eMERGE Genome Informed Risk Assessment

FAQ

Find answers to frequently asked questions about the eMERGE phase 4 research study.

General information

What is the eMERGE Network?

The Electronic Medical Records and GEnomics (eMERGE) Network is a group of research teams across the U.S. that are working together to study genetics and genomics. They are helping clinicians treat and prevent disease.

What is the eMERGE study?

In the eMERGE phase 4 research study, the network is gathering data from 25,000 people from diverse backgrounds across 11 sites. The network also is working to incorporate genetic and other risk information more efficiently into clinical care. Unlike a single research study focused on a specific condition or group of people, this study will be a national resource on the utility of polygenic risk scores in clinical practice.

The eMERGE study focuses on polygenic risk scores, which estimate the risk of getting a disease from variants in multiple genes. The study aims to learn how these scores can be used to identify people at high risk of common conditions. The study also investigates if getting this risk information helps participants and their healthcare teams make decisions to improve participants' overall health.

What diseases and conditions does the eMERGE study look at?

The eMERGE study assesses adult participants' risk of getting nine diseases and conditions:

Atrial fibrillation.
Breast cancer.
Colorectal cancer.
Chronic kidney disease.
Coronary heart disease.
Hypercholesterolemia.
Prostate cancer.
Obesity.
Type 2 diabetes.

For children who participate, the study assesses the risk of getting four diseases and conditions:

Asthma.
Obesity.
Type 1 diabetes.
Type 2 diabetes.

What information is used to estimate a participant's risk?

The eMERGE study uses genetic results, family history and clinical risk factors to estimate a participant's risk of getting the common conditions mentioned above. The GIRA report outlines whether participants are at high risk of getting a condition based on several factors:

Polygenic results. Polygenic risk describes the chance of getting certain health conditions based on adding up the small effects of several genetic variants across the genome. A polygenic risk score can be calculated from hundreds or even millions of genetic markers in a participant's DNA.

Studies have proven that these scores link to risk of a given condition. For most conditions in the study, the study team reports these results as percentile and odds ratios — not an absolute risk. This is because there are no available risk equations combining family history, clinical risk factors such as lifestyle and genetic risk factors for most conditions. The exceptions are breast cancer and coronary heart disease, for which there are more complex clinical risk calculators.

In the eMERGE study, each condition has a specific polygenic risk score percentile cutoff that the study team has defined as high risk. The team set these thresholds based on the risk related to family history for each condition. The team advises participants if they have a high-risk status but doesn't tell them their exact percentile of risk.

Monogenic results. Some people have a higher risk of a certain disease or condition because they have a variant in a gene that is strongly related to that condition. This is called monogenic risk. For example, certain variants in the BRCA1 gene are related to hereditary breast and ovarian cancer. Monogenic risk follows a Mendelian pattern of inheritance.
Family history. The eMERGE study team asks participants to give their family health history for the conditions included in the study. Participants use the MeTree online tool developed at Duke University or fill out a survey to do this. The study team uses family history as one factor to assess the risk of some conditions.
Clinical risk factors. The eMERGE study team uses data from participant surveys and electronic health records to calculate risk or put high genetic risk in context. Clinical risk factors include the most recent hemoglobin A1C, reported physical activity and body mass index (BMI).

How does the eMERGE study define 'high-risk'?

For the eMERGE study, 'high risk' means that a participant has a higher chance of getting a disease compared with healthy individuals. The study team uses the following factors to determine if a participant is at high risk of getting a certain condition:

Polygenic risk. The eMERGE study team considers a participant to be at high risk if they have a polygenic risk score above the study threshold for a condition. For most conditions, the study provides polygenic risk scores as percentile and odds ratios — not absolute risk. For example, if a participant is in the top 2% of the type 2 diabetes polygenic risk score distribution, they have 2.6 to 6.9 times the risk of getting type 2 diabetes, compared with the general public. The participant is at high risk.
Monogenic risk. The eMERGE study team considers participants at high risk if genetic testing shows that they have variants in any of the following genes:
- APOB.
- BRCA1.
- BRCA2.
- EPCAM.
- LDLR.
- LDLR1A.
- LMNA.
- MLH1.
- MSH2.
- MSH6.
- PALB2.
- PMS2.
- STK11.
- TP53.
Family history. The eMERGE study team considers participants at high risk of certain conditions if they have one or more close family members with the condition. This applies only to the following conditions:
- Atrial fibrillation.
- Chronic kidney disease.
- Coronary heart disease.
- Prostate cancer.
Integrated risk scores. The study team combines clinical risk and polygenic risk scores and reports them as an absolute risk — not a percentile or odds ratio. This is done for two conditions:
- Breast cancer. Calculations are done using the BOADICEA, which combines monogenic, polygenic, family history and clinical risk factors.
- Coronary heart disease. The study team combines clinical risk factors from the pooled cohort equation and the polygenic risk score. This is included as additional information only on the reports of participants who have been classified as being at high risk of developing coronary heart disease.

