Exposure to benzene and other hydrocarbons and risk of bladder cancer among male offshore petroleum workers.

BACKGROUND: Occupational exposures constitute the second leading cause of urinary bladder cancer after tobacco smoking. Increased risks have been found in the petroleum industry, but high-quality exposure data are needed to explain these observations. METHODS: Using a prospective case-cohort design, we analysed 189 bladder cancer cases (1999-2017) and 2065 randomly drawn non-cases from the Norwegian Offshore Petroleum Workers cohort. Cases were identified in the Cancer Registry of Norway, while work histories (1965-1998) and lifestyle factors were recorded by questionnaire at baseline (1998). Occupational petroleum-related hydrocarbon exposures were assessed by expert-developed job-exposure matrices. Hazard ratios were estimated by weighted Cox-regressions, adjusted for age, tobacco smoking, education, and year of first employment, and with lagged exposures. RESULTS: Increased risks were found in benzene-exposed workers, either long-term exposure (≥18.8 years, HR = 1.89, 95% CI: 1.14-3.13; p-trend = 0.044) or high-level cumulative benzene exposure (HR = 1.60, 95% CI: 0.97-2.63; p-trend = 0.065), compared with the unexposed. Associations persisted with 20-year exposure lag. No associations were found with skin or inhalation exposure to crude oil, mineral oil (lubrication, hydraulics, turbines, drilling), or diesel exhaust. CONCLUSIONS: The results suggest that exposures in the benzene fraction of the petroleum stream may be associated with increased bladder cancer risk.

The cure model in perinatal epidemiology.

In the statistical literature, the class of survival analysis models known as cure models has received much attention in recent years. Cure models seem not, however, to be part of the statistical toolbox of perinatal epidemiologists. In this paper, we demonstrate that in perinatal epidemiological studies where one investigates the relation between a gestational exposure and a condition that can only be ascertained after several years, cure models may provide the correct statistical framework. The reason for this is that the hypotheses being tested often concern an unobservable outcome that, in view of the hypothesis, should be thought of as occurring at birth, even though it is only detectable much later in life. The outcome of interest can therefore be viewed as a censored binary variable. We illustrate our argument with a simple cure model analysis of the possible relation between gestational exposure to paracetamol and attention-deficit hyperactivity disorder, using data from the Norwegian Mother, Father and Child Cohort Study conducted by the Norwegian Institute of Public Health, and information about the attention-deficit hyperactivity disorder diagnoses obtained from the Norwegian Patient Registry.

Adjusting for unmeasured confounding using validation data: Simplified two-stage calibration for survival and dichotomous outcomes.

In epidemiology, one typically wants to estimate the risk of an outcome associated with an exposure after adjusting for confounders. Sometimes, outcome and exposure and maybe some confounders are available in a large data set, whereas some important confounders are only available in a validation data set that is typically a subset of the main data set. A generally applicable method in this situation is the two-stage calibration (TSC) method. We present a simplified easy-to-implement version of the TSC for the case where the validation data are a subset of the main data. We compared the simplified version to the standard TSC version for incidence rate ratios, odds ratios, relative risks, and hazard ratios using simulated data, and the simplified version performed better than our implementation of the standard version. The simplified version was also tested on real data and performed well.

Re-examining the link between prenatal maternal anxiety and child emotional difficulties, using a sibling design.

