Resources & FAQs

Resources

The resources below contain more information:

Web sites

• The eMERGE Network
• Polygenic Risk Scores
• BOADICEA Score

Publications

• Polygenic Risk: What's the Score? 
• Polygenic Scores in Biomedical Research
• eMERGE Phase IV PRSs
• Asthma
• Breast Cancer
• Chronic Kidney Disease
• Coronary Heart Disease
• Prostate Cancer
• Type I Diabetes
• Type II Diabetes
• 2018 Guideline on the Management of Blood Cholesterol
• 2019 Guideline on the Primary Prevention of Cardiovascular Disease
• 2020 KDOQI Clinical Practice Guidelines for Nutrition in CKD
• 2021 KDIGO Clinical Practice Guideline for the Management of Blood Pressure in CKD
• 2023 American Diabetes Association Standards of Medical Care: Prevention

Videos

• What are Polygenic Risk Scores?
• The Role of Genetic Testing in Cardiovascular Disease

Frequently Asked Questions

What is the eMERGE Network?
The eMERGE (Electronic Medical Records and Genomics) Network is a group of research teams across the United States working together to study genetics and genomics to help healthcare providers treat and prevent disease. In phase IV, the Network plans to gather data from 25,000 people from diverse backgrounds across 11 sites and accelerate the incorporation of genetic and other risk information into clinical care.

The ultimate goal is to improve population health. Unlike a single research study focused on a specific condition or population, eMERGE IV will serve as a national resource to inform how polygenic risk scores (PRS) can be used to identify people at high risk for common conditions and understand if receiving this risk information helps patients and their doctors make healthcare decisions to improve overall health.

Participants will receive a risk report, called the "Genomic Informed Risk Assessment" (GIRA) that includes polygenic risk, monogenic risk (adults only), family history, and clinical risk factors such as demographics, lab results, other diagnoses and lifestyle.

What conditions will be studied?
Adult participants will be assessed for risk of nine conditions:

• Atrial Fibrillation
• Breast Cancer
• Colorectal Cancer
• Chronic Kidney Disease
• Coronary Heart Disease
• Hypercholesterolemia
• Prostate Cancer
• Obesity/BMI
• Type II Diabetes

Pediatric participants will be assessed for risk of four conditions:

• Asthma
• Obesity/BMI
• Type I Diabetes
• Type II Diabetes

What is the value of polygenic risk?
In addition to family history and clinical risk factors, PRS can be used to estimate disease risk with predictive value beyond family history and clinical risk calculators. This is especially the case when limited data is available - for example, the sensitivity of family history as a screening tool decreases with small family size and competing causes of death. Similarly, clinical risk factors such as hypertension and hyperlipidemia take time to develop and may not be detected until later in life when prevention is less effective.

PRS can be another tool that helps to identify individuals who are at increased risk for certain conditions. A high PRS can confer disease risk similar in magnitude to monogenic risk with odds ratios 2.4-3.2 times average risk in some cases and up to 20 times average risk for Type 1 diabetes. Additionally, PRS may capture a larger percent of the at-risk population than monogenic variants. In eMERGE, for example, we expect approximately 25% of participants to have at least one high risk condition by PRS while only 3% are expected to show monogenic findings.

Using PRS along with other risk factors, the eMERGE study aims to provide patients and providers with comprehensive risk information for common conditions. Stratifying individuals by risk enables directing preventative treatment and screening towards these at the highest risk.

What information is used to estimate a participant's risk?
Genetic results, along with family and medical history are used to estimate the participant's risk of developing the common conditions mentioned above. The GIRA classifies participants at 'high' or 'not high' risk of developing a condition based on several factors:

• Polygenic results: Polygenic risk describes the chance of developing certain health conditions based on adding up the small effects of a large number of genetic variants across the genome. A polygenic risk score (PRS) can be calculated from hundreds or even millions of genetic markers in a participant's DNA. Studies have established that these scores are correlated with risk for a given condition. For most conditions in the study, this is provided as a percentile and odds ratio - not an absolute risk. This is because there are no available risk equations combining family history, lifestyle and behavioral risk factors, and genetic risk factors for most conditions except for breast cancer and coronary heart disease. In the eMERGE study, each phenotype has a specific PRS percentile threshold cut-off that is associated with high risk. Thresholds were set based on the risk associated with family history of each condition. "High-risk" status will be provided, but the participant's exact percentile will not.
• Monogenic results: Some people have an increased risk because they have one DNA change that significantly impacts the risk to develop a condition. This is called monogenic risk and follows a Mendelian pattern of inheritance. An example is a DNA change in the BRCA1 gene associated with hereditary breast and ovarian cancer.
• Family history: Participants are asked to provide their family health history for the conditions studied in eMERGE. They do so using an online tool called MeTree, developed at Duke University. Family history is used to help assess risk for some of the conditions.
• Clinical risk factors: Data from participant self-report surveys and the EHR will be used to calculate risk or contextualize high genetic risk. Examples of these clinical risk factors include most recent hemoglobin A1C, reported physical activity, and BMI, when available.

