mesa-cfdna 0.2.0

Multimodal Epigenetic Sequencing Analysis (MESA) is a flexible and sensitive method of capturing and integrating multimodal epigenetic information of cfDNA using a single experimental assay.

Multimodal Epigenetic Sequencing Analysis (MESA)

A flexible and sensitive method for capturing and integrating multimodal epigenetic information from cell-free DNA (cfDNA) using a single experimental assay.

Overview

MESA (Multimodal Epigenetic Sequencing Analysis) provides a comprehensive framework for analyzing multimodal epigenetic data from cfDNA. The package features a sklearn-compatible API that seamlessly integrates preprocessing, scaling, feature selection, model training, and cross-validation workflows.

Key Features

• Multimodal Integration: Combine multiple epigenetic data modalities using ensemble stacking
• Advanced Feature Selection: Boruta algorithm combined with univariate selection to keep a balance between computation time and biomarker discovery
• Robust Cross-Validation: Built-in evaluation framework with performance metrics for easy finetuning
• Flexible Pipeline: Customizable preprocessing and classification components
• Missing Value Handling: Intelligent filtering and imputation strategies

Installation

# Install package with pip
pip install mesa-cfdna

Quick Start

from mesa import MESA_modality, MESA, MESA_CV
from sklearn.ensemble import RandomForestClassifier
import pandas as pd

# Load your data
X_train, y_train = load_data()  # Your data loading function

# Single modality analysis
modality_1 = MESA_modality(top_n=50, classifier=RandomForestClassifier(random_state=0), variance_threshold=0, normalization=True)
modality_1.fit(X_train, y_train)
predictions = modality_1.transform_predict_proba(X_test)

modality_2 = MESA_modality(top_n=100, classifier=LogisticRegression(random_state=0), variance_threshold=0, normalization=False, missing=0)
modality_2.fit(X_train, y_train)
predictions = modality_2.transform_predict_proba(X_test)

# Multi-modality ensemble
modalities = [modality_1, modality_2]
mesa = MESA(modalities)
mesa.fit([X1_train, X2_train], y_train)
mesa_predictions = mesa.predict_proba([X1_test, X2_test])

API Reference

MESA_modality

Single modality analysis with comprehensive preprocessing and feature selection pipeline.

Parameters

Parameter	Type	Default	Description
top_n	int	100	Number of features to select using Boruta algorithm
variance_threshold	float	0	Minimum variance threshold for feature filtering
normalization	bool	False	Whether to apply L2 normalization
missing	float	0.1	Maximum proportion of missing values allowed per feature
classifier	estimator	RandomForestClassifier()	Final classifier for predictions
selector	int/estimator	GenericUnivariateSelect()	Univariate feature selector
boruta_estimator	estimator	RandomForestClassifier()	Base estimator for Boruta selection
random_state	int	0	Random seed for reproducibility

Methods

• fit(X, y): Fit the preprocessing pipeline and classifier
• transform(X): Apply preprocessing pipeline only
• predict(X): Predict class labels for preprocessed data
• predict_proba(X): Predict class probabilities for preprocessed data
• transform_predict(X): Apply pipeline and predict in one step
• transform_predict_proba(X): Apply pipeline and predict probabilities
• get_support(step=None): Get indices of selected features
• get_params(deep=True): Get model parameters

MESA

Multi-modality ensemble with stacking architecture for integrating multiple data types.

Parameters

Parameter	Type	Default	Description
modalities	list	Required	List of MESA_modality objects
meta_estimator	estimator	LogisticRegression()	Meta-learner for ensemble combination
random_state	int	0	Random seed for reproducibility
cv	cv generator	RepeatedStratifiedKFold()	Cross-validation strategy for meta-features

Methods

• fit(X_list, y): Fit all modalities and meta-estimator
• predict(X_list_test): Predict class labels using ensemble
• predict_proba(X_list_test): Predict class probabilities using ensemble
• get_support(step=None): Get feature support from all modalities

MESA_CV

Cross-validation wrapper for performance evaluation of MESA models.

