Misclassification Bias in the Assessment of Gene-by-Environment Interactions.

BACKGROUND: Misclassification bias is a common concern in epidemiologic studies. Despite strong bias on main effects, gene-environment interactions have been shown to be biased towards the null under gene-environment independence. In the context of a recent article examining the interaction between nerve agent exposure and paraoxonase-1 gene on Gulf War Illness, we aimed to assess the impact of recall bias-a common misclassfication bias-on the identification of gene-environment interactions when the independence assumption is violated. METHODS: We derive equations to quantify the bias of the interaction, and numerically illustrate these results by simulating a case-control study of 1000 cases and 1000 controls. Simulation input parameters included exposure prevalence, strength of gene-environment dependence, strength of the main effect, exposure specificity among cases, and strength of the gene-environment interaction. RESULTS: We show that, even if gene-environment independence is violated, we can bound possible gene-environment interactions by knowing the strength and direction of the gene-environment dependence ( ) and the observed gene-environment interaction ( )-thus often still allowing for the identification of such interactions. Depending on whether is larger or smaller than the inverse of , is a lower (if ) or upper (if ) bound for the true interaction. In addition, the bias magnitude is somewhat predictable by examining other characteristics such as exposure prevalence, the strength of the exposure main effect, and directions of the recall bias and gene-environment dependence. CONCLUSIONS: Even if gene-environment dependence exists, we may still be able to identify gene-environment interactions even when misclassification bias is present.

Association of Long-term Exposure to Air Pollution With Late-Life Depression in Older Adults in the US.

Importance: Emerging evidence has suggested harmful associations of air pollutants with neurodegenerative diseases among older adults. However, little is known about outcomes regarding late-life mental disorders, such as geriatric depression. Objective: To investigate if long-term exposure to air pollution is associated with increased risk of late-life depression diagnosis among older adults in the US. Design, Setting, and Participants: This population-based longitudinal cohort study consisted of US Medicare enrollees older than 64 years. Data were obtained from the US Centers for Medicare and Medicaid Services Chronic Conditions Warehouse. The participants were continuously enrolled in the Fee-for-Service program and both Medicare Part A and Part B. After the 5-year washout period at entry, a total of 8 907 422 unique individuals were covered over the study period of 2005 to 2016, who contributed to 1 526 690 late-onset depression diagnoses. Data analyses were performed between March 2022 and November 2022. Exposures: The exposures consisted of residential long-term exposure to fine particulate matter (PM2.5), measured in micrograms per cubic meter; nitrogen dioxide (NO2), measured in parts per billion; and ozone (O3), measured in parts per billion. Main Outcomes and Measures: Late-life depression diagnoses were identified via information from all available Medicare claims (ie, hospital inpatient, skilled nursing facility, home health agency, hospital outpatient, and physician visits). Date of the first occurrence was obtained. Hazard ratios and percentage change in risk were estimated via stratified Cox proportional hazards models accounting for climate coexposures, neighborhood greenness, socioeconomic conditions, health care access, and urbanicity level. Results: A total of 8 907 422 Medicare enrollees were included in this study with 56.8% being female individuals and 90.2% being White individuals. The mean (SD) age at entry (after washout period) was 73.7 (4.8) years. Each 5-unit increase in long-term mean exposure to PM2.5, NO2, and O3 was associated with an adjusted percentage increase in depression risk of 0.91% (95% CI, 0.02%-1.81%), 0.61% (95% CI, 0.31%- 0.92%), and 2.13% (95% CI, 1.63%-2.64%), respectively, based on a tripollutant model. Effect size heterogeneity was found among subpopulations by comorbidity condition and neighborhood contextual backgrounds. Conclusions and Relevance: In this cohort study among US Medicare enrollees, harmful associations were observed between long-term exposure to air pollution and increased risk of late-life depression diagnosis.

Multi-modality human phenotyping to examine subjective and objective health afflictions in former professional American-style football players: The In-Person Assessment (IPA) protocol.

