Search

Background: Paroxysmal Nocturnal Haemoglobinuria (PNH) is an ultra-rare, acquired disorder that is challenging to diagnose due to varied symptoms, heterogeneous patient presentations, and lack of awareness among healthcare professionals. This leads to frequent misdiagnosis and delays in diagnosis. This study evaluated the feasibility of a machine learning model to identify undiagnosed PNH patients using structured electronic health records. Methods: The study used data from the Optimum Patient Care Research Database, which contains electronic health records from general practitioner (GP) practices across the United Kingdom. PNH patients were identified by the presence, and control patients by the absence of a PNH diagnosis code in their records. Clinical features (symptoms, diagnoses, healthcare utilisation) from 131 patients in the PNH group and 593,838 patients in the control group, were inputted to a tree-based XGBoost machine learning model to classify patients as either "positive" or "negative" for PNH suspicion. The algorithm was finalised after additional exclusions and inclusions applied. Performance was assessed using positive predictive value (PPV), recall and specificity. As the sample used to develop the algorithm was not representative of the true population prevalence, PPV was additionally adjusted to reflect performance in the wider population. Results: Of all the patients in the PNH group, 27% were classified as positive (recall). 99.99% of the control group were classified as negative (specificity). Of all the patients classified as positive, 60.4% had a diagnosis of PNH in their record (PPV). The PPV adjusted for the population prevalence of PNH was 19.59 suggesting nearly 1 in 5 patients flagged may warrant further PNH investigation. The key clinical features in the model were aplastic anaemia, pancytopenia, haemolytic anaemia, myelodysplastic syndrome, and Budd-Chiari syndrome. Conclusion: This is the first study to combine clinical understanding of PNH with machine learning, demonstrating the ability to discriminate between PNH and control patients in retrospective electronic health records. With further investigation and validation, this algorithm could be deployed on live health data, potentially leading to earlier diagnosis for patients who currently experience long diagnostic delays or remain undiagnosed. [ABSTRACT FROM AUTHOR]

The EA-QOL questionnaire measures quality-of-life specifically for children born with esophageal atresia (EA) aged 8–18 and was completed in Sweden and Germany. This study aimed to describe an international collaborative initiative to establish a semantically equivalent linguistic version of the EA-QOL questionnaires in 12 new countries. The 24-item EA-QOL questionnaire was translated into the target languages and the translated questionnaire was evaluated through cognitive debriefing interviews with children with EA aged 8–18 and their parents in each new country. Participants rated an item as to whether an item was easy to understand and sensitive/uncomfortable to answer. They could choose not to reply to a non-applicable/problematic item and provide open comments. Data were analyzed using predefined psychometric criteria; item clarity ≥80%, item sensitive/uncomfortable to answer ≤20%, item feasibility(missing item responses ≤5%). Decision to improve any translation was made by native experts–patient stakeholders and the instrument developer. Like in Sweden and Germany, all items in the cross-cultural analysis of child self-report (ntot = 82, 4–10 children/country) met the criteria for item clarity in all 12 new countries, and in parent-report (ntot = 86, 5–10 parents/country) in 8/12 countries. All items fulfilled the criteria for sensitive/uncomfortable to answer (child-report 1.2–9.9%; parent-report 0–11.6%) and item feasibility. Poor translations were resolved. Hence, this study has established semantically equivalent linguistic versions of the EA-QOL questionnaire for use in children aged 8–18 with repair of EA in and across 14 countries. [ABSTRACT FROM AUTHOR]

Genome sequencing is available as a clinical test in the UK through the Genomic Medicine Service (GMS). The GMS analytical strategy predominantly filters genome data on preselected gene panels. Whilst this reduces variants requiring assessment by reporting laboratories, pathogenic variants outside applied panels may be missed, and variants in genes without established disease–gene relationships are largely ignored. This study compares the analysis of a research exome to a GMS clinical genome for the same patients. For the research exome, we applied a panel-agnostic approach filtering for variants with High Pathogenic Potential (HiPPo) using ClinVar, allele frequency, and in silico prediction tools. We then restricted HiPPo variants to Gene Curation Coalition (GenCC) disease genes. These results were compared with the GMS genome panel-based approach. Twenty-four participants from eight families underwent parallel research exome and GMS genome sequencing. Exome HiPPo analysis identified a similar number of variants as the GMS panel-based approach. GMS genome analysis returned two pathogenic variants and one de novo variant. Exome HiPPo analysis returned the same variants plus an additional pathogenic variant and three further de novo variants in novel genes, where case series are underway. When HiPPo was restricted to GenCC disease genes, statistically fewer variants required assessment to identify more pathogenic variants than reported by the GMS, giving a diagnostic rate per variant assessed of 20% for HiPPo versus 3% for the GMS. With UK plans to sequence 5 million genomes, strategies are needed to optimise genome analysis beyond gene panels whilst minimising the burden of variants requiring clinical assessment. [ABSTRACT FROM AUTHOR]

