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

From: Singla, Sumeet K <sumeet-singla>
Date: Wed, 20 Nov 2019 05:23:10 +0000

Jakob,

Yes, in the pooled dataset from different studies, one dataset didn’t have BMI values. Initially, I used “missing_values_token” option in the PsN command line and by default it is -99. However, power model still gave errors. Now I just checked the dataset in model run directory and it shows that despite using that option, PsN never replaced missing values with -99. Maybe, I should manually enter it and run it again. Also, because its negative value, I thought it doesnt make sense, and instead I provided median BMI in place of missing values. Didn’t work that way either.

Regards,
Sumeet Singla



On Nov 19, 2019, at 11:10 PM, Jakob Ribbing <jakob.ribbing

 Hi Sumeet,

It is great that you have considered already that covarite values do not include zero or negative values, as that would not work with the power model.
Did you have any missing values, and how were they coded?

I would recommend to code these (in your data file) using the default -99 in your datafile.
You can check the PsN file “covariate_statistics.txt” for your scm run: For BMI in particular, were there missing values detected by PsN and is the minimum value >0 or is it -99?

Best regards

Jakob

On 20 Nov 2019, at 05:42, 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 Wed Nov 20 2019 - 00:23:10 EST

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