American Journal of Epidemiology update - june 7
Alcohol Drinking and Colorectal Cancer in Japanese: A Pooled Analysis of Results from Five Cohort Studies
Colorectal cancer is an alcohol-related malignancy; however, the association appears to be stronger among Asian populations with a relatively high prevalence of the slow-metabolizing aldehyde dehydrogenase variant. To examine the association between alcohol consumption and colorectal cancer in Japanese, the authors analyzed original data from five cohort studies that measured alcohol intake using validated questionnaires at baseline. Hazard ratios were calculated in the individual studies, with adjustment for a common set of variables, and then combined using a random-effects model. During 2,231,010 person-years of follow-up (ranging variously from 1988 to 2004), 2,802 colorectal cancer cases were identified. In men, multivariate-adjusted pooled hazard ratios for alcohol intakes of 23–45.9 g/day, 46–68.9 g/day, 69–91.9 g/day, and ?92 g/day, compared with nondrinking, were 1.42 (95% confidence interval (CI): 1.21, 1.66), 1.95 (95% CI: 1.53, 2.49), 2.15 (95% CI: 1.74, 2.64), and 2.96 (95% CI: 2.27, 3.86), respectively (p for trend < 0.001). The association was evident for both the colon and the rectum. A significant positive association was also observed in women. One fourth of colorectal cancer cases in men were attributable to an alcohol intake of ?23 g/day. An alcohol-colorectal cancer association seems to be more apparent in Japanese than in Western populations. Whether this difference can be ascribed to genetic or environmental factors needs to be clarified.
Conjugated Equine Estrogens and Breast Cancer Risk in the Women’s Health Initiative Clinical Trial and Observational Study
The Women’s Health Initiative randomized controlled trial found a trend (p = 0.09) toward a lower breast cancer risk among women assigned to daily 0.625-mg conjugated equine estrogens (CEEs) compared with placebo, in contrast to an observational literature that mostly reports a moderate increase in risk with estrogen-alone preparations. In 1993–2004 at 40 US clinical centers, breast cancer hazard ratio estimates for this CEE regimen were compared between the Women’s Health Initiative clinical trial and observational study toward understanding this apparent discrepancy and refining hazard ratio estimates. After control for prior use of postmenopausal hormone therapy and for confounding factors, CEE hazard ratio estimates were higher from the observational study compared with the clinical trial by 43% (p = 0.12). However, after additional control for time from menopause to first use of postmenopausal hormone therapy, the hazard ratios agreed closely between the two cohorts (p = 0.82). For women who begin use soon after menopause, combined analyses of clinical trial and observational study data do not provide clear evidence of either an overall reduction or an increase in breast cancer risk with CEEs, although hazard ratios appeared to be relatively higher among women having certain breast cancer risk factors or a low body mass index.
Invited Commentary: Postmenopausal Unopposed Estrogen and Breast Cancer Risk in the Women’s Health Initiative–Before and Beyond
Three large clinical trials provoked major debate when hormone replacement therapy (HRT) did not reduce coronary heart disease in postmenopausal women as expected from observational epidemiologic studies. Less discussion has ensued about breast cancer or other adverse events. In this issue of the Journal, investigators from the Women’s Health Initiative (WHI) compare breast cancer findings from the randomized trial of unopposed estrogen with those from the large WHI observational study. This commentary briefly summarizes historical highlights of menopausal hormone use; risk-versus-benefit evaluations; scientific, clinical, and policy influences immediately before and during the WHI trial; breast cancer incidence trends; and the posttrial response in US clinical practice. Factors complicating interpretation of the results include differences in breast cancer risk profiles between women in the trial and those in the observational study cohort as well as heterogeneity in the definitions of menopause and prior use of HRT as applied by the WHI investigators to the two populations. Because millions of women use HRT, it is important to consider how the WHI and other research investigations might contribute to reducing gaps in understanding the relation between HRT and breast cancer risk.
Are Patients with Skin Cancer at Lower Risk of Developing Colorectal or Breast Cancer?
