Curr Opin Pediatr. 2025 Feb 1;37(1):56-58. doi: 10.1097/MOP.0000000000001421. Epub 2024 Nov 28.

ABSTRACT

PURPOSE OF REVIEW: Due to the infrequent nature of rare pediatric cancers, rigorously studied treatment algorithms are usually nonexistent, and experience with a given tumor may be limited at a single institution. Development of treatment plans for these populations often requires extensive literature review and outreach to experts at other institutions. National or international virtual tumor boards provide a streamlined, collaborative approach to discussing diagnosis and management of these patients through dissemination of collective experience and knowledge. This review highlights current virtual tumor boards for rare pediatric cancers and their benefit as a resource for patient care.

RECENT FINDINGS: Over the last several years, national virtual tumor boards sponsored by government and academic institutions and cancer foundations have expanded access of pediatric oncologists to rare tumor expertise and guidance. Recommendations from these tumor boards often have an impact on medical decision making, and some serve as a resource for enduring educational reference materials.

SUMMARY: National virtual tumor boards are a valuable resource to clinicians caring for patients with rare pediatric tumors. These conferences provide real-time management advice from peers and subject matter experts and provide essential educational content not easily accessible in other formats.

PMID:39699101 | DOI:10.1097/MOP.0000000000001421

Health Qual Life Outcomes. 2024 Dec 19;22(1):108. doi: 10.1186/s12955-024-02324-0.

ABSTRACT

BACKGROUND: Rare diseases often entail significant challenges in clinical management and health-related quality of life (HRQoL) assessment. HRQoL assessment tools for rare diseases show substantial variability in outcomes, influenced by disease heterogeneity, intervention types, and scale characteristics. The variability in reported quality of life (QoL) improvements following interventions reflects a need to evaluate the effectiveness of HRQoL assessment tools and understand their suitability across diverse contexts.

OBJECTIVE: This systematic review aims to analyse the effectiveness of various assessment scales in evaluating QoL and explores the general trends observed in the studies using the same and different assessment scales on rare diseases.

METHODS: A comprehensive literature search was conducted across various databases to identify studies that reported QoL outcomes related to interventions for rare diseases. Search terms included various synonyms, and both the generic and specific terms related to rare diseases and QoL. Key variables, including intervention types, patient demographics, study design, and geographical factors, were analysed to determine their role in influencing the reported HRQoL outcomes. The findings were then compared with existing literature to identify consistent patterns and discrepancies.

RESULTS: A total of 39 studies were included, comprising randomised controlled trials, observational studies, and cohort studies, with 4737 participants. Significant variations were observed in QoL improvements across studies, even when using the same assessment scales. These differences were primarily attributed to the heterogeneity in disease severity, intervention types, and patient characteristics. Studies employing disease-specific scales reported more nuanced outcomes than generic ones. Additionally, methodological differences, including study design and intervention type, contributed to variations in results and geographical factors influencing patients' perceptions of health and well-being.

CONCLUSION: The reported differences in QoL outcomes across studies can be explained by a combination of factors, including disease heterogeneity, treatment modalities, patient demographics, and assessment scale characteristics. These findings underscore the importance of selecting appropriate HRQoL assessment tools based on the research context and patient population. For more accurate comparisons across studies, it is crucial to consider these factors alongside consistent methodology and cultural adaptability of scales. Future research should focus on developing standardised guidelines for QoL assessments that accommodate the diverse needs of patients with rare diseases.

PMID:39696506 | DOI:10.1186/s12955-024-02324-0

BMC Pediatr. 2024 Dec 19;24(1):823. doi: 10.1186/s12887-024-05304-x.

ABSTRACT

BACKGROUND: Kidney transplantation is the gold standard treatment for end-stage kidney disease in children. Rare genetic systemic diseases associated with cystic kidney disease such as COL4A1-related disorder and oral facial digital syndrome type 1 could contribute to end-stage kidney disease in the pediatric population but there is scarce evidence in the literature regarding kidney transplant outcomes in these cases.

CASE PRESENTATION: We report a case of a 5-year-old male with COL4A1-related disorder who received a living-related donor kidney transplant from his mother. To our knowledge this is the first reported kidney transplant in a pediatric recipient with COL4A1-related disorder. We also present a case of a 16-year-old female with oral facial digital syndrome type 1 who received a deceased donor kidney transplant.

