Download Editorial The Framingham Heart Study: past

International Journal of Epidemiology, 2015, 1763–1766
doi: 10.1093/ije/dyv336
Editorial
Editorial
The Framingham Heart Study: past, present and future
The Framingham Heart Study (FHS) is widely recognized
for its lasting contributions to cardiovascular epidemiology. In this article we review the study’s history, past accomplishments, current research agenda and future
research directions.
Where we came from
With the rapidly rising prevalence of cardiovascular disease
(CVD) in the early 20th century, public health and political
leaders of the USA agreed that national investment in research must be undertaken towards CVD prevention. The
National Heart Institute, which later became the National
Heart, Lung and Blood Institute, was formed in 1948. Since
CVD encompasses conditions with prolonged subclinical
course, a prospectively-followed healthy cohort was
deemed to be the perfect sample in which to study development of CVD. Thus, in 1948, the U.S. Public Health Service
embarked upon the first large-scale cardiovascular epidemiology study in the country—the FHS.1 Investigators
sampled 2 of every three adults aged 30–59 years in the
town of Framingham, Massachusetts, yielding a sample of
5209 men and women enrolled. Data collected included detailed medical and family history and physical examination,
as well as X-ray, electrocardiogram and blood tests including cholesterol and glucose, to detect abnormalities thought
to play a role in development of CVD.
The initial observations from FHS provided many of the
central tenets of cardiovascular epidemiology that have
held true over time. Published in 1957 and 1959, the first
publications from 4- and 6-year follow-up reported such
findings as greater incidence of coronary artery disease
(CAD) associated with older age and male sex.2,3 The FHS
was the first to describe a graded relationship of CVD with
obesity, systolic blood pressure, cholesterol and cigarette
smoking. Furthermore, the authors noted that these conditions may amplify synergistically, as cholesterol levels were
greater in smokers as compared with non-smokers.3 The
initial findings from the FHS revolutionized primary
prevention of CVD. In a seminal 1961 manuscript, Dr
William Kannel, who subsequently led the FHS, described
the key ‘factors of risk’ associated with atherosclerotic
CVD, including age, sex, hypertension, elevated cholesterol, diabetes and electrocardiographic left ventricular
hypertrophy.4 This singular work popularized the ubiquitous term ‘risk factors’ used today and defined key variables
determining CVD risk in adults. FHS investigators also
introduced the notion of multivariable risk, combining several risk factors into a risk score to estimate the absolute
risk of developing CAD, stroke and CVD. The
Framingham Risk Score5 has stood the test of time and remains a benchmark for evaluation of patients in a multitude
of clinical settings. FHS also identified major risk factors
for stroke, including the key role of atrial fibrillation. As
the study evolved, measurements of high-density lipoprotein [HDL] cholesterol concentrations underscored the cardioprotective role of this lipid trait. The epidemiology of
different forms of CVD, including peripheral arterial disease and heart failure, were also characterized by several
landmark FHS reports. Overall, FHS identified the role of
lifestyle in mediating CVD risk and origin of several risk
factors.
Where we are
In the decades since the FHS was conceived as a single cohort studying now-accepted ‘traditional’ cardiovascular risk
factors, it has evolved exponentially in breadth of both participants and measured phenotypes. In addition to the
Original Cohort members, the FHS now includes the
Offspring Cohort, comprising 5124 of the Original Cohort
members’ descendants and their spouses, and the Third
Generation Cohort which includes 4000 of the children of
the Offspring Cohort.6,7 Thus, FHS represents a multigenerational cohort study with availability of multiple longitudinal observations (see below). Furthermore, to address
concerns of predominant enrolment of individuals of
Western European ancestry, the OMNI study was created
C The Author 2015; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association
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in 1995 to include examinations on 506 ethnically and racially diverse community members, thereby capturing the
changing demographic profile of the town over time. A second minority cohort was enrolled at the time of recruitment of the Third Generation Cohort. Each of these cohorts
has been serially followed with in-person examinations
every 3–4 years since enrolment, with virtually no loss to
follow-up.8,9 At each examination, history and physical
examination, including anthropometric, blood pressure,
symptoms, risk factors and medication, data have been
collected. A large biorepository of blood samples has
been established with nearly 1.6 million biosamples (stored
at -80 C). Measures include complete blood count, routine
blood chemistry and lipid panels as well as urine biomarkers. The availability of serial longitudinal data facilitated ‘lifecourse epidemiology’ studies and statistical
methods such as multilevel modelling. Repeated samples
over time have allowed for studies describing temporal
trends in risk factors and have facilitated investigations
relating risk factor trajectories and cumulative exposure to
the incidence of CVD. The concept of lifetime risk of developing CAD, stroke and CVD was established using FHS
data. Additionally, state of the art non-invasive imaging
tests including echocardiography,10 cardiovascular magnetic
resonance,11 cardiovascular computed tomography,12
applanation tonometry,13 flow-mediated dilation14 and carotid ultrasound15 have characterized cardiovascular function and atherosclerotic burden in these cohorts over time.
