Discriminating Neoplastic from Nonneoplastic Tissues Using an miRNA-Based Deep Cancer Classifier.

Next-generation sequencing has enabled the collection of large biological data sets, allowing novel molecular-based classification methods to be developed for increased understanding of disease. miRNAs are small regulatory RNA molecules that can be quantified using next-generation sequencing and are excellent classificatory markers. Herein, a deep cancer classifier (DCC) was adapted to differentiate neoplastic from nonneoplastic samples using comprehensive miRNA expression profiles from 1031 human breast and skin tissue samples. The classifier was fine-tuned and evaluated using 750 neoplastic and 281 nonneoplastic breast and skin tissue samples. Performance of the DCC was compared with two machine-learning classifiers: support vector machine and random forests. In addition, performance of feature extraction through the DCC was also compared with a developed feature selection algorithm, cancer specificity. The DCC had the highest performance of area under the receiver operating curve and high performance in both sensitivity and specificity, unlike machine-learning and feature selection models, which often performed well in one metric compared with the other. In particular, deep learning had noticeable advantages with highly heterogeneous data sets. In addition, our cancer specificity algorithm identified candidate biomarkers for differentiating neoplastic and nonneoplastic tissue samples (eg, miR-144 and miR-375 in breast cancer and miR-375 and miR-451 in skin cancer).

Exploring microRNA Regulation of Cancer with Context-Aware Deep Cancer Classifier.

BACKGROUND: MicroRNAs (miRNAs) are small, non-coding RNA that regulate gene expression through post-transcriptional silencing. Differential expression observed in miRNAs, combined with advancements in deep learning (DL), have the potential to improve cancer classification by modelling non-linear miRNA-phenotype associations. We propose a novel miRNA-based deep cancer classifier (DCC) incorporating genomic and hierarchical tissue annotation, capable of accurately predicting the presence of cancer in wide range of human tissues. METHODS: miRNA expression profiles were analyzed for 1746 neoplastic and 3871 normal samples, across 26 types of cancer involving six organ sub-structures and 68 cell types. miRNAs were ranked and filtered using a specificity score representing their information content in relation to neoplasticity, incorporating 3 levels of hierarchical biological annotation. A DL architecture composed of stacked autoencoders (AE) and a multi-layer perceptron (MLP) was trained to predict neoplasticity using 497 abundant and informative miRNAs. Additional DCCs were trained using expression of miRNA cistrons and sequence families, and combined as a diagnostic ensemble. Important miRNAs were identified using backpropagation, and analyzed in Cytoscape using iCTNet and BiNGO. RESULTS: Nested four-fold cross-validation was used to assess the performance of the DL model. The model achieved an accuracy, AUC/ROC, sensitivity, and specificity of 94.73%, 98.6%, 95.1%, and 94.3%, respectively. CONCLUSION: Deep autoencoder networks are a powerful tool for modelling complex miRNA-phenotype associations in cancer. The proposed DCC improves classification accuracy by learning from the biological context of both samples and miRNAs, using anatomical and genomic annotation. Analyzing the deep structure of DCCs with backpropagation can also facilitate biological discovery, by performing gene ontology searches on the most highly significant features.