Eleni Mina

Using a suite of ontologies for preserving workflow-centric research objects

Scientific workflows are a popular mechanism for specifying and automating data-driven in silico experiments. A significant aspect of their value lies in their potential to be reused. Once shared, workflows become useful building blocks that can be combined or modified for developing new experiments. However, previous studies have shown that storing workflow specifications alone is not sufficient to ensure that they can be successfully reused, without being able to understand what the workflows aim to achieve or to re-enact them. To gain an understanding of the workflow, and how it may be used and repurposed for their needs, scientists require access to additional resources such as annotations describing the workflow, datasets used and produced by the workflow, and provenance traces recording workflow executions.In this article, we present a novel approach to the preservation of scientific workflows through the application of research objects-aggregations of data and metadata that enrich the workflow specifications. Our approach is realised as a suite of ontologies that support the creation of workflow-centric research objects. Their design was guided by requirements elicited from previous empirical analyses of workflow decay and repair. The ontologies developed make use of and extend existing well known ontologies, namely the Object Reuse and Exchange (ORE) vocabulary, the Annotation Ontology (AO) and the W3C PROV ontology (PROVO). We illustrate the application of the ontologies for building Workflow Research Objects with a case-study that investigates Huntingtons disease, performed in collaboration with a team from the Leiden University Medial Centre (HG-LUMC). Finally we present a number of tools developed for creating and managing workflow-centric research objects.

Structuring research methods and data with the research object model: genomics workflows as a case study.

BackgroundOne of the main challenges for biomedical research lies in the computer-assisted integrative study of large and increasingly complex combinations of data in order to understand molecular mechanisms. The preservation of the materials and methods of such computational experiments with clear annotations is essential for understanding an experiment, and this is increasingly recognized in the bioinformatics community. Our assumption is that offering means of digital, structured aggregation and annotation of the objects of an experiment will provide necessary meta-data for a scientist to understand and recreate the results of an experiment. To support this we explored a model for the semantic description of a workflow-centric Research Object (RO), where an RO is defined as a resource that aggregates other resources, e.g., datasets, software, spreadsheets, text, etc. We applied this model to a case study where we analysed human metabolite variation by workflows.ResultsWe present the application of the workflow-centric RO model for our bioinformatics case study. Three workflows were produced following recently defined Best Practices for workflow design. By modelling the experiment as an RO, we were able to automatically query the experiment and answer questions such as “which particular data was input to a particular workflow to test a particular hypothesis?”, and “which particular conclusions were drawn from a particular workflow?”.ConclusionsApplying a workflow-centric RO model to aggregate and annotate the resources used in a bioinformatics experiment, allowed us to retrieve the conclusions of the experiment in the context of the driving hypothesis, the executed workflows and their input data. The RO model is an extendable reference model that can be used by other systems as well.AvailabilityThe Research Object is available at http://www.myexperiment.org/packs/428The Wf4Ever Research Object Model is available at http://wf4ever.github.io/ro

Integration of targeted metabolomics and transcriptomics identifies deregulation of phosphatidylcholine metabolism in Huntington’s disease peripheral blood samples

IntroductionMetabolic changes have been frequently associated with Huntington’s disease (HD). At the same time peripheral blood represents a minimally invasive sampling avenue with little distress to Huntington’s disease patients especially when brain or other tissue samples are difficult to collect.ObjectivesWe investigated the levels of 163 metabolites in HD patient and control serum samples in order to identify disease related changes. Additionally, we integrated the metabolomics data with our previously published next generation sequencing-based gene expression data from the same patients in order to interconnect the metabolomics changes with transcriptional alterations.MethodsThis analysis was performed using targeted metabolomics and flow injection electrospray ionization tandem mass spectrometry in 133 serum samples from 97 Huntington’s disease patients (29 pre-symptomatic and 68 symptomatic) and 36 controls.ResultsBy comparing HD mutation carriers with controls we identified 3 metabolites significantly changed in HD (serine and threonine and one phosphatidylcholine—PC ae C36:0) and an additional 8 phosphatidylcholines (PC aa C38:6, PC aa C36:0, PC ae C38:0, PC aa C38:0, PC ae C38:6, PC ae C42:0, PC aa C36:5 and PC ae C36:0) that exhibited a significant association with disease severity. Using workflow based exploitation of pathway databases and by integrating our metabolomics data with our gene expression data from the same patients we identified 4 deregulated phosphatidylcholine metabolism related genes (ALDH1B1, MBOAT1, MTRR and PLB1) that showed significant association with the changes in metabolite concentrations.ConclusionOur results support the notion that phosphatidylcholine metabolism is deregulated in HD blood and that these metabolite alterations are associated with specific gene expression changes.

