bims-curels 2023-09-03 papers

bims-curels

Biomed News

on Leigh syndrome

Issue of 2023–09–03
seventeen papers selected by
Cure Mito Foundation

"I think there has to be a mutual respect for there to be value": Evaluating patient engagement in a national clinical trial on de-implementation of low value care.
The mitochondrial tRNA MT-TW m.5537_5538insT variant presents with significant intra-familial clinical variability.
Evaluating the impacts of patient engagement on a national health research network: results of a case study of the Chronic Pain Network.
Overcoming challenges in rare disease registry integration using the semantic web - a clinical research perspective.
Vitamin B1 deficiency leads to high oxidative stress and mtDNA depletion caused by SLC19A3 mutation in consanguineous family with Leigh syndrome.
Designing infographics in health research with patients and the public: A scoping review protocol.
Navigating Life With Primary Mitochondrial Myopathies: The Importance of the Patient Voice and Implications for Clinical Practice.
Mutation on MT-CO2 gene induces mitochondrial disease associated with neurodegeneration and intracerebral iron accumulation (NBIA).
Mitochondrial dysfunction characterized in human induced pluripotent stem cell disease models in MELAS syndrome: A brief summary.
Research progress in mitochondrial gene editing technology.
Initiatives to promote access to medicines after publication of the Brazilian Policy on the Comprehensive Care of People with Rare Diseases.
Genetic services survey-experience of people with rare diseases and their families accessing genetic services in the Irish Republic.
Patient and public involvement in Nordic healthcare research: a scoping review of contemporary practice.
T cell differentiation drives the negative selection of pathogenic mitochondrial DNA variants.
Patient and public involvement to inform priorities and practice for research using existing healthcare data for children's and young people's cancers.
Composite endpoints, including patient reported outcomes, in rare diseases.
Artificial intelligence in rare disease diagnosis and treatment.

Res Involv Engagem. 2023 Aug 26. 9(1): 70

"I think there has to be a mutual respect for there to be value": Evaluating patient engagement in a national clinical trial on de-implementation of low value care.

Holly Etchegary, Stefanie Linklater, D 'Arcy Duquette, Gloria Wilkinson, Vanessa Francis, Erin Gionet, Andrea M Patey, Jeremy M Grimshaw.

   BACKGROUND: The evaluation of patient engagement in research is understudied and under-reported, making it difficult to know what engagement strategies work best and when. We provide the results of an evaluation of patient engagement in a large Canadian research program focused on the de-implementation of low-value care. We aimed to evaluate the experience and impact of patient engagement in the study.
METHODS: An online cross-sectional survey was administered using Microsoft Forms to (1) researchers and study staff and (2) patient partners. The survey was developed following iterative reviews by the project's patient partnership council and evaluation committee. Survey content areas included opinions on patient engagement to date, including challenges to engagement and suggestions for improvement. Patient partners also evaluated the partnership council. Descriptive statistics including counts and percentages described Likert scale survey items, while open comments were analyzed using descriptive content analysis.
RESULTS: The survey response rate was 46% (17/37). There were positive attitudes about the value of patient engagement in this project. There was also a high degree of willingness to be involved with patient engagement in future projects, whether as a patient partner or as a researcher including patients on the research team. Most patient partners felt their contributions to the project were valued by researchers and study research staff. Open comments revealed that a co-design approach and full inclusion on the research team were integral to demonstrating the value of patient partner input. Areas for improvement included more frequent and ongoing communication among all team members, as well as earlier training about patient engagement, particularly addressing role expectations and role clarity.
CONCLUSIONS: Our data revealed that despite some challenges, team members recognized the value of patient engagement in research and agreed project decisions had been impacted by patient partner input. Ongoing communication was highlighted as an area for improvement, as well as earlier training and ongoing support for all team members, but particularly researchers and study staff. In response to evaluation data, the team has reinstated a quarterly newsletter and plans to use specific patient engagement planning templates across study sites for all project activities. These tools should help make expectations clear for all team members and contribute to a positive patient engagement experience. Findings can inform patient engagement planning and evaluation for other health research projects.

Keywords:  Choosing Wisely; De-implementation; Evaluation; Low value care; Patient engagement; Trial

DOI:  https://doi.org/10.1186/s40900-023-00483-w
Am J Med Genet A. 2023 Aug 31.

The mitochondrial tRNA MT-TW m.5537_5538insT variant presents with significant intra-familial clinical variability.

Lauren Strasser, Asif Doja, Jorge Davila, Pranesh Chakraborty, Danielle K Bourque.

  Mitochondrial disorders can present with a wide range of clinical and biochemical phenotypes. Mitochondrial DNA variants may be influenced by factors such as degree of heteroplasmy and tissue distribution. We present a four-generation family in which 10 individuals carry a pathogenic mitochondrial variant (m.5537_5538insT, MT-TW gene) with differing levels of heteroplasmy and clinical features. This genetic variant has been documented in two prior reports, both in individuals with Leigh syndrome. In the current family, three individuals have severe mitochondrial symptoms including Leigh syndrome (patient 1, 100% in blood), MELAS (patient 2, 97% heteroplasmy in muscle), and MELAS-like syndrome (patient 3, 50% heteroplasmy in blood and 100% in urine). Two individuals have mild mitochondrial symptoms (patient 4, 50% in blood and 67% in urine and patient 5, 50% heteroplasmy in blood and 30% in urine). We observe that this variant is associated with multiple mitochondrial presentations and phenotypes, including MELAS syndrome for which this variant has not previously been reported. We also demonstrate that the level of heteroplasmy of the mitochondrial DNA variant correlates with the severity of clinical presentation; however, not with the specific mitochondrial syndrome.

Keywords:  Leigh syndrome; heteroplasmy; lactic acidosis; mitochondrial disorders; mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS); phenotypic variability

DOI:  https://doi.org/10.1002/ajmg.a.63378
Res Involv Engagem. 2023 Aug 30. 9(1): 73

Evaluating the impacts of patient engagement on a national health research network: results of a case study of the Chronic Pain Network.

Laura Tripp, Dawn P Richards, Jennifer Daly-Cyr, Therese Lane, Delane Linkiewich, Kimberly N Begley, Norman Buckley, Maria Hudspith, Patricia Poulin, Julia Abelson.

   BACKGROUND: The Chronic Pain Network (CPN) is a pan-Canadian research network focused on innovating and improving the quality and delivery of pain prevention, assessment, management and research for all Canadians. An important focus of the CPN is to work in collaboration with patient partners. Patient partners, researchers and clinicians work together in all aspects of the research network including on funded research projects and in the governance of the Network. Given this focus, the CPN identified the importance of evaluating their patient engagement work to understand its functioning and impact.
METHODS: The objective of this exploratory evaluation case study was to understand the impacts of patient engagement on the CPN. The CPN worked with an external evaluation team which established an arms-length approach to the evaluation. Interviews were conducted with CPN members, including patient partners, leadership, funded researchers and committee co-chairs, at three discrete time points to trace the evolution of the patient engagement program within the Network. Key Network documents were also collected and reviewed. Data were analyzed following each set of interviews using content analysis guided by the principles of constant comparison and qualitative description. A final round of analysis was conducted using the Engage with Impact Toolkit, an impact measurement framework, to identify impacts of engagement.
RESULTS: Impacts of patient engagement were identified at the individual, network, funded research project and research community levels. These impacts were observed in the following areas: (1) building community; (2) developing knowledge, skills and resources; (3) increasing confidence; (4) influencing priorities and decisions; (5) enabling additional opportunities; (6) promoting culture change; and, (7) coping with experiences of living with chronic pain.
CONCLUSIONS: While not without challenges, the patient engagement efforts of the CPN demonstrates the impact engaging patient partners can have on a national research network and related policy activities. Understanding the approaches to, and impacts of, patient engagement on health research networks can illuminate the value of having patient partners engaged in all aspects of a research network and should serve as encouragement to others who look to take on similar work.

Keywords:  Evaluation; Patient and public involvement; Patient engagement

DOI:  https://doi.org/10.1186/s40900-023-00491-w
Orphanet J Rare Dis. 2023 Aug 29. 18(1): 253

Overcoming challenges in rare disease registry integration using the semantic web - a clinical research perspective.

Karl Gisslander, Aladdin J Mohammad, Augusto Vaglio, Mark A Little.

