Non-invasive prenatal diagnostic test accuracy for fetal sex using cell-free DNA a review and meta-analysis

Background: Cell-free fetal DNA (cffDNA) can be detected in maternal blood during pregnancy, opening the possibility of early non-invasive prenatal diagnosis for a variety of genetic conditions. Since 1997, many studies have examined the accuracy of prenatal fetal sex determination using cffDNA, particularly for pregnancies at risk of an X-linked condition. Here we report a review and meta-analysis of the published literature to evaluate the use of cffDNA for prenatal determination (diagnosis) of fetal sex. We applied a sensitive search of multiple bibliographic databases including PubMed (MEDLINE), EMBASE, the Cochrane library and Web of Science. Results: Ninety studies, incorporating 9,965 pregnancies and 10,587 fetal sex results met our inclusion criteria. Overall mean sensitivity was 96.6% (95% credible interval 95.2% to 97.7%) and mean specificity was 98.9% (95% CI = 98.1% to 99.4%). These results vary very little with trimester or week of testing, indicating that the performance of the test is reliably high. Conclusions: Based on this review and meta-analysis we conclude that fetal sex can be determined with a high level of accuracy by analyzing cffDNA. Using cffDNA in prenatal diagnosis to replace or complement existing invasive methods can remove or reduce the risk of miscarriage. Future work should concentrate on the economic and ethical considerations of implementing an early non-invasive test for fetal sex

Detecting Progression of Treated Choroidal Melanomas: Is Ultrasonography Necessary?

Prompt detection and treatment of local treatment failure after radiotherapy for choroidal melanoma optimises any opportunities for conserving vision and the eye, possibly reducing an increased risk of metastatic disease. Long-term surveillance is therefore required but is hampered by the perceived need to perform ultrasonography, which may not be available at a patient’s local hospital. The aim of this study was to determine whether local treatment failure can reliably be detected with colour fundus photography alone, and, if so, in which patients. Patients were included in the study if diagnosed with local treatment failure between April 2016 and February 2021 after eye-conserving therapy for choroidal melanoma. Wide-field colour and fundal autofluorescence (FAF) images, optical coherence tomography (OCT), and ultrasonography (US) were analysed by two of the authors (GN and UH). The cohort included 87 patients with local treatment failure. In 75 patients with clear media, tumour progression was detected by colour photography alone in 74 (98.7%) patients. Sensitivity was not increased by the addition of either OCT or AF. One patient with clear media developed extraocular extension detected with US without visible change in the intraocular part of the tumour. In the other 12 patients, US was required because of opaque media and a consequently poor fundal view. Local treatment failure after radiotherapy for choroidal melanoma is detected in 98.7% of cases with colour photography when the media are clear. Ultrasonography is useful when photography is prevented by opaque media or tumours having locations in the far periphery

A Toolkit to assess health needs for congenital disorders in low- and middle-income countries: an instrument for public health action.

BACKGROUND: In 2010 the World Health Assembly called for action to improve the care and prevention of congenital disorders, noting that technical guidance would be required for this task, especially in low- and middle-income countries. Responding to this call, we have developed a freely available web-accessible Toolkit for assessing health needs for congenital disorders. METHODS: Materials for the Toolkit website (http://toolkit.phgfoundation.org) were prepared by an iterative process of writing, discussion and modification by the project team, with advice from external experts. A customized database was developed using epidemiological, demographic, socio-economic and health-services data from a range of validated sources. Document-processing and data integration software combines data from the database with a template to generate topic- and country-specific Calculator documents for quantitative analysis. RESULTS: The Toolkit guides users through selection of topics (including both clinical conditions and relevant health services), assembly and evaluation of qualitative and quantitative information, assessment of the potential effects of selected interventions, and planning and prioritization of actions to reduce the risk or prevalence of congenital disorders. CONCLUSIONS: The Toolkit enables users without epidemiological or public health expertise to undertake health needs assessment as a prerequisite for strategic planning in relation to congenital disorders in their country or region

