Breakthroughs in sequencing technologies led to an exponential growth of genomic data, providing novel biological insights and therapeutic applications. However, analyzing large amounts of sensitive data raises key data privacy concerns, specifically when the information is outsourced to untrusted third-party infrastructures for data storage and processing (e.g., cloud computing). We introduce Gyosa, a secure and privacy-preserving distributed genomic analysis solution. By leveraging trusted execution environments (TEEs), Gyosa allows users to confidentially delegate their GWAS analysis to untrusted infrastructures. Gyosa implements a computation partitioning scheme that reduces the computation done inside the TEEs while safeguarding the users' genomic data privacy. By integrating this security scheme in Glow, Gyosa provides a secure and distributed environment that facilitates diverse GWAS studies. The experimental evaluation validates the applicability and scalability of Gyosa, reinforcing its ability to provide enhanced security guarantees.

SUMMARY: APAtizer is a tool designed to analyze alternative polyadenylation events on RNA-sequencing data. The tool handles different file formats, including BAM, htseq, and DaPars bedGraph files. It provides a user-friendly interface that allows users to generate informative visualizations, including Volcano plots, heatmaps, and gene lists. These outputs allow the user to retrieve useful biological insights such as the occurrence of polyadenylation events when comparing two biological conditions. In addition, it can perform differential gene expression, gene ontology analysis, visualization of Venn diagram intersections, and correlation analysis. AVAILABILITY AND IMPLEMENTATION: Source code and example case studies for APAtizer are available at https://github.com/GeneRegulationi3S/APAtizer/.

Abstract Aging involves complex biological processes leading to the decline of living organisms. As population lifespan increases worldwide, the importance of identifying factors underlying healthy aging has become critical. Integration of multi-modal datasets is a powerful approach for the analysis of complex biological systems, with the potential to uncover novel aging biomarkers. In this study, we leveraged publicly available epigenomic, transcriptomic and telomere length data along with histological images from the Genotype-Tissue Expression project to build tissue-specific regression models for age prediction. Using data from two tissues, lung and ovary, we aimed to compare model performance across data modalities, as well as to assess the improvement resulting from integrating multiple data types. Our results demostrate that methylation outperformed the other data modalities, with a mean absolute error of 3.36 and 4.36 in the test sets for lung and ovary, respectively. These models achieved lower error rates when compared with established state-of-the-art tissue-agnostic methylation models, emphasizing the importance of a tissue-specific approach. Additionally, this work has shown how the application of Hierarchical Image Pyramid Transformers for feature extraction significantly enhances age modeling using histological images. Finally, we evaluated the benefits of integrating multiple data modalities into a single model. Combining methylation data with other data modalities only marginally improved performance likely due to the limited number of available samples. Combining gene expression with histological features yielded more accurate age predictions compared with the individual performance of these data types. Given these results, this study shows how machine learning applications can be extended to/in multi-modal aging research. Code used is available at https://github.com/zroger49/multi_modal_age_prediction .

Symbolic Regression (SR) algorithms attempt to learn analytic expressions which fit data accurately and in a highly interpretable manner. Conventional SR suffers from two fundamental issues which we address here. First, these methods search the space stochastically (typically using genetic programming) and hence do not necessarily find the best function. Second, the criteria used to select the equation optimally balancing accuracy with simplicity have been variable and subjective. To address these issues we introduce Exhaustive Symbolic Regression (ESR), which systematically and efficiently considers all possible equations—made with a given basis set of operators and up to a specified maximum complexity— and is therefore guaranteed to find the true optimum (if parameters are perfectly optimised) and a complete function ranking subject to these constraints. We implement the minimum description length principle as a rigorous method for combining these preferences into a single objective. To illustrate the power of ESR we apply it to a catalogue of cosmic chronometers and the Pantheon+ sample of supernovae to learn the Hubble rate as a function of redshift, finding 40 functions (out of 5.2 million trial functions) that fit the data more economically than the Friedmann equation. These low-redshift data therefore do not uniquely prefer the expansion history of the standard model of cosmology. We make our code and full equation sets publicly available.

