100,000 Genomes Pilot on Rare-Disease Diagnosis in Health Care - Preliminary Report.

BACKGROUND: The U.K. 100,000 Genomes Project is in the process of investigating the role of genome sequencing in patients with undiagnosed rare diseases after usual care and the alignment of this research with health care implementation in the U.K. National Health Service. Other parts of this project focus on patients with cancer and infection. METHODS: We conducted a pilot study involving 4660 participants from 2183 families, among whom 161 disorders covering a broad spectrum of rare diseases were present. We collected data on clinical features with the use of Human Phenotype Ontology terms, undertook genome sequencing, applied automated variant prioritization on the basis of applied virtual gene panels and phenotypes, and identified novel pathogenic variants through research analysis. RESULTS: Diagnostic yields varied among family structures and were highest in family trios (both parents and a proband) and families with larger pedigrees. Diagnostic yields were much higher for disorders likely to have a monogenic cause (35%) than for disorders likely to have a complex cause (11%). Diagnostic yields for intellectual disability, hearing disorders, and vision disorders ranged from 40 to 55%. We made genetic diagnoses in 25% of the probands. A total of 14% of the diagnoses were made by means of the combination of research and automated approaches, which was critical for cases in which we found etiologic noncoding, structural, and mitochondrial genome variants and coding variants poorly covered by exome sequencing. Cohortwide burden testing across 57,000 genomes enabled the discovery of three new disease genes and 19 new associations. Of the genetic diagnoses that we made, 25% had immediate ramifications for clinical decision making for the patients or their relatives. CONCLUSIONS: Our pilot study of genome sequencing in a national health care system showed an increase in diagnostic yield across a range of rare diseases. (Funded by the National Institute for Health Research and others.).

Secondary (additional) findings from the 100,000 Genomes Project: Disease manifestation, health care outcomes, and costs of disclosure.

PURPOSE: The UK 100,000 Genomes Project offered participants screening for additional findings (AFs) in genes associated with familial hypercholesterolemia (FH) or hereditary cancer syndromes including breast/ovarian cancer (HBOC), Lynch, familial adenomatous polyposis, MYH-associated polyposis, multiple endocrine neoplasia (MEN), and von Hippel-Lindau. Here, we report disclosure processes, manifestation of AF-related disease, outcomes, and costs. METHODS: An observational study in an area representing one-fifth of England. RESULTS: Data were collected from 89 adult AF recipients. At disclosure, among 57 recipients of a cancer-predisposition-associated AF and 32 recipients of an FH-associated AF, 35% and 88%, respectively, had personal and/or family history evidence of AF-related disease. During post-disclosure investigations, 4 cancer-AF recipients had evidence of disease, including 1 medullary thyroid cancer. Six women with an HBOC AF, 3 women with a Lynch syndrome AF, and 2 individuals with a MEN AF elected for risk-reducing surgery. New hyperlipidemia diagnoses were made in 6 FH-AF recipients and treatment (re-)initiated for 7 with prior hyperlipidemia. Generating and disclosing AFs in this region cost £1.4m; £8680 per clinically significant AF. CONCLUSION: Generation and disclosure of AFs identifies individuals with and without personal or familial evidence of disease and prompts appropriate clinical interventions. Results can inform policy toward secondary findings.

QALYs and rare diseases: exploring the responsiveness of SF-6D, EQ-5D-5L and AQoL-8D following genomic testing for childhood and adult-onset rare genetic conditions in Australia.