  The growing number of disease-specific patient registries for rare diseases has highlighted the need for registry interoperability and data linkage, leading to large-scale rare disease data integration projects using Semantic Web based solutions. These technologies may be difficult to grasp for rare disease experts, leading to limited involvement by domain expertise in the data integration process. Here, we propose a data integration framework starting from the perspective of the clinical researcher, allowing for purposeful rare disease registry integration driven by clinical research questions.

Keywords:  Data integration; FAIRification; Rare disease; Registry; Semantic web; Vasculitis

DOI:  https://doi.org/10.1186/s13023-023-02841-z
Metab Brain Dis. 2023 Aug 29.

Vitamin B1 deficiency leads to high oxidative stress and mtDNA depletion caused by SLC19A3 mutation in consanguineous family with Leigh syndrome.

Rahma Felhi, Lamia Sfaihi, Majida Charif, Fakher Frikha, Nissaf Aoiadni, Thouraya Kamoun, Guy Lenaers, Faiza Fakhfakh.

  Leigh syndrome (LS) and Leigh-like spectrum are the most common infantile mitochondrial disorders characterized by heterogeneous neurologic and metabolic manifestations. Pathogenic variants in SLC carriers are frequently reported in LS given their important role in transporting various solutes across the blood-brain barrier. SLC19A3 (THTR2) is one of these carriers transporting vitamin-B1 (vitB1, thiamine) into the cell. Targeted NGS of nuclear genes involved in mitochondrial diseases was performed in a patient belonging to a consanguineous Tunisian family with LS and revealed a homozygous c.1264 A > G (p.T422A) variant in SLC19A3. Molecular docking revealed that the p.T422A aa change is located at a key position interacting with vitB1 and causes conformational changes compromising vitB1 import. We further disclosed decreased plasma antioxidant activities of CAT, SOD and GSH enzymes, and a 42% decrease of the mtDNA copy number in patient blood.Altogether, our results disclose that the c.1264 A > G (p.T422A) variant in SLC19A3 affects vitB1 transport, induces a mtDNA depletion and reduces the expression level of oxidative stress enzymes, altogether contributing to the LS phenotype of the patient.

Keywords:  Antioxidant; Encephalopathy; Mitochondrial disorder; Molecular docking; Thiamine

DOI:  https://doi.org/10.1007/s11011-023-01280-w
PLoS One. 2023 ;18(9): e0291066

Designing infographics in health research with patients and the public: A scoping review protocol.

Blaze Beecher, Alan O'Doherty, Beatriz Goulao, Amirhossein Jalali, Jon Salsberg, Liz Dore, Ailish Hannigan.

Information graphics or infographics combine visual representations of information or data with text. They have been used in health research to disseminate research findings, translate knowledge and address challenges in health communication to lay audiences. There is emerging evidence of the design of infographics with the involvement of patients and the public in health research. Approaches to involvement include public and patient involvement, patient engagement and participatory research approaches. To date, there has been no comprehensive review of the literature on the design of infographics with patients and the public in health research. This paper presents a protocol and methodological framework for a scoping review to identify and map the available evidence for the involvement of patients and the public in infographics design in health research. It has been informed by preliminary searches and discussions and will guide the conduct and reporting of this review.

DOI: https://doi.org/10.1371/journal.pone.0291066
J Prim Care Community Health. 2023 Jan-Dec;14:14 21501319231193875

Navigating Life With Primary Mitochondrial Myopathies: The Importance of the Patient Voice and Implications for Clinical Practice.

Margaret Moore, Philip Yeske, Sumit Parikh.

  Primary mitochondrial myopathies (PMM) are rare disorders with diverse and progressive symptom presentations that cause a substantial, detrimental impact on the quality of life of patients and their caregivers. The burden of symptoms is compounded by their visibility and their unpredictable, progressive nature, leading to a sense of social stigmatization, limited autonomy, social isolation, and grief. There is also a lack of awareness and expertise in the medical community, which presents huge obstacles to diagnosis and provision of coordinated multidisciplinary care for these patients, along with a lack of disease-modifying treatments. The present commentary serves to raise awareness of the challenges faced by patients with PMM and their caregivers in their own words, including diagnostic delays, the burden of disease, and the need for further trials to develop disease-modifying treatments and improved understanding of the disease course. We also provide commentary on considerations for clinical practice, including the need for holistic care and multidisciplinary care teams, details of common 'red flag' symptoms, proposed diagnostic approaches, and suggested descriptions of multisystemic symptoms for physician-patient dialogue. In addition, we highlight the role patient advocacy and support groups play in supporting patients and providing access to reliable, up-to-date information and educational resources on these rare diseases.

