Working Group on Future Research Opportunities in the
Women's Health (WHI) Extension to 2015
Meeting Summary July 1, 2008
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TABLE OF CONTENTS
Welcome and Charge
Background and Process for Renewal
Objectives for Renewal and Investigator Presentations
Discussion and Prioritization by Working Group
Working Group Members, NHLBI, NIAMS, NIA Staff, and WHI Investigators
Welcome and Charge
Dr. Lauer outlined
the charge to recommend areas of research that WHI can contribute to
during an extension from 2010 to 2015, particularly in regard to
understudied health issues in older women. By virtue of its origins, the
scope of WHI research goes beyond that of most NHLBI programs. The advice
of the working group on the science is an important initial step in the
process as NHLBI considers renewal of the program. NHLBI will consider the
proposed research in the light of its overall research portfolio, its
strategic priorities, and available funding.
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Background and Process for Renewal
Dr. Rossouw reviewed the objectives and design of the original WHI (1993-2005) program:
- To address the etiology and prevention of the major causes of morbidity and mortality in post-menopausal women
- Enrolled 68,132 women aged 50-79 in three clinical trials
- Hormone therapies to prevent CHD
- Dietary modification to prevent cancer
- Calcium and vitamin D supplementation to prevent fractures
- Enrolled 93,676 women in an observational study.
He summarized the main findings from the 3 trials and
the impact the hormone trials had on medical practice. The clinical trials
provide the opportunity to evaluate long-term effects of the interventions on
disease outcomes, and the observational study data provide an opportunity to
compare associations in the observational study with findings in the clinical
trials.
During the current WHI Extension study (2005-2010) 115,405
women have been re-consented, with high retention rates and near-complete
adjudication of outcomes, yielding a one-third increase in number of outcomes
to date. To date, the extension study has yielded about 50 publications and 7
new ancillary studies per year, in addition to core studies and 12 Broad Agency
Announcement (BAA) studies. He outlined the resources created, to which is
being added a medications inventory and CMS linkage. The most heavily studied
outcomes include CHD, stroke, VTE, breast and colorectal cancer, and hip
fracture, but even in those categories blood and DNA samples remain available
for further study. A shift in focus to other outcomes during a further
extension could take advantage of unused blood samples. Several avenues for
sharing the resource are being utilized, including the BAA mechanism and making
available genome-wide association data. Approximately one-half of ancillary
studies and one-third of publications are led by non-WHI investigators.
The process for a potential renewal includes internal NHLBI meetings and external
review by the Board of Extramural Experts and the NHLB Council prior to
issuance of a solicitation in 2009.
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Objectives for Renewal and Investigator Presentations
Dr. Stefanick presented the objectives for a proposed WHI
extension to 2015 as being similar to those for the current extension in some
respects:
- Enhance ability to study subgroups and rarer outcomes
- Serve as platform for additional studies (core, ancillary, BAA, consortis)
- Study longer term effects of clinical trial interventions
New research proposed for the extension to 2015 is focused
on use of the cohort to investigate conditions that affect health of an aging
population of women:
- Aging (functional status and frailty, healthy
aging, osteoporosis and risk for fracture, cognitive function)
- Cardiovascular (heart failure, atrial
fibrillation, venous thromboembolism)
- Cancer (longer term effects of interventions,
cancer risk factors and pathogenesis, discovery and validation of biomarkers
for early detection, breast cancer survivorship and management
- Overarching themes (improving dietary and physical
activity methodology, applications of genomic and proteomic technologies,
social and built environment).
Specific aims:
- Maintain the current infrastructure of 39 field
centers, a coordinating center, and study committees
- Maintain central database, data analysis
capabilities, and bio-repository
- Further enhance the WHI resource (additional 5
years of outcome data, CMS and other linkages, medications inventory, ancillary
studies)
- Conduct new research on aging (~100,000 women
expected to participate, of whom ~80% will be >70 years old)
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Dr. LaCroix presented an overview of the aging proposals, stating
the overall question as “What are the factors that determine whether an older
woman can live a long, healthy, relatively independent life?” She noted that by
2010 the WHI cohort is projected to include ~54000 women aged >70, and
~38000 aged >80 years. WHI has multiple measures of frailty, disability,
and healthy aging including those that have been used in other studies. WHI
investigators are currently conducting studies on the inflammatory pathway and
incident frailty (drugs, biomarkers, candidate genes). Questions that WHI can
address in regard to longevity include adult nutritional patterns using
calibrated measures, biomarkers (including genomic and proteomic markers), use
of medications, lifestyle and behavioral characteristics, race/ethnicity,
exposure to trial interventions. WHI has a strong osteoporosis/fracture
component and can address a similar variety of factors that relate to
osteoporotic fracture in older women, and can also address novel osteoporotic
phenotypes. She also stated that the cohort could be considered for potential
randomized controlled trials of prevention strategies.
