Causal Effect Of Physical Activity Research Articles

An emulated target trial assessing the impact of physical activity on 14-year cancer risk: Insights from the Cancer Prevention Study-II.

10541 Background: The American Cancer Society, along with the World Cancer Research Fund/American Institute of Cancer Research, recommends a weekly regimen of physical activity (at least 75 minutes of vigorous or 150 minutes of moderate-intensity aerobic physical activity) for cancer prevention. The positive impact of physical activity on reducing cancer risk is well-known; however, the causal link between physical activity and cancer risk reduction is not established, primarily due to the observational nature of the current evidence. Given the ethical considerations involved in assigning physical activity levels below the recommended minimum, coupled with the impracticality of conducting decades-long trials due to the latency period of cancer development, there is a need for an innovative approach beyond traditional observational and randomized trial methodologies. This highlights the importance of applying alternative strategies like emulated target trials to produce evidence of the causal effect of physical activity on cancer risk that would otherwise be difficult to obtain. This study aims to estimate the causal effect of adherence to recommended physical activity levels on the 14-year total cancer and obesity-related cancer risk using an emulated target trial framework. Methods: Data from 79,668 participants who were non-current smokers and without prevalent cancer diagnosis at pre-baseline in the Cancer Prevention Study-II were analyzed. This study estimated the effect of different physical activity levels (<7.5, 7.5-<15, and ≥15 MET-hrs/wk) on 14-year cancer risks using a parametric g-formula. Models adjusted for confounders include age, sex, education, years since quitting smoking, family history of cancer, physical activity, body mass index, alcohol consumption, diet quality (measured by the ACS diet score), history of cardiovascular disease, and diabetes. Results: Under no intervention, the estimated 14-year risk for any cancer was 27.9% (95% CI: 27.6%, 28.4%), and for obesity-related cancers, it was 11.2% (95% CI: 11.0%, 11.5%). Compared with no intervention, engaging in 7.5-<15 MET-hrs/wk of physical activity (minimum recommended) was linked with a 0.31% reduction in the risk of any cancer (95% CI: -0.41%, -0.06%) and a 0.19% reduction in the risk of obesity-related cancers (95% CI: -0.37%, -0.04%). Engaging in ≥15 MET-hrs/wk of physical activity (twice the minimum recommended level) was linked with a 1.31% risk reduction for any cancer (95% CI: -1.67%, -1.20%) and a 0.91% risk reduction for obesity-related cancers (95% CI: -1.09%, -0.80%), compared with no intervention. Conclusions: Incremental adherence to physical activity recommendations for cancer prevention could significantly lower the risk of developing cancers, including those related to obesity.

Causal effect of physical activity and sedentary behavior on the risk of alcohol dependence: A bidirectional two-sample Mendelian randomization study

BackgroundAlcohol dependence, influenced by physical activity (PA) and sedentary behavior, lacks clear causal clarity. This study aims to clarify causal relationships by estimating these effects using bidirectional two-sample Mendelian randomization (MR). MethodsA bidirectional multivariable two-sample MR framework was employed to assess the causal effects of PA and sedentary behavior on alcohol dependence. Summarized genetic association data were analyzed for four PA-related activity patterns—moderate to vigorous physical activity (MVPA), vigorous physical activity (VPA), accelerometer-based physical activity with average acceleration (AccAve), and accelerometer-based physical activity with accelerations greater than 425 milli-gravities (Acc425)—and three sedentary behavior patterns—sedentary, TV watching, and computer use. The study was expanded to include the examination of the relationship between sedentary behavior or PA and general drinking behavior, quantified as drinks per week (DPW). We obtained summarized data on genetic associations with four PA related activity patterns (MVPA, VPA, AccAve and Acc425) and three sedentary behavior related behavior patterns (sedentary, TV watching and computer use). ResultsMR analysis found AccAve inversely associated with alcohol dependence risk (OR: 0.87; 95% CI: 0.80–0.95; p < 0.001), MVPA positively associated (OR: 2.86; 95%CI: 1.45–5.66; p = 0.002). For sedentary behavior and alcohol dependence, only TV watching was positively associated with the risk of alcohol dependence (OR: 1.43; 95%CI: 1.09–1.88; p = 0.009). No causal links found for other physical or sedentary activities. Reverse analysis and sensitivity tests showed consistent findings without pleiotropy or heterogeneity. Multivariate MR analyses indicated that while MVPA, AccAve and TV watching are independently associated with alcohol dependence, DPW did not show a significant causal relationship. ConclusionsOur results suggest that AccAve is considered a protective factor against alcohol dependence, while MVPA and TV watching are considered risk factors for alcohol dependence. Conversely, alcohol dependence serves as a protective factor against TV watching. Only TV watching and alcohol dependence might mutually have a significant causal effect on each other.

