Recenti Prog Med. 2025 May;116(5):310-321. doi: 10.1701/4495.44951.

ABSTRACT

INTRODUCTION: Duchenne muscular dystrophy (DMD) is a rare disease that causes a progressive loss of muscle function in males, presenting at the age of two years, and involving respiratory and heart function starting from teenage years. This retrospective observational study has identified patients potentially affected by DMD and described their utilization of healthcare resources and direct healthcare costs charged to the Italian National Healthcare Service (INHS).

METHODS: From the Foundation Ricerca e Salute (ReS), through a specific algorithm based only on administrative healthcare data of 5.4 million inhabitants in 2021 (index date), male patients aged <30 years potentially affected by DMD were identified. Comorbidities at baseline, and utilization of healthcare resources and direct healthcare costs charged to the INHS during the year following index date, were described.

RESULTS: In 2021, 120 male patients aged <30 years were identified as potentially affected with DMD (2.2/100,000 inhabitants; 16.1/100,000 males aged <30 years). Chronic airway disease and cardiomyopathy were found in 19.2% and 15.0% of patients, respectively. During follow-up: 41.7% of patients were treated with deflazacort, 2.5% with ataluren and about one third with cardiac drugs; 29.2% and 42.5% were admitted to overnight and day hospitalization, respectively, mainly due to neurological, cardiac, and respiratory diseases; 12.5% accessed the emergency department, mainly for traumatisms and fractures; 70.8% received local outpatient specialist care, half of which were specialist visits, and about 15% cardiac diagnostics. On average, the per capita annual total cost charged to the -INHS was € 6713; ataluren accounted for more than half of this expenditure. After having excluded the dispensation of ataluren during follow-up, the mean per capita total cost was € 2548, more than half of which due to hospitalizations.

CONCLUSIONS: This study of administrative data has identified patients potentially affected by DMD, a rare disease, from a large sample of INHS beneficiaries, and assessed their healthcare pathway. This is useful for regulatory purposes and for improved access to emerging innovative therapies.

PMID:40376903 | DOI:10.1701/4495.44951

Fam Process. 2025 Jun;64(2):e70041. doi: 10.1111/famp.70041.

ABSTRACT

Parents caring for children with rare diseases are more impaired regarding health-related quality of life (HRQoL) and mental health than healthy controls and norm data. To address the research gap in psychological care for these parents, this study evaluates the effectiveness of two family-based interventions. The children affected by rare disease and their families network (CARE-FAM-NET) study is a multicenter randomized controlled 2 × 2 factorial trial for affected families with children (0-21 years). This paper focuses on evaluating the impact of two interventions, one face-to-face (CARE-FAM) and one online (WEP-CARE), on the HRQoL and mental health of parents. One thousand, one hundred sixty-eight parents participated: TAU = 291, CARE-FAM = 296, WEP-CARE = 300, and CARE-FAM + WEP-CARE combined = 281. Data were collected at four time points over a period of 18 months using standardized questionnaires. The results had to be interpreted exploratively. The results indicate that there are no clinically relevant differences in the parents' HRQoL and mental health between the treatment groups. However, time-dependent differences in the intervention effects for WEP-CARE were observed. Although the results did not show clear relevant differences between conditions, trends in improvement in HrQoL and mental health were identified. CARE-FAM shows a greater reduction in parental distress and WEP-CARE shows a greater distortion of distress, particularly at T3 and T4. Given the exploratory nature of this study, it highlights the urgent need for further confirmatory research in this area.

PMID:40375458 | DOI:10.1111/famp.70041

Orphanet J Rare Dis. 2025 May 15;20(1):231. doi: 10.1186/s13023-025-03692-6.

ABSTRACT

BACKGROUND: Genomic newborn screening (gNBS) offers the potential to detect genetic conditions early, enhancing outcomes through timely treatment. It can serve as an additional tool to identify conditions that are not detectable via metabolic screening. The Screen4Care project seeks to develop a systematic approach for selecting treatable rare diseases (RDs) for inclusion in gNBS through the creation of the TREAT-panel.

METHODS: A set of six selection criteria containing treatability, clinical validity, age of onset, disease severity, penetrance, and genetic feasibility was applied to a comprehensive list of gene-disease pairs. Genes meeting a defined threshold score were included in the TREAT-panel. This automated scoring process was complemented by expert review from clinicians and patient representatives to ensure clinical relevance and adherence to current medical guidelines.

