1. Writing The New NIH Grant 2010
A Systematic Approach
©Christopher Dant
Department of Immunology/Microbiology

2. Grantsmanship
There is no grantsmanship that will turn a bad idea into a good one…
but there are many ways to disguise a good one!
-William Raub, Past Deputy Director, NIH 

3. This Class Introduction The NEW Research Strategy 2010
Organization, aesthetics, writing

4. “Show Me The Money!”
DO NOT write the application for yourself unless you are going to fund it yourself
Write the application to satisfy the research priorities of the funding Institute

5. Research Priorities

6. NIH 5 Review Criteria
Significance: relevance to human health and disease
Innovation: originality of approach
Approach: feasibility of your methods and appropriateness of the budget
Investigator: PI training and experience
Environment: suitability of facilities and adequacy of support from your institution
EACH receive a score from 1 (exceptional) to 9 (poor)

7. Review Criteria Alignment
Core Review Criteria
New Application
Significance
Research strategy
a. Significance
Investigators
Biosketch
Personal Statement
Innovation
b. Innovation
Approach
c. Approach
Environment
Resources

8. NIH 5 Review Criteria
Each criteria addressed and considered in assigning overall score, weighting them as appropriate for each application
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, PI may propose important work that is not innovative but is essential to move the field forward

9. Research Plan Research Strategy
Align structure/content of application with review criteria
Shorten to facilitate peer review

10. Biographical Sketch Changes
Personal Statement: Tell us why your experience and qualifications make you particularly well-suited for your role in the project
Publications: Keep to 15
5 most recent
5 best
5 most relevant to application
Page limit remains at 4

11. Biosketch Personal Statement
Briefly state your role in this grant
Experience—educational background and training addressing why you are suited for this research (job interview)
How do you fit into the team?
The current application builds logically on my prior work, and I have chosen
co-investigators (Drs. A and B) who provide additional expertise in X, Y, Z.

12. Biosketch Personal Statement
This is place you get scored for Principal Investigator, including
Background
Grants and publications you produced relevant to proposal
Your track record
Overall training and experience
Each grant has a different personal statement
See example at end of this presentation

13. Other SF424 Information Project Summary/Abstract Project Narrative
Project Summary – succinct and accurate description of the proposed work
Informative to other persons working in the same/related field and for scientifically/technically literate reader
No longer than 30 lines of text
Project Narrative
This is the second component of the “abstract” that defines the “relevance”
Using no more than 2-3 sentences, describe the relevance of this research to public health
Use plain language understood by the general public

14. Research Plan Restructure
Current Research Plan
Restructured Research Plan
1. Introduction to Application
2. Specific Aims
3. Background and Significance
3. Research Strategy
Significance
Innovation
Approach (incl. Preliminary Studies)
4. Preliminary Studies/Progress Report
5. Research Design and Methods
6-12
4-10 (renumbered)
13. Select Agent Research
11. Select Agent Research (Modified)
14-17
12-15 (renumbered)

15. Page Limits
Page limit for new Research Strategy will be 6 or 12 pages (+1 page for Specific Aims)
Follow FOA page limit instructions (some may differ)
Content reduced by ~50%
Current Page Limit
New Page Limit
<25 pages (e.g., R03, R21)
6 pages
25 pages (e.g., R01)
12 pages
≥25 pages
Follow FOA Instructions

16. What do I intend to accomplish and why is it worth funding?
2. Specific Aims
What do I intend to accomplish and why is it worth funding?

17. 2. Specific Aims NIH Requirement
State concisely the goals of the proposed research and summarize the expected outcome(s), including the impact that the results of the proposed research will exert on the research field(s) involved.
List succinctly the specific objectives of the research proposed, e.g.
test a stated hypothesis
create a novel design
solve a specific problem
challenge an existing paradigm or clinical practice
address a critical barrier to progress in the field, or
develop new technology

18. 2. Specific Aims The Problem Gaps in Knowledge
Proposed Hypothesis/Solution
Specific Aims
Impact: How research fills gap

19. 2. Specific Aims: Structure
FIRST paragraph– Define the problem/critical need and gap(s) in knowledge—short background leading up to the stated problem and knowledge gap
Proposed solution to problem and gap by proposing hypothesis(es)
Specific Aims –Objectives that test the hypotheses addressing the critical need
e.g., to develop, determine, identify…
Avoid vague aims, e.g., “to explore”
Expected Outcomes leading to impact on the field
Impact – probability your study will be successful and will exert a powerful sustained influence on the field (derived from significance and innovation)
If it won’t work, it has no impact, even with high significance
Address the immediate problem AND your long-term goals

