RELEASE DATE:  September 29, 2003
RFA Number:  RFA-RM-04-002 (formerly RFA-DK-04-001, see NOT-OD-04-008)

Department of Health and Human Services (DHHS) 


National Institutes of Health (NIH)

This RFA is developed as a roadmap initiative. All NIH Institutes and 
Centers participate in roadmap initiatives.




o Purpose of this RFA
o Research Objectives
o Mechanisms 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 Supplementary Instructions
o Peer Review Process
o Review Criteria
o Receipt and Review Schedule
o Award Criteria
o Required Federal Citations


The Institutes and Centers of the National Institutes of Health invite 
applications for development and application of new technologies in 
metabolomics to enable research aimed at elucidating biological 
pathways and networks. The purpose of this initiative is to encourage 
the development of highly innovative and sensitive tools for 
identifying and quantifying cellular metabolites and their fluxes at 
high anatomical, spatial, and temporal resolution.

The general aim of metabolomics is to identify, measure and interpret 
the complex time-related concentration, activity and flux of endogenous 
metabolites in cells, tissues, and other biosamples such as blood, 
urine, and saliva.  For the purposes of this solicitation, metabolites 
include small molecules that are the products and intermediates of 
metabolism, but also carbohydrates, peptides, and lipids. The need for 
innovative technologies for measuring and quantifying metabolites 
involved in cellular pathways and networks was articulated in the 2003 
NIH Roadmapping Initiative.  It is expected that the technologies 
developed under this initiative will play a major role in transferring 
capabilities to laboratories and research institutes that are 
investigating the underlying pathways involved in cellular homeostasis, 
perturbation, development, and aging.

Many ongoing research programs focus on development of new genomics and 
proteomics tools and utilization of those approaches for studying 
cellular function.  In contrast, relatively few research programs focus 
on metabolomics technology development and application. This initiative 
is to encourage the development of highly innovative and sensitive 
tools for identifying and quantifying cellular metabolites and their 
fluxes at high anatomical resolution---extending to subcellular--- and 
at a temporal resolution that would be appropriate to understanding 
cellular processes at biologically relevant timescales. The scope of 
projects that would be appropriate ranges from techniques for improving 
and refining the process of sample separation and processing; to new 
methods, reagents or instrumentation for identifying and measuring 
metabolites and their fluxes; to the development and utilization of 
data reduction, management, and analysis tools needed to establish 
proof of principle for the technology. New technologies that, if 
successful, have the potential to be scalable, either as high-
throughput applications or as advances that would be used in a large 
number of laboratories, are especially encouraged.  While it is also 
important to develop data storage, data mining, and pathway modeling 
capabilities for metabolomics, these issues are explicitly not included 
in this particular solicitation.

Metabolomics presents unique challenges for sample collection and 
extraction and for determining analyte identity, concentration, 
structure, activity and flux in cells. The cellular metabolome is 
complex, involving several compound classes of small molecules 
(peptides, lipids, amino acids, carbohydrates) that vary in subunit 
concentration, size, structure, polarity, and functional groups.  
Technologies currently in use for metabolomic analysis include NMR, 
chromatography and mass spectrometry, each of which has significant 
limitations in quantification, scope, and/or throughput.  No one 
technology can effectively measure, identify and quantify, with 
sufficient sensitivity and precision, the diverse range of metabolites 
and their dynamic fluctuations in cells.  An integrated set of 
technologies is needed to address the entire spectrum of challenges for 
metabolomics. Ideally, new technologies should yield quantitative, 
comprehensive data and be applicable to achieving anatomical resolution 
at the cellular and subcellular level. 

This initiative seeks to encourage technology developments to address 
three interrelated components of metabolomics: (1) sample collection, 
extraction, recovery and validation for specific classes of 
metabolites; (2) analyte detection, identification, quantification, and 
structure elucidation; and (3) and data management, reduction and 
analysis. Specific areas of research emphasis include approaches to 
address the large dynamic range of metabolite concentration in 
biological samples, the complexity of metabolite mixtures, the inherent 
noise of the metabolite profile, the vast number of unidentified 
compounds present within single samples, and the rapidly changing 
temporal and spatial variability (flux) of the cell's metabolite 
complement.  It is imperative that new technology incorporate 
approaches for data management, reduction and analysis to support the 
technology development. This initiative encourages applications that 
seek to improve existing technologies, including scaling up to high 
throughput application, as well as those that seek to develop new 
approaches that have the potential for measuring entire cellular 
metabolomes or subsets (e.g., amino acid derivatives, peptide 
derivatives) whose analysis provides enabling technologies, including 
appropriate tools for data reduction and analysis. Applications will be 
evaluated for the potential of the proposed activities to address all 
three components of metabolomics that are listed above. However, it is 
anticipated that these components, collectively, might be too broad for 
a single application to address all three comprehensively. Accordingly, 
applications may focus on any of the components of metabolomics listed 
above and may propose single or multiple technologies. Investigators 
will be expected to clearly define the scope of their activities, and 
to justify why the specific type(s) of data that the technologies will 
address are likely to be important to understanding cellular pathways 
and networks. 