RESULTS: The initial gene list, derived from multiple data sources, included 484 gene-disease pairs. After applying the scoring system and two rounds of expert curation, a final list of 245 genes was selected. These genes predominantly represent disorders in metabolic, neurological, and immunological categories, with treatability and early disease onset as key inclusion factors.

CONCLUSION: The Screen4Care TREAT-panel provides a curated, scientifically robust gene set for gNBS, focusing on treatable RDs with early onset and clinical actionability. The panel will be tested in a European pilot project involving approximately 20,000 newborns, contributing to the growing body of evidence for the implementation of next-generation sequencing (NGS) in newborn screening programs.

PMID:40375093 | DOI:10.1186/s13023-025-03692-6

Orphanet J Rare Dis. 2025 May 15;20(1):230. doi: 10.1186/s13023-025-03674-8.

ABSTRACT

The traditional process of intercultural adaptation, while suitable for one or a few target languages, is not optimal for developing instruments for rare connective tissue diseases (CTDs) in multiple languages simultaneously. The European Reference Network ReCONNET presents the protocol for a novel methodology for cross-cultural adaptation of instruments for research and care in the context of rare CTDs (ReCONNET-CROSSADAPT). It is initiated by the identification of 'key-terms' that are crucial for maintaining the original meaning of the source document. Each language group, led by a senior member and two collaborators, independently assesses the existence and equivalence of these key terms in target languages. Reconciliation meetings are held to establish agreed-upon terms for consistent usage across translations when difficulties arise with key-terms. Subsequently, each language group translates the source document, followed by a reconciliation meeting involving one CTD patient in each group. The purpose of this meeting is to address potential discrepancies among translations, ensuring a comprehensive assessment from a linguistic, cultural and patient perspective. Collective feedback and consensus-based decision-making guide the resolution process. This methodology eliminates the need for backward translation, optimizing time and cost utilization. This new ReCONNET-CROSSADAPT methodology ensures linguistic accuracy, cultural relevance, and contextual appropriateness for the cross-cultural adaptation of instruments for research and care in the context of rare CTDs.

PMID:40375068 | DOI:10.1186/s13023-025-03674-8

Eur J Hum Genet. 2025 May 15. doi: 10.1038/s41431-025-01863-4. Online ahead of print.

ABSTRACT

WD40 and SOCS box protein-2 (WSB2), a member of the large family of suppressor of cytokine signaling (SOCS)-box proteins, has recently been identified as a substrate receptor of cullin 5 E3 ligase that plays an important role in proteomic regulation through substrate ubiquitination and proteasomal degradation. Here we report five patients from four unrelated families presenting with neurodevelopmental delay, dysmorphic features, brain structural abnormalities with or without growth restriction, hypotonia, and microcephaly, all of whom are homozygous for extremely rare and predicted loss-of-function (pLoF) or missense variants in WSB2, inherited from consanguineous parents. The Wsb2-mutant mice exhibited several neurological findings that included hyperactivity, altered exploration, and hyper alertness. They also weighed less, had a lower heart rate, and presented an abnormal retinal blood vessel morphology and vasculature pattern along with decreased total thickness of the retina. Our findings suggest that homozygous LoF WSB2 variants cause a novel neurodevelopmental disorder in humans with similar neurologic and developmental findings seen in Wsb2-mutant mouse models.

PMID:40374945 | DOI:10.1038/s41431-025-01863-4

Fam Syst Health. 2025 Mar;43(1):173. doi: 10.1037/fsh0000910.

ABSTRACT

This short 55-word story highlights a clinical psychology doctoral student's work in therapy with individuals diagnosed with rare diseases. Upon diagnosis, clients may experience a range of emotions and feel isolated. Connection with a social network and support can increase hope and promote well-being. (PsycInfo Database Record (c) 2025 APA, all rights reserved).

PMID:40372839 | DOI:10.1037/fsh0000910

Int J Mol Sci. 2025 Apr 25;26(9):4072. doi: 10.3390/ijms26094072.