20. 2. Specific Aims State your hypothesis clearly
Understandable
Testable
Specific
Are your aims obtainable within the stated timeframe?
Focus your research
Focus aims in areas for which you have strong supporting data
Aims should be related and cohesive

21. Specific Aims Dissected
The Problem Colon cancer is a fatal disease if not detected early. Current medical practice in the US is screening colonoscopies for all over age 50, but colonoscopies are expensive and invasive. Screening for occult blood in stool is inexpensive but ineffective, and many cancers are missed. A blood test that could accurately detect colon cancer very early would save lives.
Gaps in Knowledge Current approaches for measuring proteins in blood are relatively insensitive, and unlikely to detect cancers early enough. Human variability and low signal means many independent patient samples must be measured.

22. Specific Aims Dissected
The Solution New proteomic technologies developed by my group offer both the sensitivity and throughput needed to identify and validate blood biomarkers for early detection of colon cancer.
Hypothesis We hypothesize that colon cancers can be more effectively detected using sensitive blood biomarkers.

23. Specific Aims Dissected
Action Plan
Specific Aim 1: Identification of plasma proteins associated with early stages of colon cancer using novel mass spectrometric approaches that provide absolute protein abundance measurements down to pg/ml levels. These measurements will be applied to a unique cohort of colon cancer patients available from clinical collaborators
Specific Aim 2: Bioinformatic analysis of over-represented proteins for enrichment of specific functions using a variety of software tools including KEGG, BIND, and MetaCor
Specific Aim 3: Selection and Validation of candidate biomarkers
Candidate biomarkers selected on the basis of functions known to be associated with carcinogenesis will be verified by orthogonal approaches. The top ten ten verified candidates will be assessed in 1000 prospectively collected plasma samples from early stage colon cancer patients, using a novel high throughput proteomics approach

24. Specific Aims Dissected
Expected Outcomes and Impact
The end product of this research will be an affordable accurate blood test for early detection of colon cancer without colonoscopy. Our approach will use many previously successful methods (preliminary studies) to increase the probably of success in this proposal.
Successful demonstration of this approach in colon cancer will enable application to other cancers in need of early detection biomarkers. Future directions of this research also include the application of a systems biology approach to the large datasets generated in the discovery phase that will provide new insights about the earliest stages of colon cancer.

25. 2. Specific Aims Common Errors
Lack of original or innovative ideas
Unrealistic or unfocused
Are the aims specific and focused?
If there are risks, justify why it’s important to pursue and how knowledge would move the field if the aim was not met
Poorly justified
Relationship of aims to what’s known and what’s unknown should be obvious
Purely descriptive, not hypothesis-driven
“This proposal looks more like a collection of experiments in which the applicants are simply listing experiments according to their expertise in specific techniques instead of testing an underlying hypothesis”
“Our enthusiasm was dampened by lack of a hypothesis driven by a specific mechanism.”

26. 2. Specific Aims Common Errors
Lack of cohesiveness
Must be thematically related and form a cohesive unit
Think of a central hypothesis unifying aims
Excessive interdependence of aims for success
Aim 2 to study novel monoclonal antibodies in animal disease model should not depend on Aim 1 to generate those antibodies

27. 2. Specific Aims Common Errors
Describing techniques
Do not provide details of methods in Aims
Overly ambitious
2-4 Aims (R01), 1-2 Aims (R03,R21)
Gives impression proposal is unfocused or you have not thought the proposal through
No significant impact (even if aims achieved) on the field

28. Most reviewers make up their minds after reading this page
2. Specific Aims
Most reviewers make up their minds after reading this page
Then they read the rest of the proposal looking for support of their opinion

29. Research Plan Restructure
Current Research Plan
Restructured Research Plan
1. Introduction to Application
2. Specific Aims
3. Background and Significance
3. Research Strategy
Significance
Innovation
Approach (incl. Preliminary Studies)
4. Preliminary Studies/Progress Report
5. Research Design and Methods
6-12
4-10 (renumbered)
13. Select Agent Research
11. Select Agent Research (Modified)
14-17
12-15 (renumbered)

30. Why is this work important?
Significance
Why is this work important?

31. Significance: NIH Requirement
Explain the importance of the problem or critical barrier to progress in the field that the proposed project addresses.
Explain how the proposed project will improve scientific knowledge, technical capability, and/or clinical practice in one or more broad fields.
Describe how the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field will be changed if the proposed aims are achieved.

