Attachment 7 OSMB Minutes

MINUTES
Observational Study Monitoring Board
For Framingham Heart Study
Meeting, December 11, 2014
PARTICIPANTS:
OSMB Members Present: Russell Luepker, Chair; Pamela Douglas, Phil Greenland, Svati
Shah (by phone), Lewis Smith, Jason Umans (by phone), Alexander Wilson
OSMB Members Absent: James Neaton
Framingham Investigators: Vasan Ramachandran, PI; Dan Levy (NHLBI intramural),
Adrienne Cupples, Caroline Fox (NHLBI Intramural), Joanne Murabito, Joseph Massaro
NHLBI Extramural Staff: Richard Fabsitz, Executive Secretary; Cashell Jaquish, Cheryl
Jennings, George Papanicolaou, Phyliss Sholinsky, Elizabeth Zoller
INTRODUCTION
The regularly scheduled annual meeting was called to order at 8:58 am. No conflict of interest
declarations were reported by the OSMB members in attendance, and all (including the absent
Board member) were up to date on their conflict of interest forms prior to the meeting. Two new
OSMB members were introduced: Dr. Svati Shah, a cardiologist and omics expert from Duke
University, and Dr. Jason Umans, a hypertension, renal disease, and chemistry laboratory
expert, with joint appointments at MedStar Health Research Institute and Georgetown
University.
DESCRIPTION OF THE STUDY
The Framingham Heart Study (FHS) was initiated by NHLBI in 1948 and currently comprises
three cohorts representing three generations that have participated in multiple exams over
varying lengths of time and time intervals between exams. The Original cohort has been
examined every two years since 1948. The Offspring cohort has been examined periodically
since 1971. The third generation (Gen 3) has been examined twice since 2000. In 2009, the
Omni Group 1 and Omni Group 2 cohorts, previously supported by grants, were integrated into
the Framingham contract. Funding for FHS’ current contract was continued in 2008 for seven
years and is now in the process of renewal. A reexamination of all three cohorts, as well as the
Omni cohorts, is part of the current contract. The second exam of Gen 3 and Omni Group 2
were completed in 2011, and the 32nd exam of the original cohort was also competed. The
Offspring cohort exam 9 and Omni Group 1 exam 4 started in 2011 and are now complete.
Plans for NHLBI support of the study will change significantly for funding beginning with the
contract renewal in 2015. Current plans call for a reduced funding commitment for the next
phase of the Framingham Heart Study with a focus on infrastructure and morbidity and mortality
follow-up with the possibility for core exam funding for the Gen 3, Exam 3 if grant applications
requiring an exam receive awards.
RESPONSE TO THE CONCERNS AND RECOMMENDATIONS OF THE PRIOR MEETING
Responses to the concerns and recommendations were addressed in an interim response
delivered in mid-2014 and were not reviewed in detail at the meeting. The Board was very
pleased with the response of the investigators to previous recommendations and thought all
were thoroughly addressed. The Board was particularly pleased that the NHLBI revised its
approach to funding the core examination in the current solicitation.

REPORT ON ADVERSE EVENTS
One adverse event was reported. One participant was found to have high blood pressure and
talked with a physician regarding the finding. He was able to complete only part of the exam and
was referred to his physician for follow-up. A total of 34 referrals were made as a result of the
exam; 5 required urgent medical follow-up.
BRIEF DESCRIPTION OF AGENDA ITEMS COVERED
Dr. Vasan Ramachandran presented to summary report in his new role as Principal Investigator.
Dr. Ramachandran indicated it was a year of transition with careful considerations from multiple
perspectives on how the study operates. Reviews were provided by a group of outside experts
and a consulting team. The goal is a more efficient process of conducting exams and boosting
scientific productivity. Productivity of the study was excellent given the transition and focus on
renewal of funding: 200 papers were published, 86 of which were genetically-focused and 25 of
which were without FHS investigators (using shared data/samples). Exams were completed for
the Offspring, Exam 9, the Omni cohort 1, Exam 4, and the original cohort, Exam 32.
Accounting for home visits and other forms of contact, overall retention remains above 90%.
Dr. Ramachandran presented the pulmonary function measurement and analysis plans. He
noted the progress with lung imaging and the automated lung density analysis based on pixel
density. These images provide new measures that can be used in GWAS analyses, for
example. Other imaging provides a measure of blood vessel volume from which total blood
volume in the lungs can be derived. Finally, the second CT scans of the lungs include greater
coverage with full thoracic CT – apex to base images.
Dr. Cupples provided a report on the DNA Committee, noting an increase in requests for DNA
that is linked to the AHA funding opportunities initiated in 2014. Requests remain largely
Boston-centric. Many requests for genetic data are now fulfilled by dbGaP and these come
primarily from outside Boston. There were 10 proposals for biospecimens, 8 of which were
approved. The AHA CVGPS program was responsible for a significant portion of the requests;
AHA recently made 8 awards as a result of this program.
Dr. Ramachandran summarized the creation of the Boston University Service Center to request
fees for data and sample sharing in the wake of funding reductions. Discussion by the Board
centered on the equality of fees for requests from commercial and academic institutions and the
size of the fee given the associated costs of managing such a system. FHS Investigators and
the Board discussed early stage investigators and their potential inability to pay the fee
structure.
Dr. Fox presented an innovative effort to increase the participation of early stage investigators
in the Framingham Heart Study that included WebEx seminars, multidisciplinary journal club,
invited speakers, theme-based sessions, innovation forums, professional boot camp and workin-progress meetings. The Board was very pleased with this set of activities.
Dr. Cupples reported on the genetic and non-genetic sample sharing and data sharing activities.
Efforts are currently underway to develop a living tissue/cell based distribution policy, promote
the genomic data commons, expand collaborations with commercial entities, and develop a plan
for return of whole genome sequencing results. Dr. Murabito presented on the latter and
indicated it has proven difficult for many reasons including confidence in data quality, need for
CLIA approval, evolving knowledge regarding variants that may offer clinical actionability, and

