Part I Overview Information

Department of Health and Human Services

Participating Organizations
National Institutes of Health (NIH), (http://www.nih.gov)

Components of Participating Organizations
National Human Genome Research Institute (NHGRI), (http://www.nhgri.nih.gov)

Title: Near-Term Technology Development for Genome Sequencing (R01, R21, R21/R33)

Announcement Type
This funding opportunity announcement is a reissue of RFA-HG-04-002, which was previously released February 12, 2004.

Updates: The following updates relating to this announcement have been issued:

Request For Applications (RFA) Number: RFA-HG-05-003

Catalog of Federal Domestic Assistance Number(s)
93.172

Key Dates
Release Date: December 15, 2005
Letters of Intent Receipt Date: January 17, 2006
Application Receipt Date: February 17, 2006
Peer Review Date: June-July 2006
Council Review Date: September 12, 2006
Earliest Anticipated Start Date: September 29, 2006
Additional Information To Be Available Date (Url Activation Date): Not applicable
Expiration Date: February 18, 2006

Due Dates for E.O. 12372
Not Applicable

Additional Overview Content

Executive Summary

The National Human Genome Research Institute (NHGRI) solicits grant applications to develop novel technologies that will substantially reduce the cost of genomic DNA sequencing. Current technologies are able to produce the sequence of a mammalian-sized genome of the desired data quality for $10 to $50 million; the goal of this initiative is to reduce costs by at least two orders of magnitude. It is anticipated that emerging technologies are sufficiently advanced that, with additional investment, it may be possible to achieve proof of principle or even early stage commercialization of multiple different approaches for genome-scale sequencing within five years.

Table of Contents

Part I Overview Information

Part II Full Text of Announcement

Section I. Funding Opportunity Description
1. Research Objectives

Section II. Award Information
1. Mechanism(s) of Support
2. Funds Available

Section III. Eligibility Information
1. Eligible Applicants
A. Eligible Institutions
B. Eligible Individuals
2.Cost Sharing or Matching
3. Other - Special Eligibility Criteria

Section IV. Application and Submission Information
1. Address to Request Application Information
2. Content and Form of Application Submission
3. Submission Dates and Times
A. Receipt and Review and Anticipated Start Dates
1. Letter of Intent
B. Sending an Application to the NIH
C. Application Processing
4. Intergovernmental Review
5. Funding Restrictions
6. Other Submission Requirements

Section V. Application Review Information
1. Criteria
2. Review and Selection Process
A. Additional Review Criteria
B. Additional Review Considerations
C. Sharing Research Data
D. Sharing Research Resources
3. Anticipated Announcement and Award Dates

Section VI. Award Administration Information
1. Award Notices
2. Administrative and National Policy Requirements
3. Reporting

Section VII. Agency Contact(s)
1. Scientific/Research Contact(s)
2. Peer Review Contact(s)
3. Financial/ Grants Management Contact(s)

Section VIII. Other Information - Required Federal Citations

Part II - Full Text of Announcement

Section I. Funding Opportunity Description

1. Research Objectives

PURPOSE

The National Human Genome Research Institute (NHGRI) solicits grant applications under this Request for Applications (RFA) funding opportunity announcement to develop novel technologies that will substantially reduce the cost of genomic DNA sequencing. Current technologies are able to produce the sequence of a mammalian-sized genome of the desired data quality for $10 to $50 million; the goal of this initiative is to reduce costs by at least two orders of magnitude. It is anticipated that emerging technologies are sufficiently advanced that, with additional investment, it may be possible to achieve proof of principle or even early stage commercialization of multiple different approaches for genome-scale sequencing within five years. Parallel RFAs of identical scientific scope (RFA-HG-06-002, RFA-HG-06-003) solicit applications under the Small Business Innovation Research (SBIR) and the Small Business Technology Transfer (STTR) grant programs. Related RFAs (RFA-HG-05-004, RFA-HG-06-004, RFA-HG-06-005) solicit grant applications to develop technologies to meet the more challenging goal of achieving cost reduction by four orders of magnitude in about ten years.

BACKGROUND

The ability to sequence complete genomes and the free dissemination of the sequence data have dramatically changed the nature of biological and biomedical research. Sequence and other genomic data have the potential to lead to remarkable improvement in many facets of human life and society, including the understanding, diagnosis, treatment and prevention of disease; advances in agriculture, environmental science and remediation; and the understanding of evolution and ecological systems.

The ability to sequence many genomes completely has been made possible by the enormous reduction of the cost of sequencing in the past two decades, from tens of dollars per base in the 1980s to a few cents per base today. However, even at current prices, the cost of sequencing a mammalian-sized genome is tens of millions of dollars and, accordingly, we must still be very selective when choosing new genomes to sequence. In particular, we remain very far away from being able to afford to use comprehensive genomic sequence information in individual health care. For this, and many other reasons, the rationale for achieving the ability to sequence entire genomes very inexpensively is very strong.

There are many areas of high priority research to which genomic sequencing at dramatically reduced cost would make vital contributions.

Given the broad utility and high importance of dramatically reducing DNA sequencing costs, the NHGRI is engaged in two parallel technology development programs. The first, described in this RFA and parallel RFAs for small business grants, has the objective of reducing the cost of producing a high quality sequence of a mammalian-sized genome by two orders of magnitude. The goal of the second program is the development of technology to sequence a genome for a cost that is reduced by four orders of magnitude. For both programs, the cost targets are defined in terms of a mammalian-sized genome, about 3 gigabases (Gb), with a target sequence quality equivalent to, or better than, that of the mouse assembly published in December 2002 (Nature 420:520, 2002).

The ultimate goal of these programs is to obtain technologies that can produce assembled sequence (i.e., de novo sequencing). However, an accompanying shorter-term goal is to obtain highly accurate sequence data at the single base level, i.e., without assembly information, that can be overlaid onto a reference sequence for the same organism (i.e., re-sequencing). This could be achieved, for example, with short reads that have no substantial information linking them to other reads. While the sequence product of this kind of technology would lack some important information, such as information about genomic rearrangements, it would nevertheless potentially be available more rapidly and produce data of great value for certain uses in studying disease etiology and in individualized medicine. Therefore, both programs’ objectives include a balanced portfolio of projects developing both de novo and re-sequencing technologies. As for de novo sequencing, the goal of technology development for re-sequencing is to reduce costs by two orders of magnitude, and ultimately four orders of magnitude, from the current cost of producing comparable data.

