The Confounder-Mediator Dilemma: Should We Control for Obesity to Estimate the Effect of Perfluoroalkyl Substances on Health Outcomes?

Inoue, Kosuke; Goto, Atsushi; Sugiyama, Takehiro; Ramlau‐Hansen, Cecilia Høst; Liew, Zeyan

doi:10.3390/toxics8040125

Cited by 25 publications

(19 citation statements)

References 47 publications

(68 reference statements)

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“…2017 ; Jain and Ducatman 2019 ). However, cautious interpretation is recommended because stratification by baseline BMI could introduce (collider stratification) bias ( Inoue et al. 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Per- and Polyfluoroalkyl Substances and Risk of Myocardial Infarction and Stroke: A Nested Case–Control Study in Sweden

Schillemans

Donat‐Vargas

Lindh

et al. 2022

Environ Health Perspect

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Background: Per- and polyfluoroalkyl substances (PFAS) are widespread and persistent pollutants that have been associated with elevated cholesterol levels. However, data on incident cardiovascular disease (CVD) is lacking. Objectives: We investigated the association of exposure to PFAS with risk of myocardial infarction and stroke and, subsidiary, with baseline blood lipids. Methods: This population-based nested case–control study included first incident myocardial infarction and stroke cases with matched controls from two Swedish cohorts: the Swedish Mammography Cohort-Clinical (SMC-C) and the Cohort of 60-year-olds (60YO). Baseline blood sampling occurred during 2003–2009 and 1997–1999 with follow-up through 2017 and 2014 for the SMC-C and the 60YO, respectively. Eight plasma PFAS concentrations were measured using targeted liquid chromatography–triple quadrupole mass spectrometry. Five of these were quantifiable in both cohorts; individual values and their standardized sum were categorized into tertiles based on the controls. First incident myocardial infarction ( ) and ischemic stroke ( ) cases were ascertained via linkage to the National Inpatient Register and the Cause of Death Register. Controls were randomly selected from each cohort after matching for age, sex, and sample date. Baseline blood lipids were measured in plasma or serum after overnight fasting. Results: Among the 1,528 case–control subjects, the mean (standard deviation) age was 66 (7.7) y and 67% of them were women. In multivariable-adjusted analyses, the third tertile of the standardized sum of five PFAS associated with higher cholesterol and lower triglyceride levels among controls at baseline ( ). The corresponding results were [95% confidence interval (CI): 0.53, 0.93] for CVD, 0.60 (95% CI: 0.39, 0.92) for myocardial infarction, and 0.83 (95% CI: 0.46, 1.50) for stroke. Discussion: This study indicated that exposure to PFAS, although associated with increased cholesterol levels, did not associate with an increased risk of myocardial infarction, stroke, or their composite end point. The findings improve our knowledge on potential health effects of environmental contaminants in the CVD context. https://doi.org/10.1289/EHP9791

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Section: Discussionmentioning

confidence: 99%

Per- and Polyfluoroalkyl Substances and Risk of Myocardial Infarction and Stroke: A Nested Case–Control Study in Sweden

Schillemans

Donat‐Vargas

Lindh

et al. 2022

Environ Health Perspect

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“…Fifth, we added body mass index (BMI) as an additional covariate. BMI was not included in the primary analyses, because conditioning on BMI may introduce collider stratification bias [ 35 , 36 ] and because the sample size was reduced through missing data on height and weight. The sixth sensitivity analysis repeated the analyses with alcohol intake modelled across the full range of consumptions (eight points from ‘almost daily’ to ‘not at all in the past 12 months’) instead of categorization as a binary variable.…”

