Advice on how to apply for the NIH K99/R00 Pathway to Independence Award

I received a lot of high-level advice on my NIH K99/R00 Pathway to Independence Award: start early, training is important, but the most actionable pearls were accumulated over a period of 6 months. Here they are, distilled for you.

While the emphasis is on the K99/R00 Pathway to Independence Award, most of this advice applies to NIH grants in general.

A little about my credentials. I applied for the K99 from @NHGRI in February 2020. I was funded on first submission, with a Summary Statement that included, “The GNOM-G review panel expressed outstanding enthusiasm for this outstanding application.”

The K99/R00 mechanism is very competitive, and some institutes are more competitive than others at some NIH institutes. The funding lines for the K99 at different NIH Institutes are publicly available. If you have a choice of where to submit your Proposal, this could be one important piece of information to consider. See Training…>Career Development Awards: https://report.nih.gov/funding/nih-budget-and-spending-data-past-fiscal-years/success-rates

Some good news: There is no citizenship requirement for the K99.


It is important to note that US citizens or permanent residents are also eligible for other NIH career transition awards (e.g., K08, K21). Contact your Program Officer to see what awards you are eligible for.

1. Which NIH Institute? A major consideration is to decide up front which NIH institute your grant will be submitted to. If it is not obvious, use matchmaker to decide potential NIH Institutes, and contact Program Officers at those potential Institutes.


Use NIH Matchmaker to assess your fit. Do you know about NIH Matchmaker? I didn’t. Submit a string of text (i.e., your Specific Aims page), and you will see which institute your text most aligns to. Here are the results of my Specific Aims page. https://reporter.nih.gov/matchmaker


The point is not to hack the system. The point is to see how the presentation of your research aligns with the institute you are targeting. One note: this does not factor in the size of the institute. NCI’s budget is 10x that of NHGRI. Just because your grant aligns more with NCI may partly reflect the size of the institute.


Matchmaker also points you to related grants. These are funded and thus important data points. What are the titles of these grants? What keywords are in the abstracts of these grants? Pay careful attention here.


More broadly, do the same thing for grants funded by the institute you will be applying to. What types of grants are funded? What keywords do those grants use?


Look at the mission statement of the NIH institute you are applying to. What keywords are used? You will want to frame your application in a way that naturally fits in with the mission of the institute. Include mission-specific language in your grant proposal.


2. Talk to the Program Officer (PO) Before You Apply. Does your research fit with the mission of the specific NIH Institute? Ask the Program Officer at that Institute! This conversation starts with a Specific Aims page, and the email looks something like this, “Would you have time to discuss the topical fit of my current research for a K99 at NHGRI? Attached is a Specific Aims document.”


The Program Officer I spoke to at NHGRI, Mike Pazin (@MikePazin), was generous with his time and helped me to understand the mission of the institute and what aspects of my research proposal fit.


I believe that it is best to speak with your Program Officer on the phone or by Zoom. There is a lot of nuance that can’t be communicated by email. They won’t say they will fund you. But they may say, “I really like Aim 1. But Aim 2 is outside of our mission.” Politely ask why. In my experience, aims may need minor adjustment rather than completely new science.


These conversations are valuable to learn about institute-specific guidelines.


3. Get a hold of as many applications as possible from your colleagues. Ask for the full application. This will include not just the research plan, but the training plan, the biosketch, and many letters of recommendation.

It is particularly helpful if your colleagues are willing to share their Summary Statement that they received after their application was reviewed. What landed well? What didn’t? These applications don’t need to be in your field. Funded applications are great, but unfunded applications are also valuable.


As with research papers, weigh and consider these applications. Just because it was funded, does not mean it is flawless. Take notes on the components you like, which you would like to draw from (how a Training Plan is structured, the components of a Specific Aims page).


4. Talk to People Who Were Funded by the Institute You are Applying to. For example, the two people who were funded by NHGRI said their first submission was criticized for not having a professor who specialized in statistics on their advisory committee.


Is that a requirement for a K99 at NHGRI? I don’t know, but @jkpritch had already given me very valuable advice on my project. He graciously agreed to be on my advisory committee.

5. Your Project Should be Interesting AND Important. Many projects are one or the other but not both. Ask your colleagues. Find the people who will give you critical feedback. Cordial will not serve you! Is this interesting and important? If they say no, maybe they don’t understand your grant. Maybe your reviewer won’t understand it either, though. Take their advice seriously.

6. Allocation of Your Time During Your Writing Process. The Research and Training Plan are 12 pages combined. The Specific Aims is 1 page. You should spend at least half of your time on your Specific Aims page.


