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Compute the Conditional Weighted Residuals

Source: R/compute.cwres.R, R/xpose.calculate.cwres.R
compute.cwres.Rd

This function computes the conditional weighted residuals (CWRES) from a NONMEM run. CWRES are an extension of the weighted residuals (WRES), but are calculated based on the first-order with conditional estimation (FOCE) method of linearizing a pharmacometric model (WRES are calculated based on the first-order (FO) method). The function requires a NONMEM table file and an extra output file that must be explicitly asked for when running NONMEM, see details below.

Usage

compute.cwres(
  run.number,
  tab.prefix = "cwtab",
  sim.suffix = "",
  est.tab.suffix = ".est",
  deriv.tab.suffix = ".deriv",
  old.file.convention = FALSE,
  id = "ALL",
  printToOutfile = TRUE,
  onlyNonZero = TRUE,
  ...
)

xpose.calculate.cwres(
  object,
  cwres.table.prefix = "cwtab",
  tab.suffix = "",
  sim.suffix = "sim",
  est.tab.suffix = ".est",
  deriv.tab.suffix = ".deriv",
  old.file.convention = FALSE,
  id = "ALL",
  printToOutfile = TRUE,
  onlyNonZero = FALSE,
  classic = FALSE,
  ...
)

Arguments

run.number

The run number of the NONMEM from which the CWRES are to be calculated.

tab.prefix

The prefix to two NONMEM file containing the needed values for the computation of the CWRES, described in the details section.

sim.suffix

The suffix ,before the ".", of the NONMEM file containing the needed values for the computation of the CWRES, described in the details section. For example, the table files might be named cwtab1sim.est and cwtab1sim.deriv, in which case sim.suffix="sim".

est.tab.suffix

The suffix, after the ".", of the NONMEM file containing the estimated parameter values needed for the CWRES calculation.

deriv.tab.suffix

The suffix, after the ".", of the NONMEM file containing the derivatives of the model with respect to the random parameters needed for the CWRES calculation.

old.file.convention

For backwards compatibility. Use this if you are using the previous file convention for CWRES (table files named cwtab1, cwtab1.50, cwtab1.51, ... , cwtab.58 for example).

id

Can be either "ALL" or a number matching an ID label in the datasetname. Value is fixed to "ALL" for xpose.calculate.cwres.

printToOutfile

Logical (TRUE/FALSE) indicating whether the CWRES values calculated should be appended to a copy of the datasetname. Only works if id="ALL". If chosen the resulting output file will be datasetname.cwres. Value is fixed to TRUE for xpose.calculate.cwres.

onlyNonZero

Logical (TRUE/FALSE) indicating if the return value (the CWRES values) of compute.cwres should include the zero values associated with non-measurement lines in a NONMEM data file.

...

Other arguments passed to basic functions in code.

object

An xpose.data object.

cwres.table.prefix

The prefix to the NONMEM table file containing the derivative of the model with respect to the etas and epsilons, described in the details section.

tab.suffix

The suffix to the NONMEM table file containing the derivative of the model with respect to the etas and epsilons, described in the details section.

classic

Indicates if the function is to be used in the classic menu system.

Value

xpose.calculate.cwres

Returns an Xpose data object that contains the CWRES. If simulated data is present, then the CWRES will also be calculated for that data.

Details

The function reads in the following two files:

paste(tab.prefix,run.number,sim.suffix,est.tab.suffix,sep="")

paste(tab.prefix,run.number,sim.suffix,deriv.tab.suffix,sep="")

Which might be for example:

 cwtab1.est cwtab1.deriv

and (depending on the input values to the function) returns the CWRES in vector form as well as creating a new table file named:

paste(tab.prefix,run.number,sim.suffix,sep="")

Which might be for example:

 cwtab1

Functions

  • xpose.calculate.cwres(): This function is a wrapper around the function compute.cwres. It computes the CWRES for the model file associated with the Xpose data object input to the function. If possible it also computes the CWRES for any simulated data associated with the current Xpose data object. If you have problems with this function try using compute.cwres and then rereading your dataset into Xpose.

Setting up the NONMEM model file

In order for this function to calculate the CWRES, NONMEM must be run while requesting certain tables and files to be created. How these files are created differs depending on if you are using $PRED or ADVAN as well as the version of NONMEM you are using. These procedures are known to work for NONMEM VI but may be different for NONMEM V and NONMEM VII. We have attempted to indicate where NONMEM V may be different, but this has not been extensively tested! For NONMEM VII the CWRES are calculated internally so this function is rarely needed.

