<?xml version="1.0" encoding="ASCII"?>
<!DOCTYPE nm:output SYSTEM "output.dtd">
<nm:output
xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"
xsi:schemaLocation="http://namespaces.oreilly.com/xmlnut/address output.xsd"
xmlns:nm="http://namespaces.oreilly.com/xmlnut/address"
>
<nm:start_datetime>2018-09-17T11:33:55.690</nm:start_datetime>
<nm:control_stream><![CDATA[
$PROB PHENOBARBITAL IV P:ROOT F:BASE
$INPUT ID TIME AMT BWT APGA DV MDV EVID
$DATA ../PHENO
$SUBR ADVAN1 TRANS2
$PK
  CL = THETA(1) * EXP(ETA(1))
  V  = THETA(2) * EXP(ETA(2))
  S1 = V

$ERROR
  IPRE = F
  W = SQRT(THETA(3)**2*IPRE**2 + THETA(4)**2)
  Y = IPRE + W*EPS(1)
  IRES = DV-IPRE
  IWRE = IRES/W

$THETA
  (0, 1)  ; CL
  1.40664 FIX
  (0, .1) ; Prop.RE (sd)
  (0, 1)  ; Add.RE (sd)

$OMEGA
  0.1
  0.1

$SIGMA 1 FIX
$EST MAX=9999 PRINT= 5 METHOD=COND INTER MSFO=THIS.MSF
     NOTBT NOOBT NOSBT NOABORT

$TAB ID TIME DV MDV EVID IPRE IWRE CWRES
     file = sdtab NOPRINT ONEHEADER
$TAB CL V ETA(1) ETA(2)
     FILE =patab NOPRINT ONEHEADER NOAPPEND
$TAB ID BWT APGA
     FILE= cotab NOPRINT ONEHEADER NOAPPEND
;$TAB ID APGA
;     FILE=catab NOPRINT ONEHEADER NOAPPEND
]]></nm:control_stream>
<nm:nmtran><![CDATA[

 WARNINGS AND ERRORS (IF ANY) FOR PROBLEM    1

 (WARNING  2) NM-TRAN INFERS THAT THE DATA ARE POPULATION.
]]></nm:nmtran>
<nm:nonmem nm:version='7.4.3'>
<nm:license_information><![CDATA[
License Registered to: Asan Medical Center
Expiration Date:    14 DEC 2018
Current Date:       17 SEP 2018
Days until program expires :  87
]]></nm:license_information>
<nm:program_information><![CDATA[
1NONLINEAR 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.
]]></nm:program_information>
<nm:theta_lb>
<nm:val nm:name='1'>0.0000000000000000</nm:val>
<nm:val nm:name='2'>1.4066399999999999</nm:val>
<nm:val nm:name='3'>0.0000000000000000</nm:val>
<nm:val nm:name='4'>0.0000000000000000</nm:val>
</nm:theta_lb>
<nm:theta_in>
<nm:val nm:name='1'>1.0000000000000000</nm:val>
<nm:val nm:name='2'>1.4066399999999999</nm:val>
<nm:val nm:name='3'>0.10000000000000001</nm:val>
<nm:val nm:name='4'>1.0000000000000000</nm:val>
</nm:theta_in>
<nm:theta_ub>
<nm:val nm:name='1'>1000000.0000000000</nm:val>
<nm:val nm:name='2'>1.4066399999999999</nm:val>
<nm:val nm:name='3'>1000000.0000000000</nm:val>
<nm:val nm:name='4'>1000000.0000000000</nm:val>
</nm:theta_ub>
<nm:problem nm:number='1' nm:subproblem='0' nm:superproblem1='0' nm:iteration1='0' nm:superproblem2='0' nm:iteration2='0'>
<nm:problem_title>PHENOBARBITAL IV P:ROOT F:BASE</nm:problem_title>
<nm:problem_information><![CDATA[

