570 Biowissenschaften; Biologie
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Correction to: Knowledge bases and software support for variant interpretation in precision oncology
(2021)
Eatomics
(2021)
Quantitative proteomics data are becoming increasingly more available, and as a consequence are being analyzed and interpreted by a larger group of users. However, many of these users have less programming experience. Furthermore, experimental designs and setups are getting more complicated, especially when tissue biopsies are analyzed. Luckily, the proteomics community has already established some best practices on how to conduct quality control, differential abundance analysis and enrichment analysis. However, an easy-to-use application that wraps together all steps for the exploration and flexible analysis of quantitative proteomics data is not yet available. For Eatomics, we utilize the R Shiny framework to implement carefully chosen parts of established analysis workflows to (i) make them accessible in a user-friendly way, (ii) add a multitude of interactive exploration possibilities, and (iii) develop a unique experimental design setup module, which interactively translates a given research hypothesis into a differential abundance and enrichment analysis formula. In this, we aim to fulfill the needs of a growing group of inexperienced quantitative proteomics data analysts. Eatomics may be tested with demo data directly online via https://we.analyzegenomes.com/now/eatomics/or with the user's own data by installation from the Github repository at https://github.com/Millchmaedchen/Eatomics.
A core operator of evolutionary algorithms (EAs) is the mutation. Recently, much attention has been devoted to the study of mutation operators with dynamic and non-uniform mutation rates. Following up on this area of work, we propose a new mutation operator and analyze its performance on the (1 + 1) Evolutionary Algorithm (EA). Our analyses show that this mutation operator competes with pre-existing ones, when used by the (1 + 1) EA on classes of problems for which results on the other mutation operators are available. We show that the (1 + 1) EA using our mutation operator finds a (1/3)-approximation ratio on any non-negative submodular function in polynomial time. We also consider the problem of maximizing a symmetric submodular function under a single matroid constraint and show that the (1 + 1) EA using our operator finds a (1/3)-approximation within polynomial time. This performance matches that of combinatorial local search algorithms specifically designed to solve these problems and outperforms them with constant probability. Finally, we evaluate the performance of the (1 + 1) EA using our operator experimentally by considering two applications: (a) the maximum directed cut problem on real-world graphs of different origins, with up to 6.6 million vertices and 56 million edges and (b) the symmetric mutual information problem using a four month period air pollution data set. In comparison with uniform mutation and a recently proposed dynamic scheme, our operator comes out on top on these instances.
Gene expression data provide the expression levels of tens of thousands of genes from several hundred samples. These data are analyzed to detect biomarkers that can be of prognostic or diagnostic use. Traditionally, biomarker detection for gene expression data is the task of gene selection. The vast number of genes is reduced to a few relevant ones that achieve the best performance for the respective use case. Traditional approaches select genes based on their statistical significance in the data set. This results in issues of robustness, redundancy and true biological relevance of the selected genes. Integrative analyses typically address these shortcomings by integrating multiple data artifacts from the same objects, e.g. gene expression and methylation data. When only gene expression data are available, integrative analyses instead use curated information on biological processes from public knowledge bases. With knowledge bases providing an ever-increasing amount of curated biological knowledge, such prior knowledge approaches become more powerful. This paper provides a thorough overview on the status quo of biomarker detection on gene expression data with prior biological knowledge. We discuss current shortcomings of traditional approaches, review recent external knowledge bases, provide a classification and qualitative comparison of existing prior knowledge approaches and discuss open challenges for this kind of gene selection.
Polygenic risk scores (PRS) aggregating results from genome-wide association studies are the state of the art in the prediction of susceptibility to complex traits or diseases, yet their predictive performance is limited for various reasons, not least of which is their failure to incorporate the effects of gene-gene interactions. Novel machine learning algorithms that use large amounts of data promise to find gene-gene interactions in order to build models with better predictive performance than PRS. Here, we present a data preprocessing step by using data-mining of contextual information to reduce the number of features, enabling machine learning algorithms to identify gene-gene interactions. We applied our approach to the Parkinson's Progression Markers Initiative (PPMI) dataset, an observational clinical study of 471 genotyped subjects (368 cases and 152 controls). With an AUC of 0.85 (95% CI = [0.72; 0.96]), the interaction-based prediction model outperforms the PRS (AUC of 0.58 (95% CI = [0.42; 0.81])). Furthermore, feature importance analysis of the model provided insights into the mechanism of Parkinson's disease. For instance, the model revealed an interaction of previously described drug target candidate genes TMEM175 and GAPDHP25. These results demonstrate that interaction-based machine learning models can improve genetic prediction models and might provide an answer to the missing heritability problem.
Precision oncology is a rapidly evolving interdisciplinary medical specialty. Comprehensive cancer panels are becoming increasingly available at pathology departments worldwide, creating the urgent need for scalable cancer variant annotation and molecularly informed treatment recommendations. A wealth of mainly academia-driven knowledge bases calls for software tools supporting the multi-step diagnostic process. We derive a comprehensive list of knowledge bases relevant for variant interpretation by a review of existing literature followed by a survey among medical experts from university hospitals in Germany. In addition, we review cancer variant interpretation tools, which integrate multiple knowledge bases. We categorize the knowledge bases along the diagnostic process in precision oncology and analyze programmatic access options as well as the integration of knowledge bases into software tools. The most commonly used knowledge bases provide good programmatic access options and have been integrated into a range of software tools. For the wider set of knowledge bases, access options vary across different parts of the diagnostic process. Programmatic access is limited for information regarding clinical classifications of variants and for therapy recommendations. The main issue for databases used for biological classification of pathogenic variants and pathway context information is the lack of standardized interfaces. There is no single cancer variant interpretation tool that integrates all identified knowledge bases. Specialized tools are available and need to be further developed for different steps in the diagnostic process.