International Rare Diseases Research Consortium Research Articles

Phenotypic similarity-based approach for variant prioritization for unsolved rare disease: a preliminary methodological report

Rare diseases (RD) have a prevalence of not more than 1/2000 persons in the European population, and are characterised by the difficulty experienced in obtaining a correct and timely diagnosis. According to Orphanet, 72.5% of RD have a genetic origin although 35% of them do not yet have an identified causative gene. A significant proportion of patients suspected to have a genetic RD receive an inconclusive exome/genome sequencing. Working towards the International Rare Diseases Research Consortium (IRDiRC)’s goal for 2027 to ensure that all people living with a RD receive a diagnosis within one year of coming to medical attention, the Solve-RD project aims to identify the molecular causes underlying undiagnosed RD. As part of this strategy, we developed a phenotypic similarity-based variant prioritization methodology comparing submitted cases with other submitted cases and with known RD in Orphanet. Three complementary approaches based on phenotypic similarity calculations using the Human Phenotype Ontology (HPO), the Orphanet Rare Diseases Ontology (ORDO) and the HPO-ORDO Ontological Module (HOOM) were developed; genomic data reanalysis was performed by the RD-Connect Genome-Phenome Analysis Platform (GPAP). The methodology was tested in 4 exemplary cases discussed with experts from European Reference Networks. Variants of interest (pathogenic or likely pathogenic) were detected in 8.8% of the 725 cases clustered by similarity calculations. Diagnostic hypotheses were validated in 42.1% of them and needed further exploration in another 10.9%. Based on the promising results, we are devising an automated standardized phenotypic-based re-analysis pipeline to be applied to the entire unsolved cases cohort.

Next-generation sequencing-based newborn screening initiatives in Europe: an overview

Aim: This article describes results from a survey targeting healthcare professionals (HCPs) leading newborn screening (NBS) initiatives in Europe. The survey was developed within the framework of a dedicated working group set up by the International Rare Diseases Research Consortium (IRDiRC) to gather collective efforts relating to NBS. The objectives of the survey were to gain a better understanding of approaches being tested for the expansion of NBS and to raise awareness of the significant momentum across Europe to evaluate novel technologies for use in future NBS programs. Methods: A web-based survey including 57 questions was developed to gather information about genomic newborn screening initiatives in Europe that are using next-generation sequencing (NGS) as a first-tier test. Responses were analyzed qualitatively, and aggregated results are presented herein. The identity of some initiatives is not presented to preserve confidentiality. Results: The findings of the survey indicated that most initiatives are in the planning stage and have not yet started. Although all 14 studies are heterogeneous in design, there is broad consensus that NGS approaches to NBS will, in the short term, be implemented in parallel with current screening programs. The results of this survey can be used to inform the design of studies still in the early planning stages. Conclusion: Here, we provide an overview of NGS-based initiatives in Europe. Importantly, the initiatives described herein will generate evidence to evaluate the utility and feasibility of NGS approaches to NBS, thereby shortening the pathway to responsible implementation of NGS in NBS and informing future research efforts.

Towards the international interoperability of clinical research networks for rare diseases: recommendations from the IRDiRC Task Force

BackgroundMany patients with rare diseases are still lacking a timely diagnosis and approved therapies for their condition despite the tremendous efforts of the research community, biopharmaceutical, medical device industries, and patient support groups. The development of clinical research networks for rare diseases offers a tremendous opportunity for patients and multi-disciplinary teams to collaborate, share expertise, gain better understanding on specific rare diseases, and accelerate clinical research and innovation. Clinical Research Networks have been developed at a national or continental level, but global collaborative efforts to connect them are still lacking. The International Rare Diseases Research Consortium set a Task Force on Clinical Research Networks for Rare Diseases with the objective to analyse the structure and attributes of these networks and to identify the barriers and needs preventing their international collaboration. The Task Force created a survey and sent it to pre-identified clinical research networks located worldwide.ResultsA total of 34 responses were received. The survey analysis demonstrated that clinical research networks are diverse in their membership composition and emphasize community partnerships including patient groups, health care providers and researchers. The sustainability of the networks is mostly supported by public funding. Activities and research carried out at the networks span the research continuum from basic to clinical to translational research studies. Key elements and infrastructures conducive to collaboration are well adopted by the networks, but barriers to international interoperability are clearly identified. These hurdles can be grouped into five categories: funding limitation; lack of harmonization in regulatory and contracting process; need for common tools and data standards; need for a governance framework and coordination structures; and lack of awareness and robust interactions between networks.ConclusionsThrough this analysis, the Task Force identified key elements that should support both developing and established clinical research networks for rare diseases in implementing the appropriate structures to achieve international interoperability worldwide. A global roadmap of actions and a specific research agenda, as suggested by this group, provides a platform to identify common goals between these networks.

