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A Field Synopsis and Meta-Analysis of Genetic Association Studies in Peripheral Arterial Disease: The CUMAGAS-PAD Database

In an electronic search of the literature, the authors systematically retrieved all published studies that investigated genetic susceptibility to peripheral arterial disease (PAD). They created a comprehensive database of all eligible studies, collecting detailed genetic and bioinformatics data on each polymorphism. Data from eligible studies were synthesized using meta-analysis techniques. Gene variants were classified into distinct pathophysiologic pathways, and their potential involvement in PAD pathogenesis was determined. Forty-one publications that examined 44 gene polymorphisms were included. For 37 polymorphisms, the variant form had a functional effect. Twenty-three polymorphisms in 22 potential PAD candidate genes (F2, FGB, MTHFR, ITGB3, ACE, AGT, IL6, CCL2, ICAM1, SELE, MMP9, PPARG, MMP1, ADD1, P2RY12, LIPC, PLA2G7, SCARB1, MMP3, MTTP, LPA, CHRNA3) showed a significant association in individual studies. Eighty-eight percent of the studies had statistical power of less than 50%, and in 15 studies the genotype distribution in the control group did not conform to Hardy-Weinberg equilibrium. Data on 12 polymorphisms (F5 1691 G/A, MTHFR 677C/T, F2 20210 G/A, ITGB3 1565 T/C, ACE I/D, AGT 704C/T, AGT -6G/A, AGT 733C/T, IL6 -174 G/C, MMP9 -1562C/T, ICAM1 1462A/G, CHRNA3 831C/T) were synthesized, and a positive association was found for 3 (IL6 -174 G/C, ICAM1 1462A/G, CHRNA3 831C/T).

Benefits and Risks of Postmenopausal Hormone Therapy When It Is Initiated Soon After Menopause

The authors further analyzed results from the Women's Health Initiative randomized trials (1993–2004) of conjugated equine estrogens, with or without medroxyprogesterone acetate, focusing on health benefits versus risks among women who initiated hormone therapy soon after menopause. Data from the Women's Health Initiative observational study (1993–2004) were included in some analyses for additional precision. Results are presented here for incident coronary heart disease, stroke, venous thromboembolism, breast cancer, colorectal cancer, endometrial cancer, or hip fracture; death from other causes; a summary global index; total cancer; and total mortality. Hazard ratios for breast cancer and total cancer were comparatively higher (P < 0.05) among women who initiated hormone therapy soon after menopause, for both regimens. Among these women, use of conjugated equine estrogens appeared to produce elevations in venous thromboembolism and stroke and a reduction in hip fracture. Estrogen plus progestin results among women who initiated use soon after menopause were similar for venous thromboembolism, stroke, and hip fracture but also included evidence of longer-term elevations in breast cancer, total cancer, and the global index. These analyses provide little support for the hypothesis of favorable effects among women who initiate postmenopausal estrogen use soon after menopause, either for coronary heart disease or for health benefits versus risk indices considered.

Invited Commentary: Hormone Therapy Risks and Benefits--The Women's Health Initiative Findings and the Postmenopausal Estrogen Timing Hypothesis

Worldwide evidence on menopausal hormone therapy shows that it does not reduce coronary heart disease (CHD) risk and that it increases the risks of breast cancer, stroke, and venous thromboembolism. These risks are not offset by reductions in hip fracture risk. Consequently, the Food and Drug Administration and other drug regulatory authorities agree that hormone therapy should be used chiefly for short-term relief of menopausal symptoms. Continuing speculation relates to the "postmenopausal estrogen timing" hypothesis, which proposes that hormone therapy initiated soon after menopause will prevent CHD while therapy started later will have a null or adverse effect. The detailed analyses of Women's Health Initiative data reviewed here specifically address the timing hypothesis. For hormone therapy initiated soon after menopause versus therapy started later, the findings demonstrate 1) similar null or adverse effects on CHD risk; 2) similar adverse effects on the risks of stroke and venous thrombosis; and 3) possibly greater adverse effects on breast cancer risk. Therefore, Women's Health Initiative data do not support the hypothesis of favorable effects in women starting hormone therapy soon after menopause. Hence, the overall trial findings, including net harm for combined estrogen-progestin and the lack of a net benefit for estrogen-only therapy, also apply to women initiating hormone therapy soon after menopause.

Fast-Food Consumption, Diet Quality, and Neighborhood Exposure to Fast Food: The Multi-Ethnic Study of Atherosclerosis

The authors examined associations among fast-food consumption, diet, and neighborhood fast-food exposure by using 2000–2002 Multi-Ethnic Study of Atherosclerosis data. US participants (n = 5,633; aged 45–84 years) reported usual fast-food consumption (never, <1 time/week, or ≥1 times/week) and consumption near home (yes/no). Healthy diet was defined as scoring in the top quintile of the Alternate Healthy Eating Index or bottom quintile of a Western-type dietary pattern. Neighborhood fast-food exposure was measured by densities of fast-food outlets, participant report, and informant report. Separate logistic regression models were used to examine associations of fast-food consumption and diet; fast-food exposure and consumption near home; and fast-food exposure and diet adjusted for site, age, sex, race/ethnicity, education, and income. Those never eating fast food had a 2–3-times higher odds of having a healthy diet versus those eating fast food ≥1 times/week, depending on the dietary measure. For every standard deviation increase in fast-food exposure, the odds of consuming fast food near home increased 11%–61% and the odds of a healthy diet decreased 3%–17%, depending on the model. Results show that fast-food consumption and neighborhood fast-food exposure are associated with poorer diet. Interventions that reduce exposure to fast food and/or promote individual behavior change may be helpful.

