Additional file 1 of Genomic risk prediction of coronary artery disease in women with breast cancer: a prospective cohort study

Additional file 1. Supplementary appendix containing additional description of methods and tables and figures for sensitivity analyses described in the main text

Telomere length and risk of incident fracture and arthroplasty: findings from UK Biobank.

We investigated independent associations between telomere length and risk of fracture and arthroplasty in UK Biobank participants. Leucocyte telomere length (LTL) was measured in baseline samples using a validated PCR method. We used, in men and women separately, Cox proportional hazards models to calculate the hazard ratio for incident fracture (any, osteoporotic) or arthroplasty (hip or knee) over 1,186,410 person-years of follow-up. Covariates included age, white cell count, ethnicity, smoking, alcohol, physical activity and menopause (women). In further analyses we adjusted for either estimated bone mineral density from heel quantitative ultrasound, handgrip strength, gait speed, total fat mass (bioimpedance) or blood biomarkers, all measured at baseline (2006-2010). We studied 59,500 women and 51,895 men, mean(SD) age 56.4(8.0) and 57.0(8.3) years respectively. During follow-up there were 5,619 fractures; 5,285 hip and 4,261 knee arthroplasties. In confounder-adjusted models, longer LTL was associated with reduced risk of incident knee arthroplasty in both men [hazard ratio/SD (95%CI): 0.93 (0.88,0.97)] and women [0.92 (0.88,0.96)] and hip arthroplasty in men [0.91 (0.87,0.95)] but not women [0.98 (0.94,1.01)]. Longer LTL was weakly associated with reduced risk of any incident fracture in women [hazard ratio/SD (95% CI): 0.96 (0.93,1.00)] with less evidence in men [0.98 (0.93,1.02)]. Associations with incident outcomes were not materially altered by adjustment for heel estimated bone mineral density, grip strength, gait speed, fat mass or blood biomarker measures. In this, the largest study to date, longer LTL was associated with lower risk of incident knee or hip arthroplasty, but only weakly associated with lower risk of fracture. The relative risks were low at a population level, but our findings suggest that common factors acting on the myeloid and musculoskeleletal systems might influence later life musculoskeletal outcomes. This article is protected by copyright. All rights reserved

Modifiable traits, healthy behaviours, and leucocyte telomere length: a population-based study in UK Biobank

Background Telomere length is associated with risk of several age-related diseases and cancers. We aimed to investigate the extent to which telomere length might be modifiable through lifestyle and behaviour, and whether such modification has any clinical consequences. Methods In this population-based study, we included participants from UK Biobank who had leukocyte telomere length (LTL) measurement, ethnicity, and white blood cell count data. We investigated associations of LTL with 117 potentially modifiable traits, as well as two indices of healthy behaviours incorporating between them smoking, physical activity, diet, maintenance of a healthy bodyweight, and alcohol intake, using both available and imputed data. To help interpretation, associations were summarised as the number of equivalent years of age-related change in LTL by dividing the trait β coefficients with the age β coefficient. We used mendelian randomisation to test causality of selected associations. We investigated whether the associations of LTL with 22 diseases were modified by the number of healthy behaviours and the extent to which the associations of more healthy behaviours with greater life expectancy and lower risk of coronary artery disease might be mediated through LTL. Findings 422 797 participants were available for the analysis (227 620 [53·8%] were women and 400 036 [94·6%] were White). 71 traits showed significant (p Interpretation Although several potentially modifiable traits and healthy behaviours have a quantifiable association with LTL, at least some of which are likely to be causal, these effects are not of a sufficient magnitude to substantially alter the association between LTL and various diseases or life expectancy. Attempts to change telomere length through lifestyle or behavioural changes might not confer substantial clinical benefit.</p

Relative risks (RRs) for diseases associated with systolic blood pressure (SBP).

<p>The figure shows RRs for 10 mmHg higher usual SBP. The figure shows RRs converted to comparable age group as described in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0065174#s2" target="_blank">Methods</a>. See <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0065174#pone.0065174.s001" target="_blank">Table S1</a> for RRs in original age groups from each study. RRs for rheumatic heart disease and inflammatory heart disease apply only to deaths and those for other outcomes to deaths and incidence. The percentage of variation in the pooled estimates that is due to statistical heterogeneity was evaluated using the I² statistic for each age group and outcome. Of all outcomes and age groups analyzed, only two age groups in the pooled analysis for hemorrhagic stroke had non-zero I² values: I² = 44.4% for ages 35–44 years, and I² = 24.3% for ages 55–64 years.</p

Relative risks (RRs) for diseases associated with fasting plasma glucose (FPG).