32. Significance Recommendations
Make a compelling case—why is this research important for the field (broadly and more specifically)?
Review of published/unpublished work (incl. your own)
Point out how your research will fill knowledge gaps
Show that you are aware of the opportunities, gaps, roadblocks, and research being done
If possible, tie significance to the mission of the NIH institute — what are their research priorities?
Check institute website for research priorities
Check institute PAs/RFAs objectives

33. Significance Common Errors
Too diffuse and long
Showcasing comprehensive and exhaustive background
This should be ~0.5-1 page focused on addressing the NIH requirements for significance
Significance not related to stated problem and aims
If you follow your Specific Aims, you will keep the reviewer (and yourself) focused

34. Significance Common Errors
Equating significance with illness
Don’t argue that a particular disease is significant
Significance is what you will do to treat the disease
Low impact research
‘Incremental changes’
‘Confirmatory research—duplicative’

35. Innovation
How is this work novel?

36. Innovation NIH Requirement
Explain how the application challenges and seeks to shift current research or clinical practice paradigms.
Describe any novel theoretical concepts, approaches or methodologies, instrumentation or intervention(s) to be developed or used, and any advantage over existing methodologies, instrumentation or intervention(s).
Explain any refinements, improvements, or new applications of theoretical concepts, approaches or methodologies, instrumentation or interventions.
Understand what innovation means for an NIH grant application and what the reviewers are looking for

37. What is Innovation?
Research does not necessarily have to create a new paradigm
To be innovative it can
Shift a current paradigm
Offer new combination of known methods leading to new perspective
Refine existing model, technology

38. Innovation Balance
It’s less risky to use an innovative approach to solve an existing problem than to take on a problem that’s highly innovative
It can be harder to gain acceptance if your ideas are clearly outside the mainstream, especially if you are less experienced
If your proposal is highly innovative, you'll need to make a strong case for why you are challenging the existing paradigm and have data to support your innovative approach
But because innovation is a review criterion, you want to show how you will break new ground

39. What have I already found? AND How will I accomplish my Specific Aims
Approach
What have I already found?
AND
How will I accomplish my
Specific Aims

40. Preliminary Studies/Progress Report
Not separate sections as before
Each woven into Approach by Aim
For NEW applications for each Specific Aim, describe not only your research approach but what preliminary studies you have to support that aim
For COMPETING renewals, describe:
Progress you have made toward each aim and the approach you will use
Significant changes to the aims and new directions

41. Approach NIH Requirement
Describe the overall strategy, methodology, and analyses to be used to accomplish the specific aims of the project.
How will data be collected, analyzed, and interpreted as well as any resource sharing plans as appropriate?
Discuss potential problems, alternative strategies, and benchmarks for success anticipated to achieve the aims.
If the project is in the early stages of development, describe any strategy to establish feasibility, and address the management of any high-risk aspects of the proposed work.

42. Approach Organization
Preliminary Studies/Progress Report
Study design/study strategy
Experimental approach
Experiments to address each SA
Emphasize
Unique methods but abbreviate standard methods, especially if used in “Preliminary Studies”
Methods not previously used — collaborators
Use tables and figures to illustrate complex experiments with multiple arms or repetitions under different conditions
Interpretation of results
Even if your experiment is well designed, its interpretation is vital to the reviewer
Link the interpretation to your proposed SA and hypothesis

43. Approach Organization

44. Approach Organization
Potential Pitfalls and Alternative Approach
Roadblocks to your experimental approach and how you would adjust the approach to move forward
Failure to see weak points gives reviewers impression your approach is careless and less likely to succeed
For early-stage PI, strategy to establish feasibility with methods
A new investigator is given leeway with some aspects of the grant, such as preliminary data, but NOT with approach, anticipated results, and lack of plans for possible problems

45. Approach Organization
Future Directions
Discuss what’s likely not feasible for this grant period, and what future studies will focus on
Milestones and Timeline
By each aim, provide quantitative benchmarks for assessing your progress over the grant years

46. Approach Common Errors
Excessive detail on approaches or inconsistency in detail
Level of detail proportional to the novelty of the method
Standard techniques should not have detail — reference or show in preliminary studies
Feasibility of each aim not shown
Listing your experiments without tying them to the SAs will kill your grant

