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Transforming Rapid Diagnostic Tests for Precision Public Health: Open Guidelines for Manufacturers and Users

Transforming Rapid Diagnostic Tests for Precision Public Health: Open Guidelines for... Background: Precision public health (PPH) can maximize impact by targeting surveillance and interventions by temporal, spatial, and epidemiological characteristics. Although rapid diagnostic tests (RDTs) have enabled ubiquitous point-of-care testing in low-resource settings, their impact has been less than anticipated, owing in part to lack of features to streamline data capture and analysis. Objective: We aimed to transform the RDT into a tool for PPH by defining information and data axioms and an information utilization index (IUI); identifying design features to maximize the IUI; and producing open guidelines (OGs) for modular RDT features that enable links with digital health tools to create an RDT-OG system. Methods: We reviewed published papers and conducted a survey with experts or users of RDTs in the sectors of technology, manufacturing, and deployment to define features and axioms for information utilization. We developed an IUI, ranging from 0% to 100%, and calculated this index for 33 World Health Organization–prequalified RDTs. RDT-OG specifications were developed to maximize the IUI; the feasibility and specifications were assessed through developing malaria and COVID-19 RDTs based on OGs for use in Kenya and Indonesia. Results: The survey respondents (n=33) included 16 researchers, 7 technologists, 3 manufacturers, 2 doctors or nurses, and 5 other users. They were most concerned about the proper use of RDTs (30/33, 91%), their interpretation (28/33, 85%), and reliability (26/33, 79%), and were confident that smartphone-based RDT readers could address some reliability concerns (28/33, 85%), and that readers were more important for complex or multiplex RDTs (33/33, 100%). The IUI of prequalified RDTs ranged from 13% to 75% (median 33%). In contrast, the IUI for an RDT-OG prototype was 91%. The RDT open guideline system that was developed was shown to be feasible by (1) creating a reference RDT-OG prototype; (2) implementing its features and capabilities on a smartphone RDT reader, cloud information system, and Fast Healthcare Interoperability Resources; and (3) analyzing the potential public health impact of RDT-OG integration with laboratory, surveillance, and vital statistics systems. Conclusions: Policy makers and manufacturers can define, adopt, and synergize with RDT-OGs and digital health initiatives. The RDT-OG approach could enable real-time diagnostic and epidemiological monitoring with adaptive interventions to facilitate control or elimination of current and emerging diseases through PPH. (JMIR Biomed Eng 2022;7(2):e26800) doi: 10.2196/26800 KEYWORDS rapid diagnostic test; precision public health; digital health; diagnostic; testing; guideline; manufacture; surveillance; FHIR; Fast Healthcare Interoperability Resources https://biomedeng.jmir.org/2022/2/e26800 JMIR Biomed Eng 2022 | vol. 7 | iss. 2 | e26800 | p. 1 (page number not for citation purposes) XSL FO RenderX JMIR BIOMEDICAL ENGINEERING Lubell-Doughtie et al of features (RDT’s hardware and software features) that would Introduction be needed to implement these axioms, and select a final evidence-based set of features that could be used by health Background policy and program implementers in integrating RDTs as tools Rapid diagnostic tests (RDTs), specifically for frontline health care workers at the community and clinic immunochromatographic lateral flow assays, can provide levels [3,4]. accurate real-time point-of-care diagnoses in low-resource Challenges Facing the Current RDT Ecosystem settings and have been an important tool in the global health arsenal. Advances in microfluidics have enabled the medical There are 3 core challenges faced within the current RDT device community to design smaller RDTs—as small as half ecosystem, which impede application and widespread the area of a business card and the thickness of a watch—that implementation for PPH. can be used to diagnose more conditions and are low cost—less Lack of Data Standards than US $1 per device [1]. Manufacturers and international health organizations have collaborated to deliver hundreds of The lack of uniformity in RDT hardware and software millions of RDTs to countries and communities [2]. However, substantially limits the integration of public health data from the full potential of RDTs as a public health tool has not yet RDTs into current health information systems, thereby impeding been realized. This is due to field deployment challenges their ability to respond to emerging crises [5]. Under these amplified by a fragmented market, nonstandard designs, and conditions, bridging these limitations requires analytics-intensive lack of features that facilitate systematic capture and use of tasks to convert, code, recode, and integrate data. Current RDT RDT results and patient data. Fortunately, current versions require specific knowledge and tools that are typically technology—computer vision, widely deployed smartphones, not compatible (Figure 1), leading to a combinatorial explosion and mobile networks—applied to RDTs provides a scalable of integration and data interoperability requirements. Without path to improved health and well-being through the emerging uniformity, health professionals and individual consumers using paradigm of precision public health (PPH). PPH is a field that RDTs cannot benefit from integration with point-of-care aims to maximize impact with the active use of data for smartphone apps to enable personal tailored care guided by surveillance and targeted interventions by temporal, spatial, and modern machine learning techniques that can calculate the prior epidemiological characteristics of populations. probabilities of having a condition from data on demography, the environment, and etiology. Therefore, we aimed to define axioms to underpin steps to incorporate RDTs into a PPH approach, identify an initial set Figure 1. Current rapid diagnostic test processes (left) use undefined or proprietary standards, which lead to multiple incompatible protocols (ie, incompatible apps and devices). The rapid diagnostic test open guideline process (right) uses standard guidelines to produce modular reference rapid diagnostic tests that are compatible and can be read by a well-defined protocol for devices and apps. ID: identifier code or number for each device; ML: machine learning; POC: point-of-care; RDT: rapid diagnostic test. https://biomedeng.jmir.org/2022/2/e26800 JMIR Biomed Eng 2022 | vol. 7 | iss. 2 | e26800 | p. 2 (page number not for citation purposes) XSL FO RenderX JMIR BIOMEDICAL ENGINEERING Lubell-Doughtie et al several studies have documented the challenges faced by health Heterogeneity of RDT Reader Hardware care workers in translating their competency to use one RDT One strategy to improve the uniformity, amount, and quality of to comparable competency with another (ie, those for similar information collected from RDTs is to use custom hardware diseases, from other manufacturers, or with revised procedures). readers and image capture and analysis devices (eg, the The lack of consistency contributes to high error rates in RDT DekiReader [6], specialized microscopes, and device holders). usage and interpretation and limits their impact [7]. However, these devices can be problematic owing to the expense, continuous supply, and maintenance required. As such, Solving These Challenges With Open Guidelines custom hardware is incompatible with large-scale deployments Based on these challenges, we define 3 axioms that underpin and the broad consumer use necessary for RDTs to cover high- solutions (Table 1). To solve the challenges and maximize and emerging-risk areas; therefore, such devices hinder the information usage for PPH, RDTs should adhere to a set of open continuous stream of accurate diagnostic data needed to expose guidelines (OGs), and use smartphone readers and data protocols outbreaks of known diseases and predict the emergence of new that standardize the information—both horizontally between diseases. different manufacturers or providers and vertically between different steps in the RDT life cycle (Figure 1). These axioms Diversity of RDT Form Factors and Instructions can transform the current state of the RDT ecosystem into one Any diagnostics integrated with smartphones would still involve that supports PPH. RDT-OGs address the data uniformity manual use of an RDT and interaction with patients. However, challenge of RDTs by standardizing the capture and use of data. Table 1. Rapid diagnostic test open guideline axioms. Axiom Description Axiom 1: Maximize rapid diagnostic test To address the custom hardware challenge, we designed RDT open guidelines (OGs) in line with the (RDT) data usage by capturing and structur- existing realities of the rapid diagnostic test manufacturing world. Manufacturers focused on creating ing information for integration tests simple enough to be used in clinical, community, and household settings by minimally trained community health workers, and eventually clients themselves. This need for widespread use leads us to define RDT-OGs to satisfy and facilitate these needs. Axiom 2: Any solution must rely on only This allows implementers of RDT-OGs to create solutions accessible by locally available technology readily available local resources and capability, including those that use pre-existing devices in target communities, such as low-cost smartphones [8]. RDT-OGs address the problems caused by lack of physical device uniformity by de- signing for human and device interoperability. Axiom 3: Diagnostic interfaces should re- This applies to RDT hardware, the software