The impact of digital technologies on point of care diagnostics in resource limited settings

1. Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=iero20 Expert Review of Molecular Diagnostics ISSN: 1473-7159 (Print) 1744-8352 (Online) Journal homepage: http://www.tandfonline.com/loi/iero20 The impact of digital technologies on point-of-care diagnostics in resource-limited settings Natasha Gous, Debrah I. Boeras, Ben Cheng, Jeff Takle, Brad Cunningham & Rosanna W. Peeling To cite this article: Natasha Gous, Debrah I. Boeras, Ben Cheng, Jeff Takle, Brad Cunningham & Rosanna W. Peeling (2018): The impact of digital technologies on point-of- care diagnostics in resource-limited settings, Expert Review of Molecular Diagnostics, DOI: 10.1080/14737159.2018.1460205 To link to this article: https://doi.org/10.1080/14737159.2018.1460205 Published online: 10 Apr 2018. Submit your article to this journal View related articles View Crossmark data

2. REVIEW The impact of digital technologies on point-of-care diagnostics in resource-limited settings Natasha Gousa , Debrah I. Boerasb,c , Ben Chengc , Jeff Takled , Brad Cunninghama and Rosanna W. Peelinge a Global Health Department, SystemOne LLC, Johannesburg, South Africa; b Global Health Impact Group, Atlanta, GA, USA; c International Diagnostics Centre, London, UK; d Global Health Department, SystemOne LLC, Springfield, MA, USA; e Department of Clinical Research, London School of Hygiene and Tropical Medicine, London, UK ABSTRACT Introduction: Simple, rapid tests that can be used at the point-of-care (POC) can improve access to diagnostic services and overall patient management in resource-limited settings where laboratory infrastructure is limited. Implementation of POC tests places tremendous strain on already fragile health systems as the demand for training, supply management and quality assurance are amplified. Digital health has a major role to play in ensuring effective delivery and management of POC testing services. Area covered: The ability to digitise laboratory and POC platforms, including lateral flow rapid diagnostic test results, can standardize the interpretation of results and allows data to be linked to proficiency testing to ensure testing quality, reducing interpretation and transcription errors. Remote monitoring of POC instrument functionality and utilization through connectivity, allows programs to optimize instrument placement, algorithm adoption and supply management. Alerts can be built into the system to raise alarm at unusual trends such as outbreaks. Expert commentary: Digital technology has had a powerful impact on POC testing in resource limited settings. Technology, markets, and medical devices have matured to enable connected diagnostics to become a useful tool for epidemiology, patient care and tracking, research, and antimicrobial resistance and outbreak surveillance. However, to unlock this potential, digital tools must first add value at the point of patient care. The global health community need to propose models for protecting intellectual property to foster innovation and for safeguarding data confidentiality. ARTICLE HISTORY Received 27 November 2017 Accepted 29 March 2018 KEYWORDS Digital technology; connected diagnostic system; health system strengthening; quality assurance; data governance 1. Introduction Infectious diseases impose a huge burden in the developing world. Every year, millions of people worldwide die from infectious diseases such as human immunodeficiency virus (HIV), tuberculosis (TB), malaria, pneumonia, and diarrhoea [1]. Diagnostics play a critical role in clinical decision-making and disease control and prevention. Sensitive and specific laboratory- based diagnostic assays are commercially available for the detection of most infectious diseases of public health importance, but they are costly and often not accessible to patients in the developing world where laboratory services are often limited. Laboratory networks in resource-limited settings (RLS) may struggle with sustaining the basics needed to support centralized testing, and infrastructure for surveillance of infectious pathogens, and outbreak detection and response, is often lacking. Point-of-care (POC) testing (POCT) refers to testing that can be performed at the site of patient care and can improve access to diagnostic services, turnaround time for results, and overall patient management. The development and deployment of simple, rapid tests and devices that can be used at the POC to screen for HIV, diagnose TB, and guide malaria treatment has led to significant reductions in morbidity and mortality in the developing world where access to laboratory services is limited. However, despite its many benefits, a number of challenges exist, mostly related to the quality of tests and of decentralized testing, the management and oversight of POC programs, and the high cost and utilization of POCT services [2,3]. The Joint United Nations Programme of HIV/AIDS (UNAIDS) have a set of ambitious targets for HIV known as the 90-90-90 targets, calling on countries to ensure 90% of infected individuals know their HIV status, 90% of those known to be infected are on antiretroviral treatment (ART), and 90% of those on treatment are virally suppressed by 2020 [4]. Attainment of these 90-90-90 targets depends on increasing access to POC tests for marginalized and hard-to-reach populations, POC molecular assays for early infant diagnosis (EID), and HIV viral load (VL) monitoring. Similarly, the global com- mitment to eliminate mother-to-child transmission of HIV and syphilis requires ensuring access to POC tests for screening pregnant women at every antenatal clinic [4]. In 2015, countries committed to a Sustainable Development Agenda with 17 Sustainable Development Goals (SDGs) calling for the United Nations and its partners to build a better world with no one left behind [5]. The efforts toward Universal Health CONTACT Rosanna W. Peeling Rosanna.peeling@lshtm.ac.uk Department of Clinical Research, London School of Hygiene and Tropical Medicine, Keppel Street, London, UK EXPERT REVIEW OF MOLECULAR DIAGNOSTICS, 2018 https://doi.org/10.1080/14737159.2018.1460205 © 2018 Informa UK Limited, trading as Taylor & Francis Group

