Mobile Device for Disease Diagnosis and Data Tracking inResource-Limited Settings

Curtis D. Chin,1† Yuk Kee Cheung,1† Tassaneewan Laksanasopin,1 Mario M. Modena,1 Sau Yin Chin,1

Archana A. Sridhara,1 David Steinmiller,2 Vincent Linder,2 Jules Mushingantahe,3 Gisele Umviligihozo,4

Etienne Karita,4 Lambert Mwambarangwe,5 Sarah L. Braunstein,5,6 Janneke van de Wijgert,5,7

Ruben Sahabo,8 Jessica E. Justman,6,8 Wafaa El-Sadr,6,8 and Samuel K. Sia1*

BACKGROUND: Collection of epidemiological data andcare of patients are hampered by lack of access to lab-oratory diagnostic equipment and patients’ health re-cords in resource-limited settings. We engineered alow-cost mobile device that combines cell-phone andsatellite communication technologies with fluid min-iaturization techniques for performing all essentialELISA functions.

METHODS: We assessed the device’s ability to performHIV serodiagnostic testing in Rwanda and synchronizeresults in real time with electronic health records. Wetested serum, plasma, and whole blood samples col-lected in Rwanda and on a commercially available sam-ple panel made of mixed antibody titers.

RESULTS: HIV testing on 167 Rwandan patients evalu-ated for HIV, viral hepatitis, and sexually transmittedinfections yielded diagnostic sensitivity and specificityof 100% and 99%, respectively. Testing on 40 Rwan-dan whole-blood samples— using 1 �L of sampleper patient—resulted in diagnostic sensitivity andspecificity of 100% and 100%. The mobile devicealso successfully transmitted all whole-blood test re-sults from a Rwandan clinic to a medical recordsdatabase stored on the cloud. For all samples in thecommercial panel, the device produced results inagreement with a leading ELISA test, including de-tection of weakly positive samples that were missedby existing rapid tests. The device operated autono-mously with minimal user input, produced each re-sult 10 times faster than benchtop ELISA, and con-sumed as little power as a mobile phone.

CONCLUSIONS: A low-cost mobile device can perform ablood-based HIV serodiagnostic test with laboratory-level accuracy and real-time synchronization of patienthealth record data.© 2012 American Association for Clinical Chemistry

In resource-limited settings, the rapid adoption of mo-bile phones has enabled remote communication ofvoice and limited data at a low cost. Such mobile tech-nologies are beginning to be used to improve publichealth and patient care (1, 2 ); examples include textmessaging for improving adherence to malaria (3 ) andHIV treatment (4, 5 ), transmission of images for tele-microscopy (6 ), and personal digital assistants for col-lecting laboratory results (7 ). However, there are majorareas of healthcare services—including preventive di-agnostics—that remain unavailable to patients in re-mote settings. Ideally, these services would also belinked with mobile technologies that could accesshealth records and hence provide a full context of pa-tient history. Reflecting the view that access to patientrecords has the potential to markedly improve patientcare, over 2 dozen countries in the developing worldare implementing electronic databases that collectivelycontain hundreds of thousands of patient records(8, 9 ). Rwanda alone has over 90 000 HIV/AIDS pa-tients for whom care is currently facilitated by elec-tronic records (10 ).

A handheld device that could perform laboratory-quality diagnostic tests and access patient health re-cords (11, 12 ) would be valuable for many reasons(13 ), including improved monitoring of disease out-

1 Department of Biomedical Engineering, Columbia University, New York, NY;2 OPKO Diagnostics, LLC, Woburn, MA; 3 Muhima Hospital, Nyarugenge District,Kigali, Rwanda; 4 Rwanda Zambia HIV Research Group, Project San Francisco,Kigali, Rwanda; 5 Projet Ubuzima, Kigali, Rwanda; 6 Department of Epidemiol-ogy, Columbia University, New York, NY; 7 Academic Medical Center of theUniversity of Amsterdam and the Amsterdam Institute for Global Health andDevelopment, Amsterdam, the Netherlands; 8 Mailman School of Public Health,ICAP, Columbia University, New York, NY

† C.D. Chin and Y.K. Cheung contributed equally to the work, and both should beconsidered first authors.

* Address correspondence to this author at: Department of Biomedical Engineer-ing, Columbia University, 500 West 120th St., 351 Engineering Terrace, NewYork, NY, 10027. Fax 212-854-7273; e-mail ss2735@columbia.edu.

