0WARNING: PARAMETER LPAR2 NOT SET CORRECTLY 0WARNING: PARAMETER LPAR3 NOT SET CORRECTLY 0WARNING: PARAMETER MTHVR NOT SET CORRECTLY 1NONLINEAR MIXED EFFECTS MODEL PROGRAM (NONMEM) DOUBLE PRECISION NONMEM VERSION V LEVEL 1.0 DEVELOPED AND PROGRAMMED BY STUART BEAL AND LEWIS SHEINER PROBLEM NO.: 1 Steve's new interaction model 0DATA CHECKOUT RUN: NO DATA SET LOCATED ON UNIT NO.: 2 THIS UNIT TO BE REWOUND: NO NO. OF DATA RECS IN DATA SET: 95 NO. OF DATA ITEMS IN DATA SET: 4 ID DATA ITEM IS DATA ITEM NO.: 1 DEP VARIABLE IS DATA ITEM NO.: 4 0LABELS FOR DATA ITEMS: ID OP HY INT 0FORMAT FOR DATA: (4E6.0) TOT. NO. OF OBS RECS: 95 TOT. NO. OF INDIVIDUALS: 20 0LENGTH OF THETA: 6 0OMEGA HAS BLOCK FORM: 1 0 2 0 0 3 0 0 0 4 0 0 0 0 5 0 0 0 0 0 6 0INITIAL ESTIMATE OF THETA: LOWER BOUND INITIAL EST UPPER BOUND .1000E+01 .1070E+01 .3000E+02 .1000E+01 .8900E+01 .2000E+02 .1000E+00 .8600E+00 .5000E+01 .1000E+00 .5000E+01 .7000E+01 .1000E+00 .5300E+00 .1000E+02 .1000E+00 .9230E+00 .1000E+02 0INITIAL ESTIMATE OF OMEGA: BLOCK SET NO. BLOCK FIXED 1 NO .7000E-01 2 YES .0000E+00 3 NO .5000E-01 4 NO .8000E+00 5 YES .0000E+00 6 YES .0000E+00 0ESTIMATION STEP OMITTED: NO CONDITIONAL ESTIMATES USED: YES CENTERED ETA: NO EPS-ETA INTERACTION: NO LAPLACIAN OBJ. FUNC.: YES NUMERICAL 2ND DERIVATIVES: NO PRED F SET TO A LIKELIHOOD: YES NO. OF FUNCT. EVALS. ALLOWED: 2000 NO. OF SIG. FIGURES REQUIRED: 3 INTERMEDIATE PRINTOUT: YES ESTIMATE OUTPUT TO MSF: NO ABORT WITH PRED EXIT CODE 1: NO 0COVARIANCE STEP OMITTED: NO EIGENVLS. PRINTED: NO SPECIAL COMPUTATION: NO COMPRESSED FORMAT: NO 1 MONITORING OF SEARCH: 0ITERATION NO.: 0 OBJECTIVE VALUE: .1001E+03 NO. OF FUNC. EVALS.: 8 CUMULATIVE NO. OF FUNC. EVALS.: 8 PARAMETER: .1000E+00 .1000E+00 .1000E+00 .1000E+00 .1000E+00 .1000E+00 .1000E+00 .1000E+00 .1000E+00 GRADIENT: .5914E+02 .1466E+04 -.6367E+03 .9473E+02 .1082E+04 .1339E+04 -.2792E+02 .3649E+00 .7680E+02 0ITERATION NO.: 5 OBJECTIVE VALUE: .7620E+02 NO. OF FUNC. EVALS.:10 CUMULATIVE NO. OF FUNC. EVALS.: 64 PARAMETER: .1008E+00 .7123E-01 .9127E-01 .1257E+00 .1027E+00 .1024E+00 .9033E-01 .9691E-01 .1036E+00 GRADIENT: .4590E+01 -.1422E+02 .4123E+02 -.8200E+01 -.8669E+02 .1471E+03 .1257E+02 .2106E+02 .2616E+02 0ITERATION NO.: 10 OBJECTIVE VALUE: .7475E+02 NO. OF FUNC. EVALS.: 9 CUMULATIVE NO. OF FUNC. EVALS.: 114 PARAMETER: .2818E-01 .7478E-01 .8743E-01 .1246E+00 .1004E+00 .9978E-01 .1801E-01 .1070E+00 .9017E-01 GRADIENT: .4716E+01 .1697E+03 -.1741E+03 -.3665E+02 .7495E+02 .2911E+03 -.1144E+02 -.6521E+02 -.2455E+02 0ITERATION NO.: 15 OBJECTIVE VALUE: .7288E+02 NO. OF FUNC. EVALS.:11 CUMULATIVE NO. OF FUNC. EVALS.: 163 PARAMETER: .3793E-01 .8064E-01 .8807E-01 .1438E+00 .9556E-01 .9419E-01 .3544E-01 .9027E-01 .1149E+00 GRADIENT: -.1347E+03 -.4630E+04 .4773E+04 .2026E+03 -.2479E+04 -.6448E+04 .7611E+03 .2342E+04 .2941E+03 0ITERATION NO.: 19 OBJECTIVE VALUE: .6996E+02 NO. OF FUNC. EVALS.:15 CUMULATIVE NO. OF FUNC. EVALS.: 226 PARAMETER: .2757E-01 .8256E-01 .8956E-01 .1448E+00 .9420E-01 .9417E-01 .3912E-01 .8594E-01 .1187E+00 GRADIENT: -.3445E+04 -.3519E+03 .9196E+03 .1622E+04 .1246E+04 -.6519E+03 .1285E+04 .1100E+04 .2694E+04 0MINIMIZATION SUCCESSFUL NO. OF FUNCTION EVALUATIONS USED: 226 NO. OF SIG. DIGITS IN FINAL EST.: 3.8 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: -.24E-02 .00E+00 .91E-03 .20E+00 .00E+00 .00E+00 P VAL.: .68E+00 .10E+01 .97E+00 .17E+00 .10E+01 .10E+01 1 ************************************************************************************************************************ ******************** ******************** ******************** MINIMUM VALUE OF OBJECTIVE FUNCTION ******************** ******************** ******************** ************************************************************************************************************************ ************************************************** 69.959 ************************************************** 1 ************************************************************************************************************************ ******************** ******************** ******************** FINAL PARAMETER ESTIMATE ******************** ******************** ******************** ************************************************************************************************************************ THETA - VECTOR OF FIXED EFFECTS PARAMETERS ********* TH 1 TH 2 TH 3 TH 4 TH 5 TH 6 