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Motivation: Cancer is a very heterogeneous disease that can be difficult to treat without addressing the specific mechanisms driving tumour progression in a given patient. High-throughput screening and sequencing data from cancer cell-lines has driven many developments in drug development, however, there are important aspects crucial to precision medicine that are often overlooked, namely the inherent differences between tumours in patients and the cell-lines used to model them in vitro. Recent developments in transfer learning methods for patient and cell-line data have shown progress in translating results from cell-lines to individual patients in silico. However, transfer learning can be forceful and there is a risk that clinically relevant patterns in the omics profiles of patients are lost in the process., Results: We present MODAE, a novel deep learning algorithm to integrate omics profiles from cell-lines and patients for the purposes of exploring precision medicine opportunities. MODAE implements patient survival prediction as an additional task in a drug-sensitivity transfer learning schema and aims to balance autoencoding, domain adaptation, drug-sensitivity prediction, and survival prediction objectives in order to better preserve the heterogeneity between patients that is relevant to survival. While burdened with these additional tasks, MODAE performed on par with baseline survival models, but struggled in the drug-sensitivity prediction task. Nevertheless, these preliminary results were promising and show that MODAE provides a novel AI-based method for prioritizing drug treatments for high-risk patients., Availability and Implementation: https://github.com/UEFBiomedicalInformaticsLab/MODAE., (© The Author(s) 2024. Published by Oxford University Press.)

Motivation: Gene expression-based classifiers are often developed using historical data by training a model on a small set of patients and a large set of features. Models trained in such a way can be afterwards applied for predicting the output for new unseen patient data. However, very often the accuracy of these models starts to decrease as soon as new data is fed into the trained model. This problem, known as concept drift, complicates the task of learning efficient biomarkers from data and requires special approaches, different from commonly used data mining techniques., Results: Here, we propose an online ensemble learning method to continually validate and adjust gene expression-based biomarker panels over increasing volume of data. We also propose a computational solution to the problem of feature drift where gene expression signatures used to train the classifier become less relevant over time. A benchmark study was conducted to classify the breast tumors into known subtypes by using a large-scale transcriptomic dataset (∼3500 patients), which was obtained by combining two datasets: SCAN-B and TCGA-BRCA. Remarkably, the proposed strategy improves the classification performances of gold-standard biomarker panels (e.g. PAM50, OncotypeDX and Endopredict) by adding features that are clinically relevant. Moreover, test results show that newly discovered biomarker models can retain a high classification accuracy rate when changing the source generating the gene expression profiles., Availability and Implementation: github.com/UEFBiomedicalInformaticsLab/OnlineLearningBD., Supplementary Information: Supplementary data are available at Bioinformatics Advances online., (© The Author(s) 2022. Published by Oxford University Press.)

Motivation: In modern translational research, the development of biomarkers heavily relies on use of omics technologies, but implementations with basic data mining algorithms frequently lead to false positives. Non-dominated Sorting Genetic Algorithm II (NSGA2) is an extremely effective algorithm for biomarker discovery but has been rarely evaluated against large-scale datasets. The exploration of the feature search space is the key to NSGA2 success but in specific cases NSGA2 expresses a shallow exploration of the space of possible feature combinations, possibly leading to models with low predictive performances., Results: We propose two improved NSGA2 algorithms for finding subsets of biomarkers exhibiting different trade-offs between accuracy and feature number. The performances are investigated on gene expression data of breast cancer patients. The results are compared with NSGA2 and LASSO. The benchmarking dataset includes internal and external validation sets. The results show that the proposed algorithms generate a better approximation of the optimal trade-offs between accuracy and set size. Moreover, validation and test accuracies are better than those provided by NSGA2 and LASSO. Remarkably, the GA-based methods provide biomarkers that achieve a very high prediction accuracy (>80%) with a small number of features (<10), representing a valid alternative to known biomarker models, such as Pam50 and MammaPrint., Availability and Implementation: The software is publicly available on GitHub at github.com/UEFBiomedicalInformaticsLab/BIODAI/tree/main/MOO., Supplementary Information: Supplementary data are available at Bioinformatics online., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The network approach is quickly becoming a fundamental building block of computational methods aiming at elucidating the mechanism of action (MoA) and therapeutic effect of drugs. By modeling the effect of drugs and diseases on different biological networks, it is possible to better explain the interplay between disease perturbations and drug targets as well as how drug compounds induce favorable biological responses and/or adverse effects. Omics technologies have been extensively used to generate the data needed to study the mechanisms of action of drugs and diseases. These data are often exploited to define condition-specific networks and to study whether drugs can reverse disease perturbations. In this review, we describe network data mining algorithms that are commonly used to study drug's MoA and to improve our understanding of the basis of chronic diseases. These methods can support fundamental stages of the drug development process, including the identification of putative drug targets, the in silico screening of drug compounds and drug combinations for the treatment of diseases. We also discuss recent studies using biological and omics-driven networks to search for possible repurposed FDA-approved drug treatments for SARS-CoV-2 infections (COVID-19)., (© The Author(s) 2022. Published by Oxford University Press.)

