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Chaigneau M, Bowman M, Grabell J, Conboy M, Johnson A, Thorpe K, Guerin A, Dinchong R, Paterson A, Good D, Mahar A, Callum J, Wheaton L, Leung J, Khalife R, Sholzberg M, Lillicrap D, James PD. Genomic testing for bleeding disorders (GT4BD): protocol for a randomised controlled trial evaluating the introduction of whole genome sequencing early in the diagnostic pathway for patients with inherited bleeding disorders as compared with standard of care. BMJ Open 2025; 15:e102041. [PMID: 40246558 PMCID: PMC12015236 DOI: 10.1136/bmjopen-2025-102041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2025] [Accepted: 03/24/2025] [Indexed: 04/19/2025] Open
Abstract
INTRODUCTION The current diagnostic pathway for patients with a suspected inherited bleeding disorder is long, costly, resource intensive, emotionally draining for patients and often futile, as half of patients will remain without a diagnosis and be labelled 'bleeding disorder of unknown cause'. Advances in understanding the genetic basis of the inherited bleeding disorders, coupled with both increasing infrastructure for genetic/genomic testing and decreasing costs, have increased the feasibility of introducing genomic testing into the clinical diagnostic pathway as a potential solution to improve the care of these patients. Yet, there remain evidence gaps on the optimal integration of genomic analysis into the diagnostic pathway. METHODS AND ANALYSIS Using a multicentre randomised-controlled trial design, we will evaluate an early genomic testing strategy for the diagnosis of newly referred patients with a suspected inherited bleeding disorder. Eligible participants will be randomised to early genomic testing diagnostic pathway (intervention) or standard diagnostic pathway (control) and will be followed for a 12-month period. Patients in the control group who remain undiagnosed at study end will be offered identical early genomic testing to ensure equitable access to the intervention. The study will follow a parallel fixed design with waitlist control group and a 1:1 allocation ratio. The study will be conducted at three tertiary care centres in Ontario, Canada, with a target sample size of 212 participants. Clinical utility will be evaluated via the primary outcome of diagnostic yield, as well as the secondary outcome of time to diagnosis. Additional secondary outcomes will allow for assessment of patient impact via health-related quality of life and patient burden measures, as well as evaluation of economic impact through a cost-effectiveness analysis and budget impact analysis. ETHICS AND DISSEMINATION This investigator-initiated study was approved by the Queen's University Health Sciences and Affiliated Teaching Hospitals Research Ethics Board through Clinical Trials Ontario (CTO-4909). Participant informed consent/assent is required. Findings will be disseminated through academic publications. TRIAL REGISTRATION NUMBER ClinicalTrials.gov, NCT06736158.
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Affiliation(s)
- Megan Chaigneau
- Department of Medicine, Queen's University, Kingston, Ontario, Canada
| | - Mackenzie Bowman
- Department of Medicine, Queen's University, Kingston, Ontario, Canada
| | - Julie Grabell
- Department of Medicine, Queen's University, Kingston, Ontario, Canada
| | | | - Ana Johnson
- Department of Public Health Sciences, Queen's University, Kingston, Ontario, Canada
| | - Kevin Thorpe
- University of Toronto Dalla Lana School of Public Health, Toronto, Ontario, Canada
- The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Andrea Guerin
- Department of Pediatrics, Division of Medical Genetics, Queen's University, Kingston, Ontario, Canada
| | - Rachelle Dinchong
- Department of Pediatrics, Division of Medical Genetics, Kingston Health Sciences Centre, Kingston, Ontario, Canada
| | - Andrew Paterson
- Genetics and Genome Biology, Hospital for Sick Children, Toronto, Ontario, Canada
- Divisions of Epidemiology and Biostatistics, University of Toronto Dalla Lana School of Public Health, Toronto, Ontario, Canada
| | - David Good
- Department of Pathology and Molecular Medicine, Queen's University, Kingston, Ontario, Canada
| | - Alyson Mahar
- School of Nursing, Queen's University, Kingston, Ontario, Canada
| | - Jeannie Callum
- Department of Pathology and Molecular Medicine, Queen's University, Kingston, Ontario, Canada
| | - Laura Wheaton
- Department of Pediatrics, Queen's University, Kingston, Ontario, Canada
| | - Jennifer Leung
- Department of Medicine, Queen's University, Kingston, Ontario, Canada
| | - Roy Khalife
- Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada
- The Ottawa Hospital, Ottawa, Ontario, Canada
| | - Michelle Sholzberg
- Department of Medicine, Laboratory Medicine, and Pathobiology, St. Michael's Hospital Li Ka Shing Knowledge Institute, Toronto, Ontario, Canada
| | - David Lillicrap
- Department of Pathology and Molecular Medicine, Queen's University, Kingston, Ontario, Canada
| | - Paula D James
- Department of Medicine, Queen's University, Kingston, Ontario, Canada
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Arora K, Balwani M, Wakchaure A, Passi GR. Yield of Genetic Testing in Children with Autism Spectrum Disorder - A Single-Center Experience. Ann Indian Acad Neurol 2025; 28:253-256. [PMID: 40117183 PMCID: PMC12049228 DOI: 10.4103/aian.aian_724_24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2024] [Revised: 12/27/2024] [Accepted: 01/11/2025] [Indexed: 03/23/2025] Open
Abstract
Identifying genetic etiologies is an important consideration in the comprehensive management of autism spectrum disorder (ASD). In this study, we aimed to evaluate and compare the diagnostic yield of genetic tests in ASD. This retrospective descriptive study evaluated and compared the diagnostic yield of genetic tests in patients with ASD in a teaching hospital from Central India between 2018 and 2023. Fifty-four patients were tested. Pathogenic/likely pathogenic variants were identified in 13 (24.07%) patients. Yield of whole exome sequencing (WES), 12/27 (44.49%), was more than that of chromosomal microarray (CMA) 1/30 (3.3%) ( P < 0.05). Fragile-X gene mutation was detected in 0/14 patients tested. Patients with motor delay and hand stereotypes were more likely to have pathogenic variants on WES. The most common pathogenic gene identified was the MECP2 gene (5/12, 41.66%). Genetic abnormalities were identified in 24.07% of children with ASD. WES had higher diagnostic yield than CMA.
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Affiliation(s)
- Kriti Arora
- Department of Pediatrics, Mahatma Gandhi Mission’s Medical College and Hospital, Kamothe, Navi Mumbai, Maharashtra, India
| | - Minakshi Balwani
- Department of Pediatrics, Apollo Hospital, Chennai, Tamil Nadu, India
| | - Akash Wakchaure
- Department of Pediatrics, Saisuman Child Neuro Care, Nashik, Maharashtra, India
| | - Gouri R Passi
- Department of Pediatrics, Choithram Hospital and Research Centre, Indore, Madhya Pradesh, India
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Al-Beltagi M, Saeed NK, Bediwy AS, Bediwy EA, Elbeltagi R. Decoding the genetic landscape of autism: A comprehensive review. World J Clin Pediatr 2024; 13:98468. [PMID: 39350903 PMCID: PMC11438927 DOI: 10.5409/wjcp.v13.i3.98468] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2024] [Revised: 07/29/2024] [Accepted: 08/01/2024] [Indexed: 08/30/2024] Open
Abstract
BACKGROUND Autism spectrum disorder (ASD) is a complex neurodevelopmental condition characterized by heterogeneous symptoms and genetic underpinnings. Recent advancements in genetic and epigenetic research have provided insights into the intricate mechanisms contributing to ASD, influencing both diagnosis and therapeutic strategies. AIM To explore the genetic architecture of ASD, elucidate mechanistic insights into genetic mutations, and examine gene-environment interactions. METHODS A comprehensive systematic review was conducted, integrating findings from studies on genetic variations, epigenetic mechanisms (such as DNA methylation and histone modifications), and emerging technologies [including Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-Cas9 and single-cell RNA sequencing]. Relevant articles were identified through systematic searches of databases such as PubMed and Google Scholar. RESULTS Genetic studies have identified numerous risk genes and mutations associated with ASD, yet many cases remain unexplained by known factors, suggesting undiscovered genetic components. Mechanistic insights into how these genetic mutations impact neural development and brain connectivity are still evolving. Epigenetic modifications, particularly DNA methylation and non-coding RNAs, also play significant roles in ASD pathogenesis. Emerging technologies like CRISPR-Cas9 and advanced bioinformatics are advancing our understanding by enabling precise genetic editing and analysis of complex genomic data. CONCLUSION Continued research into the genetic and epigenetic underpinnings of ASD is crucial for developing personalized and effective treatments. Collaborative efforts integrating multidisciplinary expertise and international collaborations are essential to address the complexity of ASD and translate genetic discoveries into clinical practice. Addressing unresolved questions and ethical considerations surrounding genetic research will pave the way for improved diagnostic tools and targeted therapies, ultimately enhancing outcomes for individuals affected by ASD.
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Affiliation(s)
- Mohammed Al-Beltagi
- Department of Pediatric, Faculty of Medicine, Tanta University, Alghrabia, Tanta 31511, Egypt
- Department of Pediatric, University Medical Center, King Abdulla Medical City, Arabian Gulf University, Manama 26671, Bahrain
| | - Nermin Kamal Saeed
- Medical Microbiology Section, Department of Pathology, Salmaniya Medical Complex, Ministry of Health, Kingdom of Bahrain, Manama 12, Bahrain
- Medical Microbiology Section, Department of Pathology, Irish Royal College of Surgeon, Muharraq, Busaiteen 15503, Bahrain
| | - Adel Salah Bediwy
- Department of Pulmonology, Faculty of Medicine, Tanta University, Alghrabia, Tanta 31527, Egypt
- Department of Pulmonology, University Medical Center, King Abdulla Medical City, Arabian Gulf University, Manama 26671, Bahrain
| | - Eman A Bediwy
- Internal Medicine, Faculty of Medicine, Tanta University, Algharbia, Tanta 31527, Egypt
| | - Reem Elbeltagi
- Department of Medicine, The Royal College of Surgeons in Ireland-Bahrain, Muharraq, Busiateen 15503, Bahrain
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Tsiplova K, Ungar WJ. Why it is so challenging to perform economic evaluations of interventions in autism and what to do about it. Autism Res 2023; 16:2061-2070. [PMID: 37606004 DOI: 10.1002/aur.3014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Accepted: 07/29/2023] [Indexed: 08/23/2023]
Abstract
Economic evaluation is used to determine the optimal provision of services and programs under budget constraints and to inform public and private payer funding decisions. To maximize value-for-money in the design and delivery of programs and services for persons with autism spectrum disorder (ASD), it's essential to generate high-quality economic evidence to inform budget allocation. There is a paucity however, of economic evaluations of interventions for ASD. This is due in part to challenges in conducting economic evaluations in this population and the lack of guidance on suitable approaches. These challenges are related to the inherent heterogeneity of the autistic population; establishing short- and long-term effectiveness; measurement of costs and the availability of valid instruments for collecting economic data; the appropriateness of outcomes for use in economic evaluation; and achieving statistical power. This commentary addresses a lack of awareness and needed guidance on these issues by discussing the challenges and providing recommendations for how economic evaluations in ASD could be improved to generate high-quality evidence for program funding decision-making.