ABSTRACT

The growing availability of protein structural data from experimental methods and accurate predictive models provides the opportunity to investigate the molecular origins of rare diseases (RDs) reviewed in the Orpha.net database. In this study, we analyzed the topology of 5728 missense mutation sites involved in Mendelian RDs (MRDs), forming the basis of our structural bioinformatics investigation. Each mutation site was characterized by side-chain position within the overall 3D protein structure and side-chain orientation. Atom depth quantitation, achieved by using SADIC v2.0, allowed the classification of all the mutation sites listed in our database. Particular attention was given to mutations where smaller amino acids replaced bulky, outward-oriented residues in the outer structural layers. Our findings reveal that structural features that could lead to the formation of void spaces in the outer protein region are very frequent. Notably, we identified 722 cases where MRD-associated mutations could generate new surface pockets with the potential to accommodate pharmaceutical ligands. Molecular dynamics (MD) simulations further supported the prevalence of cryptic pocket formation in a subset of drug-binding protein candidates, underscoring their potential for structure-based drug discovery in RDs.

PMID:40362311 | DOI:10.3390/ijms26094072

Int J Mol Sci. 2025 May 4;26(9):4367. doi: 10.3390/ijms26094367.

ABSTRACT

The scarcity of robust models and therapeutic options for rare diseases continues to hamper their preclinical investigation. Traditional animal models and two-dimensional cell cultures are limited in their ability to replicate human heredity-associated traits and complex pathological features. Organoids-on-a-chip approaches open up new frontiers in rare-disease research via the integration of organ chips and organoid technology. This integrative strategy offers immense opportunities for the mimicry of disease-related traits, the clarification of the mechanisms underlying disease, and the prediction of treatment responses in a highly human-related manner. This forward-looking perspective suggests organoids on chips are transformative tools for parsing rare-disease pathogenesis, accelerating therapeutic discovery, and bridging the gap between basic research and precision medicine.

PMID:40362604 | DOI:10.3390/ijms26094367

Nat Commun. 2025 May 13;16(1):4449. doi: 10.1038/s41467-025-59478-8.

ABSTRACT

Artificial intelligence applications in oncology imaging often struggle with diagnosing rare tumors. We identify significant gaps in detecting uncommon thyroid cancer types with ultrasound, where scarce data leads to frequent misdiagnosis. Traditional augmentation strategies do not capture the unique disease variations, hindering model training and performance. To overcome this, we propose a text-driven generative method that fuses clinical insights with image generation, producing synthetic samples that realistically reflect rare subtypes. In rigorous evaluations, our approach achieves substantial gains in diagnostic metrics, surpasses existing methods in authenticity and diversity measures, and generalizes effectively to other private and public datasets with various rare cancers. In this work, we demonstrate that text-guided image augmentation substantially enhances model accuracy and robustness for rare tumor detection, offering a promising avenue for more reliable and widespread clinical adoption.

PMID:40360460 | DOI:10.1038/s41467-025-59478-8

Orphanet J Rare Dis. 2025 May 10;20(1):222. doi: 10.1186/s13023-025-03751-y.

ABSTRACT

PURPOSE: Patients with rare diseases often undergo a long diagnostic odyssey. However, there is little empirical evidence on the cost incurred during the diagnostic pathway for patients with suspected rare diseases. This study provides a comprehensive analysis of healthcare costs and utilization during the diagnostic pathway for a heterogeneous sample of patients with suspected rare diseases but unclear diagnosis.

METHODS: Using claims data from five German statutory health insurance organizations for the years 2014-2019, we analyzed costs and healthcare utilization of 1,243 patients (aged 0 to 82 years) with suspected rare diseases referred to a rare disease center. A control cohort was assigned using 1:75 exact matching on age, sex and place of residence.

RESULTS: In the years prior to referral to an expert center, healthcare utilization of patients with suspected rare diseases was, on average, substantially and significantly higher compared to a matched control cohort during the same observation period - e.g. in terms of the number of hospitalizations (3.1 (95%CI: 2.9-3.4) vs. 0.5 (95%CI: 0.5-0.5)), different diagnoses (50.0 (95%CI: 48.1-51.9) vs. 26.4 (95%CI: 26.2-26.5)), different active substances prescribed (12.7 (95%CI: 12.2-13.3) vs. 8.2 (95%CI: 8.2-8.3)) and the number of genetic tests (14.7 (95%CI: 12.6-16.7) vs. 0.3 (95%CI: 0.3-0.3)). We found evidence of heterogeneity in utilization by age and sex. On average, direct costs (inpatient, outpatient and prescription drug costs) of patients with suspected rare diseases during the diagnostic pathway were 7.6-fold higher than the costs of matched controls (€26,999 (95%CI: €23,751 - 30,247) vs. €3,561 (95% CI: € 3,455-3,667)). Inpatient costs were the main cost component, accounting for 62.5% of total costs.

