Deep learning features encode interpretable morphologies within histological images.

Convolutional neural networks (CNNs) are revolutionizing digital pathology by enabling machine learning-based classification of a variety of phenotypes from hematoxylin and eosin (H&E) whole slide images (WSIs), but the interpretation of CNNs remains difficult. Most studies have considered interpretability in a post hoc fashion, e.g. by presenting example regions with strongly predicted class labels. However, such an approach does not explain the biological features that contribute to correct predictions. To address this problem, here we investigate the interpretability of H&E-derived CNN features (the feature weights in the final layer of a transfer-learning-based architecture). While many studies have incorporated CNN features into predictive models, there has been little empirical study of their properties. We show such features can be construed as abstract morphological genes ( mones ) with strong independent associations to biological phenotypes. Many mones are specific to individual cancer types, while others are found in multiple cancers especially from related tissue types. We also observe that mone-mone correlations are strong and robustly preserved across related cancers. Importantly, linear mone-based classifiers can very accurately separate 38 distinct classes (19 tumor types and their adjacent normals, AUC = [Formula: see text] for each class prediction), and linear classifiers are also highly effective for universal tumor detection (AUC = [Formula: see text]). This linearity provides evidence that individual mones or correlated mone clusters may be associated with interpretable histopathological features or other patient characteristics. In particular, the statistical similarity of mones to gene expression values allows integrative mone analysis via expression-based bioinformatics approaches. We observe strong correlations between individual mones and individual gene expression values, notably mones associated with collagen gene expression in ovarian cancer. Mone-expression comparisons also indicate that immunoglobulin expression can be identified using mones in colon adenocarcinoma and that immune activity can be identified across multiple cancer types, and we verify these findings by expert histopathological review. Our work demonstrates that mones provide a morphological H&E decomposition that can be effectively associated with diverse phenotypes, analogous to the interpretability of transcription via gene expression values. Our work also demonstrates mones can be interpreted without using a classifier as a proxy

Machine Learning for Multiclass Classification and Prediction of Alzheimer\u27s Disease

Alzheimer\u27s disease (AD) is an irreversible neurodegenerative disorder and a common form of dementia. This research aims to develop machine learning algorithms that diagnose and predict the progression of AD from multimodal heterogonous biomarkers with a focus placed on the early diagnosis. To meet this goal, several machine learning-based methods with their unique characteristics for feature extraction and automated classification, prediction, and visualization have been developed to discern subtle progression trends and predict the trajectory of disease progression. The methodology envisioned aims to enhance both the multiclass classification accuracy and prediction outcomes by effectively modeling the interplay between the multimodal biomarkers, handle the missing data challenge, and adequately extract all the relevant features that will be fed into the machine learning framework, all in order to understand the subtle changes that happen in the different stages of the disease. This research will also investigate the notion of multitasking to discover how the two processes of multiclass classification and prediction relate to one another in terms of the features they share and whether they could learn from one another for optimizing multiclass classification and prediction accuracy. This research work also delves into predicting cognitive scores of specific tests over time, using multimodal longitudinal data. The intent is to augment our prospects for analyzing the interplay between the different multimodal features used in the input space to the predicted cognitive scores. Moreover, the power of modality fusion, kernelization, and tensorization have also been investigated to efficiently extract important features hidden in the lower-dimensional feature space without being distracted by those deemed as irrelevant. With the adage that a picture is worth a thousand words, this dissertation introduces a unique color-coded visualization system with a fully integrated machine learning model for the enhanced diagnosis and prognosis of Alzheimer\u27s disease. The incentive here is to show that through visualization, the challenges imposed by both the variability and interrelatedness of the multimodal features could be overcome. Ultimately, this form of visualization via machine learning informs on the challenges faced with multiclass classification and adds insight into the decision-making process for a diagnosis and prognosis

Machine Learning and Integrative Analysis of Biomedical Big Data.

Recent developments in high-throughput technologies have accelerated the accumulation of massive amounts of omics data from multiple sources: genome, epigenome, transcriptome, proteome, metabolome, etc. Traditionally, data from each source (e.g., genome) is analyzed in isolation using statistical and machine learning (ML) methods. Integrative analysis of multi-omics and clinical data is key to new biomedical discoveries and advancements in precision medicine. However, data integration poses new computational challenges as well as exacerbates the ones associated with single-omics studies. Specialized computational approaches are required to effectively and efficiently perform integrative analysis of biomedical data acquired from diverse modalities. In this review, we discuss state-of-the-art ML-based approaches for tackling five specific computational challenges associated with integrative analysis: curse of dimensionality, data heterogeneity, missing data, class imbalance and scalability issues

A novel framework for parsimonious multivariate analysis

This paper proposes a framework in which a multivariate analysis method (MVA) guides a selection of input variables that leads to a sparse feature extraction. This framework, called parsimonious MVA, is specially suited for high dimensional data such as gene arrays, digital pictures, etc. The feature selection relies on the analysis of consistency in the behaviour of the input variables through the elements of an ensemble of MVA projection matrices. The ensemble is constructed following a bootstrap that builds on an efficient and generalized MVA formulation that covers PCA, CCA and OPLS. Moreover, it allows the estimation of the relative relevance of each selected input variable. Experimental results point out that the features extracted by the parsimonious MVA have excellent discrimination power, comparing favorably with state-of-the-art methods, and are potentially useful to build interpretable features. Besides, the parsimonious feature extractor is shown to be robust against to parameter selection, as we all computationally efficient.This work has been partly funded by the Spanish MINECO grant TEC2014-52289R and TEC2013-48439-C4-1-R. The authors want to thank the action editor and the reviewers for their valuable feedback