One of the main obstacles to the successful treatment of cancer is the phenomenon of drug resistance. A common strategy to overcome resistance is the use of combination therapies. However, the space of possibilities is huge and efficient search strategies are required. Machine Learning (ML) can be a useful tool for the discovery of novel, clinically relevant anti-cancer drug combinations. In particular, deep learning (DL) has become a popular choice for modeling drug combination effects. Here, we set out to examine the impact of different methodological choices on the performance of multimodal DL-based drug synergy prediction methods, including the use of different input data types, preprocessing steps and model architectures. Focusing on the NCI ALMANAC dataset, we found that feature selection based on prior biological knowledge has a positive impact-limiting gene expression data to cancer or drug response-specific genes improved performance. Drug features appeared to be more predictive of drug response, with a 41% increase in coefficient of determination (R2) and 26% increase in Spearman correlation relative to a baseline model that used only cell line and drug identifiers. Molecular fingerprint-based drug representations performed slightly better than learned representations-ECFP4 fingerprints increased R2 by 5.3% and Spearman correlation by 2.8% w.r.t the best learned representations. In general, fully connected feature-encoding subnetworks outperformed other architectures. DL outperformed other ML methods by more than 35% (R2) and 14% (Spearman). Additionally, an ensemble combining the top DL and ML models improved performance by about 6.5% (R2) and 4% (Spearman). Using a state-of-the-art interpretability method, we showed that DL models can learn to associate drug and cell line features with drug response in a biologically meaningful way. The strategies explored in this study will help to improve the development of computational methods for the rational design of effective drug combinations for cancer therapy.

BACKGROUND: Gene expression studies are an important tool in biological and biomedical research. The signal carried in expression profiles helps derive signatures for the prediction, diagnosis and prognosis of different diseases. Data science and specifically machine learning have many applications in gene expression analysis. However, as the dimensionality of genomics datasets grows, scalable solutions become necessary. METHODS: In this paper we review the main steps and bottlenecks in machine learning pipelines, as well as the main concepts behind scalable data science including those of concurrent and parallel programming. We discuss the benefits of the Dask framework and how it can be integrated with the Python scientific environment to perform data analysis in computational biology and bioinformatics. RESULTS: This review illustrates the role of Dask for boosting data science applications in different case studies. Detailed documentation and code on these procedures is made available at https://github.com/martaccmoreno/gexp-ml-dask . CONCLUSION: By showing when and how Dask can be used in transcriptomics analysis, this review will serve as an entry point to help genomic data scientists develop more scalable data analysis procedures.

Predicting the sensitivity of tumors to specific anti-cancer treatments is a challenge of paramount importance for precision medicine. Machine learning(ML) algorithms can be trained on high-throughput screening data to develop models that are able to predict the response of cancer cell lines and patients to novel drugs or drug combinations. Deep learning (DL) refers to a distinct class of ML algorithms that have achieved top-level performance in a variety of fields, including drug discovery. These types of models have unique characteristics that may make them more suitable for the complex task of modeling drug response based on both biological and chemical data, but the application of DL to drug response prediction has been unexplored until very recently. The few studies that have been published have shown promising results, and the use of DL for drug response prediction is beginning to attract greater interest from researchers in the field. In this article, we critically review recently published studies that have employed DL methods to predict drug response in cancer cell lines. We also provide a brief description of DL and the main types of architectures that have been used in these studies. Additionally, we present a selection of publicly available drug screening data resources that can be used to develop drug response prediction models. Finally, we also address the limitations of these approaches and provide a discussion on possible paths for further improvement. Contact: [email protected].

Cancer genome projects are characterizing the genome, epigenome and transcriptome of a large number of samples using the latest high-throughput sequencing assays. The generated data sets pose several challenges for traditional statistical and machine learning methods. In this work we are interested in the task of deriving the most informative genes from a cancer gene expression data set. For that goal we built denoising autoencoders (DAE) and stacked denoising autoencoders and we studied the influence of the input nodes on the final representation of the DAE. We have also compared these deep learning approaches with other existing approaches. Our study is divided into two main tasks. First, we built and compared the performance of several feature extraction methods as well as data sampling methods using classifiers that were able to distinguish the samples of thyroid cancer patients from samples of healthy persons. In the second task, we have investigated the possibility of building comprehensible descriptions of gene expression data by using Denoising Autoencoders and Stacked Denoising Autoencoders as feature extraction methods. After extracting information related to the description built by the network, namely the connection weights, we devised post-processing techniques to extract comprehensible and biologically meaningful descriptions out of the constructed models. We have been able to build high accuracy models to discriminate thyroid cancer from healthy patients but the extraction of comprehensible models is still very limited.