Time-varing covariate

On 23/08/2013 6:00 p.m., siwei Dai wrote: > Hi, Dear NMusers: > > I want to add a time-varing covariate in my model. For example, blood pressure or blood flow as covariates. But I am not sure how to do it. I see some earlier threads to discuss it but they all use complicated methods. I am wondering if there are any new way to do it in NM 7.2? I see in the user guide that EVID=4 can indicate physiological change. Is this what I should use? > > Thank you very much for any suggestions. > Best regards, > Siwei -- Nick Holford, Professor Clinical Pharmacology Dept Pharmacology & Clinical Pharmacology, Bldg 503 Room 302A University of Auckland,85 Park Rd,Private Bag 92019,Auckland,New Zealand office:+64(9)923-6730 mobile:NZ +64(21)46 23 53 FR +33(7)85 36 84 99 email: [email protected] http://holford.fmhs.auckland.ac.nz/ Holford NHG. Disease progression and neuroscience. Journal of Pharmacokinetics and Pharmacodynamics. 2013;40:369-76 http://link.springer.com/article/10.1007/s10928-013-9316-2 Holford N, Heo Y-A, Anderson B. A pharmacokinetic standard for babies and adults. J Pharm Sci. 2013: http://onlinelibrary.wiley.com/doi/10.1002/jps.23574/abstract Holford N. A time to event tutorial for pharmacometricians. CPT:PSP. 2013;2: http://www.nature.com/psp/journal/v2/n5/full/psp201318a.html Holford NHG. Clinical pharmacology = disease progression + drug action. British Journal of Clinical Pharmacology. 2013: http://onlinelibrary.wiley.com/doi/10.1111/bcp.12170/abstract

From: [email protected] [mailto:[email protected]] On Behalf Of siwei Dai Sent: Friday, August 23, 2013 12:01 PM To: [email protected] Subject: [NMusers] Time-varing covariate Hi, Dear NMusers: I want to add a time-varing covariate in my model. For example, blood pressure or blood flow as covariates. But I am not sure how to do it. I see some earlier threads to discuss it but they all use complicated methods. I am wondering if there are any new way to do it in NM 7.2? I see in the user guide that EVID=4 can indicate physiological change. Is this what I should use? Thank you very much for any suggestions. Best regards, Siwei

From: [email protected] [mailto:[email protected]] On Behalf Of Denney, William S. Sent: 23 August 2013 20:09 To: siwei Dai; [email protected] Subject: RE: [NMusers] Time-varing covariate Hi Siwei, If you are using an algebraic model (i.e. no differential equations), then you can simply include it in your equation: e.g. assuming that SBP is systolic blood pressure in your original data set: EFF=THETA(1)+SBP*THETA(2) If you have a differential equation model and you want the time varying covariate to have an effect that is not a step change, you will need to interpolate the covariate. Within your data set, you'll need a column for the next time and the next value of the time varying covariate. Using the same assumption that you have SBP in your data set as your time varying covariate, you will want to make two new columns to allow for interpolation: ID TIME NTIME SBP NSBP DV 1 0 1 110 115 5 1 1 2 115 112 3 1 2 4 112 108 4 Then to use your parameter, you will need code like the following in your $DES section to linearly interpolate: $DES . ;; Current SBP CSBP = (NSBP - SBP)/(NTIME - TIME) * (T - TIME) + SBP . The parameter T is the current time for the differential equation solver which will be somewhere between TIME and NTIME. TIME is an important column name for NONMEM. Thanks, Bill From: [email protected] [mailto:[email protected]] On Behalf Of siwei Dai Sent: Friday, August 23, 2013 12:01 PM To: [email protected] Subject: [NMusers] Time-varing covariate Hi, Dear NMusers: I want to add a time-varing covariate in my model. For example, blood pressure or blood flow as covariates. But I am not sure how to do it. I see some earlier threads to discuss it but they all use complicated methods. I am wondering if there are any new way to do it in NM 7.2? I see in the user guide that EVID=4 can indicate physiological change. Is this what I should use? Thank you very much for any suggestions. Best regards, Siwei