CONCLUSIONS: In this case series, we discuss surgical technique, indication for kidney transplant, influence of comorbidities and intellectual disability in transplant outcomes.

PMID:39696129 | DOI:10.1186/s12887-024-05304-x

JMIR Med Inform. 2024 Dec 18;12:e60665. doi: 10.2196/60665.

ABSTRACT

BACKGROUND: Rare diseases affect millions worldwide but sometimes face limited research focus individually due to low prevalence. Many rare diseases do not have specific International Classification of Diseases, Ninth Edition (ICD-9) and Tenth Edition (ICD-10), codes and therefore cannot be reliably extracted from granular fields like "Diagnosis" and "Problem List" entries, which complicates tasks that require identification of patients with these conditions, including clinical trial recruitment and research efforts. Recent advancements in large language models (LLMs) have shown promise in automating the extraction of medical information, offering the potential to improve medical research, diagnosis, and management. However, most LLMs lack professional medical knowledge, especially concerning specific rare diseases, and cannot effectively manage rare disease data in its various ontological forms, making it unsuitable for these tasks.

OBJECTIVE: Our aim is to create an end-to-end system called automated rare disease mining (AutoRD), which automates the extraction of rare disease-related information from medical text, focusing on entities and their relations to other medical concepts, such as signs and symptoms. AutoRD integrates up-to-date ontologies with other structured knowledge and demonstrates superior performance in rare disease extraction tasks. We conducted various experiments to evaluate AutoRD's performance, aiming to surpass common LLMs and traditional methods.

METHODS: AutoRD is a pipeline system that involves data preprocessing, entity extraction, relation extraction, entity calibration, and knowledge graph construction. We implemented this system using GPT-4 and medical knowledge graphs developed from the open-source Human Phenotype and Orphanet ontologies, using techniques such as chain-of-thought reasoning and prompt engineering. We quantitatively evaluated our system's performance in entity extraction, relation extraction, and knowledge graph construction. The experiment used the well-curated dataset RareDis2023, which contains medical literature focused on rare disease entities and their relations, making it an ideal dataset for training and testing our methodology.

RESULTS: On the RareDis2023 dataset, AutoRD achieved an overall entity extraction F1-score of 56.1% and a relation extraction F1-score of 38.6%, marking a 14.4% improvement over the baseline LLM. Notably, the F1-score for rare disease entity extraction reached 83.5%, indicating high precision and recall in identifying rare disease mentions. These results demonstrate the effectiveness of integrating LLMs with medical ontologies in extracting complex rare disease information.

CONCLUSIONS: AutoRD is an automated end-to-end system for extracting rare disease information from text to build knowledge graphs, addressing critical limitations of existing LLMs by improving identification of these diseases and connecting them to related clinical features. This work underscores the significant potential of LLMs in transforming health care, particularly in the rare disease domain. By leveraging ontology-enhanced LLMs, AutoRD constructs a robust medical knowledge base that incorporates up-to-date rare disease information, facilitating improved identification of patients and resulting in more inclusive research and trial candidacy efforts.

PMID:39693482 | DOI:10.2196/60665

Zhonghua Liu Xing Bing Xue Za Zhi. 2024 Dec 10;45(12):1700-1704. doi: 10.3760/cma.j.cn112338-20240705-00401.

ABSTRACT

Due to the limited number of cases, conducting large-scale clinical trials for rare diseases is challenging. This review introduces several small sample statistical designs tailored for rare diseases, including crossover design, n-of-1 design, randomized placebo-phase design, randomized withdrawal design, group sequential design, and adaptive design. It discusses the advantages, disadvantages, and application scenarios of these designs. Additionally, it explores the benefits of Bayes decision-making in clinical trials for rare diseases. The aim is to provide a reference for designing and implementing small sample clinical trials for rare diseases.

PMID:39681428 | DOI:10.3760/cma.j.cn112338-20240705-00401

Brain. 2024 Dec 16:awae395. doi: 10.1093/brain/awae395. Online ahead of print.

