Dear NM
users
I am
currently developing a PK PD model for local anesthetics using a sequential
approach with ADVAN6. The PD model is a sigmoid Emax with an effect compartment
(Ce).
The
intensity and duration of nerve blockade are monitored throughout the
perioperative period in patients using a quantitative
pharmacodynamic endpoint, i.e, the current perception threshold (CPT) REF: Can.
J. Anesth, 57 (S1) 2010). Briefly, CPT
is evaluated before and after the administration of the local anesthectic. Data
are normalized by baseline using the following equation :
(observed-baseline)
/ (max-baseline) *100 (%)
Here is the
problem. The device only goes to a maximum of 10 mA. In some patients, the real
Emax is much higher. Any ideas on how handle a truncated Emax ?
Thanks in
advance
--
François Gaudreault, Ph.D. Candidate
Pharmacométrie / Pharmacometrics
Charger de cours / Lecturer
Faculté de pharmacie / Faculty of Pharmacy
Université de Montréal
Truncated Emax
Hi Francois,
For pain measurements it is not uncommon to analyze data with a upper limit of quantitation. You can follow the literature on BQL, only reversing from a lower limit to an upper limIt. In my experience just deleting censored data works fine, certainly as a first attempt, as long as censoring stays below ~1/3 of total data.
Best regards,
Jeroen
J. Elassaiss-Schaap
Scientist PK/PD
MSD
PO Box 20, 5340 BH Oss, Netherlands
Phone: + 31 412 66 9320
Fax: + 31 412 66 2506
e-mail: jeroen.elassaiss
Quoted reply history
________________________________
From: owner-nmusers
Behalf Of Francois Gaudreault
Sent: Monday, December 19, 2011 21:40
To: nmusers
Subject: [NMusers] Truncated Emax
Dear NM users
I am currently developing a PK PD model for local anesthetics using a sequential approach with ADVAN6. The PD model is a sigmoid Emax with an effect compartment (Ce).
The intensity and duration of nerve blockade are monitored throughout the perioperative period in patients using a quantitative pharmacodynamic endpoint, i.e, the current perception threshold (CPT) REF: Can. J. Anesth, 57 (S1) 2010). Briefly, CPT is evaluated before and after the administration of the local anesthectic. Data are normalized by baseline using the following equation :
(observed-baseline) / (max-baseline) *100 (%)
Here is the problem. The device only goes to a maximum of 10 mA. In some patients, the real Emax is much higher. Any ideas on how handle a truncated Emax ?
Thanks in advance
--
Franois Gaudreault, Ph.D. Candidate
Pharmacomtrie / Pharmacometrics
Charger de cours / Lecturer
Facult de pharmacie / Faculty of Pharmacy
Universit de Montral
Notice: This e-mail message, together with any attachments, contains
information of Merck & Co., Inc. (One Merck Drive, Whitehouse Station,
New Jersey, USA 08889), and/or its affiliates Direct contact information
for affiliates is available at
http://www.merck.com/contact/contacts.html) that may be confidential,
proprietary copyrighted and/or legally privileged. It is intended solely
for the use of the individual or entity named on this message. If you are
not the intended recipient, and have received this message in error,
please notify us immediately by reply e-mail and then delete it from
your system.
Hi Francois,
For pain measurements it is not uncommon to analyze data with a upper limit of
quantitation. You can follow the literature on BQL, only reversing from a lower
limit to an upper limIt. In my experience just deleting censored data works
fine, certainly as a first attempt, as long as censoring stays below ~1/3 of
total data.
Best regards,
Jeroen
J. Elassaiss-Schaap
Scientist PK/PD
MSD
PO Box 20, 5340 BH Oss, Netherlands
Phone: + 31 412 66 9320
Fax: + 31 412 66 2506
e-mail: [email protected]
Quoted reply history
________________________________
From: [email protected] [mailto:[email protected]] On
Behalf Of Francois Gaudreault
Sent: Monday, December 19, 2011 21:40
To: [email protected]
Subject: [NMusers] Truncated Emax
Dear NM users
I am currently developing a PK PD model for local anesthetics using a
sequential approach with ADVAN6. The PD model is a sigmoid Emax with an effect
compartment (Ce).
