I only have 5x z-wave devices: 3x Kwikset 914, 1x Aeotec Siren Gen5 and 1x Minoston miniplug. They were all communicating fine in my ISY 5.3.0 (Firmware and UI) with the upgraded Z-wave Series 500 dongle (Version 6.82.01) added on a few months ago.  While we were away for a few days a neighbor could hear the siren going off from the street. She contacted us and we gave her the codes to enter and unplug/disarm the Siren. That fixed the main problem except for why the siren went off in the first place.  In our normal away mode, it would go off for a while if and only if someone opened one of the doors and triggered one of the Insteon in-the-jamb Open/Close sensors.  These events would have sent us a notification, but none of that happened.  I was left to think when we returned that the Siren had just gone off in the weeds. Fine. I only got it over a year ago because I thought I needed a repeater in between the straight line of sight between the front door and back door.  The back door lock wasn't always working with Series 300 Z-wave without it.  My office (location of the ISY) is only about 15 feet from (nearly line of sight of) the front door lock, which works well.  The third lock is also about 15 feet away from the ISY but through one wall into the garage.

Also when we got home none of the 4 remaining Z-wave devices were working reliably, so I quickly ordered another Minoston miniplug to go where the Siren was and repeat the signal. That didn't solve the problem.  So is it the device(s) or network?  The third garage entry door never stopped working reliably...phew. That's one. For the front door I took it apart, removed and replaced the batteries and the put it back together and the front door was working fine...Update Neighbors, Queries all worked just fine.  Well it should, it's only 15 feet away!  For the back door, brought it back to within 12 inches of ISY, removed and added it back in.  All queries and other tests of it worked...from < 3 ft.  I moved it out 10 feet away into the long open area between the front door and its eventual destination 40 feet away.  All tests still good.  Moved it 20 feet closer to final destination...still good. Moved it the last 15 feet and couldn't communicate with it.  The same scenario was repeated for the new repeater.  Works at < 3 ft, and at 10 feet line of sight but not at 25 feet (around the corner but still only through one wall).  Also, same scenario with the siren being removed and added back in to its formerly good spot. The neighbors seem to be updating correctly at each stage from the Front Door (Show Information in Event Viewer).  And the same with the Garage Entry Door.

If I go back to the Siren going off while we were gone, I wonder whether the siren malfunction was the cause or the effect of something else in the Z-wave network.  I'm willing to do a dongle reset if needed and then add everything back in.  Could the Z-wave dongle have just failed...sort of?  Why does the back door lock work at closer ranges but not 45 feet away in direct line of sight of the front door lock.  Did the back door lock (and not the other two) just fail coincidentally with the Siren inexplicably going off?  Could it be something in the ISY z-wave dongle?  I'd like to have smart locks that can be controlled with the ISY and its other 50+ insteon devices. 

What are some other troubleshooting steps that I can take?   

You have a week mesh. The siren has always been one of the strongest/best range extenders. With it no longer there, your range has been impacted.

Zwave could have automatically healed itself over time but with limited repeaters has no other pathways which is why you've experienced the issues that you have 

I am almost to the point where I was thinking the same thing.  Not ISY. Not the locks. Not ISY z-wave dongle or network. It must be the missing siren.  Any recommendation for an equally strong repeater like the siren.  I've looked for a way to disable the siren and just have it be a repeater, but I admit not very thoroughly.  Thanks for the clear concise evaluation.