BACKGROUND: Genomic testing transforms the diagnosis and management of rare conditions. However, uncertainty exists on how to best measure genomic outcomes for informing healthcare priorities. Using the HTA-preferred method should be the starting point to improve the evidence-base. This study explores the responsiveness of SF-6D, EQ-5D-5L and AQoL-8D following genomic testing across childhood and adult-onset genetic conditions. METHOD: Self-reported patient-reported outcomes (PRO) were obtained from: primary caregivers of children with suspected neurodevelopmental disorders (NDs) or genetic kidney diseases (GKDs) (carers' own PRO), adults with suspected GKDs using SF-12v2; adults with suspected complex neurological disorders (CNDs) using EQ-5D-5L; and adults with dilated cardiomyopathy (DCM) using AQol-8D. Responsiveness was assessed using the standardised response mean effect-size based on diagnostic (having a confirmed genomic diagnosis), personal (usefulness of genomic information to individuals or families), and clinical (clinical usefulness of genomic information) utility anchors. RESULTS: In total, 254 people completed PRO measures before genomic testing and after receiving results. For diagnostic utility, a nearly moderate positive effect size was identified by the AQoL-8D in adult DCM patients. Declines in physical health domains masked any improvements in mental or psychosocial domains in parents of children affected by NDs and adult CNDs and DCM patients with confirmed diagnosis. However, the magnitude of the changes was small and we did not find statistically significant evidence of these changes. No other responsiveness evidence related to diagnostic, clinical, and personal utility of genomic testing was identified. CONCLUSION: Generic PRO measures may lack responsiveness to the diagnostic, clinical and personal outcomes of genomics, but further research is needed to establish their measurement properties and relevant evaluative space in the context of rare conditions. Expected declines in the physical health of people experiencing rare conditions may further challenge the conventional application of quality of life assessments.

Assessing adverse events in clinical trials during the era of the COVID-19 pandemic.

Interpretation of safety data for clinical trials that were ongoing at the onset of the COVID-19 pandemic or were started subsequent to the beginning of the pandemic may be affected in a variety of ways. Pandemic-related issues can influence the extent of study participation and introduce data collection gaps. A SARS-CoV-2 infection among study subjects as a post-randomization event may introduce a number of confounding factors that can alter the frequency of adverse events, in some cases appearing as an increase in the frequency of an adverse event associated with a study drug relative to a comparator. The authors discuss clinical challenges and statistical concerns, specifically the estimand framework, including examples for consideration, to address these challenges in safety evaluation wrought by the COVID-19 pandemic. Our aim is to shed light on the importance of starting an early dialogue among the drug development team on the evaluation of safety, critical for benefit-risk evaluation throughout the drug development process.

Carbon Monoxide Levels Produced by Propane/Isobutane Canister Stoves inside a Tent.

INTRODUCTION: Improper use of camp stoves in enclosed spaces has resulted in fatalities from carbon monoxide (CO) poisoning. Prior research has focused on the CO output of stoves burning white gas, unleaded gas, or kerosene. Stoves burning an isobutane/propane fuel have not been investigated and are the focus of this study. METHODS: Three stoves utilizing isobutane/propane fuel were used to heat a pot of water inside a 3-season tent under controlled settings. Multiple runs with each stove were performed, and CO measurements, in parts per million (ppm), were recorded at 1-min intervals for a total of 15 min using a RAE Systems gas monitor. Data are reported as mean with SD. Repeated measures analysis of variance was utilized to examine changes over time. Statistical significance was set at P<0.05. RESULTS: There was a statistically significant main effect of time and CO level, F (14, 168)=7.6, P<0.001. There was a statistically significant difference between-subjects effect of stove group F (2, 12)=8.6, P=0.005, indicating that CO levels were different depending on the stove. Tukey's post-hoc analyses revealed that stove A had the highest CO levels. The average level of stove A was statistically significantly higher than that of stove B and stove C, with a mean CO level difference of 79 ppm (95% CI, 3-156), P=0.043 and 117 ppm (95% CI, 40-194), P=0.004, respectively. CONCLUSIONS: Stoves utilizing isobutane/propane fuel can produce unsafe CO levels and should not be used in enclosed spaces.

Defining a Core Data Set for the Economic Evaluation of Precision Oncology.

