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Colorado Center for Personalized Medicine Ramps Up PGx Decision Support Efforts

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CHICAGO – Having begun a new five-year funding period last July, the Colorado Center for Personalized Medicine (CCPM) has unleashed a flurry of new initiatives the most recent of which is its participation in the COVID-19 Host Genetics Initiative. 

However, CCPM — a partnership between the University of Colorado's Anschutz Medical Campus in Aurora, the UCHealth provider network, Children's Hospital Colorado, and the University of Colorado Medicine billing operation — is engaged in work that stretches far beyond the current global health emergency. 

 

Much of the center's activity is happening through the CCPM Biobank, a six-year-old collaboration between the University of Colorado and the UCHealth systemIt is one of just five biobanks in the nation that have more than 40,000 genome sequences and return results to patients, the organization said. 

Colorado's biobank has amassed a roster of more than 133,000 consented participants, about half of whom have provided blood samples, according to CCPM Director Kathleen Barnes. 

The consent process is built into UCHealth's My Health Connection patient portal, courtesy of a collaboration with the IT group at UCHealth. After patients log in, they get the standard HIPAA disclosure and consent form, but they also are presented with the option of offering a sample to the biobank.  

"There's an educational video. They read the consent. They can sign it electronically, and once they agree to do that, that automatically triggers an order for a dedicated biospecimen that will end up going to the biobank," Barnes said. 

The next time the patient visits a UCHealth facility, staff draws blood. The biobank knows through the Epic Systems electronic health record that the vial is on its way from the clinic. 

Barnes said that the CCPM now has a goal of adding 100,000 samples annually so there are 500,000 specimens in the biobank at the end of the five years  the high end of a previously stated range of 300,000 to 500,000. 

The biobank began returning pharmacogenomics (PGx) test results to patients late last year and eventually plans on delivering disease risk and carrier screening results as well. 

 

Barnes credits the partnership between the hospital and research sides of the sprawling Anschutz Medical Campus as the "secret sauce" in advancing pharmacogenomics.  

"We have a very talented team of pharmacogeneticists on board partnering with IT folks over at the hospital to build out the clinical decision support around each of the drug-gene pairs that we wish to roll out," she said.  

The partnership relies on several working groups, including one called the Pharmacogenetics Implementation Committee of Colorado, or PICColo. 

"Within that working group, first we focus on those pharmacogenetic variants that are represented on our genotyping chip that we can validate both technically and analytically so we're certain of the relationship or the prediction, if you will, of how an individual will respond to a particular drug," Barnes explained. "Then we build out the information technology architecture around the clinical return of those results." 

Through PICColo, the center is creating drug-gene pairs. Last year and through the first quarter of 2020, the committee largely focused on matching drugs, including clopidogrel, voriconazole, selective serotonin reuptake inhibitors, clobazam, and proton-pump inhibitors to CYP2C19 variations. Now, it is moving on to statins for SCLO1B1 and nonsteroidal anti-inflammatory drugs CYP2C9. 

Barnes wants to have 17 drug-gene pairs in its EHR by the end of 2020. CCPM conducts preemptive genotyping and stores the information in the EHR for future use in the form of clinical decision support when a clinician prescribes medication. 

Barnes said that this integration of clinical and preemptive omics data supports the four pillars of precision medicine at CCPM, namely helping to improve diagnostic accuracy, reducing variation in medical practice, providing personalization "when it matters" during treatment, and raising the prospect of positive outcomes. 

UC Health runs microarrays for SNP-based genetic testing, using AutoGen's Flex-Star+ to extract DNA from a blood samples due to its automated, high-volume extraction process. While most clinical labs typically extract a patient's DNA from 100 to 200 μl of blood, the Colorado biobank wanted to extract up to 4 ml per patient in order to have as much DNA as possible to perform clinical research. 

After DNA extraction, CCPM clinical laboratory staff then genotypes the genetic material on a custom Illumina Infinium Multi-Ethnic Genotyping Array (MEGA) chip. The chip allows the biobank to interrogate methylation patterns at the genome-wide level, covering more than 850,000 sites.  

 

When she was at Johns Hopkins University prior to joining UCHealth in 2015, Barnes actually was part of a partnership with Illumina that designed the MEGA chip, which is meant to capture genetic diversity in the context of a genome-wide association study. CCPM made a decision to generate GWAS-level genotype data on as many samples as possible, Barnes said, in part to diversify research cohorts. 

