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Prediction of Incident Stroke Events Based on Retinal Vessel Caliber: A Systematic Review and Individual-Participant Meta-Analysis

The caliber of the retinal vessels has been shown to be associated with stroke events. However, the consistency and magnitude of association, and the changes in predicted risk independent of traditional risk factors, are unclear. To determine the association between retinal vessel caliber and the risk of stroke events, the investigators combined individual data from 20,798 people, who were free of stroke at baseline, in 6 cohort studies identified from a search of the Medline (National Library of Medicine, Bethesda, Maryland) and EMBASE (Elsevier B.V., Amsterdam, the Netherlands) databases. During follow-up of 5–12 years, 945 (4.5%) incident stroke events were recorded. Wider retinal venular caliber predicted stroke (pooled hazard ratio = 1.15, 95% confidence interval: 1.05, 1.25 per 20-µm increase in caliber), but the caliber of retinal arterioles was not associated with stroke (pooled hazard ratio = 1.00, 95% confidence interval: 0.92, 1.08). There was weak evidence of heterogeneity in the hazard ratio for retinal venular caliber, which may be attributable to differences in follow-up strategies across studies. Inclusion of retinal venular caliber in prediction models containing traditional stroke risk factors reassigned 10.1% of people at intermediate risk into different, mostly lower, risk categories.

The Quality of Meta-Analyses of Genetic Association Studies: A Review With Recommendations

Although there has been a rapid rise in the publication of meta-analyses of genetic association studies, little is known about their methodological quality. The authors reviewed the quality of 120 randomly selected genetic meta-analyses published between 2005 and 2007. Data extracted included issues of general relevance and other issues specific to genetic epidemiology. Quality was markedly poorer in the 26% of the meta-analyses that accompanied a report on a primary study. Such meta-analyses were predominantly published in specialist journals, and their quality was positively associated with the impact factor of the journal. Among the meta-analyses that did not accompany a primary study, Human Genome Epidemiology reviews tended to score better than the others, although the comparison was limited by relatively small numbers. Comparison of the overall quality with that of genetic meta-analyses published before 2000 showed improvement in both conduct and reporting. However, the quality of the handling of specific genetic issues remains disappointingly low. For a few key general quality issues, the authors compared their findings with findings in other fields of medicine and found that general quality was similar. On the basis of this review, the authors provide practical recommendations for the conduct and reporting of genetic meta-analyses.

Association Between the Ubiquitin Carboxyl-Terminal Esterase L1 Gene (UCHL1) S18Y Variant and Parkinson's Disease: A HuGE Review and Meta-Analysis

The ubiquitin carboxyl-terminal esterase L1 gene, UCHL1, located on chromosome 4p14, has been studied as a potential candidate gene for Parkinson's disease risk. The authors conducted a Human Genome Epidemiology review and meta-analysis of published case-control studies of the UCHL1 S18Y variant and Parkinson's disease in Asian and Caucasian samples. The meta-analysis of studies in populations of Asian ancestry showed a statistically significant association between the Y allele and reduced risk of Parkinson's disease under a recessive model (odds ratio (OR) for YY vs. SY + SS = 0.79, 95% confidence interval (CI): 0.67, 0.94; P = 0.006). For a dominant model, the association was not significant in Asian populations (OR for YY + SY vs. SS = 0.88, 95% CI: 0.68, 1.14; P = 0.33). For populations of European ancestry, the meta-analysis showed a significant association between the Y allele and decreased risk of Parkinson's disease under a dominant model (OR = 0.89, 95% CI: 0.81, 0.98; P = 0.02) but not under a recessive model (OR = 0.92, 95% CI: 0.66, 1.30; P = 0.65). Using the Venice criteria, developed by the Human Genome Epidemiology Network Working Group on the assessment of cumulative evidence, the authors concluded that moderate evidence exists for an association between the S18Y variant and Parkinson's disease.

Maternal Contributions to Preterm Delivery

Preterm delivery (PTD) is a complex trait with a significant familial component. However, no specific inheritance patterns have been established. The authors examined the contribution of PTDs in both the woman's family and her partner's family to her risk of PTD. The authors linked birth information from Danish national registers with pedigree information from the Danish Family Relations Database for 1,107,124 live singleton deliveries occurring from 1978 to 2004. Risk ratios were estimated comparing women with and without various PTD histories. Women with previous PTDs were at greatly increased risk of recurrent PTD (risk ratio = 5.6, 95% confidence interval: 5.5, 5.8); however, their PTD risk was unaffected by a partner's history of preterm children with other women. PTDs to a woman's mother, full sisters, or maternal half-sisters also increased her PTD risk (risk ratio = 1.6, 95% confidence interval: 1.5, 1.6), whereas PTDs in her paternal half-sisters, the female partners of her male relatives, or members of her partner's family did not affect her PTD risk. Inheritance patterns were similar for all gestational ages from very early through late PTD. The substantial portion of PTD risk explained by effects passed through the female line suggests a role for either imprinting or mitochondrial inheritance.

Maternal Effects for Preterm Birth: A Genetic Epidemiologic Study of 630,000 Families

This study was undertaken to disentangle the maternal genetic from the fetal genetic effects for preterm birth and to study the possibility of these effects being explained by known risk factors. By cross-linking of the population-based Swedish Multigeneration and Medical Birth registers, 989,027 births between 1992 and 2004 were identified. Alternating logistic regression was applied to model the familial clustering with pairwise odds ratios (PORs), and covariates were included to evaluate if the familial aggregation was explained by exposure to shared risk factors. Generalized linear mixed models were used to estimate the contribution of genetic and environmental effects. Sisters of women who had a preterm delivery had themselves an increased odds of having a preterm delivery (POR = 1.8, 95% confidence interval: 1.5, 2.1), while there was no corresponding increase in odds in families joined by brothers (POR = 1.1, 95% confidence interval: 0.9, 1.4). Twenty-five percent of the variation in preterm birth was explained by maternal genetic factors, whereas fetal genetic factors only marginally influenced the variation in liability. The increased odds ratio between offspring of sisters was independent of maternal risk factors for preterm birth, suggesting that the relative importance of maternal effects is not explained by these well-known risk factors.

The Genetics of Preterm Birth: Using What We Know to Design Better Association Studies

Women delivering preterm are at greatly increased risk of another preterm birth in subsequent pregnancies, reflecting effects of the environment, genetics, or both. Recent literature tells an increasingly coherent story about genetic susceptibility. Women who change partners after delivering preterm retain their elevated risk, whereas fathers who change partners do not. Women who themselves were preterm are at increased risk, an association not seen in fathers. Women with a half-sister who delivered preterm are at increased risk only if the shared parent was the mother. Concordance for preterm delivery is elevated in monozygotic compared with dizygotic twin mothers but not in monozygotic twin fathers. Several mechanisms could be operating: mitochondrial genes, maternal genes, or fetal genes expressing only the maternally derived copy. The authors compare 3 study designs for their ability to detect variants and to distinguish among mechanisms underlying heritability of this common outcome. The case-parent triad design offers robustness against self-selection and genetic population stratification, providing for estimation of genetic effects that are fetal, maternal, or that depend on the parent of origin. A case-base approach compares case-mothers with randomly sampled baby-mother pairs and permits estimation of the same relative risk parameters. Both designs offer important advantages over the commonly applied case-mother/control-mother design.

Invited Commentary: Maternal Effects in Preterm Birth--Effects of Maternal Genotype, Mitochondrial DNA, Imprinting, or Environment?

Preterm birth is an important public health problem. A wide range of risk factors has been investigated, of which the strongest established is a woman's previous history of preterm birth. In this issue of the Journal, Boyd et al. (Am J Epidemiol. 2009;170(11):1358–1364) and Svensson et al. (Am J Epidemiol. 2009;170(11):1365–1372), using data on singleton livebirths from national birth registers linked with multigeneration databases, found evidence that maternal genetic factors impact on the risk for preterm birth, whereas paternal and probably fetal genetic factors do not. Possible caveats include missing information, the range of maternal risk factors included in the analyses, possible misclassification of these risk factors, and possible vertical transmission of microbial flora or behaviors from mother to daughter. Weinberg and Shi (Am J Epidemiol. 2009;170(11):1373–1381) build on the evidence regarding potential mechanisms underlying the heritability of preterm birth from these 2 and other studies, to evaluate the comparative ability of different study designs to distinguish among these potential mechanisms. These studies have different strengths, and a portfolio of studies of different designs and with more detailed phenotyping than previously done will be needed to probe further the etiology of preterm birth and thereby provide tools for its control.

