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Clinical and Translational Science Nov 2023Artificial intelligence (AI) utilization in health care has grown over the past few years. It also has demonstrated potential in improving the efficiency of diagnosis... (Review)
Review
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.
Topics: Humans; Artificial Intelligence; Rare Diseases; Machine Learning; Precision Medicine; Delivery of Health Care
PubMed: 37646577
DOI: 10.1111/cts.13619 -
International Journal of Experimental... Aug 2023Rare diseases collectively exact a high toll on society due to their sheer number and overall prevalence. Their heterogeneity, diversity, and nature pose daunting... (Review)
Review
Rare diseases collectively exact a high toll on society due to their sheer number and overall prevalence. Their heterogeneity, diversity, and nature pose daunting clinical challenges for both management and treatment. In this review, we discuss recent advances in clinical applications of gene therapy for rare diseases, focusing on a variety of viral and non-viral strategies. The use of adeno-associated virus (AAV) vectors is discussed in the context of Luxturna, licenced for the treatment of RPE65 deficiency in the retinal epithelium. Imlygic, a herpes virus vector licenced for the treatment of refractory metastatic melanoma, will be an example of oncolytic vectors developed against rare cancers. Yescarta and Kymriah will showcase the use of retrovirus and lentivirus vectors in the autologous ex vivo production of chimeric antigen receptor T cells (CAR-T), licenced for the treatment of refractory leukaemias and lymphomas. Similar retroviral and lentiviral technology can be applied to autologous haematopoietic stem cells, exemplified by Strimvelis and Zynteglo, licenced treatments for adenosine deaminase-severe combined immunodeficiency (ADA-SCID) and β-thalassaemia respectively. Antisense oligonucleotide technologies will be highlighted through Onpattro and Tegsedi, RNA interference drugs licenced for familial transthyretin (TTR) amyloidosis, and Spinraza, a splice-switching treatment for spinal muscular atrophy (SMA). An initial comparison of the effectiveness of AAV and oligonucleotide therapies in SMA is possible with Zolgensma, an AAV serotype 9 vector, and Spinraza. Through these examples of marketed gene therapies and gene cell therapies, we will discuss the expanding applications of such novel technologies to previously intractable rare diseases.
Topics: Humans; Rare Diseases; Severe Combined Immunodeficiency; Genetic Therapy; Agammaglobulinemia
PubMed: 37177842
DOI: 10.1111/iep.12478 -
Frontiers in Genetics 2023
PubMed: 37529775
DOI: 10.3389/fgene.2023.1248435 -
American Journal of Human Genetics Aug 2023Despite advances in clinical genetic testing, including the introduction of exome sequencing (ES), more than 50% of individuals with a suspected Mendelian condition lack... (Review)
Review
Despite advances in clinical genetic testing, including the introduction of exome sequencing (ES), more than 50% of individuals with a suspected Mendelian condition lack a precise molecular diagnosis. Clinical evaluation is increasingly undertaken by specialists outside of clinical genetics, often occurring in a tiered fashion and typically ending after ES. The current diagnostic rate reflects multiple factors, including technical limitations, incomplete understanding of variant pathogenicity, missing genotype-phenotype associations, complex gene-environment interactions, and reporting differences between clinical labs. Maintaining a clear understanding of the rapidly evolving landscape of diagnostic tests beyond ES, and their limitations, presents a challenge for non-genetics professionals. Newer tests, such as short-read genome or RNA sequencing, can be challenging to order, and emerging technologies, such as optical genome mapping and long-read DNA sequencing, are not available clinically. Furthermore, there is no clear guidance on the next best steps after inconclusive evaluation. Here, we review why a clinical genetic evaluation may be negative, discuss questions to be asked in this setting, and provide a framework for further investigation, including the advantages and disadvantages of new approaches that are nascent in the clinical sphere. We present a guide for the next best steps after inconclusive molecular testing based upon phenotype and prior evaluation, including when to consider referral to research consortia focused on elucidating the underlying cause of rare unsolved genetic disorders.
Topics: Humans; Exome; Genetic Testing; Sequence Analysis, DNA; Phenotype; Exome Sequencing; Rare Diseases
PubMed: 37541186
DOI: 10.1016/j.ajhg.2023.06.009 -
Healthcare (Basel, Switzerland) Sep 2023In this Special Issue on "Musculoskeletal Pain Care and Management in Rare Disease", it is essential to make it clear that, while specialists in rare diseases (RDs) are...
In this Special Issue on "Musculoskeletal Pain Care and Management in Rare Disease", it is essential to make it clear that, while specialists in rare diseases (RDs) are often very knowledgeable about the management of the specific diseases in which they are experts, primary care physicians and other physicians who are not experts in a given disease often have very little contact with the patients who experience it [...].
PubMed: 37830665
DOI: 10.3390/healthcare11192628 -
Blood Dec 2023Rare genetic diseases affect millions, and identifying causal DNA variants is essential for patient care. Therefore, it is imperative to estimate the effect of each...
