Anne Newman - US grants

Cardiovascular disease accounts for a large proportion of illness and disability in the elderly. The relationship between the high prevalence of asymptomatic atherosclerotic disease in the elderly and known risk factors for the development and progression of disease is not well understood. The proposed research will examine the interaction between presence of lower extremity arterial disease and other cardiovascular risk factors in a high risk group of elderly individuals with systolic hypertension. Specifically, this study will: 1. Describe the prevalence of intermittent claudication and asymptomatic lower extremity arterial disease as measured non- invasively by the ratio of ankle to arm blood pressure (ankle-arm index). 2. Examine the relationship between presence of disease with other risk factors including age and sex. 3. Correlate the extent of disease with subsequent cardiovascular endpoints including MI, sudden death stroke, and overall mortality. 4. Examine the effect of treatment of systolic hypertension based on baseline characteristics, including the ankle-arm index. This study is ancillary to the Multicenter Systolic Hypertension in the Elderly Program (SHEP) and will involve at least, 2,000 individuals of the 5,000 recruited for the main study. Subjects across at least 8 of 16 SHEP centers will undergo measurement of the ankle-arm index at two annual physical exams. Data will be collected locally after training and certification of technicians and forwarded to the University of Pittsburgh. Subsequent analyses will be done with baseline and follow-up data obtained as part of the SHEP protocol. This study is unique in its ability to use an objective measure of atherosclerotic disease and correlate it with data from a large cohort of elderly high risk subjects followed longitudinally.

Recent studies indicate that coronary artery calcium is a strong predictor of coronary heart disease events in middle- aged men and women. We examined the extent and predictors of coronary artery calcium and its relationship to other non- invasive measures of atherosclerosis in 614 (89 percent) of the surviving cohort from the Pittsburgh center of the Cardiovascular Health Study (CHS). These individuals were ages 67-99 (mean 80). Key findings have been reported and include: 1) Coronary artery calcium scores were strongly age related, yet the range of scores was quite broad. Ten percent had scores of zero. 2) Other non- invasive vascular tests missed many of those with high coronary calcium scores. 3) Other than age, gender and race, traditional risk factors were relatively weak predictors of calcification. We now propose to follow these individuals to determine whether coronary artery calcification predicts cardiovascular disease and mortality in old age, and whether this is independent of other non-invasive measures of disease and traditional risk factors. The alternative hypothesis is that the risk is attenuated in old age, as it may represent stable plaque that is less prone to occlusion or rupture. The CHS is ending the ascertainment of outcomes at the end of 2001, necessitating additional funding for local follow-up of this cohort. In addition to monitoring cardiovascular events, we will evaluate the functional significance of the extent of calcification by an exercise test and will assess progression after 4 years by repeating the EBT scan, and determine the rate of new calcification in those with scores of zero at baseline. Such individuals with no calcium might be regarded as "immune from coronary artery disease." The specific aims are: 1) To determine whether the extent of coronary artery calcium is an independent predictor of total and incident myocardial infarction and total CVD morbidity and mortality in older adults. 2) To determine the functional significance of coronary artery calcification in about 312 of these older adults without clinical cardiovascular disease. 3) To determine the rate of progression over 4 years in coronary artery calcium score in an estimated 424 survivors and to determine if those with zero (n=47) develop any calcification. This study can determine the risk of cardiovascular disease events in relationship to coronary artery calcium in older adults in a time-efficient and cost- effective manner that capitalizes on the rich CHS database. This is the largest population study of coronary artery calcium in this older age group, and can rapidly produce definitive data to determine the potential for benefit of screening older adults for coronary artery calcium.

