Trial of Prasinezumab in Early-Stage Parkinson's Disease.

BACKGROUND: Aggregated α-synuclein plays an important role in the pathogenesis of Parkinson's disease. The monoclonal antibody prasinezumab, directed at aggregated α-synuclein, is being studied for its effect on Parkinson's disease. METHODS: In this phase 2 trial, we randomly assigned participants with early-stage Parkinson's disease in a 1:1:1 ratio to receive intravenous placebo or prasinezumab at a dose of 1500 mg or 4500 mg every 4 weeks for 52 weeks. The primary end point was the change from baseline to week 52 in the sum of scores on parts I, II, and III of the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS; range, 0 to 236, with higher scores indicating greater impairment). Secondary end points included the dopamine transporter levels in the putamen of the hemisphere ipsilateral to the clinically more affected side of the body, as measured by 123I-ioflupane single-photon-emission computed tomography (SPECT). RESULTS: A total of 316 participants were enrolled; 105 were assigned to receive placebo, 105 to receive 1500 mg of prasinezumab, and 106 to receive 4500 mg of prasinezumab. The baseline mean MDS-UPDRS scores were 32.0 in the placebo group, 31.5 in the 1500-mg group, and 30.8 in the 4500-mg group, and mean (±SE) changes from baseline to 52 weeks were 9.4±1.2 in the placebo group, 7.4±1.2 in the 1500-mg group (difference vs. placebo, -2.0; 80% confidence interval [CI], -4.2 to 0.2; P = 0.24), and 8.8±1.2 in the 4500-mg group (difference vs. placebo, -0.6; 80% CI, -2.8 to 1.6; P = 0.72). There was no substantial difference between the active-treatment groups and the placebo group in dopamine transporter levels on SPECT. The results for most clinical secondary end points were similar in the active-treatment groups and the placebo group. Serious adverse events occurred in 6.7% of the participants in the 1500-mg group and in 7.5% of those in the 4500-mg group; infusion reactions occurred in 19.0% and 34.0%, respectively. CONCLUSIONS: Prasinezumab therapy had no meaningful effect on global or imaging measures of Parkinson's disease progression as compared with placebo and was associated with infusion reactions. (Funded by F. Hoffmann-La Roche and Prothena Biosciences; PASADENA ClinicalTrials.gov number, NCT03100149.).

Self-Report versus Clinician Examination in Early Parkinson's Disease.

BACKGROUND: Evaluating the discrepancies between patient-reported measures and clinician examination has implications for formulating individual treatment regimens. OBJECTIVE: This study investigated the association between health outcomes and level of self-reported motor-related function impairment relative to clinician-examined motor signs. METHODS: Recently diagnosed PD patients were evaluated using the Parkinson's Progression Marker Initiative (PPMI, N = 420) and the PASADENA phase II clinical trial (N = 316). We calculated the average normalized difference between each participant's part II and III MDS-UPDRS (Movement Disorder Society Unified Parkinson's Disease Rating Scale) scores. Individuals with score differences <25th or >75th percentiles were labeled as low- and high-self-reporters, respectively (those between ranges were labeled intermediate-self-reporters). We compared a wide range of clinical/biomarker readouts among these three groups, using Kruskal-Wallis nonparametric and Pearson's χ2 tests. Spearman's correlations were tested for associations between MDS-UPDRS subscales. RESULTS: In both cohorts, high-self-reporters reported the largest impairment/symptom experience for most motor and nonmotor patient-reported variables. By contrast, these high-self-reporters were similar to or less impaired on clinician-examined and biomarker measures. Patient-reported nonmotor symptoms on MDS-UPDRS part IB showed the strongest positive correlation with self-reported motor-related impairment (PPMI rs  = 0.54, PASADENA rs  = 0.52). This correlation was numerically stronger than the part II and clinician-examined MDS-UPDRS part III correlation (PPMI rs  = 0.38, PASADENA rs  = 0.28). CONCLUSION: Self-reported motor-related impairments reflect not only motor signs/symptoms but also other self-reported nonmotor measures. This may indicate (1) a direct impact of nonmotor symptoms on motor-related functioning and/or (2) the existence of general response tendencies in how patients self-rate symptoms. Our findings suggest further investigation into the suitability of MDS-UPDRS II to assess motor-related impairments. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

A smartphone sensor-based digital outcome assessment of multiple sclerosis.

