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ABSTRACT: AIMS: The UK's Clinical Practice Research Datalink (CPRD) is increasingly used to investigate suicide- related adverse drug reactions. No studies have comprehensively validated the recording of suicide and non-fatal self-harm in the CPRD. We validated GP's 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. ICD codes were used to identify suicides/hospital admissions for self-harm in the linked ONS and HES datasets. 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. 68.4% of HES-identified cases of self-harm were identified in the CPRD using Read codes. 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: 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.
British Journal of Clinical Pharmacology 12/2012; · 2.96 Impact Factor
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Mari-Anne Rowlands,
Kate Tilling,
Jeff M P Holly, Chris Metcalfe,
David Gunnell,
Athene Lane,
Michael Davis,
Jenny Donovan,
Freddie Hamdy,
David E Neal,
Richard M Martin
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ABSTRACT: PURPOSE: Active monitoring of prostate cancer requires the selection of low-risk cancers and subsequent identification of disease progression. Our objective was to determine whether serum insulin-like growth factor (IGF)-I, IGF-II, IGF-binding protein (IGFBP)-2 or IGFBP-3 at diagnosis (potential biomarkers of prognosis), and repeated measures of IGFBP-2 (potential biomarker of tumour growth), were associated with annual change in PSA and PSA doubling time (PSADT), proxies for disease progression. METHODS: We investigated associations of circulating IGFs and IGFBPs with PSA measures using multilevel models, in 909 men (recruited between 1999 and 2009) with PSA-detected clinically localized prostate cancer undergoing active monitoring in the United Kingdom. Each man had an average of 14 measurements of PSA during a mean of 4-year follow-up. RESULTS: IGF-I, IGF-II, IGFBP-2, and IGFBP-3 were not associated with baseline PSA. There was weak evidence that IGF-I at diagnosis was positively associated with a rapid post-diagnosis PSADT (≤4 years vs. >4 years): OR 1.34 (95 % CI 0.98, 1.81) per SD increase in IGF-I. IGFBP-2 increased by 2.1 % (95 % CI 1.4, 2.8) per year between 50 and 70 years, with no association between serial IGFBP-2 levels and PSADT. There was no evidence that serum IGF-II, IGFBP-2, or IGFBP-3, or post-diagnosis IGFBP-2, were associated with PSA kinetics in men with PSA-detected localized prostate cancer. CONCLUSIONS: The weak association of IGF-I with PSADT requires replication in larger datasets, and more definitive evidence will be provided on the maturity of long-term active monitoring cohorts with relevant clinical outcomes (metastasis and prostate cancer mortality).
Cancer Causes and Control 10/2012; · 2.88 Impact Factor
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ABSTRACT: Current diagnostic tests cannot differentiate the majority of prostate cancers with a low likelihood of progression from the minority with more aggressive potential. We examined whether the measures of vitamin D were associated with prostate-specific antigen (PSA) doubling time in men undergoing active monitoring. We examined the associations of circulating 25-hydroxyvitamin D (25(OH)D), 1,25-dihydroxyvitamin D (1,25(OH)2D), and vitamin D pathway polymorphisms with PSA doubling time in 490 men undergoing active monitoring for localized prostate cancer within a UK population-based cohort study [mean follow-up 4.4 years (range: 0.3-7.6)]. Repeat PSA measurements were analyzed using multilevel models. There was no evidence that circulating 25(OH)D levels, 1,25(OH)2D levels, or vitamin D pathway polymorphisms were associated with postdiagnosis PSA doubling time. Stratifying the results by prostate cancer grade at diagnosis (high grade or low grade) did not alter the results. We found no evidence that either circulating 25(OH)D, 1,25(OH)2D, or vitamin D pathway polymorphisms were associated with PSA doubling time in men undergoing active monitoring for localized prostate cancer. Future studies should examine the associations of variation in vitamin D with clinical outcomes (metastases and death).
