Critical Path RD Explorer

Rare disease data are expensive to collect due to the diversity of rare diseases and small, dispersed patient populations, but often of low value, due to heterogeneity and sparseness. Difficulty of answering research questions with a single study places undue burden on patients to share their data repeatedly or participate in multiple studies. Integrating data across studies and diseases turns rare data into big data. The Critical Path RD Explorer combines cutting edge technology with extensive experience in building collaborations to deliver a data resource that spans patient registries, clinical trials, genomics, and more. The RD Explorer’s graph-like structure lets researchers, regulators, and patients discover new insights, analyze integrated datasets, and share their findings with others. By transforming previously low-value rare disease data into big, integrated data, the RD Explorer will accelerate the discovery of new tools and treatments, impacting the lives of rare diseases patients worldwide. 

Approximately 90% of approximately 350 million people worldwide living with a rare disease have no approved treatment, even though many rare diseases result in significant disability and mortality. The development of therapies is hampered by a limited understanding of the progression and symptoms of each rare disease, how changes in disease progression can be measured, and challenges in designing and running clinical trials, all of which are limited by the availability of data. Data that could be used to characterize the natural history of each disease are collected in electronic health records, patient-report registries, natural history studies, clinical trials, and other sources, but each data source contains a limited number of subjects and different data elements. Furthermore, data are rarely shared widely across the rare disease community, due to concerns about patient privacy and proprietary interests. Critical Path’s RD Explorer aims to provide disease patients and researchers with tools to encourage data sharing and increase data value and utility by combining them in novel ways. 

The Critical Path RD Explorer is a graphical interface that connects to multiple data sources and is accessible through a standard web browser. It lets patients, researchers, and regulators explore integrated data across rare diseases to discover new connections in previously isolated information. The RD Explorer begins with access to the curated and integrated data on Critical Path’s Data and Analytics Platform, which includes clinical, pre-clinical, and registry data. It then federates with genotype to symptom association data in the Monarch Initiative, patient resources from Orphanet, and the Virtual Platform of EJP-RD. The back-end database uses ontologies (code that make data understandable to machines) to link data on patients and their symptoms, medications, genes, population demographics, and more. The front end takes advantage of the graph-like structure (nodes and edges) of the database to provide an intuitive browsing interface where people can explore connections among different data elements. To ensure privacy and encourage sharing, the RD Explorer only shows categories of data and their types, like symptoms linked to a disease or how many patients display a symptom. These categorical data are securely linked to patient-level measurements and counts, and access to those data and C-Path’s free analytical platform can be requested for further analysis. 

The rare disease ecosystem is a complex landscape of academic investigators, biopharmaceutic companies, regulatory authorities, patient groups, patient advocates, and patients themselves. This entire ecosystem represents the target population in the context of accelerating rare disease cures. There is tremendous value in understanding underlying disease biology and the heterogeneity of the disease trajectory as well as identifying factors and biomarkers that discriminate patients and may impact responsiveness to potential therapies. Success in this setting necessitates collaboration and the sharing of knowledge and data. In order to best serve this diverse group of stakeholders, the RD explorer provides access to contributed data from the rare disease ecosystem representing completed clinical trials, natural history data, registry data, genetic data, and complimentary preclinical data. The Explorer itself is a novel graph-based interface in which any stakeholder can explore the data.The Explorer  <>links to RDCA-DAP (Critical Path’s Data and Analytics Platform) to provide customized interfaces to datasets and a suite of tools tailored to various stakeholders (e.g., patients, clinical regulatory reviewer, academic investigator, drug developer). RDCA-DAP tools include a variety of exploratory approaches to summarize and visualize data as well as approaches that exploit sophisticated models that describe disease biology and disease progression in addition to provide guidance on clinical endpoint selection and clinical trial design in general. RDCA-DAP is being built to serve a range of stakeholders, but we are adding the RD Explorer to better serve non-technical stakeholders including patients.  

Despite good intentions, sharing does not always happen in a coordinated or efficient manner and data are not always available for analysis without significant effort in curation, standardization, and other clean-up activities. The RD Explorer unlocks collaboration among patients, scientists, and health care providers by providing secured access to well-curated, standardized data that can be intuitively visualized and recombined in a customized manner along with a suite of tools available for subsequent analysis and exploitation. 

The RD Explorer is a prototype being built on top of Critical Path’s Rare Disease Cures Accelerator Data and Analytics Platform. The RDCA-DAP itself is in the pilot stage and includes basic functionality like ingestion, curation, access controls, and analysis tools. The RD Explorer is a prototype being built on top of the RDCA-DAP to provide an enhanced user experience for a broader range of people. We are just beginning development of the graph data model and user interface that will drive the RD Explorer and testing its scalability. We already have established partnerships with Monarch Initiative and EJP-RD.

The Critical Path RD Explorer is innovative in the way it uses existing but not yet widely adopted technologies to provide access to data for a variety of stakeholders. Ontologies are widely used to integrate genotype and phenotype data, but there has been much less work to semantically integrate measurement (e.g., continuous) and survey (categorical) data. Team Lead Walls has experience with just such tasks in biodiversity data and brings that novel approach to the biomedical world with this project. Another innovation is the use of a graph-browsing interface for rare disease data. Graph databases have existed for some time, but graph-based interfaces for a general audience are a rarity. We believe that the ability to explore new data connections in a graphic interface that uses the semantics encoded in existing ontologies (e.g., Monarch Disease Ontology, Gene Ontology) combined with the new ontologies we are building for continuous and categorical rare disease data, will drive discover and innovation in the development of treatments for rare diseases. For example, the hierarchical nature of disease ontologies allows people to browse data about all rare diseases that have a neurological basis or share a set of symptoms in the same are of a graph. This kind of association can suggest mechanisms or treatments for one disease based on closely related diseases. Simply putting all the data in a single knowledge graph may make the connections, but there is so much information, they may be missed. A graphical interface will allow people to discover connections they may have missed simply because they did not know what to query for.  

The core technologies underlying the RD Explorer are ontologies, graph databases, and standardization software. While none of these technologies are new, we are combining them in an innovative way to solve a specific problem. We are also using application programming interfaces (APIs) and cloud computing to federate data across multiple partners. This allows each partner to manage their data in the way that best suits their needs, but, thanks to a shared semantic model, metadata can be shared across sites. 

There are inherent privacy risks associated with sharing patient-level information. To mitigate privacy concerns, contributor data must be fully anonymized prior to integration into the RD Explorer. Data contributor agreements that address the requirements regarding the shared data must be in place before any dataset is transferred to the RD Explorer for storage, research, or analysis. To ensure secure access to the RD Explorer, interested users must obtain approval from the RD Explorer administrators prior to accessing any data or tools. All access to shared data and tools for analytics is available exclusively on the RD Explorer platform, facilitating a well-controlled environment and eliminating the need to download any data for external use. To enable the traceability of users and data usage, an automatically generated audit log of all activity performed within the RD Explorer platform is monitored by the platform administrators. The platform interface is provided by Aridhia Informatics Ltd and hosted within the Microsoft Azure cloud platform. Both entities have extensive measures in place to ensure the privacy and security of the data.  

Approximately 140 people work at the Critical Path Institute full time. Of these, 3 people are working full time and 5 people part time on the RDCA-DAP and RD Explorer.

No, although my daughter has a rare disease.