American Journal of Epidemiology - current issue

Persistent Human Papillomavirus Infection and Cervical Neoplasia: A Systematic Review and Meta-Analysis

Koshiol, J., Lindsay, L., Pimenta, J. M., Poole, C., Jenkins, D., Smith, J. S. — 2008-07-04

Detection of persistent cervical carcinogenic human papillomavirus (HPV) DNA is used as a marker for cervical cancer risk in clinical trials. The authors performed a systematic review and meta-analysis of the association between persistent HPV DNA and high-grade cervical intraepithelial neoplasia (CIN2-3), high-grade squamous intraepithelial lesions (HSIL), and invasive cervical cancer (together designated CIN2-3/HSIL+) to evaluate the robustness of HPV persistence for clinical use. MEDLINE and Current Contents were searched through January 30, 2006. Relative risks (RRs) were stratified by HPV comparison group. Of 2,035 abstracts, 41 studies were eligible for inclusion in the meta-analysis. Over 22,500 women were included in calculation of RRs for persistent HPV DNA detection and cervical neoplasia. RRs ranged from 1.3 (95% confidence interval: 1.1, 1.5) to 813.0 (95% confidence interval: 168.2, 3,229.2) for CIN2-3/HSIL+ versus 12 months), wider testing intervals, CIN2-3/HSIL+, and use of an HPV-negative reference group were consistently associated with higher RRs. Thus, HPV persistence was consistently and strongly associated with CIN2-3/HSIL+, despite wide variation in definitions and study methods. The magnitude of association varied by duration of persistence and testing interval. Precise definition and standardization of HPV testing, sampling procedure, and test interval are needed for reliable clinical testing. These findings validate HPV persistence as a clinical marker and endpoint.

Invited Commentary: Is Monitoring of Human Papillomavirus Infection for Viral Persistence Ready for Use in Cervical Cancer Screening?

Castle, P. E. — 2008-07-04

Persistent cervical infections by approximately 15 carcinogenic genotypes of human papillomavirus (HPV) cause virtually all cases of cervical cancer and its immediate precancerous precursor, cervical intraepithelial neoplasia grade 3 or carcinoma in situ. As is shown in a meta-analysis by Koshiol et al. (Am J Epidemiol 2008;168:123–137), detection of carcinogenic HPV viral persistence could be used to identify women at the greatest risk of cervical precancer. Specifically, women who have carcinogenic HPV infection that persists for at least 1 year versus those whose infections clear are at significantly elevated risk of having or developing cervical precancer. However, before detection of HPV persistence can be used in cervical cancer screening, several considerations need to be addressed: 1) validation and Food and Drug Administration approval of a reliable HPV genotyping test, 2) rational clinical algorithms based on risk of precancer and cancer for the clinical management of HPV persistence, 3) clinician and patient acceptability of monitoring of HPV infections (including not responding excessively to the first positive HPV test and waiting 1–2 years for infections to either persist or resolve), and 4) patient compliance with recommended follow-up. Investigators will need to address these and other key issues in order to realize the potential utility of HPV viral monitoring for improving the accuracy of cervical cancer screening.

The Authors Respond to "HPV Persistence and Cervical Cancer Screening"

2008-07-04

Physical Activity during Adulthood and Adolescence in Relation to Renal Cell Cancer

2008-07-04

Evidence for a relation between physical activity and renal cell cancer has been inconsistent. The authors examined physical activity in relation to renal cell cancer in a large, prospective US cohort study of 482,386 participants (289,503 men and 192,883 women) aged 50–71 years at baseline (1995–1996). At baseline, participants reported their frequency of exercise of at least 20 minutes' duration, intensity of daily routine activity, and frequency of physical activity during adolescence. During 8.2 years of follow-up (through December 2003), 1,238 cases of renal cell cancer were ascertained. In multivariate Cox regression models adjusted for renal cell cancer risk factors, the authors observed that current exercise, routine physical activity, and activity during adolescence were associated with a reduced risk of renal cell cancer. The multivariate relative risks for the highest activity level as compared with the lowest were 0.77 (95% confidence interval (CI): 0.64, 0.92; p_trend = 0.10) for current exercise, 0.84 (95% CI: 0.57, 1.22; p_trend = 0.03) for routine physical activity, and 0.82 (95% CI: 0.68, 1.00; p_trend = 0.05) for activity during adolescence. The authors conclude that increased physical activity, including activity during adolescence, is associated with reduced risk of renal cell cancer.

