MLFLHMDA: predicting human microbe-disease association based on multi-view latent feature learning

IntroductionA growing body of research indicates that microorganisms play a crucial role in human health. Imbalances in microbial communities are closely linked to human diseases, and identifying potential relationships between microbes and diseases can help elucidate the pathogenesis of diseases. However, traditional methods based on biological or clinical experiments are costly, so the use of computational models to predict potential microbe-disease associations is of great importance.MethodsIn this paper, we present a novel computational model called MLFLHMDA, which is based on a Multi-View Latent Feature Learning approach to predict Human potential Microbe-Disease Associations. Specifically, we compute Gaussian interaction profile kernel similarity between diseases and microbes based on the known microbe-disease associations from the Human Microbe-Disease Association Database and perform a preprocessing step on the resulting microbe-disease association matrix, namely, weighting K nearest known neighbors (WKNKN) to reduce the sparsity of the microbe-disease association matrix. To obtain unobserved associations in the microbe and disease views, we extract different latent features based on the geometrical structure of microbes and diseases, and project multi-modal latent features into a common subspace. Next, we introduce graph regularization to preserve the local manifold structure of Gaussian interaction profile kernel similarity and add Lp,q-norms to the projection matrix to ensure the interpretability and sparsity of the model.ResultsThe AUC values for global leave-one-out cross-validation and 5-fold cross validation implemented by MLFLHMDA are 0.9165 and 0.8942+/−0.0041, respectively, which perform better than other existing methods. In addition, case studies of different diseases have demonstrated the superiority of the predictive power of MLFLHMDA. The source code of our model and the data are available on https://github.com/LiangzheZhang/MLFLHMDA_master

A bioinformatics potpourri

© 2018 The Author(s). The 16th International Conference on Bioinformatics (InCoB) was held at Tsinghua University, Shenzhen from September 20 to 22, 2017. The annual conference of the Asia-Pacific Bioinformatics Network featured six keynotes, two invited talks, a panel discussion on big data driven bioinformatics and precision medicine, and 66 oral presentations of accepted research articles or posters. Fifty-seven articles comprising a topic assortment of algorithms, biomolecular networks, cancer and disease informatics, drug-target interactions and drug efficacy, gene regulation and expression, imaging, immunoinformatics, metagenomics, next generation sequencing for genomics and transcriptomics, ontologies, post-translational modification, and structural bioinformatics are the subject of this editorial for the InCoB2017 supplement issues in BMC Genomics, BMC Bioinformatics, BMC Systems Biology and BMC Medical Genomics. New Delhi will be the location of InCoB2018, scheduled for September 26-28, 2018

METHODS FOR HIGH-THROUGHPUT COMPARATIVE GENOMICS AND DISTRIBUTED SEQUENCE ANALYSIS

High-throughput sequencing has accelerated applications of genomics throughout the world. The increased production and decentralization of sequencing has also created bottlenecks in computational analysis. In this dissertation, I provide novel computational methods to improve analysis throughput in three areas: whole genome multiple alignment, pan-genome annotation, and bioinformatics workflows. To aid in the study of populations, tools are needed that can quickly compare multiple genome sequences, millions of nucleotides in length. I present a new multiple alignment tool for whole genomes, named Mugsy, that implements a novel method for identifying syntenic regions. Mugsy is computationally efficient, does not require a reference genome, and is robust in identifying a rich complement of genetic variation including duplications, rearrangements, and large-scale gain and loss of sequence in mixtures of draft and completed genome data. Mugsy is evaluated on the alignment of several dozen bacterial chromosomes on a single computer and was the fastest program evaluated for the alignment of assembled human chromosome sequences from four individuals. A distributed version of the algorithm is also described and provides increased processing throughput using multiple CPUs. Numerous individual genomes are sequenced to study diversity, evolution and classify pan-genomes. Pan-genome annotations contain inconsistencies and errors that hinder comparative analysis, even within a single species. I introduce a new tool, Mugsy-Annotator, that identifies orthologs and anomalous gene structure across a pan-genome using whole genome multiple alignments. Identified anomalies include inconsistently located translation initiation sites and disrupted genes due to draft genome sequencing or pseudogenes. An evaluation of pan-genomes indicates that such anomalies are common and alternative annotations suggested by the tool can improve annotation consistency and quality. Finally, I describe the Cloud Virtual Resource, CloVR, a desktop application for automated sequence analysis that improves usability and accessibility of bioinformatics software and cloud computing resources. CloVR is installed on a personal computer as a virtual machine and requires minimal installation, addressing challenges in deploying bioinformatics workflows. CloVR also seamlessly accesses remote cloud computing resources for improved processing throughput. In a case study, I demonstrate the portability and scalability of CloVR and evaluate the costs and resources for microbial sequence analysis