[unreadable] DESCRIPTION (provided by applicant): The prevalence of sleep disordered breathing (SDB) in middle aged persons in the general population is estimated to be 4 percent in men and 2 percent in women with higher rates observed in the elderly. Accumulating evidence from retrospective and cross-sectional studies suggest that SDB is associated with the presence of cardiovascular and cerebrovascular disease (CVD) and consequent increased mortality and morbidity. However, there is little prospective data indicating whether SDB is an independent risk factor for the development of CVD. The Sleep Heart Health Study (SHHS) is a longitudinal multi-center cohort study that was started in 1994 to determine the cardiovascular consequences of SDB. Initially, SHHS recruited 6441 participants (1996-98) to undergo in-home polysomnography (PSG) and acquisition of other CVD and sleep-related data. Another examination with repeat PSG (2001-2003) has just been completed. Mortality and morbidity follow-up is ongoing, but event rates have been insufficient to provide stable estimates of the effect of SDB on incident CVD and mortality. Additionally, a unique resource of SHHS is its archive of approximately 10,000 PSGs, associated scoring and clinical covariate data. Providing the scientific community access to this data has always been an important goal of SHHS, and has the potential to realize significant benefits in collaborative research ranging from novel methods of signal processing to identifying unique epidemiologic associations. Therefore, this application proposes additional mortality and morbidity follow-up of the SHHS cohort, continuation of longitudinal and cross-sectional data [unreadable] analyses focused on SDB as a risk factor for cardiovascular events and hypertension, and development of an infrastructure to facilitate access by the general scientific community to the SHHS PSG archive. These goals will be achieved by accomplishing the following specific aims: 1) to continue follow-up of the SHHS cohort in order to assess SDB as a risk factor for incident hypertension, and incident and recurrent CVD events; 2) to characterize the natural history of SDB and determine how change in RDI (# apneas or hypopneas/hour of sleep) is related to risk for interim and incident CVD events; 3) to characterize the relationship between SDB and SDB progression with quality of life and indicators of daytime sleepiness; 4) to use the PSG data as well as previous collected risk factor data from parent cohorts to develop a clinically and epidemiologically applicable model of risk relating to SDB; and 5) to develop an infrastructure to facilitate data sharing, collaborative analysis, and dissemination of data analytic tools and research findings to the scientific community. Accomplishing these goals will provide important information concerning the public health impact of SDB. [unreadable] [unreadable]

[unreadable] DESCRIPTION (provided by investigator): Functional aging, or disability-free survival, becomes increasingly exceptional as older adults reach age 80 and beyond. In the long- term survivors of the Cardiovascular Health Study (CHS) cohort, we will determine the likelihood of maintaining function, identify the trajectories that distinguish those destined to do well, and define the importance, independence and interactions of physiologic predictors of function. The CHS cohort is now aged 80 to 100+ with over 12 years of follow-up, but have not been examined for 4 years. With the long term, longitudinal data and a reassessment of functional status, we can identify critical targets and time points that could lead to potential intervention to extend functional years of life. We have shown that subclinical cardiovascular disease alone, in the absence of any clinically recognized CVD event, predicts impaired physical and cognitive function. However, CVD does not fully explain the very strong effect of age itself on decline in function. We can also determine the potential for maintaining function in the presence of CVD. We have noted that many participants over age 80 have maintained physical and cognitive function in spite of extensive subclinical CVD. The aims of this application are: 1) to identify and characterize CHS participants who have remained functional after age 80, specifically to determine the trajectories of CVD risk factors and behavioral factors, especially physical activity and CVD treatment that lead to functional aging, 2) to determine whether low levels of IL-6 and TNF-alpha, as well as CRP, high levels of adrenal androgens, and insulin-like growth factor-1 and adiponectin, and lower fasting insulin and glucose will predict continued functioning independently of cardiovascular disease, 3) to identify individuals who have maintained functional aging in the presence of a large atherosclerotic burden and to examine factors that may promote function in spite of CVD, 4) to determine whether the predictors of a functional aging predict continuous parameters of function including leg muscle strength, grip strength, gait speed, and cognitive processing speed. With longitudinal data collected over many years, the CHS is now uniquely positioned to answer these questions about aging. This study is a critical step towards the identification of the targets and the time points for intervention to preserve function in old age. [unreadable] [unreadable]

