Choosing a topic for a NIH proposal

I'm reading some excellent grantwriting advice from the Nov. 12 issue of the NIH NIAD newsletter. It frames its suggestions with the instructions given to NIH reviewers, emphasizing that the most important thing they're looking for is evidence that the proposed research will have a significant impact on the field:

"Your ultimate task is to judge the likelihood that the proposed research will have an impact on advancing our understanding of the nature and behavior of living systems and the application of that knowledge to extend healthy life and reduce the burdens of illness and disability. Thus, the first assessment should be “Is it worthwhile to carry out the proposed study?”"

This is excellent advice, and I'm going through the draft we have now, identifying places where we can point to impacts in various fields (pathogenesis, recombination, evolution).

But I have a harder time relating to another part of the advice, on how to choose a topic to propose research on. It appears to be directed at people who know they want to get a research grant but don't really care what topic they'll be researching. "I know how to do A, B and C, so I'll propose to find out D."