OBJECTIVES: Precision oncology is generating vast amounts of multiomic data to improve human health and accelerate research. Existing clinical study designs and attendant data are unable to provide comparative evidence for economic evaluations. This lack of evidence can cause inconsistent and inappropriate reimbursement. Our study defines a core data set to facilitate economic evaluations of precision oncology. METHODS: We conducted a literature review of economic evaluations of next-generation sequencing technologies, a common application of precision oncology, published between 2005 and 2018 and indexed in PubMed (MEDLINE). Based on this review, we developed a preliminary core data set for informal expert feedback. We then used a modified-Delphi approach with individuals involved in implementation and evaluation of precision medicine, including 2 survey rounds followed by a final voting conference to refine the data set. RESULTS: Two authors determined that variation in published data elements was reached after abstraction of 20 economic evaluations. Expert consultation refined the data set to 83 unique data elements, and a multidisciplinary sample of 46 experts participated in the modified-Delphi process. A total of 68 elements (81%) were selected as required, spanning demographics and clinical characteristics, genomic data, cancer treatment, health and quality of life outcomes, and resource use. CONCLUSIONS: Cost-effectiveness analyses will fail to reflect the real-world impacts of precision oncology without data to accurately characterize patient care trajectories and outcomes. Data collection in accordance with the proposed core data set will promote standardization and enable the generation of decision-grade evidence to inform reimbursement.

Eliciting risk preferences that predict risky health behavior: A comparison of two approaches.

Information on attitudes to risk could increase understanding of and explain risky health behaviors. We investigate two approaches to eliciting risk preferences in the health domain, a novel "indirect" lottery elicitation approach with health states as outcomes and a "direct" approach where respondents are asked directly about their willingness to take risks. We compare the ability of the two approaches to predict health-related risky behaviors in a general adult population. We also investigate a potential framing effect in the indirect lottery elicitation approach. We find that risk preferences elicited using the direct approach can better predict health-related risky behavior than those elicited using the indirect approach. Moreover, a seemingly innocuous change to the framing of the lottery question results in significantly different risk preference estimates, and conflicting conclusions about the ability of the indicators to predict risky health behaviors.

Factors that impact on women's decision-making around prenatal genomic tests: An international discrete choice survey.

OBJECTIVE: We conducted a survey-based discrete-choice experiment (DCE) to understand the test features that drive women's preferences for prenatal genomic testing, and explore variation across countries. METHODS: Five test attributes were identified as being important for decision-making through a literature review, qualitative interviews and quantitative scoring exercise. Twelve scenarios were constructed in which respondents choose between two invasive tests or no test. Women from eight countries who delivered a baby in the previous 24 months completed a DCE presenting these scenarios. Choices were modeled using conditional logit regression analysis. RESULTS: Surveys from 1239 women (Australia: n = 178; China: n = 179; Denmark: n = 88; Netherlands: n = 177; Singapore: n = 90; Sweden: n = 178; UK: n = 174; USA: n = 175) were analyzed. The key attribute affecting preferences was a test with the highest diagnostic yield (p < 0.01). Women preferred tests with short turnaround times (p < 0.01), and tests reporting variants of uncertain significance (VUS; p < 0.01) and secondary findings (SFs; p < 0.01). Several country-specific differences were identified, including time to get a result, who explains the result, and the return of VUS and SFs. CONCLUSION: Most women want maximum information from prenatal genomic tests, but our findings highlight country-based differences. Global consensus on how to return uncertain results is not necessarily realistic or desirable.

Public preferences for delayed or immediate antibiotic prescriptions in UK primary care: A choice experiment.

