Prospective study design and data analysis in UK Biobank.

Population-based prospective studies, such as UK Biobank, are valuable for generating and testing hypotheses about the potential causes of human disease. We describe how UK Biobank's study design, data access policies, and approaches to statistical analysis can help to minimize error and improve the interpretability of research findings, with implications for other population-based prospective studies being established worldwide.

Incorporating patient generated health data into pharmacoepidemiological research.

Epidemiology and pharmacoepidemiology frequently employ Real-World Data (RWD) from healthcare teams to inform research. These data sources usually include signs, symptoms, tests, and treatments, but may lack important information such as the patient's diet or adherence or quality of life. By harnessing digital tools a new fount of evidence, Patient (or Citizen/Person) Generated Health Data (PGHD), is becoming more readily available. This review focusses on the advantages and considerations in using PGHD for pharmacoepidemiological research. New and corroborative types of data can be collected directly from patients using digital devices, both passively and actively. Practical issues such as patient engagement, data linking, validation, and analysis are among important considerations in the use of PGHD. In our ever increasingly patient-centric world, PGHD incorporated into more traditional Real-Word data sources offers innovative opportunities to expand our understanding of the complex factors involved in health and the safety and effectiveness of disease treatments. Pharmacoepidemiologists have a unique role in realizing the potential of PGHD by ensuring that robust methodology, governance, and analytical techniques underpin its use to generate meaningful research results.

Lessons from meta-analyses of randomized clinical trials for analysis of distributed networks of observational databases.

Networks of constellations of longitudinal observational databases, often electronic medical records or transactional insurance claims or both, are increasingly being used for studying the effects of medicinal products in real-world use. Such databases are frequently configured as distributed networks. That is, patient-level data are kept behind firewalls and not communicated outside of the data vendor other than in aggregate form. Instead, data are standardized across the network, and queries of the network are executed locally by data partners, and summary results provided to a central research partner(s) for amalgamation, aggregation, and summarization. Such networks can be huge covering years of data on upwards of 100 million patients. Examples of such networks include the FDA Sentinel Network, ASPEN, CNODES, and EU-ADR. As this is a new emerging field, we note in this paper the conceptual similarities and differences between the analysis of distributed networks and the now well-established field of meta-analysis of randomized clinical trials (RCTs). We recommend, wherever appropriate, to apply learnings from meta-analysis to help guide the development of distributed network analyses of longitudinal observational databases.

Night Shift Work and Breast Cancer Incidence: Three Prospective Studies and Meta-analysis of Published Studies.

BACKGROUND: It has been proposed that night shift work could increase breast cancer incidence. A 2007 World Health Organization review concluded, mainly from animal evidence, that shift work involving circadian disruption is probably carcinogenic to humans. We therefore aimed to generate prospective epidemiological evidence on night shift work and breast cancer incidence. METHODS: Overall, 522 246 Million Women Study, 22 559 EPIC-Oxford, and 251 045 UK Biobank participants answered questions on shift work and were followed for incident cancer. Cox regression yielded multivariable-adjusted breast cancer incidence rate ratios (RRs) and 95% confidence intervals (CIs) for night shift work vs no night shift work, and likelihood ratio tests for interaction were used to assess heterogeneity. Our meta-analyses combined these and relative risks from the seven previously published prospective studies (1.4 million women in total), using inverse-variance weighted averages of the study-specific log RRs. RESULTS: In the Million Women Study, EPIC-Oxford, and UK Biobank, respectively, 673, 28, and 67 women who reported night shift work developed breast cancer, and the RRs for any vs no night shift work were 1.00 (95% CI = 0.92 to 1.08), 1.07 (95% CI = 0.71 to 1.62), and 0.78 (95% CI = 0.61 to 1.00). In the Million Women Study, the RR for 20 or more years of night shift work was 1.00 (95% CI = 0.81 to 1.23), with no statistically significant heterogeneity by sleep patterns or breast cancer risk factors. Our meta-analysis of all 10 prospective studies included 4660 breast cancers in women reporting night shift work; compared with other women, the combined relative risks were 0.99 (95% CI = 0.95 to 1.03) for any night shift work, 1.01 (95% CI = 0.93 to 1.10) for 20 or more years of night shift work, and 1.00 (95% CI = 0.87 to 1.14) for 30 or more years. CONCLUSIONS: The totality of the prospective evidence shows that night shift work, including long-term shift work, has little or no effect on breast cancer incidence.