Svensson et al. Respond to "Maternal Genes and Environment in Preterm Birth"

Timing and Trajectories of Fetal Growth Related to Cognitive Development in Childhood

The authors investigated timing and trajectories of fetal growth in relation to childhood development in the National Institute of Child Health and Human Development–Scandinavian Study of Successive Small-for-Gestational Age Births (1986–1988) (n = 1,059). Fetal size was assessed by ultrasound at 17, 25, and 33 gestational weeks and at birth. Bayley Scales of Infant Development and the Wechsler Preschool and Primary Scale of Intelligence-Revised tests were conducted at ages 1 and 5 years, respectively, producing mental and psychomotor development indexes and verbal and performance intelligence quotients. Relative fetal size was calculated as a standard deviation score at each data point; growth trajectories were explored with longitudinal mixture models. Fetal size at 17, 25, and 33 weeks was positively associated with mental development index; larger size at 33 weeks and at birth was associated with higher verbal intelligence quotient scores (2.61, 95% confidence interval: 1.06, 4.15 and 1.90, 95% confidence interval: 0.67, 3.13 increase per 1 standard deviation score, respectively); findings were similar for performance intelligence quotient. Seven trajectories were identified; scores were lower for "small" and "medium-to-small" trajectories than for "medium" and "big" (representing normal size) trajectories: mental development index (P < 0.01), performance intelligence quotient (P < 0.001), and verbal intelligence quotient (P < 0.001). Overall, larger fetal size in the second and third trimesters was positively associated with childhood development. Fetal growth trajectories may matter beyond birth.

Estimation of the Contribution of Non-Assisted Reproductive Technology Ovulation Stimulation Fertility Treatments to US Singleton and Multiple Births

Infertility treatments that include ovulation stimulation, both assisted reproductive technologies (ARTs) and non-ART ovulation stimulation, are associated with increased risks of multiple birth and concomitant sequelae and adverse outcomes, even among singletons. While a US surveillance system for ART-induced births is ongoing, no population-based tracking system exists for births resulting from non-ART treatments. The authors developed a multistage model to estimate the uncertain proportion of US infants born in 2005 who were conceived by using non-ART ovulation treatments. Using published surveillance data, they estimated proportions of US multiple births conceived naturally and by ART and assumed that the remainder were conceived with non-ART treatments. They used Bayesian meta-analyses to summarize published clinical studies on the multiple-gestation risk associated with non-ART ovulation treatments, applied a fetal survival factor, and used this multiple-birth risk estimate and their own estimate of the proportion of US multiple births attributable to non-ART ovulation stimulation to estimate the total (and, through subtraction, singleton) proportion of infants conceived with such treatments. On the basis of the model, the authors estimate that 4.6% of US infants born in 2005 (95% uncertainty range: 2.8%–7.1%) resulted from non-ART ovulation treatments. Notably, this figure is 4 times greater than the ART contribution.

Use of Fertility Drugs and Risk of Uterine Cancer: Results From a Large Danish Population-based Cohort Study

Some epidemiologic studies have indicated that uterine cancer risk may be increased after use of fertility drugs. To further assess this association, the authors used data from a large cohort of 54,362 women diagnosed with infertility who were referred to Danish fertility clinics between 1965 and 1998. In a case-cohort study, rate ratios and 95% confidence intervals were used to assess the effects of 4 groups of fertility drugs on overall risk of uterine cancer after adjustment for potentially confounding factors. Through mid-2006, 83 uterine cancers were identified. Ever use of any fertility drug was not associated with uterine cancer risk (rate ratio (RR) = 1.10, 95% confidence interval (CI): 0.69, 1.76). However, ever use of gonadotropins (follicle-stimulating hormone and human menopausal gonadotropin) increased uterine cancer risk (RR = 2.21, 95% CI: 1.08, 4.50); the risk was primarily observed after 10 years of follow-up. Furthermore, uterine cancer risk increased with number of cycles of use for clomiphene (for ≥6 cycles, RR = 1.96, 95% CI: 1.03, 3.72) and human chorionic gonadotropin (for ≥6 cycles, RR = 2.18, 95% CI: 1.16, 4.08) but not for other gonadotropins. Use of gonadotropin-releasing hormone analogs was not associated with risk. Gonadotropins, and possibly clomiphene and human chorionic gonadotropin, may increase the risk of uterine cancer, with higher doses and longer follow-up leading to greater risk.

Apolipoprotein E Genotype, Plasma Cholesterol, and Cancer: A Mendelian Randomization Study

Observational studies have shown an association between low plasma cholesterol levels and increased risk of cancer, whereas most randomized clinical trials involving cholesterol-lowering medications have not shown this association. Between 1997 and 2002, the authors assessed the association between plasma cholesterol levels and cancer risk, free from confounding and reverse causality, in a Mendelian randomization study using apolipoprotein E (ApoE) genotype. ApoE genotype, plasma cholesterol levels, and cancer incidence and mortality were measured during a 3-year follow-up period among 2,913 participants in the Prospective Study of Pravastatin in the Elderly at Risk. Subjects within the lowest third of plasma cholesterol level at baseline had increased risks of cancer incidence (hazard ratio (HR) = 1.90, 95% confidence interval (CI): 1.34, 2.70) and cancer mortality (HR = 2.03, 95% CI: 1.23, 3.34) relative to subjects within the highest third of plasma cholesterol. However, carriers of the ApoE2 genotype (n = 332), who had 9% lower plasma cholesterol levels than carriers of the ApoE4 genotype (n = 635), did not have increased risk of cancer incidence (HR = 0.86, 95% CI: 0.50, 1.47) or cancer mortality (HR = 0.70, 95% CI: 0.30, 1.60) compared with ApoE4 carriers. These findings suggest that low cholesterol levels are not causally related to increased cancer risk.

Mammographic Screening and Risk Factors for Breast Cancer

Screening mammography can distort estimated effects in breast cancer risk models due to associations with other risk factors. Mammography information was available in the Nurses’ Health Study from 1988, and 1,815 incident breast cancers were accrued through 2000 among 55,625 women with risk factor data. Logistic models were fit for screening mammography, and inverse probability weighting was used to adjust parameters in an established breast cancer risk model. Approximately 80% of women in each 2-year follow-up period had screening mammograms, which were positively associated with history of benign breast disease, family history of breast cancer, hormone therapy, alcohol use, physical activity, multivitamins, and calcium supplements, and negatively associated with postmenopause, current smoking, and body mass index. Markers of medical attention, including hypertension, high cholesterol, and osteoarthritis, were positively associated, while cardiovascular disease was negative. Inverse probability weighting led to small changes in effects of benign breast disease, family history, and hormone therapy. An apparent reduced risk associated with current smoking in unadjusted models was eliminated after weighting. Thus, several risk factors for breast cancer and cancer diagnosis are associated with mammographic screening. Adjustment for screening had some impact on breast cancer prediction in this cohort, especially for hormone therapy and smoking.

Newly Reported Respiratory Symptoms and Conditions Among Military Personnel Deployed to Iraq and Afghanistan: A Prospective Population-based Study

Concerns about respiratory conditions have surfaced among persons deployed to Iraq and Afghanistan. Data on 46,077 Millennium Cohort Study participants who completed baseline (July 2001–June 2003) and follow-up (June 2004–February 2006) questionnaires were used to investigate 1) respiratory symptoms (persistent or recurring cough or shortness of breath), 2) chronic bronchitis or emphysema, and 3) asthma. Deployers had a higher rate of newly reported respiratory symptoms than nondeployers (14% vs. 10%), while similar rates of chronic bronchitis or emphysema (1% vs. 1%) and asthma (1% vs. 1%) were observed. Deployment was associated with respiratory symptoms in both Army (adjusted odds ratio = 1.73, 95% confidence interval: 1.57, 1.91) and Marine Corps (adjusted odds ratio = 1.49, 95% confidence interval: 1.06, 2.08) personnel, independently of smoking status. Deployment length was linearly associated with increased symptom reporting in Army personnel (P < 0.0001). Among deployers, elevated odds of symptoms were associated with land-based deployment as compared with sea-based deployment. Although respiratory symptoms were associated with deployment, inconsistency in risk with cumulative exposure time suggests that specific exposures rather than deployment in general are determinants of postdeployment respiratory illness. Significant associations seen with land-based deployment also imply that exposures related to ground combat may be important.

"Proportion Explained": A Causal Interpretation for Standard Measures of Indirect Effect?

The assessment of indirect effects is an important tool for epidemiologists interested in exploring the mechanisms of exposure-disease relations. A standard way of expressing an indirect effect is in terms of the "proportion explained"; this is the proportion of the total effect that is explained by a particular mediator (or set of mediators). There are several ways to calculate the proportion explained, based on both additive and multiplicative models. However, these standard methods (particularly those based on multiplicative models) have been criticized for lacking a causal interpretation. To address this issue, the author uses a framework of potential outcomes to define the indirect effects of interest (natural effects) and assess the correspondence between the natural effects and standard measures. The author finds that standard additive measures represent an unbiased weighted average of the effects of interest; standard multiplicative measures, on the other hand, yield a biased weighted average of these effects. If the investigator is primarily interested in whether or not an indirect effect exists, standard measures for mediation will often yield the correct answer. In contrast, if valid quantification of the indirect effect is desired, counterfactual-based methods should be used.