The intensity and duration of nerve blockade are monitored throughout the
perioperative period in patients using a quantitative pharmacodynamic endpoint,
i.e, the current perception threshold (CPT) REF: Can. J. Anesth, 57 (S1) 2010).
Briefly, CPT is evaluated before and after the administration of the local
anesthectic. Data are normalized by baseline using the following equation :
(observed-baseline) / (max-baseline) *100 (%)
Here is the problem. The device only goes to a maximum of 10 mA. In some
patients, the real Emax is much higher. Any ideas on how handle a truncated
Emax ?
Thanks in advance
--
François Gaudreault, Ph.D. Candidate
Pharmacométrie / Pharmacometrics
Charger de cours / Lecturer
Faculté de pharmacie / Faculty of Pharmacy
Université de Montréal
Notice: This e-mail message, together with any attachments, contains
information of Merck & Co., Inc. (One Merck Drive, Whitehouse Station,
New Jersey, USA 08889), and/or its affiliates Direct contact information
for affiliates is available at
http://www.merck.com/contact/contacts.html) that may be confidential,
proprietary copyrighted and/or legally privileged. It is intended solely
for the use of the individual or entity named on this message. If you are
not the intended recipient, and have received this message in error,
please notify us immediately by reply e-mail and then delete it from
your system.
Dear Francois,
Maybe this work can put some light to your question
Yassen A. Pharmacokinetic-Pharmacodynamic modeling of the antinociceptive
effect of buprenorphine and fentanyl in rats, role of receptor
equilibration kinetics JPET 2005; 313: 1136-1149.
Ignacio Ortega
Pharmacokinetics and Drug Metabolism Area
Research, Development and Innovation Department
FAES FARMA
Maximo Aguirre 14. 48940 Leioa
Spain
Francois Gaudreault <f_gaudreault11
Enviado por: owner-nmusers
19/12/2011 21:40
Para
<nmusers
cc
Asunto
[NMusers] Truncated Emax
Dear NM users
I am currently developing a PK PD model for local anesthetics using a
sequential approach with ADVAN6. The PD model is a sigmoid Emax with an
effect compartment (Ce).
The intensity and duration of nerve blockade are monitored throughout the
perioperative period in patients using a quantitative pharmacodynamic
endpoint, i.e, the current perception threshold (CPT) REF: Can. J. Anesth,
57 (S1) 2010). Briefly, CPT is evaluated before and after the
administration of the local anesthectic. Data are normalized by baseline
using the following equation :
(observed-baseline) / (max-baseline) *100 (%)
Here is the problem. The device only goes to a maximum of 10 mA. In some
patients, the real Emax is much higher. Any ideas on how handle a
truncated Emax ?
Thanks in advance
--
Franois Gaudreault, Ph.D. Candidate
Pharmacomtrie / Pharmacometrics
Charger de cours / Lecturer
Facult de pharmacie / Faculty of Pharmacy
Universit de Montral
Hi Martin,
Thank you for pointing this out. I actually do agree with you! I certainly did not imply that deleting censored data is a guarantee for unbiased results.
But please keep in mind that especially with pain censoring is not arbitrary. It is actually a meaningful border, for example unbearable pain or perhaps safety of currents in this case. And as I referred to, I have compared models for pain with deletion or with M3 but could not find any difference in results even with a high amount of censoring. My finding surprised me at first, but when I discussed this with our residential senior statistician he told me that this, unbiased results after deleting of censored data, was common experience.
I would be curious about experience from others on this list! Please do share in if you have seen results one way or the other.