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Affiliation(s)
- Kate Tsiplova
- Program of Child Health Evaluative Sciences, The Hospital for Sick Children Research Institute, Toronto, Canada
| | - Wendy J Ungar
- Program of Child Health Evaluative Sciences, The Hospital for Sick Children Research Institute, Toronto, Canada
- Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Canada
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Ungar WJ, Hayeems RZ, Marshall CR, Gillespie MK, Szuto A, Chisholm C, James Stavropoulos D, Huang L, Jarinova O, Wu V, Tsiplova K, Lau L, Lee W, Venkataramanan V, Sawyer S, Mendoza-Londono R, Somerville MJ, Boycott KM. Protocol for a Prospective, Observational Cost-effectiveness Analysis of Returning Secondary Findings of Genome Sequencing for Unexplained Suspected Genetic Conditions. Clin Ther 2023; 45:702-709. [PMID: 37453830 DOI: 10.1016/j.clinthera.2023.06.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Revised: 05/05/2023] [Accepted: 06/02/2023] [Indexed: 07/18/2023]
Abstract
PURPOSE Although costly, genome-wide sequencing (GWS) detects an extensive range of variants, enhancing our ability to diagnose and assess risk for an increasing number of diseases. In addition to detecting variants related to the indication for testing, GWS can detect secondary variants in BRCA1, BRCA2, and other genes for which early intervention may improve health. As the list of secondary findings grows, there is increased demand for surveillance and management by multiple specialists, adding pressure to constrained health care budgets. Secondary finding testing is actively debated because some consider it opportunistic screening for future health risks that may not manifest. Given the economic implications of secondary finding testing and follow-up and its unproven clinical utility, the objective is to assess the incremental cost-effectiveness of secondary finding ascertainment per case detected and per unit of improved clinical utility in families of children with unexplained suspected genetic conditions undergoing clinical GWS. METHODS Those undergoing trio genome or exome sequencing are eligible for the study. Positive secondary finding index cases will be matched to negative controls (1:2) based on age group, primary result(s) type, and clinical indication. During the 2-year study, 71 cases and 142 matched controls are expected. Health service use will be collected in patients and 1 adult family member every 6 months. The per-child and per-dyad total cost will be determined by multiplying use of each resource by a corresponding unit price and summing all cost items. Costs will be estimated from the public and societal payer perspectives. The mean cost per child and per dyad for secondary finding-positive and secondary finding-negative groups will be compared statistically. If important demographic differences are observed between groups, ordinary least-squares regression, log transformation, or other nonparametric technique will be used to compare adjusted mean costs. The ratio of the difference in mean cost to the secondary finding yield will be used to estimate incremental cost-effectiveness. In secondary analyses, effectiveness will be estimated using the number of clinical management changes due to secondary findings or the Clinician-Reported Genetic Testing Utility Index (C-GUIDE) score, a validated measure of clinical utility. Sensitivity analysis will be undertaken to assess the robustness of the findings to variation in key parameters. IMPLICATIONS This study generates key evidence to inform clinical practice and funding allocation related to secondary finding testing. The inclusion of family members and a new measure of clinical utility represent important advancements in economic evaluation in genomics.
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Affiliation(s)
- Wendy J Ungar
- Program in Child Health Evaluative Sciences, Hospital for Sick Children Research Institute, Toronto, Ontario, Canada; Institute for Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada.
| | - Robin Z Hayeems
- Program in Child Health Evaluative Sciences, Hospital for Sick Children Research Institute, Toronto, Ontario, Canada; Institute for Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada
| | - Christian R Marshall
- Genome Diagnostics, Department of Paediatric Laboratory Medicine, Hospital for Sick Children, Toronto, Ontario, Canada
| | - Meredith K Gillespie
- Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada
| | - Anna Szuto
- Division of Clinical and Metabolic Genetics, Hospital for Sick Children, Toronto, Ontario, Canada
| | - Caitlin Chisholm
- Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada
| | - D James Stavropoulos
- Genome Diagnostics, Department of Paediatric Laboratory Medicine, Hospital for Sick Children, Toronto, Ontario, Canada
| | - Lijia Huang
- Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada
| | - Olga Jarinova
- Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada; Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada
| | - Vercancy Wu
- Program in Child Health Evaluative Sciences, Hospital for Sick Children Research Institute, Toronto, Ontario, Canada
| | - Kate Tsiplova
- Program in Child Health Evaluative Sciences, Hospital for Sick Children Research Institute, Toronto, Ontario, Canada
| | - Lynnette Lau
- Genome Diagnostics, Department of Paediatric Laboratory Medicine, Hospital for Sick Children, Toronto, Ontario, Canada
| | - Whiwon Lee
- Institute for Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada; Division of Clinical and Metabolic Genetics, Hospital for Sick Children, Toronto, Ontario, Canada
| | - Viji Venkataramanan
- Program in Child Health Evaluative Sciences, Hospital for Sick Children Research Institute, Toronto, Ontario, Canada
| | - Sarah Sawyer
- Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada
| | - Roberto Mendoza-Londono
- Division of Clinical and Metabolic Genetics, Hospital for Sick Children, Toronto, Ontario, Canada
| | - Martin J Somerville
- Genome Diagnostics, Department of Paediatric Laboratory Medicine, Hospital for Sick Children, Toronto, Ontario, Canada
| | - Kym M Boycott
- Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada; Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada
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Carter MT, Srour M, Au PYB, Buhas D, Dyack S, Eaton A, Inbar-Feigenberg M, Howley H, Kawamura A, Lewis SME, McCready E, Nelson TN, Vallance H. Genetic and metabolic investigations for neurodevelopmental disorders: position statement of the Canadian College of Medical Geneticists (CCMG). J Med Genet 2023; 60:523-532. [PMID: 36822643 DOI: 10.1136/jmg-2022-108962] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Accepted: 01/27/2023] [Indexed: 02/25/2023]
Abstract
PURPOSE AND SCOPE The aim of this position statement is to provide recommendations for clinicians regarding the use of genetic and metabolic investigations for patients with neurodevelopmental disorders (NDDs), specifically, patients with global developmental delay (GDD), intellectual disability (ID) and/or autism spectrum disorder (ASD). This document also provides guidance for primary care and non-genetics specialists caring for these patients while awaiting consultation with a clinical geneticist or metabolic specialist. METHODS OF STATEMENT DEVELOPMENT A multidisciplinary group reviewed existing literature and guidelines on the use of genetic and metabolic investigations for the diagnosis of NDDs and synthesised the evidence to make recommendations relevant to the Canadian context. The statement was circulated for comment to the Canadian College of Medical Geneticists (CCMG) membership-at-large and to the Canadian Pediatric Society (Mental Health and Developmental Disabilities Committee); following incorporation of feedback, it was approved by the CCMG Board of Directors on 1 September 2022. RESULTS AND CONCLUSIONS Chromosomal microarray is recommended as a first-tier test for patients with GDD, ID or ASD. Fragile X testing should also be done as a first-tier test when there are suggestive clinical features or family history. Metabolic investigations should be done if there are clinical features suggestive of an inherited metabolic disease, while the patient awaits consultation with a metabolic physician. Exome sequencing or a comprehensive gene panel is recommended as a second-tier test for patients with GDD or ID. Genetic testing is not recommended for patients with NDDs in the absence of GDD, ID or ASD, unless accompanied by clinical features suggestive of a syndromic aetiology or inherited metabolic disease.
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Affiliation(s)
| | - Myriam Srour
- Division of Neurology, McGill University Health Centre, Montreal, Québec, Canada
- Department of Pediatrics, McGill University, Montréal, QC, Canada
| | - Ping-Yee Billie Au
- Department of Medical Genetics, Alberta Children's Hospital, Calgary, Alberta, Canada
| | - Daniela Buhas
- Division of Medical Genetics, Department of Specialized Medicine, McGill University Health Centre, McGill University, Montreal, Québec, Canada
- Department of Human Genetics, McGill University, Montreal, QC, Canada
| | - Sarah Dyack
- Division of Medical Genetics, IWK Health Centre, Halifax, Nova Scotia, Canada
- Department of Pediatrics, Dalhousie University, Halifax, NS, Canada
| | - Alison Eaton
- Department of Medical Genetics, Stollery Children's Hospital, Edmonton, Alberta, Canada
- Department of Medical Genetics, University of Alberta, Edmonton, AB, Canada
| | - Michal Inbar-Feigenberg
- Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Heather Howley
- Office of Research Services, CHEO Research Institute, Ottawa, Ontario, Canada
| | - Anne Kawamura
- Division of Developmental Pediatrics, Holland Bloorview Kids Rehabilitation Hospital, Toronto, Ontario, Canada
- Department of Paediatrics, University of Toronto, Toronto, ON, Canada
- Mental Health and Developmental Disability Committee, Canadian Pediatric Society, Ottawa, ON, Canada
- Canadian Paediatric Society, Toronto, Ontario, Canada
| | - Suzanne M E Lewis
- Department of Medical Genetics, BC Children's and Women's Hospital, Vancouver, British Columbia, Canada
| | - Elizabeth McCready
- Department of Pathology and Molecular Medicine, McMaster University, McMaster University, Hamilton, ON, Canada, Hamilton, Ontario, Canada
- Hamilton Regional Laboratory Medicine Program, Hamilton Health Sciences Centre, Hamilton, ON, Canada
| | - Tanya N Nelson
- Department of Pathology and Laboratory Medicine, BC Children's Hospital, University of British Columbia, Vancouver, British Columbia, Canada
| | - Hilary Vallance
- Department of Pathology and Laboratory Medicine, BC Children's Hospital, University of British Columbia, Vancouver, British Columbia, Canada
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Rezapour A, Souresrafil A, Barzegar M, Sheikhy-Chaman M, Tatarpour P. Economic evaluation of next-generation sequencing techniques in diagnosis of genetic disorders: A systematic review. Clin Genet 2023; 103:513-528. [PMID: 36808726 DOI: 10.1111/cge.14313] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Revised: 02/12/2023] [Accepted: 02/14/2023] [Indexed: 02/23/2023]
Abstract
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.