Body Mass Index and Waist Circumference in Relation to Lung Cancer Risk in the Women's Health Initiative

Kabat, G. C., Kim, M., Hunt, J. R., Chlebowski, R. T., Rohan, T. E. — 2008-07-04

Investigators in several epidemiologic studies have observed an inverse association between body mass index (BMI) and lung cancer risk, while others have not. The authors used data from the Women's Health Initiative to study the association of anthropometric factors with lung cancer risk. Over 8 years of follow-up (1998–2006), 1,365 incident lung cancer cases were ascertained among 161,809 women. Cox proportional hazards models were used to estimate hazard ratios adjusted for covariates. Baseline BMI was inversely associated with lung cancer in current smokers (highest quintile vs. lowest: hazard ratio (HR) = 0.62, 95% confidence interval (CI): 0.42, 0.92). When BMI and waist circumference were mutually adjusted, BMI was inversely associated with lung cancer risk in both current smokers and former smokers (HR = 0.40 (95% CI: 0.22, 0.72) and HR = 0.61 (95% CI: 0.40, 0.94), respectively), and waist circumference was positively associated with risk (HR = 1.56 (95% CI: 0.91, 2.69) and HR = 1.50 (95% CI: 0.98, 2.31), respectively). In never smokers, height showed a borderline positive association with lung cancer. These findings suggest that in smokers, BMI is inversely associated with lung cancer risk and that waist circumference is positively associated with risk.

Perinatal Factors and the Risk of Asthma in Childhood--A Population-based Register Study in Finland

2008-07-04

The aim of the study was to assess whether perinatal factors are associated with the risk of asthma in childhood in a register-based, nested case-control study in Finland. All children born between January 1, 1996, and April 30, 2004, who were entitled to a special reimbursement for antiasthmatic drugs (i.e., had diagnosed asthma by 2006 and had purchased inhaled corticosteroids or montelukast at least once), were identified (n = 21,038). For each case, one matched control child was selected. The associations between perinatal factors, derived from the Finnish Medical Birth Register, and the risk of asthma were analyzed by conditional logistic regression. In the final multivariate model, maternal asthma, young age, smoking, previous miscarriages, and a high number of previous deliveries, as well as cesarean section, low gestational age, and low ponderal index, were associated with an increased risk of asthma in children diagnosed before the age of 3 years. Among children diagnosed at the age of 3 years or later, maternal asthma, low gestational age, and low ponderal index were associated with an increased risk, and a high number of previous deliveries was associated with a decreased risk of asthma. In conclusion, perinatal factors play a role in the development of asthma in childhood, but the etiology may differ in early and late-onset asthma.