From: Mats Karlsson [email protected] Date: Sat, 24 Aug 2013 10:02:00 +0200 To: [email protected], [email protected], [email protected] Subject: RE: [NMusers] Time-varing covariate Dear Bill and Siwei, Although the thought in Bill's reply is right, I think there is an error in the code. NONMEM by default uses the present values to update from the previous time. Further, it is possible to do this interpolation on the fly in the model file without changes to the data set. $INPUT ID TIME DV COV ;Cov is time-varying covariate $PK IF(NEWIND.NE.2) OTIM=0 ;initialize variable to store old time IF(NEWIND.NE.2) OCOV=0 ;initialize variable to store old covariate value $DES CCOV=OCOV IF(TIME.GT.OTIM) CCOV=OCOV+(T-TIME)*(COV-OCOV)/(TIME-OTIM) ;CCOV is linear interpolation between observed covariate values $ERROR OCOV =COV ;store previous time OTIM =TIME ;store previous time (NB haven't tested the code). Best regards, Mats Mats Karlsson, PhD Professor of Pharmacometrics Dept of Pharmaceutical Biosciences Faculty of Pharmacy Uppsala University Box 591 75124 Uppsala Phone: +46 18 4714105 Fax + 46 18 4714003 http://www.farmbio.uu.se/research/researchgroups/pharmacometrics/ www.farmbio.uu.se/research/researchgroups/pharmacometrics/ From: [email protected] [mailto:[email protected]] On Behalf Of Denney, William S. Sent: 23 August 2013 20:09 To: siwei Dai; [email protected] Subject: RE: [NMusers] Time-varing covariate Hi Siwei, If you are using an algebraic model (i.e. no differential equations), then you can simply include it in your equation: e.g. assuming that SBP is systolic blood pressure in your original data set: EFF=THETA(1)+SBP*THETA(2) If you have a differential equation model and you want the time varying covariate to have an effect that is not a step change, you will need to interpolate the covariate. Within your data set, you'll need a column for the next time and the next value of the time varying covariate. Using the same assumption that you have SBP in your data set as your time varying covariate, you will want to make two new columns to allow for interpolation: ID TIME NTIME SBP NSBP DV 1 0 1 110 115 5 1 1 2 115 112 3 1 2 4 112 108 4 Then to use your parameter, you will need code like the following in your $DES section to linearly interpolate: $DES . ;; Current SBP CSBP = (NSBP - SBP)/(NTIME - TIME) * (T - TIME) + SBP . The parameter T is the current time for the differential equation solver which will be somewhere between TIME and NTIME. TIME is an important column name for NONMEM. Thanks, Bill From: [email protected] [mailto:[email protected]] On Behalf Of siwei Dai Sent: Friday, August 23, 2013 12:01 PM To: [email protected] Subject: [NMusers] Time-varing covariate Hi, Dear NMusers: I want to add a time-varing covariate in my model. For example, blood pressure or blood flow as covariates. But I am not sure how to do it. I see some earlier threads to discuss it but they all use complicated methods. I am wondering if there are any new way to do it in NM 7.2? I see in the user guide that EVID=4 can indicate physiological change. Is this what I should use? Thank you very much for any suggestions. Best regards, Siwei -------------------------------------------------------------------- mail2web.com – Enhanced email for the mobile individual based on Microsoft® Exchange - http://link.mail2web.com/Personal/EnhancedEmail

> From: Mats Karlsson [email protected] > Date: Sat, 24 Aug 2013 10:02:00 +0200 > To: [email protected], [email protected], > [email protected] > Subject: RE: [NMusers] Time-varing covariate > > > Dear Bill and Siwei, > > > > Although the thought in Bill's reply is right, I think there is an error in > the code. NONMEM by default uses the present values to update from the > previous time. > > Further, it is possible to do this interpolation on the fly in the model > file without changes to the data set. > > > > $INPUT ID TIME DV COV ;Cov is time-varying covariate > > $PK > > IF(NEWIND.NE.2) OTIM=0 ;initialize variable to store old time > > IF(NEWIND.NE.2) OCOV=0 ;initialize variable to store old covariate value > > > > $DES > > CCOV=OCOV > > IF(TIME.GT.OTIM) CCOV=OCOV+(T-TIME)*(COV-OCOV)/(TIME-OTIM) ;CCOV is linear > interpolation between observed covariate values > > > > $ERROR > > OCOV =COV ;store previous time > > OTIM =TIME ;store previous time > > > > (NB haven't tested the code). > > Best regards, > > Mats > > Mats Karlsson, PhD > > Professor of Pharmacometrics > > > > Dept of Pharmaceutical Biosciences > > Faculty of Pharmacy > > Uppsala University > > Box 591 > > 75124 Uppsala > > > > Phone: +46 18 4714105 > > Fax + 46 18 4714003 > > http://www.farmbio.uu.se/research/researchgroups/pharmacometrics/ > www.farmbio.uu.se/research/researchgroups/pharmacometrics/ > > > > From: [email protected] [mailto:[email protected]] On > Behalf Of Denney, William S. > Sent: 23 August 2013 20:09 > To: siwei Dai; [email protected] > Subject: RE: [NMusers] Time-varing covariate > > > > Hi Siwei, > > > > If you are using an algebraic model (i.e. no differential equations), then > you can simply include