ABSTRACT

Congenital hydrocephalus (CH), characterized by cerebral ventriculomegaly (CV), is among the most common and least understood pediatric neurosurgical disorders. We have identified in the largest-assembled CV cohort (>2,697 parent-proband trios) an exome-wide significant enrichment of protein-altering de novo variants (DNVs) in LDB1 (p = 1.11 x 10-15). Eight unrelated patients with ventriculomegaly, developmental delay, and dysmorphic features harbored loss-of-function DNVs that truncate LDB1's carboxy-terminal LIM interaction domain, which regulates assembly of LIM homeodomain-containing transcriptional modulators. Integrative multiomic analyses suggest LDB1 is a key transcriptional regulator in ventricular neuroprogenitors through it's binding to LIM-homeodomain proteins, including SMARCC1 and ARID1B. Indeed, LIM-homeodomain-containing genes carry a disproportionate burden of protein-damaging DNVs in our cohort, with SMARCC1 (p = 5.83 x 10-9) and ARID1B (p = 1.80 x 10-17) surpassing exome-wide significance thresholds. These data identify LBD1 as a novel neurodevelopmental disorder gene and suggest an LDB1-regulated transcriptional program is essential for human brain morphogenesis.

PMID:39680505 | DOI:10.1093/brain/awae395

Pediatr Neurol. 2025 Feb;163:46-49. doi: 10.1016/j.pediatrneurol.2024.11.001. Epub 2024 Nov 9.

ABSTRACT

To date, sparse attention has been paid to the importance of the "lived experience" of participants and their caregivers in pediatric gene therapy (GT) trials for rare genetic neurological disorders. Pediatric GT studies differ meaningfully from adult GT studies as the decision to participate involves a dyad: the child participant and their caregiver(s). As a multistakeholder group of authors, we are a diverse group with expert perspectives on the social, emotional, physical, and logistical burdens/benefits of trial participation and the myriad ways they affect pediatric GT research. For both pragmatic and ethical reasons, it is essential to prioritize addressing child participant and adult caregiver needs and concerns when designing and conducting GT clinical trials in pediatric populations with rare genetic neurological disorders. We use the term "lived experience" in reference to how people think about and make decisions regarding participation in research studies and how they articulate the emotional, social, ethical, and equity tradeoffs that impact their lives and illness experience. In this article, we describe why accounting for child participants' and adult caregivers' lived experience and addressing pertinent equity issues are essential when designing and conducting pediatric GT trials for rare genetic neurological diseases.

PMID:39671832 | DOI:10.1016/j.pediatrneurol.2024.11.001

Genet Med Open. 2023 Sep 28;1(1):100834. doi: 10.1016/j.gimo.2023.100834. eCollection 2023.

ABSTRACT

A novel syndrome was suspected in individuals sharing short stature, microcephaly, distinctive facial features, and congenital anomalies. We enrolled 6 patients in an institutional review board approved study and evaluated medical history, findings, facial photographs, and test results across this original cohort. Four additional cases with similar findings were contributed by clinicians from outside institutions, bringing the number of reported cases to 10 and supporting the existence of this novel syndrome. The 6 individuals enrolled into the institutional review board approved study shared microcephaly, short stature, and distinctive facial features. Congenital malformations included cleft palate, talipes equinovarus or rocker bottom feet, and chordee or hypospadias. Short, broad thumbs, single palmar crease, and mild 2,3 toe syndactyly were present. A hypoplastic corpus callosum was noted in 3 of 5 with appropriate evaluation. Their growth and physical findings were suggestive of Smith-Lemli-Opitz syndrome. Biochemical studies shortly after delivery indicated abnormalities in the cholesterol metabolism pathway that subsequently resolved. No shared genomic or genetic cause was identified. All individuals were born after a pregnancy complicated by prenatal exposure to nonprescription opioids, particularly fentanyl, suggesting fentanyl as a teratogen. Prenatal fentanyl exposure possibly interfered with cholesterol metabolism, giving rise to findings resembling Smith-Lemli-Opitz syndrome. This novel syndrome is clinically recognizable. Four additional cases contributed clinically shared similar findings, increasing the number of cases to 10 and supporting a novel syndrome associated with prenatal fentanyl exposure. Assessment of Shepard and Bradford Hill criteria could be consistent with fentanyl as teratogen, though caution is necessary before assigning causality and data replication is needed.

PMID:39669238 | PMC:PMC11613603 | DOI:10.1016/j.gimo.2023.100834

Brain. 2025 Jan 7;148(1):39-46. doi: 10.1093/brain/awae308.

