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Dec 21, 2017 · Robin Patel, M.D., Appointed to NIAID Council

Robin Patel, M.D., Chair of the Division of Clinical Microbiology in the Department of Laboratory Medicine and Pathology, has been appointed to the council of the National Institute of Allergy and Infectious Diseases (NIAID). She will serve a four-year term.

The council will advise, assist, consult with, and make recommendations to the Secretary of Health and Human Services and the Director of the National Institutes of Health on matters related to immunology, immunologic and allergic diseases, microbiology and infectious diseases, virology, epidemiology, tropical diseases, sexually transmitted diseases, AIDS, and biodefense research. The advisory council will also review and make recommendations regarding grant applications to support biomedical research and research training activities.

About the National Institute of Allergy and Infectious Diseases
In mid-1948, the National Institute of Health became the National Institutes of Health (NIH) with the creation of several individual institutes. Later that year, the Rocky Mountain Laboratory and the Biologics Control Laboratory joined the NIH Division of Infectious Diseases and Division of Tropical Diseases to form the National Microbiological Institute. In 1955, Congress changed the name of the National Microbiological Institute to the National Institute of Allergy and Infectious Diseases to reflect the inclusion of allergy and immunologic research.

As NIAID continues to pursue progress in understanding, treating, and preventing infectious and immunologic diseases, it recognizes that new challenges to public health continue to emerge. NIAID will continue its tradition of supporting innovative scientific approaches to address the causes of these diseases and find better ways to prevent, diagnose, and treat them.

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In addition to serving as chair of Mayo Clinic’s Division of Clinical Microbiology, Dr. Patel also holds a number of leadership roles including serving as director of the Infectious Diseases Research Laboratory.

This article was originally published on Insights, the online news publication of Mayo Medical Laboratories.

Dec 5, 2017 · MASTERMIND: A Smarter Search for Microbial Diagnostics

By Barbara J. Toman

In the war against microbes, human beings are vastly outnumbered—and losing the weapons race.

The introduction of antibiotics into clinical practice in the 1940s spurred hope that infectious diseases might be defeated as a public health problem. But bacterial microbes are cunning foes, adept at acquiring resistance to antibiotics faster than scientists can develop new drugs. At least 2 million people in the United States become infected each year with bacteria that are resistant to antibiotics, and at least 23,000 people die each year as a direct result of these infections.*

Mayo Clinic is part of the Antibacterial Resistance Leadership Group (ARLG), a clinical effort launched in 2013 by the National Institute of Allergy and Infectious Diseases. The ARLG is developing and managing clinical trials aimed at reducing the impact of antibacterial and antimicrobial resistance.

“Antibacterial resistance is a huge crisis in the world today that doesn’t get the recognition it deserves,” says Robin Patel, M.D., Chair of the Division of Clinical Microbiology, Co-Director of its Bacteriology Laboratory, and Director of the Infectious Diseases Research Laboratory at Mayo Clinic in Rochester, Minnesota.

Robin Patel, M.D., Chair of the Division of Clinical Microbiology at Mayo Clinic.

“One solution to antibacterial resistance is to use increasingly broader-spectrum antibiotics to ‘cover’ for resistance,” she says. “But if there’s enough resistance, the broader-spectrum antibiotic won’t work. And using broader-spectrum antibiotics is the very practice that has bred the resistance we have today.”

Dr. Patel directs the diagnostics arm of ARLG and, within that area, the MASTERMIND project. MASTERMIND (which stands for “MASTER protocol for evaluating Multiple INfection Diagnostics”) is one part of ARLG’s smarter approach to fighting antibacterial resistance.

Conventional diagnostic approaches, such as bacterial culture and routine antimicrobial susceptibility testing, can provide a diagnosis for some infectious syndromes. But it can be days before those tests yield actionable results. Facing diagnostic uncertainty, physicians feel compelled to prescribe broad-spectrum antibiotics for patients needing immediate treatment.