Sequencing strategy and quality

State-of-the-art technology, fluorescence detection of dideoxynucleotide-terminated DNA extension reactions resolved by capillary array electrophoresis (CAE), allows the determination of sequence “read” segments approximately 1000 nucleotides long. If all of the DNA in a 2-3 Gb genome were unique, it would be possible to determine the sequence of the entire genome by generating a sufficient number (10s of millions) of randomly-overlapping thousand-base reads and aligning their overlaps. However, the human and the majority of other interesting genomes contain a substantial amount of repetitive DNA (short [tens to thousands of nucleotides], nearly or completely identical sequences present in multiple [tens to thousands of] copies). To cope with the complexities of repetitive DNA elements and to assemble the thousand-base reads in the correct long-range order across the genome, current genomic sequencing methods involve a variety of additional strategies, such as the sequencing of both ends of cloned DNA fragments, use of libraries of cloned fragments of different lengths, incorporation of map information, achievement of substantial redundancy (multiple reads of each nucleotide from overlapping fragments) and application of sophisticated assembly algorithms to align and filter the reads.

The “gold standard” for genomic sequencing is 99.99% accuracy (not more than one error per 10,000 nucleotides) with essentially no gaps (http://www.genome.gov/10000923). At present, the final steps in achieving that very high sequence quality cannot be automated and require substantial hand-crafting. However, recent experience suggests that the majority of comparative sequence information can be obtained from automatically generated sequence assemblies that have been variously identified as “high-quality draft” or “comparative grade.” Therefore, while the ultimate goal is sequencing technology that produces perfect accuracy, the goal of the current de novo sequencing program is to develop technology for automatically generating sequence of at least the quality of the mouse draft genome sequence that was published in December 2002 (Nature 420:520, 2002).

For re-sequencing technologies, in which newly-determined sequence is overlaid on a scaffold of a known reference sequence from other individuals of the same organism, the challenges include the production of sequence of sufficiently high quality to distinguish between sequencing errors and real polymorphism. The presence of gene families with very similar sequence presents another complication, particularly when using technologies that produce short sequence reads. Additional challenges for short-read sequencing include the identification of genomic rearrangements, and the identification of haplotypes (i.e., linear juxtapositioning of particular single nucleotide polymorphism [SNP] alleles along a single chromosome) in diploid organisms. Thus, in proposing the development of re-sequencing technologies, it is essential to state the goals clearly in terms of the technical capability and costs associated with meeting these challenges.

Technology path

Most investigators interested in reducing DNA sequencing costs anticipate that a few additional two-fold decreases in cost can be achieved with the current CAE-based technology, with a realistic lower limit of perhaps $5 million per mammalian-sized genome. However, it is likely that this efficiency will only be achieved in a few very large, well-capitalized, experienced, automated laboratories. To achieve the broadest benefit from DNA sequencing technology for biology and medicine, systems are needed that are not only substantially more efficient but also are easier to use by the average research laboratory.

One set of current technology development efforts is aimed at increasing parallel sample processing while integrating the sample preparation and analysis steps on a single platform. Thus, in one approach, lithography is used to create a large number of microchannels on a single device and to integrate an efficient sample injector with each separation channel. Chambers for on-chip DNA amplification, cycle sequencing reactions and sample clean-up have been also developed, and experiments to integrate these steps, an approach that effectively places much of the sequencing process and process control onto the device, are being conducted in several laboratories. Improvements in separation polymers and fluorescent dyes will facilitate these developments. As these approaches are based largely on the experience of currently successful high-throughput CAE-based methods, they have potential to produce cost savings in the range of several factors of two beyond the CAE-based system itself. They also have the potential to widen the user base for the technology, as the infrastructure and knowledge needed to conduct relatively high-throughput sequencing, or clinical diagnostic sequencing, would be substantially reduced and simplified.

Other approaches to improving sequencing technology involve methods that are independent of the Sanger dideoxynucleotide chain termination reaction and electrophoretic separation of the termination products. Two methods that were proposed in the early days of the Human Genome Project involve the use of mass spectrometry and sequencing by hybridization. Both methods have been pursued, with some limited success for sequencing, but substantial success for other types of DNA analysis. Both continue to hold additional potential utility for sequencing, although certain inherent limitations will need to be overcome.

More recently, additional methodologies have been investigated. These may be classified into two approaches. One is sequencing-by-extension, in which template DNA is elongated in stepwise fashion, and each sequential extension product is detected. Extension is generally achieved by the action of a polymerase that adds a deoxynucleotide, followed by detection of a fluorescent or chemiluminescent signal, and the cycle is then repeated. Variants of this approach rely on other enzymes and detection of hybridization of labeled oligonucleotides. To obtain sufficient throughput, the method is implemented at a high level of multiplexing, by arraying large numbers of sequencing extension reactions on a surface. Key factors in this general approach include the manner in which the fluorescent signal is generated and the system requirements thus imposed. Depending on the specific approach, challenges of template extension methods include the synthesis of appropriate labeled nucleotide analogues of high purity; identifying processive polymerases that incorporate nucleotide analogs with high fidelity; discriminating fluorescent nucleotides that have been incorporated into the growing chain from those present in the reaction mix (background); distinguishing subsequent nucleotide additions from previous ones; accurate enumeration of homopolymer runs (multiple sequential occurrence of the same nucleotide); maintaining synchrony among the multiple copies of DNA being extended to generate a detectable signal or achievement of sensitivity that detects extension of individual DNA molecules; and developing fluidics, surface chemistry, and automation to build and run the system. Current efforts to develop such methods have generally produced short sequence reads (less than or equal to 100 bases), so a continuing challenge is to extend read length and develop sequence assembly strategies. The NHGRI anticipates that the state of the art for this approach is sufficiently advanced that, with additional investment, it should be possible to achieve proof of principle or even early commercialization of multiple different approaches for genome-scale sequencing within five years. It is anticipated that the cost of genome sequencing with this technology could be reduced by two orders of magnitude from today’s costs. It is important to note that sequencing by extension is one prototype for achieving these time and cost goals, but other technological approaches may also be viable. Achieving these goals is the subject of this RFA funding opportunity announcement.

