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From: Ahmed Suleiman <a.a.s.a.suleiman_at_gmail.com>

Date: Mon, 8 Feb 2016 10:45:50 +0100

Hi Achim,

After some quick testing, and for some reason (which I am not aware of), if

a compartment (e.g. a PK compartment) is added before these adverse events

compartments, then it works fine. I would be also interested to know why.

Best regards,

Ahmed Suleiman

On Mon, Feb 8, 2016 at 8:22 AM, Achim Fritsch <a.fritsch_at_uni-bonn.de> wrote=

:

*> Dear all,
*

*>
*

*>
*

*>
*

*> I am currently trying to model the transitions from CTCAE grade 0 - 3 (4
*

*> states) for several
*

*>
*

*> toxicities using a markov approach in Nonmem.
*

*>
*

*> However, I am facing some problems with the data set, which I cannot solv=
*

e

*> by myself.
*

*>
*

*>
*

*>
*

*> The set looks like this:
*

*>
*

*>
*

*>
*

*> C
*

*>
*

*> ID
*

*>
*

*> TIME
*

*>
*

*> DOSE
*

*>
*

*> DV
*

*>
*

*> EVID
*

*>
*

*> CMT
*

*>
*

*> AMT
*

*>
*

*> MDV
*

*>
*

*> 0
*

*>
*

*> 1
*

*>
*

*> 0
*

*>
*

*> 0
*

*>
*

*> 0
*

*>
*

*> 1
*

*>
*

*> 1
*

*>
*

*> 1
*

*>
*

*> 1
*

*>
*

*> 0
*

*>
*

*> 1
*

*>
*

*> 1
*

*>
*

*> 50
*

*>
*

*> 1
*

*>
*

*> 0
*

*>
*

*> 1
*

*>
*

*> 0
*

*>
*

*> 0
*

*>
*

*> 0
*

*>
*

*> 1
*

*>
*

*> 1
*

*>
*

*> 50
*

*>
*

*> 0
*

*>
*

*> 2
*

*>
*

*> -1
*

*>
*

*> 0
*

*>
*

*> 1
*

*>
*

*> 0
*

*>
*

*> 1
*

*>
*

*> 1
*

*>
*

*> 50
*

*>
*

*> 0
*

*>
*

*> 2
*

*>
*

*> -2
*

*>
*

*> 0
*

*>
*

*> 1
*

*>
*

*> 0
*

*>
*

*> 1
*

*>
*

*> 1
*

*>
*

*> 50
*

*>
*

*> 0
*

*>
*

*> 2
*

*>
*

*> -3
*

*>
*

*> 0
*

*>
*

*> 1
*

*>
*

*> 0
*

*>
*

*> 1
*

*>
*

*> 1
*

*>
*

*> 50
*

*>
*

*> 0
*

*>
*

*> 2
*

*>
*

*> -4
*

*>
*

*> 0
*

*>
*

*> 1
*

*>
*

*> 0
*

*>
*

*> 1
*

*>
*

*> 1
*

*>
*

*> 50
*

*>
*

*> 0
*

*>
*

*> 1
*

*>
*

*> 1
*

*>
*

*> 1
*

*>
*

*> 1
*

*>
*

*> 0
*

*>
*

*> 1
*

*>
*

*> 1
*

*>
*

*> 50
*

*>
*

*> 0
*

*>
*

*> 2
*

*>
*

*> 2
*

*>
*

*> 0
*

*>
*

*> 1
*

*>
*

*> 0
*

*>
*

*> 1
*

*>
*

*> 1
*

*>
*

*> 50
*

*>
*

*> 0
*

*>
*

*> 2
*

*>
*

*> 3
*

*>
*

*> 0
*

*>
*

*> 1
*

*>
*

*> 0
*

*>
*

*> 1
*

*>
*

*> 1
*

*>
*

*> 50
*

*>
*

*> 0
*

*>
*

*> 2
*

*>
*

*> 4
*

*>
*

*> 0
*

*>
*

*> 1
*

*>
*

*>
*

*>
*

*> To implement the markov property the compartments are emptied and
*

*> initialized after each observation.
*

*>
*

*> When I try to execute the model I get the following error message for
*

*> every record where the compartment without
*

*>
*

*> a previous observation is emptied :
*

*>
*

*>
*

*>
*

*> COMPARTMENT ASSOCIATED WITH THE PREDICTION IS OFF
*

*>
*

*>
*

*>
*

*> In the example above this error refers to record 4 - 6.
