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Molecular Sequence Data of Hepatitis B Virus and Genetic Diversity After Vaccination

The effect of vaccination programs on transmission of infectious disease is usually assessed by monitoring programs that rely on notifications of symptomatic illness. For monitoring of infectious diseases with a high proportion of asymptomatic cases or a low reporting rate, molecular sequence data combined with modern coalescent-based techniques offer a complementary tool to assess transmission. Here, the authors investigate the added value of using viral sequence data to monitor a vaccination program that was started in 1998 and was targeted against hepatitis B virus in men who have sex with men in Amsterdam, the Netherlands. The incidence in this target group, as estimated from the notifications of acute infections with hepatitis B virus, was low; therefore, there was insufficient power to show a significant change in incidence. In contrast, the genetic diversity, as estimated from the viral sequence collected from the target group, revealed a marked decrease after vaccination was introduced. Taken together, the findings suggest that introduction of vaccination coincided with a change in the target group toward behavior with a higher risk of infection. The authors argue that molecular sequence data provide a powerful additional monitoring instrument, next to conventional case registration, for assessing the impact of vaccination.

Invited Commentary: Evaluating Vaccination Programs Using Genetic Sequence Data

Genomic data will become an increasingly important component of epidemiologic studies in coming years. The authors of the accompanying Journal article, van Ballegooijen et al. (Am J Epidemiol. 2009;170(12):1455–1463), are to be commended for attempting to use the coalescent analysis of viral sequence data to evaluate a hepatitis B vaccination program. Coalescent theory attempts to link the phylogenetic history of populations with rates of population growth and decline. In particular, under certain assumptions, a reduction in genetic diversity can be interpreted as a reduction in disease incidence. However, the authors of this commentary contend that van Ballegooijen et al.’s interpretation of changes in viral genetic diversity as a measure of hepatitis B vaccine effectiveness has major limitations. Because of the potential use of these methods in future vaccination studies, the authors discuss the utility of these methods and the data requirements needed for them to be convincing. First, data sets should be large enough to provide sufficient epidemiologic-scale resolution. Second, data need to reflect sufficiently fine-grained temporal sampling. Third, other processes that can potentially influence genetic diversity and confuse demographic inferences should be considered.

Van Ballegooijen et al. Respond to "Evaluating Vaccination Programs Using Genetic Sequence Data"

Sporadic Gastroenteritis and Recreational Swimming in a Longitudinal Community Cohort Study in Melbourne, Australia

The relation between sporadic gastroenteritis and recreational swimming was examined in a cohort of 2,811 people in Melbourne, Australia, over a 15-month period (September 1997–February 1999). Data from a prospective community-based study of gastroenteritis were used for a Poisson analysis of temporality between reported swimming (in public or private pools/spas and in marine or freshwater settings) and a highly credible gastroenteritis (HCG) event. Overall, HCG events were more likely in participants who had swum in a public pool/spa (incidence rate ratio (IRR) = 1.25, 95% confidence interval (CI): 1.10, 1.42; P = 0.001) or river/lake/dam (IRR = 1.77, 95% CI: 1.13, 2.79; P = 0.014) during the previous week or had swum in a public pool/spa (IRR = 1.29, 95% CI: 1.13, 1.46; P < 0.001) during the previous 2 weeks. Subanalysis by age showed that HCG episodes were also more likely in adults who had swum in a private pool/spa (IRR = 1.56, 95% CI: 1.02, 2.39; P = 0.042) during the previous week or swum at an ocean/beach (IRR = 1.78, 95% CI: 1.12, 2.81; P = 0.014) during the previous 2 weeks, demonstrating significant associations between all swimming locations and gastrointestinal symptoms. This study showed that although the incremental risk of recreational swimming is significant, it is relatively small.

