PharmAI

Analyze medication profiles using machine learning.

This project was started to provide clean and adaptable code building on medorder_prediction.

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Motivation

Health-system pharmacists review almost all medication orders for hospitalized patients. Considering that most orders contain no errors, especially in the era of CPOE with CDS,¹ pharmacists have called for technology to enable the triage of routine orders to less extensive review, in order to focus pharmacist attention on unusual orders requiring.^2,3,4

Description

We propose a machine learning model that can do different things:

1. In prospective mode, it learns medication order patterns from historical data, and then predicts the next medication order given a patient's previous order sequence, and currently active drugs. The predictions would be compared to actual orders. Our hypothesis is that orders ranking low in predictions would be unusual, while orders ranking high would be more likely to be routine or unremarkable.
2. In retrospective mode, the order patterns are learned from "stable" medication profiles, that is when no orders have been placed in a given period of time. We assume that when no orders have been entered in a certain period, the prescribed medications represent a stable and correct medication profile. We then try to predict each drug in the stable profile from what happened before this drug (the pre sequence), what happened after this drug (the post sequence) and what is currently active.
3. In retrospective autoencoder mode, the order patters are also learned from "stable" medication profiles. This mode uses an autoencoder to encode the order sequence up to the point the stable profile was sampled as well as what is currently active, to a latent space. From the latent space, the model reconstructs the active medication profile.

This repository presents the code used to preprocess the data from our institution's dataset or from the MIMIC dataset, and to train and evaluate a machine learning model performing either of the tasks described above. Because we are unable to share our dataset, we provide a working implementation on MIMIC-III as a demonstration (see caveats below). The model uses three inputs:

1. The sequence of previous drug orders (the pre sequence), represented as word2vec embeddings.
2. The sequence of orders that happened after the prescribed drug, and before the time when orders stopped being entered for a given period of time (the post sequence), represented as word2vec embeddings. This sequence is not used in prospective mode or in retrospective autoencoder mode.
3. The currently active drugs and pharmacological classes, as well as the ordering department, represented as a bag-of-words, transformed into a multi-hot vector through binary count vectorization.

The output is (the drug only, not the dose, route and frequency):

• In prospective mode, the prediction of the next medication order
• In retrospective mode, the prediction of the drug which was prescribed at the given point in the sequence and which fits given what is currently prescribed to the patient.
• In retrospective autoencoder mode, the active medications.

Caveats about using the MIMIC dataset with our approach

There are important limitations to using the MIMIC dataset with this approach as compared to to real, unprocessed data. We do not believe the results of the model on the MIMIC dataset would reliable enough for use in research or in practice. The mimic files should only be used for demonstration purposes.

There are four main characteristics of the MIMIC dataset which make it less reliable for this model:

1. The MIMIC data only comes from ICU patients. As shown in our paper, ICU patients were one of the populations where our model showed the worst performance, probably because of the variability and the complexity of these patients. It would be interesting to explore how to increase the performance on this subset of patients, possibly by including more clinical data as features. Also, the same drugs may be used in patients in and out of ICU, and the information about the usage trends outside of ICU may be useful to the model, especially for the word2vec embeddings. This data is not present in MIMIC.
2. The MIMIC data was time-shifted inconsistently between patients. Medication use patterns follow trends over time, influcended by drug availability (new drugs on the market, drugs withdrawn from markets, drug shortages) and clinical pratices following new evidence being published. The inconsistent time-shifting destroys these trends; the dataset becomes effectiely pre-shuffled. In our original implementation, we were careful to use only the Scikit-Learn TimeSeries Split in cross-validation to preserve these patterns, and our test set was chronologically after our training-validation set and was preprocessed separately. In our MIMIC demonstration, we changed these to regular shuffle splits and our preprocessor generates the training-validation and test sets from the raw MIMIC files using a random sampling strategy.
3. The MIMIC prescription data does not include the times of the orders, only the dates. This destroys the sequence of orders within a single day. In NLP, this would be equivalent to shuffling each sentence within a text and then trying to extract sequence information. This makes the creation of word2vec embeddings much more difficult because the exact context of the orders (i.e. those that occured immediately before and after) is destroyed. This shows in analogy accuracy which does not go above 20-25% on MIMIC while we achived close to 80% on our data. The sequence of orders, an important input to the model, is therefore inconsistent. Also, it becomes impossible to reliably know whether orders within the same day as the target were discontinued or not when the target was prescribed, descreasing the reliability of our multi-hot vector input.
4. The MIMIC dataset does not include the pharmacological classes of the drugs. The GSN (generic sequence number) allows linkage of the drug data to First Databank, which could allow extraction of classes, but this database is proprietary. One of our model inputs is therefore eliminated.

Files

We present the files in the order they should be run to go from the original data files to a trained and evaluated model. The python script files are provided as commented files that can be used to generate Jupyter Notebooks or can be run as-is in the terminal. Some files are also provided directly as Jupyter Notebooks.

We provide all the code to work from our local dataset or from the MIMIC dataset. Although we cannot share our dataset, this code could be adapted and used by other researchers to replicate our approach on data from other hospitals.

preprocessor.py / mimic_preprocessor.py

This file is not formatted to generate a Jupyter notebook, can only be run as a script.

This script will transform the source files, which should be essentialy lists of orders and associated data, into several pickle files containing dictionaries where the keys are encounter ids and the values are the features for this encounter, in chronological order.

enc_list.pkl is a simple list of encounter ids, to allow for easy splitting into sets. profiles_list.pkl is the list of the raw order sequences in each encounter, to train the word2vec embeddings.