The international rare disease research consortium (IRDiRC): making rare disease research efforts more efficient and collaborative around the world

The International Rare Disease Research Consortium, or IRDiRC, is a global consortium of key stakeholders from different facets of rare disease research that together seek to drive advances in diagnostics, therapeutics, and patient outcomes. The consortium facilitates a global and cross-disciplinary exchange of ideas to tackle key issues in rare diseases through the development of recommendations, data standards, tools, and guidelines that harmonize research efforts and improve efficiency. While IRDiRC has made significant contributions to the development of new therapies and diagnostics since its establishment in 2011, much work remains to alleviate the burden of rare diseases. The consortium has demonstrated its success in providing a global platform to advance rare disease research through collaborative efforts worldwide and continues to identify and address barriers to health equity for all rare disease patients.

The IRDiRC Chrysalis Task Force: making rare disease research attractive to companies.

The International Rare Diseases Research Consortium (IRDiRC) is an international initiative that aims to use research to facilitate rapid diagnosis and treatment of rare diseases. IRDiRC launched the Chrysalis Task Force to identify key financial and nonfinancial factors that make rare disease research and development attractive to companies. The Chrysalis Task Force was comprised of thought leaders from companies, patient advocacy groups, regulatory agencies, and research funders. The Task Force created a survey that was distributed to companies of different sizes with varied investment portfolios and interests in rare disease research. Based on the survey results, the Task Force then conducted targeted interviews. The survey and interview respondents identified several factors that make rare disease research and development attractive (e.g. a good understanding of the underlying biology) as well as barriers (e.g. absence of an advocacy organization representing the affected community's needs). The concept of Return On Investment allowed the exploration of factors that were weighed differently by survey and interview respondents, depending on a number of intrinsic and extrinsic issues. The Chrysalis Task Force identified factors attributable to rare disease research and development that may be of interest to and actionable by funders, academic researchers, patients and their families, companies, regulators, and payers in the medium term to short term. By addressing the identified challenges, involved parties may seek solutions to significantly advance the research and development of treatments for rare diseases.

Sustainable approaches for drug repurposing in rare diseases: recommendations from the IRDiRC Task Force

Drug repurposing represents a real opportunity to address unmet needs and improve the lives of rare disease patients. It is often presented as a faster, safer and cheaper path for bringing drugs into new indications. However, several economic, regulatory and scientific barriers can impede the successful repurposing of drugs for rare diseases. The International Rare Diseases Research Consortium (IRDiRC) set up the Task Force on Sustainable Models in Drug Repurposing with the objective of identifying key factors for achieving sustainable repurposing approaches in rare diseases. In order to help inform expert opinion, the Task Force investigated six cases of medicinal products repurposed into new rare indications and four cases of ongoing development programs. A questionnaire addressing the major steps of the repurposing approach was developed by the Task Force and sent to contact points of the organizations. In addition, interviews were conducted with the relevant organization representatives to conduct a deeper dive into the sustainability of the repurposing approach for each of the selected cases. Based on the collective experience of the members of the Task Force and the output from the questionnaires/interviews, we have identified ten key factors that should be considered by those embarking on repurposing projects. These factors include the identification of unmet patient needs and partnership with patients, collection of evidence concerning disease prevalence, patient numbers, drug pharmacology and disease etiology, drug industrial property status, off-label or compounding use, data from past clinical studies and needs for extended non-clinical and clinical studies. The development of a collaborative funding framework and early discussion with regulators and payers are additional factors to implement early in the development of sustainable drug repurposing projects.

Diagnostic delay in rare diseases: data from the Spanish rare diseases patient registry

BackgroundAccording to the International Rare Diseases Research Consortium (IRDiRC), a known rare disease (RD) should be diagnosable within a year. This study sought: firstly, to ascertain how long it takes to obtain the diagnosis of a RD in Spain, along with its associated time trend; and secondly, to identify and measure diagnostic delay (defined by the IRDiRC as any period exceeding a year) by reference to the characteristics of RDs and the persons affected by them.MethodsUsing data sourced from the Spanish Rare Diseases Patient Registry, we performed a descriptive analysis of the time elapsed between symptom onset and diagnosis of each RD, by sex, age and date of symptom onset, and type of RD. We analysed the time trend across the period 1960–2021 and possible change points, using a Joinpoint regression model and assuming a Poisson distribution. The multivariate analysis was completed with backward stepwise logistic regression.ResultsDetailed information was obtained on 3304 persons with RDs: 56.4% had experienced delay in diagnosis of their RDs, with the mean time taken being 6.18 years (median = 2; IQR 0.2–7.5). Both the percentage of patients with diagnostic delay and the average time to diagnosis underwent a significant reduction across the study period (p < 0.001). There was a higher percentage of diagnostic delays: in women (OR 1.25; 95% CI 1.07–1.45); in cases with symptom onset at age 30–44 years (OR 1.48; 95% CI 1.19–1.84): and when analysed by type of RD, in mental and behavioural disorders (OR 4.21; 95% CI 2.26–7.85), followed by RDs of the nervous system (OR 1.39; 95% CI 1.02–1.88).ConclusionsThis is the first study to quantify time to diagnosis of RDs in Spain, based on data from a national registry open to any RD. Since over half of all persons affected by RDs experience delay in diagnosis, new studies are needed to ascertain the factors associated with this delay and the implications this has on the lives of patients and their families.

Recommendations from the IRDiRC Working Group on methodologies to assess the impact of diagnoses and therapies on rare disease patients

Rare disease patients face many challenges including diagnostic delay, misdiagnosis and lack of therapies. However, early access to diagnosis and therapies can modify the management and the progression of diseases, which in return positively impacts patients, families and health care systems. The International Rare Diseases Research Consortium set up the multi-stakeholder Working Group on developing methodologies to assess the impact of diagnoses and therapies on rare disease patients. Using the patients’ journey on the diagnostic paradigm, the Working Group characterized a set of metrics, tools and needs required for appropriate data collection and establishment of a framework of methodologies to analyze the socio-economic burden of rare diseases on patients, families and health care systems. These recommendations are intended to facilitate the development of methodologies and to better assess the societal impact of rare diseases.

CIBERER: Spanish national network for research on rare diseases: A highly productive collaborative initiative.

CIBER (Center for Biomedical Network Research; Centro de Investigación Biomédica En Red) is a public national consortium created in 2006 under the umbrella of the Spanish National Institute of Health Carlos III (ISCIII). This innovative research structure comprises 11 different specific areas dedicated to the main public health priorities in the National Health System. CIBERER, the thematic area of CIBER focused on rare diseases (RDs) currently consists of 75 research groups belonging to universities, research centers, and hospitals of the entire country. CIBERER's mission is to be a center prioritizing and favoring collaboration and cooperation between biomedical and clinical research groups, with special emphasis on the aspects of genetic, molecular, biochemical, and cellular research of RDs. This research is the basis for providing new tools for the diagnosis and therapy of low‐prevalence diseases, in line with the International Rare Diseases Research Consortium (IRDiRC) objectives, thus favoring translational research between the scientific environment of the laboratory and the clinical setting of health centers. In this article, we intend to review CIBERER's 15‐year journey and summarize the main results obtained in terms of internationalization, scientific production, contributions toward the discovery of new therapies and novel genes associated to diseases, cooperation with patients' associations and many other topics related to RD research.

Availability and Accessibility of Essential Drugs for Rare Disorders in Canada

In 2021, the Rare Disease Treatment Access Working Group (RDTAWG) of the International Rare Diseases Research Consortium, a European Union funded organization, published a list of medicinal products that they considered to be essential for the treatment of rare conditions. This study assesses the availability and accessibility of the RDTAWG medicines in Canada by comparing whether the rare disorder medicines approved for marketing in the United States also had regulatory approval for the same indication in Canada, and whether those medicines are ultimately covered under the 10 provincial government drug plans and the federal Non-Insured Health Benefits plan for indigenous persons. Data available at the end of August 2021 were accessed from the relevant online drug formularies. Most (85%) of the medicines with regulatory approval in the United States were also approved for the same indication in Canada. However, only just over half were covered by either open or conditional access in government drug plans, with the proportion ranging from under 36% in Manitoba to two-thirds in New Brunswick. Approximately 20% of the medicines had open access in all the plans, whereas the proportion with conditional access ranged from 13% in Manitoba to 45% in Ontario and New Brunswick. The average rate of coverage for medicines for disorders with a prevalence of ≤1 per 100,000 was only 28%, compared with 56% for disorders with a prevalence ranging from &gt;1 case per 100,000 persons up to 1 case per 10,000 persons, and 60% for disorders with a prevalence of &gt;1 case per 10,000 persons. Access to many medicines regarded by experts in the RDTAWG as essential for the welfare of individuals with rare disorders is inadequate to poor in Canada, especially for ultra-rare conditions. The federal Liberals and NDP are keen to introduce some type of national pharmacare. Any program developed by Canada’s governments must ensure that Canadians will have publicly funded access to all rare disorder medicines.

Essential list of medicinal products for rare diseases: recommendations from the IRDiRC Rare Disease Treatment Access Working Group

BackgroundTreatments are often unavailable for rare disease patients, especially in low-and-middle-income countries. Reasons for this include lack of financial support for therapies and onerous regulatory requirements for approval of drugs. Other barriers include lack of reimbursement, administrative infrastructure, and knowledge about diagnosis and drug treatment options. The International Rare Diseases Research Consortium set up the Rare Disease Treatment Access Working Group with the first objective to develop an essential list of medicinal products for rare diseases.ResultsThe Working Group extracted 204 drugs for rare diseases in the FDA, EMA databases and/or China’s NMPA databases with approval and/or marketing authorization. The drugs were organized in seven disease categories: metabolic, neurologic, hematologic, anti-inflammatory, endocrine, pulmonary, and immunologic, plus a miscellaneous category.ConclusionsThe proposed list of essential medicinal products for rare diseases is intended to initiate discussion and collaboration among patient advocacy groups, health care providers, industry and government agencies to enhance access to appropriate medicines for all rare disease patients throughout the world.

COVID-19 and rare diseases: reflections and recommendations by the International Rare Diseases Research Consortium

Aim: The ambitious goals set by the International Rare Diseases Research Consortium (IRDiRC) by 2027 to fulfill the vision of providing diagnosis and treatments to rare diseases (RDs) patients within one year of coming to medical attention have been challenged by the COVID-19 pandemic. This article aims to identify the needs and challenges of the RD community during the COVID-19 pandemic and to understand whether the pandemic would hinder achievement of the IRDiRC goals. Methods: A survey was developed in 2020 to answer key issues related to the potential impact of the pandemic on RD research and distributed to all 96 IRDiRC Constituent Committee members and Scientific Committee experts. Results: The overall participation rate was 46%, with the highest response rates from the Patient Advocates, Funders, and Therapies Committees. Most respondents reported impacts on various aspects of RD research including decreased access to healthcare, clinical trials, and diagnostics for patients, as well as disrupted operations for patient and funding organizations and restrictions in access to workplaces for researchers. Despite these challenges, there was overall optimism that the IRDiRC goals could still be met by 2027, although there would be an inevitable slowdown in RD research activities. Conclusions: Maintaining funding for RD research and implementing new workflows to ensure that patients have continued access to diagnostics, therapies, and clinical trials will be key to ensuring that IRDiRC meets it goals by 2027.

Barriers and Considerations for Diagnosing Rare Diseases in Indigenous Populations.

Advances in omics and specifically genomic technologies are increasingly transforming rare disease diagnosis. However, the benefits of these advances are disproportionately experienced within and between populations, with Indigenous populations frequently experiencing diagnostic and therapeutic inequities. The International Rare Disease Research Consortium (IRDiRC) multi-stakeholder partnership has been advancing toward the vision of all people living with a rare disease receiving an accurate diagnosis, care, and available therapy within 1 year of coming to medical attention. In order to further progress toward this vision, IRDiRC has created a taskforce to explore the access barriers to diagnosis of rare genetic diseases faced by Indigenous peoples, with a view of developing recommendations to overcome them. Herein, we provide an overview of the state of play of current barriers and considerations identified by the taskforce, to further stimulate awareness of these issues and the passage toward solutions. We focus on analyzing barriers to accessing genetic services, participating in genomic research, and other aspects such as concerns about data sharing, the handling of biospecimens, and the importance of capacity building.

Quantitative retrospective natural history modeling for orphan drug development.

The natural history of most rare diseases is incompletely understood and usually relies on studies with low level of evidence. Consistent with the goals for future research of rare disease research set by the International Rare Diseases Research Consortium in 2017, the purpose of this paper is to review the recently developed method of quantitative retrospective natural history modeling (QUARNAM) and to illustrate its usefulness through didactically selected analyses examples in an overall population of 849 patients worldwide with seven (ultra-) rare neurogenetic disorders. A quantitative understanding of the natural history of the disease is fundamental for the development of specific interventions and counseling afflicted families. QUARNAM has a similar relationship to a published case study as a meta-analysis has to an individual published study. QUARNAM relies on sophisticated statistical analyses of published case reports focusing on four research questions: How long does it take to make the diagnosis? How long do patients live? Which factors predict disease severity (eg, genotypes, signs/symptoms, biomarkers)? Where can patients be recruited for studies? Useful statistical techniques include Kaplan-Meier estimates, cluster analysis, regression techniques, binary decisions trees, word clouds, and geographic mapping. In comparison to other natural history study methods (prospective studies or retrospective studies such as chart reviews), QUARNAM can provide fast information on hard clinical endpoints (ie, survival, diagnostic delay) with a lower effort. The choice of method for a particular drug development program may be driven by the research question and may encompass combinatory approaches.