Received December 5, 2012; accepted December 10, 2012.Previously published online at DOI: 10.1373/clinchem.2012.1995969 Nonstandard abbreviations: mChip, mobile microfluidic chip for immunoassay

on protein markers; GSM, Global System for Mobile Communications; GPRS,General Pocket Radio Service; SMS, short message service; HBV, hepatitis Bvirus; HSV-2, herpes simplex virus 2; POC, point-of-care.

Clinical Chemistry 59:4000 – 000 (2013)

Point-of-Care Testing

1

http://hwmaint.clinchem.org/cgi/doi/10.1373/clinchem.2012.199596The latest version is at Papers in Press. Published January 17, 2013 as doi:10.1373/clinchem.2012.199596

Copyright (C) 2013 by The American Association for Clinical Chemistry

breaks (14 ), rapid transmission of field results to healthexperts, increased effectiveness in allocating medica-tions to different communities (15 ), immediate treat-ment or quarantine of patients in difficult-to-reach set-tings, and reduction in human-caused error in datatranscription for health records. Previously, we showedhow a low-cost microfluidics test, with no external in-strumentation other than a syringe, could perform aheterogeneous immunoassay similar to an ELISA inresource-limited settings (16 ). A limitation for thisprevious setup was that a trained user was needed torun the test, interpret the signal, and record the results.Until now, it has remained unclear if an automatedmobile device could be built that could run a sophisti-cated laboratory assay and be inexpensive and robustenough to achieve an impact in resource-limited set-tings. We aimed to show that all the essential functionsof ELISA, the gold standard for detecting many proteinbiomarkers, could be engineered into a compact devicethat required no previous laboratory training of theuser, similar to a glucose meter, and that consumed aslittle power as a mobile phone. This mobile device wasdesigned to wirelessly synchronize with a central elec-tronic server to transmit blood test results collected insettings with or without access to cell-phone towers, byusing data formats compatible with standard electronichealth record keeping.

We sought to use the device for HIV testing invulnerable populations located in settings without ac-cess to diagnostic services. We focused on a mobiledevice for HIV-antibody detection, among other pos-sible markers for initial testing, for 3 reasons. First, HIVantibody is a widely accepted marker in resource-limited settings, with well-defined clinical manage-ment algorithms depending upon the diagnostic result(17, 18 ). Second, current rapid tests have substantialroom for improvement in performance, e.g., the ability todetect weak-positive results (19, 20), objectivity of use byeliminating subjective user interpretation of band inten-sities (21), and easy linkage to patient records. Third,adoption of a mobile device that performs an HIV immu-noassay, a test already familiar to field workers, could pro-mote adoption of other “lab-on-a-chip” tests in the futurefor other disease markers.

Materials and Methods

OVERALL DESIGN AND DEVICE ENGINEERING

We designed a handheld device, which we call the mo-bile microfluidic chip for immunoassay on proteinmarkers (mChip) device, that captures the essentialfunctions of ELISA as performed by pipetting robots,microplate readers, desktop computers, and commu-nication hardware, all without the need for grid-basedpower and at sufficiently low cost and energy con-

sumption to be suitable for resource-limited settings(Fig. 1). The device includes components for liquidhandling, signal detection, and remote data communi-cation, which are powered by a single 9-volt battery(Fig. 1, A and B) and controlled by an 8-bit microcon-troller and a custom-designed circuit (see the Supple-mental Data that accompanies the online version ofthis article at http://www.clinchem.org/content/vol59/issue4/). For data communication with a remoteserver, we incorporated 2 wireless technologies: a sat-ellite transceiver for global coverage and a Global Sys-tem for Mobile Communications (GSM)/GeneralPacket Radio Service (GPRS) transceiver for local cell-phone towers. The choice and design of materials, formfactor, and user interface (i.e., a single-button casingwith results displayed on a liquid crystal display) werebased on surveys of clinical and laboratory workers inRwanda, as conducted with an industrial design part-ner (Fig. 2A; see also the online Supplemental Data).

POWER CONSUMPTION AND CONTROL OVER FLOW RATE

Automation of a handheld device that is simple tocharge and use (like a mobile phone) could be a majorstep toward usability and rapid adoption of medicaldevices in resource-limited settings. To estimate powerconsumption, we measured the current drawn fromthe device during an HIV immunoassay on wholeblood (Fig. 2B; also see the online Supplemental Data).The single component that consumed the most powerwas the diaphragm pump. To drastically minimize thepower consumption of the device, we designed a vac-uum chamber that was connected to the pump and atunable vacuum regulator; this setup conserved energyby minimizing the time the pump was turned on. Themean power consumption per test, including wirelessdata transmission, was 0.62 W, comparable to a meanpower consumption of 0.75 W for a mobile phone andmuch less than the 20 – 60 W required for a laptopcomputer (22 ). All the incubation and washing steps ofa benchtop ELISA were accurately replicated in ourmobile device, as shown by a complete mChip devicerun in only 17 min on a whole-blood sample withknown HIV-positive status (Fig. 2B).