3. Care coverage to achieve the SDGs will need to be under- pinned by affordable and accessible POC tests. The WHO End TB Strategy, that aims to bring the global TB epidemic to an end by 2035, is the first to acknowledge the role of digital health in ensuring more effective and efficient service delivery and ultimately achieving global health targets [6]. Digital health refers to the convergence of information technology, digital media, and mobile devices with health care and is enabling patients and health-care providers easier access to data and health information in order to improve quality and outcomes [7]. Various digital technologies, including but not limited to, connected diagnostics devices, decision support systems, mobile health Applications (Apps), connected biometric sensors, and electronic health records [8], are able to gen- erate and transmit electronic data (whether it be wirelessly or by wired connection) to the Internet to digitally report results in real time and hold great promise to improve the efficiency of the health-care system. With the increasing demand for POC diagnostics, the convergence of digital technologies with a range of POC platforms that vary from simple rapid diagnostic tests (RDTs) in lateral flow formats to POC molecular devices is transforming patient care and disease surveillance in RLS beyond that of data transmission. This review presents the potential impact and benefits of digitizing POC diagnostics in RLS by discussing the role of digital technologies in improving linkage to care and data collection, optimizing placement and usage within the health-care system, facilitating outbreak control and remote program management, addressing quality concerns, and improving overall return of investment for programs and funders. The review also highlights the importance of data governance frameworks for effective data management when considering digital technologies. 2. Digitizing POCT programs 2.1. Application to rapid diagnostic testing RDTs are a double-edged sword. While RDTs can greatly improve access to testing services, the implementation of RDT programs places tremendous strain on already fragile health systems as the demand for training, supply chain management, and quality assurance are amplified. RDT results have to be read visually and this subjective interpretation can result in reader variation in interpretation of results. New innovations and strategies to digitize RDT result interpretation using optical readers and mobile phones may improve the interpretation and allow result data to be transmitted in an electronic format. FIONET (Fio Corporation, Toronto, Canada), as an example, combines a device-based RDT reader, termed Deki, with a configurable cloud information system to ensure that program managers can remotely monitor field activities and performance. This system has been deployed in Ghana to collect data on malaria RDTs as well as microscopy results for quality and comprehensive reporting [9]. The Deki Reader provides guidance on the testing process and objectively interprets RDT results based on line intensity thus reducing or eliminating common processing errors and improving diagnostic accuracy. In Cameroon, the Deki Reader is showing potential for strengthening their RDT malaria program and initial trials demonstrated >98% agreement with visual result interpretation of malaria RDTs [10]. Similarly, for HIV, RDTs are the critical entry point for the HIV treatment and care cascade and the cornerstone of national reporting on country epidemiological and surveillance data. However, although the HIV RDT is one of the easiest and least expensive tests to perform, it has been shown to pose great challenges with regards to ensuring compliance to the testing algorithm, external quality control, and accuracy of reading the visual result [11–13]. Various mobile applications have been developed, or are in development, for application to HIV RDT programs in RLS to improve the overall quality and reliability of results (Table 1) [14]. One such platform, developed by Global Solutions for Infectious Diseases, is an App-based reader that was piloted in Zimbabwe for HIV and malaria test result interpretation and real-time reporting [15]. By uploading test result images through the App, the central laboratory is able to monitor nurses test administration and quickly identify issues related to result reporting and data collection. Electronic self-testing instruments for sexually transmitted infections (STI) are also in development [16]. The UK Clinical Research Collaboration Translational Infection Research Initiative Consortium is supporting research to reduce burden of STI (current test for chlamydia) by developing rapid POC tests that can work with a noninvasive, easyto-use sample collection device (p-stick) – 4 mL urine, vaginal swab for Table 1. Examples of automated RDT readers either commercially available or in the developmental pipeline. Reader Reader format Data format Deki Reader (Fio Corporation, Toronto, Canada) Commercially available, universal device-based reader that can interpret commercially available RDTs Results can be automatically transmitted to FIONET cloud database via 3G or Wi-Fi Infectious Disease Reader (iStoc, Koulukatu, Finland) Commercially available, universal reader consists of software that runs on standard smartphone or iPad Results can be sent to a Immediate Diagnostics and Analytics (IDA) cloud- based server Holomic LLC (Holomic, Los Angeles, CA, USA) Commercially available, universal reader that consists of an attachment that clips onto a mobile phone An application on phone transmits data to a central server and can interface with Holomics Cloud mReader (MobileAssay™, Denver, CO, USA) Commercially available, universal reader that consists of software that runs on a standard smartphone or iPad device Results can be uploaded via Wi-Fi or cellular network to Mobile Assay cloud server Global Solutions for Infectious Diseases system (University of Washington, Dimagi, Boston, MA, USA) Universal reader consists of software that runs on standard smartphone or iPad. SIM card can be used to store and transmit results NovarumDx (BBI Solutions and Albagaia, Scotland and Wales, UK) Commercially available, customizable software that runs on a smartphone device Results can be transmitted to a BBI server RDTs: rapid diagnostic tests. 2 N. GOUS ET AL.

4. females with a time to result of 30 min. Patients are then linked to an electronic pathway for treatment and contract tracing without having to see a doctor. In general, automated RDT readers, through their ability to capture, digitize, and transmit RDT results, will have a critical role to play in not only strengthening data collection and management for RDT programs but also improve the overall quality of POC RDT testing and surveillance efforts [14]. Thus, it seems that investments in digital technologies to enhance visual readings of lateral flow assays and improve result reporting could provide huge returns on investment for RDT programs. 2.2. Application to POC molecular diagnostic platforms Underneath a medical instrument’s diagnostic result is a rich set of sub-result data (‘deep instrument data’) that are still largely untapped as a resource. Pathogen or human genetic profiles, thermal temperatures, cycle threshold (Ct) values, and similar data are merged, analyzed, and distilled into a ‘Positive’ or ‘Negative’ result in many instruments and this is typically where the health-care system steps in to take action. But those genetics, temperatures, curves, and values indicate clusters of genetic mutations when matched to age, sex, or prior treatment history; or over time can indicate an emerging resistance to antibiotics in a rural province; or when married to treat- ments and outcome monitoring, hold the potential for personalized medicine. Accessing this data was impossible before as the data were either entirely inaccessible or manually imprac- tical to record, e.g. thousands of interim measurements that compile a curve. However, through emerging digital technologies in the new generation of POC molecular devices (most have inbuilt connectivity capabilities), the ability to natively collect electronic diagnostic and deep instrument data is now possible. Programs with connected diagnostic platforms are able to remotely collect data coming from both decentralized POC technologies and readers in near real time. These data can potentially be merged through a middleware solution and linked to Ministries of Health (MoH) and used to provide critical information on testing coverage, disease trends, epidemiological surveillance, supply chain management, and quality monitoring of the tests and testing process (Table 2) across national programs, as well as international systems thus increasing the efficiency of health- care systems and improving patient outcomes. In RLS, these advances can also form the basis of early warning systems to optimize control and elimination interventions through building in automated alerts to raise alarms for outliers and erroneous results and to monitor the performance of instruments. With Global Positioning System data transmission capabilities, diagnostic data can be linked to geographical locations to report national and global testing trends to central data- bases to optimize programs, report on outbreaks, inform disease control strategies, and monitor progress towards elimination. Geographic Information Systems (GIS) are also being used to map existing laboratory networks, collect information on testing volumes and needs, in order to appropriately place POC instruments within the network, and improve the overall health system. Such systems can also be used for tracking progress towards elimination of diseases. 3. The impact of digital technologies on POCT programs 3.1. Rapid return of diagnostic results and linkage to care Reduced time to diagnosis and rapid treatment initiation have been shown to improve TB patient outcomes and reduce transmission rates [17]. However, one of the weaknesses of many health systems is that they are oftentimes not equipped to support rapid diagnostic systems, such as the GeneXpert, with prompt return of patient results and thus end up negat- ing the impact of the technology [18,19]. This is especially pertinent with many countries opting for centralized GeneXpert testing. Although laboratory turnaround times are short, the return of paper-based results back to referring clinics has been reported to delay patient initiation onto treatment [20]. Even though POCT is designed to provide rapid return of results during the patient visit, a few studies have shown that in reality, same-day results are not always possible due to device throughput, logistics, and clinical work- flows [21,22]. Thus, one of the most compelling arguments for digital technologies is the capability to return diagnostic test results to the health-care provider or even the patient, in real-time, via short message service (SMS) or e-mail notifications to link them to care. An exciting application of this is in HIV RDT self- testing programs. The standard algorithm for HIV diagnosis is Table 2. Summary of the potential impact of digitizing data on POC technologies. Parameters Local impact Health system impact Rapid return of diagnostic results Reducing time for management of patients Increasing health systems efficiency Improving data quality/ reliability Reducing transcription errors Monitoring POC instrument placement and utilization Reduce stock outs by optimizing instrument placement and supply management Quality assurance Improving diagnostic accuracy by linking proficiency results to testing centers allows for corrective action and remedial training Improving patient outcomes Monitoring adherence to diagnostic algorithms Improving the correct use of diagnostics to guide patient management Alerts for unusual trends Faster recognition of emerging or reemerging health security issues Allowing timely surveillance and alerts for outbreaks and antimicrobial resistance POC instrument operation Alerts for instrument errors Facilitates innovation; improving return on investment on POC instruments Alerts for instrument breakdown Reminders for maintenance and warranty EXPERT REVIEW OF MOLECULAR DIAGNOSTICS 3

