Can you clarify the U01 mechanism?
The U01 is a cooperative agreement award mechanism in which the NIH and extramural scientists work in cooperation and partnership with each other. Under the cooperative agreement, the NIH role is to support and stimulate the recipients' activities through involvement in the research activities and by generally working jointly with the award recipients in a partnership role. NIH staff does not assume direction, primary responsibility, or a dominant role in the activities.

How does the U01 differ from the R01 mechanism?
The major distinction between the U01 and R01 mechanisms regards collaboration between NIH and extramural researchers. Under the R01, all executive decisions are made by the PI without collaboration with NIH. Under the U01, the NIH has input on some decisions through input on the Steering Committee. An NIH Project Scientist will be assigned to each of the awarded U01 projects. There will be no more that 4 NIH Project Scientists participating as members of the GEDI Steering Committee; however, there will be only one NIH vote, reached by consensus. In addition, as with the R01 mechanism, a Program Director will be responsible for the normal scientific and programmatic stewardship of the U01 award. Additional information can be found in the RFA under section 2.A.2 NIH Responsibilities and section 2.A.3 Collaborative Responsibilities.

What is meant by longitudinal research?
Longitudinal research involves the measurement of key variables (e.g., behaviors, traits, disorders) at more than one period of time.

What constitutes two developmental periods?
The RFA provides a general guideline, stating that developmental periods include in utero, infancy, early childhood, childhood, early adolescence, late adolescence, emerging adulthood, and adulthood. Developmental periods within adulthood also qualify. Whatever developmental periods are chosen, the application should make the case as to how the periods are distinct and justify the choice of these periods in terms of their salience to the GEDI goals and their relevance for substance abuse and other outcomes. In addition, these developmental periods must be assessed within the same individual at two points in time. Finally, data on two developmental periods must either already be collected or they need to be collected under another funding mechanism that is identified in the application and assured by the time that GEDI funding decisions are made. Funds cannot be requested under the GEDI mechanism to collect these data.

Does a maternal-child dyad count as two periods covered?
No. Two developmental periods need to be from one person.

Do I need to have DSMIIIR or DSMIV collected?
Yes. Qualified studies need to be able to provide data from which DSM IIIR or DSM IV diagnoses of substance use disorders and relevant psychiatric disorders can be validly made, from at least one time point in the longitudinal study. If these data are not available on a particular cohort, then they need to be collected under another funding mechanism that is identified in the application and assured by the time that GEDI funding decisions are made. Funds cannot be requested under the GEDI mechanism to collect diagnostic data.

If we have multiple cohorts that have considerable overlap in assessments, but are not identical, can we propose to do analytic work on the developmental phenotypes across the longitudinal samples prior to the genetic analyses themselves? Would this be an appropriate budget item for the GEDI?
Yes. This is encouraged.

Can you provide a sample consent form and data sharing plan?
http://www.nida.nih.gov/about/organization/Genetics/FAQ_NGC.html (links to FAQs about the NIDA Genetics Consortium and all human genetic studies at NIDA: includes information on membership, sharing plans, and sample consent forms) NIH data sharing policy: http://grants.nih.gov/grants/policy/data_sharing/data_sharing_brochure.pdf  NIDA data sharing guidelines: http://www.nida.nih.gov/about/organization/Genetics/GeneticsHome.html (A general website for information on NIDA genetics resources and programs) http://www.nida.nih.gov/about/organization/Genetics/FAQ_NCGS.html (links to FAQs on the NIDA Center for Genetic Studies and how to access the repository for sending blood samples and requesting DNA and data) http://www.nida.nih.gov/about/organization/genetics/DistPol.html (links to the NIDA distribution agreement document that must be signed by qualified investigators accessing samples within the repository). http://grants.nih.gov/grants/guide/notice-files/NOT-OD-07-088.html (links to new policy for sharing of data obtained in NIH supported or conducted genome wide association studies).

What is the data sharing requirement timeline?
Each application needs to include a timetable specifying when various elements of the data (e.g., diagnostic assessments or genetic data) and DNA will be available for distribution. In general, DNA and data will be made available for distribution by the NIDA Center for Genetic Studies (NCGS) 12 months after the termination of the grant period, including extensions, or immediately upon first publication of the data, whichever comes first. DNA and data are distributed only to qualified investigators who have been approved by the NIDA Genetic Data Access Request Committee and who have signed the Distribution Agreement.

