Prediction and Monitoring of Progression of Alzheimer’s Disease : Multivariable approaches for decision support

Alzheimerin tauti, yksi yleisimmistä muistisairauksista, on hitaasti etenevä aivoja rappeuttava tauti, jolle ei ole vielä parantavaa hoitoa. Tietyt lääkkeet ja elämäntapainterventiot voivat kuitenkin hidastaa taudin etenemistä ja lievittää sen oireita, mikä parantaa potilaiden elämänlaatua ja terveydenhuollon kustannusvaikuttavuutta. Alzheimerin taudin varhainen diagnostiikka on erittäin tärkeää, koska erilaiset interventiot pitäisi aloittaa jo taudin varhaisessa vaiheessa, jotta niillä saataisiin aikaan paras mahdollinen vaikutus. Taudin varhainen diagnostiikka on kuitenkin haastavaa, koska muutokset aivoissa alkavat vuosia tai vuosikymmeniä ennen ensimmäisten oireiden ilmaantumista. Lisäksi viime vuosien tutkimus on tuottanut tietoa suuresta määrästä erilaisia testejä ja biomarkkereita, jotka voivat vaikuttaa taudin diagnoosiin ja prognoosiin. Tiedon suuri määrä saattaa aiheuttaa informaatioähkyä kliinikoille vaikeuttaen heidän päätöksentekoaan. Datalähtöiset analytiikka- ja visualisointimenetelmät voivat auttaa suuren ja heterogeenisen tietomäärän tulkinnassa ja hyödyntämisessä. Ne voivat siten tukea kliinikkoa hänen päätöksenteossaan. Lisäksi nämä menetelmät voivat auttaa tunnistamaan sopivia potilaita kliinisiin lääketutkimuksiin, joiden tavoitteena on kehittää Alzheimerin taudin etenemistä hidastavia lääkkeitä. Tämän väitöskirjan tavoitteena oli kehittää datalähtöisiä menetelmiä Alzheimerin taudin etenemisen ennustamiseen ja seurantaan taudin eri vaiheisiin alkaen normaalista kognitiosta ja edeten kuolemaan. Mallien kehittämisessä hyödynnettiin kognitiivisten ja neuropsykologisten testien tuloksia, magneettikuvantamista (MRI), selkäydinnestenäytteitä, ja genetiikkaa (apolipoproteiini E). Väitöskirja koostuu neljästä alkuperäisestä tutkimuksesta, jotka on julkaistu kansainvälisissä tieteellisissä lehdissä. Ensimmäinen osatutkimus keskittyi Alzheimerin taudin varhaiseen vaiheeseen. Tutkimuksessa käytettiin ohjattua koneoppimisen menetelmää Disease State Index (DSI, taudin tilan indeksi) ennustamaan, kenellä subjektiivisesti koettu kognition heikkeneminen etenee taudin vakavampaan vaiheeseen eli lievään kognition heikentymiseen (mild cognitive impairment, MCI) tai dementiaan. Tutkimuksen aineisto koostui 647 henkilöstä kolmesta eurooppalaisesta muisti- klinikkakohortista. Kun yhdistettiin useita eri muuttujia DSI-menetelmällä, ROC- käyrän (engl. Receiver Operating Characteristic curve) alle jäävä pinta-ala (AUC) oli 0.81 ja tasapainotettu tarkkuus oli 74%. Negatiivinen ennustearvo oli korkea (93%) ja positiivinen ennustearvo oli matala (38%). Kun DSI-malli validoitiin erillisellä testikohortilla, mallin AUC huononi 11%. Lisäanalyysit osoittivat, että useat erot kohorttien välillä voivat selittää suorituskyvyn alenemista. Toinen osatutkimus keskittyi taudin myöhäisempään vaiheeseen. DSI-menetelmällä analysoitiin pitkittäistä dataa, joka koostui 273 henkilön MCI-kohortista. Kohortti hankittiin Alzheimer’s Disease and Neuroimaging (ADNI 1) tietokannasta. DSI-arvojen muutokset ajan kuluessa olivat erilaiset niillä, joiden tauti eteni Alzheimerin taudin dementiaksi, ja niillä, joilla tauti pysyi MCI-vaiheessa. Lisäksi huomattiin, että stabiilina pysynyt MCI-ryhmä koostui kahdesta aliryhmästä: ensimmäisessä ryhmässä DSI-arvot pysyivät vakaina ja toisessa ryhmässä DSI-arvot kohosivat. Tämä indikoi, että toisessa ryhmässä tauti saattaa edetä dementiaksi tulevaisuudessa. Näiden analyysien lisäksi DSI:in oleellisesti liittyvä Disease State Fingerprint (DSF, taudin tilan sormenjälki) -visualisointimenetelmä laajennettiin pitkittäiselle datalle. Kolmas osatutkimus ennusti hippokampuksen surkastumista 24 kuukauden ai- kana lähtötilanteen mittausten perusteella. Tutkimuskohortti koostui henkilöistä, joilla oli normaali kognitio, MCI tai Alzheimerin taudin dementia, ja se hankittiin ADNI 1 (n=530) ja Australian Imaging Biomarkers and Lifestyle Flagship Study of Ageing (AIBL, n=176) tutkimuksista. Useita eri datatyyppejä sisältävät mallit ennustivat hippokampuksen surkastumista tarkemmin kuin pelkistä MRI-muuttujista koostuvat mallit. Kuitenkin molemmat mallit aliarvioivat todellista surkastumista erityisesti suuremmilla surkastumisnopeuksilla, aliarviointi oli suurempaa pelkästään MRI-muuttujiin perustuvilla malleilla. Kun ennustettiin kaksiluokkaista vastemuuttujaa, eli nopea vs. hidas surkastuminen, mallien tarkkuus oli 79-87%. MRI-mallien suorituskyky oli hyvä, kun testauksessa käytettiin erillistä AIBL-aineistoa. Viimeinen osatutkimus keskittyi Alzheimerin taudin viimeisimpiin vaiheisiin. Siinä tutkittiin, mitkä tautiin liittyvät tekijät ovat yhteydessä kuolleisuuteen potilailla, joilla oli Alzheimerin taudin dementia. Aineisto koostui 616 henkilöstä Amsterdam Dementia Cohort -aineistosta. Iällä ja sukupuolella vakioidun Coxin suhteellisen vaaran mallin mukaan vanhempi ikä, miessukupuoli, huonommat pisteet kognitiivisessa toimintakyvyssä, ja aivojen kuoriosien ja mediaalisen ohimolohkon surkastuminen olivat yhteydessä kuolleisuuteen. Optimaalinen muuttujien yhdistelmä sisälsi iän, sukupuolen, tulokset kahdesta kognitiivisesta testistä (digit span backward, Trail Ma- king Test A), mediaalisen ohimolohkon surkastumisen ja selkäydinnestenäytteestä mitatun kohdasta 181 (treoniini) fosforyloidun tau-proteiinin määrän. Yhteenvetona todetaan, että datalähtöisillä menetelmillä voidaan ennustaa ja seu- rata Alzheimerin taudin etenemistä varhaisesta vaiheesta myöhäiseen vaiheeseen. Yhdistämällä useita eri datatyyppejä saadaan parempia tuloksia kuin käyttämällä vain yhtä datatyyppiä. Tulokset