Smoking and Risk of Tuberculosis Incidence, Mortality, and Recurrence in South Korean Men and Women

The authors explored the association of cigarette smoking with tuberculosis incidence, recurrence, and mortality. A 14-year prospective cohort study (1992–2006) was carried out in 1,294,504 South Koreans. Participants were grouped by smoking history, and the authors assessed tuberculosis incidence, mortality, and recurrence risk for each group. Unadjusted and adjusted Cox proportional hazards models were used to investigate the association between smoking history and the 3 outcomes of interest, adjusting for age and alcohol use. Compared with never smokers, current smokers had increased mortality from tuberculosis among both men (adjusted hazard ratio (HR) = 1.6, 95% confidence interval (CI): 1.3, 2.0) and women (HR = 1.6, 95% CI: 1.0, 2.4). Current male smokers had greater risk of incident tuberculosis than former smokers (HR = 1.4, 95% CI: 1.3, 1.5), and risk among current smokers increased with number of cigarettes smoked daily. In females, cigarette smoking was not associated with incident tuberculosis. There was interaction between smoking and sex for incidence (P = 0.00047). The effect of smoking was generally reduced with adjustment for body mass index. Among men, the highest alcohol consumption category (≥100 g/day) was associated with risk of incident tuberculosis (HR = 1.5, 95% CI: 1.3, 1.7). This study provides longitudinal evidence that smoking increases risk of incident tuberculosis, mortality from tuberculosis, and tuberculosis recurrence.

Effect of Supplemental Folic Acid in Pregnancy on Childhood Asthma: A Prospective Birth Cohort Study

This study aimed to investigate the effect of the timing, dose, and source of folate during pregnancy on childhood asthma by using data from an Australian prospective birth cohort study (n = 557) from 1998 to 2005. At 3.5 years and 5.5 years, 490 and 423 mothers and children participated in the study, respectively. Maternal folate intake from diet and supplements was assessed by food frequency questionnaire in early (<16 weeks) and late (30–34 weeks) pregnancy. The primary outcome was physician-diagnosed asthma, obtained by maternal-completed questionnaire. Asthma was reported in 11.6% of children at 3.5 years (n = 57) and in 11.8% of children at 5.5 years (n = 50). Folic acid taken in supplement form in late pregnancy was associated with an increased risk of childhood asthma at 3.5 years (relative risk (RR) = 1.26, 95% confidence interval (CI): 1.08, 1.43) and with persistent asthma (RR = 1.32, 95% CI: 1.03, 1.69). The effect sizes did not change with adjustment for potential confounders. The association was similar at 5.5 years but did not reach statistical significance (RR = 1.17, 95% CI: 0.96, 1.42) in univariable models. These findings on childhood asthma support previous observations that supplementation with folate in pregnancy leads to an allergic asthma phenotype in mice via epigenetic mechanisms and is associated with poorer respiratory outcomes in young children.

Functional Variants in the Catalase and Myeloperoxidase Genes, Ambient Air Pollution, and Respiratory-related School Absences: An Example of Epistasis in Gene-Environment Interactions

The individual effect of functional single nucleotide polymorphisms within the catalase and myeloperoxidase genes (CAT and MPO) has been studied in relation to asthma; however, their interrelationship with ambient air pollution exposures has yet to be determined. The authors investigated the interrelationships between variants in CAT and MPO, ambient air pollutants, and acute respiratory illness. Health information, air pollution, and incident respiratory-related school absences were ascertained in January–June 1996 for 1,136 Hispanic and non-Hispanic white US elementary schoolchildren as part of the prospective Children's Health Study. Functional and tagging single nucleotide polymorphisms for the CAT and MPO loci were genotyped. The authors found epistasis between functional polymorphisms in the CAT/MPO loci, which differed by levels of oxidant-stress-producing air pollutants. Risk of respiratory-related school absences was elevated for children with the CAT (G/G) and MPO (G/A or A/A) genes (relative risk = 1.35, 95% confidence interval: 1.03, 1.77; P-interaction = 0.005). The epistatic effect of CAT and MPO variants was most evident in communities exhibiting high ambient ozone levels (P-interaction = 0.03). The association of respiratory-illness absences with functional variants in CAT and MPO that differ by air pollution levels illustrates the need to consider genetic epistasis in assessing gene-environment interactions.

Visceral Fat Volume and the Prevalence of Colorectal Adenoma

Few epidemiologic investigations of visceral adiposity and colorectal neoplasms have attempted the direct quantification of visceral fat. The authors measured visceral fat volume among middle-aged and elderly Japanese men and women who underwent colonoscopy and positron emission tomography/computed tomography for cancer screening in Tokyo, Japan, between February 2004 and February 2005, and examined the association between visceral adiposity and colorectal adenoma in 1,205 eligible subjects. Odds ratios and 95% confidence intervals for colorectal adenoma were estimated by using an unconditional logistic regression model after adjustment for potential confounders. Despite its high correlation with body mass index, visceral fat volume was associated with the prevalence of colorectal adenoma independently of body mass index in both sexes. After further adjustment for body mass index, the odds ratio of colorectal adenoma for the highest compared with the lowest quartile of visceral fat volume was 1.58 (95% confidence interval: 1.11, 2.24) for men and women combined. Conversely, body mass index was unlikely to modify the association between visceral fat volume and colorectal adenoma (Pinteraction = 0.39). These findings add to accumulating evidence that visceral adiposity exerts an important influence on the pathogenesis of colorectal neoplasms. The mechanisms of this potential association between visceral adiposity and colorectal carcinogenesis warrant further investigation.

Use of Nonsteroidal Antiinflammatory Drugs and Risk of Endometrial Cancer

Results of 3 previous studies suggest that use of aspirin is related to a reduced risk of endometrial cancer, at least in obese women (body mass index, ≥30 kg/m2). Using data obtained in a population-based, case-control study in western Washington State, the authors examined this question. Between 2003 and 2005, 410 women diagnosed with invasive endometrial cancer and 356 controls were interviewed regarding the use of aspirin and other nonsteroidal antiinflammatory drugs (NSAIDs). A history of use of NSAIDs was not associated with the risk of endometrial cancer (odds ratio = 1.04, 95% confidence interval: 0.76, 1.42). The lack of association was also present specifically for use of aspirin (odds ratio = 1.06, 95% confidence interval: 0.73, 1.53). NSAID use was unrelated to risk of endometrial cancer in both obese and nonobese women. Results from this study suggest that the use of aspirin or other NSAIDs has little or no influence on the risk of endometrial cancer.

Adherence to the Mediterranean Diet and Risk of Coronary Heart Disease in the Spanish EPIC Cohort Study

No known cohort study has investigated whether the Mediterranean diet can reduce incident coronary heart disease (CHD) events in a Mediterranean population. This study examined the relation between Mediterranean diet adherence and risk of incident CHD events in the 5 Spanish centers of the European Prospective Investigation into Cancer and Nutrition. Analysis included 41,078 participants aged 29–69 years, recruited in 1992–1996 and followed up until December 2004 (mean follow-up:10.4 years). Confirmed incident fatal and nonfatal CHD events were analyzed according to Mediterranean diet adherence, measured by using an 18-unit relative Mediterranean diet score. A total of 609 participants (79% male) had a fatal or nonfatal confirmed acute myocardial infarction (n = 468) or unstable angina requiring revascularization (n = 141). After stratification by center and age and adjustment for recognized CHD risk factors, high compared with low relative Mediterranean diet score was associated with a significant reduction in CHD risk (hazard ratio = 0.60, 95% confidence interval: 0.47, 0.77). A 1-unit increase in relative Mediterranean diet score was associated with a 6% reduced risk of CHD (95% confidence interval: 0.91, 0.97), with similar risk reductions by sex. Mediterranean diet adherence was associated with a significantly reduced CHD risk in this Mediterranean country, supporting its role in primary prevention of CHD in healthy populations.

