Rare Disease Patient Registries Research Articles

Co-developing The Canadian MPS Registry: A longitudinal rare disease patient registry

Co-developing The Canadian MPS Registry: A longitudinal rare disease patient registry

A Resource for Guiding Data Stewards to Make European Rare Disease Patient Registries FAIR

A Resource for Guiding Data Stewards to Make European Rare Disease Patient Registries FAIR

OPA1 Dominant Optic Atrophy: Pathogenesis and Therapeutic Targets.

OPA1 Dominant Optic Atrophy: Pathogenesis and Therapeutic Targets.

A Quality Assessment of the ARM-Net Registry Design and Data Collection

BackgroundRegistries are important in rare disease research. The Anorectal Malformation Network (ARM-Net) registry is a well-established European patient registry collecting demographic, clinical, and functional outcome data. We assessed the quality of this registry through review of the structure, data elements, collected data, and user experience. Material and methodsDesign and data elements were assessed for completeness, consistency, usefulness, accuracy, validity, and comparability. An intra- and inter-user variability study was conducted through monitoring and re-registration of patients. User experience was assessed via a questionnaire on registration, design of registry, and satisfaction. ResultsWe evaluated 119 data elements, of which 107 were utilized and comprised 42 string and 65 numeric elements. A minority (37.0%) of the 2278 included records had complete data, though this improved to 83.5% when follow-up elements were excluded. Intra-observer variability demonstrated 11.7% incongruence, while inter-observer variability was 14.7%. Users were predominantly pediatric surgeons and typically registered patients within 11–30 min. Users did not experience any significant difficulties with data entry and were generally satisfied with the registry, but preferred more longitudinal data and patient-reported outcomes. ConclusionsThe ARM-Net registry presents one of the largest ARM cohorts. Although its collected data are valuable, they are susceptible to error and user variability. Continuous evaluations are required to maintain relevant and high-quality data and to achieve long-term sustainability. With the recommendations resulting from this study, we call for rare disease patient registries to take example and aim to continuously improve their data quality to enhance the small, but impactful, field of rare disease research. Level of EvidenceV.

The Italian registry for patients with Prader–Willi syndrome

BackgroundPrader–Willi syndrome (PWS) is a rare and complex genetic disease, with numerous implications on metabolic, endocrine, neuropsychomotor systems, and with behavioural and intellectual disorders. Rare disease patient registries are important scientific tools (1) to collect clinical and epidemiologic data, (2) to assess the clinical management including the diagnostic delay, (3) to improve patients’ care and (4) to foster research to identify new therapeutic solutions. The European Union has recommended the implementation and use of registries and databases. The main aims of this paper are to describe the process of setting up the Italian PWS register, and to illustrate our preliminary results.Materials and methodsThe Italian PWS registry was established in 2019 with the aims (1) to describe the natural history of the disease, (2) to determine clinical effectiveness of health care services, (3) to measure and monitor quality of care of patients. Information from six different variables are included and collected into this registry: demographics, diagnosis and genetics, patient status, therapy, quality of life and mortality.ResultsA total of 165 patients (50.3% female vs 49.7% male) were included into Italian PWS registry in 2019–2020 period. Average age at genetic diagnosis was 4.6 years; 45.4% of patients was less than 17 years old aged, while the 54.6% was in adult age (> 18 years old). Sixty-one percent of subjects had interstitial deletion of the proximal long arm of paternal chromosome 15, while 36.4% had uniparental maternal disomy for chromosome 15. Three patients presented an imprinting centre defect and one had a de novo translocation involving chromosome 15. A positive methylation test was demonstrated in the remaining 11 individuals but the underlying genetic defect was not identified. Compulsive food-seeking and hyperphagia was present in 63.6% of patients (prevalently in adults); 54.5% of patients developed morbid obesity. Altered glucose metabolism was present in 33.3% of patients. Central hypothyroidism was reported in 20% of patients; 94.7% of children and adolescents and 13.3% of adult patients is undergoing GH treatment.ConclusionsThe analyses of these six variables allowed to highlight important clinical aspects and natural history of PWS useful to inform future actions to be taken by national health care services and health professionals.

