Bioequivalence and Bioavailability Forum

Hideehoo!

❝ Sorry. What was the question (see subject line)?

Rana asked:

❝ In what cases we do observe an intersubject variability is less than intrasubject variability?

And I answered that I have no idea why. Sounds counterintuitive first, but it happens.

❝ ❝ ❝ Is it a convergence/optimizer thing?

❝ ❝ Don’t think so. If you give me some days I will dig out a data set.*

❝ Can play with the data if my SAS is again in reach to me.

Stupid enough PHX/WNL has no problems with this dataset. A while ago I explored some of my studies. Checked the six most extreme ones where CV_intra > CV_inter. All could be fitted with a mixed-effects model. Crazy when you want a software to crash and it doesn’t. Will try to find a problematic dataset (no promises).

❝ Using ML or REML usually implies that variance-covariance terms are fitted with the constraints that they must be >= 0. At least in SAS this is the default setting which must be overred if you want an unconstrained solution.

Same in PHX/WNL.

❝ Maybe the WinNonlin doesn't obey this reasonable rule? And therefore the between-subject variance may come out as negative. Or what is meant here?

I’ve I recall it right (where the hell is my dataset?), the analysis is performed but the warning is thrown.

❝ BTW: Liu & Chow have a chapter dealing with negative between-subject variance in the context of ordinary ANOVA (i.e. using the least square optimizer in fitting the model with all effects fixed). Don't remember the chapter number exactly.

7.3.1