Title: Optimising EXome PREnatal Sequencing Services - EXPRESS
Funder: Department of Health and Social Care

Abstract: Genome and exome sequencing are new tests that will soon be offered more widely in the NHS. Every cell in our bodies has a set of instructions for making us, just like a recipe book. This set of instructions is called our genome. Our genome is made of DNA (deoxyribonucleic acid) that has four chemical 'letters' (A, C, G and T) arranged in different sequences. Exomes are part of our genomes. The DNA from our exomes holds the information for making the proteins that play an important role in how we develop. Changes in our DNA sequence can cause genetic conditions that can be diagnosed by sequencing tests that look in detail at our DNA. _x000D_ _x000D_ A new national NHS Genomic Medicine Service based around 7 laboratory hubs located across England began in October 2018. Prenatal exome sequencing will be offered to pregnant women when ultrasound scans suggest the baby may have a genetic condition that cannot be diagnosed using standard tests. This will increase the chance of finding a cause for the unexpected findings seen on the scan. If a genetic condition is diagnosed this can give parents important information about the outlook for their baby. It can also help with their decisions about whether to continue or end the pregnancy, pregnancy management, post-birth care and future pregnancies. _x000D_ _x000D_ This study aims to investigate the new prenatal exome sequencing service to provide evidence that will improve pregnancy care. _x000D_ _x000D_ We will;_x000D_ _x000D_ 1. Study all 7 laboratory hubs to see what the exome sequencing service looks like in practice. Information will be collected using surveys, interviews and observations to get a clear picture of what happens when a problem is found in pregnancy and exome sequencing is offered_x000D_ _x000D_ 2. Interview parents to ask what they think of exome sequencing, what they understand, and how support and information could be improved_x000D_ _x000D_ 3. Look at how many parents have exome sequencing, test results and pregnancy outcomes. Any differences between the seven laboratory hubs will be studied to work out why they occur. We will also look carefully at whether any particular groups are less likely to access testing, e.g. people of different ages, ethnic minority groups, or those living in certain parts of the country_x000D_ _x000D_ 4. Arrange interviews with parents and workshops with health professionals to identify any practical or ethical problems that arise when exome sequencing is offered_x000D_ _x000D_ 5. Look at the cost of exome sequencing and compare it to other prenatal tests that are offered to diagnose genetic conditions in pregnancy_x000D_ _x000D_ 6. Gather all our findings together to see what works and what doesn’t work. We will make recommendations for best practice that include how to make sure everyone has equal access to exome sequencing and high quality information to help them to make informed decisions_x000D_ _x000D_ Our research team includes experts in prenatal testing, patient advocates and academics experienced in this type of research. A Steering Committee with academic researchers, members of professional groups, parents and the public will guide our research. A Patient and Public Involvement Advisory Group (PPIAG), including parents with experience of prenatal diagnosis of genetic conditions, will work closely with the research team to design the study and develop useful materials. The PPIAG will also help us understand our findings to make sure the information and recommendations that come out of our research will be helpful to parents, families and the NHS.

Lay abstract: BACKGROUND: In 2020 the new NHS Genomic Medicine Service will begin to offer fetal exome sequencing (ES) for pregnancies where fetal anomalies identified by ultrasound are likely to have a genetic aetiology, as judged by a clinical geneticist. Fetal ES will be delivered through seven new genomic laboratory hubs (GLHs) across England. Fetal ES is an innovative new test with the potential to significantly improve NHS prenatal diagnostic services by increasing genetic diagnoses in a timeframe that informs prenatal decision-making. Fetal ES has not, however, previously been offered routinely in a national healthcare system and there are only minimal guidelines for its use. Research is urgently needed to guide implementation to maximise benefits for parents while optimising NHS resources._x000D_ _x000D_ AIM: To conduct a formative and summative mixed-methods evaluation of the new fetal ES service that will provide feedback to ensure national delivery of an equitable, acceptable, ethical, robust and cost-effective care pathway that improves the quality of care for parents undergoing prenatal diagnosis in fetuses with anomalies likely to have a genetic aetiology._x000D_ _x000D_ METHODS: A Steering Committee with academic, professional and patient members will provide oversight and a Patient and Public Involvement Advisory Group will input into all activities. Study design draws on a framework developed in previous studies of major system innovation as well as Normalisation Process Theory. There are six interrelated workstreams (WSs). WS1 will use staff interviews, surveys, non-participant observations and documentary analysis to determine clinical care pathways and produce in-depth case studies at each GLH. Data collection at multiple time points will allow tracking of service changes over time. In WS2 qualitative interviews with parents offered fetal ES or with previous experience of fetal anomalies will explore views and establish information and support needs. WS3 will analyse testing data over a 12-month period to establish service outcomes (diagnostic yield, referral rates, referral sources, final diagnoses). Data sources include; the new National Genomic Information System (NGIS) and GLH and fetal medicine databases. Statistical comparisons will identify factors (individual or service-related) associated with variation in outcomes. WS4 will analyse ethical issues associated with introducing fetal ES and develop an ethical framework for an optimal and equitable service. WS5 will determine costs and cost-effectiveness of fetal ES versus standard tests and evaluate costs of implementing an optimal fetal ES pathway. WS6 will integrate all findings and conduct workshops to determine the key features of an optimal care pathway from a service delivery, patient and professional perspective. Wide dissemination will include peer reviewed publications, reports, policy statements and lay summaries._x000D_ _x000D_ MAIN BENEFITS: The proposed formative and summative research will inform the development of a fetal ES service that delivers equity of access and high standards of care across England with an associated improvement in prenatal diagnostic services and benefits for patients. Findings will be shared on a regular basis to facilitate improvements in service delivery. This work will also be an exemplar for evaluating other aspects of the Genomic Medicine Service and, as the NHS is an early adopter, our findings may be useful to others internationally as they implement similar services.

Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH