Results from genome-wide association studies (GWAS) can be used to infer causal relationships between phenotypes, using a strategy known as 2-sample Mendelian randomization (2SMR) and bypassing the ...need for individual-level data. However, 2SMR methods are evolving rapidly and GWAS results are often insufficiently curated, undermining efficient implementation of the approach. We therefore developed MR-Base (<ext-link ext-link-type="uri" xlink:href="http://www.mrbase.org">http://www.mrbase.org</ext-link>): a platform that integrates a curated database of complete GWAS results (no restrictions according to statistical significance) with an application programming interface, web app and R packages that automate 2SMR. The software includes several sensitivity analyses for assessing the impact of horizontal pleiotropy and other violations of assumptions. The database currently comprises 11 billion single nucleotide polymorphism-trait associations from 1673 GWAS and is updated on a regular basis. Integrating data with software ensures more rigorous application of hypothesis-driven analyses and allows millions of potential causal relationships to be efficiently evaluated in phenome-wide association studies.
Abstract
There has been an exponential growth in the performance and output of sequencing technologies (omics data) with full genome sequencing now producing gigabases of reads on a daily basis. ...These data may hold the promise of personalized medicine, leading to routinely available sequencing tests that can guide patient treatment decisions. In the era of high-throughput sequencing (HTS), computational considerations, data governance and clinical translation are the greatest rate-limiting steps. To ensure that the analysis, management and interpretation of such extensive omics data is exploited to its full potential, key factors, including sample sourcing, technology selection and computational expertise and resources, need to be considered, leading to an integrated set of high-performance tools and systems. This article provides an up-to-date overview of the evolution of HTS and the accompanying tools, infrastructure and data management approaches that are emerging in this space, which, if used within in a multidisciplinary context, may ultimately facilitate the development of personalized medicine.
Osteoarthritis is the most common musculoskeletal disease and the leading cause of disability globally. Here, we performed a genome-wide association study for osteoarthritis (77,052 cases and 378,169 ...controls), analyzing four phenotypes: knee osteoarthritis, hip osteoarthritis, knee and/or hip osteoarthritis, and any osteoarthritis. We discovered 64 signals, 52 of them novel, more than doubling the number of established disease loci. Six signals fine-mapped to a single variant. We identified putative effector genes by integrating expression quantitative trait loci (eQTL) colocalization, fine-mapping, and human rare-disease, animal-model, and osteoarthritis tissue expression data. We found enrichment for genes underlying monogenic forms of bone development diseases, and for the collagen formation and extracellular matrix organization biological pathways. Ten of the likely effector genes, including TGFB1 (transforming growth factor beta 1), FGF18 (fibroblast growth factor 18), CTSK (cathepsin K), and IL11 (interleukin 11), have therapeutics approved or in clinical trials, with mechanisms of action supportive of evaluation for efficacy in osteoarthritis.
Abstract
Motivation
The wealth of data resources on human phenotypes, risk factors, molecular traits and therapeutic interventions presents new opportunities for population health sciences. These ...opportunities are paralleled by a growing need for data integration, curation and mining to increase research efficiency, reduce mis-inference and ensure reproducible research.
Results
We developed EpiGraphDB (https://epigraphdb.org/), a graph database containing an array of different biomedical and epidemiological relationships and an analytical platform to support their use in human population health data science. In addition, we present three case studies that illustrate the value of this platform. The first uses EpiGraphDB to evaluate potential pleiotropic relationships, addressing mis-inference in systematic causal analysis. In the second case study, we illustrate how protein–protein interaction data offer opportunities to identify new drug targets. The final case study integrates causal inference using Mendelian randomization with relationships mined from the biomedical literature to ‘triangulate’ evidence from different sources.
Availability and implementation
The EpiGraphDB platform is openly available at https://epigraphdb.org. Code for replicating case study results is available at https://github.com/MRCIEU/epigraphdb as Jupyter notebooks using the API, and https://mrcieu.github.io/epigraphdb-r using the R package.
Supplementary information
Supplementary data are available at Bioinformatics online.
The human proteome is a major source of therapeutic targets. Recent genetic association analyses of the plasma proteome enable systematic evaluation of the causal consequences of variation in plasma ...protein levels. Here we estimated the effects of 1,002 proteins on 225 phenotypes using two-sample Mendelian randomization (MR) and colocalization. Of 413 associations supported by evidence from MR, 130 (31.5%) were not supported by results of colocalization analyses, suggesting that genetic confounding due to linkage disequilibrium is widespread in naïve phenome-wide association studies of proteins. Combining MR and colocalization evidence in cis-only analyses, we identified 111 putatively causal effects between 65 proteins and 52 disease-related phenotypes ( https://www.epigraphdb.org/pqtl/ ). Evaluation of data from historic drug development programs showed that target-indication pairs with MR and colocalization support were more likely to be approved, evidencing the value of this approach in identifying and prioritizing potential therapeutic targets.
Nowadays, much research is concerned with execution of long-term continuous tasks, which produce data in real time, e.g. monitoring applications. These tasks can be run for months or years and they ...are usually resource intensive in terms of the large amounts of data which is processed per time unit. A Grid can potentially provide the amount of resources necessary to execute these tasks, but it might prove to be impossible or non-beneficial for a Grid to allocate resources for such long durations as these resources can be also requested by other clients or might join a Grid only for some periods of time. To resolve these differences, a client and a Grid Resource Allocator negotiate, and a client has to agree for a shorter execution period at the end of which it needs to negotiate again. In this paper, we discuss in detail a decision-making mechanism for a client as part of its negotiation strategy, which aims to increase the duration of execution periods and to decrease the duration of interruptions. This new strategy, ConTask, has been tested on a realistic Grid resource simulator, and it demonstrates better utilities than our strategy which has not been specifically designed for continuous tasks under various conditions.
Up to 80% of cases of prostate cancer present with multifocal independent tumour lesions leading to the concept of a field effect present in the normal prostate predisposing to cancer development. In ...the present study we applied Whole Genome DNA Sequencing (WGS) to a group of morphologically normal tissue (n = 51), including benign prostatic hyperplasia (BPH) and non-BPH samples, from men with and men without prostate cancer. We assess whether the observed genetic changes in morphologically normal tissue are linked to the development of cancer in the prostate.
Single nucleotide variants (P = 7.0 × 10
, Wilcoxon rank sum test) and small insertions and deletions (indels, P = 8.7 × 10
) were significantly higher in morphologically normal samples, including BPH, from men with prostate cancer compared to those without. The presence of subclonal expansions under selective pressure, supported by a high level of mutations, were significantly associated with samples from men with prostate cancer (P = 0.035, Fisher exact test). The clonal cell fraction of normal clones was always higher than the proportion of the prostate estimated as epithelial (P = 5.94 × 10
, paired Wilcoxon signed rank test) which, along with analysis of primary fibroblasts prepared from BPH specimens, suggests a stromal origin. Constructed phylogenies revealed lineages associated with benign tissue that were completely distinct from adjacent tumour clones, but a common lineage between BPH and non-BPH morphologically normal tissues was often observed. Compared to tumours, normal samples have significantly less single nucleotide variants (P = 3.72 × 10
, paired Wilcoxon signed rank test), have very few rearrangements and a complete lack of copy number alterations.
Cells within regions of morphologically normal tissue (both BPH and non-BPH) can expand under selective pressure by mechanisms that are distinct from those occurring in adjacent cancer, but that are allied to the presence of cancer. Expansions, which are probably stromal in origin, are characterised by lack of recurrent driver mutations, by almost complete absence of structural variants/copy number alterations, and mutational processes similar to malignant tissue. Our findings have implications for treatment (focal therapy) and early detection approaches.
Probabilistic record linkage is a well established topic in the literature. Fellegi–Sunter probabilistic record linkage and its enhanced versions are commonly used methods, which calculate match and ...non-match weights for each pair of records. Bayesian network classifiers–naive Bayes classifier and TAN have also been successfully used here. Recently, an extended version of TAN (called ETAN) has been developed and proved superior in classification accuracy to conventional TAN. However, no previous work has applied ETAN to record linkage and investigated the benefits of using naturally existing hierarchical feature level information and parsed fields of the datasets. In this work, we extend the naive Bayes classifier with such hierarchical feature level information. Finally we illustrate the benefits of our method over previously proposed methods on four datasets in terms of the linkage performance (
F
1
score). We also show the results can be further improved by evaluating the benefit provided by additionally parsing the fields of these datasets.
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