Upon my review, A(4) is defined as GR and Kill rate. Without initial value of A(4), A(4) will remain 0.
Also you defined GR for control only and control groups were ignored. There will be no growth rate defined for all other groups. For A(5) CLPAR was given by amount of A(4) but corresponding amount was not shown in A(4). May also need to update that. Hope it helps. On Wed, Aug 9, 2023, 5:56 AM 차준석(약리학교실) <blueclou...@yuhs.ac> wrote: > Dear Ali Duchu, > > > > Hello. > > Please allow me to add my opinion. > > > > I think that you did not initialize A(4) properly. > > There are three ways to initialize A(4) that I can think of > > 1) Using the dosing record in your dataset > > 2) Adding a column containing the amount of parasites at time 0 for > each individual and drawing from that column by using ‘A_0(4) = “that > column”’ > > 3) Estimating the initial parasite amount itself by adding to $PK, > “TVBASELINEPARASITE = THETA(5)”, “BASELINEPARASITE = > TVBASELINEPARASITE*EXP(ETA(2))”, and “A_0(4) = BASELINEPARASITE” > > > > My conjecture is that you did not do “1)” and do not intend to do “1)” > either, but would like to do “3)”. Am I correct? > > > > If my conjecture is correct that you did not do “1)”, it is not surprising > that the gradient is zero. > > The reason is that your PD model will be 0 along the whole timeframe. > > You see, “DADT(4) = (GR - KILL)*A(4)” is your differential equation and if > it starts from zero, then A(4) and A(5) will stay zero. > > > > Also, I observe that you ignore the control group in the dataset > (“IGNORE(GROUP.EQ.1)”) > and then define a parameter inside an IF statement in the $PK > (“IF(GROUP.EQ.1) GR = THETA(1)”). > > I’m not sure if it will cause a problem, but wouldn’t that cause GR to be > not defined, while you do use it in $DES? > > > > Sincerely, > > Jun Seok Cha > ------------------------------ > *보낸 사람:* Ali Duchu <ali.duchu2...@gmail.com> 대신 > owner-nmus...@globomaxnm.com <owner-nmus...@globomaxnm.com> > *보낸 날짜:* 2023년 8월 9일 수요일 오후 4:16 > *받는 사람:* nmusers@globomaxnm.com <nmusers@globomaxnm.com> > *제목:* [NMusers] Help on reviewing codes > > > Dear NM users > > I have a problem I need your help, please. > > I’m trying to fit the PD model where I used PK parameters as variables in > the dataset. The model file is below, it runs BUT it seems the parameter > does not affect prediction, and hence the model terminated due to zero > gradient (see the output). > > I will appreciate your help. > > Thanks, > > Ali > > > > 0ITERATION NO.: 0 OBJECTIVE VALUE: 1255.70665291810 NO. OF > FUNC. EVALS.: 5 > > CUMULATIVE NO. OF FUNC. EVALS.: 5 > > NPARAMETR: 1.0000E-03 1.0500E+00 1.0000E-03 9.0000E-02 > > PARAMETER: 1.0000E-01 1.0000E-01 1.0000E-01 1.0000E-01 > > GRADIENT: 0.0000E+00 0.0000E+00 0.0000E+00 0.0000E+00 > > > > 0ITERATION NO.: 2 OBJECTIVE VALUE: 1255.70665291810 NO. OF > FUNC. EVALS.: 9 > > CUMULATIVE NO. OF FUNC. EVALS.: 14 > > NPARAMETR: 1.0000E-03 1.0500E+00 1.0000E-03 9.0000E-02 > > PARAMETER: 1.0000E-01 1.0000E-01 1.0000E-01 1.0000E-01 > > GRADIENT: 0.0000E+00 0.0000E+00 0.0000E+00 0.0000E+00 > > > > Here is how I wrote the model > > > > $INPUT ID TIME TAD AMT AMT2 DV EVID MDV LLOQ > > IVMAX IV2 IKA IQ IV3 IKM GROUP DOSELEV DOSE > > DOSED1 DOSED2 DOSED3 DOSED4 STUDYN TRT PBASE > > $DATA data_pd_08082023.csv IGNORE=@ IGNORE(GROUP.EQ.1) > > $SUBROUTINE ADVAN9 TOL=3 > > $MODEL COMP=(ABS DEFDOSE) > > COMP=(CENTRAL DEFOBS) > > COMP=(PERIPH1) > > COMP=(PALIVE) > > COMP=(PDEAD) > > $PK > > BSV_EC50 = ETA(1) > > > > VMAX = IVMAX > > V2 = IV2 > > KA = IKA > > Q = IQ > > V3 = IV3 > > KM = IKM > > ; scale predictions based on dose (mg) and Cp (ng/mL) > > S2 = V2 > > > > ;DEFINE PD RARAMETERS > > IF(GROUP.EQ.1) GR = THETA(1) ; Growth rate of parasite (to be > estimated from control group only) > > EC50 = THETA(2)*EXP(BSV_EC50) > > HILL = THETA(3) > > CLPAR = THETA(4) ; parasite clearance > > > > EMAX = 1/48*3.54 + 0.048 > > > > $DES > > CC = A(2)/V2 > > DADT(1) = -KA*A(1) > > DADT(2) = KA*A(1) - VMAX*CC/(KM+CC) - (Q/V2)*A(2) + (Q/V3)*A(3) > > DADT(3) = (Q/V2)*A(2) - (Q/V3)*A(3) > > > > ;;PD > > IF(CC.LE.0) CC=0.000001 > > DEN = CC**HILL + EC50**HILL > > KILL = EMAX*(CC**HILL)/DEN > > > > DADT(4) = (GR-KILL)*A(4) > > DADT(5) = KILL*A(4) - CLPAR*A(5) > > > > $ERROR > > ;OBSERVED PARASITEMIA > > PALIVE = A(4) > > PDEAD = A(5) > > > > POBS = PALIVE + PDEAD > > > > IPRED = POBS > > Y = IPRED + ERR(1) > > > > ;PD > > $THETA 0.001 ; 1 GR > > $THETA 1.05; 2 EC50 > > $THETA 2 FIX ; 3 HILL > > $THETA 0.001 ; 4 CLPAR > > ; > > $OMEGA 0.09 ; IIVBSV_EC50 > > > > $SIGMA 1 FIX > > ; Use conditional estimation with interaction > > $ESTIMATION METHOD=1 INTER MAXEVAL=9999 PRINT=5 MSFO=run400.msf > > 상기 메일은 지정된 수신인 만을 위한 것이며 부정경쟁 방지 및 영업비밀보호에 관한 법률을 포함하여 관련 법령에 따라 보호의 대상이 > 되는 영업비밀, 산업기술 등을 포함하고 있을 수 있습니다. 본 문서에 포함된 정보의 전부 또는 일부를 무단으로 제3자에게 공개, > 배포, 복사 또는 사용하는 것은 엄격히 금지됩니다. 본 메일이 잘못 전송된 경우, 발신인에게 알려주시고 즉시 삭제하여 주시기 > 바랍니다. 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