exhaufs 0.94

Exhaustive Feature Selection

ExhauFS

Exhaustive feature selection for classification and survival analysis. Please cite this paper if you are using ExhauFS in your work:

Nersisyan S, Novosad V, Galatenko A, Sokolov A, Bokov G, Konovalov A, Alekseev D, Tonevitsky A. ExhauFS: exhaustive search-based feature selection for classification and survival regression. bioRxiv. 2021 Aug 04. doi: 10.1101/2021.08.03.454798.

Table of Contents

Introduction
Installation
Tutorial
Running ExhauFS
Functions and classes

Introduction

The main idea behind ExhauFS is the exhaustive search of feature subsets to construct the most powerful classification and survival regression models. Since computational complexity of such approach grows exponentially with respect to combination length, we first narrow down features list in order to make the search practically feasible. Briefly, a pipeline is implemented as follows:

1. Feature pre-selection: filter features by specified method.
2. Feature selection: select "best" n features for exhaustive search.
3. Exhaustive search: iterate through all possible k-element feature subsets and fit classification/regression models.
4. Evaluation: evaluate each model and make summary of all passed feature subsets

Values n and k also define running time of the pipeline (there are C_n^k feature subsets). And, for example, iterating through all 8-gene signatures composed of n = 20 genes is possible (see example breast cancer data below), while search over n = 1000 genes is impossible due to time constraints.

Input data can consist from different batches (datasets), and each dataset should be labeled by one of the following types:

1. Training set: samples from training datasets will be used for tuning classification/regression models. At least one such dataset is required; if multiple given, the union will be used.
2. Filtration set: all tuned models will be first evaluated on training and filtration sets. If specified thresholds for accuracy are reached, model will be evaluated on validation (test) sets. The use of filtration sets is optional.
3. Validation (test) set: performance of models that passed filtration thresholds then evaluated on validation sets. At least one such dataset is required; if multiple given, model will be evaluated on all test sets independently.

Installation

Prerequisites:

Make sure you have installed all of the following prerequisites on your development machine:

• python3.6+
• pip3

ExhauFS installation:

pip3 install exhaufs

Tutorial

In this section we illustrate the main functionality of ExhauFS, and together with that show how to reproduce the results present in the manuscript.

A toy example (classification)

We illustrate ExhauFS basics by using a small cervical cancer toy dataset with 72 samples and 19 features. All necessary data for this example can be found in tutorial/cervical_cancer directory.

We start from data.csv and annotation.csv files: the first one contains data matrix and the second one maps each sample to class label and dataset type (training or validation). In this example we brute force all existing feature triples - this information is reflected in n_k.csv file (n = 19 is the total number of features). Prior to ExhauFS run we should also create a configuration file. Here we use random forest classifier and standard accuracy metrics (config_for_build_classifiers.json). Since all 19 features are used, we do not specify any feature selector and pre-selector. In order to get only highly accurate classifiers, we impose 0.9 threshold on the minimum of sensitivity (TPR) and specificity (TNR) on the training set.

Now we are ready to execute ExhauFS:

exhaufs build classifiers -c config_for_build_classifiers.json

Output files are located in results_build_classifiers directory. In this example, we focus only on two reports:

• models.csv

This file contains accuracy metrics for all models which passed 0.9 threshold filtration on the training set. The file is sorted according to the classifier accuracy on the training set, so we can see that almost all models have sensitivity and specificity equal to 1.0. Among these models there are multiple cases with particularly high accuracy on the validation set, e.g.

• summary_features.csv

Here we see a number of occurrences of each feature in the set of constructed models which passed 0.9 accuracy threshold. The most important features could be picked, e.g., by taking rows with FDR < 0.05.

Let us take a closer look to the particular classifier built on perception_vulnerability, socialSupport_instrumental and empowerment_desires features. To do that, we should create an additional configuration file with features_subset parameter set to the desired triple (config_for_summary_classifiers.json). To run ExhauFS in the summary mode, simply execute the following command:

exhaufs summary classifiers -c config_for_summary_classifiers.json

Note, that we do not specify any feature selection/pre-selection or accuracy threshold parameters for the summary mode. The most important of generated files are:

• report.txt: accuracy scores for the training and the validation datasets.
• ROC_CervicalCancerBehaviorRisk_Training.pdf: ROC curve for the training set. The red dot stands for actual sensitivity and specificity. For example, the classifier does not work ideally on the training set despite AUC equals 1.
• ROC_CervicalCancerBehaviorRisk_Validation.pdf: ROC curve for validation set.

