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Clinical Genetics May 2023In recent years, massively parallel sequencing or next generation sequencing (NGS) has considerably changed both the research and diagnostic fields, and rapid... (Review)
Review
In recent years, massively parallel sequencing or next generation sequencing (NGS) has considerably changed both the research and diagnostic fields, and rapid developments have led to the combination of NGS techniques in clinical practice, ease of analysis, and detection of genetic mutations. This article aimed at reviewing the economic evaluation studies of the NGS techniques in the diagnosis of genetic diseases. In this systematic review, scientific databases (PubMed, EMBASE, Web of Science, Cochrane, Scopus, and CEA registry) were searched from 2005 to 2022 to identify the related literature on the economic evaluation of NGS techniques in the diagnosis of genetic diseases. Full-text reviews and data extraction were all performed by two independent researchers. The quality of all the articles included in this study was evaluated using the Checklist of Quality of Health Economic Studies (QHES). Out of 20 521 screened abstracts, 36 studies met the inclusion criteria. The mean score of the QHES checklist for the studies was 0.78 (high quality). Seventeen studies were conducted based on modeling. Cost-effectiveness analysis, cost-utility analysis, and cost-minimization analysis were done in 26 studies, 13 studies, and 1 study, respectively. Based on the available evidence and findings, exome sequencing, which is one of the NGS techniques, could have the potential to be used as a cost-effective genomic test to diagnose children with suspected genetic diseases. The results of the present study support the cost-effectiveness of exome sequencing in diagnosing suspected genetic disorders. However, the use of exome sequencing as a first- or second-line diagnostic test is still controversial. Most studies have been conducted in high-income countries, and research on the cost-effectiveness of NGS methods is recommended in low- and middle-income countries.
Topics: Child; Humans; Cost-Benefit Analysis; Mutation; Cost-Effectiveness Analysis; High-Throughput Nucleotide Sequencing
PubMed: 36808726
DOI: 10.1111/cge.14313 -
Annali Di Igiene : Medicina Preventiva... 2017Familial hypercholesterolemia (FH) is a genetic disorder that leads to elevated plasma LDL-cholesterol levels and premature coronary heart disease (CHD). An... (Review)
Review
BACKGROUND
Familial hypercholesterolemia (FH) is a genetic disorder that leads to elevated plasma LDL-cholesterol levels and premature coronary heart disease (CHD). An understanding of the mutations responsible for FH and the effectiveness of statins in lowering the risk of CHD in FH patients has increased interest in genetic screening strategies to improve FH diagnosis. In this study, we aimed to evaluate the cost-effectiveness of such strategies.
METHODS
We performed a systematic review of full economic evaluations that assessed the cost-effectiveness of FH genetic screening strategies. We used relevant search terms to investigate Medline, Scopus, Web of Science, the Database of Abstracts of Reviews of Effects, the Health Technology Assessment Database, and the National Health Service Economic Evaluation Database. Data extraction and assessment of the quality of the studies were performed independently by two reviewers. The key features of the included studies are summarized in a narrative synthesis.
RESULTS
We included seven economic evaluations that assessed the cost-effectiveness of genetic screening for FH, published mainly in Europe between 2002 and 2015. Most studies had a no-screening strategy as a comparator, focused on relatives of index cases with genetic or clinical diagnosis of FH (cascade screening), considered a lifetime horizon and adopted a health care payer viewpoint. Cascade screening, based on genetic testing of relatives of an index case with confirmed clinical or genetic diagnosis of FH, was shown to be cost-effective in most settings.
CONCLUSIONS
Our review confirms the cost-effectiveness of cascade genetic screening for the diagnosis of FH. Further research may be needed to assess the cost-effectiveness of cascade screening following the introduction of newly recommended therapeutic regimes and next-generation sequencing.
Topics: Cost-Benefit Analysis; Databases, Factual; Family Health; Genetic Testing; High-Throughput Nucleotide Sequencing; Humans; Hyperlipoproteinemia Type II; Mass Screening
PubMed: 28715059
DOI: 10.7416/ai.2017.2178 -
Value in Health : the Journal of the... May 2024To comprehensively identify and map an exhaustive list of value criteria for the assessment of next-generation sequencing/comprehensive genomic profiling (NGS/CGP), to... (Review)
Review
OBJECTIVES
To comprehensively identify and map an exhaustive list of value criteria for the assessment of next-generation sequencing/comprehensive genomic profiling (NGS/CGP), to be used as an aid in decision making.
