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From: HUI, Ka Ho <matthew.hui_at_link.cuhk.edu.hk>

Date: Thu, 19 Nov 2015 13:56:55 +0000

Thank you Zheng. Yes most subjects have only 1 point between doses. I was j=

ust wondering if there are techniques that may improve the results.

And thank you Kajsa. Yes I updated my PsN and tried again. It still did not=

work at first but later I spotted some coding mistakes in my control file.=

Under $INPUT block I used CP=DV instead DV, which caused the error.

Thanks and regards,

Matthew

From: Kajsa Harling [mailto:kajsa.harling_at_farmbio.uu.se]

Sent: Monday, November 16, 2015 9:41 PM

To: HUI, Ka Ho <matthew.hui_at_link.cuhk.edu.hk>; nmusers_at_globomaxnm.com

Cc: Kaila, Nitin <Nitin.Kaila_at_pfizer.com>; Abu Helwa, Ahmad Yousef Mohammad=

- abuay010 <ahmad.abuhelwa_at_mymail.unisa.edu.au>; felix boakye-agyeman <boa=

kyefe_at_gmail.com>

Subject: Re: [NMusers] RE: Large errors in the estimation of volume of dist=

ribution (Vd) for sparse data

Regarding the error message from PsN vpc: I can see from the message that y=

ou are using a *very* old version of PsN. I suggest that you install the la=

test version and try again.

Best regards,

Kajsa Harling

From: Zheng Liu [mailto:Zheng.Liu_at_rch.org.au]

Sent: Monday, November 16, 2015 1:08 PM

To: HUI, Ka Ho <matthew.hui_at_link.cuhk.edu.hk>; Kaila, Nitin <Nitin.Kaila_at_pf=

izer.com>; Abu Helwa, Ahmad Yousef Mohammad - abuay010 <ahmad.abuhelwa_at_myma=

il.unisa.edu.au>; felix boakye-agyeman <boakyefe_at_gmail.com>; nmusers_at_globom=

axnm.com

Subject: RE: Large errors in the estimation of volume of distribution (Vd) =

for sparse data

Hi Matthew,

Very large standard error and bias of Vd suggest that Vd is not well identi=

fied. Or in other word, your data didn't contain sufficient information to =

fit Vd. Loosely speaking it is a problem of over-parameterization, because =

you have only one measurement point, but you try to fit 2 parameters (Vd an=

d clearance).

Zheng

On 11/10/2015 05:12 AM, HUI, Ka Ho wrote:

Thanks for your responses!

Nitin, I encountered an error when generating VPC by PsN. It says "No DV va=

lues found after filtering original data. At lib/tool/npc.subs.pm line 2215=

." What does it mean?

Felix, Past published data suggested similar parameter estimates and models=

compared to my final model. This is PO and I fixed Ka at a pre-estimated v=

alue (So no estimation of fixed or random effect).

Ahmad, Yes. The CV is even larger.

Matthew

From: Abu Helwa, Ahmad Yousef Mohammad - abuay010 [mailto:ahmad.abuhelwa_at_my=

mail.unisa.edu.au]

Sent: Tuesday, November 10, 2015 5:34 AM

To: HUI, Ka Ho <matthew.hui_at_link.cuhk.edu.hk><mailto:matthew.hui_at_link.cuhk.=

edu.hk>; nmusers_at_globomaxnm.com<mailto:nmusers_at_globomaxnm.com>

Subject: RE: Large errors in the estimation of volume of distribution (Vd) =

for sparse data

Hi Mathew,

Have you tried using an exponential model for vd ? like this: Vd = TEHTA=

(1)*EXP(ETA(1))

Ahmad.

From: felix boakye-agyeman [mailto:boakyefe_at_gmail.com]

Sent: Tuesday, November 10, 2015 12:41 AM

To: HUI, Ka Ho <matthew.hui_at_link.cuhk.edu.hk><mailto:matthew.hui_at_link.cuhk.=

edu.hk>

Subject: Re: [NMusers] Large errors in the estimation of volume of distribu=

tion (Vd) for sparse data

Hello,

Do you have historical data to compare you data to? (Do you know if you =

are hitting a local minimum)

Is this iv or po, if its po how is your Ka?

You may also be over-parameterized due to your data

From: Kaila, Nitin [mailto:Nitin.Kaila_at_pfizer.com]

Sent: Tuesday, November 10, 2015 12:14 AM

To: HUI, Ka Ho <matthew.hui_at_link.cuhk.edu.hk><mailto:matthew.hui_at_link.cuhk.=

edu.hk>

Subject: RE: Large errors in the estimation of volume of distribution (Vd) =

for sparse data

Matthew.

