Extraction and Integration of Genetic Networks from Short-Profile Omic Data Sets.

Mass spectrometry technologies are widely used in the fields of ionomics and metabolomics to simultaneously profile the intracellular concentrations of, e.g., amino acids or elements in genome-wide mutant libraries. These molecular or sub-molecular features are generally non-Gaussian and their covariance reveals patterns of correlations that reflect the system nature of the cell biochemistry and biology. Here, we introduce two similarity measures, the Mahalanobis cosine and the hybrid Mahalanobis cosine, that enforce information from the empirical covariance matrix of omics data from high-throughput screening and that can be used to quantify similarities between the profiled features of different mutants. We evaluate the performance of these similarity measures in the task of inferring and integrating genetic networks from short-profile ionomics/metabolomics data through an analysis of experimental data sets related to the ionome and the metabolome of the model organism S. cerevisiae. The study of the resulting ionome-metabolome Saccharomyces cerevisiae multilayer genetic network, which encodes multiple omic-specific levels of correlations between genes, shows that the proposed measures can provide an alternative description of relations between biological processes when compared to the commonly used Pearson's correlation coefficient and have the potential to guide the construction of novel hypotheses on the function of uncharacterised genes

Multiple-testing correction in metabolome-wide association studies.

BACKGROUND: The search for statistically significant relationships between molecular markers and outcomes is challenging when dealing with high-dimensional, noisy and collinear multivariate omics data, such as metabolomic profiles. Permutation procedures allow for the estimation of adjusted significance levels without assuming independence among metabolomic variables. Nevertheless, the complex non-normal structure of metabolic profiles and outcomes may bias the permutation results leading to overly conservative threshold estimates i.e. lower than those from a Bonferroni or Sidak correction. METHODS: Within a univariate permutation procedure we employ parametric simulation methods based on the multivariate (log-)Normal distribution to obtain adjusted significance levels which are consistent across different outcomes while effectively controlling the type I error rate. Next, we derive an alternative closed-form expression for the estimation of the number of non-redundant metabolic variates based on the spectral decomposition of their correlation matrix. The performance of the method is tested for different model parametrizations and across a wide range of correlation levels of the variates using synthetic and real data sets. RESULTS: Both the permutation-based formulation and the more practical closed form expression are found to give an effective indication of the number of independent metabolic effects exhibited by the system, while guaranteeing that the derived adjusted threshold is stable across outcome measures with diverse properties

The impact of acute nutritional interventions on the plasma proteome

Context: Humans respond profoundly to changes in diet, while nutrition and environment have a great impact on population health. It is therefore important to deeply characterize the human nutritional responses. Objective: Endocrine parameters and the metabolome of human plasma are rapidly responding to acute nutritional interventions such as caloric restriction or a glucose challenge. It is less well understood whether the plasma proteome would be equally dynamic, and whether it could be a source of corresponding biomarkers. Methods: We used high-throughput mass spectrometry to determine changes in the plasma proteome of i) 10 healthy, young, male individuals in response to 2 days of acute caloric restriction followed by refeeding; ii) 200 individuals of the Ely epidemiological study before and after a glucose tolerance test at 4 time points (0, 30, 60, 120 minutes); and iii) 200 random individuals from the Generation Scotland study. We compared the proteomic changes detected with metabolome data and endocrine parameters. Results: Both caloric restriction and the glucose challenge substantially impacted the plasma proteome. Proteins responded across individuals or in an individual-specific manner. We identified nutrient-responsive plasma proteins that correlate with changes in the metabolome, as well as with endocrine parameters. In particular, our study highlights the role of apolipoprotein C1 (APOC1), a small, understudied apolipoprotein that was affected by caloric restriction and dominated the response to glucose consumption and differed in abundance between individuals with and without type 2 diabetes. Conclusion: Our study identifies APOC1 as a dominant nutritional responder in humans and highlights the interdependency of acute nutritional response proteins and the endocrine system

Novel regression models for discrete response

This thesis was submitted for the award of Doctor of Philosophy and was awarded by Brunel University LondonIn a regression context, the aim is to analyse a response variable of interest conditional to a set of covariates. In many applications the response variable is discrete. Examples include the event of surviving a heart attack, the number of hospitalisation days, the number of times that individuals benefit of a health service, and so on. This thesis advances the methodology and the application of regression models with discrete response. First, we present a difference-in-differences approach to model a binary response in a health policy evaluation framework. In particular, generalized linear mixed methods are employed to model multiple dependent outcomes in order to quantify the effect of an adopted pay-for-performance program while accounting for the heterogeneity of the data at the multiple nested levels. The results show how the policy had a positive effect on the hospitals’ quality in terms of those outcomes that can be more influenced by a managerial activity. Next, we focus on regression models for count response variables. In a parametric framework, Poisson regression is the simplest model for count data though it is often found not adequate in real applications, particularly in the presence of excessive zeros and in the case of dispersion, i.e. when the conditional mean is different to the conditional variance. Negative Binomial regression is the standard model for over-dispersed data, but it fails in the presence of under-dispersion. Poisson-Inverse Gaussian regression can be used in the case of over-dispersed data, Generalised-Poisson regression can be employed in the case of under-dispersed data, and Conway-Maxwell Poisson regression can be employed in both cases of over- or under-dispersed data, though the interpretability of these models is ot straightforward and they are often found computationally demanding. While Jittering is the default non-parametric approach for count data, inference has to be made for each individual quantile, separate quantiles may cross and the underlying uniform random sampling can generate instability in the estimation. These features motivate the development of a novel parametric regression model for counts via a Discrete Weibull distribution. This distribution is able to adapt to different types of dispersion relative to Poisson, and it also has the advantage of having a closed form expression for the quantiles. As well as the standard regression model, generalized linear mixed models and generalized additive models are presented via this distribution. Simulated and real data applications with different type of dispersion show a good performance of Discrete Weibull-based regression models compared with existing regression approaches for count data