Flow rates in microfluidic systems can affect assayperformance (23 ). In benchtop ELISA, control of in-cubation times, volumes, and mixing is achieved bypipetting robots. In this device, we could adjust thestrength of the vacuum pump in the device to preciselycontrol the flow rate in the microfluidic card from 2.5to 20 �L/min (see the online Supplemental Data).

TRACnet AND MOBILE COMMUNICATION

TRACnet (www.tracnet.rw) is a PEPFAR (President’sEmergency Plan For AIDS Relief)-funded health-monitoring network in Rwanda hosted by the telecom-

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Fig. 1. Overview of the mChip device.

(A), Images of benchtop equipment for an ELISA vs an mChip device, a handheld instrument that performs all essential functionsof an ELISA, namely signal amplification and detection, automated delivery of multiple biochemical reagents, and dataprocessing and communication. The image of the mChip device shown here includes a cassette inside. (B), (Left) Inside viewof the mobile device, with 3 main modules for liquid handling (orange), signal detection (red), and data communication (green).All modules are controlled by an 8-bit microcontroller along with peripheral components packaged onto a printed circuit board(PCB); (right) illustration of the microfluidic cassette, with areas for reagent storage, sample metering, analyte capture anddetection, and waste storage. At the time of assay, a fingerprick of blood is collected in a capillary tube (connecting regionsof reagent storage with biochemical analysis) and drawn through the cassette by vacuum generated by a micropump. Sampleand reagents are eventually collected and stored as waste in a membrane filter. (C), Comparison of features of a benchtop ELISA(a relatively inexpensive semiautomated setup) vs rapid test (a collection of WHO-approved tests) vs mChip device. In the mChipdevice, fluid handling, signal detection, and data communication via satellite and SMS are integrated in a device which takesup less space, consumes less power, costs less, and requires less sample and reagent volume than benchtop ELISA. Additionally,the mChip device cost per test compares with cost per rapid test, but allows an objective interpretation of result and cancommunicate with EMRs. Cost per test for the mChip device is anticipated market price based on sales volumes of millions peryear (similar to rapid HIV tests). LCD, liquid crystal display. 9V, 9-volt; NA, Not applicable.

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Clinical Chemistry 59:4 (2013) 3

munications company Voxiva. It allows healthcareworkers using mobile communication such as interac-tive voice recording to track the health status of over90 000 HIV/AIDS patients at 295 health facilities offer-ing antiretroviral treatment in Rwanda (10 ). To dem-

onstrate the ability to transmit diagnostic results to thisnetwork database without interfering with live data,our device transmitted test results to a separate dem-onstration version of TRACnet (see the online Supple-mental Data).

Fig. 2. Operation of the mChip device.

(A), Step-by-step illustration: (1) user draws �1 �L of whole blood in a capillary tube; (2) user connects the tube into amicrofluidic cassette, and inserts the cassette into device; the tube forms a fluidic connection between the preloaded reagentsand the detection zones; (3) user starts assay with a single button push, and after completing the assay, a liquid crystal display(LCD) displays the test results; (4) LCD displays option to transmit test results via the Iridium satellite network; (5) device sendsan encoded message to a predesignated email address; (6) alternatively, device sends message by GSM/GPRS to a cellularphone. Shown in inset is the message, decoded and translated from short-burst form to meaningful data values (test ID, patientID, and optical density values of the 4 detection zones). (B), Measured drawn current (black) and absorbance in the HIV zone(red) over time, using less than 1 �L of HIV-positive blood sample. In the absorbance trace, high absorbance during sampleincubation resulted from opacity of whole blood, and the absorbance peaks in between washes were due to air gaps betweenplugs of reagents. The current is predominately at the baseline value of 48 mA, with sharp spikes powering diaphragm pumpbefore entry of blood and silver reagents and powering data transmission (here, via satellite network). Small peaks at beginningand end of silver indicate transmittance readings taken by LEDs and photodetectors (not labeled). The device validates thepositive HIV status of the sample, as absorbance at the end of silver enhancement is above the cutoff value of 0.10 for wholeblood assays. 9V, 9-volt; Au-label, gold label.

