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  • 1.
    Javed, Farrukh
    et al.
    Business School, Örebro University.
    Thomas, Ilias
    Dalarna University, School of Technology and Business Studies, Microdata Analysis.
    Memedi, Mevludin
    Business School, Örebro University.
    A comparison of feature selection methods when using motion sensors data: a case study in Parkinson’s disease2018In: 2018 40th Annual International Conference of the IEEE Engineering in Medicine and Biology Society (EMBC), 2018, p. 5426-5429Conference paper (Refereed)
    Abstract [en]

    The objective of this study is to investigate the effects of feature selection methods on the performance of machine learning methods for quantifying motor symptoms of Parkinson's disease (PD) patients. Different feature selection methods including step-wise regression, Lasso regression and Principal Component Analysis (PCA) were applied on 88 spatiotemporal features that were extracted from motion sensors during hand rotation tests. The selected features were then used in support vector machines (SVM), decision trees (DT), linear regression, and random forests models to calculate a so-called treatment-response index (TRIS). The validity, testretest reliability and sensitivity to treatment were assessed for each combination (feature selection method plus machine learning method). There were improvements in correlation coefficients and root mean squared error (RMSE) for all the machine learning methods, except DTs, when using the selected features from step-wise regression inputs. Using step-wise regression and SVM was found to have better sensitivity to treatment and higher correlation to clinical ratings on the Unified PD Rating Scale as compared to the combination of PCA and SVM. When assessing the ability of the machine learning methods to discriminate between tests performed by PD patients and healthy controls the results were mixed. These results suggest that the choice of feature selection methods is crucial when working with data-driven modelling. Based on our findings the step-wise regression can be considered as the method with the best performance.

  • 2. Johansson, D.
    et al.
    Ericsson, A.
    Johansson, A.
    Medvedev, A.
    Nyholm, D.
    Ohlsson, F.
    Senek, M.
    Spira, J.
    Thomas, Ilias
    Dalarna University, School of Technology and Business Studies, Microdata Analysis.
    Westin, Jerker
    Dalarna University, School of Technology and Business Studies, Computer Engineering.
    Individualization of levodopa treatment using a microtablet dispenser and ambulatory accelerometry2018In: CNS Neuroscience & Therapeutics, ISSN 1755-5930, E-ISSN 1755-5949, Vol. 24, no 5, p. 439-447Article in journal (Refereed)
    Abstract [en]

    Aim

    This 4‐week open‐label observational study describes the effect of introducing a microtablet dose dispenser and adjusting doses based on objective free‐living motor symptom monitoring in individuals with Parkinson's disease (PD).

    Methods

    Twenty‐eight outpatients with PD on stable levodopa treatment with dose intervals of ≤4 hour had their daytime doses of levodopa replaced with levodopa/carbidopa microtablets, 5/1.25 mg (LC‐5) delivered from a dose dispenser device with programmable reminders. After 2 weeks, doses were adjusted based on ambulatory accelerometry and clinical monitoring.

    Results

    Twenty‐four participants completed the study per protocol. The daily levodopa dose was increased by 15% (112 mg, < 0.001) from period 1 to 2, and the dose interval was reduced by 12% (22 minutes, P = 0.003). The treatment adherence to LC‐5 was high in both periods. The MDS‐UPDRS parts II and III, disease‐specific quality of life (PDQ‐8), wearing‐off symptoms (WOQ‐19), and nonmotor symptoms (NMS Quest) improved after dose titration, but the generic quality‐of‐life measure EQ‐5D‐5L did not. Blinded expert evaluation of accelerometry results demonstrated improvement in 60% of subjects and worsening in 25%.

    Conclusions

    The introduction of a levodopa microtablet dispenser and accelerometry aided dose adjustments improve PD symptoms and quality of life in the short term.

  • 3. Johansson, Dongni
    et al.
    Thomas, Ilias
    Dalarna University, School of Technology and Business Studies, Microdata Analysis.
    Ericsson, Anders
    Johansson, Anders
    Medvedev, Alexander
    Memedi, Mevludin
    Nyholm, Dag
    Ohlsson, Fredrik
    Westin, Jerker
    Dalarna University, School of Technology and Business Studies, Computer Engineering.
    Bergquist, Filip
    Evaluation of a sensor algorithm for motor state rating in Parkinson's disease2019In: Parkinsonism & Related Disorders, ISSN 1353-8020, E-ISSN 1873-5126Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION: A treatment response objective index (TRIS) was previously developed based on sensor data from pronation-supination tests. This study aimed to examine the performance of TRIS for medication effects in a new population sample with Parkinson's disease (PD) and its usefulness for constructing individual dose-response models.