A call for global action for rare diseases in Africa.

The 11th International Conference on Rare Diseases and Orphan Drugs (ICORD), South Africa, included the Africa-Rare initiative launch and facilitated multi-stakeholder engagement in the challenges facing, and opportunities for, Africans living with rare diseases. The following ICORD Global Call to Action, developed in collaboration with the International Rare Diseases Research Consortium, synthesizes the outcomes of the deliberations and emphasizes the international collaborative efforts required to address the global effects of rare diseases on public health.

The use or generation of biomedical data and existing medicines to discover and establish new treatments for patients with rare diseases \u2013 recommendations of the IRDiRC Data Mining and Repurposing Task Force

The number of available therapies for rare diseases remains low, as fewer than 6% of rare diseases have an approved treatment option. The International Rare Diseases Research Consortium (IRDiRC) set up the multi-stakeholder Data Mining and Repurposing (DMR) Task Force to examine the potential of applying biomedical data mining strategies to identify new opportunities to use existing pharmaceutical compounds in new ways and to accelerate the pace of drug development for rare disease patients. In reviewing past successes of data mining for drug repurposing, and planning for future biomedical research capacity, the DMR Task Force identified four strategic infrastructure investment areas to focus on in order to accelerate rare disease research productivity and drug development: (1) improving the capture and sharing of self-reported patient data, (2) better integration of existing research data, (3) increasing experimental testing capacity, and (4) sharing of rare disease research and development expertise. Additionally, the DMR Task Force also recommended a number of strategies to increase data mining and repurposing opportunities for rare diseases research as well as the development of individualized and precision medicine strategies.

Ethical, legal, and social issues (ELSI) in rare diseases: a landscape analysis from funders.

Recent interest in personalized medicine has highlighted the importance of research in ethical, legal, and social issues (ELSI). Issues in ELSI research may be magnified in the rare diseases population (i.e., small numbers of affected individuals, challenges in maintaining confidentiality, and paucity of treatments for diseases where natural history information may be limited). More than other areas of research, potential barriers include the lack of funding opportunities and appropriate review processes for applications to funding agencies. The ELSI Working Group of the International Rare Diseases Research Consortium (IRDiRC) performed an informal survey on ELSI funding initiatives to learn more about different funding mechanisms and to identify potential gaps in funding opportunities. The Working Group discusses these challenges and highlights the role of funding agencies and partners such as patient advocacy groups, specialists in social sciences and humanities, and clinicians to advance ELSI research in rare diseases.