Breast cancer (classification)

As a real-life example of the classification module of the tool we used multi-cohort breast cancer dataset. The objective is to predict whether a patient will have cancer recurrence within first 5 years after the surgery based on gene expression profile in the removed tumor (see our manuscript for the details). Configuration and output files for this example are located in tutorial/breast_cancer folder, input data can be downloaded here. The microarray data are split into independent training, filtration and validation sets.

The following options are used (config_for_build_classifiers.json):

• "feature_pre_selector": "f_test" - this is for pre-selection of genes whose expression distribution is similar in training and filtration datasets (the batch effect removal approach).
• "feature_selector": "t_test" - top n most differentially expressed genes are selected. Additional option "use_filtration": true means that Student's t-test will be applied to the union of training and filtration sets.
• "preprocessor": "StandardScaler" - prior classifier fitting, data are centered and scaled (z-score transformation).
• "model": "SVC" - Support Vector machine Classifier (SVC) is used. Additional arguments are used to specify linear kernel, normalization for unbalanced classes and a cross-validation grid for penalty parameter (C) estimation.

Classifier construction with the given n_k.csv file could be done by the same command as in the previous toy example (however, this will take several days to finish). Here we review two output reports which were not covered in the toy example:

• summary_n_k.csv

For each n, k pair the number of classifiers which passed the 0.65 accuracy threshold on the training and the filtration sets is presented (num_training_reliable). All these classifiers were evaluated on the validation set; num_validation_reliable and percentage_reliable columns contain the fraction of these classifiers which also passed 0.65 accuracy threshold on the validation set. For all values of k above 10 we see almost 100% passability, which means the absence of overfitting and successful victory over the batch effects (all classifiers which demonstrated reliable performance on the training and the filtration sets were also good on the validation one).

• sorted_features.txt

This is a technical though useful file: the list of pre-selected genes is sorted according to the rate of differential expression (t_test feature selection). Each pipeline iteration begins from the selection of the first n entries from this file.

As in the previous toy example, let us take a closer look to the single gene signature (see config_for_summary_classifiers.json). The following output files were not covered in the toy example:

• feature_importances.pdf (contains coefficients of the linear SVM classifier)
• model.pkl (Python-pickled classifier and pre-processor objects)

ExhauFS also allows one to evaluate constucted classifiers on time-to-event data. For example, let us evaluate the same ten-gene signature on additional RNA-seq TCGA-BRCA dataset. To do that, we should include to desired feature subset and pickled model path to the configuration file (config_for_km_plot.json). The analysis could be done by running

exhaufs km_plot -c config_for_km_plot.json

This will generate the Kaplan-Meier plot (results_km_plot/KM_TCGA-BRCA_Validation.pdf).

Colorectal cancer (survival regression)

As a real-life example of the regression part of the tool we used colorectal cancer dataset.

Transformed data and config used for pipeline can be found here.

Same with classification, the main objective was to analyse contribution of different feature [pre]selection techniques and accuracy scores using Cox Regression as a main model.
We achieved best results using concordance_index as a feature selector and as a main scoring function.

Again, same with classification, firstly we need to make n, k grid table for the pipeline.
As a result of exhaufs estimate regressors -c confifg_for_estimate_regressors.json --max_estimated_time 3 --max_k 20 we got the estimated_times.csv table with n/k grid and predicted running time for each pair of values.

Same with examples above, we can build regression models or make summary for one specific set of features as follows:

• exhaufs build regressors -c confifg_for_build_regressors.json will produce same files as for classification task.
• exhaufs summary regressors -c confifg_for_summary_regressors.json will produce a detailed report for the specified set of features and also a Kaplan-Meier plots for each dataset type.

Where confifg_for_build_regressors.json and confifg_for_summary_regressors.json can be found in the tutorial/colorectal_cancer directory.

