Field-portable MDx

By: John Brunstein   
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There is an enduring appeal to the concept of point-of-care (POC) or near-POC diagnostic methods. Having the ability to perform a diagnostic test in the doctor’s office while a patient is present, rather than having to send a sample off to a centralized lab for testing, means that what would otherwise need to be two patient visits could be replaced by a single session. It also suggests the potential for a more timely response with a specific rather than empirical treatment strategy, with particular implications for the appropriate, limited use of antibiotics. Carrying the POC concept a step further, one can imagine the potential utility if cheap, effective, reliable diagnostic systems could be made small, portable, simple, and rugged enough for use in low-resource settings, where they might have the greatest human impact.

Of course, many such diagnostic methods exist, but they are most frequently some form of a rapid immunological test. While these excel in simplicity, low cost, and speed, they generally lack the sensitivity and specificity that a molecular method would provide. That they are so widely used even with these shortcomings underscores the need for POC/near-POC testing and the potential for growth in this field if suitable molecular devices and tests can be developed. (If you wanted to put numbers on this potential, a 2016 report by Grand View Research predicts a global market of $3.9B in POC molecular by 2024.1)

Challenges to POC MDx

The challenges that face POC or more ruggedized field portable MDx use are significant. Extreme sensitivity also means extreme sensitivity to contamination; reagents may have limited shelf life without refrigeration; some form of sample extraction/release of nucleic acids is required as an initial step; and interpretation of results may require in-depth expertise and familiarity with the assay.

Increasingly, however, there are approaches that address those challenges. Foremost among these is the designing of systems around unitary disposable cartridges that combine sample extraction with molecular processing and detection. Use of stabilized (likely, lyophilized) reagents inside such a cartridge addresses the stability issue. Interpretational complexity can be simplified through the use of multiplexing (in-reaction controls for sample inhibition, reagent function, sample sufficiency, and extraction function). As we take an overview of currently available and some in-development POC/portable molecular MDx platforms, it should not come as a surprise to see that these design features are present.

What’s out there now

What, then, are some of the currently available FDA-approved systems that could pass for field portable MDx?

The Cepheid GeneXpert Omni is based around the same unitary cartridges used in the other GeneXpert systems, which were the first approved “sample-to-answer” device on the market. While one might be tempted to consider this technology to be a bit long in the tooth, the manufacturer’s claim of it being “proven technology” is indisputable. These particular assays have been around long enough to be well understood and are available for a wide range of targets, including many of interest in low-resource settings. In contrast to the other, lab-environment versions of the GeneXpert platform (which range from moderate benchtop to wall filling, depending on throughput), the Omni is intended as a field portable stand-alone unit. It weighs barely two pounds and is small enough to fit in an airplane carry-on with a supply of cartridges, a pipettor and some tips, and a box of gloves. It includes integral battery power (claimed operational life, four hours) which can be supplemented with additional larger capacity rechargeable battery packs, allowing for extended day or even multi-day use in remote settings. The device handles its own data storage needs, making for an appealing package if there’s a cartridge for your test of interest and you want to bring reliable rapid molecular testing to low-resource settings.

Another system that the reader may have come across, as it’s been around for several years, is Roche’s cobas Liat (“Lab in a Tube”) System. Accurately described by its manufacturer as being “about the size of a single-serve coffee maker,” and complete with a small display screen showing results of the core real-time PCR technology, this system has tests available for a number of applications in infectious diseases and has sample-to-answer turnaround times on the order of 15 to 30 minutes. While this device does require external power, the consumption is low; a small battery pack with integrated inverter could provide required portable off-grid power. A larger challenge to remote application of this device—with current assays—is the need for refrigeration, but for a day out in the field away from infrastructure, a cooler and cold packs or ice would suffice. And even with these add-ons, the whole package is vehicle-portable for use for hours to possibly a few days in low-resource settings.

Another example, not really designed for “in the field” use but more targeted to the physician office (it’s described as “near-patient testing”) MDx setting, is the Alere I system. If the definition of “field-portable” were expanded to include, say, labs shoehorned into a portable lab along the lines of a converted recreational vehicle, this system could be included in our list, with at present two CLIA waived assays available.

