|Policies and Procedures for Requesting Materials (DNA) and Genetic Data|
|Framingham Home Page|
|Important Announcement Regarding Requests for Framingham|
Genotype/Phenotype Data: The distribution of data from the
Framingham Heart Study genotyping studies (100K and 550K
SNPs) in combination with the phenotypic data is now available
through the Framingham SHARe (SNP Health Association Re-
source). Applications for DNA, for addendum applications to
previously approved projects, or for genotyping data not yet
available on the Framingham SHARe website, should continue
to follow the procedures listed on this page. New applications
for genotype data linked to phenotypes should follow the process
listed at the following web site (once at this dbGaP site, click on
the link to Framingham SHARe):
|Purpose of DNA and Genetic Data Distribution Policies|
|Overview of Procedures for Requesting DNA and Genetic Data
|Framingham Study: Design, Rationale and Objectives
|Framingham Heritability Data
|Power Calculation for DNA Applications (PDF file)
|DNA Samples and Genetic Data Available for Distribution
|Detailed Procedures for Requesting DNA and Genetic Data
|Overview of Data and Materials Distribution Agreement
|Data and Materials Distribution Agreement Form
|Process for Review of Proposals
|Submitting Addenda to Previously Approved Applications
|Abstracts of Approved Research Proposals
|Genes Proposed, In Progress, or Completed
|Purpose of DNA and Genetic Data Distribution Policies||Back to Top|
The National Heart, Lung, and Blood Institute (NHLBI), in collaboration with Boston University, has supported collection of blood samples and clinical data from participants in the Framingham Heart Study since 1948. This clinically and genetically well-characterized population provides a rare and valuable scientific resource maintained under the joint stewardship of Boston University and the NHLBI. The NHLBI and the researchers it supports have a responsibility to the public in general, and to the scientific community in particular, to encourage as rapid scientific progress as possible using these resources, subject to appropriate terms and conditions.
To protect the confidentiality and privacy of these participants and their families, investigators granted access to these data and materials must adhere to the requirements of a formal Data and Materials Distribution Agreement. Failure to comply with the Data and Materials Distribution Agreement could result in denial of further access to Framingham samples and data. Violation of its confidentiality requirements is considered a breach of confidentiality and may leave requesting investigators liable to legal action on the part of Framingham Study participants, their families, or the U. S. Government.
The Framingham investigators (both from Boston University and the NHLBI) have made a substantial long-term contribution in establishing and maintaining the clinical database and the genetic database and samples. The NHLBI and Boston University seek to encourage use of these data and materials by investigators not affiliated with the Framingham Study or Boston University, to foster collaborative relationships where appropriate, and to ensure that the Framingham investigators are appropriately acknowledged. Collaboration with Framingham investigators (past or present) is not required as a condition of receiving DNA and/or genetic data. The NHLBI and Boston University further seek to promote the development of valuable discoveries and inventions beneficial to the public health based upon use of this Framingham Study repository of valuable materials and data.
|Overview of Procedures for Requesting DNA and Genetic Data||Back to Top|
Although not a requirement, investigators interested in utilizing DNA and/or genetic data from the Framingham Study are encouraged to contact and work with Framingham investigators having similar or complementary interests since the data sets for this long-term study are quite complex. Although every attempt has been made to provide documentation of the highest quality (and limited user support is available), collaboration with the existing investigators when feasible is likely to enhance the efficiency and productivity of many research efforts.
Applications for use of Framingham DNA or genetic data are accepted quarterly, on January 15, April 15, July 15, October 15 of each year. Investigators wishing to request DNA or genetic data will need to complete and submit:Biologic Materials and Genetic Analysis Data Application and Proposal Form
Applications will be evaluated by the Framingham Research Committee and the Framingham DNA Committee using specific Evaluation Criteria and a standard DNA Application Review Form. Outcome of the review will be communicated to the applicant as quickly as possible, generally within four to six weeks of the application receipt date. Applications must be submitted for review prior to submission for grant or other funding..
Application materials should be submitted by e-mail to: DNA Coordinator
Prior to receipt of DNA or genetic data (but not required at the time of application), the requester will also need to submit:Data and Materials Data and Materials Distribution Agreement
Human Subjects Approval from the Institutional Review Board (IRB) of the requester's institution is required prior to receipt of DNA or genetic data.
