NEAR-TERM TECHNOLOGY DEVELOPMENT FOR GENOME SEQUENCING RELEASE DATE: February 12, 2004 RFA Number: RFA-HG-04-002 (This RFA has been reissued, see RFA-HG-05-003) EXPIRATION DATE: October 15, 2004 Department of Health and Human Services (DHHS) PARTICIPATING ORGANIZATION: National Institutes of Health (NIH) (http://www.nih.gov) COMPONENT OF PARTICIPATING ORGANIZATION: National Human Genome Research Institute (NHGRI) (http://www.nhgri.nih.gov) CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER(S): 93.172 LETTER OF INTENT RECEIPT DATE: March 15, 2004, September 14, 2004 APPLICATION RECEIPT DATE: April 15, 2004, October 14, 2004 THIS RFA CONTAINS THE FOLLOWING INFORMATION o Purpose of this RFA o Research Objectives o Mechanism(s) of Support o Funds Available o Eligible Institutions o Individuals Eligible to Become Principal Investigators o Special Requirements o Where to Send Inquiries o Letter of Intent o Submitting an Application o Supplementary Instructions o Peer Review Process o Review Criteria o Receipt and Review Schedule o Award Criteria o Required Federal Citations PURPOSE OF THIS RFA The purpose of this Request for Applications (RFA) is to solicit 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 for genome-scale sequencing within five years. A parallel RFA HG-04-003 (http://grants.nih.gov/grants/guide/rfa-files/RFA-HG-04-003.html) solicits grant applications to develop technologies to meet the longer- term goal of achieving four-orders of magnitude cost reduction in about ten years. RESEARCH OBJECTIVES 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. o Expanded comparative genomic analysis across species, which will yield great insights into the structure and function of the human genome and, consequently, the genetics of human health and disease. Studies to date that have been able to compare small regions of several genomes, and draft versions of full genomes, have clearly demonstrated the need for much more complete data sets. While some of the needed data will be obtained over the next two or three years using existing DNA sequencing technology, and while costs will continue their gradual decline, the cost of current approaches to sequence acquisition will continue to limit the amount of useful data that can be produced. o Studies of human genetic variation and the application of such information to individual health care, which will also require much cheaper sequencing technology. Today, genetic variation must be assessed by genotyping the relatively few known differences at a relatively small number of loci within the human population. A richer and better characterized catalog of such variable sites is being generated to support more detailed and powerful analyses. While these methods are, and will become even more, powerful and likely to provide a significant amount of important new information, they are nevertheless only a surrogate for determining the full, contiguous sequence of individual human genomes, and are not as informative as sequencing would be. For example, current genotyping methods are likely to miss rare differences between people at any particular location in the genome and have limited ability to determine long-range information (e.g., genomic rearrangements). Therefore, new methods based on complete genomic sequencing will be needed to use genomic information for individual health care in the most effective manner possible. o While the genomes of a few agriculturally important animals and plants have been sequenced, the most informative studies will require comparisons between different individuals, different domesticated breeds and several wild variants of each species. o Sequence analysis of microbial communities, many members of which cannot be cultured, would provide a rich source of medically and environmentally useful information. And accurate, rapid sequencing may also be the best approach to microbial monitoring of food and the environment, including rapid detection and mitigation of bioterrorism threats. Given the broad utility and high importance of dramatically reducing DNA sequencing costs, NHGRI is launching two parallel technology development programs. The first, described in this RFA, 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 (see accompanying RFA HG-04-003) 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 this program 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 pharmacogenomics, and for comparative genomics between closely-related organisms. Therefore, both programs objectives include a balanced portfolio of projects developing both de novo and re-sequencing technologies. Sequencing strategy and quality State-of-the-art technology (i.e., 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 (millions) of randomly-overlapping thousand-base reads and align them by 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 read information. 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 program is to develop technology for producing automatically generated sequence of at least the quality of the mouse draft genome sequence that was published in December 2002 (Nature 420:520, 2002). Emerging technologies, collectively characterized as sequencing-by- synthesis or sequencing-by-extension, may be able to achieve large numbers of sequence reads by extending very large numbers of different DNA templates simultaneously, but generally only for a few tens of bases as currently practiced. Even if it is possible to extend these reads to several hundred bases, it will still be necessary to link those reads to achieve long-range sequence contiguity. For some purposes, long-range sequence contiguity may not be required. For example, the re-sequencing of genomes (determination of the DNA sequence for many individuals of a species after a reference sequence for that species has been determined), such as might be used for medical diagnostic purposes, could be achieved by aligning individual reads on the reference sequence. However, short reads, particularly ones with lower per-base quality, can be very difficult to align given the nature of repetitive DNA and of closely-related gene families in complex genomes. Also, chromosomal rearrangements may be difficult to detect without high quality sequence information bridging the breakpoints with enough sequence to know in which repeat the breakpoint lies. The determination of single nucleotide polymorphisms (SNPs) and their phase (for haplotypes) also requires contiguity of varying length. The ultimate goal and a high priority for the NHGRI’s sequencing technology development efforts, as exemplified in these two RFAs, continues to be de novo, assembled sequence. However, because of the value of re-sequencing for many future purposes, these RFAs also solicit the development of very inexpensive technology for very high quality re-sequencing (without assembly). Technology path Most investigators interested in reducing DNA sequencing costs anticipate that a few additional two-fold decreases in cost can yet 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 that are not only substantially more efficient but also more usable by the average research laboratory are needed. 