Proposals using genome wide association studies must comply with NIH's Policy for Sharing of Data Obtained in NIH Supported or Conducted Genome-Wide Association Studies (GWAS), Notice OD-07-088, which can be found at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-07-088.html.  

For extensive longitudinal studies, all data that are proposed or used for GEDI analyses are expected to be sent to the NIDA Center for Genetic Studies repository.

Suppose I have DNA on all subjects in my longitudinal study, but some subjects do not agree to make their data public. How does this affect what I can publish?
You are able to publish a paper using data on subjects that is in accord with the subjects' consent forms, and it the responsibility of the PI to make sure that the consent forms are followed. GEDI is a large public investment, and as such NIDA seeks to encourage the community to use the resource that GEDI will create to tackle public health issues, especially related to substance abuse. Applicants are advised to state (or estimate) within the application how many subjects do and do not allow for sharing. To help reviewers understand how the sharing consent rate will affect the power of the study, it may be advisable to include a table showing the ramifications for power if you meet, do not meet, or exceed, the expected number of consenters.

How will I be sure that our subjects are protected from being identified?
The NIDA Center for Genetic Studies (NCGS) is devoted to protecting the confidentiality of research participants. The potential for public benefit to be achieved through sharing GEDI data is significant. However, genotypic and phenotypic information generated on individuals, such as data related to the presence or risk of developing particular diseases or conditions, including highly stigmatizing disorders, and information regarding paternity or ancestry, may be sensitive and substantial. Therefore, it is critically important that the privacy and confidentiality of the participants be protected. Risks to individuals, groups, or communities should be carefully balanced with potential benefits of the knowledge to be gained through GEDI. The nature of GEDI information about participants and the broad data distribution goals of the NIH repositories highlight the importance of the informed consent process to this research. In order to protect research participants, NIDA has established mechanisms to oversee the repository and to monitor GEDI data access and use practices.

Depositing all GEDI study information into the NIDA Center for Genetic Studies repository provides several safeguards to protect subject confidentiality. First, biomaterials and clinical data sent to the NCGS are stripped of all subject identifiers and given a code by the Principal Investigator sending the samples. The NCGS then provides a new identifier number for the sample and informs the Principal Investigator of the new identifier number that corresponds to the code given by the Principal Investigator. Any samples containing subject identifiers submitted to the NCGS are returned immediately to the investigator. Second, through an exemption from IRB review and a Certificate of Confidentiality (CoC) (http://grants1.nih.gov/grants/policy/coc/), investigators are afforded protection from court orders and subpoenas to release information from the NCGS in most cases. (Note that a CoC does not mean that you cannot receive a subpoena.) Third, the NCGS must operate in accordance with the United States Department of Health and Human Services regulation at 45 CFR Part 46 concerning human subjects and its local institutional review board, and so do the studies housed in the NCGS. Fourth, anyone given access to clinical data and DNA is forbidden to attempt to discover the identity of the research participants from DNA and biomaterials obtained from the NCGS. This is stipulated as a term and condition in the Distribution Agreement, http://www.nida.nih.gov/about/organization/genetics/DistPol.html. A data enclave may also be established, provided there is a link to the NCGS with clear instruction on how to access the enclave. A data enclave is a secure database maintained by the PI with no connections to the outside, therefore requiring access locally rather than remotely.

Finally, because the data will be housed in the NCGS, a data access committee will be responsible for the review of applications to make sure that data requests are from qualified investigators, and that there is a data distribution agreement in each case.

What is the GEDI Steering Committee (GSC) going to steer? Will each site still need to do what it proposes to do, or will the proposed work at each site be changed by the GSC?
The role of the GSC is to coordinate and stimulate activities across the different projects funded under the GEDI initiative, while taking advantage of the scientific expertise within the funded studies. The GSC will also set milestones for the overall GEDI initiative, identify opportunities for collaboration among the different projects, such as replicating findings across projects, and assess the genotyping design, approaches and platforms to try and make them as consistent and as standard as possible so that a consensus strategy is achieved. Decisions of the GSC are made based upon input from each funded project (one vote per PI) and the NIH (one vote). The PIs and NIH are expected to accept and implement all decisions made by the GSC. We envision that each study is independent and the PI will be responsible for making sure the aims are met for the proposed work specified by their particular application.

