Point-of-care diagnostics with digital microscopy and artificial intelligence

The lack of access to diagnostics is a global problem which causes underdiagnosis of various common and treatable diseases. In certain areas, the access to laboratory services and medical experts is extremely limited, such as in sub-Saharan Africa, with often less than one practising pathologist per one million inhabitants. Annually, hundreds of millions of microscopy samples are analysed to diagnose e.g. infectious diseases and cancers, but the need for more is significant. During the last decade, technological advancements and reduced prices of optical components have enabled the construction of inexpensive, portable devices for digitization of microscopy samples; a procedure traditionally limited to well-equipped laboratories with expensive high-end equipment. By allowing digitization of samples directly at the point of care (POC), advanced digital diagnostic techniques, such as the analysis of samples with medical ‘artificial intelligence’ (AI) algorithms, can be utilized also outside high-end laboratories – which is precisely where the need for improved diagnostics is often most significant. The aim of this thesis is to study how low-cost, POC digital microscopy, supported by automatized digital image analysis and AI can be applied for routine microscopy diagnostics with an emphasis on potential areas of application in low-resource settings. We describe, implement and evaluate various techniques for POC digitization and analysis of samples using both visual methods and digital algorithms. Specifically, we evaluate the technologies for the analysis of breast cancer tissue samples (assessment of hormone receptor expression), intraoperative samples from cancer surgeries (detection of metastases in lymph node frozen sections), cytological samples (digital Pap smear screening) and parasitological samples (diagnostics of neglected tropical diseases). Our results show how the digitization of a variety of routine microscopy samples is feasible using systems suitable POC usage with sufficient image quality for diagnostic applications. Furthermore, the findings demonstrate how digital methods, based on computer vision and AI, can be utilized to facilitate the sample analysis process to e.g. quantify tissue stains and detect atypical cells and infectious pathogens in the samples with levels of accuracy comparable to conventional methods. In conclusion, our findings show how technological advancements can be leveraged to create general-purpose digital microscopy diagnostic platforms, which are implementable and feasible to use for diagnostic purposes at the POC. This allows the utilization of modern digital algorithms and AI to aid in analysis of samples and facilitate the diagnostic process by automatically extracting information from the digital samples. These findings are important steps in the effort to develop novel diagnostic technologies which are usable also in areas without access to high-end laboratories, and the technologies described here are also likely to be applicable for diagnostics of other diseases which are currently diagnosed with light microscopy.Bristande åtkomst till medicinsk diagnostik är ett signifikant globalt problem som resulterar i att många vanliga, behandlingsbara sjukdomar förblir underdiagnostiserade. I vissa områden är tillgängligheten av laboratorietjänster och medicinisk personal kraftigt begränsad, liksom exempelvis i subsahariska Afrika där det totala antalet patologer ofta är lägre än en per miljoner invånare. Under det senaste decenniet har den tekniska utvecklingen möjliggjort utvecklingen av portabla, förmånliga instrument för att digitalisera biologiska prov även i fältmiljö; något som traditionellt begränsats till högklassiga laboratorier på grund av kravet på avancerad och dyr teknik. Genom att möjliggöra patientnära (’point of care’) digitalisering av prov kan avancerade digitala metoder, som provanalys med ’artificiell intelligens’, tillämpas även i fältmiljö – dvs. där behovet av förbättrad diagnostik är störst. Målet med avhandlingen är att undersöka hur förmånlig, patientnära digitalmikroskopi, kombinerat med digital bildanalys och artificiell intelligens, kan tillämpas för att effektivera rutinmässig mikroskopidiagnostik med tyngdpunkt på eventuella användningsområden i lågresursmiljöer. I arbetet beskriver, implementerar och utvärderar vi olika metoder för patientnära digitalisering av mikroskopiprov och analys av proven både visuellt och med automatiserade, digitala metoder. Arbetet är uppdelat i olika områden som undersöker teknologin för olika användningsområden. Dessa är: 1) onkologisk vävnadspatologi (bestämning av hormonreceptorstatus), 2) analys av intraoperativa vävnadsprov (fryssnitt för detektion av metastaser), 3) analys av cytologiska cellprov (Papa-prov) samt 4) diagnostik av de vanligaste tropiska parasitsjukdomarna (’neglected tropical diseases’). Resultaten visar hur digitaliseringen av mikroskopiprov är möjlig med miniatyriserade digitalmikroskop som lämpar sig för användning i fältmiljö, med en tillräcklig bildkvalitet för medicinsk diagnostik. Utöver detta kan provanalysen effektiveras med hjälp av automatiserad digital bildanalys, för att ex. mäta nivåer av vävnadsfärger samt identifiera premaligna cellförändringar samt parasiter i proven. Sammanfattningsvis tyder resultaten på att metoderna här är lämpliga för patientnära mikroskopidiagnostik av ett flertal olika sjukdomar. Genom att tillämpa moderna digitala bildanalysmetoder kan provanalysen automatiseras och effektiveras. Resultaten är betydande steg i utvecklingen av digitaldiagnostiska metoder som är användbara även i områden utan tillgång till högklassig laboratorieinfrastruktur. Utöver detta är metoderna beskrivna här sannolikt även möjliga att tillämpa för diagnostik av ett flertal övriga sjukdomar vars diagnostik för tillfället baserar sig på ljusmikroskopi

