Charlie Harper

Background Many adults in high-income countries carry a device capable of measuring physical- activity behaviour. Thus, there is public health need to understand whether such data can enhance prediction of future health outcomes. We aimed to investigate whether device-measured daily-step count and walking cadence improve the prediction of mortality beyond traditional risk-factors. Methods Risk models were developed to predict five-year all-cause mortality using data from the UK Biobank accelerometer sub-study, with external validation in the US 2011-2014 National Health and Nutrition Examination Survey (NHANES). Median daily-step count and peak one-minute walking cadence were derived using self-supervised machine learning models from seven-day wrist-worn accelerometer data. Cox models were used to develop a baseline model incorporating traditional risk- factors, and a baseline model plus accelerometer data (i.e. daily-steps and walking cadence). Changes in model performance were assessed using Harrell’s C-index, net reclassification index (NRI; 10% threshold), and the Nam-D’Agostino calibration test. Findings Among 79,717 UK Biobank participants, 1,640 died within 5-years. Adding accelerometer data to the baseline model modestly improved risk discrimination and classification with a change in c- index of 0.008 (95% confidence interval [CI] 0.005-0.011) and 3.3% NRI (95%CI 2.1%-4.5%). Greatest improvements in prediction were observed in participants with prior disease at baseline, showing a change in c-index of 0.028 (95%CI 0.019-0.039) and 5.9% NRI (95%CI 3.1%-8.6%). In the NHANES external validation cohort (n=4,713; deaths=378), similar improvements in prediction were observed (change in c-index: 0.015, 95%CI 0.007-0.025; NRI: 4.0%, 95%CI 0.7%-7.4%). All models were well calibrated (Nam-D’Agostino χ² range: 6.8-13.2). Interpretation Device-measured daily-step count and walking cadence consistently demonstrated modest improvements in predicting mortality risk beyond traditional risk-factors, with the most significant enhancements seen in individuals with prior disease. These findings suggest that incorporating information from wearables does provide important new ways to improve risk stratification for targeted intervention in high-risk individuals.

Importance Higher physical activity levels have been suggested as a potential modifiable risk factor for lowering the risk of incident Parkinson’s disease (PD). This study uses objective measures of physical activity to investigate the role of reverse causation in the observed association. Objective To investigate the association between accelerometer-derived daily step count and incident PD, and to assess the impact of reverse causation on this association. Design This prospective cohort study involved a follow-up period with a median duration of 7.9 years, with participants who wore wrist-worn accelerometers for up to 7 days. Setting The study was conducted within the UK Biobank, a large, population-based cohort. Participants The analysis included 94,696 participants aged 43-78 years (56% female) from the UK Biobank who provided valid accelerometer data and did not have prevalent PD. Exposure Daily step counts were derived using machine learning models to determine the median daily step count over the monitoring period. Main Outcomes and Measures The primary outcome was incident PD, identified through hospital admission and death records. Cox proportional hazards regression models estimated hazard ratios (HR) and 95% confidence intervals (CI) for the association between daily step count and incident PD, with adjustments for various covariates and evaluation of reverse causation by splitting follow-up periods. Results During a median follow-up of 7.9 years (IQR: 7.4-8.4), 407 incident PD cases were identified. An inverse linear association was observed between daily step count and incident PD. Participants in the highest quintile of daily steps (>12,369 steps) had an HR of 0.41 (95% CI 0.31-0.54) compared to the lowest quintile (Conclusions and Relevance The observed association between higher daily step count and lower incident PD is likely influenced by reverse causation, suggesting changes in physical activity levels occur years before PD diagnosis. While step counts may serve as a predictor for PD, they may not represent a modifiable risk factor. Further research with extended follow-up periods is warranted to better understand this relationship and account for reverse causation. Question Is there an association between accelerometer-derived daily step count and the risk of incident Parkinson’s disease, considering the potential impact of reverse causation? Findings In this prospective cohort study of 94,696 UK Biobank participants, an inverse association was found between daily step count and incident Parkinson’s disease over a median follow-up of 7.9 years. However, this association was attenuated when excluding the first six years of follow-up. Meaning While daily step counts may be associated with incident Parkinson’s disease, these observations are likely influenced by reverse causation, indicating changes in daily behaviours years before diagnosis.

Background Low physical activity (PA) has been shown to be associated with higher risk of non-alcoholic fatty liver disease (NAFLD). However, the strength and shape of this association are currently uncertain due to a reliance on self-reported PA measures. This report aims to investigate the relationship of PA with NAFLD using accelerometer-derived step count from a large prospective cohort study. Methods The wrist-worn accelerometer sub-study of the UK Biobank (N=∼100,000) was used to characterise median daily step count over a seven-day period. NAFLD cases were ascertained via record linkage with hospital inpatient data and death registers or by using a measure of liver fat from imaging. Cox proportional hazards models were employed to assess the association between step count and NAFLD, adjusting for age, sociodemographic, and lifestyle factors. Mediation analyses were conducted. Results Among 91,031 participants (709,440 person-years of follow-up), there were 762 incident NAFLD cases. Higher step count was log-linearly and inversely associated with risk of NAFLD. A 1000 step increase (representing 10 minutes of walking) was associated with a 12% (95% CI: 10%–14%) lower hazard of NAFLD. When using imaging to identify NAFLD, a 1,000-step increase was associated with a 6% (95% CI: 6%–7%) lower risk. There was evidence for some mediation by adiposity. Conclusion Physical activity, a modifiable risk factor, is log-linearly and inversely associated with NAFLD. This association was only partially explained by adiposity. These findings from a large cohort study may have important implications for strategies to lower NAFLD risk.

Objective To assess how reliable UK routine data are for ascertaining major bleeding events compared with adjudicated follow-up. Methods The ASCEND (A Study of Cardiovascular Events iN Diabetes) primary prevention trial randomised 15 480 UK people with diabetes to aspirin versus matching placebo. The primary safety outcome was major bleeding (including intracranial haemorrhage, sight-threatening eye bleeding, serious gastrointestinal bleeding and other major bleeding (epistaxis, haemoptysis, haematuria, vaginal and other bleeding)) ascertained by direct-participant mail-based follow-up, with >90% of outcomes undergoing adjudication. Nearly all participants were linked to routinely collected hospitalisation and death data (ie, routine data). An algorithm categorised bleeding events from routine data as major/minor. Kappa statistics were used to assess agreement between data sources, and randomised comparisons were re-run using routine data. Results When adjudicated follow-up and routine data were compared, there was agreement for 318 major bleeding events, with routine data identifying 281 additional-potential events, and not identifying 241 participant-reported events (kappa 0.53, 95% CI 0.49 to 0.57). Repeating ASCEND’s randomised comparisons using routine data only found estimated relative and absolute effects of allocation to aspirin versus placebo on major bleeding similar to adjudicated follow-up (adjudicated follow-up: aspirin 314 (4.1%) vs placebo 245 (3.2%); rate ratio (RR) 1.29, 95% CI 1.09 to 1.52; absolute excess +6.3/5000 person-years (mean SE±2.1); vs routine data: 327 (4.2%) vs 272 (3.5%); RR 1.21, 95% CI 1.03 to 1.41; absolute excess +5.0/5000 (±2.2)). Conclusions Analyses of the ASCEND randomised trial found that major bleeding events ascertained via UK routine data sources provided relative and absolute treatment effects similar to adjudicated follow-up. Trial registration number ISRCTN60635500; NCT00135226.