# Re: More Levels of Random Effects

From: Leonid Gibiansky <LGibiansky>
Date: Wed, 22 Oct 2008 17:46:41 -0400

Hi Bill,
I think, description in \$PRIOR and nwpri help entries are the most
helpful. The simplest 1-compartment problem example is below.
Good luck!
Leonid

--------------------------------------
Leonid Gibiansky, Ph.D.
President, QuantPharm LLC
web: www.quantpharm.com
e-mail: LGibiansky at quantpharm.com
tel: (301) 767 5566

----------
\$PROBLEM 001, example
\$INPUT ID,TIME,AMT,DV,MDV,EVID
\$DATA data.csv
\$PRIOR NWPRI NTHETA=3 NETA=2 NEPS=1 NTHP=3 NETP=2 NPEXP=1
\$PK
CL = THETA(1)*EXP(ETA(1))
V = THETA(2)*EXP(ETA(2))
K=CL/V
SD1 = THETA(3)
S1=V

\$ERROR
Y=A(1)/V*EXP(SD1*EPS(1))

\$THETA ; INITIAL ESTIMATES FOR THETAS
(0,1) ; 1 CL
(0,1) ; 2 V
(0,0.3) ; 3 error SD

\$THETA ; PRIOR MEAN OF THETAS
2 FIXED ; 1 CL
2 FIXED ; 2 V
0.3 FIXED ; 3 error SD

\$THETA ; degrees of freedom for OMEGAs
20 FIXED ; 1 CL
20 FIXED ; 2 V1

\$OMEGA ; current-problem omegas
0.1 ;[P] 1 V1
0.1 ;[P] 2 CL

\$OMEGA ; variances of the distribution for thetas
1.5 FIXED ;[P] 1 CL
1.5 FIXED ;[P] 2 V
0.1 FIXED ;[P] 3 error SD

\$OMEGA ; mode of priors for omegas
0.15 FIXED ; 1 CL
0.15 FIXED ; 2 V1

\$SIGMA
1 FIXED ;[P]

\$EST MAXEVAL=9999 NOABORT METHOD=1
----------
data.csv:

1,0,1000,0,1,1
1,0.1,0,1000,0,0
1,0.2,0,900,0,0
1,0.3,0,800,0,0
1,0.4,0,600,0,0
1,0.5,0,500,0,0
1,1,0,200,0,0
1,2,0,100,0,0
1,3,0,50,0,0
1,4,0,25,0,0
1,5,0,10,0,0
2,0,1000,0,1,1
2,0.1,0,1000,0,0
2,0.2,0,900,0,0
2,0.3,0,800,0,0
2,0.4,0,600,0,0
2,0.5,0,500,0,0
2,1,0,200,0,0
2,2,0,100,0,0
2,3,0,50,0,0
2,4,0,25,0,0
2,5,0,10,0,0