    METHODS: Twenty-five patients with PD performed a series of tasks throughout a levodopa challenge while wearing sensors. TRIS was used to determine motor changes in pronation-supination tests following a single levodopa dose, and was compared to clinical ratings including the Treatment Response Scale (TRS) and six sub-items of the UPDRS part III.

    RESULTS: As expected, correlations between TRIS and clinical ratings were lower in the new population than in the initial study. TRIS was still significantly correlated to TRS (rs = 0.23, P < 0.001) with a root mean square error (RMSE) of 1.33. For the patients (n = 17) with a good levodopa response and clear motor fluctuations, a stronger correlation was found (rs = 0.38, RMSE = 1.29, P < 0.001). The mean TRIS increased significantly when patients went from the practically defined off to their best on state (P = 0.024). Individual dose-response models could be fitted for more participants when TRIS was used for modelling than when TRS ratings were used.

    CONCLUSION: The objective sensor index shows promise for constructing individual dose-response models, but further evaluations and retraining of the TRIS algorithm are desirable to improve its performance and to ensure its clinical effectiveness.

  • 4.
    Thomas, Ilias
    Dalarna University, School of Technology and Business Studies, Microdata Analysis.
    Automating levodopa dosing schedules for Parkinson’s disease2019Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Parkinson’s disease (PD) is the second most common neurodegenerative disease. Levodopa is mainly used to manage the motor symptoms of PD. However, disease progression and long-term use of levodopa cause reduced medication efficacy and side effects. When that happens, precise individualized dosing schedules are required.

    This doctoral thesis in the field of Micro-data analysis introduces an end-to-end solution for the automation of the pharmacological management of PD with levodopa, and offers some insight on levodopa pharmacodynamics. For that purpose, an algorithm that derives objective ratings for the patients’ motor function through wearable sensors is introduced, a method to construct individual patient profiles is developed, and two dosing algorithms for oral and intestinal administration of levodopa are presented. Data from five different sources were used to develop the methods and evaluate the performance of the proposed algorithms.

    The dose automation algorithms can work both with clinical and objective ratings (through wearable devices), and their application was evaluated against dosing adjustments from movement disorders experts. Both dosing algorithms showed promise and their dosing suggestions were similar to those of the clinicians.

    The objective ratings algorithm had good test-retest reliability and its application during a clinical study was successful. Furthermore, the method of fitting individual patient models was robust and worked well with the objective ratings algorithm. Finally, a study was carried out that showed that about half the patients on levodopa treatment show reduced response during the afternoon hours, pointing to the need for more precise modelling of levodopa pharmacodynamics.

  • 5.
    Thomas, Ilias
    Dalarna University, School of Technology and Business Studies, Microdata Analysis.
    Optimizing levodopa dosing routines for Parkinson’s disease2017Licentiate thesis, comprehensive summary (Other academic)
    Abstract [en]

