Drugst.One - a plug-and-play solution for online systems medicine and network-based drug repurposing.

In recent decades, the development of new drugs has become increasingly expensive and inefficient, and the molecular mechanisms of most pharmaceuticals remain poorly understood. In response, computational systems and network medicine tools have emerged to identify potential drug repurposing candidates. However, these tools often require complex installation and lack intuitive visual network mining capabilities. To tackle these challenges, we introduce Drugst.One, a platform that assists specialized computational medicine tools in becoming user-friendly, web-based utilities for drug repurposing. With just three lines of code, Drugst.One turns any systems biology software into an interactive web tool for modeling and analyzing complex protein-drug-disease networks. Demonstrating its broad adaptability, Drugst.One has been successfully integrated with 21 computational systems medicine tools. Available at https://drugst.one, Drugst.One has significant potential for streamlining the drug discovery process, allowing researchers to focus on essential aspects of pharmaceutical treatment research.

The FeatureCloud Platform for Federated Learning in Biomedicine: Unified Approach.

BACKGROUND: Machine learning and artificial intelligence have shown promising results in many areas and are driven by the increasing amount of available data. However, these data are often distributed across different institutions and cannot be easily shared owing to strict privacy regulations. Federated learning (FL) allows the training of distributed machine learning models without sharing sensitive data. In addition, the implementation is time-consuming and requires advanced programming skills and complex technical infrastructures. OBJECTIVE: Various tools and frameworks have been developed to simplify the development of FL algorithms and provide the necessary technical infrastructure. Although there are many high-quality frameworks, most focus only on a single application case or method. To our knowledge, there are no generic frameworks, meaning that the existing solutions are restricted to a particular type of algorithm or application field. Furthermore, most of these frameworks provide an application programming interface that needs programming knowledge. There is no collection of ready-to-use FL algorithms that are extendable and allow users (eg, researchers) without programming knowledge to apply FL. A central FL platform for both FL algorithm developers and users does not exist. This study aimed to address this gap and make FL available to everyone by developing FeatureCloud, an all-in-one platform for FL in biomedicine and beyond. METHODS: The FeatureCloud platform consists of 3 main components: a global frontend, a global backend, and a local controller. Our platform uses a Docker to separate the local acting components of the platform from the sensitive data systems. We evaluated our platform using 4 different algorithms on 5 data sets for both accuracy and runtime. RESULTS: FeatureCloud removes the complexity of distributed systems for developers and end users by providing a comprehensive platform for executing multi-institutional FL analyses and implementing FL algorithms. Through its integrated artificial intelligence store, federated algorithms can easily be published and reused by the community. To secure sensitive raw data, FeatureCloud supports privacy-enhancing technologies to secure the shared local models and assures high standards in data privacy to comply with the strict General Data Protection Regulation. Our evaluation shows that applications developed in FeatureCloud can produce highly similar results compared with centralized approaches and scale well for an increasing number of participating sites. CONCLUSIONS: FeatureCloud provides a ready-to-use platform that integrates the development and execution of FL algorithms while reducing the complexity to a minimum and removing the hurdles of federated infrastructure. Thus, we believe that it has the potential to greatly increase the accessibility of privacy-preserving and distributed data analyses in biomedicine and beyond.

Drugst.One - A plug-and-play solution for online systems medicine and network-based drug repurposing.

In recent decades, the development of new drugs has become increasingly expensive and inefficient, and the molecular mechanisms of most pharmaceuticals remain poorly understood. In response, computational systems and network medicine tools have emerged to identify potential drug repurposing candidates. However, these tools often require complex installation and lack intuitive visual network mining capabilities. To tackle these challenges, we introduce Drugst.One, a platform that assists specialized computational medicine tools in becoming user-friendly, web-based utilities for drug repurposing. With just three lines of code, Drugst.One turns any systems biology software into an interactive web tool for modeling and analyzing complex protein-drug-disease networks. Demonstrating its broad adaptability, Drugst.One has been successfully integrated with 21 computational systems medicine tools. Available at https://drugst.one, Drugst.One has significant potential for streamlining the drug discovery process, allowing researchers to focus on essential aspects of pharmaceutical treatment research.

dsMTL: a computational framework for privacy-preserving, distributed multi-task machine learning.