A Bidirectional Label Propagation Based Computational Model for Potential Microbe-Disease Association Prediction

A growing number of clinical observations have indicated that microbes are involved in a variety of important human diseases. It is obvious that in-depth investigation of correlations between microbes and diseases will benefit the prevention, early diagnosis, and prognosis of diseases greatly. Hence, in this paper, based on known microbe-disease associations, a prediction model called NBLPIHMDA was proposed to infer potential microbe-disease associations. Specifically, two kinds of networks including the disease similarity network and the microbe similarity network were first constructed based on the Gaussian interaction profile kernel similarity. The bidirectional label propagation was then applied on these two kinds of networks to predict potential microbe-disease associations. We applied NBLPIHMDA on Human Microbe-Disease Association database (HMDAD), and compared it with 3 other recent published methods including LRLSHMDA, BiRWMP, and KATZHMDA based on the leave-one-out cross validation and 5-fold cross validation, respectively. As a result, the area under the receiver operating characteristic curves (AUCs) achieved by NBLPIHMDA were 0.8777 and 0.8958 ± 0.0027, respectively, outperforming the compared methods. In addition, in case studies of asthma, colorectal carcinoma, and Chronic obstructive pulmonary disease, simulation results illustrated that there are 10, 10, and 8 out of the top 10 predicted microbes having been confirmed by published documentary evidences, which further demonstrated that NBLPIHMDA is promising in predicting novel associations between diseases and microbes as well

Application of Machine Learning in Microbiology

Microorganisms are ubiquitous and closely related to people’s daily lives. Since they were first discovered in the 19th century, researchers have shown great interest in microorganisms. People studied microorganisms through cultivation, but this method is expensive and time consuming. However, the cultivation method cannot keep a pace with the development of high-throughput sequencing technology. To deal with this problem, machine learning (ML) methods have been widely applied to the field of microbiology. Literature reviews have shown that ML can be used in many aspects of microbiology research, especially classification problems, and for exploring the interaction between microorganisms and the surrounding environment. In this study, we summarize the application of ML in microbiology

Gut microbiota functions: metabolism of nutrients and other food components

The diverse microbial community that inhabits the human gut has an extensive metabolic repertoire that is distinct from, but complements the activity of mammalian enzymes in the liver and gut mucosa and includes functions essential for host digestion. As such, the gut microbiota is a key factor in shaping the biochemical profile of the diet and, therefore, its impact on host health and disease. The important role that the gut microbiota appears to play in human metabolism and health has stimulated research into the identification of specific microorganisms involved in different processes, and the elucidation of metabolic pathways, particularly those associated with metabolism of dietary components and some host-generated substances. In the first part of the review, we discuss the main gut microorganisms, particularly bacteria, and microbial pathways associated with the metabolism of dietary carbohydrates (to short chain fatty acids and gases), proteins, plant polyphenols, bile acids, and vitamins. The second part of the review focuses on the methodologies, existing and novel, that can be employed to explore gut microbial pathways of metabolism. These include mathematical models, omics techniques, isolated microbes, and enzyme assays

Unsupervised approaches for time-evolving graph embeddings with application to human microbiome

More and more diseases have been found to be strongly correlated with disturbances in the microbiome constitution, e.g., obesity, diabetes, and even some types of cancer. Advances in high-throughput omics technologies have made it possible to directly analyze the human microbiome and its impact on human health and physiology. Microbial composition is usually observed over long periods of time and the interactions between their members are explored. Numerous studies have used microbiome data to accurately differentiate disease states and understand the differences in microbiome profiles between healthy and ill individuals. However, most of them mainly focus on various statistical approaches, omitting microbe-microbe interactions among a large number of microbiome species that, in principle, drive microbiome dynamics. Constructing and analyzing time-evolving graphs is needed to understand how microbial ecosystems respond to a range of distinct perturbations, such as antibiotic exposure, diseases, or other general dynamic properties. This becomes especially challenging due to dozens of complex interactions among microbes and metastable dynamics. The key to addressing this challenge lies in representing time-evolving graphs constructed from microbiome data as fixed-length, low-dimensional feature vectors that preserve the original dynamics. Therefore, we propose two unsupervised approaches that map the time-evolving graph constructed from microbiome data into a low-dimensional space where the initial dynamic, such as the number of metastable states and their locations, is preserved. The first method relies on the spectral analysis of transfer operators, such as the Perron--Frobenius or Koopman operator, and graph kernels. These components enable us to extract topological information such as complex interactions of species from the time-evolving graph and take into account the dynamic changes in the human microbiome composition. Further, we study how deep learning techniques can contribute to the study of a complex network of microbial species. The method consists of two key components: 1) the Transformer, the state-of-the-art architecture used in the sequential data, that learns both structural patterns of the time-evolving graph and temporal changes of the microbiome system and 2) contrastive learning that allows the model to learn the low-dimensional representation while maintaining metastability in a low-dimensional space. Finally, this thesis will address an important challenge in microbiome data, specifically identifying which species or interactions of species are responsible for or affected by the changes that the microbiome undergoes from one state (healthy) to another state (diseased or antibiotic exposure). Using interpretability techniques of deep learning models, which, at the outset, have been used as methods to prove the trustworthiness of a deep learning model, we can extract structural information of the time-evolving graph pertaining to particular metastable states