The impact of persistence with bisphosphonates on health resource utilization and fracture risk in the UK: a study of patient records from the UK Clinical Practice Research Datalink.

RATIONALE, AIMS AND OBJECTIVES: Clinical trial data suggest that patients who have received bisphosphonates continue to benefit from them after discontinuation. However, data from real-world clinical practice are inconclusive. We assessed the impact of persistence and discontinuation on health resource utilization (HRU) and fracture rate in women who were prescribed oral bisphosphonates. METHOD: The study used data from the UK Clinical Practice Research Datalink. Women aged 50 years or older with a first prescription of oral bisphosphonate therapy between January 2000 and December 2007 were included. Multivariate modelling compared rate ratios for fracture and HRU between patients who had discontinued medication (shorter persistence group) and patients who took their medication for longer (longer persistence group). The interactions of elapsed time (measured as 6-month intervals) with HRU and with fracture rate for all patients within paired groups were also assessed. RESULTS: Overall, 36 320 patients were included. Pairwise comparisons showed that HRU and fracture rates were lower in longer persistence groups than in shorter persistence groups. Analysis by 6-month interval showed that, across all patients in persistence group pairs, HRU significantly increased for each additional 6 months elapsed; trends towards increased risk of fracture were also seen. CONCLUSION: In contrast to results from clinical trials, in this patient population the protective effect of oral bisphosphonates after discontinuation was not sufficient to reduce HRU and fracture rates to the levels that would be seen if patients had continued on therapy. Reducing the rate of treatment discontinuation may decrease the burden that osteoporosis places on both patients and health care systems.

Switch patterns of osteoporosis medication and its impact on persistence among postmenopausal women in the U.K. General Practice Research Database.

OBJECTIVE: This study aims to describe the switch patterns of osteoporosis medication in postmenopausal women and to explore the impact of switching on persistence. METHODS: This study used a cohort of postmenopausal women who initiated the first treatment with osteoporosis medication between 1995 and 2008. Selected women had switched at least once to a different frequency or type of osteoporosis medication during follow-up. For each study woman, we identified the first therapy (initial osteoporosis medication), second therapy (medication received at first switch), and, where available, third therapy (medication received at second switch), regardless of how many times she switched during follow-up. Persistence was defined as the number of days from the index date to the end of the last prescription within each episode of use. The Kaplan-Meier method was used to calculate persistence rates at 6 months, 1 year, 3 years, and 5 years. RESULTS: Of 20,638 women who switched osteoporosis treatment at least once in the study period, approximately 67% switched once, 21% switched twice, and 12% switched three times or more. Persistence rates for the second therapy were highest (% [95% CI], 46.6 [46.1-47.1], 35.0 [34.5-35.5], 18.8 [18.3-19.3], and 11.4 [10.9-11.7] at 6 mo, 1 y, 3 y, and 5 y, respectively), whereas persistence rates for the first therapy were lowest (% [95% CI], 34.3 [33.9-34.8], 21.6 [21.2-21.9], 5.90 [5.68-6.13], and 1.57 [1.45-1.69], respectively). CONCLUSIONS: Among women who switch their initial medication, even though switching to the second medication improves persistence during the initial therapy, persistence on the second and subsequent therapies remains suboptimal.

Characteristics of the Million Women Study participants who have and have not worked at night.

