K99/R00 Research Strategy Writing

Workshop

Andrew Derrington

19 May 2015

Contents

I. How Study Sections Work:Implications for Style and Structure 3

1. The way a study section works favours grant-applications with certain attributes. 31.1. Easy to find and summarise the detail . . . . . . . . . . . . . . . . . . . . . . . . . . . 41.2. Easy to ’speed read’ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41.3. Easy to understand and remember it . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4

2. How to give your grant-application the right attributes:Key Statements and Tag Phrases help the reader 42.1. Key Statements Make it Easy to find and summarise the detail. . . . . . . . . . . . . . 42.2. Structure & Layout Make it Easy to Speed Read . . . . . . . . . . . . . . . . . . . . . 52.3. ’Tag Phrases’ make it easy to understand and remember . . . . . . . . . . . . . . . . . 5

3. Key Statements Help you Write 6

II. Trust Me: I’m a Scientist 7

4. What should your first Key Statement say? 74.1. Gathering information for a first Key Statement . . . . . . . . . . . . . . . . . . . . . . 74.2. Writing the First Key Statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

III. K99/R00 Application: Choosing the Key Statements 9

5. Principles of Key Statements 9

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6. Key Statements for the Research Strategy 96.1. Research Strategy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96.2. Key Statements in the Research Strategy . . . . . . . . . . . . . . . . . . . . . . . . . 106.3. Re-using Key Statements in Specific Aims . . . . . . . . . . . . . . . . . . . . . . . . . 106.4. Re-using Key Statements in Summary/Abstract . . . . . . . . . . . . . . . . . . . . . . 11

7. Key Statements and Assessment Criteria 12

8. Conclusions: Key Statement List 12

IV. K99/R00 Application: Start Writing the Research Strategy 13

9. Decide on your Specific Aims 13

10.Decide what Key Statements you need 13

11.Decide how to use Preliminary Data 14

12.Start Writing 14

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Part I.

How Study Sections Work:Implications for Style andStructure1. The way a study section works favours grant-applications

with certain attributes.Study Section: Before the Meeting

• Each grant is assigned to 2 or 3 reviewers

• Reviewer reads application

– Scores it against specified criteria– Writes a critique - against specified criteria

• Applications with low scores may not be discussed at meeting

Study Section: At the Meeting

• Reviewers present oral summary of their critiques

• Whole panel discusses application

– Non-reviewers may not bother to read the Research Plan– They can read it during the discussion

• Whole panel assigns scores by secret ballot

• Grants are ranked by score and go for funding decision

– Percentile ranking determines funding

Study Section: Points to note

• The reviewers will not know your research project as well as you do.

– They will have several grants to review for each meeting– You know what information they are looking for

⇤ Can you make it easy for them to find it?

– You know what they have to say about your grant

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⇤ Can you help them find the words?

• All study-section members have busy, demanding jobs

– Most of them will feel too busy to read the detail of grants they do not have to review

⇤ But they will vote on them.⇤ How can you make them feel they understand your grant and like it?

1.1. Easy to find and summarise the detail

1.2. Easy to ’speed read’

1.3. Easy to understand and remember it

Study Section: Implications

• Your grant-application will have a better chance if it has certain properties

– Easy to find and summarise the detail (Reviewer)– Speed-readable (Study-Section Member).– Easy to understand & remember (Study-Section Member).

• These properties depend on the style and the structure

2. How to give your grant-application the right attributes:Key Statements and Tag Phrases help the reader

2.1. Key Statements Make it Easy to find and summarise the detail.

Key Statements make it easy to find and summarise the detail.

• Key Statements make the main points of your case

• How would you sum up your whole grant application in a single statement?

• You use them to introduce the sections of your key documents.

– e.g. Each Specific Aim can generate 2 or 3 Key Statements

1. Significance of Aim - definitely needed2. Contribution of Aim to Innovation - possibly needed3. Approach to achieve Specific Aim - definitely needed

• Use detail to back up Key Statements

– The Key Statements are the essence of your grant application

⇤ They would be a good set of headings for the reviewers’ notes

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2.2. Structure & Layout Make it Easy to Speed Read

Structure & Layout make it Easy to Speed Read

• Message at the top of paragraph (ASSERT then JUSTIFY)

– First sentence of para ASSERTS (message sentence)– Remainder of para JUSTIFIES

⇤ This is where you cite literature⇤ This is how you avoid citing too much literature.

• White space above each paragraph

– Clear, consistent layout– Top line of every paragraph conveys the story– Headings & Subheadings can reinforce structure

⇤ But you shouldn’t need them

2.3. ’Tag Phrases’ make it easy to understand and remember

’Tag Phrases’ make it easy to understand and remember.

• Repetition is good.

– Important things should be said several times

⇤ In several different places

– Always use same words– Each key statement contains 1 or 2 ’Tag Phrases’

• Use lists of 3 (or 4) items

– Always use same list order when you repeat the lists

• ’Tag phrases’ link the proposal together

– Use ’tag phrases’ to link related elements in different parts

⇤ ’A specific aim is to understand + tag phrase...’⇤ ’We need to know + tag phrase ...’ in ’Significance’⇤ ’The innovative aspect of our study of tag phrase...’ in ’Innovation’.⇤ ’This will tell us + tag phrase’ in ’Approach’

• Summary/Abstract and Specific Aims introduce key terms as ’Tag Phrases’

– Tag Phrases are consistent in all sections of the grant

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3. Key Statements Help you WriteKey Statements Help you to Write Effectively and Quickly

• Draft your Key Statements before you start writing.

– Use the Key Statements to structure your writing– Refine them as you redraft

• Adapt Key Statements for the different components of the application.

– Key Statements in Specific Aims are repeated in Summary/Abstract and Research Strategy– May have long and short versions for different documents.

• Recognisably the same statement.

