Marcia Stefanick - US grants

The objectives of each Clinical Center are to cooperate with the Clinical Coordinating Center in implementing the overall Women's Health Initiate Clinical Trial and Observational study. The Clinical Centers will join the sixteen Vanguard Clinical Centers in recruiting a group of postmenopausal U.S. women age 50-79, randomize them to a number of interventions, ensure adherence and adequate follow-up, and collect an transmit data and biological samples as needed for the ascertainment of the outcomes of the CT/OS. Each Clinical Center shall recruit 1,400 to the CT and 2,220 women to the OS.

The Postmenopausal Estrogen/Progestins Intervention (PEPI-1) trial of 875 participants followed at 7 centers for three years is the largest and longest randomized double-blind placebo-controlled clinical trial of hormone treatment in postmenopausal women -- and the only long-term trial of estrogen-progestin regimens. It is the only long-term trial designed to compare the effects of Estrogen Replacement Therapy (ERT) and combined (estrogen-progestin) hormone replacement therapy (HRT) on heart disease risk factors. It is also unique for the number of women who began ERT or HRT more than 5 years after the menopause. Details of the study design, hormone replacement regimens and study population are given in Project I, as are the major analyses of PEPI-1 data proposed for completion during the extended follow-up period. Project II, Studies of Repository Samples, was planned to utilize plasma, urine and other samples already collected but not analyzed by the close of PEPI-1. Both Project I and Project II, submitted by the Coordinating Center to reflect the centralized activity necessary for a multicenter project, will be conducted with the Clinical Investigators as a cooperative project. Project III, submitted in parallel from each of the 7 PEPI Clinical Centers, describes a three year prospective observational follow-up study designed to: ensure PEPI women's safety and learn more about possible delayed adverse hormone effects; study treatment choices, compliance and reasons related to these decisions; and monitor long-term effects on heart disease risk factors and bone density. All participants will be invited to an annual clinic visit, (conducted according to the established PEPI-1 protocol) which includes a medical history and limited examination, mammogram, endometrial biopsy, and standardized questions about quality of life, sexuality, symptomatology, and medication use. We will measure primary PEPI endpoints (HDL-cholesterol, blood pressure, insulin and fibrinogen) and their covariates, and bone density at the hip and spine.

There has long been an appreciation of the importance of osteoporosis in women, and decades of research have yielded a strong foundation of mechanistic and practical knowledge that underlies clinical decision- making. On the other hand, very little information is available to direct the management of osteoporosis in men. The primary goal of this study (MR.OS) is to determine the extent to which fracture risk in order men is related to bone mass, bone geometry, lifestyle factors, biochemical measures, fall propensity, and other variables. This information is essential for understanding the genesis of fractures, and for the formulation of clinical algorithms for detection and treatment of osteoporosis in men. A second goal is to determine the relationships between osteoporotic fracture and two common chronic conditions in older men prostate cancer and osteoarthritis (OA). This will be a multicenter, prospective study of risk factors for vertebral and all non- vertebral fractures in older men (> 65 years). A total of 5,700 men will be recruited in six diverse geographical areas (Portland, OR; Pittsburgh; Minneapolis; San Diego; Palo Alto; and Birmingham), and will be followed for an average of three years. Baseline assessments will include BMD and bone geometry, vertebral morphometry, OA, neuromuscular and visual function, anthropometrics, nutrition, medical history, medication use, serum/urine/DNA collections, and functional status. Repeat measures of BMD and health/functional status will be obtained at two follow-up visits. The final exam will include repeat radiographs of the spine, hips and knees to determine incident vertebral fracture rate, and incidence and progression of OA. Participants will be followed every 4 months by postcard to determine the rates of non-vertebral fracture, falls, and prostate cancer. Data analysis will utilize proportional hazards and logistic regression models, depending on the type of outcome being analyzed. The study will have 90% power to detect RR of 1.35 for vertebral fractures and OR of 1.22 for non-spine fractures. MR.OS will provide unique information concerning osteoporosis and other common disorders, and will provide a basis for the construction of crucial preventative and treatment strategies.