Best regards,
Jeroen
Quoted reply history
________________________________
From: Martin Bergstrand [mailto:martin.bergstrand
Sent: Tuesday, December 20, 2011 08:27
To: 'Francois Gaudreault'; nmusers
Cc: 'Waqas Sadiq'; Elassaiss - Schaap, J. (Jeroen)
Subject: RE: [NMusers] Truncated Emax
Dear Franois,
I do not agree with Jeroen that less than ~1/3 of total data censored is a guarantee for that these observations can be ignored without substantial bias. I think this is highly dependent on the nature of the model (system), the limit of quantification in relationship to Emax etc. To make a statement on what percentage of censored data (out of the total) that will result in negligible bias is never a good idea since it might be that only a small portion of the total data speaks to a specific parameter. If a substantial amount of that small portion of data is censored it can have important implications while it is still just a minor percentage that is missing out of the total. But importantly you do not need to take anyone's word for this since you can test it you self with simulation based diagnostics and/or simulation and re-estimation with the applied censoring.
The way that I would go about this issue is that I would take into account also the censored observations. The below code is just a slight alteration of the M3 method suggested by S. Beal for the handling of observations below the limit o detection (BQL)[1]. More detail on how this is best implemented in NONMEM is given in a paper by Anh et.al [2]. Me and others have also several times discussed how to best diagnose models in the presence of censored observations (see NMusers archive).
;;; ---------------------------------------------------------
$ERROR
W = THETA(.) ; Residual error model (in this example simple additive)
ULOQ = 10 ; Upper limit of detection (10mA)
IPRED = PT ; Individual prediction of perception threshold according to your desired model
DUM = (IPRED-ULOQ)/SIG
CUMD = PHI(DUM)
; Flag variable CENS in dataset. CENS=1 => observation >ULOQ
IF(CENS.EQ.0) THEN ; <ULOQ
F_FLAG = 0
Y = IPRED+SIG*ERR(1)
ENDIF
IF(ALQ.EQ.1) THEN ; >ULOQ
F_FLAG = 1
Y = CUMD
ENDIF
;;; ---------------------------------------------------------
Obs. When applying this code the SIGMA variance is fixed to 1 ($SIGMA 1 FIX) and the Lapalcian estimation option needs to be utilized (or possibly SAEM etc.) [2].
This type of coding have previously been successfully applied by my colleague Waqas Sadiq. A manuscript on this project is currently in preparation and might be referenced once published (look out).
[1] Beal SL. Ways to fit a PK model with some data below the quantification limit. J Pharmacokinet Pharmacodyn. 2001 Oct;28(5):481-504.
[2] Ahn JE, Karlsson MO, Dunne A, Ludden TM. Likelihood based approaches to handling data below the quantification limit using NONMEM VI. J Pharmacokinet Pharmacodyn. 2008 Aug 7.
Kind regards,
Martin Bergstrand, PhD
Pharmacometrics Research Group
Dept of Pharmaceutical Biosciences
Uppsala University, Sweden
martin.bergstrand
Visiting scientist:
Mahidol-Oxford Tropical Medicine Research Unit,
Bangkok, Thailand
Phone: +66 8 9796 7611
From: owner-nmusers
Behalf Of Elassaiss - Schaap, J. (Jeroen)
Sent: Tuesday, December 20, 2011 4:12 AM
To: Francois Gaudreault; nmusers
Subject: RE: [NMusers] Truncated Emax
Hi Francois,
For pain measurements it is not uncommon to analyze data with a upper limit of quantitation. You can follow the literature on BQL, only reversing from a lower limit to an upper limIt. In my experience just deleting censored data works fine, certainly as a first attempt, as long as censoring stays below ~1/3 of total data.
Best regards,
Jeroen
J. Elassaiss-Schaap
Scientist PK/PD
MSD
PO Box 20, 5340 BH Oss, Netherlands
Phone: + 31 412 66 9320
Fax: + 31 412 66 2506
e-mail: jeroen.elassaiss
________________________________
From: owner-nmusers
ilto:owner-nmusers
Sent: Monday, December 19, 2011 21:40
To: nmusers
Subject: [NMusers] Truncated Emax
Dear NM users
I am currently developing a PK PD model for local anesthetics using a sequential approach with ADVAN6. The PD model is a sigmoid Emax with an effect compartment (Ce).
