A problem with numerical integration difficulties for a complex model

4 messages 3 people Latest: Jan 05, 2017

A problem with numerical integration difficulties for a complex model

From: Penny Zhu Date: January 04, 2017 technical
Dear all Sorry to bother you. I have encountered a problem with a complex model, involve a full TMDD PK model lined to a complicated multi-compartment PD model. I was only doing a simulation based on a published paper so I would prefer not to alter or simplify the model. The model kept having numerical difficulties no matter how I modify the TOL value (I have changed it from 0 to 6). And I am using ADVAN 8. Does someone have any idea what else I should try to do to resolve it? Here is the error message. The nonmem code and data are quite long and I could send you the code/data as files if requested. Many many thanks in advance for your kind help. NUMERICAL DIFFICULTIES WITH INTEGRATION ROUTINE. NO. OF REQUIRED SIGNIFICANT DIGITS IN SOLUTION VECTOR TO DIFFERENTIAL EQUATIONS, 6, MAY BE TOO LARGE. MESSAGE ISSUED FROM SIMULATION STEP Best Thank you very much and best regards! Penny (Peijuan) Zhu, Ph.D. PD Bio-Pharma CDMA Sandoz 1N025, 100 College Road West Princeton, NJ 08540

Re: A problem with numerical integration difficulties for a complex model

From: Sam Liao Date: January 04, 2017 technical
Hi Penny, You could try other ODE solver, such as ADVAN13 to see if you can get around this problem. But, If the data are too sparse, the time gap between two data points might be too long to solve the ODE, you may want to consider adding some dummy data points with EVID=2. Good luck with your TMDD modeling. Best regards, Sam Liao, PhD. Pharmax Research
Quoted reply history
On 1/4/2017 8:53 AM, Zhu, Penny wrote: > Dear all > > Sorry to bother you. > > I have encountered a problem with a complex model, involve a full TMDD PK model lined to a complicated multi-compartment PD model. I was only doing a simulation based on a published paper so I would prefer not to alter or simplify the model. > > The model kept having numerical difficulties no matter how I modify the TOL value (I have changed it from 0 to 6). And I am using ADVAN 8. > > Does someone have any idea what else I should try to do to resolve it? Here is the error message. The nonmem code and data are quite long and I could send you the code/data as files if requested. Many many thanks in advance for your kind help. > > NUMERICAL DIFFICULTIES WITH INTEGRATION ROUTINE. > NO. OF REQUIRED SIGNIFICANT DIGITS IN SOLUTION VECTOR > TO DIFFERENTIAL EQUATIONS, 6, MAY BE TOO LARGE. > MESSAGE ISSUED FROM SIMULATION STEP > > Best > > Thank you very much and best regards! > > *Penny (Peijuan) Zhu, Ph.D.* > > PD Bio-Pharma CDMA > > Sandoz > > 1N025, 100 College Road West > > Princeton, NJ 08540 -- Sam Liao Pharmax Research Inc. 14 Upland, Irvine, CA 92602 Phone: 201-9882043 efax: 720-2946783 www.pharmaxresearch.com

RE: A problem with numerical integration difficulties for a complex model

From: Penny Zhu Date: January 05, 2017 technical
Dear Ankekatrin, Jeroen and Sam Many thanks for your kind suggestions. I tried ADVAN9, ADVAN13 with different TOL numbers. They both returned errors as well. For ADVAN13 ERROR IN LSODI1: CODE 205 ERROR IN LSODI1: CODE 205 For ADVAN9 ERROR IN LSODA -1 ERROR IN LSODA -5 I also tried adding more simulation timepoints. I don’t think it made a difference. Does anybody have other suggestion? Should I try Monolix given that NONMEM has numerical difficulties Thank you very much and best regards! Penny (Peijuan) Zhu, Ph.D. Associate Director Clinical Pharmacology Cell: 862-926-9079 PD Bio-Pharma CDMA Sandoz 1N025, 100 College Road West Princeton, NJ 08540
Quoted reply history
From: [email protected] [mailto:[email protected]] Sent: Wednesday, January 04, 2017 3:33 PM To: Zhu, Penny <[email protected]> Subject: Re: [NMusers] A problem with numerical integration difficulties for a complex model Hey Penny, From my little experience with the TMDD modeling ADVAN 13 or 9 works better. Good luck Katrin Von: Sam Liao Gesendet: Mittwoch, 4. Januar 21:28 Betreff: Re: [NMusers] A problem with numerical integration difficulties for a complex model An: Zhu, Penny, [email protected]<mailto:[email protected]> Hi Penny, You could try other ODE solver, such as ADVAN13 to see if you can get around this problem. But, If the data are too sparse, the time gap between two data points might be too long to solve the ODE, you may want to consider adding some dummy data points with EVID=2. Good luck with your TMDD modeling. Best regards, Sam Liao, PhD. Pharmax Research On 1/4/2017 8:53 AM, Zhu, Penny wrote: Dear all Sorry to bother you. I have encountered a problem with a complex model, involve a full TMDD PK model lined to a complicated multi-compartment PD model. I was only doing a simulation based on a published paper so I would prefer not to alter or simplify the model. The model kept having numerical difficulties no matter how I modify the TOL value (I have changed it from 0 to 6). And I am using ADVAN 8. Does someone have any idea what else I should try to do to resolve it? Here is the error message. The nonmem code and data are quite long and I could send you the code/data as files if requested. Many many thanks in advance for your kind help. NUMERICAL DIFFICULTIES WITH INTEGRATION ROUTINE. NO. OF REQUIRED SIGNIFICANT DIGITS IN SOLUTION VECTOR TO DIFFERENTIAL EQUATIONS, 6, MAY BE TOO LARGE. MESSAGE ISSUED FROM SIMULATION STEP Best Thank you very much and best regards! Penny (Peijuan) Zhu, Ph.D. PD Bio-Pharma CDMA Sandoz 1N025, 100 College Road West Princeton, NJ 08540 -- Sam Liao Pharmax Research Inc. 14 Upland, Irvine, CA 92602 Phone: 201-9882043 efax: 720-2946783 http://www.pharmaxresearch.com