How to Advance Research, Education, and Training in the Study of Rare Diseases

Multiple challenges are faced by patients, clinicians, and researchers in accessing and providing care for rare diseases. Rare diseases, defined as a reported prevalence of <200,000 people in the United States and a prevalence of ≤1 in 2000 people in Europe, can involve any organ system. The majority of the >7000 recognized rare disorders, impacting around 9% of the US population, have a genetic basis and, as such, their effects can be multi-system and may evolve over time and with age. Table 1 lists prevalence of some rare diseases. Although individual rare diseases can be uncommon to encounter, when taken together rare diseases represent a major health burden. Rare diseases are associated with significant economic and financial burdens, both direct and indirect, which are further impacted by whether an approved pharmaceutical treatment is available.1Angelis A. Tordrup D. Kanavos P. Socio-economic burden of rare diseases: a systematic review of cost of illness evidence.Health Policy. 2015; 119: 964-979Crossref PubMed Scopus (121) Google ScholarTable 1Estimated Prevalence of Select Rare Diseases per 100,000 PeopleCrigler-Najjar syndrome1.0Cystic fibrosis7.4Eosinophilic esophagitis40.08Familial adenomatous polyposis6.0Gastrointestinal stromal tumor13.0Hepatic veno-occlusive disease11.0Hereditary chronic pancreatitis0.43Hirschsprung diseases10.9 (birth prevalence)Peutz-Jeghers syndrome0.4Short bowel syndrome3.4Data from www.orpha.net/orphacom/cahiers/docs/GB/Prevalence_of_rare_diseases_by_alphabetical_list.pdf. Open table in a new tab Data from www.orpha.net/orphacom/cahiers/docs/GB/Prevalence_of_rare_diseases_by_alphabetical_list.pdf. These considerations, as well as the challenges faced by patients (Table 2), underscore the need to advance awareness of rare diseases in the medical community. It is an opportunity for the trainee/junior faculty to harness these challenges into opportunities for their professional growth and learn skill-sets such as engaging non-traditional tools like patient advocacy groups (PAGs), social media and patient community. This review highlights the need to advance research in rare disease and discusses ways to accomplish this goal using education, mentoring and training as the foundations (Figure 1).Table 2Challenges Faced by Patients with Rare DiseasesKnowledge gap in providersLengthy, costly, and difficult journey to diagnosisPerceived/real lack of sensitivity in health care teamUnaware of/limited access to specialists/subject matter expertsDifficult connecting with similar patientsSocial isolation/societal acceptanceSchool and employment issues Open table in a new tab A core foundational method to enhance the study of rare diseases is exposing learners to these conditions during their medical education journey. The platforms include didactic lectures in the medical school curriculum, case-based studies, small group discussions, and the consideration of rare diseases when generating differential diagnoses at the bedside. The breadth and depth of lectures and formal teaching sessions on rare diseases should evolve from medical school curriculum to fellowship training (Table 3). Hands-on care of patients with rare diseases promotes medical training and helps learners to gain insights into fundamental pathophysiologic principles, acquire the instinct to recognize unique disease states, consider rare diseases in uncommon clinical scenarios, and understand that, although rare diseases affect a limited number of individuals, they may impact a disproportionate amount of health care resources.2Picoraro J.A. Gupta S.K. Rare diseases enrich our field. AGA Perspectives. April 2019.http://agaperspectives.gastro.org/rare-diseases-enrich-our-field/#.XV70rOhKhPYDate accessed: August 22, 2019Google Scholar Establishing the diagnosis of a rare disease can involve ongoing testing and potential treatment of more common conditions as a “rule out.”Table 3A Checklist of Tools to Self-advance: from Medical Student to FacultyDidactic lecturesCase-based studiesSmall group discussionsDifferential diagnosis at bedsideHands-on care in inpatient and clinic settingsAttend rare diseases conferencesHarness nontraditional research methodsEngage patient advocacy groupsNetwork and collaborate with rare disease researchers through consortiaApply for mentoring/internship programs via professional organizationsEnhance engagement in research projectsBe exposed to centers of excellence, expert consensus opinions, and clinical guidelinesAccess various web-based resourcesCreate databases Open table in a new tab In addition to on-site patient-centered and didactic teaching, program directors/mentors should enable learners to attend rare disease conferences, engage PAGs, and work with rare disease researchers at the local institution or at a distant institution as an elective. One tool to support this could be training/electives grants offered by various national organizations; professional gastrointestinal diseases societies have mentor–mentee programs, summer internships, etc. These programs could also serve as portals for faculty with interests in rare diseases to engage prospective learners, especially if at same institution, and involve them in clinics, research projects, multi-disciplinary conferences etc. To facilitate knowledge and care of patients, learners could access tools such as centers of excellence, expert consensus opinions, and clinical guidelines that help provide evidence-based care. It is important to be familiar with PAGs and multicenter consortia such as Consortium of Eosinophilic Gastrointestinal Disease Researchers (CEGIR), a multicenter collaboration in the National Center for Advancing Translational Sciences’ (NCATS) Rare Diseases Clinical Research Network (RDCRN) which is managed in collaboration with several institutes of the National Institutes of Health (NIH).3Gupta S.K. Falk G.W. Aceves S.S. et al.Consortium of Eosinophilic Gastrointestinal Disease Researchers: advancing the field of eosinophilic GI disorders through collaboration.Gastroenterology. 2019; 4: 838-842Abstract Full Text Full Text PDF Scopus (12) Google Scholar In addition to local resources, other tools to accomplish physician education include online webinars such as the CEGIR-driven web-based lecture series on eosinophilic GI disorders (EGIDs) and rare diseases research.4Consortium of Eosinophilic Gastrointestinal Disease ResearchersEducation videos.www.rarediseasesnetwork.org/cms/cegir/Learn-More/Educational-VideosDate accessed: August 22, 2019Google Scholar Other sources of information include the Genetic and Rare Diseases Information Center through NCATS, which includes information for health care professionals such as International Classification of Diseases coding of rare diseases, and caring for patients with rare diseases; the Toolkit supported by the Office of Rare Diseases Research (ORDR) at NCATS; and National Organization of Rare Disorders (NORD), which provides an online physician guide for clinicians on how to facilitate the timely diagnosis and treatment of specific rare disorders. Engagement of trainees or junior faculty in rare diseases research is important, both for their career development and for advancing knowledge in the field. Because it may not be practical for someone at this career stage to conduct a large-scale prospective research project, identifying appropriate and feasible studies is key, as is leveraging existing resources. The mentoring and training model from CEGIR can provide some practical examples in the GI field, although similar models can be found in other areas. Survey studies using Internet-based platforms are generally straightforward to conduct and can yield important insights and preliminary data on under examined questions. In CEGIR, investigators used this approach to study variability in upper GI tract biopsy practices during endoscopy as way to establish best practices.5Dellon E.S. Collins M.H. Bonis P.A. et al.Substantial variability in biopsy practice patterns among gastroenterologists for suspected eosinophilic gastrointestinal disorders.Clin Gastroenterol Hepatol. 