Interpreting information on diagnostic accuracy is an area that health professionals struggle with. In this paper, we use the example of Mr Samways, a 45-year-old man with joint symptoms, to illustrate how to apply the results of a diagnostic accuracy study in clinical practice. We consider the various measures used to quantify diagnostic accuracy and discuss their clinical utility. We provide an overview of potential biases to consider when evaluating a diagnostic accuracy study and consider how to determine whether the results can be applied to a particular patient.
Good bone and joint health is essential for the physical tasks of daily living and poorer indicators of physical capability in older adults have been associated with increased mortality rates. Genetic variants of indicators of bone and joint health may be associated with measures of physical capability.
As part of the Healthy Ageing across the Life Course (HALCyon) programme, men and women aged between 52 and 90 + years from six UK cohorts were genotyped for a polymorphism associated with serum calcium (rs1801725, CASR), two polymorphisms associated with bone mineral density (BMD) (rs2941740, ESR1 and rs9594759, RANKL) and one associated with osteoarthritis risk rs3815148 (COG5). Meta-analysis was used to pool within-study effects of the associations between each of the polymorphisms and measures of physical capability: grip strength, timed walk or get up and go, chair rises and standing balance.
Few important associations were observed among the several tests. We found that carriers of the serum calcium-raising allele had poorer grip strength compared with non-carriers (pooled p = 0.05, n = 11,239) after adjusting for age and sex. Inconsistent results were observed for the two variants associated with BMD and we found no evidence for an association between rs3815148 (COG5) and any of the physical capability measures.
Our findings suggest elevated serum calcium levels may lead to lower grip strength, though this requires further replication. Our results do not provide evidence for a substantial influence of these variants in ESR1, RANKL and COG5 on physical capability in older adults.
► We examined associations between bone-related genotypes and physical capability. ► We conducted a meta-analysis on 12,836 middle-age adults. ► We found CASR may be associated with grip strength. ► No substantial support for specific bone mineral density variants and physical capability.
BMD, bone mineral density; OA, osteoarthritis; BMI, body mass index; SNP, single nucleotide polymorphism; CaPS, Caerphilly Prospective Study; ELSA, English Longitudinal Study of Ageing; HAS, Hertfordshire Ageing Study; HCS, Hertfordshire Cohort Study; LBC1921, The Lothian Birth Cohort 1921; NSHD, National Survey of Health and Development; HWE, Hardy–Weinberg equilibrium; WHR, waist–hip ratio; GWAS, genome-wide association studies; Aging; Grip strength; Calcium; Bone mineral density; Osteoarthritis
The association between functioning of the hypothalamic pituitary adrenal (HPA) axis and physical performance at older ages remains poorly understood. We carried out meta-analyses to test the hypothesis that dysregulation of the HPA axis, as indexed by patterns of diurnal cortisol release, is associated with worse physical performance. Data from six adult cohorts (ages 50–92 years) were included in a two stage meta-analysis of individual participant data. We analysed each study separately using linear and logistic regression models and then used meta-analytic methods to pool the results. Physical performance outcome measures were walking speed, balance time, chair rise time and grip strength. Exposure measures were morning (serum and salivary) and evening (salivary) cortisol. Total sample sizes in meta-analyses ranged from n = 2146 for associations between morning Cortisol Awakening Response and balance to n = 8448 for associations between morning cortisol and walking speed. A larger diurnal drop was associated with faster walking speed (standardised coefficient per SD increase 0.052, 95% confidence interval (CI) 0.029, 0.076, p < 0.001; age and gender adjusted) and a quicker chair rise time (standardised coefficient per SD increase −0.075, 95% CI −0.116, −0.034, p < 0.001; age and gender adjusted). There was little evidence of associations with balance or grip strength. Greater diurnal decline of the HPA axis is associated with better physical performance in later life. This may reflect a causal effect of the HPA axis on performance or that other ageing-related factors are associated with both reduced HPA reactivity and performance.
HPA axis; Physical capability; Healthy ageing
The ACTN3 R577X (rs1815739) genotype has been associated with athletic status and muscle phenotypes, though not consistently. Our objective was to conduct a meta-analysis of the published literature on athletic status and investigate its associations with physical capability in several new population-based studies. Relevant data were extracted from studies in the literature, comparing genotype frequencies between controls and sprint/power and endurance athletes. For lifecourse physical capability, data were used from two studies of adolescents and seven studies in the Healthy Ageing across the Life Course (HALCyon) collaborative research programme, involving individuals aged between 53 and 90+ years. We found evidence from the published literature to support the hypothesis that in Europeans the RR genotype is more common among sprint/power athletes compared with their controls. There is currently no evidence that the X allele is advantageous to endurance athleticism. We found no association between R577X and grip strength (p-value=0.09, n=7672 in males; p-value=0.90, n=7839 in females), standing balance, timed get up and go or chair rises in our studies of physical capability. The ACTN3 R577X genotype is associated with sprint/power athletic status in Europeans, but does not appear to be associated with objective measures of physical capability in the general population.
ACTN3; Actinin-3; athlete; aging; SNP; grip strength
Socioeconomic influences over a lifetime impact on health and may contribute to poor physical functioning in old age.
We examined the impact of both childhood and adulthood socioeconomic factors on locomotor function at 63-86 years (measured with the get up and go timed walk and flamingo balance test), in the UK-based Boyd Orr (n=405) and Caerphilly (n=1,196) prospective cohorts.
There was a marked reduction in walking speed and balance time with increasing age. Each year of age was associated with a 1.7% slower walk time and a 14% increased odds of poor balance. Participants who moved from a low socioeconomic position in childhood to a high socioeconomic position in adulthood had walking times 3% slower (95% CI: -2%, 8%) than people with high socioeconomic position in both periods. Participants who moved from a high socioeconomic position in childhood to a low adulthood socioeconomic position had walking times 5% slower (95% CI: -2%, 12%). Participants with a low socioeconomic position in both periods had walking times 10% slower (95% CI: 5%, 16%; P for trend <0.001).
In Boyd Orr, low socioeconomic position in childhood was associated with poor balance in old age (OR per worsening category = 1.26; 95% CI 1.01, 1.57; P=0.043), as was socioeconomic position in adulthood (OR = 1.71; 95% CI 1.20, 2.45; P=0.003). Similar associations were not observed in Caerphilly.
Accumulating socioeconomic disadvantage from childhood to adulthood is associated with slower walking time in old age, with mixed results for balance ability.
Aged; Gait; Physical performance; Social Class; Socioeconomic Factors
The ACTN3 R577X (rs1815739) genotype has been associated with
athletic status and muscle phenotypes, although not consistently. Our objective
was to conduct a meta-analysis of the published literature on athletic status
and investigate its associations with physical capability in several new
population-based studies. Relevant data were extracted from studies in the
literature, comparing genotype frequencies between controls and sprint/power and
endurance athletes. For life course physical capability, data were used from two
studies of adolescents and seven studies in the Healthy Ageing across the Life
Course (HALCyon) collaborative research program, involving individuals aged
between 53 and 90+ years. We found evidence from the published literature
to support the hypothesis that in Europeans the RR genotype is more common among
sprint/power athletes compared with their controls. There is currently no
evidence that the X allele is advantageous to endurance athleticism. We found no
association between R577X and grip strength (P = 0.09,
n = 7,672 in males; P =
0.90, n = 7,839 in females), standing balance, timed get
up and go, or chair rises in our studies of physical capability. The
ACTN3 R577X genotype is associated with sprint/power
athletic status in Europeans, but does not appear to be associated with
objective measures of physical capability in the general population. Hum Mutat
32:1–11, 2011. © 2011 Wiley-Liss, Inc.
ACTN3; Actinin-3; athlete; aging; SNP; grip strength
In large-scale epidemiology, bloodspot sampling by fingerstick onto filter paper has many advantages, including ease and low costs of collection, processing and transport. We describe the development of an enzyme-linked immunoassay (ELISA) for quantifying insulin from dried blood spots and demonstrate its application in a large trial.
We adapted an existing commercial kit (Mercodia Human Insulin ELISA, 10-1113-01) to quantify insulin from two 3-mm diameter discs (≈6 µL of blood) punched from whole blood standards and from trial samples. Paediatricians collected dried blood spots in a follow-up of 13,879 fasted children aged 11.5 years (interquartile range 11.3–11.8 years) from 31 trial sites across Belarus. We quantified bloodspot insulin levels and examined their distribution by demography and anthropometry.
Mean intra-assay (n = 157) coefficients of variation were 15% and 6% for ‘low’ (6.7 mU/L) and ‘high’ (23.1 mU/L) values, respectively; the respective inter-assay values (n = 33) were 23% and 11%. The intraclass correlation coefficient between 50 paired whole bloodspot versus serum samples, collected simultaneously, was 0.90 (95% confidence interval 0.85 to 0.95). Bloodspot insulin was stable for at least 31 months at −80°C, for one week at +30°C and following four freeze-thaw cycles. Paediatricians collected a median of 8 blood spots from 13,487 (97%) children. The geometric mean insulin (log standard deviation) concentrations amongst 12,812 children were 3.0 mU/L (1.1) in boys and 4.0 mU/L (1.0) in girls and were positively associated with pubertal stage, measures of central and peripheral adiposity, height and fasting glucose.
Our simple and convenient bloodspot assay is suitable for the measurement of insulin in very small volumes of blood collected on filter paper cards and can be applied to large-scale epidemiology studies of the early-life determinants of circulating insulin.
Background Weight gain during infancy may programme later health outcomes, but examination of this hypothesis requires appropriate lifecourse methods and detailed weight gain measures during childhood. We examined associations between weight gain in infancy and early childhood and blood pressure at the age of 6.5 years in healthy children born at term.
Methods We carried out an observational analysis of data from a cluster-randomized breastfeeding promotion trial in Belarus. Of 17 046 infants enrolled between June 1996 and December 1997, 13 889 (81.5%) had systolic and diastolic blood pressure measured at 6.5 years; 10 495 children with complete data were analysed. A random-effects linear spline model with three knot points was used to estimate each individual's birthweight and weight gain from birth to 3 months, 3 months to 1 year and 1–5 years. Path analysis was used to separate direct effects from those mediated through subsequent weight gain.
Results In boys, after controlling for confounders and prior weight gain, the change in systolic blood pressure per z-score increase in weight gain was 0.09 mmHg [95% confidence interval (95% CI) −0.14 to 0.31] for birthweight; 0.41 mmHg (95% CI 0.19–0.64) for birth to 3 months; 0.69 mmHg (95% CI 0.47–0.92) for 3 months to 1 year and 0.82 mmHg (95% CI 0.58–1.06) for 1–5 years. Most of the associations between weight gain and blood pressure were mediated through weight at the age of 6.5 years. Findings for girls and diastolic blood pressure were similar.
Conclusions Children who gained weight faster than their peers, particularly at later ages, had higher blood pressure at the age of 6.5 years, with no association between birthweight and blood pressure.
Birthweight; blood pressure; lifetime; multi-level model; path analysis; weight gain
Epidemiological studies suggest that vitamin D protects against prostate cancer, although evidence is limited and inconsistent. We investigated associations of circulating total 25-hydroxyvitamin D (25(OH)D) with PSA-detected prostate cancer in a case-control study nested within the Prostate Testing for Cancer and Treatment (ProtecT) trial. Conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) quantifying the association between circulating total 25(OH)D and prostate cancer. In case-only analyses, we used unconditional logistic regression to quantify associations of total 25(OH)D with stage (advanced vs localized) and Gleason grade (high-grade (≥7) vs low-grade (<7)). Pre-determined categories of total 25(OH)D were defined as: high: ≥30ng/mL; adequate: 20-<30ng/mL; insufficient: 12-<20ng/mL; deficient: <12ng/mL. Fractional polynomials were used to investigate the existence of any U-shaped relationship. We included 1,447 prostate cancer cases (153 advanced, 469 high-grade) and 1,449 healthy controls. There was evidence that men deficient in vitamin D had a two-fold increased risk of advanced versus localized cancer (OR for deficient vs adequate total 25(OH)D=2.33, 95% CI: 1.26,4.28) and high-grade versus low-grade cancer (OR for deficient vs adequate total 25(OH)D=1.78, 95% CI: 1.15,2.77). There was no evidence of a linear association between total 25(OH)D and prostate cancer (p=0.44) or of an increased risk of prostate cancer with high and low vitamin D levels. Our study provides evidence that lower 25(OH)D concentrations were associated with more aggressive cancers (advanced versus localized cancers and high- versus low- Gleason grade), but there was no evidence of an association with overall prostate cancer risk.
Prostate cancer; vitamin D; 25-hydroxyvitamn D
Circulating insulin-like growth factor-I (IGF-I) has been studied extensively in prostate cancer, but there is still little information about IGFs and IGF binding proteins (IGFBPs) in cancers detected by the prostate-specific antigen (PSA) test. Here we report the findings of a United Kingdom-based case-control study to investigate circulating IGFs and IGFBPs in PSA-detected prostate cancer with regard to their potential associations with different cancer stages or grades. PSA testing was offered to 110,000 men aged 50-69 years from 2002-2009. Participants with an elevated level of PSA (≥ 3.0 ng/ml) underwent prostate biopsy and measurements of blood serum IGF-I, IGF-II, IGFBP-2 and IGFBP-3 obtained at recruitment. We found that serum levels of IGF-II (OR per standard deviation increase: 1.16; 95%CI 1.08,1.24;ptrend<0.001), IGFBP-2 (1.18;1.06,1.31;ptrend<0.01) and IGFBP-3 (1.27;1.19,1.36;ptrend<0.001), but not IGF-I (0.99;0.93,1.04;ptrend=0.62), were associated with PSA-detected prostate cancer. After controlling for IGFBP-3, IGF-II was no longer associated (0.99;0.91,1.08;ptrend=0.62) and IGF-I was inversely associated (0.85;0.79,0.91;ptrend<0.001) with prostate cancer. In addition, no strong associations existed with cancer stage or grade. Overall, these findings suggest potentially important roles for circulating IGF-II, IGFBP-2 and IGFBP-3 in PSA-detected prostate cancer, in support of recent in vitro evidence. While our findings for IGF-I agree with previous results from PSA-screening trials, they contrast with positive associations in routinely-detected disease, suggesting that reducing levels of circulating IGF-I might not prevent the initiation of prostate cancer but might nonetheless prevent its progression.
case-control study; insulin-like growth factors; insulin-like growth factor binding proteins; prostate cancer
Several age-related traits are associated with shorter telomeres, the structures that cap the end of linear chromosomes. A common polymorphism near the telomere maintenance gene TERT has been associated with several cancers, but relationships with other ageing traits such as physical capability have not been reported.