it in your equation: > > > > e.g. assuming that SBP is systolic blood pressure in your original data set: > > > > EFF=THETA(1)+SBP*THETA(2) > > > > If you have a differential equation model and you want the time varying > covariate to have an effect that is not a step change, you will need to > interpolate the covariate. Within your data set, you'll need a column for > the next time and the next value of the time varying covariate. Using the > same assumption that you have SBP in your data set as your time varying > covariate, you will want to make two new columns to allow for interpolation: > > > > ID TIME NTIME SBP NSBP DV > > 1 0 1 110 115 5 > > 1 1 2 115 112 3 > > 1 2 4 112 108 4 > > > > Then to use your parameter, you will need code like the following in your > $DES section to linearly interpolate: > > > > $DES > > . > > ;; Current SBP > > CSBP = (NSBP - SBP)/(NTIME - TIME) * (T - TIME) + SBP > > . > > > > The parameter T is the current time for the differential equation solver > which will be somewhere between TIME and NTIME. TIME is an important column > name for NONMEM. > > > > Thanks, > > > > Bill > > > > From: [email protected] [mailto:[email protected]] On > Behalf Of siwei Dai > Sent: Friday, August 23, 2013 12:01 PM > To: [email protected] > Subject: [NMusers] Time-varing covariate > > > > Hi, Dear NMusers: > > > > I want to add a time-varing covariate in my model. For example, blood > pressure or blood flow as covariates. But I am not sure how to do it. I see > some earlier threads to discuss it but they all use complicated methods. > > > > I am wondering if there are any new way to do it in NM 7.2? I see in the > user guide that EVID=4 can indicate physiological change. Is this what I > should use? > > > > Thank you very much for any suggestions. > > > > Best regards, > > > > Siwei > > > > -------------------------------------------------------------------- > mail2web.com – Enhanced email for the mobile individual based on Microsoft® > Exchange - http://link.mail2web.com/Personal/EnhancedEmail > >

On Fri, Aug 23, 2013 at 1:10 PM, Nick Holford <[email protected]>wrote: > Siwei, > > I don't know why you think this complicated. Suppose you have age (AGE) as > a covariate. This must of course be a time varying covariate if it is > intended to be the current age. And you might have weight (WT) or > creatinine clearance (CLCR) as covariates which typically change with time. > So just code the $INPUT data items and use them as you wish e.g. > > $INPUT ID TIME AGE WT CLCR etc > ... > > $PK > ; CL=(CLnon-renal*f(age) + CLrenal*f(renal_function)) * allometric WT > CL=(THETA(1)*EXP(THETA(2)*(**AGE-40)) + THETA(3)*CLCR/100)*(WT/70)**0.**75 > > EVID=4 has nothing to do with using time varying covariates. > > Perhaps you could explain more clearly what your problem is and why you > think it is complicated to use time varying covariates? > > Best wishes, > > Nick > > > On 23/08/2013 6:00 p.m., siwei Dai wrote: > >> Hi, Dear NMusers: >> I want to add a time-varing covariate in my model. For example, blood >> pressure or blood flow as covariates. But I am not sure how to do it. I see >> some earlier threads to discuss it but they all use complicated methods. >> I am wondering if there are any new way to do it in NM 7.2? I see in the >> user guide that EVID=4 can indicate physiological change. Is this what I >> should use? >> Thank you very much for any suggestions. >> Best regards, >> Siwei >> > > -- > Nick Holford, Professor Clinical Pharmacology > Dept Pharmacology & Clinical Pharmacology, Bldg 503 Room 302A > University of Auckland,85 Park Rd,Private Bag 92019,Auckland,New Zealand > office:+64(9)923-6730 mobile:NZ +64(21)46 23 53 FR +33(7)85 36 84 99 > email: [email protected] > http://holford.fmhs.auckland.ac.nz/ > > Holford NHG. Disease progression and neuroscience. Journal of > Pharmacokinetics and Pharmacodynamics. 2013;40:369-76 > http://link.springer.com/article/10.1007/s10928-013-9316-2 > Holford N, Heo Y-A, Anderson B. A pharmacokinetic standard for babies and > adults. J Pharm Sci. 2013: http://onlinelibrary.wiley.** > http://onlinelibrary.wiley.com/doi/10.1002/jps.23574/abstract > Holford N. A time to event tutorial for pharmacometricians. CPT:PSP. > 2013;2: > http://www.nature.com/psp/journal/v2/n5/full/psp201318a.html > Holford NHG. Clinical pharmacology = disease progression + drug action. > British Journal of Clinical Pharmacology. 2013: > http://onlinelibrary.wiley.com/doi/10.1111/bcp.12170/abstract > > >