5. two sequential RDTs; one for screening and one for confirmation. For HIV self-testing, the same algorithm applies but, in this case, the person self-tests in private and needs to be linked to care for their confirmatory testing. New digital innovations, such as the HIVSmart! App developed by McGill University, allow persons to download an open-source App on their mobile phone, which provides guidance on testing and result interpretation, educational information and attempts to link positive patients to health-care facilities to ensure confirmatory testing [23]. In Nigeria, the GxAlert connectivity platform by SystemOne (Boston, MA, USA) is being used to reduce the turnaround time for reporting of GeneXpert multidrug resistant (MDR)-TB results, whether they initiate from centralized or POC sites, to the TB government supervisor, state program manager, and national program enrolment officer [24,25]. Since implementation of the GxAlert system for real-time reporting of drug resistant-TB results via SMS alerts, the proportion of patients initiated onto treatment has significantly increased from 20% in 2014 to 85% in 2015 [11]. A further concern with POCT is that results are often not captured electronically, and once the patient leaves the health facility, are no longer available for reporting, statistical analysis, monitoring, and billing purposes [26]. Traditionally, POC results are manually captured in paper registers that may or may not be transcribed into the laboratory information system (LIS) or electronic medical record (EMR). The advantage of a connected POC device is that results will automatically be incorporated into the LIS or EMR to ensure better management, faster response, automated billing, and inclusion of data for reporting. 3.2. Improved data quality To ensure the appropriate planning, monitoring, and resource allocation to meet global HIV and TB diagnostic and treatment goals, the need for collection of data representative of the populations being served, as well as geographic locations of services being offered, is imperative to understanding program performance and future planning needs [27]. It is worth noting, however, that nationwide EMR or nationwide LIS are generally not present in the developing world and continue to have little penetration. Lacking a nationwide underpinning of these systems, which typically capture demographic patient data, treatment history, and other important metadata about a patient or diagnosis, emerging connectivity solutions are filling those gaps by making modest adjustments to which data are collected at the diagnostic instrument itself. By prompting the capture of additional information alongside the diagnostic test result, for example, indicators such as gender, age, HIV/TB status, previous treatment history, and referring facility, programmatic reporting is enriched and allows monitoring of which populations are being reached and those that are missed. As an example, the National TB program in the Philippines is capturing very granular data alongside their GeneXpert TB results such as gender, age, specimen, and facility details, etc. and in doing so, is collecting a rich data set to improve on their programmatic reporting. Capture of this information is facilitated through GxConnect (SystemOne), a small piece of software installed on the GeneXpert instrument which is able to collect these custom fields together with the TB result, transmit it to the in-county server and then displays all data on the GxAlert dashboard. Program managers can remotely monitor what populations are being tested and where, identify gaps, determine if interventions are working and further intervention needs. 3.3. Optimizing POC technology placement and remote oversight Countries often struggle with the optimal placement of POC instruments. When the decision to adopt a new digital technology is made, it is important to understand the necessary infrastructure and systems needed to maintain these new technologies and ensure optimal usage. Most POC devices for CD4 enumeration, as an example, have inherent connectivity capabilities but countries have lacked the necessary resources to support the information technology and troubleshooting, such as lack of data plans and skilled human resources. This resulted in inappropriate placement of devices, inoperative devices, and fragmented laboratory networks. In South Africa, the National Health Laboratory Service gathered electronic data on CD4 testing volumes, instrument placement, and GIS-mapped clinical locations to develop a tiered CD4 testing model, incorporating both centralized and POCT [28]. Through this model, they have successfully managed to improve not only the turnaround times for CD4 service delivery but also have the potential to save in HIV programmatic costs. The ‘optimal’ pace for adding new instruments into a country should be a balance between the need to increase catchment, the speed with which underlying demand generation strategies are employed (e.g. clinical sensitization and specimen referral), and the rate at which the population of instruments’ utilization rate climbs. Lack of reporting on commodity consumption can also result in major stock outs and delays in issuing of new stock, leading to instrument downtimes, as was experienced in Kenya during the rollout of the Pima™ CD4 (Alere Technologies, GmbH) and BD FACSPresto™ CD4 devices (BD Biosciences) [29]. Test purchasing and consumption rate can also be tracked in real time against purchases using connectivity software if procurement data are captured and can help avoid interruptions in service delivery and wastage of resources [27]. For example, by analyzing the average useful life left in Xpert® MTB/RIF cartridges at the time they are consumed, the government can extrapolate whether they are purchasing fre- quently enough or receiving stock with sufficient lifespan remaining to prevent expired cartridges. Ideally, one would want to see smaller more frequent procurements to ensure fewer stock outs (Figure 1). Similarly, the monitoring of instruments or modules on a monthly basis quickly allows central program managers to identify if a diagnostic instrument is out of service and prompt appropriate action (Figure 2). Interruptions in diagnostic testing may be due to several possible causes, including 4 N. GOUS ET AL.

