NEW YORK (GenomeWeb) – Nathan Ledeboer is an associate professor of pathology and the medical director for the clinical microbiology and molecular diagnostics laboratories at the Medical College of Wisconsin, Milwaukee's Froedtert Hospital, and Dynacare Laboratories.
He argued in a recent article that clinical labs will be moving toward more automation because of higher testing volumes and fewer available skilled workers. Now, in a review of emerging technologies in Clinical Microbiology Reviews, Ledeboer has expanded this thesis to describe the trends he sees every day.
The review is intended to help labs navigate the evolving diagnostics landscape. It outlines "the applications, performance, advantages, and potential shortcomings" of a number of technologies and diagnostic methods. These run the gamut from isothermal nucleic acid amplification tests (NAATs) and multiplexed panels, to digital PCR, as well as electrospray ionization (ESI) mass spectrometry and matrix-assisted laser desorption ionization-time of flight (MALDI-TOF), a subject he has discussed with GenomeWeb in the past, particularly with respect to microbe detection.
In an interview last week ─ immediately following a US Centers for Disease Control and Prevention inspection of his hospital to certify it a category 1 Ebola response center ─ Ledeboer talked to GenomeWeb about the changing roles and responsibilities of the clinical lab director. He also described some of the major trends in molecular diagnostics, particularly point-of-care methods such as the Alere i influenza assay, which launched into an already-crowded flu diagnostics space this past June.
The following is an edited version of the conversation.
How did the inspection go?
It actually went really well, I was pleased. The lab section looks really good, the hospital looks really good, and the CDC was extremely helpful.
GenomeWeb recently covered Emergency Use Authorization for Ebola diagnostics. As a clinical lab director, what do these tests mean to you?
That is one of the things we spent a lot of time today talking about with the CDC. We have the BioFire assay here, and we've got it up and ready to run. Our diagnostic is ultimately still the CDC's PCR. But we're using [the BioFire] basically as an initial piece of information to make decisions on what we want to work up on a patient, just to give an initial risk assessment. We're actually required ─ and this is different in each state ─ to notify the department of health that we we're going to perform the assay. They were supportive of us doing it, with the agreement that we would still send a specimen to them in parallel, and we would perform the testing in parallel. There are some concerns that BioFire's [limit of detection] may be higher than the LOD of the CDC PCR. That's one of the big concerns. One of the reps from the CDC mentioned that ... Emory has used a lot of the BioFire assay [to follow] patients as they go negative, indicating their clinical progress. I thought that was really quite interesting.
So, it's going to be used generally in parallel with public health. The majority of public health labs now in the country have the ability to do the CDC Ebola PCR, and if they don't, they have another nearby lab that can. The State of Wisconsin public health system has basically set up a rapid response hotline. If we have a suspected patient, we would call them, they will mobilize the resources on the part of the laboratory, and either we would deliver the specimen to them, or they've talked about the potential of having the state patrol carry a specimen to the public health lab to get it there and get the information out as quickly as possible.
Do you think an Ebola outbreak is likely in Wisconsin?
I think that the chance of seeing an outbreak in the US is virtually non-existent. Will we continue to see a smattering of cases here and there from various high-risk people? Sure, that’s a possibility. But I don't see a massive initiation of disease here. Preparation is important because it's a transferrable, blood-borne illness. If you have a patient who presents to a community hospital that hasn't spent three months preparing, and doesn't deal with these types of things all the time, the risk is higher for a healthcare-associated transmission.
Your recent review is very comprehensive ─ what motivated you to write it?
We were asked to write the review by the editors of CMR because technology is changing so quickly. We wanted something that laboratories could utilize as kind of a bench reference when considering different technologies, and to understand how they are going to change the future.
Clinicians don't want to turn into laboratorians.
Is there any technology that clinical labs are using now that they weren't using a year ago, for example?
Lab automation is something we weren't using a year ago that we're using today. That's changing laboratory workflows, it's changing how laboratories interact with their specimens, how they interact with clinicians, and how they report results back. It's going to totally transform how laboratories do their work. My hope is that automation will enable results to be much more actionable.
Along the same lines, I think we're seeing two big trends in molecular in particular. One is the panelization of molecular infectious disease testing. I think that's a really important trend and that is going to reshape the world. The GI panels, for example, are going to push laboratories to provide results a lot faster, and they're going to be clinically actionable. They're actually detecting more cases because they are more sensitive.
The other big trend that we're really on the cusp of is near-point-of-care and point-of-care molecular devices. There is a lot of debate around the new Alere i NAAT assay, whether it is sensitive enough, and I think more studies will come out on that in the next year or so. But, for the very first time, we're going to have a molecular test that can be performed near the point of care with minimal intervention and probably, in the future, will be performed at the point of care as a CLIA-waived device. This is certainly just the first. … I think that really is the number one trend today. We're approaching the point where molecular diagnostics are going to be available, at least for select pathogens, at the point of care.
Does your lab have any affiliation with Alere?
We do not, at the moment. We are talking about doing a clinical study with them, but for the moment I do not have any affiliations with them. … We've got a protocol that we're proposing to them but we have not gotten the device yet. We actually want to look at some outcomes associated [with the platform]; if we were to use it, do we get an outcome benefit?
The one thing that has been brought up in the literature is whether the sensitivity is as good as other molecular tests. I think that remains to be seen. We need to see what that sensitivity is compared to other molecular targets for influenza, and certainly the same question will apply as we get into Strep and other things.
So, you think that POC will be the most dynamic trend in the clinical lab of the future?
I think for certain pathogens, it is going to be a big trend. I think for other pathogens, it's a little bit more difficult to make that justification.