<p>The figure shows RRs for 1 mmol/L higher usual or baseline FPG. The figure shows RRs converted to comparable age group as described in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0065174#s2" target="_blank">Methods</a>. See <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0065174#pone.0065174.s001" target="_blank">Table S1</a> for RRs in original age groups from each study. The percentage of variation in the pooled estimates that is due to statistical heterogeneity was evaluated using the I² statistic for each age group and outcome. All I² values for these outcomes and age groups were zero.</p

Relative risks (RRs) for diseases associated with body mass index (BMI).

<p>The figure shows RRs for 5 kg/m² higher baseline BMI. The figure shows RRs converted to comparable age group as described in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0065174#s2" target="_blank">Methods</a>. See <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0065174#pone.0065174.s001" target="_blank">Table S1</a> for RRs in original age groups from each study. The percentage of variation in the pooled estimates that is due to statistical heterogeneity was evaluated using the I² statistic for each age group and outcome. Of all the outcomes and age groups analyzed, the three age groups below age 65 years in the pooled analysis for hypertensive heart disease had non-zero I² values: 79.2% for ages 35–44 years, 69.0% for ages 45–54 years, and 37.2% for ages 55–64 years. *The associations with haemorrhagic stroke are for BMIs above 25 kg/m² as described in text.</p

Additional file 1: of Recruitment and representativeness of blood donors in the INTERVAL randomised trial assessing varying inter-donation intervals

INTERVAL trial – statistical analysis plan for principal paper. (PDF 74 kb

Outcomes associated with each risk factor, studies from which RRs were extracted, and procedures for estimating RRs by age group.

a<p>RRs apply to mortality but not to incidence and is included because of the benefits of lower blood pressure for reduced heart failure mortality.</p>b<p>This residual category contains a number of ICD codes. The proportion of deaths from the constituent diseases is likely to vary across world regions and even across cohorts in the same meta-analysis.</p>c<p>A quadratic age model was used instead of a log-linear age model as this fit the data better.</p

Association of shorter leucocyte telomere length with risk of frailty

Background Frailty is a multidimensional syndrome of decline that affects multiple systems and predisposes to adverse health outcomes. Although chronological age is the major risk factor, inter-individual variation in risk is not fully understood. Leucocyte telomere length (LTL), a proposed marker of biological age, has been associated with risk of many diseases. We sought to determine whether LTL is associated with risk of frailty. Methods We utilized cross-sectional data from 441 781 UK Biobank participants (aged 40–69 years), with complete data on frailty indicators and LTL. Frailty was defined as the presence of at least three of five indicators: weaker grip strength, slower walking pace, weight loss in the past year, lower physical activity, and exhaustion in the past 2 weeks. LTL was measured using a validated qPCR method and reported as a ratio of the telomere repeat number (T) to a single-copy gene (S) (T/S ratio). Association of LTL with frailty was evaluated using adjusted (chronological age, sex, deprivation, smoking, alcohol intake, body mass index, and multimorbidity) multinomial and ordinal regression models, and results are presented as relative risk (RRR) or odds ratios (OR), respectively, alongside the 95% confidence interval (CI). Mendelian randomization (MR), using 131 genetic variants associated with LTL, was used to assess if the association of LTL with frailty was causal. Results Frail participants (4.6%) were older (median age difference (95% CI): 3 (2.5; 3.5) years, P = 2.73 × 10−33), more likely to be female (61%, P = 1.97 × 10−129), and had shorter LTL (−0.13SD vs. 0.03SD, P = 5.43 × 10−111) than non-frail. In adjusted analyses, both age and LTL were associated with frailty (RRR = 1.03 (95% CI: 1.02; 1.04) per year of older chronological age, P = 3.99 × 10−12; 1.10 (1.08; 1.11) per SD shorter LTL, P = 1.46 × 10−30). Within each age group (40–49, 50–59, 60–69 years), the prevalence of frailty was about 33% higher in participants with shorter (−2SD) versus longer telomeres (+2SD). MR analysis showed an association of LTL with frailty that was directionally consistent with the observational association, but not statistically significant (MR-Median: OR (95% CI): 1.08 (0.98; 1.19) per SD shorter LTL, P = 0.13). Conclusions Inter-individual variation in LTL is associated with the risk of frailty independently of chronological age and other risk factors. Our findings provide evidence for an additional biological determinant of frailty.</p

Relative risks (RRs) for diseases associated with serum total cholesterol (TC).

<p>The figure shows RRs for 1 mmol/L higher usual TC. The figure shows RRs converted to comparable age group as described in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0065174#s2" target="_blank">Methods</a>. See <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0065174#pone.0065174.s001" target="_blank">Table S1</a> for RRs in original age groups from each study. The percentage of variation in the pooled estimates that is due to statistical heterogeneity was evaluated using the I² statistic for each age group and outcome. Of all the outcomes and age groups analyzed, only ages 35–44 years in the pooled analysis for IHD had a non-zero I² value of 58.8%.</p