This tip was suggested by an inquiry to nmusers from Klaas
Prins:
Dear nm-users,
Currently I am working on a study that consisted of 4 different
study parts in which several dosing schemes were tested, i.e.
3 schemes of multiple dosing and 1 of continuous infusion.
Initially, I created separate data sets for each study part
and inserted intermediate time points to get smooth curves
when plotting observed and predicted versus time. Using either
the MDV (0=observation, 1=missing) or EVID (0=observation,
1=dosing, 2=other/simulation) data item, I managed to get
decent fits for each study part. Also combining data from
different study parts resulted in succesful NM runs.
However, I did not feel satisfied with making more than one
dataset and a couple of control streams. Therefore, I set
out to put together a single dataset containing data of all
study parts. Then, the aim was to flag out the study parts
that did not need to be evaluated in specific run, by setting
EVID to 2 (other event). In this manner, I created 6 different
evaluation schemes and listed them in data items EV1 to EV6.
For instance, scheme EV4 was created to evaluate study parts
1 and 4 only, then all records for those parts were set to
0, 1 and 2 (see above) and all other records were set to 2
(flagged as 'other'). The $INPUT control stream read the following:
$INPUT ID TIME AMT RATE DV SEX WT PART EV1=DROP EV2=DROP EV3=DROP
EV4=EVID EV5=DROP EV6=DROP
So, by toggling on and off the EVx=EVID/DROP, I hoped to get
my desired evaluation.
It did not work since the nm-tran reported for the data records
of study parts that were flagged out: THE DV DATA ITEM IS POSITIVE,
BUT THE MDV DATA ITEM IS 1 I did not specify a MDV data item,
so this must refer to a 'generated MDV'. I do understand this,
since for these parts, the observations are read and NM is suprised
that it is asked to consider this as a simulation record. Now,
after this exhausting problem description, could somebody comment
on this issue and provide hints on how to surpass this? Any
suggestion is much appreciated.
Thanks in advance and have a nice weekend, Klaas Prins
Actually, Klaas was very close to the solution of his problem.
The issue Klaas encountered was that not only do you need to
"pre-specify" the EVID for NONMEM, you also need to pre-specify
the MDV and ANY DOSING-RELATED data items such as AMT and RATE
because this scheme relies on:
pre-defining to NM-TRAN those records which you choose
not to analyze as MDV=1 (missing) and that DV is not expected
to be positive for MDV=1
other data item records (EVID=2) may not specify dosing
information.
To circumenvent these limitations one must apriori create columns
in your data representing all the combinations of data you wish
to subset for analysis by specifying the EVID, MDV, AMT (and
RATE if needed).
I have created an example data file, test.csv, in which I make
four subsets of the full data set:
subset 0: all of the data, specified by data columns EV0,
MV0, AM0
subset 1: subjects 1-4, specified by data columns EV1,
MV1, AM1
subset 2: subjects 5-8, specified by data columns EV2,
MV2, AM2
subset 3: subjects 9-12, specified by data columns EV3,
MV3, AM3
subset 4: subjects 1-4 & 9-12, specified by data columns
EV4, MV4, AM4
(This will, of course, increase the number of columns in your
original datafile, but NOT in the number of columns in the datafile
used by NONMEM, FDATA, becuause the columns not used in a given
run will be excluded using "DROP=" and because NM-TRAN will
ordinarily add columns for EVID, MDV and AMT anyway.)
To analyze all to the data, specify EVID=EV0, MDV=MV0, AMT=AM0
in $DATA of your control stream (and DROP= is specified for
the remaining columns), e.g.:
;Model Desc: NONMEM & PDx-Pop compliant control stream
;Project Name: TIPS
;Project ID: NO PROJECT DESCRIPTION
$PROB RUN# 011 DATA
$INPUT C ID TIME DV WT
AMT=AM0 DROP=AM1 DROP=AM2 DROP=AM3 DROP=AM4
EVID=EV0 DROP=EV1 DROP=EV2 DROP=EV3 DROP=EV4
MDV=MV0 DROP=MV1 DROP=MV2 DROP=MV3 DROP=MV4
$DATA test.CSV IGNORE=C
$SUBROUTINES ADVAN2
$PK KA=THETA(1)*EXP(ETA(1)) K =THETA(2)*EXP(ETA(2)) CL=THETA(3)*EXP(ETA(3)) SC=CL/K
$THETA
(0,3)
(0,.08)
(0,.04)
$OMEGA
0.1 ;[p]
0.1 ;[p]
0.1 ;[p]
$ERROR Y=F+EPS(1)
$SIGMA
.1 ;[A]
$EST MAXEVAL=450 PRINT=5 MSF=011.MSF
$COV
$TABLE ID AMT TIME WT EVID MDV FILE=011.TAB ONEHEADER NOPRINT
To analyze subset 1 of the data, specify EVID=EV1, MDV=MV1,
AMT=AM1 in $DATA of your control stream (and DROP= is specified
for the remaining columns), e.g.:
$INPUT C ID TIME DV WT
DROP=AM0 AMT=AM1 DROP=AM2 DROP=AM3 DROP=AM4
DROP=EV0 EVID=EV1 DROP=EV2 DROP=EV3 DROP=EV4
DROP=MV0 MDV=MV1 DROP=MV2 DROP=MV3 DROP=MV4
The control stream, tip7.ctl, and the complete datafile, test.csv,
for this example may be found in the NONMEM
Repository@GloboMax.
[Generic Disclaimer: Verify that this code or any other code
you receive from an outside source works with YOUR DATA.]
PRODUCTS:
NONMEM® USER TIPS
KA=THETA(1)*EXP(ETA(1))