individual SES with arthritis severity and progression; 3) to determine whether there is an independent association between community and individual SES with disability; 4) to determine whether there is an independent association between SES (community and individual) and mortality; 5) to develop a measure of observational assessment for community health characteristics and develop a scale to assess participants' perceptions of these characteristics; 6) to test hypothesized mediators of relationships between individual and community SES with knee and hip OA prevalence and outcomes. PUBLIC HEALTH RELEVANCE: The gap in health outcomes is multifactorial, incompletely understood, and potentially difficult to redress in its entirety. However, a better understanding of the individual and community factors that influence health outcomes in racial and ethnic groups will provide an invaluable foundation for designing interventions and creating policies to reduce these gaps. [unreadable] [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Rheumatoid arthritis (RA) is a multisystem autoimmune disease associated with considerable morbidity and mortality worldwide. African Americans (AAs) have been markedly underrepresented in research on RA. The strong association between lower levels of individual socioeconomic status (SES) with poorer health outcomes in RA is well-established in whites, but less so in AAs. Recent data suggest that community social determinants, e.g., the socioeconomic environment of an individual's neighborhood and environmental exposures, may be operant in this regard, as well. In addition, racial segregation sorts individuals of comparable SES into vastly different neighborhood environments. AAs are often segregated from the white population, which may result in community influences differing for AAs and whites. The long-term goal of this proposal is to examine the relationship of social determinants across the lifecourse with health outcomes in AAs with RA. This project will be the first study to examine individual and community-level social determinants in an AA population with RA, by examining social position (childhood, current and lifecourse individual-level SES) and social context (community-level SES, environmental exposures, access to services and racial residential segregation). It will also be the first to examine perceptions (control, discrimination and neighborhood) that may act as mediators of outcomes in RA. The proposed project will be conducted using extensive demographic, socioeconomic, environmental, clinical and radiographic data collected through the Consortium for the Longitudinal Evaluation of African Americans with Early RA (CLEAR) registry and network, which consists of a Coordinating Center at the University of Alabama (UAB) and clinical sites at UAB and 4 other universities across the southeast. CLEAR has two components: CLEAR I with 350 AA participants with <2 years of disease duration who are already enrolled and will be followed to year 5 of their disease;and CLEAR II with an anticipated 600 AA RA participants of any disease duration who are currently being enrolled for a single cross-sectional examination. Specific aims include: 1) To evaluate associations between social position across the lifecourse with disease severity in AAs with RA, 2) to determine whether there are independent associations between social context and social position across the lifecourse with disease severity in AAs with RA, and 3) to test hypothesized mediators in the relationships between social position (across the lifecourse) and social position with disease severity in AAs with RA. PUBLIC HEALTH RELEVANCE: African Americans have been markedly underrepresented in research on rheumatoid arthritis (RA), so there are many important unanswered questions regarding the disease in this racial/ethnic group. This project aims to clarify the role social determinants with health outcomes in African Americans with RA, and is the first to examine socioeconomic status issues specifically in an African American population with RA. A better understanding of these issues will provide an invaluable foundation for designing clinical interventions and creating policies to reduce these gaps.

DESCRIPTION (provided by applicant): The long-term goal of this proposed project is to better clarify the role of both individual and community social determinants with health outcomes in 4337 non-Hispanic African-Americans and non-Hispanic Caucasians with OA. This will be accomplished in a unique, prospective, population-based study of knee and hip OA in Johnston County, a predominantly rural county in North Carolina. This goal will be accomplished using multi- methodology through the following aims: 1) to determine whether there is an independent association between community and individual SES with knee and hip OA prevalence; 2) to determine whether there is an independent association between community and individual SES with arthritis severity and progression; 3) to determine whether there is an independent association between community and individual SES with disability; 4) to determine whether there is an independent association between SES (community and individual) and mortality; 5) to develop a measure of observational assessment for community health characteristics and develop a scale to assess participants' perceptions of these characteristics; 6) to test hypothesized mediators of relationships between individual and community SES with knee and hip OA prevalence and outcomes. PUBLIC HEALTH RELEVANCE: The gap in health outcomes is multifactorial, incompletely understood, and potentially difficult to redress in its entirety. However, a better understanding of the individual and community factors that influence health outcomes in racial and ethnic groups will provide an invaluable foundation for designing interventions and creating policies to reduce these gaps.