BACKGROUND: Participation in American-style football (ASF), one of the most popular sports worldwide, has been associated with adverse health outcomes. However, prior clinical studies of former ASF players have been limited by reliance on subjective self-reported data, inadequate sample size, or focus on a single disease process in isolation. OBJECTIVE: To determine the burden of objective multi-system pathology and its relationship with subjective health complaints among former professional ASF players. METHODS: The In-Person Assessment is a case-control, multi-day, deep human phenotyping protocol designed to characterize and quantify pathology among former professional ASF players. Participants, recruited from an on-going large-scale longitudinal cohort study, will include 120 men who report either no health conditions, a single health condition, or multiple health conditions across the key domains of cardiometabolic disease, disordered sleep, chronic pain, and cognitive impairment. Data will be collected from validated questionnaires, structured interviews, physical examinations, multi-modality imaging, and functional assessments over a 3-day study period. A pilot study was conducted to assess feasibility and to obtain participant feedback which was used to shape the final protocol. RESULTS: This study provides a comprehensive assessment of objective multi-system pathology and its relationship with subjective health complaints among former professional ASF players. CONCLUSION: The study will determine whether subjective health complaints among former professional ASF players are explained by objective explanatory pathology and will provide novel opportunities to examine the interrelatedness of co-morbidities. It is anticipated that this protocol will be applicable to other clinical and occupational populations.

Gestational exposure to fatal police violence and pregnancy loss in US core based statistical areas, 2013-2015.

BACKGROUND: Fatal police violence in the United States disproportionately affects Black, Native American, and Hispanic people, and for these groups it is a racially oppressive population-level stressor that we hypothesize increases the risk of pregnancy loss. Focusing on core based statical areas (CBSAs) surrounding small and large urban centers, we accordingly tested whether gestational exposure to fatal police violence decreased the number of live births, which is reflective of a rise in lost pregnancies. METHODS: Our observational study linked microdata for all births (N = 7,709,300) in 520 CBSAs with at least one incident of fatal police violence in 2013-2015 to Fatal Encounters, a database that prospectively identified 2594 police-related fatalities using online media reports and public records. We estimated the association between month-to-month fatal police violence and conceptions resulting in live births using distributed lag quasi-Poisson models with CBSA-level fixed effects, adjusted for seasonality and stratified by maternal race/ethnicity. FINDINGS: For each additional police-related fatality that occurred in the first through sixth months of gestation, we observed a 0.14% decrease (95% confidence interval: 0.05%, 0.23%) in the total number of live births within CBSAs, and a 0.29% decrease in births to Black women (95% CI: 0.11%, 0.48%). The association was null for births to White women. INTERPRETATION: Our findings suggest fatal police violence may have population-level consequences for pregnancy loss and adds to the evidence regarding the importance of preventing these fatalities.

Feasibility of Lead Exposure Assessment in Blood Spots using Energy-Dispersive X-ray Fluorescence.

Collecting blood spots from newborns is a common procedure used to diagnose multiple health conditions. Fingerstick blood samples are routinely collected from children to diagnose elevated blood lead levels. In our study, we wanted to test the feasibility of using a high-power energy-dispersive X-ray fluorescence (EDXRF) device to accurately measure the concentration of lead in blood spots. We created spotted standards of a known concentration of lead on a filter paper at different volumes and concentrations. We determined the detection limit for lead through repeated measurements of our standards and calibration line slopes. We also tested the variability of the measured lead concentration across procedures and spotted blood volumes and found no significant additions to uncertainty in measurements. Finally, we compared blood lead concentrations measured by EDXRF and atomic absorption spectroscopy (AAS) and found EDXRF to be a significant predictor of blood lead (n = 22, R = 0.98, p value <0.001) with an average detection limit of 1.7 µg/dL of blood lead. This detection limit is similar to that of the AAS technique, which is commonly used in clinical testing laboratories for blood lead surveillance. These findings provide a proof of concept that blood spots measured by EDXRF may be used as a surveillance tool for lead exposure, even at elevated blood lead levels of 2-3 µg/dL.

Spatiotemporal distribution of autism spectrum disorder prevalence among birth cohorts during 2000-2011 in Israel.