1.01E+00 6.68E+00 7.16E-01 6.90E+00 4.82E-01 8.32E-01 OMEGA - COV MATRIX FOR RANDOM EFFECTS - ETAS ******** ETA1 ETA2 ETA3 ETA4 ETA5 ETA6 ETA1 + 1.07E-02 ETA2 + 0.00E+00 0.00E+00 ETA3 + 0.00E+00 0.00E+00 3.69E-02 ETA4 + 0.00E+00 0.00E+00 0.00E+00 1.13E+00 ETA5 + 0.00E+00 0.00E+00 0.00E+00 0.00E+00 0.00E+00 ETA6 + 0.00E+00 0.00E+00 0.00E+00 0.00E+00 0.00E+00 0.00E+00 1 ************************************************************************************************************************ ******************** ******************** ******************** STANDARD ERROR OF ESTIMATE ******************** ******************** ******************** ************************************************************************************************************************ THETA - VECTOR OF FIXED EFFECTS PARAMETERS ********* TH 1 TH 2 TH 3 TH 4 TH 5 TH 6 2.44E-05 1.31E-03 2.66E-05 8.21E-03 3.93E-03 4.48E-05 OMEGA - COV MATRIX FOR RANDOM EFFECTS - ETAS ******** ETA1 ETA2 ETA3 ETA4 ETA5 ETA6 ETA1 + 2.28E-04 ETA2 + ......... ......... ETA3 + ......... ......... 1.24E-05 ETA4 + ......... ......... ......... 9.71E-03 ETA5 + ......... ......... ......... ......... ......... ETA6 + ......... ......... ......... ......... ......... ......... 1 ************************************************************************************************************************ ******************** ******************** ******************** COVARIANCE MATRIX OF ESTIMATE ******************** ******************** ******************** ************************************************************************************************************************ TH 1 TH 2 TH 3 TH 4 TH 5 TH 6 OM11 OM12 OM13 OM14 OM15 OM16 OM22 OM23 OM24 OM25 OM26 OM33 OM34 OM35 OM36 OM44 OM45 OM46 OM55 OM56 OM66 TH 1 + 5.94E-10 TH 2 + -3.03E-08 1.70E-06 TH 3 + 4.03E-10 -2.42E-08 7.08E-10 TH 4 + 2.00E-07 -1.04E-05 1.43E-07 6.74E-05 TH 5 + -9.53E-08 4.98E-06 -7.01E-08 -3.22E-05 1.54E-05 TH 6 + 3.59E-10 -9.45E-09 5.40E-10 1.20E-07 -5.89E-08 2.01E-09 OM11 + -5.53E-09 2.89E-07 -4.07E-09 -1.87E-06 8.95E-07 -3.42E-09 5.19E-08 OM12 + ......... ......... ......... ......... ......... ......... ......... ......... OM13 + ......... ......... ......... ......... ......... ......... ......... ......... ......... OM14 + ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... OM15 + ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... OM16 + ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... OM22 + ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... OM23 + ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... OM24 + ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... OM25 + ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... OM26 + ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... OM33 + 3.01E-10 -1.55E-08 2.21E-10 1.02E-07 -4.86E-08 2.16E-10 -2.82E-09 ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... 1.54E-10 OM34 + ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... 1 TH 1 TH 2 TH 3 TH 4 TH 5 TH 6 OM11 OM12 OM13 OM14 OM15 OM16 OM22 OM23 OM24 OM25 OM26 OM33 OM34 OM35 OM36 OM44 OM45 OM46 OM55 OM56 OM66 OM35 + ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... OM36 + ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... OM44 + -2.36E-07 1.23E-05 -1.70E-07 -7.97E-05 3.81E-05 -1.42E-07 2.21E-06 ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... -1.20E-07 ......... ......... ......... 9.44E-05 OM45 + ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... OM46 + ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... OM55 + ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... OM56 + ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... OM66 + ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... 