ABSTRACT

Over the past two decades there has been increased interest in orphan drug development for rare diseases. However, hurdles to clinical trial design for these disorders remain. This phase 1a/1b study addressed several challenges, while evaluating the safety and tolerability of the novel oral molecule KL1333 in healthy volunteers and subjects with primary mitochondrial disease. KL1333 aims to normalize the NAD+:NADH ratio that is critical for ATP production. The trial incorporated innovative design elements with potential translatability to other rare diseases including patient involvement, adaptive design and exploratory objectives, all of which have subsequently informed the protocol of an ongoing phase 2, pivotal efficacy study of KL1333. Results indicate KL1333 is safe and well tolerated, with dose-dependent gastrointestinal side effects, and validate potential novel outcome measures in primary mitochondrial disease including the 30-s Sit to Stand, and the patient-reported fatigue scales. Importantly, the data from the trial support efficacy of KL1333 based on improvements in fatigue and functional strength and endurance. Furthermore, the study highlights the value in using phase 1 studies to capture data that helps optimize later phase efficacy trial design.

PMID:39657714 | PMC:PMC11706290 | DOI:10.1093/brain/awae308

J Inherit Metab Dis. 2024 Dec 10. doi: 10.1002/jimd.12827. Online ahead of print.

ABSTRACT

Successful transition to independent adulthood requires intact executive and adaptive function. These neurocognitive domains are frequently impaired in inherited metabolic disorders (IMD), despite optimal management. For many IMDs, the impact of executive and adaptive dysfunction on long-term outcomes remains undefined. Standardized assessments linking neurocognitive status with functional outcomes are needed to improve prognostication and tailor support for affected emerging adults. Maple syrup urine disease (MSUD), a relatively prevalent IMD, is primarily diagnosed in the first week of life through newborn screening. Despite early intervention, executive and adaptive dysfunction persist. We designed a remote, interactive battery of neurocognitive and functional assessments for adults (≥21 years) with MSUD to correlate neurocognition and long-term outcomes. Participants were selectively recruited for racial, ethnic, socio-economic, and geographic diversity. Assessments completed by 28 adults with MSUD (82% diagnosed after symptom onset, 25% from minority communities) show a wide range in educational attainment, employment, and residence. Executive and adaptive function were significantly impaired in adults with MSUD compared to controls. Executive and adaptive deficits correlated negatively with educational attainment, employment, and obtaining skills needed for adult-oriented healthcare or independent living. Clinical history did not predict functional outcomes, but neurocognitive assessments suggest the benefits of pre-symptomatic diagnosis. Independent adulthood is attainable for individuals with MSUD. Routine assessment of neurocognition and interventions targeting executive and adaptive function may improve long-term functional outcomes in IMD.

PMID:39655455 | DOI:10.1002/jimd.12827

J Glob Health. 2024 Dec 9;14:04249. doi: 10.7189/jogh.14.04249.

ABSTRACT

BACKGROUND: Rare endocrine diseases (RED) often pose chronic and life-threatening challenges, yet their economic costs and societal impact remains have not been precisely quantified.

METHODS: We obtained patient data from the 2018 Nationwide Inpatient Sample (NIS) and the Nationwide Readmissions Database (NRD), identifying RED patients through International Classification of Diseases, 10th revision codes. The difference of economic burden between RED patients and the control group, including hospital length of stay, hospitalisation costs, and readmission rates, was assessed using chi-square tests.

RESULTS: We extracted 638 083 (2.98%) RED-related records from the NIS database. Compared to patients with common conditions, RED patients showed an exceedingly high burden of disease, including significantly extended hospital stays (P < 0.05), elevated total charges (P < 0.05), and heightened mortality rates (P < 0.05). They also had a substantially increased 30-day all-cause readmission rate based on the NRD database (P < 0.05). Although the different subgroups of RED patients had varying patterns of health care utilisation and economic burdens, they all surpassed those of patients with common conditions.

CONCLUSIONS: There is a need for novel strategies aimed at mitigating the substantial RED-related burdens borne by individuals, families, and society in general, as well as funding for research and clinical trials.

PMID:39651662 | DOI:10.7189/jogh.14.04249

Eur J Cancer. 2025 Jan;214:115147. doi: 10.1016/j.ejca.2024.115147. Epub 2024 Nov 27.