A Dictionary of Epidemiology, Fifth Edition: Edited by Miquel Porta

International Ethical Guidelines for Epidemiological Studies: By the Council for International Organizations of Medical Sciences (CIOMS)

RE: "GOOD SEMEN QUALITY AND LIFE EXPECTANCY: A COHORT STUDY OF 43,277 MEN"

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Prediction of Incident Stroke Events Based on Retinal Vessel Caliber: A Systematic Review and Individual-Participant Meta-Analysis

The Quality of Meta-Analyses of Genetic Association Studies: A Review With Recommendations

Association Between the Ubiquitin Carboxyl-Terminal Esterase L1 Gene (UCHL1) S18Y Variant and Parkinson's Disease: A HuGE Review and Meta-Analysis

Maternal Contributions to Preterm Delivery

Maternal Effects for Preterm Birth: A Genetic Epidemiologic Study of 630,000 Families

The Genetics of Preterm Birth: Using What We Know to Design Better Association Studies

Invited Commentary: Maternal Effects in Preterm Birth--Effects of Maternal Genotype, Mitochondrial DNA, Imprinting, or Environment?

Svensson et al. Respond to "Maternal Genes and Environment in Preterm Birth"

Timing and Trajectories of Fetal Growth Related to Cognitive Development in Childhood

Estimation of the Contribution of Non-Assisted Reproductive Technology Ovulation Stimulation Fertility Treatments to US Singleton and Multiple Births

Use of Fertility Drugs and Risk of Uterine Cancer: Results From a Large Danish Population-based Cohort Study

Apolipoprotein E Genotype, Plasma Cholesterol, and Cancer: A Mendelian Randomization Study

Mammographic Screening and Risk Factors for Breast Cancer

Newly Reported Respiratory Symptoms and Conditions Among Military Personnel Deployed to Iraq and Afghanistan: A Prospective Population-based Study

"Proportion Explained": A Causal Interpretation for Standard Measures of Indirect Effect?

A Dictionary of Epidemiology, Fifth Edition: Edited by Miquel Porta

International Ethical Guidelines for Epidemiological Studies: By the Council for International Organizations of Medical Sciences (CIOMS)

RE: "GOOD SEMEN QUALITY AND LIFE EXPECTANCY: A COHORT STUDY OF 43,277 MEN"

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Towards Reducing Disparities in Disparities Research

Discovery Properties of Genome-wide Association Signals From Cumulatively Combined Data Sets

Genetic effects for common variants affecting complex disease risk are subtle. Single genome-wide association (GWA) studies are typically underpowered to detect these effects, and combination of several GWA data sets is needed to enhance discovery. The authors investigated the properties of the discovery process in simulated cumulative meta-analyses of GWA study-derived signals allowing for potential genetic model misspecification and between-study heterogeneity. Variants with null effects on average (but also between-data set heterogeneity) could yield false-positive associations with seemingly homogeneous effects. Random effects had higher than appropriate false-positive rates when there were few data sets. The log-additive model had the lowest false-positive rate. Under heterogeneity, random-effects meta-analyses of 2–10 data sets averaging 1,000 cases/1,000 controls each did not increase power, or the meta-analysis was even less powerful than a single study (power desert). Upward bias in effect estimates and underestimation of between-study heterogeneity were common. Fixed-effects calculations avoided power deserts and maximized discovery of association signals at the expense of much higher false-positive rates. Therefore, random- and fixed-effects models are preferable for different purposes (fixed effects for initial screenings, random effects for generalizability applications). These results may have broader implications for the design and interpretation of large-scale multiteam collaborative studies discovering common gene variants.

Meta- and Pooled Analyses of the Methylenetetrahydrofolate Reductase (MTHFR) C677T Polymorphism and Colorectal Cancer: A HuGE-GSEC Review

Worldwide, over 1 million cases of colorectal cancer (CRC) were reported in 2002, with a 50% mortality rate, making CRC the second most common cancer in adults. Certain racial/ethnic populations continue to experience a disproportionate burden of CRC. A common polymorphism in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene has been associated with a lower risk of CRC. The authors performed both a meta-analysis (29 studies; 11,936 cases, 18,714 controls) and a pooled analysis (14 studies; 5,068 cases, 7,876 controls) of the C677T MTHFR polymorphism and CRC, with stratification by racial/ethnic population and behavioral risk factors. There were few studies on different racial/ethnic populations. The overall meta-analysis odds ratio for CRC for persons with the TT genotype was 0.83 (95% confidence interval (CI): 0.77, 0.90). An inverse association was observed in whites (odds ratio = 0.83, 95% CI: 0.74, 0.94) and Asians (odds ratio = 0.80, 95% CI: 0.67, 0.96) but not in Latinos or blacks. Similar results were observed for Asians, Latinos, and blacks in the pooled analysis. The inverse association between the MTHFR 677TT polymorphism and CRC was not significantly modified by smoking status or body mass index; however, it was present in regular alcohol users only. The MTHFR 677TT polymorphism seems to be associated with a reduced risk of CRC, but this may not hold true for all populations.

Genetic Variations in Xenobiotic Metabolic Pathway Genes, Personal Hair Dye Use, and Risk of Non-Hodgkin Lymphoma

From 1996 to 2000, the authors conducted a population-based case-control study among Connecticut women to test the hypothesis that genetic variation in xenobiotic metabolic pathway genes modifies the relation between hair dye use and risk of non-Hodgkin lymphoma. No effect modifications were found for women who started using hair dyes in 1980 or afterward. For women who started using hair dye before 1980 as compared with never users, a statistically significantly increased risk of non-Hodgkin lymphoma was found for carriers of CYP2C9 Ex3-52C>T TT/CT genotypes (odds ratio (OR) = 2.9, 95% confidence interval (CI): 1.4, 6.1), CYP2E1 -332T>A AT/AA genotypes (OR = 2.0, 95% CI: 1.2, 3.4), a homozygous or heterozygous 3-base-pair deletion in intron 6 of GSTM3 (OR = 2.3, 95% CI: 1.3, 4.1), GSTP1 Ex5-24A>G AA genotypes (OR = 1.8, 95% CI: 1.1, 2.9), or NAT2 genotypes conferring intermediate/rapid acetylator status (OR = 1.6, 95% CI: 1.0, 2.7). The observed associations were mainly seen for follicular lymphoma. In contrast, no significantly increased risk was observed for starting hair dye use before 1980 (relative to never use) among women who were homozygous wild-type for the CYP2C9, CYP2E1, or GSTM3 polymorphisms, women carrying 1 or 2 copies of the variant GSTP1 allele, or women who were slow NAT2 acetylators. A possible role of genetic variation in xenobiotic metabolism in the carcinogenicity of hair dye use needs to be confirmed in larger studies.

Body Size, Recreational Physical Activity, and B-Cell Non-Hodgkin Lymphoma Risk Among Women in the California Teachers Study

Nutritional status and physical activity are known to alter immune function, which may be relevant to lymphomagenesis. The authors examined body size measurements and recreational physical activity in relation to risk of B-cell non-Hodgkin lymphoma (NHL) in the prospective California Teachers Study. Between 1995 and 2007, 574 women were diagnosed with incident B-cell NHL among 121,216 eligible women aged 22–84 years at cohort entry. Multivariable-adjusted relative risks and 95% confidence intervals were estimated by fitting Cox proportional hazards models for all B-cell NHL combined and for the 3 most common subtypes: diffuse large B-cell lymphoma, follicular lymphoma, and B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma. Height was positively associated with risk of all B-cell NHLs (for >1.70 vs. 1.61–1.65 m, relative risk = 1.50, 95% confidence interval: 1.16, 1.96) and chronic lymphocytic leukemia/small lymphocytic lymphoma (relative risk = 1.93, 95% confidence interval: 1.09, 3.41). Weight and body mass index at age 18 years were positive predictors of B-cell NHL risk overall. These findings indicate that greater height, which may reflect genetics, early life immune function, infectious exposures, nutrition, or growth hormone levels, may play a role in NHL etiology. Adiposity at age 18 years may be more relevant to NHL etiology than that in later life.