    This thesis in the field of microdata analysis aims to introduce dose optimizing algorithms for the pharmacological management of Parkinson’s disease (PD). PD is a neurodegenerative disease that mostly affects the motor functions of the patients and it is characterized as a movement disorder. The core symptoms of PD are: bradykinesia, postural instability, rigidity, and tremor. There is no cure for PD and the use of levodopa to manage the core symptoms is considered the gold standard. However, long term use of levodopa causes reduced medication efficacy, and side effects, such as dyskinesia, which can also be attributed to overmedication. When that happens precise individualized dosing schedules are required. The goal of this thesis is to examine if algorithmic methods can be used to find dosing schedules that treat PD symptoms and minimize manifestation of side effects. Data from three different sources were used for that purpose: data from a clinical study in Uppsala University hospital in 2015, patient admission chart data from Uppsala University hospital during 2011-2015, and data from a clinical study in Gothenburg University during 2016-2017. The data were used to develop the methods and evaluate the performance of the proposed algorithms.The first algorithm that was developed was a sensor-based method that derives objective measurements (ratings) of PD motor states. The construction of the sensor index was based on subjective ratings of patients’ motor functions made by three movement disorder experts. This sensor-based method was used when deriving algorithmic dosing schedules. Afterwards, a method that uses medication information and ratings of the patients’ motor states to fit individual patient models was developed. This method uses mathematical optimization to individualize specific parameters of dose-effects models for levodopa intake, through minimizing the distance between motor state ratings and dose-effect curves. Finally, two different dose optimization algorithms were developed and evaluated, that had as input the individual patient models. The first algorithm was specific to continuous infusion of levodopa treatment, where the patient’s state was set to a specific target value and the algorithm made dosing adjustments to keep that patients motor functions on that state. The second algorithm concerned oral administration of microtables of levodopa. The ambition with this algorithm was that the suggested doses would find the right balance between treating the core symptoms of PD and, at the same time, minimizing the side effects of long term levodopa use, mainly dyskinesia. Motor state ratings for this study were obtained through the sensor index. Both algorithms followed a principle of deriving a morning dose and a maintenance dose for the patients, with maintenance dose being an infusion rate for the first algorithm, and oral administration doses at specific time points for the second algorithm.The results showed that the sensor-based index had good test-retest reliability, sensitivity to levodopa treatment, and ability to make predictions in unseen parts of the dataset. The dosing algorithm for continuous infusion of levodopa had a good ability to suggest an optimal infusion rating for the patients, but consistently suggested lower morning dose than what the treating personnel prescribed. The dosing algorithm for oral administration of levodopa showed great agreement with the treating personnel’s prescriptions, both in terms of morning and maintenance dose. Moreover, when evaluating the oral medication algorithm, it was clear that the sensor index ratings could be used for building patient specific models.

  • 6.
    Thomas, Ilias
    et al.
    Dalarna University, School of Technology and Business Studies, Microdata Analysis.
    Alam, Moudud
    Dalarna University, School of Technology and Business Studies, Statistics.
    Bergquist, Filip
    Johansson, Dongni
    Memedi, Mevludin
    Nyholm, Dag
    Westin, Jerker
    Dalarna University, School of Technology and Business Studies, Computer Engineering.
    Sensor-based algorithmic dosing suggestions for oral administration of levodopa/carbidopa microtablets for Parkinson's disease: a first experience2019In: Journal of Neurology, ISSN 0340-5354, E-ISSN 1432-1459, Vol. 266, no 3, p. 651-658Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Dosing schedules for oral levodopa in advanced stages of Parkinson's disease (PD) require careful tailoring to fit the needs of each patient. This study proposes a dosing algorithm for oral administration of levodopa and evaluates its integration into a sensor-based dosing system (SBDS).

    MATERIALS AND METHODS: In collaboration with two movement disorder experts a knowledge-driven, simulation based algorithm was designed and integrated into a SBDS. The SBDS uses data from wearable sensors to fit individual patient models, which are then used as input to the dosing algorithm. To access the feasibility of using the SBDS in clinical practice its performance was evaluated during a clinical experiment where dosing optimization of oral levodopa was explored. The supervising neurologist made dosing adjustments based on data from the Parkinson's KinetiGraph™ (PKG) that the patients wore for a week in a free living setting. The dosing suggestions of the SBDS were compared with the PKG-guided adjustments.

    RESULTS: The SBDS maintenance and morning dosing suggestions had a Pearson's correlation of 0.80 and 0.95 (with mean relative errors of 21% and 12.5%), to the PKG-guided dosing adjustments. Paired t test indicated no statistical differences between the algorithmic suggestions and the clinician's adjustments.

    CONCLUSION: This study shows that it is possible to use algorithmic sensor-based dosing adjustments to optimize treatment with oral medication for PD patients.

  • 7.
    Thomas, Ilias
    et al.
    Dalarna University, School of Technology and Business Studies, Statistics.
    Alam, Moudud
    Dalarna University, School of Technology and Business Studies, Statistics.
    Bergquist, Filip
    Senek, Marina
    Nyholm, Dag
    Westin, Jerker
    Dalarna University, School of Technology and Business Studies, Computer Engineering.
    Individual levodopa dosing suggestions based on a single dose test2016Conference paper (Other academic)
  • 8.
    Thomas, Ilias
    et al.
    Dalarna University, School of Technology and Business Studies, Microdata Analysis.
    Alam, Moudud
    Dalarna University, School of Technology and Business Studies, Statistics.
    Nyholm, Dag
    Senek, Marina
    Westin, Jerker
    Dalarna University, School of Technology and Business Studies, Computer Engineering.
    Individual dose-response models for levodopa infusion dose optimization2018In: International Journal of Medical Informatics, ISSN 1386-5056, E-ISSN 1872-8243, Vol. 112, p. 137-142Article in journal (Refereed)
    Abstract [en]

    Background and Objective

    To achieve optimal effect with continuous infusion treatment in Parkinson’s disease (PD), the individual doses (morning dose and continuous infusion rate) are titrated by trained medical personnel. This study describes an algorithmic method to derive optimized dosing suggestions for infusion treatment of PD, by fitting individual dose-response models. The feasibility of the proposed method was investigated using patient chart data.