OBJECTIVES: The aim of this study was to compare the characteristics of women who had and had not worked at night in terms of their risk factors for common disease, indicators of general health, social activities, employment, and sleep behavior. METHODS: The Million Women Study is a large prospective cohort study of women's health in the United Kingdom with 1.3 million women recruited during 1996-2001 (aged 50-64 years) through 66 National Health Service breast screening centers. We analyzed the data from a random sample of 41 652 participants who, in 2009-2010, reported their history of night work. RESULTS: Of the participants, 1 in 8 women (13%) reported that they had ever worked at night and 1 in 50 (2%) reported working at night for ≥20 years. For 33 sociodemographic, behavioral, reproductive, and hormonal factors examined, 20 showed highly significant differences between "ever" and "never" night workers (P<0.0001); 12 showed significant trends by duration of night work (P<0.01). In particular, compared to women who had never worked at night, women who had worked at night were more likely to (i) be of lower socioeconomic status [the odds ratio (OR) for ever versus never night workers of being in the lowest third of socioeconomic status was 1.15, 99% confidence interval (95% CI) 1.06-1.25]; (ii) have ever used hormone replacement therapy (HRT) for the menopause (OR 1.43, 99% CI 1.33-1.55); (iii) be current smokers (OR 1.37, 99% CI 1.19-1.58); and (iv) be obese (OR 1.26, 99% CI 1.15-1.37). Compared to women who had never worked at night, women who had worked at night for ≥20 years were more likely to be (i) of lower socioeconomic status (OR 1.28, 99% CI 1.04-1.57); (ii) nulliparous (OR 1.47, 99% CI 1.12-1.91); (iii) current smokers (OR 1.63, 99% CI 1.18-2.25); and (iv) obese (OR 1.55, 99% CI 1.25-1.93). Former night workers were more likely than never night workers to report a range of sleep disturbances, including poor quality of sleep (OR 1.15, 99% CI 1.01-1.31) and having to take medication to sleep (OR 1.35, 99% CI 1.15-1.60). CONCLUSIONS: Women who reported having worked at night were substantially different from those who reporting never having worked at night and many of the differences would put "ever night workers" at increased risks of cancer, vascular disease, and many other common conditions.

Persistence with osteoporosis medications among postmenopausal women in the UK General Practice Research Database.

OBJECTIVE: The aims of this study were to estimate persistence with osteoporosis therapies and to assess persistence by different users (stable and switching), type of osteoporosis drug, and calendar year of initiation among postmenopausal women. METHODS: This study was conducted using the data from the UK General Practice Research Database. We identified all women in the General Practice Research Database who had a first-ever recording of a prescription for an oral bisphosphonate, oral raloxifene, or oral strontium ranelate between January 1, 1995, and March 31, 2008, and who were 50 years or older or had a diagnosis to indicate menopause at an earlier age.Persistence was estimated as the proportion of women who continued therapy at 6 months and at 1, 3, and 5 years, using Kaplan-Meier methodology. Because women could have multiple episodes (of one or more therapies) over the follow-up period, persistence was evaluated for each individual episode. RESULTS: There were 66,116 eligible postmenopausal women who received at least one prescription for one of the osteoporosis therapy drugs in this study during the period 1995 to 2008. Overall, the women were continuing with osteoporosis therapy at 6 months after the index date in the full study population in 44% of episodes and in 32%, 16%, and 9% of episodes at 1, 3, and 5 years later, respectively. CONCLUSIONS: Persistence with osteoporosis therapies has improved over the study period, but persistence in the first 6 months remains below 50%, leaving a large unmet need to improve the management of postmenopausal women through novel adherence programs and therapies.

Menopausal hormone therapy and risk of gastrointestinal cancer: nested case-control study within a prospective cohort, and meta-analysis.

