Bioequivalence and Bioavailability Forum

All is good so far.

But here's the bad: The dark forces are upon us. The lurk on every corner and we cannot escape the consequences of their hideous actions. They talk about... ... oh, forgive the typos, for my hands are shaking the very moment I think of it... they talk about "Subject nested in Sequence" and feel smug about it because it sounds fancy.


AAAAAAAAAAaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaarggggh. Gimme some garlic and some holy water. Make them go away, send them to work in the salt mines for 50 years, anything. ANYTHING!


When we talk about "Subject nested in Sequence" or "Subject in Sequence" or "Subject(Sequence)", which is all the same, then it means we try to introduce columns in X corresponding to any combo of Subject (N levels) AND Sequence (2 levels).
Let's just look at a few columns in X for subject 1 in sequence TR and subject 1 in sequence RT:


See? This is the ugly. There was only one subject called "Subject 1", she was assigned to sequence TR, so it makes absolutely no sense to speak of subject 1 in sequence RT; the corresponding column will be one of pure zero's which does not convey any info of any sort (if 0*a = 0 then what can you tell me about a?).

Does it means that people who talk about "Subject nested in Sequence" are full of sh!t?
If you ask me, then by and large yes. In some cases it makes a little sense, though.
Imagine we do not call our subjects 1,2,3 ... N like in the examples above.

In stead we assign number 1,2,3... to each subject in sequence TR.
And we assign number 1,2,3... to each subject in sequence RT.
And we make sure to keep those numbers apart. Talking about "subject 1" is now no longer sufficent for identification, so to identify the subject we need to know which sequence he/she was assigned to.

If you number your subjects this way and you construct your X following the rules above then it will make a little sense to do it, and you will arrive at EXACTLY the same columns in X as if you do it with unquely numbered subjects.

In my years of working with clinical documentation I have never ever seen a CRO or clinic use anything but uniquely numbered subject identifiers. Actually these are always the randomsation codes and these are always unique, right? This is why it really doesn't make practical sense to speak of "Subject nested in Sequence". It isn't wrong per se but it involves a lot ridiculous and meaningless matrix algebra which doesn't give any info at all.
So stay good: if you work with unique randomisation numbers assigned to the subjects (and you do, I know you do!) then just forget about the nesting stuff.