This initiative encourages applications involving multi-disciplinary 
teams representing self-assembled groups of collaborating 
investigators, at one or several sites, with specific expertise in 
metabolomics technology as well as data management and statistical 
approaches relevant to the proposed technology. Partnerships between 
academia and industry are encouraged, to facilitate technology transfer 
and capacity building at academic institutions.

This solicitation seeks to encourage highly innovative and potentially 
risky approaches. However, it is likely that some proposed technologies 
will be more mature, at the onset, than others. Accordingly, this RFA 
will use the NIH Phased Innovation (R21/R33) and 
Exploratory/Development Research Grant Phase 2 (R33) award mechanisms.  
Applicants may submit a combined R21/R33 application, or a stand-alone 
R33 application if technological feasibility can be documented at the 
time of submission. Applicants may request up to three years of 
funding, either using the R33 mechanism for the entire time, or via a 
phased format that begins as an R21 award and transitions to an R33 
award. The duration of the R21 phase may be either one year or two 
years.  A grant may be considered for renewal or supplementation after 
the three year period of support if it is obvious that a newly 
developed technology will have exceptionally high impact on the field, 
but additional time is required to optimize it. Applicants for a phased 
award cannot request more than $800,000 in direct costs per year of the 
R21 phase. Applicants may not request more than $1.5 million in direct 
costs per year of the R33 phase, or per year of the entire award if it 
is solely R33. It is emphasized that the figures above are a maximum. 
We envisage that a range of activities could be appropriate for this 
solicitation, from an individual well-focused goal, to a set of closely 
related or well-integrated technology development aims. 

The R21 award mechanism supports innovative, high-risk/high-impact 
research requiring preliminary testing or development; exploration of 
the use of approaches and concepts new to a specific substantive area; 
or research and development of new technologies, techniques, or 
methods. Applications will be considered high-impact if they 
demonstrate the potential for ground-breaking significance, and high-
risk because they either lack sufficient preliminary data to ensure 
their feasibility, or propose use of a new model or a unique system. 

Eligibility for transition to the R33 phase will be based on successful 
completion of the negotiated milestones, which must be specified in the 
application, and programmatic review. The objective of the R33 phase is 
continuation of innovative exploratory and developmental research 
initiated during the R21 mechanism. Research conducted in the R33 phase 
will focus on demonstrating proof of principle for application of the 
technology to elucidate functional components and interactions of 
metabolites within biological pathways and networks. While the intent 
of the R21 award is to encourage the development of highly innovative 
technologies, the potential for the proposed technology to advance our 
understanding of biological pathways and networks will be an important 
criterion for evaluating the R33 phase of an application or the entire 
application, if it is for a stand—alone R33 award.  Development of 
complex, integrated technologies for metabolomics problems will require 
a context within which methods development can proceed.  Accordingly, 
investigators should select a model system, defined at the cellular or 
subcellular level, to serve as a framework for demonstrating the 
technological capabilities of the resource. 


This RFA will use the NIH Phased Innovation (R21/R33) and 
Exploratory/Development Research Grant Phase 2 (R33) award mechanisms.  
As an applicant you will be solely responsible for planning, directing, 
and executing the proposed project.  This RFA is a one-time 
solicitation.  Future unsolicited, competing-continuation applications 
based on this project will compete with all investigator-initiated 
applications and will be reviewed according to the customary peer 
review procedures.  The anticipated award date is September 30, 2004. 
Applications that are not funded in the competition described in this 
RFA may be resubmitted as NEW investigator-initiated applications using 
the standard receipt dates for NEW applications described in the 
instructions to the PHS 398 application.