Assessing the interaction effects of mitochondrial DNA polymorphisms and lifestyle on heel bone mineral density.

Bone mineral density (BMD) is a major predictor of osteoporotic fractures, and previous studies have reported the effects of mitochondrial dysfunction and lifestyle on BMD, respectively. However, their interaction effects on BMD are still unclear. Therefore, we aimed to investigate the possible interaction of mitochondrial DNA (mtDNA) and common lifestyles contributing to osteoporosis. Our analysis included 119,120 white participants (Nfemale=65,949 and Nmale=53,171) from the UK Biobank with heel BMD phenotype data. A generalized linear regression model of PLINK was performed to assess the interaction effects of mtDNA and five life environmental factors on heel BMD, including smoking, drinking, physical activity, dietary diversity score, and vitamin D. In addition, we also performed linear regression analysis for total body BMD. Finally, we assessed the potential causal relationships between mtDNA copy number (mtDNA-CN) and life environmental factors using Mendelian randomization (MR) analysis. Our study identified four mtDNA loci showing suggestive evidence of heel BMD, such as m.16356T>C (MT-DLOOP; P =1.50×10-3) in total samples. Multiple candidate mtDNA×lifetsyle interactions were also detected for heel BMD, such as MT-ND2×physical activity (P = 2.88×10-3) in total samples and MT-ND1×smoking (P = 8.54×10-4) in males. Notably, MT-CYB was a common candidate mtDNA loci for heel BMD to interact with five life environmental factors. Multivariable MR analysis indicated a causal effect of physical activity on heel BMD when mtDNA-CN was considered (P =1.13×10-3). Our study suggests the candidate interaction between mitochondria and lifestyles on heel BMD, providing novel clues for exploring the pathogenesis of osteoporosis.

Physical Activity, Sedentary Behavior, and Pancreatic Cancer Risk: A Mendelian Randomization Study.

Pancreatic cancer is currently the seventh leading cause of cancer death worldwide. Understanding whether modifiable factors increase or decrease the risk of this disease is central to facilitating primary prevention. Several epidemiological studies have described the benefits of physical activity, and the risks associated with sedentary behavior, in relation to cancer. This study aimed to assess evidence of causal effects of physical activity and sedentary behavior on pancreatic cancer risk. We conducted a two-sample Mendelian randomization study using publicly available data for genetic variants associated with physical activity and sedentary behavior traits and genetic data from the Pancreatic Cancer Cohort Consortium (PanScan), the Pancreatic Cancer Case-Control Consortium (PanC4), and the FinnGen study for a total of 10 018 pancreatic cancer cases and 266 638 controls. We also investigated the role of body mass index (BMI) as a possible mediator between physical activity and sedentary traits and risk of developing pancreatic cancer. We found evidence of a causal association between genetically determined hours spent watching television (hours per day) and increased risk of pancreatic cancer for each hour increment (PanScan-PanC4 odds ratio = 1.52, 95% confidence interval 1.17-1.98, P = .002). Additionally, mediation analysis showed that genetically determined television-watching time was strongly associated with BMI, and the estimated proportion of the effect of television-watching time on pancreatic cancer risk mediated by BMI was 54%. This study reports the first Mendelian randomization-based evidence of a causal association between a measure of sedentary behavior (television-watching time) and risk of pancreatic cancer and that this is strongly mediated by BMI. Summary: Pancreatic cancer is a deadly disease that is predicted to become the second leading cause of cancer-related deaths by 2030. Physical activity and sedentary behaviors have been linked to cancer risk and survival. However, there is limited research on their correlation with pancreatic cancer. To investigate this, we used a Mendelian randomization approach to examine the genetic predisposition to physical activity and sedentariness and their relation to pancreatic cancer risk, while excluding external confounders. Our findings revealed a causal link between the time spent watching television and an increased risk of pancreatic cancer. Additionally, we determined that over half of the effect of watching television on pancreatic risk is mediated by the individual's BMI.

Distilling causality between physical activity traits and obesity via Mendelian randomization

BackgroundWhether obesity is a cause or consequence of low physical activity levels and more sedentary time has not yet been fully elucidated. Better instrumental variables and a more thorough consideration of potential confounding variables that may influence the causal inference between physical activity and obesity are needed.MethodsLeveraging results from our recent genome-wide association study for leisure time moderate-to-vigorous intensity (MV) physical activity and screen time, we here disentangle the causal relationships between physical activity, sedentary behavior, education—defined by years of schooling—and body mass index (BMI), using multiple univariable and multivariable Mendelian Randomization (MR) approaches.ResultsUnivariable MR analyses suggest bidirectional causal effects of physical activity and sedentary behavior with BMI. However, multivariable MR analyses that take years of schooling into account suggest that more MV physical activity causes a lower BMI, and a higher BMI causes more screen time, but not vice versa. In addition, more years of schooling causes higher levels of MV physical activity, less screen time, and lower BMI.ConclusionsIn conclusion, our results highlight the beneficial effect of education on improved health and suggest that a more physically active lifestyle leads to lower BMI, while sedentary behavior is a consequence of higher BMI.

The causal relationship between physical activity, sedentary time and idiopathic pulmonary fibrosis risk: a Mendelian randomization study

BackgroundSeveral observational studies have found that physical inactivity and sedentary time are associated with idiopathic pulmonary fibrosis (IPF) risk. However, the causality between them still requires further investigation. Therefore, our study aimed to investigate the causal effect of physical activity (PA) and sedentary time on the risk of IPF via two-sample Mendelian randomization (MR) analysis.MethodsMultiple genome-wide association study (GWAS) data involving individuals of European ancestry were analyzed. The datasets encompassed published UK Biobank data (91,105–377,234 participants) and IPF data (2018 cases and 373,064 controls) from FinnGen Biobank. The inverse variance weighting (IVW) method was the primary approach for our analysis. Sensitivity analyses were implemented with Cochran’s Q test, MR-Egger regression, MR-PRESSO global test, and leave-one-out analysis.ResultsGenetically predicted self-reported PA was associated with lower IPF risk [OR = 0.27; 95% CI 0.09–0.82; P = 0.02]. No causal effects of accelerometry-based PA or sedentary time on the risk of IPF were observed.ConclusionsOur findings supported a protective relationship between self-reported PA and the risk for IPF. The results suggested that enhancing PA may be an effective preventive strategy for IPF.

Causal effect of physical activity and sedentary behaviors on the risk of osteoarthritis: a univariate and multivariate Mendelian randomization study

There is still a lot of ambiguity about the link between physical activity (PA), sedentary behaviors (SBs) and osteoarthritis (OA). This study aimed to investigate the causal relationship of PA/SBs on the risk of OA. A univariate and multivariate Mendelian randomization (MR) analysis was conducted to investigate the causal effect of five PA phenotypes and three SB phenotypes on overall OA, knee OA, hip OA, total hip arthroplasty, and total knee arthroplasty (TKA). MR methods used were inverse-variance weighting, MR-Egger regressions, and weighted median. Sensitivity analysis examined horizontal pleiotropy and heterogeneity, and confirmed the reliability of the results. After false discovery rate, light do-it-yourself (DIY) activities decreased the risk for overall OA (OR: 0.32, 95% CI 0.16–0.65), and knee OA (OR: 0.26, 95% CI 0.12–0.51). Resulting in a decreased risk of walking for pleasure on overall OA (OR: 0.87, 95% CI 0.70–1.04) and knee OA (OR: 0.14, 95% CI 0.06–0.32) was also observed. Television viewing, however, significantly increased the risk of OA, knee OA, hip OA, and TKA. MVMR findings revealed independent causal impacts of walking for pleasure and watching television on overall and knee OA, taking into account BMI, smoking, and education. This study suggested that light DIY and walking for pleasure were beneficial for preventing OA, and the risk of OA and TKA increased with prolonged television watching.