What if there is a dissenting group? Will the PO make the PI comply with the GSC?
Dissention is possible, but we hope this will not happen. Under a cooperative agreement, decisions should be reached by consensus. We could envision that some groups may dissent for good reason and the GSC recognizes the dissent as appropriate. The GEDI Advisory Board can also weigh in on decisions. In addition, there is an arbitration process to address any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between award recipients and the NIH. An Arbitration Panel composed of three members will be convened. It will have three members: a designee of the GSC chosen without NIH staff voting, one NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two; in the case of individual disagreement, the first member may be chosen by the individual awardee. This special arbitration procedure in no way affects the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulations 42 CFR Part 50, Subpart D and HHS regulations 45 CFR Part 16.

Is blood the preferred source for DNA? Are there other options?
Blood is the desired resource for DNA. DNA from cheek swabs, buccal cells, and saliva can be used, provided that sufficient amounts of DNA from the entire genome of each individual subject can be generated and made available to the scientific community at the expense of the investigator. Genotyping call rates (accuracy of the genotype call) are best from DNA from blood, and saliva is better than buccal. If you collect DNA from saliva or buccal samples, you will need to justify: 1) that the quality of the DNA is good, and 2) that you will have sufficient amounts to share with other qualified investigators who may want to test particular genetic markers in your samples for other research questions. The amount of DNA available for sharing will be considered as part of the review when considering the sharing research data and resources.

What if I already have DNA collected?
If you already have DNA, you will not be able to send it to the NIDA Repository. You will need to budget for distribution of the already collected samples, and provide information on how much of the DNA is available for sharing.

The RFA says data collection costs for DNA only are permitted. If we already have DNA, but need to reconsent subjects to include archiving/sharing their data, is that an appropriate budget item?
Yes.

Can we propose to genotype our existing DNA samples if these DNA samples could not be shared with the repository?
If DNA is already available, it is not necessary to send it to the repository. However, you will need to provide access to the DNA one way or another; provisions for access to the DNA need to be clearly stated in the application. For example, a statement on how much DNA will be available to other qualified investigators will be needed. You will have to demonstrate that it is of good quality and in sufficient quantity to permit sharing. You will also need to specify how the DNA can be accessed.

If the DNA cannot be shared by any means, the sample would not be appropriate for GEDI.

Is it essential that we be able to submit the genotyping results with the NIDA Repository even if not the DNA?
If DNA is already available, the genotyping results (as well as the phenotypic and environmental data) will need to be deposited into the NIDA Repository. In this case, reconsenting may be necessary and should be budgeted.

What is a reasonable (acceptable) proportion of buccal/saliva vs. blood samples in the full sample?
Blood samples are preferred on all subjects. However if a subject refuses to give blood, but would consent to saliva, then this is acceptable. Provisions would need to be made for accessing the DNA from buccal/saliva since it will not be processed or stored in the NIDA Repository. Additionally, the amount of DNA available to other investigators will need to be specified and pass peer review. There is no fixed proportion, but an estimate on the percentage of buccal/saliva samples with regard to the total sample would be helpful for review.

Should I budget for in-house genotyping or outsource the genotyping?
Costs for genotyping must be budgeted in each application. In addition, the design and approach of the genotyping methods are not stipulated in the RFA. Genotyping platforms are rapidly evolving and may change by the time your samples are ready to be genotyped. In addition, once the GEDI applications are awarded, among the first orders of business will be to form the GEDI Steering Committee (GSC). The GSC will be charged with evaluating the genotyping approaches and platforms proposed in the awarded applications and come up with an agreed upon approach for all GEDI studies (allowing for exceptions). Therefore, in terms of the application and the study section review, you will need to justify the approach that you envision for your study (whole genome scan, linkage, candidate gene, etc.) and budget it in a timely and appropriate manner. For example, if you propose to collect blood samples over the next three years, it is not advised to put a genotyping budget in for years 1-3.

There may also be studies that already have DNA collected, and genotyping could be done almost immediately. In this case budgeting for genotyping in the first year is appropriate. Once the GSC is formed, it may be decided that genotyping could be delayed for that study-or some done now and some done later. In this case the budget for that study will be administratively modified. If other scenarios are encountered, it should be noted that budgets may be administratively modified to reflect the changes.

