In a study published in Nature Medicine, researchers report details of how they set up a genetic assay for six common diseases and developed explanatory reports to help bridge the gap between science and clinical care.
The assay and reports were created for the GenoVA study, a clinical trial that aims to determine whether polygenic risk scores (PRSs), also known as polygenic scores (PGSs), could be used effectively in a primary care setting. The randomized trial will enroll 1000 patients at the Veterans Affairs Boston Healthcare System and will follow them for 2 years.
The authors report early data from the new laboratory test. For the 227 participants enrolled so far, 11% had a high risk for atrial fibrillation, 7% were at risk for coronary artery disease, 8% for type 2 diabetes, 6% for colorectal cancer, 15% of men had an increased prostate cancer risk, and 13% of women were at increased risk for breast cancer.
Polygenic scores are promising for informing screening and treatment decisions, with the goal of preventing chronic disease. Jason Vassy, MD, of Brigham and Women's Hospital and VA Boston, says, "It is important to think of PRS as one risk factor for disease, not a diagnostic test or an indication that an individual will certainly develop the disease."
He continues, "Most diseases have complex, multifactorial etiologies, and a high PRS is just one piece of the puzzle. PRS do not replace the traditional risk factors we usually think about in clinical medicine, such as diet and exercise to prevent type 2 diabetes and smoking cessation to lower cardiovascular disease risk."
Currently, clinical genetic testing is typically performed when a patient is suspected of having a specific disease or a family history of a condition, such as sickle cell disease or breast cancer. Tests for these types of conditions are often monogenic, detecting only select mutations.
PRS tests have the potential to inform clinical decisions years before patients become symptomatic. The PRS testing in this study combines large quantities of genetic information to assess a patient's risk for multiple conditions. The risk for common chronic conditions can involve hundreds to millions of small genetic variations. Alone, these variations have minimal impact on a person's risk for disease, but together they can lead to an increased risk for specific conditions.
Certain PRS tests are currently available from direct-to-consumer laboratories, in oncology, and through some clinical trials, but they're not commonly used in general practice.
Vassy and colleagues developed and validated PRSs for atrial fibrillation, coronary artery disease, type 2 diabetes, breast cancer, colorectal cancer, and prostate cancer at the Mass General Brigham Laboratory for Molecular Medicine.
The team calculated the final PRS on the basis of individual patient genotyping combined with statistical population models.
In the GenoVA study, adults aged 50–70 years who have no previous history of disease provide saliva or blood for PRS testing at the Boston VA. Participants are stratified by risk result and are randomly assigned to receive test results either immediately or after 24 months.
Enrollees are then followed for 2 years to observe how they and their primary care providers use risk score information and whether any preventive measures or other clinical tests are employed. Guidelines are provided to patients and clinicians throughout the study, along with genetic counseling. Ultimately, the study seeks to determine whether PRS implementation improves health outcomes.
Study participants are from diverse backgrounds; 52% of the first 227 patients report non-White, non-Hispanic ethnicity. To adjust for the fact that most genomic research to date has been based on European populations, researchers used statistical methods to calculate scores across racial groups.
Genome wide association studies (GWASs) from more inclusive datasets are needed to improve the relevance of PRS across ancestry groups, the authors write.
Vassy points out, "The risk estimates from GWAS are the underpinnings of the polygenic scores, so a score is only as valid as its original." Fortunately, he adds, "advances are occurring on multiple fronts, and this will be key to promoting the equitable implementation of polygenic scores. Larger, more diverse cohorts are being recruited for GWAS studies, and more sophisticated, trans-ancestry statistical GWAS methods are being developed to analyze these more diverse data."
In England, researchers are considering the benefits of using polygenic scores in National Health Service checks for cardiovascular disease, a well-studied area of genetic risk. The new article and the English effort draw from the PGS Catalogue, an open database built by Samuel Lambert, of the University of Cambridge Department of Public Health and Primary Care, and his colleagues to provide scores and methods that can be reused and adapted for clinical use.
He says he'd recommend PRS with confidence to his family members — in particular, certain in-depth cancer assays — "provided [the results] would be interpreted in collaboration with a healthcare professional who understands genetics (eg, a genetic counselor) with carefully vetted information on the validity and actionability of the test result."
Lambert feels it's important to understand that PRS testing isn't deterministic. "The risk information is inherently probabilistic and relative (eg, you have a four times' higher risk than the average person, but if the disease prevalence is 0.5%, this is a small absolute difference)," he says.
"The PRS also explains a fraction of the variability of risk in the population and thus shouldn't be used alone but in combination with other established risk factors and tools to predict future risk when they exist," Lambert says.
"And thirdly, most current PRS are less accurate in those of non-European ancestry due to a lack of ancestral diversity in the cohorts and datasets that have been used to develop these PRS; special attention must be paid to make sure that the PRS results are valid for the individual," he adds.
Funding for the study was provided by the NIH National Human Genome Research Institute and the NIH, the American Heart Association, the National Heart, Lung and Blood Institute, the National Institute of Diabetes and Digestive and Kidney Diseases, and Massachusetts General Hospital. Vassy is an employee of the US Department of Veterans Affairs; the views expressed do not represent those of the VA or the US government. Lambert is an employee of Cambridge-Baker Systems Genomics Initiative, Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care.
Nat Med. Published online April 22, 2022. Full text
Alyse Gray is a pathologists' assistant and writer who has authored two books. She holds a bachelor's degree in psychology from Geneva College and a master's degree in pathology from the University of Maryland, Baltimore.
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