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Coming to terms with the realities of mass genomic testing

Mass genomic testing asymptomatic people is currently underway and under discussion in many places throughout the world. However, there needs to be a realistic assessment of how it will improve healthcare.

The Times Newspaper on January 2nd 2023 stated that “Millions of Britons will have their DNA analysed in two groundbreaking projects that scientists expect to confirm the UK as a world leader in genomics.” One project, “Our Future Health” will have the DNA extracted, genotype about 900,000 variants, and potentially perform whole genome sequencing in the future, on five million UK adults with the results linked to routine medical records. The cost is £229 million, about one third from public and the rest from biopharmaceutical companies.1 The other project, the “Newborn Genomes Programme” will determine the genomes of 100,000 babies. The estimated cost of the project is about £105 million.2 These projects, and the debate over the expected value of mass genomic testing have an immediate relevance to the UK but the discussion over its merits will undoubtedly have an international relevance where similar projects are underway or under discussion.

Exactly how these projects and other similar ones will improve healthcare is unclear. Mass genomic sequencing asymptomatic people may come up with occasional insights but there is a high probability that it will be a waste of public money and an unwise diversion of resources. The two projects are what some call “fishing expeditions” using a technology (DNA analysis) in search of worthwhile applications. These projects however are based upon the misconception that applying the technology on an increasingly massive scale must be a worthwhile research application. Genomic sequencing has given birth to the field of genomics with many scientific insights and clinical uses; this has led to a view that population-scale mass application of the technology is bound to be a good use of research resources. Though, in our view, mistaken, it is easy to see how it can be thought that it must be in the national interest to exploit these advantages by applying them in mass testing.

Both the two new projects are effectively screening projects with little consideration given to the requirements of such testing, including the requirement that associations between a risk factor (including a genetic factor) and a disease must be very strong for the risk factor to be a useful screening test3 and that an effective intervention is available that is more effective early in the natural history of the disease than at clinical presentation.4 Early detection of disease is not enough; the early detection of a disease without an effective intervention causes more harm than good with significant human and financial costs to medical staff and those being tested. False positives are likely to be a serious concern. Almost everyone tested will have a pathogenic genetic variant, even if this is limited to carriers of autosomal recessive disorders. The genomic data from the projects may identify new or improved methods of worthwhile screening for, as yet, unspecified medical disorders but the chances are slim because of weak genetic–disease associations as shown in studies on polygenic risk scores.5 It would be more cost-effective to specify a medical condition for which there may be a remedy and then carry out a genomic case-control study to determine the presence and strength of any genetic variant. The idea that the incremental gains from sequencing ever more individual genomes will be useful is not self-evident.

Mass genomic testing may lead to the discovery of a genetic variant associated with a disease. Even if it explains a small fraction of cases of the disease it might provide a clue to developing a treatment that could be useful for people with the disease but without the genetic variant, perhaps by identifying a causal pathway to reveal such a possibility. Such an objective, for which large scale mass testing is probably unnecessary, is a ‘long shot’ that should not be conflated with unjustified claims that the information from mass genomic tests will be useful in screening and disease prediction.

We are witnessing a DNA bandwagon. Technically, DNA sequencing has come of age and in the process of looking for a useful application has generated considerable ‘hype’ based more on hope than expectation. This is not to say that genomic research is unnecessary. On the contrary, it is important, but its use should be focused to important medical questions. It is also not to deny the value of serendipity in research but this is not really a justification for mass genomic sequencing. The mass application of a technology, just because it is possible, is not a good use of resources.

There is a need to take stock of the realistic expectations from mass genomic analysis. At the same time it would be appropriate to review research priorities to focus on the prevention and treatment of serious diseases, such as dementia and multiple sclerosis, that require multiple technologies rather than on a single technology in search of multiple diseases.

Nicholas J. Wald FRS and Robert Old PhD.

1. Mullard, A. (2023). Disease interception at scale: how a five-million-person study plans to transform healthcare. Nature Reviews Drug Discovery, 22, pp. 10-11.
2. Department of Health and Social Care, (2022, December 13). Over £175 million for cutting-edge genomics research. gov.uk. Retrieved from https://www.gov.uk/government/news/over-175-million-for-cutting-edge-genomics-research
3. Wald, N., Hackshaw, A., & Frost, C. (1999). When can a risk factor be used as a worthwhile screening test? British Medical Journal (Clinical research ed.), 319(7224), pp. 1562-1565.
4. Wald, N., & Law, M. (2010). Medical Screening. In D. Warrell, T. Cox, & J. Firth, Oxford Textbook of Medicine (5th Edn ed) Oxford: Oxford University Press, pp. 94-108.
5. Wald, N. J., & Old, R. (2019). The illusion of polygenic disease risk prediction. Genetics in Medicine, 21(8), 1705-1707. doi:https://doi.org/10.1038/s41436-018-0418-5

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