47. Approach Common Errors
Lack of “pitfalls and alternative approaches”
Being able to propose alternative approaches to your aims if your plan fails, or provide new directions if your hypotheses need revision, score big with reviewers
Overly ambitious in scope
This is a blueprint for your work, not a wish list for experiments that you think impressive
If the studies are not achievable in the timeframe of the grant, this may become future work

48. Approach Common Errors
Lack of a section “Interpretation of Results”
Meaning of the results is not always clear to reviewers
Demonstrates your capacity to
predict the results
consider alternative results
refine your hypothesis
adjust the plan
assess the impact of the data
Lack of clear logistical organization and plan for the grant period
Provide a timeline for completing the aims

49. Approach Common Errors
Your experimental approach is not hypothesis-driven
“Fishing expedition” without clear goals
Focus and prioritize experiments around your aims/hypothesis
Excessive dependence of experimental plans
Aims that depend on one other for success are susceptible to criticism
Interdependence of thematically related aims is necessary, but the experiments and aims should be diverse enough to assure some level of success

50. Approach Quantitative Milestones
Quantitative benchmarks for comprehensively assessing the annual progress of the projects-- not be simply a restatement of the specific aims.
Timeline and a “pathway” for the development of the proposed technology.
Examples:
-Detect one cancer cell in 106 normal blood cells.
-Increase the therapeutic index of an agent >3-fold by nanoparticle-based therapeutic solution relative to the non-nanoparticle bound agent.
-Achieve >95% selectivity in targeting mixed cell populations in vitro.

51. Approach
Summarize how these studies and this design will answer each of your aims
Include milestones and timeline

52. Approach

53. How to Write a Shorter Application
Outline the application
Focus on strategy rather than experimental details
Use graphics to convey complex info in a small space
Do not decrease fonts, margins, white space
More time to write shorter—thoughtful revising necessary
Reduce redundancies—outline
Use active voice and write short, direct sentences
Read long sections aloud
Give to an editor
You cannot edit a 25/12-page document to 12/6

54. Your Overall Score
Why is my research important (significant) to health/disease?
Plus
Can I do it…and qualified to do it?
And
Will it have significant impact on the field?

55. Organization
Aesthetics
Writing

56. An NIH Grant Reviewer’s Views
“…psychological mechanisms came into play…once I lost patience with an applicant for writing a disorganized section, I was much more likely to notice other faults in the proposal. Also, when a proposal was sloppy, it was difficult not to extrapolate that the applicant’s labwork was sloppy as well.”
“At the other extreme, the easier the applicant made it for me to get the information necessary to assess the application, the more likely I was—if the science was sound—to have a positive feeling about the proposal.”

57. A Grant Reviewer’s Views
“In >20 years of reviewing, during which time I have seen >1000 R01s, the most common shortcoming I have seen has been poor writing…”
Bernard L. Trumpower, PhD Dartmouth Biochemist

58. Follow an Outline
Consider the grant as a unit to establish a logical progression from Specific Aims through Approach
Eliminates disorganized, illogical thought and poor transitions
Eliminates redundancies and omissions
Provides fixed points of reference that reduces complex revisions and eliminates redundancies
Forces brevity, clarity, and a cohesive application

59. Organization Organization is key! Start with an outline
Number headings— help reviewers navigate with ease
5.0, 5.1, 5.1.1, 5.2
Summary statements at end of each section
Tables of timelines, figures of program organization
Assure you have included all requirements in each section of the grant. Double check the PHS398 (and PA or RFP) instructions

60. Fonts and Margins

61. Fonts and Margins

62. Summary
Don’t jump into writing — Write your Aims page and give it to an experienced PI for evaluation.
Propose something significant — Are you dealing with key controversies and problems in the field or rehashing a previous project or idea?
Good ideas don’t always sell themselves — Tell me why it’s important up front in the significance section…tell me what’s known and what isn’t known and how you’ll move the field forward or answer important questions.
Don’t cram your application like a suitcase — Pay attention to fonts, margins, and spacing.

63. Summary
Aim each aim — Spend time on the Expected Outcomes, Data Interpretation, Pitfalls, and Contingencies section for accomplishing each aim.
Pull it together — At the end of your approach section, write a succinct, one-paragraph summary of what you intend to do, how you intend to do it, and what it is going to tell you — write it like a manuscript abstract.
Have a good editor/writer proofread your application — Many unnecessary errors may kill your application.