– Create ’Tag Phrases’ from technical language– Tag Phrases are constant in Key Statements– Tag Phrases may appear in several Key Statements

• Align the key statements with the assessment criteria

– Use the assessment criteria to create key statements.

Resources

• NIH Website, especially

– Peer review process

⇤ https://www.youtube.com/watch?v=fBDxI6l4dOA

– K99/R00 FOA– NIH Reporter

• Books (Yang is good for principles, Gerin et al has extensive examples)

– Guide to Effective Grant-Writing by Otto Yang. Available as Kindle - make sure you get thesecond edition. The first edition is still on Kindle.

– Writing the NIH Grant Proposal: A Step-by-Step Guide, Gerin et al. Also on Kindle

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Part II.

Trust Me: I’m a Scientist4. What should your first Key Statement say?What should your first Key Statement say?

• What is the first thing the reviewer wants to know?

– What outcome does this promise?– Is there any reason to believe the project will deliver the promised outcome?– Is there any reason to believe that the team can do the project?– Is it important?

• Ways to think about it

– Think ’Elevator Pitch’– Think ’Opening Remarks of Reviewer to Study Section’

4.1. Gathering information for a first Key Statement

Gathering information for a first key statementAsk your neighbour about their project. Try to understand and remember:-

• What will the project achieve?

• Why would that achievement be significant?

• How will the project achieve it?

• Why would they be a good person to carry out the project?

After 3 minutes, change roles and repeat.

4.2. Writing the First Key Statement

Write a first key statement

1. Imagine that you are writing the script for the reviewer presenting your neighbour’s project to astudy section.

• Write a single statement that will excite the study section• You have 2 minutes.

2. Imagine that you are writing the script for the reviewer presenting your own project to a studysection. .

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• Write a single statement that will excite the study section• You have 2 minutes.

We’ll compare statements as a group

• What are the elements of a good first sentence?

– A promise of what the project will deliver– A reason to believe the project will deliver– A reason to believe the applicant can deliver– Significance

Resources

• NIH Peer Review

– https://www.youtube.com/watch?v=fBDxI6l4dOA

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Part III.

K99/R00 Application: Choosingthe Key Statements5. Principles of Key StatementsPrinciples of Key Statements

• Key Statements define the structure of a document

– They state the main points

⇤ They introduce the main sections⇤ Follow-up text justifies and reinforces them

– They use simple language– They re-use key terms as Tag Phrases

• If you have to say essentially the same thing in 2 documents

– You re-use the same key statements

⇤ Recognisably the same statements (even to a lay person)

– In the same order

• So, what key statements do we want for the Research Strategy?

6. Key Statements for the Research Strategy

6.1. Research Strategy

Application Guide: Research Strategy

• Significance

– 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.

• Innovation– Explain how the application challenges current research or clinical practice paradigms.

– Describe any novel theoretical concepts, approaches or methodologies, instrumentation or interventions

to be developed or used, and any advantage over existing methodologies, instrumentation, or interventions.

• Approach

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– Describe the overall strategy, methodology, and analyses to be used to accomplish the specificaims of the project. Unless addressed separately in the Resource Sharing Plan, include how the data will 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.

– Preliminary Studies for New Applications:

⇤ For new applications, include information on Preliminary Studies.

⇤ Discuss the PD/PI’s preliminary studies, data, and or experience pertinent to this appli-cation.

6.2. Key Statements in the Research Strategy

Key Statements in the Research Strategy

• Use Key Statements to state the main points of your Research Strategy

– They are potentially headings for the reviewers’ notes.

• Research Strategy Key Statements

– Elevator Pitch Statement– For each Specific Aim

⇤ Statement in Approach about how you will deliver it.⇤ Statement in Significance about why it’s important.⇤ Possibly statement in Innovation about how it contributes to innovation

– Maybe statement about implications of results for Science or Medical Practice

• ’Tag Phrases’ tie key statements together

– So the non-expert can understand the science.⇤ “Our aim is to characterise the deficits in interval timing in autism”⇤ “The deficits in interval timing in autism will extend our understanding of the cognitive

components of autistic spectrum conditions”

6.3. Re-using Key Statements in Specific Aims

Application Guide: Specific Aims

• Application Guide says the Specific Aims Should

– State precisely 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., to test a stated hypothe-sis, create a novel design, solve a specific problem, challenge an existing paradigm or clinicalpractice, address a critical barrier to progress in the field, or develop new technology.

• All these elements are also part of the Research Strategy and so you should use a common set ofkey statements.

– They might be shortened versions of the key statements in the Research Strategy– But they would have identical tag phrases.

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6.4. Re-using Key Statements in Summary/Abstract

Application Guide: Summary/Abstract

• Application Guide says the Summary/Abstract Should

– Provide an abstract of the entire application ( candidate, environment, and research).– Include the candidate’s immediate and long-term career goals, key elements of the research

career development plan, and a description of the research project, as indicated in Part I.4.4.6.– State the application’s broad, long-term objectives and specific aims, making reference to

the health relatedness of the project (i.e., relevance to the mission of the agency).– Describe concisely the research design and methods for achieving the stated goals.

• These parts overlap with the Research Strategy and use the same Key Statements.

• These parts require new Key Statements.

– They should link together the Research Plan and the Candidate Information– The assessment criteria make this clear.

Re-using Key Statements from the Research Strategy

• Re-use (most of) them in the ’Specific Aims’

• Also in the ’Summary / Abstract

• If research plan has an ’Introduction’ re-use key statements there.

• By having the same key statements in all these sections you allow the reader to develop a completelycoherent view of your application.

• The tag phrases tie everything together.

– A study-section member who has read the Summary/Abstract OR the Specific Aims will findit easier to understand the Research Plan.

– A Reviewer who has read the Summary/Abstract and the Specific Aims will find it easy tosummarise the Research Plan

• Do the K99/R00 Criteria and Instructions suggest any other Key Statements?

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7. Key Statements and Assessment CriteriaAssessment Criteria Emphasise Developmental Requirements

• Candidate must have high potential but NOT be ready for independence.