CONCLUSIONS: The diagnostic odyssey of patients with suspected rare diseases is associated with extensive healthcare utilization and high cost. Against this background, new ways to shorten the diagnostic journey have a high potential to decrease the financial burden related to rare diseases.

PMID:40349051 | DOI:10.1186/s13023-025-03751-y

Calcif Tissue Int. 2025 May 9;116(1):73. doi: 10.1007/s00223-025-01382-w.

ABSTRACT

Transition care (TC) is crucial for young persons with rare bone and mineral conditions (RBMCs) as they move from pediatric to adult healthcare. Effective TC prevents care disruptions and supports medical and psychosocial needs. However, gaps in communication, a shortage of adult RBMC specialists, and challenges in navigating adult healthcare necessitate standardized care. This study aimed to develop consensus-based recommendations for TC in RBMCs, focusing on best practices for seamless transition and patient empowerment. A two-round Delphi survey (September 2023-April 2024) was conducted among European RBMC experts, including 3 pediatric and 8 adult clinicians and 3 patient representatives from the European Calcified Tissue Society (ECTS). The panel formulated and refined statements through literature review and iterative scoring. Statements reaching ≥ 70% consensus were retained. A total of 81 statements were finalized across seven domains: initiation and planning, TC requirements, patient empowerment, organization and communication, service infrastructure and funding, and clinical care. Consensus was achieved on 64 out of 81 statements, with strong agreement on general and RBMC-specific recommendations. Key priorities included structured coordination among healthcare providers and a patient-centered approach that fosters self-advocacy and self-management. This Delphi consensus provides a structured framework for TC in young persons with RBMCs, emphasizing multidisciplinary care and patient empowerment. Future studies should assess the feasibility and impact of these guidelines across diverse healthcare systems.

PMID:40346280 | DOI:10.1007/s00223-025-01382-w

Nurs Clin North Am. 2025 Jun;60(2):349-368. doi: 10.1016/j.cnur.2024.12.005. Epub 2025 Mar 3.

ABSTRACT

Rare diseases (RDs) are predominantly genetic in etiology and characterized by low frequency and high medical complexity. Although individually infrequent, the cumulative public health impact of ∼7000 RDs is significant, and patients and families experience significant psychosocial burden. Health disparities stem from delays in diagnosis (diagnostic odyssey), difficulty accessing care, and lack of effective treatments. This article provides an overview of rare genetic diseases and highlights exemplar cases demonstrating nursing's role in advancing comprehensive, person-centered care for rare genetic diseases. Resources and recommendations are provided for nurses to enhance quality care for individuals and families living with RDs.

PMID:40345765 | DOI:10.1016/j.cnur.2024.12.005

Funct Integr Genomics. 2025 May 9;25(1):101. doi: 10.1007/s10142-025-01608-y.

ABSTRACT

Mulvihill-Smith Syndrome (MSS) is a clinically complex and genetically unsolved nano-rare disorder with only 12 patients reported in the literature. Most patients (91%) have immunological impairments, succumb to infection, and might develop cancer later in life. Its pathogenesis remains elusive and therapeutic options are limited. We used single-cell MULTI-omics (sc-MULTI-omics), combining transcriptomics (gene expression, TCR, and BCR repertoire) and proteogenomic (Cellular Indexing of Transcriptomes and Epitopes by Sequencing; CITE-seq), to decipher the pathophysiology of nano-rare disease patient. We report a new patient who is a 16-year-old girl. She had an increased leukocyte counts and typical manifestations of MSS such as short stature, older appearance, multiple pigmented nevi, microcephaly, monolateral keratoconus, Marcus-Gunn syndrome, hearing loss, vitamin D deficiency, mild hypercortisolism, and diabetes mellitus with very high insulin resistance (T3DM). sc-MULTI-omics CITE-seq showed that the MSS patient had increased central memory CD4+ T cells as well as effector memory CD8+ T cells, whilst reduced naïve T cells (both CD4+ and CD8+ T cells). Furthermore, we identified genes and pathways associated with the progeria-like phenotype, inflammation, and cancer progression, which may contribute to the clinical signs of MSS. sc-MUTLI-omics CITE-seq analyses improve our understanding of complex human disease pathophysiology and provides an alternative approach in personalized medicine in nano-rare disease.

