+--------------------------------------------------------------------+
 |                                                                    |
 |                            BIND EXAMPLE                            |
 |                                                                    |
 +--------------------------------------------------------------------+

 EXAMPLES OF THE USE OF $BIND

 Case 1.

 Suppose a fragment of the dose records looks like this:

        TIME AMT PREP    X
          0  100    4    .
         10  100    1   90
         20    0    0   80

 Suppose $INPUT and $PK include this code:

 $INPUT ID TIME AMT DV PREP X
 $PK
     F1=1
     IF (PREP.EQ.4) F1=THETA(3)
     ALAG1=THETA(5)
     CL=THETA(1)*X*EXP(ETA(1))

 It  is  intended  that  theta(3)  be the ratio of bioavailabilities of
 preparation 4 to preparation 1.  However, calls to PK are made only at
 event  times 0, 10 and 20. Suppose the value of theta(5) (lag time) is
 5.  After 5 time units, the first dose enters the system.   The  value
 of PREP (dose preparation type) is taken from the event record at time
 10, which is 1.  F1 is computed incorrectly.  If the  estimation  step
 is run, the gradient with theta(3) will be 0, indicating the problem.

 Case 2.

 If  lag  time  is  not  modeled (no ALAG1), but the doses are multiple
 (ADDL>0, II>0), a more subtle error can occur.  Suppose a fragment  of
 the data records looks like this:

        TIME AMT PREP    X  II  ADDL
          0  100    4    .   5     1
         10  100    1   90   5     1
         20    0    0   80   .     .

 Suppose $INPUT and $PK include this code:

 $INPUT ID TIME AMT DV PREP X II ADDL
 $PK
     F1=1
     IF (PREP.EQ.4) F1=THETA(3)
     CL=THETA(1)*X*EXP(ETA(1))

 F1  is  computed  correctly for the initiating dose records at times 0
 and 10, and for the additional dose at time 15,  but  incorrectly  for
 the  additional  dose  at  time 5.  Theta(3) applies only to the first
 dose having PRED=4.  (The gradient for theta(3) is not 0.)   The  same
 problem  could  have occurred with the dose having PREP=1, except that
 by an accident of coding, PREP=0 (on the  record  having  TIME=20)  is
 treated the same as PREP=1, so that the additional dose at time 15 has
 F1=1 as it should.

 On the other hand, the values of X are presumably recorded so that  90
 is  valid  for  the  time 0 through 10 and 80 is valid for the time 10
 through 20.  Therefore, the model for CL is correct in both examples.

 In either of these two examples, the model can  be  corrected  by  the
 insertion of $BIND and CALLFL=-2:

 $INPUT ID TIME AMT DV PREP X II ADDL ; II & ADDL only in case 2
 $BIND   -    -   -  - DOSE NEXT
 $PK
     CALLFL=-2

 Because  of  CALLFL=-2 in the abbreviated code, additional calls to PK
 are made at the nonevent dose times (5 in case 1; 5 and 15 in case 2).
 Because  of  the  $BIND record, PREP has the value at these calls from
 the initiating dose record (4 at time 5, 1 at time 15).   F1  is  com-
 puted  appropriately for the dose preparation. X still has values from
 the next event record, so the computation of CL is unchanged, e.g., it
 is the same from time=0 to time=5 as it is from  time=5 to time=10.

 (See $BIND).

REFERENCES: Guide IV Section V.C.2, V.C.5

REFERENCES: Guide VI Section III.B.2, V.K


  
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