6. instrument failures, laptop/computer issues, or test/consumable stock-outs, absence of testing personnel, and each will display a different pattern of interruption. If diagnostic instruments are connected, these patterns can be identified and rectified [30]. This would allow automated notifications to the in-country service provider to fast track and improve Figure 1. Cartridge useful life left. Red bars indicate Xpert cartridge stock with less than 2 months to expiry. Green bars indicate stock with more than 6 months expiry. By monitoring useful life, test purchasing practices can be better informed. (a) When smaller, more frequent purchases are made, stock is less likely to expire before use, but this will have supply chain and logistical implications. (b) Larger, less frequent purchases may result in stock expiring before it can be used. Full color available online. Figure 2. Monitoring of instrument down-time: Stoppages in testing can easily be identified and prompt investigation as to possible causes. EXPERT REVIEW OF MOLECULAR DIAGNOSTICS 5

7. service and maintenance and facilitate backup plans such as reallocation of samples to other laboratories for testing. 3.4. Quality assurance Ensuring the accuracy of diagnostic testing improves patient outcomes. The quality of tests and testing can be monitored through the use of external quality assessment (EQA) or Proficiency Testing (PT). EQA for POCT is often difficult due to a range of factors including the cadre of staff performing the EQA (non-laboratory or non-technical), difficulty in ensuring compliance with EQA schedules and protocols, obtaining EQA results back in a timely manner, and reporting back to POC sites [31]. Connectivity solutions that can link EQA/PT results to POCT sites would allow assessment of adequacy of training, need for corrective action and/or remedial training, and should be seen as a complementary approach to EQA [32,33]. This is especially important in POC sites with high staff turnovers. The benefit of having connected POC devices was demonstrated in Zimbabwe for managing their CD4 EQA program. Usually, the Pima CD4 EQA program is a time-intensive process requiring sample shipping to remote sites, testing and reporting back to the central facility, a process which can take up to 12 weeks [33]. In 2015, an automated EQA program was piloted with Oneworld Accuracy, whereby an application program interface for their informatics system, OASYS (Oneworld Accuracy System), was developed to automatically query Alere Data Point every hour for any new data that had been identified as an EQA sample. This automated system resulted in a significant reduction in time to reporting, with Oneworld Accuracy receiving EQA results within 60 min of the test being performed on the PIMA [33]. Monitoring of device errors is also an important way to monitor the quality of POCT programs. As with laboratory testing, errors can occur during any stage of the POCT process and much focus has been applied to the analytical and post-analytical phases. Connected POC devices allow remote monitoring of test failures or unsuccessful tests (operator and instrument errors, no or invalid results). Instrument failure rates can vary significantly within countries, across instruments, regions, or time. Given the ability to have all unsuccessful test data automatically reporting to a server allows central monitoring of distribution, frequency, and trends. These data can be visua- lized down to a peripheral site-level and on a per user basis, without ever having to travel to those sites and without the missing or erroneous data typical of paper-based self-reporting. General patterns exist in terms of expected errors, what per- centages to anticipate, and what remediation might be most effective. Figure 3 illustrates how monitoring of error rates by testing sites over a specific period of time can facilitate rapid identification of problem sites and (automatically) trigger an investigation into potential causes [34]. This process can serve to proactively alert National Reference Laboratories (NRLs), quality assurance teams, and partners when an instrument is ‘out of the norm.’ The cate- gorization of errors according to their cause (instrument, user, assay) is also an important activity for NRLs to facilitate rapid response and implement corrective actions. 3.5. Monitoring adherence to diagnostic testing algorithms Through a connectivity system, a health-care system can monitor the adoption of new algorithms and report on the intervention to determine if it is being implemented appropriately, Figure 3. Bar chart showing the diagnostic instrument error rates for 16 laboratories over a specific time period. Red bars show laboratories with higher than the average national error rate of 6.3% (grey line), whilst green bars depict laboratories performing below the acceptable benchmark of 5% (green dashed line). Full color available online. 6 N. GOUS ET AL.

8. whether it is cost-effective, and what other factors are needed for implementation to be successful [35]. Connectivity can also inform scalability and adoption of a diagnostic program by providing information on adherence and/or any deviations at a country, regional, or site level [36]. The Global Laboratory Initiative has stated that the GeneXpert TB diagnostic algorithm should be dictated by the epidemiological disease profile of the country [37]; however, a few studies in Africa have shown poor adherence to TB diagnostic algorithms [38–40]. Figure 4. Example of how a connectivity solution can facilitate monitoring of a new diagnostic algorithm adopted within a given country. One would expect to see variability in certain indicators, in this case TB positivity rates, at programme adoption (2013) due to unfamiliarity and novelty of the diagnostic algorithm. However, as the programme evolves and compliance with the algorithm is achieved, the TB positivity pattern should become more uniform and meet expected rates (2016). Figure 5. Identifying outliers. Scatter plots can be used to identify whether indicators such as TB and Rifampicin resistance fall within expected rates for given countries/regions/laboratories. EXPERT REVIEW OF MOLECULAR DIAGNOSTICS 7