Parameters

Parameter	Type	Default	Description
modality	estimator	Required	MESA_modality or MESA object to evaluate
random_state	int	0	Random seed for reproducibility
cv	cv generator	StratifiedKFold(n_splits=5)	Cross-validation strategy

Methods

• fit(X, y): Perform cross-validation on provided data
• get_performance(): Calculate mean ROC AUC score across CV folds

Attributes

• cv_result: List of (y_pred, y_true) tuples from each CV fold
• modality: The fitted modality estimator being evaluated

Usage Examples

Example 1: Single Modality Analysis

import pandas as pd
import numpy as np
from mesa import MESA_modality, MESA_CV
from sklearn.ensemble import RandomForestClassifier
from sklearn.model_selection import StratifiedKFold

# Load single modality data
X = pd.read_csv('methylation_data.csv', index_col=0)
y = pd.read_csv('labels.csv', index_col=0).values.ravel()

# Create and configure modality
modality = MESA_modality(
    top_n=50,
    missing=0.2,
    normalization=True,
    classifier=RandomForestClassifier(n_estimators=100, random_state=42)
)

# Fit the modality
modality.fit(X, y)

# Make predictions on new data
X_test = pd.read_csv('test_data.csv', index_col=0)
predictions = modality.transform_predict_proba(X_test)
print(f"Prediction probabilities shape: {predictions.shape}")

# Get selected features
selected_features = modality.get_support()
print(f"Number of selected features: {len(selected_features)}")

# Cross-validation evaluation
cv_eval = MESA_CV(
    modality=MESA_modality(top_n=50, missing=0.2),
    cv=StratifiedKFold(n_splits=10, shuffle=True, random_state=42)
)
cv_eval.fit(X, y)
auc_score = cv_eval.get_performance()
print(f"Cross-validation AUC: {auc_score:.3f}")

Example 2: Multi-Modality Ensemble

import pandas as pd
from mesa import MESA_modality, MESA, MESA_CV
from sklearn.ensemble import RandomForestClassifier
from sklearn.linear_model import LogisticRegression
from sklearn.svm import SVC

# Load multi-modal data
methylation_data = pd.read_csv('methylation.csv', index_col=0)
histone_data = pd.read_csv('histone_marks.csv', index_col=0)
chromatin_data = pd.read_csv('chromatin_accessibility.csv', index_col=0)
y = pd.read_csv('labels.csv', index_col=0).values.ravel()

# Define modality-specific configurations
modalities = [
    MESA_modality(
        top_n=100,
        missing=0.1,
        classifier=RandomForestClassifier(n_estimators=200, random_state=42),
        normalization=True
    ),
    MESA_modality(
        top_n=80,
        missing=0.15,
        classifier=SVC(probability=True, random_state=42),
        normalization=False
    ),
    MESA_modality(
        top_n=60,
        missing=0.2,
        classifier=LogisticRegression(random_state=42),
        normalization=True
    )
]

# Create MESA ensemble
mesa = MESA(
    modalities=modalities,
    meta_estimator=LogisticRegression(random_state=42),
    random_state=42
)

# Fit the ensemble
X_list = [methylation_data, histone_data, chromatin_data]
mesa.fit(X_list, y)

# Make ensemble predictions
X_test_list = [
    pd.read_csv('methylation_test.csv', index_col=0),
    pd.read_csv('histone_test.csv', index_col=0),
    pd.read_csv('chromatin_test.csv', index_col=0)
]
ensemble_predictions = mesa.predict_proba(X_test_list)
print(f"Ensemble predictions shape: {ensemble_predictions.shape}")

# Get feature support from all modalities
feature_supports = mesa.get_support()
for i, support in enumerate(feature_supports):
    print(f"Modality {i+1}: {len(support)} features selected")

Example 3: Cross-Validation for Multi-Modality

from mesa import MESA, MESA_modality, MESA_CV
from sklearn.model_selection import RepeatedStratifiedKFold

# Define ensemble for CV evaluation
modalities = [
    MESA_modality(top_n=50, missing=0.1),
    MESA_modality(top_n=40, missing=0.15),
    MESA_modality(top_n=60, missing=0.2)
]

mesa_ensemble = MESA(
    modalities=modalities,
    cv=RepeatedStratifiedKFold(n_splits=5, n_repeats=5, random_state=42)
)