Use of menopausal hormone therapy (HT) has been associated with reduced risk of colorectal cancer; evidence for its effect on other gastrointestinal cancers is limited. We conducted a nested case-control study within a UK cohort, and meta-analyses combining our results with those from published studies. Our study included women aged 50+ in the UK General Practice Research Database (GPRD): 1,054 with oesophageal, 750 with gastric and 4,708 with colorectal cancer, and 5 age- and practice-matched controls per case. Relative risks (RRs) and 95% confidence intervals (CIs) for cancer in relation to prospectively-recorded HT prescriptions were estimated by conditional logistic regression. Women prescribed HT had a reduced risk of oesophageal cancer (adjusted RR for 1+ vs. no HT prescriptions, 0.68, 95% CI 0.53-0.88; p = 0.004), gastric cancer (0.75, 0.54-1.05; p = 0.1) and colorectal cancer (0.81, 0.73-0.90; p < 0.001). There were no significant differences in cancer risk by HT type, estimated duration of HT use or between past and current users. In meta-analyses, risks for ever vs. never use of HT were significantly reduced for all three cancers (summary RR for oesophageal cancer, 0.68, 0.55-0.84, p < 0.001; for gastric cancer, 0.78, 0.65-0.94, p = 0.008; for colorectal cancer, 0.84, 0.81-0.88, p < 0.001). In high-income countries, estimated incidence over 5 years of these three cancers combined in women aged 50-64 was 2.9/1,000 in HT users and 3.6/1,000 in never users. The absolute reduction in risk of these cancers in HT users is small compared to the HT-associated increased risk of breast cancer.

Fruit and vegetable intake and mortality from ischaemic heart disease: results from the European Prospective Investigation into Cancer and Nutrition (EPIC)-Heart study.

AIMS: A higher intake of fruits and vegetables has been associated with a lower risk of ischaemic heart disease (IHD), but there is some uncertainty about the interpretation of this association. The objective was to assess the relation between fruit and vegetable intake and risk of mortality from IHD in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Heart study. METHODS AND RESULTS: After an average of 8.4 years of follow-up, there were 1636 deaths from IHD among 313 074 men and women without previous myocardial infarction or stroke from eight European countries. Participants consuming at least eight portions (80 g each) of fruits and vegetables a day had a 22% lower risk of fatal IHD [relative risk (RR) = 0.78, 95% confidence interval (CI): 0.65-0.95] compared with those consuming fewer than three portions a day. After calibration of fruit and vegetable intake to account for differences in dietary assessment between the participating centres, a one portion (80 g) increment in fruit and vegetable intake was associated with a 4% lower risk of fatal IHD (RR = 0.96, 95% CI: 0.92-1.00, P for trend = 0.033). CONCLUSION: Results from this large observational study suggest that a higher intake of fruits and vegetables is associated with a reduced risk of IHD mortality. Whether this association is causal and, if so, the biological mechanism(s) by which fruits and vegetables operate to lower IHD risks remains unclear.

Red meat, dietary nitrosamines, and heme iron and risk of bladder cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC).

BACKGROUND: Previous epidemiologic studies found inconsistent results for the association between red meat intake, nitrosamines [NDMA: N-nitrosodimethylamine, and ENOC (endogenous nitroso compounds)], and the risk of bladder cancer. We investigated the association between red meat consumption, dietary nitrosamines, and heme iron and the risk of bladder cancer among participants of the European Prospective Investigation into Cancer and Nutrition (EPIC). METHODS: Data on food consumption and complete follow-up for cancer occurrence were available for a total of 481,419 participants, recruited in 10 European countries. Estimates of HRs were obtained by proportional hazard models, stratified by age at recruitment, gender, and study center and adjusted for total energy intake, smoking status, lifetime intensity of smoking, duration of smoking, educational level, and BMI. RESULTS: After a mean follow-up of 8.7 years, 1,001 participants were diagnosed with bladder cancer. We found no overall association between intake of red meat (log2 HR: 1.06; 95% CI: 0.99-1.13), nitrosamines (log2 HR: 1.09; 95% CI: 0.92-1.30 and HR: 0.98; 95% CI: 0.92-1.05 for ENOC and NDMA, respectively) or heme iron (log2 HR: 1.05; 95 CI: 0.99-1.12) and bladder cancer risk. The associations did not vary by sex, high- versus low-risk bladder cancers, smoking status, or occupation (high vs. low risk). CONCLUSIONS: Our findings do not support an effect of red meat intake, nitrosamines (endogenous or exogenous), or heme iron intake on bladder cancer risk.