METHODS
We conducted a systematic review to identify existing value frameworks (VFs) applicable to any type of healthcare technology. VFs and criteria were mapped to a previously published Latin American (LA) VF to harmonize definitions and identify additional criteria and or subcriteria. Based on this analysis, we extracted a comprehensive, evidence-based list of criteria and subcriteria to be considered in the design of a NGS/CGP VF.
RESULTS
A total of 42 additional VFs were compared with the LA VF, 88% were developed in high-income countries, 30% targeted genomic testing, and 16% specifically targeted oncology. A total of 242 criteria and subcriteria were extracted; 227 (94%) were fully/partially included in the LA VF; and 15 (6%) were new. Clinical benefit and economic aspects were the most common criteria. VFs oriented to genomic testing showed significant overlap with other VFs. Considering all criteria and subcriteria, a total of 18 criteria and 36 individual subcriteria were identified.
CONCLUSIONS
Our study provides an evidence-based set of criteria and subcriteria for healthcare decision making useful for NGS/CGP as well as other health technologies. The resulting list can be beneficial to inform decision making and will serve as a foundation to co-create a multistakeholder NGS/CGP VF that is aligned with the needs and values of health systems and could help to improve patient access to high-value technologies.
Topics: Humans; Genomics; High-Throughput Nucleotide Sequencing; Cost-Benefit Analysis; Genetic Testing; Decision Making
PubMed: 38403113
DOI: 10.1016/j.jval.2024.02.002 -
Briefings in Functional Genomics May 2017High-throughput next-generation sequencing (NGS) technologies have rapidly generated a large volume of genomic data. To aid the development and evaluation of new... (Review)
Review
High-throughput next-generation sequencing (NGS) technologies have rapidly generated a large volume of genomic data. To aid the development and evaluation of new statistical models and computational methods, NGS-based simulators have been proposed to construct better experimental workflows. However, the comparative performance of these NGS simulators remains unclear. In this review, we conducted a comprehensive investigation of NGS simulators for various sequencing techniques, including DNA sequencing, metagenomic sequencing, RNA-seq, ChIP-seq and bisulfite sequencing for methylation.
Topics: Genomics; High-Throughput Nucleotide Sequencing; Sequence Analysis, DNA; Sequence Analysis, RNA
PubMed: 27069250
DOI: 10.1093/bfgp/elw012 -
Genetics in Medicine : Official Journal... Aug 2022The study aimed to determine the diagnostic yield, optimal timing, and methodology of next generation sequencing data reanalysis in suspected Mendelian disorders. (Meta-Analysis)
Meta-Analysis Review
PURPOSE
The study aimed to determine the diagnostic yield, optimal timing, and methodology of next generation sequencing data reanalysis in suspected Mendelian disorders.
METHODS
We conducted a systematic review and meta-analysis of studies that conducted data reanalysis in patients with suspected Mendelian disorders. Random effects model was used to pool the estimated outcome with subgroup analysis stratified by timing, sequencing methodology, sample size, segregation, use of research validation, and artificial intelligence (AI) variant curation tools.
RESULTS
A search of PubMed, Embase, Scopus, and Web of Science between 2007 and 2021 yielded 9327 articles, of which 29 were selected. Significant heterogeneity was noted between studies. Reanalysis had an overall diagnostic yield of 0.10 (95% CI = 0.06-0.13). Literature updates accounted for most new diagnoses. Diagnostic yield was higher after 24 months, although this was not statistically significant. Increased diagnoses were obtained with research validation and data sharing. AI-based tools did not adversely affect reanalysis diagnostic rate.
CONCLUSION
Next generation sequencing data reanalysis can improve diagnostic yield. Owing to the heterogeneity of the studies, the optimal time to reanalysis and the impact of AI-based tools could not be determined with confidence. We propose standardized guidelines for future studies to reduce heterogeneity and improve the quality of the conclusions.
Topics: Artificial Intelligence; High-Throughput Nucleotide Sequencing; Humans; Exome Sequencing
PubMed: 35550369
DOI: 10.1016/j.gim.2022.04.021 -
BMC Medical Genomics Aug 2016Whole-exome sequencing (WES) consists in the capture, sequencing and analysis of all exons in the human genome. Originally developed in the research context, this... (Review)
Review
BACKGROUND
Whole-exome sequencing (WES) consists in the capture, sequencing and analysis of all exons in the human genome. Originally developed in the research context, this technology is now increasingly used clinically to inform patient care. The implementation of WES into healthcare poses significant organizational, regulatory, and ethical hurdles, which are widely discussed in the literature.