BACKGROUND: Delayed (or "backup") antibiotic prescription, where the patient is given a prescription but advised to delay initiating antibiotics, has been shown to be effective in reducing antibiotic use in primary care. However, this strategy is not widely used in the United Kingdom. This study aimed to identify factors influencing preferences among the UK public for delayed prescription, and understand their relative importance, to help increase appropriate use of this prescribing option. METHODS AND FINDINGS: We conducted an online choice experiment in 2 UK general population samples: adults and parents of children under 18 years. Respondents were presented with 12 scenarios in which they, or their child, might need antibiotics for a respiratory tract infection (RTI) and asked to choose either an immediate or a delayed prescription. Scenarios were described by 7 attributes. Data were collected between November 2018 and February 2019. Respondent preferences were modelled using mixed-effects logistic regression. The survey was completed by 802 adults and 801 parents (75% of those who opened the survey). The samples reflected the UK population in age, sex, ethnicity, and country of residence. The most important determinant of respondent choice was symptom severity, especially for cough-related symptoms. In the adult sample, the probability of choosing delayed prescription was 0.53 (95% confidence interval (CI) 0.50 to 0.56, p < 0.001) for a chesty cough and runny nose compared to 0.30 (0.28 to 0.33, p < 0.001) for a chesty cough with fever, 0.47 (0.44 to 0.50, p < 0.001) for sore throat with swollen glands, and 0.37 (0.34 to 0.39, p < 0.001) for sore throat, swollen glands, and fever. Respondents were less likely to choose delayed prescription with increasing duration of illness (odds ratio (OR) 0.94 (0.92 to 0.96, p < 0.001)). Probabilities of choosing delayed prescription were similar for parents considering treatment for a child (44% of choices versus 42% for adults, p = 0.04). However, parents differed from the adult sample in showing a more marked reduction in choice of the delayed prescription with increasing duration of illness (OR 0.83 (0.80 to 0.87) versus 0.94 (0.92 to 0.96) for adults, p for heterogeneity p < 0.001) and a smaller effect of disruption of usual activities (OR 0.96 (0.95 to 0.97) versus 0.93 (0.92 to 0.94) for adults, p for heterogeneity p < 0.001). Females were more likely to choose a delayed prescription than males for minor symptoms, particularly minor cough (probability 0.62 (0.58 to 0.66, p < 0.001) for females and 0.45 (0.41 to 0.48, p < 0.001) for males). Older people, those with a good understanding of antibiotics, and those who had not used antibiotics recently showed similar patterns of preferences. Study limitations include its hypothetical nature, which may not reflect real-life behaviour; the absence of a "no prescription" option; and the possibility that study respondents may not represent the views of population groups who are typically underrepresented in online surveys. CONCLUSIONS: This study found that delayed prescription appears to be an acceptable approach to reducing antibiotic consumption. Certain groups appear to be more amenable to delayed prescription, suggesting particular opportunities for increased use of this strategy. Prescribing choices for sore throat may need additional explanation to ensure patient acceptance, and parents in particular may benefit from reassurance about the usual duration of these illnesses.

Snakebites Reported to the Kentucky Regional Poison Control Centers for the Years 2012-2016.

INTRODUCTION: Snake envenomations cause significant morbidity and mortality. The goals of this study were to assess the epidemiology of snakebites in Kentucky and treatment strategies used by physicians reporting to the Kentucky Regional Poison Control Centers. METHODS: This was a descriptive epidemiologic study compiling clinical data on snakebites reported to the Kentucky Regional Poison Control Centers from 2012 to 2016. We built a database of the patient demographics, treatment, and clinical course of each snakebite reported in the study period. Attention was paid to all antivenom interventions and use of contraindicated therapies. RESULTS: We compiled 674 total records. Patient age was 34±18 y (mean±SD), with males (71%) predominating. Most (97%) bites were to a distal upper or lower extremity. The majority (78%) occurred at a private residence. Most reports came between May and September (88%). Of the 674 patients, 24% (n=159) were classified as moderate or severe. Two hundred thirty (34%) patients were admitted to the hospital. Forty-six patients (7%) received surgical consultation, and 12 (2%) underwent surgical intervention. One hundred fifty-three patients received antivenom, with 6±3 vials used per patient. Length of stay was 3±2 d when antivenom was administered and 2±2 d when not administered. Six cases of coagulopathy were noted. Multiple contraindicated therapies were noted. CONCLUSIONS: Snake envenomations are a prevalent public health concern for residents of Kentucky, chiefly during summer months. Significant medical intervention is being performed for many patients, with a high prevalence of contraindicated therapies. More data are needed to fully characterize the epidemiologic impact and appropriateness of the interventions being applied.

Why do hospital prescribers continue antibiotics when it is safe to stop? Results of a choice experiment survey.