Genetic Variation in the Progesterone Receptor and Metabolism Pathways and Hormone Therapy in Relation to Breast Cancer Risk

The relevance of progesterone to breast carcinogenesis is highlighted by evidence indicating that use of combined estrogen-progesterone therapy (EPT) is more strongly related to breast cancer risk than is use of unopposed estrogen therapy. However, few investigators have assessed how genetic variation in progesterone-related genes modifies the effect of EPT on risk. In an analysis combining data from 2 population-based case-control studies of postmenopausal breast cancer (1,296 cases and 1,055 controls) conducted in Washington State in 1997–1999 and 2000–2004, the authors evaluated how 51 single nucleotide polymorphisms in 7 progesterone-related genes (AKR1C1, AKR1C2, AKR1C3, CYP3A4, SRD5A1, SRD5A2, and PGR) influenced breast cancer risk. There was no appreciable association with breast cancer risk overall for any single nucleotide polymorphism. For rs2854482 in AKR1C2, carrying 1 or 2 A alleles was associated with a 2.0-fold increased breast cancer risk in EPT users (95% confidence interval: 1.0, 4.0) but not in never users (Pheterogeneity = 0.03). For rs12387 in AKR1C3, the presence of 1 or 2 G alleles was associated with a 1.5-fold increased risk among EPT users (95% confidence interval: 1.1, 2.2) but not in never users (Pheterogeneity = 0.02). Interpretation of these subgroup associations must await the results of similar studies conducted in other populations.

Physical Activity's Impact on the Association of Fat and Fiber Intake With Survival After Breast Cancer

This study examined whether, after a breast cancer diagnosis, high intake of animal fat was associated with increased breast cancer mortality and high intake of fiber was associated with decreased breast cancer mortality. Participants were 3,846 US female nurses diagnosed with stages I–III breast cancer between 1976 and 2001 and followed until death or May 2006. Breast cancer mortality was calculated according to dietary intake quintiles first assessed at least 12 months after diagnosis and was cumulatively averaged and updated. There were 446 breast cancer deaths. In simple models adjusted for time since diagnosis, age, and energy intake, animal fat intake was associated with increased breast cancer death, and cereal fiber intake was associated with reduced breast cancer death. However, no associations were found in fully adjusted models: for animal fat, the relative risks for increasing quintiles were 1.00, 0.89, 0.86, 0.85, and 0.89 (95% confidence interval: 0.61, 1.28), P = 0.68; for cereal fiber, they were 1.00, 0.95, 0.76, 0.81, and 1.00 (95% confidence interval: 0.71, 1.40), P = 0.59. Results of simple models adjusted additionally for physical activity were similar to those for full multivariate models. Results show that physical activity strongly confounds the association between diet and survival.

Postmenopausal Breast Cancer Risk and Dietary Patterns in the E3N-EPIC Prospective Cohort Study

Since evidence relating diet to breast cancer risk is not sufficiently consistent to elaborate preventive proposals, the authors examined the association between dietary patterns and breast cancer risk in a large French cohort study. The analyses included 2,381 postmenopausal invasive breast cancer cases diagnosed during a median 9.7-year follow-up period (1993–2005) among 65,374 women from the E3N-EPIC cohort. Scores for dietary patterns were obtained by factor analysis, and breast cancer hazard ratios were estimated by Cox proportional hazards regression for the highest quartile of dietary pattern score versus the lowest. Two dietary patterns were identified: "alcohol/Western" (essentially meat products, French fries, appetizers, rice/pasta, potatoes, pulses, pizza/pies, canned fish, eggs, alcoholic beverages, cakes, mayonnaise, and butter/cream) and "healthy/Mediterranean" (essentially vegetables, fruits, seafood, olive oil, and sunflower oil). The first pattern was positively associated with breast cancer risk (hazard ratio = 1.20, 95% confidence interval (CI): 1.03, 1.38; P = 0.007 for linear trend), especially when tumors were estrogen receptor-positive/progesterone receptor-positive. The "healthy/Mediterranean" pattern was negatively associated with breast cancer risk (hazard ratio = 0.85, 95% CI: 0.75, 0.95; P = 0.003 for linear trend), especially when tumors were estrogen receptor-positive/progesterone receptor-negative. Adherence to a diet comprising mostly fruits, vegetables, fish, and olive/sunflower oil, along with avoidance of Western-type foods, may contribute to a substantial reduction in postmenopausal breast cancer risk.

Association of Perfluorooctanoic Acid and Perfluorooctane Sulfonate With Serum Lipids Among Adults Living Near a Chemical Plant

Perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) are compounds that do not occur in nature but have been widely used since World War II and persist indefinitely in the environment. They are present in the serum of Americans with median levels of 4 ng/mL and 21 ng/mL, respectively. PFOA has been positively associated with cholesterol in several studies of workers. A cross-sectional study of lipids and PFOA and PFOS was conducted among 46,294 community residents aged 18 years or above, who drank water contaminated with PFOA from a chemical plant in West Virginia. The mean levels of serum PFOA and PFOS in 2005–2006 were 80 ng/mL (median, 27 ng/mL) and 22 ng/mL (median, 20 ng/mL), respectively. All lipid outcomes except high density lipoprotein cholesterol showed significant increasing trends by increasing decile of either compound; high density lipoprotein cholesterol showed no association. The predicted increase in cholesterol from lowest to highest decile for either compound was 11–12 mg/dL. The odds ratios for high cholesterol (≥240 mg/dL), by increasing quartile of PFOA, were 1.00, 1.21 (95% confidence interval (CI): 1.12, 1.31), 1.33 (95% CI: 1.23, 1.43), and 1.40 (95% CI: 1.29, 1.51) and were similar for PFOS quartiles. Because these data are cross-sectional, causal inference is limited. Nonetheless, the associations between these compounds and lipids raise concerns, given their common presence in the general population.

Correlates of Multiple Chronic Disease Behavioral Risk Factors in Canadian Children and Adolescents

The authors assessed individual, social, and school correlates of multiple chronic disease behavioral risk factors (physical inactivity, sedentary behavior, tobacco smoking, alcohol drinking, and high body mass index) in a representative sample of Canadian youth aged 10–15 years (mean = 12.5 years) attending public schools. Cross-sectional data (n = 1,747) from cycle 4 (2000–2001) of the National Longitudinal Survey of Children and Youth were used. Ordinal regression models were constructed to investigate associations between selected covariates and multiple behavioral risk-factor levels (0/1, 2, 3, or 4/5 risk factors). Older age (odds ratio (OR) = 1.95, 95% confidence interval (CI): 1.21, 3.13), caregiver smoking (OR = 1.49, 95% CI: 1.09, 2.03), reporting that most/all of one's peers smoked (OR = 7.31, 95% CI: 4.00, 13.35) or drank alcohol (OR = 3.77, 95% CI: 2.18, 6.53), and living in a lone-parent family (OR = 1.94, 95% CI: 1.31, 2.88) increased the likelihood of having multiple behavioral risk factors. Youth with high self-esteem (OR = 0.92, 95% CI: 0.85, 0.99) and youth from families with postsecondary education (OR = 0.58, 95% CI: 0.41, 0.82) were less likely to have a higher number of risk factors. Although several individual and social characteristics were associated with multiple behavioral risk factors, no school-related correlates emerged. These variables should be considered when planning prevention programs.

The Aftermath of Hip Fracture: Discharge Placement, Functional Status Change, and Mortality

The authors prospectively explored the consequences of hip fracture with regard to discharge placement, functional status, and mortality using the Survey on Assets and Health Dynamics Among the Oldest Old (AHEAD). Data from baseline (1993) AHEAD interviews and biennial follow-up interviews were linked to Medicare claims data from 1993–2005. There were 495 postbaseline hip fractures among 5,511 respondents aged ≥69 years. Mean age at hip fracture was 85 years; 73% of fracture patients were white women, 45% had pertrochanteric fractures, and 55% underwent surgical pinning. Most patients (58%) were discharged to a nursing facility, with 14% being discharged to their homes. In-hospital, 6-month, and 1-year mortality were 2.7%, 19%, and 26%, respectively. Declines in functional-status-scale scores ranged from 29% on the fine motor skills scale to 56% on the mobility index. Mean scale score declines were 1.9 for activities of daily living, 1.7 for instrumental activities of daily living, and 2.2 for depressive symptoms; scores on mobility, large muscle, gross motor, and cognitive status scales worsened by 2.3, 1.6, 2.2, and 2.5 points, respectively. Hip fracture characteristics, socioeconomic status, and year of fracture were significantly associated with discharge placement. Sex, age, dementia, and frailty were significantly associated with mortality. This is one of the few studies to prospectively capture these declines in functional status after hip fracture.

