Sequencing projects will screen 200,000 newborns for disease.

U.K. and New York City efforts face cost and ethical issues.

Whole genome sequencing in oncology: using scenario drafting to explore future developments.

BACKGROUND: In oncology, Whole Genome Sequencing (WGS) is not yet widely implemented due to uncertainties such as the required infrastructure and expertise, costs and reimbursements, and unknown pan-cancer clinical utility. Therefore, this study aimed to investigate possible future developments facilitating or impeding the use of WGS as a molecular diagnostic in oncology through scenario drafting. METHODS: A four-step process was adopted for scenario drafting. First, the literature was searched for barriers and facilitators related to the implementation of WGS. Second, they were prioritized by international experts, and third, combined into coherent scenarios. Fourth, the scenarios were implemented in an online survey and their likelihood of taking place within 5 years was elicited from another group of experts. Based on the minimum, maximum, and most likely (mode) parameters, individual Program Evaluation and Review Technique (PERT) probability density functions were determined. Subsequently, individual opinions were aggregated by performing unweighted linear pooling, from which summary statistics were extracted and reported. RESULTS: Sixty-two unique barriers and facilitators were extracted from 70 articles. Price, clinical utility, and turnaround time of WGS were ranked as the most important aspects. Nine scenarios were developed and scored on likelihood by 18 experts. The scenario about introducing WGS as a clinical diagnostic with a lower price, shorter turnaround time, and improved degree of actionability, scored the highest likelihood (median: 68.3%). Scenarios with low likelihoods and strong consensus were about better treatment responses to more actionable targets (26.1%), and the effect of centralizing WGS (24.1%). CONCLUSIONS: Based on current expert opinions, the implementation of WGS as a clinical diagnostic in oncology is heavily dependent on the price, clinical utility (both in terms of identifying actionable targets as in adding sufficient value in subsequent treatment), and turnaround time. These aspects and the optimal way of service provision are the main drivers for the implementation of WGS and should be focused on in further research. More knowledge regarding these factors is needed to inform strategic decision making regarding the implementation of WGS, which warrants support from all relevant stakeholders.

Early technology assessment of using whole genome sequencing in personalized oncology.

Introduction: Personalized medicine-based treatments in advanced cancer hold the promise to offer substantial health benefits to genetic subgroups, but require efficient biomarker-based patient stratification to match the right treatment and may be expensive. Standard molecular diagnostics are currently very heterogeneous, and tests are often performed sequentially. The alternative to whole genome sequencing (WGS) i.e. simultaneously testing for all relevant DNA-based biomarkers thereby allowing immediate selection of the most optimal therapy, is more costly than current techniques. In the current implementation stage, it is important to explore the added value and cost-effectiveness of using WGS on a patient level and to assess optimal introduction of WGS on the level of the healthcare system.Areas covered: First, an overview of current worldwide initiatives concerning the use of WGS in clinical practice for cancer diagnostics is given. Second, a comprehensive, early health technology assessment (HTA) approach of evaluating WGS in the Netherlands is described, relating to the following aspects: diagnostic value, WGS-based treatment decisions, assessment of long-term health benefits and harms, early cost-effectiveness modeling, nation-wide organization, and Ethical, Legal and Societal Implications.Expert opinion: This study provides evidence to guide further development and implementation of WGS in clinical practice and the healthcare system.

Micro-costing diagnostics in oncology: from single-gene testing to whole- genome sequencing.

Purpose: Predictive diagnostics play an increasingly important role in personalized medicine for cancer treatment. Whole-genome sequencing (WGS)-based treatment selection is expected to rapidly increase worldwide. This study aimed to calculate and compare the total cost of currently used diagnostic techniques and of WGS in treatment of non-small cell lung carcinoma (NSCLC), melanoma, colorectal cancer (CRC), and gastrointestinal stromal tumor (GIST) in the Netherlands.Methods: The activity-based costing (ABC) method was conducted to calculate total cost of included diagnostic techniques based on data provided by Dutch pathology laboratories and the Dutch-centralized cancer WGS facility. Costs were allocated to four categories: capital costs, maintenance costs, software costs, and operational costs.Results: The total cost per cancer patient per technique varied from € 58 (Sanger sequencing, three amplicons) to € 2925 (paired tumor-normal WGS). The operational costs accounted for the vast majority (over 90%) of the total per cancer patient technique costs.Conclusion: This study outlined in detail all costing aspects and cost prices of current and new diagnostic modalities used in treatment of NSCLC, melanoma, CRC, and GIST in the Netherlands. Detailed cost differences and value comparisons between these diagnostic techniques enable future economic evaluations to support decision-making.

Real-World Utilization of Biomarker Testing for Patients with Advanced Non-Small Cell Lung Cancer in a Tertiary Referral Center and Referring Hospitals.