Development of an Interactive Dashboard for OSSE Rare Disease Registries.

The Open Source Registry System for Rare Diseases (OSSE), a web-based tool to create rare disease patient registries, currently offers no possibility to view aggregated registry data within the system. Here, we present the development and implementation of a dashboard for the registry of the German NEOCYST (Network for early onset cystic kidney diseases) consortium. Based on user requirements from NEOCYST, we developed a general dashboard for all OSSE registries, which was extended with NEOCYST-specific statistics. The dashboard now allows users to gain a quick overview of key data, such as patient counts or the availability of biospecimens. This work represents a first prototypical approach for an OSSE dashboard, demonstrated in an existing rare disease registry, to be further evaluated and enhanced in the future.

The multiple stakeholder approach to real-world evidence (RWE) generation: observing multidisciplinary expert consensus on quality indicators of rare disease patient registries (RDRs)

Introduction Those invested in the outcome of specific decisions may seek to inform the decision-maker by generating relevant evidence. With multiple decision-makers, the evidence generator benefits from understanding whether their needs differ. This was explored using relevant stakeholders’ preferences on quality indicators (QIs) of rare disease patient registries (RDRs), a common vehicle for generating evidence, to support the adoption of new medicines. Methods The Jandhyala method was used to compare the observed consensus on RDR quality indicators from each stakeholder group (SHG) and between the combined pharmaceutical (pharma) and non-pharmaceutical (non-pharma) SHG population. Results All non-pharmaceutical stakeholder groups were equally unique – suggesting QIs peculiar to themselves – Patients (13/102; 12.75%); Payors (5/102; 4.90%); Prescribers (7/102; 6.86%) to the same degree. Non-pharmaceutical stakeholders generated 31/102 (30.39%) unique QIs. Pharma stakeholder generated 25/102 (24.51%). This totals 56/102 (54.90%) QIs without a match. Two QIs were unanimously suggested and agreed upon by all SHGs (7/7; 100%) – “Engages with patients and gains their buy-in” and “Includes a core data set as part of outcomes”. There was homogenous consensus on common QIs between: Commercial – Market Access (13/52; 25%; p = .005) SHGs; Commercial – Medical Affairs (9/47; 19.15%; p = .001) SHGs; Commercial – Payor (11/41; 21.15%; p = .012) SHGs, and Market Access – Regulatory Affairs (10/41; 19.61%; p = .008) SHGs. Conclusions A multiple stakeholder approach for generating real-world evidence can be justified. The potential mismatch of 54.9% between pharma and non-pharma stakeholders indicates a critical misalignment between generator and consumer of its RWE. Pharmaceutical SHG’s were highlighted for greater alignment with Patients and Payor (non-pharma) groups.

How to design a registry for undiagnosed patients in the framework of rare disease diagnosis: suggestions on software, data set and coding system