Why? The amount of time you spend on each section should be commensurate with the importance of that section. There is a good chance that the Specific Aims page is the only page read by the entire review committee. It needs to be flawless.


It is difficult to overstate the importance of this page. The reviewers should understand your whole grant from this one page. You also need to include training in the Specific Aims page. This helps to show that you are taking the training seriously.


Remember, use the Bible to help you craft a compelling Specific Aims document. Share your document with as many people as possible. I shared my Specific Aims with over 15 people over the course of 5 months. I had more than 50 revisions before it was finished.


Once your Specific Aims is flawless, you will be able to effortlessly write the other sections (maybe not effortlessly, but you get my point). I started sharing my Specific Aims document with colleagues 5 months before the NIH deadline.


7. Advice for your Specific Aims. Here are some points on your Aims. When writing your Specific Aims, we often want to promise the world, only to hear that our Research Plan is unrealistic.


Let me emphasize this point: I don’t know of anyone whose Research Plan was criticized for being too incremental. Many are deemed unrealistic, though. When in doubt, narrow your focus.


Format for each of the Specific Aims: To WHY, I will WHAT. Most Specific Aims are just WHAT you will do. Remember, your reviewers are likely NOT in your field! Tell them why you want to do that thing! For example, “To develop a modular tool to regulate gene expression, I will synthesize and test synthetic transcription factors that target the repeat expansion in frataxin.”


Make it clear what parts will be completed during the K99 phase and what parts are for the R00 phase. Not doing so is a common critique.


Your aims can be dependent. This may depend on institute, so check with your Program officer. Nevertheless, if your aims are dependent on one another, you need to convince your reviewers that the aims are achievable.

Ways to convince reviewers are 1) your previous experience and success in this or related fields and 2) preliminary data.

8. Show a Logical Progression in Your Research Trajectory. I have seen critiques wondering about the career progression of a trainee. A logical career progression suggests you have a vision, and you will be successful. An aside, I love this commencement speech from Steve Jobs, who gives a related point.


“You can’t connect the dots looking forward; you can only connect them looking backward. So you have to trust that the dots will somehow connect in your future.” https://youtu.be/UF8uR6Z6KLc?t=212

9. Distinguish Yourself from Your Mentor. My project is focused on DNA repeats, which is different than my advisor’s interest, @SnyderShot, so I was fine here. But this is important, and you need to take it seriously. Your advisor’s letter of recommendation MUST mention that you can take this research with you.

10. Buy this Book. I refer to this book as the Bible. Crystal Botham, director of the Grantwriting Academy at Stanford @SUGrantWriting, first recommended it to me (and many others!). Lots of nuts and bolts advice on how to structure your grant. http://www.grantcentral.com/workbooks/national-institutes-of-health/


It is formatted for NIH. When I saw the price ($90), I thought it was steep, but I trusted Crystal. After having used this book for a couple of years, I now think it’s worth much more.


This book provides templates for how to format every section of an NIH R01 grant. Personally, I have all the ideas in my head, but putting them down logically takes so much time. This book saves you much of that time by telling you what to write where.


After you draft your document following the template, it will evolve and feel less like the template and more like your own in successive rounds of revision.


As an aside, when I showed someone my Specific Aims at our first meeting, they said, “Oh I see. You followed the book.” Your prose comes out much more polished by following a template.

11. Find Peers who will Read Your Proposal. I was a part of a @SUGrantWriting bootcamp where we met in a group of four to share documents. Peer review was SO helpful. I highly recommend you do this with a group. The best advice always came from people outside of my field. Remember, your reviewers will likely NOT be in your specific field. Those outside your field will see the gaps in logic that you and your labmates are missing. Finding someone to read your entire proposal is unrealistic. Instead, smaller request like, "Will you reach my Significance and Innovation sections?" are much more likely to be successful.

12. Your Training Plan. The most common pitfall is not taking your Training Plan seriously. You need to thread the needle. I am amazing, AND I need more training. Remember this is a Pathway to Independence Award, not an Independence Award. Do *not* overlook the training component of the award. You need to convince the reviewers that you are highly skilled, and, at the same time, in need of more training. Do that with this sentence:


“While I have extensive training in W and X, I am new to Y and Z. Therefore, my overall objective is to obtain addition training in Y and Z and [insert objective of the research proposal here].” For me, W is chemical biology and X is molecular biology. Y and Z are bioinformatics and human genetics.


I would also mention training again in the final paragraph of your Specific Aims page. You want to show the reviewers that you are taking this component seriously.