# Cross-validation evaluation
cv_eval = MESA_CV(
    modality=mesa_ensemble,
    cv=StratifiedKFold(n_splits=5, shuffle=True, random_state=42)
)

# Perform CV on multi-modal data
X_list = [methylation_data, histone_data, chromatin_data]
cv_eval.fit(X_list, y)

# Get performance metrics
mean_auc = cv_eval.get_performance()
print(f"Multi-modal ensemble CV AUC: {mean_auc:.3f}")

# Access individual fold results
for i, (y_pred, y_true) in enumerate(cv_eval.cv_result):
    fold_auc = roc_auc_score(y_true, y_pred[:, 1])
    print(f"Fold {i+1} AUC: {fold_auc:.3f}")

Example 4: Custom Feature Selection Pipeline

from mesa import MESA_modality
from sklearn.feature_selection import SelectKBest, f_classif
from sklearn.ensemble import GradientBoostingClassifier

# Custom modality with different feature selection
custom_modality = MESA_modality(
    top_n=30,
    variance_threshold=0.01,
    missing=0.05,
    normalization=True,
    selector=SelectKBest(score_func=f_classif, k=1000),
    classifier=GradientBoostingClassifier(n_estimators=100, random_state=42),
    boruta_estimator=GradientBoostingClassifier(n_estimators=50, random_state=42)
)

# Fit and evaluate
custom_modality.fit(X, y)
custom_predictions = custom_modality.transform_predict_proba(X_test)

# Compare with default configuration
default_modality = MESA_modality()
cv_custom = MESA_CV(custom_modality)
cv_default = MESA_CV(default_modality)

cv_custom.fit(X, y)
cv_default.fit(X, y)

print(f"Custom configuration AUC: {cv_custom.get_performance():.3f}")
print(f"Default configuration AUC: {cv_default.get_performance():.3f}")

Example 5: Feature Importance Analysis

# Analyze feature importance across modalities
modality = MESA_modality(top_n=100)
modality.fit(X, y)

# Get feature support at different pipeline steps
missing_support = modality.get_support(step=0)  # After missing value filtering
variance_support = modality.get_support(step=1)  # After variance filtering
univariate_support = modality.get_support(step=2)  # After univariate selection
final_support = modality.get_support()  # Final selected features

print(f"Features after missing value filter: {len(missing_support)}")
print(f"Features after variance filter: {len(variance_support)}")
print(f"Features after univariate selection: {len(univariate_support)}")
print(f"Final selected features: {len(final_support)}")

# Get feature names if using DataFrame
if hasattr(X, 'columns'):
    selected_feature_names = X.columns[final_support]
    print(f"Selected features: {selected_feature_names.tolist()}")

Performance Tips

1. Memory Management: For large datasets, consider reducing top_n and using n_jobs=1 for Boruta
2. Feature Selection: Adjust missing threshold based on data quality
3. Cross-Validation: Use fewer repeats for initial exploration, more for final evaluation
4. Ensemble Size: Start with 2-3 modalities, add more based on performance gains

Citation

If you use MESA in your research, please cite:

Li, Y., Xu, J., Chen, C. et al. Multimodal epigenetic sequencing analysis (MESA) of cell-free DNA for non-invasive colorectal cancer detection. Genome Med 16, 9 (2024). https://doi.org/10.1186/s13073-023-01280-6

Authors

• Chaorong Chen - Lead Developer - [e-mail]
• Wei Li - Principal Investigator - [e-mail]

License

This project is licensed under the MIT License - see the LICENSE file for details.

Contributing

1. Fork the repository
2. Create a feature branch (git checkout -b feature/amazing-feature)
3. Commit your changes (git commit -m 'Add amazing feature')
4. Push to the branch (git push origin feature/amazing-feature)
5. Open a Pull Request

Support

For questions and support:

• Open an issue on GitHub
• Email: [e-mail]
• Documentation: [Link to full documentation]

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Keywords: cfDNA, epigenetics, multimodal analysis, machine learning, feature selection, ensemble learning, stacking, bioinformatics, biomarker discovery, methylation, computational biology, early detection