korostavat myös, että datalähtöiset menetelmät on tärkeä arvioida erillisellä aineistolla, jota ei ole käytetty menetelmien kehittämiseen. Lisäksi näiden menetelmien käyttöönotto eri ympäristöissä tai maissa saattaa vaatia potilaan tutkimusmenetelmien ja diagnoosikriteereiden harmonisointia.Alzheimer’s disease (AD), the most common form of dementia, is a slowly progressing neurodegenerative disease, which cannot be cured yet. However, certain medications and lifestyle interventions can delay progression of the disease and its symptoms, thereby positively influencing both quality of life of patients as well as cost- effectiveness of healthcare. Early diagnosis of AD is important because such interventions should be started already at an early phase of the disease to have the best effect. However, early diagnosis is challenging because pathological changes in the brain occur years before the clinical symptoms become visible. In addition, the re- search during the past years has produced information from a large number of different tests and biomarkers that can potentially contribute to diagnosis and prognosis of AD. This excessive amount of data can cause information overload for clinicians, thus hampering the clinicians’ decision making. Data-driven analysis and visualization methods may help with interpretation and utilization of large amounts of heterogeneous patient data and support the clinicians’ decision-making process. Furthermore, the methods may aid in identifying suitable patients for clinical drug trials. The aim of the work described in this thesis was to develop and validate data- driven methods for predicting and monitoring progression of Alzheimer’s disease at the different phases of the disease spectrum, starting from normal cognition and ending to death, using data from neuropsychological and cognitive tests, magnetic resonance imaging (MRI), cerebrospinal fluid samples (CSF), comorbidities, and genetics (apolipoprotein E). The thesis consists of four original studies published as international journal articles. The first study focused on the early phase of AD. A supervised machine learning method called Disease State Index (DSI) was utilized to predict who of the individuals with subjective cognitive decline (SCD) will progress to a more severe condition, i.e., mild cognitive impairment (MCI) or dementia. The study population included 647 subjects from three different memory clinic-based cohorts in Europe. When all data modalities were combined, the area under the receiver operating characteristic curve (AUC) was 0.81 and balanced accuracy was 74%. Negative predictive value was high (93%), whereas positive predictive value was low (38%). Performance of the DSI method in terms of AUC decreased by 11% when validated with an in- dependent test set. Additional analyses suggested that several differences between the cohorts may explain the decrease in the performance. The second study focused on a more advanced disease stage. The DSI method was applied to longitudinal data collected from an MCI cohort of 273 subjects obtained from the Alzheimer’s Disease and Neuroimaging (ADNI 1) study. Longitudinal profiles of the DSI values differed between the subjects progressing to dementia due to AD and subjects remaining as MCI. In addition, two subgroups were found in the group remaining as MCI: one group with stable DSI values over time and another group with increasing DSI values, suggesting the latter group may progress to dementia due to AD in the future. This study also extended the Disease State Fingerprint (DSF) data visualization method for longitudinal data. The third study predicted hippocampal atrophy over 24 months using baseline data and penalized linear regression. The cohorts consisted of subjects with normal cognition, MCI, and dementia due to AD and were obtained from the ADNI 1 (n=530) and the Australian Imaging Biomarkers and Lifestyle Flagship Study of Ageing (AIBL, n=176) studies. The models including different data modalities per- formed better than the models including only MRI features. However, both models underestimated the real change at higher atrophy rate levels, the MRI-only models showing a greater underestimation. When predicting dichotomized outcome, i.e., fast vs. slow atrophy, the models obtained a prediction accuracy of 79-87%. The MRI-only models performed well when evaluated with an independent validation cohort (AIBL). The last study focused on the latest phase of AD by identifying which disease- related determinants are associated with mortality in patients with dementia due to AD. The cohort included 616 patients from the Amsterdam Dementia Cohort. Age- and sex-adjusted Cox proportional hazards models revealed that older age, male sex, and worse scores on cognitive functioning, as well as more severe medial temporal lobe and global cortical atrophy were associated with an increased risk of mortality. An optimal combination of variables comprised age, sex, performance on digit span backward test and Trail Making Test A, medial temporal lobe atrophy, and tau phosphorylated at threonine 181 in CSF. In conclusion, data-driven methods can be used for predicting and monitoring progression of AD from the mildest stages to the more advanced stages. Combining information from several data modalities provides better prediction performance than individual data modalities alone. The results also highlight the importance of the validation of the methods with independent validation cohorts. Introduction of these methods to different environments and countries may require harmonization of patient examination methods and diagnostic criteria