Survival analysis following enucleation for uveal melanoma

OBJECTIVES: To determine survival outcomes following enucleation for uveal melanoma. To compare these outcomes with the 8th edition AJCC classification and determine the influence of cytogenetics, using Fluorescent in situ Hybridisation (FISH), on survival. To determine whether failure to gain sufficient sample for cytogenetics using Fine Needle Aspiration Biopsy (FNAB) correlates with survival. SUBJECTS/METHODS: All patients undergoing primary enucleation for uveal melanoma at Moorfields Eye Hospital between 2012 and 2015 were included. Clinical, pathological, cytological and survival data were analysed for all patients. RESULTS: In total, 155 subjects were included. Mean age at enucleation was 65.9 years (SD 14.13). 88 (56.8%) patients died at a mean of three (SD 1.9) years following enucleation. Of these, 52 (33.5%) died from metastatic melanoma, 16 (10.3%) from other causes and 20 (12.9%) causes of death were unknown. Cumulative incidence analysis demonstrated AJCC grade, chromosome 8q gain and monosomy three all predict metastatic mortality. The greatest 5-year mortality rate (62%, SD10.1%) was in those with both chromosome abnormalities and AJCC stage III (Stage IV patients excluded due to low numbers). Largest basal diameter and chromosome status, both independently (p = 0.02 and p < 0.001) predicted metastatic mortality on multivariable regression analysis. Those who had an insufficient sample of cells gained during FNAB (n = 16) had no different prognosis. CONCLUSIONS: This study confirms, in this population, the poor survival of patients enucleated for uveal melanomas. It confirms the prognostic utility of adding AJCC grade to cytogenetic information. It demonstrates that the lack of sample in patients undergoing FNAB is not related to prognosis

Cost-effectiveness of a new autoantibody test added to Computed Tomography (CT) compared to CT surveillance alone in the diagnosis of lung cancer amongst patients with indeterminate pulmonary nodules

Oncimmune's EarlyCDT®-Lung is a simple ELISA blood test that measures seven lung cancer specific autoantibodies and is used in the assessment of malignancy risk in patients with indeterminate pulmonary nodules (IPNs). The objective of this study was to examine the cost-effectiveness of EarlyCDT-Lung in the diagnosis of lung cancer amongst patients with IPNs in addition to CT surveillance, compared to CT surveillance alone which is the current recommendation by the British Thoracic Society guidelines. A model consisting of a combination of a decision tree and Markov model was developed using the outcome measure of the quality adjusted life year (QALY). A life-time time horizon was adopted. The model was parameterized using a range of secondary sources. At £70 per test, EarlyCDT-Lung and CT surveillance was found to be cost-effective compared to CT surveillance alone with an incremental cost-effectiveness ratio (ICER) of less than £2,500 depending on the test accuracy parameters used. It was also found that EarlyCDT-Lung can be priced up to £1,177 and still be cost-effective based on cost-effectiveness acceptance threshold of £20,000 / QALY. Further research to resolve parameter uncertainty, was not found to be of value. The results here demonstrate that at £70 per test the EarlyCDT-Lung will have a positive impact on patient outcomes and coupled with CT surveillance is a cost-effective approach to the management of patients with IPNs. The conclusions drawn from this analysis are robust to realistic variation in the parameters used in the model

Adjuvant External Beam Radiotherapy Following Enucleation of Eyes With Extraocular Extension From Uveal Melanoma

PURPOSE: To report local disease control and all-cause mortality in patients with extraocular extension (EOE) of uveal melanoma undergoing enucleation followed by observation or external beam radiotherapy (EBRT). METHODS: Charts of patients enucleated between January 1, 1997 and December 31, 2019, with histopathological evidence of EOE of uveal melanoma were reviewed. RESULTS: The cohort comprised 51 patients with a mean age of 67 ± 15 years, 22 (43%) of whom underwent adjuvant postenucleation EBRT. Risk factors for metastasis included presence of epithelioid cells (29/45; 88%), closed loops (20/43; 47%), monosomy 3 (16/25; 64%), and gain of 8q (20/22; 91%). Patients undergoing EBRT had more extensive EOE (median: 5.1 mm vs. 2.6 mm, p = 0.008) and surgical excision was less likely to be histologically complete (2/20; 10% vs. 14/25; 56%, p = 0.002). Local side effects following EBRT were seen in 64% (14/22). At latest follow up, 59% of patients (30/51) were alive, with a median follow up of 1.8 years (interquartile range: 2.9; range: 0.1-6.5]. By Kaplan-Meier survival analysis, the 5- and 10-year overall survival rates were 56% and 12%, respectively. There was no difference in all-cause mortality between those receiving adjuvant EBRT and those who were observed (log rank, p = 0.273). No cases of orbital recurrence were documented. CONCLUSIONS: Orbital EBRT causes significant morbidity. Cases with relatively small EOE undergoing enucleation can be safely observed, without adjuvant EBRT. Multicenter studies are required to better assess the role of EBRT when EOE is more extensive