Construct visual predictive check (VPC) plots, using all the estimates of t=

he bootstrap runs, as that will be a more true estimate of overall variabil=

ity in the Cp predictions.

Use the -rawres option in PsN to perform the VPC, and then compare your ori=

ginal final model VPC plot with the VPC plot with all estimates of the boot=

strap.

Nitin

From: owner-nmusers_at_globomaxnm.com<mailto:owner-nmusers_at_globomaxnm.com> [ma=

ilto:owner-nmusers_at_globomaxnm.com] On Behalf Of HUI, Ka Ho

Sent: Monday, November 9, 2015 9:43 AM

To: nmusers_at_globomaxnm.com<mailto:nmusers_at_globomaxnm.com>

Subject: [NMusers] Large errors in the estimation of volume of distribution=

(Vd) for sparse data

Dear all,

I have some population PK data which are in general very sparse (95% have o=

nly 1 blood sample between 2 successive doses). I developed a population PK=

model with the one-compartment model with 1st order absorption. The progre=

ss is generally okay except that whenever a random effect, i.e. *(1+ETA(1))=

, is used to describe distribution of Vd, OMEGA would be estimated to be ve=

ry large (around 45% in terms of CV, with 80% Shrinkage), despite statistic=

al significance (dOF approx. -5.5). So I dropped the random effect and expr=

essed Vd in terms of a single fixed effect. When the final model has come o=

ut, I performed bootstrap and found that most estimates are accurate except=

Vd, which has a very large standard error and bias (mean 232, bias 49, SE =

156), while the estimates for CL and other parameters look normal. I then c=

onstructed the predictive plots for the developed model using both the orig=

inal estimates (i.e. estimates using my original dataset) (#1) and estimate=

s from one of the bootstrap runs which has an extreme estimate of Vd (9xx) =

(#2), and found out that the two plots of plasma profiles are quite differe=

nt in terms of the shape (#1 is "taller", #2 is much flatter) but have simi=

lar average Cp.

These seem to be suggesting that given my sparse data, it is impossible to =

require accurate estimations of both CL and Vd. Apart from fixing Vd to a f=

ixed value, is there any other possible solutions? Or is there anything tha=

t I might have overlooked?

Thanks and regards,

Matthew

Received on Thu Nov 19 2015 - 08:56:55 EST

Date: Thu, 19 Nov 2015 13:56:55 +0000

Thank you Zheng. Yes most subjects have only 1 point between doses. I was j=

ust wondering if there are techniques that may improve the results.

And thank you Kajsa. Yes I updated my PsN and tried again. It still did not=

work at first but later I spotted some coding mistakes in my control file.=

Under $INPUT block I used CP=DV instead DV, which caused the error.

Thanks and regards,

Matthew

From: Kajsa Harling [mailto:kajsa.harling_at_farmbio.uu.se]

Sent: Monday, November 16, 2015 9:41 PM

To: HUI, Ka Ho <matthew.hui_at_link.cuhk.edu.hk>; nmusers_at_globomaxnm.com

Cc: Kaila, Nitin <Nitin.Kaila_at_pfizer.com>; Abu Helwa, Ahmad Yousef Mohammad=

- abuay010 <ahmad.abuhelwa_at_mymail.unisa.edu.au>; felix boakye-agyeman <boa=

kyefe_at_gmail.com>

Subject: Re: [NMusers] RE: Large errors in the estimation of volume of dist=

ribution (Vd) for sparse data

Regarding the error message from PsN vpc: I can see from the message that y=

ou are using a *very* old version of PsN. I suggest that you install the la=

test version and try again.

Best regards,

Kajsa Harling

From: Zheng Liu [mailto:Zheng.Liu_at_rch.org.au]

Sent: Monday, November 16, 2015 1:08 PM

To: HUI, Ka Ho <matthew.hui_at_link.cuhk.edu.hk>; Kaila, Nitin <Nitin.Kaila_at_pf=

izer.com>; Abu Helwa, Ahmad Yousef Mohammad - abuay010 <ahmad.abuhelwa_at_myma=

il.unisa.edu.au>; felix boakye-agyeman <boakyefe_at_gmail.com>; nmusers_at_globom=

axnm.com

Subject: RE: Large errors in the estimation of volume of distribution (Vd) =

for sparse data

Hi Matthew,

Very large standard error and bias of Vd suggest that Vd is not well identi=

fied. Or in other word, your data didn't contain sufficient information to =

fit Vd. Loosely speaking it is a problem of over-parameterization, because =

you have only one measurement point, but you try to fit 2 parameters (Vd an=

d clearance).

