Are whole-exome and whole-genome sequencing approaches cost-effective? A systematic review of the literature.
TL;DR: The current health economic evidence base to support the more widespread use of WES and WGS in clinical practice is very limited and studies that carefully evaluate the costs, effectiveness, and cost-effectiveness of these tests are urgently needed to support their translation into clinical practice.
About: This article is published in Genetics in Medicine.The article was published on 2018-02-15 and is currently open access. It has received 327 citations till now. The article focuses on the topics: Systematic review & Centre for Reviews and Dissemination.
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TL;DR: In this paper, the authors developed an evidence-based clinical practice guideline for the use of exome and genome sequencing (ES/GS) in the care of pediatric patients with one or more congenital anomalies (CA) with onset prior to age 1 year or developmental delay (DD) or intellectual disability (ID).
148 citations
TL;DR: Application of existing biological databases and bioinformatics tools to address the bottleneck in data processing and analysis are presented, including the need for new generation big data analytics for the multi-omics challenges of personalized medicine.
Abstract: There is a growing attention toward personalized medicine. This is led by a fundamental shift from the 'one size fits all' paradigm for treatment of patients with conditions or predisposition to diseases, to one that embraces novel approaches, such as tailored target therapies, to achieve the best possible outcomes. Driven by these, several national and international genome projects have been initiated to reap the benefits of personalized medicine. Exome and targeted sequencing provide a balance between cost and benefit, in contrast to whole genome sequencing (WGS). Whole exome sequencing (WES) targets approximately 3% of the whole genome, which is the basis for protein-coding genes. Nonetheless, it has the characteristics of big data in large deployment. Herein, the application of WES and its relevance in advancing personalized medicine is reviewed. WES is mapped to Big Data "10 Vs" and the resulting challenges discussed. Application of existing biological databases and bioinformatics tools to address the bottleneck in data processing and analysis are presented, including the need for new generation big data analytics for the multi-omics challenges of personalized medicine. This includes the incorporation of artificial intelligence (AI) in the clinical utility landscape of genomic information, and future consideration to create a new frontier toward advancing the field of personalized medicine.
131 citations
TL;DR: The cost of genome sequencing is underestimated if only sequencing costs are considered, and likely surpasses $1000/genome in a single laboratory if consumable costs are considerably reduced and sequencing is performed at scale.
120 citations
TL;DR: The authors discuss the application of next-generation sequencing (NGS) to the diagnosis of CMT and present a method for incorporating NGS into CMT clinical practice and propose an algorithm for incorporating WGS into the CMT diagnostic pathway.
Abstract: Charcot-Marie-Tooth disease and the related disorders hereditary motor neuropathy and hereditary sensory neuropathy, collectively termed CMT, are the commonest group of inherited neuromuscular diseases, and they exhibit wide phenotypic and genetic heterogeneity. CMT is usually characterized by distal muscle atrophy, often with foot deformity, weakness and sensory loss. In the past decade, next-generation sequencing (NGS) technologies have revolutionized genomic medicine and, as these technologies are being applied to clinical practice, they are changing our diagnostic approach to CMT. In this Review, we discuss the application of NGS technologies, including disease-specific gene panels, whole-exome sequencing, whole-genome sequencing (WGS), mitochondrial sequencing and high-throughput transcriptome sequencing, to the diagnosis of CMT. We discuss the growing challenge of variant interpretation and consider how the clinical phenotype can be combined with genetic, bioinformatic and functional evidence to assess the pathogenicity of genetic variants in patients with CMT. WGS has several advantages over the other techniques that we discuss, which include unparalleled coverage of coding, non-coding and intergenic areas of both nuclear and mitochondrial genomes, the ability to identify structural variants and the opportunity to perform genome-wide dense homozygosity mapping. We propose an algorithm for incorporating WGS into the CMT diagnostic pathway.
