Re: advan8 vs. advan13

----- Original Message ----- From: Nick Holford Date: Monday, November 2, 2009 3:00 pm Subject: Re: [NMusers] advan8 vs. advan13 To: nmusers > Pavel, > > Your model for bioavailability (BIO) (as interpreted by Bob) > uses a > random effects model that is based on the normal distribution: > > BIO=THETA(1) + ETA(1) > > Because there is no constraint on ETA(1) this can lead to > negative > values or positive values greater than 1 for individual BIO > which is not > realistic. > > You could avoid negative individual values of BIO by using this > parameter random effect model which is based on a lognormal > distribution: > BIO=THETA(1) * EXP(ETA(1)) > > However, the lognormal distribution can generate BIO values > greater than > 1 which once again is not realistic. > > So Bob has illustrated how to use a different random effects > model based > on the logistic distribution. This will constrain BIO to lie > between 0 > and 1. > > MU_1=THETA(1) > EXPP=MU_1+ETA(1) > BIO=1/(1+EXP(-EXP(EXPP))) > > The value of THETA(1) will be a bit harder to interpret because > it will > be the logit of bioavailability. You can get a more > interpretable value > of THETA(1) with this code: > > LBIO=LOG(THETA(1)) > MU_1=LBIO/(1-LBIO) > EXPP=MU_1+ETA(1) > BIO=1/(1+EXP(-EXP(EXPP))) > > Bob, > > I think you can avoid the test for values of EXPW which could > cause > overflow by calculating BIO as shown above. This relies on the > compiler > rounding large negative values of exp() to a value of zero which > is the > usual behaviour. > > Best wishes, > > Nick > > Bauer, Robert wrote: > > Pavel: > > Regarding your statement: > > Another thing I noted is that when IMP is used, the lower > boundary for > > bioavailability cannot be 0 > > > > Typically, Monte Carlo methods try a large number of etas, > from > > negative infinity to positive infinity. You may want to > remodel your > > bioavailability to something like: > > > > MU_1=THETA(1) > > EXPP=MU_1+ETA(1) > > IE (EXPP>100.0) EXPP=100.0 ;protect against floating overflow > > EXPW=EXP(EXPP) > > BIO=EXPW/(1.0+EXPW) > > > > This way, BIO will always be between 0 and 1, regardless of > eta value > > You can now remove the boundaries to the theta. > > > > > > > > *Robert J. Bauer, Ph.D. > > Vice President, Pharmacometrics > > ICON Development Solutions* > > > > *Tel:* (215) 616-6428 > > *Mob: *(925) 286-0769 > > *Email: Robert.Bauer > > *Web:* www.icondevsolutions.com > > > > > > > > > > > > > > > > --------------------------------------------------------------- > --------- > > *From:* owner-nmusers > > [mailto:owner-nmusers > > *Sent:* Sunday, November 01, 2009 1:57 PM > > *To:* nmusers > > *Subject:* Re: [NMusers] advan8 vs. advan13 > > > > Pavel, > > > > The TRANSn option is only meaningful for those ADVANs (i.e. 1- > 4,11,12) > > which implement a closed form solution of the PK model. TRANS1 > does > > nothing except keep the linker happy. Because it is the > default it > > need never be explicitly specified for ADVAN5-9,13. > > > > "TRANS1 Dummy, or null, translator; may be used with all > ADVAN > > routines. It is the default." NONMEM7 Help > > > > Adding it to those ADVANs which solve ODEs or use matrix > exponential > > solutions should make no difference to anything. If you find > that > > adding TRANS1 changes the behaviour of ADVAN8 then this is a bug. > > > > Nick > > > > > > nonmem > > > Hello Nonmem Users, > > > > > > When I tried simple simulations and changed advan13 to > advan8, some > > concentrations changed. Equations were stiff. Then I added > TRANS1 to > > the $SUBROUTINE statements. ADVAN13 output did not change. > ADVAN8 > > output changed and looked exactly like ADVAN13 output. Do you > know > > what happened? > > > > > > (Another thing I noted is that when IMP is used, the lower > boundary > > for bioavailability cannot be 0.) > > > > > > Thanks, > > > Pavel > > > > > > ----- Original Message ----- > > > From: nonmem > > > Date: Sunday, November 1, 2009 8:34 am > > > Subject: Re: [NMusers] advan8 vs. advan13 > > > To: nmusers > > > > > > > It seems like advan8 has integration difficulties when > both LAG > > > > time and variability in Ka are implemented. Method=IMP has > > > > dificulties when advan8 has integration difficulties. Instead > > > > if reporting issues, it keeps running. The objective function > > > > is very low even when bioavailability is almost zero. Removing > > > > LAG and eta of Ka may fix it. > > > > > > > > ----- Original Message ----- > > > > From: nonmem > > > > Date: Sunday, November 1, 2009 12:04 am > > > > Subject: [NMusers] advan8 vs. advan13 > > > > To: nmusers > > > > > > > > > Hello NONMEM users, > > > > > > > > > > Because advan13 was recomended for both stiff and nonstiff > > > > > differential equations, I used it for stiff differential > > > > > equations. It appeared that some results looked too sensitive > > > > > to a parameters representing a "slow" processes. I did not > > > > > observe it with nonmem6. When I used advan8, the objective > > > > > function changed from 10228.853 (the final value; diagnostic > > > > > plots looked good) to 5512.594 (the first value; I im still > > > > > waiting for the final value of the objective function). > > > > > > > > > > Does it mean that advan13 should be used with caution > when the > > > > > equations are stiff or advan13 cannot replace advan8? > > > > > > > > > > Thanks, > > > > > Pavel > > > > > > > > > > > > > -- > > Nick Holford, Professor Clinical Pharmacology > > Dept Pharmacology & Clinical Pharmacology > > University of Auckland, 85 Park Rd, Private Bag 92019, > Auckland, New > > Zealand > > n.holford > > mobile: +64 21 46 23 53 > > http://www.fmhs.auckland.ac.nz/sms/pharmacology/holford > > > >