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 Purpose of DNA and Genetic Data Distribution Policies
The National Heart, Lung, and Blood Institute (NHLBI), in collaboration with Boston University, has supported the collection of biological specimens and clinical data from participants in the Framingham Heart Study (FHS) 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 Framingham investigators have made a long-term commitment to establishing and maintaining clinical, genetic and bio-sample databases. The
NHLBI and the Framingham investigators share a duty to the general public and to the scientific community in particular, to facilitate access to these resources in order to promote timely scientific progress, subject to terms and conditions. The NHLBI and Boston University specifically seek to promote the use of the Framingham Study resources in research beneficial to public health. The NHLBI and Boston University encourage the 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 or genetic data, though investigators are encouraged to collaborate since the data sets for this long-term study are quite complex. Though every attempt has been made to provide documentation of the highest quality (and limited user support is available), working with the existing investigators is likely to enhance the efficiency and productivity of most research efforts. To protect the confidentiality and privacy of these participants and their families, investigators granted access to data and materials must adhere to the requirements of a formal Data and Materials Distribution Agreement (DMDA). Failure to comply with the Data and Materials Distribution Agreement could result in denial of further access to Framingham resources and may leave violators liable to legal action on the part of Framingham Study participants, their families, or the U. S. Government.
Overview of Procedures for Requesting Genetic Materials and Genetic 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 Resource). 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): http://www.ncbi.nlm.nih.gov/sites/entrez?db=gap
Applications for DNA, addendum applications to previously approved projects, or applications for genetic data not yet available on the Framingham SHARe website, should follow the procedures listed on this page.
DNA and Genetic Analysis Data Application and Proposal forms and Addendum to an Approved DNA Application forms are accepted quarterly. The Expedited DNA Application is accepted at any time. All applications must be accompanied by a biographical sketch and supporting documentation.
DNA Samples and Genetic Data Available for Distribution Files
There are three types of files available that can be used for performing genetic studies:
Family Structure File
The participants in the Framingham Study are readily divided into three groups, those recruited in 1948 as part of the Original Cohort (Gen1), those recruited in 1971 as part of the Offspring Cohort (Gen2), and those recruited in 2002 as part of the third Generation (Gen3) Cohort. The Original Cohort consists of 5209 participants. The Offspring Cohort consists of 5124 participants and includes biological descendants of the Original Cohort as well as spouses and adopted offspring. The Third Generation Cohort consists of 4095 participants and is the biological descendants of the Offspring Cohort and adopted offspring. The Family Structure File contains information for biologically related Framingham participants. A total of 1538 families are present; the mean pedigree size is 10 and ranges from 3 to 639. Of note is that there are siblings (brothers and sisters) among the participants of the Original Cohort as well as parent-offspring pairs. Thus, the extended family relationships in the Framingham Study can include parents and offspring from the same Cohort, and sibships in which members are from different Cohorts. Also of note is that not all members of the three cohorts have biological relatives and thus are absent from the Family File, and conversely not all individuals present in the Family File are Framingham Study participants. Place holding individuals were imputed when necessary to reflect biological relationships among participants. For example, parents of the Original Cohort, who are not Framingham Study participants, were created for the Family Structure File, to identify sibships in the Original Cohort. The Framingham Study has no biological samples or direct phenotypic data for these place holders.
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. 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.
The variables in the file are:
Genotype Files
The genetic data sets described below are available through the dbGaP website: http://www.ncbi.nlm.nih.gov/sites/entrez?db=gap Note that participants may refuse to participate in genetic studies (while continuing to participate in other aspects of the Study). The data in the genotype files are from those individuals who have given explicit permission for genetic studies. As Framingham is an ongoing study, the participants can revoke their permission at any time. The genotype files are updated periodically to reflect changes in permission.