    Methods

    Patient records were collected at Uppsala University hospital which provided dosing information and dose-response evaluations. Mathematical optimization was used to fit individual patient models using the records’ information, by minimizing an objective function. The individual models were passed to a dose optimization algorithm, which derived an optimized dosing suggestion for each patient model.

    Results

    Using data from a single day’s admission the algorithm showed great ability to fit appropriate individual patient models and derive optimized doses. The infusion rate dosing suggestions had 0.88 correlation and 10% absolute mean relative error compared to the optimal doses as determined by the hospital’s treating team. The morning dose suggestions were consistency lower that the optimal morning doses, which could be attributed to different dosing strategies and/or lack of on-off evaluations in the morning.

    Conclusion

    The proposed method showed promise and could be applied in clinical practice, to provide the hospital personnel with additional information when making dose adjustment decisions.

  • 9.
    Thomas, Ilias
    et al.
    Dalarna University, School of Technology and Business Studies, Statistics.
    Alam, Moudud
    Dalarna University, School of Technology and Business Studies, Statistics.
    Senek, Marina
    Uppsala University Hospital.
    Dag, Nyholm
    Uppsala University Hospital.
    Westin, Jerker
    Dalarna University, School of Technology and Business Studies, Computer Engineering.
    Minimizing levodopa titration period for Parkinson’s disease2016Conference paper (Other academic)
  • 10.
    Thomas, Ilias
    et al.
    Dalarna University, School of Technology and Business Studies, Microdata Analysis.
    Bergquist, Filip
    Gothenburg University.
    Constantinescu, Radu
    Gothenburg University.
    Nyholm, Dag
    Dept. of Neuroscience, Neurology, Uppsala University.
    Senek, Marina
    Dept. of Neuroscience, Neurology, Uppsala University.
    Memedi, Mevludin
    Dalarna University, School of Technology and Business Studies, Computer Engineering. Informatics, School of Business, Örebro University.
    Using measurements from wearable sensors for automatic scoring of Parkinson's disease motor states: Results from 7 patients2017In: Engineering in Medicine and Biology Society (EMBC), 2017 39th Annual International Conference of the IEEE, IEEE, 2017, p. 131-134Conference paper (Refereed)
    Abstract [en]

    The objective of this study was to investigate the validity of an objective gait measure for assessment of different motor states of advanced Parkinson's disease (PD) patients. Seven PD patients performed a gait task up to 15 times while wearing sensors on their upper and lower limbs. Each task was performed at specific points during a test day, following a single dose of levodopa-carbidopa. At the time of the tasks the patients were video recorded and three movement disorder experts rated their motor function on three clinical scales: a treatment response scale (TRS) that ranged from −3 (very bradykinetic) to 0 (ON) to +3 (very dyskinetic), a dyskinesia score that ranged from 0 (no dyskinesia) to 4 (extreme dyskinesia), and a bradykinesia score that ranged from 0 (no bradykinesia) to 4 (extreme bradykinesia). Raw accelerometer and gyroscope data of the sensors were processed and analyzed with time series analysis methods to extract features. The utilized features quantified separate limb movements as well as movement symmetries between the limbs. The features were processed with principal component analysis and the components were used as predictors for separate support vector machine (SVM) models for each of the three scales. The performance of each model was evaluated in a leave-one-patient out setting where the observations of a single patient were used as the testing set and the observations of the other 6 patients as the training set. Root mean square error (RMSE) and correlation coefficients for the predictions showed a good ability of the models to map the sensor data into the rating scales. There were strong correlations between the SVM models and the mean ratings of TRS (0.79; RMSE=0.70), bradykinesia score (0.79; RMSE=0.47), and bradykinesia score (0.78; RMSE=0.46). The results presented in this paper indicate that the use of wearable sensors when performing gait tasks can generate measurements that have a good correlation to subjective expert assessments.

