Sorry, but a hardware-based solution isn't going to be much different.
I say this because for years, software applications like 3DS Max/Viz required a hardware dongle latched onto the back of one's workstation before the app would even launch (it was replaced by a software version of C_DILLA eventually). Before and after, it was almost trivial to emulate the hardware, its responses, and 'plug' the emulated hardware into a virtual port. Today, most mobos don't have as much variety of hardware I/O (you're lucky to find a serial port nowadays), which probably means USB, HDMI, or Thunderbolt... and the original 3DS dongle required a parallel port, FFS.
Even comparisons of input-to-screen don't mean much, because the eventual circumvention/cheat will emulate one, the other, or both, and send the 'results' to who/whatever is monitoring the user's gameplay.
Furthermore, I daresay that once money gets involved (via eSports), the incentive to built/implement a seamless means of circumventing the cheat-detector will be far greater than the motivation of some asshat griefer who wants to punk on a few pub server players.