Polygenic risk score tests don’t meet expectations, U.K. study shows

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Polygenic risk scores “perform poorly in screening and prediction of common disease,” failing to identify nearly 90% of patients who develop disease, according to a U.K. study.

Researchers say commercial genetic tests based on polygenic risk scores (PRSs) are giving the public unrealistic expectations and could overburden health systems with too many false-positive results. Calling for such commercial tests to be regulated, they say consumers need to be better informed about detection and false-positive rates to judge whether they are useful, according to a new study published in BMJ Medicine.

“We found that, when held to the same standards as employed for other tests in medicine, polygenic risk scores performed poorly for prediction and screening across a range of common diseases,” said lead author Aroon Hingorani of University College London’s (UCL’s) Institute of Cardiovascular Science.

PRSs look at thousands of genetic variants across a person’s genome to estimate their risk of developing a specific disease, such as heart disease. There is debate about their utility and how commercial tests that use them are being promoted.

The U.K.’s largest health research program, Our Future Health, which aims to cover up to 5 million patients, is using the risk scores as part of efforts to inform clinical decisions, including access to screening. The UCL team looked at the performance of 926 PRSs for 310 diseases in population screening, individual risk prediction, and population risk stratification. The researchers used an open-access database, the Polygenic Score Catalog, to determine what the detection rate and false-positive rate of the scores would be if used in screening.

They found that, on average, only 11% of individuals who develop disease are identified through the scores, while 5% of people who do not develop the disease test positive. Unaffected people usually outnumber those affected, which results in far more false- than true-positive predictions, say researchers. For breast cancer and coronary artery disease, the risk scores identified only 10% and 12% of eventual cases, respectively, using a cut-off that resulted in 5% of unaffected individuals testing positive.

The scientists said that adding PRS tests as first-stage screening to determine who should be prioritized for mammography would miss most women who later develop breast cancer and generate many false positives, adding to the burden on healthcare systems.

“It has been suggested that polygenic risk scores could be introduced early on to help prevent breast cancer and heart disease but, in the examples we looked at, we found that the scores contributed little, if any, health benefit while adding cost and complexity,” said co-author Professor Sir Nicholas Wald of the UCL Institute of Health Informatics.

The researchers recommend that consumers of commercial PRS tests be informed of the detection rates and false-positive rates of the polygenic risk scores, as well as the absolute risk with and without a polygenic score result so they can better judge whether the test is useful. Hingorani and others have previously argued that most disease will occur in people who do not have a high score and say the focus on genetic risks should not divert resources away from other far greater contributors to disease and modifiable environmental risk factors.

Furthermore, most studies on PRSs have looked at patients with European ancestry, leading to concerns they will have lower predictive accuracy in other population groups. Our Future Health has highlighted the potential for polygenic and integrated risk scores to assist researchers in identifying who is at higher risk of developing diseases such as Parkinson's disease.

The UCL study was supported by the British Heart Foundation, UK Research and Innovation, the National Institute for Health and Care Research (NIHR), and the NIHR Biomedical Research Centre at University College London Hopspitals National Health Service Foundation Trust.

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