Title: Reliable Accurate Prenatal non-Invasive Diagnosis (RAPID) - an integrated project to refine and implement safer antenatal testing.
Funder: Department of Health (England)

Abstract: AIM To improve the quality of NHS prenatal diagnostic services by evaluating early non-invasive prenatal diagnosis (NIPD) based on cell free fetal (cff) DNA and RNA extracted from maternal plasma. We will: 1.Confirm laboratory standards for NIPD for: a.Fetal sex determination b.Single gene disorders c.Down’s syndrome (DS) 2.Evaluate NIPD for those indications using the ACCE framework (Analytic and Clinical validity, Clinical utility, and Ethical, legal and social aspects) including: a.Evaluating cost effectiveness b.Determining couples’ choices, preferences and needs c.Considering wider ethical, legal and social issues d.Developing competences for health professionals 3.Develop an implementation plan for use by commissioners to establish NIPD as an NHS service. BACKGROUND Current prenatal genetic diagnosis requires invasive testing from 11 weeks and carries a 1% miscarriage risk. cffDNA and cffRNA in maternal blood offer a source of fetal genetic material which will be safer to obtain, requiring only a maternal blood sample, allowing earlier diagnosis and potential health service savings due to fewer invasive tests and patient episodes. Some NHS laboratories already offer limited NIPD and there is an urgent need to evaluate it thoroughly including the sensitivity, specificity and clinical utility with development of laboratory and clinical standards before it ‘seeps’ further into practice. RESEARCH PLANS Our work will focus on developing an implementation plan. It forms three integrated workstreams: 1.Technology development 2.Evaluation 3.Implementation We will address three uses for NIPD: a. Medically indicated sex determination b. Single gene disorder diagnosis c. DS diagnosis Clinical cohorts will form the study base including women: i. undergoing fetal sex determination using NIPD for medical reasons ii. having standard prenatal diagnosis for cystic fibrosis, thalassaemia & HbSC, FGFR2 & FGFR3 mutations (Achondroplasia, Aperts etc) iii. undergoing NIPD for conditions in (ii) iv. with a high DS screening risk in 3 district hospitals v. recruited at booking before DS screening 1. Technology development For fetal sexing and single gene disorders NIPD will be based on detection or exclusion of paternally inherited alleles or those arising denovo.Thus for X-linked and recessive conditions detection of Y sequences or the paternal allele indicates need for invasive testing but absence suggest an unaffected fetus. For DS, the utility of cffRNA single nucleotide polymorphisms (SNPs) allelic ratios in UK populations will be evaluated using published SNPs and others we have developed. For all uses, the sensitivity and specificity of NIPD using cffDNA and RNA extracted from maternal blood will be evaluated, and standard operating procedures and reference materials developed NIPD for sex determination is already in limited use and standards for this will be developed early in the project. We anticipate offering NIPD for the other conditions later in the programme. 2. Evaluation a. Economic analysis will evaluate cost, cost-effectiveness and budget impact of NIPD for all 3 uses using standard methods and data collected from the clinical cohorts. b. Couples views and information needs will be determined using one-to-one interviews, questionnaires and focus groups with those at risk of disorders being tested. Conjoint analysis will be used to determine their preferences for testing. c. Wider ethical issues will be explored using conceptual ethical analysis and a vignette study of health professionals to determine whether NIPD will impair counselling and informed choice. d. Education requirements will be determined by needs analysis mapped against the national competences 3. Implementation Workshops with stakeholders will identify implementation issues. These will be used with data from workstreams 1 and 2 to produce a comprehensive plan to aid commissioners with the introduction of NIPD RESEARCHERS AND ENVIRONMENT The team includes most UK groups interested in NIPD, members of relevant national bodies, lay groups and a combination of reference, service and academic labs supported by clinicians and social scientists experienced in genetic health service delivery OUTPUTS A detailed implementation plan with standards for NIPD Evaluation of NIPD for DS If the project results in increased use of NIPD a further output will be the impact on the NHS and pregnant women from potentially fewer invasive tests and miscarriages. PUBLIC INVOLVEMENT GIG is a co-applicant. The public are very involved as a key element is to understand public perceptions of and preferences for prenatal diagnosis ETHICAL IMPLICATIONS Ethical aspects associated with safer, more accessible prenatal diagnosis will be explored. We have ethics approval for some work. It will be sought for other aspects of the study JUSTIFICATION We seek funding to recruit cases, perform laboratory analysis and disseminate information


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS;8.1 ORGANISATION AND DELIVERY OF SERVICES;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH