The Solve-RD project objectives include solving undiagnosed rare diseases (RD) through collaborative research on shared genome-phenome datasets. The RD-Connect Genome-Phenome Analysis Platform (GPAP), for data collation and analysis, and the European Genome-Phenome Archive (EGA), for file storage, are two key components of the Solve-RD infrastructure. Clinical researchers can identify candidate genetic variants within the RD-Connect GPAP and, thanks to the developments presented here as part of joint ELIXIR activities, are able to remotely visualize the corresponding alignments stored at the EGA. The Global Alliance for Genomics and Health (GA4GH) htsget streaming application programming interface (API) is used to retrieve alignment slices, which are rendered by an integrated genome viewer (IGV) instance embedded in the GPAP. As a result, it is no longer necessary for over 11,000 datasets to download large alignment files to visualize them locally. This work highlights the advantages, from both the user and infrastructure perspectives, of implementing interoperability standards for establishing federated genomics data networks.

Rare disease patients are more likely to receive a rapid molecular diagnosis nowadays thanks to the wide adoption of next-generation sequencing. However, many cases remain undiagnosed even after exome or genome analysis, because the methods used missed the molecular cause in a known gene, or a novel causative gene could not be identified and/or confirmed. To address these challenges, the RD-Connect Genome-Phenome Analysis Platform (GPAP) facilitates the collation, discovery, sharing, and analysis of standardized genome-phenome data within a collaborative environment. Authorized clinicians and researchers submit pseudonymised phenotypic profiles encoded using the Human Phenotype Ontology, and raw genomic data which is processed through a standardized pipeline. After an optional embargo period, the data are shared with other platform users, with the objective that similar cases in the system and queries from peers may help diagnose the case. Additionally, the platform enables bidirectional discovery of similar cases in other databases from the Matchmaker Exchange network. To facilitate genome-phenome analysis and interpretation by clinical researchers, the RD-Connect GPAP provides a powerful user-friendly interface and leverages tens of information sources. As a result, the resource has already helped diagnose hundreds of rare disease patients and discover new disease causing genes.

An amendment to this paper has been published and can be accessed via the original article.

An amendment to this paper has been published and can be accessed via the original article.

Recent advances in computational and algorithmic power are evolving the field of medical imaging rapidly. In cancer research, many new directions are sought to characterize patients with additional imaging features derived from radiology and pathology images. The emerging field of Computational Pathology targets the high-throughput extraction and analysis of the spatial distribution of cells from digital histopathology images. The associated morphological and architectural features allow researchers to quantify and characterize new imaging biomarkers for cancer diagnosis, prognosis, and treatment decisions. However, while the image feature space grows, exploration and analysis become more difficult and ineffective. There is a need for dedicated interfaces for interactive data manipulation and visual analysis of computational pathology and clinical data. For this purpose, we present IIComPath, a visual analytics approach that enables clinical researchers to formulate hypotheses and create computational pathology pipelines involving cohort construction, spatial analysis of image-derived features, and cohort analysis. We demonstrate our approach through use cases that investigate the prognostic value of current diagnostic features and new computational pathology biomarkers.

Reanalysis of inconclusive exome/genome sequencing data increases the diagnosis yield of patients with rare diseases. However, the cost and efforts required for reanalysis prevent its routine implementation in research and clinical environments. The Solve-RD project aims to reveal the molecular causes underlying undiagnosed rare diseases. One of the goals is to implement innovative approaches to reanalyse the exomes and genomes from thousands of well-studied undiagnosed cases. The raw genomic data is submitted to Solve-RD through the RD-Connect Genome-Phenome Analysis Platform (GPAP) together with standardised phenotypic and pedigree data. We have developed a programmatic workflow to reanalyse genome-phenome data. It uses the RD-Connect GPAP's Application Programming Interface (API) and relies on the big-data technologies upon which the system is built. We have applied the workflow to prioritise rare known pathogenic variants from 4411 undiagnosed cases. The queries returned an average of 1.45 variants per case, which first were evaluated in bulk by a panel of disease experts and afterwards specifically by the submitter of each case. A total of 120 index cases (21.2% of prioritised cases, 2.7% of all exome/genome-negative samples) have already been solved, with others being under investigation. The implementation of solutions as the one described here provide the technical framework to enable periodic case-level data re-evaluation in clinical settings, as recommended by the American College of Medical Genetics.

The COVID-19 pandemic has posed and is continuously posing enormous societal and health challenges worldwide. The research community has mobilized to develop novel projects to find a cure or a vaccine, as well as to contribute to mass testing, which has been a critical measure to contain the infection in several countries. Through this article, we share our experiences and learnings as a group of volunteers at the Centre for Genomic Regulation (CRG) in Barcelona, Spain. As members of the ORFEU project, an initiative by the Government of Catalonia to achieve mass testing of people at risk and contain the epidemic in Spain, we share our motivations, challenges and the key lessons learnt, which we feel will help better prepare the global society to address similar situations in the future.

The COVID-19 pandemic has posed and is continuously posing enormous societal and health challenges worldwide. The research community has mobilized to develop novel projects to find a cure or a vaccine, as well as to contribute to mass testing, which has been a critical measure to contain the infection in several countries. Through this article, we share our experiences and learnings as a group of volunteers at the Centre for Genomic Regulation (CRG) in Barcelona, Spain. As members of the ORFEU project, an initiative by the Government of Catalonia to achieve mass testing of people at risk and contain the epidemic in Spain, we share our motivations, challenges and the key lessons learnt, which we feel will help better prepare the global society to address similar situations in the future.