PURPOSE: Studies indicate an apparent sharp increasing trend in autism spectrum disorder (ASD) incidence and prevalence worldwide. This nationwide study aims at depicting ASD prevalence distribution in Israel in both space and time. METHODS: Based on data from Israel National Insurance Institute, the study population included all children born in Israel 2000-2011 (n = 1,786,194), of whom 11,699 (0.655%) were subsequently diagnosed with ASD (until December 31, 2016). Prevalence was calculated and mapped by dividing the number of ASD cases within each year of birth by the number of births during that year, for each spatial unit, and similarly for several spatiotemporal levels of aggregation. RESULTS: ASD prevalence varies substantially across different geographic areas in Israel, with considerably higher prevalence concentrated in central Israel. Strong associations were found between locality-level socioeconomic index, ethnicity, and peripherality and ASD prevalence, and even after adjustment for them, excess prevalence for ASD still persisted in certain localities. No spatial dependence of prevalence, with and without adjustment for the locality-level variables, was found (Moran's I = -0.000546, -0.00335, respectively). CONCLUSIONS: Our findings provide important insights regarding health disparities affecting ASD diagnosis, directing further health policy intervention and further research.

Race in association with physical and mental health among former professional American-style football players: findings from the Football Players Health Study.

PURPOSE: Race differences in health are pervasive in the United States. American-style football players are a racially diverse group with social status and other benefits that may reduce health disparities. Whether race disparities in health exist among former professional football players, and whether they differ by era of play, is unknown. METHODS: We examined the association of self-reported race with health outcomes (e.g., physical and cognitive function, pain, depression, and anxiety), among 3747 participants in the Football Players Health Study, comprising former National Football League players who played since 1960. We conducted analyses stratified by age. RESULTS: Black players had increased risk of all five adverse health outcomes versus white players (risk ratio range = 1.36 to 1.89). Native Hawaiians and men of other races had greater risk of all health outcomes except impaired physical functioning, compared with white players (risk ratio range = 1.25 to 1.64). No clear patterns were observed by era of play. In general, race disparities were not accounted for by health-related exposures during playing years. Adjustment for current BMI somewhat attenuated associations. CONCLUSIONS: Social and economic advantages of playing professional football did not appear to equalize race disparities in health.

Incidence time trends and socioeconomic factors in the observed incidence of autism spectrum disorder in israel: A nationwide nested case-control study.

Autism spectrum disorder (ASD) trends have been gaining a great deal of focus in recent decades, as many studies worldwide show a continued rise in incidence rates. Many researchers have begun analyzing socioeconomic data in relation to ASD in an effort to understand the source of these changing rates and the role of awareness and access to resources. In this study, we aim to contribute to this body of knowledge by examining incidence time trends of ASD in Israel according to socioeconomic factors. While similar studies have been conducted in Israel, this study is the first of its kind to include the total population. Individual-level data from the Israeli National Insurance Institute were used to determine cumulative incidence of ASD, first for the total population, and then stratified by population group and income categories. Multivariable logistic regression models were fit to analyze associations between income category and both risk of ASD and risk of ASD diagnosis in later age. A total of 431,348 children were examined in this study, with 13,841 cases of ASD. The cumulative incidence of all children aged 8 in 2015 was 0.64%, marking an increase compared to previous literature from Israel. Within our study period, ASD incidence followed this increase until the 2009 birth cohort, where it began to stabilize. Our initial findings from regression models showed strong positive associations between household income and ASD incidence, as expected. After factoring in population group, however, the elevated ASD incidence rates in the highest income bracket decreased. Autism Res 2019, 12: 1870-1879. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: This study contributes comprehensive and current data on ASD trends overtime in Israel and introduces crucial insights regarding the impact of socioeconomic factors on ASD diagnoses. We found a rise in ASD that began leveling off in 2009. We identified more ASD diagnoses occurring in families with higher incomes and in the General Population, pointing to the important role of sociodemographic factors on ASD diagnoses.

A Dosimetry Study of Portable X-ray Fluorescence in Vivo Metal Measurements.