BACKGROUND: Sensor-based monitoring tools fill a critical gap in multiple sclerosis (MS) research and clinical care. OBJECTIVE: The aim of this study is to assess performance characteristics of the Floodlight Proof-of-Concept (PoC) app. METHODS: In a 24-week study (clinicaltrials.gov: NCT02952911), smartphone-based active tests and passive monitoring assessed cognition (electronic Symbol Digit Modalities Test), upper extremity function (Pinching Test, Draw a Shape Test), and gait and balance (Static Balance Test, U-Turn Test, Walk Test, Passive Monitoring). Intraclass correlation coefficients (ICCs) and age- or sex-adjusted Spearman's rank correlation determined test-retest reliability and correlations with clinical and magnetic resonance imaging (MRI) outcome measures, respectively. RESULTS: Seventy-six people with MS (PwMS) and 25 healthy controls were enrolled. In PwMS, ICCs were moderate-to-good (ICC(2,1) = 0.61-0.85) across tests. Correlations with domain-specific standard clinical disability measures were significant for all tests in the cognitive (r = 0.82, p < 0.001), upper extremity function (|r|= 0.40-0.64, all p < 0.001), and gait and balance domains (r = -0.25 to -0.52, all p < 0.05; except for Static Balance Test: r = -0.20, p > 0.05). Most tests also correlated with Expanded Disability Status Scale, 29-item Multiple Sclerosis Impact Scale items or subscales, and/or normalized brain volume. CONCLUSION: The Floodlight PoC app captures reliable and clinically relevant measures of functional impairment in MS, supporting its potential use in clinical research and practice.

Measuring Health-Related Quality of Life With Multimodal Data: Viewpoint.

The ability to objectively measure aspects of performance and behavior is a fundamental pillar of digital health, enabling digital wellness products, decentralized trial concepts, evidence generation, digital therapeutics, and more. Emerging multimodal technologies capable of measuring several modalities simultaneously and efforts to integrate inputs across several sources are further expanding the limits of what digital measures can assess. Experts from the field of digital health were convened as part of a multi-stakeholder workshop to examine the progress of multimodal digital measures in two key areas: detection of disease and the measurement of meaningful aspects of health relevant to the quality of life. Here we present a meeting report, summarizing key discussion points, relevant literature, and finally a vision for the immediate future, including how multimodal measures can provide value to stakeholders across drug development and care delivery, as well as three key areas where headway will need to be made if we are to continue to build on the encouraging progress so far: collaboration and data sharing, removal of barriers to data integration, and alignment around robust modular evaluation of new measurement capabilities.

A Remote Digital Monitoring Platform to Assess Cognitive and Motor Symptoms in Huntington Disease: Cross-sectional Validation Study.

