Tips From NIH Grant Reviewers Tips From NIH Grant Reviewers

Claire E. Hulsebosch, Ph.D.Claire E. Hulsebosch, Ph.D.Director of Spinal Cord Injury ResearchDirector of Spinal Cord Injury Research

Mission ConnectMission Connect

Program DirectorProgram Director

UTMB Spinal Cord Injury ProgramUTMB Spinal Cord Injury Program

NIH GoalsThe goals of NIH-supported research are to advance the understanding of biological systems,improve the control of disease, and enhance health.

New Roadmap Initiative: Emphasizes initiatives that will dramatically change the content or process of medical research. Elias Zerhouni, Director NIH, Science: 302:63-74, 2003.

Remember: It is the National Institute of Health not the National Institute of Mechanisms

Reviewer Instructions from NIH

1. Significance: a) Study addresses an important problem, b) How will aims advance knowledge, c) Impact of study on concepts or methods in field.

2. Approach: a) Conceptual framework, design, methods, analyses are developed and appropriate, b) Potential problems and alternative approaches are acknowledged.

3. Innovation: a) Novel concepts, approaches or methods, b) Aims original and innovative, c) Challenge existing paradigms or develop new methods or techniques.

4. Investigator: a) PI is trained and productive, b) Collaborators provide appropriate expertise needed, c) Publications together.

5. Environment: a) Environment contribute to success, b) Proposed experiments take advantage of unique features of environment and/or useful collaborations, c) Evidence of institutional support.

What Reviewers Read

Two critical sections are the Abstract and the Specific Aims Section. The Reviewers read these first and form their opinions.

Abstract: Addresses overall long term objectives, specific aims or hypotheses, health relatedness. Describe methods and techniques. Add “importance of data” statement.

Specific Aims: a) Conceptual framework, model to be used b) Hypotheses to be tested (no more than four), c) Specific Aims that will test the stated hypotheses in a logical manner, d) novelty and potential impact of project

What Reviewers Would Like to Read

Outcomes of cortical stroke are usually devastating, are poorly understood and severely affect quality of life. The proposed project uses a mammalian model of focal cortical ischemia to examine the role of substance excitement (sub E) in improved recovery of function. The central hypothesis of this project is that sub E is a critical factor in improved recovery after cortical ischemia and that it serves as a key factor in inhibition of the inflammatory pathway. Although increased subE is known to reduce pain in peripheral neuropathy and other inflammation models by altering the prostaglandin pathways, its role in stroke is unexplored. We begin to test the role of sub E by testing three hypotheses:

Hypothesis 1. A general statement that you wish to test. Sub E is important in recovery of function after focal cortical lesions.

Hypothesis 2. The mechanism of SubE mediated recovery after focal brain injury is through the inflammatory cascade by inhibition of prostaglandin synthesis.

Hypothesis 3. Another broad statement, perhaps more mechanistic still.

Techniques include behavioral analyses, behavioral pharmacology, immunocytochemistry, Western blot analyses, RIAs, ELISAs and imaging quantification. It is the long-range goal of this group to provide insights that will aid in developing novel therapeutic interventions for the treatment of stroke to improve functional recovery.

Abstract:

What Reviewers Would Like to Read

a. SPECIFIC AIMS

The majority of patients with traumatic spinal cord injury (SCI) report moderate to severe chronic pain sensations (Bonica, 1991) that can be divided into spontaneous pain and altered sensations to peripheral stimuli or evoked pain. Unfortunately, these pain syndromes have remained refractory to clinical treatment using conventional analgesics such as morphine and related compounds. We have recently characterized a mammalian model of chronic central pain after SCI that is reproducible and demonstrates the development of mechanical and thermal allodynia (Christensen et al., 1996, appendix). This model of central chronic pain will allow an investigation of mechanisms and possible novel therapeutic interventions. We will focus on the evoked pain component as this component is well characterized in our model. In addition, we will also investigate spontaneous pain, which is not as well studied but clinically significant. We will examine the effects of two endogenous inhibitory transmitters systems that offer efficacious treatment options: the serotonergic and GABAergic systems (SPECIFIC AIM 1)….. The present project will use a spinal cord hemisection (T13) injury that results in mechanical and thermal allodynia. Changes in motor function following hemisection will be scored using the Basso, Beattie and Bresnahan (BBB) open field test (Basso et al., 1995) to ensure that a motor impairment does not compromise the nociceptive tests. Past experience with this model has demonstrated the development of behavior consistent with mechanical and thermal allodynia by 24 days (see Christensen, et. al., appendix). Consequently, we will begin testing the drug interventions at 30 days postsurgery.