Confounding by Dietary Patterns of the Inverse Association Between Alcohol Consumption and Type 2 Diabetes Risk

The ability to interpret epidemiologic observations is limited because of potential residual confounding by correlated dietary components. Dietary pattern analyses by factor analysis or partial least squares may overcome the limitation. To examine confounding by dietary pattern as well as standard risk factors and selected nutrients, the authors modeled the longitudinal association between alcohol consumption and 7-year risk of type 2 diabetes mellitus in 2,879 healthy adults enrolled in the Framingham Offspring Study (1991–2001) by Cox proportional hazard models. After adjustment for standard risk factors, consumers of ≥9.0 drinks/week had a significantly lower risk of type 2 diabetes mellitus compared with abstainers (hazard ratio = 0.47, 95% confidence interval (CI): 0.27, 0.81). Adjustment for selected nutrients had little effect on the hazard ratio, whereas adjustment for dietary pattern variables by factor analysis significantly shifted the hazard ratio away from null (hazard ratio = 0.33, 95% CI: 0.17, 0.64) by 40.0% (95% CI: 16.8, 57.0; P = 0.002). Dietary pattern variables by partial least squares showed similar results. Therefore, the observed inverse association, consistent with past studies, was confounded by dietary patterns, and this confounding was not captured by individual nutrient adjustment. The data suggest that alcohol intake, not dietary patterns associated with alcohol intake, is responsible for the observed inverse association with type 2 diabetes mellitus risk.

Familial Recurrence of Midline Birth Defects--A Nationwide Danish Cohort Study

If birth defects resulting from fusion failure in the midline have a common etiology, as previously hypothesized, persons with a family history of 1 type of midline defect should have an increased risk of dissimilar midline defects. The authors examined this hypothesis by linking information from the National Patient Register, the Causes of Death Register, and the Danish Family Relations Database for all Danish residents registered in the Civil Registration System during 1977–2005. Linkage yielded a cohort of 1.7 million persons with 1 or more relatives, including 9,063 persons with 1 or more midline defects. The authors investigated familial clustering of midline defects by estimating relative risks of similar and dissimilar midline defects according to family history of midline defects. Given a history of similar defects in first-degree relatives, relative risks for neural tube defects, conotruncal defects, oral facial clefts, anal/rectal defects, and diaphragmatic defects were 8.2 (95% confidence interval (CI): 3.1, 21.7), 7.7 (95% CI: 4.3, 13.8), 13.2 (95% CI: 10.8, 16.2), 10.3 (95% CI: 2.6, 41.1), and 11.2 (95% CI: 1.6, 79.7), respectively. However, given a dissimilar defect in a family member, the relative risk for any midline defect was null. Thus, similar defects but not dissimilar defects clustered in families, providing no evidence of a shared etiology for dissimilar midline defects.

Height and Site-specific Cancer Risk: A Cohort Study of a Korean Adult Population

To evaluate the association between height and risk of cancer in an East Asian, middle-income population, the authors followed up a cohort of 788,789 Koreans (449,214 men and 339,575 women) aged 40–64 years for cancer incidence between 1994 and 2003. Cox proportional hazards regression analysis was used to evaluate the association. Each 5-cm increment in height was associated with 5% and 7% higher risk of all-sites cancer in men and women, respectively, after adjustment for age, body mass index, and behavioral and socioeconomic factors. When the associations were evaluated for site-specific cancers, a positive association was observed for cancer of the colon and thyroid in both men and women. Among gender-specific cancers, prostate cancer was positively associated with height in men. In women, there was a positive association between height and cancers of the breast and ovary, which did not change even after additional adjustment for reproductive factors. Although more clarification is needed for some site-specific cancers, the same positive association of height with cancer in a middle-income Korean population as found in high-income Western populations supports the influence of early life environment on cancer development in adulthood.

Impact of X Chromosome Genes in Explaining the Excess Risk of Cancer in Males

The authors examined cancer incidence sex ratios in Denmark for 1943–2003 by age group. At nongenital/nonbreast sites, incidences were consistently higher in males. While environmental factors dominate cancer risk, the authors hypothesized that the higher risk in males might be explained by unspecified X chromosome genes’ protecting female cells from genotoxic damage. If so, cancer susceptibility would be passed from parent to offspring differently by sex. The authors compared relative risks in offspring of parents with and without cancer histories. For all comparisons, relative risks were similar in offspring of fathers with cancer (relative risk (RR) = 1.14, 95% confidence interval: 1.08, 1.20). Risks in offspring were higher for parents diagnosed before age 50 years and for cancers at the same site rather than different sites. Genital cancer risks were increased in same-sex offspring of parents with genital cancers. Breast cancer risks were high in both daughters (RR = 2.37) and sons (RR = 4.63) of mothers with breast cancer and in daughters (RR = 5.96) of fathers with breast cancer. Thus, X chromosome genetic factors were not responsible for the excess risk of cancer in males. Susceptibility to genital cancer was increased in same-sex offspring, and breast cancer risks were increased in both sons and daughters when either parent had had breast cancer.

Birth Weight, Postnatal Growth, and Age at Menarche

Larger body size in childhood is correlated with earlier age at menarche; whether birth and infant body size changes are also associated with age at menarche is less clear. The authors contacted female participants enrolled in the New York site of the US National Collaborative Perinatal Project born between 1959 and 1963 (n = 262). This racially and ethnically diverse cohort (38% white, 40% African American, and 22% Puerto Rican) was used to investigate whether maternal (body size, pregnancy weight gain, age at menarche, smoking) and birth (birth weight, birth length, placental weight) variables and early infant body size changes were associated with age at menarche even after considering later childhood body size. Higher percentile change in weight from ages 4 months to 1 year was associated with earlier age at menarche even after adjustment for later childhood growth (β = –0.15, 95% confidence interval: –0.27, –0.02 years per 10-percentile change in weight from ages 4 months to 1 year). The association was in the same direction for all 3 racial/ethnic groups but was largest for the white group. These New York Women's Birth Cohort Adult Follow-up data (2001–2006) suggest that infant weight gain, in addition to childhood weight gain, may be associated with earlier age at menarche.