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Although satellite transmission is traditionallyconsidered expensive, our data transmission requiresonly short data strings; hence, we used the inexpensiveshort-burst data service (24 ) with the Iridium satelliteservice to ensure global data coverage for our device ata similar cost as short message service (SMS) messagesvia a cell-phone network (around 10 cents per test re-sult, depending on the network provider). To mini-mize the size of data to be transmitted, we formatted allthe data, including date/time of test, patient’s informa-tion, and test results, into short binary strings (see theonline Supplemental Data). The data transmission wassecure (see the online Supplemental Data).

DIAGNOSTIC EVALUATIONS ON SERA/PLASMA AND WHOLE

BLOOD

For HIV testing on fingerprick volumes of serum/plasma (Figs. 3 and 5), we used procedures for surfacetreatment and reagent loading in PE tubing as de-scribed previously (16 ). The online Supplemental Datacontains all details on methods of assay preparation,format, operation, data and statistical analyses, and re-jection criteria. For HIV testing using fingerprick vol-umes of whole blood (Fig. 2B and Fig. 4), we preloadedreagents on the cassette instead of in plastic tubes. Foreach run, the intensity of the silver film could be inter-preted by eye as positive or negative, as in current rapidtests for pregnancy or HIV. The absorbance of eachzone was objectively measured by the device (Fig. 3E).Similar to the design of commercial immunoassays, weused a negative reference zone for monitoring nonspe-cific background signals, as well as a positive referencezone for monitoring gold–silver enhancement (by de-tecting gold-labeled secondary antibodies), and insome experiments, a second positive reference zone forensuring sample integrity (by detecting human IgG an-tibodies). For each data set, the signal was determinedby measuring the absorbance of each zone (either on itsown or normalized to the positive reference zone), anda cutoff value was chosen to balance diagnostic sensi-tivity and specificity on the basis of analysis of its ROCcurve (see the online Supplemental Data). Signal-to-cutoff ratios were plotted for each data set. To analyzethe effect of using different cutoff values, we plottedROC curves and calculated the area under the curve foreach experiment. To determine the statistical robust-ness of the diagnostic sensitivity and specificity esti-mates, we calculated 95% CIs (see the online Supple-mental Data). Each test, starting from initial handlingof the sample to the digital display of results or remotereceipt of results, took �20 min.

All work in Rwanda was approved by the Ministryof Health in Rwanda. We tested 167 archived sera/plasma collected from Projet San Francisco and ProjetUbuzima, both of which are nongovernmental organi-

zations located in Kigali, Rwanda, respectively (Fig. 3).Samples from Projet San Francisco were from couplesseeking HIV voluntary counseling and testing, andsamples from Projet Ubuzima were collected fromhigh-risk women (most self-identified as sex workers)participating in a separate HIV incidence study (25 ). Inaddition to HIV serostatus, samples from Projet SanFrancisco were tested for hepatitis B virus (HBV) andHCV, and samples from Projet Ubuzima were testedfor syphilis and herpes simplex virus 2 (HSV-2) (see theonline Supplemental Data). We also tested wholeblood samples validated for HIV at Muhima Hospital,a district-level hospital in Kigali, Rwanda, which doesnot perform ELISAs and relies solely on rapid tests fordiagnosing HIV (Fig. 4). Whole-blood samples werecollected by venipuncture from patients recently pre-senting to the clinic for antenatal care, voluntary coun-seling, and/or HIV/AIDS testing. Over the span of 2weeks, we tested 40 patient samples, of which 26 werepositive and 14 were negative, based on sample avail-ability from patients recently presenting to the clinic(see the online Supplemental Data). In addition, foreach whole-blood sample tested at Muhima, we at-tempted wireless data transmission with both satelliteand SMS.

We also tested 25 plasma samples from a commer-cially available HIV mixed-titer panel (SeracarePRB204) (Fig. 5). For each sample, the supplier pro-vided reference results from ELISA (reported as signal-to-cutoff values) and from 5 commercial rapid tests(reported as positive, negative, or indeterminate). TheAbbott HIV-1/2 ELISA test was chosen as the referenceHIV antibody test because it produced the most accu-rate results, as determined by the supplier’s confirma-tory assays (26 ). We interpreted test results to beweakly positive if they exhibited signal/cutoff valuesbetween 1.0 and 10.0 on an Abbott HIV-1/2 ELISA test(which has a range of 18.0) or between 1.0 and 2.0 onthe mChip device.