Common disease signatures from gene expression analysis in Huntington’s disease human blood and brain

BackgroundHuntington’s disease (HD) is a devastating brain disorder with no effective treatment or cure available. The scarcity of brain tissue makes it hard to study changes in the brain and impossible to perform longitudinal studies. However, peripheral pathology in HD suggests that it is possible to study the disease using peripheral tissue as a monitoring tool for disease progression and/or efficacy of novel therapies. In this study, we investigated if blood can be used to monitor disease severity and progression in brain. Since previous attempts using only gene expression proved unsuccessful, we compared blood and brain Huntington’s disease signatures in a functional context.MethodsMicroarray HD gene expression profiles from three brain regions were compared to the transcriptome of HD blood generated by next generation sequencing. The comparison was performed with a combination of weighted gene co-expression network analysis and literature based functional analysis (Concept Profile Analysis). Uniquely, our comparison of blood and brain datasets was not based on (the very limited) gene overlap but on the similarity between the gene annotations in four different semantic categories: “biological process”, “cellular component”, “molecular function” and “disease or syndrome”.ResultsWe identified signatures in HD blood reflecting a broad pathophysiological spectrum, including alterations in the immune response, sphingolipid biosynthetic processes, lipid transport, cell signaling, protein modification, spliceosome, RNA splicing, vesicle transport, cell signaling and synaptic transmission. Part of this spectrum was reminiscent of the brain pathology. The HD signatures in caudate nucleus and BA4 exhibited the highest similarity with blood, irrespective of the category of semantic annotations used. BA9 exhibited an intermediate similarity, while cerebellum had the least similarity. We present two signatures that were shared between blood and brain: immune response and spinocerebellar ataxias.ConclusionsOur results demonstrate that HD blood exhibits dysregulation that is similar to brain at a functional level, but not necessarily at the level of individual genes. We report two common signatures that can be used to monitor the pathology in brain of HD patients in a non-invasive manner. Our results are an exemplar of how signals in blood data can be used to represent brain disorders. Our methodology can be used to study disease specific signatures in diseases where heterogeneous tissues are involved in the pathology.

Opening new gateways to workflows for life scientists

The combination of highly complex biology problems and varying IT skills among life scientists poses a unique challenge in designing bioinformatics programs. The set of tools and initiatives described in this work shows new ways of making life science workflows more accessible to the community. Our aim is to help bioinformaticians help biologists. We present how to make Taverna workflows available from within Galaxy, both widely used bioinformatics platforms. Calling Galaxy tools from Taverna is also discussed. In addition, we describe a web application that allows a user to run arbitrary Taverna workflows by only using a web browser.

The Implicitome: A Resource for Rationalizing Gene-Disease Associations

High-throughput experimental methods such as medical sequencing and genome-wide association studies (GWAS) identify increasingly large numbers of potential relations between genetic variants and diseases. Both biological complexity (millions of potential gene-disease associations) and the accelerating rate of data production necessitate computational approaches to prioritize and rationalize potential gene-disease relations. Here, we use concept profile technology to expose from the biomedical literature both explicitly stated gene-disease relations (the explicitome) and a much larger set of implied gene-disease associations (the implicitome). Implicit relations are largely unknown to, or are even unintended by the original authors, but they vastly extend the reach of existing biomedical knowledge for identification and interpretation of gene-disease associations. The implicitome can be used in conjunction with experimental data resources to rationalize both known and novel associations. We demonstrate the usefulness of the implicitome by rationalizing known and novel gene-disease associations, including those from GWAS. To facilitate the re-use of implicit gene-disease associations, we publish our data in compliance with FAIR Data Publishing recommendations [https://www.force11.org/group/fairgroup] using nanopublications. An online tool (http://knowledge.bio) is available to explore established and potential gene-disease associations in the context of other biomedical relations.