METHODS
In order to inform future policy decisions on the integration of WES into standard clinical practice, we performed a systematic literature review to identify the most important challenges directly reported by technology users.
RESULTS
Out of 2094 articles, we selected and analyzed 147 which reported a total of 23 different challenges linked to the production, analysis, reporting and sharing of patients' WES data. Interpretation of variants of unknown significance, incidental findings, and the cost and reimbursement of WES-based tests were the most reported challenges across all articles.
CONCLUSIONS
WES is already used in the clinical setting, and may soon be considered the standard of care for specific medical conditions. Yet, technology users are calling for certain standards and guidelines to be published before this technology replaces more focused approaches such as gene panels sequencing. In addition, a number of infrastructural adjustments will have to be made for clinics to store, process and analyze the amounts of data produced by WES.
Topics: Exome; Genomics; High-Throughput Nucleotide Sequencing; Humans; Sequence Analysis, DNA
PubMed: 27514372
DOI: 10.1186/s12920-016-0213-6 -
Otology & Neurotology : Official... Jan 2019To describe the genetic and phenotypic spectrum of Usher syndrome after 6 years of studies by next-generation sequencing, and propose an up-to-date classification of... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
To describe the genetic and phenotypic spectrum of Usher syndrome after 6 years of studies by next-generation sequencing, and propose an up-to-date classification of Usher genes in patients with both visual and hearing impairments suggesting Usher syndrome, and in patients with seemingly isolated deafness.
STUDY DESIGN
The systematic review and meta-analysis protocol was based on Cochrane and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We performed 1) a meta-analysis of data from 11 next-generation sequencing studies in 684 patients with Usher syndrome; 2) a meta-analysis of data from 21 next-generation studies in 2,476 patients with seemingly isolated deafness, to assess the involvement of Usher genes in seemingly nonsyndromic hearing loss, and thus the proportion of patients at high risk of subsequent retinitis pigmentosa (RP); 3) a statistical analysis of differences between parts 1) and 2).
RESULTS
In patients with both visual and hearing impairments, the biallelic disease-causing mutation rate was assessed for each Usher gene to propose a classification by frequency: USH2A: 50% (341/684) of patients, MYO7A: 21% (144/684), CDH23: 6% (39/684), ADGRV1: 5% (35/684), PCDH15: 3% (21/684), USH1C: 2% (17/684), CLRN1: 2% (14/684), USH1G: 1% (9/684), WHRN: 0.4% (3/684), PDZD7 0.1% (1/684), CIB2 (0/684). In patients with seemingly isolated sensorineural deafness, 7.5% had disease-causing mutations in Usher genes, and are therefore at high risk of developing RP. These new findings provide evidence that usherome dysfunction is the second cause of genetic sensorineural hearing loss after connexin dysfunction.
CONCLUSION
These results promote generalization of early molecular screening for Usher syndrome in deaf children.
Topics: High-Throughput Nucleotide Sequencing; Humans; Mutation; Pedigree; Usher Syndromes
PubMed: 30531642
DOI: 10.1097/MAO.0000000000002054 -
Journal of Clinical Microbiology Aug 2014Ethambutol (EMB) is a first-line antituberculosis drug; however, drug resistance to EMB has been increasing. Molecular drug susceptibility testing (DST), based on the... (Meta-Analysis)
Meta-Analysis Review
Ethambutol (EMB) is a first-line antituberculosis drug; however, drug resistance to EMB has been increasing. Molecular drug susceptibility testing (DST), based on the embB gene, has recently been used for rapid identification of EMB resistance. The aim of this meta-analysis was to establish the accuracy of molecular assay for detecting drug resistance to EMB. PubMed, Embase, and Web of Science were searched according to a written protocol and explicit study selection criteria. Measures of diagnostic accuracy were pooled using a random effects model. A total of 34 studies were included in the meta-analysis. The respective pooled sensitivities and specificities were 0.57 and 0.93 for PCR-DNA sequencing that targeted the embB 306 codon, 0.76 and 0.89 for PCR-DNA sequencing that targeted the embB 306, 406, and 497 codons, 0.64 and 0.70 for detecting Mycobacterium tuberculosis isolates, 0.55 and 0.78 for detecting M. tuberculosis sputum specimens using the GenoType MTBDRsl test, 0.57 and 0.87 for pyrosequencing, and 0.35 and 0.98 for PCR-restriction fragment length polymorphism. The respective pooled sensitivities and specificities were 0.55 and 0.92 when using a lower EMB concentration as the reference standard, 0.67 and 0.73 when using a higher EMB concentration as the reference standard, and 0.60 and 1.0 when using multiple reference standards. PCR-DNA sequencing using multiple sites of the embB gene as detection targets, including embB 306, 406, and 497, can be a rapid method for preliminarily screening for EMB resistance, but it does not fully replace phenotypic DST. Of the reference DST methods examined, the agreement rates were the best using MGIT 960 for molecular DST and using the proportion method on Middlebrook 7H10 media.