European journal of cancer prevention: the official journal of the European Cancer Prevention Organisation (ECP) 09/2012; · 2.21 Impact Factor
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ABSTRACT: Some epidemiological studies suggest that vitamin A (retinol), vitamin E, and vitamin D (total 25-hydroxyvitamin D, 25(OH)D; 1,25-dihydroxyvitamin, 1,25(OH)(2)D) are protective against prostate cancer. However, the evidence is not conclusive, with positive and null associations reported for all three vitamins. Limitations of previous studies include small sample size, lack of population controls, and reliance on self-reported dietary intake. Few studies have explored the interactions of circulating 25(OH)D with 1,25(OH)(2)D or retinol, which are biologically plausible interactions.
We investigated the associations of circulating retinol, vitamin E, and 1,25(OH)(2)D with PSA-detected prostate cancer risk, stage, and grade in a case-control study nested within the Prostate Testing for Cancer and Treatment (ProtecT) trial. We investigated the possibility of an interaction between 25(OH)D and 1,25(OH)(2)D and whether the previously observed association between 25(OH)D and prostate cancer may be modified by retinol levels.
We included 1,433 prostate cancer cases and 1,433 healthy controls. There was no evidence of associations of circulating retinol, vitamin E, or 1,25(OH)(2)D with overall prostate cancer risk, stage (advanced vs localized), or Gleason grade (high- (≥7) vs low (<7) grade). There was no evidence of an interaction of 1,25(OH)(2)D and 25(OH)D with prostate cancer risk, stage, or grade (p interaction ≥ 0.24). The association between 25(OH)D and prostate cancer did not differ by retinol level (p interaction = 0.34).
We found no evidence that retinol, vitamin E, or 1,25(OH)(2)D concentrations were associated with overall prostate cancer risk or more aggressive prostate cancer phenotypes. There was no evidence of an interaction between 25(OH)D and 1,25(OH)(2)D or retinol.
Cancer Causes and Control 08/2012; 23(11):1865-73. · 2.88 Impact Factor
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Nicholas J Young, Chris Metcalfe,
David Gunnell,
Mari-Anne Rowlands,
J Athene Lane,
Rebecca Gilbert,
Kerry N L Avery,
Michael Davis,
David E Neal,
Freddie C Hamdy,
Jenny Donovan,
Richard M Martin,
Jeff M P Holly
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ABSTRACT: There is evidence of associations between insulin-like growth factor I (IGF-I), IGF-II, insulin-like binding protein-2 (IGFBP-2), IGFBP-3, and prostate cancer risk. This study examines the association between dietary factors associated with prostate cancer and serum levels of these peptides.
A cross-sectional analysis of self-reported 12-month dietary intake with serum IGF and IGFBP levels was performed using data from 1,798 subjects screened negative for prostate cancer as part of a UK multicenter trial comparing treatments for this condition. Multivariable linear regression models tested associations of diet with IGFs and IGFBPs.
For a one standard deviation (SD) increase in dairy product and dairy protein intake, IGF-I increased by 5.28 ng/mL (95 % confidence interval: 2.64, 7.92 ng/mL) and 6.02 ng/mL (3.34, 8.71 ng/mL), respectively. A 25 % increase in calcium and selenium intake was associated with an increase in IGF-I of 5.92 ng/mL (3.77, 8.07 ng/mL) and 2.61 ng/mL (1.10, 4.13 ng/mL), respectively. A one SD increase in animal protein was associated with a decrease in IGFBP-2 of 6.20 % (-8.91, -3.41 %), and there was some evidence of an inverse association with dairy protein and calcium. There was no evidence of any dietary associations with IGFBP-3 or IGF-II.
Diet is associated with IGF-I and IGFBP-2 levels in men in the UK, and these peptides warrant further investigation as part of randomized trials of dietary interventions to reduce the risk or progression of prostate cancer. There is no evidence that IGF-II or IGFBP-3 are mediators of dietary associations with prostate cancer.
Cancer Causes and Control 04/2012; 23(6):907-17. · 2.88 Impact Factor
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ABSTRACT: Circulating 25-hydroxyvitamin D (25(OH)D) may protect against prostate and other cancers. Few epidemiology studies have measured 25(OH)D on all participants, weakening the evidence-base through reduced statistical power and the potential for bias. We developed a score to predict individual 25(OH)D based on potential predictors, including sun exposure, nutrient intake, and vitamin D pathway genes, providing a method of substituting missing values. We assessed the usefulness of predicted 25(OH)D by comparison with multiple imputation of 25(OH)D levels.
