The eMERGE(Electronic Medical Records and Genomics Network) Study is a non-profit group of research teams across the United States working together to study genetics and help health care providers treat and prevent disease. We hope to gather data from 25,000 people from diverse backgrounds across 10 sites, and accelerate incorporation of genetic and other risk information into clinical care. Our ultimate goal is to improve population health. Unlike a single research study focused on a specific condition or population, eMERGE will serve as a national research resource to inform how polygenic risk scores (PRSs) 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 have the opportunity to 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.

Adult participants will be assessed for risk in 9 conditions:

• Colorectal Cancer
• Atrial Fibrillation
• Breast Cancer
• Chronic Kidney Disease
• Coronary Heart Disease
• Hypercholesterolemia
• Prostate Cancer
• Obesity/BMI
• Type 2 Diabetes (T2D)

Child participants will be assessed for risk in 4 conditions

• Obesity/BMI
• Type 1 Diabetes
• T2D
• Asthma

In addition to using family history and clinical risk factors to predict disease risk, PRS can offer a way to measure disease risk with predictive value beyond and in addition to family history and clinical risk calculators (Lambert et al., 2019). 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 patients who are at increased risk for certain conditions. PRS can predict disease risk similar in magnitude to monogenic risk with odds ratios 3-20 times average risk in some cases. Additionally, PRS may capture a larger percent of the at-risk population than monogenic variants. In eMERGE, for example, we expect approximately 25% of patient 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 creates the opportunity to direct preventative treatment and screening towards these high risk individuals building on current standards of care.

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 typical polygenic risk score can be calculated from hundreds or even millions of genetic markers in a patient’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.

In the eMERGE study, each phenotype has a specific PRS percentile cut-off that is associated with high risk. The participant’s exact percentile will not be provided.

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 a 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.

“High risk” means that your patient has a higher chance of developing that particular disease than other people.

A patient may be considered high risk if at least one or more of the following conditions are met:

• If the patient has 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 T2D PRS distribution, it is associated with a 3-6-times increased risk compared to the general population.
• A positive monogenic result (Hereditary Breast and Ovarian Cancer, Familial Hypercholesterolemia, Lynch syndrome, etc.)
  • The following genes will be sequenced in adults: BRCA1, BRCA2, PALB2, TP53, STK11, MLH1, MSH2, MSH6, EPCAM, PMS2, APOB, LDLR, LDLR1A, and LMNA.
• If the patient reports having one or more close family members with the condition.
  • This applies only to atrial fibrillation, CKD, CHD, and prostate cancer.
• If the patient has 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.
  • CHD: The Pooled Cohort Equation (ASCVD risk calculator) is combined with the CHD PRS score.

The vast majority of genomic research(>75%) has been performed on individuals of European ancestry (Fatumo et al., 2022). Therefore, those of non-European genetic 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 patients.

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 a very 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.

No, providers are not responsible for collecting their patients’ biosamples. When a participant is asked to provide biosamples, they will be directed to a local site for sample collection. Participants may also provide biospecimens via mail at some sites.

Providers and participants will receive an integrated study report called the GIRA (Genome Informed Risk Assessment) incorporating four risk domains including monogenic, polygenic risk, family history and clinical risk depending on the condition and if the participant is an adult or child. The individual genetic testing reports (monogenic and polygenic risk score) may also be separately entered into the participant electronic health record (EHR) and provided to the patient. Pediatric participants will not have monogenic testing.

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 will likely contact their provider directly with follow-up questions about the result.

Because 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 may communicate with the participant’s health care team directly about these results.

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.

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.

PRS have not yet moved into routine clinical practice, and there are no current 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 create a better risk assessment than each factor individually (Slunecka et al., 2021, Lewis et al., 2020). The goal of the GIRA is to incorporate these factors together.

For those found to be at high risk for one or more conditions, general recommendations are provided to patients and providers based on consensus from phenotype and genomics working groups in the eMERGE consortium. We have also leveraged existing guidelines such as USPSTF (US Preventive Services Task Force), AHA (American Heart Association), ACS (American Cancer Society).

This could conceivably occur under certain circumstances; however, the study may be able to cover certain healthcare costs. Providers and patients should contact their individual site contacts.

If you have additional questions about the eMERGE Study, please contact your site contact here

After participants consent to take part in the study, a kit will be sent to their home to collect a saliva sample or a blood sample can be collected by an eMERGE team member or at their next doctor’s visit. Participants will also be asked to answer questions about their health and their family’s health by completing several surveys, and will be asked 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.

• Time from enrollment to completion of the last survey will be up to 18 months.
• It takes about 20 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.
  • Baseline Survey – ~10 minutes
  • Pre-Result Return Survey – ~10 minutes
  • Family History Questionnaire – ~20 minutes
• 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 genetic test result.

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.

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 a patient 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.

Because eMERGE is a research study performing clinical grade testing, the study will use identifiable data, de-identified data, and anonymized data.

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: 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

Broad and Invitae can use the sample and data to improve clinical tests, but the participant will have the option to consent or not consent for it during the consenting process.