Keywords:  mitochondrial disorders; patient perspectives; patient-centeredness; practice management; primary mitochondrial disease; primary mitochondrial myopathies

DOI:  https://doi.org/10.1177/21501319231193875
Biochim Biophys Acta Mol Basis Dis. 2023 Aug 26. pii: S0925-4439(23)00222-3. [Epub ahead of print] 166856

Mutation on MT-CO2 gene induces mitochondrial disease associated with neurodegeneration and intracerebral iron accumulation (NBIA).

Sarah Courtois, Chloé Angelini, Christelle M Durand, Nivea Dias Amoedo, Armelle Courreges, Elodie Dumon, Mégane Le Quang, Cyril Goizet, Marie-Laure Martin-Negrier, Rodrigue Rossignol, Didier Lacombe, Isabelle Coupry, Aurélien Trimouille.

  Mitochondrial diseases are genetic disorders impairing mitochondrial functions. Here we describe a patient with a neurodegenerative condition associated with myopia, bilateral sensorineural hearing loss and motor disorders. Brain MRIs showed major cortico-subcortical and infra-tentorial atrophies, as well as intracerebral iron accumulation and central calcifications, compatible with a NBIA-like phenotype. Mitochondrial DNA analysis revealed an undescribed variant: m.8091G>A in the MT-CO2 gene, associated with a complex IV deficiency and a decrease of the mitochondrial respiratory chain capabilities. We report here this pathogenic variant, associated with a NBIA-like phenotype.

Keywords:  Complex IV; MT-CO2; Mitochondriopathies; NBIA; iron accumulation

DOI:  https://doi.org/10.1016/j.bbadis.2023.166856
Mitochondrion. 2023 Aug 25. pii: S1567-7249(23)00071-5. [Epub ahead of print]72 102-105

Mitochondrial dysfunction characterized in human induced pluripotent stem cell disease models in MELAS syndrome: A brief summary.

Kumarie Latchman, Mario Saporta, Carlos T Moraes.

Human induced pluripotent stem cells (hiPSCs) for MELAS syndrome (mitochondrial myopathy, encephalopathy, lactic acidosis, stroke-like episodes) may allow deeper understanding of how tissue-specific mitochondrial dysfunction result in multi-systemic disease. Here, we summarize how the m.3243G mtDNA mutation affects mitochondrial function in different tissues using iPSC and iPSC-differentiated cell type disease models and what significant findings have been replicated in the independent studies. Through this brief review and with a focus on mitochondrial dysfunction in iPSC-differentiated cell types, namely fibroblast, neuron, and retinal pigment epithelium cells, we aim to bring awareness of hiPSC as a robust mitochondrial disease model even if many unanswered questions remain.

DOI: https://doi.org/10.1016/j.mito.2023.08.003
Zhejiang Da Xue Xue Bao Yi Xue Ban. 2023 Aug 25. pii: 1008-9292(2023)04-0460-13. [Epub ahead of print]52(4): 460-472

Research progress in mitochondrial gene editing technology.

Yichen Wang, Ying Wang, Yu Chen, Qingfeng Yan, Aifu Lin.

  Mitochondrial DNA (mtDNA) mutations result in a variety of genetic diseases. As an emerging therapeutic method, mtDNA editing technology recognizes targets more based on the protein and less on the nucleic acid. Although the protein recognition type mtDNA editing technology represented by zinc finger nuclease technology, transcription activator like effector nuclease technology and base editing technology has made some progress, the disadvantages of complex recognition sequence design hinder further popularization. Gene editing based on nucleic acid recognition by the CRISPR system shows superiority due to the simple structure, easy design and modification. However, the lack of effective means to deliver nucleic acids into mitochondria limits application in the field of mtDNA editing. With the advances in the study of endogenous and exogenous import pathways and the deepening understanding of DNA repair mechanisms, growing evidence shows the feasibility of nucleic acid delivery and the broad application prospects of nucleic acid recognition type mtDNA editing technology. Based on the classification of recognition elements, this article summarizes the current principles and development of mitochondrial gene editing technology, and discusses its application prospects.

