Simulations: Can subject specific initial values be used?

From: Pavel Kovalenko musor000@optonline.net Subject: [NMusers] Simulations: Can subject specific initial values be used? Date: Sunday, March 28, 2004 12:15 PM Dear, Nonmem users, I wrote a simulatin code for a problem similar to problem #45 descibed by Gabrielson and Weiner. The code works, but it is obvious that if a problem is more complex or sandard deviations of ETAs are large, then the approach will not work. There are the following problems: 1. NONMEM generates few negative dependent variables. It here a way to make them equal to zero (IF (CP.LT.0) CP=0) without changing the $SIGMA record? 2. For some subjects/simulations optimization procedure may not converge well. Is there a way to provide subject specific initial values of THETA (or initial estimates of ETAs)? Ideally, subject specific initial estimates should be taken from simulation problem and used in the estimation problem. The code and data are below. Kind regards, Pavel Kovalenko $PROB 0. DUMMY SIMULATION (SINGLE SUBJECT, TWO DOSES) ;This problem is only here to allow the use of the seed (-1) later on. ;THIS PROBLEM MUST BE OUTSIDE OF THE SUPERPROBLEM; OTHERWISE, ;THE SEED OF -1 CANNOT BE USED $INPUT EVID TIME CP=DV DOSE=AMT MDV ID $DATA PK45DIF3.DA IGNORE # $SUBROUTINES ADVAN6 TOL=5 ;TOL - THE NUMBER OF ACCURATE DIGITS $MODEL COMP=(DEPOT,DEFDOSE) COMP=(CENTRAL,DEFOBS,NOOFF) $THETA (.04,4,40) (.1,10,100) (.001,0.33,10) $OMEGA DIAGONAL(3) 0.8 2 0.066 ;VARIANCE OF ETA $SIGMA 1 ;$EST MAXEVAL=9990 SIG=5 PRINT=5 $PK K1=THETA(1)+ETA(1) V2=THETA(2)+ETA(2) K2=THETA(3)+ETA(3) S2=V2 CL2=K2*V2 $DES DADT(1)=-K1*A(1) DADT(2)= K1*A(1)-K2*A(2) ;A(2) = CP $ERROR CONC=F Y=CONC+ERR(1) ER=ERR(1) ;IPRED=CONC ; individual-specific prediction ;IRES=DV-IPRED ; individual-specific residual ;IWRES=IRES/CONC ; individual-specific weighted residual $SIMULATION (73010) ONLY SUBPROBLEMS=1; ;*********************************************************************; $SUPER SCOPE=2 ITERATIONS=10 $PROB 1. SIMULATION -- SINGLE SUBJECT -- SUPERPROBLEM ;THIS PROBLEM SHOULD NOT INCLUDE PK AND DES STATEMENTS. ;OTHERWISE, NONMEM REQUESTS $SUBROUTINE LIBRARY. ;IF $SUBROUTINE LIBRARY IS ADDED, G77 GENERATES ERROR: ;G77.EXE: FSUBS.FOR NO SUCH FILE OR DIRECTORY. $INPUT EVID TIME CP=DV DOSE=AMT MDV ID $DATA PK45DIF3.DA REWIND $THETA (.4,4,30) (1,10,50) (.03,0.33,5) $OMEGA DIAGONAL(3) 0.64 4 0.00436 ;SIGMAS OF THETA = 0.8 2 0.066 $SIGMA 1 $SIMULATION (-1) ONLY; $TABLE