Aim and Objective: To explore the experience of healthcare transition from paediatric to adult health care for adults born with oesophageal atresia and tracheo‐oesophageal fistula (OA/TOF) and parents. Background: OA/TOF is a rare and chronic health condition that can require lifelong medical follow‐up and management. There is evidence to suggest that transitioning from paediatric to adult health care can be problematic for people with rare and chronic conditions, including OA/TOF. The previous literature suggests that the experience of transitioning with a rare condition is more complex than transitioning with a common chronic condition. Design: The current study was a qualitative, cross‐sectional, survey‐based study. Methods: Data were collected through an online survey. Parents of children born with OA/TOF (n = 23) and adults born with OA/TOF (n = 16) were recruited through a UK‐based OA/TOF patient charity. Data from six open‐ended questions were analysed using a hybrid approach combining elements of inductive and deductive thematic analyses. Throughout the research process, the SRQR were followed. Results: Five themes were constructed during the analysis, reflecting the experience of parents and adults transitioning from paediatric to adult health care: thrown into the unknown; a cultural shift; stepping back and stepping up; 'no transition as such'; and living with uncertainty. Conclusions: The findings suggested that a formalised, managed healthcare transition is not commonly experienced by people born with OA/TOF and parents. Relevance to Clinical Practice: We recommend a formalised healthcare transition process in OA/TOF, including preparation for transition and having a named key worker to manage the multidisciplinary transition process. The results also highlighted the need for adults born with OA/TOF to have access to a specialist health service with knowledge and understanding of issues related to OA/TOF. [ABSTRACT FROM AUTHOR]

Introduction: Acid sphingomyelinase deficiency (ASMD) type B is a rare genetic disorder leading to enlargement of the spleen and liver, pulmonary dysfunction, and other symptoms. Cost-utility analyses are often conducted to quantify the value of new treatments, and these analyses require health state utilities. Therefore, the purpose of this study was to estimate utilities associated with varying levels of severity of adult and pediatric ASMD type B., Methods: Seven adult and seven child health state vignettes describing ASMD were developed based on published literature, clinical trial results, and interviews with clinicians, patients with ASMD, and parents of children with ASMD. The health states were valued in time trade-off interviews with adult general population respondents in the UK., Results: Interviews were completed with 202 participants (50.0% female; mean age = 41.3 years). The health state representing ASMD without impairment had the highest mean utility for both the adult and child health states (0.92/0.94), and severe ASMD had the lowest mean utility (0.33/0.45). Every child health state had a significantly greater utility than the corresponding adult health state. Differences between adult/child paired states ranged from 0.02 to 0.13. Subgroup analyses explored the impact of parenting status on valuation of child health states., Discussion: Greater severity of ASMD was associated with lower mean utility. Results have implications for valuation of pediatric health states. The resulting utilities may be useful in cost-utility modeling estimating the value of treatment for ASMD., (© 2024. The Author(s).)

Introduction: This study investigates the frequency of hospital attendances, emergency care attendances and geographical influences on service interaction in cohorts of patients with primary and secondary antibody deficiency, to inform future service planning and delivery., Methods: The COVID-19 in Antibody Deficiency (COV-AD) study was a United Kingdom study that enrolled 525 participants between April 2021 and September 2022. Data on health care utilisation was extracted from a screening cohort of participants at one participating site (Birmingham, UK). Hospital attendance (i.e. all outpatient and inpatient care episodes, including hospital-based IVIG treatment) and emergency care attendance patterns were analysed. Geographical differences in travel times to hospitals and associated costs were considered for all participants at all recruiting sites., Results: Individuals with antibody deficiency had a median of 7 hospital attendances per year. A diagnosis of secondary antibody deficiency, and antibody deficiency severe enough to require treatment with immunoglobulin replacement were associated with an increased frequency of hospital attendance. 12.7% of the cohort attended the Emergency Department at least once in the preceding twelve months. Individuals with secondary antibody deficiency were at greater risk of requiring emergency care over the preceding one-year and five-year periods. Individuals receiving subcutaneous immunoglobulin lived further from their local immunology centre and were more likely to engage with the COV-AD research study remotely, via dried blood spots sampling., Conclusion: This study highlights the utilisation of emergency and secondary care usage amongst patient with immunodeficiency and may inform service adaptation and development to better accommodate patient needs and circumstances., (© 2024. The Author(s).)

