Calling Protocol for ERROR

From: Stu Beal To: NONMEM UsersNet Participants Subject: Calling Protocol for ERROR Date: February 11 2004 I would like to call attention to some poor practice related to the use of PREDPP. With some event records, a proportional error model is used in the ERROR routine, e.g. Y=F+F*ERR(1) or the data are log transformed, and then Y=LOG(F)+ERR(1) is used. It may happen that the value F (the scaled drug amount) can be 0 with a nonobservation event record, as for example, with a dose event record at time 0 when there is first-order absorption from a drug depot and the default observation compartment is the central compartment. If the statistical error (F*ERR(1) in this example) is 0, NONMEM produces an error message (or if the logarithm of 0 is taken, the operating system produces an error message), and the run terminates. Some people guard against this occurrence by using code like W=F IF (F.EQ.0) W=F+.0001 Y=F+W*ERR(1) This code will usually not cause a problem, but on occasion there may be observation event records where F=0, and this code is masking a problem about which the user should become aware. Or use of this code may encourage use of W=F+.0001 Y=F+W*ERR(1) reflecting the thinking that the addition of a small number in this way will not significantly alter the results. However, this will very often alter the results, especially when during the Estimation Step parameter values are considered that lead to smaller values of F than might be ima- gined. Similarly, the codes FF=F IF (F.EQ.0) FF=F+.0001 Y=LOG(FF)+ERR(1) or FF=.0001 Y=LOG(FF)+ERR(1) are sometimes used. In general, when it can be avoided, any use of a fudge factor (e.g. the .0001) is poor practice. In the situation described above, a fudge factor can be avoided by using the calling protocol "OBSERVATION ONLY" with the ERROR routine: $ERROR (OBSERVATION ONLY) Y=F+F*ERR(1) or $ERROR (OBSERVATION ONLY) Y=LOG(F)+ERR(1) Then ERROR is called only with an observation event record. When the Simulation Step is being implemented, the calling protocol "OBSER- VATION ONLY" does not apply, and ERROR is called with every event record. For example, to log transform the data, a simulation block in ERROR can appear as follows. IF (ICALL.EQ.4) THEN IF (F.NE.0) Y=LOG(F) ENDIF Here an explicit check concerning F=0 is needed because ERROR will be called with nonobservation event records. However, as the value of the DV data item usually is unimportant for such a record, the logarithm needn't be taken with such a record. ______________________________________________________________________

From: "Ludden, Thomas (MYD)" - luddent@iconus.com Subject: [NMusers] Use of PREDPP Date: 2/11/2004 3:37 PM Professor Stuart Beal has asked that I post the following message to nmusers. Tom Ludden