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[A few replies - db]
From: "Edward O'Connor"Date: Wed, 30 Jan
2002 21:31:27 -0600
To: david.aaa.boomer.org
Subject: Re: PharmPK Significant digits / rounding
The following message was posted to: PharmPK
the curve then acutally goes from 0.500 ng/mL to 300 ng/mL (three sig
figs)
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From: "Edward O'Connor"Date: Wed, 30 Jan
2002 21:58:31 -0600
To: david.-at-.boomer.org
Subject: PharmPK Re: Statistical weight for calibration data
The following message was posted to: PharmPK
r is misleading when the range of values is great-over several orders of
conc and when the fit is non linear. Weighting using 1/y or 1/y2 (1/x,
1/x2 adjusts for the bias imparted by the points at the higher ends of
the curve upon the predictive values at the lower end. When using a
linear model weighting may be used balancing the positive impact of the
weighting on the accuracy and the negative impact it has upon the r. In
non linear relationships, weighting's impact is again balanced against
the fit, this time as the SSQ or MSQ of the fit. Using a polynomial fit
becomes challenging particularly where both a high and a low value X can
give the same response. In those cases practical limits have to be set
on the extenst of the fit range. The simplest fit is always a choice but
weighting and other fit are valid if justified, and what do we use to
justify? we use accuracy, correlation (ssq or msq), and logic. 5 or 6
order fits will connect all the dots but.........
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From: "Weber, Cornelia {PDC5~Basel}"Date:
Thu, 31 Jan 2002 08:40:02 +0100
To: david.-a-.boomer.org
Subject: RE: PharmPK Significant digits / rounding
The following message was posted to: PharmPK
Dear Jaime Ilha,
I fully agree with your concerns and the way we handle it in our company
is as follows:
We ask any analytical laboratory that is analysing samples for our
PK-studies (in-house and external) to report analytical data with
significant figures. The number of significant figures of course always
depends on the precision of the analytical assay and may therefore be
different for different assays. We then report all PK parameters that
depend on the concentrations measured (e.g. Cmax, Cmain, AUC etc.) with
the same level of precision, meaning significant figures.
I am personally not aware of any official guidance or publication on
this issue.
Kind Regards
Dr. Cornelia Weber
Clinical Science Pharmacology
Hoffmann-La Roche Ltd.
(52/906)
Basel
E-mail cornelia.weber.aaa.roche.com
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From: jan-georg.moeller.jm.-at-.bayer-ag.de
Date: Thu, 31 Jan 2002 10:46:26 +0100
To: david.aaa.boomer.org
Subject: Antwort: PharmPK Significant digits / rounding
The following message was posted to: PharmPK
Dear Jaime,
bioanalytical methods are characterized by a wide working range -
sometimes up
to 10^4. (= Factor 10000). Within this range an accuracy and precision
of (normally) 15% need to be achieved. Thus the number of SIGNIFICANT
digits is important - not the number of digits. Using your examples one
would report a working range of 0.500 (including the zeros) to 296
mcg/L. Using four significant digits you would report, e.g.: 0.5000 to
296.3 mcg/L. Other examples are 0.1234, 123.4 or 1234000 (rounded).
>From my point of view at least 3 or 4 significant digits should be used
(reflecting a precision of about 15%). But of course, this is dependent
on the
error and / or uncertainty of the method. However, I have not found a
clear guideline on this and would appreciate any comments / hints on
guidelines if 3
significant numbers are sufficient.
Best regards,
Jan
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In Response to Jan's Comment:
If the range of a standard curve is 0.5 to 300 and the precision is
within 15%, does this mean that a concentration of 300 is 300±45. Given
this, isn't 3 significant figures too many, 2 would seem more
appropriate. I find that we often, myself included, report assay results
that are optimistically precise.
Casey
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In response to Casey's Comments:
With the precision of +/-15%, 300 is indeed 300 +/-45.