reading and interpreting RDTs, and the data schemas inte- main uniform or compatible grating with external systems. When using software-based RDT readers, following Axiom 3 leads us to link individual RDTs to uniform interactive guidance of users as they conduct a diagnostic test. software solutions, and medical systems are facing “information The Need to Catalyze the Era of RDT-OGs overload” [10]. The future trend in information use could take We have chosen to address the current challenges in RDTs with 1 of 2 diverging paths—modest growth with eventual stagnation open guidelines in order to focus directly on the systems and or a promising future with open guidelines aligned with the integration problems they face. Figure 2 shows initial progress aforementioned PPH axioms to accelerate impact by enhancing as RDTs were developed in the laboratory; as researchers information usage (Figure 2). predicted their impact, optimism surrounding their potential Below, we describe our methods, present survey results from grew. As RDT rollouts began, the ability to capture diagnostic experts in RDT technology, formally establish an information data increased, but these increases did not keep pace with global utilization index (IUI), and define how various RDT features growth in the technological capacity to store, communicate, and gather information. We use this to assess World Health analyze information [9]. Organization (WHO)–prequalified RDTs in comparison to a This changing technology landscape, combined with a lack of prototype RDT based on open guidelines and then discuss these individual RDT identifiers, inconsistent test use protocols, and results and related work in field-based hardware and software the appearance of fraudulent and counterfeit RDTs, led to a diagnostics and standards. As access to telecommunications relative decrease in information use; however, as the RDT networks improves worldwide, and advanced information community began to effectively encode and aggregate systems become more widely used by ministries of health and information and improve the training of health care workers, global health organizations, the community can dramatically information use increased. Currently, RDTs have reached a accelerate the transformational impact promised by RDTs. tipping point—there are multiple proprietary hardware and https://biomedeng.jmir.org/2022/2/e26800 JMIR Biomed Eng 2022 | vol. 7 | iss. 2 | e26800 | p. 3 (page number not for citation purposes) XSL FO RenderX JMIR BIOMEDICAL ENGINEERING Lubell-Doughtie et al Figure 2. The trajectory of information use in response to rapid diagnostic test technology innovation, which shows the introduction of rapid diagnostic tests and their initial impact (black line) followed by subsequent challenges (red line) and improvements (green line). Potential future paths are also shown: a lower growth in information utilization under the current incremental improvements (gray dashed line) or an accelerating trajectory enabled with rapid diagnostic test open guidelines (blue dashed line). GTIN: global trade item number; RDT: rapid diagnostic test. manufacturers, medical professionals, and frontline health Methods workers. These stakeholders were asked to participate in a web-based survey that comprised specific statements that Review of Published Literature corresponded to general, user-specific, manufacturer-based To identify key issues related to data capture and use from issues or issues regarding informatics. A 5-point Likert scale RDTs, we conducted a review of published papers using the was used for response: 0=strongly disagree, 1=disagree, Semantic Scholar artificial intelligence–enabled research search 2=neutral, 3=agree, 4=strongly agree, and unable to reply. engine [11]. We focused on, but did not constrain ourselves to, Replies were accrued from January 2019 to March 2019, and PubMed-indexed medical journal papers. The search was submitted entries were downloaded and tabulated. Results were conducted on December 31, 2018, and updated on December summarized by tabulations and analysis of proportions using 31, 2019, using the keywords “rdt,” “smartphone,” and “mobile Excel (version 16; Microsoft Inc). phone.” The search revealed 480 papers that were further Ethics Approval screened for the study of lateral flow immunochromatographic rapid tests, yielding 58 papers. In addition to reviewing these We note that the survey was exempt from human subjects papers, we reviewed their citations to identify additional papers research as per guidelines from the US Department of Health in telecytology, immunochromatography, and diagnostic and Human Services as it assessed a public benefit or service hardware. From these papers, we extracted themes and concepts and was not about humans, and did not collect sensitive related to barriers to information capture and usage from RDTs, information. and applied a grounded theory conceptual framework to compile Defining the IUI and code themes and concepts into core ideas and then high-level abstractions and classifications. These were discussed Survey results and the literature review were used to identify and reviewed by 3 different members of the team. We essential information features for RDTs and their integration considered this process complete when saturation was reached into health care platforms to support PPH. The presence or (ie, no additional novel ideas or abstractions emerged upon absence of a feature for a specific RDT could be used to review of additional papers). calculate an IUI defined as number of features present or the number of features defined. We then selected WHO prequalified RDT Stakeholder Survey cassette-based RDTs for malaria and HIV that had been assessed for performance [12] and calculated the IUI. Procedure The literature review and PPH axioms were used to identify the Results fundamental features and feasibility of open guidelines for RDTs that maximize information usage for PPH. A survey was Literature Review designed, which comprised 30 questions (Multimedia Appendix The review of published literature and thematic extraction of 1). Respondent-driven sampling was used and initiated by concepts related to information capture and usage from RDTs contacting authors of the papers reviewed and professional led us to identify the following core areas that affect information referrals, which included researchers, medical technologists, usage (Table 2). https://biomedeng.jmir.org/2022/2/e26800 JMIR Biomed Eng 2022 | vol. 7 | iss. 2 | e26800 | p. 4 (page number not for citation purposes) XSL FO RenderX JMIR BIOMEDICAL ENGINEERING Lubell-Doughtie et al Table 2. Core areas that affect information usage. Core areas Description Challenges in using commonly deployed This is related to issues of RDT choreography, and proper reading and interpretation even when control rapid diagnostic tests (RDTs). and results lines were clear. Existing barriers for mobile imaging of This referred to shadows from the cassette on the surface of the immunochromatographic strip, or glare RDTs. from the cassette and surface of the strip, all of which hindered image capture quality. Criteria for designing RDT standards. This included specific characteristics of RDTs that could be feasibly standardized. Barriers to RDT manufacturing standards. This referred to cost and other factors that could hinder manufacturing to an enhanced standard. Feasibility and features for smartphone-read This included the practicality of using identified features in the clinical or field setting. RDTs. Perceptions of non–human-readable RDTs This included whether or not read-out systems for RDTs would be acceptable for clinical or field person- (eg, electrochemical readouts). nel, if the actual reaction was not observable. maximize information usage, an RDT platform must function RDT Stakeholder Survey effectively in all phases of its life cycle, with added value at We contacted 81 stakeholders, and 33 completed the each phase. questionnaire (16 researchers, 7 technologists, 3 manufacturers, Specific stakeholder results are divided into discrete phases of 2 doctors or nurses, and 5 others). Respondents were most the rapid diagnostic test life cycle (Manufacture, Shipping, Use, concerned about the proper use of RDTs (agreed: 30/33, 91%), Interpretation, and Disposal), and RDT capabilities are divided their interpretation (agreed: 28/33, 85%), and reliability (agreed: into themes (Metadata, Molding of the Cassette, Printed Data, 26/33, 79%). Respondents were confident that smartphone-based and Smartphone Reader) (Figure 3). The open guidelines RDT readers could address some reliability concerns (agreed: contribute to each theme, and they are essential for the 28/33, 85%) and that readers were more important for complex Smartphone Reader theme. A conceptual framework that or multiplex RDTs (agreed: 33/33, 100%). contrasts the accumulated value of RDT open guidelines and IUI the current RDT process shows an increase at each life cycle phase. Specific capabilities drive these increases (Figure 3). Based on these results, and because RDTs are embedded in a set of protocols and practices defined by health care workers, We identified 11 essential information features for RDTs and institutions, clients, and communities, proper usage of rapid their integration into health care platforms, which define diagnostic tests depends not only on a physical device but also components of the IUI (Textbox 1). on its integration into the larger ecosystem. In this context, to Figure 3. Conceptual framework of gaps in information use through the rapid diagnostic test life cycle. Information utilization (vertical axis) is quantified relative to 5 distinct phases of the rapid diagnostic test life cycle (horizontal axis): Manufacturing, Shipping, Use, Interpretation, and Disposal. Over the life cycle, the information utilization of the current process increases (black line), but with the use of rapid diagnostic test open guidelines, information utilization would increase (blue line) as a result of several features (list at bottom). https://biomedeng.jmir.org/2022/2/e26800 JMIR Biomed Eng 2022 | vol. 7 | iss. 2 | e26800 | p. 5 (page number not for citation purposes) XSL FO RenderX JMIR BIOMEDICAL ENGINEERING Lubell-Doughtie et al Textbox 1. Components of the information utilization index. 