The kidney-specific gene UMOD encodes for uromodulin, the most abundant protein excreted in normal urine. Rare large-effect variants in UMOD cause autosomal dominant tubulointerstitial kidney disease (ADTKD), while common low-impact variants strongly associate with kidney function and the risk of chronic kidney disease (CKD) in the general population. It is unknown whether intermediate-effect variants in UMOD contribute to CKD. Here, candidate intermediate-effect UMOD variants were identified using large-population and ADTKD cohorts. Biological and phenotypical effects were investigated using cell models, in silico simulations, patient samples, and international databases and biobanks. Eight UMOD missense variants reported in ADTKD are present in the Genome Aggregation Database (gnomAD), with minor allele frequency (MAF) ranging from 10-5 to 10-3. Among them, the missense variant p.Thr62Pro is detected in ~1/1,000 individuals of European ancestry, shows incomplete penetrance but a high genetic load in familial clusters of CKD, and is associated with kidney failure in the 100,000 Genomes Project (odds ratio [OR] = 3.99 [1.84 to 8.98]) and the UK Biobank (OR = 4.12 [1.32 to 12.85). Compared with canonical ADTKD mutations, the p. Thr62Pro carriers displayed reduced disease severity, with slower progression of CKD and an intermediate reduction of urinary uromodulin levels, in line with an intermediate trafficking defect in vitro and modest induction of endoplasmic reticulum (ER) stress. Identification of an intermediate-effect UMOD variant completes the spectrum of UMOD-associated kidney diseases and provides insights into the mechanisms of ADTKD and the genetic architecture of CKD. [ABSTRACT FROM AUTHOR]

Background: Rare diseases collectively affect up to 10% of the population, but often lack effective treatment, and typically little is known about their pathophysiology. Major challenges include suboptimal phenotype mapping and limited statistical power. Population biobanks, such as the UK Biobank, recruit many individuals who can be affected by rare diseases; however, investigation into their utility for rare disease research remains limited. We hypothesized the UK Biobank can be used as a unique population assay for rare diseases in the general population. Methods: We constructed a consensus mapping between ICD-10 codes and ORPHA codes for rare diseases, then identified individuals with each rare condition in the UK Biobank, and investigated their age at recruitment, sex bias, and comorbidity distributions. Using exome sequencing data from 167,246 individuals of European ancestry, we performed genetic association controlling for case/control imbalance (SAIGE) to identify potential rare pathogenic variants for each disease. Results: Using our mapping approach, we identified and characterized 420 rare diseases affecting 23,575 individuals in the UK Biobank. Significant genetic associations included JAK2 V617F for immune thrombocytopenic purpura (p = 1.24 × 10−13) and a novel CALR loss of function variant for essential thrombocythemia (p = 1.59 × 10−13). We constructed an interactive resource highlighting demographic information (http://www.personal.umich.edu/~mattpat/rareDiseases.html) and demonstrate transferability by applying our mapping to a medical claims database. Conclusions: Enhanced disease mapping and increased power from population biobanks can elucidate the demographics and genetic associations for rare diseases. [ABSTRACT FROM AUTHOR]

