Protocol for training MERGE: A federated multi-input neural network for COVID-19 prognosis.

Federated learning is a cooperative learning approach that has emerged as an effective way to address privacy concerns. Here, we present a protocol for training MERGE: a federated multi-input neural network (NN) for COVID-19 prognosis. We describe steps for collecting and preprocessing datasets. We then detail the process of training a multi-input NN. This protocol can be adapted for use with datasets containing both image- and table-based input sources. For complete details on the use and execution of this protocol, please refer to Casella et al.1.

MERGE: A model for multi-input biomedical federated learning.

Driven by the deep learning (DL) revolution, artificial intelligence (AI) has become a fundamental tool for many biomedical tasks, including analyzing and classifying diagnostic images. Imaging, however, is not the only source of information. Tabular data, such as personal and genomic data and blood test results, are routinely collected but rarely considered in DL pipelines. Nevertheless, DL requires large datasets that often must be pooled from different institutions, raising non-trivial privacy concerns. Federated learning (FL) is a cooperative learning paradigm that aims to address these issues by moving models instead of data across different institutions. Here, we present a federated multi-input architecture using images and tabular data as a methodology to enhance model performance while preserving data privacy. We evaluated it on two showcases: the prognosis of COVID-19 and patients' stratification in Alzheimer's disease, providing evidence of enhanced accuracy and F1 scores against single-input models and improved generalizability against non-federated models.

Bringing Cell Subpopulation Discovery on a Cloud-HPC Using rCASC and StreamFlow.

The idea behind novel single-cell RNA sequencing (scRNA-seq) pipelines is to isolate single cells through microfluidic approaches and generate sequencing libraries in which the transcripts are tagged to track their cell of origin. Modern scRNA-seq platforms are capable of analyzing up to many thousands of cells in each run. Then, combined with massive high-throughput sequencing producing billions of reads, scRNA-seq allows the assessment of fundamental biological properties of cell populations and biological systems at unprecedented resolution.In this chapter, we describe how cell subpopulation discovery algorithms, integrated into rCASC, could be efficiently executed on cloud-HPC infrastructure. To achieve this task, we focus on the StreamFlow framework which provides container-native runtime support for scientific workflows in cloud/HPC environments.

An ambient assisted living architecture for hospital at home coupled with a process-oriented perspective.

The growing number of next-generation applications offers a relevant opportunity for healthcare services, generating an urgent need for architectures for systems integration. Moreover, the huge amount of stored information related to events can be explored by adopting a process-oriented perspective. This paper discusses an Ambient Assisted Living healthcare architecture to manage hospital home-care services. The proposed solution relies on adopting an event manager to integrate sources ranging from personal devices to web-based applications. Data are processed on a federated cloud platform offering computing infrastructure and storage resources to improve scientific research. In a second step, a business process analysis of telehealth and telemedicine applications is considered. An initial study explored the business process flow to capture the main sequences of tasks, activities, events. This step paves the way for the integration of process mining techniques to compliance monitoring in an AAL architecture framework.

Machine learning for cardiology.

This paper reviews recent cardiology literature and reports how artificial intelligence tools (specifically, machine learning techniques) are being used by physicians in the field. Each technique is introduced with enough details to allow the understanding of how it works and its intent, but without delving into details that do not add immediate benefits and require expertise in the field. We specifically focus on the principal Machine learning based risk scores used in cardiovascular research. After introducing them and summarizing their assumptions and biases, we discuss their merits and shortcomings. We report on how frequently they are adopted in the field and suggest why this is the case based on our expertise in machine learning. We complete the analysis by reviewing how corresponding statistical approaches compare with them. Finally, we discuss the main open issues in applying machine learning tools to cardiology tasks, also drafting possible future directions. Despite the growing interest in these tools, we argue that there are many still underutilized techniques: while neural networks are slowly being incorporated in cardiovascular research, other important techniques such as semi-supervised learning and federated learning are still underutilized. The former would allow practitioners to harness the information contained in large datasets that are only partially labeled, while the latter would foster collaboration between institutions allowing building larger and better models.

An explainable AI system for automated COVID-19 assessment and lesion categorization from CT-scans.

COVID-19 infection caused by SARS-CoV-2 pathogen has been a catastrophic pandemic outbreak all over the world, with exponential increasing of confirmed cases and, unfortunately, deaths. In this work we propose an AI-powered pipeline, based on the deep-learning paradigm, for automated COVID-19 detection and lesion categorization from CT scans. We first propose a new segmentation module aimed at automatically identifying lung parenchyma and lobes. Next, we combine the segmentation network with classification networks for COVID-19 identification and lesion categorization. We compare the model's classification results with those obtained by three expert radiologists on a dataset of 166 CT scans. Results showed a sensitivity of 90.3% and a specificity of 93.5% for COVID-19 detection, at least on par with those yielded by the expert radiologists, and an average lesion categorization accuracy of about 84%. Moreover, a significant role is played by prior lung and lobe segmentation, that allowed us to enhance classification performance by over 6 percent points. The interpretation of the trained AI models reveals that the most significant areas for supporting the decision on COVID-19 identification are consistent with the lesions clinically associated to the virus, i.e., crazy paving, consolidation and ground glass. This means that the artificial models are able to discriminate a positive patient from a negative one (both controls and patients with interstitial pneumonia tested negative to COVID) by evaluating the presence of those lesions into CT scans. Finally, the AI models are integrated into a user-friendly GUI to support AI explainability for radiologists, which is publicly available at http://perceivelab.com/covid-ai. The whole AI system is unique since, to the best of our knowledge, it is the first AI-based software, publicly available, that attempts to explain to radiologists what information is used by AI methods for making decisions and that proactively involves them in the decision loop to further improve the COVID-19 understanding.

Advantages of using graph databases to explore chromatin conformation capture experiments.

BACKGROUND: High-throughput sequencing Chromosome Conformation Capture (Hi-C) allows the study of DNA interactions and 3D chromosome folding at the genome-wide scale. Usually, these data are represented as matrices describing the binary contacts among the different chromosome regions. On the other hand, a graph-based representation can be advantageous to describe the complex topology achieved by the DNA in the nucleus of eukaryotic cells. METHODS: Here we discuss the use of a graph database for storing and analysing data achieved by performing Hi-C experiments. The main issue is the size of the produced data and, working with a graph-based representation, the consequent necessity of adequately managing a large number of edges (contacts) connecting nodes (genes), which represents the sources of information. For this, currently available graph visualisation tools and libraries fall short with Hi-C data. The use of graph databases, instead, supports both the analysis and the visualisation of the spatial pattern present in Hi-C data, in particular for comparing different experiments or for re-mapping omics data in a space-aware context efficiently. In particular, the possibility of describing graphs through statistical indicators and, even more, the capability of correlating them through statistical distributions allows highlighting similarities and differences among different Hi-C experiments, in different cell conditions or different cell types. RESULTS: These concepts have been implemented in NeoHiC, an open-source and user-friendly web application for the progressive visualisation and analysis of Hi-C networks based on the use of the Neo4j graph database (version 3.5). CONCLUSION: With the accumulation of more experiments, the tool will provide invaluable support to compare neighbours of genes across experiments and conditions, helping in highlighting changes in functional domains and identifying new co-organised genomic compartments.

The CLAIRE COVID-19 initiative: approach, experiences and recommendations.

A volunteer effort by Artificial Intelligence (AI) researchers has shown it can deliver significant research outcomes rapidly to help tackle COVID-19. Within two months, CLAIRE's self-organising volunteers delivered the World's first comprehensive curated repository of COVID-19-related datasets useful for drug-repurposing, drafted review papers on the role CT/X-ray scan analysis and robotics could play, and progressed research in other areas. Given the pace required and nature of voluntary efforts, the teams faced a number of challenges. These offer insights in how better to prepare for future volunteer scientific efforts and large scale, data-dependent AI collaborations in general. We offer seven recommendations on how to best leverage such efforts and collaborations in the context of managing future crises.

Machine learning-based prediction of adverse events following an acute coronary syndrome (PRAISE): a modelling study of pooled datasets.

