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Re: Error in Power-model for covariate selection

From: Ayyappa Chaturvedula <ayyappach>
Date: Wed, 20 Nov 2019 08:27:17 -0600

Hi Sumeet:
Couple of points, may not be solutions for the modeling problem you are havi=
ng 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 t=
ime?
4. Try fitting the model out of SCM for power function and try to find the i=
ssue.

Regards,
Ayyappa

> On Nov 19, 2019, at 10:48 PM, Singla, Sumeet K <sumeet-singla
rote:
>
> 
> Hello Everyone,
>
> I am using PsN enabled SCM option in Pirana to analyze selection of covari=
ates in the PK 2- Comp model. As long as I am using just linear and exponent=
ial covariate model, everything runs fine. However, as soon as I add power-m=
odel in the mix, “some” power models involving continuous co=
variates on parameters fail to run and it gives me the following error:
> “HESSIAN OF POSTERIOR DENSITY IS NON-POSITIVE-DEFINITE DURING SEAR=
CH”
> 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 succ=
ess. I have set lower bounds, removed lower bounds, changed order of model i=
n valid states option in scm configuration file, dataset doesn’t con=
tain any 0 or negative value, but nothing is working. FYI: I don’t n=
eed to test hockey-stick relation as literature and data doesn’t sup=
port it, power model can only be used on continuous covariates and I have tu=
rned on parallel states option.
> This is how part of my scm results, followed by scm configuration file, fo=
llowed by base model for PK 2-Comp looks like:
>
> MODEL TEST BASE OFV NEW OFV TEST OFV (DROP) G=
OAL 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 distribut=
ion 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 Wed Nov 20 2019 - 09:27:17 EST

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