Preferences for Prenatal Tests for Cystic Fibrosis: A Discrete Choice Experiment to Compare the Views of Adult Patients, Carriers of Cystic Fibrosis and Health Professionals

As new technologies enable the development of non-invasive prenatal diagnosis (NIPD) for cystic fibrosis (CF), research examining stakeholder views is essential for the preparation of implementation strategies. Here, we compare the views of potential service users with those of health professionals who provide counselling for prenatal tests. A questionnaire incorporating a discrete choice experiment examined preferences for key attributes of NIPD and explored views on NIPD for CF. Adult patients (n = 92) and carriers of CF (n = 50) were recruited from one children’s and one adult NHS specialist CF centre. Health professionals (n = 70) were recruited via an e-mail invitation to relevant professional bodies. The key attribute affecting service user testing preferences was no miscarriage risk, while for health professionals, accuracy and early testing were important. The uptake of NIPD by service users was predicted to be high and includes couples that would currently decline invasive testing. Many service users (47%) and health professionals (55.2%) thought the availability of NIPD for CF would increase the pressure to undergo prenatal testing. Most service users (68.5%) thought NIPD for CF should be offered to all pregnant women, whereas more health professionals (68.2%) thought NIPD should be reserved for known carrier couples. The implications for clinical practice are discussed

The role of sonographic phenotyping in delivering an efficient non-invasive prenatal diagnosis (NIPD) service for FGFR3-related skeletal dysplasias

Objectives: To evaluate the diagnostic yield of noninvasive prenatal diagnosis (NIPD) for FGFR3‐related skeletal dysplasias and assess the accuracy of referrals based on sonographic findings to inform guidelines for referral. Methods: We retrospectively reviewed laboratory and referral records from 2012 to 2018 to ascertain all NIPD tests performed using our next generation sequencing panel to detect FGFR3 mutations. We calculated the diagnostic yield of the test overall and when sub‐divided according to the phenotypic features identified on ultrasound before testing. Pregnancy outcomes were ascertained wherever possible from referring centers. Results: Of 335 tests, 261 were referred because of sonographic findings, of which 80 (31.3%) had a mutation. The diagnostic yield when short limbs were the only abnormal sonographic feature reported was 17.9% (30/168), increasing to 48.9% (23/47) in the presence of one, and 82.6% (19/23) in the presence of two or more characteristic features in addition to short limbs. Conclusions: Accurate sonographic phenotyping can maximise the diagnostic yield of NIPD in fetuses suspected to have FGFR3‐related skeletal dysplasias. We suggest that clear guidelines for referral are necessary to increase benefits, decrease costs by preventing unnecessary NIPD, and potentially allow first‐line broader spectrum testing for fetuses where the aetiology may be more heterogeneous

Evaluation of a novel assay for detection of the fetal marker RASSF1A: facilitating improved diagnostic reliability of noninvasive prenatal diagnosis

BackgroundAnalysis of cell free fetal (cff) DNA in maternal plasma is used routinely for non invasive prenatal diagnosis (NIPD) of fetal sex determination, fetal rhesus D status and some single gene disorders. True positive results rely on detection of the fetal target being analysed. No amplification of the target may be interpreted either as a true negative result or a false negative result due to the absence or very low levels of cffDNA. The hypermethylated RASSF1A promoter has been reported as a universal fetal marker to confirm the presence of cffDNA. Using methylation-sensitive restriction enzymes hypomethylated maternal sequences are digested leaving hypermethylated fetal sequences detectable. Complete digestion of maternal sequences is required to eliminate false positive results.MethodscfDNA was extracted from maternal plasma (n = 90) and digested with methylation-sensitive and insensitive restriction enzymes. Analysis of RASSF1A, SRY and DYS14 was performed by real-time PCR.ResultsHypermethylated RASSF1A was amplified for 79 samples (88%) indicating the presence of cffDNA. SRY real time PCR results and fetal sex at delivery were 100% accurate. Eleven samples (12%) had no detectable hypermethylated RASSF1A and 10 of these (91%) had gestational ages less than 7 weeks 2 days. Six of these samples were male at delivery, five had inconclusive results for SRY analysis and one sample had no amplifiable SRY.ConclusionUse of this assay for the detection of hypermethylated RASSF1A as a universal fetal marker has the potential to improve the diagnostic reliability of NIPD for fetal sex determination and single gene disorders