 PROBLEM NO.:         1
 PHENOBARBITAL IV P:ROOT F:BASE
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 BWT APGA DV MDV EVID
0(NONBLANK) LABELS FOR PRED-DEFINED ITEMS:
 CL V IPRE IWRE
0FORMAT FOR DATA:
 (8E6.0)

 TOT. NO. OF OBS RECS:      155
 TOT. NO. OF INDIVIDUALS:       59
0LENGTH OF THETA:   4
0DEFAULT THETA BOUNDARY TEST OMITTED:   YES
0OMEGA HAS SIMPLE DIAGONAL FORM WITH DIMENSION:   2
0DEFAULT OMEGA BOUNDARY TEST OMITTED:   YES
0SIGMA HAS SIMPLE DIAGONAL FORM WITH DIMENSION:   1
0DEFAULT SIGMA BOUNDARY TEST OMITTED:   YES
0INITIAL 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
0INITIAL ESTIMATE OF OMEGA:
 0.1000E+00
 0.0000E+00   0.1000E+00
0INITIAL ESTIMATE OF SIGMA:
 0.1000E+01
0SIGMA CONSTRAINED TO BE THIS INITIAL ESTIMATE
0TABLES STEP OMITTED:    NO
 NO. OF TABLES:           3
 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:                S1PE11.4
 LFORMAT:
 RFORMAT:
 FIXED_EFFECT_ETAS:
0USER-CHOSEN ITEMS:
 ID TIME DV MDV EVID IPRE IWRE CWRES
0-- TABLE   2 --
0RECORDS ONLY:    ALL
04 COLUMNS APPENDED:    NO
 PRINTED:                NO
 HEADER:                YES
 FILE TO BE FORWARDED:   NO
 FORMAT:                S1PE11.4
 LFORMAT:
 RFORMAT:
 FIXED_EFFECT_ETAS:
0USER-CHOSEN ITEMS:
 CL V ETA1 ETA2
0-- TABLE   3 --
0RECORDS ONLY:    ALL
04 COLUMNS APPENDED:    NO
 PRINTED:                NO
 HEADER:                YES
 FILE TO BE FORWARDED:   NO
 FORMAT:                S1PE11.4
 LFORMAT:
 RFORMAT:
 FIXED_EFFECT_ETAS:
0USER-CHOSEN ITEMS:
 ID BWT APGA
1DOUBLE PRECISION PREDPP VERSION 7.4.3

 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.
]]></nm:problem_information>
<nm:problem_options
 nm:data_checkout_run='no' nm:data_unit='2' nm:data_rewind='no' nm:data_nrec='744' nm:data_nitems='8' nm:data_id='1'
 nm:data_l2='0' nm:data_dv='6' nm:data_mdv='7' nm:data_mrg='0' nm:data_raw='0' nm:data_rpt='0' nm:data_sub_array1='0'
 nm:data_sub_array2='0' nm:data_sub_array3='0' nm:data_pred_indices='8,2,3,0,0,0,0,0,0,0,0'
 nm:data_format='(8e6.0)' nm:data_nobs='155' nm:data_nind='59' nm:data_mdv100='0' nm:nthetat='4'
 nm:theta_bound_test_omitted='no' nm:omega_diagdim='2' nm:omega_bound_test_omitted='no' nm:sigma_diagdim='1'
 nm:sigma_bound_test_omitted='no' nm:tab_omitted='no' nm:tab_number='3' nm:tab_seed='11456' nm:tab_ranmethod='3u'
 nm:tab_esample='300' nm:tab_wres='eigenvalue' nm:tab_fixedetas_01='BLANK' nm:tab_fixedetas_02='BLANK'
 nm:tab_fixedetas_03='BLANK' nm:pred_advan='1' nm:pred_evid='8' nm:pred_time='2' nm:pred_amt='3'
/>
<nm:estimation nm:number='1' nm:type='0'>
<nm:table_series>1</nm:table_series>
<nm:estimation_method>focei</nm:estimation_method>
<nm:estimation_title>First Order Conditional Estimation with Interaction</nm:estimation_title>
<nm:estimation_information><![CDATA[
 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