From: [email protected] [mailto:[email protected]] On Behalf Of siwei Dai Sent: 26 August 2013 18:13 To: [email protected] Subject: Re: [NMusers] Time-varing covariate Hi, Sebastien, Bill, Nick, Leonid, Mats and Hans: Thank you all very much for the suggestions and nice discussions. I enjoyed to learn from this thread and I am very clear how this should be handled now. I believe this thread also provided a nice record for other new folks like me to learn from. Thanks a lot. Best regards, Siwei On Fri, Aug 23, 2013 at 1:10 PM, Nick Holford <[email protected]> wrote: Siwei, I don't know why you think this complicated. Suppose you have age (AGE) as a covariate. This must of course be a time varying covariate if it is intended to be the current age. And you might have weight (WT) or creatinine clearance (CLCR) as covariates which typically change with time. So just code the $INPUT data items and use them as you wish e.g. $INPUT ID TIME AGE WT CLCR etc ... $PK ; CL=(CLnon-renal*f(age) + CLrenal*f(renal_function)) * allometric WT CL=(THETA(1)*EXP(THETA(2)*(AGE-40)) + THETA(3)*CLCR/100)*(WT/70)**0.75 EVID=4 has nothing to do with using time varying covariates. Perhaps you could explain more clearly what your problem is and why you think it is complicated to use time varying covariates? Best wishes, Nick On 23/08/2013 6:00 p.m., siwei Dai wrote: Hi, Dear NMusers: I want to add a time-varing covariate in my model. For example, blood pressure or blood flow as covariates. But I am not sure how to do it. I see some earlier threads to discuss it but they all use complicated methods. I am wondering if there are any new way to do it in NM 7.2? I see in the user guide that EVID=4 can indicate physiological change. Is this what I should use? Thank you very much for any suggestions. Best regards, Siwei -- Nick Holford, Professor Clinical Pharmacology Dept Pharmacology & Clinical Pharmacology, Bldg 503 Room 302A University of Auckland,85 Park Rd,Private Bag 92019,Auckland,New Zealand office:+64(9)923-6730 <tel:%2B64%289%29923-6730> mobile:NZ +64(21)46 23 53 <tel:%2B64%2821%2946%2023%2053> FR +33(7)85 36 84 99 <tel:%2B33%287%2985%2036%2084%2099> email: [email protected] http://holford.fmhs.auckland.ac.nz/ Holford NHG. Disease progression and neuroscience. Journal of Pharmacokinetics and Pharmacodynamics. 2013;40:369-76 http://link.springer.com/article/10.1007/s10928-013-9316-2 Holford N, Heo Y-A, Anderson B. A pharmacokinetic standard for babies and adults. J Pharm Sci. 2013: http://onlinelibrary.wiley.com/doi/10.1002/jps.23574/abstract Holford N. A time to event tutorial for pharmacometricians. CPT:PSP. 2013;2: http://www.nature.com/psp/journal/v2/n5/full/psp201318a.html Holford NHG. Clinical pharmacology = disease progression + drug action. British Journal of Clinical Pharmacology. 2013: http://onlinelibrary.wiley.com/doi/10.1111/bcp.12170/abstract

On Fri, Aug 23, 2013, at 10:51 AM, siwei Dai wrote: Hi, Nick: Thank you for the response. I meant to say EVID = 2 but not '4', my mistake. In the user guide, it says: 2 Other-type event. The DV data item is ignored. Dose-related data items must be zero. Examples of other-type events are: A compartment is turned on or off (CMT specifies which compartment is to be turned on or off); a prediction is obtained at a speci- fied time so that it may be displayed in a table or scatterplot (PCMT specifies the compartment from which the prediction is obtained); a physiological variable changes. I am asking the question because I thought that usually the covariates stay the same, but I want to add a covariate that changes during the day, so every observation line will have a different covariate value. If I understand your email correctly, I don't need to do anything special to treat this type covariates then? Thanks! Best regards, Siwei On Fri, Aug 23, 2013 at 1:10 PM, Nick Holford <[1][email protected]> wrote: Siwei, I don't know why you think this complicated. Suppose you have age (AGE) as a covariate. This must of course be a time varying covariate if it is intended to be the current age. And you might have weight (WT) or creatinine clearance (CLCR) as covariates which typically change with time. So just code the $INPUT data items and use them as you wish e.g. $INPUT ID TIME AGE WT CLCR etc ... $PK ; CL=(CLnon-renal*f(age) + CLrenal*f(renal_function)) * allometric WT CL=(THETA(1)*EXP(THETA(2)*(AGE-40)) + THETA(3)*CLCR/100)*(WT/70)**0.75 EVID=4 has nothing to do with using time varying covariates. Perhaps you could explain more clearly what your problem is and why you think it is complicated to use time varying covariates? Best wishes, Nick On 23/08/2013 