1. Smartphone or other device reader exists 2. Instructions included 3. Cassette is not reflective 4. Test strip is not reflective 5. Shadow does not exist on test window 6. Expiration date printed on device 7. Identifier printed on device 8. Color calibration panel on device 9. 2D barcode on device 10. Test name clearly printed on device 11. Regulator (eg, World Health Organization) approved for lab and field use values ranging from 0 to 0.75 (mean 0.27; median 0.30, IQR Assessment of Current Rapid Diagnostic Tests 0.25) (Figure 4). The large bracket shows that 70% of this The IUI—which provides an overview of how much information information usage score can be attributed to printed or other current diagnostics can capture and where there is room for nonphysical changes, while the remaining 30% require physical improvement—for prequalified RDTs and an OG RDT had changes to the RDT. Figure 4. Information utilization index for WHO prequalified rapid diagnostic tests (RDTs). Scores were calculated for 33 WHO prequalified devices that had accessible information (blue, names listed below), as well as an RDT based on the RDT Open Guidelines (grey). The median information utilization score was 0.30 (magenta line), in contrast to 0.91, the score for an Open Guidelines RDT. 70% (top bracket) of the Open Guidelines RDT score can be attributed to non-physical changes, while the remaining 30% (bottom bracket) requires physical changes to the RDT. with colored overlays identifying the core modifications is Discussion shown. These include a 2D barcode to embed information needed for an app to identify, read, and interpret the RDT; RDT Open Guidelines fiducials as reference points to assist the camera and phone to Our RDT-OGs recommend the horizontal integration of RDT quickly and accurately identify the RDT areas of interest and hardware through consistent physical modules, thereby enabling reference; and a color calibration panel to enable reliable vertical integration of RDT software through consistent colorimetric inference. In addition, 3 WHO-prequalified RDTs protocols linking supply chain, test choreography, and with overlays are shown to highlight current inconsistencies interpretation. In Figure 5, a reference example of RDT-OGs between tests (Figure 5). https://biomedeng.jmir.org/2022/2/e26800 JMIR Biomed Eng 2022 | vol. 7 | iss. 2 | e26800 | p. 6 (page number not for citation purposes) XSL FO RenderX JMIR BIOMEDICAL ENGINEERING Lubell-Doughtie et al In comparing the optimized IUI and design of the reference outcomes. This workflow, like the RDT-OG, is not tied to a RDT-OGs to others, we observed both the heterogeneity and particular diagnostic and is designed to accommodate both common structures across all RDTs. We have designed existing and emerging diagnostics. RDTs can increase their IUI RDT-OGs to be useful whether adopting all recommendations, by using a universal RDT-OG–compatible reader and data a subset of modules, or using existing cassettes linked to an storage. New RDTs that become available in the market can RDT-OG–compatible software platform. Defining common further increase their IUI by using the hardware data models and schemas provides an information architecture recommendations of the RDT-OGs (Figure 6). The workflow that would encapsulate data from any module combination that integrates automatic result interpretation modules using machine exists on the RDT. The RDT-OG data schema can be effectively learning from image libraries or template-based approaches and encoded by the 2D barcode and easily drive the process forward can dynamically accommodate new RDTs through via a reader app. The design and production aspects have proved database-backed parameters defining rapid diagnostic test feasible given the successful production of the prototype, and components and hyperparameters identifying the specific RDT the field assessments, such as assessment of integration with (Figure 7). The rapidly growing number of COVID-19 serology epidemiological monitoring systems, are ongoing. and antigen-based RDTs show the critical role of dynamically supporting newly released RDTs [13,14]. Creating a systematic way (Figure 6) to collect and aggregate structured RDT data allows the community to continuously To the best of our knowledge, this is the first paper to propose monitor device performance, disease prevalence, and the guidelines to harmonize the hardware, software, and data relationship between demographic priors and diagnostic standard used to read and interpret RDTs. Figure 5. Unifying rapid diagnostic test functionalities based on formal guidelines. A rapid diagnostic test based on the rapid diagnostic test open guidelines (left) should have certain functional components, as indicated by the color-coded overlay. In contrast, 3 RDTs currently on the World Health Organization–prequalified list have only some of these components (right, with color-coded overlays). https://biomedeng.jmir.org/2022/2/e26800 JMIR Biomed Eng 2022 | vol. 7 | iss. 2 | e26800 | p. 7 (page number not for citation purposes) XSL FO RenderX JMIR BIOMEDICAL ENGINEERING Lubell-Doughtie et al Figure 6. In a system that incorporates rapid diagnostic test open guidelines, data are captured and digitized data from rapid diagnostic tests using a smartphone app that is compatible with the rapid diagnostic test open guidelines. These data are transmitted to a health information system platform and integrated with health system data, laboratory data, and other relevant data, then used to build machine learning models that both feed upstream, to smartphone apps to model symptoms and to be used to better interpret results, as well as downstream, for monitoring. Planners, managers, and researchers can use the real-time data to decide on modifications to existing programs and plan new programs. The color of the lines identifies the primary participant in that portion of the workflow, and the badges depict where to apply the features of the rapid diagnostic test open guideline. ML: machine learning; RDT: rapid diagnostic tests. Figure 7. A Fast Healthcare Interoperability Resources–based workflow using the Device Definition resource for Open Guidelines based rapid diagnostic tests connected to Device, Observation, and Patient resources. Medical devices are defined using the DeviceDefinition resource (to specify their physical characteristics and links to external information systems). Each rapid diagnostic test used corresponds to a Device resource linked to the appropriate DeviceDefinition resource, as well as to Patient and Observation resources that store patient information and test results, respectively. DekiReader is a portable device that guides users through a Diagnostics malaria RDT, reads, and automatically interprets test results; it is notable that its results are not significantly different from Overview human readings [6,15]. Similarly, NutriPhone pairs a lateral It is useful to review the RDT-OG system with related hardware, flow cassette with a hardware device and app to guide users and software, and standard-based approaches to field diagnostics, process images of test results to measure vitamin B levels. It and to note limitations and next steps to integrate the RDT-OGs has not been tested at scale; however, in a sample of 12 into the digital health ecosystem. participants, there was a correlation of 0.93 with the results Integrated Hardware-Based Field Diagnostics from an immunoassay [16]. Hardware-based field diagnostics require reusable equipment to function and connect to software systems. For example, the https://biomedeng.jmir.org/2022/2/e26800 JMIR Biomed Eng 2022 | vol. 7 | iss. 2 | e26800 | p. 8 (page number not for citation purposes) XSL FO RenderX JMIR BIOMEDICAL ENGINEERING Lubell-Doughtie et al vaccine vials would be warranted based on performance Software-Based Field Diagnostics degradation from heat exposure [34]. In addition, use of the In contrast, software-based field diagnostics do not require Fast Healthcare Interoperability Resources (FHIR) [35] can additional hardware to function, while having accuracy define clinical data as a graph of well-defined fields and data comparable to human interpretations of RDTs or images of used types (Figure 7). A number of current digital lab data platforms tests [17]. Dell and Borriello [18] made use of the pre-existing and application programming interfaces already handle related Open Data Kit to read various cassette-based RDTs using only diagnostic and laboratory information management with FHIR smartphones and 3D printable stands for consistent image as a common standard [36]. capture. Similarly, Ozkan and Kayhan [19] developed an RDT holder that clips onto smartphones to improve image consistency Regulators, such as the US Food and Drug Administration, and data interpretation. Demonstrating the utility beyond define pathways to classify novel medical devices, including cassette-based RDT formats, Ra et al [20] combined a urine test communication-enabled RDTs, for which there are no similar strip with color calibration markers and a smartphone app to existing devices [37]. Similarly, the Medical Device improve automated urinalysis accuracy across various lighting Communications Testing Project from the National Institute of conditions. There are also proprietary RDT-reading platforms, Standards