]]></nm:estimation_information>
<nm:estimation_options
 nm:estim_omitted='no' nm:analysis_type='pop' nm:saddle_reset='0' nm:saddle_hess='0' nm:slow_gradient='noslow'
 nm:cond_estim='yes' nm:centered_eta='no' nm:epseta_interaction='yes' nm:laplace='no' nm:predflag='0' nm:maxfn='9999'
 nm:nsig='3' nm:msfo='yes' nm:abort='no' nm:objsort='no' nm:numder='0' nm:optmap='0' nm:etader='0' nm:mceta='0' nm:siglo='100'
 nm:sigl='100' nm:noprior='0' nm:nocov='0' nm:dercont='0' nm:atol='0' nm:fnleta='1' nm:etastype='0' nm:noninfeta='0'
 nm:file='2006.ext' nm:notitle='0' nm:nolabel='0' nm:format='s1pe12.5' nm:order='tsol' nm:wishtype='0' nm:knuthsumoff='0'
 nm:lntwopi='0' nm:priorc='0' nm:olntwopi='0' nm:ctype='0'
/>
<nm:monitor>
<nm:obj nm:iteration='0'>14540.298873210528</nm:obj>
<nm:obj nm:iteration='5'>1177.8201634801007</nm:obj>
<nm:obj nm:iteration='10'>1176.5973330128563</nm:obj>
<nm:obj nm:iteration='15'>1170.0850516070700</nm:obj>
<nm:obj nm:iteration='20'>1151.1888303312599</nm:obj>
<nm:obj nm:iteration='25'>945.60227899265089</nm:obj>
<nm:obj nm:iteration='30'>864.65572075263060</nm:obj>
<nm:obj nm:iteration='35'>732.75973837057950</nm:obj>
<nm:obj nm:iteration='40'>731.29068103235829</nm:obj>
<nm:obj nm:iteration='45'>731.24403108187960</nm:obj>
<nm:obj nm:iteration='50'>730.81968986504569</nm:obj>
<nm:obj nm:iteration='55'>727.16490913694884</nm:obj>
<nm:obj nm:iteration='60'>725.89763971174295</nm:obj>
<nm:obj nm:iteration='65'>725.85890918761208</nm:obj>
<nm:obj nm:iteration='70'>725.73798890559419</nm:obj>
<nm:obj nm:iteration='74'>725.73777473231178</nm:obj>
</nm:monitor>
<nm:termination_status>0</nm:termination_status>
<nm:termination_nfuncevals>660</nm:termination_nfuncevals>
<nm:termination_sigdigits>3.8745502794616105</nm:termination_sigdigits>
<nm:termination_information><![CDATA[
0MINIMIZATION SUCCESSFUL
 NO. OF FUNCTION EVALUATIONS USED:      660
 NO. OF SIG. DIGITS IN FINAL EST.:  3.9
]]></nm:termination_information>
<nm:termination_txtmsg>
<nm:val nm:name='1'>37</nm:val>
</nm:termination_txtmsg>
<nm:etabar>
<nm:row nm:rname='SUBPOP1'>
<nm:col nm:cname='ETA1'>1.91824682893822242E-002</nm:col>
<nm:col nm:cname='ETA2'>5.08373219063932950E-003</nm:col>
</nm:row>
</nm:etabar>
<nm:etabarse>
<nm:row nm:rname='SUBPOP1'>
<nm:col nm:cname='ETA1'>4.15122506784880579E-002</nm:col>
<nm:col nm:cname='ETA2'>5.65323538142317172E-002</nm:col>
</nm:row>
</nm:etabarse>
<nm:etabarn>
<nm:row nm:rname='SUBPOP1'>
<nm:col nm:cname='ETA1'>59</nm:col>
<nm:col nm:cname='ETA2'>59</nm:col>
</nm:row>
</nm:etabarn>
<nm:etabarpval>
<nm:row nm:rname='SUBPOP1'>