MOTIVATION: In multi-cohort machine learning studies, it is critical to differentiate between effects that are reproducible across cohorts and those that are cohort-specific. Multi-task learning (MTL) is a machine learning approach that facilitates this differentiation through the simultaneous learning of prediction tasks across cohorts. Since multi-cohort data can often not be combined into a single storage solution, there would be the substantial utility of an MTL application for geographically distributed data sources. RESULTS: Here, we describe the development of 'dsMTL', a computational framework for privacy-preserving, distributed multi-task machine learning that includes three supervised and one unsupervised algorithms. First, we derive the theoretical properties of these methods and the relevant machine learning workflows to ensure the validity of the software implementation. Second, we implement dsMTL as a library for the R programming language, building on the DataSHIELD platform that supports the federated analysis of sensitive individual-level data. Third, we demonstrate the applicability of dsMTL for comorbidity modeling in distributed data. We show that comorbidity modeling using dsMTL outperformed conventional, federated machine learning, as well as the aggregation of multiple models built on the distributed datasets individually. The application of dsMTL was computationally efficient and highly scalable when applied to moderate-size (n < 500), real expression data given the actual network latency. AVAILABILITY AND IMPLEMENTATION: dsMTL is freely available at https://github.com/transbioZI/dsMTLBase (server-side package) and https://github.com/transbioZI/dsMTLClient (client-side package). SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Federated machine learning for a facilitated implementation of Artificial Intelligence in healthcare - a proof of concept study for the prediction of coronary artery calcification scores.

The implementation of Artificial Intelligence (AI) still faces significant hurdles and one key factor is the access to data. One approach that could support that is federated machine learning (FL) since it allows for privacy preserving data access. For this proof of concept, a prediction model for coronary artery calcification scores (CACS) has been applied. The FL was trained based on the data in the different institutions, while the centralized machine learning model was trained on one allocation of data. Both algorithms predict patients with risk scores ≥5 based on age, biological sex, waist circumference, dyslipidemia and HbA1c. The centralized model yields a sensitivity of c. 66% and a specificity of c. 70%. The FL slightly outperforms that with a sensitivity of 67% while slightly underperforming it with a specificity of 69%. It could be demonstrated that CACS prediction is feasible via both, a centralized and an FL approach, and that both show very comparable accuracy. In order to increase accuracy, additional and a higher volume of patient data is required and for that FL is utterly necessary. The developed "CACulator" serves as proof of concept, is available as research tool and shall support future research to facilitate AI implementation.

Federated Random Forests can improve local performance of predictive models for various healthcare applications.

MOTIVATION: Limited data access has hindered the field of precision medicine from exploring its full potential, e.g. concerning machine learning and privacy and data protection rules.Our study evaluates the efficacy of federated Random Forests (FRF) models, focusing particularly on the heterogeneity within and between datasets. We addressed three common challenges: (i) number of parties, (ii) sizes of datasets and (iii) imbalanced phenotypes, evaluated on five biomedical datasets. RESULTS: The FRF outperformed the average local models and performed comparably to the data-centralized models trained on the entire data. With an increasing number of models and decreasing dataset size, the performance of local models decreases drastically. The FRF, however, do not decrease significantly. When combining datasets of different sizes, the FRF vastly improve compared to the average local models. We demonstrate that the FRF remain more robust and outperform the local models by analyzing different class-imbalances.Our results support that FRF overcome boundaries of clinical research and enables collaborations across institutes without violating privacy or legal regulations. Clinicians benefit from a vast collection of unbiased data aggregated from different geographic locations, demographics and other varying factors. They can build more generalizable models to make better clinical decisions, which will have relevance, especially for patients in rural areas and rare or geographically uncommon diseases, enabling personalized treatment. In combination with secure multi-party computation, federated learning has the power to revolutionize clinical practice by increasing the accuracy and robustness of healthcare AI and thus paving the way for precision medicine. AVAILABILITY AND IMPLEMENTATION: The implementation of the federated random forests can be found at https://featurecloud.ai/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Privacy-Preserving Artificial Intelligence Techniques in Biomedicine.