A second alternative to CAE sequencing seeks to read the linear sequence of nucleotides without copying the DNA and without incorporating labels, relying instead on extraction of signal from the native DNA nucleotides. One now-familiar model for this approach, but almost certainly not the only way to achieve 10,000-fold reduction in sequencing costs, is nanopore sequencing, first introduced in the mid-1990s. Generally, this approach requires a sensor, perhaps comparable in size to the DNA molecule itself, that interacts sequentially with individual nucleotides in a DNA chain and distinguishes between them on the basis of chemical, physical or electrical properties. Optimal implementation of such a method would analyze intact, native genomic DNA molecules isolated from biological, medical or environmental samples without amplification or modification, and would provide very long sequence reads (tens of thousands to millions of bases) rapidly and at sufficiently high redundancy to produce assembled sequence of high quality. NHGRI seeks to support high quality projects to pursue novel technologies for decreasing sequencing costs by four orders of magnitude. NHGRI anticipates that it may take ten years to conduct the substantial basic research and technology development that are needed to achieve such a dramatic reduction of sequencing costs. Achieving this goal is the subject of the parallel RFAs.

RESEARCH SCOPE

The goal of research supported under this RFA funding opportunity announcement is to develop new or improved technology to enable rapid, efficient genomic DNA sequencing. The specific goal is to reduce sequencing costs by at least two orders of magnitude -- $100,000 serves as a useful target cost for a mammalian-sized genome because the availability of complete genomic sequences at that cost would revolutionize biological research and medicine. While not in a cost range that would enable the use of sequencing in individualized medicine, such technology would permit the sequencing of many genomes for a small fraction of current costs. A 100-fold cost reduction would make possible extensive studies of human variation for disease gene studies, substantially expanded comparative genomics to understand the human genome, and many other studies relevant to NIH, other federal agencies and the private sector. Entirely new lines of investigation would be enabled by making “large-scale sequencing” accessible to the diverse interests of many research laboratories and companies.

Many projects aimed at next-generation DNA sequencing technologies require substantial advances in a combination of fields such as signal detection, enzymology, chemistry, engineering, bioinformatics, etc. It is therefore anticipated that proposals responding to this RFA will involve fundamental and engineering research conducted by multidisciplinary teams of investigators. The guidance for budget requests accommodates the formation of groups having investigators at several institutions, in cases where that is needed to assemble a team of the appropriate balance, breadth and experience.

The scientific and technical challenges inherent in achieving a 100-fold reduction in sequencing costs are considerable. Achieving this goal may require research projects that entail substantial risk. That risk should be balanced by an outstanding scientific and management plan designed to achieve the very high payoff goals of this solicitation. High risk, high payoff projects may fail for legitimate reasons; applicants proposing such projects should describe plans to terminate the project if key milestones cannot be achieved in a reasonable time.

Applicants may propose to develop full-scale sequencing systems, or to investigate key components of such systems. For the latter, applicants must describe how the knowledge gained as a result of their project would be incorporated into a full system that they might subsequently propose to develop, or that is being developed by other groups. Such independent proposals are an important path for pursuing novel, high risk/high pay-off ideas.

Research conducted under this RFA may include development of the computational tools associated with the technology, e.g., to extract sequence information, including image analysis and signal processing, and to evaluate sequence quality and assign confidence scores. It may also address strategies to assemble the sequence from the information being obtained from the technology or by merging the sequence data with information from parallel technology. However, this RFA will not support development of sequence assembly software independent of technology development to obtain the sequence.

The quality of sequence to be generated by the technology is of paramount importance for this solicitation. Two major factors contributing to genomic sequence quality are per-base accuracy and contiguity of the assembly. Much of the utility of comparative sequence information will derive from characterization of sequence variation between species, and between individuals of a species. Therefore, per-base accuracy must be high enough to distinguish polymorphism at the single-nucleotide level (substitutions, insertions, deletions). Experience and resulting policy have established a target accuracy of not more than one error per 10,000 bases. All applications in response to this RFA, whether to develop re-sequencing or de novo sequencing technologies, must propose achieving per-base quality at least to this standard.

Assembly information is needed for determining sequence of new genomes, and ultimately also for genomes for which a reference sequence exists, to detect rearrangements, insertions and deletions. Rearrangements are known to cause diseases, and knowledge of rearrangements can reveal new biological mechanisms. The phase of single nucleotide polymorphisms to define haplotypes is important in understanding and diagnosing disease. Achieving a high level of sequence contiguity may be essential to achieve the full benefit from the use of sequencing for individualized medicine, e.g., to evaluate genomic contributions to risk for specific diseases and syndromes, and drug responsiveness. Nevertheless, it is recognized that perfect sequence assembly from end to end of each chromosome is unlikely to be achievable with most technologies in a fully automated fashion and without adding considerable cost. Therefore, for the purpose of this solicitation, grant applications proposing technology development for de novo sequencing shall describe how they will achieve, for about $100,000, a draft-quality assembly that is at least comparable to that represented by the mouse draft sequence produced by December 2002: 7.7-fold coverage, 6.5-fold coverage in Q20 bases, assembled into 225,000 sequence contigs connected by at least two read-pair links into supercontigs [total of 7,418 supercontigs at least 2 kb long], with N50 length for contigs equal to 24.8 kb and for supercontigs equal to 16.9 Mb (Nature 420:520, 2002). Grant applications that propose technology development for re-sequencing should explain how they will achieve a two-order-of magnitude reduction in cost compared to technologies that can produce similar quality of data, today.

The grant applications will be evaluated, and funding decisions made, in such a way as to develop a balanced portfolio that has strong potential to develop both robust re-sequencing and de novo sequencing technologies. If the estimate is correct, that achieving the goal of a 100-fold cost reduction for de novo genome sequencing will require about 5 years, then low-cost re-sequencing technologies might be expected to be demonstrated in a shorter time. Grant applications that present a plan to achieve high quality re-sequencing while on the path to high quality de novo sequencing will receive high priority.

The major focus of this RFA funding opportunity announcement is on the development of new technologies for detection of nucleotide sequence. Any new technology will eventually have to be incorporated effectively into the entire sequencing workflow, starting with a biological sample and ending with sequence data of the desired quality, and this issue should be addressed. Sample preparation requirements are a function of the detection method and the sample detection method affects the way in which output data are handled. Therefore, these aspects of the problem are clearly relevant and should be addressed in an appropriate timeframe in the research plan. However, applicants should address the most critical and highest-risk aspects of the project, on which the rest of the project is dependent, as early as possible in the research plan.

Practical implementation issues related to workflow and process control for efficient, high quality, high-throughput DNA sequencing should be considered early in system design. Some technology development groups lack practical experience in high throughput sequencing, and in testing of methods and instruments for robust, routine operation. Applicants may therefore wish to include such expertise as they develop their suite of collaborations and capabilities.