Participation

Who is eligible to participate in the eMERGE study?

Participants must be between ages 13 and 75 years old. They need to be willing to receive results and name their clinician. People who have had a bone marrow transplant can't participate.

What is expected of participants?

Participants are expected to complete several surveys, provide a blood sample and give access to their electronic health records. Participants are asked to complete a survey when they enroll and three more surveys later, the last of which will be approximately six months after returning results. The surveys ask about their health history, lifestyle habits and environmental exposures.

All participants are expected to be willing to receive results and discuss them with their healthcare team.

If a participant is found to be at high genetic risk of one or more conditions, they are asked to meet with the study team to discuss the results.

How much time does it take to enroll and to participate?

The screening survey and the consent process to join the eMERGE study take about 10 to 30 minutes.

Time from enrollment to completion of the last survey is up to 18 months.

How are samples collected?

Participants go to local study sites to provide a blood sample. Participants' healthcare professionals are not responsible for collecting biospecimens.

Results

What is a GIRA report?

Each participant in the eMERGE study receives a Genomic Informed Risk Assessment (GIRA) report. This report includes information about the participant's:

Polygenic risk. Polygenic risk scores estimate the risk from common variants in multiple genes.
Monogenic risk. Monogenic risk estimates the risk from rare variants in one gene. The GIRA report only provides this information for adult participants.
Family history. Family history takes into account whether participants' immediate or, sometimes, their extended family members have had a certain disease or condition.
Clinical risk factors. Clinical risk factors include participants' demographic information, lab results, other diagnoses and lifestyles.

Each participant will also receive a monogenic report and a polygenic risk report, in addition to the GIRA report.

How were the recommendations in the GIRA report developed?

The recommendations in the GIRA report are based on consensus from working groups in the eMERGE Network. These working groups are made up of experts in many specialties. The GIRA reports combine working group recommendations with feedback from participants' healthcare professionals and guidelines from organizations such as the U.S. Preventive Services Task Force, the American Heart Association and the American Cancer Society.

How are results returned to participants?

Participants who are not at high risk of any condition receive their GIRA reports by mail, email or through a patient portal, depending on their study site.

The study team asks all participants who receive high-risk results to meet with a genetic counselor or a study staff member with appropriate training.

Regardless of risk level, results are added to the participants' electronic health records (EHRs).

Do clinicians have access to study results? Will clinicians be notified when results are available?

Clinicians receive electronic notification when the GIRA report and other reports are available. They'll also be able to access them in the EHR after they're notified.

What type of study results do clinicians receive for their participating patients?

Both clinicians and participants receive four types of results in the GIRA report: monogenic risk, polygenic risk, family history and clinical risk. But not every condition receives all four types of results.

Reports for participants who are children also include fewer types of results. Participating children do not undergo monogenic testing.

Where are the study results in the EHR?

Each study site determines where study results for its participants appear in the EHR.

How will results from the eMERGE study affect the way clinicians treat patients?

Participants and clinicians should decide together how to use information from the study.

The eMERGE study identifies participants that are at a greater risk of disease. The GIRA report will contain some general recommendations for care and lifestyle modifications.

Data privacy, insurance and discrimination

Could participants incur additional healthcare costs from the study?

Study funds will cover some of the medical costs for participants of the eMERGE study. The study will cover the cost of some of the tests that the Genome Informed Risk Assessment (GIRA) report recommends for those who have high polygenic risk of certain conditions; review the Costs page for more information.

Will the study have access to participants' EHRs?

The study requires access to participants' EHRs to get data to create the GIRA reports. Study team members have general access during the study, including post-results analyses. But access to each participant's EHR is limited to study team members at that participant's specific study site. This access is monitored and audited.

How are genetic tests results protected legally?

If the study results show a risk factor, some insurance companies could use this information to adjust the participant's premiums. The Genetic Information Nondiscrimination Act (GINA) makes it illegal for health insurance companies, group health plans and most employers to discriminate against people based on their genetic information. But GINA doesn't apply to life insurance, long-term disability insurance or long-term care insurance. While GINA does not protect active-duty military, the military has other privacy protection policies. Some states have additional protections.

Importantly, GINA does not apply to employers with fewer than 15 employees.

Mayo Clinic offers patient education information (PDF) about genetic information discrimination and the protection that the Genetic Information Nondiscrimination Act (GINA) offers. If you have additional questions after reviewing the PDF, please contact the study team.