Leukemia multiclass assessment and classification from Microarray and RNA-seq technologies integration at gene expression level

In more recent years, a significant increase in the number of available biological experiments has taken place due to the widespread use of massive sequencing data. Furthermore, the continuous developments in the machine learning and in the high performance computing areas, are allowing a faster and more efficient analysis and processing of this type of data. However, biological information about a certain disease is normally widespread due to the use of different sequencing technologies and different manufacturers, in different experiments along the years around the world. Thus, nowadays it is of paramount importance to attain a correct integration of biologically-related data in order to achieve genuine benefits from them. For this purpose, this work presents an integration of multiple Microarray and RNA-seq platforms, which has led to the design of a multiclass study by collecting samples from the main four types of leukemia, quantified at gene expression. Subsequently, in order to find a set of differentially expressed genes with the highest discernment capability among different types of leukemia, an innovative parameter referred to as coverage is presented here. This parameter allows assessing the number of different pathologies that a certain gen is able to discern. It has been evaluated together with other widely known parameters under assessment of an ANOVA statistical test which corroborated its filtering power when the identified genes are subjected to a machine learning process at multiclass level. The optimal tuning of gene extraction evaluated parameters by means of this statistical test led to the selection of 42 highly relevant expressed genes. By the use of minimum- Redundancy Maximum-Relevance (mRMR) feature selection algorithm, these genes were reordered and assessed under the operation of four different classification techniques. Outstanding results were achieved by taking exclusively the first ten genes of the ranking into consideration. Finally, specific literature was consulted on this last subset of genes, revealing the occurrence of practically all of them with biological processes related to leukemia. At sight of these results, this study underlines the relevance of considering a new parameter which facilitates the identification of highly valid expressed genes for simultaneously discerning multiple types of leukemia.This work was supported by Project TIN2015-71873-R (Spanish Ministry of Economy and Competitiveness -MINECO- and the European Regional Development Fund -ERDF) and Junta de Andalucı´a (P12–TIC–2082)

Artificial intelligence used in genome analysis studies

Next Generation Sequencing (NGS) or deep sequencing technology enables parallel reading of multiple individual DNA fragments, thereby enabling the identification of millions of base pairs in several hours. Recent research has clearly shown that machine learning technologies can efficiently analyse large sets of genomic data and help to identify novel gene functions and regulation regions. A deep artificial neural network consists of a group of artificial neurons that mimic the properties of living neurons. These mathematical models, termed Artificial Neural Networks (ANN), can be used to solve artificial intelligence engineering problems in several different technological fields (e.g., biology, genomics, proteomics, and metabolomics). In practical terms, neural networks are non-linear statistical structures that are organized as modelling tools and are used to simulate complex genomic relationships between inputs and outputs. To date, Convolutional Neural Networks (CNNs) and Recurrent Neural Networks (RNN) have been demonstrated to be the best tools for improving performance in problem solving tasks within the genomic field

Bioinformatics applied to human genomics and proteomics: development of algorithms and methods for the discovery of molecular signatures derived from omic data and for the construction of co-expression and interaction networks

[EN] The present PhD dissertation develops and applies Bioinformatic methods and tools to address key current problems in the analysis of human omic data. This PhD has been organised by main objectives into four different chapters focused on: (i) development of an algorithm for the analysis of changes and heterogeneity in large-scale omic data; (ii) development of a method for non-parametric feature selection; (iii) integration and analysis of human protein-protein interaction networks and (iv) integration and analysis of human co-expression networks derived from tissue expression data and evolutionary profiles of proteins. In the first chapter, we developed and tested a new robust algorithm in R, called DECO, for the discovery of subgroups of features and samples within large-scale omic datasets, exploring all feature differences possible heterogeneity, through the integration of both data dispersion and predictor-response information in a new statistic parameter called h (heterogeneity score). In the second chapter, we present a simple non-parametric statistic to measure the cohesiveness of categorical variables along any quantitative variable, applicable to feature selection in all types of big data sets. In the third chapter, we describe an analysis of the human interactome integrating two global datasets from high-quality proteomics technologies: HuRI (a human protein-protein interaction network generated by a systematic experimental screening based on Yeast-Two-Hybrid technology) and Cell-Atlas (a comprehensive map of subcellular localization of human proteins generated by antibody imaging). This analysis aims to create a framework for the subcellular localization characterization supported by the human protein-protein interactome. In the fourth chapter, we developed a full integration of three high-quality proteome-wide resources (Human Protein Atlas, OMA and TimeTree) to generate a robust human co-expression network across tissues assigning each human protein along the evolutionary timeline. In this way, we investigate how old in evolution and how correlated are the different human proteins, and we place all them in a common interaction network. As main general comment, all the work presented in this PhD uses and develops a wide variety of bioinformatic and statistical tools for the analysis, integration and enlighten of molecular signatures and biological networks using human omic data. Most of this data corresponds to sample cohorts generated in recent biomedical studies on specific human diseases

Gene masking - a technique to improve accuracy for cancer classification with high dimensionality in microarray data

Background: High dimensional feature space generally degrades classification in several applications. In this paper, we propose a strategy called gene masking, in which non-contributing dimensions are heuristically removed from the data to improve classification accuracy. Methods: Gene masking is implemented via a binary encoded genetic algorithm that can be integrated seamlessly with classifiers during the training phase of classification to perform feature selection. It can also be used to discriminate between features that contribute most to the classification, thereby, allowing researchers to isolate features that may have special significance. Results: This technique was applied on publicly available datasets whereby it substantially reduced the number of features used for classification while maintaining high accuracies. Conclusion: The proposed technique can be extremely useful in feature selection as it heuristically removes non-contributing features to improve the performance of classifiers