Tracking Population Health Based on Self-reported Impairments: Trends in the Prevalence of Hearing Loss in US Adults, 1976-2006

Trends in the prevalence of hearing loss among US adults remain ambiguous because of variation across surveys in question wording and limited use of audiometric examinations. Pooling samples of participants aged 20–69 years in 4 nationally representative cross-sectional survey series conducted from 1976 to 2006 (N = 990,609), the authors performed logistic regression to quantify self-reporting biases compared with audiometric measurements. Statistically significant underreporting or overreporting of hearing loss was observed, with various patterns of bias across age groups and surveys. Substantial upward reporting biases appeared among young adults in the National Health and Nutrition Examination Survey since 1999 and in the National Health Interview Survey since 1997. Trends in age-standardized prevalence of bilateral hearing loss were estimated with corrections for self-reporting biases. Prevalence in men shifted from 9.6% (95% confidence interval (CI): 7.8, 11.8) in 1978 to 12.2% (95% CI: 10.1, 14.7) in 1993 and declined to 8.1% (95% CI: 7.0, 9.5) in 2000. In women, prevalence was relatively constant at approximately 6%–7% until the early 1990s and decreased from 7.0% (95% CI: 5.5, 9.1) in 1993 to 4.2% (95% CI: 3.4, 5.3) in 2000. Prevalence was stable in both sexes in the early 2000s. This approach to adjust for biases in self-reported impairments by using measured performance may be useful in various health domains.

Comparing Methods for Accounting for Seasonal Variability in a Biomarker When Only a Single Sample Is Available: Insights From Simulations Based on Serum 25-Hydroxyvitamin D

In biomarker-disease association studies, the long-term average level of a biomarker is often considered the optimal measure of exposure. Long-term average levels may not be accurately measured from a single sample, however, because of systematic temporal variation. For example, serum 25-hydroxyvitamin D (25(OH)D) concentrations may fluctuate because of seasonal variation in sun exposure. Association studies of 25(OH)D and cancer risk have used different strategies to minimize bias from such seasonal variation, including adjusting for date of sample collection (DOSC), often after matching on DOSC, and/or using season-specific cutpoints to assign subjects to exposure categories. To evaluate and understand the impact of such strategies on potential bias, the authors simulated a population in which 25(OH)D levels varied between individuals and by season, and disease risk was determined by long-term average 25(OH)D. Ignoring temporal variation resulted in bias toward the null. When cutpoints that did not account for DOSC were used, adjustment for DOSC sometimes resulted in bias away from the null. Using season- or month-specific cutpoints reduced bias toward the null and did not cause bias away from the null. To avoid potential bias away from the null, using season- or month-specific cutpoints may be preferable to adjusting for DOSC.

Validity of Estimated Dietary Eicosapentaenoic Acid and Docosahexaenoic Acid Intakes Determined by Interviewer-Administered Food Frequency Questionnaire Among Older Adults With Mild-to-Moderate Cognitive Impairment or Dementia

Epidemiologic research is increasingly being focused on elderly persons, many of whom exhibit mild-to-moderate cognitive impairment. This presents a challenge for collection and interpretation of self-reported dietary data. There are few reports on the impact of cognitive function and dementia on the validity of self-reported dietary intakes. Using plasma phospholipid fatty acid profiles as a biomarker of intake, the authors assessed the validity of an interviewer-administered food frequency questionnaire (FFQ) to estimate intakes of 2 marine-based omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), among 273 community-dwelling adults aged ≥60 years participating in the Nutrition, Aging, and Memory in Elders Study (Boston, Massachusetts, 2002–2008). Age- and energy-adjusted Pearson correlation coefficients for correlations between dietary intakes and plasma phospholipids were consistent across categories of high and low cognitive function (r = 0.48), based on Mini-Mental State Examination score, and were similar across clinically diagnosed categories of normal functioning (r = 0.49), mild cognitive impairment (r = 0.45), and dementia (r = 0.52). The FFQ ranked 78% of subjects to within 1 quartile of their plasma phospholipid EPA + DHA quartile. This frequency was consistently high across all cognitive categories. With interviewer administration, this FFQ seems to be a valid method of assessing dietary EPA + DHA intake in older adults with mild-to-moderate cognitive impairment.

Estimating Nutrient Intake From a Food Frequency Questionnaire: Incorporating the Elements of Race and Geographic Region

Assignment of nutrient values to food frequency questionnaire (FFQ) items does not usually account for participant characteristics (besides age or sex) that may influence eating patterns. For the Southern Community Cohort Study, the authors developed and assessed results from a nutrient database system incorporating sex-, race-, and census-region-specific food lists, using 24-hour recall data from the National Health and Nutrition Examination Survey (NHANES III, NHANES 1999–2000, NHANES 2001–2002, and NHANES 2003–2004) and the Continuing Survey of Food Intakes by Individuals that permitted estimation of nutrients tailored to participants’ characteristics. For each of 15 nutrients, comparisons were made to a "standard" nutrient scoring system based on nationwide race-blind 24-hour recalls from these same sources. Using FFQ data from 67,926 Southern Community Cohort Study participants (47,038 African-American, 20,888 non-Hispanic white) aged 40–79 years who enrolled in the study during 2002–2008, the region- and race-informed system tended to produce increased estimated intake for most nutrients for black women, particularly for saturated fat (7.1%), monounsaturated fat (8.3%), and polyunsaturated fat (7.2%); smaller but significant changes (<5%) were also observed for nutrient intake for men and white women. These types of refinements in nutrient databases can be considered a means of enhancing the accuracy of dietary estimation using FFQs.