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Affiliation(s)
- Aziz Rezapour
- Health Management and Economics Research Center, Health Management Research Institute, Iran University of Medical Sciences, Tehran, Iran
| | - Aghdas Souresrafil
- Department of Health Services and Health Promotion, School of Health, Occupational Environment Research Center, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Mohammad Barzegar
- Department of English Language, School of Health Management and Information Sciences, Iran University of Medical Sciences, Tehran, Iran
| | - Mohammadreza Sheikhy-Chaman
- Department of Health Economics, School of Health Management and Information Sciences, Iran University of Medical Sciences, Tehran, Iran
| | - Parvin Tatarpour
- School of Health Management and Information Sciences, Iran University of Medical Sciences, Tehran, Iran
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Abbott M, McKenzie L, Moran BVG, Heidenreich S, Hernández R, Hocking-Mennie L, Clark C, Gomes J, Lampe A, Baty D, McGowan R, Miedzybrodzka Z, Ryan M. Continuing the sequence? Towards an economic evaluation of whole genome sequencing for the diagnosis of rare diseases in Scotland. J Community Genet 2022; 13:487-501. [PMID: 34415556 PMCID: PMC9530076 DOI: 10.1007/s12687-021-00541-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Accepted: 07/15/2021] [Indexed: 11/21/2022] Open
Abstract
Novel developments in genomic medicine may reduce the length of the diagnostic odyssey for patients with rare diseases. Health providers must thus decide whether to offer genome sequencing for the diagnosis of rare conditions in a routine clinical setting. We estimated the costs of singleton standard genetic testing and trio-based whole genome sequencing (WGS), in the context of the Scottish Genomes Partnership (SGP) study. We also explored what users value about genomic sequencing. Insights from the costing and value assessments will inform a subsequent economic evaluation of genomic medicine in Scotland. An average cost of £1,841 per singleton was estimated for the standard genetic testing pathway, with significant variability between phenotypes. WGS cost £6625 per family trio, but this estimate reflects the use of WGS during the SGP project and large cost savings may be realised if sequencing was scaled up. Patients and families valued (i) the chance of receiving a diagnosis (and the peace of mind and closure that brings); (ii) the information provided by WGS (including implications for family planning and secondary findings); and (iii) contributions to future research. Our costings will be updated to address limitations of the current study for incorporation in budget impact modelling and cost-effectiveness analysis (cost per diagnostic yield). Our insights into the benefits of WGS will guide the development of a discrete choice experiment valuation study. This will inform a user-perspective cost-benefit analysis of genome-wide sequencing, accounting for the broader non-health outcomes. Taken together, our research will inform the long-term strategic development of NHS Scotland clinical genetics testing services, and will be of benefit to others seeking to undertake similar evaluations in different contexts.
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Affiliation(s)
- Michael Abbott
- Health Economics Research Unit, University of Aberdeen, Aberdeen, UK.
| | - Lynda McKenzie
- Health Economics Research Unit, University of Aberdeen, Aberdeen, UK
| | | | - Sebastian Heidenreich
- Health Economics Research Unit, University of Aberdeen, Aberdeen, UK
- Evidera Inc., London, UK
| | - Rodolfo Hernández
- Health Economics Research Unit, University of Aberdeen, Aberdeen, UK
| | | | - Caroline Clark
- Department of Medical Genetics, University of Aberdeen, Aberdeen, UK
- NHS Grampian Regional Genetics Service, Aberdeen Royal Infirmary, Aberdeen, UK
| | - Joana Gomes
- NHS Grampian Regional Genetics Service, Aberdeen Royal Infirmary, Aberdeen, UK
| | - Anne Lampe
- South East Scotland Clinical Genetics Service, Western General Hospital, Edinburgh, UK
| | - David Baty
- NHS Tayside Regional Genetics Service, Ninewells Hospital, Dundee, UK
| | - Ruth McGowan
- South East Scotland Clinical Genetics Service, Queen Elizabeth University Hospital, Glasgow, UK
| | | | - Mandy Ryan
- Health Economics Research Unit, University of Aberdeen, Aberdeen, UK
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Recent Developments in Autism Genetic Research: A Scientometric Review from 2018 to 2022. Genes (Basel) 2022; 13:genes13091646. [PMID: 36140813 PMCID: PMC9498399 DOI: 10.3390/genes13091646] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Revised: 09/12/2022] [Accepted: 09/12/2022] [Indexed: 12/13/2022] Open
Abstract
Genetic research in Autism Spectrum Disorder (ASD) has progressed tremendously in recent decades. Dozens of genetic loci and hundreds of alterations in the genetic sequence, expression, epigenetic transformation, and interactions with other physiological and environmental systems have been found to increase the likelihood of developing ASD. There is therefore a need to represent this wide-ranging yet voluminous body of literature in a systematic manner so that this information can be synthesised and understood at a macro level. Therefore, this study made use of scientometric methods, particularly document co-citation analysis (DCA), to systematically review literature on ASD genetic research from 2018 to 2022. A total of 14,818 articles were extracted from Scopus and analyzed with CiteSpace. An optimized DCA analysis revealed that recent literature on ASD genetic research can be broadly organised into 12 major clusters representing various sub-topics. These clusters are briefly described in the manuscript and potential applications of this study are discussed.
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Jegathisawaran J, Tsiplova K, Hayeems RZ, Marshall CR, Stavropoulos DJ, Pereira SL, Thiruvahindrapuram B, Liston E, Reuter MS, Manshaei R, Cohn I, Jobling R, Kim RH, Mital S, Ungar WJ. Trio genome sequencing for developmental delay and pediatric heart conditions: A comparative microcost analysis. Genet Med 2022; 24:1027-1036. [PMID: 35219592 DOI: 10.1016/j.gim.2022.01.020] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Revised: 01/24/2022] [Accepted: 01/25/2022] [Indexed: 11/29/2022] Open
Abstract
PURPOSE Genome sequencing (GS) can aid clinical management of multiple pediatric conditions. Insurers require accurate cost information to inform funding and implementation decisions. The objective was to compare the laboratory workflows and microcosts of trio GS testing in children with developmental delay (DD) and in children with cardiac conditions. METHODS Cost items related to each step in trio GS (child and 2 parents) for both populations were identified and measured. Program costs over 5 years were estimated. Probabilistic and deterministic analyses were conducted. RESULTS The mean cost per trio GS was CAD$6634.11 (95% CI = 6352.29-6913.40) for DD and CAD$8053.10 (95% CI = 7699.30-8558.10) for cardiac conditions. The 5-year program cost was CAD$28.11 million (95% CI = 26.91-29.29) for DD and CAD$5.63 million (95% CI = 5.38-5.98) for cardiac conditions. Supplies constituted the largest cost component for both populations. The higher cost per sample for the population with cardiac conditions was due to the inclusion of pharmacogenomics, higher bioinformatics labor costs, and a more labor intensive case review. CONCLUSION This analysis indicated important variation in trio GS workflow and costs between pediatric populations in a single institution. Enhanced understanding of the clinical utility and costs of GS can inform harmonization and implementation decision-making.
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Affiliation(s)
- Jathishinie Jegathisawaran
- Program of Child Health Evaluative Sciences, The Hospital for Sick Children Research Institute, Toronto, Ontario, Canada
| | - Kate Tsiplova
- Program of Child Health Evaluative Sciences, The Hospital for Sick Children Research Institute, Toronto, Ontario, Canada
| | - Robin Z Hayeems
- Program of Child Health Evaluative Sciences, The Hospital for Sick Children Research Institute, Toronto, Ontario, Canada; Institute of Health Policy, Management and Evaluation, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada
| | - Christian R Marshall
- Department of Pediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
| | - Dimitri J Stavropoulos
- Department of Pediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
| | - Sergio L Pereira
- The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada
| | | | - Eriskay Liston
- Cardiac Genome Clinic, Ted Rogers Centre for Heart Research, Toronto, Ontario, Canada
| | - Miriam S Reuter
- Cardiac Genome Clinic, Ted Rogers Centre for Heart Research, Toronto, Ontario, Canada
| | - Roozbeh Manshaei
- The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Iris Cohn
- Clinical Pharmacology and Toxicology & Translational Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Rebekah Jobling
- Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Raymond H Kim
- Cardiac Genome Clinic, Ted Rogers Centre for Heart Research, Toronto, Ontario, Canada; Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, Ontario, Canada; Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Sinai Health System, Toronto, Ontario, Canada; Department of Medicine, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Seema Mital
- Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Sinai Health System, Toronto, Ontario, Canada; Division of Cardiology, Department of Pediatrics, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Wendy J Ungar
- Program of Child Health Evaluative Sciences, The Hospital for Sick Children Research Institute, Toronto, Ontario, Canada; Institute of Health Policy, Management and Evaluation, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada.