• Research Plan must contain 2 components

– K99 (mentored) component. Must develop candidate’s research and other skills to transitionto independence.

– R00 Independent component. Must be clearly different from the mentor’s research.

• Career Development plan must prepare candidate for independence and R00 phase

• Mentor must have track record, commitment and a plan for separating candidate’s research tra-jectory from their own.

• Institution must have track record, facilities & commitment

• Should have Key Statements to link career development plan to the research plan.

8. Conclusions: Key Statement ListConclusions: Key Statement List

• ’Research Strategy’, ’Specific Aims’ and “Summary/Abstract’ use the following Research StrategyKey Statements

– Elevator Pitch Statement– For each Specific Aim

⇤ Statement in Approach about how you will deliver it.⇤ Statement in Significance about why it’s important.⇤ Possibly statement in Innovation about how it contributes to innovation

– Maybe statement about implications of results for Science or Medical Practice (may be partof Elevator Pitch)

• Summary/Abstract probably needs at least one more Key Statement linking Research Strategy toDevelopment Plan.

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Part IV.

K99/R00 Application: StartWriting the Research Strategy9. Decide on your Specific AimsDecide on your Specific Aims

• Decide on your Specific Aims (Suggest a total of 3)

– How many K99?– How many transitional?– How many R00?

• What developmental need do you have to step up from K99 to R00?

– How will the project contribute?– How will your training plan contribute?

10. Decide what Key Statements you needDecide what Key Statements you need

• ’Research Strategy’, ’Specific Aims’ and “Summary/Abstract’ use the following Research StrategyKey Statements

– Elevator Pitch Statement– For each Specific Aim

⇤ Statement in Approach about how you will deliver it.⇤ Statement in Significance about why it’s important.⇤ Possibly statement in Innovation about how it contributes to innovation

– Maybe statement about implications of results for Science or Medical Practice (may be partof Elevator Pitch)

• Summary/Abstract probably needs at least one more Key Statement linking Research Strategy toDevelopment Plan.

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11. Decide how to use Preliminary DataDecide how to use Preliminary Data

• Decide what preliminary data you want to show

• Decide what points you want to make with it

– Demonstration of what kind of data will be collected and how it will be treated?– Demnstration of feasibility of approach?– Demonstration of starting point for specific aim?– Other

• Decide which Key Statement is supported by the data

• Check that none of your Key Statements is discredited by the data

– e.g. demonstration of competence to deliver R00 Specific Aim.

12. Start WritingStart Writing

• You should be able to draft your key statements in 2 or 3 hours.

• These will be rough drafts but good enough to use as a framework.

• Create Major Headings for ’Research Strategy’

– Introduction– Significance– Innovation– Approach

• Key Statements should make first sentences for Subsections in Significance, Innovation and Ap-proach

• Key Statements are a very rough draft of the Introduction.

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NIH Guidance Relevant to the K99/R00Research Plan

May 17, 2015

Contents

1 Extracts from the Funding Opportunity Announcement (FOA) 31.1 General . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3

1.1.1 K99 Phase: Up to 2 Years . . . . . . . . . . . . . . . . . . . . . . . . 31.1.2 R00 Phase: Up to 3 Years . . . . . . . . . . . . . . . . . . . . . . . . 31.1.3 Candidate Information . . . . . . . . . . . . . . . . . . . . . . . . . . 41.1.4 Project Summary/Abstract . . . . . . . . . . . . . . . . . . . . . . . 4

1.2 Elements Assessed with the Research Plan . . . . . . . . . . . . . . . . . . . 41.2.1 Candidates Background . . . . . . . . . . . . . . . . . . . . . . . . . 41.2.2 Career Goals and Objectives . . . . . . . . . . . . . . . . . . . . . . . 41.2.3 Candidate’s Plan for Career Development/Training Activities During

Award Period . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41.2.4 Research Plan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

1.3 Scored Review Criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61.3.1 Candidate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71.3.2 Career Development Plan/Career Goals and Objectives . . . . . . . . 71.3.3 Research Plan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71.3.4 Mentor(s), Co-Mentor(s), Consultant(s), Collaborator(s) . . . . . . . 81.3.5 Environment & Institutional Commitment to the Candidate . . . . . . 9

1.4 Additional Review Criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

2 Extracts from the the SF424 (R&R) Application Guide 92.1 Project Summary/Abstract (page I-76) . . . . . . . . . . . . . . . . . . . . . 102.2 Research Plan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102.3 Career Goals and Objectives . . . . . . . . . . . . . . . . . . . . . . . . . . . 112.4 Candidates Plan for Career Development/ Training Activities During Award

Period . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112.5 Specific Aims . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122.6 Research Strategy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

2.6.1 Significance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

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2.6.2 Innovation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122.6.3 Approach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132.6.4 Progress Report for Revision Applications. . . . . . . . . . . . . . . . 13

Disclaimer

Most of the text in this document comes from the NIH web pages and is current in May 2015.It is assembled here for convenience of classroom use. The source documents, the FundingOpportunity Announcement (FOA) and the SF424 (R&R) Application Guide should be usedfor definitive reference.

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1 Extracts from the Funding Opportunity Announcement(FOA)

Note that the FOA applies specifically to K99/R00 awards and so should override statementsin the SF424 (R&R) Application Guide. All black text is copied directly from the FOA webpages. I have added formatting to make the text readable as a pdf. My comments are inmagenta text.

1.1 General

1.1.1 K99 Phase: Up to 2 Years

• The candidate must propose a research project that will be pursued during the K99phase and be carried forward into an independent project during the R00 phase of theaward.

• The candidate must also propose a career development plan of activities that will helpprepare the individual for his/her career as an independent researcher.

• The candidate and mentor(s) together should be involved in developing all aspects ofthe mentored (K99) career development and research programs.