Early economic evaluation of an intervention to improve uptake of the NHS England Diabetes Prevention Programme (NDPP)

Background Despite reported increases in referral numbers, a large proportion of those with prediabetes still decline participation in the NHS England Diabetes Prevention Programme (NDPP). The aim of this study was to explore whether investment in interventions to improve uptake of the programme has the potential to be cost-effective. Methods An early cost-utility analysis was conducted using a Markov model parameterized based on secondary data sources. We explored different uptake scenarios and the impact that this had on the maximum allowable intervention price based on cost-effectiveness at the UK NICE willingness to pay threshold of £20,000 (US$25,913). Value of information analyses were conducted to explore the potential value of further research to resolve uncertainty at each uptake level. Results As uptake levels increase, the maximum allowable intervention price and overall expected value of removing decision uncertainty increases. For 5 percentage and 50 percentage points increase in uptake levels, the maximum allowable intervention price is £41.86 (US$ 54.23) and £418.59 (US$542.34) per person, and the overall expected value of removing decision uncertainty are £361,818,839 (US$ 468,786,625) and £1,468,712,316 (US$ 1,902,921,063) respectively. Conclusion There is headroom for investment in interventions that improve uptake to the NDPP, thereby allowing the programme itself to be delivered in a manner that remains cost-effective

Early Economic Evaluation of Diagnostic Technologies: Experiences of the NIHR Diagnostic Evidence Co-operatives

Diagnostic tests are expensive and time-consuming to develop. Early economic evaluation using decision modeling can reduce commercial risk by providing early evidence on cost-effectiveness. The National Institute for Health Research Diagnostic Evidence Co-operatives (DECs) was established to catalyze evidence generation for diagnostic tests by collaborating with commercial developers; DEC researchers have consequently made extensive use of early modeling. The aim of this article is to summarize the experiences of the DECs using early modeling for diagnostics. We draw on 8 case studies to illustrate the methods, highlight methodological strengths and weaknesses particular to diagnostics, and provide advice. The case studies covered diagnosis, screening, and treatment stratification. Treatment effectiveness was a crucial determinant of cost-effectiveness in all cases, but robust evidence to inform this parameter was sparse. This risked limiting the usability of the results, although characterization of this uncertainty in turn highlighted the value of further evidence generation. Researchers evaluating early models must be aware of the importance of treatment effect evidence when reviewing the cost-effectiveness of diagnostics. Researchers planning to develop an early model of a test should also 1) consult widely with clinicians to ensure the model reflects real-world patient care; 2) develop comprehensive models that can be updated as the technology develops, rather than taking a “quick and dirty” approach that may risk producing misleading results; and 3) use flexible methods of reviewing evidence and evaluating model results, to fit the needs of multiple decision makers. Decision models can provide vital information for developers at an early stage, although limited evidence mean researchers should proceed with caution

Cost evaluation of point-of-care testing for community-acquired influenza in adults presenting to the emergency department

Background Rapid molecular point-of-care tests (POCTs) for influenza have potential to produce cost savings in emergency departments (EDs) and acute care settings. To date, published projected savings have been based on estimated costs. Objectives This study aimed to describe the cost implications of a rapid influenza POCT using accurate real-world patient level costing data. 204 adult patients receiving point-of-care (POC) influenza testing in the ED as part of a routine clinical service were identified retrospectively, alongside a control cohort of 104 patients from the same influenza season. Costs for all were calculated at the individual patient level. Cost comparison was performed using an instrumental variable (IV) regression to overcome potential bias within the observational dataset. Results Patients who had a POCT on average cost 67 % less than those who did not (average cost reduction: £2066: 95 % CI: £624 and £2665). Moderate to high NEWS score at arrival, presence of ≥1 comorbidity, and age ≥70 years increased overall costs across both groups (p < 0.05). Conclusions Savings from POC testing can be attributed to more targeted treatments, fewer admissions and reduced lengths of stay. The IV regression results are supported by a second method (ordinary least square against baseline characteristics). They are also in line with existing work that use estimated costs but indicate greater savings than predicted previously. In conclusion, POC influenza testing in the emergency department produces significant cost savings, this is demonstrated here through an analysis using individual real-world patient level costing data