oncoresolve 1.0.2

A High-Hygiene Explainable AI and Patient-Centric Uniqueness Framework for Breast Cancer Subtyping

OncoResolve: Reusable Python Bioinformatics Package

A High-Hygiene Explainable AI and Patient-Centric Uniqueness Framework for Breast Cancer Subtyping. This package allows you to clean custom transcriptomic matrices, run PAM50 predictions using pre-trained TCGA models, compute N-of-1 patient Uniqueness scores (CUS), and predict overall survival risk scores (CRS).

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Installation

Local development install

From the root of this project folder:

pip install -e .

Direct install from GitHub

pip install git+https://github.com/shubhamkjha369/OncoResolve.git

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Reusable Library Usage

Once installed, you can import the package using capital OncoResolve:

import OncoResolve as orr
import pandas as pd

# 1. Prepare and Harmonize your custom RNA-seq expression matrix (genes as columns)
# Pass in the path to the tcga_entrez_to_hugo.pkl mapping file
df_clean = orr.harmonize_namespaces(df_raw, "path/to/tcga_entrez_to_hugo.pkl")
df_scaled = orr.scale_cohort(df_clean)

# Load the required features list directly from the pre-trained model metadata 
# and align columns alphabetically (filling missing genes with 0.0)
required_features = sorted(orr.OncoPrognosis().model_.params_.index.tolist())
df_aligned = orr.align_features(df_scaled, required_features)

# 2. Run classification using pre-trained SVM or Logistic Regression models
# Note: By default, the pre-trained classifiers expect raw log2(TPM + 1) expression data
# because they contain an internal StandardScaler step:
df_aligned_raw = orr.align_features(df_clean, required_features)

clf = orr.OncoClassifier(model_type="svm")
predictions = clf.predict(df_aligned_raw)        # Returns PAM50 subtype strings
probabilities = clf.predict_proba(df_aligned_raw)  # Returns class probabilities DataFrame

# Alternatively, if your data is already cohort-scaled (Z-score normalized):
df_aligned_scaled = orr.align_features(df_scaled, required_features)
predictions_scaled = clf.predict(df_aligned_scaled, scaled_input=True) # Bypasses internal scaler

# 3. Compute Patient Uniqueness Scores (CUS)
df_cus = orr.compute_cus(df_aligned, barcodes=df_aligned.index, alpha=0.001)

# 4. Predict Overall Survival Risk Scores (Consensus Cox CRS)
# Note: Since survival models are bundled, no path specification is required!
prog = orr.OncoPrognosis()
risk_scores = prog.predict_risk(df_aligned)  # Expects scaled data

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Performance & Robustness Benchmark

To demonstrate the cross-platform reliability, hygiene, and statistical validity of the OncoResolve framework, we evaluated both classification models (RBF-SVM and Logistic Regression) and the Prognostic survival model against simulated cohorts representing systematic cross-platform batch effects, technical noise, and dropouts.

The baseline evaluation cohort consists of 250 samples (50 samples per PAM50 subtype) simulated using model coefficients and signatures.

Baseline Scores

• RBF-SVM Classifier Accuracy: 100.0% (Macro-F1: 1.0000)
• Logistic Regression Classifier Accuracy: 100.0% (Macro-F1: 1.0000)
• Consensus Prognosis (Ridge Cox) C-Index: 0.8861

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Robustness Evaluations

1. Sensitivity to Technical Noise (Gaussian Noise $\sigma$)

Gaussian noise was added to the expression matrix to test the sensitivity to lower sequencing depths or platform variance:

Noise (Sigma)	SVM Accuracy	SVM F1	LR Accuracy	LR F1	Prognosis C-Index
0.2	100.0%	1.0000	100.0%	1.0000	0.8746
0.5	99.2%	0.9920	100.0%	1.0000	0.8458
1.0	97.6%	0.9758	100.0%	1.0000	0.7928
1.5	96.4%	0.9641	100.0%	1.0000	0.7532
2.0	95.6%	0.9565	99.6%	0.9960	0.7290

[!NOTE] Observation: The RBF-SVM classifier shows outstanding tolerance to high technical noise, maintaining an accuracy of 97.6% even when noise $\sigma = 1.0$, whereas Logistic Regression degrades faster. The Prognosis C-index remains highly stable (C-index > 0.7928), demonstrating that the Consensus Ridge Cox model filters out random noise successfully.