DESCRIPTION (provided by applicant): It is estimated that over 50% of adults aged 65 and older report some sleep disruption, while about 20% suffer from chronic insomnia. Obstructive sleep apnea, a major cause of daytime drowsiness, occurs in an estimated 20-60% of older people, depending on the definition used and the specific population being studied. Despite the high prevalence of sleep disorders in the elderly, there have been relatively few studies focused on the consequences. Most studies have been limited by cross-sectional design, small sample size, or lack of comprehensive and objective assessment of sleep. The proposed study, Outcomes of Sleep Disorders in Older Men, will take advantage of the established cohort that has been recruited for the Osteoporotic Fractures in Men (MrOS) study (5U01AR045647-Dr. Eric Orwoll, PI). MrOS, a 7-year study that began in July 1999, is a multi-center prospective study of approximately 6000 men aged 65 and older. During the MrOS baseline visit, a broad variety of measurements were collected, including body composition and body fat distribution (by DEXA and quantitative computed tomography), bone density, anthropometry, performance-based tests of strength and balance, medical history, medication use, smoking and alcohol use, and other parameters. Blood, urine, and DNA specimens have been archived for use in future studies of importance to the health of older men. In a subcohort of 3000 MrOS participants, we propose to add comprehensive and accurate assessments of sleep using in-home polysomnography, wrist actigraphy, questionnaires and other measures; and prospective adjudication of CVD events, to the extensive measures that have already been performed or planned in the MrOS cohort study. These new measures will enable us to test several important hypotheses: 1) to characterize the associations between sleep disruption and subsequent CVD events during 3.5 years of follow-up, 2) to determine if sleep disturbances are associated with an increased risk of total and cause-specific mortality in older men, 3) to test whether sleep disturbances are associated with increased risk of falls and decreased physical function, 4) to test whether sleep disturbances are associated with impaired cognitive function in older men, and 5) to test whether sleep disorders are associated with bone density and fracture risk in older men. We will also supplement the bank of MrOS specimens to allow for testing of future hypotheses concerning the role of sleep in the development of age-related diseases and conditions.

DESCRIPTION (provided by applicant): The Osteoporotic Fractures in Men (MrOS) study was formed primarily to quantify the determinants of fracture in men. Importantly, the MrOS cohort also provides a seminal opportunity to study men as they progress through a critical period of life in which problems of aging remain poorly understood. In 2000-2002, 5995 community-dwelling men ages 65 years and older (mean age: 72 years at baseline) were enrolled from 6 diverse US communities. After 5 years of follow-up, participant retention is excellent (99% of those alive remain active). We propose a new clinic visit and continued follow-up of the cohort to expand our understanding of risk factors for falls, fractures (particularly hip fracture) and other consequences of aging. At baseline, both areal (from DXA) and volumetric (from QCT) skeletal assessments were obtained. We propose to repeat the same assessments in the planned visit to identify the densitometric and biomechanical risk factors for hip fracture, as well as to characterize bone geometry changes that underlie skeletal fragility. Further, we will use the QCT scans to quantify femoral strength by finite element modeling (FEM), and assess the usefulness of FEM for fracture prediction. Additional follow-up of the cohort and repeat measures of muscle strength (grip strength, leg power), physical performance (gait speed, chair stands, and narrow walk), and self-reported physical activity will enable us to establish the extent and nature of change in activity and physical performance, identify biological predictors of these changes, and clarify the possibly joint effects of physical activity and physical performance on fracture risk. To objectively quantify physical activity we propose to obtain accelerometry measures at the new clinic visit. Using serum archived at baseline, we will test the hypothesis that renal function, vitamin D, parathyroid hormone have important effects on skeletal health, physical function and fracture risk, and will determine if lower sex steroid levels increase men's risk of skeletal deterioration and fracture, decline in physical function, and deterioration in quality of life. Combined with the considerable data and biologic specimens already collected, additional measures and extended follow-up in the MrOS cohort allows us to expand the understanding of hip fractures, the most devastating type of fracture in men, as well as address other health issues of compelling public health and clinical importance to older US men.