"Most of the commercially available GWAS chips prior to this particular chip had really been targeting European ancestry populations and was missing a lot of important content," Barnes said. 

With customization to the MEGA chip and enrichment for tasks including pharmacogenomics, UCHealth captures about 94 percent of data that whole-exome sequencing would. Microarray platforms such as MEGA also can predict 92 percent of actionable genetic variation as whole-genome sequencing, but at less than one-tenth the cost, she Barnes noted. 

For now, the center's biggest challenge is educating primary care physicians and patients alike about PGx, Barnes said. If the clinical decision support system results in the change of a prescription something, patients often want to see a specialist.  

"And many of the primary care providers want them to go to a specialist because they don't feel prepared to answer a lot of these questions," Barnes said. 

She called pharmacists "absolutely essential" to the PGx program. 

The center partners with the Skaggs School of Pharmacy at the Anschutz Medical Campus, and made a decision early on to get CLIA certification for the biobank, which was achieved in 2017. Barnes called this "probably the best decision we made." This has allowed the center to maintain clinical custody of samples while serving both research and clinical users.

The biobank is now going through the CAP certification process.  

As the CCPM has rolled out pharmacogenomic clinical decision support involving CYP2C19 and the blood thinner Plavix (clopidogrel), pharmacists have had to educate all providers of cardiovascular care within the UCHealth network, not just at the flagship UCHealth University of Colorado Hospital. 

This is equally important in the case of SSRIs. In the US, the majority of SSRI antidepressant drugs are not prescribed by psychiatrists but rather by primary care physicians and other non-mental health specialists. 

"Depending on the drug-gene pair, we really have to tailor that whole education process around that particular group," Barnes said. Then the process repeats for each subsequent drug. 

Another key component of the CCPM's operations is its partnership with BC Platforms. Barnes and Liisa Koivukoski, BC Platforms' director of healthcare development, were to co-present last month at the 2020 Healthcare Information and Management Systems Society (HIMSS) conference that was canceled due to the COVID-19 pandemic. 

Barnes said that as a researcher at Johns Hopkins, she was just the second US customer of Zurich, Switzerland-based BC Platforms. She brought that association with her when the University of Colorado recruited her out to the Denver area five years ago. 

The vendor helps the CCPM generate data from the biobank and translate that information into clinical decision support for integration into the Epic EHR by joining the data with local and outside knowledgebases.  

BC Platforms automates data ingestion, quality assurance, PGx interpretation, and report delivery. The system sends results to the EHR via the Health Level Seven International messaging standard. 

"[BC Platforms] creates the platforms that enable the analyses and also the technical and analytical validation that takes place inside the biobank," Barnes said.  

The CCPM is a user of BCRquest, BC Platforms' system for analyzing and viewing deidentified genomic and clinical data from multiple biobanks. BCRquest acts as a matchmaker of sorts between biobanks and pharma companies to facilitate the design and implementation of clinical trials for novel therapies and drug targets. 

 

With the database that the center has built, Barnes sees plenty of research opportunitiesBarnes believes that the CCPM is creating "pushbutton opportunities" for those looking for a GWAS on a common condition like asthma or atrial fibrillation to find data very quickly. However, Barnes added that the GWAS database can be "very representative of a multitude of different diseases." 

The center has begun looking into aggregating GWAS data from other biobanks, including those at Mount Sinai Health System, Vanderbilt University Medical Center, and Partners HealthCare, as well as overseas projects like UK Biobank.  

"When we start to put all these biobank GWAS data together, we can begin to see patterns and come up with predictive algorithms, Barnes said. 

CCPM is starting to explore putting together polygenic risk scores at the Anschutz campus. This is a pet project for Barnes, who studies asthma, a complex disease for which patients would benefit from knowing their polygenic risk. 

"That's a space that I really see the field moving forward in a very rapid way. At CCPM, we're thinking a lot about polygenic risk scores and how to move that eventually into the clinical stage," Barnes said. 

She expects to have polygenic risk scores in clinical practice for asthma and atrial fibrillation within the next 12 months.  

The center also is just beginning to expand into delivering clinically actionable results on heritable disease risk such as mutations predicting risk of breast cancer, colon cancer, or a cardiomyopathy. 

"That's a much heavier lift because that involves genetic counselors," Barnes said. 

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