Introduction: This study implemented MendelScan, a primary care rare disease case-finding tool, into a UK National Health Service population. Rare disease diagnosis is challenging due to disease complexity and low physician awareness. The 2021 UK Rare Diseases Framework highlights as a key priority the need for faster diagnosis to improve clinical outcomes.Methods and Results: A UK primary care locality with 68,705 patients was examined. MendelScan encodes diagnostic/screening criteria for multiple rare diseases, mapping clinical terms to appropriate SNOMED CT codes (UK primary care standardised clinical terminology) to create digital algorithms. These algorithms were applied to a pseudo-anonymised structured data extract of the electronic health records (EHR) in this locality to "flag" at-risk patients who may require further evaluation. All flagged patients then underwent internal clinical review (a doctor reviewing each EHR flagged by the algorithm, removing all cases with a clear diagnosis/diagnoses that explains the clinical features that led to the patient being flagged); for those that passed this review, a report was returned to their GP. 55 of 76 disease criteria flagged at least one patient. 227 (0.33%) of the total 68,705 of EHR were flagged; 18 EHR were already diagnosed with the disease (the highlighted EHR had a diagnostic code for the same RD it was screened for, e.g. Behcet's disease algorithm identifying an EHR with a SNOMED CT code Behcet's disease). 75/227 (33%) EHR passed our internal review. Thirty-six reports were returned to the GP. Feedback was available for 28/36 of the reports sent. GP categorised nine reports as "Reasonable possible diagnosis" (advance for investigation), six reports as "diagnosis has already been excluded", ten reports as "patient has a clear alternative aetiology", and three reports as "Other" (patient left study locality, unable to re-identify accurately). All the 9 cases considered as "reasonable possible diagnosis" had further evaluation.Conclusions: This pilot demonstrates that implementing such a tool is feasible at a population level. The case-finding tool identified credible cases which were subsequently referred for further investigation. Future work includes performance-based validation studies of diagnostic algorithms and the scalability of the tool. [ABSTRACT FROM AUTHOR]

Background: An estimated 3.5 million people in the UK live with a rare disease however due to the rarity of each individual condition this is not currently reflected in mainstream medical education. As a result, common features of living with a rare condition include diagnostic delay, poor coordination of health and social care and lack of access to specialist care and treatment. This is well documented in reports published by patient advocacy groups collating the patient experience and has been highlighted by the Department of Health and Social Care in its UK Rare Diseases Framework. One of the four priority areas outlined in this policy published in 2021 is 'increasing awareness amongst healthcare professionals'. Medics4RareDiseases (M4RD), a charity based in the UK, has proposed a disease-agnostic approach to educating doctors about rare disease, focusing on the common challenges experienced across this heterogeneous collection of conditions, rather than on the minutiae of each of the > 7000 rare conditions. A literature search using MEDLINE, PubMed Central and Bookshelf confirmed a lack of broad rare disease teaching in medical literature; none of the 10 final resources identified focused on the topic as a whole., Results: To address this, M4RD created the course 'Rare Disease 101'. It is accessed online using a learning management system that is free, contains interactive lessons, hosts a discussion board and is easily updated. In the 29 months since going live, 942 individuals have registered with 204 having completed the course; early feedback from 33 respondents was unanimously positive (all participants rated at least good (76%: excellent)) demonstrating that both clinicians and patients can benefit from broad rare disease education. The course is freely available to all at https://learn.m4rd.org/ ., Conclusions: Disease-agnostic training about rare disease as a large patient population, focusing on its unique profile of unmet needs, is required. Rare Disease 101 provides a pragmatic approach to an educational challenge that leads to poor patient outcomes. Early results suggest that the educational programme is well-received but further evaluation and assessment is needed., (© 2024. The Author(s).)

Inherited metabolic diseases (IMDs) are a group of heterogeneous genetic disorders resulting in substrate accumulation, energy deficiency, or complex molecular defects due to the failure of specific molecules to act as enzymes, cofactors, transporters, or receptors in specific metabolic pathways. The pathophysiological changes seen in IMDs are sometimes associated with intellectual disability (ID) or neurocognitive decline, necessitating multidisciplinary input. We here describe our experience at one tertiary metabolic centre in the UK. We reviewed the case prevalence and existing service provision in one adult IMD service covering a multi-ethnic population of 10 million in North England. In our cohort of 2268 IMD patients, 1598 patients had general metabolic conditions (70.5%), and 670 had lysosomal storage disease/disorders (LSD)s (29.5%). The overall prevalence of ID and neurocognitive decline was found to be 15.7% ( n = 357), with patients with LSDs accounting for 23.5% ( n = 84) of affected patients. Given the prevalence of ID in adults with IMDs, access to multidisciplinary input from neuropsychology and neuropsychiatry services is important. Education of healthcare professionals to diagnose IMDs in patients with ID, in addition to neurocognitive and neuropsychiatric presentations, will avoid missed diagnoses of IMD and will have a positive effect on patient outcomes.