Optimizing Influenza Sentinel Surveillance at the State Level

Influenza-like illness data are collected via an Influenza Sentinel Provider Surveillance Network at the state level. Because participation is voluntary, locations of the sentinel providers may not reflect optimal geographic placement. The purpose of this study was to determine the "best" locations for sentinel providers in Iowa by using a maximal coverage model (MCM) and to compare the population coverage obtained with that of the current sentinel network. The authors used an MCM to maximize the Iowa population located within 20 miles (32.2 km) of 1–143 candidate sites and calculated the coverage provided by each additional site. The first MCM location covered 15% of the population; adding a second increased coverage to 25%. Additional locations provided more coverage but with diminishing marginal returns. In contrast, the existing 22 Iowa sentinel locations covered 56% of the population, the same coverage achieved with just 10 MCM sites. Using 22 MCM sites covered more than 75% of the population, an improvement over the current site placement, adding nearly 600,000 Iowa residents. Given scarce public health resources, MCMs can help surveillance efforts by prioritizing recruitment of sentinel locations.

Analyses of Injury Count Data: Some Do's and Don'ts

The analysis of injury data requires different considerations from the analysis of other types of outcomes because an individual can experience the outcome many times. When describing injury patterns using numerator-only data (e.g., proportion of upper-extremity injuries vs. lower-extremity injuries), simple comparisons of proportions are inappropriate because 1) individuals are compared with themselves and 2) multiple testing increases the potential for incorrect inference. Bootstrapping (resampling) techniques can be used to determine confidence intervals and whether the frequencies significantly differ across categories. When describing injury rates, the authors suggest plotting the observed injury rate against the number of exposures to obtain a visual representation of the heterogeneity of risk across individuals. Because the distribution of injury rates is often skewed, some research questions may be best addressed by comparing the weighted median injury rates instead of the weighted mean injury rates (which are given by standard formulae). Again, resampling techniques can be used to obtain a null distribution for injury rates in order to determine whether there are subjects who have unexpectedly high injury rates. More advanced analyses are required to account for multiplicity.

Applying Quantitative Bias Analysis to Epidemiologic Data: By Timothy L. Lash, Matthew P. Fox, and Aliza K. Fink

Statistical Modeling for Biomedical Researchers: A Simple Introduction to the Analysis of Complex Data, 2nd Edition: By William D. Dupont

Re: "Determinants of Quality of Interview and Impact on Risk Estimates in a Case-Control Study of Bladder Cancer"

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Re: "Methods of Covariate Selection: Directed Acyclic Graphs and the Change-in-Estimate Procedure"

Three of the Authors Reply

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Editorial: Breathing New Life Into Pneumonia Epidemiology

Socioeconomic Position and the Tracking of Physical Activity and Cardiorespiratory Fitness From Childhood to Adulthood

This study examined the influence of childhood socioeconomic position (SEP) and social mobility on activity and fitness tracking from childhood into adulthood. In a prospective cohort of 2,185 Australian adults (aged 26–36 years), first examined in 1985 (at ages 7–15 years), self-reported physical activity and cardiorespiratory fitness (subsample only) were measured. SEP measures included retrospectively reported parental education (baseline) and own education (follow-up). There was little evidence of a relation between childhood SEP and activity tracking, but high childhood SEP (maternal education) was associated with a 59% increased likelihood of persistent fitness, and medium childhood SEP (paternal and parental education) was associated with a 33%–36% decreased likelihood of persistent fitness. Upward social mobility was associated with a greater likelihood of increasing activity (38%–49%) and fitness (90%), and persistently high SEP was associated with a greater likelihood of increasing activity (males: 58%) and fitness (males and females combined: 89%). In conclusion, persistently high SEP and upward social mobility were associated with increases in activity and fitness from childhood to adulthood. Findings highlight socioeconomic differentials in activity and fitness patterns and suggest that improvements in education may represent a pathway through which physical activity levels can be increased and health benefits achieved.

Invited Commentary: Physical Activity Over the Life Course--Whose Behavior Changes, When, and Why?

Physical activity tends to decline from childhood into adulthood. Maintaining high levels of physical activity throughout life is therefore an important public health objective. Relatively little is known about changes in physical activity behavior over the life course, the domains of physical activity in which they occur, the characteristics of those whose physical activity declines, and the factors associated with such changes. In the future, incorporating more accurate measures of physical activity in large population studies would help to establish more accurate estimates of associations in this area. Determinants of behavior change, including the effects of socioeconomic position and social mobility on physical activity and fitness, are likely to change constantly throughout life, but it is largely unknown which determinants are most important at each life stage, let alone whether and at what times those determinants change. Better evidence on determinants of behavior change throughout the life course would contribute greatly to understanding when and how to intervene to help create and sustain lifelong healthy behavior patterns in those who have the most to gain from adopting them.

Cleland et al. Respond to "Physical Activity Over the Life Course"

Declines in Physical Activity and Higher Systolic Blood Pressure in Adolescence

The authors examined the potential association between changes in the number of moderate-to-vigorous physical activity (MVPA) sessions per week, adiposity, and systolic blood pressure (SBP) during adolescence. SBP and anthropometric factors were assessed biannually (1999/2000, 2002, and 2004) in a cohort of 1,293 Canadian adolescents aged 12–13 years in 1999. Self-reported 7-day recall data on MVPA sessions ≥5 minutes in duration were collected every 3 months over the 5-year period. Estimates of initial level and rate of decline in number of MVPA sessions per week from individual growth models were used as predictors of SBP in linear regression models. A decline of 1 MVPA session per week with each year of age was associated with 0.29-mm Hg and 0.19-mm Hg higher SBPs in girls and boys, respectively, in early adolescence (ages 12.8–15.1 years) and 0.40-mm Hg and 0.18-mm Hg higher SBPs, respectively, in late adolescence (ages 15.2–17.0 years). The associations were not attenuated by changes in body mass index, waist circumference, or skinfold thickness in girls during late adolescence. Although weaker, associations were evident in boys during late adolescence, as well as in both girls and boys during early adolescence. These results support prevention of declines in MVPA during adolescence to prevent higher blood pressure in youth.

Recreational Physical Activity and Steroid Hormone Levels in Postmenopausal Women

Recreational physical activity has been both positively and inversely associated with cancer risk for postmenopausal women, acting presumably through hormonal mechanisms. Relatively little is known about the effects of exercise on postmenopausal steroid hormone levels. The authors evaluated the association between recreational activity and plasma steroid hormones among 623 US healthy, postmenopausal women in the Nurses’ Health Study not using exogenous hormones at the time of blood draw (1989–1990). Participants self-reported recreational physical activity by questionnaire in 1986, 1988, and 1992. Plasma samples were assayed for estrogens, androgens, and sex hormone-binding globulin. Geometric mean hormone levels adjusted and not adjusted for body mass index were calculated. In general, estrogen and androgen levels were lower in the most- and the least-active women compared with those reporting moderate activity, suggesting a U-shaped relation. For example, estrone sulfate levels in quintiles 1–5 of metabolic equivalent task-hours were 197, 209, 222, 214, and 195 pg/mL, respectively. Tests for nonlinearity using polynomial regression were significant for several estrogens, androgens, and sex hormone-binding globulin (2-sided P ≤ 0.01). These results suggest the possibility of a nonlinear relation between recreational physical activity and hormone levels in postmenopausal women.

Prospective Study of Urban Form and Physical Activity in the Black Women's Health Study

The authors used data from the Black Women's Health Study to assess the association between neighborhood urban form and physical activity. Women reported hours/week of utilitarian and exercise walking and of vigorous activity in 1995 and on biennial follow-up questionnaires through 2001. Housing density, road networks, availability of public transit, sidewalks, and parks were characterized for the residential neighborhoods of 20,354 Black Women's Health Study participants living in New York, New York; Chicago, Illinois; and Los Angeles, California. The authors quantified the associations between features of the environment and physical activity using odds ratios for ≥5 relative to <5 hours/week of physical activity. For all women, housing density had the strongest association with utilitarian walking (odds ratio for the most- compared with the least-dense quintile = 2.72, 95% confidence interval: 2.22, 3.31), followed by availability of public transit. Women who moved during follow-up to neighborhoods of lower density were 36% more likely to decrease their levels of utilitarian walking, and those who moved to neighborhoods of higher density were 23% more likely to increase their levels of utilitarian walking, relative to women who moved to neighborhoods of similar density. These data suggest that increases in housing density may lead to increases in utilitarian walking among African-American women.

Risk of Autism and Increasing Maternal and Paternal Age in a Large North American Population

Previous studies are inconsistent regarding whether there are independent effects of maternal and paternal age on the risk of autism. Different biologic mechanisms are suggested by maternal and paternal age effects. The study population included all California singletons born in 1989–2002 (n = 7,550,026). Children with autism (n = 23,311) were identified through the California Department of Developmental Services and compared with the remainder of the study population, with parental ages and covariates obtained from birth certificates. Adjusted odds ratios and 95% confidence intervals were used to evaluate the risk of autism associated with increasing maternal and paternal age. In adjusted models that included age of the other parent and demographic covariates, a 10-year increase in maternal age was associated with a 38% increase in the odds ratio for autism (odds ratio = 1.38, 95% confidence interval: 1.32, 1.44), and a 10-year increase in paternal age was associated with a 22% increase (odds ratio = 1.22, 95% confidence interval: 1.18, 1.26). Maternal and paternal age effects were seen in subgroups defined by race/ethnicity and other covariates and were of greater magnitude among first-born compared with later-born children. Further studies are needed to help clarify the biologic mechanisms involved in the independent association of autism risk with increasing maternal and paternal age.