BackgroundAbout 30 million people in the EU and USA, respectively, suffer from a rare disease. Driven by European legislative requirements, national strategies for the improvement of care in rare diseases are being developed. To improve timely and correct diagnosis for patients with rare diseases, the development of a registry for undiagnosed patients was recommended by the German National Action Plan. In this paper we focus on the question on how such a registry for undiagnosed patients can be built and which information it should contain.ResultsTo develop a registry for undiagnosed patients, a software for data acquisition and storage, an appropriate data set and an applicable terminology/classification system for the data collected are needed. We have used the open-source software Open-Source Registry System for Rare Diseases (OSSE) to build the registry for undiagnosed patients. Our data set is based on the minimal data set for rare disease patient registries recommended by the European Rare Disease Registries Platform. We extended this Common Data Set to also include symptoms, clinical findings and other diagnoses. In order to ensure findability, comparability and statistical analysis, symptoms, clinical findings and diagnoses have to be encoded. We evaluated three medical ontologies (SNOMED CT, HPO and LOINC) for their usefulness. With exact matches of 98% of tested medical terms, a mean number of five deposited synonyms, SNOMED CT seemed to fit our needs best. HPO and LOINC provided 73% and 31% of exacts matches of clinical terms respectively. Allowing more generic codes for a defined symptom, with SNOMED CT 99%, with HPO 89% and with LOINC 39% of terms could be encoded.ConclusionsWith the use of the OSSE software and a data set, which, in addition to the Common Data Set, focuses on symptoms and clinical findings, a functioning and meaningful registry for undiagnosed patients can be implemented. The next step is the implementation of the registry in centres for rare diseases. With the help of medical informatics and big data analysis, case similarity analyses could be realized and aid as a decision-support tool enabling diagnosis of some undiagnosed patients.

Stigma and psychological distress among pediatric participants in the FD/MAS Alliance Patient Registry

BackgroundStigma, both enacted and internalized, is part of the illness experience of many chronic conditions / diseases and has been found to increase psychological distress, lower self-esteem, and impact social engagement lowering quality of life (QOL). Stigma among pediatric patients is of particular concern due to its potential impact on identity formation. Using patient data from the online FD/MAS Alliance Patient Registry (FDMASAPR), this study seeks to 1) determine levels of enacted and self-stigma in a pediatric population of fibrous dysplasia (FD) / McCune Albright syndrome (MAS) patients and 2) to explore the relationship between stigma and anxiety and depression.MethodsThis is a cross sectional analysis of deidentified self-report data from 18 pediatric patients. Key analytic variables include the Neuro-QOL stigma short form, the Hospital Anxiety and Depression Scale (HADS), diagnostic category and craniofacial involvement, and select demographics. Sample means and score distributions are examined. Bivariate relationships between stigma, anxiety and depression and patient’s personal and medical characteristics are established through analysis of variance and correlation.ResultsComposite stigma levels for FD/MAS pediatric patients were comparable to those of children with multiple sclerosis, epilepsy, and muscular dystrophy. Self-stigma was more frequently reported than enacted/felt stigma, but few patients indicated complete freedom from either type of stigma. Diagnosis was significantly related to self-stigma. Significant bivariate relationships were found between depression and enacted/felt and self-stigma and between anxiety and self-stigma.ConclusionsThis study establishes the illness experience of pediatric patients with FD / MAS is impacted by stigma and suggests they should be regularly screened for stigma and psychological distress. It supports the integration of clinical psychologists/ therapists in regular patient care, referral of families to advocacy organizations, and indicates that rare disease patient registries can be a useful tool in efforts to improve the QOL of patients.

The international X-linked hypophosphataemia (XLH) registry (NCT03193476): rationale for and description of an international, observational study

BackgroundX-linked hypophosphataemia (XLH) is a rare, hereditary, progressive and lifelong phosphate wasting disorder characterised by pathological elevations in fibroblast growth factor (FGF) 23 concentration and activity; XLH has an incidence of approximately 1 in 20–25,000 individuals. Excess FGF23 activity leads to increased phosphate excretion in the kidneys – mediated by downregulation of renal tubular phosphate transporters – and reduced phosphate absorption in the intestines – due to impaired vitamin D activation. This results in impaired bone growth and mineralisation, short and disproportionate stature, leg bowing, musculoskeletal pain, spontaneous dental abscesses, rickets, and osteomalacia. The spectrum of manifestations differs between paediatric and adult patients. Those involved in the treatment of this condition face many challenges, including a lack of robust natural history and demographic data. This multicentre, international, rare-disease patient registry (XLH Registry) was established to address the paucity of data in XLH and to help inform future clinical practice.ResultsThe XLH Registry collects standard diagnostic and monitoring practice data, including (where applicable) diagnosis and disease progression history, treatment regimens and family history; the protocol does not mandate any interventions or clinical assessments. The XLH Registry aims to recruit 1200 paediatric and adult patients with XLH over 10 years, and several data analyses and peer-reviewed publications are expected to be generated throughout this period. A post-authorisation safety study for Bburosumab, for which the registry Sponsor is the marketing authorisation holder, will be nested as a sub-study within the XLH Registry via a subsequent protocol amendment.ConclusionThe data collected within this rare-disease patient registry will be utilised to synthesise real-world evidence to inform the management of XLH, to improve the quality of life and standard of care of patients living with this rare debilitating disease.

