Effects of Disease Misclassification on Exposure–Disease Association

Objectives. We explore how misclassification in disease status can distort the exposure–disease association in a study with dichotomous disease and exposure status.Methods. We define the difference in population odds ratios between populations with and without disease misclassification as population-level bias and derive the bias as a function of sensitivity and specificity for observed disease status. The magnitude and direction of bias can be elucidated through analytic derivations, as illustrated with numerical examples.Results. Patterns of bias exist not only for nondifferential misclassification but also for some differential misclassification scenarios. We have provided conditions defined in terms of sensitivity and specificity that correspond to each pattern of bias.Conclusions. Caution is needed in interpreting results when misclassification is present. Our findings can be used to assess the effects of disease misclassification in a population when sensitivity and specificity are known or can be estimated.In epidemiological and clinical studies, we are often interested in the association between a dichotomous exposure and a dichotomous health outcome such as disease status. However, misclassification is often present in these measures when the gold standard assessment is too expensive to apply and a more affordable but less accurate assessment is used instead. For example, misclassification for disease status is likely to occur when psychiatric disorder status is assessed through self-reported surveys instead of in-person clinical diagnosis. Likewise, misclassification for exposure status is likely to occur when individual exposure to air pollution is assessed by measurements recorded at neighborhood monitoring stations rather than by personal monitoring devices.Misclassification can alter the odds ratio (OR) that measures the exposure–disease association in a population. This difference can sometimes present significant problems in drawing conclusions about the nature and strength of the exposure–disease association, because the direction of the deviation is unclear and the magnitude of the deviation can be large. Here we focus on the impact of disease misclassification on the exposure–disease relationship when the exposure category is correctly classified.Two types of disease misclassification can arise in an exposure–disease association study: nondifferential and differential. Nondifferential misclassification occurs when neither sensitivity nor specificity for disease classification varies by exposure category. By contrast, differential misclassification occurs when misclassification of disease status varies by exposure category.1,2 It is usually believed that nondifferential misclassification in either exposure or disease status results in an estimate that has the same sign as the true association but reduced magnitude, unless the misclassification is so severe that the estimate might switch over to the opposite side of the null.3–9 However, differential misclassification can have effects with indeterminate direction,6 away from the null, toward the null, or even switched to the opposite side of the null. It is unclear what conditions cause specific deviations. Chyou studied patterns of effects in the OR estimation attributable to differential misclassification by case–control status in a case–control study, with limited numerical examples.10 However, conclusions based on limited numerical examples may be sensitive to the conditions chosen for the study. Thus it is desirable to use analytic derivation to examine the pattern of misclassification effects in the exposure–disease association, especially when differential misclassification occurs.Here we focus on the difference in population parameters (here the OR) between populations with and without disease misclassification, referred to as population-level bias. This population-level bias is different from the bias of an estimator, which represents the difference between an estimator’s expectation and the true value of the parameter being estimated. For sample-based estimation, the parameters estimated are consistent asymptotically for the corresponding population parameters; thus the patterns of bias for the sample estimators are the same asymptotically as the patterns for the population parameters. We focus on population parameters without estimation error and refer to population-level bias simply as bias.     

Subclinical Neuropathy at “Safe” Levels of Lead Exposure

Electrophysiological methods revealed subclinical neuropathy in 26 workers, exposed from 1 to 17 years to lead and whose blood lead (PbB) values had never exceeded 70μg/100 ml, as ascertained by checking the monitor reports of the factory and by careful exposure history. The PbB determinations had been tested repeatedly and had been found valid.

The main findings were slowing of the maximal motor conduction velocities of the median and ulnar nerves and particularly the conduction velocity of the slower fibers of the ulnar nerve. Electromyographical abnormalities comprised fibrillations, diminution of the number of motor units on maximal contraction, and an abnormally long duration of the units. Earlier similar measurements from heavily exposed workers had been even more abnormal.

Thus, a dose-response relationship exists on a group basis. Since the regular monitoring of PbBs in most workers during their entire period of exposure excludes the possibility of a body burden out of proportion to the PbB slight neurological damage is produced at exposures hitherto regarded as quite safe.     