The goal of this research is to develop technology to produce sequence from entire genomes. It is conceivable that sequence from selected important regions (e.g., all of the genes) could be determined in the near future. Grant applications that propose to meet the cost targets by sequencing only selected regions of a genome will be considered unresponsive. However, applications that propose novel ways to sequence selected genomic regions, cost-effectively, while on a path to whole-genome sequencing, will be considered.

See Section VIII, Other Information - Required Federal Citations, for policies related to this announcement.

Section II. Award Information

1. Mechanism(s) of Support

This RFA funding opportunity will use the Research Project (R01), Exploratory/Developmental Grants (R21), and Exploratory/Developmental/Phase II Exploratory/Developmental Grants (R21/R33) grant mechanisms. Applications for the R33 award alone will not be accepted.

As an applicant, you will be solely responsible for planning, directing, and executing the proposed project.

This funding opportunity uses just-in-time concepts. It also uses the modular as well as the non-modular budget formats (see the research grant application instructions for the PHS 398 at http://grants.nih.gov/grants/funding/phs398/phs398.doc, Part I, Section C.4., “Budget Instructions”).

Specifically, if you are submitting an application with direct costs in each year of $250,000 or less, use the modular budget format described in the PHS 398 application instructions. Otherwise, follow the instructions for non-modular research grant applications.

Applicants may request an R01 Research Project Grant if sufficient preliminary data are available to support such an application.

Applicants requiring support to demonstrate feasibility may apply for either an R21 Exploratory/ Developmental project or an R21/R33 Phased Innovation award, which offers single submission and evaluation of both the exploratory (R21) and an expanded development phase (R33) in one application. The R21/R33 should be used when both quantitative milestones for the feasibility demonstration, and an explicit research plan for the follow-on research, can be presented. The transition from the R21 award to the R33 award will be expedited by administrative review. The R21 alone is appropriate when the possible outcomes of the proposed feasibility study are unclear and it is not possible to propose sufficiently clear-cut and quantitative milestones for administrative evaluation, nor would it be possible to describe the R33 phase of the research in sufficient detail to allow adequate initial review. Outside of the R21/R33 mechanism, applications to continue research after a successful R21 Exploratory/Developmental project should be submitted using the R01 grant mechanism.

2. Funds Available

The NHGRI intends to commit approximately 2 million dollars in FY 2006 to fund 2-7 new and/or competing continuation grants in response to this RFA. The anticipated start date is September 29, 2006.

An applicant may request a project period of up to 3 years for R21 grants with a budget not to exceed $200,000 direct costs per year. The total project period for R21/R33 grants may not exceed 3 years; the R21 may request up to $200,000 direct costs per year with a duration of 1 or 2 years, and the R33 phase may request up to $1.5 million direct costs per year. R01 grant applications may request a project period up to 3 years with direct costs up to $1.5 million per year.

Because the nature and scope of the proposed research will vary from application to application, it is anticipated that the size and duration of each award will also vary. Although the financial plans of the NHGRI provide support for this program, awards pursuant to this funding opportunity are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications.

Facilities and administrative costs requested by consortium participants are not included in the direct cost limitation; see NOT-OD-05-004.

Section III. Eligibility Information

1. Eligible Applicants

1.A. Eligible Institutions

You may submit an application(s) if your organization has any of the following characteristics:

1.B. Eligible Individuals

Any individual with the skills, knowledge, and resources necessary to carry out the proposed research is invited to work with their institution to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH programs.

2. Cost Sharing or Matching

This program does not require cost sharing as defined in the current NIH Grants Policy Statement. Applicants should describe any institutional commitment being offered in support of the project. Institutional commitment may take many forms, including space, equipment, and other resources devoted to and improved for the project, time and effort of investigators, etc. This information should be incorporated into the management plan (see Section IV.6., “Other Submission Requirements”).

3. Other-Special Eligibility Criteria
Not Applicable

Section IV. Application and Submission Information

1. Address to Request Application Information

The PHS 398 application instructions are available at http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. Applicants must use the currently approved version of the PHS 398. For further assistance contact GrantsInfo, Telephone (301) 435-0714, Email: GrantsInfo@nih.gov.

Telecommunications for the hearing impaired: TTY 301-451-5936.

2. Content and Form of Application Submission

Applications must be prepared using the most current PHS 398 research grant application instructions and forms. Applications must have a Dun and Bradstreet (D&B) Data Universal Numbering System (DUNS) number as the universal identifier when applying for Federal grants or cooperative agreements (see http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-055.html). The D&B number can be obtained by calling (866) 705-5711 or through the Internet at http://www.dnb.com/us/. The D&B number should be entered on line 11 of the face page of the PHS 398 form.

The title and number of this RFA funding opportunity must be typed on line 2 of the face page of the application form and the “YES” box must be checked.

Follow page limitations described in the PHS 398 form (http://grants.nih.gov/grants/funding/phs398/instructions2/p1_general_instructions.htm#Page_Limitations) with the following modifications:

R21: Items a - d of the Research Plan (Specific Aims, Background and Significance, Preliminary Studies, and Research Design and Methods) may not exceed a total of 15 pages. No preliminary data are required but they may be included if available.

R21/R33: The R21/R33 Phased Innovation Award application must be submitted as a single application with one face page. Although it is submitted as a single application, it should be clearly organized into two phases. To achieve a clear distinction between the two phases, applicants should submit Sections a, b, c and d for the R21 phase (with R21 milestones in section d), and then sections a and d (but not b and c) for the R33 (including R33 milestones). A discussion of the milestones relative to the progress of the R21 phase, as well as the implications of successful completion of the milestones for the R33, should be included. The PHS 398 form Table of Contents should be modified to show the sections for each phase as well as the milestones. There is a page limit of 35 pages for the composite research plan. Section a-d of the R21 research plan must not exceed 15 pages, with the remainder available for sections a and d for the R33.

R01: Sections a-d will not exceed 35 pages.

All applications: Up to four additional pages labeled “Management Plan” and inserted between sections d (Research Design and Methods) and Literature Cited, should describe all aspects of project management, incorporating, e.g., how multiple investigators and disciplinary approaches will be coordinated, coordination among distant sites, decision-making processes, use of progress toward milestones as inputs to decision-making, etc. Contents of the Management Plan are further describe below (see Section IV, 6., “Other Submission Requirements”).

Foreign Organizations

Several special provisions apply to applications submitted by foreign organizations:

Proposed research should provide a unique research opportunity not available in the United States.