HYPOTHESIS 1: Activation of endogenous inhibitory transmitter systems will ameliorate the chronic pain behavior that develops after spinal cord injury.

SPECIFIC AIM 1: To determine if serotonergic and GABA receptor agonists will reduce the evoked somatosensory behavior after spinal cord hemisection in a dose dependent manner. Experiment 1: 5-HT1A and 5-HT3 serotonergic receptor agonists and GABAA and GABAB receptor agonists will each be administered intrathecally, 30 days after spinal hemisection, at different doses in an effort to reverse the allodynia in response to mechanical and thermal stimuli. The drugs to be used will include 8-OH-DPAT (5-HT1A agonist), 1-phenylbiguanide (5-HT3 agonist), muscimol (GABAA agonist) and baclofen (GABAB agonist). Vehicle injections will be used as controls. Outcome measures will be evoked somatosensory, locomotor and spontaneous behavioral assays.

SPECIFIC AIM 2: To determine if serotonergic and GABA transporter inhibitors will reduce the evoked somatosensory behavior after spinal cord hemisection in a dose dependent manner. Experiment 2: 5-HT transport inhibitor (fluoxetine, 6-nitroquipazine) or GABA transporter inhibitor (guavacine, SKF

Specific Aims:

Tips for Writing Specific Aims Section

1. Must be strong, solid hypotheses and straightforward means of testing the hypotheses.

2. Provide rationale for hypotheses to be tested. Justify the selection of the ones chosen in the context of current scientific literature.

3. An outstanding hypothesis addresses an important biological process, disease, treatments and increases the understanding in that area.

4. The proposal should not be driven by advances in technology. Avoid fishing expeditions: ex. DNA microarray analyses or proteomics with no evidence of feasibility and no data.

5. Write the abstract from exact statements made in Specific Aims section.

6. Spend the most time in developing the specific aims page (1 ½ pages to 2 pages maximum).

7. Add a simple line drawing to clarify the overall proposal.8. DO submit the specific aims page to experienced NIH grantees for

presubmission critiques.

What Reviewers Read

The next MOST critical section is Preliminary Studies. 1. Must present data to support hypotheses.2. Must demonstrate that proposed experiments are feasible

by PI and collaborators.3. Explain how results are valid and how early studies will

be expanded.4. Interpret results critically and offer alternative

interpretations and ways to test.5. Preliminary data may be previously published by PI,

unpublished data and publications from others.

What Reviewers Would Like to Read

c. Preliminary Studies. The following pilot data have been collected in our laboratory to support the following hypotheses:

Data to support (or test) Hypothesis 1. Restate hypothesis

Experiment 1: To test for xxx, we performed focal cortical injuries using the model of X and Z….Describe what you did, n per group, statistical treatment, this is where you can showcase how rigorous and careful you are as a scientist. Most reviewers begin with the specific aims page and decide if they are enthusiastic about the project (which is true for about 90% of the submissions) and then skip to the preliminary studies section to determine if the investigator has the technical skills to do what she/he described. If you demonstrate feasibility of techniques for all your hypotheses, you will be in good shape. Some high risk, high impact techniques can be added at the very end but be certain to ensure success at that juncture by letters of collaborations of investigators who can do that technique.

Figures 1 and 2 (above) demonstrate statistically significant attenuation of xxx (figure 1) and xxx (figure 2) after focal cortical lesion. Elaborate more here…..

Preliminary Studies:

What Reviewers Read

The next MOST critical section is Research Design and Methods.

Most Investigators spend the most time writing the Introduction but in fact, this is the least critical section.

What Reviewers Would Like to Read

d. Research Design and Methods

Our overall goal is to test if and how control of the expression of Sub E contributes to improved recovery of function after focal cortical ischemia and to begin to understand the mechanisms that underlie the improved recovery. The general experimental design will be to use a naïve control group (n=10), a sham control group (n=10), a focal lesion group (n=10) and a focal lesion group with treatment (n=10). The numbers that we have selected have been obtained using power analyses and data from experiment XX above. These numbers are needed to determine the statistical significance to an alpha level = 0.001 (here find a statistician to determine numbers, include her/his letter of support). Another method is to have a section on statistics for each section or for the whole grant at the end of this Design section.