Amongst 1,091 controls from a population-based case-control study (ProtecT), we quantified relationships of sun exposure, demographic, clinical, anthropologic, nutrient, and genetic data with circulating 25(OH)D and constructed several prediction scores from subsets of these measures. We investigated associations of three prostate cancer risk factors (PSA level, BMI, family history of prostate cancer) with 25(OH)D levels in sensitivity analyses based upon participants with measured 25(OH)D only and based upon the addition of all participants with missing 25(OH)D levels substituted by prediction score values or by multiple imputation.
Our score accounted for 27.7% of the variation in measured 25(OH)D. Associations with risk factors of prostate cancer were consistent across the different estimates of 25(OH)D. However, standard deviations for the prediction score did not incorporate extra error from prediction. Multiple imputation of missing 25(OH)D values predicted a more realistic range of 25(OH)D.
In epidemiological studies of cancer risk associated with vitamin D, multiple imputation of missing 25(OH)D is preferable to prediction scores, as a wider range of 25(OH)D levels are imputed and appropriate confidence intervals calculated.
Cancer Causes and Control 03/2012; 23(4):575-88. · 2.88 Impact Factor
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ABSTRACT: Little is known about factors influencing men's decisions to undergo screening and diagnostic tests for prostate cancer (PCa).
Identify predictors of attendance for prostate-specific antigen (PSA) testing and prostate biopsy.
Literature searches and interviews with men undergoing PSA testing and prostate biopsy formed the basis of a self-report questionnaire designed to identify predictors of health behaviour, which was completed by men eligible for PSA invitation and prostate biopsy. Multitrait scaling analyses established the final questionnaire content. This revised instrument was distributed to a new cohort of men before PSA testing and biopsy invitations were received. Ethical committee approval was obtained from Trent Multicentre Research Ethics Committee (MREC/01/4/025-21/06/2001).
Predictors of health behaviour and attendance rates for PSA test or prostate biopsy were measured. Associations between questionnaire scores and health behaviour (PSA and prostate biopsy attendance) were examined using logistic regression.
The provisional 49-item health behaviour questionnaire was completed by 468 of 810 men (57.8%). Multitrait scaling refined the questionnaire to 26 items in six scales (A: health benefits, B: threats to health, C: barriers to testing, D: health intentions, E: external influences, F: current general health). A total of 1455 of 2657 men (54.8%) completed the revised instrument before invitations for PSA test or biopsy were received; 395 (43.4%) and 434 (91.6%) attended. Strong associations between men's health intentions (scale D) and PSA and biopsy attendance (odds ratio: 1.56 or 3.67, respectively; p<0.001) were observed with modest associations between the other five scales and attendance for PSA testing. Average questionnaire response rates represent the major limitation of this study.
Knowledge and beliefs about PCa and testing predict men's intentions and attendance for PSA testing and prostate biopsy. Understanding men's health behaviour is important for the management of patients seeking PSA testing in general practice.
European urology 01/2012; 62(4):649-55. · 7.67 Impact Factor
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Derek J Rosario,
J Athene Lane, Chris Metcalfe,
Jenny L Donovan,
Andy Doble,
Louise Goodwin,
Michael Davis,
James W F Catto,
Kerry Avery,
David E Neal,
Freddie C Hamdy
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ABSTRACT: To measure the effect of the adverse events within 35 days of transrectal ultrasound guided biopsy from the perspective of asymptomatic men having prostate specific antigen (PSA) testing; to assess early attitude to re-biopsy; to estimate healthcare resource use associated with adverse events due to biopsy; and to develop a classification scheme for reporting adverse events after prostate biopsy.