Results

Current HIV rapid tests could produce inaccurate re-sults for patients with viral hepatitis infections (27, 28 )or sexually transmitted infections such as syphilis(29, 30 ) and genital herpes (31 ). To explore the perfor-mance of the mChip device on such coinfected sam-ples, we evaluated the HIV accuracy of the mChip de-vice on 167 Rwandan patient samples: 100 plasmasamples from Rwandan patients who were also testedfor HBV and HCV at Projet San Francisco, as well as67 serum samples from patients who were also testedfor syphilis and HSV-2 at Projet Ubuzima (Fig. 3).Despite the high prevalence of viral hepatitis (99positive for HBV and/or HCV) in the sample set

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Clinical Chemistry 59:4 (2013) 5

Fig. 3. Performance of HIV immunoassay on the mChip device on Rwandan sera and plasma samples (n � 167) witha range of clinical statuses for viral hepatitis and sexually transmitted infections.

(A), Schematic of HIV immunoassay on the mChip device and the biochemical reactions occurring after the passing of reagents.Four zones are individually treated with proteins: BSA for internal negative reference, HIV antigen for capturing anti-HIVantibodies (Ab), antigoat antibody for capturing gold (Au)-labeled goat antibodies for internal positive reference, andanti-human IgG antibody for capturing human IgG antibody for second internal positive reference. Sera/plasma samples withknown HIV status are loaded along with washes and Au-labeled antibodies in tubes (see the online Supplemental Data). (B),Table listing number of truly HIV-positive and HIV-negative samples which are positive (pos) or negative (neg) for HBV and HCV,and the number of truly HIV-negative samples which are positive or negative for syphilis and HSV-2. (C), Vertical scatter plotof the mChip device signal-to-cutoff ratios (S/Co) for HIV-positive and HIV-negative samples. (D), ROC curve, with dashed lineas random guess and reported area under curve (AUC). (E), mChip device detection zones, absorbance values (optical densities),and S/Co values for samples with positive, negative, and weak positive HIV serostatuses.

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(Fig. 3B) and the substantial number of sexuallytransmitted infections (31 positive for syphilisand/or HSV-2), the diagnostic sensitivity of themChip device was high (100%, 86.8%–100.0%), aswas the diagnostic specificity (99%, 95.0%–99.8%),with 2 false positives (Fig. 3, C and D). For calculat-ing 95% CIs, we used binomial proportions, a moreexact method than the normal approximation. TheWHO has recommended the normal approximation

for evaluating new diagnostic tests (32) and used them inevaluations of HIV commercial tests with data sets of sim-ilar sample size and performance (18, 33, 34). With theuse of the normal approximation, the CIs for diagnosticsensitivity and specificity in this data set were 98.8%–100.0% and 98.0%–100.0%, respectively. The ability ofthe mChip device to objectively measure absorbance val-ues minimized variability in user interpretation of posi-tive and negative results (Fig. 3E).

Fig. 4. Performance of HIV immunoassay on the mChip device on whole blood samples (n � 40) in Rwanda.

(A), Schematic of HIV immunoassay on the mChip device and the biochemical reactions occurring after passing of reagents. Fourzones are individually treated with proteins, with BSA for negative reference, HIV antigen for capturing anti-HIV antibodies (Ab),and antigoat antibody for positive reference. For each test, 1 �L of whole blood was drawn into a capillary tube and connectedto a cassette preloaded with washes, gold (Au)-labeled antibodies and silver enhancement reagents. (B), Vertical scatter plotsof the mChip device signal-to-cutoff ratios for whole blood samples positive and negative for HIV. (C), ROC curve of resultsshown in (B), with reported area under the curve (AUC). (D), Completed (filled bars) and not completed (open bars) transmissionof HIV results via satellite and SMS. For each sample tested, we attempted data transmission with both modes (see Materialsand Methods for further information). (E), Comparison of data transmission via satellite network vs SMS. Asterisk (*) denotesmean cost per message sent by SMS across different US carriers. (F), HIV results, communicated remotely, are uploaded anddisplayed in the secure, private demonstration version of the TRACnet system (http://www.tracnet.rw) (see the onlineSupplemental Data). These results can also be automatically and instantaneously updated onto a global map upon eachsuccessful data transmission. A red icon (denoted with a “�” sign) and a blue icon (denoted with a “�” sign) representpositive and negative tests, respectively.

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Fig. 5. Performance of HIV immunoassay on the mChip device on a commercial plasma sample panel with low andhigh antibody titers (n � 25).