Association of Cumulative Lead Exposure with Parkinson’s Disease

Background

Research using reconstructed exposure histories has suggested an association between heavy metal exposures, including lead, and Parkinson’s disease (PD), but the only study that used bone lead, a biomarker of cumulative lead exposure, found a nonsignificant increase in risk of PD with increasing bone lead.

Objectives

We sought to assess the association between bone lead and PD.

Methods

Bone lead concentrations were measured using ¹⁰⁹Cd excited K-shell X-ray fluorescence from 330 PD patients (216 men, 114 women) and 308 controls (172 men, 136 women) recruited from four clinics for movement disorders and general-community cohorts. Adjusted odds ratios (ORs) for PD were calculated using logistic regression.

Results

The average age of cases and controls at bone lead measurement was 67 (SD = 10) and 69 (SD = 9) years of age, respectively. In primary analyses of cases and controls recruited from the same groups, compared with the lowest quartile of tibia lead, the OR for PD in the highest quartile was 3.21 [95% confidence interval (CI), 1.17–8.83]. Results were similar but slightly weaker in analyses restricted to cases and controls recruited from the movement disorders clinics only (fourth-quartile OR = 2.57; 95% CI, 1.11–5.93) or when we included controls recruited from sites that did not also contribute cases (fourth-quartile OR = 1.91; 95% CI, 1.01–3.60). We found no association with patella bone lead.

Conclusions

These findings, using an objective biological marker of cumulative lead exposure among typical PD patients seen in our movement disorders clinics, strengthen the evidence that cumulative exposure to lead increases the risk of PD.     

A Meta-analysis of Asbestos and Lung Cancer: Is Better Quality Exposure Assessment Associated with Steeper Slopes of the Exposure–Response Relationships?

Background: Asbestos is a well-recognized cause of lung cancer, but there is considerable between-study heterogeneity in the slope of the exposure–response relationship.Objective: We considered the role of quality of the exposure assessment to potentially explain heterogeneity in exposure–response slope estimates.Data sources: We searched PubMed MEDLINE (1950–2009) for studies with quantitative estimates of cumulative asbestos exposure and lung cancer mortality and identified 19 original epidemiological studies. One was a population-based case–control study, and the others were industry-based cohort studies.Data extraction: Cumulative exposure categories and corresponding risks were abstracted. Exposure–response slopes [K_L (lung cancer potency factor of asbestos)] were calculated using linear relative risk regression models.Data synthesis: We assessed the quality of five exposure assessment aspects of each study and conducted random effects univariate and multivariate meta-regressions. Heterogeneity in exposure–response relationships was greater than expected by chance (I² = 64%). Stratification by exposure assessment characteristics revealed that studies with well-documented exposure assessment, larger contrast in exposure, greater coverage of the exposure history by exposure measurement data, and more complete job histories had higher meta-K_L values than did studies without these characteristics. The latter two covariates were most strongly associated with the K_L value. Meta-K_L values increased when we incrementally restricted analyses to higher-quality studies.Conclusions: This meta-analysis indicates that studies with higher-quality asbestos exposure assessment yield higher meta-estimates of the lung cancer risk per unit of exposure. Potency differences for predominantly chrysotile versus amphibole asbestos-exposed cohorts become difficult to ascertain when meta-analyses are restricted to studies with fewer exposure assessment limitations.     

Assessment of Occupational Exposure Among Pakistani Medical Staff During 2007–2011

The data analysis of occupationally exposed medical workers in Nuclear Medicine (NM), Radiotherapy (RT) and Diagnostic Radiology (DR) at the Institute of Nuclear Medicine and Oncology (INMOL), Pakistan is presented for the time interval (2007-2011). The whole-body exposure doses of the workers were measured by using the Film Badge Dosimetry technique. The annual average effective doses in NM, RT and DR have been found well below the permissible annual limit of 20?mSv (averaged over a period of 5 consecutive years), with no over-exposure detected. This declining trend of annual average effective dose is the consequence of improved radiation protection practices at INMOL during the recent years.     