and Technology is relevant to any form of medical including BBI Solutions’ Novarum Smartphone Reader and device communication and applicable to RDTs which Abingdon Health’s AppDx Smartphone Reader, that integrate communicate via radio frequency or electrochemical means on-cassette QR codes but with limited information (such as [38]. These regulatory bodies also promote innovation (eg, the RDT type) [21,22]. National Institute of Standards and Technology Text Retrieval Conference, where annual precision medicine competitions Though these approaches integrate modern software, their model the most effective treatments) exemplifying how generalizability is limited by having been designed in the communities can benefit from well-structured data [39]. absence of guidelines that standardize their solutions, and therefore do not adhere to PPH axioms 2 and 3. Vashist et al Limitations [23] reviewed how smartphone-based health care apps and This study has some limitations. First, the response rate from devices, including related medical, privacy, and data standards, the survey was 40% (33/81), and the survey results may have remain fractured without guidelines or standards. A recent benefited from additional feedback from a broader group. review [24] further extended the number of diagnostic devices Nevertheless, there was strong thematic concordance between and companies involved, and again concluded there is a lack of core responses from the survey and findings from the literature unification. review. Second, after designing the open guidelines, we did not solicit additional feedback from the same and similar groups of General Challenges in Field Diagnostics persons who were contacted for the survey. This additional step Yager et al [25] describe the biomedical engineering community would serve to validate the utility of the open guidelines. We as historically focused on laboratory-based diagnostics and note that our goal was to collect feedback from RDT producers highlight the work needed to adapt tools for settings in low- and users of RDT-OGs. Third, we limited ourselves to and middle-income countries. Improvement in test instructions, information usage issues and solutions for cassette-based rapid health worker training, and performance monitoring all correlate tests and did not include the simpler dipstick type strips. with reduced preanalytical errors, improved test performance, However, the same concepts would apply and would need to and increased result reliability [7,26,27]. be implemented in a way that is compatible with the lower space There is a growing consensus that point-of-care diagnostics and and cost profile of such tests [40]. Despite these caveats, the smartphones equipped with digital health solutions are proposed RDT-OG approach is clearly applicable to the majority converging and that this advancement may significantly expand of RDTs currently deployed globally, and to those likely to be self-managed care [28,29]. However, we currently lack digital produced in the future as multiplex and complex tests become health interventions with diagnostics linked to clinical care the norm. pathways and infectious disease surveillance systems [30], as Conclusions and Policy Recommendations well as solutions to the privacy and data stewardship challenges necessary for large-scale deployment [28]. Despite these In response to the goals and ambitions of the RDT community, challenges, researchers have outlined numerous promising future we defined PPH axioms and derived RDT-OGs. The point-of-care linkages: handheld ultrasounds and software recommended modular foundation is designed to accelerate platforms with standardized databases integrating artificial current RDT development, fieldwork, and successfully translate intelligence [31], telecytology platforms for test-and-not-treat RDTs into effective field evaluations and deployments at scale. strategies [32], and accurate diagnoses of oral cancer using These guidelines thus confer functionality to diagnostic devices, convolutional neural networks [33]. the smartphone apps interpreting them, and the health information system analyzing them. For example, temperature Related Regulations and Standards sensors may be essential to assure proper storage and quality Existing standards for diagnostics encompass RDTs, including of some rapid diagnostic tests [34], and the modularity of open several related standards in health technology, medical devices, guidelines can accommodate this need. Although modifying and precision medicine. For example, given that most rapid supply chains may be infeasible in areas with rigid logistics or diagnostic tests have maximal temperature limits for storage fixed asset costs, the RDT-OGs gives the community a pathway and use, temperature exposure monitors such as those used on to extend the functionality of pre-existing field-based diagnostics https://biomedeng.jmir.org/2022/2/e26800 JMIR Biomed Eng 2022 | vol. 7 | iss. 2 | e26800 | p. 9 (page number not for citation purposes) XSL FO RenderX JMIR BIOMEDICAL ENGINEERING Lubell-Doughtie et al through advances in machine learning, which do not require Thus, by providing guidance for RDT hardware, software, and RDT modifications. data interoperability, standards-setting organizations can transform RDTs into a formidable public health tool for disease National and global policy makers have shown a willingness prevention and treatment, in addition to diagnosis. These and ability to convene communities around guidelines that innovations can accelerate long-term disease control efforts, benefit RDT stakeholders; for example, the WHO such as for malaria, which is responsible for 7.8% of the annual prequalification of medicines program, FHIR, SNOMED, and deaths of children under 5 years old (20,000 children worldwide LOINC. As the WHO, the Global Fund, Foundation for [43]). Furthermore, these innovations can accelerate rapidly Innovative New Diagnostics, and others continue this work, evolving disease control efforts, such as for COVID-19, where there is ample opportunity to adopt formal guidelines around serological or antigen detection investigations face challenges RDTs and their usage. For example, the WHO’s role in creating in obtaining case information; these challenges are expected to and promoting prequalified malaria RDTs has incentivized further increase as testing efforts continue to scale up, and with manufacturers to increase low-cost RDT production [41,42]. A transition from mitigation to containment [44]. Therefore, in similar approach to incentivize machine-readable RDT both routine and emergency scenarios, adopting RDT-OGs identifiers, and data schemas to interpret them, would likely would apply key advances in information technology to close address challenges currently faced. the critical gap between diagnostics and public health interventions, and enable a new era of precision public health. Acknowledgments This research was supported by the Bill and Melinda Gates Foundation where Arunan Skandarajah provided helpful insights, discussion, and review of these ideas during his tenure. The technical and implementation teams at the Summit Institute for Development, the Kenya Medical Research Institute, and Ona assisted in the operationalization of this work, results of which will be published elsewhere; Craig Appl, Samuel Githengi, and Vincent Karuri provided insightful commentary on applying Fast Healthcare Interoperability Resources (FHIR) and software engineering techniques to this work. We thank Ted Prusik and Mohannad Abdo of Temptime Corp. and Zebra Technologies Corp. for helpful guidance and support. Conflicts of Interest None declared. Multimedia Appendix 1 Survey instrument. [PDF File (Adobe PDF File), 96 KB-Multimedia Appendix 1] References 1. Tay A, Pavesi A, Yazdi SR, Lim CT, Warkiani ME. Advances in microfluidics in combating infectious diseases. Biotechnology Advances 2016 Jul;34(4):404-421. [doi: 10.1016/j.biotechadv.2016.02.002] 2. The Academy of Medical Sciences; 2016. Improving the Development and Deployment of Rapid Diagnostic Tests in LMICs. 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Lancet Infect Dis 2020 Jul;20(7):809-815 [FREE Full text] [doi: 10.1016/S1473-3099(20)30273-5] [Medline: 32330439] Abbreviations FHIR: Fast Healthcare Interoperability Resources IUI: information utilization index OG: open guideline PPH: precision public health RDT: rapid diagnostic test WHO: World Health Organization Edited by T Leung; submitted 31.12.20; peer-reviewed by H Mehdizadeh; comments to author 26.02.21; revised version received 24.07.21; accepted 14.04.22; published 29.07.22 Please cite as: Lubell-Doughtie P, Bhatt S, Wong R, Shankar AH JMIR Biomed Eng 2022;7(2):e26800 URL: https://biomedeng.jmir.org/2022/2/e26800 doi: 10.2196/26800 PMID: https://biomedeng.jmir.org/2022/2/e26800 JMIR Biomed Eng 2022 | vol. 7 | iss. 2 | e26800 | p. 12 (page number not for citation purposes) XSL FO RenderX JMIR BIOMEDICAL ENGINEERING Lubell-Doughtie et al ©Peter Lubell-Doughtie, Shiven Bhatt, Roger Wong, Anuraj H Shankar. Originally published in JMIR Biomedical Engineering (http://biomsedeng.jmir.org), 29.07.2022. This is an open-access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work, first published in JMIR Biomedical Engineering, is properly cited. The complete bibliographic information, a link to the original publication on https://biomedeng.jmir.org/, as well as this copyright and license information must be included. https://biomedeng.jmir.org/2022/2/e26800 JMIR Biomed Eng 2022 | vol. 7 | iss. 2 | e26800 | p. 13 (page number not for citation purposes) XSL FO RenderX http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png JMIR Biomedical Engineering JMIR Publications

Transforming Rapid Diagnostic Tests for Precision Public Health: Open Guidelines for Manufacturers and Users