BACKGROUND: Remote monitoring of Huntington disease (HD) signs and symptoms using digital technologies may enhance early clinical diagnosis and tracking of disease progression, guide treatment decisions, and monitor response to disease-modifying agents. Several recent studies in neurodegenerative diseases have demonstrated the feasibility of digital symptom monitoring. OBJECTIVE: The aim of this study was to evaluate a novel smartwatch- and smartphone-based digital monitoring platform to remotely monitor signs and symptoms of HD. METHODS: This analysis aimed to determine the feasibility and reliability of the Roche HD Digital Monitoring Platform over a 4-week period and cross-sectional validity over a 2-week interval. Key criteria assessed were feasibility, evaluated by adherence and quality control failure rates; test-retest reliability; known-groups validity; and convergent validity of sensor-based measures with existing clinical measures. Data from 3 studies were used: the predrug screening phase of an open-label extension study evaluating tominersen (NCT03342053) and 2 untreated cohorts-the HD Natural History Study (NCT03664804) and the Digital-HD study. Across these studies, controls (n=20) and individuals with premanifest (n=20) or manifest (n=179) HD completed 6 motor and 2 cognitive tests at home and in the clinic. RESULTS: Participants in the open-label extension study, the HD Natural History Study, and the Digital-HD study completed 89.95% (1164/1294), 72.01% (2025/2812), and 68.98% (1454/2108) of the active tests, respectively. All sensor-based features showed good to excellent test-retest reliability (intraclass correlation coefficient 0.89-0.98) and generally low quality control failure rates. Good overall convergent validity of sensor-derived features to Unified HD Rating Scale outcomes and good overall known-groups validity among controls, premanifest, and manifest participants were observed. Among participants with manifest HD, the digital cognitive tests demonstrated the strongest correlations with analogous in-clinic tests (Pearson correlation coefficient 0.79-0.90). CONCLUSIONS: These results show the potential of the HD Digital Monitoring Platform to provide reliable, valid, continuous remote monitoring of HD symptoms, facilitating the evaluation of novel treatments and enhanced clinical monitoring and care for individuals with HD.

Beacon-Based Remote Measurement of Social Behavior in ASD Clinical Trials: A Technical Feasibility Assessment.

In this work, we propose a Bluetooth low energy (BLE) beacon-based algorithm to enable remote measurement of the social behavior of the participants of an observational Autism Spectrum Disorder (ASD) clinical trial (NCT03611075). We have developed a mobile application for a smartphone and a smartwatch to collect beacon signals from BLE beacon sensors as well as to store information about the participants' household rooms. Our goal is to collect beacon information about the time the participants spent in different rooms of their household to infer sociability information. We applied the same technology and setup in an internal experiment with healthy volunteers to evaluate the accuracy of the proposed algorithm in 10 different home setups, and we observed an average accuracy of 97.2%. Moreover, we show that it is feasible for the clinical study participants/caregivers to set up the BLE beacon sensors in their homes without any technical help, with 96% of them setting up the technology on the first day of data collection. Next, we present results from one-week location data from study participants collected through the proposed technology. Finally, we provide a list of good practice guidelines for optimally applying beacon technology for indoor location monitoring. The proposed algorithm enables us to estimate time spent in different rooms of a household that can pave the development of objective sociability features and eventually support decisions regarding drug efficacy in ASD.

Gait Characteristics Harvested During a Smartphone-Based Self-Administered 2-Minute Walk Test in People with Multiple Sclerosis: Test-Retest Reliability and Minimum Detectable Change.

The measurement of gait characteristics during a self-administered 2-minute walk test (2MWT), in persons with multiple sclerosis (PwMS), using a single body-worn device, has the potential to provide high-density longitudinal information on disease progression, beyond what is currently measured in the clinician-administered 2MWT. The purpose of this study is to determine the test-retest reliability, standard error of measurement (SEM) and minimum detectable change (MDC) of features calculated on gait characteristics, harvested during a self-administered 2MWT in a home environment, in 51 PwMS and 11 healthy control (HC) subjects over 24 weeks, using a single waist-worn inertial sensor-based smartphone. Excellent, or good to excellent test-retest reliability were observed in 58 of the 92 temporal, spatial and spatiotemporal gait features in PwMS. However, these were less reliable for HCs. Low SEM% and MDC% values were observed for most of the distribution measures for all gait characteristics for PwMS and HCs. This study demonstrates the inter-session test-retest reliability and provides an indication of clinically important change estimates, for interpreting the outcomes of gait characteristics measured using a body-worn smartphone, during a self-administered 2MWT. This system thus provides a reliable measure of gait characteristics in PwMS, supporting its application for the longitudinal assessment of gait deficits in this population.

Look me in the eye: evaluating the accuracy of smartphone-based eye tracking for potential application in autism spectrum disorder research.