64. Questions

65. Backup Slides

66. STRENGHTS/WEAKNESSES
NIH Scoring System
IMPACT S
COR E
DESCRIPTOR
STRENGHTS/WEAKNESSES
High 1
Exceptional 2
Outstanding 3
Excellent
Moderate 4
Very Good 5
Good 6
Satisfactory
Low 7
Fair 8
Marginal 9
Poor
Strengths
Weaknesses
Non-numeric scores: NR=Not recommended for further consideration DF=Deferred AB=Abstention CF=Conflict
NP=Not present ND=Not discussed

67. NIH Scoring System
Discussed applications receive impact/priority scores from all eligible reviewers in whole numbers only (no decimal ratings).
Assigned reviewers also provide ratings for each review criterion [e.g. Significance, Investigator, Innovation, Approach, Environment] using the same 9-point scale.
These criterion ratings are provided in the summary statement for applications, both discussed and not discussed. Criterion ratings should be considered in determining the overall impact/priority score, but reviewers should determine the relative importance of each criterion for the science or work being proposed.

68. Application Starters Which PA, RFP, Institute?
Read the PHS398 and PA/RFA instructions!
Formulate a solid hypothesis and write your Specific Aims (SAs) first
Run your SA page past several colleagues
Center research plan around SAs
Follow a timeline

69. PAs & RFAs Program Announcement (PA) Request for Application (RFA)
Broad funding announcements for areas of priority and emphasis using particular funding mechanisms
Ongoing, open for 3 years
Multiple receipt dates
PA Development, Application, and Evaluation of Prediction Models for Cancer Risk and Prognosis (R01)
Request for Application (RFA)
More narrow than PA, by institute
One-time solicitations for grant applications addressing a defined research topic
Single receipt date
Competition depends on # applications and $$ set aside
CA09-026 The Biology of Estrogen Receptor-Negative Breast Cancer in Various Racial and Ethnic Groups (U01)

70. Human Subjects
Does your research involve human subjects or are you just analyzing human data?
Protection of Human Subjects
Identify the risks
Describe protection against those risks
Consent (IRB)
Justify inclusion of Women, Minorities, Children
Inclusion Enrollment Table (ethnic & racial categories)
Research on transplantation of human fetal tissue
Human embryonic stem cells
Data and safety monitoring plan (for clinical trials)
Some exemptions

71. Vertebrate Animals
Describe use of animals outlined in Section D: species, strains, ages, sex, numbers
Justify use of animals, choice of species, and numbers
Describe veterinary care
Procedures to minimize discomfort, pain, injury
Describe methods for euthanasia consistent with Panel on Euthanasia of the American Veterinary Medical Association (AVMA)

72. Budget and Justification
Must match your research plan
Must use NIH budget forms and justify all expenses (OSP can help)
Personnel
Consultants
Supplies
Travel
Human subject payments
For multi-institutional applications, must be separate budgets for each subcontractor
Justification: no length requirement, but be succinct and accurate

73. Resources & Environment
Describe in detail the core facilities (not personnel) used in the study
Physical resources—departmental offices, labs, etc.
Equipment—describe those used, those needed
Other university resources—MRI facilities, testing labs, etc.
Provide space description (sq. ft., # offices, labs, etc).
Be specific
Be sure this section is consistent with budget/justification
About 3-4 pages
Use specified forms

74. Appendices
Color illustrations from the grant must be included in all copies
Manuscripts (10 max) from your lab supporting the application
Protocols and Procedures used in your research
Large tables & Figures supporting the application
Don’t include critical information — appendices are not required to be read by reviewers
Don’t include consultant letters (they are in “Section 16”)

75. DOs and DON’Ts
Always discuss potential problem areas and alternative approaches.
Never assume that reviewers will know what you mean.
Be explicit about what you want the reviewers to know and what they need to know.
READ the application instructions carefully.
Stay within page limits.

76. DOs and DON’Ts
Secure collaborators for areas you lack experience and training.
There are no competitors in science, only potential collaborators.
“Independent Researcher” does not mean that you work in isolation.
“Independent Researcher” does mean that you set the direction of the research.
Don’t give the impression of being intellectually “Isolated”.

77. DOs and DON’Ts
If your application is a renewal or supplement request, know that study section members will not have the benefit of your previous application but rather only the previous summary statement.
Be sure to explain your progress carefully in the current application.
Publish, Publish, Publish - be productive.