The promise of multi-omics approaches to discover biological alterations with clinical relevance in Alzheimer's disease

Beyond the core features of Alzheimer's disease (AD) pathology, i.e. amyloid pathology, tau-related neurodegeneration and microglia response, multiple other molecular alterations and pathway dysregulations have been observed in AD. Their inter-individual variations, complex interactions and relevance for clinical manifestation and disease progression remain poorly understood, however. Heterogeneity at both pathophysiological and clinical levels complicates diagnosis, prognosis, treatment and drug design and testing. High-throughput "omics" comprise unbiased and untargeted data-driven methods which allow the exploration of a wide spectrum of disease-related changes at different endophenotype levels without focussing a priori on specific molecular pathways or molecules. Crucially, new methodological and statistical advances now allow for the integrative analysis of data resulting from multiple and different omics methods. These multi-omics approaches offer the unique advantage of providing a more comprehensive characterisation of the AD endophenotype and to capture molecular signatures and interactions spanning various biological levels. These new insights can then help decipher disease mechanisms more deeply. In this review, we describe the different multi-omics tools and approaches currently available and how they have been applied in AD research so far. We discuss how multi-omics can be used to explore molecular alterations related to core features of the AD pathologies and how they interact with comorbid pathological alterations. We further discuss whether the identified pathophysiological changes are relevant for the clinical manifestation of AD, in terms of both cognitive impairment and neuropsychiatric symptoms, and for clinical disease progression over time. Finally, we address the opportunities for multi-omics approaches to help discover novel biomarkers for diagnosis and monitoring of relevant pathophysiological processes, along with personalised intervention strategies in AD

Cancer evolution: Darwin and beyond

Clinical and laboratory studies over recent decades have established branched evolution as a feature of cancer. However, while grounded in somatic selection, several lines of evidence suggest a Darwinian model alone is insufficient to fully explain cancer evolution. First, the role of macroevolutionary events in tumour initiation and progression contradicts Darwin's central thesis of gradualism. Whole-genome doubling, chromosomal chromoplexy and chromothripsis represent examples of single catastrophic events which can drive tumour evolution. Second, neutral evolution can play a role in some tumours, indicating that selection is not always driving evolution. Third, increasing appreciation of the role of the ageing soma has led to recent generalised theories of age-dependent carcinogenesis. Here, we review these concepts and others, which collectively argue for a model of cancer evolution which extends beyond Darwin. We also highlight clinical opportunities which can be grasped through targeting cancer vulnerabilities arising from non-Darwinian patterns of evolution

Functional and Topological Properties in Hepatocellular Carcinoma Transcriptome

Hepatocellular carcinoma (HCC) is a leading cause of global cancer mortality. However, little is known about the precise molecular mechanisms involved in tumor formation and pathogenesis. The primary goal of this study was to elucidate genome-wide molecular networks involved in development of HCC with multiple etiologies by exploring high quality microarray data. We undertook a comparative network analysis across 264 human microarray profiles monitoring transcript changes in healthy liver, liver cirrhosis, and HCC with viral and alcoholic etiologies. Gene co-expression profiling was used to derive a consensus gene relevance network of HCC progression that consisted of 798 genes and 2,012 links. The HCC interactome was further confirmed to be phenotype-specific and non-random. Additionally, we confirmed that co-expressed genes are more likely to share biological function, but not sub-cellular localization. Analysis of individual HCC genes revealed that they are topologically central in a human protein-protein interaction network. We used quantitative RT-PCR in a cohort of normal liver tissue (n = 8), hepatitis C virus (HCV)-induced chronic liver disease (n = 9), and HCC (n = 7) to validate co-expressions of several well-connected genes, namely ASPM, CDKN3, NEK2, RACGAP1, and TOP2A. We show that HCC is a heterogeneous disorder, underpinned by complex cross talk between immune response, cell cycle, and mRNA translation pathways. Our work provides a systems-wide resource for deeper understanding of molecular mechanisms in HCC progression and may be used further to define novel targets for efficient treatment or diagnosis of this disease