Also by that expanded definition, another system that has been around for a while and would fit the bill is the Biofire (bioMérieux) FilmArray. With a softwall pouch cartridge format allowing for rollers to enact in-pouch fluidics by moving solutions between various pouch subchambers, allowing for extraction, amplification, and finally microarray hybridization and detection, this system may be the most multiplex-capable of the systems we are considering. Its cleared available assays make use of that in the form of multitarget symptomatic-based panels for respiratory, GI, positive blood culture, and meningitis/encephalitis presentations.

What may be coming

A theme that is common to these devices is integration of small, low-power computer, optical, and mechanical/thermal control systems. As device engineering advances make these subsystems smaller, less expensive, more power-efficient, and more reliable, we should expect to see more portable MDx devices emerge to take advantage of this. A number of as-yet uncleared/unapproved devices are publicly in development. That is a process that can notoriously take longer than hoped for or expected by the developer(s), so expect them when you see them.

A necessarily incomplete list of some of these would include the QuantuMDx Q-POC (intended to be freestanding, cassette-based, and battery-operated and provide sample-to-answer multiplex MDx capabilities); the LaCAR LC-Genie (battery-powered, based around 8-well strip tubes, and intended for SNP assays on already extracted nucleic acid samples); the DxNA GeneSTAT cartridge-based real-time PCR system, which is not battery-powered but can operate in a laptop-free, self-contained mode and which employs RFID tagged cartridges with lyophilized reagents for stability and minimal user training requirements; the ERBA Molecular Lumora PDQ, based on isothermal amplification with luminescent monitoring of real-time target amplification for up to 96 samples at a time; and the Ahram Biosystems’ Palm PCR S1, a 24- well, 6-optical channel real-time PCR machine with integrated display that includes an internal battery capable of supporting ~4 hours operation (or 200 tests, according to the manufacturer).

Doubtless there are many other similar designs on drawing boards and in various stages of prototyping around the world, and while not all of these may make it to market, as end users we should be encouraged that so much interest and effort is being employed in bringing simplified, portable MDx to clinical needs. An analogy to the delivery of telephone services in the third world is apt; in that case, the explosion of cheap cellular technology meant that in many remote places the first available telephone systems have not been old-fashioned wired networks; rather, these locations went from nothing directly to cellular systems. Similarly we may find that low-resource settings may pass right over antigen-based systems and, through portable MDx, go directly to high-sensitivity and high-specificity molecular methods in the near future. In settings that are less remote but still dependent on central labs, we should expect to see a similar emergence of at least a limited number of simple but high-value POC molecular tests that will both speed up time to appropriate care and reduce “simple” workload for core labs. Such core labs should see this as an opportunity that frees them up to focus resources on the development and performance of emerging tests that still require extensive instrumentation, staff training, bioinformatics, and other infrastructure—such as many next generation sequencing (NGS) applications.

The expected emergence of such portable/POC MDx devices to take on aspects of a core lab will not be without some shortcomings. One which regular readers of this column may recall being raised before is that sample-to-answer instruments—or at least, all the ones this author has familiarity with—don’t allow for subsequent alternative use of any nucleic acid extract prepared on-system. (There’s a good reason for this; the entire function of sealed, single-use cartridge format assays in avoiding PCR contamination would be compromised if they could be opened and closed at will). This can be a disadvantage for scenarios where limited sample is available, such as pediatric CSF, and a negative test result is obtained. Unlike a full core lab with separated nucleic acid extraction and testing capacities that allow for subsequent extract redirection to additional or confirmatory testing, these portable/POC/all-in-one devices require a whole new sample (or at least aliquot thereof) to perform another test.

Regardless of such shortcomings, though, the benefits inherent in moving the accuracy and power of MDx closer to the patient, in small hospitals or rural settings, will continue to drive the development of portable simple use technology for a range of clinical applications. We should expect to see such systems become increasingly common.

Reference
1. Grand View Research. Point of care molecular diagnostics market worth $3.9 billion by 2024. June 2016.

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