115 citations
TL;DR: Research on the nonfoodborne spread of AMR is reviewed, with a focus on domesticated animals and the environment and possible exposures to humans, including underpinning the genetics important to human and animal health.
Abstract: Antimicrobial resistance (AMR) is a significant threat to both human and animal health. The spread of AMR bacteria and genes across systems can occur through a myriad of pathways, both related and unrelated to agriculture, including via wastewater, soils, manure applications, direct exchange between humans and animals, and food exposure. Tracing origins and drivers of AMR bacteria and genes is challenging due to the array of contexts and the complexity of interactions overlapping health practice, microbiology, genetics, applied science and engineering, as well as social and human factors. Critically assessing the diverse and sometimes contradictory AMR literature is a valuable step in identifying tractable mitigation options to stem AMR spread. In this article we review research on the nonfoodborne spread of AMR, with a focus on domesticated animals and the environment and possible exposures to humans. Attention is especially placed on delineating possible sources and causes of AMR bacterial phenotypes, including underpinning the genetics important to human and animal health.
90 citations
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TL;DR: The fourth edition of the Methods for the Economic Evaluation of Health Care Programmes as mentioned in this paper has been thoroughly revised and updated, making it essential reading for anyone commissioning, undertaking, or using economic evaluations in health care, including health service professionals, health economists, and health care decision makers.
Abstract: The purpose of economic evaluation is to inform decisions intended to improve healthcare. The new edition of Methods for the Economic Evaluation of Health Care Programmes equips the reader with the necessary tools and understanding required to undertake evaluations by providing an outline of key principles and a 'tool kit' based on the authors' own experiences of undertaking economic evaluations. Building on the strength of the previous edition, the accessible writing style ensures the text is key reading for the non-expert reader, as no prior knowledge of economics is required. The book employs a critical appraisal framework, which is useful both to researchers conducting studies and to decision-makers assessing them. Practical examples are provided throughout to aid learning and understanding. The book discusses the analytical and policy challenges that face health systems in seeking to allocate resources efficiently and fairly. New chapters include 'Principles of economic evaluation' and 'Making decisions in healthcare' which introduces the reader to core issues and questions about resource allocation, and provides an understanding of the fundamental principles which guide decision making. A key part of evidence-based decision making is the analysis of all the relevant evidence to make informed decisions and policy. The new chapter 'Identifying, synthesising and analysing evidence' highlights the importance of systematic review, and how and why these methods are used. As methods of analysis continue to develop, the chapter on 'Characterising, reporting and interpreting uncertainty' introduces the reader to recent methods of analysis and why characterizing uncertainty matters for health care decisions. The fourth edition of Methods for the Economic Evaluation of Health Care Programmes has been thoroughly revised and updated, making it essential reading for anyone commissioning, undertaking, or using economic evaluations in health care, including health service professionals, health economists, and health care decision makers.
8,314 citations
01 Jan 1998
TL;DR: The second edition of the first edition of this book was published in 1987 as discussed by the authors, and the second edition includes new chapters on collection and analysis of data and on the presentation and use of data.
