Sun Sep 22 19:01:08 UTC 2024
;; Fitting common example dataset from:
;; Grasela and Donn (1985), Developmental 
;; Pharmacology and Therapeutics, 8, 374-383.
;; Description: Reparameterized final model
$PROB PPK Model for Phenobarbitol in neonates

$INPUT
ID TIME AMT WT APGR DV MDV EVID
$DATA data.csv IGNORE=@
$SUBROUTINE ADVAN1 TRANS2 

$PK
TVCL = THETA(1)*WT
MU_1 = LOG(TVCL)
CL = EXP(MU_1 + ETA(1))

TVV = THETA(2)*WT
MU_2 = LOG(TVV)
V = EXP(MU_2 + ETA(2))

S1 = V
RUVADD = THETA(3)

$ERROR
IPRED = F
 
W = RUVADD
 
Y =  IPRED+W*EPS(1)
IRES = DV - IPRED
IWRES = IRES/W

$THETA
(0, 0.01) ; CLpkg
(0, 1) ; Vpkg
(0, 0.1) ; RUVADD

$OMEGA BLOCK(2)
1 ; IIVCL
0.1 1 ; IIVV

$SIGMA
1 FIX

$ESTIMATION METH=SAEM INTER NBURN=10000 NITER=1000 ISAMPLE=5 IACCEPT=0.3 CINTERVAL=25 CTYPE=3 NOABORT PRINT=100
$ESTIMATION METH=IMP INTER PRINT=1 NITER=25 ISAMPLE=10000 EONLY=1 IACCEPT=0.3  MAPITER=0
$COV	PRINT=E UNCONDITIONAL

; Monolithic table
$TAB ID TIME AMT WT APGR MDV EVID IPRED IRES IWRES
	 CL V ETAS(1:LAST) 
	 PRED CRES CWRES NPDE NOPRINT FORMAT=s1PE13.7 
	 FILE=run16tab
NM-TRAN MESSAGES
  
 WARNINGS AND ERRORS (IF ANY) FOR PROBLEM    1
             
 (WARNING  2) NM-TRAN INFERS THAT THE DATA ARE POPULATION.

 (MU_WARNING 26) DATA ITEM(S) USED IN DEFINITION OF MU_(S) SHOULD BE CONSTANT FOR INDIV. REC.:
  WT

License Registered to: Pfizer (with RADAR5NM)
Expiration Date:    14 JUN 2025
Current Date:       22 SEP 2024
Days until program expires : 267
1NONLINEAR MIXED EFFECTS MODEL PROGRAM (NONMEM) VERSION 7.5.0
 ORIGINALLY DEVELOPED BY STUART BEAL, LEWIS SHEINER, AND ALISON BOECKMANN
 CURRENT DEVELOPERS ARE ROBERT BAUER, ICON DEVELOPMENT SOLUTIONS,
 AND ALISON BOECKMANN. IMPLEMENTATION, EFFICIENCY, AND STANDARDIZATION
 PERFORMED BY NOUS INFOSYSTEMS.

 PROBLEM NO.:         1
 PPK Model for Phenobarbitol in neonates
0DATA CHECKOUT RUN:              NO
 DATA SET LOCATED ON UNIT NO.:    2
 THIS UNIT TO BE REWOUND:        NO
 NO. OF DATA RECS IN DATA SET:      744
 NO. OF DATA ITEMS IN DATA SET:   8
 ID DATA ITEM IS DATA ITEM NO.:   1
 DEP VARIABLE IS DATA ITEM NO.:   6
 MDV DATA ITEM IS DATA ITEM NO.:  7
0INDICES PASSED TO SUBROUTINE PRED:
   8   2   3   0   0   0   0   0   0   0   0
0LABELS FOR DATA ITEMS:
 ID TIME AMT WT APGR DV MDV EVID
0(NONBLANK) LABELS FOR PRED-DEFINED ITEMS:
 CL V IPRED IRES IWRES
0FORMAT FOR DATA:
 (8E6.0)