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11
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Lejeune C, Robert-Viard C, Meunier-Beillard N, Borel MA, Gourvès L, Staraci S, Soilly AL, Guillemin F, Seror V, Achit H, Bouctot M, Asensio ML, Briffaut AS, Delmas C, Bruel AL, Benoit A, Simon A, Gerard B, Hadj Abdallah H, Lyonnet S, Faivre L, Thauvin-Robinet C, Odent S, Heron D, Sanlaville D, Frebourg T, Muller J, Duffourd Y, Boland A, Deleuze JF, Espérou H, Binquet C, Dollfus H. The Economic, Medical and Psychosocial Consequences of Whole Genome Sequencing for the Genetic Diagnosis of Patients With Intellectual Disability: The DEFIDIAG Study Protocol. Front Genet 2022; 13:852472. [PMID: 35444683 PMCID: PMC9013934 DOI: 10.3389/fgene.2022.852472] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Accepted: 03/08/2022] [Indexed: 11/13/2022] Open
Abstract
Introduction: Like other countries, France has invested in a national medical genomics program. Among the four pilot research studies, the DEFIDIAG project focuses on the use of whole genome sequencing (WGS) for patients with intellectual disability (ID), a neurodevelopmental condition affecting 1–3% of the general population but due to a plethora of genes. However, the access to genomic analyses has many potential individual and societal issues in addition to the technical challenges. In order to help decision-makers optimally introduce genomic testing in France, there is a need to identify the socio-economic obstacles and leverages associated with the implementation of WGS. Methods and Analysis: This humanities and social sciences analysis is part of the DEFIDIAG study. The main goal of DEFIDIAG is to compare the percentage of causal genetic diagnoses obtained by trio WGS (including the patient and both parents) (WGST) to the percentage obtained using the minimal reference strategy currently used in France (Fragile-X testing, chromosomal microarray analysis, and gene panel strategy including 44 ID genes) for patients with ID having their first clinical genetics consultation. Additionally, four complementary studies will be conducted. First, a cost-effectiveness analysis will be undertaken in a subsample of 196 patients consulting for the first time for a genetic evaluation; in a blinded fashion, WGST and solo (index case, only) genomic analysis (WGSS) will be compared to the reference strategy. In addition, quantitative studies will be conducted: the first will estimate the cost of the diagnostic odyssey that could potentially be avoidable with first-line WGST in all patients previously investigated in the DEFIDIAG study; the second will estimate changes in follow-up of the patients in the year after the return of the WGST analysis compared to the period before inclusion. Finally, through semi-directive interviews, we will explore the expectations of 60 parents regarding genomic analyses. Discussion: Humanities and social sciences studies can be used to demonstrate the efficiency of WGS and assess the value that families associate with sequencing. These studies are thus expected to clarify trade-offs and to help optimize the implementation of genomic sequencing in France. Ethics Statement: The protocol was approved by the Ethics Committee Sud Méditerranée I (June 2019)—identification number: 2018-A00680-55 and the French data privacy commission (CNIL, authorization 919361). Clinical Trial Registration: (ClinicalTrials.gov), identifier (NCT04154891).
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Affiliation(s)
- Catherine Lejeune
- CHU Dijon Bourgogne, Inserm, Université de Bourgogne, CIC 1432, Module Épidémiologie Clinique, Dijon, France.,Inserm, Université Bourgogne-Franche-Comté, UMR 1231, EPICAD, Dijon, France
| | - Charley Robert-Viard
- CHU Dijon Bourgogne, Inserm, Université de Bourgogne, CIC 1432, Module Épidémiologie Clinique, Dijon, France.,CHU Dijon Bourgogne, Délégation à la Recherche Clinique et à l'Innovation, USMR, Dijon, France
| | - Nicolas Meunier-Beillard
- CHU Dijon Bourgogne, Inserm, Université de Bourgogne, CIC 1432, Module Épidémiologie Clinique, Dijon, France.,CHU Dijon Bourgogne, Délégation à la Recherche Clinique et à l'Innovation, USMR, Dijon, France
| | | | - Léna Gourvès
- CHU Dijon Bourgogne, Direction de la Recherche Clinique, Dijon, France
| | - Stéphanie Staraci
- Unité Fonctionnelle de Génétique Médicale et Centre de Référence « Déficiences Intellectuelles de Causes Rares », APHP Sorbonne Université, Groupe Hospitalier Pitié-Salpêtrière et Hôpital Trousseau, Paris, France
| | - Anne-Laure Soilly
- CHU Dijon Bourgogne, Délégation à la Recherche Clinique et à l'Innovation, USMR, Dijon, France
| | - Francis Guillemin
- CIC1433-Epidémiologie Clinique, Centre Hospitalier Régional et Universitaire, Inserm, Université de Lorraine, Nancy, France
| | - Valerie Seror
- Aix Marseille Univ, IRD, APHM, SSA, VITROME, IHU-Méditerranée Infection, Marseille, France
| | - Hamza Achit
- CIC1433-Epidémiologie Clinique, Centre Hospitalier Régional et Universitaire, Inserm, Université de Lorraine, Nancy, France
| | - Marion Bouctot
- CHU Dijon Bourgogne, Inserm, Université de Bourgogne, CIC 1432, Module Épidémiologie Clinique, Dijon, France
| | - Marie-Laure Asensio
- CHU Dijon Bourgogne, Inserm, Université de Bourgogne, CIC 1432, Module Épidémiologie Clinique, Dijon, France
| | - Anne-Sophie Briffaut
- CHU Dijon Bourgogne, Inserm, Université de Bourgogne, CIC 1432, Module Épidémiologie Clinique, Dijon, France
| | | | - Ange-Line Bruel
- CHU Dijon Bourgogne, Fédération Hospitalo-Universitaire Médecine Translationnelle et Anomalies du Dévelopment (TRANSLAD), Inserm, Université Bourgogne-Franche-Comté, UMR1231, Équipe GAD, Dijon, France
| | - Alexia Benoit
- Laboratoires de Diagnostic Génétique, Institut de Génétique Médicale d'Alsace (IGMA), Hôpitaux Universitaires de Strasbourg, Strasbourg, France
| | - Alban Simon
- Inserm UMRS_1112, Institut de Génétique Médicale d'Alsace, Université de Strasbourg, France et Service de Génétique Médicale Hôpitaux Universitaires de Strasbourg, Strasbourg, France
| | - Bénédicte Gerard
- Laboratoires de Diagnostic Génétique, Institut de Génétique Médicale d'Alsace (IGMA), Hôpitaux Universitaires de Strasbourg, Strasbourg, France
| | - Hamza Hadj Abdallah
- Inserm, IHU Imagine-Institut des Maladies Génétiques, Université Paris Cité, Paris, France.,Fédération de Génétique et Médecine Génomique, Hôpital Necker-Enfants Malades, GHU APHP. Centre-Université Paris Cité, Paris, France
| | - Stanislas Lyonnet
- Inserm, IHU Imagine-Institut des Maladies Génétiques, Université Paris Cité, Paris, France.,Fédération de Génétique et Médecine Génomique, Hôpital Necker-Enfants Malades, GHU APHP. Centre-Université Paris Cité, Paris, France
| | - Laurence Faivre
- CHU Dijon Bourgogne, Fédération Hospitalo-Universitaire Médecine Translationnelle et Anomalies du Dévelopment (TRANSLAD), Inserm, Université Bourgogne-Franche-Comté, UMR1231, Équipe GAD, Dijon, France
| | - Christel Thauvin-Robinet
- CHU Dijon Bourgogne, Fédération Hospitalo-Universitaire Médecine Translationnelle et Anomalies du Dévelopment (TRANSLAD), Inserm, Université Bourgogne-Franche-Comté, UMR1231, Équipe GAD, Dijon, France
| | - Sylvie Odent
- Service de Génétique Clinique, Centre de Référence Anomalies du Dévelopment CLAD- Ouest, CNRS, IGDR UMR6290 (Institut de Génétique et Dévelopment de Rennes), ERN ITHACA, Université de Rennes, Rennes, France
| | - Delphine Heron
- Unité Fonctionnelle de Génétique Médicale et Centre de Référence « Déficiences Intellectuelles de Causes Rares », APHP Sorbonne Université, Groupe Hospitalier Pitié-Salpêtrière et Hôpital Trousseau, Paris, France
| | - Damien Sanlaville
- Hospices Civils de Lyon, GHE, Service de Génétique, Université Claude Bernard Lyon 1, Lyon, France
| | - Thierry Frebourg
- CHU de Rouen, Service de Génétique, Rouen, France.,Inserm, UMR1245, Centre de Génomique et de Médecine Personnalisée, Université de Normandie, Rouen, France
| | - Jean Muller
- Laboratoires de Diagnostic Génétique, Institut de Génétique Médicale d'Alsace (IGMA), Hôpitaux Universitaires de Strasbourg, Strasbourg, France.,Inserm UMRS_1112, Institut de Génétique Médicale d'Alsace, Université de Strasbourg, France et Service de Génétique Médicale Hôpitaux Universitaires de Strasbourg, Strasbourg, France.,Unité Fonctionnelle de Bioinformatique Médicale Appliquée au Diagnostic (UF7363), Hôpitaux Universitaires de Strasbourg, Strasbourg, France
| | - Yannis Duffourd
- CHU Dijon Bourgogne, Fédération Hospitalo-Universitaire Médecine Translationnelle et Anomalies du Dévelopment (TRANSLAD), Inserm, Université Bourgogne-Franche-Comté, UMR1231, Équipe GAD, Dijon, France
| | - Anne Boland
- CEA, Centre National de Recherche en Génomique Humaine (CNRGH), Université Paris-Saclay, Evry, France
| | - Jean-François Deleuze
- CEA, Centre National de Recherche en Génomique Humaine (CNRGH), Université Paris-Saclay, Evry, France
| | | | - Christine Binquet
- CHU Dijon Bourgogne, Inserm, Université de Bourgogne, CIC 1432, Module Épidémiologie Clinique, Dijon, France
| | - Hélène Dollfus
- Inserm UMRS_1112, Institut de Génétique Médicale d'Alsace, Université de Strasbourg, France et Service de Génétique Médicale Hôpitaux Universitaires de Strasbourg, Strasbourg, France
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12
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Hayeems RZ, Marshall CR, Gillespie MK, Szuto A, Chisholm C, Stavropoulos DJ, Venkataramanan V, Tsiplova K, Sawyer S, Price EM, Lau L, Khan R, Lee W, Huang L, Jarinova O, Ungar WJ, Mendoza-Londono R, Somerville MJ, Boycott KM. Comparing genome sequencing technologies to improve rare disease diagnostics: a protocol for the evaluation of a pilot project, Genome-wide Sequencing Ontario. CMAJ Open 2022; 10:E460-E465. [PMID: 35609929 PMCID: PMC9259466 DOI: 10.9778/cmajo.20210272] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
BACKGROUND Genome-wide sequencing has emerged as a promising strategy for the timely diagnosis of rare diseases, but it is not yet available as a clinical test performed in Canadian diagnostic laboratories. We describe the protocol for evaluating a 2-year pilot project, Genome-wide Sequencing Ontario, to offer high-quality clinical genome-wide sequencing in Ontario, Canada. METHODS The Genome-wide Sequencing Ontario protocol was codesigned by the Ontario Ministry of Health, the Hospital for Sick Children in Toronto and the Children's Hospital of Eastern Ontario in Ottawa. Enrolment of a prospective cohort of patients began on Apr. 1, 2021. Eligible cases with blood samples available for the index case and both parents (i.e., trios) are randomized to receive exome sequencing or genome sequencing. We will collect patient-level data and ascertain costs associated with the laboratory workflow for exome sequencing and genome sequencing. We will compare point estimates for the diagnostic utility and timeliness of exome sequencing and genome sequencing, and we will determine an incremental cost-effectiveness ratio (expressed as the incremental cost of genome sequencing versus exome sequencing per additional patient with a causal variant detected). INTERPRETATION Findings from this work will provide robust evidence for the diagnostic utility, cost-effectiveness and timeliness of exome sequencing and genome sequencing, and will be disseminated via academic publications and policy briefs. Findings will inform provincial and cross-provincial policy related to the long-term organization, delivery and reimbursement of clinical-grade genome diagnostics for rare disease.