Portable x-ray fluorescence devices have grown in popularity for possible metal exposure assessment using in vivo measurements of bone and toenail. These measurements are accompanied by a small radiation dose, which is typically assessed by radiation safety committees to be minimal. However, an understanding of precise dose under different instrument conditions is still needed. This study set out to do a thorough investigation of the exact dose measurements using optically stimulated dosimeters, thermoluminescent dosimeters, and simulation with a Monte Carlo N-Particle transport code to assess the skin and total-body effective dose typical of portable x-ray fluorescence devices. We showed normal linear relationships between measurement time, x-ray tube current, and radiation dose with the device, and we showed a second order polynomial relationship with increasing voltage and radiation dose. Dose was quantified using thermoluminescent dosimeters, optically stimulated dosimeters, and simulations, which gave similar dose estimations. Skin dose for a standard 50-kV, 40-µA measurement for bone and toenail in vivo was 48.5 and 28.7 mSv, respectively, according to simulation results. Total-body effective dose was shown as 3.4 and 2.0 µSv for in vivo bone and toenail measurements, respectively, for adults using the portable x-ray fluorescence device.

The Association Between Air Pollution and Onset of Depression Among Middle-Aged and Older Women.

Despite recently reported associations between air pollution and acute psychiatric outcomes, the association with depression onset has not, to our knowledge, been previously examined. We conducted a prospective cohort study among 41,844 women in the Nurses' Health Study, in the United States. The women had an average age of 66.6 (standard deviation, 7.6) years, were depression-free in 1996, and were followed through 2008. May-September ozone exposures were predicted by interpolating concentrations from the 5 nearest monitors. One-, 2-, and 5-year average concentrations of particulate matter with an aerodynamic diameter less than or equal to 2.5 µm (PM2.5) were predicted at each participant's residence using a spatiotemporal model. We defined depression as report of doctor's diagnosis or use of antidepressant medication. We estimated adjusted hazard ratios with time-varying Cox models. Hazard ratios for both pollutants were elevated (per 10-parts-per-billion increase in ozone, hazard ratio (HR) = 1.06; 95% confidence interval (CI): 1.00, 1.12; per 10-µg/m3 increase in 1-year PM2.5, HR = 1.08; 95% CI: 0.97, 1.20). Associations were stronger when only antidepressant use was used to define cases (for ozone, HR = 1.08; 95% CI: 1.02, 1.14; for PM2.5, HR = 1.12; 95% CI: 1.00, 1.25). To our knowledge, these results represent the first identification of a possible association between both long-term ozone and PM2.5 exposure and depression onset. Although the stronger association specifically with antidepressant use may reflect that this endpoint better captures the onset time and milder cases, our findings should be interpreted with caution.

Theoretical modeling of a portable x-ray tube based KXRF system to measure lead in bone.

OBJECTIVE: K-shell x-ray fluorescence (KXRF) techniques have been used to identify health effects resulting from exposure to metals for decades, but the equipment is bulky and requires significant maintenance and licensing procedures. A portable x-ray fluorescence (XRF) device was developed to overcome these disadvantages, but introduced a measurement dependency on soft tissue thickness. With recent advances to detector technology, an XRF device utilizing the advantages of both systems should be feasible. APPROACH: In this study, we used Monte Carlo simulations to test the feasibility of an XRF device with a high-energy x-ray tube and detector operable at room temperature. MAIN RESULTS: We first validated the use of Monte Carlo N-particle transport code (MCNP) for x-ray tube simulations, and found good agreement between experimental and simulated results. Then, we optimized x-ray tube settings and found the detection limit of the high-energy x-ray tube based XRF device for bone lead measurements to be 6.91 µg g-1 bone mineral using a cadmium zinc telluride detector. SIGNIFICANCE: In conclusion, this study validated the use of MCNP in simulations of x-ray tube physics and XRF applications, and demonstrated the feasibility of a high-energy x-ray tube based XRF for metal exposure assessment.

The relation between past exposure to fine particulate air pollution and prevalent anxiety: observational cohort study.

