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1.  Effects of Promoting Longer Term and Exclusive Breastfeeding on Cardiometabolic Risk Factors at Age 11.5 Years: A Cluster-Randomized, Controlled Trial 
Circulation  2013;129(3):321-329.
Background
The duration and exclusivity of breastfeeding in infancy have been inversely associated with future cardiometabolic risk. We investigated the effects of an experimental intervention to promote increased duration of exclusive breastfeeding on cardiometabolic risk factors in childhood.
Methods and results
We followed-up children in the Promotion of Breastfeeding Intervention Trial, a cluster-randomized trial of a breastfeeding promotion intervention based on the World Health Organization/United Nations Children’s Fund Baby-Friendly Hospital Initiative. 17,046 breastfeeding mother-infant pairs were enrolled in 1996/7 from 31 Belarussian maternity hospitals and affiliated polyclinics (16 intervention vs 15 control sites); 13,879 (81.4%) children were followed-up at 11.5 years, with 13,616 (79.9%) fasted and without diabetes. The outcomes were blood pressure; fasting insulin, adiponectin, glucose and apolipoprotein A1; and presence of metabolic syndrome. Analysis was by intention to treat, accounting for clustering within hospitals/clinics. The intervention substantially increased breastfeeding duration and exclusivity compared with the control arm (43% vs. 6% and 7.9% vs. 0.6% exclusively breastfed at 3 and 6 months, respectively). Cluster-adjusted mean differences at 11.5 years between experimental vs control groups were: 1.0mmHg (95% CI: −1.1, 3.1) for systolic and 0.8mmHg (−0.6, 2.3) for diastolic blood pressure; −0.1mmol/l (−0.2, 0.1) for glucose; 8% (−3%, 34%) for insulin; −0.33μ/ml (−1.5, 0.9) for adiponectin; and 0.0g/l (−0.1, 0.1) for ApoA1. The cluster-adjusted odds ratio for metabolic syndrome, comparing experimental vs control groups, was 1.21 (0.85, 1.72).
Conclusions
An intervention to improve breastfeeding duration and exclusivity among healthy term infants did not influence cardiometabolic risk factors in childhood.
Clinical Trial Registration Information
Current Controlled Trials: ISRCTN37687716 (http://www.controlled-trials.com/ISRCTN37687716); Clinicaltrials.gov. Identifier: NCT01561612.
doi:10.1161/CIRCULATIONAHA.113.005160
PMCID: PMC3946966  PMID: 24300437
Breastfeeding; lactation; blood pressure; fasting insulin; glucose; adiponectin; lipids; randomized controlled trial; childhood
2.  Genetic variation in protein specific antigen detected prostate cancer and the effect of control selection on genetic association studies 
Background
Only a minority of the genetic component of prostate cancer (PrCa) risk has been explained. Some observed associations of single nucleotide polymorphisms (SNPs) with PrCa might arise from associations of these SNPs with circulating prostate specific antigen (PSA) because PSA values are used to select controls.
Methods
We undertook a genome-wide association study (GWAS) of screen detected PrCa (ProtecT 1146 cases and 1804 controls); meta-analysed the results with those from the previously published UK Genetic Prostate Cancer Study (1854 cases and 1437 controls); investigated associations of SNPs with PrCa using either ‘low’ (PSA <0.5ng/ml) or ‘high’ (PSA ≥3ng/ml, biopsy negative) PSA controls; and investigated associations of SNPs with PSA.
Results
The ProtecT GWAS confirmed previously reported associations of PrCa at 3 loci: 10q11.23, 17q24.3 and 19q13.33. The meta-analysis confirmed associations of PrCa with SNPs near 4 previously identified loci (8q24.21,10q11.23, 17q24.3 and 19q13.33). When comparing PrCa cases with low PSA controls, alleles at genetic markers rs1512268, rs445114, rs10788160, rs11199874, rs17632542, rs266849 and rs2735839 were associated with an increased risk of PrCa, but the effect-estimates were attenuated to the null when using high PSA controls (p for heterogeneity in effect-estimates<0.04). We found a novel inverse association of rs9311171-T with circulating PSA.
Conclusions
Differences in effect estimates for PrCa observed when comparing low vs. high PSA controls, may be explained by associations of these SNPs with PSA.
Impact
These findings highlight the need for inferences from genetic studies of PrCa risk to carefully consider the influence of control selection criteria.
doi:10.1158/1055-9965.EPI-13-0889
PMCID: PMC4082405  PMID: 24753544
Prostate Specific Antigen; research design; prostate cancer; case-control studies; genome wide association studies
3.  The Association of Early Childhood Cognitive Development and Behavioural Difficulties with Pre-Adolescent Problematic Eating Attitudes 
PLoS ONE  2014;9(8):e104132.
Objectives
Few studies have prospectively investigated associations of child cognitive ability and behavioural difficulties with later eating attitudes. We investigated associations of intelligence quotient (IQ), academic performance and behavioural difficulties at 6.5 years with eating attitudes five years later.
Methods
We conducted an observational cohort study nested within the Promotion of Breastfeeding Intervention Trial, Belarus. Of 17,046 infants enrolled at birth, 13,751 (80.7%) completed the Children's Eating Attitude Test (ChEAT) at 11.5 years, most with information on IQ (n = 12,667), academic performance (n = 9,954) and behavioural difficulties (n = 11,098) at 6.5 years. The main outcome was a ChEAT score ≥85th percentile, indicative of problematic eating attitudes.
Results
Boys with higher IQ at 6.5 years reported fewer problematic eating attitudes, as assessed by ChEAT scores ≥85th percentile, at 11.5 years (OR per SD increase in full-scale IQ = 0.87; 0.79, 0.94). No such association was observed in girls (1.01; 0.93, 1.10) (p for sex-interaction = 0.016). In both boys and girls, teacher-assessed academic performance in non-verbal subjects was inversely associated with high ChEAT scores five years later (OR per unit increase in mathematics ability = 0.88; 0.82, 0.94; and OR per unit increase in ability for other non-verbal subjects = 0.86; 0.79, 0.94). Behavioural difficulties were positively associated with high ChEAT scores five years later (OR per SD increase in teacher-assessed rating = 1.13; 1.07, 1.19).
