Comparative safety of conjugated estrogens/bazedoxifene versus estrogen/progestin combination hormone therapy among women in the United States: a multidatabase cohort study.

OBJECTIVE: To assess the risk of select safety outcomes including endometrial cancer, endometrial hyperplasia, and breast cancer among women using conjugated estrogens/bazedoxifene (CE/BZA) as compared with estrogen/progestin combination hormone therapy (EP). METHODS: We conducted a new-user cohort study in five US healthcare claims databases representing more than 92 million women. We included CE/BZA or EP new users from May 1, 2014, to August 30, 2019. EP users were propensity score (PS) matched to users of CE/BZA. Incidence of endometrial cancer, endometrial hyperplasia, breast cancer, and eight additional cancer and cardiovascular outcomes were ascertained using claims-based algorithms. Rate ratios (RR) and differences pooled across databases were estimated using random-effects models. RESULTS: The study population included 10,596 CE/BZA and 33,818 PS-matched EP new users. Rates of endometrial cancer and endometrial hyperplasia were slightly higher among CE/BZA users (1.6 and 0.4 additional cases per 10,000 person-years), although precision was limited because of small numbers of cases (endometrial cancer: RR, 1.50 [95% confidence interval {CI}, 0.79-2.88]; endometrial hyperplasia: RR, 1.69 [95% CI, 0.51-5.61]). Breast cancer incidence was lower in CE/BZA users (9.1 fewer cases per 10,000 person-years; RR, 0.79; 95% CI, 0.58-1.05). Rates of other outcomes were slightly higher among CE/BZA users, but with confidence intervals compatible with a wider range of possible associations. CONCLUSIONS: CE/BZA users might experience slightly higher rates of endometrial cancer and endometrial hyperplasia, and a lower rate of breast cancer, than EP users in the first years of use.

Bias Amplification in Epidemiologic Analysis of Exposure to Mixtures.

BACKGROUND: The analysis of health effects of exposure to mixtures is a critically important issue in human epidemiology, and increasing effort is being devoted to developing methods for this problem. A key feature of environmental mixtures is that some components can be highly correlated, raising the issues of confounding by coexposure and colinearity. A relatively unexplored topic in epidemiologic analysis of mixtures is the impact of residual confounding bias due to unmeasured or unknown variables. OBJECTIVES: This paper examines the potential amplification of such biases when correlated exposure variables are included in regression models. METHODS: We use directed acyclic graphs (DAGs) to describe different simple scenarios involving residual confounding. We derive expressions for the expected value of the resulting bias using linear models and multiple linear regression. RESULTS: Approaches to the analysis of mixtures that involve regressing the outcome on several exposures simultaneously can in some cases amplify rather than reduce confounding bias. DISCUSSIONS: The problem of bias amplification can worsen with stronger correlation between mixture components or when more mixture components are included in the model. CONCLUSIONS: Investigators must consider steps to minimize possible bias amplification in the design and analysis of epidemiologic studies of multiple correlated exposures. This may be particularly important when biomarkers of exposure are used. https://doi.org/10.1289/EHP2450.

Occupational formaldehyde and amyotrophic lateral sclerosis.

Prior studies have yielded inconsistent evidence regarding the association between formaldehyde exposure and amyotrophic lateral sclerosis (ALS). We conducted a population case-control study in the Danish National Registries on the relationship between occupationally-derived formaldehyde exposure and ALS. Occupational history was obtained from a comprehensive and prospectively recorded pension database of all paid work in Denmark since 1964, and was linked to a job-exposure matrix to derive individual exposure estimates. Each case was matched to 4 age- and sex-matched population controls alive on the date of the case diagnosis via risk set sampling, and odds ratios and confidence intervals (CI) were calculated via conditional logistic regression, adjusting for potential confounders. There were 3650 incident cases of ALS in the Danish National Patient Register from 1982 to 2009. Among controls, 25% were ever employed in jobs with a positive prevalence of formaldehyde exposure. Exposure to formaldehyde was associated with a 1.3-fold increased rate of ALS (95% CI 1.2-1.4). This study suggests that formaldehyde exposure, or employment in formaldehyde-exposed occupations, is related to the risk of ALS.