Topics: Antitubercular Agents; Ethambutol; Humans; Microbial Sensitivity Tests; Molecular Diagnostic Techniques; Mycobacterium tuberculosis; Pentosyltransferases; Polymerase Chain Reaction; Sensitivity and Specificity; Sequence Analysis, DNA
PubMed: 24899018
DOI: 10.1128/JCM.00560-14 -
Frontiers in Cellular and Infection... 2022A prosthetic joint infection (PJI) is a devastating complication following total joint arthroplasties with poor prognosis. Identifying an accurate and prompt diagnostic... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
A prosthetic joint infection (PJI) is a devastating complication following total joint arthroplasties with poor prognosis. Identifying an accurate and prompt diagnostic method is particularly important for PJI. Recently, the diagnostic value of metagenomic next-generation sequencing (mNGS) in detecting PJI has attracted much attention, while the evidence of its accuracy is quite limited. Thus, this study aimed to evaluate the accuracy of mNGS for the diagnosis of PJI.
METHODS
We summarized published studies to identify the potential diagnostic value of mNGS for PJI patients by searching online databases using keywords such as "prosthetic joint infection", "PJI", and "metagenomic sequencing". Ten of 380 studies with 955 patients in total were included. The included studies provided sufficient data for the completion of 2-by-2 tables. We calculated the sensitivity, specificity, and area under the SROC curve (AUC) to evaluate mNGS for PJI diagnosis.
RESULTS
We found that the pooled diagnostic sensitivity and specificity of mNGS for PJI were 0.93 (95% CI, 0.83 to 0.97) and 0.95 (95% CI, 0.92 to 0.97), respectively. Positive and negative likelihood ratios were 18.3 (95% CI, 10.9 to 30.6) and 0.07 (95% CI, 0.03 to 0.18), respectively. The area under the curve was 0.96 (95% CI, 0.93 to 0.97).
CONCLUSION
Metagenomic next-generation sequencing displays high accuracy in the diagnosis of PJI, especially for culture-negative cases.
Topics: Arthritis, Infectious; High-Throughput Nucleotide Sequencing; Humans; Metagenomics; Prosthesis-Related Infections; Sensitivity and Specificity; Synovial Fluid
PubMed: 35755833
DOI: 10.3389/fcimb.2022.875822 -
International Journal of Molecular... Jan 2023Multiple Sclerosis (MS) is, to date, an incurable disease of the nervous system characterized by demyelination. Several genetic mutations are associated with the disease... (Review)
Review
Multiple Sclerosis (MS) is, to date, an incurable disease of the nervous system characterized by demyelination. Several genetic mutations are associated with the disease but they are not able to explain all the diagnosticated cases. Thus, it is suggested that altered gene expression may play a role in human pathologies. In this review, we explored the role of the transcriptomic profile in MS to investigate the main altered biological processes and pathways involved in the disease. Herein, we focused our attention on RNA-seq methods that in recent years are producing a huge amount of data rapidly replacing microarrays, both with bulk and single-cells. The studies evidenced that different MS stages have specific molecular signatures and non-coding RNAs may play a key role in the disease. Sex-dependence was observed before and after treatments used to alleviate symptomatology activating different biological processes in a drug-dependent manner. New pathways, such as neddylation, were found deregulated in MS and inflammation was linked to neuron degeneration areas through spatial transcriptomics. It is evident that the use of RNA-seq in the study of complex pathologies, such as MS, is a valid strategy to shed light on new involved mechanisms.
Topics: Humans; Transcriptome; Multiple Sclerosis; Gene Expression Profiling; RNA-Seq
PubMed: 36674968
DOI: 10.3390/ijms24021448