DESCRIPTION (provided by applicant): The goal of this ancillary proposal to the Johnston County Osteoarthritis (JoCo OA) Project: Arthritis and Disability (1U01DP003206-01 - funded by the CDC) is to create a repository of enhanced vital status, date and cause of death for participants during their current follow-up and to examine the contribution of knee and/or hip OA to mortality in non-Hispanic African-American (AA) and Caucasian men and women. The parent study was designed to encompass multiple aspects of the OA process from the biomedical to the psychosocial and from the pre-clinical to disability. Examining mortality in this cohort with u to 25 years of observation and extensive OA and chronic conditions data over multiple time points provides the perfect opportunity to answer these questions in ways other studies could not, and additionally, enhance the parent project. The goal will be accomplished with these 3 specific aims and a 4th exploratory aim: 1) to create a repository of enhanced vital status data in the 20+ year follow-up of the JoCo OA with the date and cause of death; 2) to determine whether knee and/or hip OA at baseline is associated with excess all-cause or disease-specific mortality, independent of concomitant comorbidities and obesity, and whether it is modified separately by gender, by race, and by socioeconomic status; 3) to evaluate the combined impact of OA and obesity, diabetes mellitus or cardiovascular disease on all-cause and disease specific mortality; and 4) to explore whether OA severity and persistence of symptoms of OA impacts all-cause and disease-specific mortality.

DESCRIPTION (provided by applicant): Breast cancer is the second most common cancer among women in the U.S., with an estimated 207,090 new diagnoses in 2010 and a lifetime risk among women born today of 1 in 8. Most breast cancer cases are diagnosed among postmenopausal women at an early and treatable stage, and most of their tumors (70-80%) are hormone-receptor positive. For these women, standard adjuvant endocrine treatment is aromatase inhibitor (AI) therapy to prolong disease-free survival and time-to-recurrence. Unfortunately, joint pain/stiffness/ achiness is a common side-effect of AIs, with estimates of joint complaints ranging from 46% to 74% among survivors seen in clinical practice. The precise etiology of AI-associated musculoskeletal symptoms (AIMSS) remains unclear and is complicated by the high prevalence of benign and non-specific musculoskeletal symptoms in the general population of older women, such as arthritis. AI discontinuation due to side-effect severity is an estimated 20-32%, and is of great concern among oncologists. Research is needed to identify effective, easy-to-use, sustainable, and safe alternative or adjunct approaches to AIMSS management, so that breast cancer survivors are able to remain on AI therapy and have a life that is as pain-free as possible. We propose to investigate whether moderate-intensive physical activity (PA) can provide relief from AIMSS within a sample of female breast cancer survivors on AI therapy who report moderate to severe joint symptoms. Specifically, we propose to adapt and test the Arthritis Foundation's Walk With Ease (WWE) program, which is evidence-based for reducing joint pain, stiffness and fatigue among adults with arthritis and is available in a self-directed (non-group) format. Our proof of concept hypotheses are that: (a) it is feasible to adapt WWE for our target patient population and (b) that an adapted WWE can provide joint pain/symptom relief for patients with AIMSS similar to that of adults with arthritis. To investigate these hypotheses, we propose to: (1) develop an initial adaptation of WWE-Breast Cancer (WWE-BC) based on interviews with breast cancer survivors (N=20) focused on barriers and facilitators to engaging in PA; (2) conduct a preliminary assessment of the effect of WWE-BC within a new sample of survivors (N=60) with regard to (a) engaging in PA, (b) managing joint pain/symptoms and (c) remaining on AI therapy; and (3) develop WWE-BC messages and communication strategies based on interviews with survivors and oncology physicians, nurse practitioners and nurse navigators. Data on the acceptability, feasibility, safety and promise of WWE-BC gathered through this study will inform the development of a larger study to test the effectiveness of WWE-BC, identify potential effect mediators and/or moderators, and establish generalizability. All aspects of our study will be informed by Patient Advisors who are part of our Study Team as well as by oncologists who are actively engaged in the design, implementation and analysis of our study.

DESCRIPTION (provided by applicant): Responding to an urgent call to action from the 2012 Institute of Medicine report. Living Well with Chronic Illness: A call for public health action and the 2010 National Public Health Agenda for Osteoarthritis (NPHAOA), this application proposes a new Multidisciplinary Clinical Research Center (MCRC) at the Thurston Arthritis Research Center (TARC) at the University of North Carolina (UNC), entitled Mitigating The Public Health Impact of OA. The proposed MCRC draws together multiple units and investigators new to OA research into novel collaborative relationships with the long-term goals of: 1) understanding the etiologic factors associated with development and progression of OA and Its resultant disability; 2) Identifying best practices to Inform adoption of critical public health recommendations in communities to prevent the occurrence and progression of these outcomes, and 3) transforming the face of OA research on the UNC campus by serving as a hub for Innovation, training, and collaboration. The NPHAOA recommends addressing joint injury prevention, increased physical activity, weight control, and arthritis self-management education to slow this looming public health crisis. This MCRC will use these themes as its focus and leverages 2 distinctive UNC studies: 1) the Johnston County OA Project, a 20+ year prospective cohort of OA and disability in African American and White men and women in NC, and 2) JUMP-ACL, a unique cohort studying knee injury in men and women military cadets in whom pre-injury biomechanics data and biological specimens are available. Project #1 addresses basic mechanisms behind the role of partner support in the initiation and maintenance of increased physical activity in insufficienty active people with OA. Project #2 examines the relationship between biomechanics and biomarkers in predicting knee injury and development of injury-mediated OA. The Methodology Core is central and will support the 2 proposed projects and multiple other extant projects relevant to the mission of NIAMS and will foster new research and provide training in research methodology and mentoring to the next generation of arthritis researchers. An Administrative Core with an Executive Committee and Internal and External Advisory Boards will support the Center. By bringing together our established investigators with new expertise in physical activity measurement, biomechanics, and biomarkers, and newly trained young investigators, this vibrant center will advance the public health OA agenda and lay the foundation for implementing future interventions to treat and prevent OA and its consequences.

? DESCRIPTION (provided by applicant): Obesity is a modifiable risk factor for knee osteoarthritis (OA), and weight loss is an effective non- pharmacologic treatment to reduce pain. Recently, we determined that under ideal, highly controlled circumstances, a diet-induced weight loss of 10% combined with exercise was significantly better at reducing pain than either intervention alone. Compared to previous long-term weight loss and exercise trials of knee OA, our diet-induced weight loss and exercise group was twice as effective at relieving pain. Whether our groundbreaking results can be generalized to less rigorously monitored patient cohorts is unknown. Thus, the policy relevant and clinically significant question is: How can we adapt this successful solution to a pervasive public health problem so that it provides a cost-effective intervention for real-world clinical and community settings? This study aims to develop and to demonstrate the effectiveness of a systematic, practical, cost-effective diet-induced weight loss and exercise intervention that communities can implement to reduce pain and improve other clinical outcomes in knee OA patients. This pragmatic community-based trial will determine if the important benefits realized by participants in our previous trial translate to rea-world settings. Participants will be 820 ambulatory, community-dwelling, overweight and obese (BMI = 27 kg/m2) men and women aged = 50 years who meet the American College of Rheumatology clinical criteria for knee OA which includes knee pain on most days of the week plus at least 3 of the following 6: age = 50 years; stiffness < 30 min/day; crepitus; bony tenderness; bony enlargement; no palpable warmth. The primary aim is to determine whether a pragmatic, community-based 18-month diet-induced weight loss and exercise intervention implemented in three North Carolina counties with diverse residential (from urban to rural) and socioeconomic composition significantly decreases knee pain in overweight and obese adults with knee OA relative to an attention control group. Secondary aims will determine whether this intervention improves self-reported function, health-related quality of life, and mobility. We will also establish the cost-effectiveness of this pragmatic, community-based intervention by conducting cost-effectiveness and budgetary impact analyses using data from the current trial in a validated computer-simulated model of knee OA. Many physicians who treat people with knee OA have no practical means to implement weight loss and exercise treatments. This study is significant in that it will test the effectiveness of a long-awaited and much needed community program that will serve as a blueprint for clinicians and public health officials in urban and rura communities to implement a weight loss and exercise program designed to reduce knee pain and improve other clinical outcomes in overweight and obese adults with knee OA.