The intensity and duration of nerve blockade are monitored throughout the perioperative period in patients using a quantitative pharmacodynamic endpoint, i.e, the current perception threshold (CPT) REF: Can. J. Anesth, 57 (S1) 2010). Briefly, CPT is evaluated before and after the administration of the local anesthectic. Data are normalized by baseline using the following equation :
(observed-baseline) / (max-baseline) *100 (%)
Here is the problem. The device only goes to a maximum of 10 mA. In some patients, the real Emax is much higher. Any ideas on how handle a truncated Emax ?
Thanks in advance
--
Franois Gaudreault, Ph.D. Candidate
Pharmacomtrie / Pharmacometrics
Charger de cours / Lecturer
Facult de pharmacie / Faculty of Pharmacy
Universit de Montral
Notice: This e-mail message, together with any attachments, contains
information of Merck & Co., Inc. (One Merck Drive, Whitehouse Station,
New Jersey, USA 08889), and/or its affiliates Direct contact information
for affiliates is available at
http://www.merck.com/contact/contacts.html) that may be confidential,
proprietary copyrighted and/or legally privileged. It is intended solely
for the use of the individual or entity named on this message. If you are
not the intended recipient, and have received this message in error,
please notify us immediately by reply e-mail and then delete it from
your system.
Dear Francois,
Maybe this work can put some light to your question
Yassen A. Pharmacokinetic-Pharmacodynamic modeling of the antinociceptive
effect of buprenorphine and fentanyl in rats, role of receptor
equilibration kinetics JPET 2005; 313: 1136-1149.
Ignacio Ortega
Pharmacokinetics and Drug Metabolism Area
Research, Development and Innovation Department
FAES FARMA
Maximo Aguirre 14. 48940 Leioa
Spain
Francois Gaudreault <[email protected]>
Enviado por: [email protected]
19/12/2011 21:40
Para
<[email protected]>
cc
Asunto
[NMusers] Truncated Emax
Dear NM users
I am currently developing a PK PD model for local anesthetics using a
sequential approach with ADVAN6. The PD model is a sigmoid Emax with an
effect compartment (Ce).
The intensity and duration of nerve blockade are monitored throughout the
perioperative period in patients using a quantitative pharmacodynamic
endpoint, i.e, the current perception threshold (CPT) REF: Can. J. Anesth,
57 (S1) 2010). Briefly, CPT is evaluated before and after the
administration of the local anesthectic. Data are normalized by baseline
using the following equation :
(observed-baseline) / (max-baseline) *100 (%)
Here is the problem. The device only goes to a maximum of 10 mA. In some
patients, the real Emax is much higher. Any ideas on how handle a
truncated Emax ?
Thanks in advance
--
François Gaudreault, Ph.D. Candidate
Pharmacométrie / Pharmacometrics
Charger de cours / Lecturer
Faculté de pharmacie / Faculty of Pharmacy
Université de Montréal
Dear François,
I do not agree with Jeroen that less than ~1/3 of total data censored is a
guarantee for that these observations can be ignored without substantial
bias. I think this is highly dependent on the nature of the model (system),
the limit of quantification in relationship to Emax etc. To make a statement
on what percentage of censored data (out of the total) that will result in
negligible bias is never a good idea since it might be that only a small
portion of the total data speaks to a specific parameter. If a substantial
amount of that small portion of data is censored it can have important
implications while it is still just a minor percentage that is missing out
of the total. But importantly you do not need to take anyones word for
this since you can test it you self with simulation based diagnostics and/or
simulation and re-estimation with the applied censoring.
The way that I would go about this issue is that I would take into account
also the censored observations. The below code is just a slight alteration
of the M3 method suggested by S. Beal for the handling of observations below
the limit o detection (BQL)[1]. More detail on how this is best implemented
in NONMEM is given in a paper by Anh et.al [2]. Me and others have also
several times discussed how to best diagnose models in the presence of
censored observations (see NMusers archive).