9. To illustrate, Figure 4 shows the adoption of the GeneXpert MTB/RIF® assay as the national first-line TB diagnostic in a new setting. Connectivity was instrumental for monitoring specific indicators. For example, connectivity monitored if the pre- sumed TB or MDR-TB prevalence is within the range expected [41] given the new intervention, and hence if the country algorithm is being followed. By delving deeper and observing data on a per-facility basis, one can quickly identify outliers or particular testing sites that are not following the diagnostic process appropriately, i.e. if their rates of disease do not fall within expected ranges (Figure 5). For example, if an instrument or site is focused on screening all prisoners for TB regardless of whether they are symptomatic or not, one would expect that site to have very low TB positivity rates. In contrast, sites attached to MDR treatment wards or in-country algorithms using the GeneXpert primarily for rifampicin resistance confirmation would display very high TB positivity and rifampicin resistance rates several times higher than the average. Rates falling outside of expected ranges could therefore prompt further investigation. Ideally, if all instruments in all countries were reporting to a connected diagnostic solution, the algorithm could be much more precise, country-specific, and evolving as the situation evolves. This is the focus of some connectivity software platforms like GxAlert™ that are not only connecting the GeneXpert for TB diagnosis, but also the GenoScan for Line Probe Assay (Hain LifeScience, GmbH) drug resistance testing and MGIT liquid culture system (Becton Dickinson) for monitoring response to treatment. Under a Challenge TB pro- ject in Mozambique, the integration of all three TB diagnostics within the algorithm will allow the treatment cascade across instruments to be looked at in more detail and provide a unified view of drug resistance by tracking patients using a connected diagnostics patient ID solution. 3.6. Harnessing the power of digital technologies for global health security Outbreak response and real-time disease surveillance are an urgent global health priority. The Ebola crisis of 2014–2016 is just one example of a global health crisis that served to demonstrate the importance of integrating digital technologies with the new generation of POC molecular tests that are highly sensitive and specific. During the outbreak, GeneXpert devices located in mobile laboratories in Guinea and Sierra Leone were interfaced to GxAlert. This enabled automatic, real-time reporting of positively identified cases directly to the laboratory directors via SMS and e-mail alerts giving key decision-makers accurate, reliable, and timely information, improving the time to coordinate a response. Similarly, digitized data from antimicrobial resistance (AMR) surveillance testing within a connected national surveillance system would allow real-time monitoring of the impact of antibiotic stewardship strategies and continuous improvement and optimization. Another benefit of these digital tools is the ability for a country to set outbreak algorithms to automatically trigger based on statistical anomalies in disease data [42] or too many diagnostic results falling outside of preset criteria. Responding immediately – literally within seconds of a confirmed diagnosis – helps the health-care system respond faster and interrupt person-to-person transmission. Tracing of infected contacts and containment of infected persons becomes exponentially more difficult and expensive with each passing day and the ability to have a latent early warning system running in the background can save valuable days that can be used to address the outbreak at 0 instead of Patient 231. In Nigeria, a mobile App, dashboard, and GIS mapping tool have been used to speed up the timeliness of reporting and communication for new Ebola case detection and response [43]. Since implementation of this system, improvement has been seen in reporting of daily follow-ups of contacts, turnaround time between identification of symptomatic contacts and evacuation, and reporting of laboratory results. Furthermore, although many information systems exist today to monitor infectious disease outbreaks, they rely on manually reported information and, as the prior Ebola, H1N1, SARS, and various other outbreaks repeatedly demonstrate, the decision to declare an outbreak has been constrained; either the data was not of sufficient quality to merit a political response sooner, or the data was ‘shaped’ prior to public release in order to minimize the political or economic penalty for being ‘an Ebola country’ [44]. Connected diagnostics equip all stakeholders with the same, unadulterated set of information against which to coordinate and take action; namely the actual phenomenon of an outbreak as it happens, rather than personal reporting and interpretation of the outbreak after it happens. Connected diagnostic systems can also improve a county’s ability to monitor disease trends and inform intervention needs. In South Africa, the GeneXpert Xpert MTB/RIF national testing footprint is connected to the in-country LIS, allowing diagnostic and operational data to be collected centrally. The National TB program is using this data, specifically the Ct values, as an audit indicator for program and laboratory performance as well as identifying variability in bacterial burden and clusters of drug resistance [45]. Not only does this allow the program to monitor and improve on algorithm adherence but also improves upon molecular surveillance. Similarly, a spatial decision support system is being used in the South West Pacific to automatically locate and map the distribution of confirmed malaria cases in order to rapidly identify hotspots for transmission and guide response efforts [46]. 3.7. Improving return of investment of a diagnostic instrument The benefits of a connected diagnostic platform also become apparent in the ability to inform programmatic implementation of new diagnostic purchases. Typically, POC programs and diagnostic networks, in general, have been plagued by over- capacity and underutilization of instruments [47]. Between 2011 and 2013, a survey of HIV VL, EID, and CD4 instrument availability and utilization was conducted in 127 WHO countries [48]. Major gaps were found; underutilization of VL and CD4 instrumentation was widespread, with only 13.7% utilization of CD4 capacity and 36.5% utilization of VL capacity being reported in 2013 [48]. 8 N. GOUS ET AL.