• However, a significant component of the proposed K99/R00 research project must bedistinct from projects to be continued in the mentors laboratory after the K99 PD/PItransitions to research independence.

• When a candidates project requires collaborators and/or facilities at other institu-tions/organizations, the application should describe how the mentors, collaborators,and resources will be coordinated among the different environments.

• K99 Phase Research expenses may include (a) tuition and fees related to career devel-opment activities; (b) supplies, equipment and technical personnel; c) travel to researchmeetings or training; and (d) statistical services including personnel and computer time.

1.1.2 R00 Phase: Up to 3 Years

• K99 awardees who have been offered, and have accepted, a full-time, tenure-track assis-tant professor position (or equivalent) at an extramural sponsoring institution/organizationmay request up to 3 years of support to continue their research as independent scientists.

• This R00 phase support is designed to allow the individual to establish his/her ownindependent research program and prepare an application for additional research grantsupport (e.g. NIH R01).

• Support for the R00 phase is not automatic and is contingent upon obtaining an ap-propriate extramural position at an eligible institution, an appropriate start-up package,and the successful NIH programmatic review of the individuals progress during the K99phase of the award.

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1.1.3 Candidate Information

All instructions in the SF424 (R&R) Application Guide must be followed, with the followingadditional instructions:

1.1.4 Project Summary/Abstract

Include a description of the research proposed for the mentored and independent phases.

1.2 Elements Assessed with the Research Plan

1.2.1 Candidates Background

• Describe the candidates commitment to a career in a biomedical, behavioral, or clinicalresearch field relevant to the mission of one of the participating NIH ICs.

• Describe the candidates potential to develop into a successful, independent investigator.

1.2.2 Career Goals and Objectives

• Describe the candidates current and long-term research and career objectives.

• Present a scientific history that:

1. shows a logical progression from the candidates prior research and training experi-ences to the training and research experiences proposed for the mentored phase ofthe award (K99) and subsequently to the independent phase of the award (R00);and

2. justifies the need for further mentored career development to become an indepen-dent research investigator.

• If currently supported by an institutional or individual Ruth L. Kirschstein NRSA, de-scribe the candidates current research training or fellowship program.

• Describe how the candidate plans to separate scientifically from his/her mentor andadvance to research independence.

1.2.3 Candidate’s Plan for Career Development/Training Activities During AwardPeriod

• A systematic plan should be presented for obtaining the biomedical, behavioral, or clini-cal science background, research experience, and career development activities necessaryto launch the stated independent research career.

• Describe current activities and how they relate to the candidates career developmentplans and career goals.

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• Describe proposed activities, e.g., those that will lead to new and/or enhanced researchskills and knowledge, as well as related skills such as grant-writing, communication,leadership, and laboratory management.

• The career development plan must be specifically tailored to meet the needs of thecandidate and the goal of achieving independence as a researcher.

• Describe how the skills and knowledge obtained during the mentored phase will enhanceresearch productivity and facilitate the development of new approaches and directionsfor investigation.

• Describe how the career development plan will promote the candidates success andtransition to scientific independence.

• Candidates must justify the need for the award, particularly the mentored (K99) phase,and must provide a convincing case that the proposed period of support (1-2 yearsas a mentored candidate followed by up to 3 years as an independent scientist) willsubstantially enhance his/her career and/or will allow the pursuit of a novel or promisingapproach to a particular research problem.

• Candidates should make clear why additional mentored research training and careerdevelopment are critical before transitioning to research independence and pursuit ofthe proposed independent phase research.

• The candidate must describe a plan, including a timeline with milestones, for evaluationof his/her progress during the mentored phase and for the transition to the independentphase.The candidate and K99ŋphase-mentor (see below) must describe a specific planfor the transition to the independent phase.

1.2.4 Research Plan

All instructions in the SF424 (R&R) Application Guide, including Supplemental Instructionsto the SF424 (R&R) for Preparing an Individual Research Career Development Award (CDA)Application (K Series), must be followed, with the following additional instructions:

Research Strategy

• The research plan must span both phases of the K99/R00 award. The candidate shouldclearly indicate the research planned for each phase. This narrative should describewhat the candidate will accomplish during the mentored phase research that will enablehim/her to launch an independent research program (i.e., what does the candidate stillneed to accomplish during the mentored phase in order to compete successfully onceindependence is achieved).

• The research plan should state the significance, innovation and approach of the proposedresearch during the K99 and R00 phases of the award.

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• The research plan should provide a detailed rationale, experimental approach, and ex-pected/alternative outcomes for the proposed studies. Although it is anticipated thatcandidates will be best able to describe their current and past research, the researchplan for the R00 phase of the award should be described in sufficient detail for reviewersto evaluate the merit of this component of the application.

• Describe the relationship between the mentors research and the candidates proposedresearch. Describe how the candidate will gain independence from his/her mentors andseparate his/her scientific research program from that of the mentor(s).

Note that the page limits specify 12 pages total for the four sections described above. Thereview criteria make it clear that these documents cannot be treated in isolation and coherencebetween them is important. The following points should be considered.

• Candidate’s Background,

Although it should be clear that the candidate has great potential, it is essential toshow that they need a period of mentored training (K99) before they can competeindependently, and, presumably, before they can move to the R00 phase of the award.

– Career Goals and Objectives

∗ It should be clear that the research and training to be carried out in the awardwill contribute to the candidate’s career goals.

– Candidate’s Plan for Career Development/Training Activities During Award Pe-riod; and

∗ It should be clear that the training and development activities, combined withthe experience of the K99 research, will move the candidate from dependentto independent.

∗ It might be that training in specific skills would be needed to carry out theR00 research.

– Research Plan

∗ Must have a K99 phase that the candidate is already equipped to carry out(with mentorship)

∗ Must have a R00 phase that the candidate will be able to carry out withoutfurther mentorship after the K99 phase.

∗ Both phases should be significant and innovative.