Instead of relying on broader-spectrum antibiotics—in hopes of hitting whatever microbe is causing an individual’s illness or infection—the ARLG wants to support the creation, regulatory approval, and appropriate clinical use of tests that can rapidly pinpoint the bacterial culprit. Then, a drug likely to work against that particular pathogen can be prescribed. Or, if there is no bacterial infection, no antibiotic treatment can be recommended.

“There wasn’t as much of a need for microbial diagnostics when antibiotics worked predictably. A patient could be clinically diagnosed and managed,” Dr. Patel says. “Now, with resistance, we really need better diagnostics. And it’s no trivial exercise to develop them and then figure out how to use them properly in clinical practice.”

Maximizing Trial Efficiency

For diagnostics companies, validating diagnostic tests and obtaining approval for clinical use from the U.S. Food and Drug Administration (FDA) is challenging. The return on investment can be uncertain, and the necessary clinical trials are complex.

MASTERMIND seeks to solve those problems with a new clinical-trial design that brings together infectious disease physicians, clinical microbiologists, statisticians, and potentially interested companies. The innovative concept uses a single individual’s clinical sample (or samples) to evaluate multiple tests, providing efficiencies of scale for simultaneous or successive investigations by companies.

“It’s typical for more than one company to be performing clinical trials of similar diagnostics, often contemporaneously,” Dr. Patel says. “Or companies might be working on distinct diagnostics but need the same kind of patient samples for their trials.”

Depending on the disease or diagnostic assay being studied, high-quality patient specimens may be limited. Companies also might find themselves competing to partner with the limited number of medical centers capable of performing a complex clinical trial.

MASTERMIND seeks to solve those problems with a new clinical-trial design that brings together infectious disease physicians, clinical microbiologists, statisticians, and potentially interested companies.

“All of these studies need approval by regulatory bodies and institutional review boards. But with those approvals, it’s possible to enroll a patient in a trial that involves distributing the patient’s specimen to testing using multiple companies’ platforms,” Dr. Patel says.

In addition to patient specimens, clinical data might be consolidated and test results shared to inform the performance of other tests within a study. “It’s not typical for companies to work together like this,” Dr. Patel says. “But the ARLG can serve as the middle ground for these discussions between companies and also with the FDA.”

Pilot MASTERMIND for Extra-Genital Sexually Transmitted Infections

Multiple companies are participating in the first MASTERMIND study, which aims to validate nucleic acid amplification tests (NAATs) for rectal and throat Chlamydiatrachomatis and Neisseria gonorrhoeae. Although the U.S. Centers for Disease Control and Prevention (CDC) recommends the use of NAATs for chlamydia and gonorrhea bacteria, no FDA-approved assays exist for detecting those bacteria in the extra-genital sites being studied.

“Antibiotic resistance is not an easy problem. We have to think differently.”
Robin Patel, M.D., Chair of the Division of Clinical Microbiology at Mayo Clinic

“The goal of this MASTERMIND study is to produce data that the companies can submit to the FDA to get clearance for their assays,” Dr. Patel says. “It’s clearly advantageous to the companies involved, and we hope that it will ultimately be advantageous for patients.”

Future MASTERMIND studies may tackle direct-from-blood and direct-from-urine diagnostic tests for various conditions. In addition to diagnostics, the ARLG is focusing on:

  • Infections caused by carbapenem-resistant Gram-negative bacteria, such as Escherichia coli and Klebsiella pneumoniae.
  • Infections caused by Gram-positive bacteria, such as methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci.
  • Antimicrobial stewardship and infection prevention and control.

“Antibiotic resistance is not an easy problem. We have to think differently,” says Dr. Patel. “It’s a new approach for the National Institutes of Health to be undertaking MASTERMIND studies with companies to help them get FDA clearance for new diagnostics. But it just makes sense as a way to further the development of diagnostics so these can be used in clinical practice to improve human health.”

Read the rest of the article to learn about the 12-antibiotic-resistant bacteria, also known as “superbugs,” identified by the World Health Organization (WHO) as “priority pathogens.”

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*Antibiotic/Antimicrobial resistance. Centers for Disease Control and Prevention. https://www.cdc.gov/drugresistance/.

The full article is available in INSIGHTS – the online magazine published by Mayo Medical Laboratories.

