Perspectives on Diagnostics for Global Health

By Elain Fu, Paul Yager, Pierre N. Floriano, Nicolaos Christodoulides, and John T. McDevitt

NOTE: This is an overview of the article, which appeared in the November/December 2011 issue of the IEEE Pulse magazine.
Click here to read the article.

Diagnostic applications for global health have exploded in the past ten years. Numerous articles have been generated on global health priorities, constraints of resource-limited settings, and technological innovations for diagnostics development, including several comprehensive reviews. In this article, the authors provide 1) a focused summary of the most highly needed diagnostics, 2) a discussion of noteworthy recent developments of technologies in the field, and 3) a perspective on the evolution, challenges, and future directions of diagnostics for global health applications.

Need for Early Detection and Treatment

Disease treatment in the absence of a diagnostic test is often based on syndromic management (i.e., observing clinical symptoms and factoring in local prevalence of the disease). This situation can result in incorrect treatment of patients manifesting symptoms common to multiple diseases with local prevalence. Unnecessary treatment may compromise the patient (from harmful side effects of a treatment) or the community (through accelerated drug resistance, as has been found in the case of malaria). Further, the patient remains untreated for the relevant condition, potentially leading to higher mortality and morbidity. A diagnostic test that can provide an accurate and timely diagnosis enables 1) earlier interventions before the appearance of advanced symptoms, 2) correct diagnosis and treatment for each patient, and 3) effective use of limited resources. Thus, appropriate point-of-care (POC) diagnostics development for high-impact diseases can significantly reduce the global disease burden.

The article reviews unmet needs for diagnostic tests for both infectious and non-communicable diseases in the developing world. Existing tests often require multistep protocols, long processing times and delays, presence of trained personnel, specialized equipment, and electrical power. Any or all of these are often incompatible with the constraints of resource-limited settings. The World Health Organization has coined an acronym for the characteristics of POC diagnostics that are appropriate for even the lowest-resource global health settings: affordable, sensitive, specific, user friendly, rapid and robust, equipment free, and deliverable to users (ASSURED). Thus, the overall challenge has been and continues to be to create high-performance assays that are relevant for global health applications, including the lowest-resource settings.

Dedicated Global Health Lab-on-a-Chip

While significant progress has been recently made in genomics, proteomics, and other disciplines, few of the scientific discoveries have impacted clinical practice globally. There is a strong potential to leverage these discoveries for a broad impact in diagnostics for global heath applications using chip-based approaches. An important trend relevant here is the miniaturization of designs afforded by the small dimension scales of microfluidic-based devices. This allows for portability and the use of small sample and reagent volumes. These also enable rapid POC results at the bedside, in the ambulance, or at other remote locations. The lab-on-a-chip (LOC) technology is often configured with a permanent instrument and disposable cards. The instrumentation can often be battery powered, and the cards can incorporate reagents stored in dry form to remove the immediate need for a power grid. Automation of the processes results in the ease of use for minimally trained users.

Yet, very few complete workable POC clinical devices have emerged despite tremendous progress in microelectromechanical systems (MEMS), microfabrication, microfluidics, and related areas. Indeed, while the core of typical LOC systems is substantially smaller than that of the bench-top counterparts, they still rely on a network of macroscopic laboratory-based infrastructure for sample processing, sample introduction, analyte detection, data processing, and reagent handling, thus limiting their utility for POC applications. The paper includes selected examples of LOC approaches which highlight efforts to address the challenges of evolving from chips-in-a-lab to a true LOC.

A Fully Integrated Standards-Based Systems Approach

Another viable strategy to reduce instrumentation costs for resource-limited settings, which is in development in the McDevitt laboratory, is to leverage the capabilities of a global network of diagnostic devices based on universal standards.

The programmable bionanochip (PBNC) system is inspired by the microelectronics industry, in which a standard operating system is used in conjunction with modular software programs specific to a variety of applications, to provide significant cost reductions and produce increasing performance. The PBNC system is a platform that enables new test configurations to be quickly adapted, developed, and applied for a variety of diagnostic indications through the insertion of reagent-specific molecular level code. As such, the PBNC system has the capacity to serve cell counting, typing, and differentiating functions. Alternatively, PBNCs can complete analysis of chemical, genomic, and proteomic analytes using bead-based microreactors. These two distinct PBNC assay platforms are packaged within a disposable, single-use injection-molded plastic laboratory card comprised of a network of microfluidic components for the complete transfer and processing of biological samples. screening and monitoring

A schematic of the evolution of POC diagnostics development.

Click to enlarge

A schematic of the evolution of POC diagnostics development. The gold-standard laboratory assays are appropriate for settings with a high level of resources. There has been much progress in the development of promising chip-in-a-lab technologies that have, in some cases, been converted to true lab-on-a chip systems for use at the POC. However, the costs of the systems are often a barrier to their use in settings with lower levels of resources. One viable strategy is to push toward fully integrated standards-based systems that leverage the microelectronics and software industries. Also underway is a movement to create instrument-free diagnostics that will not only have a cost appropriate for the lowest-resource settings but will also fulfill the equipment-free requirement that is so critical to those settings.

The bead-based PBNC is now moving through six major clinical trials and has been successfully applied to serve a variety of important health applications, including ovarian, prostate and oral cancer screening and monitoring, cardiac risk assessment, and diagnosis of acute myocardial infarction. Compared with gold standard and laboratory-confined methods, the miniaturized bead-based PBNCs exhibit assay times in minutes instead of hours, limits of detection two or more orders of magnitude lower, and a proven capacity to multiplex.

The membrane-based PBNC serves as a miniaturized analysis system that mimics flow cytometry instrumentation in their capacity to complete important cell-counting applications, such as HIV immune function testing using CD4 cell counts. In addition to lymphocyte enumeration in resource-limited settings, the same membrane system is now being applied for oral cancer screens for the analysis of minimally invasive brush biopsies of oral mucosal lesions. This dedicated PBNC approach has the potential to turn around biopsy results in a matter of minutes as compared to days for traditional pathology methods.

Challenges

The paper outlines a number of challenges in meeting the needs for diagnostics in the global health arena. One especially compelling need in the lowest-resource settings is for equipment-free diagnostics, such that ongoing maintenance and repair are not required. The paper explores this area, and steps that have been made to address it. For instance, the ubiquitous cellphone camera has been used to provide assay readouts.

The paper points out the importance of the performance of the diagnostic equipment, as there can be severe adverse consequences if the equipment produces significant numbers of false positive or false negative findings.

ABOUT THE AUTHORS

Elain Fu (efu@u.washington.edu) and Paul Yager (yagerp@u.washington.edu) are with the Department of Bioengineering, University of Washington.

Pierre N. Floriano (pfloriano@rice.edu), Nicolaos Christodoulides (nchristo@rice.edu), and John T. McDevitt (mcdevitt@rice.edu) are with the Department of Bioengineering, Rice University. John T. McDevitt also serves as the scientific founder for LabNow, Inc. The Rice authors have applied for patents in areas related to PNBC sensor systems.