1.3 Scored Review Criteria

Reviewers will consider each of the review criteria below in the determination of scientificmerit, and give a separate score for each. An application does not need to be strong in allcategories to be judged likely to have major scientific impact.

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1.3.1 Candidate

• Based on the candidates prior research and training experience, track record, refereesevaluations, and the quality and originality of prior research and the current application,what is the candidates potential to become a highly successful, independent investigatorwho will contribute significantly to his/her chosen field of biomedical, behavioral, orclinical related research?

• Considering the years of postdoctoral research experience to date, what is the candi-dates record of research productivity, including the quality of peer-reviewed scientificpublications?

• What is the quality of the candidate’s pre- and postdoctoral research training, withrespect to development of appropriate scientific and technical expertise?

• Given the candidates prior training, proposed career development plan, and the refereesevaluations, is it reasonable to expect that the candidate will be able to achieve an in-dependent, tenure-track or equivalent faculty position within the time period requestedfor the K99 phase of this award?

1.3.2 Career Development Plan/Career Goals and Objectives

• Are the content and duration of the proposed components of the career developmentplan appropriate and well-justified for the candidates current stage of scientific andprofessional development and proposed research career goals?

• To what extent does the proposed career development plan enhance or augment theapplicants research training and skills acquisition to date?

• Is the proposed career development plan likely to contribute substantially to the sci-entific and professional development of the candidate, and facilitate his/her successfultransition to independence?

• To what extent are the plans for evaluating the K99 awardees progress adequate andappropriate for guiding the applicant towards a successful transition to the independentphase of the award?

• Is the timeline planned for transition to the independent phase of the award appropriatefor the candidates current stage of scientific and professional development, anticipatedproductivity, and the career development proposed for the K99 phase of the award?

1.3.3 Research Plan

• Is the proposed K99 phase research significant and scientifically sound?

• Are the scientific and technical merits of the K99 research appropriate for developing theresearch skills described in the career development plan, and appropriate for developinga highly successful R00 research program?

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• Is the proposed R00 phase research significant, scientifically sound, and a logical exten-sion of the K99 phase research?

• Is there evidence of long-term viability of the proposed R00 phase research plan?

• Does the R00 phase project address an innovative hypothesis or challenge existingparadigms?

• Does the project develop or employ novel concepts, approaches, methodologies, tools,or technologies?

• To what extent is the proposed R00 phase research likely to foster the career of thecandidate as a successful, independent investigator in biomedical, behavioral, or clinicalresearch?

1.3.4 Mentor(s), Co-Mentor(s), Consultant(s), Collaborator(s)

• To what extent does the mentor(s) have a strong track record in training future inde-pendent researchers?

• To what extent are the mentors research qualifications and experience, scientific stature,and mentoring track record appropriate for the applicants career development needs?

• Is the supervision proposed for the mentored phase of support adequate, and is thecommitment of the mentor(s) to the applicants career development appropriate andsufficient?

• Does the mentor provide an appropriate plan that addresses the candidates trainingneeds, and that is likely to foster the candidates continued development and transitionto independence?

• Does the mentor describe an acceptable plan for clear separation of the candidatesresearch and research career from the mentors research, including identifying the com-ponents of the research plan that the K99 candidate may take to an independentresearch position?

– This should link to the research plan

• Are the consultants/collaborators research and/or mentoring qualifications appropriatefor their roles in the proposed K99 phase of the award? Do they provide letters ofsupport that affirm their commitment? If applicable, are the Advisory Committeemembers qualifications appropriate for their roles in the proposed K99 phase of theaward? Do they provide letters of support that affirm their commitment?

– This should link to the research plan

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1.3.5 Environment & Institutional Commitment to the Candidate

• To what extent does the institution provide a high quality environment appropriate forthe candidates development during the K99 phase of the award?

• To what extent are the research facilities and educational opportunities, including col-laborating faculty, adequate and appropriate for the candidates research and careerdevelopment goals during the K99 phase of the award? Is adequate evidence providedthat the K99 sponsoring institution is strongly committed to fostering the candidatesdevelopment and preparation for transition to independence?

– Necessary facilities should be mentioned in the research plan

• Is there adequate assurance that the required minimum of 9 personŋmonths (75% ofthe candidates fullŋtime professional effort) will be devoted directly to the researchtraining, career development, and research activities proposed for the K99 phase of theaward?

1.4 Additional Review Criteria

As applicable for the project proposed, reviewers will evaluate the following additional itemswhile determining scientific and technical merit, and in providing an overall impact score, butwill not give separate scores for these items.

• Protections for Human Subjects

• Inclusion of Women, Minorities, and Children

• Vertebrate Animals

• Biohazards

• Resubmissions

• Training in the Responsible Conduct of Research

• Select Agent

• Research Budget and Period of Support

2 Extracts from the the SF424 (R&R) Application Guide

Note that the SF424 (R&R) Application Guide,applies to all K awards and so is subordinateto the statements about the FOA in section 1 of this document Except where noted, all theinstructions in the remainder of this section come from section 7.4 K-Specific Instructions forK Applications using the SF424 (R&R) of the application guide

Application Standard Instructions found in Parts I.1 I.6 should be followed with the ex-ceptions found in this section. Section numbers referenced below (e.g. 4.2 5.6) reflect thosefound in Part I.

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2.1 Project Summary/Abstract (page I-76)

(Do not exceed 1 page): Provide an abstract of the entire application (candidate, environment,and research). Include the candidate’s immediate and long-term career goals, key elements ofthe research career development plan, and a description of the research project, as indicatedin Part I.4.4.6.

I think the ref to 4.4.6 is a typo. The following 3 paragraphs come from section 4.4.7 ofthe Application Guide.

7. Project Abstract The Project Summary must contain a summary of the proposedactivity suitable for dissemination to the public. It should be a self-contained description ofthe project and should contain a statement of objectives and methods to be employed. Itshould be informative to other persons working in the same or related fields and insofar aspossible understandable to a scientifically or technically literate lay reader. This Summarymust not include any proprietary/confidential information. Please click the Add Attachmentbutton to the right of this field to complete this entry.