Background: Prenatal exposure to maternal anxiety has been associated with child emotional difficulties in a number of epidemiological studies. One key concern, however, is that this link is vulnerable to confounding by pleiotropic genes or environmental family factors. Methods: Data on 82 383 mothers and children from the population-based Mother and Child Cohort Study and data on 21 980 siblings were used in this study. Mothers filled out questionnaires for each unique pregnancy, for infant difficulties at 6 months and for emotional difficulties at 36 months. The link between prenatal maternal anxiety and child difficulties were examined using logistic regression analyses and multiple linear regression analyses for the full study sample and the sibling sample. Results: In the conventional full-cohort analyses, prenatal exposure to maternal anxiety was associated with child difficulties at both 6 months [odds ratio (OR) = 2.1 (1.94-2.27)] and 36 months [OR = 2.72 (2.47-2.99)]. The findings were essentially the same whether we examined difficulties at 6 months or at 36 months. However, these associations were no longer present once we controlled for potential social and genetic confounders in the sibling comparison analyses, either at 6 months [OR = 1.32 (0.91-1.90)] or at 36 months [OR = 1.28 (0.63-2.60)]. Findings from multiple regression analyses with continuous measures were essentially the same. Conclusions: Our finding lends little support for there being an independent prenatal effect on child emotional difficulties; rather, our findings suggest that the link between prenatal maternal anxiety and child difficulties could be confounded by pleiotropic genes or environmental family factors.

Long Term Association between Serum 25-Hydroxyvitamin D and Mortality in a Cohort of 4379 Men.

OBJECTIVE: A number of observational studies have shown an inverse association between circulating 25-hydroxyvitamin D and total mortality, but a reverse J-shaped association has also been reported. In a large nested case-control study, serum-25-hydroxyvitamin D (s-25(OH)D) was positively associated with incident prostate cancer. Based on the same study population, the primary aim of the present study was to investigate the association between s-25(OH)D and total mortality. METHODS: Men participating in population based health screenings during 1981-1991 and enrolled in a nested case-control study were followed throughout 2007 with respect to all-cause and cause-specific mortality. Hazard ratios (HR) with 95% confidence intervals (CI) were calculated using Cox proportional hazards regression. RESULTS: In men with prostate cancer (n = 2282), there was a significant inverse association between s-25(OH)D and total mortality after controlling for potential confounders (HR = 1.25 (95% CI 1.05-1.50), s-25(OH)D <50 nmol/l versus s-25(OH)D ≥ 50 nmol/l). The corresponding figure among controls (n = 2147) was HR = 1.15 (95% CI 0.88-1.50) and in the total study population HR = 1.19 (95% CI 1.03-1.38). For cause-specific deaths, we found no significant associations. CONCLUSIONS: In this study population, s-25(OH)D was inversely associated with total mortality during more than two decades of follow-up, despite, as previous reported, high s-25(OH)D was associated with increased risk of prostate cancer.

Fetal death and placental weight/birthweight ratio: a population study.

OBJECTIVE: To study the association of placental weight and placental weight/birthweight ratio with gestational age-specific fetal death. DESIGN: Population-based study. SETTING: Medical Birth Registry of Norway. POPULATION: All singleton births in Norway, 1999-2008 (n = 534 892). METHODS: Gestational age-specific quartiles of placental weight and placental weight/birthweight ratio were estimated, and proportions of fetal deaths and live births within the lowest and highest quartile were compared. The risk of fetal death associated with placental weight/birthweight ratio was estimated as crude and adjusted odds ratios. MAIN OUTCOME MEASURES: Offspring vital status. RESULTS: Pregnancies with fetal death were overrepresented in the lowest quartile of placental weight and placental weight/birthweight ratio in term and preterm deliveries. In preterm deliveries, fetal deaths were also overrepresented in the highest placental weight/birthweight ratio. Adjusted odds ratio of fetal death in preterm deliveries was 1.67 (95% confidence interval 1.44-1.94) for placental weight/birthweight ratio in the lowest quartile and 1.79 (95% confidence interval 1.55-2.08) in the highest quartile. Corresponding odds ratios for deliveries at term were 1.76 (95% confidence interval 1.50-2.06) and 1.18 (95% confidence interval 0.99-1.41). CONCLUSIONS: Both small and large placentas relative to birthweight were associated with fetal death in preterm births. At term, only small placentas relative to birthweight were associated with fetal death. Understanding the mechanisms behind the increased risk of adverse pregnancy outcomes in pregnancies with disproportionate placental weight/birthweight ratio may be important for prevention of fetal deaths.