ABSTRACT

BACKGROUND: Rare cancers correspond to approximately 200 clinical entities, which can be grouped into 12 families. Updated data are available for childhood and haematological cancers, ie, for only two of the 12 families of rare cancer. We provide incidence and survival for the remaining ten families of rare adult solid cancers (RAC), across 29 EU Member States and over time. We also evaluate the association between resources invested in health and survival from RACs.

METHODS: We used the EUROCARE-6 database, which includes data from 108 cancer registries from 29 countries. We calculated incidence rates (IR) and 5-year relative survival (RS) for cases diagnosed during 2006-2013. We calculated 5-year RS in the follow-up period 2010-2014 using the period approach (last follow-up: December 31, 2014). We estimated changes in 5-year RS and IR over the period 2000-2013. We used a forest plot to report the differences in RS among countries with the highest and lowest health spending.

RESULTS: RACs are heterogeneous in terms of incidence, survival, sex, and age distribution. Several RACs (eg, those of the hypopharynx, small intestine, and trachea) still have a 5-year RS < 30 %, which is not improving. Survival differs among European countries and is higher in countries with the greatest investments in health. The incidence of smoking-related RACs is decreasing but rising in HPV-related RACs.

CONCLUSION: Investments in health and healthcare networks at national and European level can help increase the survival of RACs, especially those requiring centralisation of care (eg, bone sarcomas, penile cancer). These investments are critical considering that survival from RACs is not significantly improving. Our results unmask the heterogeneity of RACs, which needs to be considered in clinical trial design. Finally, our findings support the importance of prevention strategies for known risk factors such as smoking.

PMID:39647345 | DOI:10.1016/j.ejca.2024.115147

Orphanet J Rare Dis. 2024 Dec 4;19(1):456. doi: 10.1186/s13023-024-03459-5.

ABSTRACT

BACKGROUND: The global public health burden of rare diseases has become an increasingly discussed topic, and its societal impact cannot be overstated. While it may seem counterintuitive to discuss broad healthcare and public health impact in the context of rarity, taken together, over 400 million people worldwide are estimated to live with a rare disease. Over half of people living with a rare disease are children. Providing robust and comprehensive services to the rare disease community requires coordinated efforts of numerous experts and partners. Globally, there are many initiatives focused on improving the lives of people living with a rare disease. Most of these networks and organizations are region or country based and have historically centered on three focal areas: research; provision of education, support, and/or information; and direct clinical care. While all these efforts recognize the importance of a coordinated system of partners across a spectrum of disciplines to improve care for the rare disease community, one group has been largely untapped: hospital administrators and leadership. To address this gap, the International Hospital Federation (IHF) convened the Global Rare Pediatric Disease Network (GRPDN), composed of hospital leaders from around the world. To assess how hospital leadership can assist in providing the infrastructure for improving care for patients and families living with a rare disease, the GRPDN created a survey to gather feedback on hospital administrators' perspectives on needed efforts to improve global rare disease care.

RESULTS: The survey identified five themes: increased public awareness of rare diseases and support for families, diagnostic management and treatment guidelines, lifelong, multidisciplinary care, data and research, and funding.

CONCLUSIONS: Until recently, hospital leadership has been an untapped partner in addressing challenges faced by rare disease patients, and they are uniquely positioned to bridge existing gaps. The GRPDN will continue to focus on identifying practical strategies that hospital leaders-regardless of resource level-can implement to improve care for children living with a rare disease.

PMID:39633381 | DOI:10.1186/s13023-024-03459-5

Sci Rep. 2024 Dec 4;14(1):30206. doi: 10.1038/s41598-024-80670-1.

ABSTRACT

Genetic variants identified through genome-wide association studies (GWAS) are typically non-coding, exerting small regulatory effects on downstream genes. However, which downstream genes are ultimately impacted and how they confer risk remains mostly unclear. By contrast, variants that cause rare Mendelian diseases are often coding and have a more direct impact on disease development. Here we demonstrate that common and rare genetic diseases can be linked by studying how common disease-associated variants influence gene co-expression in 57 different tissues and cell types. We implemented this method in a framework called Downstreamer and applied it to 88 GWAS traits. We find that predicted downstream "genes" are enriched with Mendelian disease genes, e.g. key genes for height are enriched for genes that cause skeletal abnormalities and Ehlers-Danlos syndromes. 78% of these key genes are located outside of GWAS loci, suggesting that they result from complex trans regulation rather than being impacted by disease-associated variants in cis. Based on our findings, we discuss the challenges in reconstructing gene regulatory networks and provide a roadmap to improve the identification of these highly connected genes linked to common traits and diseases.

