Every year, thousands of newborns in the UK have a tiny blood sample taken from their heel to screen for rare but treatable diseases. This project aims to give the UK National Screening Committee a clear, practical guide on how to properly evaluate the accuracy of those screening tests—something that is surprisingly difficult to do when a condition affects only a handful of babies per year. The core problem is that the evidence used to decide whether to introduce a new screening test is often weak. Small patient numbers, variable disease severity, and the need for years of follow-up to catch missed cases make standard study designs unreliable. Without robust methods, the UK risks either missing babies who could benefit from early treatment or causing harm through false positives and overdiagnosis. If this guidance succeeds, it will directly improve how the UK decides which rare diseases to screen for at birth. Better study designs will produce stronger evidence, leading to screening programmes that catch more treatable conditions while minimising unnecessary anxiety and medical intervention. The framework will also cover emerging technologies like whole genome sequencing, ensuring the NHS is prepared for the next generation of newborn screening.
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Background: Newborn bloodspot (NBS) screening offers the potential to detect rare diseases early, enabling timely treatment that can reduce mortality and morbidity. Decision-making about screening programme introduction in the UK is guided by a broad set of evidence criteria. These criteria ensure that the benefits gained from screening are considered alongside the potential harms, including overdiagnosis and treatment, the impact of false positive results and uncertain findings including variants of unknown significance. The evidence base for newborn screening for rare conditions usually relies on observational studies about test accuracy and benefits from earlier intervention. Challenges in conducting high quality research include small numbers of cases, variation in the spectrum of disease and complexities in defining the target condition, and the requirement for lengthy follow-up for either screen positives (who may receive treatment that modifies the course of disease) or screen negative (where variable time to manifestation of disease could affect ascertainment of false negatives). The aim of this project is to provide the UK NSC with guidance on the evidence needed to evaluate the accuracy of NBS screening, and ultimately, to improve the quality of the available evidence base in order to support better decision making about new or modified screening programmes. This guidance will specifically consider the merits and limitations of available study designs for evaluating test accuracy at each phase of development and will explicitly address known methodological challenges in NBS screening. Approach: The project will be conducted in four phases. 1. a representative sample of recently published primary studies evaluating screening tests in the NBS screening setting will be reviewed and characterised to establish current practice for evaluation of the accuracy of NBS screening and gain empirically based insights into methodological challenges of evaluating the clinical performance of tests in NBS screening settings, 2. a conceptual framework for the development and evaluation of tests and testing strategies for NBS screening will be developed. The framework will specifically consider designs relevant for establishing the accuracy of tests suitable for NBS screening and the accuracy of NBS screening programmes as a whole, while taking into account the explanatory-pragmatic continuum of test evaluation questions. The framework will be designed to cover both ‘traditional’ approaches to NBS screening and screening using molecular genetic tests such as whole genome sequencing. 3. the review of primary studies and conceptual framework will inform the development of a UK NSC position paper providing guidance on available test accuracy study designs suitable for use in an NBS screening setting. The advantages and disadvantages of available methods will be considered and outlined, 4. options for future research activity that could help to guide researchers towards test accuracy study design and delivery that meets UK NSC needs will be outlined. Study registration: The protocol is registered on the Open Science Framework (https://doi.org/10.17605/OSF.IO/85MV6) Funding details: This study is funded by the NIHR Evidence Synthesis Programme (ESG_HTA_NIHR168057). The views expressed are those of the author(s) and not necessarily those of the NIHR, the Department of Health and Social Care or the UK NSC.
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