As part of the Healthy Ageing across the Life Course (HALCyon) collaborative research programme, men and women aged between 44 and 90 years from 9 UK cohorts were genotyped for the single nucleotide polymorphism (SNP) rs401681. We then investigated relationships between the SNP and 30 age-related phenotypes, including cognitive and physical capability, blood lipid levels and lung function, pooling within-study genotypic effects in meta-analyses.
No significant associations were found between the SNP and any of the cognitive performance tests (e.g. pooled beta per T allele for word recall z-score=0.02, 95% CI: -0.01- 0.04, p-value=0.12, n=18,737), physical performance tests (e.g. pooled beta for grip strength=-0.02, 95% CI:-0.045- 0.006, p-value=0.14, n=11,711), blood pressure, lung function or blood test measures. Similarly, no differences in observations were found when considering follow-up measures of cognitive or physical performance after adjusting for its measure at an earlier assessment.
The lack of associations between SNP rs401681 and a wide range of age-related phenotypes investigated in this large multi-cohort study suggests that whilst this SNP may be associated with cancer, it is not an important contributor to other markers of ageing.
Aging; ageing; middle-aged; telomere; cognition; physical
Background: Socio-economic differences in the prevalence of overweight/obesity may be one factor through which health inequalities arise and may vary by the population studied. Methods: Analysing a cohort of 13 889 children born in Belarus between June 1996 and December 1997, the authors investigated associations of parental educational attainment and highest household occupation with: (i) measured body mass index (BMI), waist circumference and skinfold thicknesses at age 6.5 years and (ii) the parents’ reported BMI. Results: Overall, 10% of children, 37% of mothers and 53% of fathers were either overweight or obese. Children from non-manual households were 27% [95% confidence interval (CI): 10%, 47%] more likely to be overweight/obese (based on BMI) than those from manual households. They also had larger waist circumferences and higher percentage body fat (calculated from subscapular and triceps skinfolds). Similar associations for being overweight/obese were seen for fathers [odds ratio (OR), 1.10; 95% CI: 1.02, 1.18], but mothers from non-manual households were less likely to be overweight/obese: (OR, 0.84; 95% CI: 0.79, 0. 90). Associations of childhood and parental overweight/obesity with higher educational status of either parent were similar to those observed for non-manual households. Conclusion: We observed socio-economic differentials in overweight/obesity prevalence among children and their parents in Belarus. More affluent children and their fathers were more likely to be overweight/obese but the reverse was found for mothers.
body fat; obesity; overweight; socio-economic factors; waist circumference
Previous studies suggest that over-nutrition in early infancy may programme long-term susceptibility to insulin resistance.
To assess the association of breast milk and quantity of infant formula and cows' milk intake during infancy with insulin resistance measures in early adulthood.
Long-term follow-up of the Barry Caerphilly Growth cohort, into which mothers and their offspring had originally been randomly assigned, between 1972–1974, to receive milk supplementation or not. Participants were the offspring, aged 23–27 years at follow-up (n = 679). Breastfeeding and formula/cows' milk intake was recorded prospectively by nurses. The main outcomes were insulin sensitivity (ISI0) and insulin secretion (CIR30).
573 (84%) individuals had valid glucose and insulin results and complete covariate information. There was little evidence of associations of breastfeeding versus any formula/cows' milk feeding or of increasing quartiles of formula/cows' milk consumption during infancy (<3 months) with any outcome measure in young adulthood. In fully adjusted models, the differences in outcomes between breastfeeding versus formula/cows' milk feeding at 3 months were: fasting glucose (−0.07 mmol/l; 95% CI: −0.19, 0.05); fasting insulin (8.0%; −8.7, 27.6); ISI0 (−6.1%; −11.3, 12.1) and CIR30 (3.8%; −19.0, 32.8). There was also little evidence that increasing intakes of formula/cows' milk at 3 months were associated with fasting glucose (increase per quartile of formula/cows' milk intake = 0.00 mmol/l; −0.03, 0.03); fasting insulin (0.8%; −3.2, 5.1); ISI 0 (−0.9%; −5.1, 3.5) and CIR30 (−2.6%; −8.4, 3.6).
We found no evidence that increasing consumption of formula/cows' milk in early infancy was associated with insulin resistance in young adulthood.
To assess the association of having been breast fed with social class mobility between childhood and adulthood.
Historical cohort study with a 60‐year follow‐up from childhood into adulthood.
16 urban and rural centres in England and Scotland.
3182 original participants in the Boyd Orr Survey of Diet and Health in Pre‐War Britain (1937–39) were sent follow‐up questionnaires between 1997 and 1998. Analyses are based on 1414 (44%) responders with data on breast feeding measured in childhood and occupational social class in both childhood and adulthood.
Odds of moving from a lower to a higher social class between childhood and adulthood in those who were ever breast fed versus those who were bottle fed.
The prevalence of breast feeding varied by survey district (range 45–86%) but not with household income (p = 0.7), expenditure on food (p = 0.3), number of siblings (p = 0.7), birth order (p = 0.5) or social class (p = 0.4) in childhood. Participants who had been breast fed were 41% (95% CI 10% to 82%) more likely to move up a social class in adulthood (p = 0.007) than bottle‐fed infants. Longer breastfeeding duration was associated with greater odds of upward social mobility in fully adjusted models (p for trend = 0.003). Additionally controlling for survey district, household income and food expenditure in childhood, childhood height, birth order or number of siblings did not attenuate these associations. In an analysis comparing social mobility among children within families with discordant breastfeeding histories, the association was somewhat attenuated (OR 1.16; 95% CI 0.74 to 1.8).
Breast feeding was associated with upward social mobility. Confounding by other measured childhood predictors of social class in adulthood did not explain this effect, but we cannot exclude the possibility of residual or unmeasured confounding.
Insulin and the insulin-like growth factor (IGF) system regulate growth and are involved in determining muscle mass, strength and body composition. We hypothesised that IGF-I and IGF-II are associated with improved, and insulin with worse, physical performance in old age.
Physical performance was measured using the get-up and go timed walk and flamingo balance test at 63–86 years. We examined prospective associations of insulin, IGF-I, IGF-II and IGFBP-3 with physical performance in the UK-based Caerphilly Prospective Study (CaPS; n = 739 men); and cross-sectional insulin, IGF-I, IGF-II, IGFBP-2 and IGFBP-3 in the Boyd Orr cohort (n = 182 men, 223 women).
In confounder-adjusted models, there was some evidence in CaPS that a standard deviation (SD) increase in IGF-I was associated with 1.5% faster get-up and go test times (95% CI: −0.2%, 3.2%; p = 0.08), but little association with poor balance, 19 years later. Coefficients in Boyd Orr were in the same direction as CaPS, but consistent with chance. Higher levels of insulin were weakly associated with worse physical performance (CaPS and Boyd Orr combined: get-up and go time = 1.3% slower per SD log-transformed insulin; 95% CI: 0.0%, 2.7%; p = 0.07; OR poor balance 1.13; 95% CI; 0.98, 1.29; p = 0.08), although associations were attenuated after controlling for body mass index (BMI) and co-morbidities. In Boyd Orr, a one SD increase in IGFBP-2 was associated with 2.6% slower get-up and go times (95% CI: 0.4%, 4.8% slower; p = 0.02), but this was only seen when controlling for BMI and co-morbidities. There was no consistent evidence of associations of IGF-II, or IGFBP-3 with physical performance.
There was some evidence that high IGF-I and low insulin levels in middle-age were associated with improved physical performance in old age, but estimates were imprecise. Larger cohorts are required to confirm or refute the findings.
Circulating vitamin B12 (cobalamin/B12) and total transcobalamin (tTC) have been associated with increased and reduced risk, respectively, of prostate cancer. Mendelian randomization has the potential to determine whether these are causal associations. We estimated associations of single nucleotide polymorphisms in B12-related genes (MTR, MTRR, FUT2, TCN2, TCN1, CUBN, and MUT) with plasma concentrations of B12, tTC, holo-transcobalamin, holo-haptocorrin, folate, and homocysteine and with prostate cancer risk in a case-control study (913 cases, 895 controls) nested within the UK-wide population-based ProtecT study of prostate cancer in men age 45-69 years. Instrumental variable (IV) analysis was used to estimate odds ratios for effects of B12 and tTC on prostate cancer. We observed that B12 was lower in men with FUT2 204G>A (rs492602), CUBN 758C>T (rs1801222) and MUT 1595G>A (rs1141321) alleles (Ptrend<0.001); tTC was lower in men with the TCN2 776C>G (rs1801198) allele (Ptrend<0.001). FUT2 204G>A and CUBN 758C>T were selected as instruments for B12; TCN2 776C>G for tTC. Conventional and IV estimates for the association of loge(B12) with prostate cancer were: OR=1.17 (95% CI 0.90-1.51), P=0.2 and OR=0.60 (0.16-2.15), P=0.4, respectively. Conventional and IV estimates for the association of loge(tTC) with prostate cancer were: OR=0.81 (0.54-1.20), P=0.3 and OR=0.41 (0.13-1.32), P=0.1, respectively. Confidence intervals around the IV estimates in our study were too wide to allow robust inference. Sample size estimates based on our data indicated that Mendelian randomization in this context requires much larger studies or multiple genetic variants that explain all of the variance in the intermediate phenotype.
Vitamin B12/cobalamin; transcobalamin; prostate cancer; Mendelian Randomization
This study aims to validate a biostatistical approach to predict the likely effectiveness of screening in reducing advanced disease in the absence of data on incident screen and interval cancers.
We derived the predicted relative reduction in advanced stage disease following screening from the expected proportion of advanced disease following screening and the observed proportion of advanced disease detected clinically among the controls. We compared the predicted estimates to those observed in a randomised trial.
Using our method, the predicted estimates of relative reduction in node positive breast cancer following screening were comparable to the observed estimates for the age groups 50-59 and 60-69 in the screening study (predicted 32% vs. observed 40% (p=0.274) and predicted 34% vs. observed 45% (p=0.068), respectively). However, for the age groups 40-49 and 70-74 the predicted values were overestimates of the likely effectiveness of screening compared to the observed values (predicted 38% vs. observed 16% (p=0.014) and predicted 34% vs. observed 0% (p=0.001), respectively).
When the number of cancer cases is more than hundred, the method of prediction using only prevalence screen data may be accurate. Where cancers are less common, for example in small populations or young age groups, further data from interval cancers or incidence screens may be necessary.
Screening; prevalence screen; incident cancer; relative reduction; advanced cancer; overdiagnosis; prediction
To investigate the associations of body mass index (BMI) and grip strength with objective measures of physical performance (chair rise time, walking speed and balance) including an assessment of sex differences and non-linearity.
Cross-sectional data from eight UK cohort studies (total N = 16 444) participating in the Healthy Ageing across the Life Course (HALCyon) research programme, ranging in age from 50 to 90+ years at the time of physical capability assessment, were used. Regression models were fitted within each study and meta-analysis methods used to pool regression coefficients across studies and to assess the extent of heterogeneity between studies.
Higher BMI was associated with poorer performance on chair rise (N = 10 773), walking speed (N = 9 761) and standing balance (N = 13 921) tests. Higher BMI was associated with stronger grip strength in men only. Stronger grip strength was associated with better performance on all tests with a tendency for the associations to be stronger in women than men; for example, walking speed was higher by 0.43 cm/s (0.14, 0.71) more per kg in women than men. Both BMI and grip strength remained independently related with performance after mutual adjustment, but there was no evidence of effect modification. Both BMI and grip strength exhibited non-linear relations with performance; those in the lowest fifth of grip strength and highest fifth of BMI having particularly poor performance. Findings were similar when waist circumference was examined in place of BMI.
Older men and women with weak muscle strength and high BMI have considerably poorer performance than others and associations were observed even in the youngest cohort (age 53). Although causality cannot be inferred from observational cross-sectional studies, our findings suggest the likely benefit of early assessment and interventions to reduce fat mass and improve muscle strength in the prevention of future functional limitations.
Prostate-specific antigen (PSA) measurements are increasingly used to monitor men with localised prostate cancer (PCa), but there is little consensus about the method to use.
To apply age-specific predictions of PSA level (developed in men without cancer) to one cohort of men with clinically identified PCa and one cohort of men with PSA-detected PCa. We hypothesise that among men with clinically identified cancer, the annual increase in PSA level would be steeper than in men with PSA-detected cancer.
Design, setting, and participants
The Scandinavian Prostatic Cancer Group 4 (SPCG-4) cohort consisted of 321 men assigned to the watchful waiting arm of the SPCG-4 trial. The UK cohort consisted of 320 men with PSA-detected PCa in the Prostate Testing for Cancer and Treatment (ProtecT) study in nine UK centres between 1999 and 2007 who opted for monitoring rather than treatment. Multilevel models describing changes in PSA level were fitted to the two cohorts, and average PSA level at age 50, change in PSA level with age, and predicted PSA values were derived.
Results and limitations
In the SPCG-4 cohort, mean PSA at age 50 was similar to the cancer-free cohort but with a steeper yearly increase in PSA level (16.4% vs 4.0%). In the UK cohort, mean PSA level was higher than that in the cancer-free cohort (due to a PSA biopsy threshold of 3.0 ng/ml) but with a similar yearly increase in PSA level (4.1%). Predictions were less accurate for the SPCG-4 cohort (median observed minus predicted PSA level: −2.0 ng/ml; interquartile range [IQR]: −7.6–0.7 ng/ml) than for the UK cohort (median observed minus predicted PSA level: −0.8 ng/ml; IQR: −2.1–0.1 ng/ml).