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Dr. Shumaker outlined the suite of studies related to cognition
and dementia in WHI that are all nested within the hormone trial. Strengths
of the studies include their size, follow-up for more than 10 years, high
retention rate, assessment of multiple cognitive domains using clinically
sensitive measures, the inclusion of pre-clinical outcomes (mild cognitive
impairment, vascular cognitive impairment, MRI) and careful ascertainment and
adjudication of dementia. She noted that the adverse effects of hormone therapy
persist during the follow-up. Future research directions that will be enhanced
with continued follow-up of the cohort include risk factors for cognitive
decline and impairment, relationships between cognitive function and physical
function/disability, cognitive reserve, and biomarker discovery.
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Dr. Manson emphasized that heart failure and atrial
fibrillation are major and growing epidemics, with a disproportionate burden in
women (because of the large number of older women). Venous thromboembolism also
increases rapidly with age and remains understudied. Studies on CVD fit into
the overarching theme of determinants of healthy aging.
Specifically, heart failure in women differs from
that in men (more non-ischemic causes, preserved systolic function,
co-morbidity, symptomatic and worse clinical outcomes, impairment of
health-related quality of life and activities of daily living). WHI can
contribute to understanding heart failure in older women and in minority women.
WHI will need to resume adjudication of self-reported heart failure and
standardize classification, perhaps using algorithms similar to those used in
Framingham (for hospitalized cases) and the Atherosclerosis Risk in Communities
study (for ambulatory cases). Research questions include whether risk factors
for incident heart failure differ by age or race/ethnicity, preserved versus
impaired systolic function, mortality rates by type of heart failure,
relationships between heart failure type and functional status, cognition,
other CVD, and HRQOL, biomarker and genetic, proteomic, and metabolomic
studies. Geocoding could contribute information on air quality, particulate
matter, social and built environment. CMS linkage could contribute information
on cardiovascular service use and costs.
Atrial fibrillation is understudied in women in other
cohorts. Ascertainment of atrial fibrillation will occur through a combination
of methods: self-report followed by records review (including for clinical
diagnosis, ECGs, imaging data), ECGs done serially in clinical trial
participants, and CMS linkage. Research opportunities include improvement of
risk prediction including traditional CHD risk factors, demographic factors,
sleep disorders, biomarkers, genetic and proteomic predictors, dietary factors,
medications use. The interrelationships of atrial fibrillation with heart
failure, stroke, other CVD, physical and cognitive function, depression, and
HRQOL could be studied.
WHI has the potential to become one of the largest
prospective cohort studies of venous thromboembolism worldwide, with
1200 projected cases in the hormone trial cohorts by 2015, and could study
genetic, biomarker, and lifestyle risk factors relevant to the pathways of risk
for VTE. The relationship to air pollution/particulate matter and the
interrelationships with frailty, other CVD, cancer, and all-cause mortality are
other research opportunities.
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Dr. Prentice focused on initiatives that cut across study
diseases: dietary and physical activity epidemiology, use of genomic and
proteomic technologies, and social and built environment, in addition to
specific studies of longer term effects of clinical trial interventions, cancer
risk factors and pathogenesis, early detection of cancer, and breast cancer
survivorship and management. Nutrition and physical activity epidemiology:
WHI has established comprehensive nutrition and physical activity resources
(Food Frequency Questionnaire (FFQ), 4 Day Food Records (4DFR), 24-hour recall,
physical activity questionnaire (PAQ), calibration studies of energy and
protein consumption, and biomarkers of nutrient intake). Using regression coefficients
from calibration models, the FFQ underestimates both energy intake and protein
intake. Several cancers that appear not to be related to energy intake are
significantly associated after calibration of FFQ data. During the current
extension these FFQ-based association studies for energy and protein can be
extended to CVD, diabetes, and weight change; also, analyses of the broader
range of dietary instruments, expenditure studies, and biomarkers will be
completed. During a further extension to 2015 the potential of the respiratory
quotient from indirect calorimetry to calibrate fat and carbohydrate intake can
be examined, and applied to FFQ and 4DFR to examine associations with cancer,
CVD, diabetes, and weight change. Similarly, calibrated PAQ-based association
for these same outcomes can be performed.