Methodological Issues in a Retrospective Cancer Incidence Study

The authors traced incidence of central nervous system cancer in a large occupational cohort of jet engine manufacturing workers from 1976 to 2004 in the 24 US states that comprised 95% of the cohort deaths. The cohort of approximately 224,000 employees was matched with cancer registry data; all central nervous system cancer matches were requested with their diagnostic data. This paper highlights the obstacles encountered while conducting this retrospective cancer incidence study. The authors spent approximately 700 hours completing applications and obtaining the cohort matches. Approximately 70% of the cases were identified in the state in which the facility of interest is located. In addition to the large amount of time involved, identified issues include complicated approval processes, high costs, temporal differences among the registries, and registry agency difficulty in performing the matching. Several states do not allow individual-level data to be used for research purposes. Researchers can gain important cancer incidence information by matching retrospective cohorts to multiple state cancer registries. However, they should carefully weigh the time and costs required and plan accordingly. Despite some serious obstacles, many of which are potentially resolvable, cancer incidence studies of retrospective cohorts using multiple cancer registries are feasible.

The Nicaraguan Pediatric Dengue Cohort Study: Study Design, Methods, Use of Information Technology, and Extension to Other Infectious Diseases

Dengue is a mosquito-borne viral disease that is a major public health problem worldwide. In 2004, the Pediatric Dengue Cohort Study was established in Managua, Nicaragua, to study the natural history and transmission of dengue in children. Here, the authors describe the study design, methods, and results from 2004 to 2008. Initially, 3,721 children 2–9 years of age were recruited through door-to-door visits. Each year, new children aged 2 years are enrolled in the study to maintain the age structure. Children are provided with medical care through the study, and data from each medical visit are recorded on systematic study forms. All participants presenting with suspected dengue or undifferentiated fever are tested for dengue by virologic, serologic, and molecular biologic assays. Yearly blood samples are collected to detect inapparent dengue virus infections. Numerous information and communications technologies are used to manage study data, track samples, and maintain quality control, including personal data assistants, barcodes, global information systems, and fingerprint scans. Close collaboration with the Nicaraguan Ministry of Health and use of almost entirely local staff are essential components for success. This study is providing critical data on the epidemiology and transmission of dengue in the Americas needed for future vaccine trials.

Basic Biostatistics for Geneticists and Epidemiologists: A Practical Approach: By Robert C. Elston and William D. Johnson

RE: "CHANGES IN PERCEIVED JOB STRAIN AND THE RISK OF MAJOR DEPRESSION: RESULTS FROM A POPULATION-BASED LONGITUDINAL STUDY"

THREE AUTHORS REPLY

RE: "ABSTRACTS OF THE 42ND ANNUAL MEETING OF THE SOCIETY FOR EPIDEMIOLOGIC RESEARCH"

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Editorial Board

A Field Synopsis and Meta-Analysis of Genetic Association Studies in Peripheral Arterial Disease: The CUMAGAS-PAD Database

Benefits and Risks of Postmenopausal Hormone Therapy When It Is Initiated Soon After Menopause

Invited Commentary: Hormone Therapy Risks and Benefits--The Women's Health Initiative Findings and the Postmenopausal Estrogen Timing Hypothesis

Fast-Food Consumption, Diet Quality, and Neighborhood Exposure to Fast Food: The Multi-Ethnic Study of Atherosclerosis

Confounding by Dietary Patterns of the Inverse Association Between Alcohol Consumption and Type 2 Diabetes Risk

Familial Recurrence of Midline Birth Defects--A Nationwide Danish Cohort Study

Height and Site-specific Cancer Risk: A Cohort Study of a Korean Adult Population

Impact of X Chromosome Genes in Explaining the Excess Risk of Cancer in Males

Birth Weight, Postnatal Growth, and Age at Menarche

Tracking Population Health Based on Self-reported Impairments: Trends in the Prevalence of Hearing Loss in US Adults, 1976-2006

Comparing Methods for Accounting for Seasonal Variability in a Biomarker When Only a Single Sample Is Available: Insights From Simulations Based on Serum 25-Hydroxyvitamin D

Validity of Estimated Dietary Eicosapentaenoic Acid and Docosahexaenoic Acid Intakes Determined by Interviewer-Administered Food Frequency Questionnaire Among Older Adults With Mild-to-Moderate Cognitive Impairment or Dementia

Estimating Nutrient Intake From a Food Frequency Questionnaire: Incorporating the Elements of Race and Geographic Region

Methodological Issues in a Retrospective Cancer Incidence Study

The Nicaraguan Pediatric Dengue Cohort Study: Study Design, Methods, Use of Information Technology, and Extension to Other Infectious Diseases

Basic Biostatistics for Geneticists and Epidemiologists: A Practical Approach: By Robert C. Elston and William D. Johnson

RE: "CHANGES IN PERCEIVED JOB STRAIN AND THE RISK OF MAJOR DEPRESSION: RESULTS FROM A POPULATION-BASED LONGITUDINAL STUDY"

THREE AUTHORS REPLY

RE: "ABSTRACTS OF THE 42ND ANNUAL MEETING OF THE SOCIETY FOR EPIDEMIOLOGIC RESEARCH"

Editorial Consultants

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Occupation as Socioeconomic Status or Environmental Exposure? A Survey of Practice Among Population-based Cardiovascular Studies in the United States

Decisions about how occupation is used in epidemiologic research can affect conclusions about the importance of socioeconomic and environmental factors in explaining disparities for outcomes such as cardiovascular disease. A review of practices in the collection and use of occupational data was conducted among population-based cardiovascular studies in the United States. Studies were identified for review from the National Heart, Lung, and Blood Institute website and the biomedical database, Computer Retrieval of Information on Scientific Projects, by use of selected criteria. Data collection instruments and study publications were retrieved and reviewed for 30 of 33 studies (91%). Most of the studies (83%) collected at least descriptive occupational data, and more than half (60%) collected data on workplace hazards. The reviewed studies produced 80 publications in which occupational data were used in analyses, most often as an indicator of socioeconomic status. Authors rarely acknowledged known conceptual and empirical links among socioeconomic status, employment stability, and working conditions. Underutilization of data on workplace conditions was found. Existing data could be used more effectively to examine the contribution of work-related social and environmental conditions to the development of modifiable cardiovascular disease through multiple pathways.