This procedure can be done automatically using Perl Speaks NONMEM (PsN) and we highly recommend using PsN for this purpose. After installing PsN just type 'execute [modelname] -cwres'. See https://uupharmacometrics.github.io/PsN/ for more details.

There are five main insertions needed in your NONMEM control file:

  1. $ABB COMRES=X.

    Insert this line directly after your $DATA line. The value of X is the number of ETA() terms plus the number of EPS() terms in your model. For example for a model with three ETA() terms and two EPS() terms the code would look like this:

    $DATA temp.csv IGNORE=@ 
$ABB COMRES=5 
$INPUT ID TIME DV MDV AMT EVID 
$SUB ADVAN2 TRANS2

  2. Verbatim code.

    • Using ADVAN.

      If you are using ADVAN routines in your model, then Verbatim code should be inserted directly after the $ERROR section of your model file. The length of the code depends again on the number of ETA() terms and EPS() terms in your model. For each ETA(y) in your model there is a corresponding term G(y,1) that you must assign to a COM() variable. For each EPS(y) in your model, there is a corresponding HH(y,1) term that you must assign to a COM() variable.

      For example for a model using ADVAN routines with three ETA() terms and two EPS() terms the code would look like this:

      
"LAST 
"  COM(1)=G(1,1) 
"  COM(2)=G(2,1) 
"  COM(3)=G(3,1) 
"  COM(4)=HH(1,1) 
"  COM(5)=HH(2,1)

    • Using PRED.

      If you are using $PRED, the verbatim code should be inserted directly after the $PRED section of your model file. For each ETA(y) in your model there is a corresponding term G(y,1) that you must assign to a COM() variable. For each EPS(y) in your model, there is a corresponding H(y,1) term that you must assign to a COM() variable. The code would look like this for three ETA() terms and two EPS() terms:

      
"LAST 
"  COM(1)=G(1,1) 
"  COM(2)=G(2,1) 
"  COM(3)=G(3,1) 
"  COM(4)=H(1,1) 
"  COM(5)=H(2,1)

  3. INFN routine.

    • Using ADVAN with NONMEM VI and higher.

      If you are using ADVAN routines in your model, then an $INFN section should be placed directly after the $PK section using the following code. In this example we are assuming that the model file is named something like 'run1.mod', thus the prefix to these file names 'cwtab' has the same run number attached to it (i.e. 'cwtab1'). This should be changed for each new run number.

      $INFN
IF (ICALL.EQ.3) THEN
  OPEN(50,FILE='cwtab1.est')
  WRITE(50,*) 'ETAS'
  DO WHILE(DATA)                                                       
    IF (NEWIND.LE.1) WRITE (50,*) ETA                                    
  ENDDO                                                                
  WRITE(50,*) 'THETAS'
  WRITE(50,*) THETA
  WRITE(50,*) 'OMEGAS'
  WRITE(50,*) OMEGA(BLOCK)
  WRITE(50,*) 'SIGMAS'
  WRITE(50,*) SIGMA(BLOCK)
ENDIF

    • Using ADVAN with NONMEM V.

      If you are using ADVAN routines in your model, then you need to use an INFN subroutine. If we call the INFN subroutine 'myinfn.for' then the $SUBS line of your model file should include the INFN option. That is, if we are using ADVAN2 and TRANS2 in our model file then the $SUBS line would look like:

      $SUB ADVAN2 TRANS2 INFN=myinfn.for

      The 'myinfn.for' routine for 4 thetas, 3 etas and 1 epsilon is shown below. If your model has different numbers of thetas, etas and epsilons then the values of NTH, NETA, and NEPS, should be changed respectively. These vales are found in the DATA statement of the subroutine. additionally, in this example we are assuming that the model file is named something like 'run1.mod', thus the prefix to the output file names ('cwtab') in this subroutine has the same run number attached to it (i.e. 'cwtab1'). This number should be changed for each new run number (see the line beginning with 'OPEN'). 