Antenatal and Postnatal Iron Supplementation and Childhood Mortality in Rural Nepal: A Prospective Follow-up in a Randomized, Controlled Community Trial

The long-term benefits of antenatal iron supplementation in child survival are not known. In 1999–2001, 4,926 pregnant women in rural Nepal participated in a cluster-randomized, double-masked, controlled trial involving 4 alternative combinations of micronutrient supplements, each containing vitamin A. The authors examined the impact on birth weight and early infant mortality in comparison with controls, who received vitamin A only. They followed the surviving offspring of these women at approximately age 7 years to study effects of in utero supplementation on survival. Of 4,130 livebirths, 209 infants died in the first 3 months and 8 were lost to follow-up. Of those remaining, 3,761 were followed, 150 died between ages 3 months and 7 years, and 152 were lost to follow-up. Mortality rates per 1,000 child-years from birth to age 7 years differed by maternal supplementation group, as follows: folic acid, 13.4; folic acid-iron, 10.3; folic acid-iron-zinc, 12.0; multiple micronutrients; 14.0; and controls, 15.2. Hazard ratios were 0.90 (95% confidence interval (CI): 0.65, 1.22), 0.69 (95% CI: 0.49, 0.99), 0.80 (95% CI: 0.58, 1.11), and 0.93 (95% CI: 0.66, 1.31), respectively, in the 4 supplementation groups. Maternal iron-folic acid supplementation reduced mortality among these children by 31% between birth and age 7 years. These results provide additional motivation for strengthening antenatal iron-folic acid programs.

Maternal Licorice Consumption and Detrimental Cognitive and Psychiatric Outcomes in Children

Overexposure to glucocorticoids may link prenatal adversity with detrimental outcomes in later life. Glycyrrhiza, a natural constituent of licorice, inhibits placental 11-beta-hydroxysteroid dehydrogenase type 2, the feto-placental "barrier" to higher maternal levels of cortisol. The authors studied whether prenatal exposure to glycyrrhiza in licorice exerts detrimental effects on cognitive performance (subtests of the Wechsler Intelligence Scale for Children III as well as the Children's Developmental Neuropsychological Assessment and the Beery Developmental Test of Visual-Motor Integration) and psychiatric symptoms (Child Behavior Checklist) in 321 Finnish children 8.1 years of age born in 1998 as healthy singletons at 35–42 weeks of gestation. In comparison to the group with zero–low glycyrrhiza exposure (0–249 mg/week), those with high exposure (≥500 mg/week) had significant decrements in verbal and visuospatial abilities and in narrative memory (range of mean differences in standard deviation units, –0.31 to –0.41; P < 0.05) and significant increases in externalizing symptoms and in attention, rule-breaking, and aggression problems (range of odds ratios, 2.15 to 3.43; P < 0.05). The effects on cognitive performance appeared dose related. Data are compatible with adverse fetal "programming" by overexposure to glucocorticoids and caution against excessive intake of licorice-containing foodstuffs during pregnancy.

Association of White Matter Lesions and Lacunar Infarcts With Executive Functioning: The SMART-MR Study

The authors investigated the association of white matter lesions and lacunar infarcts with cognitive performance and whether brain atrophy mediates these associations. Within the Second Manifestations of Arterial Disease-Magnetic Resonance study (2001–2005, the Netherlands), cross-sectional analyses of 522 patients were performed (mean age, 57 years (standard deviation, 10); 76% male). Brain segmentation was used to quantify volumes of brain tissue, cerebrospinal fluid, and white matter lesions. Infarcts were rated visually. Brain volume, ventricular volume, and gray matter volume were divided by intracranial volume to obtain indicators of brain atrophy. Neuropsychological tests assessing executive functioning and memory were performed, and scores were transformed into z scores. The authors used linear regression analyses, adjusted for age, sex, education, intelligence, and vascular risk factors, to investigate the association of white matter lesions and number of lacunar infarcts with cognitive performance. A 1-standard-deviation higher volume of white matter lesions (β = –0.12, 95% confidence interval: –0.20, –0.04) and the presence of ≥2 lacunar infarcts (β = –0.48, 95% confidence interval: –0.87, –0.09) were associated with worse executive functioning. These associations remained after adjusting for brain atrophy. Both were not associated with worse memory. Results suggest that subcortical ischemic vascular lesions are associated with decreased executive functioning, but not with memory functioning, independent of brain atrophy.

Blood Cadmium and Lead and Chronic Kidney Disease in US Adults: A Joint Analysis

Environmental cadmium and lead exposures are widespread, and both metals are nephrotoxic at high exposure levels. Few studies have evaluated the associations between low-level cadmium and clinical renal outcomes, particularly with respect to joint cadmium and lead exposure. The geometric mean levels of blood cadmium and lead were 0.41 µg/L (3.65 nmol/L) and 1.58 µg/dL (0.076 µmol/L), respectively, in 14,778 adults aged ≥20 years who participated in the National Health and Nutrition Examination Survey (1999–2006). After adjustment for survey year, sociodemographic factors, chronic kidney disease risk factors, and blood lead, the odds ratios for albuminuria (≥30 mg/g creatinine), reduced estimated glomerular filtration rate (eGFR) (<60 mL/minute/1.73 m2), and both albuminuria and reduced eGFR were 1.92 (95% confidence interval (CI): 1.53, 2.43), 1.32 (95% CI: 1.04, 1.68), and 2.91 (95% CI: 1.76, 4.81), respectively, comparing the highest with the lowest blood cadmium quartiles. The odds ratios comparing participants in the highest with the lowest quartiles of both cadmium and lead were 2.34 (95% CI: 1.72, 3.18) for albuminuria, 1.98 (95% CI: 1.27, 3.10) for reduced eGFR, and 4.10 (95% CI: 1.58, 10.65) for both outcomes. These findings support consideration of cadmium and lead as chronic kidney disease risk factors in the general population and provide novel evidence of risk with environmental exposure to both metals.

Meat and Meat-related Compounds and Risk of Prostate Cancer in a Large Prospective Cohort Study in the United States

The authors examined associations between meat consumption (type, cooking method, and related mutagens), heme iron, nitrite/nitrate, and prostate cancer in a cohort of 175,343 US men aged 50–71 years. During 9 years of follow-up (1995–2003), they ascertained 10,313 prostate cancer cases (1,102 advanced) and 419 fatal cases. Hazard ratios comparing the fifth intake quintile with the first revealed elevated risks associated with red and processed meat for total (red meat: hazard ratio (HR) = 1.12, 95% confidence interval (CI): 1.04, 1.21; processed meat: HR = 1.07, 95% CI: 1.00, 1.14) and advanced (red meat: HR = 1.31, 95% CI: 1.05, 1.65; processed meat: HR = 1.32, 95% CI: 1.08, 1.61) prostate cancer. Heme iron, barbecued/grilled meat, and benzo[a]pyrene were all positively associated with total (HR = 1.09 (95% CI: 1.02, 1.17), HR = 1.11 (95% CI: 1.03, 1.19), and HR = 1.09 (95% CI: 1.00, 1.18), respectively) and advanced (HR = 1.28 (95% CI: 1.03, 1.58), HR = 1.36 (95% CI: 1.10, 1.69), and HR = 1.28 (95% CI: 1.00, 1.65), respectively) disease. Nitrite (HR = 1.24, 95% CI: 1.02, 1.51) and nitrate (HR = 1.31, 95% CI: 1.07, 1.61) intakes were associated with advanced prostate cancer. There were no clear associations for fatal prostate cancer. Red and processed meat may be positively associated with prostate cancer via mechanisms involving heme iron, nitrite/nitrate, grilling/barbecuing, and benzo[a]pyrene.

Using Time-dependent Covariate Analysis to Elucidate the Relation of Smoking History to Warthin's Tumor Risk

The authors aimed to elucidate the relation of the time-dependent smoking history parameters—age at smoking initiation and smoking intensity, duration, and latency—to the risk of Warthin's tumor, a benign tumor of the salivary gland for which cigarette smoking is a strong risk factor. They studied 117 cases of Warthin's tumor and 336 matched controls included in an Israeli nationwide case-control study of parotid gland tumors conducted from 2002 to 2003 by using the Cox regression model with time-dependent covariates, with age as the time axis. When current age and smoking duration were included in the statistical model, the authors show that the coefficient of a latency variable does not represent latency as such, but a balancing of the effects of age at initiation and time since cessation. They found a strong positive linear effect of duration of smoking, together with a positive nonlinear effect of intensity that levels off at higher intensities, and a negative effect of latency from 25 years onward. The latter finding implies that the effect of time since cessation dominates the effect of age at initiation, with risk decreasing sharply after smoking cessation. The relation of smoking variables to Warthin's tumor agrees with the patterns reported for lung cancer.

