Causal associations of central and peripheral risk factors with knee osteoarthritis: a longitudinal and Mendelian Randomisation study using UK Biobank data.

ABSTRACT: Our aim was to investigate relative contributions of central and peripheral mechanisms to knee osteoarthritis (OA) diagnosis and their independent causal association with knee OA. We performed longitudinal analysis using data from UK-Biobank participants. Knee OA was defined using International Classification of Diseases manual 10 codes from participants' hospital records. Central mechanisms were proxied using multisite chronic pain (MCP) and peripheral mechanisms using body mass index (BMI). Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated, and proportional risk contribution (PRC) was estimated from receiver-operator-characteristic (ROC) analysis. To estimate the causal effects, we performed 2-sample multivariable Mendelian Randomisation (MR) analysis. We selected genetic instruments from the largest Genome Wide Association Study of BMI (N = 806,834) and MCP (N = 387,649) and estimated the instruments genetic associations with knee OA in the largest available dataset (62,497 cases and 333,557 control subjects). The multivariable MR was performed using modified inverse-variance weighting methods. Of the 203,410 participants, 6% developed knee OA. Both MCP (OR 1.23, 95% CI; 1.21-1.24) and BMI (1.10, 95% CI; 1.10-1.11) were associated with knee OA diagnosis. The PRC was 6.9% (95% CI; 6.7%-7.1%) for MCP and 21.9% (95% CI; 21.4%-22.5%) for BMI; the combined PRC was 38.8% (95% CI; 37.9%-39.8%). Body mass index and MCP had independent causal effects on knee OA (OR 1.76 [95% CI, 1.64-1.88] and 1.83 [95% CI, 1.54-2.16] per unit change, respectively). In conclusion, peripheral risk factors (eg, BMI) contribute more to the development of knee OA than central risk factors (eg, MCP). Peripheral and central factors are independently causal on knee OA.

Short-term local predictions of COVID-19 in the United Kingdom using dynamic supervised machine learning algorithms.

Background: Short-term prediction of COVID-19 epidemics is crucial to decision making. We aimed to develop supervised machine-learning algorithms on multiple digital metrics including symptom search trends, population mobility, and vaccination coverage to predict local-level COVID-19 growth rates in the UK. Methods: Using dynamic supervised machine-learning algorithms based on log-linear regression, we explored optimal models for 1-week, 2-week, and 3-week ahead prediction of COVID-19 growth rate at lower tier local authority level over time. Model performance was assessed by calculating mean squared error (MSE) of prospective prediction, and naïve model and fixed-predictors model were used as reference models. We assessed real-time model performance for eight five-weeks-apart checkpoints between 1st March and 14th November 2021. We developed an online application (COVIDPredLTLA) that visualised the real-time predictions for the present week, and the next one and two weeks. Results: Here we show that the median MSEs of the optimal models for 1-week, 2-week, and 3-week ahead prediction are 0.12 (IQR: 0.08-0.22), 0.29 (0.19-0.38), and 0.37 (0.25-0.47), respectively. Compared with naïve models, the optimal models maintain increased accuracy (reducing MSE by a range of 21-35%), including May-June 2021 when the delta variant spread across the UK. Compared with the fixed-predictors model, the advantage of dynamic models is observed after several iterations of update. Conclusions: With flexible data-driven predictors selection process, our dynamic modelling framework shows promises in predicting short-term changes in COVID-19 cases. The online application (COVIDPredLTLA) could assist decision-making for control measures and planning of healthcare capacity in future epidemic growths.