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American Journal of Medical Genetics.... Dec 2022Children with genetic diseases endure a prolonged and costly "diagnostic odyssey." The use of whole exome sequencing (WES) and whole genome sequencing (WGS) has improved...
Children with genetic diseases endure a prolonged and costly "diagnostic odyssey." The use of whole exome sequencing (WES) and whole genome sequencing (WGS) has improved the diagnosis rate, ending the odyssey. However, the additional costs associated WES/WGS has impeded their adoption in Asian settings. We aim to estimate the expected change to the mean number of diagnostic tests used, and the associated costs from a decision to use WES early in the diagnostic pathways of pediatric phenotypes, as compared to Existing Practice. Retrospective data from a patient cohort recruited under the Singapore Undiagnosed Disease Program from a tertiary hospital in Singapore, for the period October 2004 to September 2020, was analyzed. Four phenotype-specific subgroups were used: multiple congenital anomalies (MCA) without developmental delay; global developmental delay (GDD); neuromuscular disorder (NMD) and primary immunodeficiency disorder (PID). Patients had undergone a traditional diagnostic pathway and received a diagnosis either through clinical exome or WES or WGS. A costs only analysis was performed, by tabulating the outcomes "test quantity" and "test costs" incurred by patients. The outcomes were compared with alternate diagnostic pathways which incorporates the early introduction of WES trio testing. To include uncertainty in cost outcomes, simulation studies were done on uncertain parameters. Cost outcomes are reported in Singapore dollars (S$). The 92 included patients had MCA (n = 48), GDD (n = 29), NMD (n = 10), or PID (n = 5). Patients were aged between 18 days and 26 years, 52.2% were males. The majority were of Chinese ethnicity (81.5%). If patients had access to WES directly, test quantity reduced by 97.38% for MCA, 96.98% for GDD, 96.56% for NMD, and 99.84% for PID. The expected cost savings per patient were $5940 for MCA (US$4433), $5342 for GDD (US$3986), $4622 for NMD (US$3449), and $58,497 for PID (US$43,654). Uncertainty assessment for MCA and GDD patients showed a respective likelihood of 86.9% and 97.4% for cost savings. Adoption of alternate diagnostic pathways with early WES in selected pediatric subgroups are likelt to reduce costs, when compared to Existing Practice. Benefits arising from earlier diagnosis, and the potential cost savings could mitigate the large initial cost of implementing WES in Asian settings.
Topics: Humans; Male; Female; Retrospective Studies; High-Throughput Nucleotide Sequencing; Exome Sequencing; Exome; Phenotype; Abnormalities, Multiple; Rare Diseases; Genetic Testing
PubMed: 36156406
DOI: 10.1002/ajmg.a.62974 -
Clinical Genetics Jul 2023Cardiomyopathies are diseases of the heart muscle with variable clinical expressivity. Most of forms are inherited as dominant trait, and with incomplete penetrance...
Cardiomyopathies are diseases of the heart muscle with variable clinical expressivity. Most of forms are inherited as dominant trait, and with incomplete penetrance until adulthood. Severe forms of cardiomyopathies were observed during the antenatal period with a pejorative issue leading to fetal death or medical interruption of pregnancy. Variable phenotypes and genetic heterogeneity make etiologic diagnosis difficult. We report 11 families (16 cases) whose unborn, newborn or infant with early onset cardiomyopathies. Detailed morphological and histological examinations of hearts were implemented, as well as genetic analysis on a cardiac targeted NGS panel. This strategy allowed the identification of the genetic cause of the cardiomyopathy in 8/11 families. Compound heterozygous mutations in dominant adulthood cardiomyopathy genes were found in two, pathogenic variants in co-dominant genes in one, de novo mutations in 5 including a germline mosaicism in one family. Parental testing was systematically performed to detect mutation carriers, and to manage cardiological surveillance and propose a genetic counseling. This study highlights the great diagnostic value of the genetic testing of severe antenatal cardiomyopathy both for genetic counseling and to detect presymptomatic parents at higher risk of developing cardiomyopathy.