The Project Summary is meant to serve as a succinct and accurate description of theproposed work when separated from the application. State the application’s broad, long-term objectives and specific aims, making reference to the health relatedness of the project(i.e., relevance to the mission of the agency). Describe concisely the research design andmethods for achieving the stated goals. This section should be informative to other personsworking in the same or related fields and insofar as possible understandable to a scientificallyor technically literate reader. Avoid describing past accomplishments and the use of the firstperson. Finally, please make every effort to be succinct. This section must be no longer than30 lines of text, and follow the required font and margin specifications. An abstract whichexceeds this allowable length may be flagged as an error by the agency upon submission. Thiswould require a corrective action before the application will be accepted.

As noted above, do not include proprietary, confidential information or trade secrets in thedescription section. If the application is funded, the Project Description will be entered intoan NIH database and made available on the NIH Research Portfolio Online Reporting Tool(RePORT, available at http://report.nih.gov) and will become public information.

The attachment must be in PDF format. (See Section 2.6 for additional information onpreparing attachments.)

2.2 Research Plan

A Research Plan is required for all types of individual K awards. The Research Plan is amajor part of the research career development plan. It is important to relate the researchto the candidate’s scientific career goals. Describe how the research, coupled with otherdevelopmental activities, will provide the experience, knowledge, and skills necessary to achievethe objectives of the career development plan and launch and conduct an independent researchcareer, or enhance an established research career.

For mentored K awards, explain the relationship between the candidates research on theCDA and the mentors ongoing research program. For most types of research, the plan should

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include: a specific hypothesis; a list of the specific aims and objectives that will be usedto examine the hypothesis; a description of the methods/approaches/techniques to be usedin each aim; a discussion of possible problems and how they will be managed; and, whenappropriate, alternative approaches that might be tried if the initial approaches do not work.

The Research Plan of a CDA is expected to be appropriate for, and tailored to the experiencelevel of the candidate, and allow him/her to develop the necessary skills needed for furthercareer advancement, and reviewers will evaluate the plan accordingly. The plan should beachievable within the requested time period. Pilot or preliminary studies and routine datagathering are generally not appropriate as the sole part(s) of a CDA research plan.

Although candidates for mentored K awards are expected to write the Research Plan,the mentor should review a draft of the plan and discuss it in detail with the candidate.Review by other knowledgeable colleagues is also helpful. Although it is understood thatCDA applications do not require the extensive detail usually incorporated into regular researchapplications, a fundamentally sound Research Plan and a reasonably detailed Approach sectionshould be provided.

In general, less detail will be expected in descriptions of research planned for the futureyears of the proposed CDA. However, sufficient detail should be provided to enable the peerreviewers to determine that the plans for those years, including the approach to be used, areworthwhile and are likely to enable the candidate to achieve the objectives of the ResearchPlan.

The PHS 398 Career Development Award Supplemental Form is comprised of sectionsfor: Candidate Information; Statement of Support (Mentors); Environment & InstitutionalCommitment to the Candidate; and the Research Plan (including Human Subjects and OtherResearch Plan Sections). Begin each text section of the Candidate Information and ResearchPlan with a section header (e.g., Introduction, Specific Aims, Background & Significance,etc). See Specific FOA for additional information.

2.3 Career Goals and Objectives

This attachment is required. Follow the page limits for the Career Development Award Firstthree items of Candidate Information in the Table of Page Limits at http://grants.nih.gov/grants/forms_page_limits.htm,unless specified otherwise in the FOA. Describe your past scientific history, indicating how theaward fits into past and future research career development. If there are consistent themes orissues that have guided previous work, these should be made clear; if your work has changeddirection, the reasons for the change should be indicated. It is important to justify the awardand how it will enable you to develop or expand your research career. You may include atimeline, including plans to apply for subsequent grant support.

2.4 Candidates Plan for Career Development/ Training Activities DuringAward Period

This attachment is required. Follow the page limits for the Career Development Award Firstthree items of Candidate Information in the Table of Page Limits unless specified otherwise inthe FOA. Stress the new enhanced research skills and knowledge you will acquire as a result

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of the proposed award. If you have considerable research experience in the same areas as theproposed research, reviewers may determine that the application lacks potential to enhanceyour research career. For mentored awards, describe structured activities, such as course workor technique workshops, which are part of the developmental plan. If course work is included,provide course numbers and descriptive titles. Briefly discuss each of the activities, exceptresearch, in which you expect to participate. Include a percentage of time involvement foreach activity by year, and explain how the activity is related to the proposed research and thecareer development plan.

2.5 Specific Aims

State precisely 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., to testa stated hypothesis, create a novel design, solve a specific problem, challenge an existingparadigm or clinical practice, address a critical barrier to progress in the field, or develop newtechnology.

2.6 Research Strategy

Follow the page limits for the Career Development Award Research Strategy, unless specifiedotherwise in the FOA. Organize the Research Strategy in the specified order and using theinstructions provided below. Start each section with the appropriate section heading Signif-icance, Innovation, Approach. Cite published experimental details in the Research Strategysection and provide the full reference in the Bibliography and References Cited section (PartI Section 4.4.9).

2.6.1 Significance

• Explain the importance of the problem or critical barrier to progress in the field thatthe 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 preventativeinterventions that drive this field will be changed if the proposed aims are achieved.

2.6.2 Innovation

• Explain how the application challenges current research or clinical practice paradigms.

• Describe any novel theoretical concepts, approaches or methodologies, instrumentationor interventions to be developed or used, and any advantage over existing methodolo-gies, instrumentation, or interventions.

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2.6.3 Approach

• Describe the overall strategy, methodology, and analyses to be used to accomplish thespecific aims of the project. Unless addressed separately in the Resource Sharing Plan,include how the data will be collected, analyzed, and interpreted as well as any resourcesharing plans as appropriate.