For flu testing, I think there is a lot of value in [POC]. To have a flu test result before a patient leaves the clinic is really important. You can make an informed decision on prescribing oseltamivir. Similarly, if I know that a patient has Group A Strep, I don't have to send a confirmatory test, and if a test is negative, I can say with a high degree of certainty 'you have something other than Group A Strep.' I think there is value in knowing that.
For other targets, I think it's a little bit more difficult to make that justification. For inpatients, it may also be more difficult. It's the cost-benefit aspect of it; is the additional cost of a point-of-care test worth the time that it's going to take the care providers? Is it going to deliver enough value in the care of the patient, versus a less expensive laboratory-based test?
I think that's going to be the balancing act. Clinicians don't want to turn into laboratorians. Picking out those high value markers is going to be very important. A point-of-care test for just anything, it's neat, but at the end of the day we don't want our clinicians to walk around like traveling salesmen, where they open up their jacket and pull out a point-of-care test for every individual thing. Until we develop better diagnostics that can be more comprehensive, we're going to have to be somewhat selective.
Is the relationship between the clinician and the clinical lab changing because of these new technologies?
Absolutely it is. I'm relatively young in my career, I've been in my career for about seven years, and the world is changing tremendously. My role is becoming much more clinically consultative, and less of being a technical expert. I spend a great deal of my time every day talking to my clinical counterparts, guiding them on what a diagnostic means, what test to order, that type of thing. That's going to change the role of the clinical laboratorian, and it's also going to change the role of the lab. The lab is going to be in some cases a bit more centralized and in some cases a bit more decentralized. … You'll see increased centralization of things like microbacteriology, things like mycology. But in other places, where it makes sense, we're going to have to push the laboratory out closer to the point where the patient is receiving care because there's value in receiving that information as quickly as possible.
What about platforms that can do comprehensive diagnosis but may be more expensive? Where will those fit, in your opinion?
I think for those types of tests, whether it be [Abbott's] Iridica or next-generation sequencing, it is a balancing act. Many of these tests have a lot of cost associated with them. I think one has to ask: what is the patient mix that's ultimately going to benefit most from them? For all of these tests, if you have a patient mix that's [susceptible to] certain kinds of infections, i.e. immunocompromised patients, organ transplant patients, oncology patients, you'll probably be considering one of those options. If you're a community hospital, you don't deal quite as much with those types of infections, it may not make sense for you to do that testing in house, simply because of the cost of the instrumentation as well as the cost of the individual tests.
I think one of the challenges of each of those tests is going to be showing value. Ultimately, these are tests that are going to be done on the inpatient, so they're all part of a bundled reimbursement. Let's just pick a blood culture test, for example. My laboratory does about 80,000 to 100,000 blood cultures a year. Are we going to run one of those tests on every single patient that gets a blood culture? Quite honestly, probably not, because it is going to increase our budget into the tens of millions of dollars. You're going to have to be selective about who gets them, and the cost of the instrumentation alone is going to limit who performs those types of tests. It will probably be the major tertiary medical centers that initially adopt them, as they become cleared.
The challenge becomes the fact that the low-hanging fruit is already gone. The BioFires and the Nanospheres that have a rapid diagnostic for blood culture have already achieved that five-day savings. … New tests are really going to have to show their value in those first couple of days, or based on increased sensitivity. That's going to be a big challenge for them going forward, proving their value.
Your review also mentions the importance of maintaining expertise in classical techniques. Others have also argued this, with respect to culturing gonorrhea to test for resistance genes, for example. As testing becomes more automated and panel-based, will classical techniques continue to be useful?
I think they are going to be absolutely critical. Take the example of stool. We'll use a molecular stool panel as, essentially, our screen. We can screen out the vast majority of our specimens because more than 90 percent of them are going to be negative. Where we are going to want culture is when we get that positive result, when we get Shigella, for example. We want to be able to type that isolate [and] be able to tell the clinician 'this is what the susceptibility is.' In the case of stool cultures, as just an example, we're not going to be doing as many of them, but being able to do them so that we can then do susceptibility testing is going to be important.
Issues such as platform footprint, technician expertise, and cost, were recently cited by clinical lab directors and researchers as factors that shape purchasing decisions. What is the biggest concern for you, and what would a company who wanted to market to someone like you need to think about?
The face of the medical technologist is changing dramatically. We can't find medical technologists anymore. A lot of the laboratorians of the future are going to be people with bachelor's degrees and medical laboratory technicians, or two-year degree people. Making things on the molecular side that are easy, that are relatively straightforward, I think is going to be very important going forward.
I also think that the idea of having somebody that's trained across all sections of the laboratory, across all areas of microbiology, for example, probably isn't going to happen going forward. … You're going to have to pick areas that you are specialized in; you might be a molecular technologist or you might be a mycologist. I think we're very quickly seeing that molecular pathology isn't its own subspecialty, it's a technique. And so we need people that are trained as good microbiologists first, and then ultimately also good molecular biologists. We're going to use molecular, it is a continually important technique, and so we need good microbiologists that are also good molecular technologists.
Why aren't people showing up to the lab with an advanced degree or trained across all areas of microbiology? Are the jobs not available, or is the cost of hiring someone who is cross-trained too high?
There just aren't as many medical technology training programs any longer. It's also because the salaries are a little lower than what they are for other fields in medicine. Again, there is so much to know. I do only microbiology, and I struggle enough knowing microbiology, without having to know clinical chemistry and everything else. The field of medicine, and laboratory medicine is no different, has become much more detailed, and the amount of information you have to know has become much greater.