Does Genetic Testing for Opioid Addiction Really Work?

By Roger Chriss, Columnist

Prescient Medicine recently announced LifeKit Predict, a gene screening test to determine who is at risk for opioid addiction. The company states that it “can identify with 88% specificity that someone may have a risk for opioid dependency” and “provides assurance -- with 97% sensitivity -- that an individual may not have increased genetic risk for opioid dependency.”

Those are strong claims. The idea that medical conditions and behavior can be predicted by gene variants is appealing. But any such test has to answer two questions:

Is it possible in principle? And does it work in practice?

Genes and Behavior

The pathway from gene variant to behavior is very complicated. Research on the genetics of opioid addiction has found “evidence for genetic susceptibility to substance use disorders” in twin studies, but non-genetic factors are known to play a significant role as well.

Moreover, the connection between gene test results and clinically useful information is complicated. Genetic testing often finds pathogenic variants with no clinical significance. A person can be a perfect match for a rare disorder in the most advanced genetic test available but have no symptoms, so at a clinical level that person does not have the disorder. Only in a handful of cases does a specific gene variant lead to a precise fate: Huntington's disease is the standard example in textbooks.

Addiction is generally thought of in terms of the biopsychosocial model of medicine, as Maia Szalavitz explains in her book, Unbroken Brain.

“There are three critical elements to it; the behavior has a psychological purpose; the specific learning pathways involved make it become nearly automatic and compulsive; and it doesn’t stop when it is no longer adaptive,” she wrote.

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The National Institute on Drug Abuse reports that “genetic factors account for between 40 and 60 percent of a person’s vulnerability to addiction; this includes the effects of environmental factors on the function and expression of a person’s genes.”

Thus, genes may play a significant role, but many other factors are also at work. A genetic test to identify an increased risk for opioid addiction is plausible in principle. But non-genetic factors make it tricky in practice.


Real World Performance

Prescient Medicine has not yet validated its product with large-scale testing in the clinical setting. There have been no clinical studies of efficacy, nor real-world reports of success or failure rates with the LifeKit Predict tool. These findings are important to know for effective use.

In research published on LifeKit Predict, Prescient acknowledges that “the use of genetic algorithms to determine predictive risk scores is still a relativey [sic] new science. Prospective, longitudinal studies are needed to better definne [sic] the breadth of the test’s importance."

A prospective trial of chronic pain patients with LifeKit Predict to see who develops opioid use disorder would be optimal. But for a variety of reasons, including ethical considerations, this test may not be practicable. Instead, Prescient could test people on long-term opioid therapy who did not develop opioid use disorder and compare the results with people who did develop opioid use disorder. Findings here would shed light on the validity of the 16 gene alleles that Prescient is using.

For now, Prescient is reporting on sensitivity and specificity. These two terms have a precise meaning in statistics, but the following medical example captures the essentials:

A molar (butterfly) rash is very sensitive for lupus but not very specific. It is rarely seen in any disorder other than lupus, so if a person has it, lupus should be suspected. But it is only seen in about half of people with lupus, so not having a butterfly rash doesn't mean you can rule out lupus.

But the sensitivity and specificity of LifeKit Predict in the ranges given by Prescient represent a significant risk for false positives and false negatives, potentially limiting the real-world value of the test.

GenomeWeb reported that Yale University professor Joel Gelertner, an expert in genetics and addiction, was skeptical that LifeKit’s “predictive power would hold up when applied to larger datasets, and argued that in the absence of better validation, physicians should not use this type of testing."

Further, LifeKit has not been compared with established tools for opioid risk assessment. The Current Opioid Misuse Measure (COMM-9) and the Opioid Risk Tool (ORT) are both simple and familiar instruments for evaluating the major risk factors for opioid use disorder.

Both COMM-9 and ORT are very inexpensive, easy to use, and give results quickly. By contrast, a gene test is expensive and requires weeks to get results. It is not clear at this point if a gene test offers any advantages over these existing instruments.

Opioid addiction risk is at present more readily assessed using tools that are already available and understood. Prescient has developed a novel and intriguing new tool, but still must prove its reliability in clinical settings before the costs and risks of such a test can be justified.

For now it is probably premature to expect this kind of genetic testing to be as useful as it would need to be to be adopted clinically.