In PSA-detected men, yearly change in PSA was similar to that in cancer-free men, whereas in men with symptomatic PCa, the yearly change in PSA level was considerably higher. Our method needs further evaluation but has promise for refining active monitoring protocols.
active surveillance; localised prostate cancer; PSA doubling time; PSA velocity; reference ranges
It is suggested that maternal adiposity has a stronger association with offspring adiposity than does paternal adiposity. Furthermore, a recent small study reported gender assortment in parental-offspring adiposity associations. We aimed to examine these associations in one of the largest studies to date using data from a low-middle income country that has recently undergone a major political and economic transition.
Methods and Principal Findings
In a cross-sectional study of 12,181 parental-offspring trios from Belarus (mean age (SD) of mothers 31.7 (4.9), fathers 34.1 (5.1) and children 6.6 (0.3) at time of assessment), we found positive graded associations of mother's and father's BMI with offspring adiposity. There was no evidence that these associations differed between mothers and fathers. For example, the odds ratio of offspring overweight or obesity (based on BMI) comparing obese and overweight mothers to normal weight mothers was 2.03 (95%CI 1.77, 2.31) in fully adjusted models; the equivalent result for father's overweight/obesity was 1.81 (1.58, 2.07). Equivalent results for offspring being in the top 10% waist circumference were 1.91 (1.67, 2.18) comparing obese/overweight to normal weight mothers and 1.72 (1.53, 1.95) comparing obese/overweight to normal weight fathers. Similarly, results for offspring being in the top 10% of percent fat mass were 1.58 (1.36, 1.84) and 1.76 (1.49, 2.07), for mother's and father's obese/overweight exposures respectively. There was no strong or consistent evidence of gender assortment - i.e. associations of maternal adiposity exposures with offspring outcomes were similar in magnitude for their daughters compared to equivalent associations in their sons and paternal associations were also similar in sons and daughters.
These findings suggest that genetic and/or shared familial environment explain family clustering of adiposity. Interventions aimed at changing overall family lifestyle are likely to be important for population level obesity prevention.
Grip strength, walking speed, chair rising and standing balance time are objective measures of physical capability that characterise current health and predict survival in older populations. Socioeconomic position (SEP) in childhood may influence the peak level of physical capability achieved in early adulthood, thereby affecting levels in later adulthood. We have undertaken a systematic review with meta-analyses to test the hypothesis that adverse childhood SEP is associated with lower levels of objectively measured physical capability in adulthood.
Methods and Findings
Relevant studies published by May 2010 were identified through literature searches using EMBASE and MEDLINE. Unpublished results were obtained from study investigators. Results were provided by all study investigators in a standard format and pooled using random-effects meta-analyses. 19 studies were included in the review. Total sample sizes in meta-analyses ranged from N = 17,215 for chair rise time to N = 1,061,855 for grip strength. Although heterogeneity was detected, there was consistent evidence in age adjusted models that lower childhood SEP was associated with modest reductions in physical capability levels in adulthood: comparing the lowest with the highest childhood SEP there was a reduction in grip strength of 0.13 standard deviations (95% CI: 0.06, 0.21), a reduction in mean walking speed of 0.07 m/s (0.05, 0.10), an increase in mean chair rise time of 6% (4%, 8%) and an odds ratio of an inability to balance for 5s of 1.26 (1.02, 1.55). Adjustment for the potential mediating factors, adult SEP and body size attenuated associations greatly. However, despite this attenuation, for walking speed and chair rise time, there was still evidence of moderate associations.
Policies targeting socioeconomic inequalities in childhood may have additional benefits in promoting the maintenance of independence in later life.
Levels of the proinflammatory cytokine interleukin-18 (IL-18) are raised in old age and are associated with reduced physical functioning. Previous studies have indicated that the C allele of the rs5744256 polymorphism in the IL-18 gene is strongly associated with reduced circulating IL-18 levels. This variant has previously been associated with improved locomotor performance in old age, but the finding requires independent replication.
We examined the association between the IL-18 polymorphism rs5744256 and physical functioning in three cohorts with a total of 4,107 participants aged 60–85 years: the English Longitudinal Study of Ageing, Caerphilly, and Boyd Orr. We meta-analyzed (N = 6,141) the results with data from the original paper reporting this association: Iowa-Established Populations for Epidemiological Study of the Elderly and InCHIANTI cohorts. Physical functioning was assessed by timed walks or the get up and go test. As locomotor performance tests differed between the cohorts and the distributions of times to complete the test (in seconds) were positively skewed, we used the reciprocal transformation and computed study-specific z scores.
Based on the three new studies, the estimated linear regression coefficient per C allele was 0.011 (95% confidence interval [95% CI]: −0.04 to 0.06). A meta-analysis that pooled the data from all studies showed weak evidence of an effect, with a regression coefficient of 0.047 (95% CI: 0.010 to 0.083).
We did not replicate an association between the IL-18 rs5744256 polymorphism and the physical function in people aged 60–85 years. However, pooling data from all studies suggested a weak association of the C allele of the rs5744256 single nucleotide polymorphism on improving walking times in old age.
