The influence of feature selection methods on accuracy, stability and interpretability of molecular signatures

Motivation: Biomarker discovery from high-dimensional data is a crucial problem with enormous applications in biology and medicine. It is also extremely challenging from a statistical viewpoint, but surprisingly few studies have investigated the relative strengths and weaknesses of the plethora of existing feature selection methods. Methods: We compare 32 feature selection methods on 4 public gene expression datasets for breast cancer prognosis, in terms of predictive performance, stability and functional interpretability of the signatures they produce. Results: We observe that the feature selection method has a significant influence on the accuracy, stability and interpretability of signatures. Simple filter methods generally outperform more complex embedded or wrapper methods, and ensemble feature selection has generally no positive effect. Overall a simple Student's t-test seems to provide the best results. Availability: Code and data are publicly available at http://cbio.ensmp.fr/~ahaury/

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

Robust selection of cancer survival signatures from high-throughput genomic data using two-fold subsampling

Identifying relevant signatures for clinical patient outcome is a fundamental task in high-throughput studies. Signatures, composed of features such as mRNAs, miRNAs, SNPs or other molecular variables, are often non-overlapping, even though they have been identified from similar experiments considering samples with the same type of disease. The lack of a consensus is mostly due to the fact that sample sizes are far smaller than the numbers of candidate features to be considered, and therefore signature selection suffers from large variation. We propose a robust signature selection method that enhances the selection stability of penalized regression algorithms for predicting survival risk. Our method is based on an aggregation of multiple, possibly unstable, signatures obtained with the preconditioned lasso algorithm applied to random (internal) subsamples of a given cohort data, where the aggregated signature is shrunken by a simple thresholding strategy. The resulting method, RS-PL, is conceptually simple and easy to apply, relying on parameters automatically tuned by cross validation. Robust signature selection using RS-PL operates within an (external) subsampling framework to estimate the selection probabilities of features in multiple trials of RS-PL. These probabilities are used for identifying reliable features to be included in a signature. Our method was evaluated on microarray data sets from neuroblastoma, lung adenocarcinoma, and breast cancer patients, extracting robust and relevant signatures for predicting survival risk. Signatures obtained by our method achieved high prediction performance and robustness, consistently over the three data sets. Genes with high selection probability in our robust signatures have been reported as cancer-relevant. The ordering of predictor coefficients associated with signatures was well-preserved across multiple trials of RS-PL, demonstrating the capability of our method for identifying a transferable consensus signature. The software is available as an R package rsig at CRAN (http://cran.r-project.org)

Overview of Random Forest Methodology and Practical Guidance with Emphasis on Computational Biology and Bioinformatics

The Random Forest (RF) algorithm by Leo Breiman has become a standard data analysis tool in bioinformatics. It has shown excellent performance in settings where the number of variables is much larger than the number of observations, can cope with complex interaction structures as well as highly correlated variables and returns measures of variable importance. This paper synthesizes ten years of RF development with emphasis on applications to bioinformatics and computational biology. Special attention is given to practical aspects such as the selection of parameters, available RF implementations, and important pitfalls and biases of RF and its variable importance measures (VIMs). The paper surveys recent developments of the methodology relevant to bioinformatics as well as some representative examples of RF applications in this context and possible directions for future research

Integrated Machine Learning and Bioinformatics Approaches for Prediction of Cancer-Driving Gene Mutations

Cancer arises from the accumulation of somatic mutations and genetic alterations in cell division checkpoints and apoptosis, this often leads to abnormal tumor proliferation. Proper classification of cancer-linked driver mutations will considerably help our understanding of the molecular dynamics of cancer. In this study, we compared several cancer-specific predictive models for prediction of driver mutations in cancer-linked genes that were validated on canonical data sets of functionally validated mutations and applied to a raw cancer genomics data. By analyzing pathogenicity prediction and conservation scores, we have shown that evolutionary conservation scores play a pivotal role in the classification of cancer drivers and were the most informative features in the driver mutation classification. Through extensive comparative analysis with structure-functional experiments and multicenter mutational calling data from PanCancer Atlas studies, we have demonstrated the robustness of our models and addressed the validity of computational predictions. We evaluated the performance of our models using the standard diagnostic metrics such as sensitivity, specificity, area under the curve and F-measure. To address the interpretability of cancer-specific classification models and obtain novel insights about molecular signatures of driver mutations, we have complemented machine learning predictions with structure-functional analysis of cancer driver mutations in several key tumor suppressor genes and oncogenes. Through the experiments carried out in this study, we found that evolutionary-based features have the strongest signal in the machine learning classification VII of driver mutations and provide orthogonal information to the ensembled-based scores that are prominent in the ranking of feature importance