The continued introduction of biomarkers and innovative testing methods makes already complex diagnosis in patients with stage IV non-small-cell lung cancer (NSCLC) even more complex. This study primarily analyzed variations in biomarker testing in clinical practice in patients referred to a comprehensive cancer center in the Netherlands. The secondary aim was to compare the cost of biomarker testing with the cost of whole-genome sequencing. The cohort included 102 stage IV NSCLC patients who received biomarker testing in 2017 or 2018 at the comprehensive cancer center. The complete biomarker testing history of the cohort was identified using linked data from the comprehensive cancer center and the nationwide network and registry of histopathology and cytopathology in the Netherlands. Unique biomarker-test combinations, costs, turnaround times, and test utilization were examined. The results indicate substantial variation in test utilization and sequences. The mean cost per patient of biomarker testing was 2259.92 ± 1217.10 USD, or 1881.23 ± 1013.15 EUR. Targeted gene panels were most frequently conducted, followed by IHC analysis for programmed cell death protein ligand 1. Typically, the most common biomarkers were assessed within the first tests, and emerging biomarkers were tested further down the test sequence. At the cost of current biomarker testing, replacing current testing with whole-genome sequencing would have led to cost-savings in only two patients (2%).

Study protocol: Whole genome sequencing Implementation in standard Diagnostics for Every cancer patient (WIDE).

BACKGROUND: 'Precision oncology' can ensure the best suitable treatment at the right time by tailoring treatment towards individual patient and comprehensive tumour characteristics. In current molecular pathology, diagnostic tests which are part of the standard of care (SOC) only cover a limited part of the spectrum of genomic changes, and often are performed in an iterative way. This occurs at the expense of valuable patient time, available tissue sample, and interferes with 'first time right' treatment decisions. Whole Genome Sequencing (WGS) captures a near complete view of genomic characteristics of a tumour in a single test. Moreover, WGS facilitates faster implementation of new treatment relevant biomarkers. At present, WGS mainly has been applied in study settings, but its performance in a routine diagnostic setting remains to be evaluated. The WIDE study aims to investigate the feasibility and validity of WGS-based diagnostics in clinical practice. METHODS: 1200 consecutive patients in a single comprehensive cancer centre with (suspicion of) a metastasized solid tumour will be enrolled with the intention to analyse tumour tissue with WGS, in parallel to SOC diagnostics. Primary endpoints are (1) feasibility of implementation of WGS-based diagnostics into routine clinical care and (2) clinical validation of WGS by comparing identification of treatment-relevant variants between WGS and SOC molecular diagnostics. Secondary endpoints entail (1) added clinical value in terms of additional treatment options and (2) cost-effectiveness of WGS compared to SOC diagnostics through a Health Technology Assessment (HTA) analysis. Furthermore, the (3) perceived impact of WGS-based diagnostics on clinical decision making will be evaluated through questionnaires. The number of patients included in (experimental) therapies initiated based on SOC or WGS diagnostics will be reported with at least 3 months follow-up. The clinical efficacy is beyond the scope of WIDE. Key performance indicators will be evaluated after every 200 patients enrolled, and procedures optimized accordingly, to continuously improve the diagnostic performance of WGS in a routine clinical setting. DISCUSSION: WIDE will yield the optimal conditions under which WGS can be implemented in a routine molecular diagnostics setting and establish the position of WGS compared to SOC diagnostics in routine clinical care.

The complete costs of genome sequencing: a microcosting study in cancer and rare diseases from a single center in the United Kingdom.

PURPOSE: The translation of genome sequencing into routine health care has been slow, partly because of concerns about affordability. The aspirational cost of sequencing a genome is $1000, but there is little evidence to support this estimate. We estimate the cost of using genome sequencing in routine clinical care in patients with cancer or rare diseases. METHODS: We performed a microcosting study of Illumina-based genome sequencing in a UK National Health Service laboratory processing 399 samples/year. Cost data were collected for all steps in the sequencing pathway, including bioinformatics analysis and reporting of results. Sensitivity analysis identified key cost drivers. RESULTS: Genome sequencing costs £6841 per cancer case (comprising matched tumor and germline samples) and £7050 per rare disease case (three samples). The consumables used during sequencing are the most expensive component of testing (68-72% of the total cost). Equipment costs are higher for rare disease cases, whereas consumable and staff costs are slightly higher for cancer cases. CONCLUSION: The cost of genome sequencing is underestimated if only sequencing costs are considered, and likely surpasses $1000/genome in a single laboratory. This aspirational sequencing cost will likely only be achieved if consumable costs are considerably reduced and sequencing is performed at scale.

Rapid and affordable genome-wide bisulfite DNA sequencing by XmaI-reduced representation bisulfite sequencing.

AIM: To develop a reduced representation bisulfite sequencing (RRBS) approach for rapid and affordable genome-wide DNA methylation analysis. METHODS: We have selected restriction endonuclease XmaI to produce RRBS library fragments. After digestion and partial fill-in DNA fragments were ligated to barcoded adapters, bisulfite converted, size-selected, and sequenced on the Ion Torrent Personal Genome Machine. XmaI-RRBS results were compared with the previously published RRBS data. RESULTS: We have developed an XmaI-RRBS method for rapid and affordable genome-wide DNA methylation analysis, with library preparation taking only 4 days and sequencing possible within 4 h. We have also addressed several challenges in order to further improve the RRBS technology. XmaI-RRBS may be performed on degraded DNA samples and is compatible with the bench-top next-generation sequencing machines.