Transcript Document

Tips From NIH Grant Reviewers
Claire E. Hulsebosch, Ph.D.
Director of Spinal Cord Injury Research
Mission Connect
Program Director
UTMB Spinal Cord Injury Program
NIH Goals
The 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
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Significance: a) Study addresses an important problem, b) How
will aims advance knowledge, c) Impact of study on concepts or
methods in field.
Approach: a) Conceptual framework, design, methods, analyses
are developed and appropriate, b) Potential problems and
alternative approaches are acknowledged.
Innovation: a) Novel concepts, approaches or methods, b) Aims
original and innovative, c) Challenge existing paradigms or
develop new methods or techniques.
Investigator: a) PI is trained and productive, b) Collaborators
provide appropriate expertise needed, c) Publications together.
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
Abstract:
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.
What Reviewers Would Like to Read
Specific Aims:
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 8OH-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, 6nitroquipazine) or GABA transporter inhibitor (guavacine, SKF
Tips for Writing Specific Aims Section
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Must be strong, solid hypotheses and straightforward means of
testing the hypotheses.
Provide rationale for hypotheses to be tested. Justify the selection of
the ones chosen in the context of current scientific literature.
An outstanding hypothesis addresses an important biological
process, disease, treatments and increases the understanding in that
area.
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.
Write the abstract from exact statements made in Specific Aims
section.
Spend the most time in developing the specific aims page (1 ½
pages to 2 pages maximum).
Add a simple line drawing to clarify the overall proposal.
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
Preliminary Studies:
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…..
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
Research Design and Methods:
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
Common Mistakes in Writing Grants
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Ideas not original or significant.
Unrealistic amount of work proposed (overambitious).
Project too diffuse, lacks focus.
Rationale to do project not clear or valid.
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 Grants
9. 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 NIH
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Discuss the summary statement and reviewers’ comments with an
experienced NIH grantee who can help interpret what the
reviewers’ really meant.
Address all of the reviewers’ comments in your revision.
Be polite. No PI has ever received funding by pointing out that
the reviewers were wrong or missed something in the original
application.
Put ALL ego aside. If in doubt, do it their way.
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
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Call the Program Director before submission to determine
program relevance of your planned proposal.
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.
Look up NIH awards. There may be one tailored for you.
Read the instructions. Do not assume the reviewers’ will have
expertise in your field. Define all abbreviations, be clear, etc.
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
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Writing scientifically sound proposals is a challenge.
As in experiments, there are certain formulae to ensure that the
reviewers’ will understand your proposal.
Call the Program Director and Executive Secretaries for
presubmission and post-review information.
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