Nicola Orsini

Meta-Analysis for Linear and Nonlinear Dose-Response Relations: Examples, an Evaluation of Approximations, and Software

Two methods for point and interval estimation of relative risk for log-linear exposure-response relations in meta-analyses of published ordinal categorical exposure-response data have been proposed. The authors compared the results of a meta-analysis of published data using each of the 2 methods with the results that would be obtained if the primary data were available and investigated the circumstances under which the approximations required for valid use of each meta-analytic method break down. They then extended the methods to handle nonlinear exposure-response relations. In the present article, methods are illustrated using studies of the relation between alcohol consumption and colorectal and lung cancer risks from the ongoing Pooling Project of Prospective Studies of Diet and Cancer. In these examples, the differences between the results of a meta-analysis of summarized published data and the pooled analysis of the individual original data were small. However, incorrectly assuming no correlation between relative risk estimates for exposure categories from the same study gave biased confidence intervals for the trend and biased P values for the tests for nonlinearity and between-study heterogeneity when there was strong confounding by other model covariates. The authors illustrate the use of 2 publicly available user-friendly programs (Stata and SAS) to implement meta-analysis for dose-response data.

Diabetes mellitus and risk of endometrial cancer: a meta-analysis

Aims/hypothesisDiabetes has been associated with a statistically significantly increased risk of endometrial cancer in most, but not all studies. To provide a quantitative assessment of the association between diabetes and risk of endometrial cancer, we conducted a meta-analysis of case-control studies and cohort studies.Subjects and methodsWe identified studies by a literature search of PubMed and Embase through to January 2007 and by searching the reference lists of relevant articles. Summary relative risks (RRs) with 95% CIs were calculated using random-effects model.ResultsThe analysis of diabetes (largely type 2) and endometrial cancer is based on 16 studies (three cohort and 13 case-control studies), including 96,003 participants and 7,596 cases of endometrial cancer. Twelve of the studies showed a statistically significantly increased risk and four a non-significant increased risk of endometrial cancer. In our meta-analysis we found that diabetes was statistically significantly associated with an increased risk of endometrial cancer (summary RR 2.10, 95% CI 1.75–2.53). The risk estimates were somewhat stronger among case-control (RR 2.22, 95% CI 1.80–2.74) than among cohort studies (RR 1.62, 95% CI 1.21–2.16), stronger among studies adjusting only for age (RR 2.74, 95% CI 1.87–4.00) compared with multivariate adjustment (RR 1.92, 95% CI 1.58–2.33) and slightly lower in studies performed in the USA than in those performed Europe. The analysis of type 1 diabetes and endometrial cancer was based on three studies and found a statistically significant positive association (summary RR 3.15, 95%CI 1.07–9.29).Conclusions/interpretationResults from the meta-analysis support a relationship between diabetes and increased risk of endometrial cancer.

Non-vigorous physical activity and all-cause mortality: systematic review and meta-analysis of cohort studies

BACKGROUND Although previous studies have found physical activity to be associated with lower mortality, the dose-response relationship remains unclear. In this systematic review and meta-analysis we quantify the dose-response relationship of non-vigorous physical activity and all-cause mortality. METHODS We aimed to include all cohort studies in adult populations with a sample size of more than 10 000 participants that estimated the effect of different levels of light or moderate physical activity on all-cause mortality. We searched Medline, Embase, Cochrane (DARE), Web of Science and Global Health (June 2009). We used dose-response meta-regression models to estimate the relation between non-vigorous physical activity and mortality. RESULTS We identified 22 studies that met our inclusion criteria, containing 977 925 (334 738 men and 643 187 women) people. There was considerable variation between the studies in their categorization of physical activity and adjustment for potential confounders. We found that 2.5 h/week (equivalent to 30 min daily of moderate intensity activity on 5 days a week) compared with no activity was associated with a reduction in mortality risk of 19% [95% confidence interval (CI) 15-24], while 7 h/week of moderate activity compared with no activity reduced the mortality risk by 24% (95% CI 19-29). We found a smaller effect in studies that looked at walking alone. CONCLUSION Being physically active reduces the risk of all-cause mortality. The largest benefit was found from moving from no activity to low levels of activity, but even at high levels of activity benefits accrue from additional activity.

