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

From: Ayyappa Chaturvedula <[email protected]<mailto:[email protected]>> Sent: Wednesday, November 20, 2019 8:27 AM To: Singla, Sumeet K <[email protected]<mailto:[email protected]>> Cc: [email protected]<mailto:[email protected]> 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 <[email protected]<mailto:[email protected]>> wrote:  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