Objective: To determine the utility of wearable technologies in physical activity assessment in three paediatric diseases, namely, Niemann-Pick C (NP-C), Juvenile Idiopathic Arthritis (JIA) and Duchenne Muscular Dystrophy (DMD). Design: Exploratory study Setting and Patients: Thirty children were recruited across three UK hospitals (Royal Manchester's Children Hospital, Great Ormond Street Children's Hospital, and the Great North Children's Hospital). Ten were diagnosed with NP-C, eight with DMD and twelve with JIA. Intervention: All participants completed the 6-min walk test (6MWT) at enrolment. Patients were provided with disease-specific smartphone apps paired with a wearable device via Bluetooth. Ambulation was recorded in 30-min epochs measuring average daily maximum (ADM), average daily steps (ADS) and average daily steps per 30-min epoch (ASE). Results: Median 6MWT results were 450 m, 325 m and 434.5 m for the NP-C, DMD and JIA cohorts, respectively. Wearable data capture was feasible in all three disease cohorts, although complete data capture was not sustained. A statistically significant between-cohort difference was identified for ADM, ADS and ASE. Statistically significant differences were found between DMD/JIA for ADM; NP-C/DMD for ADS and DMD/JIA for ASE. Discussion: Wearable sensor technologies have the potential to provide additional information for our understanding of ambulation in chronic paediatric disease. The wearable devices were easy to use and popular with patients although key features need to be addressed to appropriately meet study objectives. As the technology continues to evolve at a rapid pace, opportunities to implement child friendly solutions are already available. [ABSTRACT FROM AUTHOR]

Background: In the absence of a framework designed to evaluate medicines for rare diseases in the UK, most orphan medicines are appraised by the National Institute for Health and Care Excellence (NICE) through the Single Technology Appraisal (STA) process.Results: An analysis of STA appraisals of orphan and non-orphan medicines revealed that orphan medicines were subject to a significantly longer mean time in the NICE process than non-orphan medicines [370 days (n = 44) vs. 277 days (n = 118), p =  < 0.0001]. A higher proportion of orphan STAs required more than one Appraisal Committee Meeting (ACM) versus non-orphan STAs, and orphan STAs were disadvantaged by worse outcomes with respect to positive recommendations than those orphan medicines assessed by Highly Specialised Technology evaluation (HST).Conclusions: The uncertainties inherent to developing orphan medicines may contribute to these disadvantages. Improved understanding of the challenges in drug development for orphan medicines and clearer guidance for decision makers on navigating uncertainty in the HTA process may promote greater equity in access to medicines across rare and common conditions. [ABSTRACT FROM AUTHOR]

Individualised behaviour change interventions can result in greater effects than one-size-fits-all approaches. Factors linked to success include dynamic (vs. static) tailoring, and tailoring on behaviour, multiple theoretical variables, and participant characteristics. XP is a very rare (∼100 UK patients) genetic disease, involving an inability to repair ultraviolet radiation (UVR)-induced damage, resulting in skin cancers and eye damage from an early age, and mean life expectancy of 32-years. Management involves rigorous UVR photoprotection, which is often inadequate, and no interventions have been published. UK-based care is personalised and delivered by a multidisciplinary team at the National XP Service in London. Following an intensive, mixed-methods formative phase with patients diagnosed with XP (n-of-1, qualitative interviews, objective UVR measurement, cross-sectional survey) and relevant stakeholder consultation (clinical and patient/public teams), the 'XPAND' intervention was developed. This paper describes the comprehensive and novel tailoring and personalisation processes used to deliver the intervention. XPAND consists of core and personalised modules targeting cue-based (time of day, weather, symptoms), belief-based (motivation, priority), self-regulatory (effort, barriers, planning), and emotional (stress, self-consciousness, mental exhaustion) factors, social support, disclosure, habit, and willingness, using appropriately-matched BCTs. A-priori, phase I data and a baseline profiling questionnaire (data sources) were used to allocate modules to participants ('personalisation') and to adapt module content ('tailoring'). Iterative decisions about delivery were based on patient response to feedback, identification of additional barriers (e.g. reasons for varying protection across contexts), and emergence of new barriers as improvements in protection were attempted or achieved (e.g. appearance concerns). Dynamic multi-level personalisation and tailoring based on mixed-methods in XPAND allowed for insights and decision-making not possible with cross-sectional quantitative or qualitative methods alone. Data collection and allocation/adaptation methods may be of use in other rare conditions where small patient numbers mean that within-participant, individual-level delivery is well-suited and feasible. [ABSTRACT FROM AUTHOR]

Aim: NICE's highly specialized technology (HST) evaluations are highly restrictive in terms of entry criteria and as a consequence, the vast majority of rare disease medicines are assessed through NICE's standard, single technology appraisal (STA) route. We explored whether NICE shows flexibility and pragmatism when evaluating treatments for rare diseases through its STA process. Materials & methods: We matched a sample of recent, randomly selected STAs for rare diseases to STAs for non-rare diseases and conducted a thematic analysis to identify patterns in NICE's decision-making, with a specific focus on the application of NICE's published methods and the handling of uncertainty. Results: Three themes emerged where some flexibility was shown: 'handling of uncertainty and discretion', 'application of NICE methods' and 'commercial arrangements'. Rare disease technologies were generally subject to longer appraisal times than those for non-rare diseases. Conclusion: Although NICE shows a degree of flexibility and pragmatism toward uncertainties in the evidence base for rare disease medicines, this is often off-set by a lengthy appraisal process, which can lead to delays in patients receiving vital treatment.

