This document provides guidance on key sections of an NIH R01 grant application, including Significance, Innovation, and review criteria. It discusses that Significance refers to how the project will advance scientific knowledge or improve clinical practice if successful, not just the importance of the disease topic. Reviewers evaluate the rigor of prior research supporting the project and the applicant's plans to address weaknesses. Innovation can involve novel concepts, approaches, technologies, or new applications of existing methods. The simplified NIH review framework focuses on whether the proposed research should be conducted based on Significance and Approach.

1. Significance and Innovation
Bill Parks, PhD
Department of Medicine
Cedars-Sinai Medical Center

2. R01 Grant Sections
• Face Page
• Table of Contents
• Performance Site
• Project Description: Abstract
• Project Narrative: 2 sentences
• References Cited
• Facilities and Other Resources
• Equipment
• Key Personnel
• Biosketches
• Budget (all years)
• Budget Justification
• Introduction
(resubmission only)
• Specific Aims
• Research Strategy
• Significance
• Innovation
• Approach
• Protection of Human Subjects
• Women & Minorities
• Planned Enrollment Table
• Children
• Vertebrate Animals
• Select Agents
• Multiple PI Plan
• Letters of Support
• Resource Sharing
• Authentication of Key
Biological and/or Chemical
Resources
• PHS Assignment Form

3. Scored Review Criteria
Investigator Initiated
R-series Grants
• Significance
• Investigator
• Approach
• Innovation
• Environment
Overall
Impact
Overall Impact or
Criterion Strength
Score Descriptor
High
1 Exceptional
2 Outstanding
3 Excellent
Moderate
4 Very Good
5 Good
6 Satisfactory
Low
7 Fair
8 Marginal
9 Poor
• Criterion Score
• Whole numbers: 1-9
• 1 (exceptional); 9 (well let’s just hope you never get a 9)
• Given by reviewers but not discussed at study section
• Provided in Summary Statement of all applications
• Overall Impact Score
• Not the mean of the criteria scores
• Different criteria are weighted by each reviewer
• Final Impact Score, Percentile
• Mean of all scores x 10 ➤ 10 – 90
• Percentiled against R01s applications across 3 meetings

4. New ‘Simplified’ Review Framework
• January 2025
• https://grants.nih.gov/policy/peer/simplifying-review.htm
• "Should the proposed research project be conducted?”
• Significance
• Approach

5. Innovation

6. Innovation
• Does the application challenge and seek to shift current research or
clinical practice paradigms by utilizing novel theoretical concepts,
approaches or methodologies, instrumentation, or interventions?
• Are the concepts, approaches or methodologies, instrumentation, or
interventions novel to one field of research or novel in a broad
sense?
• Is a refinement, improvement, or new application of theoretical
concepts, approaches or methodologies, instrumentation, or
interventions proposed?
Current Instructions to Reviewers

7. Innovation
• Two flavors
1. New concepts or challenges to existing paradigms or dogma
2. New reagents, assays, technologies, etc.
• However, “proposals do not need to be innovative”
• Thus, not a major review criteria – but can be a big plus
• Not mentioned in instructions to reviewers for K applications

8. Innovation
Applicant’s
Assessment
of their
Innovative
Strengths
Reviewers’
Assessment
of the
Innovative
Strengths

9. Innovation
• Keep it short
• 1-2 paragraphs
• Bulleted list
• Be realistic
Our data will provide new information on how specific functions of macrophages
are regulated. Conceptually, our project will demonstrate that macrophages are not
necessarily bad players in fibrosis and furthers the idea, which we were among the
first to propose, that MMPs function primarily to affect the behavior of immune cells.

10. Significance

11. Significance
• Does the project address an important problem or a critical barrier to
progress in the field?
• Is the prior research that serves as the key support for the proposed
project rigorous?
• If the aims of the project are achieved, how will scientific knowledge,
technical capability, and/or clinical practice be improved?
• How will successful completion of the aims change the concepts,
methods, technologies, treatments, services, or preventative interventions
that drive this field?
Instructions to Reviewers

12. What is Significance and How is it Evaluated?
• Not related to the disease or cellular process you are studying
• After all, all diseases are significant
• Basic science research can have an impact
• Rather, if the aims are achieved, will scientific knowledge, technical
capability, and/or clinical practice be improved?
• Hence, Research Approach impacts Significance
• A wet-lab proposal that is descriptive or derivative or will gather
correlative information will not be significant
- Epidemiology or clinical studies may seek associative findings
• Evaluation of and attention to rigor

13. Common Misconception
• Significance only means translational science, clinical importance, and/or
disease related
• Not true: basic research can have a great an impact
• “NIH’s mission is to seek fundamental knowledge about the nature and
behavior of living systems and the application of that knowledge to
enhance health, lengthen life, and reduce illness and disability.”
• An application does not need to show the potential for clinical impact
• You do not need to develop a new drug!

14. • Describe the strengths and weaknesses/gaps in the rigor of the prior research (published
and unpublished) that serves as the key support for the proposed project and plans to
address weaknesses/gaps.
• Rigor: Strict application of the scientific method to ensure robust and unbiased
experimental design, methodology, analysis, interpretation, and reporting of results.
• Variables: sample size, sex, age, weight, health condition, etc.
• Must address sex (approach)
• Authentication of key biological and/or chemical resources (1 page)
• Rigor is addressed by reviewers under both Significance (previous) and Approach
(planned)
• https://grants.nih.gov/grants/peer/guidelines_general/Reviewer_Guidance_on_Rigor_and_Transparency.pdf
• https://grants.nih.gov/grants/guide/notice-files/NOT-OD-18-228.html
Significance – Rigor of Previous Work, Yours and Others

16. 1. Discuss the rigor of the research and data – both yours and
others – that form the foundation of your project.
2. Discuss how will you address any weaknesses pointed out in #1.
3. Include strategies that assure a lack of bias and an overall robust
approach.
4. Address relevant variables, especially sex.
How to Address Rigor in the Research Strategy
Significance
Approach

17. Significance (Background)
• 1-1.5 pages
• Critically review the literature and provide a clear
premise
• No limit on number of citations
• Original, timely papers over reviews
• Rigor: Point out gaps and flaws; strengths, too
• Do not be afraid to say you disagree with something
(but explain why and how you will correct this travesty)
• Be diplomatic
• Limit discussion to things (pathways, diseases, molecules, etc.)
you will study
• Show (tempered) enthusiasm
• Know your audience
• Get the reviewers interested
Pet Peeves
• Needlessly long
• Not focused
• Not timely nor scholarly
• Reliance on reviews
• Uses the word “exciting” more than
once
• Poorly developed premise
• Does not address rigor

18. Overall Impact vs. Significance
Overall Impact
• Likelihood of making a sustained,
powerful influence on the field
• Integrates the 5 scored criteria
• Not the mean of the 5 criteria
Significance
• Focus on relevance and likelihood
of making a meaningful advance if
the aims are achieved.
• Addresses an important problem or
critical barrier to progress
• Topic ≠ Significance