Meta-analysis of the gut microbiota in predicting response to cancer immunotherapy in metastatic melanoma

BACKGROUND. Identifying factors conferring responses to therapy in cancer is critical to select the best treatment for patients. For immune checkpoint inhibition (ICI) therapy, mounting evidence suggests that the gut microbiome can determine patient treatment outcomes. However, the extent to which gut microbial features are applicable across different patient cohorts has not been extensively explored. METHODS. We performed a meta-analysis of 4 published shotgun metagenomic studies (Ntot = 130 patients) investigating differential microbiome composition and imputed metabolic function between responders and nonresponders to ICI. RESULTS. Our analysis identified both known microbial features enriched in responders, such as Faecalibacterium as the prevailing taxa, as well as additional features, including overrepresentation of Barnesiella intestinihominis and the components of vitamin B metabolism. A classifier designed to predict responders based on these features identified responders in an independent cohort of 27 patients with the area under the receiver operating characteristic curve of 0.625 (95% CI: 0.348–0.899) and was predictive of prognosis (HR = 0.35, P = 0.081). CONCLUSION. These results suggest the existence of a fecal microbiome signature inherent across responders that may be exploited for diagnostic or therapeutic purposes

Synergies of systems biology and synthetic biology in human microbiome studies

A number of studies have shown that the microbial communities of the human body are integral for the maintenance of human health. Advances in next generation sequencing have enabled rapid and large-scale quantification of the composition of microbial communities in health and disease. Microorganisms mediate diverse host responses including metabolic pathways and immune responses. Using a system biology approach to further understand the underlying alterations of the microbiota in physiological and pathological states, can help reveal potential novel therapeutic and diagnostic interventions within the field of synthetic biology. Tools such as biosensors, memory arrays and engineered bacteria can rewire the microbiome environment. In this article, were view the computational tools used to study microbiome communities and the current limitations of these methods. We evaluate how genome-scale metabolic models can advance our understanding of the microbe-microbe and microbe-host interactions. Moreover, we present how synergies between these system biology approaches and synthetic biology can be harnessed in human microbiome studies to improve future therapeutics and diagnostics and highlight important knowledge gaps for future research in these rapidly evolving fields

Improved Prediction of Bacterial Genotype-Phenotype Associations Using Interpretable Pangenome-Spanning Regressions

Discovery of genetic variants underlying bacterial phenotypes and the prediction of phenotypes such as antibiotic resistance are fundamental tasks in bacterial genomics. Genome-wide association study (GWAS) methods have been applied to study these relations, but the plastic nature of bacterial genomes and the clonal structure of bacterial populations creates challenges. We introduce an alignment-free method which finds sets of loci associated with bacterial phenotypes, quantifies the total effect of genetics on the phenotype, and allows accurate phenotype prediction, all within a single computationally scalable joint modeling framework. Genetic variants covering the entire pangenome are compactly represented by extended DNA sequence words known as unitigs, and model fitting is achieved using elastic net penalization, an extension of standard multiple regression. Using an extensive set of state-of-the-art bacterial population genomic data sets, we demonstrate that our approach performs accurate phenotype prediction, comparable to popular machine learning methods, while retaining both interpretability and computational efficiency. Compared to those of previous approaches, which test each genotype-phenotype association separately for each variant and apply a significance threshold, the variants selected by our joint modeling approach overlap substantially. IMPORTANCE Being able to identify the genetic variants responsible for specific bacterial phenotypes has been the goal of bacterial genetics since its inception and is fundamental to our current level of understanding of bacteria. This identification has been based primarily on painstaking experimentation, but the availability of large data sets of whole genomes with associated phenotype metadata promises to revolutionize this approach, not least for important clinical phenotypes that are not amenable to laboratory analysis. These models of phenotype-genotype association can in the future be used for rapid prediction of clinically important phenotypes such as antibiotic resistance and virulence by rapid-turnaround or point-of-care tests. However, despite much effort being put into adapting genome-wide association study (GWAS) approaches to cope with bacterium-specific problems, such as strong population structure and horizontal gene exchange, current approaches are not yet optimal. We describe a method that advances methodology for both association and generation of portable prediction models.Peer reviewe