Assessment of causal effects of physical activity on the risk of osteoarthritis: a two-sample Mendelian randomization study

BackgroundGrowing evidence supports an association between physical activity (PA) and the risk of osteoarthritis (OA), but this may be influenced by confounding and reverse causality. Therefore, we performed a two-sample Mendelian randomization (MR) analysis to reveal the causal relationship between PA and OA.MethodsMR was performed to explore the causation of PA and OA with genetic variants as instrumental variables. The genetic variants were derived from the summary statistics of a large genome-wide association study meta-analysis based on the European population (n = 661,399), including self-reported leisure screen time (LST) and moderate-to-vigorous physical activity (MVPA), and Arthritis Research UK Osteoarthritis Genetics Consortium cohorts (417,596, 393,873 and 403,124 for overall, hip and knee OA, respectively). The major MR analysis used in this work was the inverse variance weighted (IVW) approach, and sensitivity, pleiotropy, and heterogeneity studies were performed to evaluate the validity of the findings.ResultsIVW estimates indicated that LST had a risk effect on overall OA (odds ratio (OR) = 1.309, 95% confidence interval (CI): 1.198–1.430, P = 2.330 × 10-9), hip OA (OR = 1.132, 95% CI: 1.009–1.269, P = 0.034) and knee OA (OR = 1.435. 95% CI: 1.286–1.602, P = 1.225 × 10-10). In contrast, no causal relationship was found between MVPA and OA (overall OA: OR = 0.895, 95% CI: 0.664–1.205, P = 0.465; hip OA: OR = 1.189, 95% CI: 0.792–1.786, P = 0.404; knee OA: OR = 0.707, 95% CI: 0.490 -1.021, P = 0.064). In addition, we observed significant heterogeneity in instrumental variables, but no horizontal pleiotropy was detected.ConclusionsRecent findings demonstrated a protective impact of reducing LST on OA, independent of MVPA. This provides valuable insights into the role of physical activity in OA and offers lifestyle recommendations, such as reducing recreational sedentary behaviors and promoting appropriate exercise, for individuals at risk of OA.

Causal effects of physical activity on the risk of overall ovarian cancer: A Mendelian randomization study.

Inconsistent results were reported on the association of physical activity with ovarian cancer. However, given the limitations of confounders and inverse causation, the validity of the association remained unclear. Therefore, we conducted a two-sample Mendelian randomization analysis, which can effectively avoid the aforementioned interference, to evaluate whether physical activity had a protective effect on ovarian cancer. The exposure of interest was physical activity (both self-reported moderate-to-vigorous physical activity and accelerometer-measured physical activity). Summary statistics for physical activity traits were recruited from the UK Biobank (n = 91,084-377,234), whereas ovarian cancer summary genetic data were obtained from a genome-wide association study involving 25,509 cases and 40,941 healthy individuals. The inverse variance weighted approach was used as the primary Mendelian randomization method. Sensitivity analyses using Mendelian randomization-Egger regression, weighted median, and Mendelian randomization pleiotropy residual sum and outlier were also performed. The Mendelian randomization analyses indicated that there was no effect of moderate-to-vigorous physical activity (odds ratio, 1.11; 95% confidence interval: 0.66-1.85; P = 0.702), accelerometer-measured "average acceleration" (0.99 [0.91-1.08]; P = 0.848), and "overall activity" physical activity (0.97 [ 0.48-1.95]; P = 0.927) on the risk of overall ovarian cancer. However, "overall accelerations" physical activity (0.18 [0.05-0.64]; P = 0.008) were suggestively related to a lower risk of endometrioid ovarian cancer. The Mendelian randomization analyses suggested that physical activity may not help to decrease the risk of overall ovarian cancer.

Estimating causal effects of physical activity and sedentary behaviours on the development of type 2 diabetes in at-risk children from childhood to late adolescence: an analysis of the QUALITY cohort

