eMERGE Project Combines Genomic Research With Electronic Health Records to Improve Care

By Jill Schlabig Williams

Senthilkumar Sadhasivam, MD.

Senthilkumar Sadhasivam, MD

Senthilkumar Sadhasivam, MD, is tapping into the power of genomics multiplied by the power of electronic health records (EHRs) to make pain management in children safer and easier.

As a post-surgery pain management specialist and researcher, Sadhasivam is searching for solutions to a long-standing issue in pain control. While most children respond well to medications like codeine, some receive little to no pain relief from typical dosages. Meanwhile, an unlucky few suffer severe drug reactions, including brain damage or death from opioid-induced respiratory depression.

Controlling post-surgical pain in children has long been a complex challenge. Codeine, a common pain medication for adults, is no longer recommended for children undergoing outpatient tonsillectomy because of its wildly variable effects. Sadhasivam is working to find better and alternative analgesic options by developing a genomics-based method that can predict how individual children are most likely to react to opioid pain medications.

Sadhasivam’s project is among several genomics-based clinical efforts receiving a boost from the Electronic Medical Records and Genomics (eMERGE) project, a federal initiative that supports work at Cincinnati Children’s and nine other sites. The goal: to develop methods and best practices for using electronic health records to move genomic research into clinical care.

Sadhasivam and colleagues have developed a genetic test that helps predict how children are likely to respond to pain medications. Through the eMERGE project, he is working with an informatics team to merge those test results into patient records to help surgeons provide more accurate dosing and optimize pain relief.

CONNECTING CLINICIANS & RESEARCHERS

The National Human Genome Research Institute launched eMERGE in 2007. Pediatric sites including Cincinnati Children’s were added in May 2012. A new four-year, $52.4 million phase (eMERGEIII) was launched in September 2015.

This initiative represents one of the largest cross-divisional efforts in translational medicine at Cincinnati Children’s. Overall, eMERGE involves 17 distinct aims involving more than 50 faculty scattered among many Cincinnati Children’s research divisions.

Plans include collecting the DNA sequences of more than 100 genes, most of which are known to have serious pathological variants, from 3,000 Cincinnati Children’s patients. That data will become part of a collection of 30,000 sequencing records from the entire eMERGE network.

The genomics of specific diseases will be studied, with a special focus on identifying somatic mutations, which are not inherited and randomly occur in life. Other aspects of the eMERGE project include addressing ethical concerns, supporting clinical decision making, and developing best practices for returning genomic results to patients and families.

John Harley, MD, PhD, director of the Center for Autoimmune Genomics and Etiology (CAGE) and the principal investigator on the project, aims to leverage eMERGE to make clinical implementation of genetic results routine. “This effort is an infrastructure project,” he says. “We are putting the tools in place to help our clinicians and researchers work together to find practical utility from the tsunami of genomic data that is being generated.”

He describes the eMERGE project as a suite of options that can connect researchers and clinicians, allowing them to mine EHRs for clinical clues that inform genomic research, and then, for those that do, to use those same EHRs to return genetic results and guide care decisions. He also emphasizes that eMERGE is constantly seeking new opportunities to use genomics and the EHR to improve care.

Bahram Namjou-Khales, MD.

Bahram Namjou-Khales, MD, is a member of our Center for Autoimmune Genomics and Etiology (CAGE). He supports the eMERGE project by organizing searches for disease causing genes.

HUNTING FOR COMPUTABLE PHENOTYPES

At the heart of eMERGE are activities to define and develop algorithms that can identify distinct groups of patients who share certain characteristics or conditions (phenotypes), along with developing tools in the electronic medical record to support clinical decision-making.

First, investigators select conditions that have attractive properties for genomic study. Pain management is just one of several conditions to be studied through the eMERGE project. Another project will focus on non-alcoholic steatohepatitis (NASH), commonly called ‘fatty liver,’ which is increasing in frequency along with the epidemic in childhood obesity.

Then, the researchers transform raw EHR data into a computable format. They also write complex computer algorithms and often use natural language processing tools to hunt through that data, including free text from clinical notes, to find groups of patients with similar conditions. The EHR data of these patients are analyzed along with their genomic data in order to determine whether any of the genetic markers are causal.

These algorithms for “computable phenotypes” are shared and validated at the other eMERGE sites and are also being used locally to help deliver targeted decision support to clinicians.

All of these activities are supported by a multi-disciplinary team that includes Yizhao Ni, PhD, Todd Lingren, MS, and Keith Marsolo, PhD, from the Division of Biomedical Informatics; collaborators from the Department of Information Services; input from clinical experts; along with Harley, Bahram Namjou-Khales, MD, Kenneth Kaufman, PhD, and Beth Cobb, MBA, from CAGE.

IDENTIFYING CAUSATIVE GENES

Namjou-Khales is organizing these activities with the goal of using genome-wide and phenome-wide association studies to hunt down causative genes in a wide range of disorders.

For the pain medication project, researchers grouped patients who had adverse reactions to codeine and other opioids into cohorts with similar characteristics. By analyzing the biological samples, researchers identified causative genetic variants for each phenotype and used that knowledge to create a genetic test to identify patients likely to suffer adverse reactions.

In another eMERGE initiative, more than 80 genes that can affect individual responses to drugs due to differences in metabolic pathways have been sequenced in 9,000 samples across the eMERGE network. Algorithms are being developed to help target drugs more closely to individual needs.

