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.ribb...@pharmetheus.com> wrote: 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-sin...@uiowa.edu<mailto:sumeet-sin...@uiowa.edu>> 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 sumeet-sin...@uiowa.edu<mailto:sumeet-sin...@uiowa.edu> 518.577.5881