Uncertainty remains regarding the causal effect of physical activity and sedentary behaviours on the development of type 2 diabetes in children. We aimed to estimate average treatment effects of physical activity and sedentary behaviours on risk of type 2 diabetes in individuals who are at risk during childhood and adolescence. We used data from the Quebec Adipose and Lifestyle Investigation in Youth (QUALITY) cohort of children of western European descent (white non-Hispanic race or ethnicity) with a parental history of obesity (defined as a BMI of 30 kg/m2 or more, or a waist circumference of more than 102 cm in men and 88 cm in women) evaluated at the ages of 8-10 years (baseline), 10-12 years (first follow-up cycle), and 15-17 years (second follow-up cycle) in Québec, Canada. We measured moderate-to-vigorous physical activity (MVPA) and sedentary time by accelerometry, and leisure screen time by questionnaire at each cycle. Outcomes included fasting and 2 h post-load glycaemia and validated indices of insulin sensitivity and insulin secretion. We estimated average treatment effects of MVPA, sedentary time, and screen time on markers of type 2 diabetes using longitudinal marginal structural models with time-varying exposures, outcomes, and confounders from the ages of 8-10 to 15-17 years and inverse probability of treatment and censoring weighting. We considered both the current and cumulative effects of exposures on outcomes. 630 children were evaluated at baseline (age 8-10 years) between July, 2005, and December, 2008, 564 were evaluated at the first follow-up (age 10-12 years) between July, 2007, and March, 2011, and 377 were evaluated at the second follow-up (age 15-17 years) between September, 2012, and May, 2016. Based on cumulative exposure results, estimated average treatment effects for MVPA were 5·6% (95% CI 2·8 to 8·5) on insulin sensitivity and -3·8% (-7·1 to -0·5) on second-phase insulin secretion per 10 min daily increment from the ages of 8-10 years to age 15-17 years. Average treatment effects for sedentary time and reported screen time resulted in reduced insulin sensitivity (-8·2% [-12·3 to -3·9] and -6·4% [-10·1 to -2·5], respectively), increased second-phase insulin secretion (5·9% [1·9 to 10·1] and 7·0% [-0·1 to 14·7], respectively), and higher fasting glycaemia (0·03 mmol/L [0·003 to 0·05] and 0·02 mmol/L [0·01 to 0·03], respectively) per additional daily hour from the ages of 8-10 years to 15-17 years. Using modern causal inference approaches strengthened the evidence of MVPA and sedentary behaviours as key drivers of development of type 2 diabetes in at-risk children and adolescents, and should be considered as key targets for prevention. Canadian Institutes of Health Research, Heart and Stroke Foundation of Canada, and Fonds de Recherche du Québec-Santé. For the French translation of the abstract see Supplementary Materials section.

Acute effects of a motor coordination intervention on executive functions in kindergartners: a proof-of-concept randomized controlled trial

BackgroundExecutive functions are pivotal for future academic and social functioning. Causal effects of physical activity on executive functions have been shown in adults. The primary objective of this study was to test the proof-of-concept (i.e., feasibility of implementation and acceptance) of a motor coordination intervention and a sedentary control condition in kindergartners and its preliminary effectiveness on subsequent executive function performance.MethodsThe study used a two-group post-test only design. All children aged between 4 and 7 years old were eligible. One hundred and three children (46% girls; age: M = 5.71 years, 95% CI = 5.50 to 5.92) recruited in a middle-sized town in Germany were randomly assigned to a 20-min motor coordination intervention (n = 51) or a sedentary control condition (n = 52), both of which were conducted in a one-on-one experimenter-child setting in the university or kindergarten. A second blinded-to-condition experimenter assessed the executive function outcomes directly following the conditions. Proof-of-concept criteria were the implementation of the intervention with a moderate-to-vigorous physical activity level assessed via heart rate sensors, and with motor coordination demands, analyzed via video recordings; children’s acceptance via self-reported enjoyment of the conditions; and the post-assessments of executive functions with a behavioral and computerized task.ResultsThe motor coordination intervention and the control condition were feasible in a one-on-one setting with kindergartners. The intervention revealed heart rate increases and challenging motor coordination tasks. Children in both conditions indicated they enjoy them. Performance in the two executive function tasks did not differ between children in the motor coordination intervention and the control condition.ConclusionsA one-on-one experimenter-child setting was feasible to deliver in kindergartners. Future intervention studies should consider pre-testing of executive functions and take into account children’s characteristics as potential moderators, such as motor coordination skills.

An Empirical Analysis of the Effects of Physical Exercise on Adolescent Mental Health and Its Mediating Mechanisms.

The use of physical exercise for the purpose of maintaining adolescents' mental health is an important topic of psychological research. However, there is no unified conclusion on the effect of physical exercise time on the level of mental health. This paper investigates the causal effect of physical activity on adolescent mental health using a multilayer linear modeling approach and a Bootstrap method to test for possible mediating effects. The results of the study showed that there was a nonlinear inverted U-shaped relationship between physical activity time and adolescent mental health, with a threshold value of 105 min, and the results of the mediating effect analysis showed that self-assessment of health, self-confidence, academic stress, peer relationships, and positive peer behaviour were important mediating mechanisms between physical activity and mental health. The results of the mediation effect analysis showed that physical exercise was an important mediating mechanism between self-assessment, confidence, academic stress, peer relationship, and positive peer behaviour.

