Error when nesting more than one level of variability

[liuxl17]

Hi!

I am trying to simulate the PK based on a simple one-compartment model with first-order absorption and run into problems when adding IIV and IOV at the same time. The error message is:

Error: 'omega' needs to be a matrix or a numeric vector that can be converted to a matrix

We put both IIV and IOV on bioavailability and we coded it by adapting the script from this example (https://nlmixrdevelopment.github.io/RxODE-manual/examples.html#inter-occasion-and-other-nesting-examples)

The code is as followed:

library(rxode2)
library(dplyr)
#Set model code
model <-
    RxODE({
    #Parameters
    KA <- KA * exp(eta.KA)
    Fa <- Fa * exp(eta.Fa + iov.Fa) # IIV and IOV on bioavailability
      
    #Initial conditions
    A2(0) = 0
      
    #Model
    d/dt(DEPOT) = -KA * DEPOT 
    f(DEPOT) = Fa
    d/dt(A2) = KA * DEPOT - (CL/V)*A2

    Cp = A2/V * 1000
    })

  #Define thetas
  theta <- c(KA = 0.925,   # Absorption rate constant (hr-1)
             V  = 0.431,   # Central volume (mL) 
             CL = 0.137,  # Central clearance (mL/hr)
             Fa = 0.134)  # Bioavailability
  
  #Define omegas
  omega <- lotri(lotri(eta.KA ~ 0.293^2,
                       eta.Fa ~ 0.0836^2) | id(nu=20),
                   lotri(iov.Fa ~ 0.767^2) | occ(nu=10))
  
  #Define event table
  ev <- et(amount.units = "mg", time.units = "hours") %>% 
    et(amt = 30*0.25 , cmt = "DEPOT", addl = 9, ii = 12) %>% #Dose is 30mg/kg, multiply by average rat weight of 250 grams
    et(0,120) %>% 
    et(id = 1:20) %>% 
    mutate(occ = ceiling(as.numeric(time) / 12)) %>% # 10 occasions in total
    mutate(occ = ifelse(occ == 0, 1, occ))
    
  
  #Solve model
  results <- rxSolve(object=model, params=theta, events=ev, omega=omega, sigma=NULL)

[mattfidler]

This is a different error than I get;

library(rxode2)
#> rxode2 3.0.3 using 8 threads (see ?getRxThreads)
#>   no cache: create with `rxCreateCache()`
library(dplyr)
#> 
#> Attaching package: 'dplyr'
#> The following objects are masked from 'package:stats':
#> 
#>     filter, lag
#> The following objects are masked from 'package:base':
#> 
#>     intersect, setdiff, setequal, union

#Set model code
model <-
  RxODE({
    #Parameters
    KA <- KA * exp(eta.KA)
    Fa <- Fa * exp(eta.Fa + iov.Fa) # IIV and IOV on bioavailability

    #Initial conditions
    A2(0) = 0

    #Model
    d/dt(DEPOT) = -KA * DEPOT
    f(DEPOT) = Fa
    d/dt(A2) = KA * DEPOT - (CL/V)*A2

    Cp = A2/V * 1000
  })

#Define thetas
theta <- c(KA = 0.925,   # Absorption rate constant (hr-1)
           V  = 0.431,   # Central volume (mL)
           CL = 0.137,  # Central clearance (mL/hr)
           Fa = 0.134)  # Bioavailability

#Define omegas
omega <- lotri(lotri(eta.KA ~ 0.293^2,
                     eta.Fa ~ 0.0836^2) | id(nu=20),
               lotri(iov.Fa ~ 0.767^2) | occ(nu=10))

#Define event table
ev <- et(amount.units = "mg", time.units = "hours") %>%
  et(amt = 30*0.25 , cmt = "DEPOT", addl = 9, ii = 12) %>% #Dose is 30mg/kg, multiply by average rat weight of 250 grams
  et(0,120) %>%
  et(id = 1:20) %>%
  mutate(occ = ceiling(as.numeric(time) / 12)) %>% # 10 occasions in total
  mutate(occ = ifelse(occ == 0, 1, occ))


#Solve model
results <- rxSolve(object=model, params=theta, events=ev, omega=omega, sigma=NULL)
#> Model:
#> 
#> iov.Fa=(occ==1)*ETA[1]+(occ==2)*ETA[11]+(occ==3)*ETA[21]+(occ==4)*ETA[31]+(occ==5)*ETA[41]+(occ==6)*ETA[51]+(occ==7)*ETA[61]+(occ==8)*ETA[71]+(occ==9)*ETA[81]+(occ==10)*ETA[91];
#> KA=KA*exp(eta.KA);
#> Fa=Fa*exp(eta.Fa+iov.Fa);
#> A2(0)=0;
#> d/dt(DEPOT)=-KA*DEPOT;
#> f(DEPOT)=Fa;
#> d/dt(A2)=KA*DEPOT-(CL/V)*A2;
#> Cp=A2/V*1000;
#> Error in rxSolveSEXP(object, .ctl, .nms, .xtra, params, events, inits, : The following parameter(s) are required for solving: ETA[91], ETA[81], ETA[71], ETA[61], ETA[51], ETA[41], ETA[31], ETA[21], ETA[11]

^{Created on 2025-01-20 with reprex v2.1.1}

So, I am assuming you are not using the latest rxode2.

I will have to look at this further.

[liuxl17]

Yes I got the same error after updating to the latest version. Looking forward to hearing from you.

[mattfidler]

This is fixed in #844