Polygenic risk scores performed poorly in population screening, individual risk prediction, and population risk prediction for common diseases, according to a review of available evidence.
Polygenic risk scores (PRS) estimate a person's disease risk based on thousands or millions of common genetic variants. The authors of a new study, published in BMJ Medicine, noted that impressive claims had been made that these scores generate "substantial" improvements in risk prediction and would "power a transformative change to healthcare".
However, new research, led by University College London (UCL), found that these endorsements for the role of PRS in healthcare "seem to be disproportionate to their performance".
Study co-author Dr Jasmine Gratton from UCL's Institute of Cardiovascular Science commented that these scores "seem attractive" because genotyping had become inexpensive, was the same for all diseases, and was performed only once because a person's genotype did not change. "However, these features are irrelevant if the test is not useful", she underlined.
Poor Performance for Prediction and Screening
For the observational study, researchers looked at 926 PRS for 310 diseases to generate estimates of performance in population screening, individual risk, and population risk stratification.
They found that for performance in population screening, the median detection rate for a 5% false positive rate for all PRS and all diseases studied was 11%. In two examples, for breast cancer and coronary artery disease, the risk scores identified only 10% and 12% of eventual cases, respectively.
Lead author Professor Aroon Hingorani from UCL's Institute of Cardiovascular Science said the "strong claims" about the potential of PRS in medicine were "not justified". He stressed that when held to the same standards as other medical testing, PRS "performed poorly for prediction and screening" across a range of common diseases.
"No Role" in Public Health Screening Programmes
The authors warned that if used alongside conventional risk factors, several thousand people would need to be PRS-profiled to guide statin prescriptions that would prevent one additional heart attack or stroke.
That the performance of PRS in the prediction of coronary artery disease was sometimes "compared favourably" with that of blood pressure and cholesterol was to "benchmark one poor predictor against another", the authors said. Indeed, using age alone to guide statin prescription would be "simpler and more effective" at preventing heart attacks and strokes without the need for genetic testing, and "broadening rather than limiting eligibility" for such interventions yielded greater public health benefits.
The researchers commented that adding PRS as first stage screening to determine who should be prioritised for mammography would "miss most women" who later developed breast cancer, "generate many false positives", and add to the burden on healthcare systems. They postulated that reducing the cutoff age for mammography for all women without determining their PRS might be more sensible.
"We found that the scores contributed little, if any, health benefit while adding cost and complexity", remarked study co-author Professor Sir Nicholas Wald from UCL's Institute of Health Informatics. He said the findings contributed to evidence that PRS "do not have a role in public health screening programmes".
Regulation and Accurate Information Needed to Protect Consumers
The researchers also suggested there was a need for regulation of commercial genetic tests based on PRS to "protect the public from unrealistic expectations and already stretched public health systems from becoming overburdened by the management of false positive results".
They added that consumers should be informed of the detection rate and false positive rate of the PRS as well as the absolute risk with and without a PRS result so they could "better judge whether the test is useful". Also, they suggested that commercial providers should communicate individual test results to customers with greater clarity and demonstrate the relevance to performance in disease prediction.
"Reality Check" on Exaggerated Claims
Commenting on the findings for the Science Media Centre, Dusko Ilic, a professor of stem cell sciences at King's College London, said the poor performance of PRS came as "no surprise" because they "overlook the significant impact of epigenetic regulation and the environment on an individual's overall health". The study served as a "necessary reality check to be wary around exaggerated claims surrounding the influence of polygenic risk scores on healthcare and health outcomes", he emphasised.
Laurence Hurst, professor of evolutionary genetics at Bath University, said the study served as a necessary caution to the current "hype" and enthusiasm for PRS methods, and that "promises for a brighter medical future" seemed more like "optimistic marketing".
However, PRS might have a use in cases in which current diagnostics were poor, such as prostate cancer, he added.