BACKGROUND: The accuracy of current prediction tools for ischaemic and bleeding events after an acute coronary syndrome (ACS) remains insufficient for individualised patient management strategies. We developed a machine learning-based risk stratification model to predict all-cause death, recurrent acute myocardial infarction, and major bleeding after ACS. METHODS: Different machine learning models for the prediction of 1-year post-discharge all-cause death, myocardial infarction, and major bleeding (defined as Bleeding Academic Research Consortium type 3 or 5) were trained on a cohort of 19 826 adult patients with ACS (split into a training cohort [80%] and internal validation cohort [20%]) from the BleeMACS and RENAMI registries, which included patients across several continents. 25 clinical features routinely assessed at discharge were used to inform the models. The best-performing model for each study outcome (the PRAISE score) was tested in an external validation cohort of 3444 patients with ACS pooled from a randomised controlled trial and three prospective registries. Model performance was assessed according to a range of learning metrics including area under the receiver operating characteristic curve (AUC). FINDINGS: The PRAISE score showed an AUC of 0·82 (95% CI 0·78-0·85) in the internal validation cohort and 0·92 (0·90-0·93) in the external validation cohort for 1-year all-cause death; an AUC of 0·74 (0·70-0·78) in the internal validation cohort and 0·81 (0·76-0·85) in the external validation cohort for 1-year myocardial infarction; and an AUC of 0·70 (0·66-0·75) in the internal validation cohort and 0·86 (0·82-0·89) in the external validation cohort for 1-year major bleeding. INTERPRETATION: A machine learning-based approach for the identification of predictors of events after an ACS is feasible and effective. The PRAISE score showed accurate discriminative capabilities for the prediction of all-cause death, myocardial infarction, and major bleeding, and might be useful to guide clinical decision making. FUNDING: None.

The Genome Conformation As an Integrator of Multi-Omic Data: The Example of Damage Spreading in Cancer.

Publicly available multi-omic databases, in particular if associated with medical annotations, are rich resources with the potential to lead a rapid transition from high-throughput molecular biology experiments to better clinical outcomes for patients. In this work, we propose a model for multi-omic data integration (i.e., genetic variations, gene expression, genome conformation, and epigenetic patterns), which exploits a multi-layer network approach to analyse, visualize, and obtain insights from such biological information, in order to use achieved results at a macroscopic level. Using this representation, we can describe how driver and passenger mutations accumulate during the development of diseases providing, for example, a tool able to characterize the evolution of cancer. Indeed, our test case concerns the MCF-7 breast cancer cell line, before and after the stimulation with estrogen, since many datasets are available for this case study. In particular, the integration of data about cancer mutations, gene functional annotations, genome conformation, epigenetic patterns, gene expression, and metabolic pathways in our multi-layer representation will allow a better interpretation of the mechanisms behind a complex disease such as cancer. Thanks to this multi-layer approach, we focus on the interplay of chromatin conformation and cancer mutations in different pathways, such as metabolic processes, that are very important for tumor development. Working on this model, a variance analysis can be implemented to identify normal variations within each omics and to characterize, by contrast, variations that can be accounted to pathological samples compared to normal ones. This integrative model can be used to identify novel biomarkers and to provide innovative omic-based guidelines for treating many diseases, improving the efficacy of decision trees currently used in clinic.

PWHATSHAP: efficient haplotyping for future generation sequencing.

BACKGROUND: Haplotype phasing is an important problem in the analysis of genomics information. Given a set of DNA fragments of an individual, it consists of determining which one of the possible alleles (alternative forms of a gene) each fragment comes from. Haplotype information is relevant to gene regulation, epigenetics, genome-wide association studies, evolutionary and population studies, and the study of mutations. Haplotyping is currently addressed as an optimisation problem aiming at solutions that minimise, for instance, error correction costs, where costs are a measure of the confidence in the accuracy of the information acquired from DNA sequencing. Solutions have typically an exponential computational complexity. WHATSHAP is a recent optimal approach which moves computational complexity from DNA fragment length to fragment overlap, i.e., coverage, and is hence of particular interest when considering sequencing technology's current trends that are producing longer fragments. RESULTS: Given the potential relevance of efficient haplotyping in several analysis pipelines, we have designed and engineered PWHATSHAP, a parallel, high-performance version of WHATSHAP. PWHATSHAP is embedded in a toolkit developed in Python and supports genomics datasets in standard file formats. Building on WHATSHAP, PWHATSHAP exhibits the same complexity exploring a number of possible solutions which is exponential in the coverage of the dataset. The parallel implementation on multi-core architectures allows for a relevant reduction of the execution time for haplotyping, while the provided results enjoy the same high accuracy as that provided by WHATSHAP, which increases with coverage. CONCLUSIONS: Due to its structure and management of the large datasets, the parallelisation of WHATSHAP posed demanding technical challenges, which have been addressed exploiting a high-level parallel programming framework. The result, PWHATSHAP, is a freely available toolkit that improves the efficiency of the analysis of genomics information.