Abstract: We are witnessing a paradigm shift in the way medicine is practiced, taught, and evaluated. It was relatively recently that medicine knew no limits. New diagnostic procedures led to more medical and surgical procedures and to greater expense. It was assumed that patients would be the recipient of these advances. However, the uncontrolled costs of medical care and the poor documentation of patient benefit ushered in a new era of cost conscientiousness. Now, there is a need to show that medicine produces value for money. As a result, new methodologies such as cost-effectiveness analysis, cost-benefit analysis, and cost-utility analysis have become commonplace in medical journals. This has created a need to revise medical education and postgraduate training in order to accommodate new methodologies and new controversies. Within the last few years, several influential publications have emerged. Perhaps the most important of these is the book Cost-Effectiveness in Health and Medicine edited by Martha Gold and colleagues.1 This book summarizes the consensus of an expert panel convened to review cost-effectiveness analysis in health care. The Gold book covers the theory but does not teach the methods. Methods for the Economic Evaluation of Health Care Programmes by Michael Drummond and colleagues offers specific, step-by-step methodologies for conducting economic evaluations. This is the second edition of a book originally published in 1987. During the ten years between editions, there were very substantial advances in theory and methods for economic evaluations of health care programs. The revised edition brings the text up to date. Methods for the Economic Evaluation of Health Care Programmes arises from the teaching of health economics at McMaster University. The McMaster Centre for Health Economics and Policy Analysis is internationally regarded as a focal point for economic evaluations of health care. Among other advances, researchers at the Centre have produced a widely used methodology, known as the Health Utilities Index, for estimating the cost/utility of health programs. The book was originally developed for a course at McMaster and for a workshop offered by the McMaster faculty. The second edition adds one new author (Bernie O’Brien) who has more recently joined the McMaster faculty. The second edition also introduces substantial changes in the chapters on cost-effectiveness, cost-utility, and cost-benefit analysis. These are important improvements because of the profound methodological developments in these areas. In addition, the second edition includes new chapters on collection and analysis of data and on the presentation and use of data. These new chapters add discussion on the pros and cons of economic evaluations and on some of the difficulties in the interpretation of economic data. In addition, the second edition includes many more boxes and illustrations to facilitate the interpretation of the text. Perhaps the greatest contribution of the book is the very detailed presentation of cost/utility analysis. It is now common to offer discussions of the cost to produce a year of life adjusted for life quality. This is known as a quality adjusted life year (QALY). There are a variety of different methods for estimating QALYs. Nevertheless, QALYs estimated using different methods are often found in the same comparison or “league” table. This book goes into considerable detail in how QALYs are estimated and describes some of the methodological issues and problems in estimating these outcomes. Unlike other texts, the book provides systematic stepby-step instruction in how both costs and health benefits can be estimated. In summary, the role of health economics is becoming firmly established in the evaluation of health care programs. In combination with Gold and colleagues’ book,1 which provides a detailed theoretical discussion of economic analysis, Methods for the Economic Evaluation of Health Care Programmes offers systematic training in the application of economic methodologies. This book can serve as a basic text for students hoping to understand the complex methodologies of economic evaluation. In addition, the book is a handy reference for advanced practitioners of economic analysis.
6,537 citations
TL;DR: W whole-exome sequencing identified the underlying genetic defect in 25% of consecutive patients referred for evaluation of a possible genetic condition.
Abstract: Background Whole-exome sequencing is a diagnostic approach for the identification of molecular defects in patients with suspected genetic disorders. Methods We developed technical, bioinformatic, interpretive, and validation pipelines for whole-exome sequencing in a certified clinical laboratory to identify sequence variants underlying disease phenotypes in patients. Results We present data on the first 250 probands for whom referring physicians ordered whole-exome sequencing. Patients presented with a range of phenotypes suggesting potential genetic causes. Approximately 80% were children with neurologic phenotypes. Insurance coverage was similar to that for established genetic tests. We identified 86 mutated alleles that were highly likely to be causative in 62 of the 250 patients, achieving a 25% molecular diagnostic rate (95% confidence interval, 20 to 31). Among the 62 patients, 33 had autosomal dominant disease, 16 had autosomal recessive disease, and 9 had X-linked disease. A total of 4 probands re...
1,727 citations
TL;DR: De novo mutations represent an important cause of intellectual disability; exome sequencing was used as an effective diagnostic strategy for their detection.