Using a Longitudinal Model to Estimate the Effect of Methicillin-resistant Staphylococcus aureus Infection on Length of Stay in an Intensive Care Unit

Health-care-associated methicillin-resistant Staphylococcus aureus (MRSA) infection may cause increased hospital stay, or sometimes death. Quantifying this effect is complicated because the exposure is time dependent: infection may prolong hospital stay, while longer stays increase infection risk. In this paper, the authors overcome these problems by using a multinomial longitudinal model to estimate the daily probability of death and discharge. They then extend the basic model to estimate how the effect of MRSA infection varies over time and to quantify number of excess days in the intensive care unit due to infection. They found that infection decreased the relative risk of discharge (relative risk ratio = 0.68, 95% credible interval: 0.54, 0.82). Infection on the first day of admission resulted in a mean extra stay of 0.3 days (95% credible interval: 0.1, 0.5) for a patient with an Acute Physiology and Chronic Health Evaluation II score of 10 and 1.2 days (95% credible interval: 0.5, 2.0) for a patient with a score of 30. The decrease in the relative risk of discharge remained fairly constant with day of MRSA infection but was slightly stronger closer to the start of infection. Results confirm the importance of MRSA infection in increasing stay in an intensive care unit but suggest that previous work may have systematically overestimated the effect size.

Volume 138 Issue 01

Epidemiology and Infection, Volume 138 Issue 01 Increased frequency in 2007 - now 8 issues per year! Epidemiology and Infection publishes original reports and reviews on all aspects of infection in humans and animals. Particular emphasis is given to the epidemiology, prevention and control of infectious diseases. The field covered is broad and includes the zoonoses, tropical infections, food hygiene, vaccine studies, statistics and the clinical, social and public-health aspects of infectious disease. Papers covering microbiology and immunology which have an epidemiological relevance are part of this broad field. Papers come from medical and veterinary scientists worldwide. It has become the key periodical in which to find the latest reports on recently discovered infections and new technology. For those concerned with policy and planning for the control of infections, the papers on mathematical modelling of epidemics caused by historical, current and emergent infections, will be of particular value. To celebrate 100 years of the journal, a series of important papers has been selected and each, together with a modern commentary on the paper by an expert, will be published on-line. This journal has now moved over to electronic submission, using the Scholar One system. Click here to go to the submission website. Guidance on how to upload your manuscript is available on the site by clicking "User Tutorials". Online manuscript submission (now) available, please go to http://mc.manuscriptcentral.com/cup/hyg

HYG volume 138 issue 1 Cover and Front matter

Miscellaneous Epidemiology and Infection, Volume 138 Issue 01 , pp f1-f2Abstract

HYG volume 138 issue 1 Cover and Back matter

Miscellaneous Epidemiology and Infection, Volume 138 Issue 01 , pp b1-b2Abstract

Using syndromic surveillance systems to detect pneumonic plague

Review ArticlesS. M. BABIN, Epidemiology and Infection, Volume 138 Issue 01 , pp 1-8Abstract

Geographical variation of sporadic Legionnaires' disease analysed in a grid model

Research ArticlesM. RUDBECK, M. R. JEPSEN, I. B. SONNE, S. A. ULDUM, S. VISKUM, K. MØLBAK, Epidemiology and Infection, Volume 138 Issue 01 , pp 9-14Abstract

An outbreak of Pontiac fever due to Legionella longbeachae serogroup 2 found in potting mix in a horticultural nursery in New Zealand

Brief ReportG. J. CRAMP, D. HARTE, N. M. DOUGLAS, F. GRAHAM, M. SCHOUSBOE, K. SYKES, Epidemiology and Infection, Volume 138 Issue 01 , pp 15-20Abstract

Coxiella burnetii (Q fever) seroprevalence in cattle

Research ArticlesC. McCAUGHEY, L. J. MURRAY, J. P. McKENNA, F. D. MENZIES, S. J. McCULLOUGH, H. J. O'NEILL, D. E. WYATT, C. R. CARDWELL, P. V. COYLE, Epidemiology and Infection, Volume 138 Issue 01 , pp 21-27Abstract

Enterobius vermicularis infection in schoolchildren: a large-scale survey 6 years after a population-based control

Research ArticlesL.-C. WANG, K.-P. HWANG, E.-R. CHEN, Epidemiology and Infection, Volume 138 Issue 01 , pp 28-36Abstract

Prevalence of Burkholderia pseudomallei in Guangxi, China

Brief ReportG. MA, D. ZHENG, Q. CAI, Z. YUAN, Epidemiology and Infection, Volume 138 Issue 01 , pp 37-39Abstract

High prevalence of HBV genotype D in Syria and the clinical characteristics of hepatitis B e antigen-negative chronic hepatitis B

Research ArticlesN. ANTAKI, S. HAFFAR, S. ALI DEEB, F. ASSAAD, R. ABOU HARB, N. ZEIBANE, M. NASSERELDDINE, N. IBRAHIM, N. ALHAJ, E. JABBOUR, R. AARAJ, F. ANTAKI, K. KEBBEWAR, Epidemiology and Infection, Volume 138 Issue 01 , pp 40-44Abstract

Can we know the immunization status of healthcare workers? Results of a feasibility study in hospital trusts, England, 2008

Research ArticlesL. PEZZOLI, K. NOAKES, P. GATES, F. BEGUM, R. G. PEBODY, Epidemiology and Infection, Volume 138 Issue 01 , pp 45-52Abstract

Streptococcus pyogenes emm and T types within a decade, 1996–2005: implications for epidemiology and future vaccines

Research ArticlesR. NIR-PAZ, Z. KORENMAN, M. RON, A. MICHAEL-GAYEGO, R. COHEN-PORADOSU, L. VALINSKY, B. BEALL, A. E. MOSES, Epidemiology and Infection, Volume 138 Issue 01 , pp 53-60Abstract

Serotype and antibiotic resistance of isolates from patients with invasive pneumococcal disease in Japan

Research ArticlesN. CHIBA, M. MOROZUMI, K. SUNAOSHI, S. TAKAHASHI, M. TAKANO, T. KOMORI, K. SUNAKAWA, K. UBUKATA, Epidemiology and Infection, Volume 138 Issue 01 , pp 61-68Abstract

Experience with an external quality assurance scheme for antimicrobial susceptibility testing of Neisseria gonorrhoeae in India, 2001–2007

Research ArticlesM. BALA, J. W. TAPSALL, A. LIMNIOS, S. SOOD, K. RAY, Epidemiology and Infection, Volume 138 Issue 01 , pp 69-75Abstract

Characterization and epidemiological relationships of Spanish Brachyspira hyodysenteriae field isolates

Research ArticlesÁ. HIDALGO, A. CARVAJAL, M. PRINGLE, P. RUBIO, C. FELLSTRÖM, Epidemiology and Infection, Volume 138 Issue 01 , pp 76-85Abstract

Quinolone-resistant Salmonella Typhi in South Africa, 2003–2007

Brief ReportA. M. SMITH, N. GOVENDER, K. H. KEDDY, Epidemiology and Infection, Volume 138 Issue 01 , pp 86-90Abstract

Environmental and ecological potential for enzootic cycles of Puumala hantavirus in Great Britain

Research ArticlesE. BENNETT, J. CLEMENT, P. SANSOM, I. HALL, S. LEACH, J. M. MEDLOCK, Epidemiology and Infection, Volume 138 Issue 01 , pp 91-98Abstract

Relationship of cholera incidence to El Niño and solar activity elucidated by time-series analysis

Research ArticlesK. OHTOMO, N. KOBAYASHI, A. SUMI, N. OHTOMO, Epidemiology and Infection, Volume 138 Issue 01 , pp 99-107Abstract

Episodic outbreaks bias estimates of age-specific force of infection: a corrected method using measles as an example

Research ArticlesM. J. FERRARI, A. DJIBO, R. F. GRAIS, B. T. GRENFELL, O. N. BJØRNSTAD, Epidemiology and Infection, Volume 138 Issue 01 , pp 108-116Abstract

Respiratory symptoms and the case definition of gastroenteritis: an international analysis of the potential impact on burden estimates

Research ArticlesG. HALL, L. McDONALD, S. E. MAJOWICZ, E. SCALLAN, M. KIRK, P. SOCKETT, F. J. ANGULO, Epidemiology and Infection, Volume 138 Issue 01 , pp 117-124Abstract