Prospective cohort study (Prostate Biopsy Effects: ProBE) nested within Prostate Testing for Cancer and Treatment (ProtecT) study. Participants Between 1999 and 2008, 227,000 community dwelling men aged 50-69 years were identified at 352 practices and invited to counselling about PSA testing. 111,148 attended a nurse led clinic in the community, and 10,297 with PSA concentrations of 3-20 ng/mL were offered biopsy within ProtecT. Between February 2006 and May 2008, 1147/1753 (65%) eligible men (mean age 62.1 years, mean PSA 5.4 ng/mL) having 10 core transrectal ultrasound guided biopsy under antibiotic cover in the context of ProtecT were recruited to the ProBE study.
Purpose designed questionnaire administered at biopsy and 7 and 35 days after the procedure to measure frequency and effect of symptoms related to pain, infection, and bleeding; patients' attitude to repeat biopsy assessed immediately after biopsy and 7 days later; participants' healthcare resource use within 35 days of biopsy evaluated by questionnaire, telephone follow-up, and medical note review; each man's adverse event profile graded according to symptoms and healthcare use.
Pain was reported by 429/984 (43.6%), fever by 172/985 (17.5%), haematuria by 642/976 (65.8%), haematochezia by 356/967 (36.8%), and haemoejaculate by 605/653 (92.6%) men during the 35 days after biopsy. Fewer men rated these symptoms as a major/moderate problem-71/977 (7.3%) for pain, 54/981 (5.5%) for fever, 59/958 (6.2%) for haematuria, 24/951 (2.5%) for haematochezia, and 172/646 (26.6%) for haemoejaculate. Immediately after biopsy, 124/1142 (10.9%, 95% confidence interval 9.2 to 12.8) men reported that they would consider further biopsy a major or moderate problem: seven days after biopsy, this proportion had increased to 213/1085 (19.6%, 17.4% to 22.1%). A negative attitude to repeat biopsy was associated with unfavourable experience after the first biopsy, particularly pain at biopsy (odds ratio 8.2, P<0.001) and symptoms related to infection (7.9, P<0.001) and bleeding (4.2, P<0.001); differences were evident between centres (P<0.001). 119/1147 (10.4%, 8.7% to 12.3%) men reported consultation with a healthcare professional (usually their general practitioner), most commonly for infective symptoms. Complete data for all index symptoms at all time points were available in 851 participants. Symptoms and healthcare use could be used to grade these men as follows: grade 0 (no symptoms/contact) 18 (2.1%, 1.3% to 3.3%); grade 1 (minor problem/no contact) 550 (64.6%, 61.4% to 67.8%); grade 2 (moderate/major problem or contact) 271 (31.8%, 28.8% to 35.1%); grade 3 (hospital admission) 12 (1.4%, 0.8% to 2.4%); and grade 4 (death) 0. Grade of adverse event was associated with an unfavourable attitude to repeat biopsy (Kendall's τ-b ordinal by ordinal 0.29, P<0.001).
This study with a high response rate of 89% at 35 days in men undergoing biopsy in the context of a randomised controlled trial has shown that although prostate biopsy is well tolerated by most men, it is associated with significant symptoms in a minority and affects attitudes to repeat biopsy and primary care resource use. These findings will inform men who seek PSA testing for detection of prostate cancer and assist their physicians during counselling about the potential risks and effect of biopsy. Variability in the adverse event profile between centres suggests that patients' outcomes could be improved and healthcare use reduced with more effective administration of local anaesthetic and antibiotics. Trial registration Current Controlled Trials ISRCTN20141297.
BMJ (Clinical research ed.). 01/2012; 344:d7894.
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ABSTRACT: 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 prostate specific antigen-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 (ORs) and 95% confidence intervals (CIs) 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)). Predetermined categories of total 25(OH)D were defined as: high: ≥30 ng/mL; adequate: 20 – <30 ng/mL; insufficient: 12 – <20 ng/mL; deficient: <12 ng/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 2-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.
International Journal of Cancer 12/2011; 131(5):1187 - 1196. · 5.44 Impact Factor
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ABSTRACT: 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 prostate specific antigen-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 (ORs) and 95% confidence intervals (CIs) 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)). Predetermined categories of total 25(OH)D were defined as: high: ≥30 ng/mL; adequate: 20-<30 ng/mL; insufficient: 12-<20 ng/mL; deficient: <12 ng/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 2-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.
International Journal of Cancer 10/2011; 131(5):1187-96. · 5.44 Impact Factor
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ABSTRACT: OBJECTIVE • To estimate rates of prostate-specific antigen (PSA) testing in UK general practices by age, deprivation index and geographical location. SUBJECTS AND METHODS • Practice-based, retrospective data on PSA testing patterns in 2007 were collected from a random sample of 87 general practices using EMIS LV computer systems within the passively observed non-intervention arm of a cluster-randomized controlled trial. • Information for a total of 126 716 men aged 45-89 years with no recorded diagnosis of prostate cancer prior to 1 January 2007 was collected. RESULTS • In all, 7902 (6.2%) of 126 716 men aged 45-89 without a prior diagnosis of prostate cancer underwent at least one PSA test from their general practitioner during 2007 [95% confidence interval (CI) 5.6-7.0%; practice-based inter-quartile range 3.6-8.4%]. • PSA testing rates were 1.4% (95% CI 1.1-1.6%) in men aged 45-49, rising to 11.3% (95% CI 10.0-12.9%) at age 75-79 years (P for trend <0.001). • Testing rates were lowest in the three northern centres (3.5-5.7%) vs the three more southern centres (7.1-8.9%; P < 0.001). • For every 20 points increase in the index of multiple deprivation score, the proportion of men tested fell by 1.7% (95% CI -2.5 to -0.8%; P < 0.001). • Lower proportions of men were subsequently diagnosed with prostate cancer in practices testing more men (odds ratio for a one unit increase in the natural log of testing 0.76; 95% CI 0.60-0.97; P= 0.025). CONCLUSION • Overall levels of PSA testing in UK general practice remain low, but for those tested there are important variations by age, deprivation and geographical location that do not appear to reflect clinical need or the intention of current policy. • PSA testing in general practice is currently skewed towards older men, and current policy enabling all men to make an informed choice about PSA testing is not being effectively implemented as uptake clearly varies by socioeconomic status. • This reinforces the need for robust evidence regarding the costs and benefits of using the PSA test for the detection of localized prostate cancer in the UK, a full assessment of the health economic implications and a revision of the current policy.
BJU International 04/2011; 108(9):1402-8. · 2.84 Impact Factor
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ABSTRACT: We systematically reviewed and meta-analyzed literature examining associations of vitamin D (dietary intake, circulating 25-hydroxy-vitamin-D (25(OH)D), and 1,25-dihydroxy-vitamin-D (1,25(OH)(2)D) concentrations) with prostate cancer.
We searched over 24,000 papers from seven electronic databases (to October 2010) for exposures related to vitamin D. We conducted dose-response random-effects meta-analyses pooling the log odds ratio (OR) and 95% confidence intervals (CI) per change in natural units of each exposure. The I(2) statistic quantified between-study variation due to heterogeneity.
Twenty-five papers were included. In prospective studies, the OR per 1,000 IU increase in dietary intake was 1.14 (6 studies; CI: 0.99, 1.31; I (2) = 0%) for total prostate cancer and 0.93 (3 studies; 0.63, 1.39; I (2) = 25%) for aggressive prostate cancer. Five case-control studies examined dietary intake, but there was a high degree of inconsistency between studies (I (2) = 49%). The OR per 10 ng/mL increase in 25(OH)D was 1.04 (14 studies; 0.99, 1.10; I (2) = 0%) for total prostate cancer and 0.98 (6 studies; 0.84, 1.15; I (2) = 32%) for aggressive prostate cancer. The OR per 10 pg/mL increase in 1,25(OH)(2)D was 1.00 (7 studies; 0.87, 1.14; I (2) = 41%) for total prostate cancer and 0.86 (2 studies; 0.72, 1.02; I (2) = 0%) for aggressive prostate cancer.
Published literature provides little evidence to support a major role of vitamin D in preventing prostate cancer or its progression.
Cancer Causes and Control 03/2011; 22(3):319-40. · 2.88 Impact Factor
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ABSTRACT: • To assess whether a seasonal change in prostate specific antigen (PSA) levels can be detected in men recruited to a large clinical trial.
