NEW YORK (GenomeWeb) – Molecular diagnostics, including PCR-based multiplex panels, are transforming the clinical lab workflow. However, as more firms develop and attempt to commercialize PCR panels, a debate has developed over their appropriate design and use.
This debate was highlighted in an article recently published in the Journal of Clinical Microbiology.
In the piece, two clinical lab directors took the pro and con sides on whether large multiplex PCR panels should be the first-line tests for detecting respiratory and intestinal pathogens.
GenomeWeb caught up with the authors of the article to get a sense of the dynamics of this debate.
Surprisingly, even the author of the opposing viewpoint, Alexander McAdam, director of the infectious diseases diagnostic laboratory at Boston Children's Hospital, believes that multiplex panels are, overall, "terrific."
"I think in general there's enthusiasm for them, and I like them ... I am mainly expressing some concerns about the way the panels are constructed, the things that are combined together in the panels," McAdam told GenomeWeb.
Of course multiplex panels run on larger systems or platforms, and lab directors consider breadth of menu, platform size, closed or open systems, technical complexity, hands-on time, batch processing and number of samples per run, as well as the cost of the platforms themselves, before choosing to purchase any particular diagnostics solution.
However, the JCM article emphasized the panels, specifically focusing on issues of how panel size and target choice impacts clinical management and patient outcomes. The authors also drove home the message that peer-reviewed literature, peer opinion, and personal experience can tip the balance in purchasing decisions, and that more research is needed to gauge clinical utility.
Panel size, target choice
A primary point of contention in the JCM debate was panel size. McAdam asserted that testing for uncommon pathogens should usually follow testing for common ones, and first-line assays should not look for organisms whose presence is extremely unlikely.
Responding to similar feedback from labs, Becton Dickinson has chosen to develop a line of smaller, focused panels for its BD Max platform, an executive told GenomeWeb recently, by separating viral, bacterial, and parasitic targets for its GI panels.
But this is absolutely the wrong path, according to Paul Schreckenberger, author of the pro-panel position in the JCM article and director of the clinical microbiology laboratory at Loyola Medicine.
Large panels are ultimately more similar to the syndromic testing historically done by microbiology labs, he said. "We've always done syndromic testing; physicians don't know what caused the patients urinary tract infection, or what's causing their pneumonia ... they order cultures to see what's causing it," he explained.
As in the case with BD, "Nanosphere's approach, for example, is to provide multiple systems; one for bacteria, a different one for parasites, a different one for viruses — even with their blood culture they have one panel if it's gram positive, a different panel for gram negative — I think that's the wrong strategy because it gets away from the syndromic panel," Schreckenberger asserted.
Firms with small, focused panels claim to save the user money "because you don't have to do all 27 targets, you can do these 15, and then if you don't like that you can do these 15," he said. "But that's terrible. That's taking us back to where we were before. We want specimen to result, period."
Smaller panels also mean physicians will be ordering tests piecemeal, Schreckenberger said. "I can tell you, our physicians don't want to do that, they want to send one sample and in an hour they want to know what the answer is."
Perhaps an institution that has already adopted large panels could also add an option for smaller ones? McAdam was not so sure that is a good idea.
"The appeal would mainly be cost savings — having a small panel available would cost the laboratory less, and more importantly it would cost the patient less, [but] the trouble you get into is people ordering both, or ordering the small one, and when it's negative, ordering the large one," McAdam said.
"It's a difficult calculation, I am not resolved in my mind whether having a small panel and a large panel together is the way to go," he said.
Another point in the debate was target choice and performance characteristics for all targets in a panel.
BD, for example, asserted recently that false-positive results on unlikely targets could potentially confuse physicians. And even firms with large panels have made choices regarding targets in order to best balance sensitivity and specificity. BioFire Diagnostics, a subsidiary of BioMerieux, deliberately chose a less sensitive pertussis target in order to avoid detecting "pseudo-outbreaks" due to vaccine contamination and other factors.
McAdam agreed that for pertussis, the trade-off between sensitivity and specificity is very real. "I'm glad to know that [BioFire was] thoughtful in their approach to this," he said, but for other analytes specificity and sensitivity do not compete, yet commercial products still vary. This is often well represented in studies, he said, "so people just have to read the literature and realize what they're getting."
In fact, both authors agreed that peer-reviewed literature helps guide their purchasing decisions.
"The main thing we would think about when choosing a test are, what analytes or pathogens does the test detect, what data [support whether] the test is a good test — we would look mainly to the peer-reviewed literature for that, and also the package insert, though I tend to rely more on the peer-reviewed literature," McAdam said.
Some panel makers also think peer review is a deciding factor. BD just completed a multi-center evaluation of its enteric bacterial panel, and hopes the favorable study will be a selling point for new customers, a company representative told GenomeWeb recently.
Schreckenberger and McAdam also cited a listserv of lab directors and conference discussions as other ways they learn about panel performance. "We network in many ways ... we are communicating daily asking, 'what are you trying, what have you heard,'" Schreckenberger said.