 TOT. NO. OF OBS RECS:      155
 TOT. NO. OF INDIVIDUALS:       59
0LENGTH OF THETA:   3
0DEFAULT THETA BOUNDARY TEST OMITTED:    NO
0OMEGA HAS BLOCK FORM:
  1
  1  1
0DEFAULT OMEGA BOUNDARY TEST OMITTED:    NO
0SIGMA HAS SIMPLE DIAGONAL FORM WITH DIMENSION:   1
0DEFAULT SIGMA BOUNDARY TEST OMITTED:    NO
0INITIAL ESTIMATE OF THETA:
 LOWER BOUND    INITIAL EST    UPPER BOUND
  0.0000E+00     0.1000E-01     0.1000E+07
  0.0000E+00     0.1000E+01     0.1000E+07
  0.0000E+00     0.1000E+00     0.1000E+07
0INITIAL ESTIMATE OF OMEGA:
 BLOCK SET NO.   BLOCK                                                                    FIXED
        1                                                                                   NO
                  0.1000E+01
                  0.1000E+00   0.1000E+01
0INITIAL ESTIMATE OF SIGMA:
 0.1000E+01
0SIGMA CONSTRAINED TO BE THIS INITIAL ESTIMATE
0COVARIANCE STEP OMITTED:        NO
 EIGENVLS. PRINTED:             YES
 SPECIAL COMPUTATION:            NO
 COMPRESSED FORMAT:              NO
 GRADIENT METHOD USED:     NOSLOW
 SIGDIGITS ETAHAT (SIGLO):                  -1
 SIGDIGITS GRADIENTS (SIGL):                -1
 EXCLUDE COV FOR FOCE (NOFCOV):              NO
 Cholesky Transposition of R Matrix (CHOLROFF):0
 KNUTHSUMOFF:                                -1
 RESUME COV ANALYSIS (RESUME):               NO
 SIR SAMPLE SIZE (SIRSAMPLE):
 NON-LINEARLY TRANSFORM THETAS DURING COV (THBND): 1
 PRECONDTIONING CYCLES (PRECOND):        0
 PRECONDTIONING TYPES (PRECONDS):        TOS
 FORCED PRECONDTIONING CYCLES (PFCOND):0
 PRECONDTIONING TYPE (PRETYPE):        0
 FORCED POS. DEFINITE SETTING DURING PRECONDITIONING: (FPOSDEF):0
 SIMPLE POS. DEFINITE SETTING: (POSDEF):-1
0TABLES STEP OMITTED:    NO
 NO. OF TABLES:           1
 SEED NUMBER (SEED):    11456
 RANMETHOD:             3U
 MC SAMPLES (ESAMPLE):    300
 WRES SQUARE ROOT TYPE (WRESCHOL): EIGENVALUE
0-- TABLE   1 --
0RECORDS ONLY:    ALL
04 COLUMNS APPENDED:    YES
 PRINTED:                NO
 HEADER:                YES
 FILE TO BE FORWARDED:   NO
 FORMAT:                s1PE13.7
 IDFORMAT:
 LFORMAT:
 RFORMAT:
 FIXED_EFFECT_ETAS:
0USER-CHOSEN ITEMS:
 ID TIME AMT WT APGR MDV EVID IPRED IRES IWRES CL V ETA1 ETA2 CRES CWRES NPDE
1DOUBLE PRECISION PREDPP VERSION 7.5.0

 ONE COMPARTMENT MODEL (ADVAN1)
0MAXIMUM NO. OF BASIC PK PARAMETERS:   2
0BASIC PK PARAMETERS (AFTER TRANSLATION):
   ELIMINATION RATE (K) IS BASIC PK PARAMETER NO.:  1

 TRANSLATOR WILL CONVERT PARAMETERS
 CLEARANCE (CL) AND VOLUME (V) TO K (TRANS2)
0COMPARTMENT ATTRIBUTES
 COMPT. NO.   FUNCTION   INITIAL    ON/OFF      DOSE      DEFAULT    DEFAULT
                         STATUS     ALLOWED    ALLOWED    FOR DOSE   FOR OBS.
    1         CENTRAL      ON         NO         YES        YES        YES
    2         OUTPUT       OFF        YES        NO         NO         NO
1
 ADDITIONAL PK PARAMETERS - ASSIGNMENT OF ROWS IN GG
 COMPT. NO.                             INDICES
              SCALE      BIOAVAIL.   ZERO-ORDER  ZERO-ORDER  ABSORB
                         FRACTION    RATE        DURATION    LAG
    1            3           *           *           *           *
    2            *           -           -           -           -
             - 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.:      8
   TIME DATA ITEM IS DATA ITEM NO.:          2
   DOSE AMOUNT DATA ITEM IS DATA ITEM NO.:   3

0PK SUBROUTINE CALLED WITH EVERY EVENT RECORD.
 PK SUBROUTINE NOT CALLED AT NONEVENT (ADDITIONAL OR LAGGED) DOSE TIMES.
0ERROR SUBROUTINE CALLED WITH EVERY EVENT RECORD.
1


