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RE: M3 method - WRES, and CWRES

From: Bill Denney <wdenney>
Date: Tue, 1 Sep 2020 20:32:17 -0400

Hi Mutaz,

Matt Hutmacher described it well here:

A very brief summary of his excellent post is that subjects with a
combination of censored (BLQ) an uncensored (above the LLOQ and below the
ULOQ) will be biased in their reporting of CWRES because you cannot
calculate CWRES for BLQ values. (I say this before looking up what MDVRES

My guess that Bob or someone else can confirm is that the bias is
anticipated to be relatively small compared to the value of being able to
compare CWRES values the other observations for a subject. It does not
definitively mean that the results are unbiased (see Matt’s Tmax ex=
but generally, the CWRES values previously omitted are more useful than
excluding them from calculation.



*From:* owner-nmusers
Behalf Of *Mu'taz Jaber
*Sent:* Tuesday, September 1, 2020 7:25 PM
*To:* nmusers
*Subject:* [NMusers] M3 method - WRES, and CWRES


Back in April 2010, Sebastian Bihorel and Martin Bergstrand initiated a
discussion regarding using the M3 and M4 methods for handling BQL data and
how it seemed to be a bug that NONMEM wouldn't compute WRES for the entire
set of subject data records whenever a BQL was included ( Tom Ludden
responded with the following post (

This issue was discussed with Stuart Beal. He believed that weighted

residuals would be incorrect for an individual that had both continuous

dependent variables and a likelihood in the calculation of their

contribution to the objective function value, as is the case with his M3

or M4 BQL methods The code for both RES and WRES are intentionally

bypassed in these cases.

Since then, we now have easy functionality with the F_FLAG=1 condition of
the M3/M4 code in $ERROR to tack on MDVRES=1 that allows the calculation =
WRES and CWRES to be available in output tables.

My questions are: Is Stuart Beal's original concern still valid? Do these
NONMEM updates give us appropriate WRES and CWRES for plotting purposes for
individuals whose records contain BQL data?

Thank you,

Mutaz Jaber

PhD student

University of Minnesota


*Mutaz M. Jaber, PharmD.*

PhD student, Pharmacometrics

Experimental and Clinical Pharmacology

University of Minnesota

717 Delaware St SE; Room 468

Minneapolis, MN 55414

Email: jaber038

Phone: +1 651-706-5202

*~ Stay curious*

Received on Tue Sep 01 2020 - 20:32:17 EDT

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