Cardiovascular disease and diagnosis of amyotrophic lateral sclerosis: A population based study.

Amyotrophic lateral sclerosis (ALS) is a rapidly fatal neurodegenerative disease of unknown etiology. We investigated the association between ALS diagnosis and prior cardiovascular disease (CVD), and CVD-specific, hospital admissions in the Danish population. We conducted a population based nested case-control study, including 3182 Danish residents diagnosed with ALS at age ≥20 years (1982-2009) and 100 randomly selected controls for each case, matched on age, gender and vital status. We estimated odds ratios (OR) associated with CVD, and CVD-specific hospital admissions, adjusting for socioeconomic and marital status, region of residence and past diabetes and obesity diagnoses. The estimated adjusted OR for any CVD admission at least three years prior to the date of ALS diagnosis was 1.15 (95% CI 1.04-1.27). Our results varied across cause-specific admissions; for atherosclerosis the OR was 1.36 (95% CI 1.02-1.80) and for ischemic heart disease 1.14 (95% CI 0.99-1.31), while we observed no association with hypertensive and cerebrovascular diseases. Adjusting for or stratifying by COPD status, a cigarette-smoking correlate, did not change our results. In conclusion, in our population based study we found evidence for a moderately elevated association with CVD that was stronger for specific conditions, such as atherosclerosis. Our findings may have important implications for ALS pathogenesis.

Physical Trauma and Amyotrophic Lateral Sclerosis: A Population-Based Study Using Danish National Registries.

Prior studies have suggested that physical trauma might be associated with the development of amyotrophic lateral sclerosis (ALS). We conducted a population-based, individually matched case-control study in Denmark to assess whether hospitalization for trauma is associated with a higher risk of developing ALS. There were 3,650 incident cases of ALS in the Danish National Patient Register from 1982 to 2009. We used risk-set sampling to match each case to 100 age- and sex-matched population controls alive on the date of the case's diagnosis. Odds ratios and 95% confidence intervals were calculated using a conditional logistic regression model. History of trauma diagnosis was also obtained from the Danish Patient Register. When traumas in the 5 years prior to the index date were excluded, there was a borderline association between any trauma and ALS (odds ratio (OR) = 1.09, 95% confidence interval (CI): 0.99, 1.19). A first trauma before age 55 years was associated with ALS (OR = 1.22, 95% CI: 1.08, 1.37), whereas first traumas at older ages were not (OR = 0.97, 95% CI: 0.85, 1.10). Our data suggest that physical trauma at earlier ages is associated with ALS risk. Age at first trauma could help explain discrepancies in results of past studies of trauma and ALS.

Amyotrophic Lateral Sclerosis and the Military: A Population-based Study in the Danish Registries.

BACKGROUND: Prior studies have suggested that military service may be associated with the development of amyotrophic lateral sclerosis (ALS). We conducted a population-based case-control study in Denmark to assess whether occupation in the Danish military is associated with an increased risk of developing ALS. METHODS: There were 3,650 incident cases of ALS recorded in the Danish National Patient Registry between 1982 and 2009. Each case was matched to 100 age- and sex-matched population controls alive and free of ALS on the date of the case diagnosis. Comprehensive occupational history was obtained from the Danish Pension Fund database, which began in 1964. RESULTS: 2.4% (n = 8,922) of controls had a history of employment in the military before the index date. Military employees overall had an elevated rate of ALS (odds ratio [OR] = 1.3; 95% confidence interval [CI]: 1.1, 1.6). A 10-year increase in years employed by the military was associated with an OR of 1.2 (95% CI: 1.0, 1.4), and all quartiles of time employed were elevated. There was little suggestion of a pattern across calendar year of first employment, but there was some evidence that increasing age at first employment was associated with increased ALS rates. Rates were highest in the decade immediately following the end of employment (OR = 1.6; 95% CI: 1.2, 2.2). CONCLUSIONS: In this large population-based case-control study, employment by the military is associated with increased rates of ALS. These findings are consistent with earlier findings that military service or employment may entail exposure to risk factors for ALS.