BACKGROUND: Deciding whether to discontinue antibiotics at early review is a cornerstone of hospital antimicrobial stewardship practice worldwide. In England, this approach is described in government guidance ('Start Smart then Focus'). However, < 10% of hospital antibiotic prescriptions are discontinued at review, despite evidence that 20-30% could be discontinued safely. We aimed to quantify the relative importance of factors influencing prescriber decision-making at review. METHODS: We conducted an online choice experiment, a survey method to elicit preferences. Acute/general hospital prescribers in England were asked if they would continue or discontinue antibiotic treatment in 15 hypothetical scenarios. Scenarios were described according to six attributes, including patients' presenting symptoms and whether discontinuation would conflict with local prescribing guidelines. Respondents' choices were analysed using conditional logistic regression. RESULTS: One hundred respondents completed the survey. Respondents were more likely to continue antibiotics when discontinuation would 'strongly conflict' with local guidelines (average marginal effect (AME) on the probability of continuing + 0.194 (p < 0.001)), when presenting symptoms more clearly indicated antibiotics (AME of urinary tract infection symptoms + 0.173 (p < 0.001) versus unclear symptoms) and when patients had severe frailty/comorbidities (AME = + 0.101 (p < 0.001)). Respondents were less likely to continue antibiotics when under no external pressure to continue (AME = - 0.101 (p < 0.001)). Decisions were also influenced by the risks to patient health of continuing/discontinuing antibiotic treatment. CONCLUSIONS: Guidelines that conflict with antibiotic discontinuation (e.g. pre-specify fixed durations) may discourage safe discontinuation at review. In contrast, guidelines conditional on patient factors/treatment response could help hospital prescribers discontinue antibiotics if diagnostic information suggesting they are no longer needed is available.

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.

Addressing Challenges of Economic Evaluation in Precision Medicine Using Dynamic Simulation Modeling.

OBJECTIVES: The objective of this article is to describe the unique challenges and present potential solutions and approaches for economic evaluations of precision medicine (PM) interventions using simulation modeling methods. METHODS: Given the large and growing number of PM interventions and applications, methods are needed for economic evaluation of PM that can handle the complexity of cascading decisions and patient-specific heterogeneity reflected in the myriad testing and treatment pathways. Traditional approaches (eg, Markov models) have limitations, and other modeling techniques may be required to overcome these challenges. Dynamic simulation models, such as discrete event simulation and agent-based models, are used to design and develop mathematical representations of complex systems and intervention scenarios to evaluate the consequence of interventions over time from a systems perspective. RESULTS: Some of the methodological challenges of modeling PM can be addressed using dynamic simulation models. For example, issues regarding companion diagnostics, combining and sequencing of tests, and diagnostic performance of tests can be addressed by capturing patient-specific pathways in the context of care delivery. Issues regarding patient heterogeneity can be addressed by using patient-level simulation models. CONCLUSION: The economic evaluation of PM interventions poses unique methodological challenges that might require new solutions. Simulation models are well suited for economic evaluation in PM because they enable patient-level analyses and can capture the dynamics of interventions in complex systems specific to the context of healthcare service delivery.

Swimming rhythm generation in the caudal hindbrain of the lamprey.

The spinal cord has been well established as the site of generation of the locomotor rhythm in vertebrates, but studies have suggested that the caudal hindbrain in larval fish and amphibians can also generate locomotor rhythms. Here, we investigated whether the caudal hindbrain of the adult lamprey ( Petromyzon marinus and Ichthyomyzon unicuspis) has the ability to generate the swimming rhythm. The hindbrain-spinal cord transition zone of the lamprey contains a bilateral column of somatic motoneurons that project via the spino-occipital (S-O) nerves to several muscles of the head. In the brainstem-spinal cord-muscle preparation, these muscles were found to burst and contract rhythmically with a left-right alternation when swimming activity was evoked with a brief electrical stimulation of the spinal cord. In the absence of muscles, the isolated brainstem-spinal cord preparation also produced alternating left-right bursts in S-O nerves (i.e., fictive swimming), and the S-O nerve bursts preceded the bursts occurring in the first ipsilateral spinal ventral root. After physical isolation of the S-O region using transverse cuts of the nervous system, the S-O nerves still exhibited rhythmic bursting with left-right alternation when glutamate was added to the bathing solution. We conclude that the S-O region of the lamprey contains a swimming rhythm generator that produces the leading motor nerve bursts of each swimming cycle, which then propagate down the spinal cord to produce forward swimming. The S-O region of the hindbrain-spinal cord transition zone may play a role in regulating speed, turning, and head orientation during swimming in lamprey. NEW & NOTEWORTHY Although it has been well established that locomotor rhythm generation occurs in the spinal cord of vertebrates, it was unknown whether the hindbrain of the adult vertebrate nervous system can also generate the locomotor rhythm. Here, we show that the isolated hindbrain-spinal cord transition zone of adult lamprey can generate the swimming rhythm. In addition, the swimming bursts of the hindbrain lead the bursts occurring in the first segment of the spinal cord.