From this aggregate discussion, McAdam said he has a sense that the debate over multiplex panels continues among his colleagues. "It remains very much unresolved, [and] it's not one question, there are lots of questions around the issues [raised by] the use of multiplex PCR panels."
Cost of test, cost of care, clinical utility
Another pivot point in the debate is cost.
Although the cost of reagents for multiplex panels is admittedly higher, the cost of labor is lower, Schreckenberger said, adding that proponents of this argument often haven't considered total cost of care, which is "so myopic."
A major driver of cost of care is length of hospital stay, he said. It costs Loyola Medicine $1,500 a day to keep someone in the hospital, while large multiplex PCR panel reagents cost $100. "Would you spend $100 to save $1,500?" Schreckenberger asked.
Patient and physician satisfaction are also intangibles that, while they can't be readily assigned a dollar value, make a difference. For infectious diseases, "no one is satisfied with a negative result," Schreckenberger said. Even if there is no treatment for the pathogen, a specific diagnosis enhances satisfaction.
Schreckenberger has worked with BioFire in the past, as reported previously by GenomeWeb, and, while validating panels in his hospital he found that word of mouth led physicians to seek him out and request that he run their patient's samples using panels.
He described one incident in which a physician called for Shiga toxin testing for a child with bloody diarrhea. "We don't do [that test] in our lab, we have to send it to the state," Schreckenberger explained. It was a Friday, and the state lab wouldn't be able to run the test until Monday or Tuesday, but the physician said she'd heard the lab was validating a one-hour multiplex panel. "We got the sample from the child, we ran it, and turned out the child had salmonella," Schreckenberger said.
While validating the BioFire GI multiplex panel, his lab was running all its negative Clostridium difficile samples through the platform. One patient, who had been hospitalized and had been on antibiotics, and for whom the only test ordered was the most logical — C. difficile — turned out to have norovirus. "The physician didn't even think to order that test," Schreckenberger said, "so for anyone to say 'the physicians should be allowed to order what they need,' my answer is, how would they know."
"What they know is a symptom ... if they give [the sample] to me, I'll tell them what it is; if I let them start picking from a menu, they're just guessing."
In terms of cost, Schreckenberger also cited a case handled by his lab in which a two-month old was airlifted to his hospital with a severe respiratory illness. Days earlier, the child had been sent home from the emergency room of a small community hospital after doctors there combined a negative result on a low-sensitivity respiratory syncytial virus immunoassay with the clinical picture to conclude that the child probably had RSV.
When the child arrived at Loyola Medicine by helicopter he was cyanotic with apnea episodes. One hour later, the BioFire panel showed the child had pertussis.
"Three days later the patient went home, cured. You tell me that's not a compelling story. Why would you let a physician, for example, order only virus PCR because they think its RSV?" Schreckenberger said.
"The stories are just building like this. To argue that it's not cost effective ... look at what it cost that family — I wonder how much the helicopter ride cost."
The BioFire platform costs about $29,000, Schreckenberger said, while the panels cost around $130. To run the panel "takes two minutes of tech time — we bill tech time at $0.55 per minute, so the total cost is $131.10."
Schreckenberger said his lab uses the BioFire respiratory panel and just finished validations for blood culture and GI, which the lab will introduce soon. "We also completed the clinical trials for the BioFire meningitis panels, which is going to the FDA very soon, so we intend to use all of those panels," he said.
Among the other manufacturers of large multiplex panels, Schreckenberger believes GenMark will "make a big splash," and that Nanosphere, a firm that also makes smaller, focused panels, is another notable player.
"I think the players are going to be BioFire, GenMark, and Nanosphere, but Nanosphere will not survive," he said.
Impact on clinical management, convincing payers
Schreckenberger sees the adoption of molecular growing even more rapidly in the future.
"There are more companies producing these products, and there are more menus. Instead of just respiratory panels, now we have GI and blood culture, we have meningitis panels coming out soon, pneumonia panels, so there is an explosion of the technology. As labs begin to purchase these, the prices are coming down, which makes it more affordable, and the clinicians have learned about them and are asking for them," he said.
McAdam also noted that more labs are adopting panels, with larger and academic institutions probably being early adopters. "We [at Boston Children's] are doing our best to bring in a multiplex respiratory test very soon," he noted.
But platforms to run panels can be a big investment, McAdam noted. "It is a lot of money. Labs have to think about it and make the right decision, but then they also face the hurdle of convincing their institutional leaders that this is a good thing to spend their money on."
In terms of calculating cost of testing, cost of care, and clinical utility, McAdam said, "I think we have to be driven by high-quality data in making these decisions, and we lack enough data. There is a little bit out there regarding costs of implementing these tests, but I don't think we really have a good idea of whether they save money overall for the patient or for the institution. It's an issue that is absolutely ripe for study."