Revert to pre-NONMEM 7.5.1 interpretation of loss of degrees of freedom (LDF).

In pre-7.5.1 version, for EM methods and MCMC Bayesian methods, NONMEM's default correction for degrees of freedom was \(N/(N-\text{LDF})\), where N is the number of subjects, and LDF is the loss of degrees of freedom. The LDF for EM/BAYES methods was 1 by default. Such a correction was not used in FOCE/Laplace analysis. Normally, this correction is very small, as M should be at least 10 for a proper population analysis. However, a difference in FOCE versus EM analysis may be noticed if the number of subjects is less than 10.

Because the correction is very small, for most problems, the LDF need not be adjusted. On the occasions with very few subjects, it would be more accurate to have LDF(I) be the number of to-be-estimated THETAs corresponding to MU_I. For example, you could enter the following (note the LDF must be accessed with verbatim code):

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“ LDF(3)=2.0
MU_3=THETA(4)+LOG(BWT)*THETA(5)
CL=EXP(MU_3+ETA(3))

In NM v751+, by default LDF=0 for EM/BAYES. When user modifies degrees of freedom with LDF, and the change will be made to all analysis methods. Alternatively, one can request NONMEM to evaluate the most appropriate LDF for you by setting the LDF to a negative value, e.g.

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“ LDF(1:4)=-1.0

This will specify LDF according to the number of non-fixed THETAs associated with a particular MU reference. Therefore, when setting LDF=-1, it is necessary to have proper mu referencing, even for FOCE/Laplace. If you are curious about what the NONMEM assessed LDF values are, you can access them with:

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$PK
Include nonmem_reserved_general
…
“ write(*,*) TLDF(1),TLDF(2)

The LDF=-1 will correct for all analysis methods. If you set LDF>0, this will use that degrees of freedom for all methods. You can of course filter as follows:

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Include nonmem_reserved_general
LDF(3)=2.0
If(IBMETHOD==EST_BAYES) LDF(3)=0.0

In summary, for vNM751+, to correct for degrees of freedom loss, let NONMEM determine the best values and for which methods, and make sure THETAs are MU referenced. Thus

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$PK
LDF=-1
MU_1=THETA(1)+THETA(2)*LOG(AGE)
MU_2=THETA(3)

will determine the correct degrees of freedom loss, and impose this correction for EM/FOCE/Laplace.

On the other hand, to handle LDF’s in the manner of previous NONMEM versions, insert the following after $PROBLEM:

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  $PROB My problem
    $LDFOLD

Only the new methods (ITS/IMP/SAEM/BAYES) are affected by a change in default behavior regarding LDF’s of NONMEM version 7.5.0 to 7.5.1.