TAKING IMPLICATIONS INTO ACCOUNT

The ethical, legal, and social implications of genomic work are front and center in the eMERGE project.

Cindy Prows, MSN, APRN, manages several projects in the Division of Human Genetics. She and colleagues, including Melanie Myers, PhD, MS, are exploring how and when to return genomic results to patients. What are the best ways to share findings with doctors, patients, and guardians? Should all results be shared? Or only those that are actionable, where a change in care can improve the outcome? How do the wishes of adolescents and their parents fit into the picture?

Armand Antommaria, MD, PhD, Director of the Ethics Center at Cincinnati Children’s, is collaborating with colleagues in the University of Cincinnati College of Law on a project exploring responsibilities for re-analysis of genetic sequencing results. “As our knowledge expands, the interpretations of these results change over time,” says Antommaria. “Are there moral and legal obligations to reanalyze results? On the provider side, what is the responsibility for communicating evolving results?”

Costs of treatment also will be studied. While Sadhasivam’s codeine project did not have an economic focus, he did find that using an inexpensive genetic test to guide pain medications resulted in shorter lengths of stay for patients in the post-anesthesia care unit, saving an average of $160 per patient. The eMERGE team at Cincinnati Children’s is considering a more formal cost-benefit analysis of genetic tests used to guide treatment of babies with neonatal abstinence syndrome.

Yizhao Ni, PhD; Cindy Prows, MSN; Keith Marsolo, PhD; and Todd Lingren, MS.

A team including (left to right) Yizhao Ni, PhD; Cindy Prows, MSN; Keith Marsolo, PhD; and Todd Lingren, MS, supports the eMERGE project by hunting for computable phenotypes and studying how best to share genomic data with patients and clinicians.

LOCAL EXPERTISE, NATIONAL SCOPE

The promise of precision medicine is to tailor treatments to individuals. The eMERGE project seeks to help fulfill that promise both locally and nationally.

Locally, the team at Cincinnati Children’s is well-equipped to lead the way into this brave new world. The Cincinnati Biobank Core Facility contains DNA samples from more than 60,000 patients. Several on-site laboratories run increasingly sophisticated gene panels and other tests. And a state-of-the-art data center provides the secure, scalable computational power needed to work with huge genomic data sets.

With its national scope, the eMERGE project helps researchers across the country share data to maximize statistical sampling power and tap into larger cohorts to study diseases. By playing a lead role in this project, Cincinnati Children’s has gained a seat at the table where decisions about the future of genomics and healthcare are being made.

All for the benefit of our patients.

 


Key Aims of eMERGE III

 

  • Help identify at least 100 genes to be included in a DNA sequence analysis panel to be run on more than 30,000 samples provided by eMERGE research sites.
  • Provide consented biological samples from at least 3,000 Cincinnati Children’s patients to be sequenced and included in a national database.
  • Reinterpret 4,000 targeted gene panels previously run at Cincinnati Children’s to identify candidate gene variants.
  • Generate computer algorithms to mine electronic health records (EHRs) to identify genomic subgroups in disorders including appendicitis, hypermobility, migraine, primary pulmonary hypertension, and pyloric stenosis.
  • Explore variants in the eMERGEIII gene panel to discover new disease patterns.
  • Test EHR-based algorithms against the PCORnet Common Data Model, a standardized approach to managing medical data.
  • Apply an eMERGE algorithm to data from the Million Veterans Project.
  • Study how patients, guardians, and physicians learn about genetic results; develop tools to assess adolescent preferences; assess the value of MyChart as a portal for returning results.
  • Evaluate the genetics of outpatient pain after tonsillectomy.
  • Assess the economic impact of CYP3A5 genotype-guided dosing of tacrolimus, an immunosuppressant medication used after organ transplantation.
  • Integrate clinical decision support processes into the EHR to guide treatment decisions.
  • Explore and integrate ethical, legal, and social considerations.

 


Cincinnati Children’s Plays Leading Roles in Large-Scale Genomic Research Projects

In addition to the multi-center eMERGE program, Cincinnati Children’s serves in leading roles on two other national-scale genomics projects.

In March 2016, Cincinnati Children’s was selected to receive a five-year, $32.5 million grant from the National Institute of Health’s Bench to Bassinet program, a national effort to accelerate research into the causes and potential treatments for congenital heart defects. Cincinnati Children’s will serve as the coordinating center for the multi-center project and as the program’s genomic data hub.

Eileen C. King, PhD, a member of our Division of Biostatistics and Epidemiology, will serve as principal investigator. Learn more about this project.

In March 2015, our Division of Biomedical Informatics was awarded a $2.2 million grant to develop and maintain the Longitudinal Pediatric Data Resource for the Newborn Screening Translational Research Network.

Researchers will use this national database to pilot new technologies and treatments while tracking life-long health outcomes of children who screen positive for a large number of rare and often devastating genetic disorders. The still-growing list of diseases included in the project includes lysosomal storage disorders, inborn errors of metabolism, and severe combined immunodeficiency disorders.

Learn more about this project.
 


Get Involved

IT’S NOT TOO LATE TO PLAY A ROLE IN SHAPING THE FUTURE OF GENOMIC MEDICINE

Interested scientists and clinicians can join the eMERGE project in various ways, including serving on working groups on topics ranging from phenotyping to data integration to ethical implications.

For more information:

Contact eMERGE project manager
Beth Cobb at Beth.Cobb@cchmc.org