*

*>
*

*>
*

*>
*

*> When I remove these records the model works, but then I am violating the
*

*> markovian assumption, if I am not mistaken.
*

*>
*

*>
*

*>
*

*> Am I missing something important? Any help is highly appreciated!
*

*>
*

*>
*

*>
*

*> Here are the relevant parts of the control file:
*

*>
*

*>
*

*>
*

*> $DES
*

*>
*

*>
*

*>
*

*> K01_F = K01 * EXP(-GAM*T) + DOSE*SLP
*

*>
*

*> K02_F = K02 * EXP(-GAM*T) + DOSE*SLP
*

*>
*

*> K03_F = K03 * EXP(-GAM*T) + DOSE*SLP
*

*>
*

*> K12_F = K12 * EXP(-GAM*T) + DOSE*SLP
*

*>
*

*> K23_F = K23 * EXP(-GAM*T) + DOSE*SLP
*

*>
*

*>
*

*>
*

*> KB10 = KB * EXP(-BA*DOSE)
*

*>
*

*> KB21 = KB * EXP(-BA*DOSE)
*

*>
*

*> KB32 = KB * EXP(-BA*DOSE)
*

*>
*

*> KB20 = KB * EXP(-BA*DOSE)
*

*>
*

*> KB30 = KB * EXP(-BA*DOSE)
*

*>
*

*>
*

*>
*

*> DADT(1) = A(2)*KB10 + A(3)*KB20 + A(4)*KB30 - A(1) * (K01_F + K02_F +
*

*> K03_F) ; No grade
*

*>
*

*> DADT(2) = A(1)*K01_F - A(2) * (K12_F +
*

*> KB10) ; Grade 1
*

*>
*

*> DADT(3) = A(2)*K12_F + A(1)*K02_F - A(3) * (K23_F + KB21 +
*

*> KB20) ; Grade 2
*

*>
*

*> DADT(4) = A(3)*K23_F + A(1)*K03_F - A(4) * (KB32 + KB30)
*

*> ; Grade 3
*

*>
*

*>
*

*>
*

*> $ERROR
*

*>
*

*>
*

*>
*

*> PB0 = A(1)
*

*>
*

*> PB1 = A(2)
*

*>
*

*> PB2 = A(3)
*

*>
*

*> PB3 = A(4)
*

*>
*

*>
*

*>
*

*> Y = 1
*

*>
*

*> IF(DV.EQ.1.AND.CMT.EQ.1) Y = A(1)
*

*>
*

*> IF(DV.EQ.1.AND.CMT.EQ.2) Y = A(2)
*

*>
*

*> IF(DV.EQ.1.AND.CMT.EQ.3) Y = A(3)
*

*>
*

*> IF(DV.EQ.1.AND.CMT.EQ.4) Y = A(4)
*

*>
*

*>
*

*>
*

*> $ESTIMATION SIG=3 MAXEVAL=9999 PRINT=1 METHOD=1 LAPLACIAN LIKE NO=
*

ABORT

*>
*

*>
*

*>
*

*>
*

*>
*

*>
*

*>
*

*> Thank you very much in advance!
*

*>
*

*>
*

*>
*

*> Kind regards
*

*>
*

*>
*

*>
*

*>
*

*>
*

*>
*

*>
*

*> ____________________
*

*>
*

*> *Achim Fritsch*
*

*>
*

*> Pharmacist
*

*>
*

*>
*

*>
*

*> Klinische Pharmazie
*

*>
*

*> Pharmazeutisches Institut
*

*>
*

*> Universität Bonn
*

*>
*

*> An der Immenburg 4
*

*>
*

*> 53121 Bonn
*

*>
*

*>
*

*>
*

*> Tel.: 0228 / 73 5229
*

*>
*

*> Fax.: 0228 / 73 9757
*

*>
*

*>
*

*>
*

*> a.fritsch_at_uni-bonn.de
*

*>
*

*>
*

*>
*

*>
*

*>
*

Received on Mon Feb 08 2016 - 04:45:50 EST

Date: Mon, 8 Feb 2016 10:45:50 +0100

Hi Achim,

After some quick testing, and for some reason (which I am not aware of), if

a compartment (e.g. a PK compartment) is added before these adverse events

compartments, then it works fine. I would be also interested to know why.

Best regards,

Ahmed Suleiman

On Mon, Feb 8, 2016 at 8:22 AM, Achim Fritsch <a.fritsch_at_uni-bonn.de> wrote=

:

e

ABORT

Received on Mon Feb 08 2016 - 04:45:50 EST

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