Nature Ambience in a Lunch Restaurant Has the Potential to Evoke Positive Emotions, Reduce Stress, and Support Healthy Food Choices and Sustainable Behavior:A Field Experiment among Finnish Customers

Laboratory experiments have indicated that exposure to restorative ambiences in food environments can lead to beneficial outcomes for consumers, but there is little evidence if this positive effect holds true in real-life consumption conditions. Therefore, the aim of this study was to analyze the effects of lunch restaurant ambience on customers’ emotional responses, stress recovery, food choices, and generation of plate waste. The expectation was that ambience inducing positive emotional responses would lead to alleviated stress, healthier food choices, and reduced plate waste. A field experiment with a baseline and two experimental ambiences (‘nature ambience’ to induce positive emotions and ‘fast food ambience’ to induce less positive emotions) including visual and auditory stimuli was conducted in a lunch restaurant for one week per ambience. Emotional responses, and objective and subjective stress were measured from a subgroup of participants (n = 32). Food choices and plate waste were measured for all customers (n = 1610–1805 depending on the study week). During ‘nature ambience’ week, customers more often chose vegetarian dishes and generated less plate waste. The results on emotional responses and stress recovery were partially in line with the expectations. The study provides real-life evidence that restaurant ambience modification could lead to beneficial consequences for customers

Intelligent Customer-driven Solution for Orthopedic and Pediatric Surgery Care (ICory): Final Report