      
     SUBROUTINE INFN(ICALL,THETA,DATREC,INDXS,NEWIND)
     DIMENSION THETA(*),DATREC(*),INDXS(*)
     DOUBLE PRECISION THETA
     COMMON /ROCM6/ THETAF(40),OMEGAF(30,30),SIGMAF(30,30)
     COMMON /ROCM7/ SETH(40),SEOM(30,30),SESIG(30,30)
     COMMON /ROCM8/ OBJECT
     COMMON /ROCM9/ IERE,IERC
     DOUBLE PRECISION THETAF, OMEGAF, SIGMAF
     DOUBLE PRECISION OBJECT
     REAL SETH,SEOM,SESIG
     DOUBLE PRECISION ETA(10)
     INTEGER J,I
     INTEGER IERE,IERC
     INTEGER MODE
     INTEGER NTH,NETA,NEPS
     DATA NTH,NETA,NEPS/4,3,1/
     IF (ICALL.EQ.0) THEN
C      open files here, if necessary
       OPEN(50,FILE='cwtab1.est')
     ENDIF
     IF (ICALL.EQ.3) THEN
       MODE=0
       CALL PASS(MODE)
       MODE=1
       WRITE(50,*) 'ETAS'
20     CALL PASS(MODE)
       IF (MODE.EQ.0) GO TO 30
       IF (NEWIND.NE.2) THEN
         CALL GETETA(ETA)
         WRITE (50,97) (ETA(I),I=1,NETA)
       ENDIF
       GO TO 20
30     CONTINUE
       WRITE (50,*) 'THETAS'
       WRITE (50,99) (THETAF(J),J=1,NTH)
       WRITE(50,*) 'OMEGAS'
       DO 7000 I=1,NETA
7000     WRITE (50,99) (OMEGAF(I,J),J=1,NETA)
       WRITE(50,*) 'SIGMAS'
       DO 7999 I=1,NEPS
7999     WRITE (50,99) (SIGMAF(I,J),J=1,NEPS)
     ENDIF
99   FORMAT (20E15.7)
98   FORMAT (2I8)
97   FORMAT (10E15.7)
     RETURN
     END

    • Using $PRED with NONMEM VI and higher.

      If you are using $PRED, then an the following code should be placed at the end of the $PRED section of the model file (together with the verbatim code). In this example we are assuming that the model file is named something like 'run1.mod', thus the prefix to these file names 'cwtab' has the same run number attached to it (i.e. 'cwtab1'). This should be changed for each new run number.

      IF (ICALL.EQ.3) THEN
  OPEN(50,FILE='cwtab1.est')
  WRITE(50,*) 'ETAS'
  DO WHILE(DATA)                                                       
    IF (NEWIND.LE.1) WRITE (50,*) ETA                                    
  ENDDO                                                                
  WRITE(50,*) 'THETAS'
  WRITE(50,*) THETA
  WRITE(50,*) 'OMEGAS'
  WRITE(50,*) OMEGA(BLOCK)
  WRITE(50,*) 'SIGMAS'
  WRITE(50,*) SIGMA(BLOCK)
ENDIF

    • Using $PRED with NONMEM V.

      If you are using $PRED with NONMEM V, then you need to add verbatim code immediately after the $PRED command. In this example we assume 4 thetas, 3 etas and 1 epsilon. If your model has different numbers of thetas, etas and epsilons then the values of NTH, NETA, and NEPS, should be changed respectively. These vales are found in the DATA statement below. 

      
$PRED
"FIRST  
"     COMMON /ROCM6/ THETAF(40),OMEGAF(30,30),SIGMAF(30,30) 
"     COMMON /ROCM7/ SETH(40),SEOM(30,30),SESIG(30,30) 
"     COMMON /ROCM8/ OBJECT 
"     DOUBLE PRECISION THETAF, OMEGAF, SIGMAF 
"     DOUBLE PRECISION OBJECT 
"     REAL SETH,SEOM,SESIG 
"     INTEGER J,I 
"     INTEGER MODE 
"     INTEGER NTH,NETA,NEPS 
"     DATA NTH,NETA,NEPS/4,3,1/

      After this verbatim code you add all of the abbreviated code needed for the $PRED routine in your model file. After the abbreviated code more verbatim code is needed. This verbatim code should be added before the verbatim code discussed above under point 2. In the example below we are assuming that the model file is named something like 'run1.mod', thus the prefix to the output file names ('cwtab') has the same run number attached to it (i.e. 'cwtab1'). This number should be changed for each new run number (see the line beginning with 'OPEN').