The advances in high-throughput digitization, digital pathology systems, and quantitative image analysis opened new horizons in pathology. The diagnostic work of the pathologists and their role is likely to be augmented with computer-assistance and more quantitative information at hand. The recent success of artificial intelligence (AI) and computer vision methods demonstrated that in the coming years machines will support pathologists in typically tedious and highly subjective tasks and also in better patient stratification. In spite of clear future improvements in the diagnostic workflow, questions on how to effectively support the pathologists and how to integrate current data sources and quantitative information still persist. In this context, Visual Analytics (VA) - as the discipline that aids users to solve complex problems with an interactive and visual approach - can play a vital role to support the cognitive skills of pathologists and the large volumes of data available. To identify the main opportunities to employ VA in digital pathology systems, we conducted a survey with 20 pathologists to characterize the diagnostic practice and needs from a user perspective. From our findings, we discuss how VA can leverage quantitative image data to empower pathologists with new advanced digital pathology systems.

The increasing quantity of data in biomedical informatics is leading towards better patient profiling and personalized medicine. Lab tests, medical images, and clinical data represent extraordinary sources for patient characterization. While retrospective studies focus on finding correlations in this sheer volume of data, potential new biomarkers are difficult to identify. A common approach is to observe patient mortality with respect to different clinical variables in what is called survival analysis. Kaplan-Meier plots, also known as survival curves, are generally used to examine patient survival in retrospective and prognostic studies. The plot is very intuitive and hence very popular in the medical domain to disclose evidence of poor or good prognosis. However, the Kaplan-Meier plots are mostly static and the data exploration of the plotted cohorts can be performed only with additional analysis. There is a need to make survival plots interactive and to integrate potential prognostic data that may reveal correlations with disease progression. We introduce SurviVIS, a visual analytics approach for interactive survival analysis and data integration on Kaplan-Meier plots. We demonstrate our work on a melanoma dataset and in the perspective of a potential use case in precision imaging.

Computer-Aided-Diagnosis (CAD) systems supporting the diagnostic process are widespread in radiology. Digital Pathology is still behind in the introduction of such solutions. Several studies investigated pathologists' behavior but only a few aimed to improve the diagnostic and report process with novel applications. In this work we designed and implemented a first protocol-based CAD viewer supported by visual analytics. The system targets the optimization of the diagnostic workflow in breast cancer diagnosis by means of three image analysis features that belong to the standard grading system (Nottingham Histologic Grade). A pathologist's routine was tracked during the examination of breast cancer tissue slides and diagnostic traces were analyzed from a qualitative perspective. Accordingly, a set of generic requirements was elicited to define the design and the implementation of the CAD-Viewer. A first qualitative evaluation conducted with five pathologists shows that the interface suffices the diagnostic workflow and diminishes the manual effort. We present promising evidence of the usefulness of our CAD-viewer and opportunities for its extension and integration in clinical practice. As a conclusion, the findings demonstrate that it is feasibile to optimize the Nottingham Grading workflow and, generally, the histological diagnosis by integrating computational pathology data with visual analytics techniques.

We introduce PathoVA, a visual analytics system for computer aided pathology diagnosis. The diagnostic work of a pathologist involves characterizing cells and the appearance of histological sections of tissues, which are stained by techniques that highlight particular elements. Our system supports this work by recording activities in a digital tissue slide viewer, from which a diagnostic trace is constructed automatically. The visualization of the trace is enhanced with quantitative data about the tissue obtained by image analysis. Using the trace visualization, the pathologist can fill out the pathology report according to the required protocol. We demonstrate our approach on a use case of breast tissue examination. Our qualitative evaluation shows that PathoVA supports the diagnostic procedure and simplifies reporting.

In a typical healthcare setting, specific clinical care pathways can be defined by the hospitals. Process mining provides a way of analyzing the care pathways by analyzing the event data extracted from the hospital information systems. Process mining can be used to optimize the overall care pathway, and gain interesting insights into the actual execution of the process, as well as to compare the expectations versus the reality. In this paper, a generic novel tool called InterPretA, is introduced which builds upon pre-existing process mining and visual analytics techniques to enable the user to perform such process oriented analysis. InterPretA contains a set of options to provide high level conformance analysis of a process from different perspectives. Furthermore, InterPretA enables detailed investigative analysis by letting the user interactively analyze, visualize and explore the execution of the processes from the data perspective.

Digital platforms in healthcare institutions enable tracking and recording of patient care pathways. Besides the Electronic Health Records (EHRs), the event logs from Hospital Information Systems (HIS) are a very efficient source of information, from both operational and clinical point of view. Process mining allows comparison of a patient care pathway with the event log(s) from HIS, to understand how well the reality as depicted in the event log fits the expectation as modeled using a care pathway. In this paper, we present SepVis, a visual analytics tool which aims to fill the gap in current process-centric applications by looking at patients' pathways from a clinical point of view. We demonstrate the utility of SepVis in selected use cases derived by the guidelines in the management of sepsis patients.

Digital Pathology is a recent clinical environment in which Electronic Health Records (EHRs), biopsy data and whole-slide- images (WSI) come together to provide pathologists the necessary information for making a diagnosis. Integration of this heterogeneous data into a single application is still one of the challenges in the evolution of pathology to a digital practice. While pathologists can perform diagnoses routinely on digital slides only, this is not the case in clinical research. For such purposes, the link between clinicopathological information of patients and images is essential. For example, image analysis researchers who develop automated diagnostic (support) algorithms need to select a representative set of slides to evaluate their methods. To achieve this, they need applications that combine cohort specification, slide image exploration, and selection of suitable images. We present the visualization tool PATHONE, which enables users to perform these steps on a single screen, integrating cohort and WSI selection.