;;; ---------------------------------------------------------
$ERROR
W = THETA(.) ; Residual error model (in this example simple
additive)
ULOQ = 10 ; Upper limit of detection (10mA)
IPRED = PT ; Individual prediction of perception threshold
according to your desired model
DUM = (IPRED-ULOQ)/SIG
CUMD = PHI(DUM)
; Flag variable CENS in dataset. CENS=1 => observation >ULOQ
IF(CENS.EQ.0) THEN ; <ULOQ
F_FLAG = 0
Y = IPRED+SIG*ERR(1)
ENDIF
IF(ALQ.EQ.1) THEN ; >ULOQ
F_FLAG = 1
Y = CUMD
ENDIF
;;; ---------------------------------------------------------
Obs. When applying this code the SIGMA variance is fixed to 1 ($SIGMA 1 FIX)
and the Lapalcian estimation option needs to be utilized (or possibly SAEM
etc.) [2].
This type of coding have previously been successfully applied by my
colleague Waqas Sadiq. A manuscript on this project is currently in
preparation and might be referenced once published (look out).
[1] Beal SL. Ways to fit a PK model with some data below the quantification
limit. J Pharmacokinet Pharmacodyn. 2001 Oct;28(5):481-504.
[2] Ahn JE, Karlsson MO, Dunne A, Ludden TM. Likelihood based approaches to
handling data below the quantification limit using NONMEM VI. J
Pharmacokinet Pharmacodyn. 2008 Aug 7.
Kind regards,
Martin Bergstrand, PhD
Pharmacometrics Research Group
Dept of Pharmaceutical Biosciences
Uppsala University, Sweden
[email protected]
Visiting scientist:
Mahidol-Oxford Tropical Medicine Research Unit,
Bangkok, Thailand
Phone: +66 8 9796 7611
Quoted reply history
From: [email protected] [mailto:[email protected]] On
Behalf Of Elassaiss - Schaap, J. (Jeroen)
Sent: Tuesday, December 20, 2011 4:12 AM
To: Francois Gaudreault; [email protected]
Subject: RE: [NMusers] Truncated Emax
Hi Francois,
For pain measurements it is not uncommon to analyze data with a upper limit
of quantitation. You can follow the literature on BQL, only reversing from a
lower limit to an upper limIt. In my experience just deleting censored data
works fine, certainly as a first attempt, as long as censoring stays below
~1/3 of total data.
Best regards,
Jeroen
J. Elassaiss-Schaap
Scientist PK/PD
MSD
PO Box 20, 5340 BH Oss, Netherlands
Phone: + 31 412 66 9320
Fax: + 31 412 66 2506
e-mail: [email protected]
_____
From: [email protected] [mailto:[email protected]] On
Behalf Of Francois Gaudreault
Sent: Monday, December 19, 2011 21:40
To: [email protected]
Subject: [NMusers] Truncated Emax
Dear NM users
I am currently developing a PK PD model for local anesthetics using a
sequential approach with ADVAN6. The PD model is a sigmoid Emax with an
effect compartment (Ce).
The intensity and duration of nerve blockade are monitored throughout the
perioperative period in patients using a quantitative pharmacodynamic
endpoint, i.e, the current perception threshold (CPT) REF: Can. J. Anesth,
57 (S1) 2010). Briefly, CPT is evaluated before and after the administration
of the local anesthectic. Data are normalized by baseline using the
following equation :
(observed-baseline) / (max-baseline) *100 (%)
Here is the problem. The device only goes to a maximum of 10 mA. In some
patients, the real Emax is much higher. Any ideas on how handle a truncated
Emax ?
Thanks in advance
--
François Gaudreault, Ph.D. Candidate
Pharmacométrie / Pharmacometrics
Charger de cours / Lecturer
Faculté de pharmacie / Faculty of Pharmacy
Université de Montréal
Hi Martin,
Thank you for pointing this out. I actually do agree with you! I certainly did
not imply that deleting censored data is a guarantee for unbiased results.
But please keep in mind that especially with pain censoring is not arbitrary.