• A total of 66 969 men aged 50-69 years were drawn from a large study conducted at general practices across the UK between 2002 and 2007. • Trigonometric algorithms and regression methods were used to assess the relationship between the time of year and serum PSA and blood pressure measurements. • We obtained local daily mean temperatures and hours of sunlight per day to assess whether these factors were potential mechanisms for seasonal variation in PSA levels or blood pressure. • The proportion of participants who would be considered clinically at risk according to their PSA or blood pressure measurement, by month, was also assessed. • The strength of associations between time of year and blood pressure were used to reinforce conclusions from the PSA models.
• There was no relationship between time of year and PSA levels (P= 0.11) or between climate and PSA levels (P= 0.42). • No difference was found in the prevalence of clinically raised PSA content by month (P= 0.50). • This lack of an association with PSA content was despite our data being sufficient to provide clear evidence of an association between blood pressure and time of year (systolic P < 0.001; diastolic P < 0.001), and to show that this association was largely explained by climatic factors (temperature and sunlight).
• There was no pattern in PSA levels by time of year, air temperature or levels of sunlight in this cohort, so there is no need to take these factors into account when reviewing PSA results.
BJU International 03/2011; 108(9):1409-14. · 2.84 Impact Factor
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ABSTRACT: Observational studies suggest that diabetes is associated with a decreased risk of prostate cancer, but few are population based or have investigated associations with cancer stage or duration of diabetes. We report a case-control study nested within the population-based Prostate testing for cancer and Treatment (ProtecT) study ISRCTN20141297. Men aged 50-69 years based around 9 UK cities were invited for a prostate-specific antigen (PSA) test between June 2002 and November 2006. Amongst 55,215 PSA-tested men, 1,966 had histologically confirmed prostate cancer; of these, 1,422 (72.3%) completed the questionnaire and 1,291 (65.7%) had complete data for analysis. We randomly selected 6,479 age- (within 5 years) and general practice-matched controls. The prevalence of diabetes was 89/1,291 (6.9%) in cases and 555/6,479 (8.6%) in controls. Diabetes was associated with a reduced risk of prostate cancer (odds ratio = 0.78; 95% confidence interval: 0.61-0.99). There was weak evidence that the inverse association was greater for well- versus poorly differentiated cancers (p = 0.07). The magnitude of the inverse association did not change with increasing duration of diabetes (p for trend = 0.95). Diabetes is associated with a decreased risk of PSA-detected prostate cancer. These data add to the evidence of the association of diabetes with prostate cancer in the PSA era.
International Journal of Cancer 01/2011; 128(2):440-6. · 5.44 Impact Factor
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Simon M Collin, Chris Metcalfe,
Tom M Palmer,
Helga Refsum,
Sarah J Lewis,
George Davey Smith,
Angela Cox,
Michael Davis,
Gemma Marsden,
Carole Johnston,
J Athene Lane,
Jenny L Donovan,
David E Neal,
Freddie C Hamdy,
A David Smith,
Richard M Martin
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ABSTRACT: Circulating vitamin B(12) (cobalamin/B(12)) and total transcobalamin (tTC) have been associated with increased and reduced risk, respectively, of prostate cancer. Mendelian randomization has the potential to determine whether these are causal associations. We estimated associations of single nucleotide polymorphisms in B(12)-related genes (MTR, MTRR, FUT2, TCN2, TCN1, CUBN, and MUT) with plasma concentrations of B(12), tTC, holo-transcobalamin, holo-haptocorrin, folate, and homocysteine and with prostate cancer risk in a case-control study (913 cases, 895 controls) nested within the UK-wide population-based ProtecT study of prostate cancer in men age 45-69 years. Instrumental variable (IV) analysis was used to estimate odds ratios for effects of B(12) and tTC on prostate cancer. We observed that B(12) was lower in men with FUT2 204G>A (rs492602), CUBN 758C>T (rs1801222) and MUT 1595G>A (rs1141321) alleles (P(trend)<0.001); tTC was lower in men with the TCN2 776C>G (rs1801198) allele (P(trend)<0.001). FUT2 204G>A and CUBN 758C>T were selected as instruments for B(12); TCN2 776C>G for tTC. Conventional and IV estimates for the association of log(e)(B(12)) with prostate cancer were: OR=1.17 (95% CI 0.90-1.51), P=0.2 and OR=0.60 (0.16-2.15), P=0.4, respectively. Conventional and IV estimates for the association of loge(tTC) with prostate cancer were: OR=0.81 (0.54-1.20), P=0.3 and OR=0.41 (0.13-1.32), P=0.1, respectively. Confidence intervals around the IV estimates in our study were too wide to allow robust inference. Sample size estimates based on our data indicated that Mendelian randomization in this context requires much larger studies or multiple genetic variants that explain all of the variance in the intermediate phenotype.