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10.2196/26800
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Abstract

Background: Precision public health (PPH) can maximize impact by targeting surveillance and interventions by temporal, spatial, and epidemiological characteristics. Although rapid diagnostic tests (RDTs) have enabled ubiquitous point-of-care testing in low-resource settings, their impact has been less than anticipated, owing in part to lack of features to streamline data capture and analysis. Objective: We aimed to transform the RDT into a tool for PPH by defining information and data axioms and an information utilization index (IUI); identifying design features to maximize the IUI; and producing open guidelines (OGs) for modular RDT features that enable links with digital health tools to create an RDT-OG system. Methods: We reviewed published papers and conducted a survey with experts or users of RDTs in the sectors of technology, manufacturing, and deployment to define features and axioms for information utilization. We developed an IUI, ranging from 0% to 100%, and calculated this index for 33 World Health Organization–prequalified RDTs. RDT-OG specifications were developed to maximize the IUI; the feasibility and specifications were assessed through developing malaria and COVID-19 RDTs based on OGs for use in Kenya and Indonesia. Results: The survey respondents (n=33) included 16 researchers, 7 technologists, 3 manufacturers, 2 doctors or nurses, and 5 other users. They were most concerned about the proper use of RDTs (30/33, 91%), their interpretation (28/33, 85%), and reliability (26/33, 79%), and were confident that smartphone-based RDT readers could address some reliability concerns (28/33, 85%), and that readers were more important for complex or multiplex RDTs (33/33, 100%). The IUI of prequalified RDTs ranged from 13% to 75% (median 33%). In contrast, the IUI for an RDT-OG prototype was 91%. The RDT open guideline system that was developed was shown to be feasible by (1) creating a reference RDT-OG prototype; (2) implementing its features and capabilities on a smartphone RDT reader, cloud information system, and Fast Healthcare Interoperability Resources; and (3) analyzing the potential public health impact of RDT-OG integration with laboratory, surveillance, and vital statistics systems. Conclusions: Policy makers and manufacturers can define, adopt, and synergize with RDT-OGs and digital health initiatives. The RDT-OG approach could enable real-time diagnostic and epidemiological monitoring with adaptive interventions to facilitate control or elimination of current and emerging diseases through PPH. (JMIR Biomed Eng 2022;7(2):e26800) doi: 10.2196/26800 KEYWORDS rapid diagnostic test; precision public health; digital health; diagnostic; testing; guideline; manufacture; surveillance; FHIR; Fast Healthcare Interoperability Resources https://biomedeng.jmir.org/2022/2/e26800 JMIR Biomed Eng 2022 | vol. 7 | iss. 2 | e26800 | p. 1 (page number not for citation purposes) XSL FO RenderX JMIR BIOMEDICAL ENGINEERING Lubell-Doughtie et al of features (RDT’s hardware and software features) that would Introduction be needed to implement these axioms, and select a final evidence-based set of features that could be used by health Background policy and program implementers in integrating RDTs as tools Rapid diagnostic tests (RDTs), specifically for frontline health care workers at the community and clinic immunochromatographic lateral flow assays, can provide levels [3,4]. accurate real-time point-of-care diagnoses in low-resource Challenges Facing the Current RDT Ecosystem settings and have been an important tool in the global health arsenal. Advances in microfluidics have enabled the medical There are 3 core challenges faced within the current RDT device community to design smaller RDTs—as small as half ecosystem, which impede application and widespread the area of a business card and the thickness of a watch—that implementation for PPH. can be used to diagnose more conditions and are low cost—less Lack of Data Standards than US $1 per device [1]. Manufacturers and international health organizations have collaborated to deliver hundreds of The lack of uniformity in RDT hardware and software millions of RDTs to countries and communities [2]. However, substantially limits the integration of public health data from the full potential of RDTs as a public health tool has not yet RDTs into current health information systems, thereby impeding been realized. This is due to field deployment challenges their ability to respond to emerging crises [5]. Under these amplified by a fragmented market, nonstandard designs, and conditions, bridging these limitations requires analytics-intensive lack of features that facilitate systematic capture and use of tasks to convert, code, recode, and integrate data. Current RDT RDT results and patient data. Fortunately, current versions require specific knowledge and tools that are typically technology—computer vision, widely deployed smartphones, not compatible (Figure 1), leading to a combinatorial explosion and mobile networks—applied to RDTs provides a scalable of integration and data interoperability requirements. Without path to improved health and well-being through the emerging uniformity, health professionals and individual consumers using paradigm of precision public health (PPH). PPH is a field that RDTs cannot benefit from integration with point-of-care aims to maximize impact with the active use of data for smartphone apps to enable personal tailored care guided by surveillance and targeted interventions by temporal, spatial, and modern machine learning techniques that can calculate the prior epidemiological characteristics of populations. probabilities of having a condition from data on demography, the environment, and etiology. Therefore, we aimed to define axioms to underpin steps to incorporate RDTs into a PPH approach, identify an initial set Figure 1. Current rapid diagnostic test processes (left) use undefined or proprietary standards, which lead to multiple incompatible protocols (ie, incompatible apps and devices). The rapid diagnostic test open guideline process (right) uses standard guidelines to produce modular reference rapid diagnostic tests that are compatible and can be read by a well-defined protocol for devices and apps. ID: identifier code or number for each device; ML: machine learning; POC: point-of-care; RDT: rapid diagnostic test. https://biomedeng.jmir.org/2022/2/e26800 JMIR Biomed Eng 2022 | vol. 7 | iss. 2 | e26800 | p. 2 (page number not for citation purposes) XSL FO RenderX JMIR BIOMEDICAL ENGINEERING Lubell-Doughtie et al several studies have documented the challenges faced by health Heterogeneity of RDT Reader Hardware care workers in translating their competency to use one RDT One strategy to improve the uniformity, amount, and quality of to comparable competency with another (ie, those for similar information collected from RDTs is to use custom hardware diseases, from other manufacturers, or with revised procedures). readers and image capture and analysis devices (eg, the The lack of consistency contributes to high error rates in RDT DekiReader [6], specialized microscopes, and device holders). usage and interpretation and limits their impact [7]. However, these devices can be problematic owing to the expense, continuous supply, and maintenance required. As such, Solving These Challenges With Open Guidelines custom hardware is incompatible with large-scale deployments Based on these challenges, we define 3 axioms that underpin and the broad consumer use necessary for RDTs to cover high- solutions (Table 1). To solve the challenges and maximize and emerging-risk areas; therefore, such devices hinder the information usage for PPH, RDTs should adhere to a set of open continuous stream of accurate diagnostic data needed to expose guidelines (OGs), and use smartphone readers and data protocols outbreaks of known diseases and predict the emergence of new that standardize the information—both horizontally between diseases. different manufacturers or providers and vertically between different steps in the RDT life cycle (Figure 1). These axioms Diversity of RDT Form Factors and Instructions can transform the current state of the RDT ecosystem into one Any diagnostics integrated with smartphones would still involve that supports PPH. RDT-OGs address the data uniformity manual use of an RDT and interaction with patients. However, challenge of RDTs by standardizing the capture and use of data. Table 1. Rapid diagnostic test open guideline axioms. Axiom Description Axiom 1: Maximize rapid diagnostic test To address the custom hardware challenge, we designed RDT open guidelines (OGs) in line with the (RDT) data usage by capturing and structur- existing realities of the rapid diagnostic test manufacturing world. Manufacturers focused on creating ing information for integration tests simple enough to be used in clinical, community, and household settings by minimally trained community health workers, and eventually clients themselves. This need for widespread use leads us to define RDT-OGs to satisfy and facilitate these needs. Axiom 2: Any solution must rely on only This allows implementers of RDT-OGs to create solutions accessible by locally available technology readily available local resources and capability, including those that use pre-existing devices in target communities, such as low-cost smartphones [8]. RDT-OGs address the problems caused by lack of physical device uniformity by de- signing for human and device interoperability. Axiom 3: Diagnostic interfaces should re- This applies to RDT hardware, the software reading and interpreting RDTs, and the data schemas inte- main uniform or compatible grating with external