Diabetes mellitus and risk of bladder cancer: a meta-analysis

Aims/hypothesisEpidemiological evidence indicates that individuals with diabetes mellitus have an increased risk of several cancers. We performed a systematic review with meta-analysis to evaluate the association between diabetes and risk of bladder cancer.MethodsPertinent studies were identified by searching MEDLINE (from January 1966 to July 2006) and by reviewing the reference lists of retrieved articles. We included case–control and cohort studies reporting relative risk (RR) estimates with 95% CIs (or data to calculate them) of bladder cancer associated with diabetes. Studies of type 1 diabetes were not included. Summary RRs were calculated using a random-effects model.ResultsA total of 16 studies (seven case–control studies, three cohort studies and six cohort studies of diabetic patients) fulfilled the inclusion criteria. Analysis of all studies showed that diabetes was associated with an increased risk of bladder cancer, compared with no diabetes (RR = 1.24, 95% CI 1.08–1.42). There was strong evidence of heterogeneity among these studies (p < 0.0001). Stratification by study design found that diabetes was associated with an increased risk of bladder cancer in case–control studies (RR = 1.37, 95% CI 1.04–1.80, pheterogeneity = 0.005) and cohort studies (RR = 1.43, 95% CI 1.18–1.74, pheterogeneity = 0.17), but not in cohort studies of diabetic patients (RR = 1.01, 95% CI 0.91–1.12, pheterogeneity = 0.35).Conclusions/interpretationFindings from this meta-analysis suggest that individuals with diabetes may have a modestly increased risk of bladder cancer.

Body mass index and pancreatic cancer risk: A meta-analysis of prospective studies.

A number of studies have examined the association between body mass index (BMI) and risk of pancreatic cancer, but uncertainty about the relationship remains. We performed a meta‐analysis to summarize the evidence from prospective studies investigating this association. We searched MEDLINE for studies published in any language from 1966 to November 2006. Prospective studies were included if they reported relative risks (RRs) with 95% confidence intervals (CIs) for the association between BMI and pancreatic cancer incidence or mortality. Study‐specific RR estimates were combined by use of a random‐effects model. A total of 21 independent prospective studies, involving 3,495,981 individuals and 8,062 pancreatic cancer cases, met the inclusion criteria. The estimated summary RR of pancreatic cancer per 5 kg/m2 increase in BMI was 1.12 (95% CI, 1.06–1.17; p‐heterogeneity = 0.13) in men and women combined, 1.16 (95% CI, 1.05–1.28; p‐heterogeneity = 0.001) in men, and 1.10 (95% CI, 1.02–1.19; p‐heterogeneity = 0.12) in women. There was no evidence of publication bias (p = 0.58). Findings from this meta‐analysis of prospective studies support a positive association between BMI and risk of pancreatic cancer in men and women.

Association of Leisure-Time Physical Activity With Risk of 26 Types of Cancer in 1.44 Million Adults