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 actual process and process control onto the device, are being conducted in several laboratories. Attendant improvements in separation polymers and in 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 or of electrophoretic separation of the termination products. Two methods that were proposed in the early days of the HGP 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 stepwise and each 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; the cycle is then repeated. Modifications of this approach rely on other types of enzymes and detection of hybridization of labeled oligonucleotides. To obtain sufficient throughput, the method is implemented at a high level of multiplexing, e.g., by arraying large numbers of sequencing extension reactions on a surface. A key factor in this general approach is 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 labeled nucleotide analogues; identification of processive polymerases that can incorporate nucleotide analogs with high fidelity; discrimination of fluorescent nucleotides that have been incorporated into the growing chain from those present in the reaction mix (background); distinction of subsequent nucleotide additions from previous ones; accurate enumeration of homopolymer runs (multiple sequential occurrence of the same nucleotide); maintenance of 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 development of fluidics, surface chemistry, and automation to build and run the system. Current efforts to develop such methods have produced, at best, short sequence reads (less than or equal to 100 bases), so a continuing challenge is to extend read length and develop sequence assembly strategies. NHGRI anticipates that the state of the art for this approach is sufficiently advanced that, with additional investment, it may be possible to achieve proof of principle or even early commercialization 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. Developing technology with which to reduce the cost of genome sequencing by 100-fold is the subject of this RFA. A second alternative to CAE sequencing seeks to read out the linear sequence of nucleotides without copying the DNA and without incorporating labels, relying instead on extraction of signal from the native DNA nucleotides themselves. The most 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 anticipates that the science and technology needed to reduce sequencing costs by four orders of magnitude, whether by the nanopore or some other approach, will require substantial basic research and development, and may take as long as ten years to achieve. Reaching this goal is the subject of a parallel RFA, HG-04-003 (http://grants.nih.gov/grants/guide/rfa-files/RFA-HG-04-003.html). RESEARCH SCOPE The goal of research supported under this RFA is to develop or improve 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 research programs responding to this RFA will involve 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. Although the ultimate goal of this RFA is to develop full-scale sequencing systems, independent research on essential components will also be considered to be responsive. However, it will be important for applicants proposing research on system components or concepts to 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 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; knowledge of rearrangement 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 will 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 $1000, 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). 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 that achieving the goal of 100-fold reduction in cost for genome sequencing incorporating substantial assembly information will require about 5 years to achieve is correct, then 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 is on the development of new technologies for detection of nucleotide sequence. However, any new technology will eventually have to be effectively incorporated 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. Given that sample preparation requirements are a function of the detection method and the sample detection method affects the way in which output data are handled, these aspects of the problem are clearly relevant and should be addressed in an appropriate timeframe. However, NHGRI is interested in seeing that the most critical and highest-risk aspects of the project, on which the rest of the project is dependent, are addressed and proven as early as possible. NHGRI anticipates that successful projects funded through this RFA may be sufficiently advanced as to be approaching early stages of commercialization within about five years. Therefore, practical implementation issues related to workflow and process control for efficient, high quality, high-throughput DNA sequencing should be considered early. 