1. Marshfield scan data
Ten cM genome scan data in FHS family members, 453 from the original and 1380 from the offspring cohort. Genotyping of approximately 400 markers per individual was performed by the Mammalian Genotyping Service in Marshfield, Wisconsin, in six batches (composed of different sub-samples of individuals) between 1996 and 2005. URL: http://research.marshfieldclinic.org/genetics/home/index.asp Due to changes in markers present in Marshfield Screening sets from 8 to 13 during that period, as well as the addition of markers genotyped in the FHS Genetics Laboratory, a total of 604 markers are present in the file. An accompanying map file is included. 2. 100k data
Affymetrix GeneChip Human Mapping 100K set SNP genotype results for 1345 FHS family members, 258 in the original and 1087 in the offspring cohort. Genotyping was performed through an ancillary study to Drs. Michael Christman and Alan Herbert in the Department of Genetics and Genomics at Boston University School of Medicine. Genotypes were determined using the Dynamic Modeling (DM) algorithm. A file with selected information about each SNP is also included. 3. CardioGenomics PGA data
Genotyping results for 709 SNPs from 1754 FHS offspring cohort members. This genotyping was performed through an ancillary study at the Genomics of Cardiovascular Development, Adaptation, and Remodeling, an NHLBI Program for Genomic Applications, Harvard Medical School. (NHLBI Grant Number 1U01HL66582, 10/01/00-07/31/05, PGA PI Dr. S. Izumo and Project 5 PI Dr. EJ Benjamin, Functional Genomics of the Cardiovascular System: Component 5, Framingham Heart Study. URL: http://cardiogenomics.med.harvard.edu/component-detail?project_id=239 These SNPs come from candidate genes believed to be associated with echocardiographic measures of left ventricular size and function. A file with selected information about each SNP is also included. 4. Framingham Obesity Genetics data
Genotyping results for 1485 SNPs in 1343 FHS family members; 257 from the original and 1086 from the offspring cohort. This genotyping was performed at Illumina Inc. by the Framingham Obesity Genetics (FOG) project supported by NIDDK grant number R01 DK66241, Dr. Larry Atwood, principal investigator, Department of Neurology at Boston University School of Medicine). The SNPs compose fine mapping data from regions on chromosomes 6, 10 and 11. The accompanying SNP information file provided from Illumina is also included. 5. ApoE and ApoA4
Genotyping results of APoE and ApoA4 polymorphisms in 5198 FHS members; 1258 from the original and 3940 from the offspring cohort. Please see relevant FHS publications for genotype information. 6. SHARe data
Affymetrix GeneChip Human Mapping 500K Array and the 50K Human Gene Focused Panel results for 9274 unique FHS participants, including 1529 original cohorts, 3753 offspring, 99 offspring spouses, and 3893 third generation participants. Genotypes were determined using the BRLMM algorithm. A file with selected information about the 549,915 SNPs is also included. Phenotype Files
The phenotype data sets described below are available through the dbGaP website: http://www.ncbi.nlm.nih.gov/sites/entrez?db=gap The phenotype files provide for each study participant phenotypes measured over the course of the study. The Original Cohort began Exam 1 in 1948 (9/1948 - 4/1953) and has continued with biennial examinations to the present. The Offspring Cohort began Exam 1 in 1971 (8/1971 - 9/1975) and has on average been examined every 3 to 4 years since enrollment. However, there was an eight year window between exam 1 and exam 2. At this time, the first examination has been performed in the third generation (4/2002 - 7/2005). In addition to these core study examinations, a number of ancillary studies involving Framingham participants were also performed over the years and their phenotypic results are also posted. A total of 27 original cohort examination files are present, as well as files of ancillary study phenotype data. A total of 7 Offspring cohort examination files are present, as well as files of ancillary study phenotype data. The data from the sole GEN3 examination that was performed 4/2002 - 7/2005 is present, as well as files of ancillary study phenotype data. Finally, files with data from the various cohorts combined are also included. Extensive documentation for each data set and variable definitions are available at the dbGAP website.
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 participants for whom lymphoblast cell lines have been established.
All DNA samples will be distributed in 96 well plates at a concentration of10 ng/ul.
Currently, there are four standard plate sets: Gen1 plate set is the Original Cohort, Gen 2A and Gen 2B plate sets are the Offspring Cohort, and the Gen 3 plate set is the Third Generation Cohort.
Requests for DNA will be filled from these plate sets. However, additional samples are available, including a random sampling of approximately 400 participants without cell lines.
Custom DNA plate sets may be requested. For example, sample sets of persons with CHD and age and sex matched controls, may be requested. Custom DNA requests require detailed justification. Custom DNA requests are filled when the lab has time available and there is no guaranteed timeline.
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
Please read these instructions carefully before completing an application for DNA samples or genetic data from the Framingham Heart Study. Applications for DNA, and/or applications for clinical or genetic data not yet available on the Framingham SHARe website are accepted quarterly; on January 15, April 15, July 15, and October 15 of each year. All applications must be accompanied by a Biographical Sketch and any additional documentation that would be helpful in the evaluation of the proposal, such as a pending grant application, grant award statement, accepted or published manuscripts or abstracts, recent supporting literature, etc.