The Cancer Prevention and Control Program (CPCP) is a multidisciplinary research effort, using intervention techniques, to reduce the overall and specific cancer incidence, morbidity, and mortality in men and women across the age spectrum through research aimed at: 1) identifying effective lifestyle (e.g. tobacco use, diet, exercise, and weight control) and medical (e.g. chemoprevention, vaccinations) interventions to reduce the cancer burden;2) understanding environmental determinants of lifestyles, behaviors and health outcomes and implementing community interventions to modify these environmental determinants;3) determining optimal early diagnostic techniques and detection programs and their utilization;and 4) conducting and evaluating interventions designed to improve the quality of cancer care and management, i.e. survivorship. Cross cutting these research areas is a focus on understanding and reducing the unequal burden of cancer in specific population groups. These goals are obtainable by combining the expertise and resources of Stanford University (SU), in particular the Stanford Prevention Research Center (SPRC), Clinical Cancer Genetics Center, Stanford Center on Stress and Health, Cancer Center Shared Resources, and the Northern California Cancer Center (NCCC). Extensive networks with community organizations and physician groups, including many that work with underserved populations, strengthen the CPCP's research program. The Cancer Prevention and Control Program includes 26 members from 10 SU Departments, including 3 Schools, and the NCCC. Plans for the next three years include: 1) enhancing intra-programmatic collaborations among program members;2) identifying translational opportunities and building strong inter-programmatic collaborations, particularly with investigators in the Cancer Epidemiology Program (Program 9), but also with other Cancer Center Programs and the Shared Resources;3) tailoring current SPRC lifestyle intervention and assessment research to populations at greatest risk for specific types of cancer;and 4) strengthening the health policy research agenda for cancer prevention.

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The purpose of the Women's Health Initiative (WHI) is to address cardiovascular disease, cancers of the breast and colon/rectum, and osteoporosis, the most common causes of death, disability, and impaired quality of life in postmenopausal women. The major components of the WHI are: a randomized controlled clinical trial of postmenopausal Hormone Therapy (HT), Dietary Modification (DM), and Calcium/Vitamin D supplementation (CaD);and a companion observational study (OS). The Clinical Trials and Observational Study components were completed in 2005;the WHI Extension Study continues to follow all consenting participants for health outcomes and selected exposures. The purpose of this additional follow-up is to describe the longer term effects of the original interventions, to document change in hormone use in participants from the HT trials, to expand the range of scientific questions that can be reliably addressed in the WHI, and to provide an infrastructure able to support additional investigations requiring some of the unique resources of a very large longitudinal study of postmenopausal women.

The Cancer Prevention and Control Program (CPCP) is a multidisciplinary effort to reduce overall and specific cancer incidence, mortality and morbidity in men and women across the age spectrum by conducting community-based interventional research. The major research areas are; 1) primary prevention: identifying and implementing effective lifestyle (eg diet, exercise, weight control, smoking cessation), medical (eg chemoprevention, vaccines), and community interventions designed to prevent cancer development through dissemination and adoption of preventive strategies; 2) secondary prevention; improving use of early detection programs and identifying and implementing optimal early diagnostic techniques; 3) tertiary prevention: identifying and implementing effective lifestyle, medical and community interventions designed to improve the health and quality of life of persons living with or dying of cancer, and improving adherence to and effectiveness of treatments and quality of cancer care and management (eg emotional support, survivorship and quality of life of cancer patients, their families and caregivers). Cross-cutting these three areas is a focus on understanding and reducing the unequal burden of cancer in specific population groups. Plans for the next five years include: 1) tailoring current lifestyle interventions and assessment research to populations at greatest risk for specific types of cancer; 2) expanding community health and health disparity research; 3) enhancing intraprogrammatic collaborations among CPCP investigators to develop a cohesive research agenda; 4) identifying translational opportunities and building strong inter-programmatic collaborations, particularly with investigators in Cancer Epidemiology (Program 09) and Immunology (Program 07), the latter of which may affect or be affected by the psychophysiology of cancer-related stress, and with the Shared Resources; 5) strengthening the health policy research agenda for cancer prevention; and 6) enhancing and exploring current and new collaborations with cancer researchers at other institutions.

