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: (4E4.0) 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: 4 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: .7611E+02 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: .3082E+02 .2447E+02 -.5381E+03 -.2366E+03 .2764E+03 .1374E+03 -.2241E+03 -.2566E+03 .5071E+02 0ITERATION NO.: 5 OBJECTIVE VALUE: .7510E+02 NO. OF FUNC. EVALS.:14 CUMULATIVE NO. OF FUNC. EVALS.: 80 PARAMETER: .9998E-01 .1014E+00 .1014E+00 .1015E+00 .1013E+00 .9980E-01 .1004E+00 .1009E+00 .1004E+00 GRADIENT: .1113E+00 -.1288E+02 .2080E+03 -.2072E+03 .1397E+04 -.1502E+04 -.3338E+02 .2533E+02 -.1534E+03 0ITERATION NO.: 10 OBJECTIVE VALUE: .7398E+02 NO. OF FUNC. EVALS.:17 CUMULATIVE NO. OF FUNC. EVALS.: 161 PARAMETER: .9965E-01 .9345E-01 .1071E+00 .1012E+00 .1083E+00 .1077E+00 .9897E-01 .1020E+00 .9942E-01 GRADIENT: .2876E+04 .1646E+05 -.4501E+05 -.1446E+05 .5165E+05 .7275E+04 -.1904E+05 -.1853E+05 .9200E+03 0ITERATION NO.: 15 OBJECTIVE VALUE: .7298E+02 NO. OF FUNC. EVALS.:10 CUMULATIVE NO. OF FUNC. EVALS.: 242 PARAMETER: .9964E-01 .9342E-01 .1072E+00 .1011E+00 .1083E+00 .1077E+00 .9907E-01 .1019E+00 .9959E-01 GRADIENT: -.4026E+04 -.2885E+04 .7367E+05 .2926E+05 .5289E+05 -.2256E+05 .3015E+05 .2962E+05 -.2723E+04 0ITERATION NO.: 20 OBJECTIVE VALUE: .7277E+02 NO. OF FUNC. EVALS.:26 CUMULATIVE NO. OF FUNC. EVALS.: 314 RESET HESSIAN, TYPE I PARAMETER: .9965E-01 .9342E-01 .1072E+00 .1011E+00 .1083E+00 .1077E+00 .9907E-01 .1019E+00 .9962E-01 GRADIENT: -.9595E+04 -.9568E+04 .9836E+05 .4919E+05 .7074E+05 -.3296E+05 .6761E+05 .6572E+05 -.3291E+04 0ITERATION NO.: 25 OBJECTIVE VALUE: .7232E+02 NO. OF FUNC. EVALS.:18 CUMULATIVE NO. OF FUNC. EVALS.: 387 RESET HESSIAN, TYPE I PARAMETER: .9965E-01 .9342E-01 .1072E+00 .1011E+00 .1083E+00 .1077E+00 .9907E-01 .1019E+00 .9964E-01 GRADIENT: .8138E+04 .6821E+05 .1274E+06 .5592E+05 .1290E+06 -.2629E+04 -.2808E+05 -.2595E+05 -.4100E+04 0ITERATION NO.: 30 OBJECTIVE VALUE: .7100E+02 NO. OF FUNC. EVALS.:18 CUMULATIVE NO. OF FUNC. EVALS.: 468 PARAMETER: .9963E-01 .9342E-01 .1072E+00 .1011E+00 .1083E+00 .1077E+00 .9907E-01 .1019E+00 .9981E-01 GRADIENT: -.7528E+04 -.5334E+04 .5512E+04 .7463E+04 -.1181E+05 .2556E+05 -.2724E+07 -.2636E+07 .8940E+05 0ITERATION NO.: 32 OBJECTIVE VALUE: .6860E+02 NO. OF FUNC. EVALS.:13 CUMULATIVE NO. OF FUNC. EVALS.: 496 PARAMETER: .9963E-01 .9342E-01 .1072E+00 .1011E+00 .1083E+00 .1077E+00 .9907E-01 .1019E+00 .9980E-01 GRADIENT: -.8840E+04 -.5432E+04 .5509E+04 .7545E+04 -.1173E+05 .2398E+05 .6277E+04 .5698E+04 -.6749E+04 0MINIMIZATION SUCCESSFUL NO. OF FUNCTION EVALUATIONS USED: 496 NO. OF SIG. DIGITS IN FINAL EST.: 5.5 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: -.18E-01 .00E+00 .14E-01 .25E+00 .00E+00 .00E+00 P VAL.: .64E+00 .10E+01 .65E+00 .55E-02 .10E+01 .10E+01 1 ************************************************************************************************************************ ******************** ******************** ******************** MINIMUM VALUE OF OBJECTIVE FUNCTION ******************** ******************** ******************** ************************************************************************************************************************ ************************************************** 68.604 ************************************************** 1 ************************************************************************************************************************ ******************** ******************** ******************** FINAL PARAMETER ESTIMATE ******************** ******************** ******************** ************************************************************************************************************************ THETA - VECTOR OF FIXED EFFECTS PARAMETERS ********* TH 1 TH 2 TH 3 TH 4 TH 5 TH 6 1.07E+00 8.04E+00 9.66E-01 5.07E+00 6.04E-01 1.05E+00 OMEGA - COV MATRIX FOR RANDOM EFFECTS - ETAS ******** ETA1 ETA2 ETA3 ETA4 ETA5 ETA6 ETA1 + 6.87E-02 ETA2 + 0.00E+00 0.00E+00 ETA3 + 0.00E+00 0.00E+00 5.19E-02 ETA4 + 0.00E+00 0.00E+00 0.00E+00 7.97E-01 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 9.50E-07 1.05E-05 9.00E-07 1.59E-05 3.90E-06 2.56E-05 OMEGA - COV MATRIX FOR RANDOM EFFECTS - ETAS ******** ETA1 ETA2 ETA3 ETA4 ETA5 ETA6 ETA1 + 1.56E-07 ETA2 + ......... ......... ETA3 + ......... ......... 7.73E-08 ETA4 + ......... ......... ......... 