Heuristic ensembles of filters for accurate and reliable feature selection

Feature selection has become increasingly important in data mining in recent years. However, the accuracy and stability of feature selection methods vary considerably when used individually, and yet no rule exists to indicate which one should be used for a particular dataset. Thus, an ensemble method that combines the outputs of several individual feature selection methods appears to be a promising approach to address the issue and hence is investigated in this research. This research aims to develop an effective ensemble that can improve the accuracy and stability of the feature selection. We proposed a novel heuristic ensemble of filters (HEF). It combines two types of filters: subset filters and ranking filters with a heuristic consensus algorithm in order to utilise the strength of each type. The ensemble is tested on ten benchmark datasets and its performance is evaluated by two stability measures and three classifiers. The experimental results demonstrate that HEF improves the stability and accuracy of the selected features and in most cases outperforms the other ensemble algorithms, individual filters and the full feature set. The research on the HEF algorithm is extended in several dimensions; including more filter members, three novel schemes of mean rank aggregation with partial lists, and three novel schemes for a weighted heuristic ensemble of filters. However, the experimental results demonstrate that adding weight to filters in HEF does not achieve the expected improvement in accuracy, but increases time and space complexity, and clearly decreases stability. Therefore, the core ensemble algorithm (HEF) is demonstrated to be not just simpler but also more reliable and consistent than the later more complicated and weighted ensembles. In addition, we investigated how to use data in feature selection, using ALL or PART of it. Systematic experiments with thirty five synthetic and benchmark real-world datasets were carried out

Classifying distinct data types: textual streams protein sequences and genomic variants