Does anyone outside Mayo Clinic receive eMERGE data?

The study shares the following types of data with the following organizations:

Identifiable data. This type of data includes identifying information including participants' names, birth dates and other personal information.
- MeTree. This is the platform in charge of collecting family history information.
- Broad Institute. This laboratory completes clinical polygenic risk score testing.
- Invitae. This laboratory completes clinical monogenic testing for adult participants.
- Vanderbilt University Medical Center. This is the eMERGE coordinating center, which collects and stores study data and documentation.
De-identified data.
- De-identified data is shared with the Analysis, Visualization and Informatics Lab-space (AnVIL) database, which the National Institutes of Health supports and provides access to.
- Other eMERGE sites and Vanderbilt University Medical Center, where results are stored.
Anonymized data.
- Anonymized data is shared with the ClinVar public database.

Polygenic risk scores

Why study polygenic risk?

Polygenic risk scores estimate a person's risk of getting a disease from variants in multiple genes. This is valuable knowledge that goes beyond family history and clinical risk.

Polygenic risk scores are especially valuable when limited data are available. For example, looking at family history to estimate risk is less accurate for people with small families that have experienced causes of death other than the disease or condition in question. But polygenic testing can show people's genetic risk without knowing anything about their family members.

Similarly, clinical risk factors such as high blood pressure and high levels of fat particles in the blood take time to develop. If clinicians rely on measuring gradual changes in these levels to estimate risk, they may not become "red flags" for disease until later in life, when the disease is harder to prevent. Polygenic risk scores, on the other hand, can give insights into risk early in life.

Polygenic risk scores can be another tool that helps find people at greater risk of certain conditions. A high polygenic risk score can mean that a person has two or three times the average risk, in some cases, or up to 20 times the average risk of diseases such as type 1 diabetes. And, measuring polygenic risk scores may identify more at-risk people than does testing for monogenic variants. In the eMERGE study, for example, researchers expect about 25% of participants to have at least one high-risk condition due to variants in multiple genes — that is, due to polygenic risk. In contrast, researchers expect only 3% of participants to be at risk due to variants in one gene, called monogenic risk.

The study uses polygenic risk scores and other risk factors to estimate risk of common conditions. Separating people into different risk-level groups allows healthcare teams to help those at the highest risk get appropriate screening and preventive treatment.

Do polygenic risk scores perform equally well in all ancestry groups?

More than 75% of genomic research has been performed on people of European ancestry. Polygenic risk scores for people of non-European ancestry may overestimate or underestimate risk. For example, the confidence intervals may be wider for predicted odds ratios of disease among people of non-European ancestry. Confidence intervals are used to have a sense of how good the estimate is. The wider the confidence interval, the more caution is needed when using the estimate.

To address this discrepancy, the eMERGE study looked at large data sets from people of different ancestries. The study team found variants in each ancestry group related to disease risk and combined them into a single score. Then the study validated the polygenic risk scores using more diverse groups of people.

The GIRA report includes information about which groups of people the study team evaluated polygenic risk scores for. This is intended to help put the results in context.

The eMERGE study aims to include as many participants of non-European ancestry as possible to better estimate risk in the future.

Related publication:

A roadmap to increase diversity in genomic studies.

Do polygenic risk scores have sensitivity, specificity, or positive and negative predictive values?

Although the eMERGE study team sees polygenic risk scores as valuable risk-stratification tools, we do not see them as screening or diagnostic tests, which typically would calculate sensitivity, specificity, or positive and negative predictive values.

To form a better risk profile, polygenic risk scores can be used as one of several sources of information, along with:

Traditional risk factors, including lifestyle factors, such as diet.
Physical parameters, such as BMI.
Biochemical markers, such as lipid levels.
Family history.

The hope is that polygenic risk scores can help prevent some diseases and find some diseases earlier than traditional risk factors would allow. But if polygenic risk scores were used in the same way as a colonoscopy screening test, for example, they would perform poorly. That's because genetics are only a small part of the cause of most cases of colon cancer, and polygenic risk scores would miss many cases of atypical polyps, colorectal cancer and other risks. Therefore, polygenic risk scores should not be assessed using diagnostic indicators such as specificity, sensitivity, and positive and negative predictive values. In theory, though, those indicators could be calculated.

Are there any guidelines for clinical use of polygenic risk scores in screening or prevention?

Healthcare professionals have not yet started using polygenic risk scores in routine clinical practice, and there are no guidelines for their clinical use. Studies suggest that genomics-informed risk scoring that includes polygenic risk scores, clinical risk based on physical signs, demographics, lifestyle and family history can provide a more accurate risk assessment than looking at each factor separately. The GIRA report seeks to combine these factors and test the clinical value of using these reports in clinical practice.