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1.  Validation of suicide and self-harm records in the Clinical Practice Research Datalink 
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.
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.
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.
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.
PMCID: PMC3703237  PMID: 23216533
Clinical Practice Research Datalink; General Practice Research Database; nonfatal self-harm; suicide; validation
2.  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 
Evidence that increased duration and exclusivity of breastfeeding reduces child obesity risk is based on observational studies that are prone to confounding.
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).
Cluster-randomized controlled trial.
31 Belarusian maternity hospitals and their affiliated polyclinics, randomized to usual practices (n=15) or a breastfeeding promotion intervention (n=16).
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.
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.
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.
PMCID: PMC3752893  PMID: 23483175
Breast feeding; lactation; adiposity; body mass index; randomized controlled trial; insulin-like growth factor-1; childhood
3.  Associations of postnatal weight and length/height gain with wheeze, asthma and atopy: The PROBIT Study 
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.
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.
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.
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.
PMCID: PMC3711479  PMID: 23374010
wheeze; asthma; atopy; postnatal growth; weight gain; length gain
4.  Using genetic proxies for lifecourse sun exposure to assess the causal relationship of sun exposure with circulating vitamin D and prostate cancer risk 
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.
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.
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.
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.
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.
PMCID: PMC3616836  PMID: 23441100
pigmentation; tanning; sun exposure; vitamin D; prostate cancer
5.  Risk of childhood cancer with symptoms in primary care: a population-based case-control study 
Guidelines describing symptoms in children that should alert GPs to consider cancer have been developed, but without any supporting primary-care research.
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.
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.
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.
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.
PMCID: PMC3529289  PMID: 23336454
cancer; child; diagnosis; primary health care
6.  Physicians' prescribing preferences were a potential instrument for patients' actual prescriptions of antidepressants☆ 
Journal of Clinical Epidemiology  2013;66(12):1386-1396.
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.
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).
The main instrumental variable assumptions held, suggesting that physicians' prescribing preferences are valid instruments for evaluating the short-term effects of antidepressants.
PMCID: PMC3824069  PMID: 24075596
Instrumental variables; Clinical Practice Research Datalink (CPRD); Physicians' prescribing preferences; Confounding by indication; Causality; Translational epidemiology
7.  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.
PMCID: PMC3476828  PMID: 22542496
diet; physical performance; walking speed; standing balance; older people
8.  Circulating folate, vitamin B12, homocysteine, vitamin B12 transport proteins and risk of prostate cancer: a case-control study, systematic review and meta-analysis 
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.
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.
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).
Vitamin B12 and (in cohort studies) folate were associated with increased prostate cancer risk.
Given current controversies over mandatory fortification, further research is needed to determine whether these are causal associations.
PMCID: PMC3759018  PMID: 20501771
folate; vitamin B12; cobalamin; transcobalamin; haptocorrin; homocysteine; folate-mediated one-carbon metabolism; prostate cancer
9.  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.
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).
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.
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.
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.
PMCID: PMC3731301  PMID: 23936498
10.  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.
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.
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.
Multivariable linear regression was used to examine associations in a cohort of 13 889 children.
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.
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.
PMCID: PMC3719034  PMID: 21591995
Height; leg length; trunk length; socioeconomic factors
11.  “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 
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.
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.
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.
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.
PMCID: PMC3682867  PMID: 23734773
Medical record; Informed consent; Selection bias; Secondary research; Confidentiality
12.  Association of fascin-1 with mortality, disease progression and metastasis in carcinomas: a systematic review and meta-analysis 
BMC Medicine  2013;11:52.
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.
This systematic review was conducted in accordance with PRISMA guidelines, using fixed and random effects models, as appropriate, to undertake meta-analysis.
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).
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.
PMCID: PMC3635876  PMID: 23442983
Fascin-1; carcinoma; mortality; metastasis; meta-analysis
13.  Body Mass Index, Muscle Strength and Physical Performance in Older Adults from Eight Cohort Studies: The HALCyon Programme 
PLoS ONE  2013;8(2):e56483.
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.
PMCID: PMC3577921  PMID: 23437142
14.  Trends in procedures for infertility and caesarean sections: was NICE disinvestment guidance implemented? NICE recommendation reminders 
BMC Public Health  2013;13:112.
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.
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.
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%).
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.
PMCID: PMC3608251  PMID: 23388377
NICE; Clinical guidelines; Fertility; Caesarean
15.  How to apply the results of a research paper on diagnosis to your patient 
JRSM Short Reports  2013;4(1):7.
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.
PMCID: PMC3572661  PMID: 23413409
16.  Genetic markers of bone and joint health and physical capability in older adults: the HALCyon programme 
Bone  2013;52(1):278-285.
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.
PMCID: PMC3526776  PMID: 23072920
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
17.  Dysregulation of the hypothalamic pituitary adrenal (HPA) axis and physical performance at older ages: An individual participant meta-analysis 
Psychoneuroendocrinology  2013;38(1):40-49.
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.
PMCID: PMC3533133  PMID: 22658392
HPA axis; Physical capability; Healthy ageing
18.  Socioeconomic disadvantage from childhood to adulthood and locomotor function in old age: a lifecourse analysis of the Boyd Orr and Caerphilly prospective studies 
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.
PMCID: PMC3381706  PMID: 20644236
Aged; Gait; Physical performance; Social Class; Socioeconomic Factors
19.  ACTN3 genotype, athletic status and lifecourse physical capability: meta-analysis of the published literature and findings from nine studies 
Human mutation  2011;32(9):1008-1018.
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.
PMCID: PMC3174315  PMID: 21542061
ACTN3; Actinin-3; athlete; aging; SNP; grip strength
20.  ACTN3 Genotype, Athletic Status, and Life Course Physical Capability: Meta-Analysis of the Published Literature and Findings from Nine Studies 
Human Mutation  2011;32(9):1008-1018.
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.
PMCID: PMC3174315  PMID: 21542061
ACTN3; Actinin-3; athlete; aging; SNP; grip strength
21.  Filter Paper Blood Spot Enzyme Linked Immunoassay for Insulin and Application in the Evaluation of Determinants of Child Insulin Resistance 
PLoS ONE  2012;7(10):e46752.
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.
PMCID: PMC3466324  PMID: 23056434
22.  Is infant weight associated with childhood blood pressure? Analysis of the Promotion of Breastfeeding Intervention Trial (PROBIT) cohort 
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.
PMCID: PMC3383097  PMID: 22039193
Birthweight; blood pressure; lifetime; multi-level model; path analysis; weight gain
23.  Associations of Circulating 25-hydroxyvitamin D with prostate cancer diagnosis, stage and grade 
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.
PMCID: PMC3378478  PMID: 22033893
Prostate cancer; vitamin D; 25-hydroxyvitamn D
24.  Circulating insulin-like growth factors (IGFs) and IGF binding proteins (IGFBPs) in PSA-detected prostate cancer: the large case control study ProtecT 
Cancer research  2011;72(2):503-515.
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.
PMCID: PMC3272440  PMID: 22106399
case-control study; insulin-like growth factors; insulin-like growth factor binding proteins; prostate cancer
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.
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.
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.
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.
PMCID: PMC2083668  PMID: 17301108

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