Topics: Pregnancy; Humans; Female; Cardiomyopathies; Genetic Testing; Mutation; Phenotype; Genetic Counseling
PubMed: 37209000
DOI: 10.1111/cge.14333 -
The Journal of Applied Laboratory... Sep 2023Body fluid testing in the clinical chemistry laboratory is a cornerstone in the diagnostic workup of pathological effusions. Laboratorians may not be aware of the... (Review)
Review
BACKGROUND
Body fluid testing in the clinical chemistry laboratory is a cornerstone in the diagnostic workup of pathological effusions. Laboratorians may not be aware of the preanalytical workflows used in the collection of body fluids though the value is evident whenever processes change or issues arise. The analytical validation requirements can vary depending on the regulations dictated by the laboratories' jurisdiction and accreditor requirements. Much of analytical validation hinges on how useful testing is to clinical care. Usefulness of testing varies with how well established and incorporated the tests and interpretation are in practice guidelines.
CONTENT
Body fluid collections are depicted and described so clinical laboratorians have a basic appreciation of what specimens are submitted to the laboratory for testing. A review of validation requirements by major laboratory accreditation entities is presented. A review of the usefulness and proposed decision limits for common body fluid chemistry analytes is presented. Body fluid tests that show promise and those that are losing (or lost long ago) value are also reviewed.
SUMMARY
The total testing process from collection to result interpretation can be complicated and easily overlooked by the clinical laboratory. This review aims to improve the understanding and awareness of collections, validation, result interpretation, and provide an update on recent trends.
Topics: Humans; Body Fluids; Laboratories; Chemistry, Clinical; Clinical Laboratory Services; Laboratories, Clinical
PubMed: 37207691
DOI: 10.1093/jalm/jfad014 -
PloS One 2023Diagnostic network optimization (DNO) is an analytical approach that enables use of available country data to inform evidence-based decision-making to optimize access to...
Optimizing diagnostic networks to increase patient access to TB diagnostic services: Development of the diagnostic network optimization (DNO) approach and learnings from its application in Kenya, India and the Philippines.
Diagnostic network optimization (DNO) is an analytical approach that enables use of available country data to inform evidence-based decision-making to optimize access to diagnostic services. A DNO methodology was developed using available data sources and a commercial supply chain optimization software. In collaboration with Ministries of Health and partners, the approach was applied in Kenya, India and the Philippines to map TB diagnostic networks, identify misalignments, and determine optimal network design to increase patient access to TB diagnostic services and improve device utilization. The DNO analysis was successfully applied to evaluate and inform TB diagnostic services in Kenya, India and the Philippines as part of national strategic planning for TB. The analysis was tailored to each country's specific objectives and allowed evaluation of factors such as the number and placement of different TB diagnostics, design of sample referral networks and integration of early infant diagnosis for HIV at national and sub-national levels and across public and private sectors. Our work demonstrates the value of DNO as an innovative approach to analysing and modelling diagnostic networks, particularly suited for use in low-resource settings, as an open-access approach that can be applied to optimize networks for any disease.
Topics: Humans; Philippines; Kenya; Referral and Consultation; Diagnostic Services; India
PubMed: 38033120
DOI: 10.1371/journal.pone.0279677 -
BMC Health Services Research Sep 2022Effective care services for people whose work participation is at risk require low-threshold access, a comprehensive diagnostic clarification of intervention needs, a...
BACKGROUND
Effective care services for people whose work participation is at risk require low-threshold access, a comprehensive diagnostic clarification of intervention needs, a connection to the workplace and job demands, and interdisciplinary collaboration between key stakeholders at the interface of rehabilitation and occupational medicine. We have developed a comprehensive diagnostic service to clarify intervention needs for employees with health restrictions and limited work ability: this service is initiated by occupational health physicians.
METHODS/DESIGN
Our randomized controlled trial tests the effectiveness of a comprehensive diagnostic service for clarifying intervention needs (GIBI: Comprehensive clarification of the need for intervention for people whose work participation is at risk). The comprehensive intervention comprises three elements: initial consultation, two-day diagnostics at a rehabilitation center and follow-up consultations. We will include 210 employees with health restrictions and limited work ability, who are identified by occupational health physicians. All individuals will receive an initial consultation with their occupational health physician to discuss their health, work ability and job demands. After this, half the individuals are randomly assigned to the intervention group and the other half to the waiting-list control group. Individuals in the intervention group start two-day diagnostics, carried out by a multi-professional rehabilitation team in a rehabilitation center, shortly after the initial consultation. The diagnostics will allow first recommendations for improving work participation. The implementation of these recommendations is supported by an occupational health physician in four follow-up consultations. The control group will receive the comprehensive two-day diagnostic service and subsequent follow-up consultations six months after the initial consultation. The primary outcome of the randomized controlled trial is self-rated work ability assessed using the Work Ability Score (0 to 10 points) six months after study inclusion. Secondary outcomes include a range of patient-reported outcomes regarding physical and mental health, impairment, and the physical and mental demands of jobs.