Nanopublications for exposing experimental data in the life-sciences: a Huntington's Disease case study

Data from high throughput experiments often produce far more results than can ever appear in the main text or tables of a single research article. In these cases, the majority of new associations are often archived either as supplemental information in an arbitrary format or in publisher-independent databases that can be difficult to find. These data are not only lost from scientific discourse, but are also elusive to automated search, retrieval and processing. Here, we use the nanopublication model to make scientific assertions that were concluded from a workflow analysis of Huntington’s Disease data machine-readable, interoperable, and citable. We followed the nanopublication guidelines to semantically model our assertions as well as their provenance metadata and authorship. We demonstrate interoperability by linking nanopublication provenance to the Research Object model. These results indicate that nanopublications can provide an incentive for researchers to expose data that is interoperable and machine-readable for future use and preservation for which they can get credits for their effort. Nanopublications can have a leading role into hypotheses generation offering opportunities to produce large-scale data integration.

Identifying impact of software dependencies on replicability of biomedical workflows

Complex data driven experiments form the basis of biomedical research. Recent findings warn that the context in which the software is run, that is the infrastructure and the third party dependencies, can have a crucial impact on the final results delivered by a computational experiment. This implies that in order to replicate the same result, not only the same data must be used, but also it must be run on an equivalent software stack. In this paper we present the VFramework that enables assessing replicability of workflows. It identifies whether any differences in software dependencies among two executions of the same workflow exist and whether they have impact on the produced results. We also conduct a case study in which we investigate the impact of software dependencies on replicability of Taverna workflows used in biomedical research of Huntingtons disease. We re-execute analysed workflows in environments differing in operating system distribution and configuration. The results show that the VFramework can be used to identify the impact of software dependencies on the replicability of biomedical workflows. Furthermore, we observe that despite the fact that the workflows are executed in a controlled environment, they still depend on specific tools installed in the environment. The context model used by the VFramework improves the deficiencies of provenance traces and documents also such tools. Based on our findings we define guidelines for workflow owners that enable them to improve replicability of their workflows.

Multidisciplinary Collaboration to Facilitate Hypotheses Generation in Huntington's Disease

Biomedical research has become more computational and approaches now typically rely on the collaboration between laboratory researchers and bioinformaticians. Large biomedical datasets already exist and that creates the need for efficient data analysis that will facilitate the process of generating new insights for developing treatments for rare diseases such as Huntingtons Disease. In this paper we demonstrate our approach of investigating the epigenetic mechanisms that are involved in Huntingtons disease, using a workflow centric e-Science approach. Our results rely on a collaborative schema that loops over design and execution of computational workflows while maintaining close collaboration with experts of Huntingtons Disease and epigenetics, to discuss new biological insights and follow-up experiments (both computational and wet-lab). Our computational tools further support the collaboration by providing suggestions about mechanisms and genes that may be implicated in the disease and that can serve as hypotheses for further investigation. We publish our results and methods using the nanopublication and Research Object model respectively, for future availability and preservation.

A07 A comparative study on blood and brain hd signatures: comparing mouse and human hd gene expression data

Background While the genetic cause of Huntington’s Disease (HD) is known since 1993, still no cure exists. Therapeutic development would benefit from a method to monitor disease progression and treatment efficacy, ideally using blood biomarkers. We previously showed that HD specific functional signatures in human blood adequately represent signatures in human brain and hence could be used as biomarkers. Aims Since potential drugs are first screened in rodent models, we aimed to determine whether the previously identified human signatures are also present in the YAC128 HD mouse model. Methods We isolated and sequenced RNA from blood collected at 12 and 20 months and four end stage brain regions from 8 YAC128 mice and 8 wild type mice. Differential gene expression analysis was applied to identify genes differentially expressed (DE) and weighted gene coexpression network analysis to identify groups of genes strongly co-expressed (modules). To technically validate RNAseq results, qPCR and western blot were performed. Results RNAseq data was validated by qPCR and western blot, confirming our gene expression analysis. Early stage blood displayed modest changes related to immune response(7 DE genes; 2 modules). At 20 months, an intermediate pathology was detected in blood (162 DE genes; 22 modules), including additional processes such as autophagy, protein transport and modification and DNA repair. In terms of differential gene expression, cortex and brainstem exhibited a mild phenotype (33 and 60 DE genes respectively), while cerebellum and striatum showed intermediate to moderate changes (145 and 101 DE genes respectively). Cerebellum and striatum showed respectively 26 and 11 modules significantly associated with HD, while this was 16 for cortex and 14 for brainstem. Representative annotations presented by all four brain regions were immune response, DNA repair, protein transport, chromatin modification and myelination. Conclusions Similar modules were present in blood and brain gene expression data from mouse and human related to immune response, protein transport and chromatin remodelling. Our next step is to statistically determine similarities between blood and brain signatures in mouse with a computational randomization experiment.