Design and user experience testing of a polygenic score report: a qualitative study of prospective users

Background Polygenic scores—which quantify inherited risk by integrating information from many common sites of DNA variation—may enable a tailored approach to clinical medicine. However, alongside considerable enthusiasm, we and others have highlighted a lack of standardized approaches for score disclosure. Here, we review the landscape of polygenic score reporting and describe a generalizable approach for development of a polygenic score disclosure tool for coronary artery disease. Methods We assembled a working group of clinicians, geneticists, data visualization specialists, and software developers. The group reviewed existing polygenic score reports and then designed a two-page mock report for coronary artery disease. We then conducted a qualitative user-experience study with this report using an interview guide focused on comprehension, experience, and attitudes. Interviews were transcribed and analyzed for themes identification to inform report revision. Results Review of nine existing polygenic score reports from commercial and academic groups demonstrated significant heterogeneity, reinforcing the need for additional efforts to study and standardize score disclosure. Using a newly developed mock score report, we conducted interviews with ten adult individuals (50% females, 70% without prior genetic testing experience, age range 20–70 years) recruited via an online platform. We identified three themes from interviews: (1) visual elements, such as color and simple graphics, enable participants to interpret, relate to, and contextualize their polygenic score, (2) word-based descriptions of risk and polygenic scores presented as percentiles were the best recognized and understood, (3) participants had varying levels of interest in understanding complex genomic information and therefore would benefit from additional resources that can adapt to their individual needs in real time. In response to user feedback, colors used for communicating risk were modified to minimize unintended color associations and odds ratios were removed. All 10 participants expressed interest in receiving a polygenic score report based on their personal genomic information. Conclusions Our findings describe a generalizable approach to develop a polygenic score report understandable by potential patients. Although additional studies are needed across a wider spectrum of patient populations, these results are likely to inform ongoing efforts related to polygenic score disclosure within clinical practice. Supplementary Information The online version contains supplementary material available at 10.1186/s12920-021-01056-0.


Fewer individuals have increased risk WHAT IS A POLYGENIC SCORE?
The genetic code we are born with is mostly the same between any two individuals. However, everyone has subtle differences in their genetic code, called genetic variants. Genetic variants can explain why some people are more likely to develop common diseases.
A polygenic score takes into account millions of genetic variants to estimate your risk to develop a particular disease. Each variant on its own tends to contribute little to risk of disease, but when added together these small differences can have a larger impact.

Additional information and limitations
A polygenic score is neither deterministic nor diagnostic. Some people with a high polygenic score will never develop the disease while others with a low polygenic score will.
Limitations of a polygenic score It does not take into account non-genetic factors, such as lifestyle habits and history of other diseases, which could affect your risk.
It only estimates your risk of coronary artery disease, not other diseases.
It does not look for rare genetic variants such as familial hypercholesterolemia -present in 1 in every 250 people -that can greatly increase risk for coronary artery disease on their own.
Although the polygenic score predicts risk in all ancestries, the scores have been best validated in individuals of European ancestry. Your polygenic score is in the 51st percentile. This does not mean that you have a 51% chance of developing coronary artery disease. Rather, it means that out of every 100 people, your polygenic score is higher than 51 people, and the same or lower than 49. This means that your genetic background places you at average risk to develop the disease. In the United States, up to 5% of individuals develop coronary artery disease by age 50, and up to 25% develop coronary artery disease by age 80.

Fewer individuals have increased risk WHAT IS A POLYGENIC SCORE?
The genetic code we are born with is mostly the same between any two individuals. However, everyone has subtle differences in their genetic code, called genetic variants. Genetic variants can explain why some people are more likely to develop common diseases.
A polygenic score takes into account millions of genetic variants to estimate your risk to develop a particular disease. Each variant on its own tends to contribute little to risk of disease, but when added together these small differences can have a larger impact.

Additional information and limitations
A polygenic score is neither deterministic nor diagnostic. Some people with a high polygenic score will never develop the disease while others with a low polygenic score will.
Limitations of a polygenic score It does not take into account non-genetic factors, such as lifestyle habits and history of other diseases, which could affect your risk.
It only estimates your risk of coronary artery disease, not other diseases.
It does not look for rare genetic variants such as familial hypercholesterolemia -present in 1 in every 250 people -that can greatly increase risk for coronary artery disease on their own.
Although the polygenic score predicts risk in all ancestries, the scores have been best validated in individuals of European ancestry. Your polygenic score is in the 2nd percentile. This does not mean that you have a 2% chance of developing coronary artery disease. Rather, it means that out of every 100 people, your polygenic score is higher than 2 people, and the same or lower than 98. This means that your genetic background places you at significantly decreased risk to develop the disease. In the United States, up to 5% of individuals develop coronary artery disease by age 50, and up to 25% develop coronary artery disease by age 80.

