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RE: lab values

From: Martin Bergstrand <martin.bergstrand>
Date: Wed, 13 Jan 2010 15:37:40 +0100

Dear Dirk and Jakob,


I agree with all of Jakobs suggestions but would like to come with an
additional suggestion. If you are going to use any type of imputation =
(LOCF, LOCB, linear interpolation, random imputation, baseline =
substitution with population/individual median etc.) then create =
data-set using several imputation methods (that at least make some =
Choose the data-set with your primary choice of imputation and perform =
model building with this data-set. With you final model it can be wise =
make sure that the conclusions and parameter estimates based on this =
is not heavily dependent on the imputations made in your data-set. To do
this you can re-estimate parameter estimates of your final model using
data-sets with one or more alternative imputation methods. Similarly you =
reassess important likelihood ratio tests with the alternative =


Last I would like to point out that the imputation methods all rely on =
fact that the missingness of the observation is completely random and =
dependent on your primary dependent variable of interest. If this is
suspected only simultaneous modeling of the two variables are likely to =
unbiased results.


Best regards,


Martin Bergstrand, MSc, PhD student


Pharmacometrics Research Group,

Department of Pharmaceutical Biosciences,

Uppsala University





From: owner-nmusers
Behalf Of Ribbing, Jakob
Sent: den 13 januari 2010 14:34
To: Garmann, Dirk; nmusers
Subject: RE: [NMusers] lab values




I think the approach is influenced by what this lab value represents. If =
is a biomarker/endpoint that is influenced by drug treatment then the =
approach is to include this in your PK-PD model as a dependent variable. =
you treat this as a traditional covariate it should not be influenced by
treatment. Assuming your drug improves disease symptom or progression =
measured by this biomarker) it would not be ideal to use either LOCF or
LOCB. The baseline for this biomarker (DAY -1 in your case) can be used =
as a
covariate in your PK model, as it is not influenced by drug treatment.


If you can not spend the time to build a proper PK-PD model but still
believe this covariate is important for your PK model then maybe you can =
something simple, like assuming a linear slope in this biomarker between =
two measurements and use the two observed values for interpolation?


Best regards





From: owner-nmusers
Behalf Of Garmann, Dirk
Sent: 13 January 2010 12:41
To: nmusers
Subject: [NMusers] lab values




I would like to ask for some opinions regarding the handling of missing =
values in a NONMEM Dataset;


Our normal procedure:

Parameter values will be carried backward to the first visit if the =
visit value is missing, it will be carry forward to the last visit if no
value is available at the last visit and will be set at the median value =
two adjacent visits in other cases.


Now we have a phase III study (multiple doses), one safety lab at day -1 =
one safety lab at final examination only, no lab in between (>6 month)


Two main strategies are possible


1.) Different from our standard procedure:

Carry the lab value at final examination backward to day -1.


2.) According to our standard: Use the median (or perhaps a =
between the first and final examination)


My assumptions:

The first strategy might be useful to reflect the influence of the drug =
lab values and will reflect the steady state situation.


The second strategy might be better to characterize the influence of the =
values on the PK of the drug, e.g if a disease worsens during the study.


As our main focus will be the last one, I would use the standard =


I know that this is quite basic, however as this was discussed during a
meeting I would appreciate to have your opinion.


Many thanks in advance




Dirk Garmann, PhD

Clinical Scientific Expert /Pharmacokineticist

Merz Pharmaceuticals

Eckenheimer Landstrasse 100

60318 Frankfurt

Phone +49 (69) 1503 720



Merz Pharmaceuticals GmbH, Frankfurt am Main

Amtsgericht Frankfurt am Main, HRB 53808

Geschäftsführung: Dr. Martin Zügel (Vors.), Dr. Alexander Gebauer, =

Dr. Karsten Schlemm, Dr. Eugen Wilbert


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Received on Wed Jan 13 2010 - 09:37:40 EST

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