Definitions of digital biomarkers: a systematic mapping of the biomedical literature.

BACKGROUND: Technological devices such as smartphones, wearables and virtual assistants enable health data collection, serving as digital alternatives to conventional biomarkers. We aimed to provide a systematic overview of emerging literature on 'digital biomarkers,' covering definitions, features and citations in biomedical research. METHODS: We analysed all articles in PubMed that used 'digital biomarker(s)' in title or abstract, considering any study involving humans and any review, editorial, perspective or opinion-based articles up to 8 March 2023. We systematically extracted characteristics of publications and research studies, and any definitions and features of 'digital biomarkers' mentioned. We described the most influential literature on digital biomarkers and their definitions using thematic categorisations of definitions considering the Food and Drug Administration Biomarkers, EndpointS and other Tools framework (ie, data type, data collection method, purpose of biomarker), analysing structural similarity of definitions by performing text and citation analyses. RESULTS: We identified 415 articles using 'digital biomarker' between 2014 and 2023 (median 2021). The majority (283 articles; 68%) were primary research. Notably, 287 articles (69%) did not provide a definition of digital biomarkers. Among the 128 articles with definitions, there were 127 different ones. Of these, 78 considered data collection, 56 data type, 50 purpose and 23 included all three components. Those 128 articles with a definition had a median of 6 citations, with the top 10 each presenting distinct definitions. CONCLUSIONS: The definitions of digital biomarkers vary significantly, indicating a lack of consensus in this emerging field. Our overview highlights key defining characteristics, which could guide the development of a more harmonised accepted definition.

Clinical trial evidence of quality-of-life effects of disease-modifying therapies for multiple sclerosis: a systematic analysis.

BACKGROUND: Increasingly, patients, clinicians, and regulators call for more evidence on the impact of innovative medicines on quality of life (QoL). We assessed the effects of disease-modifying therapies (DMTs) on QoL in people with multiple sclerosis (PwMS). METHODS: Randomized trials assessing approved DMTs in PwMS with results for at least one outcome referred to as "quality of life" were searched in PubMed and ClinicalTrials.gov. RESULTS: We identified 38 trials published between 1999 and 2023 with a median of 531 participants (interquartile range (IQR) 202 to 941; total 23,225). The evaluated DMTs were mostly interferon-beta (n = 10; 26%), fingolimod (n = 7; 18%), natalizumab (n = 5; 13%), and glatiramer acetate (n = 4; 11%). The 38 trials used 18 different QoL instruments, with up to 11 QoL subscale measures per trial (median 2; IQR 1-3). QoL was never the single primary outcome. We identified quantitative QoL results in 24 trials (63%), and narrative statements in 15 trials (39%). In 16 trials (42%), at least one of the multiple QoL results was statistically significant. The effect sizes of the significant quantitative QoL results were large (median Cohen's d 1.02; IQR 0.3-1.7; median Hedges' g 1.01; IQR 0.3-1.69) and ranged between d 0.14 and 2.91. CONCLUSIONS: Certain DMTs have the potential to positively impact QoL of PwMS, and the assessment and reporting of QoL is suboptimal with a multitude of diverse instruments being used. There is an urgent need that design and reporting of clinical trials reflect the critical importance of QoL for PwMS.

Use of pragmatic randomized trials in multiple sclerosis: A systematic overview.

BACKGROUND: Pragmatic trials are increasingly recognized for providing real-world evidence on treatment choices. OBJECTIVE: The objective of this study is to investigate the use and characteristics of pragmatic trials in multiple sclerosis (MS). METHODS: Systematic literature search and analysis of pragmatic trials on any intervention published up to 2022. The assessment of pragmatism with PRECIS-2 (PRagmatic Explanatory Continuum Indicator Summary-2) is performed. RESULTS: We identified 48 pragmatic trials published 1967-2022 that included a median of 82 participants (interquartile range (IQR) = 42-160) to assess typically supportive care interventions (n = 41; 85%). Only seven trials assessed drugs (15%). Only three trials (6%) included >500 participants. Trials were mostly from the United Kingdom (n = 18; 38%), Italy (n = 6; 13%), the United States and Denmark (each n = 5; 10%). Primary outcomes were diverse, for example, quality-of-life, physical functioning, or disease activity. Only 1 trial (2%) used routinely collected data for outcome ascertainment. No trial was very pragmatic in all design aspects, but 14 trials (29%) were widely pragmatic (i.e. PRECIS-2 score ⩾ 4/5 in all domains). CONCLUSION: Only few and mostly small pragmatic trials exist in MS which rarely assess drugs. Despite the widely available routine data infrastructures, very few trials utilize them. There is an urgent need to leverage the potential of this pioneering study design to provide useful randomized real-world evidence.