Denney, William S. wrote:
> Hi Leonid,
>
> It is not obvious to me how to make use of the next level of random
> effects using the PRIOR subroutine in the html help. Can you point me
> to an example or other documentation of how to use PRIOR for this?
>
> Thanks,
>
> Bill
>
> -----Original Message-----
> From: owner-nmusers
> On Behalf Of Leonid Gibiansky
> Sent: Friday, October 17, 2008 10:35 AM
> To: Michael.J.Fossler
> Cc: nmusers; Nick Holford
> Subject: Re: [NMusers] More Levels of Random Effects
>
> The next level of random effects can be introduced in NONMEM using PRIOR
>
> subroutine. It existed as undocumented feature even in Nonmem V. Now (in
>
> Nonmem VI) it is official (see help).
> Leonid
>
> --------------------------------------
> Leonid Gibiansky, Ph.D.
> President, QuantPharm LLC
> web: www.quantpharm.com
> e-mail: LGibiansky at quantpharm.com
> tel: (301) 767 5566
>
>
>
>
> Michael.J.Fossler
>>
>> I suppose it really comes down to what you are going to do with the
>> model. Many times I have checked the SAME assumption when modeling
>> inter-occasional variability, and found that sometimes, removing it
> does
>> indeed improve the fit significantly. In almost every case I've
>> retained it (despite the better fit) for the exact reasons Leonid
> cites:
>> it makes your model completely data-dependent. I suppose if the model
>> was meant as a description or summary of the data, then it would not
>> matter, but I make all of my models work for a living...
>>
>> There is a related topic which I'd be interested in hearing from the
>> group about. Many times, we take several Phase 1 studies and put them
>> together in order to develop a population model early in development.
>> I've learned through experience to be careful when doing this, because
>
>> often, one or more studies will appear to have a different mean
> response
>> for some parameter, e.g., CL or V2. Of course, you can introduce study
>
>> as a covariate, but this intrduces the same problem as above; in a
>> simulation context, which CL value is correct? There is a work-around
>> for this (use both values) but this doubles the number of simulations
>> you have to do, and from a scientific stand-point it is not very
>> satisfying. What we need is another level of random effects at the
> STUDY
>> level, similar to what is routinely done when performing hierarchical
>> modeling in something like WinBUGS. I'd love to see this feature in a
>> future version of NONMEM.
>>
>>
>>
>>
>>
>>
>> *"Leonid Gibiansky" <LGibiansky
>> Sent by: owner-nmusers
>>
>> 17-Oct-2008 09:30
>>
>>
>> To
>> "Nick Holford" <n.holford
>> cc
>> "nmusers" <nmusers
>> Subject
>> Re: [NMusers] More Levels of Random Effects
>>
>>
>>
>>
>>
>>
>>
>>
>> Nick,
>>
>> This is exactly what I meant. If you have a model for English, Irish
> and
>> Welsh, you may at least extrapolate it to Australians and New
> Zealanders
>> (of British descent :) ). With occasion treated as non-ordered
>> categorical covariate, you cannot extrapolate the model at all because
>> time cannot be repeated, so your covariate (occasion) will have
>> different value (level) at any future trial.
>>
>> Leonid
>>
>> --------------------------------------
>> Leonid Gibiansky, Ph.D.
>> President, QuantPharm LLC
>> web: www.quantpharm.com
>> e-mail: LGibiansky at quantpharm.com
>> tel: (301) 767 5566
>>
>>
>>
>>
>> Nick Holford wrote:
>> > Leonid,
>> >
>> > I dont understand what you mean by "we lose predictive power of the
>> > model: we do not know what will be
>> > the variability on the next occasion.".
>> >
>> > Or are you concerned about the situation where you have say 3
> occasions
>> > and the IOV seems to be different on each occasion but you now want
> to
>> > predict the IOV for a future study on the 4th occasion?
>> >
>> > I agree it is hard to extrapolate to future occasions but this
> seems to
>> > be just like any other non-ordered categorical covariate - e.g. if
> we
>> > see differences between English, Irish and Welsh what difference
> would
>> > you expect for Russians? :-)
>> >
>> > Nick
>> >
>> >
>> > Leonid Gibiansky wrote:
>> >> Hi Xia, Nick
>> >> Technically, one can use different variances on different
> occasions but
>> >> then we loose predictive power of the model: we do not know what
> will be
>> >> the variability on the next occasion. One can use
> occasion-dependent IOV
>> >> variance to check for trends (for example, to investigate the time
>> >> dependence of the IOV variability, or to check whether the first
>> >> occasion (e.g., after the first dose of a long-term study) is for
> some
>> >> reasons different from the others) but the final model should have
> some
>> >> condition that specifies the relations of IOV variances at
> different
>> >> occasion (SAME being the simplest, most reasonable and the
> most-often
>> >> used option).
>> >>
>> >> Thanks
>> >> Leonid
>> >>
>> >> --------------------------------------
