From: Singla, Sumeet K <*sumeet-singla*>

Date: Wed, 20 Nov 2019 04:42:58 +0000

Hello Everyone,

I am using PsN enabled SCM option in Pirana to analyze selection of covaria=

tes 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-=

model in the mix, "some" power models involving continuous covariates on pa=

rameters 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 h=

ave 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-st=

ick relation as literature and data doesn't support it, power model can onl=

y be used on continuous covariates and I have turned on parallel states opt=

ion.

This is how part of my scm results, followed by scm configuration file, fol=

lowed 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 distributi=

on 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 Tue Nov 19 2019 - 23:42:58 EST

Date: Wed, 20 Nov 2019 04:42:58 +0000

Hello Everyone,

I am using PsN enabled SCM option in Pirana to analyze selection of covaria=

tes 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-=

model in the mix, "some" power models involving continuous covariates on pa=

rameters 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 h=

ave 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-st=

ick relation as literature and data doesn't support it, power model can onl=

y be used on continuous covariates and I have turned on parallel states opt=

ion.

This is how part of my scm results, followed by scm configuration file, fol=

lowed 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 distributi=

on 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 Tue Nov 19 2019 - 23:42:58 EST