Potential causal effect of physical activity on reducing the risk of dementia: a 6-year cohort study from the Japan Gerontological Evaluation Study

BackgroundThe causal effect of physical activity on reducing dementia risk has been questioned due to the possibility of reverse causation. This study examined the potential causal effects of physical activity on reducing dementia risk using residency in a snowy area as an instrumental variable (IV) representing the physical activity of older adults.MethodsWe used cohort data from the Japan Gerontological Evaluation Study, a longitudinal cohort enrolling people aged 65 or older who were physically and cognitively independent in 2013; study participants were followed for an average of 5.7 years. Participants in the present study included 73,260 individuals living in 19 municipalities in Japan. Physical activity was measured by self-report questionnaires and the incidence of dementia was ascertained by linking participants to the public registries of long-term care insurance. IV estimation was obtained from a piecewise Cox proportional hazard model using a two-stage regression procedure.ResultsDuring the study period, we ascertained 8714 cases (11.9%) of dementia onset. In the IV analysis, we found that the frequency of physical activity per week was negatively associated with dementia risk, though the association weakened over time (Year 1: hazard ratio = 0.53, 95% confidence interval: 0.39–0.74; Year 4: 0.69, 0.53–0.90; Year 6: 0.85, 0.66–1.10).ConclusionsOur IV analysis indicated a potential causal effect of physical activity on reducing dementia risk that persisted for at least 4 years of follow-up. Thus, we conclude that physical activity should be recommended for older adults to reduce dementia risk.

Causal effects of physical activity or sedentary behaviors on kidney function: an integrated population-scale observational analysis and Mendelian randomization study.

An investigation into the causality of the effects of physical activity and specific sedentary activities on kidney function in the general population is warranted. In this observational cohort study, first, the clinical associations of the prevalence of stages 3-5 chronic kidney disease (CKD) and the estimated glomerular filtration rate (eGFR) with physical activity, determined by self-report or objective wrist-band accelerometer results, and sedentary activities (watching television, using a computer and driving) were investigated in 329 758 UK Biobank participants. To assess causality, a two-sample Mendelian randomization (MR) analysis was performed to investigate the associations of a genetic predisposition to physical activity and a sedentary lifestyle with the risk of kidney function impairment in an independent CKDGen genome-wide association study (N = 567 460). The findings were replicated with the 321 024 UK White British Biobank participants in the allele-score-based one-sample MR. A higher degree of self-reported or accelerometer-determined moderate-to-vigorous physical activity was associated with a higher eGFR, while a longer time spent watching television was significantly associated with a lower eGFR and a higher prevalence of CKD. The two-sample MR demonstrated that the genetic predisposition to a higher degree of physical activity was associated with a lower risk of CKD and a higher eGFR, while the genetically predicted television watching duration was associated with a higher risk of CKD and a lower eGFR. The other sedentary behaviors yielded inconsistent results. The findings were similarly replicated in the one-sample MR. Physical activity and television watching causally affect kidney function in the general population.

Assessment of causal effects of physical activity on neurodegenerative diseases: A Mendelian randomization study

BackgroundPhysical activity has been hypothesized to play a protective role in neurodegenerative diseases. However, effect estimates previously derived from observational studies were prone to confounding or reverse causation. MethodsWe performed a two-sample Mendelian randomization (MR) analysis to explore the causal association of accelerometer-measured physical activity with 3 common neurodegenerative diseases: Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). We selected genetic instrumental variants reaching genome-wide significance (p < 5 × 10−8) from 2 largest meta-analyses of about 91,100 UK Biobank participants. Summary statistics for AD, PD, and ALS were retrieved from the up-to-date studies in European ancestry led by the international consortia. The random-effect, inverse-variance weighted MR was employed as the primary method, while MR pleiotropy residual sum and outlier (MR-PRESSO), weighted median, and MR-Egger were implemented as sensitivity tests. All statistical analyses were performed using the R programming language (Version 3.6.1; R Foundation for Statistical Computing, Vienna, Austria). ResultsPrimary MR analysis and replication analysis utilized 5 and 8 instrumental variables, which explained 0.2% and 0.4% variance in physical activity, respectively. In each set, one variant at 17q21 was significantly associated with PD, and MR sensitivity analyses indicated them it as an outlier and source of heterogeneity and pleiotropy. Primary results with the removal of outlier variants suggested odds ratios (ORs) of neurodegenerative diseases per unit increase in objectively measured physical activity were 1.52 for AD (95% confidence interval (95%CI): 0.88–2.63, p = 0.13) and 3.35 for PD (95%CI: 1.32–8.48, p = 0.01), while inconsistent results were shown in the replication set for AD (OR = 1.06, 95%CI: 1.01–1.12, p = 0.02) and PD (OR = 0.99, 95%CI: 0.88–0.12, p = 0.97). Similarly, the beneficial effect of physical activity on ALS (OR = 0.51, 95%CI: 0.29–0.91, p = 0.02) was not confirmed in the replication analysis (OR = 0.96, 95%CI: 0.91–1.02, p = 0.22). ConclusionGenetically predicted physical activity was not robustly associated with risk of neurodegenerative disorders. Triangulating evidence across other studies is necessary in order to elucidate whether enhancing physical activity is an effective approach in preventing the onset of AD, PD, or ALS.