>> >> Leonid Gibiansky, Ph.D.
>> >> President, QuantPharm LLC
>> >> web: www.quantpharm.com
>> >> e-mail: LGibiansky at quantpharm.com
>> >> tel: (301) 767 5566
>> >>
>> >>
>> >>
>> >>
>> >> Nick Holford wrote:
>> >>> Xia,
>> >>>
>> >>> There is no requirement to use the SAME option. However, it is a
>> >>> reasonable model for IOV that it has the same variability on each
>> >>> occasion.
>> >>>
>> >>> If you dont use the SAME option then you just need to estimate an
>> >>> extra OMEGA parameter for each occasion you dont use SAME. You
> can
>> >>> test if the SAME assumption is supported by your data or not by
>> >>> comparing models with and without SAME.
>> >>>
>> >>> Nick
>> >>>
>> >>> PS Your computer clock seems to be more than 2 years out of date.
>> >>> Your email claimed it was sent in 17 Jan 2006.
>> >>>
>> >>> Xia Li wrote:
>> >>>> Dear All,
>> >>>> Do we have to assume the variability between all occasions are
> the
>> >>>> same when
>> >>>> we estimate IOV? What will happen if I don't use the 'same'
>> >>>> constrain in the
>> >>>> \$OMEGA BLOCK statement? Any input will be appreciated.
>> >>>>
>> >>>> Best,
>> >>>>
>> >>>> Xia Li
>> >>>>
>> >>>> -----Original Message-----
>> >>>> From: owner-nmusers
>> >>>> [mailto:owner-nmusers
>> >>>> Behalf Of Johan Wallin
>> >>>> Sent: Wednesday, October 15, 2008 9:17 AM
>> >>>> To: nmusers
>> >>>> Subject: RE: [NMusers] More Levels of Random Effects
>> >>>>
>> >>>> Bill,
>> >>>> Is it really an eta you want, or is this rather solved by
> different
>> >>>> error
>> >>>> models for the different machines?
>> >>>>
>> >>>> If still want etas, one way would be to model in the same way as
>> >>>> IOV. In the
>> >>>> case of intermachine-variability you would have to assume the
>> >>>> variability
>> >>>> between all machines are the same... Or would you rather assume
>> >>>> interindividual variability is different with
>> >>>> different machine, and you then would want one eta for TH(X) for
> every
>> >>>> machine...? It depends on what you mean by different slope every
> day,
>> >>>> regarding on what your experiments like, but calibration
> differences
>> >>>> should
>> >>>> perhaps be taken care of by looking into your error model, eta
> on
>> >>>> epsilon
>> >>>> for starters...
>> >>>>
>> >>>> Without knowing your structure of data, a short example of
> IOV-like
>> >>>> variability would be:
>> >>>>
>> >>>> MA1=0
>> >>>> MA2=0
>> >>>> IF(MACH=1)MA1=1
>> >>>> IF(MACH=2)MA2=1
>> >>>> ;Intermachine variability:
>> >>>> ETAM = MA1*ETA(Y)+MA2*ETA(Z)
>> >>>>
>> >>>> PAR= TH(X) *EXP(ETA(X)+ETAM)
>> >>>>
>> >>>> \$OMEGA value1
>> >>>> \$OMEGA BLOCK(1) value2
>> >>>> \$OMEGA BLOCK(1) same
>> >>>>
>> >>>> /Johan
>> >>>>
>> >>>>
>> >>>> _________________________________________
>> >>>> Johan Wallin, M.Sci./Ph.D.-student
>> >>>> Pharmacometrics Group
>> >>>> Div. of Pharmacokinetics and Drug therapy
>> >>>> Uppsala University
>> >>>> _________________________________________
>> >>>>
>> >>>>
>> >>>> -----Original Message-----
>> >>>> From: owner-nmusers
>> >>>> [mailto:owner-nmusers
>> >>>> Behalf Of Denney, William S.
>> >>>> Sent: den 15 oktober 2008 14:39
>> >>>> To: nmusers
>> >>>> Subject: [NMusers] More Levels of Random Effects
>> >>>>
>> >>>> Hello,
>> >>>>
>> >>>> I'm trying to build a model where I need to have ETAs generated
> on
>> >>>> separately for the ID and another variable (MACH). What I have
> is
>> a PD
>> >>>> experiment that was run on several different machines (MACH).
> Each
>> >>>> machine appears to have a different slope per day and a
> different
>> >>>> calibration. I still need to keep some ETAs on the ID column,
> so I
>> >>>> can't just assign MACH=ID.
>> >>>>
>> >>>> I've heard that there are ways to do similar to this, but I have
> been
>> >>>> unable to find examples of how to set etas to key off of
> different
>> >>>> columns.
>> >>>>
>> >>>> Thanks,
>> >>>>
>> >>>> Bill
> Notice: This e-mail message, together with any attachments, contains
> information of Merck & Co., Inc. (One Merck Drive, Whitehouse Station,
> New Jersey, USA 08889), and/or its affiliates (which may be known
> outside the United States as Merck Frosst, Merck Sharp & Dohme or
> MSD and in Japan, as Banyu - direct contact information for affiliates is
> available at http://www.merck.com/contact/contacts.html) that may be
> confidential, proprietary copyrighted and/or legally privileged. It is
> intended solely for the use of the individual or entity named on this
> message. If you are not the intended recipient, and have received this
> message in error, please notify us immediately by reply e-mail and
> then delete it from your system.
>
>
Received on Wed Oct 22 2008 - 17:46:41 EDT

The NONMEM Users Network is maintained by ICON plc. Requests to subscribe to the network should be sent to: nmusers-request@iconplc.com.

Once subscribed, you may contribute to the discussion by emailing: nmusers@globomaxnm.com.