2016; 14: 1842-1844Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar Another study used a survey approach for needs assessment in patients with EGIDs, leveraging social media, email lists, and websites maintained by collaborating PAGs.6Hiremath G. Kodroff E. Strobel M.J. et al.Individuals affected by eosinophilic gastrointestinal disorders have complex unmet needs and frequently experience unique barriers to care.Clin Res Hepatol Gastroenterol. 2018; 42: 483-493Crossref PubMed Scopus (20) Google Scholar Collaboration with PAGs is crucial and facilitates access to rare disease populations in many fields. Using retrospective data from multiple centers to answer focused questions is also a strategy to engage mentees with feasible projects. For example, investigators collected data from 6 sites within CEGIR to compile what became the largest study of the non-esophageal EGIDs yet to be published and were able to assess diagnostic trends over time, presenting symptoms, and treatment outcomes. Similarly, CEGIR investigators were able to assess the accuracy of billing codes for eosinophilic colitis to understand difficulties with identifying and enrolling this very rare EGID subtype. CEGIR has provided opportunities for trainees and junior faculty to write review articles with which they are able to familiarize themselves with the literature in the field, gain experience compiling a publication, and being able to establish a track record of scholarship. Additionally, one-on-one mentoring relationships are invaluable; CEGIR mentees conduct important formative research, including identifying biomarkers, developing new models for study of disease pathogenesis, and using novel devices to characterize disease severity. To facilitate these efforts and learner growth, CEGIR has a training core directed toward learners and exposes learners to resources outside of local institution. These strategies need not be limited to GI or EGIDs research, but could be applied to any rare disease to develop a program of research (Table 3). Moreover, recognizing that rare diseases may have a serious impact on patients and the health care system, journal editors may consider publishing case reports on rare diseases to highlight knowledge of these disorders to practitioners and students. Trainees’ and learners’ interests in rare disease, once initiated via exposures through formal didactic sessions and other informal methods, should evolve to research endeavors. Rare diseases research requires a nontraditional skill set, including using a multidisciplinary team beyond physicians. As highlighted, owing to the wide geographic distribution of these patients, it helps to collaborate with multiple sites and be creative and innovative with study designs. Besides case reports and case series, other possibilities include meta-analysis, database mining, systematic reviews, and prospective longitudinal studies. The creation of a database at the local institution or via a collaborative process facilitates research in rare diseases, as does familiarity with processes such as orphan drug development. The Orphan Drug Act grants special orphan designation status to drugs, both small molecules and biologics, for rare diseases and provides various development incentives, including tax credits, because innovative treatment strategies for rare diseases can be costly. New investigators have extensive opportunities for research activities in rare diseases. Some unmet needs include the characterization of the natural history of rare diseases and conditions, identification of genotypic and phenotypic subpopulations, development and/or validation of clinical outcome measures, biomarkers and/or companion diagnostics, and therapy and device product development; treatments are available for only approximately 600 of the overall 7000 rare diseases. To succeed, it is essential to use the strengths of academia, government, industry, and venture philanthropy to develop collaborative efforts. These efforts can lead to participation in research consortia and international networks using federated platforms of data gathering and sharing. Increasing advances in medical bioinformatics with interoperability of information resources and access to big datasets and electronic health records will expand research opportunities such as to identify pathways and possible interventions for rare diseases. In fact, technological advances have facilitated community partnerships through tools such as PAGs and social media networks. It is, however, imperative to recognize and understand the cultural, ethical, legal, and social issues related to data gathering and sharing from diverse populations. There are substantial benefits to engaging PAGs and patient community in research activities. Investigators can contribute to PAGs and build relationships by volunteering for activities, such as PAGs’ medical, scientific, and patient advisory boards. Investigators can also enable and empower their patients to initiate local support groups. Many of these efforts are directed to support research and new investigator training programs, which can benefit the learner, and to translate research results to patient communities. PAGs help to recruit for patient registries, biospecimen repositories, natural history studies, and various stages of clinical studies and trials. Additionally, PAGs can identify patient-driven needs assessment in areas of research and key outcomes that are important to patients themselves.6Hiremath G. Kodroff E. Strobel M.J. et al.Individuals affected by eosinophilic gastrointestinal disorders have complex unmet needs and frequently experience unique barriers to care.Clin Res Hepatol Gastroenterol. 2018; 42: 483-493Crossref PubMed Scopus (20) Google Scholar Patients are a powerful tool to mobilize the community via social media and nonmedical interactions. The strengths of PAGs is exemplified by their role in the enactment of the Orphan Drug Act. PAGs have been invaluable for awareness generation and fundraising; >280 PAGs form NORD, which serves as a central repository of information and efforts in rare diseases care. Often families acquire greater expertise in their rare condition than most of their health care providers, and this empowerment has carried fundamental advancements in enhancing their lives. In DGAT1 deficiency, for example, unremitting diarrhea from birth can necessitate dependence on total parenteral nutrition and early death. As children were identified by genetic testing, and families connected through online media, their collective experiences contributed to the identification of tailored dietary fat restriction as central to disease management. This citizen science outpaced any individual academic center, because the feedback and modifications occurred in real-time with a collaborative patient and family base.2Picoraro J.A. Gupta S.K. Rare diseases enrich our field. AGA Perspectives. April 2019.http://agaperspectives.gastro.org/rare-diseases-enrich-our-field/#.XV70rOhKhPYDate accessed: August 22, 2019Google Scholar The RDCRN has 21 consortia studying >190 diseases, and works to improve rare disease understanding and awareness, in both the patient and medical communities. The consortiums have provided multicenter collaborations and cross-institutional mentorships that have accelerated the research of early stage investigators and mobilized the necessary resources for robust clinical research. The International Rare Diseases Research Consortium (IRDiRC) was formed in 2011 by the NIH and the European Commission to advance study of rare diseases and foster international collaboration. Orphanet, established in France in 1997, has grown to a consortium of >40 countries around the globe and among other things maintains the Orphanet rare disease nomenclature (ORPHAnumber).