Early Life Growth and Hemostatic Factors: The Barry Caerphilly Growth Study

2008-07-04

Associations between early life growth trajectories and a range of adult (aged ~25 years) hemostatic factors were assessed in the Barry Caerphilly Growth study (N = 517) in South Wales, 1974–1999. Associations of birth weight, birth length, and weight and height velocities during three periods ("immediate": 0–<5 months, "infant": 5 months–<1 year 9 months, and "childhood": 1 year 9 months–5 years) with adult levels of hemostatic factors were assessed. Birth weight was inversely associated with fibrinogen (β per 1-unit change in z score = –0.08, 95% confidence interval (CI): –0.15, –0.02). Immediate weight velocity was inversely associated with factor VII (β = –1.88, 95% CI: –3.84, 0.09), factor VIII (β = –2.58, 95% CI: –4.07, –0.45), and von Willebrand factor antigen (β = –4.07, 95% CI: –7.25, –0.89). Birth length was inversely associated with fibrinogen (β = –0.07, 95% CI: –0.14, –0.01). Evidence was weaker for an inverse association of immediate height velocity with factor VIII (β = –2.16, 95% CI: –4.62, 0.29) and von Willebrand factor antigen (β = –2.85, 95% CI: –6.52, 0.81). Childhood height velocity was positively associated with D-dimer (ratio of geometric means = 1.11, 95% CI: 1.01, 1.23). Results support the view that the immediate postnatal period may be particularly important, possibly through impaired liver development and/or infection in early life, in determining cardiovascular disease risk.

A Longitudinal Study of Vaginal Douching and Bacterial Vaginosis--A Marginal Structural Modeling Analysis

2008-07-04

The etiology of bacterial vaginosis is unknown, and there are no long-term therapies for preventing this frequently recurring condition. Vaginal douching has been reported to be associated with bacterial vaginosis in observational studies. However, this association may be due to confounding by indication—that is, confounding by women douching in response to vaginal symptoms associated with bacterial vaginosis. The authors used marginal structural modeling to estimate the causal effect of douching on bacterial vaginosis risk while controlling for this confounding effect. In 1999–2002, nonpregnant women (n = 3,620) were recruited into a prospective study when they visited one of 12 public health clinics in Birmingham, Alabama, for routine care. Participants were assessed quarterly for 1 year. Bacterial vaginosis was based on a Nugent's Gram stain score of 7 or higher. Thirty-two percent of participants douched in every study interval, and 43.0% never douched. Of the 12,349 study visits, 40.2% were classified as involving bacterial vaginosis. The relative risk for regular douching as compared with no douching was 1.21 (95% confidence interval: 1.08, 1.38). These findings indicate that douching confers increased risk of disruption of vaginal flora. In the absence of a large randomized trial, these findings provide the best evidence to date for a risk of bacterial vaginosis associated with douching.

Population Stratification Bias in the Case-Only Study for Gene-Environment Interactions

Wang, L.-Y., Lee, W.-C. — 2008-07-04

The case-only study is a convenient approach and provides increased statistical efficiency in detecting gene-environment interactions. The validity of a case-only study hinges on one well-recognized assumption: The susceptibility genotypes and the environmental exposures of interest are independent in the population. Otherwise, the study will be biased. The authors show that hidden stratification in the study population could also ruin a case-only study. They derive the formulas for population stratification bias. The bias involves three terms: 1) the coefficient of variation of the exposure prevalence odds, 2) the coefficient of variation of the genotype frequency odds, and 3) the correlation coefficient between the exposure prevalence odds and the genotype frequency odds. The authors perform simulation to investigate the magnitude of bias over a wide range of realistic scenarios. It is found that the estimated interaction effect is frequently biased by more than 5%. For a rarer gene and a rarer exposure, the bias becomes even larger (>30%). Because of the potentially large bias, researchers conducting case-only studies should use the boundary formula presented in this paper to make more prudent interpretations of their results, or they should use stratified analysis or a modeling approach to adjust for population stratification bias in their studies.

Using Sexually Transmitted Infection Biomarkers to Validate Reporting of Sexual Behavior within a Randomized, Experimental Evaluation of Interviewing Methods