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Affiliation(s)
- Robin Z Hayeems
- Program in Child Health Evaluative Sciences (Hayeems, Venkataramanan, Tsiplova, Lee, Ungar), Hospital for Sick Children Research Institute; Department of Paediatric Laboratory Medicine (Marshall, Stavropoulos, Lau, Somerville), Hospital for Sick Children, Toronto, Ont.; Department of Laboratory Medicine and Pathobiology, (Marshall, Stavropoulos, Somerville), University of Toronto, Toronto, Ont.; Children's Hospital of Eastern Ontario Research Institute (Gillespie, Price, Boycott), University of Ottawa, Ottawa, Ont.; Division of Clinical and Metabolic Genetics (Szuto, Khan, Lee, Mendoza-Londono), Hospital for Sick Children, Toronto, Ont.; Department of Genetics (Chisholm, Sawyer, Huang, Jarinova, Boycott), Children's Hospital of Eastern Ontario, Ottawa, Ont.
| | - Christian R Marshall
- Program in Child Health Evaluative Sciences (Hayeems, Venkataramanan, Tsiplova, Lee, Ungar), Hospital for Sick Children Research Institute; Department of Paediatric Laboratory Medicine (Marshall, Stavropoulos, Lau, Somerville), Hospital for Sick Children, Toronto, Ont.; Department of Laboratory Medicine and Pathobiology, (Marshall, Stavropoulos, Somerville), University of Toronto, Toronto, Ont.; Children's Hospital of Eastern Ontario Research Institute (Gillespie, Price, Boycott), University of Ottawa, Ottawa, Ont.; Division of Clinical and Metabolic Genetics (Szuto, Khan, Lee, Mendoza-Londono), Hospital for Sick Children, Toronto, Ont.; Department of Genetics (Chisholm, Sawyer, Huang, Jarinova, Boycott), Children's Hospital of Eastern Ontario, Ottawa, Ont
| | - Meredith K Gillespie
- Program in Child Health Evaluative Sciences (Hayeems, Venkataramanan, Tsiplova, Lee, Ungar), Hospital for Sick Children Research Institute; Department of Paediatric Laboratory Medicine (Marshall, Stavropoulos, Lau, Somerville), Hospital for Sick Children, Toronto, Ont.; Department of Laboratory Medicine and Pathobiology, (Marshall, Stavropoulos, Somerville), University of Toronto, Toronto, Ont.; Children's Hospital of Eastern Ontario Research Institute (Gillespie, Price, Boycott), University of Ottawa, Ottawa, Ont.; Division of Clinical and Metabolic Genetics (Szuto, Khan, Lee, Mendoza-Londono), Hospital for Sick Children, Toronto, Ont.; Department of Genetics (Chisholm, Sawyer, Huang, Jarinova, Boycott), Children's Hospital of Eastern Ontario, Ottawa, Ont
| | - Anna Szuto
- Program in Child Health Evaluative Sciences (Hayeems, Venkataramanan, Tsiplova, Lee, Ungar), Hospital for Sick Children Research Institute; Department of Paediatric Laboratory Medicine (Marshall, Stavropoulos, Lau, Somerville), Hospital for Sick Children, Toronto, Ont.; Department of Laboratory Medicine and Pathobiology, (Marshall, Stavropoulos, Somerville), University of Toronto, Toronto, Ont.; Children's Hospital of Eastern Ontario Research Institute (Gillespie, Price, Boycott), University of Ottawa, Ottawa, Ont.; Division of Clinical and Metabolic Genetics (Szuto, Khan, Lee, Mendoza-Londono), Hospital for Sick Children, Toronto, Ont.; Department of Genetics (Chisholm, Sawyer, Huang, Jarinova, Boycott), Children's Hospital of Eastern Ontario, Ottawa, Ont
| | - Caitlin Chisholm
- Program in Child Health Evaluative Sciences (Hayeems, Venkataramanan, Tsiplova, Lee, Ungar), Hospital for Sick Children Research Institute; Department of Paediatric Laboratory Medicine (Marshall, Stavropoulos, Lau, Somerville), Hospital for Sick Children, Toronto, Ont.; Department of Laboratory Medicine and Pathobiology, (Marshall, Stavropoulos, Somerville), University of Toronto, Toronto, Ont.; Children's Hospital of Eastern Ontario Research Institute (Gillespie, Price, Boycott), University of Ottawa, Ottawa, Ont.; Division of Clinical and Metabolic Genetics (Szuto, Khan, Lee, Mendoza-Londono), Hospital for Sick Children, Toronto, Ont.; Department of Genetics (Chisholm, Sawyer, Huang, Jarinova, Boycott), Children's Hospital of Eastern Ontario, Ottawa, Ont
| | - Dimitri J Stavropoulos
- Program in Child Health Evaluative Sciences (Hayeems, Venkataramanan, Tsiplova, Lee, Ungar), Hospital for Sick Children Research Institute; Department of Paediatric Laboratory Medicine (Marshall, Stavropoulos, Lau, Somerville), Hospital for Sick Children, Toronto, Ont.; Department of Laboratory Medicine and Pathobiology, (Marshall, Stavropoulos, Somerville), University of Toronto, Toronto, Ont.; Children's Hospital of Eastern Ontario Research Institute (Gillespie, Price, Boycott), University of Ottawa, Ottawa, Ont.; Division of Clinical and Metabolic Genetics (Szuto, Khan, Lee, Mendoza-Londono), Hospital for Sick Children, Toronto, Ont.; Department of Genetics (Chisholm, Sawyer, Huang, Jarinova, Boycott), Children's Hospital of Eastern Ontario, Ottawa, Ont
| | - Viji Venkataramanan
- Program in Child Health Evaluative Sciences (Hayeems, Venkataramanan, Tsiplova, Lee, Ungar), Hospital for Sick Children Research Institute; Department of Paediatric Laboratory Medicine (Marshall, Stavropoulos, Lau, Somerville), Hospital for Sick Children, Toronto, Ont.; Department of Laboratory Medicine and Pathobiology, (Marshall, Stavropoulos, Somerville), University of Toronto, Toronto, Ont.; Children's Hospital of Eastern Ontario Research Institute (Gillespie, Price, Boycott), University of Ottawa, Ottawa, Ont.; Division of Clinical and Metabolic Genetics (Szuto, Khan, Lee, Mendoza-Londono), Hospital for Sick Children, Toronto, Ont.; Department of Genetics (Chisholm, Sawyer, Huang, Jarinova, Boycott), Children's Hospital of Eastern Ontario, Ottawa, Ont
| | - Kate Tsiplova
- Program in Child Health Evaluative Sciences (Hayeems, Venkataramanan, Tsiplova, Lee, Ungar), Hospital for Sick Children Research Institute; Department of Paediatric Laboratory Medicine (Marshall, Stavropoulos, Lau, Somerville), Hospital for Sick Children, Toronto, Ont.; Department of Laboratory Medicine and Pathobiology, (Marshall, Stavropoulos, Somerville), University of Toronto, Toronto, Ont.; Children's Hospital of Eastern Ontario Research Institute (Gillespie, Price, Boycott), University of Ottawa, Ottawa, Ont.; Division of Clinical and Metabolic Genetics (Szuto, Khan, Lee, Mendoza-Londono), Hospital for Sick Children, Toronto, Ont.; Department of Genetics (Chisholm, Sawyer, Huang, Jarinova, Boycott), Children's Hospital of Eastern Ontario, Ottawa, Ont
| | - Sarah Sawyer
- Program in Child Health Evaluative Sciences (Hayeems, Venkataramanan, Tsiplova, Lee, Ungar), Hospital for Sick Children Research Institute; Department of Paediatric Laboratory Medicine (Marshall, Stavropoulos, Lau, Somerville), Hospital for Sick Children, Toronto, Ont.; Department of Laboratory Medicine and Pathobiology, (Marshall, Stavropoulos, Somerville), University of Toronto, Toronto, Ont.; Children's Hospital of Eastern Ontario Research Institute (Gillespie, Price, Boycott), University of Ottawa, Ottawa, Ont.; Division of Clinical and Metabolic Genetics (Szuto, Khan, Lee, Mendoza-Londono), Hospital for Sick Children, Toronto, Ont.; Department of Genetics (Chisholm, Sawyer, Huang, Jarinova, Boycott), Children's Hospital of Eastern Ontario, Ottawa, Ont
| | - E Magda Price
- Program in Child Health Evaluative Sciences (Hayeems, Venkataramanan, Tsiplova, Lee, Ungar), Hospital for Sick Children Research Institute; Department of Paediatric Laboratory Medicine (Marshall, Stavropoulos, Lau, Somerville), Hospital for Sick Children, Toronto, Ont.; Department of Laboratory Medicine and Pathobiology, (Marshall, Stavropoulos, Somerville), University of Toronto, Toronto, Ont.; Children's Hospital of Eastern Ontario Research Institute (Gillespie, Price, Boycott), University of Ottawa, Ottawa, Ont.; Division of Clinical and Metabolic Genetics (Szuto, Khan, Lee, Mendoza-Londono), Hospital for Sick Children, Toronto, Ont.; Department of Genetics (Chisholm, Sawyer, Huang, Jarinova, Boycott), Children's Hospital of Eastern Ontario, Ottawa, Ont
| | - Lynette Lau
- Program in Child Health Evaluative Sciences (Hayeems, Venkataramanan, Tsiplova, Lee, Ungar), Hospital for Sick Children Research Institute; Department of Paediatric Laboratory Medicine (Marshall, Stavropoulos, Lau, Somerville), Hospital for Sick Children, Toronto, Ont.; Department of Laboratory Medicine and Pathobiology, (Marshall, Stavropoulos, Somerville), University of Toronto, Toronto, Ont.; Children's Hospital of Eastern Ontario Research Institute (Gillespie, Price, Boycott), University of Ottawa, Ottawa, Ont.; Division of Clinical and Metabolic Genetics (Szuto, Khan, Lee, Mendoza-Londono), Hospital for Sick Children, Toronto, Ont.; Department of Genetics (Chisholm, Sawyer, Huang, Jarinova, Boycott), Children's Hospital of Eastern Ontario, Ottawa, Ont
| | - Reem Khan