Fluid intake and the risk of urothelial cell carcinomas in the European Prospective Investigation into Cancer and Nutrition (EPIC).

Results from previous studies investigating the association between fluid intake and urothelial cell carcinomas (UCC) are inconsistent. We evaluated this association among 233,236 subjects in the European Prospective Investigation into Cancer and Nutrition (EPIC), who had adequate baseline information on water and total fluid intake. During a mean follow-up of 9.3 years, 513 first primary UCC occurred. At recruitment, habitual fluid intake was assessed by a food frequency questionnaire. Multivariable hazard ratios were estimated using Cox regression stratified by age, sex and center and adjusted for energy intake, smoking status, duration of smoking and lifetime intensity of smoking. When using the lowest tertile of intake as reference, total fluid intake was not associated with risk of all UCC (HR 1.12; 95%CI 0.86-1.45, p-trend = 0.42) or with risk of prognostically high-risk UCC (HR 1.28; 95%CI 0.85-1.93, p-trend = 0.27) or prognostically low-risk UCC (HR 0.93; 95%CI 0.65-1.33, p-trend = 0.74). No associations were observed between risk of UCC and intake of water, coffee, tea and herbal tea and milk and other dairy beverages. For prognostically low-risk UCC suggestions of an inverse association with alcoholic beverages and of a positive association with soft drinks were seen. Increased risks were found for all UCC and prognostically low-risk UCC with higher intake of fruit and vegetable juices. In conclusion, total usual fluid intake is not associated with UCC risk in EPIC. The relationships observed for some fluids may be due to chance, but further investigation of the role of all types of fluid is warranted.

Hip fracture risk in relation to vitamin D supplementation and serum 25-hydroxyvitamin D levels: a systematic review and meta-analysis of randomised controlled trials and observational studies.

BACKGROUND: Vitamin D supplementation for fracture prevention is widespread despite conflicting interpretation of relevant randomised controlled trial (RCT) evidence. This study summarises quantitatively the current evidence from RCTs and observational studies regarding vitamin D, parathyroid hormone (PTH) and hip fracture risk. METHODS: We undertook separate meta-analyses of RCTs examining vitamin D supplementation and hip fracture, and observational studies of serum vitamin D status (25-hydroxyvitamin D (25(OH)D) level), PTH and hip fracture. Results from RCTs were combined using the reported hazard ratios/relative risks (RR). Results from case-control studies were combined using the ratio of 25(OH)D and PTH measurements of hip fracture cases compared with controls. Original published studies of vitamin D, PTH and hip fracture were identified through PubMed and Web of Science databases, searches of reference lists and forward citations of key papers. RESULTS: The seven eligible RCTs identified showed no significant difference in hip fracture risk in those randomised to cholecalciferol or ergocalciferol supplementation versus placebo/control (RR = 1.13[95%CI 0.98-1.29]; 801 cases), with no significant difference between trials of <800 IU/day and > or = 800 IU/day. The 17 identified case-control studies found 33% lower serum 25(OH)D levels in cases compared to controls, based on 1903 cases. This difference was significantly greater in studies with population-based compared to hospital-based controls (chi(2)(1) (heterogeneity) = 51.02, p < 0.001) and significant heterogeneity was present overall (chi(2)(16) (heterogeneity) = 137.9, p < 0.001). Serum PTH levels in hip fracture cases did not differ significantly from controls, based on ten case-control studies with 905 cases (chi(2)(9) (heterogeneity) = 149.68, p < 0.001). CONCLUSIONS: Neither higher nor lower dose vitamin D supplementation prevented hip fracture. Randomised and observational data on vitamin D and hip fracture appear to differ. The reason for this is unclear; one possible explanation is uncontrolled confounding in observational studies. Post-fracture PTH levels are unrelated to hip fracture risk.