Running ExhauFS

Step 1: data preparation

Before running the tool, you should prepare three csv tables containing actual data, its annotation and n / k grid. Both for classification and survival analysis data table should contain numerical values associated with samples (rows) and features (columns):

Example

	Feature 1	Feature 2
Sample 1	17.17	365.1
Sample 2	56.99	123.9
...
Sample 98	22.22	123.4
Sample 99	23.23	567.8
...
Sample 511	10.82	665.8
Sample 512	11.11	200.2

Annotation table format is different for classification and survival analysis. For classification it should contain binary indicator of sample class (e.g., 1 for recurrent tumor and 0 for non-recurrent), dataset (batch) label and dataset type (Training/Filtration/Validation).
It is important that Class = 1 represents "Positives" and Class = 0 are "negatives", otherwise accuracy scores may be calculated incorrectly.
Note that annotation should be present for each sample listed in the data table in the same order:

Example

	Class	Dataset	Dataset type
Sample 1	1	GSE3494	Training
Sample 2	0	GSE3494	Training
...
Sample 98	0	GSE12093	Filtration
Sample 99	0	GSE12093	Filtration
...
Sample 511	1	GSE1456	Validation
Sample 512	1	GSE1456	Validation

For survival analysis, annotation table should contain binary event indicator and time to event:

Example

	Event	Time to event	Dataset	Dataset type
Sample 1	1	100.1	GSE3494	Training
Sample 2	0	500.2	GSE3494	Training
...
Sample 98	0	623.9	GSE12093	Filtration
Sample 99	0	717.1	GSE12093	Filtration
...
Sample 511	1	40.5	GSE1456	Validation
Sample 512	1	66.7	GSE1456	Validation

Table with n / k grid for exhaustive feature selection:
n is a number of selected features, k is a length of each features subset.

If you are not sure what values for n k to use, see Step 3: defining a n, k grid

Example

n	k
100	1
100	2
...	...
20	5
20	10
20	15

Step 2: creating configuration file

Configuration file is a json file containing all customizable parameters for the model (classification and survival analysis)

Available parameters

🔴!NOTE! - All paths to files / directories can be either relative to the configuration file directory or absolute paths

• data_path Path to csv table of the data.

• annotation_path Path to csv table of the data annotation.

• n_k_path Path to a n/k grid file.

• output_dir Path to directory for output files. If it doesn't exist, it will be created.

• feature_pre_selector
  Name of feature pre-selection function from feature pre-selectors section.

• feature_pre_selector_kwargs
  Object/Dictionary of keyword arguments for feature pre-selector function.

• feature_selector
  Name of feature selection function from feature selectors section.

• feature_selector_kwargs
  Object/Dictionary of keyword arguments for feature selector function. Boolean use_filtration indicates whether to use Filtration dataset besides Training dataset for the selector function.

• preprocessor Name of class for data preprocessing from sklearn.preprocessing.

• preprocessor_kwargs Object/Dictionary of keyword arguments for preprocessor class initialization.
  If you are using sklearn model, use kwargs parameters from the documentation of the model.

• model
  Name of class for classification / survival analysis from Classifiers / Regressors section.

• model_kwargs Object/Dictionary of keyword arguments for model initialization.
  If you are using sklearn model, use kwargs parameters from the documentation of the model.

• model_CV_ranges Object/Dictionary defining model parameters which should be cross-validated. Keys are parameter names, values are lists for grid search.

• model_CV_folds Number of folds for K-Folds cross-validation.

• scoring_functions List with names for scoring functions (from Accuracy scores section) which will be calculated for each model. If you need to pass parameters to the function (e.g. year in dynamic auc score), you can use object {"name": function name, "kwargs": parameters object}.

• main_scoring_function Key from scoring_functions dict defining the "main" scoring function which will be optimized during cross-validation and will be used for model filtering.

• main_scoring_threshold A number defining threshold for model filtering: models with score below this threshold on training/filtration sets will not be further evaluated.

• n_processes Number of processes / threads to run on.

• random_state Random seed (set to an arbitrary integer for reproducibility).

• verbose If true, print running time for each pair of n, k.

Step 3: defining a n, k grid

To estimate running time of the exhaustive pipeline and define adequate n / k values you can run:

exhaufs estimate regressors|classifiers -c <config_file> --max_k <max_k> --max_estimated_time <max_estimated_time>

where

• config_file is the path to json configuration file.
• max_k is the maximum length of each features subset.
• max_estimated_time is the time constraint (in hours) for a pipeline running time on one pair of (n, k).

Above script calculates maximum possible values n / k for each k=1...max_k such that pipeline running time for each pair (n, k) is less then max_estimated_time

Step 4: running the exhaustive pipeline

When input data, configuration file and n / k grid are ready,
the exhaustive pipeline can be executed as follows -

• Classifiers:

exhaufs build classifiers -c <config_file>

• Regressors:

exhaufs build regressors -c <config_file>

This will generate multiple files in the specified output folder:

• models.csv: this file contains all models (classifiers or regressors) which passed the filtration together with their quality metrics.
• summary_n_k.csv: for each pair of n, k three numbers are given: number of models which passed the filtration, number of models which showed reliable performance (i.e., passed quality thresholds) on the validation set and their ratio (in %). Low percentage of validation-reliable models together with high number of filtration-reliable models is usually associated with overfitting.
• summary_features.csv: for each pair (n, k), for each feature, percentage of models carrying this feature is listed (only models which passed the filtration are considered).