IMPORTANCE Leisure-time physical activity has been associated with lower risk of heart-disease and all-cause mortality, but its association with risk of cancer is not well understood. OBJECTIVE To determine the association of leisure-time physical activity with incidence of common types of cancer and whether associations vary by body size and/or smoking. DESIGN, SETTING, AND PARTICIPANTS We pooled data from 12 prospective US and European cohorts with self-reported physical activity (baseline, 1987-2004). We used multivariable Cox regression to estimate hazard ratios (HRs) and 95% confidence intervals for associations of leisure-time physical activity with incidence of 26 types of cancer. Leisure-time physical activity levels were modeled as cohort-specific percentiles on a continuous basis and cohort-specific results were synthesized by random-effects meta-analysis. Hazard ratios for high vs low levels of activity are based on a comparison of risk at the 90th vs 10th percentiles of activity. The data analysis was performed from January 1, 2014, to June 1, 2015. EXPOSURES Leisure-time physical activity of a moderate to vigorous intensity. MAIN OUTCOMES AND MEASURES Incident cancer during follow-up. RESULTS A total of 1.44 million participants (median [range] age, 59 [19-98] years; 57% female) and 186 932 cancers were included. High vs low levels of leisure-time physical activity were associated with lower risks of 13 cancers: esophageal adenocarcinoma (HR, 0.58; 95% CI, 0.37-0.89), liver (HR, 0.73; 95% CI, 0.55-0.98), lung (HR, 0.74; 95% CI, 0.71-0.77), kidney (HR, 0.77; 95% CI, 0.70-0.85), gastric cardia (HR, 0.78; 95% CI, 0.64-0.95), endometrial (HR, 0.79; 95% CI, 0.68-0.92), myeloid leukemia (HR, 0.80; 95% CI, 0.70-0.92), myeloma (HR, 0.83; 95% CI, 0.72-0.95), colon (HR, 0.84; 95% CI, 0.77-0.91), head and neck (HR, 0.85; 95% CI, 0.78-0.93), rectal (HR, 0.87; 95% CI, 0.80-0.95), bladder (HR, 0.87; 95% CI, 0.82-0.92), and breast (HR, 0.90; 95% CI, 0.87-0.93). Body mass index adjustment modestly attenuated associations for several cancers, but 10 of 13 inverse associations remained statistically significant after this adjustment. Leisure-time physical activity was associated with higher risks of malignant melanoma (HR, 1.27; 95% CI, 1.16-1.40) and prostate cancer (HR, 1.05; 95% CI, 1.03-1.08). Associations were generally similar between overweight/obese and normal-weight individuals. Smoking status modified the association for lung cancer but not other smoking-related cancers. CONCLUSIONS AND RELEVANCE Leisure-time physical activity was associated with lower risks of many cancer types. Health care professionals counseling inactive adults should emphasize that most of these associations were evident regardless of body size or smoking history, supporting broad generalizability of findings.

Body weight and incidence of breast cancer defined by estrogen and progesterone receptor status--a meta-analysis.

Epidemiological evidence indicates that the association between body weight and breast cancer risk may differ across menopausal status as well as the estrogen receptor (ER) and progesterone receptor (PR) tumor status. To date, no meta‐analysis has been conducted to assess the association between body weight and ER/PR defined breast cancer risk, taking into account menopausal status and study design. We searched MEDLINE for relevant studies published from January 1, 1970 through December 31, 2007. Summarized risk estimates with 95% confidence intervals (CIs) were calculated using a random‐effects model. The summarized results of 9 cohorts and 22 case‐control studies comparing the highest versus the reference categories of relative body weight showed that the risk for ER+PR+ tumors was 20% lower (95% CI = −30% to −8%) among premenopausal (2,643 cases) and 82% higher (95% CI = 55–114%) among postmenopausal (5,469 cases) women. The dose‐response meta‐analysis of ER+PR+ tumors showed that each 5‐unit increase in body mass index (BMI, kg/m2) was associated with a 33% increased risk among postmenopausal women (95% CI = 20–48%) and 10% decreased risk among premenopausal women (95% CI = −18% to −1%). No associations were observed for ER−PR− or ER+PR− tumors. For discordant tumors ER+PR− (pre) and ER−PR+ (pre/post) the number of cases were too small (<200) to interpret results. The relation between body weight and breast cancer risk is critically dependent on the tumors ER/PR status and the womans menopausal status. Body weight control is the effective strategy for preventing ER+PR+ tumors after menopause.

Blood 25-hydroxyvitamin D concentration and hypertension: a meta-analysis.

Objectives Increasing evidence indicates that vitamin D may influence the risk of hypertension, which is a major risk factor for cardiovascular disease. We conducted a meta-analysis to quantitatively review and summarize the results on the association between blood 25-hydroxyvitamin D concentrations and hypertension. Methods Relevant studies were identified by a search of PubMed and EMBASE databases until November 2010. We also reviewed the references of retrieved articles. We included prospective and cross-sectional studies with blood 25-hydroxyvitamin D concentrations as the exposure and hypertension as the outcome. Studies had to report results as a relative risk or an odds ratio. We used random-effects model. Results Of the 18 studies included in the meta-analysis, 4 were prospective studies and 14 were cross-sectional studies. The pooled odds ratio of hypertension was 0.73 [95% confidence interval (CI) 0.63–0.84] for the highest versus the lowest category of blood 25-hydroxyvitamin D concentration. In a dose–response meta-analysis, the odds ratio for a 40 nmol/l (16 ng/ml) (approximately 2 SDs) increment in blood 25-hydroxyvitamin D concentration was 0.84 (95% CI 0.78–0.90). Conclusion Findings from this meta-analysis indicate that blood 25-hydroxyvitamin D concentration is inversely associated with hypertension.