Purpose: Endocrine disruptors are a rising concern due to the wide array of health issues that it can cause. Although there are tools for mode of action (MoA)-based prediction of endocrine disruption (e.g. QSAR Toolbox and iSafeRat), none of them is based on toxicogenomics data. Here, we present EDTox, an R Shiny application enabling users to explore and use a computational method that we have recently published to identify and prioritize endocrine disrupting (ED) chemicals based on toxicogenomic data. The EDTox pipeline utilizes previously trained toxicogenomic-driven classifiers to make predictions on new untested compounds by using their molecular initiating events. Furthermore, the proposed R Shiny app allows users to extend the prediction systems by training and adding new classifiers based on new available toxicogenomic data. This functionality helps users to explore the ED potential of chemicals in new, untested exposure scenarios., Availability and Implementation: This tool is available as web application (www.edtox.fi) and stand-alone software on GitHub and Zenodo (https://doi.org/10.5281/zenodo.5817093)., Supplementary Information: Supplementary data are available at Bioinformatics online., (© The Author(s) 2022. Published by Oxford University Press.)

Typical clustering analysis for large-scale genomics data combines two unsupervised learning techniques: dimensionality reduction and clustering (DR-CL) methods. It has been demonstrated that transforming gene expression to pathway-level information can improve the robustness and interpretability of disease grouping results. This approach, referred to as biological knowledge-driven clustering (BK-CL) approach, is often neglected, due to a lack of tools enabling systematic comparisons with more established DR-based methods. Moreover, classic clustering metrics based on group separability tend to favor the DR-CL paradigm, which may increase the risk of identifying less actionable disease subtypes that have ambiguous biological and clinical explanations. Hence, there is a need for developing metrics that assess biological and clinical relevance. To facilitate the systematic analysis of BK-CL methods, we propose a computational protocol for quantitative analysis of clustering results derived from both DR-CL and BK-CL methods. Moreover, we propose a new BK-CL method that combines prior knowledge of disease relevant genes, network diffusion algorithms and gene set enrichment analysis to generate robust pathway-level information. Benchmarking studies were conducted to compare the grouping results from different DR-CL and BK-CL approaches with respect to standard clustering evaluation metrics, concordance with known subtypes, association with clinical outcomes and disease modules in co-expression networks of genes. No single approach dominated every metric, showing the importance multi-objective evaluation in clustering analysis. However, we demonstrated that, on gene expression data sets derived from TCGA samples, the BK-CL approach can find groupings that provide significant prognostic value in both breast and prostate cancers., (© The Author(s) 2021. Published by Oxford University Press.)

