NONLINEAR MIXED EFFECTS MODEL PROGRAM (NONMEM) VERSION 7.4.3
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
PHENOBARBITAL IV P:ROOT F:BASE

DATA 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

INDICES PASSED TO SUBROUTINE PRED:
  8   2   3   0   0   0   0   0   0   0   0

LABELS FOR DATA ITEMS:
ID TIME AMT BWT APGA DV MDV EVID

(NONBLANK) LABELS FOR PRED-DEFINED ITEMS:
CL V IPRE IWRE

FORMAT FOR DATA:
(8E6.0)

TOT. NO. OF OBS RECS:      155
TOT. NO. OF INDIVIDUALS:       59

LENGTH OF THETA:   4

DEFAULT THETA BOUNDARY TEST OMITTED:   YES

OMEGA HAS SIMPLE DIAGONAL FORM WITH DIMENSION:   2

DEFAULT OMEGA BOUNDARY TEST OMITTED:   YES

SIGMA HAS SIMPLE DIAGONAL FORM WITH DIMENSION:   1

DEFAULT SIGMA BOUNDARY TEST OMITTED:   YES

INITIAL ESTIMATE OF THETA:
LOWER BOUND    INITIAL EST    UPPER BOUND
 0.0000E+00     0.1000E+01     0.1000E+07
 0.1407E+01     0.1407E+01     0.1407E+01
 0.0000E+00     0.1000E+00     0.1000E+07
 0.0000E+00     0.1000E+01     0.1000E+07

INITIAL ESTIMATE OF OMEGA:
0.1000E+00
0.0000E+00   0.1000E+00

INITIAL ESTIMATE OF SIGMA:
0.1000E+01

SIGMA CONSTRAINED TO BE THIS INITIAL ESTIMATE

TABLES STEP OMITTED:    NO
NO. OF TABLES:           3
SEED NUMBER (SEED):    11456
RANMETHOD:             3U
MC SAMPLES (ESAMPLE):    300
WRES SQUARE ROOT TYPE (WRESCHOL): EIGENVALUE

-- TABLE   1 --

RECORDS ONLY:    ALL

4 COLUMNS APPENDED:    YES
PRINTED:                NO
HEADER:                YES
FILE TO BE FORWARDED:   NO
FORMAT:                S1PE11.4
LFORMAT:
RFORMAT:
FIXED_EFFECT_ETAS:

USER-CHOSEN ITEMS:
ID TIME DV MDV EVID IPRE IWRE CWRES

-- TABLE   2 --

RECORDS ONLY:    ALL

4 COLUMNS APPENDED:    NO
PRINTED:                NO
HEADER:                YES
FILE TO BE FORWARDED:   NO
FORMAT:                S1PE11.4
LFORMAT:
RFORMAT:
FIXED_EFFECT_ETAS:

USER-CHOSEN ITEMS:
CL V ETA1 ETA2

-- TABLE   3 --

RECORDS ONLY:    ALL

4 COLUMNS APPENDED:    NO
PRINTED:                NO
HEADER:                YES
FILE TO BE FORWARDED:   NO
FORMAT:                S1PE11.4
LFORMAT:
RFORMAT:
FIXED_EFFECT_ETAS:

USER-CHOSEN ITEMS:
ID BWT APGA
DOUBLE PRECISION PREDPP VERSION 7.4.3

ONE COMPARTMENT MODEL (ADVAN1)

MAXIMUM NO. OF BASIC PK PARAMETERS:   2

BASIC 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)

COMPARTMENT 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

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

DATA 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


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

ERROR SUBROUTINE CALLED WITH EVERY EVENT RECORD.



#TBLN:      1
#METH: First Order Conditional Estimation with Interaction

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:            9999
NO. OF SIG. FIGURES REQUIRED:            3
INTERMEDIATE PRINTOUT:                   YES
ESTIMATE OUTPUT TO MSF:                  YES
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):                 OFF
NOCOV SETTING (NOCOV):                     OFF
DERCONT SETTING (DERCONT):                 OFF
FINAL ETA RE-EVALUATION (FNLETA):          ON
EXCLUDE NON-INFLUENTIAL (NON-INFL.) ETAS
      IN SHRINKAGE (ETASTYPE):             NO
NON-INFL. ETA CORRECTION (NONINFETA):      OFF
RAW OUTPUT FILE (FILE): 2006.ext
EXCLUDE TITLE (NOTITLE):                   NO
EXCLUDE COLUMN LABELS (NOLABEL):           NO
FORMAT FOR ADDITIONAL FILES (FORMAT):      S1PE12.5
PARAMETER ORDER FOR OUTPUTS (ORDER):       TSOL
WISHART PRIOR DF INTERPRETATION (WISHTYPE):0
KNUTHSUMOFF:                               0
INCLUDE LNTWOPI:                           NO
INCLUDE CONSTANT TERM TO PRIOR (PRIORC):   NO
INCLUDE CONSTANT TERM TO OMEGA (ETA) (OLNTWOPI):NO
ADDITIONAL CONVERGENCE TEST (CTYPE=4)?:    NO
EM OR BAYESIAN METHOD USED:                 NONE


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

MONITORING OF SEARCH:



ITERATION NO.:    0    OBJECTIVE VALUE:   14540.2988732105        NO. OF FUNC. EVALS.:   5
CUMULATIVE NO. OF FUNC. EVALS.:        5
NPARAMETR:  1.0000E+00  1.0000E-01  1.0000E+00  1.0000E-01  1.0000E-01
PARAMETER:  1.0000E-01  1.0000E-01  1.0000E-01  1.0000E-01  1.0000E-01
GRADIENT:   4.3334E+03 -1.3505E+03 -7.9292E+03 -1.8372E+04 -1.3478E+02


ITERATION NO.:    5    OBJECTIVE VALUE:   1177.82016348010        NO. OF FUNC. EVALS.:  31
CUMULATIVE NO. OF FUNC. EVALS.:       36
NPARAMETR:  5.3211E-01  9.0146E-02  8.1890E-01  2.7686E+00  1.4810E-01
PARAMETER: -5.3091E-01 -3.7417E-03 -9.9794E-02  1.7605E+00  2.9636E-01
GRADIENT:   1.7541E+02 -4.8606E+01 -1.0519E+01 -6.4322E+02 -9.6531E+00


ITERATION NO.:   10    OBJECTIVE VALUE:   1176.59733301286        NO. OF FUNC. EVALS.:  38
CUMULATIVE NO. OF FUNC. EVALS.:       74
NPARAMETR:  5.2542E-01  9.0621E-02  8.0275E-01  2.7597E+00  1.4827E-01
PARAMETER: -5.4357E-01  1.5187E-03 -1.1971E-01  1.7589E+00  2.9694E-01
GRADIENT:   1.7546E+02 -4.8502E+01 -1.0043E+01 -6.4116E+02 -9.5228E+00


ITERATION NO.:   15    OBJECTIVE VALUE:   1170.08505160707        NO. OF FUNC. EVALS.:  70
CUMULATIVE NO. OF FUNC. EVALS.:      144
NPARAMETR:  5.2536E-01  1.2336E-01  8.0254E-01  2.7609E+00  1.4826E-01
PARAMETER: -5.4367E-01  3.0992E-01 -1.1997E-01  1.7591E+00  2.9691E-01
GRADIENT:   1.7265E+02  3.9672E+00 -1.6512E+00 -6.2358E+02 -4.6484E+00


ITERATION NO.:   20    OBJECTIVE VALUE:   1151.18883033126        NO. OF FUNC. EVALS.:  41
CUMULATIVE NO. OF FUNC. EVALS.:      185
NPARAMETR:  5.2381E-01  1.9186E-01  8.0217E-01  3.0853E+00  1.4861E-01
PARAMETER: -5.4662E-01  7.5160E-01 -1.2044E-01  1.8146E+00  2.9808E-01
GRADIENT:   1.5116E+02  5.2169E+01  5.2138E-01 -5.2368E+02  7.0396E+00


ITERATION NO.:   25    OBJECTIVE VALUE:   945.602278992651        NO. OF FUNC. EVALS.:  33
CUMULATIVE NO. OF FUNC. EVALS.:      218
NPARAMETR:  5.0188E-01  1.3838E-01  7.9674E-01  1.5396E+01  1.5373E-01
PARAMETER: -5.8940E-01  4.2483E-01 -1.2723E-01  2.6183E+00  3.1502E-01
GRADIENT:   3.4423E+01  3.8708E+01  1.1088E+00 -4.5336E+01  1.0183E+01