Smartwatch-derived sleep and heart rate measures complement step counts in explaining established metrics of MS severity.

BACKGROUND: Passive remote monitoring of patients with MS (PwMS) with sensor-based wearable technologies promises near-continuous evaluation with high ecological validity. Step counts correlate strongly with traditional measures of MS severity. We hypothesized that remote monitoring of sleep and heart rate will yield complementary information. METHODS: We recruited 31 PwMS and 31 age- and sex-matched healthy volunteers (HV) as part of the dreaMS feasibility study (NCT04413032). Fitbit Versa 2 smartwatches were worn for 6 weeks and provided a total of 25 features for activity, heart rate, and sleep. Features were selected based on their pairwise intercorrelation (Pearson |r| < 0.6), test-retest reliability (intraclass correlation coefficient ≥ 0.6 or median coefficient of variation < 0.2) and group comparisons between HV and PwMS with moderate disability (expanded disability status scale (EDSS) ≥ 3.5) (rank-biserial |r| ≥ 0.5). These selected features were correlated with clinical reference tests (EDSS, timed 25-foot walk (T25FW), MS-walking scale (MSWS-12)) in PwMS, and multivariate models adjusted for age, sex, and disease duration were compared. RESULTS: We analyzed 28 PwMS (68% female, mean age 44 years, median EDSS 3.0) and 26 HV in our primary analysis. The objectively selected features discriminated well between HV and PwMS with moderate disability with rank-biserial r = 0.83 for Total number of steps, 0.51 for Deep sleep proportion, -0.51 for Median heart rate, 0.85 for Proportion very active, and 0.65 for Total number of floors. In PwMS they correlated strongly with the three clinical reference tests EDSS (strongest Spearman ρ = -0.75 for Proportion very active), T25FW (-0.75 for Total number of floors), and MSWS-12 (-0.72 for Total number of floors). Deep sleep proportion and Median heart rate complemented Total number of steps in explaining the variance of reference tests. CONCLUSIONS: Activity, deep sleep and heart rate measures can be derived reliably from smartwatches and contain independent clinically meaningful information about MS severity, highlighting their potential for continuous passive monitoring in both clinical trials and clinical care of PwMS.

Wearable Sensor Technologies to Assess Motor Functions in People With Multiple Sclerosis: Systematic Scoping Review and Perspective.

BACKGROUND: Wearable sensor technologies have the potential to improve monitoring in people with multiple sclerosis (MS) and inform timely disease management decisions. Evidence of the utility of wearable sensor technologies in people with MS is accumulating but is generally limited to specific subgroups of patients, clinical or laboratory settings, and functional domains. OBJECTIVE: This review aims to provide a comprehensive overview of all studies that have used wearable sensors to assess, monitor, and quantify motor function in people with MS during daily activities or in a controlled laboratory setting and to shed light on the technological advances over the past decades. METHODS: We systematically reviewed studies on wearable sensors to assess the motor performance of people with MS. We scanned PubMed, Scopus, Embase, and Web of Science databases until December 31, 2022, considering search terms "multiple sclerosis" and those associated with wearable technologies and included all studies assessing motor functions. The types of results from relevant studies were systematically mapped into 9 predefined categories (association with clinical scores or other measures; test-retest reliability; group differences, 3 types; responsiveness to change or intervention; and acceptability to study participants), and the reporting quality was determined through 9 questions. We followed the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) reporting guidelines. RESULTS: Of the 1251 identified publications, 308 were included: 176 (57.1%) in a real-world context, 107 (34.7%) in a laboratory context, and 25 (8.1%) in a mixed context. Most publications studied physical activity (196/308, 63.6%), followed by gait (81/308, 26.3%), dexterity or tremor (38/308, 12.3%), and balance (34/308, 11%). In the laboratory setting, outcome measures included (in addition to clinical severity scores) 2- and 6-minute walking tests, timed 25-foot walking test, timed up and go, stair climbing, balance tests, and finger-to-nose test, among others. The most popular anatomical landmarks for wearable placement were the waist, wrist, and lower back. Triaxial accelerometers were most commonly used (229/308, 74.4%). A surge in the number of sensors embedded in smartphones and smartwatches has been observed. Overall, the reporting quality was good. CONCLUSIONS: Continuous monitoring with wearable sensors could optimize the management of people with MS, but some hurdles still exist to full clinical adoption of digital monitoring. Despite a possible publication bias and vast heterogeneity in the outcomes reported, our review provides an overview of the current literature on wearable sensor technologies used for people with MS and highlights shortcomings, such as the lack of harmonization, transparency in reporting methods and results, and limited data availability for the research community. These limitations need to be addressed for the growing implementation of wearable sensor technologies in clinical routine and clinical trials, which is of utmost importance for further progress in clinical research and daily management of people with MS. TRIAL REGISTRATION: PROSPERO CRD42021243249; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=243249.