What is the definition of "High Risk" in eMERGE and how is a participant's risk reported?
"High risk" means that the participant has a higher chance of developing that particular disease than other healthy individuals. A participant may be considered high risk if at least one or more of the following conditions are met:

• A PRS above the study threshold for a condition. For most conditions this is provided as a percentile and odds ratio and NOT an absolute risk. For example, if someone is in the top 2% of the Type 2 Diabetes PRS distribution, it is associated with a 2.6-6.9 times increased risk compared to the general population and would be classified as 'high risk'.
• A positive monogenic result for any of the following genes: BRCA1, BRCA2, PALB2, TP53, STK11, MLH1, MSH2, MSH6, EPCAM, PMS2, APOB, LDLR, LDLR1A, and LMNA.
• Having one or more close family members with the condition. This applies only to atrial fibrillation, chronic kidney disease, coronary heart disease, and prostate cancer.
• A high integrated risk score. This is reported as an absolute risk and is available for two conditions:
  • Breast Cancer: BOADICEA is an algorithm that predicts breast cancer risk using monogenic, PRS, family history, and clinical risk factors.
  • Coronary Heart Disease (CHD): The pooled cohort equation (ASCVD risk calculator) is combined with the CHD PRS. The CHD PRS will also be evaluated separately without the ASCVD risk calculator. These metrics will not be used to classify participants as high risk but will be included as additional information on the reports of participants who have been classified as high risk for CHD.

Do PRS perform equally well in all ancestry groups?
The vast majority of genomic research (>75%) has been performed on individuals of European ancestry (Fatumo et al., 2022). Therefore, those of non-European ancestry must be cautioned their PRS may be less predictive, either over or underestimating risk compared to those who have European ancestry. For example, the confidence intervals may be wider for predicted odds ratios of disease amongst non-European ancestry individuals.

To address this, eMERGE studied large datasets from people of different ancestry groups, identified variants in each population associated with disease risk, combined these variants into a single score, and validated the PRS using additional diverse populations. The GIRA indicates which populations the PRS scores have been evaluated in to help contextualize the results.

It is an important goal of the eMERGE study to maximize the presence of non-European ancestry participants in order to gain more predictive precision for them in the future.

Do PRS have Sensitivity, Specificity or Positive (PPV)/Negative Predictive (NPV) values?
We conceive future clinical use of PRS as a risk stratification tool which typically do not have these indicators calculated, rather than as a "screening" or "diagnostic" tests which typically do have these indicators calculated. PRS can be used as one of several information types along with traditional risk factors such as lifestyle (i.e., diet), physical parameters (i.e., BMI), biochemical markers (i.e., lipid levels) and family history to form a more complete risk stratification profile for an individual.

Ultimately, the hope is PRS will help to prevent some diseases and find some cases of common diseases that might not otherwise be discovered until later when using only traditional risk factors. If one attempted to use PRS in the same way we might use a colonoscopy as a screening test for example, it would perform very poorly because it would miss a high percentage of cases as a result of the fact that genetics is only a small part of the etiology of most colon cancer. Therefore, PRS should not be assessed using diagnostic indicators such as specificity, sensitivity, PPV and NPV though in theory they could be calculated.

How will the eMERGE Study affect the way I treat and interact with my patients?
This will be decided by you and your patients together and is one of the primary research questions the eMERGE study seeks to address. The eMERGE study may identify that some of your patients are at an increased risk for disease. The GIRA will contain some general recommendations for care and lifestyle modifications (see 'How were the recommendations on the GIRA developed?' below).

If my patient decides to participate in the eMERGE Study, will I be responsible for collecting blood or saliva samples?
No, providers are not responsible for collecting their patients' biospecimens. When a participant is asked to provide biospecimens, they will be directed to a local site for sample collection.

What type of study results will I receive for my patients?
Providers and participants will receive an integrated study report called the GIRA (Genomic Informed Risk Assessment) incorporating four risk domains including monogenic risk, polygenic risk, family history and clinical risk depending on the condition and if the participant is an adult or child. The participant's genetic testing reports (monogenic and polygenic risk score) may also be separately transmitted into the participant electronic health record (EHR) and provided to them. Pediatric participants will not undergo monogenic testing.

Will my patients have access to results from the study? Will they share that information with me?
Participants will have access to their personalized results from the eMERGE Study. All participants receiving a high-risk result will be asked to meet with a genetic counselor or trained study staff. Participants that are not high risk for any condition will receive their GIRA by mail, email or through a patient portal depending on recruitment site. Participants may decide to contact their provider directly with follow-up questions about the result.