Helicobacter pylori infection and severe hyperemesis gravidarum among immigrant women in Norway: a case-control study.

OBJECTIVE: To study associations between Helicobacter pylori exposure and severe hyperemesis gravidarum (HG) among immigrant women in Norway by exploring IgG seropositivity and H. pylori antigens in faeces. Additionally, we investigated whether cytotoxin-associated gene A product (CagA) and vacuolating cytotoxin A (VacA) seropositivity modulated this association. STUDY DESIGN: An institution-based case-control study among immigrant women in Norway was performed at Ullevål and Akershus University Hospitals in September 2005-December 2007. Blood samples were used to explore IgG, CagA and VacA seropositivity, and faecal samples were used to explore the presence of antigens. Multiple logistic regressions were used to study associations between HG and H. pylori exposure. RESULTS: The sample comprised 170 women: 62 cases and 108 controls. The observed proportion of IgG seropositive women did not differ between cases and controls. Neither IgG seropositivity nor CagA and VacA seropositivity were significantly associated with HG. For IgG positive and CagA and VacA negative women, the crude OR was 1.26 (95% CI: 0.57-2.82). For those being IgG positive and CagA and VacA positive, the crude OR was 0.82 (0.40-1.68). Adjustment for confounding factors, such as maternal age, body mass index and earlier HG, did not change the results. Additional adjustment for faecal antigens did not change the conclusions regarding these associations. Likewise, the crude OR for H. pylori antigens was not statistically significant. Adjustment for confounders and IgG seropositivity did not change this result. CONCLUSIONS: This study did not find H. pylori exposure to be significantly associated with severe HG among immigrant women in Norway. This was regardless of whether H. pylori exposure was investigated by IgG seropositivity, CagA and VacA seropositivity or by the presence of H. pylori antigens in faeces. These results may indicate that the association between H. pylori and HG is weaker than previously expected, particularly in populations with high prevalence of H. pylori infection.

Ageing, physical activity and mortality--a 42-year follow-up study.

BACKGROUND: Physical activity (PA) is inversely associated with mortality in the general population. We wanted to quantify the association of self-reported PA with mortality from all causes, ischaemic heart disease (IHD) and stroke, and compare it with other known risk factors in different age segments. METHODS: The Bergen Clinical Blood Pressure Survey examined a sample of 6811 Norwegian men and women in 1965-71 with follow-up until 2005-07. Cox proportional hazard regression ratio (HR) and population attributable fraction (PAF) were calculated for the old (>65), middle-aged (45-64) and young adults (22-44), respectively. We minimized confounding and bias by progressive comprehensive adjustments and subgroup-analyses (excluding early follow-up deaths, participants with self-reported disease and participants with changes in their PA-level prior baseline due to disease). RESULTS: The HR [95% confidence interval (CI)] associated with a high PA-level was 0.63(0.56-0.71), 0.66(0.52-0.83) and 0.66(0.47-0.93) for mortality from all causes, IHD and stroke, respectively (reference: no participation in any of the listed activities, adjusted for age and gender). PAF (95% CI) of no/low activity (reference: any activity) was consistent across all age groups, varying from 7.3% (3.4-11.4) in the young adults to 9.1% (3.6-15.3) in the old. PAF of smoking and high s-cholesterol declined with increasing age [smoking from 19.9% (15.3-24.7) to 1.5% (-1.3 to 6.2) and s-cholesterol from 11.5% (5.6-17.5) to -9.5% (-18.1 to -0.7)], whereas PAF of hypertension increased from 5.3% (2.1-9.1) to 18.9% (8.3-28.4). CONCLUSION: The relative importance of traditional risk factors varies between the age groups, but physical activity is a major health promoting factor across all age segments and should be encouraged particularly in an ageing population.

Analysis of alcohol and drugs in oral fluid from truck drivers in Norway.