6:00 p.m., siwei Dai wrote: Hi, Dear NMusers: I want to add a time-varing covariate in my model. For example, blood pressure or blood flow as covariates. But I am not sure how to do it. I see some earlier threads to discuss it but they all use complicated methods. I am wondering if there are any new way to do it in NM 7.2? I see in the user guide that EVID=4 can indicate physiological change. Is this what I should use? Thank you very much for any suggestions. Best regards, Siwei -- Nick Holford, Professor Clinical Pharmacology Dept Pharmacology & Clinical Pharmacology, Bldg 503 Room 302A University of Auckland,85 Park Rd,Private Bag 92019,Auckland,New Zealand office:[2]+64(9)923-6730 mobile:NZ [3]+64(21)46 23 53 FR [4]+33(7)85 36 84 99 email: [5][email protected] [6] http://holford.fmhs.auckland.ac.nz/ Holford NHG. Disease progression and neuroscience. Journal of Pharmacokinetics and Pharmacodynamics. 2013;40:369-76 [7] http://link.springer.com/article/10.1007/s10928-013-9316-2 Holford N, Heo Y-A, Anderson B. A pharmacokinetic standard for babies and adults. J Pharm Sci. 2013: [8] http://onlinelibrary.wiley.com/doi/10.1002/jps.23574/abstract Holford N. A time to event tutorial for pharmacometricians. CPT:PSP. 2013;2: [9] http://www.nature.com/psp/journal/v2/n5/full/psp201318a.html Holford NHG. Clinical pharmacology = disease progression + drug action. British Journal of Clinical Pharmacology. 2013: [10] http://onlinelibrary.wiley.com/doi/10.1111/bcp.12170/abstract References 1. mailto:[email protected] 2. tel:%2B64%289%29923-6730 3. tel:%2B64%2821%2946%2023%2053 4. tel:%2B33%287%2985%2036%2084%2099 5. mailto:[email protected] 6. http://holford.fmhs.auckland.ac.nz/ 7. http://link.springer.com/article/10.1007/s10928-013-9316-2 8. http://onlinelibrary.wiley.com/doi/10.1002/jps.23574/abstract 9. http://www.nature.com/psp/journal/v2/n5/full/psp201318a.html 10. http://onlinelibrary.wiley.com/doi/10.1111/bcp.12170/abstract -- Alison Boeckmann [email protected]

From: [email protected] [mailto:[email protected]] On Behalf Of Alison Boeckmann Sent: 27 August 2013 22:46 To: siwei Dai; ajbf Cc: [email protected] Subject: Re: [NMusers] Time-varing covariate There have been a number of interesting comments. The original issue has to do with the way this is described in on-line help for EVID. Would it be more clear if this said: a physiological variable changes (and this is at a different time than any observation or dose event). Or can someone suggest a better wording that would not add to the confusion? On Fri, Aug 23, 2013, at 10:51 AM, siwei Dai wrote: Hi, Nick: Thank you for the response. I meant to say EVID = 2 but not '4', my mistake. In the user guide, it says: 2 Other-type event. The DV data item is ignored. Dose-related data items must be zero. Examples of other-type events are: A compartment is turned on or off (CMT specifies which compartment is to be turned on or off); a prediction is obtained at a speci- fied time so that it may be displayed in a table or scatterplot (PCMT specifies the compartment from which the prediction is obtained); a physiological variable changes. I am asking the question because I thought that usually the covariates stay the same, but I want to add a covariate that changes during the day, so every observation line will have a different covariate value. If I understand your email correctly, I don't need to do anything special to treat this type covariates then? Thanks! Best regards, Siwei On Fri, Aug 23, 2013 at 1:10 PM, Nick Holford <[email protected]> wrote: Siwei, I don't know why you think this complicated. Suppose you have age (AGE) as a covariate. This must of course be a time varying covariate if it is intended to be the current age. And you might have weight (WT) or creatinine clearance (CLCR) as covariates which typically change with time. So just code the $INPUT data items and use them as you wish e.g. $INPUT ID TIME AGE WT CLCR etc ... $PK ; CL=(CLnon-renal*f(age) + CLrenal*f(renal_function)) * allometric WT CL=(THETA(1)*EXP(THETA(2)*(AGE-40)) + THETA(3)*CLCR/100)*(WT/70)**0.75 EVID=4 has nothing to do with using time varying covariates. Perhaps you could explain more clearly what your problem is and why you think it is complicated to use time varying covariates? Best wishes, Nick On 23/08/2013 6:00 p.m., siwei Dai wrote: Hi, Dear NMusers: I want to add a time-varing covariate in my model. For example, blood pressure or blood flow as covariates. But I am not sure how to do it. I see some earlier threads to discuss it but they all use complicated methods. I am wondering