Patientnära diagnostik med digital mikroskopi och artificiell intelligens

Väittelijä Oscar Holmström : Helsingin yliopisto, 2020

Detection of breast cancer lymph node metastases in frozen sections with a point-of care low-cost microscope scanner

Background Detection of lymph node metastases is essential in breast cancer diagnostics and staging, affecting treatment and prognosis. lntraoperative microscopy analysis of sentinel lymph node frozen sections is standard for detection of axillary metastases but requires access to a pathologist for sample analysis. Remote analysis of digitized samples is an alternative solution but is limited by the requirement for high-end slide scanning equipment. Objective To determine whether the image quality achievable with a low-cost, miniature digital microscope scanner is sufficient for detection of metastases in breast cancer lymph node frozen sections. Methods Lymph node frozen sections from 79 breast cancer patients were digitized using a prototype miniature microscope scanner and a high-end slide scanner. Images were independently reviewed by two pathologists and results compared between devices with conventional light microscopy analysis as ground truth. Results Detection of metastases in the images acquired with the miniature scanner yielded an overall sensitivity of 91% and specificity of 99% and showed strong agreement when compared to light microscopy (k = 0.91). Strong agreement was also observed when results were compared to results from the high-end slide scanner (k = 0.94). A majority of discrepant cases were micrometastases and sections of which no anticytokeratin staining was available. Conclusion Accuracy of detection of metastatic cells in breast cancer sentinel lymph node frozen sections by visual analysis of samples digitized using low-cost, point-of-care microscopy is comparable to analysis of digital samples scanned using a high-end, whole slide scanner. This technique could potentially provide a workflow for digital diagnostics in resource-limited settings, facilitate sample analysis at the point-of-care and reduce the need for trained experts on-site during surgical procedures.Peer reviewe

Quantification of Estrogen Receptor-Alpha Expression in Human Breast Carcinomas With a Miniaturized, Low-Cost Digital Microscope : A Comparison with a High-End Whole Slide- Scanner

Introduction: A significant barrier to medical diagnostics in low-resource environments is the lack of medical care and equipment. Here we present a low-cost, cloud-connected digital microscope for applications at the point-of-care. We evaluate the performance of the device in the digital assessment of estrogen receptor-alpha (ER) expression in breast cancer samples. Studies suggest computer-assisted analysis of tumor samples digitized with whole slide-scanners may be comparable to manual scoring, here we study whether similar results can be obtained with the device presented. Materials and methods: A total of 170 samples of human breast carcinoma, immunostained for ER expression, were digitized with a high-end slide-scanner and the point-of-care microscope. Corresponding regions from the samples were extracted, and ER status was determined visually and digitally. Samples were classified as ER negative (<1% ER positivity) or positive, and further into weakly (1-10% positivity) and strongly positive. Interobserver agreement (Cohen's kappa) was measured and correlation coefficients (Pearson's product-momentum) were calculated for comparison of the methods. Results: Correlation and interobserver agreement (r = 0.98, p < 0.001, kappa = 0.84, CI95% = 0.75-0.94) were strong in the results from both devices. Concordance of the point-of-care microscope and the manual scoring was good (r = 0.94, p < 0.001, kappa = 0.71, CI95% = 0.61-0.80), and comparable to the concordance between the slide scanner and manual scoring (r = 0.93, p < 0.001, kappa = 0.69, CI95% = 0.60-0.78). Fourteen (8%) discrepant cases between manual and device-based scoring were present with the slide scanner, and 16 (9%) with the point-of-care microscope, all representing samples of low ER expression. Conclusions: Tumor ER status can be accurately quantified with a low-cost imaging device and digital image-analysis, with results comparable to conventional computer-assisted or manual scoring. This technology could potentially be expanded for other histopathological applications at the point-of-care