It is actually a meaningful border, for example unbearable pain or perhaps
safety of currents in this case. And as I referred to, I have compared models
for pain with deletion or with M3 but could not find any difference in results
even with a high amount of censoring. My finding surprised me at first, but
when I discussed this with our residential senior statistician he told me that
this, unbiased results after deleting of censored data, was common experience.
I would be curious about experience from others on this list! Please do share
in if you have seen results one way or the other.
Best regards,
Jeroen
Quoted reply history
________________________________
From: Martin Bergstrand [mailto:[email protected]]
Sent: Tuesday, December 20, 2011 08:27
To: 'Francois Gaudreault'; [email protected]
Cc: 'Waqas Sadiq'; Elassaiss - Schaap, J. (Jeroen)
Subject: RE: [NMusers] Truncated Emax
Dear François,
I do not agree with Jeroen that less than ~1/3 of total data censored is a
guarantee for that these observations can be ignored without substantial bias.
I think this is highly dependent on the nature of the model (system), the limit
of quantification in relationship to Emax etc. To make a statement on what
percentage of censored data (out of the total) that will result in negligible
bias is never a good idea since it might be that only a small portion of the
total data speaks to a specific parameter. If a substantial amount of that
small portion of data is censored it can have important implications while it
is still just a minor percentage that is missing out of the total. But
importantly you do not need to take anyone's word for this since you can test
it you self with simulation based diagnostics and/or simulation and
re-estimation with the applied censoring.
The way that I would go about this issue is that I would take into account also
the censored observations. The below code is just a slight alteration of the M3
method suggested by S. Beal for the handling of observations below the limit o
detection (BQL)[1]. More detail on how this is best implemented in NONMEM is
given in a paper by Anh et.al [2]. Me and others have also several times
discussed how to best diagnose models in the presence of censored observations
(see NMusers archive).
;;; ---------------------------------------------------------
$ERROR
W = THETA(.) ; Residual error model (in this example simple
additive)
ULOQ = 10 ; Upper limit of detection (10mA)
IPRED = PT ; Individual prediction of perception threshold
according to your desired model
DUM = (IPRED-ULOQ)/SIG
CUMD = PHI(DUM)
; Flag variable CENS in dataset. CENS=1 => observation >ULOQ
IF(CENS.EQ.0) THEN ; <ULOQ
F_FLAG = 0
Y = IPRED+SIG*ERR(1)
ENDIF
IF(ALQ.EQ.1) THEN ; >ULOQ
F_FLAG = 1
Y = CUMD
ENDIF
;;; ---------------------------------------------------------
Obs. When applying this code the SIGMA variance is fixed to 1 ($SIGMA 1 FIX)
and the Lapalcian estimation option needs to be utilized (or possibly SAEM
etc.) [2].
This type of coding have previously been successfully applied by my colleague
Waqas Sadiq. A manuscript on this project is currently in preparation and might
be referenced once published (look out).
[1] Beal SL. Ways to fit a PK model with some data below the quantification
limit. J Pharmacokinet Pharmacodyn. 2001 Oct;28(5):481-504.
[2] Ahn JE, Karlsson MO, Dunne A, Ludden TM. Likelihood based approaches to
handling data below the quantification limit using NONMEM VI. J Pharmacokinet
Pharmacodyn. 2008 Aug 7.
Kind regards,
Martin Bergstrand, PhD
Pharmacometrics Research Group
Dept of Pharmaceutical Biosciences
Uppsala University, Sweden
[email protected]<mailto:[email protected]>
Visiting scientist:
Mahidol-Oxford Tropical Medicine Research Unit,
Bangkok, Thailand
Phone: +66 8 9796 7611
From: [email protected] [mailto:[email protected]] On
Behalf Of Elassaiss - Schaap, J. (Jeroen)
Sent: Tuesday, December 20, 2011 4:12 AM
To: Francois Gaudreault; [email protected]
Subject: RE: [NMusers] Truncated Emax
Hi Francois,
For pain measurements it is not uncommon to analyze data with a upper limit of
quantitation. You can follow the literature on BQL, only reversing from a lower
limit to an upper limIt. In my experience just deleting censored data works
fine, certainly as a first attempt, as long as censoring stays below ~1/3 of
total data.