Abstract: Background The causes of intellectual disability remain largely unknown because of extensive clinical and genetic heterogeneity. Methods We evaluated patients with intellectual disability to exclude known causes of the disorder. We then sequenced the coding regions of more than 21,000 genes obtained from 100 patients with an IQ below 50 and their unaffected parents. A data-analysis procedure was developed to identify and classify de novo, autosomal recessive, and X-linked mutations. In addition, we used high-throughput resequencing to confirm new candidate genes in 765 persons with intellectual disability (a confirmation series). All mutations were evaluated by molecular geneticists and clinicians in the context of the patients' clinical presentation. Results We identified 79 de novo mutations in 53 of 100 patients. A total of 10 de novo mutations and 3 X-linked (maternally inherited) mutations that had been previously predicted to compromise the function of known intellectual-disability genes were found in 13 patients. Potentially causative de novo mutations in novel candidate genes were detected in 22 patients. Additional de novo mutations in 3 of these candidate genes were identified in patients with similar phenotypes in the confirmation series, providing support for mutations in these genes as the cause of intellectual disability. We detected no causative autosomal recessive inherited mutations in the discovery series. Thus, the total diagnostic yield was 16%, mostly involving de novo mutations. Conclusions De novo mutations represent an important cause of intellectual disability; exome sequencing was used as an effective diagnostic strategy for their detection. (Funded by the European Union and others.).
1,239 citations
TL;DR: Whole-exome sequencing provided a potential molecular diagnosis for 25% of a large cohort of patients referred for evaluation of suspected genetic conditions, including detection of rare genetic events and new mutations contributing to disease, and may offer advantages over traditional molecular diagnostic approaches in certain patients.
Abstract: Importance Clinical whole-exome sequencing is increasingly used for diagnostic evaluation of patients with suspected genetic disorders. Objective To perform clinical whole-exome sequencing and report (1) the rate of molecular diagnosis among phenotypic groups, (2) the spectrum of genetic alterations contributing to disease, and (3) the prevalence of medically actionable incidental findings such as FBN1 mutations causing Marfan syndrome. Design, Setting, and Patients Observational study of 2000 consecutive patients with clinical whole-exome sequencing analyzed between June 2012 and August 2014. Whole-exome sequencing tests were performed at a clinical genetics laboratory in the United States. Results were reported by clinical molecular geneticists certified by the American Board of Medical Genetics and Genomics. Tests were ordered by the patient’s physician. The patients were primarily pediatric (1756 [88%]; mean age, 6 years; 888 females [44%], 1101 males [55%], and 11 fetuses [1% gender unknown]), demonstrating diverse clinical manifestations most often including nervous system dysfunction such as developmental delay. Main Outcomes and Measures Whole-exome sequencing diagnosis rate overall and by phenotypic category, mode of inheritance, spectrum of genetic events, and reporting of incidental findings. Results A molecular diagnosis was reported for 504 patients (25.2%) with 58% of the diagnostic mutations not previously reported. Molecular diagnosis rates for each phenotypic category were 143/526 (27.2%; 95% CI, 23.5%-31.2%) for the neurological group, 282/1147 (24.6%; 95% CI, 22.1%-27.2%) for the neurological plus other organ systems group, 30/83 (36.1%; 95% CI, 26.1%-47.5%) for the specific neurological group, and 49/244 (20.1%; 95% CI, 15.6%-25.8%) for the nonneurological group. The Mendelian disease patterns of the 527 molecular diagnoses included 280 (53.1%) autosomal dominant, 181 (34.3%) autosomal recessive (including 5 with uniparental disomy), 65 (12.3%) X-linked, and 1 (0.2%) mitochondrial. Of 504 patients with a molecular diagnosis, 23 (4.6%) had blended phenotypes resulting from 2 single gene defects. About 30% of the positive cases harbored mutations in disease genes reported since 2011. There were 95 medically actionable incidental findings in genes unrelated to the phenotype but with immediate implications for management in 92 patients (4.6%), including 59 patients (3%) with mutations in genes recommended for reporting by the American College of Medical Genetics and Genomics. Conclusions and Relevance Whole-exome sequencing provided a potential molecular diagnosis for 25% of a large cohort of patients referred for evaluation of suspected genetic conditions, including detection of rare genetic events and new mutations contributing to disease. The yield of whole-exome sequencing may offer advantages over traditional molecular diagnostic approaches in certain patients.
1,168 citations