OBJECTIVE: To examine alcohol and drug use among truck drivers compared to car or van drivers in Norway by analyzing samples of oral fluid. METHODS: Drivers were selected for a voluntary and anonymous study using a stratified multistage cluster sampling procedure. Drivers of trucks were recruited at two control stations for heavy vehicles in southeastern Norway in collaboration with the Norwegian Roads Administration, and drivers of cars and vans were recruited in a roadside survey in collaboration with the mobile police service. Samples of oral fluid were taken by using the Statsure Saliva Sampler (Statsure Diagnostic Systems, Framingham, MA), and the drivers' gender, age, and nationality were recorded. Samples of oral fluid were analyzed for alcohol or drugs, in total 28 psychoactive substances. RESULTS: About 97 percent of the truck drivers and 94 percent of the car or van drivers agreed to participate in the study. Of the 882 studied truck drivers studied, 1.4 percent were female and 29.1 percent were Norwegian; of the 5305 car or van drivers, 27.6 percent were female and 90.9 percent were Norwegian. Alcohol or drugs were found in 1.9 and 6.6 percent of the samples from truck drivers and car/van drivers, respectively. The adjusted odds ratio (OR) for the detection of a psychoactive substance in a sample from a truck driver compared to car or van driver was 0.29; the 95 percent confidence interval (95% CI) was 0.17 to 0.53. The adjusted OR for the detection of an illegal drug was 0.42 (95% CI: 0.18-0.82), the adjusted OR for the detection of a psychoactive medicinal drug was 0.29 (95% CI: 0.13-0.68), and the adjusted OR for the detection of alcohol was 0.13 (95% CI: 0.02-1.10). CONCLUSIONS: The proportion of oral fluid samples containing psychoactive substances was lower for truck drivers than for car or van drivers.

The impact of maternal age on fetal death: does length of gestation matter?

OBJECTIVE: The objective of the investigation was to study the association of fetal death with maternal age by length of gestation. STUDY DESIGN: This was a population study including all ongoing pregnancies after 16 weeks of gestation in Norway during the period 1967-2006 (n = 2,182,756). RESULTS: The risk of fetal death was 1.4 times higher in women 40-44 years old than in women aged 20-24 years in midpregnancy but 2.8 times higher at term. In term pregnancies the relative importance of maternal age increased by additional pregnancy weeks. In gestational weeks 42-43, the crude risk was 5.1 times higher in mothers 40 years old or older. In the recent period, the elevated risk of fetal death in elderly mothers at term has been attenuated. CONCLUSION: Women 40 years old or older had the highest risk of fetal death throughout pregnancy, particularly in term and postterm pregnancies. Improved obstetric care may explain the attenuation of risk associated with age in recent time.

Maternal body composition, smoking, and hyperemesis gravidarum.

PURPOSE: To study associations between maternal prepregnant body mass index (BMI), smoking, and hyperemesis gravidarum (hyperemesis). METHODS: The sample consisted of 33,467 primiparous women from the Norwegian Mother and Child Cohort Study (1999-2008). Data on hyperemesis, BMI, education, maternal age, eating disorders, maternal and paternal smoking habits were obtained from questionnaires. All associations were studied by logistic regression. RESULTS: Altogether, 353 (1.1%) women had hyperemesis. Among non-smokers, both underweight and obese women were more likely to develop hyperemesis than normal-weighted women: odds ratio (OR), 2.36; 95% confidence interval (95% CI), 1.43-3.88 and OR, 1.48; 95% CI, 1.00-2.20, respectively. No associations were found among smokers. Women who smoked daily (OR, 0.44; 95% CI, 0.32-0.60) or occasionally (OR, 0.64; 95% CI, 0.44-0.93) had lower risk of hyperemesis than non-smokers. No effect of partner's smoking habits was observed. CONCLUSIONS: Both underweight and obesity were associated with hyperemesis, but only among non-smokers. Maternal prepregnant smoking reduced the risk of hyperemesis, whereas partner's smoking habits had no effect.