Diabetes Mellitus, Obesity, and Diagnosis of Amyotrophic Lateral Sclerosis: A Population-Based Study.

IMPORTANCE: Although prior studies have suggested a role of cardiometabolic health on pathogenesis of amyotrophic lateral sclerosis (ALS), the association with diabetes mellitus has not been widely examined. Amyotrophic lateral sclerosis is the most common motor neuron disorder. Several vascular risk factors have been associated with decreased risk for ALS. Although diabetes is also a risk factor for vascular disease, the few studies of diabetes and ALS have been inconsistent. OBJECTIVE: To examine the association between diabetes and obesity, each identified through International Statistical Classification of Diseases, Eighth or Tenth Revision codes in a hospital registry, and ALS using data from the Danish National Registers. DESIGN, SETTING, AND PARTICIPANTS: Population-based nested case-control study of 3650 Danish residents diagnosed as having ALS between January 1, 1982, and December 31, 2009, and 365,000 controls (100 for each ALS case) matched on age and sex. The analysis was conducted in September and October 2014. MAIN OUTCOMES AND MEASURES: Adjusted odds ratio for ALS associated with diabetes or obesity diagnoses at least 3 years prior to the ALS diagnosis date. RESULTS: When considering diabetes and our obesity indicator together, the estimated odds ratio for ALS was 0.61 (95% CI, 0.46-0.80) for diabetes and 0.81 (95% CI, 0.57-1.16) for obesity. We observed no effect modification on the association with diabetes by sex. We did find a significant modification by age at ALS diagnosis and age at first mention of diabetes in the hospital registers. The protective association was stronger with increasing age at ALS diagnosis (P = .01), and the odds ratio for first mention of diabetes was 1.66 (95% CI, 0.85-3.21) before age 40 years but 0.52 (95% CI, 0.39-0.70) for older ages. These results are consistent with different associations for type 1 vs type 2 diabetes. CONCLUSIONS AND RELEVANCE: In this Danish nationwide study to investigate the association between diabetes and ALS diagnosis, our findings are in agreement with previous reports of a protective association between vascular risk factors and ALS and suggest that type 2 diabetes, but not type 1, is protective for ALS.

Comparison of diagnoses of amyotrophic lateral sclerosis by use of death certificates and hospital discharge data in the Danish population.

Because ALS is rare, large-scale studies are difficult. Hospital and death certificate data are valuable tools, but understanding of how well they capture cases is needed. We identified 3650 incident cases in the Danish National Patient Register (NPR) between 1982 and 2009, using ICD-8 (before 1994) or ICD-10 codes. Death certificates were obtained from the Danish Register of Causes of Death. We obtained medical records for 173 of the cases identified in the NPR and classified these according to the El Escorial criteria. We compared ALS identification from death certificates to hospital discharges, and both to medical records. Results showed that the sensitivity for use of death certificates was 84.2% (95% CI 82.9-85.5%) and was significantly higher for females, subjects younger than 77 years, and when coded with ICD-8. Using only the underlying cause of death resulted in significantly lower sensitivity. The estimated overall positive predictive value (PPV) was 82.0% (95% CI 80.0-83.8%). Sensitivity and PPV were similar compared with medical records. In conclusion, we found that use of hospital discharges and death certificates is highly reliable and, therefore, a valuable tool for ALS epidemiologic studies. The possible effects on findings of slight differences by age, gender, and ICD coding should be considered.

Modification of the association between lead exposure and amyotrophic lateral sclerosis by iron and oxidative stress related gene polymorphisms.