[unreadable] DESCRIPTION (provided by applicant): We propose to recruit families of the long term survivors in the Cardiovascular Health Study (CHS) for the Multicenter Study on Exceptional Survival in Families (ESF). The CHS cohort (n=5888) was originally recruited from a random sample of Medicare enrollees in 4 US communities in 1989-90. They have been extremely well characterized regarding health and function, providing an opportunity to examine many specific as well as composite phenotypes over time. All have stored DNA or cryopreserved white blood cells. We have determined that about 400 individuals aged 90 and over will be available in CHS, with about 200 remaining free of disability and 100 with fairly large families (average 12) including sibs and their children. We would propose to characterize these family members at several levels of detail, to include the minimal data set suggested by the working group on exceptional survival. Since the disability measures proposed for the minimal data set may well not yet be expressed in the children, we also propose measures that would be [unreadable] informative across a spectrum of age as markers of aging and subclinical disease processes. We have a long history of productive collaboration on large multicenter studies and can contribute to the design of common protocols and analytic approaches. Our goal is to contribute as a study center in the design and implementation of this study. We will recruit and examine older adults who have reached age 90, their siblings and the children of the index generation (index cases and siblings). We will determine the extent of clustering of several potential important exceptional survival phenotype. We can contribute data on environmental and behavioral determinants and intermediate phenotypes that can be assessed in younger old adults and will measure core phenotypic characteristics and important environmental exposures in these families. We will participate in the evaluation of aggregation of selected traits and combination of traits to inform future studies. We would propose first determining whether "exceptional survival" is more common in families than expected and then would use combinatorial techniques (principal component analysis and pedigree discriminant analysis) to produce quantitative phenotypes for genetic analysis. [unreadable] [unreadable]

DESCRIPTION FOR CENTER APPLICATION (provided by the investigator): The Center for Healthy Aging (CHA) at the University of Pittsburgh has been funded by the CDC Prevention Research Centers (PRC) Program since October 2001. We propose to continue and enhance CHA focusing on promoting healthy aging within communities. CHA was developed to meet the needs of older people in Allegheny County and the surrounding regions of southwestern Pennsylvania (PA) by stressing whole person prevention strategies (recognizing multiple risks and multiple conditions) and ten key risk factors that have a strong evidence base for the prevention of highly prevalent chronic disease (the "10 Keys"(tm) to Healthy Aging). The evidenced-based "10 Keys"(tm) are: Control Systolic Blood Pressure;Lower LDL Cholesterol;Regulate Glucose;Stop Smoking;Get Regular Immunizations;Participate in Cancer Screenings;Prevent Bone Loss and Muscle Weakness;Increase Physical Activity;Maintain Social Contact;and Combat Depression. Our "10 Keys" (tm) Program certifies people in the community as Health Ambassadors. The Ambassadors reach out to the community speaking to their families, churches, social/civic organizations and public events about the "10 Keys"(tm). This program will continue in the community. We are also currently furthering our outreach by partnering with the Arthritis Foundation on a new core research program entitled: "Improving mobility and preventive service use in older adults at risk for arthritis disability"- We are combining the "10 Keys"(tm) to Healthy Aging Program with the Arthritis Foundation (AF) Exercise Program. The two programs will be compared, the "10 keys"(tm) alone vs. a combined AF exercise and "10 Keys"(tm) program. The target population includes: having chronic frequent knee pain, but not yet diagnosed with knee OA;overweight or obese;and age over 60. We will recruit volunteers and conduct the program collaboratively at existing sites that are available (CHA's Health Ambassador Program &Arthritis Exercise Sites). The CHA will continue utilizing its Boards, the Healthy Aging Coalition (Community Advisory Board), the Ambassador Board, and the Professional Board for the Centers direction in the next 5 years.

The Clinical and Population Research Core (CPRC, RC-i) provides recruitment, cohort study resources and clinical research expertise to promote a multidisciplinary approach to the assessment of balance and mobility in OAIC clinical research studies. In addition to continuing our highly successful Pepper Registry, Community Advisory Board, Population Studies support and Measurement Library, we propose several new initiatives to extend our effectiveness. In the period of this renewal we will i) extend support for recruitment through the Pittsburgh Long Term Care Network, 2) advance the ability to collect, record and interpret medication use via a state of the art medication coding system and 3) promote increased knowledge and use of noninvasive technology to assess mobility, balance and physical activity. The specific aims are to: 1. Engage older adults from the community and long term care settings in research 2. Provide access to ongoing cohort studies, specimens and existing databases 3. Provide expertise in clinical assessment methodology 4. Develop new clinical assessment protocols 5. Explore use of noninvasive and portable technology to assess mobility, balance and physical activity in clinics and in the field 6. Provide access to space and equipment for OAIC related studies 7. Promote adherence and retention in OAIC related studies 8. Support the research training mission of the Pepper Center. 9. Evaluate the functions and productivity of the Core and manage its productivity.