Will I have access to results from the study? Will I be notified?
As the study results will be available in the patient's EHR, providers can access these reports as soon as they are ready. The eMERGE study team will communicate with the participant's health care team directly about these results.

Where in the patient's electronic health record will I find the results from eMERGE study?
The details of result placement in the EHR will be determined by each site. You may receive electronic notification when the GIRA and other reports are available and be able to access them in the EHR after initial notification.

How will the result return process differ between high risk and not high-risk participants?
Only participants receiving a high-risk result will be asked to meet with a genetic counselor or trained eMERGE team member to review the results. Those receiving risk results classified as "not high" will be sent reports by mail and/or through a patient portal. Regardless of risk classification, results will be made available in the electronic health record (see above).

Are there any current guidelines for clinical use of PRS in screening or prevention?
PRS have not yet moved into routine clinical practice, and there are no guidelines for their clinical use. However, studies suggest that genomic informed risk scoring that incorporates PRS, clinical risk based on physiologic markers, demographics, lifestyle, and family history can provide a more accurate risk assessment than each factor separately (Slunecka et al., 2021). The goal of the GIRA is to incorporate these factors together and test the clinical utility of implementing these reports in clinical practice.

How were the recommendations on the GIRA developed?
For those found to be at high risk for one or more conditions, general recommendations are provided to patients and providers. These are based on consensus from phenotype and genomics working groups in the eMERGE consortium with expertise in many different specialties, provider feedback, and existing guidelines such as USPSTF (US Preventive Services Task Force), AHA (American Heart Association), and ACS (American Cancer Society).

Could participants incur additional healthcare costs as a result of the study?
Yes, we anticipate that participants who are high risk for any condition(s) may have additional screening tests, or medical evaluations recommended, based on the risk as part of their clinical care. Any costs from these tests will not be covered by the study.

What do I do if I have more questions that aren't answered by this information sheet or need help with a specific patients' results?
If you have additional questions about the eMERGE Study, reach out to our study team listed on the Contact page.

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 accept results and identify their healthcare provider. Individuals who have had a bone marrow transplant are ineligible to participate.

What will be expected of those who participate?
After participants consent to take part in the study, they will be asked to answer questions about their health and their family's health by completing several surveys, provide a blood sample to, and to provide access to their electronic health records. Participants are expected to be willing to receive results and discuss them with their health care provider.

How much time will it take to enroll? To participate over time?
Time from enrollment to completion of the last survey will be up to 18 months. It takes about 10-30 minutes for a participant to go through the pre-screening survey and the consent process to join the eMERGE study. Once consented, eligible participants will be asked to complete three additional self-report surveys to share information about their health history, lifestyle habits, and environmental exposures. If the participant is found to be at high genetic risk, they will be asked to meet with the study team. The final Post-Result Return Survey is sent approximately 6 months after the participant receives their GIRA report.

Will the study have access to the participant's electronic health record?
Yes, the study requires access to the EHR to extract data elements required to create a GIRA. Study team members will have general access for the duration of the study, including post-results analyses. Only study team members at the site will have access to the medical record. EHR access is monitored and audited.

What legal protections are there for genetic test results?
Employers and health insurance companies are prevented by law from discriminating against the patient based solely on genetic test results. The federal law is called the Genetic Information Non-discrimination Act (GINA). GINA does not protect active-duty military, but the military has other privacy protection policies. Some states have additional protections. Importantly, GINA does not apply to employers with fewer than 15 employees. For any additional questions, please contact the study team.

What about other types of insurance, like life insurance, long-term care insurance, or disability insurance?
If participants learn through this study that they have an increased risk for a condition, and try to get life, long-term care, or disability insurance, the cost may be higher than if they did not have these results. It might also be harder to get these types of insurance. Only Florida has a law restricting life insurers from using genetic test results, although a number of states have laws requiring insurers to get consent before doing genetic tests themselves. For any additional questions, please contact the study team.

Who will receive data and how will it be delivered?
Because eMERGE is a research study performing clinical grade testing, the study will use:

• Identifiable data:
  • MeTree: Platform in charge of collecting family history information.
  • Broad Institute: Laboratory completing clinical polygenic risk score testing.
  • Invitae: Laboratory completing clinical monogenic testing (adults only).
  • Vanderbilt University Medical Center: The eMERGE coordinating center, which collects and stores study data and documentation.
• De-identified data:
  • De-identified data will be shared with an NIH-supported access-controlled database called AnVIL.
  • De-identified genetic results and study data may be shared with other eMERGE sites (outside of your site and Vanderbilt, where results will be stored).
• Anonymized data:
  • Anonymized data will be shared with a public database called ClinVar.