Best regards,
Jeroen
J. Elassaiss-Schaap
Scientist PK/PD
MSD
PO Box 20, 5340 BH Oss, Netherlands
Phone: + 31 412 66 9320
Fax: + 31 412 66 2506
e-mail: [email protected]<mailto:[email protected]>
________________________________
From: [email protected]<mailto:[email protected]>
[mailto:[email protected]] On Behalf Of Francois Gaudreault
Sent: Monday, December 19, 2011 21:40
To: [email protected]<mailto:[email protected]>
Subject: [NMusers] Truncated Emax
Dear NM users
I am currently developing a PK PD model for local anesthetics using a
sequential approach with ADVAN6. The PD model is a sigmoid Emax with an effect
compartment (Ce).
The intensity and duration of nerve blockade are monitored throughout the
perioperative period in patients using a quantitative pharmacodynamic endpoint,
i.e, the current perception threshold (CPT) REF: Can. J. Anesth, 57 (S1) 2010).
Briefly, CPT is evaluated before and after the administration of the local
anesthectic. Data are normalized by baseline using the following equation :
(observed-baseline) / (max-baseline) *100 (%)
Here is the problem. The device only goes to a maximum of 10 mA. In some
patients, the real Emax is much higher. Any ideas on how handle a truncated
Emax ?
Thanks in advance
--
François Gaudreault, Ph.D. Candidate
Pharmacométrie / Pharmacometrics
Charger de cours / Lecturer
Faculté de pharmacie / Faculty of Pharmacy
Université de Montréal
Notice: This e-mail message, together with any attachments, contains
information of Merck & Co., Inc. (One Merck Drive, Whitehouse Station,
New Jersey, USA 08889), and/or its affiliates Direct contact information
for affiliates is available at
http://www.merck.com/contact/contacts.html) that may be confidential,
proprietary copyrighted and/or legally privileged. It is intended solely
for the use of the individual or entity named on this message. If you are
not the intended recipient, and have received this message in error,
please notify us immediately by reply e-mail and then delete it from
your system.
Hello all,
My apologies for responding to this thread late. I agree with using the BQL
method when data are censored to a certain value due to assay or measurement
restrictions. What I am not clear about is the actual suitability of the
approach for this case. I am not sure I understand the data; my inference
from François which started the thread is that the measurement device has
an upper limit of 10 mA. So in the equation 100*(obs-base)/(max-base), it
seems max (max observed presumable but not sure if within or between
subjects) and for that matter obs and base are capped at 10? That is, it
would seem the censoring occurs on the original scale and not on the
%normalized scale. If so, then I am not sure that applying the BQL
methodology directly as specified in the references below is appropriate
unless one models the original scale (mA scale). The %normalized scale will
have the censoring implicit in the scale, but how it manifests will be
somewhat individual dependent and not the same as with the mA scale. So, I
would suggest to model the mA scale and then predict the %normalized scale.
If you do not want to or cannot model the mA scale, then to account for the
10 mA maximum in a principled way when modeling the %normalized data will
require a bit more thought, and may require some additional assumptions.
Another reason to model the mA scale is the difficult distribution that
%normalized scale will likely have due to subtracting and dividing
subtracted observations.
Best regards and happy holidays to all,
Matt
PS I deleted some of the thread below with the intent only to help ensure
this message would not hit the maximum line count and not be transmitted.
Quoted reply history
From: [email protected] [mailto:[email protected]] On
Behalf Of Elassaiss - Schaap, J. (Jeroen)
Sent: Tuesday, December 20, 2011 3:23 AM
To: Martin Bergstrand; 'Francois Gaudreault'; [email protected]
Cc: 'Waqas Sadiq'
Subject: RE: [NMusers] Truncated Emax
Hi Martin,
Thank you for pointing this out. I actually do agree with you! I certainly
did not imply that deleting censored data is a guarantee for unbiased
results.
