Large-scale genetic risk analysis could make abdominal aortic aneurysm screening more cost-effective

Overview

Currently all men aged 65 in the UK are screened for a serious condition called abdominal aortic aneurysm (AAA), but there are doubts about its ongoing cost-effectiveness. This study set out to investigate whether using the technique of building polygenic risk scores (PRS) could help to target screening to those at highest risk. Findings suggest that PRS and smoking-informed screening in men over 60 who are smokers could accurately pick up those at highest risk of AAA, while reducing the overall number of people that need to be screened by 41%.

The challenge

AAA is an enlargement of the aorta, the heart’s major artery, which can lead to a fatal rupture if left untreated. In the UK, all men aged 65 are currently offered an NHS ultrasound scan to check for AAA. Although in over-65s it still accounts for 0.8% of deaths in men and 0.4% in women, fewer people now get the disease than when the screening was first introduced. This suggests that the current screening approach may no longer be cost-effective. What is more, it might also be failing to find at-risk people outside the scope of the existing screening programme such as women, or men who develop AAA after the age of 65.

The solution

AAA is known to run in families, with a heritable component accounting for up to 70% of the total risk. This study set out to develop a state-of-the-art prediction tool to stratify (group) people according to genetic traits that are linked to disease risk, as captured by polygenic risk scores (PRS). The potential use of these groups to improve screening was then evaluated.

Cigarette smoking has previously been linked to a seven-fold higher risk of AAA in men, and a 15-fold higher risk in women. Therefore, alongside the PRS, the study also incorporated information on smoking to see if that could further improve screening.

Dr Martin Kelemen and the research team, led by Dr Lois Kim at the University of Cambridge and part-funded by HDR UK, developed the PRS by combining information from 21 linked conditions from 260,911 individuals from the UK Biobank, together with summary data from other studies. The team evaluated their PRS on a withheld test dataset and then used a simulation model to see how best to use this information to inform screening for AAA and what the improvements might be.

The impact

Findings showed that if PRS and smoking status are used to determine age at invitation, the overall cost-effectiveness of screening in men could be improved. What is more, it would reduce the number of scans by 41%. Specifically, the model suggested the most cost-effective option was screening male smokers with a high PRS at age 60, and all other men at age 62 except non-smokers with low PRS. In women, offering screening to a very targeted subgroup may be cost-effective; specifically, inviting current smokers with high PRS at age 65 and ex-smokers with high PRS at 70.

“Incorporating polygenic risk and smoking stratification could reduce the number of scans without increasing the number of deaths or increasing the number of operations that would be needed. That is because this approach to grouping does a really good job of identifying the people who are at highest risk,” explains Dr Lois Kim, the senior author of the study.

Putting these findings into practice would depend on a future scenario in which genomic screening was offered to the whole population and used across a range of different diseases, in order to spread the cost. Current initiatives to support its introduction would allow approaches like the one evaluated in this study to become part of routine care.