The strengths and limitations of methods and mechanisms for evaluating the benefits and harms of newborn blood spot screening

Background: Newborn blood spot (NBS) screening offers the potential to detect rare conditions 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 overtreatment, 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 strengths and limitations of available methods and mechanisms for evaluating the benefits and harms of NBS screening. The goal is to stimulate further discussions about improving available evaluation mechanisms and pave the way for further work around approaches to improve the quality of the available evidence base for the evaluation of outcomes from NBS screening. Approach: The project will be conducted in three phases. 1. a review of published primary research studies will be conducted to provide a methodological overview of approaches (study designs, methods and mechanisms) used to evaluate the impact of NBS screening on health, social and educational outcomes 2. a review of methods literature will be conducted to identify alternative approaches to evaluating the benefits and harms from NBS screening. The review will consider methodological issues relevant to ‘traditional’ approaches to NBS screening as well as the use of genomic sequencing to potentially screen for multiple conditions at the same time. 3. the review of primary studies and methods literature, together with expert consultation, will inform the development of guidance for the UK NSC that considers the strengths and limitations of available methods and mechanisms for evaluating the benefits and harms of NBS screening.