ITERATION NO.:   30    OBJECTIVE VALUE:   864.655720752631        NO. OF FUNC. EVALS.:  62
CUMULATIVE NO. OF FUNC. EVALS.:      280
NPARAMETR:  5.6288E-04  1.3428E-01  6.0431E-01  9.9526E+00  1.3506E-01
PARAMETER: -7.3824E+00  3.9476E-01 -4.0367E-01  2.4002E+00  2.5026E-01
GRADIENT:  -9.3041E+00  1.7776E+01  1.7271E-01  5.0073E+01 -1.5478E+01


ITERATION NO.:   35    OBJECTIVE VALUE:   732.759738370579        NO. OF FUNC. EVALS.:  31
CUMULATIVE NO. OF FUNC. EVALS.:      311
NPARAMETR:  5.4928E-03  1.3430E-01  2.8739E-01  1.5188E-01  1.8848E-01
PARAMETER: -5.1043E+00  3.9489E-01 -1.1469E+00  3.0896E-01  4.1691E-01
GRADIENT:  -1.2170E+01  1.9148E+01 -1.6937E-02  5.8265E+00 -5.4919E+00


ITERATION NO.:   40    OBJECTIVE VALUE:   731.290681032358        NO. OF FUNC. EVALS.:  48
CUMULATIVE NO. OF FUNC. EVALS.:      359
NPARAMETR:  5.8233E-03  1.3430E-01  2.7991E-01  9.5926E-02  2.0391E-01
PARAMETER: -5.0459E+00  3.9491E-01 -1.1733E+00  7.9204E-02  4.5624E-01
GRADIENT:   4.0437E-03  1.0643E+01 -5.2718E-02 -6.3568E-03 -3.8994E-02


ITERATION NO.:   45    OBJECTIVE VALUE:   731.244031081880        NO. OF FUNC. EVALS.:  60
CUMULATIVE NO. OF FUNC. EVALS.:      419
NPARAMETR:  5.8250E-03  1.3430E-01  5.8853E-01  9.4574E-02  2.0488E-01
PARAMETER: -5.0456E+00  3.9491E-01 -4.3013E-01  7.2108E-02  4.5864E-01
GRADIENT:   1.6160E-02  1.3947E+01 -1.6426E-02  2.1980E-02  1.8773E-01


ITERATION NO.:   50    OBJECTIVE VALUE:   730.819689865046        NO. OF FUNC. EVALS.:  56
CUMULATIVE NO. OF FUNC. EVALS.:      475            RESET HESSIAN, TYPE II
NPARAMETR:  5.8255E-03  1.2640E-01  6.0728E-01  9.4387E-02  2.0456E-01
PARAMETER: -5.0455E+00  3.3428E-01 -3.9877E-01  7.1119E-02  4.5786E-01
GRADIENT:   6.8037E+00 -2.2102E-01 -6.3918E-01 -2.4072E+00 -1.2724E-01


ITERATION NO.:   55    OBJECTIVE VALUE:   727.164909136949        NO. OF FUNC. EVALS.:  33
CUMULATIVE NO. OF FUNC. EVALS.:      508
NPARAMETR:  5.6754E-03  8.2704E-02  2.0208E+00  1.8769E-01  2.0072E-01
PARAMETER: -5.0716E+00 -8.9907E-02  8.0350E-01  4.1482E-01  4.4836E-01
GRADIENT:  -5.4801E+00  3.9202E+00 -9.2066E-01  4.5935E-01  7.2711E-01


ITERATION NO.:   60    OBJECTIVE VALUE:   725.897639711743        NO. OF FUNC. EVALS.:  31
CUMULATIVE NO. OF FUNC. EVALS.:      539
NPARAMETR:  5.7791E-03  4.6330E-02  2.5492E+00  1.9437E-01  2.0113E-01
PARAMETER: -5.0535E+00 -6.6938E-01  1.0358E+00  4.3231E-01  4.4939E-01
GRADIENT:   7.8367E-01  3.5736E-01 -2.7827E-01 -3.1567E-01  5.3957E-02