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|DNA Samples and Genetic Data Available for Distribution||Back to Top|
There are three types of files that can be used for performing genetic studies: 1) family structure file, 2) genotyping files and 3) phenotype files. The family structure file provides the structure of the families. The genotyping files (one for each of the 22 autosomes) provide the genotyping data recorded by the Mammalian Genotyping Service in Marshfield, Wisconsin. The phenotype files provide for each study participant phenotypes measured over the course of the study: 44 years (exams 1-23) of information for the Original Cohort recruited in 1948 and 20 years (exams 1-5) of information for the offspring recruited in 1972). These files are contained in UNIX SAS data sets (.ssd01) or SAS transport files with 1 family file, 22 chromosome files, multiple phenotype files for the cohort and offspring. Individuals can be linked in these files through the variable "randomid". There is one additional SAS data set (called Markers) that provides a list by chromosome of the markers that were typed by the Mammalian Genotyping Service. This latter file is primarily for information and is not needed to perform genetic analyses.1. Family Structure File
The Family Structure File contains information for the 234 families that consist of members included in a 10 cM genome scan performed by the Mammalian Genotyping Service in Marshfield, Wisconsin. The families are drawn from the larger Framingham Study and are a sub-sample of that study.
The participants in the Framingham Study are readily subdivided into two groups, those recruited in 1948 as part of the Original Cohort and those recruited in 1972 as part of the Offspring Cohort. The Original Cohort consists of a sample of 5209 participants and the Offspring Cohort consists of a sample of 3514 biological descendants of the Original Cohort, 1576 of their spouses and 34 adopted offspring for a total sample of 5124 subjects. The Family Structure File consists of a sub-sample of the Original Cohort and their biological descendants in the Offspring Cohort, representing 234 families with 2229 participants in the Framingham Study.
Of note is that there are 1393 siblings (brothers and sisters) among the participants of the Original Cohort and 98 parent-offspring pairs. Thus, the extended family relationships in the Framingham Study include parents and offspring from the Original Cohort, and sibships in which some members are participants in the Original Cohort and other siblings are participants in the Offspring Study.
The biological relationships are coded in a manner that is commonly used in genetic epidemiological studies. Siblings are identified by having common parents. Spouse pairs are identified by having descendants. Parents of the Original Cohort, who are not Framingham Study participants, were created for the Family Structure File, to identify the sibships in the Original Cohort. In a few instances, descendants (who are not Framingham Study participants) of a spouse pair, were created in order to identify a spouse pair.
The variables in the file are:1. Family ID number (famranid) : A unique number assigned to all members of an extended kindred.
Note: Full siblings will have the same father and mother ID, while half-siblings will only share one of these IDs, either a common father or a common mother but not both.
2. Genotyping Files
A 10 cM genome scan was conducted in 3 phases between 1996 and 1998. About 400 markers were typed by the Mammalian Genotyping Service in Marshfield, Wisconsin in 3 batches (composed of different sub-samples of individuals) and were those identified collectively as Set 8A. For more information on the markers, see http://www.marshmed.org/genetics, especially the "Screening Sets of Markers" page. A few markers were changed from one phase to another; so not all markers were genotyped in every phase. The genotyping files contain the genotype information for each subject in the family structure file. The genotypes are listed in the order in which they appear on the chromosome, beginning at the p telomere, according to the Marshfield maps. Since these maps were constructed from a relatively few number of meioses for a subset of CEPH families, the order of the markers may not be well determined and may differ from other maps. The ordering given by the Marshfield Web Site is provided in the Markers File, where all markers are listed by chromosome.
Once the genotyping data were received from Marshfield, we used two approaches to clean the data. First, we used the "sib_kin" program in Aspex to verify the degree of relatedness among individuals within a family. All marker data from all 3 scans were employed for this purpose. When the output from these analyses indicated that we had incorrectly identified a biological relationship, we carefully reviewed the family structure and the results reported by this program. Some changes were made to the family structure as a result, and the Family Structure File reflects these changes. Second, we used "gentest", created by the Southwest Foundation for Biomedical Research, to identify additional genotype inconsistencies within the data. This program used the marker information for an extended pedigree to identify inconsistencies. When an inconsistency was identified, marker information for subjects in the nuclear family was replaced with missing values.
The genotyping files can be linked with the phenotyping files through the randomid variable. These two files together are sufficient to conduct linkage and association analyses. For example, traditional model-dependent methods (specifying the mode of inheritance), variance component methods and Haseman-Elston type regression methods can be employed for linkage analysis of quantitative traits. For qualitative traits, IBD sharing methods can be used.
There are 22 genotyping files, one for each of the autosomes (labeled as chrom1, chrom2, etc.). The files consist of the same individuals as those given in the Family Structure File. The same initial information as in the Family Structure File is provided (famranid, randomid, frandid, mrandid, sex) and then each genotype for each marker evaluated in any one of the 3 batches is provided. Subjects who were not included in the genome scan have no information in the genotype fields.
