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Dear Hans:
In your email of April 13, you say that you agree with my
plea for reporting and using TDM result values below the LOQ, with a
weighting based on the reciprocal of the variance of the result, just
as we should do for values above the LOQ. This is especially true
when the software used can take this into account.
I also wrote, referring to results simply reported as "less than the
LOQ":
> It is extremely wasteful of time, effort, money, and most
> important, data for the care of the patient. Again, if I were a
> government administrator, I would not pay for such a result in TDM,
> especially when it is so easy to report it so that both people get
what
> they need, as 0.3 ug/ml, +/- 0.5 ug.ml, for example, which is below
our
> usual LOQ of 1.5 ug/ml, for example, 3 SD above the blank.
And you then said:
Again you agreed, but said that "IMHO (what is IMHO, Hans?) this is
rather exaggerated. Indeed, a reported
value
of 0.3 +/- 0.5 ug/ml gives some information about the actual drug
level, but
the information is quite vague, and in general it will affect only
marginally the parameters obtained by a Maximum A Posteriori Bayesian
estimation".
"Instead of a further discussion about this subject, I suggest that
Roger
provides an example demonstrating the importance of, e.g. a reported
value
'0.3 +/- 0.5 ug/ml' compared to a reported value 'below 0.5 ug/ml'. This
might convince everybody more than words".
Now, Hans, I would like to ask you specifically what you
mean by "vague". What in this position is "rather exaggerated"? The
SD of +/- 0.5, for example, is a real number. The more data points it
is based on, in the assay error polynomial, the more confidence one
can have in this number. Remember, the CV is not important, as is
depends on both the concentration and the SD, and becomes infinite as
the concentration goes to zero, even though the SD is usually rather
small. Once again, though, The CV is simply NOT R3ELEVANT. What IS
relevant is the SD and the variance, which are always finite, and
almost always pretty small, in the region near zero. The CV may be
horrible, but the precision (the SD and the Fisher information) will
still usually be quite good.
Now, I would like to ask you, to state, specifically, what
you would do, now, with a result reported simply as "below some LOQ".
What action would you take? How would you use this value in Bayesian
feedback control of a dosage regimen for a patient? Would you discard
the point, set it to zero, set it to halfway between zero and the
LOQ, or what? Please list these steps, 1, 2, 3, etc.
Further, I would ask you to justify, in words that make
scientific, clinical, and PK sense, why you feel that any of those
policies you state above is better than using the actual measured
value, and its SD, which you said at the beginning was what you
agreed with me about.
Why do you agree with me at the beginning, but then say how
"vague" this policy is just a few words later, saying that it will
"make little difference"? Will discarding a point below the LOQ
really "make little difference"? If you will tell me your policies
for dealing with below LOQ values, and can justify any of them as
better, then let's talk, or do more. Again, I maintain that if I were
a government or QA administrator, I would not pay for an assay result
obtained for purposes of TDM (not for toxicology) which is reported
simply as "below some LOQ", especially when it is so very easy to
report the measured result, its SD, and the usual LOQ for purposes of
toxicology, as described earlier above. Please think about all this
and let me know.
Very best regards,
Roger Jelliffe
Roger W. Jelliffe, M.D. Professor of Medicine,
Division of Geriatric Medicine,
Laboratory of Applied Pharmacokinetics,
USC Keck School of Medicine
2250 Alcazar St, Los Angeles CA 90033, USA
Phone (323)442-1300, fax (323)442-1302, email= jelliffe.-a-.usc.edu
Our web site= http://www.lapk.org
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The following message was posted to: PharmPK
Dear Roger,
Thank you for your reply to my earlier comments. I will now answer to
your
remarks:
IMHO means 'in my honest opinion'. I did not invent this acronym myself.
Sorry for using undefined terms.
"Vague" is used here indeed in a vague way. I wanted to say that a
concentration reported " 0.3 ug/ml, +/- 0.5 ug/ml " provides only
limited
information: (1) the 95% confidence interval is between 0 and 1.3 ug/ml,
which is a rather broad range compared to the estimated level of 0.3
ug/ml;
(2) (as a result) this value does not provide much information, and "in
general it will affect only marginally the parameters obtained by a
Maximum
A Posteriori Bayesian estimation" (cited from my earlier message).
'Vague'
is used here in the statistical context similar to a 'vague prior', i.e.
data that contain only minimal information.
I fully agree with your comments on CV and SD.
In the section following these comments you ask me how I would handle
values
below LOQ. This is not what the discussion is about. I could copy your
numerous messages about this subject, since I fully agree with your
approach.
My concern is expressed in the following sentence of my previous
message,
cited in your message:
"Instead of a further discussion about this subject, I suggest that
Roger
provides an example demonstrating the importance of, e.g. a reported
value
'0.3 +/- 0.5 ug/ml' compared to a reported value 'below 0.5 ug/ml'. This
might convince everybody more than words".
It is quite clear from my message that there is no need to convince me
that
your approach is good, and likely the best we can do. Instead of
presenting
convincing evidence that your approach is essential for adequate patient
care since other approaches will result in bad patient care, you started
'powerplay' in your first message of 11 April:
> It is extremely wasteful of time, effort, money, and most
> important, data for the care of the patient. Again, if I were a
> government administrator, I would not pay for such a result in TDM,
> especially when it is so easy to report it so that both people get
what
> they need, as 0.3 ug/ml, +/- 0.5 ug.ml, for example, which is below
our
> usual LOQ of 1.5 ug/ml, for example, 3 SD above the blank.
and repeated in your last message:
> Again, I maintain that if I were
> a government or QA administrator, I would not pay for an assay result
> obtained for purposes of TDM (not for toxicology) which is reported
> simply as "below some LOQ"
This sounds 'exaggerated' in my ears. Again, I agree with your
approach of
reporting values with a corresponding SD, but this does not imply that
everybody who does not follow this approach is a dangerous fool. My
point
was, and still is, that this approach should be propagandized, not by
powerplay, but by convincing arguments that it really matters. Your
continuous plea for this approach is much appreciated by me, but theory
is
not enough to provide convincing evidence that this approach is really
important. That was the reason I suggested you to provide an example.
This
message does not seem to have reach its goal.
Best regards,
Hans Proost
Johannes H. Proost
Dept. of Pharmacokinetics and Drug Delivery
University Centre for Pharmacy
Antonius Deusinglaan 1
9713 AV Groningen, The Netherlands
tel. 31-50 363 3292
fax 31-50 363 3247
Email: j.h.proost.at.rug.nl
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Copyright 1995-2010 David W. A. Bourne (david@boomer.org)