BACKGROUND: Avoidance to look others in the eye is a characteristic symptom of Autism Spectrum Disorders (ASD), and it has been hypothesised that quantitative monitoring of gaze patterns could be useful to objectively evaluate treatments. However, tools to measure gaze behaviour on a regular basis at a manageable cost are missing. In this paper, we investigated whether a smartphone-based tool could address this problem. Specifically, we assessed the accuracy with which the phone-based, state-of-the-art eye-tracking algorithm iTracker can distinguish between gaze towards the eyes and the mouth of a face displayed on the smartphone screen. This might allow mobile, longitudinal monitoring of gaze aversion behaviour in ASD patients in the future. RESULTS: We simulated a smartphone application in which subjects were shown an image on the screen and their gaze was analysed using iTracker. We evaluated the accuracy of our set-up across three tasks in a cohort of 17 healthy volunteers. In the first two tasks, subjects were shown different-sized images of a face and asked to alternate their gaze focus between the eyes and the mouth. In the last task, participants were asked to trace out a circle on the screen with their eyes. We confirm that iTracker can recapitulate the true gaze patterns, and capture relative position of gaze correctly, even on a different phone system to what it was trained on. Subject-specific bias can be corrected using an error model informed from the calibration data. We compare two calibration methods and observe that a linear model performs better than a previously proposed support vector regression-based method. CONCLUSIONS: Under controlled conditions it is possible to reliably distinguish between gaze towards the eyes and the mouth with a smartphone-based set-up. However, future research will be required to improve the robustness of the system to roll angle of the phone and distance between the user and the screen to allow deployment in a home setting. We conclude that a smartphone-based gaze-monitoring tool provides promising opportunities for more quantitative monitoring of ASD.

Correction: Adherence and Satisfaction of Smartphone- and Smartwatch-Based Remote Active Testing and Passive Monitoring in People With Multiple Sclerosis: Nonrandomized Interventional Feasibility Study.

[This corrects the article DOI: 10.2196/14863.].

Adherence and Satisfaction of Smartphone- and Smartwatch-Based Remote Active Testing and Passive Monitoring in People With Multiple Sclerosis: Nonrandomized Interventional Feasibility Study.

BACKGROUND: Current clinical assessments of people with multiple sclerosis are episodic and may miss critical features of functional fluctuations between visits. OBJECTIVE: The goal of the research was to assess the feasibility of remote active testing and passive monitoring using smartphones and smartwatch technology in people with multiple sclerosis with respect to adherence and satisfaction with the FLOODLIGHT test battery. METHODS: People with multiple sclerosis (aged 20 to 57 years; Expanded Disability Status Scale 0-5.5; n=76) and healthy controls (n=25) performed the FLOODLIGHT test battery, comprising active tests (daily, weekly, every two weeks, or on demand) and passive monitoring (sensor-based gait and mobility) for 24 weeks using a smartphone and smartwatch. The primary analysis assessed adherence (proportion of weeks with at least 3 days of completed testing and 4 hours per day passive monitoring) and questionnaire-based satisfaction. In-clinic assessments (clinical and magnetic resonance imaging) were performed. RESULTS: People with multiple sclerosis showed 70% (16.68/24 weeks) adherence to active tests and 79% (18.89/24 weeks) to passive monitoring; satisfaction score was on average 73.7 out of 100. Neither adherence nor satisfaction was associated with specific population characteristics. Test-battery assessments had an at least acceptable impact on daily activities in over 80% (61/72) of people with multiple sclerosis. CONCLUSIONS: People with multiple sclerosis were engaged and satisfied with the FLOODLIGHT test battery. FLOODLIGHT sensor-based measures may enable continuous assessment of multiple sclerosis disease in clinical trials and real-world settings. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02952911; https://clinicaltrials.gov/ct2/show/NCT02952911.

Evaluation of smartphone-based testing to generate exploratory outcome measures in a phase 1 Parkinson's disease clinical trial.