  • 11.
    Thomas, Ilias
    et al.
    Dalarna University, School of Technology and Business Studies, Microdata Analysis.
    Memedi, Mevludin
    Westin, Jerker
    Dalarna University, School of Technology and Business Studies, Computer Engineering.
    Nyholm, Dag
    The effect of continuous levodopa treatment during the afternoon hours2019In: Acta Neurologica Scandinavica, ISSN 0001-6314, E-ISSN 1600-0404, Vol. 139, no 1, p. 70-75Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: The aim of this retrospective study was to investigate if patients with PD, who are treated with levodopa-carbidopa intestinal gel (LCIG), clinically worsen during the afternoon hours and if so, to evaluate whether this occurs in all LCIG-treated patients or in a sub-group of patients.

    METHODS: Three published studies were identified and included in the analysis. All studies provided individual response data assessed on the treatment response scale (TRS) and patients were treated with continuous LCIG. Ninety-eight patients from the three studies fulfilled the criteria. T-tests were performed to find differences on the TRS values between the morning and the afternoon hours, linear mixed effect models were fitted on the afternoon hours' evaluations to find trends of wearing-off, and patients were classified into three TRS categories (meaningful increase in TRS, meaningful decrease in TRS, non -meaningful increase or decrease).

    RESULTS: In all three studies significant statistical differences were found between the morning TRS values and the afternoon TRS values (p-value <= 0.001 in all studies). The linear mixed effect models had significant negative coefficients for time in two studies, and 48 out of 98 patients (49%) showed a meaningful decrease of TRS during the afternoon hours.

    CONCLUSION: The results from all studies were consistent, both in the proportion of patients in the three groups and the value of TRS decrease in the afternoon hours. Based on these findings there seems to be a group of patients with predictable "off" behavior in the later parts of the day. This article is protected by copyright. All rights reserved.

  • 12.
    Thomas, Ilias
    et al.
    Dalarna University, School of Technology and Business Studies, Microdata Analysis.
    Westin, Jerker
    Dalarna University, School of Technology and Business Studies, Computer Engineering.
    Alam, Moudud
    Dalarna University, School of Technology and Business Studies, Statistics.
    Bergquist, F.
    Nyholm, D.
    Senek, M.
    Memedi, Mevludin
    Dalarna University, School of Technology and Business Studies, Computer Engineering.
    A treatment–response index from wearable sensors for quantifying Parkinson's disease motor states2018In: IEEE journal of biomedical and health informatics, ISSN 2168-2194, E-ISSN 2168-2208, Vol. 22, no 5, p. 1341-1349Article in journal (Refereed)
    Abstract [en]

    The goal of this study was to develop an algorithm that automatically quantifies motor states (off,on,dyskinesia) in Parkinson's disease (PD), based on accelerometry during a hand pronation-supination test. Clinician's ratings using the Treatment Response Scale (TRS), ranging from -3 (very Off) to 0 (On) to +3 (very dyskinetic), was used as target. For that purpose, 19 participants with advanced PD and 22 healthy persons were recruited in a single center open label clinical trial in Uppsala, Sweden. The trial consisted of single levodopa dose experiments for the people with PD (PwP), where participants were asked to perform standardized wrist rotation tests, using each hand, before and at pre-specified time points after the dose. The participants used wrist sensors containing a 3D accelerometer and gyroscope. Features to quantify the level, variation and asymmetry of the sensor signals, three-level Discrete Wavelet Transform features and approximate entropy measures were extracted from the sensors data. At the time of the tests, the PwP were video recorded. Three movement disorder specialists rated the participants’ state on the TRS scale. A Treatment Response Index from Sensors (TRIS) was constructed to quantify the motor states based on the wrist rotation tests. Different machine learning algorithms were evaluated to map the features derived from the sensor data to the ratings provided by the three specialists. Results from cross validation, both in 10-fold and a leave-one-individual out setting, showed good predictive power of a support vector machine model and high correlation to the TRS scale. Values at the end tails of the TRS scale were under and over predicted due to the lack of observations at those values but the model managed to accurately capture the dose - effect profiles of the patients. In addition, the TRIS had good test-retest reliability on the baseline levels of the PD participants (Intraclass correlation coefficient of 0.83) and reasonable sensitivity to levodopa treatment (0.33 for the TRIS). For a series of test occasions the proposed algorithms provided dose - effect time profiles for participants with PD, which could be useful during therapy individualization of people suffering from advanced PD

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