Wed Apr  9 13:28:51 CEST 2008
$PROBLEM PSMValidation
$INPUT ID HOUR EVID DV CMT AMT MDV SDE TIME
$DATA NONMEMinputdata.csvSDE  IGNORE "
$SUBROUTINE ADVAN6 TOL 6 DP
$MODEL
COMP=(CENTRAL)
COMP=(PERIPH)
       COMP = (P1)
       COMP = (P2)
       COMP = (P3)

$THETA (0 9.01 )       ; W
$THETA (0 4.97 50)     ; V1
$THETA (0 1)           ; SGW2

$OMEGA 0.5     ; V1

$SIGMA 1 FIX

$PK
M1 = 0.005
M2 = 0.005
M3 = 0.002  
V1 = THETA(2) * EXP(ETA(1))
SGW2 = THETA(3)

IF(NEWIND.NE.2) THEN
  AHT1 = 0
  AHT2 = 0
  PHT1 = 0
  PHT2 = 0
  PHT3 = 0
ENDIF

IF(EVID.NE.3) THEN
  A1 = A(1)
  A2 = A(2)
  A3 = A(3)
  A4 = A(4)
  A5 = A(5)
ELSE
  A1 = A1
  A2 = A2
  A3 = A3
  A4 = A4
  A5 = A5
ENDIF

IF(EVID.EQ.0) OBS = DV

IF(EVID.GT.2.AND.SDE.EQ.2) THEN
  RVAR = A3/(V1**2)+THETA(1)**2
  K1   = A3*(1/V1)/RVAR
  K2   = A4*(1/V1)/RVAR
  AHT1 = A1 + K1*(OBS -(A1/V1))
  AHT2 = A2 + K2*(OBS -(A1/V1))
  PHT1 = A3 - K1*RVAR*K1
  PHT2 = A4 - K1*RVAR*K2
  PHT3 = A5 - K2*RVAR*K2
ENDIF

IF(EVID.GT.2.AND.SDE.EQ.3) THEN
  AHT1 = A1
  AHT2 = A2
  PHT1 = 0
  PHT2 = 0
  PHT3 = 0
ENDIF

IF(EVID.GT.2.AND.SDE.EQ.4) THEN
  AHT1 = 0
  AHT2 = 0
  PHT1 = A3
  PHT2 = A4
  PHT3 = A5
ENDIF

IF(A_0FLG.EQ.1) THEN
  A_0(1) = AHT1
  A_0(2) = AHT2
  A_0(3) = PHT1
  A_0(4) = PHT2
  A_0(5) = PHT3
ENDIF

$DES
DADT(1)= -(M1+M3)*A(1) + M2*A(2)
DADT(2)= M1*A(1)-M2*A(2) + 0
DADT(3) = (-(M1+M3))*(A(3))+(M2)*(A(4))+(-(M1+M3))*(A(3))+(M2)*(A(4))
DADT(4) = (-(M1+M3))*(A(4))+(M2)*(A(5))+(M1)*(A(3))+(-M2)*(A(4))
DADT(5) = (M1)*(A(4))+(-M2)*(A(5))+(M1)*(A(4))+(-M2)*(A(5))+SGW2*SGW2

$ERROR
IPRED=A(1)/V1
IRES=DV-IPRED
W=SQRT(A(3)/(V1**2)+THETA(1)**2)
IWRES=IRES/W
Y=IPRED+W*EPS(1)
$ESTIMATION MAXEVALS=9999 METHOD=1 INTERACTION NOABORT SIGDIGITS=3 PRINT=5
$COVARIANCE
$TABLE ID TIME EVID IPRED IRES IWRES W ETA(1)
       NOPRINT ONEHEADER FILE=TABLE.PAR
 
 
1NONLINEAR MIXED EFFECTS MODEL PROGRAM (NONMEM)    DOUBLE PRECISION NONMEM    VERSION VI LEVEL 1.2  
 DEVELOPED AND PROGRAMMED BY STUART BEAL AND LEWIS SHEINER
 