TuberOus SClerosis Registry to Increase Disease Awareness: A Review on Alignment of Its Planning, Execution, and Publications With European Medicines Agency Guidelines.

Patient registries offer a powerful and practical means of real-world data collection system for rare diseases. Many guidelines have been released to standardize patient registries, although most of them do not address issues specific to rare disease patient registries. In November 2018, the European Medicines Agency (EMA) released a draft discussion paper on methodological and operational aspects of disease registries and made proposals on good registry practice (henceforth referred to as EMA guidance). This guidance was highly anticipated by all stakeholders with a strong interest toward governance, operationalization, and study conduct in registries. With improved clarity toward conduct of patient registries, this guidance will encourage overall registry use in regulatory decision making. TuberOus SClerosis registry to increase disease Awareness (TOSCA) was an international, multicenter patient registry to assess the manifestations, interventions, and outcomes in patients with tuberous sclerosis complex (TSC). The planning of TOSCA was initiated in 2011, patient enrolment commenced in August 2012, and final analysis database was locked in August 2017, long before the EMA guidance was released. Moreover, initial publications of TOSCA, such as first interim analysis, had also been published before the release of the EMA guidance. Extensive feedback and lessons learned from the TOSCA registry have provided insights into rare disease registry planning and operations. In this paper, we tested the recommendations from the EMA guidance on a rare disease registry, that is, the TOSCA registry. We elaborated the compliance and deviations of the TOSCA registry from the EMA guidance on a point-by-point basis. A careful observation revealed that in most aspects, TOSCA was in compliance with EMA. However, there were several practical issues identified in TOSCA, which deviated from EMA guidance. These issues demonstrate that deviations from EMA guidance, particularly in rare disease registries, do not signify compromised registry quality and can be somewhat expected in small populations. Despite multiple deviations of TOSCA from the EMA guidance, TOSCA was able to meet its objectives to enhance our understanding of TSC and its manifestations.

Establishing Patient Registries for Rare Diseases: Rationale and Challenges.

Globally, an estimated 350 million people are affected by a rare disease diagnosis. Knowledge limitations persist for the majority of rare conditions due to systemic and structural challenges in healthcare and research. Disease-specific patient populations are often small and geographically dispersed; funding support for research is restricted; and diagnostic delays are common due to disease complexities, limited medical training for practitioners, and evolving foundational knowledge related to disease characterization. Patient registries can be effective, convenient, and cost-efficient tools to support documentation of the natural history of a disease, centering patients as research partners in the process while uniting rare communities around a common initiative. Current global trends towards innovative and patient-centered healthcare are enabling patient registries to increasingly emerge as valuable tools for use within rare disease research and drug development. This article describes the value of and rationale for establishing rare disease patient registries and the considerations and challenges that stakeholders, such as researchers, industry, health care providers, and patient community organizations, may encounter.

Factors Influencing the Generation of Evidence from Simple Data Held in International Rare Disease Patient Registries.

