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RE: Truncated Emax

From: Martin Bergstrand <martin.bergstrand>
Date: Tue, 20 Dec 2011 14:27:03 +0700

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

martin.bergstrand

 

Visiting scientist:

Mahidol-Oxford Tropical Medicine Research Unit,

Bangkok, Thailand

Phone: +66 8 9796 7611

 

 

From: owner-nmusers
On
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
On
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

 



--


François Gaudreault, Ph.D. Candidate
Pharmacométrie / Pharmacometrics
Charger de cours / Lecturer

Faculté de pharmacie / Faculty of Pharmacy
Université de Montréal

 


Received on Tue Dec 20 2011 - 02:27:03 EST

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