 PROBLEM NO.:         1
 PSMValidation                                                           
0DATA CHECKOUT RUN:              NO 
 DATA SET LOCATED ON UNIT NO.:    2
 THIS UNIT TO BE REWOUND:        NO 
 NO. OF DATA RECS IN DATA SET: 1300
 NO. OF DATA ITEMS IN DATA SET:   9
 ID DATA ITEM IS DATA ITEM NO.:   1
 DEP VARIABLE IS DATA ITEM NO.:   4
 MDV DATA ITEM IS DATA ITEM NO.:  7
0INDICES PASSED TO SUBROUTINE PRED:
  3  9  6  0  0  0  5  0  0
  0  0
0LABELS FOR DATA ITEMS:
   ID    HOUR    EVID      DV     CMT     AMT     MDV     SDE    TIME
0(NONBLANK) LABELS FOR PRED-DEFINED ITEMS:
 IPRE    IRES       W    IWRE
0FORMAT FOR DATA:
 (E3.0,E8.0,E2.0,E9.0,E2.0,E6.0,2E2.0,E8.0)                                      
 
 TOT. NO. OF OBS RECS:     410
 TOT. NO. OF INDIVIDUALS:   10
0LENGTH OF THETA:  3
0OMEGA HAS SIMPLE DIAGONAL FORM WITH DIMENSION:  1
0SIGMA HAS SIMPLE DIAGONAL FORM WITH DIMENSION:  1
0INITIAL ESTIMATE OF THETA:
 LOWER BOUND    INITIAL EST    UPPER BOUND
  0.0000E+00     0.9010E+01     0.1000E+07
  0.0000E+00     0.4970E+01     0.5000E+02
  0.0000E+00     0.1000E+01     0.1000E+07
0INITIAL ESTIMATE OF OMEGA:
 0.5000E+00
0INITIAL ESTIMATE OF SIGMA:
 0.1000E+01
0SIGMA CONSTRAINED TO BE THIS INITIAL ESTIMATE
0ESTIMATION STEP OMITTED:           NO 
 CONDITIONAL ESTIMATES USED:       YES 
 CENTERED ETA:                      NO 
 EPS-ETA INTERACTION:              YES 
 LAPLACIAN OBJ. FUNC.:              NO 
 NO. OF FUNCT. EVALS. ALLOWED:    9999
 NO. OF SIG. FIGURES REQUIRED:       3
 INTERMEDIATE PRINTOUT:            YES 
 ESTIMATE OUTPUT TO MSF:            NO 
 ABORT WITH PRED EXIT CODE 1:       NO 
 IND. OBJ. FUNC. VALUES SORTED:     NO 
0COVARIANCE STEP OMITTED:    NO 
 EIGENVLS. PRINTED:          NO 
 SPECIAL COMPUTATION:        NO 
 COMPRESSED FORMAT:          NO 
0TABLES STEP OMITTED:    NO 
 NO. OF TABLES:           1
0-- TABLE  1 --
 PRINTED:                NO 
 HEADERS:               ONE
 FILE TO BE FORWARDED:   NO 
0USER-CHOSEN ITEMS 
 IN THE ORDER THEY WILL APPEAR IN THE TABLE:
   ID    TIME    EVID    IPRE    IRES    IWRE       W    ETA1
1DOUBLE PRECISION PREDPP VERSION V LEVEL 1.0  
 