Ultraviolet exposure may reduce the risk of colorectal and breast cancer as the result of rising vitamin D levels. Because skin cancer is positively related to sun exposure, the authors hypothesized a lower incidence of breast and colorectal cancer after skin cancer diagnosis. They analyzed the incidence of colorectal and breast cancer diagnosed from 1972 to 2002 among 26,916 Netherlands skin cancer patients (4,089 squamous cell carcinoma (SCC), 19,319 basal cell carcinoma (BCC), and 3,508 cutaneous malignant melanoma (CMM)). Standardized incidence ratios were calculated. A markedly decreased risk of colorectal cancer was found for subgroups supposedly associated with the highest accumulated sun exposure: men (standardized incidence ratio (SIR) = 0.83, 95% confidence interval (CI): 0.71, 0.97); patients with SCC (SIR = 0.64, 95% CI: 0.43, 0.93); older patients at SCC diagnosis (SIR = 0.59, 95% CI: 0.37, 0.88); and patients with a SCC or BCC lesion on the head and neck area (SIR = 0.59, 95% CI: 0.36, 0.92 for SCC and SIR = 0.78, 95% CI: 0.63, 0.97 for BCC). Patients with CMM exhibited an increased risk of breast cancer, especially advanced breast cancer (SIR = 2.20, 95% CI: 1.10, 3.94) and older patients at CMM diagnosis (SIR = 1.87, 95% CI: 1.14, 2.89). Study results suggest a beneficial effect of continuous sun exposure against colorectal cancer. The higher risk of breast cancer among CMM patients may be related to socioeconomic class, both being more common in the affluent group.
Analgesic Drug Use and Risk of Epithelial Ovarian Cancer
Analgesic use may reduce ovarian cancer risk, possibly through antiinflammatory or antigonadotropic effects. The authors conducted a population-based, case-control study in Washington State that included 812 women aged 35–74 years who were diagnosed with epithelial ovarian cancer between 2002 and 2005 and 1,313 controls. Use of analgesics, excluding use within the previous year, was assessed via in-person interviews. Logistic regression was used to calculate odds ratios and 95% confidence intervals. Overall, acetaminophen and aspirin were associated with weakly increased risks of ovarian cancer. These associations were stronger after more than 10 years of use (acetaminophen: odds ratio (OR) = 1.8, 95% confidence interval (CI): 1.3, 2.6; aspirin: OR = 1.6, 95% CI: 1.1, 2.2) and were present for indications of headache, menstrual pain, and other pain/injury. Reduced risk was observed among aspirin users who began regular use within the previous 5 years (OR = 0.6, 95% CI: 0.4, 1.0) or used this drug for prevention of heart disease (OR = 0.7, 95% CI: 0.5, 1.0). These results, in the context of prior findings, do not provide compelling evidence of a true increase in risk of ovarian cancer among women who use these drugs. However, they add to the weight of evidence that, in the aggregate, provides little support for the use of analgesic drugs as chemoprevention for this disease.
Insulin-like Growth Factor 1, Insulin-like Growth Factor-Binding Protein 3, and Testicular Germ-Cell Tumor Risk
Studies have consistently shown that taller men are at increased risk of testicular germ-cell tumors. Thus, it is plausible that factors associated with height may also influence risk of these tumors. The authors examined associations between testicular germ-cell tumor risk and circulating concentrations of insulin-like growth factor 1 (IGF-1) and insulin-like growth factor-binding protein 3 (IGFBP-3) among 517 cases and 790 controls from the US Servicemen’s Testicular Tumor Environmental and Endocrine Determinants (STEED) Study (2002–2005). Odds ratios and 95% confidence intervals were estimated using logistic regression models, adjusting for age, race/ethnicity, height, and body mass index. All tests of significance were two-sided. Overall, there were no associations between IGF-1 or IGFBP-3 concentrations and risk of testicular germ-cell tumors (p > 0.05). However, when cases were separated by histologic type, there was a suggestion of a reduction in seminoma risk associated with the highest concentrations of IGF-1 as compared with the lowest concentrations (odds ratio = 0.66, 95% confidence interval: 0.40, 1.09). Although there were no overall associations with insulin-like growth factor, contrary to expectation, there was a suggestion that IGF-1 concentrations may be inversely associated with risk of seminoma.