The drug discovery process starts with identification of a disease-modifying target. This critical step traditionally begins with manual investigation of scientific literature and biomedical databases to gather evidence linking molecular target to disease, and to evaluate the efficacy, safety and commercial potential of the target. The high-throughput and affordability of current omics technologies, allowing quantitative measurements of many putative targets (e.g. DNA, RNA, protein, metabolite), has exponentially increased the volume of scientific data available for this arduous task. Therefore, computational platforms identifying and ranking disease-relevant targets from existing biomedical data sources, including omics databases, are needed. To date, more than 30 drug target discovery (DTD) platforms exist. They provide information-rich databases and graphical user interfaces to help scientists identify putative targets and pre-evaluate their therapeutic efficacy and potential side effects. Here we survey and compare a set of popular DTD platforms that utilize multiple data sources and omics-driven knowledge bases (either directly or indirectly) for identifying drug targets. We also provide a description of omics technologies and related data repositories which are important for DTD tasks., (© The Author(s) 2019. Published by Oxford University Press.)

Summary: Estimating efficacy of gene-target-disease associations is a fundamental step in drug discovery. An important data source for this laborious task is RNA expression, which can provide gene-disease associations on the basis of expression fold change and statistical significance. However, the simply use of the log-fold change can lead to numerous false-positive associations. On the other hand, more sophisticated methods that utilize gene co-expression networks do not consider tissue specificity. Here, we introduce Transcriptome-driven Efficacy estimates for gene-based TArget discovery (ThETA), an R package that enables non-expert users to use novel efficacy scoring methods for drug-target discovery. In particular, ThETA allows users to search for gene perturbation (therapeutics) that reverse disease-gene expression and genes that are closely related to disease-genes in tissue-specific networks. ThETA also provides functions to integrate efficacy evaluations obtained with different approaches and to build an overall efficacy score, which can be used to identify and prioritize gene(target)-disease associations. Finally, ThETA implements visualizations to show tissue-specific interconnections between target and disease-genes, and to indicate biological annotations associated with the top selected genes., Availability and Implementation: ThETA is freely available for academic use at https://github.com/vittoriofortino84/ThETA., Contact: vittorio.fortino@uef.fi., Supplementary Information: Supplementary data are available at Bioinformatics online., (© The Author(s) 2020. Published by Oxford University Press.)

Motivation: Omics technologies have the potential to facilitate the discovery of new biomarkers. However, only few omics-derived biomarkers have been successfully translated into clinical applications to date. Feature selection is a crucial step in this process that identifies small sets of features with high predictive power. Models consisting of a limited number of features are not only more robust in analytical terms, but also ensure cost effectiveness and clinical translatability of new biomarker panels. Here we introduce GARBO, a novel multi-island adaptive genetic algorithm to simultaneously optimize accuracy and set size in omics-driven biomarker discovery problems., Results: Compared to existing methods, GARBO enables the identification of biomarker sets that best optimize the trade-off between classification accuracy and number of biomarkers. We tested GARBO and six alternative selection methods with two high relevant topics in precision medicine: cancer patient stratification and drug sensitivity prediction. We found multivariate biomarker models from different omics data types such as mRNA, miRNA, copy number variation, mutation and DNA methylation. The top performing models were evaluated by using two different strategies: the Pareto-based selection, and the weighted sum between accuracy and set size (w = 0.5). Pareto-based preferences show the ability of the proposed algorithm to search minimal subsets of relevant features that can be used to model accurate random forest-based classification systems. Moreover, GARBO systematically identified, on larger omics data types, such as gene expression and DNA methylation, biomarker panels exhibiting higher classification accuracy or employing a number of features much lower than those discovered with other methods. These results were confirmed on independent datasets., Availability and Implementation: github.com/Greco-Lab/GARBO., Contact: dario.greco@tuni.fi., Supplementary Information: Supplementary data are available at Bioinformatics online., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Summary: Quantitative structure-activity relationship (QSAR) modelling is currently used in multiple fields to relate structural properties of compounds to their biological activities. This technique is also used for drug design purposes with the aim of predicting parameters that determine drug behaviour. To this end, a sophisticated process, involving various analytical steps concatenated in series, is employed to identify and fine-tune the optimal set of predictors from a large dataset of molecular descriptors (MDs). The search of the optimal model requires to optimize multiple objectives at the same time, as the aim is to obtain the minimal set of features that maximizes the goodness of fit and the applicability domain (AD). Hence, a multi-objective optimization strategy, improving multiple parameters in parallel, can be applied. Here we propose a new multi-niche multi-objective genetic algorithm that simultaneously enables stable feature selection as well as obtaining robust and validated regression models with maximized AD. We benchmarked our method on two simulated datasets. Moreover, we analyzed an aquatic acute toxicity dataset and compared the performances of single- and multi-objective fitness functions on different regression models. Our results show that our multi-objective algorithm is a valid alternative to classical QSAR modelling strategy, for continuous response values, since it automatically finds the model with the best compromise between statistical robustness, predictive performance, widest AD, and the smallest number of MDs., Availability and Implementation: The python implementation of MaNGA is available at https://github.com/Greco-Lab/MaNGA., Supplementary Information: Supplementary data are available at Bioinformatics online., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Summary: Detecting and interpreting responsive modules from gene expression data by using network-based approaches is a common but laborious task. It often requires the application of several computational methods implemented in different software packages, forcing biologists to compile complex analytical pipelines. Here we introduce INfORM (Inference of NetwOrk Response Modules), an R shiny application that enables non-expert users to detect, evaluate and select gene modules with high statistical and biological significance. INfORM is a comprehensive tool for the identification of biologically meaningful response modules from consensus gene networks inferred by using multiple algorithms. It is accessible through an intuitive graphical user interface allowing for a level of abstraction from the computational steps., Availability and Implementation: INfORM is freely available for academic use at https://github.com/Greco-Lab/INfORM., Supplementary Information: Supplementary data are available at Bioinformatics online.