the cost of return. The investigators hope for further guidance from the NHLBI and/or the NIH
as opportunities for data collections increase.
Dr. Levy reported on the progress of the SABRe study. Three of the four components had
completed their lab work; the multiplex immunoassays project was slowed due to sequester cuts
but progress is now more apparent. Presentation of results from the SABRe project suggests
tremendous progress in discovery, consistency in findings between gene expression and
methylation projects, and replication in other cohorts. A number of high profile papers were
published. Integrative network analyses have been found to link previously unknown phenotype
linkages. It was noted that three of the AHA CVGPS grants awarded were based on SABRe
data.
Dr. Murabito reviewed the status of the ten ancillary study applications previously approved by
the OSMB that were proposed for funding in association with the Framingham Heart Study
renewal. It appears that several may have fundable scores. As a result it is expected that the
NHLBI will likely support a basic exam of Gen 3 in the coming contract renewal. Two new
proposals and six resubmissions may potentially be part of the exam as well. As a result, the
Board was unsure of how to track the total burden of participants and requested a table be
submitted as part of all ancillary study approvals that summarizes the existing and potential
participant burden to allow the Board to better assess this issue in their review of new ancillary
studies.
Scientific presentations were provided by Dr. Murabito on the genetics of age at natural
menopause and by Dr. Fox on the validation of e-epidemiology as an alternate way to collect
data in the Framingham Heart Study. Both were well-received by the Board.
The Board inquired as NHLBI moves to consortium cohorts, is there a way for individual study
OSMBs to work with other study OSMBs to address common issues, tasks, etc. This possibility
may be addressed at the expected cohort consortium planned for this spring.
RECOMMENDATIONS
The Board voted unanimously to continue the study.
The following specific recommendations to the NHLBI were provided:
1) The Board commends Dr. Ramachandran and the Framingham Heart Study
investigators on an excellent transition of leadership and advancement of the ongoing
and new science during the previous year.
2) The Board acknowledged the effort to generate additional ways to offset costs of
managing and distributing data and specimens in the spirit of sharing but questioned the
fee structure that treats academic and commercial interests equally and at a level that
does not appear to be cost effective given the associated accounting burden.
3) The Board commended the investigators for accelerating the scientific productivity of the
SABRe project and for the compelling scientific findings of this project.
4) The Board recognized the scientific opportunity of the successful application for whole
genome sequencing in the Framingham Heart Study but questioned the value of initial
efforts to conduct whole genome sequencing on six FHS trios across all sequencing
platforms without a timely plan for analysis and action based on the results of that effort.
5) The Board recognized that that the Framingham Heart Study investigators were on the
leading edge of addressing the questions of when and how to return of genetic research
results and urged the investigators to provide a plan to address this issue.

6) The Board urged the NHLBI to explore opportunities to support the development of
infrastructure for the Framingham Heart Study and other NHLBI–supported studies that
would facilitate the sharing of the wide range of imaging data currently available.
7) The Board commended the investigators for expanding the pulmonary technologies
currently being employed in the study and the outstanding science derived therefrom.
8) The Board requested that a table be routinely provided in OSMB meetings and with
ancillary study reviews that provides current and potential participant burden for
approved and pending ancillary studies.
9) The Board urged the investigators to be more proactive in marketing the opportunities
for early stage investigators in the Framingham Heart Study, particularly for individuals
outside Boston.
10) The Board urged the investigators to develop a plan for conducting functional studies to
confirm the functional status of identified variants from the various discovery techniques.

NEXT MEETING
The next meeting is scheduled for Thursday, December 3, 2015.
SIGNATURES
Approved

Richard R. Fabsitz, Executive Secretary, FHS OSMB

12/16/2014

Approved

Russell Luepker, Chair, FHS OSMB

12/15/2014

Approved

Michael Lauer, Director, DCVS, NHLBI

12/17/2014