Conclusion
Lower IQ, worse non-verbal academic performance and behavioural problems at early school age are positively associated with risk of problematic eating attitudes in early adolescence.
doi:10.1371/journal.pone.0104132
PMCID: PMC4125275  PMID: 25102171
4.  Associations of vitamin D pathway genes with circulating 25-hydroxyvitamin-D, 1,25-dihydroxyvitamin-D, and prostate cancer: a nested case–control study 
Cancer Causes & Control  2014;26:205-218.
Purpose
Vitamin D pathway single nucleotide polymorphisms (SNPs) are potentially useful proxies for investigating whether circulating vitamin D metabolites [total 25-hydroxyvitamin-D, 25(OH)D; 1,25-dihydroxyvitamin, 1,25(OH)2D] are causally related to prostate cancer. We investigated associations of sixteen SNPs across seven genes with prostate-specific antigen-detected prostate cancer.
Methods
In a nested case–control study (within the ProtecT trial), we estimated odds ratios and 95 % confidence intervals (CIs) quantifying associations between SNPs and prostate cancer. Subgroup analyses investigated whether associations were stronger in men who had high/low sun exposure [a proxy for 25(OH)D]. We quantified associations of SNPs with stage (T1–T2/T3–T4) and grade (<7/≥7). Multiple variant scores included SNPs encoding proteins involved in 25(OH)D synthesis and metabolism.
Results
We included 1,275 prostate cancer cases (141 locally advanced, 385 high grades) and 2,062 healthy controls. Vitamin D-binding protein SNPs were associated with prostate cancer (rs4588-A: OR 1.20, CI 1.01, 1.41, p = 0.04; rs7041-T: OR 1.19, CI 1.02, 1.38, p = 0.03). Low 25(OH)D metabolism score was associated with high (vs low) grade (OR 0.76, CI 0.63, 0.93, p = 0.01); there was a similar association of its component variants: rs6013897-A in CYP24A1 (OR 0.78, CI 0.60, 1.01, p = 0.06) and rs10877012-T in CYP27B1 (OR 0.80, CI 0.63, 1.02, p = 0.07). There was no evidence that associations differed by level of sun exposure.
Conclusion
We found some evidence that vitamin D pathway SNPs were associated with prostate cancer risk and grade, but not stage. There was no evidence of an association in men with deficient vitamin D (measured by having low sun exposure).
Electronic supplementary material
The online version of this article (doi:10.1007/s10552-014-0500-5) contains supplementary material, which is available to authorized users.
doi:10.1007/s10552-014-0500-5
PMCID: PMC4298668  PMID: 25488826
Prostate cancer; Vitamin D; Vitamin D pathway genes; 25 hydroxyvitamin-D; 1,25-dihydroxyvitamin-D
5.  Reporting of drug induced depression and fatal and non-fatal suicidal behaviour in the UK from 1998 to 2011 
Background
Psychiatric adverse drug reactions (ADRs) are distressing for patients and have important public health implications. We identified the drugs with the most frequent spontaneous reports of depression, and fatal and non-fatal suicidal behaviour to the UK’s Yellow Card Scheme from 1998 to 2011.
Methods
We obtained Yellow Card data from the Medicines and Healthcare products Regulatory Agency for the drugs with the most frequent spontaneous reports of depression and suicidal behaviour from 1964 onwards. Prescribing data were obtained from the NHS Information Centre and the Department of Health. We examined the frequency of reports for drugs and estimated rates of reporting of psychiatric ADRs using prescribing data as proxy denominators from 1998 to 2011, as prescribing data were not available prior to 1998.
Results
There were 110 different drugs with ≥ 20 reports of depression, 58 with ≥10 reports of non-fatal suicidal behaviour and 33 with ≥5 reports of fatal suicidal behaviour in the time period. The top five drugs with the most frequent reports of depression were the smoking cessation medicines varenicline and bupropion, followed by paroxetine (a selective serotonin reuptake inhibitor), isotretinoin (used in acne treatment) and rimonabant (a weight loss drug). Selective serotonin reuptake inhibitors, varenicline and the antipsychotic medicine clozapine were included in the top five medicines with the most frequent reports of fatal and non-fatal suicidal behaviour. Medicines with the highest reliably measured reporting rates of psychiatric ADRs per million prescriptions dispensed in the community included rimonabant, isotretinoin, mefloquine (an antimalarial), varenicline and bupropion. Robust denominators for community prescribing were not available for two drugs with five or more suicide reports, efavirenz (an antiretroviral medicine) and clozapine.
Conclusions
Depression and suicide-related ADRs are reported for many nervous system and non-nervous system drugs. As spontaneous reports cannot be used to determine causality between the drug and the ADR, psychiatric ADRs which can cause significant public alarm should be specifically assessed and reported in all randomised controlled trials.
doi:10.1186/2050-6511-15-54
PMCID: PMC4184159  PMID: 25266008
Adverse drug reaction; Suicide; Non-fatal suicidal behaviour; Self injury; Depression; Yellow card; Adverse effects
6.  An Assessment of the Shared Allelic Architecture between Type II Diabetes and Prostate Cancer 
Background
To determine whether the alleles that influence type II diabetes risk and glycemic traits also influence prostate cancer risk.
Methods
We used a multiple single-nucleotide polymorphisms (SNP) genotypic risk score to assess the average effect of alleles that increase type II diabetes risk or worsen glycemic traits on risk of prostate cancer in 19,662 prostate cancer cases and 19,715 controls from the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium and 5,504 prostate cancer cases and 5,834 controls from the Cancer Research UK (CRUK) prostate cancer study.