Are whole-exome and whole-genome sequencing approaches cost-effective? A systematic review of the literature.

PURPOSE: We conducted a systematic literature review to summarize the current health economic evidence for whole-exome sequencing (WES) and whole-genome sequencing (WGS). METHODS: Relevant studies were identified in the EMBASE, MEDLINE, Cochrane Library, EconLit and University of York Centre for Reviews and Dissemination databases from January 2005 to July 2016. Publications were included in the review if they were economic evaluations, cost studies, or outcome studies. RESULTS: Thirty-six studies met our inclusion criteria. These publications investigated the use of WES and WGS in a variety of genetic conditions in clinical practice, the most common being neurological or neurodevelopmental disorders. Study sample size varied from a single child to 2,000 patients. Cost estimates for a single test ranged from $555 to $5,169 for WES and from $1,906 to $24,810 for WGS. Few cost analyses presented data transparently and many publications did not state which components were included in cost estimates. CONCLUSION: The current health economic evidence base to support the more widespread use of WES and WGS in clinical practice is very limited. Studies that carefully evaluate the costs, effectiveness, and cost-effectiveness of these tests are urgently needed to support their translation into clinical practice.

Valuation of Health and Nonhealth Outcomes from Next-Generation Sequencing: Approaches, Challenges, and Solutions.

BACKGROUND: Next-generation sequencing (NGS) technologies have seen variable adoption in the clinic. This is partly due to a lack of clinical and economic studies, with the latter increasingly challenged to examine patient preferences for health and nonhealth outcomes (e.g., false-positive rate). OBJECTIVES: To conduct a structured review of studies valuing patients' preference-based utility for NGS outcomes, to highlight identified methodological challenges, and to consider how studies addressed identified challenges. METHODS: We searched MEDLINE (PubMed), Embase (Ovid), and Web of Science for published studies examining outcomes from health care decisions informed by NGS. We focused our search on direct elicitations of preference-based utility. We reviewed included studies and qualitatively grouped and summarized stated challenges and solutions by theme. RESULTS: Eleven studies were included. Most of them (n = 6) used discrete choice experiments to value utility. We categorized challenges into four themes: 1) valuing the full range of NGS outcomes, 2) accounting for accuracy and uncertainty surrounding effectiveness, 3) allowing for simultaneous multiple and cascading risks, and 4) incorporating downstream consequences. Studies found strong evidence of utility for NGS information, regardless of health improvement. Investigators addressed challenges by simplifying complex choices, by including health outcomes alongside nonhealth outcomes, and by using multiple elicitation techniques. CONCLUSIONS: The breadth and complexity of NGS-derived information makes the technology a unique and challenging application for utility valuation. Failing to account for the utility or disutility of NGS-related nonhealth outcomes may lead to overinvestment or underinvestment in NGS, and so there is a need for research addressing unresolved challenges.

Methodological Issues in Assessing the Economic Value of Next-Generation Sequencing Tests: Many Challenges and Not Enough Solutions.