Keywords:  CRISPR; Gene editing; Mitochondrion; Nucleic acid delivery; Review

DOI:  https://doi.org/10.3724/zdxbyxb-2023-0129
Orphanet J Rare Dis. 2023 Aug 31. 18(1): 259

Initiatives to promote access to medicines after publication of the Brazilian Policy on the Comprehensive Care of People with Rare Diseases.

Cássia Cunico, Geison Vicente, Silvana Nair Leite.

   BACKGROUND: Rare diseases affect a small number of people compared to prevalent diseases. The vast majority of these diseases are of genetic origin, have no cure, are chronic and can lead to death. Although the right to access medicines is included in the constitutionally guaranteed right to health in Brazil, problems in the supply of medicines for rare diseases are reported in the country. This study aimed to describe and analyse the initiatives to promote access to medicines for treating rare diseases in the Unified Health System, Brazil, after the publication of the Brazilian Policy on the Comprehensive Care of People with Rare Diseases. Based on the model published by the WHO Regional Office for Europe, which described access to medicines in prelaunch, perilaunch and postlaunch policies, the initiatives referring to each category were summarized based on documentary research searched in online databases from January 2014 to December 2020.
RESULTS: Different actions and policy interventions were identified, which went through the expansion of resources for research and development, health regulations, incorporation of new drugs, review and publication of clinical guidelines, and expansion of the network of care facilities by the Ministry of Health. On the other hand, aspects related to care policies, pricing methods, technological development, and development of pharmaceutical service processes were not implemented.
CONCLUSIONS: Although it is impossible to determine the explicit motivation of such actions concerning the Policy, its publication certainly was a landmark in Brazilian society, allowing greater recognition of the needs of rare disease patients and the specificities of treatment'. However, this study suggests that the steps that make up the life cycle of medicines are not linked, lacking articulation and integration of the care network, and consequently, there is no evidence that rare disease policy publication has generated a broad impact on the promotion of access to medicines to treat rare diseases in Brazil.

Keywords:  Access to medicines; Brazil; Health policy; Health technologies; Rare diseases

DOI:  https://doi.org/10.1186/s13023-023-02881-5
J Community Genet. 2023 Aug 26.

Genetic services survey-experience of people with rare diseases and their families accessing genetic services in the Irish Republic.

A J Ward, D M Lambert, D Butterly, J J O'Byrne, V McGrath, S A Lynch.

  Irish Health Service objectives state that patients with rare diseases should have timely access to genomic diagnostics with appropriate pre and post-test counselling. However, waiting times for clinical genetics outpatient appointments, during the study period, were up to two years as staffing levels remain low. A targeted public online survey was conducted in January 2022 to capture the experiences of Rare Disease families trying to access genetic testing and clinical genetic clinics in the Irish Republic. Irish patients experience significant waiting times to access clinical genetic services and self-report anxiety and stress, related to delayed access to diagnosis, clarity around recurrence risk and follow-up management. This negatively impacts personal decisions around family planning, education and employment and has a significant impact on family members seeking clarity on their own risk. Mainstream genetic testing activity is significant. Families report concern over the competency of health care professionals arranging and delivering genetic results and delays in accessing clinical genetics expertise to take them through the clinical implications. Timely access to clinical genetics expertise is important to ensure families with rare diseases have an appropriate understanding of the medical and reproductive implications of a genetic diagnosis and access to relevant care pathways. A national framework to develop competency in genomic literacy for health-care professionals including a national genetic test directory may be beneficial. Clinical genetics teams require ongoing support and investment to ensure the delivery of a safe and effective service for Irish families with rare diseases.

Keywords:  Genetic services; Genetic testing; Genomic mainstreaming; Patient experience

DOI:  https://doi.org/10.1007/s12687-023-00664-w
Res Involv Engagem. 2023 Aug 30. 9(1): 72

Patient and public involvement in Nordic healthcare research: a scoping review of contemporary practice.

Kristine Elberg Dengsø, Sofie Tscherning Lindholm, Suzanne Forsyth Herling, Maja Pedersen, Kristina Holmegaard Nørskov, Marie Oxenbøll Collet, Iben Husted Nielsen, Mille Guldager Christiansen, Mette Schaufuss Engedal, Helga Wallin Moen, Karin Piil, Ingrid Egerod, Mogens Hørder, Mary Jarden.