if there are any new way to do it in NM 7.2? I see in the user guide that EVID=4 can indicate physiological change. Is this what I should use? Thank you very much for any suggestions. Best regards, Siwei -- Nick Holford, Professor Clinical Pharmacology Dept Pharmacology & Clinical Pharmacology, Bldg 503 Room 302A University of Auckland,85 Park Rd,Private Bag 92019,Auckland,New Zealand office:+64(9)923-6730 <tel:%2B64%289%29923-6730> mobile:NZ +64(21)46 23 53 <tel:%2B64%2821%2946%2023%2053> FR +33(7)85 36 84 99 <tel:%2B33%287%2985%2036%2084%2099> email: [email protected] http://holford.fmhs.auckland.ac.nz/ Holford NHG. Disease progression and neuroscience. Journal of Pharmacokinetics and Pharmacodynamics. 2013;40:369-76 http://link.springer.com/article/10.1007/s10928-013-9316-2 Holford N, Heo Y-A, Anderson B. A pharmacokinetic standard for babies and adults. J Pharm Sci. 2013: http://onlinelibrary.wiley.com/doi/10.1002/jps.23574/abstract Holford N. A time to event tutorial for pharmacometricians. CPT:PSP. 2013;2: http://www.nature.com/psp/journal/v2/n5/full/psp201318a.html Holford NHG. Clinical pharmacology = disease progression + drug action. British Journal of Clinical Pharmacology. 2013: http://onlinelibrary.wiley.com/doi/10.1111/bcp.12170/abstract -- Alison Boeckmann [email protected]

On 27/08/2013 10:45 p.m., Alison Boeckmann wrote: > There have been a number of interesting comments. > > The original issue has to do with the way this is described in on-line help for EVID. > > Would it be more clear if this said: > > > a physiological variable changes (and this is at a different time than any observation or dose event). > > Or can someone suggest a better wording that would not add to the confusion? > > On Fri, Aug 23, 2013, at 10:51 AM, siwei Dai wrote: > > > Hi, Nick: > > Thank you for the response. > > > > I meant to say EVID = 2 but not '4', my mistake. In the user guide, it says: > > > > 2 Other-type event. The DV data item is ignored. Dose-related > > data items must be zero. Examples of other-type events are: A > > compartment is turned on or off (CMT specifies which compartment > > is to be turned on or off); a prediction is obtained at a speci- > > fied time so that it may be displayed in a table or scatterplot > > (PCMT specifies the compartment from which the prediction is > > obtained); a physiological variable changes. > > > > I am asking the question because I thought that usually the covariates stay the same, but I want to add a covariate that changes during the day, so every observation line will have a different covariate value. If I understand your email correctly, I don't need to do anything special to treat this type covariates then? > > > > Thanks! > > Best regards, > > Siwei > > > > On Fri, Aug 23, 2013 at 1:10 PM, Nick Holford < [email protected] < mailto: [email protected] >> wrote: > > > > Siwei, > > > > I don't know why you think this complicated. Suppose you have age > > (AGE) as a covariate. This must of course be a time varying > > covariate if it is intended to be the current age. And you might > > have weight (WT) or creatinine clearance (CLCR) as covariates > > which typically change with time. So just code the $INPUT data > > items and use them as you wish e.g. > > > > $INPUT ID TIME AGE WT CLCR etc > > ... > > > > $PK > > ; CL=(CLnon-renal*f(age) + CLrenal*f(renal_function)) * allometric WT > > CL=(THETA(1)*EXP(THETA(2)*(AGE-40)) + > > THETA(3)*CLCR/100)*(WT/70)**0.75 > > > > EVID=4 has nothing to do with using time varying covariates. > > > > Perhaps you could explain more clearly what your problem is and > > why you think it is complicated to use time varying covariates? > > > > Best wishes, > > > > Nick > > > > On 23/08/2013 6:00 p.m., siwei Dai wrote: > > > > Hi, Dear NMusers: > > I want to add a time-varing covariate in my model. For > > example, blood pressure or blood flow as covariates. But I am > > not sure how to do it. I see some earlier threads to discuss > > it but they all use complicated methods. > > I am wondering if there are any new way to do it in NM 7.2? > > I see in the user guide that EVID=4 can indicate > > physiological change. Is this what I should use? > > Thank you very much for any suggestions. > > Best regards, > > Siwei > > > > -- > > Nick Holford, Professor Clinical Pharmacology > > Dept Pharmacology & Clinical Pharmacology, Bldg 503 Room 302A > > University of Auckland,85 Park Rd,Private Bag 92019,Auckland,New > > Zealand > > office:+64(9)923-6730 <tel:%2B64%289%29923-6730> mobile:NZ > > +64(21)46 23 53 <tel:%2B64%2821%2946%2023%2053> FR +33(7)85 36 84 > > 99 <tel:%2B33%287%2985%2036%2084%2099> > > email: [email protected] <mailto:[email protected]> > > http://holford.fmhs.auckland.ac.nz/ > > > > Holford NHG. Disease progression and neuroscience. Journal of > > Pharmacokinetics and Pharmacodynamics. 