Body mass index and incidence of localized and advanced prostate cancer—a dose–response meta-analysis of prospective studies

BACKGROUND The relationship between obesity and risk of prostate cancer (PCa) is unclear; however, etiologic heterogeneity by subtype of PCa (localized, advanced) related to obesity was suggested. Therefore, we conducted a dose-response meta-analysis of prospective studies to assess the association between body mass index (BMI) and risk of localized and advanced PCa. MATERIALS AND METHODS Relevant prospective studies were identified by a search of Medline and Embase databases to 03 October 2011. Twelve studies on localized PCa (1,033,009 men, 19,130 cases) and 13 on advanced PCa (1,080,790 men, 7067 cases) were identified. We carried out a dose-response meta-analysis using random-effects model. RESULTS For localized PCa, we observed an inverse linear relationship with BMI [Ptrend<0.001, relative risk (RR): 0.94 (95% confidence interval, 95% CI, 0.91-0.97) for every 5 kg/m2 increase]; there was no evidence of heterogeneity (Pheterogeneity=0.27). For advanced PCa, we observed a linear direct relationship with BMI (Ptrend=0.001, RR: 1.09 (95% CI 1.02-1.16) for every 5 kg/m2 increase); there was weak evidence of heterogeneity (Pheterogeneity=0.08). Omitting one study that contributed substantially to the heterogeneity yielded a pooled RR of 1.07 (95% CI 1.01-1.13) for every 5 kg/m2 increase (Pheterogeneity=0.26). CONCLUSIONS The quantitative summary of the accumulated evidence indicates that obesity may have a dual effect on PCa-a decreased risk for localized PCa and an increased risk for advanced PCa.

Systematic review and meta-analysis of reduction in all-cause mortality from walking and cycling and shape of dose response relationship

Background and objectiveWalking and cycling have shown beneficial effects on population risk of all-cause mortality (ACM). This paper aims to review the evidence and quantify these effects, adjusted for other physical activity (PA).Data sourcesWe conducted a systematic review to identify relevant studies. Searches were conducted in November 2013 using the following health databases of publications: Embase (OvidSP); Medline (OvidSP); Web of Knowledge; CINAHL; SCOPUS; SPORTDiscus. We also searched reference lists of relevant texts and reviews.Study eligibility criteria and participantsEligible studies were prospective cohort design and reporting walking or cycling exposure and mortality as an outcome. Only cohorts of individuals healthy at baseline were considered eligible.Study appraisal and synthesis methodsExtracted data included study population and location, sample size, population characteristics (age and sex), follow-up in years, walking or cycling exposure, mortality outcome, and adjustment for other co-variables. We used random-effects meta-analyses to investigate the beneficial effects of regular walking and cycling.ResultsWalking (18 results from 14 studies) and cycling (8 results from 7 studies) were shown to reduce the risk of all-cause mortality, adjusted for other PA. For a standardised dose of 11.25 MET.hours per week (or 675 MET.minutes per week), the reduction in risk for ACM was 11% (95% CI = 4 to 17%) for walking and 10% (95% CI = 6 to 13%) for cycling. The estimates for walking are based on 280,000 participants and 2.6 million person-years and for cycling they are based on 187,000 individuals and 2.1 million person-years. The shape of the dose-response relationship was modelled through meta-analysis of pooled relative risks within three exposure intervals. The dose-response analysis showed that walking or cycling had the greatest effect on risk for ACM in the first (lowest) exposure interval.Conclusions and implicationsThe analysis shows that walking and cycling have population-level health benefits even after adjustment for other PA. Public health approaches would have the biggest impact if they are able to increase walking and cycling levels in the groups that have the lowest levels of these activities.Review registrationThe review protocol was registered with PROSPERO (International database of prospectively registered systematic reviews in health and social care) PROSPERO 2013: CRD42013004266.