Re: A problem with numerical integration difficulties for a complex model

From: Leonid Gibiansky Date: January 05, 2017 technical
I think it would help if you provide the code and the reference and the sample data set: some published papers contain typos, so it is hard to give a general advice based on limited information Thanks Leonid
Quoted reply history
On 1/5/2017 10:44 AM, Zhu, Penny wrote: > Dear Ankekatrin, Jeroen and Sam > > Many thanks for your kind suggestions. > > I tried ADVAN9, ADVAN13 with different TOL numbers. They both returned > errors as well. > > For ADVAN13 > > ERROR IN LSODI1: CODE 205 > > ERROR IN LSODI1: CODE 205 > > For ADVAN9 > > ERROR IN LSODA -1 > > ERROR IN LSODA -5 > > I also tried adding more simulation timepoints. I don’t think it made a > difference. > > Does anybody have other suggestion? Should I try Monolix given that > NONMEM has numerical difficulties > > Thank you very much and best regards! > > * * > > *Penny (Peijuan) Zhu, Ph.D.* > > Associate Director Clinical Pharmacology > > Cell: 862-926-9079 > > PD Bio-Pharma CDMA > > Sandoz > > 1N025, 100 College Road West > > Princeton, NJ 08540 > > *From:*[email protected] > [mailto:[email protected]] > *Sent:* Wednesday, January 04, 2017 3:33 PM > *To:* Zhu, Penny <[email protected]> > *Subject:* Re: [NMusers] A problem with numerical integration > difficulties for a complex model > > Hey Penny, > From my little experience with the TMDD modeling ADVAN 13 or 9 works > better. > Good luck > Katrin > > Von: Sam Liao > Gesendet: Mittwoch, 4. Januar 21:28 > Betreff: Re: [NMusers] A problem with numerical integration difficulties > for a complex model > An: Zhu, Penny, [email protected] <mailto:[email protected]> > > Hi Penny, > You could try other ODE solver, such as ADVAN13 to see if you can get > around this problem. > But, If the data are too sparse, the time gap between two data points > might be too long to solve the ODE, you may want to consider adding some > dummy data points with EVID=2. Good luck with your TMDD modeling. > > Best regards, > Sam Liao, PhD. > Pharmax Research > > On 1/4/2017 8:53 AM, Zhu, Penny wrote: > > Dear all > > Sorry to bother you. > > I have encountered a problem with a complex model, involve a full TMDD > PK model lined to a complicated multi-compartment PD model. I was only > doing a simulation based on a published paper so I would prefer not to > alter or simplify the model. > > The model kept having numerical difficulties no matter how I modify the > TOL value (I have changed it from 0 to 6). And I am using ADVAN 8. > > Does someone have any idea what else I should try to do to resolve it? > Here is the error message. The nonmem code and data are quite long and > I could send you the code/data as files if requested. Many many thanks > in advance for your kind help. > > NUMERICAL DIFFICULTIES WITH INTEGRATION ROUTINE. > NO. OF REQUIRED SIGNIFICANT DIGITS IN SOLUTION VECTOR > TO DIFFERENTIAL EQUATIONS, 6, MAY BE TOO LARGE. > MESSAGE ISSUED FROM SIMULATION STEP > > Best > > Thank you very much and best regards! > > *Penny (Peijuan) Zhu, Ph.D.* > > PD Bio-Pharma CDMA > > Sandoz > > 1N025, 100 College Road West > > Princeton, NJ 08540 > > -- Sam Liao Pharmax Research Inc. 14 Upland, Irvine, CA 92602 Phone: > 201-9882043 efax: 720-2946783 www.pharmaxresearch.com > http://www.pharmaxresearch.com