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Roger Chriss lives with Ehlers Danlos syndrome and is a proud member of the Ehlers-Danlos Society. Roger is a technical consultant in Washington state, where he specializes in mathematics and research.

The information in this column should not be considered as professional medical advice, diagnosis or treatment. It is for informational purposes only and represents the author’s opinions alone. It does not inherently express or reflect the views, opinions and/or positions of Pain News Network.

Controversial Genetic Testing Company in Receivership

By Pat Anson, Editor

A controversial genetic testing firm under federal investigation for healthcare fraud has been placed into court-ordered receivership – a form of bankruptcy – that could lead to the restructuring and sale of the company. The CEO and founder of Proove Biosciences has also left the company.

In an interview with STAT, former CEO Brian Meshkin blamed the company's financial problems on “erroneous and damaging” reports that were based on “false allegations” by disgruntled former employees.

Proove Biosciences specializes in DNA testing that the company claims can improve the effectiveness of pain management treatment and determine whether a patient is at risk of opioid addiction.

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In June, FBI agents raided the company’s headquarters in Irvine, California. Former and current employees who were interviewed by STAT said the agents were focused on possible kickbacks to doctors who encouraged patients to take Proove’s DNA tests. Physicians reportedly could make $144,000 a year in kickbacks that were called “research fees.”

In July, PNN reported that Proove was linked to a Medicare fraud case, in which three Indiana healthcare providers allegedly “caused Proove Bioscience… to falsely and fraudulently bill various health care programs for genetic tests... that were not medically necessary and never interpreted."

Proove was not named as a defendant in the Indiana case. In an email to PNN, Meshkin said Proove had cooperated with investigators.

“Proove has cooperated with both the FBI and US Attorney’s office on this case," said Meshkin. "With regards to tests being 'medically necessary', Proove received written and signed determinations of medical necessity supporting the tests ordered and billed to insurance carriers just like every other laboratory which requires such a determination on a test requisition form. Thus Proove operated appropriately and consistent with usual and customary practices."

Meshkin also defended Proove research, published in the Journal of Addiction Research & Therapy, which claimed to show the effectiveness of its genetic tests.The publisher of the journal, OMICS International, has been accused by the Federal Trade Commission (FTC) of deceiving researchers and readers about the true nature of its publications and peer review process.

"Proove can only speak to its experience with this particular journal,” Meshkin said in an email to PNN. "Specifically for papers submitted to this journal, our R&D team and academic collaborators engaged in documented, extensive peer-review, received suggested edits and provided responses to the suggested edits to the manuscripts submitted for review and publication. Thus, Proove would certainly consider the publications accepted from Proove-affiliated authors in that journal to be 'peer-reviewed'."

According to the FTC complaint filed last August, OMICS  has created hundreds of "open access" online medical journals that publish articles with little or no peer review. Researchers are also charged significant fees to get their articles published by OMICS, a "pay to play" policy that some consider unethical because it diminishes the quality of academic journals and the peer review process.

Proove has aggressively promoted its genetic tests with healthcare providers around the country. A pain clinic in Montana, for example, had a Proove “patient engagement representative” employed on site at the Benefis Pain Management Center in Great Falls.

“We had a meeting one day and here are these people from Proove Biosciences. They told us they were doing a research project,” said Rodney Lutes, a physician assistant who was later fired by Benefis. “They wanted to come to Benefis, into the pain department, and test our patients.  We were told this would be at no cost to the patient. My understanding was that they weren’t going to charge anybody, but I found out afterwards they were charging insurance companies.

“They said providers who participated in this would get some form of payment for participating in the program and for filling out all the paperwork.”

Lutes’ supervising physician at the clinic was Katrina Lewis, MD, a pain management specialist at Benefis who is listed as a member of Proove’s Medical Advisory Board.  Lewis apparently plays a significant role at the clinic, even though she only works there part time. Benefis has denied that Lewis or any of its employees received kickbacks from Proove for referring business to them.

STAT reported that Proove’s restructuring was apparently ordered by Mike Leavitt, a Proove board member, who also served as Utah governor and secretary of the Department of Health and Human Services. Leavitt’s investment firm, Leavitt Equity Partners, provided about $7 million in funding to Proove, according to Meshkin.