2013;40:369-76 > > http://link.springer.com/article/10.1007/s10928-013-9316-2 > > Holford N, Heo Y-A, Anderson B. A pharmacokinetic standard for > > babies and adults. J Pharm Sci. 2013: > > http://onlinelibrary.wiley.com/doi/10.1002/jps.23574/abstract > > Holford N. A time to event tutorial for pharmacometricians. > > CPT:PSP. 2013;2: > > http://www.nature.com/psp/journal/v2/n5/full/psp201318a.html > > Holford NHG. Clinical pharmacology = disease progression + drug > > action. British Journal of Clinical Pharmacology. 2013: > > http://onlinelibrary.wiley.com/doi/10.1111/bcp.12170/abstract > > -- > Alison Boeckmann > [email protected] <mailto:[email protected]> -- Nick Holford, Professor Clinical Pharmacology Dept Pharmacology & Clinical Pharmacology, Bldg 503 Room 302A University of Auckland,85 Park Rd,Private Bag 92019,Auckland,New Zealand office:+64(9)923-6730 mobile:NZ +64(21)46 23 53 FR +33(7)85 36 84 99 email: [email protected] http://holford.fmhs.auckland.ac.nz/ Holford NHG. Disease progression and neuroscience. Journal of Pharmacokinetics and Pharmacodynamics. 2013;40:369-76 http://link.springer.com/article/10.1007/s10928-013-9316-2 Holford N, Heo Y-A, Anderson B. A pharmacokinetic standard for babies and adults. J Pharm Sci. 2013: http://onlinelibrary.wiley.com/doi/10.1002/jps.23574/abstract Holford N. A time to event tutorial for pharmacometricians. CPT:PSP. 2013;2: http://www.nature.com/psp/journal/v2/n5/full/psp201318a.html Holford NHG. Clinical pharmacology = disease progression + drug action. British Journal of Clinical Pharmacology. 2013: http://onlinelibrary.wiley.com/doi/10.1111/bcp.12170/abstract

On Wed, Aug 28, 2013, at 12:53 AM, Nick Holford wrote: Alison, I think the problem with the on-line help arose because a relatively inexperienced nmuser was searching through the help to find some clues on what to do. The use of the "physiological variable changes" expression to describe an EVID=2 event seems to have been interpreted as something special within NONMEM that knew about physiological changes. Of course, this was a misunderstanding. To avoid the misunderstanding I suggest you make it clearer that the change in a physiological variable is just an example of a covariate change at a non-dose and non-observation event time e.g. "Examples of other-type events are: A compartment is turned on or off (CMT specifies which compartment is to be turned on or off); a prediction is obtained at a specified time so that it may be displayed in a table or scatterplot ; some event occurs at a different time than any observation or dose event e.g. a covariate such as weight changes, an intervention such as hemodialysis is started or stopped." Adding more specific examples of the use of EVID=2 would perhaps be useful. Does anyone have any other examples? I also suggest removing reference to PCMT "(PCMT specifies the compartment from which the prediction is obtained)" because it is not directly relevant to EVID=2. An inexperienced user might interpret the remark about PCMT to imply that PCMT is required for use with EVID=2. In my own experience I have never found the need to use PCMT. I usually do not rely on the default compartment with complex models but use the compartment explicitly in $ERROR to define the prediction I want to output. Best wishes, Nick On 27/08/2013 10:45 p.m., Alison Boeckmann wrote: There have been a number of interesting comments. The original issue has to do with the way this is described in on-line help for EVID. Would it be more clear if this said: a physiological variable changes (and this is at a different time than any observation or dose event). Or can someone suggest a better wording that would not add to the confusion? On Fri, Aug 23, 2013, at 10:51 AM, siwei Dai wrote: Hi, Nick: Thank you for the response. I meant to say EVID = 2 but not '4', my mistake. In the user guide, it says: 2 Other-type event. The DV data item is ignored. Dose-related data items must be zero. Examples of other-type events are: A compartment is turned on or off (CMT specifies which compartment is to be turned on or off); a prediction is obtained at a speci- fied time so that it may be displayed in a table or scatterplot (PCMT specifies the compartment from which the prediction is obtained); a physiological variable