Insulin-like growth factor 1 (IGF1), IGF binding protein 3 (IGFBP3), and breast cancer risk: pooled individual data analysis of 17 prospective studies.

BACKGROUND: Insulin-like growth factor 1 (IGF1) stimulates mitosis and inhibits apoptosis. Some published results have shown an association between circulating IGF1 and breast-cancer risk, but it has been unclear whether this relationship is consistent or whether it is modified by IGF binding protein 3 (IGFBP3), menopausal status, oestrogen receptor status or other factors. The relationship of IGF1 (and IGFBP3) with breast-cancer risk factors is also unclear. The Endogenous Hormones and Breast Cancer Collaborative Group was established to analyse pooled individual data from prospective studies to increase the precision of the estimated associations of endogenous hormones with breast-cancer risk. METHODS: Individual data on prediagnostic IGF1 and IGFBP3 concentrations were obtained from 17 prospective studies in 12 countries. The associations of IGF1 with risk factors for breast cancer in controls were examined by calculating geometric mean concentrations in categories of these factors. The odds ratios (ORs) with 95% CIs of breast cancer associated with increasing IGF1 concentrations were estimated by conditional logistic regression in 4790 cases and 9428 matched controls, with stratification by study, age at baseline, and date of baseline. All statistical tests were two-sided, and a p value of less than 0.05 was considered significant. FINDINGS: IGF1 concentrations, adjusted for age, were positively associated with height and age at first pregnancy, inversely associated with age at menarche and years since menopause, and were higher in moderately overweight women and moderate alcohol consumers than in other women. The OR for breast cancer for women in the highest versus the lowest fifth of IGF1 concentration was 1.28 (95% CI 1.14-1.44; p<0.0001). This association was not altered by adjusting for IGFBP3, and did not vary significantly by menopausal status at blood collection. The ORs for a difference in IGF1 concentration between the highest and lowest fifth were 1.38 (95% CI 1.14-1.68) for oestrogen-receptor-positive tumours and 0.80 (0.57-1.13) for oestrogen-receptor-negative tumours (p for heterogeneity=0.007). INTERPRETATION: Circulating IGF1 is positively associated with breast-cancer risk. The association is not substantially modified by IGFBP3, and does not differ markedly by menopausal status, but seems to be confined to oestrogen-receptor-positive tumours. FUNDING: Cancer Research UK.

Association between pre-diagnostic circulating vitamin D concentration and risk of colorectal cancer in European populations:a nested case-control study.

OBJECTIVE: To examine the association between pre-diagnostic circulating vitamin D concentration, dietary intake of vitamin D and calcium, and the risk of colorectal cancer in European populations. DESIGN: Nested case-control study. Setting The study was conducted within the EPIC study, a cohort of more than 520 000 participants from 10 western European countries. PARTICIPANTS: 1248 cases of incident colorectal cancer, which developed after enrolment into the cohort, were matched to 1248 controls MAIN OUTCOME MEASURES: Circulating vitamin D concentration (25-hydroxy-vitamin-D, 25-(OH)D) was measured by enzyme immunoassay. Dietary and lifestyle data were obtained from questionnaires. Incidence rate ratios and 95% confidence intervals for the risk of colorectal cancer by 25-(OH)D concentration and levels of dietary calcium and vitamin D intake were estimated from multivariate conditional logistic regression models, with adjustment for potential dietary and other confounders. RESULTS: 25-(OH)D concentration showed a strong inverse linear dose-response association with risk of colorectal cancer (P for trend <0.001). Compared with a pre-defined mid-level concentration of 25-(OH)D (50.0-75.0 nmol/l), lower levels were associated with higher colorectal cancer risk (<25.0 nmol/l: incidence rate ratio 1.32 (95% confidence interval 0.87 to 2.01); 25.0-49.9 nmol/l: 1.28 (1.05 to 1.56), and higher concentrations associated with lower risk (75.0-99.9 nmol/l: 0.88 (0.68 to 1.13); >or=100.0 nmol/l: 0.77 (0.56 to 1.06)). In analyses by quintile of 25-(OH)D concentration, patients in the highest quintile had a 40% lower risk of colorectal cancer than did those in the lowest quintile (P<0.001). Subgroup analyses showed a strong association for colon but not rectal cancer (P for heterogeneity=0.048). Greater dietary intake of calcium was associated with a lower colorectal cancer risk. Dietary vitamin D was not associated with disease risk. Findings did not vary by sex and were not altered by corrections for season or month of blood donation. CONCLUSIONS: The results of this large observational study indicate a strong inverse association between levels of pre-diagnostic 25-(OH)D concentration and risk of colorectal cancer in western European populations. Further randomised trials are needed to assess whether increases in circulating 25-(OH)D concentration can effectively decrease the risk of colorectal cancer.