Harold A. Kahn (1920-2009): A Remembrance of a Life Devoted to Public Health

Importance of Routine Public Health Influenza Surveillance: Detection of an Unusual W-Shaped Influenza Morbidity Curve

Seasonal influenza causes excess morbidity and mortality at the extremes of age: It disproportionately affects the very young and the very old, typically resulting in "U"-shaped age-distributed curves. By means of a well-established public health department surveillance system using positive influenza tests submitted from sentinel sites, the authors generated annual influenza-specific morbidity curves over a 10-year period (1998–2008) for St. Louis County, Missouri. The authors detected an unusually high incidence of cases of medically attended test-positive influenza, particularly in young adults, during the 2007–2008 season, resulting in an unexpected "W"-shaped age-distributed morbidity curve that was distinctly unique in comparison with the prior 9 influenza seasons. Public health influenza surveillance programs are useful tools for detecting emerging epidemiologic trends that may have clinical importance.

Population-based, Case-Control-Family Design to Investigate Genetic and Environmental Influences on Melanoma Risk: Australian Melanoma Family Study

Discovering and understanding genetic risk factors for melanoma and their interactions with phenotype, sun exposure, and other risk factors could lead to new strategies for melanoma control. This paper describes the Australian Melanoma Family Study, which uses a multicenter, population-based, case-control-family design. From 2001 to 2005, the authors recruited 1,164 probands including 629 cases with histopathologically confirmed, first-primary cutaneous melanoma diagnosed before age 40 years, 240 population-based controls frequency matched for age, and 295 spouse/friend controls. Information on lifetime sun exposure, phenotype, and residence history was collected for probands and nearly 4,000 living relatives. More than 3,000 subjects donated a blood sample. Proxy-reported information was collected for childhood sun exposure and deceased relatives. Important features of this study include the population-based, family-based design; a focus on early onset disease; probands from 3 major cities differing substantially in solar ultraviolet exposure and melanoma incidence; a population at high risk because of high ultraviolet exposure and susceptible pigmentation phenotypes; population-based, spouse/friend, and sibling controls; systematic recruitment of relatives of case and control probands; self and parent reports of childhood sun exposure; and objective clinical skin examinations. The authors discuss methodological and analytical issues related to the study design and conduct, as well as the potentially novel insights the study can deliver.

A Family Longevity Selection Score: Ranking Sibships by Their Longevity, Size, and Availability for Study

Family studies of exceptional longevity can potentially identify genetic and other factors contributing to long life and healthy aging. Although such studies seek families that are exceptionally long lived, they also need living members who can provide DNA and phenotype information. On the basis of these considerations, the authors developed a metric to rank families for selection into a family study of longevity. Their measure, the family longevity selection score (FLoSS), is the sum of 2 components: 1) an estimated family longevity score built from birth-, gender-, and nation-specific cohort survival probabilities and 2) a bonus for older living siblings. The authors examined properties of FLoSS-based family rankings by using data from 3 ongoing studies: the New England Centenarian Study, the Framingham Heart Study, and screenees for the Long Life Family Study. FLoSS-based selection yields families with exceptional longevity, satisfactory sibship sizes and numbers of living siblings, and high ages. Parameters in the FLoSS formula can be tailored for studies of specific populations or age ranges or with different conditions. The first component of the FLoSS also provides a conceptually sound survival measure to characterize exceptional longevity in individuals or families in various types of studies and correlates well with later-observed longevity.

Validity of Adolescent Diet Recall 48 Years Later

Few studies have evaluated the validity of adolescent diet recall after many decades. Between 1943 and 1970, yearly diet records were completed by parents of adolescents participating in an ongoing US study. In 2005–2006, study participants who had been 13–18 years of age when the diet records were collected were asked to complete a food frequency questionnaire regarding their adolescent diet. Food frequency questionnaires and diet records were available for 72 participants. The authors calculated Spearman correlation coefficients between food, food group, and nutrient intakes from the diet records and food frequency questionnaire and deattenuated them to account for the effects of within-person variation measured in the diet records on the association. The median deattenuated correlation for foods was 0.30, ranging from –0.53 for a beef, pork, or lamb sandwich to 0.99 for diet soda. The median deattenuated correlation for food groups was 0.31 (range: –0.48 for breads to 0.70 for hot beverages); for nutrient intakes, it was 0.25 (range: –0.08 for iron to 0.82 for vitamin B12). Some dietary factors were reasonably recalled 3–6 decades later. However, this food frequency questionnaire did not validly measure overall adolescent diet when completed by middle-aged and older adults on average 48 years after adolescence.