International Journal of Molecular Epidemiology and Genetics 01/2011; 2(4):316-27.
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Chris Metcalfe
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ABSTRACT: The statistical power of cross-over trials can be increased by taking 'baseline' measurements of the outcome variable at the start of each treatment period. Analysis of covariance (ANCOVA), rather than analysis of change scores, takes best advantage of this. However, ANCOVA can give biased treatment effect estimates in observational studies with true baseline imbalance. While in truth balanced, chance baseline imbalance is possible in individual randomized cross-over studies due to their typically small sample size. Although such chance imbalance does not cause biased estimation on average over repeated trials, this simulation study will aim to confirm the appropriateness of ANCOVA when faced with the analysis of data from an individual trial in which chance baseline imbalance is clearly apparent. Randomized cross-over trials were simulated, varying in sample size and the pattern and strength of correlation between repeated measures. Estimates from ANCOVA, change scores, and post-treatment difference were unbiased on average across each set of simulated data sets. ANCOVA and change scores could use baseline information to improve precision, but change scores could also reduce precision if baseline measures were uninformative. Change scores only were correlated with chance within-subject baseline imbalance. All three estimators could be correlated with chance between-subjects imbalance in the first period baseline measurements, the strongest associations being with the post-treatment difference. Consistent results were obtained from a real data example. In conclusion, ANCOVA took best advantage of baseline measures to improve precision, and avoided bias in the widest set of circumstances with chance imbalance in those baseline measures.
Statistics in Medicine 12/2010; 29(30):3211-8. · 1.88 Impact Factor
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Simon M Collin, Chris Metcalfe,
Helga Refsum,
Sarah J Lewis,
George Davey Smith,
Angela Cox,
Michael Davis,
Gemma Marsden,
Carole Johnston,
J Athene Lane,
Jenny L Donovan,
David E Neal,
Freddie C Hamdy,
A David Smith,
Richard M Martin
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ABSTRACT: Vitamin B(12), holo-haptocorrin, and the folate-pathway single-nucleotide polymorphisms MTR 2756A>G and SHMT1 1420C>T have been associated with an increased risk of prostate cancer. We investigated whether these and other elements of folate metabolism were associated with prostate-specific antigen (PSA) velocity (PSAV) as a proxy measure of prostate cancer progression in men with localized prostate cancer.
We measured plasma folate, B(12), holo-haptocorrin, holo-transcobalamin, total transcobalamin, and total homocysteine at diagnosis in 424 men (ages 45-70 years) with localized prostate cancer in a U.K.-wide population-based cohort. Thirteen folate-pathway single-nucleotide polymorphisms were genotyped for 311 of these men. Postdiagnosis PSAV (continuous measure and with a threshold set a priori at 2 ng/mL/y) was estimated from repeat PSA measurements.
Median follow-up time was 2.5 (range, 0.8-5.6) years. Vitamin B(12), holo-haptocorrin, holo-transcobalamin, total transcobalamin, and total homocysteine were not associated with postdiagnosis PSAV. Folate was associated with an increased risk of PSAV >2 ng/mL/y [odds ratio (OR) per unit increase in log(e) concentration, 1.57; 95% confidence interval (95% CI), 0.98-2.51; P = 0.06]. MTRR 66A>G (rs1801394) was associated with a reduced risk (recessive model OR, 0.33; 95% CI, 0.11-0.97; P = 0.04), and SHMT1 1420C>T (rs1979277) with an increased risk (per-allele OR, 1.49; 95% CI, 0.93-2.37; P = 0.09) of PSAV >2 ng/mL/y.
