Digital Biomarkers最新文献

Background: The proliferation and increasing maturity of biometric monitoring technologies allow clinical investigators to measure the health status of trial participants in a more holistic manner, especially outside of traditional clinical settings. This includes capturing meaningful aspects of health in daily living and a more granular and objective manner compared to traditional tools in clinical settings.

Summary: Within multidisciplinary teams, statisticians and data scientists are increasingly involved in clinical trials that incorporate digital clinical measures. They are called upon to provide input into trial planning, generation of evidence on the clinical validity of novel clinical measures, and evaluation of the adequacy of existing evidence. Analysis objectives related to demonstrating clinical validity of novel clinical measures differ from typical objectives related to demonstrating safety and efficacy of therapeutic interventions using established measures which statisticians are most familiar with.

Key messages: This paper discusses key considerations for generating evidence for clinical validity through the lens of the type and intended use of a clinical measure. This paper also briefly discusses the regulatory pathways through which clinical validity evidence may be reviewed and highlights challenges that investigators may encounter while dealing with data from biometric monitoring technologies.

Introduction: Telehealth/remote assessment using readily available 2D mobile cameras and deep learning-based analyses is rapidly becoming a viable option for detecting orofacial and speech impairments associated with neurological and neurodegenerative disease during telehealth practice. However, the psychometric properties (e.g., internal consistency and reliability) of kinematics obtained from these systems have not been established, which is a crucial next step before their clinical usability is established.

Methods: Participants were assessed in lab using a 3 dimensional (3D)-capable camera and at home using a readily-available 2D camera in a tablet. Orofacial kinematics was estimated from videos using a deep facial landmark tracking model. Kinematic features quantified the clinically relevant constructs of velocity, range of motion, and lateralization. In lab, all participants performed the same oromotor task. At home, participants were split into two groups that each performed a variant of the in-lab task. We quantified within-assessment consistency (Cronbach's α), reliability (intraclass correlation coefficient [ICC]), and fitted linear mixed-effects models to at-home data to capture individual-/task-dependent longitudinal trajectories.

Results: Both in lab and at home, Cronbach's α was typically high (>0.80) and ICCs were often good (>0.70). The linear mixed-effect models that best fit the longitudinal data were those that accounted for individual- or task-dependent effects.

Discussion: Remotely gathered orofacial kinematics were as internally consistent and reliable as those gathered in a controlled laboratory setting using a high-performance 3D-capable camera and could additionally capture individual- or task-dependent changes over time. These results highlight the potential of remote assessment tools as digital biomarkers of disease status and progression and demonstrate their suitability for novel telehealth applications.

Background: Digital health technologies are attracting attention as novel tools for data collection in clinical research. They present alternative methods compared to in-clinic data collection, which often yields snapshots of the participants' physiology, behavior, and function that may be prone to biases and artifacts, e.g., white coat hypertension, and not representative of the data in free-living conditions. Modern digital health technologies equipped with multi-modal sensors combine different data streams to derive comprehensive endpoints that are important to study participants and are clinically meaningful. Used for data collection in clinical trials, they can be deployed as provisioned products where technology is given at study start or in a bring your own "device" (BYOD) manner where participants use their technologies to generate study data.

Summary: The BYOD option has the potential to be more user-friendly, allowing participants to use technologies that they are familiar with, ensuring better participant compliance, and potentially reducing the bias that comes with introducing new technologies. However, this approach presents different technical, operational, regulatory, and ethical challenges to study teams. For example, BYOD data can be more heterogeneous, and recruiting historically underrepresented populations with limited access to technology and the internet can be challenging. Despite the rapid increase in digital health technologies for clinical and healthcare research, BYOD use in clinical trials is limited, and regulatory guidance is still evolving.

Key messages: We offer considerations for academic researchers, drug developers, and patient advocacy organizations on the design and deployment of BYOD models in clinical research. These considerations address: (1) early identification and engagement with internal and external stakeholders; (2) study design including informed consent and recruitment strategies; (3) outcome, endpoint, and technology selection; (4) data management including compliance and data monitoring; (5) statistical considerations to meet regulatory requirements. We believe that this article acts as a primer, providing insights into study design and operational requirements to ensure the successful implementation of BYOD clinical studies.

Introduction: Digital biomarkers have significant potential to transform drug development, but only a few have contributed meaningfully to bring new treatments to market. There are uncertainties in how they will generate quantifiable benefits in clinical trial performance and ultimately to the chances of phase 3 success. Here we have proposed a statistical framework and ran a proof-of-concept model with hypothetical digital biomarkers and visualized them in a familiar manner to study power calculation.

Methods: A Monte Carlo simulation for Parkinson's disease (PD) was performed using the Captario SUM® platform and illustrative study technology impact calculations were generated. We took inspiration from the EMA-qualified wearable-derived digital endpoint stride velocity 95^th centile (SV95C) for Duchenne muscular dystrophy, and we imagined a similar measurement for PD would be available in the future. DaTscan enrichment and "SV95C-like" endpoint biomarkers were assumed on a hypothetical disease-modifying drug pivotal trial aiming for an 80% probability of achieving a study p value of less than 0.05.

Results: Four scenarios with different combinations of technologies were illustrated. The model illustrated a way to quantify the magnitude of the contributions that enrichment and endpoint technologies could make to drug development studies.

Discussion/conclusion: Quantitative models could be valuable not only for the study sponsors but also as an interactive and collaborative engagement tool for technology players and multi-stakeholder consortia. Establishing values of digital biomarkers could also facilitate business cases and financial investments.