A former Proove manager told STAT that she initially felt good about going to work for the company, but soon had misgivings about Proove's research and billing practices.

“It sucked the life out of me, on an integrity level,” said Rhonda Frantz-Smith. “It got more and more corrupt.”

Genetic Testing Company Raided by FBI

By Pat Anson, Editor

FBI agents have raided the headquarters of Proove Biosciences, a controversial genetic testing company that claims its DNA tests can improve the effectiveness of pain management and determine whether a patient is at risk of opioid addiction.

Over two dozen FBI agents appeared at Proove offices in Irvine, California Wednesday as part of a healthcare fraud investigation. They were later seen carrying dozens of boxes out of two buildings

“It is an ongoing investigation out of our San Diego office. It involves healthcare fraud. And unfortunately we are unable to say anything more about it at this time. The affidavit supporting the search warrant is under seal,” Cathy Kramer, an FBI special agent, told KABC-TV.

STAT News reported in February that the FBI and the Inspector General for the Department of Health and Human Services (HHS) were investigating possible criminal activity at Proove.

Former and current employees who were interviewed by the FBI told STAT the agents were focused on possible kickbacks to doctors who encouraged patients to take Proove’s DNA tests. Physicians reportedly could make $144,000 a year in kickbacks that were called “research fees.”

The HHS Inspector General issued a Special Fraud Alert in 2014 warning physicians that any payments, referrals, rent or reimbursements from lab testing companies could be seen as violations of anti-kickback laws.

Proove promotes itself as the “leader in personalized pain medicine” and claims its genetic tests can identify medications that would be most effective at treating pain. The company recently claimed that 94% of patients experienced significant pain relief within 60 days of treatment changes recommended by Proove. Critics say most Proove studies are not peer-reviewed and one genetic expert has called them “hogwash.”

According to STAT, doctors affiliated with Proove in California, Florida and Kentucky were also raided by the FBI. Proove said it was cooperating with the investigation, and that no arrests or charges have been made.

"Proove has been subject to a handful of inaccurate stories initiated by STAT News that we believe have contributed to this latest action," the company said in a statement. "While we originally chose not to dignify these outlandish accusations with a response, we now understand that we can no longer ignore these false stories based on unreliable sources, and filled with erroneous accusations... spread by a few disgruntled former employees and consultants.  Proove is confident that the facts supported by verifiable and reliable sources will clearly restore our reputation."

Proove Linked to Montana Pain Clinic

Proove is the second laboratory testing company raided by the FBI that has been linked to Benefis Pain Management Center, a pain clinic in Great Falls, Montana. 

As PNN has reported, FBI agents last November raided the offices of Confirmatrix Laboratories near Atlanta. Two days later, the company filed for Chapter 11 bankruptcy protection. Confirmatrix was founded by Khalid Satary, a convicted felon and Palestinian national that the federal government has been trying to deport for years.

In 2013, Medicare identified Confirmatrix as the most expensive urine drug testing lab in the country, charging an average of $2,406 for each Medicare patient.

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Benefis has continued to send urine drug samples to Confirmatrix for testing even after the company filed for bankruptcy. Some Benefis patients have recently been contacted by collection agencies seeking payment for urine tests costing well over $1,000 that their insurance refused to pay for. Similar tests by other labs cost only a few hundred dollars.

According to its bankruptcy filing, Confirmatrix has 152 employees in 15 different states, including one employee in Montana who apparently works on site at the Benefis pain clinic. PNN has also learned that Proove Biosciences has had employees working at the clinic. A Proove “patient engagement representative” was employed there as early as May 2016.

“We had a meeting one day and here are these people from Proove Biosciences. They told us they were doing a research project,” says Rodney Lutes, a physician assistant (PA) who was later fired by Benefis. “They wanted to come to Benefis, into the pain department, and test our patients.  We were told this would be at no cost to the patient. My understanding was that they weren’t going to charge anybody, but I found out afterwards they were charging insurance companies.

“They said providers who participated in this would get some form of payment for participating in the program and for filling out all the paperwork.  What they did is they had a technician there in the department and every day I would get a list from that technician of patients that they would like to try to include in the program.”