PMID:39632930 | DOI:10.1038/s41598-024-80670-1

Bratisl Lek Listy. 2024;125(12):807-812. doi: 10.4149/BLL_2024_124.

ABSTRACT

BACKGROUND: The Roma population is a genetically isolated population with a shared origin, totaling between 10 to 14 million individuals worldwide, stemming from a limited number of "genetic founders". Roma individuals exhibit specific hereditary diseases, often stemming from recessive genetic variants due to a higher degree of consanguinity, with recent molecular-genetic investigations shedding light on several conditions prevalent within the Czech Roma population. However, an overview of stomatological issues in diagnosing such diseases proves challenging, leading to frequent underdiagnosis or misdiagnosis.

METHODS: The contribution monitors the clinical description, typical symptoms and treatment options including dental abnormalities in rare genetic diseases in the Roma population which are treated in ERN CRANIO centre at Motol University Hospital in Prague.

RESULTS: Our research provides examples of autosomal recessive diseases, which can be molecularly confirmed, and prevalent within the Roma community. These include congenital cataract syndrome, facial dysmorphism and demyelinating neuropathy, non-syndromic prelingual e.g. deafness with GJB2 gene impairment, and myasthenic syndrome.

CONCLUSION: Our report aimed to provide a systematic review of dental phenotypes which can relate to Czech Roma's rare genetic disorders therapy including dental treatment. Understanding is important for preventing unterdiagnosis or treatment for the patients affected review of observed (Fig. 6, Ref. 27).

PMID:39629652 | DOI:10.4149/BLL_2024_124

Nat Neurosci. 2024 Dec;27(12):2278-2291. doi: 10.1038/s41593-024-01827-9. Epub 2024 Dec 3.

ABSTRACT

Single-cell and single-nucleus genomic approaches can provide unbiased and multimodal insights. Here, we discuss what constitutes a molecular cell atlas and how to leverage single-cell omics data to generate hypotheses and gain insights into cell transitions in development and disease of the nervous system. We share points of reflection on what to consider during study design and implementation as well as limitations and pitfalls.

PMID:39627588 | DOI:10.1038/s41593-024-01827-9

JCO Clin Cancer Inform. 2024 Dec;8:e2400056. doi: 10.1200/CCI.24.00056. Epub 2024 Dec 3.

ABSTRACT

PURPOSE: Research on rare diseases and atypical health care demographics is often slowed by high interparticipant heterogeneity and overall scarcity of data. Synthetic data (SD) have been proposed as means for data sharing, enlargement, and diversification, by artificially generating real phenomena while obscuring the real patient data. The utility of SD is actively scrutinized in health care research, but the role of sample size for actionability of SD is insufficiently explored. We aim to understand the interplay of actionability and sample size by generating SD sets of varying sizes from gradually diminishing amounts of real individuals' data. We evaluate the actionability of SD in a highly heterogeneous and rare demographic: adolescents and young adults (AYAs) with cancer.

METHODS: A population-based cross-sectional cohort study of 3,735 AYAs was subsampled at random to produce 13 training data sets of varying sample sizes. We studied four distinct generator architectures built on the open-source Synthetic Data Vault library. Each architecture was used to generate SD of varying sizes on the basis of each aforementioned training subsets. SD actionability was assessed by comparing the resulting SD with their respective real data against three metrics-veracity, utility, and privacy concealment.

RESULTS: All examined generator architectures yielded actionable data when generating SD with sizes similar to the real data. Large SD sample size increased veracity but generally increased privacy risks. Using fewer training participants led to faster convergence in veracity, but partially exacerbated privacy concealment issues.

CONCLUSION: SD is a potentially promising option for data sharing and data augmentation, yet sample size plays a significant role in its actionability. SD generation should go hand-in-hand with consistent scrutiny, and sample size should be carefully considered in this process.

PMID:39626135 | DOI:10.1200/CCI.24.00056

PLoS One. 2024 Dec 3;19(12):e0312936. doi: 10.1371/journal.pone.0312936. eCollection 2024.