He summarized the WHI involvement (and some preliminary
data) in genome-wide association studies (GWAS) and confirmation studies
on CHD, stroke, breast cancer, hip fracture, pancreatic cancer, and SHARe. Some
of these GWAS/confirmation studies are done with core resources, others are
ancillary studies, BAA studies, collaborations with NCI, or funded directly by
NHLBI in the case of SHARe. There is considerable potential for further
studies, including studies of gene-environment interaction, given the large
numbers and rich phenotyping of the cohort (including trial exposures). WHI has
several proteomic initiatives, again funded through a variety of
mechanisms including collaboration with NCI. Most of these are at the stage of
discovery prior to validation with ELISA. The results from a core study of
proteome changes in response to hormone therapy could be validated in several
instances by ELISA and are biologically plausible.
Longer-term effects of interventions will benefit from further follow-up; interesting (and
somewhat concerning) initial data on cancer during the first several years of
follow-up of the E+P trial have been published. The post-intervention data can
help interpret national trends breast cancer following changes in patterns of
hormone therapy use. In the DM trial a low-level maintenance of the
intervention is being implemented and it is expected that any effects on cancer
will take a decade or more to emerge. Numbers of incident cancers are expected
to be 80-100% greater by 2015 compared to 2005 and will include substantial
numbers of less common cancers (e.g., ~1200 for ovary and NHL; ~700 for
bladder, pancreas, leukemia, kidney) and for less common subtypes of cancer
(e.g., ~1800 for ER-, PR- breast cancer) or for less common exposure subtypes
(e.g., ~450 lung cancers among never-smokers). The outcome and exposure data
can be used for a wide array of risk factor and etiologic studies,
including the development of improved prediction models. Work on discovery and
validation of cancer early detection biomarkers will continue, using
quality-controlled pre-diagnostic serum and plasma. He gave examples of studies
of breast cancer survivorship and management that could be done. He
proposed that WHI collect tumor blocks to allow for improved tumor
profiling by gene expression and other molecular profiling of tumor tissue.
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Discussion and Prioritization by Working Group
For this part of the discussion, two
investigators (Drs. Stefanick and Prentice) were invited to remain as
observers and resources; the Chair had the option of calling for a
closed session.
The working group discussed each of the research
areas proposed, and prioritized the areas (this activity was finalized
by a brief questionnaire completed after the meeting). The group also
commented on the general structure of any follow-up.
The comments, recommendations, and priorities
summarized are those of the working group and do not reccessarily
reflect the views of NHLBI. These and other inputs will be considered
by NHLBI through internal processes, with eventual further reviews by
external experts.
General comments:
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There was a dichotomy of opinion as to how the cohort
could best be leveraged; one group favored specific hypotheses to be
explored in subsets of the cohort (or a smaller overall cohort), while the
other viewed the cohort as an invaluable resource for high-dimensional
studies requiring large numbers of well-phenotyped outcomes and therefore
recommended following all participants.
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The CT cohort was seen as more valuable than the OS
cohort because of the specific randomized exposures, which for example
make it ideal for studies of gene-environment interactions.
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The group acknowledged the collaborative record of
the WHI group, and encouraged training workshops for younger investigators
in the use of WHI data, and special programs for minority investigators.
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Some recommended streamlining of outcomes data
collection, e.g., further centralization of outcome data collection, or
passive data collection, in lieu of field centers.
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Do not need precise diagnosis for studies of health
resources/cost, do need for etiologic studies.
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If interviewer-administered questionnaires, physical
measurements or blood collection are needed for specific substudies, home
visits by research staff may be more cost-effective than clinic visits
(there are companies that offer this service on national basis)
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Need to bring in additional expertise in areas where
WHI investigators are not expert (e.g., use of CMS data would need
outcomes researchers, heart failure, atrial fibrillation research).