- Program in Child Health Evaluative Sciences (Hayeems, Venkataramanan, Tsiplova, Lee, Ungar), Hospital for Sick Children Research Institute; Department of Paediatric Laboratory Medicine (Marshall, Stavropoulos, Lau, Somerville), Hospital for Sick Children, Toronto, Ont.; Department of Laboratory Medicine and Pathobiology, (Marshall, Stavropoulos, Somerville), University of Toronto, Toronto, Ont.; Children's Hospital of Eastern Ontario Research Institute (Gillespie, Price, Boycott), University of Ottawa, Ottawa, Ont.; Division of Clinical and Metabolic Genetics (Szuto, Khan, Lee, Mendoza-Londono), Hospital for Sick Children, Toronto, Ont.; Department of Genetics (Chisholm, Sawyer, Huang, Jarinova, Boycott), Children's Hospital of Eastern Ontario, Ottawa, Ont
| | - Whiwon Lee
- Program in Child Health Evaluative Sciences (Hayeems, Venkataramanan, Tsiplova, Lee, Ungar), Hospital for Sick Children Research Institute; Department of Paediatric Laboratory Medicine (Marshall, Stavropoulos, Lau, Somerville), Hospital for Sick Children, Toronto, Ont.; Department of Laboratory Medicine and Pathobiology, (Marshall, Stavropoulos, Somerville), University of Toronto, Toronto, Ont.; Children's Hospital of Eastern Ontario Research Institute (Gillespie, Price, Boycott), University of Ottawa, Ottawa, Ont.; Division of Clinical and Metabolic Genetics (Szuto, Khan, Lee, Mendoza-Londono), Hospital for Sick Children, Toronto, Ont.; Department of Genetics (Chisholm, Sawyer, Huang, Jarinova, Boycott), Children's Hospital of Eastern Ontario, Ottawa, Ont
| | - Lijia Huang
- Program in Child Health Evaluative Sciences (Hayeems, Venkataramanan, Tsiplova, Lee, Ungar), Hospital for Sick Children Research Institute; Department of Paediatric Laboratory Medicine (Marshall, Stavropoulos, Lau, Somerville), Hospital for Sick Children, Toronto, Ont.; Department of Laboratory Medicine and Pathobiology, (Marshall, Stavropoulos, Somerville), University of Toronto, Toronto, Ont.; Children's Hospital of Eastern Ontario Research Institute (Gillespie, Price, Boycott), University of Ottawa, Ottawa, Ont.; Division of Clinical and Metabolic Genetics (Szuto, Khan, Lee, Mendoza-Londono), Hospital for Sick Children, Toronto, Ont.; Department of Genetics (Chisholm, Sawyer, Huang, Jarinova, Boycott), Children's Hospital of Eastern Ontario, Ottawa, Ont
| | - Olga Jarinova
- Program in Child Health Evaluative Sciences (Hayeems, Venkataramanan, Tsiplova, Lee, Ungar), Hospital for Sick Children Research Institute; Department of Paediatric Laboratory Medicine (Marshall, Stavropoulos, Lau, Somerville), Hospital for Sick Children, Toronto, Ont.; Department of Laboratory Medicine and Pathobiology, (Marshall, Stavropoulos, Somerville), University of Toronto, Toronto, Ont.; Children's Hospital of Eastern Ontario Research Institute (Gillespie, Price, Boycott), University of Ottawa, Ottawa, Ont.; Division of Clinical and Metabolic Genetics (Szuto, Khan, Lee, Mendoza-Londono), Hospital for Sick Children, Toronto, Ont.; Department of Genetics (Chisholm, Sawyer, Huang, Jarinova, Boycott), Children's Hospital of Eastern Ontario, Ottawa, Ont
| | - Wendy J Ungar
- Program in Child Health Evaluative Sciences (Hayeems, Venkataramanan, Tsiplova, Lee, Ungar), Hospital for Sick Children Research Institute; Department of Paediatric Laboratory Medicine (Marshall, Stavropoulos, Lau, Somerville), Hospital for Sick Children, Toronto, Ont.; Department of Laboratory Medicine and Pathobiology, (Marshall, Stavropoulos, Somerville), University of Toronto, Toronto, Ont.; Children's Hospital of Eastern Ontario Research Institute (Gillespie, Price, Boycott), University of Ottawa, Ottawa, Ont.; Division of Clinical and Metabolic Genetics (Szuto, Khan, Lee, Mendoza-Londono), Hospital for Sick Children, Toronto, Ont.; Department of Genetics (Chisholm, Sawyer, Huang, Jarinova, Boycott), Children's Hospital of Eastern Ontario, Ottawa, Ont
| | - Roberto Mendoza-Londono
- Program in Child Health Evaluative Sciences (Hayeems, Venkataramanan, Tsiplova, Lee, Ungar), Hospital for Sick Children Research Institute; Department of Paediatric Laboratory Medicine (Marshall, Stavropoulos, Lau, Somerville), Hospital for Sick Children, Toronto, Ont.; Department of Laboratory Medicine and Pathobiology, (Marshall, Stavropoulos, Somerville), University of Toronto, Toronto, Ont.; Children's Hospital of Eastern Ontario Research Institute (Gillespie, Price, Boycott), University of Ottawa, Ottawa, Ont.; Division of Clinical and Metabolic Genetics (Szuto, Khan, Lee, Mendoza-Londono), Hospital for Sick Children, Toronto, Ont.; Department of Genetics (Chisholm, Sawyer, Huang, Jarinova, Boycott), Children's Hospital of Eastern Ontario, Ottawa, Ont
| | - Martin J Somerville
- Program in Child Health Evaluative Sciences (Hayeems, Venkataramanan, Tsiplova, Lee, Ungar), Hospital for Sick Children Research Institute; Department of Paediatric Laboratory Medicine (Marshall, Stavropoulos, Lau, Somerville), Hospital for Sick Children, Toronto, Ont.; Department of Laboratory Medicine and Pathobiology, (Marshall, Stavropoulos, Somerville), University of Toronto, Toronto, Ont.; Children's Hospital of Eastern Ontario Research Institute (Gillespie, Price, Boycott), University of Ottawa, Ottawa, Ont.; Division of Clinical and Metabolic Genetics (Szuto, Khan, Lee, Mendoza-Londono), Hospital for Sick Children, Toronto, Ont.; Department of Genetics (Chisholm, Sawyer, Huang, Jarinova, Boycott), Children's Hospital of Eastern Ontario, Ottawa, Ont
| | - Kym M Boycott
- Program in Child Health Evaluative Sciences (Hayeems, Venkataramanan, Tsiplova, Lee, Ungar), Hospital for Sick Children Research Institute; Department of Paediatric Laboratory Medicine (Marshall, Stavropoulos, Lau, Somerville), Hospital for Sick Children, Toronto, Ont.; Department of Laboratory Medicine and Pathobiology, (Marshall, Stavropoulos, Somerville), University of Toronto, Toronto, Ont.; Children's Hospital of Eastern Ontario Research Institute (Gillespie, Price, Boycott), University of Ottawa, Ottawa, Ont.; Division of Clinical and Metabolic Genetics (Szuto, Khan, Lee, Mendoza-Londono), Hospital for Sick Children, Toronto, Ont.; Department of Genetics (Chisholm, Sawyer, Huang, Jarinova, Boycott), Children's Hospital of Eastern Ontario, Ottawa, Ont
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13
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Nurchis MC, Riccardi MT, Radio FC, Chillemi G, Bertini ES, Tartaglia M, Cicchetti A, Dallapiccola B, Damiani G. Incremental net benefit of Whole Genome Sequencing for newborns and children with suspected genetic disorders: systematic review and meta-analysis of cost-effectiveness evidence. Health Policy 2022; 126:337-345. [DOI: 10.1016/j.healthpol.2022.03.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Revised: 02/16/2022] [Accepted: 03/01/2022] [Indexed: 11/16/2022]
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Tal-Ben Ishay R, Shil A, Solomon S, Sadigurschi N, Abu-Kaf H, Meiri G, Flusser H, Michaelovski A, Dinstein I, Golan H, Davidovitch N, Menashe I. Diagnostic Yield and Economic Implications of Whole-Exome Sequencing for ASD Diagnosis in Israel. Genes (Basel) 2021; 13:genes13010036. [PMID: 35052376 PMCID: PMC8774872 DOI: 10.3390/genes13010036] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Revised: 12/15/2021] [Accepted: 12/17/2021] [Indexed: 11/16/2022] Open
Abstract
Whole-exome sequencing (WES) is an effective approach to identify the susceptibility of genetic variants of autism spectrum disorder (ASD). The Israel Ministry of Health supports WES as an adjunct tool for ASD diagnosis, despite its unclear diagnostic yield and cost effectiveness. To address this knowledge gap, we applied WES to a population-based sample of 182 Bedouin and Jewish children with ASD from southern Israel, and assessed its yield in a gene panel of 205 genes robustly associated with ASD. We then compared the incremental cost-effectiveness ratios (ICERs) for an ASD diagnosis by WES, chromosomal microarray analysis (CMA), and CMA + WES. Overall, 32 ASD candidate variants were detected in 28 children, corresponding to an overall WES diagnostic yield of 15.4%. Interestingly, the diagnostic yield was significantly higher for the Bedouin children than for the Jewish children, i.e., 27.6% vs. 11.1% (p = 0.036). The most cost-effective means for genetic testing was the CMA alone, followed closely by the CMA + WES strategy (ICER = USD 117 and USD 124.8 per child). Yet, WES alone could become more cost effective than the other two approaches if there was to be a 25% increase in its yield or a 50% decrease in its cost. These findings suggest that WES should be recommended to facilitate ASD diagnosis in Israel, especially for highly consanguineous populations, such as the Bedouin.