 #TBLN:      1
 #METH: Stochastic Approximation Expectation-Maximization

 ESTIMATION STEP OMITTED:                 NO
 ANALYSIS TYPE:                           POPULATION
 NUMBER OF SADDLE POINT RESET ITERATIONS:      0
 GRADIENT METHOD USED:               NOSLOW
 CONDITIONAL ESTIMATES USED:              YES
 CENTERED ETA:                            NO
 EPS-ETA INTERACTION:                     YES
 LAPLACIAN OBJ. FUNC.:                    NO
 NO. OF FUNCT. EVALS. ALLOWED:            288
 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
 NUMERICAL DERIVATIVE
       FILE REQUEST (NUMDER):               NONE
 MAP (ETAHAT) ESTIMATION METHOD (OPTMAP):   0
 ETA HESSIAN EVALUATION METHOD (ETADER):    0
 INITIAL ETA FOR MAP ESTIMATION (MCETA):    0
 SIGDIGITS FOR MAP ESTIMATION (SIGLO):      100
 GRADIENT SIGDIGITS OF
       FIXED EFFECTS PARAMETERS (SIGL):     100
 NOPRIOR SETTING (NOPRIOR):                 0
 NOCOV SETTING (NOCOV):                     OFF
 DERCONT SETTING (DERCONT):                 OFF
 FINAL ETA RE-EVALUATION (FNLETA):          1
 EXCLUDE NON-INFLUENTIAL (NON-INFL.) ETAS
       IN SHRINKAGE (ETASTYPE):             NO
 NON-INFL. ETA CORRECTION (NONINFETA):      0
 RAW OUTPUT FILE (FILE): run18.ext
 EXCLUDE TITLE (NOTITLE):                   NO
 EXCLUDE COLUMN LABELS (NOLABEL):           NO
 FORMAT FOR ADDITIONAL FILES (FORMAT):      S1PE12.5
 PARAMETER ORDER FOR OUTPUTS (ORDER):       TSOL
 KNUTHSUMOFF:                               0
 INCLUDE LNTWOPI:                           NO
 INCLUDE CONSTANT TERM TO PRIOR (PRIORC):   NO
 INCLUDE CONSTANT TERM TO OMEGA (ETA) (OLNTWOPI):NO
 EM OR BAYESIAN METHOD USED:                STOCHASTIC APPROXIMATION EXPECTATION MAXIMIZATION (SAEM)
 MU MODELING PATTERN (MUM):
 GRADIENT/GIBBS PATTERN (GRD):
 AUTOMATIC SETTING FEATURE (AUTO):          0
 CONVERGENCE TYPE (CTYPE):                  3
 CONVERGENCE INTERVAL (CINTERVAL):          25
 CONVERGENCE ITERATIONS (CITER):            10
 CONVERGENCE ALPHA ERROR (CALPHA):          5.000000000000000E-02
 BURN-IN ITERATIONS (NBURN):                10000
 FIRST ITERATION FOR MAP (MAPITERS):          NO
 ITERATIONS (NITER):                        1000
 ANNEAL SETTING (CONSTRAIN):                 1
 STARTING SEED FOR MC METHODS (SEED):       11456
 MC SAMPLES PER SUBJECT (ISAMPLE):          5
 RANDOM SAMPLING METHOD (RANMETHOD):        3U
 EXPECTATION ONLY (EONLY):                  0
 PROPOSAL DENSITY SCALING RANGE
              (ISCALE_MIN, ISCALE_MAX):     1.000000000000000E-06   ,1000000.00000000
 SAMPLE ACCEPTANCE RATE (IACCEPT):          0.300000000000000
 METROPOLIS HASTINGS SAMPLING FOR INDIVIDUAL ETAS:
 SAMPLES FOR GLOBAL SEARCH KERNEL (ISAMPLE_M1):          2
 SAMPLES FOR NEIGHBOR SEARCH KERNEL (ISAMPLE_M1A):       0
 SAMPLES FOR MASS/IMP/POST. MATRIX SEARCH (ISAMPLE_M1B): 2
 SAMPLES FOR LOCAL SEARCH KERNEL (ISAMPLE_M2):           2
 SAMPLES FOR LOCAL UNIVARIATE KERNEL (ISAMPLE_M3):       2
 PWR. WT. MASS/IMP/POST MATRIX ACCUM. FOR ETAS (IKAPPA): 1.00000000000000
 MASS/IMP./POST. MATRIX REFRESH SETTING (MASSRESET):      -1


 THE FOLLOWING LABELS ARE EQUIVALENT
 PRED=PREDI
 RES=RESI
 WRES=WRESI
 IWRS=IWRESI
 IPRD=IPREDI
 IRS=IRESI

 EM/BAYES SETUP:
 THETAS THAT ARE MU MODELED:
   1   2
 THETAS THAT ARE SIGMA-LIKE:
 

 MONITORING OF SEARCH:

 Stochastic/Burn-in Mode
 iteration       -10000  SAEMOBJ=   165939.45383425662
 iteration        -9900  SAEMOBJ=   37484.160749533534
 iteration        -9800  SAEMOBJ=   35096.417649104136
 iteration        -9700  SAEMOBJ=   32697.707297194920
 iteration        -9600  SAEMOBJ=   30307.024250605340
 iteration        -9500  SAEMOBJ=   27913.167814729819
 iteration        -9400  SAEMOBJ=   25526.869134385797
 iteration        -9300  SAEMOBJ=   23149.077951300525
 iteration        -9200  SAEMOBJ=   20752.294436117329
 iteration        -9100  SAEMOBJ=   18370.302360925911
 iteration        -9000  SAEMOBJ=   15980.800122251372
 iteration        -8900  SAEMOBJ=   13598.849856495088
 iteration        -8800  SAEMOBJ=   11220.635639967040
 iteration        -8700  SAEMOBJ=   8858.4470587717606
 iteration        -8600  SAEMOBJ=   6496.8780830661017
 iteration        -8500  SAEMOBJ=   4156.2883783367815
 iteration        -8400  SAEMOBJ=   1852.5292926360141
 iteration        -8300  SAEMOBJ=   171.93213762023345
 iteration        -8200  SAEMOBJ=   123.50632468470485
 iteration        -8100  SAEMOBJ=   139.41964403806662
 Convergence achieved
 iteration        -8025  SAEMOBJ=   103.48258933183240
 Reduced Stochastic/Accumulation Mode
 iteration            0  SAEMOBJ=   97.746800717875203
 iteration          100  SAEMOBJ=   91.949637429063984
 iteration          200  SAEMOBJ=   92.827795658355143
 iteration          300  SAEMOBJ=   93.323377260733679
 iteration          400  SAEMOBJ=   93.362551282939222
 iteration          500  SAEMOBJ=   93.326792496599424
 iteration          600  SAEMOBJ=   93.386225941050768
 iteration          700  SAEMOBJ=   93.556206028860416
 iteration          800  SAEMOBJ=   93.713099518309079
 iteration          900  SAEMOBJ=   93.796663439105401
 iteration         1000  SAEMOBJ=   93.817415427248264

 #TERM:
 STOCHASTIC PORTION WAS COMPLETED
 REDUCED STOCHASTIC PORTION WAS COMPLETED

 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:         6.5270E-06  1.9415E-06
 SE:             1.9093E-02  1.8509E-02
 N:                      59          59

 P VAL.:         9.9973E-01  9.9992E-01

 ETASHRINKSD(%)  2.0287E+01  1.1846E+01
 ETASHRINKVR(%)  3.6458E+01  2.2289E+01
 EBVSHRINKSD(%)  2.0294E+01  1.1849E+01
 EBVSHRINKVR(%)  3.6469E+01  2.2295E+01
 RELATIVEINF(%)  1.4774E+01  3.0771E+01
 EPSSHRINKSD(%)  1.9141E+01
 EPSSHRINKVR(%)  3.4618E+01

  
 TOTAL DATA POINTS NORMALLY DISTRIBUTED (N):          155
 N*LOG(2PI) CONSTANT TO OBJECTIVE FUNCTION:    284.87094529344853     
 OBJECTIVE FUNCTION VALUE WITHOUT CONSTANT:    93.817415427248264     
 OBJECTIVE FUNCTION VALUE WITH CONSTANT:       378.68836072069678     
 REPORTED OBJECTIVE FUNCTION DOES NOT CONTAIN CONSTANT
  
 TOTAL EFFECTIVE ETAS (NIND*NETA):                           118
 NIND*NETA*LOG(2PI) CONSTANT TO OBJECTIVE FUNCTION:    216.86949383630275     
 OBJECTIVE FUNCTION VALUE WITHOUT CONSTANT:    93.817415427248264     
 OBJECTIVE FUNCTION VALUE WITH CONSTANT:       310.68690926355100     
 REPORTED OBJECTIVE FUNCTION DOES NOT CONTAIN CONSTANT
  
 #TERE:
 Elapsed estimation  time in seconds:    58.85
 Elapsed covariance  time in seconds:     0.01
1
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 ************************************************************************************************************************
 ********************                                                                                ********************
 ********************                STOCHASTIC APPROXIMATION EXPECTATION-MAXIMIZATION               ********************
 #OBJT:**************                        FINAL VALUE OF LIKELIHOOD FUNCTION                      ********************
 ********************                                                                                ********************
 ************************************************************************************************************************
 





 #OBJV:********************************************       93.817       **************************************************
1
 ************************************************************************************************************************
 ********************                                                                                ********************
 ********************                STOCHASTIC APPROXIMATION EXPECTATION-MAXIMIZATION               ********************
 ********************                             FINAL PARAMETER ESTIMATE                           ********************
 ********************                                                                                ********************
 ************************************************************************************************************************
 


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


         TH 1      TH 2      TH 3     
 
         4.79E-03  1.00E+00  2.80E+00
 


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


         ETA1      ETA2     
 
 ETA1
+        3.44E-02
 
 ETA2
+        2.26E-02  2.65E-02
 


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


         EPS1     
 
 EPS1
+        1.00E+00
 
1


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


         ETA1      ETA2     
 
 ETA1
+        1.86E-01
 
 ETA2
+        7.49E-01  1.63E-01
 


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


         EPS1     
 
 EPS1
+        1.00E+00
 
1
 ************************************************************************************************************************
 ********************                                                                                ********************
 ********************                STOCHASTIC APPROXIMATION EXPECTATION-MAXIMIZATION               ********************
 ********************                          STANDARD ERROR OF ESTIMATE (S)                        ********************
 ********************                                                                                ********************
 ************************************************************************************************************************
 


