Upper limb movements as digital biomarkers in people with ALS.

BACKGROUND: Objective evaluation of people with amyotrophic lateral sclerosis (PALS) in free-living settings is challenging. The introduction of portable digital devices, such as wearables and smartphones, may improve quantifying disease progression and hasten therapeutic development. However, there is a need for tools to characterize upper limb movements in neurologic disease and disability. METHODS: Twenty PALS wore a wearable accelerometer, ActiGraph Insight Watch, on their wrist for six months. They also used Beiwe, a smartphone application that collected self-entry ALS Functional Rating Scale-Revised (ALSFRS-RSE) survey responses every 1-4 weeks. We developed several measures that quantify count and duration of upper limb movements: flexion, extension, supination, and pronation. New measures were compared against ALSFRS-RSE total score (Q1-12), and individual responses to specific questions related to handwriting (Q4), cutting food (Q5), dressing and performing hygiene (Q6), and turning in bed and adjusting bed clothes (Q7). Additional analysis considered adjusting for total activity counts (TAC). FINDINGS: At baseline, PALS with higher Q1-12 performed more upper limb movements, and these movements were faster compared to individuals with more advanced disease. Most upper limb movement metrics had statistically significant change over time, indicating declining function either by decreasing count metrics or by increasing duration metric. All count and duration metrics were significantly associated with Q1-12, flexion and extension counts were significantly associated with Q6 and Q7, supination and pronation counts were also associated with Q4. All duration metrics were associated with Q6 and Q7. All duration metrics retained their statistical significance after adjusting for TAC. INTERPRETATION: Wearable accelerometer data can be used to generate digital biomarkers on upper limb movements and facilitate patient monitoring in free-living environments. The presented method offers interpretable monitoring of patients' functioning and versatile tracking of disease progression in the limb of interest. FUNDING: Mitsubishi-Tanabe Pharma Holdings America, Inc.

Advancing clinical development for neuronopathic Hunter syndrome through a quantitatively-driven reverse translation framework.

A quantitatively-driven evaluation of existing clinical data and associated knowledge to accelerate drug discovery and development is a highly valuable approach across therapeutic areas, but remains underutilized. This is especially the case for rare diseases for which development is particularly challenging. The current work outlines an organizational framework to support a quantitatively-based reverse translation approach to clinical development. This approach was applied to characterize predictors of the trajectory of cognition in Hunter syndrome (Mucopolysaccharidosis Type II; MPS-II), a rare X-linked lysosomal storage disorder, highly heterogeneous in its course. Specifically, we considered ways to refine target populations based on age, cognitive status, and biomarkers, that is, cerebrospinal fluid glycosaminoglycans (GAG), at trial entry. Data from a total of 138 subjects (age range 2.5 to 10.1 years) from Takeda-sponsored internal studies and external natural history studies in MPS-II were included. Quantitative analyses using mixed-effects models were performed to characterize the relationships between neurocognitive outcomes and potential indicators of disease progression. Results revealed a specific trajectory in cognitive development across age with an initial progressive phase, followed by a plateau between 4 and 8 years and then a variable declining phase. Additionally, results suggest a faster decline in cognition among subjects with lower cognitive scores or with higher cerebrospinal fluid GAG at enrollment. These results support differences in the neurocognitive course of MPS-II between distinct groups of patients based on age, cognitive function, and biomarker status at enrollment. These differences should be considered when designing future clinical trials.

Wearable device and smartphone data quantify ALS progression and may provide novel outcome measures.

Amyotrophic lateral sclerosis (ALS) therapeutic development has largely relied on staff-administered functional rating scales to determine treatment efficacy. We sought to determine if mobile applications (apps) and wearable devices can be used to quantify ALS disease progression through active (surveys) and passive (sensors) data collection. Forty ambulatory adults with ALS were followed for 6-months. The Beiwe app was used to administer the self-entry ALS functional rating scale-revised (ALSFRS-RSE) and the Rasch Overall ALS Disability Scale (ROADS) surveys every 2-4 weeks. Each participant used a wrist-worn activity monitor (ActiGraph Insight Watch) or an ankle-worn activity monitor (Modus StepWatch) continuously. Wearable device wear and app survey compliance were adequate. ALSFRS-R highly correlated with ALSFRS-RSE. Several wearable data daily physical activity measures demonstrated statistically significant change over time and associations with ALSFRS-RSE and ROADS. Active and passive digital data collection hold promise for novel ALS trial outcome measure development.

