Profitability of one route in a network is difficult to calculate objectively and is not of much use. A network's value is much more than the sum of its parts (the individual routes).

Sure, something like the NE Shuttle is primarily O&D, where most passengers don't care what kind of network the airline has. But even then, you have to consider the value of the DCA and LGA slots -- i.e., what flights are NOT being flown in order to fly between LGA and DCA (i.e., what is the opportunity cost?)

On the flip side of this discussion, the use in looking for least profitable routes (e.g., to cut costs) can be overused. If TWA, which has been continuously losing money, decided to drop all routes except LAX-JFK, would they stay in business? Maybe so, but I doubt it. For one thing, FF miles would be practically useless on a one-route airline.