Objective: For the UK Biobank, standardized phenotype codes are associated with patients who have been hospitalized but are missing for many patients who have been treated exclusively in an outpatient setting. We describe a method for phenotype recognition that imputes phenotype codes for all UK Biobank participants., Materials and Methods: POPDx (Population-based Objective Phenotyping by Deep Extrapolation) is a bilinear machine learning framework for simultaneously estimating the probabilities of 1538 phenotype codes. We extracted phenotypic and health-related information of 392 246 individuals from the UK Biobank for POPDx development and evaluation. A total of 12 803 ICD-10 diagnosis codes of the patients were converted to 1538 phecodes as gold standard labels. The POPDx framework was evaluated and compared to other available methods on automated multiphenotype recognition., Results: POPDx can predict phenotypes that are rare or even unobserved in training. We demonstrate substantial improvement of automated multiphenotype recognition across 22 disease categories, and its application in identifying key epidemiological features associated with each phenotype., Conclusions: POPDx helps provide well-defined cohorts for downstream studies. It is a general-purpose method that can be applied to other biobanks with diverse but incomplete data., (© The Author(s) 2022. Published by Oxford University Press on behalf of the American Medical Informatics Association.)

Background: Patients with rare and ultra-rare diseases make heavy demands on the resources of both health and social services, but these resources are often used inefficiently due to delays in diagnosis, poor and fragmented care. We analysed the national service for an ultra-rare disease, Alstrom syndrome, and compared the outcome and cost of the service to the standard care.Methods: Between the 9th and 26th of March 2014 we undertook a cross-sectional study of the UK Alstrom syndrome patients and their carers. We developed a semi-structured questionnaire to assess our rare patient need, quality of care and costs incurred to patients and their careers. In the UK all Alstrom syndrome patients are seen in two centres, based in Birmingham, and we systematically evaluated the national service and compared the quality and cost of care with patients' previous standard of care.Results: One quarter of genetically confirmed Alstrom syndrome UK patients were enrolled in this study. Patients that have access to a highly specialised clinical service reported that their care is well organised, personalised, holistic, and that they have a say in their care. All patients reported high level of satisfaction in their care. Patient treatment compliance and clinic attendance was better in multidisciplinary clinic than the usual standard of NHS care. Following a variable costing approach based on personnel and consumables' cost, our valuation of the clinics was just under £700/patient/annum compared to the standard care of £960/patient/annum. Real savings, however, came in terms of patients' quality of life. Furthermore there was found to have been a significant reduction in frequency of clinic visits and ordering of investigations since the establishment of the national service.Conclusions: Our study has shown that organised, multidisciplinary "one stop" clinics are patient centred and individually tailored to the patient need with a better outcome and comparable cost compared with the current standard of care for rare disease. Our proposed care model can be adapted to several other rare and ultra-rare diseases. [ABSTRACT FROM AUTHOR]

Background: Life-saving orphan drugs are some of the most expensive medicines. European Union governments aim to accommodate their provision within stretched healthcare budgets but face pressure to reduce funding of such treatments. Patients struggle to retain or gain access to them as their special status is questioned, causing distress and in some cases, fears of premature death. In the UK and EU reimbursement and pricing model of drugs, and orphan drugs in particular, is being re-evaluated. Methods: Using the United Kingdom as a case study we present, for the first time, legal arguments which compel governments to provide orphan medicinal products. These include (i) disability legislation, (ii) national and organisational constitutions, (iii) judicial review, (iv) tort law and (v) human rights legislation. We then address directly potential objections to our analysis and counter arguments which aim to limit provision of orphan drugs to the intended patient recipients. Results: We demonstrate that a compelling case can be made that the law demands the treatment of orphan diseases. Conclusions: Our legal framework will assist doctors and patients in ensuring the continued provision of treatments despite significant economic pressure to reduce funding. These legal avenues will empower stakeholders in drafting funding guidelines throughout the EU. The legal right to treatment extends beyond rare diseases and our analysis may therefore affect allocation of healthcare budgets throughout the EU. [ABSTRACT FROM AUTHOR]