A novel deep learning-based point-of-care diagnostic method for detecting Plasmodium falciparum with fluorescence digital microscopy

Background Malaria remains a major global health problem with a need for improved field-usable diagnostic tests. We have developed a portable, low-cost digital microscope scanner, capable of both brightfield and fluorescence imaging. Here, we used the instrument to digitize blood smears, and applied deep learning (DL) algorithms to detect Plasmodium falciparum parasites. Methods Thin blood smears (n = 125) were collected from patients with microscopy-confirmed P. falciparum infections in rural Tanzania, prior to and after initiation of artemisinin-based combination therapy. The samples were stained using the 4′,6-diamidino-2-phenylindole fluorogen and digitized using the prototype microscope scanner. Two DL algorithms were trained to detect malaria parasites in the samples, and results compared to the visual assessment of both the digitized samples, and the Giemsa-stained thick smears. Results Detection of P. falciparum parasites in the digitized thin blood smears was possible both by visual assessment and by DL-based analysis with a strong correlation in results (r = 0.99, p <0.01). A moderately strong correlation was observed between the DL-based thin smear analysis and the visual thick smear-analysis (r = 0.74, p <0.01). Low levels of parasites were detected by DL-based analysis on day three following treatment initiation, but a small number of fluorescent signals were detected also in microscopy-negative samples. Conclusion Quantification of P. falciparum parasites in DAPI-stained thin smears is feasible using DL-supported, point-of-care digital microscopy, with a high correlation to visual assessment of samples. Fluorescent signals from artefacts in samples with low infection levels represented the main challenge for the digital analysis, thus highlighting the importance of minimizing sample contaminations. The proposed method could support malaria diagnostics and monitoring of treatment response through automated quantification of parasitaemia and is likely to be applicable also for diagnostics of other Plasmodium species and other infectious diseases.Peer reviewe

Servitization, digitization and supply chain interdependency

This study draws on literature at the intersection of servitization, digital business models and supply chain management. Work empirically explores how digital disruption has affected Business-to-Business (B2B) interdependencies. Dematerialization of physical products is transforming the way firms are positioned in the supply chain due to a reduction in production and transport costs and the different ways business engage with customers. Specifically, we propose that these new market conditions can empower downstream firms. We further propose that upstream firms can still capture additional value through digital service if their servitized offer includes difficult to imitate elements. The context of the analysis is the publishing industry. The Payment Card method employed is used to test UK and US consumer’s perceptions of digital formats (eBooks) and assess their willingness to pay in relation to printed formats. The method undertaken enables us to elicit aggregated consumer demand for eBooks which in turn identifies optimal pricing strategies for the digital services. Analysis demonstrates that during digital servitization upstream firms should seek to deploy unique resources to ensure their strategic position in the supply chain is not diminished

Point-of-Care Digital Cytology With Artificial Intelligence for Cervical Cancer Screening in a Resource-Limited Setting