Rare diseases (defined as affecting < 1 in 2000 Europeans) may collectively affect up to approximately 8% of the population. The low prevalence of individual diseases limits patient studies and data collection is a key challenge; international rare disease patient registries are essential for optimal data collection and research. Registry data achieves value when research conducted on them are published-this is termed evidence generation. The aim of this study was to examine selected factors and their association with evidence generation, via scientific publication, from international rare disease patient registry data. All international rare disease patient registries listed in the Orphanet 2018 report were analysed. Rates of scientific publications were compared by funding stream, disease area and registry size using multivariable regression analyses. Publication characteristics, such as novelty of findings, were also compared by registry funding stream, disease area and duration of operation. Privately funded registries had approximately two to four times higher rates of scientific publication compared with publically funded registries, with adjusted rate ratios of 1.85 (95% confidence interval [CI] 1.07-3.22) and 4.18 (95% CI 2.54-6.87) for private not-for-profit and private for-profit funding, respectively. The inclusion of outcomes, use of pharmaceutical medicines, novel findings and citation rate for publications generated from patient registries with any private funding was not significantly different from those attributed to only publicly funded registries. The results of this study indicate that privately funded international rare disease patient registries produce significantly more evidence than their publicly funded counterparts. Examination of the quality indicators of these publications showed they were of the same high quality as those generated from publicly funded patient registry data.

RD-RAP: beyond rare disease patient registries, devising a comprehensive data and analytic framework

Within the 21 APEC economies alone, there are an estimated 200 million individuals living with a rare disease. As such, health data on these individuals, and hence patient registries, are vital. However, registries can come in many different forms and operating models in different jurisdictions. They possess a varying degree of functionality and are used for a variety of purposes. For instance registries can facilitate service planning as well as underpin public health and clinical research by providing de-identified data to researchers. Furthermore, registries may be used to create and disseminate new knowledge to inform clinical best practice and care, to identify and enrol participants for clinical trials, and to enable seamless integration of patient data for diagnostic testing and cascade screening. Registries that add capability such as capturing patient reported outcomes enable patients, and their carers, to become active partners in their care, rapidly furthering research and ensuring up-to-date practice-based evidence. Typically, a patient registry centres around the notion of health data ‘capture’, usually for only one or a small subset of the functions outlined above, thereby creating fragmented datasets that, despite the best efforts and intentions, make it difficult to exchange the right data for the right purpose to the right stakeholder under appropriate governance arrangements. Trying to incorporate maximum functionality into a registry is an obvious strategy, but monolithic software solutions are not desirable. As an alternative, we propose that it is important to incorporate analytics as core to a patient registry, rather than just utilising registries as a ‘data capture’ solution. We contend that embracing an analytics-centric focus makes it reasonable to imagine a future where it will be possible to evaluate the individual outcomes of health interventions in real time. The purposeful and, importantly, the repurposable application of health data will allow stakeholders to extract, create and reuse knowledge to improve health outcomes, assist clinical decision making, and improve health service design and delivery. To realise this vision, we introduce and describe the concept of a Rare Disease Registry and Analytics Platform (RD-RAP); one that we hope will make a meaningful difference to the lives of those living with a rare disease.

Use of a rare disease patient registry in long-term post-authorisation drug studies: a model for collaboration with industry

Use of a rare disease patient registry in long-term post-authorisation drug studies: a model for collaboration with industry

Linked Registries: Connecting Rare Diseases Patient Registries through a Semantic Web Layer.

Patient registries are an essential tool to increase current knowledge regarding rare diseases. Understanding these data is a vital step to improve patient treatments and to create the most adequate tools for personalized medicine. However, the growing number of disease-specific patient registries brings also new technical challenges. Usually, these systems are developed as closed data silos, with independent formats and models, lacking comprehensive mechanisms to enable data sharing. To tackle these challenges, we developed a Semantic Web based solution that allows connecting distributed and heterogeneous registries, enabling the federation of knowledge between multiple independent environments. This semantic layer creates a holistic view over a set of anonymised registries, supporting semantic data representation, integrated access, and querying. The implemented system gave us the opportunity to answer challenging questions across disperse rare disease patient registries. The interconnection between those registries using Semantic Web technologies benefits our final solution in a way that we can query single or multiple instances according to our needs. The outcome is a unique semantic layer, connecting miscellaneous registries and delivering a lightweight holistic perspective over the wealth of knowledge stemming from linked rare disease patient registries.