2008-07-04

This paper examines the reporting of sexual and other risk behaviors within a randomized experiment using a computerized versus face-to-face interview mode. Biomarkers for sexually transmitted infection (STI) were used to validate self-reported behavior by interview mode. As part of a parent study evaluating home versus clinic screening and diagnosis for STIs, 818 women aged 18–40 years were recruited in 2004 at or near a primary care clinic in São Paulo, Brazil, and were randomized to a face-to-face interview or audio computer-assisted self-interviewing. Ninety-six percent of participants were tested for chlamydia, gonorrhea, and trichomoniasis. Reporting of STI risk behavior was consistently higher with the computerized mode of interview. Stronger associations between risk behaviors and STI were found with the computerized interview after controlling for sociodemographic factors. These results were obtained by using logistic regression approaches, as well as statistical methods that address potential residual confounding and covariate endogeneity. Furthermore, STI-positive participants were more likely than STI-negative participants to underreport risk behavior in the face-to-face interview. Results strongly suggest that computerized interviewing provides more accurate and reliable behavioral data. The analyses also confirm the benefits of using data on prevalent STIs for externally validating behavioral reporting.

On the Estimation of Additive Interaction by Use of the Four-by-two Table and Beyond

Zou, G. Y. — 2008-07-04

A four-by-two table with its four rows representing the presence and absence of gene and environmental factors has been suggested as the fundamental unit in the assessment of gene-environment interaction. For such a table to be more meaningful from a public health perspective, it is important to estimate additive interaction. A confidence interval procedure proposed by Hosmer and Lemeshow has become widespread. This article first reveals that the Hosmer-Lemeshow procedure makes an assumption that confidence intervals for risk ratios are symmetric and then presents an alternative that uses the conventional asymmetric intervals for risk ratios to set confidence limits for measures of additive interaction. For the four-by-two table, the calculation involved requires no statistical programs but only elementary calculations. Simulation results demonstrate that this new approach can perform almost as well as the bootstrap. Corresponding calculations in more complicated situations can be simplified by use of routine output from multiple regression programs. The approach is illustrated with three examples. A Microsoft Excel spreadsheet and SAS codes for the calculations are available from the author and the Journal's website, respectively.

Impact of New Biomarkers of Myocardial Damage on Trends in Myocardial Infarction Hospital Admission Rates from Population-based Administrative Data

Sanfilippo, F. M., Hobbs, M. S. T., Knuiman, M. W., Hung, J. — 2008-07-04

Use of troponin testing in the diagnosis of myocardial infarction substantially increases the number of cases diagnosed as myocardial infarction among suspected cases in comparison with previous criteria. However, the impact of troponin testing on rates reported in national statistics that use routinely collected hospital morbidity data is uncertain. The authors developed Poisson regression models to estimate the effect of troponin testing on long-term trends in hospital admission rates in Perth, Western Australia, from 1980 to 2004. Troponin tests were used for 10.5% of patients with suspected myocardial infarction in 1996, rising rapidly to more than 90% of patients from 2001 onward. Fitted models that assumed a continuing linear decline estimated that 100% use of troponin testing in cases of suspected myocardial infarction would lead to an apparent increase in hospital admission rates of 42% (95% confidence interval (CI): 28, 56) in men and 21% (95% CI: 4, 41) in women as compared with rates that would be expected if previous linear trends had continued. Smaller effects of 30% (95% CI: 14, 48) in men and –2% (95% CI: –21, 20) in women were found in fitted models that assumed an underlying attenuating trend in the rates. Similarly constructed logistic regression trend models found no significant effect of troponin testing on trends in 28-day case-fatality.

RE: "PREVALENCE OF AND RISK FACTORS FOR URINE LEAKAGE IN A RACIALLY AND ETHNICALLY DIVERSE POPULATION OF ADULTS: THE BOSTON AREA COMMUNITY HEALTH (BACH) SURVEY"

McGrother, C. W., Donaldson, M. M. K., Thompson, J. R. — 2008-07-04

THE AUTHORS REPLY

Tennstedt, S. L., Link, C. L., Steers, W. D., McKinlay, J. B. — 2008-07-04

THE AUTHOR OF THE INVITED COMMENTARY REPLIES

Thom, D. H. — 2008-07-04

RE: "MATERNAL FISH INTAKE DURING PREGNANCY, BLOOD MERCURY LEVELS, AND CHILD COGNITION AT AGE 3 YEARS IN A US COHORT"

Groth, E. — 2008-07-04