changes. I am asking the question because I thought that usually the covariates stay the same, but I want to add a covariate that changes during the day, so every observation line will have a different covariate value. If I understand your email correctly, I don't need to do anything special to treat this type covariates then? Thanks! Best regards, Siwei On Fri, Aug 23, 2013 at 1:10 PM, Nick Holford <[1][email protected]> wrote: Siwei, I don't know why you think this complicated. Suppose you have age (AGE) as a covariate. This must of course be a time varying covariate if it is intended to be the current age. And you might have weight (WT) or creatinine clearance (CLCR) as covariates which typically change with time. So just code the $INPUT data items and use them as you wish e.g. $INPUT ID TIME AGE WT CLCR etc ... $PK ; CL=(CLnon-renal*f(age) + CLrenal*f(renal_function)) * allometric WT CL=(THETA(1)*EXP(THETA(2)*(AGE-40)) + THETA(3)*CLCR/100)*(WT/70)**0.75 EVID=4 has nothing to do with using time varying covariates. Perhaps you could explain more clearly what your problem is and why you think it is complicated to use time varying covariates? Best wishes, Nick On 23/08/2013 6:00 p.m., siwei Dai wrote: Hi, Dear NMusers: I want to add a time-varing covariate in my model. For example, blood pressure or blood flow as covariates. But I am not sure how to do it. I see some earlier threads to discuss it but they all use complicated methods. I am wondering if there are any new way to do it in NM 7.2? I see in the user guide that EVID=4 can indicate physiological change. Is this what I should use? Thank you very much for any suggestions. Best regards, Siwei -- Nick Holford, Professor Clinical Pharmacology Dept Pharmacology & Clinical Pharmacology, Bldg 503 Room 302A University of Auckland,85 Park Rd,Private Bag 92019,Auckland,New Zealand office:[2]+64(9)923-6730 mobile:NZ [3]+64(21)46 23 53 FR [4]+33(7)85 36 84 99 email: [5][email protected] [6] http://holford.fmhs.auckland.ac.nz/ Holford NHG. Disease progression and neuroscience. Journal of Pharmacokinetics and Pharmacodynamics. 2013;40:369-76 [7] http://link.springer.com/article/10.1007/s10928-013-9316-2 Holford N, Heo Y-A, Anderson B. A pharmacokinetic standard for babies and adults. J Pharm Sci. 2013: [8] http://onlinelibrary.wiley.com/doi/10.1002/jps.23574/abstract Holford N. A time to event tutorial for pharmacometricians. CPT:PSP. 2013;2: [9] http://www.nature.com/psp/journal/v2/n5/full/psp201318a.html Holford NHG. Clinical pharmacology = disease progression + drug action. British Journal of Clinical Pharmacology. 2013: [10] http://onlinelibrary.wiley.com/doi/10.1111/bcp.12170/abstract -- Alison Boeckmann [11][email protected] -- Nick Holford, Professor Clinical Pharmacology Dept Pharmacology & Clinical Pharmacology, Bldg 503 Room 302A University of Auckland,85 Park Rd,Private Bag 92019,Auckland,New Zealand office:+64(9)923-6730 mobile:NZ +64(21)46 23 53 FR +33(7)85 36 84 99 email: [12][email protected] [13] http://holford.fmhs.auckland.ac.nz/ Holford NHG. Disease progression and neuroscience. Journal of Pharmacokinetics a nd Pharmacodynamics. 2013;40:369-76 [14] http://link.springer.com/article/10.1007 /s10928-013-9316-2 Holford N, Heo Y-A, Anderson B. A pharmacokinetic standard for babies and adults . J Pharm Sci. 2013: [15] http://onlinelibrary.wiley.com/doi/10.1002/jps.23574/ab stract Holford N. A time to event tutorial for pharmacometricians. CPT:PSP. 2013;2: [16 ] http://www.nature.com/psp/journal/v2/n5/full/psp201318a.html Holford NHG. Clinical pharmacology = disease progression + drug action. British Journal of Clinical Pharmacology. 2013: [17] http://onlinelibrary.wiley.com/doi/1 0.1111/bcp.12170/abstract References 1. mailto:[email protected] 2. tel:%2B64%289%29923-6730 3. tel:%2B64%2821%2946%2023%2053 4. tel:%2B33%287%2985%2036%2084%2099 5. mailto:[email protected] 6. http://holford.fmhs.auckland.ac.nz/ 7. http://link.springer.com/article/10.1007/s10928-013-9316-2 8. http://onlinelibrary.wiley.com/doi/10.1002/jps.23574/abstract 9. http://www.nature.com/psp/journal/v2/n5/full/psp201318a.html 10. http://onlinelibrary.wiley.com/doi/10.1111/bcp.12170/abstract 11. mailto:[email protected] 12. mailto:[email protected] 13. http://holford.fmhs.auckland.ac.nz/ 14. http://link.springer.com/article/10.1007/s10928-013-9316-2 15. http://onlinelibrary.wiley.com/doi/10.1002/jps.23574/abstract 16. http://www.nature.com/psp/journal/v2/n5/full/psp201318a.html 17. http://onlinelibrary.wiley.com/doi/10.1111/bcp.12170/abstract -- Alison Boeckmann [email protected]