ITERATION NO.:   65    OBJECTIVE VALUE:   725.858909187612        NO. OF FUNC. EVALS.:  34
CUMULATIVE NO. OF FUNC. EVALS.:      573
NPARAMETR:  5.7535E-03  3.0316E-02  2.6769E+00  1.9896E-01  2.0121E-01
PARAMETER: -5.0579E+00 -1.0935E+00  1.0847E+00  4.4397E-01  4.4960E-01
GRADIENT:   1.2019E-01 -5.1615E-02 -7.4757E-01  6.3267E-02 -1.5288E-01


ITERATION NO.:   70    OBJECTIVE VALUE:   725.737988905594        NO. OF FUNC. EVALS.:  48
CUMULATIVE NO. OF FUNC. EVALS.:      621
NPARAMETR:  5.9194E-03  2.8627E-02  2.7012E+00  1.9556E-01  2.0159E-01
PARAMETER: -5.0295E+00 -1.1508E+00  1.0937E+00  4.3534E-01  4.5054E-01
GRADIENT:   8.2833E-02  1.1222E-02  4.9954E-02 -8.1287E-02  4.5019E-02


ITERATION NO.:   74    OBJECTIVE VALUE:   725.737774732312        NO. OF FUNC. EVALS.:  39
CUMULATIVE NO. OF FUNC. EVALS.:      660
NPARAMETR:  5.9175E-03  2.7583E-02  2.7069E+00  1.9609E-01  2.0151E-01
PARAMETER: -5.0298E+00 -1.1880E+00  1.0958E+00  4.3670E-01  4.5032E-01
GRADIENT:  -3.8602E-03  2.2407E-04  3.0401E-03  4.9653E-03 -1.4494E-03

#TERM:

MINIMIZATION SUCCESSFUL
NO. OF FUNCTION EVALUATIONS USED:      660
NO. OF SIG. DIGITS IN FINAL EST.:  3.9

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:         1.9182E-02  5.0837E-03
SE:             4.1512E-02  5.6532E-02
N:                      59          59

P VAL.:         6.4402E-01  9.2835E-01

ETASHRINKSD(%)  2.7375E+01  2.4354E+00
ETASHRINKVR(%)  4.7256E+01  4.8116E+00
EBVSHRINKSD(%)  2.7865E+01  3.4804E+00
EBVSHRINKVR(%)  4.7966E+01  6.8396E+00
EPSSHRINKSD(%)  3.3297E+01
EPSSHRINKVR(%)  5.5507E+01


TOTAL DATA POINTS NORMALLY DISTRIBUTED (N):          155
N*LOG(2PI) CONSTANT TO OBJECTIVE FUNCTION:    284.87094529344853
OBJECTIVE FUNCTION VALUE WITHOUT CONSTANT:    725.73777473231178
OBJECTIVE FUNCTION VALUE WITH CONSTANT:       1010.6087200257602
REPORTED OBJECTIVE FUNCTION DOES NOT CONTAIN CONSTANT

TOTAL EFFECTIVE ETAS (NIND*NETA):                           118

#TERE:
Elapsed estimation  time in seconds:     4.92
Elapsed postprocess time in seconds:     0.02





















************************************************************************************************************************
********************                                                                                ********************
********************               FIRST ORDER CONDITIONAL ESTIMATION WITH INTERACTION              ********************
#OBJT:**************                       MINIMUM VALUE OF OBJECTIVE FUNCTION                      ********************
********************                                                                                ********************
************************************************************************************************************************






#OBJV:********************************************      725.738       **************************************************

************************************************************************************************************************
********************                                                                                ********************
********************               FIRST ORDER CONDITIONAL ESTIMATION WITH INTERACTION              ********************
********************                             FINAL PARAMETER ESTIMATE                           ********************
********************                                                                                ********************
************************************************************************************************************************



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


        TH 1      TH 2      TH 3      TH 4

        5.92E-03  1.41E+00  2.76E-02  2.71E+00



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


        ETA1      ETA2

ETA1    1.96E-01

ETA2    0.00E+00  2.02E-01



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


        EPS1

EPS1    1.00E+00




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


        ETA1      ETA2

ETA1    4.43E-01

ETA2    0.00E+00  4.49E-01



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


        EPS1

EPS1    1.00E+00

Elapsed finaloutput time in seconds:     0.21
#CPUT: Total CPU Time in Seconds,        4.359