DISCUSSION
This randomized controlled trial is designed to test the effects of a new complex intervention involving a comprehensive clarification of intervention needs in order to promote work participation and prevent the worsening of health and work disability.
TRIAL REGISTRATION
German Clinical Trials Register (DRKS00027577, February 01, 2022).
Topics: Diagnostic Services; Humans; Medicine; Occupational Health Physicians; Occupational Medicine; Randomized Controlled Trials as Topic; Rehabilitation Centers
PubMed: 36085150
DOI: 10.1186/s12913-022-08513-1 -
Expert Review of Pharmacoeconomics &... Jun 2021: Predictive diagnostics play an increasingly important role in personalized medicine for cancer treatment. Whole-genome sequencing (WGS)-based treatment selection is... (Comparative Study)
Comparative Study
: Predictive diagnostics play an increasingly important role in personalized medicine for cancer treatment. Whole-genome sequencing (WGS)-based treatment selection is expected to rapidly increase worldwide. This study aimed to calculate and compare the total cost of currently used diagnostic techniques and of WGS in treatment of non-small cell lung carcinoma (NSCLC), melanoma, colorectal cancer (CRC), and gastrointestinal stromal tumor (GIST) in the Netherlands.: The activity-based costing (ABC) method was conducted to calculate total cost of included diagnostic techniques based on data provided by Dutch pathology laboratories and the Dutch-centralized cancer WGS facility. Costs were allocated to four categories: capital costs, maintenance costs, software costs, and operational costs.: The total cost per cancer patient per technique varied from € 58 (Sanger sequencing, three amplicons) to € 2925 (paired tumor-normal WGS). The operational costs accounted for the vast majority (over 90%) of the total per cancer patient technique costs.: This study outlined in detail all costing aspects and cost prices of current and new diagnostic modalities used in treatment of NSCLC, melanoma, CRC, and GIST in the Netherlands. Detailed cost differences and value comparisons between these diagnostic techniques enable future economic evaluations to support decision-making.
Topics: Costs and Cost Analysis; Genetic Testing; Humans; Neoplasms; Netherlands; Precision Medicine; Whole Genome Sequencing
PubMed: 33852815
DOI: 10.1080/14737167.2021.1917385 -
Clinical Genetics Jul 2024The gold standard for facioscapulohumeral muscular dystrophy (FSHD) genetic diagnostic procedures was published in 2012. With the increasing complexity of the genetics... (Review)
Review
The gold standard for facioscapulohumeral muscular dystrophy (FSHD) genetic diagnostic procedures was published in 2012. With the increasing complexity of the genetics of FSHD1 and 2, the increase of genetic testing centers, and the start of clinical trials for FSHD, it is crucial to provide an update on our knowledge of the genetic features of the FSHD loci and renew the international consensus on the molecular testing recommendations. To this end, members of the FSHD European Trial Network summarized the evidence presented during the 2022 ENMC meeting on Genetic diagnosis, clinical outcome measures, and biomarkers. The working group additionally invited genetic and clinical experts from the USA, India, Japan, Australia, South-Africa, and Brazil to provide a global perspective. Six virtual meetings were organized to reach consensus on the minimal requirements for genetic confirmation of FSHD1 and FSHD2. Here, we present the clinical and genetic features of FSHD, specific features of FSHD1 and FSHD2, pros and cons of established and new technologies (Southern blot in combination with either linear or pulsed-field gel electrophoresis, molecular combing, optical genome mapping, FSHD2 methylation analysis and FSHD2 genotyping), the possibilities and challenges of prenatal testing, including pre-implantation genetic testing, and the minimal requirements and recommendations for genetic confirmation of FSHD1 and FSHD2. This consensus is expected to contribute to current clinical management and trial-readiness for FSHD.
