Commentary

Stuart, Elizabeth A.; Hanna, David B.

doi:10.1097/ede.0b013e3182782468

Cited by 22 publications

(16 citation statements)

References 6 publications

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“…adjacent CpG often showed similar signals despite being analyzed separately). Our study compared extremes of arsenic exposure in the Strong Heart Study population, reducing potential biases from exposure misclassification (Stuart and Hanna, 2013; Zubizarreta et al, 2013). The major limitation was the sample size, which limited the study power and limited our ability to control for confounders.…”

Section: Discussionmentioning

confidence: 99%

“…To maximize efficiency of this relatively small epigenetic study and reduce exposure misclassification (Stuart and Hanna, 2013; Zubizarreta et al, 2013), we used a stratified random sample to select eight participants with moderate arsenic exposure and eight participants with low arsenic exposure from each region (16 from Arizona, 16 from Oklahoma and 16 from North or South Dakota), resulting in a total of 48 participants. Based on the Strong Heart Study distributions, relatively low and moderate arsenic exposures were defined as urine concentrations < 7.2 µg/L (tertile 1) and ≥ 14.0 µg/L (tertile 3), respectively, for the sum of inorganic and methylated arsenic species in 1989 – 1991.…”

Section: Methodsmentioning

confidence: 99%

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Differential methylation of the arsenic (III) methyltransferase promoter according to arsenic exposure

et al. 2013

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Inorganic arsenic is methylated in the body by arsenic (III) methyltransferase. Arsenic methylation is thought to play a role in arsenic-related epigenetic phenomena including aberrant DNA and histone methylation. However, it is unclear whether the promoter of the AS3MT gene, which codes for arsenic (III) methyltransferase, is differentially methylated as a function of arsenic exposure. In this study we evaluated AS3MT promoter methylation according to exposure, assessed by urinary arsenic excretion in a stratified random sample of 48 participants from the Strong Heart Study who had urine arsenic measured at baseline and DNA available from 1989–1991 and 1998–1999. For this study, all data are from the 1989–1991 visit. We measured AS3MT promoter methylation at its 48 CpG loci by bisulphite sequencing. We compared mean % methylation at each CpG locus by arsenic exposure group using linear regression adjusted for study centre, age and sex. A hypomethylated region in the AS3MT promoter was associated with higher arsenic exposure. In vitro, arsenic induced AS3MT promoter hypomethylation and it increased AS3MT expression in human peripheral blood mononuclear cells. These findings may suggest that arsenic exposure influences the epigenetic regulation of a major arsenic metabolism gene.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Differential methylation of the arsenic (III) methyltransferase promoter according to arsenic exposure

et al. 2013

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“…A total of 517 participants met those criteria. To maximize the efficiency of this relatively small epigenetic study (Stuart and Hanna 2013; Zubizarreta et al 2013), we used a stratified random sample to select 8 participants with moderate arsenic exposure and 8 participants with low arsenic exposure from each region (16 from Arizona, 16 from Oklahoma, and 16 from North or South Dakota), resulting in a total of 48 participants. On the basis of SHS distributions in 1989–1991, we defined relatively low and moderate arsenic exposures of the sum of inorganic and methylated arsenic species as urinary concentrations < 7.2 μg/g (tertile 1) and ≥ 14.0 μg/g (tertile 3), respectively.…”

Section: Methodsmentioning

confidence: 99%

Association of Global DNA Methylation and Global DNA Hydroxymethylation with Metals and Other Exposures in Human Blood DNA Samples