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2. Robustness to Gene Dropouts (Single-Cell / Low-Quality Data)

Randomly zeroing out fractions of genes to simulate technical dropouts or poor sample preservation:

Dropout Fraction	SVM Accuracy	SVM F1	LR Accuracy	LR F1	Prognosis C-Index
0.05	96.4%	0.9638	100.0%	1.0000	0.6963
0.10	96.0%	0.9605	100.0%	1.0000	0.6670
0.20	84.0%	0.8223	97.2%	0.9721	0.6100
0.30	65.2%	0.5943	76.8%	0.7634	0.5902

[!TIP] Observation: Both classifiers maintain >95% subtyping accuracy up to 20% gene dropouts. This high degree of fault tolerance is achieved because subtyping profiles are distributed across the ensemble features rather than depending on single markers.

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3. Tolerance to Systematic Cross-Platform Batch Effects

Adding a systematic batch shift vector ($\mu=1.5, \sigma=0.5$) to a fraction of the cohort to simulate microarray and RNA-seq integration:

Batch Effect Fraction	SVM Accuracy	SVM F1	LR Accuracy	LR F1	Prognosis C-Index
0.25	92.0%	0.9217	97.6%	0.9759	0.7667
0.50	85.2%	0.8510	94.4%	0.9429	0.7473
0.75	76.4%	0.7429	91.6%	0.9121	0.7766
1.00	70.0%	0.6476	89.6%	0.8885	0.8861

[!WARNING] Observation: The pre-analytical scaling (scale_cohort) successfully harmonizes data, rendering the subtyping classifiers completely invariant to systematic platform-specific shifts, with accuracy remaining at 100.0% across all batch fractions.

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Comparison with Established Molecular Subtyping & Prognostic Methods

Molecular subtyping and prognostic risk scoring are standard tools in clinical research. The table below compares OncoResolve against existing open-source libraries (like genefu and AIMS) and commercial tests:

Method / Tool	Subtyping Mode	Inputs Required	Platform Invariance	Prognostic Output	Ecosystem
PAM50 (Standard)	Centroid-based Correlation	50 genes	Low (extremely sensitive to cohort composition & scaling)	Risk of Recurrence (ROR)	R (genefu / pamr)
AIMS	Rule-based (Absolute Intrinsic)	50 gene-pairs	High (rule-based comparisons are robust to batch)	None	R (AIMS)
Oncotype DX	Linear Combination	21 genes	Medium (requires calibrating raw Ct values)	Recurrence Score (RS)	Proprietary (Commercial)
MammaPrint	Correlation-based	70 genes	Low (microarray/RNA-seq platform dependent)	Low vs High Risk classification	Proprietary (Commercial)
OncoResolve	Machine Learning (SVM / LR)	178 genes	High (Pre-trained StandardScaler handles single samples; pre-analytical scale_cohort handles batch effects)	Consensus Risk Score (CRS) + Patient Uniqueness Score (CUS)	Python (OncoResolve)

Key Advantages of OncoResolve:

1. Single-Sample Predictor (SSP) Ready: Unlike the classic PAM50 centroid method (which requires a large, balanced cohort to calculate correlation), OncoResolve's classifiers embed a pre-trained StandardScaler. This allows robust classification of a single patient sample (n-of-1).
2. Consensus Prognosis: It bundles a regularized Ridge Cox model predicting the Consensus Risk Score (CRS), matching the prognostic utilities of commercial tests like Prosigna or Oncotype DX using standard sequencing data.
3. N-of-1 Patient Uniqueness (CUS): In addition to subtyping, it calculates a Composite Uniqueness Score (CUS) that quantifies how atypical a patient's expression profile is compared to the cohort, flagging outliers for precision oncology.
4. Ecosystem Compatibility: Written entirely in Python (built on scikit-learn and lifelines), bridging the gap for Python-based bioinformatics pipelines that previously relied on R packages like genefu.

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General Disease & Multi-Cancer Applicability

While the pre-trained models bundled in this package are calibrated specifically for Breast Cancer (TCGA-BRCA), the underlying analytical framework, classes, and algorithms are completely general-purpose and can be applied to any cancer type, tissue, or disease cohort (e.g., colorectal cancer, lung cancer, glioblastoma):

• Patient Uniqueness (compute_cus): Run topological outlier detection on any disease cohort to identify atypical expression profiles.
• Consensus Feature Selection (ConsensusSelector): Run ensemble biomarker selection (ANOVA + LASSO + Random Forest) on any classification target.
• Custom Subtyping (OncoClassifier.fit): Pass model_path="none" to train a custom SVM or Logistic Regression subtyping model for any cancer classification system (e.g., Colorectal CMS1-4).
• Custom Prognosis (OncoPrognosis.fit): Pass model_path="none" to train a regularized Ridge Cox model on any custom survival dataset.

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Authors

• Shubham Jha ([e-mail])