Determinants of Percentage and Area Measures of Mammographic Density

Mammographic density is one of the strongest predictors of breast cancer risk. Typically expressed as a percentage of the breast area occupied by radiologically dense tissue on a mammogram, its full value may not be realized because of its negative association with body mass index. A simpler measure of mammographic density, independent of other breast cancer risk factors and equally predictive of risk, would be preferable for risk prediction models. Percentage and area measures of mammographic density were determined for 815 women at high risk for breast cancer from the baseline assessments in the International Breast Cancer Intervention Study I, a trial of tamoxifen for breast cancer prevention conducted between 1992 and 2001. Multivariate linear regression was used to assess associations between risk factors and the mammographic measures. Percent dense area was negatively associated with age, body mass index, menopausal status, predicted risk, and smoking status (R2 = 24%). Dense area was negatively associated with only age and body mass index (R2 = 7%), and the latter association was much weaker than for percent dense area. Nondense area was positively associated with age, body mass index, and predicted risk (R2 = 36%). Dense area was not associated with the multitude of risk factors that percent dense area was, making it a simpler biomarker for risk prediction modeling. Both dense area and percent dense area should be presented whenever possible for comparisons in research.

Eras in Epidemiology: The Evolution of Ideas: By Mervyn Susser and Zena Stein

RE: "ASSOCIATIONS OF GESTATIONAL WEIGHT GAIN WITH SHORT- AND LONGER-TERM MATERNAL AND CHILD HEALTH OUTCOMES"

RE: "ARE AMERICANS FEELING LESS HEALTHY? THE PUZZLE OF TRENDS IN SELF-RATED HEALTH"

THE FIRST AUTHOR REPLIES

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Molecular Sequence Data of Hepatitis B Virus and Genetic Diversity After Vaccination

Invited Commentary: Evaluating Vaccination Programs Using Genetic Sequence Data

Van Ballegooijen et al. Respond to "Evaluating Vaccination Programs Using Genetic Sequence Data"

Sporadic Gastroenteritis and Recreational Swimming in a Longitudinal Community Cohort Study in Melbourne, Australia

Smoking and Risk of Tuberculosis Incidence, Mortality, and Recurrence in South Korean Men and Women

Effect of Supplemental Folic Acid in Pregnancy on Childhood Asthma: A Prospective Birth Cohort Study

Functional Variants in the Catalase and Myeloperoxidase Genes, Ambient Air Pollution, and Respiratory-related School Absences: An Example of Epistasis in Gene-Environment Interactions

Visceral Fat Volume and the Prevalence of Colorectal Adenoma

Use of Nonsteroidal Antiinflammatory Drugs and Risk of Endometrial Cancer

Adherence to the Mediterranean Diet and Risk of Coronary Heart Disease in the Spanish EPIC Cohort Study

Harold A. Kahn (1920-2009): A Remembrance of a Life Devoted to Public Health

Importance of Routine Public Health Influenza Surveillance: Detection of an Unusual W-Shaped Influenza Morbidity Curve

Population-based, Case-Control-Family Design to Investigate Genetic and Environmental Influences on Melanoma Risk: Australian Melanoma Family Study

A Family Longevity Selection Score: Ranking Sibships by Their Longevity, Size, and Availability for Study

Validity of Adolescent Diet Recall 48 Years Later

Determinants of Percentage and Area Measures of Mammographic Density

Eras in Epidemiology: The Evolution of Ideas: By Mervyn Susser and Zena Stein

RE: "ASSOCIATIONS OF GESTATIONAL WEIGHT GAIN WITH SHORT- AND LONGER-TERM MATERNAL AND CHILD HEALTH OUTCOMES"

RE: "ARE AMERICANS FEELING LESS HEALTHY? THE PUZZLE OF TRENDS IN SELF-RATED HEALTH"

THE FIRST AUTHOR REPLIES

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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.