Maternal BMI before pregnancy, maternal weight gain during pregnancy, and risk of persistent positivity for multiple diabetes-associated autoantibodies in children with the high-risk HLA genotype: the MIDIA study.

OBJECTIVE: To assess whether maternal BMI before pregnancy and weight gain during pregnancy predicted the risk of islet autoimmunity in genetically susceptible children. RESEARCH DESIGN AND METHODS: Of 46,939 newborns screened for the high-risk HLA genotype DR4-DQ8/DR3-DQ2, 1,003 were positive and 885 were followed with serial blood samples tested for autoantibodies to insulin, GAD, and insulinoma-associated protein 2 (IA2). The end point was defined as repeated positivity for two or three autoantibodies or the onset of type 1 diabetes (islet autoimmunity). RESULTS: Thirty-six children developed islet autoimmunity, of whom 10 developed type 1 diabetes. Both maternal BMI > or =30 kg/m(2) before pregnancy and maternal weight gain > or =15 kg predicted the increased risk of islet autoimmunity (hazard ratio [HR] 2.5, P = 0.023, and HR 2.5, P = 0.015, respectively), independent of maternal diabetes. CONCLUSIONS: Maternal weight may predict risk of islet autoimmunity in offspring with a high genetic susceptibility for type 1 diabetes.

A simulation study of three methods for detecting disease clusters.

BACKGROUND: Cluster detection is an important part of spatial epidemiology because it can help identifying environmental factors associated with disease and thus guide investigation of the aetiology of diseases. In this article we study three methods suitable for detecting local spatial clusters: (1) a spatial scan statistic (SaTScan), (2) generalized additive models (GAM) and (3) Bayesian disease mapping (BYM). We conducted a simulation study to compare the methods. Seven geographic clusters with different shapes were initially chosen as high-risk areas. Different scenarios for the magnitude of the relative risk of these areas as compared to the normal risk areas were considered. For each scenario the performance of the methods were assessed in terms of the sensitivity, specificity, and percentage correctly classified for each cluster. RESULTS: The performance depends on the relative risk, but all methods are in general suitable for identifying clusters with a relative risk larger than 1.5. However, it is difficult to detect clusters with lower relative risks. The GAM approach had the highest sensitivity, but relatively low specificity leading to an overestimation of the cluster area. Both the BYM and the SaTScan methods work well. Clusters with irregular shapes are more difficult to detect than more circular clusters. CONCLUSION: Based on our simulations we conclude that the methods differ in their ability to detect spatial clusters. Different aspects should be considered for appropriate choice of method such as size and shape of the assumed spatial clusters and the relative importance of sensitivity and specificity. In general, the BYM method seems preferable for local cluster detection with relatively high relative risks whereas the SaTScan method appears preferable for lower relative risks. The GAM method needs to be tuned (using cross-validation) to get satisfactory results.

Association of head circumference at birth among sibling pairs.

The objective of the study was to estimate and compare the correlation coefficients of head circumference and weight at birth among sibling pairs. Pairs of singleton siblings were ascertained among children born in Norway to the same mother between 1978 and 1997. Head circumference, birthweight and other perinatal factors were registered in the Medical Birth Registry of Norway. Head circumference measurements were obtained for first- and second-born in 287 448 sibling pairs. The correlation coefficient of head circumference among first- and second-born siblings was 0.343 (standard error 0.002) compared with 0.477 (standard error 0.002) for birthweight. These results were similar for later-born sibling pairs and only slightly influenced by other factors such as sex, fatherhood and time between pregnancies. Sensitivity analyses showed that substantial measurement error is required to explain the lower correlation for head circumference. In conclusion, the sibling correlation of head circumference was consistently weaker than that of birthweight.

Pregnancy complications and the risk of asthma among Norwegians born between 1967 and 1993.