systems. When using software-based RDT readers, following Axiom 3 leads us to link individual RDTs to uniform interactive guidance of users as they conduct a diagnostic test. software solutions, and medical systems are facing “information The Need to Catalyze the Era of RDT-OGs overload” [10]. The future trend in information use could take We have chosen to address the current challenges in RDTs with 1 of 2 diverging paths—modest growth with eventual stagnation open guidelines in order to focus directly on the systems and or a promising future with open guidelines aligned with the integration problems they face. Figure 2 shows initial progress aforementioned PPH axioms to accelerate impact by enhancing as RDTs were developed in the laboratory; as researchers information usage (Figure 2). predicted their impact, optimism surrounding their potential Below, we describe our methods, present survey results from grew. As RDT rollouts began, the ability to capture diagnostic experts in RDT technology, formally establish an information data increased, but these increases did not keep pace with global utilization index (IUI), and define how various RDT features growth in the technological capacity to store, communicate, and gather information. We use this to assess World Health analyze information [9]. Organization (WHO)–prequalified RDTs in comparison to a This changing technology landscape, combined with a lack of prototype RDT based on open guidelines and then discuss these individual RDT identifiers, inconsistent test use protocols, and results and related work in field-based hardware and software the appearance of fraudulent and counterfeit RDTs, led to a diagnostics and standards. As access to telecommunications relative decrease in information use; however, as the RDT networks improves worldwide, and advanced information community began to effectively encode and aggregate systems become more widely used by ministries of health and information and improve the training of health care workers, global health organizations, the community can dramatically information use increased. Currently, RDTs have reached a accelerate the transformational impact promised by RDTs. tipping point—there are multiple proprietary hardware and https://biomedeng.jmir.org/2022/2/e26800 JMIR Biomed Eng 2022 | vol. 7 | iss. 2 | e26800 | p. 3 (page number not for citation purposes) XSL FO RenderX JMIR BIOMEDICAL ENGINEERING Lubell-Doughtie et al Figure 2. The trajectory of information use in response to rapid diagnostic test technology innovation, which shows the introduction of rapid diagnostic tests and their initial impact (black line) followed by subsequent challenges (red line) and improvements (green line). Potential future paths are also shown: a lower growth in information utilization under the current incremental improvements (gray dashed line) or an accelerating trajectory enabled with rapid diagnostic test open guidelines (blue dashed line). GTIN: global trade item number; RDT: rapid diagnostic test. manufacturers, medical professionals, and frontline health Methods workers. These stakeholders were asked to participate in a web-based survey that comprised specific statements that Review of Published Literature corresponded to general, user-specific, manufacturer-based To identify key issues related to data capture and use from issues or issues regarding informatics. A 5-point Likert scale RDTs, we conducted a review of published papers using the was used for response: 0=strongly disagree, 1=disagree, Semantic Scholar artificial intelligence–enabled research search 2=neutral, 3=agree, 4=strongly agree, and unable to reply. engine [11]. We focused on, but did not constrain ourselves to, Replies were accrued from January 2019 to March 2019, and PubMed-indexed medical journal papers. The search was submitted entries were downloaded and tabulated. Results were conducted on December 31, 2018, and updated on December summarized by tabulations and analysis of proportions using 31, 2019, using the keywords “rdt,” “smartphone,” and “mobile Excel (version 16; Microsoft Inc). phone.” The search revealed 480 papers that were further Ethics Approval screened for the study of lateral flow immunochromatographic rapid tests, yielding 58 papers. In addition to reviewing these We note that the survey was exempt from human subjects papers, we reviewed their citations to identify additional papers research as per guidelines from the US Department of Health in telecytology, immunochromatography, and diagnostic and Human Services as it assessed a public benefit or service hardware. From these papers, we extracted themes and concepts and was not about humans, and did not collect sensitive related to barriers to information capture and usage from RDTs, information. and applied a grounded theory conceptual framework to compile Defining the IUI and code themes and concepts into core ideas and then high-level abstractions and classifications. These were discussed Survey results and the literature review were used to identify and reviewed by 3 different members of the team. We essential information features for RDTs and their integration considered this process complete when saturation was reached into health care platforms to support PPH. The presence or (ie, no additional novel ideas or abstractions emerged upon absence of a feature for a specific RDT could be used to review of additional papers). calculate an IUI defined as number of features present or the number of features defined. We then selected WHO prequalified RDT Stakeholder Survey cassette-based RDTs for malaria and HIV that had been assessed for performance [12] and calculated the IUI. Procedure The literature review and PPH axioms were used to identify the Results fundamental features and feasibility of open guidelines for RDTs that maximize information usage for PPH. A survey was Literature Review designed, which comprised 30 questions (Multimedia Appendix The review of published literature and thematic extraction of 1). Respondent-driven sampling was used and initiated by concepts related to information capture and usage from RDTs contacting authors of the papers reviewed and professional led us to identify the following core areas that affect information referrals, which included researchers, medical technologists, usage (Table 2). https://biomedeng.jmir.org/2022/2/e26800 JMIR Biomed Eng 2022 | vol. 7 | iss. 2 | e26800 | p. 4 (page number not for citation purposes) XSL FO RenderX JMIR BIOMEDICAL ENGINEERING Lubell-Doughtie et al Table 2. Core areas that affect information usage. Core areas Description Challenges in using commonly deployed This is related to issues of RDT choreography, and proper reading and interpretation even when control rapid diagnostic tests (RDTs). and results lines were clear. Existing barriers for mobile imaging of This referred to shadows from the cassette on the surface of the immunochromatographic strip, or glare RDTs. from the cassette and surface of the strip, all of which hindered image capture quality. Criteria for designing RDT standards. This included specific characteristics of RDTs that could be feasibly standardized. Barriers to RDT manufacturing standards. This referred to cost and other factors that could hinder manufacturing to an enhanced standard. Feasibility and features for smartphone-read This included the practicality of using identified features in the clinical or field setting. RDTs. Perceptions of non–human-readable RDTs This included whether or not read-out systems for RDTs would be acceptable for clinical or field person- (eg, electrochemical readouts). nel, if the actual reaction was not observable. maximize information usage, an RDT platform must function RDT Stakeholder Survey effectively in all phases of its life cycle, with added value at We contacted 81 stakeholders, and 33 completed the each phase. questionnaire (16 researchers, 7 technologists, 3 manufacturers, Specific stakeholder results are divided into discrete phases of 2 doctors or nurses, and 5 others). Respondents were most the rapid diagnostic test life cycle (Manufacture, Shipping, Use, concerned about the proper use of RDTs (agreed: 30/33, 91%), Interpretation, and Disposal), and RDT capabilities are divided their interpretation (agreed: 28/33, 85%), and reliability (agreed: into themes (Metadata, Molding of the Cassette, Printed Data, 26/33, 79%). Respondents were confident that smartphone-based and Smartphone Reader) (Figure 3). The open guidelines RDT readers could address some reliability concerns (agreed: contribute to each theme, and they are essential for the 28/33, 85%) and that readers were more important for complex Smartphone Reader theme. A conceptual framework that or multiplex RDTs (agreed: 33/33, 100%). contrasts the accumulated value of RDT open guidelines and IUI the current RDT process shows an increase at each life cycle phase. Specific capabilities drive these increases (Figure 3). Based on these results, and because RDTs are embedded in a set of protocols and practices defined by health care workers, We identified 11 essential information features for RDTs and institutions, clients, and communities, proper usage of rapid their integration into health care platforms, which define diagnostic tests depends not only on a physical device but also components of the IUI (Textbox 1). on its integration into the larger ecosystem. In this context, to Figure 3. Conceptual framework of gaps in information use through the rapid diagnostic test life cycle. Information utilization (vertical axis) is quantified relative to 5 distinct phases of the rapid diagnostic test life cycle (horizontal axis): Manufacturing, Shipping, Use, Interpretation, and Disposal. Over the life cycle, the information utilization of the current process increases (black line), but with the use of rapid diagnostic test open guidelines, information utilization would increase (blue line) as a result of several features (list at bottom). https://biomedeng.jmir.org/2022/2/e26800 JMIR Biomed Eng 2022 | vol. 7 | iss. 2 | e26800 | p. 5 (page number not for citation purposes) XSL FO RenderX JMIR BIOMEDICAL ENGINEERING Lubell-Doughtie et al Textbox 1. Components of the information utilization index. 