 GENERAL NONLINEAR KINETICS MODEL (ADVAN6)
0MODEL SUBROUTINE USER-SUPPLIED - ID NO. 9999
0MAXIMUM NO. OF BASIC PK PARAMETERS:   4
0COMPARTMENT ATTRIBUTES 
 COMPT. NO.   FUNCTION   INITIAL    ON/OFF      DOSE      DEFAULT    DEFAULT
                         STATUS     ALLOWED    ALLOWED    FOR DOSE   FOR OBS.
    1         CENTRAL      ON         YES        YES        YES        YES
    2         PERIPH       ON         YES        YES        NO         NO 
    3         P1           ON         YES        YES        NO         NO 
    4         P2           ON         YES        YES        NO         NO 
    5         P3           ON         YES        YES        NO         NO 
    6         OUTPUT       OFF        YES        NO         NO         NO 
0NRD VALUE FROM SUBROUTINE TOL:   6
1
 ADDITIONAL PK PARAMETERS - ASSIGNMENT OF ROWS IN GG
 COMPT. NO.                             INDICES
              SCALE      BIOAVAIL.   ZERO-ORDER  ZERO-ORDER  ABSORB
                         FRACTION    RATE        DURATION    LAG  
    1           *           *           *           *           *
    2           *           *           *           *           *
    3           *           *           *           *           *
    4           *           *           *           *           *
    5           *           *           *           *           *
    6           *           -           -           -           -
             - PARAMETER IS NOT ALLOWED FOR THIS MODEL
             * PARAMETER IS NOT SUPPLIED BY PK SUBROUTINE;
               WILL DEFAULT TO ONE IF APPLICABLE
0DATA ITEM INDICES USED BY PRED ARE:
   EVENT ID DATA ITEM IS DATA ITEM NO.:      3
   TIME DATA ITEM IS DATA ITEM NO.:          9
   DOSE AMOUNT DATA ITEM IS DATA ITEM NO.:   6
   COMPT. NO. DATA ITEM IS DATA ITEM NO.:    5
 
0PK SUBROUTINE CALLED WITH EVERY EVENT RECORD.
 PK SUBROUTINE NOT CALLED AT NONEVENT (ADDITIONAL OR LAGGED) DOSE TIMES.
0PK SUBROUTINE INDICATES THAT COMPARTMENT AMOUNTS ARE INITIALIZED.
0PK SUBROUTINE INDICATES THAT DERIVATIVES OF COMPARTMENT AMOUNTS ARE USED.
0ERROR SUBROUTINE CALLED WITH EVERY EVENT RECORD.
0ERROR SUBROUTINE INDICATES THAT DERIVATIVES OF COMPARTMENT AMOUNTS ARE USED.
0DES SUBROUTINE USES COMPACT STORAGE MODE.
1
 MONITORING OF SEARCH:

0ITERATION NO.:    0    OBJECTIVE VALUE:  0.22820E+04    NO. OF FUNC. EVALS.: 5
 CUMULATIVE NO. OF FUNC. EVALS.:    5
 PARAMETER:  0.1000E+00  0.1000E+00  0.1000E+00  0.1000E+00
 GRADIENT:   0.9317E+02  0.2739E+02 -0.4065E+02  0.4604E+01
0ITERATION NO.:    5    OBJECTIVE VALUE:  0.21252E+04    NO. OF FUNC. EVALS.:17
 CUMULATIVE NO. OF FUNC. EVALS.:   50
 PARAMETER: -0.2490E+00 -0.1316E+01  0.3206E+01  0.5145E-01
 GRADIENT:   0.7643E+02 -0.5679E+02  0.4574E+02 -0.7307E+02
0ITERATION NO.:   10    OBJECTIVE VALUE:  0.20705E+04    NO. OF FUNC. EVALS.: 9
 CUMULATIVE NO. OF FUNC. EVALS.:   96
 PARAMETER: -0.2876E+00  0.5645E-02  0.2590E+01 -0.1173E+00
 GRADIENT:   0.2014E+01 -0.4051E+01 -0.3012E+00 -0.3134E+01
0ITERATION NO.:   15    OBJECTIVE VALUE:  0.20703E+04    NO. OF FUNC. EVALS.: 6
 CUMULATIVE NO. OF FUNC. EVALS.:  139
 PARAMETER: -0.2892E+00  0.8544E-01  0.2593E+01 -0.5142E-01
 GRADIENT:  -0.6817E-02  0.8832E-03 -0.1557E-02 -0.6076E-03
0MINIMIZATION SUCCESSFUL
 NO. OF FUNCTION EVALUATIONS USED:  139
 NO. OF SIG. DIGITS IN FINAL EST.:  3.7

 ETABAR IS THE ARITHMETIC MEAN OF THE ETA-ESTIMATES,
 AND THE P-VALUE IS GIVEN FOR THE NULL HYPOTHESIS THAT THE TRUE MEAN IS 0.

