RE: Error in Power-model for covariate selection
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 during
estimation). Given your problem is power function and BMI and cannot correctly
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
model. In my experience exponential models are less prone to numerical
stability than power models. Maybe examine the exponential fit to see the
general 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
drastically different from a power model. It might give you a hint as to why
the power 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 still
keeping the threshold at 3.84, so won't you be getting more than expected
false-positive detection of a significant covariate?
Warm regards,
Douglas Eleveld
Quoted reply history
From: [email protected] [mailto:[email protected]] On
Behalf Of Singla, Sumeet K
Sent: woensdag 20 november 2019 05:43
To: [email protected]
Subject: [NMusers] Error in Power-model for covariate selection
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
[email protected]<mailto:[email protected]>
518.577.5881
________________________________