DESCRIPTION (provided by applicant): The goal of this revised competing renewal for the Cardiovascular Health Study (CHS) All Stars Study is to determine how aging unfolds across systems and predicts disability-free survival. Based on observations made between 1992/93 and 1998/99 and relating changes within and across systems to disability-free survival over the subsequent 15 years, we will seek to determine whether observed changes are upstream predictors of disease events, are concurrent with disease changes, or are adaptive responses that maintain homeostasis. The proposed approach will allow the design of prevention intervention strategies aimed at pivotal morbidities and tracked by associated biomarkers in a window of time where age related functional decline is modifiable. The specific aims are: 1. To continue to follow the remaining 1260 men and women in CHS cohort to characterize their long term survival and disability-free survival. This will provide an accurate assessment of rates and predictors of very long active and disabled life span overall and by sex, race and birth cohort. 2. To determine the levels and changes in subclinical disease measures and aging biomarkers that are associated with long term survival and disability free survival. We will evaluate whether changes in aging biomarkers are explained by existing disease, change concurrently with subclinical disease markers, and/or predict future mortality and disability, independently of subclinical disease. 3. To examine the correspondence between changes across multiple systems, using repeated measures of subclinical disease and biomarkers of aging. We hypothesize that measures of subclinical disease and biomarkers of aging significantly cluster in the individuals with the longest term disability free survival. We will explore novel metabolic factors to further address the hypothesis that energy homeostasis is key to survival.

DESCRIPTION (provided by applicant): We will exploit the multicenter Long Life Family Study (LLFS), a unique resource for research on human longevity and healthy aging, to find genetic variants associated with these traits. In the current period, we successfully enrolled and extensively phenotyped 4,953 individuals in 539 two-generational families that demonstrate clustering for exceptional survival in the upper generation. Fewer than 1% of the Framingham Heart Study (FHS) families (a roughly random sample of families) would meet the minimal entrance criteria for exceptional survival required in the LLFS. Thus our least exceptional families show more clustering for exceptional longevity than 99% of the Framingham families. Further, the children's generation have significantly lower rates of major diseases of aging including diabetes, chronic pulmonary disease, peripheral artery disease and show significantly more favorable profiles of quantitative mariners of healthy aging such as blood pressure, lipids, functional performance, and cognitive indices compared to FHS. These endophenotypes show greater clustering (with high heritability) in the LLFS familiesthan in FHS. Thus, LLFS has likely greatly enriched the prevalence of any gene variants for longevity and healthy aging endophenotypes, thereby increasing detection power. Most importantly, the family design of LLFS provides additional power and analytic opportunities to discover genetic influences than would be possible in a study of unrelated individuals, especially with regard to rare alleles. Our specific aims are to: 1) continue phenotyping by assaying biomarkers of healthy aging on stored samples, annually tracking subjects for new significant medical and health events, and comparing Medicare (and Danish equivalent) disease and utilization data with reference samples;2) identiy common genetic variants for healthy aging and excepional survival using GWAS;3) identify rare variants for exceptional survival and healthy aging by targeted sequencing;and 4) more clearly dissect the genetic architecture of exceptional survival an healthy aging through a systems approach involving genet networks and pathways, to better understand the complex interplay between genetic variants, exposures, and covariates in the development of endophenotypes. Taking a multidisciplinary approach involving clinicians, demographers, geneticists, epidemiologists, and computational scientists, we propose to capitalize on the investments already made in creating this unique cohort to further our understanding of the nature of exceptional survival and healthy aging. PUBLIC HEALTH RELEVANCE: Exceptional longevity and healthy aging are highly enriched in the families enrolled in the LLFS thus allowing us a unique opportunity to discover both common and rare genetic associations with these traits. Such associations will not only markedly enhance our understanding of why some people age so much better than others, but will also lead to enhanced prognostication for healthy and unhealthy aging and potentially disease prevention strategies.