(A), Signal-to-cutoff values of the mChip device for samples from a HIV mixed-titer panel (Seracare PRB204), which are classifiedas positive (pos), weakly positive (weak pos), or negative (neg) on the basis of signal-to-cutoff values from a leading HIVantibody ELISA (Abbott HIV-1/2). For the mChip device, we considered weak positives to have signal-to-cutoff values between1.0 and 2.0, and for the Abbott HIV-1/2 considered weak positives to have signal-to-cutoff values between 1.0 and 10.0. (B),ROC curve for a mixed-titer panel with a dashed line as a random guess and reported AUC. (C), Table comparing the mChipdevice, Abbott HIV-1/2 ELISA, and rapid tests on samples. Interpretations of HIV status from ELISAs and rapid tests were basedon results supplied by Seracare. Red indicates discrepancy in rapid test result with the Abbott HIV-1/2 ELISA.

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Many technologies work well in a laboratory butnot in resource-limited settings, which exhibit addi-tional complexities not replicated in a research labora-tory, such as local pathogen strain and unexpectedlylimited infrastructures (32 ). When we tested our de-vice in Rwanda on 40 whole-blood samples from pa-tients presenting to Muhima Hospital as part of theirroutine healthcare for HIV testing and monitoring, weobserved that the diagnostic sensitivity and specificity(with 95% CIs) of our point-of-care (POC) device inclassifying the HIV status were 100% (86.8%–100.0%)and 100% (76.8%–100.0%) (98.8%–100.0% and 98.3%–100.0% using normal approximations of CIs), respec-tively (Fig. 4, B and C).

At the end of a test, the mobile device was designedto transmit the test result, encoded into a small datapacket, from any remote setting to a central computerserver. Via satellite, the data were sent to a predesig-nated e-mail address along with the global position co-ordinates of the test; via SMS, a message with the datawas sent to a predesignated phone number. In our trialat Muhima Hospital, the device successfully sent re-sults either through satellite or SMS for all samplestested (Fig. 4D). The device successfully transmitted 38of 40 test results by use of GSM, with the failures pre-sumably due to high traffic in the cell phone network.Also, 33 of 40 test results were successfully sent by sat-ellite, with the failures presumably due to poor weatherconditions resulting in unclear line of sight of the sky.Because the satellite module demanded more powerand relied on fair weather conditions to send messagessuccessfully, we envision the satellite system as abackup in the event of cell-phone network failure. Incontrast to the cell-phone network, the satellite systempotentially allows us to send results from every regionof the world (Fig. 4E), independent of local cell-phonecarrier identity or extent of coverage. The complete testrecord was uploaded and displayed within a secure sec-tion of the TRACnet electronic patient health recordsdatabase (see the online Supplemental Data). Thetime-stamped and geolocation-tagged diagnostic re-sults could be easily displayed on a map in real time(Fig. 4F).

Previous studies have shown that rapid tests oftenfail to correctly identify weakly positive samples (19 )such as those from recent HIV infections, which canconstitute 0.3% to 3% of HIV-infected patients inhigh-risk populations with patients seeking care forbacterial sexually transmitted infections at sexuallytransmitted disease clinics and patients reporting feverin areas of high HIV prevalence (35, 36 ). Furthermore,rapid tests operated in resource-limited settings haveexhibited lower accuracy due in part to the difficulty ininterpreting weak signals (18, 19 ). In quality assuranceevaluations across 4 sub-Saharan African countries im-

plementing rapid HIV test programs, concordance be-tween on-site rapid testing and reference laboratoryretesting (using primarily ELISA and also repeatingrapid tests) among HIV-positive samples was as low as82% (21 ). We tested the mChip device on a commer-cial panel of 25 mixed-titer plasma samples whose ref-erence results had been established at Seracare and atinternationally recognized noncommercial referencelaboratories (Fig. 5). In this panel, none of the com-mercial rapid HIV tests, including 2 rapid tests that arecurrently recommended for HIV screening inresource-limited settings (21 ), achieved 100% accu-racy compared with the Abbott HIV-1/2 (Fig. 5C); pa-tients with such rapid test results would have been clas-sified as “HIV negative” in a screening situationwithout laboratory ELISA or Western blot experi-ments. By contrast, using any reasonable cutoff valuesthat did not compromise the diagnostic specificity ofthe test, as shown by the ROC curves in Fig. 5C, theHIV test results obtained by the mChip device were inagreement with those by the Abbott HIV-1/2, includ-ing accurate detection of weak-positive samples (Fig. 5,A and C). Overall, the data suggest that the HIV im-mmunoassay on the mChip device can detect weaklypositive samples missed by rapid tests currently used inHIV test algorithms for HIV screening in the develop-ing world.