Oct 25, 2017 · Unnecessary Test for Venous Thromboembolism: Inefficient and Costly

Closeup illustration of a clot in a blood vessel.

A recent Mayo Clinic study has found that many U.S. health care providers are habitually ordering a mostly unnecessary and quite expensive genetic test to identify a patient’s hereditary risk of venous thromboembolism (VTE). Further, if other institutions followed Mayo’s VTE test utilization example, there is significant potential to reduce costs and economic impact in this area of clinical pathology.

Venous thromboembolism is a potentially life-threatening condition when, for example, a blood clot occurs in the leg veins and moves to the lungs. Clotting can also locate in other veins of the body.

The study demonstrates that the costly genetic test, which detects the condition called activated protein C resistance (or APC-R) due to the mutation factor V Leiden (FVL), was not needed in approximately 80 percent of cases studied. Factor V Leiden, a mutated form of the protein human factor V, causes an increase in blood clotting. The variant can be found in both men and women.

“Factor V Leiden is the genetic basis for activated protein C resistance,” says Rajiv Pruthi, M.B.B.S., co-director of Mayo Clinic’s Special Coagulation Laboratory and Molecular Hematology Laboratory and senior author on the study. “It is the most common genetic risk factor for VTE among the white population . . . . About seven out of every 100 whites in the U.S. carry this mutation.”

Rajiv Pruthi, M.B.B.S.

Dr. Pruthi adds, “Only about 10 percent of those who carry it will develop VTE over their lifetimes. Nevertheless, if you extrapolate even that 10 percent from the 7 percent of the entire white population, that’s a lot of people who will develop blood clots that can lead to serious complications.”

Background on Testing and Cost Savings
Typically, for VTE, there are two tests health care providers can order: the APC-R assay, which is a more inexpensive functional test preferred by Mayo Clinic, or the FVL genetic test, which is about twice as expensive as the APC-R assay.

To analyze ordering patterns on a national scope, the study team partnered with OptumLabs Data Warehouse, a database of de-identified, linked clinical and administrative claims information, to gain access to more than 19 million tested patients. Insurance claims for these two test methods were compared (for calendar year 2013) with the Mayo Clinic Special Coagulation Laboratory database. The Centers for Medicare and Medicaid Services Clinical Laboratory Fee Schedule was then used to assign costs.

Findings revealed that physicians at other institutions were ordering the Factor V Leiden test much more often, as the only test, which contradicts how it’s long been done at Mayo.

“Back in the mid-90s, we decided to go with a functional APC-R as the initial screening test for this disease,” says Dr. Pruthi. “And if the patient result is normal, you don’t need the genetic test. If it’s abnormal, then one can go on and confirm the genetic basis with the FVL test—and the importance of that would be to determine whether the patient carries one copy of the gene or two copies.”

The cost savings comes from ordering the APC-R test first. A negative result in this functional test means there is essentially no possibility the condition exists—in which case the more expensive genetic test would, indeed, be highly unnecessary.

The Hard Numbers
Looking at the OptumLabs data for 74,242 tested individuals, 90.1 percent of them received only FVL genotyping, compared to a mere 2.9 percent who received only the APC-R profile. And 7 percent of patients received both. (The data did not show why each test was ordered, nor tell how many were duplicates.) Conversely, at Mayo’s Special Coagulation Laboratory, of the 1,317 tests performed in 2013, only 4.6 percent of patients were tested for FVL, while 95.4 percent of patients received the APC-R assay.

“At eye level, we were clearly using a more cost-effective approach,” says Dr. Pruthi. “But the only objective way of getting at these hard numbers was to look at the Medicaid reimbursement.”

Based on this comparison, the cost-per-evaluated individual was $83.77 in the national data from OptumLabs and only $36.38 at Mayo Clinic, with a potential cost savings of $47.39 per individual.

Besides lowering costs, reliance on the APC-R profile also reflects best practice, according to Dr. Pruthi.

“Value-based medicine is an important part of health care moving forward, and we want to show that, ‘Look, we’re doing it right. We’re providing high-quality patient care in a cost-effective way,’” he says.