1. Smartphone or other device reader exists 2. Instructions included 3. Cassette is not reflective 4. Test strip is not reflective 5. Shadow does not exist on test window 6. Expiration date printed on device 7. Identifier printed on device 8. Color calibration panel on device 9. 2D barcode on device 10. Test name clearly printed on device 11. Regulator (eg, World Health Organization) approved for lab and field use values ranging from 0 to 0.75 (mean 0.27; median 0.30, IQR Assessment of Current Rapid Diagnostic Tests 0.25) (Figure 4). The large bracket shows that 70% of this The IUI—which provides an overview of how much information information usage score can be attributed to printed or other current diagnostics can capture and where there is room for nonphysical changes, while the remaining 30% require physical improvement—for prequalified RDTs and an OG RDT had changes to the RDT. Figure 4. Information utilization index for WHO prequalified rapid diagnostic tests (RDTs). Scores were calculated for 33 WHO prequalified devices that had accessible information (blue, names listed below), as well as an RDT based on the RDT Open Guidelines (grey). The median information utilization score was 0.30 (magenta line), in contrast to 0.91, the score for an Open Guidelines RDT. 70% (top bracket) of the Open Guidelines RDT score can be attributed to non-physical changes, while the remaining 30% (bottom bracket) requires physical changes to the RDT. with colored overlays identifying the core modifications is Discussion shown. These include a 2D barcode to embed information needed for an app to identify, read, and interpret the RDT; RDT Open Guidelines fiducials as reference points to assist the camera and phone to Our RDT-OGs recommend the horizontal integration of RDT quickly and accurately identify the RDT areas of interest and hardware through consistent physical modules, thereby enabling reference; and a color calibration panel to enable reliable vertical integration of RDT software through consistent colorimetric inference. In addition, 3 WHO-prequalified RDTs protocols linking supply chain, test choreography, and with overlays are shown to highlight current inconsistencies interpretation. In Figure 5, a reference example of RDT-OGs between tests (Figure 5). https://biomedeng.jmir.org/2022/2/e26800 JMIR Biomed Eng 2022 | vol. 7 | iss. 2 | e26800 | p. 6 (page number not for citation purposes) XSL FO RenderX JMIR BIOMEDICAL ENGINEERING Lubell-Doughtie et al In comparing the optimized IUI and design of the reference outcomes. This workflow, like the RDT-OG, is not tied to a RDT-OGs to others, we observed both the heterogeneity and particular diagnostic and is designed to accommodate both common structures across all RDTs. We have designed existing and emerging diagnostics. RDTs can increase their IUI RDT-OGs to be useful whether adopting all recommendations, by using a universal RDT-OG–compatible reader and data a subset of modules, or using existing cassettes linked to an storage. New RDTs that become available in the market can RDT-OG–compatible software platform. Defining common further increase their IUI by using the hardware data models and schemas provides an information architecture recommendations of the RDT-OGs (Figure 6). The workflow that would encapsulate data from any module combination that integrates automatic result interpretation modules using machine exists on the RDT. The RDT-OG data schema can be effectively learning from image libraries or template-based approaches and encoded by the 2D barcode and easily drive the process forward can dynamically accommodate new RDTs through via a reader app. The design and production aspects have proved database-backed parameters defining rapid diagnostic test feasible given the successful production of the prototype, and components and hyperparameters identifying the specific RDT the field assessments, such as assessment of integration with (Figure 7). The rapidly growing number of COVID-19 serology epidemiological monitoring systems, are ongoing. and antigen-based RDTs show the critical role of dynamically supporting newly released RDTs [13,14]. Creating a systematic way (Figure 6) to collect and aggregate structured RDT data allows the community to continuously To the best of our knowledge, this is the first paper to propose monitor device performance, disease prevalence, and the guidelines to harmonize the hardware, software, and data relationship between demographic priors and diagnostic standard used to read and interpret RDTs. Figure 5. Unifying rapid diagnostic test functionalities based on formal guidelines. A rapid diagnostic test based on the rapid diagnostic test open guidelines (left) should have certain functional components, as indicated by the color-coded overlay. In contrast, 3 RDTs currently on the World Health Organization–prequalified list have only some of these components (right, with color-coded overlays). https://biomedeng.jmir.org/2022/2/e26800 JMIR Biomed Eng 2022 | vol. 7 | iss. 2 | e26800 | p. 7 (page number not for citation purposes) XSL FO RenderX JMIR BIOMEDICAL ENGINEERING Lubell-Doughtie et al Figure 6. In a system that incorporates rapid diagnostic test open guidelines, data are captured and digitized data from rapid diagnostic tests using a smartphone app that is compatible with the rapid diagnostic test open guidelines. These data are transmitted to a health information system platform and integrated with health system data, laboratory data, and other relevant data, then used to build machine learning models that both feed upstream, to smartphone apps to model symptoms and to be used to better interpret results, as well as downstream, for monitoring. Planners, managers, and researchers can use the real-time data to decide on modifications to existing programs and plan new programs. The color of the lines identifies the primary participant in that portion of the workflow, and the badges depict where to apply the features of the rapid diagnostic test open guideline. ML: machine learning; RDT: rapid diagnostic tests. Figure 7. A Fast Healthcare Interoperability Resources–based workflow using the Device Definition resource for Open Guidelines based rapid diagnostic tests connected to Device, Observation, and Patient resources. Medical devices are defined using the DeviceDefinition resource (to specify their physical characteristics and links to external information systems). Each rapid diagnostic test used corresponds to a Device resource linked to the appropriate DeviceDefinition resource, as well as to Patient and Observation resources that store patient information and test results, respectively. DekiReader is a portable device that guides users through a Diagnostics malaria RDT, reads, and automatically interprets test results; it is notable that its results are not significantly different from Overview human readings [6,15]. Similarly, NutriPhone pairs a lateral It is useful to review the RDT-OG system with related hardware, flow cassette with a hardware device and app to guide users and software, and standard-based approaches to field diagnostics, process images of test results to measure vitamin B levels. It and to note limitations and next steps to integrate the RDT-OGs has not been tested at scale; however, in a sample of 12 into the digital health ecosystem. participants, there was a correlation of 0.93 with the results Integrated Hardware-Based Field Diagnostics from an immunoassay [16]. Hardware-based field diagnostics require reusable equipment to function and connect to software systems. For example, the https://biomedeng.jmir.org/2022/2/e26800 JMIR Biomed Eng 2022 | vol. 7 | iss. 2 | e26800 | p. 8 (page number not for citation purposes) XSL FO RenderX JMIR BIOMEDICAL ENGINEERING Lubell-Doughtie et al vaccine vials would be warranted based on performance Software-Based Field Diagnostics degradation from heat exposure [34]. In addition, use of the In contrast, software-based field diagnostics do not require Fast Healthcare Interoperability Resources (FHIR) [35] can additional hardware to function, while having accuracy define clinical data as a graph of well-defined fields and data comparable to human interpretations of RDTs or images of used types (Figure 7). A number of current digital lab data platforms tests [17]. Dell and Borriello [18] made use of the pre-existing and application programming interfaces already handle related Open Data Kit to read various cassette-based RDTs using only diagnostic and laboratory information management with FHIR smartphones and 3D printable stands for consistent image as a common standard [36]. capture. Similarly, Ozkan and Kayhan [19] developed an RDT holder that clips onto smartphones to improve image consistency Regulators, such as the US Food and Drug Administration, and data interpretation. Demonstrating the utility beyond define pathways to classify novel medical devices, including cassette-based RDT formats, Ra et al [20] combined a urine test communication-enabled RDTs, for which there are no similar strip with color calibration markers and a smartphone app to existing devices [37]. Similarly, the Medical Device improve automated urinalysis accuracy across various lighting Communications Testing Project from the National Institute of conditions. There are also proprietary RDT-reading platforms, Standards and Technology is relevant to any form of medical including BBI Solutions’ Novarum Smartphone Reader