OBJECTIVE: To determine whether higher past exposure to particulate air pollution is associated with prevalent high symptoms of anxiety. DESIGN: Observational cohort study. SETTING: Nurses' Health Study. PARTICIPANTS: 71,271 women enrolled in the Nurses' Health Study residing throughout the contiguous United States who had valid estimates on exposure to particulate matter for at least one exposure period of interest and data on anxiety symptoms. MAIN OUTCOME MEASURES: Meaningfully high symptoms of anxiety, defined as a score of 6 points or greater on the phobic anxiety subscale of the Crown-Crisp index, administered in 2004. RESULTS: The 71,271 eligible women were aged between 57 and 85 years (mean 70 years) at the time of assessment of anxiety symptoms, with a prevalence of high anxiety symptoms of 15%. Exposure to particulate matter was characterized using estimated average exposure to particulate matter <2.5 µm in diameter (PM2.5) and 2.5 to 10 µm in diameter (PM2.5-10) in the one month, three months, six months, one year, and 15 years prior to assessment of anxiety symptoms, and residential distance to the nearest major road two years prior to assessment. Significantly increased odds of high anxiety symptoms were observed with higher exposure to PM2.5 for multiple averaging periods (for example, odds ratio per 10 µg/m(3) increase in prior one month average PM2.5: 1.12, 95% confidence interval 1.06 to 1.19; in prior 12 month average PM2.5: 1.15, 1.06 to 1.26). Models including multiple exposure windows suggested short term averaging periods were more relevant than long term averaging periods. There was no association between anxiety and exposure to PM2.5-10. Residential proximity to major roads was not related to anxiety symptoms in a dose dependent manner. CONCLUSIONS: Exposure to fine particulate matter (PM2.5) was associated with high symptoms of anxiety, with more recent exposures potentially more relevant than more distant exposures. Research evaluating whether reductions in exposure to ambient PM2.5 would reduce the population level burden of clinically relevant symptoms of anxiety is warranted.

Childhood and adult socioeconomic position, cumulative lead levels, and pessimism in later life: the VA Normative Aging Study.

Pessimism, a general tendency toward negative expectancies, is a risk factor for depression and also heart disease, stroke, and reduced cancer survival. There is evidence that individuals with higher lead exposure have poorer health. However, low socioeconomic status (SES) is linked with higher lead levels and greater pessimism, and it is unclear whether lead influences psychological functioning independently of other social factors. The authors considered interrelations among childhood and adult SES, lead levels, and psychological functioning in data collected on 412 Boston area men between 1991 and 2002 in a subgroup of the VA Normative Aging Study. Pessimism was measured by using the Life Orientation Test. Cumulative (tibia) lead was measured by x-ray fluorescence. Structural equation modeling was used to quantify the relations as mediated by childhood and adult SES, controlling for age, health behaviors, and health status. An interquartile range increase in lead quartile was associated with a 0.37 increase in pessimism score (P < 0.05). Low childhood and adult SES were related to higher tibia lead levels, and both were also independently associated with higher pessimism. Lead maintained an independent association with pessimism even after childhood and adult SES were considered. Results demonstrate an interrelated role of lead burden and SES over the life course in relation to psychological functioning in older age.

Assessment of occupational exposure to manganese and other metals in welding fumes by portable X-ray fluorescence spectrometer.

Elemental analysis of welding fume samples can be done using several laboratory-based techniques. However, portable measurement techniques could offer several advantages. In this study, we sought to determine whether the portable X-ray fluorescence spectrometer (XRF) is suitable for analysis of five metals (manganese, iron, zinc, copper, and chromium) on 37-mm polytetrafluoroethylene filters. Using this filter fitted on a cyclone in line with a personal pump, gravimetric samples were collected from a group of boilermakers exposed to welding fumes. We assessed the assumption of uniform deposition of these metals on the filters, and the relationships between measurement results of each metal obtained from traditional laboratory-based XRF and the portable XRF. For all five metals of interest, repeated measurements with the portable XRF at the same filter area showed good consistency (reliability ratios are equal or close to 1.0 for almost all metals). The portable XRF readings taken from three different areas of each filter were not significantly different (p-values = 0.77 to 0.98). This suggested that the metal rich PM(2.5) deposits uniformly on the samples collected using this gravimetric method. For comparison of the two XRFs, the results from the portable XRF were well correlated and highly predictive of those from the laboratory XRF. The Spearman correlation coefficients were from 0.325 for chromium, to 0.995 for manganese and 0.998 for iron. The mean differences as a percent of the mean laboratory XRF readings were also small (<5%) for manganese, iron, and copper. The differences were greater for zinc and chromium, which were present at very low amounts in our samples and below the limits of detection of the portable XRF for many of the samples. These five metals were moderately to strongly correlated with the total fine particle fraction on filters (Spearman rho = 0.41 for zinc to 0.97 for iron). Such strong correlations and comparable results suggested that the portable XRF could be used as an effective and reliable tool for exposure assessment in many studies.