Mapping microarray gene expression data into dissimilarity spaces for tumor classification

Microarray gene expression data sets usually contain a large number of genes, but a small number of samples. In this article, we present a two-stage classification model by combining feature selection with the dissimilarity-based representation paradigm. In the preprocessing stage, the ReliefF algorithm is used to generate a subset with a number of topranked genes; in the learning/classification stage, the samples represented by the previously selected genes are mapped into a dissimilarity space, which is then used to construct a classifier capable of separating the classes more easily than a feature-based model. The ultimate aim of this paper is not to find the best subset of genes, but to analyze the performance of the dissimilarity-based models by means of a comprehensive collection of experiments for the classification of microarray gene expression data. To this end, we compare the classification results of an artificial neural network, a support vector machine and the Fisher’s linear discriminant classifier built on the feature (gene) space with those on the dissimilarity space when varying the number of genes selected by ReliefF, using eight different microarray databases. The results show that the dissimilarity-based classifiers systematically outperform the feature-based models. In addition, classification through the proposed representation appears to be more robust (i.e. less sensitive to the number of genes) than that with the conventional feature-based representation

Meta-analysis of host response networks identifies a common core in tuberculosis

Tuberculosis remains a major global health challenge worldwide, causing more than a million deaths annually. To determine newer methods for detecting and combating the disease, it is necessary to characterise global host responses to infection. Several high throughput omics studies have provided a rich resource including a list of several genes differentially regulated in tuberculosis. An integrated analysis of these studies is necessary to identify a unified response to the infection. Such data integration is met with several challenges owing to platform dependency, patient heterogeneity, and variability in the extent of infection, resulting in little overlap among different datasets. Network-based approaches offer newer alternatives to integrate and compare diverse data. In this study, we describe a meta-analysis of host’s whole blood transcriptomic profiles that were integrated into a genome-scale protein–protein interaction network to generate response networks in active tuberculosis, and monitor their behaviour over treatment. We report the emergence of a highly active common core in disease, showing partial reversals upon treatment. The core comprises 380 genes in which STAT1, phospholipid scramblase 1 (PLSCR1), C1QB, OAS1, GBP2 and PSMB9 are prominent hubs. This network captures the interplay between several biological processes including pro-inflammatory responses, apoptosis, complement signalling, cytoskeletal rearrangement, and enhanced cytokine and chemokine signalling. The common core is specific to tuberculosis, and was validated on an independent dataset from an Indian cohort. A network-based approach thus enables the identification of common regulators that characterise the molecular response to infection, providing a platform-independent foundation to leverage maximum insights from available clinical data

Cooperative Profit Random Forests With Application in Ocean Front Recognition.

Random Forests are powerful classification and regression tools that are commonly applied in machine learning and image processing. In the majority of random classification forests algorithms, the Gini index and the information gain ratio are commonly used for node splitting. However, these two kinds of node-split methods may pay less attention to the intrinsic structure of the attribute variables and fail to find attributes with strong discriminate ability as a group yet weak as individuals. In this paper, we propose an innovative method for splitting the tree nodes based on the cooperative game theory, from which some attributes with good discriminate ability as a group can be learned. This new random forests algorithm is called Cooperative Profit Random Forests (CPRF). Experimental comparisons with several other existing random classification forests algorithms are carried out on several real-world data sets, including remote sensing images. The results show that CPRF outperforms other existing Random Forests algorithms in most cases. In particular, CPRF achieves promising results in ocean front recognition

Future perspectives on in-vitro diagnosis of drug allergy by the lymphocyte transformation test

Acknowledgement We thank the European fund for regional development (EFRE), the German Federal State North Rhine-Westphalia (LeitmarktAgentur.NRW), Federal Institute for Drugs and Medical Devices (BfArM), and the Leibniz Institute for Analytical Sciences - ISAS-e.V. for the research project grant. The position of A.F. is financed by the research grant. Funding source The manuscript was written in context with a study related to the improvement of the lymphocyte transformation test which was funded by the European Fund for Regional Development (EFRE) and the German Federal State North Rhine-Westphalia (LeitmarktAgentur.NRW) (funding number: EFRE-0801755) and from own resources of the Federal Institute for Drugs and Medical Devices (BfArM) and the Leibniz Institute for Analytical Sciences - ISAS-e.V., Dortmund, Germany.Peer reviewedPublisher PD

