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Re: Honest measurements

From: Nick Holford <n.holford>
Date: Tue, 25 Aug 2009 09:55:01 +1200

Joachim,

Thanks for your proposal to make our lives as PK modellers even more
challenging :-)

I have indeed thought of the idea of just trying to get the raw
measurement data e.g. absorbance, and including a 'standard curve' model
in addition to the PK model. But there are practical problems -- not
least of which (as Marc Sale describes) is persuading the chemical
analysts to report their data honestly. It is very hard to persuade them
to understand that their measurements should not be deliberately
contaminated by censoring -- see Ed Connor's "sense and nonsense"
posting which shows he continues to miss the point after years of
battling with me and Roger Jelliffe on PharmPK.

Any simultaneous modelling approach runs the risk of model
misspecification (see Liping Zhang's paper Zhang L, Beal SL, Sheiner
LB. Simultaneous vs. sequential analysis for population PK/PD data II:
robustness of methods. J Pharmacokinet Pharmacodyn. 2003;30(6):405-16.)
so I think I would want to at least start with a sequential analysis if
I was ever in a position to try a PH-PK model (PH=Peak height).

If the chemical analysts can be persuaded to provide uncensored
observations (there is nothing stopping them except tradition and
mis-interpretaton of regulatory guidances by regulatory policemen and
others) then it could make PK modelling more reliable. While it is
possible to deal with censored data this is still less informative than
actually having the data.

Nick


Grevel, Joachim wrote:
> Dear all,
>
> I am thinking back to early days of pharmacodynamics. The clinical people would report to us "early" modellers response data in the form of percent change from baseline. Very soon we asked for the raw data rejecting their "model" of generating response data as being subjective and biased (how was that "baseline" established?).
>
> It was Nick among others who rejected any delivered baseline. He insisted that the model "will tell us the baseline and its error". I somehow hear Nick telling us something similar about bioanalytical data: Do not truncate the data by some criterion established months (years) before the actual measurement. Give us the raw data and let us find the error in it.
>
> Perhaps it is indeed time to rethink the ideas of validated methods and standard curves. Couldn't the standard curve be part of our modelling, and couldn't the error in the standard curve be integrated into the error structure for our PK (PKPD) model?
>
> I have a feeling that our current practice may have all the flaws we found years ago in the "two-stage" PK modelling approach. We gave up on the two-stage approach because it did not describe variability correctly. (Mats, there were "millions" of two-stage analyses published and in submissions... and in the end we gave it up for something we had learned was better).
>
> It will take a lot of theoretical work to make the case for an integrated bioanalytical-pharmacokinetic analysis. Nick, are you already working along these lines?
>
> Good luck to all,
>
> Joachim
>
>
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> -----Original Message-----
> From: owner-nmusers
> [mailto:owner-nmusers
> Sent: 24 August 2009 13:36
> To: 'Stephen Duffull'; 'Nick Holford'; 'nmusers'
> Subject: RE: [NMusers] Honest measurements
>
>
> Sense and nonsense.
>
> Analysts are constrained certainly but good analytical science is good
> analytical science. During the method development stage several parameters
> are examined.
>
> One parameter for example is recovery of analyte from a set of spiked
> individual (matrices). Another exercise is the recovery of material from
> spiked matrix after exposure to a number of stability challenging
> conditions, e.g., freeze thaw. During these tests it is certainly possible
> to "find less or, even "none" of the response(s) to the analyte(s).
>
> Analysts would then "improve" the assay using a number of techniques
> including the addition of preservatives or specifying the handling and
> storage conditions. Too often however, the clinical collection parameters
> may have been defined before the conclusion or event the start of analytical
> method development and perhaps "if pushed too far and incessantly" the
> analyst will release "nonsense data" or instrument responses free of
> "interpretation".
>
> For people at the next rung to use data this in any rational way suggests
> that those people should perhaps be using a seer rather than an analyst.
> When they are stung by the results of their data analysis, they will
> immediately revert and "blame" the analyst (or if they do not, regulatory
> agencies will) for releasing "bad" data.
>
> PK/PD and Analytical scientists usually work together during the analytical
> process. PK/PD driving with LLOQ, suggesting metabolites, Analytical
> providing the best approach to meet that requirement including meeting all
> current method validation and reporting guidelines.
>
>
> Edward F. O'Connor, PhD
> 78 Marbern Drive
> Suffield, CT 06078
>
> Tel 860-668=6201
> Cel 860-324-6780
> efoconnor
>
> Edward F. O'Connor, PhD
> 78 Marbern Drive
> Suffield, CT 06078
>
> Tel 860-668=6201
> Cel 860-324-6780
> efoconnor
>
> -----Original Message-----
> From: owner-nmusers
> Behalf Of Stephen Duffull
> Sent: Monday, August 24, 2009 4:18 AM
> To: Nick Holford; nmusers
> Subject: RE: [NMusers] Honest measurements
>
> Mats
>
> I agree with Nick. Negative "observed" concns do occur for assays, even in
> my limited time working with HPLC I have seen them, however due to LOD/LOQ
> they are never really looked for and certainly never reported...
>
> Steve
>
>
>> -----Original Message-----
>> From: owner-nmusers
>> nmusers
>> Sent: Monday, 24 August 2009 6:25 p.m.
>> To: nmusers
>> Subject: [NMusers] Honest measurements
>>
>>
>>
>> Mats Karlsson wrote:
>>
>> << Chemists, however pushed, would never report negative
>> concentrations, not
>> for past studies, not for future studies. The methods they use don't
>> even
>> report them.>>
>>
>> I am working with a chemist using LC/MS who has been persuaded to look
>> honestly at his data without preconceived ideas of limits of
>> quantitation and detection. Indeed when he opened his eyes he found
>> that his system was indeed giving negative concentration measurements
>> (at times when concentrations were expected to be very low).
>>
>> Of course we must do other things when the data is censored by bad
>> scientific practice in the chemist's lab but with honest measurments an
>> additive residual error model is required.
>>
>> Nick
>>
>>
>> --
>> Nick Holford, Professor Clinical Pharmacology
>> Dept Pharmacology & Clinical Pharmacology
>> University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New
>> Zealand
>> n.holford
>> mobile: +64 21 46 23 53
>> http://www.fmhs.auckland.ac.nz/sms/pharmacology/holford
>>
>
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>
>

--
Nick Holford, Professor Clinical Pharmacology
Dept Pharmacology & Clinical Pharmacology
University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New Zealand
n.holford
mobile: +64 21 46 23 53
http://www.fmhs.auckland.ac.nz/sms/pharmacology/holford
Received on Mon Aug 24 2009 - 17:55:01 EDT

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