• Discuss potential problems, alternative strategies, and benchmarks for success antici-pated to achieve the aims.

• If the project is in the early stages of development, describe any strategy to establishfeasibility, and address the management of any high risk aspects of the proposed work.

• Point out any procedures, situations, or materials that may be hazardous to personneland precautions to be exercised. A full discussion on the use of select agents shouldappear in Item 18 below.

• If research on Human Embryonic Stem Cells (hESCs) is proposed but an approved cellline from the NIH hESC Registry cannot be identified, provide a strong justification forwhy an appropriate cell line cannot be chosen from the Registry at this time.

• If an applicant has multiple Specific Aims, then the applicant may address Significance,Innovation and Approach for each Specific Aim individually, or may address Significance,Innovation and Approach for all of the Specific Aims collectively.

• As applicable, also include the following information as part of the Research Strategy,keeping within the three sections listed above: Significance, Innovation, and Approach.

• Preliminary Studies for New Applications:

– For new applications, include information on Preliminary Studies.

– Discuss the PD/PIs preliminary studies, data, and or experience pertinent to thisapplication.

2.6.4 Progress Report for Revision Applications.

• Provide a Progress Report. Provide the beginning and ending dates for the periodcovered since the last competitive review. Summarize the specific aims of the previousproject period and the importance of the findings, and emphasize the progress madetoward their achievement.

• Explain any significant changes to the specific aims and any new directions includingchanges to the specific aims and any new directions including changes resulting fromsignificant budget reductions.

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Sample Abstracts from NIH Reporter

May 17, 2015

1 CONTROL OF SKILLED FORELIMB MOVEMENTS BYCEREBELLAR FEEDBACK CIRCUITS

Clarifying how neural circuits shape forelimb behaviors can provide insight into motor dysfunction causedby disease or injury, and can potentially improve diagnosis and treatment. The precision of skilledforelimb movements is thought to depend on the conveyance of internal copies of motor commands tocerebellar circuits that refine motor behavior. The inability to access internal copy pathways selectively,however, has made it difficult to assess their function. The goal of this proposal is to evaluate howforelimb behavior is controlled by a set of cervical propriospinal neurons (PNs) that have a simpleanatomical means by which to convey copies of pre-motor signals internally; PNs receive descendingmotor command input, and send bifurcating axonal output to forelimb motor neurons as well as to thelateral reticular nucleus (LRN), a pre-cerebellar relay. These dual projections raise the issue of whetherinformation relayed by the PN internal copy branch regulates forelimb movement. We took advantage ofthe genetic tractability of mice to: i) ablate PNs, uncovering a selective disruption of reaching behavior;and ii) manipulate PN axonal input to the LRN selectively, revealing a rapid cerebellar-motor feedbackloop. Based on these observations, we hypothesize that PN internal feedback circuits contribute tothe on-line correction of motor output during reaching. In this proposal, I aim to address three centralquestions about the organization and function of the PN circuit. During the K99 phase of the award,I will identify which aspects of forelimb movement recruit this feedback pathway by characterizing thedynamics of PN-LRN circuit activity during behavior (Aim 1). To enable assessment of the role ofPN feedback, I will develop viral tools to inhibit the PN-LRN circuit, and behavioral approaches tointroduce precisely timed perturbations of the limb (Aim 2; K99). With these methods in hand, duringthe R00 phase I will silence PN output during imposed limb perturbation to investigate the contributionof PN feedback to on-line reaching correction (Aim 2; R00). Finally, I will characterize the supraspinalcircuits that are recruited by PN feedback durin reaching correction (Aim 3). Together, these studieswill help clarify how cerebellar feedback pathways establish motor precision. The training plan, under theprimary mentorship of Dr. Thomas Jessell at Columbia University, provides a comprehensive strategyfor acquiring the necessary experimental and professional skills within an exemplary and collaborativeneuroscience environment. An experienced team of mentors and collaborators will provide training inskills critical for my short- and long-term success, including: in vivo imaging of neurl activity, acutesilencing of synaptic output, electrophysiological mapping of neural circuits, and rigorous design offorelimb behavioral assays. Focused mentor guidance, alongside frequent data presentation and formaland informal instruction, will provide the communication and leadership skills vital for my transition toindependence. In the long-term, this support will equi me to lead a laboratory that merges molecularand systems approaches to explore the neural basis of skilled movement.

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2 DISSECTION OF THE ANXIETY SUPPRESSION CIR-CUITRY

Avoidance of potential threats is highly adaptive, and decreases unnecessary exposure to risks. However,excessive anxiety and fear leads to anxiety disorders, which impact many aspects of life, from theinterpersonal to professional spheres. Although each anxiety disorder has different symptoms, they allshare a core feature: mal-adaptive expression of high levels anxiety. Here, we will study how the brainsuppresses anxiety. Prior studies showed the amygdala is largely responsible for generating high anxietyand fear, while the ventral medial prefrontal cortex (vmPFC) decreases these behaviors, possibly byinhibiting amygdala output. Indeed, in humans higher vmPFC activation correlates with lower amygdalaactivation and decreased anxiety. These data suggest the vmPFC-amygdala pathway may decreaseanxiety and fear, but they rely on correlative measures, and can’t directly test this hypothesis. I usedoptogenetics to directly test if the vmPFC-amygdala projection suppresses anxiety and fear. Remarkably,optogenetic activation of the vmPFC-amygdala pathway robustly inhibits innate anxiety and learned fear,while inhibition of this pathway increases anxiety. Intriguingly, these behavioral effects were mediated bya poorly studied region of the amygdala called the basomedial amygdala (BMA), as direct activation ofthe BMA also decreases anxiety. Now, I will map neural activity in the vmPFC-BMA circuit and dissecthow activation of this circuit decreases anxiety. I will first investigate how vmPFC activiy affects theBMA in vitro (Aim 1), uncovering the microcircuit-level dynamics underlying our behavioral findings.Next, to map the activity of the vmPFC-BMA projection, I will monitor calcium transients in the vmPFCterminals in the BMA during exploration of control and anxiogenic environments (Aim 2), revealing howactivity of this projection differs in animals with high and low anxiety. Lastly, during the independentphase, in Aim 3, I will use the skills acquired during the mentored year to characterize activity of theBMA and of its output projections during anxiety and fear. Completion of these aims will make meproficient in patch-clamping and in vivo calcium monitoring. I will learn these skills under the guidanceof a mentoring (Profs. K. Deisseroth and R.C. Malenka) and consulting (Profs. A. Losonczy and M.R.Warden) teams who have pioneering experience in using these methods and in training other researchersto employ them. Combining these new skills with my prior expertise in vivo electrophysiology will ensurea methodologically strong foundation to launch an independent lab, while dissecting how the poorly-studied BMA decreases anxiety will provide new research avenues. Importantly, my mentors have aremarkable track record in training independent researchers. This project involves experiments rangingfrom microcircuit dissection to optogenetic control of behavior, and will give us critical insight abouthow the brain dampens anxiety, and how and when it fails to do so.

