Re: Question regarding Calculation Process in $DES BLOCK

Alison, Thank you for the additional information. Especially the part about $DES computing at the event time in a data record for output to the $TABLE. I would like to make sure that I understand a specific point correctly. During a step from t=T1 to t=T2, NONMEM may still take on a value of t=T2+i (i=a tiny number) and compute the equations at this time point. When it is done, it goes back and computes the values at t=T2 for output to the table file. So if you have an expression like the following in your $DES block, would you still need to set flags to 'help' processing along at t=T2. (context of example from a previous note from Li Li) Example: integrating from TIME=T1 to TIME=T2 (which = a multiple of 24) RM=THETA(1) $DES TS=T-24*INT(T/24) KIN=TS*RM DADT(1) = -KIN*A(1) This function for Kin creates a cusp at every multiple of 24. So the limit of Kin as you approach a multiple of 24 from the left is a maximum and as you approach from the right the limit of Kin=0 (similar if not same situation that occurs for an absorption alag). So if an integral step of size h (within the advance from T1 to T2) encompasses a multiple of 24 should flags be set to allow the integration routine to use TS=T- 24*INT(time at beginning of interval h/24) for the full step? Or in terms of the an ALAG situation: What happens if NONMEM is taking a step (size h within an advance from T1 to T2) that encompasses the value of ALAG? Does it use DADT(1) = 0*A(1) until t=ALAG and then switch to DADT(1)=-Ka*A(1) at t >= ALAG (creating a cusp within the interval h)? or Does it use DAD(1) = 0 until t=end of the h interval (even though it's a small bit past ALAG) and then switch to DADT(1)=-Ka*A(1) at the end of the h interval? I really appreciate that you take the time to continue expanding our knowledge about NONMEM. Best Regards, Luann Phillips Director PK/PD Cognigen Corporation (716) 633-3463 ext. 236 Alison Boeckmann wrote: > Here is a little background on how it works. > > ADVAN routines such as ADVAN6 use a subroutine from third party sources > to do the integration. For example, ADVAN6 calls DVERK from IMSL, > ADVAN13 calls LSODA, etc. These subroutines are the ones that call DES. > They call DES with various values of T during the integration > ("advance") from T1 to T2. (T1 and T2 are beginning and ending event > time. Typically, these are the times on a pair of event records.) The > integrating subroutine may decide it has enough information after a call > with a value of T that is not exactly T2 (might be a little less or a > little more.) > > A change was made with NONMEM V so that, after an advance, DES is called > by the ADVAN routine itself (i.e., $DES statements are evaluated) at the > exact value of the event time. > > From the NONMEM V Supplemental Guide of March 1998 (guides/supp.pdf): > 39. Displayed DES-defined Items > DES-defined items may be displayed in tables or scatterplots and are > computed at the event time in the data record. With previous versions > of PREDPP, the displayed items might have been computed at a slightly > different time and might have had slightly different values. > > This fixes the difficulty that Luann mentioned. > > Paul says: > A related caveat is that during integration between two time points, > the value of data items (in the $DES block) are set to the values > defined at the end time, not the start time. I'm afraid that I can't > give you a good explanation for this design decision. > > Every variable displayed via $TABLE has the value that was calculated by > the last call to DES with the current event record. This is not a design > decision; it is inevitable. Values created by PREDPP for display by > NONMEM are stored in a common area (formerly COMMON NMPRD4; now MODULE > NMPRD4). To display values at the start time would require PREDPP to > save the values and to restore that part of NMPRD4. This could be rather > difficult. Also, Stuart Beal preferred to see DES-computed values at > the end time and that is why the change for a final call to DES at the > event time was made. > > This also explains why the values for the first event record of the > individual are those from the last event record of the previous > individual. If there is no advance in time, then there is no call to > the integrating subroutine, and no call to DES, so the values in NMPRD4 > are unchanged. Warning 48 was new with NONMEM V in 1998. Why did we not > at that time add a call to DES from the ADVAN routine with the first > event record? I can't remember. Stuart Beal may have been afraid that > some of the computations in a complicated DES might fail with values > from the first event record, whereas they were ok with values from the > second and subsequent event records. >