Extraction and Integration of Genetic Networks from Short-Profile Omic Data Sets

Mass spectrometry technologies are widely used in the fields of ionomics and metabolomics to simultaneously profile the intracellular concentrations of, e.g., amino acids or elements in genome-wide mutant libraries. These molecular or sub-molecular features are generally non-Gaussian and their covariance reveals patterns of correlations that reflect the system nature of the cell biochemistry and biology. Here, we introduce two similarity measures, the Mahalanobis cosine and the hybrid Mahalanobis cosine, that enforce information from the empirical covariance matrix of omics data from high-throughput screening and that can be used to quantify similarities between the profiled features of different mutants. We evaluate the performance of these similarity measures in the task of inferring and integrating genetic networks from short-profile ionomics/metabolomics data through an analysis of experimental data sets related to the ionome and the metabolome of the model organism S. cerevisiae. The study of the resulting ionome−metabolome Saccharomyces cerevisiae multilayer genetic network, which encodes multiple omic-specific levels of correlations between genes, shows that the proposed measures can provide an alternative description of relations between biological processes when compared to the commonly used Pearson’s correlation coefficient and have the potential to guide the construction of novel hypotheses on the function of uncharacterised genes

cpgQA: A Benchmark Dataset for Machine Reading Comprehension Tasks on Clinical Practice Guidelines and a Case Study Using Transfer Learning

Biomedical machine reading comprehension (bio-MRC), a crucial task in natural language processing, is a vital application of a computer-assisted clinical decision support system. It can help clinicians extract critical information effortlessly for clinical decision-making by comprehending and answering questions from biomedical text data. While recent advances in bio-MRC consider text data from resources such as clinical notes and scholarly articles, the clinical practice guidelines (CPGs) are still unexplored in this regard. CPGs are a pivotal component of clinical decision-making at the point of care as they provide recommendations for patient care based on the most up-to-date information available. Although CPGs are inherently terse compared to a multitude of articles, often, clinicians find them lengthy and complicated to use. In this paper, we define a new problem domain – bio-MRC on CPGs – where the ultimate goal is to assist clinicians in efficiently interpreting the clinical practice guidelines using MRC systems. To that end, we develop a manually annotated and subject-matter expert-validated benchmark dataset for the bio-MRC task on CPGs – cpgQA. This dataset aims to evaluate intelligent systems performing MRC tasks on CPGs. Hence, we employ the state-of-the-art MRC models to present a case study illustrating an extensive evaluation of the proposed dataset. We address the problem of lack of training data in this newly defined domain by applying transfer learning. The results show that while the current state-of-the-art models perform well with 78% exact match scores on the dataset, there is still room for improvement, warranting further research on this problem domain. We release the dataset at https://github.com/mmahbub/cpgQA

PhenoMeNal: processing and analysis of metabolomics data in the cloud

BACKGROUND: Metabolomics is the comprehensive study of a multitude of small molecules to gain insight into an organism's metabolism. The research field is dynamic and expanding with applications across biomedical, biotechnological, and many other applied biological domains. Its computationally intensive nature has driven requirements for open data formats, data repositories, and data analysis tools. However, the rapid progress has resulted in a mosaic of independent, and sometimes incompatible, analysis methods that are difficult to connect into a useful and complete data analysis solution. FINDINGS: PhenoMeNal (Phenome and Metabolome aNalysis) is an advanced and complete solution to set up Infrastructure-as-a-Service (IaaS) that brings workflow-oriented, interoperable metabolomics data analysis platforms into the cloud. PhenoMeNal seamlessly integrates a wide array of existing open-source tools that are tested and packaged as Docker containers through the project's continuous integration process and deployed based on a kubernetes orchestration framework. It also provides a number of standardized, automated, and published analysis workflows in the user interfaces Galaxy, Jupyter, Luigi, and Pachyderm. CONCLUSIONS: PhenoMeNal constitutes a keystone solution in cloud e-infrastructures available for metabolomics. PhenoMeNal is a unique and complete solution for setting up cloud e-infrastructures through easy-to-use web interfaces that can be scaled to any custom public and private cloud environment. By harmonizing and automating software installation and configuration and through ready-to-use scientific workflow user interfaces, PhenoMeNal has succeeded in providing scientists with workflow-driven, reproducible, and shareable metabolomics data analysis platforms that are interfaced through standard data formats, representative datasets, versioned, and have been tested for reproducibility and interoperability. The elastic implementation of PhenoMeNal further allows easy adaptation of the infrastructure to other application areas and 'omics research domains