ABSTRACT

BACKGROUND: In clinical research, the most appropriate way to assess the effect of an intervention is to conduct a randomized controlled trial (RCT). In the field of rare diseases, conducting an RCT is challenging, resulting in a low rate of clinical trials, with a high frequency of early termination and unpublished trials. The aim of the EPISTOP trial was to compare outcomes in infants with tuberous sclerosis (TSC) who received vigabatrin preventively before the seizures onset with those who received it conventionally after. The study was designed as a prospective, multicentre, randomized clinical trial. However, ethics committees at four centres did not approve this RCT design, resulting in an open-label trial (OLT) in these four centres and an RCT in the other six centres. In this paper, we re-analyse the data from the EPISTOP trial using methods to investigate the influence of allocation bias on the results of the EPISTOP trial.

METHOD: A bias-corrected analysis is used to support and strengthen the published results. We included a term representing the effect of selection bias as an influencing factor on the corresponding endpoint in the statistical model. Thus, the treatment effect estimates for the primary endpoint of time to first seizure and additional secondary endpoints are adjusted for the bias effect.

RESULT: The bias-corrected analyses for the primary endpoint show that the estimated hazard ratio and associated confidence intervals are in a very similar range (original analysis: HR 2.91, 95%-CI [1.11 to 7.67], p-value 0.0306; bias-corrected analysis: HR 2.89, 95%-CI [1.10 to 7.58], p-value 0.0316). This was also the case for the secondary endpoints.

CONCLUSION: The statistical re-analysis of the raw trial data therefore supports the published results and confirms that there is no additional bias introduced by randomization, thereby increasing the value of the results. However, this highlights that this aspect needs to be considered in future trials, especially in rare diseases, to avoid additional biases in an already small sample size where it may be difficult to reach significance.

PMID:39625912 | DOI:10.1371/journal.pone.0312936

Pulmonology. 2025 Dec 31;31(1):2429911. doi: 10.1080/25310429.2024.2429911. Epub 2024 Dec 3.

ABSTRACT

Alpha-1 Antitrypsin Deficiency (AATD) is a co-dominant condition associated with an increased risk of lung and liver disease. Since it is commonly thought that 95% of severe cases of AATD have PI*ZZ genotype, most studies about AATD have been focused on the Z variant. Nevertheless, over 500 single nucleotide variations in the SERPINA1 gene have been identified. We investigated the clinical presentation of subjects with severe AAT deficiency due to rare genotypes of the SERPINA1 gene. We enrolled patients from the Italian Registry for AATD (RIDA1) with the following inclusion criteria: diagnosis of severe AATD; age >18 years; full clinical data available at diagnosis; three years of follow-up respiratory function data. A total of 281 patients were enrolled from the RIDA1 Registry and subdivided into 3 cohorts: PI*ZZ genotype (n = 160), PI*SZ genotype (n = 54), and rare genotypes PI*R (n = 67). We did not observe any statistical differences among the cohorts regarding sex, smoking habits, occupational exposure and age at diagnosis. Patients with severe AATD due to rare genotypes have clinical characteristics and respiratory profiles similar to PI*ZZ subjects, and differed from the PI*SZ patient group. Early and accurate diagnosis of PI*R subjects is therefore important for their appropriate clinical management.

PMID:39624947 | DOI:10.1080/25310429.2024.2429911

NPJ Genom Med. 2024 Dec 2;9(1):60. doi: 10.1038/s41525-024-00441-9.

ABSTRACT

Boston Children's Hospital has established a genomic sequencing and analysis research initiative to improve clinical care for pediatric rare disease patients. Through the Children's Rare Disease Collaborative (CRDC), the hospital offers CLIA-grade exome and genome sequencing, along with other sequencing types, to patients enrolled in specialized rare disease research studies. The data, consented for broad research use, are harmonized and analyzed with CRDC-supported variant interpretation tools. Since its launch, 66 investigators representing 26 divisions and 45 phenotype-based cohorts have joined the CRDC. These studies enrolled 4653 families, with 35% of analyzed cases having a finding either confirmed or under further investigation. This accessible and harmonized genomics platform also supports additional institutional data collections, research and clinical, and now encompasses 13,800+ patients and their families. This has fostered new research projects and collaborations, increased genetic diagnoses and accelerated innovative research via integration of genomics research with clinical care.

PMID:39622807 | DOI:10.1038/s41525-024-00441-9