From: Mark Sale - Next Level Solutions <*mark*>

Date: Mon, 19 Mar 2007 11:32:54 -0700

Dear Colleagues,

I've lately been reviewing the literature on model building/selection

algorithms. I have been unable to find any even remotely rigorous

discussion of the way we all build NONMEM models. The structural

first, then variances/forward addition/backward elimination is

generally mentioned in a number of places (Ene Ettes in Ann

Pharmacother, 2004, Jaap Mandemas series on POP PK series J PK Biopharm

in 1992, Jose Pinheiros paper from the Joint Stats meeting in 1994,

Peter Bonates AAPS journal article in 2005, Mats Karlsons AAPS

PharmSci, 2002, the FDA guidance on Pop PK). It is most explicitly

stated in the NONMEM manuals (Vol 5, figure 11.1) - without any

reference. From the NONMEM manuals it is reproduced in many courses,

and has become axiomatic. I've looked at the stats literature on

forward addition/backwards elimination in both linear and logistic

regression, where it is at least formally discussed (with some

disagreement about whether it is "correct"). But, I am unable to find

any justification for the structural first, then covariates (drive by

post-hoc plots), then variance effects approach we use (I'm sure many

people will point out that it is not nearly that linear a process,

although in figure 11.1, Vol 5 of the NONMEM manuals, it is depicted as

a step-by-step algorithm, without any looping back). Can anyone point

me to any rigorous discussion of this model building strategy?

Mark Sale MD

Next Level Solutions, LLC

www.NextLevelSolns.com

Received on Mon Mar 19 2007 - 14:32:54 EDT

Date: Mon, 19 Mar 2007 11:32:54 -0700

Dear Colleagues,

I've lately been reviewing the literature on model building/selection

algorithms. I have been unable to find any even remotely rigorous

discussion of the way we all build NONMEM models. The structural

first, then variances/forward addition/backward elimination is

generally mentioned in a number of places (Ene Ettes in Ann

Pharmacother, 2004, Jaap Mandemas series on POP PK series J PK Biopharm

in 1992, Jose Pinheiros paper from the Joint Stats meeting in 1994,

Peter Bonates AAPS journal article in 2005, Mats Karlsons AAPS

PharmSci, 2002, the FDA guidance on Pop PK). It is most explicitly

stated in the NONMEM manuals (Vol 5, figure 11.1) - without any

reference. From the NONMEM manuals it is reproduced in many courses,

and has become axiomatic. I've looked at the stats literature on

forward addition/backwards elimination in both linear and logistic

regression, where it is at least formally discussed (with some

disagreement about whether it is "correct"). But, I am unable to find

any justification for the structural first, then covariates (drive by

post-hoc plots), then variance effects approach we use (I'm sure many

people will point out that it is not nearly that linear a process,

although in figure 11.1, Vol 5 of the NONMEM manuals, it is depicted as

a step-by-step algorithm, without any looping back). Can anyone point

me to any rigorous discussion of this model building strategy?

Mark Sale MD

Next Level Solutions, LLC

www.NextLevelSolns.com

Received on Mon Mar 19 2007 - 14:32:54 EDT