Cigarette smoking, environmental tobacco smoke exposure and pancreatic cancer risk in the European Prospective Investigation into Cancer and Nutrition.

Cigarette smoking is an established risk factor for pancreatic cancer. However, prospective data for most European countries are lacking, and epidemiologic studies on exposure to environmental tobacco smoke (ETS) in relation to pancreatic cancer risk are scarce. We examined the association of cigarette smoking and exposure to ETS with pancreatic cancer risk within the European Prospective Investigation into Cancer and Nutrition (EPIC). This analysis was based on 465,910 participants, including 524 first incident pancreatic cancer cases diagnosed after a median follow-up of 8.9 years. Estimates of risk were obtained by Cox proportional hazard models and adjusted for weight, height, and history of diabetes mellitus. An increased risk of pancreatic cancer was found for current cigarette smokers compared with never smokers (HR = 1.71, 95% CI = 1.36-2.15), and risk increased with greater intensity and pack-years. Former cigarette smokers who quit for less than 5 years were at increased risk of pancreatic cancer (HR = 1.78, 95% CI = 1.23-2.56), but risk was comparable to never smokers after quitting for 5 years or more. Pancreatic cancer risk was increased among never smokers daily exposed to ETS (for many hours) during childhood (HR = 2.61, 95% CI = 0.96-7.10) and exposed to ETS at home and/or work (HR = 1.54, 95% CI = 1.00-2.39). These results suggest that both active cigarette smoking, as well as exposure to ETS, is associated with increased risk of pancreatic cancer and that risk is reduced to levels of never smokers within 5 years of quitting.

Serum levels of IGF-I, IGFBP-3 and colorectal cancer risk: results from the EPIC cohort, plus a meta-analysis of prospective studies.

Several prospective studies have shown a moderate positive association between increasing circulating insulin-like growth factor-I (IGF-I) levels and colorectal cancer risk. However, the associations were often statistically nonsignificant, and the relationship of cancer risk with IGF-I's major binding protein, IGFBP-3, showed major discrepancies between studies. We investigated the association of colorectal cancer risk with serum IGF-I, total and intact IGFBP-3, in a case-control study nested within the EPIC cohort (1,121 cases of colorectal cancer and 1,121 matched controls). Conditional logistic regression was used to adjust for possible confounders. Our present study results were combined in a meta-analysis with those from 9 previous prospective studies to examine the overall evidence for a relationship of prediagnostic serum IGF-I with colorectal cancer risk. In the EPIC study, serum concentrations of IGF-I and IGFBP-3 showed no associations with risk of colorectal cancer overall. Only in subgroup analyses did our study show moderate positive associations of IGF-I levels with risk, either among younger participants only (and only for colon cancer) or among participants whose milk intakes were in the lowest tertile of the population distribution (RR for an increase of 100 ng/ml = 1.43 [95% CI = 1.13-1.93]). Nevertheless, in the meta-analysis a modest positive association remained between serum IGF-I and colorectal cancer risk overall (RR = 1.07 [1.01-1.14] for 1 standard deviation increase in IGF-I). Overall, data from our present study and previous prospective studies combined indicate a relatively modest association of colorectal cancer risk with serum IGF-I.

