Re: Transit Absorption Model in NONMEM

On 11 December 2013 04:06, Nick Holford <[email protected]> wrote: > Siwei, > > Any kind of model misspecification will lead to inflation of the residual > error. The residual error is by definition trying to describe what has not > already been explained by the rest of the model. If the rest of the model > is mis-specified (i.e. wrong) then the residual error must become larger. > > Nick > > On 11/12/2013 8:18 a.m., siwei Dai wrote: > > Hi, Nick: > > Have been enjoying learning from you. > > A follow up question: you mentioned in your last message that model > misspecification can result in large negative simulated predictions. Can > you be more specific on this issue? In which situation it would happen? Any > type of model misspecification, or certain type of model misspecification? > I run into some situations where the diagnosis plots and VPC look alright, > but large negative predictions existed. I used exponential error > model to avoid the negative values, but have been wondering what was going > wrong. > > I appreciate your comments. > > Thanks! > > Siwei > > > > > On Tue, Dec 10, 2013 at 1:22 PM, Nick Holford <[email protected]>wrote: > >> Xinting, >> >> You are correct. Negative simulated measurements occur when you have an >> additive residual error component which is normally distributed with mean >> zero. This means that half of the additive residual errors will be >> negative. When the simulated prediction is similar in size to the standard >> deviation of the additive error distribution then adding a negative >> residual error to the non-negative prediction can make the simulated >> measurement negative. This is what happens in reality when the true >> concentration approaches the baseline noise of the measurement method. >> >> If the estimated additive residual error standard deviation is similar to >> the estimated baseline noise standard deviation then it would be reasonable >> to accept non-positive simulated measurements. On the other hand if the >> estimated additive residual error is much larger e.g. due to model >> misspecification, then it might be more sensible to use DOWHILE to reject >> the non-positive simulated values. >> >> Best wishes, >> >> Nick >> >> On 10/12/2013 10:21 p.m., Xinting Wang wrote: >> >> Dear Nick, >> >> Thanks very much for your comment. I want to follow up with you on the >> negative simulated measurements. From my experience, I also noticed that >> simulation could result in negative simulated results. This usually happens >> in the terminal elimination phase of the PK profile. I am just not very >> familiar with the origin of these values. Is it because we have the >> additive error in the model, so that some results might be negative? >> >> Thank you. >> >> >> On 10 December 2013 13:38, Nick Holford <[email protected]> wrote: >> >>> Xinting, >>> >>> The use of THETA with SIGMA 1 FIX is just a matter of style. It should >>> make no real difference to the results if you do it this way or with SIGMA >>> to describe the residual error. Others may wish to debate that fine >>> point. >>> >>> The DOWHILE loop with SIMEPS is used to enforce a simulation constraint >>> that the simulated measured value is always positive. The NEPS is there to >>> avoid getting stuck in the DOWHILE loop. >>> >>> I don't think I would bother with this DOWHILE loop today. It is quite >>> possible to have negative measured values when you use an additive residual >>> error component. I think its a more honest simulation of the residual error >>> to allow negative simulated measurements. >>> >>> Best wishes, >>> >>> Nick >>> >>> On 10/12/2013 6:13 p.m., Xinting Wang wrote: >>> >>> Dear all, >>> >>> I have some naive questions to ask you about the implementation of >>> transit absorption model in nonmem. Below is a demo code from Prof. Holford >>> in which some part of it I can not understand quite well. >>> >>> $PROB Transit delay >>> $DATA sd.csv >>> $INPUT ID TIME AMT WT DV >>> $SIM (20050830 NEW) NSUB=1 >>> $EST MAX=9990 SIG=6 ;PRINT=1 >>> METHOD=CONDITIONAL INTERACTION >>> >>> $THETA >>> (0,3) ; pop_cl >>> (1,10) ; pop_v >>> (0.1,1) ; pop_ka h-1 >>> (0.1,1) ; pop_mtt h >>> (1,5) ; pop_nt >>> $OMEGA >>> 0.09 ; ppv_cl >>> 0.09 ; ppv_v >>> 0.09 ; ppv_ka >>> 0.09 ; ppv_mtt >>> >>> $THETA >>> (0.001,0.1) ; RUV_CV >>> (0.001,1) ; RUV_SD >>> $SIGMA 1 FIX ; EPS1 >>> $SIGMA 1 FIX ; EPS2 >>> >>> $SUBR ADVAN6 TOL=3 >>> $MODEL >>> COMP (TRANSIT) >>> COMP (CENTRAL) >>> >>> $PK >>> IF (NEWIND.LE.1) THEN >>> DOSE=0 >>> TDOSE=0 >>> TLAST=0 >>> ENDIF >>> IF (AMT.GT.0) THEN >>> DOSE=AMT >>> TDOSE=TIME >>> ENDIF >>> CL=POP_CL*EXP(PPV_CL) >>> V=POP_V*EXP(PPV_V) >>> KA=POP_KA*EXP(PPV_KA) >>> MTT=POP_MTT*EXP(PPV_MTT) >>> NT=POP_NT >>> KTR=(NT+1)/MTT >>> NFAC= SQRT(2*3.1415)*NT**(NT+0.5)*EXP(-NT) >>> >>> ;Very important! >>> F1=0 >>> >>> $DES >>> DCP=A(2)/V >>> RATEIN=KA*A(1) >>> GUT=DOSE*EXP(-KTR*(T-TLAST)) >>> DADT(1)=GUT*KTR*(KTR*(T-TLAST))**NT/NFAC - RATEIN >>> DADT(2)=RATEIN - CL*DCP >>> >>> >>> >>> >>> >>> >>> >>> >>> >>> >>> >>> >>> >>> *$ERROR CP=A(2)/V Y=CP*(1+RUV_CV*EPS1) + RUV_SD*EPS2 IF (ICALL.EQ.4) >>> THEN NEPS=0 DOWHILE(Y.LE.0.AND.NEPS.LT.100) CALL SIMEPS(EPS) >>> Y=CP*(1+RUV_CV*EPS1) + RUV_SD*EPS2 NEPS=NEPS+1 ENDDO ENDIF >>> TLAST=TDOSE * >>> $TABLE ID TIME >>> CL V KA MTT >>> CP Y >>> ONEHEADER NOPRINT FILE=transit.fit >>> >>> >>> *My questions are in the $ERROR part of this code.* >>> >>> 1. I noticed that EPS1 and EPS2 is fixed, and the error is simulated >>> using RUV_CV and RUV_SD as thetas. What is the difference if I use below >>> equation: >>> Y=CP*EPS1+EPS2, and let the program to estimate EPS1 and EPS2? >>> >>> 2. What's the purpose of SIMEPS(EPS) here? From my understanding is >>> that if ICALL equals 4, then conduct a limited number of >>> Y=CP*(1+RUV_CV*EPS1)+RUV_SD*EPS2. >>> >>> Thanks to you all for your kind support. >>> >>> -- >>> Xinting >>> >>> >>> -- >>> Nick Holford, Professor Clinical Pharmacology >>> Dept Pharmacology & Clinical Pharmacology, Bldg 503 Room 302A >>> University of Auckland,85 Park Rd,Private Bag 92019,Auckland,New Zealand >>> office:+64(9)923-6730 mobile:NZ +64(21)46 23 53 >>> email: [email protected] http://holford.fmhs.auckland.ac.nz/ >>> >>> Holford NHG. Disease progression and neuroscience. Journal of >>> Pharmacokinetics and Pharmacodynamics. 2013;40:369-76 >>> http://link.springer.com/article/10.1007/s10928-013-9316-2 >>> Holford N, Heo Y-A, Anderson B. A pharmacokinetic standard for babies and >>> adults. J Pharm Sci. 2013: >>> http://onlinelibrary.wiley.com/doi/10.1002/jps.23574/abstract >>> Holford N. A time to event tutorial for pharmacometricians. CPT:PSP. >>> 2013;2: http://www.nature.com/psp/journal/v2/n5/full/psp201318a.html >>> Holford NHG. Clinical pharmacology = disease progression + drug action. >>> British Journal of Clinical Pharmacology. 2013: >>> http://onlinelibrary.wiley.com/doi/10.1111/bcp.12170/abstract >>> >>> >> >> >> -- >> Xinting >> >> >> -- >> Nick Holford, Professor Clinical Pharmacology >> Dept Pharmacology & Clinical Pharmacology, Bldg 503 Room 302A >> University of Auckland,85 Park Rd,Private Bag 92019,Auckland,New Zealand >> office:+64(9)923-6730 mobile:NZ +64(21)46 23 53 >> email: [email protected] http://holford.fmhs.auckland.ac.nz/ >> >> Holford NHG. Disease progression and neuroscience. Journal of >> Pharmacokinetics and Pharmacodynamics. 2013;40:369-76 >> http://link.springer.com/article/10.1007/s10928-013-9316-2 >> Holford N, Heo Y-A, Anderson B. A pharmacokinetic standard for babies and >> adults. J Pharm Sci. 2013: >> http://onlinelibrary.wiley.com/doi/10.1002/jps.23574/abstract >> Holford N. A time to event tutorial for pharmacometricians. CPT:PSP. 2013;2: >> http://www.nature.com/psp/journal/v2/n5/full/psp201318a.html >> Holford NHG. Clinical pharmacology = disease progression + drug action. >> British Journal of Clinical Pharmacology. 2013: >> http://onlinelibrary.wiley.com/doi/10.1111/bcp.12170/abstract >> >> > > -- > Nick Holford, Professor Clinical Pharmacology > Dept Pharmacology & Clinical Pharmacology, Bldg 503 Room 302A > University of Auckland,85 Park Rd,Private Bag 92019,Auckland,New Zealand > office:+64(9)923-6730 mobile:NZ +64(21)46 23 53 > email: [email protected] http://holford.fmhs.auckland.ac.nz/ > > Holford NHG. Disease progression and neuroscience. Journal of > Pharmacokinetics and Pharmacodynamics. 2013;40:369-76 > http://link.springer.com/article/10.1007/s10928-013-9316-2 > Holford N, Heo Y-A, Anderson B. A pharmacokinetic standard for babies and > adults. J Pharm Sci. 2013: > http://onlinelibrary.wiley.com/doi/10.1002/jps.23574/abstract > Holford N. A time to event tutorial for pharmacometricians. CPT:PSP. 2013;2: > http://www.nature.com/psp/journal/v2/n5/full/psp201318a.html > Holford NHG. Clinical pharmacology = disease progression + drug action. > British Journal of Clinical Pharmacology. 2013: > http://onlinelibrary.wiley.com/doi/10.1111/bcp.12170/abstract > > -- Xinting