From: TBTZENG@aol.com
Subject: [NMusers] Problem in using $PRED
Date: Fri, 22 Mar 2002 07:50:05 EST

Dear NONMEM Users:

I am exploring the function of user-written using $PRED and find that the 
program appears not to function right in $PRED as compared to $PREDPP in the 
same set of data.  Under $PREDPP, the parameter estimates and program 
iteration are reasonable and normal with 1779 iterations and MOF value of 
-460.51.  However, under $PRED , program appears to reach local convergence 
(minimization was successful with no warning signs) with only 16 iterations, 
MOF value of  1708.311 and the parameter estimates are exactly the same as 
the initial estimates. Included here are my two control streams and one 
partial data set. Any clue about the problems in my control stream and/or 
data format using $PRED is appreciated. Data are from a cross-over oral 
bioequivalence study for two formula with same active ingredient. Plasma 
concentrations were transformed into log scale.  Thanks a lot!

Tsang-Bin Tzeng
MegaMed PRI/PPC USA
(609) 870-0248

Here are my two control streams

$PROB Test1 bioavailability
$INPUT FORM ID TIME CON MDV AMT LCON=DV
$DATA  TEST1BIO.PRN 
$PRED                ;$SUBROUTINES ADVAN2 TRANS2 
                     ;$PK CALFL=1 ; once per individual 
 CL    = THETA(1) * EXP(ETA(1))
 V     = THETA(2) * EXP(ETA(2))
 
 IF (FORM.EQ.1) THEN
 KA    = THETA(3) * EXP(ETA(3))
 ALAG1 = THETA(4) * EXP(ETA(4)) 
 F1    = THETA(5) * EXP(ETA(5))
 ELSE
 KA    = THETA(6) * EXP(ETA(6))
 ALAG1 = THETA(7) * EXP(ETA(7))
 F1    = 1.0000
 ENDIF
 DT=TIME-ALAG1
 S2    = V/1000 
 F=KA*F1*AMT/S2/(KA-CL/V)*(EXP(-CL/V*DT)-EXP(-KA*DT))
 
         ;$ERROR CALLFL=0
 IF (F.GT.0) THEN
 IPRE=LOG(F)
 ELSE
 IPRE=LOG(10)
 ENDIF
 IRES= DV - IPRE
 
 QQ=1
 IF(FORM.EQ.1) QQ=0
 Y=IPRE + (1-QQ)* ERR(1)+ QQ*ERR(2)

$THETA
 (0 4.7 100);           1   CL
 (1 129 400);             2 V
 (0 2 10);                3 KA1
 (0 0.1 5);             4   TLAG1
 (0 1 3);               5       F
 (0 2 10);          6   KA2
 (0 0.1 5);     7   TLAG2

$OMEGA  0.1  0.1  0.1  0.2  0.1  0.1  0.2
$SIGMA 0.01 0.01
$EST MSFO=msf MAX=9990 PRINT=10 POSTHOC; METHOD=1
  ;$COV
$SCATTER IPRE VS DV




$PROB Test1 bioavailability
$INPUT FORM ID TIME CON MDV AMT LCON=DV
$DATA  TEST1BIO.PRN 
$SUBROUTINES ADVAN2 TRANS2 
$PK CALFL=1 ; once per individual
 
 CL    = THETA(1) * EXP(ETA(1))
 V     = THETA(2) * EXP(ETA(2))
 
 IF (FORM.EQ.1) THEN
 KA    = THETA(3) * EXP(ETA(3))
 ALAG1 = THETA(4) * EXP(ETA(4)) 
 F1    = THETA(5) * EXP(ETA(5))
 ELSE
 KA    = THETA(6) * EXP(ETA(6))
 ALAG1 = THETA(7) * EXP(ETA(7))
 F1    = 1.0000
 ENDIF
 S2    = V/1000

$ERROR CALLFL=0
 IF (F.GT.0) THEN
 IPRE=LOG(F)
 ELSE
 IPRE=LOG(10)
 ENDIF
 IRES= DV - IPRE
 
 QQ=1
 IF(FORM.EQ.1) QQ=0
 Y=IPRE + (1-QQ)* ERR(1)+ QQ*ERR(2)

$THETA
 (0 4.7 100);           1   CL
 (1 129 400);           2   V
 (0 2 10);          3   KA1
 (0 0.1 5);     4   TLAG1
 (0 1 3);               5       F
 (0 2 10);          6   KA2
 (0 0.1 5);     7   TLAG2

$OMEGA  0.1  0.1  0.1  0.2  0.1  0.1  0.2

$SIGMA 0.01 0.01

$EST MSFO=msf MAX=9990 PRINT=10 POSTHOC; METHOD=1

  ;$COV
$SCATTER IPRE VS DV



My data file is (The first 4 subjects are provided here):