Physical activity and lung function-Cause or consequence?

Concerns exist that the positive association of physical activity with better lung function, which has been suggested in previous longitudinal studies in smokers, is due to reverse causation. To investigate this, we applied structural equation modeling (SEM), an exploratory approach, and marginal structural modeling (MSM), an approach from the causal inference framework that corrects for reverse causation and time-dependent confounding and estimates causal effects, on data from participants in the European Community Respiratory Health Survey (ECRHS, a multicentre European cohort study initiated in 1991–1993 with ECRHS I, and with two follow-ups: ECRHS II in 1999–2003, and ECRHS III in 2010–2014). 753 subjects who reported current smoking at ECRHS II, with repeated data on lung function at ECRHS I, II and III, physical activity at ECRHS II and III, and potential confounders at ECRHS I and II, were included in the analyses. SEM showed positive associations between physical activity and lung function in both directions. MSM suggested a protective causal effect of physical activity on lung function (overall difference in mean β (95% CI), comparing active versus non-active individuals: 58 mL (21–95) for forced expiratory volume in one second and 83 mL (36–130) for forced vital capacity). Our results suggest bi-directional causation and support a true protective effect of physical activity on lung function in smokers, after accounting for reverse causation and time-dependent confounding.

Causal effects of physical activity and sedentary behaviour on health deficits accumulation in older adults.

Increasing physical activity (PA) and reducing sedentary behaviour (SB) have been associated with healthy ageing, but their effects when adjusted for reverse causation and selection bias remain unclear. A deficits accumulation (DA) index based on the number and severity of 51 health deficits (0-100%) was calculated at baseline and three biannual follow-up visits, in a representative cohort of 3228 community-dwelling older adults in Spain. Average differences in DA index by previous recreational PA, household PA, mentally-active SB and passive SB were estimated using marginal structural models with inverse probability of exposure and censoring weights. Compared with participants with previous recreational PA of 10-19.9 metabolic equivalent hours/week (MET-hours/week), average differences in DA index (95% confidence intervals) were 0.19 (-1.09, 1.48), 0.69 (-0.23, 1.61), -0.66 (-1.34, 0.02), -0.87 (-1.59, -0.13) and -0.55 (-1.37, 0.28) for 0, 0.1-9.9, 20-29.9, 30-39.9 and ≥40 MET-hours/week, respectively (P for trend = 0.006). Household PA showed no effect on subsequent DA after adjusting for reverse causation. Women, but not men, who spent 7-14.9, 15-20.9 and ≥21 h/week on mentally active SB had DA decreases of 0.09 (-1.00, 1.19), 1.08 (-0.28, 2.45) and 2.17 (0.58, 3.75), respectively, compared with 1-6.9 h/week (P for trend = 0.005); whereas women who spent 3-3.9, 4-4.9 and ≥5 h/day on passive SB showed DA increases of 0.41 (-0.52, 1.35), 1.35 (0.13, 2.57) and 2.13 (0.78, 3.47), respectively, compared with 2-2.9 h/day (P for trend = 0.001). The proposed methodology allows estimation of the causal effects of PA and SB on ageing, by simulating a random assignment in which all subjects have the same probability of exposure.