After being loaded and processed by the data loader in components.py, each order gets considered as a label (targets.pkl). The features associated with this label are:

1. The sequence of orders preceding it within the encounter (pre_seq_list.pkl). Orders happening at the exact same time are kept in the sequence. In MIMIC, because order times are precise to the day, this means each order that happened in the same day is present in the sequence (except the label).
2. The sequence of orders after the target within the encounter until orders stopped being entered for a given period of time (post_seq_list.pkl). Orders happening at the exact same time are kept in the sequence. In MIMIC, because order times are precise to the day, this means each order that happened in the same day is present in the sequence (except the label).
3. The active drugs at the time the label was ordered (active_meds_list.pkl). Orders happening at the same time as the label are considered active.
4. The active pharmacological classes at the time the label was ordered (active_classes_list.pkl). This is not created by the MIMIC preprocessor.
5. The departement where the order happened (depa_list.pkl).

original version

Arguments:

--mode	'retrospective' or 'prospective' depending on how the preprocessed data will be used.
--sourcefile	indicates where the original data, in csv format, is located.
--definitionsfile	indiciates a separate file linking medication numbers to full medication names and pharmacological classes.
--numyears	indicates how many years of data to process from the file (starting from the most recent). Defaults to 5.

mimic version

Arguments:

--mode	'retrospective' or 'prospective' depending on how the preprocessed data will be used. Retrospective autoencoder mode is not yet implemented for the mimic preprocessor.

w2v_embeddings.py

Find the best word2vec training hyperparameters to maximize the accuracy on a list of analogies. We provide a list of pairs for the mimic dataset where the semantic relationship is going from a drug in tablet form to a drug in oral solution form (mimic/data/pairs.txt), as described in our paper. The file utils/w2v_analogies.py transforms these pairs into an analogy file (mimic/data/eval_analogy.txt) matching specifications for the gensim accuracy evaluation method that is used for scoring.

The script performs grid search with 3-fold cross-validation to explore the hyperparameter space, and then refits on the whole data with the best hyperparameters returns the analogy accuracy on the entire dataset. Clustering on 3d UMAP projected word2vec embeddings is explored to qualitatively evaluate if clusters correlate to clinical concepts and a 3d plot is returned showing the 3d projected embeddings with color-coded clusters. The clustering part is not used in the subsequent neural network.

We provide a Jupyter Notebook showing our summary exploration of the hyperparameter space on the MIMIC dataset. Performance is poor on this dataset, see caveats above.

Once the word2vec hyperparameters are found, they should be adjusted in the train.py file.

train.py

This file is used to begin training and resume training a partially trained model. The file contains a parameter dictionary used to adjust the training mode and parameters as well as training hyperparameters. First, this script should be used to explore the hyperparameter space and configuration of the neural network by enabling the CROSS_VALIDATE flag. Experiments with a validation set but without cross-validation can be performed by setting the CROSS-VALIDATE flag to False and the VALIDATE flag to True. A final model can be trained on the entire dataset by setting both flags to False.

This parameter dictionary contains a RESTRICT_DATA flag that can be enabled to use only a sample of orders instead of the whole dataset. The sample size can be adjusted. This can be useful to try different things and to debug faster.

evaluate.py

This script uses the test subset of the data to determine the final performance metrics of the model. Will compute global metrics and metrics by patient category, using a dictionary mapping of departments to patient categories specified in a department file which must be manually encoded.

In autoencoder mode, will show samples of reconstructed patient profiles.

components.py

This file is not meant to be run, but is a collection of classes and functions used in the previous scripts. The neural network architecture can be adjusted within this file.

utils/dummy_class.py

This script acts as a dummy classifier, calculating accuracy metrics if the top1, top10 and top30 most popular drugs in the dataset were always predicted. It also returns the number of classes within that set and a frequency histogram of the 50 most popular classes.

utils/extract_druginfo_mimic.py

This script extracts the drug information from the MIMIC PRESCRIPTIONS table to a definitions.csv file providing the formulary drug code in relation to a computed string including the drug name, product strength and pharmaceutical form. This can be useful to match formulary drug codes to human-readable strings. Be careful, some formulary codes match to multiple strings.

utils/w2v_analogies.py

This script takes a list of pairs of drugs and computes analogies, see w2v_embeddings above.

Prerequisites

Developed using Python 3.7

Requires:

• Joblib
• Numpy
• Pandas
• Scikit-learn
• Scikit-plot
• UMAP
• Matplotlib
• Pydot
• Graphviz
• TQDM
• Seaborn
• Gensim
• Tensorflow 2.0 or later
• Jupyter

Contributors

Maxime Thibault.

References

Paper currently under peer review for publication.
Abstract presented at the Machine Learning for Healthcare 2019 conference
Abstract (spotlight session 6 abstract 2)
Spotlight presentation (from 52:15 to 54:15)
Poster

License

GNU GPL v3

Copyright (C) 2019 Maxime Thibault

This program is free software: you can redistribute it and/or modify it under the terms of the GNU General Public License as published by the Free Software Foundation, either version 3 of the License, or (at your option) any later version.

This program is distributed in the hope that it will be useful, but WITHOUT ANY WARRANTY; without even the implied warranty of MERCHANTABILITY or FITNESS FOR A PARTICULAR PURPOSE. See the GNU General Public License for more details.