WARNING 48

Dear NM group, I am running my own DES defined PD model and Nonmem generates the following warning. What does this warning mean and does it have any implications even if I get successful minimization. (WARNING 48) DES-DEFINED ITEMS ARE COMPUTED ONLY WHEN EVENT TIME INCREASES. E.G., DISPLAYED VALUES ASSOCIATED WITH THE FIRST EVENT RECORD OF AN INDIVIDUAL RECORD ARE COMPUTED WITH (WITH LAST ADVANCE TO) AN EVENT TIME OF THE PRIOR INDIVIDUAL RECORD. Kindly advice...MNS

Mahesh, This is just a warning that the table output of values computed in $DES is not exactly what you would expect. For mysterious reasons NONMEM is unable to remember the values of $DES variables computed at the first event for an individual. The table output shows the value from the last record of the previous individual for these $DES variables. There is rarely any good reason to look at the values of variables in $DES. It should always be possible to compute the same value in $ERROR and then you will get consistent values for each individual. Nick > "Samtani, Mahesh [PRDUS]" wrote: > > Dear NM group, > I am running my own DES defined PD model and Nonmem generates the following > warning. What does this warning mean and does it have any implications even > if I get successful minimization. > > (WARNING 48) DES-DEFINED ITEMS ARE COMPUTED ONLY WHEN EVENT TIME > INCREASES. E.G., DISPLAYED VALUES ASSOCIATED WITH THE FIRST EVENT RECORD > OF AN INDIVIDUAL RECORD ARE COMPUTED WITH (WITH LAST ADVANCE TO) AN EVENT > TIME OF THE PRIOR INDIVIDUAL RECORD. > > Kindly advice...MNS -- Nick Holford, Dept Pharmacology & Clinical Pharmacology University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New Zealand email:[EMAIL PROTECTED] tel:+64(9)373-7599x86730 fax:373-7556 http://www.health.auckland.ac.nz/pharmacology/staff/nholford/

Mahesh, You have what is called in other ODE solvers a "state vector", basically a vector containing the quantities in each of the "compartments" This state vector is advances through time from one time point to the next. So, at if you have events at time= 1 and time =2, at time =2, it starts with the state vector values of time = 1, then does the integration to bring it to time = 2. But, it doesn't know the values of the state vector until it is done. If you are calculating something inside the $DES block, e.g. DADT(1) = -KA*A(1) DADT(2) = KA*A(2)-K*A(2) CONC =A(2)/S2 You'll get this message because CONC is initially calculated, at TIME = 2, with the value of A(2) from TIME = 1, i.e. it is the wrong value for TIME = 2. The value is still left over from the last time, it hasn't (yet) been updated. Further, when you change to a new subject, the value of CONC is still left over from the last subject. This is all OK for the minimization, you just need to be aware of it when interpreting output, plots, tables etc. that the first value for CONC for a subject will not be correct. Mark Mark Sale MD Next Level Solutions, LLC www.NextLevelSolns.com

Mark is basically correct, but might be giving a slight wrong impression. The value of CONC in the table is correct for the corresponding value of TIME. During the integration from time=1 to time=2, the value of the state vector at time=1 is used initially, but, once the integration to time=2 is finished, then all values computed in $DES are appropriate to time=2, including CONC. It is unusual for anyone to display variables computed in $DES, so people are probably not familar with warning 48. The warning refers to two situations. First, the (common) case of the first record for an individual record. Mark is correct, $DES has not been evaluated yet, and CONC remains as it was with the prior individual record's last data record. This does no harm, but looks odd in the table. Second, (the uncommon case), one might have an individual record with two records having the same value of TIME. Suppose some user-defined variable X has a different value on each of the two records. If X is used in $DES to compute (say) XX, and XX is displayed in the table, then XX will be the same in both lines of the table. Because TIME did not change with the second record, $DES was not evaluated, and XX remains unchanged. Again, this does no harm, but looks odd in the table. On Mon, 26 Feb 2007 06:45:57 -0700, "Mark Sale - Next Level Solutions" <[EMAIL PROTECTED]> said: > > Mahesh, You have what is called in other ODE solvers a "state > vector", basically a vector containing the quantities in each of the > "compartments" This state vector is advances through time from one > time point to the next. So, at if you have events at time= 1 and time > =2, at time =2, it starts with the state vector values of time = 1, > then does the integration to bring it to time = 2. But, it doesn't > know the values of the state vector until it is done. If you are > calculating something inside the $DES block, e.g. DADT(1) = -KA*A(1) > DADT(2) = KA*A(2)-K*A(2) CONC =A(2)/S2 > > You'll get this message because CONC is initially calculated, at TIME > = 2, with the value of A(2) from TIME = 1, i.e. it is the wrong value > for TIME = 2. The value is still left over from the last time, it > hasn't (yet) been updated. > > Further, when you change to a new subject, the value of CONC is still > left over from the last subject. This is all OK for the minimization, > you just need to be aware of it when interpreting output, plots, > tables etc. that the first value for CONC for a subject will not be > correct. > > Mark > > Mark Sale MD Next Level Solutions, LLC www.NextLevelSolns.com > > > -------- Original Message -------- Subject: [NMusers] WARNING 48 > > From: "Samtani, Mahesh [PRDUS]" <[EMAIL PROTECTED]> Date: Mon, > > February 26, 2007 6:09 am To: [email protected] > > > > WARNING 48 > > > > Dear NM group, I am running my own DES defined PD model and Nonmem > > generates the following warning. What does this warning mean and > > does it have any implications even if I get successful minimization. > > > > (WARNING 48) DES-DEFINED ITEMS ARE COMPUTED ONLY WHEN EVENT TIME > > INCREASES. E.G., DISPLAYED VALUES ASSOCIATED WITH THE FIRST EVENT > > RECORD OF AN INDIVIDUAL RECORD ARE COMPUTED WITH (WITH LAST ADVANCE > > TO) AN EVENT TIME OF THE PRIOR INDIVIDUAL RECORD. > > > > Kindly advice...MNS > > > -- Alison Boeckmann [EMAIL PROTECTED]