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 gene regions) could be determined in the near future, using more conventional technologies, at very low cost. However, that is not the purpose of this initiative, and grant applications that propose to meet the cost targets by sequencing only selected regions of a genome will be considered unresponsive. MECHANISM OF SUPPORT This RFA will use NIH R21, R21/R33, R01 and P01 award mechanism(s). As an applicant you will be solely responsible for planning, directing, and executing the proposed project. Applicants may request an R01 or P01 (depending on the organization of the proposed project) if sufficient preliminary data are available to support such an application. A fully integrated management and research plan should use the R01 mechanism. The P01 mechanism should be used if multiple projects under different leadership must proceed in parallel; however, the issue of synergy in a multi-focal effort is of great importance and must be addressed in the application. Applicants requiring support to demonstrate feasibility may apply for either an R21 pilot/exploratory project or an R21/R33 award, which offers single submission and evaluation of both a feasibility/pilot phase (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 a 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. This RFA uses just-in-time concepts. It also uses the modular budgeting as well as the non-modular budgeting formats (see http://grants.nih.gov/grants/funding/modular/modular.htm). Specifically, if you are submitting an application with direct costs in each year of $250,000 or less, use the modular budget format. Otherwise follow the instructions for non-modular budget research grant applications. This program does not require cost sharing as defined in the current NIH Grants Policy Statement at http://grants.nih.gov/grants/policy/nihgps_2001/part_i_1.htm. However, cost-sharing is permitted as a component of institutional commitment. FUNDS AVAILABLE The NHGRI intends to commit approximately $8 million in FY 2004 to fund 4 to 10 new and/or competitive continuation grants in response to this RFA, and an additional $5 million in FY 2005. For the R21 mechanism, an applicant may request a project period of up to 2 years and a budget of up to $200,000 direct costs per year. For R21/R33 applications, the total project period may not exceed 3 years, distributed as required for the project; the R21 phase may request a budget up to $200,000 direct cost and the R33 phase up to $2 million direct cost per year. For R01 and P01 mechanisms, an applicant may request a project period of up to 3 years and a budget of up to $2 million direct cost per year. Budgets may exceed this guidance only to accommodate indirect costs to subcontracts. Applicants should be aware that NHGRI intends to fund as many promising projects, of varying scope, as possible in order to pursue multiple approaches to solving these difficult problems and mitigate risk. Therefore, awards may not be made at the maximum budget level. Instead, the nature and scope of the proposed research will vary, and it is anticipated that the size and duration of awards will also vary. Although the financial plans of NHGRI provide support for this program, awards pursuant to this RFA are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications. ELIGIBLE INSTITUTIONS You may submit (an) application(s) if your institution has any of the following characteristics: o For-profit or non-profit organizations o Public or private institutions, such as universities, colleges, hospitals, and laboratories o Units of State and local governments o Eligible agencies of the Federal government o Domestic or foreign institutions/organizations INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS Any individual with the skills, knowledge, and resources necessary to carry out the proposed research is invited to work with his/her 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. SPECIAL REQUIREMENTS NHGRI anticipates that the development of technologies needed to meet these goals will require approximately five years. Therefore, a timeline for 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. The applicant must also present a much more detailed timeline for the initial grant period, which may vary from 1 year to 3 years. This detailed timeline should be accompanied by quantitative milestones (see below) that address the key scientific and technical challenges central to the approach under investigation. The timeline and milestones will be essential for use by both the grantee and 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 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. NHGRI appreciates that these projects will require research, not just engineering; progress toward milestones will be evaluated accordingly. However, 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. In all cases, prior to funding an application, NHGRI will negotiate the milestones with the applicant, incorporating recommendations from the review panel and the National Advisory Council for Human Genome Research. 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, for a total of up to five years, 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 is dependent upon completion of negotiated milestones. Once these milestones have been achieved, the investigator will submit a progress report to NHGRI. Receipt of this report will trigger a review to determine if the R33 should be awarded. The release of R33 funds will be based on successful completion of negotiated milestones, negotiation of revised milestones for the R33 phase, program priorities, and availability of funds. Applicants must plan to submit progress reports twice per year once at the time of the non-competing continuation and once at a time to be determined by NHGRI staff. The latter may coincide with grantee meetings or meetings of advisors to NHGRI. NHGRI will use information from reports, 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. It is anticipated that five years will be required to achieve the goals of this program. Progress during the first two years will be assessed by NHGRI and its advisors, and P.I.s and their team leaders will receive advice about the NHGRI’s interest in accepting a competing application to extend the initial award. 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. Applicants should request travel funds in their budgets for the principal investigator and two additional lead investigators to attend the annual meeting. Grantees will be asked to host the annual grantee meetings on a rotating basis. At the time of award, 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. 