Critical parameters for modelling the spread of foot-and-mouth disease in wildlife

Research ArticlesL. D. HIGHFIELD, M. P. WARD, S. W. LAFFAN, B. NORBY, G. G. WAGNER, Epidemiology and Infection, Volume 138 Issue 01 , pp 125-138Abstract

Initial high rate of misdiagnosis in Crimean Congo haemorrhagic fever patients in an endemic region of Turkey

Research ArticlesN. TASDELEN FISGIN, L. DOGANCI, E. TANYEL, N. TULEK, Epidemiology and Infection, Volume 138 Issue 01 , pp 139-144Abstract

Editorial - ETOX turned twenty

Pathogenomics of mobile genetic elements of toxigenic bacteria

Host cell modulation by human, animal and plant pathogens

In silico identification of novel bacterial ADP-ribosyltransferases

The multi-talented bacterial adenylate cyclases

Pathways followed by protein toxins into cells

Retrograde transport of cholera toxin into the ER of host cells

Analysing the action of bacterial toxins in living cells with fluorescence resonance energy transfer (FRET)

The Pasteurella multocida toxin interacts with signalling pathways to perturb cell growth and differentiation

E. coli CNF1 toxin: a two-in-one system for host-cell invasion

Molecular and cell biology of Legionella pneumophila

Superantigens: Structure-function relationships

Novel activities of the Helicobacter pylori vacuolating cytotoxin: from epithelial cells towards the immune system

Exploitation of host cells by Burkholderia pseudomallei

Clostridium botulinum C2 toxin - New insights into the cellular up-take of the actin-ADP-ribosylating toxin

Inverted pathogenicity: the use of pathogen-specific molecular mechanisms for prevention or therapy of disease

The adenylate cyclase toxin from Bordetella pertussis - a novel promising vehicle for antigen delivery to dendritic cells

Recombinant immunotoxins for treating cancer

Bordetella pertussis: from functional genomics to intranasal vaccination

The multiple cellular activities of the VacA cytotoxin of Helicobacter pylori

Pore worms: Using Caenorhabditis elegans to study how bacterial toxins interact with their target host

Enterococcal cytolysin: activities and association with other virulence traits in a pathogenicity island

In vivo Bacillus anthracis gene expression requires PagR as an intermediate effector of the AtxA signalling cascade

Microbiology RSS : Gourt

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Table of contents

Prediction of Incident Stroke Events Based on Retinal Vessel Caliber: A Systematic Review and Individual-Participant Meta-Analysis

The Quality of Meta-Analyses of Genetic Association Studies: A Review With Recommendations

Association Between the Ubiquitin Carboxyl-Terminal Esterase L1 Gene (UCHL1) S18Y Variant and Parkinson's Disease: A HuGE Review and Meta-Analysis

Maternal Contributions to Preterm Delivery

Maternal Effects for Preterm Birth: A Genetic Epidemiologic Study of 630,000 Families

The Genetics of Preterm Birth: Using What We Know to Design Better Association Studies

Invited Commentary: Maternal Effects in Preterm Birth--Effects of Maternal Genotype, Mitochondrial DNA, Imprinting, or Environment?

Svensson et al. Respond to "Maternal Genes and Environment in Preterm Birth"

Timing and Trajectories of Fetal Growth Related to Cognitive Development in Childhood

Estimation of the Contribution of Non-Assisted Reproductive Technology Ovulation Stimulation Fertility Treatments to US Singleton and Multiple Births

Use of Fertility Drugs and Risk of Uterine Cancer: Results From a Large Danish Population-based Cohort Study

Apolipoprotein E Genotype, Plasma Cholesterol, and Cancer: A Mendelian Randomization Study

Mammographic Screening and Risk Factors for Breast Cancer

Newly Reported Respiratory Symptoms and Conditions Among Military Personnel Deployed to Iraq and Afghanistan: A Prospective Population-based Study

"Proportion Explained": A Causal Interpretation for Standard Measures of Indirect Effect?

A Dictionary of Epidemiology, Fifth Edition: Edited by Miquel Porta

International Ethical Guidelines for Epidemiological Studies: By the Council for International Organizations of Medical Sciences (CIOMS)

RE: "GOOD SEMEN QUALITY AND LIFE EXPECTANCY: A COHORT STUDY OF 43,277 MEN"

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Prediction of Incident Stroke Events Based on Retinal Vessel Caliber: A Systematic Review and Individual-Participant Meta-Analysis

The Quality of Meta-Analyses of Genetic Association Studies: A Review With Recommendations

Association Between the Ubiquitin Carboxyl-Terminal Esterase L1 Gene (UCHL1) S18Y Variant and Parkinson's Disease: A HuGE Review and Meta-Analysis

Maternal Contributions to Preterm Delivery

Maternal Effects for Preterm Birth: A Genetic Epidemiologic Study of 630,000 Families

The Genetics of Preterm Birth: Using What We Know to Design Better Association Studies

Invited Commentary: Maternal Effects in Preterm Birth--Effects of Maternal Genotype, Mitochondrial DNA, Imprinting, or Environment?

Svensson et al. Respond to "Maternal Genes and Environment in Preterm Birth"

Timing and Trajectories of Fetal Growth Related to Cognitive Development in Childhood

Estimation of the Contribution of Non-Assisted Reproductive Technology Ovulation Stimulation Fertility Treatments to US Singleton and Multiple Births

Use of Fertility Drugs and Risk of Uterine Cancer: Results From a Large Danish Population-based Cohort Study

Apolipoprotein E Genotype, Plasma Cholesterol, and Cancer: A Mendelian Randomization Study

Mammographic Screening and Risk Factors for Breast Cancer

Newly Reported Respiratory Symptoms and Conditions Among Military Personnel Deployed to Iraq and Afghanistan: A Prospective Population-based Study

"Proportion Explained": A Causal Interpretation for Standard Measures of Indirect Effect?

A Dictionary of Epidemiology, Fifth Edition: Edited by Miquel Porta

International Ethical Guidelines for Epidemiological Studies: By the Council for International Organizations of Medical Sciences (CIOMS)

RE: "GOOD SEMEN QUALITY AND LIFE EXPECTANCY: A COHORT STUDY OF 43,277 MEN"

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Towards Reducing Disparities in Disparities Research

Discovery Properties of Genome-wide Association Signals From Cumulatively Combined Data Sets

Meta- and Pooled Analyses of the Methylenetetrahydrofolate Reductase (MTHFR) C677T Polymorphism and Colorectal Cancer: A HuGE-GSEC Review

Genetic Variations in Xenobiotic Metabolic Pathway Genes, Personal Hair Dye Use, and Risk of Non-Hodgkin Lymphoma

Body Size, Recreational Physical Activity, and B-Cell Non-Hodgkin Lymphoma Risk Among Women in the California Teachers Study

Genetic Variation in the Progesterone Receptor and Metabolism Pathways and Hormone Therapy in Relation to Breast Cancer Risk

Physical Activity's Impact on the Association of Fat and Fiber Intake With Survival After Breast Cancer

Postmenopausal Breast Cancer Risk and Dietary Patterns in the E3N-EPIC Prospective Cohort Study

Association of Perfluorooctanoic Acid and Perfluorooctane Sulfonate With Serum Lipids Among Adults Living Near a Chemical Plant

Correlates of Multiple Chronic Disease Behavioral Risk Factors in Canadian Children and Adolescents

The Aftermath of Hip Fracture: Discharge Placement, Functional Status Change, and Mortality

Optimizing Influenza Sentinel Surveillance at the State Level

Analyses of Injury Count Data: Some Do's and Don'ts

Applying Quantitative Bias Analysis to Epidemiologic Data: By Timothy L. Lash, Matthew P. Fox, and Aliza K. Fink

Statistical Modeling for Biomedical Researchers: A Simple Introduction to the Analysis of Complex Data, 2nd Edition: By William D. Dupont

Re: "Determinants of Quality of Interview and Impact on Risk Estimates in a Case-Control Study of Bladder Cancer"

Three Authors Reply

Re: "Methods of Covariate Selection: Directed Acyclic Graphs and the Change-in-Estimate Procedure"

Three of the Authors Reply

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Editorial: Breathing New Life Into Pneumonia Epidemiology

Socioeconomic Position and the Tracking of Physical Activity and Cardiorespiratory Fitness From Childhood to Adulthood

Invited Commentary: Physical Activity Over the Life Course--Whose Behavior Changes, When, and Why?

Cleland et al. Respond to "Physical Activity Over the Life Course"

Declines in Physical Activity and Higher Systolic Blood Pressure in Adolescence

Recreational Physical Activity and Steroid Hormone Levels in Postmenopausal Women

Prospective Study of Urban Form and Physical Activity in the Black Women's Health Study

Risk of Autism and Increasing Maternal and Paternal Age in a Large North American Population