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Re: [External] Re: Error in Power-model for covariate selection

From: Jakob Ribbing <jakob.ribbing>
Date: Thu, 21 Nov 2019 22:32:40 +0100

Great to hear it is now working.

If you want to set the same limits for all power models, you can even =
write this in a more generic form:
*:*-5 = -5

And if you want to apply only for one parameter or one covariate that is =
possible as well, e.g.:
V2:*-5 = -5

Best regards

Jakob


> On 21 Nov 2019, at 18:46, Singla, Sumeet K <sumeet-singla
wrote:
>
> I figured out the problem. Apparently, SCM in PsN, by default sets a =
very large lower and upper limits for thetas of covariate-parameter =
relationship, if you don’t provide those bounds. NONMEM runs =
into numerical difficulty when raising a very small or very big quantity =
to a power of say 10000.There is a way around it. Set this in your =
configuration file as shown below:
>
> [lower_bounds]
> V2:USER-5 = -5
>
> [inits]
> V2:USER-5= 0.1
>
> [upper_bounds]
>
> V2:USER-5 = 5
>
> You can define as many “parameter:covariate-model” as =
you want, in the above format. Note that, order should be: lower_bound, =
inits, upper bound, and if you are defining more than one =
parameter-covariate relation, they should be in same order in =
lower_bound, inits and upper_bounds section.
>
> Regards,
> Sumeet
>
> From: Ayyappa Chaturvedula <ayyappach
<mailto:ayyappach
> Sent: Wednesday, November 20, 2019 8:27 AM
> To: Singla, Sumeet K <sumeet-singla
<mailto:sumeet-singla
> Cc: nmusers
> Subject: [External] Re: [NMusers] Error in Power-model for covariate =
selection
>
> Hi Sumeet:
> Couple of points, may not be solutions for the modeling problem you =
are having but in general:
> 1. Use INTERACTION in your $EST because you are using proportional =
error
> 2. Make sure you have enough range of covariates in the data to =
describe the relationships quantitatively
> 3. Are there any correlated covariates that you are trying to include =
same time?
> 4. Try fitting the model out of SCM for power function and try to find =
the issue.
>
> Regards,
> Ayyappa
>
>
> On Nov 19, 2019, at 10:48 PM, Singla, Sumeet K =
<sumeet-singla
>
> 
> Hello Everyone,
>
> I am using PsN enabled SCM option in Pirana to analyze selection of =
covariates in the PK 2- Comp model. As long as I am using just linear =
and exponential covariate model, everything runs fine. However, as soon =
as I add power-model in the mix, “some” power models =
involving continuous covariates on parameters fail to run and it gives =
me the following error:
> “HESSIAN OF POSTERIOR DENSITY IS NON-POSITIVE-DEFINITE DURING =
SEARCH”
> I understand that individual PK parameter search might be moving into =
0 or negative territory. I am trying to fix it but didn’t have =
much success. I have set lower bounds, removed lower bounds, changed =
order of model in valid states option in scm configuration file, dataset =
doesn’t contain any 0 or negative value, but nothing is working. =
FYI: I don’t need to test hockey-stick relation as literature =
and data doesn’t support it, power model can only be used on =
continuous covariates and I have turned on parallel states option.
> This is how part of my scm results, followed by scm configuration =
file, followed by base model for PK 2-Comp looks like:
>
> MODEL TEST BASE OFV NEW OFV TEST OFV (DROP) =
   GOAL dDF SIGNIFICANT PVAL
> CLAGE-2 PVAL 2618.02603 2616.67228 1.35375 =
> 3.84150 1 0.244620
> CLAGE-5 PVAL 2618.02603 2616.36273 1.66330 =
> 3.84150 1 0.197160
> CLAGE-4 PVAL 2618.02603 2616.65232 1.37371 =
> 3.84150 1 0.241180
> CLBMI-2 PVAL 2618.02603 2612.96657 5.05946 =
> 3.84150 1 YES! 0.024492
> CLBMI-5 PVAL 2618.02603 FAILED FAILED =
> 3.84150 1 999
>
> SCM FILE:
> “
> search_direction=both
> p_forward=0.05
> p_backward=0.01
> continuous_covariates=BMI,AGE
> categorical_covariates=USER,SEX
> parallel_states=1
> retries=2
> threads=6
> tweak_inits=1
> ;;1-NotIncluded, 2-LINEAR, 3-Hockey Stick Relation, 4-Exponential, =
5-Power
> [test_relations]
> CL=AGE,SEX,BMI,USER
> V1=AGE,SEX,BMI,USER
> V2=AGE,SEX,BMI,USER
> Q=AGE,SEX,BMI,USER
> [valid_states]
> continuous = 1,2,5,4
> categorical = 1,2
> “
> NONMEM Control Stream:
>
> $SUBROUTINE ADVAN3 TRANS4
>
> $PK
>
> TVV1 = THETA(1) ;Central Volume of =
distribution in L
> V1 = TVV1*EXP(ETA(1))
> TVCL = THETA(2)
> CL = TVCL*EXP(ETA(2)) ; Clearance L/h
> TVQ = THETA(3)
> Q = TVQ*EXP(ETA(3)) ;Intercompartment Clearance
> TVV2 = THETA(4)
> V2 = TVV2*EXP(ETA(4)) ;Peripheral volume in L
> S1=V1
>
> $ERROR
> IPRED=F
> Y= F + F*ERR(1); Proportional Error
>
> $THETA
> (0, 16); [V1] based on PK 2 Comp
> (0, 255); [CL] based on PK 2 Comp
> (0, 33.5); [Q] based on PK 2 Comp
> (0, 29.7); [V2] based on PK 2 Comp
>
> $OMEGA
> (0, 0.08); [P] omega(1,1)
> (0, 0.159); [P] omega(2,2)
> (0, 0.140); [P] omega(3,3)
> (0, 0.19); [P] omega(4,4)
>
> $SIGMA
> (0, 0.06) ;sigma1
>
> $EST METHOD=1 PRINT=5 MAXEVAL=9999 SIG=3 NOABORT
>
>
> Regards,
>
> Sumeet K. Singla
> Ph.D. Candidate
> Division of Pharmaceutics and Translational Therapeutics
> College of Pharmacy | University of Iowa
> Iowa City, Iowa
> sumeet-singla
> 518.577.5881


Received on Thu Nov 21 2019 - 16:32:40 EST

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