ABSTRACT ? OVERALL The overall goal of the University of North Carolina at Chapel Hill (UNC) Core Center for Clinical Research (CCCR) is to enhance the design and conduct of clinical studies in Rheumatic and Musculoskeletal Diseases (RMDs) with a focus on osteoarthritis (OA), a particular strength of our research community. The pain and loss of function that results from arthritis, combined with its prevalence, make it a leading cause of disability. OA is the most common form of arthritis. Efforts are urgently needed to improve the management of people with OA, as well as the many other RMDs, to reduce pain, improve function and slow or stop disease progression. Like other chronic conditions, RMDs are not single diseases but rather heterogeneous conditions consisting of multiple phenotypes that differ in their underlying pathobiological mechanisms. If not taken into consideration, these phenotypic differences result in the testing of interventions designed to address specific mechanisms of action in the ?wrong? patients. Therefore, successful treatments for RMDs need to be targeted to, and tested in, specific subgroups or subtypes that share distinct underlying pathobiological, psychosocial and pain mechanisms consistent with the goal of precision medicine. Understanding and incorporating information about these phenotypes in clinical observational studies and trials will be crucial to move the field forward and is a major goal of our CCCR. Importantly, this pursuit will address the NIAMS long- range plan for clinical research which emphasizes that, ?clinical characterization of disease subtypes is critical to assessment of epidemiological data and efficient design of clinical trials in these disease areas.? The proposed UNC CCCR will build on our transformative Multidisciplinary Clinical Research Center (MCRC), Mitigating the Public Health Impact of OA. Although the CCCR will have a focus on OA, the analytical methods used for phenotyping and precision medicine will also be applied to other RMDs that are strengths within our research community including RA, lupus, and vasculitis. Our goal is to optimize the design, analysis and implementation of clinical studies and trials in OA and other RMDs to advance clinical care and public health efforts targeted toward individuals with these conditions through the following aims: 1) Administrative Core: Provide leadership, oversight, coordination, evaluation, and general administrative support for all CCCR activities; 2) Methodology Core: Provide a comprehensive and integrated set of RMD-focused services to optimize the quality, efficiency and innovation of the CCCR research community that includes local, national and international members; 3) Phenotyping and Precision Medicine Resource Core: Provide services that will add value to and optimize the design and implementation of clinical studies as well as develop innovative strategies to maximize the use and success of clinical phenotyping and precision medicine in RMDs, with a focus on OA.

ABSTRACT ? ADMINISTRATIVE CORE The purpose of the Administrative Core is to provide leadership, oversight, coordination, and general administrative support for all activities of the University of North Carolina (UNC) Core Center for Clinical Research (CCCR). The Administrative Core's specific goal is to maximize the scientific integrity and dissemination of the CCCR's work, which is focused on optimizing clinical research and clinical trials that will advance clinical care and public health efforts targeted toward individuals with osteoarthritis (OA) and other Rheumatic and Musculoskeletal Diseases (RMDs). This Core will facilitate the delivery of novel, innovative, and exciting services provided by our Methodology and our Phenotyping and Precision Medicine Resource Cores to our research community at UNC, throughout the state of North Carolina (NC) and beyond. Our research community also includes members of the Internal (IAB) and External (EAB) Advisory Boards, and specific collaborations with the NC Translational and Clinical Sciences Institute (NC TraCS), home to our Clinical and Translational Science This CCCR will build on the strong success of the current Multidisciplinary Clinical Research Center (MCRC) housed at the Thurston Arthritis Research Center (TARC), Mitigating the Public Health Impact of OA. The CCCR will leverage TARC's Communications and Development Officers, as well as the Osteoarthritis Action Alliance (OAAA), a coalition of more than 100 organizations committed to elevating OA as a national health priority, which is housed at TARC. The Administrative Core's purpose will be accomplished through the following specific aims: 1) Provide leadership and vision to guide the CCCR in its focus on optimizing clinical research and clinical trials to advance clinical care and public health efforts targeted toward people with OA and other RMDs within the mission of NIAMS; 2) Provide oversight, coordination and general administrative support to the Methodology Core, Phenotyping and Precision Medicine Resource Core, and the Pilot and Feasibility grant program and their goals, including the training of students and junior investigators; 3) Provide structure and oversight of interactions and communications between the CCCR and the extensive ongoing TARC research activities, OAAA, NC TraCS, and other UNC Schools, Departments, Centers, and Programs, as well as with public and private organizations at the state, national, and international levels; 4) Maintain communication links among the Executive Committee, Methodology Core, Phenotyping and Precision Medicine Resource Core, IAB, EAB, Stakeholder Advisory Board (SAB), the CCCR Research Community, and the other NIAMS funded CCCRs; 5) Conduct ongoing evaluation and assessment of CCCR activities to ensure that goals, expected outcomes and outputs set forth in the application are met.