Detailed and extensive longitudinal data characterized
by the FHS have been collected in all cohorts and have expanded in recent decades to include not only CVD phenotypes, but those of multiple organ systems. Functional and
imaging studies have pioneered understanding of the brain,
lungs, kidneys, liver, fat tissue, bones and metabolic systems in health and disease. In addition, harnessing the
power of the large community-based sample and sophisticated statistical modelling, data from the FHS have been
used to analyse patterns in social networks and related behavioural changes impacting on obesity,16 as well as air
pollutants and brain health in the region.17 With the expansive breadth of research, perhaps ‘the Framingham
Heart Study’ may more appropriately be shortened to simply ‘the Framingham Study’.
Truly a transformative organization, the FHS has integrated clinical epidemiology with translational research. In
addition to ‘macro-phenotypes’ described, the FHS has
also been able to study ‘micro-phenotypes’ using novel
serological testing, furthering our understanding of human
pathophysiology. The FHS has been at the forefront of
identification of novel biomarkers predictive of CVD, and
has embarked upon extensive genetic and ‘omics’ data.
The three-tiered family structure has been particularly
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advantageous for genotyping, where 40 million single nucleotide polymorphisms ‘SNPs’ have been measured or
imputed by the 1000 Genomes project, facilitated by the
availability of immortalized lymphoblastoid cell lines in
over 9000 participants across the different generations.
The FHS participates in numerous national and international genetic consortia, including the Cohorts for Heart
and Aging Research in Genomic Epidemiology, which
have been responsible for uncovering genetic variations
associated with multiple CVD and non-CVD phenotypes.
In addition, the human exome has been investigated using
the Exome chip, Exome Sequence Project and wholegenome sequencing with high fidelity.8 FHS ‘omics’ data
collected include whole-blood DNA methylation, transcriptomics, microRNA, metabolomics and proteomics.
Embodying collaboration and innovation in genetic studies, the FHS has led several pivotal investigations of the
role of genetics in multiple aspects of CVD.8,18–20 A successful FHS training programme in cardiovascular epidemiology has contributed to the training of a large
number of scientists. In summary, FHS currently is a very
richly phenotyped and genotyped population health laboratory in which novel hypotheses can be tested. It brings
together such a dense array of phenotypes such that it can
be likened to a human phenome project.
In addition to the epidemiological foundations laid by
FHS, the FHS legacy can be seen in the formation of additional epidemiological cohort studies in the wake of FHS
successes. Such cohorts as Atherosclerosis Risk in
Communities and the Cardiovascular Health Study in middle-aged and older adults, respectively, and the MultiEthnic Study of Atherosclerosis created in recent decades,
were designed similarly to the FHS, including longitudinally followed examination cycles and standardized protocols in measures and to define outcomes of interest. These
studies, which have included greater racial and ethnic diversity in their participants, likewise have been critical in
defining epidemiological associations of subclinical CVD.
Thus, the legacy of the FHS is far-reaching and the principles established decades ago have only expanded to
greater depths.