Topics: Muscular Dystrophy, Facioscapulohumeral; Humans; Genetic Testing; Practice Guidelines as Topic
PubMed: 38685133
DOI: 10.1111/cge.14533 -
The Journal of Molecular Diagnostics :... May 2020Testing asymptomatic individuals for unsuspected conditions is not new to the medical and public health communities. Protocols to develop screening tests are well... (Review)
Review
Testing asymptomatic individuals for unsuspected conditions is not new to the medical and public health communities. Protocols to develop screening tests are well established. However, the application of screening principles to inherited diseases presents unique challenges. Unlike most screening tests, the natural history and disease prevalence of most rare inherited diseases in an unselected population are unknown. It is difficult or impossible to obtain a truth set cohort for clinical validation studies. As a result, it is not possible to accurately calculate clinical positive and negative predictive values for likely pathogenic variants, which are commonly returned in genetic screening assays. In addition, many of the genetic conditions included in screening panels do not have clinical confirmatory tests. All these elements are typically required to justify the development of a screening test, according to the World Health Organization screening principles. Nevertheless, as the cost of DNA sequencing continues to fall, more individuals are opting to undergo genomic testing in the absence of a clinical indication. Despite the challenges, reasonable estimates can be deduced and used to inform test design strategies. Herein, we review basic test design principles and apply them to genetic screening.
Topics: Genetic Association Studies; Genetic Diseases, Inborn; Genetic Predisposition to Disease; Genetic Testing; Genetic Variation; Humans; Mass Screening; Research Design
PubMed: 32092541
DOI: 10.1016/j.jmoldx.2020.01.014 -
Journal of Paediatrics and Child Health Nov 2019To investigate the diagnostic and service impact of chromosomal microarray and whole exome sequencing (WES) in a neonatal intensive care unit (NICU).
AIM
To investigate the diagnostic and service impact of chromosomal microarray and whole exome sequencing (WES) in a neonatal intensive care unit (NICU).
METHODS
This was a retrospective medical record review of NICU patients referred for genetics consultation at three time points over a 9-year period at a single centre to determine referral indications, genetic consultation outcomes and time to diagnosis.
RESULTS
The number of NICU patients referred for genetics consultation increased from 44 in 2007 to 95 in 2015. The proportion of NICU patients suspected of having a genetic condition following clinical geneticist assessment remained stable, averaging 5.3% of all admissions. The proportion of patients receiving a confirmed diagnosis rose from 21% in 2007 to 53% in 2015, with a shift from primarily chromosomal abnormalities to a broad range of monogenic disorders, increasingly diagnosed by WES as a first-tier test. The average age at diagnosis in 2015 was 19 days (range 12-38 days) for chromosomal abnormalities and 138 days (range 10-309 days) for monogenic conditions.
CONCLUSIONS
The adoption of new genetic technologies at our centre has increased the proportion of patients receiving a confirmed genetic diagnosis. This study provides important benchmark data to measure further improvements as turn-around times for genomic testing decrease.
Topics: Australia; Female; Genetic Testing; Humans; Intensive Care Units, Neonatal; Male; Microarray Analysis; Retrospective Studies; Exome Sequencing
PubMed: 30756437
DOI: 10.1111/jpc.14398 -
Radiology. Imaging Cancer Mar 2020Lung cancer remains the overwhelmingly greatest cause of cancer death in the United States, accounting for more annual deaths than breast, prostate, and colon cancer... (Review)
Review
Lung cancer remains the overwhelmingly greatest cause of cancer death in the United States, accounting for more annual deaths than breast, prostate, and colon cancer combined. Accumulated evidence since the mid to late 1990s, however, indicates that low-dose CT screening of high-risk patients enables detection of lung cancer at an early stage and can reduce the risk of dying from lung cancer. CT screening is now a recommended clinical service in the United States, subject to guidelines and reimbursement requirements intended to standardize practice and optimize the balance of benefits and risks. In this review, the evidence on the effectiveness of CT screening will be summarized and the current guidelines and standards will be described in the context of knowledge gained from lung cancer screening studies. In addition, an overview of the potential advances that may improve CT screening will be presented, and the need to better understand the performance in clinical practice outside of the research trial setting will be discussed. © RSNA, 2020.
Topics: Early Detection of Cancer; Humans; Lung Neoplasms; Mass Screening; Tomography, X-Ray Computed; United States
PubMed: 32300760
DOI: 10.1148/rycan.2020190058