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

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

rote:

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:

CH”

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.

llowed by base model for PK 2-Comp looks like:

OAL dDF SIGNIFICANT PVAL

.84150 1 0.244620

.84150 1 0.197160

.84150 1 0.241180

.84150 1 YES! 0.024492

.84150 1 999

ion in L

Received on Wed Nov 20 2019 - 09:27:17 EST