Where we are headed
Epidemiological cohort studies including the FHS have led
to dramatic advances in our understanding and reduction
in the prevalence and incidence of CVD in the USA over
the past several decades. Greater amounts of data collected
on individuals, including digital data, e-health data (electronic health record and CMS data), m-health data (collected using mobile devices) and the notion of the
‘quantified self’ may result in greater scientific discoveries.
International Journal of Epidemiology, 2015, Vol. 44, No. 6
Efforts are ongoing to better capture the diversity of the
‘exposome’, including that of the ‘built environment’.
Critics remark upon the high cost: incremental knowledge
ratio, lack of replication of findings and failure to pursue
highest merit studies.21 Yet one only needs to skim scientific journals and PubMed to discover the continued plethora of epidemiology research answering critical questions,
shaping our understanding of disease. In the current and
anticipated future era, the field is faced with unique challenges including the push for ‘big data’, fuelled by the ability of advanced technology to characterize phenotypes and
genotypes with increasing granularity, coupled with the dichotomy of increasingly limited resources and funding in
which to conduct the research.
Clearly, for epidemiology cohort studies to remain successful, adaptation must occur at multiple levels. It would
be advantageous for the FHS and other epidemiological cohort studies to expand the studied phenotypes and outcomes
of interest, apply novel technologies to population science,
develop sophisticated algorithms to integrate different aspects of the data, analyse pooled individual participant data
from different cohorts (the notion of a ‘data Commons’), all
while optimizing use of scarce resources. At the level of each
individual cohort study, centralization must replace fragmentation of data storage within each constituent cohort,
and the infrastructure to hold such expanded datasets must
be put in place. Such data centralization would facilitate
cross-phenotype and interdisciplinary studies. In addition,
to truly harness the power of the modern epidemiology,
data access and data sharing should be fostered among diverse cohort studies for collaboration and replication. There
is an increasing emphasis on cardiovascular epidemiological
results being directly applicable to patient outcomes. Thus,
results from cohort studies should be integrated with those
of clinical trial data, for example by conducting trials in cohort samples. In addition, for the scientific community to
advance, forums are essential in which all results, both positive and negative, may be presented and disseminated.
Approaching this task ‘from the ground up’, it is important
to share these ideals to bring about a cultural shift in our
methods of studying the epidemiology of CVD. Paralleling
these changes is the evolution of a multidisciplinary training
programme in cardiovascular epidemiology that integrates
clinical epidemiology with knowledge of statistical genetics
and bioinformatics. Thus there is much more work to be
done in the field of cardiovascular epidemiology, and if the
FHS continues to evolve, scientific discoveries will follow to
benefit researchers worldwide and to impact on public
health.
The FHS has come a long way from the initial formation of a large cohort which identified elevated blood pressure, cholesterol and biobehavioural factors for conferring
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risk of CVD, to a multigenerational study of 15 000 participants who have contributed to hundreds of cutting-edge
imaging, biomarker and ‘omic’ measures (systems biology
approach) extending across nearly every human organ system. The rich array of expanded data collection, close longitudinal follow-up of participants and interdisciplinary
and cross-cohort partnerships will ensure a wide spectrum
of epidemiological discoveries and fruitful collaborations
for generations to come.
Connie W Tsao1,2*
1
Framingham Heart Study, Framingham, MA, USA and
2
Department of Medicine, Cardiovascular Division,
Beth Israel Deaconess Medical Center and Harvard
Medical School, Boston, MA, USA
Ramachandran S Vasan1,3
1
Framingham Heart Study, Framingham, MA, USA and
3
Sections of Cardiology and Preventative Medicine,
Boston University School of Medicine, and Department
of Epidemiology, Boston University School of Public
Health, Boston, MA, USA
*Corresponding author. Cardiovascular Division,
Beth Israel Deaconess Medical Center, 330 Brookline
Avenue,
Boston,
MA
02215,
USA.
E-mail:
[email protected]
Acknowledgements
The FHS is indebted to the dedication of its participants and staff
for making the decades-long journey and groundbreaking discoveries in cardiovascular disease possible.
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