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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

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Molecular Sequence Data of Hepatitis B Virus and Genetic Diversity After Vaccination

Invited Commentary: Evaluating Vaccination Programs Using Genetic Sequence Data

Van Ballegooijen et al. Respond to "Evaluating Vaccination Programs Using Genetic Sequence Data"

Sporadic Gastroenteritis and Recreational Swimming in a Longitudinal Community Cohort Study in Melbourne, Australia

Smoking and Risk of Tuberculosis Incidence, Mortality, and Recurrence in South Korean Men and Women

Effect of Supplemental Folic Acid in Pregnancy on Childhood Asthma: A Prospective Birth Cohort Study

Functional Variants in the Catalase and Myeloperoxidase Genes, Ambient Air Pollution, and Respiratory-related School Absences: An Example of Epistasis in Gene-Environment Interactions

Visceral Fat Volume and the Prevalence of Colorectal Adenoma

Use of Nonsteroidal Antiinflammatory Drugs and Risk of Endometrial Cancer

Adherence to the Mediterranean Diet and Risk of Coronary Heart Disease in the Spanish EPIC Cohort Study

Harold A. Kahn (1920-2009): A Remembrance of a Life Devoted to Public Health

Importance of Routine Public Health Influenza Surveillance: Detection of an Unusual W-Shaped Influenza Morbidity Curve

Population-based, Case-Control-Family Design to Investigate Genetic and Environmental Influences on Melanoma Risk: Australian Melanoma Family Study

A Family Longevity Selection Score: Ranking Sibships by Their Longevity, Size, and Availability for Study

Validity of Adolescent Diet Recall 48 Years Later

Determinants of Percentage and Area Measures of Mammographic Density

Eras in Epidemiology: The Evolution of Ideas: By Mervyn Susser and Zena Stein

RE: "ASSOCIATIONS OF GESTATIONAL WEIGHT GAIN WITH SHORT- AND LONGER-TERM MATERNAL AND CHILD HEALTH OUTCOMES"

RE: "ARE AMERICANS FEELING LESS HEALTHY? THE PUZZLE OF TRENDS IN SELF-RATED HEALTH"

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Molecular Sequence Data of Hepatitis B Virus and Genetic Diversity After Vaccination

Invited Commentary: Evaluating Vaccination Programs Using Genetic Sequence Data

Van Ballegooijen et al. Respond to "Evaluating Vaccination Programs Using Genetic Sequence Data"

Sporadic Gastroenteritis and Recreational Swimming in a Longitudinal Community Cohort Study in Melbourne, Australia

Smoking and Risk of Tuberculosis Incidence, Mortality, and Recurrence in South Korean Men and Women

Effect of Supplemental Folic Acid in Pregnancy on Childhood Asthma: A Prospective Birth Cohort Study

Functional Variants in the Catalase and Myeloperoxidase Genes, Ambient Air Pollution, and Respiratory-related School Absences: An Example of Epistasis in Gene-Environment Interactions

Visceral Fat Volume and the Prevalence of Colorectal Adenoma

Use of Nonsteroidal Antiinflammatory Drugs and Risk of Endometrial Cancer

Adherence to the Mediterranean Diet and Risk of Coronary Heart Disease in the Spanish EPIC Cohort Study

Harold A. Kahn (1920-2009): A Remembrance of a Life Devoted to Public Health

Importance of Routine Public Health Influenza Surveillance: Detection of an Unusual W-Shaped Influenza Morbidity Curve

Population-based, Case-Control-Family Design to Investigate Genetic and Environmental Influences on Melanoma Risk: Australian Melanoma Family Study

A Family Longevity Selection Score: Ranking Sibships by Their Longevity, Size, and Availability for Study

Validity of Adolescent Diet Recall 48 Years Later

Determinants of Percentage and Area Measures of Mammographic Density

Eras in Epidemiology: The Evolution of Ideas: By Mervyn Susser and Zena Stein

RE: "ASSOCIATIONS OF GESTATIONAL WEIGHT GAIN WITH SHORT- AND LONGER-TERM MATERNAL AND CHILD HEALTH OUTCOMES"

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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)

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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