BACKGROUND: Ubiquitous digital technologies such as smartphone sensors promise to fundamentally change biomedical research and treatment monitoring in neurological diseases such as PD, creating a new domain of digital biomarkers. OBJECTIVES: The present study assessed the feasibility, reliability, and validity of smartphone-based digital biomarkers of PD in a clinical trial setting. METHODS: During a 6-month, phase 1b clinical trial with 44 Parkinson participants, and an independent, 45-day study in 35 age-matched healthy controls, participants completed six daily motor active tests (sustained phonation, rest tremor, postural tremor, finger-tapping, balance, and gait), then carried the smartphone during the day (passive monitoring), enabling assessment of, for example, time spent walking and sit-to-stand transitions by gyroscopic and accelerometer data. RESULTS: Adherence was acceptable: Patients completed active testing on average 3.5 of 7 times/week. Sensor-based features showed moderate-to-excellent test-retest reliability (average intraclass correlation coefficient = 0.84). All active and passive features significantly differentiated PD from controls with P < 0.005. All active test features except sustained phonation were significantly related to corresponding International Parkinson and Movement Disorder Society-Sponsored UPRDS clinical severity ratings. On passive monitoring, time spent walking had a significant (P = 0.005) relationship with average postural instability and gait disturbance scores. Of note, for all smartphone active and passive features except postural tremor, the monitoring procedure detected abnormalities even in those Parkinson participants scored as having no signs in the corresponding International Parkinson and Movement Disorder Society-Sponsored UPRDS items at the site visit. CONCLUSIONS: These findings demonstrate the feasibility of smartphone-based digital biomarkers and indicate that smartphone-sensor technologies provide reliable, valid, clinically meaningful, and highly sensitive phenotypic data in Parkinson's disease. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

A hybrid approach identifies metabolic signatures of high-producers for chinese hamster ovary clone selection and process optimization.

In-depth characterization of high-producer cell lines and bioprocesses is vital to ensure robust and consistent production of recombinant therapeutic proteins in high quantity and quality for clinical applications. This requires applying appropriate methods during bioprocess development to enable meaningful characterization of CHO clones and processes. Here, we present a novel hybrid approach for supporting comprehensive characterization of metabolic clone performance. The approach combines metabolite profiling with multivariate data analysis and fluxomics to enable a data-driven mechanistic analysis of key metabolic traits associated with desired cell phenotypes. We applied the methodology to quantify and compare metabolic performance in a set of 10 recombinant CHO-K1 producer clones and a host cell line. The comprehensive characterization enabled us to derive an extended set of clone performance criteria that not only captured growth and product formation, but also incorporated information on intracellular clone physiology and on metabolic changes during the process. These criteria served to establish a quantitative clone ranking and allowed us to identify metabolic differences between high-producing CHO-K1 clones yielding comparably high product titers. Through multivariate data analysis of the combined metabolite and flux data we uncovered common metabolic traits characteristic of high-producer clones in the screening setup. This included high intracellular rates of glutamine synthesis, low cysteine uptake, reduced excretion of aspartate and glutamate, and low intracellular degradation rates of branched-chain amino acids and of histidine. Finally, the above approach was integrated into a workflow that enables standardized high-content selection of CHO producer clones in a high-throughput fashion. In conclusion, the combination of quantitative metabolite profiling, multivariate data analysis, and mechanistic network model simulations can identify metabolic traits characteristic of high-performance clones and enables informed decisions on which clones provide a good match for a particular process platform. The proposed approach also provides a mechanistic link between observed clone phenotype, process setup, and feeding regimes, and thereby offers concrete starting points for subsequent process optimization. Biotechnol. Bioeng. 2016;113: 2005-2019. © 2016 Wiley Periodicals, Inc.

Prediction of VH-VL domain orientation for antibody variable domain modeling.

The antigen-binding site of antibodies forms at the interface of their two variable domains, VH and VL, making VH-VL domain orientation a factor that codetermines antibody specificity and affinity. Preserving VH-VL domain orientation in the process of antibody engineering is important in order to retain the original antibody properties, and predicting the correct VH-VL orientation has also been recognized as an important factor in antibody homology modeling. In this article, we present a fast sequence-based predictor that predicts VH-VL domain orientation with Q(2) values ranging from 0.54 to 0.73 on the evaluation set. We describe VH-VL orientation in terms of the six absolute ABangle parameters that have recently been proposed as a means to separate the different degrees of freedom of VH-VL domain orientation. In order to assess the impact of adjusting VH-VL orientation according to our predictions, we use the set of antibody structures of the recently published Antibody Modeling Assessment (AMA) II study. In comparison to the original AMAII homology models, we find an improvement in the accuracy of VH-VL orientation modeling, which also translates into an improvement in the average root-mean-square deviation with regard to the crystal structures.