Téllez-Plaza

Tang

Shang

et al. 2014

Environ Health Perspect

107

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Background: The association between human blood DNA global methylation and global hydroxymethylation has not been evaluated in population-based studies. No studies have evaluated environmental determinants of global DNA hydroxymethylation, including exposure to metals.Objective: We evaluated the association between global DNA methylation and global DNA hydroxymethylation in 48 Strong Heart Study participants for which selected metals had been measured in urine at baseline and DNA was available from 1989–1991 (visit 1) and 1998–1999 (visit 3).Methods: We measured the percentage of 5-methylcytosine (5-mC) and 5-hydroxymethylcytosine (5-hmC) in samples using capture and detection antibodies followed by colorimetric quantification. We explored the association of participant characteristics (i.e., age, adiposity, smoking, and metal exposure) with both global DNA methylation and global DNA hydroxymethylation.Results: The Spearman’s correlation coefficient for 5-mC and 5-hmC levels was 0.32 (p = 0.03) at visit 1 and 0.54 (p < 0.001) at visit 3. Trends for both epigenetic modifications were consistent across potential determinants. In cross-sectional analyses, the odds ratios of methylated and hydroxymethylated DNA were 1.56 (95% CI: 0.95, 2.57) and 1.76 (95% CI: 1.07, 2.88), respectively, for the comparison of participants above and below the median percentage of dimethylarsinate. The corresponding odds ratios were 1.64 (95% CI: 1.02, 2.65) and 1.16 (95% CI: 0.70, 1.94), respectively, for the comparison of participants above and below the median cadmium level. Arsenic exposure and metabolism were consistently associated with both epigenetic markers in cross-sectional and prospective analyses. The positive correlation of 5-mC and 5-hmC levels was confirmed in an independent study population.Conclusions: Our findings support that both epigenetic measures are related at the population level. The consistent trends in the associations between these two epigenetic modifications and the characteristics evaluated, especially arsenic exposure and metabolism, suggest the need for understanding which of the two measures is a better biomarker for environmental epigenetic effects in future large-scale epidemiologic studies.Citation: Tellez-Plaza M, Tang WY, Shang Y, Umans JG, Francesconi KA, Goessler W, Ledesma M, Leon M, Laclaustra M, Pollak J, Guallar E, Cole SA, Fallin MD, Navas-Acien A. 2014. Association of global DNA methylation and global DNA hydroxymethylation with metals and other exposures in human blood DNA samples. Environ Health Perspect 122:946–954; http://dx.doi.org/10.1289/ehp.1306674

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“…In observational studies, it is known that certain patterns of treatment effects are more resistant than others to being explained away as the consequence of unmeasured biases in treatment assignment; see, for instance, Rosenbaum (2004), Zubizarreta et al (2013), Stuart and Hanna (2013).…”

Section: Notation For Causal Effects Nonrandom Treatment Assignmentmentioning

confidence: 99%

Discovering Effect Modification in an Observational Study of Surgical Mortality at Hospitals with Superior Nursing

Lee

Small

Hsu

et al. 2017

Journal of the Royal Statistical Society Series A: Statistics in Society

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Summary. There is effect modification if the magnitude or stability of a treatment effect varies systematically with the level of an observed covariate. A larger or more stable treatment effect is typically less sensitive to bias from unmeasured covariates, so it is important to recognize effect modification when it is present. We illustrate a recent proposal for conducting a sensitivity analysis that empirically discovers effect modification by exploratory methods, but controls the family-wise error rate in discovered groups. The example concerns a study of mortality and use of the intensive care unit in 23,715 matched pairs of two Medicare patients, one of whom underwent surgery at a hospital identified for superior nursing, the other at a conventional hospital. The pairs were matched exactly for 130 four-digit ICD-9 surgical procedure codes and balanced 172 observed covariates. The pairs were then split into five groups of pairs by CART in its effort to locate effect modification. The evidence of a beneficial effect of magnet hospitals on mortality is least sensitive to unmeasured biases in a large group of patients undergoing rather serious surgical procedures, but in the absence of other life-threatening conditions, such as a comorbidity of congestive heart failure or an emergency admission leading to surgery. Superior nurse staffing, surgical mortality and resource utilization in MedicareHospitals vary in the extent and quality of their staffing, technical capabilities and nursing work environments. Does superiority in these areas confer benefits to patients undergoing forms of Lee, D. S. Small, J. Y. Hsu, J. H. Silber and P. R. Rosenbaum (2000). Additionally, it is relatively easy to use Medicare files to determine the quantity of nurse staffing in the form of the nurse-to-bed ratio. The study compared patient outcomes at 35 magnet hospitals with nurse-to-bed ratios of 1 or more to outcomes for patients at 293 hospitals without magnet designation and with nurse-to-bed ratios less than 1. Table 1). Does a patient undergoing perhaps comparatively routine general surgery benefit from all of these capabilities or are they wasted on such a patient?The distinction in the previous paragraph may be restated as follows. The counter-factual under study is: What would happen to a specific patient if that patient were treated at a hospital having the superior staffing of magnet hospitals when compared to what would happen to this same patient if treated at a control hospital? The counter-factual refers to sending the patient to one hospital or another. What would happen if patients were allocated to existing hospitals in a different way? The counter-factual does not contemplate changing the staffing at any hospital. Beds in hospitals with superior staffing are in limited supply, and it is a matter of considerable public importance that this limited resource be allocated to the patients most likely to benefit from it. Some patients are in relatively good health and require relatively routine care; perhaps these pa...

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Commentary

Cited by 22 publications

References 6 publications

Differential methylation of the arsenic (III) methyltransferase promoter according to arsenic exposure

Differential methylation of the arsenic (III) methyltransferase promoter according to arsenic exposure

Association of Global DNA Methylation and Global DNA Hydroxymethylation with Metals and Other Exposures in Human Blood DNA Samples

Discovering Effect Modification in an Observational Study of Surgical Mortality at Hospitals with Superior Nursing

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