BACKGROUND: Fetal life events may affect the development of the immune and/or respiratory system and increase the risk of asthma and allergic diseases. The objective of this study was to test the hypothesis that pregnancy complications are associated with the risk of developing asthma in the off-spring. METHODS: The study population comprised Norwegian live births 1967-1993 (n = 1,548,429) linking the Medical Birth Registry of Norway (MBRN) (exposure variables) and the National Insurance Administration Register (NIAR) (outcome variables), which covers all Norwegians. The MBRN variables included pregnancy complications, pregnancy outcomes and diseases of the mother. The NIAR provided data on all Norwegians who had received cash benefit for treatment of asthma from 1967 to 1996 (n = 5938, 3.9/1000 persons). RESULTS: In multiple logistic regression analysis, pregnancy complications (International Classification of Diseases (ICD)-8-codes: 630-634) were associated with the risk of asthma (odds ratio 1.82, 95% confidence interval: 1.67-1.98). This was also the case if analyses were performed in different strata according to year of birth, plurality, maternal atopy, geographical district of birth, and maternal education. CONCLUSIONS: Pregnancy complications may represent risk factors for the development of asthma in the offspring or express early signs of increased risk for developing the disease.

Hearing loss induced by noise, ear infections, and head injuries: results from the Nord-Trøndelag Hearing Loss Study.

Pure-tone audiometry was administered to the adult population in Nord-Trøndelag County, Norway, 1995-97. The 51,975 participants also provided questionnaire information about occupational and leisure noise exposure, previous ear infections, and head injury. Values averaged over both ears were calculated for low (250 and 500 Hz), middle (1 and 2 kHz) and high frequencies (3, 4, 6 and 8 kHz). The aim was to estimate the magnitude of hearing loss associated with various types of exposure by age and sex. Noise, ear infections and head injury explained 1-6% of the variance in hearing loss (varying with age, sex, and frequency range), in addition to what could be explained by age alone (30-58%). Only moderate effects of noise could be detected among women. The upper tenth percentile regarding occupational noise among men older than 44 years had on average an 8-9-dB high-frequency loss, adjusted for other predictors. Exposure to impulse noise (hunting, sports shooting) caused a 7-8-dB high-frequency loss in the same group. No significant effects of frequent use of personal stereo players or regular attendance at discotheques or rock concerts could be demonstrated. There were clear effects of recurrent ear infections and head injury.

Birth weight and hearing impairment in norwegians born from 1967 to 1993.

OBJECTIVES: To estimate the association between birth weight and hearing impairment among Norwegians born between 1967 and 1993, taking other pregnancy-related conditions into consideration. METHODS: A cohort study was conducted of all Norwegian live births from 1967 to 1993 (n = 1 548 429) linking information of the Medical Birth Registry of Norway and the register for the National Insurance Administration, which covers all Norwegians. The Medical Birth Registry of Norway has recorded information on birth weight and other pregnancy-related conditions as well as diseases of the mother before and during pregnancy. The register of the National Insurance Administration contains information on all Norwegians who have received cash benefits for a disease/disability, including hearing impairment. Data up to 1997 are included; thus, the follow-up period varies between 29 and 3 years. RESULTS: The occurrence of hearing impairment was 11 per 10 000, decreasing from 60 per 10 000 for birth weights <1500 g to 6 per 10 000 for birth weights >4499 g. Compared with birth weights between 3000 g and 3499 g, the adjusted rate ratio of hearing impairment was 7.55 (95% confidence interval: 4.81-11.87) for birth weights <1500 g and 0.50 (95% confidence interval: 0.34-0.73) for birth weights >4499 g. The association did not change substantially with adjustment for other pregnancy-related conditions. Restricting the analyses to term born, the association between hearing impairment and low birth weight became stronger. CONCLUSIONS: Birth weight was a strong predictor of hearing impairment in the Norwegian population. Children who were born at term with a low birth weight seemed to be a particularly vulnerable group.