BACKGROUND: Artificial intelligence (AI) has been successfully applied in numerous scientific domains. In biomedicine, AI has already shown tremendous potential, e.g., in the interpretation of next-generation sequencing data and in the design of clinical decision support systems. OBJECTIVES: However, training an AI model on sensitive data raises concerns about the privacy of individual participants. For example, summary statistics of a genome-wide association study can be used to determine the presence or absence of an individual in a given dataset. This considerable privacy risk has led to restrictions in accessing genomic and other biomedical data, which is detrimental for collaborative research and impedes scientific progress. Hence, there has been a substantial effort to develop AI methods that can learn from sensitive data while protecting individuals' privacy. METHOD: This paper provides a structured overview of recent advances in privacy-preserving AI techniques in biomedicine. It places the most important state-of-the-art approaches within a unified taxonomy and discusses their strengths, limitations, and open problems. CONCLUSION: As the most promising direction, we suggest combining federated machine learning as a more scalable approach with other additional privacy-preserving techniques. This would allow to merge the advantages to provide privacy guarantees in a distributed way for biomedical applications. Nonetheless, more research is necessary as hybrid approaches pose new challenges such as additional network or computation overhead.

sPLINK: a hybrid federated tool as a robust alternative to meta-analysis in genome-wide association studies.

Meta-analysis has been established as an effective approach to combining summary statistics of several genome-wide association studies (GWAS). However, the accuracy of meta-analysis can be attenuated in the presence of cross-study heterogeneity. We present sPLINK, a hybrid federated and user-friendly tool, which performs privacy-aware GWAS on distributed datasets while preserving the accuracy of the results. sPLINK is robust against heterogeneous distributions of data across cohorts while meta-analysis considerably loses accuracy in such scenarios. sPLINK achieves practical runtime and acceptable network usage for chi-square and linear/logistic regression tests. sPLINK is available at https://exbio.wzw.tum.de/splink .

Privacy-aware multi-institutional time-to-event studies.

Clinical time-to-event studies are dependent on large sample sizes, often not available at a single institution. However, this is countered by the fact that, particularly in the medical field, individual institutions are often legally unable to share their data, as medical data is subject to strong privacy protection due to its particular sensitivity. But the collection, and especially aggregation into centralized datasets, is also fraught with substantial legal risks and often outright unlawful. Existing solutions using federated learning have already demonstrated considerable potential as an alternative for central data collection. Unfortunately, current approaches are incomplete or not easily applicable in clinical studies owing to the complexity of federated infrastructures. This work presents privacy-aware and federated implementations of the most used time-to-event algorithms (survival curve, cumulative hazard rate, log-rank test, and Cox proportional hazards model) in clinical trials, based on a hybrid approach of federated learning, additive secret sharing, and differential privacy. On several benchmark datasets, we show that all algorithms produce highly similar, or in some cases, even identical results compared to traditional centralized time-to-event algorithms. Furthermore, we were able to reproduce the results of a previous clinical time-to-event study in various federated scenarios. All algorithms are accessible through the intuitive web-app Partea (https://partea.zbh.uni-hamburg.de), offering a graphical user interface for clinicians and non-computational researchers without programming knowledge. Partea removes the high infrastructural hurdles derived from existing federated learning approaches and removes the complexity of execution. Therefore, it is an easy-to-use alternative to central data collection, reducing bureaucratic efforts but also the legal risks associated with the processing of personal data to a minimum.

Flimma: a federated and privacy-aware tool for differential gene expression analysis.

Aggregating transcriptomics data across hospitals can increase sensitivity and robustness of differential expression analyses, yielding deeper clinical insights. As data exchange is often restricted by privacy legislation, meta-analyses are frequently employed to pool local results. However, the accuracy might drop if class labels are inhomogeneously distributed among cohorts. Flimma ( https://exbio.wzw.tum.de/flimma/ ) addresses this issue by implementing the state-of-the-art workflow limma voom in a federated manner, i.e., patient data never leaves its source site. Flimma results are identical to those generated by limma voom on aggregated datasets even in imbalanced scenarios where meta-analysis approaches fail.