Understanding Sequelae of Injury Mechanisms and Mild Traumatic Brain Injury Incurred during the Conflicts in Iraq and Afghanistan: Persistent Postconcussive Symptoms and Posttraumatic Stress Disorder
A cross-sectional study of military personnel following deployment to conflicts in Iraq or Afghanistan ascertained histories of combat theater injury mechanisms and mild traumatic brain injury (TBI) and current prevalence of posttraumatic stress disorder (PTSD) and postconcussive symptoms. Associations among injuries, PTSD, and postconcussive symptoms were explored. In February 2005, a postal survey was sent to Iraq/Afghanistan veterans who had left combat theaters by September 2004 and lived in Maryland; Washington, DC; northern Virginia; and eastern West Virginia. Immediate neurologic symptoms postinjury were used to identify mild TBI. Adjusted prevalence ratios and 95% confidence intervals were computed by using Poisson regression. About 12% of 2,235 respondents reported a history consistent with mild TBI, and 11% screened positive for PTSD. Mild TBI history was common among veterans injured by bullets/shrapnel, blasts, motor vehicle crashes, air/water transport, and falls. Factors associated with PTSD included reporting multiple injury mechanisms (prevalence ratio = 3.71 for three or more mechanisms, 95% confidence interval: 2.23, 6.19) and combat mild TBI (prevalence ratio = 2.37, 95% confidence interval: 1.72, 3.28). The strongest factor associated with postconcussive symptoms was PTSD, even after overlapping symptoms were removed from the PTSD score (prevalence ratio = 3.79, 95% confidence interval: 2.57, 5.59).
Familial Aggregation of Cryptorchidism–A Nationwide Cohort Study
Although cryptorchidism is the most common birth defect in boys affecting 4–9 percent of newborns and 1–2 percent of boys 1 year of age, the etiology remains largely unknown. The authors investigated the contribution of genetic and environmental factors to familial aggregation of cryptorchidism. Using Danish health registers, they identified 25,395 boys diagnosed with cryptorchidism in a cohort of 1,022,713 boys born in 1977–2005. Using binomial log-linear regression, they estimated recurrence risk ratios (RRRs) of cryptorchidism for male twin pairs and first-, second-, and third-degree relatives of a cryptorchidism case. The RRR in same-sex twins was 10.1 (95% confidence interval (CI): 7.78, 13.1). The RRR among first-degree relatives was significantly higher among brothers (RRR = 3.52, 95% CI: 3.26, 3.79) than for offspring of a cryptorchidism case (RRR = 2.31, 95% CI: 2.09, 2.54). The RRR was also found to be significantly higher in maternal (RRR = 2.12, 95% CI: 1.74, 2.60) than paternal (RRR = 1.28, 95% CI: 1.01, 1.61) half brothers. In conclusion, inherited factors were found to have a moderate influence on the risk of cryptorchidism. The data are compatible with the hypothesis that maternal factors operating in utero are important for the risk of cryptorchidism.
Parental Subfecundity and Risk of Decreased Semen Quality in the Male Offspring: A Follow-up Study
A few studies have found poor semen quality in sons whose mothers have received fertility treatment, but it is unknown whether the poor semen quality is related to the infertility treatment or to infertility per se, for example, whether it is caused by hereditable factors. Using data from a population-based, Danish follow-up study conducted in 2005–2006, the authors of the present study examined whether sons of subfertile couples who had not received fertility treatment had poorer semen quality than sons of fertile couples. Among the 311 participants, an inverse association between parental waiting time to pregnancy and both semen volume and total sperm count was observed (p trend = 0.04 and p trend = 0.046, respectively). Semen volume in sons of subfertile parents (pregnant after ?1 years) was 19% lower in comparison with that in sons of parents whose waiting time to pregnancy was 0–6 months (p = 0.02). Additionally, sperm concentration and percentage of morphologically normal sperm were, respectively, 22% (p = 0.15) and 23% (p = 0.13) lower in sons of subfertile parents. Results suggest a small-to-moderate effect of parental subfecundity on semen quality in sons, comparable with the hypothesis that low fecundity has at least partly hereditable causes.