Our objective was to examine whether functional polymorphisms in hemochromatosis (HFE; H63D and C282Y), transferrin (TfC2), and glutathione-s-transferase Pi1 (GSTP1; Ile105Val) genes modify any lead-ALS association. We measured blood lead using atomic absorption spectroscopy and bone lead - a biomarker of cumulative lead exposure - using K-shell-X-ray fluorescence in 100 neurologist-confirmed ALS cases and 194 controls, the latter recruited as part of two separate studies; all subjects lived in New England. Participants were considered variant carriers or wild-type for each polymorphism. To assess effect modification, we included cross-product terms between lead biomarkers and each polymorphism in separate adjusted polytomous logistic regression models. Compared with wild-type, the odds ratio (OR) per 15.6 µg/g patella lead (interquartile range; IQR) was 8.24 (95% CI 0.94-72.19) times greater among C282Y variant carriers, and 0.34 (95% CI 0.15-0.78) times smaller among H63D variant carriers. Results were weaker for tibia lead. Compared with wild-type the OR per 2 µg/dl blood lead (IQR) was 0.36 (95% CI 0.19-0.68) times smaller among H63D variant carriers, and 1.96 (95% CI 0.98-3.92) times greater among GSTP1 variant carriers. In conclusion, we found that HFE and GSTP1 genotypes modified the association between lead biomarkers and ALS. Contrasting modification by the HFE polymorphisms H63D and C282Y may suggest that the modification is not simply the result of increased iron.

Age-period-cohort analysis of trends in amyotrophic lateral sclerosis in Denmark, 1970-2009.

Amyotrophic lateral sclerosis (ALS) is a disease of the motor neuron with poorly understood etiology. Recent studies have suggested that the incidence rate of ALS and the rate of death from ALS are increasing, but it is unclear whether this is due to changing exposures or improvements in diagnosis. We used age-period-cohort models to investigate trends in ALS incidence (hospitalization) from 1982 to 2009 and ALS mortality from 1970 to 2009 in Denmark. Among those 45 years of age or older, 4,265 deaths (incidence rate = 5.35 per 100,000 person-years) and 3,228 incident diagnoses (incidence rate = 5.55 per 100,000 person-years) were recorded. Age-adjusted mortality rates increased by an average of 3.0% annually between 1970 and 2009 and by an average of 2.1% annually after 1982. Age-period-cohort analyses suggested that the full age-period-cohort model provided the best fit to the mortality data (P < 0.001), although restriction to the post-1982 period suggested that the age-cohort model provided the best fit. Age-adjusted incidence rates increased by 1.6% annually after 1982 (P < 0.001), which was best explained by the age-period model, with borderline significant cohort effects (P = 0.08). A consistent finding regardless of parameterization or data subset appeared to be an increase in ALS incidence and mortality rate with later birth cohorts, up to a birth year of at least 1910.

Diversity of release patterns for jail detainees: implications for public health interventions.

OBJECTIVES: We sought to develop a detailed description of the variety of jail release patterns and to learn what factors affect the length of stay (LOS). METHODS: The main data set for the study came from a biennial Bureau of Justice Statistics survey on felony defendants in large urban counties. RESULTS: The median LOS for the felony defendants was 7 days. One quarter of the jails had a median LOS of less than 2 days; median LOS for 75% of the jails was less than 15 days. Median regression showed that male gender, previous arrests, and violent charges were predictive of longer LOS. CONCLUSIONS: The diversity in release patterns among jails has not been previously described. A public health intervention feasible in one jail may not be feasible in another because of the heterogeneity of release patterns. Individual inmate characteristics could predict a slower rate of release.

Prisoner survival inside and outside of the institution: implications for health-care planning.