10. The ability to monitor utilization rates in real-time can provide important insights into appropriate purchasing models for instruments and consumables, as well as identify where alternative investments into infrastructure or specimen transport may be more pertinent. In general, utilization rates will differ by country but tend to cluster into three distinct categories: (1) countries accelerating instrument utilization, (2) countries that have hit a ceiling in instrument utilization, and (3) countries that are lagging or declining in instrument utilization (Figure 6). A country showing an upward trend in utilization may indicate that new instruments introduced into this system are being adopted more quickly and effectively due to leveraging of the existing infrastructure; countries with declining utilization rates may be suggestive that too many instruments are being purchased too quickly for appropriate absorption into the health-care system. In this case, it may be prudent to channel investments into improving and strengthening underlying demand such as improving specimen referral and transport systems or clinical sensitization programs. Over the last 60 years, rapid advances in portable commu- nications devices such as the smart phone have improved the speed, efficiency and cost of data acquisition, processing and storage. Mobile phones are now in widespread use, even in the hardest to reach areas. Smartphone-based devices with the ability to power and interpret serological assays in microfluidic formats have been developed and are in clinical trials [49,50]. Smartphone-based molecular assays are now under development. Test results can be displayed on the smartphone as well as transmitted to a central database. These are suitable for self- use or by health providers in a facility or in a community setting. Testing using these smartphone-based diagnostic devices will complement laboratory-based diagnostic testing system, especially for outbreak investigations. 4. Data governance Any private or public legal entity processing or storing personal information needs to do so in an appropriate manner to protect the right to privacy of the individuals [51]. Diagnostic and patient identifiable information falls under this category, and as such, a burden of responsibility is placed on protecting this information. The South African Protection of Personal Information (POPI) Act [52] provides (in part) some clarity: To promote the protection of personal information processed by public and private bodies; to introduce certain conditions so as to establish minimum requirements for the processing of personal information. As present, in all industries influenced by continuous advances in information technology, the regulatory and legislative fra- mework which governs the process will always lag behind the current state of technology. Legislation simply cannot be updated at the same rate as technology progresses; and this is a common threat across many industries. The major governance frameworks which influence the connected diagnostics industry are General Data Protection Regulation (GDPR) [53], Data Protection Act [54], POPI [52], and the Privacy Shield [55]. All four of these frameworks span from a similar purpose and reflect minor differences in the nuances around the terminology and processes, with the same goal in Figure 6. Illustrative example of trends in diagnostic instrument utilization for the GeneXpert. The bar chart plots the average number of tests performed (Y axis) per instrument per month (X axis). A theoretical maximum utilization of 200 tests is used as the benchmark for a four module GeneXpert instrument. The blue line plot depicts the overall trend in instrument utilization as a percentage (alternative Y axis). EXPERT REVIEW OF MOLECULAR DIAGNOSTICS 9

11. mind. These policies/acts should not be viewed as mechanisms to thwart or prevent the sharing of diagnostic data. These policies should be regarded as processes which promote the sharing of diagnostic data and information by appropriate means. Although these legislative processes are well established in the developed world, they are generally absent in the developing world, and are not likely to find widespread adoption within the next 5 years. The inherent risk in the lack of legal requirement to ensure appropriate mechanisms for storing, processing, and sharing health-care information is that developed systems may abuse this process. Due diligence should still be conducted to meet international security standards and the responsible and appropriate protection of this information is still required. Failing to do so will likely result in the abuse of this information; or inappropriate dissemination of personal information; data breaches and further reputational and trust violations can stunt the growth of this industry. A number of international companies and organizations such as mSTAR, Foundation for Innovative New Diagnostics, SystemOne, London School of Hygiene and Tropical Medicine are all working to promote the establishment of best practice for connected diagnostic systems to ensure adequate protection which promotes the sharing of information to a new ecosystem being established to process and consume data which the ultimate goal of improving patient treatment and ultimately, patient outcomes. 4.1. Data ownership The legislation referenced above deals with the storage and processing of personal and special personal information and the necessary requirements to do so appropriately. The legislation, however, does not delineate data ownership [56]. The entity which owns the data is not necessarily obvious and if often a contentious topic in the developing world due to the nature of the industry and the dynamics of funding agencies, implementing partners, technology providers, and MoH. As an example, a funding agency funds the implementation of a third-party contracted solution, via an implementing partner, to be utilized by the MoH to interface a number of diagnostic instruments. Under this arrangement, at least four different groups would like to have access to various sets of data for different activities, and the right to access this data is determined by the Data Controller using GDPR/POPI parlance [54]. The Data Controller determines the reasons for collection and processing of the data and is legally liable to ensure the protection of this data – but the Data Controller is not necessarily the owner of the data. For the industry of connected diagnostics, the most appropriate assignment would be the entity responsible for the treatment of the patient owns the data. If more than one entity is involved, a joint responsibility model is inherent with both entities responsible for the protection and processing of this information and a written agreement outlining such is required under POPI and the GDPR binding these entities. This assignment of ownership of connected diagnostic information to the MoH (or branch thereof) is fair since (a) they are responsible for the care of the patient; and (b) if ever a data breach was identified, the MoH would likely be the liable entity incurring legal damages over the implementing partners, third-party providers, or global funders. 4.2. Data glossary/data dictionary Diagnostic device makers, especially smaller firms, have a singular focus to innovate and invent faster, more sensitive, and cheaper means to provide a diagnosis. However, a nota- ble gap in the development process is the lack of a standard set of information, data, or reportable fields which should be included as part of the diagnostic result. The state of technology has progressed well beyond the need for a diagnostic device to simply produce a result and an entire ecosystem has been created (the connected diagnostics industry) processing the metadata reported with the test result. The metadata which accompanies a test result is able to provide and inform a wealth of activities which allow MoH’s and organizations the ability to ● Ensure the quality and accuracy of a reported result (first and foremost) ● Track inventory and consumable expiration ● Monitor the quality of consumable lots and inform man- ufacturing requirements ● Analyze the difference in testing quality at high- vs. low- infrastructure facilities ● Inform supply chain and sample logistics ● Identify potential specimen contamination ● Proactively monitor and predict instrument failures, cali- bration, and maintenance requirements. ● Monitor instrument utilization and uptime . . . among many others. Providing a standardized list of requirements for these reportable fields for new devices would significantly improve the remote monitoring and reporting capabilities present in the industry. Similarly, MoHs are discovering the richness of reporting and analysis which additional patient demographic information (age, gender, region, etc.) can provide national programs and imposing additional requirements on new devices to be flexible enough to support this kind of information. 5. Conclusion Health systems need to evolve to take advantage of this convergence of POC and digital technologies [57, 58]. New technologies and devices should, by default, utilize open interface and standards to provide digital output as well any necessary metadata required for quality control verification and analysis. Commonly used open-interface formats such as HL-7, ASTM, and the POC-1A/2A standards are appropriate for these devices. In the future, laboratories need to take on a novel role as the central command of a digitized diagnostic system that extends beyond laboratories across all POCT sites, assuring quality, supply chain, providing training and monitoring patient outcomes [59]. The connected diagnostic system is critical in providing data for disease surveillance to inform disease control strategies, and outbreak investigations and in combating AMR. 10 N. GOUS ET AL.