BACKGROUND: Over the past decades, there has been a growing international interest in user involvement in healthcare research. However, evidence on the management and impact of patient and public involvement in Nordic healthcare research remains limited.
OBJECTIVE: The aim was to explore and delineate the current state, practice, and impact of patient and public involvement in healthcare research across different areas of healthcare and patient populations in the Nordic countries.
METHODS: We conducted a scoping review using nine scientific databases and gray literature from 1992-2023. Sources were categorized as empirical or non-empirical. We used the Guidance for Reporting Involvement of Patients and the Public Short Form 2 checklist for reporting of patient and public involvement in healthcare research and the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews.
RESULTS: A total of 56 publications were included, consisting of 39 empirical and 17 non-empirical sources. Gray literature varied among countries and institutions encompassing different types of documents. We found an increase in the number of publications on patient and public involvement in Nordic healthcare research. This was evidenced by the growing number of references and institutional initiatives intended at involving the public, indicating the increasing emphasis on patient and public involvement in Nordic healthcare research. The terminology used to describe patient and public involvement varied over time. However, there has been a gradual narrowing down of terms as the concept of PPI has become more integrated into research practices, particularly with the involvement of funding agencies.
CONCLUSION: The utilization of patient and public involvement in Nordic healthcare research has substantially increased, proliferated, and gained widespread acceptance across diverse healthcare domains. The variety of approaches challenged our scoping review in terms of systematic description and impact. Patient and public involvement was applied in one or more research stages using different methodologies and terms. International agreement on terms and definitions is needed for reliable interpretation of the use of patient and public involvement in Nordic healthcare research.

DOI: https://doi.org/10.1186/s40900-023-00490-x
Life Sci Alliance. 2023 Nov;pii: e202302271. [Epub ahead of print]6(11):

T cell differentiation drives the negative selection of pathogenic mitochondrial DNA variants.

Imogen G Franklin, Paul Milne, Jordan Childs, Róisín M Boggan, Isabel Barrow, Conor Lawless, Gráinne S Gorman, Yi Shiau Ng, Matthew Collin, Oliver M Russell, Sarah J Pickett.

Pathogenic mitochondrial DNA (mtDNA) single-nucleotide variants are a common cause of adult mitochondrial disease. Levels of some variants decrease with age in blood. Given differing division rates, longevity, and energetic requirements within haematopoietic lineages, we hypothesised that cell-type-specific metabolic requirements drive this decline. We coupled cell-sorting with mtDNA sequencing to investigate mtDNA variant levels within progenitor, myeloid, and lymphoid lineages from 26 individuals harbouring one of two pathogenic mtDNA variants (m.3243A>G and m.8344A>G). For both variants, cells of the T cell lineage show an enhanced decline. High-throughput single-cell analysis revealed that decline is driven by increasing proportions of cells that have cleared the variant, following a hierarchy that follows the current orthodoxy of T cell differentiation and maturation. Furthermore, patients with pathogenic mtDNA variants have a lower proportion of T cells than controls, indicating a key role for mitochondrial function in T cell homeostasis. This work identifies the ability of T cell subtypes to selectively purify their mitochondrial genomes, and identifies pathogenic mtDNA variants as a new means to track blood cell differentiation status.

DOI: https://doi.org/10.26508/lsa.202302271
Res Involv Engagem. 2023 Aug 29. 9(1): 71

Patient and public involvement to inform priorities and practice for research using existing healthcare data for children's and young people's cancers.

Nicola F Hughes, Lorna A Fern, Angela Polanco, Chris Carrigan, Richard G Feltbower, Ashley Gamble, Emily Connearn, Angela Lopez, Ellen Bisci, Kathy Pritchard-Jones.