Invited Commentary: The Search for Preventable Causes of Cardiovascular Disease--Whither Work?

The incidence and mortality of the major cardiovascular disorders vary sharply by occupation, but this is usually attributed to broad socioeconomic factors; the contributions of physical and psychosocial stressors at work remain obscure or controversial. Review of the ongoing studies of cardiovascular disease in the United States in this issue of the Journal demonstrates that few have either collected sufficient occupational data or used these data in published analyses to address this issue. There are compelling reasons to study this issue, starting with the sheer magnitude of the occupational gradient and disease prevalence. If only 5%–15% prove causally linked to preventable factors, an enormous disease-control opportunity would present itself. Moreover, the most suspect work factors—job stress, fine particulate dust, heat, noise, and shiftwork—are highly prevalent in the US workforce. Thankfully, there is evidence that many of the large ongoing studies are moving toward enhancing their occupational data and using what they have already collected. However, because of the complexity of studying these relations, the better solution is not retrofitting but designing studies in the future that combine de novo the conceptual frameworks and technical skills of occupational and social epidemiologists with those of more biologically focused investigators.

MacDonald et al. Respond to "Search for Preventable Causes of Cardiovascular Disease"

Birth Weight, Early Weight Gain, and Subsequent Risk of Type 1 Diabetes: Systematic Review and Meta-Analysis

Previous studies suggest that birth weight and weight gain during the first year of life are related to later risk of type 1 diabetes. The authors performed a systematic review and meta-analysis on these associations. Twelve studies involving 2,398,150 persons of whom 7,491 had type 1 diabetes provided odds ratios and 95% confidence intervals of type 1 diabetes associated with birth weight. Four studies provided data on weight and/or weight gain during the first year of life. High birth weight (>4,000 g) was associated with increased risk of type 1 diabetes (odds ratio = 1.17, 95% confidence interval (CI): 1.09, 1.26). According to sensitivity analysis, this result was not influenced by particular study characteristics. The pooled confounder-adjusted estimate was 1.43 (95% CI: 1.11, 1.85). No heterogeneity was found (I2 = 0%) and no publication bias. Low birth weight (<2,500 g) was associated with a nonsignificantly decreased risk of type 1 diabetes (odds ratio = 0.82, 95% CI: 0.54, 1.23). Each 1,000-g increase in birth weight was associated with a 7% increase in type 1 diabetes risk. In all studies, patients with type 1 diabetes showed increased weight gain during the first year of life, compared with controls. This meta-analysis indicates that high birth weight and increased early weight gain are risk factors for type 1 diabetes.

Serum and Dietary Magnesium and Risk of Ischemic Stroke: The Atherosclerosis Risk in Communities Study

The authors sought to examine the relation between serum or dietary magnesium and the incidence of ischemic stroke among blacks and whites. Between 1987 and 1989, 14,221 men and women aged 45–64 years took part in the first examination of the Atherosclerosis Risk in Communities Study cohort. The incidence of stroke was ascertained from hospital records. Higher serum magnesium levels were associated with lower prevalence of hypertension and diabetes mellitus at baseline. During the 15-year follow-up, 577 ischemic strokes occurred. Serum magnesium was inversely associated with ischemic stroke incidence. The age-, sex-, and race-adjusted rate ratios of ischemic stroke for those with serum magnesium levels of ≤1.5, 1.6, 1.7, and ≥1.8 mEq/L were 1.0, 0.78 (95% confidence interval (CI): 0.62, 0.96), 0.70 (95% CI: 0.56, 0.88), and 0.75 (95% CI: 0.59, 0.95) (Ptrend = 0.005). After adjustment for hypertension and diabetes, the rate ratios were attenuated to nonsignificant levels. Dietary magnesium intake was marginally inversely associated with the incidence of ischemic stroke (Ptrend = 0.09). Low serum magnesium levels could be associated with increased risk of ischemic stroke, in part, via effects on hypertension and diabetes.

Coffee Intake, Smoking, and Pulmonary Function in the Atherosclerosis Risk in Communities Study

Coffee contains polyphenolic antioxidants and caffeine, which may favorably affect pulmonary function. Therefore, the authors studied cross-sectional associations (1987–1989) between coffee intake and pulmonary function in the Atherosclerosis Risk in Communities Study, a population-based cohort study (analytic sample = 10,658). They also conducted analyses stratified by smoking status, since smoking is a strong risk factor for respiratory disease and could influence the effects of caffeine and antioxidants. Self-reported coffee intake was categorized as rare/never, <7 cups/week, 1 cup/day, 2–3 cups/day, and ≥4 cups/day. Pulmonary function was characterized by the spirometric measures forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV1). After adjustment for demographic factors, lifestyle characteristics, and dietary factors, pulmonary function values increased across increasing categories of coffee consumption in never and former smokers but not in current smokers. In never or former smokers who consumed ≥4 cups of coffee daily, FVC and FEV1 were 2%–3% greater than in never or former smokers who rarely/never consumed coffee (Ptrend values: in never smokers, 0.04 for FVC and 0.07 for FEV1; in former smokers, <0.001 for FVC and <0.001 for FEV1). These data show a possible beneficial effect of coffee (or a coffee ingredient) on pulmonary function, but it appears to be limited to nonsmokers.

Is There a Clear Threshold for Fasting Plasma Glucose That Differentiates Between Those With and Without Neuropathy and Chronic Kidney Disease?: The Singapore Prospective Study Program

Recent studies suggest that no distinct glycemic threshold consistently differentiates individuals with or without retinopathy. The authors sought to determine whether the same was true for other microvascular complications. They studied 5,094 participants with fasting plasma glucose values and concurrent microvascular complications from 4 previous cross-sectional surveys carried out in Singapore (1982–1998) who attended a follow-up examination in 2004–2007. Peripheral neuropathy was diagnosed based on abnormal responses to a 10-g monofilament or neurothesiometer test. Chronic kidney disease was defined in various ways by using albuminuria (urine albumin:creatinine ratio >30 µg/mg) and estimated glomerular filtration rate, alone and in combination. Prevalence of peripheral neuropathy was 7.5%. For chronic kidney disease, prevalence of albuminuria only was 10.5%, estimated glomerular filtration rate of <60 mL/minute per 1.73 m2 only was 4.1%, and both was 2.1%. Prevalence of peripheral neuropathy and chronic kidney disease gradually increased in relation to fasting plasma glucose, beginning at levels below the existing diagnostic threshold for diabetes mellitus of 7.0 mmol/L (126 mg/dL). For chronic kidney disease, these associations persisted after adjustment for age, gender, ethnic group, and hypertension. Current diagnostic thresholds for diabetes mellitus have limited sensitivity for identifying individuals with these microvascular complications. Ascertaining these individuals may require development and application of novel screening strategies.

Time-Varying Effects of Prognostic Factors Associated With Disease-Free Survival in Breast Cancer

Early detection and effective treatments have dramatically improved breast cancer survivorship, yet the risk of relapse persists even 15 years after the initial diagnosis. It is important to identify prognostic factors for late breast cancer events. The authors investigated time-varying effects of tumor characteristics on breast-cancer-free survival using data on 3,088 breast cancer survivors from 4 US states who participated in a randomized dietary intervention trial in 1995–2006, with maximum follow-up through 15 years (median, 9 years). A piecewise constant penalized spline approach incorporating time-varying coefficients was adopted, allowing for deviations from the proportional hazards assumption. This method is more flexible than standard approaches, provides direct estimates of hazard ratios across time intervals, and is computationally tractable. Having a stage II or III tumor was associated with a 3-fold higher hazard of breast cancer than having a stage I tumor during the first 2.5 years after diagnosis; this hazard ratio decreased to 2.1 after 7.7 years, but higher tumor stage remained a significant risk factor. Similar diminishing effects were found for poorly differentiated tumors. Interestingly, having a positive estrogen receptor status was protective up to 4 years after diagnosis but detrimental after 7.7 years (hazard ratio = 1.5). These results emphasize the importance of careful statistical modeling allowing for possibly time-dependent effects in long-term survivorship studies.

Quantitative Exposure to Metalworking Fluids and Bladder Cancer Incidence in a Cohort of Autoworkers

Occupations with mineral oil exposure have been associated with bladder cancer in population-based case-control studies. The authors report results from the first cohort study to examine bladder cancer incidence in relation to quantitative exposures to metalworking fluids (MWFs), based on 21,999 male Michigan automotive workers, followed from 1985 through 2004. Cox regression was used to estimate hazard ratios based on categorical exposure variables for straight, soluble, and synthetic MWFs, as well as duration of exposure to ethanolamines and nitrosamines. Penalized splines were also fit to estimate the functional form of the exposure-response relation. Increased bladder cancer risk was associated with straight MWFs but not with any other exposure. The hazard ratio increased with cumulative exposure to a maximum of 2-fold observed at 75 mg/m3-year straight MWF exposure (lagged 20 years). Calendar time windows relevant to polycyclic aromatic hydrocarbon exposure were examined but could not be distinguished from the lagged (10-, 20-year) metrics. No association was observed between any exposure and incident lung cancer, suggesting that smoking is unlikely to confound the associations observed here. The quantitative relation with straight MWFs strengthens the evidence for mineral oils as a bladder carcinogen.

Exposure to Farm Crops, Livestock, and Farm Tasks and Risk of Glioma: The Upper Midwest Health Study

Some studies of brain cancer have found an excess risk for farmers. The National Institute for Occupational Safety and Health previously found no increased glioma risk for ever (vs. never) being exposed to pesticides on a farm among 798 cases and 1,175 population-based controls (adult (ages 18–80 years) nonmetropolitan residents of Iowa, Michigan, Minnesota, and Wisconsin). For this analysis (1995–1998), 288 cases and 474 controls (or their proxies) who had lived on farms at age 18 years or after were asked about exposure to crops, livestock, and farm tasks. Logistic regression was used to calculate odds ratios adjusted for age, age group, sex, state, and education. Never immediately washing up (adjusted odds ratio (OR) = 3.08, 95% confidence interval (CI): 1.78, 5.34) or changing clothes (OR = 2.84, 95% CI: 1.04, 7.78) after applying pesticides was associated with increased glioma risk. Living on a farm on which corn, oats, soybeans, or hogs were raised was associated with decreased risk (corn—OR = 0.37, 95% CI: 0.20, 0.69; oats—OR = 0.63, 95% CI: 0.40, 1.00; soybeans—OR = 0.69, 95% CI: 0.48, 0.98; hogs—OR = 0.63, 95% CI: 0.43, 0.93). Negative associations may be due to chance or a "healthy farmer" effect. Farmers’ increased risk of glioma may be due to work practices, other activities, or an inverse association with allergies (reported by other investigators).

Obesity, Lifestyle Factors, and Risk of Myelodysplastic Syndromes in a Large US Cohort

The etiology of myelodysplastic syndromes (MDS) is not well understood. The authors examined the relations of obesity and lifestyle factors to MDS in a cohort of 471,799 persons aged 50–71 years who were recruited into the National Institutes of Health-AARP Diet and Health Study, a large US prospective study, in 1995–1996. Incident MDS was diagnosed in 193 persons during 2001–2003. A significant positive association was observed between body mass index (BMI; weight (kg)/height (m)2) at baseline and MDS. Compared with persons with a BMI less than 25.0, the hazard ratios for persons with BMIs of 25.0–<30.0 and ≥30.0 were 1.15 (95% confidence interval (CI): 0.81, 1.64) and 2.18 (95% CI: 1.51, 3.17; P for trend < 0.001), respectively. The association was not affected by physical activity, cigarette smoking, or alcohol intake. As reported in previous studies, the risk of MDS was elevated among former smokers (hazard ratio = 1.68, 95% CI: 1.17, 2.41) and current smokers (hazard ratio = 3.17, 95% CI: 2.02, 4.98) as compared with never smokers. Physical activity, alcohol consumption, meat intake, and fruit and vegetable intake did not appear to significantly influence the risk of MDS in this analysis. This prospective investigation of MDS implicates both obesity and smoking as modifiable risk factors.