Results
Calculating the average additive effect of type II diabetes or glycemic trait risk alleles on prostate cancer risk using a logistic model revealed no evidence of a shared allelic architecture between type II diabetes, or worsened glycemic status, with prostate cancer risk [OR for type II diabetes alleles: 1.00 (P = 0.58), fasting glycemia alleles: 1.00 (P = 0.67), HbA1c alleles: 1.00 (P = 0.93), 2-hour OGTT alleles: 1.01 (P = 0.14), and HOMA-B alleles: 0.99 (P = 0.57)].
Conclusions
Using genetic data from large consortia, we found no evidence for a shared genetic etiology of type II diabetes or glycemic risk with prostate cancer.
Impact
Our results showed that alleles influencing type II diabetes and related glycemic traits were not found to be associated with the risk of prostate cancer.
doi:10.1158/1055-9965.EPI-13-0476
PMCID: PMC4158605  PMID: 23704474
7.  Socioeconomic differences in childhood length/height trajectories in a middle-income country: a cohort study 
BMC Public Health  2014;14(1):932.
Background
Socioeconomic disadvantage is associated with shorter adult stature. Few studies have examined socioeconomic differences in stature from birth to childhood and the mechanisms involved, particularly in middle-income former Soviet settings.
Methods
The sample included 12,463 Belarusian children (73% of the original cohort) born in 1996–1997, with up to 14 stature measurements from birth to 7 years. Linear spline multi-level models with 3 knots at 3, 12 and 34 months were used to analyse birth length and growth velocity during four age-periods by parental educational achievement (up to secondary school, advanced secondary/partial university, completed university) and occupation (manual, non-manual).
Results
Girls born to the most (versus least) educated mothers were 0.43 cm (95% confidence interval (CI): 0.28, 0.58) longer at birth; for boys, the corresponding difference was 0.30 cm (95% CI: 0.15, 0.46). Similarly, children of the most educated mothers grew faster from birth-3 months and 12–34 months (p-values for trend ≤0.08), such that, by age 7 years, girls with the most (versus least) educated mothers were 1.92 cm (95% CI: 1.47, 2.36) taller; after controlling for urban/rural and East/West area of residence, this difference remained at 1.86 cm (95% CI: 1.42, 2.31), but after additionally controlling for mid-parental height, attenuated to 1.10 cm (95% CI: 0.69, 1.52). Among boys, these differences were 1.95 cm (95% CI: 1.53, 2.37), 1.89 cm (95% CI: 1.47, 2.31) and 1.16 cm (95% CI: 0.77, 1.55), respectively. Additionally controlling for breastfeeding, maternal smoking and older siblings did not substantively alter these findings. There was no evidence that the association of maternal educational attainment with growth differed in girls compared to boys (p for interaction = 0.45). Results were similar for those born to the most (versus least) educated fathers, or who had a parent with a non-manual (versus manual) occupation.
Conclusions
In Belarus, a middle-income former Soviet country, socioeconomic differences in offspring growth commence in the pre-natal period and generate up to approximately 2 cm difference in height at age 7 years. These associations are partly explained by genetic or other factors influencing parental stature.
Trial Registration
Current Controlled Trials: NCT01352247 assigned 9 Sept 2005; ClinicalTrials.gov. Identifier: NCT01561612 received 20 Mar 2012.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2458-14-932) contains supplementary material, which is available to authorized users.
doi:10.1186/1471-2458-14-932
PMCID: PMC4181044  PMID: 25200513
Length; Height; Growth trajectory; Socioeconomic factors; Belarus
8.  The association of time between diagnosis and major resection with poorer colorectal cancer survival: a retrospective cohort study 
BMC Cancer  2014;14(1):642.
Background
Colorectal cancer survival in the UK is lower than in other developed countries, but the association of time interval between diagnosis and treatment on excess mortality remains unclear.
Methods
Using data from cancer registries in England, we identified 46,511 patients with localised colorectal cancer between 1996–2009, who were 15 years and older, and who underwent a major surgical resection within 62 days of diagnosis. We used relative survival and excess risk modeling to investigate the association of time between diagnosis and major resection (exposure) with survival (outcome).
Results
Compared to patients who had major resection within 25–38 days of diagnosis, patients with a shorter time interval between diagnosis and resection and those waiting longer for resection had higher excess mortality (Excess Hazards Ratio, EHR <25 vs 25–38 days: 1.50; 95% Confidence Interval, CI: 1.37 to 1.66; EHR 39–62 vs 25–38 days : 1.16; 95% CI: 1.04 to 1.29). Excess mortality was associated with age (EHR 75+ vs. 15–44 year olds: 2.62; 95% CI: 2.00 to 3.42) and deprivation (EHR most vs. least deprived: 1.27; 95% CI: 1.12 to 1.45), but time between diagnosis and resection did not explain these differences.
Conclusion
Within 62 days of diagnosis, a U-shaped association of time between diagnosis and major resection with excess mortality for localised colorectal cancer was evident. This indicates a complicated treatment pathway, particularly for patients who had resection earlier than 25 days, and requires further investigation.
doi:10.1186/1471-2407-14-642
PMCID: PMC4159515  PMID: 25175937
Colorectal cancer; Cancer survival; Waiting times; Inequalities; England
9.  Associations between APOE and low-density lipoprotein cholesterol genotypes and cognitive and physical capability: the HALCyon programme 
Age  2014;36(4):9673.
The APOE ε2/3/4 genotype has been associated with low-density lipoprotein cholesterol (LDL-C) and Alzheimer disease. However, evidence for associations with measures of cognitive performance in adults without dementia has been mixed, as it is for physical performance. Associations may also be evident in other genotypes implicated in LDL-C levels. As part of the Healthy Ageing across the Life Course (HALCyon) collaborative research programme, genotypic information was obtained for APOE ε2/3/4, rs515135 (APOB), rs2228671 (LDLR) and rs629301 (SORT1) from eight cohorts of adults aged between 44 and 90 + years. We investigated associations with four measures of cognitive (word recall, phonemic fluency, semantic fluency and search speed) and physical capability (grip strength, get up and go/walk speed, timed chair rises and ability to balance) using meta-analyses. Overall, little evidence for associations between any of the genotypes and measures of cognitive capability was observed (e.g. pooled beta for APOE ε4 effect on semantic fluency z score = −0.02; 95 % CI = −0.05 to 0.02; p value = 0.3; n = 18,796). However, there was borderline evidence within studies that negative effects of APOE ε4 on nonverbal ability measures become more apparent with age. Few genotypic associations were observed with physical capability measures. The findings from our large investigation of middle-aged to older adults in the general population suggest that effects of APOE on cognitive capability are at most modest and are domain- and age-specific, while APOE has little influence on physical capability. In addition, other LDL-C-related genotypes have little impact on these traits.