Exposure study on chemosensory effects of ε-caprolactam in the low concentration range

Objective Aim of the study was to examine possible chemosensory effects of ε-caprolactam in the low concentration range relevant to indoor environmental conditions. Methods Twenty healthy subjects (10 male, 10 female) aged from 21 to 38 years were exposed for 6 h, respectively, to 0, 0.15, 0.5 and 5 mg/m³ ε-caprolactam vapours in a randomized and double-blind method. As a measure of trigeminal stimulation of the eye, blink frequency was video-recorded four times per day and evaluated by using a new semi-automatic, computer-assisted method compared to baseline recording and manual counting. Digital slit lamp photographs were taken at the same time to examine conjunctival hyperaemia. A standardized ophthalmologic grading scale was used to measure redness of the eyes objectively. Active anterior rhinomanometry compared nasal resistance before and after exposure. Subjective ratings of discomfort and mental orientation were assessed using the German version of the Swedish Performance Evaluation system (SPES). As a measure of personality traits, positive and negative affectivity was determined (PANAS). Results Six hour exposures to ε-caprolactam revealed no significant dose–response relationship concerning blink frequency, nasal resistance and redness of the bulbar conjunctiva. Subjective ratings of discomfort (sum scores) significantly increased only at the highest concentration of 5 mg/m³. However, the increase in discomfort was only moderate, ranging between “not at all” and “somewhat”. Significant increases of the subjective detection of malodour (subscore) already occurred at 0.15 mg/m³, showing no adaptation over time. Irritation of the eyes or upper airways was not reported. Conclusions Exposure to ε-caprolactam vapour did not elicit any acute health effects in a concentration range up to 0.5 mg/m³. Even at the highest concentration of 5 mg/m³, we could only find a slight increase in subjective symptoms, mainly due to an unincisive increase of perception of malodour.     

Sperm Aneuploidy in Faroese Men with Lifetime Exposure to Dichlorodiphenyldichloroethylene (p,p′-DDE) and Polychlorinated Biphenyl (PCB) Pollutants

Background:

Although it is known that sperm aneuploidy contributes to early pregnancy losses and congenital abnormalities, the causes are unknown and environmental contaminants are suspected.

Objectives:

Our goal was to evaluate associations between lifetime exposure to organochlorines, specifically dichlorodiphenyldicholorethylene (p,p´-DDE) and polychlorinated biphenyls (PCBs), and sperm aneuploidy in men from the general population of the Faroe Islands, a population with a known history of organochlorine exposures.

Methods:

Serum and semen samples from men (n = 90) 22–44 years old who participated in Faroe Islands health studies were analyzed for p,p´-DDE and PCBs 118, 138, 153, and 180 and adjusted for total lipids. Cord blood and age-14 serum were available for a subgroup (n = 40) and were also analyzed for p,p´-DDE and PCBs. Sperm fluorescence in situ hybridization (FISH) for chromosomes X, Y, and 18 was used to determine rates of XX18, XY18, YY18, and total disomy. Multivariable adjusted Poisson models were used to estimate the relationship between organochlorine exposure and sperm disomy outcomes.

Results:

Adult p,p´-DDE and total PCB serum concentrations were both associated with significantly increased rates of XX18, XY18, and total disomy. Age-14 p,p´-DDE and PCB concentrations were both associated with significantly increased rates of XX, XY, and total disomy in adulthood. Associations between cord blood concentrations of p,p´-DDE and PCBs and sperm disomy in adulthood were not consistently significant.

Conclusions:

Organochlorine exposures measured at age 14 and in adulthood were associated with sperm disomy in this sample of high-exposure men, suggesting that the impacts of persistent pollutants on testicular maturation and function require further investigation.

Citation:

Perry MJ, Young HA, Grandjean P, Halling J, Petersen MS, Martenies SE, Karimi P, Weihe P. 2016. Sperm aneuploidy in Faroese men with lifetime exposure to dichlorodiphenyldichloroethylene (p,p´-DDE) and polychlorinated biphenyl (PCB) pollutants. Environ Health Perspect 124:951–956; http://dx.doi.org/10.1289/ehp.1509779     

Sex-Specific Effects of Fetal Exposure to the 1959–1961 Chinese Famine on Risk of Adult Hypertension