Molecular polygamy: The promiscuity of l-phenylalanyl-tRNA-synthetase triggers misincorporation of meta- and ortho-tyrosine in monoclonal antibodies expressed by Chinese hamster ovary cells.

In-depth analytical characterization of biotherapeutics originating from different production batches is mandatory to ensure product safety and consistent molecule efficacy. Previously, we have shown unintended incorporation of tyrosine (Tyr) and leucine/isoleucine (Leu/Ile) at phenylalanine (Phe) positions in a recombinant produced monoclonal antibody (mAb) using an orthogonal MASCOT/SIEVE based approach for mass spectrometry data analysis. The misincorporation could be avoided by sufficient supply of phenylalanine throughout the process. Several non-annotated signals in the primarily chromatographic peptide separation step for apparently single Phe→Tyr sequence variants (SVs) suggest a role for isobar tyrosine isoforms. Meta- and ortho-Tyr are spontaneously generated during aerobic fed-batch production processes using Chinese hamster ovary (CHO) cell lines. Process induced meta- and ortho-Tyr but not proteinogenic para-Tyr are incorporated at Phe locations in Phe-starved CHO cultures expressing a recombinant mAb. Furthermore, meta- and ortho-Tyr are preferably misincorporated over Leu. Structural modeling of the l-phenylalanyl-tRNA-synthetase (PheRS) substrate activation site indicates a possible fit of non-cognate ortho-Tyr and meta-Tyr substrates. Dose-dependent misincorporations of Tyr isoforms support the hypothesis that meta- and ortho-Tyr are competing, alternative substrates for PheRS in CHO processes. Finally, easily accessible at-line surrogate markers for Phe→Tyr SV formation in biotherapeutic production were defined by the calculation of critical ratios for meta-Tyr/Phe and ortho-Tyr/Phe to support early prediction of SV probability, and finally, to allow for immediate process controlled Phe→Tyr SV prevention.

Aggregation and chemical modification of monoclonal antibodies under upstream processing conditions.

PURPOSE: To investigate antibody stability and formation of modified species under upstream processing conditions. METHODS: The stability of 11 purified monoclonal human IgG1 and IgG4 antibodies, including an IgG1-based bispecific CrossMab, was compared in downscale mixing stress models. One of these molecules was further evaluated in realistic bioreactor stress models and in cell culture fermentations. Analytical techniques include size exclusion chromatography (SEC), turbidity measurements, cation exchange chromatography (cIEX), dynamic light scattering (DLS) and differential scanning calorimetry (DSC). RESULTS: Sensitivity in downscale stress models varies among antibodies and results in formation of high molecular weight (HMW) aggregates. Stability is increased in cell culture medium and in bioreactors. Media components stabilizing the proteins were identified. Extensive chemical modifications were detected both in stress models as well as during production of antibodies in cell culture fermentations. CONCLUSIONS: Protective compounds must be present in chemically defined fermentation media in order to stabilize antibodies against the formation of HMW aggregates. An increase in chemical modifications is detectable in bioreactor stress models and over the course of cell culture fermentations; this increase is dependent on the expression rate, pH, temperature and fermentation time. Consequently, product heterogeneity increases during upstream processing, and this compromises the product quality.

Physiological sensor data cleaning with autoencoders.