Assessment of cognitive performance in multiple sclerosis using smartphone-based training games: a feasibility study.

BACKGROUND: Cognitive impairment occurs in up to 70% of people with MS (pwMS) and has a large impact on quality of life and working capacity. As part of the development of a smartphone-app (dreaMS) for monitoring MS disease activity and progression, we assessed the feasibility and acceptance of using cognitive games as assessment tools for cognitive domains. METHODS: We integrated ten cognitive games in the dreaMS app. Participants were asked to play these games twice a week for 5 weeks. All subjects underwent a battery of established neuropsychological tests. User feedback on acceptance was obtained via a five-point Likert-scale questionnaire. We correlated game performance measures with predetermined reference tests (Spearman's rho) and analyzed differences between pwMS and Healthy Controls (rank biserial correlation). RESULTS: We included 31 pwMS (mean age 43.4 ± 12.0 years; 68% females; median Expanded Disability Status Scale score 3.0, range 1.0-6.0) and 31 age- and sex-matched HC. All but one game showed moderate-strong correlations with their reference tests, (|rs|= 0.34-0.77). Performance improved in both groups over the 5 weeks. Average ratings for overall impression and meaningfulness were 4.6 (range 4.2-4.9) and 4.7 (range 4.5-4.8), respectively. CONCLUSION: Moderate-strong correlations with reference tests suggest that adaptive cognitive games may be used as measures of cognitive domains. The practice effects observed suggest that game-derived measures may capture change over time. All games were perceived as enjoyable and meaningful, features crucial for long-term adherence. Our results encourage further validation of adaptive cognitive games as monitoring tools for cognition in larger studies of longer duration. STUDY REGISTER: ClinicalTrials.gov: NCT04413032.

Reliability and acceptance of dreaMS, a software application for people with multiple sclerosis: a feasibility study.

BACKGROUND: There is an unmet need for reliable and sensitive measures for better monitoring people with multiple sclerosis (PwMS) to detect disease progression early and adapt therapeutic measures accordingly. OBJECTIVE: To assess reliability of extracted features and meaningfulness of 11 tests applied through a smartphone application ("dreaMS"). METHODS: PwMS (age 18-70 and EDSS ≤ 6.5) and matched healthy volunteers (HV) were asked to perform tests installed on their smartphone once or twice weekly for 5 weeks. Primary outcomes were test-retest reliability of test features (target: intraclass correlation [ICC] ≥ 0.6 or median coefficient of variation [mCV] < 0.2) and reported meaningfulness of the tests by PwMS. Meaningfulness was self-assessed for each test on a 5-point Likert scale (target: mean score of > 3) and by a structured interview. CLINICALTRIALS: gov Identifier: NCT04413032. RESULTS: We included 31 PwMS (21 [68%] female, mean age 43.4 ± 12.0 years, median EDSS 3.0 [range 1.0-6.0]) and 31 age- and sex-matched healthy volunteers. Out of 133 features extracted from 11 tests, 89 met the preset reliability criteria. All 11 tests were perceived as highly meaningful to PwMS. CONCLUSION: The dreaMS app reliably assessed features reflecting key functional domains meaningful to PwMS. More studies with longer follow-up are needed to prove validity of these measures as digital biomarkers in PwMS.

Health impact of seven herpesviruses on (pre)diabetes incidence and HbA1c: results from the KORA cohort.

AIMS/HYPOTHESIS: The prevalence of type 2 diabetes is increasing worldwide, and previous studies have suggested that it is higher in individuals who are seropositive for herpesviruses. This study examines the prospective association of herpesviruses with (pre)diabetes to evaluate their potential role in diabetes aetiology. METHODS: Two follow-up examinations of the German population-based KORA cohort (F4 and FF4) were used to identify participants with normal glucose tolerance at baseline, thus being at risk for (pre)diabetes (n = 1257). All participants had repeated OGTTs and antibody measurements for herpes simplex virus (HSV) 1 and 2, varicella-zoster virus, Epstein-Barr virus, cytomegalovirus (CMV) and human herpesvirus 6 and 7. Regression models were used to evaluate the association between serostatus with (pre)diabetes incidence after a 7 year follow-up and HbA1c. RESULTS: HSV2 and CMV were associated with (pre)diabetes incidence after adjustment for sex, age, BMI, education, smoking, physical activity, parental diabetes, hypertension, lipid levels, insulin resistance and fasting glucose. Seropositivity of both viruses was also cross-sectionally associated with higher HbA1c at baseline, with the association of HSV2 being independent of confounders, including the prevalence of (pre)diabetes itself. While seropositivity for multiple herpesviruses was associated with a higher incidence of (pre)diabetes, this association was not independent of confounders. CONCLUSIONS/INTERPRETATION: The associations of HSV2 and CMV serostatus with (pre)diabetes incidence indicate that these herpesviruses may contribute to the development of impaired glucose metabolism. Our results highlight the link between viral infection and (pre)diabetes, and the need for more research evaluating viral prevention strategies.