Interleukin-18 polymorphism; IL-18; Ageing; Physical function; Gait speed; Walk time
There is substantial evidence implicating environmental factors in the progression of prostate cancer. The metabolic consequences of a western lifestyle, such as obesity, insulin resistance and abnormal hormone production have been linked to prostate carcinogenesis through multiple overlapping pathways. Insulin resistance results in raised levels of the mitogens insulin and insulin-like growth factor-1, both of which may affect prostate cancer directly, or through their effect on other metabolic regulators. Obesity is associated with abnormal levels of adipocyte-derived peptides (adipokines), sex hormones and inflammatory cytokines. Adipokines have been shown to influence prostate cancer in both cell culture studies and observational, population level studies. Testosterone appears to have a complex relationship with prostate carcinogenesis, and it has been suggested that the lower levels associated with obesity may select for more aggressive androgen independent prostate cancer cells. Prostatic inflammation, caused by infection, urinary reflux or dietary toxins, frequently occurs prior to cancer development and may influence progression to advanced disease. High levels of ω-6 fatty acids in the diet may lead to the production of further inflammatory molecules that may influence prostate cancer. Increased fatty acid metabolism occurs within tumour cells, providing a potential target for prostate cancer therapies. Aberrations in amino acid metabolism have also been identified in prostate cancer tissue, particularly in metastatic cancer. This evidence indicates lifestyle interventions may be effective in reducing the incidence of clinical disease. However, much more research is needed before recommendations are made.
Prostate cancer; obesity; adipokines; insulin-like growth factors; diabetes; inflammation; metabolism
There is continuing controversy over the most appropriate treatment for screen-detected and clinically localised prostate cancer and increasing interest in monitoring such men initially, with radical treatment targeted at cancers showing signs of progressive potential but while still curable. Current evidence on monitoring protocols and biomarkers used to predict disease progression was systematically reviewed.
MEDLINE and Excerpta Medica (EMBASE) bibliographic databases were searched from 1988 to October 2004, supplemented by manual searches of reference lists, focusing on studies reporting monitoring of men with localised prostate cancer.
48 potentially eligible papers were found, but only five studies (451 men) restricted entry criteria to men with clinically localised (T1-2) prostate cancer. Monitoring protocols varied with little consensus, although the majority used PSA levels and digital rectal examination, with some adding re-biopsy to assess progression. Actuarial probabilities of freedom from disease progression at 4-5 years of follow-up were 67%-72%. However, up to 50% of men abandoned monitoring within 2 years, largely because of anxiety related to rising PSA levels rather than objective evidence of disease progression. There was no robust evidence to support the use of PSA doubling times or velocity to identify men in whom disease may progress. Studies were characterised by small sample size, short-term follow-up, observer bias, and uncertain validity around variable definitions of progression.
Current evidence suggests that some form of monitoring would be a suitable treatment option for men with localised prostate cancer, but there is little consensus over what markers should be used in such a programme, or how ‘progression’ should be properly defined. The search for a method that safely identifies men with prostate cancer who could avoid radical intervention must continue.
Review Literature; Prostatic Neoplasms; Prognosis; Disease Progression; Natural History; Prostate Specific Antigen
There is currently no means of primary prevention for prostate cancer. Increased exposure to ultraviolet-radiation may be protective, but the literature is inconclusive. We investigated associations of life-course exposure to sunlight with prostate cancer. The study design was a UK-wide nested case-control study, based on 1,020 PSA-detected cases and 5,044 matched population controls and a systematic review with meta-analysis. Men with olive/brown skin (OR= 1.47; 95% CI: 1.00 to 2.17), men who burnt rarely/never (OR= 1.11; 0.95 to 1.29) and men with the lowest levels of intense sun exposure in the 2 years prior to diagnosis (OR = 1.24; 1.03 to 1.50) had an increased prostate cancer risk. However, amongst men with prostate cancer, spending less time outside was associated with a reduced risk of advanced cancer (OR = 0.49; 0.27 to 0.89) and high Gleason grade (OR = 0.62; 0.43 to 0.91), and men who burnt rarely/never had a reduced risk of advanced cancer (OR = 0.71; 0.47 to 1.08). The meta-analysis provided weak evidence that men with the lowest (versus highest) sunlight exposure had an increased prostate cancer risk (4 studies, random-effects pooled relative risk = 1.13; 0.98 to 1.29) and higher advanced or fatal prostate cancer risk (6 studies, random-effects pooled relative risk = 1.14; 0.98 to 1.33). Our data and meta-analyses provide limited support for the hypothesis that increased exposure to sunlight may reduce prostate cancer risk. The findings warrant further investigation because of their implications for vitamin D chemoprevention trials.
Prostate cancer; sun exposure; pigmentation