Computational strategies to combat COVID-19: useful tools to accelerate SARS-CoV-2 and coronavirus research.

SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) is a novel virus of the family Coronaviridae. The virus causes the infectious disease COVID-19. The biology of coronaviruses has been studied for many years. However, bioinformatics tools designed explicitly for SARS-CoV-2 have only recently been developed as a rapid reaction to the need for fast detection, understanding and treatment of COVID-19. To control the ongoing COVID-19 pandemic, it is of utmost importance to get insight into the evolution and pathogenesis of the virus. In this review, we cover bioinformatics workflows and tools for the routine detection of SARS-CoV-2 infection, the reliable analysis of sequencing data, the tracking of the COVID-19 pandemic and evaluation of containment measures, the study of coronavirus evolution, the discovery of potential drug targets and development of therapeutic strategies. For each tool, we briefly describe its use case and how it advances research specifically for SARS-CoV-2. All tools are free to use and available online, either through web applications or public code repositories. Contact:evbc@unj-jena.de.

Lessons from the COVID-19 pandemic for advancing computational drug repurposing strategies.

Responding quickly to unknown pathogens is crucial to stop uncontrolled spread of diseases that lead to epidemics, such as the novel coronavirus, and to keep protective measures at a level that causes as little social and economic harm as possible. This can be achieved through computational approaches that significantly speed up drug discovery. A powerful approach is to restrict the search to existing drugs through drug repurposing, which can vastly accelerate the usually long approval process. In this Review, we examine a representative set of currently used computational approaches to identify repurposable drugs for COVID-19, as well as their underlying data resources. Furthermore, we compare drug candidates predicted by computational methods to drugs being assessed by clinical trials. Finally, we discuss lessons learned from the reviewed research efforts, including how to successfully connect computational approaches with experimental studies, and propose a unified drug repurposing strategy for better preparedness in the case of future outbreaks.

Individuating Possibly Repurposable Drugs and Drug Targets for COVID-19 Treatment Through Hypothesis-Driven Systems Medicine Using CoVex.

Coronavirus disease 2019 (COVID-19), caused by the SARS-CoV-2 virus, has developed into a pandemic causing major disruptions and hundreds of thousands of deaths in wide parts of the world. As of July 3, 2020, neither vaccines nor approved drugs for effective treatment are available. In this article, we showcase how to individuate drug targets and potentially repurposable drugs in silico using CoVex a recently presented systems medicine platform for COVID-19 drug repurposing. Starting from initial hypotheses, CoVex leverages network algorithms to individuate host proteins involved in COVID-19 disease mechanisms, as well as existing drugs targeting these potential drug targets. Our analysis reveals GLA, PLAT, and GGCX as potential drug targets, and urokinase, argatroban, dabigatran etexilate, betrixaban, ximelagatran and anisindione as potentially repurposable drugs.

Exploring the SARS-CoV-2 virus-host-drug interactome for drug repurposing.

Coronavirus Disease-2019 (COVID-19) is an infectious disease caused by the SARS-CoV-2 virus. Various studies exist about the molecular mechanisms of viral infection. However, such information is spread across many publications and it is very time-consuming to integrate, and exploit. We develop CoVex, an interactive online platform for SARS-CoV-2 host interactome exploration and drug (target) identification. CoVex integrates virus-human protein interactions, human protein-protein interactions, and drug-target interactions. It allows visual exploration of the virus-host interactome and implements systems medicine algorithms for network-based prediction of drug candidates. Thus, CoVex is a resource to understand molecular mechanisms of pathogenicity and to prioritize candidate therapeutics. We investigate recent hypotheses on a systems biology level to explore mechanistic virus life cycle drivers, and to extract drug repurposing candidates. CoVex renders COVID-19 drug research systems-medicine-ready by giving the scientific community direct access to network medicine algorithms. It is available at https://exbio.wzw.tum.de/covex/.