Andrews, Jason R.

Bogoch, Isaac I.

Coulibaly, Jean T.

Keiser, Jennifer

Lo, Nathan C.

Mondry, Michael K.

Rajchgot, Jason

Utzinger, Jürg

PLoS Neglected Tropical Diseases

Jason Rajchgot

Jean T Coulibaly

Jennifer Keiser

Jürg Utzinger

Nathan C Lo

Michael K Mondry

Jason R Andrews

Isaac I Bogoch

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Mobile-phone and handheld microscopy for neglected tropical diseases.

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FROM INNOVATION TO APPLICATIONMobile-phone and handheld microscopy forneglected tropical diseasesJason Rajchgot1, Jean T. Coulibaly2,3,4,5, Jennifer Keiser4,5, Ju¨rg Utzinger4,5, NathanC. Lo6,7, Michael K. Mondry8, Jason R. Andrews6☯, Isaac I. Bogoch1,9☯*1 Department of Medicine, University of Toronto, Toronto, Canada, 2 Unite´ de Formation et de RechercheBiosciences, Universite´ Fe´lix Houphoue¨t-Boigny, Abidjan, Coˆte d’Ivoire, 3 Centre Suisse de RecherchesScientifiques en Coˆte d’Ivoire, Abidjan, Coˆte d’Ivoire, 4 Swiss Tropical and Public Health Institute, Basel,Switzerland, 5 University of Basel, Basel, Switzerland, 6 Division of Infectious Diseases and GeographicMedicine, Stanford University School of Medicine, Stanford, California, United States of America, 7 Divisionof Epidemiology, Stanford University School of Medicine, Stanford, California, United States of America,8 Department of Mechanical Engineering, Stanford University, Stanford, California, United States of America,9 Divisions of General Internal Medicine and Infectious Diseases, Toronto General Hospital, Toronto,Canada☯ These authors contributed equally to this work.* isaac.bogoch@uhn.caDiagnostic laboratory infrastructure in low- and middle-income countries (LMICs) is notori-ously scarce, with limited resources typically clustered in urban settings where they are inac-cessible to much of the population [1]. One attempt to mitigate these issues is the developmentand implementation of handheld and mobile-phone microscope technologies. Theseapproaches aim to deliver high-quality laboratory diagnostic capability to resource-con-strained settings by bringing the diagnostics to the people rather than transferring people orclinical specimens to distant laboratories. The goal is to provide robust, inexpensive, and accu-rate devices that can be utilized at the point of care in the most austere of settings. Despite awealth of technological innovation in this field meeting many of these criteria, there remainkey challenges in implementing mobile-microscopy programs in resource-constrained envi-ronments [2]. Here, we review some of the recent approaches, discuss their strengths andlimitations, and offer considerations for a way forward in bringing mobile microscopy to com-munities in need.While there have been many publications over the past decade reporting on portable ormobile-phone microscopes, comparably few studies have been performed in which real clini-cal specimens were tested under field conditions. Table 1 summarizes recent field studies inwhich the accuracy of mobile microscopes for detection of neglected tropical diseases (NTDs)in clinical specimens was evaluated. One early, very low-cost device utilized a glass ball lensmounted to the camera lens of a mobile phone for magnification. This approach was rathercumbersome to use, given the small field of view and movement of the ball lens, which resultedin poor image quality and insufficient diagnostic sensitivity and specificity for soil-transmittedhelminth infections [3]. The paper-based Foldscope is an inexpensive and lightweight device,also utilizing a ball lens for magnification, as well as a battery-powered LED for illumination[4]. When mounted to a mobile phone, the Foldscope demonstrated low sensitivity (althoughit had high specificity) for the diagnosis of Schistosoma haematobium infection, possibly due tothe small field of view and challenges with slide navigation under the lens [5]. The reversed-lens CellScope is a lightweight plastic attachment with an embedded lens that harnesses thelight source from a mobile phone. This device is manually maneuvered over a sample andPLOS Neglected Tropical Diseases | https://doi.org/10.1371/journal.pntd.0005550 July 6, 2017 1 / 4a1111111111a1111111111a1111111111a1111111111a1111111111OPENACCESSCitation: Rajchgot J, Coulibaly JT, Keiser J,Utzinger J, Lo NC, Mondry MK, et al. (2017)Mobile-phone and handheld microscopy forneglected tropical diseases. PLoS Negl Trop Dis 11(7): e0005550. https://doi.org/10.1371/journal.pntd.0005550Editor: Patrick J. Lammie, Task Force for ChildSurvival and Developmentorce for Global Health,UNITED STATESPublished: July 6, 2017Copyright: © 2017 Rajchgot et al. This is an openaccess article distributed under the terms of theCreative Commons Attribution License, whichpermits unrestricted use, distribution, andreproduction in any medium, provided the originalauthor and source are credited.Funding: IIB is supported by Grand ChallengesCanada 0631-01-10 (www.grandchallenges.ca)and a grant from the MSH UHN AMO InnovationFund. JTC is supported by the Programme d’AppuiStrate´gique à la Recherche Scientifique (PASRES),Coˆte d’Ivoire (project no. 113). NCL is supportedby the National Institutes of Health MedicalScientist Training Program (MSTP). The fundershad no role in study design, data collection andanalysis, decision to publish, or preparation of themanuscript.Competing interests: The authors have declaredthat no competing interests exist.when tested on S. haematobium samples, it demonstrated modest sensitivity with excellentspecificity [5].The results from the aforementioned technologies were obtained by expert microscopistsunder near-ideal conditions. However, a critical issue is understanding how well these deviceswill perform in routine clinical or public-health settings. Only a few mobile-phone micro-scopes have been evaluated in “real world” settings by individuals who would use these devicesin their routine practice. Coulibaly and colleagues trained local laboratory technicians how touse a reversed-lens CellScope and the Newton Nm1 handheld microscope with a mobile-phone attachment as part of a community-based screening program for schistosomiasis inCoˆte d’Ivoire [6]. Local laboratory technicians successfully used these devices, and the NewtonNm1 microscope demonstrated diagnostic sensitivities for S. mansoni and S. haematobiumeggs of 91.7% and 81.1%, respectively, and specificities of 99.5% and 97.1%, respectively, whilethe CellScope demonstrated sensitivities for S. mansoni and S. haematobium of 50.0% and35.6%, respectively, and specificities of 99.5% and 100%, respectively [6]. A version of the Cell-Scope is currently under revision to enable improved sensitivity, as microscopists had somechallenges manually navigating the device around a slide.Another device, the CellScope Loa, was tested to identify and quantify Loa loa microfilare-mia in Cameroon by mobilizing a reversed-lens microscope attachment in combination with acustom application [7]. The device uses video microscopy and computer vision to identifymotion of L. loa microfilaria and can process a blood film within 2 min. In an initial test of 33patients, the device achieved a sensitivity of 100% and specificity of 94% when compared toconventional light microscopy [7]. It is currently being evaluated in a larger cohort. Lastly,Ivorian laboratory technicians used the Newton Nm1 handheld microscope with a mobile-phone attachment to detect Plasmodium falciparum in a community-based screening programin rural Coˆte d’Ivoire, with sensitivity and specificity of 80.2% and 100.0%, respectively, com-pared to “gold” standard microscopy [8]. These studies highlight that novel devices can beused in routine public health practice in resource-constrained settings and ongoing studies arecurrently building on this early success.Table 1. Recent field validation studies involving mobile and handheld light microscopy for neglected tropical infections in clinical specimens inendemic settings.Device Organism detected SamplesizeSensitivity/specificity* (%)PPV/NPV(%)ReferenceBall lens mounted to mobile-phone cameraAscaris lumbricoides, Trichuris trichiura,and hookworm199 69.4/61.5 92.3/23.2 Bogoch et al. 2013[3]Mobile phone–mountedFoldscopeSchistosoma haematobium 49 55.9/93.3 95.0/48.3 Ephraim et al. 2015[5]Reversed-lens CellScope S. haematobium 49 67.6/100.0 100.0/57.7 Ephraim et al. 2015[5]Newton Nm1 with mobile phoneattachedS. mansoni 226 91.7/99.5 91.7/99.5 Coulibaly et al. 2016[6]Newton Nm1 with mobile phoneattachedS. haematobium 226 81.1/97.1 94.8/88.6 Coulibaly et al. 2016[6]CellScope Loa Loa loa 33 100/94 D’Ambrosio et al.2015 [7]Newton Nm1 with mobile phoneattachedPlasmodium falciparum 223 80.2/100.0 100.0/65.6 Coulibaly et al. 2016[8]*Sensitivity and specificity of mobile-phone or handheld microscopes for the diagnosis of S. mansoni, S. haematobium, and soil-transmitted helminths wascompared to conventional light microscopy.Abbreviations: NPV, negative predictive value; PPV, positive predictive valuehttps://doi.org/10.1371/journal.pntd.0005550.t001PLOS Neglected Tropical Diseases | https://doi.org/10.1371/journal.pntd.0005550 July 6, 2017 2 / 4The ubiquity of mobile phones in LMICs and the growing quality of and access to mobilenetworks across the globe continue to make mobile-phone microscopy a compelling technol-ogy [2,9]. In addition, the impressive capabilities of mobile-phone microscopes continue to bedemonstrated in laboratories with plans for validation and scale in real world settings. Recentdevelopments include imaging of single DNA molecules [10] and computer-vision andmachine-learning technology for the automated detection and quantification of pathogens[11]. The ability of these devices to connect with databases and global positioning system(GPS) devices provides compelling potential public health, clinical, and research applications(Table 2).Microscopes for use in LMICs should be able to maintain appropriate sensitivity and speci-ficity in rugged environments with variable sample quality. Current designs focus on usabilityby all members of the healthcare team. Ideally, microscopes would be designed with intuitive,foolproof operation in mind so that they could be used even by untrained individuals, muchlike the automatic external defibrillator. Similarly, sample preparation must be simplified suchthat diagnoses at the point of care are possible [12] and systems designed to ensure appropriatequality-control measures are adhered to. It is also important