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


         TH 1      TH 2      TH 3     
 
         2.10E-04  2.89E-02  2.84E-01
 


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


         ETA1      ETA2     
 
 ETA1
+        1.91E-02
 
 ETA2
+        1.08E-02  8.25E-03
 


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


         EPS1     
 
 EPS1
+        0.00E+00
 
1


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


         ETA1      ETA2     
 
 ETA1
+        5.15E-02
 
 ETA2
+        4.39E-01  2.54E-02
 


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


         EPS1     
 
 EPS1
+       .........
 
1
 ************************************************************************************************************************
 ********************                                                                                ********************
 ********************                STOCHASTIC APPROXIMATION EXPECTATION-MAXIMIZATION               ********************
 ********************                        COVARIANCE MATRIX OF ESTIMATE (S)                       ********************
 ********************                                                                                ********************
 ************************************************************************************************************************
 

            TH 1      TH 2      TH 3      OM11      OM12      OM22      SG11  
 
 TH 1
+        4.40E-08
 
 TH 2
+        6.29E-07  8.37E-04
 
 TH 3
+        1.33E-06 -1.73E-03  8.07E-02
 
 OM11
+       -7.63E-09 -9.67E-06 -2.77E-03  3.65E-04
 
 OM12
+        1.02E-07 -9.35E-05  1.39E-03  8.48E-06  1.18E-04
 
 OM22
+       -2.98E-07 -3.57E-05 -1.12E-03  4.48E-05  1.15E-06  6.81E-05
 
 SG11
+       ......... ......... ......... ......... ......... ......... .........
 
1
 ************************************************************************************************************************
 ********************                                                                                ********************
 ********************                STOCHASTIC APPROXIMATION EXPECTATION-MAXIMIZATION               ********************
 ********************                        CORRELATION MATRIX OF ESTIMATE (S)                      ********************
 ********************                                                                                ********************
 ************************************************************************************************************************
 

            TH 1      TH 2      TH 3      OM11      OM12      OM22      SG11  
 
 TH 1
+        2.10E-04
 
 TH 2
+        1.04E-01  2.89E-02
 
 TH 3
+        2.23E-02 -2.10E-01  2.84E-01
 
 OM11
+       -1.90E-03 -1.75E-02 -5.10E-01  1.91E-02
 
 OM12
+        4.47E-02 -2.98E-01  4.51E-01  4.09E-02  1.08E-02
 
 OM22
+       -1.72E-01 -1.50E-01 -4.76E-01  2.84E-01  1.28E-02  8.25E-03
 
 SG11
+       ......... ......... ......... ......... ......... ......... .........
 
1
 ************************************************************************************************************************
 ********************                                                                                ********************
 ********************                STOCHASTIC APPROXIMATION EXPECTATION-MAXIMIZATION               ********************
 ********************                    INVERSE COVARIANCE MATRIX OF ESTIMATE (S)                   ********************
 ********************                                                                                ********************
 ************************************************************************************************************************
 

            TH 1      TH 2      TH 3      OM11      OM12      OM22      SG11  
 
 TH 1
+        2.39E+07
 
 TH 2
+       -1.43E+04  1.42E+03
 
 TH 3
+        2.27E+03  4.60E+01  3.30E+01
 
 OM11
+        2.32E+03  2.15E+02  2.05E+02  4.27E+03
 
 OM12
+       -6.03E+04  5.71E+02 -3.74E+02 -2.57E+03  1.36E+04
 
 OM22
+        1.34E+05  1.29E+03  4.46E+02  7.26E+02 -4.64E+03  2.29E+04
 
 SG11
+       ......... ......... ......... ......... ......... ......... .........
 
1
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 ************************************************************************************************************************
 ********************                                                                                ********************
 ********************                STOCHASTIC APPROXIMATION EXPECTATION-MAXIMIZATION               ********************
 ********************                    EIGENVALUES OF COR MATRIX OF ESTIMATE (S)                   ********************
 ********************                                                                                ********************
 ************************************************************************************************************************
 