      
"     IF (ICALL.EQ.0) THEN 
"C    open files here, if necessary 
"       OPEN(50,FILE='cwtab1.est') 
"     ENDIF 
"     IF (ICALL.EQ.3) THEN 
"       MODE=0 
"       CALL PASS(MODE) 
"       MODE=1 
" 	     WRITE(50,*) 'ETAS' 
"20     CALL PASS(MODE) 
"       IF (MODE.EQ.0) GO TO 30 
"       IF (NEWIND.NE.2) THEN 
"         CALL GETETA(ETA) 
"         WRITE (50,97) (ETA(I),I=1,NETA) 
"       ENDIF 
"       GO TO 20 
"30     CONTINUE 
"       WRITE (50,*) 'THETAS' 
"       WRITE (50,99) (THETAF(J),J=1,NTH) 
"       WRITE (50,*) 'OMEGAS' 
"       DO 7000 I=1,NETA 
"7000     WRITE (50,99) (OMEGAF(I,J),J=1,NETA) 
"       WRITE (50,*) 'SIGMAS' 
"       DO 7999 I=1,NEPS 
"7999     WRITE (50,99) (SIGMAF(I,J),J=1,NEPS) 
"     ENDIF 
"99   FORMAT (20E15.7) 
"98   FORMAT (2I8) 
"97   FORMAT (10E15.7)

  4. cwtab*.deriv table file.

    A special table file needs to be created to print out the values contained in the COMRES variables. In addition the ID, IPRED, MDV, DV, PRED and RES data items are needed for the computation of the CWRES. The following code should be added to the NONMEM model file. In this example we continue to assume that we are using a model with three ETA() terms and two EPS() terms, extra terms should be added for new ETA() and EPS() terms in the model file. We also assume the model file is named something like 'run1.mod', thus the prefix to these file names 'cwtab' has the same run number attached to it (i.e. 'cwtab1'). This should be changed for each new run number.

    
$TABLE ID COM(1)=G11 COM(2)=G21 COM(3)=G31 COM(4)=H11 COM(5)=H21 
       IPRED MDV NOPRINT ONEHEADER FILE=cwtab1.deriv

  5. $ESTIMATION.

    To compute the CWRES, the NONMEM model file must use (at least) the FO method with the POSTHOC step. If the FO method is used and the POSTHOC step is not included then the CWRES values will be equivalent to the WRES. The CWRES calculations are based on the FOCE approximation, and consequently give an idea of the ability of the FOCE method to fit the model to the data. If you are using another method of parameter estimation (e.g. FOCE with interaction), the CWRES will not be calculated based on the same model linearization procedure.

References

Hooker AC, Staatz CE, Karlsson MO. Conditional weighted residuals, an improved model diagnostic for the FO/FOCE methods. PAGE 15 (2006) Abstr 1001 [http://www.page-meeting.org/?abstract=1001].

Hooker AC, Staatz CE and Karlsson MO, Conditional weighted residuals (CWRES): a model diagnostic for the FOCE method, Pharm Res, 24(12): p. 2187-97, 2007, [doi:10.1007/s11095-007-9361-x ].

See also

Other data functions: add_transformed_columns, change_graphical_parameters, change_misc_parameters, data.checkout(), data_extract_or_assign, db.names(), export.graph.par(), export.variable.definitions(), import.graph.par(), import.variable.definitions(), make.sb.data(), nsim(), par_cov_summary, read.TTE.sim.data(), read.nm.tables(), read_NM_output, read_nm_table(), simprazExample(), tabulate.parameters(), xlabel(), xpose.data, xpose.print(), xpose4-package, xsubset()

Author

Andrew Hooker

Examples


if (FALSE) {
## Capture CWRES from cwtab5.est and cwtab5.deriv
cwres <- compute.cwres(5)
mean(cwres)
var(cwres)

## Capture CWRES from cwtab1.est and cwtab1.deriv, do not print out, allow zeroes
cwres <- compute.cwres("1", printToOutFile = FALSE,
  onlyNonZero = FALSE)

## Capture CWRES for ID==1
cwres.1 <- compute.cwres("1", id=1)

## xpdb5 is an Xpose data object
## We expect to find the required NONMEM run and table files for run
## 5 in the current working directory
xpdb5 <- xpose.data(5)

## Compare WRES, CWRES
xpdb5 <- xpose.calculate.cwres(xpdb5)
cwres.wres.vs.idv(xpdb5) 

}