We found weak evidence that higher folate levels may be associated with faster progression of localized prostate cancer.
Long-term follow-up is needed to test associations with metastases and mortality, and the observed genetic effects require replication.
Cancer Epidemiology Biomarkers & Prevention 11/2010; 19(11):2833-8. · 4.12 Impact Factor
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American journal of men's health 09/2010; 4(3):186-8. · 1.15 Impact Factor
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ABSTRACT: To investigate trends in mortality rates due to both myocardial infarction and gastrointestinal haemorrhage before and after rofecoxib withdrawal and the release of regulatory guidance regarding the use of other COX-2 inhibitors.
International ecological study of temporal trends in deaths from myocardial infarction and gastrointestinal haemorrhage around 2004 when regulatory activity restricted the use of COX-2 inhibitors. Mortality data in countries with low child and adult male mortality (WHO mortality stratum A) were analysed.
Comparing, on a country-by-country basis, post-2004 mortality rates with those expected from a continuation of preceding trends, there was no evidence of a deviation from the earlier trends in mortality from gastrointestinal haemorrhage or acute myocardial infarction in 50-69 year olds. Amongst 70+ year olds however, there was evidence of lower gastrointestinal haemorrhage mortality (rate ratio 0.963, 95% confidence interval 0.948 to 0.977) and of lower acute myocardial infarction mortality (rate ratio 0.981, 95% confidence interval 0.977 to 0.986) after 2004. These associations were similar for males and females.
We did not find evidence of an increase in mortality due to gastrointestinal haemorrhage following the withdrawal of rofecoxib in 2004, and coincident concern amongst regulatory bodies about other COX-2 inhibitors. In fact in men and women aged 70 years or older there appeared to be reduced mortality due to gastrointestinal haemorrhage and acute myocardial infarction compared to what was expected from mortality trends before 2004.
Pharmacoepidemiology and Drug Safety 08/2010; 19(8):778-85. · 2.53 Impact Factor
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Simon M Collin, Chris Metcalfe,
Helga Refsum,
Sarah J Lewis,
Luisa Zuccolo,
George Davey Smith,
Lina Chen,
Ross Harris,
Michael Davis,
Gemma Marsden, [......],
Kaare Harald Bønaa,
Ottar Nygård,
Per Magne Ueland,
Maria V Grau,
John A Baron,
Jenny L Donovan,
David E Neal,
Freddie C Hamdy,
A David Smith,
Richard M Martin
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ABSTRACT: Disturbed folate metabolism is associated with an increased risk of some cancers. Our objective was to determine whether blood levels of folate, vitamin B(12), and related metabolites were associated with prostate cancer risk.
Matched case-control study nested within the U.K. population-based Prostate testing for cancer and Treatment (ProtecT) study of prostate-specific antigen-detected prostate cancer in men ages 50 to 69 years. Plasma concentrations of folate, B(12) (cobalamin), holo-haptocorrin, holo-transcobalamin total transcobalamin, and total homocysteine (tHcy) were measured in 1,461 cases and 1,507 controls. ProtecT study estimates for associations of folate, B(12), and tHcy with prostate cancer risk were included in a meta-analysis, based on a systematic review.
In the ProtecT study, increased B(12) and holo-haptocorrin concentrations showed positive associations with prostate cancer risk [highest versus lowest quartile of B(12) odds ratio (OR) = 1.17 (95% confidence interval, 0.95-1.43); P(trend) = 0.06; highest versus lowest quartile of holo-haptocorrin OR = 1.27 (1.04-1.56); P(trend) = 0.01]; folate, holo-transcobalamin, and tHcy were not associated with prostate cancer risk. In the meta-analysis, circulating B(12) levels were associated with an increased prostate cancer risk [pooled OR = 1.10 (1.01-1.19) per 100 pmol/L increase in B(12); 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 B(12) 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.
Cancer Epidemiology Biomarkers & Prevention 06/2010; 19(6):1632-42. · 4.12 Impact Factor