Waist Circumference and Mortality
The authors examined the association between waist circumference and mortality among 154,776 men and 90,757 women aged 51–72 years at baseline (1996–1997) in the NIH-AARP Diet and Health Study. Additionally, the combined effects of waist circumference and body mass index (BMI; weight (kg)/height (m)2) were examined. All-cause mortality was assessed over 9 years of follow-up (1996–2005). After adjustment for BMI and other covariates, a large waist circumference (fifth quintile vs. second) was associated with an approximately 25% increased mortality risk (men: hazard ratio (HR) = 1.22, 95% confidence interval (CI): 1.15, 1.29; women: HR = 1.28, 95% CI: 1.16, 1.41). The waist circumference-mortality association was found in persons with and without prevalent disease, in smokers and nonsmokers, and across different racial/ethnic groups (non-Hispanic Whites, non-Hispanic Blacks, Hispanics, and Asians). Compared with subjects with a combination of normal BMI (18.5–<25) and normal waist circumference, those in the normal-BMI group with a large waist circumference (men: ?102 cm; women: ?88 cm) had an approximately 20% higher mortality risk (men: HR = 1.23, 95% CI: 1.08, 1.39; women: HR = 1.22, 95% CI: 1.09, 1.36). The finding that persons with a normal BMI but a large waist circumference had a higher mortality risk in this study suggests that increased waist circumference should be considered a risk factor for mortality, in addition to BMI.
Does Temperature Modify the Association between Air Pollution and Mortality? A Multicity Case-Crossover Analysis in Italy
Adverse health effects of particulate matter <10 µm in aerodynamic diameter (PM10) and high temperatures are well known, but the extent of their interaction on mortality is less clear. This paper describes effect modification of temperature in the PM10–mortality association and tests the hypothesis that higher PM10 effects in summer are due to enhanced exposure to particles. All deaths of residents of nine Italian cities between 1997 and 2004 were selected. The case-crossover approach was adopted to estimate the effect of PM10 on mortality by season and temperature level. Three strata of temperature corresponding to low, medium, and high “ventilation” were identified, and the interaction between PM10 and temperature within each stratum was examined. Season and temperature levels strongly modified the PM10–mortality association: for a 10-µg/m3 variation in PM10, a 2.54% increase in risk of death in summer (95% confidence interval: 1.31, 3.78) compared with 0.20% (95% confidence interval: –0.08, 0.49) in winter. Analysis of the interaction between PM10 and temperature within temperature strata resulted in positive but, in most cases, nonstatistically significant coefficients. The authors found much higher PM10 effects on mortality during warmer days. The hypothesis that such an effect is attributable to enhanced exposure to particles in summer could not be rejected.
Diabetic Control and Risk of Tuberculosis: A Cohort Study
Diabetes mellitus is associated with tuberculosis. A cohort of 42,116 clients aged 65 years or more, enrolled at 18 Elderly Health Service centers in Hong Kong in 2000, were followed up prospectively through the territory-wide tuberculosis registry for development of tuberculosis from 3 months after enrollment to December 31, 2005, by use of their identity card numbers as unique identifier. The effects of diabetes mellitus and diabetic control on tuberculosis risk were assessed with adjustment for sociodemographic and other background variables. Diabetes mellitus was associated with a modest increase in the risk of active, culture-confirmed, and pulmonary (with or without extrapulmonary involvement) but not extrapulmonary (with or without pulmonary involvement) tuberculosis, with adjusted hazard ratios of 1.77 (95% confidence interval: 1.41, 2.24), 1.91 (95% confidence interval: 1.45, 2.52), 1.89 (95% confidence interval: 1.48, 2.42), and 1.00 (95% confidence interval: 0.54, 1.86), respectively. Diabetic subjects with hemoglobin A1c <7% at enrollment were not at increased risk. Among diabetic subjects, higher risks of active, culture-confirmed, and pulmonary but not extrapulmonary tuberculosis were observed with baseline hemoglobin A1c ?7% (vs. <7%), with adjusted hazard ratios of 3.11 (95% confidence interval: 1.63, 5.92), 3.08 (95% confidence interval: 1.44, 6.57), 3.63 (95% confidence interval: 1.79, 7.33), and 0.77 (95% confidence interval: 0.18, 3.35), respectively.
