I was finding some strange results (or at least perceived as strange) after using the Skyline feature detection, which made me wonder if some parameters in Hardklor/Bullseye needed to be tweaked. At the moment, I don't think that was the problem, but I was actually having issues with the pre-existing parameters in the blank skyline file from which the feature detection wizard is started. If I open Skyline and request a blank document, I now know to check in the molecule settings whether any libraries have been checked. If so, then at some point the feature detection wizard and Skyline crashes. I think you already know about that. The other thing that I'm pretty sure about is that the 'ion type' in the filter tab of transition settings has to be just 'p'. For some reason, I once had 'p,f', which resulted in very strange precursor transition predictions. To my eye, the C12, 1xC13, and 2xC13 relative ratios might look really good, but Skyline would say the idotp was really crappy, like 0.4. Then I noticed that the library predictions for the precursor were that C12 had no intensity (zero), and C13 and 2xC13 had predicted intensities. There may be other parameters of the blank skyline file that are important, but those two were pretty big. The impute boundaries for missing peaks probably should be checked, too.
Oh, there was something in the wizard that I didn't understand. My ms1 scans are actually all centroided, but if I say they are centroided and click 'next', the following window says that I'm using an orbitrap at resolution 60000 at m/z 400. I'm not sure if that affects Hardklor, given that I'm actually using centroided data acquired at a resolution of 30000 at m/z 200. So if I click 'back' and change it to orbitrap/30000/200 and click next, then click 'back', then change it from orbitrap to centroid, then 'next' again, the window then correctly has the parameters of resolution 30000 at m/z 200. Sometimes in that window those parameters are greyed out and can't be changed, but sometimes they aren't greyed out (usually they are). Anyway, I don't know whether that matters, but it seemed like odd behavior.
In the end, I think I can get Skyline to do what I want.