Rare Disease Biospecimens and Patient Registries: Interoperability for Research Promotion, a European Example: EuroBioBank and SpainRDR-BioNER.

Well-annotated and properly preserved specimens are crucial both for diagnostic purposes and for use in basic and pre-clinical research, and are especially important for rare disease (RD) studies. Several consortia have been established in the recent years in order to facilitate research and to maximise access to rare biological samples and data stored in rare disease biobanks and registries, among them the EuroBioBank network and the Spain National Rare Disease Registry (RDR) and Biobank (BioNER).EuroBioBank, established in 2001, was the first network of RD biobanks to operate in Europe as a service distributing human DNA, cells, and tissue to the scientific community conducting research on rare diseases.The Spanish RDR and BioNER were created for facilitating rare disease research and health-related matters. The coordination of these two bodies represents an example of great scientific value as biological samples donated by patients at BioNER are linked to clinical information collected in the RDR.Rare disease biobanks and registries will need for the future to increase their effort to improve interconnection so to enable investigators to better locate samples and associated data, while protecting security of the data and privacy of the participants and adhering to international ethical and legal requirements.

A knowledge federation architecture for rare disease patient registries and biobanks

Patient registries are a source of standardized electronic patient information. These records are vital to identify and coordinate a proper cohort, especially for the rare disease domain. Likeness, biobanks are currently an essential instrument for biomedical research, since they provide the very first piece of the biomedical research cycle, i.e. the biological samples. However, connection between rare diseases, patient registries and biobanks has been very limited, due to the lack of common data models and procedures. As they were built with security and privacy in mind, available tools lack comprehensive data access mechanisms, thus making data sharing a complex process. To tackle these challenges, we introduce a semantic web-based architecture to connect distributed and heterogeneous registries and samples. The outcome is a unique knowledge layer, connecting miscellaneous datasets and enabling state-of-the-art semantic data sharing mechanisms.

Utility of patients’ registries to gather clinical, epidemiological and molecular information

Rare disease patient registries are indispensable tools for translating research into improved care and therapeutic solutions. During the race to identify a safe and effective treatment, they come into play at many stages of the translational research cycle: collection of mutational data, description of the disease, support for patient recruitment for clinical trials and scientific studies (such as natural history studies), collection of epidemiological data, evaluation/monitoring of the efficacy/safety of a treatment, elaboration of guidelines for diagnosis and management of the disease, etc. In the field of rare disease, the main challenges that patient registries face are sustainability, better interoperability with the establishment of common data standards (for data collection, data quality, data security, legal and ethical issues) and support for translational collaborations to constitute large cohorts of patients. To work out these questions, the IRDiRC (International Rare Disease Research Consortium) initiative is a major force to encourage cooperation at international level. In this process, patients and families are becoming more active participants and must continue to raise their voice to drive innovation in collaboration with all stakeholders.

Consensus on the criteria needed for creating a rare-disease patient registry. A Delphi study.

Patient registries (PRs) are important tools for public-health surveillance and rare-disease research. The purpose of this study is to identify the most important criteria for the creation of a rare-disease PR that could be used by public-health authorities to develop health policies. A consensus-development Delphi study was used, with participants selected for their expertize in rare diseases and registries. Participants were asked to complete a questionnaire on the most important criteria for creating PRs. Three rounds were performed. Agreement was reached on half the questions in the first round and on 89% of questions in the final round, with a total expert participation rate of around 60% by the final stage. This study made it possible to reach a broader consensus starting from experts' initial assessment of the features that should be considered for the creation of a rare-disease PR. The consensus method used made it possible to define the characteristics of a PR based on expert opinion within a rare-disease framework. This study may serve as a guide for helping other researchers plan and build a rare-disease PR.