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3 MEDULLARY CIRCUITRY REGULATING SLOW-WAVE-SLEEP

The sub-cortical structures regulating slow-wave-sleep (SWS) and its electroencephalogram (EEG) cor-relate are incompletely understood. Continued existence of this fundamental knowledge gap representsan important problem because it reduces our ability to modulate or appropriately manipulate the brain’ssleep circuitry and hampers our ability to treat and alleviate the physiological disorders that result fromsleep disruption. My long- term goal is to understand how Neurons in the medullary parafacial zone(PZ) contribute to the regulation of SWS and cortical slow-wave-activity (SWA), the latter of whichis linked to fundamental neurobiological processes like memory consolidation, synaptic homeostasis andcortical plasticity. The objectives in this particular application is to determine ) if selective activation ofGABAergic PZ Neurons promotes SWS and cortical SWA in freely behaving animals; 2) how GABAergicPZ Neurons are functionally, synaptically connected with circuitry capable of modulating the corticalEEG; and 3) how other non-GABAergic PZ Neurons might contribute to the regulation of SWS and cor-tical SWA. The central hypothesis is that subpopulations of GABAergic and non-GABAergic PZ Neuronscomprise a delimited node of SWS-promoting Neurons, which generate SWS and cortical SWA throughascending projections to the parabrachial nucleus and basal forebrain. The rationale for the proposedresearch is that identifying the relevant PZ Neurons that regulate SWS and cortical SWA represents acritical first step towards manipulating them and reducing the dysfunction experienced by individualswith sleep disorders. Guided by strong preliminary data, this hypothesis will be tested by pursuing threespecific aims: 1) using a newly developed and genetically targeted technique, determine if acute and se-lective activation of GABAergic Parafacial Zone (PZ) Neurons is capable of generating SWS and corticalSWA in freely behaving animals; 2) using a combination of genetically targeted mapping and optogenet-ics, determine the synaptic basis by which GABAergic PZ Neurons potently drive SWS and SWA in vivo;3) using a new cre-driver mouse line and similar techniques to those employed in Aims 1 and 2, determineif non-GABAergic PZ Neurons contribute to the regulation of SWS and cortical SWA. The approachis intellectually and technically innovative because it represents a new and substantive departure fromcontemporary circuit models of sleep regulation and because it employs a novel combination of newlydeveloped and validated genetically-driven approaches. The proposed research is significant, because itis expected to vertically advance and expand understanding of the cellular and synaptic mechanisms bywhich brain sleep is generated and the role of the PZ in this regulation. Ultimately, such knowledge hasthe potential to inform the development of treatments to reduce the dysfunction and negative healtheffects experienced by a growing number of patients with sleep disorders in the United States.

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4 THE ROLE OF CORTICAL PROJECTION NEURONS SUS-CEPTIBLE TO PROGRESSIVE DEGENERATION W

Dementia is a debilitating Neurological disorder resulting in the dysfunction of the cerebral cortex, thepart of the brain controlling perception, memory, thoughts, language, and consciousness. Frontotempo-ral lobar degeneration (FTLD) is the most common cause of Neurological impairment in the geriatricpopulation, and represents a group of clinically, neuropathologically, and genetically heterogeneous dis-orders, with significant overlap between the neurodegenerative mechanism and the clinical phenotype.Amyotrophic Lateral Sclerosis (ALS) and FTLD are highly related conditions that are considered aspart of a pathobiological spectrum, which begins in distinct regions of the body and propagates withage. Clinical pathology reveals the presence of aggregated protein inclusions that correspond to a lossof function in specific neuronal cell populations. To characterize how these pathobiological processesoccur in the neuronal populations most susceptible to disease, I developed methods to direct the dif-ferentiation of human induced pluripotent stem (iPS) cells, derived from healthy and FTLD diseasedhuman patient fibroblasts, into multiple cortical neuronal populations in vitro. Through a combina-tion of hypothesis-driven and discovery-driven approaches, cortical Neurons will be used to search fordisease-relevant differences between healthy and ALS/FTLD patient- derived Neurons. These corticalNeurons will be compared in the presence or absence of environmental stressors to search for differencesin survival, morphology, Electrophysiology, and transcriptional profiles. Furthermore, the effect of mu-tations in the chromosome 9 open reading frame 72 (C9orf72), a gene implicated for its prominent rolein both ALS and FTLD, will be studied from both transgenic mouse models and patient-derived humanIPS cells. Taken together, these studies have the potential to identify novel environmental and geneticfactors implicated in the progression of FTLD. Through the development of a human cell-based platformto model disease, coupled with known clinical and pathological symptoms, these studies would providethe foundation necessary to unravel the biological mechanisms of degeneration that occur in the agingbrain.

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