Conditions for choosing quantifying and qualifying ion in LC-MS/MS

In my PhD-work, we are trying to develop LC-MS/MS methods for targeted analysis. Usually, I determine my quantifying ion/fragment based on a few different criteria:

• If there is a 13C internal standard of identical structure, stick with the same fragment for both.
• If not, look for the lowest noise/highest area/lowest LOD
• If two fragments are similar in the previous manner, I have a look if there are different levels of contamination in the method blanks

For most compounds, that works, but for a small subset I have the case where the method blanks are similar, but for the fragment with the lowest LOD, noise is highest and/or areas are lowest between the two fragments we analyze for.

Would you go for the fragment with the highest area, highest noise (assuming a large number is more robust against small changes) and the highest LOD, or the lowest one? Is there a best practice I can refer to? There is a 1-2 order of magnitude difference between the LODs, so I really don't want to misrepresent the data.

Thanks in advance!