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With Enrollment at 200K, VA's Million Veteran Program Inks Contracts for Genetic Analysis

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Originally published Nov. 11.

In less than a year, the US Department of Veterans Affairs has more than doubled the participants enrolled in its Million Veteran Program, an ambitious longitudinal genomics research study in which the government agency is aiming to enroll one million veterans by 2017.

Through MVP, the VA hopes to discover genes linked to various diseases and advance personalized treatment strategies. With informed consent from participants, VA researchers are collecting biological samples for genetic analysis and are giving volunteers questionnaires to gather data on their lifestyle, health, and military exposure. Researchers will then investigate the relationship between veterans' genes, their environment, and their health.

Launched in 2011, MVP had enrolled its 100,000th veteran by December 2012 (PGx Reporter 12/5/2012). Earlier this month, the number of enrollees was more than 200,000.

With steadily increasing enrollment, the VA has also enlisted the services of genetic testing firms to genotype veterans and sequence the exomes of certain participants. The BioProcessing Solutions Alliance – a partnership between Rutgers University, and BioStorage Technologies – recently announced it had won a five-year contract to genotype 100,000 DNA samples from MVP.

Separately, the VA has contracted Claritas and Personalis to perform exome analysis on a small subset of MVP participants who will serve has the reference cohort for a number of ongoing genomic studies within the VA on Lou Gehrig's disease, post-traumatic stress disorder, and mental illness. Exome sequencing "will be employed in different ways in support of targeted populations to ask specific scientific questions rather than to provide broad information about everybody," Timothy O'Leary, acting chief research and development officer at the Veterans Health Administration, told PGx Reporter.

"The cost of sequencing is quite reasonable in comparison to the cost of the first human genome sequence," O'Leary said. "It is nonetheless still high and would be cost prohibitive at this point [to sequence] at the exome level the entire MVP population."

The VA has currently allocated $18 million for the exome sequencing effort. BioProcessing Solutions Alliance announced in a statement that the VA will provide $7.5 million for the first year of genotyping, with additional funding yet to be determined.

"The contracts have been awarded in a way so that if the scientific need is there and financial resources are needed, we can continue expand them beyond the funding level that's already been provided," O'Leary said.

To date, the VA hasn't yet genetically tested too many of the enrolled MVP participants. However, the program has already amassed a significant amount of phenotypic data.

The majority of enrollees to date have completed the self-reported baseline questionnaire that asks participants about their medical history, family history, military deployments, ethnic background, and demographic data. Some have also completed an optional 19-page lifestyle questionnaire that delves deeper into participants' dietary information, occupational history, mental and physical health, smoking and drinking behaviors, and sleep problems.

"The phenotypic data is actually very extensive. Sometimes the challenge then is narrowing that down into a study phenotype," O'Leary said, noting that many veterans in MVP are in their 60s or older and suffer from multiple health conditions. "So, I think a phenotypic analysis for any particular study can be a challenge. Do you want somebody that's experiencing one disease and only one disease or are you fine with all comers?

"Taking this information and distilling it down for analysis is the greater problem," he continued. "Having the information is not."

Through MVP participants' medical records and with the help of these questionnaires, VA researchers will also identify from the reference cohort, candidates for various studies, and those who will receive exome sequencing. For example, for a study on bipolar disease and schizophrenia, researchers are looking in the MVP population for enrollees without serious mental illness. But they could suffer from other unrelated illnesses, for example diabetes or cardiovascular disease.

"The ideal reference cohort would be thousands and thousands of people who are, say, 100 years or older and have no evidence of disease," O'Leary said. "While we certainly have subjects that are over 100 years old, finding 100-year-olds without any disease is rare if it occurs at all. So, the reference cohorts for these studies have to be defined by the scientific question we're trying to answer."

Data from MVP is being stored in a different database than the EMR system containing veterans' healthcare information. MVP findings are for research use only and the genetic testing is not being performed under clinical laboratory conditions that would enable using this information to inform patient care, according to O'Leary.

"We are working with others in VHA to figure out the best way to use genomic information to benefit veterans," he said. "We have within the VHA program [the ability] to look for Lynch syndrome in patients with colorectal cancer, for example, and we are looking at how to best incorporate genomic information into the electronic health record. We're not there yet in terms of enabling widespread adoption."

Through the MVP research effort, VA is hoping to add to the expanding knowledge about the genetic underpinning of disease. However, it remains to be seen how quickly the findings from the project, as well as the growing body of gene-disease knowledge in the published literature, will be translated into actionable recommendations that personalize and improve the care of veterans. "We'll work closely with clinicians providing care, including clinical geneticists so that ultimately the benefits of this can be brought more directly to veterans," O'Leary said.

Gholson Lyon from Cold Spring Harbor Laboratory's cognitive genomics institute recently published an article in the open access journal PeerJ about performing whole-genome sequencing analysis on a 37-year old veteran with obsessive compulsive disorder and identifying a number of genetic variants implicated with mental illness in the literature. Although Lyon and his colleagues informed the patient of the key genetic findings from their research, VA officials were unable to incorporate this information into the patient's VistA EMR record. "We hope to eventually incorporate his genetic data into his electronic health record if and when the VistA health information system is upgraded to allow entry of such data," the study authors wrote.

For veterans' day-to-day care through the VHA, the agency stores patients' data in an EMR system, called VistA, which has been in operation for nearly two decades. VistA links 152 hospitals and around 1,000 outpatient clinics that provide veterans care, who in turn can access parts of their record and provide information on their medical and family history through a secure portal, called My HealtheVet. "The VA's EMR program provides great strength to MVP so with consent from participants we can access that record in support of our research efforts," O'Leary said.

In the study published by Lyon and colleagues, they noted that when they contacted their patient's doctors at the VA, they said that "the VistA health information system does not currently have the capability to incorporate any genomic variant data."

According to O'Leary, however, the EMR system does have the ability to store certain genetic information from veterans. "We do genetic tests on our veterans on a regular basis depending on what a clinician feels is necessary. It may be some things that are common, such as Factor V leiden and BRCA1/2 mutations … and we can bring [in] this information in non-computable form," he said, explaining that this information would be stored as text information and "may not be completely identical" to the format in which the test results were reported.

"I think one of the challenges for clinical use of genetic information is the use of uniform nomenclature for description of mutations and polymorphisms," O'Leary said. "This is a challenge not only for the VA but in healthcare in general." Lyon and colleagues have used the so-called GVFclin format to store variant data identified through whole-genome sequencing.

However, regardless of whether or not participating veterans can directly benefit from the research they're facilitating, the VA continues to report strong enrollment in MVP. Approximately 20 percent of those the VA approaches about participating in MVP end up enrolling. Of those who agree to participate in MVP, one-third are walk-ins, who the VA hasn't invited or hasn't reached out to recently about the project.

"I think that the participation rate and the walk-in rate, which are pretty high if you think about it, are an example of the generosity of the veterans who are participating in the program knowing that there are no guarantees that it will benefit them personally," O'Leary said. "That reflects the same generosity that caused them to volunteer for uniformed service to begin with."

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