Artificial Intelligence (AI) is an interdisciplinary field combining different research areas with the end goal to automate processes in the everyday life and industry. The fundamental components of AI models are an “intelligent” model and a functional component defined by the end-application. That is, an intelligent model can be a statistical model that can recognize patterns in data instances to distinguish differences in between these instances. For example, if the AI is applied in car manufacturing, based on an image of a part of a car, the model can categorize if the car part is in the front, middle or rear compartment of the car, as a human brain would do. For the same example application, the statistical model informs a mechanical arm, the functional component, for the current car compartment and the arm in turn assembles this compartment, of the car, based on predefined instructions, likely as a human hand would follow human brain neural signals. A crucial step of AI applications is the classification of input instances by the intelligent model. The classification step in the intelligent model pipeline allows the subsequent steps to act in similar fashion for instances belonging to the same category. We define as classification the module of the intelligent model, which categorizes the input instances based on predefined human-expert or data-driven produced patterns of the instances. Irrespectively of the method to find patterns in data, classification is composed of four distinct steps: (i) input representation, (ii) model building (iii) model prediction and (iv) model assessment. Based on these classification steps, we argue that applying classification on distinct data types holds different challenges. In this thesis, I focus on challenges for three distinct classification scenarios: (i) Textual Streams: how to advance the model building step, commonly used for static distribution of data, to classify textual posts with transient data distribution? (ii) Protein Prediction: which biologically meaningful information can be used in the input representation step to overcome the limited training data challenge? (iii) Human Variant Pathogenicity Prediction: how to develop a classification system for functional impact of human variants, by providing standardized and well accepted evidence for the classification outcome and thus enabling the model assessment step? To answer these research questions, I present my contributions in classifying these different types of data: temporalMNB: I adapt the sequential prediction with expert advice paradigm to optimally aggregate complementary distributions to enhance a Naive Bayes model to adapt on drifting distribution of the characteristics of the textual posts. dom2vec: our proposal to learn embedding vectors for the protein domains using self-supervision. Based on the high performance achieved by the dom2vec embeddings in quantitative intrinsic assessment on the captured biological information, I provide example evidence for an analogy between the local linguistic features in natural languages and the domain structure and function information in domain architectures. Last, I describe GenOtoScope bioinformatics software tool to automate standardized evidence-based criteria for pathogenicity impact of variants associated with hearing loss. Finally, to increase the practical use of our last contribution, I develop easy-to-use software interfaces to be used, in research settings, by clinical diagnostics personnel.Künstliche Intelligenz (KI) ist ein interdisziplinäres Gebiet, das verschiedene Forschungsbereiche mit dem Ziel verbindet, Prozesse im Alltag und in der Industrie zu automatisieren. Die grundlegenden Komponenten von KI-Modellen sind ein “intelligentes” Modell und eine durch die Endanwendung definierte funktionale Komponente. Das heißt, ein intelligentes Modell kann ein statistisches Modell sein, das Muster in Dateninstanzen erkennen kann, um Unterschiede zwischen diesen Instanzen zu unterscheiden. Wird die KI beispielsweise in der Automobilherstellung eingesetzt, kann das Modell auf der Grundlage eines Bildes eines Autoteils kategorisieren, ob sich das Autoteil im vorderen, mittleren oder hinteren Bereich des Autos befindet, wie es ein menschliches Gehirn tun würde. Bei der gleichen Beispielanwendung informiert das statistische Modell einen mechanischen Arm, die funktionale Komponente, über den aktuellen Fahrzeugbereich, und der Arm wiederum baut diesen Bereich des Fahrzeugs auf der Grundlage vordefinierter Anweisungen zusammen, so wie eine menschliche Hand den neuronalen Signalen des menschlichen Gehirns folgen würde. Ein entscheidender Schritt bei KI-Anwendungen ist die Klassifizierung von Eingabeinstanzen durch das intelligente Modell. Unabhängig von der Methode zum Auffinden von Mustern in Daten besteht die Klassifizierung aus vier verschiedenen Schritten: (i) Eingabedarstellung, (ii) Modellbildung, (iii) Modellvorhersage und (iv) Modellbewertung. Ausgehend von diesen Klassifizierungsschritten argumentiere ich, dass die Anwendung der Klassifizierung auf verschiedene Datentypen unterschiedliche Herausforderungen mit sich bringt. In dieser Arbeit konzentriere ich uns auf die Herausforderungen für drei verschiedene Klassifizierungsszenarien: (i) Textdatenströme: Wie kann der Schritt der Modellerstellung, der üblicherweise für eine statische Datenverteilung verwendet wird, weiterentwickelt werden, um die Klassifizierung von Textbeiträgen mit einer instationären Datenverteilung zu erlernen? (ii) Proteinvorhersage: Welche biologisch sinnvollen Informationen können im Schritt der Eingabedarstellung verwendet werden, um die Herausforderung der begrenzten Trainingsdaten zu überwinden? (iii) Vorhersage der Pathogenität menschlicher Varianten: Wie kann ein Klassifizierungssystem für die funktionellen Auswirkungen menschlicher Varianten entwickelt werden, indem standardisierte und anerkannte Beweise für das Klassifizierungsergebnis bereitgestellt werden und somit der Schritt der Modellbewertung ermöglicht wird? Um diese Forschungsfragen zu beantworten, stelle ich meine Beiträge zur Klassifizierung dieser verschiedenen Datentypen vor: temporalMNB: Verbesserung des Naive-Bayes-Modells zur Klassifizierung driftender Textströme durch Ensemble-Lernen. dom2vec: Lernen von Einbettungsvektoren für Proteindomänen durch Selbstüberwachung. Auf der Grundlage der berichteten Ergebnisse liefere ich Beispiele für eine Analogie zwischen den lokalen linguistischen Merkmalen in natürlichen Sprachen und den Domänenstruktur- und Funktionsinformationen in Domänenarchitekturen. Schließlich beschreibe ich ein bioinformatisches Softwaretool, GenOtoScope, zur Automatisierung standardisierter evidenzbasierter Kriterien für die orthogenitätsauswirkungen von Varianten, die mit angeborener Schwerhörigkeit in Verbindung stehen

To aggregate or not to aggregate high-dimensional classifiers

<p>Abstract</p> <p>Background</p> <p>High-throughput functional genomics technologies generate large amount of data with hundreds or thousands of measurements per sample. The number of sample is usually much smaller in the order of ten or hundred. This poses statistical challenges and calls for appropriate solutions for the analysis of this kind of data.</p> <p>Results</p> <p>Principal component discriminant analysis (PCDA), an adaptation of classical linear discriminant analysis (LDA) for high-dimensional data, has been selected as an example of a base learner. The multiple versions of PCDA models from repeated double cross-validation were aggregated, and the final classification was performed by majority voting. The performance of this approach was evaluated by simulation, genomics, proteomics and metabolomics data sets.</p> <p>Conclusions</p> <p>The aggregating PCDA learner can improve the prediction performance, provide more stable result, and help to know the variability of the models. The disadvantage and limitations of aggregating were also discussed.</p