Causal Effect of Physical Activity on Reducing the Risk of Dementia: Instrumental Variable Analysis Using 2013-16 Cohort Data from JAGES

Background: To examine the causal effect of physical activity on the risk of dementia, we conducted competing-risks survival analysis using the instrumental variable (IV) method. Residency in a snowy area was treated as an IV for frequency of physical activity. We obtained prospective cohort data from the Japan Gerontological Evaluation Study (JAGES). Methods: The baseline study was conducted in 23 municipalities in Japan from October to December 2013. Participants included 97,821 individuals aged 65 or older who completed the JAGES and were physically and cognitively independent at baseline. The incidence of dementia was ascertained by linking to registries of public long-term care insurance through 2016. During the mean follow-up of 3·2 years, we ascertained the incidence of dementia in 4,633 cases (4·7%). Findings: Through IV estimation, we found protective effects of physical activity at various levels of intensity on the risk of dementia: vigorous intensity (sub-distribution hazard ratio 0·62, 95% confidence interval 0·49 to 0·78), moderate intensity (0·69, 0·60 to 0·79), and light intensity (0·56, 0·47 to 0·68). Interpretations: Physical activity should be recommended for older adults to reduce the risk of dementia. Funding Statement: This study used data from the Japan Gerontological Evaluation Study (JAGES), which was supported by JSPS(Japan Society for the Promotion of Science) KAKENHI Grant Number (JP15H01972), Health Labour Sciences Research Grant (H28-Choju-Ippan-002), Japan Agency for Medical Research and Development (AMED) (JP17dk0110017, JP18dk0110027, JP18ls0110002, JP18le0110009), the Research Funding for Longevity Sciences from National Center for Geriatrics and Gerontology (29-42). Declaration of Interests: The authors state there are no conflicts of interest to declare. Ethics Approval Statement: This study was reviewed and approved by ethics committees at the University of Tokyo, Nihon Fukushi University, National Center for Geriatrics and Gerontology, and Chiba University.

Physical activity, common brain pathologies, and cognition in community-dwelling older adults

To examine the associations of physical activity, Alzheimer disease (AD), and other brain pathologies and cognition in older adults. We studied 454 brain autopsies from decedents in a clinical-pathologic cohort study. Nineteen cognitive tests were summarized in a global cognitive score. Total daily physical activity summarized continuous multiday recordings of activity during everyday living in the community setting. A global motor ability score summarized 10 supervised motor performance tests. A series of regression analyses were used to examine associations of physical activity, AD, and other brain pathologies with global cognition proximate to death controlling for age, sex, education, and motor abilities. Higher levels of total daily activity (estimate 0.148, 95% confidence interval 0.053-0.244, SE 0.049, p = 0.003) and better motor abilities (estimate 0.283, 95% confidence interval, 0.175-0.390, SE 0.055, p < 0.001) were independently associated with better cognition. These independent associations remained significant when terms for AD and other pathologies were added as well as in sensitivity analyses excluding cases with poor cognition or dementia. Adding interaction terms, the associations of total daily activity and motor abilities with cognition did not vary in individuals with and without dementia. The associations of AD and other pathologies with cognition did not vary with the levels of total daily activity or motor abilities. Physical activity in older adults may provide cognitive reserve to maintain function independent of the accumulation of diverse brain pathologies. Further studies are needed to identify the molecular mechanisms underlying this potential reserve and to ensure the causal effects of physical activity.

Time-Dependent Associations Between Body Composition, Physical Activity, and Current Asthma in Women: A Marginal Structural Modeling Analysis

The role of obesity in adult asthma is well-known and has been partly attributed to a confounding role of physical inactivity. However, the interrelationships between obesity, physical activity, and asthma have been incompletely addressed, probably because their time-dependent and bidirectional nature represents a methodologically challenging research question. We aimed to estimate the independent causal effects of body mass index (BMI; weight (kg)/height (m)2) and physical activity on current asthma using marginal structural models (MSMs). MSMs were applied to 15,353 adult women from a 2011 case-control study of asthma (Asthma-E3N) nested within the French E3N study (Etude Epidémiologique auprès de Femmes de la Mutuelle Générale de l'Education Nationale). Three time periods (1997-2000-2002, 2000-2002-2005, and 2002-2005-2011) were defined, where exposures (BMI and physical activity) were measured at time t, outcome (current asthma) was measured at time t+1, and covariates were measured at time t-1 or at baseline. A strong significant and positive dose-response relationship between BMI and current asthma was observed (odds ratios were 0.90 (95% confidence interval (CI): 0.79, 1.03), 1.29 (95% CI: 1.17, 1.42), and 1.87 (95% CI: 1.60, 2.18) for the BMI groups <20.0, 25.0-29.9, and ≥30.0, respectively, versus the normal-weight group (BMI 20.0-24.9)). We found no association between physical activity and current asthma. Our results suggest an independent causal deleterious effect of overweight and obesity on current asthma, whereas no independent causal effect of physical activity was found.