Privacy-Preserving Linkage of Genomic and Clinical Data Sets.

The capacity to link records associated with the same individual across data sets is a key challenge for data-driven research. The challenge is exacerbated by the potential inclusion of both genomic and clinical data in data sets that may span multiple legal jurisdictions, and by the need to enable re-identification in limited circumstances. Privacy-Preserving Record Linkage (PPRL) methods address these challenges. In 2016, the Interdisciplinary Committee of the International Rare Diseases Research Consortium (IRDiRC) launched a task team to explore approaches to PPRL. The task team is a collaboration with the Global Alliance for Genomics and Health (GA4GH) Regulatory and Ethics and Data Security Work Streams, and aims to prepare policy and technology standards to enable highly reliable linking of records associated with the same individual without disclosing their identity except under conditions in which the use of the data has led to information of importance to the individual's safety or health, and applicable law allows or requires the return of results. The PPRL Task Force has examined the ethico-legal requirements, constraints, and implications of PPRL, and has applied this knowledge to the exploration of technology methods and approaches to PPRL. This paper reports and justifies the findings and recommendations thus far.

International collaborative actions and transparency to understand, diagnose, and develop therapies for rare diseases

Rare diseases, which affect over 350 million people worldwide and frequently go undiagnosed or misdiagnosed for years, suffer from sparse and dispersed medical knowledge leading to even rarer approved and effective therapeutic options for patients. A vast, unmet need for research and investment to advance diagnostic capabilities and therapeutic development must be confronted, despite the myriad of challenges faced. Several fundamental shifts are changing the landscape of rare diseases research and development, particularly with the application and extension of results to common diseases and the advancement of personalized medicine initiatives. Collaborative strategies that pool resources and knowledge are vital, including team science, research networks, novel funding models, shared knowledge platforms, and innovative regulatory frameworks. Importantly, patients are also increasingly involved as research partners and funders, pushing for open science and transparency, and breaking down data silos and geographical borders, often enabled by online platforms accessible from across the globe. The International Rare Diseases Research Consortium (IRDiRC), established in 2011, has been working diligently to unify stakeholders (e.g., funding bodies, companies, umbrella patient advocacy groups, researchers, and experts) to seek and drive solutions that aim to accelerate diagnosis and therapeutic development for rare diseases worldwide. Further and future advances will depend on continued collaborations and cooperation among stakeholders, working hand in hand with patients, and exponentially improving research and development efficiency. Critically, engagement with stakeholders from underrepresented populations and less‐developed countries must be prioritized, to enable all people living with a rare disease to receive an accurate diagnosis, care, and therapy.