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.
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,
...)
The run number of the NONMEM from which the CWRES are to be calculated.
The prefix to two NONMEM file containing the needed values for the computation of the CWRES, described in the details section.
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".
The suffix, after the ".", of the NONMEM file containing the estimated parameter values needed for the CWRES calculation.
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.
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).
Can be either "ALL" or a number matching an ID label in the
datasetname. Value is fixed to "ALL" for xpose.calculate.cwres.
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.
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.
An xpose.data object.
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.
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.
Indicates if the function is to be used in the classic menu system.
Other arguments passed to basic functions in code.
Returns a vector containing the values of the 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.
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. We have attempted to indicate where NONMEM V may be different, but this has not been extensively tested!
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 http://psn.sourceforge.net for more details. PsN does not currently
do this computation for NONMEM 7.
There are five main insertions needed in your NONMEM control file:
$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
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)
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'). Please note that the 4th and 5th lines of
code should be one line with the '...' removed from each line,
reading: COMMON /ROCM6/
THETAF(40),OMEGAF(30,30),SIGMAF(30,30).
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. Please note that
the 3rd and 4th lines of
code should be one line with the '...' removed from each line,
reading: \" COMMON /ROCM6/
THETAF(40),OMEGAF(30,30),SIGMAF(30,30)
.
$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)
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
$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.
compute.cwresThis function is the computational 'brains' of the CWRES computation and does not require an Xpose data object to work. The function simply 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
xpose.calculate.cwresThis 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.
Hooker A, 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].
## 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)
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