Rare genetic diseases affect millions, and identifying causal DNA variants is essential for patient care. Therefore, it is imperative to estimate the effect of each independent variant and improve their pathogenicity classification. Our study of 140 214 unrelated UK Biobank (UKB) participants found that each of them carries a median of 7 variants previously reported as pathogenic or likely pathogenic. We focused on 967 diagnostic-grade gene (DGG) variants for rare bleeding, thrombotic, and platelet disorders (BTPDs) observed in 12 367 UKB participants. By association analysis, for a subset of these variants, we estimated effect sizes for platelet count and volume, and odds ratios for bleeding and thrombosis. Variants causal of some autosomal recessive platelet disorders revealed phenotypic consequences in carriers. Loss-of-function variants in MPL, which cause chronic amegakaryocytic thrombocytopenia if biallelic, were unexpectedly associated with increased platelet counts in carriers. We also demonstrated that common variants identified by genome-wide association studies (GWAS) for platelet count or thrombosis risk may influence the penetrance of rare variants in BTPD DGGs on their associated hemostasis disorders. Network-propagation analysis applied to an interactome of 18 410 nodes and 571 917 edges showed that GWAS variants with large effect sizes are enriched in DGGs and their first-order interactors. Finally, we illustrate the modifying effect of polygenic scores for platelet count and thrombosis risk on disease severity in participants carrying rare variants in TUBB1 or PROC and PROS1, respectively. Our findings demonstrate the power of association analyses using large population datasets in improving pathogenicity classifications of rare variants.
Topics: Humans; Genome-Wide Association Study; Biological Specimen Banks; Hemostasis; Hemorrhage; Thrombosis; Rare Diseases
PubMed: 37647632
DOI: 10.1182/blood.2023020118 -
Journal of Translational Medicine Jun 2023In the United States, rare disease (RD) is defined as a condition that affects fewer than 200,000 individuals. Collectively, RD affects an estimated 30 million...
BACKGROUND
In the United States, rare disease (RD) is defined as a condition that affects fewer than 200,000 individuals. Collectively, RD affects an estimated 30 million Americans. A significant portion of RD has an underlying genetic cause; however, this may go undiagnosed. To better serve these patients, the Mayo Clinic Program for Rare and Undiagnosed Diseases (PRaUD) was created under the auspices of the Center for Individualized Medicine (CIM) aiming to integrate genomics into subspecialty practice including targeted genetic testing, research, and education.
METHODS
Patients were identified by subspecialty healthcare providers from 11 clinical divisions/departments. Targeted multi-gene panels or custom exome/genome-based panels were utilized. To support the goals of PRaUD, a new clinical service model, the Genetic Testing and Counseling (GTAC) unit, was established to improve access and increase efficiency for genetic test facilitation. The GTAC unit includes genetic counselors, genetic counseling assistants, genetic nurses, and a medical geneticist. Patients receive abbreviated point-of-care genetic counseling and testing through a partnership with subspecialty providers.
RESULTS
Implementation of PRaUD began in 2018 and GTAC unit launched in 2020 to support program expansion. Currently, 29 RD clinical indications are included in 11 specialty divisions/departments with over 142 referring providers. To date, 1152 patients have been evaluated with an overall solved or likely solved rate of 17.5% and as high as 66.7% depending on the phenotype. Noteworthy, 42.7% of the solved or likely solved patients underwent changes in medical management and outcome based on genetic test results.
CONCLUSION
Implementation of PRaUD and GTAC have enabled subspecialty practices advance expertise in RD where genetic counselors have not historically been embedded in practice. Democratizing access to genetic testing and counseling can broaden the reach of patients with RD and increase the diagnostic yield of such indications leading to better medical management as well as expanding research opportunities.
Topics: United States; Humans; Rare Diseases; Undiagnosed Diseases; Tertiary Healthcare; Genomic Medicine; Genetic Testing; Genetic Counseling
PubMed: 37353797
DOI: 10.1186/s12967-023-04183-7 -
The Lancet. Global Health Mar 2024
Topics: Humans; Rare Diseases
PubMed: 38365397
DOI: 10.1016/S2214-109X(24)00056-1 -
Laeknabladid
Topics: Humans; Iceland; Rare Diseases
PubMed: 38420957
DOI: 10.17992/lbl.2024.03.783 -
Nature Medicine Jul 2023Critically ill infants and children with rare diseases need equitable access to rapid and accurate diagnosis to direct clinical management. Over 2 years, the Acute Care...
Critically ill infants and children with rare diseases need equitable access to rapid and accurate diagnosis to direct clinical management. Over 2 years, the Acute Care Genomics program provided whole-genome sequencing to 290 families whose critically ill infants and children were admitted to hospitals throughout Australia with suspected genetic conditions. The average time to result was 2.9 d and diagnostic yield was 47%. We performed additional bioinformatic analyses and transcriptome sequencing in all patients who remained undiagnosed. Long-read sequencing and functional assays, ranging from clinically accredited enzyme analysis to bespoke quantitative proteomics, were deployed in selected cases. This resulted in an additional 19 diagnoses and an overall diagnostic yield of 54%. Diagnostic variants ranged from structural chromosomal abnormalities through to an intronic retrotransposon, disrupting splicing. Critical care management changed in 120 diagnosed patients (77%). This included major impacts, such as informing precision treatments, surgical and transplant decisions and palliation, in 94 patients (60%). Our results provide preliminary evidence of the clinical utility of integrating multi-omic approaches into mainstream diagnostic practice to fully realize the potential of rare disease genomic testing in a timely manner.
Topics: Infant; Child; Humans; Rare Diseases; Critical Illness; Multiomics; Whole Genome Sequencing; Exome Sequencing
PubMed: 37291213
DOI: 10.1038/s41591-023-02401-9