Previous research is inconsistent about the effects of prenatal famine exposure on risk of adult hypertension. Follow-up of persons exposed to the 1959–1961 Chinese famine, the largest in human history, provides an opportunity to examine the long-term impact of prenatal famine exposure on adult cardiovascular disease (CVD). We investigated the effects of fetal-infant exposure to the famine on risk of hypertension in adulthood. We included 1,415 participants from the 2009 China Health and Nutrition Survey born September 1, 1956–December 31, 1964. Blood pressure (BP) measurements, self-reported previous diagnosis of hypertension and current anti-hypertension drug use were obtained from the survey. Differences in mean BP and risk of adult hypertension by famine exposure status were determined using linear and logistic regression analyses, after adjusting for confounders. Women with fetal-infant exposure to famine had higher mean systolic blood pressure (4.24 mmHg; 95 % confidence interval (CI) 1.50–6.98) than those unexposed. They also had increased odds of a prior diagnosis of hypertension (odds ratio (OR) 2.16; 95 % CI 1.16–4.02), and were more likely to be currently taking anti-hypertensive medications (OR 2.81; 95 % CI 1.32–5.97) than unexposed women after adjusting for covariates. No statistically significant increases in mean BP or hypertension were seen among men. Exposure to famine during the fetal-infant period or early childhood has deleterious effects on adult health, but the effects may be greater for women. Gender-specific intervention strategies for CVD may be warranted for populations exposed to under-nutrition during critical time periods of fetal development.     

Exposure of the Inuit Population of Nunavik (Arctic Québec) to Lead and Mercury

The authors conducted a survey during 1992 to evaluate blood levels of lead and mercury in Inuit adults of Nunavik (Arctic Québec, Canada). Blood samples obtained from 492 participants (209 males and 283 females; mean age = 35 yr) were analyzed for lead and total mercury; mean (geometric) concentrations were 0.42 μmol/l (range = 0.04–2.28 μmol/l) and 79.6 nmol/l (range = 4–560 nmol/l), respectively. Concentrations of omega-3 fatty acid in plasma phospholipids–a biomarker of marine food consumption–were correlated with mercury (r = .56, p < .001) and, to a lesser extent, with blood lead levels (r = .31, p < .001). Analyses of variance further revealed that smoking, age, and consumption of waterfowl were associated with lead concentrations (r ² = .30, p < .001), whereas age and consumption of seal and beluga whale were related to total mercury levels (r ² = .30, p < .001). A significant proportion of reproductive-age women had lead and mercury concentrations that exceeded those that have been reportedly associated with subtle neurodevelopmental deficits in other populations.     

Cancer Health Risk Assessment of Exposure to Arsenic by Workers of AngloGold Ashanti–Obuasi Gold Mine

No abstract available.     

Residues of p,p′-DDE and mercury in lake trout as a function of age

Lake trout (Salvelinus namaycush) of known age from 1 to 12 years were taken from Cayuga Lake in central New York State in 1991 and p,p-DDE and mercury were determined in their flesh. The concentrations of p,p-DDE and mercury increased significantly (p<0.001) with increasing age of the fish. The concentration of p,p-DDE also increased significantly (p<0.001) with increasing fat content. The concentrations of p,p-DDE were much lower than those found in Cayuga Lake trout of similar age captured in 1978.     

DNA–Protein Crosslinks and Sister Chromatid Exchanges as Biomarkers of Exposure to Formaldehyde

Abstract

Formaldehyde is classified as a probable human carcinogen. DNA–protein crosslinks (DPCs) and sister chromatid exchanges. (SCEs) may represent early lesions in the carcinogenic process. The authors examined the OPCs and, SCEs in peripheral-blood lymphocytes of 12 and 13 workers exposed to formaldehyde and eight and 20 unexposed workers, respectively. The amounts of DPCs and SCEs in the exposed and the unexposed differed significantly after adjustment for smoking. There was a linear relationship between years of exposure and the amounts DPC and SCE. The authors conclude that the data indicate a possible Mechanism of carcinogenicity of formaldehyde, and that formaldehyde is mutagenic to humans. These results support the use of DPCs as a biomarker of occupational exposure to formaidehyde and to detect high risk populations for secondary prevention.     