But please keep in mind that especially with pain censoring is not
arbitrary. It is actually a meaningful border, for example unbearable pain
or perhaps safety of currents in this case. And as I referred to, I have
compared models for pain with deletion or with M3 but could not find any
difference in results even with a high amount of censoring. My finding
surprised me at first, but when I discussed this with our residential senior
statistician he told me that this, unbiased results after deleting of
censored data, was common experience.
I would be curious about experience from others on this list! Please do
share in if you have seen results one way or the other.
Best regards,
Jeroen
_____
From: Martin Bergstrand [mailto:[email protected]]
Sent: Tuesday, December 20, 2011 08:27
To: 'Francois Gaudreault'; [email protected]
Cc: 'Waqas Sadiq'; Elassaiss - Schaap, J. (Jeroen)
Subject: RE: [NMusers] Truncated Emax
Dear François,
I do not agree with Jeroen that less than ~1/3 of total data censored is a
guarantee for that these observations can be ignored without substantial
bias. I think this is highly dependent on the nature of the model (system),
the limit of quantification in relationship to Emax etc. To make a statement
on what percentage of censored data (out of the total) that will result in
negligible bias is never a good idea since it might be that only a small
portion of the total data speaks to a specific parameter. If a substantial
amount of that small portion of data is censored it can have important
implications while it is still just a minor percentage that is missing out
of the total. But importantly you do not need to take anyones word for
this since you can test it you self with simulation based diagnostics and/or
simulation and re-estimation with the applied censoring.
The way that I would go about this issue is that I would take into account
also the censored observations. The below code is just a slight alteration
of the M3 method suggested by S. Beal for the handling of observations below
the limit o detection (BQL)[1]. More detail on how this is best implemented
in NONMEM is given in a paper by Anh et.al [2]. Me and others have also
several times discussed how to best diagnose models in the presence of
censored observations (see NMusers archive).
Obs. When applying this code the SIGMA variance is fixed to 1 ($SIGMA 1 FIX)
and the Lapalcian estimation option needs to be utilized (or possibly SAEM
etc.) [2].
This type of coding have previously been successfully applied by my
colleague Waqas Sadiq. A manuscript on this project is currently in
preparation and might be referenced once published (look out).
[1] Beal SL. Ways to fit a PK model with some data below the quantification
limit. J Pharmacokinet Pharmacodyn. 2001 Oct;28(5):481-504.
[2] Ahn JE, Karlsson MO, Dunne A, Ludden TM. Likelihood based approaches to
handling data below the quantification limit using NONMEM VI. J
Pharmacokinet Pharmacodyn. 2008 Aug 7.
Kind regards,
Martin Bergstrand, PhD
Pharmacometrics Research Group
Dept of Pharmaceutical Biosciences
Uppsala University, Sweden
[email protected]
Visiting scientist:
Mahidol-Oxford Tropical Medicine Research Unit,
Bangkok, Thailand
Phone: +66 8 9796 7611
_____
From: [email protected] [mailto:[email protected]] On
Behalf Of Francois Gaudreault
Sent: Monday, December 19, 2011 21:40
To: [email protected]
Subject: [NMusers] Truncated Emax
Dear NM users
I am currently developing a PK PD model for local anesthetics using a
sequential approach with ADVAN6. The PD model is a sigmoid Emax with an
effect compartment (Ce).
The intensity and duration of nerve blockade are monitored throughout the
perioperative period in patients using a quantitative pharmacodynamic
endpoint, i.e, the current perception threshold (CPT) REF: Can. J. Anesth,
57 (S1) 2010). Briefly, CPT is evaluated before and after the administration
of the local anesthectic. Data are normalized by baseline using the
following equation :
(observed-baseline) / (max-baseline) *100 (%)
Here is the problem. The device only goes to a maximum of 10 mA. In some
patients, the real Emax is much higher. Any ideas on how handle a truncated
Emax ?
Thanks in advance
--
François Gaudreault, Ph.D. Candidate
Pharmacométrie / Pharmacometrics
Charger de cours / Lecturer
Faculté de pharmacie / Faculty of Pharmacy
Université de Montréal