The life expectancy of persons cycling through the prison system is unknown. The authors sought to determine the 15.5-year survival of 23,510 persons imprisoned in the state of Georgia on June 30, 1991. After linking prison and mortality records, they calculated standardized mortality ratios (SMRs). The cohort experienced 2,650 deaths during follow-up, which were 799 more than expected (SMR = 1.43, 95% confidence interval (CI): 1.38, 1.49). Mortality during incarceration was low (SMR = 0.85, 95% CI: 0.77, 0.94), while postrelease mortality was high (SMR = 1.54, 95% CI: 1.48, 1.61). SMRs varied by race, with black men exhibiting lower relative mortality than white men. Black men were the only demographic subgroup to experience significantly lower mortality while incarcerated (SMR = 0.66, 95% CI: 0.58, 0.76), while white men experienced elevated mortality while incarcerated (SMR = 1.28, 95% CI: 1.10, 1.48). Four causes of death (homicide, transportation, accidental poisoning, and suicide) accounted for 74% of the decreased mortality during incarceration, while 6 causes (human immunodeficiency virus infection, cancer, cirrhosis, homicide, transportation, and accidental poisoning) accounted for 62% of the excess mortality following release. Adjustment for compassionate releases eliminated the protective effect of incarceration on mortality. These results suggest that the low mortality inside prisons can be explained by the rarity of deaths unlikely to occur in the context of incarceration and compassionate releases of moribund patients.

Pairing HIV-positive prisoners with volunteer life coaches to maintain health-promoting behavior upon release: a mixed-methods needs analysis and pilot study.

Drawing on individuals who volunteer in US prisons to mentor HIV-infected inmates returning to the community may promote successful transitions. Evaluations published in the scientific literature of such community linkage programs are scant. Our quantitative and qualitative methods needs analysis and pilot study entailed interviewing convenience samples of 24 HIV-positive persons recently released from Georgia correctional facilities and 12 potential volunteer mentors. Both releasees and potential mentors were open to the establishment of a mentoring program. Releasees wanted nonjudgmental mentors. Releasees and volunteers had statistically significant differences in marital status, education, current employment, and possession of a driver's license but not in degree of religious involvement and attitudes toward condom use. A volunteer-staffed program, perhaps more aptly named "life coaching" than mentoring, to help HIV-infected persons to transition from prison to the community may be feasible. Success will require adequately trained volunteers and a straightforward program.

HIV/AIDS among inmates of and releasees from US correctional facilities, 2006: declining share of epidemic but persistent public health opportunity.

Because certain groups at high risk for HIV/AIDS (human immunodeficiency virus/acquired immunodeficiency syndrome) come together in correctional facilities, seroprevalence was high early in the epidemic. The share of the HIV/AIDS epidemic borne by inmates of and persons released from jails and prisons in the United States (US) in 1997 was estimated in a previous paper. While the number of inmates and releasees has risen, their HIV seroprevalence rates have fallen. We sought to determine if the share of HIV/AIDS borne by inmates and releasees in the US decreased between 1997 and 2006. We created a new model of population flow in and out of correctional facilities to estimate the number of persons released in 1997 and 2006. In 1997, approximately one in five of all HIV-infected Americans was among the 7.3 million who left a correctional facility that year. Nine years later, only one in seven (14%) of infected Americans was among the 9.1 million leaving, a 29.3% decline in the share. For black and Hispanic males, two demographic groups with heightened incarceration rates, recently released inmates comprise roughly one in five of those groups' total HIV-infected persons, a figure similar to the proportion borne by the correctional population as a whole in 1997. Decreasing HIV seroprevalence among those admitted to jails and prisons, prolonged survival and aging of the US population with HIV/AIDS beyond the crime-prone years, and success with discharge planning programs targeting HIV-infected prisoners could explain the declining concentration of the epidemic among correctional populations. Meanwhile, the number of persons with HIV/AIDS leaving correctional facilities remains virtually identical. Jails and prisons continue to be potent targets for public health interventions. The fluid nature of incarcerated populations ensures that effective interventions will be felt not only in correctional facilities but also in communities to which releasees return.