and device communication and applicable to RDTs which Abingdon Health’s AppDx Smartphone Reader, that integrate communicate via radio frequency or electrochemical means on-cassette QR codes but with limited information (such as [38]. These regulatory bodies also promote innovation (eg, the RDT type) [21,22]. National Institute of Standards and Technology Text Retrieval Conference, where annual precision medicine competitions Though these approaches integrate modern software, their model the most effective treatments) exemplifying how generalizability is limited by having been designed in the communities can benefit from well-structured data [39]. absence of guidelines that standardize their solutions, and therefore do not adhere to PPH axioms 2 and 3. Vashist et al Limitations [23] reviewed how smartphone-based health care apps and This study has some limitations. First, the response rate from devices, including related medical, privacy, and data standards, the survey was 40% (33/81), and the survey results may have remain fractured without guidelines or standards. A recent benefited from additional feedback from a broader group. review [24] further extended the number of diagnostic devices Nevertheless, there was strong thematic concordance between and companies involved, and again concluded there is a lack of core responses from the survey and findings from the literature unification. review. Second, after designing the open guidelines, we did not solicit additional feedback from the same and similar groups of General Challenges in Field Diagnostics persons who were contacted for the survey. This additional step Yager et al [25] describe the biomedical engineering community would serve to validate the utility of the open guidelines. We as historically focused on laboratory-based diagnostics and note that our goal was to collect feedback from RDT producers highlight the work needed to adapt tools for settings in low- and users of RDT-OGs. Third, we limited ourselves to and middle-income countries. Improvement in test instructions, information usage issues and solutions for cassette-based rapid health worker training, and performance monitoring all correlate tests and did not include the simpler dipstick type strips. with reduced preanalytical errors, improved test performance, However, the same concepts would apply and would need to and increased result reliability [7,26,27]. be implemented in a way that is compatible with the lower space There is a growing consensus that point-of-care diagnostics and and cost profile of such tests [40]. Despite these caveats, the smartphones equipped with digital health solutions are proposed RDT-OG approach is clearly applicable to the majority converging and that this advancement may significantly expand of RDTs currently deployed globally, and to those likely to be self-managed care [28,29]. However, we currently lack digital produced in the future as multiplex and complex tests become health interventions with diagnostics linked to clinical care the norm. pathways and infectious disease surveillance systems [30], as Conclusions and Policy Recommendations well as solutions to the privacy and data stewardship challenges necessary for large-scale deployment [28]. Despite these In response to the goals and ambitions of the RDT community, challenges, researchers have outlined numerous promising future we defined PPH axioms and derived RDT-OGs. The point-of-care linkages: handheld ultrasounds and software recommended modular foundation is designed to accelerate platforms with standardized databases integrating artificial current RDT development, fieldwork, and successfully translate intelligence [31], telecytology platforms for test-and-not-treat RDTs into effective field evaluations and deployments at scale. strategies [32], and accurate diagnoses of oral cancer using These guidelines thus confer functionality to diagnostic devices, convolutional neural networks [33]. the smartphone apps interpreting them, and the health information system analyzing them. For example, temperature Related Regulations and Standards sensors may be essential to assure proper storage and quality Existing standards for diagnostics encompass RDTs, including of some rapid diagnostic tests [34], and the modularity of open several related standards in health technology, medical devices, guidelines can accommodate this need. Although modifying and precision medicine. For example, given that most rapid supply chains may be infeasible in areas with rigid logistics or diagnostic tests have maximal temperature limits for storage fixed asset costs, the RDT-OGs gives the community a pathway and use, temperature exposure monitors such as those used on to extend the functionality of pre-existing field-based diagnostics https://biomedeng.jmir.org/2022/2/e26800 JMIR Biomed Eng 2022 | vol. 7 | iss. 2 | e26800 | p. 9 (page number not for citation purposes) XSL FO RenderX JMIR BIOMEDICAL ENGINEERING Lubell-Doughtie et al through advances in machine learning, which do not require Thus, by providing guidance for RDT hardware, software, and RDT modifications. data interoperability, standards-setting organizations can transform RDTs into a formidable public health tool for disease National and global policy makers have shown a willingness prevention and treatment, in addition to diagnosis. These and ability to convene communities around guidelines that innovations can accelerate long-term disease control efforts, benefit RDT stakeholders; for example, the WHO such as for malaria, which is responsible for 7.8% of the annual prequalification of medicines program, FHIR, SNOMED, and deaths of children under 5 years old (20,000 children worldwide LOINC. As the WHO, the Global Fund, Foundation for [43]). Furthermore, these innovations can accelerate rapidly Innovative New Diagnostics, and others continue this work, evolving disease control efforts, such as for COVID-19, where there is ample opportunity to adopt formal guidelines around serological or antigen detection investigations face challenges RDTs and their usage. For example, the WHO’s role in creating in obtaining case information; these challenges are expected to and promoting prequalified malaria RDTs has incentivized further increase as testing efforts continue to scale up, and with manufacturers to increase low-cost RDT production [41,42]. A transition from mitigation to containment [44]. Therefore, in similar approach to incentivize machine-readable RDT both routine and emergency scenarios, adopting RDT-OGs identifiers, and data schemas to interpret them, would likely would apply key advances in information technology to close address challenges currently faced. the critical gap between diagnostics and public health interventions, and enable a new era of precision public health. Acknowledgments This research was supported by the Bill and Melinda Gates Foundation where Arunan Skandarajah provided helpful insights, discussion, and review of these ideas during his tenure. The technical and implementation teams at the Summit Institute for Development, the Kenya Medical Research Institute, and Ona assisted in the operationalization of this work, results of which will be published elsewhere; Craig Appl, Samuel Githengi, and Vincent Karuri provided insightful commentary on applying Fast Healthcare Interoperability Resources (FHIR) and software engineering techniques to this work. We thank Ted Prusik and Mohannad Abdo of Temptime Corp. and Zebra Technologies Corp. for helpful guidance and support. Conflicts of Interest None declared. Multimedia Appendix 1 Survey instrument. [PDF File (Adobe PDF File), 96 KB-Multimedia Appendix 1] References 1. Tay A, Pavesi A, Yazdi SR, Lim CT, Warkiani ME. Advances in microfluidics in combating infectious diseases. Biotechnology Advances 2016 Jul;34(4):404-421. [doi: 10.1016/j.biotechadv.2016.02.002] 2. The Academy of Medical Sciences; 2016. Improving the Development and Deployment of Rapid Diagnostic Tests in LMICs. 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Lancet Infect Dis 2020 Jul;20(7):809-815 [FREE Full text] [doi: 10.1016/S1473-3099(20)30273-5] [Medline: 32330439] Abbreviations FHIR: Fast Healthcare Interoperability Resources IUI: information utilization index OG: open guideline PPH: precision public health RDT: rapid diagnostic test WHO: World Health Organization Edited by T Leung; submitted 31.12.20; peer-reviewed by H Mehdizadeh; comments to author 26.02.21; revised version received 24.07.21; accepted 14.04.22; published 29.07.22 Please cite as: Lubell-Doughtie P, Bhatt S, Wong R, Shankar AH JMIR Biomed Eng 2022;7(2):e26800 URL: https://biomedeng.jmir.org/2022/2/e26800 doi: 10.2196/26800 PMID: https://biomedeng.jmir.org/2022/2/e26800 JMIR Biomed Eng 2022 | vol. 7 | iss. 2 | e26800 | p. 12 (page number not for citation purposes) XSL FO RenderX JMIR BIOMEDICAL ENGINEERING Lubell-Doughtie et al ©Peter Lubell-Doughtie, Shiven Bhatt, Roger Wong, Anuraj H Shankar. Originally published in JMIR Biomedical Engineering (http://biomsedeng.jmir.org), 29.07.2022. This is an open-access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work, first published in JMIR Biomedical Engineering, is properly cited. The complete bibliographic information, a link to the original publication on https://biomedeng.jmir.org/, as well as this copyright and license information must be included. https://biomedeng.jmir.org/2022/2/e26800 JMIR Biomed Eng 2022 | vol. 7 | iss. 2 | e26800 | p. 13 (page number not for citation purposes) XSL FO RenderX

Journal

JMIR Biomedical EngineeringJMIR Publications

Published: Jul 29, 2022

Keywords: rapid diagnostic test; precision public health; digital health; diagnostic; testing; guideline; manufacture; surveillance; FHIR; Fast Healthcare Interoperability Resources

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