Electronic supplementary material
The online version of this article (doi:10.1007/s11357-014-9673-9) contains supplementary material, which is available to authorized users.
doi:10.1007/s11357-014-9673-9
PMCID: PMC4150901  PMID: 25073452
Ageing; Apolipoprotein E; Cognition; Single nucleotide polymorphism
10.  Validation of suicide and self-harm records in the Clinical Practice Research Datalink 
Aims
The UK Clinical Practice Research Datalink (CPRD) is increasingly being used to investigate suicide-related adverse drug reactions. No studies have comprehensively validated the recording of suicide and nonfatal self-harm in the CPRD. We validated general practitioners' recording of these outcomes using linked Office for National Statistics (ONS) mortality and Hospital Episode Statistics (HES) admission data.
Methods
We identified cases of suicide and self-harm recorded using appropriate Read codes in the CPRD between 1998 and 2010 in patients aged ≥15 years. Suicides were defined as patients with Read codes for suicide recorded within 95 days of their death. International Classification of Diseases codes were used to identify suicides/hospital admissions for self-harm in the linked ONS and HES data sets. We compared CPRD-derived cases/incidence of suicide and self-harm with those identified from linked ONS mortality and HES data, national suicide incidence rates and published self-harm incidence data.
Results
Only 26.1% (n = 590) of the ‘true’ (ONS-confirmed) suicides were identified using Read codes. Furthermore, only 55.5% of Read code-identified suicides were confirmed as suicide by the ONS data. Of the HES-identified cases of self-harm, 68.4% were identified in the CPRD using Read codes. The CPRD self-harm rates based on Read codes had similar age and sex distributions to rates observed in self-harm hospital registers, although rates were underestimated in all age groups.
Conclusions
The CPRD recording of suicide using Read codes is unreliable, with significant inaccuracy (over- and under-reporting). Future CPRD suicide studies should use linked ONS mortality data. The under-reporting of self-harm appears to be less marked.
doi:10.1111/bcp.12059
PMCID: PMC3703237  PMID: 23216533
Clinical Practice Research Datalink; General Practice Research Database; nonfatal self-harm; suicide; validation
11.  Using genetic proxies for lifecourse sun exposure to assess the causal relationship of sun exposure with circulating vitamin D and prostate cancer risk 
Background
Ecological and epidemiological studies have identified an inverse association of intensity and duration of sunlight exposure with prostate cancer, which may be explained by a reduction in vitamin D synthesis. Pigmentation traits influence sun exposure and therefore may affect prostate cancer risk. Because observational studies are vulnerable to confounding and measurement error, we used Mendelian randomization to examine the relationship of sun exposure with both prostate cancer risk and the intermediate phenotype, plasma levels of vitamin D.
Methods
We created a tanning, a skin color and a freckling score as combinations of SNPs that have been previously associated with these phenotypes. A higher score indicates propensity to burn, have a lighter skin color and freckles. The scores were tested for association with vitamin D levels (25-hydroxyvitamin-D and 1,25-dihydroxyvitamin-D) and PSA-detected prostate cancer in 3123 white British individuals enrolled in the Prostate Testing for cancer and Treatment (ProtecT) study.
Results
The freckling score was inversely associated with 25(OH)D levels (change in 25(OH)D per score unit −0.27; 95%CI: −0.52, −0.01), and the tanning score was positively associated with prostate cancer risk (OR 1.05; 95%CI: 1.02,1.09), after adjustment for population stratification and potential confounders.
Conclusions
Individuals who tend to burn are more likely to spend less time in the sun and consequently have lower plasma vitamin D levels and higher susceptibility to prostate cancer.
Impact
The use of pigmentation related genetic scores is valuable for the assessment of the potential benefits of sun exposure with respect to prostate cancer risk.
doi:10.1158/1055-9965.EPI-12-1248
PMCID: PMC3616836  PMID: 23441100
pigmentation; tanning; sun exposure; vitamin D; prostate cancer
12.  Effects of promoting increased duration and exclusivity of breastfeeding on adiposity and insulin-like growth factor-I at age 11.5 years: a randomized trial 
Importance
Evidence that increased duration and exclusivity of breastfeeding reduces child obesity risk is based on observational studies that are prone to confounding.
Objective
To investigate effects of an intervention to promote increased duration and exclusivity of breastfeeding on child adiposity and circulating insulin-like growth factor (IGF)-I (which regulates growth).
Design
Cluster-randomized controlled trial.
Setting
31 Belarusian maternity hospitals and their affiliated polyclinics, randomized to usual practices (n=15) or a breastfeeding promotion intervention (n=16).
Participants
17,046 breastfeeding mother-infant pairs enrolled in 1996/7, of whom 13,879 (81.4%) were followed-up between January 2008 and December 2010 at a median age of 11.5 years.
Intervention
Breastfeeding promotion intervention modeled on the WHO/UNICEF Baby Friendly Hospital Initiative.
Main outcome measures
Body mass index (BMI), fat and fat-free mass indices (FMI and FFMI), percent body fat, waist circumference, triceps and subscapular skinfold thicknesses, overweight and obesity, and whole-blood IGF-I. Primary analysis was based on modified intention-to-treat (without imputation), accounting for clustering within hospitals/clinics.
