Re: advan8 vs. advan13

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: [email protected]* > *Web:* www.icondevsolutions.com > > ------------------------------------------------------------------------ > > *From:* [email protected] [ mailto: [email protected] ] *On Behalf Of *Nick Holford > > *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 > > [email protected] wrote: > > 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 -----