Quite a while back, I began--but never completed--a series on how to structure an effective R01 application. So far we have covered the Specific Aims and Background & Significance sections. Although the next consecutive section of an R01 app is the Preliminary Studies, in response to reader requests, we will skip over that for now and treat the Research Design & Methods. This is the section of the grant where you flesh out your Specific Aims in detail, and provide the specifics of your experimental plans.
(Detailed guidelines are inside the crack.)
The Research Design & Methods section begins with a paragraph or two that essentially summarize the entire Background & Significance and Preliminary Studies sections. This is in keeping with the idea that every section of the grant application should be comprehensible when standing alone. You can use language like this:
In order to blah, blah, blah, it is necessary that yadda, yadda, yadda. Thus, determing the bleh, bleh, bleh and the blargh, blargh, blargh are key issues in the field of blecch. In our Prelminary Studies we have begun to explore novel approaches to determining bleh, bleh, bleh and blargh, blargh, blargh, and observe that ying, yang, yaggity. These Preliminary Studies lead to the following testable hypotheses: (1) whatevs; (2) double whatevs; (3) infinity whatevs. The two (or three) Specific Aims test these hypotheses.
Then, go ahead and list your two (or three) Specific Aims in bold and/or italic typeface. After listing the Aims, write a paragraph with one sentence for each Aim that summarizes the experimental approach for that aim, like this:
Blibbity methods will be used to fling flang flog in blerg cells and measure effects on flub flab flib (Specific Aim #1). Splippity methods will be used to determine the effects of semplenter in blurg cells on flappity fling flong (Specific Aim #2).
Now you get into the nitty gritty for each of your Specific Aims individually. My practice is to break down each Specific Aim into sub-sections where each subsection corresponds to an experimental effort that would likely end up corresponding to a single figure in a manuscript. I do not number or letter these subsections, and definitely do not get into any of this "in Sub-Aim #3(A)(1)(b)(ii) blah, blah, blah". The important things to explicitly treat are not--in my opinion--really ticky tacky shit like concentrations of reagents (unless you're doing an explciti dose-response or something), but to explain the basic experimental design, including negative and positive controls.
I have never included explicit "Expected Outcomes", "Possible Pitfalls", or "Alternative Approaches" sections in my Research Design & Methods. Now that R01s are going to soon be 12 pages, no one is going to be able to include that happy horseshit, and good riddance. I do provide some basic explanation of how the possible outcomes of the experiments relate back to the hypotheses to be tested by the Specific Aims.
After the detailed treatment of the Specific Aims individually, I then conclude with two additional subsections. First, is one paragraph headed "Summary and Conclusions", which should be a completely self-contained summary of the grant application, followed by a forward-looking explanation of what the value of the proposed studies will be for the field:
We have demonstrated in Premiminary Studies using a combination of blah approaches and bleh approaches that yadda yadda is an effective tool for YAHOO! Using this novel tool, we have presented preliminary evidence for HOLY FUCKING SHIT COOL YEAH! These preliminary studies lead to specific hypotheses concerning this, that, and the other HOLY FUCKING SHIT COOL YEAH thing. Using a combination of all sorts of TOTALLY FUCKING COOL NOVEL techniques, we test these hypotheses through the experiments proposed in the Specific Aims. The proposed studies will provide valuable information about TOTALLY FUCKING AWESOME IMPORTANT SHIT YAHOOOOO!!!!!, and thus be of great value to people who care about TOTALLY FUCKING AWESOME IMPORTANT SHIT YAHOOOOO!!!!! These studies will also provide extensive validation of TOTALLY FUCKING COOL NOVEL techniques as a general platform for investigating FUCKTONS OF OTHER TOTALLY FUCKING AWESOME IMPORTANT SHIT!! YAY!
Then you provide a brief timeline that breaks down very broadly what Specific Aims will be pursued in what years of the award, and include some justification for why certain shit will take a long time, while other shit will not. The point here is to justify your request for a full five year budget.
Having said all of this, I will also say that in my own grant reviewing, I first read the Specific Aims, and then the Preliminary Studies/Progress Report. At that point, I have already 90% made up my mind about the score, and I will look at the Research Design & Methods mostly just to see if there are any egregious problems, like impossible experiments or horribly deficient controls.