Cervical cancer is highly preventable but remains a common and deadly cancer in areas without screening programs. The creation of a diagnostic system to digitize Papanicolaou test samples and analyze them using a cloud-based deep learning system (DLS) may provide needed cervical cancer screening to resource-limited areas.To determine whether artificial intelligence–supported digital microscopy diagnostics can be implemented in a resource-limited setting and used for analysis of Papanicolaou tests.In this diagnostic study, cervical smears from 740 HIV-positive women aged between 18 and 64 years were collected between September 1, 2018, and September 30, 2019. The smears were digitized with a portable slide scanner, uploaded to a cloud server using mobile networks, and used to train and validate a DLS for the detection of atypical cervical cells. This single-center study was conducted at a local health care center in rural Kenya.Detection of squamous cell atypia in the digital samples by analysis with the DLS.The accuracy of the DLS in the detection of low- and high-grade squamous intraepithelial lesions in Papanicolaou test whole-slide images.Papanicolaou test results from 740 HIV-positive women (mean [SD] age, 41.8 [10.3] years) were collected. The DLS was trained using 350 whole-slide images and validated on 361 whole-slide images (average size, 100 387 × 47 560 pixels). For detection of cervical cellular atypia, sensitivities were 95.7\95\ 85.5\99.5\ and 100\95\ 82.4\100\, and specificities were 84.7\95\ 80.2\88.5\ and 78.4\95\ 73.6\82.4\, compared with the pathologist assessment of digital and physical slides, respectively. Areas under the receiver operating characteristic curve were 0.94 and 0.96, respectively. Negative predictive values were high (99\100\, and accuracy was high, particularly for the detection of high-grade lesions. Interrater agreement was substantial compared with the pathologist assessment of digital slides (κ = 0.72) and fair compared with the assessment of glass slides (κ = 0.36). No samples that were classified as high grade by manual sample analysis had false-negative assessments by the DLS.In this study, digital microscopy with artificial intelligence was implemented at a rural clinic and used to detect atypical cervical smears with a high sensitivity compared with visual sample analysis.Peer reviewe

Microplastics Shedding from Textiles—Developing Analytical Method for Measurement of Shed Material Representing Release during Domestic Washing

The topic of shedding of micro-sized polymeric particles, so called microplastics, from textiles has been covered by an increasing number of studies over the past years. However, the methods with which the shedding of microplastics from textiles has been measured so far has shown a large variation. Consequently, the results regarding the amount of shed particles also vary, from 120 to 728,289 particles from similar garments in recent studies. This article presents research enabling for identification of whether the shedding of microplastics from different types of fabric was dependent on construction parameters. As none of the methods in the existing literature could be used for evaluating shedding of microplastics from textiles, a method was developed for this purpose. The resulting final method is described in this paper as well as the work with minimizing the error sources and consequently the standard deviation of the results through selection of material samples, equipment and procedure for sample preparation, washing, filtering the washing water and analyzing the shed microplastics. Comparing the environmental load of different garments, or identifying improvement possibilities in garment construction are two examples of how the method can be utilized