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Encourage efforts to re-enroll women who have dropped
out.
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Consider layered consent, e.g., women could agree to
participation in studies involving matching to administrative
files/obtaining surgical specimens/questionnaires.
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Generalizability to US population can be improved by
weighted analyses.
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Better integration of ancillary study data into study
database.
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Invest in getting more phenotypes in women who were
studied in more detail, e.g., GWAS substudy, DXA substudy.
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Uncertain about use of cohort for new trials.
Consider high-dose vitamin D trial.
CMS linkage—very high priority
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CMS linkage supported for case-finding (annual
cycles), ascertainment of other outcomes e.g., Parkinson’s, and
co-morbidities. For health services research data can be obtained in
batches, less frequent than annually.
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CMS data could be used at regional differences in
medical practices and outcomes, health services outcomes associated with
cognitive impairment, congestive heart failure.
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Need to involve experts—data are “dirty”.
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CMS data increasingly important in aging cohort, who
have high likelihood of suffering an event or death before annual
self-report.
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Consider substituting for ascertainment of most
outcomes to reduce costs
Medications inventory—very high priority
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Support collecting data on medication use more
proximal to event. Note polypharmacy in elderly, potential for medications
to be associated with adverse outcomes. Useful for disease classification,
e.g., self-report of T2DM plus medication, self-report of Parkinson’s plus
medication.
Aging—very high priority overall
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Ideal cohort to study aging. Aging multidimensional,
need systems biology approach, thus needs large sample size and measures
that fit a specific paradigm. Pick aging as focus, need to integrate
initiatives into overall concept. All diseases are related to aging, try
to coordinate biomarker measurements relevant to all outcomes. Integrate
studies of physical and cognitive function into studies of diseases of old
age.
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However, the lack of physical measures would impair
the ability to do aging work, as would the lack of data on cognitive
function are lacking in the majority of women.
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Aging as continuum (health---disability---death) vs.
separate trajectories.
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Focus on products, e.g. WHI risk calculators.
Functional status and frailty—very high
priority
Successful aging and longevity—very high
priority
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Rapid fall-off due to death in women after 85 makes
large cohort necessary to study extreme longevity.
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Weakness—no continued measurements of mental health,
social support, gait/walking/mobility—perhaps assessment by proxy, or
telephone administered measures could be implemented.
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One member recommended “aging research cohort”
comprised of CT participants.
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While there are many other studies of frailty, WHI
offers exceptional opportunity to study successful aging, paradoxical
phenotype (have risk factors but do not get disease).
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Recommend continued data collection on obesity and
diabetes in follow-up, others have experience in self-report of body size
measurement (weight, height, waist circumference).
Cognition—very high priority
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Need more information on effects of HT on cognition
in women starting close to the menopause. Suggest study broader age range
in all CT cohort.
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Information on co-morbidity needs to be built into
study of aging and cognition.
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For applications of genomics/proteomics technologies
to cognition WHI cohort is unique.
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Need functional measures during follow-up.
Osteoporosis and fracture—moderate
priority (however, note osteoporosis expert could not
attend meeting).
Cardiovascular disease—moderate to high
priority overall
Continued ascertainment of CHD, stroke—high
priority.
Heart failure—high priority only if can
be better characterized
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Important and understudied disease, especially heart
failure with preserved systolic function. Difficult to study, but somebody
has to do it.
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Problem with characterization is common to all
epidemiologic studies of heart failure. Potential solution: can we get
digital record of echo at time of hospitalization to read centrally,
quantify parameters in standard fashion. Not convinced Framingham heart
failure algorithm works for obese people, does not work for diastolic
dysfunction. Get BNP from chart.
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Good opportunity for studies by race/ethnicity,
health services disparities.
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Need good phenotyping for etiologic studies, not
necessary for studies of health care utilization/costs.
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Additional expertise would be needed.
Atrial fibrillation—high priority only if
can be better characterized
Venous thromboembolism—moderate priority
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Factors underlying increased risk with aging and with
hormone therapy are not well documented
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Relationships to physical activity, renal function,
hemostasis, functional outcomes of VTE, relationship of VTE to future CVD
not well studied.
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Potential for gene-environment interaction studies.