 ETABAR:  -0.11E-03
 SE:       0.19E+00

 P VAL.:   0.10E+01
1
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 ************************************************************************************************************************
 ********************                                                                                ********************
 ********************                           MINIMUM VALUE OF OBJECTIVE FUNCTION                  ********************
 ********************                                                                                ********************
 ************************************************************************************************************************
 





 **************************************************       2070.289     **************************************************
1
 ************************************************************************************************************************
 ********************                                                                                ********************
 ********************                                  FINAL PARAMETER ESTIMATE                      ********************
 ********************                                                                                ********************
 ************************************************************************************************************************
 


 THETA - VECTOR OF FIXED EFFECTS PARAMETERS   *********


            TH 1      TH 2      TH 3
 
         6.11E+00  4.91E+00  1.21E+01
 


 OMEGA - COV MATRIX FOR RANDOM EFFECTS - ETAS  ********


            ETA1
 
 ETA1
+        3.69E-01
 


 SIGMA - COV MATRIX FOR RANDOM EFFECTS - EPSILONS  ****


            EPS1
 
 EPS1
+        1.00E+00
 
1
 ************************************************************************************************************************
 ********************                                                                                ********************
 ********************                             STANDARD ERROR OF ESTIMATE                         ********************
 ********************                                                                                ********************
 ************************************************************************************************************************
 


 THETA - VECTOR OF FIXED EFFECTS PARAMETERS   *********


            TH 1      TH 2      TH 3
 
         1.59E-01  9.40E-01  1.17E+00
 


 OMEGA - COV MATRIX FOR RANDOM EFFECTS - ETAS  ********


            ETA1
 
 ETA1
+        1.08E-01
 


 SIGMA - COV MATRIX FOR RANDOM EFFECTS - EPSILONS  ****


            EPS1
 
 EPS1
+       .........
 
1
 ************************************************************************************************************************
 ********************                                                                                ********************
 ********************                          COVARIANCE MATRIX OF ESTIMATE                         ********************
 ********************                                                                                ********************
 ************************************************************************************************************************
 

            TH 1      TH 2      TH 3      OM11      SG11
 
 TH 1
+        2.52E-02
 
 TH 2
+       -3.65E-02  8.84E-01
 
 TH 3
+        4.38E-02  2.86E-01  1.37E+00
 
 OM11
+        1.69E-03  2.64E-02  5.67E-02  1.17E-02
 
 SG11
+       ......... ......... ......... ......... .........
 
1
 ************************************************************************************************************************
 ********************                                                                                ********************
 ********************                         CORRELATION MATRIX OF ESTIMATE                         ********************
 ********************                                                                                ********************
 ************************************************************************************************************************
 

            TH 1      TH 2      TH 3      OM11      SG11
 
 TH 1
+        1.00E+00
 
 TH 2
+       -2.44E-01  1.00E+00
 
 TH 3
+        2.35E-01  2.59E-01  1.00E+00
 
 OM11
+        9.87E-02  2.60E-01  4.48E-01  1.00E+00
 
 SG11
+       ......... ......... ......... ......... .........
 
1
 ************************************************************************************************************************
 ********************                                                                                ********************
 ********************                  INVERSE COVARIANCE MATRIX OF ESTIMATE                         ********************
 ********************                                                                                ********************
 ************************************************************************************************************************
 

            TH 1      TH 2      TH 3      OM11      SG11
 
 TH 1
+        4.71E+01
 
 TH 2
+        2.67E+00  1.40E+00
 
 TH 3
+       -1.91E+00 -2.87E-01  1.02E+00
 
 OM11
+       -3.58E+00 -2.15E+00 -4.00E+00  1.10E+02
 
 SG11
+       ......... ......... ......... ......... .........
 
Wed Apr  9 13:29:00 CEST 2008