Integrating multi-omic features exploiting Chromosome Conformation Capture data.

The representation, integration, and interpretation of omic data is a complex task, in particular considering the huge amount of information that is daily produced in molecular biology laboratories all around the world. The reason is that sequencing data regarding expression profiles, methylation patterns, and chromatin domains is difficult to harmonize in a systems biology view, since genome browsers only allow coordinate-based representations, discarding functional clusters created by the spatial conformation of the DNA in the nucleus. In this context, recent progresses in high throughput molecular biology techniques and bioinformatics have provided insights into chromatin interactions on a larger scale and offer a formidable support for the interpretation of multi-omic data. In particular, a novel sequencing technique called Chromosome Conformation Capture allows the analysis of the chromosome organization in the cell's natural state. While performed genome wide, this technique is usually called Hi-C. Inspired by service applications such as Google Maps, we developed NuChart, an R package that integrates Hi-C data to describe the chromosomal neighborhood starting from the information about gene positions, with the possibility of mapping on the achieved graphs genomic features such as methylation patterns and histone modifications, along with expression profiles. In this paper we show the importance of the NuChart application for the integration of multi-omic data in a systems biology fashion, with particular interest in cytogenetic applications of these techniques. Moreover, we demonstrate how the integration of multi-omic data can provide useful information in understanding why genes are in certain specific positions inside the nucleus and how epigenetic patterns correlate with their expression.

Sequence alignment tools: one parallel pattern to rule them all?

In this paper, we advocate high-level programming methodology for next generation sequencers (NGS) alignment tools for both productivity and absolute performance. We analyse the problem of parallel alignment and review the parallelisation strategies of the most popular alignment tools, which can all be abstracted to a single parallel paradigm. We compare these tools to their porting onto the FastFlow pattern-based programming framework, which provides programmers with high-level parallel patterns. By using a high-level approach, programmers are liberated from all complex aspects of parallel programming, such as synchronisation protocols, and task scheduling, gaining more possibility for seamless performance tuning. In this work, we show some use cases in which, by using a high-level approach for parallelising NGS tools, it is possible to obtain comparable or even better absolute performance for all used datasets.

On designing multicore-aware simulators for systems biology endowed with OnLine statistics.

The paper arguments are on enabling methodologies for the design of a fully parallel, online, interactive tool aiming to support the bioinformatics scientists .In particular, the features of these methodologies, supported by the FastFlow parallel programming framework, are shown on a simulation tool to perform the modeling, the tuning, and the sensitivity analysis of stochastic biological models. A stochastic simulation needs thousands of independent simulation trajectories turning into big data that should be analysed by statistic and data mining tools. In the considered approach the two stages are pipelined in such a way that the simulation stage streams out the partial results of all simulation trajectories to the analysis stage that immediately produces a partial result. The simulation-analysis workflow is validated for performance and effectiveness of the online analysis in capturing biological systems behavior on a multicore platform and representative proof-of-concept biological systems. The exploited methodologies include pattern-based parallel programming and data streaming that provide key features to the software designers such as performance portability and efficient in-memory (big) data management and movement. Two paradigmatic classes of biological systems exhibiting multistable and oscillatory behavior are used as a testbed.

Parallel stochastic systems biology in the cloud.

The stochastic modelling of biological systems, coupled with Monte Carlo simulation of models, is an increasingly popular technique in bioinformatics. The simulation-analysis workflow may result computationally expensive reducing the interactivity required in the model tuning. In this work, we advocate the high-level software design as a vehicle for building efficient and portable parallel simulators for the cloud. In particular, the Calculus of Wrapped Components (CWC) simulator for systems biology, which is designed according to the FastFlow pattern-based approach, is presented and discussed. Thanks to the FastFlow framework, the CWC simulator is designed as a high-level workflow that can simulate CWC models, merge simulation results and statistically analyse them in a single parallel workflow in the cloud. To improve interactivity, successive phases are pipelined in such a way that the workflow begins to output a stream of analysis results immediately after simulation is started. Performance and effectiveness of the CWC simulator are validated on the Amazon Elastic Compute Cloud.