Pesticide Exposure and Respiratory Health of Indigenous Women in Costa Rica

A cross-sectional study was conducted in 2007 to evaluate the relation between pesticide exposure and respiratory health in a population of indigenous women in Costa Rica. Exposed women (n = 69) all worked at plantain plantations. Unexposed women (n = 58) worked at organic banana plantations or other locations without pesticide exposure. Study participants were interviewed using questionnaires to estimate exposure and presence of respiratory symptoms. Spirometry tests were conducted to obtain forced vital capacity and forced expiratory volume in 1 second. Among the exposed, prevalence of wheeze was 20% and of shortness of breath was 36% versus 9% and 26%, respectively, for the unexposed. Prevalence of chronic cough, asthma, and atopic symptoms was similar for exposed and unexposed women. Among nonsmokers (n = 105), reported exposures to the organophosphate insecticides chlorpyrifos (n = 25) and terbufos (n = 38) were strongly associated with wheeze (odd ratio = 6.7, 95% confidence interval: 1.6, 28.0; odds ratio = 5.9, 95% confidence interval: 1.4, 25.6, respectively). For both insecticides, a statistically significant exposure-effect association was found. Multiple organophosphate exposure was common; 81% of exposed women were exposed to both chlorpyrifos and terbufos. Consequently, their effects could not be separated. All findings were based on questionnaire data. No relation between pesticide exposure and ventilatory lung function was found.

Activity Energy Expenditure and Mobility Limitation in Older Adults: Differential Associations by Sex

In this study, the authors aimed to determine whether higher activity energy expenditure, assessed by using doubly labeled water, was associated with a reduced decline in mobility limitation among 248 older community-dwelling US adults aged 70–82 years enrolled in 1998–1999. Activity energy expenditure was calculated as total energy expenditure (assessed over 2 weeks by using doubly labeled water) minus resting metabolic rate (measured with indirect calorimetry), with adjustment for the thermic effect of food. Across sex-specific tertiles of activity energy expenditure, men in the lowest activity group experienced twice the rate of mobility limitation as men in the highest activity group (41% (n = 18) vs. 18% (n = 8)). Conversely, women in the lowest and highest activity groups exhibited similarly high rates of mobility limitation (40% (n = 16) vs. 38% (n = 15)). After adjustment for potential confounders, men with higher activity energy expenditure levels continued to show reduced risk of mobility limitation (per standard deviation (284 kcal/day): hazard ratio = 0.61, 95% confidence interval: 0.41, 0.92). Women showed no association (per standard deviation (226 kcal/day): hazard ratio = 1.34, 95% confidence interval: 0.98, 1.85). Greater energy expenditure from any and all physical activity was significantly associated with reduced risk of developing mobility limitation among men, but not among women.

Optimal Dosing and Dynamic Distribution of Vaccines in an Influenza Pandemic

Limited production capacity and delays inherent in vaccine development are major hurdles to the widespread use of vaccines to mitigate the effects of a new influenza pandemic. Antigen-sparing vaccines have the most potential to increase population coverage but may be less efficacious. The authors explored this trade-off by applying simple models of influenza transmission and dose response to recent clinical trial data. In this paper, these data are used to illustrate an approach to comparing vaccines on the basis of antigen supply and inferred efficacy. The effects of delays in matched vaccine availability and seroconversion on epidemic size during pandemic phase 6 were also studied. The authors infer from trial data that population benefits stem from the use of low-antigen vaccines. Delayed availability of a matched vaccine could be partially alleviated by using a 1-dose vaccination program with increased coverage and reduced time to full protection. Although less immunogenic, an overall attack rate of up to 6% lower than a 2-dose program could be achieved. However, if prevalence at vaccination is above 1%, effectiveness is much reduced, emphasizing the need for other control measures.

The Effect of Question Order on Self-rated General Health Status in a Multilingual Survey Context

Current practices recommend placing a self-rated health question before specific health items in survey questionnaires to minimize potential order effects. Because this recommendation is based on data collected in English, its applicability to other languages is unknown. This study examines whether there is an order effect associated with self-rated health for interviews conducted in English and Spanish languages. An experiment was conducted by using the 2007 California Health Interview Survey, where questions on self-rated health were inserted in 1 of 2 locations: preceding and following question items on specific chronic conditions. Respondents were randomly assigned to 1 of 2 versions of the locations by the split-half method. Although no order effect was present in the English interviews, the authors found a significant and large effect with Spanish interviews: Self-rated health appeared much worse when asked before chronic conditions than when asked after them. This order effect was larger among females than males. Order effects for self-rated health differ by interview language; inferences about the health status of Spanish-speaking populations (and potentially Latinos) depend on question order. If maintaining comparability is important, the authors’ finding contradicts current recommendations, as inserting the self-rated health question before specific questions led to larger differences in health status between English and Spanish speakers.