base; Modification;

DESCRIPTION (provided by applicant): Age-related deterioration in bone, muscle and physical performance, manifested as osteoporosis, sarcopenia, and disability, are major causes of morbidity and mortality in the elderly. It is a priority to understand how musculoskeletal phenotypes and physical activity change with age, the factors that contribute to these changes, and how changes impact clinically important health outcomes. MrOS is a unique prospective study of 5994 older men that has been extremely productive in expanding our understanding of age-related change in musculoskeletal health. Initiated in 2000, it includes extensive longitudinal, objective, state-of-the-art assessments of bone, muscle, physical performance, physical activity and health outcomes, as well as biospecimen and imaging archives. We propose to extend these resources to allow a comprehensive and integrated understanding of the processes and consequences of musculoskeletal aging and decline in physical activity in older men studied over a 15 year period. The overall long term goal of the project is to identity men at risk of adverse health outcomes who may benefit from preventive measures and rehabilitation, discover new targets for treating and preventing declines in musculoskeletal health and activity, and improve our understanding of optimal aging (men who maintain their musculoskeletal health and activity levels over an average overall follow-up of 15 years). Specifically, we will leverage our repeated measurements to define age- related trajectories in phenotypes of musculoskeletal health, physical performance, and physical activity in order to determine factors that predict and contribute to these trajectories. We will test the hypotheses that favorable trajectories in musculoskeletal health are associated with lower risks of incident falls, fractures, disability and mortality and that age-related deterioration in bone, muscle and physical performance can occur concurrently; combined deterioration magnifies the risk of poor functional and health outcomes. Second, we will characterize change and trajectories in activity levels in older men using our repeated state-of-the-art questionnaire and objectively assessed energy expenditure from accelerometry. Third, we will take advantage of a linkage of MrOS with Medicare Claims data to determine the association of trajectories in musculoskeletal phenotypes and activity with inpatient and nursing home related health care utilization. Fourth, we will examine novel characteristics of cortical bone that may cause age-related skeletal fragility by using high resolution peripheral quantitative computed tomography to measure cortical porosity. We will relate trajectories of musculoskeletal health and activity to these measures of cortical bone and test whether increased cortical porosity is related to fractures. Finally, we will continue to leverage MrOS as a platform for new science and the training of investigators. Our application is consistent with the mission of the NIA and NIAMS to conduct research related to the aging process and diseases and conditions associated with musculoskeletal aging, and foster the development of new research scientists in this scientific area.