1. The Applications
a) The standard application, DNA and Genetic Analysis Data Application and Proposal Form is a two-page form describing the data and materials requested and research proposal. The research proposal is included in the form and is a summary of intended research activities including: a clear description of the aims and of the significance of the study; the proposed study design; analysis plan and power calculations to justify sample size; justification for the use of Framingham specimens, as opposed to specimens from other studies; characteristics of participants from which specimens should be selected, and a description of the type of gene/polymorphism/mutation to be studied; experience of the requesting laboratory in this or similar assays; amount of DNA requested with a justification; and proposed date of project completion. b) The Addendum Application to an Approved DNA Application Form allows investigators to extend the scientific aims of the originally approved standard application. This may involve following up on original results by applying to perform additional genotyping using either new DNA or already shipped DNA. Sometimes an addendum application will propose analysis of new phenotypes in relation to existing genotypes. A research proposal that is substantially new or has substantially expanded scientific aims requires a new standard application.
c) The Expedited DNA Application is available for rapid turn-around to follow-up on genetic results, such as genome-wide association study (GWAS) results and may be submitted at any time. Please submit a signed DMDA and full or expedited IRB approval along with this application. Applications will not be reviewed unless these documents accompany the application.
2. The Evaluation
The Standard Genetics Application
The Framingham DNA Committee and Research Committee Chairperson review the applications for Framingham DNA or data. The DNA Committee is composed of a group of seven investigators and collaborators from various fields of study within the Framingham Study as well as independent investigators and includes clinical investigators, molecular geneticists and biostatisticians. Three committee members make up the review team for each application. The team members will also fill out a Review Form, which details the assessment 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 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:
The Addendum Application
The Framingham DNA Committee and Research Committee Chairperson review the applications for Framingham DNA or data. 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 and includes clinical investigators, molecular geneticists and biostatisticians. Three committee members make up the review team for each application. The team members will also fill out an Evaluation Form, which details the assessment 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. Evaluation of the addendum by the DNA Committee will take into consideration the following:
The Expedited DNA Application
Two DNA Committee members instead of three will review an Expedited DNA Application. The purpose of this application is for quick turnaround to follow-up on genome-wide association study results. Permission will only be granted if the preliminary data you wish to follow-up reaches genome-wide significance. The phenotype in the initial GWAS must be clearly described, with a description of the analogous trait in the Framingham Heart Study. Careful justification of the relevance of the requested phenotype is required. DNA requests may only be for standard plate sets. Use of extant genetic material may be requested through this mechanism. Please keep in mind, however, this request must be limited to follow up of GWAS findings as described above. Request for SHARe genotypes may not occur via this mechanism.
3. The Evaluation Outcome
Upon receipt of the DNA Committee's review form, the DNA Coordinator will mail a Decision Letter and the Review Forms to the applicant, usually within six weeks of the application deadline. Expedited DNA Applications will be reviewed and a Decision Letter sent to investigators within 10 business days. Generally, there are three possible outcomes from an evaluation:
a) Approved
The DNA Committee approves the application and upon notification, the applicant will be responsible for compiling, in triplicate, the following documents and obtaining the appropriate signatures on the DMDA on behalf all "Recipient Entities" indicated in the application. A complete Project Documents Package is comprised of:
No DNA or data will be distributed without completed documentation for all "Recipient Entities". The Framingham Study will usually deliver requested material within four (4) weeks of receiving the completed 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.
b) Postponed
An application approval may be postponed temporarily in the event that the DNA Committee desires more information about the proposed study. Usually, when an application is postponed, it needs minor clarifications and the Committee expects that approval can be made without a formal re-application. Applicants must respond to Committee concerns by letter within 90 days of the dated Decision Letter. Responses deemed satisfactory by the Committee will result in approval and the applicant will receive a follow-up Decision Letter to that effect. Default on a response will result in closing the application and will require a new application to be submitted. c) Disapproved
In the event that the application does not satisfy the major points of considerations for approval, the DNA Committee may disapprove it. The Reviewers will detail the reasons for the disapproval in the Evaluation Forms sent with the Decision Letter. If the investigator feels that the concerns of the committee can be adequately addressed, the applicant can submit a new proposal for the next application deadline or any subsequent application deadline.
Application materials should be submitted by e-mail to: DNA Coordinator
Approved Projects Documents Package should be mailed (please DO NOT fax) to: Heather Arruda DNA Coordinator, Framingham Heart Study Boston University School of Medicine 715 Albany Street, B604 Boston, MA 02118 TEL: 617-414-1244 Email: harruda@bu.edu | |||