Results
The experimental intervention substantially increased breastfeeding duration and exclusivity (43% vs. 6% and 7.9% vs. 0.6% exclusively breastfed at 3 and 6 months, respectively) versus the control intervention. Cluster-adjusted mean differences in outcomes at 11.5 years between experimental vs. control groups were: 0.19 kg/m2 (95% 4 CI: −0.09, 0.46) for BMI; 0.12 kg/m2 (−0.03, 0.28) for FMI; 0.04 kg/m2 (−0.11, 0.18) for FFMI; 0.47% (−0.11, 1.05) for % body fat; 0.30 cm (−1.41, 2.01) for waist circumference; −0.07 mm (−1.71, 1.57) for triceps and −0.02 mm (−0.79, 0.75) for subscapular skinfold thicknesses; and −0.02 standard deviations (−0.12, 0.08) for IGF-I. The cluster-adjusted odds ratio for overweight / obesity (BMI ≥85th percentile vs <85th percentile) was 1.18 (1.01, 1.39) and for obesity (BMI ≥95th vs <85th percentile) was 1.17 (0.97, 1.41).
Conclusions and relevance
Among healthy term infants in Belarus, an intervention that succeeded in improving the duration and exclusivity of breastfeeding did not prevent overweight or obesity, nor did it affect IGF-I levels, at age 11.5 years. Breastfeeding has many advantages, but population strategies to increase the duration and exclusivity of breastfeeding are unlikely to curb the obesity epidemic.
doi:10.1001/jama.2013.167
PMCID: PMC3752893  PMID: 23483175
Breast feeding; lactation; adiposity; body mass index; randomized controlled trial; insulin-like growth factor-1; childhood
13.  Associations of postnatal weight and length/height gain with wheeze, asthma and atopy: The PROBIT Study 
Background
It has been hypothesised that postnatal weight and length/height gain are variously related to wheeze, asthma and atopy, however supporting evidence is limited and inconsistent.
Methods
Weights and lengths/heights of 12,171 term-infants were measured from birth to 12 months and at 6.5 years, and extracted from polyclinic records prospectively obtained between 12 and 60 months. Atopic phenotypes were ascertained at 6.5 years with the International Study of Asthma and Allergy in Childhood questionnaire and skin-prick tests. Logistic regression models investigated whether rates of weight and length/height gain from infancy to mid-childhood were associated with atopy phenotypes that have occurred ever or in the last 12 months.
Results
After controlling for confounders and prior weight and length/height gain, all weight gain variables except birthweight were positively associated with ever having wheezed (p<0.1). A one SD increase in weight gain rate between 0–3 months was associated with a 12% increase (2%–23%) in allergic rhinitis ever. No other consistent patterns of association were found for weight gain or length/height gain rate between 0–60 months with atopic outcomes at 6.5 years. In contrast, all atopy outcomes except for ever having asthma were associated with current weight and height, even after controlling for prior growth.
Conclusion
Current height and weight are more strongly associated with the development of atopic phenotypes in childhood than patterns of infant and early childhood growth, which may well reflect reverse causality (atopy effects on growth) or residual confounding by an unknown common cause of growth and atopy.
doi:10.1111/pai.12049
PMCID: PMC3711479  PMID: 23374010
wheeze; asthma; atopy; postnatal growth; weight gain; length gain
14.  Risk of childhood cancer with symptoms in primary care: a population-based case-control study 
Background
Guidelines describing symptoms in children that should alert GPs to consider cancer have been developed, but without any supporting primary-care research.
Aim
To identify symptoms and signs in primary care that strongly increase the likelihood of childhood cancer, to assist GPs in selection of children for investigation.
Design and setting
A population-based case-control study in UK general practice.
Method
Using electronic primary care records from the UK General Practice Research Database, 1267 children aged 0–14 years diagnosed with childhood cancer were matched to 15 318 controls. Clinical features associated with subsequent diagnosis of cancer were identified using conditional logistic regression, and likelihood ratios and positive predictive values (PPVs) were estimated for each.
Results
Twelve symptoms were associated with PPVs of ≥0.04%, which represents a greater than tenfold increase in prior probability. The six symptoms with the highest PPVs were pallor (odds ratio, OR = 84; PPV = 0.41% (95% confidence interval [CI] = 0.12% to 1.34%), head and neck masses (OR = 17; PPV = 0.30%; 95% CI = 0.10% to 0.84%), masses elsewhere (OR = 22; PPV = 0.11%; 95% CI = 0.06% to 0.20%), lymphadenopathy (OR = 10; PPV = 0.09%; 95% CI = 0.06% to 0.13%), symptoms/signs of abnormal movement (OR = 16; PPV = 0.08%; 95% CI = 0.04% to 0.14%), and bruising (OR = 12; PPV = 0·08%; 95% CI = 0.05% to 0.13%). When each of these 12 symptoms was combined singly with at least three consultations in a 3-month period, the probability of cancer was between 11 and 76 in 10 000.
Conclusion
Twelve features of childhood cancers were identified, each of which increased the risk of cancer at least tenfold. These symptoms, particularly when combined with multiple consultations, warrant careful evaluation in general practice.
doi:10.3399/bjgp13X660742
PMCID: PMC3529289  PMID: 23336454
cancer; child; diagnosis; primary health care
15.  Physicians' prescribing preferences were a potential instrument for patients' actual prescriptions of antidepressants☆ 
Journal of Clinical Epidemiology  2013;66(12):1386-1396.
Objectives
To investigate whether physicians' prescribing preferences were valid instrumental variables for the antidepressant prescriptions they issued to their patients.
Study Design and Setting
We investigated whether physicians' previous prescriptions of (1) tricyclic antidepressants (TCAs) vs. selective serotonin reuptake inhibitors (SSRIs) and (2) paroxetine vs. other SSRIs were valid instruments. We investigated whether the instrumental variable assumptions are likely to hold and whether TCAs (vs. SSRIs) were associated with hospital admission for self-harm or death by suicide using both conventional and instrumental variable regressions. The setting for the study was general practices in the United Kingdom.