Free-Living Gait Cadence Measured by Wearable Accelerometer: A Promising Alternative to Traditional Measures of Mobility for Assessing Fall Risk.

BACKGROUND: Wearable devices have become widespread in research applications, yet evidence on whether they are superior to structured clinic-based assessments is sparse. In this manuscript, we compare traditional, laboratory-based metrics of mobility with a novel accelerometry-based measure of free-living gait cadence for predicting fall rates. METHODS: Using negative binomial regression, we compared traditional in-clinic measures of mobility (6-minute gait cadence, speed, and distance, and 4-m gait speed) with free-living gait cadence from wearable accelerometers in predicting fall rates. Accelerometry data were collected with wrist-worn Actigraphs (GT9X) over 7 days in 432 community-dwelling older adults (aged 77.29 ± 5.46 years, 59.1% men, 80.2% White) participating in the Study to Understand Fall Reduction and Vitamin D in You. Falls were ascertained using monthly calendars, quarterly contacts, and ad hoc telephone reports. Accelerometry-based free-living gait cadence was estimated with the Adaptive Empirical Pattern Transformation algorithm. RESULTS: Across all participants, free-living cadence was significantly related to fall rates; every 10 steps per minute higher cadence was associated with a 13.2% lower fall rate (p = .036). Clinic-based measures of mobility were not related to falls (p > .05). Among higher-functioning participants (cadence ≥100 steps/minute), every 10 steps per minute higher free-living cadence was associated with a 27.7% lower fall rate (p = .01). In participants with slow baseline gait (gait speed <0.8 m/s), all metrics were significantly associated with fall rates. CONCLUSION: Data collected from biosensors in the free-living environment may provide a more sensitive indicator of fall risk than in-clinic tests, especially among higher-functioning older adults who may be more responsive to intervention. CLINICAL TRIAL REGISTRATION: NCT02166333.

Smartphone-Based Gait Cadence to Identify Older Adults with Decreased Functional Capacity.

Background: Functional capacity assessment is a critical step in the preoperative evaluation to identify patients at increased risk of cardiac complications and disability after major noncardiac surgery. Smartphones offer the potential to objectively measure functional capacity but are limited by inaccuracy in patients with poor functional capacity. Open-source methods exist to analyze accelerometer data to estimate gait cadence (steps/min), which is directly associated with activity intensity. Here, we used an updated Step Test smartphone application with an open-source method to analyze accelerometer data to estimate gait cadence and functional capacity in older adults. Methods: We performed a prospective observational cohort study within the Frailty, Activity, Body Composition and Energy Expenditure in Aging study at the University of Chicago. Participants completed the Duke Activity Status Index (DASI) and performed an in-clinic 6-min walk test (6MWT) while using the Step Test application on a study smartphone. Gait cadence was measured from the raw accelerometer data using an adaptive empirical pattern transformation method, which has been previously validated. A 6MWT distance of 370 m was used as an objective threshold to identify patients at high risk. We performed multivariable logistic regression to predict walking distance using a priori explanatory variables. Results: Sixty patients were enrolled in the study. Thirty-seven patients completed the protocol and were included in the final data analysis. The median (IQR) age of the overall cohort was 71 (69-74) years, with a body mass index of 31 (27-32). There were no differences in any clinical characteristics or functional measures between participants that were able to walk 370 m during the 6MWT and those that could not walk that distance. Median (IQR) gait cadence for the entire cohort was 110 (102-114) steps/min during the 6MWT. Median (IQR) gait cadence was higher in participants that walked more than 370 m during the 6MWT 112 (108-118) versus 106 (96-114) steps/min; p = 0.0157). The final multivariable model to identify participants that could not walk 370 m included only median gait cadence. The Youden's index cut-point was 107 steps/min with a sensitivity of 0.81 (95% CI: 0.77, 0.85) and a specificity of 0.57 (95% CI: 0.55, 0.59) and an AUCROC of 0.69 (95% CI: 0.51, 0.87). Conclusions: Our pilot study demonstrates the feasibility of using gait cadence as a measure to estimate functional capacity. Our study was limited by a smaller than expected sample size due to COVID-19, and thus, a prospective study with preoperative patients that measures outcomes is necessary to validate our findings.