Non-invasive prenatal testing for aneuploidy, copy number variants and single gene disorders

The discovery of cell-free fetal DNA (cffDNA) in maternal plasma has enabled a paradigm shift in prenatal testing, allowing for safer, earlier detection of genetic conditions of the fetus. Non-invasive prenatal testing (NIPT) for fetal aneuploidies has provided an alternative, highly efficient approach to first-trimester aneuploidy screening, and since its inception has been rapidly adopted worldwide. Due to the genome-wide nature of some NIPT protocols, the commercial sector has widened the scope of cell-free DNA (cfDNA) screening to include sex chromosome aneuploidies, rare autosomal trisomies and sub-microscopic copy-number variants. These developments may be marketed as ‘expanded NIPT’ or ‘NIPT Plus’ and bring with them a plethora of ethical and practical considerations. Concurrently, cfDNA tests for single-gene disorders, termed non-invasive prenatal diagnosis (NIPD), have been developed for an increasing array of conditions but are less widely available. Despite the fact that all these tests utilise the same biomarker, cfDNA, there is considerable variation in key parameters such as sensitivity, specificity and positive predictive value depending on what the test is for. The distinction between diagnostics and screening has become blurred, and there is a clear need for the education of physicians and patients regarding the technical capabilities and limitations of these different forms of testing. Furthermore, there is a requirement for consistent guidelines that apply across health sectors, both public and commercial, to ensure that tests are validated and robust and that careful and appropriate pre-test and post-test counselling is provided by professionals who understand the tests offered

Non-invasive prenatal testing for aneuploidy: a systematic review of Internet advertising to potential users by commercial companies and private health providers.

BACKGROUND: The development of non-invasive prenatal testing has increased accessibility of fetal testing. Companies are now advertising prenatal testing for aneuploidy via the Internet. OBJECTIVES: The aim of this systematic review of websites advertising non-invasive prenatal testing for aneuploidy was to explore the nature of the information being provided to potential users. METHODS: We systematically searched two Internet search engines for relevant websites using the following terms: 'prenatal test', 'antenatal test', 'non-invasive test', 'noninvasive test', 'cell-free fetal DNA', 'cffDNA', 'Down syndrome test' or 'trisomy test'. We examined the first 200 websites identified through each search. Relevant web-based text was examined, and key topics were identified, tabulated and counted. To analyse the text further, we used thematic analysis. MAIN RESULTS: Forty websites were identified. Whilst a number of sites provided balanced, accurate information, in the majority supporting evidence was not provided to underpin the information and there was inadequate information on the need for an invasive test to definitely diagnose aneuploidy. CONCLUSIONS: The information provided on many websites does not comply with professional recommendations. Guidelines are needed to ensure that companies offering prenatal testing via the Internet provide accurate and comprehensible information

Process improvement for ST-10 applications for exemption certificate processing

Delayed processing time for ST-10 exemption certificates to be issued to the taxpayers of South Carolina. The goal of this project is to reduce the processing time of the issuance of the exemption certificates to the taxpayers of South Carolina (currently a forty-five day response as a standard guideline)

Time and travel costs incurred by women attending antenatal tests: A costing study

OBJECTIVE: to estimate the costs to women, their friends and family for different antenatal tests in the Down's syndrome (DS) screening pathway. DESIGN: questionnaire-based costing study. SETTING: eight maternity clinics across the UK. PARTICIPANTS: pregnant women (n=574) attending an appointment for DS screening, NIPT or invasive testing between December 2013 and September 2014. MEASUREMENTS: using data collected from the questionnaires we calculated the total costs to women by multiplying the time spent at the hospital and travelling to and from it by the opportunity costs of the women and accompanying person and adding travel and childcare costs. Assumptions about the value of opportunity costs were tested in one-way sensitivity analyses. The main outcome measure was the mean cost to the women and friends/family for each test (DS screening, NIPT, and invasive testing). FINDINGS: mean costs to women and their family/friend were £33.96 per visit, of which £22.47 were time costs, £9.15 were travel costs and £2.34 were childcare costs. Costs were lowest for NIPT (£22), £32 for DS screening (£44 if combined with NIPT), and highest for invasive testing (£60). Sensitivity analysis revealed that variations around the value of leisure time opportunity costs had the largest influence on the results. KEY CONCLUSIONS: there are considerable costs to women, their friends and family when attending different tests in the DS screening pathway. IMPLICATIONS FOR PRACTICE: when assessing the cost-effectiveness of changes to this pathway, costs to women should be considered

Prenatal management of disorders of Sex development

Disorders of sex development (DSD) rarely present prenatally but, as they are very complex conditions, management should be directed by highly specialised medical teams to allow consideration of all aspects of diagnosis, treatment and ethical issues. In this brief review, we present an overview of the prenatal presentation and management of DSD, including the sonographic appearance of normal genitalia and methods of determining genetic sex, the prenatal management of pregnancies with the unexpected finding of genital ambiguity on prenatal ultrasound and a review of the prenatal management of pregnancies at high risk of DSD. As this is a rapidly developing field, management options will change over time, making the involvement of clinical geneticists, paediatric endocrinologists and urologists, as well as fetal medicine specialists, essential in the care of these complex pregnancies. The reader should also bear in mind that local social, ethical and legal aspects may also influence management

Non-invasive prenatal diagnosis (NIPD) for single gene disorders: cost analysis of NIPD and invasive testing pathways

OBJECTIVE: Evaluate the costs of offering non-invasive prenatal diagnosis (NIPD) for single gene disorders compared to traditional invasive testing to inform NIPD implementation into clinical practice. METHOD: Total costs of diagnosis using NIPD or invasive testing pathways were compared for a representative set of single gene disorders. RESULTS: For autosomal dominant conditions, where NIPD molecular techniques are straightforward, NIPD cost £314 less than invasive testing. NIPD for autosomal recessive and X-linked conditions requires more complicated technical approaches and total costs were more than invasive testing, e.g. NIPD for spinal muscular atrophy was £1090 more than invasive testing. Impact of test uptake on costs was assessed using sickle cell disorder as an example. Anticipated high uptake of NIPD resulted in an incremental cost of NIPD over invasive testing of £48 635 per 100 pregnancies at risk of sickle cell disorder. CONCLUSIONS: Total costs of NIPD are dependent upon the complexity of the testing technique required. Anticipated increased demand for testing may have economic implications for prenatal diagnostic services. Ethical issues requiring further consideration are highlighted including directing resources to NIPD when used for information only and restricting access to safe tests if it is not cost-effective to develop NIPD for rare conditions

Constitutive Soil Properties for Unwashed Sand and Kennedy Space Center

Accurate soil models are required for numerical simulations of land landings for the Orion Crew Exploration Vehicle. This report provides constitutive material models for one soil, unwashed sand, from NASA Langley's gantry drop test facility and three soils from Kennedy Space Center (KSC). The four soil models are based on mechanical and compressive behavior observed during geotechnical laboratory testing of remolded soil samples. The test specimens were reconstituted to measured in situ density and moisture content. Tests included: triaxial compression, hydrostatic compression, and uniaxial strain. A fit to the triaxial test results defines the strength envelope. Hydrostatic and uniaxial tests define the compressibility. The constitutive properties are presented in the format of LS-DYNA Material Model 5: Soil and Foam. However, the laboratory test data provided can be used to construct other material models. The four soil models are intended to be specific to the soil conditions discussed in the report. The unwashed sand model represents clayey sand at high density. The KSC models represent three distinct coastal sand conditions: low density dry sand, high density in-situ moisture sand, and high density flooded sand. It is possible to approximate other sands with these models, but the results would be unverified without geotechnical tests to confirm similar soil behavior