This RFA uses just-in-time concepts.  It also uses the non-modular 
budgeting format.  Please 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  

The participating ICs intend to commit approximately $7.4 million in FY 
2004 to fund 6 to 8 new grants in response to this RFA. An applicant 
may request a project period of 3 years and a budget for direct costs 
of up to $800,000 per year for the one or two year R21 phase, and up to 
$1.5 million per year for the R33 phase or for each year of a stand-
alone R33 award. Because the nature and scope of the proposed research 
will vary from application to application, it is anticipated that the 
size of each award will also vary. Although the financial plans of the 
ICs 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. 
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 Eligible agencies of the federal government
o Domestic or foreign institutions/organizations

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.  

Principal investigators, plus key personnel if appropriate, are 
expected to participate in an annual meeting of grantees.  The purpose 
of these meetings is to discuss scientific advances; the potential for 
collaborations, data and technology sharing; and other research 
opportunities.  Funds for travel to the meeting should be requested in 
the budget. 


We encourage inquiries concerning this RFA and welcome the opportunity 
to answer questions from potential applicants.  Inquiries may fall into 
two areas:  scientific/research and financial or grants management 

o Direct your questions about scientific/research issues to:

Maren R. Laughlin, Ph.D. 
Division of Diabetes, Endocrinology and Metabolism 
National Institute of Diabetes and Digestive and Kidney Diseases 
6707 Democracy Boulevard, Room 6101, MSC 5460 
Bethesda, MD  20892-5460 
Telephone:  (301) 594-8802         
FAX:  (301) 480-3503 

o Direct your questions about financial or grants management matters 

Ms. Kathleen Shino 
Grants Administration Branch 
Division of Extramural Activities 
National Institute of Diabetes and Digestive and Kidney Diseases 
6707 Democracy Boulevard, Room 708, MSC 5456 
Bethesda, MD  20892-5456 
Telephone:  (301) 594-8869 
FAX:  (301) 594-9523 
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:
Maren R. Laughlin, Ph.D. 
Division of Diabetes, Endocrinology and Metabolism 
National Institute of Diabetes and Digestive and Kidney Diseases 
6707 Democracy Boulevard, Room 6101, MSC 5460 
Bethesda, MD  20892-5460 
Telephone:  (301) 594-8802 
FAX:  (301) 480-3503 


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 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 in 
an interactive format.  For further assistance contact GrantsInfo, 
Telephone (301) 710-0267, Email:

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:
SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten 
original of the application, including the Checklist, and five 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)
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.  

Upon receipt, applications will be reviewed for completeness and 
responsiveness by the NIH). Incomplete and nonresponsive 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) 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 an appropriate National Advisory 
Council or Board 


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 an important problem? If the aims 
of the application are achieved, how will scientific knowledge be 
advanced? What will be the effect of these studies on the concepts or 
methods that drive this field?

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?

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 

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)?

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 item will be considered in the determination of scientific 
merit and the priority score, for applications utilizing the R21/R33 
phased innovation mechanism:

Milestones: How appropriate are the proposed milestones against which 
to evaluate the demonstration of feasibility for transition to the R33 
development phase?
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).
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).

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.  


Sharing Research Data

Applicants requesting more than $500,000 in direct costs in any year of 
the proposed research must include a data sharing plan in their 
application. 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 priority score. The 
NIH policy on data sharing, as well as guidance on this subject, can be 
found at

BUDGET:  The reasonableness of the proposed budget and the requested 
period of support in relation to the proposed research.


Letter of Intent Receipt Date:   February 24, 2004
Application Receipt Date:   March 24, 2004
Peer Review Date:   June/July 2004
Council Review:   September 2004
Earliest Anticipated Start Date:   September 30, 2004


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

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. 

SHARING RESEARCH DATA: Starting with the October 1, 2003 receipt date, 
investigators submitting an NIH application seeking more than $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.  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.

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, 

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

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

HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of 
research on hESCs can be found at and at  
Only research using hESC lines that are registered in the NIH Human 
Embryonic Stem Cell Registry will be eligible for Federal funding (see   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. 

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

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.

(if applicable) 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 
( 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

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 

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

AUTHORITY AND REGULATIONS: This program is described in the Catalog of 
Federal Domestic Assistance at 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)(cite appropriate authorizations) and 
under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92 (cite 
relevant regulations). 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 (also cite 
other relevant policies)

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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