1 ************************************************************************************************************************ ******************** ******************** ******************** CORRELATION MATRIX OF ESTIMATE ******************** ******************** ******************** ************************************************************************************************************************ TH 1 TH 2 TH 3 TH 4 TH 5 TH 6 OM11 OM12 OM13 OM14 OM15 OM16 OM22 OM23 OM24 OM25 OM26 OM33 OM34 OM35 OM36 OM44 OM45 OM46 OM55 OM56 OM66 TH 1 + 1.00E+00 TH 2 + -9.53E-01 1.00E+00 TH 3 + 6.22E-01 -6.97E-01 1.00E+00 TH 4 + 9.98E-01 -9.67E-01 6.56E-01 1.00E+00 TH 5 + -9.96E-01 9.70E-01 -6.71E-01 -9.99E-01 1.00E+00 TH 6 + 3.29E-01 -1.61E-01 4.53E-01 3.25E-01 -3.34E-01 1.00E+00 OM11 + -9.96E-01 9.71E-01 -6.71E-01 -9.99E-01 1.00E+00 -3.34E-01 1.00E+00 OM12 + ......... ......... ......... ......... ......... ......... ......... ......... OM13 + ......... ......... ......... ......... ......... ......... ......... ......... ......... OM14 + ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... OM15 + ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... OM16 + ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... OM22 + ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... OM23 + ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... OM24 + ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... OM25 + ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... OM26 + ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... OM33 + 9.95E-01 -9.55E-01 6.69E-01 9.97E-01 -9.98E-01 3.89E-01 -9.98E-01 ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... 1.00E+00 OM34 + ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... 1 TH 1 TH 2 TH 3 TH 4 TH 5 TH 6 OM11 OM12 OM13 OM14 OM15 OM16 OM22 OM23 OM24 OM25 OM26 OM33 OM34 OM35 OM36 OM44 OM45 OM46 OM55 OM56 OM66 OM35 + ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... OM36 + ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... OM44 + -9.98E-01 9.67E-01 -6.56E-01 -1.00E+00 9.99E-01 -3.27E-01 9.99E-01 ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... -9.97E-01 ......... ......... ......... 1.00E+00 OM45 + ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... OM46 + ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... OM55 + ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... OM56 + ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... OM66 + ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... 1 ************************************************************************************************************************ ******************** ******************** ******************** INVERSE COVARIANCE MATRIX OF ESTIMATE ******************** ******************** ******************** ************************************************************************************************************************ TH 1 TH 2 TH 3 TH 4 TH 5 TH 6 OM11 OM12 OM13 OM14 OM15 OM16 OM22 OM23 OM24 OM25 OM26 OM33 OM34 OM35 OM36 OM44 OM45 OM46 OM55 OM56 OM66 TH 1 + 9.06E+14 TH 2 + -8.43E+11 4.97E+09 TH 3 + 1.99E+12 -8.27E+09 2.74E+10 TH 4 + 2.44E+13 -1.12E+10 3.18E+10 6.96E+11 TH 5 + -9.17E+13 4.96E+10 -1.61E+11 -2.47E+12 1.15E+13 TH 6 + -9.56E+11 -1.24E+10 9.37E+09 -6.11E+10 2.07E+11 5.50E+10 OM11 + 1.40E+15 -8.90E+11 2.72E+12 3.72E+13 -1.77E+14 -2.78E+12 2.75E+15 OM12 + ......... ......... ......... ......... ......... ......... ......... ......... OM13 + ......... ......... ......... ......... ......... ......... ......... ......... ......... OM14 + ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... OM15 + ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... OM16 + ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... OM22 + ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... OM23 + ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... OM24 + ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... OM25 + ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... OM26 + ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... OM33 + 7.21E+12 -6.88E+11 1.43E+12 -1.52E+12 8.64E+12 1.58E+12 -1.16E+14 ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... 1.46E+14 OM34 + ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... 1 TH 1 TH 2 TH 3 TH 4 TH 5 TH 6 OM11 OM12 OM13 OM14 OM15 OM16 OM22 OM23 OM24 OM25 OM26 OM33 OM34 OM35 OM36 OM44 OM45 OM46 OM55 OM56 OM66 OM35 + ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... OM36 + ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... OM44 + 2.72E+13 -1.23E+10 3.60E+10 7.74E+11 -2.78E+12 -6.89E+10 4.20E+13 ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... -1.76E+12 ......... ......... ......... 8.61E+11 OM45 + ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... OM46 + ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... OM55 + ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... OM56 + ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... OM66 + ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... .........