Geographic Prevalence and Multilevel Determination of Community-level Factors Associated with Herpes Simplex Virus Type 2 Infection in Chennai, India
Herpes simplex virus type 2 (HSV-2) is one of the most prevalent sexually transmitted infections, and it increases the risk of transmission of human immunodeficiency virus type 1 at least twofold. Individual-level factors are insufficient to explain geographic and population variation in HSV-2, suggesting the need to identify ecologic factors. The authors sought to determine the geographic prevalence and community-level factors associated with HSV-2 after controlling for individual-level factors among slums in Chennai, India. From March to June 2001, participants aged 18–40 years voluntarily completed a survey and were tested for HSV-2. Community characteristics were assessed through interviews with key informants and other secondary data sources. Multilevel nonlinear analysis was conducted. Eighty-five percent of eligible persons completed the survey; of these, 98% underwent HSV-2 testing, producing a final sample of 1,275. Participants were of Tamil ethnicity, were predominantly female and married, and were on average 30 years old. Fifteen percent were infected with HSV-2, and there was significant variation in HSV-2 prevalence among communities. After controlling for individual-level factors, the authors identified community-level factors, including socioeconomic status and the presence of injection drug users, that were independently associated with HSV-2 and explained 11% of the variance in prevalence. Future studies are needed to test mechanisms through which these community-level factors may be operating.
Assessment of Selection Bias in the Canadian Case-Control Study of Residential Magnetic Field Exposure and Childhood Leukemia
The authors evaluated the role of selection bias in the 1999 Canadian case-control study of residential magnetic field exposure and childhood leukemia. They included cases, participating controls, and first-choice nonparticipating controls in their analyses. Exposure was assessed by wire coding, a classification system based on the distribution line characteristics near homes. Although an imperfect measure of magnetic field exposure, wire coding is the only method applicable to nonparticipating subjects. First-choice nonparticipant controls tended to be of lower socioeconomic status than their replacements (non-first-choice participant controls), and lower socioeconomic status was related to higher wire code categories. The odds ratios for developing childhood leukemia in the highest exposure category were 1.6 (95% confidence interval: 1.0, 2.6) when the actual participating controls were used and 1.3 (95% confidence interval: 0.8, 2.1) when the first-choice ideal controls were used, regardless of their participation. Overall, the authors conclude that, although there is some evidence for control selection or participation bias in the Canadian study, it is unlikely to explain entirely the observed association between magnetic field exposure and childhood leukemia. Inherent problems in exposure assessment for nonparticipating subjects, however, limit the interpretations of these results, and the role of selection bias cannot entirely be dismissed on the basis of these results alone.
A Regression Approach for Estimating Multiday Adverse Health Effects of PM10 When Daily PM10 Data Are Unavailable
The authors propose a regression-based approach for obtaining multiday estimates of the adverse health effects of ambient particulate matter less than 10 µm in diameter (PM10) when daily PM10 time-series data are unavailable. This situation is common in the United States, because most US cities take PM10 measurements every 6 days. Current evidence suggests that adverse effects of PM10 are not concentrated on a single day but rather are spread out over multiple days, so the unavailability of daily PM10 data presents a problem for the estimation of these effects. The proposed model estimates weights that are used to construct a linear combination of single-lag PM10 effect estimates obtained from the available PM10 data. It is shown that this new approach provides estimates of the effect of PM10 on mortality that have less bias and mean squared error than currently available methods. Application of this method to the US cities contained in the National Morbidity, Mortality, and Air Pollution Study database produces an estimated national average effect of PM10 on nonaccidental mortality in persons over age 65 years, corresponding to a 0.32% increase per 10-µg/m3 increment in PM10. The estimated effects for cardiorespiratory mortality and other mortality are 0.34% and 0.22%, respectively.
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