Digital biomarkers such as wearables are of increasing interest in monitoring rheumatic diseases, but they usually lack disease specificity. In this study, we apply convolutional neural networks (CNN) to real-world hand photographs in order to automatically detect, extract, and analyse dorsal finger fold lines as a correlate of proximal interphalangeal (PIP) joint swelling in patients with rheumatoid arthritis (RA). Hand photographs of RA patients were taken by a smartphone camera in a standardized manner. Overall, 190 PIP joints were categorized as either swollen or not swollen based on clinical judgement and ultrasound. Images were automatically preprocessed by cropping PIP joints and extracting dorsal finger folds. Subsequently, metrical analysis of dorsal finger folds was performed, and a CNN was trained to classify the dorsal finger lines into swollen versus non-swollen joints. Representative horizontal finger folds were also quantified in a subset of patients before and after resolution of PIP swelling and in patients with disease flares. In swollen joints, the number of automatically extracted deep skinfold imprints was significantly reduced compared to non-swollen joints (1.3, SD 0.8 vs. 3.3, SD 0.49, p < 0.01). The joint diameter/deep skinfold length ratio was significantly higher in swollen (4.1, SD 1.4) versus non-swollen joints (2.1, SD 0.6, p < 0.01). The CNN model successfully differentiated swollen from non-swollen joints based on finger fold patterns with a validation accuracy of 0.84, a sensitivity of 88%, and a specificity of 75%. A heatmap of the original images obtained by an extraction algorithm confirmed finger folds as the region of interest for correct classification. After significant response to disease-modifying antirheumatic drug ± corticosteroid therapy, longitudinal metrical analysis of eight representative deep finger folds showed a decrease in the mean diameter/finger fold length (finger fold index, FFI) from 3.03 (SD 0.68) to 2.08 (SD 0.57). Conversely, the FFI increased in patients with disease flares. In conclusion, automated preprocessing and the application of CNN algorithms in combination with longitudinal metrical analysis of dorsal finger fold patterns extracted from real-world hand photos might serve as a digital biomarker in RA.

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.

Introduction: Clinical research and treatment of childhood obesity is challenging, and objective biomarkers obtained in a home-setting are needed. The aim of this study was to determine the potential of novel digital endpoints gathered by a home-monitoring platform in pediatric obesity.

Methods: In this prospective observational study, 28 children with obesity aged 6-16 years were included and monitored for 28 days. Patients wore a smartwatch, which measured physical activity (PA), heart rate (HR), and sleep. Furthermore, daily blood pressure (BP) measurements were performed. Data from 128 healthy children were utilized for comparison. Differences between patients and controls were assessed via linear mixed effect models.

Results: Data from 28 patients (average age 11.6 years, 46% male, average body mass index 30.9) and 128 controls (average age 11.1 years, 46% male, average body mass index 18.0) were analyzed. Patients were recruited between November 2018 and February 2020. For patients, the median compliance for the measurements ranged from 55% to 100% and the highest median compliance was observed for the smartwatch-related measurements (81-100%). Patients had a lower daily PA level (4,597 steps vs. 6,081 steps, 95% confidence interval [CI] 862-2,108) and peak PA level (1,115 steps vs. 1,392 steps, 95% CI 136-417), a higher nighttime HR (81 bpm vs. 71 bpm, 95% CI 6.3-12.3) and daytime HR (98 bpm vs. 88 bpm, 95% CI 7.6-12.6), a higher systolic BP (115 mm Hg vs. 104 mm Hg, 95% CI 8.1-14.5) and diastolic BP (76 mm Hg vs. 65 mm Hg, 95% CI 8.7-12.7), and a shorter sleep duration (difference 0.5 h, 95% CI 0.2-0.7) compared to controls.

Conclusion: Remote monitoring via wearables in pediatric obesity has the potential to objectively measure the disease burden in the home-setting. The novel endpoints demonstrate significant differences in PA level, HR, BP, and sleep duration between patients and controls. Future studies are needed to determine the capacity of the novel digital endpoints to detect effect of interventions.

The assessment of health and disease requires a set of criteria to define health status and progression. These health measures are referred to as "endpoints." A "digital endpoint" is defined by its use of sensor-generated data often collected outside of a clinical setting such as in a patient's free-living environment. Applicable sensors exist in an array of devices and can be applied in a diverse set of contexts. For example, a smartphone's microphone might be used to diagnose or predict mild cognitive impairment due to Alzheimer's disease or a wrist-worn activity monitor (such as those found in smartwatches) may be used to measure a drug's effect on the nocturnal activity of patients with sickle cell disease. Digital endpoints are generating considerable excitement because they permit a more authentic assessment of the patient's experience, reveal formerly untold realities of disease burden, and can cut drug discovery costs in half. However, before these benefits can be realized, effort must be applied not only to the technical creation of digital endpoints but also to the environment that allows for their development and application. The future of digital endpoints rests on meaningful interdisciplinary collaboration, sufficient evidence that digital endpoints can realize their promise, and the development of an ecosystem in which the vast quantities of data that digital endpoints generate can be analyzed. The fundamental nature of health care is changing. With coronavirus disease 2019 serving as a catalyst, there has been a rapid expansion of home care models, telehealth, and remote patient monitoring. The increasing adoption of these health-care innovations will expedite the requirement for a digital characterization of clinical status as current assessment tools often rely upon direct interaction with patients and thus are not fit for purpose to be administered remotely. With the ubiquity of relatively inexpensive sensors, digital endpoints are positioned to drive this consequential change. It is therefore not surprising that regulators, physicians, researchers, and consultants have each offered their assessment of these novel tools. However, as we further describe later, the broad adoption of digital endpoints will require a cooperative effort. In this article, we present an analysis of the current state of digital endpoints. We also attempt to unify the perspectives of the parties involved in the development and deployment of these tools. We conclude with an interdependent list of challenges that must be collaboratively addressed before these endpoints are widely adopted.