7.65E-06 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 + 9.02E-13 TH 2 + 9.80E-12 1.11E-10 TH 3 + -8.45E-13 -9.25E-12 8.09E-13 TH 4 + -1.51E-11 -1.63E-10 1.41E-11 2.52E-10 TH 5 + 3.70E-12 4.03E-11 -3.46E-12 -6.18E-11 1.52E-11 TH 6 + -2.43E-11 -2.64E-10 2.28E-11 4.07E-10 -9.97E-11 6.56E-10 OM11 + -1.48E-13 -1.60E-12 1.38E-13 2.47E-12 -6.06E-13 3.99E-12 2.43E-14 OM12 + ......... ......... ......... ......... ......... ......... ......... ......... OM13 + ......... ......... ......... ......... ......... ......... ......... ......... ......... OM14 + ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... OM15 + ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... OM16 + ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... OM22 + ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... OM23 + ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... OM24 + ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... OM25 + ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... OM26 + ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... OM33 + -7.34E-14 -7.90E-13 6.86E-14 1.23E-12 -3.00E-13 1.98E-12 1.20E-14 ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... 5.97E-15 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 + 7.27E-12 7.90E-11 -6.81E-12 -1.21E-10 2.98E-11 -1.96E-10 -1.19E-12 ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... -5.91E-13 ......... ......... ......... 5.85E-11 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 + 9.80E-01 1.00E+00 TH 3 + -9.89E-01 -9.77E-01 1.00E+00 TH 4 + -1.00E+00 -9.75E-01 9.88E-01 1.00E+00 TH 5 + 9.99E-01 9.83E-01 -9.86E-01 -9.99E-01 1.00E+00 TH 6 + -1.00E+00 -9.78E-01 9.88E-01 1.00E+00 -9.99E-01 1.00E+00 OM11 + -1.00E+00 -9.76E-01 9.88E-01 1.00E+00 -9.99E-01 1.00E+00 1.00E+00 OM12 + ......... ......... ......... ......... ......... ......... ......... ......... OM13 + ......... ......... ......... ......... ......... ......... ......... ......... ......... OM14 + ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... OM15 + ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... OM16 + ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... OM22 + ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... OM23 + ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... OM24 + ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... OM25 + ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... OM26 + ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... OM33 + -9.99E-01 -9.71E-01 9.87E-01 1.00E+00 -9.97E-01 9.99E-01 1.00E+00 ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... 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 + 1.00E+00 9.81E-01 -9.89E-01 -1.00E+00 9.99E-01 -1.00E+00 -1.00E+00 ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... -9.99E-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 + 2.52E+18 TH 2 + -1.56E+16 1.18E+14 TH 3 + 3.55E+16 -2.44E+14 6.71E+14 TH 4 + 2.69E+16 -2.35E+14 4.83E+14 5.56E+14 TH 5 + 1.05E+16 -8.62E+13 -1.27E+14 1.96E+13 1.74E+15 TH 6 + 5.01E+16 -3.27E+14 6.39E+14 5.29E+14 7.65E+14 1.19E+15 OM11 + 1.57E+18 -1.20E+16 2.91E+16 2.59E+16 -1.82E+15 2.91E+16 2.06E+18 OM12 + ......... ......... ......... ......... ......... ......... ......... ......... OM13 + ......... ......... ......... ......... ......... ......... ......... ......... ......... OM14 + ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... OM15 + ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... OM16 + ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... OM22 + ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... OM23 + ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... OM24 + ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... OM25 + ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... OM26 + ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... OM33 + 3.07E+18 -1.94E+16 4.88E+16 3.38E+16 -3.35E+16 4.64E+16 1.38E+18 ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... 6.41E+18 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 + -6.96E+15 -2.23E+14 2.95E+14 8.21E+14 1.43E+14 5.08E+13 3.26E+16 ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... -1.41E+16 ......... ......... ......... 3.52E+15 OM45 + ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... OM46 + ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... OM55 + ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... OM56 + ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... OM66 + ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... .........