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

> On 21 Nov 2019, at 18:46, Singla, Sumeet K <sumeet-singla wrote: > > I figured out the problem. Apparently, SCM in PsN, by default sets a very large lower and upper limits for thetas of covariate-parameter relationship, if you don’t provide those bounds. NONMEM runs into numerical difficulty when raising a very small or very big quantity to a power of say 10000.There is a way around it. Set this in your configuration file as shown below: > > [lower_bounds] > V2:USER-5 = -5 > > [inits] > V2:USER-5= 0.1 > > [upper_bounds] > > V2:USER-5 = 5 > > You can define as many “parameter:covariate-model” as you want, in the above format. Note that, order should be: lower_bound, inits, upper bound, and if you are defining more than one parameter-covariate relation, they should be in same order in lower_bound, inits and upper_bounds section. > > Regards, > Sumeet > > From: Ayyappa Chaturvedula <ayyappach <mailto:ayyappach > Sent: Wednesday, November 20, 2019 8:27 AM > To: Singla, Sumeet K <sumeet-singla <mailto:sumeet-singla > Cc: nmusers > Subject: [External] Re: [NMusers] Error in Power-model for covariate selection > > Hi Sumeet: > Couple of points, may not be solutions for the modeling problem you are having 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 time? > 4. Try fitting the model out of SCM for power function and try to find the issue. > > Regards, > Ayyappa > > > On Nov 19, 2019, at 10:48 PM, 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 MAXEVAL99 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