3. Submission Dates and Times
See Section IV.3.A. for details.

3.A. Receipt, Review, and Anticipated Start Dates

Letters of Intent Receipt Date: January 17, 2006
Application Receipt Date: February 17, 2006
Peer Review Date: June-July 2006
Council Review Date: September 12, 2006
Earliest Anticipated Start Date: September 29, 2006

3.A.1. Letter of Intent

Prospective applicants are asked to submit a letter of intent that includes the following information:

Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows NHGRI staff to estimate the potential review workload and plan the review.

The letter of intent is to be sent by the date listed in Section IV.3.A.

The letter of intent should be sent to:

Jeffery A. Schloss, Ph.D.
Division of Extramural Research

National Human Genome Research Institute, NIH
5635 Fishers Lane, Suite 4076
Bethesda, MD 20892-9305
Telephone: (301) 496-7531
Email: schlossj@exchange.nih.gov

3.B. Sending an Application to the NIH

Applications must be prepared using the research grant applications found in the PHS 398 instructions for preparing a research grant application. Submit a signed, typewritten original of the application, including the checklist, and three signed photocopies in one package to:

Center for Scientific Review
National Institutes of Health
6701 Rockledge Drive, Room 1040, MSC 7710
Bethesda, MD 20892-7710 (U.S. Postal Service Express or regular mail)
Bethesda, MD 20817 (for express/courier service; non-USPS service)

Personal deliveries of applications are no longer permitted (see http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-040.html).

At the time of submission, two additional copies of the application and all copies of the appendix material must be sent to:

Ken Nakamura, Ph.D.
Scientific Review Branch
National Human Genome Research Institute, NIH
5635 Fishers Lane, Suite 4076
Bethesda, MD 20892-930 6 (U.S. Postal Service Express or regular mail)
Rockville, MD 20852 (for express/courier service, non-USPS service)
Telephone: (301) 402-0838

Using the RFA Label: The RFA label available in the PHS 398 application instructions must be affixed to the bottom of the face page of the application. Type the RFA number on the label. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, the RFA title and number must be typed on line 2 of the face page of the application form and the “YES” box must be marked. The RFA label is also available at: http://grants.nih.gov/grants/funding/phs398/labels.pdf.

3.C. Application Processing

Applications must be received on or before the application receipt date listed in Section IV.3.A. If an application is received after that date, it will be returned to the applicant without review. Upon receipt, applications will be evaluated for completeness by the Center for Scientific Review (CSR), NIH and responsiveness by the NHGRI. Incomplete and non-responsive applications will not be reviewed.

The NIH will not accept any application in response to this funding opportunity that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. However, when a previously unfunded application, originally submitted as an investigator-initiated application, is to be submitted in response to a funding opportunity, it is to be prepared as a NEW application. That is, the application for the funding opportunity must not include an Introduction describing the changes and improvements made, and the text must not be marked to indicate the changes from the previous unfunded version of the application.

Although there is no immediate acknowledgement of the receipt of an application, applicants are generally notified of the review and funding assignment within eight (8) weeks.

4. Intergovernmental Review
This initiative is not subject to intergovernmental review.

5. Funding Restrictions

All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

Pre-Award Costs are allowable. A grantee may, at its own risk and without NIH prior approval, incur obligations and expenditures to cover costs up to 90 days before the beginning date of the initial budget period of a new or competing continuation award if such costs: are necessary to conduct the project, and would be allowable under the grant, if awarded, without NIH prior approval. If specific expenditures would otherwise require prior approval, the grantee must obtain NIH approval before incurring the cost. NIH prior approval is required for any costs to be incurred more than 90 days before the beginning date of the initial budget period of a new or competing continuation award.

The incurrence of pre-award costs in anticipation of a competing or non-competing award imposes no obligation on NIH either to make the award or to increase the amount of the approved budget if an award is made for less than the amount anticipated and is inadequate to cover the pre-award costs incurred. NIH expects the grantee to be fully aware that pre-award costs result in borrowing against future support and that such borrowing must not impair the grantee's ability to accomplish the project objectives in the approved time frame or in any way adversely affect the conduct of the project. See the NIH Grants Policy Statement.

6. Other Submission Requirements

The NHGRI anticipates that research to meet the goals of this program will require about five years. Therefore, a timeline for up to a 5 year project should be presented, culminating in the demonstration of sequencing a substantial amount of DNA (e.g., at least 0.5-1 gigabase) at the target cost and quality; other measures may be proposed by the applicant. A detailed research plan must be presented for the 1-3 years of requested support. The application should include a description of the level of risk of key technical challenges, alternative approaches, go/no-go decision points, etc. It should also include a detailed timeline accompanied by quantitative milestones (see below) that address the key scientific and technical challenges central to the approach. The timeline and milestones will be essential for use by both the grantee and the NHGRI for planning the research projects and assessment of progress toward goals, and by the reviewers for evaluating the proposal.

Timelines and quantitative milestones are essential for development of a realistic research plan; they provide a basis for project leaders to make decisions, assess their own progress, set priorities, and redistribute resources when needed. It will be particularly important to establish quantitative milestones in cases where subsequent steps in technology development depend upon threshold performance characteristics of earlier developments. Elaboration of timelines and milestones is primarily the responsibility of the applicant, and the quality and utility of the proposed timelines and milestones will be a review criterion, because they reflect the insights and judgment of the applicant concerning key challenges and how best to conduct the research. The NHGRI appreciates that these projects will require research, not just engineering; progress toward milestones will be evaluated accordingly. If the proposed timeline and milestones are not adequate in the case of an otherwise meritorious proposal, reviewers of the application may make recommendations to NHGRI regarding improved timelines and milestones.

To accelerate progress in the field of advanced DNA sequencing technology development, grantees will be required to participate actively and openly in at least one grantee meeting per year. Substantial information sharing will be required and is a condition of the award; failure to openly share information will be grounds for discontinuation of funding. It is understood that some information developed under the grants will be proprietary and cannot be shared immediately without damaging the commercialization potential of the technology. Applicants should describe their plans for participating in the grantee meetings and for managing the intellectual property concerns in the context of those meetings and other opportunities for information sharing. Other investigators in the field (i.e., not supported under this program) may be invited to participate in these workshops; their agreement to share information substantially will be a prerequisite to participation. Applicants should request travel funds in their budgets for the Principal Investigator and two additional lead investigators to attend the annual meetings.

Applicants may include funds for an internally appointed advisory board. However, they should not contact potential advisors, nor should potential advisors be named in the grant application, to avoid conflicts of interest in the review process.