to note that initial manufacturingcosts will likely be unimportant to the overall cost of microscope operation when factored overmany years. Microscope development should focus on building robust, high-quality devicesthat can achieve high throughput. Consider this hypothetical scenario: a US$1 microscope canprocess 30 specimens per day, which equals 7,200 specimens over the course of a year, assum-ing a laboratory technician working 5 days a week for 48 weeks per year. Incorporating labora-tory technician salary and associated costs (for example, US$4,000 per year) as well as the US$1 upfront device cost, the cost per specimen over a 10-year time span would be US$0.56.Using a similar framework, consider a microscope that initially costs US$500 but has higherthroughput (e.g., larger field of view, easier slide manipulation, or image-detection software)and can process 40 specimens per day (96,000 samples over 10 years). In this same hypothetical10-year time span with the annual laboratory technician salary of US$4,000, the cost per speci-men would be only US$0.42, despite the higher up-front investment. It follows that, ratherthan focusing primarily on reducing instrument costs, products should be designed to ensureease of use and rapid throughput of specimens. In addition, ultra-low-cost devices may have asignificantly shorter life span and may not have the most reliable diagnostic operating charac-teristics compared to more expensive and more robust equipment.One of the key barriers to implementation of mobile microscopy for NTDs is the need forslide preparation from blood, stool, urine, and tissue specimens. Many slide-preparation tech-niques require centrifugation or filtration as well as organism staining. There has beenTable 2. Advantages and disadvantages of handheld and mobile-phone microscopy.Advantages Disadvantages• Devices are portable and can be easilytransported to rural and remote settings.• Portable imaging technology continues to evolve andstill requires design improvement to increasediagnostic sensitivity and user friendliness.• Mobile phones are ubiquitous. • Sample preparation is still required, as withconventional microscopy.• Devices are battery powered and not affected byintermittent power outages.• Diagnostic devices require further validation in clinicaland public-health settings, and wider applicationacross multiple pathogens will be necessary.• Image-processing algorithms can enableautomated diagnoses; global positioning systemsand transmission features of phones can facilitatedata sharing for better disease-burden estimates.• Some devices remain an expensive option whencompared to traditional light microscopy.https://doi.org/10.1371/journal.pntd.0005550.t002PLOS Neglected Tropical Diseases | https://doi.org/10.1371/journal.pntd.0005550 July 6, 2017 3 / 4comparatively little work done on simple, low-cost, laboratory-free means for microscopysample preparation, and yet, without solving this challenge, the potential of mobile microscopyfor use in remote settings without laboratory infrastructure will not be realized.An important consideration with any new technology is the potential barriers to implemen-tation and scale. Currently, there is no set of standards that exists to ensure quality of thesedevices. These technologies will likely only last if they are properly maintained and functional,and healthcare practitioners will need to be trained to use a novel technology. Hence, there is aneed for innovative manufacturing pathways and viable business models. Lastly, the devicesmust be shown to provide significant value to current models, such as ease of use, portability,and improving access to care.Portable microscopes hold potential for expanding access to diagnosis for NTDs inresource-constrained settings. A number of innovative approaches have appeared in the litera-ture, and early field testing has yielded promising results. Further work is needed to createsample-to-answer solutions that address current obstacles to sample preparation, object identi-fication, and high-throughput use. Once these challenges are addressed, portable microscopycould yield timely information on the distribution and of disease in remote settings and trans-form the approach to treatment, control, surveillance, and elimination of NTDs at the point ofcare.References1. Petti CA, Polage CR, Quinn TC, Ronald AR, Sande MA. Laboratory medicine in Africa: a barrier to effec-tive health care. Clin Infect Dis. 2006; 42: 377–382. https://doi.org/10.1086/499363 PMID: 163920842. Howitt P, Darzi A, Yang GZ, Ashrafian H, Atun R, Barlow J, et al. Technologies for global health. Lancet.2012; 380: 507–535. https://doi.org/10.1016/S0140-6736(12)61127-1 PMID: 228579743. Bogoch II, Andrews JR, Speich B, Utzinger J, Ame SM, Ali SM, et al. Mobile phone microscopy for thediagnosis of soil-transmitted helminth infections: a proof-of-concept study. Am J Trop Med Hyg. 2013;88: 626–629. https://doi.org/10.4269/ajtmh.12-0742 PMID: 234785804. Cybulski JS, Clements J, Prakash M. 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Mobile-phone and handheld microscopy for neglected tropical diseases

Mobile-phone and handheld microscopy for neglected tropical diseases

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