DESCRIPTION (provided by applicant): This is a proposal for the competing continuation of the University of Pittsburgh Training Program in the Epidemiology of Aging. The field of the Epidemiology of Aging is a critical priority for public health. Now more than ever, we need to be providing advanced training in epidemiology and increase the cadre of experts in the study of risk factors for and prevention of disability. A critical training need is to develop epidemiologists who can effectively integrate knowledge and skills from multiple disciplines from basic science to clinical functional assessment into epidemiologic studies in a rapidly evolving research environment. We aim to develop such research scientists who are specialized in the field of the Epidemiology of Aging by providing mentored research with well-funded senior leaders in the field, formal coursework and group and individual instruction that emphasize: 1) A strong foundation in traditional epidemiologic methods and quantitative skills with emphasis on longitudinal and survival analysis, evaluation of heterogeneity and confounding by comorbidity and polypharmacy, assessment of functional health outcomes, and clinical trial methodology in older populations. 2) A strong biologic basis for the study of problems of older adults and potential targets for prevention. 3) The professional skills required for a career as an independent investigator, including developing new methodology, project management skills, as well as teaching and mentoring skills, and presenting research findings at national and international meetings, writing and publishing findings, writing grant proposals. 4) A multidisciplinary and collaborative approach that develops the ability to integrate science across disciplines so as to develop cutting-edge approaches. 5) The potential for prevention of disease and of disability in multiple domains including physical, cognitive, psychological and social function as well as the promotion of active life expectancy. The training program includes 2 pre-doctoral and 2 post-doctoral positions in epidemiology. Predoctoral trainees will be supported for 3-5 years to obtain a PhD or DrPH in epidemiology. Candidates will have a prior degree in medicine, nursing, exercise science, nutrition, public health or a related degree. Post-doctoral fellows will have a prior PhD in epidemiology or come with a degree in a health-related field such as medicine, nursing, genetics, and obtain a masters degree in public health. The extensive research program encompasses epidemiologic cohort studies and prevention clinical trials in osteoporosis, sarcopenia, cardiovascular aging, longevity cancer and aging, sleep disorders, cognitive decline and disability prevention. PUBLIC HEALTH RELEVANCE: As the number of adults reaching old age continues to increase, this program addresses a critical need train individuals with relevant scientific backgrounds in epidemiologic approaches to important public health problems engendered by our aging society. This training program will support 2 pre-doctoral trainees to obtain a PhD or DrPH degree and 2 post-doctoral fellows to develop specific expertise in Epidemiology of Aging.

