Up to 8% of the general population have a rare disease, however, for lack of ICD-10 codes for many rare diseases, this population cannot be generically identified in large medical datasets. We aimed ...to explore frequency-based rare diagnoses (FB-RDx) as a novel method exploring rare diseases by comparing characteristics and outcomes of inpatient populations with FB-RDx to those with rare diseases based on a previously published reference list.
Retrospective, cross-sectional, nationwide, multicenter study including 830,114 adult inpatients. We used the national inpatient cohort dataset of the year 2018 provided by the Swiss Federal Statistical Office, which routinely collects data from all inpatients treated in any Swiss hospital. Exposure: FB-RDx, according to 10% of inpatients with the least frequent diagnoses (i.e.1.decile) vs. those with more frequent diagnoses (deciles 2-10). Results were compared to patients having 1 of 628 ICD-10 coded rare diseases.
In-hospital death.
30-day readmission, admission to intensive care unit (ICU), length of stay, and ICU length of stay. Multivariable regression analyzed associations of FB-RDx and rare diseases with these outcomes.
464,968 (56%) of patients were female, median age was 59 years (IQR: 40-74). Compared with patients in deciles 2-10, patients in the 1. were at increased risk of in-hospital death (OR 1.44; 95% CI: 1.38, 1.50), 30-day readmission (OR 1.29; 95% CI 1.25, 1.34), ICU admission (OR 1.50; 95% CI 1.46, 1.54), increased length of stay (Exp(B) 1.03; 95% CI 1.03, 1.04) and ICU length of stay (1.15; 95% CI 1.12, 1.18). ICD-10 based rare diseases groups showed similar results: in-hospital death (OR 1.82; 95% CI 1.75, 1.89), 30-day readmission (OR 1.37; 95% CI 1.32, 1.42), ICU admission (OR 1.40; 95% CI 1.36, 1.44) and increased length of stay (OR 1.07; 95% CI 1.07, 1.08) and ICU length of stay (OR 1.19; 95% CI 1.16, 1.22).
This study suggests that FB-RDx may not only act as a surrogate for rare diseases but may also help to identify patients with rare disease more comprehensively. FB-RDx associate with in-hospital death, 30-day readmission, intensive care unit admission, and increased length of stay and intensive care unit length of stay, as has been reported for rare diseases.
The pivotal role of lysosomes in cellular processes is increasingly appreciated. An understanding of the balanced interplay between the activity of acidic hydrolases, lysosomal membrane proteins and ...cytosolic proteins is required. Lysosomal storage diseases (LSDs) are characterized by disturbances in this network and by intralysosomal accumulation of substrates, often only in certain cell types. Even though our knowledge of these diseases has increased and therapies have been established, many aspects of the molecular pathology of LSDs remain obscure. This Review aims to discuss how lysosomal storage affects functions linked to lysosomes, such as membrane repair, autophagy, exocytosis, lipid homeostasis, signalling cascades and cell viability. Therapies must aim to correct lysosomal storage not only morphologically, but reverse its (patho)biochemical consequences. As different LSDs have different molecular causes, this requires custom tailoring of therapies. We will discuss the major advantages and drawbacks of current and possible future therapies for LSDs. Study of the pathological molecular mechanisms underlying these 'experiments of nature' often yields information that is relevant for other conditions found in the general population. Therefore, more common diseases may profit from a correction of impaired lysosomal function.
Exome and genome sequencing have become the tools of choice for rare disease diagnosis, leading to large amounts of data available for analyses. To identify causal variants in these datasets, ...powerful filtering and decision support tools that can be efficiently used by clinicians and researchers are required. To address this need, we developed seqr — an open‐source, web‐based tool for family‐based monogenic disease analysis that allows researchers to work collaboratively to search and annotate genomic callsets. To date, seqr is being used in several research pipelines and one clinical diagnostic lab. In our own experience through the Broad Institute Center for Mendelian Genomics, seqr has enabled analyses of over 10,000 families, supporting the diagnosis of more than 3,800 individuals with rare disease and discovery of over 300 novel disease genes. Here, we describe a framework for genomic analysis in rare disease that leverages seqr's capabilities for variant filtration, annotation, and causal variant identification, as well as support for research collaboration and data sharing. The seqr platform is available as open source software, allowing low‐cost participation in rare disease research, and a community effort to support diagnosis and gene discovery in rare disease.
Graves' orbitopathy (GO) is an autoimmune condition, which is associated with poor clinical outcomes including impaired quality of life and socio-economic status. Current evidence suggests that the ...incidence of GO in Europe may be declining, however data on the prevalence of this disease are sparse. Several clinical variants of GO exist, including euthyroid GO, recently listed as a rare disease in Europe (ORPHA466682). The objective was to estimate the prevalence of GO and its clinical variants in Europe, based on available literature, and to consider whether they may potentially qualify as rare. Recent published data on the incidence of GO and Graves' hyperthyroidism in Europe were used to estimate the prevalence of GO. The position statement was developed by a series of reviews of drafts and electronic discussions by members of the European Group on Graves' Orbitopathy. The prevalence of GO in Europe is about 10/10,000 persons. The prevalence of other clinical variants is also low: hypothyroid GO 0.02-1.10/10,000; GO associated with dermopathy 0.15/10,000; GO associated with acropachy 0.03/10,000; asymmetrical GO 1.00-5.00/10,000; unilateral GO 0.50-1.50/10,000.
GO has a prevalence that is clearly above the threshold for rarity in Europe. However, each of its clinical variants have a low prevalence and could potentially qualify for being considered as a rare condition, providing that future research establishes that they have a distinct pathophysiology. EUGOGO considers this area of academic activity a priority.
This report describes the National Institutes of Health Undiagnosed Diseases Program, details the Program's application of genomic technology to establish diagnoses, and details the Program's success ...rate during its first 2 years.
Each accepted study participant was extensively phenotyped. A subset of participants and selected family members (29 patients and 78 unaffected family members) was subjected to an integrated set of genomic analyses including high-density single-nucleotide polymorphism arrays and whole exome or genome analysis.
Of 1,191 medical records reviewed, 326 patients were accepted and 160 were admitted directly to the National Institutes of Health Clinical Center on the Undiagnosed Diseases Program service. Of those, 47% were children, 55% were females, and 53% had neurologic disorders. Diagnoses were reached on 39 participants (24%) on clinical, biochemical, pathologic, or molecular grounds; 21 diagnoses involved rare or ultra-rare diseases. Three disorders were diagnosed based on single-nucleotide polymorphism array analysis and three others using whole exome sequencing and filtering of variants. Two new disorders were discovered. Analysis of the single-nucleotide polymorphism array study cohort revealed that large stretches of homozygosity were more common in affected participants relative to controls.
The National Institutes of Health Undiagnosed Diseases Program addresses an unmet need, i.e., the diagnosis of patients with complex, multisystem disorders. It may serve as a model for the clinical application of emerging genomic technologies and is providing insights into the characteristics of diseases that remain undiagnosed after extensive clinical workup.
The burden of rare cancers in the United States DeSantis, Carol E.; Kramer, Joan L.; Jemal, Ahmedin
CA: a cancer journal for clinicians,
July/August 2017, Volume:
67, Issue:
4
Journal Article
To systematically investigate the longer-term clinical and health economic impacts of genomic sequencing for rare-disease diagnoses.
We collected information on continuing diagnostic investigation, ...changes in management, cascade testing, and parental reproductive outcomes in 80 infants who underwent singleton whole-exome sequencing (WES).
The median duration of follow-up following result disclosure was 473 days. Changes in clinical management due to diagnostic WES results led to a cost saving of AU$1,578 per quality-adjusted life year gained, without increased hospital service use. Uninformative WES results contributed to the diagnosis of non-Mendelian conditions in seven infants. Further usual diagnostic investigations in those with ongoing suspicion of a genetic condition yielded no new diagnoses, while WES data reanalysis yielded four. Reanalysis at 18 months was more cost-effective than every 6 months. The parents of diagnosed children had eight more ongoing pregnancies than those without a diagnosis. Taking the costs and benefits of cascade testing and reproductive service use into account, there was an additional cost of AU$8,118 per quality-adjusted life year gained due to genomic sequencing.
These data strengthen the case for the early use of genomic testing in the diagnostic trajectory, and can guide laboratory policy on periodic WES data reanalysis.
The Human Phenotype Ontology in 2017 Köhler, Sebastian; Vasilevsky, Nicole A; Engelstad, Mark ...
Nucleic acids research,
01/2017, Volume:
45, Issue:
D1
Journal Article
Peer reviewed
Open access
Deep phenotyping has been defined as the precise and comprehensive analysis of phenotypic abnormalities in which the individual components of the phenotype are observed and described. The three ...components of the Human Phenotype Ontology (HPO; www.human-phenotype-ontology.org) project are the phenotype vocabulary, disease-phenotype annotations and the algorithms that operate on these. These components are being used for computational deep phenotyping and precision medicine as well as integration of clinical data into translational research. The HPO is being increasingly adopted as a standard for phenotypic abnormalities by diverse groups such as international rare disease organizations, registries, clinical labs, biomedical resources, and clinical software tools and will thereby contribute toward nascent efforts at global data exchange for identifying disease etiologies. This update article reviews the progress of the HPO project since the debut Nucleic Acids Research database article in 2014, including specific areas of expansion such as common (complex) disease, new algorithms for phenotype driven genomic discovery and diagnostics, integration of cross-species mapping efforts with the Mammalian Phenotype Ontology, an improved quality control pipeline, and the addition of patient-friendly terminology.
Rare genetic diseases are rare by themselves with prevalence of 1 in 25,000, but collectively they are a significant cause of morbidity and mortality. Till date, collectively there are more than ...9,000 rare diseases documented, which impose a devastating impact on patients, their families, and the healthcare system, including enormous societal burden. Obtaining a conclusive diagnosis for a patient with a rare genetic disease can be long and gruelling. For some patients it takes months or years to receive a definite diagnosis, and around 50% of the patients remain undiagnosed even with expert clinical and advanced high-end laboratory investigations. Owing to the large population and practice of consanguinity the Indian population is a pool of indigenous variants and unreported phenotypes or diseases. A mission program on pediatric rare diseases is an unparalleled initiative to study unique clinical conditions via the use of latest state-of-art technologies and with the combination of a mulit-omics approach. Our initiative will not only provide diagnosis to patients with rare disease but also build a platform for translational research for rare disease screening, management, and treatment.
The scale of the “rare disease problem”—thousands of rare diseases, the vast preponderance of them with no approved treatment, and decades‐long diagnostic odysseys for many patients—led to the ...realization that the time had arrived for global cooperation and collaboration among the many stakeholders active in rare diseases research, to capitalize on these proofs of principle, and maximize the output of rare diseases research efforts around the world. Major public‐sector research initiatives focused in this area have emerged or expanded in many countries, most notably from the US National Institutes of Health (NIH), the European Commission (EC), and the newly formed Japan Agency for Medical Research and Development (AMED). ...they needed to be easily understood by a wide variety of stakeholders and audiences, while also being bold and transformational. ...it was determined to organize the process on four levels—Vision, Goals, Activities, and Metrics. ...IRDiRC also believes that the Vision is achievable with all stakeholders’ commitment, cooperation, and collaboration. ...the challenge inherent in the Vision is intentional, aimed at galvanizing the broad rare disease community, within IRDiRC and outside it, to not only enable universal diagnosis and treatment, but also ensure that these interventions reach people with rare diseases, and have the intended positive impact on their health and well‐being.
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