Purpose - This paper seeks to report the key findings of two studies which were undertaken by Rare Disease UK to: understand patients' and their families' experiences of living with a rare disease; identify issues preventing research and access to good quality information, care, treatment and support; identify examples of good practice; and develop recommendations to improve service provision for patients with rare diseases and encourage research.Design/methodology/approach - Across the two reports discussed, a range of methods were used including: a survey of patients/family members; five multi-stakeholder working groups; conference workshops; a consultation paper; interviews; and desk research.Findings - There are a number of detailed findings across the two reports. At a broad level, the findings identify that despite the diverse range of rare diseases each with different symptoms and prognoses, patients often face similar issues. The report also identifies a number of possible solutions to facilitate research, speed up diagnosis, improve co-ordination of care and ensure high-quality information is available to patients and professionals.Practical implications - The findings and recommendations in the two reports discussed are informing the development of a UK plan for rare diseases by all four of the UK's health departments. This plan will be the first strategic approach to improving service provision for all patients with rare diseases in the UK.Originality/value - Very little research has been conducted into the experiences of patients with rare diseases or on how to improve service provision for all rare diseases in the UK. As a result, the two reports offer a substantial body of new evidence. [ABSTRACT FROM AUTHOR]

In 1996, the discovery of variant Creutzfeldt-Jakob disease in the UK raised serious concerns about a large-scale epidemic. These concerns have been heightened by the recent discovery of people in Britain who were infected through blood transfusion. The outbreak of variant Creutzfeldt-Jakob disease in France emerged more recently with 23 cases observed to date. We use a hidden Markov model to predict the scale of the epidemic in France. As accurate data on the most important epidemiological parameters are scarce, we incorporate estimates from previous studies. Parameter estimation is performed by using Markov chain Monte Carlo methods from which credible intervals for our predictions are obtained. The sensitivity of these predictions to important assumptions regarding population exposure is assessed. [ABSTRACT FROM AUTHOR]

Background: Rare disease patients and carers report significant impacts on mental health but studies on UK populations have focussed on relatively few, specific conditions. Collectively rare conditions represent a substantial health burden, with an estimated 3.5 million affected individuals in the UK., Method: We explored the impact on mental health of living with a rare condition, and experiences of health service support, through an online survey. The survey assessed the impact of specific experiences commonly reported by those affected by a rare condition through multiple choice questions and Likert scale items, and open text question boxes. Through a multi-stakeholder workshop that involved facilitated discussion of our findings with patients/carers, clinicians and a government advisor, we developed recommendations for policy and practice toward a more person-centred and integrated approach., Results: Eligible responses came from 1231 patients and 564 carers. Due to their rare condition, the majority of respondents (> 90%) had felt worried/anxious; stressed; and /or low/depressed. Thirty-six percent of patients and 19% of carers had had suicidal thoughts. Challenges that are particular to rare conditions and which negatively affect mental health included limited knowledge of the condition amongst healthcare professionals (88%), and not being believed or taken seriously by them. Only 23% of respondents felt healthcare professionals considered mental and physical health as equally important. Almost half reported never having been asked about mental health by healthcare professionals. Our findings indicate that access to, and appropriateness of, professional psychological support needs to be improved. Peer group support is important but signposting is inadequate. Our recommendations are for healthcare professionals to be supported to effectively and sensitively recognise and address patients' and carers' mental health needs; and for service level coordination of care to integrate professional psychological support with rare disease services., Conclusion: Living with a rare disease substantially impacts mental health. Many of the drivers of poor mental health reflect issues specific to managing rare conditions. To meet UK government commitments, there should be a focus on empowering healthcare professionals who treat rare disease patients and on integration of mental health support with rare disease services., (© 2022. The Author(s).)