Lutes says he recommended the DNA test to many of his patients, but never received any money from Proove. He says some of his patients later complained that their insurance was billed for the DNA test.

“One of the things that bothered me was that I signed a lot of the papers, but they also had my supervising doc on all of those papers,” Lutes told PNN. “I also felt like she was the one that brought them (Proove) in there.”

Lutes is referring to Katrina Lewis, MD, a pain management specialist at Benefis who is listed as a member of Proove’s Medical Advisory Board.  Lewis plays a significant role at the pain clinic even though she only works there part time. 

“Dr. Lewis works for Benefis one week a month and has been instrumental in the development of our multidisciplinary approach and current protocols,” said Keri Garman, Director of Corporate Communications at Benefis.

In a statement emailed to PNN last month, Lewis said regular urine drug testing was necessary to ensure that “appropriate levels” of medication are present. Current clinic policy is that “high risk” patients should have a urine test at least once every two months.

Presence of too high of a level of opioids or other substances in the urine can make it inappropriate and unsafe to continue prescribing opioids.  Presence of none of the prescribed opioids in the urine indicates the care plan is not being followed and further prescribing is medically unnecessary,” Lewis said.

Benefis: No Kickbacks from Testing Labs

PNN has made repeated requests to Benefis to clarify its relationship with Confirmatrix and Proove, and whether Lewis or any other Benefis employees were receiving compensation from the laboratories for referring business to them. 

“Benefis and its employees, including Dr. Katrina Lewis, do not receive kickbacks from Confirmatrix or Proove. As for any questions you have regarding the lab business practices of these facilities, these would be best answered by the companies directly,” Benefis spokesman Ben Buckridge said in a statement emailed to PNN last week. 

“We take these accusations and defamatory statements against our organization and staff seriously. We appreciate your diligence on this issue.” 

In an earlier statement, a Benefis official said the DNA tests are voluntary and only done on patients if they are appropriate.

Patients have the option to decline this testing, however, it proves to be very helpful in determining treatment plans for our patients in many cases. This testing has not been readily available until recently,” said Kathy Hills, Chief Operating Officer of Benefis Medical Group.

“Genetic testing allows us to see if the patient is appropriately synthesizing specific medications and can drastically alter treatment plans, showing us that sometimes the medications are not effectively metabolizing and therefore not as effective, which is why some patients have needed high doses. Our partners in this have an extensive patient assistance program that waives many costs, and patients are not penalized or removed from opioids if they refuse to have a genetic test performed.”

But a recent copy of the clinic’s opioid policy obtained by PNN says the tests are not voluntary for everyone. 

“All patients on dosing levels at or higher than the maximum policy dose MUST be submitted for genetic testing,” the policy states. The word "must" is capitalized in the document. 

One Benefis patient who took the DNA test said Lutes recommended it.

“He said everyone was doing it and that the insurance would be billed, but if they did not pay for it then Benefis would. I think he said something about it being a $6,000 test,” she told PNN.  “To me it was a waste of time and money. The meds it said I should be taking either didn’t work, stopped working, or made me sick. And the meds I should not be taking I do just fine on.”

It is not clear whether the pain clinic's association with Proove or Confirmatrix had anything to do with Lutes’ firing in March. The 68-year old Lutes treated several hundred pain patients and was popular with many of them. 

Lutes was discharged for violating Benefis policy about record keeping, opioid dosage and urine drug testing, but feels he was “written up for violations that do not exist.” His supervising physician – Katrina Lewis – also requested removal from that role, meaning Lutes could no longer practice at Benefis as a physician assistant.

Since his dismissal, many of Lutes former patients who were on relatively high doses of opioids say their medication has been reduced or stopped entirely. One patient, whose opioid dose was cut significantly, committed suicide. Still others complain they were labeled and treated as addicts by clinic doctors and staff, and now have trouble finding new physicians in the Great Falls area. The ones who remain at Benefis say they are being told to take new tests and exams. 

Benefis says it cannot comment on the accusations because of patient and employee privacy rights.

“Unless Rodney Lutes, PA, or the patients with whom you are speaking will sign written releases allowing us to comment fully on the facts of their employment or their care, respectively, we are simply unable to engage in any further back and forth discussions.  We have provided all the information we are able given the legal limitations governing our industry,” Buckridge said.