All applicants must describe their plan for providing access to the technology developed under this grant support. For example, the technology might be made available as a fee-for-service, through sale of instruments and/or reagents, through collaboration, through publication and posting of results, plans and methods, or by other means.

In summary, applicants must incorporate into application section d (Research Design and Methods):

In addition to sections a-d of the PHS 398 research plan, applicants must include, after section d and before Literature Cited, a management plan (not to exceed 4 pages) incorporating:

Specific Instructions for Modular Grant applications.

Applications requesting up to $250,000 per year in direct costs must be submitted in a modular budget format. The modular budget format simplifies the preparation of the budget in these applications by limiting the level of budgetary detail. Applicants request direct costs in $25,000 modules. The research grant application instructions for the PHS 398 at http://grants.nih.gov/grants/funding/phs398/phs398.doc includes step-by-step guidance for preparing modular budgets (see Part I, Section C.4., “Budget Instructions”). Applicants must use the currently approved version of the PHS 398.

Plan for Sharing Research Data

All applicants must describe their plans for disseminating information about, and providing access to the technology developed under this grant support. For example, the technology might be made available as a fee-for-service, through sale of instruments and/or reagents, through collaboration, through publication and posting of results, plans and methods, or by other means.

The reasonableness of the data sharing plan or the rationale for not sharing research data will be assessed by the reviewers. However, reviewers will not factor the proposed data sharing plan into the determination of scientific merit or the priority score.

Sharing Research Resources

NIH policy requires that grant awardee recipients make unique research resources readily available for research purposes to qualified individuals within the scientific community after publication (NIH Grants Policy Statement http://grants.nih.gov/archive/archive/grants/policy/nihgps_2003/index.htm and http://grants.nih.gov/archive/grants/policy/nihgps_2003/index.htm#_Toc54600131). Investigators responding to this funding opportunity should include a plan for sharing research resources addressing how unique research resources will be shared or explain why sharing is not possible.

The adequacy of the resources sharing plan and any related data sharing plans will be considered by NHGRI Program staff when making recommendations about funding applications. The effectiveness of the resource sharing will be evaluated as part of the administrative review of each Non-Competing Grant Progress Report (PHS 2590). See Section VI.3. Reporting.

Section V. Application Review Information

1. Criteria

The following will be considered in making funding decisions:

2. Review and Selection Process

Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by the NHGRI in accordance with the review criteria stated below.

As part of the initial merit review, all applications will:

The goals of NIH supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. In their written critiques, reviewers will be asked to comment on each of the following criteria in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. Each of these criteria will be addressed and considered in assigning the overall score, weighting them as appropriate for each application. Note that an application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a high priority score. For example, an investigator may propose to carry out important work that by its nature is not innovative but is essential to move a field forward.

Significance: Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge or clinical practice be advanced? What will be the effect of these studies on the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field? Does the study directly address the problem outlined in this RFA? Are the plans sufficiently bold to constitute a substantial advance, if they can be achieved, toward the demanding goals of the RFA?

Approach: Are the conceptual or clinical framework, design, methods, and analyses adequately developed, well integrated, well reasoned, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? Are key scientific and technological issues on which the rest of the approach depends, identified and addressed early in the project? Does the proposed technology address sequence quality and the sequencing of entire genomes? Does the application clearly state whether the goal is to develop re-sequencing, or de novo sequencing technology, and if the latter, is there an adequate plan for evaluating the achieved long-range contiguity? Is the analysis of sequencing costs well developed and well-informed? Are bold plans counterbalanced to manage the inherent risk, for example by firm theoretical basis, reasonable preliminary data (depending on the mechanism), the track record of the lead investigators, and an outstanding scientific and management plan? Are the timeline and milestones logical and realistic? Are key technical barriers and dependencies identified? Are milestones adequately developed and quantitative, to serve as effective guidance for assessment of progress by the investigators and the NHGRI? Are plans to participate actively and openly in grantee meetings sufficiently clear and forthcoming so as to contribute substantially to advancement of the field?

Innovation: Is the project original and innovative? For example: Does the project challenge existing paradigms or clinical practice; address an innovative hypothesis or critical barrier to progress in the field? Does the project develop or employ novel concepts, approaches, methodologies, tools, or technologies for this area?

Investigators: Are the investigators appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers? Does the investigative team bring complementary and integrated expertise to the project (if applicable)? Does the PD/PI and other lead investigators have sufficient experience to manage a project of the proposed complexity? Are plans to integrate activities and set priorities across the multiple disciplines and investigators (and institutions, if appropriate), adequately developed and explained?

Environment: Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed studies benefit from unique features of the scientific environment, or subject populations, or employ useful collaborative arrangements? Is there evidence of institutional support?

2.A. Additional Review Criteria:

In addition to the above criteria, the following items will continue to be considered in the determination of scientific merit and the priority score:

Protection of Human Subjects from Research Risk: The involvement of human subjects and protections from research risk relating to their participation in the proposed research will be assessed (see the Research Plan, Section E on Human Subjects in the PHS Form 398).

Inclusion of Women, Minorities and Children in Research: The adequacy of plans to include subjects from both genders, all racial and ethnic groups (and subgroups), and children as appropriate for the scientific goals of the research will be assessed. Plans for the recruitment and retention of subjects will also be evaluated (see the Research Plan, Section E on Human Subjects in the PHS Form 398).

Care and Use of Vertebrate Animals in Research: If vertebrate animals are to be used in the project, the five items described under Section F of the PHS Form 398 research grant application instructions will be assessed.

Biohazards: If materials or procedures are proposed that are potentially hazardous to research personnel and/or the environment, determine if the proposed protection is adequate.

2.B. Additional Review Considerations

Budget: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research may be assessed by the reviewers. The priority score should not be affected by the evaluation of the budget.

2.C. Sharing Research Data

Data Sharing Plan: The reasonableness of the data sharing plan or the rationale for not sharing research data will be assessed by the reviewers. However, reviewers will not factor the proposed data sharing plan into the determination of scientific merit or the priority score. The presence of a data sharing plan will be part of the terms and conditions of the award. The funding organization will be responsible for monitoring the data sharing policy. The data sharing plan includes both the plan for technology dissemination and the plan for participation in grantee meetings.

2.D. Sharing Research Resources

NIH policy requires that grant awardee recipients make unique research resources readily available for research purposes to qualified individuals within the scientific community after publication (See the NIH Grants Policy Statement http://grants.nih.gov/archive/grants/policy/nihgps/part_ii_5.htm#availofrr and http://www.ott.nih.gov/policy/rt_guide_final.html). Investigators responding to this funding opportunity should include a sharing research resources plan addressing how unique research resources will be shared or explain why sharing is not possible.