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Affiliation(s)
- Rotem Tal-Ben Ishay
- Department of Public Health, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84100, Israel; (R.T.-B.I.); (A.S.)
- Azrieli National Centre for Autism and Neurodevelopment Research, Ben-Gurion University of the Negev, Beer-Sheva 84100, Israel; (S.S.); (N.S.); (H.A.-K.); (G.M.); (H.F.); (A.M.); (I.D.); (H.G.)
| | - Apurba Shil
- Department of Public Health, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84100, Israel; (R.T.-B.I.); (A.S.)
- Azrieli National Centre for Autism and Neurodevelopment Research, Ben-Gurion University of the Negev, Beer-Sheva 84100, Israel; (S.S.); (N.S.); (H.A.-K.); (G.M.); (H.F.); (A.M.); (I.D.); (H.G.)
- Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer-Sheva 84100, Israel
| | - Shirley Solomon
- Azrieli National Centre for Autism and Neurodevelopment Research, Ben-Gurion University of the Negev, Beer-Sheva 84100, Israel; (S.S.); (N.S.); (H.A.-K.); (G.M.); (H.F.); (A.M.); (I.D.); (H.G.)
| | - Noa Sadigurschi
- Azrieli National Centre for Autism and Neurodevelopment Research, Ben-Gurion University of the Negev, Beer-Sheva 84100, Israel; (S.S.); (N.S.); (H.A.-K.); (G.M.); (H.F.); (A.M.); (I.D.); (H.G.)
- Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer-Sheva 84100, Israel
- Department of Physiology and Cell Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84100, Israel
| | - Hadeel Abu-Kaf
- Azrieli National Centre for Autism and Neurodevelopment Research, Ben-Gurion University of the Negev, Beer-Sheva 84100, Israel; (S.S.); (N.S.); (H.A.-K.); (G.M.); (H.F.); (A.M.); (I.D.); (H.G.)
- Department of Physiology and Cell Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84100, Israel
| | - Gal Meiri
- Azrieli National Centre for Autism and Neurodevelopment Research, Ben-Gurion University of the Negev, Beer-Sheva 84100, Israel; (S.S.); (N.S.); (H.A.-K.); (G.M.); (H.F.); (A.M.); (I.D.); (H.G.)
- Preschool Psychiatric Unit, Soroka University Medical Center, Beer-Sheva 84100, Israel
| | - Hagit Flusser
- Azrieli National Centre for Autism and Neurodevelopment Research, Ben-Gurion University of the Negev, Beer-Sheva 84100, Israel; (S.S.); (N.S.); (H.A.-K.); (G.M.); (H.F.); (A.M.); (I.D.); (H.G.)
- Child Development Center, Soroka University Medical Center, Beer-Sheva 84100, Israel
| | - Analya Michaelovski
- Azrieli National Centre for Autism and Neurodevelopment Research, Ben-Gurion University of the Negev, Beer-Sheva 84100, Israel; (S.S.); (N.S.); (H.A.-K.); (G.M.); (H.F.); (A.M.); (I.D.); (H.G.)
- Child Development Center, Soroka University Medical Center, Beer-Sheva 84100, Israel
| | - Ilan Dinstein
- Azrieli National Centre for Autism and Neurodevelopment Research, Ben-Gurion University of the Negev, Beer-Sheva 84100, Israel; (S.S.); (N.S.); (H.A.-K.); (G.M.); (H.F.); (A.M.); (I.D.); (H.G.)
- Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer-Sheva 84100, Israel
- Psychology Department, Ben-Gurion University of the Negev, Beer-Sheva 84100, Israel
| | - Hava Golan
- Azrieli National Centre for Autism and Neurodevelopment Research, Ben-Gurion University of the Negev, Beer-Sheva 84100, Israel; (S.S.); (N.S.); (H.A.-K.); (G.M.); (H.F.); (A.M.); (I.D.); (H.G.)
- Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer-Sheva 84100, Israel
- Department of Physiology and Cell Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84100, Israel
| | - Nadav Davidovitch
- Department of Health Systems Management, Ben-Gurion University of the Negev, Beer-Sheva 84100, Israel;
| | - Idan Menashe
- Department of Public Health, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84100, Israel; (R.T.-B.I.); (A.S.)
- Azrieli National Centre for Autism and Neurodevelopment Research, Ben-Gurion University of the Negev, Beer-Sheva 84100, Israel; (S.S.); (N.S.); (H.A.-K.); (G.M.); (H.F.); (A.M.); (I.D.); (H.G.)
- Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer-Sheva 84100, Israel
- Correspondence: ; Tel.: +972-8-6477456
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15
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Olde Keizer RACM, Henneman L, Ploos van Amstel JK, Vissers LELM, Frederix GWJ. Economic evaluations of exome and genome sequencing in pediatric genetics: considerations towards a consensus strategy. J Med Econ 2021; 24:60-70. [PMID: 34915793 DOI: 10.1080/13696998.2021.2009725] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
OBJECTIVE Next Generation Sequencing (NGS) is increasingly used for the diagnosis of rare genetic disorders. The aim of this study is to review the different approaches for economic evaluations of Next Generation Sequencing (NGS) in pediatric care used to date, to identify all costs, effects, and time horizons taken into account. METHODS A systematic literature review was conducted to identify published economic evaluations of NGS applications in pediatric diagnostics, i.e. exome sequencing (ES) and/or genome sequencing (GS). Information regarding methodological approach, costs, effects, and time horizon was abstracted from these publications. RESULTS Twenty-eight economic evaluations of ES/GS within pediatrics were identified. Costs included were mainly restricted to direct in-hospital healthcare costs and varied widely in inclusion of sort of costs and time-horizon. Nineteen studies included diagnostic yield and eight studies included cost-effectiveness as outcome measures. Studies varied greatly in terms of included sort of costs data, effects, and time horizon. CONCLUSION Large differences in inclusion of cost and effect parameters were identified between studies. Validity of outcomes can therefore be questioned, which hinders valid comparison and widespread generalization of conclusions. In addition to current health economic guidance, specific guidance for evaluations in pediatric care is therefore necessary to improve the validity of outcomes and furthermore facilitate comparable decision-making for implementing novel NGS-based diagnostic modalities in pediatric genetics and beyond.
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Affiliation(s)
- Richelle A C M Olde Keizer
- Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
- Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, The Netherlands
| | - Lidewij Henneman
- Department of Clinical Genetics, Amsterdam UMC, Vrije Universiteit, Amsterdam, The Netherlands
| | | | - Lisenka E L M Vissers
- Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, The Netherlands
| | - Gerardus W J Frederix
- Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
- Department of Genetics, Utrecht University Medical Center, Utrecht, The Netherlands
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16
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Li C, Vandersluis S, Holubowich C, Ungar WJ, Goh ES, Boycott KM, Sikich N, Dhalla I, Ng V. Cost-effectiveness of genome-wide sequencing for unexplained developmental disabilities and multiple congenital anomalies. Genet Med 2020; 23:451-460. [PMID: 33110268 DOI: 10.1038/s41436-020-01012-w] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Revised: 10/06/2020] [Accepted: 10/07/2020] [Indexed: 12/22/2022] Open
Abstract
PURPOSE Genetic testing is routine practice for individuals with unexplained developmental disabilities and multiple congenital anomalies. However, current testing pathways can be costly and time consuming, and the diagnostic yield low. Genome-wide sequencing, including exome sequencing (ES) and genome sequencing (GS), can improve diagnosis, but at a higher cost. This study aimed to assess the cost-effectiveness of genome-wide sequencing in Ontario, Canada. METHODS A cost-effectiveness analysis was conducted using a discrete event simulation from a public payer perspective. Six strategies involving ES or GS were compared. Outcomes reported were direct medical costs, number of molecular diagnoses, number of positive findings, and number of active treatment changes. RESULTS If ES was used as a second-tier test (after the current first-tier, chromosomal microarray, fails to provide a diagnosis), it would be less costly and more effective than standard testing (CAN$6357 [95% CI: 6179-6520] vs. CAN$8783 per patient [95% CI: 2309-31,123]). If ES was used after standard testing, it would cost an additional CAN$15,228 to identify the genetic diagnosis for one additional patient compared with standard testing. The results remained robust when parameters and assumptions were varied. CONCLUSION ES would likely be cost-saving if used earlier in the diagnostic pathway.