Comparison of Accelerometry-Based Measures of Physical Activity: Retrospective Observational Data Analysis Study.

BACKGROUND: Given the evolution of processing and analysis methods for accelerometry data over the past decade, it is important to understand how newer summary measures of physical activity compare with established measures. OBJECTIVE: We aimed to compare objective measures of physical activity to increase the generalizability and translation of findings of studies that use accelerometry-based data. METHODS: High-resolution accelerometry data from the Baltimore Longitudinal Study on Aging were retrospectively analyzed. Data from 655 participants who used a wrist-worn ActiGraph GT9X device continuously for a week were summarized at the minute level as ActiGraph activity count, monitor-independent movement summary, Euclidean norm minus one, mean amplitude deviation, and activity intensity. We calculated these measures using open-source packages in R. Pearson correlations between activity count and each measure were quantified both marginally and conditionally on age, sex, and BMI. Each measures pair was harmonized using nonparametric regression of minute-level data. RESULTS: Data were from a sample (N=655; male: n=298, 45.5%; female: n=357, 54.5%) with a mean age of 69.8 years (SD 14.2) and mean BMI of 27.3 kg/m2 (SD 5.0). The mean marginal participant-specific correlations between activity count and monitor-independent movement summary, Euclidean norm minus one, mean amplitude deviation, and activity were r=0.988 (SE 0.0002324), r=0.867 (SE 0.001841), r=0.913 (SE 0.00132), and r=0.970 (SE 0.0006868), respectively. After harmonization, mean absolute percentage errors of predicting total activity count from monitor-independent movement summary, Euclidean norm minus one, mean amplitude deviation, and activity intensity were 2.5, 14.3, 11.3, and 6.3, respectively. The accuracies for predicting sedentary minutes for an activity count cut-off of 1853 using monitor-independent movement summary, Euclidean norm minus one, mean amplitude deviation, and activity intensity were 0.981, 0.928, 0.904, and 0.960, respectively. An R software package called SummarizedActigraphy, with a unified interface for computation of the measures from raw accelerometry data, was developed and published. CONCLUSIONS: The findings from this comparison of accelerometry-based measures of physical activity can be used by researchers and facilitate the extension of knowledge from existing literature by demonstrating the high correlation between activity count and monitor-independent movement summary (and other measures) and by providing harmonization mapping.

Quantification of acceleration as activity counts in ActiGraph wearable.

Digital clinical measures based on data collected by wearable devices have seen rapid growth in both clinical trials and healthcare. The widely-used measures based on wearables are epoch-based physical activity counts using accelerometer data. Even though activity counts have been the backbone of thousands of clinical and epidemiological studies, there are large variations of the algorithms that compute counts and their associated parameters-many of which have often been kept proprietary by device providers. This lack of transparency has hindered comparability between studies using different devices and limited their broader clinical applicability. ActiGraph devices have been the most-used wearable accelerometer devices for over two decades. Recognizing the importance of data transparency, interpretability and interoperability to both research and clinical use, we here describe the detailed counts algorithms of five generations of ActiGraph devices going back to the first AM7164 model, and publish the current counts algorithm in ActiGraph's ActiLife and CentrePoint software as a standalone Python package for research use. We believe that this material will provide a useful resource for the research community, accelerate digital health science and facilitate clinical applications of wearable accelerometry.

Estimation of free-living walking cadence from wrist-worn sensor accelerometry data and its association with SF-36 quality of life scores.