Step 5: generating report for a single model

To get detailed report on the specific model (== specific set of features):

• Create configuration file (use ./examples/make_(classifier | regressor)_summary/config.json as a template) and set following key parameters:
  • data_path - path to dataset used for search of classifiers or regressors
  • annotation_path - path to annotation file
  • output_dir - path to output directory for detailed report
  • features_subset - set of features belonging to the classifier or regressor of interest;
  • saving_format - either "tiff" or "pdf": format of the saved plots documents;
• • For classifier run exhaufs summary classifiers -c <config_file>
  • For regressor run exhaufs summary regressors -c <config_file>
• Check the detailed report in the output_dir

If you also have time-to-event data for classification problem, you can make Kaplan-Meier plots based on the classifier predictions.
To do so you can run exhaufs km_plot -c <config_file> and check the output_dir directory.
You can also specify KM_x_label and KM_y_label in the config to change plot axis names.

Functions and classes

Feature pre-selectors

• from_file

  Pre-select features from a given file

  name: from_file
  kwargs:

  {
    "sep": " "
  }
  

• f_test

  Pre-select features without difference between different datasets and types

  name: f_test

Feature selectors

• from_file

  Select first n features from a given file

  name: from_file
  kwargs:

  {
    "sep": " "
  }
  

• t_test

  Select n features with the lowest p-values according to t-test

  name: t_test
  kwargs:

  {
    "use_filtration": false // whether to use filtration dataset with training dataset
  }
  

• spearman_correlation

  Select n features with the highest correlation with target label

  name: spearman_correlation
  kwargs:

  {
    "use_filtration": false // whether to use filtration dataset with training dataset
  }
  

• median

  Select n features with the highest median value
  name: median
  kwargs:

  {
    "use_filtration": false // whether to use filtration dataset with training dataset
  }
  

Classification specific selectors:

• l1_logistic_regression

  Select n features with the highest concordance index on one-factor Cox regression.

  name: l1_logistic_regression
  kwargs:

  {
    "C_low": 0, // minumum inverse l1 penalizer value
    "C_high": 1000000, // maximum inverse l1 penalizer value
    "max_iter": 1000,  // maximum number of iteration until non-convergance error
    "use_filtration": false // whether to use filtration dataset with training dataset
  }
  

Regression specific selectors:

• cox_concordance

  Select n features with the highest concordance index on one-factor Cox regression.

  name: cox_concordance
  kwargs:

  {
    "use_filtration": false // whether to use filtration dataset with training dataset
  }
  

• cox_dynamic_auc

  Select n features with the highest time-dependent auc on one-factor Cox regression.

  name: cox_dynamic_auc
  kwargs:

  {
    "year": 3, // time at which to calculate auc
    "use_filtration": false // whether to use filtration dataset with training dataset
  }
  

• cox_hazard_ratio

  Select n features with the highest hazard ratio on one-factor Cox regression.

  name: cox_hazard_ratio kwargs:

  {
    "use_filtration": false // whether to use filtration dataset with training dataset
  }
  

• cox_likelihood

  Select n features with the highest log-likelihood on one-factor Cox regression.

  name: cox_likelihood
  kwargs:

  {
    "use_filtration": false // whether to use filtration dataset with training dataset
  }
  

• l1_cox

  Select n features with sparse L1-penalized Cox model.

  name: l1_cox
  kwargs:

  {
    "p_low": 0, // minumum l1 penalizer value
    "p_high": 1000000, // maximum l1 penalizer value
    "max_iter": 1000,  // maximum number of iteration until non-convergance error
    "use_filtration": false // whether to use filtration dataset with training dataset
  }
  

Classifiers

• SVC
• KNeighborsClassifier
• RandomForestClassifier
• XGBClassifier

As a model_kwargs value - use parameters from the documentation of chosen model.

Accuracy scores

• TPR
• FPR
• TNR
• min_TPR_TNR

Regressors

• CoxRegression

Accuracy scores

• concordance_index
• dynamic_auc
• hazard_ratio
• logrank