BACKGROUND: Clinical use of next-generation sequencing (NGS) tests has been increasing, but few studies have examined their economic value. Several studies have noted that there are methodological challenges to conducting economic evaluations of NGS tests. OBJECTIVE: Our objective was to examine key methodological challenges for conducting economic evaluations of NGS tests, prioritize these challenges for future research, and identify how studies have attempted solutions to address these challenges. METHODS: We identified challenges for economic evaluations of NGS tests using prior literature and expert judgment of the co-authors. We used a modified Delphi assessment to prioritize challenges, based on importance and probability of resolution. Using a structured literature review and article extraction we then assessed whether published economic evaluations had addressed these challenges. RESULTS: We identified 11 challenges for conducting economic evaluations of NGS tests. The experts identified three challenges as the top priorities for future research: complex model structure, timeframe, and type of analysis and comparators used. Of the 15 published studies included in our literature review, four studies described specific solutions relevant to five of the 11 identified challenges. CONCLUSIONS: Major methodological challenges to economic evaluations of NGS tests remain to be addressed. Our results can be used to guide future research and inform decision-makers on how to prioritize research on the economic assessment of NGS tests.

Using "Big Data" in the Cost-Effectiveness Analysis of Next-Generation Sequencing Technologies: Challenges and Potential Solutions.

Next-generation sequencing (NGS) is considered to be a prominent example of "big data" because of the quantity and complexity of data it produces and because it presents an opportunity to use powerful information sources that could reduce clinical and health economic uncertainty at a patient level. One obstacle to translating NGS into routine health care has been a lack of clinical trials evaluating NGS technologies, which could be used to populate cost-effectiveness analyses (CEAs). A key question is whether big data can be used to partially support CEAs of NGS. This question has been brought into sharp focus with the creation of large national sequencing initiatives. In this article we summarize the main methodological and practical challenges of using big data as an input into CEAs of NGS. Our focus is on the challenges of using large observational datasets and cohort studies and linking these data to the genomic information obtained from NGS, as is being pursued in the conduct of large genomic sequencing initiatives. We propose potential solutions to these key challenges. We conclude that the use of genomic big data to support and inform CEAs of NGS technologies holds great promise. Nevertheless, health economists face substantial challenges when using these data and must be cognizant of them before big data can be confidently used to produce evidence on the cost-effectiveness of NGS.

Postsynthetic Incorporation of a Singlet Oxygen Photosensitizer in a Metal-Organic Framework for Fast and Selective Oxidative Detoxification of Sulfur Mustard.

A fullerene-based photosensitizer is incorporated postsynthetically into a Zr6 -based MOF, NU-1000, for enhanced singlet oxygen production. The structural organic linkers in the MOF platform also act as photosensitizers which contribute to the overall generation of singlet oxygen from the material under UV irradiation. The singlet oxygen generated by the MOF/fullerene material is shown to oxidize sulfur mustard selectively to the less toxic bis(2-chloroethyl)sulfoxide with a half-life of only 11 min.

Surgery versus surveillance in ulcerative colitis patients with endoscopically invisible low-grade dysplasia: a cost-effectiveness analysis.

BACKGROUND AND AIMS: There is uncertainty regarding the optimal management of endoscopically invisible (flat) low-grade dysplasia in ulcerative colitis. Such a finding does not currently provide an automatic indication for colectomy; however, a recommendation of surveillance instead of surgery is controversial. The aim of this study was to determine the clinical and cost-effectiveness of colonoscopic surveillance versus colectomy for endoscopically invisible low-grade dysplasia of the colon in ulcerative colitis. METHODS: A Markov model was used to evaluate the costs and health outcomes of surveillance and surgery over a 20-year timeframe. Outcomes evaluated were life years gained and quality-adjusted life years (QALYs). Cohorts of patients aged 25 to 75 were modeled, including estimates from a validated surgical risk calculator and considering none, 1, or both of 2 key comorbidities: heart failure and obstructive airway disease. RESULTS: Surveillance is associated with more life years and QALYs compared with surgery from age 61 for those with no comorbidities, age 51 for those with 1 comorbidity and age 25 for those with 2 comorbidities. At the current United Kingdom National Institute for Health and Care Excellence threshold of $25,800 per QALY, ongoing surveillance was cost-effective at age 65 in those without comorbidities and at age 60 in those with either 1 or more comorbidities. CONCLUSIONS: Surveillance can be recommended from age 65 for those with no comorbidities; however, in younger patients with typical postsurgical quality of life, colectomy may be more effective clinically and more cost-effective. The results were sensitive to the colorectal cancer incidence rate in patients under surveillance and to quality of life after surgery.