The use of high-throughput RNA sequencing to predict dynamic operon structures in prokaryotic genomes has recently gained popularity in bioinformatics. We provide the R implementation of a novel method that uses transcriptomic features extracted from RNA-seq transcriptome profiles to develop ensemble classifiers for condition-dependent operon predictions. The CONDOP package provides a deeper insight into RNA-seq data analysis and allows scientists to highlight the operon organization in the context of transcriptional regulation with a few lines of code., Availability and Implementation: CONDOP is implemented in R and is freely available at CRAN., Contact: vittorio.fortino@helsinki.fiSupplementary information: Supplementary data are available at Bioinformatics online., (© The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

The aim of this brief review is to summarize the recent literature on the effect of ozone (O3) on cutaneous tissues. Recently it has been reported that a chronic contact with O3 can be deleterious for the skin. Our group and others have shown a progressive depletion of antioxidant content in the stratum corneum and this can then lead to a cascade of effects resulting in an active cellular response in the deeper layers of the skin. Using an in vivo model we have shown an increase of proliferative, adaptive and proinflammatory cutaneous tissue responses. On the other hand the well known activity of O3 as a potent disinfectant and oxygen (O2) donor has been also studied for therapeutic use. Two approaches have been described. The first consists of a quasi-total body exposure in a thermostatically controlled cabin. This treatment has proved to be useful in patients with chronic limb ischaemia. The second approach is based on the topical application of ozonated olive oil in several kinds of skin infection (from soreness to diabetic ulcers, burns, traumatic and surgical wounds, abscesses and skin reactions after radiotherapy). We and other authors have observed a striking cleansing effect with improved oxygenation and enhanced healing of these conditions. It is now clear that, on the skin, O3, like other drugs, poisons and radiation, can display either a damaging effect from a long exposure or a beneficial effect after a brief exposure to O2 and O3 or to the application of ozonated oil to chronic wounds.

Preeclampsia is a disorder associated with pregnancy that affects both the mother and the fetus. Typical features of the disease are maternal hypertension, proteinuria, and edema as well as fetal growth retardation. Although the etiological details are still being debated, a consensus exists that the starting point is deficient placentation in the first half of pregnancy. The crucial early steps are reduced trophoblast invasiveness and enhanced apoptotic death. In the present review, we demonstrate that parathyroid hormone-related protein is involved not only in the maternal and fetal failures but also in the etiological aspects of the disease. We hypothesize that reduced local production of the peptide is a major causative event.