Prospective Study of Ambient Particulate Matter Exposure and Risk of Pulmonary Embolism in the Nurses’ Health Study Cohort

Background

Pulmonary embolism (PE) is the most serious manifestation of venous thromboembolism and a leading cause of sudden death. Several studies have suggested associations of venous thromboembolism with short-term particulate matter (PM) exposure; evidence on long-term PM and traffic exposure is mixed.

Objectives

We examined the association of long-term exposure to PM_2.5, PM_2.5–10, and PM₁₀ (PM with diameter of ≤ 2.5, 2.5–10, and ≤ 10 μm) and distance to roadways with overall incident PE and with PE subtypes in a cohort of U.S. women.

Methods

The study included 115,745 women from the Nurses’ Health Study, followed from 1992 through 2008. Incident PE cases were self-reported biennially. Nonidiopathic PE were cases for which the medical record revealed an underlying health condition related to PE (i.e., surgery, trauma, or malignancy); idiopathic PE were cases with no such history. We used spatiotemporal models combining spatial smoothing and geographic covariates to quantify exposure at residential addresses, and Cox proportional hazards models to calculate hazard ratios (HR) and 95% confidence intervals (CIs).

Results

PM_2.5 averaged over 1 month (HR = 1.22; 95% CI: 1.04, 1.44) or 12 months (HR = 1.17; 95% CI: 0.93, 1.48) was associated with incident PE, after adjusting for known risk factors and PM_2.5–10. Equivalent analyses restricted to PE subtypes showed a positive association for PM_2.5 with nonidiopathic PE, but not with idiopathic PE. We did not find evidence of an association between distance to roadways and PE risk.

Conclusions

We provide evidence that PM in the prior 1 and 12 months is associated with PE risk. Our results also suggest that women with underlying health conditions may be more susceptible to PE after PM exposure.

Citation

Pun VC, Hart JE, Kabrhel C, Camargo CA Jr, Baccarelli AA, Laden F. 2015. Prospective study of ambient particulate matter exposure and risk of pulmonary embolism in the Nurses’ Health Study cohort. Environ Health Perspect 123:1265–1270; http://dx.doi.org/10.1289/ehp.1408927     

Evaluation of an Elementary School–based Educational Intervention for Reducing Arsenic Exposure in Bangladesh

Background

Chronic exposure to well water arsenic (As) remains a major rural health challenge in Bangladesh and some other developing countries. Many mitigation programs have been implemented to reduce As exposure, although evaluation studies for these efforts are rare in the literature.

Objectives

In this study we estimated associations between a school-based intervention and various outcome measures of As mitigation.

Methods

We recruited 840 children from 14 elementary schools in Araihazar, Bangladesh. Teachers from 7 schools were trained on an As education curriculum, whereas the remaining 7 schools without any training formed the control group. Surveys, knowledge tests, and well-water testing were conducted on 773 children both at baseline and postintervention follow-up. Urine samples were collected from 210 children from 4 intervention schools and the same number of children from 4 control schools. One low-As (< 10 μg/L) community well in each study village was ensured during an 18-month intervention period.

Results

After adjustment for the availability of low-As wells and other sociodemographic confounders, children receiving the intervention were five times more likely to switch from high- to low-As wells (p < 0.001). We also observed a significant decline of urinary arsenic (UAs) (p = < 0.001) (estimated β = –214.9; 95% CI: –301.1, –128.7 μg/g creatinine) among the children who were initially drinking from high-As wells (> Bangladesh standard of 50 μg/L) and significantly improved As knowledge attributable to the intervention after controlling for potential confounders.

Conclusions

These findings offer strong evidence that school-based intervention can effectively reduce As exposure in Bangladesh by motivating teachers, children, and parents.

Citation

Khan K, Ahmed E, Factor-Litvak P, Liu X, Siddique AB, Wasserman GA, Slavkovich V, Levy D, Mey JL, van Geen A, Graziano JH. 2015. Evaluation of an elementary school–based educational intervention for reducing arsenic exposure in Bangladesh. Environ Health Perspect 123:1331–1336; http://dx.doi.org/10.1289/ehp.1409462     

A Case–Control Study of Prenatal Thallium Exposure and Low Birth Weight in China

Background

Thallium (Tl) is a highly toxic heavy metal widely present in the environment. Case reports have suggested that maternal exposure to high levels of Tl during pregnancy is associated with low birth weight (LBW), but epidemiological data are limited.