Discussion

HIV rapid tests have greatly extended the accessibilityof HIV testing by allowing for quick results with min-imal equipment and training. Although they performwell in controlled settings, their performance may dif-fer when used on a wide scale in resource-limited set-tings because of lack of trained staff, poor laboratoryinfrastructure, and weak quality assurance programs(21 ). At present, there are at least 3 major limitations tocurrent rapid HIV tests. First, there is decreased accu-racy in resource-limited settings. Evaluations of HIVrapid tests in resource-limited settings show decreasedaccuracy (19, 21 ), partly because of the difficulty ininterpreting weak signals (19 ). In the US, POC tests forglucose (e.g., Bayer Contour glucose meter) and preg-nancy (e.g., Clearblue DIGITAL pregnancy test) havemoved toward a digital reading for the user without theneed for subjective interpretation (37 ). The lack of anobjective result has led to greater variability betweenon-site and reference test results, a great concern ofquality assurance programs in developing countries,with concordance as low as 82% for HIV-positive sam-ples (21 ). The second limitation is a reduced diagnosticsensitivity in whole-blood samples and low-titer sam-ples. Whereas current HIV rapid tests are capable oftesting various sample matrices, diagnostic sensitivity

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is lower in samples with low antibody titers (whichcould be due to recent seroconversion, autoimmunedisorders, or immunodeficiency) and on finger-stickwhole blood (20 ). The third limitation is the potentialincrease in errors in patient record keeping when per-formed in resource-limited settings. The lack of auto-mated data transcription and connectivity betweenPOC tests and patient health record systems introduceserrors from patient identification; sample labeling andcollection; and result recording, retrieval, and format-ting (38 ). In comparison, our mobile device exhibitsthe high diagnostic sensitivity desired in front-linescreening of patients, including detection of weaklypositive samples missed by currently recommendedHIV rapid tests (Fig. 5), with very few false positives(Figs. 3–5). The 1-touch ease of use and display of anunambiguous result, independent of user interpreta-tion of band intensities, could counteract the observedlower accuracy of rapid tests when practiced inresource-limited settings. The automated wireless syn-chronization of test results with patient records in thecloud could liberate ELISA-like tests to be performedin truly remote settings with accurate and automatedupkeep of centralized patient records (Fig. 4).

This device establishes a proof of concept for howengineering innovations can improve POC healthcaredelivery. This study demonstrates how an immunoas-say that performs all essential functions of ELISA(chiefly, signal amplification and detection, automateddelivery of multiple biochemical reagents, and dataprocessing and communication) can be engineered in acompact mobile device. This goal has been difficult toachieve because of the challenge of integrating individ-ual lab-on-a-chip components into a single functionaldevice (39, 40 ). Often, components are incompatiblewith each other; even if integrated, they are not fielddeployable because of high cost, difficulty of use, orexcessive instrumentation (41 ). The cost of our deviceis under $1000, compared to over $19 000 for thebenchtop equipment needed for conventional ELISAtests in a semiautomated setup (Fig. 1C) (fully auto-mated ELISA setups are even bulkier and more expen-sive). We note that most of this cost is due to satelliteand GSM/GPRS modems (combined cost of $748),which we expect to decrease significantly in time.Moreover, our device, like a cell phone, is inexpensive,easy to use, compact, and easily recharged; the powerconsumption of our device is similar to that of cellphones (see the online Supplemental Data). Hence,this study demonstrates that a low-cost mobile devicecan be used for automated, accurate heterogeneous im-munoassays on blood samples in resource-constrainedregions. Finally, the cost-effectiveness of our microflu-idics test, measured by the cost incurred for everydisability-adjusted life year saved, is projected to be

comparable to vaccinations and oral rehydration ther-apy (16 ).

This study also addresses the rapidly emergingarea of “mobile health” (12 ) via an integrated techno-logical approach. For example, recent studies havedemonstrated how cell phones can improve patientand public health (42– 45 ), but typically use only off-the-shelf technologies with limited technical features(primarily text messaging). It is likely that mobilehealth devices with increased functionalities can de-liver a highly expanded range of healthcare servicesright to patients, no matter how remote their location.Access to high-quality laboratory testing is one of thefirst critical healthcare services needed at the POC inexamining each patient. Currently, few handheld POCdiagnostics devices have been described, with nonehaving been demonstrated in a compact mobile deviceor to work with the latest wireless communicationtechnologies. Such a process could also free on-siteworkers from data entry, reduce the number of errorsfrom manual intervention, and if desired, patient pri-vacy concerns can be addressed by entry of the resultsinto the patient records directly without displaying theresults to the health worker. In addition to GSM/GPRS,the device offers a flexible option in access to patientdata stored in the cloud via orbiting satellites (Fig. 4, Dand E), which offers potential advantages in coverage,scalability, location tracking, cost, and portability (seethe online Supplemental Data).

