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RE: Error in Power-model for covariate selection

From: Eleveld-Ufkes, DJ <d.j.eleveld>
Date: Wed, 20 Nov 2019 13:36:38 +0000

Hi Sumeet,

The most common with power covariate relationships is indeed covariate=0 =
and an exponent that is estimated negative (or traverses into that area dur=
ing estimation). Given your problem is power function and BMI and cannot co=
rrectly be 0 then I agree it should work. Double check that you have no BMI=
=0 for any individuals on any records. No missing values? Maybe NONMEM is=
 treating missing values as 0?

On possibility is outliers are causing numerical instability in the power m=
odel. In my experience exponential models are less prone to numerical stabi=
lity than power models. Maybe examine the exponential fit to see the genera=
l tendencies between CL and BMI. Exponential models don't blowup like power=
 models do. For not-all-too-extreme cases the results should not be drastic=
ally different from a power model. It might give you a hint as to why the p=
ower model is misbehaving. A single outlier can cause considerable problems=
 when N is small.

As an aside about automated SCM, is there not anywhere a correction to the =
dOFV threshold for multiple testing? You are testing 5 models on CL and sti=
ll keeping the threshold at 3.84, so won't you be getting more than expecte=
d false-positive detection of a significant covariate?

Warm regards,

Douglas Eleveld

From: owner-nmusers
 Behalf Of Singla, Sumeet K
Sent: woensdag 20 november 2019 05:43
To: nmusers
Subject: [NMusers] Error in Power-model for covariate selection

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

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Received on Wed Nov 20 2019 - 08:36:38 EST

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