<nm:col nm:cname='ETA1'>0.64401555833234947</nm:col>
<nm:col nm:cname='ETA2'>0.92834583752187849</nm:col>
</nm:row>
</nm:etabarpval>
<nm:etashrinksd>
<nm:row nm:rname='SUBPOP1'>
<nm:col nm:cname='ETA1'>27.375089122063802</nm:col>
<nm:col nm:cname='ETA2'>2.4354409454747872</nm:col>
</nm:row>
</nm:etashrinksd>
<nm:etashrinkvr>
<nm:row nm:rname='SUBPOP1'>
<nm:col nm:cname='ETA1'>47.256223199718242</nm:col>
<nm:col nm:cname='ETA2'>4.8115681649606223</nm:col>
</nm:row>
</nm:etashrinkvr>
<nm:ebvshrinksd>
<nm:row nm:rname='SUBPOP1'>
<nm:col nm:cname='EBV1'>27.865249208322862</nm:col>
<nm:col nm:cname='EBV2'>3.4803569515413413</nm:col>
</nm:row>
</nm:ebvshrinksd>
<nm:ebvshrinkvr>
<nm:row nm:rname='SUBPOP1'>
<nm:col nm:cname='EBV1'>47.965777282226355</nm:col>
<nm:col nm:cname='EBV2'>6.8395850579812674</nm:col>
</nm:row>
</nm:ebvshrinkvr>
<nm:epsshrinksd>
<nm:row nm:rname='SUBPOP1'>
<nm:col nm:cname='EPS1'>33.296779242649066</nm:col>
</nm:row>
</nm:epsshrinksd>
<nm:epsshrinkvr>
<nm:row nm:rname='SUBPOP1'>
<nm:col nm:cname='EPS1'>55.506803405961080</nm:col>
</nm:row>
</nm:epsshrinkvr>
<nm:estimation_elapsed_time>4.92</nm:estimation_elapsed_time>
<nm:final_objective_function_text>MINIMUM VALUE OF OBJECTIVE FUNCTION</nm:final_objective_function_text>
<nm:final_objective_function>725.73777473231178</nm:final_objective_function>
<nm:theta>
<nm:val nm:name='1'>5.91747796590158005E-003</nm:val>
<nm:val nm:name='2'>1.4066399999999999</nm:val>
<nm:val nm:name='3'>2.75829500136843229E-002</nm:val>
<nm:val nm:name='4'>2.7069030958903886</nm:val>
</nm:theta>
<nm:omega>
<nm:row nm:rname='1'>
<nm:col nm:cname='1'>0.19609086636797990</nm:col>
</nm:row>
<nm:row nm:rname='2'>
<nm:col nm:cname='1'>0.0000000000000000</nm:col>
<nm:col nm:cname='2'>0.20150507768040479</nm:col>
</nm:row>
</nm:omega>
<nm:sigma>
<nm:row nm:rname='1'>
<nm:col nm:cname='1'>1.0000000000000000</nm:col>
</nm:row>
</nm:sigma>
<nm:omegac>
<nm:row nm:rname='1'>
<nm:col nm:cname='1'>0.44282148363418400</nm:col>
</nm:row>
<nm:row nm:rname='2'>
<nm:col nm:cname='1'>0.0000000000000000</nm:col>
<nm:col nm:cname='2'>0.44889316956309860</nm:col>
</nm:row>
</nm:omegac>
<nm:sigmac>
<nm:row nm:rname='1'>
<nm:col nm:cname='1'>1.0000000000000000</nm:col>
</nm:row>
</nm:sigmac>
</nm:estimation>
<nm:post_process_times>
<nm:post_elapsed_time>0.02</nm:post_elapsed_time>
<nm:finaloutput_elapsed_time>0.21</nm:finaloutput_elapsed_time>
</nm:post_process_times>
</nm:problem>
</nm:nonmem>
<nm:stop_datetime>2018-09-17T11:34:00.915</nm:stop_datetime>
<nm:total_cputime>4.359</nm:total_cputime>
</nm:output>
