Warfarin data set

Warfarin data set

Warfarin is an anticoagulant normally used in the prevention of thrombosis and thromboembolism, the formation of blood clots in the blood vessels and their migration elsewhere in the body, respectively. In “Studies on coumarin anticoagulant drugs Initiation of warfarin therapy without a loading dose”, Circulation 1968;38:169-177, O’Reilly provide set of plasma warfarin concentrations and Prothrombin Complex Response in thirty normal subjects after a single loading dose. A single large loading dose of warfarin sodium, 1.5 mg/kg of body weight, was administered orally to all subjects. Measurements were made each 12 or 24h. The data set can be seen here, and the corresponding Datxplore project here (notice that both file should be in the same folder to be correctly linked).
A representation of the concentration over time for each subject is presented on the following figure (notice, that this figure was generated using Datxplore).

On the two following figure, one could see the concentration and the effect with respect to time for all subjects.


The purpose of this page is to see the construction, the definition and the use of such a data set in Datxplore and Monolix. For sake of simplicity, the focus will be done on only one subject of ID 1.

Simplified data set

The data set for subject one can be defined as follows

id time    amt dv  dvid    wt  age sex
1   0   100 .   1   66.7    50  1
1   0   .   100 2   66.7    50  1
1   24  .   9.2 1   66.7    50  1
1   24  .   49  2   66.7    50  1
1   36  .   8.5 1   66.7    50  1
1   36  .   32  2   66.7    50  1
1   48  .   6.4 1   66.7    50  1
1   48  .   26  2   66.7    50  1
1   72  .   4.8 1   66.7    50  1
1   72  .   22  2   66.7    50  1
1   96  .   3.1 1   66.7    50  1
1   96  .   28  2   66.7    50  1
1   120 .   2.5 1   66.7    50  1
1   120 .   33  2   66.7    50  1

Interpretation

One can see the following columns

  • id: the subject ID.
  • time: the time of the measurement or of the dose.
  • amt: the amount of drug provided to this subject.
  • dv: the measurement.
  • dvid: the type of measurement. In this study, one has two measurement, the concentration measurement (corresponding to the PK dynamics), and the Prothrombin Complex Response (corresponding to the PD-part)
  • wt: Weight of the subject.
  • age: Age of the subject
  • sex: Sex of the subject.

Several points can be noticed.

  1. The first line corresponds to a dose, while the other ones are measurements. This explains the dot in the CONC column for the first line and the dots in the AMT column for the other ones.
  2. The covariates columns (the continuous wt and the categorical covariates age and sex) are filled with the same values. Even though it is not necessary, we encourage the user to fill the columns for readability and usage reasons.
  3. In the presented case, both PK and PD measurements are at the same time, this is not required for data exploration using Datxplore, nor parameter estimation using Monolix.
  4. Finally, notice that no initial washout is needed at the beginning as by default, the null initial condition is used for parameter estimation.

In Mlxtran, the data set writes

[FILEINFO]
  file=./warfarin_data.txt'
  delimiter=tab
  header={id, Time, amt, dv, dvid, wt, age, sex}

[CONTENT]
  id = { use = identifier }
  Time = { use = time }
  dv = { use = observation, name={Concentration, Effect}, ytype={1,2}, type = {continuous, continuous}, ytype={1,2}}
  dvid = { use = observationType }
  wt = { use = covariate, type=continuous }
  age = { use = covariate, type=categorical }
  sex = { use = covariate, type=categorical }

Combination of continuous and categorical data in a data set

International Normalized Ratio (INR) values are commonly used in clinical practice to target optimal warfarin therapy. Low INR values (3) with high risk of bleeding, so the targeted value of INR, corresponding to optimal therapy, is between 2 and 3.
Prothrombin complex activity is inversely proportional to the INR. We can therefore associate the three ordered categories for the INR to three ordered categories for PCA: Low PCA values if PCA is less than 33% (corresponding to INR>3), medium if PCA is between 33% and 50% (INR between 2 and 3) and high if PCA is more than 50% (INR). A representation of this level in Datxplore is displayed hereafter.

Data set

This data set corresponds to the file warfarin_cat_data.txt

ID AMT TIME    CONC    LIMIT   CENS    WEIGHT  SEX 
id  time    amt dv_ori  dv  dvid    wt  age sex
1   0   100 .   .   1   66.7    50  1
1   0   .   100 3   2   66.7    50  1
1   24  .   9.2 9.2 1   66.7    50  1
1   24  .   49  2   2   66.7    50  1
1   36  .   8.5 8.5 1   66.7    50  1
1   36  .   32  1   2   66.7    50  1
1   48  .   6.4 6.4 1   66.7    50  1
1   48  .   26  1   2   66.7    50  1
1   72  .   4.8 4.8 1   66.7    50  1
1   72  .   22  1   2   66.7    50  1
1   96  .   3.1 3.1 1   66.7    50  1
1   96  .   28  1   2   66.7    50  1
1   120 .   2.5 2.5 1   66.7    50  1
1   120 .   33  1   2   66.7    50  1

Interpretation

Computation was made to get the new measurements into account and a column dv_ori was added to see the initial measurements. One can see that the data set was easy to modify and simple to use in Monolix or Datxplore.

In Mlxtran, the data set writes

[FILEINFO]
file = 'data/warfarin_cat_data.txt'
delimiter = tab
header = {id, time, amt, dv_ori, dv, dvid, wt, age, sex}

[CONTENT]
id = {use=identifier}
time = {use=time}
amt = {use=amount}
dv = {use=observation, name={Concentration, Level}, ytype={1, 2}, type={continuous, discrete}}
dvid = {use=observationType}
wt = {use=covariate, type=continuous}