Results
Prior prescriptions were strongly associated with actual prescriptions: physicians who previously prescribed TCAs were 14.9 percentage points (95% confidence interval [CI], 14.4, 15.4) more likely to prescribe TCAs, and those who previously prescribed paroxetine were 27.7 percentage points (95% CI, 26.7, 28.8) more likely to prescribe paroxetine, to their next patient. Physicians' previous prescriptions were less strongly associated with patients' baseline characteristics than actual prescriptions. We found no evidence that the estimated association of TCAs with self-harm/suicide using instrumental variable regression differed from conventional regression estimates (P-value = 0.45).
Conclusion
The main instrumental variable assumptions held, suggesting that physicians' prescribing preferences are valid instruments for evaluating the short-term effects of antidepressants.
doi:10.1016/j.jclinepi.2013.06.008
PMCID: PMC3824069  PMID: 24075596
Instrumental variables; Clinical Practice Research Datalink (CPRD); Physicians' prescribing preferences; Confounding by indication; Causality; Translational epidemiology
16.  Time from diagnosis to surgery and prostate cancer survival: a retrospective cohort study 
BMC Cancer  2013;13:559.
Background
A diagnosis of prostate cancer leads to emotional distress and anxiety, prompting calls for rapid diagnostic pathways. Nevertheless, it remains unclear what impact time between diagnosis and surgery has upon prostate cancer survival.
Methods
Using national databases for England (cancer registries, Hospital Episode Statistics and Office of National Statistics), we identified 17,043 men with prostate cancer, aged 15 years and older, diagnosed in 1996–2009, and who had surgical resection with curative intent within 6 months of diagnosis. We used relative survival to investigate associations between waiting times and five- and ten-year survival.
Results
Five- and ten-year relative survival estimates for the total study sample were 1.04 (95% CI: 1.04 to 1.05) and 1.08 (95% CI: 1.06-1.09), respectively. There were no notable differences in survival between patients who had surgery at 0–3 and 4–6 months after diagnosis. Relative survival was higher among the elderly (>65) and those with well and moderately differentiated tumours.
Conclusion
The high relative survival in our cohort probably reflects adherence to selection criteria for surgery among men with localised prostate cancer. Among men treated with surgery within 6 months of diagnosis, we found little evidence of an association between time from diagnosis to surgery and survival.
doi:10.1186/1471-2407-13-559
PMCID: PMC4219457  PMID: 24283992
Time from diagnosis to surgery; Prostate cancer; Cancer survival; Survival inequalities; Surgery
17.  Childhood milk consumption is associated with better physical performance in old age 
Age and Ageing  2012;41(6):776-784.
Background: studies have shown that milk and dairy consumption in adulthood have beneficial effects on health.
Methods: we examined the impact of childhood and adult diet on physical performance at age 63–86 years. The Boyd Orr cohort (n = 405) is a 65-year prospective study of children who took part in a 1930's survey; the Caerphilly Prospective Study (CaPS; n = 1,195) provides data from mid-life to old age. We hypothesised that higher intakes of childhood and adult milk, calcium, protein, fat and energy would be associated with a better performance.
Results: in fully adjusted models, a standard deviation (SD) increase in natural log-transformed childhood milk intake was associated with 5% faster walking times from the get-up and go test in Boyd Orr (95% CI: 1 to 9) and 25% lower odds of poor balance (OR: 0.75; 0.55 to 1.02). Childhood calcium intake was positively associated with walking times (4% faster per SD; 0 to 8) and a higher protein intake was associated with lower odds of poor balance (OR: 0.71; 0.54 to 0.92). In adulthood, protein intake was positively associated with walking times (2% faster per SD; 1 to 3; Boyd Orr and CaPS pooled data).
Conclusion: this is the first study to show positive associations of childhood milk intake with physical performance in old age.
doi:10.1093/ageing/afs052
PMCID: PMC3476828  PMID: 22542496
diet; physical performance; walking speed; standing balance; older people
18.  Circulating folate, vitamin B12, homocysteine, vitamin B12 transport proteins and risk of prostate cancer: a case-control study, systematic review and meta-analysis 
Background
Disturbed folate metabolism is associated with an increased risk of some cancers. Our objective was to determine whether blood levels of folate, vitamin B12 and related metabolites were associated with prostate cancer risk.
Methods
Matched case-control study nested within the UK population-based ProtecT study of PSA-detected prostate cancer in men aged 50–69 years. Plasma concentrations of folate, B12 (cobalamin), holo-haptocorrin, holo- and total-transcobalamin, and total homocysteine (tHcy) were measured in 1,461 cases and 1,507 controls. ProtecT study estimates for associations of folate, B12, and tHcy with prostate cancer risk were included in a meta-analysis, based on a systematic review.
Results
In the ProtecT study, increased B12 and holo-haptocorrin concentrations showed positive associations with prostate cancer risk (highest vs lowest quartile of B12 odds ratio (OR)=1.17 (95% CI 0.95–1.43), P-for-trend=0.06; highest vs lowest quartile of holo-haptocorrin OR=1.27 (1.04–1.56), P-for-trend=0.01); folate, holo-transcobalamin and tHcy were not associated with prostate cancer risk. In the meta-analysis, circulating B12 levels were associated with an increased prostate cancer risk (pooled OR=1.10 (1.01–1.19) per 100 pmol/L increase in B12, P=0.002); the pooled OR for the association of folate with prostate cancer was positive (OR=1.11 (0.96–1.28) per 10 nmol/L, P=0.2) and conventionally statistically significant if ProtecT (the only case-control study) was excluded (OR=1.18 (1.00–1.40) per 10 nmol/L, P=0.02).
Conclusion
Vitamin B12 and (in cohort studies) folate were associated with increased prostate cancer risk.
Impact
Given current controversies over mandatory fortification, further research is needed to determine whether these are causal associations.
doi:10.1158/1055-9965.EPI-10-0180
PMCID: PMC3759018  PMID: 20501771
folate; vitamin B12; cobalamin; transcobalamin; haptocorrin; homocysteine; folate-mediated one-carbon metabolism; prostate cancer
19.  Filter Paper Blood Spot Enzyme Linked Immunoassay for Adiponectin and Application in the Evaluation of Determinants of Child Insulin Sensitivity 
PLoS ONE  2013;8(8):e71315.