Objectives

This study was designed to evaluate whether prenatal Tl exposure is associated with an increased risk of LBW.

Methods

This case–control study involving 816 study participants (204 LBW cases and 612 matched controls) was conducted in Hubei Province, China, in 2012–2014. Tl concentrations were measured in maternal urine collected at delivery, and associations with LBW were evaluated using conditional logistic regression.

Results

Higher maternal urinary Tl levels were significantly associated with increased risk of LBW [crude odds ratio (OR) = 1.52; 95% CI: 1.00, 2.30 for the highest vs. lowest tertile], and the association was similarly elevated after adjustment for potential confounders (adjusted OR = 1.90; 95% CI: 1.01, 3.58 for the highest vs. lowest tertile). Stratified analyses showed slightly higher risk estimates for LBW associated with higher Tl levels for mothers < 28 years old and for mothers with lower household income; however, there was no statistical evidence of heterogeneity in risk according to maternal age (p for heterogeneity = 0.18) or household income (p for heterogeneity = 0.28).

Conclusion

To our knowledge, ours is the first case–control study to investigate the association between prenatal Tl exposure and LBW. The results suggest that prenatal exposure to high levels of Tl may be associated with an increased risk of LBW.

Citation

Xia W, Du X, Zheng T, Zhang B, Li Y, Bassig BA, Zhou A, Wang Y, Xiong C, Li Z, Yao Y, Hu J, Zhou Y, Liu J, Xue W, Ma Y, Pan X, Peng Y, Xu S. 2016. A case–control study of prenatal thallium exposure and low birth weight in China. Environ Health Perspect 124:164–169; http://dx.doi.org/10.1289/ehp.1409202     

Exposure to lead and cadmium of children living in different areas of North-West Germany: results of biological monitoring studies 1982–1986

Summary Between 1982 and 1986 several surveys were carried out to determine the levels of lead and cadmium in blood, urine, and shed deciduous teeth (incisors only) of children living in rural, suburban, urban, and industrial areas of North-West Germany. Blood lead (PbB) and blood cadmium (CdB) were measured in about 4000 children. In rural, suburban and urban areas the median PbB levels vary between 5.5 and 7 g/dl, with 98th percentiles varying between 10 and 13 g/dl. The median CdB levels are between 0.1 and 0.2 g/dl, with 95th percentiles between 0.3 and 0.4 g/l. Children from urban areas have significantly higher PbB levels than children from rural and suburban areas. Regarding CdB no differences could be detected. Children living in areas around lead and zinc smelters, particularly those living very close to the smelters, have substantially increased PbB and CdB levels. Children from lead worker families also have substantially increased PbB and CdB levels. The lead levels in shed milk teeth (PbT) were determined in about 3000 children. In rural, suburban and urban areas the median PbT levels are between 2 and 3 g/g, with 95th percentiles between 4 and 7 g/g. Children from urban areas have significantly higher PbT levels than children from rural and suburban areas. The highest PbT levels (on a group basis) are in children from nonferrous smelter areas. The median levels of lead in urine (PbU) are between 6 and 10 g/g creatinine, with 95th percentiles between 20 and 30 g/g creatinine. Children from polluted areas have higher PbU levels than children from less polluted areas. The median levels of cadmium in urine (CdU) are in the order of 0.1 g/g creatinine, with 95th percentiles being in the range of 0.5 and 1.0 g/g creatinine. Girls have higher CdU levels than boys. There are no differences between groups of children from different areas. Children from lead worker families have higher PbU and CdU levels than otherwise comparable children. The results of the present studies indicate a further decrease of PbB in children from North-West Germany since the CEC blood lead campaigns carried out in 1979 and 1981. The decrease of lead exposure also seems to be reflected by a decrease of tooth lead levels.The studies presented in this communication were supported by the Ministry of Work, Health and Social Affairs and the Ministry of Environment and Agriculture of Nordrhein-West-falen, FRG