   1       1       0       .       1      100      .
   1       1       0       .       1       0       .
   1       1      0.5      20      0       0    2.995732
   1       1       1      33.6     0       0    3.514526
   1       1      1.5     45.6     0       0    3.819908
   1       1       2      60.9     0       0    4.109233
   1       1      2.5     116      0       0     4.75359
   1       1       3      153      0       0    5.030438
   1       1       4      245      0       0    5.501258
   1       1       6      375      0       0    5.926926
   1       1       8      364      0       0    5.897154
   1       1       10     360      0       0    5.886104
   1       1       12     341      0       0    5.831882
   1       1       24     285      0       0    5.652489
   1       1       36     319      0       0    5.765191
   1       1       48     235      0       0    5.459586
   1       1       72     76.8     0       0    4.341205
   1       1       96      26      0       0    3.258097
   1       2       0       .       1      100      .
   1       2       0       .       1       0       .
   1       2      0.5      .       1       0       .
   1       2       1      28.8     0       0    3.360375
   1       2      1.5     38.5     0       0    3.650658
   1       2       2      59.8     0       0    4.091006
   1       2      2.5      83      0       0    4.418841
   1       2       3      132      0       0    4.882802
   1       2       4      146      0       0    4.983607
   1       2       6      346      0       0    5.846439
   1       2       8      421      0       0    6.042633
   1       2       10     472      0       0    6.156979
   1       2       12     439      0       0    6.084499
   1       2       24     420      0       0    6.040255
   1       2       36     285      0       0    5.652489
   1       2       48     163      0       0     5.09375
   1       2       72     40.5     0       0    3.701302
   1       2       96     16.3     0       0    2.791165
   1       3       0       .       1      100      .
   1       3       0       .       1       0       .
   1       3      0.5     11.6     0       0    2.451005
   1       3       1      22.5     0       0    3.113515
   1       3      1.5     37.8     0       0    3.632309
   1       3       2      57.1     0       0    4.044804
   1       3      2.5     104      0       0    4.644391
   1       3       3      124      0       0    4.820282
   1       3       4      172      0       0    5.147494
   1       3       6      184      0       0    5.214936
   1       3       8      191      0       0    5.252273
   1       3       10     235      0       0    5.459586
   1       3       12     319      0       0    5.765191
   1       3       24     206      0       0    5.327876
   1       3       36      .       1       0       .
   1       3       48     118      0       0    4.770685
   1       3       72     49.7     0       0    3.906005
   1       3       96     26.2     0       0    3.265759
   1       4       0       .       1      100      .
   1       4       0       .       1       0       .
   1       4      0.5      .       1       0       .
   1       4       1      14.3     0       0     2.66026
   1       4      1.5     18.4     0       0    2.912351
   1       4       2       28      0       0    3.332205
   1       4      2.5     45.7     0       0    3.822098
   1       4       3       73      0       0    4.290459
   1       4       4      127      0       0    4.844187
   1       4       6      159      0       0    5.068904
   1       4       8      177      0       0     5.17615
   1       4       10     200      0       0    5.298317
   1       4       12     237      0       0     5.46806
   1       4       24     256      0       0    5.545177
   1       4       36     118      0       0    4.770685
   1       4       48     112      0       0    4.718499
   1       4       72     29.3     0       0    3.377588
   1       4       96      15      0       0     2.70805


*******

From: "Bachman, William" 
Subject: RE: [NMusers] Problem in using $PRED
Date: Fri, 22 Mar 2002 08:12:06 -0500

Tsang-Bin,

The program is fuctioning correctly. Your data file is coded wrong for your
$PRED.  When you use $PRED you no longer have the dosing advantages of
PREDPP (e.g one record containing the dosing info).  You must either:

1. add a DOSE column with "100" for all data records and change "
F=KA*F1*AMT/S2..." to " F=KA*F1*DOSE/S2..."

or

2. add some clever coding to $PRED to calculate DOSE from the AMT at time=0
(and change " F=KA*F1*AMT/S2..." to " F=KA*F1*DOSE/S2...")

Bill

William J. Bachman, Ph.D.
GloboMax LLC
7250 Parkway Dr., Suite 430
Hanover, MD 21076
Voice (410) 782-2212
FAX (410) 712-0737
bachmanw@globomax.com

*******


From: TBTZENG@aol.com
Subject: RE: [NMusers] Problem in using $PRED
Date: Fri, 22 Mar 2002 09:36:44 EST

Dear Bill:

Thanks a lot. You are right about this. The trick is not only the dose has to 
be placed in every record, but also "AMT" is not allowed to be used for dose 
item. Otherwise, NM-TRAN would come out an error indicating that  it is 
inconsistent with MDV record.

Tsang-Bin Tzeng
MegaMed PRI/PPC USA
*******