12. 6. Expert commentary Technology, markets, and medical devices have matured to enable connected diagnostics as a tool for epidemiology, patient care and tracking, research, outbreak control, and AMR surveillance. However, to unlock this potential, digital tools must first add value at the point of the phenomenon, i.e. in a clinical context at the point of patient care. This value could be realized through assisting in automatic referrals for follow- up care, connecting a patient to nearby treatment centers, automatic ordering of drugs, or decision support for the health-care worker. These types of value-added activities encourage adoption of the technologies and, as a by-product, create comprehensive aggregate disease intelligence. Never before have millions of patient diagnoses been accumulated without data loss or integrity issues, geo-located to create real- time heat maps to track disease outbreaks while also triggering automated alerts to the relevant first responders, surrounding nations, national policy makers, and international organizations all automatically. This ability to add value at all levels of the health system simultaneously from a single data source is one of the most promising innovations in health-care. 7. Five-year view The future of disease intelligence will rely on latent outbreak algorithms assisting difficult political decisions that a country must make and allow these decisions to be made as early as possible for the right action to be taken. A faster, smarter response leads to earlier quarantine and a dramatic reduction in the cost of each outbreak as well as impact on morbidity and mortality [57]. Outbreaks cannot be prevented, but pan- demics can be prevented by establishing stronger disease surveillance and intelligence networks. Device makers are, understandably, deeply concerned about the unforeseen exposure of their deep instrument data and the potential for exposing proprietary data and their intellectual property to competitors. Some companies such as Thermo Fisher are capitalizing on this de-identified research data for their own instruments and are exposing it safely and in a controlled manner through their ‘Thermo Fisher Cloud’ for analytics in hopes of inspiring the next generation of research. Other device makers have responded by attempting to close off access to their deep instrument data, choosing protection over innovation. Careful, thoughtful business models are possible to safely harness this untapped potential in ways that can fundamen- tally transform the role connected diagnostics play in the very near future. It is the role of the global health community to communicate their strong desire for these innovations and to propose safe models that protect device makers’ intellectual property while ushering in personalized medicine 10 years faster into the market. Together, global health partners, MoH, and device manufacturers can bring the potential of connected diagnostic systems to fruition. Key issues ● Simple, rapid tests that can be used at the point-of-care (POC) can improve access to diagnostic services and overall patient management. However, ensuring quality of tests and of decentralized testing, supply chain management, increasing training needs, reporting and monitoring patient outcomes put tremendous stresses on fragile health systems in resource-limited settings ● A connected diagnostic system has positive impact at both local level and for the entire health system. The rapid return of result can reduce delay in appropriate management of patients, including initiating treatment ● Digitising diagnostic results and utilizing data connectivity capacity to transmit diagnostic results from POC instruments, linked to quality assurance and supply chain systems can facilitate health system strengthening and improve patient outcomes. ● Data privacy, confidentiality and security issues will become more complex as health data sources become more diverse, including those from mobile phone-based devices ● Digital technology has had a powerful impact on POC testing in resource limited settings. However, there are concerns about data governance and intellectual property. It is the role of the global health community to communicate their strong desire for these innovations and to propose models that protect device makers’ intellectual property and safeguard data confidentiality. Funding R Peeling would like to acknowledge funding from the UK Engineering and Physical Sciences Research Council, grant EP/K031953/1. Declaration of interest Authors N Gous, J Takle and B Cunningham are all either employees, shareholders or both, of SystemOne LLC, a connected diagnostics com- pany currently operating in the industry. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those dis- closed. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose. References Papers of special note have been highlighted as either of interest (•) or of considerable interest (••) to readers. 1. Dye C. After 2015: infectious diseases in a new era of health and development. Phil Trans R Soc B. 2014;369:20130426. 2. Shaw JLV. 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