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Perfect cohort for study of particulate matter and
VTE.
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Paucity of studies looking at VTE, important cause of
impaired QOL, health care utilization, and mortality.
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Not all members were enthusiastic, many of the
hypotheses could be explored using existing data.
Cancer—moderate to high priority overall
Longer term intervention effects—high
priority
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Not unique cancer cohort, except for trial
exposures—only WHI can do latter.
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Ethical imperative to study long term effects, given
harm observed in hormone trials.
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Question how real the difference is in fat intake
post-trial—need biomarkers. Study carotenoids.
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Body weight needed in follow up of trials to better
interpret findings in the DM trial.
Cancer risk factors and pathogenesis—moderate
to high priority
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Support getting tumor blocks—tumor genetics are going
to be much more informative than blood genetics. Tumors in CT,
specifically for breast, colon, endometrial highest priority.
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Create resources for proteomics, genomics (including
sequencing, confirmatory studies), metabolomics. Needed to pool 15 cohorts
for study of pancreatic cancer, need large studies like WHI.
Discovery and validation of biomarkers—very
high priority
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Availability of pre-diagnostic bloods, good
phenotyping.
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Opportunity to look at long-term prediction, lifetime
risks using earlier phenotyping and biological specimens.
Breast cancer survivorship and management—moderate
priority
Overarching themes:
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Applications of genomic and proteomic technologies—very
high priority
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Potential for studies of copy number variants,
epigenetics, gene-environment interactions (in trials).
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Large numbers needed for GWAS and studies of GEI.
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WHI ideal for replication studies, subphenotyping.
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Good record for opening resource, high quality
samples, large number of cases for validation.
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Divergent views on genetics in older persons: some
think not important in old survivors, while others think multiple common
genes continue to play a role.
Nutrition and physical activity epidemiology—moderate
priority
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Diet and PA affects or modulates many outcomes of
interest. Support biomarkers to calibrate reported energy, protein,
potassium intake, respiratory quotient for fat and carbohydrate energy.
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New dietary measure—web based 24 hr. recall used by
NCI.
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Problems with reported physical activity as severe as
for diet, maybe use accelerometers, heart rate variability.
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Methods research can greatly contribute to knowledge
of measurement error and correction for it.
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Continue to collect dietary and PA data on DM trial
cohort.
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Continue supporting analyses of current FFQ and PA
instruments.
Social and built environment—moderate
priority
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Opportunities by linkage to existing datasets, assess
whether independent predictors.
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Need to tailor to demographics, elderly may be
different.
Additional Research Areas:
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Parkinson’s—self-report+meds has good positive
predictive value
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Neuropathy (questionnaire and
monofilament exam)
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Sensory impairment, hearing loss, cataracts,
pneumonia, other infections
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Health services research
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Epigenetics—collect DNA during follow-up
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Death rates from liver disease could inform the issue
of screening for genetic hemochromatosis in women
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Rates of surgery, mortality for abdominal aortic
aneurysm could inform issue of screening in women
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Mitral valve disease, bypass surgery.
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Sudden death
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Working Group Members
Deborah Grady, M.D., MPH (Chair), Javed Butler, M.D.,
MPH, Tim Byers, M.D., MPH, Mary Cushman, M.D., MSc, Luigi Ferruci, M.D.,
Ph.D., Tamara Harris, M.D., Robert Hoover, M.D., Tom Pearson, M.D., Diana
Petitti, M.D., MPH, MaryFran Sowers, Ph.D. (call-in), Sudhir Srivastava,
Ph.D., MPH, Amy Subar, Ph.D., MPH, RDH, Eric Whitsel, M.D., MPH
NHLBI Staff
Lawton Cooper, M.D., MPH, Peter Kaufmann, Ph.D.,
Michael Lauer, M.D., Shari Ludlam, MPH, Peggy Mills, Nancy Morris,
George Papanicolaou, Ph.D., Richard Phillips, Jacques Rossouw, M.D.,
Jeffrey Williams
NIAMS
Joan McGowan, Ph.D.
NIA
Neil Buckholtz, Ph.D.
WHI Investigators
Andrea LaCroix, MPH, Ph.D., JoAnn Manson, M.D., Ross Prentice, Ph.D.,
Sally Shumaker, Ph.D., Marcia Stefanick, Ph.D.
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