KomUt : Development of a carpooling platform for employees

In our society there is an increased awareness of environmental impact and reducing greenhouse gas emissions. An influencing factor is transport in passenger cars to and from work. In order to increase the utilization rate of passenger cars and thereby reduce environmental impact, a possible solution is to carpool. The purpose of the project was to create a web application to help those who want to carpool. To be effective and interesting to users such a web application needs to be useful and easy to navigate, as supported in previous surveys. The report’s issue is therefore how a carpooling web application, for companies and their employees, is designed and implemented to make it useful with regard to navigability. The attempt to answer the issue was initiated by finding relevant theory of navigabil- ity and usability. After that a market survey was conducted, to better understand the needs of the target group, and a prototype was developed based on the found theory. User stories were developed to define the application’s functionality and the development of the web application took place in parallel with iterative user tests, where feedback from the tests was implemented. At the end of the project, the final result and each user test were analyzed to compare users’ response to current theory and by answering the issue of the report. Based on the results of the tests, given the theoretical framework, it was shown that two out of four test subjects got lost in the web application. The test subjects were struggling to get through the buying process. They had insufficient understanding of what happens when placing a trip in the cart, that the trips are booked inside the shopping cart and that the payment of completed trips are found on the profile page. Reasons for the result may be due to both the weaknesses of the web application navigability or the characteristics of the test subjects. Despite this the web application was considered useful in accordance with the System Usability Test performed. In its entirety, the web application can be assessed as useful, though it can not be considered to meet the theoretical requirements for navigability. The conclusion is that a navigable web application can be developed by allowing users to effectively find the most important features of the web application. This can be imple- mented with a distinct navigation bar, visual indications for links, information boxes, a natural flow for the user through the page structure, and that the user can get through it with few steps. This should be specifically applied to the buying process, which is central to a consumer web application, to reduce perceived complexity and to be useful and navigable to the user. In order for the web application to be perceived as useful, it should contain the basic functionality requirements expected of a carpooling service. These are being able to register oneself, find a trip, create a trip, find information about pricing and to be able to remove a trip.I samhället finns det en ökad medvetenhet kring miljöpåverkan och att minska utsläpp av växthusgaser. En påverkande faktor är transport i personbil till och från arbetet. För att öka nyttjandegraden av personbilar och därmed minska miljöpåverkan är en lösning att samåka. Syftet med projektet var att skapa en webbapplikation för att hjälpa de som vill samåka. För att vara effektiv och intressant för användarna behövde en sådan web- bapplikation vara användbar och lätt att navigera i, vilket stöds i tidigare undersökningar. Därför är rapportens frågeställning hur en webbapplikation för samåkning, för företag och dess anställda, designas och implementeras så att den är användbar med avseende på navigerbarhet. Besvarandet av frågeställningen inleddes med att relevant teori om navigerbarhet och användbarhet togs fram. Efter det gjordes en marknadsundersökning, för att tydliga- re förstå målgruppens behov, och en prototyp skapades utifrån den framtagna teorin. User stories användes för att definiera applikationens funktionalitet och utvecklingen av webbapplikationen skedde parallellt med iterativa användartester, där feedbacken från testerna implementerades. I slutet av projektet analyserades slutresultatet och varje enskilt användartest för att jämföra användarnas respons mot rådande teori, och genom det besvara arbetets fråge- ställning. Utifrån resultatet av testerna, sett till de teoretiska ramarna, visades det att två av fyra testpersoner var vilsna på webbapplikationen. Testpersonerna hade svårigheter att ta sig igenom köpprocessen. De hade bristande förståelse för vad som händer när man placerar resor i varukorg, att resorna bokas i varukorgen och att betalning av genomförda resor skedde på profilsidan. Anledningar till resultatet kan såväl bero på brister i web- bapplikationens navigerbarhet eller egenskaper hos testpersonerna. Trots detta ansågs webbapplikationen användbar i enlighet med de System Usability Test som utfördes. I sin helhet kan webbapplikationen därmed bedömas som användbar, däremot den kan inte anses uppfylla de teoretiska kraven för navigerbarhet. Slutsatsen dras att en navigerbar webbapplikation kan utvecklas genom att användar- na effektivt ska kunna hitta webbapplikationens mest väsentliga funktioner. Detta kan implementeras med en tydlig navigationsbar, visuella indikationer för länkar, informa- tionsrutor, ett naturligt flöde för användaren genom sidstrukturen och att användaren kan ta sig igenom den med få steg. Detta bör specifikt tillämpas i köpprocessen, som är central i en webbapplikation för konsumenter, för att minska upplevd komplexitet och att den är användbar och navigerbar för användaren. För att webbapplikationen ska upplevas som användbar bör den innehålla de grundläggande funktionalitetskraven som ställs på en samåkningstjänst. Dessa är att kunna registrera sig, hitta en resa, skapa en resa, hitta information kring prissättning och att kunna ta bort en resa