DESCRIPTION (provided by applicant): The Long Life Family Study (LLFS), established in 2005 in response to an NIA RFA, enrolled families enriched for exceptional longevity (EL), to discover factors that contribute to healthy aging and survival. From 2006 to 2009, LLFS enrolled 539 sibships (G1), their offspring (G2) and spouses (total 4,953). Comparison with a referent cohort reveals that LLFS families have strong exceptional clustering of EL. The G2 offspring have a variety of Healthy Aging Phenotypes (HAPs), defined as an unusually low age-specific prevalence of one or more specific conditions or risk factors, compared to population-based cohorts suggesting enrichment of shared (possibly genetic) protective effects in LLFS families. In the second funding period (2010-2013), we conducted a 2.5 million SNP GWAS (dbGaP phs000397); developed a high-throughput technique and sequenced ~450 candidate genes and replicated many variants and found additional ones associated with Healthy Aging Phenotypes (HAP) and longevity. 54% of LLFS G1 and 92% of G2 remain alive. Participant retention has been 94%. We now propose a third funding period to conduct a second in-person examination (V2) to prospectively study rates of change in HAPs with age and identify genetic and other factors contributing to HAPs and longevity. We hypothesize that EL and HAPs entail common and rare variants that individually have modest effects, but which in combinations strongly influence longevity and specific HAPs, and may only be detectable in family studies enriched for HAPs, such as LLFS. HAPs evaluated at the initial in-person visit show strong linkage peaks which are not explained by common haplotypes interrogated by GWAS (HLODs ranging from 6.0-45.1). These are likely driven by rare, lineage-private alleles that will only be found by sequencing specific families, and may point to important new biology. Specific Aim 1 is to conduct a second in-home examination on all surviving LLFS participants. Specific Aim 2 is to analyze cross-sectional and longitudinal phenotypes. The goal is to identify pathways for EL and HAPs by characterizing the shared and distinct LLFS phenotypes and environmental factors. We will characterize individual longitudinal patterns of HAPs to identify subgroups showing similar patterns and exceptional phenotypes. We will test whether these HAPs are heritable, and test for differences with internal and external referent groups. Specific Aim 3 is to find genes/variants associated with cross-sectional and longitudinal phenotypes using a) Whole Exome Sequencing to comprehensively search for coding variants associated with HAPs and EL and b) Targeted Regulatory Sequencing of regions under linkage peaks for HAPs in selected families showing the strongest linkage evidence. Specific Aim 4 is to replicate our genetic and epidemiological findings in other aging study cohorts. This study could lead to the discovery of pathways and potential therapeutic/prevention targets affecting HAPs and EL. A Data Management and Coordinating Center and 4 Field Centers comprise the major components of the LLFS. This renewal application is submitted by the Duke Uni./Uni. of Southern Denmark Field Center.

The Long Life Family Study (LLFS) has enrolled 4,953 participants in 539 pedigrees in the USA and Denmark that are enriched for exceptional longevity, and has measured them longitudinally in two extensive in-home visits measuring key healthy aging phenotypes in all of the major domains of the aging process. We have demonstrated through many publications that selecting on longevity in the first (proband) generation, results in the second (offspring) generation being much healthier than average in many key phenotypes. However, the pedigrees are heterogeneous by phenotype, with different families showing familial clustering of protection in cognition, grip strength, pulmonary function, blood pressure, etc. Further, comprehensive linkage analysis of the LLFS sample identifies extremely strong genetic linkage peaks for cross-sectional as well as longitudinal trajectory rates of change phenotypes for a wide variety of healthy aging domains such as exceptional cognitive performance and lack of Alzheimer?s disease. These peaks are NOT explained by GWAS SNPs (or those that can be imputed by GWAS). Pedigree specific LODs and preliminary deep sequencing suggests that these peaks are driven by rare, protective variants running in selected pedigrees. We propose to do Whole Genome Sequencing on this unique cohort, to identify the rare protective variants driving these strong linkage peaks. We propose to continue longitudinal assessment of the cohort with a third in-person visit, which will allow us to assess potential non-linear patterns of aging, and adding formal assessment of dementia diagnosis for Alzheimer?s Disease and other dementia types, which will increase specificity and power to discover and follow- up on protective variants against Alzheimer?s Disease and other dementia diagnoses. For pedigrees driving multiple strong linkage peaks, we also propose to phenotypically measure the third generation (grandchildren), as these are likely to carry more copies of the rare protective alleles running in these families, which will exponentially increase our power to resolve them. Preliminary evidence from the Danish Medical Registry suggests that, at least in Denmark, the protection persists into this third generation, with significantly lower rates of medical conditions across the disease spectrum. We also propose to do extensive transcriptomics, methylomics, and proteomics on these selected high linkage pedigrees, to begin to move from ?statistically associated variants/loci? to the biological genes of action, since we expect most of the driving variants will be regulatory and non-coding. It is critical to find the modes of action of these rare protective variants. We also propose to do metabolomics on the entire LLFS cohort, longitudinally, with the goal of identifying novel biomarkers of healthy aging and resistance to diseases such as Alzheimer?s in this unusually heathy cohort. Combined with a systems biology/network approach to data integration of the proposed ?Big Data?, such biomarkers would improve our power to detect even more novel protective genetic variants and identify the genetic signatures and pathways of genes conferring protection in this unique cohort to prevent onset of major diseases such as diabetes, cardiovascular disease, cancer and Alzheimer?s Disease and other dementia types.