Background
Adiponectin is an adipocyte-derived hormone that acts as a marker of insulin sensitivity. Bloodspot sampling by fingerstick onto filter paper may increase the feasibility of large-scale studies of the determinants of insulin sensitivity. We first describe the validation of an enzyme-linked immunoassay (ELISA) for quantifying adiponectin from dried blood spots and then demonstrate its application in a large trial (PROBIT).
Methods
We quantified adiponectin from 3-mm diameter discs (≈3 µL of blood) punched from dried blood spots obtained from: i) whole blood standards (validation); and ii) PROBIT trial samples (application) in which paediatricians collected blood spots from 13,879 children aged 11.5 years from 31 sites across Belarus. We examined the distribution of bloodspot adiponectin by demographic and anthropometric factors, fasting insulin and glucose.
Results
In the validation study, mean intra-assay coefficients of variation (n = 162) were 15%, 13% and 10% for ‘low’ (6.78 µg/ml), ‘medium’ (18.18 µg/ml) and 'high’ (33.13 µg/ml) internal quality control (IQC) samples, respectively; the respective inter-assay values (n = 40) were 23%, 21% and 14%. The correlation coefficient between 50 paired whole bloodspot versus plasma samples, collected simultaneously, was 0.87 (95% CI: 0.78 to 0.93). Recovery of known quantities of adiponectin (between 4.5 to 36 µg/ml) was 100.3–133%. Bloodspot adiponectin was stable for at least 30 months at −80°C. In PROBIT, we successfully quantified fasting adiponectin from dried blood spots in 13,329 of 13,879 (96%) children. Mean adiponectin (standard deviation) concentrations were 17.34 µg/ml (7.54) in boys and 18.41 µg/ml (7.92) in girls and were inversely associated with body mass index, fat mass, triceps and subscapular skin-fold thickness, waist circumference, height and fasting glucose.
Conclusions
Bloodspot ELISA is suitable for measuring adiponectin in very small volumes of blood collected on filter paper and can be applied to large-scale studies.
doi:10.1371/journal.pone.0071315
PMCID: PMC3731301  PMID: 23936498
20.  Socioeconomic inequalities in height, leg length and trunk length among children aged 6.5 years and their parents from the Republic of Belarus: Evidence from the Promotion of Breastfeeding Intervention Trial (PROBIT) 
Annals of human biology  2011;38(5):592-602.
Background
Lower socioeconomic position is associated with shorter stature, in particular shorter leg length, but the magnitude of these associations in non-Western countries has received little attention.
Aim
To examine socioeconomic differentials in height, leg and trunk length in 6.5 year olds from the Republic of Belarus and compare these to differentials in parental height.
Methods
Multivariable linear regression was used to examine associations in a cohort of 13 889 children.
Results
Children from non-manual households were 1.0 cm (95% confidence interval: 0.7–1.3 cm) taller than those from manual households. Mothers and fathers from non-manual backgrounds were 0.7 cm (0.5–0.8) and 1.8 cm (1.6–2.0) taller than those from manual backgrounds, respectively. Associations with higher parental educational attainment were similar. The magnitudes of the associations of socioeconomic position with leg length were similar to those with trunk length. Adjusting for mid-parental height and number of older siblings attenuated associations markedly.
Conclusions
In Belarus, similar socioeconomic differentials in height were observed in both children and their parents. Among children, height differentials were partly explained by mid-parental height and number of older siblings. Leg length was not a more sensitive indicator of childhood socioeconomic conditions than trunk length.
doi:10.3109/03014460.2011.577752
PMCID: PMC3719034  PMID: 21591995
Height; leg length; trunk length; socioeconomic factors
21.  “Let’s get the best quality research we can”: public awareness and acceptance of consent to use existing data in health research: a systematic review and qualitative study 
Background
Opt-in consent is usually required for research, but is known to introduce selection bias. This is a particular problem for large scale epidemiological studies using only pre-collected health data. Most previous studies have shown that members of the public value opt-in consent and can perceive research without consent as an invasion of privacy. Past research has suggested that people are generally unaware of research processes and existing safeguards, and that education may increase the acceptability of research without prior informed consent, but this recommendation has not been formally evaluated. Our objectives were to determine the range of public opinion about the use of existing medical data for research and to explore views about consent to a secondary review of medical records for research. We also investigated the effect of the provision of detailed information about the potential effect of selection bias on public acceptability of the use of data for research.
Methods
We carried out a systematic review of existing literature on public attitudes to secondary use of existing health records identified by searching PubMed (1966-present), Embase (1974-present) and reference lists of identified studies to provide a general overview, followed by a qualitative focus group study with 19 older men recruited from rural and suburban primary care practices in the UK to explore key issues in detail.
Results
The systematic review identified twenty-seven relevant papers and the findings suggested that males and older people were more likely to consent to a review of their medical data. Many studies noted participants’ lack of knowledge about research processes and existing safeguards and this was reflected in the focus groups. Focus group participants became more accepting of the use of pre-collected medical data without consent after being given information about selection bias and research processes. All participants were keen to contribute to NHS-related research but some were concerned about data-sharing for commercial gain and the potential misuse of information.
Conclusions
Increasing public education about research and specific targeted information provision could promote trust in research processes and safeguards, which in turn could increase the acceptability of research without specific consent where the need for consent would lead to biased findings and impede research necessary to improve public health.
doi:10.1186/1471-2288-13-72
PMCID: PMC3682867  PMID: 23734773
Medical record; Informed consent; Selection bias; Secondary research; Confidentiality
22.  Association of fascin-1 with mortality, disease progression and metastasis in carcinomas: a systematic review and meta-analysis 
BMC Medicine  2013;11:52.