KomUt : Development of a carpooling platform for employees

In our society there is an increased awareness of environmental impact and reducing greenhouse gas emissions. An influencing factor is transport in passenger cars to and from work. In order to increase the utilization rate of passenger cars and thereby reduce environmental impact, a possible solution is to carpool. The purpose of the project was to create a web application to help those who want to carpool. To be effective and interesting to users such a web application needs to be useful and easy to navigate, as supported in previous surveys. The report’s issue is therefore how a carpooling web application, for companies and their employees, is designed and implemented to make it useful with regard to navigability. The attempt to answer the issue was initiated by finding relevant theory of navigabil- ity and usability. After that a market survey was conducted, to better understand the needs of the target group, and a prototype was developed based on the found theory. User stories were developed to define the application’s functionality and the development of the web application took place in parallel with iterative user tests, where feedback from the tests was implemented. At the end of the project, the final result and each user test were analyzed to compare users’ response to current theory and by answering the issue of the report. Based on the results of the tests, given the theoretical framework, it was shown that two out of four test subjects got lost in the web application. The test subjects were struggling to get through the buying process. They had insufficient understanding of what happens when placing a trip in the cart, that the trips are booked inside the shopping cart and that the payment of completed trips are found on the profile page. Reasons for the result may be due to both the weaknesses of the web application navigability or the characteristics of the test subjects. Despite this the web application was considered useful in accordance with the System Usability Test performed. In its entirety, the web application can be assessed as useful, though it can not be considered to meet the theoretical requirements for navigability. The conclusion is that a navigable web application can be developed by allowing users to effectively find the most important features of the web application. This can be imple- mented with a distinct navigation bar, visual indications for links, information boxes, a natural flow for the user through the page structure, and that the user can get through it with few steps. This should be specifically applied to the buying process, which is central to a consumer web application, to reduce perceived complexity and to be useful and navigable to the user. In order for the web application to be perceived as useful, it should contain the basic functionality requirements expected of a carpooling service. These are being able to register oneself, find a trip, create a trip, find information about pricing and to be able to remove a trip.I samhället finns det en ökad medvetenhet kring miljöpåverkan och att minska utsläpp av växthusgaser. En påverkande faktor är transport i personbil till och från arbetet. För att öka nyttjandegraden av personbilar och därmed minska miljöpåverkan är en lösning att samåka. Syftet med projektet var att skapa en webbapplikation för att hjälpa de som vill samåka. För att vara effektiv och intressant för användarna behövde en sådan web- bapplikation vara användbar och lätt att navigera i, vilket stöds i tidigare undersökningar. Därför är rapportens frågeställning hur en webbapplikation för samåkning, för företag och dess anställda, designas och implementeras så att den är användbar med avseende på navigerbarhet. Besvarandet av frågeställningen inleddes med att relevant teori om navigerbarhet och användbarhet togs fram. Efter det gjordes en marknadsundersökning, för att tydliga- re förstå målgruppens behov, och en prototyp skapades utifrån den framtagna teorin. User stories användes för att definiera applikationens funktionalitet och utvecklingen av webbapplikationen skedde parallellt med iterativa användartester, där feedbacken från testerna implementerades. I slutet av projektet analyserades slutresultatet och varje enskilt användartest för att jämföra användarnas respons mot rådande teori, och genom det besvara arbetets fråge- ställning. Utifrån resultatet av testerna, sett till de teoretiska ramarna, visades det att två av fyra testpersoner var vilsna på webbapplikationen. Testpersonerna hade svårigheter att ta sig igenom köpprocessen. De hade bristande förståelse för vad som händer när man placerar resor i varukorg, att resorna bokas i varukorgen och att betalning av genomförda resor skedde på profilsidan. Anledningar till resultatet kan såväl bero på brister i web- bapplikationens navigerbarhet eller egenskaper hos testpersonerna. Trots detta ansågs webbapplikationen användbar i enlighet med de System Usability Test som utfördes. I sin helhet kan webbapplikationen därmed bedömas som användbar, däremot den kan inte anses uppfylla de teoretiska kraven för navigerbarhet. Slutsatsen dras att en navigerbar webbapplikation kan utvecklas genom att användar- na effektivt ska kunna hitta webbapplikationens mest väsentliga funktioner. Detta kan implementeras med en tydlig navigationsbar, visuella indikationer för länkar, informa- tionsrutor, ett naturligt flöde för användaren genom sidstrukturen och att användaren kan ta sig igenom den med få steg. Detta bör specifikt tillämpas i köpprocessen, som är central i en webbapplikation för konsumenter, för att minska upplevd komplexitet och att den är användbar och navigerbar för användaren. För att webbapplikationen ska upplevas som användbar bör den innehålla de grundläggande funktionalitetskraven som ställs på en samåkningstjänst. Dessa är att kunna registrera sig, hitta en resa, skapa en resa, hitta information kring prissättning och att kunna ta bort en resa