Section: Methodsmentioning

confidence: 99%

Systemic inflammation and emotional responses during the COVID-19 pandemic

2021

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The impact of the COVID-19 pandemic on population mental health is of global concern. Inflammatory processes are thought to contribute to mental ill-health, but their role in experiences of psychological distress during the pandemic has not been investigated. We tested the hypothesis that elevated inflammatory biomarkers (high-sensitivity plasma C-reactive protein [CRP] and plasma fibrinogen) measured pre-pandemic would be positively predictive of increased depressive symptoms experienced during the pandemic. Data were analysed from the English Longitudinal Study of Ageing (ELSA), with 3574 individuals aged >50 for CRP and 3314 for fibrinogen measured in waves 8 (2016/17) or 9 (2018/19). Depressive symptoms were measured with a short version of the Centre for Epidemiological Studies Depression Scale (CES-D) pre-pandemic (2016–2019) and during the pandemic (June/July 2020). Participants with higher baseline CRP concentrations had 40% higher odds of developing depressive symptoms during the pandemic (ORadjusted = 1.40, 95% CI 1.12–1.73, p = 0.003) after full adjustment. Fibrinogen concentrations were also associated with depressive symptoms during the pandemic (ORadjusted = 1.23, 95% CI 1.04–1.46, p = 0.019), but this association was no longer significant after controlling for lifestyle factors (smoking status, alcohol consumption and physical activity). In this large population study, systemic inflammation measured 1–3 years pre-pandemic was associated with greater depressed mood during the early months of the pandemic. This finding is consistent with the hypothesis that higher levels of inflammation increase the vulnerability of older people to impaired mental health in the presence of the widespread stress of the COVID-19 pandemic.

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“…In PA studies, given the negative feedback system of RAAS and the HPA axis, it is often challenging to assume which variables (e.g., biomarker concentrations and medical conditions) occurred first at cross-sectional data. When the variables can be both confounders and mediators, researchers need to carefully interpret the results of stratified analysis by such variables because the seemingly heterogeneous findings could be biased (74). Temporal ordering can be established in longitudinal cohorts where the extraction of biosample and other information precedes the outcome assessment.…”

Section: Overadjustment and Collider Biasmentioning

confidence: 99%

Cortisol Co-Secretion and Clinical Usefulness of ACTH Stimulation Test in Primary Aldosteronism: A Systematic Review and Biases in Epidemiological Studies

et al. 2021

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The hypothalamus-pituitary-adrenal (HPA) axis plays an important role in primary aldosteronism. Aldosterone biosynthesis is regulated not only by angiotensin II in the renin-angiotensin-aldosterone system, but also by adrenocorticotropic hormone (ACTH), one of the key components of the HPA axis. Although previous studies have reported cortisol cosecretion in primary aldosteronism, particularly aldosterone-producing adenoma (APA), the clinical relevance of such aldosterone and cortisol cosecretion from APA and hypertension or other metabolic disorders has not been fully established. Several somatic mutations including KCNJ5 and CACNA1D are known to induce autonomous production of aldosterone in APA, and the aldosterone responsiveness to ACTH may vary according to each mutation. The ACTH stimulation test has been reported to be a useful tool to distinguish the subtypes of primary aldosteronism (e.g., unilateral vs bilateral) in some studies, but it has not been commonly applied in clinical practice due to limited evidence. Given the recent advancement of imaging, omics research, and computational approach, it is important to summarize the most updated evidence to disentangle the potential impact of cortisol excess in primary aldosteronism and whether the ACTH stimulation test needs to be considered during the diagnostic process of primary aldosteronism. In this article, we conducted a systematic review of epidemiological studies about (i) cortisol cosecretion in primary aldosteronism and (ii) the ACTH stimulation test for the diagnosis of primary aldosteronism (including subtype diagnosis). Then, we discussed potential biases (e.g., confounding bias, overadjustment, information bias, selection bias, and sampling bias) in the previous studies and introduced some advanced epidemiological/statistical methods to minimize these limitations. A better understanding of biases and epidemiological perspective on this topic would allow us to produce further robust evidence and balanced discussion about the causal mechanisms involving the HPA axis and clinical usefulness of the ACTH stimulation test among patients with primary aldosteronism.

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The Confounder-Mediator Dilemma: Should We Control for Obesity to Estimate the Effect of Perfluoroalkyl Substances on Health Outcomes?

Cited by 25 publications

References 47 publications

Per- and Polyfluoroalkyl Substances and Risk of Myocardial Infarction and Stroke: A Nested Case–Control Study in Sweden

Per- and Polyfluoroalkyl Substances and Risk of Myocardial Infarction and Stroke: A Nested Case–Control Study in Sweden

Systemic inflammation and emotional responses during the COVID-19 pandemic

Cortisol Co-Secretion and Clinical Usefulness of ACTH Stimulation Test in Primary Aldosteronism: A Systematic Review and Biases in Epidemiological Studies

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