Each genotype is given as the allele size of the amplicon on the gel. The largest allele is given first and the smaller is given second. The variable label for the first allele for each genotype begins with an "A" and the variable label for the second begins with a "B". Hence, A1, B1 identify the genotype for the 1st marker on the chromosome; A5, B5 identify the 5th marker on the chromosome. The markers that were genotyped on a given chromosome thus determine the number of variables in each chromosome file.
Hence, the variables on the file are1. Family ID number (famranid) : A unique number assigned to all members of an extended kindred
3. Marker File
The purpose of this file is primarily informational. It provides all the markers that were evaluated in any one of the 3 scans conducted by the Mammalian Genotyping Service in Marshfield, Wisconsin. For each marker, the chromosome on which it is located is identified as well as its heterozygosity and its location in cM on the chromosome.
The variables in the file are:1. Marker (marker): The name of the marker. These names were the ones given to files that came to us from Marshfield. In some cases portions of the names are missing. For example, those markers that begin with "AFM" have these 3 letters missing. So marker AFM280we5 is identified as 280we5 in the Marker file.
4. Offspring Phenotype Files: Components of past examinations are listed in the Study Component Schedules. Other useful references include Data Collection Forms and List of Variables.5. Cohort Phenotype File: Components of past examinations are listed in the Study Component Schedules. Other useful references include Data Collection Forms and List of Variables.
B. DNA Samples
DNA samples will be aliquoted and shipped at NO COST to the requester. Costs of preparation and shipment to the requester will be borne by the NHLBI. Costs for return of unused materials from the requester to Boston University, however, will be borne BY THE REQUESTER.
DNA will be available from the Framingham Study for those study participants for whom lymphoblast cell lines have been established.
All DNA samples will be distributed in 100 ng/ul concentration, and in quantities ranging from 200ng to 10ug of DNA.
Standard sets of DNA will be distributed in 96 well plate format in two sets:
Random samples: DNA sample sets of unrelated persons followed in the Framingham Offspring study will be available. These sets represent a randomly selected sample of unrelated study participants and may be requested in 96 well plate increments from 1 plate to 20 plates (1888 total specimens available).
Family Samples: DNA samples from the 320 largest extended families in the Framingham study will be made available. Approximately 1,500 DNA samples will be available from these families. Smaller samples of 100 or 200 families may also be requested. Descriptive statistics will be provided when the final selection of these specimens is made.
When possible, requests for DNA will be filled from these two sets of specimens. However, additional samples are available, including a random sampling of approximately 400 unrelated members of the Original Framingham Cohort. Descriptive statistics will be provided when the final selection of these specimens is made.
Additional custom sample sets may be requested. For example, sample sets of persons with CHD and age and sex matched controls, may be requested. However, custom sets may take longer to fill.
The time to distribute standard sets of DNA samples will be four weeks from the date that the Data and Materials Distribution Agreement has been signed by the applicant's institution, Boston University and the NHLBI.
|Detailed Procedures for Requesting DNA and Genetic Data||Back to Top|
Please read these instructions carefully before completing the request forms for DNA samples or genetic data from the Framingham Heart Study.
Applications for use of Framingham DNA or genetic data are accepted quarterly, on January 15, April 15, July 15, October 15 of each year. Investigators wishing to request DNA or genetic data should complete and submit:1. Biologic Materials and Genetic Analysis Data Application and Proposal Form: two-page form describing data and materials requested and research proposal
3. Biographical Sketch: include listing of recent, representative publications for the requesting principal investigator. The standard two-page NIH BioSketch is acceptable.
4. Supporting Documentation: any additional documentation that would be helpful in evaluation of the proposal, such as a pending grant application, grant award statement, accepted or published manuscripts or abstracts, recent supporting literature, etc.
Application materials should be submitted by e-mail to: DNA Coordinator
It is mandatory for the proposed study to be approved by the Human Subjects Institutional Review Board (IRB) of the applicant's institution to assure that it meets local IRB approval. Requesters should contact their institution's IRB office to obtain local IRB approval for the application, documentation of which should be submitted with the Data and Materials Distribution Agreement form.
On receipt and approval of the signed Data and Materials Distribution Agreement and copy of the IRB approval, DNA samples and/or a CD-ROM with the appropriate genetic data set will be mailed to the requester, typically within four weeks.
|Overview of Data and Materials Distribution Agreement||Back to Top|
It is imperative that the recipient agrees not to use the DNA or genetic data received, either alone or in conjunction with any other information, in any effort whatsoever to establish the individual identities or to make contact with any of the Framingham Study participants or their relatives.