SPECIFIC AIM 1. Restate specific aim 1.

Experiment 1.1. Restate but elaborate here.

Rationale:

Experimental Protocol: Groups that will be compared,

Predicted Results: Most grants have pilot data collected so that the predicted results are already known. Remember, if the data is not published it is not “real” so it becomes eligible for pilot data.

Potential Problems: Here is the place to suggest alternative approaches.

Significance: Sentence or two on the import of the data produced by this experiment.

Statistical Treatment: Describe statistical methods. Include Power Analysis to demonstrate feasilbility of approach. If you have pilot data, you can do a Power Analysis.

Experiment 1.2. Test whether xxxx

Details in Methods

Research Design and Methods:

Common Mistakes in Writing Grants

1. Ideas not original or significant.

2. Unrealistic amount of work proposed (overambitious).

3. Project too diffuse, lacks focus.

4. Rationale to do project not clear or valid.

5. Project is fishing expedition and/or lacks hypothesis driven research.

6. Studies are based on a shaky hypothesis or shaky data.

7. Proposed experiments are descriptive and do not test a hypothesis.

8. The proposal is technology driven not hypothesis driven.

Common Mistakes in Writing Grants9. Rationale for experiments not given.10. Direction or sense of priority not clearly defined.11. Lack of alternative methodological approaches in case

primary approach does not work out.12. Insufficient methodological detail to support feasibility

(no recognition of potential problems).13. If initial experiment fails, the subsequent experiments

fail.14. Proposed model system does not address the proposed

question.15. Experiments lack relevant controls.16. Proposal innovative but lacks preliminary data.

Common Mistakes in Writing Grants

17. PI has no experience with proposed techniques and no collaborator who does.

18. Preliminary data does not support feasibility of the project or hypotheses.

19. Proposal lacks critical literature references so that reviewers think the PI does not know literature or purposely neglected critical publications.

20. Not clear which data were obtained by PI and which data were obtained by others.

21. PI has not been productive, no recognition in the field for which the proposal is submitted.

Revising for Resubmission to NIH1. Discuss the summary statement and reviewers’ comments with

an experienced NIH grantee who can help interpret what the reviewers’ really meant.

2. Address all of the reviewers’ comments in your revision. 3. Be polite. No PI has ever received funding by pointing out that

the reviewers were wrong or missed something in the original application.

4. Put ALL ego aside. If in doubt, do it their way.5. If reviewers recommend elimination of critical experiments,

either explain the rationale to keep them or cut them. My recommendation is never argue with the reviewers. Revise according to the recommendations, get the funding and do the experiments anyway.

NOTE: Very few grants are funded after first time submission. Consequently, you will be revising. Our study section is funding at the 12.5 percentile. Obviously, 87.5% of the proposals are not funded, including Nobel Laureates, Howard Hughes and Javitts Award recipients.

Practical Tips for Addressing Reviewers’ Concerns

1. Call the Program Director before submission to determine program relevance of your planned proposal.

2. Call the Executive Secretary after the review when you receive you priority scores. The notes that are taken during the discussion may not match the written critiques submitted prior to the study section meeting.

3. Look up NIH awards. There may be one tailored for you.

4. Read the instructions. Do not assume the reviewers’ will have expertise in your field. Define all abbreviations, be clear, etc.

5. BECOME A REVIEWER. Call up an Executive Secretary, introduce yourself on the phone and offer to review grants in your area of expertise as an Ad Hoc reviewer. This experience will change how you write grants.

Summary

1. Writing scientifically sound proposals is a challenge.

2. As in experiments, there are certain formulae to ensure that the reviewers’ will understand your proposal.

3. Call the Program Director and Executive Secretaries for presubmission and post-review information.

4. Put yourself in the reviewers’ shoes. What would you like to read, late at night?

Finally, thank you for your attention and GOOD LUCK !!!

Claire E. Hulsebosch, Ph.D.

Vice Chair and Professor

Neuroscience and Cell Biology