PMID:40343591 | DOI:10.1007/s10142-025-01608-y

Am Soc Clin Oncol Educ Book. 2025 Jun;45(3):e473106. doi: 10.1200/EDBK-25-473106. Epub 2025 May 8.

ABSTRACT

Rare uterine malignancies present treatment challenges because of their clinical and biological heterogeneity. Among the rarest of the uterine cancers are leiomyosarcomas, uterine stromal tumors, and the mesonephric-like and serous carcinomas. In this article, we review recent advancements in diagnostic precision, risk stratification, and identification of biomarker-guided therapeutic options for these rare subtypes of uterine tumors. The improved understanding of the molecular profile of these tumors has led to the development of targeted treatment approaches. Further progress will depend on a coordinated, global effort to further characterize these diseases and enroll patients on biomarker-driven clinical trials.

PMID:40340459 | DOI:10.1200/EDBK-25-473106

JAMA Netw Open. 2025 May 1;8(5):e258330. doi: 10.1001/jamanetworkopen.2025.8330.

ABSTRACT

IMPORTANCE: Treatments are urgently needed for the more than 9500 rare diseases with no US Food and Drug Administration-approved therapies. Although repurposing can be less time- and cost-intensive compared with novel drug development, hurdles have impeded systematic repurposing. Rare disease nonprofit organizations (RDNPs) are well-positioned to overcome barriers and have spearheaded rare disease repurposing efforts for decades. However, no comprehensive data are available on the state of rare disease repurposing or features of successful efforts.

OBJECTIVE: To characterize the state of rare disease drug repurposing, identify factors associated with successful outcomes, and share thematic insights using the interactive Repurposing of All Drugs, Mapping All Paths (ROADMAP) Project web tool.

DESIGN, SETTING, AND PARTICIPANTS: The ROADMAP study was a qualitative study using a mixed-methods analysis of US-based RDNP leaders and their stakeholders, including a national survey and semistructured interviews of RDNP leaders, conducted from September 29, 2021, to January 6, 2022. Surveys and interviews revealed themes associated with RDNP strategies, timelines, and support mechanisms. Data were analyzed from January 22, 2024, to April 23, 2024.

MAIN OUTCOMES AND MEASURES: The primary survey outcome was the repurposing project stage (abandoned, early, clinical, late, or successful). Qualitative outcomes included themes characterizing repurposing experiences. Two random forest models of drug- and disease- specific as well as organization-specific variables were used to evaluate factor importance toward inferring the project stage. Orthogonal significance testing was conducted using Spearman rank correlation, and P values in each model were corrected for multiple hypothesis testing using a Benjamini-Hochberg procedure.

RESULTS: Representative organizations submitted survey responses, including 147 of 698 potential US-based RDNPs. The median RDNP age was 10 years (IQR, 5-20 years), and the median annual revenue was $355 390 (IQR, $90 028-$946 108). Among 34 leaders who were interviewed, representing 25 RDNPs, 23 were female (67.6%), and the RDNPs had a median age of 15 years (IQR, 6-19 years) and a median revenue of $670 719 (IQR, $193 587-$1 830 890). Among the surveyed RDNPs, 58 of 138 (42.0%) specifically identifying their involvement in repurposing supported repurposing projects, and 94 drugs were in various stages of repurposing, of which 23 met success criteria (5 with US Food and Drug Administration approval and 18 with off-label use with subjective benefit). Survey factors associated with successful outcomes included nonprofit-supported patient recruitment into trials (Gini importance, 3.90; ρ = 0.50; adjusted P < .001) and provision of nonfinancial research support (Gini importance, 0.69; ρ = 0.33; adjusted P = .02). Interview themes were synthesized into a 5-stage repurposing framework with roadblocks and recommendations that included (1) enabling drug repurposing, (2) identifying a drug therapy, (3) validating a drug therapy, (4) clinical use and testing, and (5) reaching an optimal end point for clinical practice.