With regards to the number of significant figures, the sensitivity of
the analytical method (or lowest amount quantitated) need to be
considered among other things. For example, if the LOQ is at pico- or
femento gram/mL level, and plasma analyte concentrations are given in
ng/mL, one may express analyte concentrations in significant figures
representing up to the pico or femento level.
Chandra
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The following message was posted to: PharmPK
I would like to throw my two cents in this thread. Philosophically there
is no hard and fast rule for significant digits and rounding. Typically
you have to set your own rule keeping in view of the study objectives in
mind. rounding off the assay values should not introduce error in your
final parameters and clinical interpretations. Imagine a situation where
you round off plasma concentrations and then round of pk parmaeters and
then round of statistics introducing additive error at every stage.
Bottom line is that we have to % CV at the lowest possible end (accepted
% CV is < 20%) and rounding off should not artificially present higher
CV.
In my honest opinion it would be advisable to basic analytical measures
upto two decimal points (eg. 2.12 ng/mL or ug/ml). There is one and only
official guidance available in literature is under Significant Figures
and Tolerances, USP 2002 page 4.
It clearly states "Limits which are fixed numbers not rounded off" and
it continues stating " When rounding off is required consider only one
digit in the decimal place to the right......" and lists few examples
Clearly folks argue about the pros and cons of reporting values upto two
decimal points and there is no end for it. When designing studies or
programs responsible individuals should discuss all of the above points
and make a determination on the reporting strategy, to avoid confusion
it is better to have a uniform policy of reporting across all the
developmental projects.
There can be exceptions but exceptions can not make rules.
Hope my two cents is sensible and helps this discussion.
Regards,
Prasad Tata
Tyco Healthcare-Mallinckrodt, Inc.
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The following message was posted to: PharmPK
Frankly, I do not think so. Usually 3 significant digits (at times only
2, occasionally 4) are meaningful regardless of the distance from the
LOQ. Going
downwards to different units would introduce 3 or even 6 additional
digits. The
nonsignificant digits could be represented by zeros or, better, the
exponential
notation could be used.
Laszlo Endrenyi
University of Toronto
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The following message was posted to: PharmPK
I suggest people have a read of Gerhard Levy's Letter to the Editor:
Significant figures or significant nonsense? Clinical Pharmacology and
Therapeutics 59: 363, 1996.
Andrew Somogyi
Assoc Prof Andrew Somogyi
Department of Clinical and Experimental Pharmacology University of
Adelaide
Adelaide 5005
Australia
email: andrew.somogyi.-a-.adelaide.edu.au
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The following message was posted to: PharmPK
Dear colleagues,
With respect to rounding and significant digits, three comments:
1) Better using too many digits than too few, for at least two reasons:
using too many never introduces inaccuracies (the false feeling of
accuracy does not hurt, except in final results), and in many cases the
numbers are used further in the process (e.g. analytical data in PK
analysis). We all know that rounding should be done ONLY in the final
result, e.g. the parameters of a population model. As a rule of thumb,
all interim-results should have at least one more significant digit.
2) In presenting results, avoid using '1234000' if you mean 1.234E+6,
and using '0.5' if you mean '0.500'. On the other hand, it is quite
appropriate to describe the range of a calibration curve as, e.g., 0.5
to 20000. In this case (not a result) everybody will understand that the
concentration at the lower end was not 0.46 and that the upper
concentration was perhaps 20007.
3) Prasad Tata wrote:
>In my honest opinion it would be advisable to basic analytical measures
upto two decimal points (eg. 2.12 ng/mL or ug/ml).
I don't understand this recommenation. '2.12' means three significant
digits. The number of decimal points is irrelevant (exept for optical
reasons).
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
Email: j.h.proost.-at-.farm.rug.nl
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It is invalid to extend precision beyond the accuracy of the tools
used for the
production of the data. The increased precision is meaningless and leads
to a false sense
of robustness of the calculations. Variance around a particular
determination is a useful
way to decide on an acceptable number of significant digits.
D. Sitar, University of Manitoba
Daniel S. Sitar, PhD
Professor and Head
Department of Pharmacology and Therapeutics sitar.-at-.ms.UManitoba.ca
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