The NHGRI Program staff will be responsible for the administrative review of the plan for sharing research resources, if any are generated.

The adequacy of the resources sharing plan will be considered by NHGRI Program staff when making recommendations about funding applications. Program staff may negotiate modifications of the data and resource sharing plans with the awardee before recommending funding of an application. The final version of the data and resource sharing plans negotiated by both will become a condition of the award of the grant. The effectiveness of the resource sharing will be evaluated as part of the administrative review of each Non-Competing Grant Progress Report (PHS 2590). See Section VI.3. Reporting.

3. Anticipated Announcement and Award Dates
Not applicable

Section VI. Award Administration Information

1. Award Notices

If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant. For details, applicants may refer to the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General.

A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization. The NoA signed by the grants management officer is the authorizing document. Once all administrative and programmatic issues have been resolved, the NoA will be generated via email notification from the awarding component to the grantee business official (designated in item 13 on the PHS 398 Application Face Page). If a grantee is not email enabled, a hard copy of the NoA will be mailed to the business official.

Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs. See Also Section IV.5., “Funding Restrictions.”

2. Administrative and National Policy Requirements

Prior to funding an application, the NHGRI will negotiate the milestones with the applicant, beginning with the applicant’s stated milestones and incorporating recommendations from the review panel, the National Advisory Council for Human Genome Research, and staff. The negotiated milestones will become a condition of the award, including appropriate language to recognize that the project includes research whose outcomes are unpredictable. In the case of research programs projected to require longer than the initial grant period, the decision to fund beyond the initial period will be based on a competitive renewal process that will take into account overall progress in the field as well as progress on the individual research effort, as compared to the negotiated milestones.

For R21/R33 awards, the transition from the R21 to the R33 will depend upon completion of negotiated milestones. Once these milestones have been achieved, the PD/PI will submit a progress report to NHGRI. Receipt of this report will trigger administrative review to determine if the R33 should be awarded. Administrative review may engage the use of outside consultants. The decision to award the R33 will be based on successful completion of negotiated milestones, negotiation of revised milestones for the R33 phase, program priorities, and availability of funds.

To accelerate progress in the field of advanced DNA sequencing technology development, grantees will be expected to participate actively and openly in at least one grantee meeting per year. Substantial information sharing will be required and is a condition of the award; failure to openly share information will be grounds for discontinuation of funding. It is understood that some information developed under the grants will be proprietary and cannot be shared immediately without damaging the commercialization potential of the technology. Applicants should describe their plans for participating in the grantee meetings and for managing the intellectual property concerns in the context of those meetings and other opportunities for information sharing. Other investigators in the field (i.e., not supported under this program) may be invited to participate in these workshops; their agreement to share information substantially will be a prerequisite to their participation. The applicant’s participation plan, after negotiation with NHGRI staff, will become the minimum standard for continued funding.

Grantees will be asked to host the annual grantee meetings on a rotating basis. The NHGRI will negotiate a schedule for the grantee meetings and will adjust budgets to accommodate these meetings. Holding these meetings at grantee sites will facilitate information sharing and participation of a larger portion of the research staff than would otherwise occur.

All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the Notice of Award. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General and Part II Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Grantees, and Activities.

3. Reporting

Applicants must plan to submit two progress reports per year – one at the time of the non-competing continuation and one at a time to be determined by NHGRI staff. The latter may coincide with grantee meetings, meetings of advisors to NHGRI, or site visits. The NHGRI will use information from reports, meetings, site visits, etc. to evaluate each grantee’s progress and the success of the overall program; this information will be used to determine if funding levels should be increased or decreased for future years, for each grant, and for the program.

Awardees will be required to submit the Non-Competing Grant Progress Report (PHS 2590) annually and financial statements as required in the NIH Grants Policy Statement.

Section VII. Agency Contacts

We encourage your inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants. Inquiries may fall into three areas: scientific/research, peer review, and financial or grants management issues:

1. Scientific/Research Contacts:

Jeffery A. Schloss, Ph.D.
Division of Extramural Research
National Human Genome Research Institute, NIH
5635 Fishers Lane, Suite 4076
Bethesda, MD 20892-9305
Telephone: (301) 496-7531
Fax: (301) 480-2770
Email: schlossj@exchange.nih.gov

2. Peer Review Contacts:

Ken Nakamura, Ph.D.
Scientific Review Branch
National Human Genome Research Institute, NIH
5635 Fishers Lane, Suite 4076
Bethesda, MD 20892-9306
Phone: (301) 402-0838
Fax: (301) 435-1580
Email: kn24c@nih.gov

3. Financial or Grants Management Contacts:

Cheryl Chick
Grants Administration Branch
National Human Genome Research Institute, NIH
5635 Fishers Lane, Suite 4076
Bethesda, MD 20892-9306
Phone: (301) 435-7858
Fax: (301) 402-1951
E-mail: chickc@mail.nih.gov

Section VIII. Other Information

Required Federal Citations

Use of Animals in Research:
Recipients of PHS support for activities involving live, vertebrate animals must comply with PHS Policy on Humane Care and Use of Laboratory Animals (http://grants.nih.gov/grants/olaw/references/PHSPolicyLabAnimals.pdf) as mandated by the Health Research Extension Act of 1985 (http://grants.nih.gov/grants/olaw/references/hrea1985.htm), and the USDA Animal Welfare Regulations (http://www.nal.usda.gov/awic/legislat/usdaleg1.htm) as applicable.

Human Subjects Protection:
Federal regulations (45CFR46) require that applications and proposals involving human subjects must be evaluated with reference to the risks to the subjects, the adequacy of protection against these risks, the potential benefits of the research to the subjects and others, and the importance of the knowledge gained or to be gained (http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm).

Data and Safety Monitoring Plan:
Data and safety monitoring is required for all types of clinical trials, including physiologic toxicity and dose-finding studies (Phase I); efficacy studies (Phase II); efficacy, effectiveness and comparative trials (Phase III). Monitoring should be commensurate with risk. The establishment of data and safety monitoring boards (DSMBs) is required for multi-site clinical trials involving interventions that entail potential risks to the participants (“NIH Policy for Data and Safety Monitoring,” NIH Guide for Grants and Contracts, http://grants.nih.gov/grants/guide/notice-files/not98-084.html).

Sharing Research Data:
Investigators submitting an NIH application seeking $500,000 or more in direct costs in any single year are expected to include a plan for data sharing or state why this is not possible (http://grants.nih.gov/grants/policy/data_sharing).