CONCLUSIONS AND RELEVANCE: The findings of this qualitative study of RDNP repurposing suggest that several opportunities were associated with successful outcomes and can be considered to optimize systematic repurposing among RDNPs, external collaborators, and policymakers with the use of an interactive tool showcasing insights to facilitate data-driven drug repurposing.

PMID:40323602 | DOI:10.1001/jamanetworkopen.2025.8330

Cancer Radiother. 2025 Apr 30;29(2):104622. doi: 10.1016/j.canrad.2025.104622. Online ahead of print.

ABSTRACT

PURPOSE: Lung cancers associated with interstitial lung disease are challenging to diagnose and manage. We investigated the prevalence of interstitial lung disease among consecutively irradiated cancer patients, and the tolerance and prognosis of patients with or without interstitial lung disease after thoracic radiotherapy.

MATERIAL AND METHODS: This bicentric study was designed as a case-control study of patients with interstitial lung disease prior to radiotherapy (cases) and controls without interstitial lung disease. Patients were irradiated with curative intent for localized, locally advanced or oligometastatic non-small cell lung cancer. Consecutive lung cancer patients undergoing curative radiotherapy between January 2018 and December 2020 had centralized review of their baseline and 6-month CT scans by a multidisciplinary board. Functional evaluation, radiological scores, clinical toxicities, best objective response, progression-free survival and overall survival were assessed.

RESULTS: Twelve cases were detected out of 166 patients (7.2 %), including six diagnosed a posteriori by central review (50 %). Initial patient, tumour and lung cancer treatment characteristics were similar between cases and controls except for performance status (P=0.004), Kazerooni scores of fibrosis and ground glass patterns (P<0.001). Cases and controls underwent three-dimensional radiotherapy in 0 and 37 (24.2 %), intensity-modulated radiotherapy in eight (66.7 %) and 60 (39.2 %), stereotactic body radiotherapy in four (33.3 %) and 56 (36.6 %), respectively (P=0.079). Grade≥2 pneumonitis occurred in 41.7 % of cases versus 11 %, of controls (P=0.01). Hospitalization rates were 16 % in cases versus 2 % in controls and one case died of lung toxicity. Best objective response was worse for cases (P=0.046). Median progression-free survival was 9.35 months for cases and 18.56 months for controls. Median overall survival was 17 months for cases and not reached for controls (P=0.002). Sex, tumour stage, histology, and interstitial pulmonary fibrosis were prognostic factors for overall survival on univariate analysis.

CONCLUSION: Interstitial lung disease was present in 7 % of the patients with lung cancer. Patients with interstitial lung disease had higher risks of toxicity events and poorer prognosis, suggesting the lungs should be assessed carefully and that specific management strategies are warranted.

PMID:40311519 | DOI:10.1016/j.canrad.2025.104622

J Genet Couns. 2025 Jun;34(3):e70015. doi: 10.1002/jgc4.70015.

ABSTRACT

In recent years, an increasing number of affected children have been diagnosed through whole-exome sequencing (WES); however, it remains unclear whether the problems faced by the patients' parents during the undiagnosed period were resolved. This exploratory qualitative study aimed to clarify the needs of the parents of children who have been diagnosed with rare genetic diseases and determine the factors that may help provide the environment necessary for the family to understand and accept the symptoms and characteristics associated with the disease and live with their affected child. Semi-structured interviews were conducted with the parents of children (less than 18 years old) who participated in a research project, namely the Initiative on Undiagnosed and Rare Diseases (IRUD), at Kyoto University Hospital between November 2016 and December 2021. A reflective thematic analysis generated three themes: the benefits of diagnosis from the perspective of parents, the challenges to be solved after diagnosis, and the significance and issues of revealing genetic information. The results showed that the diagnoses provided psychological satisfaction for the parents. However, diagnosis of a hereditary and rare disease can lead to social and medical isolation, and it was necessary to improve the environment around the affected children's families, mainly by taking advantage of the IRUD research system. The analysis indicated the need for psychological support, which can be provided by the clinical genetic department, the need for a follow-up system in collaboration with various clinical departments, and the need to improve the general public's understanding of human genetics.

PMID:40305385 | DOI:10.1002/jgc4.70015

Sci Rep. 2025 Apr 29;15(1):15093. doi: 10.1038/s41598-025-99539-y.