Objective.Physiological sensor data (e.g. photoplethysmograph) is important for remotely monitoring patients' vital signals, but is often affected by measurement noise. Existing feature-based models for signal cleaning can be limited as they might not capture the full signal characteristics.Approach.In this work we present a deep learning framework for sensor signal cleaning based on dilated convolutions which capture the coarse- and fine-grained structure in order to classify whether a signal is noisy or clean. However, since obtaining annotated physiological data is costly and time-consuming we propose an autoencoder-based semi-supervised model which is able to learn a representation of the sensor signal characteristics, also adding an element of interpretability.Main results.Our proposed models are over 8% more accurate than existing feature-based approaches with half the false positive/negative rates. Finally, we show that with careful tuning (that can be improved further), the semi-supervised model outperforms supervised approaches suggesting that incorporating the large amounts of available unlabeled data can be advantageous for achieving high accuracy (over 90%) and minimizing the false positive/negative rates.Significance.Our approach enables us to reliably separate clean from noisy physiological sensor signal that can pave the development of reliable features and eventually support decisions regarding drug efficacy in clinical trials.

Preliminary validity of the Draw a Shape Test for upper extremity assessment in multiple sclerosis.

OBJECTIVE: To validate the smartphone sensor-based Draw a Shape Test - a part of the Floodlight Proof-of-Concept app for remotely assessing multiple sclerosis-related upper extremity impairment by tracing six different shapes. METHODS: People with multiple sclerosis, classified functionally normal/abnormal via their Nine-Hole Peg Test time, and healthy controls participated in a 24-week, nonrandomized study. Spatial (trace accuracy), temporal (mean and variability in linear, angular, and radial drawing velocities, and dwell time ratio), and spatiotemporal features (trace celerity) were cross-sectionally analyzed for correlation with standard clinical and brain magnetic resonance imaging (normalized brain volume and total lesion volume) disease burden measures, and for capacity to differentiate people with multiple sclerosis from healthy controls. RESULTS: Data from 69 people with multiple sclerosis and 18 healthy controls were analyzed. Trace accuracy (all shapes), linear velocity variability (circle, figure-of-8, spiral shapes), and radial velocity variability (spiral shape) had a mostly fair/moderate-to-good correlation (|r| = 0.14-0.66) with all disease burden measures. Trace celerity also had mostly fair/moderate-to-good correlation (|r| = 0.18-0.41) with Nine-Hole Peg Test performance, cerebellar functional system score, and brain magnetic resonance imaging. Furthermore, partial correlation analysis related these results to motor impairment. People with multiple sclerosis showed greater drawing velocity variability, though slower mean velocity, than healthy controls. Linear velocity (spiral shape) and angular velocity (circle shape) potentially differentiate functionally normal people with multiple sclerosis from healthy controls. INTERPRETATION: The Draw a Shape Test objectively assesses upper extremity impairment and correlates with all disease burden measures, thus aiding multiple sclerosis-related upper extremity impairment characterization.

Personalized Longitudinal Assessment of Multiple Sclerosis Using Smartphones.

Personalized longitudinal disease assessment is central to quickly diagnosing, appropriately managing, and optimally adapting the therapeutic strategy of multiple sclerosis (MS). It is also important for identifying idiosyncratic subject-specific disease profiles. Here, we design a novel longitudinal model to map individual disease trajectories in an automated way using smartphone sensor data that may contain missing values. First, we collect digital measurements related to gait and balance, and upper extremity functions using sensor-based assessments administered on a smartphone. Next, we treat missing data via imputation. We then discover potential markers of MS by employing a generalized estimation equation. Subsequently, parameters learned from multiple training datasets are ensembled to form a simple, unified longitudinal predictive model to forecast MS over time in previously unseen people with MS. To mitigate potential underestimation for individuals with severe disease scores, the final model incorporates additional subject-specific fine-tuning using data from the first day. The results show that the proposed model is promising to achieve personalized longitudinal MS assessment; they also suggest that features related to gait and balance as well as upper extremity function, remotely collected from sensor-based assessments, may be useful digital markers for predicting MS over time.

Assessment of Upper Extremity Function in Multiple Sclerosis: Feasibility of a Digital Pinching Test.