Zheng

On 11/10/2015 05:12 AM, HUI, Ka Ho wrote:

Thanks for your responses!

Nitin, I encountered an error when generating VPC by PsN. It says "No DV va=

lues found after filtering original data. At lib/tool/npc.subs.pm line 2215=

." What does it mean?

Felix, Past published data suggested similar parameter estimates and models=

compared to my final model. This is PO and I fixed Ka at a pre-estimated v=

alue (So no estimation of fixed or random effect).

Ahmad, Yes. The CV is even larger.

Matthew

From: Abu Helwa, Ahmad Yousef Mohammad - abuay010 [mailto:ahmad.abuhelwa_at_my=

mail.unisa.edu.au]

Sent: Tuesday, November 10, 2015 5:34 AM

To: HUI, Ka Ho <matthew.hui_at_link.cuhk.edu.hk><mailto:matthew.hui_at_link.cuhk.=

edu.hk>; nmusers_at_globomaxnm.com<mailto:nmusers_at_globomaxnm.com>

Subject: RE: Large errors in the estimation of volume of distribution (Vd) =

for sparse data

Hi Mathew,

Have you tried using an exponential model for vd ? like this: Vd = TEHTA=

(1)*EXP(ETA(1))

Ahmad.

From: felix boakye-agyeman [mailto:boakyefe_at_gmail.com]

Sent: Tuesday, November 10, 2015 12:41 AM

To: HUI, Ka Ho <matthew.hui_at_link.cuhk.edu.hk><mailto:matthew.hui_at_link.cuhk.=

edu.hk>

Subject: Re: [NMusers] Large errors in the estimation of volume of distribu=

tion (Vd) for sparse data

Hello,

Do you have historical data to compare you data to? (Do you know if you =

are hitting a local minimum)

Is this iv or po, if its po how is your Ka?

You may also be over-parameterized due to your data

From: Kaila, Nitin [mailto:Nitin.Kaila_at_pfizer.com]

Sent: Tuesday, November 10, 2015 12:14 AM

To: HUI, Ka Ho <matthew.hui_at_link.cuhk.edu.hk><mailto:matthew.hui_at_link.cuhk.=

edu.hk>

Subject: RE: Large errors in the estimation of volume of distribution (Vd) =

for sparse data

Matthew.

Construct visual predictive check (VPC) plots, using all the estimates of t=

he bootstrap runs, as that will be a more true estimate of overall variabil=

ity in the Cp predictions.

Use the -rawres option in PsN to perform the VPC, and then compare your ori=

ginal final model VPC plot with the VPC plot with all estimates of the boot=

strap.

Nitin

From: owner-nmusers_at_globomaxnm.com<mailto:owner-nmusers_at_globomaxnm.com> [ma=

ilto:owner-nmusers_at_globomaxnm.com] On Behalf Of HUI, Ka Ho

Sent: Monday, November 9, 2015 9:43 AM

To: nmusers_at_globomaxnm.com<mailto:nmusers_at_globomaxnm.com>

Subject: [NMusers] Large errors in the estimation of volume of distribution=

(Vd) for sparse data

Dear all,

I have some population PK data which are in general very sparse (95% have o=

nly 1 blood sample between 2 successive doses). I developed a population PK=

model with the one-compartment model with 1st order absorption. The progre=

ss is generally okay except that whenever a random effect, i.e. *(1+ETA(1))=

, is used to describe distribution of Vd, OMEGA would be estimated to be ve=

ry large (around 45% in terms of CV, with 80% Shrinkage), despite statistic=

al significance (dOF approx. -5.5). So I dropped the random effect and expr=

essed Vd in terms of a single fixed effect. When the final model has come o=

ut, I performed bootstrap and found that most estimates are accurate except=

Vd, which has a very large standard error and bias (mean 232, bias 49, SE =

156), while the estimates for CL and other parameters look normal. I then c=

onstructed the predictive plots for the developed model using both the orig=

inal estimates (i.e. estimates using my original dataset) (#1) and estimate=

s from one of the bootstrap runs which has an extreme estimate of Vd (9xx) =

(#2), and found out that the two plots of plasma profiles are quite differe=

nt in terms of the shape (#1 is "taller", #2 is much flatter) but have simi=

lar average Cp.

These seem to be suggesting that given my sparse data, it is impossible to =

require accurate estimations of both CL and Vd. Apart from fixing Vd to a f=

ixed value, is there any other possible solutions? Or is there anything tha=

t I might have overlooked?

Thanks and regards,

Matthew

Received on Thu Nov 19 2015 - 08:56:55 EST