Reminds me of tripwire which creates cryptographic checksums of the files you specify. Install a copy of the system you are checking from known good source (DVD for example), install the same updates of the target system), have tripwire create the checksum file. Copy tripwire's checksum file to the target system, have tripwire compare checksum file with target system's files.
Out of sync updates / upgrades / installs / system specific configuration files will of course be flagged / marked as changed.
I should also add that the target system must be checked offline. If the target has been compromised, the hardware, boot firmware, os kernel, kernel drivers, system libraries, binaries may have already been compromised and interfere or return false positives. Even running across a network into the target system might not be safe since the (compromised) target system would be processing the network packets, file system, block device, etc. localy.
The smallest comparable scenario that comes to mind are smart cards (EMV used in credit cards, PIV used by federal government, etc.). Disregarding wireless interfaces, and all the hw/electrical/rf protections, the contact interface is essentially a serial port, three wire, or two wire. The API is standardized and white boxed so everyone agrees it is impervious. Did they protect the data in transit, in runtime memory, at rest in flash memory?
But the implementation is closed source. A backdoor may exist in the hardware to copy the entire runtime and flash memory out. Others may manipulate the data in transit between the hardware and the internal memories, Smart Card OS, or I/O from/to the card. Even if hw/fw/sw/compilers are open source, you would have to audit everything at every step and still you could miss something you/everyone else didn't think of. The paranoia can send you into a white rubber room.
Sorry for running off on a paranoia tangent. Seriously, take the target drives out to test. You only have to worry about the target drive hw/fw then. Better yet, just take out the HDD platters / SSD flash chips to test (assuming your test system is golden). ;)