Physical Activity and the Risk of Liver Cancer: A Systematic Review and Meta-Analysis of Prospective Studies and a Bias Analysis

Abstract

Background Physical inactivity is an established risk factor for several cancers of the digestive system and female reproductive organs, but the evidence for liver cancers is less conclusive. Methods The aim of this study was to synthesize prospective observational studies on the association of physical activity and liver cancer risk by means of a systematic review and meta-analysis. We searched Medline, Embase, and Scopus from inception to January 2019 for prospective studies investigating the association of physical activity and liver cancer risk. We calculated mean hazard ratios (HRs) and 95% confidence intervals (CIs) using a random-effects model. We quantified the extent to which an unmeasured confounder or an unaccounted selection variable could shift the mean hazard ratio to the null. Results Fourteen prospective studies, including 6,440 liver cancers, were included in the systematic review and meta-analysis. The mean hazard ratio for high compared with low physical activity was 0.75 (95% CI = 0.63 to 0.89; 95% prediction interval = 0.52 to 1.07; I² = 64.2%). We estimated that 67.6% (95% CI = 56.6% to 78.5%) of all true effect estimates would have a hazard ratio less than 0.8. Bias analysis suggested than an unobserved confounder would have to be associated with a 1.99-fold increase in the risk of physical activity or liver cancer to explain away the observed mean hazard ratio. An unaccounted for selection variable would have to be related to exposure and endpoint with a relative risk of 1.58 to explain away the mean hazard ratio. Conclusions Physical activity is inversely related to the risk of liver cancer. Further studies with objectively measured physical activity and quasi-experimental designs addressing confounding are needed.

Dialysis Initiation and All-Cause Mortality Among Incident Adult Patients With Advanced CKD: A Meta-analysis With Bias Analysis

“…We therefore believe that supplementing a standard meta-analysis with a bias analysis of the effects of unmeasured confounding has important benefits. 21 , 23 Nevertheless, observational studies, even when meta-analyzed with sensitivity analyses, still cannot replace randomized controlled trials to confidently rule out the possibility of spurious results due to unmeasured confounding. Our analyses suggest promising results in observational studies that appear robust to unmeasured confounding and conducting randomized trials on this topic would therefore be warranted if ethically feasible.…”

“… 14 We estimated the minimum strength of bias factor that, if present in all studies, would “explain away” the pooled results of random-effects meta-analysis in the sense of reducing the proportion of studies with true effects more protective than HR of 0.80 (HR<0.80) to only 10%. 23 We then estimated the minimum strength of the bias factor such that half of all studies would have concluded that dialysis initiation was harmful rather than protective. This bias factor would have to increase the proportion of studies with true effects concluding HRs > 1.0 to 50%.…”

Physical activity and cancer risk: Findings from the UK Biobank, a large prospective cohort study

“…Whilst we note that some of our models for specific cancer sites may have been impacted by unmeasured confounding (e.g. hepatitis disease for hepatobiliary cancers [61]), our models were adjusted for a very comprehensive set of covariates. During peer-review, our approach was critiqued for not applying causal inference methodologies.…”

A Physically Active Status Affects the Circulating Profile of Cancer-Associated miRNAs

“…Published articles on circulating miRNAs associated with cancer were selected on PubMed by searching for “serum miRNAs”, “serum microRNAs”, “plasma miRNAs”, “plasma microRNAs”, “circulating miRNAs”, “circulating microRNAs” with “cancer diagnosis” for five cancers: lung cancer (LC), prostate cancer (PC), colon cancer (CC), liver cancer (HC) and gastroesophageal cancer (GEC) and related subtypes. These cancers were chosen as the five most frequent cancers in males worldwide, according to the “Global Cancer Observatory” ( , accessed on 31 December 2020), for which exist evidence, through meta-analysis (published from 2010 to 2020), on association with physical activity (all-cancer risk/mortality [ 25 , 26 , 27 , 28 , 29 ]; LC [ 30 , 31 ]; PC [ 32 ]; CC [ 33 , 34 , 35 ]; HC [ 36 ]; GEC [ 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 ]). Only studies on human, published from 2010, and demonstrating a clinical relevance for single serum/plasma miRNA or serum/plasma miRNA signatures including at least one of the modulated miRNAs in our trained cohort were considered.…”