TWO AUTHORS REPLY

RE: "NEONATAL HAIR NICOTINE LEVELS AND FETAL EXPOSURE TO PATERNAL SMOKING AT HOME"

RE: "DETERMINANTS OF THE INCIDENCE OF CHILDHOOD ASTHMA: A TWO-STAGE CASE-CONTROL STUDY"

THE AUTHORS REPLY

Author Index

ABSTRACTS OF THE 42nd Annual Meeting of the Society for Epidemiologic Research June 23-26, 2009

Latebreaker

Volume 137 Issue 08

Epidemiology and Infection, Volume 137 Issue 08 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 137 issue 8 Cover and Front matter

Miscellaneous Epidemiology and Infection, Volume 137 Issue 08 , pp f1-f2Abstract

HYG volume 137 issue 8 Cover and Back matter

Miscellaneous Epidemiology and Infection, Volume 137 Issue 08 , pp b1-b3Abstract

Risk of transmitting meningococcal infection by transient contact on aircraft and other transport

Review ArticlesT. RACHAEL, K. SCHUBERT, W. HELLENBRAND, G. KRAUSE, J. M. STUART, Epidemiology and Infection, Volume 137 Issue 08 , pp 1057-1061Abstract

A comparative study of the 1918–1920 influenza pandemic in Japan, USA and UK: mortality impact and implications for pandemic planning

Research ArticlesS. A. RICHARD, N. SUGAYA, L. SIMONSEN, M. A. MILLER, C. VIBOUD, Epidemiology and Infection, Volume 137 Issue 08 , pp 1062-1072Abstract

Association between indicators of livestock farming intensity and hospitalization rate for acute gastroenteritis

Research ArticlesY. FEBRIANI, P. LEVALLOIS, G. LEBEL, S. GINGRAS, Epidemiology and Infection, Volume 137 Issue 08 , pp 1073-1085Abstract

Feasibility of screening broiler chicken flocks for risk markers as an aid for meat inspection

Research ArticlesC. LUPO, S. Le BOUQUIN, L. BALAINE, V. MICHEL, J. PERASTE, I. PETETIN, P. COLIN, C. CHAUVIN, Epidemiology and Infection, Volume 137 Issue 08 , pp 1086-1098Abstract

Campylobacter in housed broiler chickens: a longitudinal study of risk factors

Research ArticlesS. P. RUSHTON, T. J. HUMPHREY, M. D. F. SHIRLEY, S. BULL, F. JØRGENSEN, Epidemiology and Infection, Volume 137 Issue 08 , pp 1099-1110Abstract

Epidemiological surveillance of Campylobacter jejuni in chicken, dairy cattle and diarrhoea patients

Research ArticlesJ. L. HUANG, H. Y. XU, G. Y. BAO, X. H. ZHOU, D. J. JI, G. ZHANG, P. H. LIU, F. JIANG, Z. M. PAN, X. F. LIU, X. A. JIAO, Epidemiology and Infection, Volume 137 Issue 08 , pp 1111-1120Abstract

Farm-level risk factors for fluoroquinolone resistance in E. coli and thermophilic Campylobacter spp. on finisher pig farms

Research ArticlesN. M. TAYLOR, F. A. CLIFTON-HADLEY, A. D. WALES, A. RIDLEY, R. H. DAVIES, Epidemiology and Infection, Volume 137 Issue 08 , pp 1121-1134Abstract

Factors related to the carriage of Verocytotoxigenic E. coli , Salmonella , thermophilic Campylobacter and Yersinia enterocolitica in cattle, sheep and pigs at slaughter

Research ArticlesA. S. MILNES, A. R. SAYERS, I. STEWART, F. A. CLIFTON-HADLEY, R. H. DAVIES, D. G. NEWELL, A. J. C. COOK, S. J. EVANS, R. P. SMITH, G. A. PAIBA, Epidemiology and Infection, Volume 137 Issue 08 , pp 1135-1148Abstract

Quantitative assessment of the risk of rabies entering Japan through the importation of dogs and cats from the USA

Brief ReportH. KAMAKAWA, M. KOIWAI, S. SATOMURA, M. ETO, K. SUGIURA, Epidemiology and Infection, Volume 137 Issue 08 , pp 1149-1154Abstract

Lagos bat virus virulence in mice inoculated by the peripheral route

Research ArticlesW. MARKOTTER, I. V. KUZMIN, C. E. RUPPRECHT, L. H. NEL, Epidemiology and Infection, Volume 137 Issue 08 , pp 1155-1162Abstract

The continuous spread of West Nile virus (WNV): seroprevalence in asymptomatic horses

Brief ReportJ. ALONSO-PADILLA, E. LOZA-RUBIO, E. ESCRIBANO-ROMERO, L. CÓRDOBA, S. CUEVAS, F. MEJÍA, R. CALDERÓN, F. MILIÁN, A. TRAVASSOS DA ROSA, S. C. WEAVER, J. G. ESTRADA-FRANCO, J. C. SAIZ, Epidemiology and Infection, Volume 137 Issue 08 , pp 1163-1168Abstract

Walking the dog: exploration of the contact networks between dogs in a community

Research ArticlesC. WESTGARTH, R. M. GASKELL, G. L. PINCHBECK, J. W. S. BRADSHAW, S. DAWSON, R. M. CHRISTLEY, Epidemiology and Infection, Volume 137 Issue 08 , pp 1169-1178Abstract

Assessing the effects of temperature on dengue transmission

Research ArticlesH. M. YANG, M. L. G. MACORIS, K. C. GALVANI, M. T. M. ANDRIGHETTI, D. M. V. WANDERLEY, Epidemiology and Infection, Volume 137 Issue 08 , pp 1179-1187Abstract

Assessing the effects of temperature on the population of Aedes aegypti , the vector of dengue

Research ArticlesH. M. YANG, M. L. G. MACORIS, K. C. GALVANI, M. T. M. ANDRIGHETTI, D. M. V. WANDERLEY, Epidemiology and Infection, Volume 137 Issue 08 , pp 1188-1202Abstract

Impact of insecticide interventions on the abundance and resistance profile of Aedes aegypti

Research ArticlesP. M. LUZ, C. T. CODEÇO, J. MEDLOCK, C. J. STRUCHINER, D. VALLE, A. P. GALVANI, Epidemiology and Infection, Volume 137 Issue 08 , pp 1203-1215Abstract

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