Background
Fascin-1 is an actin-bundling protein expressed in many human carcinomas, although absent from most normal epithelia. Fascin-1 promotes filopodia formation, migration and invasion in carcinoma cells; in mouse xenograft tumor models it contributes to metastasis. Fascin-1 is an interesting candidate biomarker for aggressive, metastatic carcinomas but data from individual studies of human tumors have not yet been pooled systematically.
Methods
This systematic review was conducted in accordance with PRISMA guidelines, using fixed and random effects models, as appropriate, to undertake meta-analysis.
Results
A total of 26 immunohistochemical studies of 5 prevalent human carcinomas were identified for meta-analysis. Fascin-1 was associated with increased risk of mortality for breast (pooled hazard ratio, (HR) = 2.58; 95% confidence interval (CI) 1.48 to 4.52; P = 0.001), colorectal (HR = 1.60 (1.37 to 1.86; P <0.001) and esophageal carcinomas (HR = 1.35; CI 1.13 to 1.60; P = 0.001). There was no evidence of association of fascin-1 with mortality in gastric and lung carcinomas. Fascin-1 was associated with increased risk of disease progression in breast (HR = 2.48; CI 1.38 to 4.46; P = 0.002) and colorectal carcinomas (HR = 2.12; CI 1.00 to 4.47; P = 0.05), but not with progression of lung carcinomas (HR = 0.95; CI 0.49 to 1.85; P = 0.9). Fascin-1 was associated with increased risk of lymph node metastasis in colorectal (pooled risk ratio (RR) = 1.47; CI 1.26 to 1.71; P <0.001) and gastric carcinomas (RR = 1.43; CI 1.21 to 1.70; P <0.001). There was no evidence of association of fascin-1 with lymph node metastasis in lung or esophageal carcinomas. Fascin-1 was associated with increased risk of distant metastasis in colorectal (RR = 1.70; CI 1.18 to 2.45; P = 0.004) and gastric carcinomas (RR = 1.93; CI 1.21 to 3.33; P = 0.02). No association with distant metastasis in esophageal carcinomas was observed. Pooling across all the carcinomas provided strong evidence for association of fascin-1 with increased risk of mortality (HR = 1.44; CI 1.24 to 1.68; P <0.001; n = 3,645), lymph node metastasis (RR = 1.36; CI 1.18 to 1.55; P <0.001; n = 2,906) and distant metastasis (1.76; 1.34 to 2.32; P <0.001; n = 1,514).
Conclusions
Fascin-1 is associated consistently with increased risk of mortality in breast, colorectal and esophageal carcinomas and with metastasis in colorectal and gastric carcinomas. The results were stable to various sensitivity analyses and did not vary by predefined subgroups. These data will assist rational decision making for focusing investigations of fascin-1 as a biomarker or therapeutic target onto the most relevant carcinomas.
doi:10.1186/1741-7015-11-52
PMCID: PMC3635876  PMID: 23442983
Fascin-1; carcinoma; mortality; metastasis; meta-analysis
23.  Body Mass Index, Muscle Strength and Physical Performance in Older Adults from Eight Cohort Studies: The HALCyon Programme 
PLoS ONE  2013;8(2):e56483.
Objective
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.
Methods
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.
Results
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.
Conclusion
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.
doi:10.1371/journal.pone.0056483
PMCID: PMC3577921  PMID: 23437142
24.  Trends in procedures for infertility and caesarean sections: was NICE disinvestment guidance implemented? NICE recommendation reminders 
BMC Public Health  2013;13:112.
Background
National Institute for Health and Clinical Excellence (NICE) clinical guidelines and subsequent NICE issued ‘recommendation reminders’ advocate discontinuing two fertility procedures and caesarean sections in women with hepatitis. We assess whether NICE guidance in 2004 and recommendation reminders were associated with a change in the rate of clinical procedures performed.
Methods
Routine inpatient Hospital Episode Statistics (HES) data were extracted from the HES database for 1st April 1998 to 31st March 2010 using OPCS procedure codes for varicocele operations in infertile men, endometrial biopsies in infertile women and caesarean sections in women with hepatitis B or C. We used Joinpoint regression to identify points in time when the trend in procedure rates changed markedly, to identify any influence of the release of NICE guidance.
Results
Between 1998-2010, planned caesarean sections in women with and without hepatitis B or C increased yearly (annual percentage change (APC) 4.9%, 95% CI 2.1% to 7.7%) in women with hepatitis, compared with women without (APC 4.0% [95% CI 2.7% to 5.3%] up to 2001, APC -0.6% [95% CI -2.8% to 1.8%] up to 2004 and 1.3% [95% CI 0.8% to 1.8%] up to 2010). In infertile women under 40 years of age, endometrial biopsies for investigation of infertility increased, APC 6.0% (95% CI 3.6% to 8.4%) up to 2003, APC 1.5% (95% CI -4.3% to 7.7%) to 2007 followed by APC 12.8% (95% CI 1.0% to 26.0%) to 2010. Varicocele procedures remained relatively static between 1998 and 2010 (APC -0.5%, 95% CI -2.3% to 1.3%).
Conclusions
There was no decline in use of the three studied procedures, contrary to NICE guidance, and no change in uptake associated with the timing of NICE guidance or recommendation reminders. ‘Do not do’ recommendation reminders may be ineffective at improving clinical practice or achieving disinvestment.
doi:10.1186/1471-2458-13-112
PMCID: PMC3608251  PMID: 23388377
NICE; Clinical guidelines; Fertility; Caesarean
25.  Breast feeding in infancy and social mobility: 60‐year follow‐up of the Boyd Orr cohort 
Archives of Disease in Childhood  2007;92(4):317-321.
Objective
To assess the association of having been breast fed with social class mobility between childhood and adulthood.
Design
Historical cohort study with a 60‐year follow‐up from childhood into adulthood.
Setting
16 urban and rural centres in England and Scotland.
Participants
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.
Main outcome
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.
Results
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).
Conclusions
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.
doi:10.1136/adc.2006.105494
PMCID: PMC2083668  PMID: 17301108

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