BACKGROUND: The development of touchscreen-based assessments of upper extremity function could benefit people with multiple sclerosis (MS) by allowing convenient, quantitative assessment of their condition. The Pinching Test forms a part of the Floodlight smartphone app (F. Hoffmann-La Roche Ltd, Basel, Switzerland) for people with MS and was designed to capture upper extremity function. OBJECTIVE: This study aimed to evaluate the Pinching Test as a tool for remotely assessing upper extremity function in people with MS. METHODS: Using data from the 24-week, prospective feasibility study investigating the Floodlight Proof-of-Concept app for remotely assessing MS, we examined 13 pinching, 11 inertial measurement unit (IMU)-based, and 13 fatigability features of the Pinching Test. We assessed the test-retest reliability using intraclass correlation coefficients [second model, first type; ICC(2,1)], age- and sex-adjusted cross-sectional Spearman rank correlation, and known-groups validity (data aggregation: median [all features], SD [fatigability features]). RESULTS: We evaluated data from 67 people with MS (mean Expanded Disability Status Scale [EDSS]: 2.4 [SD 1.4]) and 18 healthy controls. In this cohort of early MS, pinching features were reliable [ICC(2,1)=0.54-0.81]; correlated with standard clinical assessments, including the Nine-Hole Peg Test (9HPT) (|r|=0.26-0.54; 10/13 features), EDSS (|r|=0.25-0.36; 7/13 features), and the arm items of the 29-item Multiple Sclerosis Impact Scale (MSIS-29) (|r|=0.31-0.52; 7/13 features); and differentiated people with MS-Normal from people with MS-Abnormal (area under the curve: 0.68-0.78; 8/13 features). IMU-based features showed similar test-retest reliability [ICC(2,1)=0.47-0.84] but showed little correlations with standard clinical assessments. In contrast, fatigability features (SD aggregation) correlated with 9HPT time (|r|=0.26-0.61; 10/13 features), EDSS (|r|=0.26-0.41; 8/13 features), and MSIS-29 arm items (|r|=0.32-0.46; 7/13 features). CONCLUSIONS: The Pinching Test provides a remote, objective, and granular assessment of upper extremity function in people with MS that can potentially complement standard clinical evaluation. Future studies will validate it in more advanced MS. TRIAL REGISTRATION: ClinicalTrials.gov NCT02952911; https://clinicaltrials.gov/study/NCT02952911.

Neural correlates of digital measures shown by structural MRI: a post-hoc analysis of a smartphone-based remote assessment feasibility study in multiple sclerosis.

BACKGROUND: A study was undertaken to evaluate remote monitoring via smartphone sensor-based tests in people with multiple sclerosis (PwMS). This analysis aimed to explore regional neural correlates of digital measures derived from these tests. METHODS: In a 24-week, non-randomized, interventional, feasibility study (NCT02952911), sensor-based tests on the Floodlight Proof-of-Concept app were used to assess cognition (smartphone-based electronic Symbol Digit Modalities Test), upper extremity function (Draw a Shape Test, Pinching Test), and gait and balance (Static Balance Test, Two-Minute Walk Test, U-Turn Test). In this post-hoc analysis, digital measures and standard clinical measures (e.g., Nine-Hole Peg Test [9HPT]) were correlated against regional structural magnetic resonance imaging outcomes. Seventy-six PwMS aged 18-55 years with an Expanded Disability Status Scale score of 0.0-5.5 were enrolled from two different sites (USA and Spain). Sixty-two PwMS were included in this analysis. RESULTS: Worse performance on digital and clinical measures was associated with smaller regional brain volumes and larger ventricular volumes. Whereas digital and clinical measures had many neural correlates in common (e.g., putamen, globus pallidus, caudate nucleus, lateral occipital cortex), some were observed only for digital measures. For example, Draw a Shape Test and Pinching Test measures, but not 9HPT score, correlated with volume of the hippocampus (r = 0.37 [drawing accuracy over time on the Draw a Shape Test]/ - 0.45 [touching asynchrony on the Pinching Test]), thalamus (r = 0.38/ - 0.41), and pons (r = 0.35/ - 0.35). CONCLUSIONS: Multiple neural correlates were identified for the digital measures in a cohort of people with early MS. Digital measures showed associations with brain regions that clinical measures were unable to demonstrate, thus providing potential novel information on functional ability compared with standard clinical assessments.