? DESCRIPTION (provided by applicant): The number of Americans aged 65 and older is projected to double to 88.5 million by 2050 (55% women). The significant aging of the U.S. population creates a public health mandate to identify effective interventions for preserving the health and independence of older people, especially women. Compelling evidence over the past several decades supports the importance of physical activity (PA) for preventing cardiovascular (CV) and other chronic diseases, and preserving physical and cognitive health, in older adults. Yet, despite the steady emergence of evidence-based interventions for increasing PA in older adults, which could potentially be delivered at a population level, we lack large-scale randomized trial data showing that these interventions can prevent clinical CV events or impact the public's health. To address this critical gap, we propose to conduct a large-scale, randomized controlled pragmatic trial, the Women's Health Initiative Strong & Healthy (WHISH) trial. This pragmatic trial will be embedded in the large, race/ethnicity diverse, WHI Extension cohort, now aged 63-99 years, which is both novel and resource-efficient. The trial will test the hypothesis that a centralized public health intervention designed to increase and/or maintain PA to levels recommended for older U.S. adults will reduce major CV events (e.g., myocardial infarction (MI), stroke, and CVD death) in older women over ~4 years of follow-up. The study will also evaluate the safety of the intervention by examining risks of total clinical fracture, hi fracture, falls, and non-CVD mortality. Preliminary screening indicates that 50,500 WHI women will meet eligibility criteria; the PA intervention and usual activity comparison groups will eac contain ~25,250 participants (mean age ~80 years). We will use a randomized consent design, with the observational comparison group and non-consenters followed as usual within the WHI Extension study. The WHISH intervention builds upon evidence-based, state-of-the-science behavioral approaches and intervention components that have proven to be effective in increasing PA in older women, with innovative adaptive strategies to tailor the intervention. We will use an algorithm-driven interactive voice response (IVR) system, a technology of increasing familiarity to older adults, built to complement National Institute on Aging (NIA) Go4Life(R) Exercise & Physical Activity materials. The evidence-based IVR system provides tailored advice, with personalized feedback and a means for self-monitoring (logging activity) and personal goal setting. PA behavior will be monitored by self-reported questionnaire and an accelerometry substudy in both study groups. Based on observed rates in the WHI cohort, we project 80% power to detect a 12.5% effect size for major CV events over the follow-up period. The WHI infrastructure, combined with innovative, evidence-based methods to deliver the PA intervention at a population level, provides a unique opportunity to address the critical question, Can a public health PA intervention reduce CVD events in older women? Determining the answer to this question, using a resource-efficient, scalable intervention, has major public health significance.

? DESCRIPTION (provided by applicant): The number of Americans aged 65 and older is projected to double to 88.5 million by 2050 (55% women). The significant aging of the U.S. population creates a public health mandate to identify effective interventions for preserving the health and independence of older people, especially women. Compelling evidence over the past several decades supports the importance of physical activity (PA) for preventing cardiovascular (CV) and other chronic diseases, and preserving physical and cognitive health, in older adults. Yet, despite the steady emergence of evidence-based interventions for increasing PA in older adults, which could potentially be delivered at a population level, we lack large-scale randomized trial data showing that these interventions can prevent clinical CV events or impact the public's health. To address this critical gap, we propose to conduct a large-scale, randomized controlled pragmatic trial, the Women's Health Initiative Strong & Healthy (WHISH) trial. This pragmatic trial will be embedded in the large, race/ethnicity diverse, WHI Extension cohort, now aged 63-99 years, which is both novel and resource-efficient. The trial will test the hypothesis that a centralized public health intervention designed to increase and/or maintain PA to levels recommended for older U.S. adults will reduce major CV events (e.g., myocardial infarction (MI), stroke, and CVD death) in older women over ~4 years of follow-up. The study will also evaluate the safety of the intervention by examining risks of total clinical fracture, hi fracture, falls, and non-CVD mortality. Preliminary screening indicates that 50,500 WHI women will meet eligibility criteria; the PA intervention and usual activity comparison groups will eac contain ~25,250 participants (mean age ~80 years). We will use a randomized consent design, with the observational comparison group and non-consenters followed as usual within the WHI Extension study. The WHISH intervention builds upon evidence-based, state-of-the-science behavioral approaches and intervention components that have proven to be effective in increasing PA in older women, with innovative adaptive strategies to tailor the intervention. We will use an algorithm-driven interactive voice response (IVR) system, a technology of increasing familiarity to older adults, built to complement National Institute on Aging (NIA) Go4Life(R) Exercise & Physical Activity materials. The evidence-based IVR system provides tailored advice, with personalized feedback and a means for self-monitoring (logging activity) and personal goal setting. PA behavior will be monitored by self-reported questionnaire and an accelerometry substudy in both study groups. Based on observed rates in the WHI cohort, we project 80% power to detect a 12.5% effect size for major CV events over the follow-up period. The WHI infrastructure, combined with innovative, evidence-based methods to deliver the PA intervention at a population level, provides a unique opportunity to address the critical question, Can a public health PA intervention reduce CVD events in older women? Determining the answer to this question, using a resource-efficient, scalable intervention, has major public health significance.