Hip fracture incidence in relation to age, menopausal status, and age at menopause: prospective analysis.

BACKGROUND: Bone mineral density is known to decrease rapidly after the menopause. There is limited evidence about the separate contributions of a woman's age, menopausal status and age at menopause to the incidence of hip fracture. METHODS AND FINDINGS: Over one million middle-aged women joined the UK Million Women Study in 1996-2001 providing information on their menopausal status, age at menopause, and other factors, which was updated, where possible, 3 y later. All women were registered with the UK National Health Service (NHS) and were routinely linked to information on cause-specific admissions to NHS hospitals. 561,609 women who had never used hormone replacement therapy and who provided complete information on menopausal variables (at baseline 25% were pre/perimenopausal and 75% postmenopausal) were followed up for a total of 3.4 million woman-years (an average 6.2 y per woman). During follow-up 1,676 (0.3%) were admitted to hospital with a first incident hip fracture. Among women aged 50-54 y the relative risk (RR) of hip fracture risk was significantly higher in postmenopausal than premenopausal women (adjusted RR 2.22, 95% confidence interval [CI] 1.22-4.04; p = 0.009); there were too few premenopausal women aged 55 y and over for valid comparisons. Among postmenopausal women, hip fracture incidence increased steeply with age (p<0.001), with rates being about seven times higher at age 70-74 y than at 50-54 y (incidence rates of 0.82 versus 0.11 per 100 women over 5 y). Among postmenopausal women of a given age there was no significant difference in hip fracture incidence between women whose menopause was due to bilateral oophorectomy compared to a natural menopause (adjusted RR 1.20, 95% CI 0.94-1.55; p = 0.15), and age at menopause had little, if any, effect on hip fracture incidence. CONCLUSIONS: At around the time of the menopause, hip fracture incidence is about twice as high in postmenopausal than in premenopausal women, but this effect is short lived. Among postmenopausal women, age is by far the main determinant of hip fracture incidence and, for women of a given age, their age at menopause has, at most, a weak additional effect. Please see later in the article for the Editors' Summary.

Vitamin D receptor and calcium sensing receptor polymorphisms and the risk of colorectal cancer in European populations.

Increased levels of vitamin D and calcium may play a protective role in colorectal cancer (CRC) risk. It has been suggested that these effects may be mediated by genetic variants of the vitamin D receptor (VDR) and the calcium sensing receptor (CASR). However, current epidemiologic evidence from European populations for a role of these genes in CRC risk is scarce. In addition, it is not clear whether these genes may modulate CRC risk independently or by interaction with blood vitamin D concentration and level of dietary calcium intake. A case-control study was conducted nested within the European Prospective Investigation into Cancer and Nutrition. CRC cases (1,248) were identified and matched to 1,248 control subjects. Genotyping for the VDR (BsmI: rs1544410; Fok1: rs2228570) and CASR (rs1801725) genes was done by Taqman, and serum vitamin D (25OHD) concentrations were measured. Conditional logistic regression was used to estimate the incidence rate ratio (RR). Compared with the wild-type bb, the BB genotype of the VDR BsmI polymorphism was associated with a reduced risk of CRC [RR, 0.76; 95% confidence interval (CI), 0.59-0.98). The association was observed for colon cancer (RR, 0.69; 95% CI, 0.45-0.95) but not rectal cancer (RR, 0.97; 95% CI, 0.62-1.49). The Fok1 and CASR genotypes were not associated with CRC risk in this study. No interactions were noted for any of the polymorphisms with serum 25OHD concentration or level of dietary calcium. These results confirm a role for the BsmI polymorphism of the VDR gene in CRC risk, independent of serum 25OHD concentration and dietary calcium intake.