             1         2         3         4         5         6
 
         2.24E-01  6.25E-01  7.16E-01  1.04E+00  1.43E+00  1.97E+00
 
1


 #TBLN:      2
 #METH: Objective Function Evaluation by Importance Sampling

 ESTIMATION STEP OMITTED:                 NO
 ANALYSIS TYPE:                           POPULATION
 NUMBER OF SADDLE POINT RESET ITERATIONS:      0
 GRADIENT METHOD USED:               NOSLOW
 CONDITIONAL ESTIMATES USED:              YES
 CENTERED ETA:                            NO
 EPS-ETA INTERACTION:                     YES
 LAPLACIAN OBJ. FUNC.:                    NO
 NO. OF FUNCT. EVALS. ALLOWED:            288
 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
 NUMERICAL DERIVATIVE
       FILE REQUEST (NUMDER):               NONE
 MAP (ETAHAT) ESTIMATION METHOD (OPTMAP):   0
 ETA HESSIAN EVALUATION METHOD (ETADER):    0
 INITIAL ETA FOR MAP ESTIMATION (MCETA):    0
 SIGDIGITS FOR MAP ESTIMATION (SIGLO):      100
 GRADIENT SIGDIGITS OF
       FIXED EFFECTS PARAMETERS (SIGL):     100
 NOPRIOR SETTING (NOPRIOR):                 0
 NOCOV SETTING (NOCOV):                     OFF
 DERCONT SETTING (DERCONT):                 OFF
 FINAL ETA RE-EVALUATION (FNLETA):          1
 EXCLUDE NON-INFLUENTIAL (NON-INFL.) ETAS
       IN SHRINKAGE (ETASTYPE):             NO
 NON-INFL. ETA CORRECTION (NONINFETA):      0
 RAW OUTPUT FILE (FILE): run18.ext
 EXCLUDE TITLE (NOTITLE):                   NO
 EXCLUDE COLUMN LABELS (NOLABEL):           NO
 FORMAT FOR ADDITIONAL FILES (FORMAT):      S1PE12.5
 PARAMETER ORDER FOR OUTPUTS (ORDER):       TSOL
 KNUTHSUMOFF:                               0
 INCLUDE LNTWOPI:                           NO
 INCLUDE CONSTANT TERM TO PRIOR (PRIORC):   NO
 INCLUDE CONSTANT TERM TO OMEGA (ETA) (OLNTWOPI):NO
 EM OR BAYESIAN METHOD USED:                IMPORTANCE SAMPLING (IMP)
 MU MODELING PATTERN (MUM):
 GRADIENT/GIBBS PATTERN (GRD):
 AUTOMATIC SETTING FEATURE (AUTO):          0
 CONVERGENCE TYPE (CTYPE):                  3
 CONVERGENCE INTERVAL (CINTERVAL):          25
 CONVERGENCE ITERATIONS (CITER):            10
 CONVERGENCE ALPHA ERROR (CALPHA):          5.000000000000000E-02
 ITERATIONS (NITER):                        25
 ANNEAL SETTING (CONSTRAIN):                 1
 STARTING SEED FOR MC METHODS (SEED):       11456
 MC SAMPLES PER SUBJECT (ISAMPLE):          10000
 RANDOM SAMPLING METHOD (RANMETHOD):        3U
 EXPECTATION ONLY (EONLY):                  1
 PROPOSAL DENSITY SCALING RANGE
              (ISCALE_MIN, ISCALE_MAX):     0.100000000000000       ,10.0000000000000
 SAMPLE ACCEPTANCE RATE (IACCEPT):          0.300000000000000
 LONG TAIL SAMPLE ACCEPT. RATE (IACCEPTL):   0.00000000000000
 T-DIST. PROPOSAL DENSITY (DF):             0
 NO. ITERATIONS FOR MAP (MAPITER):          0
 INTERVAL ITER. FOR MAP (MAPINTER):         0
 MAP COVARIANCE/MODE SETTING (MAPCOV):      1
 Gradient Quick Value (GRDQ):               0.00000000000000


 THE FOLLOWING LABELS ARE EQUIVALENT
 PRED=PREDI
 RES=RESI
 WRES=WRESI
 IWRS=IWRESI
 IPRD=IPREDI
 IRS=IRESI

 EM/BAYES SETUP:
 THETAS THAT ARE MU MODELED:
   1   2
 THETAS THAT ARE SIGMA-LIKE:
 

 MONITORING OF SEARCH:

 iteration            0  OBJ=   587.97056380337858 eff.=    9988. Smpl.=   10000. Fit.= 0.98391
 iteration            1  OBJ=   587.96249220490154 eff.=    2993. Smpl.=   10000. Fit.= 0.73116
 iteration            2  OBJ=   587.95936633291399 eff.=    2998. Smpl.=   10000. Fit.= 0.73135
 iteration            3  OBJ=   587.82045179311808 eff.=    3001. Smpl.=   10000. Fit.= 0.73143
 iteration            4  OBJ=   587.65836494009102 eff.=    3010. Smpl.=   10000. Fit.= 0.73222
 iteration            5  OBJ=   587.58621282462934 eff.=    3012. Smpl.=   10000. Fit.= 0.73192
 iteration            6  OBJ=   587.98922750797010 eff.=    2987. Smpl.=   10000. Fit.= 0.73067
 iteration            7  OBJ=   588.15595938853778 eff.=    2985. Smpl.=   10000. Fit.= 0.73119
 iteration            8  OBJ=   587.87561841356558 eff.=    3009. Smpl.=   10000. Fit.= 0.73218
 iteration            9  OBJ=   587.95816857196837 eff.=    3003. Smpl.=   10000. Fit.= 0.73182
 iteration           10  OBJ=   588.17346614349060 eff.=    2992. Smpl.=   10000. Fit.= 0.73166
 iteration           11  OBJ=   588.05308204920527 eff.=    3002. Smpl.=   10000. Fit.= 0.73200
 iteration           12  OBJ=   588.15550780861088 eff.=    2998. Smpl.=   10000. Fit.= 0.73213
 iteration           13  OBJ=   588.13941902989029 eff.=    3001. Smpl.=   10000. Fit.= 0.73194
 iteration           14  OBJ=   588.06352462005054 eff.=    2998. Smpl.=   10000. Fit.= 0.73181
 iteration           15  OBJ=   587.88030051843907 eff.=    3009. Smpl.=   10000. Fit.= 0.73225
 iteration           16  OBJ=   588.06971904482475 eff.=    3000. Smpl.=   10000. Fit.= 0.73185
 iteration           17  OBJ=   587.93325425659884 eff.=    2999. Smpl.=   10000. Fit.= 0.73173
 iteration           18  OBJ=   587.78493430037258 eff.=    3009. Smpl.=   10000. Fit.= 0.73187
 iteration           19  OBJ=   588.07676415554783 eff.=    2993. Smpl.=   10000. Fit.= 0.73133
 iteration           20  OBJ=   588.10472716740844 eff.=    2992. Smpl.=   10000. Fit.= 0.73140
 iteration           21  OBJ=   588.21549044476774 eff.=    2999. Smpl.=   10000. Fit.= 0.73191
 iteration           22  OBJ=   587.83946917632147 eff.=    3005. Smpl.=   10000. Fit.= 0.73169
 iteration           23  OBJ=   587.93190984638704 eff.=    3008. Smpl.=   10000. Fit.= 0.73200
 iteration           24  OBJ=   587.98867346996542 eff.=    2997. Smpl.=   10000. Fit.= 0.73179
 iteration           25  OBJ=   587.71420078592939 eff.=    3007. Smpl.=   10000. Fit.= 0.73175

 #TERM:
 EXPECTATION ONLY PROCESS WAS NOT COMPLETED


 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:         2.3136E-04 -2.1164E-04
 SE:             1.9271E-02  1.8501E-02
 N:                      59          59

 P VAL.:         9.9042E-01  9.9087E-01

 ETASHRINKSD(%)  1.9542E+01  1.1882E+01
 ETASHRINKVR(%)  3.5265E+01  2.2352E+01
 EBVSHRINKSD(%)  2.0426E+01  1.1738E+01
 EBVSHRINKVR(%)  3.6680E+01  2.2098E+01
 RELATIVEINF(%)  1.3932E+01  2.9827E+01
 EPSSHRINKSD(%)  1.9269E+01
 EPSSHRINKVR(%)  3.4825E+01

  
 TOTAL DATA POINTS NORMALLY DISTRIBUTED (N):          155
 N*LOG(2PI) CONSTANT TO OBJECTIVE FUNCTION:    284.87094529344853     
 OBJECTIVE FUNCTION VALUE WITHOUT CONSTANT:    587.71420078592939     
 OBJECTIVE FUNCTION VALUE WITH CONSTANT:       872.58514607937786     
 REPORTED OBJECTIVE FUNCTION DOES NOT CONTAIN CONSTANT
  
 TOTAL EFFECTIVE ETAS (NIND*NETA):                           118
  
 #TERE:
 Elapsed estimation  time in seconds:    70.44
 Elapsed covariance  time in seconds:    17.24
1
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 ************************************************************************************************************************
 ********************                                                                                ********************
 ********************               OBJECTIVE FUNCTION EVALUATION BY IMPORTANCE SAMPLING             ********************
 #OBJT:**************                        FINAL VALUE OF OBJECTIVE FUNCTION                       ********************
 ********************                                                                                ********************
 ************************************************************************************************************************
 





 #OBJV:********************************************      587.714       **************************************************
1
 ************************************************************************************************************************
 ********************                                                                                ********************
 ********************               OBJECTIVE FUNCTION EVALUATION BY IMPORTANCE SAMPLING             ********************
 ********************                             FINAL PARAMETER ESTIMATE                           ********************
 ********************                                                                                ********************
 ************************************************************************************************************************
 


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


         TH 1      TH 2      TH 3     
 
         4.79E-03  1.00E+00  2.80E+00
 


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


         ETA1      ETA2     
 
 ETA1
+        3.44E-02
 
 ETA2
+        2.26E-02  2.65E-02
 


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


         EPS1     
 
 EPS1
+        1.00E+00
 
1


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


         ETA1      ETA2     
 
 ETA1
+        1.86E-01
 
 ETA2
+        7.49E-01  1.63E-01
 


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


         EPS1     
 
 EPS1
+        1.00E+00
 
1
 ************************************************************************************************************************
 ********************                                                                                ********************
 ********************               OBJECTIVE FUNCTION EVALUATION BY IMPORTANCE SAMPLING             ********************
 ********************                         STANDARD ERROR OF ESTIMATE (RSR)                       ********************
 ********************                                                                                ********************
 ************************************************************************************************************************
 