Objective. We evaluate the stride segmentation performance of the Adaptive Empirical Pattern Transformation (ADEPT) for subsecond-level accelerometry data collected in the free-living environment using a wrist-worn sensor.Approach. We substantially expand the scope of the existing ADEPT pattern-matching algorithm. Methods are applied to subsecond-level accelerometry data collected continuously for 4 weeks in 45 participants, including 30 arthritis and 15 control patients. We estimate the daily walking cadence for each participant and quantify its association with SF-36 quality of life measures.Main results. We provide free, open-source software to segment individual walking strides in subsecond-level accelerometry data. Walking cadence is significantly associated with the role physical score reported via SF-36 after adjusting for age, gender, weight and height.Significance. Methods provide automatic, precise walking stride segmentation, which allows estimation of walking cadence from free-living wrist-worn accelerometry data. Results provide new evidence of associations between free-living walking parameters and health outcomes.

Connectivity-informed adaptive regularization for generalized outcomes.

One of the challenging problems in neuroimaging is the principled incorporation of information from different imaging modalities. Data from each modality are frequently analyzed separately using, for instance, dimensionality reduction techniques, which result in a loss of mutual information. We propose a novel regularization method, generalized ridgified Partially Empirical Eigenvectors for Regression (griPEER), to estimate associations between the brain structure features and a scalar outcome within the generalized linear regression framework. griPEER improves the regression coefficient estimation by providing a principled approach to use external information from the structural brain connectivity. Specifically, we incorporate a penalty term, derived from the structural connectivity Laplacian matrix, in the penalized generalized linear regression. In this work, we address both theoretical and computational issues and demonstrate the robustness of our method despite incomplete information about the structural brain connectivity. In addition, we also provide a significance testing procedure for performing inference on the estimated coefficients. Finally, griPEER is evaluated both in extensive simulation studies and using clinical data to classify HIV+ and HIV- individuals.

L'un des défis en imagerie cérébrale consiste à établir les principes pour incorporer de l'information provenant de différentes modalités d'imagerie. Les données de chaque modalité sont fréquemment analysées séparément, exploitant par exemple des techniques de réduction de la dimension, ce qui conduit à une perte d'information mutuelle. Les auteurs proposent une nouvelle méthode de régularisation, griPEER (ou par vecteurs propres ridgifiés partiellement empiriques généralisés pour la régression) afin d'estimer l'association entre des caratéristiques de structures du cerveau et une variable réponse scalaire dans le cadre d'une régression linéaire généralisée. Les griPEER améliorent l'estimation des coefficients de régression en établissant les principes d'une approche permettant d'utiliser des informations externes de connectivité des structures du cerveau. À cet effet, les auteurs ajoutent au modèle de régression pénalisée généralisé un terme de pénalité dérivé de la matrice laplacienne de connectivité structurelle. Les auteurs résolvent des problèmes théoriques et calculatoires, puis démontrent la robustesse de leur méthode lorsque l'information à propos de la connectivité du cerveau est incomplète. De plus, ils présentent une procédure de test d'hypothèse permettant de l'inférence au sujet des paramètres estimés. Finalement, les auteurs évaluent les griPEER dans de vastes études de simulation et en utilisant des données cliniques afin de classifier les individus en VIH+ et VIH−.

Adaptive empirical pattern transformation (ADEPT) with application to walking stride segmentation.

Quantifying gait parameters and ambulatory monitoring of changes in these parameters have become increasingly important in epidemiological and clinical studies. Using high-density accelerometry measurements, we propose adaptive empirical pattern transformation (ADEPT), a fast, scalable, and accurate method for segmentation of individual walking strides. ADEPT computes the covariance between a scaled and translated pattern function and the data, an idea similar to the continuous wavelet transform. The difference is that ADEPT uses a data-based pattern function, allows multiple pattern functions, can use other distances instead of the covariance, and the pattern function is not required to satisfy the wavelet admissibility condition. Compared to many existing approaches, ADEPT is designed to work with data collected at various body locations and is invariant to the direction of accelerometer axes relative to body orientation. The method is applied to and validated on accelerometry data collected during a $450$-m outdoor walk of $32$ study participants wearing accelerometers on the wrist, hip, and both ankles. Additionally, all scripts and data needed to reproduce presented results are included in supplementary material available at Biostatistics online.