Investigators should seek guidance from their institutions on issues related to institutional policies and local IRB rules, as well as local, State and Federal laws and regulations, including the Privacy Rule. Reviewers will consider the data sharing plan but will not factor the plan into the determination of scientific merit or the priority score.

Access to Research Data through the Freedom of Information Act:
The OMB Circular A-110 has been revised to provide access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are (1) first produced in a project that is supported in whole or in part with Federal funds and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through the FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm. Applicants may wish to place data collected under this funding opportunity in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award.

Sharing of Model Organisms:
NIH is committed to support efforts that encourage sharing of important research resources including the sharing of model organisms for biomedical research (see http://grants.nih.gov/grants/policy/model_organism/index.htm). At the same time, the NIH recognizes the rights of grantees and contractors to elect and retain title to subject inventions developed with Federal funding pursuant to the Bayh Dole Act (see the NIH Grants Policy Statement). Beginning October 1, 2004, all investigators submitting an NIH application or contract proposal are expected to include in the application/proposal a description of a specific plan for sharing and distributing unique model organism research resources generated using NIH funding or state why such sharing is restricted or not possible. This will permit other researchers to benefit from the resources developed with public funding. The inclusion of a model organism sharing plan is not subject to a cost threshold in any year and is expected to be included in all applications where the development of model organisms is anticipated.

Inclusion of Women And Minorities in Clinical Research:
It is the policy of the NIH that women and members of minority groups and their sub-populations must be included in all NIH-supported clinical research projects unless a clear and compelling justification is provided indicating that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing clinical research should read the "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); a complete copy of the updated Guidelines is available at http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm. The amended policy incorporates: the use of an NIH definition of clinical research; updated racial and ethnic categories in compliance with the new OMB standards; clarification of language governing NIH-defined Phase III clinical trials consistent with the SF424 (R&R); and updated roles and responsibilities of NIH staff and the extramural community. The policy continues to require for all NIH-defined Phase III clinical trials that: a) all applications or proposals and/or protocols must provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable; and b) investigators must report annual accrual and progress in conducting analyses, as appropriate, by sex/gender and/or racial/ethnic group differences.

Inclusion of Children as Participants in Clinical Research:
The NIH maintains a policy that children (i.e., individuals under the age of 21) must be included in all clinical research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them.

All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines" on the inclusion of children as participants in research involving human subjects (http://grants.nih.gov/grants/funding/children/children.htm).

Required Education on the Protection of Human Subject Participants:
NIH policy requires education on the protection of human subject participants for all investigators submitting NIH applications for research involving human subjects and individuals designated as key personnel. The policy is available at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.

Human Embryonic Stem Cells (hESC):
Criteria for federal funding of research on hESCs can be found at http://stemcells.nih.gov/index.asp and at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html. Only research using hESC lines that are registered in the NIH Human Embryonic Stem Cell Registry will be eligible for Federal funding (http://escr.nih.gov). It is the responsibility of the applicant to provide in the project description and elsewhere in the application as appropriate, the official NIH identifier(s) for the hESC line(s)to be used in the proposed research. Applications that do not provide this information will be returned without review.

NIH Public Access Policy:
NIH-funded investigators are requested to submit to the NIH manuscript submission (NIHMS) system (http://www.nihms.nih.gov) at PubMed Central (PMC) an electronic version of the author's final manuscript upon acceptance for publication, resulting from research supported in whole or in part with direct costs from NIH. The author's final manuscript is defined as the final version accepted for journal publication, and includes all modifications from the publishing peer review process.

NIH is requesting that authors submit manuscripts resulting from 1) currently funded NIH research projects or 2) previously supported NIH research projects if they are accepted for publication on or after May 2, 2005. The NIH Public Access Policy applies to all research grant and career development award mechanisms, cooperative agreements, contracts, Institutional and Individual Ruth L. Kirschstein National Research Service Awards, as well as NIH intramural research studies. The Policy applies to peer-reviewed, original research publications that have been supported in whole or in part with direct costs from NIH, but it does not apply to book chapters, editorials, reviews, or conference proceedings. Publications resulting from non-NIH-supported research projects should not be submitted.

For more information about the Policy or the submission process please visit the NIH Public Access Policy Web site at http://PublicAccess.nih.gov/ and view the Policy or other Resources and Tools including the Authors' Manual.

Standards for Privacy of Individually Identifiable Health Information:
The Department of Health and Human Services (DHHS) issued final modification to the "Standards for Privacy of Individually Identifiable Health Information", the "Privacy Rule", on August 14, 2002. The Privacy Rule is a federal regulation under the Health Insurance Portability and Accountability Act (HIPAA) of 1996 that governs the protection of individually identifiable health information, and is administered and enforced by the DHHS Office for Civil Rights (OCR).

Decisions about applicability and implementation of the Privacy Rule reside with the researcher and his/her institution. The OCR Website (http://www.hhs.gov/ocr/) provides information on the Privacy Rule, including a complete Regulation Text and a set of decision tools on "Am I a covered entity?" Information on the impact of the HIPAA Privacy Rule on NIH processes involving the review, funding, and progress monitoring of grants, cooperative agreements, and research contracts can be found at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-025.html.

URLs in NIH Grant Applications or Appendices:
All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in an NIH solicitation, Internet addresses (URLs) should not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites. Furthermore, we caution reviewers that their anonymity may be compromised when they directly access an Internet site.

Healthy People 2010:
The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS-led national activity for setting priority areas. This PA is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople.

Authority and Regulations:
This program is described in the Catalog of Federal Domestic Assistance at http://www.cfda.gov/ and is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

The PHS strongly encourages all grant recipients to provide a smoke-free workplace and discourage the use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care, or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.

Loan Repayment Programs:
NIH encourages applications for educational loan repayment from qualified health professionals who have made a commitment to pursue a research career involving clinical, pediatric, contraception, infertility, and health disparities related areas. The LRP is an important component of NIH's efforts to recruit and retain the next generation of researchers by providing the means for developing a research career unfettered by the burden of student loan debt. Note that an NIH grant is not required for eligibility and concurrent career award and LRP applications are encouraged. The periods of career award and LRP award may overlap providing the LRP recipient with the required commitment of time and effort, as LRP awardees must commit at least 50% of their time (at least 20 hours per week based on a 40 hour week) for two years to the research. For further information, please see: http://www.lrp.nih.gov.


Weekly TOC for this Announcement
NIH Funding Opportunities and Notices


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