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From: Achim Fritsch <a.fritsch_at_uni-bonn.de>

Date: Mon, 8 Feb 2016 08:22:42 +0100

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 =

solve

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 =

NOABORT

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 - 02:22:42 EST

Date: Mon, 8 Feb 2016 08:22:42 +0100

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 =

solve

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 =

NOABORT

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 - 02:22:42 EST