IMPORTANCE Wearable-based measures of walking (as proxy for physical activity) may quantify disease progression and modification thereof in early-stage Parkinson’s disease (PD).

OBJECTIVES Establishing the validity of digital measures of walking and non-walking in PD.

DESIGN Retrospective longitudinal analyses of data from cohorts within 3 larger studies, consisting of wearable sensor, demographic, and clinical data collected during 2017-2023, with 1-2 year follow up.

SETTING Three independent multicenter cohort studies.

PARTICIPANTS People with PD, and age/sex matched non-PD cohort.

MAIN OUTCOMES AND MEASURES Digital measures’ test-retest reliability, analyzed using intraclass correlation coefficients across consecutive monthly-aggregated data. Digital measures’ sensitivity: ability to detect within-participant changes, analyzed over 24 months using linear mixed-effect models, and analyzed as effect-size changes-from-baseline comparing 1- and 2-year longitudinal Cohen’s-d (mean and 95% CIs) vs conventional clinical endpoints. Analyses replicated in two independent PD cohorts (internal validation and external evaluation). Compared within-participant changes between PD and non-PD cohorts using linear mixed-effect model slopes.

RESULTS We analyzed 57 digital measures (51 individual, 6 composite) in a development cohort (N=171), selecting 32 (26 individual, 6 composite) for further study based on their sensitivity and test-retest reliability. During internal validation (N=101), 20 measures could detect statistically significant within-participant changes and 7 showed larger 2-year effect-size changes than conventional clinical measures; non-walking bout (NWB) duration (12.4% yearly change; 2-year Cohen’s-d 0.623 [95% CI: 0.461,0.811]) and 95th percentile of NWB duration (17.1% yearly change; 2-year Cohen’s-d, 0.623 [95% CI: 0.461,0.811]) performed best. Measures could detect significant and persisting changes from baseline at 10 months. During external evaluation (N=67), 15 measures could detect statistically significant within-participant changes and 12 showed larger 1-year effect-size changes than conventional clinical measures; 12 measures showed significantly greater change in people with PD than in matched non-PD individuals (N=171).

CONCLUSION AND RELEVANCE Internal validation and external evaluation of 32 digital measures that quantified walking and non-walking behaviors in patients with early-stage PD showed that they could have greater sensitivity to detect longitudinal changes than conventional measures, and that these changes were disease-specific (e.g., separate from aging), making them candidates for disease-specific progression markers.

Question Can wearable sensor-based digital measures of physical activity and mobility serve as markers of disease progression in early-stage Parkinson’s disease (PD)?

Findings In two independent longitudinal cohorts of people with PD, digital measures detected statistically-significant changes in walking and non-walking behaviors after 1 and 2 years of follow-up; additionally, a comparison between people with and without PD (from a third cohort) showed that these changes were disease-specific. Compared with MDS-UPDRS-based conventional metrics, measures of non-walking behavior showed greater effect size (such as mean non-walking bout duration, with an annual increase of 12.4% and a 2-year Cohen’s-d of 0.623).

Meaning Wearable sensor-based digital measures can detect and quantify disease-specific changes in walking and non-walking behaviors over time in people with early-stage PD.

KCH, SL, CSA, NK, ER, CC, WJM, RK, SS report employment and equity ownership in Verily Life Sciences. BRB, LHS, LCS, AS, LJWE report no conflicts of interest.

NCT03364894; NCT03154346

Study funding statement: This analysis was sponsored by Verily Life Sciences (Dallas, TX). Data used in the preparation of this article was obtained from the Personalized Parkinson Project (PPP), funded by Radboud University Medical Center, Radboud University, the city of Nijmegen and the Province of Gelderland, and the PPP Allowance made available by Health∼Holland, Top Sector Life Sciences & Health, to stimulate public-private partnerships. Data used in the preparation of this article was obtained from the Project Baseline Health Study (PBHS), funded by Verily Life Sciences (Dallas, TX). Data used in the preparation of this article was obtained on 2022-12-13 from the Parkinson's Progression Markers Initiative (PPMI) database (www.ppmi-info.org/access-data-specimens/download-data), RRID:SCR_006431. For up-to-date information on the study, visit www.ppmi-info.org. PPMI -a public-private partnership- is funded by the Michael J. Fox Foundation (MJFF) for Parkinson's Research, and funding partners; including the Aligning Science Across Parkinson's (ASAP) initiative. Other partners include 4D Pharma, Abbvie, AcureX, Allergan, Amathus Therapeutics, Aligning Science Across Parkinson's, AskBio, Avid Radiopharmaceuticals, BIAL, BioArctic, Biogen, Biohaven, BioLegend, BlueRock Therapeutics, Bristol-Myers Squibb, Calico Labs, Capsida Biotherapeutics, Celgene, Cerevel Therapeutics, Coave Therapeutics, DaCapo Brainscience, Denali, Edmond J. Safra Foundation, Eli Lilly, Gain Therapeutics, GE HealthCare, Genentech, GSK, Golub Capital, Handl Therapeutics, Insitro, Jazz Pharmaceuticals, Johnson & Johnson Innovative Medicine, Lundbeck, Merck, Meso Scale Discovery, Mission Therapeutics, Neurocrine Biosciences, Neuron23, Neuropore, Pfizer, Piramal, Prevail Therapeutics, Roche, Sanofi, Servier, Sun Pharma Advanced Research Company, Takeda, Teva, UCB, Vanqua Bio, Verily, Voyager Therapeutics, the Weston Family Foundation and Yumanity Therapeutics.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

PPP. The Commissie Mensgebonden Onderzoek Region Arnhem Nijmegen (reference number 2016-2934; NL59694.091.17) approved the study protocol and communication materials. PPMI. The PPMI was approved by the local ethics committees of the participating sites. PBHS. A central institutional review board (the WCG IRB; approval tracking number 20170163, work order number 1-1506365-1) and those of all participating institutions (Duke University, Stanford University, California Health and Longevity Institute) approved the study.

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Yes

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