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Affiliation(s)
- Chunmei Li
- Ontario Health (Quality), Toronto, ON, Canada.
| | | | | | - Wendy J Ungar
- Program of Child Health Evaluative Sciences, The Hospital for Sick Children Research Institute, Toronto, ON, Canada.,Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, ON, Canada
| | - Elaine S Goh
- Laboratory Medicine and Genetics, Trillium Health Partners, Mississauga, ON, Canada
| | - Kym M Boycott
- Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON, Canada
| | | | - Irfan Dhalla
- Ontario Health (Quality), Toronto, ON, Canada.,Unity Health Toronto, Toronto, ON, Canada
| | - Vivian Ng
- Ontario Health (Quality), Toronto, ON, Canada
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17
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Tammimies K, Li D, Rabkina I, Stamouli S, Becker M, Nicolaou V, Berggren S, Coco C, Falkmer T, Jonsson U, Choque-Olsson N, Bölte S. Association between Copy Number Variation and Response to Social Skills Training in Autism Spectrum Disorder. Sci Rep 2019; 9:9810. [PMID: 31285490 PMCID: PMC6614458 DOI: 10.1038/s41598-019-46396-1] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2019] [Accepted: 06/28/2019] [Indexed: 12/18/2022] Open
Abstract
Challenges in social communication and interaction are core features of autism spectrum disorder (ASD) for which social skills group training (SSGT) is a commonly used intervention. SSGT has shown modest and heterogeneous effects. One of the major genetic risk factors in ASD is rare copy number variation (CNV). However, limited information exists whether CNV profiles could be used to aid intervention decisions. Here, we analyzed the rare genic CNV carrier status for 207 children, of which 105 received SSGT and 102 standard care as part of a randomized clinical trial for SSGT. We found that being a carrier of rare genic CNV did not have an impact on the SSGT outcome measured by the parent-report Social Responsiveness Scale (SRS). However, when stratifying by pathogenicity and size of the CNVs, we identified that carriers of clinically significant and large genic CNVs (>500 kb) showed inferior SRS outcomes at post-intervention (P = 0.047 and P = 0.036, respectively) and follow-up (P = 0.008 and P = 0.072, respectively) when adjusting for standard care effects. Our study provides preliminary evidence that carriers of clinically significant and large genic CNVs might not benefit as much from SSGT as non-carriers. Our results indicate that genetic information might help guide the modifications of interventions in ASD.
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Affiliation(s)
- Kristiina Tammimies
- Center of Neurodevelopmental Disorders (KIND), Division of Neuropsychiatry, Centre for Psychiatry Research, Department of Women's and Children's Health, Karolinska Institutet, Solna, Sweden.
| | - Danyang Li
- Center of Neurodevelopmental Disorders (KIND), Division of Neuropsychiatry, Centre for Psychiatry Research, Department of Women's and Children's Health, Karolinska Institutet, Solna, Sweden
| | - Ielyzaveta Rabkina
- Center of Neurodevelopmental Disorders (KIND), Division of Neuropsychiatry, Centre for Psychiatry Research, Department of Women's and Children's Health, Karolinska Institutet, Solna, Sweden
| | - Sofia Stamouli
- Center of Neurodevelopmental Disorders (KIND), Division of Neuropsychiatry, Centre for Psychiatry Research, Department of Women's and Children's Health, Karolinska Institutet, Solna, Sweden
| | - Martin Becker
- Center of Neurodevelopmental Disorders (KIND), Division of Neuropsychiatry, Centre for Psychiatry Research, Department of Women's and Children's Health, Karolinska Institutet, Solna, Sweden
| | - Veronika Nicolaou
- Center of Neurodevelopmental Disorders (KIND), Division of Neuropsychiatry, Centre for Psychiatry Research, Department of Women's and Children's Health, Karolinska Institutet, Solna, Sweden
| | - Steve Berggren
- Center of Neurodevelopmental Disorders (KIND), Division of Neuropsychiatry, Centre for Psychiatry Research, Department of Women's and Children's Health, Karolinska Institutet, Solna, Sweden
- Child and Adolescent Psychiatry, Stockholm Health Services, Region, Stockholm, Sweden
| | - Christina Coco
- Center of Neurodevelopmental Disorders (KIND), Division of Neuropsychiatry, Centre for Psychiatry Research, Department of Women's and Children's Health, Karolinska Institutet, Solna, Sweden
- Child and Adolescent Psychiatry, Stockholm Health Services, Region, Stockholm, Sweden
| | - Torbjörn Falkmer
- Curtin Autism Research Group, School of Occupational Therapy, Social Work and Speech Pathology, Curtin University, Bentley, Australia
- Pain and Rehabilitation Centre, Department of Medical and Health Sciences, Linköping University, Linköping, Sweden
| | - Ulf Jonsson
- Center of Neurodevelopmental Disorders (KIND), Division of Neuropsychiatry, Centre for Psychiatry Research, Department of Women's and Children's Health, Karolinska Institutet, Solna, Sweden
- Child and Adolescent Psychiatry, Stockholm Health Services, Region, Stockholm, Sweden
- Department of Neuroscience, Child and Adolescent Psychiatry, Uppsala University, Uppsala, Sweden
| | - Nora Choque-Olsson
- Center of Neurodevelopmental Disorders (KIND), Division of Neuropsychiatry, Centre for Psychiatry Research, Department of Women's and Children's Health, Karolinska Institutet, Solna, Sweden
- Center for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
| | - Sven Bölte
- Center of Neurodevelopmental Disorders (KIND), Division of Neuropsychiatry, Centre for Psychiatry Research, Department of Women's and Children's Health, Karolinska Institutet, Solna, Sweden.
- Child and Adolescent Psychiatry, Stockholm Health Services, Region, Stockholm, Sweden.
- Curtin Autism Research Group, School of Occupational Therapy, Social Work and Speech Pathology, Curtin University, Bentley, Australia.
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18
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Allocating healthcare resources to genomic testing in Canada: latest evidence and current challenges. J Community Genet 2019; 13:467-476. [PMID: 31273679 DOI: 10.1007/s12687-019-00428-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2018] [Accepted: 06/14/2019] [Indexed: 12/30/2022] Open
Abstract
Precision medicine (PM) informed by next-generation sequencing (NGS) poses challenges for health technology assessment (HTA). To date, there has been limited reimbursement of genomic testing with NGS in Canada, particularly for whole-genome and whole-exome sequencing (WGS/WES). Through a structured literature review, we examine Canadian economic evidence and evidentiary challenges for the adoption of genomic testing. We searched Medline (PubMed) for published Canadian studies generating economic evidence for PM informed by NGS. Our search focused on studies examining the costs and/or value of NGS. We reviewed included studies and summarized results according to evaluation type, clinical context, NGS technology, and test strategy. We then grouped HTA challenges encountered by authors when evaluating NGS. Our review included twenty-five studies. To determine the economic impacts of NGS-informed PM in Canada, studies applied cost-effectiveness analysis (52%, n = 13), stated preference analysis (20%, n = 5), cost-consequence analysis (16%, n = 4), and healthcare resource utilization or costing analysis (12%, n = 3). NGS panels were the most common technology evaluated (n = 13), followed by WGS and/or WES (n = 8). The included studies highlighted multiple challenges when generating economic evidence, many of which remain unaddressed. Challenges were broadly related to (1) accounting for all NGS outcomes; (2) addressing uncertainty; and (3) improving consistency of economic approaches. Canadian studies are beginning to produce estimates of the economic impacts of NGS-informed PM, yet challenges for HTA remain. While solutions and real-world evidence are generated, lifecycle health technology management methods can be designed to better support resource allocation decisions for genomic testing in Canada.
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Lovato DV, Herai RR, Pignatari GC, Beltrão-Braga PCB. The Relevance of Variants With Unknown Significance for Autism Spectrum Disorder Considering the Genotype-Phenotype Interrelationship. Front Psychiatry 2019; 10:409. [PMID: 31231258 PMCID: PMC6567929 DOI: 10.3389/fpsyt.2019.00409] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2019] [Accepted: 05/23/2019] [Indexed: 11/13/2022] Open
Abstract
Several efforts in basic and clinical research have been contributing to unveiling the genetics behind autism spectrum disorders (ASD). However, despite these advancements, many individuals diagnosed with ASD and related neuropsychiatric conditions have been genetically investigated without elucidative results. The enormous genetic complexity of ASD-related conditions makes it a significant challenge to achieve, with a growing number of genes (close to a thousand) involved, belonging to different molecular pathways and presenting distinct genetic variations. Next-generation sequencing (NGS) is the approach most used in genetic research related to ASD, identifying de novo mutation, which is closely related to more severe clinical phenotypes, especially when they affect constrained and loss-of-function intolerant genes. On the other hand, de novo mutation findings contribute to a small percentage of the ASD population, since most of the cases and genetic variants associated with neuropsychiatric conditions are inherited and phenotypes are results of additive polygenic models, which makes statistical efforts more difficult. As a result, NGS investigation can sound vainly or unsuccessful, and new mutations on genes already related with ASD are classified as variants of unknown significance (VUS), hampering their endorsement to a clinical phenotype. This review is focused on currently available strategies to clarify the impact of VUS and to describe the efforts to identify more pieces of evidence throughout clinical interpretation and genetic curation process.
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Affiliation(s)
- Diogo V Lovato
- Laboratory of Disease Modeling, Department of Microbiology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | - Roberto R Herai
- Experimental Multiuser Laboratory, Graduate Program in Health Sciences, School of Medicine, Pontifícia Universidade Católica do Paraná, Curitiba, Brazil.,Lico Kaesemodel Institute (ILK), Curitiba, Brazil
| | - Graciela C Pignatari
- Laboratory of Disease Modeling, Department of Microbiology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | - Patricia C B Beltrão-Braga
- Laboratory of Disease Modeling, Department of Microbiology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.,Laboratory of Disease Modeling, Scientific Platform Pasteur-USP, São Paulo, Brazil
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