ID K1 K2 V2 CL2 ETA1 ETA2 ETA3 ;NOAPPEND ONEHEADER NOPRINT FORWARD FILE=PK45DIF3.SIM ;NOHEADER NOFORWARD NOPRINT FILE=PK45DIF3.SIM ;$TABLE ID K V KA ETA1 ETA2 ETA3 NOAPPEND FIRSTONLY ;********************************************************************; $PROB 2. ESTIMATION ;IT IS NOT CLEAR WHAT CAN BE DONE WHEN AN INITIAL ESTIMATE ;FOR ONE SUBJECT IS NOT GOOD. UNFORTUNATELY, INITIAL ESTIMATES ARE NOT ;SUBJECT SPECIFIC. $INPUT EVID TIME CP=DV DOSE=AMT MDV ID $THETA (.04,4,40) (.1,10,100) (.001,0.33,10) NOABORT $OMEGA DIAGONAL(3) 0.8 2 0.066 $SIGMA 1 $EST MAXEVAL=9990 SIG=5 PRINT=5 MSFO=msf POSTHOC NOABORT $TABLE ID MDV TIME DOSE CP ETA1 ETA2 ETA3 $TABLE ID K1 K2 V2 CL2 ETA1 ETA2 ETA3 NOAPPEND FIRSTONLY NOHEADER NOPRINT FORWARD FILE=PK45DIF3.EST ;$TABLE ID TIME K1 K2 V2 CL2 ETA1 ETA2 ETA3 NOAPPEND FIRSTONLY ;ONEHEADER NOPRINT FORWARD FILE=TEST.EST 4 0.00 . 400 1 1 0 0.00 0.74 . 0 1 0 0.25 2.84 . 0 1 0 0.57 6.57 . 0 1 0 1.12 10.50 . 0 1 0 2.02 9.66 . 0 1 0 3.82 8.58 . 0 1 0 5.10 8.36 . 0 1 0 7.03 7.47 . 0 1 0 9.05 6.89 . 0 1 0 12.12 5.94 . 0 1 0 24.37 3.28 . 0 1 0 25 . . 1 1 4 0.00 . 400 1 2 0 0.00 0.74 . 0 2 0 0.25 2.84 . 0 2 0 0.57 6.57 . 0 2 0 1.12 10.50 . 0 2 0 2.02 9.66 . 0 2 0 3.82 8.58 . 0 2 0 5.10 8.36 . 0 2 0 7.03 7.47 . 0 2 0 9.05 6.89 . 0 2 0 12.12 5.94 . 0 2 0 24.37 3.28 . 0 2 0 25 . . 1 2 4 0.00 . 400 1 3 0 0.00 0.74 . 0 3 0 0.25 2.84 . 0 3 0 0.57 6.57 . 0 3 0 1.12 10.50 . 0 3 0 2.02 9.66 . 0 3 0 3.82 8.58 . 0 3 0 5.10 8.36 . 0 3 0 7.03 7.47 . 0 3 0 9.05 6.89 . 0 3 0 12.12 5.94 . 0 3 0 24.37 3.28 . 0 3 0 25 . . 1 3 4 0.00 . 400 1 4 0 0.00 0.74 . 0 4 0 0.25 2.84 . 0 4 0 0.57 6.57 . 0 4 0 1.12 10.50 . 0 4 0 2.02 9.66 . 0 4 0 3.82 8.58 . 0 4 0 5.10 8.36 . 0 4 0 7.03 7.47 . 0 4 0 9.05 6.89 . 0 4 0 12.12 5.94 . 0 4 0 24.37 3.28 . 0 4 0 25 . . 1 4 4 0.00 . 400 1 5 0 0.00 0.74 . 0 5 0 0.25 2.84 . 0 5 0 0.57 6.57 . 0 5 0 1.12 10.50 . 0 5 0 2.02 9.66 . 0 5 0 3.82 8.58 . 0 5 0 5.10 8.36 . 0 5 0 7.03 7.47 . 0 5 0 9.05 6.89 . 0 5 0 12.12 5.94 . 0 5 0 24.37 3.28 . 0 5 0 25 . . 1 5 4 0.00 . 400 1 6 0 0.00 0.74 . 0 6 0 0.25 2.84 . 0 6 0 0.57 6.57 . 0 6 0 1.12 10.50 . 0 6 0 2.02 9.66 . 0 6 0 3.82 8.58 . 0 6 0 5.10 8.36 . 0 6 0 7.03 7.47 . 0 6 0 9.05 6.89 . 0 6 0 12.12 5.94 . 0 6 0 24.37 3.28 . 0 6 0 25 . . 1 6 4 0.00 . 400 1 7 0 0.00 0.74 . 0 7 0 0.25 2.84 . 0 7 0 0.57 6.57 . 0 7 0 1.12 10.50 . 0 7 0 2.02 9.66 . 0 7 0 3.82 8.58 . 0 7 0 5.10 8.36 . 0 7 0 7.03 7.47 . 0 7 0 9.05 6.89 . 0 7 0 12.12 5.94 . 0 7 0 24.37 3.28 . 0 7 0 25 . . 1 7 #