Many novel therapies are now available for rare neuromuscular conditions that were previously untreatable. Hereditary transthyretin amyloidosis and spinal muscular atrophy are two examples of diseases with new medications that have transformed our field. The United States and the United Kingdom have taken disparate approaches to the approval and coverage of medications, despite both providing incentives to develop therapies targeting rare diseases. The US requires less evidence for approval when compared with medications for common diseases and does not have a mechanism to ensure or even encourage cost-effectiveness. The Institute of Clinical and Economic Review provides in-depth cost-effectiveness analyses in the US, but does not have the authority to negotiate drug costs. In contrast, the UK has maintained a similar scientific threshold for approval of all therapies, while requiring negotiation with National Institute for Health and Care Excellence to ensure that medications are cost-effective for rare diseases. These differences have led to approval of medications for rare diseases in the US that have less evidence than required for common diseases. Importantly, these medications have not been approved in the UK. Even when medications meet traditional scientific thresholds, they uniformly arrive with high list prices in the US, whereas they are available at cost-effective prices in the UK. The main downsides to the UK approach are that cost-effective medications are often available months later than in the US, and some medications remain unavailable., (© 2021 Wiley Periodicals LLC.)

Genome sequencing (GS) will have a profound impact on the diagnosis of rare and inherited diseases in children and young people. We conducted 27 semi-structured interviews with young people aged 11–19 having GS through the UK 100, 000 Genomes Project. Participants demonstrated an understanding of the role and function of genes and DNA, however the terms 'genome' and 'genome sequencing' were less well understood. Participants were primarily motivated to take part to get a diagnosis or identify the gene causing their condition. The majority of participants understood they might not receive a diagnostic result. Most were unconcerned about data security or access, however anxieties existed around what the results might show and the potential for disappointment if the result was negative. Signing an assent form empowered young people, formalised the process and instilled a sense of responsibility for their choice to participate. Most young people (≥16 years) had consented to receive secondary findings and had come to that decision without parental influence. Our research suggests that at least some young people are capable of making informed decisions about taking part in GS, and that involving them in discussions about testing can empower them to take responsibility over healthcare decisions that affect them. [ABSTRACT FROM AUTHOR]

Aims: Familial chylomicronemia syndrome (FCS) is a rare genetic disorder with no currently approved therapies. Treatments are in development, and cost-utility analyses will be needed to examine their value. These models will require health state utilities representing FCS. Therefore, the purpose of this study was to estimate utilities for FCS and an associated episode of acute pancreatitis (AP). Methods: Because it is not feasible to gather a large enough sample of patients with this extremely rare condition to complete standardized preference-based measures, vignette-based methods were used to estimate utilities. In time trade-off interviews, general population participants in the UK and Canada valued health state vignettes drafted based on literature review, clinician input, and interviews with patients. Four health states described variations of FCS. A fifth health state, describing AP, was added to one of the other health states to evaluate its impact on utility. Results: A total of 308 participants provided utility data (208 UK; 100 Canada). Mean utilities for FCS health states ranged from 0.46 to 0.83, with higher triglycerides, more severe symptoms, and a history of AP associated with lower utility values. The disutility (i.e. utility decrease) of AP ranged from -0.17 to -0.25, with variations depending on the health state to which it was added. Utility means were similar in the UK and Canada. Conclusions: The vignette-based approach is useful for estimating utilities of a rare disease. The health state utilities derived in this study would be useful in models examining cost-effectiveness of treatments for FCS.

Introduction: Pigmented villonodular synovitis (PVNS), also known as giant-cell tumour of the tendon sheath (GCTT), is a rare, benign proliferative tumour affecting the inner lining of synovial joints and tendon sheets. Information on treatment needs of PVNS patients to inform drug development is currently scarce. We conducted an exploratory qualitative study with PVNS patients to generate insights into the objective and emotional aspects related to their medical journey and experiences of living with this disease., Methods: A 4-day study using an online bulletin board (OBB), an asynchronous, online qualitative research platform, was conducted with patients recruited via physician referral who underwent screening questions to ensure eligibility for the study and willingness to participate. The discussion was moderated, was structured and allowed open answers in response to other participants' posts., Results: Eleven patients (4 from the USA, 4 from the UK and 3 from Canada; 45% female), aged 28-57 years, suffering from PVNS for 2-27 years participated in the study. Key patient insights from the study were: (1) pain was the topmost, spontaneous thought that the participants associated with PVNS, constituting a significant emotional and psychological burden; (2) surgery (arthroscopy) did not completely ameliorate symptoms associated with PVNS, as the relapse rate was high in these patients; (3) PVNS has a substantial negative financial impact on patients, their families and the healthcare system; (4) orthopaedic specialists/surgeons predominantly managed PVNS, as surgery is currently the only therapeutic option., Conclusion: PVNS patients expressed an urgent need for a medical drug treatment, which can reduce pain, avoid relapses and provide an alternative to surgery, the current standard of care.