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


         TH 1      TH 2      TH 3     
 
         2.40E-04  2.67E-02  2.57E-01
 


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


         ETA1      ETA2     
 
 ETA1
+        1.64E-02
 
 ETA2
+        8.47E-03  8.63E-03
 


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


         EPS1     
 
 EPS1
+        0.00E+00
 
1


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


         ETA1      ETA2     
 
 ETA1
+        4.43E-02
 
 ETA2
+        2.46E-01  2.65E-02
 


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


         EPS1     
 
 EPS1
+       .........
 
1
 ************************************************************************************************************************
 ********************                                                                                ********************
 ********************               OBJECTIVE FUNCTION EVALUATION BY IMPORTANCE SAMPLING             ********************
 ********************                       COVARIANCE MATRIX OF ESTIMATE (RSR)                      ********************
 ********************                                                                                ********************
 ************************************************************************************************************************
 

            TH 1      TH 2      TH 3      OM11      OM12      OM22      SG11  
 
 TH 1
+        5.77E-08
 
 TH 2
+        1.60E-07  7.14E-04
 
 TH 3
+        1.26E-05  1.56E-03  6.61E-02
 
 OM11
+       -7.31E-07  1.92E-05 -8.77E-04  2.70E-04
 
 OM12
+        6.65E-07  4.11E-05 -6.83E-05  8.20E-05  7.18E-05
 
 OM22
+       -9.32E-08  7.49E-05  1.77E-04 -4.51E-05 -8.18E-06  7.45E-05
 
 SG11
+       ......... ......... ......... ......... ......... ......... .........
 
1
 ************************************************************************************************************************
 ********************                                                                                ********************
 ********************               OBJECTIVE FUNCTION EVALUATION BY IMPORTANCE SAMPLING             ********************
 ********************                       CORRELATION MATRIX OF ESTIMATE (RSR)                     ********************
 ********************                                                                                ********************
 ************************************************************************************************************************
 

            TH 1      TH 2      TH 3      OM11      OM12      OM22      SG11  
 
 TH 1
+        2.40E-04
 
 TH 2
+        2.50E-02  2.67E-02
 
 TH 3
+        2.03E-01  2.27E-01  2.57E-01
 
 OM11
+       -1.85E-01  4.38E-02 -2.08E-01  1.64E-02
 
 OM12
+        3.26E-01  1.81E-01 -3.13E-02  5.89E-01  8.47E-03
 
 OM22
+       -4.50E-02  3.25E-01  7.99E-02 -3.18E-01 -1.12E-01  8.63E-03
 
 SG11
+       ......... ......... ......... ......... ......... ......... .........
 
1
 ************************************************************************************************************************
 ********************                                                                                ********************
 ********************               OBJECTIVE FUNCTION EVALUATION BY IMPORTANCE SAMPLING             ********************
 ********************                   INVERSE COVARIANCE MATRIX OF ESTIMATE (RSR)                  ********************
 ********************                                                                                ********************
 ************************************************************************************************************************
 

            TH 1      TH 2      TH 3      OM11      OM12      OM22      SG11  
 
 TH 1
+        2.73E+07
 
 TH 2
+        1.19E+04  1.76E+03
 
 TH 3
+       -3.11E+03 -4.26E+01  1.74E+01
 
 OM11
+        2.43E+05 -2.02E+02  5.19E+01  8.83E+03
 
 OM12
+       -5.26E+05 -1.15E+03  1.39E+01 -1.17E+04  3.24E+04
 
 OM22
+        1.19E+05 -1.90E+03  3.06E+01  4.44E+03 -3.03E+03  1.78E+04
 
 SG11
+       ......... ......... ......... ......... ......... ......... .........
 
1
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 ************************************************************************************************************************
 ********************                                                                                ********************
 ********************               OBJECTIVE FUNCTION EVALUATION BY IMPORTANCE SAMPLING             ********************
 ********************                   EIGENVALUES OF COR MATRIX OF ESTIMATE (RSR)                  ********************
 ********************                                                                                ********************
 ************************************************************************************************************************
 

             1         2         3         4         5         6
 
         2.10E-01  5.12E-01  8.27E-01  1.17E+00  1.50E+00  1.77E+00
 
 Elapsed postprocess time in seconds:     0.11
 Elapsed finaloutput time in seconds:     0.03
 #CPUT: Total CPU Time in Seconds,      146.450
Stop Time:
Sun Sep 22 19:03:39 UTC 2024