This report summarizes main activities and achieved results of the ICory project, a co-innovation project funded by Business Finland and carried out during 2018-2021. ICory aimed at 1) co-creating an intelligent patient-centric digital solution for orthopedic and pediatric surgery care journeys; 2) assessing impact of the developed solution from both medical, patient, and business perspectives; 3) and developing ecosystemic business model for speeding up companies’ access to the international market. In ICory, the patient journey solutions were co-developed together with researchers, hospitals, and companies; effectiveness of the solutions were evaluated in two randomized controlled trials in Finland; Rehaboo! Exercise Game is being evaluated in a RCT in Singapore; a medicine delivery robot was developed and tested; research on business models was conducted; collaboration with three hospitals in Singapore and one Australian University was built. Results of the studies have been published in 27 scientific journal and conferences articles, and 2 doctoral dissertations were done during the project. The COVID-19 pandemic has affected functioning of the participating hospitals, delaying recruitment of patients and progression of the RCT studies. Analysis of the RCT data has started and the results will be published in several scientific articles after the project

A Decision Support System for Diagnostics and Treatment Planning in Traumatic Brain Injury.

Traumatic brain injury (TBI) occurs when an external force causes functional or structural alterations in the brain. Clinical characteristics of TBI vary greatly from patient to patient, and a large amount of data is gathered during various phases of clinical care in these patients. It is hard for clinicians to efficiently integrate and interpret all of these data and plan interventions in a timely manner. This paper describes the technical architecture and functionality of a web-based decision support system (DSS), which not only provides advanced support for visualizing complex TBI data but also predicts a possible outcome by using a state-of-the-art Disease State Index machine-learning algorithm. The DSS is developed by using a three-layered architecture and by employing modern programming principles, software design patterns, and using robust technologies (C#, ASP.NET MVC, HTML5, JavaScript, Entity Framework, etc.). The DSS is comprised of a patient overview module, a disease-state prediction module, and an imaging module. After deploying it on a web-server, the DSS was made available to two hospitals in U.K. and Finland. Afterwards, we conducted a validation study to evaluate its usability in clinical settings. Initial results of the study indicate that especially less experience clinicians may benefit from this type of decision support software tool

Short-term effects of a digital patient journey solution on patient-reported outcomes and health care utilization in arthroplasty : a pragmatic randomized controlled trial

Mobile health solutions for patient support have been proposed as promising and safe alternatives to usual care in adults undergoing primary total hip and knee arthroplasty. Studies of such applications, however, have produced conflicting results and only moderate- to low-quality evidence. This study aims to evaluate the short-term effects of a digital patient journey solution on patient-reported outcomes and health care utilization in patients undergoing total hip and knee arthroplasty using a pragmatic randomized controlled trial design. Randomly allocated patients in the control arm (n = 35, 64 ± 9 years) received usual care, while patients in the intervention arm (n = 34, 62 ± 11 years) received the digital patient journey solution in addition to usual care. The primary outcome was health-related quality of life as measured by the EuroQol EQ-5D-5L scale. Secondary outcomes included functional recovery, pain, self-efficacy, patient experience, adherence to fast-track protocol, and health care utilization. Participants were followed from a preoperative surgical visit until a postoperative follow-up visit at 6–12 weeks. The health-related quality of life, functional recovery, pain, patient experience, adherence to the fast-track protocol, and health care utilization did not differ between the arms. During the study, however, the self-efficacy to use digital health services (p=0.027) increased in the intervention arm. The use of the digital patient journey solution was not superior to usual care in terms of patient-reported outcomes and health care utilization. However, the solution improved the self-efficacy of patients to use digital health services, which may lead to greater demand for similar digital offerings as patient become more familiar with mobile health solutions.Peer reviewe

Tratamiento informativo sobre el tema la ruptura de relaciones diplomáticas entre El Salvador y la República de China-Taiwán y el establecimiento de relaciones con China Continental, en los periódicos El Diario de Hoy y Co-Latino. período de análisis: de agosto a septiembre de 2018

La ruptura de relaciones diplomáticas entre El Salvador y la República de China-Taiwán y el establecimiento de relaciones con China Continental, en los periódicos El Diario de Hoy y Co-latino se analizó cómo los medios de comunicación informaron o desinformaron, a través de la manera en que redactaron las noticias, sobre este acontecimiento que influye a los salvadoreños. A través de un estudio minucioso de las notas publicadas en estos medios impresos se analizó si estos informaron de manera objetiva sobre la ruptura de relaciones diplomáticas con China-Taiwán o, por el contrario, redactaron las noticias con fines de favorecer la línea editorial del medio de comunicación. En ese sentido, esta investigación es importante porque servirá como un documento que abonará al análisis de cómo los medios de comunicación en nuestro país, dan tratamiento a la información sobre hechos que afectan a los salvadoreños, que a final de cuentas son quienes terminan tomando decisiones sobre la base de lo que les informan