A Disconnect between Labs and Clinicians
If using the APC-R functional assay is much less costly and more efficient, why are so many institutions doing otherwise?

“As clinicians, we all want the best for our patients, and we want to get the information that we need,” says Juliana Perez Botero, M.D., who was a Mayo Clinic fellow in the Hematology/Oncology Division at the time of the study, which she co-authored. “But it turns out that some are misinformed and may be ordering redundant testing, and they don’t even know it.”

One reason is that clinicians may get confused or overwhelmed by the many tests to choose from on a lab’s electronic ordering portal. Thus, some patients are given the wrong test altogether. And even if a clinician chooses the correct test, it might not be the least expensive option. Further, the chosen laboratory may not be equipped to handle it and has to send it to another reference laboratory.

“Maybe there’s an opportunity here for laboratories to better educate their clients and work on making sure the testing information is out there and available to them—what is offered and why,” says Dr. Perez Botero, now associate medical director of the BloodCenter of Wisconsin in Milwaukee. “Because in hematology, unlike orthopedics or neurosurgery where you have X-rays and images to look at, you rely heavily on your lab for everything. In hematology, you’re only as good as your laboratory and lab staff are.”

Dong Chen, M.D., Ph.D., chair of Mayo’s Division of Hematopathology, also co-authored the paper. He agrees that educating physicians about “the pros and cons” of each test would help them order the correct ones. Unfortunately, such an undertaking leans toward a pipe dream.

Dong Chen, M.D., Ph.D.

“Physicians are busy and really don’t have time to manage the details of test utilization,” he says. “So, therefore, they haven’t been very good at complying with and staying current on test utilization in this field.”

Simplifying Is Key
To facilitate test compliance, the Mayo Clinic Special Coagulation and Molecular Hematology Laboratories have simplified the test-ordering process and made it straightforward for clients, which saves them precious time for more urgent matters. The way in which a lab presents its ordering menu and, in turn, the way health providers perceive it, is key in tackling the cost-effectiveness issue.

“We will set up the functional [APC-R] assay as the initial screen, and then we only do the genetic testing if the functional screen is abnormal,” says Dr. Chen. “So, our clients only see one test to order, rather than having to figure out the testing algorithm themselves.”

The study recommends that laboratories program their electronic ordering menus and defaults to assist the provider in choosing the right test and help reduce duplicate orders.

“The lab still offers genetic testing up front,” says Dr. Perez Botero. “But when ordering through the institution, you have to go through specific order sets, and when you try to choose the factor V Leiden test, the software gives you a warning and tells you that the APC-R is the preferred test. Then, it asks if you’re sure about selecting the genetic option. So that’s something that works really well in clinical practice, when labs work together with clinicians in helping them make the right choice for the patient.”

Laboratories should take a proactive approach in implementing testing utilization, rather than asking clinicians to make testing decisions on their own.

“We’re not waiting or relying only on the physician to do effective testing,” says Dr. Chen. “We’re doing something to help them make the best decision.”

Mayo’s highly integrated practice makes this proactive approach easier than it would be at, for example, a private practice.

“We have a number-one ranked hospital attached to our reference labs,” says Dr. Chen. “And our [Division of Hematopathology] is served by a very diverse group of consultants that includes hematopathologists, hematologists, cardiologists, and pediatric hematologists. Therefore, in a sense, our lab consultants know exactly what clinicians are thinking, and so they can help design better test utilization practices, not only for themselves, but also to help their colleagues and peers in the field.”

So, how can laboratories and institutions that do not have Mayo’s integrated clinical and laboratory expertise reduce unnecessary costs and improve efficiency? By cultivating more cooperation and open communication among references labs and the providers doing the ordering.

“Labs should be partnering with the health care providers who order these tests,” says Dr. Pruthi. “So they can to do the right test at the right time for the right patient.”

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This piece was written by Christoph Bahn, who covers emerging research and discovery for Mayo Medical Laboratories. His writing has also appeared in The New York Times, Los Angeles Times, and Smithsonian Air & Space.

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