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, because of the conflicts of interest this may produce 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. Applicants should describe any institutional commitment being offered to the 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 SUPPLEMENTARY INSTRUCTIONS). WHERE TO SEND INQUIRIES We encourage inquiries concerning this RFA 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: o Direct your questions about scientific/research issues to: Jeffery A. Schloss, Ph.D. Division of Extramural Research National Human Genome Research Institute Building 31, Room B2B07 Bethesda, MD 20892-2033 Telephone: (301) 496-7531 FAX: (301) 480-2770 Email: jeff_Schloss@nih.gov o Direct your questions about peer review issues to: Ken Nakamura, Ph.D. Scientific Review Branch National Human Genome Research Institute Building 31, Room B2B37 31 Center Drive, MSC 2032 Bethesda, MD 20892-2032 Telephone: (301) 402-0838 FAX: (301) 435-1580 Email: nakamurk@exchange.nih.gov o Direct your questions about financial or grants management matters to: Jean Cahill Grants Administration Branch National Human Genome Research Institute Building 31, Room B2B34 31 Center Drive Bethesda, MD 20892-2031 Telephone: (301) 402-0733 FAX: (301) 402-1951 Email: jc166o@nih.gov LETTER OF INTENT Prospective applicants are asked to submit a letter of intent that includes the following information: o Descriptive title of the proposed research o Name, address, and telephone number of the Principal Investigator o Names of other key personnel o Participating institutions o Number and title of this RFA 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 IC staff to estimate the potential review workload and plan the review. The letter of intent is to be sent by the date listed at the beginning of this document. The letter of intent should be sent to: Jeffery A. Schloss, Ph.D. Division of Extramural Research National Human Genome Research Institute Building 31, Room B2B07 31 Center Drive Bethesda, MD 20892-2033 Telephone: (301) 496-7531 FAX: (301) 480-2770 Email: jeff_Schloss@nih.gov SUBMITTING AN APPLICATION Applications must be prepared using the PHS 398 research grant application instructions and forms (rev. 5/2001). 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. The DUNS number can be obtained by calling (866) 705-5711 or through the web site at http://www.dunandbradstreet.com/. The DUNS number should be entered on line 11 of the face page of the PHS 398 form. The PHS 398 document is available at http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. For further assistance contact GrantsInfo, Telephone (301) 710-0267, Email: GrantsInfo@nih.gov. SUPPLEMENTARY INSTRUCTIONS: 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: All mechanisms: Research to meet the goals of this program is anticipated to require about five years. All applications that propose long-term projects should present an outline plan to achieve the overall goal in that time. The research plan must be well developed for all years for which a budget is requested and should include a well laid out research plan, a description of the level of risk of key technical challenges, alternative approaches, go/no-go decision points, etc. Using this approach, it should be possible to prepare well- justified plans in succinct text that complies with the following page limits. 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, then the R21 milestones, and then sections a and d (but not b and c) for the R33 phase (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 phase, 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 be longer than 15 pages, with the remainder available for the milestones and the a and d sections for the R33 phase. R01: Sections a-d are not to exceed 35 pages. Up to three additional pages explicitly labeled Management Plan and inserted between sections d and e should describe all aspects of project management, incorporating, e.g., how multiple investigators/disciplinary approaches will be coordinated, coordination between distant sites, decision- making processes, use of progress toward milestones as inputs to decision-making, etc. P01: The combined sections a-d for all of the projects and cores are not to exceed 35 pages so that P01, R01 and R21/R33 applicants will be on an even playing field for describing their research progress and plans. P01 applicants may refer to background and significance sections of one subproject in the text for other projects, to save space. Up to three additional pages explicitly labeled Management Plan and inserted at the beginning of the Experimental Design section should describe all aspects of project management, incorporating, e.g., how multiple investigators/disciplinary approaches will be coordinated, coordination between distant sites, decision-making processes, use of progress toward milestones as inputs to decision-making, etc. For P01 applications, separate budgets should be provided for each project, preceded by a composite budget for the entire grant. USING THE RFA LABEL: The RFA label available in the PHS 398 (rev. 5/2001) application form 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. SENDING AN APPLICATION TO THE NIH: 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 Bethesda, MD 20817 (for express/courier service) 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 Building 31, Room B2B37 31 Center Drive, MSC 2032 Bethesda, MD 20892-2032 Telephone: (301) 402-0838 Email: nakamurk@exchange.nih.gov APPLICATION PROCESSING: Applications must be received on or before the application receipt date listed in the heading of this RFA. If an application is received after that date, it will be returned to the applicant without review. Although there is no immediate acknowledgement of the receipt of an application, applicants are generally notified of the review and funding assignment within 8 weeks. The Center for Scientific Review (CSR) will not accept any application in response to this RFA 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 an RFA, it is to be prepared as a NEW application. That is, the application for the RFA 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. PEER REVIEW PROCESS Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by the NHGRI. Incomplete applications will not be reviewed. 