The Data and Materials Distribution Agreement describes the following restrictions placed upon the requester as a condition of receiving the DNA or genetic data set:1. use of the DNA or data for the sole purpose of the described research project;
|Institutional Review Board Approval||Back to Top|
Human Subject Protection for Framingham Heart Study Participants
All who request the data and/or DNA must comply with the Data and Materials Distribution Agreement for ensuring study subject confidentiality. The IRB at the institution of each requester is responsible for determining whether the project protects the privacy and confidentiality of Framingham participants. An IRB approval (either full approval or expedited approval) is required. The Framingham Heart Study and the NHLBI cannot accept an IRB letter stating that the proposed study is exempt from review as there still exists a possibility an individual could be identified given the large amount of data, and as access to this data is not available unconditionally to the public but restricted to those agreeing to the terms of the Distribution Agreements. Investigators who do not agree to sign the Distribution Agreement or do not submit an IRB approval will not be sent the requested data or materials.
A copy of the IRB approval document should be sent to the to the DNA Coordinator along with the signed Data and Materials Distribution Agreement Form.
|Process for Review of Proposals||Back to Top|
A. Committee Evaluation
Two committees, the Framingham Research Committee, and the Framingham DNA Committee review the applications for Framingham DNA or data. All applications are submitted to the Research Committee and then forwarded to the DNA Committee for review. The DNA Committee is composed of a group of investigators and collaborators from various fields of study within the Framingham Study as well as independent investigators. The DNA Committee creates primary review teams for each application cycle, each consisting of a clinical investigator, a molecular geneticist and a biostatistician. Each team member will be assigned up to two applications per cycle, and will perform a full review of the application. The team member will also fill out a review form, which details the evaluation of the application. If there are main concerns about the application, the DNA Committee may contact the Project Director to clarify any questions before a final decision is met. The DNA Committee will evaluate the final reviews and forward its comments to the Research Committee with a summary recommendation.
B. Evaluation Criteria
The DNA Committee carefully evaluates the research proposal described in the "DNA/data Application" section. The Committee will also consider the following topics when evaluating a DNA/data application:
a. Rationale: Scientific justification, logistics and robustness of the proposal
b. Feasibility: Capability of the Framingham Study to provide the requested materials to the applicant
c. Amount of DNA requested: A reasonable amount of DNA for the proposed methodology of the study
d. Study Design, Statistical Analyses and Power: Appropriate study design and statistical analyses; strength of the study (power) to detect the proposed effect
e. Preliminary Data: Supporting data that will confirm the validity of the study
f. Scientific Merit: A reasonable hypothesis that follows the basic goals of the Framingham Study
g. Strength of genotyping facilities: Experience of the affiliated laboratory with the proposed or similar DNA assays and an indication of familiarity with standard DNA methodologies
C. Review Outcome:
Upon receipt of the DNA Committee's review, and the performance of its own review, the Research Committee will respond to the applicant usually within four to six weeks of the application deadline. Generally, there are three possible outcomes from an evaluation:
After notification of approval of the application, the requester will gather the necessary signatures for the Data and Materials Distribution Agreement included in the application package and send it to the Framingham Study contact person (Meredith Selin, Boston University School of Medicine, Dept of Neurology - E613, 715 Albany Street, B-603, Boston, MA 02215). Specific procedures for data and DNA distribution are determined by personal communication with the current Project Director. A timetable for DNA/data delivery is dependent upon the numbers of samples requested, and the number of requests that were approved on a given cycle. The Framingham Study will aim for delivery within four (4) weeks of receiving the Data and Materials Distribution Agreement signed by the applicant's institution, Boston University and the NHLBI, and after receiving the copy of the IRB approval from the applicant's institution.
In the event that the application does not satisfy the major points of considerations for approval, the Research Committee may reject it. The Research Committee will detail the reasons for a negative outcome.
All disapproved applications are automatically sent to the Framingham DNA Board (composed of BU staff, NHLBI staff and an independent chair), that reviews the activities of the Framingham DNA Committee. Any disapproved application can be resubmitted for the next application deadline or any subsequent application deadline, if the investigator feels that the concerns of the committee can be adequately addressed. There is no limit to the number of resubmissions that can be made.
An application approval may be postponed temporarily in the event that the review committee desires more information about the proposed study. Usually, when an application is postponed, it needs minor clarification of the application materials and the Committee expects that approval can be made without requiring a formal re-application. When the requested information is received, the primary review team reviews these and determines if a recommendation for approval can be made. A summary of recommendations will be forwarded to the Research Committee, who will make a final decision, and inform the applicant of that decision.
G. Contact Persons
For general questions about DNA samples or data application and distribution process:Mona Pandy