Practice Effects of Mobile Tests of Cognition, Dexterity, and Mobility on Patients With Multiple Sclerosis: Data Analysis of a Smartphone-Based Observational Study.

BACKGROUND: Smartphones and their built-in sensors allow for measuring functions in disease-related domains through mobile tests. This could improve disease characterization and monitoring, and could potentially support treatment decisions for multiple sclerosis (MS), a multifaceted chronic neurological disease with highly variable clinical manifestations. Practice effects can complicate the interpretation of both improvement over time by potentially exaggerating treatment effects and stability by masking deterioration. OBJECTIVE: The aim of this study is to identify short-term learning and long-term practice effects in 6 active tests for cognition, dexterity, and mobility in user-scheduled, high-frequency smartphone-based testing. METHODS: We analyzed data from 264 people with self-declared MS with a minimum of 5 weeks of follow-up and at least 5 repetitions per test in the Floodlight Open study, a self-enrollment study accessible by smartphone owners from 16 countries. The collected data are openly available to scientists. Using regression and bounded growth mixed models, we characterized practice effects for the following tests: electronic Symbol Digit Modalities Test (e-SDMT) for cognition; Finger Pinching and Draw a Shape for dexterity; and Two Minute Walk, U-Turn, and Static Balance for mobility. RESULTS: Strong practice effects were found for e-SDMT (n=4824 trials), Finger Pinching (n=19,650), and Draw a Shape (n=19,019) with modeled boundary improvements of 40.8% (39.9%-41.6%), 86.2% (83.6%-88.7%), and 23.1% (20.9%-25.2%) over baseline, respectively. Half of the practice effect was reached after 11 repetitions for e-SDMT, 28 repetitions for Finger Pinching, and 17 repetitions for Draw a Shape; 90% was reached after 35, 94, and 56 repetitions, respectively. Although baseline performance levels were highly variable across participants, no significant differences between the short-term learning effects in low performers (5th and 25th percentile), median performers, and high performers (75th and 95th percentile) were found for e-SDMT up to the fifth trial (ß=1.50-2.00). Only small differences were observed for Finger Pinching (ß=1.25-2.5). For U-Turn (n=15,051) and Static Balance (n=16,797), only short-term learning effects could be observed, which ceased after a maximum of 5 trials. For Two Minute Walk (n=14,393), neither short-term learning nor long-term practice effects were observed. CONCLUSIONS: Smartphone-based tests are promising for monitoring the disease trajectories of MS and other chronic neurological diseases. Our findings suggest that strong long-term practice effects in cognitive and dexterity functions have to be accounted for to identify disease-related changes in these domains, especially in the context of personalized health and in studies without a comparator arm. In contrast, changes in mobility may be more easily interpreted because of the absence of long-term practice effects, even though short-term learning effects might have to be considered.

Chi3l3 induces oligodendrogenesis in an experimental model of autoimmune neuroinflammation.

In demyelinating diseases including multiple sclerosis (MS), neural stem cells (NSCs) can replace damaged oligodendrocytes if the local microenvironment supports the required differentiation process. Although chitinase-like proteins (CLPs) form part of this microenvironment, their function in this differentiation process is unknown. Here, we demonstrate that murine Chitinase 3-like-3 (Chi3l3/Ym1), human Chi3L1 and Chit1 induce oligodendrogenesis. In mice, Chi3l3 is highly expressed in the subventricular zone, a stem cell niche of the adult brain, and in inflammatory brain lesions during experimental autoimmune encephalomyelitis (EAE). We find that silencing Chi3l3 increases severity of EAE. We present evidence that in NSCs Chi3l3 activates the epidermal growth factor receptor (EGFR), thereby inducing Pyk2-and Erk1/2- dependent expression of a pro-oligodendrogenic transcription factor signature. Our results implicate CLP-EGFR-Pyk2-MEK-ERK as a key intrinsic pathway controlling oligodendrogenesis.