ALEC: Active learning with ensemble of classifiers for clinical diagnosis of coronary artery disease

Invasive angiography is the reference standard for coronary artery disease (CAD) diagnosis but is expensive and associated with certain risks. Machine learning (ML) using clinical and noninvasive imaging parameters can be used for CAD diagnosis to avoid the side effects and cost of angiography. However, ML methods require labeled samples for efficient training. The labeled data scarcity and high labeling costs can be mitigated by active learning. This is achieved through selective query of challenging samples for labeling. To the best of our knowledge, active learning has not been used for CAD diagnosis yet. An Active Learning with Ensemble of Classifiers (ALEC) method is proposed for CAD diagnosis, consisting of four classifiers. Three of these classifiers determine whether a patient’s three main coronary arteries are stenotic or not. The fourth classifier predicts whether the patient has CAD or not. ALEC is first trained using labeled samples. For each unlabeled sample, if the outputs of the classifiers are consistent, the sample along with its predicted label is added to the pool of labeled samples. Inconsistent samples are manually labeled by medical experts before being added to the pool. The training is performed once more using the samples labeled so far. The interleaved phases of labeling and training are repeated until all samples are labeled. Compared with 19 other active learning algorithms, ALEC combined with a support vector machine classifier attained superior performance with 97.01% accuracy. Our method is justified mathematically as well. We also comprehensively analyze the CAD dataset used in this paper. As part of dataset analysis, features pairwise correlation is computed. The top 15 features contributing to CAD and stenosis of the three main coronary arteries are determined. The relationship between stenosis of the main arteries is presented using conditional probabilities. The effect of considering the number of stenotic arteries on sample discrimination is investigated. The discrimination power over dataset samples is visualized, assuming each of the three main coronary arteries as a sample label and considering the two remaining arteries as sample features

HMGB1 Protein Interactions in Prostate and Ovary Cancer Models Reveal Links to RNA Processing and Ribosome Biogenesis through NuRD, THOC and Septin Complexes

[Abstract] This study reports the HMGB1 interactomes in prostate and ovary cancer cells lines. Affinity purification coupled to mass spectrometry confirmed that the HMGB1 nuclear interactome is involved in HMGB1 known functions such as maintenance of chromatin stability and regulation of transcription, and also in not as yet reported processes such as mRNA and rRNA processing. We have identified an interaction between HMGB1 and the NuRD complex and validated this by yeast-two-hybrid, confirming that the RBBP7 subunit directly interacts with HMGB1. In addition, we describe for the first time an interaction between two HMGB1 interacting complexes, the septin and THOC complexes, as well as an interaction of these two complexes with Rab11. Analysis of Pan-Cancer Atlas public data indicated that several genes encoding HMGB1-interacting proteins identified in this study are dysregulated in tumours from patients diagnosed with ovary and prostate carcinomas. In PC-3 cells, silencing of HMGB1 leads to downregulation of the expression of key regulators of ribosome biogenesis and RNA processing, namely BOP1, RSS1, UBF1, KRR1 and LYAR. Upregulation of these genes in prostate adenocarcinomas is correlated with worse prognosis, reinforcing their functional significance in cancer progression.This research was funded by the Wellcome Trust (grant no. 206194/Z/17/Z) and by Plan Estatal I+D+i, Instituto Carlos III (ISCIII, Spain) (grants no. PI14/01031 and PI18/01417) cofunded by the Fondo Europeo de Desarrollo Regional-FEDER (The European Regional Development Fund-ERDF) “A way of Making Europe”, and by Xunta de Galicia (Consolidación Grupos Referencia Competitiva grant no. ED431C 2020-08)Reino Unido. Wellcome Trust; 206194/Z/17/ZXunta de Galicia; ED431C 2020-0