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: o Undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of the applications under review, will be discussed and assigned a priority score o Receive a written critique o Receive a second level review by the National Advisory Council for Human Genome Research. REVIEW CRITERIA The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. In the written comments, reviewers will be asked to evaluate the application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. The scientific review group will address and consider each of the following criteria in assigning the application’s overall score, weighting them as appropriate for each application. o Significance o Approach o Innovation o Investigator o Environment The 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 the problem outlined in the RFA, the development of technology that has the potential to reduce the cost of sequencing a complete genome by two orders of magnitude? APPROACH: Are the conceptual framework, design, methods, and analyses adequately developed, well-integrated, 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 incorporate assessment of sequence quality and address 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 accurate? INNOVATION: Does the project employ novel concepts, approaches or methods? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? INVESTIGATOR: Is the investigator 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 (if any)? Do the P.I. 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 experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, the following items will be considered in the determination of scientific merit and the priority score: o Are the plans sufficiently bold to constitute a substantial advance, if they can be achieved, toward the demanding goals of the RFA? Are the bold plans counterbalanced to manage the inherent risk, for example by firm theoretical basis, reasonable preliminary data, the track record of the lead investigators, and an outstanding scientific and management plan? o Are the timeline and milestones logical and realistic? Do they identify key technology barriers and dependencies? Are they adequately developed and quantitative, to serve as effective guidance for assessment of progress by the investigators and the NHGRI? o Are plans to participate actively and openly in grantee meetings sufficiently clear and forthcoming so as to contribute substantially to advancement of the field? o Is the plan for technology dissemination appropriate and adequate? 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 criteria included in the section on Federal Citations, below). 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. Plans for the recruitment and retention of subjects will also be evaluated. (See Inclusion Criteria in the sections on Federal Citations, below). 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 398 research grant application instructions (rev. 5/2001) will be assessed. ADDITIONAL REVIEW CONSIDERATIONS: BUDGET: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. RECEIPT AND REVIEW SCHEDULE Letter of Intent Receipt Date: March 15, 2004, September 14, 2004 Application Receipt Date: April 15, 2004, October 14, 2004 Peer Review Date: June-July, 2004, Feb-March, 2005 Council Review: September 2004, May 2005 Earliest Anticipated Start Date: September 30, 2004, June 1, 2005 AWARD CRITERIA Award criteria that will be used to make award decisions include: o Scientific merit (as determined by peer review) o Availability of funds o Programmatic priorities, including maximizing the possibility for successfully achieving the goal of substantial reduction in the cost of genomic DNA sequencing. REQUIRED FEDERAL CITATIONS 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 SHARING RESEARCH DATA: Starting with the October 1, 2003 receipt date, 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, 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 the scientific merit or the priority score. 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 - Amended, October, 2001," published in the NIH Guide for Grants and Contracts on October 9, 2001 (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); a complete copy of the updated Guidelines are 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 new PHS Form 398; 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 RESEARCH INVOLVING HUMAN SUBJECTS: The NIH maintains a policy that children (i.e., individuals under the age of 21) must be included in all human subjects research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them. This policy applies to all initial (Type 1) applications submitted for receipt dates after October 1, 1998. 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 that is available at 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 proposals for research involving human subjects. You will find this policy announcement in the NIH Guide for Grants and Contracts Announcement, dated June 5, 2000, 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 (see 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. PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT: The Office of Management and Budget (OMB) Circular A-110 has been revised to provide public 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 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 PA 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. 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). Those who must comply with the Privacy Rule (classified under the Rule as covered entities ) must do so by April 14, 2003 (with the exception of small health plans which have an extra year to comply). 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 RFA is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.healthypeople.gov/. AUTHORITY AND REGULATIONS: This program is described in the Catalog of Federal Domestic Assistance at http://www.cfda.gov/ (No. 93.172) 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 NIH Grants Policy Statement can be found at http://grants.nih.gov/grants/policy/policy.htm. 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.

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