Rather than modifying existing technologies, tech-nologies that bypass a generation of traditional devicescould potentially dramatically improve the health ofpeople in low-resource settings. For example, the engi-neering of cell phones has enabled remote voice com-munication at a low cost, with the number of users insub-Saharan Africa rapidly surpassing those using tra-ditional fixed-line communication (46 ). Althoughthere has been interest in a handheld and mobile-connected rapid blood test, it has been unclear whethersuch a device can be built to match the performance ofELISA, let alone at sufficiently low cost to make animpact in low-resource settings. This proof-of-conceptstudy establishes the feasibility of this concept by dem-onstrating that all essential functions of benchtopELISA, as well as synchronization of patient recorddata, can be combined into a handheld mobile devicethat can be operated in a hands-free manner. Such alow-cost mobile device could improve epidemiologicalsurveillance as well as patient care by increasing accu-racy to match that of ELISA (for HIV and other bio-markers) and by enabling automatic upkeep and track-ing of test results. Before such an impact can be made,additional work would have to be performed, includ-ing an expanded evaluation by untrained users, an ex-panded evaluation of the device’s performance with

10 Clinical Chemistry 59:4 (2013)

early-seroconversion samples (for example, by using acombined antigen/antibody immunoassay as found inrecent generations of HIV ELISAs) (34 ), and integra-tion with live electronic patient records.

Author Contributions: All authors confirmed they have contributed tothe intellectual content of this paper and have met the following 3 re-quirements: (a) significant contributions to the conception and design,acquisition of data, or analysis and interpretation of data; (b) draftingor revising the article for intellectual content; and (c) final approval ofthe published article.

Authors’ Disclosures or Potential Conflicts of Interest: Upon man-uscript submission, all authors completed the author disclosure form.Disclosures and/or potential conflicts of interest:

Employment or Leadership: A.A. Sridhara, Columbia University; D.Steinmiller, OPKO Diagnostics; V. Linder, OPKO Diagnostics.Consultant or Advisory Role: S.K. Sia, Claros Diagnostics, Inc.Stock Ownership: D. Steinmiller, OPKO Health, Inc.; V. Linder,OPKO Health, Inc.Honoraria: None declared.Research Funding: Columbia University, Coulter Foundation andNIH to Columbia University, Wallace H. Coulter Foundation PhaseI and Phase II Early Career Awards, NIH (5R41NR10753), and Sav-

ing Lives at Birth transition grant (United States Agency for Interna-tional Development, Gates Foundation, Government of Norway,Grand Challenges Canada, and the World Bank); C.D. Chin, FrankH. Buck Scholarship.Expert Testimony: None declared.Patents: D. Steinmiller, patent number: 8,202,492.

Role of Sponsor: The funding organizations played no role in thedesign of study, choice of enrolled patients, review and interpretationof data, or preparation or approval of manuscript.

Acknowledgments: We thank Dr. Agnes Binagwaho, Dr. Anita Asi-imwe, Rwandan Ministry of Health, and Dr. Julius Kamwesiga forfacilitatiing access to clinical samples and for approval of study pro-tocols in Rwanda; Chantal Mutezemariya for providing clinical sam-ples and reference test results (Muhima Hospital); EmmanuelManzi, Eliachim Ishimwe, Carlos Rafael, Kayumba Kizito, and Er-nesto Gozzer for access to the TRACnet demonstration site (Voxiva);Veronicah Mugisha, David Hoos, and ICAP-Rwanda for facilitatingstudies in Rwanda; John Kymissis and members of the Sia Laboratory(Columbia University) for helpful discussions; Eric Freitag, MikeSchumann, and Jonathan Cedar for help with prototyping and in-dustrial design of the device (Smart Design); Deborah Johnson andSamuel Cochran for help with industrial design and consultationswith Rwandan end users (Pratt Incubator); Enqing Tan for help inassay development and Jason Taylor for help with instrumentation(Claros Diagnostics); Sue Wong (Da-Yeh University), Shing Lee, andJimmy Duong (Columbia University) for advising on biostatistics.

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