Your training plan should be integrated into your research plan. At the end of each Aim, I had a Training section that described how the aim contributed to my career development. I also mentioned, by name, each member of my advisory team at the location where my research plan aligned with their skillset. This shows the reviewer that I have thought about the training and how each member of my advisory team is an integral part to my training.


Writing the Training Plan. Read as many other Training Plans as possible to get to get a sense for the formatting. My Training Plan is broadly divided into Research Techniques, Formal Training in Bioinformatics and Statistics, and Career Development.


I included a table to highlight the expertise of my mentor and each of my co-advisors.

Be specific! When I discussed courses that I will take, I listed their days and times, and the quarter that I planned to take them. “I will also complete GENE 218 Computational Analysis of Biological Information (Summer 2021, Tues/Thurs 1:00–3:00PM).” My goal was to show that I have thought about the course, when it is offered, and how much time it will take up.



13. Grant Figures. Grant figures could Grant figures are NOT manuscript figures. In a manuscript, your figures will have all the proper controls and convey lots of information. These manuscript figures may have very long legends to explain the figures.


You do not have that luxury in your Research Proposal. Grant figures should stand alone and require very little to no figure legends. With grant figures, you can add arrows and captions to explain what is going on, which is rarely or never done in a manuscript.


Should you add a co-mentor? It is common to add a co-mentor who will teach you skills that you have not already acquired in your current environment. Consider adding a co-mentor if you were to be trained in a new area that is beyond your current mentor’s expertise OR if your current mentor is a junior PI. Adding a co-mentor requires additional paperwork from the co-mentor. I did not add a co-mentor, and no reviewer commented on this.

14. Letters of Recommendation. For my K99, there were a total of 9 letters submitted by others on my behalf. 1 mentor letter of support, 4 letters of support from each co-advisor, 1 letter of institutional commitment from the department chair, and 3 letters of reference.


You may be asked to write a draft of the letters. I offered to write a draft of the letters to make this easier on my advisory team, who receives many such requests.


Your Mentor’s Letter of Recommendation (Mentor’s Letter). This letter is different from a standard letter of recommendation. In addition to the common elements of a letter (a description of the relationship between advisor and mentee and a description of your successes in their lab and how you compare to other trainees at a similar stage), your advisor should list their qualifications. It is helpful if they have mentored trainees who have 1) received a K99 in the past and/or 2) have gone on to successful careers in academia. Your advisor can be specific (name names and institutions!). Your advisor should also discuss the state of funding in their lab, and mention that they will cover costs in excess of your K99 allowance. The letter should also describe, in detail, your training plan. It should be consistent with the Training Plan that you wrote! Finally, the letter must [ST1] state that you can take your research with you!


Letters of recommendation from your co-advisors. These should 1) describe the expertise of the co-advisor and 2) describe how the co-advisor will assist you, the Mentee, in accomplishing your Training Goals that you described in your Training Plan. They should be specific (e.g., how often will you meet, where will you meet, what will you discuss). These letters should be consistent with your Training Plan!


15. Grantsmanship. I like Research Proposals that begin with a figure that provides an overview of the entire proposal, and end with a timeline. Here is the timeline I used to conclude my Proposal.

16. Acknowledgments. Finally, I want to acknowledge all of the people who helped my scientific career up to this point. The list is long, and I am grateful :) Aseem Ansari (@AnsariLab) is where it all began. Laura Kiessling (@ChemicalBiology) and Jay Bradner (@jaybradner) have supported me since my time in Madison. Mike Snyder (@SnyderShot) has been my biggest advocate at Stanford. Gamze Gursoy (@gamzeandgursoy) is a fantastic collaborator and friend. Looking forward to working with her for years to come.


My advisory committee is world-class. Jonathan Pritchard (@jkpritch) Steve Artandi (@SCIDirector), Alex Urban, and last but certainly not least Mark Gerstein (@MarkGerstein). The dream team!


Many people shared their proposals with me or read mine. @StevenTangPhD, @CenikLab and @KVBortle were incredibly generous, along with @ElisaTZhang, @MortezaRoodgar, @joshuagruber, @dphansti, and Dave Marciano.


Prof. Jennifer Wilson @BioEngUCLA is brilliant. Her advice was over-the-top good.


17. Great Resources. There are several other resources on the K99/R00 Pathway to Independence award. Do you have additional helpful articles? Let me know, and I’ll add them here! These are particularly good:


https://www.brains-explained.com/guide-to-applying-for-the-k99-r00/

https://k99.sbamin.com/

https://www.nia.nih.gov/research/training/k99-r00-sample-applications

http://k99advice.blogspot.com/2011/03/general-advice.html

http://pathway2insanity.blogspot.com/