   BACKGROUND: In the United Kingdom, healthcare data is collected on all patients receiving National Health Service (NHS) care, including children and young people (CYP) with cancer. This data is used to inform service delivery, and with special permissions used for research. The use of routinely collected health data in research is an advancing field with huge potential benefit, particularly in CYP with cancer where case numbers are small and the impact across the life course can be significant. Patient and public involvement (PPI) exercise aims: Identify current barriers to trust relating to the use of healthcare data for research. Determine ways to increase public and patient confidence in the use of healthcare data in research. Define areas of research importance to CYP and their carers using healthcare data.
METHODS: Young people currently aged between 16 and 25 years who had a cancer diagnosis before the age of 20 years and carers of a young person with cancer were invited to take part via social media and existing networks of service users. Data was collected during two interactive online workshops totalling 5 h and comprising of presentations from health data experts, case-studies and group discussions. With participant consent the workshops were recorded, transcribed verbatim and analysed using thematic analysis.
RESULTS: Ten young people and six carers attended workshop one. Four young people and four carers returned for workshop two. Lack of awareness of how data is used, and negative media reporting were seen as the main causes of mistrust. Better communication and education on how data is used were felt to be important to improving public confidence. Participants want the ability to have control over their own data use. Late effects, social and education outcomes and research on rare tumours were described as key research priorities for data use.
CONCLUSIONS: In order to improve public and patient trust in our use of data for research, we need to improve communication about how data is used and the benefits that arise.

Keywords:  Children and young people with cancer; Healthcare data; Outcomes research; Participatory patient and public involvement methods

DOI:  https://doi.org/10.1186/s40900-023-00485-8
Orphanet J Rare Dis. 2023 Sep 01. 18(1): 262

Composite endpoints, including patient reported outcomes, in rare diseases.

Johan Verbeeck, Maya Dirani, Johann W Bauer, Ralf-Dieter Hilgers, Geert Molenberghs, Rima Nabbout.

   BACKGROUND: When assessing the efficacy of a treatment in any clinical trial, it is recommended by the International Conference on Harmonisation to select a single meaningful endpoint. However, a single endpoint is often not sufficient to reflect the full clinical benefit of a treatment in multifaceted diseases, which is often the case in rare diseases. Therefore, the use of a combination of several clinically meaningful outcomes is preferred. Many methodologies that allow for combining outcomes in a so-called composite endpoint are however limited in a number of ways, not in the least in the number and type of outcomes that can be combined and in the poor small-sample properties. Moreover, patient reported outcomes, such as quality of life, often cannot be integrated in a composite analysis, in spite of their intrinsic value.
RESULTS: Recently, a class of non-parametric generalized pairwise comparisons tests have been proposed, which members do allow for any number and type of outcomes, including patient reported outcomes. The class enjoys good small-sample properties. Moreover, this very flexible class of methods allows for prioritizing the outcomes by clinical severity, allows for matched designs and for adding a threshold of clinical relevance. Our aim is to introduce the generalized pairwise comparison ideas and concepts for rare disease clinical trial analysis, and demonstrate their benefit in a post-hoc analysis of a small-sample trial in epidermolysis bullosa. More precisely, we will include a patient relevant outcome (Quality of life), in a composite endpoint. This publication is part of the European Joint Programme on Rare Diseases (EJP RD) series on innovative methodologies for rare diseases clinical trials, which is based on the webinars presented within the educational activity of EJP RD. This publication covers the webinar topic on composite endpoints in rare diseases and includes participants' response to a questionnaire on this topic.
CONCLUSIONS: Generalized pairwise comparisons is a promising statistical methodology for evaluating any type of composite endpoints in rare disease trials and may allow a better evaluation of therapy efficacy including patients reported outcomes in addition to outcomes related to the diseases signs and symptoms.

Keywords:  Composite endpoints; EJP-RD; Epidermolysis bullosa; Generalized pairwise comparisons; Patient reported outcomes; Quality of life; Rare disease

DOI:  https://doi.org/10.1186/s13023-023-02819-x
Clin Transl Sci. 2023 Aug 30.

Artificial intelligence in rare disease diagnosis and treatment.

Magda Wojtara, Emaan Rana, Taibia Rahman, Palak Khanna, Heshwin Singh.

Artificial intelligence (AI) utilization in health care has grown over the past few years. It also has demonstrated potential in improving the efficiency of diagnosis and treatment. Some types of AI, such as machine learning, allow for the efficient analysis of vast datasets, identifying patterns, and generating key insights. Predictions can then be made for medical diagnosis and personalized treatment recommendations. The use of AI can bypass some conventional limitations associated with rare diseases. Namely, it can optimize traditional randomized control trials, and may eventually reduce costs for drug research and development. Recent advancements have enabled researchers to train models based on large datasets and then fine-tune these models on smaller datasets typically associated with rare diseases. In this mini-review, we discuss recent advancements in AI and how AI can be applied to streamline rare disease diagnosis and optimize treatment.

DOI: https://doi.org/10.1111/cts.13619