The most cost-effective approach is desired. Please consider consulting several resources to find the most cost-effective approach. The following are links to some of the resources, but there are others as well. Center for Inherited Disease Research http://www.cidr.jhmi.edu/, The Microarray Consortium http://arrayconsortium.tgen.org/np2/public/overview.jsp offers investigators access to state-of-the-art technologies for gene expression (activity) profiling and SNP genotyping (identifying DNA sequence variations). All of the data generated by the centers is made publicly available through a web database.
deCode: http://www.decode.com/genotyping/
Rutgers: http://www.rucdr.org/services.htm

For genotyping, is this RFA emphasizing (1) "fishing" for unknown genes/SNPs, or (2) emphasizing use of known genes/SNPs to correlate with an emerging phenotype within the cohort?
We suggest the PI use the most appropriate design for the cohort. Any of these approaches is reasonable if justified in the application.

What data are required to be submitted to the NIDA Center for Genetics Studies Repository?
All data proposed to be studied in the GEDI application will need to be submitted. These include genotypes, DSM IIIR and/or DSM IV, and data obtained via questionnaires and instruments used for drug abuse, psychiatric co-morbidity, family information, and environmental information.

How many blood samples will be paid for by NIH/NIDA?
For all studies joining the NGC, funds to cover up to 15,000 total blood samples (or 3,000-5,000 per award) [for mailing the samples (mailers, collection tubes, postage, etc), blood processing, DNA extraction, storage, and distribution] will be provided. A budget needs to be presented if more than 5,000 samples/per study will be collected. Additionally, a fee structure for distribution of DNA from the NIDA Repository can be found at: http://www.nida.nih.gov/about/organization/Genetics/FAQ_NCGS.html. Investigators are allowed three 10 µg aliquots of DNA per sample at no charge. Applicants should determine if additional budgetary allocations are needed for DNA requests exceeding the NIDA Repository allowances.

NIH/NIDA does not cover phlebotomy; NIDA will pay for only the mailing, processing, storing, and distribution of blood samples. You may need to budget for a phlebotomist. If collecting saliva or buccal cells, you will need to budget for all aspects of the collection.

Therefore, there are two main budget issues regarding the DNA: 1) DNA collection and 2) genotyping. Most of the blood collections will be covered by NIDA. All other issues should be budgeted accordingly.

The RFA requires replication of analyses within the 5-year period of support. Is there a recommended or preferred approach/plan/design for replication? For example, can the first half of the cohort be replicated by the second half of the cohort, followed by publication using the entire cohort?
There are no recommended or preferred approaches to replication. Because there are many ways to replicate results (some examples are presented in the RFA), the PI should justify the approach(es) proposed within the application.

If the application proposes a multisite project, must a single 25-page proposal be submitted? Or, is it permissible to submit separate applications from each site? Can appendices be used to describe each sample?
Multisite studies need to submit only ONE proposal. Information on each of the sites will need to be provided in the body of the application. Although appendices are allowed, review groups are not obliged to review the appendices. We encourage you to provide sufficient information on the multisite contributions in the body of the proposal.

How can we find suitable collaborators for our proposals?
In addition to searching the literature and networking among your colleagues, you may consult the link: http://www.nida.nih.gov/about/organization/genetics/consortium/index.html and click on NGC contact information, which lists researchers who have been involved in the NIDA Genetics Consortium meetings. Using Pubmed searches on some of the names may help you identify potential collaborators.  You may also wish to search the CRISP database, www.crisp.cit.nih.gov to identify funded studies and investigators that may qualify for this announcement, and you are welcomed to contact any of the NIDA staff listed below.

GEDI Program Staff
Naimah Weinberg, M.D., NIDA/DESPR
NW46W@nih.gov
301-402-1908
Longitudinal developmental studies of psychopathology, genetic epidemiology, technical questions regarding U01 application

Kathy Etz., Ph.D., NIDA/DESPR
ketz@nida.nih.gov
301-402-1749
Longitudinal studies considering developmental timing and transitions, puberty, ethnic subpopulations, intergenerational influences; studies of etiology nested in intervention trials

Kevin Conway, Ph.D., NIDA/DESPR
kconway@nida.nih.gov
301-443-6504
Lifecourse epidemiology, methodology, phenotyping, externalizing problems, neurobiology

Vince Smeriglio, Ph.D., NIDA/DCNBR
vsmerigl@nida.nih.gov
301-443-4877
Longitudinal cohort studies of children exposed to drugs in utero

Joni Rutter, Ph.D., NIDA/DBNBR
jrutter@mail.nih.gov
301-435-0298
Human genetics, population genetics, applied genetics, and the NIDA Genetics Consortium (NGC)