Predicting Subjective Recovery from Lower Limb Surgery Using Consumer Wearables.

INTRODUCTION: A major challenge in the monitoring of rehabilitation is the lack of long-term individual baseline data which would enable accurate and objective assessment of functional recovery. Consumer-grade wearable devices enable the tracking of individual everyday functioning prior to illness or other medical events which necessitate the monitoring of recovery trajectories. METHODS: For 1,324 individuals who underwent surgery on a lower limb, we collected their Fitbit device data of steps, heart rate, and sleep from 26 weeks before to 26 weeks after the self-reported surgery date. We identified subgroups of individuals who self-reported surgeries for bone fracture repair (n = 355), tendon or ligament repair/reconstruction (n = 773), and knee or hip joint replacement (n = 196). We used linear mixed models to estimate the average effect of time relative to surgery on daily activity measurements while adjusting for gender, age, and the participant-specific activity baseline. We used a sub-cohort of 127 individuals with dense wearable data who underwent tendon/ligament surgery and employed XGBoost to predict the self-reported recovery time. RESULTS: The 1,324 study individuals were all US residents, predominantly female (84%), white or Caucasian (85%), and young to middle-aged (mean age 36.2 years). We showed that 12 weeks pre- and 26 weeks post-surgery trajectories of daily behavioral measurements (steps sum, heart rate, sleep efficiency score) can capture activity changes relative to an individual's baseline. We demonstrated that the trajectories differ across surgery types, recapitulate the documented effect of age on functional recovery, and highlight differences in relative activity change across self-reported recovery time groups. Finally, using a sub-cohort of 127 individuals, we showed that long-term recovery can be accurately predicted, on an individual level, only 1 month after surgery (AUROC 0.734, AUPRC 0.8). Furthermore, we showed that predictions are most accurate when long-term, individual baseline data are available. DISCUSSION: Leveraging long-term, passively collected wearable data promises to enable relative assessment of individual recovery and is a first step towards data-driven intervention for individuals.

Accelerometry data in health research: challenges and opportunities.

Wearable accelerometers provide detailed, objective, and continuous measurements of physical activity (PA). Recent advances in technology and the decreasing cost of wearable devices led to an explosion in the popularity of wearable technology in health research. An ever-increasing number of studies collect high-throughput, sub-second level raw acceleration data. In this paper, we discuss problems related to the collection and analysis of raw accelerometry data and refer to published solutions. In particular, we describe the size and complexity of the data, the within- and between-subject variability, and the effects of sensor location on the body. We also discuss challenges related to sampling frequency, device calibration, data labeling and multiple PA monitors synchronization. We illustrate these points using the Developmental Epidemiological Cohort Study (DECOS), which collected raw accelerometry data on individuals both in a controlled and the free-living environment.

Brain connectivity-informed regularization methods for regression.

One of the challenging problems in brain imaging research is a principled incorporation of information from different imaging modalities. Frequently, each modality is analyzed separately using, for instance, dimensionality reduction techniques, which result in a loss of mutual information. We propose a novel regularization-method to estimate the association between the brain structure features and a scalar outcome within the linear regression framework. Our regularization technique provides a principled approach to use external information from the structural brain connectivity and inform the estimation of the regression coefficients. Our proposal extends the classical Tikhonov regularization framework by defining a penalty term based on the structural connectivity-derived Laplacian matrix. Here, we address both theoretical and computational issues. The approach is first illustrated using simulated data and compared with other penalized regression methods. We then apply our regularization method to study the associations between the alcoholism phenotypes and brain cortical thickness using a diffusion imaging derived measure of structural connectivity. Using the proposed methodology in 148 young male subjects with a risk for alcoholism, we found a negative associations between cortical thickness and drinks per drinking day in bilateral caudal anterior cingulate cortex, left lateral OFC and left precentral gyrus.