ABSTRACT

Computational methods for identifying gene-disease associations can use both genomic and phenotypic information to prioritize genes and variants that may be associated with genetic diseases. Phenotype-based methods commonly rely on comparing phenotypes observed in a patient with databases of genotype-to-phenotype associations using measures of semantic similarity. They are constrained by the quality and completeness of these resources as well as the quality and completeness of patient phenotype annotation. Genotype-to-phenotype associations used by these methods are largely derived from the literature and coded using phenotype ontologies. Large Language Models (LLMs) have been trained on large amounts of text and data and have shown their potential to answer complex questions across multiple domains. Here, we evaluate the effectiveness of LLMs in prioritizing disease-associated genes compared to existing bioinformatics methods. We show that LLMs can prioritize disease-associated genes as well, or better than, dedicated bioinformatics methods relying on pre-defined phenotype similarity, when gene sets range from 5 to 100 candidates. We apply our approach to a cohort of undiagnosed patients with rare diseases and show that LLMs can be used to provide diagnostic support that helps in identifying plausible candidate genes. Our results show that LLMs may offer an alternative to traditional bioinformatics methods to prioritize disease-associated genes based on disease phenotypes. They may, therefore, potentially enhance diagnostic accuracy and simplify the process for rare genetic diseases.

PMID:40301638 | DOI:10.1038/s41598-025-99539-y

J Manag Care Spec Pharm. 2025 May;31(5):491-498. doi: 10.18553/jmcp.2025.31.5.491.

ABSTRACT

BACKGROUND: More than 10,000 rare diseases affect more than 30 million Americans, nearly 70% of which manifest in childhood. The drug development pipeline boasts hundreds of candidates for pediatric-onset rare disease, but little is known about the impact of potential approvals.

OBJECTIVE: To quantify US projected product approvals, patients treated, and product revenues for pediatric-onset rare disease treatments through 2033.

METHODS: Four-stage model consisting of a Markov Chain Monte Carlo simulation of US Food and Drug Administration approvals, calculation of eligible patients per clinical trial criteria, and projection of adoption and list price revenues, all using publicly available data.

RESULTS: By 2033 the pipeline will yield approximately 45 new product approvals, a 14% growth in annual treated patients, and an incremental $10.7B in list price drug revenues ($28.2B: 2023; $38.9B: 2033) prior to any health care cost offsets, caregiving impacts, long-term social benefits, or other benefits from treating the additional patients.

CONCLUSIONS: The projected approvals over the next decade will undoubtedly be transformational for the patient communities impacted, many of whom have no currently approved treatments. However, the number of newly identified rare diseases is likely to outpace the rate of new therapies to treat them. Resources are needed to accelerate progress as 95% of pediatric-onset rare diseases are projected to still have no approved treatments in the next decade, and even for the 5% that have some options, more is needed.

PMID:40298308 | DOI:10.18553/jmcp.2025.31.5.491

BMC Med Res Methodol. 2025 Apr 26;25(1):114. doi: 10.1186/s12874-025-02559-5.

ABSTRACT

INTRODUCTION: Rare events data have proven difficult to explain and predict. Standard statistical procedures can sharply underestimate the probability of rare events, such as intravenous immune globulin therapy (IVIg) for bullous pemphigoid.

METHODS: This retrospective cross-sectional study used Department of Defense TRICARE data to determine factors associated with IVIg therapy among bullous pemphigoid patients. We used prior and weighted correction methods for logit regression to solve rare event bias.

RESULTS: We identified 2,720 individuals diagnosed with bullous pemphigoid from 2019 to 2022, of which 14 were treated with IVIg. Patients who received IVIg therapy were younger (65.07 vs. 75.85, P =.0016) and more likely to be female (13 vs. 1, P =.0036). The underestimation with the standard regression model for event probabilities ranged from 11% to 102% using the prior correction method and from 15% to 107% using the weighted correction method.

CONCLUSION: Rare events are low-frequency, high-severity problems that can have significant consequences. Rare diseases and rare therapies are individually unique but collectively contribute to substantial health and social needs. Therefore, correct estimation of the events is the first step toward assessing the burden of rare diseases and the pricing of their therapies.

PMID:40287629 | DOI:10.1186/s12874-025-02559-5