Fewer individuals have increased risk WHAT IS A POLYGENIC SCORE?
The genetic code we are born with is mostly the same between any two individuals. However, everyone has subtle differences in their genetic code, called genetic variants. Genetic variants can explain why some people are more likely to develop common diseases.
A polygenic score takes into account millions of genetic variants to estimate your risk to develop a particular disease. Each variant on its own tends to contribute little to risk of disease, but when added together these small differences can have a larger impact.

Additional information and limitations
A polygenic score is neither deterministic nor diagnostic. Some people with a high polygenic score will never develop the disease while others with a low polygenic score will.
Limitations of a polygenic score It does not take into account non-genetic factors, such as lifestyle habits and history of other diseases, which could affect your risk.
It only estimates your risk of coronary artery disease, not other diseases.
It does not look for rare genetic variants such as familial hypercholesterolemia -present in 1 in every 250 people -that can greatly increase risk for coronary artery disease on their own.
Although the polygenic score predicts risk in all ancestries, the scores have been best validated in individuals of European ancestry. Coronary artery disease (CAD) occurs due to buildup of plaque in the blood vessels that supply oxygen-rich blood to the heart muscle, and remains a leading cause of death in the U.S. and globally. Starting as early as our 20's, plaques can build up and ultimately increase risk of a totally clogged vessel, referred to as a myocardial infarction or 'heart attack.' In the United States, about 5% (1 in 20) of individuals develop CAD by age 50, and up to 25% (1 in 4) develop CAD by age 80.
How can I decrease my risk of coronary artery disease? A polygenic score for coronary artery disease is based only on the genetic code you were born with. Even though you can't change your polygenic score, 'DNA is not destiny' -both a healthy lifestyle and cholesterol lowering medications ('statins') can significantly decrease your risk of coronary artery disease.
The American Heart Association has outlined seven key factors that contribute to ideal cardiovascular health ('Life's Simple 7'). Individuals with at least five of these healthy factors have a 78% reduced risk for heart-related death compared to people without any healthy factors. 1, 2 3 4 'Simple 7' factors for ideal cardiovascular health: 1) maintain a normal weight, 2) stop smoking, 3) control cholesterol levels, 4) follow a heart-healthy diet, 5) exercise regularly, 6) maintain a normal blood pressure, and 7) reduce blood sugar.
Should my other family members get their polygenic score for this disease?
Your family members will share some of your genetic code, passed on from generation to generation. Because the polygenic score is based on variation in this code, close relatives of an individual with a high polygenic score may have an elevated score as well. In current clinical practice, there is not yet good evidence for testing all family members based on your score.
What does my polygenic score tell me if I already have this disease? Your polygenic score report may help you understand how your genetic background contributed to you developing this condition. In the future, this report may help to better inform your medical care and the medical care of your family members.

How might this information affect my insurance or employment?
The Genetic Information Nondiscrimination Act of 2008 is a federal law that prevents health insurers and potential employers from discriminating against you based on genetic test results. However, this protection may not apply to other types of insurance, including life insurance or long-term care insurance.
How might these results affect my medical care? Based on the results of this test, your healthcare provider may suggest additional screening, testing, or medications to reduce your risk of coronary artery disease. We recommend that you share and discuss these results with your doctor.

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How is the polygenic score calculated?
Step 1: Pre-processing your genomic data Your DNA was analyzed using low-coverage genome sequencing (lcWGS) to read single nucleotide polymorphisms (SNPs) across your genome. A SNP is a place in the DNA where one individual's genetic code may be slightly different from another's. Each individual has many SNPs, and together can contribute to disease susceptibility. In addition to SNPs observed on lcWGS, we examine millions of other SNPs that you have by comparing your data to thousands of other genomes, a statistical process known as imputation.

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Step 2: CAD polygenic score development Genome-Wide Association Studies or GWAS compared every common SNP in tens of thousands of people with and without CAD. This analysis produced for each SNP a statistical association with CAD, some SNPs increase risk and others decrease risk. We have developed and tested multiple scores in hundreds of thousands of people to find the best one. About 6 million SNPs are included in this score. The CAD polygenic score in a single individual represents the sum of the risk related to each of the SNPs present in your DNA.